Forskolin studies

TETRAHEDRON

Pergamon

Tetrahedron 56 (2000) 1081–1095

Forskolin Studies

b

Dirk Behnke,^aLothar Hennig,^aMatthias Findeisen,^aPeter Welzel,^a,Dietrich Muller,

*

¨

c

c,

*

¨

Michael Thormann and Hans-Jorg Hofmann

a

¨

Fakultat fur Chemie und Mineralogie der Universitat Leipzig, Johannisallee 29, D-04103 Leipzig, Germany

b

¨

Fakultat fur Chemie der Ruhr-Universitat, D-44780 Bochum, Germany

Institut fur Biochemie der Universitat Leipzig, Talstr. 33, 04103 Leipzig, Germany

c

¨

Received 1 December 1999; accepted 23 December 1999

Abstract—A new nucleophilic isoprenoid C₅reagent is introduced which allowed synthesis of an advanced and optically active forskolin

intermediate in a very efﬁcient way. In addition, docking experiments that are based on X-ray results indicate that there might exist forskolin

analogues with improved properties as far as binding to adenylyl cyclases and synthetic accessibility are concerned. ᭧ 2000 Elsevier Science

Introduction

has been suggested that forskolin activates adenylyl cyclase

by promoting C₁/C₂association resulting in formation of an

active site.

Forskolin (1a) is a labdane diterpene that has been shown

to interact with different membrane proteins including

adenylyl cyclase, the glucose transporter, the voltage-

gated potassium channel and ligand-gated ion channels.¹

The ability of forskolin to stimulate adenylyl cyclase in

intact cells in the absence of hormonal agonists has been

exploited by many laboratories for investigation of the role

of cyclic AMP in various physiological functions. Nine

isoforms of adenylylcyclase have been identiﬁed. With the

exception of one, all of them are stimulated by forskolin.

They all contain a short cytosolic amino terminus followed

by two repeats of six transmembrane helices and a cytosolic

domain. Each of the two cytoplasmic domains, designated

as C₁and C₂, respectively, are implicated in catalysis. The

cytosolic domains can be overexpressed in bacteria. These

proteins have been shown to have forskolin-stimulated

catalytic activity when they are mixed ore tethered.^2,3Two

crystal structures have been reported some time ago by

Zhang and coworkers⁴and by the Sprang group,⁵respec-

tively. The Zhang group crystallized a C₂construct of type

II rat adenylyl cyclase with forskolin. The structure was

shown to be a homo dimer containing two molecules of

forskolin. The structure indicates that forskolin has polar

interactions to both C₂units, i.e. hydrogen bonds from

1 a-OH and the 11-oxo group to one (A) and hydrogen

bonds of the other (B) to the 7-acetyl group (see Fig. 1). It

The Sprang group on the other hand determined the crystal

structure of a complex consisting of the C₁and C₂units of

two different adenylyl cyclases, an activated G_saprotein

(G_sa·GTPgS), and a forskolin derivative. The binding of

this forskolin analogue (one molecule only) to the two C

units is analogous to that in the homo dimer as described

above. It is interesting to note that according to the X-ray

structures neither the 9- nor the 6-OH groups are involved in

hydrogen bonds to the enzyme.

Knowledge of the X-ray structure of forskolin-binding

partners and the essential ligand–protein interactions open

new possibilities to stimulate the synthesis of analogues

with comparable or even improved activity. This is of

special importance in the case of forskolin, since the total

syntheses performed so far, although they are of a high

degree of sophistication, suffer from the fact that about 35

steps are needed to reach the target compound from a

readily accessible starting material.⁶The search for more

easily accessible analogues, which nevertheless fulﬁl the

binding prerequisites of forskolin, may be supported by

systematic docking studies, which provide the binding

conformations of the potential ligands at their targets and

the interaction energies as a measure for the stability of the

complexes.

Keywords: nucleophilic isoprenoid C₅reagent; forskolin intermediate;

adenylyl cyclase.

* Corresponding authors. Tel.: ϩ49-0-341-97-36551; fax: ϩ49-0-341-97-

36599; e-mail: welzel@organik.chemie.uni-leipzig.de

Tel.: ϩ49-0-341-97-36839; e-mail: hofmann@rz.uni-leipzig.de

In the present paper, we wish to discuss some results of

molecular modeling experiments and a new approach

that allows preparation of an advanced forskolin synthetic

intermediate in a very efﬁcient way.

PII: S0040-4020(00)00005-3

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D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

Figure 1. Schematic representation of polar interactions between forskolin and adenylyl cyclases according to Ref. 4.

Docking Experiments

procedure are given in the Experimental section. In order to

test the reliability of the docking formalism for our

purposes, forskolin (1a) was the ﬁrst object of the docking

studies. Fig. 2(a) shows the excellent agreement between the

arrangements resulting from the X-ray for a protein obtained

from rat brain and the most stable one provided by the

docking studies.

On the basis of Zhang’s X-ray analysis,⁴docking experi-

ments were performed for forskolin 1a and the analogues

1b–e to study the consequences of structure variations for

the binding behaviour and to ﬁnd out possibilities of struc-

ture simpliﬁcation for synthesis. The docking experiments

were carried out employing the Lamarckian GA-LS (genetic

algorithm with local search) hybrid formalism of the latest

version of the docking program AutoDock 3.0,⁷that predicts

the bound conformations of ﬂexible ligands to macro-

molecular targets. This formalism represents a combination

of a genetic search algorithm for global searching and a

local search strategy to perform energy minimisation

using a fast grid-based energy evaluation method for the

protein–ligand interactions and an empirical binding free

energy function to estimate afﬁnity constants. The results

of this procedure for numerous protein–ligand complexes

demonstrate good agreement between the experimental and

theoretical data.⁸The computational details of the docking

The theoretically estimated K_D-value amounts to 14.8 nM

(Table 1) and agrees fairly well with the experimental value

of 18 nM.⁹Details of the docking results, which may be

useful for an evaluation of the data that are given in Table

1. It is very interesting to see that the docking procedure

reproduces both bindings sites of the dimer (denoted by A

and B in Fig. 1) with nearly the same arrangement of the

ligand in the various docking runs. This conﬁrms the high

efﬁciency of the method. The forskolin arrangement is also

the distinctly preferred one for all analogues 1b–e. The

estimated K_D-values differ depending on structure modiﬁca-

tions (Table 1). Three details should explicitly be

Figure 2a. Visualisation of forskolin (1a) rings A and C polar interactions

with a catalytic adenylyl cylase domain. Superposition of the practically

coincident crystal⁴(dark grey) and the most stable docking structures

(grey).

Figure 2b. Visualisation of rings A and C polar interactions of 1b with the

catalytic adenylyl cyclase domain as obtained from docking experiments.

For details see text.

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

1083

Table 1. Details of the docking studies

1a

1b

5.2

1c

1d

1e

8.1

K_D(nM)

14.8

19.2

33.8

Number of torsions

6

11

Ϫ11.9

(Ϫ11.6)

Ϫ11.6

(Ϫ11.3)

6

5

13

Ϫ12.4

(Ϫ12.4)

Ϫ12.0

(Ϫ11.7)

6

4

5

4

5

8

Number of clusters^a

Structures in cluser 1

A^b

B^b

E(A)^c

Ϫ11.5

(Ϫ11.3)

Ϫ11.4

(Ϫ11.4)

Ϫ11.4

(Ϫ11.3)

Ϫ11.1

(Ϫ11.0)

Ϫ12.0

(Ϫ11.9)

Ϫ11.6

(Ϫ11.5)

E(B)^c

^aFor computational details, see Experimental part.

^bNumber of structures found in the equivalent binding sites A and B of the dimer.

^cInteraction energy in kcal mol^Ϫ1; ﬁrst value: most stable structure in cluster 1, average value for all structures of cluster 1 in parentheses.

mentioned. The 1a-amino-1-deoxy derivative 1b exhibits a

higher afﬁnity than forskolin with a K_D-value of 5.2 nM.

This can well be explained by an additional hydrogen

bond to the protein (Fig. 2b). Removal of the 1-OH group

in 1d decreases the afﬁnity considerably. Contrary to this,

removal of the 6-OH group in 1e does not change the

afﬁnity. This hydroxyl group is obviously not essential for

binding, thus conﬁrming the corresponding conclusions

from the X-ray data.

to 6-deoxyforskolin (1e) might be an even simpler useful

target.

Our previous work has demonstrated that racemic tricyclic

labdane derivatives of type rac-2 can be obtained from a

precursor of type rac-4, which is itself available from

rac-drimenal (rac-3) and an isoprenoid C₅unit (Scheme 1).

Racemic drimenal is accessible from (E,E)-farnesol in two

steps.¹²A number of nucleophilic isoprenoid C₅synthons

can be envisaged. In a ﬁrst series of experiments the vinyl-

lithium reagent 5 was coupled to rac-3 to furnish the

labdane derivative rac-8 (Scheme 2). The oxygen function-

ality at C-13 was then introduced by a diastereoselective

Sharpless I epoxidation.¹³This route allowed preparation

of the advanced forskolin intermediate rac-2c in eight

steps.¹⁴

Synthetic Design

As mentioned above, the known total syntheses of forskolin

suffer from the high number (Ϸ35, vide supra) of synthetic

steps.⁶It is our intention to develop a synthetic scheme for

forskolin that is considerably shorter. Since 1,9-dideoxy

forskolin (2a) can be converted into forskolin by a combi-

nation of chemical¹⁰and enzymatic steps¹¹we selected 2a as

our immediate synthetic target. The X-ray results and dock-

ing experiments (vide supra) indicate that the 6-OH group of

forskolin is most probably of minor importance for the

biological activity. This means that 2c as an intermediate

We reasoned that an allylic alcohol intermediate of type

rac-9 might be even more rewarding because we expected

to have then the option of introducing the 13-oxygen func-

tional group via a Katsuki–Sharpless epoxidation¹⁵and thus

perform a kinetic resolution at this step.¹⁶It appeared to us

Scheme 1.

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D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

Wurtz coupling product 14 (66%). In order to avoid this

unwanted reaction, 11b was converted into the allyl

stannane 13a and this in turn into the dianion with n-butyl-

lithium (2 equiv.). After subsequent trapping with

benzaldehyde the desired C–C bond formation was

observed, however, with allylic inversion. A mixture of

the racemic diastereoisomers 15a and 16a was obtained in

55% yield. It is known that the problem of allylic inversion

can be overcome by a sequence of two S_E⁰reactions.^21,22

When, for example an allyl stannane is treated with a

Lewis acid such as SnCl₄, it is assumed that a reactive

trichlorostannane intermediate is formed with the SnCl₃

substituent in the g position which then reacts with the

aldehyde with a second allylic inversion. Under these con-

ditions rac-17a was obtained in 25% yield from 13a and

benzaldehyde. The conﬁguration at the double bond was

determined by NMR spectroscopy and found to be (Z) as

expected from the mechanistic rationale of Thomas.²²

Besides rac-17a the g-products rac-15a and rac-16a were

isolated (40%).

Scheme 2.

that reagent control was more likely for rac-9 than for rac-8.

rac-9 should be attainable from racemic drimenal using an

allylic nucleophilic reagent of type 6.¹⁷

It turned out to be impossible to couple 11a with drimenal

via a Grignard reagent even when the reaction was

performed at Ϫ78ЊC using the highly active magnesium

powder obtained from magnesium anthracene (10). The

only product obtained from 11a was isoprene (12).¹⁶Guided

by work of Seebach,¹⁸Barluenga¹⁹and Kessler,²⁰11b was

converted into its alkoxide on reaction with n-BuLi and

subsequently into the dianion with lithium naphthalenide

at Ϫ100ЊC. No reaction with benzaldehyde was observed

(Scheme 3). The sole product formed from 11b was the

When the same sequence of reactions was performed start-

ing from 13b the overall yield was higher (82%), but again

the g-products (rac-15b and rac-16b) were formed in

excess.²³

It is the purpose of the present paper

• to describe experiments that allowed eventually to

perform the reaction rac-3ϩ6, as desired

• to discuss the Katsuki–Sharpless epoxidation of rac-22d

Scheme 3.

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

1085

Scheme 4.

• to introduce a new nucleophilic C₅reagent of type 7 that

simpliﬁes the synthesis of 2c considerably.

of FeCl₃/Ac₂O and subsequent base hydrolysis as described

by Holton²⁷provided rac-22d in 72% yield. The epoxida-

tion of rac-22d (stochiometric amounts of (l)-(ϩ)-DIPT,

complete consumption of rac-22d) gave an epoxide

fraction in 65% yield displaying a single spot on TLC and

a single set of ¹H NMR signals, i.e. contrary to our expecta-

tions, it was not a mixture of diastereoisomers. The reaction

product was then treated with the acid chloride of Mosher’s

acid [(R)-(Ϫ) enantiomer]. According to TLC a mixture of

Synthesis of rac-22d²⁴

Some time ago, Marshall demonstrated that in the case of a-

oxygenated allylic stannanes the a-selective reaction with

aldehydes proﬁts from the use of InCl₃as Lewis acid.²⁵We

were interested whether similar improvements could be

established with d-alkoxy allylic stannanes such as 13b.

