Facially controlled C-methylation of oxolanyl and cyclopentyl acetate enolates: Application to the total synthesis of (+)-nephromopsinic acid

FULL PAPER

Facially Controlled C-Methylation of Oxolanyl and Cyclopentyl Acetate

Enolates: Application to the Total Synthesis of (+)-Nephromopsinic Acid

Johann Mulzer,*^[a]Ulrich Steffen,^[a]Harry J. Martin,^[a]and Ludwig Zorn^[a]

Keywords: Alkylation / Configuration determination / Enolates / Natural product synthesis / Paraconic acids / Stereoelec-

tronic effects

The stereoselectivity of the C-methylation of oxolanyl and cy-

clopentyl acetate enolates 5a–22a was investigated. The con-

figuration of the C-methyl diastereomers was elucidated by

a combination of crystal structure analysis, NMR spec-

troscopy and chemical correlations. Generally, the methyla-

tion proceeded re*-selectively, although with very different

degrees of selectivity. The most important stereodirecting ef-

fect was a steric one exerted by the 5-phenethyl substituent,

and this steric effect was strongly increased by the stereodi-

recting effect of a 3-OR group. Contrary to previous literature

evidence, the endocyclic oxolanyl oxygen does not exert an

effect. These findings were applied in a highly stereoselec-

tive synthesis of (+)-nephromopsinic acid (94).

Germany, 2005)

explained by McGarvey and Williams^[2]as being due to a

stereoelectronic effect of the oxygen lone pair anti to the

ring bond, which donates electrons into the π*-orbital of

the enolate and activates the re*-face towards electrophilic

attack (Figure 2, structure I). In light of this assumption,

the enhanced selectivity exhibited by esters 1 [Scheme 1;

eq. (4)] and 3 [Scheme 1; eq. (5)] may be attributed to the

combined effects of the endocyclic oxygen and the lone

Introduction

Alkylations of ester enolates in which the enolate carbon

is adjacent to a suitably substituted cyclopentane ring pro-

ceed with high stereoselectivity [Scheme 1; eq. (1) and (2)].^[1]

On the other hand, the oxolanyl-substituted acetate in

Scheme 1 [eq. (3)] exhibits only a moderate selectivity of

67:33.^[2]If, however, there is an ether function in the cis-3-

position, as in esters 1 (with various R groups) and 3, the C-

methyl derivatives 2 and 4 are formed with extremely high

(Ͼ99%) stereocontrol [Scheme 1; eqs. (4) and (5)].^[3]

As proposed by Frater,^[4]the facial selectivity found in

eqs. (1) and (2) can be rationalized by an A^1,3-strain-con-

trolled transition-state conformation,^[5]which is attacked by

the electrophile from the less-hindered (re*) face^[6](Fig-

ure 1). The stereochemical course in eq. (3), however, was

Figure 1. Transition state of the enolate alkylation

[a] Institut für Organische Chemie der Universität Wien,

Währinger Strasse 38, 1090 Wien, Austria

Fax: +43-14277-52190

E-mail: johann.mulzer@univie.ac.at

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

Figure 2. Facial stereoelectronic effects in the enolate alkylation

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Facially Controlled C-Methylation of Oxolanyl- and Cyclopentyl Acetate Enolates

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Scheme 1.C-Methylation of oxolanyl and cyclopentyl acetate enolates

pairs at O-3, which donate electrons into the σ*-orbital of

the electrophile and direct it to the re*-face of the enolate

(Figure 2, structure II).

To validate these assumptions we synthesized the model

compounds 5a–22a (see reaction conditions a, b in

Scheme 2), which are partially or completely devoid of these

oxygen functions, and investigated the facial selectivity in

the C-methylation of the corresponding enolates.

Results and Discussion

The methyl 2-[5-(2Ј-phenethyl)oxolan-4-yl]acetates 5a–

16a were prepared in racemic form, and C-methylated via

the ester enolates to give diastereomeric mixtures of 5b,c–

16b,c [eq. (6) in Table 1]. The details of the synthesis and

the configurational assignments are given below. Table 1

shows that the general preference for the re*-facial attack

is maintained, although the selectivity in most cases is sig-

nificantly lower than for esters 1 and 3.

Scheme 2. R¹= CH₂CH₂Ph; reagents and conditions: a) vinylmag-

nesium bromide, THF, room temp.; b) NaH, DMF, BnCl; c) O₃,

–78 °C, MeOH, then Me₂S; d) (EtO)₂POCH₂CO₂Me, NaH, THF;

e) DIBALH, toluene; f) MeC(OMe)₂NMe₂, 120 °C, toluene; g) Na,

NH₃(l), THF; h) NaOH, MeOH

In particular, the 3-methyl derivatives 5a–10a give dia-

stereomeric ratios of only 62:38 to 82:18 depending on the

relative configurations at C-2, C-3, and C-5. Remarkably,

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Table 1. Diastereomeric ratios and combined yields for the C-methylation of esters 5–16a

the relative configurations at C-5 and C-3 are of minor im- racemic form and methylated as before [eq. (7) in Table 2].

portance. For compounds 11–14, the anomeric center at C- Surprisingly, the re*-facial selectivities are about the same

2 acts very much like the 3-OR group in 1 and 3, as a 2- as for the oxolanyl derivatives. Now the only stereodirecting

OMe in the position cis to the C-4 appendage enhances the effect is a steric one exerted by the 5-phenethyl substituent.

re*-selectivity relative to the corresponding trans-1-OMe Indeed, if the bulkiness of this residue is enhanced by intro-

derivatives. The presence of the 3-Me group in systems 5– ducing a 1Ј-O-benzyl function (as in 17–20), the re*-selec-

10 neutralizes this effect. The still existing re*-preference in tivity is higher in most cases than in the unbranched ana-

all systems can only be due to the stereoelectronic effect logs 21 and 22. Unlike the 3-OR functions in compounds 1

of the endocyclic oxygen and the steric shielding of the 5- and 3, the O-benzyl ether functions in 17–20 are not prop-

phenethyl residue, both of which should induce re*-facial erly located to exert an attractive effect on the incoming

selectivity despite a counteracting steric effect from the 3- alkyl halide that would direct them towards the si*-face of

methyl substituents. In fact, the absence of the 3-methyl the enolate. In conclusion, the observed re*-facial selectivity

group in model compounds 11a–14a results in a pro- can be interpreted in terms of a steric effect exerted by a

nounced increase of the re*-facial selectivity, which is also phenethyl appendage in the 5-position. This selectivity may

observed for the 2,3-unsubstituted systems 15a and 16a.

be enhanced by a stereoelectronic effect from the 3-OR sub-

It remained to clarify the influence of the endocyclic oxy- stituents on the ring. The presence of an endocyclic oxygen

gen. Thus, the cyclopentyl analogs 17–22a were prepared in is of no importance.

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Facially Controlled C-Methylation of Oxolanyl- and Cyclopentyl Acetate Enolates

Table 2. Diastereomeric ratios and combined yields for the C-methylation of esters 17–22a

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Synthesis and Configurational Assignments of Compounds

5–22(a–c)

jected to a Claisen–Eschenmoser rearrangement to form a

diastereomeric mixture of amides 26. Without separation,

this mixture was transformed into the lactones 27 and 28,

which are easily separable by chromatography. The relative

configurations were safely assigned by ¹H NMR spec-

The synthesis (Scheme 2) started with aldehyde 23, which

was first converted into the allylic alcohol 25 and then sub-

Scheme 3. R¹= CH₂CH₂Ph; reagents and conditions: a) LDA, THF, –78 °C, MeI; b) DIBALH, –70 °C, toluene; c) MeOH, pTsOH; d)

9-BBN, THF, then H₂O₂, NaOH; e) DMSO, DCC, pyridine, TFA, toluene; f) KMnO₄, tBuOH, pH 7 buffer; g) CH₂N₂, diethyl ether

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Scheme 4. R¹= CH₂CH₂Ph; reagents and conditions: a) LDA, THF, –78 °C, MeI; b) DIBALH, –70 °C, toluene; c) MeOH, pTsOH; d)

9-BBN, THF, then H₂O₂, NaOH; e) DMSO, DCC, pyridine, TFA, toluene; f) KMnO₄, tBuOH, pH 7 buffer; g) CH₂N₂, diethyl ether

Scheme 5. R¹= CH₂CH₂Ph; reagents and conditions: a) DIBALH; b) MeOH, pTsOH; c) 9-BBN, H₂O₂; d) DMSO, DCC; e) KMnO₄,

tBuOH, pH 7 buffer; f) CH₂N₂

troscopy. Thus, the signals of both 4- and 5-H in the trans-

compound 27 are shifted upfield by about 0.3 ppm com-

pared to 28. Additional evidence came from NOE experi-

ments. On monomethylation with LDA/MeI (Scheme 3) 27

forms the diastereomers 29 and 30, which were separated

and structurally assigned by NOE difference spectroscopy.

Both 29 and 30 were converted into mixtures of the ano-

mers 31/32 and 33/34, respectively. After chromatographic

separation the relative configurations of the anomers could

1

be assigned by H NMR spectroscopy; for instance, the 2-

OMe group induces an anisotropic effect on the 1Ј-CH₂

group of the 5-cis-phenethyl side-chain in 31 and 33, which

appears in the form of two one-proton multiplets at δ =

1.65 and 1.85 ppm. In 32 and 34, the 1Ј-CH₂group appears

Scheme 6. R¹= CH₂CH₂Ph; reagents and conditions: a) LAH; b)

as one, two-proton multiplet at δ = 1.70 ppm.

