Stereoselective synthesis of hexahydroisobenzofuran-4(1H)-ones from chiral substituted cyclohex-2-enyl carbamates via asymmetric homoaldol reaction and THF cyclocondensation

FULL PAPER

DOI: 10.1002/ejoc.200700220

Stereoselective Synthesis of Hexahydroisobenzofuran-4(1H)-ones from Chiral

Substituted Cyclohex-2-enyl Carbamates via Asymmetric Homoaldol Reaction

and THF Cyclocondensation

Jochen Becker,^[a]Roland Fröhlich,^[a][‡]Olga Kataeva,^[a][‡]and Dieter Hoppe*^[a]

Dedicated to Professor Peter Welzel on the occasion of his 70th birthday

Keywords: Asymmetric synthesis / Heterocycles / Metallated allyl carbamates / Homoaldol reactions / Tetrahydrofuran

synthesis

The diastereofacial selectivity of the homoaldol reaction of

metalated substituted cyclohex-2-enyl carbamates with alde-

hydes is controlled by the nature of the metal complex. Allyl-

lithiums yield syn-configured products whereas transmetal-

aldehydes. Analogous cis,trans,cis-substituted hexahydroiso-

benzofuran-4(1H)-ones, the core structure of many biolo-

gically active natural products, were synthesized starting

from anti-configured homoaldol products. The configurations

lation to Ti(NEt₂)₃gives access to anti-configured 3-(1-hy- of the products were determined by ¹H NMR coupling con-

droxyalkyl)cyclohexenes. The syn-configured homoaldol stants, nOe-studies, and X-ray crystal structure analysis.

products were transformed into annulated all-cis-tetra- (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

hydrofurans by Lewis acid-mediated cyclocondensation with

Germany, 2007)

tures have recently been published.^[4]In the preceeding pa-

per^[5]we reported a highly stereocontrolled synthesis of sim-

pler all-cis-hexahydroisobenzo-furan-4(1H)-ones which is

based on the asymmetric deprotonation^[6]of cyclohex-2-

enyl N,N-diisopropylcarbamate, its homoaldol reaction

with aldehydes,^[7]and subsequent cyclocondensation with

aldehydes^[8](Figure 1).

Introduction

The eunicellin and briarelin diterpenes,^[1]such as sclero-

phytin A (1a)^[2]or briarelin E (1b)^[3]have a tetra-C-substi-

tuted hydroisobenzofuran core within the cyclic framework.

Several strategies for the synthesis of these important struc-

One crucial feature is the question whether it is possible

to construct a 1,3-cis-3,3a-trans-3a,7a-cis-tetrasubstituted

hexahydroisobenzofuran-4(1H)-one instead of the all-cis-

substituted tetrahydrofuran moiety.

We now investigated the homoaldol reaction and tetra-

hydrofuran cyclocondensation of substituted cyclohex-2-

enyl carbamates 2 and 3 (Figure 2), which were previously

found to be easily lithiated with retention of the configura-

tion as shown in a study of lithiation-stannylation reac-

tions.^[6]

Figure 1. Sclerophytin A (1a), briarelin E (1b) and synthesis of all-

cis-hexahydroisobenzofuran-4(1H)-ones

clohex-2-enyl carbamates B.

A from metalated cy-

[a] Organisch-Chemisches Institut, Westfälische Wilhelms-Uni-

versität Münster,

Corrensstr. 40, 48149 Münster, Germany

Fax: +49-251-83-36531

E-mail: dhoppe@uni-muenster.de

[‡] X-ray crystal structure analysis.

Figure 2. Investigated substituted cyclohex-2-enyl N,N-diisopropyl-

carbamates.

Eur. J. Org. Chem. 2007, 3349–3364

3349

J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe

FULL PAPER

configured as determined by comparison of the coupling

pattern of 3-H, 4-H_ax, and 4-H_eqwith that of 11b. The small

axial-equatorial coupling constants observed at the 4-H

proton J_3,4ax= 5.0 Hz (11a) and 4.8 Hz (11b) support the

trans substitution.

Results and Discussion

Synthesis of the Carbamates 2 and 3

3

Carbamates 2 and 3 were obtained from the correspond-

ing alcohols by the usual method via acylation of the so-

dium alcoholates with N,N-diisopropylcarbamoyl chloride

(4) (Scheme 1).^[9](5R)-cis-Carveol (6) is readily available by

reduction of commerically available (R)-(–)-carvone (5).^[10]

The cis-isomer 2 (99% ee) was isolated after carbamo-

ylation and chromatography. Reduction of (R)-(–)-crypton

(8) by LiAlH₄afforded a mixture (80:20) of trans-(1S,4R)-

and cis-(1R,4R)-4-isopropyl-cyclohex-2-enol (9 and 10).^[11]

Their carbamates 3 (trans) and cis-3 were obtained in ste-

reoisomerically pure form after chromatography.

Figure 3. Solid state structure of the benzophenone adduct

11b.^[12,13]

With naphthalene-2-carbaldehyde (12a) and cyclohex-

anecarbaldehyde (12b) the trans-diastereoselectivity is

maintained, but syn/anti mixtures of 18a/19a (79%, 90:10)

and 18b/19b (71%, 75:25) were obtained, which could be

separated by flash chromatography. The syn-trans configu-

ration of 18a was determined by nOe-experiments after

conversion to the annulated tetrahydrofuran 35a and by

comparisation of the analytical data with those of the dia-

stereomers which were obtained in the titanium-mediated

reaction (vide infra).

Scheme 1. Carbamoylation of cyclohex-2-en-1-ols.

Usually, lithium–titanium exchange inverts the configu-

ration.^[7,14]From the aldehyde addition of metalated 2 in

principle four diastereomers can be formed (Scheme 3).

Lithiation and Homoaldol Reactions

We previously reported that the cyclohex-2-enyl carba-

mates 2 and 3 are deprotonated by means of alkyllithium/

diamine with retention of the configuration to form config-

urationally stable allyllithiums, which reacted stereospecifi-

cally in an anti-S_EЈ-process with tin-electrophiles.^[6]Our ac-

tual investigations show, that the reaction of the lithium

intermediate 2·Li with acetone or benzophenone affords the

pure trans-homoaldol products 11a or 11b, respectively

(Scheme 2). The stereochemistry of the subsequent car-

bonyl addition is determined by the configuration of the

metal-bearing carbon atom, proceeding in a strict suprafa-

cial manner, which also is supported by the steric shielding

of the “rear face” by the bulky isopropenyl group and the

axial protons in 4 and 6 position.

Scheme 2. Homoaldol reaction of 2·Li with ketones.

The configuration of 11b was determined by an X-ray

Scheme 3. Possible diastereomers 18–21 arising from the homoal-

crystal structure analysis (Figure 3).^[12,13]11a is also trans- dol reaction of 2·Li with aldehydes.

3350

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3349–3364

Asymmetric Homoaldol Reaction

FULL PAPER

[15]

Metal-exchange of lithium with ClTi(NEt₂)₃

in inter-

mediate 2·Li is expected to proceed as an antarafacial pro-

cess to form 13 which subsequently reacts with aldehydes

12a–g through a Zimmerman–Traxler transition state^[16]

leading to the anti-cis or syn-cis diatereomers 20 or 21,

respectively. The stereochemical pathway of the reaction of

cyclic allyltitaniums with aldehydes or imines is not exclu-

sively controlled by the 1,3-diaxial interactions of the sub-

stituents R of the aldehyde and the β-substituent of the al-

lylmetal. Here steric interactions with the cycloalkene moi-

ety are of great influence. Thus, many diversities are found

in the literature for the diastereofacial selectivity, and a sure

prediction is not available: 7-, 8- and nine-membered cyclic

diisopropoxytitaniumallyl compounds have shown to yield

syn products after addition of aldehydes, whereas a cyclo-

hexenyltitanium afforded only a low (2:1) stereoselectivity

in favor of the syn product.^[17]In contrast, the reaction of

a cyclooctenyltitanium species with imines yielded addition

products with anti-configuration, which was explained by a

six-membered chair-like transition state in which the imine

substituent occupies an axial position.^[18]An anti selectivity

was also observed in the reaction of a cyclic six-membered

β-silyloxy-substituted allyltitanium compound with alde-

hydes.^[19]The reaction of 13 with several aldehydes 12a–

g yielded anti-cis-configured diastereomers 20a–g in good

yields, but these were accompanied by up to 20% of anti-

trans diastereomers 19a–g if the TMEDA complex of 2·Li

was the intermediate (Scheme 4, Table 1, for an example see

Entry 3). These results can be explained by a highly ordered

chair-like transition state TS-16, in which the substituent R

has to occupy an axial position. Here, the – usually large –

1,3-diaxial interactions of the methyl group and substituent

R have to be smaller than the severe interactions of R with

the cyclohexene moiety. A twist-boat-like transition state

Scheme 4. Mechanism of the titanium-mediated homoaldol reac-

tions of 2.

can not be excluded and would also explain the simple dia- the best stereospecifities with a diastereoselectivity of up to

stereoselectivity.^[20,21]The formation of the minor dia- 95:5 (Table 1; Entries 5–11).

stereomers 19 via TS-22 is the result of a not completely

The observed anti-selectivity even in the trans-series is a

stereospecific metal exchange, presuambly due to steric in- hint for a complete metal exchange. The optimization reac-

teractions with the isopropenyl group. We increased the ste- tions were performed using benzaldehyde, which afforded

ric demand of the diamine ligand by applying (–)-sparteine inseparable mixtures of 20c/19c (R = Ph), all other dia-

(25)

or

rac-trans-1,2-bis(dimethylamino)cyclohexane stereomeric pairs 20/19 could be separated by flash

(TMCDA, rac-26) in order to hinder the attack of the tita- chromatography. A mixture of separable diastereomers 20a

nium reagent from the “upper face”. TMCDA (rac-26) gave and 19a (R = 2-naphthyl) was oxidized with PDC in 89%

Table 1. Results of the homolaldol reactions of 2.

Entry

Diamine

ClTi(NEt₂)₃

Aldehyde, R

% Yield^[a]

Product dr^[b]

1

2

TMEDA

25

rac-26

–

12a, 2-naphthyl

12b, cyclohexyl

12c, Ph

78

71

69

71

65

81

58

71

80

55

35

18a/19a = 90:10

18b/19b = 75:25

20c/19c = 80:20

20c/19c = 87:13

20c/19c = 95:5

20a/19a = 94:6

20d/19d = 93:7

20e/19e = 95:5

20f/19f = 95:5

20g/19g = 93:7

20b/19b = 91:9

3^[c]

4^[c]

5

1.6 equiv.

2.0 equiv.

1.6 equiv.

12c, Ph

6

7

8

9

10

11

12a, 2-naphthyl

12d, 4-BrPh

12e, vinyl

12f, C(=CH₂)(CH₃)

12g, CH(CH₃)₂

12b, cyclohexyl

[a] Isolated yields. [b] The diastereomeric ratio was determined from the crude product by GC (HP-5). [c] Other aldehydes yielded the

same diastereoselectivity when applying these conditions.^[22]

Eur. J. Org. Chem. 2007, 3349–3364

www.eurjoc.org

3351

J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe

FULL PAPER

yield. The diastereomeric ratio remained; 20a yielded the Indeed, the transmetallation proceeded stereospecifically

cis-configured ketone 23 and 19a the trans-diastereomer 24, with inversion of the configuration, but besides the major

which were easily separable by chromatography. The cis anti-trans diastereomers 31, small amounts of the syn-trans

configurations of the anti-cis products 20 and of ketone 23 homoaldol products 32 were obtained (Table 2). The con-

1

were secured by the large constants of the H NMR coup- figuration of the minor diastereomers 32 was prooven by

ling of 3-H and 4-H_ax, which were in the range of 10.2 Hz the PDC oxidation of rac-31a and rac-32a (R = Ph), which

(20d) to 11.6 Hz (23). Starting from 20a the hexahydroiso- yielded the same trans-configured ketone rac-33. The en-

benzofuran-4(1H)-one 38a was obtained, clearly establishing ergy difference of transition states TS-29 and TS-30 de-

the anti configuration for the series of compounds 20 (see pends on the substituent R of the aldehyde and is not as

Scheme 9). The reversal of syn (M = Li) to anti (M = TiR₃) large as observed for the transition states in the investi-

diastereoselectivity can be rationalized in terms of an open gations of the carveyl carbamate 2.^[20]

transition state in the lithium-method (TS-14, Scheme 3).

Interestingly, the reaction of the six-membered cyclic tri-

chlorotitaniumallyl carbamate with aldehydes afforded ex-

clusively syn-homoaldol products.^[5,23]

Homoaldol Reactions with 3

The lithiated trans-configured cryptyl carbamate 3·Li

was not subjected to a direct carbonyl addition. We ex-

pected that the isopropyl group in 4-position would hinder

a syn addition of the carbonyl electrophile. But the pre-

ferred conformation of 3·Li bears good conditions for an

metal-exchange with inversion by ClTi(NEt₂)₃(Scheme 5).

The reaction of the allyltitanium intermediate rac-27 with

benzaldehyde afforded a solid product rac-31a from which

crystals suitable for X-ray crystallographic analysis were ob-

tained (Figure 4).^[12,24]It conclusively established the antici-

pated anti-trans-configuration for this series of compounds.

Figure 4. Solid state structure of rac-31a.^[12,24]

Table 2. Results of the homoaldol reactions of carbamate 3.

[a] Isolated yields. [b] 99% ee (HPLC). [c] Yield and dr of the race-

mate starting from rac-3. [d] The dr was determined from the crude

product by GC (HP-5). [e] The dr was determined by ¹H NMR

spectroscopy. [f] 59% of the chiral aldehyde 28d were reisolated.

Good drs are observed for arylic and vinylic aldehydes as

well as for enantiopure TBDPS protected (R)-lactaldehyde

28a^[25](Table 2, Entry 4). The major products 31 have a

higher polarity than 32 and all diastereomeric pairs 31a–c/

32a–c are easily separable by flash chromatography. Unfor-

tunately, the allyltitanium compound 27 seems to suffer

Scheme 5. Transmetallation and homoaldol reactions of 3.

3352

partially from decomposition because the reaction with the

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3349–3364

Asymmetric Homoaldol Reaction

FULL PAPER

usual excess (3.0 equiv.) of the aldehyde afforded only low

yields. Increasing the amount of the aldehyde to 7–12 equiv.

resulted in acceptable yields (45–83%). As expected, the en-

antio-enrichments of 3 (99% ee) and 31a (99% ee) are

equal, indicating that the stereogenic centres of the alkyl-

substituted cyclohex-2-enyl carbamates do not epimerize at

all in the homoaldol reactions.

Cyclizations to Form Hexahydroisobenzofuran-4(1H)-ones

The syn homoaldol product 18a (R = 2-naphthyl) was

subjected to the Mukaiyama-type reaction conditions^[8]by

addition of 1.3 equiv. aldehyde 34 and BF₃·OEt₂to yield

the diastereomerically pure bicycles 35 in good yields

(Scheme 6). As observed with unsubstituted cyclohex-2-enyl

carbamate the syn configuration of the homoaldol product

leads to all-cis-configured hexahydroisobenzofuran-4(1H)-

ones,^[5]which is not influenced by substituents on the cyclo-

hexene ring. The configuration of the tetrahydrofuran moi-

ety of 35b (R = 2-naphthyl, RЈ = Ph) was determined by

nOe-experiments.

Scheme 7. Synthesis of 1,3-cis-3,3a-trans-3a,7a-cis-6-isopropenyl-

hexahydroisobenzofuran-4(1H)-ones 38 and solid-state structure of

38a (R = 2-naphthyl, RЈ = Ph).^[12,26]

Table 3. Synthesis of annulated cis,trans,cis-tetrahydrofurans 38.

Entry 20

R

Aldehyde, RЈ 38

% Yield^[a]

1

2

3

4

5

20a

2-naphthyl

p-BrPh

C(CH₂)Me 36c, CHMe₂38c

CHMe₂

36a, Ph

36b, Me

38a

38b

73

83

73

80

83

20d

20f

20g

20b

36a, Ph

38d

38e

cyclohexyl

[a] Isolated yields. dr Ͼ98:2 for all reactions as determined by GC

(HP-5) from the crude product.

Scheme 6. Synthesis of all-cis-6-isopropenylhexahydroisobenzofu-

ran-4(1H)-ones 35.

When anti-cis-configured homoaldol products 20 were

treated with BF₃·OEt₂and aldehydes 36, again dia-

stereomerically pure bicycles were obtained (Scheme 7,

Table 3). The X-ray crystal structure analysis^[12,26]of solid

compound 38a established that the homoaldol products 20

formed hexahydroisobenzofuran-4(1H)-ones 38 with the

desired 1,3-cis-3,3a-trans-3a,7a-cis-substitution pattern at

the tetrahydrofuran moiety. The “carbamoyl-protected

enolate” 37 is even nucleophilic enough to form the quater-

nary stereocentre at the carbon atom 3a.

The annulation proceeded in a cis-fashion, but the anti-

configuration of the starting material afforded the (E)-ox-

onium ion TS-37, whose conformational bias lead to an

Si,Si-attack. Aryl, α,β-unsaturated, and aliphatic aldehydes

provided the diastereomerically pure products 38 in good

yields (73–83%).

The condensation of anti-configured homoaldol product

31a (R = Ph) with 4-bromobenzaldehyde (39a) resulted in

the formation of diastereomerically pure tetrahydrofuran

41a (Scheme 8, Table 4, Entry 1). As shown by HPLC mea-

surements, the enantio-enrichment of the starting carba-

Scheme 8. Synthesis of 1,3-cis-3,3a-trans-3a,7a-cis-7-isopropyl-

hexahydroisobenzofuran-4(1H)-ones 41 and solid-state structure of

41a (R = Ph, RЈ = 4-BrPh).^[12,27,28]

The configuration of all four stereogenic centres at the

mate 3 (99% ee) remains unchanged after homoaldol reac- tetrahydrofuran moiety arises from the stereoselective re-

tion and THF cyclocondensation. The absolute configura- duction of (R)-(–)-crypton, the anti-selective homoaldol re-

tion of the solid product 41a was secured by X-ray structure action and the cis-selective annulation via the (E)-oxonium

analysis with anomalous dispersion.^[12,27,28]

intermediate 40. In order to obtain potential precursors for

Eur. J. Org. Chem. 2007, 3349–3364

www.eurjoc.org

3353

J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe

FULL PAPER

(1R,5R)-5-Isopropenyl-2-methylcyclohex-2-enyl

N,N-Diisopropyl-

Table 4. Results of the cyclocondensation reactions.

carbamate (2): NaH (3.84 g, 96 mmol, 1.2 equiv.), (5R)-carveol^[10]

Entry 31

R

Aldehyde, RЈ

41

% Yield^[a]

91 (84)^[b]

(12.25 g, 80.5 mmol, 6/7

= 97:3) and 4 (18.3 g, 112 mmol,

1

2

3

31a

Ph

39a, 4-Br-Ph

41a

1.4 equiv.) were refluxed in THF (170 mL) for 18 h. Purification

and separation of the diastereomers by FCC (TBME/PE = 1:16 to

1:8) yielded 20.61 g (74 mmol, 92%)^[30]2:trans-2 = 97:3^[31]as color-

less liquids. 2: t_R= 13.98 min (HP-5). R_F= 0.59 (Et₂O/PE = 1:9).

¹H NMR (400 MHz, CDCl₃): δ = 1.18, 1.20 (2 s, 12 H, N-iPr

rac-31a Ph

39b, CH₂C(CH₂)Me rac-41b 70

rac-31b C(CH₂)Me 39b, CH₂C(CH₂)Me rac-41c 68

[a] Isolated Yields. dr Ͼ98:2 for all reactions as determined by GC

(HP-5) from the crude product. [b] Yield of the racemate starting

from rac-31a.

3

2

(CH₃)₂), 1.49 (ddd, J_5,6A= 12.0 Hz, J_6A,6B= 11.7 Hz, 1 H, 6-

H_A), 1.64 (s, 3 H, 5-C(CH₂)(CH₃)), 1.70 (s, 3 H, 2-CH₃), 1.95 (ddm,

2

³J_4A,5= 12.0 Hz, J_4A,4B= 17.1 Hz, 1 H, 4-H_A), 2.06 (dm, J_4A,4B

the soft coral diterpenes (Figure 1) we performed condensa-

tion reactions with 3-methyl-3-butenal diethyl acetal 48b^[29]

(Table 4, Entries 2 and 3). The annulation proceeded again

smoothly and stereoselectively to yield compounds rac-41b

and rac-41c with an exo-double bound. The great variety of

olefin and ketone reactions makes this compounds versatile

chiral building blocks for further transformations.

