8-Iodonaphtalene-1-carbaldehyde: a Versatile Building ... · and q stand for multiplet, singlet,...

8-Iodonaphtalene-1-carbaldehyde: a Versatile

Building Block for Diversity-Oriented Synthesis

Lidia Herrera, † Pablo Barrio,* † Ignacio Ibáñez, ‡ Raquel Román, ‡

Natalia Mateu,§ Santos Fustero*†‡

†Departamento de Química Orgánica, Universidad de Valencia, E-46100 Burjassot, Spain

‡Laboratorio de Moléculas Orgánicas, Centro de Investigación Príncipe Felipe, E-46012

Valencia, Spain.

§Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW,

UK

[email protected] ; [email protected]

SUPPORTING INFORMATION

Table of contents:

General methods………………………………………………..S2

Experimental procedures and characterizations………...............S2

Optimization Tables S1 and S2..………………...…………….S30

Computational analysis: Principal Moment of Inertia (PMI) .. S31

1H,

13C and

19F Spectra of all new compounds……..………... S53

HPLC chromatograms of final products……...…...…………S171

General methods:

Reactions were carried out under a nitrogen atmosphere unless otherwise indicated. The

solvents were purified prior to use: THF and PhMe were distilled from sodium/benzophenone;

CH2Cl2 was distilled from calcium hydride; anhydrous 1,4-dioxane, CHCl3 and MeOH were

purchased from Aldrich and used as received. All reagents were obtained from commercial

suppliers and used without further purification. The reactions were monitored with the aid of

thin-layer chromatography (TLC) on 0.25 mm E. Merck pre-coated silica gel plates.

Visualization was carried out with UV light and aqueous ceric ammonium molybdate solution

or vanilla stain. Flash column chromatography was performed with the indicated solvents on

silica gel 60 (particle size 0.040-0.063 mm). Melting points were measured on a Büchi Melting

Point P-450 apparatus and are uncorrected. Optical rotations were measured on a Jasco P-1020

polarimeter. 1H,

19F and

13C NMR spectra were recorded on a 300 MHz Bruker Advance AC-

300 spectrometer. Chemical shifts are given in ppm (δ), with reference to the residual proton

resonance of the solvents. Coupling constants (J) are given in Hertz (Hz). The letters m, s, d, t,

and q stand for multiplet, singlet, doublet, triplet and quartet, respectively. The letters br

indicate that the signal is broad. High-resolution mass spectra were carried out on VG Autospec

(VG Analytical, Micromass Instruments) by the Universidad de Valencia Mass Spectrometry

Service. Microwave reactions were carried out in a 2–5 mL or 15 mL sealed vial with a Biotage

InitiatorTM 2.0 microwave synthesizer.

Experimental procedures and characterizations:

Synthesis of N-tert-Butanesulfinyl Imines I.

A solution of 8-iodonaphthalene-1-carbaldehyde 1 (1.0 equiv) and Ti(OEt)4 (5.0 equiv) in

dichloromethane (0.1 M) was stirred for 5 minutes. (R)-N-tert-Butanesulfinyl amine was added

to the resulting solution and the mixture was stirred at room temperature for 20 hours. Then,

saturated aqueous NaHCO3 was added until white titanium salts precipitated. The suspension

was filtered through a short pad of Celite® washing with small portions of ethyl acetate. The

filtrate was extracted with ethyl acetate and the combined organic layers were washed with

brine, dried over anhydrous Na2SO4, concentrated under vacuum and purified by means of flash

chromatography on silica gel employing mixtures of n-hexane: ethyl acetate as eluents.1

(RS)-(E)-N-[(8-Iodonaphthalen-1-yl)methylene]-2-methylpropane-2-sulfinamide (I)

Compound I was synthesized following the procedure for the condensation

with Ellman’s auxiliary described above starting from 12 (500 mg, 1.77 mmol) affording I as a

colorless oil (614 mg, 90 % yield). [α]25D= – 240.5 (c 1.0, CHCl3).

1H NMR (300 MHz, CDCl3):

1.35 (s, 9H), 7.40 (dd, J = 7.4, 8.1 Hz, 1H), 7.53 (dd, J = 11.5, 3.9 Hz, 1H), 7.87 (dd, J = 8.2,

1.2 Hz, 2H), 7.96-7.89 (m, 2H), 10.00 (s, 1H). 13C NMR (75.5 MHz, CDCl3): 23.0 (3xCH3),

58.6 (C), 90.1 (C), 125.7 (CH), 127.3 (CH), 129.7 (CH), 130.1 (CH), 133.0 (CH), 133.5 (2xC),

135.5 (2xC), 141.6 (CH), 164.1 (CH). HRMS (EI): m/z calcd for C15H16INOS: 386.0070 [M +

H+]; found: 386.0072.

Diastereoselective addition of the Ruppert Prakash reagent: CF3TMS was slowly added to a

mixture of imine I (1.0 equiv) and tetrabutylammonium acetate (1.2 equiv) in THF (0.1 M) at

-55°C. The reaction mixture was then stirred at -55°C until TLC revealed the disappearance of

the starting material. Next, saturated NH4Cl solution was added at this temperature, and the

reaction mixture was warmed to room temperature. The quenched reaction mixture was

extracted three times with ethyl acetate and the combined organic layers were dried over

anhydrous Na2SO4. Solvents were removed under reduced pressure and the crude mixture was

purified by flash chromatography on silica gel using mixtures of n-hexane: ethyl acetate as

eluents to afford compounds 2a.

(RS)-2-Methyl-N-[(S)-2,2,2-trifluoro-1-(8-iodonaphthalen-1-yl)ethyl]propane-2-sulfinamide

(2a)

Compound 2a was synthesized following the procedure for the

trifluoromethylation described above starting from I (500 mg, 1.3 mmol) affording 2a as a

yellowish oil (260 mg, 44 % yield). [α]25

D= -133.8 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3):

1 Fustero, S.; Ibañez, I.; Barrio, P.; Maestro, M. A.; Catalán S. Org. Lett. 2013, 15, 832. 2 Bailey. R. J.; Card. P.; Shechter. H. J. Am. Chem. Soc. 1983, 105, 6096.

1.26 (s, 9H), 3.89 (d, J = 6.7 Hz, 1H), 7.09 (dd, J = 7.3, 1.1 Hz, 1H), 7.54 (dd, J = 7.7, 0.9 Hz,

1H), 7.80 (ddd, J = 7.0, 3.5, 2.4 Hz, 1H), 7.86 (m, 2H), 8.37 (dd, J = 7.4, 1.3 Hz, 1H). 19F NMR

(282.4 MHz, CDCl3) δ - 72.53 (d, J = 7.3 Hz). 13C NMR (75.5 MHz, CDCl3): 22.5 (3xCH3),

53.9 (q, 2JCF = 30.8 Hz, CH), 57.1 (C), 87.8 (C),119.3 (C), 125.5 (CH), 126.7 (q,

1JCF = 281.4

Hz, CF3), 127.0 (CH), 128.5 (CH), 131.0 (CH), 131.2 (C), 131.4 (C), 132.1 (CH), 136.1 (C),

144.7 (CH). HRMS (EI): m/z calcd for C16H17INOSF3: 456.0100 [M + H+]; found: 456.0115.

Aza-Reformatsky reaction: the required Reformatsky reagent was prepared as follows: to a

suspension of activated Zn (200 mg, 1.3 equiv) in refluxing Et2O (5 mL) ethyl bromoacetate

(0.30 mL) was added dropwise. After refluxing the reaction mixture for 1 h a light green

solution was obtained.3 This solution was titrated with iodine and its concentration was found to

be around 0.4 M. 0.42 mL of this solution (0.17 mmol, 1.7 equiv) were added dropwise at 0 ºC

to a solution of I (31 mg, 0.1 mmol) in dry THF (1 mL). After stirring for 15 min at this

temperature the reaction was allowed to reach room temperature, and stirred for another hour.

The reaction was quenched with saturated NH4Cl(aq.) (1 mL) and extracted with AcOEt (3 x 1

mL). Flash chromatography afforded 2b as a colorless oil.

Ethyl (3S)-3-[(RS)(tert-butylsulfinyl)amino)-3-(8-iodonaphthalen-1-yl]propanoate (2b)

Compound 2b was synthesized following the procedure described above

starting from I (500 mg, 1.3 mmol) affording 2b as a yellowish oil (430 mg, 70 % yield). [α]25

D

= +2.7 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.13 (t, J = 7.1 Hz, 3H), 1.24 (s, 9H),

2.91 (dd, J = 7.8, 5.9 Hz, 1H), 3.17 (dd, J = 15.9, 4.3 Hz, 1H), 4.05 (q, J = 7.1 Hz, 2H), 5.01 (d,

J = 5.1 Hz, 1H), 7.04 (dd, J = 8.0, 7.4 Hz, 1H), 7.14 (dd, J = 7.8, 7.4 Hz, 1H), 7.48 (dd, J = 7.7,

1.5 Hz, 1H), 7.75 (dd, J = 8.1, 1.3 Hz, 1H), 7.83 (dd, J = 8.2, 1.5 Hz, 2H), 8.31 (dd, J = 7.4, 1.3

Hz, 1H). 13C NMR (75.5 MHz, CDCl3): 14.2 (CH3), 22.8 (3xCH3), 43.2 (CH2), 49.7 (CH), 55.9

(C), 60.9 (CH2), 87.6 (C), 125.5 (CH), 126.4 (CH), 127.9 (CH), 130.2 (CH), 130.8 (CH), 131.2

(C), 136.1 (C), 137.3 (C), 143.7 (CH), 171.5 (C). HRMS (EI): m/z calcd for C19H24INO3S:

474.0591 [M + H+]; found: 474.0594.

Reaction of Compound I with Allylzinc Bromide: A 1M solution of allylzinc bromide in THF

was prepared by stirring 0.4 mL of allyl bromide and 1.0 g of activated Zn in 2.5 mL of

anhydrous THF at 50 ºC. 2 equivalents of this freshly prepared solution were then added to a

solution of substrate I in dry THF at -40 ºC. After stirring 10 min at 0 ºC the reaction mixture

3 Greszler, S. N.; Johnson, J. S. Angew. Chem. Int. Ed. 2009, 48, 3689.

was quenched with saturated NH4Cl(aq.) and extracted three times with AcOEt. Flash

chromatography afforded compound 2c as a colorless oil.

N-(RS)-1-[(S)-8-Iodonaphthalen-1-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide (2c)

Compound 2c was synthesized following the procedure described above

starting from I (500 mg, 1.3 mmol) affording 2c as a colorless oil (333 mg, 60 % yield). [α]25

D =

–57.1 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.21 (s, 9H), 2.48 (dt, J = 14.1, 8.3 Hz,

1H), 2.94–3.01 (m, 1H), 3.87 (d, J = 2.4 Hz, 1H), 5.20 (m, 2H), 5.83 (dddd, J = 16.6, 10.3, 8.3,

5.9 Hz, 1H), 6.83 (m, 1H), 7.02 (m, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.7 (m, 1H), 7.82 (dd, J = 7.6,

1.3 Hz, 2H), 8.30 (d, J = 15.8 Hz, 1H). 13

C NMR (75.5 MHz, CDCl3): 22.7 (CH3), 44.4 (CH2),

50.4 (CH), 55.8 (C), 87.5 (C), 119.6 (CH2), 125.4 (CH), 126.2 (CH), 127.9 (CH), 129.7 (CH),

130.8 (CH), 131.6 (C), 134.2 (CH), 136.1 (C), 138.4 (C). 143.5 (CH). HRMS (EI): m/z calcd

for C18H22INOS: 428.0540 [M + H+]; found: 428.0540.

General procedure for the deprotection and Boc protection of sulfonamides 2a-c.

Hydrogen chloride (4.0 equiv, 4 M solution in 1,4-dioxane) was added at 0ºC to a solution of

the corresponding sulfinyl amine 2a-c (1.0 equiv) in MeOH (1 M). After 20 minutes the

deprotection was completed and the solution was concentrated to dryness. The residue was

redissolved in CH2Cl2 (0.1 M) and 2 M NaOH was added and extracted three times with

dichloromethane and the combined organic layers were dried over anhydrous Na2SO4. Solvents

were then removed under reduced pressure. The crude material was dissolved in anhydrous 1,4-

dioxane (0.2 M) and treated with K2CO3 (1.1 equiv) and di-tert-butyl dicarbonate (Boc2O) (1.1

equiv) at room temperature until TLC revealed the disappearance of the free amine. The

suspension was then filtered through a short pad of Celite® washing with small portions of ethyl

acetate. Solvents were removed under reduced pressure and the residue was purified by means

of flash chromatography on silica gel (5:1 n-hexane:ethyl acetate) affording carbamates 3a-c.

tert-Butyl (S)-(2,2,2-trifluoro-1-(8-iodonaphthalen-1-yl)ethyl)carbamate (3a)

Compound 3a was synthesized following the general procedure described above

starting from 2a (300 mg, 0.66 mmol) affording 3a as a colorless oil (125 mg, 42 % yield).

[α]25D = –46.3 (c = 1.0 in CHCl3) er (92:8). 1H NMR (300 MHz, CDCl3): 1.46 (s, 9H), 5.58 (br

s, 1H), 7.07 (dd, J = 7.3, 1.1 Hz, 1H), 7.52 (dd, J = 7.8, 0.9 Hz, 1H), 7.70 (m, 1H), 7.83 (m,

2H), 8.38 (dd, J = 7.1, 1.5 Hz, 1H). 19

F NMR (282.4 MHz, CDCl3) δ –72.6 (s). 13

C NMR (75.5

MHz, CDCl3): 28.4 (3xCH3), 49.6 (q, 2JCF= 31.3 Hz, CH), 81.0 (C), 88.0 (C), 123.0 (C), 125.4

(CH), 126.7 (CH), 128.2 (CH), 130.8 (CH), 131.0 (C), 131.5 (C), 131.7 (CH), 136.0 (C), 144.5

(CH), 154.7 (C). HRMS (EI): m/z calcd for C17H17INOF3: 452.0329 [M + H+]; found: 452.0344.

HPLC (Chiralpak AD, 90:10 hexane/iPrOH, 1 mL min-1

, 240 nm) tR(major) = 5.44 min,

tR(minor) = 6.64 min.