The diastereomers 31–34 were transformed into the pTsCl, pyridine, DMAP; c) 9-BBN, H₂O₂; d) DMSO, DCC; e)

KMnO₄, tBuOH, pH 7 buffer; f) CH₂N₂

methyl acetates 5a, 6a, 9a, and 10a by a hydroboration/oxi-

dation sequence (Scheme 3). By an analogous procedure,

methyl esters 7a and 8a were prepared from 28 (Scheme 4), in an optically active form from d-glucose following a ste-

11a/12a from 27 and 13a/14a from 28 (Scheme 5), and 15a reochemically unambiguous route.^[3]

from 27 and 16a from 28 (Scheme 6). Compounds 7a/8a

For the configurational assignment of 5b and 9b the

and 11a/12a can be distinguished by the above-mentioned pseudosymmetrical relationship between C-3 and C-1Ј was

1

anisotropy criterion of the 1ЈЈ-CH₂group in the H NMR utilized (Scheme 7). Thus, 5b and 9b were converted into

spectra. Additionally, 11a has previously been synthesized the benzyl ethers 42 and 46, respectively. The ketal was hy-

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Scheme 7. R¹= CH₂CH₂Ph; reagents and conditions: a) LAH, THF, ∆; b) NaH, DMF, BnCl, ∆; c) pTsOH, acetonitrile, water; d) Swern

oxidation

drolyzed to an anomeric mixture of the hemi-ketals 43 and

The synthesis of the racemic cyclopentyl derivatives 21a

47, which were reduced to the diols and selectively mono- and 22a (Scheme 10) began with aldehyde 61, which was

benzylated at the primary position to give the dibenzyl converted via 62 into enoate 63. Free-radical cyclization^[7]

ethers 44 and 48. After Swern oxidation the ketones 45 and was used to close the cyclopentane ring and the dia-

49 were generated. Compound 45 contains a pseudoasym- stereomeric esters 21a and 22a were formed in good yield.

metric center at C-4, and, as a meso compound, shows only After separation of the diastereomers an inspection of the

one ¹H NMR signal for the two methyl groups. In contrast, ¹H NMR spectra made clear that the signals had too much

49 contains a chirotopic nonstereogenic center at C-4, and overlap to allow a safe assignment of the configurations

thus the two methyl groups appear as two individual signals (see Supporting Information for spectra). The same obser-

1

in the H NMR spectrum (see Supporting Information for vation was made after methylation of 21a and 22a to 21b,c

spectra). Following an analogous sequence, 49 was pre- and 22b,c, respectively, and after transformation into the

pared from 5c. The configurations of 6b,c, 7b,c, 8b,c, 9c, benzyl ethers 64a,b and 65a,b, respectively. To obtain better

1

and 10b,c were assigned in a similar manner.

suited H NMR spectra we decided to prepare the oxygen-

Esters 11b and 12b were converted into the benzyl ethers ated derivatives 17–20a and to correlate them later with 21

50 and 51; identical products were obtained after chromato- and 22 (vide infra; Scheme 11).

graphic separation from 35 via intermediate 52 along the

Thus, the trans-fused lactones 70 and 72 were formed by

obvious route outlined in Scheme 8. Similarly, 13b and 14b debenzylation of 17a and 17b, respectively, upon activation

were converted into 53 and 54, and these compounds were with TMSCl, whereas the formation of the cis-lactones 75

correlated, via 55, with 29. Additionally, 52 was trans- and 77 from 19a and 20a proceeded spontaneously.

formed into 55 by a Mitsunobu inversion. Compounds 30

Compounds 71a,b were generated from 70, 73a,b from

and 13c were correlated via relay compounds 56 and 57. To 72, 76a,b from 75, and 78a,b from 77, all by monomethyl-

assign the configurations of 15b, 16b, and 16c, intermedi- ation. The diastereomeric pairs were separated and struc-

ates 52, 55, and 56 were transformed into 58, 59, and 60, turally assigned by extensive NOE difference spectroscopy.

respectively, which were obtained in diastereomerically Additionally, 78a was crystallized and subjected to a single-

identical form from 15b, 16b, and 16c (Scheme 9).

crystal structural analysis (Figure 3).^[8]In the crystal struc-

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Scheme 8. R¹= CH₂CH₂Ph; reagents and conditions: a) LAH; b) NaH, DMF, BnCl; c) DHP, PPTS; d) 9-BBN, H₂O₂; e) DCC, DMSO;

f) MeOH, PPTS; g) DEAD, PPh₃, PhCO₂H, THF; h) NaOH, MeOH

ture the lactone ring adopts an approximate B_1,4-boat con-

Additionally, 71a,b were converted into 74a,b, 76a into

formation with the benzyl appendage in the equatorial and 80a, and 78a into 80b. Compounds 74a,b were monodeoxy-

the methyl group in the axial position. The trans-lactone genated to 64a,b and 80a,b to 65a. These compounds were

enolates react virtually unselectively with methyl iodide shown to be identical with the corresponding products ob-

(Scheme 12), whereas the cis-lactones show moderate selec- tained from 21a,b and 22a (Schemes 10, 12, and 13).

tivity (Scheme 13). The monomethylated lactones 71a,b,

73a,b, 76a,b, and 78a,b were obtained in identical form

upon hydrogenation/lactonization of 17b,c–20b,c, thus

Application to the Synthesis of Nephromopsinic Acid

proving the configurations of these compounds given in

Schemes 11–13.

In effect, the C-methylation of ester enolates such as 1

and 3 provides a highly stereoselective access to compounds

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Facially Controlled C-Methylation of Oxolanyl- and Cyclopentyl Acetate Enolates

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Scheme 9. R¹= CH₂CH₂Ph; reagents and conditions: a) 9-BBN,

H₂O₂; b) pTsCl, pyridine; c) LiAlH₄, THF; d) NaH, DMF, BnCl

with the general functionalization pattern 81 (Scheme 14).

Whilst looking for natural products fitting into this general

pattern we came across the paraconic acids 82, i.e. γ-butyro-

lactones having a carboxylic acid in the 3-position.^[9]Para-

conic acids occur naturally in lichens and show antineoplas-

tic and antibiotic properties. A number of stereoselective

syntheses have been developed for a variety of paraconic

acids in racemic and optically active form.^[10]

In earlier work we have described the preparation of roc-

cellaric acid^[11]and (–)-nephromopsinic acid.^[12]In the cur-

rent context, we realized that (+)-nephromopsinic acid (94),

the unnatural enantiomer, stereochemically matched our C-

methylation protocol. Thus, the known^[3]methyl ester 83

was converted into 84 by selective degradation of the exocy-

clic acetonide moiety (Scheme 15). As expected, 84 was-

Scheme 11. Reagents and conditions: a) vinylmagnesium bromide,

THF; b) NaH, DMF, BnCl; c) O₃, MeOH, –78 °C, then PPh₃; d)

(4-pentenyl)magnesium bromide, THF; e) TBSCl, imidazole,

DMF; f) Ph₃P=CHCO₂Me, MeOH; g) 80% HOAc, THF; h)

PhOCSCl, pyridine, DMAP, CH₂Cl₂; i) nBu₃SnH, AIBN, toluene,

reflux; j) LDA, THF, –78 °C, MeI; k) H₂/Pd, MeOH, 1 bar, 22 °C;

l) TMSCl, diethyl ether, lactonization; for yields see Supporting

Information

Scheme 10. Reagents and conditions: a) (4-pentenyl)magnesium bromide, THF; b) TBSCl, imidazole, DMF; c) O₃, MeOH, –78 °C, then

PPh₃; d) Ph₃P=CHCO₂Me, MeOH; e) 80% HOAc, THF; f) PhOCSCl, pyridine, DMAP, CH₂Cl₂; g) nBu₃SnH, AIBN, toluene, reflux;

h) LDA, THF, –78 °C, MeI; i) LiAlH₄, THF; j) NaH, DMF, BnCl

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J. Mulzer, U. Steffen, H. J. Martin, L. Zorn

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methylated with greater than 98% stereoselectivity to give

diastereomer 85, which, on the basis of our previous results,

was tentatively assigned to have a (1ЈR)-configuration.

Next, the furanose template had to be disconnected without

affecting the newly created stereogenic center. Hence, 85

was transformed into the benzyl ether 86 and the ketal was

cleaved with acetic anhydride in the presence of BF₃as cata-

lyst to give diacetate 88 stereoselectively. This result may be

interpreted by formation of a dioxolanylium intermediate

87, which is attacked by an acetate anion from the less-

hindered face. Basic hydrolysis of the acetate groups led to a

dihydroxyaldehyde, which immediately cyclized to hydroxy

lactol 89. Glycol cleavage followed by reduction gave diol

90. After protection-reprotection alcohol 91 was formed,

which furnished hydroxy lactol 92 on Pfitzner–Moffat oxi-

dation followed by acidic workup to remove the THP

group. Oxidation to lactone 93, TBS removal, and oxi-

dation with PDC yielded (+)-nephromopsinic acid (94),

which was identical in all respects, except the sign of the

optical rotation, with the enantiomer obtained pre-

viously.^[9,12]

Figure 3. Crystal structure of lactone 78a (enantiomer shown)

Scheme 12. Reagents and conditions: a) H₂, Pd/C, MeOH, 1 bar, 22 °C; b) TMSCl, diethyl ether; c) LDA, THF, –78 °C, MeI; d) LiAlH₄,

THF; e) NaH, DMF, BnCl; f) PhOCSCl, pyridine, DMAP; g) nBu₃SnH, AIBN, toluene, reflux

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Scheme 13. Reagents and conditions: a) H₂, Pd/C, MeOH, 1 bar, 22 °C; b) TMSCl, diethyl ether; c) LDA, THF, –78 °C, MeI; d) LiAlH₄,

THF; e) NaH, DMF, BnCl; f) PhOCSCl, pyridine, DMAP; g) nBu₃SnH, AIBN, toluene, reflux

late carbon atom can be methylated with a stereoselectivity

of up to 99% depending on the substituents on the ring.

The stereoelectronic effect of an endocyclic oxygen pos-

tulated by McGarvey and Williams could not be confirmed

for our systems. Our results were applied to a stereocon-

trolled synthesis of (+)-nephromopsinic acid.

Scheme 14.

Experimental Section

General Methods:¹H and ¹³C spectra were recorded on Bruker AC

250 or Bruker AM 270 (¹H at 250 or 270 MHz, ¹³C at 62.5 or

67.5 MHz) spectrometers, with CDCl₃as internal standard. IR

Conclusions

We have shown that ester enolates containing a five-

spectra were recorded on a Perkin–Elmer 580B or 125 spectrome-

membered oxolanyl or cyclopentyl ring adjacent to the eno- ter. Mass spectra were recorded on Finigan MAT 112 S (EI, CI)

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J. Mulzer, U. Steffen, H. J. Martin, L. Zorn

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Scheme 15. Reagents and conditions: a) 50% HOAc, 2 d, 22 °C, 89%; b) Pb(OAc)₄, CH₂Cl₂, 22 °C, then added to C₁₁H₂₃C=PPh₃in THF,

14 h, 22 °C, 51%; c) Pd/C (10), MeOH/EtOAc (10:1), 2 bar H₂, 22 °C, 90%; d) LDA, THF, –50 °C, MeI, 3 h, 96%; e) LiAlH₄, Et₂O, 1 h,

22 °C, 98%; f) BnCl, NaH, DMF, 22 °C, 12 h, 81%; g) Ac₂O, BF₃-etherate, CH₂Cl₂, 5 h, 22 °C, 8%; h) NaOMe in MeOH, 3 h, 22 °C,

91%; i) H₅IO₆, THF, 1 h, 22 °C, then LiAlH₄, Et₂O, 1 h, 22 °C, 86%; k) TBDPSCl, DMF, imidazole, 5 h, 22 °C, 85%; l) dihydropyran,

pTsOH, Et₂O, 14 h, 22 °C, 72%; m) Na, NH₃, –50 °C, Et₂O, Na, 83%; n) DMSO, DCC, pyridine, TFA, toluene, 3 h, 22 °C, then pTsOH,

THF/H₂O, 1 h, 22 °C, 80%; o) PCC, CH₂Cl₂, 14 h, 22 °C, 77%; p) TBAF, THF, 5 h, 22 °C, 74%; q) PDC, DMF, 15 h, 22 °C, 81%

or Finigan MAT 711 (high resolution) spectrometers. Elemental

analyses were performed with a Perkin–Elmer 240 or 2400 CHN

Elemental Analyzer. Melting points are uncorrected and were ob-

tained with a Buechi SMP 20. All solvents were dried according to

standard procedures, and DMF was dried over 4-Å molecular si-

eves. Flash chromatography was performed with silica gel 60

(0.040–0.063 mm, 230–400 mesh) purchased from Merck. Reac-

tions were monitored by TLC on DC Alufolien Kieselgel 60 F₂₅₄

(from Merck) and visualized by spraying with 60% sulfuric acid

and appropriate heating. HPLC analyses and separations were per-

formed with equipment from Knauer and Waters-Millipore.

stereomeric mixtures were separated by HPLC (vide infra for 5b/

c).