= 17.1 Hz, 1 H, 4-H_B), 2.19 (ddt, ³J_5,6B= 5.9 Hz, ²J_6A,6B= 11.7 Hz,

3

1 H, 6-H_B), 2.29 (tt, J_4A,5

= = =

³J_5,6A= 12.0 Hz, J_4B,5³J_5,6B

5.9 Hz, 1 H, 5-H), 3.88 (br. s, 2 H, N-iPr CH), 4.69 (s, 2 H, 5-

C(CH₂)(CH₃)), 5.40 (m, 1 H, 1-H), 5.52 (m, 1 H, 3-H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 19.0 (CH₃, 2-CH₃), 20.5 (CH₃,

5-C(CH₂)(CH₃)), 20.9 (CH₃, N-iPr (CH₃)₂), 30.7 (CH₂, C-4), 34.5

(CH₂, C-6), 40.4 (CH, C-5), 45.6 (CH, N-iPr CH), 73.6 (CH, C-1),

109.0 (CH₂, 5-C(CH₂)(CH₃)), 124.9 (CH, C-3), 134.1 (C_q, C-2),

148.5 (C , 5-C(CH )(CH )), 155.4 (C , C=O) ppm. IR (film): ν =

˜

q

2

3

q

2999 (m), 2968 (s), 2930 (m) [ν(C_aliph-H)], 1681 (s) [ν(C=O)], 1644

(s) [ν(C=C)] cm^–1. MS (ESI): m/z = 302.21 [M + Na]⁺. C₁₇H₂₉NO₂

(279.42): calcd. C 73.07, H 10.46, N 5.01; found C 72.86, H 10.40,

N 4.90. [α]²_D⁰= +5.1 (c = 0.97, CHCl₃) at 99% ee; HPLC Chiralcel

OD-H (4.6ϫ250 mm), λ = 200 nm, iPrOH:n-hexane = 1:2000,

1.0 mL/min, 8.98 min (ent-2), 13.03 min (2). rac-2 was prepared by

mixing equal amounts of 2 and ent-2, which was prepared from

(S)-(+)-carvon.

Conclusions

We have shown, that the simple diastereoselectivity of the

homoaldol reaction of metalated substituted cyclohex-2-

enyl N,N-diisopropylcarbamates with aldehydes can be con-

trolled by the nature of the applied metal (Scheme 9). The

tris(diethylamino)titanium complexes led preferentially to

anti-configured homoaldol products, whereas the lithium

complexes afforded syn homoaldol products, which were

also observed with trichlorotitaniumallyl carbamates.^[5]

Condensation of the anti products with aldehydes in a Mu-

kaiyama-type reaction yielded cis,trans,cis-substituted hexa-

hydroisobenzofuran-4(1H)-ones; syn homoaldol products

afforded an all-cis-substitution pattern. This methodology

provides a stereoselective approach to valuable building

blocks in a two step sequence starting from metalated cyclo-

hexenyl carbamates.

(1S,4R)-4-Isopropylcyclohex-2-enyl N,N-Diisopropylcarbamate (3):

NaH (370 mg, 9.24 mmol, 1.2 equiv.), (4R)-cryptol^[11](1.080 g,

7.70 mmol, 9/10 = 80:20) and 4 (1.38 g, 10.8 mmol, 1.4 equiv.) were

refluxed in THF (25 mL) for 3.5 h. Purification and separation of

the diastereomers by FCC (Et₂O/PE = 1:12) yielded 1.450 g

(5.42 mmol, 70%) 3 and 377 mg (1.41 mmol, 18%) cis-3 (total yield

89%, 3:cis-3 = 80:20^[31]) as colorless liquids. rac-3 and rac-cis-3

were obtained from NaH (3.1 g, 77 mmol, 1.2 equiv.), rac-cryptol

(9.0 g, 64 mmol, rac-9:rac-10 = 80:20) and 4 (14.8 g, 90 mmol,

1.4 equiv.). Yield 15.91 g (60 mmol, 93%)^[30]rac-3: rac-cis-3 =

80:20.^[31]rac-3 becomes a colourless solid when stored in a freezer

1

at 4 °C. 3: t_R= 13.08 min (HP-5). R_F= 0.40 (Et₂O/PE = 1:9). H

3

NMR (600 MHz, CDCl₃): δ = 0.80, 0.83 (2 d, J_{4-iPrCH,4-iPr(Me)}

=

7.1 Hz, 6 H, 4-iPr (CH₃)₂), 1.13 (s, 12 H, N-iPr (CH₃)₂), 1.32 (m,

1 H, 5-H_A), 1.50 (m, 2 H, 6-H_A, 4-iPr CH), 1.70 (m, 1 H, 5-H_B),

1.94 (m, 1 H, 4-H), 2.07 (m, 1 H, 6-H_B), 3.62, 4.06 (2 br. s, 2 H,

N-iPr CH), 5.17 (m, 1 H, 1-H), 5.65 (m, 2 H, 2-H, 3-H) ppm. ¹³C

NMR (600 MHz, CDCl₃): δ = 19.3, 19.6 (CH₃, 4-iPr (CH₃)₂), 20.8,

21.4 (CH₃, N-iPr (CH₃)₂), 23.4 (CH₂, C-5), 28.8 (CH₂, C-6), 31.9

(CH, 4-iPr CH), 41.6 (CH₂, C-4), 45.0, 46.2 (CH, N-iPr CH), 70.1

(CH, C-1), 128.4 (CH, C-2), 133.6 (CH, C-3), 155.6 (C_q, C=O)

ppm. IR (film): ν = 2996 (m), 2961 (s), 2935 (s), 2871 (s) [ν(C

–

˜

aliph

H)], 1688 (s) [ν(C=O)] cm^–1. MS (ESI): m/z

= 290.2088

[M + Na]⁺. C₁₆H₂₉NO₂(267.41): calcd. C 71.86, H 10.93, N 5.24;

found C 71.99, H 11.05, N 5.11. [α]²_D⁰= –117.4 (c = 0.70, CHCl₃)

at 99% ee; HPLC Chiralcel OD-H (4.6ϫ250 mm), λ = 210 nm,

iPrOH:n-hexane = 1:600, 0.3 mL/min, 35.62 min (ent-3), 38.83 min

Scheme 9. Diversity in the stereoselective synthesis of 3-(1-hy-

droxyalkyl)cyclohexenes and hexahydroisobenzofuran-4(1H)-ones.

1

(3). cis-3: t_R= 12.84 min (HP-5). R_F= 0.28 (Et₂O/PE = 1:9). H

3

Experimental Section

NMR (600 MHz, CDCl₃): δ = 0.90, 0.92 (2 d, J_{4-iPrCH,4-iPr(Me)}

=

7.0 Hz, 6 H, 4-iPr (CH₃)₂), 1.20, 1.21 (2 br. s, 12 H, N-iPr

(CH₃)₂), 1.50 (m, 1 H, 5-H_A), 1.61 (m, 1 H, 5-H_B), 1.69 (m, 2 H,

6-H_A, 4-iPr CH), 1.95 (m, 2 H, 6-H_B, 4-H), 3.89 (br. s, 2 H, N-iPr

CH), 5.14 (m, 1 H, 1-H), 5.86 (s, 2 H, 2-H, 3-H) ppm. ¹³C NMR

(600 MHz, CDCl₃): δ = 19.1, 19.5 (CH₃, 4-iPr (CH₃)₂), 20.6 (CH₂,

C-5), 20.9 (CH₃, N-iPr (CH₃)₂), 28.2 (CH₂, C-6), 31.7 (CH, 4-iPr

General Remarks: Details concerning purification of solvents, rea-

gents and a list of the applied analysis systems can be found in the

preceeding puplication.^[5]

Carbamoylation of Cyclohex-2-enols: A detailed procedure can be

found in the preceeding paper.^[5]

3354

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3349–3364

Asymmetric Homoaldol Reaction

CH), 41.8 (CH, C-4), 45.8 (CH, N-iPr CH), 66.7 (CH, C-1), 125.9 2.05 (dd, ³J_5,6A= 10.4 Hz, ²J_6A,6B= 17.6 Hz, 1 H, 6-H_A), 2.23 (dd,

FULL PAPER

2

3

(CH, C-2), 136.2 (CH, C-3), 155.6 (C , C=O) ppm. IR (film): ν =

³J_5,6B= 7.0 Hz, J_6A,6B= 17.6 Hz, 1 H, 6-H_B), 3.06 (dddd, J_4A,5

˜

q

3

2995 (m), 2961 (m), 2940 (m), 2873 (m) [ν(C_aliph–H)], 1688 (s)

[ν(C=O)] cm^–1. MS (ESI): m/z = 290.2072 [M + Na]⁺. C₁₆H₂₉NO₂

(267.41): calcd. C 71.86, H 10.93, N 5.24; found C 71.71, H 11.10,

N 5.10. [α]²_D⁰= +129.1 (c = 0.70, CHCl₃).

= 13.2 Hz, J_4B,5= 2.5 Hz, J_5,6A= 10.4 Hz, J_5,6B= 7.0 Hz, 1 H,

5-H), 3.58 (br. s, 1 H, 3-H), 3.77, 4.09 (2 br. s, 2 H, N-iPr CH),

4.52, 4.55 (2 s, 2 H, 5-C(CH₂)(CH₃)), 7.12 (m, 2 H, p-PhCH), 7.25

(m, 4 H, o-PhCH), 7.68, 7.79 (2 m, 4 H, m-PhCH) ppm. ¹³C NMR

(75 MHz, CDCl₃):

δ = 16.8 (CH₃, 2-CH₃), 20.3 (CH₃, 5-

Deprotonation of Cyclohex-2-enyl Carbamates and Trapping with

Carbonyl Electrophiles. General Procedure A (GP A): A Solution of

the cyclohex-2-enyl carbamate (1.0 mmol) and TMEDA (151 mg,

1.3 equiv.) or TMCDA rac-26 (221 mg, 1.3 equiv.) in Et₂O (5 mL)

was cooled to –78 °C. 1.36  sec-BuLi solution (0.95 mL,

1.3 equiv.) was added dropwise and the solution was stirred for 2 h.

The carbonyl compound (3.0 equiv.) was then added dropwise by

syringe and stirring at –78 °C was continued for 2–14 h until com-

plete consumption of the starting material (TLC). The reaction was

quenched with satd. aq. NH₄Cl solution (2 mL) and the mixture

was warmed to room temperature. The layers were separated and

the aqueous layer was extracted with TBME (3ϫ10 mL). The com-

bined organic layers were dried with MgSO₄, filtered and the sol-

vent was removed in vacuo. FCC on silica gel and removal of the

solvent in vacuo yielded the addition products.

C(CH₂)(CH₃)), 21.5 (CH₃, N-iPr (CH₃)₂), 30.7 (CH₂, C-4), 32.4

(CH₂, C-6), 35.8 (CH, C-5), 45.5, 46.9 (CH, N-iPr CH), 48.0 (CH,

C-3), 78.8 (CH, C-OH), 108.3 (CH₂, 5-C(CH₂)(CH₃)), 120.3 (C_q,

C-2), 125.6, (CH, m-Ph), 126.2 (CH, p-Ph), 127.8 (CH, o-Ph), 145.7

(C-1), 149.2 (C_q, 5-C(CH₂)(CH₃)), 149.6 (C_q, i-C-Ph), 153.9 (C_q,

C=O) ppm. IR (KBr): ν = 3492 (br.) [ν(OH)], 3076 (m) [ν(C

–

˜

arom

H)], 2972 (s), 2937 (m), 2919 (m) [ν(C_aliph–H)], 1700 (s) [ν(C=O)],

1642 (m) [ν(C=C)] cm^–1. MS (ESI): m/z = 484.28 [M + Na]⁺.

C₃₀H₃₉NO₃(461.64): calcd. C 78.05, H 8.52, N 3.01; found

C 77.87, H 8.51, N 2.92. [α]²_D⁰= –34.7 (c = 1.01, CHCl₃).

[3R,3(1S),5R]- and [3R,3(1R),5R]-3-[1-Hydroxy-1-(naphthalen-2-

yl)-methyl]-5-isopropenyl-2-methylcyclohex-1-enyl N,N-Diisopropyl-

carbamate (18a and 19a): (1R,5R)-Carveyl carbamate 2 (849 mg,

3.0 mmol) was lithiated according to GP A with TMEDA (453 mg,

3.9 mmol, 1.3 equiv.) and 0.59  sBuLi solution (6.6 mL, 3.9 mmol,

1.3 equiv.) in Et₂O (15 mL) at –78 °C for 2 h. 2-Naphthaldehyde

(12a, 1.4 g, 9.0 mmol, 3.0 equiv.) in Et₂O (10 mL) was added and

the solution was stirred for 2 h at –78 °C. Purification and separa-

tion of the diastereomers by FCC (TBME/PE = 1:4 to 1:3) yielded

yielded 914 mg (2.10 mmol, 70%) 18a and 103 mg (0.24 mmol, 8%)

19a (total yield 78%, 18a/19a = 90:10^[31]) as colourless oils. 18a: t_R

= 24.30 min (HP-5). R_F= 0.42 (Et₂O/PE = 1:2). ¹H NMR

(300 MHz, CDCl₃): δ = 1.27 (br. s, 12 H, N-iPr (CH₃)₂), 1.56 (m,

1 H, 4-H_A), 1.60 (s, 3 H, 2-CH₃), 1.71 (s and m, 4 H, 5-

C(CH₂)(CH₃), 4-H_B), 2.15 (m, 2 H, 6-H), 2.58 (br. s, 1 H, 3-H),

3.06 (br. m, 1 H, 5-H), 3.87, 4.09 (2 br. s, 2 H, N-iPr CH), 4.62 (s,

2 H, 5-C(CH₂)(CH₃)), 5.25 (d, J = 3.7 Hz, 1 H, CH-O), 7.44 (m, 3

H, ArCH), 7.82 (m, 3 H, ArCH), 7.94 (s, 7 H, ArCH) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 14.5 (CH₃, 2-CH₃), 20.6 (CH₃, 5-

C(CH₂)(CH₃)), 21.5 (CH₃, N-iPr (CH₃)₂), 27.6 (CH₂, C-4), 32.4

(CH₂, C-6), 37.9 (CH, C-5), 45.9 (CH, N-iPr CH), 46.9 (CH, C-3),

73.3 (CH, C-OH), 108.8 (CH₂, 5-C(CH₂)(CH₃)), 119.9 (C_q, C-2),

124.2, 124.5, 125.4, 125.9, 127.6, 127.7, 128.0 (CH, C-Ar), 132.6,

133.4, 140.1 (C_q, C-Ar), 145.4 (C-1), 148.8 (C_q, 5-C(CH₂)(CH₃)),

(3R,5R)-3-(1-Hydroxy-1-methylethyl)-5-isopropenyl-2-methyl-

cyclohex-1-enyl N,N-Diisopropylcarbamate (11a): (1R,5R)-Carveyl

carbamate 2 (279 mg, 1.00 mmol) was lithiated according to GP A

with TMEDA (151 mg, 1.30 mmol, 1.3 equiv.) and 1.36  sBuLi

solution (0.95 mL, 1.30 mmol, 1.3 equiv.) in Et₂O (5 mL) at –78 °C

for 2 h. Acetone (174 mg, 3.0 mmol, 3.0 equiv.) was then added and

the solution was warmed to room temperature within 8 h. FCC on

silica gel (TBME/PE = 1:20 to 1:12) yielded 263 mg (0.78 mmol,

78%) 11a (dr Ͼ 98:2) as a colourless liquid. t_R= 16.56 min (HP-

1

5). R_F= 0.33 (TBME/PE = 1:12). H NMR (300 MHz, CDCl₃): δ

= 1.24, 1.26 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.29, 1.31 (2 s, 6 H, 2Ј-

3

2

H), 1.54 (dt, J_3,4A= 5.0 Hz, J_4A,4B

H_A), 1.72 (br. s, 6 H, 2-CH₃, 5-C(CH₂)(CH₃)), 1.94 (m, 1 H, 4-

=

³J_4A,5= 13.3 Hz, 1 H, 4-

2

H_B), 2.02 (dm, J_6A,6B= 17.5 Hz, 1 H, 6-H_A), 2.22 (dm, J_6A,6B

=

17.5 Hz, 1 H, 6-H_B), 2.26 (m, 1 H, 3-H), 2.36 (s, 1 H, OH), 3.00

(m, 1 H, 5-H), 3.82, 4.09 (2 br. s, 2 H, N-iPr CH), 4.70, 4.75 (2 s,

2 H, 5-C(CH₂)(CH₃)) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 18.5

(CH₃, 2-CH₃), 20.3 (CH₃, 5-C(CH₂)(CH₃)), 21.1 (CH₃, N-iPr

(CH₃)₂), 27.8 (CH₂, C-4), 30.3 (CH, C-5), 32.4 (CH₃, C-2Ј), 36.6

(CH₂, C-6), 46.1 (CH, N-iPr CH), 49.5 (CH, C-3), 72.9 (C_q, C-

OH), 108.7 (CH₂, 5-C(CH₂)(CH₃)), 120.7 (C_q, C-2), 145.3 (C_q, C-

153.7 (C , C=O) ppm. IR (film): ν = 3422 (br.) [ν(OH)], 3052 (w)

˜

q

[ν(C_arom–H)], 2965 (s), 2930 (s), 2870 (s) [ν(C_aliph–H)], 1678 (s)

[ν(C=O)] cm^–1. MS (ESI): m/z = 458.2653 [M + Na]⁺. C₂₈H₃₇NO₃

(435.60): calcd. C 77.20, H 8.56, N 3.22; found C 77.10, H 8.54, N

2.88. [α]²_D⁰= +31.5 (c = 0.86, CHCl₃). 19a: t_R= 24.30 min (HP-5).

R_F= 0.35 (Et₂O/PE = 1:2). ¹H NMR (300 MHz, CDCl₃): δ = 1.27,

1.29 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.58 (br. s, 4 H, 4-H_A, 2-CH₃),

1.79 (s, 3 H, 5-C(CH₂)(CH₃)), 2.03, 2.18 (2 m, 4 H, 3-H, 6-H, 4-

H_B), 2.82 (m, 1 H, 5-H), 3.92, 4.04 (2 br. s, 2 H, N-iPr CH), 4.59

(s, 2 H, 5-C(CH₂)(CH₃)), 5.30 (d, J = 2.1 Hz, 1 H, CH-O), 7.45

(m, 3 H, ArCH), 7.82 (m, 3 H, ArCH), 7.89 (s, 1 H, ArCH) ppm.

1), 149.3 (C , 5-C(CH )(CH )), 153.6 (C , C=O) ppm. IR (film): ν

˜

q

2

3

q

= 3457 (br.) [ν(OH)], 2970 (s), 2934 (s), 2877 (s) [ν(C_aliph–H)], 1699

(s) [ν(C=O)], 1645 (m) [ν(C=C)] cm^–1. MS (ESI): m/z = 360.25 [M

+ Na]⁺. C₂₀H₃₅NO₃(337.50): calcd. C 71.18, H 10.45, N 4.15;

found C 70.81, H 10.52, N 4.05. [α]²_D⁰= +22.4 (c = 0.98, CHCl₃).

(3R,5R)-3-(1-Hydroxy-1,1-diphenylmethyl)-5-isopropenyl-2-methyl-

cyclohex-1-enyl N,N-Diisopropylcarbamate (11b): (1R,5R)-Carveyl

carbamate 2 (279 mg, 1.00 mmol) was lithiated according to GP A

with TMEDA (151 mg, 1.30 mmol, 1.3 equiv.) and 1.36  sBuLi ¹³C NMR (75 MHz, CDCl₃): δ = 13.4 (CH₃, 2-CH₃), 20.9 (CH₃,

solution (0.95 mL, 1.30 mmol, 1.3 equiv.) in Et₂O (5 mL) at –78 °C

for 2 h. Benzophenone (550 mg, 3.0 mmol, 3.0 equiv.) in Et₂O

(2 mL) was added and the solution was warmed to room tempera-

ture during 8 h. FCC on silica gel (TBME/PE = 1:20 to 1:10)

yielded 409 mg (0.89 mmol, 89%) 11b (dr Ͼ 98:2) as a colourless

5-C(CH₂)(CH₃)), 21.4 (CH₃, N-iPr (CH₃)₂), 27.0 (CH₂, C-4), 33.6

(CH₂, C-6), 41.0 (CH, C-5), 45.5 (CH, N-iPr CH), 47.3 (CH, C-3),

71.7 (CH, C-OH), 109.4 (CH₂, 5-C(CH₂)(CH₃)), 119.8 (C_q, C-2),

124.0, 124.3, 125.4, 125.8 127.6, 127.9, 128.0 (CH, C-Ar), 132.6,

133.4, 140.0 (C_q, C-Ar), 146.3 (C-1), 148.6 (C_q, 5-C(CH₂)(CH₃)),

solid. M.p. 174 °C (TBME/PE). t_R= 16.56 min (HP-5). R_F= 0.34

153.3 (C , C=O) ppm. IR (film): ν = 3424 (br.) [ν(OH)], 3047 (w)

˜

q

1

(TBME/PE = 1:10). H NMR (300 MHz, CDCl₃): δ = 1.02 (m, 3 [ν(C_arom–H)], 2970 (s), 2929 (s), 2872 (s) [ν(C_aliph–H)], 1683 (m)

3

H, 2-CH₃), 1.22 (d, 12 H, N-iPr (CH₃)₂), 1.44 (s and dt, J_3,4A

=

[ν(C=O)] cm^–1. MS (ESI): m/z = 458.2648 [M + Na]⁺. C₂₈H₃₇NO₃

2

4.8 Hz, J_4A,4B

1.67 (dt, J_4A,4B= 13.2 Hz, J_3,4B

=

³J_4A,5= 13.2 Hz, 4 H, 5-C(CH₂)(CH₃), 4-H_A), (435.59): calcd. C 77.20, H 8.56, N 3.22; found C 76.82, H 8.52, N

2

3

=

³J_4B,5= 2.5 Hz, 1 H, 4-H_B),

3.10. [α]²_D⁰= +117.3 (c = 0.48, CHCl₃).

