Stereoselective synthesis of a new class of potent and selective inhibitors of human Δ8,7-sterol isomerase

DOI: 10.1016/j.bmc.2013.01.041

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Bioorganic and Medicinal Chemistry p. 1925 - 1943 (2013)

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Authors:

K?nig, Mathias

Müller, Christoph

Bracher, Franz

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Article abstract of DOI:10.1016/j.bmc.2013.01.041

Starting from Grundmann′s ketone a new chemotype of inhibitors of the post-squalene part of cholesterol biosynthesis was developed. Stereoselective introduction of an angular methyl group at C-3a, followed by a plethora of functionalisations at C-4 and C-5 led to cis-configured amino alcohols as a new chemotype of inhibitors of cholesterol biosynthesis. In cell-based screening systems these compounds were identified to be selective inhibitors of human Δ8,7-sterol isomerase, inhibiting total cholesterol biosynthesis with IC₅₀ values in the low nanomolar range. The most active compounds did not affect fungal Δ8,7-sterol isomerase (in ergosterol biosynthesis), neither showed noteworthy antimicrobial and cytotoxic effects.

Full text of DOI:10.1016/j.bmc.2013.01.041

Bioorganic & Medicinal Chemistry 21 (2013) 1925–1943

Contents lists available at SciVerse ScienceDirect

Bioorganic & Medicinal Chemistry

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Stereoselective synthesis of a new class of potent and selective

inhibitors of human

8,7-sterol isomerase

⇑

Mathias König, Christoph Müller, Franz Bracher

Ludwig-Maximilians University, Department of Pharmacy, Center for Drug Research, Butenandtstr. 5-13, 81377 Munich, Germany

a r t i c l e i n f o

a b s t r a c t

Starting from Grundmann⁰s ketone a new chemotype of inhibitors of the post-squalene part of cholesterol

biosynthesis was developed. Stereoselective introduction of an angular methyl group at C-3a, followed by

a plethora of functionalisations at C-4 and C-5 led to cis-conﬁgured amino alcohols as a new chemotype

of inhibitors of cholesterol biosynthesis. In cell-based screening systems these compounds were identi-

Article history:

Received 1 May 2012

Revised 10 January 2013

Accepted 14 January 2013

Available online 31 January 2013

ﬁed to be selective inhibitors of human

with IC₅₀values in the low nanomolar range. The most active compounds did not affect fungal

8,7-sterol isomerase, inhibiting total cholesterol biosynthesis

8,7-ste-

Keywords:

Amino alcohols

Stereoselective synthesis

Cholesterol biosynthesis inhibitors

rol isomerase (in ergosterol biosynthesis), neither showed noteworthy antimicrobial and cytotoxic

effects.

Human

D8,7-sterol isomerase

HL-60 cells

1. Introduction

pathway by action of the enzyme 3b-hydroxy-steroid-D

²⁴-reduc-

tase (for details see Supplementary data).

The invention of enzyme inhibitors represents a major strategy

in the development of novel drugs, and almost one third of the

current top 50 drugs are enzyme inhibitors.¹The enzymes of cho-

lesterol biosynthesis are part of these interesting targets. Choles-

terol is essential for the inducement of many crucial functions of

vertebral plasma membranes.²It is the most representative sterol

present in these membranes and it is the product of a multistep

biosynthetic pathway. Two major pathways for cholesterol biosyn-

thesis, the Kandutsch–Russell^3,4and the Bloch⁵pathway are

known. 7-Dehydrocholesterol is the immediate biosynthetic pre-

cursor of cholesterol in the Kandutsch–Russell pathway, and its

reduction to cholesterol is catalyzed by the enzyme 3b-hydroxy-

Cholesterol is important for the formation of so called ‘rafts’

(DRMs—detergents resistant micro domains) which regulate sev-

eral functions of the eukaryotic lipid membrane and are linked

with the pathogenesis of certain diseases.^7,8Cholesterol is also a

precursor for steroid hormones and bile acids as well as it is rele-

vant for the embryonic progress and morphogenesis.⁹Because of

its eminent physiological role, disruptions in cholesterol metabo-

lism cause various diseases. The most common are cardiovascular

indispositions induced by an increased blood cholesterol level.¹⁰

The most prominent drugs marketed for treatment of hyperlip-

idaemia are the statins, inhibitors of 3-hydroxy-3-methylglutaryl

(HMG)-CoA reductase, an enzyme acting early in the pre-squalene

part of cholesterol biosynthesis. Since therapy with statins is

accompanied by a number of side-effects¹¹like muscle toxicity,

causing muscle weakness and cramps or even myopathy requiring

hospitalization and life-threatening rhabdomyolysis, new choles-

terol-lowering drugs having other molecular mechanisms are

desirable. For this purpose the post-squalene part of the choles-

terol biosynthesis pathway offers attractive targets.¹²

steroid-D

⁷-reductase. Desmosterol is the direct biosynthetic pre-

cursor of cholesterol in the Bloch pathway and differs from choles-

terol only in a double bond in the side chain. Conversion of

desmosterol to cholesterol is catalyzed by the enzyme 3b-hydro-

xy-steroid-D

²⁴-reductase in the ﬁnal step of this pathway (Fig. 1).⁶

In mammals the preferred pathway for cholesterol biosynthesis

starts with the Bloch pathway and ends with the last steps of the

Kandutsch–Russell pathway. This switch between the pathways

can occur since certain intermediates of the Bloch pathway can

be converted to the corresponding ones of the Kandutsch–Russell

Contrariwise, the inborn lack of late enzymes of cholesterol bio-

synthesis is known to generate rare but serious disorders. Thus,

speciﬁc inhibitors of such enzymes should be valuable tools for

getting deeper insight into these disorders.^13,14For example, CHILD

(congenital hemidysplasia with ichthyosiform erythroderma and

limb defects) syndrome¹⁵and Conradi–Hünermann–Happle syn-

drome^16,17are dysmorphogenetic syndromes of variable severity

⇑

Corresponding author. Tel.: +49 89 2180 77301; fax: +49 89 2180 77802.

E-mail address: Franz.Bracher@cup.uni-muenchen.de (F. Bracher).

http://dx.doi.org/10.1016/j.bmc.2013.01.041

1926

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

Figure 1. Chemical structures of the biosynthetic precursors of cholesterol: desmosterol (Bloch pathway) and 7-dehydrocholesterol (Kandutsch–Russel pathway).

due to mutations of the gene encoding the human 3b-hydroxyster-

oid

mil-binding protein, EBP).¹⁸

EBP is a vertebrate 8,7-sterol isomerase which has been

shown to exhibit equally high binding afﬁnity for both enantio-

mers of the calcium channel blocker emopamil.¹⁹Human

8,7-ste-

D8,7-sterol isomerase (hSI; EC 5.3.3.5; also known as emopa-

rol isomerase catalyzes the shift of the double bond from C8–C9 to

C7–C8 position in one of the last steps in both cholesterol biosyn-

thesis pathways. In humans, such isomerisation occurs through a

trans proton addition-elimination reaction^20,21from either 5

a-cho-

lesta-8,24-dien-3b-ol (zymosterol, 1a) to 5a-cholesta-7,24-dien-

3b-ol (2a) for the Bloch pathway or alternatively from cholesta-

8-en-3b-ol (zymostenol, 1b) to lathosterol (2b) for the Kan-

dutsch–Russell pathway (Fig. 2). In case of a selective inhibition

D8,7-sterol isomerase not the primary substrate zymosterol

(1a), but zymostenol (1b) is the accumulating sterol. As mentioned

above, the biosynthesis of cholesterol can switch from the Bloch to

the Kandutsch–Russel pathway, and consequently, accumulating

zymosterol (1a, Bloch pathway) can further be converted to zym-

ostenol (1b, Kandutsch–Russel pathway) before the biosynthesis

becomes deﬁnitely blocked.

The yeast counterpart ERG2p catalyses the corresponding step

in ergosterol biosynthesis with the major difference that the isom-

erisation follows a cis proton addition-elimination reaction.^20,21

This stereoselectivity of both reaction mechanisms should allow

for a selective inhibition of either the human or fungal

D8,7-sterol

isomerase (EBP or ERG2p) by appropriately tailored inhibitors.

After the identiﬁcation of morpholines (e.g., tridemorph) as

inhibitors of

Figure 2. Human

carbocationic high energy intermediate (HEI).

D8,7-sterol isomerase-catalysed isomerisation going through a

8,7-sterol isomerase in fungi²²and plants²³a num-

ber of other inhibitors (e.g., 3–10, Fig. 3) have been described that

show more or less selective afﬁnity for the human or the fungal en-

zyme.^24,25Moreover, some of these inhibitors show multi-enzyme

inhibition in the post-squalene part of sterol biosynthesis. Such a

multi-enzyme inhibition can be advantageous in case of develop-

ing new antifungal agents by reducing fungal resistance. However

it is estimated as a great drawback for inhibitors of cholesterol

biosynthesis, since the resulting accumulation of particular precur-

sors of cholesterol might cause severe side-effects.^13–17

The reason for this disadvantageous multi-enzyme inhibition is

connected with the molecular mode of action of the inhibitors. Not

only sterol

D8,7-isomerisation passes through a carbocationic high

energy intermediate (HEI; Fig. 2), but also the steps mediated by

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1927

Figure 3. Structures of established

8,7-sterol isomerase (EBP or ERG2p) inhibitors.

the

7-sterol reductase,

24-sterol reductase, and

14-sterol

building block covering rings C+D of the sterol scaffold, as well

as the lipophilic steroid side chain, is Grundmann⁰s ketone³⁶(11).

Recently, this ketone was used by us as a precursor of cytotoxic

azasteroid analogues.^37,38Before attaching amino residues to the

six-membered ring, the well-known problem of epimerisation at

position C-3a of Grundmann⁰s ketone (11) had to be abolished. In

literature it is reported that this epimerisation can occur in pres-

ence of alkaline as well as acidic reagents and so causes a loss of

stereochemical integrity.³⁹A stereoselective introduction of an

angular methyl group at position C-3a, under retention of the trans

connection of both rings, would eliminate the possibility of

reductases do so.²⁶Suitable structures containing protonable

nitrogen atoms, and in some cases thionium ions,^27,28in pertinent

positions of the scaffold are able to mimic the cationic HEIs, and in-

hibit the enzymes due to the resulting high afﬁnity to the active

site.²⁶The established inhibitors shown in Figure 3 contain, with-

out exception, protonable amine functions. Besides inhibition of

8,7-sterol isomerase, ifenprodil (3) and MDL28815 (4) also

inhibit

14-sterol reductase,²⁹triﬂuperidol (5), AY9944 (6), and

fenpropimorph (7) show additional inhibition of 7-sterol

reductase,^30,31triﬂuoperazine (8), tamoxifen (9), and U18666A

(10) additionally inhibit

24-sterol reductase.^32,33Furthermore, a

number of azasteroids are known to exert their antifungal

activities through imitation of carbocationic HEIs in ergosterol

biosynthesis.^27,28,34

In continuation of our research on new inhibitors of ergosterol²⁸

and cholesterol³⁵biosynthesis we designed a new chemotype of

selective inhibitors of human

D8,7-sterol isomerase. In order to

achieve selective inhibition of the enzyme we invented HEI mimik-

ries with high structural similarity to the steroidal substrate on the

one side, and variable protonable amino groups localised in a do-

main matching ring B of the sterol on the other side. A versatile

Figure 4. Grundmann⁰s ketone (11) and modiﬁed ketone 12.

1928

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

Figure 5. Target structures: a-aminoketones (I) and a-aminoalcohols (II).

epimerisation at this position and should also direct reactions per-

formed at C-4 and C-5 (Fig. 4).

The ﬁrst group of target structures (see Fig. 5, type I), the amino

ketones 17a–e, were prepared from bromoketone 16 (Scheme 2).

This intermediate was obtained by treating ketone 12 in anhydrous

THF with lithium diisopropylamide and trimethylsilyl chloride⁴⁵to

give the silyl enol ether 15 in good yield (83%), followed by stere-

oselective bromination (90% yield) with N-bromosuccinimide⁴⁶in

Starting from modiﬁed ketone 12 various stereoselective func-

tionalisations at C-4 and C-5 should lead to an

a-bromoketone,

and further on to amino ketones I and trans- and cis-conﬁgured

amino alcohols II (Fig. 5). In cell-based screening systems^20,32these

compounds were to be tested for their inhibition of cholesterol and

ergosterol biosynthesis.

sodium acetate-buffered THF-water. The

a-bromoketone 16 and

the particular primary or secondary amine were reﬂuxed in

DMF⁴⁷to give the amino ketones 17a–e under clean inversion at

C-5 (Scheme 2).

2. Chemistry

First attempts to simply reduce the carbonyl function of amino

ketones 17a–e with lithium aluminium hydride⁴⁸in THF resulted

partially in epimeric mixtures of the corresponding amino alco-

hols. Reductions of 17a–c occurred stereoselectively to give the

cis-conﬁgured 4R,5S-amino alcohols, whereas reductions of 17d

and 17e were not stereoselective (Scheme 2).

We could not ﬁnd a structural explanation for the partially

selective or non-selective reductions of ketones 17a–e, and since

the epimeric mixtures 18d and 18e could not be separated by silica

column chromatography, sophisticated stereoselective transfor-

mations were elaborated to provide optionally each trans- and

cis-conﬁgured amino alcohols II (Fig. 5) in a predictable manner.

The central building block 23 for the preparation of trans-(4S,5S)-

conﬁgured amino alcohols was obtained starting from ketone 12

The synthesis of ketone 12 has previously been described rudi-

mentarily by Corey et al.⁴¹and therefore the reaction conditions

and work-up processes for the single steps had to be optimised.

Conversion of Grundmann⁰s ketone (11) to the trimethylsilyl enol

ether 13 was done in dichloromethane with trimethylsilyl chloride

(TMSCl) and lithium iodide in presence of hexamethyldisilazane

((TMS)₂NH) in good yield (64%).⁴²The silyl enol ether 13 was con-

verted to the cyclopropane derivative 14 (yield 80%) in a Simmons–

Smith-like reaction by using the Furukawa reagent diethylzinc

(Et₂Zn) and diiodomethane in diethyl ether.^43,44The ﬁnal alkaline

hydrolysis⁴³of the cyclopropane derivative 14 with sodium

hydroxide in ethanol–water provided the trans-fused

ated ketone 12 in good yield (88%) (Scheme 1).

a-methyl-

Scheme 1. Reagents and conditions: (a) trimethylsilyl chloride, 1,1,1,3,3,3-hexamethyldisilazane, lithium iodide, dichloromethane, rt, 24 h (64%); (b) 1 M diethylzinc solution

in hexane, diiodomethane, diethyl ether, reﬂux, 12 h (80%); (c) 2 M aqueous sodium hydroxide solution, ethanol, reﬂux, 12 h (88%).

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1929

R₂N = N,N-dimethylamino

92 % (4R, cis)

88 % (4R, cis)

96 % (4R, cis)

98 % (4R,S)

R₂N = N,N-dimethylamino

50 %

72 %

68 %

59 %

82 %

R₂N = 4-methylpiperazin-1-yl

R₂N = (pyridin-3-yl)methylamino

R₂N = 2,6-dimethylmorpholin-4-yl

R₂N = 2,3-dimethylanilino

R₂N = 4-methylpiperazin-1-yl

R₂N = (pyridin-3-yl)methylamino

R₂N = 2,6-dimethylmorpholin-4-yl

R₂N = 2,3-dimethylanilino

97 % (4R,S)

Scheme 2. Reagents and conditions: (a) lithium diisopropylamide, trimethylsilyl chloride, THF, ꢀ78 °C ? rt, 14 h (83%); (b) N-bromosuccinimide, sodium acetate, THF/water,

rt, 12 h (90%); (c) amine, DMF, reﬂux, 12 h; (d) lithium aluminium hydride, THF, 0 °C, 30 min.

Scheme 3. Reagents and conditions: (a) lithium aluminium hydride, THF, 0 °C, 30 min (99%); (b) phosphorous oxychloride, pyridine, rt, 30 min (78%); (c) m-chloroperbenzoic

acid, sodium bicarbonate, dichloromethane, 5 °C ? rt, 2 h (93%); (d) sodium azide, DMF, 130 °C (microwave, 150 W, 4 psi), 2 h (86%); (e) lithium aluminium hydride, THF,

0 °C, 30 min (99%).

by lithium aluminium hydride reduction to give alcohol 19 (99%

yield), followed by dehydration with phosphorous oxychloride⁴⁹

(78% yield) to give the oleﬁn 20. Stereoselective epoxidation of

the oleﬁn with m-chloroperbenzoic acid⁵⁰gave the epoxide 21 in

high yield (93%). Subsequent regio- and stereoselective micro-

wave-accelerated ring opening with sodium azide⁵¹led to the azi-

do alcohol 22 (86% yield), which ﬁnally was reduced with lithium

aluminium hydride⁵²to give the trans-(4S,5S)-conﬁgured amino

alcohol 23 in almost quantitative yield (Scheme 3).

ketone 24 in high yield (87%), followed by lithium aluminium hy-

dride⁵²reduction of both the azido and keto groups (99% yield)

(Scheme 4).

The relative conﬁgurations of the residues at C-3a, C-4 and C-5

of the epimeric amino alcohols were elucidated by DPFGSE-NOE

experiments, and since conﬁguration at C-3a was known, these

data also lead to the absolute conﬁgurations of the molecules

(see Supplementary data). With 25, irradiation at the resonance

frequency of 4-H lead to an enhancement of the resonances of both

the angular methyl group at C-3a and 5-H, clearly indicating that

4-H is located at the same side of the six-membered ring as these

two groups. In the analogous experiment with the trans-amino

alcohol 23 a nuclear Overhauser effect was observed neither with

The epimeric cis-(4R,5S)-conﬁgured building block 25 for the

preparation of amino alcohols of type II was obtained stereoselec-

tively from

-bromo ketone 16 (Scheme 2) by substitution with so-

-azido

dium azide^53,54under clean inversion at C-5 to give the

1930

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

Scheme 4. Reagents and conditions: (a) sodium azide, DMF, 0 °C, 2 h (87%); (b) lithium aluminium hydride, THF, 0 °C, 30 min (99%).

a. R = benzyl

85%

75%

79%

84%

79%

89%

77%

58%

86%

79%

67%

56%

73%

85%

b. R = (5-iodofuran-2-yl)methyl

c. R = 3-chlorobenzyl

d. R = (furan-3-yl)methyl

e. R = pent-4-en-1-yl

f. R = 2,4-dichlorobenzyl

g. R = 2,3-dichlorobenzyl

Scheme 5. Reagents and conditions: (a) aldehyde, sodium cyanoborohydride, acetic acid, methanol, 40 °C, 12 h.

the methyl group, nor with 5-H, in full accordance with the pro-

posed conﬁguration.

The amino alcohols 23 and 25 were conveniently converted to a

library of stereochemically pure secondary amines 26a–g and 27a–

g by reductive N-alkylations⁵⁵using various aldehydes and sodium

cyanoborohydride (Scheme 5).

Since in a ﬁrst screening for inhibition of cholesterol biosynthe-

sis the cis-(4R,5S)-conﬁgured amino alcohols 27a–g, especially the

N-benzyl derivative (27a) and the N-pent-4-en-1-yl derivative

plete inhibition of growth) against 3 model strains (Candida glabra-

ta, Saccharomyces cerevisiae, Yarrowia lipolytica) according to DIN

58940-84.^56,57As we determined MIC values in the range from

25 to 50

C. glabrata 2.5

g/mL (MIC values of reference inhibitor clotrimazole:

g/mL; S. cerevisiae 0.5 g/mL; Y. lipolytica 1.0 g/

mL) it could be assumed that the compounds described here do

not show noteworthy inhibition of cell growth, and hence do not

affect ergosterol biosynthesis to a mentionable extent. For this rea-

son investigations on the interaction of the compounds with ergos-

terol biosynthesis were abandoned.

(27e), showed signiﬁcant inhibition of the

D8,7-sterol isomerase,

further modiﬁcations were accomplished in order to increase the

activity of the cis-(4R,5S)-conﬁgured amino alcohols. Secondary

amines 28a–c were obtained by reductive N-alkylation⁵⁵of pri-

mary amine 25 under the conditions as described above

(Scheme 6). With regard to 27a and 27e these additional com-

pounds feature increased electron density in the aromatic system

and a different length of the aliphatic chain, respectively.

Another modiﬁcation within this work was the synthesis of tertiary

amines, again based on the two most promising structures 27a and

27e. N-Methylation was carried out using formaldehyde and sodium

cyanoborohydride to give 29a and 30 (Scheme 7). Additionally, differ-

ent combinations of the most interesting N-residues (N-benzyl, N-

pent-4-en-1-yl) were carried out by reductive N-alkylations of 27a

using either benzaldehyde or pent-4-enal and sodium cyanoborohy-

dride to give the amino alcohols 29b and 29c (Scheme 7).

