Ring-expansion approaches for the total synthesis of salimabromide

Accepted Manuscript

Matthias Schmid, Adriana S. Grossmann, Peter Mayer, Thomas Müller, Thomas

Magauer

PII:

S0040-4020(19)30285-6

https://doi.org/10.1016/j.tet.2019.03.010

TET 30196

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 1 February 2019

Revised Date: 1 March 2019

Accepted Date: 8 March 2019

Please cite this article as: Schmid M, Grossmann AS, Mayer P, Müller T, Magauer T, Ring-expansion

approaches for the total synthesis of salimabromide, Tetrahedron (2019), doi: https://doi.org/10.1016/

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ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

Ring-Expansion Approaches for the Total Synthesis of Salimabromide

Matthias Schmid^a,b,†, Adriana S. Grossmann^a,†, Peter Mayer^a, Thomas Müller^band Thomas Magauer^b*

^aDepartment of Chemistry and Pharmacy, Ludwig-Maximilians-University Munich, Butenandtstraße 5–13, Munich 81377, Germany.

^bInstitute of Organic Chemistry and Center for Molecular Biosciences, University of Innsbruck, Innrain 80–82, 6020 Innsbruck, Austria.

ARTICLE INFO

ABSTRACT

Article history:

Received

We describe the evolution of a synthetic strategy for the construction of the marine polyketide

salimabromide. Combining

a bicyclo[3.1.0]hexan-2-one ring-expansion to build up a

Received in revised form

Accepted

Available online

functionalized naphthalene and an unprecedented rearrangement/cyclization cascade, enabled

synthesis of a dearomatized tricyclic subunit of the target compound. Alternatively, an

intramolecular ketiminium [2+2]-cycloaddition and subsequent Baeyer–Villiger ring-expansion

gave access to the sterically encumbered architecture of salimabromide. Sequential oxidation of

the carbon framework finally enabled the total synthesis of this unusual natural product.

Keywords:

Polyketides

Natural product synthesis

Ring-expansion

.

[2+2]-Cycloaddition

Wagner–Meerwein rearrangement

1. Introduction

Myxobacteria are a unique class of δ-proteobacteria with an

elaborate ability for intercellular communication [1]. In an

impressive process of cooperative morphogenesis, these rod-

shaped gliding bacteria can aggregate and pile up on starvation

conditions, forming so-called fruiting bodies. Within the

maturing fruiting body, the cells differentiate into myxospores

that are resistant to desiccation. Most myxobacteria also have a

fascinating predatory activity on other microorganisms and can

lyse a variety of bacteria and fungi to feed on the lysis products

[2]. More than 100 natural product scaffolds with a broad range

of biological activities were isolated from terrestrial

myxobacteria since the last three decades [3]. Only in 1998, the

first member of currently ten known marine myxobacterial

strains was reported by Iizuka [4]. Difficulties in the cultivation

of these bacteria complicate the isolation of natural products and

only seven natural product classes have been identified so far

(Figure 1) [5]. These include enhygrolide A (1) and B (2) [6],

enhygromic acid (3) [7], haliamide (4) [8], haliangicins (5) [9],

salimyxins (6) [6] and salimabromide (7) [10].

Figure 1 | Natural product classes from marine myxobacteria.

screens were limited as only 0.5ꢀmg of 7 could be isolated [10].

However, they revealed a moderate antibiotic activity against

Arthrobacter cristallopoedes with a MIC value of 16ꢀµgꢀmL^–1.

The group of Menche began first synthetic studies shortly

after the isolation of 7 in 2013 [11]. In their approach, the crucial

quaternary stereocenter was set via an asymmetric Denmark

crotylation (95% ee) employing aldehyde 9. It is interesting to

note that 9, derived from acid 8 in four steps, already contains the

sterically demanding bromide substituents. The alcohol 10 was

converted to the tetraline 11 within further six steps. For the

introduction of the remaining carbon atoms, an additional ten

steps were required to give the eight-membered lactone 12.

Unfortunately, the final ring closure of the γ-butyrolactone by an

intramolecular Michael-addition as well as the elimination of the

neopentylic methoxy group could not be achieved at this stage.

Of those seven classes, the organobromine compound

salimabromide (7) contains a unique C₂₀framework that does not

show any resemblance to other known natural products. Its

tetrahydronaphthalene moiety features two contiguous quaternary

carbon centers, one of which is asymmetric, and is annealed to a

γ-butyrolactone. An enone motif connects the lactone and the

saturated half of the tetrahydronaphthalene. The two bromides

are located on the aromatic half, resulting in a penta-substituted

arene with an uncommon ethyl side chain. First biological

1

with copper(II) bromide (19 to 20) [18,19] followed by

ACCEPTED MANUSCRIPT

elimination and subsequent cyclopropanation with methyl

dichloroacetate (MDA, 20 to 21) [13,20]. The fragmentation was

conducted in sulfolane at 190ꢀ°C affording naphthol 22 in good

yield (77%) on gram-scale [13]. Negishi cross-coupling using

freshly prepared diethylzinc introduced the ethyl side chain of 15

in excellent yield [21]. To achieve the dearomatization of the

naphthalene we pursued the sequence shown in Scheme 4. First,

Scheme 1 | Synthetic studies towards salimabromide (7) by Menche. TBDPS

= tert-butyldiphenylsilyl; Bz = benzoyl.

2. Results and discussion

In our retrosynthetic analysis, we envisioned a complementary

approach to the one developed by Menche and decided to

introduce the bromide substituents of 7 at the very end of the

synthesis (Scheme 2). This decision was based on the hypothesis

Scheme 4 | A tandem Claisen/Cope-rearrangement of phenyl allyl ether 23

and dearomatization of 26. a) Allyl bromide, K₂CO₃, DMF, 65ꢀ°C, 90%; b)

sulfolane, 190ꢀ°C, 31%; c) allyl chloroformate, Et₃N, THF, 0ꢀ°C, 80%; d)

Pd(PPh₃)₄, toluene/n-hexane (9:1), 45ꢀ°C, 69%. THF = tetrahydrofuran,

DMF = N,N-dimethylformamide.

Scheme 2 | Initial retrosynthesis of salimabromide (7).

15 was allylated under standard conditions (allyl bromide,

K₂CO₃, DMF, 65 °C) to give 23 in 92% yield. Heating a solution

of 23 in sulfolane at 190ꢀ°C induced a tandem Claisen/Cope-

that the biosynthesis involves a late-stage bromination and on

steric arguments [10]. The enone of 7 was disconnected via a

dynamic kinetic aldol reaction to provide 13 [12]. Further

disconnection was accomplished by removal of the lactone and

masking of the aldehyde function as an alkene to give 14. For the

construction of 14, a dearomatization sequence of 15 was

planned. Guided by our previously developed ring-expansion

methodology, we envisioned to directly trace back 15 to 16 [13–

15].

rearrangement/cyclization sequence to afford

–

via the

intermediacy of 24 and p-quinomethide 25 – the lactone 26 in

31% yield. For the crucial dearomatization, 26 was converted to

its allyl carbonate 27 [22]. Exposure to palladium(0) induced the

decarboxylative allylation to provide 28 as a mixture of two

diastereomers (69%, dr = 2.1:1) [23]. Unfortunately, all attempts

to selectively reduce the enone to 29 lead to decomposition, no

reaction, isomerization of the vinyl group or reduction of the

ketone [24–26].

2.1. First Generation Route

We commenced our synthesis with commercially available 5-

bromo-1-indanone (17) (Scheme 3). From there, cyclopropanated

indanone 21 was generated in six steps involving a three-step

methylation procedure (17 to 18 to 19) [16,17], a bromination

We therefore decided to go back to 15 and first concentrate on

the installation of the gem-dimethyl group (Scheme 5). For this

purpose, 15 was dearomatized following an analogous procedure

as above. In this way, the dearomatized product 24 was obtained

in good yields (79% over two steps). Isomerization of the allylic

double bond – required for the intended ozonolysis towards 13 –

was accomplished by conditions developed by Skrydstrup

(Pd(dba)₂, t-Bu₃P, i-PrCOCl, PhMe) in 84% yield [27]. With 31

in hand, we investigated introduction of the gem-dimethyl group.

First, Wittig olefination proceeded smoothly to give 32 [28].

Unfortunately we were not able to cyclopropanate this alkene by

employing the Simmons–Smith protocol (CH₂I₂, ZnEt₂) [29], the

use of dichlorocarbene or dibromocarbene [30]. In a second

approach, a Kluge–Wittig reaction/hydrolysis sequence gave

aldehyde 34 which was α-methylated. Noteworthy, rigorous

degassing of the solvent (THF) was mandatory to avoid

competing oxidation of the enolate and diminished yields of 35.

Attempts to directly reduce this aldehyde by the protocol of

Wolff–Kishner [31] or the formation of a thioacetal followed by

nickel catalyzed hydrogenation (Mozingo protocol) [32] failed.

Therefore, 34 was reduced to the primary alcohol 36. While it

was possible to tosylate this alcohol (36 to 37), 33 could not be

generated by reduction with lithium aluminum hydride even

Scheme 3 | Synthesis of naphthol 15 by fragmentation of cyclopropanated

indanone 21. a) DMC, NaH, THF, 0 to 70ꢀ°C; b) K₂CO₃, MeI, DMSO, 0 to

23ꢀ°C; c) HCl (37%), AcOH, 100ꢀ°C; d) CuBr₂, EtOAc/CHCl₃, 70ꢀ°C; e) DBU,

benzene, 0 to 23ꢀ°C; f) MDA, LHMDS, THF, –78ꢀ°C, 50% over 6 steps; g)

sulfolane, 190ꢀ°C, 77%; h) Et₂Zn, Pd(dppf)Cl₂, 1,4-dioxane, 0 to 90ꢀ°C, 93%.

DMC

= dimethylcarbonate, DMSO = dimethylsulfoxide, DBU = 1,8-

diazabicyclo[5.4.0]undec-7-ene, MDA = methyl dichloroacetate, LHMDS =

lithium bis(trimethylsilyl)amide, dppf = 1,1'-Bis(diphenylphosphino)ferrocene.

2

ACCEPTED MANUSCRIPT

Scheme 5 | Attempts towards the gem-dimethylation of dearomatized naphthol 30. a) Allyl chloroformate, Et₃N, THF, 0 °C, 99%; b) Pd(PPh₃)₄, toluene/n-hexane

(10:1), 45ꢀ°C, 80%; c) Pd(dba)₂, t-Bu₃P, i-PrCOCl, toluene, 80ꢀ°C, 84%; d) MePPh₃Br, t-BuOK, THF, 0 to 23ꢀ°C, 99%; e) Ph₃P(Cl)CH₂OCH₃, n-BuLi, THF, 0 to

23ꢀ°C, 81%; f) HClO₄, Et₂O, 23ꢀ°C, 79%; g) NaH, MeI, THF, 0 to 23ꢀ°C, 69%; h) NaBH₄, MeOH, 0ꢀ°C, 80%; i) p-TsCl, pyridine, 23ꢀ°C, 73%; j) CS₂, NaHMDS,

THF, –78 to –65ꢀ°C, 83%; g) TiCl₄, ZnMe₂, CH₂Cl₂, 0ꢀ°C, 61%. dba

= dibenzylideneacetone, p-Ts = p-toluenesulfonyl, NaHMDS = sodium

bis(trimethylsilyl)amide, py = pyridine.

under elevated temperature (60ꢀ°C). Finally, a radical Barton–

McCombie deoxygenation of 38 was investigated [33]. However,

the intended product was not formed but a complex product

mixture was obtained. Direct dimethylation of the ketone using

Reetz conditions [34] failed as the strongly Lewis acidic

conditions induced a Wagner–Meerwein rearrangement (39 to 40

to 41) to give 42 as the sole product [35].

2.2 Second Generation Route

Realizing that introduction of the two quaternary carbon centers

is highly problematic at this stage of the synthesis, we abandoned

the indanone ring-expansion route and tried to set both centers at

an earlier stage. Starting with commercially available

methoxytetralone 43, addition of methylmagnesium bromide and

acid-mediated elimination gave known 44 [36]. Epoxidation with

concomitant Meinwald-rearrangement afforded ß-tetralone 45 in

44% yield over two steps [37]. Methylation under

thermodynamic control using potassium hydride as the base set

the gem-dimethyl group and afforded tetralone 46 [38]. The

vicinal methyl group of 47 was introduced by Grignard addition

employing Knochel’s conditions (LaCl₃ꢀ•ꢀ2 LiCl, MeMgBr) [39].

Benzylic oxidation with cobalt acetylacetonate [40] gave clean

48 [41] and subsequent acid-mediated elimination afforded enone

49 [42] in good yield [43]. A three-step procedure, involving

demethylation, triflation [44] and Negishi cross-coupling [21]

with diethylzinc was used to replace the methoxy with an ethyl

group yielding 52 (via 50 and 51, 86% over three steps).

Allylation with allylmagnesium bromide (52 to 53) followed by

an anionic oxy-Cope rearrangement set the quaternary

stereocenter of 54 [45,46]. For the isomerization of the allyl

group, Skrydrup’s conditions again proved to be the method of

choice affording 55 in 92% yield [27]. Surprisingly, despite

extensive efforts tetralone 55 proved to be reluctant to react at its

α-position. We examined several α-acylation and alkylation

procedures to introduce the carboxylate for the γ-butyrolactone,

however, no carbon-carbon bond formation to give 56 was

observed. We reasoned that steric hindrance by the adjacent

quaternary stereocenter impedes nucleophilic attack of the

enolate.

Scheme 6| Synthesis of tetralone 55. a) MeMgBr, THF, 0ꢀ°C, then HCl,

23ꢀ°C; b) m-CPBA, CH₂Cl₂/TFE, p-TsOH, 0ꢀ°C, 44% over 2 steps; c) KH,

MeI, THF, 0 to 23ꢀ°C, 71%; d) MeMgBr, LaCl₃ꢀ•ꢀ2ꢀLiCl, THF, 0ꢀ°C, 96%; e)

Co(acac)₂, t-BuOOH, Me₂CO, 23ꢀ°C, 95%; f) H₂SO₄, AcOH, 100ꢀ°C, 88%; g)

BBr₃, CH₂Cl₂, –78 to 0ꢀ°C; h) Tf₂O, Et₃N, CH₂Cl₂, –78 to 23ꢀ°C, 98% over

two steps; i) Et₂Zn, Pd(dppf)Cl₂, 1,4-dioxane, 90ꢀ°C, 88%; j) allylMgBr, THF,

0ꢀ°C; g) t-BuOK, 18-crown-6, THF, 0 to 23ꢀ°C, 38% over 2 steps; h) Pd(dba)₂,

t-Bu₃P, i-PrCOCl, toluene, 80ꢀ°C, 92%. m-CPBA

=

meta-

chloroperoxybenzoic acid, TFE 2,2,2-trifluoroethanol, acac

=

acetylacetonate, Tf = trifluoromethanesulfonate, 18-crown-6 = 1,4,7,10,13,16-

hexaoxacyclooctadecane.

As steric hindrance prevented α-functionalization of the ketone,

we considered an alternative [2+2]-cycloaddition strategy using

the readily available 49 (Scheme 7). Conversion of 49 to 58a

proceeded uneventfully via the intermediacy of 57 and involved a

Wittig–Still rearrangement to construct the quaternary

3

ACCEPTED MANUSCRIPT

Scheme 7 Investigation of the [2+2]-cycloadditon on 58. a) NaBH₄, CeCl₃ꢀ•ꢀ7 H₂O, MeOH, 0ꢀ°C; b) KH, ICH₂SnBu₃, THF, 0ꢀ°C; c) n-BuLi, –78 to –45ꢀ°C, 48%

over 3 steps; d) 61a: Ac₂O, NEt₃, CH₂Cl₂, 0ꢀ°C, 86%; 61b: DIPEA, MOMCl, CH₂Cl₂, 0ꢀ°C, 94%; 61c: TBSCl, imH, DMF, 0 to 23ꢀ°C, 68%; 61d: NaH, MeI,

DMF, 0 to 23 °C, 80%; e) NaH, ClCH₂CONEt₂, (CH₂OMe)₂, 0 to 23ꢀ°C, 97%; e) Tf₂O, 2,4,6-collidine, (CH₂Cl)₂, 80ꢀ°C, then K₂CO₃, Me₂CO, 70ꢀ°C, 70%.

DIPEA = N,N-diisopropylethylamine, DMP = Dess–Martin periodinane, TBS = tert-butyldimethylsilyl, MOM = methoxymethyl, Ac = acetyl, imH = imidazole.

stereocenter (48% over three steps) [47,48]. We envisioned the

primary alcohol to serve as a handle to control the facial

selectivity of the ketene [2+2]-cycloaddition. First, we

investigated the use of Lewis acids (AlMe₃; MeAlCl₂) to control

the trajectory of the ketene derived from 59 via coordination to

the alkoxide. Unfortunately, no cycloaddition product 60 was

observed and only traces of the corresponding ester together with

polymeric byproducts were formed. Protection of the primary

alcohol (61a-d = Ac, MOM, TBS, Me) and cycloaddition with

dichloroketene to give 62 was equally unproductive.

Facing the problems of ketene oligo-and polymerization we

resorted to keteniminium salts, which are known to be more

electrophilic and reluctant to dimerization [49,50]. Treatment of

58 with 2-chloro-N,N-diethylacetamide (63) gave 64. We were

pleased to see that upon treatment with freshly distilled

trifluoromethanesulfonic anhydride and sym-collidine at 80ꢀ°C,

64 underwent the intramolecular cycloaddition to the iminium

Scheme 9 | Synthesis of cyclobutanone 71 a) SmI₂, THF/MeOH, 0ꢀ°C,

quant.; b) LiAlH₄, Et₂O, 0ꢀ°C, 99%; c) (COCl)₂, DMSO, Et₃N, CH₂Cl₂, –78

to 23ꢀ°C, 95%.

salt 70. The cycloaddition product 65 was formed after

At this point, we realized that synthesis of 13, the key-

hydrolysis in 70% yield and excellent regioselectivity affording

substrate for the intended kinetic dynamic aldol condensation,

exclusively the 6/4- instead of the 5/4-system. The

might not be possible via the investigated routes. Therefore, we

regioselectivity finds its basis in

a stepwise mechanism

reassessed our strategy once again. Encouraged by the high

selectivity of the keteniminium mediated cycloaddition of 64 we

decided to investigate an [2+2]-cycloaddition approach using a

carbon chain tether (Scheme 10) [52]. For this purpose, we

resorted to alcohol 58a. Since synthesis of 58a was rather low-

yielding so far, we considered other synthetic options to get rapid

access to the tetraline core. Inspired by the work of El-Fouty [53]

and our desire to rapidly introduce both quaternary carbon

centers, we envisioned the synthesis of 80 by a Wagner–

Meerwein cyclization sequence of epoxide 79. [54] When

conducting this reaction in 1,1,1,3,3,3-hexafluoroisopropanol

(HFIP), 41% of the desired product could be isolated, giving

access to large amounts of 80 in four steps involving only two

presumably proceeding via the benzylic cation 69 (Scheme 8).

This cation should be favored over the secondary cation 67

leading to regioisomer 68.

With 65 in hand, we cleaved the ether bridge by treatment with

Scheme

8 | Proposed mechanism of the intramolecular [2+2]-

cycloaddition of keteniminium ion 64.

samarium iodide to give lactol 71 (Scheme 9) [51]. Reduction

with lithium aluminum hydride afforded diol 72 and oxidation

under Swern conditions provided cyclobutanone 73 in 95% yield.

All efforts to functionalize the cyclobutanone ring and to convert

73 to 74a-d failed. Under basic conditions formation of 77 was

observed in minor amounts. We believe that 77 is formed via

ring-opening of the enolate 75 (stepwise or electrocyclic) and

subsequent aldol condensation of 76.

Scheme 10 | Second generation approach to 58ab. a) H₂SO₄, HFIP, 23ꢀ°C,

41%; b) TBDPSCl, imidazole, DMAP, DMF, 23ꢀ°C; c) DDQ, 1,4-dioxane,

93ꢀ°C, 91% over two steps; d) TBAF, THF, 23ꢀ°C, 85–99%; e) LiPPh₂, THF,

60ꢀ°C; f) PhNTf₂, NEt₃, THF, 23ꢀ°C, 99% over two steps; g) ZnEt₂,

Pd(dppf)Cl₂, 1,4-dioxane, 70ꢀ°C, 92%; h) AlCl₃, EtMgBr, Ni(cod)₂, dcype,

PhMe, i-Pr₂O, 100ꢀ°C, 7%. HFIP = 1,1,1,3,3,3-hexafluoroisopropanol, DDQ

=

2,3-dichloro-5,6-dicyano-1,4-benzoquinone, cod

= 1,5-cyclooctadiene,

dcype = 1,2-bis(dicyclohexylphosphino)ethane.

4

purification steps [54]. For the oxidation to the styrene 81 with

oxidation. Efforts to realize the oxidation with rhodium (e.g.

bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)]

[60]) or manganese based catalysts (e.g Mn(OAc)₃[61]) in

combination with tert-butylhydroperoxide were unsuccessful.

