Enantioselective synthesis of functionalised decalones by robinson annulation of substituted cyclohexanones, derived from R-(-)-carvone

TETRAHEDRON

Pergamon

Tetrahedron 56 (2000) 2075±2094

Enantioselective Synthesis of Functionalised Decalones by

Robinson Annulation of Substituted Cyclohexanones, Derived

from R-(2)-Carvone

Ben J. M. Jansen,^aCindy C. J. Hendrikx,^aNikolai Masalov,^bGerrit A. Stork,^a

Tommi M. Meulemans,^aFliur Z. Macaev^cand Aede de Groot^a,

*

^aLaboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, Netherlands

^bDepartment of Organic and Polymer Chemistry, Belarussian State University, F. Skoriny av. 4, Minsk, 220050, Belarus

^cInstitute of Chemistry, Moldavian Academy of Sciences, str. Academiei 3, MD-2028, Kishinev, Republic of Moldova

Received 23 November 1999; revised 19 January 2000; accepted 3 February 2000

AbstractÐThe copper catalysed conjugate addition of methyl magnesium iodide to cyclohexenones and trapping of the enolate as its

trimethylsilyl enol ether, followed by a trityl hexachloroantimonate (TrSbCl₆) catalysed Mukaiyama-reaction, was applied to R-(2)-carvone.

This proved to be an ef®cient method for the preparation of C-2, C-3 functionalised chiral cyclohexanones. These compounds were converted

into their a-cyano ketones, which were submitted to Robinson annulation reactions with methyl vinyl ketone. The scope and limitations of

these annulations were investigated. A series of highly functionalised chiral decalones were obtained that can be used as starting compounds

Introduction

as their silyl enol ethers. A Lewis acid catalysed Mukaiyama

reaction then allows the introduction of a second sub-

stituent. When these two reactions are applied to one of

the enantiomers of carvone, highly functionalised chiral

The copper catalysed conjugate addition of methyl mag-

nesium iodide to enones leads to enolates that can be captured

Scheme 1.

Keywords: carvone; Mukaiyama reaction; a-cyano ketones; Robinson annulation.

* Corresponding author. Tel.: 131-317-482370; fax: 131-317-484914; e-mail: aede.degroot@bio.oc.wag-ur.nl

PII: S0040-4020(00)00110-1

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Figure 1. a, RH; b, RCHO; c, RCN.

cyclohexanones are obtained that are excellent starting

compounds for the total synthesis of enantiomerically pure

natural products.^1,2Carvone is especially useful in such total

syntheses because the isopropenyl group ®rst determines the

stereochemistry of the cuprate conjugate addition and of the

Mukaiyama reaction, and later on it can be transformed into

an additional functional group at C-5, such as a hydroxyl

group,³an acetate,³a double bond,⁴or a carbonyl group.⁵

To achieve these goals, carvone (1a) and its substituted

derivatives 10a±16a were prepared, converted into their

6-formyl and 6-cyano derivatives (see Fig. 1), and submitted

to Robinson annulation reactions with methyl vinyl

ketone (MVK). The choice of compounds 10±16 with the

formyl or cyano group at C-6 was done for the following

reasons.

² (i) Compounds 1 and 10±14 show an increase in steric

hindrance so that the in¯uence of this factor on the annu-

lation reaction with MVK (addition and ring closure) can

be studied.

² (ii) Compounds 11 have the geminal methyl groups at

C-2 that are present in many terpenoid natural products.

² (iii) Compounds 13 and 14 can provide for ¯exible inter-

mediates in the synthesis of clerodanes.

² (iv) The reaction of compounds 1 and 10±14 will reveal

the in¯uence of the isopropenyl group on the stereo-

chemistry of the annulation.

² (v) Compounds 15 and 16 will be studied to investigate

the in¯uence of the substituents at C-2 on the stereo-

chemistry of the annulation reaction. Also in these

cases suitable intermediates for the synthesis of clero-

danes will be obtained.

² (vi) The formyl group was chosen as a substituent at C-6

because a formyl group is present in many ring A bridged

clerodanes; at the same time it is an intermediate in the

synthesis of the corresponding cyano compounds.

² (vii) The cyano group was chosen because it can be

converted into a formyl group. Also, this group is

known to activate the a hydrogen atoms so that an easy

addition of the enolate to MVK may be expected, and it

activates the carbonyl group for the subsequent ring

closure reaction.⁸Both effects are effectuated with the

least possible additional steric hindrance. For these

reasons the cyano group has to be preferred over the

ester group in this type of reaction and therefore the

ester substituent was not included in these investigations.

Several examples of the copper catalysed conjugate addition

of methyl magnesium iodide to carvone, followed by

trapping of the enolate as its trimethylsilyl enol ether,

followed by the introduction of a functionalised sidechain

via a Mukaiyama reaction have been investigated, and the

results of this research have been reported (step 1, Scheme

1).⁶This sequence of reactions leads to highly func-

tionalised chiral cyclohexanones, which have been and

can be used for the enantioselective total synthesis of

clerodanes starting from carvone.

The next step in such a total synthesis is the introduction of

an oxidised functional group at C-6 and the annulation of

ring A (steps 2 and 3, Scheme 1). The Robinson annulation

seemes particularly suitable to construct the decalin moiety

in the synthesis of ring A bridged clerodanes like 5 and 9,

because it will provide for a carbonyl group at C-2, which

after reduction could form one end of this bridge. For the

construction of the other end of the bridge, a suitable func-

tional group must be introduced at C-6 in the intermediate

cyclohexanones 2 or 6, which should end up as the func-

tionalised substituent at C-5 in the clerodane as is indicated

in the compounds 4 and 8 (Scheme 1). It would be nice if

this functional group would facilitate the annulation

reaction as well and a formyl group, an ester group or a

cyano group should be considered to achieve that goal. In

this way an enantioselective synthesis of this special type of

ring A bridged clerodanes, which show a high activity as

antifeedant,⁷may become feasible.

Therefore Robinson annulations of highly substituted

carvone derived cyclohexanones were to give the annulated

compounds in good yield and with the correct stereo-

chemistry for the synthesis of clerodanes. A second goal

is to gather more information about the scope, the limi-

tations, and the stereochemistry of the Robinson annulation

in heavily substituted cyclohexanones. A third goal is to

extend and to demonstrate the reaction possibilities of

carvone as a chiral starting material in the synthesis of

natural products.

Results and Discussion

Compounds 1b,c, 10a±c, 11a±c and 12a±c were prepared

according to standard procedures. Compounds 13a±c, and

14a±c also could be obtained easily using standard con-

ditions for the conjugate addition, followed by a Mukaiyama

reaction for the introduction of the dioxolanyl group or the

furofuranyl sidechain.⁹Formylation of these compounds

generally proceeded in good yield and the conversion of

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2077

Scheme 2. (a) i, MeMgI, CuBr´Me₂S, TMSiCl, ii, Et₃N. (b) i, TrSbCl₆, 2788C, CH₂Cl₂, alkylating agent; ii, aqueous NaHCO₃. (c) NaH, HCOOEt. (d) H₂NOH,

CH₃COONa. (e) NaOCH₃, CH₃OH. (f) i, O₃, CH₂Cl₂, MeOH; ii, Cu(OAc)₂, FeSO₄. (g) Pd/H₂.

the formyl compounds into the cyano compounds could be

achieved via basic decomposition of the intermediate isoxa-

zoles (see Scheme 2). In general the products were obtained

in good yield as described in the general procedure in the

experimental part.

The formylation of carvone followed by Michael addition to

methyl vinyl ketone proceeded without dif®culties and in

good yield. Further cyclisation of the adduct 17 went

together with deformylation to give the bicyclic skeleton

18 in 40±78% yield.^11,12However in the more hindered

compound 10b an alternative reaction possibility already

appeared. In this case the formylation of 10 to 10b and its

base catalysed addition to MVK to give 19 proceeded

normally, but in the base catalysed cyclisation reaction

only a small amount of the `normal' cyclisation product

20 was obtained together with products that resulted

from retro Michael and deformylation reactions. Under

Knoevenagel conditions a condensation with the less

hindered aldehyde group was preferred, and the spiro

compounds 21 and 22 were obtained as the main reaction

product in a 2:7 ratio (Scheme 3). This behaviour has been

observed regularly in steric congested situations^13,14and

must be considered as the preferred behaviour in these

cases (vide infra). For these reasons the cyclisation reactions

of the even more hindered formyl compounds 11b±16b

were not investigated further.

For the introduction of the furofuranyl sidechain, racemic

2-methoxy-hexahydro-furo[2,3-b]furan was used, so in

principle eight stereoisomers can be formed. In practice

only two were obtained in a 1:1 mixture, which can be

explained by an approach of the convex side of the hexa-

hydro-furo[2,3-b]furanyl cation to that side of the silyl enol

ether which is cis to the isopropenyl group and trans to the

C-3 methyl group.⁹Compound 14a can be separated from

its diastereoisomer by crystallisation from diisopropyl ether,

and the structure of 14a was determined by X-ray crys-

tallography.¹⁰The isopropenyl group was removed by

ozonolysis of 13a and 14a followed by oxidation of the

intermediate methoxy hydroperoxide by addition of

4

Cu(OAc)₂and FeSO₄(see Scheme 2). In this way the

enones were obtained, which could be reduced catalytically

to the saturated ketones 15a and 16a. The formyl

compounds 15b and 16b and the cyano ketones 15c and

16c were prepared as mentioned above.

Instead it was decided to investigate the annulation reac-

tions of the cyano ketones 1c and 10c±16c. The cyano

Scheme 3. (a) NaH, HCOOEt. (b) KOH, Et₃N, MVK, EtOAc. (c) KOH, MeOH, H₂O. (d) MeMgI, CuBr´Me₂S. (e) Pyrrolidine, AcOH, pH7, THF.

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Table 1. The entries 1, 3 and 5 have also been investigated for S-(1)-carvone (see Experimental). The Methods A±C and 1±6 are also described in the

Experimental section

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2079

group is a good activator for Michael additions and after that

it activates the carbonyl group for condensation in the cycli-

sation reaction. At the same time its own reactivity towards

condensation is less than that of an aldehyde so that a

`normal' cyclisation to the decalin system may be expected

as the main reaction. The results of these experiments are

summarised in Table 1.

which made these compounds unsuitable as intermediates

for the total synthesis of clerodanes. This stereochemical

result was not unexpected and these reactions were carried

out in the ®rst place to establish the scope of the annulation

sequence.

Nevertheless, one of the main goals of our research is the

synthesis of ring A bridged clerodanes and therefore the

annulation of the cyano ketones 15c and 16c was investi-

gated also. In these compounds it was expected that

the group R¹at C-9 should be the determining factor for

the stereochemistry at C-5. This large group should

occupy the equatorial position in the starting cyano enolates

so that the axial methyl group at C-9 should disfavour an

approach of MVK from the a side. The 1,3 diaxial position

of the methyl and cyano groups in the addition products 36

and 37 should not cause serious steric interaction, and the

subsequent ring closure reaction also was expected to

proceed via less hindered intermediates to the desired

dehydrated products 40 and 41.

The cyano ketones can be roughly divided into two groups:

compounds 1c, 10c, and 11c, which react properly with

MVK under basic conditions to give the annulated

compounds in good yield, and compounds 12c±16c,

which react with dif®culty with MVK to cyclised products

using basic reaction conditions.

Some peculiar features were noticed in the reaction of 10c

with MVK; on TLC and GLC it was shown that the starting

mixture of stereoisomers was converted into several stereo-

isomeric intermediates, but ultimately the reaction led to the

most stable enantiomerically pure annulated product 26

(Scheme 4).

In practice the outcome showed some modi®cations of these

expectations. In both keto nitriles 15c and 16c a mixture of

addition products 36, 38 and 37, 39 was obtained respec-

tively.¹⁵These mixtures of adducts could be separated in the

case of 36 and 38 and both isomers were subjected to

Knoevenagel ring closure conditions. The isomer 36 gave

a smooth reaction to what proved to be the dehydrated

cyclised enone 40. The other isomer 38 gave, after a much

longer reaction time, the same cyclised reaction product 40

together with a small amount of its epimer 42 as a byproduct

(Scheme 5).

Problems began to appear when the steric hindrance

increased to the level in compounds 12c±14c. Here the

Michael addition of MVK could still be realised using the

standard basic conditions, but the ring closure of 27, 28, and

29 under basic conditions (0.6 equiv. NaOMe in benzene)

did not occur, instead a retro Michael reaction took place to

give back the starting cyano ketones 12c±14c. However in

practically all cases the ring closure of 27, 28, and 29 could

be achieved using Knoevenagel conditions. Even in the

most sterically crowded addition products ring closure

under Knoevenagel conditions gave the cyclised enones

33,¹⁰34, and 35. In these reactions the intermediate hydroxy

ketones 30±32 were not observed or could not be isolated,

and the reaction proceeded smoothly to the enones. In the

cyclisation of 28 and 29 the retro Michael reaction still

proved to be a major side reaction, as under the more neutral

Knoevenagel conditions.

The mixture of 37 and 39 could not be separated and the

mixture was submitted to Knoevenagel cyclisation con-

ditions to give the enone 41 as the only isolated product.

The outcome of these two cyclisation reactions con®rmed

that under Knoevenagel conditions retro Michael reactions

and re-additions can take place. Additional con®rmation for

this behaviour was obtained from an experiment in which an

excess of ethyl vinyl ketone was added to the cyclisation

reaction of compound 38 under Knoevenagel conditions.

Together with the cyclised compounds 40 and 42, a small

amount of 43, the ethyl vinyl ketone adduct of 15c, could be

isolated.

In all these cases the stereochemistry of the Michael

addition was determined by the isopropenyl group, directing

the incoming MVK to the trans position. This means that in

these addition products and in the cyclised products the

cyano group and the substituent R¹were in a cis position,

Scheme 4. (a) 0.2 equiv. NaOCH₃, MVK, C₆H₆. (b) 0.6 equiv. NaOCH₃, C₆H₆.

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Scheme 5. (a) NaOCH₃, MVK, C₆H₆. (b) Pyrrolidine, CH₃COOH, MVK, C₆H₅CH₃.

For this reason also the addition±cyclisation±dehydra-

tion reaction of the cyano ketones with MVK under

Knoevenagel conditions, which should lead to the

desired most stable enones in a one-pot reaction, was

tried out with the cyano ketones 10c, 12c and 13c. It

proved to be possible to obtain the enones 26, 33 and

34 with the indicated stereochemistry, which was proven

by X-ray diffraction for 33. However, the reactions were

slow and in practice the two step procedure via base

catalysed Michael addition followed by cyclisation of

the adducts under Knoevenagel conditions proved to be

preferrable.

An explanation of these results can be found by application

of the considerations of Nussbaumer¹⁶who states that cycli-

sation of the Michael adducts should take place via one of

Figure 2.

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2081

the three types of chair-like transition states A, B and C of

the intermediate enolates that are depicted in Fig. 2.

be observed, although in that case a small amount of the

cyclised diastereoisomer 42 is also obtained (Scheme 5).

The trans equatorial pathway A leads to the thermodynamic

and more stable trans decalin. This is normally the preferred

pathway when there is no, or just a small, substituent at the

angular position (C-5). Steric hindrance between an axial

substituent at C-8 will cause the strongest interaction in the

transition state that is depicted as path B, and this interaction

usually will prevent ring closure along path B. The axial

position of a large substituent at C-9 together with the axial

position of the enolate sidechain is an unlikely conformation

and will prevent cyclisation following path C. When all

three transition states will have unfavourable steric inter-

actions or when unlikely conformations are necessary,

then ring closure does not take place and the retro Michael

reaction prevails.

The conclusion that can be drawn from these experiments is

that Robinson annulations under basic conditions suffer

from steric hindrance that favour a cyclisation to spiro

compounds in the formyl ketones and lead to retro Michael

reactions in steric congested cyano ketones. The Robinson

annulation of a-cyano ketones gives good results, also in

steric congested situations, using base catalysed Michael

addition followed by a separate cyclisation reaction under

Knoevenagel conditions.

The stereochemistry of the annulation of 6-cyano-5-iso-

propenyl cyclohexanones occurs trans with respect to the

isopropenyl group, which results in a cis position of the

nitrile group and the major substituent at C-2. The stereo-

chemistry of the annulation of 6-cyano-2-methyl-2-substi-

tuted cyclohexanones occurs mainly cis with respect to the

substituent at C-2, which results in a trans position of the

nitrile group and the major substituent at C-2. The equilibria

that play a role under Knoevenagel annulation conditions

ultimately lead to good yields of annulated products with a

trans position of the nitrile group and the major substituent

at C-2, which can be good chiral intermediates in the

synthesis of ring A bridged clerodanes.

These considerations can also explain the results that are

described in Scheme 3 for the cyclisation of compound

19, which is depicted in the upper row of Fig. 2. The steric

interaction between the aldehyde group and the enolate

prevents cyclisation along path A, the steric hindrance

between the axial methyl group at C-8 and the enolate

prevents cyclisation along path B, and the axial positions

of the isopropenyl group and the enolate that are necessary

for cyclisation along path C, prevent that route. It is clear

that cyclisation with the aldehyde group is an attractive

alternative for cyclisation in compound 19 and this is

what was observed.

Experimental

General information and instrumentation

In the cyano ketones this alternative cyclisation route is not

available and in the less hindered cyano ketones 1c, 10c and

11c a smooth base catalysed Robinson annulation to the

decalins 23, 24, and 26 takes place in good yield (Scheme

4). When the steric crowding increases as in the cyano

ketones 12c±14c, cyclisation under basic conditions does

not take place and the retro Michael reaction is observed

as the only reaction. Nevertheless annulation can be

achieved in a two-step sequence in which the Michael

addition is performed under basic conditions at room

temperature and the cyclisation is carried out in a separate

reaction under Knoevenagel conditions at higher tempera-

ture. These more neutral Knoevenagel conditions do not

favour the retro Michael reaction and the higher temperature

allows to overcome the steric interactions for cyclisation,

although in the sterically most crowded compounds the retro

Michael reaction is still observed as a major side reaction.

