Diastereoselective synthesis of highly substituted polycyclic scaffolds via a one-pot four-step tandem catalytic process

Accepted Manuscript

Diastereoselective synthesis of highly substituted polycyclic scaffolds via a one-pot

four-step tandem catalytic process

Mark W. Grafton , Stuart A. Johnson , Louis J. Farrugia , Andrew Sutherland

PII:

S0040-4020(14)00866-7

10.1016/j.tet.2014.06.020

TET 25685

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 24 March 2014

Revised Date: 22 May 2014

Accepted Date: 3 June 2014

Please cite this article as: Grafton MW, Johnson SA, Farrugia LJ, Sutherland A, Diastereoselective

synthesis of highly substituted polycyclic scaffolds via a one-pot four-step tandem catalytic process,

Tetrahedron (2014), doi: 10.1016/j.tet.2014.06.020.

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Diastereoselective synthesis of highly

substituted polycyclic scaffolds via a one-pot

four-step tandem catalytic process

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Mark W. Grafton, Stuart A. Johnson, Louis J. Farrugia and Andrew Sutherland

WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK

1

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Tetrahedron

journal homepage: www.elsevier.com

Diastereoselective synthesis of highly substituted polycyclic scaffolds via a one-pot

four-step tandem catalytic process

Mark W. Grafton, Stuart A. Johnson, Louis J. Farrugia and Andrew Sutherland*

WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

A rapid and diastereoselective synthesis of highly substituted aminobicyclo[4.3.0]nonanes and

bicyclo[4.4.0]decanes from alkyne derived allylic alcohols has been developed using a one-pot

multi-bond forming tandem catalytic process. Overman rearrangement of the allylic

trichloroacetimidates was followed by a ring closing enyne metathesis/cross metathesis sequence

of reactions in which both steps were catalysed by Grubbs 2^ndgeneration catalyst. The resulting

exo-diene was then subjected to a hydrogen bonding directed Diels-Alder reaction forming an

endo-adduct as a single diastereomer. Variation of the cross metathesis partner and dienophile

allowed examination of the scope of this one-pot process and the preparation of a diverse series

of highly substituted polycyclic scaffolds.

Available online

Keywords:

Carbocycles

Overman rearrangement

Ring closing enyne metathesis

Cross metathesis

Diels-Alder reaction

1. Introduction

Amino substituted polycyclic compounds are found widely

throughout the natural world and as key components in many

medicinally important compounds.¹In particular, saturated and

partially

saturated

forms

of

amino

substituted

bicyclo[4.3.0]nonanes and bicyclo[4.4.0]decanes are present in a

diverse structural range of natural products such as the guanidine

alkaloid netamine A (1),²the neurotrophic agent (+)-nankakurine

A (2)³and the potent analgesic (–)-morphine (3) (Fig. 1).⁴These

motifs are also found in many synthetically generated medicines

that are used to treat a range of diseases associated with the

central nervous system⁵and inhibit processes such as the

proliferation of malignant cells.⁶As a result of the natural

abundance and significant pharmacological activity of amino

substituted bicyclo[4.3.0]nonanes and bicyclo[4.4.0]decanes,

many synthetic approaches have been developed for their

preparation.^3b,7–13In general, these bicyclic compounds have

typically been prepared from functionalised monocyclic species

where the second ring system is formed through pericyclic

reactions such as Diels-Alder^3b,10and 1,3-dipolar cycloadditions.⁸

For example, Brummond and co-workers utilised a Rh(I)-

catalysed cycloisomerisation of an allene-ynone and the resulting

2-alkylidene-3-vinylcyclopentenone could be trapped in a Diels-

Fig. 1. Amino substituted bicyclo[4.3.0]nonane and bicyclo[4.4.0]decane

containing natural products.

In an alternative approach to these compounds, we recently

reported the rapid and efficient diastereoselective synthesis of

amino

substituted

bicyclo[4.3.0]nonanes

and

bicyclo[4.4.0]decanes using a one-pot multi-reaction process that

utilised an Overman rearrangement of alkyne derived allylic

alcohols, a ring closing enyne metathesis (RCEYM) reaction and

a hydrogen bonding directed Diels-Alder reaction (e.g. Scheme

1).¹²This strategy allowed the consecutive formation of both

rings, the late-stage incorporation of functional groups through

the Diels-Alder reaction and gave a variety of structural types

with up to four stereogenic centres. Although adapting this

process for the synthesis of C1-amino substituted indanes and

tetralins,¹³we were interested in extending this series of reactions

to access compounds of greater complexity through a higher level

of substitution. We now report the development and scope of a

novel one-pot four-step multi-reaction process that incorporates a

cross metathesis (CM) reaction and is conducted using the same

Ru(II)-complex that catalyses a RCEYM step. Overall, this

tandem catalytic process allows the preparation of highly

Alder

reaction

to

give

the

corresponding

aminobicyclo[4.3.0]nonane in good overall yield.^10bOther

strategies have involved the stereoselective hydroboration of

hexahydroindenes and octahydronaphthalenes which, following

syn-migration gave secondary organoboranes.¹¹Subsequent

amination allowed access to both amino substituted

bicyclo[4.3.0]nonanes and bicyclo[4.4.0]decanes.

2

Tetrahedron

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Table 1. Optimisation of the one-pot RCEYM/CM process.

substituted

aminobicyclo[4.3.0]nonanes

and

bicyclo[4.4.0]decanes with up to five stereogenic centres. We

also describe preliminary studies in the use of a disubstituted

alkyne as a substrate for a one-pot three-step multi-reaction

process resulting in the preparation of a 5-aryl amino substituted

bicyclo[4.3.0]nonane in good overall yield.

Cat.

Temp.

(°C)

Reaction

Yield (%)

of 11^b

Yield (%)

of 12^b

Entry

Loading

(mol%)^a

Conc. (M)

1

2

3

4

0.05

0.025

0.1

7.5

10

75

rt

16

9

41

74

65

53

65

rt

22

30

14

rt

5

0.05

rt

Scheme 1. One-pot synthesis of aminobicyclo[4.4.0]decanes.

a

Grubbs 2^ndgeneration catalyst was added in two batches (5 and 2.5 mol%

for entries 1–4 and 7.5 and 2.5 mol% for entry 5). ^bIsolated yield.

2. Results and discussion

The optimised conditions for the RCEYM/CM sequence were

then incorporated into the entire one-pot multi-reaction process

for the preparation of aminobicyclo[4.3.0]nonanes from (2E)-

hepta-2-en-6-yn-1-ol (8) (Scheme 3). Initially, allylic alcohol 8

was converted to the corresponding allylic trichloroacetimidate.

The one-pot sequence was then initiated by Overman

rearrangement under thermal conditions. The reaction mixture

was cooled to room temperature and 1-pentene and Grubbs 2^nd

generation catalyst (5 mol%) were added. After addition of a

second batch of the catalyst (2.5 mol%) and completion of the

RCEYM/CM steps, the Diels-Alder reaction was instigated by

the addition of N-phenyl maleimide and an increase in

temperature to 75 °C. On purification, this gave

aminobicyclo[4.3.0]nonane 13 as a single diastereomer in 47%

yield over the five-steps. The relative stereochemistry of 13 was

confirmed by difference NOE experiments which showed a syn-

relationship of the hydrogen atoms at C-3a, C-4, C-8, C-8a and

C-8b.¹⁷As observed previously with less substituted dienes,¹²the

stereochemical outcome of the Diels-Alder reaction of diene 12

with N-phenyl maleimide is controlled by the formation of a

hydrogen bonding directed endo-transition state between the

trichloroacetamide hydrogen atom and the oxygen atom in the

In this study, (2E)-hept-2-en-6-yn-1-ol (8) and (2E)-oct-2-en-

7-yn-1-ol (9) were used as substrates for the one-pot multi-

reaction processes. As previously reported, these were prepared

from 4-pentyn-1-ol (4) and 5-hexyn-1-ol (5), respectively, using

a highly efficient approach involving a one-pot Swern oxidation

and Horner-Wadsworth-Emmons reaction to give the

corresponding (E)-α,β-unsaturated esters (Scheme 2).^12,13

Reduction with DIBAL-H gave allylic alcohols 8 and 9 in

excellent overall yield.

Scheme 2. Synthesis of alkyne derived allylic alcohols 8 and 9.

Before attempting a one-pot four-step multi-reaction process,

optimisation studies were performed on the tandem catalytic

RCEYM/CM sequence of reactions.^14,15Initially, (2E)-hept-2-en-

6-yn-1-ol (8) was converted to the corresponding allylic

trichloroacetamide 10 in 96% overall yield by formation of the

imidate, followed by an Overman rearrangement under thermal

conditions (Table 1).¹⁶Using 1-pentene as the CM partner and

batch addition of Grubbs 2^ndgeneration catalyst (5 and then 2.5

mol%), the one-pot RCEYM/CM of enyne 10 was investigated.

Based on our previous experience of RCEYM reactions of

compounds such as 10, the first attempt was conducted at 75 °C

(entry 1). This gave the RCEYM/CM product 12 in 41% yield

with intermediate compound 11 also isolated in 16% yield. It was

proposed that despite the process being conducted in a sealed

tube, the elevated temperature could be restricting the CM

reaction with the relatively volatile 1-pentene. Therefore, the

second attempt was conducted at room temperature and gave an

improved 74% yield of 12 (entry 2). Other variables such as

decreasing or increasing the reaction concentration (entries 3 and

4) or increasing the catalyst loading (entry 5) were briefly

investigated, however, these led to no improvement in the yield

of 12.

side-chain of the dienophile resulting in

a

highly

diastereoselective process and the formation of five stereogenic

centres. To explore the scope of this process, the one-pot

procedure was repeated using 1-octene, styrene and 4-

fluorostyrene as CM partners. Using these less volatile alkenes, it

was found that the temperature of the RCEYM/CM sequence

could be increased (40 °C), resulting in the isolation of

aminobicyclo[4.3.0]nonanes 14–16 in improved yields over the

five steps (52–62%). Further evidence of the relative

stereochemistry of these compounds was achieved from the X-

ray structure of 15 (Fig. 2).¹⁸Bicyclo[4.3.0]nonane 15 crystallises

in the monoclinic space group P2₁/n and the structure clearly

shows the syn-relationship of the hydrogen atoms at the five

stereocentres. Using 1-octene as the optimal CM partner, the

scope of the dienophile was next investigated. The use of 4-

phenyl-1,2,4-triazole-3,5-dione and tetracyanoethylene gave

compounds 17 and 18 respectively, as single diastereomers in

good overall yields.