Ethyl 3-((S)-(tert-butoxycarbonyl)amino)-3-(8-iodonaphthalen-1-yl)propanoate (3b)

Compound 3b was synthesized following the general procedure described

above starting from 2b (300 mg, 0.64 mmol) affording 3b as a colorless oil (161 mg, 54 %

yield). [α]25D = +18.6 (c = 1.0 in CHCl3) er (99:1). 1H NMR (300 MHz, CDCl3): 1.03 (t, J = 7.1

Hz, 3H), 1.43 (s, 9H), 2.99 (m, 2H), 3.96 (m, 2H), 5.91 (br s, 1 H), 7.02 (dd, J = 7.9, 7.5 Hz,

1H), 7.26 (br s, 1H), 7.44 (m, 1H), 7.71 (d, J = 7.8, 2H), 7.81 (dd, J = 8.1, 1.1, 1H), 8.31 (dd, J

= 7.4, 1.3, 1H). 13

C NMR (75.5 MHz, CDCl3): 14.1 (CH3), 21.6 (3 x CH3), 28.5 (CH), 42.0

(CH2), 60.6 (CH2), 79.7 (C), 125.5 (CH), 126.0 (CH), 126.3 (CH), 129.9 (C), 130.7 (CH), 131.3

(CH), 136.3 (C), 143.5 (CH), 155.0 (C), 171.0 (C). HRMS (EI): m/z calcd for C20H24INO4:

470.0823 [M + H+]; found: 470.0813.

tert-Butyl (S)-(1-(8-iodonaphthalen-1-yl)but-3-en-1-yl)carbamate (3c)

Compound 3c was synthesized following the general procedure described

above starting from 2c (300 mg, 0.7 mmol) affording 3c as a colorless oil (166 mg, 56 % yield).

[α]25D = +15.9 (c = 1.0 in CHCl3) er (98:2). 1H NMR (300 MHz, CDCl3): 1.44 (s, 9H), 2.35 (m,

1H), 2.83 (m, 1H), 5.02 (m, 1H) 5.15 (m, 2H), 5.77 (br s, 1H), 7.03 (dd, J = 7.42, 0.75 Hz, 1H),

7.46 (dd, J = 7.8, 0.7 Hz, 1H), 7.65 (m, 1H), 7.72 (dd, J = 8.0, 1.4 Hz, 1H), 7.83 (dd, J = 8.0,

1.3 Hz, 2H), 8.32 (dd, J = 7.4, 1.4 Hz, 1H). 13

C NMR (75.5 MHz, CDCl3): 21.7 (3xCH3), 28.5

(CH), 42.9 (CH2), 56.3 (C), 79.7 (C), 118.5 (CH2), 125.3 (CH), 125.6 (2xC), 126.2 (CH), 129.5

(CH), 130.7 (CH), 131.5 (C), 133.9 (CH), 143.4 (CH), 155.3 (C). HRMS (EI): m/z calcd for

C19H22INO2: 424.0768 [M + H*]; found: 424.0763.

General procedure for the aminocarbonylation of carbamates 3a-c.

CO was bubbled for 10 minutes into a suspension of the corresponding carbamate 3, Pd(PPh3)4

(10 mol%) and Et3N (4 equiv) in toluene (0.1 M). Then, the reaction mixture was heated at 90

ºC under an atmosphere of CO until TLC revealed the disappearance of the starting material.

The reaction mixture was filtered through a short pad of Celite®, concentrated under reduced

pressure and purified by means of column chromatography on silica gel using mixtures of n-

hexane: ethyl acetate as eluent.

tert-Butyl (S)-1-oxo-3-(trifluoromethyl)-1H-benzo[de]isoquinoline-2(3H)-carboxylate (4a)


starting from 3a (100 mg, 0.22 mmol) affording 4a as a yellowish oil (66 mg, 85 % yield).

[α]25D = –56.5 (c = 1.0 in CHCl3) er (92:8). 1H NMR (300 MHz, CDCl3): 1.61 (s, 9H), 6.34 (dd,

J = 14.5, 7.2 Hz, 1 H), 7.64 (m, 3H), 7.96 (dd, J = 7.9, 1.5 Hz, 1H), 8.09 (dd, J = 8.1, 1.1 Hz,

1H), 8.51 (dd, J = 7.4, 1.3 Hz, 1H). 19F NMR (282.4 MHz. CDCl3) δ –76.0 (d, J = 8.2 Hz). 13C

NMR (75.5 MHz, CDCl3): 28.1 (3xCH3), 58.6 (q, 2JCF = 32.4 Hz, CH), 84.7 (C), 122.4 (C),

124.93 (CH), 126.2 (CH), 126.3 (CH), 126.7 (CH), 127.3 (CH), 128.1 (C), 128.7 (CH), 129.1

(CH), 129.4 (CH), 131.3 (C), 132.3 (CH), 133.5 (CH), 146.5 (C), 152.0 (C), 162.5 (C). HRMS

(EI): m/z calcd for C18H16F3NO3: 296.0529 [M - tBu + H+]; found: 296.0536.

HPLC (Chiralpak IC, 95:5 hexane/iPrOH, 1 mL min-1

, 240 nm) tR(major) = 8.92 min,


tert-Butyl (S)-1-(2-ethoxy-2-oxoethyl)-3-oxo-1H-benzo[de]isoquinoline-2(3H)-carboxylate

(4b)


above starting from 3b (100 mg, 0.21 mmol) affording 4b as a yellowish oil (58 mg, 74 %

yield). [α]25

D = +86.5 (c = 1.0 in CHCl3) er (99:1). 1H NMR (300 MHz, CDCl3): 1.10 (t, J = 7.2

Hz, 3 H), 1.61 (s, 9H), 2.73 (dd, J = 14.8, 8.4 Hz, 1H), 3.03 (dd, J = 14.8, 4.1 Hz, 1H), 3.98 (q,

J = 7.4 Hz, 2H), 6.01 (dd, J = 8.4, 4.2 Hz, 1 H), 7.38 (m, 1H), 7.51 (m, 2H), 7.65 (dd, J = 7.2,

0.9 Hz, 1H), 7.85 (dd, J = 6.8, 3.0 Hz, 1H), 8.08 (dd, J = 8.5, 1.1 Hz, 1H), 8.48 (dd, J = 7.3, 1.4

Hz, 1H). 13

C NMR (75.5 MHz, CDCl3): 14.1 (CH3), 28.3 (3xCH3), 44.5 (CH2), 56.0 (CH), 60.9

(CH2), 83.8 (C), 124.4 (CH), 125.3 (C), 126.4 (CH), 126.5 (CH), 127.4 (CH), 127.5 (CH), 127.8

(CH), 128.7 (CH), 130.4 (CH), 131.4 (C), 132.7 (C), 133.5 (CH), 135.3 (CH), 135.4 (CH),

153.0 (C), 163.8 (C), 169.9 (C). HRMS (EI): m/z calcd for C21H23NO5: 270.1125 [M - Boc +

H+]; found: 270.1125.

HPLC (Chiralpak ODH, 98:2 hexane/iPrOH, 1 mL min-1

, 240 nm) tR(major) = 17.25 min,


tert-Butyl (S)-1-allyl-3-oxo-1H-benzo[de]isoquinoline-2(3H)-carboxylate (4c)

Compound 4c was synthesized following the general procedure described

above starting from 3c (100 mg, 0.24 mmol) affording 4c as a yellowish oil (31 mg, 40 %

yield). [α]25

D = +12.5 (c = 1.0 in CHCl3) er (98:2). 1

H NMR (300 MHz, CDCl3): 1.61 (s, 9H),

2.70-2.53 (m, 2H), 4.96–4.83 (m, 2H), 5.49 (d, J = 7.2 Hz, 1 H), 5.64 (dd, J = 7.0, 5.1 Hz, 1 H),

7.42–7.36 (m, 1H), 7.53 (dd, J = 8.3, 7.0 Hz, 1H), 7.64 (dd, J = 8.2, 7.3, 1H), 7.83 (dd, J = 8.3,

1.1, 1H), 8.07 (dd, J = 8.1, 1.1, 1H), 8.46 (dd, J = 7.3, 1.2, 1H). 13C NMR (75.5 MHz, CDCl3):

28.3 (3xCH3), 44.5 (CH2), 59.0 (CH), 83.4 (C), 119.6 (CH2), 124.2 (CH), 125.9 (C), 126.2

(CH), 126.4 (CH), 126.9 (CH), 127.9 (C), 128.5 (CH), 131.9 (C), 132.6 (CH), 133.3 (CH),

153.2 (C), 164.2 (C). HRMS (EI): m/z calcd for C20H21NO3: 324.1591 [M + H+]; found:

324.1594.


, 240 nm) tR(major) = 8.15 min,


Experimental procedure for the deprotection of carbamate 4a.

TFA (10 equiv) was added to a solution of 5 in DCM (0.1 M) at 0 ºC and the reaction mixture

was refluxed until TLC analysis revealed complete consumption of the starting material. The

reaction is then quenched with saturated NaHCO3 (aq) and extracted with DCM (3 times). The

combined organic layers are dried over anhydrous Na2SO4, concentrated under reduced

pressure and the crude material purified by column chromatography on silica gel using mixtures

of hexane and ethyl acetate as eluent.

(S)-3-(trifluoromethyl)-2,3-dihydro-1H-benzo[de]isoquinolin-1-one (IV)

Compound IV was synthesized following the general procedure described above

starting from 4a (100 mg, 0.22 mmol) affording IV as a yellowish oil (70 mg, 88 % yield).

[α]25D = –102.4 (c = 1.0 in CHCl3) er (92:8). 1H NMR (300 MHz, CDCl3): 5.38 (qd, J = 13.9,

5.4 Hz, 1 H), 7.58 (m, 2H), 7.65 (dd, J = 8.4, 7.2 Hz, 1H), 7.95 (dd, J = 7.8, 2.4 Hz, 1H), 8.07

(dd, J = 8.2, 1.1 Hz, 1H), 8.43 (dd, J = 7.1, 0.9 Hz, 1H). 19

F NMR (282.4 MHz. CDCl3) δ –78.5

(d, J = 6.00 Hz). 13

C NMR (75.5 MHz, CDCl3): 57.7 (q, 2JCF = 31.1 Hz, CH), 121.6 (C), 123.2

(C), 125.9 (q, 1JCF = 283.3 Hz, CF3), 126.1 (CH), 126.6 (CH), 126.9 (CH), 127.7 (CH), 129.1

(C), 129.2 (CH), 132.6 (C), 132.9 (CH), 165.0 (C).


, 240 nm) tR(major) = 9.49 min,


General procedure for the Buchwald-Hartwig amination of carbamates 3a,b.

A suspension of the corresponding carbamate 3, Pd(OAc)2 (5 mol%), DPEPhos (10 mol%) and

Cs2CO3 (1.4 equiv) in toluene (0.1 M) was heated at 120 ºC for 4 h under microwave

irradiation. The reaction mixture was filtered through a short pad of Celite®, concentrated under

reduced pressure and purified by means of column chromatography on silica gel using mixtures

of hexane: ethyl acetate (5:1) as eluent.

tert-Butyl (R)-2-(trifluoromethyl)benzo[cd]indole-1(2H)-carboxylate (5a)


starting from 3a (100 mg, 0.22 mmol) affording 5a as a yellow oil (28 mg, 40 % yield). [α]25

D=

-25.5 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 1.56 (s, 9H), 5.98 (br s, 1H), 7.46 (m, 5H),

7.70 (m, 1H). 19F NMR (282.4 MHz, CDCl3) δ –75.1 (s, CF3). 13C NMR (75.5 MHz, CDCl3) δ

28.14 (3 x CH3), 65.17 (CH, q, J = 33.3), 82.94 (C), 109.51 (CH), 119.07 (CH), 119.36 (CH),

123.78 (CF3, q, J = 282.2), 125.31 (CH), 127.95 (CH), 129.12 (CH), 129.81 (C), 130.75 (C),

131.02 (C), 142.40 (C), 151.95 (C). HRMS (EI) calcd for C17H16F3NO2 [M- tBu +H+]:

268.0580, found 268.0587.


, 240 nm) tR(major) = 4.52 min,


tert-Butyl (R)-2-(2-ethoxy-2-oxoethyl)benzo[cd]indole-1(2H)-carboxylate (5b).


above starting from 3b (100 mg, 0.22 mmol) affording 5b as a yellow oil (31 mg, 43 % yield).

[α]25

D= +62.3 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 1.16 (s, 3H), 1.65 (s, 9H), 2.79 (dd,

J = 8.9, 15.5 Hz, 1 H), 3.40 (br s, 1H), 4.14 (q, J = 7.5 Hz, 2H), 5.88 (br s, 1H), 7.40 (m, 5H),

7.65 (dd, J = 1.8, 0.9 Hz, 1H). 13

C NMR (75.5 MHz, CDCl3) δ 14.1 (CH3), 28.4 (3xCH3), 60.6

(CH2), 62.3 (CH), 108.0 (CH), 108.9 (C), 117.2 (CH), 118.1 (CH), 118.9 (C), 123.7 (CH), 128.1

(CH), 129.0 (CH), 131.3 (C), 139.1 (C), 170.5 (C). HRMS (EI) calcd for C20H23NO4 [M+H+]:

342.1700, found 342.1697.


, 240 nm) tR(major) = 6.84 min,


General procedure for the intramolecular Heck reaction of N-tert-Butanesulfinyl Imine 2c.

A suspension of the corresponding N-tert-butanesulfinyl imine 2c, Pd(OAc)2 (10 mol%), PPh3

(15 mol%) and Ag2CO3 (1 equiv) in toluene (0.1 M) was heated at 120 ºC for 1 h under

microwave irradiation. The reaction mixture was filtered through a short pad of Celite®,

concentrated under reduced pressure and purified by means of column chromatography on silica

gel using mixtures of hexane: ethyl acetate (10:1) as eluent.

2-Methyl-N-((R)-3-methylene-2,3-dihydro-1H-phenalen-1-yl)propane-2-sulfinamide (6).

Compound 6 was synthesized following the general procedure described

above starting from 2c (100 mg, 0.24 mmol) affording 6 as a yellow oil (31 mg, 44% yield).

[α]25D= +23.5 (c 1.0, CHCl3).

1H NMR (300 MHz, CDCl3) δ 1.16 (s, 9H), 2.99 (dd, J = 13.1, 6.4

Hz, 1 H), 3.17 (dd, J = 13.1, 4.2 Hz, 1H), 3.62 (d, J = 9.4 Hz, 1H), 4.86 (m, 1H), 5.31 (d, J = 1.3

Hz, 1H), 5.74 (s, 1H), 7.51 (m, 3H), 7.73 (dd, J = 7.4, 1.4 Hz, 1H), 7.81 (ddd, J = 7.3, 5.4, 1.2

Hz, 2H). 13

C NMR (75.5 MHz, CDCl3) δ 22.8 (3xCH3), 41.2 (CH2), 56.4 (C), 56.8 (CH), 113.3

(CH2), 121.4 (CH), 125.0 (CH), 125.8 (CH), 126.0 (CH), 128.0 (CH), 128.3 (CH), 133.5 (C),

133.7 (C), 135.7 (C), 140.3 (C). HRMS (EI) calcd for C18H21NOS [M+H+]: 299.1098, found

299.1100.

tert-Butyl (S)-(3-methylene-2,3-dihydro-1H-phenalen-1-yl)carbamate (6’).