3.2. Qualitative and quantitative test for inhibition of

cholesterol biosynthesis

For qualitative screening of potential cholesterol biosynthesis

inhibitors, two concentrations (1 and 50 lM) were initially pre-

tested in a whole cell assay on HL-60 cells. This screening system,

worked out by us previously,⁴⁰allows for the identiﬁcation of tar-

get enzymes in the post-squalene part of cholesterol biosynthesis

by GC–MS analysis of the changes in the sterol pattern, as exempli-

ﬁed by the chromatograms shown in Figure 6. Whereas the un-

treated cells contained cholesterol as the only detectable sterol

(chromatogram A), incubation with cis-amino alcohol 27a (chro-

matogram B) led to a signiﬁcant accumulation of zymostenol

(1b), identiﬁed by comparing its relative retention time and MS

data with those of an authentic sample.⁴⁰Since 1b is a substrate

3. Biological assays

of human

D8,7-sterol isomerase, the target enzyme was identiﬁed

unambiguously. In contrast, the unselective inhibitor tamoxifen (9)

led to an accumulation of both zymostenol (1b) and zymosterol

(1a) in accordance with its dual mechanism^32,33,58as inhibitor of

3.1. Antifungal activity and inhibition of ergosterol biosynthesis

All substances were subjected to a biological assay deﬁning

their MIC (Minimal Inhibitory Concentration; this value is deﬁned

as the lowest concentration that leads to a visibly detectable com-

both

D8,7-sterol isomerase and D24-sterol reductase (chromato-

gram C). The amino ketones 17a–e and the trans-amino alcohols

26a–g did not induce noteworthy changes in the sterol pattern.

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1931

cholesterol biosynthesis in the cellular system were calculated

(Table 1).

3.3. MTT-test for cytotoxic effects

To determine possible cyctotoxic effects, the substances were

subjected to the standard MTT test developed by Mosmann.⁶⁰Cis-

platin was used as a reference, the results are shown in Table 1.

R = 4-methoxybenzyl

R = 2,4-dimethoxybenzyl 57%

R = ethyl 75%

73%

4. Discussion

Starting from Grundmann⁰s ketone (11) and via its derivative 12

with an angular methyl group at C-3a, we prepared a collection of

secosteroids containing amino ketone and amino alcohol moieties

as potential inhibitors of cholesterol biosynthesis. Since reduction

Scheme 6. Reagents and conditions: (a) aldehyde, sodium cyanoborohydride,

acetic acid, methanol, 40 °C, 12 h.

of the

a-aminoketones 17a–e gave epimeric mixtures of amino

alcohols 18a–e in certain cases, we worked out fully stereoselec-

tive approaches to the primary amino alcohols 23 and 25, from

which the trans-(4S,5S)-conﬁgured amino alcohols 26a–g and the

cis-(4R,5S)-conﬁgured amino alcohols 27a–g, 28a–c, 29a–c and

30 were readily accessible by standard reductive alkylation

protocols.

These substances were subjected to several screening systems

to determine their biological proﬁle. The in vitro antifungal activi-

ties were assessed against the yeasts C. glabrata, S. cerevisiae, and Y.

lipolytica. The compounds did not show noteworthy antifungal

R = methyl

83%

84%

82%

R = benzyl

R = pent-4-en-1-yl

activity (MIC values higher than 25 lg/mL), and hence no inhibi-

tion of ergosterol biosynthesis could be adopted. The effect on cho-

lesterol biosynthesis was determined in a HL-60 cells based whole-

cell assay with GC–MS analysis of the changes in the sterol pattern.

Whereas the amino ketones 17a–e and the trans-conﬁgured amino

alcohols 26a–g were inactive in this assay, selective inhibition of

human

D8,7-sterol isomerase could be shown for a considerable

number of cis-conﬁgured amino alcohols. The most promising sub-

stances from this qualitative investigation were subjected to a

quantitative screening to determine their effects on overall choles-

terol biosynthesis (Table 1). In addition, a MTT test was performed

to deﬁne the cytotoxicity of the substances (Table 1).

Scheme 7. Reagents and conditions: (a) aldehyde, sodium cyanoborohydride,

acetic acid, methanol, 40 °C, 12 h; (b) formaldehyde (38% aqueous solution), sodium

cyanoborohydride, acetic acid, methanol, 40 °C, 12 h.

From the results from Table 1 and the structures of the other,

inactive compounds from the cis-amino alcohol series some con-

clusions on structure-activity relationships can be drawn. The

activity of the inhibitors is greatly inﬂuenced by the size of the

amino group. Whereas compounds bearing very small substituents

(primary amine 25, N,N-dimethylamine 18a) have IC₅₀values in

the submicromolar range, compounds bearing very bulky substitu-

ents like substituted benzyl residues are inactive. IC₅₀values in the

low nanomolar range can be found for compounds bearing one

medium-sized substituent (benzyl, pent-4-en-1-yl) in combination

with hydrogen (secondary amine 27a) or a methyl group (tertiary

amines 29a and 30). Combination of two of the medium-sized

groups leads to a decrease (29c) or complete loss of activity

(N,N-dibenzyl derivative 29b).

For quantitative screening we selected the substances that in-

duced signiﬁcant accumulation of zymostenol (1b) in the qualita-

tive pre-screening. In this whole-cell assay⁴⁰HL-60 cells are

incubated with various concentrations of the test substances in

the presence of 2-¹³C-acetate. Due to the incorporation of 4–7

¹³C atoms into cholesterol molecules biosynthesised during the

incubation period, newly synthesised cholesterol can be distin-

guished from unlabelled matrix cholesterol that was present in

the cells before incubation, by GC–MS. From the dose–response

curves obtained by determination of ¹³C-labelled cholesterol and

after normalisation to the protein content by a Bradford assay,⁵⁹

the IC₅₀values describing the overall effects of the inhibitors on

Figure 6. Extracted ion chromatograms of the accumulating sterols after incubation of HL-60 cells with inhibitors (with respective qualiﬁer ions in brackets); (A) untreated

control; (B) 27a 1 M; (C) tamoxifen (9) 1 M; peak 1 cholestane (internal standard, 357 + 217 + 203), peak 2 cholesterol (458 + 368 + 329), peak 3 zymostenol (1b)

(458 + 353 + 213), peak 4 zymosterol (1a) (456 + 441 + 351).

1932

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

Table 1

SIL G/UV₂₅₄from Marcherey & Nagel. Merck Silica Gel 60 (particle

size 0.040–0.063 mm) was used for silica column chromatography

(SCC). Yields refer to chromatographically and spectroscopically

(¹H NMR) homogeneous materials, unless otherwise stated. Struc-

ture assignment for all prepared compounds was done by

using ¹H NMR, ¹³C NMR, as well as DEPT, HMQC, and HMBC tech-

niques. NMR spectra were recorded on JEOL Eclipse plus NMR

workstations (Jeol GSX 400 or JNMR GX 500 instrument), respec-

tively, at 500.1599 or 399.7820 MHz for ¹H and 125.7653 or

100.5253 MHz for ¹³C. Spectra were calibrated by using residual

undeuterated solvent as an internal reference (CHCl₃with ¹H at

7.26 ppm, ¹³C at 77.00 ppm). Mass spectra were recorded on a

Hewlett–Packard 5989A, using electron impact ionisation (EI) at

70 eV and chemical ionisation with methane (CI). Electron impact

high resolution mass spectra (EI-HRMS) were recorded on GC Mate

II Jeol. The substances were directly injected. IR spectra were ob-

tained on Perkin-Elmer Paragon 1000 spectrometer. The UV spec-

IC₅₀values (nM) obtained in the MTT (see Section 3.3) test and in the assay for

inhibition of overall cholesterol biosynthesis (see Section 3.2)

Compound MTT test

(nM)

IC₅₀value

(nM)

Conﬁdence interval

(nM)

R²

18a

17,000

11,000

8000

15,000

7000

27,000

17,000

7000

576

581

462-720

477–638

14-18

54–62

10-13

0.899

0.948

0.959

0.967

0.928

27a

27e

29a

29b

29c

>1000

71-95

16-20

—

0.965

0.973

—

Cisplatin

—

5000

IC₅₀values (determined in triplicate) for the inhibition of total cell growth (MTT

test) and total cholesterol biosynthesis through determination of ¹³C incorporation

into newly synthesised cholesterol. Conﬁdence interval for the IC₅₀value, 95%; R²,

goodness of ﬁt of the dose response curves.

trophotometer Hitachi

U 1100 was from Hitachi (Krefeld,

Germany). Melting points were determined on a Büchi 540

apparatus.

Comparison of the corresponding IC₅₀values (MTT test vs cho-

lesterol biosynthesis assay) of the most promising substances 27a,

29a, and 30 shows that there is a large difference in activity (factor

390–630), and therefore cytotoxicity should not matter. As these

most active compounds obviously do not affect the yeast ergos-

5.2. Determination of the MIC values

For the determination of antifungal activity against C. glabrata,

C. cerevisiae and Y. lipolytica, all substances were dissolved in abso-

lute ethanol to give standard solutions with a concentration of

0.8 mg/mL. The solutions were diluted stepwise with ethanol to

terol biosynthesis, highly selective inhibitors of human

D8,7-sterol

isomerase that inhibit total cholesterol biosynthesis with IC₅₀val-

ues in the low nanomolar range could be developed.

An inborn lack of the

D8,7-sterol isomerase is known to gener-

give the test concentrations of 50, 25 and 12.5 lg/mL. All dilutions

were done like described in the SANCO guideline.⁵⁷The dilutions

were added to the 24-well plate, each row containing, respectively,

two wells with the same concentration. Additionally, each well

plate contained a control row consisting of two wells to which only

2.0 mL of medium had been added (sterility control), two wells to

ate rare but serious disorders, so the inhibitors described here are

not likely to be drug candidates. But due to their potent and spe-

ciﬁc inhibition of this enzyme they should be valuable tools for

investigations aimed at a better understanding of disorders caused

by defects in the gene encoding

D8,7-sterol isomerase.

which only 10

two wells containing a concentration of 0.5

(positive control). Each testing day additionally one row on a single

plate was treated with ketoconazole (4, 2, 1, 0.5, 0.25, 0.125 g/mL)

L of ethanol had been added (negative control) and

5. Experimental section

g/mL clotrimazole

5.1. Analysis and materials

as ‘MIC control’. The subsequent general process and the visual

determination of the MIC values were described in literature

before.²⁸

All solvents were of HPLC or p.a. grade, otherwise they were dis-

tilled before use over appropriate drying agents. Unless stated

otherwise, the chemicals were purchased from Sigma–Aldrich

(Schnelldorf, Germany) and Acros (Geel, Belgium), and were used

without further puriﬁcation. MSTFA and TSIM were from Marche-

rey & Nagel (Düren, Germany) Bondesil PSA was from Varian, 24-

well plates were from Peske (Aindling–Arnhofen, Germany). Cho-

lestane was obtained from Steraloids Inc. (Birmingham, UK), Brad-

ford colour solution for protein determination was from Carl Roth

GmbH + Co. KG (Karlsruhe, Germany), RPMI 1640 medium and fe-

tal bovine serum (FBS) were from PAA Laboratories GmbH (Cölbe,

Germany), medium for HL-60 cells (lipid free medium) and lipo-

protein deﬁcient serum (LPDS) were purchased from PAN Biotech

(Aidenbach, Germany). The yeast-culture mediums consisted of

yeast extract 10 g/L, peptone 20 g/L and glucose 20 g/L. Each yeast

culture was splitted once a week to keep the cultures in log phase.

Each yeast culture was maintained at 28 °C. The 0.5 Mc Farland

5.3. GC–MS analysis

5.3.1. Qualitative analysis of the sterol fractions

For qualitative analysis a Varian GC 3800 equipped with a CTC

Combi Pal autosampler coupled to a Varian Saturn 2000 ion trap

with a Varian Factor Four EZ Guard VF 5 MS 30 m ꢁ 0.25 mm ꢁ

0.25 lm column was used. The 1177 injector was held at 250 °C

and operated in splitless mode for 1 min. The transfer line was held

at 270 °C. The oven program started at 50 °C held for 1 min, and

ramped to 260 °C with 50 °C per min, followed by a gradient of

4 °C per min to 310 °C held for 0.5 min. The MS was operated in full

scan mode from 9 to 12 min at a mass range from 50 to 450 m/z and

from12 to 18 min at a mass range from 100 to 650 m/z. For substance

identiﬁcation three qualiﬁer ions were chosen for each sterol (Fig. 6).

standard was prepared from 0.05 mL solution

A (0.117 g

BaCl₂ꢁ 2H₂O in 10 mL of water) and 9.95 mL 10% (w/v) H₂SO₄.

The Candida glabrata, Candida cerevisiae and Yarrowia lipolytica test

cultures were purchased from DSMZ (Deutsche Sammlung für

Mikroorganismen und Zellkulturen, Braunschweig, Germany). HL-

60 cells were purchased from DSMZ and were maintained in RPMI

1640 medium containing 10% FBS without antibiotics at 37 °C in a

humidiﬁed atmosphere containing 5% CO₂.

For syntheses, all anhydrous reactions were carried out under

an inert atmosphere using Schlenk techniques. Reactions were

monitored by TLC using pre-coated plastic sheets POLYGRAM^Ò

5.3.2. Quantitative analysis of labelled cholesterol

Quantitative analysis was carried out with a Varian GC 3800

equipped with a CTC Combi Pal autosampler coupled to a Varian

Saturn 1200 triple quad. The column used was again a Varian Fac-

tor Four EZ Guard VF 5 MS 30 m ꢁ 0.25 mm ꢁ 0.25

lm. The 1177

injector was held at 250 °C and operated in splitless mode for

1 min. The transfer line was held at 270 °C. The oven program

started at 50 °C held for 1 min, and ramped to 260 °C with 50 °C

per min, followed by a gradient of 4 °C per min to 310 °C held for

0.5 min. Quantiﬁcation of the labelled cholesterol was carried out

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1933

by analysing the ions 372–379 and 462–469 m/z. For cholestane

(I.S.) 217 and 357 m/z were chosen as quantiﬁer ions.

5.4. Incubation and work-up procedures for the identiﬁcation

of the target enzyme and for quantiﬁcation of the inhibition of

cholesterol biosynthesis

Figure 7. Calculation formula for the percentage inhibition; A_Sarea sample; A_I.S.C.

area internal standard control; PC_Cprotein content control; A_Carea control; A_I.S.S.

area internal standard sample; PC_Sprotein content sample.

For the qualitative screening, two test concentrations (1 and

(2 M, 10 mL). The reaction mixture was stirred under reﬂux for

12 h. After evaporating ethanol under reduced pressure, the aque-

ous layer was extracted with ethyl acetate (3 ꢁ 20 mL). The com-

bined organic extracts were washed with a aqueous hydrochloric

acid (2 M, 30 mL) and water (30 mL), dried over sodium sulphate,

and evaporated under reduced pressure. The crude product was

subjected to SCC (petroleum ether/ethyl acetate 9:1) to afford ke-

tone 12 as a colourless oil (242 mg, 88%). ¹H NMR (CDCl₃,

400 MHz): d 2.55–2.40 (m, 2H, H-5, H-6), 2.27–2.20 (m, 1H, H-5),

1.93–1.67 (m, 5H, H-1⁰, H-2, H-3, H-7), 1.55–1.46 (m, 1H, H-5⁰),

1.45–1.19 (m, 5H, H-1, H-2⁰, H-3⁰, H-6), 1.15–1.05 (m, 4H, H-2, H-

4⁰, H-7), 1.06 (s, 3H, CH₃-3a), 1.01–0.96 (m, 1H, H-2⁰), 0.92 (d, 3H,

CH₃-1⁰, J = 6.3 Hz), 0.86 (d, 3H, H-6⁰, J = 6.2 Hz), 0.85 (d, 3H, CH₃-

5⁰, J = 6.2 Hz), 0.84 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

216.0 (CO), 60.8 (3a-C), 49.6 (7a-C), 47.0 (1-CH), 39.79 (5-CH₂),

38.0 (3-CH₂), 36.2 (7-CH₂), 35.3 (1⁰-CH), 31.5 (4⁰-CH₂), 28.9 (6-

CH₂), 28.3 (5⁰-CH), 25.5 (2-CH₂), 24.6 (3⁰-CH₂), 23.2 (6⁰-CH₃), 22.9

(CH₃-5⁰), 21.8 (2⁰-CH₂), 19.9 (CH₃-3a), 19.1 (CH₃-7a), 18.2 (CH₃-

1⁰). HRMS Found 278.4701 (Calcd 278.4727). IR (NaCl, ﬁlm,

and the initial weight was calculated for the matter that there was

a ﬁnal concentration of 50 M if 10 L of this solution were added

to 990 L of lipid-free medium containing 1% LPDS without antibi-

otics. An aliquot of this 50 M solution was diluted by 1:50 in or-

der to obtain the second needed concentration of 1 M if 10 L of

L of lipid free medium containing

lM) were established. The substances were dissolved in ethanol

this solution were added to 990

1% LPDS without antibiotics.

HL-60 cells (10⁶cells) were incubated in 24-well plates in 1 mL

(990 lL of lipid free medium containing 1% LPDS + 10 lL of respective

inhibitor solution). After a 24 h incubation period (conditions: 37 °C in

a humidiﬁed atmosphere containing 5% CO₂) the content of each well

was transferred into a 2 mL plastic tube and the wells were washed

with 750 lL of phosphate-buffered saline (PBS). The cells were col-

lected by centrifugation at 540ꢁg for 5 min, washed once with 1 mL

of PBS, and centrifuged again. After decantation 1 mL of 1 M NaOH

was added to each tube, saponiﬁcation was carried out at 70 °C for

60 min. Fifty microlitres of internal standard solution (cholestane in

cm^ꢀ1): 2931, 2862, 1723, 1451, 1379, 1105, 887, 860. ½a ²_D⁰

ꢂ

ꢀ42

TBME, 10 lg/mL) and 700 lL of TBME were added and the tubes were

shaken vigorously for 1 min and then centrifuged at 9200ꢁg for 5 min.

(0.5; CHCl₃).

The organic layer was separated with a pipette, and extraction was re-

peated with another 750 lL of TBME in the same manner. The com-

5.6.2. [(1R,7aR)-1-((R)-1,5-Dimethylhexyl)-7a-methyl-

bined organic extracts were stirred vigorously over 35 mg of dried

sodium sulphate and 5 mg of Bondesil PSA and then centrifuged for

5 min at 9200ꢁg. One millilitre of the puriﬁed extract was transferred

into an autosampler vial and evaporated to dryness under mild stream

2,3,5,6,7,7a-hexahydro-1H-inden-4-yloxy]-trimethylsilane (13)

To a stirred solution of Grundmann⁰s ketone 11 (500 mg,

1.91 mmol) in anhydrous dichloromethane (10 mL) under nitrogen

atmosphere was added 1,1,1,3,3,3-hexamethyldisilazane (335

2.05 mmol), lithium iodide (280 mg, 2.10 mmol) and trimethylsilyl

chloride (500 L, 4.12 mmol) at room temperature. The reaction

lL,

of nitrogen. To each vial, 950 lL of TBME and 50 lL of N-trimethylsi-

lylimidazole (TSIM) were added. Silylation reaction was carried out

for 1 h at room temperature. The trimethylsilyl ethers were analysed

as described in Section 5.3.1.

mixture was obstructed from light and stirred for 24 h. Then trieth-

ylamine (2 mL) and a mixture of diethyl ether (50 mL) and a satu-

rated aqueous solution of sodium bicarbonate (50 mL) were added.

The organic layer was separated and the remaining aqueous layer

was extracted with diethyl ether (2 ꢁ 40 mL). The combined or-

ganic extracts were washed once with an aqueous hydrochloric

acid (1 M, 50 mL) and once with water (50 mL), dried over sodium

sulphate and evaporated to dryness under reduced pressure. The

crude product was subjected to silica column chromatography

(SCC) (petroleum ether/ethyl acetate 99:1) to afford the silyl enol

ether 13 as a colourless oil (411 mg, 64%). ¹H NMR (CDCl₃,

400 MHz): d 2.22–2.07 (m, 1H, H-5), 2.03–1.91 (m, 1H, H-5),

1.90–1.81 (m, 1H, H-1⁰), 1.79–1.50 (m, 5H, H-3, H-6, H-7), 1.41–

1.32 (m, 1H, H-5⁰), 1.31–1.09 (m, 4H, H-1, H-2, H-2⁰, H-6), 1.07–

0.84 (m, 6H, H-2⁰, H-2, H-3⁰, H-4⁰), 0.77 (d, 3H, CH₃-1⁰, J = 6.6 Hz),

0.76–0.72 (m, 3H, H-6⁰, with underneath s, 3H, CH₃-7a at

0.75 ppm), 0.71 (d, 3H, CH₃-5⁰, J = 6.2 Hz), 0.00 (s, 9H, Si(CH₃)₃).

¹³C NMR (CDCl₃, 125 MHz): d 139.1 (4-CH), 126.6 (3a-C), 55.8

(7a-C), 42.2 (1-CH), 38.1 (3-CH₂), 36.0 (5-CH₂), 34.5 (7-CH₂), 33.4

(1⁰-CH), 27.9 (4⁰-CH₂), 26.5 (6-CH₂), 26.1 (5⁰-CH), 22.3 (2-CH₂),

22.1 (2⁰-CH₂), 21.3 (3⁰-CH₂), 21.1 (CH₃-7a), 18.6 (6⁰-CH₃), 17.4

(CH₃-5⁰), 16.9 (CH₃-1⁰), 0.0 (3C, Si(CH₃)₃). HRMS Found 336.6389

(Calcd 336.6384). IR (NaCl, ﬁlm, cm^ꢀ1): 3032, 2967, 2915, 1450,

For the determination of labelled cholesterol (quantitative screen-

ing), the protocol was altered in the following manner: To each incu-

bation well 10

(6.25 mg/mL) were added before addition of the inhibitor solution,

leading to a ﬁnal ¹³C-acetate concentration of 62.5

g/mL. After sapon-

L aliquots were taken for protein determination

lL of a

sterile sodium 2-¹³C-acetate solution

iﬁcation 3 ꢁ 25

according to Bradford,⁵⁹using bovine serum albumin as standard. After

work-up and silylation, GC–MS analysis was performed as described in

Section 5.3.2. The percentage inhibition (Fig. 7, formula) relative to un-

treated control samples (0% inhibition) was plotted against the loga-

rithmic inhibitor concentration using Graph Pad Prism 4. A bottom

level constant equal to 0 was set as constraint using a sigmoidal

dose–response model with a various slope. All samples were norma-

lised to their protein content taking into account the number of cells.