3

partners. For example, the use of styrene and 4-fluorosytrene

ACCEPTED MANUSCRIPT

during

the

one-pot

four-step

process

gave

aminobicyclo[4.4.0]decanes 21 and 22 in 54% and 50% yields,

respectively from allylic alcohol 9. Other dienophiles were also

utilised in combination with both alkyl and aryl derived CM

partners giving aminobicyclo[4.4.0]decanes such as 23 and 24 in

39–44% yield over the five steps.

a

Scheme 3. One-pot synthesis of aminobicyclo[4.3.0]nonanes 13–18.

RCEYM/CM steps were conducted at room temperature.

reaction was performed at 50 ºC.

b

Diels-Alder

C9

C6

C116

C7

C10

O3

C111

C8

C3

C11

C5

C4

C12

a

N2

Scheme 4. One-pot synthesis of aminobicyclo[4.4.0]decanes 19–24. Diels-

Alder reaction was performed at 50 ºC.

Cl1

C1

C13

O2

C2

N1

O1

Having shown that aminobicyclo[4.3.0]nonanes could be

substituted at the 4-position using a CM reaction as part of a one-

pot multi-reaction process, we were also interested in developing

an approach that would generate compounds with C-5

substitution. It was proposed that compounds with this

substitution pattern could be generated using an allylic alcohol

bearing a disubstituted alkyne. Another reason for investigating

such substrates was to discover whether the Overman

rearrangement step of disubstituted alkyne derived allylic

alcohols could be performed using a Pd(II)-catalyst. All previous

multi-step reaction processes involving mono-substituted alkyne

derived allylic alcohols such as 8 and 9 have used a thermally

mediated Overman rearrangement.^12,13This was because

preliminary studies with these compounds which investigated a

Pd(II)-catalysed rearrangement showed that high catalyst loading

(up to 25 mol%) and long reaction times were required for good

conversion. This sluggish reactivity was attributed to catalyst

binding to the alkyne. Therefore, we reasoned a hindered

disubstituted alkyne would facilitate a more efficient Pd(II)-

catalysed Overman rearrangement as part of a one-pot multi-step

C121

Cl3

C122

Cl2

Fig. 2. ORTEP view of compound 15. Thermal ellipsoids are drawn at 50%

probability level and H-atoms are drawn with spheres of arbitrary radius.

To further expand the scope of the one-pot multi-reaction

process, the use of (2E)-octa-2-en-7-yn-1-ol (9) for the

diastereoselective synthesis of aminobicyclo[4.4.0]decanes was

explored (Scheme 4). While imidate formation, Overman

rearrangement and RCEYM proceeded as expected, the CM step

of the resulting exo-diene with various alkenes showed poor

conversion (29%). A better conversion (62%) could be achieved

by increasing the temperature of the RCEYM/CM stage to 70 ºC

and the loading of Grubbs 2^ndgeneration catalyst to 10 mol%.

The overall process using N-phenyl maleimide as the dienophile

and with less reactive alkyl substituted alkenes such as 1-octene

process. We were also interested to investigate how

a

and

1-hexane

gave

the

corresponding

disubstituted alkyne would affect the RCEYM step and the

subsequent overall efficiency of these one-pot processes.

aminobicyclo[4.4.0]decanes 19 and 20 in modest yields (37–

38%). The use of H NMR spectroscopy and difference NOE

1

experiments again confirmed the isolation of single

diastereomers from each process and the relative stereochemistry

of the five stereocentres formed during this one-pot process.¹⁷An

improvement in yield was observed using more reactive CM

To investigate these aspects of the one-pot multi-reaction

process, a four-step synthesis of a disubstituted alkyne derived

allylic alcohol was developed (Scheme 5). A Sonogashira

reaction of 4-pentyn-1-ol (4) with iodobenzene gave coupled

4

Tetrahedron

ACCEPTED MANUSCRIPT

product 25 in 98% yield.¹⁹A one-pot Swern oxidation and

these multi-step processes, the Overman rearrangement could be

Horner-Wadsworth-Emmons reaction gave (E)-α,β-unsaturated

ester 26 in 86% yield and this was followed by reduction with

DIBAL-H under standard conditions,¹²which gave allylic alcohol

27. Before attempting a one-pot multi-reaction process with 27,

the key steps were optimised. Following allylic imidate

formation, the Overman rearrangement was found to proceed

using 10 mol% of bis(acetonitrile)palladium(II) chloride in 18

hours giving allylic trichloroacetamide 28 in 81% yield over the

two steps. As expected, attempted RCEYM reaction with enyne

28 under typical conditions (75 ºC) using Grubbs 2^ndgeneration

catalyst showed minimal conversion. However, an increase in the

reaction temperature to 90 ºC and the use of 1,7-octadiene as in

situ source of ethylene to speed up the reaction,²⁰gave diene 29

in 74% yield for this step. Using these optimised conditions for a

one-pot process, which included a Diels-Alder reaction with N-

phenyl maleimide gave 5-phenyl aminobicyclo[4.3.0]nonane 30

as a single diastereomer in 49% overall yield from allylic alcohol

27. These preliminary results show that not only can this type of

substitution pattern be formed but more importantly that with a

performed efficiently using a Pd(II)-catalyst, which gave a 5-aryl

aminobicyclo[4.3.0]nonane in good overall yield. Work is

currently underway to examine the scope of disubstituted alkyne

derived allylic alcohols and the use of chiral Pd(II)-catalysts in

these one-pot multi-reaction processes for the asymmetric

synthesis of medicinally important compounds and natural

products.

4. Experimental section

4.1 General Methods

All reagents and starting materials were obtained from

commercial sources and used as received. All dry solvents were

purified using a PureSolv 500 MD solvent purification system.

All reactions were performed under an atmosphere of argon

unless otherwise mentioned. Brine refers to a saturated solution

of sodium chloride. Flash column chromatography was carried

out using Fisher matrix silica 60. Macherey-Nagel aluminium-

backed plates pre-coated with silica gel 60 (UV₂₅₄) were used for

thin layer chromatography and were visualised by staining with

relatively hindered alkyne,

a

Pd(II)-catalysed Overman

KMnO₄. H NMR and ¹³C NMR spectra were recorded on a

1

rearrangement can be utilised during these one-pot multi-reaction

processes. This is significant as the use of chiral Pd(II)-catalysts

for the Overman rearrangement during these one-pot multi-

reaction processes would allow for the first time, the asymmetric

synthesis of these compounds using this approach.

Bruker DPX 400 spectrometer with chemical shift values in ppm

relative to TMS (δ_H0.00 and δ_C0.0) or residual chloroform (δ_H

7.28 and δ_C77.2) as standard. Proton and carbon assignments are

based on two-dimensional COSY and DEPT experiments,

respectively. Mass spectra were obtained using a JEOL JMS-700

spectrometer. Infrared spectra were obtained neat using a

Shimadzu IRPrestige-21 spectrometer. Melting points were

determined on a Reichert platform melting point apparatus.

4.1.1. Ethyl (2E)-hept-2-en-6-ynoate (6).²¹Dimethyl sulfoxide

(3.60 mL, 50.8 mmol) was added to a stirred solution of oxalyl

chloride (2.49 mL, 28.4 mmol) in dichloromethane (100 mL) at

−78 °C. The mixture was stirred for 0.3 h before 4-pentyn-1-ol

(4) (1.70 g, 20.3 mmol) in dichloromethane (25 mL) was slowly

added. The mixture was stirred for a further 0.3 h before

triethylamine (14.1 mL, 102 mmol) was added. This reaction

mixture was stirred for 0.5 h at −78 °C and then allowed to warm

to room temperature and stirred for a further 3 h. A solution of

lithium chloride (1.55 g, 36.5 mmol), triethyl phosphonoacetate

(7.24 mL, 36.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene

(5.14 mL, 36.5 mmol) in acetonitrile (70 mL) was then prepared

and stirred for 1 h. The Swern solution was concentrated in

vacuo, then the Horner Wadsworth Emmons solution was added

and the reaction mixture was stirred at room temperature

overnight. The reaction was quenched with a saturated solution

of ammonium chloride (50 mL) and concentrated to give an

orange residue, which was then extracted with diethyl ether (4 ×

75 mL). The organic layers were combined, dried (MgSO₄),

filtered and concentrated to give an orange oil. Purification by

flash column chromatography (diethyl ether/petroleum ether, 1:9)

gave ethyl (2E)-hept-2-en-6-ynoate (6) (2.95 g, 96%) as a yellow

oil. Spectroscopic data was as reported in the literature.²¹R_f(25%

diethyl ether/petroleum ether) 0.63; ν_max(neat) 3302 (C≡C−H),

2984 (CH), 1715 (CO), 1657 (C=C), 1445, 1368, 1267, 1155,

1038, 756 cm⁻¹; δ_H(400 MHz, CDCl₃) 1.30 (3H, t, J 7.1 Hz,

OCH₂CH₃), 2.01 (1H, t, J 2.5 Hz, 7-H), 2.34‒2.39 (2H, m, 5-H₂),

2.41‒2.48 (2H, m, 4-H₂), 4.20 (2H, q, J 7.1 Hz, OCH₂CH₃), 5.90

(1H, dt, J 15.7, 1.5 Hz, 2-H), 6.97 (1H, dt, J 15.7, 6.7 Hz, 3-H);

δ_C(126 MHz, CDCl₃) 14.3 (CH₃), 17.4 (CH₂), 31.0 (CH₂), 60.3

(CH₂), 69.4 (CH), 82.7 (C), 122.6 (CH), 146.3 (CH), 166.4 (C);

m/z (CI) 153 (MH⁺, 100%), 139 (5), 113 (10), 97 (5), 81 (15), 69

(15).

Scheme 5. Synthesis of 5-phenyl aminobicyclo[4.3.0]nonane 30.

3. Conclusions

In summary, a one-pot multi-step process involving a thermal

Overman rearrangement, a tandem catalytic RCEYM/CM stage

and a hydrogen bonding directed Diels-Alder reaction has been

developed

for

the

diastereoselective

synthesis

of

aminobicyclo[4.3.0]nonanes. Variation of the CM partner and the

dienophile allowed the preparation of a range of compounds with

up to five stereogenic centres and in good overall yields. This

process could be extended for the diastereoselective synthesis of

aminobicyclo[4.4.0]decanes but a slow CM step meant that with

less reactive alkyl substituted alkenes, overall yields were

slightly lower compared to the nonane series. A one-pot multi-

reaction process was also developed utilising a disubstituted

alkyne derived allylic trichloroacetimidate. For the first time in

5

4.1.2. Ethyl (2E)-oct-2-en-7-ynoate (7).²²The reaction was

carried out as described for the synthesis of ethyl (2E)-hept-2-en-

6-ynoate (6) using 5-hexyn-1-ol (5) (3.00 g, 30.6 mmol).