(2RS,3SR,4RS,5RS)-2-Methoxy-4-[(1RS)-1-(methoxycarbonyl)-

ethyl]-3-methyl-5-phenethyloxolane (5b) and (2RS,3SR,4RS,5RS)-2-

Methoxy-4-[(1SR)-1-(methoxycarbonyl)ethyl]-3-methyl-5-phenethyl-

oxolane (5c): Analytical HPLC: hexane/ethyl acetate = 90:10,

2 mL min^–1, 100 bar, Nucleosil 50-5, 4 × 250 mm, UV = 254 nm.

t_R(5b) = 3.02 min, t_R(5c) = 3.39 min. Mechanical integration: 5b/

5c = 70:30 [1.98 g were separated by HPLC (hexane/ethyl acetate

= 90:10, 80 mL min^–1, 40 bar, Nucleosil 50-7, 32 × 250 mm, UV =

254 nm)].

Methylation of Methyl Esters 5a–22a: A lithium diisopropylamide

solution was prepared as follows. At 0 °C, 1 molar equivalent of

nBuLi (1.6 m in hexane) was added dropwise to 1.01 molar equiva-

lents of anhydrous diisopropylamine in anhydrous THF (1.6–

2.3 mL/mmol). The solution was stirred for 15 min at 0 °C and

30 min at room temperature. At –78 °C, a solution of the ester in

anhydrous THF (4.5–5.5 mL/mmol) was added dropwise to the

LDA solution in THF. After stirring for 3 h, methyl iodide (1 mL

per gram of ester) was added. The reaction mixture was stirred for

an additional 30 min at –78 °C, the cooling bath was removed, and

the reaction mixture was allowed to reach room temperature. Water

was added (1 mL per 2 mL of THF), the layers were separated, and

the aqueous phase was extracted with hexane (3 × 2 mL per 1 mL

of water). The combined organic phases were dried with magne-

sium sulfate and concentrated on a rotary evaporator. The dia-

5b: Yield: 1.329 g (66%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 1.08 (d, J = 7.5 Hz, 3 H), 1.16 (d, J = 7 Hz, 3 H), 1.62 (ddd,

J = 8.5, 7.5, 4.5 Hz, 1 H), 1.69–1.94 (m, 2 H), 2.06 (m_c, 1 H), 2.55

[dq, J (d) = 8.5, J (q) = 7 Hz, 1 H], 2.66 (ddd, J = 13.5, 9.5, 7.5 Hz,

1 H), 2.85 (ddd, J = 13.5, 9.5, 5 Hz, 1 H), 3.32 (s, 3 H), 3.58 (s, 3

H), 3.79 [dt, J (t) = 8, J (d) = 3.5 Hz, 1 H), 4.61 (s, 1 H), 7.14–7.34

(m, 5 H) ppm. ¹³C NMR (CDCl₃): δ = 15.16 (1Ј-p), 19.56 (p), 32.42

(s), 37.14 (s), 41.74 (t), 43.55 (t), 51.17 (p), 53.99 (t), 54.10 (p),

80.54 (t), 110.13 (t), 125.58 (t), 128.14 (t), 128.34 (t), 141.88 (q),

175.86 (q) ppm. IR (NaCl): ν = 3110 (vw), 3090 (w), 3070 (m),

˜

3030 (m), 2960 (s), 2940 (s), 2920 (s), 2890 (s), 2840 (m), 1945 (vw),

1875 (vw), 1805 (vw), 1735 (vs), 1605 (m), 1585 (w), 1500 (m), 1460

(s), 1435 (s), 1380 (m), 1370 (m), 1350 (m), 1300 (m), 1260 (s), 1200

(s), 1170 (s), 1145 (m), 1125 (s), 1100 (s), 1070 (s), 1030 (s), 1010

(s), 960 (s), 930 (m), 885 (m), 855 (m), 835 (w), 825 (w), 770 (w),

1038

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1028–1043

Facially Controlled C-Methylation of Oxolanyl- and Cyclopentyl Acetate Enolates

750 (m), 700 (s) cm^–1. C₁₈H₂₆O₄(306.41): calcd. C 70.56, H 8.55; 16.48 (1Ј-p), 32.57 (s), 32.73 (s), 38.44 (t), 39.80 (t), 48.95 (t), 51.13

FULL PAPER

found C 69.65, H 8.58. MS (EI, 80 eV, 40 °C): m/z (%) = 306 (0.27)

[M⁺], 274 (22.29), 234 (8.17), 187 (70.29), 169 (19.34), 109 (20.35),

104 (32.47), 91 (100), 85 (78.77), 55 (27.84), 41 (30.1). HRMS calcd.

for C₁₈H₂₆O₄[M⁺] 306.18311; found 306.18284.

(p), 54.68 (p), 78.38 (t), 105.51 (t), 125.60 (t), 128.14 (t), 128.31 (t),

141.93 (q), 175.61 (q) ppm. IR (KBr): ν = 3110 (w), 3090 (m), 3060

˜

(m), 3030 (s), 2980 (s), 2950 (s), 2910 (s), 2830 (m), 1940 (w), 1870

(w), 1800 (w), 1735 (vs), 1600 (m), 1580 (w), 1535 (w), 1495 (s),

1450 (s), 1430 (s), 1380 (s), 1360 (s), 1330 (s), 1275 (s), 1260 (s),

1190 (s), 1155 (s), 1120 (s), 1100 (s), 1080 (vs), 1060 (s), 1025 (vs),

990 (s), 955 (s), 935 (m), 915 (s), 880 (m), 860 (m), 840 (m), 825

(m), 780 (m), 750 (s), 725 (m), 700 (s), 675 (w), 660 (m), 620 (w),

585 (m), 550 (m), 500 (m), 475 (w) cm^–1. C₁₈H₂₆O₄(306.41): calcd.

C 70.56, H 8.55; found C 70.97, H 8.36.

5c: Yield: 0.572 g (28%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 1.07 (d, J = 7.5 Hz, 6 H), 1.62 (ddd, J = 9.5, 7, 3.5 Hz, 1 H),

1.76–2.04 (m, 3 H), 2.59 [dq, J (d) = 9.5, J (q) = 7.5 Hz, 1 H), 2.70

(ddd, J = 13.5, 9.5, 7.5 Hz, 1 H), 2.84 (ddd, J = 13.5, 9.5, 5 Hz, 1

H), 3.31 (s, 3 H), 3.65 (s, 3 H), 3.80 (ddd, J = 8.5, 7.5, 3.5 Hz, 1

H), 4.60 (s, 1 H), 7.14–7.34 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ

= 15.69 (1Ј-p), 19.29 (p), 32.52 (s), 38.07 (s), 42.82 (t), 45.22 (t),

51.36 (p), 53.52 (t), 54.13 (p), 79.97 (t), 110.15 (t), 125.70 (t), 128.24

1

8b: Yield: 0.68 g (59%) of a clear, colorless oil. H NMR (CDCl₃):

δ = 1.19 (d, J = 7 Hz, 3 H), 1.24 (d, J = 7.5 Hz, 3 H, 1Ј-Me), 1.47–

1.62 (m, 1 H), 1.80–1.96 (m, 1 H), 2.06 [dquint, J (quint) = 7, J

(d) = 3 Hz, 1 H], 2.19 [dt, J (d) = 10, J (t) = 7 Hz, 1 H], 2.52–2.67

(m, 2 H), 2.93 (ddd, J = 14, 10, 5 Hz, 1 H), 3.44 (s, 3 H), 3.60 (s,

3 H), 4.16 (ddd, J = 12, 7, 2.5 Hz, 1 H), 4.60 (d, J = 3 Hz, 1 H),

7.12–7.32 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ = 16.97 (1Ј-p), 18.90

(p), 32.61 (s), 33.17 (s), 39.48 (t), 43.09 (t), 50.94 (t), 51.21 (p),

55.39 (p), 80.85 (t), 112.66 (t), 125.43 (t), 128.03 (t), 128.20 (t),

(t), 128.38 (t), 141.84 (q), 176.01 (q) ppm. IR (NaCl): ν = 3110 (w),

˜

3090 (m), 3070 (m), 3030 (m), 2960 (s), 2940 (s), 2920 (s), 2880 (s),

2840 (m), 1950 (w), 1875 (w), 1805 (w), 1735 (vs), 1605 (m), 1585

(w), 1500 (m), 1455 (s), 1435 (s), 1380 (s), 1370 (m), 1360 (m), 1300

(m), 1285 (m), 1260 (s), 1235 (m), 1210 (s), 1195 (s), 1165 (s), 1125

(s), 1100 (s), 1085 (s), 1070 (s), 1050 (m), 1030 (s), 1010 (s), 985

(m), 965 (s), 945 (s), 930 (m), 890 (m), 850 (w), 835 (w), 825 (w),

815 (vw), 775 (w), 750 (m), 700 (s), 670 (w) cm^–1. C₁₈H₂₆O₄

(306.41): calcd. C 70.56, H 8.55; found C 70.78, H 8.92.

141.98 (q), 176.08 (q) ppm. IR (KBr): ν = 3110 (w), 3090 (m), 3070

˜

(m), 3030 (s), 2960 (s), 2940 (s), 2880 (s), 2840 (m), 1950 (w), 1870

(w), 1800 (w), 1735 (vs), 1605 (m), 1585 (w), 1540 (w), 1495 (s),

1455 (s), 1435 (s), 1385 (s), 1370 (s), 1360 (m), 1330 (s), 1255 (s),

1195 (s), 1170 (s), 1140 (s), 1100 (vs), 1080 (s), 1025 (s), 1015 (s),

965 (s), 920 (s), 885 (m), 855 (m), 835 (m), 805 (m), 770 (m), 750

(m), 700 (s), 680 (m), 655 (w), 640 (w), 625 (w), 580 (m), 565 (m),

535 (w), 500 (m), 485 (m) cm^–1. C₁₈H₂₆O₄(306.41): calcd. C 70.56,

H 8.55; found C 70.70, H 8.63.

6b/c: Mixture, not separable by HPLC. ¹H NMR (CDCl₃): δ = 0.98

(d, J = 6.5 Hz, 3 H, major isomer), 1.00 (d, J = 6.5 Hz, 3 H, minor

isomer), 1.09 (d, J = 7.5 Hz, 3 H, 1Ј-Me/major isomer), 1.14 (d, J

= 7.5 Hz, 3 H, 1Ј-Me/minor isomer), 1.72–2.12 (m, 8 H), 2.45–2.60

(m, 2 H), 2.61–2.76 (m, 2 H), 2.84–2.98 (m, 2 H), 3.38 (s, 6 H),

3.63 (s, 3 H, minor isomer), 3.65 (s, 3 H, major isomer), 3.88 (m_c,

2 H), 4.74 (d, J = 4.5 Hz, 2 H), 7.14–7.34 (m, 10 H) ppm. Accord-

ing to the ¹H NMR analysis the ratio was 82:18. ¹³C NMR

(CDCl₃): δ = 11.98 (p), 12.41 (p), 13.54 (1Ј-p), 13.65 (1Ј-p), 32.73

(s), 39.62 (t), 39.75 (s), 40.31 (t), 41.40 (t), 42.60 (t), 50.97 (t), 51.12

(p), 54.16 (p), 80.95 (t), 81.80 (t), 106.15 (t), 106.33 (t), 125.46 (t),

128.08 (t), 128.16 (t), 141.96 (q), 175.14 (q), 175.39 (q) ppm.