Thus, InCl₃was sonicated in ethyl acetate and to this solu-

tion benzaldehyde was added. Then at Ϫ78ЊC the allylic

stannane 13b was added and the mixture was allowed to

warm to ambient temperature. After work-up rac-21 was

isolated in 98% yield probably via 20 and the cyclic transi-

tion state 19.^22,26Under the same conditions from 13b and

racemic drimenal (rac-3) labdane rac-22a was obtained in

66% yield, and the MEM-protected allylic stannane 13c was

coupled to rac-3 to furnish rac-22b in 66% yield (Scheme

4). In neither case was a g-product found. The conﬁguration

around the side chain double bond was (Z) as shown by ¹³C

NMR ꢀdꢀCH₃ Ͼ 20:

1

two new compounds was formed. The H NMR spectrum

clearly showed the compounds to be the desired Mosher

esters. The resolution was not sufﬁcient to determine the

ratio of the stereoisomers. However, from the ¹⁹F NMR

spectrum it was obvious that the two Mosher esters were

present in a 1:1 ratio. The results are only compatible

with the assumption that the Katsuki–Sharpless epoxi-

dation in the case of rac-22d was completely substrate-

controlled and that a racemic mixture of 23a or 23b was

obtained. The conﬁguration around the oxirane ring was not

determined.

Katsuki–Sharpless epoxidation of rac-22d

For the next phase of the synthesis some protecting group

manipulations were necessary. Thus, the 11-OH group of

rac-22b was silylated (tBuMe₂SiOTf) to give rac-22c in a

rather sluggish reaction (65% yield, 30% of rac-22b

were recovered) and the MEM group was removed under

carefully optimized reactions. With ZnBr₂under various

conditions only decomposition was observed. Finally, use

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D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

Scheme 5.

Development of a new nucleophilic isoprenoid reagent

was treated with silyl ether 31a and subsequently benzalde-

hyde was added, TLC indicated the formation of many

products and no addition products could be isolated. On

the other hand, submitting the MEM-protected (R)-methyl-

glycidol 31b to the same reaction conditions nicely led to

the formation of the desired addition products in 82% yield

as a 1:1 mixture of two stereoisomers (33 and 34). Thus, in

agreement with previous results¹⁸no reagent control was

observed. The stereoisomers were separated after removal

of the protecting group.

In view of the above results we decided to perform the

Katsuki–Sharpless epoxidation already at the C₅stage. In

a series of model experiments, which were based on results

of the Seebach group,¹⁸chlorohydrin 24 was converted into

the dianion 25 ((1) alkoxide formation with n-BuLi, (2)

reductive replacement of Cl by Li with lithium naphthale-

nide). Subsequent trapping at low temperatures with

benzaldehyde and rac-drimenal, respectively, gave the

corresponding additon products rac-26 and rac-27 in good

yields (75% and 69%, respectively) (Scheme 5). With rac-3

a single (racemic) diastereoisomer was formed which

probably has (11SR) conﬁguration, according to previous

results.¹²

Encouraged by these results chlorohydrin 29a was

converted into the corresponding epoxide (with n-BuLi)

and the free OH group was protected to give MEM ether

35 (80% over two steps). 35 was submitted to the reaction

conditions of the model series and the intermediate b-lithio

alkoxide was treated with rac-drimenal to provide the

desired addition products in a combined yield of 69%. Of

the four possible stereoisomers only two were formed as

indicated by ¹³C NMR. In this case, in agreement with the

above results, only substrate control was operating. We

assume that the steric course is the same as was observed

previously for the addition of other organolithium

compounds to drimenal.¹²Thus, the conﬁguration at C-11

in the stereoisomers should be as indicated in formulae 37a

and 38a. We were not able to separate the stereoisomers at

this stage. In order to achieve this goal and to determine the

conﬁguration by chemical correlation an exchange of the

protecting group was performed (37a!37b!37c and

38a!38b!38c) and the 11-OH group was oxidised to

give a mixture of 39 and 40. The ¹³C NMR spectrum

displayed two sets of signals in a 1:1 ratio and both in the

¹H and ¹³C NMR spectra the signals of the known

compound rac-39 could be identiﬁed. But still, the mixture

could not be separated. Therefore, we went one step further

in the synthesis and converted 39 and 40 into their respec-

tive epoxides. Happily, at this stage the separation could be

performed and the more polar compound (TLC: petrol–

ethyl acetate 5:1) was identical with an authentic sample

Encouraged by these results, we prepared compound 29a by

Katsuki–Sharpless epoxidation ((d)-(Ϫ)-DET, 11b!28),

followed by REDAL reductive opening of the oxirane ring

(28!29a). The yield in the epoxidation reaction was 69%,

and the e.e. was determined by GC (chiral b-cyclodextrin

stationary phase) to be 93%. When the reaction was

performed with (d)-(Ϫ)-DIPT the yield was higher (93%)

but the e.e. was somewhat lower (90%). The primary OH

group of 29a was then selectively protected to give 29b.

When 29b was submitted to the experimental conditions

successful in the model series no dianionic species was

formed, i.e. no trapping product could be isolated after addi-

tion of rac-drimenal. Instead, epoxide 30 was obtained in

78% yield. The reason, why in this case the nucleophilic

substitution reaction is favoured is not clear (Scheme 6).

There exist a number of other methods^28–34that allow to

prepare b-lithio alkoxides of type 7. We choose the reduc-

tive opening of epoxides with Freeman’s^35,36radical anion

of 4,4⁰-di-tert-butylbiphenyl.³⁷In model experiments the

commercially available (R)-methylglycidol was converted

into the silyl- and MEM-protected derivatives 31a and 31b,

respectively (Scheme 7). When the Freeman radical anion

Scheme 6.

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

1087

Scheme 7.

of rac-41 as far as TLC behaviour and ¹H NMR spectra are

concerned. To correlate the conﬁguration with chiroptical

properties the CD spectrum of 41 was measured. It

displayed a positive Cotton effect at 307 nm ꢀDeϩ5:8

(Scheme 8).

steps. The conversion of rac-41 into rac-2c has already been

achieved. If the protecting group exchange at the end of the

synthesis (which here was performed with the aim of deter-

mining the conﬁguration) is omitted, the MEM analogue of

41 may be available from (E,E)-farnesol in ﬁve steps. The

optically active C₅compound 35 can be prepared from

isoprene in ﬁve steps. The synthesis is devoid of all

problems connected with double stereoselection.

Conclusions

In addition, docking experiments that are based on X-ray

results indicate that there might exist forskolin analogues

with improved properties as far as binding to adenylyl

cyclases and synthetic accessibility are concerned.

We have been able to develop a new isoprenoid C₅reagent

that could be coupled to rac-drimenal to furnish a mixture of

37a and 38a. The advanced optically active forskolin inter-

mediate 41 has been obtained from (E,E)-farnesol in seven

Scheme 8.

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D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

Experimental

(E)-4-Benzyloxy-1-(tributylstannyl)-2-methyl-2-butene

(13b). To a stirred solution of 13a (410.4 mg, 1.09 mmol) in

THF (2 mL) NaH (28.8 mg, 1.20 mmol) was added. After

10 min benzyl bromide (93.5 mg, 65 mL, 0.54 mmol) and

tetrabutylammonium iodide (40.3 mg, 0.11 mmol) were

added to the reaction mixture. When all benzyl bromide

was consumed (18 h, TLC), the mixture was hydrolysed

with H₂O (1 mL). Usual work-up and FC (petrol–ethyl

acetate 5:1) yielded 13b (196.9 mg, 79%, based on benzyl

All O₂- or moisture-sensitive reactions were performed in

oven-dried glassware under a positive pressure of argon.

Liquids and solutions were transferred by syringe. Small-

scale reactions were performed in Wheaton serum bottles

sealed with aluminum caps with open top and Teﬂon-faced

septum (Aldrich). Usual work-up means partitioning the

reaction mixture between an aqueous phase and CH₂Cl₂,

drying the combined organic solutions over Na₂SO₄, and

removing the solvent by distillation using a rotatory

evaporator (bath temperature 45ЊC). Solvents were puriﬁed

by standard techniques. The following materials and meth-

ods were used for chromatographic separations: preparative

gravitational liquid chromatography (LC): silica gel 63–

100 mm (ICN Biomedicals); ﬂash chromatography (FC):³⁸

silica gel 32–63 mm (ICN Biomedicals); medium-pressure

liquid chromatography (MPLC): silica gel 40–60 mm

(Grace), Duramat pump (CfG); preparative HPLC: Jasco

PU-987 pump and Jasco Lichrosorb column (Si 60,

10 mm, 250×25 mm), ﬂow rate: 4.5 mL min^Ϫ1, detection

with the multi wavelength UV detector Jasco 875-UV;

analytical TLC: Merck precoated silica gel 60 F₂₅₄plates

(0.2 mm), spots were identiﬁed under a UV lamp (Camag 29

200) and with a 2.22 mol L^Ϫ1H₂SO₄solution which

1

bromide). H NMR (200 MHz, CDCl₃): d0.83–0.93 (m,

15H, 3 CH₃, 3 CH₂Sn, butyl), 1.21–1.38 (m, 6H, 3 CH₂,

butyl), 1.39–1.63 (m, 6H, 3 CH₂, butyl), 1.65 (s with an

indication of a long range coupling, J_5/3Ϸ1 Hz, 3H,

CH₃-5), 1.81 (s, 2H, CH₂-1), 4.01 (d, 2H, J_4/37.0 Hz,

CH₂-4), 4.49 (s, 2H, OCH₂Ph), 5.26 (t, with an indication

of a long range coupling, J_3/47.0 Hz, J_3/5Ϸ1 Hz, 1H, 3-H),

7.28–7.36 (m, 5H, Ar–H). ¹³C NMR (50.3 MHz, CDCl₃):

d10.04 (3 CH₂Sn, butyl), 14.17 (3 CH₂, butyl), 19.25

(CH₃-5), 23.05 (CH₂-1), 27.85 (3 CH₂, butyl), 29.60 (3

CH₂, butyl), 67.28 (CH₂-4), 71.95 (OCH₂Ph), 116.75

(CH-3), 127.85 (Ar–C-p), 128.19 (Ar–C-o), 128.76

(Ar–C-m), 139.39 (C_q-2), 142.33 (Ar–C-ipso). IR (ﬁlm):

1455 (CyC), 1081 (C–O), 735 cm^Ϫ1. C₂₄H₄₂OSn (465.28),

EI MS m/z (%): 341 (37), 269 (19), 235 (37), 177 (54), 91

(100).

contained Ce(SO₄)₂4H₂O (10 g L^Ϫ1

(Mo₃O₉)₄]H₂O (25 g L^{Ϫ1 39}

and heating at 140ЊC; GC: HP

)

and H₃[PO₄-

)

Reaction of 13b with benzaldehyde in the presence of

SnCl₄

5890 Series II (Hewlett–Packard), 25 m×0.25 mm CP-

Chirasil-Dex CB, Chrompack, carrier gas: H₂(4.24 kPA),

90ЊC, FID. NMR and MS equipment: NMR: UNITY 400

(Varian), DRX 400 (Bruker), DRX 600 (Bruker), GEMINI

200 (Varian), GEMINI 2000 (Varian); MS: VG-Autospec

(Fisons). IR: Carl Zeiss Specord M80, Genesis FTIR (ATI

Mattson), solvent was in all cases CHCl₃, concentration

5 mg/0.2 mL. UV: Beckman DU 650. CD: Jasco J-715

(10 mm cuvette).

To a stirred solution of 13b (73.0 mg, 0.157 mmol) in

CH₂Cl₂(1 mL) a SnCl₄-solution (173 mL of 1 M solution

in CH₂Cl₂, 0.173 mmol) was added at Ϫ78ЊC. After 5 min a

precooled solution of benzaldehyde (18.4 mg, 0.173 mmol,

17.6 mL) in CH₂Cl₂(0.5 mL) was added. The brown solu-

tion was stirred for 1 h and then quenched with H₂O (1 mL).

Warming to ambient temperature, treatment with NEt₃to

remove tin byproducts followed by usual work up and FC

(petrol–ethyl acetate 8:1ϩ0.1 vol% NEt₃) yielded a mixture

of rac-15b and rac-16b (29.7 mg, 67%) alongside with rac-

17b (6.8 mg, 15%, identical with the sample described

below).

(E)-4-(Tributylstannyl)-3-methyl-2-buten-1-ol (13a). To

a stirred solution of hexabutylditin (6.10 g, 5.32 mL,

10.52 mmol) in THF (25 mL) n-BuLi (10.52 mmol,

7.01 mL of a 1.50 M solution in hexane) was added at

0ЊC. After 15 min the resulting solution of tributylstannyl-

lithium (10.52 mmol) was treated at Ϫ78ЊC with a solution

of 11b (1.2691 g, 10.52 mmol) in THF (15 mL). The

reaction mixture was stirred for 1 h at this temperature.