The use of bromine or selenium dioxide did not lead to any

functionalization of the desired position. Next, we tried inversion

of the overall sequence and investigated the allylic oxidation

first. Exposure of 90a to a large excess of selenium dioxide (10

equiv) in the presence of fine quartz sand – to prevent selenium

dioxide from agglomeration [62] – and terminating the reaction at

around 40% conversion to avoid overoxidation, gave 93a in 25%

yield. This alcohol was converted to the lactones 94a and 94b by

careful treatment with an equimolar amount of m-CPBA

followed by DMP oxidation of the allylic alcohol. While we were

pleased to observe the desired oxidation, we were confronted

ACCEPTED MANUSCRIPT

2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), protection of

the free alcohol was mandatory as otherwise tetrahydrofuran

formation was observed. Deprotection of 81 using

tetrabutylammonium fluoride completed the synthesis of 58a.

This sequence shortens the route from nine to seven steps, uses

inexpensive reagents and enables large scale synthesis of 58a. In

addition, 81 was used for the installation of the ethyl side chain.

A four-step protocol involving demethylation, triflate formation,

Negishi cross-coupling using diethylzinc (82 to 83 to 84) and

cleavage of the silyl protecting group gave 58b. We also

investigated the direct nickel(0)-catalyzed coupling of 81 using

the conditions developed by Rueping and Schoenebeck [55].

Under these conditions 84 was only formed in low yields (7%).

With 58a and 58b in hand, we continued with the

cycloaddition approach. Dess–Martin periodinane (DMP) gave

aldehyde 85ab in 80–96% yield (Scheme 11). A Z-selective

Wittig olefination [56] afforded ester 86ab that could be

converted into amide 87ab by heating in neat pyrrolidine [57].

We were pleased to see that 87ab underwent the envisioned

[2+2] cycloaddition in good yields (67% for 90a, 82–89% for

90b) and excellent regioselectivity (> 30:1). Only 2% of the

undesired [2+2] product 89a and trace amounts of 89b were

formed. We later found that a very similar approach was

investigated by Menche [58,59]. Having successfully built up the

full carbon framework of salimabromide (7), only Baeyer–

Villiger oxidation to expand the cyclobutanone to the γ-

butyrolactone and allylic oxidation of the alkene to give the

enone were left. Baeyer–Villiger oxidation of the cyclobutanone

90a promoted by meta-chloroperoxybenzoic acid (m-CPBA)

proceeded smoothly, however, the undesired regioisomer 92

prevailed (91:92 = 1:1.4). As separation of this mixture was

impossible at this stage, we directly investigated the allylic

with an unfavorable regioselectivity (94a:95a

= 1:1.4).

Employing conditions previously developed by Bolm (Cu(OAc)₂,

t-BuCHO, O₂) we were able to invert this ratio to favor the

desired lactone 94a (94a:95a = 2.5:1) [63–65]. Since the overall

route using 58b turned out to be more efficient, we turned our

attention to the completion of the synthesis using 90b. While

allylic oxidation of 90b proceeded with comparable yields, we

observed in the Baeyer–Villiger oxidation of 93b the formation

of many sideproducts and a significant drop of selectivity on

scales larger than 50ꢀmg. Despite a balanced ratio of the

regioisomeric lactones (94b:95b = 1:1), we found that copper(I)

thiophene carboxylate in wet benzene, followed by DMP

oxidation in dichloromethane gives reproducible yields of both

94b and 95b even on gram scale (see Experimental for details).

Introduction of the remaining bromine substituents was

accomplished by treatment of 94b with bromine and silver

trifluoroacetate to give 296ꢀmg of salimabromide (7) in a single

Scheme 12 | Total synthesis of salimabromide. Br₂, CF₃CO₂Ag, TFA, 0ꢀ°C,

45–50%.

batch (Scheme 12). The use of silver trifluoroacetate to form

highly reactive trifluoroacetyl hypobromite was essential [66,67].

Other bromination reagents (NBS; n-Bu₄NBr₃/ZnCl₂; Br₂/FeBr₃)

only lead to monobromination or decomposition of 94b [54]. The

analytical data for synthetic salimabromide matched those

reported in the literature [10].

3. Conclusion

We presented two complementary strategies for the total

synthesis of salimabromide. In our initial route we targeted a

highly-substituted keto-aldehyde that was thought to be

synthesized via ring-expansion of a cyclopropanated indanone

and subsequent dearomatization. Although both key-

transformations were realized, efforts to introduce the gem-

dimethyl group as well as the stereocenters connecting the

lactone and the tetrahydronaphthalene core failed. In our second

approach, we relied on a [2+2]-cycloaddition to construct the

carbon skeleton. While intermolecular cycloaddition reactions

were unsuccessful, an intramolecular ketiminium [2+2]-

cycloaddition showed to be high-yielding and proceeded with

excellent regioselectivity. Three regioselective oxidations

(allylic, Baeyer–Villiger, late-stage bromination) enabled

completion of the total synthesis in 18 steps (longest linear

Scheme 11 | Synthesis of the carbon skeleton of salimabromide (7). a) DMP,

CH₂Cl₂, 0 to 23ꢀ°C; b) NaHMDS, Ph₃P(Br)(CH₂)₃CO₂Et, THF, –78 to 23ꢀ°C;

c) pyrrolidine, 100ꢀ°C; d) Tf₂O, 2,4,6-collidine, (CH₂Cl)₂, 80_ꢀ°C, then CCl₄,

H₂O, reflux; e) SeO₂, SiO₂, 1,4-dioxane, 120–125_ꢀ°C; f) Cu(OAc)₂, t-BuCHO,

O₂, (CH₂Cl)₂, 23ꢀ°C, then DMP, 0 to 23ꢀ°C.

5

sequence). The developed route allowed production of 296 mg of

salimabromide in a single batch.

Hz. All raw fid files were processed and the spectra analyzed

using the program MestReNOVA 9.0 from Mestrelab Research

S. L. All mass spectra were measured by the analytic section of

the Department of Chemistry, Ludwig-Maximilians-Universität

München and the group of Thomas Müller at the Department of

Chemisty, Leopold-Franzens Universität Innsbruck. Mass spectra

were recorded on the following spectrometers (ionization mode

in brackets): MAT 95 (EI), MAT 90 (ESI) from Thermo

Finnigan GmbH and Q Exactive Orbitrap (ESI) from Thermo

Fisher Scientific. Mass spectra were recorded in high-resolution.

The method used is reported at the relevant section of the

ACCEPTED MANUSCRIPT

Experimental

All reactions were performed in flame-dried glassware fitted

with rubber septa under a positive pressure of argon, unless

otherwise noted. Air- and moisture-sensitive liquids were

transferred via syringe or stainless-steel cannula through rubber

septa. Solids were added under inert gas counter flow or were

dissolved in appropriate solvents. Low temperature-reactions

were carried out in a Dewar vessel filled with a cooling agent:

acetone/dry ice (−78ꢀ°C), water/ice (0ꢀ°C). Reaction temperatures

above room temperature were conducted in a heated oil bath. The

reactions were magnetically stirred and monitored by NMR

spectroscopy or analytical thin-layer chromatography (TLC),

using aluminum plates precoated with silica gel (0.25ꢀmm, 60-Å

pore size, Merck) impregnated with a fluorescent indicator

(254ꢀnm). TLC plates were visualized by exposure to ultraviolet

light (UV), were stained by submersion in aqueous potassium

permanganate solution (KMnO₄), ceric ammonium molybdate

solution (CAM) or p-anisaldehyde solution (Anis), and were

experimental section. IR spectra were recorded on

a

PerkinElmer Spectrum BX II FT-IR system. If required,

substances were dissolved in CH₂Cl₂or CDCl₃prior to direct

application on the ATR unit. Data are represented as follows:

frequency of absorption (cm⁻¹) and intensity of absorption (vs =

very strong, s = strong, m = medium, w = weak, br = broad).

3.1. Methyl 5-bromo-2-methyl-1-oxo-2,3-dihydro-1H-indene-2-

carboxylate (18)

To a suspension of sodium hydride (60% dispersion in mineral

oil, 19.9ꢀg, 497ꢀmmol, 2.00ꢀequiv) and dimethyl carbonate

(39.9ꢀmL, 474ꢀmmol, 2.00ꢀequiv) in tetrahydrofuran (470ꢀmL) in

a 3-necked 1-liter round bottom flask fitted with a reflux

condenser, dropping funnel and thermometer was added 5-

bromo-1-indanone (17) (50.0ꢀg, 237ꢀmmol, 1ꢀequiv) in

tetrahydrofuran (680ꢀmL) at 0ꢀ°C over 45ꢀmin. The dark brown

reaction mixture was stirred at 0ꢀ°C for 30ꢀmin, warmed very

slowly to 23ꢀ°C and carefully heated to 70ꢀ°C for 15ꢀh. The

solution was cooled to 0ꢀ°C and diluted with saturated aqueous

ammonium chloride solution (200ꢀmL), aqueous hydrogen

developed by heating with

a

heat gun. Flash-column

chromatography was performed as described by Still [68]

employing silica gel (60ꢀÅ, 40–63ꢀꢁm, Merck KGaA). The yields

refer to chromatographically and spectroscopically (¹H and ¹³C

NMR) pure material. Tetrahydrofuran (THF) and diethyl ether

(Et₂O) were distilled under nitrogen atmosphere from sodium and

benzophenone or sodium/potassium alloy prior to use.

Dichloromethane (CH₂Cl₂), Acetonitrile (MeCN), acetone and

methanol (MeOH) were purchased from Acros Organics as 'extra

dry' reagents and used as received. All other reagents and

solvents were purchased from chemical suppliers (Sigma-

Aldrich, TCI, Acros Organics, Alfa Aesar, Strem Chemicals,

ABCR, Fluorochem) and were used as received. Solvents for

extraction, crystallization and flash column chromatography were

purchased in technical grade and distilled under reduced pressure

prior to use. The molarity of n-butyllithium and tert-butyllithium

solutions was determined by titration against diphenylacetic acid

as an indicator (average of three determinations). NMR spectra

were measured on a Bruker Avance III HD 400 MHz

spectrometer equipped with a CryoProbeTM, Bruker Avance

Neo 400 MHz spectrometer, Bruker Avance II 600MHz

spectrometer, Bruker AXR300, a Varian VXR400 S, Bruker

AMX600 or Bruker Avance HD 800. Proton chemical shifts are

expressed in parts per million (ppm, δ scale) and are referenced

to residual proton in the NMR solvent (CHCl₃: δ 7.26, acetone-

d₅: δ 2.05, C₆D₅H: δ 7.16). Carbon chemical shifts are expressed

in parts per million (δ scale, assigned carbon atom) and are

referenced to the carbon resonance of the NMR solvent (CDCl₃:

chloride solution (2ꢀM; 200 mL) and diethyl ether (300 mL). The

layers were separated and the aqueous layer was extracted with

diethyl ether (3ꢀ×ꢀ400ꢀmL). The combined organic layers were

washed with saturated aqueous sodium chloride solution (300

mL) and the washed solution was dried over sodium sulfate. The

dried solution was filtered through a short pad of Celite® and the

filtrate was concentrated. The crude product S1 was afforded as a

dark brown solid and was used without additional purification for

the next step. To crude I.71 in dry dimethyl sulfoxide (240ꢀmL)

was added potassium carbonate (65.5ꢀg, 474ꢀmmol, 2.00ꢀequiv)

portionwise at 0ꢀ°C. After dropwise addition of methyl iodide

(29.5ꢀmL, 474ꢀmmol, 2.00ꢀequiv) the dark green slurry was

stirred at 23ꢀ°C for 2ꢀh. The excess methyl iodide was removed

by distillation (23ꢀ°C, 50ꢀmbar). The reaction mixture was cooled

to 0ꢀ°C, diluted with saturated aqueous ammonium chloride

solution (100ꢀmL), water (100ꢀmL) and ethyl acetate (250ꢀmL).

The layers were separated and the aqueous layer was extracted

with ethyl acetate (3ꢀ×ꢀ400ꢀmL). The combined organic layers

were washed with saturated aqueous sodium chloride solution

(300ꢀmL) and the washed solution was dried over sodium sulfate.

The dried solution was filtered through a short pad of Celite®

and the filtrate was concentrated. The crude product 18 was

afforded as a dark brown solid and was used without additional

purification for the next step. An analytical pure sample of 18

was obtained by flash column chromatography on silica gel (9%

ethyl acetate in hexanes). Analytical data for 18: TLC (20%

1

δ 77.16, acetone-d₆: δ 29.84, 206.26, C₆D₆: δ 128.06). H NMR

spectroscopic data are reported as follows: Chemical shift in ppm

(multiplicity, coupling constants J (Hz), integration intensity,

assigned proton). The multiplicities are abbreviated with s

(singlet), br s (broad singlet), d (doublet), t (triplet), q (quartet)

and m (multiplet). In case of combined multiplicities, the

multiplicity with the larger coupling constant is stated first.

Except for multiplets, the chemical shift of all signals, as well for

centrosymmetric multiplets, is reported as the center of the

resonance range. Additionally to ¹H and ¹³C NMR measurements,

2D NMR techniques such as homonuclear correlation

spectroscopy (COSY), total correlation spectroscopy (TOCSY),

heteronuclear single quantum coherence (HSQC) and

heteronuclear multiple bond coherence (HMBC) were used to

assist signal assignment. For further elucidation of 3D structures

of the products, nuclear Overhauser enhancement spectroscopy

(NOESY) was conducted. Coupling constants J are reported in

1

ethyl acetate in hexanes), R_f= 0.40 (UV, KMnO₄). H NMR

(400ꢀMHz, CDCl₃) δ: 7.63 (s, 1H), 7.60 (d, J = 7.5ꢀHz, 1H), 7.51

(d, J = 8.6ꢀHz, 1H), 3.69 (s, 1H), 3.64 (s, 3H), 2.95 (d, J =

17.3ꢀHz, 1H), 1.48 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl3) δ:

202.1, 172.0, 154.2, 133.5, 131.6, 130.9, 129.8, 126.1, 56.1, 52.9,

39.6, 21.0. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2953 (w), 1742 (s),

̃

1710 (vs), 1594 (s), 1579 (m), 1428 (m), 1317 (m), 1266 (s), 1200

(s), 1177 (s), 1095 (m), 1057 (m), 964 (s), 919 (m), 830 (m), 769

6

(m), 668 (m), 593 (m) cm⁻¹. HRMS (EI) calcd for C₁₂H₁₁O₃⁸¹Br

purification for the next step. Note: Indenones undergo facile

polymerizations and should therefore be used immediately after

preparation. For safety reasons the cyclopropanation was

carried out in two parallel batches. The crude material of both

batches was subsequently combined and purified together. To a

ACCEPTED MANUSCRIPT

[M]⁺: 283.9866; found: 283.9875.

3.2. 5-bromo-2-methyl-2,3-dihydro-1H-inden-1-one (19)

Crude 18 was dissolved in water (82 mL), glacial acetic acid

(400 mL) and aqueous hydrogen chloride solution (37%, 125ꢀmL,

924ꢀmmol, 3.90ꢀequiv). The reaction mixture was heated to

100ꢀ°C for 16ꢀh. After cooling to 23ꢀ°C, the solution was diluted

with dichloromethane (300ꢀmL) and water (300ꢀmL) and was

carefully neutralized by portionwise addition of sodium

bicarbonate (250ꢀg) and aqueous sodium hydroxide solution

(10%, 300ꢀmL). The layers were separated and the aqueous layer

was extracted with dichloromethane (3ꢀ×ꢀ400ꢀmL). The combined

organic layers were dried over sodium sulfate. The dried solution

was filtered through a short pad of Celite® and the filtrate was

concentrated. The crude product 19 was afforded as a dark brown

solid and was used without additional purification for the next

step. An analytical pure sample of 19 was obtained by flash

column chromatography on silica gel (2% ethyl acetate in

hexanes). Analytical data for 19: TLC (20% ethyl acetate in

stirred solution of lithium bis(trimethylsilyl)amide (1ꢀ

tetrahydrofuran, 137ꢀmL, 137ꢀmmol, 1.15ꢀequiv)

M

in

tetrahydrofuran (119ꢀmL) in a 3-necked 2ꢀliter round bottom flask

fitted with a reflux condenser, dropping funnel and thermometer,

was added methyl dichloroacetate (12.9ꢀmL, 125ꢀmmol,

1.05ꢀequiv) over 30ꢀmin at −78ꢀ°C. After stirring for 105ꢀmin, a

solution of crude indenone S2 in tetrahydrofuran (238ꢀmL) was

added over 1.5ꢀh and after the addition, the reaction mixture was

allowed to warm slowly to 23ꢀ°C. After 16ꢀh, the mixture was

cooled to 0ꢀ°C and diluted with saturated aqueous ammonium

chloride solution (200ꢀmL) and ethyl acetate (300ꢀmL). The

layers were separated and the aqueous layer was extracted with

diethyl ether (3ꢀ×ꢀ300ꢀmL). The combined organic layers were

washed with saturated aqueous sodium chloride solution

(200ꢀmL) and the washed solution was dried over sodium sulfate.

The dried solution was filtered and the filtrate was concentrated.

The crude product was purified by flash column chromatography

on silica gel (2 to 3% ethyl acetate in hexanes) to obtain 21

1

hexanes), R_f= 0.56 (UV, KMnO₄). HꢀNMR (400ꢀMHz, CDCl₃)

δ: 7.63 – 7.56 (m, 2H), 7.49 (d, J = 8.1ꢀHz, 1H), 3.37 (dd, J =

18.1, 8.8ꢀHz, 1H), 2.70 (dt, J = 12.1, 3.5ꢀHz, 2H), 1.29 (d, J =

7.1ꢀHz, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 208.2, 155.2, 135.3,

131.1, 130.1, 129.9, 125.3, 42.1, 34.7, 16.3. IR (Diamond-ATR,

(38.9ꢀg, 50% over

6 steps, inconsequential mixture of

diastereomers) as a yellow solid. Analytical data for 21: Note:

1

Traces of the minor diastereomer are visible in the H and ¹³C

neat) ꢀ_ꢁ̃ _ꢂꢃ: 2964 (w), 2930 (w), 1707 (vs), 1594 (vs), 1572 (m),

NMR spectra, but solely the resonances of the major

1412 (m), 1318 (m), 1265 (m), 1199 (m), 1055 (m), 963 (s), 882

(m) 858 (m), 825 (m), 764 (m), 676 (m) cm⁻¹. HRMS (EI) calcd

for C₁₀H₉O⁸¹Br [M]⁺: 225.9811; found: 225.9814.

diastereomer are listed below. TLC (20% ethyl acetate in

1

hexanes), R_f= 0.47 (UV, KMnO₄). H NMR (400ꢀMHz, CDCl₃)

δ: 7.67 (s, 1H), 7.54 (s, 2H), 3.86 (s, 3H), 3.71 (s, 1H), 1.51 (s,

3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 197.3, 165.9, 149.4, 134.5,

132.2, 129.9, 129.8, 125.3, 64.9, 53.9, 42.8, 37.3, 9.9. IR

3.3. 2,5-Dibromo-2-methyl-2,3-dihydro-1H-inden-1-one (20)

To a solution of crude indanone 19 in ethyl acetate (1ꢀL) and

chloroform (1ꢀL), was added copper(II) bromide (106ꢀg,

474ꢀmmol, 2.00ꢀequiv). The green suspension was heated to 70

°C and while stirring with a KPG stirrer. After 22ꢀh, the mixture

was allowed to cool to 23ꢀ°C, filtered through a short pad of

Celite® and the filtrate was concentrated. The crude product 20

was used without additional purification for the next step. An

analytical pure sample of 20 was obtained by flash column

chromatography on silica gel (2% ethyl acetate in hexanes).

Analytical data for 20: TLC (20% ethyl acetate in hexanes), R_f

= 0.57 (UV). ¹H NMR (400ꢀMHz, CDCl₃) δ: 7.72 (d, J = 8.2ꢀHz,

1H), 7.61 (s, 1H), 7.59 (d, J = 8.6ꢀHz, 1H), 3.77 (d, J = 18.3ꢀHz,

1H), 3.47 (d, J = 18.3ꢀHz, 1H), 1.96 (s, 3H). ¹³C NMR

(101ꢀMHz, CDCl₃) δ: 199.2, 150.7, 132.1, 131.7, 131.4, 129.8,

(Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2954 (w), 1717 (vs), 1597 (s), 1579

̃

(m), 1435 (m), 1356 (w), 1283 (m), 1260 (s), 1237 (s), 1206 (m),

1162 (m), 1107 (w), 1055 (m), 988 (w), 952 (m), 938 (m), 889

(m), 836 (m), 788 (w), 777 (w), 738 (m) cm⁻¹. HRMS (EI) calcd

for C₁₃H₁₀O₃⁷⁹Br³⁵Cl [M]⁺: 327.9496; found: 327.9505.

3.5. Methyl 7-bromo-1-chloro-4-hydroxy-3-methyl-2-naphthoate

(22)

Note: The reaction was carried out in two parallel batches.