C₁₈H₂₆O₄(306.41): calcd. C 70.56, H 8.55; found C 71.15, H 8.46.

MS (EI, 80 eV, 40 °C): m/z (%) = 306 (0.37) [M⁺], 274 (19.88), 234

(18.17), 217 (22.74), 187 (36.24), 169 (32.09), 109 (36.6), 104

(37.27), 91 (100), 85 (63.55), 72 (25.02), 55 (29.53), 41 (31.62).

HRMS calcd. for C₁₈H₂₆O₄[M⁺] 306.18311; found 306.18302.

1

8c: Yield: 0.42 g (36%) of a clear, colorless oil. H NMR (CDCl₃):

δ = 0.97 (d, J = 7 Hz, 3 H), 1.10 (d, J = 7 Hz, 3 H, 1Ј-Me), 1.52–

1.66 (m, 1 H), 1.84–2.13 (m, 3 H), 2.45 [dq, J (d) = 9.5, J (q) = 7

Hz, 1 H], 2.62 (ddd, J = 14, 10, 7.5 Hz, 1 H), 2.98 (ddd, J = 14,

10, 5 Hz, 1 H), 3.48 (s, 3 H), 3.66 (s, 3 H), 4.10 (ddd, J = 12, 6,

2.5 Hz, 1 H), 4.60 (d, J = 4 Hz, 1 H), 7.14–7.34 (m, 5 H) ppm. ¹³C

NMR (CDCl₃): δ = 16.43 (2 × p), 32.30 (s), 32.41 (s), 39.16 (t),

42.89 (t), 51.14 (p), 52.25 (t), 55.88 (p), 80.28 (t), 113.46 (t), 125.56

(t), 128.15 (t), 128.31 (t), 142.00 (q), 175.54 (q) ppm. IR (KBr): ν

˜

= 3110 (w), 3090 (m), 3070 (m), 3030 (s), 2980 (s), 2960 (s), 2950

(s), 2920 (s), 2880 (s), 2840 (s), 1945 (w), 1870 (w), 1800 (w), 1735

(vs), 1600 (m), 1580 (w), 1550 (w), 1540 (w), 1495 (s), 1450 (s),

1430 (s), 1375 (s), 1360 (s), 1330 (m), 1320 (m), 1270 (s), 1260 (s),

1240 (s), 1220 (m), 1195 (s), 1165 (s), 1155 (s), 1100 (s), 1080 (s),

1060 (s), 1030 (s), 1010 (s), 985 (s), 965 (s), 940 (m), 915 (m), 895

(m), 880 (m), 855 (m), 830 (w), 800 (w), 790 (w), 750 (m), 700 (s),

650 (w), 640 (w), 625 (w), 585 (m), 575 (w), 555 (w), 510 (m), 470

(w) cm^–1. C₁₈H₂₆O₄(306.41): calcd. C 70.56, H 8.55; found C 70.88,

H 8.64.

1

7b: Yield: 0.71 g (51%) of a clear, colorless oil. H NMR (CDCl₃):

δ = 1.05 (d, J = 7 Hz, 3 H), 1.20 (d, J = 7.5 Hz, 3 H, 1Ј-Me), 1.56–

1.83 (m, 2 H), 2.11–2.36 (m, 2 H), 2.51–2.70 (m, 2 H), 2.88 (ddd,

J = 15, 10, 5 Hz, 1 H), 3.37 (s, 3 H), 3.62 (s, 3 H), 4.16 (ddd, J =

10, 7, 3 Hz, 1 H), 4.80 (d, J = 5 Hz, 1 H), 7.14–7.34 (m, 5 H) ppm.

¹³C NMR (CDCl₃): δ = 13.87 (p), 15.04 (1Ј-p), 32.27 (s), 32.89 (s),

38.74 (t), 40.23 (t), 48.35 (t), 51.20 (p), 54.42 (p), 77.65 (t), 104.79

(t), 125.52 (t), 128.06 (t), 128.17 (t), 141.75 (q), 176.13 (q) ppm. IR

(KBr): ν = 3110 (w), 3090 (m), 3070 (m), 3030 (s), 2980 (s), 2960

˜

(s), 2940 (s), 2900 (s), 2840 (s), 1950 (w), 1870 (w), 1805 (w), 1735

(vs), 1605 (m), 1585 (w), 1550 (w), 1540 (w), 1495 (s), 1455 (s),

1435 (s), 1390 (s), 1365 (s), 1350 (s), 1330 (s), 1305 (m), 1255 (s),

1240 (s), 1195 (vs), 1170 (s), 1155 (s), 1110 (s), 1080 (vs), 1030 (vs),

960 (s), 930 (s), 915 (s), 880 (m), 855 (m), 830 (m), 810 (m), 770

(m), 750 (m), 725 (m), 700 (s), 670 (w), 650 (w), 580 (m), 545 (m),

525 (w), 505 (m) cm^–1. C₁₈H₂₆O₄(306.41): calcd. C 70.56, H 8.55:

calcd. C 70.95, H 8.56.

9b: Yield: 1.182 g (76%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 0.93 (d, J = 7 Hz, 3 H), 1.18 (d, J = 6.5 Hz, 3 H, 1Ј-Me), 1.61

(m_c, 2 H), 2.26–2.49 (m, 3 H), 2.66 [dt, J (d) = 14, J (t) = 8 Hz, 1

H], 2.89 [dt, J (d) = 14, J (t) = 7 Hz, 1 H], 3.37 (s, 3 H), 3.57 (s, 3

H), 3.96 (m_c, 1 H), 4.62 (s, 1 H), 7.12–7.34 (m, 5 H) ppm. ¹³C

NMR (CDCl₃): δ = 11.35 (p), 16.35 (1Ј-p), 32.52 (s), 38.44 (s),

38.29 (t), 41.62 (t), 48.04 (t), 51.03 (p), 53.78 (p), 80.24 (t), 109.23

(t), 125.43 (t), 128.06 (t), 128.18 (t), 142.09 (q), 175.75 (q) ppm. IR

1

7c: Yield 0.42 g (30%) of a clear, colorless oil. H NMR (CDCl₃): (NaCl): ν = 3110 (vw), 3090 (w), 3070 (m), 3030 (m), 2980 (s), 2950

˜

δ = 0.91 (d, J = 6 Hz, 3 H), 1.15 (d, J = 7 Hz, 3 H, 1Ј-Me), 1.71

(s), 2920 (s), 2840 (m), 1945 (vw), 1875 (vw), 1805 (vw), 1735 (vs),

(m_c, 2 H), 2.12–2.29 (m, 2 H), 2.50 (quint, J = 7 Hz, 1 H), 2.63 [dt, 1605 (m), 1585 (w), 1560 (w), 1540 (w), 1500 (m), 1455 (s), 1435

J (d) = 14, J (t) = 8 Hz, 1 H], 2.92 [dt, J (d) = 14, J (t) = 7 Hz, 1

H], 3.36 (s, 3 H), 3.64 (s, 3 H), 4.15 (m_c, 1 H), 4.79 (d, J = 4.5 Hz,

(m), 1385 (m), 1375 (m), 1365 (m), 1350 (m), 1310 (m), 1260 (s),

1235 (m), 1195 (s), 1170 (s), 1120 (m), 1110 (s), 1090 (s), 1080 (s),

1 H), 7.14–7.34 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ = 12.20 (p), 1055 (s), 1030 (s), 1005 (s), 970 (m), 955 (s), 940 (s), 930 (s), 895

Eur. J. Org. Chem. 2005, 1028–1043

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1039

J. Mulzer, U. Steffen, H. J. Martin, L. Zorn

FULL PAPER

(w), 875 (m), 855 (m), 840 (w), 820 (vw), 770 (w), 750 (m), 700 (s),

H], 3.38 (s, 3 H), 3.64 (s, 3 H), 3.83 (q, J = 6.5 Hz, 1 H), 4.96 (d,

670 (w), 660 vw cm^–1. C₁₈H₂₆O₄(306.41): calcd. C 70.56, H 8.55; J = 5 Hz, 1 H), 7.14–7.32 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ =

found C 70.51, H 8.66.

15.92 (p), 32.92 (s), 37.54 (s), 39.60 (s), 42.36 (t), 45.54 (t), 51.48

(p), 54.44 (p), 82.11 (t), 104.83 (t), 125.73 (t), 128.32 (t), 128.40 (t),

9c: Yield: 0.294 g (19%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 0.91 (d, J = 7.5 Hz, 3 H), 1.13 (d, J = 7 Hz, 3 H, 1Ј-Me), 1.76–

2.06 (m, 2 H), 2.26–2.60 (m, 3 H), 2.64 (ddd, J = 13.5, 10, 7.5 Hz,

1 H), 2.98 (dd, J = 13.5, 9 Hz, 1 H), 3.38 (s, 3 H), 3.68 (s, 3 H),

3.84 (ddd, J = 10, 7.5, 2.5 Hz, 1 H), 4.60 (s, 1 H), 7.14–7.36 (m, 5

H) ppm. ¹³C NMR (CDCl₃): δ = 12.50 (p), 17.15 (1Ј-p), 33.11 (s),

40.55 (s), 39.08 (t), 42.62 (t), 47.33 (t), 51.54 (p), 54.16 (p), 81.08

(t), 110.56 (t), 125.68 (t), 128.28 (t), 128.37 (t), 142.09 (q), 175.90

142.04 (q), 175.48 (q) ppm. IR (KBr): ν = 3110 (w), 3090 (m), 3070

˜

(m), 3030 (m), 2980 (s), 2950 (s), 2920 (s), 2860 (m), 2830 (m), 1945

(w), 1870 (w), 1805 (w), 1735 (vs), 1620 (w), 1600 (m), 1580 (w),

1545 (w), 1495 (s), 1450 (s), 1435 (s), 1380 (s), 1360 (s), 1320 (m),

1260 (s), 1195 (s), 1165 (s), 1100 (s), 1055 (s), 1030 (s), 985 (s), 960

(s), 910 (m), 895 (m), 855 (s), 835 (m), 810 (m), 785 (m), 750 (s),

725 (m), 700 (s), 675 (m), 650 (m), 620 (w), 595 (m), 580 (m), 555

(m), 520 (m), 500 (m) cm^–1. C₁₇H₂₄O₄(292.38): calcd. C 69.84, H

8.27; found C 69.73, H 8.40.

