Synthesis of Seco-Analogues of the DHCR24 Inhibitor SH-42

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Seco-Steroids

Synthesis of Seco-Analogues of the DHCR24 Inhibitor SH-42

Desirée Heerdegen,^[a]Doreen Reuter,^[b]Moritz M. Kornmayer,^[a]Katharina N. Kriegler,^[a]

Christoph Müller,^[a]Peter Mayer,^[b]and Franz Bracher*^[a]

Abstract: In a project aimed at the further development of the and 4-(arylethyl)perhydroindanes. As saturated analogues of

potent steroidal anti-inflammatory Δ²⁴-dehydrocholesterol re- the latter 4-(cyclohexylethyl)perhydroindanes were prepared.

ductase (DHCR24) inhibitor SH-42 we worked out routes to ring Moreover, aromatic and aliphatic residues were attached to

B seco-steroidal analogues. The required building blocks, bear- C-5 position of the perhydroindane scaffold. Unfortunately,

ing rings C and D of the parent steroidal structure, were synthe- none of these structurally diverse seco-analogues of SH-42

sised starting from ergocalciferol. The novel seco-analogues showed noteworthy inhibition of target enzyme DHCR24, indi-

carry aromatic residues as ring A equivalents at C-4 position cating the relevance of the intact steroidal structure for the

with variation of the linker length resulting in 4-aryl-, 4-benzyl- development of potent inhibitors of this enzyme.

Introduction

ance. Since the impact of a disturbed cholesterol biosynthesis is

a global health problem, the development and pharmacological

investigation of new inhibitors of cholesterol biosynthesis are

constantly of high necessity worldwide. A target of growing

interest within the post-squalene part of cholesterol biosynthe-

sis is the enzyme Δ²⁴-dehydrocholesterol reductase (DHCR24).

This enzyme interconnects the Bloch and Kandutsch-Russell

pathways of this biosynthesis and is responsible for the reduc-

tion of the Δ²⁴-double bond in the side chain of the cholesterol

precursors, which occurs in two steps utilising NADPH as reduc-

tant.^[12]Using isotope labelling, Mitsche et al. showed that the

Bloch pathway is mainly located in adrenal glands and testes,

while the Kandutsch-Russell pathway can be found in skin and

brain cells.^[13]The major substrates of DHCR24 are lanosterol,

zymosterol and desmosterol, whereby an inhibition of DHCR24

leads to an accumulation of desmosterol.^[12]DHCR24 plays an

important role in research studies towards CVD, Alzheimer's dis-

ease, hepatitis C virus infections, desmosterolosis and certain

types of cancer.^[14]The first clinically used DHCR24 inhibitor was

triparanol (MER-29),^[15,16]but due to harmful side effects this

drug is no longer in clinical use.^[17,18]Steroidal DHCR24 inhibi-

tors are for example U18666A and DMHCA (synthetic LXR ago-

nist).^[19–21]Recently our group described new chemotypes of

DHCR24 inhibitors.^[12,22]The first studies implied lathosterol

As precursor of various metabolic products like steroid hor-

mones^[1]and bile acids,^[2]cholesterol is an essential biomole-

cule in the mammalian organism and moreover, is responsible

for the regulation of the membrane fluidity and rigidity.^[3]The

cholesterol biosynthesis is naturally regulated in the committed

step, the conversion of HMG-CoA into mevalonic acid, catalysed

by HMG-CoA reductase (HMGCR), by the sterol regulatory

element-binding protein 2 (SREBP2).^[4,5]A consequence of a dis-

turbed cholesterol balance is hypercholesterolemia, which de-

scribes the presence of high cholesterol levels in the blood.^[6]

Deposition of cholesterol in artery walls can lead to atheroscle-

rosis,^[7]the major cause of cardiovascular disease (CVD).^[8]

A

common medical treatment against raised cholesterol levels are

statins,^[9]which inhibit the enzyme HMGCR and consequently

the complete cholesterol biosynthesis. Unfortunately, statins

come with side effects like myalgia.^[10]Genetic disorders like

neurodegenerative Niemann-Pick type C disease (cholesterol

accumulation within lysosomes)^[11]or Schnyder corneal dystro-

phy (increased cholesterol production due to HMGCR stabilisa-

tion)^[11]are also consequences of a disturbed cholesterol bal-

[a] D. Heerdegen, M. M. Kornmayer, K. N. Kriegler, Dr. C. Müller,

Prof. Dr. F. Bracher

side chain amides, e.g. selective inhibitor MGI-21 (IC₅₀

=

Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians

University,

823 n

M

),^[22]but analogues bearing larger N-alkyl substituents

lack selectivity due to additional inhibition of the enzyme sterol

C5-desaturase in the same pathway.^[12,22]Further research led

to the chemotype of “inverse esters”, whereby SH-42 proved to

be a selective and very potent inhibitor of DHCR24 with an IC₅₀

Butenandtstr. 5-13, 81377 Munich, Germany

E-mail: Franz.Bracher@cup.uni-muenchen.de

https://bracher.cup.uni-muenchen.de

[b] D. Reuter, Dr. P. Mayer

Department of Chemistry, Ludwig-Maximilians University,

Butenandtstr. 5-13, 81377 Munich, Germany

of 4.2 n

SH-42 is most likely a prodrug, since the corresponding free

diols 1 (IC₅₀= 0.1 n

) as well as its Δ⁵-double bond isomer 2

M

(Figure 1).^[12]

Supporting information and ORCID(s) from the author(s) for this article are

available on the WWW under https://doi.org/10.1002/ejoc .202001080.

article under the terms of the Creative Commons Attribution License, which

permits use, distribution and reproduction in any medium, provided the

original work is properly cited.

M

(IC₅₀= 2.5 nM) showed even lower IC₅₀values. The fact that

both, Δ⁵- (2) and Δ⁷-isomers (1) are excellent DHCR24 inhibitors

led us to the conclusion that structural modifications in the ring

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erol (vitamin D₂). In addition to literature-known ketone 3,

which is available from ergocalciferol in three steps,^[30,31]exo-

methylene compound 4 and aldehyde 5 were envisaged as cen-

tral building blocks. For seco-analogues of type A, 3 was

intended to be used for direct attachment of cyclic residues at

C-4, 4 appeared useful for the introduction of a methylene

linker, and aldehyde 5 for the introduction of an ethylene linker

between the perhydroindane and the ring A equivalent. Iso-

meric ketone 6 should be synthesised by carbonyl isomerisa-

tion from its regioisomer 3 and should be used for the synthesis

of seco-steroidal analogues of type B with direct linking at C-5.

Figure 1. Structures of DHCR24 inhibitors SH-42 and the related free diols 1

and 2.^[12]

B region might be tolerated. However, additional variations in

this region were impeded by the limited accessibility of useful

steroidal starting materials. This prompted us to undertake

more drastic changes at ring B by the design of seco-steroidal

analogues of SH-42, in which ring B is cleaved. Seco-analogues

of cyclic enzyme inhibitors show enhanced flexibility, so they

can adopt an overall geometry very similar to the parent com-

pound, but potentially can bind to the active site of a protein

also in an even more favorable conformation. Consequently,

previous research on seco-analogues of drugs has resulted in

diverse results, ranging from partial or complete loss of activ-

ity,^[23–25]preservation of activity,^[26–28]and shift in the activity

profile.^[29]

Results and Discussion

Chemistry

For the synthesis of seco-analogues of type A with bridging at

C-4, ketone 3 was required as the central intermediate. To ob-

tain the characteristic side chain and rings C and D with the

correct stereochemistry of SH-42, a chiral pool synthesis starting

from vitamin D₂(7, ergocalciferol) was applied (Scheme 2).

Literature-known ozonolysis followed by reductive work-up re-

sulted in the Inhoffen-Lythgoe diol (8) in 71 % yield.^[30,32]Selec-

tive TBDMS protection of the primary hydroxyl group in the

side chain, with subsequent oxidation of the remaining second-

ary hydroxyl group using Dess–Martin periodinane (DMP), in-

Two cutting points were considered here, the one at the

C-9,C-10-bond of the steroidal backbone (giving 4-substituted

perhydroindanes A), and the other at the C-5,C-6- and

C-7,C-8-bonds with elimination of C-6 and C-7 (giving 5-substi-

tuted perhydroindanes B) (Scheme 1).

As building blocks for the rings C and D equivalent we se- stead of toxic pyridinium dichromate which was used formerly

lected enantiopure perhydroindanes derived from ergocalcif- for this oxidation,^[31]led to the building block 3 in high yield.

Scheme 1. Overview of this work. Intended synthesis of seco-steroidal analogues of SH-42 and related bioactive diols 1 and 2 with variation of the linker

length using vitamin D₂-derived building blocks 3, 4 and 5. Seco-steroid analogues of type A should be derived from ketone 3, and seco-steroid analogues

of type B with direct linking of residues, should be available through the regioisomeric ketone 6.

Scheme 2. Synthesis of perhydroindane building blocks 3, 4 and 5 from ergocalciferol (7).

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Building blocks 4 and 5 were prepared by functionalisation Markovnikov product. Furthermore, full consumption of the ap-

of ketone 3. Wittig olefination of 3 using methyltriphenylphos- plied valuable olefinic building block in the subsequent Suzuki–

phonium bromide (MePPh₃Br) and LDA gave 4 in 91 % yield. Miyaura cross-coupling was more likely with the B-alky-BBN de-

For preparation of the 4-formyl building block, olefin 4 was rivative than with a trialkylborane derived from BH₃·THF and

hydroborated using BH₃·THF, followed by work up with H₂O₂/ three equivalents of olefin 4. Scheme 4 shows the results of the

NaOH resulting in primary alcohol 10. The stereoconfiguration reaction. While an unsubstituted benzyl group (19) and two

at C-4 was determined as S by NOESY spectroscopy (see Figure para-substituted analogues (21, 23) could be obtained in mod-

S3). Oxidation of the primary alcohol using DMP gave aldehyde erate yields over both steps (33–51 %), the meta-substituted

5 in 57 % yield.

products 20 and 22 were obtained only in 25 and 13 % yields.

Once again, the ortho-substituted aryl bromides did not un-

dergo the coupling reaction. Considerable amounts of exo-

methylene starting material 4 were recovered in all experi-

ments, indicating that steric hindrance, already but not necessa-

rily exclusively in the initial hydroboration step, is most likely a

limiting factor here.

Starting with the preparation of 4-arylperhydroindanes, se-

lected ortho-, meta- and para- brominated phenols and benzyl

alcohols were TBDMS protected under standard conditions

using imidazole and TBDMSCl. The protected meta- and para-

substituted aryl bromides were attached to C-4 via bromine-

lithium exchange, followed by addition to ketone 3 in good

yields (64–89 %, Scheme 3).

Scheme 3. Synthesis of 4-arylperhydroindan-4-ols 11, 12, 13 and 14 and

TBDMS deprotection resulting in triols 15, 16, 17 and 18.

Scheme 4. Synthesis of 4-benzylperhydroindanes 19, 20, 21, 22 and 23 and

TBDMS deprotection resulting in 24, 25, 26, 27 and 28.

The analogous ortho-substituted aryl bromides did undergo

As expected from the outcome of the hydroboration/oxid-

the Br–Li exchange according to TLC control, but the addition ation leading to primary alcohol 10 (Scheme 2), the newly built

to ketone 3 was unsuccessful, probably due to steric hindrance. stereocenter at C-4′ again was identified as R-configured by

All synthesised tertiary alcohols 11–14 were obtained in S con- NOESY spectroscopy (see Figure S5). TBDMS deprotection was

figuration at C-4′, as unambiguously elucidated by NMR experi- performed again using HF·py and pyridine and alcohols 24–28

ments (see Figure S4), clearly indicating asymmetric induction were isolated in surprisingly poor yields (13–33 %).

by the homochiral perhydroindane backbone. TBDMS deprotec-

tion giving triols was accomplished using HF·py and pyrid-

ine.^[33]The meta- and para-substituted phenols 15 and 16 were

obtained in 97 % and quantitative yields, whereby the meta-

and para-substituted benzyl alcohols 17 and 18 were isolated

in moderate yields of 41 % and 47 %.

As the most promising representative of 4-(arylethyl)per-

hydroindane-type seco-analogues of SH-42 we selected 33

bearing a meta-hydroxylated phenyl ring as equivalent of the

3-hydroxylated ring A of the steroidal lead structure (Scheme 5).

This molecule can, due to its ethylene linker, adopt a structure

which would mimic the steroidal backbone well, including cor-

For the introduction of a methylene linker, resulting in 4- rect position of the hydroxyl group. Construction of the aryl-

benzylperhydroindanes, the same TBDMS protected aryl brom- ethyl unit was envisaged via a Wittig olefination of aldehyde 5.

ides were used as in the synthesis of the 4-aryl compounds. As The required triphenylphosphonium bromide salt 29 was syn-

central building block exomethylene compound 4 was used thesised from 3-methoxybenzyl bromide in 80 % yield. Wittig

here (Scheme 4). For the intended Suzuki–Miyaura cross-cou- olefination was performed using LDA, and the E-isomer 30 was

pling a primary B-alkyl-BBN derivative was generated in situ by selectively formed and isolated in 44 % yield. The E-configura-

hydroboration of alkene 4 with 9-BBN. The 9-BBN reagent was tion of the olefinic group was obvious from the typical coupling

preferred over BH₃·THF (see synthesis of 10, Scheme 2), since constant of 15.8 Hz in the ¹H-NMR spectrum. Since E-configura-

this reagent has even higher selectivity for giving the anti- tion would prevent the molecule from adopting a steroid-like

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Scheme 5. Synthesis of 4-(arylethyl)perhydroindane 33.

conformation, we introduced the required flexibility by reduc-

tion of the olefinic group. Catalytic hydrogenation with Pd/C

and H₂resulted in seco-steroid 31 in 81 % yield. Fluoride-medi-

ated TBDMS cleavage giving 32 (74 % yield) and subsequent

methyl ether cleavage using BBr₃(61 % yield) gave the desired

phenolic compound 33.

We further attempted to prepare an analogue of 4-(aryl-

ethyl)perhydroindane 33 in which the equivalent of steroid ring

A is not a phenol but a cyclohexanol, which would be even

closer to the structure of lead compound SH-42. For this pur-

pose, a substituted cyclohexane residue was attached to C-4 via

an ethylene linker using Julia-Kocienski olefination (Scheme 7).

Wittig olefination using LDA or NaHMDS as base did not result

in the desired olefin (data not shown here). Starting from com-

mercially available racemic cis/trans-mixture of 3-methoxycyclo-

hexanecarboxylic acid (34) literature-known trans-36 and cis-36

were synthesised in two steps, namely reduction of the carb-

oxylic acid group to the carbinol using borane-dimethyl sulf-

Scheme 6. Synthesis of Julia reagents cis- and trans-38 from a racemic cis-/

trans-mixture of 3-methoxycyclohexane carboxylic acid (34).

ide,^[34]followed by bromination using Appel conditions is noteworthy, that the stereochemistry of cis-/trans-36 and cis-/

(Scheme 6).^[35]

trans-37 was determined only retrospectively after unambigu-

ous NMR analysis of Julia reagents trans-38 and cis-38 (see Fig-

ures S6 and S7).

The resulting racemic bromides trans-36 and cis-36 could be

separated on a preparative scale by column chromatography

and isolated in 41 % and 40 % yield, respectively. Both brom-

For the Julia-Kocienski olefination of the synthesised alkyl-

ides were converted into the corresponding alkylthiobenzothi- sulfonyl compounds and aldehyde 5 two bases (NaHMDS (pK_a=

azoles trans-37 (30 % yield) and cis-37 (42 % yield). Subsequent 29.5) and LDA (pK_a= 35.7)^[36]) were used. While isomer cis-38

thioether oxidation using m-CPBA gave alkylsulfonyl benzothi- did not give the desired product and only unidentifiable prod-

azole trans-38 in 91 % yield and cis-38 in quantitative yield. It ucts were isolated, isomer trans-38 did undergo the olefination

Scheme 7. Julia-Kocienski olefination of racemic trans-38 and aldehyde 5 resulting in the E/Z mixture 39 (E/Z ratio 55:45, determined by ¹H NMR spectroscopy).

*The ratio of the four isomers was determined by GC/MS analysis, but the peaks could not be assigned to the single stereoisomers. TBDMS cleavage of 39

resulting in one isolated pure Z-isomer of undisclosed absolute configuration.

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Scheme 8. Synthesis of building block ketone 6 starting from isomeric ketone 3.

with LDA as the base in 69 % yield (NaHMDS only gave traces) selectivity. Compounds 43a and 43c bear the generated

(Scheme 7).

hydroxyl function at the desired C-5 position with 5R configura-

tion for 43a and 5S configuration for 43c. This structure assign-

ment is supported by successful solution of the solid-state

structure of 43a. The last step was the oxidation of the hydroxyl

group of the 5-hydroxylated products, using DMP. Hereby, 43a

was converted into 6 in 99 % yield, and 43c gave the same

product in 97 % yield. The fact that both of these secondary

alcohols were oxidised to the same ketone product further con-

firms their structure assignment based on NMR data.

¹H NMR spectroscopy revealed an E/Z ratio of 55:45, but

since homochiral building block 5 was coupled with the race-

mic trans-38, four diastereomers can be formed in this olefin-

ation step. A closer look at the NMR spectrum (especially the

methoxy groups) showed a set of four signals, and the GC/MS

chromatogram of 39 expectedly showed four peaks in a ratio

of 4:5:43:48 (see Figure S2). Unfortunately, it could not be deter-

mined which of the diastereomers belongs to which signals.

TBDMS deprotection of the mixture of isomers proceeded

For the introduction of ring A mimetics at C-5 para-substi-

smoothly and chromatographic separation of the obtained mix- tuted aryl bromide 44 was attached to ketone 66 via bromine-

ture gave one fraction (16 % yield) which contained one pure lithium exchange with subsequent addition to the ketone, re-

Z-isomer. This configuration of the olefinic group is (in contrast sulting in the two separable diastereomers 45a in <2 % and

to the E-olefin 30 shown in Scheme 5) beneficial for adopting 45b in 44 % yield (Scheme 9). Both isomers differ only in their

a steroid-like three-dimensional shape, so hydrogenation of the configuration at C-5′, whereby the configurations could not be

double bond was not an option here. The two possible struc- determined in this step, due to fast dehydration of these terti-

tures of the isolated olefin are shown in Scheme 8. The absolute ary alcohols. TBDMS deprotection of the major isomer 45b us-

configuration in the methoxycyclohexane ring could not be an- ing HF·py and pyridine led to concomitant dehydration result-

alysed by NMR experiments. As experiments for cleavage of the ing in diol 46 with a Δ⁵double bond (for confirmation see

methoxy group were frustrating as well (yields not higher than Figure S8). Furthermore, the saturated version of 46 was synthe-

30 %, achieved with NaI and SiCl₄^[37]) this route was not fol- sised using reductive deoxygenation of tertiary alcohol 45b

lowed further.

with TES and TFA with subsequent TBDMS cleavage. Diols 47a

and 47b were isolated, whereby 47a is R configured at C-5′ and

47b S configured. It is noteworthy, that the absolute configura-

tions of these two products could not be determined with

NOESY spectroscopy here, but are based on the structure of

47b solved by X-ray crystallography.

In the second part of the project, seco-steroidal analogues of

SH-42 with direct connection of a ring A equivalent to C-5 of

the perhydroindane-type ring C and D unit were synthesised.

For this purpose, building block 6 was generated in a four step

synthesis starting from its regioisomer ketone 3 (Scheme 8).

The first step was O-triflation of ketone 3 using NaHMDS and

Furthermore, an open chain residue was attached to C-5,

phenyl triflimide, giving the Δ⁴-enol triflate 41 regioselectively once again starting from ketone 6. We selected a 4-hydroxy-

and in quantitative yield. For the following Pd-catalysed hydride butyl residue, since this flexible residue could exist in a confor-

transfer, a method of Liu et al.^[44]was used, resulting in the mation in which the terminal hydroxy group is located exactly

desired alkene 42 in 81 % yield. For introduction of a hydroxyl at the position of 3-OH of the steroidal diol lead structures 1

function at C-5, hydroboration was used, whereby the usage of and 2. Ketone 6, when treated with NaHMDS and phenyl triflim-

BH₃·THF and work-up with H₂O₂/NaOH resulted in the three ide, gave regioselectively the enol triflate 48 in 53 % yield

separable isomers 43a, 43b and 43c in 44 %, 14 % and 8 % (Scheme 10). The position of the double bond was once again

yields. 43b is the epimer of alcohol 9 (Scheme 2) with R config- determined by COSY spectroscopy (see Figure S9). Open chain

uration at C-4, and its formation shows that in this case the residues were attached via Sonogashira cross-coupling of enol

hydroboration step did not take place with complete regio- triflate 48 and but-3-yn-1-ol. The cross-coupled product 49 was

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Scheme 9. Synthesis of seco-steroidal analogues 46 and 47a and its diastereomer 47b starting from ketone 6.

Scheme 10. Synthesis of steroid-like analogues 50 and 51 starting from ketone 6.

filtered through a celite pad and was used for the following target enzyme by analogues of the lead structure. Unfortu-

steps without further purification. TBDMS deprotection using nately, none of the synthesised seco-steroids showed an inhibi-

HF·py and pyridine gave diol 50 in 86 % yield over both steps. tion of DHCR24. However, the seco-steroidal analogues 25 and

Since this enyne has a rather rigid geometry (which can be 51 inhibited the enzyme sterol C5-desaturase, as clearly indi-

beneficial or detrimental for affinity to the target enzyme), we cated by an accumulation of lathosterol in the sterol fraction of

also prepared a much more flexible fully saturated analogue. the treated cells (see Figure S1). In previous investigations we

For this purpose, crude 49 was hydrogenated using PtO₂and could demonstrate that the so-called lathosterol side chain

H₂with subsequent TBDMS cleavage, leading to diol 51 in 21 % amides bearing larger N-alkyl groups inhibit this enzyme as

yield over three steps. The configuration at C-5 could not be well, whereas amides with small N-substituents (H or methyl,

determined by NOESY spectroscopy here, since no relevant pro- e.g. MGI-21) preferably inhibited DHCR24.^[22]

tons in this molecule gave separated and well resolved signals

in the NMR spectra. Unfortunately, no solid-state structure

could be measured in this case as well.

Moreover, cytotoxicity of the new compounds was investi-

gated on HL-60 cells using an MTT assay, and only one com-

pound, phenol 46, showed moderate activity there with an IC₅₀

Nevertheless, products 50 and 51, in addition to the 5′- value of 7.3 μ

(hydroxyphenyl) derivatives 46, 47a and 47b and the 4-substi-

tuted perhydroindanes bearing ring A equivalents with spacers

M (see Supporting Information).

Conclusion

of various length, were attractive test compounds for the inves-

tigation of inhibitory activity on the target enzyme DHCR24.

Seco-steroid analogues of the potent DHCR24 inhibitor SH-42

were synthesised based on central building blocks 3, 4, 5 and 6,

which were derived from ergocalciferol. These building blocks

represent equivalents of rings C and D of the steroidal lead

Biology

All final compounds were tested in an in vitro whole-cell assay structure. Based on our hypothesis that variations of ring B

developed in our group on their inhibitory activity on enzymes might be well tolerated, we prepared ring B seco-analogues by

in cholesterol biosynthesis.^[38]This assay is able to detect inhibi- connection of these building blocks with cyclic and acyclic ring

tion of any of the enzymes in the post-squalene part of choles- A mimetics like hydroxylated aromatic and aliphatic rings as

terol biosynthesis, and would not only identify inhibitors of the well as hydroxyalkyl residues. 4-Arylperhydroindanols were

target enzyme DHCR24, but also detect a possible shift in the formed from 3 and TBDMS protected phenols and benzyl alco-

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NMR-division of the Department of Pharmacy of the LMU. Chemical

shifts δ are reported as δ-values in ppm (parts per million) and refer

to the deuterated solvent peak. Coupling constants (J) of protons

are stated in Hz. The signal multiplicities are defined using the fol-

lowing abbreviations: s (singlet), d (doublet), dd (double doublet),

dt (double triplet), t (triplet), q (quartet), p (pentet), ddd (doublet

of doublet of doublets), tdd (triplet of doublet of doublets), dtd

(doublet of triplet of doublets) and m (multiplet). The signal assign-

ment was carried out using HMQC, HMBC, COSY and DEPT spectra.