Eur. J. Org. Chem. 2007, 3349–3364

www.eurjoc.org

3355

J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe

FULL PAPER

[3R,3(1S),5R]-

and

[3R,3(1R),5R]-3-(1-Cyclohexyl-1-hydroxy- Büchner funnel. The solid residue was washed with TBME

methyl)-5-isopropenyl-2-methylcyclohex-1-enyl N,N-Diisopropylcar-

bamate (18b and 19b): (1R,5R)-Carveyl carbamate 2 (840 mg,

3.0 mmol) was lithiated according to GP A with TMEDA (453 mg,

(3ϫ10 mL), filtered and the filter cake was washed with TBME

(20 mL). The aqueous layer was separated and extracted with

TBME (3ϫ10 mL). The combined organic layers were dried with

3.9 mmol, 1.3 equiv.) and 1.36  sBuLi solution (2.9 mL, 3.9 mmol, MgSO₄, filtered, and the solvent was removed in vacuo. FCC on

1.3 equiv.) in Et₂O (15 mL) at –78 °C for 2 h. Cyclohexanecarb-

aldehyde (12b, 1.0 g, 9.0 mmol, 3.0 equiv.) was added and the solu-

tion was warmed to room temperature during 16 h. Purification

and separation of the diastereomers by FCC (TBME/PE = 1:4)

yielded 932 mg (2.14 mmol, 71%)^[30]18b/19b = 75:25^[31]as colour-

less oils. 18b: t_R= 20.47 min (HP-5). R_F= 0.48 (TBME/PE = 1:4).

¹H NMR (400 MHz, CDCl₃): δ = 0.84–1.03 (m, 2 H, CyCH₂), 1.26

(m, 14 H, N-iPr (CH₃)₂, CyCH₂), 1.43–1.54 (m, 2 H, 4-H_A, CyCH),

1.57 (s, 3 H, 2-CH₃), 1.64–1.70 (m, 3 H, CyCH₂), 1.73 (s, 3 H, 5-

silica gel (Et₂O/PE or TBME/PE mixtures) and removal of the sol-

vent in vacuo yielded the homoaldol products.

[3S,3(1S),5R]- and [3R,3(1R),5R]-3-(1-Hydroxyphenylmethyl)-5-iso-

propenyl-2-methylcyclohex-1-enyl N,N-Diisopropylcarbamate (20c

and 19c): (1R,5R)-Carveyl carbamate 2 (838 mg, 3.0 mmol) was li-

thiated according to GP

C with TMCDA (rac-26, 663 mg,

3.9 mmol, 1.3 equiv.) and 1.36  sBuLi solution (2.9 mL, 3.9 mmol,

1.3 equiv.) in Et₂O (15 mL) at –78 °C for 2 h and transmetallated

with ClTi(NEt₂)₃(1.8 g, 6.0 mmol, 2.0 equiv.) for 3 h. Benzalde-

hyde (12c, 954 mg, 9.0 mmol, 3.0 equiv.) was added and the solu-

tion was warmed to room temperature during 14 h. Purification by

FCC (TBME/PE = 1:4) yielded 749 mg (1.94 mmol, 65%) 20c/19c

= 95:5^[31]as colourless oil. The diastereomers were not separable

by chromatography. The optimisation reactions were performed

with the same conditions but with variation of the diamine ligand

(see Table 1). 20c: t_R= 20.68 min (HP-5). R_F= 0.41 (TBME/PE =

1:2). ¹H NMR (300 MHz, CDCl₃): δ = 1.23, 1.25 (2 br. s, 12 H, N-

3

C(CH₂)(CH₃)), 1.75 (m, 2 H, CyCH₂), 1.85 (dtr, J_3,4B= J_4A,5

=

2

2.7 Hz, J_4A,4B= 13.3 Hz, 1 H, 4-H_B), 2.05–2.15 (m, 2 H, 6-H),

2.22 (m, 1 H, CyCH₂), 2.33 (s, 1 H, 3-H), 2.41 (br. s, 1 H, OH),

2.95 (m, 1 H, 5-H), 3.43 (dd, J = 9.5 Hz, 2.8 Hz, 1 H, CH-OH),

3.83, 4.09 (2 br. s, 2 H, N-iPr CH), 4.72, 4.75 (2 s, 2 H, 5-

C(CH₂)(CH₃)) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 14.1 (CH₃,

2-CH₃), 20.5, 21.6 (CH₃, N-iPr (CH₃)₂), 20.7 (CH₃, 5-

C(CH₂)(CH₃)), 25.7, 26.1, 26.6, 26.9, 28.8, (CH₂, C-Cy), 31.0

(CH₂, C-4), 32.5 (CH₂, C-6), 38.0 (CH, C-5), 39.8 (CH, C-Cy),

41.4 (CH, C-3), 45.7, 46.7 (CH, N-iPr CH), 75.1 (CH, C-OH),

108.8 (CH₂, 5-C(CH₂)(CH₃)), 120.3 (C_q, C-2), 144.7 (C_q, C-1),

3

2

3

iPr (CH₃)₂), 1.38 (dt, J_3,4A= 10.6 Hz, J_4A,4B= 12.6 Hz, J_4A,5

=

12.6 Hz, 1 H, 4-H_A), 1.47 (s, 3 H, 2-CH₃), 1.68 (s, 3 H, 5-

C(CH₂)(CH₃)), 1.82 (m, 1 H, 4-H_B), 2.06, 2.09 (2 m, 2 H, 6-H),

149.3 (C , 5-C(CH )(CH )), 153.6 (C , C=O) ppm. IR (film): ν =

˜

q

2

3

q

3

2.31 (m, 1 H, 5-H), 2.40 (br. s, 1 H, OH), 2.94 (br. dd, J_3,4A

=

3473 (br.) [ν(OH)], 2998 (s), 2970 (s), 2932, 2874 (s) [ν(C_aliph–H)],

1698 (s) [ν(C=O)], 1645 (m) [ν(C=C)] cm^–1. MS (ESI): m/z =

414.2985 [M + Na]⁺. C₂₄H₄₁NO₃(391.58): calcd. C 73.61, H 10.55,

N 3.58; found C 73.41, H 10.55, N 3.43. [α]²_D⁰= +31.8 (c = 1.01,

CHCl₃). 19b: t_R= 20.50 min (HP-5). R_F= 0.34 (TBME/PE = 1:4).

¹H NMR (400 MHz, CDCl₃): δ = 0.99–1.13 (m, 3 H, CyCH₂), 1.25

(br. s, 14 H, N-iPr (CH₃)₂, CyCH₂), 1.40 (m, 1 H, CyCH), 1.58 (dt,

3

10.6 Hz, J_3,4B= 5.3 Hz, 1 H, 3-H), 3.86, 4.00 (2 br. s, 2 H, N-iPr

CH), 4.87, 4.68 (2 s, 2 H, 5-C(CH₂)(CH₃)), 4.89 (d, J = 3.8 Hz, 1

H, CH-O), 7.20–7.40 (m, 5 H, Ph-H) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 14.9 (CH₃, 2-CH₃), 20.6 (CH₃, 5-C(CH₂)(CH₃)), 21.3

(CH₃, N-iPr (CH₃)₂), 32.2 (CH₂, C-4), 33.4 (CH₂, C-6), 41.3 (CH,

C-5), 46.1 (CH, N-iPr CH), 47.2 (CH, C-3), 75.9 (CH, C-OH),

109.2 (CH₂, 5-C(CH₂)(CH₃)), 118.9 (C_q, C-2), 125.9 (CH, m-Ph),

126.8 (CH, p-Ph), 128.0 (CH, o-Ph), 143.8 (C_q, C-1), 145.3 (C_q, 5-

C(CH₂)(CH₃)), 148.6 (C_q, i-C-Ph), 153.2 (C_q, C=O) ppm. IR

2

3

³J_3,4A= 2.5 Hz, J_4A,4B= 12.8 Hz, J_4A,5= 2.5 Hz, 1 H, 4-H_A),

1.65 (s, 3 H, 2-CH₃), 1.66–1.73 (m, 2 H, CyCH₂), 1.73 (s, 3 H, 5-

C(CH₂)(CH₃)), 1.75–1.78 (m, 3 H, CyCH₂), 1.95–2.08 (m, 2 H, 4-

H

_B,6-H_A), 2.17 (dd, ³J_5,6B= 6.8 Hz, ²J_6A,6B= 16.8 Hz, 1 H, 6-H_B),

(film): ν = 3441 (s, br.) [ν(OH)], 3084 (m), 3064 (m) [ν(C_arom–H)],

˜

2969 (s), 2932 (s), 2873 (s) [ν(C_aliph–H)], 1681 (s) [ν(C=O)] cm^–1.

MS (ESI): m/z = 408.25 [M + Na]⁺. C₂₄H₃₅NO₃(385.54, mixture

of diastereomers): calcd. C 74.77, H 9.15, N 3.63; found C 74.53,

H 9.36, N 3.50. [α]²_D⁰= +1.6 (c = 1.02, CHCl₃, 20c/19c = 95:5). 19c:

t_R= 20.54 min (HP-5). R_F= 0.41 (TBME/PE = 1:2). ¹H NMR

(300 MHz, CDCl₃): δ = 1.62 (s, 6 H, 5-C(CH₂)(CH₃), 2-CH₃), 2.66

(br. m, 1 H, 3-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 16.7

(CH₃, 2-CH₃), 49.4 (CH, C-3), 109.0 (CH₂, 5-C(CH₂)(CH₃)) ppm.

2.31 (br. s, 1 H, OH), 2.49 (br. s, 1 H, 3-H), 2.72 (m, 1 H, 5-H),

3.30 (dd, J = 6.5 Hz, 4.4 Hz, 1 H, CH-O), 3.81, 4.10 (2 br. s, 2 H,

N-iPr CH), 4.71, 4.73 (2 s, 2 H, 5-C(CH₂)(CH₃)) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 17.2 (CH₃, 2-CH₃), 20.4 (CH₃, 5-

C(CH₂)(CH₃)), 20.5, 21.5 (CH₃, N-iPr (CH₃)₂), 26.2, 26.4, 26.6,

28.2, 30.0 (CH₂, C-Cy), 32.7 (CH₂, C-4), 33.2 (CH₂, C-6), 37.2

(CH, C-5), 41.6 (CH, C-Cy), 43.4 (CH, C-3), 45.6, 46.7 (CH, N-

iPr CH), 80.1 (CH₂, C-OH), 109.0 (CH₂, 5-C(CH₂)(CH₃)), 120.9

(C_q, C-2), 144.2 (C_q, C-1), 148.9 (C_q, 5-C(CH₂)(CH₃)), 153.5 (C_q,

[3S,3(1S),5R]- and [3R,3(1R),5R]-3-(1-Hydroxy-1-naphthalen-2-yl-

C=O) ppm. IR (film): ν = 3455 (br.) [ν(OH)], 2969 (s), 2925 (s),

˜

2851 (s) [ν(C_aliph–H)], 1695 (s) [ν(C=O)], 1646 (m) [ν(C=C)] cm^–1.

HR-MS (ESI, C₂₄H₄₁NO₃, 391.58): calcd. 414.2985 [M + Na]⁺,

found m/z = 414.2979 [M + Na]⁺. [α]²_D⁰= +69.8 (c = 1.00, CHCl₃).

methyl)-5-isopropenyl-2-methylcyclohex-1-enyl

N,N-Diisopropyl-

carbamate (20a and 19a): (1R,5R)-Carveyl carbamate 2 (1.397 g,

5.0 mmol) was lithiated according to GP C with TMCDA (rac-26,

1.105 g, 6.5 mmol, 1.3 equiv.) and 1.32  sBuLi solution (5.0 mL,

6.5 mmol, 1.3 equiv.) in Et₂O (25 mL) at –78 °C for 2 h and trans-

metallated with ClTi(NEt₂)₃(2.4 g, 8.0 mmol, 1.6 equiv.) for 3 h. A

Transmetallation and Homoaldol Reactions of 2. General Procedure

B (GP B): To a stirred solution of carbamate 2 (838 mg, 3.0 mmol)

and TMCDA (rac-26, 663 mg, 3.9 mmol, 1.3 equiv.) in Et₂O solution of 2-naphthaldehyde (12a, 2.3 g, 15.0 mmol, 3.0 equiv.) in

(15 mL) at –78 °C 1.36  sBuLi solution (2.9 mL, 3.9 mmol,

Et₂O (25 mL) was added and the solution was warmed to room

temperature within 14 h. Purification and separation of the dia-

stereomers by FCC (TBME/PE = 1:4 to 1:3) yielded 1.754 g

[15b]

1.3 equiv.) was added dropwise. After 2 h ClTi(NEt₂)₃

(1.44 g,

4.8 mmol, 1.6 equiv.) in Et₂O (3 mL) was added over a period of

10 min and stirring at –78 °C was continued for 3 h. The aldehyde

(9.0 mmol, 3.0 equiv.) was then added dropwise. After complete

consumption of the starting material (TLC) the reaction was

quenched with satd. aq. NH₄Cl solution (5 mL). The slurry was

stirred for 10 min at room temperature, satd. aq. K Na tartrate

solution (5 mL) was added and stirring was continued for 15 min.

The precipitate was decanted and the solution filtered through a

(4.03 mmol, 81%)^[30]20a/19a = 94:6^[31]as colourless oils. 20a: t_R

=

24.28 min (HP-5). R_F= 0.31 (Et₂O/PE = 1:2). ¹H NMR (400 MHz,

CDCl₃): δ = 1.22, 1.24 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.47 (m and

s, 4 H, 4-H_A, 2-CH₃), 1.67 (s, 3 H, 5-C(CH₂)(CH₃)), 1.89 (m, 1 H,

4-H_B), 2.04 (br. d, 1 H, 6-H_A), 2.13 (m, 1 H, 6-H_B), 2.33 (br. t, 1

H, 5-H), 2.76 (br. s, 1 H, OH), 3.05 (br. s, 1 H, 3-H), 3.82, 4.04 (2

br. s, 2 H, N-iPr CH), 4.67 (s, 2 H, 5-C(CH₂)(CH₃)), 5.04 (d,

3356

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3349–3364

Asymmetric Homoaldol Reaction

FULL PAPER

³J_3,CH–O= 3.2 Hz, 1 H, CH-O), 7.44 (m, 2 H, ArCH), 7.51 (m, 1 C 62.07, H 7.38, N 3.02; found C 62.05, H 7.52, N 2.82. [α]²_D⁰

H, ArCH), 7.79 (m, 3 H, ArCH), 7.89 (s, 1 H, ArCH) ppm. ¹³C +46.6 (c = 1.01, CHCl₃, 19d/20d = 86:14).

NMR (100 MHz, CDCl₃): δ = 15.1 (CH₃, 2-CH₃), 20.6 (CH₃, 5-

=

[3S,3(1R),5R]- and [3R,3(1S),5R]-3-(1-Hydroxyprop-2-enyl)-5-iso-

propenyl-2-methylcyclohex-1-enyl N,N-Diisopropylcarbamate (20e

and 19e): (1R,5R)-Carveyl carbamate 2 (1.397 g, 5.0 mmol) was li-

C(CH₂)(CH₃)), 21.5 (CH₃, N-iPr (CH₃)₂), 32.4 (CH₂, C-4), 33.5

(CH₂, C-6), 41.3 (CH, C-5), 46.2 (CH, N-iPr CH), 47.1 (CH, C-3),

76.0 (CH, C-OH), 109.3 (CH₂, 5-C(CH₂)(CH₃)), 119.9 (C_q, C-2),

124.2, 124.6, 125.5, 125.9, 127.5, 127.7, 128.1 (CH, C-Ar), 132.6,

133.3, 141.4 (C_q, C-Ar), 145.4 (C_q, C-1), 148.5 (C_q, 5-

thiated according to GP

C with TMCDA (rac-26, 1.105 g,

6.5 mmol, 1.3 equiv.) and 1.23  sBuLi solution (5.28 mL,

6.5 mmol, 1.3 equiv.) in Et₂O (25 mL) at –78 °C for 2 h and trans-

metallated with ClTi(NEt₂)₃(3.0 g, 10.0 mmol, 2.0 equiv.) for 3 h.

Freshly distilled acroleine (12e, 1.4 g, 15 mmol, 3.0 equiv.) was

added and the solution was stirred for 3 h at –78 °C. Purification

and separation of the diastereomers by FCC (TBME/PE = 1:4 to

1:3) yielded 886 mg (2.64 mmol, 53%)^[30]20e/19e = 94:6 and

C(CH )(CH )), 153.3 (C , C=O) ppm. IR (film): ν = 3435 (s, br.)

˜

2

3

q

[ν(OH)], 3081 (w) [ν(C_arom–H)], 2970 (s), 2932 (s), 2872 (m)

[ν(C_aliph–H)], 1677 (s) [ν(C=O)] cm^–1. MS (ESI): m/z = 458.2642

[M + Na]⁺. C₂₈H₃₇NO₃(435.60): calcd. C 77.20, H 8.56, N 3.22;

found C 77.10, H 8.57, N 3.06. [α]²_D⁰= –3.6 (c = 1.13, CHCl₃). 19a:

See above.

298 mg (0.89 mmol, 18%) 20e (total yield 71%, 20e/19e = 95:5^[31]

)

[3S,3(1S),5R]- and [3R,3(1R),5R]-3-[1-Hydroxy-1-(4-bromophenyl)-

as colourless oils. 20e: t_R= 17.24 min (HP-5). R_F= 0.19 (TBME/

PE = 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 1.24 (2 br. s, 12 H,

N-iPr (CH₃)₂), 1.30 (m, 1 H, 4-H_A), 1.59 (s, 3 H, 2-CH₃), 1.73 (s,

methyl]-5-isopropenyl-2-methylcyclohex-1-enyl

N,N-Diisopropyl-

carbamate (20d and 19d): (1R,5R)-Carveyl carbamate 2 (1.395 g,

5.0 mmol) was lithiated according to GP B with TMCDA (rac-26,

1.11 g, 6.5 mmol, 1.3 equiv.) and 1.36  sBuLi solution (4.77 mL,

6.5 mmol, 1.3 equiv.) in Et₂O (25 mL) at –78 °C for 2 h and trans-

metallated with ClTi(NEt₂)₃(3.00 g, 10.0 mmol, 2.0 equiv.) for 3 h.

A solution of 4-bromobenzaldehyde (12d, 2.31 g, 12.5 mmol,

2.5 equiv.) in Et₂O (25 mL) was added and the solution was

warmed to room temperature during 7 h. Purification and separa-

tion of the diastereomers by FCC (TBME/PE = 1:4 to 1:2) yielded

1.336 g (2.88 mmol, 58%)^[30]20d/19d = 93:7^[31]as colourless oils.

20d: t_R= 22.71 min (HP-5). R_F= 0.35 (TBME/PE = 1:2). ¹H NMR

(400 MHz, CDCl₃): δ = 1.25 (br. s, 12 H, N-iPr (CH₃)₂), 1.37 (dt,

3

3 H, 5-C(CH₂)(CH₃)), 1.90 (dm, J_4B,5= 12.7 Hz, 1 H, 4-H_B), 2.02

3

(br. d, J_6A,6B= 15.9 Hz, 1 H, 6-H_A), 2.08 (s, 1 H, OH), 2.17 (dd,

3

³J_5,6B= 12.7 Hz, J_6A,6B= 15.9 Hz, 1 H, 6-H_B), 2.33 (br. t, J_4B,5

3

= J_5,6B= 12.7 Hz, 1 H, 5-H), 2.69 (br. m, 1 H, 3-H), 3.82, 4.06 (2

br. s, 2 H, N-iPr CH), 4.56 (m, 1 H, CH-O), 4.72 (s, 2 H, 5-

2

3

C(CH₂)(CH₃)), 5.21 (dd, J_3ЈA,3ЈB= 1.6 Hz, J(Z)_2Ј,3ЈA= 10.6 Hz,

1 H, 3Ј-H_A), 5.33 (dd, J_3ЈA,3ЈB= 1.6 Hz, ³J(E)_2Ј,3ЈB= 17.3 Hz, 1

2

H, 3Ј-H_B), 5.94 (ddd, J_CH-O,2Ј= 4.3 Hz, ³J(Z)_2Ј,3ЈA= 10.6 Hz,

3

³J(E)_2Ј,3ЈB= 17.3 Hz, 1 H, 2Ј-H) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 13.6 (CH₃, 2-CH₃), 20.5, 21.5 (CH₃, N-iPr (CH₃)₂),

20.6 (CH₃, 5-C(CH₂)(CH₃)), 28.5 (CH₂, C-4), 33.3 (CH₂, C-6), 40.7

(CH, C-5), 45.2 (CH, C-3), 72.9 (CH, C-OH), 109.1 (CH₂, 5-

C(CH₂)(CH₃)), 115.2 (CH₂, C-3Ј), 119.1 (C_q, C-2), 138.0 (CH, C-

2Ј), 144.4 (C_q, C-1), 148.7 (C_q, 5-C(CH₂)(CH₃)), 153.2 (C_q, C=O)