The crude material of both batches was subsequently combined

and purified together. A solution of 21 (8.90ꢀg, 27.0ꢀmmol,

1ꢀequiv) in sulfolane (54ꢀmL) was heated to 190ꢀ°C for 5.5ꢀh and

then cooled to 23ꢀ°C. The reaction mixture was diluted with

diethyl ether (200ꢀmL) and water (200ꢀmL). The layers were

separated and the aqueous layer was extracted with diethyl ether

(3ꢀ×ꢀ300ꢀmL). The combined organic layers were washed

successively with saturated aqueous sodium chloride solution

(200ꢀmL) and water (3ꢀ×ꢀ300ꢀmL) and the washed solution was

dried over sodium sulfate. The dried solution was filtered and the

filtrate was concentrated under reduced pressure. The crude

product was purified by flash column chromatography on silica

gel (14% ethyl acetate in hexanes) to provide 22 (13.8ꢀg, 77%) as

a brown solid. Analytical data for 22: TLC (20% ethyl acetate

in hexanes), R_f= 0.18 (UV, KMnO₄). ¹H NMR (400ꢀMHz,

CDCl₃) δ: 8.18 (s, 1H), 7.94 (d, J = 8.9ꢀHz, 1H), 7.57 (d, J =

8.9ꢀHz, 1H), 5.65 (s, 1H), 4.02 (s, 3H), 2.25 (s, 3H). ¹³C NMR

(101ꢀMHz, CDCl₃) δ: 168.5, 148.4, 133.5, 130.6, 130.5, 126.8,

124.2, 123.8, 122.2, 118.9, 115.0, 53.2, 13.3. IR (Diamond-ATR,

127.0, 59.2, 46.1, 26.8. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 1723 (vs),

̃

1596 (s), 1575 (w), 1423 (w), 1320 (m), 1266 (w), 1210 (w), 1057

(m), 973 (m), 900 (w), 857 (w), 831 (w) cm⁻¹. HRMS (EI) calcd

for C₁₀H₈O⁷⁹Br₂[M]⁺: 301.8936; found: 301.8937.

3.4. Methyl 3-bromo-1-chloro-6a-methyl-6-oxo-1,1a,6,6a-

tetrahydrocyclopropa[a]indene-1-carboxylate (21)

To crude indanone 20 in benzene (474ꢀmL) was added 1,8-

diazabicyclo[5.4.0]undec-7-ene (106ꢀmL, 711ꢀmmol, 3.00ꢀequiv)

at 0ꢀ°C. After 5ꢀmin, the solution was warmed to 23ꢀ°C and was

stirred for 45ꢀmin. The reaction mixture was diluted with

saturated aqueous ammonium chloride solution (100ꢀmL) and

diethyl ether (200ꢀmL). The layers were separated and the

aqueous layer was extracted with diethyl ether (3ꢀ×ꢀ300ꢀmL). The

combined organic layers were washed with saturated aqueous

sodium chloride solution (200ꢀmL) and the washed solution was

dried over sodium sulfate. The dried solution was filtered through

a short pad of Celite® and the filtrate was concentrated

(>200ꢀmbar). The crude indenone S2 was afforded as a yellow-

brown oil and was used immediately without additional

neat) ꢀ_ꢁꢂꢃ: 3330 (w), 2951 (w), 1695 (vs), 1619 (w), 1583 (m),

̃

1558 (w), 1439 (s), 1378 (m), 1361 (m), 1275 (vs), 1247 (vs),

1177 (m), 1111 (m), 1074 (m), 1053 (m), 962 (m), 927 (s), 874

(m), 863 (m), 823 (vs), 761 (m), 741 (m) cm⁻¹. HRMS (EI) calcd

for C₁₃H₁₀O₃⁷⁹Br³⁵Cl [M]⁺: 327.9496; found: 327.9492.

7

3.6. Methyl 1-chloro-7-ethyl-4-hydroxy-3-methyl-2-naphthoate

(15)

A solution of 23 (1.56ꢀg, 4.90ꢀmmol, 1ꢀequiv) in sulfolane

(10ꢀmL) was heated to 190ꢀ°C. After 2ꢀh, water (100ꢀmL) and

diethyl ether (100ꢀmL) were added, the layers were separated and

the aqueous layer was extracted with diethyl ether (3ꢀ×ꢀ100ꢀmL).

The combined organic layers were washed successively with

water (5ꢀ×ꢀ100ꢀmL) and saturated aqueous sodium chloride

solution (100ꢀmL). The washed solution was dried over sodium

sulfate, the dried solution was filtered and the filtrate was

concentrated. The crude product was purified by flash column

chromatography on silica gel (10% ethyl acetate in hexanes) to

afford 26 (407.7ꢀmg, 31%) as a yellow solid. Analytical data for

26: TLC (20% ethyl acetate in hexanes), R_f= 0.23 (UV, CAM,

ACCEPTED MANUSCRIPT

Note: The reaction setup has to be flame-dried very carefully,

since otherwise the yield decreases significantly. To [1,1'-

Bis(diphenylphosphino)ferrocene]palladium(II) dichloride

(400ꢀmg, 0.546ꢀmmol, 0.0180ꢀequiv) was added a solution of 22

(10.0ꢀg, 30.3ꢀmmol, 1ꢀequiv) in 1,4-dioxane (25 mL). The red

suspension was cooled to 0ꢀ°C and a freshly prepared solution of

diethylzinc (1ꢀ

M in toluene, 60.1ꢀmL, 60.7ꢀmmol, 2.00ꢀequiv) was

added very carefully over 30ꢀmin. After the addition, the dark red

mixture was allowed to warm to 23ꢀ°C over 30 min and the beige

suspension was then heated carefully to 90ꢀ°C. After 3ꢀh, it was

cooled to 0ꢀ°C and methanol (20ꢀmL) was added dropwise. Water

1

KMnO₄). H NMR (400ꢀMHz, CDCl₃) δ: 8.22 (d, J = 8.7ꢀHz,

1H), 7.64 (d, J = 1.0ꢀHz, 1H), 7.53 (dd, J = 8.7, 1.7ꢀHz, 1H), 6.04

(d, J = 7.8ꢀHz, 1H), 5.92 (ddd, J = 17.0, 9.9, 7.7ꢀHz, 1H), 5.75 (d,

J = 16.8ꢀHz, 1H), 5.52 (d, J = 10.3ꢀHz, 1H), 5.50 (s, 1H), 2.83 (q,

J = 7.5ꢀHz, 2H), 2.70 (s, 3H), 1.32 (t, J = 7.6ꢀHz, 3H). ¹³C NMR

(101ꢀMHz, CDCl₃) δ: 171.4, 150.8, 143.4, 140.0, 134.7, 129.8,

126.6, 125.8, 123.1, 122.0, 121.7, 121.2, 112.4, 80.7, 29.1, 15.4,

(100ꢀmL) and aqueous hydrochloric acid solution (2ꢀM, 100ꢀmL)

were added, the layers were separated and the aqueous layer was

extracted with diethyl ether (3ꢀ×ꢀ200ꢀmL). The combined organic

layers were washed with saturated aqueous sodium chloride

solution (200ꢀmL). The washed solution was dried over sodium

sulfate, the dried solution was filtered through a short pad of

Celite® and the filtrate was concentrated under reduced pressure.

The crude product was purified by flash column chromatography

on silica gel (9% ethyl acetate in hexanes) to obtain 15 (7.82ꢀg,

93%) as a red-brown oil. Analytical data for 15: TLC (20%

9.2. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 3418 (w), 2966 (w), 1733

̃

(vs), 1582 (w), 1469 (w), 1395 (w), 1371 (w), 1299 (w), 1262 (w),

1198 (w), 1013 (m), 977 (m), 939 (w), 834 (w) cm⁻¹. HRMS (EI)

calcd for C₁₇H₁₆O₃[M]⁺: 268.1094; found: 268.1074.

1

3.9. Allyl (8-ethyl-4-methyl-3-oxo-1-vinyl-1,3-

dihydronaphtho[1,2-c]furan-5-yl) carbonate (27)

ethyl acetate in hexanes), R_f= 0.31 (UV, KMnO₄). H NMR

(400ꢀMHz, CDCl₃) δ: 8.05 (d, J = 8.6ꢀHz, 1H), 7.97 (q, J =

0.9ꢀHz, 1H), 7.45 (dd, J = 8.7, 1.7ꢀHz, 1H), 5.37 (s, 1H), 4.03 (s,

3H), 2.86 (q, J = 7.6ꢀHz, 2H), 2.32 (s, 3H), 1.63 (s, 1H), 1.36 (t, J

= 7.6ꢀHz, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 168.6, 148.2,

143.7, 132.7, 130.0, 128.3, 123.9, 122.7, 121.6, 119.6, 113.1,

To a solution of 26 (500ꢀmg, 1.86ꢀmmol, 1ꢀequiv) in

tetrahydrofuran (9.3ꢀmL) was added triethylamine (0.363ꢀmL,

2.61ꢀmmol, 1.40ꢀequiv). After 10 min, the reaction mixture was

cooled to 0ꢀ°C and allyl chloroformate (0.238ꢀmL, 2.24ꢀmmol,

1.20ꢀequiv) was added. After 15ꢀmin, water (100ꢀmL) was added,

the layers were separated and the aqueous layer was extracted

with ethyl acetate (3ꢀ×ꢀ100 mL). The combined organic layers

were washed with saturated aqueous sodium chloride solution

(70ꢀmL). The washed solution was dried over sodium sulfate, the

dried solution was filtered and the filtrate was concentrated. The

crude product was purified by flash column chromatography on

silica gel (9% ethyl acetate in hexanes) to afford 27 (528ꢀmg,

80%) as a light-yellow solid. Analytical data for 27: TLC (20%

52.9, 29.3, 15.6, 13.1. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 3475 (w),

̃

2362 (m), 1715 (s), 1438 (m), 1387 (m), 1293 (m), 1239 (vs),

1053 (m), 668 (m) cm⁻¹.HRMS (EI) calcd for C₁₅H₁₅O₃³⁵Cl [M]⁺:

278.0704; found: 278.0699.

3.7. Methyl 4-(allyloxy)-1-chloro-7-ethyl-3-methyl-2-naphthoate

(23)

To a solution of 15 (100ꢀmg, 0.359ꢀmmol, 1ꢀequiv) in

dimethylformamide (1.2ꢀmL) were successively added potassium

carbonate (74.4ꢀmg, 0.538ꢀmmol, 1.50ꢀequiv) and allyl bromide

(34.2ꢀꢁL, 47.7ꢀmmol, 1.10ꢀequiv) and the reaction mixture was

heated to 65ꢀ°C. After 1.5ꢀh, water (10ꢀmL) and diethyl ether

(15ꢀmL) were added, the layers were separated and the aqueous

layer was extracted with diethyl ether (3ꢀ×ꢀ15ꢀmL). The combined

organic layers were washed with aqueous hydrochloric acid

1

ethyl acetate in hexanes), R_f= 0.35ꢀ(UV, CAM, KMnO₄). H

NMR (400ꢀMHz, CDCl₃) δ: 7.90 (d, J = 8.7ꢀHz, 1H), 7.71 (d, J =

0.8 Hz, 1H), 7.57 (dd, J = 8.7, 1.6ꢀHz, 1H), 6.10 (d, J = 7.7ꢀHz,

1H), 6.10 – 5.88 (m, 2H), 5.80 (d, J = 16.7ꢀHz, 1H), 5.56 (d, J =

9.9ꢀHz, 1H), 5.48 (dq, J = 17.2, 1.4ꢀHz, 1H), 5.39 (dq, J = 10.4,

1.1ꢀHz, 1H), 4.81 (dt, J = 5.8, 1.3ꢀHz, 2H), 2.83 (q, J = 7.6ꢀHz,

2H), 2.66 (s, 3H), 1.31 (d, J = 7.6ꢀHz, 3H). ¹³C NMR (101ꢀMHz,

CDCl₃) δ: 170.4, 153.0, 146.1, 145.7, 143.8, 134.0, 131.3, 131.0,

128.5, 126.7, 124.4, 122.3, 122.3, 122.1, 121.8, 120.1, 80.7, 69.8,

solution (2ꢀM, 30ꢀmL) and saturated aqueous sodium chloride

solution (30ꢀmL). The washed solution was dried over sodium

sulfate, the dried solution was filtered and the filtrate was

concentrated under reduced pressure. The residue was purified by

flash column chromatography on silica gel (5% ethyl acetate in

hexanes) to yield 23 (103ꢀmg, 90%) as a colorless oil. Analytical

data for 23: TLC (20% ethyl acetate in hexanes), R_f= 0.58 (UV,

KMnO₄). ¹H NMR (400ꢀMHz, CDCl₃) δ: 8.02 (s, 1H), 8.01 (d, J

= 6.6ꢀHz, 1H), 7.45 (dd, J = 8.6, 0.9ꢀHz, 1H), 6.18 (ddt, J = 17.1,

11.6, 5.9ꢀHz, 1H), 5.50 (d, J = 17.2ꢀHz, 1H), 5.33 (d, J = 10.4ꢀHz,

1H), 4.45 (d, J = 6.6ꢀHz, 2H), 4.01 (s, 3H), 2.85 (q, J = 7.3ꢀHz,

2H), 2.37 (s, 3H), 1.34 (t, J = 7.1ꢀHz, 3H). ¹³C NMR (101ꢀMHz,

CDCl₃) δ: 168.2, 152.1, 143.6, 133.6, 133.3, 130.4, 129.0, 127.9,

123.4, 123.0 (2C), 122.6, 118.0, 75.2, 52.8, 29.3, 15.6, 13.5. IR

29.1, 15.4, 10.6. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2921 (w), 1746

̃

(vs), 1610 (w), 1411 (w), 1356 (w), 1304 (w), 1232 (s), 1196 (m),

1147 (m), 1027 (m), 1013 (m), 972 (m), 938 (m), 924 (m), 886

(m), 840 (m), 778 (m) cm⁻¹. HRMS (EI) calcd for C₂₁H₂₀O₅[M]⁺:

352.1305; found: 352.1309.

3.10. 4-Allyl-8-ethyl-4-methyl-1-vinyl-1,4-dihydronaphtho[1,2-

c]furan-3,5-dione (28)

Tetrakis(triphenylphosphine)palladium(0)

(32.8ꢀmg,

0.0284ꢀmmol, 0.100ꢀequiv) was added to a Schlenk flask and the

flask was purged with argon. Carbonate 27 (100ꢀmg, 0.284ꢀmmol,

1ꢀequiv) was added and the flask was purged with argon. The

reactants were dissolved in degassed toluene (7.5ꢀmL) and

degassed n-hexanes (0.75ꢀmL) and stirred at 45ꢀ°C for 45ꢀmin.

The reaction mixture was filtered through a plug of silica gel and

rinsed thoroughly with diethyl ether (100ꢀmL). The filtrate was

concentrated and the residue was purified by flash column

chromatography on silica gel (5% ethyl acetate in hexanes) to

(Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2965 (w), 1736 (vs), 1598 (w), 1436

̃

(m), 1385 (m), 1330 (m), 1315 (m), 1280 (m), 1231 (s), 1214 (m),

1170 (m), 1113 (m), 1051 (s), 991 (m), 972 (m), 937 (m), 877

(m), 833 (m), 757 (w) cm⁻¹. HRMS (EI) calcd for C₁₈H₁₉O₃³⁵Cl

[M]⁺: 318.1017; found: 318.1020.

3.8. 8-Ethyl-5-hydroxy-4-methyl-1-vinylnaphtho[1,2-c]furan-

3(1H)-one (26)

8

(151ꢀMHz, CDCl₃) δ: 198.4, 166.4, 151.9, 137.9, 134.4, 132.2,

^{obtain 28 (60ꢀmg, 69%, mixture of diastereome}A^rs)C^asC^aE^yeP^llT^owE^oD^il.MANUSCRIPT

Note: A small sample of the diastereomeric mixture was used to

separate the diastereomers by flash column chromatography on

silica gel (5% ethyl acetate in hexanes). Analytical data for the

major isomer 28: TLC (20% ethyl acetate in hexanes), R_f= 0.29

(UV, KMnO₄). ¹H NMR (800ꢀMHz, CDCl₃) δ: 8.11 (d, J =

8.0ꢀHz, 1H), 7.43 (dd, J = 8.0, 1.7ꢀHz, 1H), 7.28 – 7.26 (m, 1H),

5.89 (ddd, J = 17.0, 10.0, 7.9 Hz, 1H), 5.77 (d, J = 8.4ꢀHz, 1H),

5.76 (d, J = 17.0ꢀHz, 1H), 5.57 (d, J = 10.0ꢀHz, 1H), 5.33 (dddd, J

= 16.8, 10.1, 8.2, 6.6ꢀHz, 1H), 4.97 (dq, J = 16.9, 1.3ꢀHz, 1H),

4.80 (dd, J = 10.1, 1.9ꢀHz, 1H), 2.96 (dd, J = 13.5, 8.2ꢀHz, 1H),

2.81 (dd, J = 13.5, 6.5ꢀHz, 1H), 2.74 (qd, J = 7.5, 2.9ꢀHz, 2H),

1.53 (s, 3H), 1.28 (d, J = 7.6ꢀHz, 3H). ¹³C NMR (201ꢀMHz,

CDCl₃) δ: 200.8, 170.0, 153.0, 151.7, 133.5, 132.8, 132.4, 131.4,

130.7, 128.9, 128.3, 124.4, 122.5, 118.7, 80.5, 48.6, 42.6, 29.2,

129.7, 127.7, 127.6, 127.5, 125.4, 118.8, 52.5, 52.3, 44.2, 29.3,

23.7, 15.0. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2970 (w), 1729 (vs),

̃

1679 (m), 1598 (m), 1453 (w), 1434 (m), 1284 (m), 1248 (m),

1231 (m), 1195 (m), 1044 (w), 994 (w), 924 (w), 848 (w) 701 (w)

cm⁻¹. HRMS (EI) calcd for C₁₈H₁₉O₃³⁵Cl [M]⁺: 318.1017; found:

318.1016.

3.13. Methyl (E)-1-chloro-7-ethyl-3-methyl-4-oxo-3-(prop-1-en-

1-yl)-3,4-dihydronaphthalene-2-carboxylate (30)

To

bis(dibenzylidenacetone)palladium(0)

(113ꢀmg,

0.0196ꢀmmol, 10.0ꢀmol%) was added a solution of 24 (625ꢀmg,

1.96ꢀmmol, 1ꢀequiv) in degassed toluene (5.3ꢀmL), tri-t-

butylphosphine (1ꢀ

10.0ꢀmol%) and then isobutyryl chloride (0.078ꢀ

M

in toluene, 0.196ꢀmL, 0.196ꢀmmol,

in degassed

M

23.1, 15.0. IR (Diamond-ATR, neat) ꢀ̃_ꢁꢂꢃ: 2920 (m), 2363 (w),

toluene, 2.51ꢀmL, 0.196ꢀmmol, 10.0ꢀmol%). The reaction mixture

was heated to 80ꢀ°C for 41ꢀh, diluted with ethyl acetate (50ꢀmL)

and then concentrated. The residue was purified by flash column

chromatography on silica gel (2% ethyl acetate and 1% acetic

acid in hexanes) to afford 30 (523ꢀmg, 84%) as a yellow oil.

Analytical data for 30: Note: The product 30 could not be

separated from traces of remaining starting material 24 since

both were co-polar during column chromatography. TLC (20%

ethyl acetate in hexanes), R_f= 0.56 (UV, KMnO₄). ¹HꢀNMR (400

MHz, CDCl₃) δ: 7.96 (d, J = 7.9ꢀHz, 1H), 7.65 (d, J = 1.6ꢀHz,

1H), 7.33 (dd, J = 7.9, 1.6ꢀHz, 1H), 5.67 (dq, J = 15.6, 6.5ꢀHz,

1H), 5.43 (dq, J = 15.4, 1.6ꢀHz, 1H), 3.85 (s, 3H), 2.76 (q, J =

7.6ꢀHz, 2H), 1.65 (dd, J = 6.5, 1.6ꢀHz, 3H), 1.52 (s, 3H), 1.29 (t, J

= 7.6ꢀHz, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 197.0, 166.4,

151.9, 137.8, 134.3, 129.8, 129.7, 128.4, 128.2, 127.3, 127.3,

125.6, 54.2, 52.4, 29.4, 21.5, 18.2, 15.2. IR (Diamond-ATR,

1756 (vs), 1679 (m), 1600 (m), 1456 (w), 1378 (w), 1239 (m),

1015 (m), 853 (w), 797 (w) cm⁻¹. HRMS (EI) calcd for C₂₀H₂₀O₃

[M]⁺: 308.1407; found: 308.1410.

3.11. Methyl 4-(((allyloxy)carbonyl)oxy)-1-chloro-7-ethyl-3-

methyl-2-naphthoate (S3)

To

a solution of 15 (4.00ꢀg, 14.4ꢀmmol, 1ꢀequiv) in

tetrahydrofuran (72ꢀmL) was added triethylamine (2.79ꢀmL,

20.1ꢀmmol, 1.40ꢀequiv), the mixture was cooled to 0ꢀ°C and allyl

chloroformate (1.83ꢀmL, 17.2ꢀmmol, 1.20ꢀequiv) was added.