(q) ppm. IR (NaCl): ν = 3110 (vw), 3090 (w), 3070 (m), 3030 (m),

˜

2960 (s), 2920 (s), 2870 (m), 2840 (m), 1950 (vw), 1875 (vw), 1800

(vw), 1735 (vs), 1605 (m), 1585 (w), 1500 (m), 1460 (s), 1435 (m),

1385 (m), 1375 (m), 1355 (m), 1330 (m), 1320 (m), 1305 (m), 1260

(s), 1230 (m), 1215 (m), 1200 (s), 1160 (s), 1145 (s), 1105 (s), 1090

(vs), 1065 (s), 1050 (m), 1030 (s), 1010 (m), 985 (m), 960 (s), 940

(s), 930 (s), 910 (m), 895 (w), 880 (m), 855 (m), 845 (w), 820 (w),

750 (m), 700 (s), 670 (w) cm^–1. C₁₈H₂₆O₄(306.41): calcd. C 70.56,

H 8.55; found C 71.41, H 8.66. MS (EI, 80 eV, 50 °C): m/z (%) =

306 (0.12) [M⁺], 274 (35.93), 187 (79.56), 169 (31.55), 109 (40.01),

104 (33.53), 91 (100), 85 (56.31), 55 (25.88), 41 (28.43). HRMS

calcd. for C₁₈H₂₆O₄[M⁺] 306.18311; found 306.18332.

12b: Yield: 0.308 g (68%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.14 (d, J = 6.5 Hz, 3 H), 1.64–1.88 (m, 3 H), 2.00–

2.12 (m, 1 H), 2.20 (ddd, J = 13, 10.5, 5.5 Hz, 1 H), 2.54 [dq, J (d)

= 8, J (q) = 6.5 Hz, 1 H), 2.65 (ddd, J = 13.5, 10, 7.5 Hz, 1 H),

2.81 (ddd, J = 13.5, 9.5, 5.5 Hz, 1 H), 3.34 (s, 3 H), 3.58 (s, 3 H),

3.76 (ddd, J = 8.5, 6.5, 3.5 Hz, 1 H), 4.99 (dd, J = 5.5, 1.5 Hz, 1

H), 7.12–7.28 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ = 15.38 (p),

32.17 (s), 35.94 (s), 36.45 (s), 41.90 (t), 45.57 (t), 51.30 (p), 54.39

(p), 80.20 (t), 104.12 (t), 125.63 (t), 128.20 (t), 128.36 (t), 142.00

(q), 176.11 (q) ppm. IR (KBr): ν = 3110 (w), 3090 (m), 3070 (m),

˜

3030 (m), 2980 (s), 2950 (s), 2930 (s), 2910 (s), 2870 (m), 2840 (m),

1945 (w), 1875 (w), 1800 (w), 1735 (vs), 1600 (m), 1580 (w), 1545

(w), 1535 (w), 1525 (w), 1495 (m), 1455 (s), 1435 (s), 1365 (m), 1355

(m), 1345 (s), 1315 (m), 1260 (s), 1240 (s), 1210 (s), 1195 (s), 1165

(s), 1125 (s), 1105 (s), 1075 (s), 1050 (s), 1030 (s), 990 (s), 975 (s),

930 (m), 910 (m), 885 (m), 840 (m), 810 (w), 800 (w), 785 (m), 775

(m), 750 (m), 725 (m), 700 (s), 680 (m), 660 (w), 650 (w), 645 (w),

625 (w), 615 (w), 585 (m), 575 (m), 565 (m), 540 (w), 525 (m), 510

(w), 490 (w), 480 (w), 465 (w) cm^–1. C₁₇H₂₄O₄(292.38): calcd. C

69.84, H 8.27; found C 69.51, H 8.18.

1

10b/c: Not separable by HPLC. H NMR (CDCl₃): δ = 0.90 (d, J

= 7 Hz, 3 H, major isomer), 1.02 (d, J = 7.5 Hz, 3 H, minor iso-

mer), 1.08 (d, J = 7 Hz, 3 H, 1Ј-Me/major isomer), 1.19 (d, J =

7 Hz, 3 H, 1Ј-Me/minor isomer), 1.64–1.98 (m, 4 H), 2.03 (m_c, 1

H, minor isomer), 2.16–2.46 (m, 3 H), 2.58–2.90 (m, 6 H), 3.33 (s,

3 H, major isomer), 3.38 (s, 3 H, minor isomer), 3.56 (s, 3 H, minor

isomer), 3.66 (s, 3 H, major isomer), 3.89 (m_c, 1 H, major isomer),

3.96 (m_c, 1 H, minor isomer), 4.76 (d, J = 4.5 Hz, 1 H, major

isomer), 4.85 (d, J = 4.5 Hz, 1 H, minor isomer), 7.12–7.32 (m, 10

1

H) ppm. According to the H NMR analysis the ratio was 80:20.

¹³C NMR (CDCl₃): δ = 8.64 (p), 8.72 (p), 16.66 (1Ј-p), 17.32 (1Ј-

p), 31.85 (s), 37.60 (s), 38.30 (s), 39.27 (t), 39.64 (t), 39.89 (t), 40.48

(t), 46.08 (t), 48.48 (t), 50.87 (p), 51.12 (p), 54.10 (p), 54.82 (p),

79.32 (t), 79.38 (t), 105.92 (t), 106.39 (t), 125.37 (t), 125.47 (t),

128.02 (t), 128.18 (t), 141.70 (q), 141.93 (q), 175.94 (q), 177.11 (q)

ppm. C₁₈H₂₆O₄(306.41): calcd. C 70.56, H 8.55; found C 70.51, H

8.63.

12c: Yield: 0.021 g (5%) of a clear, pale-yellow oil. ¹H NMR

(CDCl₃): δ = 1.11 (d, J = 7.5 Hz, 3 H), 1.66 (ddd, J = 13.5, 5, 1 Hz,

1 H), 1.73–2.08 (m, 3 H), 2.22 (ddd, J = 13.5, 10, 5.5 Hz, 1 H),

2.61 [dq, J (d) = 9, J (q) = 7.5 Hz, 1 H], 2.69 (ddd, J = 14, 10,

7.5 Hz, 1 H), 2.85 (ddd, J = 14, 10, 5.5 Hz, 1 H), 3.33 (s, 3 H), 3.65

(s, 3 H), 3.80 (ddd, J = 8.5, 7, 3 Hz, 1 H), 5.00 (dd, J = 5.5, 1 Hz,

1 H), 7.16–7.34 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ = 16.16 (p),

32.32 (s), 37.37 (s), 37.43 (s), 42.84 (t), 45.43 (t), 51.47 (p), 54.37

(p), 79.52 (t), 104.30 (t), 125.76 (t), 128.30 (t), 128.43 (t), 141.94

11b: Yield: 0.436 g (68%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.12 (d, J = 6.5 Hz, 3 H), 1.64–1.86 (m, 3 H), 2.08

(dd, J = 12.5, 7 Hz, 1 H), 2.28–2.44 (m, 2 H), 2.68 [dt, J (d) = 14,

J (t) = 8 Hz, 1 H], 2.86 [dt, J (d) = 14, J (t) = 7 Hz, 1 H], 3.34 (s,

3 H), 3.56 (s, 3 H), 3.81 (q, J = 6.5 Hz, 1 H), 4.95 (d, J = 5 Hz, 1

H), 7.11–7.30 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ = 14.94 (p),

32.55 (s), 37.22 (s), 38.75 (s), 42.30 (t), 45.12 (t), 51.16 (p), 54.10

(p), 82.35 (t), 104.29 (t), 125.47 (t), 128.08 (t), 128.22 (t), 141.92

(q), 176.08 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m), 3070 (m),

˜

3030 (m), 2980 (s), 2950 (s), 2930 (s), 2870 (m), 2830 (m), 1945 (w),

1875 (w), 1800 (w), 1735 (vs), 1600 (m), 1580 (w), 1545 (w), 1535

(w), 1495 (m), 1450 (s), 1430 (s), 1375 (s), 1365 (s), 1350 (s), 1320

(m), 1260 (s), 1230 (s), 1210 (s), 1195 (s), 1165 (s), 1100 (s), 1055

(s), 1030 (s), 990 (s), 965 (s), 910 (m), 890 (m), 840 (m), 810 (w),

790 (m), 750 (m), 725 (m), 700 (s), 675 (m) cm^–1. C₁₇H₂₄O₄

(292.38): calcd. C 69.84, H 8.27;. found C 69.37, H 8.16.

(q), 175.42 (q) ppm. IR (KBr): ν = 3110 (w), 3090 (m), 3070 (m),

˜

3030 (s), 2980 (s), 2950 (s), 2920 (s), 2860 (m), 2830 (m), 1945 (w),

1875 (w), 1800 (w), 1735 (vs), 1600 (m), 1580 (w), 1545 (w), 1495

(m), 1455 (s), 1435 (s), 1375 (m), 1360 (s), 1345 (m), 1320 (m), 1260

(s), 1225 (s), 1195 (s), 1160 (s), 1100 (s), 1070 (s), 1050 (s), 1025 (s),

980 (s), 960 (s), 950 (s), 930 (m), 910 (m), 890 (m), 860 (m), 850

(m), 810 (m), 780 (m), 750 (m), 725 (m), 700 (s), 680 (m), 650 (w),

595 (w), 580 (w), 555 (w), 540 (w), 520 (w), 510 (w), 505 (w), 490

(w), 470 (w) cm^–1. C₁₇H₂₄O₄(292.38): calcd. C 69.84, H 8.27; found

C 69.64, H 8.35.

13b: Yield: 0.228 g (87%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.16 (d, J = 7 Hz, 3 H), 1.53–1.68 (m, 2 H), 1.76

(ddd, J = 13.5, 10, 5.5 Hz, 1 H), 1.96 (ddd, J = 13.5, 7.5, 2 Hz, 1

H), 2.42 [dq, J (d) = 9, J (q) = 7 Hz, 1 H], 2.55–2.93 (m, 3 H), 3.35

(s, 3 H), 3.59 (s, 3 H), 4.16 [dt, J (t) = 8, J (d) = 5.5 Hz, 1 H], 4.98

(d, J = 4.5 Hz, 1 H), 7.12–7.32 (m, 5 H) ppm. ¹³C NMR (CDCl₃):

δ = 16.22 (p), 32.50 (s), 32.58 (s), 35.69 (s), 39.13 (t), 41.96 (t), 51.44

(p), 54.38 (p), 78.78 (t), 103.40 (t), 125.64 (t), 128.17 (t), 128.31 (t),

11c: Yield: 0.72 g (11%) of a clear, colorless oil. ¹H NMR (CDCl₃):

141.91 (q), 176.02 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m),

˜

δ = 1.12 (d, J = 7 Hz, 3 H), 1.74–1.96 (m, 3 H), 2.08 (dd, J = 12.5, 3070 (m), 3030 (m), 2990 (s), 2950 (s), 2920 (s), 2870 (m), 2840 (m),

7.5 Hz, 1 H), 2.32 (m_c, 1 H), 2.45 (quint, J = 7 Hz, 1 H), 2.71 [dt,

J (d) = 14, J (t) = 8 Hz, 1 H], 2.92 [dt, J (d) = 14, J (t) = 7 Hz, 1

1945 (w), 1870 (w), 1805 (w), 1735 (vs), 1620 (w), 1605 (m), 1580

(w), 1525 (w), 1495 (m), 1455 (s), 1435 (s), 1375 (m), 1365 (m),

1040

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Eur. J. Org. Chem. 2005, 1028–1043

Facially Controlled C-Methylation of Oxolanyl- and Cyclopentyl Acetate Enolates

FULL PAPER

1345 (m), 1335 (m), 1285 (m), 1265 (s), 1250 (s), 1220 (m), 1195 3.73–3.86 (m, 2 H), 7.10–7.30 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ

(s), 1170 (s), 1155 (s), 1100 (s), 1075 (s), 1055 (s), 1030 (s), 1000 (s), = 14.98 (p), 29.89 (s), 32.34 (s), 36.61 (s), 41.93 (t), 46.93 (t), 51.26

985 (m), 965 (m),950 (m), 910 (m), 885 (m), 870 (m), 850 (m), 815 (p), 66.35 (s), 81.42 (t), 125.52 (t), 128.13 (t), 128.27 (t), 142.04 (q),

(w), 805 (w), 775 (m), 750 (m), 725 (m), 700 (s) cm^–1. C₁₇H₂₄O₄175.83 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m), 3060 (m), 3030

˜

(292.38): calcd. C 69.84, H 8.27; found C 69.71, H 8.24.