Purification by flash column chromatography (diethyl

ether/petroleum ether, 1:9) gave ethyl (2E)-oct-2-en-7-ynoate (7)

(4.99 g, 99%) as a yellow oil. Spectroscopic data was as reported

in the literature.²²R_f(50% diethyl ether/petroleum ether) 0.74;

ν_max(neat) 3295 (C≡C−H), 2940 (CH), 1713 (CO), 1651 (C=C),

1265, 1188, 1150, 1042, 979, 756, 633 cm⁻¹; δ_H(400 MHz,

CDCl₃) 1.29 (3H, t, J 7.1 Hz, OCH₂CH₃), 1.70 (2H, quin, J 6.9

Hz, 5-H₂), 1.98 (1H, s, 8-H), 2.23 (2H, t, J 6.9 Hz, 6-H₂), 2.33

(2H, q, J 6.9 Hz, 4-H₂), 4.18 (2H, q, J 7.1 Hz, OCH₂CH₃), 5.86

(1H, d, J 15.6 Hz, 2-H), 6.94 (1H, dt, J 15.6, 6.9 Hz, 3-H); δ_C

(101 MHz, CDCl₃) 14.3 (CH₃), 17.9 (CH₂), 26.7 (CH₂), 30.9

(CH₂), 60.2 (CH₂), 69.0 (CH), 83.5 (C), 122.1 (CH), 147.8 (CH),

166.6 (C); m/z (CI) 167 (MH⁺, 100%), 139 (42), 113 (10), 97

(12), 81 (25), 71 (30).

vacuo to give the allylic trichloroacetimidate, which was used

ACCEPTED MANUSCRIPT

without further purification. The allylic trichloroacetimidate was

dissolved in toluene (10 mL) and transferred to a Schlenk tube

containing potassium carbonate (0.05 g, 0.362 mmol) and purged

with Ar and sealed. The reaction mixture was heated to 140 °C

and stirred for 36 h. The reaction mixture was then cooled to

room temperature and the solvent was evaporated. Purification by

flash column chromatography (petroleum ether/diethyl ether

10:1) gave 3-(2’,2’,2’-trichloromethylcarbonylamino)hept-1-en-

6-yne (10) (0.866 g, 96%) as a white solid. R_f(50% diethyl

ether/petroleum ether) 0.95; Mp 35–37 °C; ν_max(neat) 3304

(NH), 3055 (CH), 2361, 1713 (CO), 1510, 1265, 822, 733 cm⁻¹;

δ_H(500 MHz, CDCl₃) 1.84–2.00 (2H, m, 4-H₂), 2.05 (1H, t, J 2.7

Hz, 7-H), 2.26–2.39 (2H, m, 5-H₂), 4.56–4.63 (1H, m, 3-H), 5.27

(1H, d, J 10.5 Hz, 1-HH), 5.30 (1H, d, J 17.2 Hz, 1-HH), 5.82

(1H, ddd, J 17.2, 10.5, 5.6 Hz, 2-H), 6.93 (1H, br s, NH); δ_C(126

MHz, CDCl₃) 14.8 (CH₂), 32.5 (CH₂), 53.0 (CH), 69.9 (CH),

83.1 (C), 92.7 (C), 116.9 (CH₂), 135.4 (CH), 161.3 (C); m/z (CI)

254 (MH⁺, 72%), 220 (55), 186 (42), 184 (37), 132 (12), 89

(100), 69 (27); HRMS (CI): MH⁺, found 253.9901.

C₉H₁₁³⁵Cl₃NO requires 253.9906.

4.1.3. (2E)-Hept-2-en-6-yn-1-ol (8).²³Ethyl (2E)-hept-2-en-6-

ynoate (6) (1.50 g, 9.87 mmol) was dissolved in diethyl ether (50

mL) and cooled to −78 °C. DIBAL-H (1 M in hexane) (21.7 mL,

21.7 mmol) was added dropwise and the reaction mixture was

stirred at −78 °C for 3 h, before warming to room temperature

overnight. The solution was cooled to 0 °C and quenched by the

addition of a saturated solution of ammonium chloride (10 mL)

and warmed to room temperature with vigorous stirring over 1 h,

producing a white precipitate. The precipitate was filtered

through a pad of Celite® and washed with diethyl ether (3 × 50

mL). The filtrate was then dried (MgSO₄), filtered and

concentrated in vacuo. Purification by flash column

chromatography (diethyl ether/petroleum ether, 1:1) gave (2E)-

4.1.6

4-(n-Pent-1”-ene)-1-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent-4-ene (12). 3-(2’,2’,2’-

Trichloromethylcarbonylamino)hept-1-en-6-yne (10) (0.11 g,

0.42 mmol) was dissolved in toluene (8 mL) and Grubbs 2^nd

generation catalyst (0.016 g, 0.019 mmol) with 1-pentene (0.204

mL, 1.866 mmol) was then added. The reaction mixture was

stirred at room temperature for 18 h. Further addition of Grubbs

2^ndgeneration catalyst (0.008 g, 0.010 mmol) with 1-pentene

(0.11 mL, 1.01 mmol) was then added and the reaction mixture

stirred at room temperature for 22 h. The reaction mixture was

then cooled and the solvent was evaporated. Purification by flash

column chromatography (petroleum ether/diethyl ether 9:1) gave

4-(n-pent-1”-ene)-1-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent-4-ene (12) (0.091 g,

74%) as a white solid. R_f(50% diethyl ether/petroleum ether)

0.82; Mp 56–58 °C; ν_max(neat) 3285 (NH), 2957 (CH), 2930,

1701, 1686 (CO), 1524, 1258, 1067, 964 cm⁻¹; δ_H(500 MHz,

CDCl₃) 0.92 (3H, t, J 7.4 Hz, 5”-H₃), 1.44 (2H, sextet, J 7.4 Hz,

4”-H₂), 1.75 (1H, ddt, J 13.0, 8.5, 4.1 Hz, 2-HH), 2.11 (2H, q, J

7.4 Hz, 3”-H₂), 2.40–2.55 (2H, m, 2-HH and 3-HH), 2.58–2.67

(1H, m, 3-HH), 4.96–5.03 (1H, m, 1-H), 5.53 (1H, br s, 5-H),

5.75 (1H, dt, J 15.7, 7.4 Hz, 2”-H), 6.27 (1H, d, J 15.7 Hz, 1”-H),

7.63 (1H, d, J 9.3 Hz, NH); δ_C(126 MHz, CDCl₃) 13.7 (CH₃),

22.4 (CH₂), 30.0 (CH₂), 31.1 (CH₂), 34.9 (CH₂), 57.8 (CH), 92.8

(C), 124.8 (CH), 125.9 (CH), 135.3 (CH), 147.3 (C), 161.1 (C);

m/z (ESI) 318 ([MNa]⁺, 86%), 296 (10), 236 (24), 184 (16), 135

(21); HRMS (ESI): [MNa]⁺, found 318.0182. C₁₂H₁₆³⁵Cl₃NNaO

requires 318.0190.

hept-2-en-6-yn-1-ol (8) (1.01 g, 93%) as

a yellow oil.

Spectroscopic data was as reported in the literature.²³R_f(50%

diethyl ether/petroleum ether) 0.33; ν_max(neat) 3360 (OH), 3295

(C≡C−H), 2915 (CH), 1670 (C=C), 1433, 1084, 997, 968 cm⁻¹;

δ_H(500 MHz, CDCl₃) 1.42 (1H, br s, OH), 1.99 (1H, t, J 2.5 Hz,

7-H), 2.28‒2.33 (4H, m, 4-H₂and 5-H₂), 4.14 (2H, d, J 4.0 Hz, 1-

H₂), 5.70‒5.81 (2H, m, 2-H and 3-H); δ_C(126 MHz, CDCl₃) 18.5

(CH₂), 31.1 (CH₂), 63.5 (CH₂), 68.8 (CH), 83.7 (C), 130.5 (CH),

130.6 (CH); m/z (CI) 111 (MH⁺, 3%), 107 (15), 93 (100), 81

(10), 69 (10).

4.1.4. (2E)-Oct-2-en-7-yn-1-ol (9).²⁴The reaction was carried out

as described for the synthesis of (2E)-hept-2-en-6-yn-1-ol (8)

using ethyl (2E)-oct-2-en-7-ynoate (7) (4.10 g, 24.7 mmol).

Purification by flash column chromatography (diethyl

ether/petroleum ether, 1:1) gave (2E)-octa-2-en-7-yn-1-ol (9)

(2.95 g, 97% yield) as a yellow oil. Spectroscopic data was as

reported in the literature.²⁴R_f(50% petroleum ether/diethyl ether)

0.29; ν_max(neat) 3361 (OH), 3302 (C≡C−H), 2932 (CH), 1674

(C=C), 1435, 1219, 1088, 972 cm⁻¹; δ_H(400 MHz, CDCl₃) 1.29

(1H, br s, OH), 1.63 (2H, quin, J 6.9 Hz, 5-H₂), 1.96 (1H, t, J 2.6

Hz, 8-H), 2.15‒2.25 (4H, m, 4-H₂and 6-H₂), 4.09‒4.15 (2H, m,

1-H₂), 5.63‒5.74 (2H, m, 2-H and 3-H); δ_C(101 MHz, CDCl₃)

17.8 (CH₂), 27.8 (CH₂), 31.1 (CH₂), 63.7 (CH₂), 68.5 (CH), 84.2

(C), 129.9 (CH), 131.9 (CH); m/z (CI) 125 (MH⁺, 20%), 107

(95), 97 (40), 81 (80), 71 (100).

4.1.7.

(3aS*,4S*,8R*,8aS*,8bR*)-4,6,7,8,8a,8b-Hexahydro-2-

phenyl-4-n-propyl-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (13). (2E)-Hept-2-en-6-yn-1-ol (8) (0.027 g,

0.24 mmol) was dissolved in dichloromethane (10 mL) and

cooled to 0 °C. To the solution 1,8-diazabicyclo[5.4.0]undec-7-

ene (0.007 mL, 0.048 mmol) and trichloroacetonitrile (0.036 mL,

0.36 mmol) were added. The reaction mixture was allowed to

warm to room temperature before stirring for 3 h. The reaction

mixture was filtered through a short pad of silica gel and the

filtrate concentrated in vacuo to give the allylic

trichloroacetimidate, which was used without further purification.