After 10ꢀmin, saturated aqueous ammonium chloride solution

(100ꢀmL) was added, the layers were separated and the aqueous

layer was extracted with ethyl acetate (3ꢀ×ꢀ100ꢀmL). The

combined organic layers were washedꢀwith saturated aqueous

hydrogen chloride solution (100 mL). The washed solution was

dried over sodium sulfate, the dried solution was filtered and the

filtrate was concentrated. The product S3 (5.15ꢀg, 99%) was

obtained as an orange oil and used without further purification.

Analytical data for S3: TLC (20% ethyl acetate in hexanes), R_f

neat) ꢀ_ꢁꢂꢃ: 2967 (w), 1729 (vs), 1683 (s), 1598 (s), 1447 (m),

̃

1433 (m), 1373 (w), 1270 (vs), 1230 (s), 1198 (s), 1121 (m), 1061

(m), 1043 (s), 983 (m), 958 (s), 846 (m), 806 (m), 698 (m) cm⁻¹.

HRMS (EI) calcd for C₁₈H₁₉O₃³⁵Cl [M]⁺: 318.1017; found:

318.1014.

1

= 0.43 (UV, KMnO₄). H NMR (599ꢀMHz, CDCl₃) δ: 8.05 (d, J

= 1.8ꢀHz, 1H), 7.79 (d, J = 8.5ꢀHz, 1H), 7.49 (dd, J = 8.7, 1.7ꢀHz,

1H), 6.24 – 5.78 (m, 1H), 5.46 (dq, J = 16.9, 1.5ꢀHz, 1H), 5.37

(dq, J = 10.6, 1.3ꢀHz, 1H), 4.88 – 4.59 (m, 2H), 4.01 (s, 3H), 2.85

(q, J = 7.6ꢀHz, 2H), 2.29 (s, 3H), 1.33 (t, J = 7.5ꢀHz, 3H). ¹³C

NMR (151ꢀMHz, CDCl₃) δ: 167.6, 152.9, 144.1, 143.8, 132.8,

131.1, 130.2, 129.9, 126.5, 126.2, 123.3, 123.1, 121.3, 120.0,

3.14. Methyl (E)-1-chloro-7-ethyl-3-methyl-4-methylene-3-(prop-

1-en-1-yl)-3,4-dihydronaphthalene-2-carboxylate (31)

To

a solution of methyltriphenylphosphonium bromide

(1.03ꢀg, 2.89ꢀmmol, 2.00ꢀequiv) in tetrahydrofuran (14ꢀmL) was

added potassium tert-butoxide (324ꢀmg, 2.89ꢀmmol, 2.00ꢀequiv).

After 1.5ꢀh, the reaction mixture was cooled to 0ꢀ°C, a solution of

30 (460ꢀmg, 1.44ꢀmmol,ꢀ1ꢀequiv) in tetrahydrofuran (9ꢀmL) was

added and the reaction mixture was allowed to warm to 23ꢀ°C.

After 4ꢀh, water (70ꢀmL) was added, the layers were separated

and the aqueous phase was extracted with ethyl acetate

(3ꢀ×ꢀ70ꢀmL). The combined organic extracts were dried over

sodium sulfate, the dried solution was filtered and the filtrate was

concentrated. The residue was purified by flash column

chromatography on silica gel (20% ethyl acetate in hexanes) to

yield 31 (455ꢀmg, 99%) as a yellow oil. Analytical data for 31:

TLC (20% ethyl acetate in hexanes), R_f= 0.56 (UV, CAM,

69.8, 52.9, 29.3, 15.6, 13.6. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2361

̃

(m), 1764 (m), 1736 (m), 1437 (w), 1232 (vs), 940 (w), 668 (w)

cm⁻¹. HRMS (EI) calcd for C₁₉H₂₀O₅³⁵Cl [M]⁺: 362.0916; found:

362.0917.

3.12. methyl 3-allyl-1-chloro-7-ethyl-3-methyl-4-oxo-3,4-

dihydronaphthalene-2-carboxylate (24)

Tetrakis(triphenylphosphine)palladium(0)

(669ꢀmg,

0.579ꢀmmol, 7.00ꢀmol%) was added to a Schlenk flask and the

flask was purged with argon. S3 (3.00ꢀg, 8.27ꢀmmol, 1ꢀequiv) was

addedꢀand the flask was purged with argon. Degassed toluene

(219ꢀmL) and degassed n-hexane (22ꢀmL) were added and the

solution was stirred at 45ꢀ°C for 15ꢀh. The reaction mixture was

filtered through a plug of silica gel and the plug was thoroughly

rinsed with diethyl ether (200ꢀmL). The filtrate was concentrated

and the residue was purified by flash column chromatography on

silica gel (2% ethyl acetate and 1% acetic acid in hexanes) to

obtain 24 (2.1ꢀg, 80%) as a light-yellow oil. Analytical data for

24: TLC (20% ethyl acetate in hexanes), R_f= 0.44 (UV,

KMnO₄) ¹H NMR (599ꢀMHz, CDCl₃) δ: 8.00 (d, J = 7.8ꢀHz, 1H),

7.67 (d, J = 1.6ꢀHz, 1H), 7.34 (dd, J = 8.2, 1.7ꢀHz, 1H), 5.74 –

5.32 (m, 1H), 4.99 (dt, J = 17.0, 1.6ꢀHz, 1H), 4.93 – 4.77 (m,

1H), 3.91 (s, 3H), 2.76 (p, J = 7.6ꢀHz, 3H), 2.52 (dd, J = 13.7,

6.5ꢀHz, 1H), 1.41 (s, 3H), 1.30 (t, J = 7.7ꢀHz, 3H). ¹³C NMR

1

KMnO₄). HꢀNMR (400ꢀMHz, CDCl₃) δ: 7.48 (d, J = 1.7ꢀHz,

1H), 7.45 (d, J = 7.8ꢀHz, 1H), 7.16 (dd, J = 7.9, 1.8ꢀHz, 1H), 5.67

– 5.56 (m, 2H), 5.44 (s, 1H), 5.18 (s, 1H), 3.80 (s, 3H), 2.68 (q, J

= 7.6ꢀHz, 2H), 1.77 – 1.66 (m, 3H), 1.42 (s, 3H), 1.26 (t, J =

7.6ꢀHz, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 167.5, 148.3, 144.8,

136.8, 133.3, 132.2, 129.4, 128.8, 128.3, 125.8, 125.3, 124.7,

112.7, 52.1, 47.3, 28.9, 23.7, 18.2, 15.6. IR (Diamond-ATR,

neat) ꢀ_ꢁꢂꢃ: 2966 (w), 1755 (vs), 1602 (w), 1485 (w), 1432 (m),

̃

1264 (s), 1235 (s), 1193 (m), 1154 (m), 1091 (w), 1043 (m), 962

(m), 898 (m), 836 (m), 737 (m) cm⁻¹. HRMS (EI) calcd for

C₁₉H₂₁O₂³⁵Cl [M]⁺: 316.1225; found: 316.1222.

9

3.15. Methyl-1-chloro-7-ethyl-4-(methoxymethylene)-3-methyl-3-

NMR (151ꢀMHz, C₆D₆) δ: 198.0, 197.6*, 166.7*, 145.2, 145.1*,

136.5, 135.1*, 133.3, 131.4, 131.1, 130.6, 130.1, 129.8, 129.3,

_{((E)-prop-1-en-1-yl)-3,4-dihydronaphthalene-2}A_-caC_rbC_oxE_ylP_atT_{e (}E_S4D_).MANUSCRIPT

129.2, 128.6, 128.5, 125.9, 125.5, 63.0, 62.3*, 51.7*, 51.6, 43.8,

42.8*, 28.9, 28.8*, 23.0, 21.6*, 18.1, 17.9*, 15.5, 15.4*. IR

To a suspension of (methoxymethyl)triphenylphosphonium

chloride (1.19ꢀg, 3.48ꢀmmol, 3.70ꢀequiv) in tetrahydrofuran

(Diamond-ATR, neat) ꢀ̃_ꢁꢂꢃ: 2967 (w), 1724 (vs), 1603 (w), 1434

(w), 1266 (s), 1203 (w), 1046 (w), 964 (w), 834 (w) cm⁻¹. HRMS

(4.7ꢀmL) was added n-butyllithium (2.36ꢀ

M in hexanes, 1.24ꢀmL,

(EI) calcd for C₁₉H₂₁O₃³⁵Cl [M]⁺: 332.1174; found: 332.1155.

2.92ꢀmmol, 3.10ꢀequiv) over 5ꢀmin at 0ꢀ°C. After the addition was

completed, the reaction mixture was warmed to 23ꢀ°C, stirred at

this temperature for 20ꢀmin and then cooled to 0ꢀ°C. A solution of

30 (300ꢀmg, 0.941ꢀmmol, 1ꢀequiv) in tetrahydrofuran (4.7ꢀmL)

was added and the reaction mixture was warmed to 23ꢀ°C. After

2ꢀh, saturated aqueous ammonium chloride solution (15ꢀmL) was

added and the layers were separated. The aqueous phase was

extracted with ethyl acetate (3ꢀ×ꢀ20ꢀmL) and the combined

organic extracts were washed with saturated aqueous sodium

chloride solution (15ꢀmL). The washed organic solution was

dried over sodium sulfate and the dried solution was filtered and

concentrated. The residue was purified by flash column

chromatography on silica gel (2% ethyl acetate in hexanes) to

afford S4 (265ꢀmg, 81%, inconsequential 1:1 mixture of

diastereomers) as a light-yellow oil. Analytical data for S4:

Note: Singals marked with an asterisk belong to the same

diastereomer. TLC (20% ethyl acetate in hexanes), R_f= 0.47

(UV, CAM). ¹H NMR (400ꢀMHz, CDCl₃) δ: 7.81 (d, J = 8.0ꢀHz,

1H)*, 7.48 (d, J = 1.9ꢀHz, 1H)*, 7.46 (d, J = 1.9ꢀHz, 1H), 7.20 (d,

J = 7.9ꢀHz, 1H), 7.15 (dd, J = 8.0, 1.9ꢀHz, 1H)*, 7.07 (dd, J = 8.0,

1.9ꢀHz, 1H), 6.43 (s, 1H), 6.14 (s, 1H)*, 5.73 – 5.63 (m, 1H),

5.62 – 5.57 (m, 1H+1H*), 5.46 (dq, J = 15.4, 6.4ꢀHz, 1H), 3.80

(s, 3H), 3.78 (s, 3H)*, 3.70 (s, 3H)*, 3.66 (s, 3H), 2.64 (qd, J =

7.6, 5.4ꢀHz, 2H+2H*), 1.75 – 1.67 (m, 3H)*, 1.64 (dd, J = 6.4,

1.6ꢀHz, 3H), 1.54 (s, 3H), 1.38 (s, 3H)*, 1.24 (td, J = 7.6, 3.6ꢀHz,

3H+3H*). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 167.6, 167.5*, 146.8,

145.9*, 142.8, 142.7*, 136.6, 136.6*, 134.6, 133.3*, 131.8,

129.3*, 129.1, 128.9*, 128.7*, 128.7*, 128.5, 128.5*, 128.0,

125.9*, 124.9, 124.7*, 123.4, 123.0, 116.6, 116.4*, 60.8*, 60.7,

52.0, 52.0*, 45.6, 45.3*, 28.9, 28.7*, 24.0*, 23.0, 18.2*, 18.0,

3.17. methyl (E)-1-chloro-7-ethyl-4-formyl-3,4-dimethyl-3-

(prop-1-en-1-yl)-3,4-dihydronaphthalene-2-carboxylate (35)

To sodium hydride (60% dispersion in mineral oil, 32.9ꢀmg,

0.823ꢀmmol, 2.00ꢀequiv) was added a degassed solution of 34

(137ꢀmg, 0.412ꢀmmol, 1ꢀequiv) and methyl iodide (0.256ꢀmL,

4.12ꢀmmol, 10.0ꢀequiv) in tetrahydrofuran (5.9ꢀmL) at 0ꢀ°C. The

solution was allowed to warm to 23ꢀ°C and after 5.5ꢀh, saturated

aqueous ammonium chloride solution (10ꢀmL) was added. The

layers were separated and the aqueous phase was extracted with

ethyl acetate (3ꢀ×ꢀ20ꢀmL). The combined organic extracts were

dried over sodium sulfate, the dried solution was filtered and the

filtrate was concentrated. The residue was purified by flash

column chromatography on silica gel (toluene) to obtain 35

(98ꢀmg, 69%) as a light-yellow oil. Analytical data for 35: TLC

(20% ethyl acetate in hexanes), R_f= 0.45 (UV, CAM, KMnO₄).

¹H NMR (800ꢀMHz, C₆D₆) δ: 9.82 (s, 1H), 7.68 (d, J = 1.9 Hz,

1H), 6.87 (d, J = 7.9 Hz, 1H), 6.83 (dd, J = 7.9, 1.9ꢀHz, 1H), 5.50

– 5.30 (m, 2H), 3.43 (s, 3H), 2.33 (q, J = 7.6ꢀHz, 2H), 1.35 (s,

3H), 1.34 – 1.30 (m, 3H), 1.24 (s, 3H), 1.00 (t, J = 7.6ꢀHz, 3H).

¹³C NMR (201ꢀMHz, C₆D₆) δ: 199.8, 166.7, 144.5, 141.5, 136.1,

133.2, 131.1, 130.3, 129.9, 127.3, 127.1, 125.9, 56.2, 51.6, 46.2,

28.7, 18.1, 18.0, 15.4, 14.0. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2969

̃

(w), 2362 (w), 1731 (vs), 1605 (w), 1434 (w), 1373 (w), 1268 (m),

1154 (w), 1102 (w), 1042 (w), 968 (w), 890 (w), 816 (w) cm⁻¹.

HRMS (EI) calcd for C₂₀H₂₃O₃³⁵Cl [M]⁺: 346.1330; found:

346.1341.

3.18. methyl (E)-1-chloro-7-ethyl-4-(hydroxymethyl)-3,4-

dimethyl-3-(prop-1-en-1-yl)-3,4-dihydronaphthalene-2-

carboxylate (36)

15.6*, 15.6. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2965 (m), 1748 (vs),

̃

1641 (s), 1432 (m), 1260 (s), 1239 (s), 1145 (m), 1103 (m), 1043

(m), 977 (m), 833 (m) cm⁻¹. HRMS (EI) calcd for C₂₀H₂₃O₃³⁵Cl

[M]⁺: 346.1330; found: 346.1330.

To a solution of 35 (15.0ꢀmg, 0.0432ꢀmmol, 1ꢀequiv) in

methanol (0.4ꢀmL) was added sodium borohydride (2.45ꢀmg,

0.0649ꢀmmol, 1.50ꢀequiv) at 0ꢀ°C. After 25ꢀmin, saturated

aqueous ammonium chloride solution (10ꢀmL) was added. The

layers were separated and the aqueous phase was extracted with

ethyl acetate (3ꢀ×ꢀ15ꢀmL). The combined organic extracts were

driedꢀover sodium sulfate, the dried solution was filtered and the

filtrate was concentrated. The residue was purified by flash

column chromatography on silica gel (11% ethyl acetate in

hexanes) to obtain I.143 (12ꢀmg, 80%, major isomer) as a

colorless oil. Analytical data for 36: Note: Signals in the ¹³C

NMR which could only be assigned by cross-coupling in the

HMBC are marked with an asterisk. The relative stereochemistry

was assigned by NOE correlations of 36: TLC (20% ethyl

3.16. Methyl (E)-1-chloro-7-ethyl-4-formyl-3-methyl-3-(prop-1-

en-1-yl)-3,4-dihydronaphthalene-2-carboxylate (34)

To S4 (265ꢀmg, 0.764ꢀmmol, 1ꢀequiv) in diethyl ether (13ꢀmL)

was added perchloric acid (70% in water, 0.395ꢀmL, 4.56ꢀmmol,

6.00ꢀequiv) and the reaction mixture was vigorously stirred for

19ꢀh. The mixturw was diluted with diethyl ether (15ꢀmL) and

water (15ꢀmL), and then sodium bicarbonate (400ꢀmg) was

carefully added. The layers were separated and the aqueous phase

was extracted with diethyl ether (3ꢀ×ꢀ20ꢀmL). The combined

organic extracts were washed with saturated sodium chloride

solution (15ꢀmL), dried over sodium sulfate and the dried

solution was filtered and concentrated. The residue was purified

by flash column chromatography on Davisil© (2% ethyl acetate

in hexanes) to yield 34 (202ꢀmg, 79%, inconsequential mixture of

diastereomers) as a colorless oil. Analytical data for 34: Note:

The singals, which could be assigned to the major diastereomer,

are marked with an asterisk. TLC (20% ethyl acetate in

1

acetate in hexanes), R_f= 0.21 (UV, CAM, ANIS, KMnO₄). H

NMR (400ꢀMHz, CDCl₃) δ: 7.53 (d, J = 1.7ꢀHz, 1H), 7.23 (d, J =

7.9ꢀHz, 1H), 7.18 (dd, J = 7.9, 1.9ꢀHz, 1H), 5.50 (dt, J = 18.0,

6.4ꢀHz, 1H), 5.34 (d, J = 15.6ꢀHz, 1H), 3.90 (dd, J = 10.9, 3.9ꢀHz,

1H), 3.82 (s, 3H), 3.51 (t, J = 9.8ꢀHz, 1H), 2.67 (q, J = 7.6ꢀHz,

2H), 1.60 (dd, J = 6.3, 1.5ꢀHz, 3H), 1.30 (s, 3H), 1.26 (t, J =

7.6ꢀHz, 3H), 1.21 (s, 3H). ¹³CꢀNMR (101ꢀMHz, CDCl₃) δ: 167.6,

143.3, 135.9, 131.0, 129.9, 129.2, 127.9*, 127.4*, 126.0, 125.4,

66.0, 52.2, 46.5, 45.8, 29.9, 28.6, 18.3, 16.4*, 16.4, 15.5. IR

1

hexanes), R_f= 0.47 (UV, CAM, KMnO₄). H NMR (599ꢀMHz,

C₆D₆) δ: 9.62 (d, J = 4.5ꢀHz, 1H), 9.54 (d, J = 4.5ꢀHz, 1H)*, 7.63

(d, J = 11.9ꢀHz, 1H+1H*), 6.88 – 6.63 (m, 2H+2H*), 5.77 – 5.59

(m, 1H), 5.51 (dqd, J = 15.3, 6.5, 2.4ꢀHz, 1H+1H*), 5.33 (dd, J =

15.6, 2.1ꢀHz, 1H*), 3.44 (app d, J = 4.06ꢀHz, 3H+3H*), 3.23 (d, J

= 4.7ꢀHz, 1H)*, 3.18 (d, J = 4.9ꢀHz, 1H), 2.31 (dq, J = 19.5,

7.5ꢀHz, 2H+2H*), 1.41 (dd, J = 6.7, 1.6ꢀHz, 3H), 1.29 – 1.25 (m,

9H*), 0.99 (t, J = 7.7ꢀHz, 3H), 0.96 (t, J = 7.7ꢀHz, 3H)*. ¹³C

(Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 3430 (w), 2964 (m), 1731 (vs), 1629

̃

(w), 1607 (w), 1433 (m), 1375 (w), 1268 (vs), 1196 (w), 1151

(m), 1040 (s), 968 (m), 890 (w), 833 (w), 723 (w) cm⁻¹. HRMS

(EI) calcd for C₂₀H₂₅O₃³⁵Cl [M]⁺: 348.1487; found: 348.1492.

10

3.19. methyl (E)-1-chloro-7-ethyl-3,4-dimethyl-3-(prop-1-en-1-

3.21. 10-Chloro-8-ethyl-3,5,5-trimethyl-3,5,9,9a-tetrahydro-1H-

benzo[g]isochromen-1-one (42)

_{yl)-4-((tosyloxy)methyl)-3,4-dihydronaphthalen}A_e-2C_-cC_arE_boP_xyT_laE_teD MANUSCRIPT

(37)

To titanium(IV) chloride (1ꢀ

M

in dichloromethane, 0.941ꢀmL,

To 36 (14.0ꢀmg, 0.0401ꢀmmol, 1ꢀequiv) and p-toluene-sulfonyl

0.941ꢀmmol, 6.00ꢀequiv) in a Schlenk tube, which was wrapped

in aluminum foil, was added dimethylzinc (15wt% in toluene,

0.784ꢀmL, 0.941ꢀmmol, 6.00ꢀequiv) over 5ꢀmin at 0ꢀ°C. After

25ꢀmin, a solution of 30 (50.0ꢀmg, 0.157ꢀmmol, 1ꢀequiv) in

dichloromethane (1.6ꢀmL) was added over 5ꢀmin. The reaction

mixture was stirred for 8ꢀh at 0ꢀ°C before saturated aqueous

ammonium chloride solution (10ꢀmL) was added. The layers

were separated and the aqueous phase was extracted with ethyl

acetate (3ꢀ×ꢀ10ꢀmL). The combined organic extracts were dried

over sodium sulfate, the dried solution was filtered and the

filtrate was concentrated. The residue was purified by flash

column chromatography on silica gel (2% ethyl acetate and 1%

acetic acid in hexanes) to yield 42 (29ꢀmg, 61%) as a light-yellow

oil. Analytical data for 42: TLC (20% ethyl acetate in hexanes),

chloride (23.0ꢀmg, 0.120ꢀmmol, 3.00ꢀequiv) was added pyridine

(0.3ꢀmL). After stirring for 48ꢀh, the reaction mixture was diluted

with saturated aqueous ammonium chloride solution (15ꢀmL), the

layers were separated and the aqueous phase was extracted with

ethyl acetate (3ꢀ×ꢀ20ꢀmL). The combined organic extracts were

dried over sodium sulfate, the dried solution was filtered and the

filtrate was concentrated. The residue was purified by flash

column chromatography on silica gel (14% ethyl acetate in

hexanes) to afford 37 (14.8ꢀmg, 73%) as a colorless oil.