(m), 2970 (s), 2940 (s), 2880 (m), 2860 (s), 1945 (w), 1870 (w), 1800

(w), 1730 (vs), 1600 (m), 1580 (w), 1540 (w), 1495 (m), 1450 (s),

1430 (s), 1375 (m), 1360 (m), 1345 (m), 1260 (s), 1190 (s), 1160 (s),

1140 (m), 1080 (s), 1060 (s), 1040 (s), 1030 (s), 985 (m), 965 (m),

950 (m), 930 (m), 910 (m), 890 (m), 870 (w), 850 (m), 835 (w), 805

(w), 750 (m), 720 (m), 700 (s), 680 (w) cm^–1. C₁₆H₂₂O₃(262.35):

calcd. C 73.25, H 8.45; found C 73.02, H 8.39.

13c: Yield: 0.015 g (6%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 1.14 (d, J = 6 Hz, 3 H), 1.60–1.80 (m, 2 H), 1.83 (ddd, J =

13.5, 6.5, 1.5 Hz, 1 H), 2.00 (ddd, J = 13.5, 8, 5.5 Hz, 1 H), 2.39–

2.72 (m, 3 H), 2.91 (ddd, J = 14, 9.5, 5.5 Hz, 1 H), 3.36 (s, 3 H),

3.65 (s, 3 H), 4.13 (ddd, J = 9.5, 6, 4.5 Hz, 1 H), 4.96 (dd, J = 5.5,

1.5 Hz, 1 H), 7.16–7.40 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ =

16.81 (p), 32.09 (s), 32.63 (s), 35.89 (s), 38.87 (t), 43.79 (t), 51.57

15c: Yield 0.056 g (11%) of a clear, colorless oil. ¹H NMR (CDCl₃):

(p), 54.68 (p), 78.67 (t), 103.91 (t), 125.84 (t), 128.36 (t), 128.47 (t), δ = 1.14 (d, J = 7 Hz, 3 H), 1.55–1.86 (m, 3 H), 1.98–2.12 (m, 2

142.04 (q), 175.88 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m), H), 2.48 (quint, J = 7 Hz, 1 H), 2.66 (ddd, J = 13.5, 10, 7.5 Hz, 1

˜

3070 (m), 3030 (m), 2980 (s), 2950 (s), 2920 (s), 2870 (m), 2840 (m), H), 2.84 (ddd, J = 13.5, 8.5, 6 Hz, 1 H), 3.60–3.69 (m, 1 H), 3.64

1945 (w), 1870 (w), 1805 (w), 1735 (vs), 1605 (m), 1580 (w), 1495 (s, 3 H), 3.72–3.88 (m, 2 H), 7.14–7.34 (m, 5 H) ppm. ¹³C NMR

(m), 1455 (s), 1440 (s), 1380 (s), 1355 (s), 1305 (m), 1280 (m), 1260 (CDCl₃): δ = 15.95 (p), 30.65 (s), 32.58 (s), 37.35 (s), 42.20 (t),

(m), 1240 (m), 1220 (s), 1200 (s), 1170 (s), 1110 (s), 1085 (m), 1065 47.24 (t), 51.42 (p), 66.56 (s), 80.97 (t), 125.71 (t), 128.29 (t), 128.38

(s), 1045 (s), 1030 (s), 1005 (m), 990 (m), 970 (s), 950 (m), 915 (m), (t), 142.06 (q), 175.84 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m),

˜

890 (m), 870 (m), 855 (m), 840 (m), 810 (w), 790 (m), 750 (m), 700

3060 (m), 3030 (m), 2970 (s), 2940 (s), 2880 (m), 2860 (m), 1945

(w), 1870 (w), 1800 (w), 1730 (vs), 1600 (m), 1580 (w), 1495 (m),

(s), 660 (w) cm^–1. MS (EI, 80 eV, 40 °C): m/z (%) = 292 (0.71) [M⁺],

260 (19.92), 173 (17.74), 155 (21.81), 104 (16.93), 91 (62.6), 71 1450 (s), 1430 (m), 1375 (m), 1360 (m), 1345 (m), 1260 (s), 1235

(100), 41 (23.14). HRMS calcd. for C₁₇H₂₄O₄292.16746 [M⁺];

found 292.16705.

(m), 1190 (s), 1160 (s), 1105 (m), 1080 (s), 1060 (m), 1040 (m), 1030

(m), 985 (m), 960 (w), 950 (w), 910 (m), 885 (m), 850 (m), 835 (m),

805 (w), 785 (w), 750 (m), 720 (m), 700 (s), 665 (w) cm^–1. C₁₆H₂₂O₃

(262.35): calcd. C 73.25, H 8.45; found C 72.90, H 8.60.

14b: Yield: 0.211 g (80%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.19 (d, J = 6.5 Hz, 3 H), 1.48–1.66 (m, 2 H), 1.83

(m_c, 1 H), 2.28–2.54 (m, 3 H), 2.60 (ddd, J = 13.5, 9.5, 7 Hz, 1 H),

2.93 (ddd, J = 13.5, 10, 4.5 Hz, 1 H), 3.46 (s, 3 H), 3.58 (s, 3 H),

4.05 (ddd, J = 12, 6, 2.5 Hz, 1 H), 5.04 (t, J = 5 Hz, 1 H), 7.12–

7.32 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ = 17.32 (p), 32.40 (s),

32.57 (s), 36.09 (s), 39.71 (t), 44.86 (t), 51.41 (p), 55.63 (p), 79.62

(t), 105.33 (t), 125.54 (t), 128.15 (t), 128.37 (t), 142.20 (q), 175.85

16b: Yield: 0.464 g (88%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.19 (d, J = 6.5 Hz, 3 H), 1.50–1.72 (m, 3 H), 1.92–

2.04 (m, 1 H), 2.32–2.52 (m, 2 H), 2.59 [dt, J (d) = 14, J (t) = 8 Hz,

1 H], 2.84 [dt, J (d) = 14, J (t) = 7 Hz, 1 H], 3.58 (s, 3 H), 3.74 (q,

J = 8 Hz, 1 H), 3.87–4.02 (m, 2 H), 7.10–7.30 (m, 5 H) ppm. ¹³C

NMR (CDCl₃): δ = 16.50 (p), 28.66 (s), 31.42 (s), 32.19 (s), 39.31

(t), 44.55 (t), 51.19 (p), 65.71 (s), 78.71 (t), 125.40 (t), 127.98 (t),

(q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m), 3070 (m), 3030 (m),

˜

2980 (s), 2950 (s), 2920 (s), 2870 (m), 2830 (m), 1945 (w), 1870 (w),

128.16 (t), 141.92 (q), 175.91 (q) ppm. IR (NaCl): ν = 3110 (w),

˜

1800 (w), 1735 (vs), 1620 (w), 1605 (m), 1585 (w), 1530 (w), 1495 3090 (m), 3060 (m), 3030 (m), 2970 (s), 2940 (s), 2880 (s), 1945 (w),

(m), 1450 (s), 1435 (s), 1375 (s), 1350 (m), 1330 (m), 1315 (m), 1295 1870 (w), 1800 (w), 1730 (vs), 1600 (m), 1580 (w), 1540 (w), 1490

(m), 1255 (s), 1230 (m), 1215 (s), 1195 (s), 1160 (s), 1105 (s), 1080

(s), 1025 (vs), 985 (m), 965 (s), 950 (s), 910 (m), 885 (m), 855 (m),

(m), 1450 (s), 1430 (s), 1375 (m), 1350 (m), 1330 (m), 1260 (s), 1210

(s), 1190 (s), 1165 (s), 1100 (m), 1080 (s), 1060 (s), 1040 (s), 990

805 (w), 795 (w), 750 (m), 725 (m), 700 (s), 680 (m), 665 (w) cm^–1. (m), 960 (m), 940 (m), 910 (m), 880 (m), 850 (m), 835 (w), 800 (w),

C₁₇H₂₄O₄(292.38): calcd. C 69.84, H 8.27; found C 69.49, H 8.30.

785 (w), 750 (m), 725 (m), 700 (s), 675 (w) cm^–1. C₁₆H₂₂O₃(262.35):

calcd. C 73.25, H 8.45;: calcd. C 72.92; H 8.28.