2

3

³J_3,4A= 10.2 Hz, J_4A,4B= 12.8 Hz, J_4A,5= 12.8 Hz, 1 H, 4-H_A),

1.43 (s, 3 H, 2-CH₃), 1.69 (s, 3 H, 5-C(CH₂)(CH₃)), 1.87 (m, 1 H,

4-H_B), 2.04 (m, 1 H, 6-H_A), 2.10 (m, 1 H, 6-H_B), 2.30 (m, 1 H, 5-

H), 2.67 (br. s, 1 H, 3-H), 2.92 (br. s, 1 H, OH), 3.83, 4.05 (2 br. s,

2 H, N-iPr CH), 4.68, 4.70 (2 s, 2 H, 5-C(CH₂)(CH₃)), 4.87 (s, 1

H, CH-O), 7.28 (d, J = 8.6 Hz, 2 H, o-ArCH), 7.44 (d, J = 8.6 Hz,

2 H, m-ArCH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 15.0 (CH₃,

2-CH₃), 20.5, 21.5 (CH₃, N-iPr (CH₃)₂), 20.7 (CH₃, 5-

C(CH₂)(CH₃)), 32.0 (CH₂, C-4), 33.5 (CH₂, C-6), 41.1 (CH, C-5),

45.7, 46.6 (CH, N-iPr CH), 47.3 (CH, C-3), 75.0 (CH, C-OH),

109.4 (CH₂, 5-C(CH₂)(CH₃)), 119.4 (C_q, C-2), 120.5 (C_q, p-Ar),

127.6 (CH, o-Ar), 131.1 (CH, m-Ar), 142.8 (C_q, C-1), 145.6 (C_q, 5-

C(CH₂)(CH₃)), 148.4 (C_q, i-C-Ar), 153.2 (C_q, C=O) ppm. IR

ppm. IR (film): ν = 3446 (s, br.) [ν(OH)], 2970 (s), 2932 (s), 2877

˜

(s) [ν(C_aliph–H)], 1682 (s) [ν(C=O)], 1645 (m) [ν(C=C)] cm^–1. MS

(ESI): m/z = 358.2300 [M + Na]⁺. C₂₀H₃₅NO₃(335.48): calcd. C

71.60, H 9.91, N 4.18; found C 71.33, H 10.03, N 3.90. [α]²_D⁰

=

+93.8 (c = 1.03, CHCl₃). 19e: t_R= 17.04 min (HP-5). R_F= 0.24

1

(TBME/PE = 1:2). H NMR (300 MHz, CDCl₃): δ = 1.24, 1.26 (2

3

2

br. s, 12 H, N-iPr (CH₃)₂), 1.58 (dt, J_3,4A= 5.5 Hz, J_4A,4B

=

3

13.0 Hz, J_4A,5= 13.0 Hz, 1 H, 4-H_A), 1.65 (s, 3 H, 2-CH₃), 1.71

2

(s, 3 H, 5-C(CH₂)(CH₃)), 1.84 (br. d, J_4A,4B= 13.0 Hz, 1 H, 4-

H_B), 1.95 (br. s, 1 H, OH), 2.05–2.16 (m, 2 H, 6-H), 2.44 (br. t,

³J_3,4A= 5.5 Hz, J = 5.5 Hz, 1 H, 3-H), 2.72 (m, 1 H, 5-H), 3.84,

(film): ν = 3429 (s, br.) [ν(OH)], 3081 (w) [ν(C_arom–H)], 2970 (s),

˜

2932 (s), 2872 (m) [ν(C_aliph–H)], 1678 [ν(C=O)] cm^–1. MS (ESI):

m/z = 486.16 [M + Na]⁺. C₂₄H₃₄BrNO₃(464.44): calcd. C 62.07,

H 7.38, N 3.02; found C 62.12, H 7.59, N 2.73. [α]²_D⁰= –9.7 (c =

1.04, CHCl₃). 19d: t_R= 22.53 min (HP-5). R_F= 0.41 (TBME/PE

4.07 (2 br. s, 2 H, N-iPr CH), 4.34 (t, ³J_CH-O,2Ј= ³J_3,CH-O= 4.8 Hz,

3

1 H, CH-O), 4.71 (s, 2 H, 5-C(CH₂)(CH₃)), 5.12 (dt, J(Z)_2Ј,3ЈA

=

2

10.5 Hz, J_3ЈA,3ЈB= 1.7 Hz, J = 1.7 Hz, 1 H, 3Ј-H_A), 5.27 (dt,

³J(E)_2Ј,3ЈB= 17.3 Hz, J_3ЈA,3ЈB= 1.7 Hz, J = 1.7 Hz, 1 H, 3Ј-H_B),

2

1

5.94 (ddd, J_CH-O,2Ј= 4.8 Hz, ³J(Z)_2Ј,3ЈA= 10.5 Hz, ³J(E)_2Ј,3ЈB

=

3

= 1:2). H NMR (300 MHz, CDCl₃): δ = 1.25, 1.26 (2 br. s, 12 H,

17.3 Hz, 1 H, 2Ј-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.2

(CH₃, 2-CH₃), 20.5, 21.5 (CH₃, N-iPr (CH₃)₂), 20.6 (CH₃, 5-

C(CH₂)(CH₃)), 26.9 (CH₂, C-4), 32.5 (CH₂, C-6), 37.5 (CH, C-5),

45.1 (CH, C-3), 75.3 (CH, C-OH), 108.9 (CH₂, 5-C(CH₂)(CH₃)),

113.9 (CH₂, C-3Ј), 119.1 (C_q, C-2), 138.0 (CH, C-2Ј), 144.4 (C_q, C-

N-iPr (CH₃)₂), 1.30 (m, 1 H, 4-H_A), 1.56 (s, 3 H, 2-CH₃), 1.59 (m,

1 H, 4-H_B), 1.63 (s, 3 H, 5-C(CH₂)(CH₃)), 2.04, 2.08 (2 m, 2 H, 6-

H), 2.34 (m, 1 H, 5-H), 2.63 (br. t, J_3,CH-O= 4.5 Hz, 1 H, 3-H),

3

3.06 (br. s, 1 H, OH), 3.82, 4.08 (2 br. s, 2 H, N-iPr CH), 4.62, 4.66

3

(2 s, 2 H, 5-C(CH₂)(CH₃)), 4.83 (d, J_3,CH-O= 4.5 Hz, 1 H, CH-

O), 7.25 (d, J = 8.6 Hz, 2 H, o-ArCH), 7.45 (d, J = 8.6 Hz, 2 H,

m-ArCH) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 16.6 (CH₃, 2-

CH₃), 20.3 (CH₃, 5-C(CH₂)(CH₃)), 20.6, 21.5 (CH₃, N-iPr (CH₃)

₂), 31.1 (CH₂, C-4), 32.5 (CH₂, C-6), 37.1 (CH, C-5), 45.8, 46.6

(CH, N-iPr CH), 47.5 (C_q, C-3), 76.1 (CH, C-OH), 109.2 (CH₂, 5-

C(CH₂)(CH₃)), 119.8 (C_q, C-2), 120.5 (C_q, p-Ar), 127.6 (CH, o-

Ar), 131.2 (CH, m-Ar), 143.6 (C_q, C-1), 145.0 (C_q, 5-

C(CH₂)(CH₃)), 148.6 (C_q, i-C-Ar), 153.5 (C_q, C=O) ppm. IR

1), 148.7 (C , 5-C(CH )(CH )), 153.5 (C , C=O) ppm. IR (film): ν

˜

q

2

3

q

= 3440 (s, br.) [ν(OH)], 2970 (s), 2933 (s), 2874 (s) [ν(C_aliph–H)],

1681 (s) [ν(C=O)], 1645 (m) [ν(C=C)] cm^–1. MS (ESI): m/z =

358.2300 [M + Na]⁺. C₂₀H₃₅NO₃(335.48): calcd. C 71.60, H 9.91,

N 4.18; found C 71.36, H 9.97, N 4.11. [α]²_D⁰= +45.9 (c = 1.01,

CHCl₃).

[3S,3(1S),5R]- and [3R,3(1R),5R]-3-(1-Hydroxy-2-methylprop-2-

(film): ν = 3423 (br.) [ν(OH)], 3081 (w) [ν(C_arom–H)], 2969 (s), 2931 enyl)-5-isopropenyl-2-methylcyclohex-1-enyl N,N-Diisopropylcarba-

˜

(s), 2874 (m) [ν(C_aliph–H)], 1701 (s), 1677 (s) [ν(C=O)] cm^–1. MS mate (20f and 19f): (1R,5R)-Carveyl carbamate

(ESI): m/z = 486.16 [M + Na]⁺. C₂₄H₃₄BrNO₃(464.44): calcd. 3.0 mmol) was lithiated according to GP C with TMCDA (rac-26,

2 (842 mg,

Eur. J. Org. Chem. 2007, 3349–3364

www.eurjoc.org

3357

J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe

FULL PAPER

665 mg, 3.9 mmol, 1.3 equiv.) and 1.37  sBuLi solution (2.85 mL,

3.9 mmol, 1.3 equiv.) in Et₂O (15 mL) at –78 °C for 2 h and trans-

metallated with ClTi(NEt₂)₃(1.44 g, 4.8 mmol, 1.6 equiv.) for 4 h.

Freshly distilled methacroleine (12f, 0.63 g, 9.0 mmol, 3.0 equiv.)

was added and the solution was stirred for 2 h at –78 °C. Purifica-

tion and separation of the mayor diastereomer by FCC (TBME/

PE = 1:4 to 1:3) yielded 642 mg (1.84 mmol, 61%)^[30]20f/19f =

94:6 and 201 mg (0.58 mmol, 19%) 20f (total yield 80%, 20f/19f =

(s, 3 H, 2-CH₃), 1.71 (br. s, 1 H, 1-H), 1.74 (s, 3 H, 5-

C(CH₂)(CH₃)), 1.88 (m, 1 H, 4-H_B), 1.94 (m, 1 H, 2Ј-H), 2.07 (br.

2

d, J_6A,6B= 14.8 Hz, 1 H, 6-H_A), 2.19 (m, 1 H, 6-H_B), 2.29 (m, 1

3

H, 5-H), 2.63 (m, 1 H, 3-H), 3.38 (dd, J_3,CH-O= 3.4 Hz, J_CH-O,2Ј

= 8.2 Hz, 1 H, CH-O), 3.86, 4.01 (2 br. s, 2 H, N-iPr CH), 4.74 (m,

2 H, 5-C(CH₂)(CH₃)) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 14.7

(CH₃, 2-CH₃), 19.5 (CH₃, 5-C(CH₂)(CH₃)), 19.6 (CH₃, C-3Ј), 20.7

(CH₃, N-iPr (CH₃)₂), 27.0 (CH₂, C-2Ј), 31.8 (CH₂, C-4), 32.0 (CH₂,

95:5^[31]) as colourless oils. 20f: t_R= 17.78 min (HP-5). R_F= 0.21 C-6), 33.6 (CH, C-5), 41.5 (CH, C-3), 46.4 (CH, N-iPr CH), 79.9

1

(TBME/PE = 1:3). H NMR (300 MHz, CDCl₃): δ = 1.24, 1.25 (2 (CH, C-OH), 109.2 (CH₂, 5-C(CH₂)(CH₃)), 120.6 (C_q, C-2), 144.3

3

2

br. s, 12 H, N-iPr (CH₃)₂), 1.43 (dt, J_3,4A= 10.7 Hz, J_4A,4B

=

(C_q, C-1), 148.8 (C_q, 5-C(CH₂)(CH₃)), 153.3 (C_q, C=O) ppm. IR

³J_4A,5= 12.7 Hz, 1 H, 4-H_A), 1.65 (s, 3 H, 2-CH₃), 1.73 (s, 3 H, 2Ј-

(film): ν = 3465 (s, br.) [ν(OH)], 2965 (s), 2926 (s), 2870 (s) [ν(C

–

˜

aliph

CH₃), 1.78 (s, 3 H, 5-C(CH₂)(CH₃)), 1.83 (m, 1 H, 4-H_B), 1.95 (br. H)], 1687 (m) [ν(C=O)], 1639 (m) [ν(C=C)] cm^–1. MS (ESI): m/z =

s, 1 H, OH), 2.05 (br. d, 1 H, 6-H_A), 2.20 (br. m, 1 H, 6-H_B), 2.48 374.2661 [M + Na]⁺. C₂₁H₃₇NO₃(351.52): calcd. C 71.75, H 10.61,

3

(m, 1 H, 5-H), 2.71 (br. dd, J_3,4A= 10.7 Hz, J_3,CH-O= 3.4 Hz, 1

N 3.98; found C 71.62, H 10.80, N 3.84. [α]²_D⁰= +28.4 (c = 1.00,

3

H, 3-H), 3.87, 4.02 (2 br. s, 2 H, N-iPr CH), 4.20 (d, J_3,CH-O

=

CHCl₃). 19g: t_R= 17.36 min (HP-5). R_F= 0.25 (TBME/PE = 1:3).

3.4 Hz, 1 H, CH-O), 4.73 (s, 2 H, 5-C(CH₂)(CH₃)), 4.90 (br. s, 1 ¹H NMR (300 MHz, CDCl₃): δ = 0.96, 0.98 (2 d, J_2Ј,3Ј= 6.4 Hz,

3

H, 3Ј-H_A), 5.05 (br. s, 1 H, 3Ј-H_B) ppm. ¹³C NMR (75 MHz,

6 H, 3Ј-H), 1.24, 1.26 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.65 (s and m,

CDCl₃): δ = 14.4 (CH₃, 2-CH₃), 19.5 (CH₃, 5-C(CH₂)(CH₃)), 20.4, 4 H, 2-CH₃, 4-H_A), 1.72 (s and m, 4 H, 5-C(CH₂)(CH₃), 2Ј-H),

21.5 (CH₃, N-iPr (CH₃)₂), 20.6 (CH₃, 2Ј-CH₃), 31.6 (CH₂, C-4), 2.05 (br. d, ²J_4A,4B= 11.4 Hz, 1 H, 4-H_B), 2.17 (m, 2 H, 6-H), 2.45

3

33.5 (CH₂, C-6), 41.3 (CH, C-5), 43.6 (CH, C-3), 46.0, 46.6 (CH, (br. s, 1 H, 3-H), 2.71 (tt, J_4A,5= J_5,6A= 10.7 Hz, J_4B,5= J_5,6B

N-iPr CH), 77.4 (CH, C-OH), 109.2 (CH₂, 5-C(CH₂)(CH₃)), 111.1 = 5.8 Hz, 1 H, 5-H), 3.28 (br. s, 1 H, CH-O), 3.82, 4.07 (2 br. s, 2 H,

(CH₂, C-3Ј), 120.3 (C_q, C-2), 144.6 (C_q, C-2Ј), 146.8 (C_q, C-1), N-iPr CH), 4.72, 4.73 (2 s, 2 H, 5-C(CH₂)(CH₃)) ppm. ¹³C NMR

148.8 (C , 5-C(CH )(CH )), 153.3 (C , C=O) ppm. IR (film): ν = (75 MHz, CDCl₃):

δ = 17.6 (CH₃, 2-CH₃), 18.2 (CH₃, 5-

˜

q

2

3

q

3443 (s, br.) [ν(OH)], 2965 (s), 2926 (s), 2874 (s) [ν(C_aliph–H)], 1687

(m) [ν(C=O)], 1644 (s) [ν(C=C)] cm^–1. MS (ESI): m/z = 372.2572

[M + Na]⁺. C₂₁H₃₅NO₃(349.51): calcd. C 72.17, H 10.09, N 4.01;

found C 71.88, H 10.12, N 3.86. [α]²_D⁰= +39.1 (c = 0.88, CHCl₃).

C(CH₂)(CH₃)), 20.1 (CH₃, C-3Ј), 20.8 (CH₃, N-iPr (CH₃)₂), 27.0

(CH, C-2Ј), 33.1 (CH₂, C-4), 33.6 (CH₂, C-6), 33.7 (CH, C-5), 37.7

(CH, C-3), 42.5 (CH, N-iPr CH), 81.4 (CH, C-OH), 109.4 (CH₂,

5-C(CH₂)(CH₃)), 121.3 (C_q, C-2), 144.7 (C_q, C-1), 149.4 (C_q, 5-

19f: t_R= 17.59 min (HP-5). R_F= 0.22 (TBME/PE = 1:3). ¹H NMR C(CH )(CH )), 154.1 (C , C=O) ppm. IR (film): ν = 3465 (s, br.)

˜

2

3

q

(400 MHz, CDCl₃): δ = 1.25 (br. s, 12 H, N-iPr (CH₃)₂), 1.56 (m,

[ν(OH)], 2965 (s), 2926 (s), 2870 (s) [ν(C_aliph–H)], 1687 (m)

1 H, 4-H_A), 1.69 (s, 3 H, 2-CH₃), 1.71 (s, 3 H, 2Ј-CH₃), 1.79 (s, 3 [ν(C=O)], 1639 (m) [ν(C=C)] cm^–1. MS (ESI): m/z = 374.2684 [M

H, 5-C(CH₂)(CH₃)), 1.81–1.85 (m, 1 H, 4-H_B), 1.98–2.11 (m, 2 H, + Na]⁺. C₂₁H₃₇NO₃(351.52): calcd. C 71.75, H 10.61, N 3.98;

OH, 6-H_A), 2.16–2.25 (br. m, 1 H, 6-H_B), 2.46 (m, 1 H, 5-H), 2.71

(m, 1 H, 3-H), 3.83, 4.07 (2 br. s, 2 H, N-iPr CH), 4.20 (br. s, 1 H,

CH-O), 4.70 (s, 2 H, 5-C(CH₂)(CH₃)), 4.86 (m, 1 H, 3Ј-H_A), 5.02

(m, 1 H, 3Ј-H_B) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.7 (CH₃,

2-CH₃), 18.1 (CH₃, 5-C(CH₂)(CH₃)), 20.4, 21.5 (CH₃, N-iPr

(CH₃)₂), 20.5 (CH₃, 2Ј-CH₃), 31.4 (CH₂, C-4), 32.6 (CH₂, C-6),

37.2 (CH, C-5), 42.7 (CH, C-3), 46.0, 46.6 (CH, N-iPr CH), 79.4

(CH, C-OH), 108.9 (CH₂, 5-C(CH₂)(CH₃)), 111.5 (CH₂, C-3Ј),

121.0 (C_q, C-2), 144.1 (C_q, C-15), 147.2 (C_q, C-1), 148.9 (C_q, 5-

found C 71.49, H 10.74, N 3.80. [α]²_D⁰= +77.4 (c = 1.00, CHCl₃).

[3S,3(1R),5R]-

methyl)-5-isopropenyl-2-methylcyclohex-1-enyl

and

[3R,3(1R),5R]-3-(1-Cyclohexyl-1-hydroxy-

N,N-Diisopropyl-

carbamate (20b and 19b): (1R,5R)-Carveyl carbamate 2 (845 mg,

3.0 mmol) was lithiated according to GP C with TMCDA rac-26

675 mg (3.9 mmol, 1.3 equiv.) and 1.37  sBuLi solution (2.85 mL,

3.9 mmol, 1.3 equiv.) in Et₂O (15 mL) at –78 °C for 2 h and trans-

metallated with ClTi(NEt₂)₃(1.44 g, 4.8 mmol, 1.6 equiv.) for 3 h.

Cyclohexancarbaldehyde (12a, 1.1 g, 9.0 mmol, 3.0 equiv.) was then

added and the solution was warmed to room temperature during

15 h. Purification and separation of the diastereomers by FCC

(TBME/PE = 1:4 Ǟ 1:3) yielded 69 mg (0.18 mmol, 6%)^[30]19b/

20b = 75:25 and 348 mg (0.89 mmol, 30%) 20b (total yield 36%,

20b/19b = 91:9^[31]) as colourless oils. 20b: t_R= 20.64 min (HP-5).

R_F= 0.23 (TBME/PE = 1:4). ¹H NMR (600 MHz, CDCl₃): δ =

C(CH )(CH )), 153.5 (C , C=O) ppm. IR (film): ν = 3443 (s, br.)

˜

2

3

q

[ν(OH)], 2969 (s), 2935 (s), 2874 (s) [ν(C_aliph–H)], 1700 (m)

[ν(C=O)], 1647 (s) [ν(C=C)] cm^–1. MS (ESI): m/z = 372.2566 [M +

Na]⁺. C₂₁H₃₅NO₃(349.51, mixture of diastereomers): calcd. C

72.17, H 10.09, N 4.01; found C 72.08, H 10.31, N 3.83. [α]²_D⁰

+45.2 (c = 1.02, 19f/20f = 23:77, CHCl₃).

=

[3S,3(1R),5R]- and [3R,3(1S),5R]-3-(1-Hydroxy-2-methylpropyl)-5- 0.93 (m, 2 H, CyCH₂), 1.12 (m, 1 H, CyCH₂), 1.22 (br. s, 14 H, N-

3

2

isopropenyl-2-methylcyclohex-1-enyl

N,N-Diisopropylcarbamate

iPr (CH₃)₂, CyCH₂), 1.43 (dt, J_3,4A= 10.6 Hz, J_4A,4B= 12.7 Hz,

(20g and 19g): (1R,5R)-Carveyl carbamate 2 (850 mg, 3.0 mmol) ³J_4A,5= 12.7 Hz, 1 H, 4-H_A), 1.50 (m, 1 H, CyCH), 1.61 (s, 3 H,

was lithiated according to GP C with 680 mg TMCDA rac-26

(3.9 mmol, 1.3 equiv.) and 1.37  sBuLi solution (2.85 mL,

3.9 mmol, 1.3 equiv.) in Et₂O (15 mL) at –78 °C for 2 h and trans-

metallated with ClTi(NEt₂)₃(1.44 g, 4.8 mmol, 1.6 equiv.) for 3 h.