Compound 6’ was synthesized following the general procedure described

above starting from 3c (100 mg, 0.24 mmol) affording 6’ as a yellow oil (23 mg, 33% yield). (c

1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 2.82 (dd, J = 13.2, 5.8 Hz, 1 H), 2.95

(m, 1H), 4.84 (d, J = 9.0 Hz, 1H), 5.25 (m, 2H), 5.72 (s, 1H), 7.48 (m, 2H), 7.60 (m, 1H), 7.73

(dd, J = 7.3, 1.4 Hz, 1H), 7.80 (ddd, J = 10.9, 8.2, 1.2 Hz, 2H). 13

C NMR (75.5 MHz, CDCl3) δ

28.6 (3xCH3), 38.9 (CH2), 50.1 (CH), 79.6 (C), 100.1 (C), 112.6 (CH2), 121.4 (CH), 125.1

(CH), 125.9 (CH), 126.0 (CH), 127.8 (CH), 128.4 (CH), 133.4 (C), 133.7 (C), 135.7 (C), 140.8

(C), 155.3 (C). HRMS (EI) calcd for C19H21NO2 [M++H]: 296.1281, found 296.1287.

Experimental procedure for the Suzuki coupling.

To a solution of 1 and potassium vinyltrifluoroborate (0.5 mmol, 1 equiv) in a 9:1 toluene/water

mixture (5ml, 0.1M) in a microwave vial, Pd(dba)2 (0.025 mmol, 5 mol%), phosphine (0.025

mmol, 5 mol%) and K3PO4 (1.5 mmol, 3 equiv) were added. The solution was heated at 100ºC

in a microwave oven for 4 hours. After this time the reaction mixture was quenched with

saturated NH4Cl aq. And extracted three times with AcOEt. The combined organic layers were

dried over anhydrous Na2SO4. Solvents were removed under reduced pressure and the residue

was purified by means of flash chromatography on silica gel.

8-Vinyl-1-naphthaldehyde (7).

Compound 7 was synthesized following the general procedure described above

starting from 1 (500 mg, 1.77 mmol) affording 7 as a colorless oil (161 mg, 50 % yield). 1H

NMR (300 MHz, CDCl3) δ 5.34 (dd, J = 10.8, 1.4 Hz, 1H), 5.66 (dd, J = 17.1, 1.3 Hz, 1H), 7.11

(ddd, J = 17.1, 10.7, 0.7 Hz, 1H), 7.44 (m, 2H), 7.56 (m, 1H), 7.75 (dd, J = 18.1, 1.3 Hz, 1H),

7.92 (m, 2H), 10.77 (d, J = 0.7 Hz, 1H). 13

C NMR (75.5 MHz, CDCl3) δ 117.1 (CH2), 125.3

(CH), 126.5 (CH), 128.3 (CH), 129.0 (CH), 129.2 (CH), 129.8 (C), 134.4 (C), 134.6 (CH),

135.0 (C), 135.7 (C), 139.0 (CH), 193.4 (C). HRMS (EI) calcd for C13H10O [M+-H]: 181.0648,

found 181.0639.

Experimental procedure for the one-pot condensation/allylation/RCM sequence.

A solution of the corresponding aldehyde (0.5 mmol, 1.0 equiv) and Ti(OEt)4

(2.5 mmol, 4.0 equiv) in dichloromethane (5 ml, 0.1 M) was stirred for 5 minutes at

room temperature. To the resulting solution (R)-N-(tert-butanesulfinyl)amine (0.6

mmol, 1.2 equiv) was added and the mixture was stirred at room temperature for 12

hours. After this time, saturated aqueous NaHCO3 was added until white titanium salts

precipitated. The suspension was filtered through a short pad of Celite® and washed

with small portions of dichloromethane. The filtrate was extracted with ethyl acetate

and the combined organic layers were washed with brine, dried over anhydrous Na2SO4

and concentrated under vacuum. The crude product was used in the next step without

purification.

Subsequently, a 1M solution of allylzinc bromide in THF was prepared by

stirring allyl bromide (0.19 mL, 2.25 mmol, 1.0 equiv) and activated Zn (0.5 g, 7.6

mmol, 3.6 equiv) in anhydrous THF (2.25 ml, 1M) at 55 ºC. 1.1 equiv (0.33 mmol, 0.33

mL) of this freshly prepared solution were added to the residue obtained from the

previous step dissolved in THF (3 ml, 0.1 M) at -40 ºC. After stirring for 30 minutes

(until TLC revealed the disappearance of the starting material) at -40 ºC the reaction

mixture was quenched with saturated NH4Cl aquous and extracted three times with

AcOEt, dried over anhydrous Na2SO4 and concentrated under vacuum.

Finally, to a solution of the corresponding allylated compound in DCM (2 ml,

0.1M) 2nd

generation Grubbs catalyst (2 mol %) was added and the mixture was stirred

at room temperature for 12 hours. 2nd

generation Grubbs catalyst (2 mol %) was added

again and stirred at room temperature for a further 10 hours. Once again, a third portion

of 2nd

generation Grubbs catalyst (2 mol %) was added followed by 6 extra hours

stirring. After that time, the reaction mixture was concentrated under vacuum and

purified by means of flash chromatography on silica gel employing mixtures of n-

hexane: ethyl acetate as eluents.

N-(7,8-Dihydrocyclohepta[de]naphthalen-7-yl)-2-methylpropane-2-sulfinamide (8).

Compound 8 was synthesized following the general procedure described

above starting from 7 (80 mg, 0.28 mmol) affording as a brown oil (25 mg, 30 % yield). [α]25

D=

+9 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3) δ 0.93 (s, 9H), 2.95 (m, 1H), 3.11 (m, 1H), 4.07

(d, J = 7.8 Hz, 1H), 5.00 (m, 1H), 5.96 (dddd, J = 11.6, 8.2, 3.4, 1.1 Hz, 1H), 6.84 (dd, J = 11.9,

2.9 Hz, 1H), 7.43 (m, 4H), 7.80 (m, 2H). 13C NMR (75.5 MHz, CDCl3) δ 22.3 (3xCH3), 35.6

(CH2), 55.6 (C), 61.8 (CH), 125.4 (CH), 126.3 (CH), 128.4 (CH), 129.2 (C), 129.4 (CH), 129.6

(CH), 131.8 (CH), 133.9 (C), 134.5 (CH), 135.7 (C), 139.6 (C). HRMS (EI) calcd for

C18H21NOS [M+H+]: 300.1417, found 300.1417.

General procedure for the Sonogashira cross-coupling reaction.

To a solution of the corresponding compound 2a-c (1 equiv) and PdCl2(PPh3)2 (0.05 equiv) in

THF:Et3N (1:10) the corresponding acetylene (1.2 equiv) was added and the mixture was stirred

for 10 min at room temperature. After that time, CuI (0.1 equiv) was added in one portion into

the reaction mixture, and the resulting brown suspension was then stirred at 65 ºC for 2 h under

microwave irradiation. The reaction mixture was then diluted with diethyl ether and the

resulting dark solution was filtered through a pad of silica gel. The filtrate was concentrated

under vacuum and purified via flash column chromatography on silica employing mixtures of n-

hexane: ethyl acetate (3:1) as the eluent to afford compounds 10aa-10cc.

Ethyl-(RS,3S)-3-((tert-butylsulfinyl)amino)-3-(8-(phenylethynyl)naphthalen-1-yl)propanoate

(10ba).

Compound 10ba was synthesized following the general procedure described

above starting from 2b (300 mg, 0.64 mmol) affording 10ba as a yellow-green oil (241 mg, 85

% yield). [α]25D = –27.3 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 0.98 (t, J = 7.3 Hz,

3H), 1.27 (s, 9H), 3.05 (dd, J = 15.9, 7.4 Hz, 1H), 3.23 (dd, J = 16.0, 4.8 Hz, 1H), 3.83 (m, 2H),

5.36 (d, J = 5.4 Hz, 1H), 7.42 (m, 5H), 7.70 (m, 2H), 7.80 (ddd, J = 4.8, 3.3, 1.4 Hz, 2H), 7.87

(m, 2H). 13


(C), 60.6 (CH2), 91.2 (C), 94.3 (C), 118.2 (C), 123.1 (C), 124.8 (CH), 125.5 (CH), 126.4 (CH),

128.4 (CH), 128.5 (2xCH), 129.5 (CH), 130.6 (CH), 131.5 (2xCH), 134.8 (C), 135.6 (2xC),

138.5 (CH), 171.9 (C). HRMS (EI): m/z calcd for C27H29NO3S: 448.1946 [M+ + 1]; found:

448.1941.

2-Methyl-N-((RS,S)-1-(8-(phenylethynyl)naphthalen-1-yl)but-3-en-1-yl)propane-2-

sulfinamide (10ca).

Compound 10ca was synthesized following the general procedure described

above starting from 2c (300 mg, 0.71 mmol) affording 10ca as a yellow-green oil (239 mg, 83

% yield). [α]25D = –23.4 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 1.25 (s, 9H), 2.62 (m,

1H), 3.02 (m, 1H), 3.93 (d, J = 3.8 Hz, 1H), 5.17 (m, 2H), 5.73 (dddd, J = 17.8, 14.3, 7.9, 6.4

Hz, 1H), 7.07 (dt, J = 8.1, 4.1 Hz, 1H), 7.42 (m, 5H), 7.72 (m, 2H), 7.79 (m, 2H), 7.87 (m, 2H).

13C NMR (75.5 MHz, CDCl3): 22.7 (3xCH3), 43.9 (CH2), 52.3 (CH), 55.8 (C), 91.4 (C), 94.3

(C), 118.4 (C), 119.5 (CH2), 123.3 (C), 124.7 (CH), 125.4 (CH), 126.2 (CH), 128.4 (CH), 128.5

(CH), 129.0 (CH), 129.8 (C), 130.5 (CH), 131.4 (2xCH), 134.3 (CH), 134.8 (C), 135.5 (CH),

139.9 (C). HRMS (EI): m/z calcd for C26H27NOS: 402.1886 [M + H+]; found: 402.1878.

2-Methyl-N-((S)-2,2,2-trifluoro-1-(8-((2-methoxyphenyl)ethynyl)naphthalen-1-

yl)ethyl)propane-2-sulfinamide (10ab).

Compound 10ab was synthesized following the general procedure

described above starting from 2a (300 mg, 0.66 mmol) affording 10ab as a yellow-green oil (66

mg, 22 % yield). [α]25

D = –1.07 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.07 (s, 9H),

3.96 (s, 3H), 4.59 (d, J = 7.2 Hz, 1H), 6.96 (dd, J = 8.4, 1.1 Hz, 1H), 7.01 (dd, J = 7.5, 1.0 Hz,

1H), 7.35 (m, 1H), 7.49 (m, 2H), 7.61 (m, 1H), 7.85 (m, 4H), 7.95 (dd, J = 7.3, 1.5 Hz, 1H). 19

F

NMR (282.4 MHz, CDCl3) δ –71.0 (d, J = 8.1 Hz, CF3). 13

C NMR (75.5 MHz, CDCl3): 22.1

(3xCH3), 55.2 (q, 2JCF = 29.8 Hz, CH), 55.4 (CH3), 56.5 (C), 92.1 (C), 94.6 (C), 110.6 (CH),

112.2 (C), 118.6 (C), 120.7 (CH), 123.7 (CF3), 125.2 (CH), 125.3 (CH), 127.4 (CH), 129.9 (C),

130.1 (CH), 130.6 (CH), 131.1 (CH), 133.4 (CH), 134.8 (C), 136.4 (CH), 159.8 (C). HRMS

(EI): m/z calcd for C25H24F3NO2S: 460.1553 [M + H+]; found: 460.1553.

Ethyl (RS,3S)-3-((tert-butylsulfinyl)amino)-3-(8-((2e-methoxyphenyl)ethynyl)naphthalen-1-

yl)propanoate (10bb).

Compound 10bb was synthesized following the general procedure

described above starting from 2b (300 mg, 0.64 mmol) affording 10bb as a yellow-green oil

(168 mg, 55 % yield). [α]25D = –39.1 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 0.94 (t, J

= 7.3 Hz, 3H), 1.26 (s, 9H), 3.05 (dd, J = 15.7, 6.5 Hz, 1H), 3.30 (dd, J = 16.0, 4.5 Hz, 1H),

3.81 (m, 2H), 3.98 (s, 3H), 5.42 (d, J = 5.7 Hz, 1H), 6.92 (dd, J = 8.2, 0.9 Hz, 1H), 6.99 (td, J =

7.5, 1.0 Hz, 1H), 7.32 (ddd, J = 9.2, 7.4, 1.7 Hz, 1H), 7.45 (m, 2H), 7.66 (ddd, J = 7.6, 1.7, 0.4

Hz, 1H), 7.77 (br s, 1H), 7.80 (br s, 1H), 7.84 (dd, J = 8.1, 7.4 Hz, 1H), 7.91 (dd, J = 7.2, 1.5

Hz, 1H). 13


(C), 55.9 (CH3), 60.5 (CH2), 91.0 (C), 95.1 (C), 110.5 (CH), 112.5 (C), 118.6 (C), 120.5 (CH),

124.8 (CH), 125.4 (CH), 126.3 (CH), 129.4 (CH), 129.5 (CH), 129.9 (CH), 130.4 (CH), 133.3

(CH), 134.8 (C), 135.7 (CH), 138.7 (C), 160.3 (C), 172.1 (C). HRMS (EI): m/z calcd for

C28H31NO4S: 478.2047 [M + H+]; found: 478.2043.

N-((RS,S)-1-(8-((2-Methoxyphenyl)ethynyl)naphthalen-1-yl)but-3-en-1-yl)-2-methylpropane-

2-sulfinamide (10cb).

Compound 10cb was synthesized following the general procedure

described above starting from 2c (300 mg, 0.71 mmol) affording 10cb as a yellow-green oil

(267 mg, 88 % yield). [α]25D = –4.1 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 1.22 (s,

9H), 2.65 (m, 1H), 3.06 (m, 1H), 3.90 (d, J = 4.2 Hz, 1H), 3.96 (s, 3H), 5.13 (m, 2H), 5.75

(dddd, J = 17.8, 14.3, 7.8, 6.5 Hz, 1H), 6.93 (dd, J = 8.4, 1.0 Hz, 1H), 7.01 (m, 2H), 7.33 (ddd, J

= 9.2, 7.4, 1.7 Hz, 1H), 7.45 (m, 2H), 7.68 (ddd, J = 7.5, 1.7, 0.4 Hz, 1H), 7.76 (m, 2H), 7.84

(ddd, J = 8.2, 1.5, 0.5 Hz, 1H), 7.91 (m, 1H). 13C NMR (75.5 MHz, CDCl3): 22.7 (3xCH3), 43.9

(CH2), 52.5 (CH3), 55.8 (C), 91.0 (C), 95.3 (C), 110.6 (CH), 112.6 (CH), 118.8 (C), 119.1

(CH2), 120.7 (C), 124.7 (CH), 125.3 (CH), 126.2 (CH), 129.0 (CH), 129.8 (CH), 129.9 (C),

130.3 (CH), 133.3 (CH), 134.6 (CH), 134.8 (C), 135.7 (CH), 139.9 (C), 160.1 (C). HRMS (EI):

m/z calcd for C27H29NO2S: 432.1996 [M + H+]; found: 432.1992.