14c: Yield: 0.016 g (6%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 1.11 (d, J = 6 Hz, 3 H), 1.48–1.71 (m, 2 H), 1.89 (m_c, 1 H), 16c: Yield: 0.040 g (8%) of a clear, colorless oil. ¹H NMR (CDCl₃):

2.21–2.50 (m, 3 H), 2.63 (ddd, J = 13.5, 10, 7.5 Hz, 1 H), 2.98 (ddd,

δ = 1.14 (d, J = 6 Hz, 3 H), 1.48–1.82 (m, 3 H), 1.86–2.00 (m, 1

J = 13.5, 10, 4.5 Hz, 1 H), 3.49 (s, 3 H), 3.66 (s, 3 H), 4.04 (ddd, J H), 2.27–2.48 (m, 2 H), 2.62 (ddd, J = 13.5, 9.5, 7.5 Hz, 1 H), 2.88

= 12, 6, 2.5 Hz, 1 H), 5.05 (dd, J = 6, 5 Hz, 1 H), 7.16–7.36 (m, 5

H) ppm. ¹³C NMR (CDCl₃): δ = 16.53 (p), 32.02 (s), 32.41 (s),

(ddd, J = 13.5, 9.5, 5 Hz, 1 H), 3.67 (s, 3 H), 3.80 (q, J = 8.5 Hz,

1 H), 3.88–4.04 (m, 2 H), 7.14–7.34 (m, 5 H) ppm. ¹³C NMR

36.39 (s), 39.78 (t), 45.55 (t), 51.57 (p), 55.94 (p), 78.99 (t), 106.11 (CDCl₃): δ = 16.60 (p), 29.08 (s), 30.87 (s), 32.25 (s), 39.66 (t),

(t), 125.79 (t), 128.38 (t), 128.51 (t), 142.25 (q), 175.99 (q) ppm. IR 45.95 (t), 51.54 (p), 66.10 (s), 78.34 (t), 125.78 (t), 128.35 (t), 128.45

(NaCl): ν = 3110 (w), 3090 (m), 3070 (m), 3030 (m), 2980 (s), 2950 (t), 142.18 (q), 176.20 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m),

˜

(s), 2920 (s), 2860 (m), 2830 (m), 1945 (w), 1870 (w), 1805 (w), 1735 3060 (m), 3030 (m), 2970 (s), 2940 (s), 2880 (s), 1945 (w), 1870 (w),

(vs), 1605 (m), 1580 (w), 1495 (m), 1450 (s), 1435 (s), 1380 (s), 1365 1800 (w), 1735 (vs), 1600 (m), 1580 (w), 1540 (w), 1495 (m), 1450

(s), 1345 (s), 1330 (m), 1285 (m), 1255 (s), 1240 (m), 1195 (s), 1155 (s), 1430 (m), 1380 (m), 1360 (m), 1340 (m), 1285 (m), 1260 (s),

(vs), 1125 (s), 1095 (vs), 1075 (s), 1055 (s), 1045 (s), 1025 (s), 995 1240 (m), 1195 (s), 1170 (s), 1160 (m), 1120 (m), 1105 (m), 1080

(s), 985 (s), 955 (m), 905 (m), 890 (m), 865 (s), 850 (s), 795 (m), 750 (s), 1060 (s), 1050 (s), 1030 (m), 1000 (m), 990 (m), 950 (m), 910

(m), 725 (m), 700 (s), 675 (m), 665 (w) cm^–1. MS (EI, 80 eV, 40 °C):

(m), 885 (m), 850 (m), 835 (w), 805 (w), 750 (m), 725 (m), 700 (s),

m/z (%) = 260 (32.66), 173 (31.07),155 (47.05), 112 (68.84), 104 680 (w) cm^–1. C₁₆H₂₂O₃(262.35): calcd. C 73.25, H 8.45; found C

(38.26), 91 (100), 71 (99.82), 41 (47.21). HRMS calcd. for C₁₆H₂₀O₃72.96, H 8.24.

[M – CH₃O⁺] 260.14125; found 260.14184.

17b: Yield: 0.439 g (84%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.07 (d, J = 7.5 Hz, 3 H), 1.30–1.87 (m, 6 H), 1.94–

15b: Yield: 0.436 (83%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 1.15 (d, J = 7.5 Hz, 3 H), 1.60–1.80 (m, 3 H), 1.97–2.16 (m, 2 2.10 (m, 1 H), 2.25 (m_c, 1 H), 2.65 (m_c, 1 H), 2.71 (dd, J = 14,

H), 2.40 [dq, J (q) = 7.5, J (d) = 7 Hz, 1 H], 2.63 [dt, J (d) = 13.5, 8 Hz, 1 H), 2.92 (dd, J = 14, 3 Hz, 1 H), 3.49 (ddd, J = 8, 6.5,

J (t) = 8 Hz, 1 H], 2.75–2.86 (m, 1 H), 3.58 (s, 3 H), 3.61 (m_c, 1 H), 3 Hz, 1 H), 3.59 (s, 3 H), 4.18 (d, J = 11.5 Hz, 1 H), 4.37 (d, J =

Eur. J. Org. Chem. 2005, 1028–1043

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1041

J. Mulzer, U. Steffen, H. J. Martin, L. Zorn

FULL PAPER

11.5 Hz, 1 H), 7.08–7.34 (m, 10 H) ppm. ¹³C NMR (CDCl₃): δ =

12.79 (p), 25.23 (s), 28.92 (s), 29.05 (s), 38.35 (s), 42.78 (t), 44.13

(t), 45.86 (t), 51.5 (p), 72.11 (s), 84.31 (t), 125.79 (t), 127.11 (t),

127.75 (t), 127.92 (t), 127.97 (t), 138.52 (q), 139.58 (q), 176.57 (q)

C₂₄H₃₀O₃(366.50): calcd. C 78.65, H 8.25; found C 78.60, H 8.26.

20c: Yield: 0.043 g (8%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 0.92 (d, J = 7 Hz, 3 H), 1.38–1.89 (m, 6 H), 1.92–2.07 (m, 2

H), 2.42 [dq, J (d) = 11, J (q) = 7 Hz, 1 H], 2.65 (dd, J = 13.5,

8.5 Hz, 1 H), 3.11 (dd, J = 13.5, 5 Hz, 1 H), 3.63 (s, 3 H), 3.72

(ddd, J = 8.5, 5, 2.5 Hz, 1 H), 4.48 (d, J = 11 Hz, 1 H), 4.58 (d, J

= 11 Hz, 1 H), 7.12–7.40 (m, 10 H) ppm. ¹³C NMR (CDCl₃): δ =

16.89 (p), 24.23 (s), 25.15 (s), 30.33 (s), 38.89 (s), 40.33 (t), 41.37

(t), 47.62 (t), 51.15 (p), 71.06 (s), 80.43 (t), 126.17 (t), 127.37 (t),

127.72 (t), 128.34 (t), 128.42 (t), 129.33 (t), 138.77 (q), 139.10 (q),

ppm. IR (NaCl): ν = 3110 (w), 3090 (m), 3060 (m), 3030 (m), 2950

˜

(s), 2870 (s), 1945 (w), 1875 (w), 1805 (w), 1730 (vs), 1600 (m),

1585 (w), 1540 (w), 1495 (s), 1450 (s), 1430 (s), 1400 (m), 1375 (m),

1350 (m), 1330 (m), 1300 (m), 1255 (m), 1195 (s), 1170 (s), 1160

(s), 1080 (s), 1070 (s), 1030 (m), 1000 (m), 990 (m), 950 (w), 910

(m), 860 (w), 850 (w), 740 (s), 700 (s), 675 (w) cm^–1. C₂₄H₃₀O₃

(366.50): calcd. C 78.65, H 8.25; found C 77.27, H 7.98.

177.27 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m), 3070 (m), 3030

˜

17c: Yield. 0.033 g (6%) of a clear, colorless oil. ¹H NMR (CDCl₃):

δ = 1.10 (d, J = 7 Hz, 3 H), 1.32–1.88 (m, 6 H, 1.96–2.21 (m, 2 H),

2.53 (quint, J = 7 Hz, 1 H), 2.72 (dd, J = 14, 7.5 Hz, 1 H), 2.91

(dd, J = 14, 3 Hz, 1 H), 3.50 (ddd, J = 7.5, 6.5, 3 Hz, 1 H), 3.60

(s, 3 H), 4.24 (d, J = 11.5 Hz, 1 H), 4.35 (d, = 11.5 Hz, 1 H), 7.10–

7.34 (m, 10 H) ppm. ¹³C NMR (CDCl₃): δ = 16.15 (p), 25.24 (s),

29.18 (s), 30.15 (s), 38.45 (s), 43.60 (t), 44.94 (t), 45.89 (t), 51.10

(p), 72.31 (s), 84.26 (t), 125.96 (t), 127.27 (t), 127.79 (t), 128.11 (t),

128.15 (t), 129.59 (t), 138.78 (q), 139.81 (q), 176.49 (q) ppm. IR

(m), 2950 (s), 2870 (s), 1945 (w), 1875 (w), 1805 (w), 1735 (vs),

1605 (m), 1585 (w), 1545 (w), 1495 (s), 1455 (s), 1435 (m), 1395

(m), 1375 (m), 1355 (m), 1310 (m), 1275 (m), 1260 (m), 1190 (s),

1175 (s), 1160 (s), 1110 (m), 1095 (s), 1070 (s), 1030 (m), 990 (m),

945 (w), 910 (w), 900 (w), 880 (vw), 850 (m), 840 (w), 810 (vw),

790 (vw), 750 (m), 735 (s), 700 (s) cm^–1. C₂₄H₃₀O₃(366.50): calcd.

C 78.65, H 8.25; found C 77.54, H 8.15.

21b: Yield: 0.262 g (82%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.07 (d, J = 7 Hz, 3 H), 1.24–1.92 (m, 10 H), 2.40

(quint, J = 7 Hz, 1 H), 2.51 (ddd, J = 14, 10, 7 Hz, 1 H), 2.67 (ddd,

J = 14, 10.5, 5 Hz, 1 H), 3.62 (s, 3 H), 7.12–7.32 (m, 5 H) ppm.

¹³C NMR (CDCl₃): δ = 13.60 (p), 23.84 (s), 28.74 (s), 31.85 (s),

34.46 (s), 37.01 (s), 42.33 (2 × t), 47.94 (t), 51.01 (p), 125.40 (t),

(NaCl): ν = 3110 (w), 3090 (m), 3060 (m), 3030 (s), 2950 (s), 2870

˜

(s), 1945 (w), 1870 (w), 1805 (w), 1730 (vs), 1600 (m), 1585 (w),

1540 (w), 1495 (s), 1450 (s), 1430 (s), 1395 (m), 1380 (s), 1345 (s),

1330 (s), 1305 (m), 1250 (s), 1190 (s), 1160 (s), 1090 (s), 1070 (vs),

1030 (s), 1000 (m), 990 (m), 945 (m), 910 (m), 860 (m), 850 (m),

780 (w), 745 (s), 700 (vs) cm^–1. C₂₄H₃₀O₃(366.50): calcd. C 78.65,

H 8.25; found C 76.14, H 7.72.

128.04 (t), 128.09 (t), 142.45 (q), 176.64 (q) ppm. IR (NaCl): ν =

˜

3110 (w), 3090 (m), 3060 (m), 3030 (s), 2940 (s), 2870 (s), 1940 (w),

1870 (w), 1800 (w), 1735 (vs), 1600 (m), 1580 (w), 1540 (w), 1495

(s), 1450 (s), 1430 (s), 1375 (m), 1355 (m), 1335 (m), 1300 (m), 1260

(m), 1225 (m), 1195 (s), 1165 (s), 1110 (m), 1095 (m), 1080 (m),

1060 (m), 1030 (m), 990 (w), 945 (w), 910 (w), 850 (w), 750 (m),

720 (w), 700 (s) cm^–1. C₁₇H₂₄O₂(260.38): calcd. C 78.42, H 9.29;

found C 78.92, H 9.25.

21c: Yield: 0.037 g (12%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.12 (d, J = 7 Hz, 3 H), 1.22–1.90 (m, 10 H), 2.44

(quint, J = 7 Hz, 1 H), 2.54 (ddd, J = 14, 10, 7 Hz, 1 H), 2.71 (ddd,

J = 14, 10.5, 5 Hz, 1 H), 3.61 (s, 3 H), 7.12–7.32 (m, 5 H) ppm.