After addition of H₂O (10 mL) the mixture was allowed to

warm to ambient temperature. Usual work-up and FC

(petrol–ethyl acetate 6:1) yielded 13a (2.0524 g, 52%)

as a colourless oil. ¹H NMR (200 MHz, CDCl₃, HETCOR):

d0.82–0.96 (m, 15H, 3 CH₃, 3 CH₂Sn, butyl), 1.24–1.36

(m, 6H, 3 CH₂, butyl), 1.41–1.60 (m, 6H, 3 CH₂, butyl),

1.68 (s, with an indication of a long range coupling,

J_5/2Ϸ1 Hz, 3H, CH₃-5), 1.78 (s, 2H, CH₂-4), 4.11 (dd,

J_1/2ϷJ_1,OH, after exchange with D₂O: d, J_1/27.0 Hz, 2H,

CH₂-1), 5.29 (t, with an indication of a long range

coupling, J_2/17.0 Hz and J_5/2Ϸ1 Hz, 1H, H-2). ¹³C NMR

(50.3 MHz, CDCl₃, APT, HETCOR): d10.03 (3 CH₂Sn,

butyl), 14.16 (3 CH₃, butyl), 18.97 (CH₃-5), 22.98

(CH₂-4), 27.83 (3 CH₂, butyl), 29.57 (3 CH₂, butyl),

60.10 (CH₂-1), 119.23 (CH-2), 141.97 (C_q-3). IR (ﬁlm):

3325 (OH), 1463 (CyC), 999 (C–O) cm^Ϫ1. C₁₇H₃₆OSn

(375.16), EI MS (m/z) (%): 319 [MϪ57]^ϩ(6), 291 (23),

251 (100).

Mixture of (1S^ء,2S^ء)- and (1S^ء,2R^ء)-2-benzyloxymethyl-

3-methyl-1-phenyl-3-buten-1-ol (rac-15b and rac-16b).

1

Diastereomer ratio 1.7 (A):1(B) (based on the CH₃-5 H

1

NMR signals). H NMR (200 MHz, CDCl₃): d1.52 (s,

indication of a long range coupling with JϷ1 Hz, 3H,

CH₃-5, A), 1.78 (s, with an indication of a long range

coupling, JϷ1 Hz, 3H, CH₃-5, B), 2.62–2.77 (m, 2H, 2-H

of A and 2-H of B), 3.33/3.40 (AB of ABX, 2H, J_6a/6b

9.5 Hz, J_6a/27.0 Hz, J_6b/25.7 Hz, 6-H_aand 6-H_bB),

3.72/3.82 (AB of ABX, 2H, J_6a/6b9.5 Hz, J_6a/27.5 Hz,

J_6b/24.6 Hz, 6-H_aand 6-H_bof A), 4.04 (broad s, 2H, OH

0

of A and B), 4.36/4.46 (AB, 2H, J_{H /H(benzyl)}12.1 Hz,

0

OCH₂Ph of B), 4.54/4.58 (AB, 2H, J_{H /H(benzyl)}11.9 Hz,

OCH₂Ph of A), 4.73–4.88 (mk, 5H, 1-H of A, 4-H_aand

4-H_bof A and B), 5.04 (m, 1H, 1-H of B), 7.26–7.38 (mk,

20H, Ar–H of A and B). ¹³C NMR (50.3 MHz, CDCl₃, trace

impurity of Bu₃SnCl): d21.43 (CH₃-5, B), 23.03 (CH₃-5,

A), 53.60 (CH-2, A), 55.21 (CH-2, B), 70.43/73.18/73.39/

73.63/74.09/78.02 (CH-1, CH₂-6, OCH₂Ph of A and B),

114.04 (CH₂-4, A), 115.61 (CH₂-4, B), 127.15 (Ar–C),

127.30 (Ar–C), 127.86 (Ar–C), 128.12 (Ar–C), 128.34

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

1089

(Ar–C), 128.43 (Ar–C), 128.52 (Ar–C), 128.72 (Ar–C),

128.87 (Ar–C), 129.05 (Ar–C), 138.02/138.61/142.72/

143.53/143.80/144.33 (Ar–C-ipso, C_q-3 of A and B). IR

(ﬁlm): 3447 (O–H), 1450 (CyC), 1100 (C–O), 739,

699 cm^Ϫ1. C₁₉H₂₂O₂(282.38), FAB MS m/z: 305.2

[MϩNa^]ϩ, 281.2 [MϩHϪH₂]^ϩ, 265.2 [MϩHϪH₂O]^ϩ.

HRMS: calcd for C₁₉H₂₂O₂Na [MϩNa]^ϩ: 305.1517, found

305.1516.

1066 (C–O), 736 cm^Ϫ. C₂₇H₄₀O₂(396.61), FAB MS m/z:

419.3 [MϩNa]^ϩ, 397.3 [MϩH]^ϩ.

(E)-1-(Tributylstannyl)-4-(methoxyethoxymethoxy)-2-

methyl-2-butene (13c). To a stirred solution of 13a

(84.2 mg, 0.224 mmol) in CH₂Cl₂(1.5 mL) diisopropyl-

ethylamine (43.4 mg, 57.1 mL, 0.336 mmol) was added at

20ЊC. After 10 min the solution was treated with MEMCl

(39.1 mg, 35.5 mL, 0.314 mmol). After stirring for 2 h H₂O

(1.5 mL) was added. Usual work-up (CH₂Cl₂) and FC

rac-(Z)-5-Benzyloxy-3-methyl-1-phenyl-3-penten-1-ol

(rac-17b). A suspension of anhydrous InCl₃(33.2 mg,

0.15 mmol) in ethyl acetate (3.7 mL) was sonicated for

15 min at 20ЊC. Then benzaldehyde (15.9 mg, 0.15 mmol,

15.3 mL) was added. The stirred solution was cooled to

Ϫ78ЊC and a solution of 13b (102.1 mg, 0.22 mmol) in

ethyl acetate (0.5 mL) was added. The reaction mixture

was allowed to warm to ambient temperature. The progress

of the reaction was monitoring by TLC. When benzalde-

hyde was consumed the mixture was quenched with cold

1 M HCl (3 mL). The reaction mixture was then treated with

NEt₃to remove tin byproducts. Usual work-up (Et₂O) and

FC (petrol–ethyl acetate 6:1ϩ0.2 vol.% NEt₃) furnished

rac-17b (42.4 mg, 98%). ¹H NMR (200 MHz, CDCl₃,

Homo decoupling): d1.85 (s, 3H, CH₃-6), 2.31/2.66 (AB

of ABX, J_2a/2b13.4 Hz, J_2a/13.9 Hz, J_2b/19.2 Hz, 2H,

2-H_aand 2-H_b), 3.24 (d, J_OH/13.4 Hz, 1H, OH), 3.85/4.02

(AB of ABX, J_5a/5b10.9 Hz, J_5a/47.0 Hz, J_5b/47.6 Hz,

2H, 5-H_aand 5-H_b), 4.55 (s, 2H, OCH₂Ph), 4.78 (td, not

completely resolved, J_1/2b9.2 Hz, J_1/2a3.9 Hz, 1H, 1-H),

5.70 (t-type dd, J_4/5a,5bϷ7 Hz, 1H, 4-H), 7.25–7.40 (m, 10

H, Ar–H). ¹³C NMR (50.3 MHz, CDCl₃, DEPT): d24.30

(CH₃-6), 43.58 (CH₂-2), 66.14 (CH₂-5), 71.82 (CH-1), 73.20

(OCH₂Ph), 124.87 (CH-4), 126.08 (Ar–C), 127.75 (Ar–C-p),

128.29 (Ar–C-p), 128.60 (Ar–C), 128.82 (Ar–C), 128.95

(Ar–C), 138.35 (Ar–C-ipso), 139.68 (Ar–C-ipso), 145.36

(C_q-3). IR (ﬁlm): 3428 (O–H), 1449 (CyC), 1060 (C–O),

745, 699 cm^Ϫ1. C₁₉H₂₂O₂(282.38), FAB MS m/z: 283.2

[MϩH]^ϩ. HRMS: calcd for C₁₉H₂₃O₂[MϩH]^ϩ: 283.1698,

found 283.1696.

1

(petrol–ethyl acetate 7:1) yielded 13c (77.3 mg, 75%). H

NMR (200 MHz, CDCl₃): d0.80–0.92 (mk, 15H, 3 CH₃, 3

CH₂Sn, butyl), 1.20–1.38 (m, 6H, 3 CH₂, butyl), 1.39–1.56

(m, 6H, 3 CH₂, butyl), 1.66 (s, indication of a longe

coupling, J_5/31.1 Hz, 3H, CH₃-5), 1.79 (s, 2H, CH₂-1),

3.40 (s, 3H, OCH₂OCH₂CH₂OCH₃), 3.54–3.60 and 3.65–

3.73 (2m, 4H, OCH₂OCH₂CH₂OCH₃), 4.06 (d, J_4/37.0 Hz,

2H, CH₂-4), 4.71 (s, 2H, OCH₂OCH₂CH₂OCH₃), 5.19 (t, J_3/4

7.0 Hz and J_3/51.1 Hz, 1H, 3-H). ¹³C NMR (50.3 MHz,

CDCl₃, APT): d10.02 (3 CH₂Sn, butyl) (ϩ), 14.15

(3 CH₃, butyl) (Ϫ), 19.15 (CH₃-5) (Ϫ), 23.05 (CH₂-1)

(ϩ), 27.82 (3 CH₂, butyl) (ϩ), 29.57 (3 CH₂, butyl) (ϩ),

59.46 (OCH₂OCH₂CH₂OCH₃) (Ϫ), 64.43 (CH₂-4) (ϩ),

67.09 and 72.35 (OCH₂OCH₂CH₂OCH₃) (ϩ), 94.72

(OCH₂OCH₂CH₂OCH₃) (ϩ), 115.95 (CH-3) (Ϫ), 142.81

(C_q-2) (ϩ). IR (ﬁlm): 1460 (CyC), 1106, 1043

(C–O) cm^Ϫ1. C₂₁H₄₄O₃Sn (463.29), EI MS (m/z) (%): 464

[M]^ϩ⅐von C₂₁H₄₄O₃¹²⁰Sn.

rac-(11S,13Z)-15-(Methoxyethoxymethoxy)-labd-7,13-

dien-11-ol (rac-22b). The InCl₃-mediated coupling of 13c

to rac-drimenal (rac-3) was performed as described above.

Quenching was performed with aq. sat. NH₄Cl. Work-up

(vide supra) and FC (petrol–ethyl acetate 4:1ϩ0.3 vol.%

NEt₃) provided rac-22b (66%). ¹H NMR (200 MHz,

CDCl₃, HETCOR): d0.86/0.89 (2s, 6H, CH₃-18,

CH₃-19), 0.96 (s, 3H, CH₃-20), 1.05–1.28 (mk, 3H),

1.36–1.68 (mk, 4H), 1.78–1.98 (mk, 10H) with 1.84

and 1.92 (2s, CH₃-16, CH₃-17), 2.02/2.86 (AB of ABX,

2H, J_12a/12b13.4 Hz, J_12a/114.0 Hz, J_12b/1110.0 Hz, 12-H_a

and 12-H_b), 3.39 (s, 3H, OCH₂OCH₂CH₂OCH₃), 3.52–3.60/

3.63–3.72 (2m, 4H, OCH₂OCH₂CH₂OCH₃), 3.98–4.16 (mk,

3H, 11-H, CH₂-15), 4.73 (s, 2H, OCH₂OCH₂CH₂OCH₃),

5.52–5.64 (mk, 2H, 7-H, 14-H). ¹³C NMR (50.3 MHz,

CDCl₃, HETCOR, APT): d14.77 (C-20) (Ϫ), 19.28 (C-2)

(ϩ), 22.70 (C-19) (Ϫ), 23.92 (C-6) (ϩ), 24.48 and 25.17

(C-16 and C-17) (Ϫ), 33.37 and 37.59 (C-4 and C-10) (ϩ),

33.86 (C-18) (Ϫ), 40.55 and 42.63 (C-1 and C-3) (ϩ), 42.93

(C-12) (ϩ), 50.53 (C-5) (Ϫ), 59.48 (OCH₂OCH₂CH₂OCH₃)

(Ϫ), 60.37 (C-9) (Ϫ), 64.04 (C-15) (ϩ), 67.30 and 72.23

(OCH₂OCH₂CH₂OCH₃) (ϩ), 67.56 (C-11) (Ϫ), 95.22

(OCH₂OCH₂CH₂OCH₃) (ϩ), 124.12 and 126.56 (C-7 and

C-14) (Ϫ), 132.87 and 139.90 (C-13 and C-8) (ϩ). IR

(ﬁlm): 3499 (O–H), 1455, 1442 (CyC), 1110 (C–O–C),

838 cm^Ϫ1. C₂₄H₄₂O₄(394.59), FAB MS m/z: 417.2

[MϩNa]^ϩ, 395.3 [MϩH]^ϩ, 377.2 [MϩHϪH₂O]^ϩ, 319.2,

297.2, 221.2. HRMS: calcd for C₂₄H₄₃O₄[MϩH]^ϩ:

395.3161, found 395.3151.