Ethyl (RS,3S)-3-((tert-butylsulfinyl)amino)-3-(8-((4-

(trifluoromethyl)phenyl)ethynyl)naphthalen-1-yl)propanoate (10bc).

Compound 10bc was synthesized following the general procedure described

above starting from 2b (300 mg, 0.64 mmol) affording 10bc as a yellow-green oil (141 mg, 43

% yield). [α]25

D = +7.4 (c = 1.0 in CHCl3). 1

H NMR (300 MHz, CDCl3): 0.99 (t, J = 7.1 Hz,


5.32 (d, J = 5.0 Hz, 1H), 7.48 (m, 2H), 7.67 (m, 2H), 7.83 (m, 4H), 7.90 (m 2H). 19

F NMR

(282.4 MHz, CDCl3) δ –62.8 (s, CF3). 13C NMR (75.5 MHz, CDCl3): 13.8 (CH3), 22.7 (3xCH3),

42.4 (CH2), 51.1 (CH), 55.8 (C), 60.7 (CH2), 92.9 (C), 93.5 (C), 117.4 (C), 124.8 (CH), 125.4

(CH), 125.5 (CH), 125.6 (CH), 126.7 (CH), 127.0 (CH). 128.0 (CF3), 128.2 (C), 129.6 (CH),

129.8 (C), 131.3 (CH), 131.7 (CH), 132.2 (C), 134.9 (C), 136.0 (CH), 138.4 (C), 171.8 (C).

HRMS (EI): m/z calcd for C28H28F3NO3S: 516.1701 [M + H+]; found: 516.1707.

2-Methyl-N-((RS,S)-1-(8-((4-(trifluoromethyl)phenyl)ethynyl)naphthalen-1-yl)but-3-en-1-

yl)propane-2-sulfinamide (10cc).

Compound 10cc was synthesized following the general procedure described

above starting from 2c (300 mg, 0.71 mmol) affording 10cc as a yellow-green oil (221 mg, 67

% yield). [α]25

D = –54.5 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.26 (s, 9H), 2.58 (m,

1H), 2.95 (m, 1H), 3.92 (d, J = 3.4 Hz, 1H), 5.17 (m, 2H), 5.68 (dddd, J = 17.9, 14.3, 7.8, 6.4

Hz, 1H), 7.04 (dt, J = 8.0, 4.0 Hz, 1H), 7.48 (m, 2H), 7.68 (m, 2H), 7.85 (m, 6H). 9F NMR

(282.4 MHz, CDCl3) δ - 62.8 (d, J = 7.2 Hz). 13C NMR (75.5 MHz, CDCl3): 22.7 (3xCH3),

44.0 (CH2), 52.1 (CH), 55.8 (C), 92.9 (C), 93.7 (C), 117.6 (C), 119.8 (CH2), 122.2 (CH), 124.7

(CH), 125.4 (CH), 125.5 (CH), 125.6 (CH), 125.8 (q, 1JCF = 271.6 Hz, CF3), 126.5 (CH), 127.1

(C), 129.1 (CH), 129.8 (C), 130.2 (C), 131.2 (CH), 131.7 (CH), 134.1 (CH), 134.8 (C), 135.9

(CH), 139.9 (C). HRMS (EI): m/z calcd for C27H26F3NOS: 470.1760 [M + H+]; found:

470.1769.

General procedure for the removal of the tert-butanesulfinyl group/N-Boc-protection

reaction to obtain carbamates 11aa-11cc.

Hydrogen chloride (4.0 equiv, 4M solution in 1,4-dioxane) was added at room

temperature to a solution of the corresponding sulfinyl amine 10aa-10cc (1.0 equiv) in MeOH

(1 M). After 20 minutes the deprotection was complete and the solution was concentrated to

dryness. The residue was redissolved in CH2Cl2 (0.1 M) and 2M NaOH was added and

extracted three times with dichloromethane and the combined organic layers were dried over

anhydrous Na2SO4. Solvents were removed under reduced pressure and the resulting crude was

dissolved in anhydrous 1,4-dioxane (0.2 M) and treated with K2CO3 (1.1 equiv) and di-tert-

butyl dicarbonate (Boc2O) (1.1 equiv) at room temperature until TLC revealed the

disappearance of the free amine. The suspension was then filtered through a short pad of Celite

washing with small portions of ethyl acetate. Solvents were removed under reduced pressure

and the residue was purified by means of flash chromatography on silica gel (10:1

nhexane:ethyl acetate) to afford carbamates 11aa-11cc.

tert-Butyl (S)-3-(8-(1-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)naphthalen-1-

yl)propiolate (11ba).


above starting from 10ba (100 mg, 0.22 mmol) affording 11ba as a yellow oil (67 mg, 68 %

yield). [α]25D = +56.4 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 0.97 (t, J = 7.2 Hz, 3H)

1.45 (s, 9H), 3.05 (m, 2H), 3.88 (m, 2H), 6.19 (br s, 1H), 7.42 (m, 6H), 7.68 (m, 2H), 7.77 (dd, J

= 4.8, 1.4 Hz, 1H), 7.86 (m, 2H). 13C NMR (75.5 MHz, CDCl3): 13.8 (3xCH3), 21.5 (CH3), 28.3

(CH), 41.2 (CH2), 60.4 (CH2), 79.3 (C), 91.3 (C), 93.9 (C), 118.3 (C), 123.5 (C), 124.7 (2xCH),

124.9 (C), 125.5 (CH), 128.3 (3xCH), 129.1 (CH), 129.5 (C), 130.5 (CH), 131.4 (CH), 134.9

(C), 135.3 (2xCH), 154.9 (C), 171.5 (C). HRMS (EI): m/z calcd for C27H29NO3S: 466.1989 [M

+ Na+]; found: 466.2009.

tert-Butyl (S)-(1-(8-(phenylethynyl)naphthalen-1-yl)but-3-en-1-yl)carbamate (11ca).


above starting from 10ca (100 mg, 0.25 mmol) affording 11ca as a yellow oil (69 mg, 70 %

yield). [α]25D = –23.4 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 1.44 (s, 9H), 2.55 (br s,

1H), 2.80 (br s, 1H), 5.07 (m, 2H), 5.67 (ddd, J = 17.1, 10.1, 7.1 Hz, 1H), 7.15 (dt, J = 7.4, 4.5

Hz, 1H), 7.43 (m, 5H), 7.62 (m, 3H), 7.77 (dd, J = 8.6, 1.6 Hz, 1H), 7.86 (m, 2H). 13C NMR

(75.5 MHz, CDCl3): 28.4 (3xCH3), 42.3 (CH2), 49.9 (CH), 79.4 (C), 91.7 (C), 93.8 (C), 118.5

(CH2), 123.6 (C), 124.2 (CH), 124.6 (3xCH), 125.5 (CH), 128.3 (CH), 128.4 (2xCH), 128.7 (C),

129.7 (C), 130.5 (2xCH), 131.4 (CH), 133.9 (C), 134.9 (C), 135.2 (CH), 155.1 (C). HRMS (EI):

m/z calcd for C27H27NO2: 398.2116 [M + H+]; found: 398.2115.

tert-Butyl (S)-(2,2,2-trifluoro-1-(8-((2-methoxyphenyl)ethynyl)naphthalen-1-

yl)ethyl)carbamate (11ab).


described above starting from 10ab (100 mg, 0.22 mmol) affording 11ab as a yellow oil (37

mg, 37% yield). [α]25


3.93 (s, 3H), 5.54 (br s, 1H), 6.96 (m, 2H), 7.33 (m, 1H), 7.47 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H),

7.65 (m, 1H), 7.87 (m, 2H), 7.95 (dd, J = 7.2, 1.4 Hz, 1H), 8.37 (m, 1H). 19

F NMR (282.4 MHz,

CDCl3) δ –73.7 (d, J = 7.2 Hz, CF3).13

C NMR (75.5 MHz, CDCl3): 28.1 (3xCH3), 29.7 (CH),

55.6 (CH3), 80.5 (C), 92.7 (C), 94.4 (C), 110.5 (2xCH), 112.6 (C), 119.2 (C), 120.4 (2xCH),

125.1 (CH), 125.3 (CH), 126.9 (CF3), 129.9 (CH), 130.2 (CH), 130.5 (C), 130.8 (CH), 133.3

(C), 134.6 (CH), 136.2 (C), 154.3 (C), 160.3 (C). HRMS (EI): m/z calcd for C26H24F3NO3:

456.1792 [M + H+]; found: 456.1781.

Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(8-((2-methoxyphenyl)ethynyl)naphthalen-1-

yl)propanoate (11bb).

Compound 11bb as synthesized following the general procedure

described above starting from 10bb (100 mg, 0.21 mmol) affording 11bb as a yellow oil (63

mg, 71 % yield). [α]25D = +34.4 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 0.95 (t, J = 7.1

Hz, 3H), 1.43 (s, 9H), 3.10 (m, 2H), 3.86 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 6.54 (br s, 1H), 6.96

(m, 2H), 7.32 (m, 1H), 7.44 (m, 2H), 7.61 (m, 1H), 7.70 (dd, J = 7.6, 1.7 Hz, 1H), 7.76 (dd, J =

8.3, 1.5 Hz, 1H), 7.83 (dd, J = 8.2, 1.6 Hz, 1H), 7.89 (dd, J = 7.3, 1.7 Hz, 1H). 13

C NMR (75.5

MHz, CDCl3): 13.8 (3xCH3), 28.4 (CH3), 40.8 (CH2), 47.7 (CH), 55.6 (CH), 60.3 (CH2), 79.1

(C), 90.4 (C), 95.3 (C), 110.5 (CH), 112.9 (C), 118.7 (C), 120.5 (CH), 124.6 (CH), 124.9 (CH),

125.5 (CH), 129.0 (CH), 129.7 (CH), 130.4 (CH), 133.3 (CH), 134.9 (C), 135.4 (CH), 138.8

(C), 154.8 (C), 160.2 (C), 172.1 (C). HRMS (EI): m/z calcd for C29H31NO5: 474.2283 [M+ + H];

found: 474.2275.

tert-Butyl (1-(8-((2-methoxyphenyl)ethynyl)naphthalen-1-yl)but-3-en-1-yl)carbamate (11cb).


described above starting from 10cb (100 mg, 0.23 mmol) affording 11cb as a yellow oil (67 mg,

68 % yield). [α]25D = +40.6 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 1.53 (s, 9H), 3.92

(s, 3H), 5.07 (m, 2H), 5.68 (dd, J = 17.2, 6.9 Hz, 1H), 6.96 (m, 2H), 7.11 (s, 1H), 7.33 (m, 1H),

7.41 (m, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 6.5 Hz, 1H), 7.75 (dd, J = 7.9, 0.9 Hz, 1H),

7.84 (d, J = 8.1 Hz, 1H), 7.88 (dd, J = 7.2, 1.4 Hz, 1H). 13

C NMR (75.5 MHz, CDCl3): 27.6

(CH3), 28.6 (CH3), 42.0 (CH2), 50.0 (CH), 55.7 (CH3), 79.2 (C), 90.6 (C), 95.8 (C), 110.7

(2xCH), 120.7 (2xCH), 124.5 (C), 124.7 (CH), 125.6 (2xCH), 128.7 (C), 129.9 (CH), 130.5

(2xCH), 133.5 (C), 134.8 (C), 135.5 (C), 160.3 (C). HRMS (EI): m/z calcd for C28H29NO3:

428.2221 [M + H+]; found: 428.2220.

Ethyl (S)-3-((tert-butoxycarbonyl)amino)-3-(8-((4-(trifluoromethyl)phenyl)ethynyl)

naphthalen-1-yl)propanoate (11bc).

Compound 11bc was synthesized following the general procedure described

above starting from 10bc (100 mg, 0.19 mmol) affording 11bc as a yellow oil (57 mg 57 %

yield). [α]25D = +46.8 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 0.97 (t, J = 7.1 Hz, 3H),

1.53 (s, 9H), 2.99 (d, J = 6.3 Hz, 2H), 3.88 (q, J = 7.1 Hz, 2H), 6.04 (br s, 1H), 7.47 (m, 2H),

7.63 (m, 2H), 7.69 (d, J = 7.4 Hz, 1H), 7.80 (m, 3H), 7.88 (br s, 1H), 7.90 (br s, 1H). 19F NMR

(282.4 MHz, CDCl3) δ –62.8 (s, CF3). 13C NMR (75.5 MHz, CDCl3): 14.0 (3xCH3), 27.6 (CH3),

28.5 (CH), 41.4 (CH2), 60.6 (CH2), 78.0 (C), 85.3 (C), 93.7 (C), 124.9 (CH), 125.4 (CH), 125.9

(CH), 127.5 (C), 129.5 (CH), 131.4 (CH), 131.9 (CH), 135.0 (C), 135.9 (CH), 138.8 (C), 155.2

(C), 171.5 (C). HRMS (EI): m/z calcd for C29H28NO4F3: 512.2043 [M + H+]; found: 512.2031

tert-Butyl (1-(8-((4-(trifluoromethyl)phenyl)ethynyl)naphthalen-1-yl)but-3-en-1-yl)

carbamate (11cc).


above starting from 10cc (100 mg, 0.21 mmol) affording 11cc as a yellow oil (59 mg, 60 %

yield). [α]25

D = +32.9 (c = 1.0 in CHCl3). 1

H NMR (300 MHz, CDCl3): 1.26 (s, 9H), 2.51 (m,

1H), 2.77 (m, 1H), 5.06 (m, 3H), 5.63 (dt, J = 24.3, 7.2 Hz, 1H), 7.13 (br s, 1H), 7.48 (m, 1H),

7.64 (m, 2H), 7.78 (dd, J = 7.9, 1.3 Hz, 2H), 7.88 (dt, J = 8.3, 3.1 Hz, 2H). 19

F NMR (282.4

MHz, CDCl3) δ –62.5 (s, CF3). HRMS (EI): m/z calcd for C28H26F3NO2: 466.1998 [M + H+];

found: 466.1990.

General procedure for gold(I)-catalyzed intramolecular hydroamination reaction.