For each concentration the percentage was determined in triplicate.

5.5. MTT test

For the determination of the cytotoxicity of the tested substances

against human leukemia HL-60 cells a standard MTT test according

to Mosmann was used. Cisplatin was utilised as reference.

1378, 890. ½a ²_D⁰

ꢂ

+13 (0.5; CHCl₃).

5.6. Syntheses

5.6.3. [(1R,3aS,4R,7aR)-1-((R)-1,5-Dimethylhexyl)-7a-

methylhexahydrocyclopropa[d]inden-4-yl-oxy]-trimethylsilane

(14)

5.6.1. (1R,3aR,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

dimethyloctahydroinden-4-one (12)

To a stirred solution of 13 (410 mg, 1.23 mmol) in anhydrous

diethyl ether (20 mL) under nitrogen atmosphere was added

Compound 14 (345 mg, 0.98 mmol) was dissolved in a mixture

of ethanol (10 mL) and an aqueous solution of sodium hydroxide

1934

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

diethylzinc (1 M solution in hexanes, 4.20 mL, 4.20 mmol) and

diiodomethane (362 L, 4.50 mmol). The reaction mixture was

allowed to warm up to room temperature and was stirred for

12 h. After evaporating THF under reduced pressure, a saturated

aqueous solution of sodium bicarbonate (50 mL) was added. The

mixture was extracted with ethyl acetate (3 ꢁ 25 mL). The com-

bined organic layers were washed with water (50 mL), dried over

sodium sulphate, and evaporated under reduced pressure. The

crude product was subjected to SCC (petroleum ether/ethyl acetate

85:15) to afford ketone 16 as a colourless oil (850 mg, 90%). ¹H

NMR (CDCl₃, 400 MHz): d 4.84 (dd, 1H, H-5, J = 1.7 Hz, J = 4.7 Hz),

2.56–2.46 (m, 1H, H-6), 2.40–2.31 (m, 1H, H-7), 2.29–2.13 (m,

1H, H-3), 1.96–1.89 (m, 1H, H-2), 1.83–1.70 (m, 2H, H-1⁰, H-3),

1.46–1.41 (m, 1H, H-5⁰), 1.37–1.10 (m, 9H), 1.04 (s, 3H, CH₃-3a),

0.94–0.89 (m, 1H, H-2⁰), 0.84 (d, 3H, CH₃-1⁰, J = 6.2 Hz,), 0.82 (s,

3H, CH₃-7a), 0.78 (d, 3H, CH₃-5⁰, J = 6.0 Hz), 0.76 (d, 3H, H-6⁰,

J = 6.0 Hz). ¹³C NMR (CDCl₃, 125 MHz): d 207.8 (CO), 59.8 (3a-C),

46.8 (5-CH), 46.5 (7a-C), 45.8 (1-CH), 37.9 (6-CH₂), 34.3 (3-CH₂),

33.3 (7-CH₂), 30.1 (1⁰-CH), 28.4 (4⁰-CH₂), 26.5 (2⁰-CH₂), 25.4 (5⁰-

CH), 23.9 (2-CH₂), 23.2 (3⁰-CH₂), 22.8 (CH₃-3a), 21.4 (6⁰-CH₃),

21.1 (CH₃-5⁰), 17.2 (CH₃-7a), 16.4 (CH₃-1⁰). HRMS Found

356.1714 (Calcd 356.1715). IR (NaCl, ﬁlm, cm^ꢀ1): 2955, 2868,

stirred under reﬂux for 18 h and then pyridine (1.20 mL) was

added dropwise. The resulting suspension was ﬁltered and the ﬁl-

trate was diluted with water (30 mL). After separating the organic

layer, the remaining aqueous layer was extracted with ethyl ace-

tate (2 ꢁ 40 mL). The combined organic extracts were washed once

with an aqueous hydrochloric acid (1 M, 50 mL) and once with

water (50 mL), dried over sodium sulphate and evaporated to dry-

ness under reduced pressure. The crude product was subjected to

silica column chromatography (SCC) (petroleum ether/ethyl ace-

tate 98:2) to afford the cyclopropane derivative 14 as a colourless

oil (345 mg, 80%). ¹H NMR (CDCl₃, 400 MHz): d 2.00–1.80 (m, 2H,

H-5), 1.72–1.62 (m, 1H, H-6), 1.55–1.47 (m, H-1⁰), 1.45–1.11 (m,

10H, H-1, H-2, H-2⁰, H-3, H-5⁰, H-6, H-7), 1.10–0.89 (m, 5H, H-2⁰,

H-3⁰, H-4⁰), 0.78 (d, 3H, CH₃-1⁰, J = 6.5 Hz), 0.75 (d, 3H, H-6⁰,

J = 6.0 Hz), 0.74 (d, 3H, CH₃-5⁰, J = 6.0 Hz), 0.58 (s, 3H, CH₃-7a),

0.49 (d, 1H, CH₂-cyclopropane, J = 5.8 Hz), 0.22 (d, 1H, CH₂-cyclo-

propane, J = 5.8 Hz), 0.00 (s, 9H, Si(CH₃)₃). ¹³C NMR (CDCl₃,

125 MHz): d 59.0 (4-CH), 57.9 (1-CH), 40.3 (3a-C), 38.1 (7a-C),

37.6 (5-CH₂), 34.6 (3-CH₂), 34.2 (6-CH₂), 32.5 (1⁰-CH), 31.2 (7-

CH₂), 28.7 (CH₂-cyclopropane), 26.7 (4⁰-CH₂), 26.6 (5⁰-CH), 22.3

(2-CH₂), 21.3 (2⁰-CH₂), 21.1 (CH₃-7a), 19.3 (3⁰-CH₂), 17.8 (6⁰-CH₃),

17.7 (CH₃-5⁰), 16.7 (CH₃-1⁰), 0.0 (3C, Si(CH₃)₃). HRMS Found

350.6496 (Calcd 350.6538). IR (NaCl, ﬁlm, cm^ꢀ1): 2960, 2910,

1718, 1466, 1432, 1382, 1201, 868, 667. ½a _D²⁰

ꢀ26 (0.5; CHCl₃).

ꢂ

5.6.6. General procedure A (nucleophilic substitution at

bromoketone 16)

To a stirred solution of bromoketone 16 (150 mg, 0.42 mmol) in

DMF (2 mL), the required amine (5–20 equiv) was added under

nitrogen atmosphere. The solution was stirred under reﬂux for

12 h and then a saturated aqueous solution of sodium bicarbonate

(20 mL) was added. The resulting mixture was extracted with ethyl

acetate (3 ꢁ 15 mL) and the combined organic extracts were

washed with water (30 mL), dried over sodium sulphate, and evap-

orated to dryness under reduced pressure. The residue was sub-

jected to SCC as speciﬁed below to afford pure compounds 17a–e

as colourless oils.

1457, 1370, 897, 863. ½a _D²⁰

ꢀ19 (0.5; CHCl₃).

ꢂ

5.6.4. [(1R,3aR,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-dimethyl-

2,3,3a,6,7,7a-hexahydro-1H-inden-4-yloxy]-trimethylsilane (15)

To a stirred solution of ketone 12 (874 mg, 3.13 mmol) in anhy-

drous THF (60 mL) under nitrogen atmosphere was added drop-

wise lithium diisopropylamide (2 M solution in hexane, 4.20 mL,

4.41 mmol) at ꢀ78 °C. The reaction mixture was stirred for 2 h

and then trimethylsilyl chloride (0.55 mL, 4.82 mmol) was added

dropwise. The reaction mixture was allowed to warm up to ambi-

ent temperature and was stirred for further 12 h. After evaporating

THF under reduced pressure, the residual was taken up in diethyl

ether (50 mL) and water (100 mL) was added. The biphasic mixture

was extracted with diethyl ether (2 ꢁ 50 mL). The combined or-

ganic layers were washed once with a saturated aqueous solution

of sodium bicarbonate (50 mL) and once with water (50 mL), dried

over sodium sulphate, and evaporated to dryness under reduced

pressure. The crude product was subjected to SCC (petroleum

ether/ethyl acetate 9:1) to afford the silyl enol ether 15 as a colour-

less oil (910 mg, 83%). ¹H NMR (CDCl₃, 400 MHz): d 4.61 (dd, 1H, H-

5, J = 2.2 Hz, J = 5.3 Hz), 2.13–1.95 (m, 2H, H-6, H-7), 1.93–1.86 (m,

1H, H-6), 1.84–1.66 (m, 2H, H-3, H-2), 1.59–1.45 (m, 2H, H-1⁰, H-3),

1.41–1.30 (m, 4H, H-1, H-3⁰, H-5⁰), 1.29–1.22 (m, 2H, H-2, H-7),

1.21–1.04 (m, 3H, H-2⁰, H-3⁰), 1.04–0.97 (m, 1H, H-2⁰), 0.95 (d,

3H, CH₃-1⁰, J = 6.2 Hz), 0.93 (s, 3H, CH₃-3a), 0.86 (d, 3H, H-6⁰,

J = 5.8 Hz), 0.85 (d, 3H, CH₃-5⁰, J = 5.8 Hz), 0.75 (s, 3H, CH₃-7a),

0.12 (s, 9H, Si(CH₃)₃). ¹³C NMR (CDCl₃, 125 MHz): d 155.6 (4-C),

100.5 (5-CH), 50.8 (3a-C), 45.3 (7a-C), 45.2 (1-CH), 39.1 (6-CH₂),

35.8 (3-CH₂), 35.0 (1⁰-CH), 30.5 (7-CH₂), 28.7 (4⁰-CH₂), 27.6 (5⁰-

CH), 26.3 (2-CH₂), 23.7 (3⁰-CH₂), 22.4 (CH₃-5⁰), 22.2 (6⁰-CH₃), 21.1

(CH₃-3a), 20.4 (2⁰-CH₂), 18.1 (CH₃-7a), 17.6 (CH₃-1⁰), 0.10 (3C,

Si(CH₃)₃). HRMS Found 350.6514 (Calcd 350.6538). IR (NaCl, ﬁlm,

5.6.6.1.

ethylhexyl)-3a,7a-dimethyloctahydroinden-4-one

(17a). Ketone 16 (150 mg, 0.42 mmol) and N,N-dimethyl-

(1R,3aR,5S,7aR)-5-Dimethylamino-1-((R)-1,5-dim-

amine (2 M solution in THF, 4.20 mL, 8.41 mmol) in DMF (2 mL)

were treated as described in procedure A. The crude product was

subjected to SCC (petroleum ether/ethyl acetate/triethylamine

10:0.5:0.1) to afford 17a (68 mg, 50%). ¹H NMR (CDCl₃,

400 MHz): d 3.32 (dd, 1H, H-5, J = 6.1 Hz, J = 12.3 Hz), 2.55–2.43

(m, 1H, H-6), 2.38 (bs, 6H, N(CH₃)₂), 2.08–1.92 (m, 2H, H-3, H-7),

1.92–1.67 (m, 3H, H-1⁰, H-2, H-6), 1.53–1.43 (m, 1H, H-5⁰), 1.40–

1.16 (m, 5H, H-1, H-2, H-3, H-3⁰), 1.16–1.01 (m, 4H, with under-

neath s, 3H, CH₃-3a at 1.09 ppm), 0.99–0.92 (m, 1H, H-2⁰), 0.90

(d, 3H, CH₃-1⁰, J = 5.8 Hz), 0.85 (d, 3H, CH₃-5⁰, J = 6.0 Hz), 0.84–

0.80 (m, 3H, H-6⁰, with underneath s, 3H, CH₃-7a at 0.83 ppm).

¹³C NMR (CDCl₃, 125 MHz): d 212.5 (CO), 67.6 (3a-C), 61.1 (5-

CH), 49.6 (7a-C), 46.5 (1-CH), 41.6 (2C, N(CH₃)₂), 39.4 (6-CH₂),

35.9 (3-CH₂), 35.0 (7-CH₂), 30.5 (1⁰-CH), 29.1 (4⁰-CH₂), 28.0 (2⁰-

CH₂), 25.3 (5⁰-CH), 24.2 (2-CH₂), 24.1 (3⁰-CH₂), 22.8 (6⁰-CH₃), 22.6

(CH₃-5⁰), 19.9 (CH₃-3a), 18.8 (CH₃-7a), 17.7 (CH₃-1⁰). HRMS Found

321.3060 (Calcd 321.3032). IR (NaCl, ﬁlm, cm^ꢀ1): 2987, 2870, 1709,

1466, 1103, 705. ½a _D²⁰

ꢀ18 (0.5; CHCl₃).

ꢂ

cm^ꢀ1): 2983, 2929, 1762, 1443, 1137, 876, 851, 711. ½a ²_D⁰

ꢂ

ꢀ27

5.6.6.2.

dimethyl-5-(4-methylpiperazine-1-yl)-octahydroinden-4-one

(17b). Ketone 16 (150 mg, 0.42 mmol) and 1-methylpipera-

(1R,3aR,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

(0.5; CHCl₃).

5.6.5. (1R,3aR,5R,7aR)-5-Bromo-1-((R)-1,5-di-methylhexyl)-

3a,7a-dimethyloctahydroinden-4-one (16)

At 0 °C, to a stirred solution of 15 (910 mg, 2.62 mmol) in THF

(40 mL) was added a mixture of N-bromosuccinimide (580 mg,

3.16 mmol) and sodium acetate (23.0 mg, 0.26 mmol), dissolved

in THF (20 mL) and water (20 mL). The reaction mixture was

zine (0.33 mL, 2.94 mmol) in DMF (2 mL) were treated as described

in procedure A. The crude product was subjected to SCC (petro-

leum ether/ethyl acetate/triethylamine 7:3:0.3) to afford 17b

(114 mg, 72%). ¹H NMR (CDCl₃, 400 MHz): d 3.31 (dd, 1H, H-5,

J = 6.2 Hz, J = 12.3 Hz,), 2.83–2.51 (m, 8H), 2.47–2.41 (m, 1H, H-6),

2.39 (s, 3H, N-CH₃), 2.07–1.95 (m, 2H, H-3, H-7), 1.85–1.64 (m,

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1935

3H, H-1⁰, H-2, H-6) 1.53–146 (m, 1H, H-5⁰), 1.39–1.16 (m, 6H),

1.15–0.97 (m, 3H, H-3⁰, H-4⁰), 1.05 (s, 3H, CH₃-3a) 0.95–0.89 (m,

1H, H-2⁰), 0.88 (d, 3H, CH₃-1⁰, J = 6.1 Hz), 0.84 (d, 3H, CH₃-5⁰,

J = 5.8 Hz), 0.83 (d, 3H, H-6⁰, J = 5.8 Hz), 0.80 (s, 3H, CH₃-7a). ¹³C

NMR (CDCl₃, 125 MHz): d 212.1 (CO), 67.7 (N-CH₃), 65.9 (3a-C),

61.0 (2C, 3⁰⁰-CH₂, 5⁰⁰-CH₂), 55.1 (2C, 2⁰⁰-CH₂, 6⁰⁰-CH₂), 49.9 (5-CH₂),

46.5 (7a-C), 45.7 (1-CH), 39.4 (6-CH₂), 35.8 (3-CH₂), 35.1 (7-CH₂),

29.3 (1⁰-CH), 28.0 (4⁰-CH₂), 25.4 (2⁰-CH₂), 24.3 (5⁰-CH), 23.6 (2-

CH₂), 22.8 (3⁰-CH₂), 22.6 (CH₃-3a), 19.9 (6⁰-CH₃), 18.8 (CH₃-5⁰),

17.8 (CH₃-7a), 15.3 (CH₃-1⁰). HRMS Found 376.3437 (Calcd

376.3454). IR (NaCl, ﬁlm, cm^ꢀ1): 3302, 2955, 2794, 2360, 1712,

leum ether/ethyl acetate/triethylamine 9:1:0.3) to afford 17e

(137 mg, 82%). H NMR (CDCl₃, 400 MHz): d 7.00 (t, 1H, H-5⁰⁰,

J = 7.8 Hz), 6.59 (d, 1H, H-6⁰⁰, J = 7.4 Hz), 6.42 (d, 1H, H-4⁰⁰,

J = 8.0 Hz), 4.17 (dd, 1H, H-5-H, J = 6.5 Hz, J = 12.3 Hz), 2.59–2.41

(m, 2H, H-6, H-7), 2.28 (s, 3H, CH₃-2⁰⁰), 2.14 (s, 3H, CH₃-3⁰⁰), 2.04–

1.78 (m, 3H, H-1⁰, H-2, H-3), 1.73–1.56 (m, 1H, H-3), 1.57–1.43

(m, 2H, H-1, H-5⁰), 1.43–1.17 (m, 5H, H-2, H-2⁰, H-3⁰, H-6, H-7),

1.16–1.07 (m, 6H, CH₃-3a, H-3⁰, H-4⁰), 1.02–0.95 (m, 1H, H-2⁰),

0.94–0.88 (m, 3H, CH₃-1⁰, with underneath s, 3H, CH₃-7a at

0.87 ppm), 0.87 (d, 3H, CH₃-5⁰, J = 5.8 Hz,), 0.85 (d, 3H, H-6⁰,

J = 5.8 Hz,). C NMR (CDCl₃, 125 MHz): d 212.2 (CO), 144.9 (1⁰⁰-

1635, 1456, 1383, 1286, 767. ½a _D²⁰

ꢂ

ꢀ23 (0.5; CHCl₃).

C), 137.1 (2⁰⁰-C), 126.1 (6⁰⁰-CH), 121.1 (3⁰⁰-C), 119.5 (4⁰⁰-CH), 107.9

(5⁰⁰-CH), 60.4 (3a-C), 58.1 (5-CH), 50.4 (7a-C), 46.6 (1-CH), 39.4

(6-CH₂), 35.9 (3-CH₂), 35.1 (1-CH), 30.4 (7-CH₂), 29.8 (4⁰-CH₂),

29.3 (2⁰-CH₂), 28.0 (5⁰-CH), 25.4 (2-CH₂), 24.4 (3⁰-CH₂), 22.9 (CH₃-

3⁰⁰), 22.6 (CH₃-2⁰⁰), 20.8 (6⁰-CH₃), 20.1 (CH₃-5⁰), 18.9 (CH₃-3a),

17.9 (CH₃-7a), 12.6 (CH₃-1⁰). HRMS Found 397.3373 (Calcd

397.3345). IR (NaCl, ﬁlm, cm^ꢀ1): 3412, 3003, 2987, 2866, 1780,

5.6.6.3.

dimethyl-5-[(pyridin-3-ylmethyl)-amino]-octahydroinden-4-

one (17c). Ketone 16 (150 mg, 0.42 mmol) and 3-(amino-

(1R,3aR,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

methyl)pyridine (0.31 mL, 2.94 mmol) in DMF (2 mL) were treated

as described in procedure A. The crude product was subjected to

SCC (petroleum ether/ethyl acetate/triethylamine 7:3:0.1) to afford

17c (112 mg, 68%). ¹H NMR (CDCl₃, 400 MHz): d 8.54 (s, 1H, H-2⁰⁰⁰),

8.49 (d, 1H, H-6⁰⁰⁰, J = 3.8 Hz), 7.76 (d, 1H, H-4⁰⁰⁰, J = 7.8 Hz), 7.25 (dd,

1H, H-5⁰⁰⁰, J = 3.8 Hz, J = 7.8 Hz), 3.84 (d, 1H, H-1⁰⁰, J = 13.3 Hz), 3.76

(d, 1H, H-1⁰⁰, J = 13.3 Hz), 3.49–3.36 (m, 1H, H-5), 2.47–2.42 (m, 1H,

H-6), 2.19–2.05 (m, 1H, H-7), 1.92 (m, 1H, H-3), 1.82–1.60 (m, 3H,

H-1⁰, H-2, H-6), 1.47 (m, 1H, H-5⁰), 1.38–1.04 (m, 9H), 1.02 (s, 3H,

CH₃-3a), 0.95–0.90 (m, 1H, H-2⁰), 0.87 (d, 3H, CH₃-1⁰, J = 6.0 Hz),

0.80 (s, 3H, CH₃-7a), 0.76 (d, 3H, CH₃-5⁰, J = 6.2 Hz), 0.74 (d, 3H,

H-6⁰, J = 6.2 Hz). ¹³C NMR (CDCl₃, 125 MHz): d 214.2 (CO), 149.7

(6⁰⁰⁰-CH), 148.6 (2⁰⁰⁰-CH), 136.1(4⁰⁰⁰-CH), 135.5 (3⁰⁰⁰-CH), 123.5 (5⁰⁰⁰-

CH), 61.3 (1⁰⁰-CH₂), 60.4 (3a-C), 50.0 (5-CH), 49.3 (7a-C), 46.5 (1-

CH), 39.4 (6-CH₂), 35.9 (3-CH₂), 35.0 (7-CH₂), 30.2 (1⁰-CH), 30.1

(2⁰-CH₂), 29.2 (4⁰-CH₂), 28.0 (5⁰-CH), 25.3 (2-CH₂), 24.3 (3⁰-CH₂),

22.8 (6⁰-CH₃), 22.5 (CH₃-5⁰), 19.8 (CH₃-3a), 18.8 (CH₃-7a), 17.8

(CH₃-1⁰). HRMS Found 384.6111 (Calcd 384.6103). IR (NaCl, ﬁlm,

cm^ꢀ1): 3444, 3012, 2958, 2901, 1704, 1469, 1424, 1382, 1026,

1723, 1489, 1372, 997, 789, 742. ½a _D²⁰

ꢀ42 (0.5; CHCl₃).