rac-(11S, 13Z)-15-Benzyloxy-labd-7,13-dien-11-ol (rac-

22a). The InCl₃-mediated coupling of 13b to rac-drimenal

(rac-3) was performed as described above. Work-up (vide

supra) and FC (petrol–ethyl acetate 12:1ϩ0.3 vol.% NEt₃)

provided rac-22a (66%). ¹H NMR (200 MHz, CDCl₃, H,H-

COSY, HETCOR (400 MHz)): d0.87/0.90/0.96 (3s, 9H,

CH₃-18, CH₃-19, CH₃-20), 1.07–1.22 (mk, 3H), 1.39–1.63

(mk, 4H), 1.80–1.98 (mk, 10H) with 1.84 and 1.88 (2s,

CH₃-16, CH₃-17), 2.03/2.81 (AB of ABX, 2H, J_12a/12b

13.4 Hz, J_12a/114.0 Hz, J_12b/1110.1 Hz, 12-H_aand

12-H_b), 3.96–4.09 (m, 1H, 11-H), 3.98 (d, 2H, J_15/14

0

7.0 Hz, CH₂-15), 4.49/4.54 (AB, J_{H (benzyl),H(benzyl)}11.7 Hz,

2H, OCH₂Ph), 5.58–5.67 (mk, 2H, 7-H, 14-H), 7.30-7.36

(m, 5H, Ar–H). ¹³C NMR (50.3 MHz, CDCl₃, APT):

d14.79 (Ϫ) (C-20), 19.28 (ϩ) (C-2), 22.71 (Ϫ) (C-19),

23.93 (ϩ) (C-6), 24.51 and 25.15 (Ϫ) (C-16 and C-17),

33.37 and 37.58 (ϩ) (C-4 and C-10), 33.86 (Ϫ) (C-18),

40.52 and 42.63 (ϩ) (C-1 and C-3), 42.98 (ϩ) (C-12),

50.53 (Ϫ) (C-5), 60.32 (Ϫ) (C-9), 66.52 (ϩ) (C-15), 67.61

(Ϫ) (C-11), 72.88 (ϩ) (OCH₂Ph), 124.56 and 126.57 (Ϫ)

(C-7 and C-14), 128.11 (Ϫ) (Ar–C-p), 128.39 (Ϫ) (Ar–C-m),

128.86 (Ϫ) (Ar–C-o), 132.92/138.63/139.80 (ϩ) (C-8, C-13,

Ar–C-ipso). IR (ﬁlm): 3472 (O–H), 1450, 1383 (CyC),

rac-(11S,13Z)-11-(tert-Butyldimethylsilyloxy)-15-(methoxy-

ethoxymethoxy)-labd-7,13-diene (rac-22c). To a stirred

solution of rac-22b (336.2 mg, 0.85 mmol) in CH₂Cl₂

(3 mL) pyridine (1010.9 mg, 1.1 mL, 12.78 mmol) and

1090

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

tert-butyldimethylsilyl triﬂate (2252.2 mg, 1.96 mL,

8.52 mmol) were added at 20ЊC. Sequentially the reaction

mixture was kept at 45ЊC for 30 h and then treated with aq.

5% NaHCO₃(5 mL). Usual work-up and FC (petrol–ethyl

acetate 4:1ϩ0.1 vol%. NEt₃) furnished rac-22c (281.1 mg,

65%). 100.6 mg of rac-22b were recovered. ¹H NMR

(200 MHz, CDCl₃): d0.07/0.10 (2s, 6H, Si(CH₃)₂), 0.82/

0.86/0.87 (3s, 9H, CH₃-18, CH₃-19, CH₃-20), 0.84 (s, 9H,

SiC(CH₃)₃), 0.98–1.24 (mk, 3H), 1.28–1.52 (mk, 4H),

1.78–2.00 (mk, 10H) with 1.81 and 1.93 (2s, CH₃-16,

C₂₆H₄₈O₂Si (420.75), FAB MS m/z: 443.3 [MϩNa]^ϩ,

421.3 [MϩH]^ϩ, 401.3, 335.2, 203.2, 73.0. HRMS: calcd

for C₂₆H₄₉O₂Si [MϩH]^ϩ: 421.3501, found 421.3486.

Katsuki–Sharpless epoxidation of rac-22d

To a stirred suspension of freshly activated molecular sieves

i

˚

(4 A powder, 6 mg) in CH₂Cl₂(0.4 mL) Ti(O Pr)₄(5.2 mg,

5.4 mL, 18.5 mmol) and l-(ϩ)-DIPT (4.3 mg, 18.5 mmol)

were added at Ϫ40ЊC. After 10 min the mixture was treated

with a solution of rac-22d (7.8 mg, 18.5 mmol) in CH₂Cl₂

CH₃-17), 2.11/2.86 (AB of ABX, poorly resolved, J_12a/12b

Ϸ

t

12 Hz, J_12a/11Ϸ12 Hz, 2H, 12-H_aand 12-H_b), 3.38 (s, 3H,

OCH₂OCH₂CH₂OCH₃), 3.51–3.57/3.62–3.72 (mk, 4H,

OCH₂OCH₂CH₂OCH₃), 4.05–4.22 (mk, 3H, 11-H, CH₂-

15), 4.72 (s, 2H, OCH₂OCH₂CH₂OCH₃), 5.42–5.52 (mk,

2H, 7-H, 14-H). ¹³C NMR (50.3 MHz, CDCl₃, APT):

dϪ4.07 and Ϫ2.12 (Si(CH₃)₂) (Ϫ), 15.79 (C-20) (Ϫ),

18.61 (SiC(CH₃)₃) (ϩ), 19.34 (C-2) (ϩ), 22.67 (C-19) (Ϫ),

23.98 (C-6) (ϩ), 24.85 and 24.91 (C-16 and C-17) (Ϫ),

26.50 (SiC(CH₃)₃) (Ϫ), 33.40 and 36.73 (C-4 and C-10)

(ϩ), 33.81 (C-18) (Ϫ), 40.50/42.55/42.70 (C-1/C-3/C-12)

(ϩ), 50.59 (C-5) (Ϫ), 56.82 (C-9) (Ϫ), 59.48 (OCH₂OCH_2-

CH₂OCH₃) (Ϫ), 64.61 (C-15) (ϩ), 67.30 and 72.25

(OCH₂OCH₂CH₂OCH₃) (ϩ), 69.07 (C-11) (Ϫ), 95.33

(OCH₂OCH₂CH₂OCH₃) (ϩ), 124.46 and 124.65 (C-7 and

C-14) (Ϫ), 134.22 and 137.52 (C-13 and C-8) (ϩ). IR

(ﬁlm): 1466 (CyC), 1254, 1047, 1105 (C–O–C), 834,

773 cm^Ϫ1. C₃₀H₅₆O₄Si (508.85), FAB MS m/z: 531.4

[MϩNa]^ϩ, 507.4 [MϩHϪH₂]^ϩ, 491.4, 449.3.

(0.2 mL) and of anhydrous BuOOH (5.5 M solution in

nonane, 3.3 mL, 18.5 mmol). After complete consumption

(18 h) the reaction mixture was treated with water (0.6 mL)

at Ϫ40ЊC and allowed to warm to ambient temperature.

Usual work-up and FC (petrol–tert-butyl methyl ether

4:1) furnished rac-23a or rac-23b (5.2 mg, 65%) and traces

of a more polar compound.

rac-(11S,13R,14S) or rac-(11S,13S,14R)-(tert-Butyldimeth-

ylsilyloxy)-13,14-epoxy-labd-7-en-15-ol (rac-23a or rac-

1

23b). H NMR (200 MHz, CDCl₃): d0.07/0.11 (2s, 6H,

Si(CH₃)₂), 0.84 (s, 9H, SiC(CH₃)₃), 0.85/0.88/0.91 (3s, 9H,

CH₃-18, CH₃-19, CH₃-20), 0.98–1.30 (mk, 3H), 1.34–1.52

(mk, 6H) with 1.43 (s, CH₃-16), 1.53–1.78 (mk, 3H), 1.79–

1.98 (mk, 5H) with 1.85 (s, indication of a longe coupling,

CH₃-17), 1.99–2.20 (m, 2H, 12-H_a, 12-H_b), 2.98 (dd, 1H,

J_14/15a7.0 Hz, J_14/15b4.2 Hz, 14-H), 3.62–3.74/3.82–3.98

(2m, 2H, 15-H_a, 15-H_b), 4.20 (dd, 1H, J_11/12a10.0 Hz,

J_11/12b3.8 Hz, 11-H), 5.42–5.54 (m, 1H, 7-H). IR (CCl₄):

3432 (O–H), 1667 (CyC), 1451, 1385, 1068 (C–O) cm^Ϫ1

.

rac-(11S, 13Z)-11-(tert-Butyldimethylsilyloxy)-labd-7,13-

dien-15-ol (rac-22d). Anhydrous FeCl₃(12.0 mg, 74 mmol)

was dissolved in acetic anhydride (264.4 mg, 270 mL,

2.59 mmol) at Ϫ60ЊC with stirring. After 10 min at

Ϫ60ЊC a solution of rac-22c (94.4 mg, 0.185 mmol) in

CH₂Cl₂(2 mL) was added. After 30 min NEt₃(2 mL) was

added and the mixture was stirred for further 15 min at

Ϫ60ЊC. The cooling bath was removed, the stirred reaction

mixture was treated with H₂O (1 mL) and then the organic

layer was separated. Usual work-up (CH₂Cl₂, washing of the

organic layer with 5 mL aq. sat. NaHCO₃) gave a mixture of

acetates as a pale yellow oil. To the crude product a satu-

rated solution of NaOCH₃in methanol (1 mL) was added.

After stirring for 1 h at 20ЊC hexane (2 mL) was added to

furnish two layers. Usual work-up and FC (petrol–ethyl

acetate 6:1) yielded rac-22d (56.1 mg, 72%). ¹H NMR

(200 MHz, CDCl₃): d0.07/0.11 (2s, 6H, Si(CH₃)₂), 0.83/

0.86/0.88 (3s, 9H, CH₃-18, CH₃-19, CH₃-20), 0.85 (s, 9H,

SiC(CH₃)₃), 0.98–1.75 (mk, 10H), 1.78–1.92 (mk, 7H) with

1.80/1.92 (2s, CH₃-16, CH₃-17), 2.13/2.82 (AB of ABX,

poorly resolved, 2H, J_12a/12bϷ12 Hz, J_12a/11Ϸ12 Hz, CH₂-

12), 4.10 (X of ABX, J_11/12a11.4 Hz, J_11/12b4.0 Hz, 1H,

11-H), 4.08–4.22 (m, 2H, CH₂-15), 5.36–5.53 (mk, 2H,

7-H, 14-H). ¹³C NMR (50.3 MHz, CDCl₃, APT):

dϪ4.07 and Ϫ2.11 (Si(CH₃)₂) (Ϫ), 15.81 (C-20) (Ϫ),

18.63 (SiC(CH₃)₃) (ϩ), 19.34 (C-2) (ϩ), 22.67 (C-19)

(Ϫ), 23.98 (C-6) (ϩ), 24.84 and 24.92 (C-16 and C-17)

(Ϫ), 26.51 (SiC(CH₃)₃) (Ϫ), 33.42 and 36.77 (C-4 and

C-10) (ϩ), 33.78 (C-18) (Ϫ), 40.65/42.55/42.68 (C-1/C-3/

C-12) (ϩ), 50.64 (C-5) (Ϫ), 56.90 (C-9) (Ϫ), 60.10 (C-15)

(ϩ), 69.11 (C-11) (Ϫ), 124.59 and 127.66 (C-7 and C-14)

(Ϫ), 134.13 and 136.42 (C-8 and C-13) (ϩ). IR (ﬁlm): 3433

C₂₆H₄₈O₃Si (436.75), FAB MS m/z: 459.4 [MϩNa]^ϩ, 437.3

[MϩH]^ϩ.

Preparation of the Mosher esters

To a stirred and cooled (0ЊC) solution of rac-23a or rac-23b

(2.8 mg, 6.41 mmol) in pyridine (0.7 mL) R-(Ϫ)-Mosher

acid chloride (2.4 mg, 9.61 mmol) were added. After 3 h

the reaction mixture was ﬁltered through a Florisil pad

and the ﬁltrate was concentrated under reduced pressure.

FC (petrol–ethyl acetate 20:1) yielded a mixture of two

diastereomeric mosher esters (4.1 mg, 98%). ¹H NMR

(200 MHz, CDCl₃): d3.57 (s, OCH₃, diastereomer A),

3.58 (s, OCH₃, diastereomer B). ¹⁹F NMR (188.2 MHz,

CDCl₃): d5.94 (s, CF₃, diastereomer A), 6.00 (s, CF₃,

diastereomer B), 1:1 ratio. C₃₆H₅₅O₅SiF₃(652.91), FAB

MS m/z: 675.4 [MϩNa]^ϩ, 653.4 [MϩH]^ϩ, 651.4

[MϩHϪH₂]^ϩ. HRMS: calcd for C₃₆H₅₅O₅SiF₃Na

[MϩNa]^ϩ: 675.3668, found 675.3667.

(2R, 3S)-4-Chloro-2,3-epoxy-3-methylbutan-1-ol (28).

d-(Ϫ)-DET: To a stirred and cooled (Ϫ25ЊC) suspension

˚

of freshly activated molecular sieves (4 A powder, 2 g) in

CH₂Cl₂(60 mL) Ti(O_iPr)₄(1677 mg, 1.73 mL, 5.9 mmol)

and d-(Ϫ)-DET (1216 mg, 1.0 mL, 5.9 mmol) were added.

After 10 min a solution of 11b (711.5 mg, 5.9 mmol,

t

1.0 equiv.) in CH₂Cl₂(4 mL) and of anhydrous BuOOH

(5.5 M solution in nonane, 2.1 mL, 11.8 mmol) were

added. This mixture was stored in a refrigerator overnight

at Ϫ23ЊC. Water (10 mL) was added and the mixture was

allowed to warm to ambient temperature. Usual work-up

(CHCl₃) and FC (CHCl₃–EtOH 20:0.5) furnished 28

(O–H), 1633, 1466 (CyC), 1254 (C–O), 834, 773 cm^Ϫ1

.

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

1091

(552.3 mg, 69%). The e.e was determined by GLC (for

conditions, vide supra). Retention times for ent-28 and 28:

15.58 and 15.97 min, respectively, ratio: 3.5:96.5.