The allylic trichloroacetimidate was dissolved in toluene (5 mL)

and transferred to a Schlenk tube containing potassium carbonate

(0.025 g, 0.18 mmol), purged with Ar and sealed. The reaction

4.1.5. 3-(2’,2’,2’-Trichloromethylcarbonylamino)hept-1-en-6-yne

(10).¹³(2E)-Hept-2-en-6-yn-1-ol (8) (0.388 g, 3.53 mmol) was

dissolved in dichloromethane (25 mL) and cooled to 0 °C. To the

solution 1,8-diazabicyclo[5.4.0]undec-7-ene (0.099 mL, 0.706

mmol) and trichloroacetonitrile (0.530 mL, 5.29 mmol) were

added. The reaction mixture was allowed to warm to room

temperature and stirred for 3 h. The reaction mixture was filtered

through a short pad of silica gel and the filtrate concentrated in

6

Tetrahedron

mixture was then heated to 140 °C and stirred for 36 h. Grubbs

CH), 131.5 (C), 145.0 (C), 162.2 (C), 175.7 (C), 179.4 (C); m/z

ACCEPTED MANUSCRIPT

2^ndgeneration catalyst (0.012 g, 0.014 mmol) was added with 1-

pentene (0.13 mL, 1.21 mmol) and the reaction mixture was

stirred for 24 h at room temperature. A further portion of Grubbs

2^ndgeneration catalyst (0.005 g, 0.006 mmol) and 1-pentene

(0.067 mL, 0.61 mmol) was added and the reaction mixture was

stirred at room temperature for 18 h. N-Phenyl maleimide (0.063

g, 0.36 mmol) was added with hydroquinone (0.005 g, 0.005

mmol). The reaction mixture was stirred for 24 h at 75 °C. The

reaction mixture was then cooled and the solvent was evaporated.

Flash column chromatography (petroleum ether/diethyl ether,

4:1) gave (3aS*,4S*,8R*,8aS*,8bR*)-4,6,7,8,8a,8b-hexahydro-2-

phenyl-4-n-propyl-8-(2’,2’,2’-

(ESI) 533 ([MNa]⁺, 100%), 413 (4), 301 (15), 236 (28), 228 (22),

218 (6), 141 (3); HRMS (ESI): [MNa]⁺, found 533.1120.

C₂₅H₂₉³⁵Cl₃N₂NaO₃requires 533.1136.

4.1.9

(3aS*,4S*,8R*,8aS*,8bR*)-2,4-Diphenyl-4,6,7,8,8a,8b-

hexahydro-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione

Diphenyl-4,6,7,8,8a,8b-hexahydro-8-(2’,2’,2’-

(15).

(3aS*,4S*,8R*,8aS*,8bR*)-2,4-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (15) was synthesised according to the above

procedure using (2E)-hept-2-en-6-yn-1-ol (8) (0.027 g, 0.24

mmol). The reaction mixture was stirred with Grubbs 2^nd

generation catalyst (0.015 g, 0.018 mmol) and styrene (0.21 mL,

1.82 mmol) for 48 h at 40 °C before N-phenyl maleimide (0.063

g, 0.36 mmol) was added. The reaction mixture was stirred for 48

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (13) (0.054 g, 47%) as a white solid. R_f(50%

diethyl ether/petroleum ether) 0.59; Mp 145–147 °C; ν_max(neat)

3304 (NH), 2957 (CH), 1695 (CO), 1516, 1499, 1389, 1182

cm⁻¹; δ_H(500 MHz, CDCl₃) 0.91 (3H, t, J 7.3 Hz, 3”-H₃), 1.37–

1.50 (2H, m, 2”-H₂), 1.61–1.71 (1H, m, 1”-HH), 1.74–1.91 (2H,

m, 1”-HH and 7-HH), 2.08 (1H, dt, J 12.4, 7.2 Hz, 7-HH), 2.23–

2.33 (2H, m, 4-H and 6-HH), 2.39 (1H, dd, J 15.4, 8.1 Hz, 6-

HH), 2.83–2.90 (1H, m, 8a-H), 3.20 (1H, dd, J 8.4, 6.9 Hz, 3a-

H), 3.35 (1H, dd, J 8.4, 6.5 Hz, 8b-H), 4.75–4.85 (1H, m, 8-H),

5.52 (1H, br s, 5-H), 7.05–7.10 (2H, m, 2 × ArH), 7.30–7.35 (1H,

m, ArH), 7.36–7.42 (2H, m, 2 × ArH), 8.90 (1H, d, J 9.7 Hz,

NH); δ_C(126 MHz, CDCl₃) 14.1 (CH₃), 21.4 (CH₂), 28.2 (CH₂)

31.7 (CH₂), 33.2 (CH₂), 38.3 (CH), 42.1 (CH), 42.2 (CH), 42.8

(CH), 52.9 (CH), 92.9 (C), 123.1 (CH), 126.5 (2 × CH), 129.0

(CH), 129.3 (2 × CH), 131.5 (C), 145.1 (C), 162.3 (C), 175.7 (C),

179.3 (C); m/z (ESI) 491 ([MNa]⁺, 75%), 413 (6), 301 (4), 236

(11), 228 (100); HRMS (ESI): [MNa]⁺, found 491.0649.

C₂₂H₂₃³⁵Cl₃N₂NaO₃requires 491.0666.

h

at 75 °C. Flash column chromatography (petroleum

ether/diethyl ether, 1:1) gave (3aS*,4S*,8R*,8aS*,8bR*)-2,4-

diphenyl-4,6,7,8,8a,8b-hexahydro-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (15) (0.063 g, 52%) as a white solid. R_f(50%

diethyl ether/petroleum ether) 0.32; Mp 154–156 °C; ν_max(neat)

3318 (NH), 2940 (CH), 1697 (CO), 1512, 1501, 1383, 1196,

1177, 822 cm⁻¹; δ_H(500 MHz, CDCl₃) 1.99 (1H, qd, J 12.4, 7.9

Hz, 7-HH), 2.23 (1H, dq, J 12.4, 7.3 Hz, 7-HH), 2.38–2.49 (1H,

m, 6-HH), 2.60 (1H, dd, J 16.5, 7.9 Hz, 6-HH), 3.08–3.16 (1H,

m, 8a-H), 3.49–3.55 (2H, m, 3a-H and 8b-H), 3.75 (1H, br s, 4-

H), 4.90–5.01 (1H, m, 8-H), 6.13–6.17 (1H, m, 5-H), 7.13 (2H, t,

J 7.6 Hz, 2 × ArH), 7.25–7.32 (3H, m, 3 × ArH), 7.35–7.40 (3H,

m, 3 × ArH), 7.41–7.46 (2H, m, 2 × ArH), 8.91 (1H, d, J 9.6 Hz,

NH); δ_C(126 MHz, CDCl₃) 28.8 (CH₂), 31.8 (CH₂), 41.9 (CH),

42.1 (CH), 43.5 (CH), 46.1 (CH), 52.8 (CH), 92.8 (C), 120.3

(CH), 126.3 (2 × CH), 127.3 (CH), 128.4 (2 × CH), 128.7 (2 ×

CH), 128.9 (CH), 129.2 (2 × CH), 131.4 (C), 138.7 (C), 146.5

(C), 162.3 (C), 174.3 (C), 178.7 (C); m/z (ESI) 501 ([M−H]⁻,

64%), 383 (100), 312 (15), 212 (22); HRMS (ESI): [M−H]⁻,

found 501.0533. C₂₅H₂₀³⁵Cl₃N₂O₃requires 501.0545.

4.1.8. (3aS*,4S*,8R*,8aS*,8bR*)-4,6,7,8,8a,8b-Hexahydro-4-n-

hexyl-2-phenyl-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione

4,6,7,8,8a,8b-Hexahydro-4-n-hexyl-2-phenyl-8-(2’,2’,2’-

(14).

(3aS*,4S*,8R*,8aS*,8bR*)-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (14) was synthesised according to the above

procedure using (2E)-hept-2-en-6-yn-1-ol (8) (0.027 g, 0.24

mmol). The reaction mixture was stirred with Grubbs 2^nd

generation catalyst (0.015 g, 0.018 mmol) and 1-octene (0.28

mL, 1.82 mmol) for 48 h at 40 °C before N-phenyl maleimide

(0.063 g, 0.36 mmol) was added. The reaction mixture was

stirred for 24 h at 75 °C. Flash column chromatography

4.1.10.

(3aS*,4S*,8R*,8aS*,8bR*)-4-(4-Fluorophenyl)-

4,6,7,8,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione

Fluorophenyl)-4,6,7,8,8a,8b-hexahydro-2-phenyl-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (16) was synthesised according to the above

procedure using (2E)-hept-2-en-6-yn-1-ol (8) (0.027 g, 0.24

mmol). The reaction mixture was stirred with Grubbs 2^nd

generation catalyst (0.015 g, 0.018 mmol) and 4-fluorostyrene

(0.22 mL, 1.82 mmol) for 48 h at 40 °C before N-phenyl

maleimide (0.063 g, 0.36 mmol) was added. The reaction mixture

was stirred for 24 h at 75 °C. Flash column chromatography

(16).

(3aS*,4S*,8R*,8aS*,8bR*)-4-(4-

(petroleum

ether/diethyl

ether,

5:1)

gave

(3aS*,4S*,8R*,8aS*,8bR*)-4,6,7,8,8a,8b-hexahydro-4-n-hexyl-2-

phenyl-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (14) (0.076 g, 62%) as a white solid. R_f(50%

diethyl ether/petroleum ether) 0.62; Mp 145–147 °C; ν_max(neat)

3310 (NH), 2928 (CH), 1697 (CO), 1516, 1499, 1389, 1186

cm⁻¹; δ_H(500 MHz, CDCl₃) 0.86–0.92 (3H, m, 6”-H₃), 1.25–1.53

(8H, m, 2”-H₂, 3”-H₂, 4”-H₂and 5”-H₂), 1.73 (1H, dtd, J 14.1,

9.4, 5.4 Hz, 1”-HH), 1.86 (1H, qd, J 12.3, 7.8 Hz, 7-HH), 1.99–

2.01 (1H, m, 1”-HH), 2.14 (1H, dt, J 12.3, 7.2 Hz, 7-HH), 2.25–

2.39 (2H, m, 4-H and 6-HH), 2.46 (1H, dd, J 16.0, 7.8 Hz, 6-

HH), 2.90–2.96 (1H, m, 8a-H), 3.27 (1H, dd, J 8.4, 6.9 Hz, 3a-

H), 3.41 (1H, dd, J 8.4, 6.5 Hz, 8b-H), 4.81–4.92 (1H, m, 8-H),

5.57–5.61 (1H, m, 5-H), 7.13–7.17 (2H, m, 2 × ArH), 7.37–7.42

(1H, m, ArH), 7.43–7.48 (2H, m, 2 × ArH), 8.98 (1H, d, J 9.7

Hz, NH); δ_C(126 MHz, CDCl₃) 14.1 (CH₃), 22.6 (CH₂), 28.2

(CH₂), 28.3 (CH₂), 29.3 (CH₂), 31.0 (CH₂), 31.7 (CH₂), 31.8

(CH₂), 38.6 (CH), 42.1 (CH), 42.2 (CH), 42.8 (CH), 52.9 (CH),

92.2 (C), 123.1 (CH), 126.6 (2 × CH), 129.0 (CH), 129.3 (2 ×

(petroleum

ether/diethyl

ether,

1:1)

gave

(3aS*,4S*,8R*,8aS*,8bR*)-4-(4-fluorophenyl)-4,6,7,8,8a,8b-

hexahydro-2-phenyl-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (16) (0.070 g, 56%) as a white solid. R_f(50%

diethyl ether/petroleum ether) 0.24; Mp 146–148 °C; ν_max(neat)