Analytical data for 37: Note: Due to severe signal broadening

in the NMR spectra some signals are missing or possess

inaccurate integrals. Signals in the ¹³C NMR which could only be

assigned by cross-coupling in the HMBC are marked with an

asterisk. TLC (20% ethyl acetate in hexanes), R_f= 0.31 (UV,

1

R_f= 0.23 (UV, CAM, KMnO₄). H NMR (599ꢀMHz, CDCl₃) δ:

1

ANIS, KMnO₄). H NMR (400ꢀMHz, CDCl₃) δ: 7.29 (s, 1H),

7.85 (d, J = 1.9ꢀHz, 1H), 7.33 (d, J = 8.0ꢀHz, 1H), 7.24 (dd, J =

8.0, 1.9ꢀHz, 1H), 5.94 (d, J = 2.9ꢀHz, 1H), 5.03 (qd, J = 6.8,

3.2ꢀHz, 1H), 2.69 (q, J = 7.7ꢀHz, 2H), 1.48 (s, 3H), 1.47 (d, J =

7.0ꢀHz, 3H), 1.43 (s, 3H), 1.26 (t, J = 7.7ꢀHz, 3H). ¹³C NMR

(151ꢀMHz, CDCl₃) δ: 163.6, 143.1, 143.0, 142.6, 136.8, 130.7,

130.2, 127.6, 123.8, 123.3, 117.9, 74.5, 38.3, 28.9, 28.6, 27.2,

7.21ꢀ–ꢀ7.10 (m, 4H), 5.44 (dq, J = 15.4, 6.4ꢀHz, 1H), 5.20 (s, 1H),

4.08 (s, 2H), 3.77 (s, 3H), 2.66 (q, J = 7.6ꢀHz, 2H), 2.41 (s, 3H),

1.55 (d, J = 4.9ꢀHz, 3H), 1.27 (t, J = 7.6ꢀHz, 6H), 1.16 (s, 3H).

¹³C NMR (151ꢀMHz, CDCl₃) δ: 167.2, 144.5, 143.3, 135.1*,

132.2, 129.8, 129.3, 129.1, 128.1, 127.8, 125.0, 72.6, 52.1, 46.6*,

44.1, 29.9*, 28.6, 21.8, 18.2, 16.7, 15.5. IR (Diamond-ATR,

22.1, 15.6. IR (Diamond-ATR, neat) ꢀ̃_ꢁꢂꢃ: 2967 (m), 1729 (vs),

neat) ꢀ_ꢁꢂꢃ: 2965 (w), 1729 (s), 1628 (w), 1451 (w), 1434 (w),

̃

1556 (m), 1463 (m), 1379 (m), 1379 (m), 1286 (m), 1210 (m),

1159 (m), 895 (w), 835 (w), 835 (w), 786 (w) cm⁻¹. HRMS (EI)

calcd for C₁₈H₁₉O₂³⁵Cl [M]⁺: 302.7975; found: 302.1071.

1361 (m), 1269 (m), 1189 (s), 1176 (vs), 1097 (m), 1041 (m), 979

(s), 912 (m), 830 (s), 813 (s), 731 (m), 666 (s) cm⁻¹. HRMS (EI)

calcd for C₂₇H₃₁O₅³⁵ClS [M]⁺: 502.1575; found: 502.1574.

3.22. 7-methoxy-4-methyl-1,2-dihydronaphthalene (44)

3.20. methyl (E)-1-chloro-7-ethyl-3,4-dimethyl-4-

((((methylthio)carbonothioyl)oxy)methyl)-3-(prop-1-en-1-yl)-3,4-

dihydronaphthalene-2-carboxylate (38)

To 6-methoxy-3,4-dihydronaphthalen-1(2H)-one (43) (10.0ꢀg,

56.7ꢀmmol, 1ꢀequiv) in tetrahydrofuran (100ꢀmL) was added

methylmagnesium bromide solution (3ꢀ

M in diethyl ether,

To a solution of 36 (12.0ꢀmg, 0.0344ꢀmmol, 1ꢀequiv) in

28.4ꢀmL, 85.1ꢀmmol, 1.50ꢀequiv) at 0ꢀ°C. The ice bath was

removed after the addition and the reaction mixture was stirred

for 17ꢀh. The mixture was cooled to 0ꢀ°C and aqueous

tetrahydrofuran

(0.26ꢀmL)

was

added

sodium

bis(trimethylsilyl)amide (1ꢀ

M

in tetrahydrofuran, 0.172ꢀmL,

0.172ꢀmmol, 5.00ꢀequiv) at −78ꢀ°C. After 30ꢀmin, carbon

disulfide (0.0415ꢀmL, 0.688ꢀmmol, 20.0ꢀequiv) was added and the

reaction was allowed to warm to −65ꢀ°C. After 30ꢀmin, methyl

iodide (0.0428ꢀmL, 0.688ꢀmmol, 20.0ꢀequiv) was added and the

reaction mixture was stirred for 75ꢀmin. Saturated aqueous

ammonium chloride solution (15ꢀmL) was added, the layers were

separated and the aqueous phase was extracted with ethyl acetate

(3ꢀ×ꢀ20ꢀmL). The combined organic extracts were dried over

sodium sulfate, the dried solution was filtered and the filtrate was

concentrated. The residue was purified by flash column

chromatography on silica gel (5% ethyl acetate in hexanes) to

obtain 38 (12.6ꢀmg, 83%) as a colorless oil. Analytical data for

38: Note: Due to severe signal broadening in the NMR spectra

some signals are missing or possess inaccurate integrals. Signals

in the ¹³C NMR which could only be assigned by cross-coupling

in the HMBC are marked with an asterisk. TLC (20% ethyl

hydrochloric acid solution (2ꢀM, 200ꢀmL) was added until pH=2.

The reaction was stirred for 5ꢀh, diluted with water (100ꢀmL) and

the layers were separated. The aqueous phase was extracted with

diethyl ether (3ꢀ×ꢀ200ꢀmL). The combined organic extracts were

washed with saturated aqueous sodium chloride solution

(200ꢀmL), the washed solution was dried over sodium sulfate, the

dried solution was filtered and the filtrate was concentrated. The

residue was used without further purification. An analytical pure

sample of 44 was obtained by flash column chromatography on

silica gel (2% ethyl acetate in hexanes). Analytical data for 44:

TLC (20% ethyl acetate in hexanes), R_f= 0.63 (KMnO₄, ANIS).

¹H NMR (400ꢀMHz, CDCl₃) δ: 7.16 (d, J = 8.2ꢀHz, 1H), 6.88 –

6.62 (m, 2H), 5.73 (ddd, J = 6.0, 3.8, 1.6ꢀHz, 1H), 3.81 (s, 3H),

2.75 (t, J = 8.0ꢀHz, 2H), 2.29 – 2.16 (m, 2H), 2.03 (q, J = 1.6ꢀHz,

3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 158.5, 138.3, 131.9, 129.2,

124.0, 123.0, 113.7, 110.9, 55.4, 29.0, 23.3, 19.5. IR (Diamond-

1

acetate in hexanes), R_f= 0.50 (UV, ANIS, KMnO₄). H NMR

ATR, neat) ꢀ_ꢁꢂꢃ: 2932 (w), 1605 (m), 1496 (s), 1427 (m), 1302

̃

(m), 1249 (vs), 1141 (s), 1032 (s), 867 (m), 819 (s), 674 (m) cm⁻¹.

HRMS (EI) calcd for C₁₂H₁₄O [M]⁺: 174.1039; found: 174.1041.

(400ꢀMHz, CDCl₃) δ: 7.58 – 7.44 (m, 1H), 7.18 (d, J = 1.2ꢀHz,

2H), 5.64 – 5.37 (m, 2H), 4.75 (s, 2H), 3.81 (s, 3H), 2.67 (q, J =

7.8ꢀHz, 2H), 2.45 (s, 3H), 1.65 (d, J = 6.1ꢀHz, 3H), 1.36 (s, 3H),

1.31 – 1.18 (m, 6H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 215.5,

167.4, 143.4, 137.3*, 135.8*, 130.2, 129.7, 129.5, 128.2, 125.3,

77.0*, 52.1, 47.2*, 44.7, 28.6, 18.9, 18.4, 17.2, 15.5, 10.6*. IR

3.23. 6-methoxy-1-methyl-3,4-dihydronaphthalen-2(1H)-one (45)

To a solution of crude 44 in dichloromethane (283ꢀmL) and

2,2,2-trifluoroethanol

(71ꢀmL)

were

added

3-chloro-

(Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2964 (w), 1730 (vs), 1607 (w), 1488

̃

peroxybenzoic acid (75% in water, 16.3ꢀg, 70.9ꢀmmol,

1.25ꢀequiv) and p-toluenesulfonic acid monohydrate (13.5ꢀg,

70.9ꢀmmol, 1.25ꢀequiv) subsequently at 0ꢀ°C. After stirring for

20ꢀmin, saturated aqueous sodium bicarbonate solution (200ꢀmL)

and dichloromethane (200ꢀmL) were added, the layers were

separated and the aqueous layer was extracted with

(w), 1449 (w), 1432 (m), 1375 (w), 1268 (s), 1253 (s), 1209 (s),

1153 (m), 1067 (vs), 1041 (m), 967 (m), 911 (w), 832 (w), 731

(w) cm⁻¹. HRMS (EI) calcd for C₂₂H₂₇O₃³⁵ClS₂[M]⁺: 438.1085;

found: 438.1077.

11

dichloromethane (3ꢀ×ꢀ200 mL). The combined organic layers

= 8.7, 2.8ꢀHz, 1H), 6.60 (d, J = 2.7ꢀHz, 1H), 3.78 (s, 3H), 2.98

(dt, J = 17.6, 7.1ꢀHz, 1H), 2.81 (dt, J = 17.5, 6.8ꢀHz, 1H), 2.04 –

1.79 (m, 2H), 1.32 (s, 3H), 1.27 (s, 6H). ¹³C NMR (101ꢀMHz,

CDCl₃) δ: 157.4, 137.4, 135.5, 128.1, 113.0, 112.8, 73.7, 55.3,

ACCEPTED MANUSCRIPT

were dried over sodium sulfate, the dried solution was filtered

and the filtrate was concentrated. The crude product was purified

by flash column chromatography on silica gel (6% ethyl acetate

in hexanes) to obtain 45 (4.76ꢀg, 44% over 2 steps) as a yellow

oil. Analytical data for 45: TLC (20% ethyl acetate in hexanes),

41.5, 32.8, 27.1, 27.0, 25.4, 24.3. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ:

̃

3470 (w), 2969 (m), 1608 (m), 1499 (vs), 1464 (m), 1373 (w),

1315 (m), 1237 (s), 1084 (m), 1037 (s), 911 (m), 818 (s) cm⁻¹.

HRMS (EI) calcd for C₁₄H₂₀O₂[M]⁺: 220.1458; found:

220.1452.

1

R_f= 0.45 (KMnO₄). H NMR (400ꢀMHz, CDCl₃) δ: 7.11 (d, J =

8.3ꢀHz, 1H), 6.83 – 6.76 (m, 2H), 3.81 (s, 3H), 3.47 (qd, J = 6.9,

0.9ꢀHz, 1H), 3.15 – 2.91 (m, 2H), 2.62 (dt, J = 17.5, 5.9ꢀHz, 1H),

2.48 (ddd, J = 17.5, 9.0, 6.1ꢀHz, 1H), 1.45 (d, J = 7.0ꢀHz, 3H).

¹³C NMR (101ꢀMHz, CDCl₃) δ: 212.5, 158.5, 138.1, 130.1,

127.3, 113.3, 112.3, 55.4, 46.8, 37.3, 28.4, 14.6. IR (Diamond-

3.26. 3-hydroxy-7-methoxy-3,4,4-trimethyl-3,4-

dihydronaphthalen-1(2H)-one (48)

ATR, neat) ꢀ̃_ꢁꢂꢃ: 2937 (w), 1713 (vs), 1610 (m), 1579 (w), 1497

To a solution of 47 (843ꢀmg, 3.83ꢀmmol, 1ꢀequiv) in dry

acetone (7.7ꢀmL) was added cobalt(II) acetylacetonate (197ꢀmg,

0.765ꢀmmol, 0.200ꢀequiv). To the resulting purple suspension

was added dropwise tert-butyl hydroperoxide (5.5ꢀM in decane,

2.78ꢀmL, 15.3ꢀmmol, 4.00ꢀequiv). After 2ꢀd, saturated aqueous

ammonium chloride solution (20ꢀmL) and ethyl acetate (20ꢀmL)

were added. The layers were separated and the aqueous layer was

extracted with ethyl acetate (3ꢀ×ꢀ20ꢀmL). The combined organic

layers were washed with saturated aqueous sodium chloride

solution (20ꢀmL) and the washed solution was dried over sodium

sulfate. The dried solution was filtered and the filtrate was

concentrated. The crude product was purified by flash column

chromatography on silica gel (25% ethyl acetate in hexanes) to

afford 48 (854ꢀmg, 95%) as a green oil. TLC (20% ethyl acetate

in hexanes), Rf = 0.056 (ANIS, UV). ¹H NMR (400ꢀMHz,

CDCl₃) δ: 7.50 (d, J = 3.0ꢀHz, 1H), 7.41 (d, J = 8.7ꢀHz, 1H), 7.14

(dd, J = 8.7, 3.0ꢀHz, 1H), 3.84 (s, 3H), 2.89 (s, 2H), 1.44 (s, 3H),

1.38 (s, 3H), 1.33 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 196.8,

158.2, 143.5, 131.8, 127.8, 122.6, 109.1, 75.7, 55.7, 55.6, 50.0,

(s), 1454 (m), 1261 (s), 1160 (m), 1037 (m), 864 (w) cm⁻¹.

HRMS (EI) calcd for C₁₂H₁₄O₂[M]⁺: 190.0988; found:

190.0994.

3.24. 6-methoxy-1,1-dimethyl-3,4-dihydronaphthalen-2(1H)-one

(46)

To a suspension of freshly washed potassium hydride (4.55ꢀg,

114ꢀmmol, 1.20ꢀequiv) in degassed tetrahydrofuran (40ꢀmL) was

added a degassed solution of 45 (18.0ꢀg, 94.6ꢀmmol, 1ꢀequiv) in

tetrahydrofuran (500ꢀmL) over 25ꢀmin at 0ꢀ°C. After 20ꢀmin, the

ice bath was removed and the reaction mixture was stirred at

23ꢀ°C. After 1ꢀh, the mixture was cooled to 0ꢀ°C, methyl iodide

(11.8ꢀmL, 189ꢀmmol, 2.00ꢀequiv) was added and the ice bath was

removed after the addition. After 25ꢀmin at 23ꢀ°C, the mixture

was again cooled to 0ꢀ°C, saturated aqueous ammonium chloride

solution (200ꢀmL) and ethyl acetate (100ꢀmL) were added, the

layers were separated and the aqueous layer was extracted with

ethyl acetate (3ꢀ×ꢀ200ꢀmL). The combined organic layers were

dried over sodium sulfate, the dried solution was filtered and the

filtrate was concentrated. The crude product was purified by flash

column chromatography on silica gel (6% ethyl acetate in

hexanes) to afford 46 (13.6ꢀg, 71%) as a yellow oil. Analytical

data for 46: TLC (20% ethyl acetate in hexanes), R_f= 0.39

42.5, 24.7, 24.6. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 3483 (m), 2975

̃

(m), 1677 (vs), 1608 (s), 1493 (s), 1418 (m), 1325 (s), 1291 (vs),

1262 (s), 1087 (m), 1032 (s), 883 (w), 830 (w), 705 (w) cm⁻¹.

HRMS (EI) calcd for C₁₄H₁₈O₃[M]⁺: 234.1250; found:

234.1249.

1

(KMnO₄, ANIS, UV). H NMR (400ꢀMHz, CDCl₃) δ: 7.29 (s,

3.27. 7-methoxy-3,4,4-trimethylnaphthalen-1(4H)-one (49)

1H), 6.84 (ddd, J = 8.7, 2.8, 0.7ꢀHz, 1H), 6.73 (d, J = 2.6ꢀHz, 1H),

3.83 (s, 3H), 3.09 (t, J = 6.9ꢀHz, 2H), 2.79 – 2.63 (m, 2H), 1.44

(s, 6H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 215.0, 158.1, 136.6,

135.8, 127.4, 113.3, 112.9, 55.4, 47.4, 37.3, 28.9, 27.2 (2C). IR

A mixture of 48 (270ꢀmg, 1.15ꢀmmol, 1ꢀequiv) in acetic acid

(11.5ꢀmL) and sulfuric acid (97%, 30 ꢁL) was heated to 100ꢀ°C

for 10ꢀmin. After cooling to 23ꢀ°C, the reaction mixture was

diluted with water (30ꢀmL) and dichloromethane (50ꢀmL).

Sodium bicarbonate was slowly added until pH=7. The layers

were separated and the aqueous layer was extracted with

dichloromethane (3ꢀ×ꢀ30 mL). The combined organic layers were

dried over sodium sulfate. The dried solution was filtered and the

filtrate was concentrated. The crude product was purified by flash

column chromatography on silica gel (25% ethyl acetate in

hexanes) to obtain 49 (220ꢀmg, 88%) as a yellow solid.

Analytical data for 49: TLC (60% ethyl acetate in hexanes), R_f

(Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2968 (w), 1709 (vs), 1609 (m), 1500

̃

(s), 1464 (m), 1307 (m), 1265 (s), 1228 (m), 1138 (m), 1035 (s),

814 (m) cm⁻¹. HRMS (EI) calcd for C₁₃H₁₆O₂[M]⁺: 204.1145;

found: 204.1133.

3.25. 6-methoxy-1,1,2-trimethyl-1,2,3,4-tetrahydronaphthalen-2-

ol (47)

To

tetrahydrofuran (13ꢀmL) was added lanthanum(III) chloride

bis(lithium chloride) complex solution (0.3 in tetrahydrofuran,

44.7ꢀmL, 13.4ꢀmmol, 1ꢀequiv). After 1ꢀh, the solution was cooled

to 0ꢀ°C and methylmagnesium bromide solution (3ꢀ in diethyl

a solution of 46 (2.74ꢀg, 13.4ꢀmmol, 1ꢀequiv) in

1

M

= 0.50 (KMnO₄, UV). H NMR (800ꢀMHz, CDCl₃) δ: 7.63 (d, J

= 3.0ꢀHz, 1H), 7.50 (d, J = 8.8ꢀHz, 1H), 7.16 (dd, J = 8.7, 3.0ꢀHz,

1H), 6.32 (q, J = 1.3ꢀHz, 1H), 3.88 (s, 3H), 2.14 (d, J = 1.3ꢀHz,

3H), 1.48 (s, 6H). ¹³C NMR (201ꢀMHz, CDCl₃) δ: 184.5, 165.9,

158.2, 144.1, 131.7, 127.9, 126.6, 121.4, 107.6, 55.7, 40.3, 28.7

M

ether, 6.71ꢀmL, 20.1ꢀmmol, 1.50ꢀequiv) was added dropwise over

20ꢀmin (syringe pump). After 20ꢀmin, saturated aqueous

ammonium chloride solution (50ꢀmL) and diethyl ether (50ꢀmL)

were added, the layers were separated and the aqueous layer was

extracted with diethyl ether (3ꢀ×ꢀ50ꢀmL). The combined organic

layers were washed with saturated aqueous sodium chloride

solution (20ꢀmL) and the washed solution was dried over sodium

sulfate. The dried solution was filtered and the filtrate was

concentrated. The crude product was purified by flash column

chromatography on silica gel (14% ethyl acetate in hexanes) to

obtain 47 (2.83ꢀg, 96%) as a colorless oil. Analytical data for

(2C), 20.3. IR (Diamond-ATR, neat) ꢀ̃_ꢁꢂꢃ: 2975 (w), 1657 (vs),

1608 (m), 1497 (s), 1425 (s), 1296 (s), 1230 (w), 1032 (w), 870

(w) cm⁻¹. HRMS (EI) calcd for C₁₄H₁₆O₂[M]⁺: 216.1145; found:

216.1145.