ꢂ

5.6.7. General procedure B (reduction of ketones 17a–e)

To a stirred solution of the required ketone 17a–e in anhydrous

THF, lithium aluminium hydride (3–5 equiv) was added at 0 °C un-

der nitrogen atmosphere. The mixture was stirred at 0 °C for

30 min, then quenched with a saturated aqueous solution of so-

dium bicarbonate (3 mL) and diluted with water (20 mL). The bi-

phasic mixture was extracted with ethyl acetate (3 ꢁ 20 mL) and

the combined organic extracts were washed with water (30 mL),

dried over sodium sulphate and evaporated to dryness under re-

duced pressure. The crude product was subjected to SCC as speci-

ﬁed below to afford amino alcohols 18a–e as colourless oils.

5.6.7.1.

ethylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(18a). Ketone 17a (150 mg, 0.47 mmol) and lithium alumin-

(1R,3aR,4R,5S,7aR)-5-Dimethylamino-1-((R)-1,5-dim-

713. ½a ²_D⁰

ꢂ

ꢀ22 (0.5; CHCl₃).

ium hydride (60.0 mg, 1.54 mmol) in anhydrous THF (2 mL) were

treated as described in procedure B. The crude product was sub-

jected to SCC (petroleum ether/ethyl acetate/triethylamine

8:2:0.3) to afford 18a (140 mg, 92%). ¹H NMR (CDCl₃, 400 MHz):

d 3.49 (d, 1H, H-4, J = 1.9 Hz), 2.37–2.27 (m, 1H, H-1⁰), 2.25 (s,

6H, N(CH₃)2), 2.03–1.76 (m, 4H, H-3, H-5, H-6, H-7), 1.65–1.38

(m, 4H, H-1, H-2, H-3, H-5⁰), 1.37–1.18 (m, 5H, H-2, H-2⁰, H-3⁰, H-

6, H-7), 1.14–1.06 (m, 3H, H-3⁰, H-4⁰), 1.04–0.95 (m, 1H, H-2⁰),

0.91 (d, 3H, CH₃-1⁰, J = 6.5 Hz), 0.87–0.82 (m, 6H, CH₃-5⁰, H-6⁰),

0.82 (s, 3H, CH₃-3a), 0.71 (s, 3H, CH₃-3a). ¹³C NMR (CDCl₃,

125 MHz): d 74.9 (4-CH), 64.5 (5-CH), 48.3 (3a-C), 46.8 (1-CH),

43.8 (7a-C), 42.3 (2C, N(CH₃)₂), 39.2 (6-CH₂), 36.1 (3-CH₂), 35.3

(1⁰-CH), 34.5 (7-CH₂), 31.3 (4⁰-CH₂), 28.8 (2⁰-CH₂), 27.6 (5⁰-CH),

23.8 (2-CH₂), 22.5 (6⁰-CH₃), 22.2 (CH₃-5⁰), 20.9 (3⁰-CH₂), 20.1

(CH₃-3a), 19.4 (CH₃-7a), 18.6 (CH₃-1⁰). HRMS Found 323.3201

(Calcd 323.3188). IR (NaCl, ﬁlm, cm^ꢀ1): 3412, 3017, 2870, 1452,

5.6.6.4.

(1R,3aR,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-(2,6-

dimethylmorpholine-4-yl)-3a,7a-dimethyloctahydroinden-4-

one (17d). Ketone 16 (150 mg, 0.42 mmol) and 2,6-dimethyl-

morpholine (0.36 mL, 2.94 mmol) in DMF (2 mL) were treated as

described in procedure A. The crude product was subjected to

SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.1) to afford

17d (98 mg, 59%). ¹H NMR (CDCl₃, 400 MHz): d 3.91–3.79 (m, 2H,

H-2⁰⁰, H-6⁰⁰), 3.32 (dd, 1H, H-5, J = 6.1 Hz, J = 12.3 Hz,), 2.82–2.69

(m, 2H, H-6, H-7), 2.49–2.38 (m 1H, H-2), 2.20–1.93 (m, 3H, H-3,

H-3⁰⁰, H-5⁰⁰), 1.85–1.67 (m, 3H, H-3⁰⁰, H-5⁰⁰, H-6), 1.55–1.40 (m,

1H, H-1⁰), 1.39–1.16 (m, 5H, H-2⁰, H-3, H-3⁰, H-7), 1.14–1.03 (m,

10H, H-2, H-2⁰, H-4⁰, CH₃-2⁰⁰, CH₃-6⁰⁰, with underneath s, 3H, CH₃-

3a at 1.09 ppm), 0.91–0.87 (d, 3H, CH₃-1⁰, J = 6.2 Hz), 0.91 (d, 3H,

CH₃-5⁰, J = 6.0 Hz), 0.91–0.85 (m, 3H, H-6⁰, with underneath s, 3H,

CH₃-7a at 0.87 ppm). ¹³C NMR (CDCl₃, 125 MHz): d 212.2 (CO),

71.6 (2C, 2⁰⁰-CH, 6⁰⁰-CH), 67.6 (3a-C), 61.1 (5-CH), 55.0 (7a-C),

49.9 (1-CH), 46.5 (6-CH₂), 39.4 (3-CH₂), 35.9 (2C, 3⁰⁰-CH₂, 5⁰⁰-CH₂),

35.1 (7-CH₂), 30.5 (1⁰-CH), 29.2 (4⁰-CH₂), 28.0 (2⁰-CH₂), 25.4 (5⁰-

CH), 24.3 (2-CH₂), 23.8 (3⁰-CH₂), 22.8 (6⁰-CH₃), 22.6 (CH₃-5⁰), 19.9

(CH₃-3a), 19.2 (CH₃-6⁰⁰), 19.1 (CH₃-2⁰⁰), 18.8 (CH₃-7a), 17.7 (CH₃-

1⁰). HRMS Found 391.3436 (Calcd 391.3450). IR (NaCl, ﬁlm,

1353, 1237, 1002, 773. ½a _D²⁰

ꢂ

+11 (0.5; CHCl₃).

5.6.7.2.

dimethyl-5-(4-methylpiperazine-1-yl)-octahydroinden-4-ol

(18b). Ketone 17b (140 mg, 0.37 mmol) and lithium alumin-

(1R,3aR,4R,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

ium hydride (72.0 mg, 1.86 mmol) in anhydrous THF (2 mL) were

treated as described in procedure B. The crude product was sub-

jected to SCC (petroleum ether/ethyl acetate/triethylamine

5:5:0.4) to afford 18b (124 mg, 88%). ¹H NMR (CDCl₃, 400 MHz):

d 3.49 (d, 1H, H-4, J = 1.6 Hz), 2.41 (m, 8H, H-2⁰⁰, H-3⁰⁰, H-5⁰⁰, H-

6⁰⁰), 2.35–2.28 (m, 1H, H-5⁰), 2.26 (s, 3H, NCH₃), 2.22–2.17 (m,

1H, H-5), 1.99–1.77 (m, 3H, H-3, H-6, H-7), 1.63–1.53 (m, 1H, H-

2), 1.53–1.39 (m, 2H, H-3, H-5⁰), 1.38–1.16 (m, 6H, H-1, H-2, H-

2⁰, H-3⁰, H-6, H-7), 1.15–1.06 (m, 3H, H-3⁰, H-4⁰), 1.02–0.95 (m,

1H, H-2⁰), 0.91 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.86 (d, 3H, CH₃-5⁰,

cm^ꢀ1): 2990, 2874, 1722, 1466, 1219, 1001, 723. ½a ²_D⁰

ꢂ

ꢀ31 (0.5;

CHCl₃).

5.6.6.5.

(1R,3aR,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-(2,3-di-

methylphenylamino)-3a,7a-dimethyloctahydroinden-4-one

(17e). Ketone 16 (150 mg, 0.42 mmol) and 2,3-dimethylani-

line (0.68 mL, 5.58 mmol) in DMF (2 mL) were treated as described

in procedure A. The crude product was subjected to SCC (petro-

1936

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

J = 6.1 Hz,), 0.84 (d, 3H, H-6⁰, J = 6.1 Hz), 0.82 (s, 3H, CH₃-3a), 0.72

(s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d 74.6 (4-CH), 62.9

(5-CH), 55.6 (2C, 3⁰⁰-CH₂, 5⁰⁰-CH₂), 49.3 (2C, 2⁰⁰-CH₂, 6⁰⁰-CH₂), 48.4

(3a-C), 47.1 (1-CH), 45.8 (NCH₃), 44.2 (7a-C), 39.4 (6-CH₂), 36.3

(3-CH₂), 35.6 (1⁰-CH), 34.8 (2⁰-CH₂), 31.4 (5-CH₂), 29.1 (7-CH₂),

27.8 (5⁰-CH), 24.2 (2-CH₂), 22.7 (6⁰-CH₃), 22.4 (CH₃-5⁰), 21.1 (CH₃-

3a), 19.6 (2C, CH₃-7a, 3⁰-CH₂), 18.8 (CH₃-1⁰). HRMS Found

378.3596 (Calcd 378.3610). IR (NaCl, ﬁlm, cm^ꢀ1): 3398, 3001,

5.6.7.5. (1R,3aR,4RS,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-(2,3-

dimethylphenylamino)-3a,7a-dimethyl-octahydroinden-4-ol

(epimeric mixture) (18e).

Ketone 17e (170 mg, 0.42 mmol)

and lithium aluminium hydride (52.0 mg, 1.28 mmol) in anhy-

drous THF (2 mL) were treated as described in procedure B. The

crude product was subjected to SCC (petroleum ether/ethyl ace-

tate/triethylamine 6:4:0.3) to afford 18e (163 mg, 97%). ¹H NMR

(CDCl₃, 400 MHz): d 7.05–6.97 (m, 1H, H-5⁰⁰), 6.67 (d, 0.85H, H-

6⁰⁰, J = 8.2 Hz), 6.64 (d, 0.85H, H-4⁰⁰, J = 7.5 Hz), 6.58 (d, 0.15H, H-

4⁰⁰, J = 7.5 Hz), 6.51 (d, 0.15H, H-6⁰⁰, J = 8.2 Hz), 3.60 (d, 0.15H, H-

4, J = 10.3 Hz), 3.54–3.45 (m, 1H, H-4, H-5), 3.29 (ddd, 0.85H, H-5,

J = 4.2 Hz, J = 7.4 Hz, J = 10.6 Hz), 2.28 (s, 2.55H, CH₃-2⁰⁰), 2.27 (s,

0.45H, CH₃-2⁰⁰), 2.08 (s, 2.55H, CH₃-3⁰⁰), 2.06 (s, 0.45H, CH₃-3⁰⁰),

2.03–1.89 (m, 4H, H-1⁰, H-6, H-7), 1.87–1.72 (m, 2H, H-3, H-2),

1.61–1.47 (m, 1H, H-5), 1.45–1.27 (m, 7H), 1.23–1.06 (m, 3H, H-

3⁰, H-4⁰), 1.07–1.00 (m, 1H, H-2⁰), 0.99 (s, 0.45H, CH₃-3a), 0.97 (s,

2.55H, CH₃-3a), 0.96–0.90 (m, 3H, CH₃-1⁰), 0.89–0.81 (m, 6H,

CH₃-5⁰, H-6⁰), 0.80 (s, 2.55H, CH₃-7a), 0.77 (s, 0.45H, CH₃-7a). ¹³C

NMR (CDCl₃, 125 MHz): d 145.7 (1⁰⁰-C), 145.0 (1⁰⁰-C), 137.0 (2⁰⁰-C),

136.9 (2⁰⁰-C), 126.2 (6⁰⁰-CH), 126.1 (6⁰⁰-CH), 121.9 (3⁰⁰-C), 120.9

(3⁰⁰-C), 120.4 (4⁰⁰-CH), 119.5 (4⁰⁰-CH), 110.3 (5⁰⁰-CH), 108.9 (5⁰⁰-

CH), 77.3 (4-CH), 75.3 (4-CH), 56.4 (5-CH), 53.1 (5-CH), 51.3 (3a-

C), 49.6 (3a-C), 47.6 (1-CH), 47.0 (1-CH), 46.4 (7a-C), 45.1 (7a-C),

39.6 (6-CH₂), 39.5 (6-CH₂), 36.6 (3-CH₂), 36.5 (3-CH₂), 36.0 (1⁰-

CH), 35.8 (1⁰-CH), 35.0 (7-CH₂), 32.8 (7-CH₂), 32.0 (4⁰-CH₂), 31.1

(4⁰-CH₂), 29.1 (5⁰-CH), 28.0 (5⁰-CH), 27.9 (2⁰-CH₂), 27.5 (2⁰-CH₂),

26.8 (2-CH₂), 26.7 (2-CH₂), 24.4 (3⁰-CH₂), 24.3 (3⁰-CH₂), 22.9

(CH₃-2⁰⁰), 22.8 (CH₃-2⁰⁰), 22.6 (CH₃-3⁰⁰), 21.5 (CH₃-3⁰⁰), 20.9 (CH₃-

3a), 20.6 (CH₃-3a), 20.0 (6⁰-CH₃), 19.1 (6⁰-CH₃), 18.9 (CH₃-5⁰), 18.7

(CH₃-5⁰), 15.7 (CH₃-7a), 14.0 (CH₃-7a), 12.9 (1⁰-CH₃), 12.7 (1⁰-

CH₃). HRMS Found 399.3483 (Calcd 393.3501). IR (NaCl, ﬁlm,

cm^ꢀ1): 3412, 3307, 3010, 2962, 1723, 1412, 1272, 983, 791, 733.

2987, 2856, 1501, 1372, 997. ½a _D²⁰

ꢂ

+17 (0.5; CHCl₃).

5.6.7.3.

dimethyl-5-[(pyridine-3-ylmethyl)-amino]-octahydroinden-4-

ol (18c). Ketone 17c (132 mg, 0.34 mmol) and lithium alu-

(1R,3aR,4R,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

minium hydride (39.0 mg, 1.02 mmol) in anhydrous THF (2 mL)

were treated as described in procedure B. The crude product was

subjected to SCC (petroleum ether/ethyl acetate/triethylamine

8:2:0.3) to afford 18c (125 mg, 96%). ¹H NMR (CDCl₃, 400 MHz):

d 8.54 (s, 1H, H-2⁰⁰⁰), 8.51 (d, 1H, H-6⁰⁰⁰, J = 3.3 Hz), 7.66 (d, 1H, H-

4⁰⁰⁰, J = 7.8 Hz), 7.30–7.23 (m, 1H, H-5⁰⁰⁰), 3.83 (d, 1H, H-1⁰⁰,

J = 13.3 Hz), 3.74 (d, 1H, H-1⁰⁰, J = 13.3 Hz), 3.46 (d, 1H, 4-4,

J = 2.6 Hz), 2.80–2.65 (m, 1H, H-5), 2.39–2.28 (m, 1H, H-1⁰), 2.01–

1.90 (m, 1H, H-6), 1.88–1.78 (m, 2H, H-3, H-7), 1.78–1.65 (m, 1H,

H-2), 1.58–1.43 (m, 2H, H-3, H-5⁰), 1.36–1.20 (m, 6H, H-1, H-2,

H-2⁰, H-3⁰, H-6, H-7), 1.17–1.08 (m, 3H, H-3⁰, H-4⁰), 1.05–0.97 (m,

1H, H-2⁰), 0.91 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.86 (d, 3H, CH₃-5⁰,

J = 6.2 Hz), 0.86–0.83 (m, 3H, H-6⁰, with underneath s, 3H, CH₃-3a

at 0.84 ppm), 0.73 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

149.5 (2⁰⁰⁰-CH), 148.6 (6⁰⁰⁰-CH), 135.8 (4⁰⁰⁰-CH), 135.4 (3⁰⁰⁰-C), 123.4

(5⁰⁰⁰-CH), 75.7 (4-CH), 56.8 (5-CH), 48.5 (1⁰⁰-CH₂), 47.9 (1-CH),

47.2 (3a-C), 44.9 (7a-C), 39.5 (6-CH₂), 36.4 (3-CH₂), 35.5 (1⁰-CH),

34.8 (7-CH₂), 31.3 (4⁰-CH₂), 29.1 (2⁰-CH₂), 27.9 (5⁰-CH), 24.2 (2-

CH₂), 23.0 (3⁰-CH₂), 22.8 (6⁰-CH₃), 22.5 (CH₃-5⁰), 21.2 (CH₃-3a),

19.9 (CH₃-7a), 19.0 (CH₃-1⁰). HRMS Found 386.3289 (Calcd

386.3297). IR (NaCl, ﬁlm, cm^ꢀ1): 3411, 3007, 2963, 2887, 1499,

5.6.8. (1R,3aR,4S,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

dimethyloctahydroinden-4-ol (19)

1713, 1312, 997, 739, 699. ½a _D²⁰

ꢂ

+37 (0.5; CHCl₃).

To a stirred solution of the ketone 12 (500 mg, 1.82 mmol) in

anhydrous THF (30 mL), lithium aluminium hydride (215 mg,

5.40 mmol) was added at 0 °C under nitrogen atmosphere. The

mixture was stirred at 0 °C for 1 h, then quenched by dropwise

addition of a saturated aqueous solution of sodium bicarbonate

(15 mL) and diluted with water (30 mL). The biphasic mixture

was extracted with ethyl acetate (3 ꢁ 50 mL) and the combined or-

ganic extracts were washed with water (100 mL), dried over so-

dium sulphate and evaporated to dryness under reduced

pressure. The crude product was subjected to SCC (petroleum

ether/ethyl acetate 9:1) to afford alcohol 19 (505 mg, 99%) as a

white solid. Mp 151 °C. ¹H NMR (CDCl₃, 400 MHz): d 3.51 (dd,

1H, H-4, J = 3.3 Hz, J = 5.4 Hz), 2.11–1.99 (m, 1H, H-5), 1.89–1.78

(m, 1H, H-6), 1.74–1.60 (m, 4H, H-2, H-3, H-5, H-7), 1.59–1.53

(m, 1H, H-1⁰), 1.51–1.45 (m, 1H, H-5⁰), 1.45–1.31 (m, 6H, H-1, H-

2, H-3, H-3⁰, H-6, H-7), 1.24–1.05 (m, 4H, H-2⁰, H-3⁰, H-4⁰), 1.04–

0.95 (m, 1H, H-2⁰), 0.92 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.88 (s, 3H,

CH₃-3a), 0.86 (d, 3H, CH₃-5⁰, J = 6.2 Hz), 0.85 (d, 3H, H-6⁰,

J = 6.2 Hz), 0.79 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

77.1 (4-CH), 50.1 (3a-C), 49.0 (5-CH₂), 45.6 (7a-C), 39.6 (1-CH),

36.1 (3-CH₂), 35.5 (1⁰-CH), 35.3 (6-CH₂), 33.0 (7-CH₂), 30.4 (4⁰-

CH₂), 28.4 (2⁰-CH₂), 28.0 (5⁰-CH), 24.3 (2-CH₂), 22.9 (3⁰-CH₂), 22.6

(6⁰-CH₃), 21.9 (CH₃-5⁰), 19.9 (CH₃-3a), 19.6 (CH₃-7a), 17.3 (CH₃-

1⁰). Anal. Cald: C, 81.36; H, 12.92. Found: C, 81.13; H, 12.93. IR

5.6.7.4. (1R,3aR,4RS,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-(2,6-

dimethylmorpholine-4-yl)-3a,7a-di-methyl-octahydroinden-4-

(epimeric mixture)

(18d).

Ketone

17d

(140 mg,

0.36 mmol) and lithium aluminium hydride (42.0 mg, 1.08 mmol)

in anhydrous THF (2 mL) were treated as described in procedure

B. The crude product was subjected to SCC (petroleum ether/ethyl

acetate/triethylamine7:3:0.3) to afford 18d (138 mg, 98%). ¹H NMR

(CDCl₃, 400 MHz): d 3.71–3.45 (m, 3H, H-2⁰⁰, H-4, H-6⁰⁰), 2.93 (dd,

1.4H, H-3⁰⁰, H-5⁰⁰, J = 6.7 Hz, J = 11.4 Hz), 2.85 (dd, 1.4H, H-3⁰⁰, H-

5⁰⁰, J = 6.3 Hz, J = 11.1 Hz), 2.60 (dd, 0.6H, H-3⁰⁰, H-5⁰⁰, J = 6.6 Hz,

J = 11.4 Hz), 2.44 (dd, 0.6H, H-3⁰⁰, H-5⁰⁰, J = 6.2 Hz, J = 11.5 Hz),

2.39–2.25 (m, 1H, H-1⁰), 2.18–2.10 (m, 0.7H, H-5), 2.04–1.75 (m,

4.3H, H-3, H-5, H-6, H-7), 1.64–1.11 (m, 17H), 1.05–0.94 (m, 1H,

H-2⁰) 0.92 (d, 0.9H, CH₃-1⁰, J = 5.9 Hz), 0.91 (d, 2.1H, CH₃-1⁰,

J = 5.9 Hz), 0.87–0.81 (m, 9H, CH₃-3a, CH₃-5⁰, H-6⁰), 0.73 (s, 0.9H,

CH₃-7a), 0.71 (s, 2.1H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

74.6 (4-CH), 72.4 (2⁰⁰-CH), 72.4 (6⁰⁰-CH), 72.3 (2⁰⁰-CH), 72.0 (6⁰⁰-

CH), 69.0 (4-CH), 65.3 (5-CH), 63.1 (5-CH), 58.3 (3a-C), 56.4 (3a-

C), 55.2 (1-CH), 50.8 (1-CH), 50.7 (7a-C), 48.5 (7a-C), 47.3 (6-

CH₂), 46.7 (6-CH₂), 46.2 (3-CH₂), 44.4 (3-CH₂), 39.6 (2⁰-CH₂), 39.5

(2⁰-CH₂), 36.5 (2C, 3⁰⁰-CH₂, 5⁰⁰-CH₂), 36.3 (2C, 3⁰⁰-CH₂, 5⁰⁰-CH₂),

36.1 (1⁰-CH), 35.8 (1⁰-CH), 34.9 (4⁰-CH₂), 33.2 (4⁰-CH₂), 31.5 (7-

CH₂), 31.3 (7-CH₂), 29.3 (5⁰-CH), 28.0 (5⁰-CH), 27.9 (2-CH₂), 26.9

(2-CH₂), 24.4 (3⁰-CH₂), 24.3 (3⁰-CH₂), 22.9 (CH₃-3a), 22.8 (CH₃-

3a), 22.6 (2C, CH₃-2⁰⁰, CH₃-6⁰⁰), 21.2 (2C, CH₃-2⁰⁰, CH₃-6⁰⁰), 19.7 (6⁰-

CH₃), 19.3 (6⁰-CH₃), 19.2 (CH₃-5⁰), 19.0 (CH₃-5⁰), 18.9 (CH₃-7a),

18.9 (CH₃-7a), 18.5 (CH₃-1⁰), 17.4 (CH₃-1⁰). HRMS Found

393.3603 (Calcd 393.3606). IR (NaCl, ﬁlm, cm^ꢀ1): 3423, 3392,

3032, 2987, 2897, 1541, 1372, 1132, 997.