To a solution of the corresponding alkynyl carbamate 11 (1 equiv) and ethanol (5 equiv)

in DCE (0.1 M) was added AuSPhosNTf2 (0.05 equiv) in DCE at 40ºC drop-wise (see

optimization table S1 below, page S29). The resulting solution was stirred at 40ºC until TLC

revealed the disappearance of the starting material. The solvent was then removed under

reduced pressure and the crude mixture was purified by flash chromatography on silica gel

using mixtures of n-hexane:ethyl acetate (3:1) as eluents to afford compounds 12aa-12cc.

tert-Butyl (S,E)-1-benzylidene-3-(2-ethoxy-2-oxoethyl)-1H-benzo[de]isoquinoline-2(3H)-

carboxylate (12ba).


above starting from 11ba (50 mg, 0.11 mmol) affording 12ba as a colorless oil (38 mg, 76%

yield). [α]25

D = +48.3 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.10 (s, 9H), 1.11 (t, J =

7.2 Hz, 3H), 2.66 (dd, J = 15.3, 6.6 Hz, 1H), 2.98 (dd, J = 15.6, 7.8 Hz, 1H), 4.04 (m, 2H), 6.30

(br s, 1H), 7.20 (m, 1H), 7.37 (m, 5H), 7.53 (dd, J = 8.2, 7.3 Hz, 1H), 7.65 (m, 2H), 7.76 (dd, J

= 7.9, 1.8 Hz, 1H), 7.82 (dd, J = 8.4, 1.0 Hz, 1H), 7.90 (dd, J = 7.3, 1.0 Hz, 1H). 13C NMR (75.5

MHz, CDCl3): 13.1 (CH3), 27.9 (3xCH3), 41.3 (CH2), 53.5 (CH), 60.6 (CH2), 80.9 (C), 104.4

(C), 120.7 (CH), 123.1 (CH), 125.3 (CH), 125.7 (CH), 125.8 (CH), 126.2 (C), 127.2 (CH),

127.8 (CH), 128.1 (CH), 128.3 (2xCH), 129.0 (CH), 131.4 (C), 132.3 (C), 133.6 (C), 134.2 (C),

135.6 (C). HRMS (EI): m/z calcd for C28H29NO4: 444.2169 [M + H+]; found: 444.2154


, 240 nm) tR(major) = 11.56 min,


tert-Butyl (S)-(1-(8-((4-(trifluoromethyl)phenyl)ethynyl)naphthalen-1-yl)but-3-en-1-

yl)carbamate (12ca)


above starting from 11ca (50 mg, 0.13 mmol) affording 12ca as a colorless oil (42 mg, 84 %

yield). [α]25D = +82.2 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 1.08 (s, 9H), 2.51 (dd, J

= 14.2, 7.2Hz, 1H), 2.78 (m, 1H), 4.96 (m, 2H), 5.83 (m, 2H), 7.27 (m, 3H), 7.40 (m, 3H), 7.53

(m, 1H), 7.73 (m, 3H), 7.82 (dd, J = 8.3, 1.0 Hz, 1H), 7.92 (dd, J = 7.4, 1.0 Hz, 1H). 13C NMR

(75.5 MHz, CDCl3): 27.9 (3xCH3), 40.8 (CH2), 57.0 (CH), 80.7 (C), 117.8 (CH2), 120.4 (CH),

123.7 (CH), 123.9 (CH), 125.4 (CH), 125.6 (CH), 126.4 (C), 126.7 (CH), 127.6 (2xCH), 128.0

(CH), 128.3 (2xCH), 129.1 (CH), 131.6 (C), 132.6 (C), 133.5 (C), 134.5 (C), 134.8 (CH), 136.1

(C). HRMS (EI): m/z calcd for C27H27NO2: 420.1934 [M + Na+]; found: 420.1936.


, 240 nm) tR(major) = 7.88 min,


tert-Butyl (S,E)-1-(2-methoxybenzylidene)-3-(trifluoromethyl)-1H-benzo[de]isoquinoline-

2(3H)-carboxylate (12ab).


described above starting from 11ab (50 mg, 0.11 mmol) affording 12ab as a colorless oil (48

mg, 96 % yield). [α]25


3.93 (s, 3H), 6.35 (d, J = 8.6 Hz, 1H), 6.96 (m, 2H), 7.29 (m, 1H), 7.53 (m, 2H), 7.58 (m, 1H),

7.68 (br s, 1H), 7.84 (dd, J = 8.4, 1.1 Hz, 1H), 7.89 (m, 1H), 7.94 (m, 1H), 8.08 (dd, J = 7.3, 1.2

Hz, 1H). 19

F NMR (282.4 MHz, CDCl3) δ –71.8 (s, CF3).13

C NMR (75.5 MHz, CDCl3): 27.5

(3xCH3), 29.7 (CH), 55.6 (CH3), 81.9 (C), 110.5 (2xCH), 117.3 (C), 120.8 (C), 121.4 (CH),

124.5 (CF3), 125.2 (C), 125.4 (C), 126.2 (2xCH), 126.7 (C), 127.7 (2xCH), 128.7 (CH), 128.8

(CH), 130.2 (C), 130.6 (CH), 133.3 (C), 157.0 (C). HRMS (EI): m/z calcd for C26H24F3NO3:

456.1785 [M + H+]; found: 456.1781

tert-Butyl (S,E)-1-(2-ethoxy-2-oxoethyl)-3-(2-methoxybenzylidene)-1H-

benzo[de]isoquinoline-2(3H)-carboxylate (12bb).

Compound 12bb was synthesized following the general procedure

described above starting from 11bb (50 mg, 0.11 mmol) affording 12bb as a colorless oil (42

mg, 83 % yield). [α]25

D = -27 (c = 1.0 in CHCl3). 1

H NMR (300 MHz, CDCl3): 1.12 (s, 9H),

1.26 (t, J = 5.1 Hz, 3H), 2.66 (dd, J = 15.6, 7.5 Hz, 1H), 2.99 (dd, J = 15.9, 7.7 Hz, 1H), 3.91 (s,

3H), 4.06 (m, 2H), 6.27 (br s, 1H), 6.93 (m, 2H), 7.24 (m, 1H), 7.40 (m, 2H), 7.53 (dd, J = 8.2,

7.4 Hz, 1H), 7.78 (m, 4H), 7.95 (dd, J = 7.4, 1.1 Hz, 1H). 13C NMR (75.5 MHz, CDCl3): 14.0

(CH3), 27.9 (3xCH3), 41.3 (CH2), 55.6 (CH), 60.6 (CH2), 80.7 (C), 110.6 (2xCH), 120.4 (CH),

125.6 (C), 125.9 (CH), 126.3 (C), 127.1 (CH), 127.8 (2xCH), 128.2 (CH), 128.9 (CH), 131.8

(C), 133.6 (C), 134.3 (C), 153.7 (C), 157.2 (C), 170.5 (C). HRMS (EI): m/z calcd for

C29H31NO5: 474.2286 [M + H+]; found: 474.2275.


, 240 nm) tR(major) = 33.05 min,

tR(minor) = 61,8 min.

tert-Butyl (S,E)-1-allyl-3-(2-methoxybenzylidene)-1H-benzo[de]isoquinoline-2(3H)-

carboxylate (12cb).


described above starting from 11cb (50 mg, 0.12 mmol) affording 12cb as a colorless oil (45

mg, 90 % yield). [α]25

D = +334 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.06 (s, 9H),

2.52 (m, 1H), 2.78 (br s, 1H), 3.91 (s, 3H), 4.96 (m, 2H), 5.78 (br s, 2H), 6.93 (m, 2H), 7.23 (m,

2H), 7.42 (dd, J = 8.3, 7.1 Hz, 1H), 7.52 (dd, J = 8.3, 7.4 Hz, 1H), 7.67 (br s, 1H), 7.74 (dd, J =

8.3, 1.2 Hz, 1H), 7.80 (dd, J = 8.3, 1.0 Hz, 1H), 7.97 (m, 2H). 13C NMR (75.5 MHz, CDCl3):

28.0 (3xCH3), 40.8 (CH2), 55.7 (CH3), 57.1 (CH), 80.6 (C), 110.6 (2xCH), 117.8 (CH2), 120.5

(CH), 120.8 (CH), 123.7 (C), 125.4 (CH), 125.9 (CH), 126.5 (C), 126.8 (CH), 127.8 (CH),

128.7 (CH), 128.8 (2xCH), 132.2 (C), 133.7 (C), 134.7 (C), 135.1 (CH), 154.1(C), 157.2 (C).

HRMS (EI): m/z calcd for C28H29NO3: 428.2220 [M + H+]; found: 428.2219.

HPLC (Chiralpak ODH, 99.5:0.5 hexane/iPrOH, 1 mL min-1

, 240 nm) tR(major) = 34.69 min,


tert-Butyl (S,E)-1-(2-ethoxy-2-oxoethyl)-3-(4-(trifluoromethyl)benzylidene)-1H-

benzo[de]isoquinoline-2(3H)-carboxylate (12bc).

Compound 12bc was synthesized following the general procedure

described above starting from 11bc (50 mg, 0.1 mmol) affording 12bc as a colorless oil (48 mg,

95 % yield). [α]25D = +22.7 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 1.08 (t, J = 7.0 Hz,


6.29 (br s, 1H), 7.29 (br s, 1H), 7.44 (m, 2H), 7.56 (m, 4H), 7.77 (m, 3H), 7.86 (dd, J = 8.3, 1.0

Hz, 1H), 7.92 (dd, J = 7.4, 1.1 Hz, 1H). 19F NMR (282.4 MHz, CDCl3) δ –62.7 (s, CF3). 13C

NMR (75.5 MHz, CDCl3): 13.9 (CH3), 27.9 (3xCH3), 29.7 (CH), 41.3 (CH2), 60.7 (CH2), 81.3

(C), 104.4 (C), 121.2 (C), 123.2 (C), 125.1 (CH), 125.2 (CH), 125.9 (2xCH), 126.2 (C), 127.3

(CH), 128.8 (CH), 129.1 (2xCH), 129.5 (CH), 130.8 (C), 133.6 (CH), 133.9 (CH), 134.8 (C),

139.2 (C), 153.3 (C), 170.4 (C). HRMS (EI): m/z calcd for C29H28F3NO4: 412.1519 [M + H+ -

Boc]; found: 412.1526.


, 240 nm) tR(major) = 12.67 min,


tert-Butyl (E)-1-allyl-3-(4-(trifluoromethyl)benzylidene)-1H-benzo[de]isoquinoline-2(3H)-

carboxylate (12cc).


above starting from 11cc (50 mg, 0.1 mmol) affording 12ba as a colorless oil (45 mg, 90 %

yield). [α]25

D = -18.0 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.56 (s, 9H), 2.51 (br s,

1H), 2.76 (br s, 1H), 5.07 (m, 3H), 5.64 (dd, J = 17.2, 9.2 Hz, 1H), 7.14 (br s, 1H), 7.46 (m,

2H), 7.64 (m, 3H), 7.79 (m, 3H), 7.88 (m, 2H). 19F NMR (282.4 MHz, CDCl3) δ –62.6 (s, CF3).

13C NMR (75.5 MHz, CDCl3): 28.6 (CH3), 29.9 (CH3), 42.5 (CH2), 50.0 (CH), 79.6 (C), 94.2

(CH2), 118.7 (C), 124.6 (C), 124.8 (2xCH), 125.5 (CH), 125.8 (CH), 127.6 (C), 129.0 (C), 129.8

(CH), 131.3 (CH), 131.9 (CH), 135.1 (C), 135.8 (CH), 140.3 (C), 155.3 (C). HRMS (EI): m/z

calcd for C28H26F3NO2: 466.1998 [M + H+]; found: 466.1988.


, 240 nm) tR(major) = 26.29 min,


General procedure for the RCEYM reaction.

In a round-bottom flask, the corresponding enyne (1 mmol, 1 equiv) was dissolved in anhydrous

dichloromethane (0.1 M) under a nitrogen atmosphere. 2nd

generation Hoveyda-Grubbs (H-G II)

catalyst (5 mol%) and 1,7-octadiene (4 equiv) were added (see optimization table S2 below,

page S29). The reaction mixture was heated at 45ºC overnight. The final products were isolated

after purification by silica gel flash chromatography with mixtures of hexane:AcOEt (4:1) of

increasing polarities as eluent.

2-Methyl-N-(10-(1-phenylvinyl)-7,8-dihydrocyclohepta[de]naphthalen-7-yl)propane-2-

sulfinamide (13a).

Compound 13a was synthesized following the general procedure

described above starting from 10ca (100 mg, 0.25 mmol) affording 13a as a brownish oil (90

mg, 90 % yield). [α]25D = +128.9 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 1.12 (s, 9H),

1.68 (br s, 1H), 2.95 (ddd, J = 14.8, 5.0, 1.5 Hz, 1H), 3.06 (ddd, J = 14.8, 8.7, 6.4 Hz, 1H), 5.07

(m, 1H), 5.44 (d, J = 1.5 Hz, 1H), 5.72 (d, J = 1.6 Hz, 1H), 6.39 (m, 1H), 7.15 (m, 3H), 7.28 (d,

J = 7.9 Hz, 1H), 7.34 (m, 2H), 7.44 (dd, J = 8.0, 7.1 Hz, 1H), 7.53 (dd, J = 7.2, 1.7 Hz, 1H),

7.65 (dd, J = 7.5, 1.4 Hz, 1H), 7.73 (dd, J = 8.0, 1.4 Hz, 1H), 7.82 (d, J = 8.0, 1.6 Hz, 1H). 13C

NMR (75.5 MHz, CDCl3): 22.6 (3xCH3), 34.1 (CH2), 55.8 (C), 63.2 (CH), 115.4 (CH2), 124.9

(CH), 125.0 (CH), 126.6 (2xCH), 127.5 (CH), 128.2 (3xCH), 128.3 (CH), 129.1 (C), 130.1

(CH), 130.2 (CH), 131.4 (CH), 133.9 (C), 135.8 (C), 139.7 (C), 140.1 (C), 145.7 (C), 152.0 (C).

HRMS (EI): m/z calcd for C26H27NOS: 402.1889 [M + H+]; found: 402.1886.

2-Methyl-N-(10-(1-(4-(trifluoromethyl)phenyl)vinyl)-7,8-dihydrocyclohepta[de]naphthalen-7-

yl)propane-2-sulfinamide (13b).