Isobutyraldehyde (12g, 0.66 g, 9.0 mmol, 3.0 equiv.) was then

added and the solution was warmed to room temperature during

14 h. Purification and separation of the diastereomers by FCC

(TBME/PE = 1:4 Ǟ 1:3) yielded 47 mg (0.13 mmol, 5%) 19g and

2-CH₃), 1.72 (s, 3 H, 5-C(CH₂)(CH₃)), 1.75 (m, 2 H, CyCH₂), 1.78

(br. s, 1 H, CyCH₂), 1.85 (m, 1 H, 4-H_B), 2.02–2.05 (m, 2 H, 6-H_A,

CyCH₂), 2.17 (dm, 1 H, 6-H_B), 2.29 (m, 1 H, 5-H), 2.63 (br. s, 1

H, 3-H), 3.36 (d, J = 7.7 Hz, 1 H, CH-O), 3.79, 4.04 (2 br. s, 2 H,

N-iPr CH), 4.71, 4.72 (2 s, 2 H, 5-C(CH₂)(CH₃)) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 14.8 (CH₃, 2-CH₃), 20.5, 21.6 (CH₃, N-iPr

(CH₃)₂), 20.7 (CH₃, 5-C(CH₂)(CH₃)), 26.1, 26.3, 26.5, 29.5, 30.0

(CH₂, C-Cy), 32.1 (CH₂, C-4), 33.5 (CH₂, C-6), 41.5 (CH, C-5),

41.9 (CH, C-Cy), 43.4 (CH, C-3), 45.6, 46.5 (CH, N-iPr CH), 78.9

(CH, C-OH), 109.1 (CH₂, 5-C(CH₂)(CH₃)), 120.5 (C_q, C-2), 144.2

530 mg (1.51 mmol, 50%) 20g (total yield 55%, 20g/19g = 93:7^[31]

as colourless oils. 20g: t_R= 17.70 min (HP-5). R_F= 0.14 (TBME/

)

1

3

PE = 1:3). H NMR (300 MHz, CDCl₃): δ = 0.94, 0.99 (2 d, J_2Ј,3Ј(C_q, C-1), 148.8 (C_q, 5-C(CH₂)(CH₃)), 153.3 (C_q, C=O) ppm. IR

= 8.2 Hz, 6 H, 3Ј-H), 1.24, 1.26 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.46 (film): ν = 3471 (s, br.) [ν(OH)], 2968 (s), 2925 (s), 2852 (s) [ν(C

–

˜

aliph

3

(dt, J_3,4A= 10.8 Hz, J_4A,4B= J_4A,5= 12.6 Hz, 1 H, 4-H_A), 1.64

H)], 1682 (s) [ν(C=O)], 1645 (m) [ν(C=C)] cm^–1. MS (ESI): m/z =

3358

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3349–3364

Asymmetric Homoaldol Reaction

FULL PAPER

414.2980 [M + Na]⁺. C₂₄H₄₁NO₃(391.58): calcd. C 73.61, H 10.55,

N 3.58; found C 73.32, H 10.45, N 3.46. [α]²_D⁰= +17.7 (c = 0.99,

CHCl₃). 19b: see above.

rial (TLC) the reaction was quenched with satd. aq. NH₄Cl solu-

tion (2 mL) and worked up as described in GP B.

[3R,3(1R),4R]- and [3R,3(1S),4R]-3-(1-Hydroxyphenylmethyl)-4-

isopropylcyclohex-1-enyl N,N-Diisopropylcarbamate (31a and 32a):

(1S,4R)-Cryptyl carbamate 3 (67 mg, 0.25 mmol, 99% ee) was lithi-

ated according to GP C with TMCDA (rac-26, 58 mg, 0.33 mmol,

1.3 equiv.) and 1.38  sBuLi solution (0.24 mL, 0.33 mmol,

1.3 equiv.) in Et₂O (2 mL) at –78 °C for 2 h and transmetallated

with ClTi(NEt₂)₃(244 mg, 0.75 mmol, 3.0 equiv.) for 3 h. Benzalde-

hyde (28a, 313 mg, 2.95 mmol, 11.9 equiv.) was added and the solu-

tion was warmed to room temperature during 17 h. Purification

and separation of the diastereomers by FCC (Et₂O/PE = 1:2)

yielded 7 mg (0.02 mmol, 7%) 32a and 52 mg (0.14 mmol, 56%)

31a as colourless solids (total yield 63%, 31a/32a = 93:7^[31]). rac-

31a/rac-32a were prepared from rac-3 (535 mg, 2.0 mmol) by lithi-

ation with TMCDA (443 mg, 2.6 mmol, 1.3 equiv.) and 1.38 

sBuLi solution (2.13 mL, 2.6 mmol, 1.3 equiv.), transmetallation

with ClTi(NEt₂)₃(1.8 g, 6.0 mmol, 3.0 equiv.) and addition of 28a

(2.54 g, 24 mmol, 12 equiv.). Yield 32 mg (0.09 mmol, 4%) 32a and

398 mg (1.07 mmol, 54%) 31a as colourless solids (total yield 58%,

rac-31a:rac-32a = 94:6^[31]). 31a: M.p. 132 °C (for 31a at 99% ee,

Et₂O/PE), m.p. 137 °C (for rac-31a, Et₂O/PE). t_R= 19.91 min (HP-

(3S,5R)- and (3R,5R)-5-Isopropenyl-2-methyl-3-(naphthalen-2-ylcar-

bonyl)cyclohex-1-enyl N,N-Diisopropylcarbamate (23 and 24): The

homoaldol products 20a/19a = 73:27 (383 mg, 0.88 mmol), dis-

solved in CH₂Cl₂(16 mL), were treated with PDC (1.65 g,

4.4 mmol, 5.0 equiv.) and powdered molecular sieves (4 Å) (30 mg)

and stirred for 3 h at room temperature. The suspension was diluted

with Et₂O (20 mL) and filtered through silica gel. Purification by

FCC (TBME/PE = 1:8 to 1:4) yielded 219 mg (0.56 mmol, 64%)

23 as colourless oil and 85 mg (0.22 mmol, 25%) 24 as colourless

solid (total yield 89%, 23/24 = 76:24^[31]). 23: t_R= 24.25 min (HP-

1

5). R_F= 0.49 (TBME/PE = 1:4). H NMR (300 MHz, CDCl₃): δ

= 1.27, 1.29 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.57 (s, 3 H, 2-CH₃),

3

2

1.73 (s, 3 H, 5-C(CH₂)(CH₃)), 1.80 (dtr, J_3,4A= 11.6 Hz, J_4A,4B

=

3

2

³J_4A,5= 12.6 Hz, 1 H, 4-H_A), 2.12 (dd, J_3,4B= 5.9 Hz, J_4A,4B

12.6 Hz, 1 H, 4-H_B), 2.34 (m, 2 H, 6-H), 2.61 (m, 1 H, 5-H), 3.91,

3

4.04 (2 br. s, 2 H, N-iPr CH), 4.36 (br. dd, J_3,4A= 11.6 Hz, J_3,4B

= 5.9 Hz, 1 H, 3-H), 4.73, 4.75 (2 s, 2 H, 5-C(CH₂)(CH₃)), 7.57 (m,

2 H, ArCH), 7.86 (d, J = 7.7 Hz, 1 H, ArCH), 7.86 (d, J = 8.9 Hz,

1 H, ArCH), 8.08 (m, 2 H, ArCH), 8.72 (s, 1 H, ArCH) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 14.2 (CH₃, 2-CH₃), 20.5 (CH₃, 5-

C(CH₂)(CH₃)), 20.7, 21.5 (CH₃, N-iPr (CH₃)₂), 33.1, 33.4 (CH₂, C-

4/C-6), 41.3 (CH, C-5), 46.4 (CH, N-iPr CH), 51.1 (CH, C-3), 109.9

(CH₂, 5-C(CH₂)(CH₃)), 118.8 (C_q, C-2), 124.4, 126.6, 127.6, 128.5,

130.0, 130.5 (CH, C-Ar), 132.7, 133.7, 135.6 (C_q, C-Ar), 144.6 (C_q,

C-1), 147.8 (C_q, 5-C(CH₂)(CH₃)), 153.3, 202.2 (C_q, C=O) ppm. IR

1

5). R_F= 0.29 (Et₂O/PE = 1:1). H NMR (400 MHz, CDCl₃): δ =

0.89, 0.98 (2 d, ³J_{4-iPrCH,4-iPr(Me)}= 7.4 Hz, 6 H, 4-iPr (CH₃)₂), 1.21,

1.23 (2 d, ³J_{N-iPrCH,N-iPr(Me)}= 3.4 Hz, 12 H, N-iPr (CH₃)₂), 1.49 (m,

1 H, 5-H_A), 1.56 (m, 1 H, 4-H), 1.82 (m, 1 H, 5-H_B), 1.98 (m, 1 H,

4-iPr CH), 2.14 (m, 2 H, 6-H), 2.60 (m, 1 H, 3-H), 3.81, 4.01 (2 br.

s, 2 H, N-iPr CH), 4.85 (d, ³J_3,CH-O= 3.4 Hz, 1 H, CH-O), 5.03 (d,

³J_2,3= 3.4 Hz, 1 H, 2-H), 7.24 (m, 1 H, p-PhCH), 7.34 (m, 4 H, o/

m-PhCH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 17.6, 21.7 (CH₃,

4-iPr (CH₃)₂), 20.9 (CH₃, N-iPr (CH₃)₂), 21.8 (CH₂, C-5), 26.6

(CH₂, C-6), 28.1 (CH, 4-iPr CH), 40.3 (CH, C-4), 45.6 (CH, C-3),

45.8 (CH, N-iPr CH), 74.5 (CH, C-OH), 111.4 (CH, C-2), 125.7

(CH, o-Ph), 126.7 (CH, p-Ph), 128.1 (CH, m-Ph), 144.2 (C_q, i-C-

(film): ν = 3059 (w) [ν(C_arom–H)], 2969 (s), 2934 (s), 2871 (m)

˜

[ν(C_aliph–H)], 1705 (s), 1676 (s) [ν(C=O)], 1627 (m) [ν(C=C)] cm^–1.

MS (ESI): m/z = 456.2477 [M + Na]⁺. C₂₈H₃₅NO₃(433.58): calcd.

C 77.56, H 8.14, N 3.23; found C 77.33, H 8.18, N 3.19. [α]²_D⁰

–7.2 (c = 0.39, CHCl₃). 24: M.p. 136.5 °C (n-hexane). t_R

=

24.37 min (HP-5). R_F= 0.21 (TBME/PE = 1:4). ¹H NMR

(300 MHz, CDCl₃): δ = 1.27, 1.29 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.58

2

Ph), 153.1 (C , C-1), 154.1 (C , C=O) ppm. IR (ATR): ν = 3416

˜

(s, 3 H, 2-CH₃), 1.66 (s, 3 H, 5-C(CH₂)(CH₃)), 2.02 (dm, J_4A,4B

=

q

3

2

(s) [ν(C–OH)], 3083 (w), 3060 (w), 3024 (w) [ν(C_arom–H)], 2965 (s),

2933 (s), 2884 (m), [ν(C_aliph–H)], 1684 (s) [ν(C=O)] cm^–1. MS (ESI):

m/z = 396.2511 [M + Na]⁺. C₂₃H₃₅NO₃(373.53): calcd. C 73.96,

H 9.44, N 3.75; found C 73.74, H 9.54, N 3.52. [α]²_D⁰= +94.5 (c =

1.02, CHCl₃) at 99% ee; HPLC Chira Grom 1 (2 ϫ 250 mm), λ =

210 nm, iPrOH:n-hexane = 1:200, 0.3 mL/min, 21.04 min (ent-31a),

27.75 min (31a). 32a: M.p. 102.2 °C (for 32a at 99% ee, Et₂O/PE),

11.3 Hz, 1 H, 4-H_A), 2.10 (dt, J_3,4B= 7.0 Hz, J_4A,4B= 11.3 Hz,

3

2

³J_4B,5= 11.4 Hz, 1 H, 4-H_B), 2.24 (dd, J_5,6A= 5.6 Hz, J_6A,6B

=

15.5 Hz, 1 H, 6-H_A), 2.35 (m, 1 H, 6-H_B), 2.49 (m, 1 H, 5-H), 3.98

3

(br. s, 2 H, N-iPr CH), 4.36 (d, J_3,4B= 7.0 Hz, 1 H, 3-H), 4.69,

4.72 (m, s, 2 H, 5-C(CH₂)(CH₃)), 7.58 (m, 2 H, ArCH), 7.90 (m, 2

H, ArCH), 8.02 (m, 2 H, ArCH), 8.53 (s, 1 H, ArCH) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 15.5 (CH₃, 2-CH₃), 20.7 (CH₃, 5-

C(CH₂)(CH₃)), 21.4 (CH₃, N-iPr (CH₃)₂), 31.2 (CH₂, C-4), 33.0

(CH₂, C-6), 37.7 (CH, C-5), 46.4 (CH, N-iPr CH), 47.8 (CH, C-3),

109.7 (CH₂, 5-C(CH₂)(CH₃)), 117.4 (C_q, C-2), 124.4, 126.8, 127.7,

128.5, 129.7, 130.0 (CH, C-Ar), 132.6, 133.7, 135.6 (C_q, C-Ar),

145.1 (C_q, C-1), 147.8 (C_q, 5-C(CH₂)(CH₃)), 153.3 (C_q, C=O),

m.p. 111.6 °C (for rac-32a, Et₂O/PE). t_R= 19.64 min (HP-5). R_F

=

1

0.40 (Et₂O/PE = 1:1). H NMR (600 MHz, CDCl₃): δ = 0.82, 0.84

3

(2 d, J_{4-iPrCH,4-iPr(Me)}= 6.7 Hz, 6 H, 4-iPr (CH₃)₂), 1.21 (m, 12 H,

N-iPr (CH₃)₂), 1.44 (m, 1 H, 4-H), 1.56 (m, 1 H, 4-iPr CH), 1.69

(m, 1 H, 5-H_A), 1.82 (m, 1 H, 5-H_B), 1.96 (m, 1 H, 6-H_A), 2.16 (m,

3

1 H, 6-H_B), 2.63 (br. d, J_2,3= 4.8 Hz, 1 H, 3-H), 3.75, 4.03 (2 br.

201.1 (C , C=O) ppm. IR (KBr): ν = 3060 (w) [ν(C_arom–H)], 2969

˜

q

s, 2 H, N-iPr CH), 4.72 (d, ³J_3,CH-O= 6.2 Hz, 1 H, CH-O), 5.03 (d,

(s), 2933 (s), 2874 (m) [ν(C_aliph–H)], 1701 (s) [ν(C=O)], 1647 (m)

[ν(C=C)] cm^–1. MS (ESI): m/z = 456.2513 [M + Na]⁺. C₂₈H₃₅NO₃

(433.58): calcd. C 77.56, H 8.14, N 3.23; found C 77.28, H 8.28, N

3.11. [α]²_D⁰= +31.0 (c = 0.21, CHCl₃).

4

³J_2,3= 4.8 Hz, 1 H, 2-H), 7.25 (tt, J_{o-PhCH,p-PhCH}= 1.4 Hz,

³J_{m-PhCH,p-PhCH}

=

7.2 Hz,

1

H, p-PhCH), 7.33 (t,

³J_{m-PhCH,p-PhCH}= 7.2 Hz, 2 H, m-PhCH), 7.37 (dd, ³J_{o-PhCH,m-PhCH}

4

= 7.2 Hz, J_{o-PhCH,p-PhCH}= 1.4 Hz, 2 H, o-PhCH) ppm. ¹³C NMR

Transmetallation and Homoaldol Reactions of 3. General Procedure

(600 MHz, CDCl₃): δ = 19.5, 21.6 (CH₃, 4-iPr (CH₃)₂), 20.5, 21.3

C (GP C): To a stirred solution of carbamate 2 (267 mg, 1.0 mmol) (CH₃, N-iPr (CH₃)₂), 21.2 (CH₂, C-5), 24.6 (CH₂, C-6), 27.6 (CH,

and TMCDA (rac-26, 179 mg, 1.05 mmol, 1.05 equiv.) in Et₂O C-7), 38.0 (CH, C-4), 44.6 (CH, C-3), 45.6 (CH, N-iPr CH), 76.1

(8 mL) at –78 °C 1.22  sBuLi solution (0.86 mL, 1.05 mmol, (CH, C-OH), 113.4 (CH, C-2), 126.5 (CH, o-Ph), 127.2 (CH, p-

[15b]

1.05 equiv.) was added dropwise.^[32]After 2 h ClTi(NEt₂)₃

(479 mg, 1.6 mmol, 1.6 equiv.) in Et₂O (2 mL) was added over a

period of 10 min and stirring at –78 °C was continued for 3 h. The

Ph), 128.1 (CH, m-Ph), 142.7 (C_q, i-C-Ph), 150.8 (C_q, C-1), 154.0

(C , C=O) ppm. IR (ATR): ν = 3442 (s, br.) [ν(C–OH)], 3086 (w),

˜

q

3061 (w), 3028 (m) [ν(C_arom–H)], 2965 (s), 2933 (s), 2873 (s)

aldehyde (10.0 mmol, 10.0 equiv.) was then added dropwise over a [ν(C_aliph–H)], 1695 (s), 1681 (s) [ν(C=O)] cm^–1. MS (ESI): m/z =

period of 15 min. After complete consumption of the starting mate-

396.2507 [M + Na]⁺. C₂₃H₃₅NO₃(373.53): calcd. C 73.96, H 9.44,

Eur. J. Org. Chem. 2007, 3349–3364

www.eurjoc.org

3359

J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe

FULL PAPER

N 3.75; found C 73.85, H 9.36, N 3.54. [α]²_D⁰= +18.9 (c = 0.76,

3

³J_{iPrCH,iPr(Me)}= 6.8 Hz, 6 H, 4-iPr (CH₃)₂), 0.97, 1.03 (2 d, J_2Ј,3Ј

CHCl₃) at 99% ee.

= 6.7 Hz, 6 H, 3Ј-H), 1.23, 1.24 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.51

3

(m, 1 H, 4-H), 1.68 (dsept, J_2Ј,CH-O= 1.9 Hz, J_2Ј,3Ј= 6.7 Hz, 1

H, 2Ј-H), 1.75–1.89 (m, 3 H, 4-iPr CH, 5-H), 2.13 (m, 2 H, 6-H),

[3RS,3(1RS),4RS]- and [3RS,3(1SR),4RS]-3-(1-Hydroxy-2-meth-

ylprop-2-enyl)-4-isopropylcyclohex-1-enyl

N,N-Diisopropylcarba-

3

2.48 (br. s, 1 H, 3-H), 3.20 (dd, J_2Ј,CH-O= 1.9 Hz, J_3,CH-O

=

mate (rac-31b and rac-32b): Cryptyl carbamate rac-3 (267 mg,

1.0 mmol) was lithiated according to GP C with TMCDA rac-26

(179 mg, 1.05 mmol, 1.3 equiv.) and 1.22  sBuLi solution

(0.86 mL, 1.05 mmol, 1.05 equiv.) in Et₂O (8 mL) at –78 °C for 2 h

and transmetallated with ClTi(NEt₂)₃(480 mg, 1.6 mmol,

1.6 equiv.) for 3 h. Methacroleine (28b, 0.70 g, 10 mmol,

10.0 equiv.) was added and the solution was warmed to room tem-

perature during 14 h. Purification and separation of the dia-

stereomers by FCC (Et₂O/PE = 1:2 Ǟ 1:1) yielded 16 mg

(0.05 mmol, 5%) rac-32b as colourless oil and 264 mg (0.78 mmol,

78%) rac-31b as colourless solid (total yield 83%, rac-31b:rac-32b

= 95:5^[31]). rac-31b: M.p. 77 °C (Et₂O/PE). t_R= 19.09 min (HP-5).