3307 (NH), 2925 (CH), 1696 (CO), 1510, 1388, 1214, 1200,

1158, 822 cm⁻¹; δ_H(500 MHz, CDCl₃) 2.00 (1H, qd, J 12.3, 7.9

Hz, 7-HH), 2.26 (1H, dq, J 12.3, 7.4 Hz, 7-HH), 2.39–2.52 (1H,

m, 6-HH), 2.62 (1H, dd, J 16.4, 7.9 Hz, 6-HH), 3.09–3.16 (1H,

m, 8a-H), 3.47 (1H, dd, J 15.5, 8.3 Hz, 3a-H), 3.54 (1H, dd, J

8.3, 6.0 Hz, 8b-H), 3.71–3.79 (1H, m, 4-H), 4.91–5.04 (1H, m, 8-

H), 6.08–6.12 (1H, m, 5-H), 7.06–7.10 (2H, m, 2 × ArH), 7.13–

7.16 (2H, m, 2 × ArH), 7.22–7.27 (2H, m, 2 × ArH), 7.38–7.43

7

(1H, m, ArH), 7.44–7.50 (2H, m, 2 × ArH), 8.92 (1H, d, J 9.6

Hz, NH); δ_C(126 MHz, CDCl₃) 28.7 (CH₂), 31.7 (CH₂), 41.8

(CH), 42.2 (CH), 42.8 (CH), 46.0 (CH), 52.8 (CH), 92.8 (C),

115.3 (d, J_C-C-F21.6 Hz, 2 × CH), 120.2 (CH), 126.3 (2 × CH),

129.0 (CH), 129.3 (2 × CH), 130.2 (d, J_C-C-C-F8.0 Hz, 2 × CH),

131.3 (C), 134.5 (C), 146.8 (C), 162.0 (d, J_C-F245.9 Hz, C),

162.3 (C), 174.4 (C), 178.6 (C); m/z (ESI) 543 ([MNa]⁺, 100%),

449 (6), 413 (7), 352 (4), 227 (6), 159 (4); HRMS (ESI): [MNa]⁺,

found 543.0410. C₂₅H₂₀³⁵Cl₃FN₂NaO₃requires 543.0416.

(CH₂), 27.9 (CH₂), 28.7 (CH₂), 28.8 (CH₂), 31.5 (CH₂), 32.8

ACCEPTED MANUSCRIPT

(CH₂), 39.3 (C), 43.3 (CH), 44.5 (C), 49.0 (CH), 55.2 (CH), 91.8

(C), 109.1 (C), 110.1 (C), 110.9 (C), 111.6 (C), 119.8 (CH),

134.6 (C), 162.3 (C); m/z (ESI) 464 ([M−H]⁻, 100%), 400 (2),

346 (10), 303 (22), 276 (8), 265 (4), 249 (4); HRMS (ESI):

[M−H]⁻, found 464.0806. C₂₁H₂₁³⁵Cl₃N₅O requires 464.0817.

4.1.13. (3aS*,4S*,9R*,9aS*,9bR*)-4-n-Hexyl-3a,4,6,7,8,9,9a,9b-

octahydro-2-phenyl-9-(2’,2’,2’-trichloromethylcarbonylamino)-

1H-benz[e]isoindole-1,3(2H)-dione (19). (2E)-Octa-2-en-7-yn-1-

ol (9) (0.03 g, 0.24 mmol) was dissolved in dichloromethane (10

4.1.11.

(5S*,9R*,9aS*)-5-n-Hexyl-7,8,9,9a-tetrahydro-9-

(2’,2’,2’-trichloromethylcarbonylamino)-1H,5H-

mL) and cooled to

0

°C. To the solution 1,8-

cyclopent[c][2,4,10]-triazolo[1,2-a]pyridazine-1,3(2H)-dione

(17). (5S*,9R*,9aS*)-5-n-Hexyl-7,8,9,9a-tetrahydro-9-(2’,2’,2’-

trichloromethylcarbonylamino)-1H,5H-cyclopent[c][2,4,10]-

triazolo[1,2-a]pyridazine-1,3(2H)-dione (17) was synthesised

according to the above procedure using (2E)-hept-2-en-6-yn-1-ol

(8) (0.027 g, 0.24 mmol). The reaction mixture was stirred with

Grubbs 2^ndgeneration catalyst (0.015 g, 0.018 mmol) and 1-

octene (0.28 mL, 1.82 mmol) for 48 h at 40 °C before N-phenyl-

1,2,4-triazoline-3,5-dione (0.063 g, 0.36 mmol) was added. The

reaction mixture was stirred for 18 h at 75 °C. Flash column

chromatography (petroleum ether/ethyl acetate, 7:3) gave

(5S*,9R*,9aS*)-5-n-hexyl-7,8,9,9a-tetrahydro-9-(2’,2’,2’-

trichloromethylcarbonylamino)-1H,5H-cyclopent[c][2,4,10]-

triazolo[1,2-a]pyridazine-1,3(2H)-dione (17) (0.066 g, 54%) as a

brown oil. R_f(50% diethyl ether/petroleum ether) 0.33; ν_max

(neat) 3412 (NH), 2928 (CH), 1775 (CO), 1711 (CO), 1503,

1416, 1265, 1140, 820 cm⁻¹; δ_H(400 MHz, CDCl₃) 0.88 (3H, t, J

6.9 Hz, 6”-H₃), 1.19–1.47 (8H, m, 2”-H₂, 3”-H₂, 4”-H₂and 5”-

H₂), 1.73–1.94 (2H, m, 1”-H₂), 2.07–2.20 (1H, m, 8-HH), 2.34–

2.43 (1H, m, 8-HH), 2.52–2.62 (2H, m, 7-H₂), 4.23–4.29 (1H, m,

9a-H), 4.62–4.68 (1H, m, 5-H), 4.87 (1H, br q, J 5.4 Hz, 9-H),

5.88–5.94 (1H, m, 6-H), 6.80 (1H, d, J 5.4 Hz, NH), 7.35–7.41

(1H, m, ArH), 7.45–7.50 (2H, m, 2 × ArH), 7.51–7.56 (2H, m, 2

× ArH); δ_C(126 MHz, CDCl₃) 14.0 (CH₃), 22.6 (CH₂), 24.9

(CH₂), 24.9 (CH₂), 27.7 (CH₂), 29.1 (CH₂), 31.5 (CH₂), 33.2

(CH₂), 52.6 (CH), 53.9 (CH), 60.7 (CH), 92.7 (C), 120.4 (CH),

125.2 (2 × CH), 128.2 (CH), 129.2 (2 × CH), 131.0 (C), 136.5

(C), 150.0 (C), 154.6 (C), 161.3 (C); HRMS (ESI): [MNa]⁺,

found 535.1023. C₂₃H₂₇³⁵Cl₃N₄NaO₃requires 535.1041.

diazabicyclo[5.4.0]undec-7-ene (0.007 mL, 0.048 mmol) and

trichloroacetonitrile (0.036 mL, 0.36 mmol) were added. The

reaction mixture was allowed to warm to room temperature

before stirring for 3 h. The reaction mixture was filtered through

a short pad of silica gel and the filtrate concentrated in vacuo to

give the allylic trichloroacetimidate, which was used without

further purification. The allylic trichloroacetimidate was

dissolved in toluene (5 mL) and transferred to a Schlenk tube

containing potassium carbonate (0.025 g, 0.18 mmol), purged

with Ar and sealed. The reaction mixture was then heated to 140

°C and stirred for 36 h. Grubbs 2^ndgeneration catalyst (0.010 g,

0.012 mmol) was added with 1-octene (0.19 mL, 1.21 mmol) and

the reaction mixture was stirred for 24 h at 70 °C. A further

portion of Grubbs 2^ndgeneration catalyst (0.005 g, 0.006 mmol)

and 1-octene (0.096 mL, 0.61 mmol) was added and the reaction

mixture was stirred at 70 °C for 18 h. A further portion of Grubbs

2^ndgeneration catalyst (0.005 g, 0.006 mmol) and 1-octene

(0.096 mL, 0.61 mmol) was added and the reaction mixture was

stirred at 70 °C for 18 h. N-Phenyl maleimide (0.063 g, 0.36

mmol) was added with hydroquinone (0.005 g, 0.005 mmol). The

reaction mixture was stirred for 24 h at 100 °C. The reaction

mixture was then cooled and the solvent was evaporated. Flash

column chromatography (petroleum ether/diethyl ether, 3:1) gave

(3aS*,4S*,9R*,9aS*,9bR*)-4-n-hexyl-3a,4,6,7,8,9,9a,9b-

octahydro-2-phenyl-9-(2’,2’,2’-trichloromethylcarbonylamino)-

1H-benz[e]isoindole-1,3(2H)-dione (19) (0.048 g, 38%) as a

colourless oil. R_f(50% diethyl ether/petroleum ether) 0.63; ν_max

(neat) 3327 (NH), 2927 (CH), 2856 (CH), 1700 (CO), 1512,

1500, 1387, 1191, 845 cm⁻¹; δ_H(400 MHz, CDCl₃) 0.89 (3H, t, J

6.8 Hz, 6”-H₃), 1.25–1.50 (8H, m, 2”-H₂, 3”-H₂, 4”-H₂and 5”-

H₂), 1.52–1.63 (1H, m, 7-HH), 1.64–1.78 (2H, m, 1”-HH and 7-

HH), 1.81–2.00 (3H, m, 1”-HH and 8-H₂), 2.08–2.20 (1H, m, 6-

HH), 2.25–2.36 (1H, m, 4-H), 2.46–2.56 (1H, m, 6-HH), 3.06

(1H, t, J 8.5 Hz, 9a-H), 3.27 (1H, dd, J 8.5, 6.0 Hz, 3a-H), 3.46

(1H, dd, J 8.5, 6.0 Hz, 9b-H), 4.58–4.69 (1H, m, 9-H), 5.61–5.66

(1H, m, 5-H), 7.13–7.19 (2H, m, 2 × ArH), 7.37–7.43 (1H, m,

ArH), 7.44–7.51 (2H, m, 2 × ArH), 8.40 (1H, d, J 9.4 Hz, NH);

δ_C(126 MHz, CDCl₃) 13.1 (CH₃), 20.9 (CH₂), 21.6 (CH₂), 27.2

(CH₂), 28.0 (CH₂), 28.2 (CH₂), 28.7 (CH₂), 29.8 (CH₂), 30.8

(CH₂), 36.1 (CH), 36.7 (CH), 41.1 (CH), 43.4 (CH), 47.2 (CH),

91.9 (C), 125.4 (2 × CH), 127.4 (CH), 127.9 (CH), 128.2 (2 ×

CH), 130.5 (C), 136.9 (C), 160.7 (C), 175.3 (C), 178.2 (C);

HRMS (ESI): [M−H]⁻, found 523.1319. C₂₆H₃₀³⁵Cl₃N₂O₃

requires 523.1327.