All spectra were evaluated using MestReNova by Mestrelab Re-

hols. With exomethylene compound 4 a methylene linker could

be introduced resulting in 4-benzylperhydroindanes. To receive

the highest similarity to the steroidal structure, Wittig olefin-

ation of aldehyde 5 gave seco-steroid 33. Moreover, a methoxy-

substituted cyclohexylethyl residue was attached to C-4 using

a Julia-Kocienski olefination. Besides the C-4 position, an aro-

matic and some open-chain residues were attached to C-5,

based on building block 6. Unfortunately, none of these struc-

turally diverse seco-analogues of SH-42 showed noteworthy in-

hibition of the target enzyme DHCR24, indicating the relevance search S.L. Infrared spectra were measured on a JASCO FT/IR-4100

infrared spectrometer, using a Smiths Detection DuraSamp IR II Dia-

of the steroidal structure for the development of potent inhibi-

tors of this enzyme. This is in contrast to our former successful

development of potent and selective inhibitors of late enzymes

in cholesterol and ergosterol biosynthesis based on truncated

steroids.^[39,40]Further, we did not observe a noteworthy shift

towards cytotoxicity, as found for other ring A and B-modified

steroids in our previous investigations^[41,42]and recently de-

scribed for a ring B-seco-steroid from the Australian desert

shrub Frankenia foliosa.^[43]Nevertheless, the chemistry de-

mond ATR sensor for detection. The measured wavenumbers ν are

˜

reported in cm^–1. High resolution mass spectra (HRMS) were re-

corded on a Jeol Mstation 700 or JMS GCmate II Jeol instrument for

electron ionisation (EI). Electrospray ionisation (ESI) was measured

on a Thermo Finnigan LTQ-FT. All measurements were performed

by the mass spectroscopy service of the LMU. The mass is reported

in m/z units with the mass of the molecular ion. Gas chromatogra-

phy (GC) for the determination of purities was performed on a

Varian 3800 gas chromatograph coupled to a Saturn 2200 ion trap

scribed here, involving sophisticated functionalisation of bi- from Varian (Darmstadt, Germany). The auto sampler was from CTC

Analytics (Zwingen, Switzerland) and the split/splitless injector was

a Varian 1177 (Darmstadt, Germany). Instrument control and data

analysis were carried out with Varian Workstation 6.9 SP1 software.

A VF-5-ms capillary column of 30 m length, 0.25 mm i.d. and

0.25 μm film thickness was used at a constant flow rate of 1.4 mL/

min. Carrier gas was helium 99.999 % from Air Liquide (Düsseldorf,

Germany). The inlet temperature was kept at 300 °C and injection

volume was 1 μL with splitless time 1.0 min. The initial column

temperature was 50 °C and was held for 1.0 min. Then temperature

was ramped up to 250 °C with 50 °C/min. Then the sterols were

eluted at a rate of 5 °C/min until 310 °C (hold time 3 min). Total run

time was 20 min. Transfer line temperature was 300 °C and the ion

trap temperature was 150 °C. The ion trap was operated with elec-

tron ionisation (EI) at 70 eV in scan mode (m/z 50–650) with a sol-

vent delay of 6.3 min.

cyclic building blocks resembling rings C and D of natural

steroids, should inspire other scientists to synthesise steroid-like

compounds from these or related building blocks. Our experi-

ments clearly showed up that functionalisations of these build-

ing blocks occur with impressing selectivity, as for example

seen for regioselective dehydrations and formation of enol tri-

flates, stereoselective nucleophilic additions to ketones, and

stereo- and regioselective hydroborations.

Experimental Section

Materials and Methods: All oxygen- and moisture-sensitive reac-

tions were carried out in oven-dried glassware under nitrogen at-

mosphere using Schlenk-technique. Anhydrous solvents and rea-

gents were transferred through syringes under nitrogen. Solvents

used for anhydrous reactions were dried by standard methods of

distillation over drying agents. DCM was dried with molecular sieves

(3Å) after distillation. THF was distilled from sodium and benzo-

phenone. All other solvents and reagents were obtained from com-

mercial sources (abcr, Acros, Fluka, Merck, Sigma-Aldrich or TCI in

the qualities puriss., p.a., or purum) and used without further purifi-

cation.

HPLC analytical measurements for determination of the purities of

the products were carried out detecting at 191 nm, 210 nm, 250 nm

and 254 nm using the following methods: method a (column:

Agilent Poroshell 120®, EC-C18 2.7μm (3.0 × 100 mm), flow rate:

0.5 mL/min, eluent: ACN/H₂O 4:6 + 0.1 % formic acid); method b

(column: Zorbax Eclipse Plus®, C18 5.0 μm (4.6 × 150 mm), flow rate:

0.5 mL/min, eluent: ACN/H₂O 7:3 + 0.1 % formic acid); method c

(column: Agilent Poroshell 120®, EC-C18 2.7 μm (3.0 × 100 mm),

flow rate: 1.0 mL/min, eluent: ACN/H₂O 9:1); method d (column:

InfinityLab Poroshell 120®, EC-C18 2.7 μm (3.0 × 100 mm), flow rate:

0.5 mL/min, eluent: ACN/MeOH 9:1); method e (column: Zorbax

Eclipse Plus®, C18 5.0 μm (4.6 × 150 mm), flow rate: 0.5 mL/min,

eluent: ACN/H₂O 95:5).

Thin layer chromatography (TLC) for qualitative reaction and frac-

tion controls was performed using pre-coated polyester sheets

Polygram SIL G/UV254 with SiO₂coating (0.2 mm, 40 × 80 mm) by

Macherey-Nagel. As visualisation method CAM stain (ceric ammon-

ium molybdate) with subsequent heating was used. Flash column

chromatography (FCC) was carried out using SiO₂60 (particle size

40–63 μm) by Merck. Melting points were measured in single deter-

mination on a Büchi Melting Point B-540 device and are stated

in °C. Values for specific rotation [α] were measured at 23 °C at a

wavelength of λ = 589 nm (Na-D-line) using a Perkin Elmer 241

Polarimeter instrument. All samples were dissolved in chloroform

(compounds 15 and 46 in methanol) (path length l = 10 cm), the

concentration is stated in g/100 mL.

Deposition Numbers 2019661 (for 43a ) and 2019660 (for 47b ) con-

tain the supplementary crystallographic data for this paper. These

data are provided free of charge by the joint Cambridge Crystallo-

graphic Data Centre and Fachinformationszentrum Karlsruhe Access

Structures service www.ccdc.cam.ac.uk/structure s.

General Procedures

General Procedure 1 (GP1) for Bromine-lithium Exchange and

Nucleophilic Addition to Ketones: In an oven-dried two-necked

Schlenk flask the appropriate aryl bromide (1.10 equiv.) was dis-

solved in dry THF to receive a concentration of 0.3 mmol/mL. The

solution was cooled to –78 °C and nBuLi (1.20 equiv.) was added.

The reaction mixture was stirred for 1 h at –78 °C. The organo-

All NMR spectra were recorded at room temperature using JNM-

Eclipse 400 (400 MHz), JNM-Eclipse 500 (500 MHz), Avance III HD

400 MHz Bruker Biospin (400 MHz) and Avance III HD 500 MHz

Bruker Biospin (500 MHz) mit CryoProbe™ Prodigy through the

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European Journal of Organic Chemistry

lithium species was used without further purification. Ketone 3/6

(1R,3aR,4S,7aR)-1-((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-

(1.00 equiv.) was dissolved in dry THF to receive a concentration of yl)-7a-methyloctahydro-1H-inden-4-ol (9): In an oven-dried flask

0.3 mmol/mL and this solution was added to the solution of the

organolithium species at –78 °C and stirred for additional 1 h. The

diol 8 (200 mg, 0.942 mmol, 1.00 equiv.) was dissolved in dry DCM

(10.0 mL) and the solution was cooled to 0 °C. TBDMSCl (161 mg,

reaction was stopped with sat. aq. NH₄Cl solution, warmed to r.t. 1.04 mmol, 1.1 equiv.), DMAP (11.5 mg, 0.0942 mmol, 10 mol-%)

and the layers were separated. The aq. layer was extracted with

EtOAc (3 × ) and the combined organic layers were washed with

brine, dried with Na₂SO₄, filtered and the solvent was removed in

vacuo. The title compound was purified via FCC (SiO₂).

and triethylamine (0.394 mL, 2.83 mmol, 3.0 equiv.) were sequen-

tially added. The mixture was slowly warmed to r.t. and stirred for

13 h. The reaction was stopped with water (5.00 mL) and extracted

with DCM (3 × 15.0 mL). The combined organic layers were dried

with Na₂SO₄, filtered and the solvent was removed in vacuo. The

title compound was purified via FCC (hexanes/EtOAc, 8:2) and iso-

lated as colourless oil (309 mg, 0.946 mmol, quantitative): R_f= 0.51

(hexanes/EtOAc, 8:2); [α]_D²³: +30 (c = 0.12, CHCl₃); ¹H NMR (500 MHz,

[D]chloroform) δ/ppm = 4.07 (d, J = 3.1 Hz, 1H, 4-OH), 3.57 (dd, J =

9.6, 3.3 Hz, 1H, 1′-H), 3.26 (dd, J = 9.6, 7.3 Hz, 1H, 1′-H), 1.99 (dt, J =

12.7, 3.1 Hz, 1H, 7-H), 1.87–1.74 (m, 3H, 2,5,6-H), 1.61–1.38 (m, 5H,

3, 5, 6, 2′-H), 1.36–1.25 (m, 3H, 2, 3a-H, 4-OH), 1.19–1.07 (m, 2H

1,7-H), 0.96 (d, J = 6.5 Hz, 3H, 2′-CH₃), 0.93 (s, 3H, 7a-CH₃), 0.88 (s,

9H, SiC(CH₃)₃), 0.02 (s, 6H, Si(CH₃)₂); ¹³C NMR (126 MHz, [D]chloro-

form) δ/ppm = 69.4 (C-4), 67.9 (C-2′), 53.3 (C-1), 52.5 (C-3a), 42.0

(C-7a), 40.4 (C-7), 38.7 (C-1′), 33.8 (C-5), 26.8 (C-2), 26.11 (SiC(CH₃)₃),

22.8 (C-3), 18.5 (SiC(CH₃)₃), 17.6 (C-6), 16.9 (1′-CH₃), 13.8 (7a-CH₃),

General Procedure 2 (GP2) for Suzuki–Miyaura Cross-coupling:

In an oven-dried two-necked Schlenk flask alkene 4 (1.00 equiv.)

was dissolved in dry THF to receive a concentration of 0.3 mmol/

mL and cooled to 0 °C. 9-BBN (0.5

M in THF, 1.10 equiv.) was added

and the mixture was warmed up slowly to r.t. and then stirred for

2 h to give a solution of the appropriate alkyl-9-BBN. The aryl brom-

ide (1.00 equiv.) and Pd(PPh₃)₄(3 mol-%) were dissolved in dry THF

to receive a concentration of 0.3

alkyl-9-BBN solution and aq. 2

M

and added to the degassed

M

NaOH (40.0 μL per 1.00 mmol

alkene) was added. The mixture was refluxed for 12 h. The reaction

mixture was diluted with water and the aq. phase was extracted

with hexanes (3 × ), washed with brine, dried with Na₂SO₄, filtered

and the crude product was purified via FCC (SiO₂).

–5.2 (Si(CH₃)₂), –5.3 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 3769, 3677, 2928,

˜

2856, 1471, 1388, 1360, 1251, 1091, 1061, 1033, 1005, 989, 942, 833,

General Procedure 3 (GP3) for TBDMS Deprotection: In an oven-

dried flask the appropriate TBDMS-protected alcohol/phenol

(1.00 equiv.), HF·pyr (ca. 30 % pyridine, ca. 70 % HF, 2.20 equiv. per

TBDMS group), pyridine (2.30 equiv. per TBDMS group) were dis-

solved in EtOAc to receive a concentration of 0.1 mmol/mL. The

reaction mixture was stirred at r.t. for 18 h. The reaction was

stopped with methoxytrimethylsilane (35.0 equiv.) and stirred for

additional 40 min. The solvent was removed in vacuo and the crude

product was purified via FCC (SiO₂).

812, 773, 723, 692, 664, 620; HRMS (EI): m/z calculated for

+

˙

C₁₉H₃₈O₂Si [M] 326.2636, found 326.2628; Purity (GC): 94 % (scan

mode m/z 50–650 (EI 70 eV)).

(1R,3aR,7aR)-1-((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-

7a-methyloctahydro-4H-inden-4-one (3): In an oven-dried flask 9

(1.12 g, 3.43 mmol, 1.00 equiv.) was dissolved in dry DCM (20.0 mL).

DMP (2.18 g, 5.14 mmol, 1.50 equiv.) was added and the reaction

mixture was stirred at r.t. for 3 h. The reaction mixture was diluted

with Et₂O (46 mL), water (46 mL) and an excess of Na₂S₂O₃and the

suspension was stirred for additional 30 min. The two layers were

separated, and the aq. phase was extracted with EtOAc (3 × ). The

combined organic layers were dried with Na₂SO₄, filtered and the

solvent was removed in vacuo. The title compound was purified

via FCC (hexanes/EtOAc, 9:1) and isolated as colourless oil (1.01 g,

3.11 mmol, 91 %): R_f= 0.40 (hexanes/EtOAc, 9:1); [α]²_D³: +1.0 (c =

0.11, CHCl₃); ¹H NMR (500 MHz, [D]chloroform) δ/ppm = 3.56 (dd,

J = 9.6, 2.7 Hz, 1H, 1′-H), 3.35–3.28 (m, 1H, 1′-H), 2.48–2.39 (m, 1H,

3a-H), 2.32–2.17 (m, 2H, 5-H), 2.11 (ddd, J = 13.1, 4.7, 2.4 Hz, 1H, 7-

H), 2.01 (dddt, J = 14.4, 7.3, 4.8, 2.3 Hz, 1H, 6-H), 1.95–1.81 (m, 2H,

2,6-H), 1.74 (dtd, J = 13.3, 11.8, 6.2 Hz, 1H, 3-H), 1.64–1.46 (m, 4H,

1, 3, 7, 2′-H), 1.39–1.29 (m, 1H, 2-H), 1.02 (d, J = 6.0 Hz, 3H, 2′-CH₃),

(1R,3aR,4S,7aR)-1-((S)-1-Hydroxypropan-2-yl)-7a-methylocta-

hydro-1H-inden-4-ol (8):^[30,32]Ergocalciferol (7, 5.00 g, 13.0 mmol,

1.00 equiv.) was dissolved in methanol p.a. (500 mL) and dry pyrid-

ine (5.00 mL) was added. The reaction mixture was cooled to

–78 °C. Ozone was passed through the reaction mixture (flow rate

60 L/h, 50 Hz). After 2 h a grey-blue colour appeared, and the ozone

flow was discontinued, and the reaction mixture was purged with

N₂to remove the remaining dissolved ozone for 10 min. The solu-

tion was warmed to 0 °C and NaBH₄(8.50 g, 225 mmol, 18.0 equiv.)

was added portion wise over a period of 1 h. The reaction mixture

was warmed up to r.t. overnight. The reaction was quenched with

1

M aq. HCl (100 mL), concentrated in vacuo (ca. 100 mL) and the

0.89 (s, 9H, SiC(CH₃)₃), 0.64 (s, 3H, 7a-CH₃), 0.03 (s, 6H, Si(CH₃)₂); ¹³

C

residue was extracted with EtOAc (3 × 200 mL). The organic layers

were dried with Na₂SO₄, filtered and the solvent was removed in

vacuo. The title compound was purified via FCC (hexanes/EtOAc,

7:3) and isolated as white crystalline solid (1.73 g, 8.15 mmol, 65 %):

R_f= 0.21 (hexanes/EtOAc, 7:3); mp: 112–114 °C [lit. 108–110 °C^[32]];

[α]²_D³: + 36 (c = 0.11, CHCl₃) [lit. + 54 (c = 1.5, CHCl₃)^[32]]; ¹H NMR

(500 MHz, [D]chloroform) δ/ppm = 4.08 (t, J = 2.8 Hz, 1H, 4-H), 3.63

(dt, J = 10.4, 3.8 Hz, 1H, 1′-H), 3.40–3.34 (m, 1H, 1′-H), 2.01–1.95 (m,

1H, 7-H), 1.88–1.76 (m, 3H, 2,5,6-H), 1.60–1.51 (m, 2H, 3, 2′-H), 1.51–

1.40 (m, 3H, 3,5,6-H), 1.38–1.29 (m, 4H, 2, 3a, 4-OH, 1′-OH), 1.21–

1.12 (m, 2H, 1,7-H), 1.02 (d, J = 6.7 Hz, 3H, 2′-CH₃), 0.95 (s, 3H, 7a-

CH₃); ¹³C NMR (126 MHz, [D]chloroform) δ/ppm = 69.4 (C-4), 67.9

NMR (126 MHz, [D]chloroform) δ/ppm = 212.1 (C-4), 67.7 (C-2′), 61.9

(C-3a), 53.3 (C-1), 50.1 (C-7a), 41.1 (C-5), 39.0 (C-7), 38.8 (C-1′), 27.1

(C-2), 26.1 (SiC(CH₃)₃), 24.2 (C-6), 19.4 (C-3), 18.5 (SiC(CH₃)₃), 17.2

(1′-CH₃), 12.7 (7a-CH₃), –5.2 (Si(CH₃)₂), –5.3 (Si(CH₃)₂); IR (ATR): ν =

˜

cm^–1= 2954, 2929, 2889, 2856, 1715, 1471, 1458, 1384, 1361, 1307,

1250, 1218, 1186, 1091, 1057, 1038, 1005, 940, 834, 773, 679; HRMS

+

˙

(EI): m/z calculated for C₁₉H₃₆O₂Si [M] 324.2479, found 324.2464;

Purity (HPLC): > 95 % (λ = 191 nm) (method c).

tert-Butyldimethyl((S)-2-((1R,3aS,7aR)-7a-methyl-4-methylene-

octahydro-1H-inden-1-yl)propoxy)silane (4): In an oven-dried

Schlenk-flask methyltriphenylphosphonium bromide (2.41 g,

(C-2′), 53.1 (C-1), 52.51 (C-3a), 42.0 (C-7a), 40.4 (C-7), 38.4 (C-1′), 33.7 6.75 mmol, 1.50 equiv.) was dissolved in dry THF (30.0 mL) and the

(C-5), 26.8 (C-2), 22.7 (C-3), 17.6 (C-6), 16.8 (1′-CH₃), 13.7 (7a-CH₃);

solution was cooled to 0 °C. LDA (2 M in THF, 4.50 mL, 9.00 mmol,

IR (ATR): ν = cm^–1= 3792, 3348, 2930, 2864, 2359, 1473, 1458, 1439, 2.00 equiv.) was added and the mixture was stirred for 30 min. A

˜

1382, 1358, 1181, 1161, 1066, 1030, 987, 957, 940, 727; HRMS (EI): solution of ketone 3 (1.46 g, 4.50 mmol, 1.00 equiv.) in dry THF

+

˙

m/z calculated for C₁₂H₂₁O₂[M – CH₃] 197.1542, found 197.1532; (10.0 mL) was added and the reaction mixture was slowly warmed

Purity (GC): > 95 % (scan mode m/z 50–650 (EI 70 eV)).

up to r.t. and stirred for 18 h. The reaction was diluted with water

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European Journal of Organic Chemistry

(20.0 mL) and the mixture was extracted with EtOAc (3 × 40.0 mL).

The combined organic layers were dried with Na₂SO₄, filtered and

the solvent was removed in vacuo. The title compound was purified

(400 MHz, [D]chloroform) δ/ppm = 10.03 (s, 1H, CHO), 3.57 (dd, J =

9.6, 3.3 Hz, 1H, 1′-H), 3.29 (dd, J = 9.6, 7.0 Hz, 1H, 1′-H), 2.52–2.46

(m, 1H, 4-H), 2.28 (dd, J = 13.7, 3.3 Hz, 1H, 2-H or 5-H), 1.96 (dt, J =

via FCC (hexanes/toluene, 9:1) and obtained as colourless oil 13.3, 3.5 Hz, 1H, 7-H), 1.93–1.87 (m, 1H, 2-H or 5-H), 1.87–1.80 (m,

(980 mg, 3.04 mmol, 68 %): R_f= 0.30 (hexanes/toluene, 9:1);

1H, 1-H), 1.80–1.69 (m, 2H, 3-H or 6-H), 1.48 (ddq, J = 13.5, 6.7,

[α]²_D³: +60 (c = 0.11, CHCl₃); ¹H NMR (400 MHz, [D]chloroform) 3.7 Hz, 3H, 2′′-H, 3-H or 6-H), 1.38–1.30 (m, 1H, 2-H or 5-H), 1.30–

δ/ppm = 4.74 (q, J = 1.9 Hz, 1H, 1′′-H), 4.46 (q, J = 2.0 Hz, 1H, 1.09 (m, 3H, 3a-H, 7-H), 0.97 (d, J = 6.6 Hz, 3H, 2′-CH₃), 0.89 (s, 9H,

1′′-H), 3.60 (dd, J = 9.6, 3.4 Hz, 1H, 1-H), 3.27 (dd, J = 9.6, 7.4 Hz,

1H, 1-H), 2.30–2.23 (m, 1H, 5′-H), 2.04–1.97 (m, 1H, 7′-H), 1.96–1.89

(m, 2H, 3a′, 5′-H), 1.88–1.81 (m, 1H, 3′-H), 1.66–1.47 (m, 5H, 2, 2′,

6′-H), 1.37–1.23 (m, 3H, 1′, 3′, 7′-H), 1.01 (d, J = 6.5 Hz, 3H, 2-CH₃),

0.90 (s, 9H, SiC(CH₃)₃), 0.57 (d, J = 0.6 Hz, 3H, 7a′-CH₃), 0.04 (s, 3H,

Si(CH₃)₂), 0.03 (s, 3H, Si(CH₃)₂); ¹³C NMR (101 MHz, [D]chloroform)

δ/ppm = 149.7 (C-4′), 105.2 (C-1′′), 68.0 (C-1), 55.2 (C-3a′), 53.1

(C-1′), 45.3 (C-7a′), 40.2 (C-7′), 39.5 (C-2), 35.6 (C-5′), 27.3 (C-3′), 26.1

(SiC(CH₃)₃), 23.9 (C-6′), 22.6 (C-2′), 18.6 (SiC(CH₃)₃), 17.2 (2-CH₃), 12.0

SiC(CH₃)₃), 0.63 (s, 3H, 7a-CH₃), 0.03 (s, 3H, Si(CH₃)₂), 0.03 (s, 3H,

Si(CH₃)₂); ¹³C NMR (101 MHz, [D]chloroform) δ/ppm = 205.0 (CHO),

67.9 (C-1′), 52.9 (C-3a), 51.2 (C-1), 48.7 (C-4), 42.9 (C-7a), 40.1 (C-7),

39.1 (C-2′), 26.9 (C-2 or C-5), 26.1 (SiC(CH₃)₃), 25.2 (C-2 or C-5), 23.2

(C-3 or C-6), 19.1 (C-3 or C-6), 18.5 (SiC(CH₃)₃), 17.1 (2′-CH₃), 12.7

(7a-CH₃), –5.2 (Si(CH₃)₂), –5.3 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 2951,

˜

2930, 2855, 2736, 2363, 1716, 1472, 1462, 1388, 1361, 1250, 1187,

1124, 981, 938, 915, 894, 833, 814, 773, 705, 666; HRMS (EI): m/z

+

˙

calculated for C₂₀H₃₈O₂Si [M] 338.2641, found 338.2632; Purity

(7a′-CH₃), –5.2 (Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 2950,

(GC): 86 % (scan mode m/z 50–650 (EI 70 eV)).