(NaCl, ﬁlm, cm^ꢀ1): 3448, 2954, 2870, 1467, 1304, 735. ½a ²_D⁰

ꢂ

(0.5; CHCl₃).

5.6.9. (1R,3R,3aR,7aS)-3-((R)-1,5-Dimethylhexyl)-3a,7a-

dimethyl-2,3,3a,6,7,7a-hexahydro-1H-indene (20)

To a stirred solution of 19 (500 mg, 1.79 mmol) in anhydrous

pyridine (4 mL), phosphorous oxychloride (0.50 mL, 5.40 mmol)

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1937

was added dropwise in a careful manner. The resulting mixture

was stirred at room temperature for 30 min. After cooling down

to ꢀ10 °C the excess of phosphorous oxychloride was quenched

slowly by dropwise addition of a saturated aqueous solution of so-

dium bicarbonate (10 mL). The mixture was diluted with water

(30 mL) and extracted with ethyl acetate (3 ꢁ 30 mL). The com-

bined organic extracts were washed with a saturated aqueous

solution of ammonium chloride (50 mL), water (50 mL), dried over

sodium sulphate, and evaporated to dryness under reduced pres-

sure. The crude product was subjected to SCC (petroleum ether/

ethyl acetate 95:5) to afford 20 (369 mg, 78%) as a colourless oil.

¹H NMR (CDCl₃, 400 MHz): d 5.43 (d, 1H, H-4, J = 3.7 Hz), 5.27

(ddd, 1H, H-5, J = 3.6 Hz, J = 6.4 Hz, J = 7.2 Hz), 2.07–1.98 (m, 1H,

H-6), 1.95–1.90 (m, 1H, H-6), 1.89–1.82 (m, 1H, H-7), 1.78–1.70

(m, 2H, H-1⁰, H-3), 1.59–1.47 (m, 2H, H-5⁰, H-7), 1.29–1.23 (m,

4H, H-1, H-2, H-3), 1.18–1.10 (m, 5H, H-2⁰, H-3⁰, H-4⁰), 1.03–0.98

(m, 1H, H-2⁰), 0.95 (d, 3H, CH₃-1⁰, J = 6.2 Hz), 0.88 (s, 3H, CH₃-3a),

0.86 (d, 3H, CH₃-5⁰, J = 6.5 Hz), 0.85 (d, 3H, H-6⁰, J = 6.5 Hz), 0.75

(s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d 138.0 (4-CH), 121.6

(5-CH), 45.6 (3a-C), 44.5 (6-CH₂), 42.5 (7a-C), 40.8 (1-CH), 38.1

(7-CH₂), 34.8 (3-CH₂), 34.1 (1⁰-CH), 27.8 (4⁰-CH₂), 26.6 (2⁰-CH₂),

25.1 (5⁰-CH), 22.8 (2-CH₂), 22.1 (3⁰-CH₂), 21.4 (CH₃-3a), 21.1

(CH₃-5⁰), 21.0 (6⁰-CH₃), 17.0 (CH₃-7a), 16.6 (CH₃-1⁰). HRMS Found

262.4815 (Calcd 262.4830). IR (NaCl, ﬁlm, cm^ꢀ1): 2980, 2873,

washed with water (30 mL), dried over sodium sulphate, and evap-

orated to dryness under reduced pressure. The crude product was

subjected to SCC (petroleum ether/ethyl acetate 9:1) to afford 22

(86 mg, 81%) as a white resin. ¹H NMR (CDCl₃, 400 MHz): d 3.40

(d, 1H, H-4, J = 10.4 Hz), 3.33 (ddd, 1H, H-5, J = 4.5 Hz, J = 7.6 Hz,

J = 10.9 Hz), 1.92–1.78 (m, 5H, H-1⁰, H-2, H-3, H-6, H-7), 1.71–

1.59 (m, 1H, H-3), 1.56–1.47 (m, 1H, H-5⁰), 1.44–1.20 (m, 6H, H-

1, H-2, H-3⁰, H-6, H-7), 1.16–1.07 (m, 3H, H-2⁰, H-4⁰), 1.03–0.95

(m, 1H, H-2⁰), 0.91 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.89–0.84 (m, 3H,

CH₃-5⁰, with underneath s, 3H, CH₃-3a at 0.86 ppm), 0.85 (d, 3H,

H-6⁰, J = 6.4 Hz), 0.76 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz):

d 74.7 (4-CH), 64.3 (5-CH), 51.6 (3a-Ca), 46.9 (7a-C), 46.2 (1-CH),

39.5 (6-CH₂), 36.5 (3-CH₂), 36.0 (1-CH), 32.7 (7-CH₂), 30.4 (4⁰-

CH₂), 28.1 (5⁰-CH), 26.6 (2⁰-CH₂), 25.5 (2-CH₂), 24.2 (3⁰-CH₂), 22.9

(6⁰-CH₃), 22.6 (CH₃-5⁰), 18.9 (CH₃-3a), 18.5 (CH₃-7a), 13.8 (CH₃-

1⁰). Anal. Cald: C, 70.98; H, 10.97; N, 13.07. Found: C, 71.33; H,

11.06; N, 13.05. IR (NaCl, ﬁlm, cm^ꢀ1): 3473, 2985, 2872, 2100,

1468, 1382, 1023, 735. ½a _D²⁰

ꢀ17 (0.5; CHCl₃).

ꢂ

5.6.12. (1R,3aR,4S,5S,7aR)-5-Amino-1-((R)-1,5-Dimethylhexyl)-

3a,7a-dimethyloctahydroinden-4-ol (23)

To a stirred solution of azide 22 (100 mg, 0.31 mmol) in anhy-

drous THF (5 mL), lithium aluminium hydride (40.0 mg,

1.04 mmol) was added at 0 °C under nitrogen atmosphere. The

mixture was stirred at 0 °C for 30 min, then quenched with a satu-

rated aqueous solution of sodium bicarbonate (3 mL) and diluted

with water (20 mL). The biphasic mixture was extracted with ethyl

acetate (3 ꢁ 20 mL) and the combined organic extracts were

washed with water (30 mL), dried over sodium sulphate and evap-

orated to dryness under reduced pressure. The crude product was

subjected to SCC (dichloromethane/methanol/triethylamine

9:1:0.2) to afford amino alcohol 23 (91 mg, 99%) as a white resin.

Mp 104 °C. ¹H NMR (CDCl₃, 400 MHz): d 3.26 (d, 1H, H-4,

J = 10.3 Hz), 2.72–2.58 (m, 2H, H-1⁰, H-5), 2.52 (bs, 3H, NH₂, OH),

1.99–1.83 (m, 3H, H-3, H-6, H-7), 1.79–1.73 (m, 1H, H-2), 1.70–

1.62 (m, 1H, H-3), 1.52–1.42 (m, 2H, H-5⁰, H-6), 1.38–1.27 (m,

5H, H-1, H-2⁰, H-2, H-3⁰, H-7), 1.18–1.05 (m, 3H, H-3⁰, H-4⁰),

1.00–0.93 (m, 1H, H-2⁰), 0.91 (d, J = 6.5 Hz, 3H, CH₃-1⁰), 0.86 (d,

J = 6.6 Hz, 3H, CH₃-5⁰), 0.85–0.79 (m, 3H, H-6⁰, with underneath s,

3H, CH₃-3a at 0.82 ppm), 0.75 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃,

125 MHz): d 76.5 (4-CH), 52.7 (5-CH), 51.1 (3a-C), 47.2 (1-CH),

46.3 (7a-C), 39.6 (6-CH₂), 36.5 (3-CH₂), 36.0 (7-CH₂), 32.8 (1⁰-CH),

31.0 (4⁰-CH₂), 29.9 (2⁰-CH₂), 28.1 (5⁰-CH), 26.7 (2-CH₂), 24.3 (3⁰-

CH₂), 22.9 (6⁰-CH₃), 22.7 (CH₃-5⁰), 19.0 (CH₃-3a), 18.8 (CH₃-7a),

14.1 (CH₃-1⁰). HRMS Found 295.2860 (Calcd 295.2875). IR (NaCl,

1465, 1381, 851, 720. ½a _D²⁰

ꢀ46 (0.5; CHCl₃).

ꢂ

5.6.10. (1aR,3aR,4R,6aR,6bS)-3a,6a-Dimethyl-4-((R)-1,5-

dimethylhexyl)-octahydro-1aH-indeno[5,4-b]-oxirene (21)

Sodium bicarbonate (82.0 mg, 0.98 mmol) and 3-chloroperben-

zoic acid (300 mg, 0.84 mmol) were suspended in dichloromethane

(5 mL) at 5 °C, and a solution of 20 (200 mg, 0.76 mmol) in dichlo-

romethane (2 mL) was added to the suspension under nitrogen

atmosphere. The resulting mixture was allowed to warm up to

ambient temperature and was stirred for 2 h. The excess of 3-chlo-

roperbenzoic acid was quenched with an aqueous 5% solution of

sodium thiosulphate (4 mL). The reaction mixture was diluted with

water and extracted with ethyl acetate (3 ꢁ 25 mL). The combined

organic extracts were washed with water (50 mL), dried over so-

dium sulphate, and evaporated to dryness under reduced pressure.

The crude product was subjected to SCC (petroleum ether/ethyl

acetate 97:3) to afford 21 (198 mg, 93%) as a colourless oil. ¹H

NMR (CDCl₃, 400 MHz): d 3.22–3.18 (m, 1H, H-5), 2.70 (d, 1H, H-

4, J = 3.8 Hz), 1.90–1.82 (m, 2H, H-6, H-7), 1.81–1.72 (m, 1H, H-

3), 1.70–1.61 (m, 2H, H-1⁰, H-3), 1.59–1.44 (m, 2H, H-6, H-2),

1.41–1.20 (m, 6H, H-1, H-2, H-2⁰, H-3, H-3⁰, H-7), 1.18–1.04 (m,

3H, H-3⁰, H-4⁰), 1.02–0.97 (m, 1H, H-2⁰), 0.97 (s, 3H, CH₃-3a), 0.93

(d, 3H, CH₃-1⁰, J = 6.7 Hz), 0.86 (d, 3H, CH₃-5⁰, J = 5.8 Hz), 0.85 (d,

3H, H-6⁰, J = 5.8 Hz), 0.65 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃,

125 MHz): d 62.6 (4-CH), 54.3 (5-CH), 46.7 (1-CH), 43.7 (3a-C),

43.2 (7a-C), 39.5 (6-CH₂), 36.6 (3-CH₂), 35.9 (7-CH₂), 34.1 (1⁰-CH),

28.0 (5⁰-CH), 26.2 (4⁰-CH₂), 25.2 (2⁰-CH₂), 24.5 (2-CH₂), 22.8 (6⁰-

CH₃), 22.6 (CH₃-5⁰), 21.4 (3⁰-CH₂), 19.6 (CH₃-3a), 18.7 (CH₃-7a),

18.0 (CH₃-1⁰). Anal. Calcd: C, 81.95; H, 12.31. Found: C, 81.99; H,

12.34. IR (NaCl, ﬁlm, cm^ꢀ1): 2943, 2870, 2830, 1412, 1381, 851,

ﬁlm, cm^ꢀ1): 3473, 2985, 2872, 2100, 1468, 1382, 1023, 735. ½a ²_D⁰

ꢂ

ꢀ10 (0.5; CHCl₃).

5.6.13. (1R,3aR,5S,7aR)-5-Azido-1-((R)-1,5-Dimethylhexyl)-

3a,7a-dimethyloctahydroinden-4-one (24)

To a stirred solution of bromoketone 16 (150 mg, 0.42 mmol) in

DMF (3 mL), sodium azide (33 mg, 0.50 mmol) was added under

nitrogen atmosphere. The solution was stirred at 0 °C for 2 h. Then

a saturated aqueous solution of sodium bicarbonate (20 mL) was

added. The resulting mixture was extracted with ethyl acetate

(3 ꢁ 15 mL) and the combined organic extracts were washed with

water (30 mL), dried over sodium sulphate, and evaporated to dry-

ness under reduced pressure. The residue was subjected to SCC

(petroleum ether/ethyl acetate 98:2) to afford 24 (117 mg, 87%)

as colourless oil. ¹H NMR (CDCl₃, 400 MHz): d 4.11 (dd, 1H, H-5,

J = 6.8 Hz, J = 12.4 Hz), 2.56–2.48 (m, 1H, H-6), 2.12–2.05 (m, 1H,

H-7), 2.03–1.96 (m, 1H, H-3), 1.92–1.73 (m, 3H, H-1⁰, H-2, H-3),

1.53–1.42 (m, 1H, H-5⁰), 1.41–1.20 (m, 6H, H-1, H-2, H-2⁰, H-3⁰,

H-6, H-7), 1.13–1.05 (m, 6H, CH₃-3a, H-3⁰, H-4⁰), 1.00–0.92 (m,

1H, H-2⁰), 0.90 (d, 3H, CH₃-1⁰, J = 6.2 Hz), 0.89–0.84 (m, 3H, CH₃-

5⁰, with underneath s, 3H, CH₃-7a at 0.88 ppm), 0.84 (d, 3H, H-6⁰,

723. ½a ²_D⁰

ꢂ

+31 (0.5; CHCl₃).

5.6.11. (1R,3aR,4S,5S,7aR)-5-Azido-1-((R)-1,5-dimethylhexyl)-

3a,7a-dimethyloctahydroinden-4-ol (22)

In a sealable microwave tube, epoxide 21 (100 mg, 0.36 mmol)

was dissolved in a mixture of DMF (2 mL) and water (0.5 mL). So-

dium azide (233 mg, 3.64 mmol) was added and the tube was

closed under nitrogen atmosphere. The reaction mixture was stir-

red under microwave irradiation (150 W, 4 psi) at 130 °C for 2 h.

After cooling a saturated aqueous solution of sodium bicarbonate

(20 mL) was added and the resulting mixture was extracted with

ethyl acetate (3 ꢁ 20 mL). The combined organic extracts were

1938

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

J = 6.2 Hz). ¹³C NMR (CDCl₃, 125 MHz): d 209.2 (CO), 63.1 (5-CH),

60.9 (3a-C), 49.7 (7a-C), 46.6 (1-CH), 39.4 (6-CH₂), 35.8 (3-CH₂),

35.0 (1⁰-CH), 29.6 (7-CH₂), 29.1 (4⁰-CH₂), 28.0 (2C, 2⁰-CH₂, 5⁰-CH),

25.3 (2-CH₂), 24.2 (3⁰-CH₂), 22.8 (6⁰-CH₃), 22.6 (CH₃-5⁰), 19.5

(CH₃-3a), 18.7 (CH₃-7a), 17.7 (CH₃-1⁰). IR (NaCl, ﬁlm, cm^ꢀ1):

0.84 ppm), 0.75 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

140.6 (1⁰⁰⁰-C), 128.5 (2C, 2⁰⁰⁰-CH, 6⁰⁰⁰-CH), 128.2 (2C, 3⁰⁰⁰-CH, 5⁰⁰⁰-

CH), 127.1 (4⁰⁰⁰-CH), 74.9 (4-CH), 58.8 (5-CH), 51.0 (3a-C), 50.9

(7a-C), 46.9 (1⁰⁰-CH₂), 46.3 (1-CH), 39.6 (6-CH₂), 36.6 (3-CH₂),

36.0 (7-CH₂), 33.0 (1⁰-CH), 31.1 (4-CH₂), 28.1 (2⁰-CH₂), 26.8 (5⁰-

CH), 26.3 (2-CH₂), 24.3 (3⁰-CH₂), 22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 19.0

(CH₃-3a), 18.7 (CH₃-7a), 14.07 (CH₃-1⁰). HRMS Found 385.3380

(Calcd 385.3345). IR (NaCl, ﬁlm, cm^ꢀ1): 3465, 3056, 2970, 2875,

2954, 2870, 2103, 1717, 1467, 1266, 952. ½a _D²⁰

ꢀ13 (0.5; CHCl₃).

ꢂ

5.6.14. (1R,3aR,4R,5S,7aR)-5-Amino-1-((R)-1,5-dimethylhexyl)-

3a,7a-dimethyloctahydroinden-4-ol (25)

1468, 1382, 1023, 750, 689. ½a _D²⁰

ꢀ13 (0.5; CHCl₃).

ꢂ

To a stirred solution of the azidoketone 24 (100 mg, 0.31 mmol)

in anhydrous THF, lithium aluminium hydride (40 mg, 1.04 mmol)

was added at 0 °C under nitrogen atmosphere. The mixture was

stirred at 0 °C for 30 min, then quenched with a saturated aqueous

solution of sodium bicarbonate (3 mL) and diluted with water

(20 mL). The biphasic mixture was extracted with ethyl acetate

(3 ꢁ 20 mL) and the combined organic extracts were washed with

water (30 mL), dried over sodium sulphate and evaporated to dry-

ness under reduced pressure. The crude product was subjected to

SCC (dichloromethane/methanol/triethylamine 9:1:0.2) to afford

amino alcohol 25 (91 mg, 99%) as a white resin. Mp 117 °C. ¹H

NMR (CDCl₃, 400 MHz): d 3.21 (d, 1H, H-4, J = 2.7 Hz), 2.90 (ddd,

1H, H-5, J = 2.7 Hz, J = 4.2 Hz, J = 12.1 Hz), 2.49 (bs, 2H, NH₂),

2.27–2.18 (m, 1H, H-1⁰), 1.90–1.81 (m, 1H, H-6), 1.80–1.69 (m,

2H, H-3, H-7), 1.68–1.56 (m, 1H, H-2), 1.49–1.34 (m, 2H, H-5⁰, H-

6), 1.32–1.17 (m, 6H, H-1, H-2, H-2⁰, H-3, H-3⁰, H-7), 1.11–0.98

(m, 3H, H-3⁰, H-4⁰), 0.97–0.89 (m, 1H, H-2⁰), 0.85 (d, 3H, CH₃-1⁰,

J = 6.6 Hz), 0.80 (d, 3H, CH₃-5⁰, J = 6.4 Hz), 0.79–0.71 (m, 3H, H-6⁰,

with underneath s, 3H, CH₃-3a at 0.75 ppm), 0.66 (s, 3H, CH₃-7a).

¹³C NMR (CDCl₃, 125 MHz): d 79.3 (4-CH), 50.4 (5-CH), 49.2 (3a-

C), 47.3 (1-CH), 44.7 (7a-C), 39.6 (6-CH₂), 36.5 (3-CH₂), 35.7 (1⁰-

CH), 34.8 (7-CH₂), 31.6 (4⁰-CH₂), 29.2 (2⁰-CH₂), 28.0 (5⁰-CH), 24.7

(2-CH₂), 24.4 (3⁰-CH₂), 22.9 (6⁰-CH₃), 22.7 (CH₃-5⁰), 21.5 (CH₃-3a),

20.0 (CH₃-7a), 19.2 (CH₃-1⁰). HRMS Found 295.2875 (Calcd

295.2875). IR (NaCl, ﬁlm, cm^ꢀ1): 3473, 2985, 2872, 2100, 1468,

5.6.15.2.

iodofuran-2-ylmethyl)-amino]-3a,7a-dimethyloctahydroinden-

4-ol (26b). Amino alcohol 23 (100 mg, 0.34 mmol) and 5-

(1R,3aR,4S,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-[(5-

iodo-2-furaldehyde (80.0 mg, 0.35 mmol) in methanol (3 mL) were

treated as described in procedure C. The crude product was sub-

jected to SCC (petroleum ether/ethyl acetate/triethylamine

8:2:0.2) to afford 26b (146 mg, 86%) as a white solid. Mp 162 °C.