4.1.12.

(1R*,5S*,7aR*)-2,3,5,6,7,7a-Hexahydro-5-n-hexyl-

6,6,7,7-tetracyano-1-(2’,2’,2’-

trichloromethylcarbonylamino)indene (18). (1R*,5S*,7aR*)-

2,3,5,6,7,7a-Hexahydro-5-n-hexyl-6,6,7,7-tetracyano-1-(2’,2’,2’-

trichloromethylcarbonylamino)indene (18) was synthesised

according to the above procedure using (2E)-hept-2-en-6-yn-1-ol

(8) (0.027 g, 0.24 mmol). The reaction mixture was stirred with

Grubbs 2^ndgeneration catalyst (0.015 g, 0.018 mmol) and 1-

octene (0.28 mL, 1.82 mmol) for 48 h at 40 °C before

tetracyanoethylene (0.046 g, 0.36 mmol) was added. The reaction

mixture was stirred for 18

h at 50 °C. Flash column

chromatography (petroleum ether/ethyl acetate, 4:1) gave

(1R*,5S*,7aR*)-2,3,5,6,7,7a-hexahydro-5-n-hexyl-6,6,7,7-

tetracyano-1-(2’,2’,2’-trichloromethylcarbonylamino)indene (18)

(0.057 g, 50%) as a white solid. R_f(50% ethyl acetate/petroleum

ether) 0.80; Mp 163–165 °C; ν_max(neat) 3316 (NH), 2930 (CH),

1688 (CO), 1530, 1458, 1265, 841, 822 cm⁻¹; δ_H(500 MHz,

CDCl₃) 0.90 (3H, t, J 8.7 Hz, 6”-H₃), 1.25–1.49 (7H, m, 2”-HH,

3”-H₂, 4”-H₂and 5”-H₂), 1.53–1.65 (1H, m, 2”-HH), 1.86–2.03

(2H, m, 1”-HH and 2-HH), 2.05–2.16 (1H, m, 1”-HH), 2.39–2.49

(1H, m, 2-HH), 2.51–2.64 (1H, m, 3-HH), 2.69–2.80 (1H, m, 3-

HH), 2.97–3.06 (1H, m, 5-H), 3.29–3.37 (1H, m, 7a-H), 4.41–

4.52 (1H, m, 1-H), 5.84–5.89 (1H, m, 4-H), 6.91 (1H, d, J 10.2

Hz, NH); δ_C(126 MHz, CDCl₃) 14.0 (CH₃), 22.5 (CH₂), 27.0

4.1.14. (3aS*,4S*,9R*,9aS*,9bR*)-4-n-Butyl-3a,4,6,7,8,9,9a,9b-

octahydro-2-phenyl-9-(2’,2’,2’-trichloromethylcarbonylamino)-

1H-benz[e]isoindole-1,3(2H)-dione

(20).

(3aS*,4S*,9R*,9aS*,9bR*)-4-n-Butyl-3a,4,6,7,8,9,9a,9b-

octahydro-2-phenyl-9-(2’,2’,2’-trichloromethylcarbonylamino)-

1H-benz[e]isoindole-1,3(2H)-dione (20) was synthesised

according to the above procedure using (2E)-octa-2-en-7-yn-1-ol

(9) (0.030 g, 0.24 mmol). The reaction mixture was stirred with

Grubbs 2^ndgeneration catalyst (0.020 g, 0.024 mmol) and 1-

8

Tetrahedron

ACCEPTED MANUSCRIPT

hexene (0.30 mL, 2.41 mmol) for 72 h at 70 °C before N-phenyl

using (2E)-octa-2-en-7-yn-1-ol (9) (0.030 g, 0.24 mmol). The

maleimide (0.063 g, 0.36 mmol) was added. The reaction mixture

was stirred for 24 h at 100 °C. Flash column chromatography

(petroleum

reaction mixture was stirred with Grubbs 2^ndgeneration catalyst

(0.020 g, 0.024 mmol) and 4-fluorostyrene (0.29 mL, 2.41 mmol)

for 72 h at 70 °C before N-phenyl maleimide (0.063 g, 0.36

mmol) was added. The reaction mixture was stirred for 48 h at

100 °C. Flash column chromatography (petroleum ether/diethyl

ether, 5:2) gave (3aS*,4S*,9R*,9aS*,9bR*)-4-(4-fluorophenyl)-

3a,4,6,7,8,9,9a,9b-octahydro-2-phenyl-9-(2’,2’,2’-

ether/diethyl

ether,

3:1)

gave

(3aS*,4S*,9R*,9aS*,9bR*)-4-n-butyl-3a,4,6,7,8,9,9a,9b-

octahydro-2-phenyl-9-(2’,2’,2’-trichloromethylcarbonylamino)-

1H-benz[e]isoindole-1,3(2H)-dione (20) (0.045 g, 37%) as a

colourless oil. R_f(50% diethyl ether/petroleum ether) 0.59; ν_max

(neat) 3328 (NH), 2929 (CH), 1698 (CO), 1499, 1387, 1191, 820

cm⁻¹; δ_H(500 MHz, CDCl₃) 0.93 (3H, t, J 7.1 Hz, 4”-H₃), 1.33–

1.49 (4H, m, 2”-H₂and 3”-H₂), 1.51–1.62 (1H, m, 7-HH), 1.65–

1.77 (2H, m, 1”-HH and 7-HH), 1.82–2.01 (3H, m, 1”-HH and 8-

H₂), 2.09–2.19 (1H, m, 6-HH), 2.26–2.35 (1H, m, 4-H), 2.48–

2.54 (1H, m, 6-HH), 3.06 (1H, t, J 8.5 Hz, 9a-H), 3.27 (1H, dd, J

8.5, 6.0 Hz, 3a-H), 3.45 (1H, dd, J 8.5, 6.0 Hz, 9b-H), 4.58–4.69

(1H, m, 9-H), 5.61–5.66 (1H, m, 5-H), 7.13–7.18 (2H, m, 2 ×

ArH), 7.37–7.42 (1H, m, ArH), 7.43–7.49 (2H, m, 2 × ArH), 8.39

(1H, d, J 9.4 Hz, NH); δ_C(126 MHz, CDCl₃) 14.0 (CH₃), 21.9

(CH₂), 22.6 (CH₂), 29.0 (CH₂), 29.7 (CH₂), 30.5 (CH₂), 30.6

(CH₂), 37.1 (CH), 37.8 (CH), 42.1 (CH), 44.4 (CH), 48.3 (CH),

92.9 (C), 126.4 (2 × CH), 128.4 (CH), 128.9 (CH), 129.3 (2 ×

CH), 131.5 (C), 138.0 (C), 161.7 (C), 176.4 (C), 179.2 (C); m/z

(CI) 497 (MH⁺, 31%), 463 (100), 429 (41), 379 (32), 335 (39),

174 (38), 122 (12), 69 (40); HRMS (CI): MH⁺, found 497.1167.

C₂₄H₂₈³⁵Cl₃N₂O₃requires 497.1166.

trichloromethylcarbonylamino)-1H-benz[e]isoindole-1,3(2H)-

dione (22) (0.065 g, 50%) as a white solid. R_f(50% diethyl

ether/petroleum ether) 0.35; Mp 144–146 °C; ν_max(neat) 3324

(NH), 2927 (CH), 1699 (CO), 1510, 1386, 1264, 1188, 820

cm⁻¹; δ_H(500 MHz, CDCl₃) 1.61–1.86 (3H, m, 7-H₂and 8-HH),

2.02 (1H, dq, J 11.8, 5.4 Hz, 8-HH), 2.22–2.33 (1H, m, 6-HH),

2.58–2.66 (1H, m, 6-HH), 3.24 (1H, t, J 6.8 Hz, 9a-H), 3.51 (1H,

dd, J 8.5, 5.7 Hz, 3a-H), 3.57 (1H, dd, J 8.5, 6.8 Hz, 9b-H), 3.68

(1H, br s, 4-H), 4.65–4.76 (1H, m, 9-H), 6.15–6.21 (1H, m, 5-H),

7.02–7.08 (2H, m, 2 × ArH), 7.11–7.15 (2H, m, 2 × ArH), 7.29–

7.47 (5H, m, 5 × ArH), 8.41 (1H, d, J 9.7 Hz, NH); δ_C(126 MHz,

CDCl₃) 21.7 (CH₂), 28.6 (CH₂), 29.8 (CH₂), 38.2 (CH), 41.2

(CH), 41.8 (CH), 47.3 (CH), 48.2 (CH), 92.9 (C), 115.2 (d, J_C-C-F

21.4 Hz, 2 × CH), 125.1 (CH), 126.3 (2 × CH), 129.0 (CH),

129.3 (2 × CH), 130.3 (d, J_C-C-C-F8.0 Hz, 2 × CH), 131.3 (C),

134.3 (C), 139.4 (C), 161.9 (C), 162.0 (d, J_C-F245.9 Hz, C),

175.1 (C), 178.5 (C); m/z (ESI) 557 ([MNa]⁺, 100%), 413 (23),

345 (8), 242 (34), 142 (3); HRMS (ESI): [MNa]⁺, found

557.0586. C₂₆H₂₂³⁵Cl₃FN₂NaO₃requires 557.0572.

4.1.15.

(3aS*,4S*,9R*,9aS*,9bR*)-2,4-Diphenyl-

3a,4,6,7,8,9,9a,9b-octahydro-9-(2’,2’,2’-

trichloromethylcarbonylamino)-1H-benz[e]isoindole-1,3(2H)-

4.1.17.

(1R*,6R*,8aR*)-1,2,3,4,6,7,8,8a-Octahydro-6-phenyl-

dione

(21).