Compound 13b was synthesized following the general

procedure described above starting from 10cc (100 mg, 0.21 mmol) affording 13b as a brownish

oil (78 mg, 78 % yield). [α]25

D = -17.3 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.12 (s,

9H), 3.02 (m, 2H), 4.01 (d, J = 8.7 Hz, 1H), 5.07 (m, 1H), 5.55 (d, J = 1.4 Hz, 1H), 5.78 (d, J =

1.3 Hz, 1H), 6.40 (dd, J = 8.3, 5.3 Hz, 1H), 7.30 (t, J = 8.1 Hz, 1H), 7.44 (m, 5H), 7.57 (m, 2H),

7.75 (dd, J = 8.2, 1.4 Hz, 1H), 7.83 (dd, J = 8.2, 1.7 Hz, 1H). 19

F NMR (282.4 MHz, CDCl3) δ –

63.06 (s, CF3). 13C NMR (75.5 MHz, CDCl3): 21.2 (3xCH3), 51.7 (CH2), 60.5 (C), 75.1 (CH),

100.2 (CH2), 113.0 (CH), 122.4 (2xCH), 122.9 (2xCH), 129.1 (C), 129.5 (3xCH), 129.7

(2xCH), 130.8 (C), 139.0 (2xC), 139.5 (C), 145.5 (2xC), 152.4 (C). HRMS (EI): m/z calcd for

C27H26F3NOS: 470.1760 [M+ + 1]; found: 470.1752.

General procedure for the Pauson-Khand reaction.

In a round-bottom flask, the corresponding enyne (1 mmol, 1 equiv) was dissolved in anhydrous

toluene (20 mL) under nitrogen. Co2(CO)8 (1 equiv) was added as a solid, and the mixture was

stirred at room temperature until the complete formation of the cobalt-alkyne complex was

detected by TLC (typically, 15-30 minutes). NMO was added to the reaction and the mixture

was stirred at room temperature overnight. The final products were isolated after purification by

silica gel flash chromatography with AcOEt as eluent.

2-Methyl-N-((10S)-2-oxo-3-phenyl-2,10,11,11a-tetrahydro-1H-naphtho[1,8-ef]azulen-10-

yl)propane-2-sulfinamide (14a)

Compound 14a was synthesized following the general procedure

described above starting from 10ca (100 mg, 0.25 mmol) affording 14a as a yellow oil (65 mg,

61 % yield). [α]25

D = -267.2 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.26 (s, 9H), 2.43

(ddd, J = 12.5, 6.6, 4.3 Hz, 1H), 2.60 (m, 2H), 2.86 (dd, J = 17.8, 6.5 Hz, 1H), 3.12 (dtd, J =

13.1, 6.4, 1,5 Hz, 1H), 3.47 (d, J = 6.3 Hz, 1H), 5.15 (m, 1H), 7.15 (d, J = 1.9 Hz, 1H), 7.22 (m,

4H), 7.36 (m, 2H), 7.46 (t, J = 7.6, 1.0 Hz, 1H), 7.73 (m, 3H). 13C NMR (75.5 MHz, CDCl3):

22.7 (3XCH3), 40.1 (CH), 45.1 (CH2), 46.7 (CH2), 56.4 (C), 56.9 (CH), 123.7 (CH), 125.1

(CH), 125.8 (CH), 127.9 (CH), 128.4 (2xCH), 128.5 (CH), 129.8 (CH), 130.1 (2xCH), 130.3

(C), 130.5 (CH), 131.4 (C), 133.7 (C), 134.6 (C), 137.7 (C), 139.2 (C), 173.1 (C), 206.0 (C).

HRMS (EI): m/z calcd for C27H27NO2S: 430.1835 [M + 1+]; found: 430.1822.

N-((10S)-3-(2-Methoxyphenyl)-2-oxo-2,10,11,11a-tetrahydro-1H-naphtho[1,8-ef]azulen-10-

yl)-2-methylpropane-2-sulfinamide (14b)

Compound 14b was synthesized following the general procedure

described above starting from 10cb (100 mg, 0.23 mmol) affording 14b as a yellow oil (46 mg,

43 % yield). [α]25D = -13.1 (c = 1.0 in CHCl3).

1H NMR (300 MHz, CDCl3): 1.33 (s, 9H), 2.45

(ddd, J = 16.9, 6.7, 4.4 Hz, 1H), 2.59 (d, J = 17.7 Hz, 1H), 2.68 (td, J = 12.2, 9.0 Hz, 1H), 2.90

(dd, J = 17.9, 6.8 Hz, 1H), 3.19 (m, 3H), 5.41 (br s, 1H), 6.75 (br s, 1H), 7.05 (br s, 1H), 7.19

(m, 2H), 7.29 (m, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.76 (m, 3H). 13

C NMR (75.5 MHz, CDCl3):

22.9 (3xCH3), 40.2 (CH), 45.2 (CH2), 47.3 (CH), 55.2 (CH3), 56.4 (CH2), 60.5 (C), 111.4 (CH),

120.8 (C), 123.6 (CH), 125.1 (CH), 125.7 (CH), 126.8 (C), 128.3 (CH), 129.6 (CH), 129.8 (C),

130.2 (CH), 131.6 (CH), 134.5 (CH), 135.3 (C), 139.5 (CH), 156.2 (C), 171.2 (C), 175.6 (C),

206.7 (C). HRMS (EI): m/z calcd for C28H29NO3S: 460.1943 [M + H+]; found: 460.1941.

2-Methyl-N-((10S)-2-oxo-3-(4-(trifluoromethyl)phenyl)-2,10,11,11a-tetrahydro-1H-

naphtho[1,8-ef]azulen-10-yl)propane-2-sulfinamide (14c).

Compound 14c was synthesized following the general

procedure described above starting from 10cc (100 mg, 0.21 mmol) affording 14c as a yellow

oil (52 mg, 49 % yield). [α]25

D = -13.1 (c = 1.0 in CHCl3). 1H NMR (300 MHz, CDCl3): 1.33 (s,

9H), 2.52 (ddd, J = 12.7, 6.4, 4.1 Hz, 1H), 2.69 (m, 2H), 2.96 (dd, J = 18.1, 6.6 Hz, 1H), 3.24

(m, 1H), 3.52 (d, J = 6.1 Hz, 1H), 5.17 (m, 1H), 7.16 (dd, J = 7.3, 1.3 Hz, 1H), 7.25 (m, 2H),

7.55 (m, 4H), 7.82 (m, 3H). 19

F NMR (282.4 MHz, CDCl3) δ –63.1 (s, CF3). 13

C NMR (75.5

MHz, CDCl3): 22.8 (3xCH3), 40.3 (CH), 45.1 (CH2), 46.6 (CH2), 56.4 (CH), 56.7 (C), 123.9

(CH), 125.2 (CH), 125.4 (CH), 126.0 (CH), 128.7 (CH), 129.1 (CH), 129.6 (C), 129.9 (C),

130.1 (CH), 130.4 (2xCH), 131.0 (CH), 133.0 (C), 134.7 (C), 135.1 (C), 136.6 (C), 139.1 (C),

174.9 (C), 205.5 (C). HRMS (EI): m/z calcd for C28H26F3NO2S: 498.1691 [M + H+]; found:

498.1709.

Experimental procedure for the deprotection of 14b

To a solution of 14b in anhydrous MeOH (0.1M), HCl (4M in dioxane, 10 equiv) was added

dropwise at 0 ºC. The reaction mixture was stirred for 15 minutes, concentrated almost to

dryness and diethyl ether was added dropwise. The supernatant was decanted and the thus

obtained solid was washed with ether (2 x 1 mL) and dried in vacuum.

(7S)-7-amino-11-(2-methoxyphenyl)-7,8,8a,9-tetrahydro-10H-naphtho[1,8-ef]azulen-10-one

hydrochloride (XVIII)

Compound XVIII was synthesized following the procedure

described above starting from 14b (46 mg, 0.10 mmol) affording XVIII as a pale yellow solid

(37 mg, 95 % yield). 1H NMR (300 MHz, CDCl3): 2.37 (1 H, ddd, J = 12.9, 5.3, 3.5 Hz), 2.59

(1 H, d, J = 18.1 Hz), 2.81 (1 H, td, J = 12.5, 9.2 Hz), 3.04 (3 H, dd, J = 18.1, 6.6 Hz), 3.43 –

3.37 (2 H, m), 5.23 (1 H, d, J = 9.9), 6.82 (1 H, s), 7.03 (1 H, s), 7.16 (1 H, d, J = 7.0), 7.34 –

7.23 (2 H, m), 7.49 (1 H, d, J = 7.3 Hz), 7.68 – 7.59 (1 H, m), 7.88 (1 H, dd, J = 8.2, 1.1 Hz),

7.96 (1 H, d, J = 8.2 Hz). 13C NMR (75.5 MHz, CDCl3): 40.9 (CH), 43.2 (CH2), 46.3 (CH), 52.9

(CH2), 55.3 (OCH3), 112.4 (CH), 121.8 (CH), 122.2 (CH), 126.7 (CH), 126.8 (CH), 130.6 (CH),

131.0 (CH), 131.6 (CH), 132.7 (C), 135.6 (C), 136.1 (CH), 209.0 (CO).

Table S1. Screening of gold(I)-catalysts, solvent, temperature and catalyst loading for the

intramolecular hydroamination reaction.

Entry [Au] (mol-1) Additive (equiv) Solvent T (ºC) T (min) Yield (%)

1 I (5) EtOH (5) MeCN 30 30 35

2 I (5) EtOH (5) THF 30 30 30

3 I (5) EtOH (5) DCE 30 30 47

4 I (5) EtOH (5) DCE 40 15 76

5 II (5) EtOH (5) DCE 40 15 66

6 III (5) EtOH (5) DCE 40 15 66

Table S2. Screening of catalysts, solvent, temperature and catalyst loading for a RCEYM

reaction.

Entry Catalysts (equiv) Solvent T (ºC) Yield (%)

1 Grubbs I DCM 40 -

2 Grubbs II DCM 40 88

3 H-G II DCM 40 90

4 H-G II Toluene 115 66

Computational analysis: Principal Moment of Inertia (PMI)

General details

Principal Moment of Inertia (PIM) was performed using Molecular Operating

Environment (MOE) software package version 2012.10 from the Chemical Computing

Group. Merck molecular force field 94X (MMFF94x), an all-atom force field

parameterised for small organic molecules with the Generalised Born solvation model,

was used to minimise the energy potential of the library members. A LowModeMD

search was employed for the conformation generation. Detailed settings for

conformational search are listed below.

Rejection Limit 100

RMS Gradient 0.005

Iteration Limit 10000

MM Iteration Limit 500

RMSD Limit 0.15

Energy window 3

Conformation Limit 100

Only the conformer with the lowest energy was retained for principal moment of inertia

(PMI) calculations. Normalized PMI ratios (I1/I3 and I2/I3) of these conformers were

obtained from MOE and then plotted on a triangular graph, with the canonical

coordinates (0,1), (0.5,0.5) and (1,1) representing a perfect rod, disc and sphere

respectively (Figure 1).

Compound collections analysed

A) Collection 1: 19 polycyclic carbo- and heterocyclic compounds from DOS (based

on the deprotected virtual derivatives)

NH2

NH2

O H

MeONH2

F3C

NH2

O H

NH2

O H

F3C

HN

CF3

HN

CO2Et

MeO

HN

CO2Et

CF3

HN

HN

MeO

HN

CO2Et

HN CF3

MeO

HN

NH2

CF3HNO CF3

HNCO2Et

HNO

CO2Et

HNO

NH2

I II III IV V

VI VIIVIII

IX X

XI XII XIII XIV XV

XVI XVII XVIII XIX

Figure S1

Exemplar scaffold deprotection

To confirm the validity of the library computational analysis, we demonstrated

experimentally that N-deprotection reactions were viable. Thus, compounds 4a and 14b

were deprotected achieving I and XVIII uneventfully, see above.

B) Collection 2: 40 high-profile synthetic drugs currently produced by the

pharmaceutical industry

See: (a) Kopp, F.; Stratton, C. F., Akella, L. B.; Tan, D. S. Nature Chem. Biol. 2012, 8, 358. (b)

Bauer, R. A.; Wurst, J. M.; Tan, D. S. Curr. Opin. Chem. Biol. 2010, 14, 308.

Figure S2.

Figure S2 (cont).

C) Collection 3: 60 randomly selected natural products

See: (a) Kopp, F.; Stratton, C. F., Akella, L. B.; Tan, D. S. Nature Chem. Biol. 2012, 8, 358. (b)

Bauer, R. A.; Wurst, J. M.; Tan, D. S. Curr. Opin. Chem. Biol. 2010, 14, 308.

H

O

HO

HO OH

OH

O

N

N

NNH

OO

OH

H

NH2

O

HO

OHHO

HO

O N N

O

O

O

O

OH

OH

OH

O

NHN

O

S

O

O

OHO

O

N

O

S

O

O

NH2

OHO

HN

O

O

HONH2

N

O

OOH

S

NH2

HO

H

H

H

O

OO

OH

O

O

HO

N

OO

O

OH

O

H

H

HO

O

OH

OO

taxol

rapamycin

forskolin

SQ26180

cephamycin Cthienamycin

artemisinin

coformycinarglabin

mizoribine

compactin

H

HH

O

O

O

O spergualin

plaunotol

O

O

OH

H

H

OH

OH

OH

NH2

HN

NH

OHN

ONH2

H2N N

O

O

HOOO

OO

O

OH

O

O

OH

O

HN

HO

HOO

OHO

HOOH

OH

OH

OH

OHHO

HO

HN

O

O

HOO

O

OO

HO

O

O O

OH

H

H

H

H

H

validamycinO

O

avermectin B1a

H

O

NH2

O

O

geldanamy

cin

O

OH

O

OO

O

HN

salicylihalamide A

H

quinine

HN

O

OHO

HOO

N

HO

N

O

Figure S3.

Figure S3 (cont).

Figure S3 (cont).