¹H NMR (CDCl₃, 400 MHz): d 6.45 (d, 1H, H-4⁰⁰⁰, J = 3.2 Hz), 6.11

(d, 1H, H-3⁰⁰⁰, J = 3.2 Hz), 3.91 (d, 1H, H-1⁰⁰, J = 14.4 Hz), 3.72 (d,

1H, H-1⁰⁰, J = 14.4 Hz), 3.29 (d, 1H, H-4, J = 10.3 Hz), 2.41 (ddd, 1H,

H-5, J = 3.7 Hz, J = 7.2 Hz, J = 10.8 Hz), 1.97–1.72 (m, 5H, H-1⁰, H-

2, H-3, H-6, H-7), 1.61–1.45 (m, 1H, H-5⁰), 1.42–1.24 (m, 7H, H-1,

H-2, H-2⁰, H-3, H-3⁰, H-6, H-7), 1.17–1.06 (m, 3H, H-3⁰, H-4⁰),

1.02–0.96 (m, 1H, H-2⁰), 0.91 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.87 (d,

3H, CH₃-1⁰, J = 5.8 Hz), 0.86–0.83 (m, 3H, H-6⁰, with underneath s,

3H, CH₃-3a at 0.83 ppm), 0.75 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃,

125 MHz): d 160.1 (5⁰⁰⁰-C), 120.9 (4⁰⁰⁰-CH), 109.8 (3⁰⁰⁰-CH), 86.2

(2⁰⁰⁰-C), 75.0 (4-CH), 58.7 (5-CH), 51.0 (3a-C), 46.9 (1-CH), 46.2

(7a-C), 43.9 (1⁰⁰-CH₂), 39.6 (6-CH₂), 36.6 (3-CH₂), 36.0 (1⁰-CH),

32.9 (7-CH₂), 31.0 (4⁰-CH₂), 28.1 (5⁰-CH), 26.8 (2⁰-CH₂), 26.3 (2-

CH₂), 24.3 (3⁰-CH₂), 23.0 (6⁰-CH₃), 22.7 (CH₃-5⁰), 19.0 (CH₃-3a),

18.8 (CH₃-7a), 14.1 (CH₃-1⁰). HRMS Found 501.2151 (Calcd

501.2104). IR (NaCl, ﬁlm, cm^ꢀ1): 3412, 3012, 2973, 1478, 1313,

1201, 1058, 839, 793. ½a _D²⁰

ꢀ29 (0.5; CHCl₃).

ꢂ

1382, 1023, 735. ½a _D²⁰

ꢂ

+13 (0.5; CHCl₃).

5.6.15.3.

dimethylhexyl)-7a-methyloctahydroinden-4-ol

(26c). Amino alcohol 23 (100 mg, 0.34 mmol) and 3-chloro-

benzaldehyde (50 L, 0.35 mmol) in methanol (3 mL) were treated

(1R,4S,5S,7aR)-5-(3-Chlorobenzylamino)-1-((R)-1,5-

5.6.15. General procedure C (reductive alkylation of amino

alcohols)

To a stirred solution of the respective amino alcohol 23 or 25

(0.30–0.40 mmol) and the required aldehyde (1.05–2.00 equiv) in

methanol, acetic acid (1.10 equiv) and sodium cyanoborohydride

(3 equiv) were added at room temperature under nitrogen atmo-

sphere. The reaction mixture was stirred at 40 °C for 12 h, then

quenched with a saturated aqueous solution of sodium bicarbon-

ate (3 mL) and diluted with water (10 mL). The mixture was ex-

tracted with ethyl acetate (3 ꢁ 15 mL) and the combined organic

extracts were washed with water (30 mL), dried over sodium sul-

phate, and evaporated to dryness under reduced pressure. The

crude product was subjected to SCC as speciﬁed below to afford

compounds 26a–g, 27a–g, 28a–c, 29a–c and 30.

as described in procedure C. The crude product was subjected to

SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.2) to afford

26c (113 mg, 79%) as colourless oil. ¹H NMR (CDCl₃, 400 MHz): d

7.33 (s, 1H, H-2⁰⁰⁰), 7.25–7.18 (m, 3H, H-4⁰⁰⁰, H-5⁰⁰⁰, H-6⁰⁰⁰), 3.92 (d,

1H, H-1⁰⁰, J = 13.1 Hz), 3.65 (d, 1H, H-1⁰⁰, J = 13.1 Hz), 3.31 (d, 1H,

H-4, J = 10.3 Hz), 2.99 (s, 1H, NH), 2.44 (ddd, 1H, H-5, J = 5.2 Hz,

J = 7.2 Hz, J = 10.3 Hz), 2.02–1.73 (m, 5H, H-1⁰, H-2, H-3, H-6, H-

7), 1.60–1.44 (m, 1H, H-5⁰), 1.44–1.24 (m, 7H, H-1, H-2, H-2⁰, H-3,

H-3⁰, H-6, H-7), 1.19–1.04 (m, 3H, H-3⁰, H-4⁰), 1.01–0.96 (m, 1H,

H-2⁰), 0.92 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.87 (d, 3H, CH₃-1⁰,

J = 6.6 Hz), 0.87–0.82 (m, 3H, H-6⁰, with underneath s, 3H, CH₃-3a

at 0.83 ppm), 0.76 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

142.8 (1⁰⁰⁰-C), 134.4 (3⁰⁰⁰-C), 128.3 (2⁰⁰⁰-CH), 129.8, 127.3, 126.3

(3C, 4⁰⁰⁰-CH, 5⁰⁰⁰-CH, 6⁰⁰⁰-CH), 74.9 (4-CH), 58.9 (5-CH), 50.9 (1⁰⁰-

CH₂), 50.6 (3a-C), 46.9 (7a-C), 46.3 (1-CH), 39.6 (6-CH₂), 36.6 (3-

CH₂), 36.0 (1⁰-CH), 33.0 (7-CH₂), 31.1 (4⁰-CH₂), 28.1 (5⁰-CH), 26.8

(2⁰-CH₂), 26.4 (2-CH₂), 24.3 (3⁰-CH₂), 23.0 (6⁰-CH₃), 22.7 (CH₃-5⁰),

19.0 (CH₃-3a), 18.7 (CH₃-7a), 14.1 (CH₃-1⁰). HRMS Found

419.2947 (Calcd 419.2955). IR (NaCl, ﬁlm, cm^ꢀ1): 3493, 3011,

5.6.15.1.

(1R,3aR,4S,5S,7aR)-5-Benzylamino-1-((R)-1,5-di-

methylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(26a).

hyde (39.0

Amino alcohol 23 (100 mg, 0.34 mmol) and benzalde-

lL, 0.35 mmol) in methanol (3 mL) were treated as de-

scribed in procedure C. The crude product was subjected to SCC

(petroleum ether/ethyl acetate/triethylamine 9:1:0.2) to afford

26a (76 mg, 58%) as a white solid. Mp 145 °C. ¹H NMR (CDCl₃,

400 MHz): d 7.34–7.29 (m, 4H, H-2⁰⁰⁰, H-3⁰⁰⁰, H- 5⁰⁰⁰, H-6⁰⁰⁰), 7.24

(dd, 1H, H-4⁰⁰⁰, J = 2.9 Hz, J = 5.9 Hz), 3.94 (d, 1H, H-1⁰⁰, J = 12.8 Hz),

3.67 (d, 1H, H-1⁰⁰, J = 12.8 Hz), 3.30 (d, 1H, H-4, J = 10.4 Hz), 2.48–

2.42 (m, 1H, H-5), 2.07–1.73 (m, 5H, H-1⁰, H-2, H-3, H-6, H-7),

1.55–1.46 (m, 1H, H-5⁰), 1.40–1.27 (m, 7H, H-1, H-2, H-2⁰, H-3, H-

3⁰, H-6, H-7), 1.16–1.06 (m, 3H, H-3⁰, H-4), 1.02–0.95 (m, 1H, H-

2⁰), 0.92 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.86 (d, 3H, CH₃-5⁰, J = 6.4 Hz),

0.88–0.81 (m, 3H, 6⁰-C, with underneath s, 3H, CH₃-3a at

2996, 2891, 1499, 1312, 1031, 852, 778. ½a _D²⁰

ꢀ11 (0.5; CHCl₃).

ꢂ

5.6.15.4.

[(furan-3-ylmethyl)-amino]-3a,7a-dimethyl-octahydroinden-4-

ol (26d). Amino alcohol 23 (100 mg, 0.34 mmol) and furan-3-

carboxaldehyde (29 L, 0.35 mmol) in methanol (3 mL) were trea-

(1R,3aR,4S,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-

ted as described in procedure C. The crude product was subjected

to SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.2) to

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1939

afford 26d (86 mg, 67%) as colourless oil. ¹H NMR (CDCl₃,

400 MHz): d 7.36 (d, 2H, H-4⁰⁰⁰, H-5⁰⁰⁰, J = 8.7 Hz), 6.39 (s, 1H, H-

2⁰⁰⁰), 3.82 (d, 1H, H-1⁰⁰, J = 13.3 Hz), 3.54 (d, 1H, H-1⁰⁰, J = 13.3 Hz),

3.30 (d, 1H, H-4, J = 10.4 Hz), 2.43 (ddd, 1H, H-5, J = 4.3 Hz,

J = 7.2 Hz, J = 10.5 Hz), 2.04–1.77 (m, 5H, H-1⁰, H-2, H-3, H-6, H-

7), 1.61–1.46 (m, 1H, H-5⁰), 1.40–1.26 (m, 7H, H-1, H-2, H-2⁰, H-3,

H-3⁰, H-6, H-7), 1.11 (s, 3H, H-3⁰, H-4⁰), 1.03–0.94 (m, 1H, H-2⁰),

0.92 (d, 3H, CH₃-1⁰, J = 6.2 Hz), 0.87 (d, 3H, CH₃-5⁰, J = 6.2 Hz),

0.86–0.81 (m, 3H, H-6⁰, with underneath s, 3H, CH₃-3a at

0.83 ppm), 0.76 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

143.2 (2⁰⁰⁰-CH), 139.7 (5⁰⁰⁰-CH), 124.1 (3⁰⁰⁰-C), 110.4 (4⁰⁰⁰-CH), 74.7

(4-CH), 58.5 (5-CH), 50.8 (1⁰⁰-CH₂), 46.8 (3a-C), 46.2 (7a-C), 41.4

(1-CH), 39.5 (6-CH₂), 36.5 (3-CH₂), 35.9 (7-CH₂), 32.9 (1⁰-CH),

31.0 (4⁰-CH₂), 28.0 (2⁰-CH₂), 26.7 (5⁰-CH), 26.0 (2-CH₂), 24.2 (3⁰-

CH₂), 22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 18.9 (CH₃-3a), 18.6 (CH₃-7a),

13.9 (CH₃-1⁰). HRMS Found 375.3125 (Calcd 375.3137). IR (NaCl,

19.1 (CH₃-1⁰). HRMS Found 453.2591 (Calcd 453.2565). IR (NaCl,

ﬁlm, cm^ꢀ1): 3446, 3009, 2991, 2792, 1488, 1291, 1093, 1002, 856,

801. ½a ²_D⁰

ꢂ

ꢀ26 (0.5; CHCl₃).

5.6.15.7.

(1R,3aR,4S,5S,7aR)-5-(2,3-Dichlorobenzylamino)-1-

((R)-1,5-dimethylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(26g). Amino alcohol 23 (100 mg, 0.34 mmol) and 2,3-dichlo-

robenzaldehyde (62 mg, 0.35 mmol) in methanol (3 mL) were trea-

ted as described in procedure C. The crude product was subjected to

SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.2) to afford

26g (132 mg, 85%) as colourless oil. ¹H NMR (CDCl₃, 400 MHz): d

7.36 (d, 1H, H-4⁰⁰⁰, J = 8.0 Hz), 7.32 (d, 1H, H-6⁰⁰⁰, J = 7.7 Hz), 7.17 (t,

1H, H-5⁰⁰⁰, J = 7.8 Hz), 4.04 (d, 1H, H-1⁰⁰, J = 13.8 Hz), 3.79 (d, 1H, H-

1⁰⁰, J = 13.8 Hz), 3.30 (d, 1H, H-4, J = 10.3 Hz), 2.99–2.91 (m, 1H, H-

5), 2.47–2.39 (m, 1H, NH), 2.02–1.74 (m, 5H, H-1⁰, H-2, H-3, H-6,

H-7), 1.58–1.43 (m, 1H, H-5⁰), 1.43–1.23 (m, 6H, H-1, H-2, H-2⁰, H-

3⁰, H-6, H-7), 1.16–1.07 (m, 3H, H-3⁰, H-4⁰), 1.00–0.95 (m, 1H, H-

2⁰), 0.91 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.86 (d, 3H, CH₃-5⁰, J = 6.2 Hz),

0.86–0.83 (m, 3H, H-6⁰, with underneath s, 3H, CH₃-3a at

0.83 ppm), 0.75 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

140.6 (1⁰⁰⁰-C), 133.3 (2⁰⁰⁰-C), 132.0 (3⁰⁰⁰-C), 129.2 (5⁰⁰⁰-CH), 128.0 (4⁰⁰⁰-

CH), 127.4 (6⁰⁰⁰-CH), 75.0 (4-CH), 59.1 (5-CH), 50.9 (3a-C), 49.5 (1⁰⁰-

CH₂), 46.9 (7a-C), 46.4 (1-CH), 39.6 (6-CH₂), 36.6 (3-CH₂), 36.0 (1⁰-

CH), 33.0 (7-CH₂), 31.1 (4⁰-CH₂), 28.1 (5⁰-CH), 26.8 (2⁰-CH₂), 26.5

(2-CH₂), 24.3 (3⁰-CH₂), 23.0 (6⁰-CH₃), 22.7 (CH₃-5⁰), 19.0 (CH₃-3a),

18.7 (CH₃-7a), 14.1 (CH₃-1⁰). HRMS Found 453.2583 (Calcd

453.2565). IR (NaCl, ﬁlm, cm^ꢀ1): 3442, 3032, 2995, 2912, 1500,

ﬁlm, cm^ꢀ1): 3501, 3066, 2981, 2870, 1472, 1378, 750, 689. ½a ²_D⁰

ꢂ

ꢀ18 (0.5; CHCl₃).

5.6.15.5.

(1R,3aR,4S,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

dimethyl-5-(pent-4-enylamino)-octahydro-inden-4-ol

(26e).

enal (36.0

Amino alcohol 23 (100 mg, 0.34 mmol) and pent-4-

lL, 0.35 mmol) in methanol (3 mL) were treated as de-

scribed in procedure C. The crude product was subjected to SCC

(petroleum ether/ethyl acetate/triethylamine 9:1:0.1) to afford

26e (69 mg, 56%) as colourless oil. ¹H NMR (CDCl₃, 400 MHz): d

5.80 (ddt, 1H, H-4⁰⁰, J = 6.7 Hz, J = 10.1 Hz, J = 16.9 Hz), 5.01 (dd,

1H, H-5⁰⁰, J = 1.8 Hz, J = 17.1 Hz), 4.95 (dd, 1H, H-5⁰⁰, J = 1.8 Hz,

J = 17.1 Hz), 3.23 (d, 1H, H-4, J = 10.4 Hz), 2.79 (dt, 1H, H-1⁰⁰,

J = 7.1 Hz, J = 9.3 Hz), 2.44 (dt, 1H, H-1⁰⁰, J = 7.1 Hz, J = 9.3 Hz), 2.32

(ddd, 1H, H-5, J = 4.5 Hz, J = 7.4 Hz, J = 10.7 Hz), 2.13–2.04 (m, 2H,

H-3⁰⁰), 1.98–1.73 (m, 5H, H-1⁰, H-2, H-3, H-6, H-7), 1.62–1.44 (m,

3H, H-2⁰⁰, H-5⁰), 1.37–1.21 (m, 7H, H-1, H-2, H-2⁰, H-3, H-3⁰, H-6,

H-7), 1.16–1.04 (m, 3H, H-3⁰, H-4⁰), 1.02–0.95 (m, 1H, H-2⁰), 0.90

(d, 3H, CH₃-1⁰, J = 5.4 Hz), 0.86 (d, 3H, CH₃-5⁰, J = 6.0 Hz), 0.85 (s,

3H, CH₃-3a), 0.84 (d, 3H, H-6⁰, J = 6.0 Hz), 0.74 (s, 3H, CH₃-7a).

¹³C NMR (CDCl₃, 125 MHz): d 138.5 (4⁰⁰-CH), 114.7 (5⁰⁰-CH₂), 74.7

(4-CH), 59.1 (5-CH), 50.7 (3a-C), 46.8 (7a-C), 46.2 (2C, 1-CH, 1⁰⁰-

CH₂), 39.5 (6-CH₂), 36.5 (3-CH₂), 35.9 (7-CH₂), 32.9 (3⁰⁰-CH₂), 31.6

(1⁰-CH₂), 31.1 (2⁰⁰-CH₂), 29.8 (4⁰-CH₂), 28.0 (2⁰-CH₂), 26.7 (5⁰-CH),

26.2 (2-CH₂), 24.2 (3⁰-CH₂), 22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 18.9

(CH₃-3a), 18.7 (CH₃-7a), 14.0 (CH₃-1⁰). HRMS Found 363.3493

(Calcd 363.3501). IR (NaCl, ﬁlm, cm^ꢀ1): 3448, 3038, 2980, 2870,

1311, 1023, 792. ½a _D²⁰

ꢀ29 (0.5; CHCl₃).

ꢂ

5.6.15.8.

methylhexyl)-3a,7a-dimethyoctahydroinden-4-ol (27a). Amino

alcohol 25 (100 mg, 0.34 mmol) and benzaldehyde (21 L,

(1R,3aR,4R,5S,7aR)-5-Benzylamino-1-((R)-1,5-di-

0.36 mmol) in methanol (3 mL) were treated as described in proce-

dure C. The crude product was subjected to SCC (petroleum ether/

ethyl acetate/triethylamine 9:1:0.1) to afford 27a (111 mg, 85%) as

a white solid. Mp 148 °C. ¹H NMR (CDCl₃, 400 MHz): d 7.46–7.13

(m, 5H, H-2⁰⁰⁰, H-3⁰⁰⁰, H-4⁰⁰⁰, H-5⁰⁰⁰, H-6⁰⁰⁰), 3.81 (d, 1H, 1⁰⁰-H,

J = 12.9 Hz), 3.67 (d, J = 12.9 Hz, 1H, 1⁰⁰-H), 3.46 (d, J = 2.3 Hz, 1H,

H-4), 2.82–2.62 (m, 1H, H-5), 2.39–2.31 (m, 1H, H-1⁰), 2.02–1.77

(m, 3H, H-3, H-6, H-7), 1.76–1.61 (m, 1H, H-2), 1.56–1.40 (m, 2H,

H-3, H-5⁰), 1.37–1.20 (m, 6H, H-1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.17–

1.07 (m, 3H, H-3⁰, H-4⁰), 1.05–0.96 (m, 1H, H-2⁰), 0.91 (d, 3H, CH₃-

1⁰, J = 6.5 Hz), 0.84 (s, 3H, CH₃-3a), 0.83 (d, 3H, CH₃-5⁰, J = 5.8 Hz),

0.82 (d, 3H, H-6⁰, J = 5.8 Hz), 0.72 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃,

125 MHz): d 140.3 (1⁰⁰⁰-C), 128.5 (2⁰⁰⁰-CH, 6⁰⁰⁰-CH), 128.2 (3⁰⁰⁰-CH, 5⁰⁰-

CH), 127.1 (4⁰⁰⁰-CH), 75.6 (4-CH), 56.7 (5-CH), 50.6 (1⁰⁰-CH₂), 48.4

(3a-C), 47.2 (1-CH), 45.0 (7a-CH), 39.6 (7-CH₂), 36.5 (3-CH₂), 35.6

(1⁰-CH), 34.9 (7-CH₂), 31.4 (4⁰-CH₂), 29.2 (2⁰-CH₂), 28.0 (5⁰-CH),

24.2 (2-CH₂), 23.2 (3⁰-CH₂), 22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 21.3 (CH₃-

3a), 20.0 (CH₃-7a), 19.10 (CH₃-1⁰). HRMS Found 385.3333 (Calcd

385.3345). IR (NaCl, ﬁlm, cm^ꢀ1): 3467, 3026, 2997, 2853, 1452,

1452, 1353, 841, 750, 689. ½a _D²⁰

ꢀ9 (0.5; CHCl₃).

ꢂ

5.6.15.6.

((R)-1,5-dimethylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(26f). Amino alcohol 23 (100 mg, 0.34 mmol) and 2,4-dichlo-

(1R,3aR,4S,5S,7aR)-5-(2,4-Dichlorobenzylamino)-1-

robenzaldehyde (62.0 mg, 0.35 mmol) in methanol (3 mL) were

treated as described in procedure C. The crude product was sub-

jected to SCC (petroleum ether/ethyl acetate/triethylamine

9:1:0.2) to afford 26f (112 mg, 73%) as colourless oil. ¹H NMR (CDCl₃,

400 MHz): d 7.37 (s, 1H, H-3⁰⁰⁰), 7.27 (d, 1H, H-6⁰⁰⁰, J = 8.2 Hz), 7.20 (d,

1H, H-5⁰⁰⁰, J = 8.2 Hz), 3.83 (d, 1H, H-1⁰⁰, J = 13.8 Hz), 3.77 (d, 1H, H-1⁰⁰,

J = 13.8 Hz), 3.46 (d, 1H, H-4, J = 10.6 Hz), 2.80–2.52 (m, 1H, H-5),

2.30–2.21 (m, 1H, H-1⁰), 2.00–1.76 (m, 3H, H-3, H-6, H-7), 1.77–

1.60 (m, 1H, H-2), 1.57–1.40 (m, 2H, H-3, H-5⁰), 1.37–1.19 (m, 6H,

H-1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.17–1.03 (m, 3H, H-3⁰, H-4⁰), 1.02–

0.95 (m, 1H, H-2⁰), 0.90 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.85 (d, CH₃-1⁰,

J = 6.4 Hz, 3H), 0.84 (d, 3H, H-6⁰, J = 6.4 Hz), 0.83 (s, CH₃-3a), 0.71

1298, 1023, 750, 689. ½a _D²⁰

ꢂ

+28 (0.5; CHCl₃).