All reagents and solvents were used as received from

commercial sources except toluene (dried by distillation

from sodium and stored on sodium wire) and ether (distilled

from sodium benzophenone ketyl and stored on sodium

wire). GC analyses were performed with a Fisons GC

8000 apparatus provided with a 30 m DB-17 fused capillary

column (internal diameter 0.25 mm, ®lm thickness

0.25 mm) and a ¯ame ionisation detector. Hydrogen was

used as the carrier gas. Thin layer chromatography (TLC)

was performed on precoated PET foil-backed plates (Fluka

silica gel with ¯uorescent indicator 254 nm) and visualised

by spraying with ceric molybdate or anisaldehyde or basic

potassium permanganate stains. Column chromatography

refers to ¯ash chromatography performed on Fluka silica

gel 60 with particle size 0.04±0.063 mm and eluents were

routinely distilled prior to use. Light petroleum refers to the

fraction with bp 40±608C. Melting points were determined

on a C. Reichert, Vienna, hot stage apparatus and are not

corrected. Optical rotations were recorded on a Perkin±

Elmer 241 polarimeter for chloroform solutions and concen-

trations are speci®ed in g/100 mL. ¹H and ¹³C NMR spectra

were, unless otherwise stated, recorded at 200 MHz and

50 MHz on a Bruker AC-E 200 spectrometer, respectively,

using CDCl₃as solvent. The chemical shift values are

expressed in ppm (parts per million) relative to the residual

CHCl₃at 7.24 (¹H) and 77.00 (¹³C) as internal standard. The

In the Michael additions of the less crowded cyano ketones

15c and 16c, the isopropenyl group no longer determines the

stereochemical course of the addition of MVK, and in both

reactions mixtures of adducts are obtained. In Fig. 2 the

transition states for the cyclisation of the two diastereomeric

adducts 37 and 39 are depicted and it is clear that in isomer

37 a smooth cyclisation can take place via the relatively

unhindered transition states 37A or 37B to give decalin

40. In isomer 39 an easy cyclisation is not possible since

in all transition states 39A, 39B and 39C unfavourable

steric interactions will operate. Instead a retro Michael

reaction takes place, followed by re-addition to 37 and

cyclisation to 40. In the corresponding dioxolanyl substi-

tuted compounds 36 and 38 a similar reaction pattern can

1

multiplicity of the H signals are expressed as: ssinglet,

ddoublet, ttriplet, qquartet, br sbroad singlet,

mmultiplet. The multiplicity of the ¹³C signals were

determined with the DEPT technique, qquartet, ttriplet,

ddoublet, ssinglet. Infrared spectra were recorded on a

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B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

FT-IR, Biorad FTS 7 or on a Hitachi EPI-G3 spectrometer.

MS and HRMS data were obtained with a Finnigan MAT 95

spectrometer. The ratios m/z and relative intensities (%) are

indicated for signi®cant peaks. Elemental analyses were

performed on a Carlo Erba 1106 elemental analyser.

¹³C NMR d 15.4 (q), 19.6 (q), 29.1 (t), 41.8 (d), 109.7 (s),

113.7 (t), 134.6 (s), 141.2 (d), 145.6 (s), 169.2 (d), 189.3 (s);

IR n_max(liquid ®lm) 3419, 3077, 2929, 2888, 1644, 1627,

1570, 1377, 1208, 1050, 898 cm²¹; MS m/z 178 (M¹, 70),

163 (21), 135 (25), 109 (100), 91 (30), 41 (14), 39 (20);

HRMS: M¹, found 178.0991. C₁₁H₁₄O₂requires 178.0994.

General procedure for the preparation of the b keto

nitriles

(4S)-4-Isopropenyl-7-methyl-4,5-dihydrobenzo[d]isoxa-

zole. This compound was synthesised as its 4R stereoisomer

in 92% yield as a light yellow oil. [a]_D150.6 (c1.9); ¹H

NMR d 1.67 (s, 3H), 1.99 (br s, 3H), 2.29±2.52 (m, 2H),

3.49 (t, J9.5 Hz, 1H), 4.73 (s, 1H), 4.77 (s, 1H), 5.70 (br s,

1H), 7.95 (s, 1H); ¹³C NMR d 15.6 (q), 19.7 (q), 30.4 (t),

38.4 (d), 112.1 (t), 112.3 (s), 124.1 (s), 127.8 (d), 145.8 (s),

148.5 (d), 166.7 (s); IR n_max(liquid ®lm) 3078, 2972, 2941,

2919, 2876, 1718, 1646, 1473, 1437, 1376, 1345, 1249, 1201,

1066, 896 cm²¹; MS m/z 175 (M¹, 100), 160 (59), 146 (19),

134 (40), 133 (25), 105 (22), 91 (22), 79 (20), 77 (20);

HRMS: M¹, found 175.0995. C₁₁H₁₃NO requires 175.0997.

To a suspension of 900 mg (30 mmol) of a 80% suspension

of NaH in mineral oil in 100 mL of dry ether was simul-

taneously added 30 mmol of the relevant ketone and 4.44 g

(60 mmol) of ethyl formate at room temperature. After

stirring overnight the reaction mixture was washed with

three portions of 100 mL of an 1 M aqueous potassium

hydroxide solution. The combined aqueous layers were

acidi®ed and extracted with three 100 mL-portions of

ether. The ethereal extracts were washed with brine and

dried over MgSO₄. Evaporation under reduced pressure

gave the corresponding crude hydroxymethylene ketone in

good yield and was used without further puri®cation in the

next reaction. An analytical sample was obtained by ¯ash

column chromatography on silica gel with light petroleum/

ethyl acetate 96/4 as eluent.

(1R,6R)-6-Isopropenyl-3-methyl-2-oxo-3-cyclohexene-

carbonitrile (1c). The synthesis of this nitrile was

performed without puri®cation of the intermediates in

64% overall yield. Crystallisation was performed from

hexane/tert-butyl methyl ether 4/1. Mp 81±838C;

1

[a]_D213.8 (c2.15); H NMR d 1.79 (s, 3H), 1.82 (s,

A solution of 25 mmol of the relevant hydroxymethylene

ketone in a mixture of 42 mL of chloroform and 18 mL of

ethanol was treated with 3.99 g (57 mmol) of NH₂OH´HCl

and 4.66 g (56 mmol) of anhydrous sodium acetate and

stirring was continued for two days. The reaction mixture

was diluted with 250 mL of ether and washed three times

with 25 mL of brine, and dried on MgSO₄. Evaporation of

the solvents sometimes gave the corresponding isoxazole,

which was used in the next reaction without puri®cation. An

analytical sample was obtained by ¯ash column chroma-

tography on silica gel with light petroleum/ethyl acetate

95/5 as eluent. Otherwise a mixture of several products

was obtained and not further analysed.

3H), 2.41±2.50 (m, 2H), 2.99 (ddd, J5.8, 9.8, 13.0 Hz,

1H), 3.58 (d, J13.0 Hz, 1H), 4.98 (d, J0.7 Hz, 1H),

5.03 (br s, 1H), 6.79 (ddd, J1.4, 3.0, 5.2 Hz, 1H); ¹³C

NMR d 16.0 (q), 19.0 (q), 30.8 (t), 45.1 (d), 46.9 (d),

115.3 (t), 115.8 (s), 134.4 (s), 142.4 (s), 144.8 (d), 189.1

(s); IR n_max(KBr) 3084, 2977, 2928, 2880, 2252, 1681,

1648, 1450, 1380, 1362, 1232, 1160, 1081, 911,

860 cm²¹; MS m/z 175 (M¹, 18), 147 (9), 135 (6), 132

(3), 83 (5), 82 (100), 77 (4), 54 (16), 53 (4), 39 (7);

HRMS: M¹, found 175.0996. C₁₁H₁₃NO requires

175.0997; Anal: found C, 75.26; H, 7.53; N, 7.88%.

C₁₁H₁₃NO requires C, 75.39; H, 7.47; N, 7.99%.

(5R)-6-Hydroxymethylene-5-isopropenyl-2-methyl-2-

cyclohexenone. This compound was obtained as a colour-

less oil as described starting with S-(1)-carvone in 97%

The residue was dissolved in 50 mL of ether and treated

with 50 mL of a 1 M solution of sodium methanolate in

methanol for 24 h. After concentration of the reaction

mixture under reduced pressure the residue was dissolved

in water and acidi®ed with 4 M aqueous HCl and extracted

with three 50 mL-portions of ether. The ethereal extracts

were washed with brine and dried over MgSO₄. Evaporation

of the solvents afforded the a-cyano ketones which were

puri®ed by crystallisation or by ¯ash column chroma-

tography on silica gel with ethyl acetate/light petroleum

30/70 as eluent.

1

yield. [a]_D17.6 (c6.6); H NMR d 1.68 (s, 3H), 1.84

(t, J1.6 Hz, 3H), 2.38±2.46 (m, 2H), 3.26 (t, J7.2 Hz,

1H), 4.78 (s, 1H), 4.84 (s, 1H), 6.48 (ddd, J1.4, 3.0,

4.4 Hz, 1H), 7.45 (br s, 1H), 14.50 (br s, 1H); ¹³C NMR d

15.4 (q), 19.6 (q), 29.1 (t), 41.8 (d), 109.7 (s), 113.7 (t),

134.6 (s), 141.2 (d), 145.6 (s), 169.2 (d), 189.3 (s); IR

n_max(liquid ®lm) 3077, 2973, 2924, 2730, 1658, 1626,

1570, 1208 cm²¹; MS m/z 178 (M¹, 71), 163 (22), 149

(9), 145 (8), 137 (14), 135 (25), 109 (100), 107 (17), 91

(31), 77 (15), 41 (14), 39 (18); HRMS: M¹, found

178.0992. C₁₁H₁₄O₂requires 178.0994.

(5R)-5-Isopropenyl-2-methyl-2-cyclohexenone [(2)-carvone]

(1a) and (5S)-5-isopropenyl-2-methyl-2-cyclohexenone

[(1)-carvone] were generous gifts from Quest Inter-

national, [a]_D259.5 (neat) and 155.7 (neat), respectively.

(4R)-4-Isopropenyl-7-methyl-4,5-dihydrobenzo[d]isoxa-

zole. This isoxazole was obtained in 92% yield as a light

1

coloured oil of limited stability. [a]_D253.5 (c1.3); H

(5S)-6-Hydroxymethylene-5-isopropenyl-2-methyl-2-cyclo-

hexenone (1b). This ketone was prepared as described

starting with R-(2)-carvone in 88% yield as a colourless

NMR d 1.70 (s, 3H), 2.02 (br s, 3H), 2.32±2.52 (m, 2H),

3.53 (t, J9.4 Hz, 1H), 4.76±4.81 (m, 1H), 5.71±5.77 (m,

1H), 7.98 (s, 1H); ¹³C NMR d 15.6 (q), 19.7 (q), 30.4 (t),

38.4 (d), 112.1 (t), 112.3 (s), 124.2 (s), 127.7 (d), 145.8 (s),

148.6 (d), 166.7 (s); IR n_max(liquid ®lm) 2985, 2980, 2940,

2873, 1725, 1642, 1590, 1472, 1433, 1378, 1344, 1220,

1

oil. [a]_D29.73 (c4.3); H NMR d 1.69 (s, 3H), 1.85

(s, 3H), 2.38±2.46 (m, 2H), 3.26 (t, J7.2 Hz, 1H), 4.77

(q, J0.8 Hz, 1H), 4.84 (q, J1.6 Hz, 1H), 6.49 (ddd,

J1.4, 3.0, 4.4 Hz, 1H), 7.45 (br s, 1H), 14.50 (br s, 1H);

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2083

1160, 1070, 980, 938, 905 cm²¹; MS m/z 175 (M¹, 100),

160 (55), 146 (22), 134 (43), 133 (26), 105 (22), 91 (22), 79

(19), 77 (20); HRMS: M¹, found 175.1005. C₁₁H₁₃NO

requires 175.0997.

179 (17), 153 (37), 152 (13), 151 (18), 120 (20), 110 (16), 55

(15), 43 (15), 41 (17); HRMS: M¹, found 194.1297.

C₁₂H₁₈O₂requires 194.1307.

(4S,6R,7S)-4-Isopropenyl-6,7-dimethyl-4,5,6,7-tetrahydro-

benzo[d]isoxazole. This compound was obtained in 88%

yield as a rather unstable oil and therefore used without

(1S,6S)-6-Isopropenyl-3-methyl-2-oxo-3-cyclohexene-

carbonitrile. The nitrile was synthesised in 75% yield from

S-(1)-carvone without puri®cation of the intermediates.

Crystallisation was performed from light petroleum/tert-

butyl methyl ether 5/1. Mp 80±80.58C; [a]_D18.5

1

puri®cation. H NMR d 1.02 (d, J6.8 Hz, 3H), 1.29 (d,

J7.0 Hz, 3H), 1.56±1.83 (m, 3H), 1.75 (br s, 3H), 2.46 (dq,

J12.8, 6.8 Hz, 1H), 3.22 (dd, J4.0, 5.4 Hz, 1H), 4.47 (br

s, 1H), 4.82 (br s, 1H), 7.99 (s, 1H); ¹³C NMR d 16.9 (q),

18.9 (q), 21.3 (q), 33.1 (d), 34.3 (t), 35.8 (d), 37.0 (d), 112.6

(t), 146.9 (s), 149.8 (d), 154.5 (s), 171.5 (s).

1

(c1.78); H NMR d 1.77 (s, 3H), 1.78 (br s, 3H), 2.38±

2.46 (m, 2H), 2.93 (ddd, J6.3, 9.5, 13.1 Hz, 1H), 3.56 (d,

J13.1 Hz, 1H), 4.92 (d, J0.8 Hz, 1H), 4.96 (q, J1.4 Hz,

1H), 6.77 (ddd, J1.4, 2.0, 5.0 Hz, 1H); ¹³C NMR d 15.7

(q), 18.7 (q), 30.5 (t), 44.8 (d), 46.7 (d), 114.8 (t), 115.6 (s),

133.9 (s), 142.2 (s), 144.9 (s), 188.9 (s); IR n_max(KBr) 3075,

3000, 2966, 2918, 2245, 1683, 1642, 1450, 1437, 1383,

1365, 1210, 1180, 1082, 997, 908, 860 cm²¹; MS m/z 175

(M¹, 35), 160 (8), 133(6), 132 (6), 117 (16), 92 (13), 82

(100), 77 (31), 54 (64), 53 (21), 52 (25), 51 (16), 39 (19);

HRMS: M¹, found 175.0998. C₁₁H₁₃NO requires 175.0997;

Anal: found C, 75.16; H, 7.53; N, 7.83%. C₁₁H₁₃NO

requires C, 75.39; H, 7.47; N, 7.99%.

(3^p,4R,6R)-6-Isopropenyl-3,4-dimethyl-2-oxo-cyclohex-

anecarbonitrile (10c). This b keto nitrile was synthesised

in the usual way but unfortunately it was isolated as an

inseparable 1:2 mixture of diastereoisomers and used as

such in the next reaction.

Major isomer: ¹H NMR (major peaks) d 1.05 (d, J6.4 Hz,

3H), 1.12 (d, J7.0 Hz, 3H), 1.70 (s, 3H), 3.08 (m, 1H),

3.81 (d, J5.8 Hz, 1H), 4.67 (s, 1H), 5.00 (s, 1H).

(3R,5R)-5-Isopropenyl-2,3-dimethylcyclohexanone (10a).

This ketone was synthesised from (R)-(2)-carvone as

described before²in 85% yield and obtained as a 3:2 dia-

stereoisomeric mixture according to GLC and NMR. An

analytical sample was obtained after column chroma-

tography on silica gel with light petroleum/ethyl acetate

9/1 as eluent.

Minor isomer: ¹H NMR (major peaks) d 0.99 (d, J4.0 Hz,

3H), 1.00 (d, J6.0 Hz, 3H), 1.70 (s, 3H), 2.87 (m, 1H),

3.66 (d, J7.2 Hz, 1H), 4.75 (s, 1H), 4.90 (br s, 1H); IR n_max

(liquid ®lm, diastereoisomeric mixture) 3087, 3075, 2972,

2935, 2880, 2250, 2206, 1722, 1650, 1647, 1452, 1377,

1197, 901 cm²¹; MS m/z 191 (M¹, 100), 176 (40), 135

(97), 134 (41), 97 (41), 95 (65), 70 (75), 69 (54), 55 (60),

41 (41); HRMS: M¹, found 191.1303. C₁₂H₁₇NO requires

191.1310; (M¹2CH₃), found 176.1070. C₁₁H₁₄NO requires

176.1075.

Major isomer: ¹H NMR d 0.79 (d, J7.2 Hz, 3H), 0.95 (d,

J6.8 Hz, 3H), 1.70 (s, 3H), 1.78±1.90 (m, 3H), 2.12±2.34

(m, 4H), 4.72 (br s, 1H), 4.73 (br s, 1H); ¹³C NMR d 11.7

(q), 13.7 (q), 20.3 (q), 36.0 (d), 37.5 (t), 40.8 (d), 46.4 (t),

48.1 (d), 109.5 (t), 147.4 (s), 212.6 (s); IR n_max(liquid ®lm)

(5R)-5-Isopropenyl-2,2-dimethylcyclohexanone

(11a).