Table S3 Normalised PMI ratio (npr) values of conformers of the DOS library and

two reference collections with the lowest energy (energy level = 0 kcal/mol)

Collection 1

Compound npr1 npr2 Compound npr1 npr2

I 0,4442 0.6915 XI 0.3597 0.7764

II 0.3783 0.7913 XII 0.3600 0.7393

III 0.5916 0.6883 XIII 0.3329 0.8874

IV 0.3353 0.7525 XIV 0.1756 0.9117

V 0.2287 0.8779 XV 0.4970 0.8918

VI 0.4836 0.5788 XVI 0.3693 0.9415

VII 0.4628 0.6161 XVII 0.4225 0.7900

VIII 0.3281 0.7822 XVIII 0.5578 0.8020

IX 0.2424 0.8261 XIX 0.3108 0.8539

X 0.3012 0.8347

Collection 2


Lipitor 0.3343 0.8427 Topomax 0.3721 0.7907

Nexium 0.2387 0.7858 Toprol 0.0854 0.9449

Prevacid 0.1367 0.9103 Zetia 0.3674 0.8320

Flonase 0.2843 0.9666 Fosamax 0.6565 0.7739

Servent 0.8749 0.9282 Ability 0.4836 0.6354

Singulair 0.3979 0.7155 Levaquin 0.2100 0.8459

Effexor 0.3994 0.7418 Lamictal 0.2412 0.9155

Plavix 0.3507 0.8350 Celebrex 0.3738 0.6824

Zocor 0.3846 0.7750 Benazepril 0.3379 0.9290

Norvasc 0.4396 0.8183 Zyrtec 0.3208 0.8402

Lexapro 0.4172 0.7481 Coreg 0.6401 0.7545

Seroquel 0.2078 0.9130 Valtrex 0.4538 0.8509

Protonix 0.2323 0.8070 Adderall 0.2184 0.9253

Ambien 0.3818 0.6870 Aciphex 0.1239 0.9138

Actos 0.1733 0.8826 Cymbalta 0.3327 0.7663

Zoloft 0.3094 0.9498 Crestor 0.3525 0.8687

Wellbutrin 0.1861 0.9472 Diovan 0.3509 0.9594

Avandia 0.0876 0.9585 Tricor 0.1028 0.9422

Risperdal 0.2654 0.7797 Concerta 0.5477 0.6565

Zyprexa 0.4262 0.6254 Imitrex 0.2068 0.9075

Collection 3


Taxol 0.4444 0.7558 Ginkgolide B 0.4546 0.8718

Actinonin 0.4418 0.7805 Vancomycin 0.5097 0.6634

Discodermolide 0.1283 0.9329 Amphotericin B 0.1342 0.9067

Validamycin 0.2010 0.9501 Radicicol 0.4995 0.8727

Monensin 0.3209 0.8721 Salicylihalamide A 0.1935 0.8944

Calyculin A 0.4042 0.9305 Telomestatin 0.4927 0.5148

Coformycin 0.3093 0.8134 Rifamycin B 0.4922 0.7587

Arglabin 0.3932 0.6626 Apoptolidin 0.1922 0.8755

Mizoribine 0.2479 0.8433 Midecamycin A1 0.3650 0.9474

Forskolon 0.5081 0.7477 Zaragozic acid A 0.5011 0.7235

SQ 26180 0.3285 0.9244 Talaromycin B 0.1546 0.9504

Cephamycin C 0.5613 0.6949 Spongistatin 1 0.4968 0.8135

Avermectin B1a 0.3723 0.8151 Brevetoxin B 0.0410 0.9818

Adriamycin 0.3135 0.7704 Quinine 0.3647 0.8711

Phorbol

myristate

acetate

0.4660 0.7501 Mycobactin S 0.3865 0.9065

Thienamycin 0.3015 0.8545 Duocarmycin A 0.1237 0.9519

Cyclosporin A 0.4809 0.8960 Bleomycin A2 0.3651 0.9343

FK506 0.4472 0.8793 Brefeldin A 0.3068 0.7850

Trapoxin B 0.7165 0.9000 Cytochalasin B 0.4974 0.6762

Vincristine 0.5370 0.9655 Epothilone A 0.3116 0.8340

Colchicine 0.4272 0.8346 Lactacystin 0.3764 0.8347

Trichostatin A 0.2197 0.8615 Calicheamicin γγγγ1 0.1774 0.9247

Fumagillin 0.0865 0.9668 Artemisinin 0.5476 0.6380

Staurosporine 0.4822 0.6733 Compactin 0.3930 0.7646

Erythromycin A 0.4902 0.7797 Lipstatin 0.4059 0.8457

Streptomycin 0.3162 0.9282 Pseudomonic

acid A 0.3896 0.6714

Penicillin G 0.3061 0.9575 Daptomycin 0.5603 0.8611

Sperguallin 0.2793 0.8633 Bestatin 0.3910 0.7358

Rapamycin 0.6347 0.8330 Plaunotol 0.4702 0.6467

Echinocandin B 0.6140 0.8022 Geldanamycin 0.3478 0.7321

Table S4 Chemical structures of conformers of the DOS library and three

reference collections in SMILE

Collection 1

I FC(F)(F)[C@H]1NC(=O)c2c3c1cccc3ccc2

II O=C1N[C@H](c2c3c1cccc3ccc2)CC(OCC)=O

III O=C1N[C@H](c2c3c1cccc3ccc2)CC=C

IV FC(F)(F)[C@H]1Nc2c3c1cccc3ccc2

V O(C(=O)C[C@@H]1Nc2c3c1cccc3ccc2)CC

VI N[C@H]1CC(c2c3c1cccc3ccc2)=C

VII N[C@H]1CC=Cc2c3c1cccc3ccc2

VIII FC(F)(F)[C@H]1N\C(\c2c3c1cccc3ccc2)=C/c1ccccc1OC

IX O(C(=O)C[C@@H]1N\C(\c2c3c1cccc3ccc2)=C/c1ccccc1)CC

X O(C)c1ccccc1\C=C\1/N[C@H](c2c3c/1cccc3ccc2)CC(OCC)=O

XI FC(F)(F)c1ccc(cc1)\C=C\1/N[C@H](c2c3c/1cccc3ccc2)CC(OCC)=O

XII N\1[C@H](c2c3c(cccc3ccc2)/C/1=C/c1ccccc1)CC=C

XIII O(C)c1ccccc1\C=C\1/N[C@H](c2c3c/1cccc3ccc2)CC=C

XIV FC(F)(F)c1ccc(cc1)\C=C\1/N[C@H](c2c3c/1cccc3ccc2)CC=C

XV N[C@H]1CC=C(c2c3c1cccc3ccc2)C(=C)c1ccccc1

XVI FC(F)(F)c1ccc(cc1)C(=C)C=1c2c3c(cccc3ccc2)[C@@H](N)CC=1

XVII O=C1C[C@@H]2C(c3c4c(cccc4ccc3)[C@@H](N)C2)=C1c1ccccc1

XVIII O(C)c1ccccc1C1=C2[C@@H](CC1=O)C[C@H](N)c1c3c2cccc3ccc1

XIX FC(F)(F)c1ccc(cc1)C1=C2[C@@H](CC1=O)C[C@H](N)c1c3c2cccc3ccc1

Collection 2

Lipitor Fc1ccc(cc1)-c1n(CC[C@@H](O)C[C@@H](O)CC(=O)[O-

])c(C(C)C)c(C(=O)Nc2ccccc2)c1-c1ccccc1

Nexium S(=O)(Cc1ncc(C)c(OC)c1C)c1[nH]c2cc(OC)ccc2n1

Prevacid S(=O)(Cc1nccc(OCC(F)(F)F)c1C)c1[nH]c2c(n1)cccc2

Flonase S(C(=O)[C@]1(OC(=O)CC)[C@@]2([C@H]([C@@H]3C[C@H](F)C4=C

C(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C2)C[C@H]1C)C)CF

Servent Oc1ccc(cc1CO)[C@H](O)C[NH2+]CCCCCCOCCCCc1ccccc1

Singulair Clc1cc2nc(ccc2cc1)\C=C\c1cc(ccc1)[C@H](SCC1(CC1)CC(=O)[O-

])CCc1ccccc1C(O)(C)C

Effexor O(C)c1ccc(cc1)[C@@H](C[NH+](C)C)C1(O)CCCCC1

Plavix Clc1ccccc1[C@H]([NH+]1CCc2sccc2C1)C(OC)=O

Zocor O1[C@@H](C[C@@H](O)CC1=O)CC[C@@H]1[C@@H]2C(=C[C@@H]

(C[C@@H]2OC(=O)C(CC)(C)C)C)C=C[C@@H]1C

Norvasc Clc1ccccc1[C@@H]1C(C(OCC)=O)=C(NC(C)=C1C(OC)=O)COCC[NH3+

]

Lexapro Fc1ccc(cc1)[C@@]1(OCc2cc(ccc12)C#N)CCC[NH+](C)C

Seroquel S1c2c(cccc2)C(=Nc2c1cccc2)N1CC[NH+](CC1)CCOCCO

Protonix S(=O)(Cc1nccc(OC)c1OC)c1[nH]c2cc(OC(F)F)ccc2n1

Ambien O=C(N(C)C)Cc1n2C=C(C=Cc2nc1-c1ccc(cc1)C)C

Actos S1[C@H](Cc2ccc(OCCc3ncc(cc3)CC)cc2)C(=O)[N-]C1=O

Zoloft Clc1cc(ccc1Cl)[C@@H]1CC[C@H]([NH2+]C)c2c1cccc2

Wellbutrin Clc1cc(ccc1)C(=O)[C@H]([NH2+]C(C)(C)C)C

Avandia S1[C@@H](Cc2ccc(OCCN(C)c3ncccc3)cc2)C(=O)[N-]C1=O

Risperdal Fc1cc2onc(c2cc1)C1CC[NH+](CC1)CCC=1C(=O)N2C(=NC=1C)CCCC2

Zyprexa S1C2=Nc3c(NC(N4CC[NH+](CC4)C)=C2C=C1C)cccc3

Topomax S(OC[C@]12OC(O[C@H]1[C@@H]1OC(O[C@@H]1CO2)(C)C)(C)C)(=O

)(=O)N

Toprol O(C[C@H](O)C[NH2+]C(C)C)c1ccc(cc1)CCOC

Zetia Fc1ccc(cc1)[C@@H](O)CC[C@@H]1[C@H](N(C1=O)c1ccc(F)cc1)c1ccc(

O)cc1

Fosamax P(=O)([O-])([O-])C(P(=O)([O-])[O-])(O)CCC[NH3+]

Ability Clc1c(N2CC[NH+](CC2)CCCCOc2cc3NC(=O)CCc3cc2)cccc1Cl

Levaquin Fc1cc2c3N(C=C(C(=O)[O-])C2=O)[C@H](COc3c1N1CC[NH+](CC1)C)C

Lamictal Clc1c(cccc1Cl)-c1nnc(nc1N)N

Celebrex S(=O)(=O)(N)c1ccc(-n2nc(cc2-c2ccc(cc2)C)C(F)(F)F)cc1

Benazepril O=C1N(c2c(CC[C@@H]1[NH2+][C@@H](CCc1ccccc1)C(OCC)=O)cccc2

)CC(=O)[O-]

Zyrtec Clc1ccc(cc1)[C@H]([NH+]1CC[NH+](CC1)CCOCC(=O)[O-])c1ccccc1

Coreg O(CC[NH2+]C[C@@H](O)COc1c2c3c([nH]c2ccc1)cccc3)c1ccccc1OC

Valtrex O=C1N=C(Nc2n(cnc12)COCCOC(=O)[C@@H]([NH3+])C(C)C)N

Adderall [NH3+][C@@H](Cc1ccccc1)C

Aciphex S(=O)(Cc1nccc(OCCCOC)c1C)c1[nH]c2c(n1)cccc2

Cymbalta s1cccc1[C@@H](Oc1c2c(ccc1)cccc2)CC[NH2+]C

Crestor S(=O)(=O)(N(C)c1nc(-

c2ccc(F)cc2)c(\C=C\[C@@H](O)C[C@@H](O)CC(=O)[O-])c(n1)C(C)C)C

Diovan O=C(N([C@@H](C(C)C)C(=O)[O-])Cc1ccc(cc1)-c1ccccc1-c1n[n-

]nn1)CCCC

Tricor Clc1ccc(cc1)C(=O)c1ccc(OC(C(OC(C)C)=O)(C)C)cc1

Concerta O(C(=O)[C@H]([C@H]1[NH2+]CCCC1)c1ccccc1)C

Imitrex S(=O)(=O)(NC)Cc1cc2c([nH]cc2CC[NH+](C)C)cc1

Collection 3

Taxol

O1[C@@H]2C[C@H](O)[C@@]3([C@H]([C@H](OC(=O)c4ccccc4)[C

@]4(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c5ccccc5)c5ccccc

5)C(=C([C@@H](OC(=O)C)C3=O)C4(C)C)C)[C@]2(OC(=O)C)C1)C

Actinonin OC[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)[C@H](CCCCC)CC(=O)N

[O-])C(C)C

Discodermolide

O1[C@@H](C[C@H](O)\C=C/[C@@H]([C@H](O)[C@H](\C=C(/C[C

@@H]([C@@H](O)[C@@H]([C@@H](OC(=O)N)[C@H](\C=C/C=C)

C)C)C)\C)C)C)[C@H](C)[C@H](O)[C@@H](C)C1=O

Validamycin

O1[C@H](CO)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O[C@H]1

[C@H](O)[C@@H](O)[C@@H]([NH2+][C@H]2C=C(CO)[C@@H](O)

[C@H](O)[C@H]2O)C[C@@H]1CO

Monensin

O1[C@@H]([C@H](C[C@@H](C)[C@]1(O)CO)C)[C@@H]1O[C@@

H]([C@]2(O[C@H](CC2)[C@]2(O[C@]3(O[C@H]([C@H]([C@@H](O

C)[C@@H](C(=O)[O-

])C)C)[C@H](C)[C@@H](O)C3)CC2)C)CC)[C@H](C1)C

Calyculin A

P(O[C@H]1[C@H](O[C@@]2(O[C@@H](C\C=C\c3nc(oc3)[C@H](CC

NC(=O)[C@@H](O)[C@@H](O)[C@@H]([NH+](C)C)COC)C)[C@@

H](C)[C@H](O)C2)C1(C)C)[C@@H](OC)C[C@H](O)[C@@H]([C@H]

(O)[C@@H](\C=C(\C(=C\C=C\C(=C/C#N)\C)\C)/C)C)C)(=O)([O-])[O-]

Coformycin O1[C@H](CO)[C@@H](O)[C@@H](O)[C@@H]1n1c2NC=[NH+]C[C

@@H](O)c2nc1

Arglabin O1[C@H]2[C@@H](CC[C@@]3(O[C@]34[C@@H]2C(=CC4)C)C)C(=

C)C1=O

Mizoribine O1[C@H](CO)[C@@H](O)[C@@H](O)[C@@H]1n1cnc(C(=O)N)c1O

Forskolon O1[C@@]2(C)[C@@](O)([C@@]3([C@@H]([C@H](O)[C@@H]2OC(

=O)C)C(CC[C@@H]3O)(C)C)C)C(=O)C[C@@]1(C=C)C

SQ 26180 S(=O)(=O)([O-])N1C[C@](OC)(NC(=O)C)C1=O

Cephamycin C S1[C@H]2N(C(C(=O)[O-

])=C(C1)COC(=O)N)C(=O)[C@@]2(OC)NC(=O)CCC[C@@H]([NH3+]

)C(=O)[O-]

Avermectin B1a

O1[C@@H]2C[C@@]3(O[C@H]([C@H](CC)C)[C@H](C=C3)C)O[C

@H](C\C=C(/C)\[C@@H](O[C@@H]3O[C@@H](C)[C@H](O[C@@H

]4O[C@@H](C)[C@H](O)[C@@H](OC)C4)[C@@H](OC)C3)[C@H](\

C=C\C=C\3/CO[C@@H]4[C@H](O)C(=C[C@H]([C@]/34O)C1=O)C)C

)C2

Adriamycin O1[C@@H](C)[C@@H](O)[C@@H]([NH3+])C[C@@H]1O[C@@H]1

c2c(C[C@](O)(C1)C(=O)CO)c(O)c1c(C(=O)c3c(cccc3OC)C1=O)c2O

Phorbol

myristate

acetate

O=C1[C@]2(O)[C@@H](C=C1C)[C@]1(O)[C@H]([C@H]3[C@@](O

C(=O)C)([C@H](OC(=O)CCCCCCCCCCCCC)[C@H]1C)C3(C)C)C=C(

C2)CO

Thienamycin S(CC[NH3+])C=1C[C@H]2N(C=1C(=O)[O-

])C(=O)[C@@H]2[C@H](O)C

Cyclosporin A

O=C1N(C)[C@@H]([C@H](O)[C@@H](C\C=C\C)C)C(=O)N[C@@H]