R_F= 0.17 (Et₂O/PE = 1:1). ¹H NMR (400 MHz, CDCl₃): δ = 0.86,

8.8 Hz, 1 H, CH-O), 3.79, 4.05 (2 br. s, 2 H, N-iPr CH), 5.21 (br.

s, 1 H, 2-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 17.2, 19.3

(CH₃, 4-iPr (CH₃)₂), 20.9 (CH₂, C-3Ј), 20.9, 21.7 (CH₃, N-iPr

(CH₃)₂), 21.8 (CH₂, C-5), 26.9 (CH₂, C-6), 27.8 (CH, 4-iPr CH),

32.1 (CH, C-2Ј), 39.8 (CH, C-3), 40.8 (CH, C-4), 45.9, 46.6 (CH,

N-iPr CH), 78.2 (CH, C-OH), 111.4 (CH, C-2), 152.2 (C_q, C-1),

154.0 (C , C=O) ppm. IR (ATR): ν = 3400 (br.) [ν(OH)], 2958 (s),

˜

q

2936 (m), 2872 (w) [ν(C_aliph–H)], 1699 (m) [ν(C=O)] cm^–1. MS

(ESI): m/z = 362.2668 [M + Na]⁺. C₂₀H₃₇NO₃(339.51): calcd. C

70.75, H 10.98, N 4.13; found C 70.57, H, 11.03, N 3.88. rac-32c:

t_R= 18.79 min (HP-5). R_F= 0.44 (Et₂O/PE = 1:1). ¹H NMR

3

(400 MHz, CDCl₃): δ = 0.93, 0.94 (2 d, J_{4-iPrCH,4-iPr(Me)}= 6.6 Hz,

3

6 H, 4-iPr (CH₃)₂), 0.95, 0.96 (2 d, J_2Ј,3Ј= 6.6 Hz, 6 H, 3Ј-H),

3

0.99 (2 d, J_{4-iPrCH,4-iPr(Me)}= 6.8 Hz, 6 H, 4-iPr (CH₃)₂), 1.22, 1.24

1.22, 1.24 (2 br. s, 12 H, N-iPr (CH₃)₂), 1.53 (m, 1 H, 4-H), 1.61

(2 s, 12 H, N-iPr (CH₃)₂), 1.53 (m, 2 H, 4-H, 4-iPr CH), 1.72 (br.

s, 3 H, 2Ј-CH₃), 1.79 (m, 1 H, 5-H_A), 1.91 (m, 1 H, 5-H_B), 2.24 (m,

2 H, 6-H), 2.35 (br. s, 1 H, OH), 2.63 (m, 1 H, 3-H), 3.83, 4.11 (2

br. s, 2 H, N-iPr CH), 4.72 (br. s, 1 H, CH-O), 4.93 (m, 1 H, 3Ј-

H_A), 5.02 (br. s, 1 H, 2-H), 5.15 (m, 1 H, 3Ј-H_B) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 17.4, 21.9 (CH₃, 4-iPr (CH₃)₂), 19.2 (CH₃,

2Ј-CH₃), 20.6, 21.2 (CH₃, N-iPr (CH₃)₂), 21.7 (CH₂, C-5), 26.7

(CH₂, C-6), 27.7 (CH, C-7), 40.1 (CH, C-4), 40.2 (CH, C-3), 46.2

(CH, N-iPr CH), 75.6 (CH, C-OH), 110.9 (CH, C-2), 111.4 (CH₂,

C-3Ј), 146.3 (C_q, C-2Ј), 151.9 (C_q, C-1), 154.0 (C_q, C=O) ppm. IR

(br. s, 1 H, OH), 1.68–1.80 (m, 2 H, 2Ј-H/4-iPr CH), 1.86–1.97 (m,

3

2 H, 5-H), 1.92, 2.20 (2 m, 2 H, 6-H), 2.36 (t, J_2,3

= =

³J_3,CH-O

5.4 Hz, 1 H, 3-H), 3.20 (t, J_2Ј,CH-O= ³J_3,CH-O= 5.4 Hz, 1 H, CH-

O), 3.77, 4.05 (2 br. s, 2 H, N-iPr CH), 5.21 (d, J_2,3= 5.4 Hz, 1

3

H, 2-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.1, 20.3 (CH₃,

4-iPr (CH₃)₂), 20.5 (CH₃, C-3Ј), 20.8, 21.9 (CH₃, N-iPr (CH₃)₂),

21.0 (CH₂, C-5), 24.0 (CH₂, C-6), 27.5 (CH, 4-iPr CH), 29.7 (CH,

C-2Ј), 38.4 (CH, C-3), 40.6 (CH, C-4), 46.0 (CH, N-iPr CH), 78.4

(CH, C-OH), 113.3 (CH, C-2), 150.3 (C_q, C-1), 154.1 (C_q, C=O)

ppm. IR (ATR): ν = 3410 (br.) [ν(OH)], 2961 (s), 2933 (m), 2873

˜

(ATR): ν = 3425 (br.) [ν(OH)], 2963 (s), 2934 (m), 2877 (w)

˜

(w) [ν(C_aliph–H)], 1682 (m) [ν(C=O)] cm^–1. MS (ESI): m/z =

362.2670 [M + Na]⁺. C₂₀H₃₇NO₃(339.51): calcd. C 70.75, H 10.98,

N 4.13; found C 70.48, H 10.96, N 3.91.

[ν(C_aliph–H)], 1691 (m) [ν(C=O)] cm^–1. MS (ESI): m/z = 360.2507

[M + Na]⁺. C₂₀H₃₅NO₃(337.50): calcd. C 71.18, H 10.45, N 4.15;

found C 71.00, H 10.57, N 3.91. rac-32b: t_R= 18.95 min (HP-5).

R_F= 0.26 (Et₂O/PE = 1:1). ¹H NMR (300 MHz, CDCl₃): δ = 0.83,

[3R,3(1R,2S),4R]-3-(2-(tert-Butyldiphenylsilyloxy)-1-hydroxy-

propyl)-4-isopropylcyclohex-1-enyl N,N-Diisopropylcarbamate (31d):

(1S,4R)-Cryptyl carbamate 3 (134 mg, 0.50 mmol, 99% ee) was li-

thiated according to GP C with TMCDA (rac-26, 116 mg,

0.65 mmol, 1.3 equiv.) and 1.36  sBuLi solution (0.48 mL,

0.65 mmol, 1.3 equiv.) in Et₂O (4 mL) at –78 °C for 2 h and trans-

metallated with ClTi(NEt₂)₃(450 mg, 1.5 mmol, 3.0 equiv.) for 3 h.

(2R)-2-(tert-Butyldiphenylsilyloxy)propanal^[25](28d, 1.13 g,

3.6 mmol, 7.3 equiv.) ([α]²_D⁰= +19.4 (c = 0.94, CHCl₃); ref.^[25][α]²_D⁰

= –15.0 (c = 1.07, CHCl₃) for (2S)-28d), were then added and the

solution was warmed to room temperature during 17 h. Purifica-

tion by FCC (Et₂O/PE = 1:4) yielded 129 mg (0.22 mmol, 45%)

31d as a colourless oil. 668 mg (2.14 mmol) of the enantiopure alde-

hyde 28d were reisolated. t_R= decomposition (HP-5). R_F= 0.18

3

0.86 (2 d, J_{4-iPrCH,4-iPr(Me)}= 6.7 Hz, 6 H, 4-iPr (CH₃)₂), 1.15, 1.17

(2 br. s, 12 H, N-iPr (CH₃)₂), 1.43 (m, 1 H, 4-H), 1.64 (m, 1 H, 4-

iPr CH), 1.69 (br. s, 3 H, 2Ј-CH₃), 1.68 (m, 1 H, 5-H_A), 1.75 (dt,

3

²J_5A,5B= 17.2 Hz, J_4,5B= J_5B,6= 4.9 Hz, 1 H, 5-H_B), 2.10 (m, 2

H, 6-H), 2.40 (br. s, 1 H, 3-H), 3.72, 3.94 (2 br. s, 2 H, N-iPr CH),

3

3.96 (d, J_3,CH-O= 6.4 Hz, 1 H, CH-O), 4.84 (br. s, 1 H, 3Ј-H_A),

4.98 (br. s, 1 H, 2-H), 5.15 (d, J = 4.4 Hz, 1 H, 3Ј-H_B) ppm. ¹³C

NMR (75 MHz, CDCl₃): δ = 18.7, 21.9 (CH₃, 4-iPr (CH₃)₂), 19.7

(CH₃, 2Ј-CH₃), 20.7, 21.2 (CH₃, N-iPr (CH₃)₂), 21.8 (CH₂, C-5),

24.6 (CH₂, C-6), 27.6 (CH, 4-iPr CH), 37.9 (CH, C-4), 40.8 (CH,

C-3), 45.7, 46.4 (CH, N-iPr CH), 77.3 (CH, C-OH), 112.2, 113.5

(CH/CH₂, C-2/C-3Ј), 145.4 (C_q, C-2Ј), 150.5 (C_q, C-1), 154.1 (C_q,

C=O) ppm. IR (ATR): ν = 3432 (br.) [ν(OH)], 2964 (s), 2930 (m),

˜

2876 (w) [ν(C_aliph–H)], 1692 (m) [ν(C=O)] cm^–1. MS (ESI): m/z =

360.2508 [M + Na]⁺. C₂₀H₃₅NO₃(337.50): calcd. C 71.18, H 10.45,

N 4.15; found C 70.94, H 10.68, N 3.82.

(Et₂O/PE = 1:1). ¹H NMR (600 MHz, CDCl₃): δ = 0.78, 0.95 (2 d,

3

³J_{4-iPrCH,4-iPr(Me)}= 6.9 Hz, 6 H, 4-iPr (CH₃)₂), 0.97 (d, J_2Ј,3Ј

=

6.4 Hz, 6 H, 3Ј-H), 1.06 (s, 9 H, C(CH₃)₃), 1.22, 1.23 (2 s, 12 H,

[3RS,3(1SR),4RS]- and [3RS,3(1RS),4RS]-3(1-Hydroxy-2-meth- N-iPr (CH₃)₂), 1.50 (m, 2 H, 4-H, 5-H_A), 1.79 (m, 1 H, 5-H_B), 1.92

3

ylpropyl)-4-isopropylcyclohex-1-enyl

N,N-Diisopropylcarbamate

(dsept, J_4,4-iPrCH= 3.6 Hz, J_{4-iPrCH,4-iPr(Me)}= 6.9 Hz, 1 H, 4-iPr

(rac-31c and rac-32c): Cryptyl carbamate rac-3 (267 mg, 1.0 mmol)

was lithiated according to GP C with rac-26 (179 mg, 1.05 mmol,

1.05 equiv.) and 1.22  sBuLi solution (0.86 mL, 1.05 mmol,

1.05 equiv.) in Et₂O (8 mL) at –78 °C for 2 h and transmetallated

CH), 2.09 (m, 1 H, 6-H_A), 2.19 (m, 1 H, 6-H_B), 2.36 (m, 1 H, 3-

3

H), 2.70 (br. s, 1 H, OH), 3.56 (dd, J_1Ј,2Ј= 6.4 Hz, ³J_1Ј,3= 2.1 Hz,

3

1 H, 1Ј-H), 3.84, 3.98 (2 br. s, 2 H, N-iPr CH), 3.91 (quint, J_1Ј,2Ј

=

³J_2Ј,3Ј= 6.4 Hz, 1 H, 2Ј-H), 5.12 (br. s, 1 H, 2-H), 7.36–7.43,

with ClTi(NEt₂)₃(479 mg, 1.6 mmol, 1.6 equiv.) for 3 h. Isobutyr- 7.70–7.72 (2 m, 10 H, PhCH) ppm. ¹³C NMR (600 MHz, CDCl₃):

aldehyde (28c, 0.72 g, 10 mmol, 10.0 equiv.) was then added and

the solution was warmed to room temperature within 14 h. Purifi-

cation and separation of the diastereomers by FCC (Et₂O/PE =

1:2) yielded 34 mg (0.10 mmol, 10%) rac-32c and 175 mg

(0.52 mmol, 52%) rac-31c as colourless oils (total yield 62%, rac-

δ = 16.9, 19.9 (CH₃, 4-iPr (CH₃)₂), 19.3 (C_q; C(CH₃)₃), 20.5, 21.3

(CH₃, N-iPr (CH₃)₂), 21.4 (CH₂, C-5), 21.8 (CH₃, C-3Ј), 26.4 (CH₂,

C-6), 27.0 (CH₃, C(CH₃)₃), 27.1 (CH, 4-iPr CH), 38.9 (CH₂, C-3),

40.9 (CH, C-4), 45.7, 46.3 (CH, N-iPr CH), 71.9 (CH, C-2Ј), 78.4

(CH, C-1Ј), 112.6 (CH, C-2), 127.5, 127.7 (CH, m-Ph), 129.6, 129.7

31c:rac-32c = 85:15). rac-31c: t_R= 18.79 min (HP-5). R_F= 0.26 (CH, p-Ph), 133.4, 134.2 (CH, i-C-Ph), 135.8, 135.9 (CH, o-Ph),

(Et₂O/PE = 1:1). ¹H NMR (400 MHz, CDCl₃): δ = 0.82, 0.88 (2 d,

150.7 (C , C-1), 153.9 (C , C=O) ppm. IR (ATR): ν = 3459 (br.)

˜

q

3360

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3349–3364

Asymmetric Homoaldol Reaction

FULL PAPER

[ν(OH)], 2961 (s), 2932 (m), 2892 (w), 2859 (w) [ν(C_aliph–H)], 1702

(m) [ν(C=O)] cm^–1. MS (ESI): m/z = 602.3636 [M + Na]⁺.

C₃₅H₅₃NO₄Si (579.89): calcd. C 72.49, H 9.21, N 2.42; found C

72.48, H 9.38, N 2.11. [α]²_D⁰= +40.8 (c = 1.04, CHCl₃).

C-3), 90.0 (CH, C-1), 111.5 (CH₂, 6-C(CH₂)(CH₃)), 123.8, 124.4,

124.7, 125.9, 126.0, 126.2, 126.3, 127.7, 127.8, 128.0, 128.2, 132.7

(CH, C-Ar), 132.9, 133.4, 136.0, 136.7 (C_q, C-Ar), 146.8 (C_q, 6-

C(CH )(CH )), 212.1 (C , C-4) ppm. IR (film): ν = 3407 (br.)

˜

2

3

q

[ν(OH)], 3052 (m) [ν(C_arom–H)], 2962 (s), 2925 (m), 2860 (w), 2859

(w) [ν(C_aliph–H)], 1695 (s) [ν(C=O)] cm^–1. MS (ESI): m/z =

469.2157 [M + Na]⁺. C₃₂H₃₀O₂(446.58): calcd. C 86.06, H 6.77;

found C 85.72, H 6.61. [α]²_D⁰= +36.2 (c = 1.00, CHCl₃).

(3RS,4RS)-3-Benzoyl-4-isopropylcyclohex-1-enyl N,N-Diisopro-

pylcarbamate (rac-33): The homoaldol product rac-31a (126 mg,

0.34 mmol), dissolved in 5 mL CH₂Cl₂, was treated with PDC

(0.64 g, 1.7 mmol, 5.0 equiv.) and powdered molecular sieves (4 Å)

(20 mg) and stirred for 16 h at room temperature. The suspension

was diluted with Et₂O (20 mL), filtered through silica gel and the

solvent was removed in vacuo. Purification by FCC (Et₂O/PE =

1:4) yielded 118 mg (0.32 mmol, 93%) rac-33 as a colourless solid.

Oxidation of rac-32a (17 mg, 0.046 mmol) for 28 h using the condi-

tions above yielded 15 mg (0.040 mmol, 88%) rac-33. M.p. 78 °C

(Et₂O/PE). t_R= 19.81 min (HP-5). R_F= 0.40 (Et₂O/PE = 1:1).

(1S,3S,3aS,6R,7aR)-6-Isopropenyl-3a-methyl-1-(naphthalen-2-yl)-3-

phenyl-hexahydroisobenzofuran-4(1H)-one (35b): According to GP

D 18a (219 mg, 0.50 mmol), benzaldehyde (34b, 70 mg, 0.65 mmol,

1.3 equiv.), and BF₃·OEt₂(92 mg, 0.65 mmol, 1.3 equiv.) were

stirred for 30 min. FCC (TBME/PE = 1:10) yielded 164 mg

(0.41 mmol, 83%) 35b as a colourless solid. M.p. 79 °C (PE). t_R

=

24.55 min (HP-5). R_F= 0.19 (TBME/PE = 1:10). ¹H NMR

(600 MHz, CDCl₃): δ = 1.31 (ddt, ²J_7A,7B= 14.1 Hz, ³J_6,7A= ³J_7a,7A

= 5.4 Hz, ⁴J_5B,7A= 2.1 Hz, 1 H, 7-H_A), 1.40 (dd, ²J_5A,5B= 16.9 Hz,

³J_5A,6= 5.9 Hz, 1 H, 5-H_A), 1.48 (s, 3 H, 6-C(CH₂)(CH₃)), 1.63 (s

3

¹H NMR (400 MHz, CDCl₃): δ = 0.85, 0.95 (2 d, J_{4-iPrCH,4-iPr(Me)}

= 6.8 Hz, 6 H, 4-iPr (CH₃)₂), 1.20, 1.21 (2 s, 12 H, N-iPr (CH₃)₂),

1.68 (m, 2 H, 5-H), 1.88 (m, 1 H, 4-iPr CH), 2.11 (m, 1 H, 6-H_A),

2.24 (m, 1 H, 6-H_B), 2.30 (m, 1 H, 4-H), 3.79, 3.99 (2 br. s, 2 H,

N-iPr CH), 4.23 (m, 1 H, 3-H), 5.27 (m, 1 H, 2-H), 7.48 (m, 2

2

3

and m, 4 H, 3a-CH₃, 7-H_B), 2.17 (ddd, J_5A,5B= 16.9 Hz, J_5B,6

=

4

3

3.9 Hz, J_5B,7A= 2.1 Hz, 1 H, 5-H_B), 2.43 (dt, J_1,7a= 5.1 Hz,

³J_7a,7A= J_7a,7B= 5.4 Hz, 1 H, 7a-H), 2.50 (br. s, 1 H, 6-H), 4.44,

3

4

H, m-PhCH), 7.57 (tt, J_{m-PhCH,p-PhCH}= 7.5 Hz, J_{o-PhCH,p-PhCH}

=

3

4.72 (2 s, 2 H, 6-C(CH₂)(CH₃)), 4.99 (s, 1 H, 3-H), 5.56 (d, J_1,7a

1.4 Hz, 1 H, p-PhCH), 8.02 (dd, J_{o-PhCH,m-PhCH}= 8.5 Hz,

⁴J_{o-PhCH,p-PhCH}= 1.4 Hz, 2 H, o-PhCH) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 18.1, 21.4 (CH₃, 4-iPr (CH₃)₂), 20.4, 21.3 (CH₃, N-iPr

(CH₃)₂), 22.0 (CH₂, C-5), 26.7 (CH₂, C-6), 29.2 (CH, 4-iPr CH),

40.4 (CH, C-4), 45.8, 46.3 (CH, N-iPr CH), 46.5 (CH, C-3), 111.1

(CH, C-2), 128.6, 128.7 (CH, o/m-Ph), 133.0 (C_q, i-C-Ph), 136.6

(CH, p-Ph), 151.0 (C_q, C-1), 153.5 (C_q, i-C-Ph), 201.2 (C_q, C=O)

= 5.1 Hz, 1 H, 1-H), 7.27 (t, J = 7.5 Hz, 1 H, p-PhCH), 7.36 (t, J

= 7.5 Hz, 2 H, m-PhCH), 7.46–7.50 (m, 4 H, ArCH, o-PhCH), 7.53

(m, 1 H, ArCH), 7.86 (d, J = 8.0 Hz, 1 H, ArCH), 7.89 (d, J =

8.5 Hz, 1 H, ArCH), 7.92 (d, J = 8.0 Hz, 1 H, ArCH), 8.06 (s, 1

H, ArCH) ppm. ¹³C NMR (600 MHz, CDCl₃): δ = 21.7 (CH₃, 3a-

CH₃), 25.9 (CH₃, 6-C(CH₂)(CH₃)), 27.0 (CH₂, C-7), 38.9 (CH, C-

6), 45.0 (CH₂, C-5), 50.4 (CH, C-7a), 60.2 (C_q, C-3a), 82.4 (CH,

C-3), 89.9 (CH, C-1), 111.5 (CH₂, 6-C(CH₂)(CH₃)), 123.8 (CH, o-

Ph), 124.4, 125.8, 126.1 (CH, C-Ar), 126.3 (CH, m-Ph), 127.7 (CH,

C-Ar), 128.0 (CH, p-Ph), 128.1 (CH, C-Ar), 132.7 (C_q, i-C-Ph),

133.4, 136.0, 139.0 (C_q, C-Ar), 146.9 (C_q, 6-C(CH₂)(CH₃)), 212.3

ppm. IR (ATR): ν = 3060 (w), 3001 (m), [ν(C_arom–H)], 2961 (s),

˜

2874 (m) [ν(C_aliph–H)], 1688 (s), [ν(C=O)] cm^–1. MS (ESI): m/z =

394.2351 [M + Na]⁺. C₂₃H₃₃NO₃(371.51): calcd. C 74.36, H 8.95,

N 3.77; found C 74.39, H 9.00, N 3.62.

Synthesis of Hexahydroisobenzofuran-4(1H)-ones: General Pro-

cedure D (GP D): To a stirred solution of the homoaldol product

(0.5 mmol) and the aldehyde (0.65 mmol, 1.3 equiv.) in CH₂Cl₂

(2 mL) at 0 °C, BF₃·OEt₂(92 mg 0.65 mmol, 1.3 equiv.) was added

through a syringe within 1 min. The solution was warmed to room

temperature and stirring was continued until complete consump-

tion of the starting material (TLC). The reaction was quenched

with satd. aq. NaCl solution (3 mL), diluted with CH₂Cl₂(5 mL)

and the aqueous layer was extracted with TBME (3ϫ10 mL). The

combined organic layers were washed with satd. aq. NaHCO₃solu-

tion (5 mL), dried with MgSO₄, and concentrated in vacuo. The

crude product was purified by FCC on silica gel (Et₂O/PE or

TBME/PE mixtures).

(C , C-4) ppm. IR (KBr): ν = 3057, 3024 (w) [ν(C_arom–H)], 2968

˜

q

(s), 2932 (w), 2866 (w) [ν(C_aliph–H)], 1691 (s) [ν(C=O)] cm^–1

.

MS (ESI): m/z = 419.1978 [M + Na]⁺. C₂₈H₂₈O₂(396.52): calcd. C

84.81, H 7.12; found C 84.46, H 7.14. [α]²_D⁰= +9.80 (c = 1.01,

CHCl₃).