(3aS*,4S*,9R*,9aS*,9bR*)-2,4-Diphenyl-

7,7,8,8-tetracyano-1-(2’,2’,2’-

3a,4,6,7,8,9,9a,9b-octahydro-9-(2’,2’,2’-

trichloromethylcarbonylamino)naphthalene

(23).

trichloromethylcarbonylamino)-1H-benz[e]isoindole-1,3(2H)-

dione (21) was synthesised according to the above procedure

using (2E)-octa-2-en-7-yn-1-ol (9) (0.030 g, 0.24 mmol). The

reaction mixture was stirred with Grubbs 2^ndgeneration catalyst

(0.020 g, 0.024 mmol) and styrene (0.27 mL, 2.41 mmol) for 72

h at 70 °C before N-phenyl maleimide (0.063 g, 0.36 mmol) was

added. The reaction mixture was stirred for 24 h at 100 °C. Flash

column chromatography (petroleum ether/diethyl ether, 13:7)

gave (3aS*,4S*,9R*,9aS*,9bR*)-2,4-diphenyl-3a,4,6,7,8,9,9a,9b-

octahydro-9-(2’,2’,2’-trichloromethylcarbonylamino)-1H-

benz[e]isoindole-1,3(2H)-dione (21) (0.067 g, 54%) as a white

solid. R_f(50% diethyl ether/petroleum ether) 0.47; Mp 153–155

°C; ν_max(neat) 3336 (NH), 2937 (CH), 1698 (CO), 1511, 1499,

1386, 1192, 819 cm⁻¹; δ_H(500 MHz, CDCl₃) 1.61–1.86 (3H, m,

7-H₂and 8-HH), 2.01 (1H, dq, J 12.5, 5.6 Hz, 8-HH), 2.23–2.34

(1H, m, 6-HH), 2.58–2.66 (1H, m, 6-HH), 3.21–3.28 (1H, m, 9a-

H), 3.53–3.60 (2H, m, 3a-H and 9b-H), 3.70 (1H, br s, 4-H),

4.66–4.76 (1H, m, 9-H), 6.23–6.28 (1H, m, 5-H), 7.11–7.16 (2H,

m, 2 × ArH), 7.26–7.46 (8H, m, 8 × ArH), 8.43 (1H, d, J 9.4 Hz,

NH); δ_C(126 MHz, CDCl₃) 21.7 (CH₂), 28.7 (CH₂), 29.9 (CH₂),

38.2 (CH), 41.8 (CH), 41.9 (CH), 47.3 (CH), 48.2 (CH), 92.9

(C), 125.2 (CH), 126.3 (2 × CH), 127.2 (CH), 128.3 (2 × CH),

128.8 (2 × CH), 128.9 (CH), 129.2 (2 × CH), 131.4 (C), 138.6

(C), 139.1 (C), 161.9 (C), 175.0 (C), 178.6 (C); m/z (ESI) 539

([MNa]⁺, 100%), 413 (10), 383 (8), 301 (6), 236 (3); HRMS

(ESI): [MNa]⁺, found 539.0652. C₂₆H₂₃³⁵Cl₃N₂NaO₃requires

539.0666.

(1R*,6R*,8aR*)-1,2,3,4,6,7,8,8a-Octahydro-6-phenyl-7,7,8,8-

tetracyano-1-(2’,2’,2’-

trichloromethylcarbonylamino)naphthalene (23) was synthesised

according to the above procedure using (2E)-octa-2-en-7-yn-1-ol

(9) (0.030 g, 0.24 mmol). The reaction mixture was stirred with

Grubbs 2^ndgeneration catalyst (0.020 g, 0.024 mmol) and styrene

(0.27 mL, 2.41 mmol) for 72

tetracyanoethylene (0.046 g, 0.36 mmol) was added. The reaction

mixture was stirred for 24 at 50 °C. Flash column

h

at 70 °C before

h

chromatography (petroleum ether/ethyl acetate, 7:3) gave

(1R*,6R*,8aR*)-1,2,3,4,6,7,8,8a-octahydro-6-phenyl-7,7,8,8-

tetracyano-1-(2’,2’,2’-

trichloromethylcarbonylamino)naphthalene (23) (0.050 g, 44%)

as a colourless oil. R_f(50% diethyl ether/petroleum ether) 0.68;

ν_max(neat) 3332 (NH), 2946 (CH), 2254 (CN), 1696 (CO), 1513,

1455, 1275, 1082, 820 cm⁻¹; δ_H(500 MHz, CDCl₃) 1.57–1.70

(1H, m, 3-HH), 1.95–2.10 (2H, m, 2-HH and 3-HH), 2.21–2.35

(2H, m, 2-HH and 4-HH), 2.63 (1H, br d, J 13.2 Hz, 4-HH), 3.68

(1H, d, J 11.3 Hz, 8a-H), 4.21–4.31 (1H, m, 1-H), 4.32–4.37 (1H,

m, 6-H), 5.85–5.90 (1H, m, 5-H), 7.10–7.18 (1H, m, NH), 7.44–

7.49 (5H, m, 5 × ArH); δ_C(126 MHz, CDCl₃) 24.2 (CH₂), 32.1

(CH₂), 35.2 (CH₂), 40.3 (C), 44.3 (C), 46.2 (CH), 46.4 (CH), 54.6

(CH), 92.0 (C), 108.8 (C), 110.2 (C), 111.5 (C), 112.4 (C), 119.8

(CH), 129.0 (2 × CH), 130.5 (CH), 130.7 (2 × CH), 131.3 (C),

136.1 (C), 161.8 (C); m/z (ESI) 470 ([M−H]⁻, 100%), 352 (21),

309 (20), 282 (15), 257 (8), 212 (4); HRMS (ESI): [M−H]⁻,

found 470.0332. C₂₂H₁₅³⁵Cl₃N₅O requires 470.0348.

4.1.16.

(3aS*,4S*,9R*,9aS*,9bR*)-4-(4-Fluorophenyl)-

4.1.18. (5S*,10R*,10aS*)-5-n-Decyl-5,7,8,9,10,10a-hexahydro-

10-(2’,2’,2’-trichloromethylcarbonylamino)-1H-[2,4,11]-

triazolo[1,2-a]cinnoline-1,3(2H)-dione (24). (5S*,10R*,10aS*)-

5-n-Decyl-5,7,8,9,10,10a-hexahydro-10-(2’,2’,2’-

3a,4,6,7,8,9,9a,9b-octahydro-2-phenyl-9-(2’,2’,2’-

trichloromethylcarbonylamino)-1H-benz[e]isoindole-1,3(2H)-

dione

(22).

(3aS*,4S*,9R*,9aS*,9bR*)-4-(4-Fluorophenyl)-

3a,4,6,7,8,9,9a,9b-octahydro-2-phenyl-9-(2’,2’,2’-

trichloromethylcarbonylamino)-1H-benz[e]isoindole-1,3(2H)-

dione (22) was synthesised according to the above procedure

trichloromethylcarbonylamino)-1H-[2,4,11]-triazolo[1,2-

a]cinnoline-1,3(2H)-dione (24) was synthesised according to the

above procedure using (2E)-octa-2-en-7-yn-1-ol (9) (0.030 g,

9

0.24 mmol). The reaction mixture was stirred with Grubbs 2^nd

generation catalyst (0.020 g, 0.024 mmol) and 1-dodecene (0.54

mL, 2.41 mmol) for 72 h at 75 °C before N-phenyl-1,2,4-

triazoline-3,5-dione (0.063 g, 0.36 mmol) was added. The

reaction mixture was stirred for 24 h at 100 °C. Flash column

chromatography (petroleum ether/ethyl acetate, 7:3) gave

(5S*,10R*,10aS*)-5-n-decyl-5,7,8,9,10,10a-hexahydro-10-

(2’,2’,2’-trichloromethylcarbonylamino)-1H-[2,4,11]-

triazolo[1,2-a]cinnoline-1,3(2H)-dione (24) (0.055 g, 39%) as a

colourless oil. R_f(50% diethyl ether/petroleum ether) 0.49; ν_max

(neat) 3415 (NH), 2923 (CH), 1709 (CO), 1503, 1416, 1141, 818

cm⁻¹; δ_H(500 MHz, CDCl₃) 0.88 (3H, t, J 7.0 Hz, 10”-H₃), 1.15–

1.59 (17H, m, 8-HH, 2”-H₂, 3”-H₂, 4”-H₂, 5”-H₂, 6”-H₂, 7”-H₂,

8”-H₂and 9”-H₂), 1.77–1.91 (3H, m, 8-HH, 9-HH and 1”-HH),

2.14–2.28 (3H, m, 7-HH, 9-HH and 1”-HH), 2.49–2.57 (1H, m,

7-HH), 4.31–4.38 (1H, m, 5-H), 4.49 (1H, br s, 10a-H), 5.11–

5.18 (1H, m, 10-H), 5.88–5.93 (1H, m, 6-H), 6.79 (1H, d, J 8.1

Hz, NH), 7.33–7.39 (1H, m, ArH), 7.44–7.53 (4H, m, 4 × ArH);

δ_C(126 MHz, CDCl₃) 14.1 (CH₃), 21.6 (CH₂), 22.7 (CH₂), 25.2

(CH₂), 28.0 (CH₂), 29.3 (CH₂), 29.5 (CH₂), 29.5 (CH₂), 29.6

(CH₂), 29.6 (CH₂), 31.9 (CH₂), 33.2 (CH₂), 33.5 (CH₂), 50.0

(CH), 54.4 (CH), 57.5 (CH), 92.8 (C), 122.7 (CH), 125.8 (2 ×

CH), 128.2 (CH), 128.3 (C), 129.1 (2 × CH), 131.1 (C), 151.6

(C), 151.9 (C), 161.2 (C); m/z (ESI) 605 ([MNa]⁺, 100%), 413

(9), 301 (4), 236 (5); HRMS (ESI): [MNa]⁺, found 605.1796.

C₂₈H₃₇³⁵Cl₃N₄NaO₃requires 605.1823.

(1.97 g, 8.64 mmol). Purification by flash column

ACCEPTED MANUSCRIPT

chromatography (ethyl acetate/petroleum ether, 7:13) gave (2E)-

7-phenylhept-2-en-6-yn-1-ol (27) (1.30 g, 81%) as a colourless

oil. R_f(50% petroleum ether/diethyl ether) 0.43; ν_max(neat) 3329

(OH), 2918 (CH), 2324, 2110, 1597, 1489, 1441, 1084, 966 cm⁻¹;

δ_H(500 MHz, CDCl₃) 1.36 (1H, br s, OH), 2.36 (2H, dt, J 7.2,

6.8 Hz, 4-H₂), 2.50 (2H, t, J 6.8 Hz, 5-H₂), 4.13 (2H, t, J 4.5 Hz,

1-H₂), 5.72–5.85 (2H, m, 2-H and 3-H), 7.25–7.31 (3H, m, 3 ×

ArH), 7.36–7.42 (2H, m, 2 × ArH); δ_C(126 MHz, CDCl₃) 19.5

(CH₂), 31.5 (CH₂), 63.6 (CH₂), 81.2 (C), 89.4 (C), 123.8 (C),

127.6 (CH), 128.2 (2 × CH), 130.4 (CH), 131.0 (CH), 131.6 (2 ×

CH); m/z (CI) 169 (MH⁺−H₂O, 100%), 143 (14), 123 (46), 105

(17), 91 (6); HMRS (CI): MH⁺−H₂O, found 169.1018. C₁₃H₁₃

requires 169.1017.