73.35 (C-3), 128.37 (Ar–C-m), 130.48 (Ar–C-p), 133.10

(Ar–C-ipso), 136.02 (Ar–C-o). IR (ﬁlm): 3476 (O–H),

1427, 1110 (C–O), 703 cm^Ϫ1. C₂₁H₂₉ClO₂Si (376.99),

FAB MS m/z: 399.1 [MϩNa]^ϩ, 377.2 [MϩH]^ϩ, 199.1

[Ph₂SiOH]^ϩ. HRMS: calcd for C₂₁H₃₀ClO₂Si [MϩH]^ϩ:

377.1704, found 377.1704.

24

1

[a]_Dϩ3.7 (c 9.83 CHCl₃). H NMR (200 MHz, CDCl₃,

homo decoupling, OH!OD exchange): d1.44 (s,

3H, CH₃-5), 2.33 (broad s, 1H, OH), 3.14 (X of ABX,

1H, J_2/1a6.5 Hz, J_2/1b4.4 Hz, 2-H), 3.45/3.53 (AB, 2H,

J_4a/4b11.4 Hz, 4-H_a, 4-H_b), 3.71/3.86 (AB of ABX, 2H,

J_1a/1b12.4 Hz, J_1a/26.5 Hz, J_1b/24.4 Hz, 1-H_a, 1-H_b).

¹³C NMR (50.3 MHz, CDCl₃, APT): d15.24 (CH₃-5)

(Ϫ), 50.80 (CH₂-4) (ϩ), 60.52 (C_q-3) (ϩ), 61.41 (CH₂-1)

(ϩ), 63.39 (CH-2) (Ϫ). IR (ﬁlm): 3397 (O–H), 1428, 1387

(C–O), 1029 (C–O), 736 (C–Cl) cm^Ϫ1. C₅H₉ClO₂(136.57),

EI MS m/z (%): 105 [MϪCH₂OH]^ϩ.

rac-3-Methyl-1-phenylbutane-1,3-diol (rac-26). A stirred

solution of 3-Chloro-2-methylpropan-2-ol (24) (217.2 mg,

0.2 mL, 2.0 mmol) in THF (15 mL) was cooled to Ϫ78ЊC.

Then n-BuLi (1.5 M solution in hexane, 1.33 mL, 2 mmol)

was added. After 15 min the temperature was decreased to

Ϫ100ЊC and the mixture was then treated with lithium-

naphthalenide (1 M solution in THF, 4 mL, 4 mmol).

After stirring for 5 h at Ϫ78ЊC benzaldehyde (318.4 mg,

0.3 mL, 3.0 mmol) was added to the resulting dianion

solution. The reaction mixture was allowed to warm to

ambient temperature and hydrolyzed with water (5 mL).

Usual work-up (CH₂Cl₂) and FC (ﬁrst petrol–ethyl acetate

3:2 and then toluol–iso-propanol 20:1) furnished rac-26

d-(Ϫ)-DIPT: The reaction was performed under the same

conditions as described above. 28 was isolated in a yield of

83%, the e.e. was 90%.

(2RS, 3SR)-4-Chloro-2,3-epoxy-3-methylbutan-1-ol (rac-

28). To a solution of 11b (62.7 mg, 0.52 mmol) in CH₂Cl₂

(3 m) mCPBA (107.7 mg, 0.62 mmol) was added in

portions. The mixture was stirred at 20ЊC for 3 h. Addition

of sat. NaHCO₃, usual work-up, and FC (petrol–ethyl

1

(270.4 mg, 75%). H NMR (200 MHz, CDCl₃): d1.27

and 1.43 (2s, 6H, CH₃-4 and CH₃-5), 1.68/1.96 (AB of

ABX, 2H, J_2a/2b14.6 Hz, J_2a/12.4 Hz, J_2b/111.0 Hz,

2-H_aand 2-H_b), 3.14 (s, 2H, 2OH), 5.06 (X of ABX, 1H,

J_1/2b11.0 Hz, J_1/2a2.4 Hz, 1-H), 7.24–7.39 (m, 5H,

Ar–H). ¹³C NMR (50.3 MHz, CDCl₃, APT): d28.05 and

32.31 (CH₃-4 and CH₃-5) (Ϫ), 50.85 (CH₂-2) (ϩ), 72.18

(C_q-3) (ϩ), 72.80 (CH-1) (Ϫ), 126.18 (Ar–C-o) (Ϫ),

127.99 (Ar–C-p) (Ϫ), 128.99 (Ar–C-m) (Ϫ), 145.28 (Ar–

C-ipso) (ϩ). IR (ﬁlm): 3336 (O–H), 699 cm^Ϫ1. C₁₁H₁₆O₂

(180.24), EI MS m/z (%): 180 [M]^ϩء(2), 162 [MϪH₂O]^ϩ

(30), 147 (22), 107 (100). HRMS: calcd for C₁₁H₁₆O₂

[M]^ϩء: 180.1150, found 180.1149.

1

acetate 3:2) provided rac-28 (61.8 mg, 87%) whose H

NMR spectrum was identical with that of 28.

(3S)-4-Chloro-3-methylbutane-1,3-diol (29a). A stirred

solution of 28 (1335.2 mg, 9.78 mmol) in THF (70 mL)

was cooled to Ϫ25ЊC. Then a 3.5 M solution of Red-Al^᭨

in toluene (3.65 mL, 12.72 mmol) was added. After 30 min

the excess of the reagent was destroyed with 1.5 N HCl

(10 mL) at Ϫ25ЊC and the mixture was allowed to warm

to ambient temperature. Usual work-up (CH₂Cl₂) and FC

(chloroform–ethanol 20:1) yielded 29a (1067.9 mg, 79%).

129.8 mg of 28 were recovered. [a]²_D⁴ϩ0.81 (c 17.24

CHCl₃). ¹H NMR (200 MHz, CDCl₃): d1.33 (s, 3H,

CH₃-5), 1.69-1.99 (dddd, 2H, 2-H_a, 2-H_b), 3.24 (s, 2H,

2OH), 3.53 (s, 2H, CH₂-4), 3.84–3.92 (ddd, 2H, CH₂-1).

¹³C NMR (50.3 MHz, CDCl₃): d25.45 (CH₃-5), 39.64

(CH₂-2), 53.58 (CH₂-4), 59.85 (CH₂-1), 73.65 (C_q-3). IR

(ﬁlm): 3366 (O–H), 1426, 1378, 1121, 1056 (C–O), 739

(C–Cl) cm^Ϫ1. C₅H₁₁ClO₂(138.59), FAB MS m/z: 139

[MϩH]^ϩ, 121 [MϩHϪH₂O]^ϩ, 93, 75, 57. HRMS: calcd

for C₅H₁₂O³₂⁷Cl [MϩH]^ϩ: 141.0496, found 141.0501.

rac-(11S)-15-Norlabd-7-ene-11,13-diol (rac-27). The

coupling reaction of 25 to rac-drimenal (rac-3) was

performed as described above. Usual work-up (CH₂Cl₂)

and FC (petrol–ethyl acetate 5:1) furnished rac-27 (69%).

¹H NMR (200 MHz, CDCl₃; HETCOR (400 MHz); H,H-

COSY, NOESY (600 MHz)): d0.87 (s, 3H, CH₃-18),

0.90 (s, 3H, CH₃-19), 1.00 (s, 3H, CH₃-20), 0.90/1.90

(2m, 2H, 1-H_a, 1-H_b), 1.10 (m, 1H, 5-H), 1.13/1.39 (2m,

2H, 3-H_a, 3-H_b), 1.25 and 1.34 (2s, 6H, CH₃-14 and CH₃-

16), 1.46/1.55 (2m, 2H, 2-H_a, 2-H_b), 1.76 (m, 1H, 9-H), 1.90

(s, 3H, CH₃-17), 1.90/1.94 (2m, 2H, 6-H_a, 6-H_b), 1.35/2.27

(unresolved and dd, 2H, J_12a/12b14.5 Hz, J_12a/1112.1 Hz,

12-H_a, 12-H_b), 2.38 (broad s, 2H, 2 OH), 4.43 (dd, 1H,

J_11/12a12.1 Hz, J_11/12b2.6 Hz, 11-H), 5.60–5.62 (m, 1H,

7-H). ¹³C NMR (50.3 MHz, CDCl₃, APT): d14.94 (C-20)

(Ϫ), 19.22 (C-2) (ϩ), 22.76 (C-19) (Ϫ), 23.86 (C-6) (ϩ),

25.37 (C-17) (Ϫ), 28.13 and 32.26 (C-14 and C-16) (Ϫ),

33.34 and 37.74 (C-4 and C-10) (ϩ), 33.87 (C-18) (Ϫ),

40.59 (C-1) (ϩ), 42.61 (C-3) (ϩ), 50.33 (C-12) (ϩ), 50.44

(C-5) (Ϫ), 61.09 (C-9) (Ϫ), 67.98 (C-11) (Ϫ), 72.11 (C-13)

(ϩ), 127.24 (C-7) (Ϫ), 132.74 (C-8) (ϩ). IR (KBr): 3432

(O–H), 1461 (CyC), 1152 (C–O), 839 cm^Ϫ1. C₁₉H₃₄O₂

(294.48), FAB MS m/z: 317.3 [MϩNa]^ϩ, 295.2 [MϩH]^ϩ,

281.1 [MϩNaϪ2H₂O]^ϩ, 259.2 [MϩHϪ2H₂O]^ϩ. HRMS:

calcd for C₁₉H₃₄O₂Na [MϩNa]^ϩ: 317.2456, found

317.2458.

(3S)-1-(tert-Butyldiphenylsilyloxy)-4-chloro-3-methyl-

butan-3-ol (29b). To a stirred solution of 29a (42.1 mg,

0.30 mmol) in CH₂Cl₂(4 mL) DMAP (9.16 mg,

0.075 mmol), triethylamine (37.9 mg, 52 mL, 0.375 mmol)

and tert-butyldiphenylchlorosilane (103.1 mg, 96 mL,

0.375 mmol) were added at 20ЊC. After stirring for 2.5 h

the reaction mixture was hydrolyzed with water (1 mL).

Usual work-up (CH₂Cl₂) and FC (petrol–ethyl acetate

10:1) furnished 29b (113.0 mg, quant.). [a]²_D⁴Ϫ2.9 (c

5.61 CHCl₃). ¹H NMR (200 MHz, CDCl₃, homo

decoupling): d1.07 (s, 9H, C(CH₃)₃), 1.34 (s, 3H,

CH₃-5), 1.76–2.04 (m, 12 lines, 2H, 2-H_a, 2-H_b), 3.53/

3.58 (AB, 2H, J_4a/4b10.9 Hz, 4-H_a, 4-H_b), 3.88–3.94

(t-type m, 2H, 1-H_a, 1-H_b), 4.08 (s, 1H, OH), 7.38–7.48

(m, 6H, Ar–H), 7.67–7.76 (m, 4H, Ar–H). ¹³C NMR

(50.3 MHz, CDCl₃): d19.49 (C(CH₃)₃), 25.71 (C-5),

27.29 (C(CH₃)₃), 39.38 (C-2), 52.79 (C-4), 61.89 (C-1),

(S)-1-(tert-Butyldiphenylsilyloxy)ethyl-1-methyloxirane

(31a). A stirred solution of 29b (75.4 mg, 0.2 mmol) in THF

1092

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

(1.5 mL) was cooled to Ϫ78ЊC. Then n-BuLi (1.5 M solu-

tion in hexane, 133 mL, 0.2 mmol) was added. After 15 min

the temperature was decreased to Ϫ100ЊC and the mixture

was treated with lithiumnaphthalenide (1 M solution in

THF, 0.4 mL, 0.4 mmol). After stirring for 5 h at Ϫ78ЊC

rac-drimenal (rac-3) (66.1 mg, 0.3 mmol) was added. The

reaction mixture was allowed to warm to ambient tempera-

ture and hydrolyzed with water (0.5 mL). Usual work-up

(CH₂Cl₂) and FC (petrol–ethyl acetate 10:1) furnished 30

butylbiphenyl (1678.4 mg, 6.3 mmol) in THF (15 mL)

lithium metal (43.7 mg, 6.3 mmol, 0.3 cm-granulate) was

added and the mixture was sonicated until a blue colour

appeared. The solution was vigorously stirred for 6 h at

0ЊC. The deep blue solution of the radical anion was cooled

to Ϫ78ЊC and epoxide 31b (528.6 mg, 3.0 mmol) was added

dropwise. The colour of the reaction mixture changed from

blue to red. 5 min after the addition was complete benz-

aldehyde (477.5 mg, 460 mL, 4.5 mmol) was added at

Ϫ78ЊC (the red colour of the reaction mixture disappeared).

At the end of the addition the mixture was stirred for 1 h,

water (3 mL) was added and the mixture was allowed to

warm to 20ЊC. After usual work-up (CH₂Cl₂) and FC

(petrol–ethyl acetate 1:2) a non-separable 1:1 mixture (¹H

NMR integrals of the CH₃-5 signals) of 33 and 34

(699.5 mg, 82%) was obtained. ¹H NMR (200 MHz,

CDCl₃): d1.25 and 1.39 (2s, 6H, 2 CH₃-5), 1.55–2.10

(mk, 4H, 2×CH₂-2), 3.37 and 3.39 (2s, 6H, 2 OCH₂OCH₂-

CH₂OCH₃), 3.44–3.89 (mk, 12H, 2 OCH₂OCH₂CH₂OCH₃,

2×CH₂-4), 4.73 and 4.79 (2s, 4H, 2 OCH₂OCH₂CH₂OCH₃),

4.95–5.14 (2 dd, 2H, 2×1-H), 7.24–7.48 (mk, 10H, Ar–H).