(1S,3S,3aR,6R,7aS)-6-Isopropenyl-3a-methyl-1-(naphthalen-2-yl)-3-

phenylhexahydroisobenzofuran-4(1H)-one (38a): According to GP D

20a (219 mg, 0.50 mmol), benzaldehyde (36a, 70 mg, 0.65 mmol,

1.3 equiv.) and BF₃·OEt₂(92 mg, 0.65 mmol, 1.3 equiv.), were

stirred for 1 h. FCC (Et₂O/PE = 1:10) yielded 145 mg (0.37 mmol,

73%) 38a as a colourless solid. M.p. 79 °C (PE). t_R= 25.54 min

(HP-5). R_F= 0.21 (Et₂O/PE = 1:10). ¹H NMR (400 MHz, CDCl₃):

2

δ = 0.92 (br. s, 3 H, 6-C(CH₂)(CH₃)), 1.56 (dt, J_7A,7B= 13.1 Hz,

3

(1S,3S,3aS,6R,7aR)-6-Isopropenyl-3a-methyl-1,3-di(naphthalen-2-

yl)-hexahydroisobenzofuran-4(1H)-one (35a): According to GP D

18a (218 mg, 0.50 mmol), 2-naphthaldehyde (34a, 101 mg,

³J_6,7A= J_7A,7a= 12.4 Hz, 1 H, 7-H_A), 1.76 (s, 3 H, 3a-CH₃), 2.14

2

3

4

(ddt, J_7A,7B= 13.1 Hz, J_6,7B= 6.5 Hz, J_5B,7B= 2.3 Hz, 1 H, 7-

3

H_B), 2.38 (dd, J_1,7a= 7.5 Hz, J_7A,7a= 12.4 Hz, 1 H, 7a-H), 2.40

0.65 mmol, 1.3 equiv.) and BF₃·OEt₂(92 mg, 0.65 mmol, (dd, ²J_5A,5B= 17.0 Hz, J_5A,6= 11.0 Hz, 1 H, 5-H_A), 2.65 (m, 1 H,

3

1.3 equiv.), were stirred for 30 min. FCC (Et₂O/PE = 1:10) yielded

183 mg (0.41 mmol, 82%) 35a as a colourless oil. t_R= 29.61 min

(HP-5). R_F= 0.10 (Et₂O/PE = 1:10). ¹H NMR (400 MHz, CDCl₃):

6-H), 2.75 (ddd, ²J_5A,5B= 17.0 Hz, ³J_5B,6= 6.5 Hz, ⁴J_5B,7B= 2.3 Hz,

3

1 H, 5-H_B), 4.74 (d, J_1,7a= 7.5 Hz, 1 H, 1-H), 4.79, 4.80 (2 s, 2

3

H, 6-C(CH₂)(CH₃)), 5.54 (s, 1 H, 3-H), 7.28 (tt, J_{m-PhCH,p-PhCH}

=

3

δ = 1.32–1.38 (m, 2 H, 5-H_A, 7-H_A), 1.47 (s, 3 H, 6-C(CH₂)(CH₃)), 7.3 Hz, J_{o-PhCH,p-PhCH}= 1.7 Hz, 1 H, p-PhCH), 7.37 (br. t,

2

3

1.69 (s and m, 4 H, 3a-CH₃, 7-H_B), 2.17 (ddd, J_5A,5B= 16.8 Hz, ³J_{m-PhCH,p-PhCH}= J_{m-PhCH,o-PhCH}= 7.5 Hz, 2 H, m-PhCH), 7.47–

4

3

³J_5B,6= 3.8 Hz, J_5B,7A= 2.0 Hz, 1 H, 5-H_B), 2.43–2.50 (m, 2 H, 7.53 (m, 2 H, ArCH), 7.59 (d, J_{m-PhCH,o-PhCH}= 7.4 Hz, 2 H, o-

7a-H, 6-H), 4.44, 4.72 (2 s, 2 H, 6-C(CH₂)(CH₃)), 4.15 (s, 1 H, 3- PhCH), 7.62 (dd, J = 8.4 Hz, J = 1.6 Hz, 2 H, ArCH), 7.84–7.89

3

H), 5.56 (d, J_1,7a= 4.8 Hz, 1 H, 1-H), 7.44–7.57 (m, J = 7.5 Hz, (m, 2 H, ArCH), 7.91 (br. s, 1 H, ArCH) ppm. ¹³C NMR

6 H, ArCH), 7.81 (d, J = 8.7 Hz, 1 H, ArCH), 7.88–7.93 (m, 3 H,

ArCH), 7.96 (d, J = 8.7 Hz, 1 H, ArCH), 8.05 (s, 1 H, ArCH), 8.13

(100 MHz, CDCl₃): δ = 20.3 (CH₃, 3a-CH₃), 23.1 (CH₃, 6-

C(CH₂)(CH₃)), 33.1 (CH₂, C-7), 41.0 (CH₂, C-6), 43.3 (CH, C-5),

(s, 1 H, ArCH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 21.7 (CH₃, 57.5 (C_q, CH, C-3a, C-7a), 83.1 (CH, C-3), 86.3 (CH, C-1), 110.3

3a-CH₃), 26.0 (CH₃, 6-C(CH₂)(CH₃)), 27.1 (CH₂, C-7), 38.9 (CH,

(CH₂, 6-C(CH₂)(CH₃)), 123.7 (CH, o-Ph), 124.6, 125.9, 126.2,

C-6), 45.2 (CH₂, C-5), 50.5 (CH, C-7a), 60.3 (C_q, C-3a), 82.5 (CH, 127.0, 127.3 (CH, C-Ar), 127.7 (CH, m-Ph), 127.8, 127.9 (CH, C-

Eur. J. Org. Chem. 2007, 3349–3364

www.eurjoc.org

3361

J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe

FULL PAPER

Ar), 128.4 (CH, p-Ph), 133.1 (CH, C-Ar), 133.2 (C_q, i-C-Ph), 138.0, (0.40 mmol, 80%) 38d as a colourless oil. t_R= 17.94 min (HP-5).

1

138.4 (C_q, C-Ar), 147.0 (C_q, 6-C(CH₂)(CH₃)), 213.7 (C_q, C=O) R_F= 0.22 (TBME/PE = 1:20). H NMR (400 MHz, CDCl₃): δ =

3

ppm. IR (KBr): ν = 3079 (w), 3057 (w), 3029 (w) [ν(C_arom–H)], 0.84 (s, 3 H, 3a-CH₃), 1.02, 1.10 (2 d, J_{1-iPr(Me),1-iPrCH}= 6.9 Hz, 6

˜

2933 (m), 2932 (w), 2865 (w) [ν(C_aliph–H)], 1698 (s) [ν(C=O)] cm^–1. H, 1-iPr (CH₃)₂), 1.50 (dt, J_6,7A

= =

³J_7a,7A= 12.2 Hz, J_7A,7B

3

2

MS (ESI): m/z = 419.1957 [M + Na]⁺. C₂₈H₂₈O₂(396.52): calcd.

C 84.81, H 7.12; found C 84.49, H 7.07. [α]²_D⁰= +72.8 (c = 0.99,

CHCl₃).

13.3 Hz, 1 H, 7-H_A), 1.76 (s, 3 H, 6-C(CH₂)(CH₃)), 1.92 (oct,

³J_1,1-iPrCH= J_{1-iPr(Me),1-iPrCH}= 6.9 Hz, 1 H, 1-iPr CH), 2.01 (dm,

3

²J_7A,7B= 13.3 Hz, 1 H, 7-H_B), 2.15 (dt, J_1,7a

=

³J_7a,7B= 6.3 Hz,

3

³J_7a,7A= 12.2 Hz, 1 H, 7a-H), 2.35 (dd, ²J_5A,5B= 16.0 Hz, J_5A,6

=

3

(1S,3S,3aR,6R,7aS)-1-(4-Bromophenyl)-6-isopropenyl-3,3a-dimeth-

yl-hexahydroisobenzofuran-4(1H)-one (38b): According to GP D

20d (232 mg, 0.50 mmol), acetaldehyde (36b, 29 mg, 0.65 mmol,

1.3 equiv.), and BF₃·OEt₂(92 mg, 0.65 mmol, 1.3 equiv.) were

stirred for 3 h. FCC (Et₂O/PE = 1:9) yielded 151 mg (0.42 mmol,

83%) 38b as a colourless oil. t_R= 19.15 min (HP-5). R_F= 0.23

(Et₂O/PE = 1:9). ¹H NMR (300 MHz, CDCl₃): δ = 1.13 (br. s, 3

2

11.4 Hz, 1 H, 5-H_A), 2.59 (m, 1 H, 6-H), 2.68 (ddd, J_5A,5B

16.0 Hz, J_5B,6= 5.3 Hz, J = 2.3 Hz, 1 H, 5-H_B), 3.39 (dd, J_1,7a

3

6.3 Hz, J_1,1-iPrCH= 6.9 Hz, 1 H, 1-H), 4.78, 4.80 (2 s, 2 H, 6-

C(CH₂)(CH₃)), 5.11 (s, 1 H, 3-H), 7.29 (m, 5 H, PhCH) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 18.8 (CH₃, 3a-CH₃), 19.3 (CH₃, 1-

iPr (CH₃)₂), 21.8 (CH₃, 6-C(CH₂)(CH₃)), 32.6 (CH, 1-iPr CH), 35.6

(CH₂, C-7), 42.1 (CH, C-6), 44.2 (CH₂, C-5), 52.4 (CH, C-7a), 57.5

(C_q, C-3a), 82.3 (CH, C-1), 90.4 (CH, C-3), 110.1 (CH₂, 6-

C(CH₂)(CH₃)), 127.0, 127.3, 127.6 (CH, o/m/p-Ph), 137.8 (C_q, i-C-

Ph), 147.2 (C_q, 6-C(CH₂)(CH₃)), 213.2 (C_q, C=O) ppm. IR (film):

3

H, 6-C(CH₂)(CH₃)), 1.35 (d, J_3,3-CH3= 6.3 Hz, 3 H, 3-CH₃), 1.48

(m, 1 H, 7-H_A), 1.74 (s, 3 H, 3a-CH₃), 2.08 (m, 1 H, 7-H_B), 2.14

2

3

(m, 1 H, 7a-H), 2.23 (dd, J_5A,5B= 17.0 Hz, J_5A,6= 11.4 Hz, 1 H,

5-H_A), 2.49–2.58 (m, 1 H, 6-H), 2.64 (ddd, ²J_5A,5B= 17.0 Hz, ³J_5B,6

= 5.4 Hz, J = 2.3 Hz, 1 H, 5-H_B), 4.74 (q, J_3,3-CH3= 6.3 Hz, 1 H,

ν = 2978 (m), 2958 (m), 2933 (m), 2917 (m) [ν(C_aliph–H)], 1699 (s)

˜

3

[ν(C=O)], 1650 (s) [ν(C=C)] cm^–1. HR-MS (ESI, C₂₁H₂₈O₂,

312.45): calcd. m/z = 335.1982 [M + Na]⁺, found m/z = 335.1950

[M + Na]⁺. [α]²_D⁰= –0.45 (c = 1.01, CHCl₃).

3

3-H), 5.54 (d, J_1,7a= 6.1 Hz, 1 H, 1-H), 4.76, 4.79 (s, m, 2 H, 6-

3

C(CH₂)(CH₃)), 7.24 (dm, J_{m-PhCH,o-PhCH}= 8.2 Hz, 1 H, o-PhCH),

7.47 (dm, ³J_{m-PhCH,o-PhCH}= 8.2 Hz, 1 H, m-PhCH) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 14.9 (CH₃, 3-CH₃), 20.2 (CH₃, 3a-CH₃),

20.8 (CH₃, 6-C(CH₂)(CH₃)), 34.2 (CH₂, C-7), 41.4 (CH₂, C-6), 43.7

(CH, C-5), 55.7 (C_q, CH, C-7a), 57.3 (C_q, C-3a), 78.1 (CH, C-3),

85.8 (CH, C-1), 110.3 (CH₂, 6-C(CH₂)(CH₃)), 121.3 (CH, p-Ph),

127.2 (CH, o-Ph), 131.6 (CH, m-Ph), 140.9 (C_q, i-C-Ph), 146.9 (C_q,

(1R,3S,3aR,6R,7aS)-1-Cyclohexyl-6-isopropenyl-3a-methyl-3-

phenyl-hexahydroisobenzo-furan-4(1H)-one (38e): According to GP

D 20b (196 mg, 0.50 mmol), benzaldehyde (36a, 70 mg, 0.65 mmol,

1.3 equiv.), and BF₃·OEt₂(92 mg, 0.65 mmol, 1.3 equiv.) were

stirred for 1 h. FCC (TBME/PE = 1:20) yielded 146 mg

(0.41 mmol, 83%) 38d as a colourless oil. t_R= 21.22 min (HP-5).

R_F= 0.37 (TBME/PE = 1:20). H NMR (400 MHz, CDCl₃): δ =

0.84 (s, 3 H, 3a-CH₃), 1.18–1.23 (m, 6 H, CyCH₂), 1.50 (dt, J_6,7a

= J_7a,7A= 12.1 Hz, J_7A,7B= 13.4 Hz, 1 H, 7-H_A), 1.61 (m, 1 H,

CyCH), 1.76 (s and m, 7 H, 6-C(CH₂)(CH₃)), CyCH₂), 1.99 (ddt,

6-C(CH )(CH )), 213.6 (C , C=O) ppm. IR (film): ν = 3084 (w),

˜

2

3

q

1

3047 (w) [ν(C_arom–H)], 2966 (s), 2934 (s), 2909 (s), 2868 (m)

[ν(C_aliph–H)], 1691 (s) [ν(C=O)] cm^–1. MS (ESI): m/z = 385.3 [M +

Na]⁺. C₁₉H₂₃BrO₂(363.29): calcd. C 62.82, H 6.38; found C 62.78,

H 6.44. [α]²_D⁰= +57.0 (c = 0.53, CHCl₃).

3

2

J = 13.4 Hz, J = 6.3 Hz, J = 2.5 Hz, 1 H, CyCH₂), 2.08 (br. d,

²J_7A,7B= 13.4 Hz, 1 H, 7-H_B), 2.18 (dt, J_1,7a

=

³J_7a,7B= 6.2 Hz,

3

(1S,3S,3aR,6R,7aS)-1,6-Diisopropenyl-3-isopropyl-3a-methyl-hexa-

hydroisobenzofuran-4(1H)-one (38c): According to GP D 20f

(174 mg, 0.50 mmol), isobutyraldehyde (36c, 47 mg, 0.65 mmol,

1.3 equiv.), and BF₃·OEt₂(92 mg, 0.65 mmol, 1.3 equiv.) were

stirred for 1 h. FCC (TBME/PE = 1:20) yielded 101 mg

(0.37 mmol, 73%) 38c as a colourless oil. t_R= 14.13 min (HP-5).

R_F= 0.24 (Et₂O/PE = 1:20). ¹H NMR (400 MHz, CDCl₃): δ =

³J_7a,7A= 12.1 Hz, 1 H, 7a-H), 2.35 (dd, ²J_5A,5B= 16.0 Hz, J_5A,6

=

3

2

11.3 Hz, 1 H, 5-H_A), 2.59 (m, 1 H, 6-H), 2.68 (ddd, J_5A,5B

16.0 Hz, J_5B,6= 5.3 Hz, J = 2.3 Hz, 1 H, 5-H_B), 3.42 (dd, J_1,7a

= 6.2 Hz, J_1,CyCH= 7.0 Hz, 1 H, 1-H), 4.78, 4.80 (2 s, 2 H, 6-

3

C(CH₂)(CH₃)), 5.09 (s, 1 H, 3-H), 7.28 (m, 5 H, PhCH) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 20.2 (3a-CH₃), 21.8 (CH₃, 6-

C(CH₂)(CH₃)), 26.0, 26.1, 26.5, 29.3, 29.9 (CH₂, C-Cy), 35.6 (CH₂,

C-7), 42.1 (CH, C-6), 42.5 (CH, C-Cy), 44.2 (CH₂, C-5), 52.2 (CH,

C-7a), 57.4 (C_q, C-3a), 82.2 (CH, C-1), 89.5 (CH, C-3), 110.1 (CH₂,

6-C(CH₂)(CH₃)), 127.0, 127.3, 127.6 (CH, o/m/p-Ph), 137.8 (C_q, i-

C-Ph), 147.3 (C_q, 6-C(CH₂)(CH₃)), 213.4 (C_q, C=O) ppm. IR

3

0.73, 1.07 (2 d, J_{3-iPr(Me),3-iPrCH}= 6.7 Hz, 6 H, 3-iPr (CH₃)₂), 1.13

(s, 3 H, 3a-CH₃), 1.72 (s and m, 4 H, 6-C(CH₂)(CH₃), 7-H_A), 1.76

(s, 3 H, 1-C(CH₂)(CH₃)), 1.88 (m, 1 H, 3-iPr CH), 1.98 (dm, ²J_5A,5B

3

= 13.8 Hz, 1 H, 5-H_A), 2.16 (ddd, ³J_1,7a= 2.8 Hz, J_7A,7a= 6.5 Hz,

³J_7B,7a= 12.4 Hz, 1 H, 7a-H), 2.48 (m, 3 H, 5-H_B, 6-H, 7-H_B), 3.85

(d, ³J_3,3-iPrCH= 8.9 Hz, 1 H, 3-iPr CH), 4.02 (br. s, 1 H, 1-H), 4.76,

4.79 (2 s, 2 H, 6-C(CH₂)(CH₃)), 4.83, 5.12 (2 s, 2 H, 1-

C(CH₂)(CH₃)) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 15.1, 18.9

(CH₃, 3-iPr (CH₃)₂), 18.2 (CH₃, 3a-CH₃), 20.3 (CH₃, 1-

C(CH₂)(CH₃)), 21.1 (CH₃, 6-C(CH₂)(CH₃)), 29.4 (CH₂, C-7), 36.3

(CH₃, 3-iPr CH), 44.3 (CH, C-6), 44.7 (CH₂, C-5), 55.0 (CH, C-

7a), 57.0 (C_q, C-3a), 87.2 (CH, C-3), 88.0 (CH, C-1), 109.5 (CH₂,

1-C(CH₂)(CH₃)), 110.1 (CH₂, 6-C(CH₂)(CH₃)), 144.8 (C_q, 1-

C(CH₂)(CH₃)), 147.1 (C_q, 6-C(CH₂)(CH₃)), 213.3 (C_q, C=O) ppm.

(film): ν = 3082 (w), 3060 (w), 3030 (w) [ν(C_arom–H)], 2960 (m),

˜

2926 (s), 2848 (s) [ν(C_aliph–H)], 1700 (s) [ν(C=O)] cm^–1. MS (ESI):

m/z = 375.2308 [M + Na]⁺. C₂₄H₃₂O₂(352.51): calcd. C 81.77,

H 9.15; found C 81.75, H 9.43. [α]²_D⁰= +70.7 (c = 0.54, CHCl₃).

(1R,3S,3aS,7R,7aR)-3-(4-Bromophenyl)-7-isopropyl-1-phenyl-hexa-

hydroisobenzofuran-4(1H)-one (41a): According to GP D 31a

(45 mg, 0.12 mmol), 4-bromobenzaldehyde (39a, 29 mg,

0.16 mmol, 1.3 equiv.) and 23 mg (0.16 mmol, 1.3 equiv.) BF₃·OEt₂

were stirred for 1 h. FCC (Et₂O/PE = 1:6) yielded 45 mg

(0.11 mmol, 91%) 41a as a colourless solid. rac-41a was prepared

from rac-31a (187 mg, 0.50 mmol), 39a (120 mg, 0.65 mmol,

1.3 equiv.) and BF₃·OEt₂(92 mg, 0.65 mmol, 1.3 equiv.). Yield

174 mg (0.42 mmol, 84%), colourless solid. M.p. 108 °C (for 41a at

99% ee, Et₂O/PE), m.p. 117 °C (for rac-41a, PE). t_R= 22.54 min

IR (film): ν = 2978 (m), 2958 (m), 2933 (m), 2917 (m) [ν(C

–

˜

aliph

H)], 1699 (s) [ν(C=O)], 1650 (s) [ν(C=C)] cm^–1. MS (ESI): m/z =

299.1983 [M + Na]⁺. C₁₈H₂₈O₂(276.41): calcd. C 78.21, H 10.21;

found C 77.93, H 10.12. [α]²_D⁰= +93.3 (c = 1.00, CHCl₃).

(1R,3S,3aR,6R,7aS)-6-Isopropenyl-1-isopropyl-3a-methyl-3-phenyl-

hexahydroisobenzofuran-4(1H)-one (38d): According to GP D 20g

1

(HP-5). R_F= 0.38 (Et₂O/PE = 1:4). H NMR (300 MHz, CDCl₃):

3

(179 mg, 0.50 mmol), benzaldehyde (36a, 70 mg, 0.65 mmol, δ = 0.67, 0.85 (2 d, J_{7-iPr(Me),7-iPrCH}= 6.8 Hz, 6 H, 7-iPr (CH₃)₂),

1.3 equiv.), and BF₃·OEt₂(92 mg, 0.65 mmol, 1.3 equiv.) were

stirred for 30 min. FCC (TBME/PE = 1:10) yielded 124 mg

1.50 (m, 2 H, 6-H_A, 7-H), 1.71 (m, 1 H, 7-iPr CH), 1.91 (m, 1 H,

6-H_B), 2.39 (m, 1 H, 5-H_A), 2.53 (dt, J_5A,5B= 17.1 Hz, J_5B,6A=

2

3

3362

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3349–3364

Asymmetric Homoaldol Reaction

FULL PAPER

³J_7,7a= 8.2 Hz, 299.1980 [M + Na]⁺. C₁₈H₂₈O₂(276.41): calcd. C 78.21, H 10.21;

³J_5B,6B= 5.4 Hz, 1 H, 5-H_B), 2.71 (dt, J_1,7a

=

3

³J_3a,7a= 10.1 Hz, 1 H, 7a-H), 2.93 (dd, J_3,3a= 6.2 Hz, J_3a,7a

=

found C 77.82, H 10.31.