Treatment of the benzylimine of (R)-(2)-carvone with a

catalytic amount of potassium tert-butoxide followed by

tert-butyllithium gave a metalloenamine, which on methy-

lation with methyl iodide afforded in 94% yield the above

mentioned ketone as a yellow oil.¹⁷[a]_D184.6 (c8.6)

[lit.¹⁸191.2 (CHCl₃, c11)]; ¹H NMR d 1.07 (s, 3H), 1.16

(s, 3H), 1.53±1.83 (m, 4H), 1.77 (s, 3H), 2.29±2.41 (m, 2H),

2.54 (dd, J13.1, 14.0 Hz, 1H), 4.73 (s, 1H), 4.77 (dd,

J1.4, 2.8 Hz, 1H); ¹³C NMR d 20.6 (q), 25.0 (q), 25.1

(q), 26.4 (t), 39.4 (t), 42.9 (t), 44.5 (s), 46.2 (d), 109.8 (d),

147.4 (s), 215.4 (s); IR n_max(liquid ®lm) 3060, 2988, 2962,

2930, 1702, 1637, 1452, 1380, 1149, 1101, 893 cm²¹; MS

m/z 166 (M¹, 40), 151 (5), 123 (14), 110 (29), 109 (25), 107

(20), 95 (63), 82 (31), 81 (37), 69 (66), 68 (34), 67 (100), 55

(37), 41 (90), 39 (33); HRMS: M¹, found 166.1363.

C₁₁H₁₈O requires 166.1358.

3083, 2962, 2924, 2871, 1710, 1447, 1379, 986, 902 cm²¹

;

MS m/z 166 (M¹, 75), 151 (8), 123 (28), 109 (31), 97 (45),

96 (25), 95 (88), 83 (46), 69 (100), 55 (22), 41 (45); HRMS:

M¹, found 166.1353. C₁₁H₁₈O requires 166.1358.

Minor isomer: ¹H NMR d 0.99 (d, J6.2 Hz, 3H), 1.04 (d,

J6.6 Hz, 3H), 1.78±1.90 (m, 3H), 2.12±2.34 (m, 4H), 4.70

(br s, 1H), 4.79 (br s, 1H); ¹³C NMR d 11.2 (q), 12.8 (q),

21.6 (q), 34.7 (d), 34.9 (t), 40.5 (d), 43.8 (t), 51.3 (d), 111.4

(t), 147.3 (s), 212.7 (s); IR n_max(liquid ®lm) 3077, 2971,

2924, 2870, 1715, 1447, 1380, 1228, 1167, 986, 894 cm²¹

;

MS m/z 166 (M¹, 78), 151 (11), 123 (21), 109 (27), 97 (35),

96 (30), 95 (83), 83 (47), 69 (100) 55 (32), 41 (37); HRMS:

M¹, found 166.1355. C₁₁H₁₈O requires 166.1358.

(2S,3R,5S)-6-Hydroxymethylene-5-isopropenyl-2,3-di-

methylcyclohexanone (10b). Obtained as usual as a colour-

(5S)-6-Hydroxymethylene-5-isopropenyl-2,2-dimethyl-

cyclohexanone (11b). Formylation in the usual way gave

this product in 88% yield and an analytical sample was

obtained by column chromatography on silica gel with

light petroleum/ethyl acetate 96/4 as eluent. [a]_D119.7

1

less oil in 92% yield. [a]_D112.6 (c1.25); H NMR d

0.96 (d, J6.2 Hz, 3H), 1.18 (d, J7.0 Hz, 3H), 1.35±1.71

(m, 2H), 1.71±1.90 (buried m, 1H), 1.79 (br s, 3H), 2.26±

2.43 (dq, J5.2, 7.0 Hz, 1H), 3.09 (m, 1H), 4.52 (br s, 1H),

4.87 (br s, 1H), 8.70 (br s, 1H), 14.62 (br s, 1H); ¹³C NMR d

15.6 (q), 20.0 (q), 21.5 (q), 30.3 (d), 33.2 (t), 40.1 (d), 42.3

(d), 109.8 (s), 113.9 (t), 148.4 (s), 185.2 (s), 191.9 (d); IR

1

(c1.9); H NMR d 1.17 (s, 6H), 1.33±1.45 (m, 1H), 1.51

(dd, J7.0, 11.7 Hz, 1H), 1.57±1.77 (m, 2H), 1.72 (s, 3H),

3.11 (dd, J5.2, 5.6 Hz, 1H), 4.61 (br s, 1H), 4.90 (br s, 1H),

8.66 (s, 1H), 14.85 (br s, 1H); ¹³C NMR d 20.6 (q), 23.3 (t),

26.7 (q), 27.0 (q), 33.7 (t), 37.0 (s), 42.3 (d), 108.8 (s), 114.2

n_max(liquid ®lm) 3079, 2969, 2933, 2876, 1732, 1642, 1590,

1453, 1361, 1332, 1181, 896 cm²¹; MS m/z 194 (M¹, 100),

2084

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

(t), 147.8 (s), 189.3 (s), 191.7 (d); IR n_max(liquid ®lm) 3079,

(12); HRMS: M¹, found 194.1302. C₁₂H₁₈O₂requires

194.1307.

2965, 2939, 2864, 1642, 1590, 1454, 1348, 1189, 896 cm²¹

;

MS m/z 194 (M¹, 100), 179 (60), 153 (26), 151 (22), 138

(20), 123 (21), 120 (21), 110 (27), 95 (29), 93 (34), 69 (26),

43 (29), 41 (44), 39 (25); HRMS: M¹, found 194.1298.

C₁₂H₁₈O₂requires 194.1307.

(4R)-4-Isopropenyl-7,7-dimethyl-4,5,6,7-tetrahydrobenzo-

[d]isoxazole. Obtained as a relatively unstable oil and used

without puri®cation in the next step. ¹H NMR (Varian EM-

390, 90 MHz) d 1.25 (s, 3H), 1.32 (s, 3H), 1.50±1.85 (m,

4H), 1.64 (br s, 3H), 3.23 (dd, J6.0, 8.0 Hz, 1H), 4.70 (br s,

1H), 4.75 (br s, 1H), 7.90 (s, 1H).

(4S)-4-Isopropenyl-7,7-dimethyl-4,5,6,7-tetrahydrobenzo-

[d]isoxazole. This product was prepared and used without

puri®cation in the next reaction due to its instability. H

1

NMR d 1.26 (s, 3H), 1.28 (s, 3H), 1.52±1.84 (m, 4H),

1.67 (s, 3H), 3.22 (dd, J5.8, 6.8 Hz, 1H), 4.63 (br s, 1H),

4.83 (br s, 1H), 7.91 (s, 1H); ¹³C NMR d 20.0 (q), 25.5 (t),

27.1 (q), 27.3 (q), 32.4 (s), 36.9 (t), 39.9 (d), 112.4 (t), 146.4

(s), 149.5 (d), 154.0 (s), 174.0 (s).

(1S,6S)-6-Isopropenyl-3,3-dimethyl-2-oxo-cyclohexane-

carbonitrile. This product was puri®ed by column chroma-

tography on silica gel followed by crystallisation from light

petroleum/di-iso-propyl ether 1/2. The yield was 64% based

on S-(1)-carvone. Mp 102±1038C; [a]_D289.3 (c2.11);

¹H NMR d 1.09 (s, 3H), 1.18 (s, 3H), 1.58±1.86 (m, 4H),

1.77 (br s, 3H), 2.52 (ddd, J5.3, 10.4, 12.6 Hz, 1H), 3.77

(d, J12.6 Hz, 1H), 4.89 (s, 1H), 4.94 (br s, 1H); ¹³C NMR

d 18.8 (q), 24.1 (q), 24.8 (q), 26.1 (t), 44.5 (d), 44.5 (s), 51.2

(d), 113.8 (t), 115.6 (s), 143.0 (s), 204.0 (s); IR n_max(KBr,

Hitachi EPI-G3) 3075, 2990, 2960, 2940, 2875, 2245, 1720,

1645, 1455, 1390, 1370, 1210, 1090, 905 cm²¹; MS m/z 191

(M¹, 19), 176 (15), 163 (15), 162 (15), 148 (31), 135 (43),

121 (16), 107 (33), 97 (18), 95 (18), 94 (30), 69 (93),

55 (70), 41 (100); HRMS: M¹, found 191.1307.

C₁₂H₁₇NO requires 191.1310; Anal: found C, 75.31;

H, 9.06; N 7.22%. C₁₂H₁₇NO requires C, 75.35; H, 8.96;

N, 7.32%.

(1R,6R)-6-Isopropenyl-3,3-dimethyl-2-oxo-cyclohexane-

carbonitrile (11c). Obtained in 71% overall yield without

puri®cation of intermediates after crystallisation from

hexane/tert-butyl methyl ether 1/2. Mp 101±1028C;

1

[a]_D194.0 (c1.15); H NMR d 1.12 (s, 3H), 1.20 (s,

3H), 1.44±1.97 (m, 4H), 1.78 (s, 3H), 2.58 (ddd, J5.4,

10.4, 12.4 Hz, 1H), 3.78 (d, J12.4 Hz, 1H), 4.92 (s, 1H),

4.98 (br s, 1H); ¹³C NMR d 19.1 (q), 24.4 (q), 25.1 (q), 26.4

(t), 39.0 (t), 44.8 (d), 44.8 (s), 51.5 (d), 114.1 (t), 115.8 (s),

143.2 (s), 204.3 (s); IR n_max(KBr) 3069, 2992, 2962, 2941,

2875, 2248, 1720, 1644, 1455, 1397, 1374, 1210, 1088,

908 cm²¹; MS m/z 191 (M¹, 14), 176 (6), 163 (7), 162

(5), 148 (34), 135 (41), 120 (16), 108 (23), 107 (21), 95

(24), 94 (24), 93 (16), 84 (18), 69 (66), 55 (46), 41 (100),

39 (60); HRMS: M¹, found 191.1309. C₁₂H₁₇NO requires

191.1310; Anal: found C, 75.41; H, 9.07; N 7.29%.

C₁₂H₁₇NO requires C, 75.35; H, 8.96; N, 7.32%.

(3R,5R)-Isopropenyl-2,2,3-trimethylcyclohexanone (12a).

An 1,4 addition of methylmagnesium iodide to (R)-

(2)-carvone catalysed by copper bromide dimethylsul®de

complex²followed by quenching the intermediate enolate

with methyl iodide gave ketone 12a in 90% yield.

1

(5S)-5-Isopropenyl-2,2-dimethylcyclohexanone. This ketone

was prepared as described for 11a starting with the

[a]_D114.8 (c1.2); H NMR d 0.86 (d, J7.0 Hz, 3H),

0.96 (s, 3H), 1.14 (s, 3H), 1.57±1.66 (m, 1H), 1.69 (s, 3H),

1.83±2.01 (m, 2H), 2.30±2.55 (m, 3H), 4.67 (br s, 1H), 4.74

(br s, 1H); ¹³C NMR d 16.2 (q), 21.1 (q), 21.2 (q), 25.4 (q),

33.0 (t), 39.4 (d), 40.6 (d), 42.1 (t), 48.2 (s), 110.4 (t), 147.4

(s), 216.2 (s); IR n_max(liquid ®lm) 3084, 2970, 2934, 2876,

1706, 1645, 1457, 1137, 892 cm²¹; MS m/z 180 (M¹, 66),

165 (8), 137 (15), 123 (17), 110 (36), 95 (54), 83 (100), 70

(48), 69 (41), 67 (29), 55 (25), 41 (22); HRMS: M¹, found

180.1516. C₁₂H₂₀O requires 180.1514.

1

benzylimine of (S)-(1)-carvone. [a]_D264.9 (c3.1); H

NMR d 1.10 (s, 3H), 1.16 (s, 3H), 1.53±1.83 (m, 4H), 1.77

(br s, 3H), 2.29±2.41 (m, 2H), 2.54 (dd, J13.0, 14.0 Hz,

1H), 4.73 (s, 1H), 4.79 (dd, J1.4, 2.6 Hz, 1H); ¹³C NMR d

20.5 (q), 25.0 (q), 25.1 (q), 26.3 (t), 39.4 (t), 43.0 (t), 44.5

(s), 46.3 (d), 109.8 (d), 147.4 (s), 215.4 (s); IR n_max(liquid

®lm) 3063, 2988, 2963, 2930, 1702, 1637, 1452, 1380,

1260, 1179, 1150, 1100, 891 cm²¹; MS m/z 166 (M¹, 44),

151 (3), 123 (20), 110 (33), 95 (63), 82 (32), 81 (38), 69

(66), 67 (100), 55 (37), 41 (91), 39 (38); HRMS: M¹, found

166.1361. C₁₁H₁₈O requires 166.1358.

(3R,5S)-6-Hydroxymethylene-isopropenyl-2,2,3-trimethyl-

cyclohexanone (12b). This compound was obtained in 79%

1

yield as a colourless oil. [a]_D125.9 (c2.5); H NMR d

(5R)-6-Hydroxymethylene-5-isopropenyl-2,2-dimethyl-

cyclohexanone. The preparation of this compound was in

conformity with the above-mentioned method starting with

the ketone derived from S-(1)-carvone and gave the

hydroxymethylene compound in 85% yield as an oil.

[a]_D218.1 (c2.81); ¹H NMR (Varian EM-390,

90 MHz) d 1.23 (s, 6H), 1.35±1.90 (m, 4H), 1.76 (s, 3H),

3.16 (dd, J4.0, 5.0 Hz, 1H), 4.63 (br s, 1H), 4.80 (br s, 1H),

8.70 (s, 1H), 14.95 (s, 1H); ¹³C NMR d 20.5 (q), 23.4 (t),

26.7 (q), 27.1 (q), 33.6 (t), 37.0 (s), 42.2 (d), 108.7 (s), 114.0

(t), 147.8 (s), 189.2 (s), 191.7 (d); IR n_max(chloroform,

Hitachi EPI-G3) 3080, 2965, 2940, 2865, 1640, 1590,

1455, 1350, 1190, 895 cm²¹; MS m/z 194 (M¹, 100), 179

(58), 153 (22), 151 (22), 138 (25), 123 (21), 120 (14),

110 (27), 95 (36), 93 (44), 69 (20), 43 (26), 41 (40), 39

0.85 (d, J4.8 Hz, 3H), 1.02 (s, 3H), 1.16 (s, 3H), 1.53±1.59

(m, 3H), 1.77 (br s, 3H), 3.04 (dd, J3.6, 4.4 Hz, 1H), 4.52

(br s, 1H), 4.90 (br s, 1H), 8.71 (d, J1.8 Hz, 1H), 14.71 (d,

J1.8 Hz, 1H); ¹³C NMR d 15.6 (q), 20.2 (q), 21.6 (q), 24.7

(q), 30.3 (t), 32.8 (d), 40.0 (s), 40.2 (d), 108.4 (s), 113.9 (t),

148.6 (s), 187.9 (s), 193.2 (d); IR n_max(liquid ®lm) 3079,

2970, 2937, 2877, 1633, 1586, 1455, 1347, 1335, 1177,

895 cm²¹; MS m/z 208 (M¹, 100), 193 (58), 167 (27), 138

(20), 123 (23), 120 (24), 110 (24), 107 (21), 95 (22), 43 (18),

41 (21); HRMS: M¹, found 208.1463. C₁₃H₂₀O₂requires

208.1463.

(1R,4R,6R)-6-Isopropenyl-3,3,4-trimethyl-2-oxo-cyclo-

hexanecarbonitrile (12c). Obtained as an oil after column

chromatography with light petroleum/ethyl acetate 4/1 as

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2085

eluent in 61% yield, based on the corresponding ketone. ¹H

NMR d 0.88 (d, J7.2 Hz, 3H), 1.08 (s, 3H), 1.25 (s, 3H),

1.59 (dt, J10.6, 3.6 Hz, 1H), 1.76 (br s, 3H), 1.95 (m, 1H),

2.09 (ddd, J4.3, 12.2, 14.0 Hz, 1H), 2.77 (td, J12.2,

4.3 Hz, 1H), 3.82 (d, J12.2 Hz, 1H), 4.89 (s, 1H), 4.93

(s, 1H); ¹³C NMR d 16.1 (q), 19.5 (q), 22.0 (q), 26.0 (q),

33.0 (t), 40.4 (d), 44.1 (d), 45.8 (d), 48.4 (s), 113.9 (t), 116.1

(s), 143.3 (s), 204.9 (s); IR n_max(liquid ®lm) 3079, 2973,

2940, 2881, 2250, 1717, 1647, 1460, 1385, 1336, 1301,

1094, 900 cm²¹; MS m/z 205 (M¹, 28), 190 (5), 177 (43),

162 (28), 148 (10), 135 (56), 120 (12), 84 (100), 83 (67), 69

(84), 55 (26), 41 (43), 39 (22); HRMS: M¹, found 205.1463.

C₁₃H₁₉NO requires 205.1467.

NMR. This mixture was used in the next reaction. After

repeated crystallisations from hexane/tert-butyl methyl

ether 1/4 the major isomer was isolated analytically pure.

1

Major isomer: mp 127±1288C; [a]_D180.7 (c1.05); H

NMR d 0.92 (d, J7.2 Hz, 3H), 1.06 (s, 3H), 1.38±1.66 (m,

1H), 1.79 (br s, 3H), 2.02±2.41 (m, 2H), 2.85 (dd, J4.9,

6.8 Hz, 1H), 3.82±3.98 (m, 4H), 4.00±4.08 (m, 1H), 4.89

(br s, 1H), 4.96 (s, 1H), 4.98 (t, J1.4 Hz, 1H); ¹³C NMR d

14.8 (q), 16.6 (q), 18.8 (q), 33.2 (t), 35.0 (d), 45.7 (d), 46.4

(d), 55.7 (s), 64.9 (t), 65.4 (t), 105.7 (d), 113.9 (t), 115.9 (s),

143.4 (s), 201.3 (s); IR n_max(liquid ®lm) 3083, 2965, 2898,

2211, 1723, 1666, 1454, 1380, 1091, 1026, 946, 900 cm²¹

.