˜

2927, 2855, 1650, 1471, 1252, 1088, 1030, 1004, 884, 833, 773, 665;

(1R,3aR,4S,7aR)-4-(3-((tert-Butyldimethylsilyl)oxy)phenyl)-1-

((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7a-methylocta-

hydro-1H-inden-4-ol (11): Alcohol 11 was synthesised according

to GP1 using TBDMS-protected 3-bromophenol (180 mg,

0.627 mmol, 1.10 equiv.) and ketone 3 (184 mg, 0.568 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 9:1) and isolated as colourless oil (195 mg, 0.366 mmol,

64 %): R_f= 0.48 (hexanes/EtOAc, 9:1); [α]²_D³: +49 (c = 0.040, CHCl₃);

¹H NMR (400 MHz, [D]chloroform) δ/ppm = 7.17 (t, J = 7.9 Hz, 1H,

5′′-H), 7.00 (ddd, J = 7.8, 1.9, 1.0 Hz, 1H, 6′′-H), 6.94 (t, J = 2.1 Hz,

+

˙

HRMS (EI): m/z calculated for C₂₀H₃₈OSi [M] 322.2686, found

322.2689; Purity (GC): > 95 % (scan mode m/z 50–650 (EI 70 eV)).

((1R,3aS,4S,7aR)-1-((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-

yl)-7a-methyloctahydro-1H-inden-4-yl)methanol (10): In an

oven-dried Schlenk flask 4 (688 mg, 2.13 mmol, 1.00 equiv.) was

dissolved in dry THF (10.0 mL) and the solution was cooled to 0 °C.

BH₃·THF (1

dropwise and the reaction mixture was warmed to r.t. and stirred

for 2 h. The reaction mixture was cooled to 0 °C and aq. 1 NaOH

M in THF, 6.40 mL, 6.40 mmol, 3.00 equiv.) was added

M

(25.0 mL) and 30 % (w/w) H₂O₂(25.0 mL) were added and the re- 1H, 2′′-H), 6.68 (ddd, J = 8.0, 2.4, 1.0 Hz, 1H, 4′′-H), 3.56 (dd, J = 9.6,

sulting mixture was stirred at r.t. for 18 h. The two layers were

separated, and the aq. phase was extracted with DCM (3 × 50.0 mL).

The combined organic layers were dried with Na₂SO₄, filtered and

the solvent was removed in vacuo. The title compound was purified

3.4 Hz, 1H, 1′-H), 3.27 (dd, J = 9.6, 7.2 Hz, 1H, 1′-H), 2.11–2.04 (m,

1H, 2, 3, 5, 6 or 7-H), 2.02–1.92 (m, 1H, 2,3,5,6-H), 1.76–1.65 (m, 4H,

3a-H, 2, 3, 5, 6 or 7-H), 1.63–1.51 (m, 2H, 2′-H, 2,3,5,6-H), 1.47 (s, 1H,

OH), 1.35–1.18 (m, 4H, 2, 3, 5, 6 or 7-H), 1.04 (s, 3H, 7a-CH₃), 1.01

via FCC (hexanes/EtOAc, 8:2) and isolated as white solid (526 mg, (d, J = 6.5 Hz, 3H, 2′-CH₃), 0.98 (s, 9H, SiC(CH₃)₃), 0.89 (s, 9H,

1.54 mmol, 72 %): R_f= 0.37 (hexanes/EtOAc, 8:2); mp: 85–87 °C;

SiC(CH₃)₃), 0.19 (s, 6H, Si(CH₃)₂), 0.02 (s, 6H, Si(CH₃)₂); ¹³C NMR

[α]²_D³: +64 (c = 0.11, CHCl₃); ¹H NMR (500 MHz, [D]chloroform) (101 MHz, [D]chloroform) δ/ppm = 155.7 (C-3′′), 150.8 (C-1′′), 129.0

δ/ppm = 3.72 (ddd, J = 10.3, 3.1, 1.2 Hz, 1H, 4-CH₂), 3.66 (t, J = (C-5′′), 117.9 (C-4′′) 117.7 (C-6′′), 116.8 (C-2′′), 76.3 (C-4), 67.8 (C-1′),

10.0 Hz, 1H, 4-CH₂), 3.57 (dd, J = 9.6, 3.3 Hz, 1H, 1′-H), 3.25 (dd, J =

9.6, 7.4 Hz, 1H, 1′-H), 1.96–1.90 (m, 2H, 4,6-H), 1.90–1.85 (m, 1H, 5-

H), 1.82–1.74 (m, 1H, 3-H), 1.58–1.41 (m, 5H, 2, 3a, 7, 2′-H), 1.37–

56.3 (C-3a), 53.5 (C-1), 43.1 (C-7a), 40.9 (C-2, 3, 5, 6 or 7), 40.3 (C-2,

3, 5, 6 or 7), 38.7 (C-2′), 26.3 (C-2, 3, 5, 6 or 7), 26.1 (SiC(CH₃)₃), 25.9

(SiC(CH₃)₃), 20.4 (C-2, 3, 5, 6 or 7), 19.6 (C-2, 3, 5, 6 or 7), 18.5

1.29 (m, 1H, 5-H), 1.27–1.19 (m, 2H, 3-H, OH), 1.17–1.08 (m, 2H, 1,6- (SiC(CH₃)₃), 18.4 (SiC(CH₃)₃), 16.9 (2′-CH₃), 13.5 (7a-CH₃), –4.2

H), 0.95 (d, J = 6.5 Hz, 3H, 2′-CH₃), 0.89 (s, 9H, SiC(CH₃)₃), 0.64 (s, (Si(CH₃)₂), –4.2 (Si(CH₃)₂), –5.2 (Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν =

3H, 7a-CH₃), 0.02 (s, 3H, Si(CH₃)₂), 0.02 (s, 3H, Si(CH₃)₂); ¹³C NMR cm^–1= 3498, 2951, 2928, 2857, 2357, 1600, 1583, 1482, 1471, 1462,

˜

(126 MHz, [D]chloroform) δ/ppm = 67.9 (C-1′), 61.7 (4-CH₂), 53.5

(C-1), 51.6 (C-3a), 42.2 (C-7a), 40.9 (C-4), 40.7 (C-6), 39.2 (C-2′), 28.1

(C-5), 26.9 (C-3), 26.1 (SiC(CH₃)₃), 23.8 (C-2), 18.5 (SiC(CH₃)₃), 18.3

(C-7), 16.9 (2′-CH₃), 13.6 (7a-CH₃), –5.2 (Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR

1427, 1388, 1361, 1004, 986, 941, 918, 830, 814, 774, 731, 698, 667;

HRMS (EI): m/z calculated for C₃₁H₅₆O₃Si₂[M] 532.3768, found

532.3771; Purity (HPLC): > 95 % (λ = 210 nm), > 95 % (λ = 250 nm)

(method d).

+

˙

(ATR): ν = cm^–1= 3298, 2945, 2928, 2854, 1471, 1250, 1087, 1019,

˜

(1R,3aR,4S,7aR)-4-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-

((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7a-methylocta-

hydro-1H-inden-4-ol (12): Alcohol 12 was synthesised according

to GP1 using TBDMS-protected 4-bromophenol 44 (159 mg,

0.553 mmol, 1.10 equiv.) and ketone 3 (164 mg, 0.505 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 9:1) and isolated as white solid (239 mg, 0.448 mmol, 89 %):

908, 859, 844, 833, 733, 734, 663; HRMS (EI): m/z calculated for

+

˙

C₂₀H₄₀O₂Si [M] 340.2792, found 340.2791; Purity (GC): > 95 % (scan

mode m/z 50–650 (EI 70 eV)).

(1R,3aS,4S,7aR)-1-((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-

yl)-7a-methyloctahydro-1H-indene-4-carbaldehyde (5): In an

oven-dried flask 10 (465 mg, 1.37 mmol, 1.00 equiv.) was dissolved

in dry DCM (10.0 mL). DMP (869 mg, 2.06 mmol, 1.50 equiv.) was R_f= 0.40 (hexanes/EtOAc, 9:1); mp: 71–73 °C; [α]²_D³: +35 (c = 0.030,

added and the reaction mixture was stirred at r.t. for 3 h. The reac-

tion mixture was diluted with Et₂O (15.0 mL), water (15.0 mL) and

an excess of Na₂S₂O₃and the suspension was stirred for additional

30 min. The two layers were separated, and the aq. phase was ex-

tracted with EtOAc (3 × 20.0 mL). The combined organic layers were

CHCl₃); ¹H NMR (400 MHz, [D₂]dichloromethane) δ/ppm = 7.30–7.25

(m, 2H, 2′′, 6′′-H), 6.80–6.74 (m, 2H, 3′′, 5′′-H), 3.57 (dd, J = 9.6,

3.3 Hz, 1H, 1′-H), 3.28 (dd, J = 9.6, 7.1 Hz, 1H, 1′-H), 2.05 (dt, J =

12.6, 3.3 Hz, 1H, 6-H), 1.94 (tt, J = 13.3, 4.3 Hz, 1H, 2 or 3-H), 1.78–

1.63 (m, 4H, 3a, 5,7-H), 1.61–1.53 (m, 2H, 2′-H, 2 or 3-H), 1.50 (s, 1H,

dried with Na₂SO₄, filtered and the solvent was removed in vacuo. OH), 1.34–1.17 (m, 5H, 1,6,7-H, 2 or 3-H), 1.03 (s, 3H, 7a-CH₃), 1.01

The title compound was purified via FCC (hexanes/EtOAc, 85:15) (d, J = 6.6 Hz, 3H, 2′-CH₃), 0.98 (s, 9H, Si(CH₃)₃), 0.89 (s, 9H, Si(CH₃)₃),

and isolated as a colourless oil (265 mg, 0.783 mmol, 57 %): R_f=

0.19 (s, 6H, Si(CH₃)₂), 0.02 (s, 6H, Si(CH₃)₂); ¹³C NMR (126 MHz, [D₂]di-

chloromethane) δ/ppm = 154.5 (C-4′′), 142.6 (C-1′′), 126.2 (C-2′′, C-

0.90 (hexanes/EtOAc, 85:15); [α]²_D³: +95 (c = 0.050, CHCl₃); ¹H NMR

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+

˙

6′′), 119.8 (C-3′′, C-5′′), 76.4 (C-4), 68.2 (C-1′), 56.8 (C-3a), 53.9 (C-7a), calculated for C₃₂H₅₇O₃Si₂[M] 545.3840, found 545.3840; Purity

43.6 (C-5), 41.5 (C-6), 40.7 (C-2′), 39.2 (C-7), 26.7 (SiC(CH₃)₃), 26.3

(SiC(CH₃)₃), 26.0 (C-2 or C-3), 20.9 (C-2 or C-3), 20.1 (SiC(CH₃)₃), 18.6

(SiC(CH₃)₃), 17.1 (2′-CH₃), 13.7 (7a-CH₃), –4.2 (Si(CH₃)₂), –5.1

(HPLC): > 95 % (λ = 210 nm) (method a).

(1R,3aR,4S,7aR)-4-(3-Hydroxyphenyl)-1-((S)-1-hydroxypropan-2-

yl)-7a-methyloctahydro-1H-inden-4-ol (15): Triol 15 was synthe-

sised according to GP3, using alcohol 11 (46.0 mg, 0.0863 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 6:4) and isolated as white solid (25.5 mg, 0.0838 mmol,

97 %): R_f= 0.21 (hexanes/EtOAc, 6:4); mp: 202–204 °C; [α]²_D³: +23

(Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 3579, 2928, 2886,

˜

2856, 2359, 1607, 1505, 1471, 1445, 1387, 1361, 1252, 1004, 986,

970, 916, 833, 811, 772, 713, 666; HRMS (EI): m/z calculated for

+

˙

C

₃₁H₅₆O₃Si₂[M] 532.3763, found 532.3763; Purity (HPLC): > 95 %

(λ = 210 nm) (method e).

1

(c = 0.060, MeOH); H NMR (400 MHz, [D₆]DMSO) δ/ppm = 9.09 (s,

1H, 3′′-OH), 7.03 (t, J = 7.8 Hz, 1H, 5′′-H), 6.88–6.84 (m, 1H, 2′′-H),

6.81 (dt, J = 7.8, 1.3 Hz, 1H, 6′′-H), 6.53 (ddd, J = 7.9, 2.4, 0.9 Hz, 1H

4′′-H), 4.35 (s, 1H, 4-OH), 4.20 (dd, J = 5.7, 4.8 Hz, 1H, 1′-OH), 3.37

(dq, J = 10.3, 4.0, 3.6 Hz, 1H, 1′-H), 3.10–2.99 (m, 1H, 1′-H), 1.94 (d,

J = 13.0 Hz, 2H, 2, 3, 5, 6 or 7-H), 1.67–1.19 (m, 9H, 3a, 2′-H, 2, 3, 5,

6 or 7-H), 1.18–1.05 (m, 2H, 1-H, 2, 3, 5, 6 or 7-H), 0.98 (s, 3H, 7a-

CH₃), 0.95 (d, J = 6.5 Hz, 3H, 2′-CH₃); ¹³C NMR (101 MHz, [D₆]DMSO)

δ/ppm = 156.8 (C-3′′), 151.8 (C-1′′), 128.4 (C-5′′), 115.5 (C-6′′), 112.4

(C-4′′), 112.2 (C-2′′), 74.4 (C-4), 65.6 (C-1′), 56.1 (C-3a), 53.0 (C-1), 42.4

(C-7a), 40.0 (C-2, 3, 5, 6 or 7), 39.9 (C-2, 3, 5, 6 or 7), 38.2 (C-2′), 25.9

(C-2, 3, 5, 6 or 7), 20.1 (C-2, 3, 5, 6 or 7), 19.2 (C-2, 3, 5, 6 or 7), 16.8

(1R,3aR,4S,7aR)-4-(3-(((tert-Butyldimethylsilyl)oxy)methyl)-

phenyl)-1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7a-

methyloctahydro-1H-inden-4-ol (13): Alcohol 13 was synthesised

according to GP1 using TBDMS-protected (3-bromophenyl)meth-

anol (190 mg, 0.631 mmol, 1.10 equiv.) and ketone 3 (186 mg,

0.573 mmol, 1.00 equiv.). The title compound was purified via FCC

(hexanes/EtOAc, 9:1) and isolated as white, oily solid (253 mg,

0.463 mmol, 81 %): R_f= 0.50 (hexanes/EtOAc, 9:1); [α]²_D³: +18 (c =

0.050, CHCl₃); ¹H NMR (500 MHz, [D]chloroform) δ/ppm = 7.39 (t,

J = 1.7 Hz, 1H, 2′′-H), 7.33 (dt, J = 7.9, 1.6 Hz, 1H, 6′′-H), 7.28 (t, J =

7.6 Hz, 1H, 5′′-H), 7.17 (dt, J = 7.5, 1.5 Hz, 1H, 4′′-H), 4.75 (s, 2H,

3′′-CH₂), 3.56 (dd, J = 9.6, 3.4 Hz, 1H, 1′-H), 3.28 (dd, J = 9.6, 7.0 Hz,

1H, 1′-H), 2.08 (dt, J = 12.8, 3.4 Hz, 1H, 2, 3, 5 or 6-H), 2.04–1.93 (m,

1H, OH), 1.74 (dq, J = 9.1, 4.8, 3.8 Hz, 3H, 3a, 7-H), 1.71–1.67 (m, 1H,

2, 3, 5 or 6-H), 1.63–1.50 (m, 3H, 2′-H, 2, 3, 5 or 6-H), 1.34–1.17 (m,

5H, 1-H, 2, 3, 5 or 6-H), 1.05 (s, 3H, 7a-CH₃), 1.02 (d, J = 6.5 Hz, 3H,

2′-CH₃), 0.94 (s, 9H, SiC(CH₃)₃), 0.89 (s, 9H, SiC(CH₃)₃), 0.09 (s, 3H,

Si(CH₃)₂), 0.09 (s, 3H, Si(CH₃)₂), 0.03 (s, 6H, Si(CH₃)₂); ¹³C NMR

(126 MHz, [D]chloroform) δ/ppm = 149.0 (C-1′′), 141.3 (C-3′′), 128.1

(C-6′′), 124.2 (C-4′′), 123.3 (C-5′′), 122.5 (C-2′′), 76.5 (C-4), 67.8 (C-1′),

65.4 (3′′-CH₂), 56.2 (C-3a), 53.5 (C-1), 43.1 (C-7a), 41.1 (C-7), 40.3 (C-

2, 3, 5 or 6), 38.7 (C-2′), 26.3 (C-2, 3, 5 or 6), 26.1 (SiC(CH₃)₃), 26.1

(SiC(CH₃)₃), 20.4 (C-2, 3, 5 or 6), 19.6 (C-2, 3, 5 or 6), 18.6 (SiC(CH₃)₃),

18.5 (SiC(CH₃)₃), 16.9 (2′-CH₃), 13.5 (7a-CH₃), –5.0 (Si(CH₃)₂), –5.2

(2′-CH₃), 13.4 (7a-CH₃); IR (ATR): ν = cm^–1= 3539, 2943, 2859, 1445,

˜

1395, 1374, 1337, 1285, 1264, 1226, 1153, 1108, 1022, 1002, 981,

941, 859, 846, 786, 715, 661; HRMS (EI): m/z calculated for C₁₉H₂₈O₃

+

˙

[M] 304.2033, found 304.2033; Purity (HPLC): > 95 % (λ = 210 nm)

(method a).

(1R,3aR,4S,7aR)-4-(4-Hydroxyphenyl)-1-((S)-1-hydroxypropan-2-

yl)-7a-methyloctahydro-1H-inden-4-ol (16): Triol 16 was synthe-

sised according to GP3, using alcohol 12 (42.0 mg, 0.0788 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 6:4) and isolated as white solid (24.0 mg, 0.0788 mmol, quan-

titative): R_f= 0.22 (hexanes/EtOAc, 6:4); mp: 211–213 °C; [α]²_D³: +104

1

(c = 0.0600, CHCl₃); H NMR (400 MHz, [D₆]DMSO) δ/ppm = 9.06 (s,

1H, 4′′-OH), 7.21–7.16 (m, 2H, 2′′-H), 6.67–6.61 (m, 2H, 3′′-H), 4.25

(s, 1H, 4-OH), 4.20 (t, J = 5.2 Hz, 1H, 1′-OH), 3.37 (dq, J = 10.3, 4.1,

3.6 Hz, 1H, 1′-H), 3.04 (dt, J = 10.3, 6.5 Hz, 1H, 1′-H), 1.96–1.83 (m,

2H, 2, 3, 5, 6 or 7-H), 1.67–1.19 (m, 9H, 3a, 2′-H, 2, 3, 5, 6 or 7-H),

1.16–1.06 (m, 2H, 1-H, 2, 3, 5, 6 or 7-H), 0.97 (s, 3H, 7a-CH₃), 0.94 (d,

J = 6.5 Hz, 3H, 2′-CH₃); ¹³C NMR (101 MHz, [D₆]DMSO) δ/ppm =

155.1 (C-4′′), 140.5 (C-1′′), 125.8 (C-2′′), 114.2 (C-3′′), 74.1 (C-4), 65.6

(C-1′), 56.4 (C-3a), 53.1 (C-1), 42.5 (C-7a), 40.3 (C-2, 3, 5, 6 or 7), 40.1

(C-2, 3, 5, 6 or 7), 38.2 (C-2′), 25.9 (C-2, 3, 5, 6 or 7), 20.2 (C-2, 3, 5,

6 or 7), 19.3 (C-2, 3, 5, 6 or 7), 16.8 (2′-CH₃), 13.4 (7a-CH₃); IR (ATR):

(Si(CH ) ), –5.2 (Si(CH ) ); IR (ATR): ν = cm^–1= 3529, 2950, 2928,

˜

3 2

2856, 2359, 2342, 1606, 1471, 1385, 1375, 1360, 1333, 1281, 1251,

1003, 985, 938, 891, 833, 814, 769, 701, 667; HRMS (EI): m/z calcu-

+

˙

lated for C₃₂H₅₉O₃Si₂[M] 547.3997, found 547.3988; Purity (HPLC):

> 95 % (λ = 210 nm) (method d).

(1R,3aR,4S,7aR)-4-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-

phenyl)-1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-2-yl)-7a-

methyloctahydro-1H-inden-4-ol (14): Alcohol 14 was synthesised

according to GP1 using TBDMS-protected (4-bromophenyl)meth-

anol (180 mg, 0.597 mmol, 1.10 equiv.) and ketone 3 (177 mg,

0.545 mmol, 1.00 equiv.). The title compound was purified via FCC

(hexanes/EtOAc, 9:1) and isolated as white solid (206 mg,

ν = cm^–1= 3399, 2956, 2891, 1596, 1517, 1454, 1377, 1336, 1300,

˜

1178, 1161, 1020, 1001, 962, 933, 856, 826, 789, 771; HRMS (EI):

+

˙

m/z calculated for C₁₉H₂₈O₃[M] 304.2033, found 304.2026; Purity

(HPLC): > 95 % (λ = 210 nm) (method a).