3

10.1 Hz, 1 H, 3a-H), 4.59 (d, J_1,7a= 8.2 Hz, 1 H, 1-H), 5.45 (d,

³J_3,3a= 6.2 Hz, 1 H, 3-H), 7.33–7.42 (m, 7 H, PhCH/ArCH), 7.49

(dt, J = 8.5 Hz, J = 2.0 Hz, 2 H, ArCH) ppm. ¹³C NMR (75 MHz,

CDCl₃): δ = 16.6, 21.4 (CH₃, 7-iPr (CH₃)₂), 22.2 (CH₂, C-6), 28.0

(CH, 7-iPr CH), 38.4 (CH₂, C-5), 41.7 (CH, C-7), 51.2 (CH, C-7a),

59.0 (CH, C-3a), 78.9 (CH, C-3), 86.4 (CH, C-1), 121.3 (C_q, p-Ar),

126.9 (CH, p-Ph), 127.7 (CH, o-Ph), 128.4 (CH, m-Ph), 128.6 (CH,

o-Ar), 131.5 (CH, o-Ar), 140.1 (C_q, i-C-Ar), 141.0 (C_q, i-C-Ph),

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft

(SFB 424) and the Fonds der Chemischen Industrie (stipend for J.

B.). J. B. thanks M. Renger for her skilful experimental assistance.

O. Kataeva thanks the Deutsche Forschungsgemeinschaft (SFB 424

and SFB 624) for financial support.

210.6 (C , C=O) ppm. IR (ATR): ν = 3092 (w), 3063 (m), 3040 (w)

˜

q

3013 (w) [ν(C_arom–H)], 2957 (s), 2848 (m) [ν(C_aliph–H)], 1707 (s)

[ν(C=O)] cm^–1. MS (ESI): m/z = 435.0934 [M + Na]⁺. C₂₃H₂₅BrO₂

[1] Reviews: a) P. Bernadelli, L. A. Paquette, Heterocycles 1998,

49, 531–556; b) P.-S. Sung, M.-C. Chen, Heterocycles 2002, 57,

1705–1715.

[2] Total synthesis: a) P. Bernadelli, O. M. Moradei, D. Friedrich,

J. Yang, F. Gallou, B. P. Dyck, R. W. Doskotch, T. Lange, L. A.

Paquette, J. Am. Chem. Soc. 2001, 123, 9021–9032; b) D. W. C.

MacMillan, L. E. Overman, L. D. Pennington, J. Am. Chem.

Soc. 2001, 123, 9033–9044.

[3] Total synthesis: O. Corminboeuf, L. E. Overman, L. D. Pen-

nington, J. Am. Chem. Soc. 2003, 125, 6650–6652.

[4] a) M. E. Jung, J. Pontillo, J. Org. Chem. 2002, 67, 6848–6851;

b) M. E. Jung, J. Pontillo, Tetrahedron 2003, 59, 2729–2736; c)

Y. Chai, D. A. Vicic, M. C. McIntosh, Org. Lett. 2003, 5, 1039–

1042; d) T. Akindele, S. P. Marsden, J. G. Cumming, Tetrahe-

dron Lett. 2005, 46, 7235–7238.

(413.35): calcd. C 66.83, H 6.10; found C 66.88, H 5.92. [α]²_D⁰

=

–41.2 (c = 1.03, CHCl₃) at 99 % ee; HPLC Chiralcel OD-H

(4.6ϫ250 mm), λ = 200 nm, iPrOH: n-hexane = 1:50, 1.0 mL/min,

11.28 min (ent-41a), 12.85 min (41a).

(1RS,3RS,3aSR,7RS,7aRS)-7-Isopropyl-3-(2-methylprop-2-enyl)-1-

phenyl-hexahydroisobenzofuran-4(1H)-one (rac-41b): According to

GP D rac-31a (93 mg, 0.25 mmol), 3-methyl-3-butenal diethyl ace-

tal^[29](39b, 52 mg, 0.33 mmol, 1.3 equiv.) and BF₃·OEt₂(46 mg,

0.33 mmol, 1.3 equiv.) were stirred for 1 h. FCC (Et₂O/PE = 1:4)

yielded 55 mg (0.18 mmol, 70%) rac-41b as a colourless liquid. t_R

=

17.18 min (HP-5). R_F= 0.32 (Et₂O/PE = 1:2). ¹H NMR (400 MHz,

3

CDCl₃): δ = 0.73, 0.91 (2 d, J_{7-iPr(Me),7-iPrCH}= 6.8 Hz, 6 H, 7-iPr

(CH₃)₂), 1.54 (m, 1 H, 7-H), 1.66 (m, 1 H, 6-H_A), 1.74 (m, 1 H, 7-

[5] J. Becker, R. Fröhlich, K. Salorinne, D. Hoppe, Eur. J. Org.

Chem. 2007, 3337–3348, preceding article.

[6] J. Becker, S. Grimme, R. Fröhlich, D. Hoppe, Angew. Chem.

2007, 119, 1672–1676; Angew. Chem. Int. Ed. 2007, 46, 1645–

1649.

iPr CH), 1.82 (s, 3 H, 2Ј-CH₃), 1.93 (m, 1 H, 6-H_B), 2.34–2.41 (m,

3

2 H, 1Ј-H), 2.43–2.49 (m, 2 H, 5-H), 2.51 (dt, J_1,7a

= =

³J_7,7a

6.4 Hz, ³J_3a,7a= 8.7 Hz, 1 H, 7a-H), 2.71 (dd, ³J_3,3a= 7.4 Hz, ³J_3a,7a

= 8.7 Hz, 1 H, 3a-H), 4.57 (dt, J_1ЈA,3= J_3,3a= 7.4 Hz, J_1ЈB,3

3

=

3

5.2 Hz, 1 H, 3-H), 4.65 (d, J_1,7a= 6.4 Hz, 1 H, 1-H), 4.84 (s, 3 H,

3Ј-H), 7.24–7.34 (m, 5 H, o/m/p-PhCH) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 16.6, 21.5 (CH₃, 7-iPr (CH₃)₂), 22.9 (CH₃, 2Ј-CH₃),

23.0 (CH₂, C-6), 28.2 (CH, 7-iPr CH), 38.4 (CH₂, C-5), 41.5 (CH,

C-7), 43.5 (CH₂, C-1Ј), 51.8 (CH, C-7a), 55.8 (CH, C-3a), 77.7

(CH, C-3), 85.6 (CH, C-1), 112.7 (CH₂, C-3Ј), 126.2, 127.7, 128.4

(CH, o/m/p-Ph), 141.7 (C_q, i-C-Ph), 142.7 (C_q, C-2Ј), 210.6 (C_q,

[7] For reviews, see: a) D. Hoppe, T. Hense, Angew. Chem. 1997,

109, 2376–2410; Angew. Chem. Int. Ed. Engl. 1997, 36, 2282–

2316; b) H. Ahlbrecht, U. Beyer, Synthesis 1999, 365–390; c)

D. Hoppe, F. Marr, M. Brüggemann, Organolithiums in Enan-

tioselective Synthesis in Top. Organomet. Chem. (Ed.: D. M.

Hodgson), Springer, Berlin, 2003, vol. 5, pp. 61–138; d) P.

Beak, T. A. Johnson, D. D. Kim, S. H. Lim, Organolithiums in

Enantioselective Synthesis in Top. Organomet. Chem. (Ed.:

D. M. Hodgson), Springer, Berlin, 2003, vol. 5, pp. 139–176; e)

D. Hoppe, G. Christoph in The Chemistry of Organolithium

Compounds (Eds.: Z. Rappoport, I. Marek), Wiley, Chichester,

2004, vol. 2, pp. 1055–1164.

C=O) ppm. IR (ATR): ν = 3071 (w), 3032 (w) [ν(C_arom–H)], 2960

˜

(s), 2877 (m) [ν(C_aliph–H)], 1708 (s) [ν(C=O)] cm^–1. MS (ESI): m/z

= 335.1985 [M + Na]⁺. C₂₁H₂₈O₂(312.45): calcd. C 80.73, H 9.03;

found C 80.51, H 9.18.

[8] a) D. Hoppe, T. Krämer, C. Freire Erdbrügger, E. Egert, Tetra-

hedron Lett. 1989, 30, 1233–1236; b) S. Ünaldi, M. Özlügedik,

R. Fröhlich, D. Hoppe, Adv. Synth. Catal. 2005, 347, 1621–

1626.

(1RS,3RS,3aSR,7RS,7aRS)-1-Isopropenyl-7-isopropyl-3-(2-meth-

ylprop-2-enyl)-hexahydroisobenzofuran-4(1H)-one (rac-41c): Ac-

cording to GP D rac-31b (193 mg, 0.52 mmol), 39b^[29](106 mg,

0.67 mmol, 1.3 equiv.) and BF₃·OEt₂(81 mg, 0.57 mmol, [9] D. Hoppe, R. Hanko, A. Brönneke, F. Lichtenberg, E.

van Hülsen, Chem. Ber. 1985, 118, 2822–2851.

1.1 equiv.) were stirred for 35 min at 0 °C. FCC (Et₂O/PE = 1:9)

yielded 97 mg (0.35 mmol, 68%) rac-41c as a colourless, volatile

[10] P. van Eikeren, L. Garver, J. Org. Chem. 1976, 41, 2773–2774.

[11] Synthesis of enantiomerically pure (R)-(–)-crypton: a) J. Evarts,

E. Torres, P. L. Fuchs, J. Am. Chem. Soc. 2002, 124, 11093–

11101; rac-crypton (Ͻ5% ee) from nopinon and reduction: b)

J. M. Coxon, G. J. Hydes, P. J. Steel, Tetrahedron 1985, 41,

5213–5217; c) H. C. Brown, S. A. Weissman, P. T. Perumal,

U. P. Dhokte, J. Org. Chem. 1990, 55, 1217–1223.

liquid. t_R= 12.42 min (HP-5). R_F= 0.22 (Et₂O/PE = 1:2). ¹H

3

NMR (400 MHz, CDCl₃): δ = 0.84, 1.00 (2 d, J_{7-iPr(Me),7-iPrCH}

=

6.8 Hz, 6 H, 7-iPr (CH₃)₂), 1.49 (m, 1 H, 7-H), 1.61 (m, 1 H, 6-

H_A), 1.71 (s, 1 H, 1-C(CH₂)(CH₃)), 1.82 (s, 3 H, 2Ј-CH₃), 1.85–

1.94 (m, 2 H, 6-H_B, 7-iPr CH), 2.25–2.48 (m, 5 H, 1Ј-H, 5-H, 7a-

3

H), 2.60 (dd, J_3,3a= 7.4 Hz, J_3a,7a= 8.5 Hz, 1 H, 3a-H), 4.12 (d,

³J_1,7a= 5.9 Hz, 1 H, 1-H), 4.43 (dt, ³J_1ЈA,3= ³J_3,3a= 7.4 Hz, ³J_1ЈB,3

= 5.3 Hz, 1 H, 3-H), 4.78, 4.80 (2 m, 1 H, 3Ј-H), 4.88, 5.00 (2 m,

1 H, 1-C(CH₂)(CH₃)) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 16.6,

21.7 (CH₃, 7-iPr (CH₃)₂), 17.4 (CH₃, 1-C(CH₂)(CH₃)), 22.9 (CH₃,

2Ј-CH₃), 23.0 (CH₂, C-6), 28.0 (CH, 7-iPr CH), 38.5 (CH₂, C-5),

41.9 (CH, C-7), 43.3 (CH₂, C-1Ј), 46.9 (CH, C-7a), 56.1 (CH, C-

3a), 77.5 (CH, C-3), 87.5 (CH, C-1), 112.5 (CH₂, 1-C(CH₂)(CH₃)),

113.0 (CH₂, C-3Ј), 142.6 (C_q, 1-C(CH₂)(CH₃)), 144.3 (C_q, C-2Ј),

[12] Data sets were collected with an Enraf–Nonius CAD4 and a

Nonius KappaCCD diffractometers. Programs used: data col-

lection EXPRESS (Nonius B. V., 1994) and COLLECT (Non-

ius B. V., 1998), data reduction MolEN (K. Fair, Enraf–Nonius

B. V., 1990) and Denzo-SMN (Z. Otwinowski, W. Minor,

Methods in Enzymology, 1997, 276, 307–326), absorption cor-

rection Denzo (Z. Otwinowski, D. Borek, W. Majewski, W.

Minor, Acta Crystallogr. Ser. A 2003, 59, 228–234), structure

solution SHELXS-97 (G. M. Sheldrick, Acta Crystallogr. Ser.

A 1990, 46, 467–473), structure refinement SHELXL-97 (G. M.

Sheldrick, University of Göttingen, 1997), graphics

SCHAKAL (E. Keller, University of Freiburg, 1997). CCDC-

210.7 (C , C=O) ppm. IR (ATR): ν = 2958 (s), 2920 (s), 2874 (m),

˜

q

2852 (m) [ν(C_aliph–H)], 1708 (s) [ν(C=O)] cm^–1. MS (ESI): m/z =

Eur. J. Org. Chem. 2007, 3349–3364

www.eurjoc.org

3363

J. Becker, R. Fröhlich, O. Kataeva, D. Hoppe

FULL PAPER

639288 to -639292 contain 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.

tions collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å^–1, 3647 inde-

pendent (R_int

= 0.041) and 3346 observed reflections

[IՆ2σ(I)], 251 refined parameters, R = 0.049, wR₂= 0.133,

Flack parameter 0.5(3), max. residual electron density 0.12

(–0.15) eÅ^–3, hydrogen atoms calculated and refined as riding

atoms.

[13]

X-ray crystal structure analysis for 11b: formula C₃₀H₃₉NO₃,

M = 461.62, colorless crystal 0.45ϫ0.20ϫ0.20 mm, a =

7.728(1), b = 10.606(1), c = 32.505(4) Å, V = 2664.2(5) Å³, ρ_calc

= 1.151 gcm^–3, µ = 0.572 mm^–1, empirical absorption correc-

tion (0.783ՅTՅ0.894), Z = 4, orthorhombic, space group

P2₁2₁2₁(No. 19), λ = 1.54178 Å, T = 223 K, ω/2θ scans, 3121

reflections collected (–h, –k, –l), [(sinθ)/λ] = 0.62 Å^–1, 3121 in-

dependent and 2227 observed reflections [IՆ2σ(I)], 315 re-

fined parameters, R = 0.048, wR₂= 0.145, Flack parameter

0.1(5), max. residual electron density 0.21 (–0.20) eÅ^–3, hydro-

gen atoms calculated and refined as riding atoms.

[25] U. Chiacchio, A. Corsaro, G. Gumina, A. Rescifina, D. Ian-

nazzo, A. Piperno, G. Romeo, R. Romeo, J. Org. Chem. 1999,

64, 9321–9327.

[26] X-ray crystal structure analysis for 38a: formula C₂₈H₂₈O₂, M

= 396.50, colorless crystal 0.55ϫ0.15ϫ0.06 mm, a = 8.811(1),

b

= 12.110(1), c = 11.188(1) Å, β = 110.23(1)°, V =

1120.1(2) Å³, ρ_calc= 1.176 gcm^–3, µ = 0.561 mm^–1, empirical

absorption correction (0.748ՅTՅ0.967), Z = 2, monoclinic,

space group P2₁(No. 4), λ = 1.54178 Å, T = 223 K, ω and

φ scans, 11166 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] =

0.58 Å^–1, 2749 independent (R_int= 0.051) and 2409 observed

reflections [IՆ2σ(I)], 273 refined parameters, R = 0.041, wR₂

= 0.110, Flack parameter –0.2(4), max. residual electron den-

sity 0.10 (–0.11) eÅ^–3, hydrogen atoms calculated and refined

as riding atoms.

[14]

[15]

P. Razon, S. Dhulut, S. Bezzenine-Lafollée, J. Courtieu, A.

Pancrazi, J. Ardisson, Synthesis 2005, 102–108; P. Razon, M.-

A. N’Zoutani, S. Dhulut, S. Bezzenine-Lafollée, A. Pancrazi,

J. Ardisson, Synthesis 2005, 109–121.

a) B. Weidmann, D. Seebach, Angew. Chem. 1983, 95, 12–26;

Angew. Chem. Int. Ed. Engl. 1983, 22, 31–45; b) M. T. Reetz in

Organometallics in Synthesis (Ed.: M. Schlosser), Wiley-VCH,

Chichester, 2002, 2nd ed., pp. 817–923; c) J. Szymoniak, C.

Moïse in Titanium and Zirconium in Organic Synthesis, Wiley-

VCH, Weinheim 2002, pp. 451–474.

[27] X-ray crystal structure analysis for 41a: formula C₂₃H₂₅BrO₂,

M = 413.34, colorless crystal 0.45ϫ0.10ϫ0.10 mm, a =

11.838(1), b = 5.945(1), c = 14.515(1) Å, β = 98.72(1)°, V =

1009.7(2) Å³, ρ_calc= 1.360 gcm^–3, µ = 2.871 mm^–1, empirical

absorption correction (0.358ՅTՅ0.761), Z = 2, monoclinic,

space group P2₁(No. 4), λ = 1.54178 Å, T = 223 K, ω and φ

scans, 6521 reflections collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] =

0.60 Å^–1, 2642 independent (R_int= 0.036) and 2560 observed

reflections [IՆ2σ(I)], 237 refined parameters, R = 0.038, wR₂

= 0.101, Flack parameter 0.07(2), max. residual electron den-

sity 0.32 (–0.45) eÅ^–3, hydrogen atoms calculated and refined

as riding atoms.

[16]

[17]

[18]

H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79,

1920–1923.

S. Hikichi, Y. Gao, F. Sato, Tetrahedron Lett. 1997, 38, 2867–

2870.

a) Y. Yamamoto, S. Nishii, K. Maruyama, T. Komatsu, W. Ito,

J. Am. Chem. Soc. 1986, 108, 7778; b) Y. Gao, F. Sato, J. Org.

Chem. 1995, 60, 8136–8137.

[19] J. Szymoniak, H. Lefranc, J. Besancon, C. Moïse, Synthesis

1995, 815–819.

[28] The relative configuration of rac-41a, which crystallizes in a

different space group than 41a, was also determined by X-ray

crystal structure analysis: formula C₂₃H₂₅BrO₂, M = 413.34,

colorless crystal 0.35ϫ0.25ϫ0.10 mm, a = 38.648(1), b =

[20] A boat-like transition state in which the substituent R occupies

an equatorial position would lead to eclipsed interactions with

the γ-substituents of the allyl carbamate. The chair-like transi-

tion states TS-16 and TS-29 explain, why the yields of the

homoaldol reactions with sterically demanding alkanals in con-

trast to arylic aldehydes are better for 3 than for β-methyl-

substituted carbamate 2, where the 1,3-diaxial interactions are

much larger.

11.462(6),

c = 17.901(1) Å, V = =

7929.8(8) Å³, ρ_calc

1.385 gcm^–3, µ = 2.924 mm^–1, empirical absorption correction

(0.428ՅTՅ0.759), Z = 16, orthorhombic, space group Fdd2

(No. 43), λ = 1.54178 Å, T = 223 K, ω and φ scans, 8967 reflec-

tions collected (Ϯh, Ϯk, Ϯl), [(sinθ)/λ] = 0.60 Å^–1, 3251 inde-

pendent (R_int

= 0.033) and 3226 observed reflections

[21] A boat-like transition state was proposed for several titanium-

mediated aldol reactions with persubstituted enolates, see: a)

S. Yamago, D. Machii, E. Nakamura, J. Org. Chem. 1991, 56,

2098–2106; b) R. Duthaler, A. Hafner, Chem. Rev. 1992, 92,

807–832.

[IՆ2σ(I)], 238 refined parameters, R = 0.028, wR₂= 0.075,

Flack parameter 0.00(7), max. residual electron density 0.44

(–0.25) eÅ^–3, hydrogen atoms calculated and refined as riding

atoms.

[29] J. W. Conforth, M. E. Firth, J. Chem. Soc. 1958, 1091–1099.

[30] Besides the pure diastereomers, fractions of diastereomeric

mixtures where obtained, which were separated by repeated

chromatography.

[31] The diastereomeric ratio was determined from the crude prod-

ucts by GC (HP-5).

[32] The concentration of the carbamate solution is critical for good

yields. 1.3 equiv. sBuLi can be used in small scale reactions

(0.25 mmol), at scales ofՆ1.0 mmol 1.0 to 1.05 equiv. of care-

fully titrated sBuLi and rac-26 are recommended for optimum

yields.

[22] J. Becker, Diploma Thesis, University of Münster, 2005.

[23] For the reversal of anti to syn diastereoselectivity in a) crotyltit-

anium or b) tiglyltitanocene reactions, see: a) J. Szymoniak, N.

Thery, C. Moïse, Synlett 1997, 1239–1240; b) J. Szymoniak, N.

Thery, C. Moïse, Bull. Soc. Chim. Fr. 1997, 134, 85–91.

[24] X-ray crystal structure analysis for rac-31a: formula

C₂₃H₃₅NO₃,

M

=

373.52,

colorless

crystal

0.50ϫ0.25ϫ0.05 mm, a = 11.395(1), b = 18.803(6), c =

10.359(1) Å, V = 2219.5(3) Å³, ρ_calc= 1.118 gcm^–3, µ =

0.572 mm^–1,

empirical

absorption

correction

(0.763ՅTՅ0.972), Z = 4, orthorhombic, space group P2₁2₁2₁

(No. 19), λ = 1.54178 Å, T = 223 K, ω and φ scans, 9789 reflec-

Received: March 12, 2007

Published Online: May 10, 2007

3364

www.eurjoc.org

Eur. J. Org. Chem. 2007, 3349–3364

Article Doi

Stereoselective synthesis of hexahydroisobenzofuran-4(1H)-ones from chiral substituted cyclohex-2-enyl carbamates via asymmetric homoaldol reaction and THF cyclocondensation

DOI: 10.1002/ejoc.200700220

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.200700220

Full text of DOI:10.1002/ejoc.200700220

Products guided by the article

R&D Labs maybe for 950178-21-9

Relevant to this article

Hot Product