3.28. 5,5,6-trimethyl-8-oxo-5,8-dihydronaphthalen-2-yl

trifluoromethanesulfonate (51)

To a solution of 49 (200ꢀmg, 0.925ꢀmmol, 1ꢀequiv) in

dichloromethane (4.6ꢀmL) was added dropwise boron tribromide

(1ꢀM, in dichloromethane, 4.62ꢀmL, 4.62ꢀmmol, 5ꢀequiv) at

1

47: TLC (20% ethyl acetate in hexanes), R_f= 0.23 (ANIS). H

NMR (400ꢀMHz, CDCl₃) δ: 7.27 (d, J = 8.7ꢀHz, 1H), 6.75 (dd, J

12

−78ꢀ°C. The reaction mixture was allowed to warm to 0ꢀ°C over

1.50ꢀequiv) at 0ꢀ°C. After 1ꢀh, the mixture was cooled to 0ꢀ°C and

saturated aqueous sodium bicarbonate solution (10ꢀmL) and

dichloromethane (10ꢀmL) were added. The layers were separated

and the aqueous layer was extracted with dichloromethane

(3ꢀ×ꢀ15ꢀmL). The combined organic layers were dried over

sodium sulfate. The dried solution was filtered and the filtrate

was concentrated. The crude product 53 was used without further

purification. A mixture of 18-crown-6 (1.45ꢀg, 5.50ꢀmmol,

2.00ꢀequiv) and potassium tert-butoxide (617ꢀmg, 5.50ꢀmmol,

2.00ꢀequiv) in tetrahydrofuran (46ꢀmL) was stirred at 0ꢀ°C for 1ꢀh.

A solution of crude 53 in tetrahydrofuran (10ꢀmL) was added

over 10 min and after complete addition, the reaction mixture

was allowed to warm to 23ꢀ°C. After 2ꢀh, saturated aqueous

sodium bicarbonate solution (40ꢀmL) and dichloromethane

(40ꢀmL) were added. The layers were separated and the aqueous

layer was extracted with dichloromethane (3ꢀ×ꢀ40ꢀmL). The

combined organic layers were dried over sodium sulfate. The

dried solution was filtered and the filtrate was concentrated. The

crude product was purified by flash column chromatography on

silica gel (2% ethyl acetate in hexanes) to obtain 54 (270ꢀmg,

38% over 2 steps) as a yellow oil. Analytical data for 54: TLC

ACCEPTED MANUSCRIPT

2ꢀh and methanol (3ꢀmL) was added dropwise. Water (40ꢀmL)

was added, the layers were separated and the aqueous layer was

extracted with dichloromethane (3ꢀ×ꢀ20ꢀmL). The combined

organic layers were dried over sodium sulfate. The dried solution

was filtered and the filtrate was concentrated. The crude product

50 was used in the next step without further purification. To a

solution of crude 50 in dichloromethane (4.6ꢀmL) was added

triethylamine at −78ꢀ°C and the mixture was stirred for 5ꢀmin

before

trifluoromethanesulfonic

anhydride

(0.230ꢀmL,

1.39ꢀmmol, 1.50ꢀequiv) was added over 10ꢀmin. The reaction was

allowed to warm to 23ꢀ°C over 3ꢀh and saturated aqueous sodium

bicarbonate solution (15ꢀmL) and dichloromethane (20ꢀmL) were

added. The layers were separated and the aqueous layer was

extracted with dichloromethane (3ꢀ×ꢀ20ꢀmL). The combined

organic layers were dried over sodium sulfate. The dried solution

was filtered and the filtrate was concentrated. The crude product

was purified by flash column chromatography on silica gel (14%

ethyl acetate in hexanes) to afford 51 (302ꢀmg, 98% over 2 steps)

as a yellow solid. Analytical data for 41: TLC (33% ethyl

acetate in hexanes), R_f= 0.26 (KMnO₄, UV). ¹H NMR

(400ꢀMHz, CDCl₃) δ: 8.05 (d, J = 2.9ꢀHz, 1H), 7.69 (d, J =

8.8ꢀHz, 1H), 7.47 (dd, J = 8.8, 2.9ꢀHz, 1H), 6.36 (t, J = 1.3ꢀHz,

1H), 2.17 (d, J = 1.3ꢀHz, 3H), 1.53 (s, 6H). ¹³C NMR (101ꢀMHz,

CDCl₃) δ: 182.5, 166.2, 151.1, 148.4, 132.8, 129.2, 126.4, 125.3,

118.9 (q, J = 320.3ꢀHz) 118.8, 40.7, 28.7 (2C), 20.5. IR

1

(20% ethyl acetate in hexanes), R_f= 0.59 (KMnO₄, UV). H

NMR (400ꢀMHz, CDCl₃) δ: 7.84 (s, 1H), 7.38 (s, 2H), 5.78 (ddt,

J = 15.0, 10.1, 7.5ꢀHz, 1H), 5.08 (dd, J = 10.1, 2.0ꢀHz, 1H), 4.98

(d, J = 17.0ꢀHz, 1H), 2.66 (q, J = 7.6ꢀHz, 2H), 2.60 (s, 2H), 2.17 –

2.13 (m, 2H), 1.35 (s, 3H), 1.34 (s, 3H), 1.25 (t, J = 7.6ꢀHz, 3H),

0.99 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 198.4, 149.9, 142.1,

134.5, 134.2, 131.3, 126.4, 125.7, 118.6, 46.1, 41.2, 40.9, 40.4,

(Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2980 (w), 1660 (s), 1579 (w), 1486

̃

(w), 1421 (s), 1314 (m), 1290 (m), 1204 (vs), 1137 (vs), 1109 (m),

918 (vs), 875 (m), 841 (s), 811 (s), 767 (m) cm⁻¹. HRMS (EI)

calcd for C₁₄H₁₃O₄F₃S [M]⁺: 334.0481; found: 334.0490.

28.3, 20.9, 15.4. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2969 (s), 1683

̃

(vs), 1639 (w), 1611 (m), 1456 (m), 1376 (m), 1296 (m), 1263

(m), 1093 (m), 999 (m), 913 (m), 835 (m) cm⁻¹. HRMS (EI) calcd

for C₁₈H₂₄O [M]⁺: 256.1822; found: 256.1820.

3.29. 7-ethyl-3,4,4-trimethylnaphthalen-1(4H)-one (52)

Note: The reaction setup has to be flame-dried very carefully,

since the yield otherwise decreases significantly. To [1,1'-

3.31. (E)-7-ethyl-3,4,4-trimethyl-3-(prop-1-en-1-yl)-3,4-

dihydronaphthalen-1(2H)-one (55)

bis(diphenylphosphino)ferrocene]palladium(II)

dichloride

To

bis(dibenzylidenacetone)palladium(0)

(66.1ꢀmg,

(41.1ꢀmg, 0.0562ꢀmmol, 0.0180ꢀequiv) was added a solution of 51

(1.04ꢀg, 3.12ꢀmmol, 1ꢀequiv) in 1,4-dioxane (2.6ꢀmL). The red

suspension was cooled to 0ꢀ°C and diethylzinc solution (15wt%

in toluene, 4.27ꢀmL, 6.25ꢀmmol, 2.00ꢀequiv) was added dropwise.

After stirring for 10ꢀmin, the yellow solution was heated to 90ꢀ°C

for 70ꢀmin, cooled to 0ꢀ°C and treated with methanol (5ꢀmL).

Water (15ꢀmL) was added, the layers were separated and the

aqueous layer was extracted with diethyl ether (3ꢀ×ꢀ20ꢀmL). The

combined organic layers were washed with aqueous hydrogen

0.115ꢀmmol, 10.0ꢀmol%) was added subsequently a solution of

54 (295ꢀmg, 1.15ꢀmmol, 1ꢀequiv) in degassed toluene (3.3ꢀmL),

tri-t-butylphosphine (1ꢀ

M

in toluene, 0.115ꢀmL, 0.115ꢀmmol,

in degassed toluene,

10.0ꢀmol%) and isobutyryl chloride (0.078ꢀ

M

1.47ꢀmL, 0.115ꢀmmol, 10.0ꢀmol%). The reaction mixture was

heated to 80ꢀ°C for 2ꢀd, diluted afterwards with ethyl acetate

(30ꢀmL) and concentrated. The residue was purified by flash

column chromatography on silica gel (20% ethyl acetate in

hexanes) to afford 55 (272ꢀmg, 92%) as a yellow oil. Analytical

data for 55: TLC (20% ethyl acetate in hexanes), R_f= 0.58

(KMnO₄, UV). ¹H NMR (400ꢀMHz, CDCl₃) δ: 7.86 (d, J =

1.9ꢀHz, 1H), 7.40 – 7.33 (m, 2H), 5.61 (d, J = 15.7ꢀHz, 1H), 5.47

(dq, J = 15.6, 6.2ꢀHz, 1H), 2.83 (d, J = 17.3ꢀHz, 1H), 2.66 (q, J =

7.6ꢀHz, 2H), 2.53 (d, J = 17.4ꢀHz, 1H), 1.67 (d, J = 6.2ꢀHz, 3H),

1.33 (s, 3H), 1.28 (s, 3H), 1.24 (t, J = 7.6ꢀHz, 3H), 1.06 (s, 3H).

¹³C NMR (101ꢀMHz, CDCl₃) δ: 198.6, 149.7, 142.0, 135.9,

134.1, 130.9, 126.4, 125.8, 124.5, 48.1, 43.5, 40.6, 28.3, 26.8,

chloride solution (2ꢀM, 20ꢀmL) and saturated aqueous sodium

chloride solution (20ꢀmL). The washed solution was dried over

sodium sulfate, the dried solution was filtered and the filtrate was

concentrated. The crude product was purified by flash column

chromatography on silica gel (17% ethyl acetate in hexanes) to

obtain 52 (590ꢀmg, 88%) as a yellow oil. TLC (20% ethyl acetate

in hexanes), R_f= 0.35 (KMnO₄, UV). ¹H NMR (599ꢀMHz,

CDCl₃) δ: 8.01 (d, J = 2.1ꢀHz, 1H), 7.50 (d, J = 8.2ꢀHz, 1H), 7.42

(dd, J = 8.2, 2.2ꢀHz, 1H), 6.32 (d, J = 1.5ꢀHz, 1H), 2.71 (q, J =

7.6ꢀHz, 2H), 2.13 (d, J = 1.1ꢀHz, 3H), 1.49 (s, 6H), 1.27 (t, J =

7.7ꢀHz, 3H). ¹³C NMR (151ꢀMHz, CDCl₃) δ: 184.9, 165.6, 148.8,

142.6, 132.5, 130.4, 126.8, 126.5, 125.2, 40.4, 28.7, 28.5, 20.3,

24.5, 21.7, 18.5, 15.4. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 2968 (m),

̃

2936 (w), 1683 (vs), 1611 (w), 1491 (w), 1452 (w), 1376 (w),

1290 (w), 1264 (w), 1096 (w), 975 (w), 834 (w) cm⁻¹. HRMS

(EI) calcd for C₁₈H₂₄O [M]⁺: 256.1822; found: 256.1821.

15.5. IR (Diamond-ATR, neat) ꢀ̃_ꢁꢂꢃ: 2971 (m), 2873 (w), 1657

(vs), 1610 (m), 1462 (w), 1427 (m), 1307 (m), 1270 (w), 1117

(w), 1011 (w), 876 (m), 837 (w) cm⁻¹. HRMS (EI) calcd for

C₁₅H₁₈O₂[M]⁺: 214.1352; found: 214.1351.

3.32. (6-methoxy-1,1,2-trimethyl-1,2-dihydronaphthalen-2-

yl)methanol (58a)

To a solution of 48 (870ꢀmg, 4.02ꢀmmol, 1ꢀequiv) in methanol

(34ꢀmL) were added cerium(III) chloride heptahydrate (1.65ꢀg,

4.42ꢀmmol, 1.10ꢀequiv) and sodium borohydride (228ꢀmg,

6.03ꢀmmol, 1.50ꢀequiv) respectively at 0ꢀ°C. After 1ꢀh, the

mixture was diluted with pH7 buffer solution (20ꢀmL) and

dichloromethane (20ꢀmL). The layers were separated and the

3.30. 3-allyl-7-ethyl-3,4,4-trimethyl-3,4-dihydronaphthalen-

1(2H)-one (54)

To a solution of 52 (590ꢀmg, 2.75ꢀmmol, 1ꢀequiv) in

tetrahydrofuran (5.5ꢀmL) was added dropwise allylmagnesium

bromide solution (1ꢀ

M in diethyl ether, 4.13ꢀmL, 4.13ꢀmmol,

13

3.34. 6-Methoxy-2-((methoxymethoxy)methyl)-1,1,2-trimethyl-

1,2-dihydronaphthalene (61b)

aqueous layer was extracted with dichloromethane (3ꢀ×ꢀ20ꢀmL).

The combined organic layers were dried over sodium sulfate, the

dried solution was filtered and the filtrate was concentrated. The

crude product was used immediately without further purification.

Note: The product is very sensitive toward acidic conditions.

Therefore, it was used immediately in the next step. To washed

potassium hydride (242ꢀmg, 6.03ꢀmmol, 1.50ꢀequiv) was added a

solution of the crude alcohol in tetrahydrofuran (60ꢀmL) at 0ꢀ°C.

After 10ꢀmin, a solution of tributyl(iodomethyl)stannane (1.91ꢀg,

4.42ꢀmmol, 1.10ꢀequiv) in tetrahydrofuran (15ꢀmL) was added.

After 105ꢀmin, the mixture was diluted with pH7 buffer solution

(30ꢀmL) and dichloromethane (30ꢀmL). The layers were separated

and the aqueous layer was extracted with dichloromethane

(3ꢀ×ꢀ30ꢀmL). The combined organic layers were dried over

sodium sulfate, the dried solution was filtered and the filtrate was

concentrated. The crude product 57 was used immediately

without further purification. To a solution of crude 57 in

ACCEPTED MANUSCRIPT

To a solution of 58a (20.0 mg, 0.0861 mmol, 1 equiv) in

dichloromethane

N,N-diisopropylethylamine (59.6 µL, 0.344 mmol, 4.00 equiv),

4-dimethylaminopyridine (1.05 mg, 0.008641 mmol,

(0.43 mL)

were

added

0.100 equiv) and chloromethyl methyl ether (22.9 µL,

0.301 mmol, 3.50 equiv) respectively at 0 °C. The reaction

mixture was allowed to warm to 23 °C and after 4 h, saturated

aqueous ammonium chloride solution (10 mL) was added. The

layers were separated, the aqueous layer was extracted with

diethyl ether (3 × 10 mL) and the combined organic layers were

washed with saturated aqueous sodium chloride solution

(10 mL). The washed solution was dried over sodium sulfate, the

dried solution was filtered and the filtrate was concentrated. The

crude product was purified by flash column chromatography on

silica gel (5% ethyl acetate in hexanes) to provide 61b (22.3 mg,

94%) as a colorless oil. Analytical data for 61b: TLC (20%

tetrahydrofuran (80ꢀmL) was added n-butyllithium (2.51ꢀ

M in

hexanes, 2.08ꢀmL, 5.23ꢀmmol, 1.30 equiv) dropwise over 5ꢀmin at

−78ꢀ°C. The reaction was allowed to warm to −45ꢀ°C over 2ꢀh

and was diluted with saturated aqueous ammonium chloride

solution (30ꢀmL) and water (20ꢀmL). The layers were separated,

the aqueous layer was extracted with ethyl acetate (3ꢀ×ꢀ40ꢀmL)

and the combined organic layers were dried over sodium sulfate.

The dried solution was filtered and the filtrate was concentrated.

The crude product was purified by flash column chromatography

on silica gel (17% ethyl acetate in hexanes) to obtain 58a

(450ꢀmg, 48% over three steps) as a yellow oil. Analytical data

for 58a: TLC (25% ethyl acetate in hexanes), R_f= 0.26

1

ethyl acetate in hexanes), R_f= 0.43 (UV, KMnO₄). H NMR

(400ꢀMHz, CDCl₃) δ: 7.18 (dd, J = 8.4, 0.6ꢀHz, 1H), 6.72 (dd, J =

8.5, 2.8ꢀHz, 1H), 6.58 (d, J = 2.8ꢀHz, 1H), 6.37 (d, J = 9.6ꢀHz,

1H), 5.77 (d, J = 9.6ꢀHz, 1H), 4.59 – 4.52 (m, 2H), 3.79 (s, 3H),

3.45 (s, 2H), 3.32 (s, 3H), 1.22 (s, 3H), 1.19 (s, 3H), 1.10 (s, 3H).

¹³C NMR (101ꢀMHz, CDCl₃) δ: 158.0, 137.0, 136.6, 133.5,

125.7, 125.2, 112.5, 112.1, 97.0, 72.3, 55.3, 55.3, 42.0, 39.1,

24.3, 22.9, 17.9. IR (Diamond-ATR, neat) ꢀ̃_ꢁꢂꢃ: 2968 (w), 2931

(w), 1602 (w), 1464 (w), 1309 (w), 1260 (m), 1149 (m), 1105 (m),

1037 (vs), 916 (w), 854 (w), 776 (w) cm⁻¹. HRMS (EI) calcd for

C₁₇H₂₄O₃[M]⁺: 276.1720; found: 276.1715.

1

(KMnO₄, CAM, UV). H NMR (400ꢀMHz, CDCl₃) δ: 7.18 (d, J

= 8.5ꢀHz, 1H), 6.73 (dd, J = 8.5, 2.8ꢀHz, 1H), 6.59 (d, J = 2.8ꢀHz,

1H), 6.46 (d, J = 9.6ꢀHz, 1H), 5.68 (d, J = 9.6ꢀHz, 1H), 3.79 (s,

3H), 3.62 (d, J = 10.8ꢀHz, 1H), 3.39 (d, J = 10.8ꢀHz, 1H), 1.29 (s,

4H), 1.13 (s, 3H), 1.09 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ:

157.9, 137.3, 135.5, 133.3, 127.3, 125.2, 112.9, 112.2, 67.8, 55.3,

3.35. tert-Butyl((6-methoxy-1,1,2-trimethyl-1,2-

dihydronaphthalen-2-yl)methoxy)dimethyl-silane (61c)

To a solution of 58a (20.0 mg, 0.0861 mmol, 1 equiv) in

dimethylformamide (0.21 mL) were added imidazole (11.7 mg,

0.172 mmol, 2.00 equiv) and tert-butyldimethylsilyl chloride

(19.5 mg, 0.129 mmol, 1.50 equiv) at 0 °C and the reaction was

allowed to warm to 23 °C. After 20 h, saturated aqueous

ammonium chloride solution (10 mL) was added and the layers

were separated. The aqueous layer was extracted with diethyl

ether (3 × 10 mL) and the combined organic layers were washed

with saturated aqueous sodium chloride solution (10 mL). The

washed solution was dried over sodium sulfate, the dried solution

was filtered and the filtrate was concentrated. The crude product

was purified by flash column chromatography on silica gel (5%

ethyl acetate in hexanes) to obtain 61c (20.2 mg, 68%) as a

colorless oil. Analytical data for 61c: TLC (20% ethyl acetate

43.0, 38.6, 25.8, 21.6, 17.7. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ: 3409

̃

(m), 2969 (m), 2877 (w), 1746 (w), 1602 (m), 1490 (m), 1309

(m), 1259 (vs), 1154 (w), 1035 (vs), 777 (w) cm⁻¹. HRMS (EI)

calcd for C₁₅H₂₀O₂[M]⁺: 232.1458; found: 232.1458.

3.33. 6-Methoxy-1,1,2-trimethyl-1,2-dihydronaphthalen-2-

yl)methyl acetate (61a)

To a solution of 58a (10.0 mg, 0.0430 mmol, 1 equiv) in

dichloromethane (0.43 mL) were added triethylamine (17.9 µL,

0.129 mmol, 3.00 equiv), acetic anhydride (10.5 µl, 0.112 mmol,

2.60 equiv)

and

4-dimethylaminopyridine

(0.526 mg,

0.00430 mmol, 0.100 equiv) at 0 °C. After 30 min, the reaction

mixture was diluted with saturated aqueous sodium bicarbonate

solution (10 mL), the layers were separated and the aqueous layer

was extracted with dichloromethane (3 × 10 mL). The combined

organic layers were dried over sodium sulfate, the dried solution

was filtered and the filtrate was concentrated. The crude product

was purified by flash column chromatography on silica gel (5%

ethyl acetate in hexanes) to afford 61a (10.2 mg, 86%) as a

colorless oil. Analytical data for 61a: TLC (20% ethyl acetate

in hexanes), R_f= 0.31 (UV, CAM).¹H NMR (599ꢀMHz, CDCl₃)

δ: 7.18 (d, J = 8.3ꢀHz, 1H), 6.72 (dd, J = 8.3, 2.8ꢀHz, 1H), 6.58

(d, J = 2.7ꢀHz, 1H), 6.39 (d, J = 9.7ꢀHz, 1H), 5.67 (d, J = 9.5ꢀHz,

1H), 4.01 (q, J = 10.7ꢀHz, 2H), 3.78 (s, 3H), 1.94 (s, 3H), 1.27 (s,

3H), 1.18 (s, 3H), 1.07 (s, 3H). ¹³C NMR (151ꢀMHz, CDCl₃) δ:

171.4, 158.0, 136.8, 135.1, 133.2, 126.7, 125.2, 112.8, 112.2,

68.6, 55.4, 41.4, 39.0, 24.7, 22.5, 21.0, 17.8. IR (Diamond-ATR,

1

in hexanes), R_f= 0.68 (UV, CAM). H NMR (400ꢀMHz, CDCl₃)

δ: 7.17 (dd, J = 8.4, 0.6ꢀHz, 1H), 6.71 (dd, J = 8.5, 2.8ꢀHz, 1H),

6.56 (d, J = 2.8ꢀHz, 1H), 6.33 (d, J = 9.6ꢀHz, 1H), 5.71 (d, J =

9.6ꢀHz, 1H), 3.79 (s, 3H), 3.51 (s, 2H), 1.21 (d, J = 3.6ꢀHz, 6H),

1.02 (s, 3H), 0.86 (s, 9H), -0.03 (d, J = 2.4ꢀHz, 6H). ¹³C NMR

(101ꢀMHz, CDCl₃) δ: 157.8, 137.5, 137.1, 133.7, 125.6, 125.1,

112.4, 111.9, 67.0, 55.3, 43.1, 39.0, 26.0, 24.5, 23.2, 18.4, 17.6, -

5.4, -5.4. IR (Diamond-ATR, neat) ꢀ̃_ꢁꢂꢃ: 2955 (m), 2928 (m),

2855 (w), 1602 (w), 1463 (m), 1360 (w), 1309 (w), 1259 (s), 1072

(s), 1038 (s), 1005 (m), 849 (vs), 835 (vs), 773 (vs), 668 (m) cm⁻¹.