0.377 mmol, 69 %): R_f= 0.45 (hexanes/EtOAc, 9:1); mp: 87–89 °C;

1

[α]²_D³: +18 (c = 0.040, CHCl₃); H NMR (400 MHz, [D₂]dichlorometh- (1R,3aR,4S,7aR)-4-(4-(Hydroxymethyl)phenyl)-1-((S)-1-hydroxy-

ane) δ/ppm = 7.43–7.37 (m, 2H, 2′′, 6′′-H), 7.29–7.24 (m, 2H, 3′′, propan-2-yl)-7a-methyloctahydro-1H-inden-4-ol (18): Triol 18

5′′-H), 4.70 (d, J = 0.8 Hz, 2H, 4′′-CH₂), 3.60–3.54 (m, 1H, 1′-H), 3.32–

3.25 (m, 1H, 1′-H), 2.07 (dt, J = 12.7, 3.3 Hz, 1H, 7-H), 1.97 (ddt, J = 0.0914 mmol, 1.00 equiv.). The title compound was purified via FCC

17.5, 9.1, 4.4 Hz, 1H, 6-H), 1.80–1.66 (m, 4H, 3a, 5,2-H), 1.62–1.48 (m, (hexanes/EtOAc, 4:6) and isolated as white solid (13.6 mg,

was synthesised according to GP3, using alcohol 14 (50 mg,

3H, 6, 2′-H, OH), 1.37–1.19 (m, 5H, 1,2,3,7-H), 1.06–1.04 (m, 3H, 7a- 0.0427 mmol, 47 %): R_f= 0.24 (hexanes/EtOAc, 4:6); mp: 166–168 °C;

CH₃), 1.02 (d, J = 6.6 Hz, 3H, 2′-CH₃), 0.94 (s, 9H, SiC(CH₃)₃), 0.89 (s, [α]²_D³: +23 (c = 0.030, CHCl₃); ¹H NMR (400 MHz, [D₆]DMSO) δ/ppm =

9H, SiC(CH₃)₃), 0.10 (s, 6H, Si(CH₃)₂), 0.03 (s, 6H, Si(CH₃)₂); ¹³C NMR

(101 MHz, [D₂]dichloromethane) δ/ppm = 148.5 (C-1′′), 139.9 (C-4′′),

7.38–7.34 (m, 2H, 2′′, 6′′-H), 7.22–7.18 (m, 2H, 3′′, 5′′-H), 5.05 (t, J =

5.7 Hz, 1H, 4′′-CH₂to OH), 4.46–4.40 (m, 3H, 4′′-CH₂, 4-OH), 4.21 (t,

126.5 (C-3′′, C-5′′), 124.9 (C-2′′, C-6′′), 76.6 (C-4), 68.2 (C-1′), 65.3 (4′′- J = 5.3 Hz, 1H, 1′-OH), 3.37 (dt, J = 8.7, 3.9 Hz, 1H, 1′-H), 3.04 (dt,

CH₂), 56.6 (C-3a), 53.9 (C-1), 43.5 (C-7a), 41.6 (C-5), 40.7 (C-7), 39.2 J = 10.3, 6.5 Hz, 1H, 1′-H), 1.93 (t, J = 13.6 Hz, 2H, 7-H, 2, 3, 5 or

(C-2′), 26.8 (C-2), 26.3 (SiC(CH₃)₃), 20.8 (C-3), 20.0 (C-6), 18.8 6-H), 1.71–1.54 (m, 4H, 2, 3, 5 or 6-H), 1.50–1.22 (m, 5H, 7-H, 2′-H,

(SiC(CH₃)₃), 17.2 (SiC(CH₃)₃), 13.7 (2′-CH₃), –5.0 (7a-CH₃), –5.1

2, 3, 5 or 6-H), 1.18–1.07 (m, 2H, 1-H, 2, 3, 5 or 6-H), 0.99 (s, 3H, 7a-

CH₃), 0.95 (d, J = 6.5 Hz, 3H, 2′-CH₃); ¹³C NMR (101 MHz, [D₆]DMSO)

δ/ppm = 148.5 (C-1′′), 139.6 (C-4′′), 125.8 (C-3′′, 5′′), 124.5 (C-2′′,

(Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 3573, 2948, 2928,

˜

2893, 2855, 2360, 1508, 1470, 1377, 1315, 1252, 1219, 1145, 1004,

985, 971, 938, 859, 832, 815, 802, 772, 751, 721, 666; HRMS (EI): m/z 6′′), 74.5 (C-4), 65.5 (C-1′), 62.8 (4′′-CH₂), 56.1 (C-3a), 52.9 (C-1), 42.5

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(C-7a), 40.2 (C-2, 3, 5 or 6), 39.9 (C-7), 38.2 (C-2′), 25.9 (C-2, 3, 5 or 13.8, 2.7 Hz, 1H, 4′-CH₂), 2.43 (dd, J = 13.4, 11.3 Hz, 1H, 4′-CH₂),

6), 20.1 (C-2, 3, 5 or 6), 19.2 (C-2, 3, 5 or 6), 16.8 (2′-CH₃), 13.4 (7a-

2.00–1.89 (m, 2H, 4′, 7′-H), 1.89–1.78 (m, 1H, 2′, 3′, 5′ or 6′-H), 1.74–

1.39 (m, 7H, 2, 7′-H, 2′, 3′, 5′ or 6′-H), 1.34–1.10 (m, 4H, 1′, 3a′-H,

CH₃); IR (ATR): ν = cm^–1= 3607, 2933, 2868, 1455, 1403, 1375, 1300,

˜

1235, 1215, 1187, 1083, 1049, 1017, 999, 959, 902, 856, 829, 793, 2′, 3′, 5′ or 6′-H), 1.00–0.97 (m, 12H, 2-CH₃, SiC(CH₃)₃), 0.90 (s, 9H,

+

˙

772; HRMS (EI): m/z calculated for C₂₀H₃₀O₃[M] 318.2189, found

SiC(CH₃)₃), 0.85 (s, 3H, 7a′-CH₃), 0.18 (s, 6H, Si(CH₃)₂), 0.04 (s, 6H,

Si(CH₃)₂); ¹³C NMR (101 MHz, [D₂]dichloromethane) δ/ppm = 156.1

(C-3′′), 146.1 (C-1′′), 129.5 (C-5′′), 122.6 (C-6′′), 121.4 (C-2′′), 117.6

(C-4′′), 68.3 (C-1), 54.4 (C-1′), 53.0 (C-3a′), 42.9 (C-7a′), 41.4 (C-7′),

40.1 (C-4′), 39.5 (4′-CH₂), 35.1 (C-2), 29.4 (2′, 3′, 5′ or 6′-H), 27.4

(2′, 3′, 5′ or 6′-H), 26.3 (SiC(CH₃)₃), 26.0 (SiC(CH₃)₃), 24.4 (2′, 3′, 5′ or

6′-H), 18.8 (SiC(CH₃)₃), 18.7 (SiC(CH₃)₃), 18.6 (2′, 3′, 5′ or 6′-H), 17.2

(2-CH₃), 14.1 (7a′-CH₃), –4.1 (Si(CH₃)₂), –5.1 (Si(CH₃)₂), –5.2 (Si(CH₃)₂);

318.2185; Purity (HPLC): > 95 % (λ = 210 nm) (method a).

(1R,3aR,4S,7aR)-4-(3-(Hydroxymethyl)phenyl)-1-((S)-1-hydroxy-

propan-2-yl)-7a-methyloctahydro-1H-inden-4-ol (17): Triol 17

was synthesised according to GP3, using alcohol 13 (168 mg,

0.307 mmol, 1.00 equiv.). The title compound was purified via FCC

(hexanes/EtOAc, 5:5) and isolated as white solid (40.0 mg,

0.126 mmol, 41 %): R_f= 0.23 (hexanes/EtOAc, 5:5); mp: 57–59 °C;

[α]²_D³: +3.0 (c = 0.17, CHCl₃); ¹H NMR (400 MHz, [D₄]methanol)

δ/ppm = 7.43 (d, J = 2.0 Hz, 1H, 6′′-H), 7.35 (dt, J = 7.8, 1.5 Hz, 1H,

2′′-H), 7.27 (t, J = 7.6 Hz, 1H, 5′′-H), 7.17 (dt, J = 7.6, 1.4 Hz, 1H,

4′′-H), 4.60 (s, 2H, 3′′-CH₂), 3.56 (dd, J = 10.6, 3.2 Hz, 1H, 1′-H), 3.25

(dd, J = 10.6, 7.1 Hz, 1H, 1′-H), 2.13–1.98 (m, 2H, 5,6-H), 1.84–1.66

(m, 4H, 7-H, 2 or 3-H, OH), 1.61–1.48 (m, 2H, 5 or 6-H, 2′-H), 1.43–

1.21 (m, 6H, 1,2,3-H, 5 or 6-H, 2 × OH), 1.09 (s, 3H, 7a-CH₃), 1.06 (d,

J = 6.6 Hz, 3H, 2′-CH₃); ¹³C NMR (101 MHz, [D₄]methanol) δ/ppm =

150.9 (C-1′′), 142.2 (C-3′′), 128.9 (C-5′′), 125.8 (C-4′′), 124.9 (C-2′′),

124.5 (C-6′′), 77.2 (C-4), 67.8 (C-1′), 65.6 (3′′-CH₂), 57.5 (C-3a), 54.7

(C-1), 44.2 (C-7a), 42.0 (C-7), 41.7 (C-5 or 6), 39.8 (C-2′), 27.4 (C-2 or

3), 21.3 (C-2 or 3), 20.6 (C-5 or 6), 17.2 (2′-CH₃), 13.9 (7a-CH₃); IR

IR (ATR): ν = cm^–1= 2927, 2856, 1585, 1471, 1362, 1273, 1252, 1157,

˜

1089, 1004, 982, 958, 835, 775, 696, 665; HRMS (EI): m/z calculated

for C₃₂H₅₈O₂Si₂[M]^·+530.3970, found 530.3966; Purity (HPLC): 87 %

(λ = 191 nm) (method e).

tert-Butyl((S)-2-((1R,3aS,4R,7aS)-4-(4-((tert-butyldimethylsilyl)-

oxy)benzyl)-7a-methyloctahydro-1H-inden-1-yl)propoxy)di-

methylsilane (21): Silyl ether 21 was synthesised according to GP2,

using alkene 4 (260 mg, 0.806 mmol, 1.00 equiv.) and bromide 44

(218 mg, 0.759 mmol, 1.00 equiv.). The title compound was purified

via FCC (hexanes/toluene, 95:5) and isolated as a colourless oil

(139 mg, 0.262 mmol, 33 %): R_f= 0.30 (hexanes/toluene, 95:5);

1

[α]²_D³: +18 (c = 0.050, CHCl₃); H NMR (400 MHz, [D₂]dichlorometh-

(ATR): ν = cm^–1= 3541, 3489, 2928, 1603, 1507, 1471, 1255, 1083,

ane) δ/ppm = 7.02–6.94 (m, 2H, 2′′, 6′′-H), 6.75–6.69 (m, 2H, 3′′,

5′′-H), 3.60 (dd, J = 9.6, 3.3 Hz, 1H, 1-H), 3.28 (dd, J = 9.6, 7.3 Hz,

1H, 1-H), 2.74–2.67 (m, 1H, 4′-CH₂), 2.41 (dd, J = 13.6, 11.4 Hz, 1H,

4′-CH₂), 2.00–1.90 (m, 2H, 4′, 7′-H), 1.87–1.78 (m, 1H, 2′, 3′, 5′ or 6′-

H), 1.72–1.40 (m, 7H, 2, 3a′, 7′-H, 2′, 3′, 5′ or 6′-H), 1.31–1.10 (m, 4H,

1′-H, 2′, 3′, 5′ or 6′-H), 1.01–0.96 (m, 12H, 2-CH₃, SiC(CH₃)₃), 0.89 (s,

9H, SiC(CH₃)₃), 0.84 (s, 3H, 7a′-CH₃), 0.17 (s, 6H, Si(CH₃)₂), 0.04 (s, 6H,

Si(CH₃)₂); ¹³C NMR (101 MHz, [D₂]dichloromethane) δ/ppm = 153.9

(C-4′′), 137.1 (C-1′′), 130.3 (C-2′′, 6′′), 120.2 (C-3′′, 5′′), 68.3 (C-1), 54.4

(C-1′), 53.1 (C-3a′), 42.9 (C-7a′), 41.4 (C-7′), 40.3 (C-4′), 39.5 (C-1′),

34.3 (4′-CH₂), 29.3 (C-2′, 3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or 6′), 26.3

(SiC(CH₃)₃), 26.0 (SiC(CH₃)₃), 24.4 (C-2′, 3′, 5′ or 6′), 18.8 (SiC(CH₃)₃),

18.6 (SiC(CH₃)₃), 18.6 (C-2′, 3′, 5′ or 6′), 17.2 (2-CH₃), 14.1 (7a′-CH₃),

˜

+

˙

913, 833, 812, 773; HRMS (EI): m/z calculated for C₂₀H₃₀O₃[M]

318.2189, found 318.2184; Purity (HPLC): > 95 % (λ = 210 nm)

(method a).

((S)-2-((1R,3aS,4R,7aS)-4-Benzyl-7a-methyloctahydro-1H-inden-

1-yl)propoxy)(tert-butyl)dimethylsilane (19): Silyl ether 19 was

synthesised according to GP2, using alkene 4 (33.0 mg, 0.102 mmol,

1.10 equiv.) and bromobenzene (14.6 mg, 0.0930 mmol, 1.00 equiv.).

The title compound was purified via FCC (hexanes/toluene, 9:1) and

isolated as a colourless oil (14.6 mg, 0.0364 mmol, 39 %): R_f= 0.55

(hexanes/toluene, 9:1); [α]²_D³: +37 (c = 0.070, CHCl₃); ¹H NMR

(400 MHz, [D₂]dichloromethane) δ/ppm = 7.32–7.05 (m, 5H, 2′′, 3′′,

4′′, 5′′, 6′′-H), 3.61 (dd, J = 9.6, 3.3 Hz, 1H, 1-H), 3.29 (ddd, J = 9.6,

7.3, 0.9 Hz, 1H, 1-H), 2.83–2.73 (m, 1H, 4′-CH₂), 2.48 (dd, J = 13.4,

11.4 Hz, 1H, 4′-CH₂), 2.03–1.92 (m, 2H, 4′, 7′-H), 1.89–1.79 (m, 1H, 2′,

3′, 5′ or 6′-H), 1.76–1.42 (m, 7H, 2, 3a′, 7′-H, 2′, 3′, 5′ or 6′-H), 1.35–

1.14 (m, 4H, 1′-H, 2′, 3′, 5′ or 6′-H), 0.99 (dd, J = 6.6, 0.9 Hz, 3H, 2-

CH₃), 0.90 (s, 9H, SiC(CH₃)₃), 0.86 (s, 3H, 7a′-CH₃), 0.04 (s, 6H,

Si(CH₃)₂); ¹³C NMR (101 MHz, [D₂]dichloromethane) δ/ppm = 144.5

(C-1′′), 129.6 (C-2′′, C-6′′), 128.7 (C-3′′, C-5′′), 125.9 (C-4′′), 68.3 (C-1),

54.4 (C-1′), 53.1 (C-3a′), 42.9 (C-7a′), 41.4 (C-7′), 40.2 (C-4′), 39.5 (C-

2), 35.1 (4′-CH₂), 29.3 (C-5′), 27.4 (C-3′), 26.3 (SiC(CH₃)₃), 24.4 (C-6′),

18.8 (SiC(CH₃)₃), 18.6 (C-2′), 17.2 (2-CH₃), 14.1 (7a′-CH₃), –5.1

–4.2 (Si(CH₃)₂), –5.1 (Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1

2926, 2856, 2361, 1509, 1471, 1253, 1094, 1007, 912, 834, 800, 772,

677; HRMS (EI): m/z calculated for C₃₂H₅₈O₂Si₂[M]^·+530.3970, found

530.3976; Purity (HPLC): > 95 % (λ = 210 nm) (method c).

=

˜

tert-Butyl((S)-2-((1R,3aS,4R,7aS)-4-(3-(((tert-butyldimethylsilyl)-

oxy)methyl)benzyl)-7a-methyloctahydro-1H-inden-1-yl)prop-

oxy)dimethylsilane (22): Silyl ether 22 was synthesised according

to GP2, using alkene 4 (156 mg, 0.484 mmol, 1.00 equiv.) and

TBDMS-protected (3-bromophenyl)methanol (146 mg, 0.484 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

toluene, 95:5) and isolated as a colourless oil (35.1 mg,

0.0644 mmol, 13 %): R_f= 0.20 (hexanes/toluene, 95:5); [α]²_D³: +56

(c = 0.0060, CHCl₃); ¹H NMR (400 MHz, [D₂]dichloromethane)

δ/ppm = 7.24–7.18 (m, 1H, 5′′-H), 7.13–7.09 (m, 2H, 2′′, 4′′-H), 7.02

(d, J = 7.5 Hz, 1H, 6′′-H), 4.70 (s, 2H, 3′′-CH₂), 3.61 (dd, J = 9.6, 3.4 Hz,

1H, 1-H), 3.29 (dd, J = 9.6, 7.3 Hz, 1H, 1-H), 2.79 (d, J = 13.3 Hz, 1H,

(Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 2856, 1470, 1385,

˜

1251, 1120, 1095, 1056, 1032, 1007, 961, 834, 811, 767, 738, 665;

HRMS (EI): m/z calculated for C₂₈H₄₄OSi [M]^·+400.3156, found

400.3163; Purity (GC): 84 % (scan mode m/z 50–650 (EI 70 eV)).

tert-Butyl((S)-2-((1R,3aS,4R,7aS)-4-(3-((tert-butyldimethylsilyl)-

oxy)benzyl)-7a-methyloctahydro-1H-inden-1-yl)propoxy)di- 4′-CH₂), 2.48 (dd, J = 13.4, 11.4 Hz, 1H, 4′-CH₂), 2.01–1.93 (m, 2H,

methylsilane (20): Silyl ether 20 was synthesised according to GP2,

using alkene 4 (245 mg, 0.759 mmol, 1.00 equiv.) and TBDMS-pro-

4′, 7′-H), 1.90–1.78 (m, 1H, 2′, 3′, 5′ or 6′-H), 1.74–1.40 (m, 7H, 2, 3a′-

H, 2′, 3′, 5′ or 6′-H), 1.35–1.09 (m, 4H, 1′, 7′-H, 2′, 3′, 5′ or 6′-H), 0.98

tected 3-bromophenol (218 mg, 0.759 mmol, 1.00 equiv.). The title (d, J = 6.5 Hz, 3H, 2-CH₃), 0.94 (s, 9H, SiC(CH₃)₃), 0.90 (s, 9H,

compound was purified via FCC (hexanes/toluene, 95:5) and iso-

SiC(CH₃)₃), 0.86 (s, 3H, 7a′-CH₃), 0.10 (s, 6H, Si(CH₃)₂), 0.04 (s, 3H,

lated as a colourless oil (102 mg, 0.192 mmol, 25 %): R_f= 0.22 (hex- Si(CH₃)₂), 0.04 (s, 3H, Si(CH₃)₂); ¹³C NMR (101 MHz, [D₂]dichloro-

anes/toluene, 95:5); [α]_D²³: +27 (c = 0.060, CHCl₃); ¹H NMR (400 MHz, methane) δ/ppm = 144.4 (C-1′′), 141.9 (C-3′′), 128.5 (C-5′′), 128.1

[D₂]dichloromethane) δ/ppm 7.15–7.06 (m, 1H, 5′′-H), 6.74 (dt, J =

7.7, 1.4 Hz, 1H, 6′′-H), 6.66–6.60 (m, 2H, 2′′-H, 4′′-H), 3.60 (dd, J =

(C-6′′), 127.5 (C-2′′), 123.9 (C-4′′), 68.3 (C-1), 65.5 (3′′-CH₂), 54.4

(C-1′), 53.1 (C-3a′), 42.9 (C-7a′), 41.4 (C-7′), 40.3 (C-4′), 39.5 (C-2), 35.1

9.6, 3.3 Hz, 1H, 1-H), 3.28 (dd, J = 9.6, 7.3 Hz, 1H, 1-H), 2.74 (dd, J = (4′-CH₂), 29.3 (C-2′, 3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or 6′), 26.3

Eur. J. Org. Chem. 2020, 6270–6288

www.eurjoc.org

6280

Full Paper

doi.org/10.1002/ejoc.202001080

EurJOC

European Journal of Organic Chemistry

(SiC(CH₃)₃), 26.3 (SiC(CH₃)₃), 24.4 (C-2′, 3′, 5′ or 6′), 18.8 (SiC(CH₃)₃), anol) δ/ppm = 7.08–7.02 (m, 1H, 5-H), 6.63–6.55 (m, 3H, 2,4,6-H),

18.8 (SiC(CH₃)₃), 18.6 (C-2′, 3′, 5′ or 6′), 17.2 (2-CH₃), 14.1 (7a′-CH₃), 3.60 (dd, J = 10.6, 3.2 Hz, 1H, 1′′-H), 3.28 (dd, J = 10.6, 7.1 Hz, 1H,

–5.0 (Si(CH₃)₂), –5.1 (Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1

=

1′′-H), 2.74 (dd, J = 13.4, 2.6 Hz, 1H, 4′-CH₂), 2.44 (dd, J = 13.3,

11.4 Hz, 1H, 4′-CH₂), 2.05–1.96 (m, 2H, 4′, 7′-H), 1.95–1.86 (m, 1H,

2′, 3′, 5′ or 6′-H), 1.82–1.29 (m, 8H, 3a′, 2′′-H, 2′, 3′, 5′ or 6′-H), 1.27–

1.15 (m, 3H, 1′, 7′-H, 2′, 3′, 5′ or 6′-H), 1.04 (d, J = 6.6 Hz, 3H,

2′′-CH₃), 0.90 (s, 3H, 7a′-CH₃); ¹³C NMR (101 MHz, [D₄]methanol)

δ/ppm = 158.3 (C-3), 146.4 (C-1), 130.1 (C-5), 121.3 (C-2), 116.8

(C-6), 113.4 (C-4), 67.9 (C-1′′), 55.0 (C-1′), 53.9 (C-3a′), 43.5 (C-7a′),

42.2 (C-7′), 40.9 (C-4′), 40.0 (C-2′′), 35.7 (4′-CH₂), 29.9 (C-2′, 3′, 5′ or

6′), 27.9 (C-2′, 3′, 5′ or 6′), 24.9 (C-2′, 3′, 5′ or 6′), 19.0 (C-2′, 3′, 5′ or

˜

2951, 2928, 2856, 1472, 1462, 1446, 1388, 1361, 1252, 1157, 1080,

1033, 1006, 833, 773, 666; HRMS (EI): m/z calculated for C₃₂H₅₇O₂Si₂

[M]^·+529.3892, found 529.3872; Purity (HPLC): 85 % (λ = 210 nm)

(method e).

tert-Butyl((S)-2-((1R,3aS,4R,7aS)-4-(4-(((tert-butyldimethylsilyl)-

oxy)methyl)benzyl)-7a-methyloctahydro-1H-inden-1-yl)prop-

oxy)dimethylsilane (23): Silyl ether 23 was synthesised according

to GP2, using alkene 4 (249 mg, 0.772 mmol, 1.00 equiv.) and

TBDMS-protected (4-bromophenyl)methanol (233 mg, 0.772 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

toluene, 7:3) and isolated as a colourless oil (243 mg, 0.261 mmol,

57 %): R_f= 0.09 (hexanes/toluene, 7:3); [α]²_D³: +100 (c = 0.0700,

CHCl₃); ¹H NMR (400 MHz, [D₂]dichloromethane) δ/ppm = 7.23–7.17

(m, 2H, 3′′, 5′′-H), 7.12–7.07 (m, 2H, 2′′, 6′′-H), 4.68 (s, 2H, 4′′-CH₂),

3.61 (dd, J = 9.6, 3.3 Hz, 1H, 1-H), 3.32–3.26 (m, 1H, 1-H), 2.78 (d,

J = 13.5 Hz, 1H, 4′-CH₂), 2.48 (dd, J = 13.4, 11.4 Hz, 1H, 4′-CH₂),

2.01–1.93 (m, 2H, 4′, 7′-H), 1.89–1.78 (m, 1H, 2′, 3′, 5′ or 6′-H), 1.75–

1.36 (m, 7H, 2, 3a′-H, 2′, 3′, 5′ or 6′-H), 1.37–1.12 (m, 4H, 1′, 7′-H, 2′,

3′, 5′ or 6′-H), 0.98 (d, J = 6.6 Hz, 3H, 2-CH₃), 0.93 (s, 9H, SiC(CH₃)₃),

0.90 (s, 9H, SiC(CH₃)₃), 0.86 (s, 3H, 7a′-CH₃), 0.10 (s, 6H, Si(CH₃)₂),

0.04 (s, 3H, Si(CH₃)₂), 0.04 (s, 3H, Si(CH₃)₂); ¹³C NMR (101 MHz, [D₂]di-

chloromethane) δ/ppm = 143.1 (C-1′′), 139.2 (C-4′′), 129.4 (C-2′′,

6′′), 126.7 (C-3′′, 5′′), 68.3 (C-1), 65.4 (4′′-CH₂), 54.4 (C-1′), 53.1

(C-3a′), 42.9 (C-7a′), 41.4 (C-7′), 40.3 (C-4′), 39.5 (C-2), 34.8 (4′-CH₂),

29.3 (C-2′, 3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or 6′), 26.3 (SiC(CH₃)₃), 24.4

(C-2′, 3′, 5′ or 6′), 18.9 (SiC(CH₃)₃), 18.8 (SiC(CH₃)₃), 18.6 (C-2′, 3′, 5′

or 6′), 17.2 (2-CH₃), 14.1 (7a′-CH₃), –5.0 (Si(CH₃)₂), –5.1 (Si(CH₃)₂),

6′), 17.2 (2′′-CH₃), 14.2 (7a′-CH₃); IR (ATR): ν = cm^–1= 3436, 3169,

˜

2928, 2874, 1616, 1588, 1367, 1268, 1251, 1180, 1157, 1027, 999,

875, 786, 763, 678; HRMS (EI): m/z calculated for C₂₀H₃₀O₂[M]^·+

302.2240, found 302.2239; Purity (HPLC): > 95 % (λ = 191 nm),

> 95 % (λ = 210 nm) (method b).