(CC)C(=O)N(CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)

C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(

=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C

@H]1C(C)C)C

FK506

O1[C@H](/C(=C/[C@H]2C[C@@H](OC)[C@H](O)CC2)/C)[C@H](C)[

C@@H](O)CC(=O)[C@@H](\C=C(\C[C@@H](C[C@H](OC)[C@H]2

O[C@](O)([C@@H](C[C@@H]2OC)C)C(=O)C(=O)N2[C@@H](CCC

C2)C1=O)C)/C)CC=C

Trapoxin B O1C[C@H]1C(=O)CCCCC[C@@H]1NC(=O)[C@@H]2N(CCC2)C(=O

)[C@@H](NC(=O)[C@@H](NC1=O)Cc1ccccc1)Cc1ccccc1

Vincristine

O(C)c1cc2N([C@@H]3[C@]4([C@H]5[NH+](CC=C[C@@]5(CC)[C@

@H](OC(=O)C)[C@]3(O)C(OC)=O)CC4)c2cc1[C@@]1(c2[nH]c3c(c2C

C[N@H+]2C[C@@](O)(C[C@@H](C1)C2)CC)cccc3)C(OC)=O)C=O

Colchicine O(C)C1=CC=C2c3c(cc(OC)c(OC)c3OC)CC[C@H](NC(=O)C)C2=CC1=

O

Trichostatin A O=C([C@@H](\C=C(\C=C\C(=O)N[O-])/C)C)c1ccc(N(C)C)cc1

Fumagillin O1[C@](C)([C@H]2[C@H](OC)[C@H](OC(=O)\C=C\C=C\C=C\C=C\

C(=O)[O-])CC[C@@]23OC3)[C@H]1C\C=C(\C)/C

Staurosporine O1[C@H]2n3c4c(c5c(CNC5=O)c5c6c(n(c45)[C@]1(C)[C@H](OC)[C@

H]([NH2+]C)C2)cccc6)c1c3cccc1

Erythromycin A

O1[C@H](CC)[C@](O)(C)[C@H](O)[C@@H](C)C(=O)[C@@H](C[C

@](O)(C)[C@H](O[C@@H]2O[C@@H](C[C@H]([NH+](C)C)[C@H]2

O)C)[C@@H](C)[C@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](O

C)(C2)C)[C@@H](C)C1=O)C

Streptomycin

O1[C@@H](CO)[C@H](O)[C@@H](O)[C@H]([NH2+]C)[C@@H]1O[

C@@H]1[C@@](O)(C=O)[C@@H](O[C@H]1O[C@@H]1[C@@H](\[

NH+]=C(\N)/N)[C@H](O)[C@@H](\[NH+]=C(\N)/N)[C@H](O)[C@H]

1O)C

Penicillin G S1[C@H]2N([C@@H](C(=O)[O-

])C1(C)C)C(=O)[C@H]2NC(=O)Cc1ccccc1

Sperguallin O=C(N[C@@H](O)C(=O)NCCCC[NH2+]CCC[NH3+])C[C@@H](O)C

CCC\[NH+]=C(\N)/N

Rapamycin

O1[C@@H](CC(=O)[C@@H](\C=C(/C)\[C@@H](O)[C@@H](OC)C(=

O)[C@@H](C[C@@H](\C=C\C=C\C=C(/C)\[C@@H](OC)C[C@H]2O[

C@](O)([C@@H](CC2)C)C(=O)C(=O)N2[C@@H](CCCC2)C1=O)C)C

)C)[C@@H](C[C@H]1C[C@@H](OC)[C@H](O)CC1)C

Echinocandin B

Oc1ccc(cc1)[C@H](O)[C@@H](O)[C@@H]1NC(=O)[C@H]2N(C[C@

H](O)C2)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)CCCCCCC\C=C/C\

C=C/CCCCC)C[C@@H](O)[C@@H](O)NC(=O)[C@H]2N(C[C@H](C)

[C@H]2O)C(=O)[C@@H](NC1=O)[C@H](O)C)[C@H](O)C

Ginkgolide B O1[C@@H]2[C@@](O)([C@]34O[C@@H]5OC(=O)[C@H](O)[C@]56

[C@]3([C@H](OC4=O)C[C@H]6C(C)(C)C)[C@H]2O)[C@H](C)C1=O

Vancomycin Clc1c2Oc3cc4[C@@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)[C@

H]([NH2+]C)CC(C)C)[C@H](O)c(c1)cc2)CC(=O)N)C(=O)N[C@@H]1c

2cc(-

c5c(cc(O)cc5O)[C@H](NC(=O)[C@@H](NC1=O)[C@H](O)c1cc(Cl)c(

Oc(c4)c3O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O[C

@@H]3O[C@@H](C)[C@@H](O)[C@@]([NH3+])(C3)C)cc1)C(=O)[O

-])c(O)cc2

Amphotericin B

O1[C@@H](C)[C@H](C)[C@H](O)[C@H](\C=C\C=C\C=C\C=C\C=C\

C=C\C=C\[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H]([NH3+])

[C@@H]2O)C[C@@H]2O[C@@](O)(C[C@H](O)[C@H]2C(=O)[O-

])C[C@@H](O)C[C@@H](O)[C@H](O)CC[C@@H](O)C[C@@H](O)

CC1=O)C

Radicicol Clc1c2c(C(O[C@@H](C[C@H]3O[C@@H]3/C=C\C=C\C(=O)C2)C)=O

)c(O)cc1O

Salicylihalamide

A

O1[C@H](C[C@@H](O)[C@H](C\C=C\Cc2c(C1=O)c(O)ccc2)C)C\C=C

\NC(=O)/C=C\C=C/CC

Telomestatin S1C2=N[C@H](c3oc(c(n3)-c3oc(c(n3)-c3occ(n3)-c3occ(n3)-c3occ(n3)-

c3occ(n3)-c3occ2n3)C)C)C1

Rifamycin B

O1c2c3c4c(c(O)c2C)c(O)c(NC(=O)/C(=C\C=C\[C@H](C)[C@H](O)[C

@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(=O)C)[C@H](C)[C@@

H](OC)\C=C\O[C@]1(C)C3=O)/C)cc4OCC(=O)[O-]

Apoptolidin

O1[C@@H](C[C@H](OC)[C@@H](O)CC\C=C(\C=C\[C@H](O[C@@

H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@@H]2O)[C@@H](C\C=

C(\C=C(\C=C(/C)\C1=O)/C)/C)C)/C)[C@@H](O)[C@@]1(O[C@H](C[

C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@H](C)[C

@@H](O)[C@H](OC)C3)[C@@](O)(C2)C)COC)[C@H](C)[C@H](O)[

C@H]1C)O

Midecamycin

A1

O1[C@@H](C\C=C\C=C\[C@H](O)[C@@H](C[C@H](CC=O)[C@H](

O[C@@H]2O[C@H](C)[C@@H](O[C@@H]3O[C@@H](C)[C@H](O

C(=O)CC)[C@](O)(C3)C)[C@H]([NH+](C)C)[C@H]2O)[C@@H](OC)[

C@H](OC(=O)CC)CC1=O)C)C

Zaragozic acid O1[C@@]2(C(=O)[O-

])[C@](O)(C(O)=O)[C@H](O[C@]1(CCC([C@@H](OC(=O)C)[C@@H

A ](Cc1ccccc1)C)=C)[C@H](O)[C@H]2OC(=O)\C=C\[C@H](C[C@H](C

C)C)C)C(=O)[O-]

Talaromycin B O1C[C@H](CO)[C@@H](O)C[C@]12OC[C@@H](CC2)CC

Spongistatin 1

ClC(\C=C\[C@@H](O)CC(C[C@H]1O[C@H]2[C@H](O)[C@@]3(O[C

@H](CCC\C=C/[C@@H]4O[C@@]5(O[C@H](CC(=O)[C@@H](C)[C

@@H](OC(=O)C)[C@H](C)C(C[C@@H]6O[C@@]7(O[C@@H](CC(

O[C@@H]([C@@H]1O)[C@H]2C)=O)C[C@H](OC(=O)C)C7)C[C@@

](O)(C6)C)=C)C[C@H](OC)C5)C[C@@H](O)C4)[C@H](C)[C@@H](

O)C3)O)=C)=C

Brevetoxin B

O1[C@@H]2[C@H](O[C@@]3([C@H](O[C@@H]4[C@H](O[C@@H

]5[C@H](O[C@H]6C[C@H]7O[C@@]8([C@H](O[C@@H]9[C@H](O

[C@@H]%10[C@H](O[C@@]%11([C@H](O[C@@H](C[C@@H]%11

O)CC(C=O)=C)C%10)C)C9)C=CC8)C[C@@]7(O[C@@]6(CC5)C)C)C)

[C@@H](C4)C)C3)C2)C)C(=CC1=O)C

Quinine O(C)c1cc2c(nccc2[C@@H](O)[C@H]2[N@@H+]3C[C@@H]([C@H](

C2)CC3)C=C)cc1

Mycobactin S

O1C[C@H](N=C1c1ccccc1O)C(=O)N[C@@H](CCCCN([O-

])C(=O)\C=C/CCCCCCCCCCCCCCC)C(O[C@H](CC(=O)N[C@H]1CC

CCN([O-])C1=O)C)=O

Duocarmycin A O(C)c1c(OC)c2[nH]c(cc2cc1OC)C(=O)N1C=2[C@]3([C@H](C3)C1)C1

=C(N[C@](C(OC)=O)(C)C1=O)C(=O)C=2

Bleomycin A2

[S+](CCCNC(=O)c1nc(sc1)-

c1nc(sc1)CCNC(=O)[C@@H](NC(=O)[C@H]([C@H](O)[C@H](NC(=

O)[C@@H](NC(=O)c1nc(nc(N)c1C)[C@@H]([NH2+]C[C@H]([NH3+]

)C(=O)N)CC(=O)N)[C@@H](O[C@@H]1O[C@@H](CO)[C@@H](O)

[C@H](O)[C@@H]1O[C@H]1O[C@H](CO)[C@@H](O)[C@H](OC(=

O)N)[C@@H]1O)c1[nH]cnc1)C)C)[C@H](O)C)(C)C

Brefeldin A O1[C@H](CCC\C=C\[C@H]2[C@@H](C[C@@H](O)C2)[C@H](O)\C

=C\C1=O)C

Cytochalasin B O1[C@@]23[C@@H]([C@H](C)C(=C)[C@@H](O)[C@@H]2\C=C\C[

C@@H](CCC[C@@H](O)\C=C\C1=O)C)[C@@H](NC3=O)Cc1ccccc1

Epothilone A s1cc(nc1C)\C=C(/C)\[C@H]1OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](

C)[C@@H](O)[C@H](CCC[C@H]2O[C@H]2C1)C

Lactacystin S(C(=O)[C@@]1(NC(=O)[C@H](C)[C@@H]1O)[C@@H](O)C(C)C)C[

C@H](NC(=O)C)C(=O)[O-]

Calicheamicin

γγγγ1

Ic1c(C)c(C(S[C@@H]2[C@H](O[C@@H](ON[C@H]3[C@H](O)[C@

@H](O[C@@H]4OC[C@H]([NH2+]CC)[C@@H](OC)C4)[C@@H](O[

C@@H]3C)O[C@@H]3C=4\C(=C/CSSSC)\[C@@](O)(CC(=O)C=4NC

(OC)=O)C#C\C=C/C#C3)C[C@@H]2O)C)=O)c(OC)c(OC)c1O[C@@H]

1O[C@@H](C)[C@H](O)[C@@H](OC)[C@H]1O

Artemisinin O1[C@@H]2O[C@@]3(OO[C@]24[C@@H](CC[C@H]([C@@H]4CC

3)C)[C@@H](C)C1=O)C

Compactin O1[C@@H](C[C@@H](O)CC1=O)CC[C@@H]1[C@@H]2C(C=C[C@

@H]1C)=CCC[C@@H]2OC(=O)[C@H](CC)C

Lipstatin O1[C@@H](C[C@@H](OC(=O)[C@@H](NC=O)CC(C)C)C\C=C/C\C=

C/CCCCC)[C@H](CCCCCC)C1=O

Pseudomonic

acid A

O1[C@@H](C[C@H]2CO[C@@H](C\C(=C\C(OCCCCCCCCC(=O)[O-

])=O)\C)[C@H](O)[C@@H]2O)[C@@H]1[C@H]([C@@H](O)C)C

Daptomycin

O1[C@H](C)[C@H](NC(=O)[C@@H](NC(=O)[C@H](NC(=O)[C@@

H](NC(=O)CCCCCCCCC)Cc2c3c([nH]c2)cccc3)CC(=O)N)CC(=O)[O-

])C(=O)NCC(=O)N[C@@H](CCC[NH3+])C(=O)N[C@@H](CC(=O)[O

-])C(=O)N[C@H](C)C(=O)N[C@@H](CC(=O)[O-

])C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@@H]([C@@H](CC(=O)[O-

])C)C(=O)N[C@@H](CC(=O)c2ccccc2N)C1=O

Bestatin O=C(N[C@@H](CC(C)C)C(=O)[O-

])[C@@H](O)[C@H]([NH3+])Cc1ccccc1

Plaunotol OC/C(=C\CC\C(=C\CO)\C)/CC\C=C(\CC\C=C(\C)/C)/C

Geldanamycin O(C)C1=C2C[C@H](C[C@H](OC)[C@H](O)[C@H](\C=C(/C)\[C@H](

OC(=O)N)[C@@H](OC)\C=C\C=C(/C)\C(=O)NC(=CC1=O)C2=O)C)C

1H,

13C and

19F Spectra of all new compounds

It should be noted that most products are tert-butyl carbamates and, as such, they show

broad signals both in the 1H and the

13C NMR spectra due to the presence of rotamers.

In addition, some signals in the 13

C NMR spectra appear duplicated. In order to

showcase that the presence of rotamers is responsible of the bad quality of these spectra

two of them have been recorded at high temperature (100 ºC) giving rise to single sets

of signals. Compound 14b also exhibits rotamers due to lack of free rotation along the

C-C bond between the Cα of the enone and the 2-methoxyphenyl ring.

8-Iodonaphtalene-1-carbaldehyde: a Versatile Building ... · and q stand for multiplet, singlet,...

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