5.6.15.9.

iodofuran-2-ylmethyl)-amino]-3a,7a-dimethyloctahydroinden-

4-ol (27b). Amino alcohol 25 (90 mg, 0.31 mmol) and 5-iodo-

(1R,3aR,4R,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-[(5-

2-furaldehyde (74 mg, 0.34 mmol) in methanol (3 mL) were trea-

ted as described in procedure C. The crude product was subjected

to SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.2) to af-

ford 27b (115 mg, 75%) as a light yellow oil. ¹H NMR (CDCl₃,

400 MHz): d 6.44 (d, 1H, H-4⁰⁰⁰, J = 3.1 Hz), 6.08 (d, 1H, H-3⁰⁰⁰,

J = 3.1 Hz), 3.78 (d, J = 14.8 Hz, 1H, H-1⁰⁰), 3.71 (d, J = 14.8 Hz, 1H,

H-1⁰⁰), 3.38 (d, 1H, H-4, J = 2.2 Hz), 2.69–2.62 (m, 1H, H-5), 2.35–

2.27 (m, 1H, H-1⁰), 2.00–1.88 (m, 1H, H-6), 1.87–1.74 (m, 2H, H-

3, H-7), 1.72–1.46 (m, 3H, H-2, H-3, H-5⁰), 1.37–1.21 (m, 6H,

H-1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.18–1.05 (m, 3H, H-3⁰, H-4⁰),

(s, 3H, CH₃-7a). C NMR (CDCl₃, 125 MHz): d 136.1 (1⁰⁰⁰-C), 134.5

(2⁰⁰⁰-C), 133.6 (4⁰⁰⁰-C), 131.1 (6⁰⁰⁰-CH), 129.5 (3⁰⁰⁰-CH), 127.2 (5⁰⁰⁰-CH),

75.6 (4-CH), 56.4 (5-CH), 48.5 (3a-C), 47.4 (1⁰⁰-CH₂), 47.2 (1-CH),

45.0 (7a-C), 39.6 (6-CH₂), 36.5 (3-CH₂), 35.6 (1⁰-CH), 34.8 (7-CH₂),

31.4 (4⁰-CH₂), 29.2 (2⁰-CH₂), 28.0 (5⁰-CH), 24.2 (2-CH₂), 23.2 (3⁰-

CH₂), 22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 21.3 (CH₃-3a), 20.0 (CH₃-7a),

1940

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1.04–0.95 (m, 1H, H-2⁰), 0.90 (d, 3H, CH₃-1⁰, J = 6.5 Hz), 0.87 (d, 3H,

CH₃-5⁰, J = 6.0 Hz), 0.84 (d, 3H, H-6⁰, J = 6.0 Hz), 0.83 (s, 3H, CH₃-

in procedure C. The crude product was subjected to SCC (petroleum

ether/ethyl acetate/triethylamine 9:1:0.2) to afford 27e (97 mg,

79%) as a colourless oil. ¹H NMR (CDCl₃, 400 MHz): d 5.79 (ddt, 1H,

H-4⁰⁰, J = 6.7 Hz, J = 10.2 Hz, J = 16.9 Hz), 5.05–4.92 (m, 2H, H-5⁰⁰),

3.35 (d, 1H, H-4, J = 2.4 Hz), 2.65–2.57 (m, 3H, H-5, H-1⁰⁰), 2.37–

2.28 (m, 1H, H-1⁰), 2.15–2.02 (m, 2H, H-3⁰⁰), 1.98–1.90 (m, 1H, H-

6), 1.88–1.76 (m, 2H, H-3, H-7), 1.70–1.39 (m, 5H, H-2, H-2⁰⁰, H-3,

H-5⁰), 1.37–1.22 (m, 6H, H-1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.15–1.04

(m, 3H, H-3⁰, H-4⁰), 1.03–0.96 (m, 1H, H-2⁰), 0.90 (d, 3H, CH₃-1⁰,

J = 6.6 Hz), 0.82 (s, 3H, CH₃-3a), 0.81 (d, 3H, CH₃-5⁰, J = 6.2 Hz), 0.79

(d, 3H, H-6⁰, J = 6.2 Hz), 0.71 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃,

125 MHz): d 138.4 (4⁰⁰-CH), 114.8 (5⁰⁰-CH₂), 75.8 (4-CH), 57.2 (5-

CH), 48.3 (3a-C), 47.2 (1-CH), 45.9 (1⁰⁰-CH₂), 45.0 (7a-C), 39.6 (6-

CH₂), 36.5 (3-CH₂), 35.6 (1⁰-CH), 34.8 (7-CH₂), 31.5 (3⁰⁰-CH₂), 31.4

(2⁰⁰-CH₂), 29.7 (4⁰-CH₂), 29.2 (2⁰-CH₂), 28.0 (5⁰-CH), 24.3 (2-CH₂),

23.2 (3⁰-CH₂), 22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 21.3 (CH₃-3a), 20.0

(CH₃-7a), 19.0 (CH₃-1⁰). HRMS Found 363.3489 (Calcd 363.3501).

3a), 0.71 (s, 3H, CH₃-7a). C NMR (CDCl₃, 125 MHz): d 159.3 (5⁰⁰⁰-

C), 120.7 (4⁰⁰⁰-CH), 110.1 (3⁰⁰⁰-CH), 86.3 (2⁰⁰⁰-C), 75.4 (4-CH), 55.6 (5-

CH), 48.4 (3a-C), 47.1 (1-CH), 44.9 (7a-C), 42.4 (1⁰-CH₂), 39.5 (7-

CH₂), 36.4 (6-CH₂), 35.5 (1⁰-CH), 34.7 (3-CH₂), 31.3 (4⁰-CH₂), 29.1

(2⁰-CH₂), 27.9 (5⁰-CH), 24.1 (2-CH₂), 22.8 (2C, 3⁰-CH₂, 6⁰-CH₃), 22.5

(CH₃-5⁰), 21.2 (CH₃-3a), 19.8 (CH₃-7a), 19.0 (CH₃-1⁰). HRMS Found

501.2151 (Calcd 501.2104). IR (NaCl, ﬁlm, cm^ꢀ1): 3400, 3008,

2996, 1532, 1413, 1121, 1013, 839, 801, 793. ½a _D²⁰

ꢂ

+23 (0.5; CHCl₃).

5.6.15.10. (1R,3aR,4R,5S,7aR)-5-(3-Chlorobenzylamino)-1-((R)-

1,5-di-methylhexyl)-7a-methyloctahydroinden-4-ol

(27c).

benzaldehyde (50

Amino alcohol 25 (100 mg, 0.34 mmol) and 3-chloro-

L, 0.35 mmol) in methanol (3 mL) were treated

as described in procedure C. The crude product was subjected to

SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.2) to afford

27c (113 mg, 79%) as a colourless oil. ¹H NMR (CDCl₃, 400 MHz): d

7.33 (s, 1H, H-2⁰⁰⁰), 7.25–7.18 (m, 3H, H-4⁰⁰⁰, H-5⁰⁰⁰, H-6⁰⁰⁰), 3.92 (d, 1H,

H-1⁰⁰, J = 13.1 Hz), 3.65 (d, 1H, H-1⁰⁰, J = 13.1 Hz), 3.31 (d, 1H, H-4,

J = 2.3 Hz), 2.99 (s, 1H, NH), 2.44 (ddd, 1H, H-5, J = 5.2 Hz,

J = 7.2 Hz, J = 10.3 Hz), 2.02–1.73 (m, 5H, H-1⁰, H-2, H-3, H-6, H-

7), 1.60–1.44 (m, 1H, H-5⁰), 1.44–1.24 (m, 7H, H-1, H-2, H-2⁰, H-3,

H-3⁰, H-6, H-7), 1.19–1.04 (m, 3H, H-3⁰, H-4⁰), 1.01–0.96 (m, 1H,

H-2⁰), 0.92 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.87 (d, 3H, CH₃-5⁰,

J = 6.6 Hz), 0.87–0.82 (m, 3H,H-6⁰, with underneath s, 3H, CH₃-3a

at 0.83 ppm), 0.76 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

142.8 (1⁰⁰⁰-C), 134.4 (3⁰⁰⁰-CH), 128.3 (2⁰⁰⁰-CH), 129.8, 127.3, 126.3

(3C, 4⁰⁰⁰-C, 5⁰⁰⁰-CH, 6⁰⁰⁰-CH), 74.9 (4-CH), 58.9 (5-CH), 50.9 (1⁰⁰-CH₂),

50.6 (3a-C), 46.9 (7a-C), 46.3 (1-CH), 39.6 (6-CH₂), 36.6 (3-CH₂),

36.0 (1⁰-CH), 33.0 (7-CH₂), 31.1 (4⁰-CH₂), 28.1 (5⁰-CH), 26.8 (2⁰-

CH₂), 26.4 (2-CH₂), 24.3 (3⁰-CH₂), 23.0 (6⁰-CH₃), 22.7 (CH₃-5⁰),

19.0 (CH₃-3a), 18.7 (CH₃-7a), 14.1 (CH₃-1⁰). HRMS Found

419.2947 (Calcd 419.2955). IR (NaCl, ﬁlm, cm^ꢀ1): 3493, 3011,

IR (NaCl, ﬁlm, cm^ꢀ1): 3399, 2995, 2867, 1511, 1291, 841, 753. ½a ²_D⁰

ꢂ

+11 (0.5; CHCl₃).

5.6.15.13. (1R,3aR,4R,5S,7aR)-5-(2,4-Dichlorobenzylamino)-1-

((R)-1,5-dimethylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(27f).

Amino alcohol 25 (90 mg, 0.31 mmol) and 2,4-dichloro-

benzaldehyde (56.0 mg, 0.32 mmol) in methanol (3 mL) were trea-

ted as described in procedure C. The crude product was subjected

to SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.2) to af-

ford 27f (123 mg, 89%) as a colourless oil. ¹H NMR (CDCl₃,

400 MHz): d 7.37 (s, 1H, H-3⁰⁰⁰), 7.27 (d, 1H, H-5⁰⁰⁰, J = 10.0 Hz),

7.20 (d, 1H, H-6⁰⁰⁰, J = 10.0 Hz), 3.83 (d, 1H, H-1⁰⁰, J = 13.8 Hz), 3.77

(d, 1H, H-1⁰⁰, J = 13.8 Hz), 3.46 (d, 1H, H-4, J = 2.5 Hz), 2.71–2.60

(m, 1H, H-5), 2.35–2.24 (m, 1H, H-1⁰), 2.01–1.77 (m, 3H, H-3, H-

6, H-7), 1.73–1.66 (m, 1H, H-2), 1.53–1.40 (m, 2H, H-3, H-5⁰),

1.36–1.20 (m, 6H, H-1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.15–0.98 (m,

3H, H-3⁰, H-4⁰), 1.04–0.93 (m, 1H, H-2⁰), 0.90 (d, 3H, CH₃-1⁰,

J = 6.6 Hz), 0.85 (d, 3H, CH₃-5⁰, J = 6.4 Hz), 0.84 (d, 3H, H-6⁰,

J = 6.4 Hz), 0.83 (s, 3H, CH₃-3a), 0.71 (s, 3H, CH₃-7a). ¹³C NMR

(CDCl₃, 125 MHz): d 136.1 (1⁰⁰⁰-C), 134.4 (2⁰⁰⁰-C), 133.4 (4⁰⁰⁰-C),

131.0 (5⁰⁰⁰-CH), 129.4 (3⁰⁰⁰-CH), 127.1 (6⁰⁰⁰-CH), 75.5 (4-CH), 56.3

(5-CH), 48.4 (3a-C), 47.4 (1⁰⁰-CH₂), 47.1 (1-CH), 44.9 (7-CH₂), 39.5

(6-CH₂), 36.4 (3-CH₂), 35.5 (1⁰-CH), 34.8 (7-CH₂), 31.3 (4⁰-CH₂),

29.1 (2⁰-CH₂), 27.9 (5⁰-CH), 24.2 (2-CH₂), 23.1 (3⁰-CH₂), 22.8 (6⁰-

CH₃), 22.5 (CH₃-5⁰), 21.2 (CH₃-3a), 19.9 (CH₃-7a), 19.0 (CH₃-1⁰).

HRMS Found 453.2596 (Calcd 453.2565). IR (NaCl, ﬁlm, cm^ꢀ1):

3431, 3012, 3007, 2996, 2890, 1432, 1311, 1121, 1093, 854, 820.

2996, 2891, 1499, 1312, 1031, 852, 778. ½a _D²⁰

ꢂ

+27 (0.5; CHCl₃).

5.6.15.11.

[(furan-3-ylmethyl)-amino]-3a,7a-dimethyloctahydroinden-4-

ol (27d). Amino alcohol 25 (100 mg, 0.34 mmol) and furan-3-

carboxaldehyde (29 L, 0.35 mmol) in methanol (3 mL) were trea-

(1R,3aR,4R,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-

ted as described in procedure C. The crude product was subjected

to SCC (petroleum ether/ethyl acetate/triethylamine 7:3:0.2) to af-

ford 27d (107 mg, 84%) as a colourless oil. ¹H NMR (CDCl₃,

400 MHz): d 7.37 (s, 1H, H-2⁰⁰⁰), 7.32 (d, 1H, H-5⁰⁰⁰, J = 4.2 Hz), 6.35

(d, 1H, H-4⁰⁰⁰, J = 4.2 Hz), 3.63 (d, 1H, H-1⁰⁰, J = 13.5 Hz), 3.57 (d,

1H, H-1⁰⁰, J = 13.5 Hz), 3.41 (d, 1H, H-4, J = 2.4 Hz), 2.70 (ddd, 1H,

H-5, J = 2.4 Hz, J = 7.6 Hz, J = 11.7 Hz), 2.37–2.30 (m, 1H, H-1⁰),

2.00–1.89 (m, 1H, H-6), 1.89–1.77 (m, 2H, H-3, H-7), 1.75–1.60

(m, 1H, H-2), 1.56–1.40 (m, 2H, H-3, H-5⁰), 1.36–1.20 (m, 6H, H-

1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.17–1.05 (m, 3H, H-3⁰, H-4⁰), 1.04–

0.94 (m, 1H, H-2⁰), 0.90 (d, 3H, CH₃-1⁰, J = 6.5 Hz), 0.86 (s, 3H,

CH₃-3a), 0.84 (d, 3H, CH₃-5⁰, J = 5.8 Hz), 0.83 (d, 3H, H-6⁰,

J = 5.8 Hz), 0.76 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃, 125 MHz): d

143.3 (2⁰⁰⁰-CH), 139.7 (5⁰⁰⁰-CH), 124.0 (3⁰⁰⁰-C), 110.4 (4⁰⁰⁰-CH), 75.6

(4-CH), 56.6 (5-CH), 48.4 (3a-C), 47.2 (1-CH), 45.0 (7a-C), 40.9 (6-

CH₂), 39.6 (1⁰⁰-CH₂), 36.5 (3-CH₂), 35.6 (1⁰-CH), 34.9 (7-CH₂), 31.4

(4⁰-CH₂), 29.2 (2⁰-CH₂), 28.0 (5⁰-CH), 24.2 (2-CH₂), 23.1 (3⁰-CH₂),

22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 21.3 (CH₃-3a), 20.0 (CH₃-7a), 19.0

(CH₃-1⁰). HRMS Found 375.3125 (Calcd 375.3137). IR (NaCl, ﬁlm,

a ²_D⁰

+34 (0.5; CHCl₃).

ꢂ

5.6.15.14. (1R,3aR,4R,5S,7aR)-5-(2,3-Dichlorobenzylamino)-1-

((R)-1,5-dimethylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(27g).

Amino alcohol 25 (90 mg, 0.31 mmol) and 2,3-dichlo-

robenzaldehyde (56.0 mg, 0.32 mmol) in methanol (3 mL) were

treated as described in procedure C. The crude product was sub-

jected to SCC (petroleum ether/ethyl acetate/triethylamine

9:1:0.2) to afford 27g (107 mg, 77%) as a colourless oil. ¹H NMR

(CDCl₃, 400 MHz): d 7.37 (d, 1H, H-4⁰⁰⁰, J = 7.9 Hz), 7.25 (d, 1H, H-

6⁰⁰⁰, J = 7.8 Hz), 7.16 (t, 1H, H-5⁰⁰⁰, J = 7.8 Hz), 3.89 (d, 1H, H-1⁰⁰,

J = 13.8 Hz), 3.83 (d, 1H, H-1⁰⁰, J = 13.8 Hz), 3.47 (d, 1H, H-4,

J = 2.5 Hz), 2.72–2.61 (m, 1H, H-5), 2.36–2.30 (m, 1H, H-1⁰), 1.96–

1.79 (m, 3H, H-3, H-6, H-7), 1.73–1.62 (m, 1H, H-2), 1.54–1.42

(m, 2H, H-3, H-5⁰), 1.36–1.19 (m, 6H, H-1, H-2, H-2⁰, H-3⁰, H-6, H-

7), 1.14–1.06 (m, 3H, H-3⁰, H-4⁰), 1.04–0.97 (m, 1H, H-2⁰), 0.90 (d,

3H, CH₃-1⁰, J = 6.6 Hz), 0.85 (d, 3H, CH₃-5⁰, J = 5.4 Hz), 0.84–0.80

(m, 3H, H-6⁰, with underneath s, 3H, CH₃-3a at 0.81 ppm), 0.71

cm^ꢀ1): 3501, 3022, 2980, 2895, 1472, 882, 750, 689. ½a ²_D⁰

ꢂ

+26

(0.5; CHCl₃).

5.6.15.12. (1R,3aR,4R,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

dimethyl-5-(pent-4-enylamino)-octahydroinden-4-ol

(s, 3H, CH₃-7a). C NMR (CDCl₃, 125 MHz): d 139.8 (1⁰⁰⁰-C), 133.3

(2⁰⁰⁰-C), 132.0 (3⁰⁰⁰-C), 129.2 (4⁰⁰⁰-CH), 128.2 (6⁰⁰⁰-CH), 127.2 (5⁰⁰⁰-

CH), 75.5 (4-CH), 56.24 (5-CH), 48.6 (1⁰⁰-CH₂), 48.4 (3a-C), 47.1

(1-CH), 44.9 (7a-C), 39.5 (6-CH₂), 36.4 (3-CH₂), 35.5 (1⁰-CH), 34.8

(27e).

(36.0

Amino alcohol 25 (100 mg, 0.34 mmol) and pent-4-enal

L, 0.35 mmol) in methanol (3 mL) were treated as described

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1941

(7-CH₂), 31.3 (4⁰-CH₂), 29.1 (2⁰-CH₂), 27.9 (5⁰-CH), 24.1 (2-CH₂),

23.1 (3⁰-CH₂), 22.8 (6⁰-CH₃), 22.5 (CH₃-5⁰), 21.2 (CH₃-3a), 19.9

(CH₃-7a), 19.0 (CH₃-1⁰). HRMS Found 453.2583 (Calcd 453.2565).

IR (NaCl, ﬁlm, cm^ꢀ1): 3442, 3032, 3002, 2983, 2871, 1413, 1332,

J = 2.8 Hz), 2.68–2.52 (m, 3H, H-1⁰⁰, H-5), 2.35–2.27 (m, 1H, H-1⁰),

1.99–1.90 (m, 1H, H-6), 1.87–1.76 (m, 2H, H-3, H-7), 1.68–1.59

(m, 1H, H-2), 1.49–1.36 (m, 2H, H-3, H-5⁰), 1.34–1.21 (m, 6H, H-

1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.14–1.04 (m, 6H, H-2⁰⁰, H-3⁰, H-4⁰),

1.01–0.93 (m, 1H, H-2⁰), 0.90 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.85 (d,

3H, CH₃-1⁰, J = 6.3 Hz), 0.84–0.79 (m, 3H, H-6⁰, with underneath s,

3H, CH₃-3a at 0.81 ppm), 0.71 (s, 3H, CH₃-7a). ¹³C NMR (CDCl3,

125 MHz): d 76.0 (4-CH), 57.1 (5-CH), 48.4 (3a-C), 47.1 (1-CH),

45.0 (7a-C), 40.7 (1⁰⁰-CH₂), 39.6 (6-CH₂), 36.5 (3-CH₂), 35.6 (1⁰-

CH), 34.8 (7-CH₂), 31.5 (4⁰-CH₂), 29.2 (2⁰-CH₂), 28.0 (5⁰-CH), 24.2

(2-CH₂), 23.2 (3⁰-CH₂), 22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 21.3 (CH₃-3a),

20.0 (CH₃-7a), 19.0 (CH₃-1⁰), 15.7 (2⁰⁰-CH₃). HRMS Found

323.3158 (Calcd 323.3188). IR (NaCl, ﬁlm, cm^ꢀ1): 3399, 2995,

1231, 1023, 773. ½a _D²⁰

ꢂ

+36 (0.5; CHCl₃).

5.6.15.15.

methoxybenzylamino)-3a,7a-dimethyloctahydroinden-4-ol

(28a). Amino alcohol 25 (100 mg, 0.34 mmol) and 4-

methoxybenzaldehyde (44 L, 0.35 mmol) in methanol (3 mL)

(1R,3aR,4R,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-(4-

were treated as described in procedure C. The crude product was

subjected to SCC (petroleum ether/ethyl acetate/triethylamine

9:1:0.2) to afford 28a (104 mg, 73%) as colourless oil. ¹H NMR

(CDCl₃, 400 MHz): d 7.20 (d, 2H, H-2⁰⁰⁰, H-6⁰⁰⁰, J = 8.6 Hz), 6.85 (d,

2H, H-3⁰⁰⁰, H-5⁰⁰⁰, J = 8.6 Hz), 3.79 (s, 3H, OCH₃), 3.74 (d, 1H, H-1⁰⁰,

J = 12.7 Hz), 3.60 (d, 1H, H-1⁰⁰, J = 12.7 Hz), 3.44 (d, 1H, 4-H, J =

2.7 Hz), 2.78–2.65 (m, 1H, H-5), 2.42–2.31 (m, 1H, H-1⁰), 2.04–

1.90 (m, 1H, H-6), 1.90–1.77 (m, 2H, H-3, H-7), 1.73–1.59 (m, 1H,

H-2), 1.55–1.40 (m, 2H, H-3, H-5⁰), 1.38–1.17 (m, 6H, H-1, H-2,

H-2⁰, H-3⁰, H-6, H-7), 1.15–1.05 (m, 3H, H-3⁰, H-4⁰), 1.03–0.96 (m,

1H, H-2⁰), 0.90 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.86 (d, 3H, CH₃-5⁰,

J = 5.8), 0.84 (d, 3H, H-6⁰, J = 5.8 Hz), 0.84 (s, 3H, CH₃-3a), 0.72 (s,

2867, 1511, 1291, 841, 753. ½a _D²⁰

ꢂ

+16 (0.5; CHCl₃).