4-(((1R,3aS,4R,7aS)-1-((S)-1-Hydroxypropan-2-yl)-7a-methyl-

octahydro-1H-inden-4-yl)methyl)phenol (26): Diol 26 was syn-

thesised according to GP3 using silyl ether 21 (250 mg, 0.471 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 7:3) and isolated as a white crystalline solid (18.0 mg,

0.0595 mmol, 13 %): R_f= 0.33 (hexanes/EtOAc, 7:3); mp: 129–131 °C;

[α]²_D³: +100 (c = 0.0600, CHCl₃); ¹H NMR (400 MHz, [D₂]dichlorometh-

ane) δ/ppm = 7.03–6.95 (m, 2H, 2,6-H), 6.75–6.68 (m, 2H, 3,5-H),

4.89 (s, 1H, 4-OH), 3.62 (dd, J = 10.3, 3.2 Hz, 1H, 1′′-H), 3.33 (dd, J =

10.5, 7.0 Hz, 1H, 1′′-H), 2.74–2.68 (m, 1H, 4′-CH₂), 2.41 (dd, J = 13.6,

11.4 Hz, 1H, 4′-CH₂), 2.00–1.88 (m, 2H, 4′, 7′-H), 1.87–1.78 (m, 1H,

2′, 3′, 5′ or 6′-H), 1.74–1.26 (m, 8H, 3a′, 2′′-H, 2′, 3′, 5′ or 6′-H), 1.23–

1.10 (m, 3H, 1′, 7′-H, 2′, 3′, 5′ or 6′-H), 1.01 (d, J = 6.6 Hz, 3H, 2′′-

CH₃), 0.85 (s, 3H, 7a′-CH₃); ¹³C NMR (101 MHz, [D₂]dichloromethane)

δ/ppm = 154.2 (C-4), 136.4 (C-1), 130.5 (C-2, 6), 115.4 (C-3, 5), 68.3

(C-1′′), 54.2 (C-1′), 53.1 (C-3a′), 42.9 (C-7a′), 41.4 (C-7′), 40.3 (C-4′),

39.2 (C-2′′), 34.1 (4-CH₂), 29.2 (C-2′, 3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or

6′), 24.3 (C-2′, 3′, 5′ or 6′), 18.6 (C-2′, 3′, 5′ or 6′), 16.9 (2′′-CH₃), 14.0

–5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 2951, 2927, 2856, 1472, 1462,

˜

1376, 1361, 1251, 1086, 1006, 944, 939, 833, 814, 773, 667; HRMS

(EI): m/z calculated for C₃₂H₅₇O₂Si₂[M]^·+529.3892, found 529.3885;

Purity (HPLC): 85 % (λ = 210 nm) (method e).

(7a′-CH₃); IR (ATR): ν = cm^–1= 3386, 2926, 1596, 1559, 1540, 1514,

˜

(S)-2-((1R,3aS,4R,7aS)-4-Benzyl-7a-methyloctahydro-1H-inden-

1-yl)propan-1-ol (24): Alcohol 24 was synthesised according to

GP3 using silyl ether 19 (35.1 mg, 0.0876 mmol, 1.00 equiv.). The

title compound was purified via FCC (hexanes/EtOAc, 85:15) and

isolated as a colourless oil (16.3 mg, 0.0569 mmol, 65 %): R_f= 0.25

(hexanes/EtOAc, 85:15); [α]²_D³: +41 (c = 0.18, CHCl₃); ¹H NMR

(400 MHz, [D₂]dichloromethane) δ/ppm = 7.28–7.12 (m, 5H, 2′′, 3′′,

4′′, 5′′, 6′′-H), 3.65–3.57 (m, 1H, 1-H), 3.38–3.28 (m, 1H, 1-H), 2.79 (d,

J = 13.6 Hz, 1H, 4′-CH₂), 2.48 (dd, J = 13.4, 11.4 Hz, 2H, 4′-CH₂),

2.01–1.95 (m, 2H, 4′, 7′-H), 1.90–1.81 (m, 1H, 2′, 3′, 5′ or 6′-H), 1.75–

1.41 (m, 7H, 2, 3a′-H, 2′, 3′, 5′ or 6′-H), 1.36–1.13 (m, 4H, 1′, 7′-H,

2′, 3′, 5′ or 6′-H), 1.02 (d, J = 6.7 Hz, 3H, 2-CH₃), 0.87 (s, 3H, 7a′-CH₃);

¹³C NMR (101 MHz, [D₂]dichloromethane) δ/ppm = 144.5 (C-1′′),

129.5 (C-2′′, 6′′), 128.7 (C-3′′, 5′′), 125.9 (C-4′′), 68.2 (C-1), 54.2 (C-1′),

53.1 (C-3a′), 42.9 (C-7a′), 41.4 (C-7′), 40.2 (C-4′), 39.3 (C-2), 35.1 (4′-

CH₂), 29.3 (C-2′, 3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or 6′), 24.4 (C-2′, 3′, 5′

or 6′), 18.6 (C-2′, 3′, 5′ or 6′), 16.9 (2-CH₃), 14.0 (7a′-CH₃); IR (ATR):

1457, 1375, 1238, 1174, 1020, 994, 872, 840, 833, 792; HRMS (EI):

m/z calculated for C₂₀H₃₀O₂[M]^·+302.2240, found 302.2239; Purity

(HPLC): > 95 % (λ = 210 nm) (method b).

(S)-2-((1R,3aS,4R,7aS)-4-(3-(Hydroxymethyl)benzyl)-7a-methyl-

octahydro-1H-inden-1-yl)propan-1-ol (27): Diol 27 was synthe-

sised according to GP3 using silyl ether 22 (250 mg, 0.459 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 7:3) and isolated as a white crystalline solid (43.0 mg,

0.136 mmol, 30 %): R_f= 0.20 (hexanes/EtOAc, 7:3); mp: 140–142 °C;

1

[α]²_D³: +45 (c = 0.050, CHCl₃); H NMR (400 MHz, [D₂]dichlorometh-

ane) δ/ppm = 7.28–7.22 (m, 1H, 5′′-H), 7.16–7.12 (m, 2H, 2′′, 4′′-H),

7.09–7.05 (m, 1H, 6′′-H), 4.63 (s, 2H, 3′′-CH₂), 3.61 (dd, J = 10.5,

3.3 Hz, 1H, 1-H), 3.37–3.31 (m, 1H, 1-H), 2.83–2.75 (m, 1H, 4′-CH₂),

2.50 (dd, J = 13.4, 11.4 Hz, 1H, 4′-CH₂), 2.02–1.94 (m, 2H, 4′, 7′-H),

1.91–1.80 (m, 1H, 2′, 3′, 5′ or 6′-H), 1.78–1.40 (m, 8H, 2, 3a′-H, 2′,

3′, 5′ or 6′-H), 1.38–1.13 (m, 3H, 1′, 7′-H, 2′, 3′, 5′ or 6′-H), 1.02 (d,

J = 6.6 Hz, 3H, 2-CH₃), 0.86 (s, 3H, 7a′-CH₃); ¹³C NMR (101 MHz,

[D₂]dichloromethane) δ/ppm = 144.7 (C-1′′), 141.7 (C-3′′), 128.8 (C-

6′′), 128.8 (C-5′′), 128.1 (C-2′′), 124.6 (C-4′′), 68.2 (C-1), 65.7 (3′′-CH₂),

54.2 (C-1′), 53.1 (C-3a′), 42.9 (C-7a′), 41.3 (C-7′), 40.2 (C-4′), 39.2

(C-2), 35.1 (4′-CH₂), 29.2 (C-2′, 3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or 6′),

24.4 (C-2′, 3′, 5′ or 6′), 18.6 (C-2′, 3′, 5′ or 6′), 16.9 (2-CH₃), 14.0 (7a′-

ν = cm^–1= 3329, 2922, 2870, 1494, 1542, 1378, 1032, 1002, 982,

˜

956, 931, 740, 699; HRMS (EI): m/z calculated for C₂₀H₃₀O [M]^·+

286.2291, found 286.2293; Purity (HPLC): 92 % (λ = 210 nm)

(method b).

3-(((1R,3aS,4R,7aS)-1-((S)-1-Hydroxypropan-2-yl)-7a-methyl-

octahydro-1H-inden-4-yl)methyl)phenol (25): Diol 25 was syn-

thesised according to GP3 using silyl ether 20 (163 mg, 0.256 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 7:3) and isolated as a white crystalline solid (25.4 mg,

CH₃); IR (ATR): ν = cm^–1= 3337, 2922, 2868, 1705, 1457, 1362, 1220,

˜

1033, 1002, 981, 735, 703; HRMS (EI): m/z calculated for C₂₁H₃₂O₂

[M]^·+316.2397, found 316.2396; Purity (HPLC): > 95 % (λ = 210 nm),

> 95 % (λ = 254 nm) (method b).

0.0840 mmol, 33 %): R_f= 0.36 (hexanes/EtOAc, 70:30); mp: 146–

(S)-2-((1R,3aS,4R,7aS)-4-(4-(Hydroxymethyl)benzyl)-7a-methyl-

1

148 °C; [α]²_D³: +55 (c = 0.070, CHCl₃); H NMR (400 MHz, [D₄]meth- octahydro-1H-inden-1-yl)propan-1-ol (28): Diol 28 was synthe-

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sised according to GP3 using silyl ether 23 (243 mg, 0.446 mmol, tert-Butyl((S)-2-((1R,3aS,4R,7aS)-4-(3-methoxyphenethyl)-7a-

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 7:3) and isolated as a white crystalline solid (27.9 mg,

methyloctahydro-1H-inden-1-yl)propoxy)dimethylsilane (31):

To a solution of olefin 30 (248 mg, 0.560 mmol, 1.00 equiv.) in EtOAc

(15.0 mL) palladium on carbon (10 % Pd/C, 24.8 mg, 0.0230 mmol,

0.0882 mmol, 20 %): R_f= 0.20 (hexanes/EtOAc, 7:3); mp: 145–147 °C;

1

[α]²_D³: +61 (c = 0.050, CHCl₃); H NMR (400 MHz, [D₂]dichlorometh- 10 wt.-%) was added. The flask was filled with H₂and stirred at r.t.

ane) δ/ppm = 7.29–7.23 (m, 2H, 3′′, 5′′-H), 7.16–7.10 (m, 2H, 2′′, 6′′- for 18 h. The Pd/C catalyst was removed by filtration with a celite

H), 4.61 (d, J = 4.5 Hz, 2H, 4′′-CH₂), 3.65–3.57 (m, 1H, 1-H), 3.37–3.29

(m, 1H, 1-H), 2.79 (dd, J = 14.2, 2.3 Hz, 1H, 4′-CH₂), 2.49 (dd, J =

pad and the resulting filtrate was concentrated under reduced pres-

sure. The crude product was purified via FCC (hexanes 100 % →

13.4, 11.4 Hz, 1H, 4′-CH₂), 2.01–1.93 (m, 2H, 4′, 7′-H), 1.90–1.80 (m, hexanes/EtOAc, 75:25) to give silyl ether 31 as a colourless oil

1H, 2′, 3′, 5′ or 6′-H), 1.77–1.28 (m, 8H, 2, 3a′-H, 2′, 3′, 5′ or 6′-H), (202 mg, 0.454 mmol, 81 %): R_f= 0.46 (hexanes 100 %); [α]²_D³= +2.5

1

1.26–1.13 (m, 3H, 1′, 7′-H, 2′, 3′, 5′ or 6′-H), 1.02 (d, J = 6.6 Hz, 3H,

(c = 0.080, CHCl₃); H NMR (400 MHz, [D]chloroform) δ/ppm = 7.19

2-CH₃), 0.86 (s, 3H, 7a′-CH₃); ¹³C NMR (101 MHz, [D₂]dichlorometh- (ddd, J = 7.6, 6.7, 2.1 Hz, 1H, 5′′-H), 6.77 (dt, J = 7.5, 1.2 Hz, 1H,

ane) δ/ppm = 143.8 (C-1′′), 138.9 (C-4′′), 129.7 (C-2′′, 6′′), 127.5

(C-3′′, 5′′), 68.2 (C-1), 65.5 (4′′-CH₂), 54.2 (C-1′), 53.1 (C-3a′), 42.9

(C-7a′), 41.3 (C-7′), 40.2 (C-4′), 39.2 (C-2), 34.8 (4′-CH₂), 29.2 (C-2′,

3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or 6′), 24.4 (C-2′, 3′, 5′ or 6′), 18.6

6′′-H), 6.72 (dd, J = 6.7, 1.1 Hz, 2H, 2′′, 4′′-H), 3.80 (s, 3H, OCH₃), 3.59

(dd, J = 9.6, 3.4 Hz, 1H, 1-H), 3.24 (dd, J = 9.6, 7.6 Hz, 1H, 1-H), 2.67

(ddd, J = 13.4, 11.3, 5.1 Hz, 1H, 1′′-CH₂), 2.45 (ddd, J = 13.5, 11.0,

5.7 Hz, 1H, 1′′-CH₂), 1.97–1.91 (m, 1H, 4′-CH₂), 1.87 (dd, J = 12.9,

3.3 Hz, 1H, 5′-H), 1.81–1.62 (m, 3H, 2′, 3′ or 6′, 7′-H), 1.60–1.41 (m,

4H, 1′, 3′ or ′6-H), 1.41–1.17 (m, 4H, 4′, 5′, 7′-H), 1.17–1.05 (m, 3H,

(C-2′, 3′, 5′ or 6′), 16.9 (2-CH₃), 14.0 (7a′-CH₃); IR (ATR): ν = cm^–1

=

˜

3220, 2928, 1772, 1654, 1636, 1576, 1559, 1540, 1508, 1490, 1458,

1418, 1375, 1003, 1002, 846, 794; HRMS (EI): m/z calculated for 2′, 3a′-H, 4′-CH₂), 1.00 (d, J = 6.5 Hz, 3H, 2-CH₃), 0.89 (s, 9H,

C

₂₁H₃₂O₂[M]^·+316.2397, found 316.2395; Purity (HPLC): > 95 % (λ =

SiC(CH₃)₂), 0.68 (s, 3H, 7a′-CH₃), 0.03 (s, 3H, Si(CH₃)₂), 0.03 (s, 3H,

Si(CH₃)₂); ¹³C NMR (101 MHz, [D]chloroform) δ/ppm = 159.73

(C-3′′), 145.3 (C-1′′), 129.3 (C-5′′), 120.9 (C-6′′), 114.3 (C-2′′), 110.9

(C-4′′), 68.1 (C-1), 55.5 (C-3a′), 55.3 (OCH₃), 53.2 (C-2), 43.3 (C-7a′),

40.2 (4′-CH₂), 39.2 (C-1′), 37.1 (C-7′), 36.4 (C-4′), 33.3 (1′′-CH₂), 32.4

(C-5′), 27.4 (C-2′), 26.1 (SiC(CH₃)₃), 25.0 (C-3′ or 6′), 22.4 (C-3′ or

6′), 18.5 (SiC(CH₃)₃), 17.1 (2-CH₃), 12.1 (7a′-CH₃), –5.2 (Si(CH₃)₂), –5.2

210 nm) (method b).

tert-Butyl((S)-2-((1R,3aS,4R,7aS)-4-((E)-3-methoxystyryl)-7a-

methyloctahydro-1H-inden-1-yl)propoxy)dimethylsilane (30):

PPh₃(1.58 g, 5.97 mmol, 1.20 equiv.) was added to a stirred solution

of 3-methoxybenzyl bromide (1.00 g, 4.97 mmol, 1.00 equiv.) in

toluene (40.0 mL) and the reaction mixture was refluxed for 12 h.

After completion of the reaction, the reaction mixture was cooled

to 0 °C and the resulting phosphonium salt precipitate was col-

lected by filtration, dried and 29 used without further purification.

A oven-dried round-bottomed flask was charged with phosphon-

ium bromide salt 29 (714 mg, 1.54 mmol, 1.20 equiv.) in dry THF

(Si(CH ) ); IR (ATR): ν = cm^–1= 2926, 2855, 2215, 1601, 1584, 1488,

˜

3 2

1462, 1387, 1360, 1255, 1152, 1083, 1041, 1004, 972, 833, 812, 772,

+

˙

713, 694, 666; HRMS (EI): m/z calculated for C₂₈H₄₈O₂Si [M]

444.3424, found 444.3419; Purity (GC): > 95 % (scan mode m/z 50–

650 (EI 70 eV)).

(S)-2-((1R,3aS,4R,7aS)-4-(3-Methoxyphenethyl)-7a-methylocta-

hydro-1H-inden-1-yl)propan-1-ol (32): Alcohol 32 was synthe-

sised according to GP3 using silyl ether 31 (47.0 mg, 0.106 mmol,

1.00 equiv.). The title compound was purified via FCC (hexanes/

EtOAc, 9:1) and isolated as colourless oil (26.0 mg, 0.0787 mmol,

74 %): R_f= 0.17 (hexanes/EtOAc, 9:1); [α]²_D³: +16 (c = 0.030, CHCl₃);

¹H NMR (400 MHz, [D]chloroform) δ/ppm = 7.23–7.14 (m, 1H, 5′′-

H), 6.81–6.75 (m, 1H, 6′′-H), 6.74–6.70 (m, 2H, 2′′, 4′′-H), 3.80 (m, 3H,

OCH₃), 3.68–3.60 (m, 1H, 1-H), 3.41–3.29 (m, 1H, 1-H), 2.72–2.60 (m,

1H, 1′′-CH₂), 2.50–2.39 (m, 1H, 1′′-CH₂), 1.97–1.84 (m, 2H, 7′-H, 2′, 3′,

5′ or 6′-H), 1.83–1.65 (m, 4H, 4′-CH₂, 2′, 3′, 5′ or 6′-H), 1.61–1.43 (m,

3H, 2, 1′-H, 2′, 3′, 5′ or 6′-H), 1.37–1.19 (m, 5H, 4′-CH₂, 2′, 3′, 5′ or

6′-H), 1.17–1.09 (m, 3H, 3a′, 7′-H, 2′, 3′, 5′ or 6′-H), 1.05 (d, J = 6.6 Hz,

3H, 2-CH₃), 0.69 (s, 3H, 7a′-CH₃); ¹³C NMR (101 MHz, [D]chloroform)

δ/ppm = 159.7 (C-3′′), 145.2 (C-1′′), 129.3 (C-5′′), 120.9

(C-6′′), 114.3 (C-2′′), 110.9 (C-4′′), 68.2 (C-1), 55.5 (C-3a′), 55.3 (OCH₃),

52.9 (C-1′), 43.3 (C-7a′), 40.2 (C-7′), 38.9 (C-2), 37.0 (4′-CH₂), 36.4

(C-4′), 33.3 (1′′-CH₂), 32.4 (C-2′, 3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or 6′),

24.9 (C-2′, 3′, 5′ or 6′), 22.4 (C-2′, 3′, 5′ or 6′), 16.9 (2-CH₃), 12.1 (7a′-

(60.0 mL) and the solution was cooled to 0 °C. LDA (2

M in THF,

0.96 mL, 1.90 mmol, 1.50 equiv.) was added and the mixture was

stirred for 30 min at 0 °C. A solution of aldehyde 5 (435 g,

1.28 mmol, 1.00 equiv.) in dry THF (15.0 mL) was added and the

reaction mixture was slowly warmed to r.t. and stirred for 17 h.

The reaction was diluted with water (50.0 mL) and the mixture was

extracted with EtOAc (3 × 30.0 mL). The combined organic layers

were dried with Na₂SO₄, filtered and the solvent was removed in

vacuo. The crude product was purified via FCC (hexanes/toluene,

8:2) and led to E-olefin 30 as a colourless oil (248 mg, 0.560 mmol,

44 %): R_f= 0.37 (hexanes/toluene, 8:2); [α]²_D³: +9.6 (c = 0.060, CHCl₃);

¹H NMR (400 MHz, [D]chloroform) δ/ppm = 7.20 (t, J = 7.9 Hz, 1H,

5′′-H), 6.93 (dt, J = 7.7, 1.4 Hz, 1H, 6′′-H), 6.87 (dd, J = 2.6, 1.6 Hz,

1H, 2′′-H), 6.75–6.72 (m, 1H, 4′′-H), 6.31 (d, J = 15.8 Hz, 1H, 1′′-CH),

6.03 (dd, J = 15.8, 8.2 Hz, 1H, 4′-CH), 3.81 (s, 3H, OCH₃), 3.58 (ddd,

J = 9.6, 4.4, 3.3 Hz, 1H, 1-H), 3.26 (ddd, J = 9.6, 7.5, 4.4 Hz, 1H, 1-H),

2.20–2.10 (m, 1H, 4′-H), 1.96 (td, J = 9.0, 4.4 Hz, 1H, 7′-H), 1.75 (qq,

J = 7.0, 3.5 Hz, 3H, 2′, 5′-H), 1.56 (tddt, J = 13.1, 9.8, 7.0, 3.6 Hz, 4H,

3′, 6′-H), 1.22–1.08 (m, 5H, 2, 1′, 2′, 3a′, 7′-H), 1.01 (d, J = 6.6 Hz, 3H,

2-CH₃), 0.89 (d, J = 1.2 Hz, 9H, SiC(CH₃)₃), 0.75 (s, 3H, 7a′-CH₃), 0.03

(s, 6H, Si(CH₃)₂); ¹³C NMR (101 MHz, [D]chloroform) δ/ppm = 159.9

(C-3′′), 139.7 (C-1′′), 136.2 (4′-CH), 129.5 (C-5′′), 128.0 (C-1′′), 118.8

CH ); IR (ATR): ν = cm^–1= 3359, 2922, 2854, 1727, 1584, 1488, 1454,

˜

3

1438, 1378, 1259, 1164, 1152, 1044, 871, 775, 733, 694; HRMS (EI):

+

˙

m/z calculated for C₂₂H₃₄O₂[M] 330.2559, found 330.2551; Purity

(GC): 89 % (scan mode m/z 50–650 (EI 70 eV)).

(C-6′′), 112.5 (C-2′′), 111.4 (C-4′′), 68.1 (C-1), 55.3 (OCH₃), 54.7 (C-3a′), 3-(2-((1R,3aS,4R,7aS)-1-((S)-1-Hydroxypropan-2-yl)-7a-methyl-

53.0 (C-2), 42.9 (C-7a′), 41.4 (C-4′), 39.9 (C-7′), 39.2 (C-1′), 33.2

(C-5′), 27.1 (C-2′), 26.1 (SiC(CH₃)₃), 25.5 (C-3′ or 6′), 21.9 (C-3′ or

6′), 18.5 (SiC(CH₃)₃), 17.1 (2-CH₃), 12.1 (7a′-CH₃), –5.2 (Si(CH₃)₂), –5.2

octahydro-1H-inden-4-yl)ethyl)phenol (33): Alcohol 32 (13.0 mg,

0.0393 mmol, 1.00 equiv.) was dissolved in dry DCM (1.00 mL) and

cooled to –78 °C. BBr₃(1

M in DCM, 0.118 mL, 0.118 mmol,

(Si(CH₃)₂); IR (ATR): ν = cm^–1= 2956, 2857, 1970, 1729, 1711, 1691,

3.00 equiv.) was added dropwise. The reaction mixture was stirred

at –78 °C for 16 h. The reaction was stopped with brine (3.00 mL),

˜

1665, 1641, 1608, 1549, 1509, 1470, 1390, 1362, 1231, 1202, 1168,

1092, 909, 836, 779, 691; HRMS (EI): m/z calculated for C₂₈H₄₆O₂Si warmed up to r.t. and stirred for 1 h. The solution was neutralised

+

˙

[M] 442.3267, found 442.3258; Purity (GC): 71 % (scan mode m/z with NaHCO₃and the aq. layer was extracted with EtOAc (3 ×

50–650 (EI 70 eV)).