HRMS (EI) calcd for C₂₁H₃₄O₂Si [M]⁺: 346.2323; found:

346.2322.

3.36. 6-Methoxy-2-(methoxymethyl)-1,1,2-trimethyl-1,2-

dihydronaphthalene (61d)

To a solution of 58a (20.0 mg, 0.0861 mmol, 1 equiv) in

dimethylformamide (0.43 mL) was added sodium hydride (60%

dispersion in mineral oil, 6.89 mg, 0.172 mmol, 2.00 equiv) at

0 °C. After 15 min, methyl iodide (9.65 mL, 0.155 mmol,

neat) ꢀ_ꢁ̃ _ꢂꢃ: 2971 (m), 1738 (s), 1603 (m), 1491 (m), 1375 (m),

1260 (s), 1237 (vs), 1154 (m), 1034 (s), 856 (s), 777

(s)ꢀcm⁻¹.HRMS (EI) calcd for C₁₇H₂₂O₃[M]⁺: 274.1563; found:

274.1564.

14

1.80 equiv) was added and the mixture was allowed to warm to

product was purified by flash column chromatography on silica

gel (14% ethyl acetate in hexanes) to yield 65 (33ꢀmg, 70%) as a

yellow oil. Analytical data for 65: TLC (25% ethyl acetate in

hexanes), R_f= 0.41 (CAM, ANIS, KMnO₄). ¹H NMR (400ꢀMHz,

CDCl₃) δ: 7.36 (d, J = 8.7ꢀHz, 1H), 6.83 (dd, J = 8.7, 2.8ꢀHz, 1H),

6.69 (d, J = 2.8ꢀHz, 1H), 4.66 (dd, J = 6.7, 4.3ꢀHz, 1H), 4.05 (dt, J

= 12.1, 0.9ꢀHz, 1H), 3.80 (s, 3H), 3.50 (d, J = 12.1ꢀHz, 1H), 3.41

(tt, J = 6.1, 0.7ꢀHz, 1H), 3.27 (dd, J = 6.0, 4.3ꢀHz, 1H), 1.41 (s,

3H), 1.08 (s, 3H), 1.06 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ:

204.8, 158.0, 139.1, 130.3, 126.3, 113.7, 113.6, 93.0, 71.9, 64.2,

55.3, 45.9, 38.1, 35.8, 30.9, 21.5, 20.8. IR (Diamond-ATR, neat)

ACCEPTED MANUSCRIPT

23 °C over 2.5 h. Saturated aqueous ammonium chloride solution

(10 mL) was added and the layers were separated. The aqueous

layer was extracted with ethyl acetate (3 × 10 mL) and the

combined organic layers were dried over sodium sulfate. The

dried solution was filtered and the filtrate was concentrated. The

crude product was purified by flash column chromatography on

silica gel (5% ethyl acetate in hexanes) to provide 61d (17 mg,

80%) as a colorless oil. Analytical data for 61d: TLC (20%

ethyl acetate in hexanes), R_f= 0.61 (UV, CAM). ¹H NMR

(400ꢀMHz, CDCl₃) δ: 7.18 (d, J = 8.4ꢀHz, 1H), 6.72 (dd, J = 8.5,

2.8ꢀHz, 1H), 6.59 (d, J = 2.7ꢀHz, 1H), 6.37 (d, J = 9.6ꢀHz, 1H),

5.75 (d, J = 9.6ꢀHz, 1H), 3.79 (s, 3H), 3.33 – 3.22 (m, 5H), 1.22

(s, 3H), 1.18 (s, 3H), 1.09 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl₃)

δ: 157.9, 137.0, 136.9, 133.5, 125.5, 125.2, 112.5, 112.0, 77.4,

59.5, 55.3, 42.2, 39.1, 24.4, 22.8, 17.8. IR (Diamond-ATR, neat)

ꢀ_ꢁ̃ _ꢂꢃ: 2975 (m), 2865 (w), 1780 (vs), 1610 (m), 1501 (m), 1465

(m), 1316 (w), 1260 (m), 1249 (m), 1153 (w), 1053 (m), 1037

(m), 908 (m), 818 (m) cm⁻¹. HRMS (EI) calcd for C₁₇H₂₀O₃[M]⁺:

272.1407; found: 272.1406.

3.39. 7-methoxy-3a,4,4-trimethyl-3,3a,4,8b-tetrahydro-1H-

benzo[f]cyclobuta[cd]isobenzofuran-1a(1a1H)-ol (71)

ꢀ_ꢁ̃ _ꢂꢃ: 2970 (m), 2932 (m), 1886 (m), 1602 (m), 1572 (m),

1489 (m), 1464 (m), 1361 (w), 1309 (m), 1282 (m), 1261 (vs),

1194 (m), 1154 (m), 1105 (vs), 1089 (s), 1037 (s), 982 (w), 871

(w), 777 (m) cm⁻¹.HRMS (EI) calcd for C₁₆H₂₂O₂[M]⁺:

246.1620; found: 246.1614.

To a degassed solution of 65 (12.0ꢀmg, 0.0441ꢀmmol, 1ꢀequiv)

in tetrahydrofuran (1.2ꢀmL) and methanol (0.6ꢀmL) was added

dropwise

tetrahydrofuran, 3.52ꢀmL, 0.352ꢀmmol, 8.00ꢀequiv) at 0ꢀ°C. After

1ꢀh, water (10 mL) and aqueous hydrochloric acid solution (2ꢀ

a

solution of samarium(II) iodide (0.1ꢀ

M

in

3.37. N,N-diethyl-2-((6-methoxy-1,1,2-trimethyl-1,2-

dihydronaphthalen-2-yl)methoxy)acetamide (64)

M

,

10ꢀmL) were added and the aqueous phase was extracted with

ethyl acetate (3ꢀ×ꢀ10ꢀmL). The combined organic layers were

dried over sodium sulfate, the dried solution was filtered and the

filtrate was concentrated. The crude product was purified by flash

column chromatography on silica gel (33% ethyl acetate in

hexanes) to afford 71 (12ꢀmg, quant.) as a colorless oil.

Analytical data for 71: TLC (33% ethyl acetate in hexanes), R_f

To a solution of 58a (100ꢀmg, 0.430ꢀmmol, 1ꢀequiv) in 1,2-

dimethoxyethane (2.2ꢀmL) was added sodium hydride (60%

dispersion in mineral oil, 51.6ꢀmg, 1.29ꢀmmol, 3.00ꢀequiv) at 0ꢀ°C

and after 20ꢀmin 2-chloro-N,N-diethylacetamide (88.7ꢀꢁL,

0.646ꢀmmol, 1.50ꢀequiv). The reaction was allowed to warm

slowly to 23ꢀ°C over 17ꢀh and diluted with saturated aqueous

ammonium chloride solution (10ꢀmL) and water (5ꢀmL). The

layers were separated, the aqueous layer was extracted with ethyl

acetate (3ꢀ×ꢀ15ꢀmL) and the combined organic layers were dried

over sodium sulfate. The dried solution was filtered and the

filtrate was concentrated. The crude product was purified by flash

column chromatography on silica gel (33% ethyl acetate in

hexanes) to afford 64 (144ꢀmg, 97%) as a colorless oil.

Analytical data for 64: TLC (33% ethyl acetate in hexanes), R_f

1

= 0.26 (CAM). H NMR (400ꢀMHz, CDCl₃) δ: 7.24 (d, J =

8.8ꢀHz, 1H), 6.73 (dd, J = 8.7, 2.8ꢀHz, 1H), 6.58 (d, J = 2.7ꢀHz,

1H), 3.78 (s, 3H), 3.68 (d, J = 8.9ꢀHz, 1H), 3.51 (d, J = 8.9ꢀHz,

1H), 3.34 (td, J = 10.4, 5.0ꢀHz, 1H), 3.05 (ddd, J = 12.9, 11.2,

1.7ꢀHz, 1H), 2.75 – 2.66 (m, 2H), 2.23 (dd, J = 13.0, 5.1ꢀHz, 1H),

1.28 (s, 6H), 1.06 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl3) δ: 157.8,

139.4, 136.8, 126.1, 112.8, 112.3, 106.4, 76.7, 55.3, 53.6, 46.6,

44.2, 37.9, 29.5, 23.6, 22.2, 21.9. IR (Diamond-ATR, neat) ꢀ_ꢁꢂꢃ:

̃

1

= 0.17 (UV, CAM). H NMR (400ꢀMHz, CDCl₃) δ: 7.16 (d, J =

3391 (w), 2971 (m), 1608 (m), 1575 (w), 1502 (m), 1424 (w),

1364 (w), 1284 (s), 1254 (s), 1216 (w), 1158 (m), 1125 (w), 1037

(vs), 867 (m), 815 (m), 728 (m) cm⁻¹. HRMS (EI) calcd for

C₁₇H₂₂O₃[M]⁺: 274.1563; found: 274.1572.

8.4ꢀHz, 1H), 6.70 (dd, J = 8.5, 2.8ꢀHz, 1H), 6.56 (d, J = 2.7ꢀHz,

1H), 6.34 (d, J = 9.6ꢀHz, 1H), 5.78 (d, J = 9.7ꢀHz, 1H), 4.04 (q, J

= 13.2ꢀHz, 2H), 3.78 (s, 3H), 3.47 – 3.25 (m, 6H), 1.26 – 1.04 (m,

15H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 168.5, 157.9, 136.9,

136.7, 133.4, 125.6, 125.2, 112.4, 112.0, 76.0, 71.3, 55.3, 42.3,

41.1, 39.8, 39.0, 24.3, 22.8, 17.9, 14.4, 12.9. IR (Diamond-ATR,

3.40. 3-(hydroxymethyl)-7-methoxy-3,4,4-trimethyl-

1,2,2a,3,4,8b-hexahydrocyclobuta[a]naphthalen-2-ol (72)

neat) ꢀ_ꢁ̃ _ꢂꢃ: 2971 (m), 2935 (m), 2874 (w), 1645 (vs), 1603 (m),

To a solution of 71 (12.0ꢀmg, 0.0437ꢀmmol, 1ꢀequiv) in diethyl

ether (3ꢀmL) was added lithium aluminum hydride (16.6ꢀmg,

0.437ꢀmmol, 10.0ꢀequiv) at 0ꢀ°C and the reaction mixture was

allowed to slowly warm to 23ꢀ°C. After 4ꢀh, the reaction mixture

was diluted with saturated aqueous ammonium chloride solution

(15ꢀmL), the layers were separated and the aqueous layer was

extracted with ethyl acetate (3ꢀ×ꢀ10ꢀmL). The combined organic

layers were washed with saturated aqueous sodium chloride

solution (10ꢀmL) and the washed solution was dried over sodium

sulfate. The dried solution was filtered and the filtrate was

concentrated. The crude product was purified by flash column

chromatography on silica gel (33% ethyl acetate in hexanes) to

yield 72 (12ꢀmg, 99%, d.r. = 30:1) as a colorless oil. Analytical

data for 72: TLC (50% ethyl acetate in hexanes), R_f= 0.20

(CAM). ¹H NMR (400ꢀMHz, CDCl₃) δ: 7.09 (d, J = 8.5ꢀHz, 1H),

6.66 (dd, J = 8.6, 2.8ꢀHz, 1H), 6.59 (d, J = 2.7ꢀHz, 1H), 4.52 (dt, J

= 9.7, 8.1ꢀHz, 1H), 3.77 (s, 3H), 3.55 – 3.44 (m, 2H), 3.35 (s,

2H), 3.12 (q, J = 8.9ꢀHz, 1H), 3.03 (dt, J = 12.0, 6.0ꢀHz, 1H),

2.90 (dtd, J = 11.3, 8.0, 3.3ꢀHz, 1H), 2.00 (q, J = 10.1ꢀHz, 1H),

1.31 (s, 3H), 1.18 (s, 3H), 1.02 (s, 3H). ¹³C NMR (101ꢀMHz,

CDCl₃) δ: 158.2, 140.7, 137.0, 124.9, 112.3, 111.1, 65.5, 65.1,

1572 (w), 1464 (m), 1431 (m), 1381 (w), 1362 (w), 1309 (m),

1261 (vs), 1222 (m), 1153 (m), 1102 (m), 1088 (m), 1036 (m),

947 (w), 871 (w), 791 (w), 779 (w), 734 (w) cm⁻¹. HRMS (EI)

calcd for C₂₁H₃₁O₃N [M]⁺: 345.2298; found: 345.2295.

3.38. 7-methoxy-3,4,4-trimethyl-2a,3,4,8b-tetrahydro-1,3-

(epoxymethano)cyclobuta[a]naphthalen-2(1H)-one (65)

To a solution of 64 (60.0ꢀmg, 0.174ꢀmmol, 1ꢀequiv) in 1,2-

dichloroethane (6ꢀmL) were added 2,4,6-collidine (11.7ꢀꢁL,

0.868ꢀmmol, 5.00ꢀequiv) and trifluoromethanesulfonic anhydride

(1ꢀ

M in dichloromethane, 0.868ꢀmL, 0.868ꢀmmol, 5.00ꢀequiv) and

the reaction mixture was heated to 80ꢀ°C. After 75ꢀmin,

potassium carbonate (120ꢀmg, 0.868ꢀmmol, 5.00ꢀequiv), acetone

(6ꢀmL) and water (6ꢀmL) were added and the mixture was heated

to 70ꢀ°C. After 2ꢀh, aqueous hydrochloric acid solution (2ꢀM,

20ꢀmL) was added and the aqueous phase was extracted with

diethyl ether (3ꢀ×ꢀ20ꢀmL). The combined organic layers were

washed with saturated aqueous sodium chloride solution (20ꢀmL)

and the washed solution was dried over sodium sulfate. The dried

solution was filtered and the filtrate was concentrated. The crude

15

55.3, 49.8, 42.9, 41.1, 40.1, 27.9, 27.3, 21.5, 18.7. IR (Diamond-

KMnO₄). ¹H NMR (400ꢀMHz, C₆D₆) δ: 7.20 (s, 1H), 6.99 (d, J =

ACCEPTED MANUSCRIPT

ATR, neat) ꢀ

̃

_ꢁꢂꢃ: 3217 (m), 2970 (m), 2934 (m), 1606 (m), 1576

8.5ꢀHz, 1H), 6.86 (dd, J = 6.0, 1.1ꢀHz, 1H), 6.78 (dd, J = 8.5,

2.8ꢀHz, 1H), 6.63 (d, J = 2.8ꢀHz, 1H), 6.24 (d, J = 6.0ꢀHz, 1H),

3.27 (s, 3H), 1.08 (s, 3H), 0.76 (s, 3H), 0.69 (s, 3H). ¹³C NMR

(101ꢀMHz, C₆D₆) δ: 194.6, 162.4, 158.9, 143.1, 139.3, 136.4,

133.0, 126.1, 124.4, 115.9, 115.0, 54.9, 49.9, 39.6, 26.3, 20.4,

(w), 1495 (m), 1465 (m), 1365 (w), 1310 (m), 1247 (s), 1198 (m),

1112 (m), 1031 (vs), 849 (m), 808 (m), 735 (s), 703 (m) cm⁻¹.

HRMS (EI) calcd for C₁₇H₂₄O₃[M]⁺: 276.1720; found:

276.1726.

20.3. IR (Diamond-ATR, neat) ꢀ̃_ꢁꢂꢃ: 2966 (w), 2929 (w), 1689

3.41. 7-methoxy-3,4,4-trimethyl-2-oxo-1,2,2a,3,4,8b-

hexahydrocyclobuta[a]naphthalene-3-carbaldehyde (73)

(vs), 1645 (vs), 1605 (m), 1566 (m), 1482 (w), 1465 (w), 1372

(w), 1322 (w), 1249 (m), 1229 (vs), 1205 (w), 1146 (w), 1082 (w),

1057 (w), 1036 (m), 853 (w), 816 (s), 709 (w) cm⁻¹. HRMS (EI)

calcd for C₁₇H₁₈O₃[M]⁺: 254.1301; found: 254.1301.

To a solution of oxalyl chloride (2ꢀ

M in dichloromethane,

151ꢀꢁL, 0.302ꢀmmol, 2.20ꢀequiv) in dichloromethane (1.5ꢀmL)

was added dimethyl sulfoxide (47.9ꢀꢁL, 0.674ꢀmmol, 4.90ꢀequiv)

at −78ꢀ°C. After stirring for 3ꢀmin, a solution of 72 (38.0ꢀmg,

0.137ꢀmmol, 1ꢀequiv) dichloromethane (1ꢀmL) was added and

after further 25ꢀmin triethylamine (191ꢀꢁL, 1.37ꢀmmol,

10.0ꢀequiv) was added. The reaction mixture was stirred for

10ꢀmin at −78ꢀ°C and was then directly warmed to 23ꢀ°C. After

10ꢀmin, saturated aqueous sodium bicarbonate solution (10ꢀmL)

was added, the layers were separated and the aqueous layer was

extracted with dichloromethane (3ꢀ×ꢀ10ꢀmL). The combined

organic layers were dried over sodium sulfate, the dried solution

was filtered and the filtrate was concentrated. The crude product

was purified by flash column chromatography on silica gel (20%

ethyl acetate in hexanes, triethylamine pretreated silica gel) to

obtain 73 (35.5ꢀmg, 95%) as a colorless oil. Note: Signals in the

¹³C NMR which could only be assigned by cross-coupling in the

HMBC are marked with an asterisk. Analytical data for 73:

TLC (20% ethyl acetate in hexanes), R_f= 0.18 (ANIS). ¹H NMR

(400ꢀMHz, C₆D₆) δ: 9.12 (br s, 1H), 6.89 (d, J = 8.5ꢀHz, 1H), 6.68

– 6.59 (m, 2H), 3.31 (s, 3H), 3.24 (br s, 1H), 3.08 (ddd, J = 17.2,

9.6, 3.8ꢀHz, 1H), 2.95 (tdt, J = 9.6, 6.0, 1.1ꢀHz, 1H), 2.83 (ddd, J

= 10.3, 3.7, 2.8ꢀHz, 1H), 1.05 (s, 3H), 1.01 (s, 3H), 0.73 (s, 3H).

¹³C NMR (101ꢀMHz, C₆D₆) δ: 206.7, 202.2, 159.2, 140.3, 135.5,

125.4, 113.4, 112.3, 63.9, 55.9, 54.7, 53.1, 39.7, 26.3, 25.9,

3.43. 6-methoxy-1,1,2-trimethyl-1,2-dihydronaphthalene-2-

carbaldehyde (85a)

To a solution of alcohol 58a (1.17ꢀg, 5.04ꢀmmol, 1ꢀequiv) in

dry dichloromethane (50ꢀmL) was added potassium carbonate

(1.39ꢀg, 10.1ꢀmmol, 2.00ꢀequiv) and Dess–Martin periodinane

(4.27ꢀg, 10.1ꢀmmol, 2.00ꢀequiv) at 0ꢀ°C. The suspension was

stirred at 0ꢀ°C for 30ꢀmin and at 23ꢀ°C for 1.5ꢀh. Excess Dess–

Martin periodinane was quenched by addition of saturated

aqueous sodium bicarbonate solution (35ꢀmL) and saturated

aqueous sodium thiosulfate solution (20ꢀmL). The organic layer

was separated and the aqueous phase was extracted with

dichloromethane (3ꢀ×ꢀ50ꢀmL). The combined organic layers were

dried over sodium sulfate and the filtrate was concentrated under

reduced pressure. Purification by flash column chromatography

(1% ethyl acetate in cyclohexane initially, grading to 5% ethyl

acetate in cyclohexane) afforded aldehyde 85a (0.92 g, 80%) as a

colorless oil. Analytical data for 85a: TLC (10% ethyl acetate

1

in cyclohexane) R_f= 0.37 (UV) H NMR (400ꢀMHz, CDCl₃) δ:

9.35 (s, 1H), 7.20 (d, J = 8.5ꢀHz, 1H), 6.77 (dd, J = 8.5, 2.7ꢀHz,

1H), 6.65 – 6.61 (m, 2H), 5.49 (d, J = 9.5ꢀHz, 1H), 3.80 (s, 3H),

1.28 (s, 3H), 1.20 (s, 3H), 1.17 (s, 3H).¹³C NMR (101ꢀMHz,

CDCl₃) δ 202.8, 158.4, 135.4, 133.1, 130.6, 129.9, 125.6, 113.6,

21.7*, 16.3. IR (Diamond-ATR, neat) ꢀ

̃

_ꢁꢂꢃ: 2973 (w), 2933 (w),

112.8, 55.4, 54.8, 38.7, 25.3, 22.5, 14.3. IR (ATR, CDCl₃) ꢀ_ꢁ̃ _ꢂꢃ:

2728 (w), 1774 (vs), 1718 (s), 1607 (m), 1574 (w), 1494 (m),

1465 (m), 1388 (m), 1298 (m), 1249 (s), 1155 (m), 1087 (m),

1034 (s), 854 (w), 820 (w) cm⁻¹. HRMS (ESI) calcd for C₁₇H₂₀O₃

[M]⁺: 272.1407; found: 272.1409.