5.6.15.18. (1R,3aR,4R,5S,7aR)-5-(N-Benzyl-N-methylamino)-1-

((R)-1,5-dimethylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(29a).

Amino alcohol 27a (112 mg, 0.29 mmol) and a 34%

L, 0.58 mmol) in metha-

aqueous solution of formaldehyde (50

nol (3 mL) were treated as described in procedure C. The crude

product was subjected to SCC (petroleum ether/ethyl acetate/tri-

ethylamine 9:1:0.1) to afford 29a (97 mg, 83%) as colourless oil.

¹H NMR (CDCl₃, 400 MHz): d 7.36–7.21 (m, 5H, H-2⁰⁰⁰, H-3⁰⁰⁰, H-

4, H-5⁰⁰⁰, H-6⁰⁰⁰), 3.75 (d, 1H, H-1⁰⁰, J = 13.3 Hz), 3.63 (d, 1H, H-4,

J = 2.8 Hz), 3.40 (d, 1H, H-1⁰⁰, J = 13.3 Hz), 2.42–2.33 (m, 2H, H-

1⁰, H-5), 2.15 (s, 3H, NCH₃), 2.04–1.83 (m, 3H, H-3, H-6, H-7),

1.75–1.64 (m, 1H, H-2), 1.63–1.41 (m, 2H, H-3, H-5⁰), 1.40–1.18

(m, 6H, H-1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.18–1.07 (m, 3H, H-3⁰,

H-4⁰), 1.06–0.98 (m, 1H, H-2⁰), 0.93 (d, 3H, CH₃-1⁰, J = 6.6 Hz),

0.87 (s, 3H, CH₃-3a), 0.85 (d, 3H, CH₃-5⁰, J = 6.0 Hz), 0.83 (d, 3H,

H-6⁰, J = 6.0 Hz), 0.74 (s, 3H, CH₃-7a). ¹³C NMR (CDCl₃,

125 MHz): d 139.34 (1⁰⁰⁰-C), 128.8 (2C, 2⁰⁰⁰-CH, 6⁰⁰⁰-CH), 128.2 (2C,

3⁰⁰⁰-CH, 5⁰⁰⁰-CH), 126.8 (4⁰⁰⁰-CH), 75.5 (4-CH), 63.0 (5-CH), 58.1

(1⁰⁰-CH₂), 48.6 (3a-C), 47.2 (1-CH), 44.3 (7a-C), 39.4 (6-CH₂),

38.2 (NCH₃), 36.4 (3-CH₂), 35.6 (1⁰-CH), 34.8 (7-CH₂), 31.7 (4⁰-

CH₂), 29.2 (2⁰-CH₂), 27.9 (5⁰-CH), 24.2 (2⁰-CH₂), 22.8 (6⁰-CH₃),

22.5 (CH₃-5⁰), 21.2 (CH₃-3a), 20.4 (3⁰-CH₂), 19.7 (CH₃-7a), 18.8

(CH₃-1⁰). HRMS Found 399.3523 (Calcd 399.3501). IR (NaCl, ﬁlm,

cm^ꢀ1): 3431, 3019, 2932, 2854, 1501, 1345, 1023, 743, 691.

3H, CH₃-7a). C NMR (CDCl₃, 125 MHz): d 156.9 (1⁰⁰⁰-C), 130.7

(4⁰⁰⁰-C), 127.5 (2C, 2⁰⁰⁰-CH, 6⁰⁰⁰-CH), 112.1 (2C, 3⁰⁰⁰-CH, 5⁰⁰⁰-CH), 73.8

(4-CH), 54.8 (5-CH), 53.5 (OCH₃), 48.2 (1⁰⁰-CH₂), 46.6 (3a-C), 45.4

(1-CH), 43.2 (7a-C), 37.8 (6-CH₂), 34.7 (3-CH₂), 33.8 (1⁰-CH), 33.1

(7-CH₂), 29.6 (4⁰-CH₂), 27.4 (2⁰-CH₂), 26.2 (5⁰-CH), 22.4 (2-CH₂),

21.4 (3⁰-CH₂), 21.1 (6⁰-CH₃), 20.8 (CH₃-5⁰), 19.5 (CH₃-3a), 18.2

(CH₃-7a), 17.29 (CH₃-1⁰). HRMS Found 415.3455 (Calcd

415.3450). IR (NaCl, ﬁlm, cm^ꢀ1): 3491, 3031, 2956, 2870, 1414,

1342, 1085, 802. ½a _D²⁰

ꢂ

+41 (0.5; CHCl₃).

5.6.15.16. (1R,3aR,4R,5S,7aR)-5-(2,4-Dimethoxybenzylamino)-1-

((R)-1,5-dimethylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(28b).

Amino alcohol 25 (100 mg, 0.34 mmol) and 2,4-dime-

thoxybenzaldehyde (62 mg, 0.35 mmol) in methanol (3 mL) were

treated as described in procedure C. The crude product was sub-

jected to SCC (petroleum ether/ethyl acetate/triethylamine

9:1:0.2) to afford 28b (86 mg, 57%) as colourless oil. ¹H NMR

(CDCl₃, 400 MHz): d 7.07 (d, 1H, H-6⁰⁰⁰, J = 8.2 Hz), 6.44 (s, 1H, H-

3⁰⁰⁰), 6.41 (d, 1H, H-5⁰⁰⁰, J = 8.2 Hz), 3.80 (s, 3H, OCH₃), 3.79 (s, 3H,

OCH₃), 3.71 (d, 1H, H-1⁰⁰, J = 13.1 Hz), 3.59 (d, 1H, H-1⁰⁰,

J = 13.1 Hz), 3.47 (d, 1H, H-4, J = 2.7 Hz), 2.66–2.60 (m, 1H, H-5),

2.38–2.29 (m, 1H, H-1⁰), 1.99–1.83 (m, 2H, H-3, H-6), 1.81–1.74

(m, 1H, H-7), 1.70–1.59 (m, 1H, H-2), 1.57–1.39 (m, 2H, H-3, H-

5⁰), 1.38–1.22 (m, 6H, H-1, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.19–1.06

(m, 3H, H-3⁰, H-4⁰), 1.05–0.97 (m, 1H, H-2⁰), 0.89 (d, 3H, CH₃-1⁰,

J = 6.6 Hz), 0.85 (d, 3H, CH₃-1⁰, J = 6.2 Hz), 0.84 (d, 3H, H-6⁰,

J = 6.2 Hz), 0.82 (s, 3H, CH₃-3a), 0.70 (s, 3H, CH₃-7a). ¹³C NMR

(CDCl₃, 125 MHz): d 160.0 (2⁰⁰⁰-C), 158.6 (4⁰⁰⁰-C), 130.3 (6⁰⁰⁰-CH),

120.8 (1⁰⁰⁰-C), 103.6 (5⁰⁰⁰-CH), 98.5 (3⁰⁰⁰-CH), 75.2 (4-CH), 55.6 (5-

CH), 55.3 (OCH₃), 55.2 (OCH₃), 48.2 (3a-C), 47.0 (1-CH), 45.0 (7a-

C), 44.9 (1⁰⁰-CH₂), 39.5 (6-CH₂), 36.4 (3-CH₂), 35.5 (1⁰-CH), 34.8

(7-CH₂), 31.4 (4⁰-CH₂), 29.0 (2⁰-CH₂), 27.9 (5⁰-CH), 24.1 (2-CH₂),

23.2 (3⁰-CH₂), 22.8 (6⁰-CH₃), 22.5 (CH₃-5⁰), 21.2 (CH₃-3a), 19.9

(CH₃-7a), 18.9 (CH₃-1⁰). HRMS Found 445.3546 (Calcd 445.3556).

IR (NaCl, ﬁlm, cm^ꢀ1): 3472, 3022, 2931, 2853, 1413, 1321, 1266,

a ²_D⁰

+19 (0.5; CHCl₃).

ꢂ

5.6.15.19. (1R,3aR,4R,5S,7aR)-5-(N,N-Dibenzylamino)-1-((R)-1,5-

dimethylhexyl)-3a,7a-dimethyloctahydroinden-4-ol

(29b).

dehyde (67

Amino alcohol 27a (150 mg, 0.39 mmol) and benzal-

L, 0.58 mmol) in methanol (3 mL) were treated as

described in procedure C. The crude product was subjected to

SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.1) to af-

ford 29b (156 mg, 84%) as colourless oil. ¹H NMR (CDCl₃,

400 MHz): d 7.35–7.17 (m, 10H, H-2⁰⁰⁰, H-3⁰⁰⁰, H-4⁰⁰⁰, H-5⁰⁰⁰, H-6⁰⁰⁰),

3.81 (d, 2H, H-1⁰⁰, J = 14.5 Hz), 3.76 (d, 2H, H-1⁰⁰, J = 14.5 Hz),

3.65 (d, 1H, H-4, J = 2.8 Hz), 2.94–2.70 (m, 1H, H-5), 2.38–2.29

(m, 1H, H-1⁰), 2.01–1.90 (m, 1H, H-6), 1.90–1.80 (m, 2H, H-3, H-

7), 1.77–1.63 (m, 1H, H-2), 1.59–1.41 (m, 3H, H-2, H-3, H-5⁰),

1.40–1.25 (m, 4H, H-1, H-2⁰, H-3⁰, 7-H), 1.24–1.17 (m, 1H, H-6),

1.21–1.05 (m, 3H, H-3⁰, H-4⁰), 1.04–0.96 (m, 1H, H-2⁰), 0.88 (d,

3H, CH₃-1⁰, J = 6.1 Hz), 0.87 (d, 3H, CH₃-5⁰, J = 5.8 Hz), 0.87 (d,

3H, H-6⁰, J = 5.8 Hz), 0.83 (s, 3H, CH₃-3a), 0.72 (s, 3H, CH₃-7a).

¹³C NMR (CDCl3, 125 MHz): d 139.8 (2C, 1⁰⁰⁰-C), 128.7 (4C, 2⁰⁰⁰-C,

6⁰⁰⁰-C), 128.3 (4C, 3⁰⁰⁰-C, 5⁰⁰⁰-C), 126.8 (2C, 4⁰⁰⁰-C), 76.6 (4-CH), 61.0

(5-CH), 53.9 (2C, 1⁰⁰-CH₂), 49.0 (3a-C), 47.3 (1-CH), 44.6 (7a-C),

39.5 (6-CH₂), 36.4 (3-CH₂), 35.6 (1⁰-CH), 34.9 (7-CH₂), 32.2 (4⁰-

CH₂), 29.2 (2⁰-CH₂), 28.0 (5⁰-CH), 24.2 (2-CH₂), 22.9 (6⁰-CH₃),

22.6 (CH₃-5⁰), 21.4 (CH₃-3a), 20.7 (3⁰-CH₂), 19.8 (CH₃-7a), 19.0

(CH₃-1⁰). HRMS Found 475.3718 (Calcd 475.3814). IR (NaCl, ﬁlm,

cm^ꢀ1): 3467, 3025, 2932, 2857, 1452, 1304, 1298, 1023, 749,

1085, 873, 802. ½a _D²⁰

ꢂ

+53 (0.5; CHCl₃).

5.6.15.17. (1R,3aR,4R,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-5-eth-

ylamino-3a,7a-dimethyloctahydroinden-4-ol (28c). Amino

alcohol 25 (100 mg, 0.34 mmol) and acetaldehyde (20 L,

0.35 mmol) in methanol (3 mL) were treated as described in proce-

dure C. The crude product was subjected to SCC (petroleum ether/

ethyl acetate/triethylamine 7:3:0.2) to afford 28c (83 mg, 75%) as

colourless oil. ¹H NMR (CDCl₃, 400 MHz): d 3.35 (d, 1H, H-4,

684. ½a ²_D⁰

ꢂ

+47 (0.5; CHCl₃).

1942

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

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5.6.15.20.

(1R,3aR,4R,5S,7aR)-5-(N-Benzyl-N-pent-4-enylami-

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4-ol (29c).

pent-4-enal (59

Amino alcohol 27a (150 mg, 0.39 mmol) and

lL, 0.58 mmol) in methanol (3 mL) were treated

6. Shrivastava, S.; Paila, Y. D.; Dutta, A.; Chattopadhyay, A. Biochemistry 2008, 47,

5668.

as described in procedure C. The crude product was subjected

to SCC (petroleum ether/ethyl acetate/triethylamine 9:1:0.1) to

afford 29c (146 mg, 82%) as colourless oil. ¹H NMR (CDCl₃,

400 MHz): d 7.40–7.17 (m, 5H, H-2⁰⁰⁰, H-3⁰⁰⁰, H-4⁰⁰⁰, H-5⁰⁰⁰, H-6⁰⁰⁰),

5.72 (ddt, 1H, H-4⁰⁰⁰⁰, J = 6.6 Hz, J = 10.2 Hz, J = 16.9 Hz), 5.02–4.73

(m, 2H, H-5⁰⁰⁰⁰), 3.78 (d, 1H, H-1⁰⁰, J = 14.1 Hz), 3.66 (d, 1H, H-1⁰⁰,

J = 14.1 Hz), 3.55 (d, 1H, H-4, J = 2.5 Hz), 2.72–2.62 (m, 1H, H-5),

2.61–2.49 (m, 2H, H-1⁰⁰⁰⁰), 2.39–2.30 (m, 1H, H-1⁰), 2.01–1.93 (m,

1H, H-6), 1.92–1.83 (m, 4H, H-3, H-3⁰⁰⁰⁰, H-7), 1.74–1.65 (m, 1H,

H-2), 1.60–1.40 (m, 5H, H-1, H-2⁰⁰⁰⁰, H-3, H-5⁰), 1.39–1.18 (m,

5H, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.19–1.05 (m, 3H, H-3⁰, H-4⁰),

1.04–0.96 (m, 1H, H-2⁰), 0.91 (d, 3H, CH₃-1⁰, J = 6.6 Hz), 0.87 (d,

3H, CH₃-5⁰, J = 5.9 Hz), 0.86–0.83 (m, 3H, H-6⁰, with underneath

s, 3H, CH₃-3a at 0.84 ppm), 0.73 (s, 3H, CH₃-7a). ¹³C NMR (CDCl3,

125 MHz): d 139.9 (1⁰⁰⁰-C), 138.2 (4⁰⁰⁰⁰-CH), 128.4 (2C, 2⁰⁰⁰-CH, 6⁰⁰⁰-

CH), 128.1 (2C, 3⁰⁰⁰-CH, 5⁰⁰⁰-CH), 126.7 (4⁰⁰⁰-CH), 114.5 (5⁰⁰⁰⁰-CH₂),

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75.8 (4-CH), 60.6 (5-CH), 53.4 (1⁰⁰-CH₂), 48.6 (3a-C), 48.1 (1⁰⁰⁰⁰

CH₂), 47.1 (1-CH), 44.3 (7a-C), 39.4 (6-CH₂), 36.3 (3-CH₂), 35.6

(1⁰-CH), 34.8 (7-CH₂), 31.8 (4⁰-CH₂), 31.3 (3⁰⁰⁰⁰-CH₂), 29.1 (2⁰-

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22.5 (CH₃-5⁰), 21.2 (CH₃-3a), 20.4 (3⁰-CH₂), 19.6 (CH₃-7a), 18.8

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cm^ꢀ1): 3442, 3012, 2949, 2867, 1412, 1319, 1023, 992, 917,

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49, 2652.

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49. Barrero, A. F.; Herrador, M. M.; Artega, P.; Catalan, J. V. Eur. J. Org. Chem. 2009,

3589.

50. Constantino, M. G.; Valdemar, L. J.; Invernize, P. R. Synth. Commun. 2007, 37,

3529.

749. ½a ²_D⁰

ꢂ

+39 (0.5; CHCl₃).

5.6.15.21. (1R,3aR,4R,5S,7aR)-1-((R)-1,5-Dimethylhexyl)-3a,7a-

dimethyl-5-(N-methyl-N-pent-4-enylamino)-octahydroinden-

4-ol (30).

aqueous solution of formaldehyde (71

Amino alcohol 27e (150 mg, 0.41 mmol) and a 34%

L, 0.58 mmol) in methanol

(3 mL) were treated as described in procedure C. The crude product

was subjected to SCC (petroleum ether/ethyl acetate/triethylamine

9:1:0.1) to afford 30 (137 mg, 87%) as colourless oil. ¹H NMR

(CDCl₃, 400 MHz): d 5.80 (ddt, 1H, H-4⁰⁰, J = 6.6 Hz, J = 10.2 Hz,

J = 16.8 Hz), 5.11–4.87 (m, 2H, H-5⁰⁰), 3.44 (d, 1H, H-4, J = 2.4 Hz),

2.67–2.47 (m, 1H, H-1⁰⁰), 2.46–2.28 (m, 2H, H-1⁰⁰, H-5), 2.26–2.19

(m, 1H, H-1⁰, with underneath s, 3H, NCH₃at 2.23 ppm), 2.11–

1.75 (m, 5H, H-3, H-3⁰⁰, H-6, H-7), 1.66–1.40 (m, 6H, H-1, H-2, H-

2⁰⁰, H-3, H-5⁰), 1.38–1.17 (m, 5H, H-2, H-2⁰, H-3⁰, H-6, H-7), 1.16–

1.06 (m, 3H, H-3⁰, H-4⁰), 1.04–0.94 (m, 1H, H-2⁰), 0.91 (d, 3H,

CH₃-1⁰, J = 5.9 Hz), 0.86 (s, 3H, CH₃-3a), 0.84 (d, 3H, CH₃-5⁰,

J = 6.0 Hz), 0.82 (d, 3H, H-6⁰, J = 6.0 Hz), 0.71 (s, 3H, CH₃-7a). ¹³C

NMR (CDCl₃, 125 MHz): d 138.6 (4⁰⁰-CH), 114.7 (5⁰⁰-CH₂), 75.5 (4-

CH), 62.7 (5-CH), 53.0 (1⁰⁰-CH₂), 48.5 (3a-C), 47.2 (1-CH), 44.3

(7a-C), 39.6 (NCH₃), 38.4 (6-CH₂), 36.5 (3-CH₂), 35.8 (1⁰-CH), 34.9

(7-CH₂), 31.8 (4⁰-CH₂), 31.5 (3⁰⁰-CH₂), 29.3 (2⁰-CH₂), 28.0 (5⁰-CH),

25.8 (2-CH₂), 24.3 (3⁰-CH₂), 22.9 (6⁰-CH₃), 22.6 (CH₃-5⁰), 21.3

(CH₃-3a), 20.5 (2⁰⁰-CH₂), 19.8 (CH₃-7a), 18.9 (CH₃-1⁰). HRMS Found

377.3659 (Calcd 377.3658). IR (NaCl, ﬁlm, cm^ꢀ1): 3401, 2951,

2867, 1497, 1346, 1201, 1037, 991, 916, 841, 753. ½a _D²⁰

ꢂ

+12 (0.5;

CHCl₃).

Supplementary data

51. Fang, Y. Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5560.

52. Sun, Q.; Cai, S.; Peterson, B. R. Org. Lett. 2009, 11, 567.

53. Serrano, P.; Casas, J.; Zucco, M.; Emeric, G.; Egido-Gabas, M.; Llebaria, A.;

Delgado, A. J. Comb. Chem. 2007, 9, 43.

Supplementary data associated with this article can be found, in

the online version, at http://dx.doi.org/10.1016/j.bmc.2013.01.041.

These data include MOL ﬁles and InChiKeys of the most important

compounds described in this article.

54. For a review on the chemistry of a-azido ketones, see: Patonay, T.; Konya, K.;

Juhasz-Toth, E. Chem. Soc. Rev. 2011, 40, 2797.

55. Brewster, W. K.; Nichols, D. E.; Riggs, R. M.; Mottola, D. M.; Lovenberg, T. W.;

Lewis, M. H.; Mailman, R. B. J. Med. Chem. 1990, 33, 1756.

References and notes

56. Susceptibility testing of microbial pathogens to antimicrobial agents—Part 84:

Microdilution—Special requirements for testing of fungi against antifungal

agents, in: DIN 58940-84, Beuth Verlag: Berlin, 2002.

1. King, F. D. Medicinal Chemistry, Principles and Practice; Royal Society of Chemistry

2002. pp 64–90.

M. König et al. / Bioorg. Med. Chem. 21 (2013) 1925–1943

1943

57. SANCO guideline (2009) Method validation and quality control procedures for

59. Bradford, M. M. Anal. Biochem. 1976, 72, 248.

60. Mosmann, T. J. Immunol. Methods 1981, 65, 55.

pesticide residues analysis in food and feed. Document No. SANCO/10684/2009.

58. Hagiwara, K.; Nakamura, Y.; Nishijima, M.; Yamakawa, Y. Biol. Pharm. Bull.

2007, 30, 835.

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