5.00 mL). The title compound was purified via FCC (hexanes/EtOAc,

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7:3) and isolated as colourless oil (7.60 mg, 0.0240 mmol, 61 %):

R_f= 0.30 (hexanes/EtOAc, 7:3); [α]²_D³: +17 (c = 0.020, CHCl₃); ¹H NMR

(500 MHz, [D]chloroform) δ/ppm = 7.16–7.10 (m, 1H, 5-H), 6.75 (tt,

J = 7.5, 1.2 Hz, 1H, 6-H), 6.68–6.60 (m, 2H, 2,4-H), 4.80 (s, 1H, OH),

3.67–3.60 (m, 1H, 1′′-H), 3.40–3.33 (m, 1H, 1′′-H), 2.68–2.59 (m, 1H,

2-((((1R,3R)-3-Methoxycyclohexyl)methyl)thio)benzo[d]thiazole

and 2-((((1S,3S)-3-Methoxycyclohexyl)methyl)thio)benzo[d]thi-

azole (trans-37): To a solution of bromide trans-36 (400 mg,

1.93 mmol, 1.00 equiv.) and 2-mercaptobenzthiazole (388 mg,

2.32 mmol, 1.20 equiv.) in DCM (32.0 mL) at 0 °C triethylamine

1-CH₂), 2.46–2.34 (m, 1H, 1-CH₂), 1.95–1.84 (m, 2H, 7′-H, 2′, 3′, 5′ or (0.54 mL, 3.86 mmol, 2.00 equiv.) was added and the reaction mix-

6′-H), 1.82–1.63 (m, 4H, 4′′-CH₂, 2′, 3′, 5′ or 6′-H), 1.61–1.46 (m, 5H, ture was stirred at r.t. for 17 h. The reaction was stopped with water

1′, 2′′-H, 2′, 3′, 5′ or 6′-H), 1.41–1.15 (m, 6H, 3a′, 4′-H, 2′, 3′, 5′ or 6′- (20.0 mL) and the extracted with DCM (3 × 35.0 mL). The combined

H), 1.05 (d, J = 6.7 Hz, 3H, 2′′-CH₃), 0.69 (s, 3H, 7a′-CH₃); ¹³C NMR organic layers were washed with water (50.0 mL), brine (50.0 mL)

(126 MHz, [D]chloroform) δ/ppm = 155.7 (C-3), 145.5 (C-1), 129.6 (C-

5), 120.9 (C-6), 115.3 (C-2), 112.6 (C-4), 68.3 (C-2′′), 55.5 (C-3a′), 52.9 in vacuo. The title compound was purified via FCC (hexanes/EtOAc,

(C-1′), 43.3 (C-7a′), 40.2 (C-7′), 38.9 (C-2′′), 36.9 (C-2′, 3′, 5′ or 6′), 36.4 9:1) and isolated as colourless oil (172 mg, 0.586 mmol, 30 %): R_f=

(C-4′), 33.1 (1′′-CH₂), 32.4 (C-2′, 3′, 5′ or 6′), 27.4 (C-2′, 3′, 5′ or 6′), 0.40 (hexanes/EtOAc, 90:10); ¹H NMR (400 MHz, [D]chloroform)

and then dried with Na₂SO₄, filtered and the solvent was removed

24.9 (4′-CH₂), 22.4 (C-2′, 3′, 5′ or 6′), 16.9 (2′′-CH₃), 12.1 (7a′-CH₃); IR

δ/ppm = 7.85 (ddd, J = 8.2, 1.2, 0.6 Hz, 1H, 4-H), 7.74 (ddd, J = 7.9,

1.3, 0.6 Hz, 1H, 7-H), 7.40 (ddd, J = 8.3, 7.3, 1.3 Hz, 1H, 5-H), 7.31–

7.25 (m, 1H, 6-H), 3.57–3.52 (m, 1H, 3′-H), 3.32–3.26 (m, 5H, OCH₃,

(ATR): ν = cm^–1= 3312, 3183, 2936, 1588, 1549, 1512, 1484, 1334,

˜

1251, 1119, 998, 884, 812; HRMS (EI): m/z calculated for C₂₁H₃₂O₂

+

˙

[M] 316.2397, found 316.2394; Purity (GC): 90 % (scan mode m/z 1′-CH₂), 2.18–2.06 (m, 2H, 1′, 2′-H), 1.94–1.80 (m, 2H, 4′, 6′-H), 1.69–

50–650 (EI 70 eV)).

1.49 (m, 3H, 4′, 5′-H), 1.41–1.31 (m, 1H, 2′-H), 1.19–1.08 (m, 1H,

6′-H); ¹³C NMR (101 MHz, [D]chloroform) δ/ppm = 167.9 (C-2), 153.3

(C-3a), 135.3 (C-7a), 126.2 (C-5), 124.3 (C-6), 121.5 (C-4), 121.0 (C-7),

75.2 (C-3′), 55.8 (OCH₃), 40.3 (1′-CH₂), 35.6 (C-2′), 32.3 (C-1′), 31.9

(1R,3R)-1-(Bromomethyl)-3-methoxycyclohexane/(1S,3S)-1-

(bromomethyl)-3-methoxycyclohexane (trans-36) and (1S,3R)-1-

(Bromomethyl)-3-methoxycyclohexane/(1R,3S)-1-(Bromo-

methyl)-3-methoxycyclohexane (cis-36): Racemic bromides trans-

36 and cis-36 were synthesised over two steps. To a solution of

cis/trans mixture of racemic 3-methoxycyclohexanecarboxylic acid

(34, 844 mg, 5.17 mmol, 1.00 equiv.) in dry THF (30.0 mL), dimethyl

(C-6′), 29.5 (C-4′), 20.2 (C-5′); IR (ATR): ν = cm^–1= 2925, 2858, 1455,

˜

1425, 1238, 1105, 1083, 991, 943, 753, 725; HRMS (EI): m/z calculated

for C₁₅H₁₉ONS₂[M]^·+293.0902, found 293.0899; Purity (HPLC):

> 95 % (λ = 210 nm), > 95 % (λ = 254 nm) (method b). *The trans

identification was performed retrospectively from trans-38.

2-((((1S,3R)-3-Methoxycyclohexyl)methyl)thio)benzo[d]thiazole

and 2-((((1R,3S)-3-Methoxycyclohexyl)methyl)thio)benzo[d]thi-

azole (cis-37): To a solution of bromide cis-36 (206 mg, 0.995 mmol,

1.00 equiv.) and 2-mercaptobenzthiazole (200 mg, 1.19 mmol,

1.20 equiv.) in DCM (16.0 mL) at 0 °C triethylamine (0.28 mL,

1.99 mmol, 2.00 equiv.) was added and the reaction mixture was

stirred at r.t. for 17 h. The reaction was stopped with water (10.0 mL)

and the extracted with DCM (3 × 17.0 mL). The combined organic

layers were washed with water (25.0 mL), brine (25.0 mL) and then

dried with Na₂SO₄, filtered and the solvent was removed in vacuo.

The title compound was purified via FCC (hexanes/EtOAc, 9:1) and

isolated as light yellow oil (122 mg, 0.416 mmol, 42 %): R_f= 0.27

(hexanes/EtOAc, 9:1); ¹H NMR (500 MHz, [D]chloroform) δ/ppm =

7.86 (ddd, J = 8.1, 1.2, 0.6 Hz, 1H, 4-H), 7.75 (ddd, J = 8.0, 1.3, 0.6 Hz,

1H, 7-H), 7.41 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H, 5-H), 7.29 (ddd, J = 8.3,

7.3, 1.2 Hz, 1H, 6-H), 3.36 (s, 3H, OCH₃), 3.31 (dd, J = 6.8, 5.2 Hz, 2H,

1′-CH₂), 3.14 (tt, J = 10.8, 4.1 Hz, 1H, 3′-H), 2.35–2.28 (m, 1H, 2′-H),

2.12–2.04 (m, 1H, 6′-H), 1.93–1.88 (m, 1H, 6′-H), 1.87–1.74 (m, 2H,

1′, 5′-H), 1.59–1.52 (m, 2H, 4′-H), 1.40–1.32 (m, 1H, 5′-H), 1.04–0.96

(m, 1H, 2′-H); ¹³C NMR (101 MHz, [D]chloroform) δ/ppm = 167.6 (C-

2), 153.4 (C-3a), 135.3 (C-7a), 126.2 (C-5), 124.3 (C-6), 121.6 (C-4),

121.1 (C-7), 79.1 (C-3′), 55.9 (OCH₃), 41.0 (C-4′), 40.1 (1′-CH₂), 38.1

sulfide borane (2

M in THF, 3.4 mL, 6.73 mmol, 1.30 equiv.) was

added dropwise at –78 °C and the mixture was stirred for 5 h at

0 °C. The reaction was stopped with aq. sat. NaHCO₃solution

(20.0 mL) and the mixture was extracted with EtOAc (3 × 30.0 mL).

The combined organic layers were dried with Na₂SO₄, filtered and

concentrated in vacuo to give (3-methoxycyclohexyl)methanol (35)

as a colourless oil (746 mg, 5.17 mmol, quantitative). To a suspen-

sion of crude alcohol 35 (746 mg, 5.17 mmol, 1.00 equiv.) and PPh₃

(2.74 g, 10.3 mmol, 2.00 equiv.) in DCM (50.0 mL) at 0 °C, CBr₄

(3.43 g, 10.3 mmol, 2.00 equiv.) was added. The reaction was

warmed up to r.t. and after 2 h the solvent was removed in vacuo

and the title compounds were separated and purified via FCC (hex-

anes/EtOAc, 97:3) and trans-36 (436 mg, 2.11 mmol, 41 %) and cis-

36 (421 mg, 2.03 mmol, 39 %) were both obtained as light yellow

oil. Analytical data of trans-36*: R_f= 0.29 (hexanes/EtOAc, 97:3);

¹H NMR (400 MHz, [D]chloroform) δ/ppm = 3.54 (p, J = 3.2 Hz, 1H,

3-H), 3.32–3.28 (m, 5H, OCH₃, 1-CH₂), 2.07–1.95 (m, 2H, 1,2-H), 1.90–

1.77 (m, 2H, 4,6-H), 1.68–1.47 (m, 2H, 5-H), 1.35–1.25 (m, 1H, 4-H),

1.20 (tt, J = 12.3, 2.5 Hz, 1H, 2-H), 1.08 (tdd, J = 12.5, 11.0, 4.0 Hz,

1H, 6-H); ¹³C NMR (101 MHz, [D]chloroform) δ/ppm = 75.1 (C-3),

55.8 (OCH₃), 41.0 (1-CH₂), 34.9 (C-2), 34.2 (C-1), 31.1 (C-6), 29.3

(C-4), 19.9 (C-8); IR (ATR): ν = cm^–1= 2929, 2858, 2821, 1738, 1445,

˜

(C-2′), 36.8 (C-1′), 31.9 (C-6′), 23.8 (C-5′); IR (ATR): ν = cm^–1= 2927,

˜

1363, 1250, 1233, 1083, 965, 944, 886, 807, 685; HRMS (EI): m/z

calculated for C₈H₁₄BrO [M – H]^·+205.0234, found 205.0220; Purity

(GC): > 95 % (scan mode m/z 50–650 (EI 70 eV)). Analytical data of

cis-36: R_f= 0.20 (hexanes/EtOAc, 97:3); ¹H NMR (400 MHz, [D]chloro-

form) δ/ppm = 3.36 (s, 3H, OCH₃), 3.31 (dd, J = 6.3, 1.5 Hz, 2H, 1-

2856, 1456, 1426, 1087, 993, 921, 755, 726, 704; HRMS (EI): m/z

calculated for C₁₅H₁₉ONS₂[M]^·+293.0908, found 293.0901; Purity

(HPLC): 62 % (λ = 210 nm), 69 % (λ = 254 nm) (method b). *The cis

identification was performed retrospectively from cis-38.

CH₂), 3.14 (tt, J = 10.8, 4.2 Hz, 1H, H-3), 2.23 (dtt, J = 11.9, 4.1, 2.0 Hz, 2-((((1S,3S)-3-Methoxycyclohexyl)methyl)sulfonyl)benzo[d]thi-

1H, 2-H), 2.08–2.00 (m, 1H, 4-H), 1.87–1.78 (m, 2H, 5,6-H), 1.74–1.63

azole and 2-((((1R,3R)-3-Methoxycyclohexyl)methyl)sulfonyl)-

benzo[d]thiazole (trans-38): To a solution of trans-37 (154 mg,

(m, 1H, 1-H), 1.33–1.20 (m, 1H, 5-H), 1.16–1.03 (m, 1H, 4-H), 1.01–

0.88 (m, 2H, 2,6-H); ¹³C NMR (101 MHz, [D]chloroform) δ/ppm = 0.525 mmol, 1.00 equiv.) in DCM (20.0 mL), m-CPBA (647 mg,

78.9 (C-3), 55.9 (OCH₃), 39.8 (1-CH₂), 38.9 (C-1), 37.2 (C-2), 31.8

2.89 mmol, 5.50 equiv.) was added and the reaction mixture was

stirred for 24 h at r.t. The reaction was stopped with sat. aq. Na₂S₂O₃

(10.0 mL) and sat. aq. NaHCO₃(10.0 mL) and the aq. phase was

extracted with DCM (3 × 30.0 mL). The combined organic layers

were washed with brine (30.0 mL), dried with Na₂SO₄, filtered and

the solvent was removed in vacuo. The title compound was purified

(C-4), 31.1 (C-6), 23.6 (C-5); IR (ATR): ν = cm^–1= 2929, 2857, 2821,

˜

1463, 1450, 1373, 1276, 1232, 1166, 1110, 1088, 976, 923; HRMS (EI):

m/z calculated for C₈H₁₄BrO [M – H]^·+205.0234, found 205.0220;

Purity (GC): 92 % (scan mode m/z 50–650 (EI 70 eV)). *The trans/cis

identification was performed retrospectively from trans/cis-38.

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via FCC (hexanes/EtOAc, 8:2) and isolated as white oily solid

(156 mg, 0.479 mmol, 91 %): R_f= 0.22 (hexanes/EtOAc, 8:2); ¹H NMR

(400 MHz, [D]chloroform) δ/ppm = 8.21 (ddd, J = 8.1, 1.4, 0.7 Hz,

1H, 4-H), 8.02 (ddd, J = 7.8, 1.5, 0.7 Hz, 1H, 7-H), 7.67–7.55 (m, 2H,

4′-CH(E)), 5.48 (m, 2H, 4′-CH(Z)), 5.25 (m, 2H, 1′′-CH(E)), 5.17 (m, 2H,

1′′-CH(Z)), 3.58 (m, 4H, 1-H), 3.51–3.44 (m, 4H, 3′′-H), 3.32–3.28 (m,

12H, OCH₃), 3.23 (m, 4H, 1-H), 2.87–2.78 (m, 2H, 4′-H(Z)), 2.67–2.54

(m, 2H, 1′′-H(Z)), 2.44–2.39 (m, 2H, 4′-H(E)), 2.38–2.29 (m, 2H,

5,6-H), 3.51–3.47 (m, 1H, 3′-H), 3.44 (t, J = 6.3 Hz, 2H, 1′-CH₂), 3.26 1′′-H(E)), 1.99–1.88 (m, 4H, 7′-H), 1.87–1.71 (m, 13H, CH₂), 1.69–1.28

(s, 3H, OCH₃), 2.57–2.46 (m, 1H, 1′-H), 2.21–2.12 (m, 1H, 2′-H), 1.93–

1.84 (m, 1H, 6′-H), 1.83–1.74 (m, 1H, 4′-H), 1.70–1.57 (m, 1H, 5′-H),

1.54–1.43 (m, 1H, 5′-H), 1.42–1.27 (m, 3H, 2′, 4′, 6′-H); ¹³C NMR

(101 MHz, [D]chloroform) δ/ppm = 166.9 (C-2), 152.8 (C-3a), 136.9

(m, 51H, 2, 3a′-H, CH₂), 1.27–1.04 (m, 20H, 1′-H, CH₂), 0.98–0.93 (m,

12H, 2-CH₃), 0.89 (s, 37H, SiC(CH₃)₃), 0.74 (m, 6H, 7a′-CH₃), 0.70 (s,

6H, 7a′-CH₃), 0.03–0.01 (m, 24H, Si(CH₃)₂); ¹³C NMR (101 MHz,

[D]chloroform) δ/ppm = 135.3 (CH), 135.2 (CH), 134.6 (CH), 129.6

(C-7a), 128.1 (C-6), 127.8 (C-5), 125.6 (C-4), 122.5 (C-7), 74.7 (C-3′), (CH), 129.4 (CH), 129.4 (CH), 75.6 (C-3′′), 75.5 (C-3′′), 75.5 (C-3′′), 68.1

60.6 (1′-CH₂), 55.8 (OCH₃), 35.5 (C-2′), 32.3 (C-6′), 29.6 (C-4′), 27.7 (C-1), 55.9 (OCH₃), 55.8 (OCH₃), 53.8 (OCH₃), 55.8 (OCH₃), 53.8

(C-1′), 20.1 (C-5′); IR (ATR): ν = cm^–1= 2929, 1471, 1323, 1315, 1146, (C-1′), 53.5 (C-1′), 52.7 (C-3a′), 52.5 (C-3a′), 52.5 (C-3a′), 42.7 (C-7a′),

˜

1105, 1082, 1023, 944, 852, 759, 729, 689; HRMS (EI): m/z calculated

42.6 (C-7a′), 40.8 (C-7′), 40.7 (C-7′), 40.7 (C-7′), 39.0 (C-4′(E)), 38.9 (C-

for C₁₅H₁₈O₃NS₂[M]^·+324.0723, found 324.0718; Purity (HPLC): 93 % 2), 36.7 (CH₂), 36.6 (CH₂), 36.5 (CH₂), 35.8 (CH₂), 35.3 (C-1′′(E)), 35.2

(λ = 210 nm), > 95 % (λ = 254 nm) (method b).

(C-1′′(E)), 34.9 (C-4′(Z)), 34.8 (C-4′(Z)), 32.9 (CH₂), 32.7 (CH₂), 32.6

(CH₂), 32.5 (CH₂), 32.3 (CH₂), 30.9 (CH₂), 30.3 (C-1′′(Z)), 30.2 (C-1′′(Z)),

29.9 (CH₂), 29.7 (CH₂), 29.5 (CH₂), 29.4 (CH₂), 29.2 (CH₂), 27.0 (CH₂),

27.0 (CH₂), 26.9 (CH₂), 26.1 (SiC(CH₃)₃), 24.9 (CH₂), 24.8 (CH₂), 24.1

(CH₂), 20.3 (CH₂), 20.2 (CH₂), 20.1 (CH₂), 18.7 (CH₂), 18.5 (SiC(CH₃)₃),

16.9 (2-CH₃), 16.9 (2-CH₃), 16.9 (2-CH₃), 14.3 (7a′-CH₃), 13.8 (7a′-CH₃),

2-((((1S,3R)-3-Methoxycyclohexyl)methyl)sulfonyl)benzo[d]thi-

azole and 2-((((1R,3S)-3-Methoxycyclohexyl)methyl)sulfonyl)-

benzo[d]thiazole (cis-38): To a solution of cis-37 (108 mg,

0.368 mmol, 1.00 equiv.) in DCM (14.0 mL), m-CPBA (349 mg,

2.02 mmol, 5.50 equiv.) was added and the reaction mixture was

stirred for 24 h at r.t. The reaction was stopped with sat. aq. Na₂S₂O₃

(8.00 mL) and sat. aq. NaHCO₃(8.00 mL) and the aq. phase was

extracted with DCM (3 × 25.0 mL). The combined organic layers

were washed with brine (15.0 mL), dried with Na₂SO₄, filtered and

the solvent was removed in vacuo. The title compound was purified

13.8 (7a′-CH ), –5.2 (Si(CH ) ), –5.2 (Si(CH ) ); IR (ATR) v/cm^–1= 3725,

˜

3

3 2

3705, 2927, 2856, 1473, 1460, 1440, 1361, 1250, 1089, 1032, 1006,

835, 773, 670, 662; HRMS (EI): m/z calculated for C₂₈H₅₂O₂Si [M]^·+

448.3731, found 448.3738; Purity (GC): > 95 % (scan mode m/z 50–

650 (EI 70 eV)).

via FCC (hexanes/EtOAc, 8:2) and isolated as white solid (120 mg, ((S)-2-((1R,3aS,4R,7aS)-4-((Z)-2-((1S,3S)-3-Methoxycyclohexyl)-

0.368 mmol, quantitative): R_f= 0.20 (hexanes/EtOAc, 8:2); mp: 54– vinyl)-7a-methyloctahydro-1H-inden-1-yl)propan-1-ol (Z-40a)

56 °C; ¹H NMR (400 MHz, [D]chloroform) δ/ppm = 8.21 (ddd, J = or ((S)-2-((1R,3aS,4R,7aS)-4-((Z)-2-((1R,3R)-3-Methoxycyclo-

8.1, 1.4, 0.7 Hz, 1H, 4-H), 8.02 (ddd, J = 7.8, 1.5, 0.7 Hz, 1H, 7-H),

7.68–7.54 (m, 2H, 5,6-H), 3.50 (d, J = 6.3 Hz, 2H, 1′-CH₂), 3.31 (s, 3H,

hexyl)vinyl)-7a-methyloctahydro-1H-inden-1-yl)propan-1-ol (Z-

40b): Z-Isomer Z-40a or Z-40b were synthesised according to GP3,

OCH₃), 3.14 (tt, J = 10.7, 4.0 Hz, 1H, 3′-H), 2.32–2.16 (m, 2H, 1′, using E/Z mixture of four isomers 39 (51.0 mg, 0.110 mmol,

2′-H), 2.06–1.89 (m, 2H, 4′, 6′-H), 1.84–1.75 (m, 1H, 5′-H), 1.37–1.22 1.00 equiv.). The Z-isomer was purified via FCC (hexanes/EtOAc, 8:2)

(m, 2H, 4′, 5′-H), 1.15–1.01 (m, 2H, 2′, 6′-H); ¹³C NMR (101 MHz, and isolated as colourless oil (6.00 mg, 0.0179 mmol, 16 %): R_f=

[D]chloroform) δ/ppm = 166.8 (C-2), 152.8 (C-3a), 136.9 (C-7a), 128.2

(C-6), 127.8 (C-5), 125.6 (C-4), 122.5 (C-7), 78.4 (C-3′), 60.7 (1′-CH₂),

55.9 (OCH₃), 38.3 (C-2′), 32.3 (C-6′), 31.4 (C-4′), 31.4 (C-1′), 23.3

0.23 (hexanes/EtOAc, 8:2); [α]²_D³: +14 (c = 0.040, CHCl₃); ¹H NMR

(800 MHz, [D]chloroform) δ/ppm = 5.48 (td, J = 10.8, 1.0 Hz, 1H,

4′-CH), 5.18 (ddd, J = 11.0, 9.9, 1.2 Hz, 1H, 1′′-CH), 3.63 (dd, J = 10.5,

(C-5′); IR (ATR): ν = cm^–1= 2935, 2859, 1474, 1309, 1198, 1143, 1111, 3.2 Hz, 1H, 1-H), 3.49–3.46 (m, 1H, 3′′-H), 3.36 (dd, J = 10.5, 6.9 Hz,