1

(2R,3R,5R)-2-(1,3-Dioxolan-2-yl)-5-isopropenyl-2,3-di-

methylcyclohexanone (13a). This ketone was obtained as a

colourless oil as described before.⁶[a]_D115.6 (c1.3);

¹H NMR d 0.87 (d, J7.2 Hz, 3H), 0.93 (s, 3H), 1.51±1.73

(m, 1H), 1.70 (s, 3H), 2.07±2.19 (m, 1H), 2.22±2.57 (m,

4H), 3.76±3.99 (m, 4H), 4.73 (s, 1H), 4.75 (br s, 1H), 5.32

(s, 1H); ¹³C NMR d 12.6 (q), 16.6 (q), 20.5 (q), 33.4 (t), 36.2

(d), 40.8 (d), 44.6 (t), 56.3 (s), 65.1 (t), 65.5 (t), 105.0 (d),

109.8 (t), 147.5 (s), 211.5 (s); IR n_max(liquid ®lm) 3079,

2960, 2940, 2890, 1712, 1653, 1457, 1388, 1089, 990, 960,

890 cm²¹; MS m/z 238 (M¹, 3), 195 (1), 165 (0.5), 74 (3),

73 (100), 69 (1), 67 (1), 55 (2), 45 (5), 41 (2); HRMS: M¹,

found 238.1564. C₁₄H₂₂O₃requires 238.1569.

Minor isomer: H NMR d 0.86 (d, J6.8 Hz, 3H), 1.16 (s,

3H), 1.38±1.66 (m, 1H), 1.77 (s, 3H), 2.02±2.41 (m, 2H),

2.78 (dd, J4.9, 11.7 Hz, 1H), 3.82±3.98 (m, 4H), 4.00±

4.10 (m, 1H), 4.84 (br s, 1H), 4.96 (s, 1H), 4.98 (t, J1.4 Hz,

1H); ¹³C NMR d 14.4 (q), 15.2 (q), 21.9 (q), 28.1 (d), 29.8

(t), 41.5 (d), 45.6 (d), 55.7 (s), 64.7 (t), 65.2 (t), 107.3 (d),

113.8 (t), 118.5 (s), 144.6 (t), 201.3 (s); IR n_max(liquid ®lm,

diastereoisomeric mixture) 3086, 2966, 2897, 2248, 2211,

1725, 1667, 1454, 1380, 1092, 946 cm²¹; MS m/z 263 (M¹,

2), 262 (2), 248 (1), 127 (1), 74 (3), 73 (100), 69 (1), 55 (2),

45 (6), 43 (2), 41 (2); HRMS: M¹, found 263.1519.

C₁₅H₂₁NO₃requires 263.1521. Anal: found C, 68.56; H,

8.11; N, 5.12%. C₁₅H₂₁NO₃requires C, 68.41; H, 8.04; N,

5.32%.

(2R,3R,5S)-2-(1,3-Dioxolan-2-yl)-6-hydroxymethylene-

5-isopropenyl-2,3-dimethylcyclohexanone (13b). The

synthesis of this compound was accomplished in 86%

(2R,3R,5R)-2-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-

2-yl]-5-isopropenyl-2,3-dimethylcyclohexanone (14a).

Prepared in 35% yield as described before as a white

1

yield in the usual way. [a]_D194.4 (c1.5); H NMR d

1

0.98 (d, J6.9 Hz, 3H), 1.21 (s, 3H), 1.46±1.73 (m, 2H),

1.79 (s, 3H), 2.11 (ddd, J3.5, 6.9, 10.3 Hz, 1H), 3.07 (t,

J4.8 Hz, 1H), 3.80±3.99 (m, 4H), 4.76 (br s, 1H), 4.93 (br

s, 1H), 5.18 (s, 1H), 8.75 (br s, 1H), 14.77 (br s, 1H); ¹³C

NMR d 15.4 (q), 17.2 (q), 21.4 (q), 26.5 (d), 31.4 (t), 40.0

(d), 47.0 (s), 65.0 (t), 65.2 (t), 108.0 (d), 110.8 (s), 114.3 (t),

147.6 (s), 185.1 (s), 192.2 (d); IR n_max(liquid ®lm) 3400,

solid.⁶Mp 120±1218C; [a]_D165.7 (c2.1); H NMR d

0.89 (s, 3H), 0.89 (d, J7.0 Hz, 3H), 1.52 (m, 1H), 1.69 (s,

3H), 1.70 (m, 2H), 2.16±2.29 (m, 4H), 2.33 (m, 1H), 2.55

(m, 1H), 2.71 (d, J12.6 Hz, 1H), 2.82 (m, 1H), 3.87 (m,

2H), 4.63 (dd, J6.2, 9.6 Hz, 1H), 4.75 (m, 2H), 5.66 (d,

J5.0 Hz, 1H); ¹³C NMR d 13.4 (q), 16.7 (q), 20.4 (q), 32.6

(t), 33.0 (t), 33.1 (t), 36.8 (d), 40.4 (d), 41.9 (d), 43.3 (t), 54.3

(s), 68.0 (t), 82.6 (t), 109.0 (d), 147.4 (s), 213.4 (s); IR n_max

(KBr) 3073, 2981, 2960, 2884, 1703, 1643, 1458, 1383,

1327, 1219, 1094, 1018, 928, 891 cm²¹; MS m/z 278

(M¹, 2), 167 (7), 166 (36), 123 (27), 114 (6), 113 (100),

95 (6), 83 (7), 70 (5), 69 (51), 67 (9), 55 (10), 43 (4), 41 (8);

HRMS: M¹, found 278.1884. C₁₇H₂₆O₃requires 278.1882;

Anal: found C, 73.44; H, 9.31%. C₁₇H₂₆O₃requires C,

73.34; H, 9.34%.

3095, 2933, 2875, 1653, 1588, 1340, 1193, 1104, 899 cm²¹

;

MS m/z 266 (M¹, 3), 183 (12), 149 (10), 77 (5), 74 (3), 73

(100), 45 (6), 43 (6); HRMS: M¹, found 266.1520.

C₁₅H₂₂O₄requires 266.1518.

(4S,6R,7S)-7-(1,3-Dioxolan-2-yl)-4-isopropenyl-6,7-dimethyl-

4,5,6,7-tetrahydrobenzo[d]isoxazole. Obtained as a rather

unstable colourless oil in 83% yield after chromatographic

puri®cation on silica gel with ethyl acetate/light petroleum

1/19. ¹H NMR d 0.96 (d, J7.0 Hz, 3H), 1.26 (s, 3H), 1.60±

1.71 (m, 1H), 1.74 (s, 3H), 1.80±1.91 (m, 1H), 2.28±2.36

(m, 1H), 3.24 (t, J6.0 Hz, 1H), 3.75±4.05 (m, 4H), 4.64 (s,

1H), 4.86 (s, 1H), 5.04 (s, 1H), 7.99 (s, 1H); MS m/z 263

(M¹, 13), 248 (1), 220 (2), 194 (5), 73 (100), 45 (6); HRMS:

M¹, found 263.1518. C₁₅H₂₁NO₃requires 263.1521. Anal:

found C, 68.26; H, 8.16; N, 4.86%. C₁₅H₂₁NO₃requires C,

68.41; H, 8.04; N, 5.32%.

(2R,3R,5S)-2-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-

2-yl]-6-hydroxymethylene-5-isopropenyl-2,3-dimethyl-

cyclohexanone (14b). Prepared in 95% yield as a light

yellowish oil, which was suf®ciently pure to use in the

1

next reaction. [a]_D146.7 (c3.9); H NMR d 0.92 (d,

J6.8 Hz, 3H), 1.14 (s, 3H), 1.49±1.73 (m, 4H), 1.76 (br

s, 3H), 1.89 (dd, J3.4, 6.8 Hz, 1H), 1.94±2.05 (m, 1H),

2.26 (ddd, J9.6, 12.8, 19.4 Hz, 1H), 2.80 (m, 1H), 2.97 (m,

1H), 3.85 (ddd, J4.0, 6.0, 8.0 Hz, 2H), 4.37 (dd, J6.2,

9.8 Hz, 1H), 4.59 (s, 1H), 4.91 (s, 1H), 5.59 (d, J5.0 Hz,

1H), 8.66 (d, J2.0 Hz, 1H), 14.79 (d, J2.0 Hz, 1H); ¹³C

NMR 16.9 (q), 17.2 (q), 21.6 (q), 27.9 (d), 30.9 (t), 32.6 (t),

33.6 (t), 40.1 (d), 42.2 (d), 46.0 (s), 68.0 (t), 84.7 (d), 109.0

(d), 110.6 (s), 114.4 (t), 148.1 (s), 186.5 (s), 192.6 (d); IR

(1^p,3R,4R,6R)-3-(1,3-Dioxolan-2-yl)-6-isopropenyl-3,4-

dimethyl-2-oxo-cyclohexanecarbonitrile (13c). Synthe-

sised in 70% yield by treatment with sodium methoxide of

the corresponding isoxazole and obtained as an oil. Puri®-

cation proved to be very troublesome and the product was

obtained as a 3:2 mixture of stereoisomers, according to

n

_max(liquid ®lm) 3080, 2962, 2875, 1640, 1588, 1455, 1337,

2086

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

1249, 1183, 1101, 1014, 901 cm²¹; MS m/z 306 (M¹, 5),

208 (5), 195 (13), 194 (100), 179 (7), 161 (9), 152 (8), 151

(6), 137 (6), 113 (65), 67 (5), 55 (5); HRMS: M¹, found

306.1832. C₁₈H₂₆O₄requires 306.1831.

1.85±1.94 (m, 1H), 2.19±2.38 (m, 3H), 3.73±3.89 (m, 4H),

5.26 (s, 1H); ¹³C NMR d 12.9 (q), 16.3 (q), 23.0 (t), 28.6 (t),

36.6 (d), 39.4 (t), 56.1 (s), 65.1 (t), 65.1 (t), 105.4 (d), 212.6

(s); IR n_max(liquid ®lm) 2947, 2879, 1709, 1461, 1392,

1309, 1246, 1208, 1162, 1123, 1060, 1034, 963, 949,

1089, 949 cm²¹; MS m/z 198 (M¹, 4), 183 (1), 155 (2),

142 (1), 127 (2), 111 (3), 74 (3), 73 (100), 55 (4), 45 (8),

41 (3); HRMS: M¹, found 198.1256. C₁₁H₁₈O₃requires

198.1256.

(1S,3R,4R,6R)-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-

2-yl]-6-isopropenyl-3,4-dimethyl-2-oxo-cyclohexanecarbo-

nitrile (14c). This keto nitrile was obtained in 84% yield

based on the corresponding ketone as a white solid after

crystallisation from hexane/tert-butyl methyl ether 1/2.

1

Mp 1358C; [a]_D1127.7 (c1.25); H NMR d 0.89 (d,

(2R,3R)-2-(1,3-Dioxolan-2-yl)-6-hydroxymethylene-2,3-

dimethylcyclohexanone (15b). This yellow oil was synthe-

sised in 85% yield in the usual way as described.

[a]_D1117.4 (c1.3); ¹H NMR d 0.75 (d, J6.9 Hz,

3H), 0.95 (s, 3H), 1.07±1.23 (m, 1H), 1.41±1.50 (m, 1H),

1.78±1.89 (m, 1H), 2.04 (dd, J4.9, 7.6 Hz, 2H), 3.55±3.63

(m, 2H), 3.65±3.75 (m, 2H), 4.88 (s, 1H), 8.41 (br s, 1H),

14.36 (br s, 1H); ¹³C NMR d 15.7 (q), 17.2 (q), 22.1 (t), 27.9

(t), 30.4 (d), 47.4 (s), 64.7 (t), 65.1 (t), 107.8 (d), 109.0

(s), 186.8 (s), 187.6 (d); IR n_max(liquid ®lm) 2973, 2933,

2883, 1635, 1590, 1462, 1392, 1330, 1212, 1188, 1143,

1105, 1050, 997, 950 cm²¹; MS m/z 226 (M¹, 2), 149 (4),

127 (8), 83 (5), 73 (100), 69 (5), 55 (7), 45 (10), 43 (8), 41

(5); HRMS: M¹, found 226.1204. C₁₂H₁₈O₄requires

226.1205.

J7.0 Hz, 3H), 0.90 (s, 3H), 1.52 (dt, J14.4, 7.2 Hz,

1H), 1.65±2.00 (buried m, 3H), 1.77 (s, 3H), 2.10 (ddd,

J3.8, 8.2, 12.6 Hz, 2H), 2.37 (dd, J2.6, 6.8 Hz, 1H),

2.77 (ddd, J3.5, 6.5, 8.8 Hz, 2H), 3.85 (dd, J5.2,

8.4 Hz, 2H), 4.05 (d, J12.2 Hz, 1H), 4.25 (dd, J5.8,

10.1 Hz, 1H), 4.91 (br s, 2H), 5.62 (d, J5.1 Hz, 1H); ¹³C

NMR d 14.6 (q), 16.5 (q), 18.8 (q), 32.5 (t), 32.6 (t), 33.9 (t),

36.3 (d), 41.7 (d), 45.2 (d), 45.9 (d), 54.3 (s), 68.6 (t), 83.3

(d), 109.1 (d), 113.8 (t), 116.4 (s), 143.6 (s), 204.1 (s); IR

n

_max(KBr) 3082, 2973, 2876, 2209, 1721, 1653, 1457, 1387,

1101, 1011 cm²¹; MS m/z 303 (M¹, 0.4), 175 (0.3), 167 (4),

114 (6), 113 (100), 83 (7), 69 (48), 67 (8), 55 (11), 41 (9);

HRMS: M¹, found 303.1831. C₁₈H₂₅NO₃requires

303.1834. Anal: found C, 71.33; H, 8.33; N, 4.41%.

C₁₈H₂₅NO₃requires C, 71.26; H, 8.31; N, 4.62%.

(3R,4R)-3-(1,3-Dioxolan-2-yl)-3,4-dimethyl-2-oxo-cyclo-

hexanecarbonitrile (15c). According to NMR a 3:2

mixture of stereoisomers was obtained in 60% yield based

on ketone 15a without puri®cation of the intermediates.

(2R,3R)-2-(1,3-Dioxolan-2-yl)-2,3-dimethyl-5-cyclohexen-

one. A stream of an ozone/oxygene mixture was bubbled

through a solution of 1.0 g (4.2 mmol) of 13a in 25 mL of

methanol and 25 mL of dichloromethane at 2788C until a

blue colour appeared. The excess of ozone was expelled by

a stream of nitrogen and 1.25 g (4.4 mmol) of FeSO₄´7H₂O

and 1.68 g (8.4 mmol) of Cu(OAc)₂´2H₂O were added and

the temperature was raised overnight to room temperature.

The solvents were evaporated and the residue was dissolved

in 25 mL of aqueous 4 M HCl and extracted with three 100-

mL portions of ether. The combined extracts were washed

with 50 mL of aqueous 2 M NaOH and with brine, dried on

magnesium sulfate, ®ltered, and evaporated to give 0.56 g

(67%) of the enone after puri®cation on silica gel with light

petroleum/ethyl acetate 3/1 as eluent. [a]_D2110.6

1

Major isomer: H NMR d 0.87 (d, J7.2 Hz, 3H), 0.99 (s,

3H), 1.43±2.35 (m, 5H), 3.80±4.08 (m, 5H), 4.99 (s, 1H);

¹³C NMR d 14.3 (q), 16.1 (q), 26.9 (t), 27.3 (t), 36.2 (d), 41.6

(d), 56.5 (s), 64.9 (t), 65.4 (t), 105.4 (d), 117.0 (s), 201.9 (s).

1

Minor isomer: H NMR d 0.89 (d, J6.8 Hz, 3H), 1.13 (s,

3H), 1.43±2.35 (m, 5H), 3.80±4.08 (m, 5H), 5.28 (s, 1H);

¹³C NMR d(14.9 (q), 15.3 (q), 24.4 (t), 26.1 (t), 33.2 (d),

40.6 (d), 54.6 (s), 64.7 (t), 65.1 (t), 107.3 (d), 118.7 (s),

202.3 (s); IR n_max(liquid ®lm, diastereoisomeric mixture)

3293, 2945,2894, 2250, 2206, 1720, 1664, 1459, 1400,

1

(c1.4); H NMR d 0.90 (d, J7.0 Hz, 3H), 0.96 (s, 3H),

1299, 1160, 1113, 1092, 1026, 990, 944 cm²¹

.

1.97±2.12 (m, 1H), 2.34±2.40 (m, 1H), 2.47±2.60 (m, 1H),

3.70±3.89 (m, 4H), 5.10 (s, 1H), 5.87 (dt, J10.0, 2.0 Hz,

1H), 6.74 (dt, J10.0, 4.0 Hz, 1H); ¹³C NMR d 12.6 (q),

16.4 (q), 31.8 (t), 33.4 (d), 52.4 (s), 65.0 (t), 65.2 (t), 105.3

(d), 128.8 (d), 147.7 (d), 201.1 (s); IR n_max(liquid ®lm)

3032, 2961, 2884, 1682, 1457, 1388, 1212, 1106, 1089,

991 cm²¹; MS m/z 196 (M¹, 2), 181 (2), 127 (3), 123 (9),

109 (4), 83 (3), 73 (100), 68 (7), 55 (4), 45 (9); HRMS: M¹,

found 196.1102. C₁₁H₁₆O₃requires 196.1099.