¹³C NMR (50.3 MHz, CDCl₃, APT): d23.65 and 27.30

(CH₃-5) (Ϫ), 46.87 and 47.52 (CH₂-2) (ϩ), 59.47 and

59.51 (OCH₂OCH₂CH₂OCH₃) (Ϫ), 71.69 and 72.23 (C-1)

(Ϫ), 67.74/72.13/72.17/73.07/73.42/75.12/77.80 (OCH₂-

OCH₂CH₂OCH₃, C-3, C-4) (ϩ), 96.63 and 96.71

(OCH₂OCH₂CH₂OCH₃) (ϩ), 126.07 and 126.18 (Ar–C-o)

(Ϫ), 127.76 and 127.86 (Ar–C-p) (Ϫ), 128.85 and 128.90

(Ar–C-m) (Ϫ), 145.28 and 145.32 (Ar–C-ipso) (ϩ). IR

1

(53.1 mg, 78%). H NMR (200 MHz, CDCl₃): d1.05 (s,

9H, C(CH₃)₃), 1.31 (s, 3H, CH₃-3), 1.58–1.77/1.85–2.00

(2m, 2H, 1⁰-H_aand 1⁰-H_b), 2.59 (dd, 1H, J_2a/2b4.9 Hz,

0

J_{2a/1 a}1.0 Hz, 2-H_a), 2.70 (d, 1H, J_2b/2a4.9 Hz, 2-H_b),

3.77 (dd, 2H, J6.9 Hz, J5.6 Hz, CH₂-2⁰), 7.31–7.42

(m, 6H, Ar–H), 7.59–7.69 (m, 4H, Ar–H). C₂₁H₂₈O₂Si

(340.53).

(S)-1-(tert-Butyldiphenylsilyloxy)methyl-1-methyloxirane

(31a). To

a stirred solution of (R)-methylglycidol

(1057.2 mg, 960 mL, 12.0 mmol) in CH₂Cl₂(80 mL)

DMAP (366.5 mg, 3.0 mmol), triethylamine (1517.8 mg,

2.1 mL, 15 mmol) and tert-butyldiphenylchlorosilane

(4122.9 mg, 3.8 mL, 15 mmol) were added at 20ЊC. After

stirring for 2.5 h the reaction mixture was hydrolysed with

water (20 mL). Usual work-up (CH₂Cl₂) and FC (petrol–

ethyl acetate 10:1) yielded 31a (3839.7 mg, 98%).

[a]²_D⁴Ϫ4.9 (c 13.38 CHCl₃). ¹H NMR (200 MHz,

CDCl₃): d1.07 (s, 9H, C(CH₃)₃), 1.39 (s, 3H, CH₃-3),

2.59/2.71 (AB, 2H, J_2a/2b5.0 Hz, CH₂-2), 3.67 (s, 2H,

CH₂-1), 7.38–7.45 (m, 6H, Ar–H), 7.66–7.72 (m, 4H,

Ar–H). ¹³C NMR (50.3 MHz, CDCl₃): d18,67 (CH₃-3),

19.69 (C(CH₃)₃), 27.19 (C(CH₃)₃), 52.08 (CH₂-2), 57.56

(C_q-1), 67.53 (CH₂-1⁰), 128.22 (Ar–C-m), 130.25 (Ar–C-p),

133.86 (Ar–C-ipso), 136.12 (Ar–C-o), 136.19 (Ar–C-o). IR

(ﬁlm): 1111 (C–O), 704 cm^Ϫ1. C₂₀H₂₆O₂Si (326.51), FAB

MS m/z: 349.2 [MϩNa]^ϩ, 327.2 [MϩH]^ϩ, 309.2

[MϩHϪH₂O]^ϩ. HRMS: calcd for C₂₀H₂₇O₂Si [MϩH]^ϩ:

327.1780, found 327.1781.

(ﬁlm): 3400 (O–H), 1115 (C–O), 1048 (C–O), 701 cm^Ϫ1

.

C₁₅H₂₄O₅(284.35), FAB MS m/z: 307 [MϩNa]^ϩ, 285

[MϩH]^ϩ, 267 [MϩHϪH₂O]^ϩ. HRMS: calcd for

C₁₅H₂₄O₅Na [MϩNa]^ϩ: 307.1521, found 307.1540.

Deprotection of 33 and 34

A solution of the 33/34 mixture (410.0 mg, 1.44 mmol) in

3 mol L^Ϫ1HCl in methanol (4 mL) was stirred at 20ЊC for

4 h. Water (2 mL) and CH₂Cl₂were added until a two-phase

system resulted. Usual work-up and FC (chloroform–

ethanol 20:1) provided the free triols (87.6 mg, 31% of

one diasteroisomer; 42.4 mg, 15% of the other and

90.4 mg, 32% of a mixture of both).

(R)-1-(Methoxyethoxymethoxy)methyl-1-methyloxirane

(31b). To

a stirred solution of (R)-methylglycidol

(1057.2 mg, 960 mL, 12.0 mmol) in CH₂Cl₂(40 mL)

diisopropylethylamine (3102.0 mg, 4.1 mL, 24.0 mmol)

and MEMCl (2242.2 mg, 2.0 mL, 18.0 mmol) were added

at 20ЊC. After stirring for 4 h the reaction mixture was

hydrolysed with water (10 mL). Usual work-up (CH₂Cl₂)

and FC (hexane–ethyl acetate 1:1) furnished 31b

(1S, 3S)-3-Methyl-1-phenyl-1,3,4-butanetriol and (1R,

3S)-3-methyl-1-phenyl-1,3,4-butanetriol (formulae not

shown). Diastereomer A: [a]²_D⁴Ϫ22.6 (c 2.83 MeOH).

¹H NMR (200 MHz, CDCl₃): d1.45 (s, 3H, CH₃-5), 1.97

1

(1903.1 mg, 92%). [a]²_D⁴Ϫ7.5 (c 7.5 CHCl₃). H NMR

(200 MHz, CDCl₃): d1.37 (s, 3H, CH₃-3), 2.62/2.76

(AB, 2H, J_2a/2b4.8 Hz, CH₂-2), 3.38 (s, 3H, OCH₂OCH_2-

CH₂OCH₃), 3.49–3.72 (mk, 6H, OCH₂OCH₂CH₂OCH₃,

CH₂-1), 4.73 (s, 2H, OCH₂OCH₂CH₂OCH₃). ¹³C NMR

(50.3 MHz, CDCl₃, APT): d19.03 (CH₃-3) (Ϫ), 52.13

(CH₂-2) (ϩ), 56.22 (C_q-1) (ϩ), 59.49 (OCH₂OCH₂-

CH₂OCH₃) (Ϫ), 67.42/71.14/72.20 (OCH₂OCH₂CH₂OCH₃,

CH₂-1⁰) (ϩ), 96.06 (OCH₂OCH₂CH₂OCH₃) (ϩ). IR (ﬁlm):

1116 (C–O), 1050 (C–O) cm^Ϫ1. C₈H₁₆O₄(176.21), EI MS

(m/z) (%): 101 [MϪOCH₂CH₂OCH₃]^ϩ(7), 89 [CH₂yOCH₂-

CH₂OCH₃]^ϩ(24), 59 (100).

(broad s, 3H, 3OH), 2.07 (ddd, 1H, J_2a/2b13.2 Hz, J_2a/1

7.0 Hz, J_2a/4a1.4 Hz, 2-H_a), 2.42 (dd, 1H, J_2b/2a13.2 Hz,

J_2b/18.2 Hz, 2-H_b), 3.68 (d, 1H, J_4b/4a9.2 Hz, 4-H_b), 3.97

(dd, 1H, J_4a/4b9.2 Hz, J_4a/2a1.4 Hz, 4-H_a), 4.99 (t-type dd,

1H, J_1/2a7.0 Hz, J_1/2b8.2 Hz, 1-H), 7.26–7.42 (m, 5H,

Ar–H). ¹³C NMR (50.3 MHz, CDCl₃, APT): d24.86

(CH₃-5) (Ϫ), 49.83 (CH₂-2) (ϩ), 79.22 (C_q-3) (ϩ), 80.71

(CH₂-4) (ϩ), 81.11 (CH-1) (Ϫ), 126.25 (Ar–C-o) (Ϫ),

128.01 (Ar–C-p) (Ϫ), 129.03 (Ar–C-m) (Ϫ), 143.09 (Ar–

C-ipso) (ϩ). IR (ﬁlm): 3400 (O–H), 1052 (C–O), 755,

699 cm^Ϫ1

[MϪ2H₂O]^ϩ.

.

C₁₁H₁₆O₃(196.24), EI MS m/z: 160

Mixture of (1S,3S)- and (1R,3S)-4-(methoxyethoxy-

methoxy)-3-methyl-1-phenylbutane-1,3-diol (33 and 34).

To a stirred solution (glass coated stirrer) of 4,4⁰-di-tert-

1

Diastereomer B: [a]_D²⁴ϩ59.5 (c 0.97 MeOH). H NMR

(200 MHz, CDCl₃): d1.46 (s, 3H, CH₃-5), 1.92 (broad s,

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

1093

3H, 3OH), 1.87 (dd, 1H, J_2a/2b13.0 Hz, J_2a/110.2 Hz,

reaction mixture was stirred for 90 min at Ϫ78ЊC and then

was hydrolysed with H₂O (2 mL) at Ϫ65ЊC. The mixture

was allowed to warm to ambient temperature. Usual work-

up (CH₂Cl₂) and FC (chloroform–ethyl acetate 5:1)

furnished a mixture of two diastereomers (probably 37a

and 38a) (85.4 mg, 69%). 39.5 mg of 35 was recovered.

¹H NMR (200 MHz, CDCl₃): d0.85 and 0.88 (2s, 12H)

0.98 and 1.00 (2s, 6H) (2 CH₃-18, 2 CH₃-19, 2 CH₃-20),

0.90–2.00 (mk, 46H) with 1.24 and 1.33 (2s, 2 CH₃, CH₃-

16), 1.89 (s, 2 CH₃, CH₃-17), 2.10–2.37 (mk, 2H, 2×12-H_a),

2.92 (d, 1H, J1.8 Hz), 3.13 (s, 1H), 3.382 and 3.385 (2s,

6H, OCH₂OCH₂CH₂OCH₃), 3.52–3.85 (mk, 12H,

OCH₂OCH₂CH₂OCH₃, CH₂-15), 4.38–4.48 (t-type m, 2H,

2×11-H), 4.70 and 4.71 (2s, 4H, OCH₂OCH₂CH₂OCH₃),

5.53–5.59 (m, 2H, 2×7-H). ¹³C NMR (50.3 MHz, CDCl₃,

APT): d14.84 (CH₃-20) (Ϫ), 19.27 (CH₂-2) (ϩ), 22.72

(Ϫ), 23.88 (ϩ), 25.39 (Ϫ), 26.20 (Ϫ), 28.86 (Ϫ), 31.03

(Ϫ), 33.35 (ϩ), 33.86 (Ϫ), 37.78 (ϩ), 37.83 (ϩ), 38.97

(ϩ), 40.69 (ϩ), 42.65 (ϩ), 49.24 (ϩ), 50.28 (ϩ), 50.52

(Ϫ), 50.58 (Ϫ), 59.52 (OCH₂OCH₂CH₂OCH₃) (Ϫ), 61.27

(Ϫ), 65.09 (ϩ), 65.51 (ϩ), 66.95 (Ϫ), 67.59 (ϩ), 72.22 (ϩ),

73.90 (ϩ), 74.13 (ϩ), 96.07 and 96.13 (OCH₂OCH₂-

CH₂OCH₃) (ϩ), 126.28 and 126.51 (CH-7) (Ϫ), 133.20

and 133.31 (C_q-8) (ϩ). IR (CCl₄): 3476 (O–H), 1729,

1456, 1387, 1117, 1044 (C–O) cm^Ϫ1. C₂₄H₄₄O₅(412.61),

FAB MS m/z: 435 [MϩNa]^ϩ, 413 [MϩH]^ϩ. HRMS: calcd

for C₂₄H₄₅O₅[MϩH]^ϩ: 413.3267, found 413.3270.

2-H_a), 2.38 (ddd, 1H, J_2b/2a13.0 Hz, J_2b/16.1 Hz, J_2b/4a

1.0 Hz, 2-H_b), 3.90 (dd, 1H, J_4a/4b9.4 Hz, J_4a/2b1.0 Hz,

4-H_a), 3.94 (d, 1H, J_4b/4a9.4 Hz, 4-H_b), 5.25 (dd, 1H,

J_1/2a10.2 Hz, J_1/2b6.1 Hz, 1-H), 7.25–7.36 (m, 5H,

Ar–H). ¹³C NMR (50.3 MHz, CDCl₃, APT): d24.92

(CH₃-5) (Ϫ), 50.38 (CH₂-2) (ϩ), 79.77 (C_q-3) (ϩ), 80.75

(CH₂-4) (ϩ), 80.98 (CH-1) (Ϫ), 126.04 (Ar–C-o) (Ϫ),

127.93 (Ar–C-p) (Ϫ), 128.95 (Ar–C-m) (Ϫ), 143.12

(Ar–C-ipso) (ϩ). IR (ﬁlm): 3398 (O–H), 1050 (C–O),

755, 699 cm^Ϫ1. C₁₁H₁₆O₃(196.24), EI MS m/z: 160

[MϪ2H₂O]^ϩ.