¹³C NMR (CDCl₃): δ = 15.81 (p), 24.18 (s), 29.89 (s), 32.30 (s),

34.69 (s), 37.83 (s), 42.08 (t), 43.00 (t), 48.75 (t), 51.12 (p), 125.59

18b/c: Yield: 0.365 g (88%) of a clear, colorless oil.¹H NMR

(CDCl₃): δ = 0.93 (d, J = 7.5 Hz, 3 H, minor isomer), 0.97 (d, J =

7 Hz, 3 H, major isomer), 1.19–1.38 (m, 2 H), 1.42–1.92 (m, 12 H),

2.00 (m_c, 1 H, minor isomer), 2.10–2.34 (m, 3 H), 2.66 (dd, J =

13.5, 8 Hz, 1 H, major isomer), 2.67 (dd, J = 13.5, 8 Hz, 1 H, minor

isomer), 2.98 (dd, J = 13.5, 6 Hz, 1 H, major isomer), 3.04 (dd, J

= 13.5, 6 Hz, 1 H, minor isomer), 3.44 (s, 3 H, minor isomer), 3.47

(s, 3 H, major isomer), 3.55 (m_c, 1 H, major isomer), 3.64 (m_c, 1

H, minor isomer), 4.40 (d, J = 11 Hz, 1 H, minor isomer), 4.44 (t,

J = 11.5 Hz; major isomer, 2 H), 4.50 (d, J = 11 Hz, 1 H, minor

isomer), 7.14–7.38 (m, 20 H) ppm.According to the ¹H NMR

analysis the ratio was 81:19.¹³C NMR (CDCl₃): δ = 13.91 (p), 15.60

(p), 24.37 (s), 24.80 (s), 25.76 (s), 25.95 (s), 29.56 (s), 29.72 (s),

39.40 (s), 39.58 (s), 42.11 (t), 42.59 (t), 43.94 (t), 44.39 (t), 44.95 (t),

45.54 (t), 50.76 (p), 50.97 (p), 71.96 (s), 72.33 (s), 81.21 (t), 81.87

(t), 125.88 (t), 127.15 (t), 127.27 (t), 127.50 (t), 127.66 (t), 127.82

(t), 128.3 (t), 128.08 (t), 128.18 (t), 129.17 (t), 138.72 (q), 138.87

(q), 139.11 (q), 139.17 (q), 176.02 (q), 176.63 (q) ppm.C₂₄H₃₀O₃

(366.50): calcd. C 78.65, H 8.25;found C 77.40, H 8.03.

(t), 128.23 (t), 128.31 (t), 142.65 (q), 176.52 (q) ppm. IR (NaCl): ν

˜

= 3110 (w), 3090 (m), 3060 (m), 3030 (s), 2940 (vs), 2870 (s), 1940

(w), 1870 (w), 1800 (w), 1735 (vs), 1600 (m), 1580 (w), 1540 (w),

1495 (s), 1450 (s), 1430 (s), 1380 (m), 1355 (m), 1335 (m), 1255 (s),

1190 (s), 1160 (vs), 1110 (m), 1085 (m), 1060 (m), 1045 (m), 1030

(m), 990 (m), 950 (w), 910 (m), 875 (w), 845 (m), 785 (w), 750 (s),

700 (s) cm^–1. C₁₇H₂₄O₂(260.38): calcd. C 78.42, H 9.29; found C

78.92, H 9.02.

22b: Yield: 0.437 g (83%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.16 (d, J = 7 Hz, 3 H), 1.14–1.33 (m, 2 H), 1.55–

2.10 (m, 8 H), 2.36–2.50 (m, 2 H), 2.71 (ddd, J = 14, 9, 5 Hz, 1 H),

3.60 (s, 3 H), 7.14–7.32 (m, 5 H) ppm. ¹³C NMR (CDCl₃): δ =

17.05 (p), 21.79 (s), 27.42 (s), 29.63 (s), 29.75 (s), 34.12 (s), 40.10

(t), 40.53 (t), 47.02 (t), 50.99 (p), 125.38 (t), 128.00 (t), 128.21 (t),

20b: Yield: 0.445 g (86%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.13 (d, J = 7.5 Hz, 3 H), 1.32–1.59 (m, 2 H), 1.62–

2.09 (m, 6 H), 2.41 [dq, J (d) = 11, J (q) = 7.5 Hz, 1 H), 2.61 (dd,

J = 13.5, 9 Hz, 1 H), 3.06 (dd, J = 13.5, 4.5 Hz, 1 H), 3.38 (s, 3

H), 3.76 (ddd, J = 9, 4.5, 1 Hz, 1 H), 4.47 (d, J = 11.5 Hz, 1 H),

4.61 (d, J = 11.5 Hz, 1 H), 7.10–7.40 (m, 10 H) ppm. ¹³C NMR

(CDCl₃): δ = 17.70 (p), 24.25 (s), 25.21 (s), 30.13 (s), 38.52 (s),

40.81 (t), 41.65 (t), 46.52 (t), 50.94 (p), 70.45 (s), 80.83 (t), 125.86

(t), 127.09 (t), 127.20 (t), 128.08 (t), 128.22 (t), 129.17 (t), 138.98

142.42 (q), 176.90 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m),

˜

3070 (m), 3030 (s), 2950 (s), 2870 (s), 1940 (w), 1870 (w), 1800 (w),

1735 (vs), 1600 (m), 1580 (w), 1540 (w), 1495 (m), 1455 (s), 1435

(m), 1375 (m), 1350 (m), 1340 (m), 1305 (m), 1255 (s), 1225 (m),

1190 (s), 1165 (s), 1100 (m), 1085 (m), 1070 (m), 1055 (m), 1030

(m), 1020 (w), 990 (m), 960 (w), 925 (w), 910 (w), 890 (vw), 855

(m), 800 (vw), 750 (m), 725 (w), 700 (s), 670 (w) cm^–1. C₁₇H₂₄O₂

(260.38): calcd. C 78.42, H 9.29; found C 78.89, H 9.20.

(q), 139.11 (q), 177.10 (q) ppm. IR (NaCl): ν = 3110 (w), 3090 (m),

˜

3060 (m), 3030 (m), 2950 (s), 2870 (s), 1945 (w), 1875 (w), 1805

(w), 1730 (vs), 1600 (m), 1585 (w), 1540 (w), 1495 (s), 1450 (s),

1430 (m), 1395 (m), 1370 (m), 1350 (m), 1330 (m), 1305 (m), 1260

(s), 1225 (m), 1190 (s), 1170 (m), 1150 (s), 1110 (s), 1095 (s), 1070

(s), 1060 (s), 1030 (s), 985 (m), 950 (w), 910 (w), 900 (w), 880 (w),

22c: Yield: 0.068 g (13%) of a clear, colorless oil. ¹H NMR

(CDCl₃): δ = 1.10 (d, J = 7 Hz, 3 H), 1.16–1.38 (m, 2 H), 1.46–

850 (m), 835 (w), 810 (vw), 750 (m), 735 (s), 700 (vs) cm^–1

.

1042

www.eurjoc.org

Eur. J. Org. Chem. 2005, 1028–1043

Facially Controlled C-Methylation of Oxolanyl- and Cyclopentyl Acetate Enolates

FULL PAPER

[2] G. J. McGarvey, J. M. Williams, J. Am. Chem. Soc. 1985, 107,

1435.

[3] J. Mulzer, U. Steffen, L. Zorn, Ch. Schneider, E. Weinhold, W.

Münch, R. Rudert, P. Luger, H. Hartl, J. Am. Chem. Soc. 1988,

110, 4640.

1.76 (m, 6 H), 1.84–2.02 (m, 2 H), 2.36 [dq, J (d) = 11, J (q) = 7

Hz, 1 H], 2.44 (ddd, J = 14, 10, 7.5 Hz, 1 H, 2.75 (ddd, J = 14, 10,

5 Hz, 1 H), 3.64 (s, 3 H), 7.12–7.32 (m, 5 H) ppm. ¹³C NMR

(CDCl₃): δ = 16.55 (p), 21.88 (s), 27.84 (s), 28.95 (s), 29.28 (s),

34.16 (s), 39.10 (t), 40.63 (t), 47.66 (t), 51.23 (p), 125.68 (t), 128.27

[4] G. Frater, in Houben-Weyl, Vol. E 21a, Stereoselective Synthe-

sis (Eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schau-

mann), Thieme, Stuttgart, 1995, p. 723.

(t), 128.32 (t), 142.53 (q), 177.37 (q) ppm. IR (NaCl): ν = 3110 (w),

˜

3090 (m), 3060 (m), 3030 (s), 2940 (vs), 2870 (s), 1940 (w), 1870

(w), 1800 (w), 1735 (vs), 1600 (m), 1580 (w), 1540 (w), 1495 (s),

[5] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841.

1450 (s), 1430 (s), 1370 (m), 1345 (m), 1310 (m), 1275 (s), 1255 (s), [6] The substrates are racemic. However, for simplicity, the re-face

specification found in the optically active compounds 1 and 2

1220 (m), 1195 (s), 1165 (vs), 1105 (m), 1080 (m), 1070 (m), 1050

(m), 1030 (m), 990 (m), 945 (w), 910 (w), 890 (w), 855 (m), 805 (w),

750 (s), 725 (m), 700 (s), 645 (w) cm^–1. C₁₇H₂₄O₂(260.38): calcd.

C 78.42, H 9.29; found C 78.76, H 9.00.

is maintained.

[7] For a review, see: D. P. Curran, N. A. Porter, B. Giese, Stereo-

chemistry of Radical Reactions, VCH, Weinheim, 1995, p. 31 ff.

[8] CCDC-248096 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

[9] S. Huneck, G. Follmann, Z. Naturforsch. B 1967, 22, 666.

[10] For reviews, see:S. S. C. Koch, A. R. Chamberlin, Enantiomer-

ically Pure γ-Butyrolactones in Natural Product Synthesis (Ed.:

Atta-ur-Rahman), Elsevier Science, Amsterdam, 1995, pp.

687–725. R. Bandichhor, B. Nosse, O. Reiser, Top. Curr. Chem.,

in press.

Supporting Information: Experimental procedures and analytical

data of all new compounds are described. ¹H NMR spectra of com-

pounds 21a, 22a, 45, 49, 85, 88, 93, and 94 are given (see also the

footnote on the first page of this article).

Acknowledgments

We thank M. Weber and Prof. Dr. P. Luger, Institut für Kristallo-

graphie der Freien Universität Berlin, for determining the crystal

structure of compound 78a.

[11] J. Mulzer, N. Salimi, H. Hartl, Tetrahedron: Asymmetry 1993,

4, 457. For later syntheses of roccelaric acid, see: C. Böhm, O.

Reiser, Org. Lett. 2001, 3, 1315 and references cited therein.

[12] J. Mulzer, L. Kattner, A. R. Strecker, C. Schröder, J. Busch-

mann, C. Lehmann, P. Luger, J. Am. Chem. Soc. 1991, 113,

4218.

[1] J. Wicha, K. Bal, J. Chem. Soc., Perkin Trans. 1 1978, 1282; G.

Stork, N. A. Saccomano, Tetrahedron Lett. 1987, 28, 2087.

Received: September 16, 2004

Eur. J. Org. Chem. 2005, 1028–1043

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Facially controlled C-methylation of oxolanyl and cyclopentyl acetate enolates: Application to the total synthesis of (+)-nephromopsinic acid

DOI: 10.1002/ejoc.200400653

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