(2R,3R)-2-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-2-yl]-

2,3-dimethyl-5-cyclohexenone. This enone was prepared

as described for the dioxolanyl-derivative (vide supra) in

82% yield. After puri®cation by column chromatography

on silica gel with light petroleum/ethyl acetate 3/1 as eluent

1

a colourless oil was obtained. [a]_D275.4 (c2.0); H

NMR d 0.97 (d, J7.2 Hz, 3H), 1.00 (s, 3H), 1.63±1.74

(m, 2H), 2.03±2.31 (m, 4H), 2.50 (ddd, J2.2, 4.6,

20.8 Hz, 1H), 2.86 (m, 1H), 3.84 (ddd, J1.4, 6.0, 6.6 Hz,

2H), 4.42 (dd, J6.4, 9.8 Hz, 1H), 5.62 (d, J5.0 Hz, 1H),

5.88 (ddd, J2.0, 4.0, 10.0 Hz, 1H), 6.75 (ddd, J4.0, 8.0,

10.0 Hz, 1H); ¹³C NMR d 13.8 (q), 16.0 (q), 31.9 (t), 32.7

(t), 33.5 (t), 35.1 (d), 42.2 (d), 50.7 (s), 67.9 (t), 82.5 (d),

109.1 (d), 129.0 (d), 146.9 (d), 202.6 (s); IR n_max(liquid

®lm) 3041, 2974, 2906, 2883, 1678, 1464, 1381, 1214,

1101, 1023, 929 cm²¹; MS m/z 236 (M¹, 5), 166 (33),

124 (87), 113 (84), 109 (56), 95 (35), 85 (32), 83 (73), 69

(100), 67 (32), 55 (34); HRMS: M¹, found 236.1416.

C₁₄H₂₀O₃requires 236.1412.

(2R,3R)-2-(1,3-Dioxolan-2-yl)-2,3-dimethylcyclohexan-

one (15a). A solution of 196 mg (1 mmol) of the above-

mentioned enone in 15 mL of ethyl acetate was stirred

under hydrogen in the presence of 15 mg of 10% Pd on

charcoal for 4 h. The reaction mixture was ®ltered and

evaporated to give 186 mg (95%) of a colourless oil

which was puri®ed by column chromatography on silica

gel with light petroleum/ethyl acetate 96/4 as eluent.

[a]_D28.11 (c1.41); ¹H NMR d 0.84 (d, J7.0 Hz,

3H), 0.93 (s, 3H), 1.42±1.50 (m, 1H), 1.74±1.80 (m, 2H),

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2087

(2R,3R)-2-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-2-

yl]-2,3-dimethylcyclohexanone (16a). This substituted

cyclohexanone was obtained as described before in 99%

yield as a colourless oil after puri®cation by column

chromatography on silica gel with light petroleum/ethyl

1198C; [a]_D1144.1 (c0.8); ¹H NMR d 0.92 (d,

J6.6 Hz, 3H), 0.92 (s, 3H), 1.40±1.51 (ddq, J7.2, 13.4,

6.6 Hz, 1H), 1.64±1.76 (m, 2H), 1.91 (t, J9.6 Hz, 1H),

1.97±2.21 (m, 3H), 2.33±2.42 (m, 2H), 2.82 (m, 1H), 3.88

(dd, J5.4, 8.2 Hz, 2H), 4.08 (dd, J7.6, 11.4 Hz, 1H), 4.31

(dd, 5.8, 10.2 Hz, 1H), 5.63 (d, 5.0 Hz, 1H); ¹³C NMR d

14.1 (q), 16.0 (q), 26.3 (t), 26.7 (t), 32.4 (t), 33.6 (t), 37.1 (d),

40.9 (d), 41.7 (d), 54.9 (s), 68.4 (t), 82.7 (d), 109.0 (d), 117.4

(s), 204.4 (s); IR n_max(CCl₄) 2964, 2878, 2252, 1726, 1458,

1

acetate 3/2 as eluent. [a]_D133.4 (c2.05); H NMR d

0.87 (d, J7.0 Hz, 3H), 0.90 (s, 3H), 1.40±1.45 (m, 1H),

1.64±1.86 (m, 5H), 1.96±2.17 (m, 3H), 2.28±2.31 (m, 1H),

2.51±2.55 (m, 1H), 2.82±2.85 (m, 1H), 3.86 (ddd, J4.2,

8.6, 9.8 Hz, 2H), 4.51 (dd, J6.4, 9.6 Hz, 1H), 5.62 (d,

J5.0 Hz, 1H); ¹³C NMR d 13.9 (q), 15.9 (q), 22.9 (t),

28.4 (t), 32.8 (t), 33.2 (t), 37.7 (d), 38.8 (t), 42.2 (d), 54.6

(s), 68.0 (t), 82.5 (d), 109.1 (d), 214.5 (s); IR n_max(liquid

®lm) 2948, 2882, 1708, 1458, 1396, 1369, 1304, 1095,

1015, 958, 928 cm²¹; MS m/z 238 (M¹, 2), 166 (11), 113

(18), 95 (13), 85 (60), 83 (100), 69 (27), 67 (11), 55 (12), 47

(19), 41 (12); HRMS: M¹, found 238.1568. C₁₄H₂₂O₃

requires 238.1569.

1389, 1270, 1214, 1181, 1144, 1099, 1065, 1013, 933 cm²¹

;

MS m/z 263 (M¹, 1), 167 (5), 114 (5), 113 (100), 83 (7), 70

(7), 69 (40), 67 (6), 55 (9), 43 (4), 41 (6); HRMS: M¹, found

263.1523. C₁₅H₂₁NO₃requires 263.1521; Anal: found C,

68.33; H, 8.22; N, 5.27%. C₁₈H₂₅NO₃requires C, 68.41;

H, 8.04; N, 5.32%.

Michael addition of methyl vinyl ketone to b keto nitriles

and b keto aldehydes

(2R,3R)-2-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-2-

yl]-6-hydroxymethylene-2,3-dimethyl-cyclohexanone

(16b). This product was synthesised as described in the

general procedure. After puri®cation by column chroma-

tography on silica gel with light petroleum/ethyl acetate

19/1 as eluent a colourless oil was obtained in 83% yield.

Method A. A solution of 10 mmol of the appropriate b keto

nitrile and 12.5 mmol of methyl vinyl ketone in 50 mL of

benzene was treated under nitrogen with 2 mmol of sodium

methanolate (2 mL of an 1 M solution in methanol) until no

starting material was detected by GC or TLC. The reaction

mixture was acidi®ed with 1 M hydrochloric acid in water to

pH1. The benzene layer was diluted with 50 mL of ether,

washed with 50 mL of brine, dried, and evaporated to afford

the corresponding diketone.

1

[a]_D181.6 (c2.0); H NMR d 0.97 (d, J6.8 Hz, 3H),

1.14 (s, 3H), 1.30±1.46 (m, 1H), 1.60±1.74 (m, 3H), 1.92±

2.14 (m, 2H), 2.27±2.36 (m, 2H), 2.48 (dd, J9.6, 12.8 Hz,

1H), 2.84±2.89 (m, 1H), 3.88 (ddd, J4.0, 8.8, 9.6 Hz, 2H),

4.35 (dd, J6.2, 9.6 Hz, 1H), 5.65 (d, J5.0 Hz, 1H), 8.63

(s, 1H), 14.35 (s, 1H); ¹³C NMR d 16.8 (q), 17.1 (q), 23.0 (t),

28.1 (t), 32.7 (t), 33.6 (d), 33.7 (t), 42.2 (d), 46.8 (s), 68.0 (t),

84.6 (d), 109.2 (d), 109.4 (s), 187.9 (d), 189.1 (s); IR n_max

(liquid ®lm) 2960, 2881, 1714, 1631, 1591, 1457, 1330,

1183, 1101, 1015, 922 cm²¹; MS m/z 266 (M¹, 1), 154

(37), 139 (14), 113 (100), 83 (10), 70 (6), 69 (63), 67

(10), 55 (20), 43 (13), 41 (13); HRMS: M¹, found

266.1514. C₁₅H₂₂O₄requires 266.1518.

Method B. A solution of 2 mmol of substrate and 250 mg

(3.6 mmol) of methyl vinyl ketone in 10 mL of THF was

treated with 60 mg (0.6 mmol) of triethylamine at room

temperature for three days. The reaction mixture was poured

into water and acidi®ed to pH2 with aqueous 1 M HCl and

extracted three times with ether. The combined extracts

were washed with brine, dried on magnesium sulfate,

®ltered, and evaporated to afford the corresponding dike-

tone.

(6,7)-7-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-2-yl]-

6,7-dimethyl-4,5,6,7-tetrahydrobenzo[d]isoxazole. This

product was isolated in 73% yield as a light yellow solid

after column chromatography on silica gel with ethyl

Method C. A stirred solution of 10 mmol of substrate and

1.50 g (14.8 mmol) of triethylamine in 25 mL of ethyl

acetate was treated with 1.05 g (15 mmol) of methyl vinyl

ketone followed by three pellets of potassium hydroxide.

Temperature and reaction time are indicated for the indi-

vidual compounds. The reaction mixture was poured into

water and acidi®ed to pH2 with aqueous 1 M HCl and

extracted three times with ether. The combined extracts

were washed with brine, dried on magnesium sufate,

®ltered, and evaporated to afford the corresponding

diketone.

1

acetate/light petroleum 1/7. Mp 115±1168C; H NMR d

0.94, (d, J6.9 Hz, 3H), 1.04 (s, 3H), 1.37±1.52 (m, 1H),

1.62±1.75 (m, 2H), 1.98±2.09 (m, 1H), 2.21±2.30 (m, 1H),

2.30±2.40 (m, 2H), 2.58 (dt, J19.2, 9.6 Hz, 1H), 2.84±

2.89 (m, 1H), 3.81 (ddd, J4.2, 5.4, 8.6 Hz, 2H), 4.31

(dd, J6.3, 9.8 Hz, 1H), 5.43 (d, J5.0 Hz, 1H), 8.11 (s,

1H); ¹³C NMR d 15.7 (q), 17.2 (q), 28.5 (t), 32.6 (t), 34.3 (t),

35.0 (d), 42.1 (d), 42.7 (s), 68.1 (t), 82.7 (d), 109.1 (d), 113.8

(s), 149.2 (d), 171.6 (s); MS m/z 263 (M¹, 6), 180 (6), 152

(9), 151 (89), 136 (10), 123 (8), 114 (6), 113 (100), 69 (54),

67 (7), 55 (7); HRMS: M¹, found 263.1521. C₁₅H₂₁NO₃

requires 263.1521; Anal: found C, 68.09; H, 8.16; N,

5.37%. C₁₈H₂₅NO₃requires C, 68.41; H, 8.04; N, 5.32%.

(1S,6S)-6-Isopropenyl-3-methyl-2-oxo-1-(3-oxo-butyl)-3-

cyclohexenecarbaldehyde (17). This yellow oily compound

was obtained via Method C in 87% yield after 3.5 h at 08C

and used without puri®cation for the next reaction.

1

[a]_D268.6 (c4.5); H NMR d 1.63 (s, 3H), 1.77 (t,

J1.6 Hz, 3H), 2.07 (s, 3H), 2.03±2.43 (m, 5H), 2.70±

2.79 (m, 1H), 2.81±2.84 (m, 1H), 4.62 (s, 1H), 4.79 (t,

J1.3 Hz, 1H), 6.85 (t, J1.6 Hz, 1H), 9.84 (s, 1H); ¹³C

NMR d 15.6 (q), 22.3 (q), 25.9 (t), 28.4 (t), 29.7 (q), 37.8 (t),

49.2 (d), 60.1 (s), 115.1 (t), 134.5 (s), 142.8 (d), 143.7 (s),

198.4 (s), 202.6 (d), 207.2 (s); IR n_max(tetra) 3087, 2977,

2929, 2851, 1727, 1669, 1659, 1435,1360, 1295, 1165,

(1S,3R,4R)-3-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-

2-yl]-3,4-dimethyl-2-oxo-cyclohexanecarbonitrile (16c).

This nitrile was obtained in 77% yield after a 4-day treat-

ment with sodium methanolate in ether of the intermediate

oxim or benzo[d]isoxazole and was puri®ed by crystal-

lisation from tert-butyl methyl ether at 2208C. Mp 118±

2088

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

1074, 1040, 904, 854, 839 cm²¹; MS m/z 248 (M¹, 11), 230

(7), 220 (22), 205 (7), 187 (9), 177 (8), 163 (17), 162 (37),

161 (20), 149 (51), 147 (32), 135 (13), 121 (82), 109 (13),

107 (10), 105 (13), 91 (22), 82 (100), 77 (16), 55 (13), 43

(50), 41 (17), 39 (15); HRMS: M¹, found 248.1416.

C₁₅H₂₀O₃requires 248.1416.

(1R,6R)-6-Isopropenyl-3-methyl-2-oxo-1-(3-oxo-butyl)-

3-cyclohexenecarbonitrile. Synthesis of this S-(1)-

carvone-derived product was performed by Method B and

the residue was puri®ed by column chromatography on

silica gel with ethyl acetate/light petroleum 1/4 to give a

95% yield of an oil with solidi®ed on standing in the

1

refrigerator. Mp 788C; [a]_D133.0 (c2.4); H NMR d

(1R,6R)-6-Isopropenyl-3-methyl-2-oxo-1-(3-oxo-butyl)-

3-cyclohexenecarbaldehyde. This bright yellow oily

compound was obtained via Method C in 88% yield after

3 h at 08C. Puri®cation was performed by column chroma-

tography on silica gel with ethyl acetate/light petroleum 1/2.

¹H NMR d 1.64 (br s, 3H), 1.79 (t, J1.6 Hz, 3H), 2.07 (s,

3H), 2.03±2.43 (m, 5H), 2.70±2.79 (m, 1H), 2.81 (d,

J1.8 Hz, 1H), 4.61 (s, 1H), 4.79 (t, J1.3 Hz, 1H), 6.64

(t, J1.6 Hz, 1H), 9.82 (s, 1H); ¹³C NMR d 15.6 (q),

22.3 (q), 26.0 (t), 28.3 (t), 29.7 (q), 37.7 (t), 49.1 (d), 60.0

(s), 115.1 (t), 134.5 (s), 142.7 (d), 143.7 (s), 198.4 (s), 202.8

(d), 207.8; IR n_max(tetra) 3086, 2979, 2930, 2850, 1726,

1666, 1659, 1435,1360, 1296, 1166, 1070, 1040, 904, 854,

839 cm²¹; MS m/z 248 (M¹, 11), 220 (22), 162 (37), 161

(20), 149 (49), 147 (32), 121 (76), 91 (22), 82 (100), 77 (13),

43 (50); HRMS: M¹, found 248.1416. C₁₅H₂₀O₃requires

248.1416.

1.79 (br s, 6H), 2.00±2.11 (m, 2H), 2.13 (s, 3H), 2.52±

2.57 (m, 1H), 2.63±2.83 (m, 4H), 4.90 (s, 1H), 4.95 (br s,

1H), 6.73 (br s, 1H); ¹³C NMR d 16.3 (q), 20.5 (q), 26.4 (t),

29.5 (t), 30.0 (d), 39.5 (t), 50.0 (s), 50.1 (d), 116.7 (t), 117.9

(s), 133.3 (s), 142.8 (s), 144.4 (d), 191.8 (s), 206.7 (s); IR

n_max(tetra) 3083, 3027, 2983, 2923, 2232, 1721, 1690,

1642, 1436, 1360, 1285, 1165, 1045, 908 cm²¹; MS m/z

245 (M¹, 2), 203 (3), 202 (5), 175 (8), 174 (4), 160 (3),

131 (3), 83 (5), 82 (100), 54 (10), 43 (8); HRMS: M¹, found

245.1413. C₁₅H₁₉NO₂requires 245.1416; Anal: found C,

73.23; H, 7.88; N, 5.73%. C₁₅H₁₉NO₂requires C, 73.44;

H, 7.81; N, 5.71%.

(1S,3S,4R,6S)-6-Isopropenyl-3,4-dimethyl-2-oxo-1-(3-oxo-

butyl)-cyclohexanecarbonitrile (25). Obtained after 1.5 h

in 88% yield via Method A and puri®ed by column chro-

matography on silica gel with light petroleum/ethyl acetate

1

4/1 as eluent. [a]_D150.3 (c1.4); H NMR d 1.00 (d,

(1S,3S,4R,6S)-6-Isopropenyl-3,4-dimethyl-2-oxo-1-(3-

oxo-butyl)-cyclohexanecarbaldehyde (19). The synthesis

of this product via Method C was performed in 18 h at room

temperature. After puri®cation by column chromatography

on silica gel with ethyl acetate/light petroleum 1/4 as eluent

a 19:1 mixture of two diastereoisomers was obtained in 97%

yield as a light coloured oil, which solidi®ed in the

refrigator. Recrystallisation from diisopropyl ether gave

colourless crystals. Mp 40±428C; [a]_D224.8 (c3.4);

¹H NMR d 0.97 (d, J5.8 Hz, 3H), 0.98 (d, J6.4 Hz,

3H), 1.57 (br s, 3H), 1.60±1.85 (m, 3H), 1.96 (s, 3H),

1.93±2.24 (m, 5H), 2.56 (m, 1H), 4.29 (s, 1H), 4.78 (br s,

1H), 10.16 (s, 1H); ¹³C NMR d 11.5 (q), 20.6 (q), 24.5 (q),

29.2 (t), 29.9 (q), 32.6 (t), 34.3 (d), 37.8 (t), 48.2 (d), 50.9

(d), 60.1 (s), 113.9 (t), 144.8 (s), 205.0 (s), 206.8 (s), 214.4

(s); IR n_max(tetra) 3083, 2975, 2934, 2875, 1723, 1715,

1694, 1648, 1455, 1374, 1285, 1217, 1169, 1094, 1024,

976, 947, 900 cm²¹; MS m/z 264 (M¹, 2), 236 (100), 221

(7), 193 (43), 178 (22), 165 (33), 163 (31), 135 (19), 121

(18), 109 (20), 95 (18), 55 (18), 43 (49), 41 (19); HRMS:

M¹, found 264.1718. C₁₆H₂₄O₃requires 264.1725;

(M¹2CO), found 236.1775. C₁₅H₂₄O₂requires 236.1776.