(1S)-1-(Methoxyethoxymethoxy)ethyl-1-methyloxirane

(35). To a stirred solution of 29a (671.0 mg, 4.85 mmol) in

THF (40 mL) n-BuLi (1.5 M solution in hexane, 6.5 mL,

9.7 mmol) was added at Ϫ78ЊC. Then the reaction mixture

was slowly allowed to warm to ambient temperature within

2 h. The mixture was ﬁltered through a ﬂorisil pad to

separate LiCl and the solvent was evaporated under reduced

pressure (not below 350 mbar!). The crude epoxy alcohol

1

was obtained as volatile oil. H NMR (200 MHz, CDCl₃):

d1.37 (s, 3H, CH₃-5), 1.76–2.03 (m, 14 lines, 2H, CH₂-2),

2.27 (broad, 1H, OH), 2.63/2.80 (AB, 2H, J_4a/4b4.4 Hz,

CH₂-4), 3.62–3.83 (m, 14 lines, 2H, CH₂-1). ¹³C NMR

(50.3 MHz, CDCl₃): d22.38 (CH₃-5), 38.17 (CH₂-2),

53.53 (CH₂-4), 56.97 (C_q-3), 59.70 (CH₂-1). IR (ﬁlm):

3400 (O–H), 1050 (C–O) cm^Ϫ1. C₅H₁₀O₂(102.13), EI MS

m/z (%): 101 (15), 87 [MϪCH₃]^ϩ(61), 71 (22), 57 [C₄H₉]^ϩ

(60), 43 (88), 41 (100). The crude product was dissolved in

CH₂Cl₂(20 mL) and the stirred solution was treated with

diisopropylethylamine (1253.7 mg, 1.66 mL, 9.7 mmol)

and MEMCl (906.8 mg, 830 mL, 7.28 mmol) at 20ЊC.

After stirring for 4.5 h the reaction mixture was hydrolysed

with H₂O (10 mL). Usual work-up (CH₂Cl₂) and FC

(petrol–ethyl acetate 1:1) furnished the optically active

epoxide 35 (738.0 mg, 80% based on 29a). [a]²_D⁴ϩ5.92

Mixture of (5S,9R,10S,11S,13S)- and (5R,9S,10R,11R,

13S)-labd-7-ene-11,13,15-triol (37b and 38b). 37a and

38a (63.5 mg, 0.154 mmol) were treated with 3 N HCl in

methanol (2 mL) and the reaction mixture was stirred for 4 h

at 20ЊC. Water (2 mL) was added and the mixture was

diluted with CH₂Cl₂until two layers appeared. Usual

work-up (CH₂Cl₂) and FC (petrol–ethyl acetate 1:1) yielded

a mixture of 37b and 38b (43.0 mg, 86%). ¹H NMR

(200 MHz, CDCl₃): d0.86/0.90/0.99 (3s, 18H, 6 CH₃,

CH₃-18, CH₃-19 and CH₃-20), 1.07–2.00 (mk, 38H) with

1.29 and 1.37 (2s, 2 CH₃, CH₃-16), 1.90 (s, 2 CH₃-17),

2.17–2.50 (m, 2H, 2×12-H_a), 3.28 (broad, 6H, 6 OH),

3.78–4.11 (m, 4H, 2 CH₂-15), 4.44–4.54 (m, 2H, 2×11-

H), 5.61 (broad s, 2H, 2×7-H). ¹³C NMR (50.3 MHz,

CDCl₃, APT): d14.96 (CH₃-20) (Ϫ), 19.20 (CH₂-2) (ϩ),

22.74 (CH₃-19) (Ϫ), 23.84 (CH₂-6) (ϩ), 25.37 (CH₃-17)

(Ϫ), 26.43 (CH₃-16) (Ϫ), 28.52 (Ϫ), 31.02 (Ϫ), 33.33

(C_q-4 or C_q-10) (ϩ), 33.86 (CH₃-18) (Ϫ), 37.75 (C_q-4 or

C_q-10) (ϩ), 40.16 (ϩ), 40.62 (ϩ), 42.57 (ϩ), 44.25 (ϩ),

48.33 (CH₂-12) (ϩ), 50.26 (ϩ), 50.42 (CH-5) (Ϫ), 60.06

and 60.36 (CH₂-15) (ϩ), 60.99 and 61.04 (CH-9) (Ϫ), 67.24

and 67.71 (CH-11) (Ϫ), 75.01 and 75.20 (C_q-13) (ϩ),

127.25 and 127.58 (CH-7) (Ϫ), 132.45 and 132.65 (C_q-8)

(ϩ). The signals of 37b were clearly identiﬁed both in the

¹H NMR and in the ¹³C NMR spectra on comparison with

the known spectra of rac-37b.10 IR (ﬁlm): 3365 (O–H),

1717, 1405, 1107 (C–O) cm^Ϫ1. C₂₀H₃₆O₃(324.50), FAB

MS m/z: 347.3 [MϩNa]^ϩ, 325.3 [MϩH]^ϩ, 307.1

[MϩHϪH₂O]^ϩ, 289.2 [MϩHϪ2H₂O]^ϩ. HRMS: calcd for

C₂₀H₃₇O₃[MϩH]^ϩ: 325.2743, found 325.2744.

1

(c 19.92 CHCl₃). H NMR (200 MHz, CDCl₃): d1.32 (s,

3H, CH₃-3), 1.71–1.97 (m with 11 lines, 2H, CH₂-1⁰), 2.56/

2.65 (AB, 2H, J_2a/2b5.0 Hz, 2-H_a, 2-H_b), 3.37 (s, 3H,

OCH₂OCH₂CH₂OCH₃), 3.51–3.69 (mk, 6H, OCH₂OCH₂-

CH₂OCH₃, CH₂-2⁰), 4.68 (s, 2H, OCH₂OCH₂CH₂OCH₃).

¹³C NMR (50.3 MHz, CDCl₃): d 21.74 (CH₃-3), 36.93

(CH₂-1⁰), 54.27 (CH₂-2), 55.70 (C_q-1), 59.43 (OCH₂-

OCH₂CH₂OCH₃), 64.63 (CH₂-2⁰), 67.28 and 72.20

(OCH₂OCH₂CH₂OCH₃), 95.95 (OCH₂OCH₂CH₂OCH₃).

IR (ﬁlm): 1392, 1116 (C–O) cm^Ϫ1. C₉H₁₈O₄(190.23),

FAB MS m/z: 213 [MϩNa]^ϩ, 191 [MϩH]^ϩ. HRMS: calcd

for C₉H₁₈O₄Na [MϩNa]^ϩ: 213.1102, found 213.1091.

Mixture of (5S,9R,10S,11S,13S)- and (5R,9S,10R,11R,

13S)-15-(methoxyethoxymethoxy)-labd-7-ene-11,13-diol

(37a and 38a). To a stirred solution (glass coated stirrer) of

4,4⁰-di-tert-butylbiphenyl (159.8 mg, 0.6 mmol) in THF

(4 mL) lithium metal (4.2 mg, 0.6 mmol, 0.3 cm pieces)

was added and then the mixture was sonicated (3 min)

until the colour of the solution turned to blue. For complete

dissolution of lithium metal, the solution was stirred for 6 h

at 0ЊC. The resulting deeply blue radical anion solution was

cooled to Ϫ78ЊC and then 35 (114.1 mg, 0.6 mmol) was

added until the colour of the reaction mixture turned to

deeply red. After 5 min the dianion was trapped at Ϫ78ЊC

with rac-drimenal (rac-3) (88.1 mg, 0.4 mmol). The

Mixture of (5S,9R,10S,11S,13S)- and (5R,9S,10R,11R,

13S)-15-(tert-butyldiphenylsilyloxy)-labd-7-ene-11,13-

diol (37c and 38c). To a stirred solution of 37b and 38b

(28.2 mg, 87 mmol) in CH₂Cl₂(3 mL) DMAP (2.6 mg,

1094

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

22 mmol), triethylamine (11.4 mg, 16 mL, 113 mmol) and

tert-butyldiphenylchlorosilane (29.8 mg, 28 mL, 109 mmol)

was added at 20ЊC. The reaction was complete after 5 h

and the mixture was hydrolysed with water (1 mL). Usual

work-up (CH₂Cl₂) and FC (petrol–ethyl acetate 10:1)

(CCl₄): 3494 (O–H), 1709 (CyO), 1389, 1106 (C–O),

702 cm^Ϫ1. C₃₆H₅₂O₃Si (560.89), FAB MS m/z: 583.5

[MϩNa]^ϩ, 561.5 [MϩH]^ϩ, 543.5 [MϩHϪH₂O]ϩ, 503.5.

HRMS: calcd for C₃₆H₅₃O₃Si [MϩH]^ϩ: 561.3763, found

561.3746.

1

furnished a mixture of 37c and 38c (47.1 mg, 96%). H

NMR (200 MHz, CDCl₃): d0.85–2.00 (mk, 78H) with

0.87/0.91 (2s, 4 CH₃, CH₃-18 and CH₃-19), 1.03 (2s, 2

CH₃, CH₃-20), 1.04/1.05 (2s, 2 C(CH₃)₃), 1.30/1.37 (2s, 2

CH₃, CH₃-16), 1.92/1.97 (2s, 2 CH₃, CH₃-17), 2.17–2.49

(m, 2H, 2×12-H_a), 3.84–4.06 (m, 4H, 2 CH₂, CH₂-15),

4.37–4.53 (m, 2H, 2×11-H), 5.85 (broad s, 2H, 2×7-H),

7.38–7.47 (m, 12H, Ar–H), 7.65–7.72 (m, 8H, Ar–H).

¹³C NMR (50.3 MHz, CDCl₃, APT): d14.69 and 14.75

(CH₃-20) (Ϫ), 19.22 (ϩ), 19.33 (ϩ), 19.38 (ϩ), 22.65

(Ϫ), 23.82 (ϩ), 25.33 (Ϫ), 25.48 (Ϫ), 26.45 (Ϫ), 27.15

and 27.20 (C(CH₃)₃) (Ϫ), 28.90 (Ϫ), 33.30 (ϩ), 33.81

(Ϫ), 37.75 (ϩ), 37.84 (ϩ), 40.16 (ϩ), 40.65 (ϩ), 40.71

(ϩ), 42.64 (ϩ), 43.93 (ϩ), 48.76 (ϩ), 50.45 (ϩ), 50.55

and 50.64 (CH-5) (Ϫ), 61.29 and 61.35 (CH-9) (Ϫ), 61.91

and 62.16 (CH₂-15) (ϩ), 66.63 and 66.77 (CH-11) (Ϫ),

74.72 and 74.93 (C_q-13) (ϩ), 125.97 and 126.09 (CH-7)

(Ϫ), 128.37 (Ar–C-m) (Ϫ), 130.47 (Ar–C-p) (Ϫ), 133.07/

133.16/133.27 (Ar–C-ipso) (ϩ), 133.63 and 133.73 (C_q-8)

(ϩ), 136.04/136.07/136.10 (Ar–C-o) (Ϫ). IR (ﬁlm): 3367

(O–H), 1720, 1528, 1349, 1100 (C–O) cm^Ϫ1. C₃₆H₅₄O₃Si

(562.90), FAB MS m/z: 585.4 [MϩNa]^ϩ, 563.4 [MϩH]^ϩ,

199.1 [Ph₂SiOH]^ϩ. HRMS: calcd for C₃₆H₅₅O₃Si [MϩH]^ϩ:

563.3920, found 563.3904.

Epoxidation of 39 and 40

To a stirred solution of mCPBA (57%, 20.6 mg, 67.9 mmol)

in chloroform (3 mL) 39 and 40 (25.4 mg, 45.3 mmol, as a

solution in 1 mL of chloroform) were added. After 2 h the

reaction was completed and the reaction mixture was treated

with aq. sat. NaHCO₃(1 mL). Usual work-up (CH₂Cl₂) and

FC (petrol–ethyl acetate 5:1) furnished a mixture of opti-

cally active epoxides 41 and 42 (22.5 mg, 86%). At this

stage TLC (petrol–ethyl acetate 10:1) showed two spots.

The more polar compound had the same R_fvalue as an

authentic sample of rac-41. The preparative separation

was not optimised. From one run (22.5 mg) the desired

epoxide 41 (4.0 mg, 15%) was obtained alongside with a

fraction containing both 41 and 42 (17.1 mg, 65%).

(5S,7R,8S,9R,10S,13S)- and (5R,7S,8R,9S,10R,13S)-15-

(tert-Butyldiphenylsilyloxy)-7,8-epoxy-13-hydroxy-labdan-

1

11-one (41 and 42). H NMR of 41 and 42 (200 MHz,

CDCl₃): d0.86/0.89/1.02 (3s, 18H, 2 CH₃-18, 2 CH₃-19,

2 CH₃-20), 1.06 (s, 18H, 2 C(CH₃)₃), 1.20 and 1.22 (2s, 6H,

2 CH₃-16), 1.29 (s, 6H, 2 CH₃-17), 1.65–1.98 (mk, 6H),

2.10 (2 overlapped dd, 2H, 2×1a-H), 2.66–2.87 (mk, 6H,

2 CH₂-12 and 2×9-H), 2.99 (m, 2H, 2×7-H), 3.73–3.96 (mk,

4H, 2 CH₂-15), 4.20 (s, 1H, OH ?), 7.39–7.43 (m, 12H,

Ar–H), 7.65–7.70 (m, 8H, Ar–H). C₃₆H₅₂O₄Si (576.89),

FAB MS m/z: 599.5 [MϩNa]^ϩ, 577.5 [MϩH]^ϩ, 559.5

[MϩHϪH₂O]^ϩ. HRMS: calcd for C₃₆H₅₂O₄SiNa

[MϩNa]^ϩ: 599.3532, found 599.3547.