˜

1072, 1024, 978, 929, 840, 756, 747, 731, 687; HRMS (EI): m/z calcu- 1H, 1-H), 3.30 (s, 3H, OCH₃), 2.85–2.79 (m, 1H, 4′-H), 2.62–2.55 (m,

lated for C₁₅H₂₀O₃NS₂[M]^·+326.0879, found 326.0877; Purity (HPLC):

1H, 1′′-H), 1.96–1.91 (m, 1H, 7′-H), 1.83–1.75 (m, 3H, 2′′, 4′′-H, 2′, 3′,

5′ or 6′-H), 1.69–1.62 (m, 2H, 2′, 3′, 5′ or 6′-H), 1.60–1.54 (m, 3H,

5′′, 6′′-H, 2′, 3′, 5′ or 6′-H), 1.54–1.41 (m, 5H, 2, 3a′, 5′′-H, 2′, 3′, 5′ or

6′-H), 1.40–1.29 (m, 2H, 4′′-H, 2′, 3′, 5′ or 6′-H), 1.27–1.22 (m, 1H,

2′, 3′, 5′ or 6′-H), 1.21–1.13 (m, 3H, 1′, 7′, 2′′-H), 1.07–1.02 (m, 1H,

6′′-H), 1.01 (d, J = 6.6 Hz, 3H, 2-CH₃), 0.76 (s, 3H, 7a′-CH₃); ¹³C NMR

(201 MHz, [D]chloroform) δ/ppm = 135.4 (1′′-CH), 129.5 (4′-CH), 75.5

(C-3′′), 68.1 (C-1), 55.9 (OCH₃), 53.2 (C-1′), 52.5 (C-3a′), 42.6 (C-7a′),

40.6 (C-7′), 38.7 (C-2), 35.8 (C-2′′), 34.8 (C-4′), 32.9 (C-6′′), 32.3 (C-2′,

3′, 5′ or 6′), 30.2 (C-1′′), 29.9 (C-4′′), 27.1 (C-2′, 3′, 5′ or 6′), 24.8 (C-

2′, 3′, 5′ or 6′), 20.2 (C-5′′), 18.7 (C-2′, 3′, 5′ or 6′), 16.7 (2-CH₃), 14.3

> 95 % (λ = 210 nm), > 95 % (λ = 254 nm) (method b).

tert-Butyl((S)-2-((1R,3aS,4R,7aS)-4-((E)-2-((1S/R,3S/R)-3-meth-

oxycyclohexyl)vinyl)-7a-methyloctahydro-1H-inden-1-yl)prop-

oxy)dimethylsilane and tert-Butyl((S)-2-((1R,3aS,4R,7aS)-4-((Z)-

2-((1R/S,3R/S)-3-methoxycyclohexyl)vinyl)-7a-methyloctahydro-

1H-inden-1-yl)propoxy)dimethylsilane (39): In an oven-dried

two-necked Schlenk-flask, sulfone trans-38 (207 mg, 0.636 mmol,

1.00 equiv.) was dissolved in dry THF (6.00 mL) and the solution

was cooled to –78 °C. LDA (2

M in THF, 0.382 mL, 0.763 mmol,

1.20 equiv.) was added and the reaction mixture was stirred for

30 min at –78 °C. A solution of aldehyde 5 (258 mg, 0.763 mmol,

1.20 equiv.) in dry THF (7.00 mL) was added dropwise. The reaction

mixture was slowly warmed to - 50 °C and stirred for 18 h. The

reaction was stopped with sat. aq. NH₄Cl (7.00 mL), the layers were

separated, and the aq. phase was extracted with EtOAc (3 ×

(7a′-CH₃); IR (ATR): ν = cm^–1= 3727, 3624, 2934, 2875, 1445, 1112,

˜

1089, 1039, 763, 671, 656; HRMS (EI): m/z calculated for C₂₂H₃₈O₂

[M]^·+334.2866, found 334.2861; Purity (GC): > 95 % (scan mode

m/z 50–650 (EI 70 eV)).

(1R,3aR,7aR)-1-((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-

20.0 mL). The combined organic layers were washed with brine 7a-methyl-2,3,3a,6,7,7a-hexahydro-1H-inden-4-yl Trifluoro-

(30.0 mL), dried with Na₂SO₄, filtered and the solvent was removed methanesulfonate (41): A solution of ketone 3 (106 mg,

in vacuo. The title compounds were purified twice via FCC (hex- 0.327 mmol, 1.00 equiv.) in dry THF (15.0 mL) was added dropwise

anes/EtOAc, 98:2) to give seco-steroids 39 as an inseparable E/Z

mixture (E/Z ratio 55:45 determined via ¹H, 4:5:43:48 determined

via GC/MS) of four isomers as a light yellow oil (196 mg,

to NaHMDS (2 M in THF, 0.410 mL, 0.820 mmol, 2.50 equiv.) at

–78 °C. After 1 h N-phenyl-bis(trifluoromethansulfonimide) (280 mg,

0.784 mmol, 2.40 equiv.) was added and stirred for additional

0.437 mmol, 69 %): The analytical data refers to the mixture of the 20 min. The reaction mixture was warmed up to r.t. and stirred for

four isomers: R_f= 0.27 (hexanes/EtOAc, 98:2); [α]²_D³: +26.9 (c = 1.03,

CHCl₃); ¹H NMR (400 MHz, [D]chloroform) δ/ppm = 5.57 (m, 2H,

additional 2 h. The reaction was stopped with water (15.0 mL) and

the organic solvent was removed in vacuo. The aq. residue was

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extracted with hexanes (3 × 20.0 mL). The combined organic layers

were washed with water (30.0 mL), dried with Na₂SO₄, filtered and

the solvent was removed in vacuo. The title compound was purified

via FCC (hexanes/EtOAc, 9:1) and isolated as colourless oil (135 mg,

0.297 mmol, 91 %): R_f= 0.81 (hexanes/EtOAc, 9:1); [α]²_D³: +17 (c =

EtOAc, 8:2) and alcohol 43a was obtained as white solid (831 mg,

2.55 mmol, 44 %), alcohol 43b as white solid (273 mg, 0.838 mmol,

14 %) and alcohol 43c as white solid (150.3 mg, 0.460 mmol, 8 %):

Analytical data of alcohol 43a: R_f= 0.39 (hexanes/EtOAc, 8:2); mp:

1

97–99 °C; [α]²_D³: +33 (c = 0.10, CHCl₃); H NMR (500 MHz, [D]chloro-

1

0.10, CHCl₃); H NMR (500 MHz, [D]chloroform) δ/ppm = 5.68–5.65

form) δ/ppm = 4.06 (p, J = 2.9 Hz, 1H, 5-H), 3.58 (dd, J = 9.6, 3.3 Hz,

1H, 1′-H), 3.26 (dd, J = 9.6, 7.5 Hz, 1H, 1′-H), 1.83–1.45 (m, 10H, 2,

3, 3a, 4, 6, 7, 2′-H), 1.37 (bs, 1H, 5-OH), 1.31–1.20 (m, 2H, 1,2-H),

1.16–1.04 (m, 1H, 3-H), 0.99 (d, J = 6.5 Hz, 3H, 2′-CH₃), 0.89 (s, 9H,

(m, 1H, 5-H), 3.56 (dd, J = 9.7, 3.3 Hz, 1H, 1′-H), 3.31 (dd, J = 9.7,

6.9 Hz, 1H, 1′-H), 2.51–2.44 (m, 1H, 3a-H), 2.34–2.28 (m, 2H, 6-H),

2.02–1.91 (m, 2H, 2-H, 2,7-H), 1.82–1.75 (m, 1H, 3-H), 1.62–1.34 (m,

5H, 1, 2, 3, 7, 2′-H), 1.01 (d, J = 6.6 Hz, 3H, 2′-CH₃), 0.89 (s, 9H, SiC(CH₃)₃), 0.66 (s, 3H, 7a-CH₃), 0.03 (s, 3H, Si(CH₃)₂), 0.02 (s, 3H,

SiC(CH₃)₃), 0.77 (s, 3H, 7a-CH₃), 0.03 (s, 6H, Si(CH₃)₂); ¹³C NMR

(126 MHz, [D]chloroform) δ/ppm = 150.0 (C-4), 118.7 (q, J_C-F

320.3 Hz, CF₃) 116.3 (C-5), 67.7 (C-1′), 50.9 (C-1), 50.1 (C-3a), 45.5 (C-

Si(CH₃)₂); ¹³C NMR (126 MHz, [D]chloroform) δ/ppm = 68.1 (C-1′),

66.7 (C-5), 52.6 (C-1), 42.4 (C-7a), 42.2 (C-3a), 39.3 (C-2′), 34.6 (C-7),

33.5 (C-4), 29.3 (C-6), 27.4 (C-2), 26.6 (C-3), 26.1 (SiC(CH₃)₃), 18.5

=

7a), 39.2 (C-2′), 34.9 (C-7), 27.9 (C-2), 26.1 (SiC(CH₃)₃), 24.0 (C-6), 21.8 (SiC(CH₃)₃), 17.1 (2′-CH₃), 10.3 (7a-CH₃), –5.2 (Si(CH₃)₂), –5.2

(C-3), 18.5 (SiC(CH₃)₃), 17.2 (2′-CH₃), 11.6 (7a-CH₃), –5.2 (Si(CH₃)₂), (Si(CH ) ); IR (ATR): ν = cm^–1= 3882, 2928, 2364, 1473, 1460, 1407,

˜

3 2

–5.3 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 3909, 3861, 2954, 2929, 2857,

1676, 1471, 1445, 1417, 1361, 1314, 1246, 1205, 1142, 1099, 1002,

1352, 1333, 1252, 1197, 1093, 1022, 997, 976, 937, 920, 812, 770,

˜

742, 700, 656, 585, 566; HRMS (EI): m/z calculated for C₁₉H₃₇O₂Si [M

899, 870, 857, 834, 812, 774, 631, 604, 567; HRMS (EI): m/z calculated – H] 325.2557, found 325.2572; Purity (GC): > 95 % (scan mode

+

˙

+

˙

for C₂₀H₃₅F₃O₄SSi [M] 456.1972, found 456.1970; Purity (HPLC):

m/z 50–650 (EI 70 eV)). Analytical data of alcohol 43b: R_f= 0.33

(hexanes/EtOAc, 8:2); mp: 76–78 °C; [α]²_D³: +9.4 (c = 0.070, CHCl₃);

¹H NMR (400 MHz, [D]chloroform) δ/ppm = 3.57 (ddd, J = 10.8, 6.7,

4.0 Hz, 2H, 4, 1′-H), 3.26 (dd, J = 9.6, 7.4 Hz, 1H, 1′-H), 2.04–1.95 (m,

1H, 5-H), 1.91–1.76 (m, 3H, 2,3,7-H), 1.67–1.46 (m, 3H, 6, 2′-H), 1.38–

1.17 (m, 5H, 1, 2, 3, 3a, OH), 1.15–1.03 (m, 2H, 5,7-H), 0.98 (d, J =

6.5 Hz, 3H, 2′-CH₃), 0.89 (s, 9H, SiC(CH₃)₃), 0.68 (s, 3H, 7a-CH₃), 0.02

(s, 3H, Si(CH₃)₂), 0.02 (s, 3H, Si(CH₃)₂); ¹³C NMR (126 MHz, [D]chloro-

form) δ/ppm = 71.3 (C-4), 67.9 (C-1′), 57.1 (C-3a), 53.2 (C-1), 44.9 (C-

7a), 39.2 (C-7), 38.8 (C-2′), 36.1 (C-5), 27.5 (C-2), 26.1 (SiC(CH₃)₃), 23.8

(C-3), 21.9 (C-6), 18.5 (SiC(CH₃)₃), 16.9 (2′-CH₃), 12.2 (7a-CH₃), –5.2

> 95 % (λ = 210 nm) (method c).

tert-Butyldimethyl((S)-2-((1R,3aS,7aS)-7a-methyl-2,3,3a,6,7,7a-

hexahydro-1H-inden-1-yl)propoxy)silane (42): To a solution of

enol triflate 41 (3.04 g, 6.69 mmol, 1.0 equiv.) in dry THF (50.0 mL)

DIPEA (4.83 mL, 27.7 mmol, 4.15 equiv.) and formic acid (0.78 mL,

20.1 mmol, 3.00 equiv.) were added and the solution was degassed

before Pd(OAc)₂(15.0 mg, 0.067 mmol, 1.00 mol-%) and PPh₃

(35.0 mg, 0.134 mmol, 2.00 mol-%) were added. The reaction mix-

ture was stirred at r.t. for 18 h. EtOAc (50.0 mL) was added and the

organic phase was washed with brine (40.0 mL), dried with Na₂SO₄,

filtered and the solvent was removed in vacuo. The crude product

was purified via FCC (hexanes/EtOAc, 99:1) and olefin 42 was ob-

tained as colourless oil (1.81 g, 5.61 mmol, 84 %): R_f= 0.88 (hex-

anes/EtOAc, 99:1); [α]_D²³: +61 (c = 0.12, CHCl₃); ¹H NMR (400 MHz,

[D]chloroform) δ/ppm = 5.66–5.52 (m, 2H, 4′-H, 5′-H), 3.60 (dd, J =

9.6, 3.4 Hz, 1H, 1-H), 3.30–3.23 (m, 1H, 1-H), 2.13–1.94 (m, 3H, 3a′,

6′-H), 1.99 (dt, J = 12.7, 4.1 Hz, 1H, 7′-H), 1.86 (dtd, J = 13.0, 9.4,

6.5 Hz, 1H, 2′-H), 1.68–1.53 (m, 2H, 3′, 2-H), 1.51–1.32 (m, 2H, 2′, 7′-

H), 1.30–1.14 (m, 2H, 1′, 3′-H), 1.02 (d, J = 6.5 Hz, 3H, 2-CH₃), 0.89

(s, 9H, SiC(CH₃)₃), 0.70 (s, 3H, 7a′-CH₃), 0.03 (s, 6H, Si(CH₃)₂); ¹³C NMR

(126 MHz, [D]chloroform) δ/ppm = 128.5 (C-4′), 126.7 (C-5′), 68.1

(C-1), 51.2 (C-1′), 48.5 (C-3a′), 42.0 (C-7a′), 39.6 (C-2), 36.7 (C-7′), 28.1

(C-2′), 26.2 (SiC(CH₃)₃), 25.2 (C-3′), 24.6 (C-6′), 18.6 (SiC(CH₃)₃), 17.2

(Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 3293, 2927, 2855,

1471, 1459, 1386, 1360, 1251, 1097, 1069, 1030, 1017, 1005, 954,

832, 812, 769, 719, 667; HRMS (EI): m/z calculated for C₁₉H₃₇O₂Si

[M] 326.2636, found 326.2641; Purity (GC): > 95 % (scan mode m/z

˜

+

˙

50–650 (EI 70 eV)). Analytical data of alcohol 43c: R_f= 0.28 (hexanes/

EtOAc, 8:2); mp: 82–84 °C; [α]²_D³: +38 (c = 0.070, CHCl₃); ¹H NMR

(400 MHz, [D]chloroform) δ/ppm = 3.68–3.53 (m, 2H, 5, 1′-H), 3.25

(dd, J = 9.6, 7.3 Hz, 1H, 1′-H), 1.92 (dt, J = 13.1, 3.6 Hz, 1H, 7-H),

1.86–1.73 (m, 3H, 3,6-H), 1.57–1.43 (m, 3H, 4, 2′-H, OH), 1.37–1.08

(m, 7H, 1, 2, 3a, 4,6,7-H), 0.98 (d, J = 6.5 Hz, 3H, 2′-CH₃), 0.89 (s, 9H,

SiC(CH₃)₃), 0.72 (s, 3H, 7a-CH₃), 0.02 (s, 6H, Si(CH₃)₂); ¹³C NMR

(101 MHz, [D]chloroform) δ/ppm = 76.8 (C-5), 71.9 (C-1′), 67.9 (C-1),

52.0 (C-3a), 48.6 (C-7a), 42.1 (C-2′), 39.2 (C-7), 37.5 (C-6), 35.3 (C-3),

31.7 (C-2), 28.3 (SiC(CH₃)₃), 26.1 (C-4), 18.5 (SiC(CH₃)₃), 17.0 (2′-CH₃),

(2-CH₃), 11.2 (7a′-CH₃) –5.2 (Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν =

˜

11.4 (7a-CH₃), –5.2 (Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1

3304, 2928, 2856, 1471, 1359, 1249, 1104, 1088, 1056, 1027, 1004,

957, 858, 812, 772, 702, 665; HRMS (EI): m/z calculated for

C₁₉H₃₈O₂Si [M] 326.2636, found 326.2630; Purity (GC): > 95 % (scan

=

cm^–1= 2950, 2857, 1639, 1471, 1458, 1388, 1361, 1251, 1127, 1085,

˜

1030, 1005, 833, 812, 772, 702, 620, 562; HRMS (EI): m/z calculated

+

˙

for C₁₈H₃₃OSi [M] 293.2301, found 293.2295; Purity (HPLC): > 95 %

+

˙

(λ = 210 nm), > 95 % (λ = 191 nm) (method e).

mode m/z 50–650 (EI 70 eV)).

(1R,3aS,5R,7aS)-1-((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-

yl)-7a-methyloctahydro-1H-inden-5-ol (43a), (1R,3aR,4R,7aR)-1-

((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-7a-methylocta-

hydro-1H-inden-4-ol (43b) and (1R,3aS,5S,7aS)-1-((S)-1-((tert-

Butyldimethylsilyl)-oxy)propan-2-yl)-7a-methyloctahydro-1H-

inden-5-ol (43c): In an oven-dried two-necked Schlenk flask 42

(1.80 g, 5.80 mmol, 1.00 equiv.) was dissolved in dry THF (25.0 mL)

and the solution was cooled to 0 °C. BH₃·THF (1 M in THF, 17.5 mL,

17.5 mmol, 3.00 equiv.) was added dropwise and the reaction mix-

ture was warmed to r.t. and stirred for 2 h. The reaction mixture

(1R,3aS,7aS)-1-((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-

7a-methyloctahydro-5H-inden-5-one (6): In an oven-dried flask

43a (888 mg, 2.72 mmol, 1.00 equiv.) was dissolved in dry DCM

(15.0 mL). DMP (1.73 g, 4.08 mmol, 1.50 equiv.) was added and the

reaction mixture was stirred at r.t. for 3 h. The reaction mixture was

diluted with Et₂O (39.0 mL), water (39.0 mL) and an excess of

Na₂S₂O₃and the suspension was stirred for additional 30 min. The

two layers were separated, and the aq. phase was extracted with

EtOAc (3 × 80.0 mL). The combined organic layers were dried with

Na₂SO₄, filtered and the solvent was removed in vacuo. The title

compound was purified via FCC (hexanes/EtOAc, 9:1) and isolated

as white solid (872 mg, 2.69 mmol, 99 %): R_f= 0.63 (hexanes/EtOAc,

was cooled to 0 °C and aq. 1

M NaOH (72.0 mL) and 30 % (w/w)

H₂O₂(72.0 mL) were added and the resulting mixture was stirred

at r.t. for 18 h. The two layers were separated, and the aq. phase

was extracted with DCM (3 × 100 mL). The combined organic layers

1

9:1); mp: 59–61 °C; [α]²_D³: +42 (c = 0.11, CHCl₃); H NMR (500 MHz,

were dried with Na₂SO₄, filtered and the solvent was removed in [D]chloroform) δ/ppm = 3.58 (dd, J = 9.6, 3.3 Hz, 1H, 1′-H), 3.30 (dd,

vacuo. The alcohols were purified and separated via FCC (hexanes/ J = 9.6, 7.1 Hz, 1H, 1′-H), 2.45–2.37 (m, 1H, 6-H), 2.35–2.23 (m, 3H,

Eur. J. Org. Chem. 2020, 6270–6288

www.eurjoc.org

6285

Full Paper

doi.org/10.1002/ejoc.202001080

EurJOC

European Journal of Organic Chemistry

4,7-H), 2.16 (ddd, J = 13.1, 7.0, 2.0 Hz, 1H, 4-H), 1.93 (dtd, J = 13.3, (hexanes/EtOAc, 7:3) and isolated as off-white solid (18.0 mg,

9.5, 6.3 Hz, 1H, 3-H), 1.85–1.76 (m, 1H, 3a-H), 1.67–1.52 (m, 3H, 2, 6,

2′-H), 1.50–1.41 (m, 1H, 3-H), 1.31–1.21 (m, 2H, 1,2-H), 1.01 (d, J =

6.6 Hz, 3H, 2′-CH₃), 0.92 (s, 3H, 7a-CH₃), 0.89 (s, 9H, Si-C(CH₃)₃), 0.03

(s, 6H, Si(CH₃)₂); ¹³C NMR (126 MHz, [D]chloroform) δ/ppm = 212.4

(C-5), 67.7 (C-1′), 51.5 (C-1), 49.9 (C-3a), 42.9 (C-7), 42.0 (C-7a), 39.0

(C-2′), 37.7 (C-4 or C-6), 37.7 (C-4 or C-6), 28.7 (C-3), 26.7 (C-2), 26.1

(SiC(CH₃)₃), 18.5 (SiC(CH₃)₃), 17.1 (2′-CH₃), 10.8 (7a-CH₃), –5.2

62.8 μmol, 67 %): R_f= 0.26 (hexanes/EtOAc, 7:3); mp: 169 °C; [α]_D²³

:

1

+68 (c = 0.030, MeOH); H NMR (400 MHz, [D₄]methanol) δ/ppm =

7.26–7.20 (m, 2H, 2,6-H), 6.75–6.69 (m, 2H, 3,5-H), 6.63 (s, 1H, 1-OH),

5.92–5.85 (m, 1H, 6′-H), 3.62 (dd, J = 10.6, 3.2 Hz, 1H, 1′′-H), 3.34–

3.28 (m, 2H, 1′′-H, collapses with [D₄]methanol), 2.48–2.35 (m, 2H,

4′, 7′-H), 2.20–2.06 (m, 2H, 4′, 7′-H), 2.01–1.91 (m, 1H, 2′ or 3′-H),

1.84–1.71 (m, 2H, 3a′-H, 2′ or 3′-H), 1.59 (m, 1H, 2′′-H), 1.49–1.26 (m,

4H, 1′, 2′, 3′-H, 1′′-OH), 1.10 (d, J = 6.5 Hz, 3H, 2′′-CH₃), 0.74 (d, J =

0.6 Hz, 3H, 7a′-CH₃); ¹³C NMR (101 MHz, [D₄]methanol) δ/ppm =

(Si(CH₃)₂), –5.3 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 2946, 2857, 1717,

˜

1470, 1412, 1361, 1250, 1226, 1200, 1144, 1081, 1045, 1017, 1005,

962, 915, 835, 813, 772, 701, 664, 619, 574; HRMS (EI): m/z calculated 157.3 (C-1), 136.7 (C-4), 135.1 (C-5′), 127.1 (C-2, 6), 122.7 (C-6′), 115.9

+

˙

for C₁₅H₂₇O₂Si [M] 267.1780, found 267.1773; Purity (HPLC): 83 %

(C-3, 5), 67.9 (C-1′′), 53.7 (C-1′), 47.4 (C-3a′), 43.3 (C-7a′), 41.9 (C-7′),

40.2 (C-2′′), 31.5 (C-4′), 28.9 (C-2′ or 3′), 27.9 (C-2′ or 3′), 17.0 (2′′-

(λ = 191 nm), > 95 % (λ = 210 nm) (method e).