J5.8 Hz, 3H), 1.01 (d, J6.4 Hz, 3H), 1.71±1.85 (buried

m, 3H), 1.75 (br s, 3H), 2.02±2.26 (m, 2H), 2.11 (s, 3H),

2.39±2.53 (m, 2H), 2.64±2.73 (m, 2H), 4.58 (s, 1H), 5.00 (q,

J0.6 Hz, 1H); ¹³C NMR d 12.1 (q), 20.4 (q), 23.6 (q), 30.1

(q), 30.6 (t), 31.9 (t), 34.4 (d), 38.7 (t), 47.1 (d), 50.2 (d),

55.6 (s), 114.9 (t), 118.9 (s), 143.5 (s), 206.2 (s), 206.4 (s);

IR n_max(KBr) 3089, 2973, 2933, 2876, 2240, 1714, 1454,

1374, 1171, 901 cm²¹; MS m/z 261 (M¹, 71), 246 (32), 233

(12), 218 (64), 204 (77), 191 (45), 190 (47), 176 (43), 148

(41), 146 (60), 122 (42), 121 (100), 106 (20), 95 (12), 79

(15), 77 (12), 55 (17), 43 (36), 41 (11); HRMS: M¹, found

261.1725. C₁₆H₂₃NO₂requires 261.1729.

(1S,6S)-6-Isopropenyl-3,3-dimethyl-2-oxo-1-(3-oxo-butyl)-

cyclohexanecarbonitrile. Obtained in 94% yield as a

viscous oil via Method A after a reaction time of 3 h. H

1

NMR d 1.05 (s, 3H), 1.18 (s, 3H), 1.40±1.75 (m, 3H), 1.84

(br s, 3H), 1.89±1.98 (m, 2H), 2.09 (s, 3H), 2.16±2.33 (m,

2H), 2.54±2.84 (m, 2H), 4.86 (s, 1H), 4.92 (q, J 1.4 Hz,

1H); ¹³C NMR d 21.0 (q), 25.3 (t), 27.1 (q), 27.3 (t), 27.4

(q), 30.0 (q), 39.4 (t), 40.0 (t), 47.1 (s), 51.1 (s), 54.6 (d),

116.1 (t), 119.2 (s), 143.0 (s), 205.8 (s), 206.9 (s).

(1S,6S)-6-Isopropenyl-3-methyl-2-oxo-1-(3-oxo-butyl)-

3-cyclohexenecarbonitrile. This R-(2)-carvone-derived

product was obtained via Method B in 78% yield as a

white solid on standing in the refrigerator. Mp 72±748C;

(1S,4R,6S)-6-Isopropenyl-3,3,4-trimethyl-2-oxo-1-(3-oxo-

butyl)-cyclohexanecarbonitrile (27). This product was

obtained in 91% yield via Method A after 2 h and puri®ed

by column chromatography on silica gel with light petro-

leum/ethyl acetate 5/1. ¹H NMR d 0.88 (d, J6.8 Hz, 3H),

1.00 (s, 3H), 1.05±1.26 (m, 1H), 1.37 (s, 3H), 1.57±1.68 (m,

1H), 1.86 (t, J0.6 Hz, 3H), 2.01 (dd, J7.4, 8.6 Hz, 2H),

2.13 (s, 3H), 2.16±2.30 (m, 1H), 2.35±2.43 (m, 1H), 2.61±

2.76 (m, 2H), 4.82 (s, 1H), 4.98 (s, 1H); ¹³C NMR d 16.0

(q), 21.2 (q), 22.7 (q), 27.1 (q), 27.9 (t), 30.0 (q), 31.4 (t),

37.4 (d), 39.7 (t), 48.5 (d), 49.7 (s), 50.8 (s), 116.1 (t), 119.2

(s), 142.9 (s), 206.9 (s), 207.1 (s); IR n_max(KBr) 3080, 2972,

1

[a]_D237.3 (c3.2); H NMR d 1.81 (s, 3H), 1.82 (s,

3H), 2.02±2.13 (m, 2H), 2.15 (s, 3H), 2.52±2.60 (m, 1H),

2.66±2.87 (m, 4H), 4.92 (s, 1H), 4.97 (t, J1.4 Hz, 1H),

6.75 (br s, 1H); ¹³C NMR d 16.4 (q), 20.5 (q), 26.4 (t), 29.5

(t), 30.0 (d), 39.5 (t), 49.9 (s), 50,2 (d), 116,7 (t), 117.9 (s),

133.4 (s), 142.8 (s), 144.3 (d), 191.8 (s), 206.8 (s); IR n_max

(tetra) 3082, 3028, 2983, 2923, 2231, 1721, 1690, 1648,

1436, 1360, 1285, 1165, 908 cm²¹; MS m/z 245 (M¹, 6),

203 (7), 202 (11), 188 (7), 187 (7), 175 (17), 174 (49), 160

(7), 135 (16), 82 (100), 54 (6), 43 (6); HRMS: M¹, found

245.1412. C₁₅H₁₉NO₂requires 245.1416.

2939, 2880, 2227, 1716, 1462, 1374, 1168, 1020, 906 cm²¹

;

MS m/z 275 (M¹, 40), 260 (4), 247 (19), 232 (28), 205 (38),

190 (24), 177 (47), 165 (23), 162 (15), 146 (53), 121 (100),

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2089

84 (70), 69 (41), 55 (27), 43 (31), 41 (18); HRMS: M¹,

found 275.1880. C₁₇H₂₅NO₂requires 275.1885.

(s), 58.2 (s), 64.9 (t), 65.4 (t), 104.0 (d), 119.1 (s), 202.6 (s),

206.6 (s); IR n_max(liquid ®lm) 2939, 2885, 2231, 1718,

1716, 1448, 1369, 1229, 1144, 1099 cm²¹; MS m/z 275

[(M218)¹, 0.4], 274 (0.3), 215 (0.2), 188 (0.7), 187 (0.4),

174 (0.6), 160 (0.6), 159 (0.5), 140 (0.7), 138 (0.7), 117

(0.6), 116 (0.9), 115 (0.7), 105 (0.6), 104 (0.5), 103 (0.5),

91 (1.3), 77 (1.0), 74 (3.0), 73 (100), 55 (2.0), 45 (9.5), 43

(1.5), 41 (1.2); HRMS: (M218)¹, found 275.1514.

C₁₆H₂₁NO₃requires 275.1521.

(1S,3R,4R,6S)-3-(1,3-Dioxolan-2-yl)-6-isopropenyl-3,4-

dimethyl-2-oxo-1-(3-oxo-butyl)-cyclohexanecarbonitrile

(28). Obtained via Method A in 76% yield as a very viscous

oil after a reaction time of three days. Puri®cation was

performed by column chromatography on silica gel with

1

ethyl acetate/light petroleum 3/7 as eluent. H NMR d

0.85 (d, J7.2 Hz, 3H), 0.98 (s, 3H), 1.53 (dd, J3.6,

10.2 Hz, 1H), 1.85 (br s, 3H), 1.92 (dd, J7.2, 8.4 Hz,

2H), 2.10 (s, 3H), 2.28±2.36 (m, 1H), 2.49±2.58 (m, 3H),

2.62±2.82 (m, 1H), 3.80±3.91 (m, 3H), 3.96±3.98 (m, 1H),

4.91 (s, 1H), 4.95 (br s, 1H), 5.68 (s, 1H); ¹³C NMR d 13.7

(q), 16.3 (q), 20.9 (q), 27.2 (t), 29.9 (q), 32.3 (t), 34.2 (t),

39.8 (t), 48.8 (d), 51.9 (s), 58.3 (s), 64.8 (t), 65.5 (t), 103.9

(d), 116.4 (t), 118.2 (s), 142.3 (s), 201.7 (s), 206.9 (s); IR

1

Minor (more polar) isomer (38): [a]_D147.6 (c1.3); H

NMR d 0.95 d, J6.8 Hz, 3H), 1.23 (s, 3H), 1.62±1.84 (m,

4H), 2.06 (s, 3H), 2.07±2.20 (m, 3H), 2.48±2.62 (m, 2H),

3.67±3.83 (m, 4H), 5.10 (s, 1H); ¹³C NMR d 15.9 (q), 16.9

(q), 27.0 (t), 29.0 (t), 29.7 (q), 34.2 (d), 34.4 (t), 38.7 (t), 47.8

(s), 56.1 (s), 64.5 (t), 65.1 (t), 106.3 (d), 119.6 (s), 204.3 (s),

206.3 (s); IR n_max(liquid ®lm) 2940, 2883, 2231, 1716,

1448, 1369, 1228, 1140, 1099 cm²¹; MS m/z 293 (M¹,

1.1), 278 (0.3), 265 (0.2), 250 (0.2), 235 (0.4), 222 (0.8),

208 (0.7), 151 (1.6), 127 (1.5), 74 (3.1), 73 (100), 69 (1.4),

55 (3.8), 45 (8.1), 43 (6.6), 41 (2.4); HRMS: M¹, found

293.1622. C₁₆H₂₃NO₄requires 293.1627.

n

_max(liquid ®lm) 3080, 2948, 2892, 2230, 1721, 1716, 1449,

1373, 1243, 1162, 1113, 1033, 992, 938 cm²¹; MS m/z 333

(M¹, 1), 263 (3), 248 (3), 176 (2), 148 (4), 135 (7), 121 (10),

105 (9), 74 (38), 73 (100), 67 (18), 55 (30), 45 (92), 43 (12),

41 (28); HRMS: M¹, found 333.1941. C₁₉H₂₇NO₄requires

333.1940.

(1R,3R,4R)-3-(1,3-Dioxolan-2-yl)-3,4-dimethyl-2-oxo-1-

(3-oxo-pentyl)-cyclohexanecarbonitrile (43) and (1S,3R,

4R)-3-(1,3-Dioxolan-2-yl)-3,4-dimethyl-2-oxo-1-(3-oxo-

pentyl)-cyclohexanecarbonitrile (44). This product was

synthesised in 87% yield as a 5:4 mixture of stereoisomers

via Method A after stirring 8 h at room temperature.

The individual isomers were obtained after column

chromatography with ethyl acetate/light petroleum 1/5 as

eluent.

(1S,3R,4R,6S)-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-

2-yl]-6-isopropenyl-3,4-dimethyl-2-oxo-1(3-oxo-butyl)-

cyclohexanecarbonitrile (29). Obtained via Method A after

19 days as white crystals in 95% yield after column chro-

matography with ethyl acetate/light petroleum 3/7 as eluent.

Mp 82±82.58C; [a]_D215.8 (c1.49); ¹H NMR d 0.91 (d,

J7.0 Hz, 3H), 0.99 (s, 3H), 1.54 (ddd, J2.8, 6.2, 9.6 Hz,

1H), 1.80 (ddd, J1.6, 5.8, 7.8 Hz, 2H), 1.93 (br s, 3H),

1.97±2.11 (m, 3H), 2.16 (s, 3H), 2.33±2.53 (m, 3H),

2.67±2.88 (m, 3H), 3.86±4.08 (m, 2H), 4.96 (s, 1H),

4.97±5.03 (m, 1H), 5.03 (br s, 1H), 5.04 (br s, 1H), 5.71

(d, J5.0 Hz, 1H); ¹³C NMR d 15.4 (q), 16.4 (q), 21.0 (q),

27.8 (t), 30.1 (q), 32.2 (t), 32.6 (t), 33.7 (t), 34.3 (d), 40.0 (t),

42.2 (d), 48.8 (d), 51.3 (s), 56.0 (s), 68.0 (t), 81.7 (d), 109.2

(d), 116.5 (t), 118.7 (s), 142.5 (s), 204.1 (s), 207.2 (s); IR

1

Minor (less polar) isomer (43): [a]_D287.0 (c1.3); H

NMR d 0.86 (d, J7.1 Hz, 3H), 0.99 (s, 3H), 1.01, (t,

J7.3 Hz, 3H), 1.50±1.59 (m, 1H), 1.74±1.93 (m, 2H),

2.09±2.24 (m, 2H), 2.35 (q, J7.3 Hz, 2H), 2.35±2.47

(m, 2H), 2.55±2.63 (m, 2H), 3.81±3.90 (m, 3H), 3.96±

4.00 (m, 1H), 5.61 (s, 1H); ¹³C NMR d 7.8 (q), 14.0 (q),

16.3 (q), 25.7 (t), 29.7 (t), 33.9 (t), 36.0 (t), 36.1 (d), 38.1 (t),

48.4 (s), 58.4 (s), 65.1 (t), 65.6 (t), 104.2 (d), 119.4 (s), 202.9

(s), 209.6 (s); IR n_max(liquid ®lm) 2979, 2941, 2884, 2231,

1717, 1461, 1393, 1375, 1261, 1201, 1138, 1113, 1032,

n

_max(KBr) 3080, 2975, 2873, 2212, 1721, 1713, 1457, 1387,

1101, 1011, 998 cm²¹; MS m/z 373 (M¹, 0.7), 260 (6), 167

(15), 114 (7), 113 (100), 83 (8), 73 (9), 69 (30), 55 (9), 43

(9), 41 (6); HRMS: M¹, found 373.2246. C₂₂H₃₁NO₄

requires 373.2253.

988 cm²¹

.

1

(1R,3R,4R)-3-(1,3-Dioxolan-2-yl)-3,4-dimethyl-2-oxo-1-

(3-oxo-butyl)-cyclohexanecarbonitrile (36) and (1S,3R,

4R)-3-(1,3-Dioxolan-2-yl)-3,4-dimethyl-2-oxo-1-(3-oxo-

butyl)-cyclohexanecarbonitrile (38). This product was

synthesised in 90% yield as a 5:4 mixture of stereoisomers

via Method A after stirring for 8 h at room temperature. The

individual isomers were obtained after column chroma-

tography with ethyl acetate/light petroleum 3/7 as eluent.

The MS spectrum of the major (less polar) isomer was

superimposable with the one obtained from the annelated

product 40, vide infra.

Major (more polar) isomer (44): [a]_D126.8 (c1.3); H

NMR d 0.95 (d, J6.8 Hz, 3H), 0.96 (t, J7.1 Hz, 3H),

1.24, (s, 3H), 1.65±1.82 (m, 3H), 2.09±2.21 (m, 3H),

2.35±2.47 (m, 1H), 2.41 (q, J7.3 Hz, 2H), 2.55±2.73

(m, 2H), 3.70±3.90 (m, 4H), 5.56 (s, 1H); ¹³C NMR d 7.6

(q), 16.0 (q), 16.9 (q), 27.1 (t), 29.1 (t), 34.3 (d), 34.5 (t),

35.7 (t), 47.9 (s), 56.2 (s), 64.6 (t), 65.2 (t), 106.4 (d), 119.7

(s), 202.4 (s), 209.3 (s); IR n_max(liquid ®lm) 2978, 2941,

2884, 2231, 1717, 1461, 1392, 1375, 1201, 1138, 1113,

1032, 988 cm²¹; MS m/z 307 (M¹, 0.8), 168 (6), 151 (2),

139 (12), 127 (5), 74 (3), 73 (100), 69 (1), 57 (18), 55 (8), 45

(5), 43 (5), 41 (2); HRMS: M¹, found 307.1777. C₁₆H₂₃NO₄

requires 307.1784.

1

Major (less polar) isomer (36): [a]_D295.4 (c1.3); H

NMR d 0.82 d, J7.1 Hz, 3H), 0.95 (s, 3H), 1.45±1.54 (m,

1H), 1.68±1.88 (m, 2H), 2.08 (s, 3H), 2.04±2.20 (m, 2H),

2.22±2.48 (m, 2H), 2.50±2.82 (m, 2H), 3.80±3.88 (m, 3H),

3.90±4.00 (m, 1H), 5.58 (s, 1H); ¹³C NMR d 13.8 (q), 16.1

(q), 25.5 (t), 29.4 (t), 29.8 (q), 33.6 (t), 35.9 (d), 39.2 (t), 47.8

(1^p,3R,4R)-[(2R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-2-

yl]-3,4-dimethyl-2-oxo-1-(3-oxo-butyl)-cyclohexanecar-

bonitrile (37) and (39). This product was synthesised

following Method A in 78% yield after 18-h reaction

2090

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

time. After column chromatography with ethyl acetate/light

petroleum 3/7 as eluent there was obtained according to ¹H

NMR and GLC an inseparable 6/5 mixture of dia-

stereoisomers.

Method 3. A stirred solution of 1 mmol of the b keto nitrile

under investigation in 15 mL of dry toluene was treated with

5 mL of a 0.2 M solution of pyrrolidine in THF, adjusted

with acetic acid at pH5.2, and 1.2 mmol of methyl vinyl

ketone. The reaction mixture was re¯uxed for 3 h, cooled,

diluted with 100 mL of ether, washed with 25 mL of a 4 M

aqueous NaOH solution and with brine, dried, and evapor-

ated to give the corresponding annelated product.

1

Major isomer (37): H NMR (selected peaks) d 0.99 (d,

J6.8 Hz, 3H), 1.19 (s, 3H), 1.70±1.90 (m, 6H), 2.08±

2.30 (m, 5H), 2.14 (s, 3H), 2.58±2.76 (m, 3H), 3.81±3.95

(m, 2H), 4.24 (dd, J7.2, 9.0 Hz, 1H), 5.63 (d, J5.0 Hz,

1H); ¹³C NMR d 15.8 (q), 16.5 (q), 26.7 (t), 29.6 (t), 29.9

(q), 32.8 (t), 33.5 (t), 33.7 (t), 36.9 (d), 39.1 (t), 42.4 (d), 48.4

(s), 55.6 (s), 67.7 (t), 82.5 (d), 109.4 (d), 119.9 (s), 204.9 (s),

206.8 (s).

Method 4. A solution of 5 mL of a 0.2 M solution of pyrro-

lidine in THF, adjusted with acetic acid at pH5.2, in

25 mL of dry toluene was heated at re¯ux temperature. A

solution of 0.5 mmol of the (3-oxo-butyl)-derivative in

10 mL of dry toluene was added and re¯uxed for another

30 min. The reaction mixture was cooled, diluted with

50 mL of ether, washed with 25 mL of an aqueous 1 M

solution of NaOH and with brine, dried, and evaporated to

afford the annelated product.