Mixture of (5S,9R,10S,13S)- and (5R,9S,10R,13S)-15-

(tert-butyldiphenylsilyloxy)-13-hydroxy-labd-7-en-11-

one (39 and 40). To a stirred solution of o-iodoxybenzoic

acid (86.2 mg, 308 mmol) in DMSO (0.8 mL) 37c and 38c

(28.9 mg, 51.3 mmol, as solution in 0.5 mL of DMSO) were

added. After stirring for 17 h the reaction mixture was

ﬁltered through a Florisil pad and the resulting ﬁltrate solu-

tion was concentrated. FC (petrol–ethyl acetate 10:1)

(5S,7R,8S,9R,10S,13S)-15-(tert-Butyldiphenylsilyloxy)-

7,8-epoxy-13-hydroxy-labdan-11-one (41). ¹H NMR

(200 MHz, CDCl₃): d0.86/0.88/1.01 (3s, 9H, CH₃-18,

CH₃-19, CH₃-20), 1.05 (s, 9H, C(CH₃)₃), 1.21, 1.28 (2s,

6H, CH₃-16, CH₃-17), 1.62–1.98 (mk, 3H, CH₂-14,

6b-H), 2.09 (dd, 1H, J_1a/1b15.3 Hz, J_1a/24.2 Hz,

1

yielded a mixture of 39 and 40 (26.8 mg, 95%). H NMR

(600 MHz, CDCl₃): d0.798/0.803 (2s, 6H) and 0.820/

0.825 (2s, 12H) (2×CH₃-18, 2×CH₃-19, 2×CH₃-20), 0.982

and 0.986 (2s, 18H, 2×C(CH₃)₃), 1.203 and 1.208 (2s, 6H,

2×CH₃-16), 1.392 and 1.419 (2s, 6H, 2×CH₃-17), 2.68/2.76

and 2.73 (AB and s, 4H, J_2a/12b18.7 Hz, 2×CH₂-12), 3.07

(broad s, 2H, W_1/2Ϸ6 Hz, 2×9-H), 3.70–3.76 (m, 2H,

CH₂-15 of diastereomer A), 3.78–3.84 (m with 7 lines,

2H, CH₂-15 of diastereomer B), 5.43 (broad s, 2H, W_1/2Ϸ

6 Hz, 2×7-H), 7.30–7.37 (m, 12H, Ar–H), 7.58–7.60 (m,

8H, Ar–H). ¹³C NMR (50.3 MHz, CDCl₃, APT): d14.96

(CH₃-20) (Ϫ), 15.01 (Ϫ), 19.04 (CH₂-2) (ϩ), 19.45

(SiC(CH₃)₃) (ϩ), 19.49 (ϩ), 21.82 (Ϫ), 22.27 (Ϫ), 21.87

(Ϫ), 24.13 (CH₂-6) (ϩ), 27.26 (SiC(CH₃)₃) (Ϫ), 27.47

(CH₃-16) (Ϫ), 27.57 (Ϫ), 30.10 (ϩ), 33.45 (C_q-4 or

C_q-10) (ϩ), 33.79 (CH₃-18) (Ϫ), 37.75 (C_q-4 or C_q-10)

(ϩ), 37.81 (ϩ), 41.78 and 42.40 (CH₂-1 and CH₂-3) (ϩ),

42.87 (ϩ), 43.48 (CH₂-14) (ϩ), 49.89 (CH-5) (Ϫ), 58.23

(CH₂-12) (ϩ), 58.43 (ϩ), 61.43 (CH₂-15) (ϩ), 61.51 (ϩ),

68.52 (CH-9) (Ϫ), 72.14 (C_q-13) (ϩ), 72.20 (ϩ), 125.27

(CH-7) (Ϫ), 125.33 (Ϫ), 128.27 (Ar–C-m) (Ϫ), 130.29

(Ar–C-p) (Ϫ), 130.60 (ϩ), 130.67 (C_q-8) (ϩ), 133.77 and

133.88 (Ar–C-ipso) (ϩ), 136.06 (Ar–C-o) (Ϫ), 214.95 and

215.33 (CyO, C-11) (ϩ). The ¹H NMR and ¹³C NMR spec-

tra displayed all signals of the known compound rac-39. IR

1a-H), 2.68 (s, 1H, 9-H), 2.77/2.91 (AB, 2H, J_12a/12b

18.3 Hz, CH₂-12), 2.99 (m, 1H, W_1/25 Hz, 7-H), 3.73–

3.94 (m, 2H, CH₂-15), 4.19 (s, 1H, OH), 7.39–7.43 (m,

6H, Ar–H), 7.65–7.70 (m, 4H, Ar–H).⁴⁰CD

(c0.21·10^Ϫ3mol L^Ϫ1

,

CH₃CN): l_max(De)306.6 nm

(5.8).

Docking procedure

The structure data for the rat type II adenylyl cyclase C2

domain/forskolin complex were taken from the Brookhaven

Protein Data Bank (1ab8). Polar hydrogens and

CHARMM22 united-atom charges were added to the

protein. Prior to docking, electrostatic potential (ESP)

charges for the ligands were calculated on the basis of

AM1-optimized geometries using the MOPAC 6.0 program.

The grid with 88×64×64 grid points in x, y, z and a grid

˚

spacing of 0.375 A was centred in such a way that it was

possible to consider the two equivalent binding sites for

forskolin. In each case, 24 independent docking runs were

performed and the resulting structures were clustered by

D. Behnke et al. / Tetrahedron 56 (2000) 1081–1095

1095

2

˚

13. See Narula, A. S. Tetrahedron Lett. 1982, 23, 5579–5582, and

references therein.

14. Zimmermann, S.; Bick, S.; Welzel, P.; Meuer, H.; Sheldrick,

W. S. Tetrahedron 1995, 51, 2947–2952.

15. For leading references, see McKee, B. H.; Kalantar, T. H.;

Sharpless, K. B. J. Org. Chem. 1991, 56, 6966–6968.

geometry allowing RMSD deviations of Յ1 A . The GA-LS

procedure was applied with 100.000 energy evaluations per

run, a mutation rate of 0.10, a crossover rate of 0.80, and a

local search frequency of 0.06 subjected to a population of

50 randomly initiated individuals for each ligand. Free

rotation around all single bonds was allowed using the

AutoTors module. Free Enthalpy costs of 0.3113 kcal mol^Ϫ1

per torsional degree of freedom with exception of those with

NH and OH groups were applied.

¨

16. Jordine, G.; Bick, S.; Moller, U.; Welzel, P.; Daucher, B.;

Maas, G. Tetrahedron 1994, 50, 139–160.

17. Cf. Depew, K. M.; Danishefsky, S. J.; Rosen, N.; Sepp-

Lorenzino, L. J. Am. Chem. Soc. 1996, 118, 12 463–12 464.

´

18. Najera, C.; Yus, M.; Seebach, D. Helv. Chim. Acta 1984, 67,

Acknowledgements

289–300.

´

19. Barluenga, J.; Florez, J.; Yus, M. J. Chem. Soc. Perkin Trans.

Financial support by the Deutsche Forschungsgemeinschaft

(Innovationskolleg ‘Chemisches Signal und Biologische

Antwort’) and the Fonds der Chemischen Industrie is kindly

acknowledged. D. B. wishes to thank the Freistaat Sachsen

for a fellowship (Graduiertenstipendium).

´

1 1983, 3019–3026; Barluenga, J.; Fernandez-Simon, J. L.;

Concellon, J. M.; Yus, M. J. Chem. Soc. Perkin Trans. 1 1988,

´

3339–3343.

20. Wittmann, V.; Kessler, H. Angew. Chem. 1993, 105, 1138–

1140; Angew. Chem., Int. Ed. Engl. 1993, 32. 1091–1093.

21. Review: Marshall, J. A. Chem. Rev. 1996, 96, 31–47.

22. Review: Carey, J. S.; Coulter, T. S.; Hallett, D. J.; Maguire,

R. J.; McNeill, A. H.; Stanway, S. J.; Teerawutgulrag, A.; Thomas,

E. J. Pure Appl. Chem. 1996, 68 707–710.

23. Behnke, D.; Hamm, S.; Hennig, L.; Welzel, P. Tetrahedron

Lett. 1997, 38, 7059–7062.

24. For a preliminary account of this work, see Ref. 23.

25. Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1996, 61, 105–

108.

References

1. For leading references and studies on the interaction of

forskolin on P-glycoprotein, see Morris, D. I.; Greenberger, L.

M.; Bruggemann, E. P.; Cardarelli, C.; Gottesman, M. M.; Pastan,

I.; Seamon, K. B. Mol. Pharmacol. 1994, 46, 329–337.

2. Yan, S.-Z.; Hahn, D.; Huang, Z.-H.; Tang, W.-J. J. Biol. Chem.

1996, 271, 10 941–10 945.

3. Whisnant, R. E.; Gilman, A. G.; Dessauer, C. W. Proc. Natl.

Acad. Sci. 1996, 93, 6621–6625, and references therein.

4. Zhang, G.; Liu, Y.; Ruoho, A. E.; Hurley, J. H. Nature 1997,

386, 247–253.

5. Tesmer, J. J. G.; Sunahara, R. K.; Gilman, A. G.; Sprang, S. R.

Science 1997, 278, 1907–1916.

6. For leading references, see Colombo, M. I.; Zinczuk, J.;

Ruveda, E. A. Tetrahedron 1992, 48, 963–1037; Calvo, D.; Port,

M.; Delpech, B.; Lett, R. Tetrahedron Lett. 1996, 37, 1023–1024;

26. A preliminary account of this work has appeared, see Ref. 18.

27. Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.;

Harusawa, S.; Lowenthal, R. E.; Yogai, S. J. Am. Chem. Soc.

1988, 110, 6558–6560.

´

28. Barluenga, J.; Fan˜anas, F. J.; Yus, M. J. Org. Chem. 1979, 44,

4798–4801.

´

29. Barluenga, J.; Fan˜anas, F. J.; Villaman˜a, J.; Yus, M. J. Org.

Chem. 1982, 47, 1560–1564.

30. Cohen, T.; Jeong, I.-H.; Mudryk, B.; Bhupathy, M.; Awad,

M. A. J. Org. Chem. 1990, 55, 1528–1536.

31. Bachki, A.; Foubelo, F.; Yus, M. Tetrahedron: Asymmetry

1996, 7, 2997–3008.

´

Pancrazi, A.; Lallemand, J.-Y.; Prange, T. Bull. Soc. Chim. Fr.

1997, 134, 203–222.

7. Morris, G. M.; Goodsell, D. S.; Halliday, R. S.; Huey, R.; Hart,

W. E.; Belew, R. K.; Olsen, A. J. J. Comput. Chem. 1998, 19,

1639–1662.

8. Cf. Ref. 7 and literature cited therein.

9. Review: Seamon, K. B.; Daly, J. W. Adv. Cyclic Nucleotide

Res., 1996, 20, 1–150.

´

32. Yus, M.; Ramon, D. J. J. Chem. Soc., Chem. Commun. 1991,

398–400.

33. Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1979, 44,

713–719.

34. Cohen, T.; Weisenfeld, R. B. J. Org. Chem. 1979, 44, 3601–

3603.

35. Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1983, 48,

4705–4713.

36. Freeman, P. K.; Hutchinson, L. L. Tetrahedron Lett. 1976,

1849–1852.

10. For the introduction of the 9-OH group see Hrib, N. J.

¨

Tetrahedron Lett. 1987, 28, 19–22; Scherkenbeck, J.; Bottger,

D.; Welzel, P. Tetrahedron 1987, 43, 3797–3802; Khandelwal,

Y. Jotwani, B. R.; Inamdar, P. K.; de Souza, N. J.; Rupp, R. H.

Tetrahedron 1989, 45, 763–766.

¨

11. For the microbial oxidation at C-1, see Aretz, W.; Bottger, D.;

37. Review: Yus, M. Chem. Soc. Rev. 1996, 155–161.

38. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,

2923–2925.

Sauber, K. Biol. Chem. Hoppe-Seyler 1986, 367 (suppl. 213);

Nadkarni, S. R.; Akut, P. M.; Ganguli, B. N.; Khandelwal, Y.;

de Souza, N. J.; Rupp, R. H.; Fehlhaber, H. W. Tetrahedron Lett.

39. Kritchevsky, D.; Kirk, M. R. Arch. Biochem. Biophys. 1952,

35, 346–351.

´

1986, 27, 5265–5268, see also Fraga, B. M.; Gonzales, P.;

´

Guillermo, R.; Hernandez, G. Tetrahedron 1998, 54, 6159–6168.

40. The spectrum was well in agreement with the published

12. Bick, S.; Zimmermann, S.; Meuer, H.; Sheldrick, W. S.;

Welzel, P. Tetrahedron 1993, 49, 2457–2468.

spectrum.¹²

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Forskolin studies

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