4.1.22.

hexahydro-8-(2’,2’,2’-

trichloromethylcarbonylamino)cyclopent[e]isoindole-

(3aS*,8R*,8aS*,8bR*)-2,5-Diphenyl-4,6,7,8,8a,8b-

1,3(2H,3aH)-dione (30). (2E)-7-Phenylhept-2-en-6-yn-1-ol (27)

(0.075 g, 0.40 mmol) was dissolved in dichloromethane (10 mL)

and cooled to 0 °C. To the solution 1,8-diazabicyclo[5.4.0]undec-

7-ene (0.011 mL, 0.008 mmol) and trichloroacetonitrile (0.062

mL, 0.60 mmol) were added. The reaction mixture was allowed

to warm to room temperature and stirred for 3 h. The reaction

mixture was filtered through a short pad of silica gel with diethyl

ether (300 mL) and the filtrate concentrated in vacuo to give the

allylic trichloroacetimidate, which was used without further

purification. The allylic trichloroacetimidate was dissolved in

toluene (10 mL) and bis(acetonitrile)palladium chloride (0.011 g,

0.040 mmol) was then added and the reaction mixture was stirred

at room temperature for 18 h. Grubbs 2^ndgeneration catalyst

(0.024 g, 0.028 mmol) was added with 1,7-octadiene (0.24 mL,

1.60 mmol) and the reaction mixture was stirred for 18 h at 90

°C. N-Phenyl maleimide (0.104 g, 0.60 mmol) was added with

hydroquinone (0.005 g, 0.005 mmol). The reaction mixture was

stirred for 18 h at 75 °C. The reaction mixture was then cooled

and the solvent was evaporated. Flash column chromatography

(petroleum ether/ethyl acetate, 1:1) gave (3aS*,8R*,8aS*,8bR*)-

2,5-diphenyl-4,6,7,8,8a,8b-hexahydro-8-(2’,2’,2’-

4.1.19.

5-Phenylpent-4-yn-1-ol

(25).²⁵

Bis(triphenylphosphine)palladium(II) dichloride (0.022 g, 0.0312

mmol) and copper iodide (0.012 g, 0.062 mmol) were dissolved

in triethylamine (43 mL) and iodobenzene (0.42 mL, 3.75 mmol)

was added and stirred at room temperature for 0.1 h. 4-Pentyn-1-

ol (0.26 g, 3.12 mmol) (4) was added and the reaction mixture

was stirred at room temperature for 48 h. The reaction mixture

was concentrated in vacuo and flash column chromatography

(petroleum ether/ethyl acetate, 3:1) gave 5-phenylpent-4-yn-1-ol

(25) (0.49 g, 98%) as a colourless oil. The spectroscopic data was

as reported in the literature.²⁵R_f(50% petroleum ether/ethyl

acetate) 0.43; δ_H(500 MHz, CDCl₃) 1.63 (1H, s, OH), 1.85 (2H,

quin, J 6.5 Hz, 2-H₂), 2.53 (2H, t, J 6.5 Hz, 3-H₂), 3.81 (2H, t, J

6.5 Hz, 1-H₂), 7.24–7.29 (3H, m, 3 × ArH), 7.36–7.40 (2H, m, 2

× ArH); δ_C(126 MHz, CDCl₃) 16.0 (CH₂), 31.4 (CH₂), 61.8

(CH₂), 81.2 (C), 89.3 (C), 123.7 (C), 127.7 (CH), 128.2 (2 × CH),

131.6 (2 × CH); m/z (EI) 160 (M⁺. 39%), 141 (100), 128 (38),

115 (71), 104 (32), 85 (35).

trichloromethylcarbonylamino)cyclopent[e]isoindole-

1,3(2H,3aH)-dione (30) (0.099 g, 49%) as a yellow solid. R_f

(50% petroleum ether/ethyl acetate) 0.76; Mp 151–153 °C; ν_max

(neat) 3358 (NH), 2936 (CH), 1695 (CO), 1517, 1498, 1387,

1154, 822 cm⁻¹; δ_H(400 MHz, CDCl₃) 1.75 (1H, dq, J 12.3, 10.2

Hz, 7-HH), 2.10–2.20 (1H, m, 7-HH), 2.53–2.66 (3H, m, 4-HH

and 6-H₂), 3.12 (1H, dd, J 9.1, 5.8 Hz, 8a-H), 3.30 (1H, dd, J

15.2, 1.4 Hz, 4-HH), 3.46–3.56 (2H, m, 3a-H and 8b-H), 4.88–

5.01 (1H, m, 8-H), 7.06–7.10 (2H, m, 2 × ArH), 7.23–7.47 (8H,

m, 8 × ArH), 8.96 (1H, d, J 9.6 Hz, NH); δ_C(126 MHz, CDCl₃)

28.4 (CH₂), 29.9 (CH₂), 31.6 (CH₂), 40.3 (CH), 41.7 (CH), 43.7

(CH), 52.8 (CH), 92.9 (C), 126.5 (2 × CH), 127.2 (CH), 127.5 (2

× CH), 128.5 (2 × CH), 129.2 (CH), 129.4 (2 × CH), 130.3 (C),

131.4 (C), 139.0 (C), 139.6 (C), 162.3 (C), 178.5 (C), 179.7 (C);

m/z (ESI) 525 ([MNa]⁺, 100%), 481 (18), 454 (7), 413 (7), 345

(24), 323 (21), 297 (9), 236 (11), 218 (7), 196 (6); HRMS (ESI):

[MNa]⁺, found 525.0497. C₂₅H₂₁³⁵Cl₃N₂NaO₃requires 525.0510.

4.1.20. Ethyl (2E)-7-phenylhept-2-en-6-ynoate (26).²⁶The

reaction was carried out as described for the synthesis of ethyl

(2E)-hept-2-en-6-ynoate (6) using 5-phenylpent-4-yn-1-ol (26)

(1.62 g, 10.1 mmol). Purification by flash column

chromatography (diethyl ether/petroleum ether, 3:17) gave ethyl

(2E)-7-phenylhept-2-en-6-ynoate (26) (1.97 g, 86%) as a yellow

oil. The spectroscopic data was as reported in the literature.²⁶R_f

(50% petroleum ether/diethyl ether) 0.66; δ_H(500 MHz, CDCl₃)

1.30 (3H, t, J 7.1 Hz, OCH₂CH₃), 2.48–2.55 (4H, m, 4-H₂and 5-

H₂), 4.20 (2H, q, J 7.1 Hz, OCH₂CH₃), 5.93 (1H, dt, J 15.7, 1.5

Hz, 2-H), 7.04 (1H, dt, J 15.7, 6.6 Hz, 3-H), 7.26–7.31 (3H, m, 3

× ArH), 7.36–7.41 (2H, m, 2 × ArH); δ_C(126 MHz, CDCl₃) 14.3

(CH₃), 18.4 (CH₂), 31.4 (CH₂), 60.3 (CH₂), 81.6 (C), 88.3 (C),

122.5 (CH), 123.6 (C), 127.8 (CH), 128.2 (2 × CH), 131.6 (2 ×

CH), 146.7 (CH), 166.5 (C); HRMS (ESI): [MNa]⁺, found

251.1040. C₁₅H₁₆NaO₂requires 251.1043.

Acknowledgments

Financial support from the University of Glasgow (University

Scholarship to M.W.G.) is gratefully acknowledged.

Supplementary data

4.1.21. (2E)-7-Phenylhept-2-en-6-yn-1-ol (27).²⁷The reaction

was carried out as described for the synthesis of (2E)-hept-2-en-

6-yn-1-ol (8) using ethyl (2E)-7-phenylhept-2-en-6-ynoate (26)

Supplementary data related to this article can be found at

http://dx.doi.org/10.1016/j.tet.XXXXX.

10

Tetrahedron

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2003, 5, 3439. (b) Nandurdikar, R. S.; Subrahmanyam, A. V.;

Kaliappan, K. P. Eur. J. Org. Chem. 2010, 2788. (c) Kurhade, S.

References and notes

E.; Sanchawala, A. I.; Ravikumar, V.; Bhuniya, D.; Reddy, D. S.

Org. Lett. 2011, 13, 3690.

16. Overman, L. E.; Carpenter, N. E. In Organic Reactions; Overman,

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references therein.

17. See supplementary data for NOE experiments for all

aminobicyclo[4.3.0]nonanes and bicyclo[4.4.0]decanes.

18. Crystallographic data (excluding structure factors) for compound

15 in this paper have been deposited with the Cambridge

Crystallographic Data Centre with code CCDC 992997. Copies of

the data can be obtained, free of charge, on application to CCDC,

12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-

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Supporting Information for:

Diastereoselective synthesis of highly substituted polycyclic scaffolds via a one-pot four-step

tandem catalytic process

Mark W. Grafton, Stuart A. Johnson, Louis J. Farrugia and Andrew Sutherland*

WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow

G12 8QQ, UK. Email: Andrew.Sutherland@glasgow.ac.uk;

Fax: 0141 330 4888; Tel: 0141 330 5936.

Table of Contents

1. Key NOE enhancements for compounds 13–24 and 30.

S2–S3

2. ¹H NMR and ¹³C NMR spectra of all novel compounds.

S4–S35

S1

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1. Key NOE enhancements for compounds 13–24 and 30.

n-hex

n-Pr

H

2.04%

2.59%

O

H

O

Cl₃C

N

H

Cl₃C

N

H

N

0.40%

0.41%

O

Ph

3.00%

1.73%

F

2.01%

3.11%

14

13

Ph

2.11%

H

2.44%

O

Cl₃C

N

H

Cl₃C

N

H

N

O

Ph

2.63%

3.39%

3.47%

2.86%

16

15

n-hex

H

CN

O

H

N

CN

O

N

Cl₃C

N

Cl₃C

N

H

CN

H

CN

N

0.10%

0.11%

O

Ph

0.33%

1.94%

18

17

n-hex

n-Bu

H

2.22%

2.06%

O

H

O

Cl₃C

N

H

O

H

Cl₃C

N

H

N

H

N

1.00%

0.84%

O

Ph

2.33%

2.44%

4.36%

3.84%

20

19

S2

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F

Ph

H

1.22%

1.15%

O

Cl₃C

N

H

Cl₃C

N

H

N

O

Ph

2.16%

2.69%

3.77%

3.84%

21

22

n-dec

Ph

H

O

CN

N

O

N

Cl₃C

N

H

Cl₃C

N

H

CN

N

H

0.14%

Ph

0.10%

O

2.23%

24

0.40%

23

Ph

O

H

O

Cl₃C

N

H

N

O

Ph

3.22%

2.63%

30

S3

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S18

Article Doi

Diastereoselective synthesis of highly substituted polycyclic scaffolds via a one-pot four-step tandem catalytic process

DOI: 10.1016/j.tet.2014.06.020

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Authors:

Article abstract of DOI:10.1016/j.tet.2014.06.020

Full text of DOI:10.1016/j.tet.2014.06.020

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