1

Minor isomer (39): H NMR (selected peaks) d 0.88 (d,

J6.8 Hz, 3H), 0.95 (s, 3H), 1.70±1.90 (m, 6H), 2.08±

2.30 (m, 5H), 2.14 (s, 3H), 2.58±2.76 (m, 3H), 3.81±3.95

(m, 2H), 4.92 (dd, J5.8, 9.8 Hz, 1H), 5.71 (d, J4.9 Hz,

1H); ¹³C NMR d 15.1 (q), 16.1 (q), 25.6 (t), 29.9 (q), 29.9

(t), 32.6 (t), 33.9 (t), 35.2 (t), 37.1 (d), 39.5 (t), 42.2 (d), 47.7

(s), 52.2 (s), 68.0 (t), 81.9 (d), 109.2 (d), 120.0 (s), 204.7 (s),

206.8 (s).

Method 5. A solution of 0.69 mL (8.33 mmol) of pyrrolidine

in 10 mL of THF was neutralised with acetic acid (pH7.0)

and 7.6 mmol of the appropriate substrate was added and

re¯uxed for the indicated time. The reaction mixture was

cooled, diluted with 50 mL of ether and 25 mL of water and

extracted three times with ether. The combined extracts

were washed with brine, dried, and evaporated to afford

the annelated product.

IR n_max(tetra, diastereoisomeric mixture) 2973, 2963, 2873,

2236, 1725, 1717, 1451, 1371, 1169, 1109, 1024, 941 cm²¹

;

MS m/z 333 (M¹, 0.9), 221 (4), 167 (17), 151 (4), 139 (8),

138 (6), 113 (100), 83 (8), 71 (6), 69 (41), 57 (6), 55 (11), 43

(13), 41 (6); HRMS: M¹, found 233.1938. C₁₉H₂₇NO₄

requires 333.1940.

Method 6. A solution of 10 mmol of the (3-oxo-butyl)-

substituted ketone in 25 mL of methanol was treated with

10 mL of a 45% aqueous solution of KOH at the indicated

temperature. After the indicated time water was added and

the aqueous phase was extracted three times with ether. The

combined organic layers were washed with brine, dried, and

evaporated to afford the annelated product.

General procedure for the Robinson annelation

Method 1. A stirred solution of 1 mmol of the appropriate b

keto nitrile and 1.2 mmol of methyl vinyl ketone in 10 mL

of benzene was treated at room temperature with 0.2 mmol

of sodium methanolate (0.2 mL of an 1 M solution in metha-

nol) until all starting material had disappeared and another

0.6 mmol of sodium methanolate was added and stirred for

the indicated time. The reaction mixture was diluted with

50 mL of ether and 5 mL of water and acidi®ed with 2 mL

of an aqueous 1 M solution of hydrochloric acid. The

organic layer was separated and washed with brine, dried

over magnesium sulfate, ®ltered, and evaporated to give the

dehydrated, annelated product.

(4aR,5R)-5-Isopropenyl-8-methyl-4,4a,5,6-tetrahydro-

naphthalen-2(3H)-one (18). This crystalline product was

obtained via Method 6 by stirring for 1 h at 08C in 78%

yield. The crude product was puri®ed by distillation under

reduced pressure (Kugelrohr, 0.02 mmHg, oven tempera-

1

ture 1708C). Mp 70±718C; H NMR d 1.42±1.56 (m, 1H),

1.70 (s, 3H), 1.84 (br s, 3H), 1.98±2.49 (m, 7H), 4.82 (m,

2H), 5.95 (br s, 1H), 6.14 (m, 1H); ¹³C NMR d 18.1 (q), 19.3

(q), 27.7 (t), 31.8 (t), 37.8 (t), 38.0 (d), 48.7 (d), 113.5 (t),

122.0 (d), 131.7 (s), 136.7 (d), 145.8 (s), 159.1 (s), 200.8 (s);

IR n_max(tetra) 3072, 2992, 2925, 2873, 1660, 1583, 1440,

1346, 1316, 1264, 1210, 910, 890 cm²¹; MS m/z 202 (M¹,

32), 160 (65), 145 (40), 132 (100), 131 (75), 118 (55), 117

(96), 115 (36), 105 (46), 91 (81), 79 (33), 65 (34), 51 (33),

41 (46), 39 (43); HRMS: M¹, found 202.1355. C₁₄H₁₈O

requires 202.1358.

Method 2. A stirred solution of 1 mmol of the appropriate b

keto nitrile and 1.2 mmol of methyl vinyl ketone in 10 mL

of benzene was treated at room temperature with 0.2 mmol

of sodium methanolate (0.2 mL of a 1 M solution in metha-

nol) until all starting material had disappeared and then

0.6 mmol of sodium methanolate (0.6 mL of a 1 M solu-

tion in methanol) was added and stirred for the indicated

time. The reaction mixture was diluted with 50 mL of ether

and 5 mL of water and acidi®ed with 2 mL of an aqueous

1 M solution of hydrochloric acid. The organic layer was

separated and washed with brine, dried over magnesium

sulfate, ®ltered, and evaporated to give the annelated b

hydroxy ketone. This ketone was dissolved in toluene and

re¯uxed for 1 h in the presence of a catalytic amount of

p-toluenesulfonic acid. The reaction mixture was washed

with brine, dried on magnesium sulfate, and evaporated to

give the corresponding dehydrated, annelated product.

(4aS,5S)-5-Isopropenyl-8-methyl-4,4a,5,6-tetrahydro-

naphthalen-2(3H)-one. This product was obtained in 75%

yield via Method 6 by stirring for 18 h at room temperature.

Puri®cation was performed by column chromatography

with ethyl acetate/light petroleum 1/9 as eluent. Mp 77±

1

808C; H NMR d 1.39 (dddd, J5.0, 11.5, 15.0, 16.5 Hz,

1H), 1.63 (t, J1.0 Hz, 3H), 1.76 (q, J1.6 Hz, 3H), 2.09±

2.41 (m, 7H), 4.75 (s, 1H), 4.76 (t, J1.6 Hz, 1H), 5.87 (d,

J1.2 Hz, 1H), 6.08 (m, 1H); ¹³C NMR d 17.8 (q), 19.0 (q),

27.4 (t), 31.5 (t), 37.5 (t), 37.7 (d), 48.4 (d), 113.2 (t), 121.7

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2091

(d), 131.4 (s), 136.4 (d), 145.5 (s), 158.7 (s), 200.3 (s); IR

_max(KBr) 3069, 2991, 2931, 2876, 1669, 1643, 1596, 1443,

(q), 26.6 (t), 31.9 (t), 34.7 (d), 35.5 (d), 36.4 (t), 45.2 (d),

47.0 (d), 112.3 (t), 126.5 (d), 146.6 (s), 169.9 (s), 200.0 (s).

n

1350, 1270, 919, 898 cm²¹; MS m/z 202 (M¹, 24), 160 (78),

145 (42), 132 (100), 131 (80), 118 (66), 117 (91), 115 (39),

105 (46), 91 (81), 79 (33), 77 (54), 65 (34), 53 (34), 51 (37),

41 (68), 39 (44); HRMS: M¹, found 202.1356. C₁₄H₁₈O

requires 202.1358; Anal: found C, 83.42; H, 8.99%.

C₁₄H₁₈O requires C, 83.12; H, 8.97%.

Minor isomer: ¹H NMR d 0.55 (d, J7.1 Hz, 3H), 0.82 (d,

J6.8 Hz, 3H), 1.48 (br s, 3H), 1.00±2.50 (m, 10H), 4.56

(m, 2H), 5.66 (d, J2.0 Hz, 1H); ¹³C NMR d 13.1 (q), 15.4

(q), 18.3 (q), 26.0 (t), 34.7 (d), 35.6 (t), 38.7 (t), 40.6 (d),

42.0 (d), 47.2 (d), 112.4 (t), 124.1 (d), 146.5 (s), 168.1 (s),

199.9 (s).

(2R,3S,5S,6S)-5-Isopropenyl-2,3-dimethyl-spiro[5.5]undec-

7-ene-1,9-dione (21) and (2S,3S,5S,6S)-5-Isopropenyl-

2,3-dimethyl-spiro[5.5]undec-7-ene-1,9-dione (22). A 4/1

mixture of diastereoisomers was obtained via Method 5 in

80% yield after column chromatography with ethyl acetate/

light petroleum 1/4 as eluent. This diastereoisomeric

mixture was separated by column chromatography with

ethyl acetate/light petroleum 1/19.

(4aR,5S)-4a-Cyano-5-isopropenyl-8-methyl-4,4a,5,6-

tetrahydronaphthalen-2(3H)-one (23). This crystalline

product was prepared via Method 1 in 79% yield after a

reaction time of 2 h. Mp 106±1088C; [a]_D2156.5

1

(c2.25); H NMR d 1.87 (ddd, J4.6, 14.2, 16.0 Hz,

1H), 1.89 (s, 3H), 1.90 (s, 3H), 2.27±2.42 (m, 3H), 2.62±

2.84 (m, 3H), 5.00 (s, 1H), 5.02 (t, J1.6 Hz, 1H), 6.02 (s,

1H), 6.27 (d, J5.6 Hz, 1H); ¹³C NMR d 19.6 (q), 20.5 (q),

30.1 (t), 31.5 (t), 34.7 (t), 39.1 (s), 50.5 (d), 116.7 (t), 118.8

(s), 123.4 (d), 130.2 (s), 137.1 (d), 142.5 (s), 152.5 (s), 197.5

(s); IR n_max(KBr) 3074, 2963, 2921, 2226, 1677, 1625,

1588, 1444, 1307, 1265, 1238, 1174, 1054, 922,

887 cm²¹; MS m/z 227 (M¹, 100), 212 (36), 210 (10), 199

(41), 185 (31), 184 (30), 172 (74), 170 (69), 156 (30), 143

(43), 130 (29), 118 (20), 115 (22), 91 (18), 77 (25), 55 (12),

43 (16), 41 (14), 39 (14); HRMS: M¹, found 227.1305.

C₁₅H₁₇NO requires 227.1310; Anal: found C, 79.05; H,

7.56; N, 6.19%. C₁₅H₁₇NO requires C, 79.25; H, 7.53; N,

6.16%.

Minor isomer (21) (isopropenyl substituent in an equatorial

position): mp 140±1418C; [a]_D169.2 (c0.46); ¹H NMR

(400 MHz, C₆D₆) d 0.70 (d, J7.2 Hz, 3H), 0.97 (d,

J6.6 Hz, 3H), 1.23 (ddd, J14.1, 3.5, 2.2 Hz, 1H), 1.51

(br s, 3H), 1.89 (m, 2H), 2.01 (ddd, J13.9, 13.9, 4.8 Hz,

1H), 2.22 (m, 1H), 2.33 (dd, J16.6, 3.5 Hz, 1H), 2.43 (m,

2H), 3.14 (ddd, J17.3, 14.1, 5.5 Hz, 1H), 4.64 (s, 1H), 4.78

(br s, 1H), 6.00 (d, J10.4 Hz, 1H), 6.59 (dd, J10.4,

2.2 Hz, 1H); ¹³C NMR (100 MHz, C₆D₆) d 12.6 (q), 13.7

(q), 21.8 (q), 29.1 (t), 34.4 (t), 35.8 (t), 36.9 (d), 46.2 (d),

51.7 (d), 55.1 (s), 115.0 (t), 130.5 (d), 144.7 (s), 146.4 (d),

197.5 (s), 207.6 (s); MS m/z 246 (M¹, 8), 231 (4), 218 (3),

204 (8), 188 (8), 175 (11), 173 (12), 162 (19), 161 (17), 152

(18), 147 (19), 133 (41), 123 (21), 120 (25), 119 (26), 106

(75), 105 (100), 95 (43), 92 (39), 91 (92), 77 (38), 65 (21),

55 (36), 41 (40), 39 (25); Anal: found C, 78.74; H, 9.24%.

C₁₆H₂₂O₂requires C, 78.01; H, 9.00%.

(4aS,5R)-4a-Cyano-5-isopropenyl-8-methyl-4,4a,5,6-tetra-

hydronaphthalen-2(3H)-one. This crystalline product was

obtained via Method 1 in 85% yield after stirring the

reaction mixture for 2 h. Mp 114±1158C; [a]_D1156.7

1

(c1.1); H NMR d 1.85 (ddd, J4.6, 14.2, 15.6 Hz, 1H),

1.87 (s, 3H), 1.88 (s, 3H), 2.27±2.41 (m, 3H), 2.61±2.83 (m,

3H), 5.00 (s, 1H), 5.01 (br s, 1H), 6.06 (s, 1H), 6.28 (d,

J5.6 Hz, 1H); ¹³C NMR d 19.5 (q), 20.5 (q), 30.1 (t),

31.4 (t), 34.7 (t), 39.1 (s), 50.5 (d), 116.6 (t), 118.8 (s),

123.3 (d), 130.2 (s), 137.1 (d), 142.5 (s), 152.4 (s), 197.4

(s); IR n_max(KBr, Hitachi EPI-G3) 3070, 2990, 2925, 2225,

1660, 1650, 1580, 1440, 1350, 1315, 1270, 1210, 910,

890 cm²¹; MS m/z 227 (M¹, 100), 212 (50), 210 (21), 199

(59), 186 (16), 185 (35), 184 (51), 172 (82), 170 (91), 158

(31), 143 (75), 130 (60), 115 (55), 91 (45), 77 (62), 51 (38),

41 (51), 39 (67); HRMS: M¹, found 227.1306. C₁₅H₁₇NO

requires 227.1310. Anal: found C, 78.95; H, 7.56; N, 5.99%.

C₁₅H₁₇NO requires C, 79.25; H, 7.53; N, 6.16%.

Major isomer (22) (isopropenyl substituent in an axial

position): mp 97±988C; [a]_D10.6 (c3.9); ¹H NMR

(400 MHz, C₆D₆) d 0.83 (d, J6.4 Hz, 3H), 1.13 (d,

J6.4 Hz, 3H), 1.28±1.97 (m, 6H), 1.50 (s, 3H), 2.25 (m,

2H), 2.39 (m, 1H), 4.57 (s, 1H), 4.86 (s, 1H), 6.17 (d,

J10.6 Hz, 1H), 7.19 (d, J10.6 Hz, 1H); ¹³C NMR

(100 MHz, C₆D₆) d 12.6, (q), 20.9 (q), 24.9 (q), 32.2 (t),

33.4 (t), 33.6 (t), 35.4 (d), 47.1 (d), 50.1 (d), 51.6 (s), 114.2

(t), 130.3 (d), 144.8 (s), 151.7 (d), 196.5 (s), 212.2 (s); MS

m/z 246 (M¹, 9), 231 (5), 218 (3), 213 (4), 204 (12),190 (9),

175 (14), 173 (14), 162 (41), 161 (23), 152 (23), 147 (24),

133 (39), 120 (26), 119 (30), 106 (76), 105 (100), 95 (77), 92

(36), 91 (92), 79 (33), 77 (40), 69 (16), 67 (26), 65 (24), 55

(41), 41 (48), 39 (28); Anal: found C, 78.58; H, 9.29%.

C₁₆H₂₂O₂requires C, 78.01; H, 9.00%.

(4aS,5S,7R,8R,8aS)-4a-Cyano-8a-hydroxy-5-isopropenyl-

7,8-dimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-2(1H)-

one. This product was synthesised via Method 2 after 2 h in

88% yield without dehydration and puri®ed by column

chromatography with ethyl acetate/light petroleum 1/4 as

(4aS,5R,7R,8^p)-5-Isopropenyl-7,8-dimethyl-4,4a,5,6,7,8-

hexahydronaphthalen-2(3H)-one (20). This product was

obtained via Method 6 after 12 h at room temperature in

20% yield. After puri®cation by column chromatography

on silica gel with light petroleum/ethyl acetate 80/20 as

eluent a 7/3 inseparable diastereoisomeric mixture was

obtained.

1

eluent. Mp 185±1888C; [a]_D12.8 (c1.5); H NMR d

0.96 (d, J7.0 Hz, 3H), 1.02 (d, J7.4 Hz, 3H), 1.52 (dt,

J13.2, 3.0 Hz, 1H), 1.84 (t, J0.6 Hz, 3H), 2.00±2.27 (m,

7H), 2.42±2.80 (m, 4H), 4.92 (br s, 1H), 5.02 (br s, 1H); ¹³C

NMR d 12.8 (q), 14.8 (q), 21.3 (q), 29.5 (t), 33.6 (d), 36.0

(t), 38.4 (t), 41.0 (d), 47.5 (s), 50.0 (t), 79.0 (s), 114.9 (t),

122.0 (s), 144.4 (s), 209.2 (s); IR n_max(KBr) 3435, 3068,

2985, 2970, 2895, 2229, 1710, 1474, 1384, 1179, 973,

907 cm²¹; MS m/z 261 (M¹, 21), 246 (4), 243 (20),

Major isomer: ¹H NMR d 0.73 (d, J7.1 Hz, 3H), 1.00 (d,

J7.3 Hz, 3H), 1.46 (br s, 3H), 1.00±2.50 (m, 10H), 4.56

(m, 2H), 5.61 (br s, 1H); ¹³C NMR d 18.4 (q), 19.9 (q), 21.2

2092

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

228(10), 202 (12), 201 (45), 186 (12), 172 (13), 149 (12),

123 (19), 95 (50), 83 (24), 69 (31), 55 (44), 43 (100), 41

(34); HRMS: M¹, found 261.1725. C₁₆H₂₃NO₂requires

261.1729; Anal: found C, 73.71; H, 8.79; N, 5.51%.

C₁₆H₂₃NO₂requires C, 73.52; H, 8.87; N, 5.36%.

905 cm²¹; MS m/z 261 (M¹, 68), 246 (5), 243 (6), 233

(6), 218 (9), 217 (12), 192 (18), 190 (11), 177 (32), 176

(100), 134 (14), 123 (7), 121 (7), 95 (9), 93 (11), 55 (19),

43 (21), 41 (26); HRMS: M¹, found 261.1723. C₁₆H₂₃NO₂

requires 261.1729; Anal: found C, 73.71; H, 8.76; N, 5.51%.