CH₃), 11.6 (7a′-CH₃); IR (ATR): ν = cm^–1= 3419, 2880, 1608, 1513,

˜

((1R,3aS,7aS)-5-(4-((tert-Butyldimethylsilyl)oxy)phenyl)-1-((S)-1-

((tert-butyldimethylsilyl)oxy)propan-2-yl)-7a-methyloctahydro-

1H-inden-5-ol (45a) and (1R,3aS,7aS)-5-(4-((tert-Butyldimethyl-

silyl)oxy)phenyl)-1-((S)-1-((tert-butyldimethylsilyl)oxy)propan-

2-yl)-7a-methyloctahydro-1H-inden-5-ol (45b): Alcohols 45a and

45b were synthesised according to GP1 using ketone 6 (264 mg,

0.814 mmol, 1.00 equiv.) and TBDMS-protected 4-bromophenol 44

(258 mg, 0.898 mmol, 1.10 equiv.). The title compounds were sepa-

rated and purified via FCC (hexanes/EtOAc, 9:1) and 45a was iso-

lated as white oily solid (6.00 mg, 0.011 mmol, 1 %) and 45b as

white solid (192 mg, 0.360 mmol, 44 %): Analytical data of 45a: R_f=

0.55 (hexanes/EtOAc, 9:1); [α]²_D³: +46 (c = 0.080, CHCl₃); ¹H NMR

(400 MHz, [D]chloroform) δ/ppm = 7.38–7.32 (m, 2H, 2′′, 6′′-H),

6.83–6.77 (m, 2H, 3′′, 5′′-H), 3.61 (dd, J = 9.6, 3.3 Hz, 1H, 1′-H), 3.29

(dd, J = 9.7, 7.4 Hz, 1H, 1′-H), 2.06–1.83 (m, 4H, 3a, 7-H, 2, 3, 4 or 6-

H), 1.83–1.73 (m, 1H, OH), 1.70–1.48 (m, 5H, 7, 2′-H, 2, 3, 4 or 6-H),

1.39–1.11 (m, 3H, 1-H, 2, 3, 4 or 6-H), 1.03 (d, J = 6.5 Hz, 3H, 2′-CH₃),

0.98 (s, 9H, SiC(CH₃)₃), 0.91 (s, 9H, SiC(CH₃)₃), 0.76 (s, 3H, 7a-CH₃),

0.19 (s, 6H, Si(CH₃)₂), 0.05 (s, 3H, Si(CH₃)₂), 0.04 (s, 3H, Si(CH₃)₂); ¹³C

NMR (101 MHz, [D]chloroform) δ/ppm = 154.5 (C-4′′), 142.5 (C-1′′),

125.7 (C-2′′, 6′′), 119.7 (C-3′′, 5′′), 73.7 (C-5), 68.0 (C-1′), 52.4 (C-1),

44.6 (C-3a), 42.0 (C-7a), 39.5 (C-2, 3, 4 or 6), 39.3 (C-2′), 35.9 (C-7),

35.9 (C-2, 3, 4 or 6), 27.8 (C-2, 3, 4 or 6), 26.4 (C-2, 3, 4 or 6), 26.2

(SiC(CH₃)₃), 25.8 (SiC(CH₃)₃), 18.5 (SiC(CH₃)₃), 18.3 (SiC(CH₃)₃), 17.1

(2′-CH₃), 10.5 (7a-CH₃), –4.3 (Si(CH₃)₂), –5.2 (Si(CH₃)₂), –5.2 (Si(CH₃)₂);

1468, 1373, 1260, 1233, 1181, 1111, 1020, 991, 974, 835, 806, 788;

+

˙

HRMS (EI): m/z calculated for C₁₉H₂₆O₂[M] 286.1927, found

286.1927; Purity (HPLC): > 95 % (λ = 210 nm), > 95 % (λ = 254 nm)

(method b).

4-((1R,3aS,5R,7aS)-1-((S)-1-Hydroxypropan-2-yl)-7a-methylocta-

hydro-1H-inden-5-yl)phenol (47a) and 4-((1R,3aS,5S,7aS)-1-((S)-

1-Hydroxypropan-2-yl)-7a-methyloctahydro-1H-inden-5-yl)-

phenol (47b): Diols 47a and 47b were prepared over two steps.

Alcohol 45b (94.9 mg, 0.178 mmol, 1.00 equiv.) was dissolved in

dry DCM (3.00 mL) and TFA (73.5 μL, 0.979 mmol, 5.50 equiv.) and

triethylsilane (71.1 μL, 0.445 mmol, 2.50 equiv.) were added. The

reaction mixture was stirred for 2 h at r.t. and then stopped with

sat. aq. NaHCO₃solution (3.00 mL). The aq. layer was extracted with

DCM (3 × 5.00 mL) and washed with water (5.00 mL). The combined

organic layers were dried with Na₂SO₄, the solvent was removed in

vacuo and the crude mixture of silyl ethers (0.178 mmol) was then

used for the preparation of diols 47a and 47b via GP3 without

further purification. The title compounds were purified and sepa-

rated via FCC (hexanes/EtOAc, 7:3) and diol 47a was obtained as

light yellow oily solid (21.0 mg, 0.0728 mmol, 41 %) and diol 47b

was obtained as beige, crystalline solid (9.00 mg, 0.0312 mmol,

18 %): Analytical data of diol 47a: R_f= 0.63 (hexanes/EtOAc, 70:30);

[α]²_D³: +4.9 (c = 0.48, CHCl₃); ¹H NMR (400 MHz, [D₄]methanol)

δ/ppm = 7.08–7.03 (m, 2H, 3,5-H), 6.73–6.68 (m, 2H, 2,6-H), 4.43 (dd,

J = 10.7, 3.4 Hz, 1H, 1′′-H), 4.17 (dd, J = 10.7, 7.1 Hz, 1H, 1′′-H), 2.52–

2.41 (m, 1H, 5′-H), 2.06 (dt, J = 12.7, 3.4 Hz, 1H, 7′-H), 1.91 (dqd, J =

13.0, 6.4, 3.1 Hz, 2H, 2′′-H, 2′, 3′, 4′ or 6′-H), 1.66 (qd, J = 10.3, 8.6,

5.2 Hz, 3H, 2′, 3′, 4′ or 6′-H), 1.59–1.22 (m, 6H, 1′, 3a′, 7′-H, 2′, 3′, 4′

or 6′-H), 1.11 (d, J = 6.7 Hz, 3H, 2′′-CH₃), 0.85 (s, 3H, 7a′-CH₃); ¹³C

NMR (101 MHz, [D₄]methanol) δ/ppm = 156.4 (C-1), 139.7 (C-4),

128.7 (C-3, 5), 116.0 (C-2, 6), 74.3 (C-1′′), 53.6 (C-1′), 51.7 (C-3a′), 45.5

(C-5′), 43.3 (C-7a′), 41.3 (C-7′), 37.1 (C-2′′), 34.8 (C-2′, 3′, 4′ or 6′), 31.7

(C-2′, 3′, 4′ or 6′), 28.5 (C-2′, 3′, 4′ or 6′), 27.5 (C-2′, 3′, 4′ or 6′), 17.3

IR (ATR): ν = cm^–1= 2928, 1603, 1508, 1471, 1251, 1084, 912, 832,

807, 773, 674; HRMS (EI): m/z calculated for C₃₁H₅₆O₃Si₂[M]

˜

+

˙

532.3768, found 532.3760; Purity (HPLC): 91 % (λ = 210 nm), > 95 %

(λ = 250 nm) (method d). Analytical data of 45b: R_f= 0.26 (hexanes/

EtOAc, 9:1); [α]²_D³: +47 (c = 0.030, CHCl₃); ¹H NMR (400 MHz, [D]-

chloroform) δ/ppm = 7.43–7.37 (m, 2H, 2′′, 6′′-H), 6.84–6.77 (m, 2H,

3′′, 5′′-H), 3.55 (dd, J = 9.6, 3.5 Hz, 1H, 1′-H), 3.17 (dd, J = 9.7, 7.7 Hz,

1H, 1′-H), 2.32–2.15 (m, 2H, 7-H, 2, 3, 4 or 6-H), 2.05–1.90 (m, 2H,

OH, 2, 3, 4 or 6-H), 1.81–1.39 (m, 5H, 3a, 7, 2′-H, 2, 3, 4 or 6-H ),

1.36–1.12 (m, 5H, 1-H, 2, 3, 4 or 6-H), 0.99 (s, 9H, SiC(CH₃)₃), 0.95 (d,

J = 6.5 Hz, 3H, 2′-CH₃), 0.87 (s, 9H, SiC(CH₃)₃), 0.83 (s, 3H, 7a-CH₃),

0.21 (s, 6H, Si(CH₃)₂), 0.00 (s, 6H, Si(CH₃)₂); ¹³C NMR (101 MHz,

[D]chloroform) δ/ppm = 154.6 (C-4′′), 135.4 (C-1′′), 125.9 (C-2′′, 6′′),

119.9 (C-3′′, 5′′), 68.1 (C-5), 52.7 (C-1′), 46.1 (C-1), 44.6 (C-2, 3, 4 or

6), 42.3 (C-3a), 40.9 (C-7), 39.2 (C-7a), 30.4 (C-2′), 28.0 (C-2, 3, 4 or

6), 27.0 (C-2, 3, 4 or 6), 26.1 (C-2, 3, 4 or 6), 25.9 (SiC(CH₃)₃), 18.6

(SiC(CH₃)₃), 18.4 (SiC(CH₃)₃), 16.8 (SiC(CH₃)₃), 11.5 (2′-CH₃), –4.3 (7a-

(2′′-CH ), 11.6 (7a′-CH ); IR (ATR): ν = cm^–1= 3726, 3705, 3623, 3598,

˜

3

2938, 2860, 1783, 1514, 1221, 1171, 1032, 831, 777, 671, 649; HRMS

+

˙

(EI): m/z calculated for C₁₉H₂₈O₂[M] 288.2084, found 288.2088;

Purity (HPLC): > 95 % (λ = 210 nm), 95 % (λ = 254 nm) (method b).

Analytical data of diol 47b: R_f= 0.30 (hexanes/EtOAc, 70:30); mp:

153–155 °C; [α]²_D³: +29 (c = 0.030, MeOH); ¹H NMR (400 MHz,

[D₄]methanol) δ/ppm = 7.07–7.01 (m, 2H, 3,5-H), 6.72–6.66 (m, 2H,

2,6-H), 3.59 (dd, J = 10.6, 3.2 Hz, 1H, 1′′-H), 3.27 (dd, J = 10.6, 7.1 Hz,

1H, 1′′-H, collapses with [D₄]methanol), 2.44 (tt, J = 10.7, 4.9 Hz, 1H,

5′-H), 2.06 (dt, J = 12.6, 3.3 Hz, 1H, 7′-H), 1.91 (dtd, J = 12.5, 9.1,

6.0 Hz, 1H, 2′, 3′, 4′ or 6′-H), 1.67–1.60 (m, 2H, 2′, 3′, 4′ or 6′-H),

1.60–1.42 (m, 5H, 3a′, 2′′-H, 1′′-OH, 2′, 3′, 4′ or 6′-H), 1.41–1.19 (m,

5H, 1, 7′-H, 2′, 3′, 4′ or 6′-H), 1.06 (d, J = 6.6 Hz, 3H, 2′′-CH₃), 0.82

(s, 3H, 7a′-CH₃); ¹³C NMR (101 MHz, [D₄]methanol) δ/ppm = 156.3

(C-1), 139.9 (C-4), 128.7 (C-3, 5), 116.0 (C-2, 6), 68.0 (C-1′′), 53.8 (C-1′),

51.8 (C-3a′), 45.6 (C-5′), 43.2 (C-7a′), 41.5 (C-7′), 40.4 (C-2′′), 34.9 (C-2′

CH₃), –5.2 (Si(CH₃)₂), –5.2 (Si(CH₃)₂); IR (ATR): ν = cm^–1= 2928, 1603,

1507, 1471, 1254, 1081, 912, 832, 807, 773; HRMS (EI): m/z calculated

for C₃₁H₅₆O₃Si₂[M] 532.3768, found 532.3755; Purity (HPLC):

> 95 % (λ = 210 nm), > 95 % (λ = 250 nm) (method d).

˜

+

˙

4-((1R,3aS,7aS)-1-((S)-1-Hydroxypropan-2-yl)-7a-methyl-

2,3,3a,4,7,7a-hexahydro-1H-inden-5-yl)phenol (46): Diol 46 was

synthesised according to GP3 using silyl ether 45b (50.0 mg,

93.8 μmol, 1.00 equiv.). The title compound was purified via FCC

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, 3′, 4′ or 6′), 31.8 (C-2′, 3′, 4′ or 6′), 28.8 (C-2′, 3′, 4′ or 6′), 27.6 (C-2′,

(C-2), 16.5 (2′′-CH₃), 11.4 (7a′-CH₃); IR (ATR): ν = cm^–1= 3347, 2933,

˜

3′, 4′ or 6′), 17.4 (2′′-CH₃), 11.7 (7a′-CH₃); IR (ATR): ν = cm^–1= 3185,

2876, 1467, 1427, 1370, 1040, 1029, 994, 968, 907, 853, 813, 731;

HRMS (EI): m/z calculated for C₁₇H₂₆O₂[M]^·+262.1927, found

262.1924; Purity (HPLC): > 95 % (λ = 210 nm), > 95 % (λ = 254 nm)

(method b).

˜

2361, 1612, 1550, 1514, 1346, 1248, 1121, 1002, 813; HRMS (EI): m/z

+

˙

calculated for C₁₉H₂₈O₂[M] 288.2084, found 288.2086; Purity (HPLC):

> 95 % (λ = 210 nm), > 95 % (λ = 254 nm) (method b).

(1R,3aS,7aS)-1-((S)-1-((tert-Butyldimethylsilyl)oxy)propan-2-yl)-

7a-methyl-2,3,3a,4,7,7a-hexahydro-1H-inden-5-yl Trifluoro-

methanesulfonate (48): A solution of 6 (350 mg, 1.08 mmol,

1.0 equiv.) in dry THF (20.0 mL) was added dropwise to NaHMDS

4-((1R,3aS,7aS)-1-((S)-1-Hydroxypropan-2-yl)-7a-methylocta-

hydro-1H-inden-5-yl)butan-1-ol (51): Diol 51 was synthesised via

three steps. For cross-coupling enol triflate 48 (260 mg, 0.569 mmol,

1.00 equiv.) was dissolved in dry THF (4.00 mL) and but-3-yn-1-ol

(49.4 mg, 0.683 mmol, 1.20 equiv.), triethylamine (0.2 mL,

1.42 mmol, 2.50 equiv.) and CuI (21.7 mg, 0.114 mmol, 20 mol-%)

were added under N₂counterflow. After purging the solution with

N₂, PdCl₂(PPh₃)₂(40.0 mg, 0.0569 mmol, 10 mol-%) was added and

the reaction mixture was stirred for 1.5 h. The reaction was stopped

with sat. aq. NH₄Cl (5.00 mL) and the aq. phase was extracted with

DCM (3 × 10 mL). The combined organic layers were dried with

Na₂SO₄, filtered and the solvent was removed in vacuo to give

crude alkyne. For the following hydrogenation, the crude alkyne

(0.569 mmol) was dissolved in EtOAc (5.00 mL) and AcOH (30.0 μL,

0.569 mmol, 1.00 equiv.). The solution was degassed and PtO₂

(2.59 mg, 0.0114 mmol, 2.00 mol-%) was added under N₂counter-

flow. The reaction mixture was stirred at H₂atmosphere for 21 h

and then filtered through a celite pad and concentrated under re-

duced pressure. The crude intermediate (0.569 mmol) was depro-

tected according to GP3 and purified via FCC (hexanes/EtOAc, 6:4)

to give diol 51 as colourless oil (32.0 mg, 0.119 mmol, 21 % over

three steps): R_f= 0.17 (hexanes/EtOAc, 6:4); [α]²_D³: +14 (c = 0.040,

CHCl₃); ¹H NMR (400 MHz, [D]chloroform) δ/ppm = 3.70–3.51 (m,

3H, 1, 1′′-H), 3.36 (dd, J = 10.5, 6.9 Hz, 1H, 1′′-H), 1.94–1.87 (m, 1H,

7′-H), 1.85–1.75 (m, 1H, 2′, 3′, 4′ or 6′-H), 1.62–1.44 (m, 7H, 5′, 2′′-H,

2, 3, 4, 2′, 3′, 4′ or 6′-H), 1.40–1.13 (m, 9H, 1′, 3a′, 7′-H, 2, 3, 4, 2′,

3′, 4′ or 6′-H), 1.04 (d, J = 6.6 Hz, 3H, 2′′-CH₃), 0.65 (s, 3H, 7a′-CH₃);

¹³C NMR (101 MHz, [D]chloroform) δ/ppm = 68.2 (C-2′′), 63.2 (C-1),

52.4 (C-1′), 50.2 (C-3a′), 42.6 (C-7a′), 39.9 (C-7′), 39.0 (C-5′), 38.2

(C-2′′), 37.2 (C-2′, 3′, 4′ or 6′), 33.2 (C-2, 3 or 4), 32.5 (C-2, 3 or 4),

29.2 (C-2′, 3′, 4′ or 6′), 27.8 (C-2′, 3′, 4′ or 6′), 26.7 (C-2′, 3′, 4′ or 6′),

(1

M in THF, 2.70 mL, 2.70 mmol, 2.50 equiv.) at –78 °C. After 1 h

N-phenyl-bis(trifluoromethansulfonimide) (925 mg, 2.59 mmol,

2.40 equiv.) was added and stirred for additional 20 min. The reac-

tion mixture was warmed up to r.t. and stirred for 2 h. The reaction

was stopped with water (25.0 mL) and the organic solvent was

removed in vacuo. The aq. residue was extracted with hexanes (3 ×

25.0 mL). The combined organic layers were washed with water

(30.0 mL), dried with Na₂SO₄, filtered and the solvent was removed

in vacuo. The title product was purified via FCC (hexanes/EtOAc,

95:5) and isolated as colourless oil (260 mg, 0.569 mmol, 53 %): R_f=

0.54 (hexanes/EtOAc, 95:5); [α]²_D³: +34 (c = 0.040, CHCl₃); ¹H NMR

(400 MHz, [D]chloroform) δ/ppm = 5.66 (dt, J = 5.7, 2.1 Hz, 1H, 6-

H), 3.57 (dd, J = 9.6, 3.3 Hz, 1H, 1′-H), 3.31 (dd, J = 9.7, 6.8 Hz, 1H,

1′-H), 2.40–2.25 (m, 2H, 4,7-H), 2.23–2.06 (m, 2H, 4,7-H), 1.99–1.68

(m, 3H, 2, 3, 3a-H), 1.60–1.51 (m, 1H, 2′-H), 1.47–1.18 (m, 3H, 1,2,3-

H), 0.99 (d, J = 6.6 Hz, 3H, 2′-CH₃), 0.89 (s, 9H, SiC(CH₃)₃)), 0.72 (s,

3H, 7a-CH₃), 0.03 (s, 6H, Si(CH₃)₂); ¹³C NMR (101 MHz, [D]chloroform)

δ/ppm = 148.8 (C-5), 120.3 (q, J_C-F= 320.2 Hz,CF₃)118.5 (C-6), 67.7

(C-1′), 51.6 (C-1), 46.3 (C-3a), 41.1 (C-7a), 38.8 (C-2′), 38.7 (C-7), 30.8

(C-4), 28.4 (C-2 or 3), 26.1 (C-2 or 3), 26.1 (SiC(CH₃)₃), 18.5 (SiC(CH₃)₃),

16.8 (2′-CH₃), 11.2 (7a-CH₃), –5.2 (Si(CH₃)₂), –5.3 (Si(CH₃)₂); IR (ATR):

ν = cm^–1= 2955, 2886, 2857, 1472, 1416, 1245, 1206, 1142, 1078,

˜

1044, 1017, 968, 906, 886, 854, 833, 774, 733, 665; HRMS (EI): m/z

calculated for C₂₀H₃₅O₄F₃SSi [M]^·+456.1972, found 456.1978; Purity

(HPLC): 90 % (λ = 210 nm), 81 % (λ = 250 nm) (method d).

(4-((1R,3aS,7aS)-1-((S)-1-Hydroxypropan-2-yl)-7a-methyl-

2,3,3a,4,7,7a-hexahydro-1H-inden-5-yl)but-3-yn-1-ol (50): Diol

50 was synthesised over two steps. In an oven-dried two-necked

Schlenk flask enol triflate 48 (260 mg, 0.569 mmol, 1.00 equiv.) was

dissolved in dry THF (5.00 mL) and 3-butyn-1-ol (53.3 μL,

0.683 mmol, 1.20 equiv.), triethylamine (0.2 mL, 1.42 mmol,

2.50 equiv.) and Cu(I)I (21.7 mg, 0.114 mmol, 20 mol-%) were added

under N₂counter-flow. After purging of the solution with N₂,

PdCl₂(PPh₃)₂(40.0 mg, 0.0569 mmol, 10 mol-%) was added and the

reaction mixture was stirred at r.t. for 1.5 h. Subsequently, the reac-

tion was quenched with sat. aq. NH₄Cl (5.00 mL) and the aq. phase

was extracted with DCM (3 × 10.0 mL). The combined organic layers

were dried with Na₂SO₄, filtered and the solvent was removed in

vacuo. The crude product was purified via a short silica plug and

was used without further purification. Diol 50 was synthesised ac-

cording to GP3, using alcohol 49 (0.569 mmol) and the title com-

pound was purified via FCC (hexanes/EtOAc, 5:5) and isolated as

white oily solid (129 mg, 0.492 mmol, 86 % over two steps): R_f=

0.33 (hexanes/EtOAc, 5:5); [α]²_D³: +84 (c = 0.040, CHCl₃); ¹H NMR

(400 MHz, [D]chloroform) δ/ppm = 5.95 (dt, J = 5.6, 2.6 Hz, 1H, 6′-

H), 3.72 (t, J = 6.2 Hz, 1H, 1-H), 3.65 (dd, J = 10.5, 3.2 Hz, 1H, 1′′-H),

3.39 (dd, J = 10.5, 6.7 Hz, 1H, 1′′-H), 2.57 (t, J = 6.2 Hz, 1H, 2-H), 2.26

(ddd, J = 18.2, 5.7, 2.3 Hz, 1H, 7′-H), 2.21–2.13 (m, 1H, 4′-H), 2.05 (d,

J = 18.6 Hz, 1H, 7′-H), 1.96–1.80 (m, 2H, 4′-H, 2′ or 3′-H), 1.76–1.53

(m, 3H, 3a′, 2′′-H, 2′ or 3′-H), 1.41–1.14 (m, 3H, 1′, 2′, 3′-H), 1.04 (d,

J = 6.6 Hz, 3H, 2′′-CH₃), 0.65 (s, 3H, 7a′-CH₃); ¹³C NMR (101 MHz,

[D]chloroform) δ/ppm = 133.9 (C-6′), 119.9 (C-5′), 84.3 (C-4), 83.6

(C-3), 68.0 (C-1′′), 61.4 (C-1), 52.3 (C-1′), 45.3 (C-3a′), 42.0 (C-7′), 40.6

(C-7a′), 38.7 (C-2′′), 32.7 (C-4′), 27.8 (C-2′ or 3′), 26.6 (C-2′ or 3′), 23.9

23.4 (C-2, 3 or 4), 16.9 (2′′-CH₃), 11.3 (7a′-CH₃); IR (ATR): ν = cm^–1

=

˜

3726, 3623, 2932, 2846, 1218, 1040, 770, 676, 657; HRMS (EI): m/z

calculated for C₁₇H₃₁O₂[M]^·+267.2319, found 267.2322; Purity (GC):

80 % (scan mode m/z 50–650 (EI 70 eV), compound undergoes de-

hydration during the measurement).

Acknowledgments

We thank Martina Stadler for the implementation of the MTT

assay and Anna Niedrig for measuring the HPLC purities. Open

access funding enabled and organized by Projekt DEAL.

Keywords: Biosynthesis · Cholesterol · DHCR24 ·

Inhibitors · Seco-Analogues

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Received: August 10, 2020

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Synthesis of Seco-Analogues of the DHCR24 Inhibitor SH-42

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