C₁₆H₂₁NO requires C, 73.52; H, 8.87; N, 5.36%.

(4aR,5S,7R,8R)-4a-Cyano-5-isopropenyl-7,8-dimethyl-

4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (26). This

product was synthesised via Method 2 in 82% yield after

a reaction time of 16 h. Puri®cation was performed by

column chromatography with ethyl acetate/light petroleum

(4aS,5R)-4a-Cyano-5-isopropenyl-8,8-dimethyl-4,4a,5,6,

7,8-hexahydronaphthalen-2(3H)-one. Obtained after 48 h

as white crystals in 74% yield after column chromatography

on silica gel with ethyl acetate/light petroleum 1/4 as eluent.

Mp 89±948C; [a]_D19.7 (c3.0); ¹H NMR d 1.17 (s, 3H),

1.38 (s, 3H), 1.40±1.82 (m, 4H), 1.88 (br s, 3H), 1.99±2.13

(m, 2H), 2.35±2.67 (m, 3H), 4.94 (s, 1H), 4.95 (q,

J1.6 Hz, 1H), 6.10 (s, 1H); ¹³C NMR d 20.8 (q), 25.0

(t), 29.7 (q), 30.0 (s), 30.2 (q), 34.0 (t), 34.2 (t), 37.6 (s),

39.3 (t), 55.0 (d), 115.9 (t), 120.0 (s), 126.0 (d), 143.0 (s),

164.7 (s), 197.3 (s); MS m/z 243 (M¹, 39), 228 (32), 201

(100), 187 (19), 186 (45), 172 (33), 145 (28), 130 (15), 91

(14), 81 (50), 55 (18), 41 (25), 39 (11); HRMS: M¹, found

243.1613. C₁₆H₂₁NO requires 243.1623; Anal: found C,

78.71; H, 8.79; N, 5.61%. C₁₆H₂₁NO requires C, 78.97; H,

8.70; N, 5.76%.

1

1/4 as eluent. Mp 84±868C; [a]_D2154.7 (c2.0); H

NMR d 0.73 (d, J7.0 Hz, 3H), 1.03 (d, J6.6 Hz, 3H),

1.51±1.57 (m, 1H), 1.82 (s, 3H), 2.07±2.50 (m, 6H), 2.83

(ddq, J2.0, 6.6, 8.8 Hz, 1H), 4.92 (s, 1H), 4.93 (t,

J1.4 Hz, 1H), 5.85 (d, J2.0 Hz, 1H); ¹³C NMR d 12.9

(q), 15.5 (q), 20.8 (q), 31.8 (t), 33.9 (t), 34.2 (d), 36.0 (t),

39.0 (d), 42.0 (s), 48.8 (d), 116.0 (t), 120.0 (s), 126.4 (d),

142.9 (s), 159.8 (s), 196.5 (s); IR n_max(KBr) 3076, 2969,

2931, 2229, 1682, 1455, 1385, 1289, 1266, 1226, 903 cm²¹

;

MS m/z 243 (M¹, 48), 228 (35), 201 (80), 186 (30), 172

(32), 158 (21), 145 (20), 144 (17), 130 (17), 118 (15), 95

(100), 91 (27), 77 (24), 55 (50), 43 (22), 41 (44), 39 (21);

HRMS: M¹, found 243.1614. C₁₆H₂₁NO requires 243.1623;

Anal: found C, 78.81; H, 8.83; N, 5.49%. C₁₆H₂₁NO

requires C, 78.97; H, 8.70; N, 5.76%.

(4aR,5S,7R)-4a-Cyano-5-isopropenyl-7,8,8-trimethyl-4,4a,

5,6,7,8-hexahydronaphthalen-2(3H)-one (33). This product

was obtained as white crystals via Method 3 in 84% yield

after puri®cation by column chromatography with ethyl

acetate/light petroleum 1/9 as eluent. Mp 119±1218C;

[a]_D2171.2 (c3.5); ¹H NMR d 0.88 (d, J7.0 Hz,

3H), 1.11 (s, 3H), 1.45 (s, 3H), 1.46 (dt, J13.6, 3.6 Hz,

1H), 1.75±1.95 (m, 1H), 1.88 (s, 3H), 2.28 (dd, J3.2, 13.2,

1H), 2.40±2.68 (m, 5H), 4.97 (s, 1H), 5.01 (t, J1.4 Hz,

1H), 6.10 (s, 1H); ¹³C NMR d 16.4 (q), 20.9 (q), 27.2 (q),

31.0 (q), 32.1 (t), 34.2 (t), 34.6 (t), 38.2 (d), 38.9 (s), 41.2 (s),

48.1 (d), 116.5 (t), 120.4 (s), 127.8 (d), 143.0 (s), 164.2 (s),

197.4 (s); IR n_max(KBr) 3074, 2971, 2949, 2875, 2222,

1682, 1600, 1455, 1380, 1304, 1271, 1185, 1093,

915 cm²¹; MS m/z 257 (M¹, 33), 242 (18), 216 (15), 215

(100), 214 (13), 200 (20), 186 (12), 173 (11), 172 (41), 158

(9), 95 (14), 41 (9); HRMS: M¹, found 257.1772. C₁₇H₂₃NO

requires 257.1780; Anal: found C, 79.33; H, 9.33; N, 5.31%.

C₁₇H₂₃NO requires C, 79.33; H, 9.01; N, 5.44%.

(4aR,5S)-4a-Cyano-5-isopropenyl-8,8-dimethyl-4,4a,5,6,

7,8-hexahydronaphthalen-2(3H)-one (24). Obtained via

Method 1 as white crystals in 94% yield after crystallisation

from hexane/tert-butyl methyl ether 95/5. The reaction was

performed in 48 h. Mp 93±948C; [a]_D211.4 (c2.5); ¹H

NMR d 1.15 (s, 3H), 1.36 (s, 3H), 1.64±1.79 (m, 4H), 1.87

(br s, 3H), 1.97±2.13 (m, 2H), 2.33±2.70 (m, 3H), 4.91 (s,

1H), 4.94 (q, J1.6 Hz, 1H), 6.07 (s, 1H); ¹³C NMR d 21.1

(q), 25.2 (t), 29.6 (s), 29.9 (q), 30.2 (q), 34.0 (t), 34.2 (t),

37.8 (s), 39.5 (t), 55.2 (d), 116.1 (t), 120.2 (s), 126.2 (d),

143.2 (s), 164.9 (s), 197.7 (s); IR n_max(KBr) 3073, 2969,

2930, 2229, 1682, 1450, 1384, 1346, 1289, 1226, 1126,

903 cm²¹; MS m/z 243 (M¹, 41), 228 (22), 201 (100), 187

(17), 186 (35), 172 (28), 145 (24), 130 (15), 91 (14), 81 (51),

55 (18), 41 (25), 39 (11); HRMS: M¹, found 243.1620.

C₁₆H₂₁NO requires 243.1623; Anal: found C, 78.91; H,

8.73; N, 5.71%. C₁₆H₂₁NO requires C, 78.97; H, 8.70; N,

5.76%.

(4aR,5S,7R,8S)-4a-Cyano-8-(1,3-dioxolan-2-yl)-5-iso-

propenyl-7,8-dimethyl-4,4a,5,6,7,8-hexahydronaphtha-

len-2(3H)-one (34). Obtained via Method 4 in 41% yield

after puri®cation with column chromatography on silica gel

with ethyl acetate/light petroleum 3/7 as eluent. From the

basic water layer b keto nitrile 13c was isolated in 48%

yield. [a]_D2145.2 (c1.2); ¹H NMR d 0.90 (d,

J7.0 Hz, 3H), 1.02 (s, 3H), 1.45 (dt, J13.8, 6.0 Hz,

1H), 1.83±1.91 (m, 1H), 1.91 (s, 3H), 2.26±2.71 (m, 6H),

3.81±3.91 (m, 3H), 3.91±4.00 (m, 1H), 4.96 (s, 1H), 5.02 (t,

J1.4 Hz, 1H), 5.55 (s, 1H), 6.15 (s, 1H); ¹³C NMR d 16.4

(q), 17.1 (q), 21.1 (q), 31.8 (t), 33.6 (d), 34.4 (t), 35.0 (t),

39.6 (s), 47.8 (d), 48.7 (s), 65.2 (t), 65.8 (t), 103.8 (d), 116.6

(t), 119.7 (s), 131.4 (d), 143.0 (s), 157.9 (s), 197.1 (s); IR

(4aR,5R,8aR)-4a-Cyano-8a-hydroxy-5-isopropenyl-8,8-

dimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalen-2(1H)-

one. This from S(1)-carvone-derived cyclised but not

dehydrated product was obtained via Method 1 after 16 h.

Puri®cation was achieved by column chromatography with

ethyl acetate/light petroleum 1/4 as eluent to give white

1

crystals in 66% yield. Mp 193±1948C; H NMR d 0.93 (s,

3H), 1.31 (s, 3H), 1.37 (dt, J13.1, 3.1 Hz, 1H), 1.54 (dq,

J13.4, 3.2 Hz, 1H), 1.75 (dt, J3.3, 13.3 Hz, 1H), 1.87 (s,

3H), 2.00 (dt, J3.2, 13.0 Hz, 1H), 2.05±2.30 (m, 2H),

2.36±2.47 (m, 3H), 2.54±2.78 (m, 2H), 2.96 (d,

J14.5 Hz, 1H), 4.94 (s, 1H), 4.95 (s, 1H); ¹³C NMR d

21.5 (q), 24.0 (q), 25.4 (t), 25.7 (q), 32.0 (t), 35.8 (t), 37.9

(t), 39.1 (s), 44.2 (s), 46.3 (t), 47.1 (d), 79.4 (s), 115.0 (t),

122.9 (s), 143.9 (s), 209.0 (s); IR n_max(KBr, Hitachi EPI-

G3) 3590, 3475, 3050, 2950, 2925, 2850, 2210, 1705, 1635,

1440, 1390, 1370, 1340, 1300, 1205, 1125, 1060, 950,

n

_max(KBr) 3075, 2987, 2958, 2227, 1682, 1609, 1454, 1384,

1268, 1232, 1166, 1113, 1080, 1065, 988, 889 cm²¹; MS

m/z 315 (M¹, 3), 87 (2), 85 (9), 83 (14), 74 (3), 73 (100), 69

(2), 47 (2), 45 (4); HRMS: M¹, found 315.1834. C₁₉H₂₅NO₃

requires 315.1834.

B. J. M. Jansen et al. / Tetrahedron 56 (2000) 2075±2094

2093

(4aR,5S,7R,8S)-4a-Cyano-8-[(2R,3aS,6aR)-hexahydro-

furo[2,3-b]furan-2-yl]-5-isopropenyl-7,8-dimethyl-4,4a,

5,6,7,8-hexahydronaphthalen-2(3H)-one (35). Obtained

via Method 4 in 40% yield as light yellow crystals. The

corresponding b keto nitrile 14c was recovered from the

basic water layer in 56% yield. Mp 201±2028C;

[a]_D255.3 (c0.97); ¹H NMR d 0.85 (d, J7.0 Hz,

3H), 0.95 (s, 3H), 1.38 (dt, J13.8, 5.8 Hz, 1H), 1.68±

1.89 (m, 4H), 1.90 (s, 3H), 1.97±2.28 (m, 2H), 2.30±2.50

(m, 4H), 2.64±2.79 (m, 2H), 3.79±4.00 (m, 2H), 4.86 (dd,

J5.8, 10.2 Hz, 1H), 4.95 (s, 1H), 5.00 (t, J1.4 Hz, 1H),

5.66 (d, J5.0 Hz, 1H), 6.03 (s, 1H); ¹³C NMR d 16.8 (q),

18.2 (q), 21.3 (q), 32.0 (t), 32.8 (t), 34.1 (t), 34.5 (t), 35.2 (d),

35.5 (t), 39.1 (s), 42.2 (d), 47.1 (s), 47.7 (d), 68.0 (t), 81.4

(d), 108.8 (d), 116.7 (t), 120.0 (s), 131.3 (d), 143.0 (s), 158.9

(s), 197.2 (s); IR n_max(tetra) 3074, 2976, 2955, 2867, 2230,

1682, 1610, 1457, 1378, 1315, 1268, 1109, 1018, 994,

909 cm²¹; MS m/z 355 (M¹, 0.1), 244 (6), 243 (36), 228

(4), 176 (6), 175 (9), 114 (6), 113 (100), 69 (42), 67 (5), 55

(7); HRMS: M¹, found 355.2134. C₂₂H₂₉NO₃requires

355.2147; [M2C₆H₈O₂1H¹]1, found 243.1625. C₁₆H₂₁NO

requires 243.1627. Anal: found C, 74.53; H, 8.33; N, 3.61%.

C₂₂H₂₉NO₃requires C, 74.33; H, 8.22; N, 3.94%.

91 (2.0), 74 (3.0), 73 (100), 59 (2.9), 55 (2.1), 45 (6.6);

HRMS: M¹, found 275.1517. C₁₆H₂₁NO₃requires 275.1521.

(4aR,5S,7R,8S)-4a-Cyano-8-[(2R,3aS,6aR)-hexahydro-

furo[2,3-b]furan-2-yl]-7,8-dimethyl-4,4a,5,6,7,8-hexa-

hydronaphthalen-2(3H)-one (41). This crystalline product

was obtained in 91% yield via Method 4 after puri®cation by

column chromatography on silica gel with ethyl acetate/

light petroleum 1/4 as eluent. Mp 121±1238C;

[a]_D1143.0 (c0.7); ¹H NMR d 1.08 (d, J6.0 Hz,

3H), 1.39 (s, 3H), 1.53 (dt, J13.8, 4.6 Hz, 1H), 1.69±

1.84 (m, 4H), 1.89±1.93 (m, 1H), 1.97±2.20 (m, 3H),

2.26±2.40 (m, 2H), 2.55±2.73 (m, 2H), 2.77±3.00 (m,

1H), 3.88±3.96 (m, 2H), 4.47 (dd, J7.0, 10.1 Hz, 1H),

5.73 (d, J5.0 Hz, 1H), 6.01 (s, 1H); ¹³C NMR d 17.9

(q), 21.0 (q), 28.2 (t), 33.1(t), 33.7 (t), 34.0 (t), 35.3 (d),

36.2 (t), 37.0 (s), 37.4 (t), 42.0 (d), 46.0 (s), 68.2 (t), 84.2

(d), 108.9 (d), 121.3 (s), 128.5 (d), 161.2 (s), 197.4 (s); IR

n_max(tetra) 2971, 2955, 2869, 2230, 1682, 1610, 1453,

1374, 1316, 1109, 1018, 912 cm²¹; MS m/z 315 (M¹, 0.5),

203 (15), 188 (5), 167 (6), 114 (6), 113 (100), 83 (7), 69 (50),

67 (7), 57 (6), 55 (14), 43 (10), 41 (9); HRMS: M¹, found

315.1833. C₁₉H₂₅NO₃requires 315.1834; Anal: found C,

72.33; H, 8.23; N, 4.41%. C₁₉H₂₅NO₃requires C, 72.35;

H, 7.99; N, 4.44%.

(4aR,7R,8S)-4a-Cyano-8-(1,3-dioxolan-2-yl)-7,8-dimethyl-

4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (40) and

(4aS,7R,8S)-4a-Cyano-8-(1,3-dioxolan-2-yl)-7,8-dimethyl-

4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one (42). Starting

from 36 a 5/1 mixture of annelated products was obtained in

88% yield via Method 4 after 90 min. Puri®cation by

column chromatography on silica gel with ethyl acetate/

light petroleum 1/4 as eluent afforded the pure annelated

products.

Acknowledgements

The authors wish to thank A. van Veldhuizen for NMR

spectroscopic data, C. J. Teunis and H. Jongejan for mass

spectroscopic data, and M. van Dijk for performing the

elemental analyses.

A reaction for 90 min under the conditions of Method 4

afforded in 92% yield only the annelated product 40,

starting from 38.

References

Major isomer (40): [a]_D1156.4 (c1.1); ¹H NMR d 1.03

(d, J6.3 Hz, 3H), 1.36 (s, 3H), 1.46±2.72 (m, 9H), 3.80±

4.05 (m, 4H), 4.92 (s, 1H), 6.44 (s, 1H); ¹³C NMR d 17.4

(q), 19.0 (q), 27.8 (t), 34.1 (t), 34.8 (d), 35.9 (t), 36.9 (t), 37.0

(s), 45.9 (s), 64.5 (t), 64.7 (t), 107.3 (d), 121.4 (s), 129.2 (d),

159.5 (s), 197.6 (s); IR n_max(liquid ®lm) 2936, 2888, 2229,

1681, 1601, 1458, 1415, 1380, 1342, 1320, 1265, 1211,

1170, 1093, 1030, 992, 958 cm²¹; MS m/z 275 (M¹, 0.5),

274 (0.3), 215 (0.2), 188 (0.7), 187 (0.4), 174 (0.6), 160

(0.6), 159 (0.5), 140 (0.7), 138 (0.9), 117 (0.6), 116 (0.7),

115 (0.7), 105 (0.6), 104 (0.5), 103 (0.5), 91 (1.6), 77 (1.2),

74 (3.0), 73 (100), 55 (1.9), 45 (9.5), 41 (1.3); HRMS: M¹,

found 275.1514. C₁₆H₂₁NO₃requires 275.1521, (M2H)¹,

found 274.1440. C₁₆H₂₀NO₃requires 274.1443.

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36.9 (t), 48.7 (s), 65.2 (t), 65.7 (t), 103.7 (d), 121.0 (s), 131.4

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Article Doi

Enantioselective synthesis of functionalised decalones by robinson annulation of substituted cyclohexanones, derived from R-(-)-carvone

DOI: 10.1016/S0040-4020(00)00110-1

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