3032 (w), 2971 (w), 2871 (w), 2833 (w), 2715 (w), 1715 (s), 1634

(w), 1601 (m), 1570 (m), 1495 (m), 1463 (m), 1427 (m), 1386

(w), 1363 (w), 1308 (m), 1283 (m), 1259 (s), 1223 (m), 1192 (w),

1175 (m), 1153 (m), 1093 (m), 1034 (s), 961 (w), 933 (w), 908

(m), 871 (m), 856 (m), 818 (m), 791 (w), 773 (s), 754 (w), 731 (s),

712 (m), 683 (w), 621 (w), 582 (w), 553 (w), 527 (m), 498 (w),

431 (w) cm^-1. HRMS (ESI) calcd for C₁₅H₁₈NaO₂[M+Na]⁺:

253.1199; found: 253.1185.

3.42. 7-methoxy-3a,4,4-trimethyl-3a,4-dihydro-1H-

cyclopenta[b]naphthalen-1-one (77)

To a solution of 73 (5.00ꢀmg, 0.0184ꢀmmol, 1ꢀequiv) in

tetrahydrofuran

bis(trimethylsilyl)amide (1ꢀ

(0.2ꢀmL)

was

added

lithium

3.44. ethyl (Z)-5-(6-methoxy-1,1,2-trimethyl-1,2-

dihydronaphthalen-2-yl)pent-4-enoate (86a)

M

in tetrahydrofuran, 22.0ꢀꢁL,

0.0220ꢀmmol, 1.20ꢀequiv) at −78ꢀ°C. After 1ꢀh, freshly distilled

trimethylsilyl chloride (over CaH₂, 3.52ꢀꢁL, 0.0275ꢀmmol,

1.50ꢀequiv) was added and the mixture was allowed to warm to

23ꢀ°C. After 3ꢀh, dichloromethane (5ꢀmL) was added, the reaction

mixture was filtered through a small plug of Celite® and the

filtrate was concentrated. The residue was used without further

purification. To acetone (2.03ꢀꢁL, 0.0276ꢀmmol, 1.50ꢀequiv) in

dichloromethane (0.1ꢀmL) was added titanium(IV) chloride

(3.04ꢀꢁL, 0.0276ꢀmmol, 1.50ꢀequiv) followed by the addition of a

solution of crude product in dichloromethane (0.3ꢀmL) at −78ꢀ°C.

The reaction mixture was allowed to warm to 23ꢀ°C over 17ꢀh.

pH7 Buffer solution (10ꢀmL) and diethyl ether (10ꢀmL) were

added, the layers were separated and the aqueous layer was

extracted with diethyl ether (3ꢀ×ꢀ10ꢀmL). The combined organic

layers were washed with saturated aqueous sodium chloride

solution (10ꢀmL) and the washed solution was dried over sodium

sulfate. The dried solution was filtered and the filtrate was

concentrated. The crude product was purified by flash column

chromatography on silica gel (20% ethyl acetate in hexanes) to

provide trace amounts of 77 as colorless oil. Analytical data for

77: TLC (20% ethyl acetate in hexanes), R_f= 0.26 (UV, CAM,

To

a

stirred

suspension

of

[3-

(ethoxycarbonyl)propyl]triphenylphosphonium bromide (2.85ꢀg,

6.23ꢀmmol, 1.60ꢀequiv) in tetrahydrofuran (25ꢀmL) was added

sodium bis(trimethylsilyl)amide (1.0ꢀ

M

in THF, 7.1ꢀmL,

7.1ꢀmmol, 1.8ꢀequiv) at 0ꢀ°C. The orange mixture was stirred for

30ꢀmin at 0ꢀ°C and was then cooled to −78ꢀ°C. A solution of

aldehyde 85a (0.90ꢀg, 3.90ꢀmmol, 1ꢀequiv) in tetrahydrofuran

(4.2ꢀmL) was added slowly. After 15ꢀmin, the reaction was

allowed to warm to 23ꢀ°C and stirred at 23ꢀ°C for 4ꢀh. Excess

amide was quenched by addition of saturated aqueous

ammonium chloride solution (21ꢀmL). The mixture was extracted

with diethyl ether (3ꢀ×ꢀ50ꢀmL). The combined organic layers were

washed with saturated aqueous sodium chloride solution (70ꢀmL)

and the washed solution was dried over sodium sulfate. The

solution was filtered and the filtrate was concentrated under

reduced pressure. The crude product was purified by flash

column chromatography on silica gel (10% ethyl acetate in

cyclohexane) to afford the title compound 86a (1.20ꢀg, 94%) as a

colorless oil. Analytical data for 86a: TLC (10% ethyl acetate

in cyclohexane) R_f= 0.45 (UV) ¹H NMR (400ꢀMHz, CDCl₃) δ:

16

1

7.18 (d, J = 8.5ꢀHz, 1H), 6.72 (dd, J = 8.4, 2.8ꢀHz, 1H), 6.58 (d, J

= 2.7ꢀHz, 1H), 6.31 (d, J = 9.6ꢀHz, 1H), 5.99 (d, J = 9.6ꢀHz, 1H),

5.46 (d, J = 12.0ꢀHz, 1H), 5.36 (dt, J = 12.0, 7.2ꢀHz, 1H), 4.14 (q,

J = 7.1ꢀHz, 2H), 3.78 (s, 3H), 2.73 – 2.62 (m, 1H), 2.50 (tdd, J =

14.7, 7.2, 1.3ꢀHz, 1H), 2.37 (t, J = 7.5ꢀHz, 2H), 1.28 (s, 3H), 1.25

(t, J = 7.2ꢀHz, 3H), 1.16 (s, 3H), 1.09 (s, 3H). ¹³C NMR

(101ꢀMHz, CDCl₃) δ: 173.1, 157.9, 139.0, 136.5, 135.7, 133.2,

129.7, 125.2, 124.6, 112.3, 112.0, 60.4, 55.2, 45.1, 40.9, 34.7,

(10% ethyl acetate in cyclohexane) R_f= 0.21 (UV, CAM) H

ACCEPTED MANUSCRIPT

NMR (400ꢀMHz, Acetone-d₆) δ: 7.20 (d, J = 8.4ꢀHz, 1H), 6.75 –

6.67 (m, 2H), 5.37 (ddt, J = 12.5, 2.7, 1.8ꢀHz, 1H), 5.11 (dddd, J

= 12.5, 5.1, 2.6, 1.1ꢀHz, 1H), 3.75 (s, 3H), 3.72 (d, J = 8.2ꢀHz,

1H), 3.67 – 3.60 (m, 1H), 3.48 (ddd, J = 8.3, 6.6, 1.9ꢀHz, 1H),

2.21 (dtd, J = 18.5, 5.1, 1.6ꢀHz, 1H), 1.98 (dq, J = 18.5, 2.8ꢀHz,

1H), 1.37 (s, 3H), 1.24 (s, 3H), 1.10 (s, 3H). ¹³C NMR

(101ꢀMHz, Acetone-d₆) δ: 209.2, 158.2, 139.7, 136.7, 134.5,

126.6, 126.5, 114.8, 112.9, 64.9, 61.7, 55.3, 41.5, 41.1, 30.6,

26.1, 24.9, 22.5, 21.6, 14.3. IR (ATR, CDCl₃) ν_max: 2972 (m),

̃

2937 (w), 2873 (w), 2833 (w), 1732 (s), 1636 (w), 1602 (m), 1571

(w), 1489 (m), 1464 (m), 1427 (w), 1371 (m), 1308 (m), 1281

(m), 1259 (s), 1214 (m), 1171 (k), 1151 (s), 1089 (m), 1062 (w),

1035 (s), 910 (m), 871 (m), 856 (m), 818 (m), 778 (m), 730 (s),

648 (w), 631 (w), 597 (w), 554 (w), 473 (w), 433 (w) cm^-1.

HRMS (ESI) calcd for C₂₁H₂₈NaO₃[M+Na]⁺: 351.1931, found:

351.1926.

28.3, 27.6, 21.9, 21.9. IR (ATR, CDCl₃) ν_m̃ _ax: 2969 (w), 2909

(w), 2834 (w), 1776 (s), 1608 (w), 1576 (w), 1497 (w), 1464 (w),

1424 (w), 1387 (w), 1370 (w), 1324 (w), 1304 (w), 1281 (w),

1255 (m), 1246 (m), 1220 (w), 1160 (w), 1112 (w), 1090 (w),

1062 (w), 1037 (w), 975 (w), 929 (w), 857 (w), 822 (w), 760 (w),

701 (w), 688 (w), 601 (w), 570 (w), 483 (w), 410 (w)ꢀ

cm^-1. HRMS (ESI) calcd for C₁₉H₂₂NaO₂[M+Na]⁺: 305.1512,

found: 305.1472. Analytical Data for 89a: TLC (10% ethyl

acetate in cyclohexane) R_f= 0.27 (UV, CAM) ¹H NMR

(600ꢀMHz, CDCl₃) δ: 7.10 (d, J = 8.6ꢀHz, 1H), 6.84 (dd, J = 2.8,

1.2ꢀHz, 1H), 6.63 (ddd, J = 8.6, 2.8, 1.0ꢀHz, 1H), 5.46 (ddd, J =

10.4, 6.7, 1.9ꢀHz, 1H), 5.42 (ddd, J = 10.2, 2.9, 1.5ꢀHz, 1H), 4.28

(dt, J = 9.8, 2.0ꢀHz, 1H), 3.71 (s, 3H), 3.62 (dddd, J = 9.9, 7.0,

3.2, 1.7ꢀHz, 1H), 3.04 (td, J = 9.8, 1.5ꢀHz, 1H), 2.28 (ddd, J =

16.9, 6.7, 1.8ꢀHz, 1H), 2.06 (dddd, J = 17.0, 7.0, 2.9, 2.0ꢀHz, 1H),

1.34 (s, 3H), 1.11 (s, 3H), 1.02 (s, 3H). ¹³C NMR (151ꢀMHz,

CDCl₃) δ: 212.6, 157.8, 137.5, 134.9, 130.9, 126.2, 125.1, 112.4,

112.0, 58.9, 55.7, 55.3, 39.9, 38.7, 34.6, 25.5, 22.1, 21.9, 20.4.

3.45. (Z)-5-(6-methoxy-1,1,2-trimethyl-1,2-dihydronaphthalen-2-

yl)-1-(pyrrolidin-1-yl)pent-4-en-1-one (87a)

The ester 86a (1.20ꢀg, 3.65ꢀmmol, 1ꢀequiv) was dissolved in

dry and colorless pyrrolidine (4.5ꢀmL, 55ꢀmmol, 15ꢀequiv) in a

pressure tube under argon. The tube was sealed and heated at

100ꢀ°C. The reaction mixture was stirred for 65ꢀh and was then

cooled to 23ꢀ°C. Excess pyrrolidine was removed under reduced

pressure. Purification by flash column chromatography on silica

gel (50% ethyl acetate in cyclohexane) afforded the title

compound 87a (1.38ꢀg, quant.) as a pale-yellow oil. Analytical

data for 87a: TLC (50% ethyl acetate in cyclohexane) R_f= 0.27

(CAM) ¹H NMR (400ꢀMHz, CDCl₃) δ: 7.17 (d, J = 8.4ꢀHz, 1H),

6.71 (dd, J = 8.4, 2.8ꢀHz, 1H), 6.57 (d, J = 2.7ꢀHz, 1H), 6.29 (d, J

= 9.6ꢀHz, 1H), 6.00 (d, J = 9.6ꢀHz, 1H), 5.46 – 5.36 (m, 2H), 3.78

(s, 3H), 3.47 (t, J = 6.8ꢀHz, 2H), 3.40 (t, J = 6.8ꢀHz, 2H), 2.73 –

2.62 (m, 1H), 2.59 – 2.47 (m, 1H), 2.31 (t, J = 7.7ꢀHz, 2H), 1.99

– 1.89 (m, 2H), 1.89 – 1.80 (m, 2H), 1.27 (s, 3H), 1.16 (s, 3H),

1.08 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ: 171.1, 157.9, 139.4,

136.8, 135.4, 133.5, 130.7, 125.3, 124.6, 112.4, 112.0, 55.3, 46.8,

45.8, 45.2, 41.0, 35.3, 26.3, 26.2, 25.1, 24.6, 22.6, 21.7. IR

IR (ATR, CDCl₃) ν_max3034 (w), 2969 (m), 2838 (w), 1775 (s),

̃

1606 (m), 1575 (w), 1496 (m), 1464 (w), 1400 (w), 1383 (w),

1369 (w), 1320 (w), 1302 (m), 1257 (m), 1229 (m), 1178 (w),

1158 (w), 1141 (w), 1117 (w), 1091 (w), 1037 (m), 1016 (w), 956

(w), 927 (w), 868 (w), 850 (w), 815 (w), 757 (w), 731 (w), 698

(m), 589 (w), 560 (w), 526 (w), 507 (w), 479 (w), 442 (w)ꢀcm^-1.

HRMS (ESI) calcd for C₁₉H₂₂NaO₂[M+Na]⁺: 305.1512, found:

305.1465.

3.47. 11-hydroxy-7-methoxy-3,4,4-trimethyl-2a,3,4,8b-

tetrahydro-3,1-prop[1]enocyclobuta[a]naphthalen-2(1H)-one

(93a)

(ATR, CDCl₃) ν_max: 2969 (m), 2872 (w), 2833 (w), 1641 (s), 1602

̃

(m), 1571 (w), 1489 (m), 1433 (s), 1380 (w), 1359 (w), 1340 (w),

1309 (w), 1282 (w), 1260 (s), 1225 (w), 1192 (w), 1171 (w), 1152

(w), 1089 (w), 1035 (m), 870 (w), 857 (w), 818 (w), 780 (w), 727

(w), 632 (w), 549 (w), 421 (w) cm^-1. HRMS (ESI) calcd for

C₂₃H₃₁NNaO₂[M+Na]⁺: 376.2247, found: 376.2240

To finely grinded selenium dioxide (2.13ꢀg, 19.2ꢀmmol,

10.0ꢀequiv) and oven-dried (100ꢀ°C) fine white quartz sand

(2.19ꢀg, 19.0ꢀequiv, particle size >230mesh) in a flame-dried

pressure tube (15ꢀmL) equipped with a magnetic stirring bar was

added cyclobutanone 90a (541ꢀmg, 1.92ꢀmmol, 1ꢀequiv). After

sparging with argon for 10ꢀmin, dry 1,4-dioxane (9.6ꢀmL) was

added. The tube was sealed and the vigorously stirred reaction

mixture was heated at 125ꢀ°C (700ꢀrpm) for 7ꢀh. The reaction

mixture was cooled to 23ꢀ°C and filtered through a pad of

Celite®. The Celite® plug was washed with ethyl acetate

(200ꢀmL) and the filtrate was concentrated under reduced

pressure. Purification by flash column chromatography (1% ethyl

acetate in cyclohexane initially, grading to 10% ethyl acetate in

cyclohexane, grading to 25% ethyl acetate in cyclohexane,

grading to 50% ethyl acetate in cyclohexane) afforded slightly

impure 93a (165ꢀmg) as an orange foam. Cyclobutanone 90a

(294ꢀmg, 54%) was recovered. Purification of the impure product

93a by flash column chromatography (10% ethyl acetate in

dichloromethane) afforded the allylic alcohol 93a (142ꢀmg, 25%)

as a colorless sticky foam. Analytical Data for 93a: TLC (25%

3.46. 7-methoxy-3,4,4-trimethyl-2a,3,4,8b-tetrahydro-3,1-

prop[1]enocyclobuta[a]naphthalen-2(1H)-one (90a)

To

a vigorously stirred solution of freshly distilled

trifluoromethanesulfonic anhydride (0.77ꢀmL, 4.55ꢀmmol,

1.20ꢀequiv) in dry 1,2-dichloroethane (47ꢀmL) at 80ꢀ°C was added

dropwise a solution of amide 87a (1.34ꢀg, 3.79ꢀmmol, 1ꢀequiv)

and 2,4,6-collidine (0.60ꢀmL, 4.55ꢀmmol, 1.20ꢀequiv) in 1,2-

dichloroethane (47ꢀmL) via a dropping funnel over a period of

2ꢀh. The initial yellowish reaction mixture turned red-brownish,

stirring was continued at 80ꢀ°C for 24ꢀh and was cooled to 23ꢀ°C.

The dark red-brownish reaction mixture was concentrated under

reduced pressure. To the crude iminium salt was added

tetrachloromethane (20ꢀmL) and water (20ꢀmL) and the dark

brown mixture was heated at reflux at 80ꢀ°C forꢀ5 h under an

atmosphere of argon. The organic layer was separated and the

aqueous phase was extracted with dichloromethane (3ꢀ×ꢀ15ꢀmL).

The combined organic layers were dried over sodium sulfate,

filtered and the filtrate was concentrated under reduced pressure.

Purification by flash column chromatography on silica gel (10%

ethyl acetate in cyclohexane) afforded cyclobutanone 90a

(0.72ꢀg, 67%) as a pale yellow solid and cyclobutanone 89a

(0.02ꢀg, 2%) as a colorless oil. Analytical Data for 90a: TLC

1

ethyl acetate in cyclohexane) R_f= 0.30 (UV, CAM) H NMR

(400ꢀMHz, CDCl₃) δ: 7.19 (d, J = 8.7ꢀHz, 1H), 6.75 (ddd, J = 8.7,

2.8, 0.7ꢀHz, 1H), 6.66 (dd, J = 2.8, 0.9ꢀHz, 1H), 5.42 (dt, J = 12.6,

1.8ꢀHz, 1H), 5.34 (ddd, J = 12.7, 2.5, 1.9ꢀHz, 1H), 4.04 – 3.97 (m,

1H), 3.83 (dddd, J = 8.6, 6.4, 4.3, 1.9ꢀHz, 1H), 3.78 (s, 3H), 3.73

(t, J = 8.5ꢀHz, 1H), 3.48 (ddd, J = 8.3, 6.6, 1.7ꢀHz, 1H), 1.98 (d, J

= 9.4ꢀHz, 1H), 1.39 (s, 3H), 1.28 (s, 3H), 1.09 (s, 3H). ¹³C NMR

17

(m), 1578 (w), 1502 (m), 1465 (w), 1426 (w), 1392 (w), 1374 (w),

1358 (w), 1341 (w), 1316 (w), 1260 (m), 1243 (m), 1204 (w),

1159 (m), 1091 (w), 1065 (w), 1019 (m), 958 (w), 925 (w), 865

(w), 844 (w), 813 (w), 783 (w), 753 (w), 705 (w), 656 (w), 607

(w), 546 (w), 514 (w), 497 (w), 447 (w)ꢀcm^-1. HRMS (ESI) calcd

for C₁₉H₂₀NaO₄[M+Na]⁺: 335.1254, found: 335.1199.

^{(101ꢀMHz, CDCl ) δ: 208.5, 157.5, 138.6, 13}A^5.8C^,C¹³E^2.3P^,T¹³E⁰D^.0,MANUSCRIPT

3

126.2, 113.9, 112.8, 68.1, 67.5, 64.7, 55.3, 42.5, 40.5, 28.4, 27.7,

22.0, 21.9. IR (ATR, CDCl₃) ν_max: 3420 (w br), 2971 (w), 2909

̃

(w), 2836 (w), 2251 (w), 1771 (s), 1607 (m), 1575 (w), 1496 (m),

1477 (w), 1464 (w), 1425 (w), 1388 (w), 1371 (w), 1325 (w),

1309 (w), 1244 (m), 1174 (m), 1163 (m), 1128 (w), 1107 (w),

1090 (w), 1057 (w), 1032 (s), 974 (w), 908 (m), 879 (m), 852 (w),

816 (m), 775 (m), 726 (s), 701 (m), 688 (m), 647 (m), 588 (m),

552 (w), 529 (w), 492 (w), 453 (w)ꢀcm^-1. HRMS (ESI) calcd for

C₁₉H₂₂NaO₃[M+Na]⁺: 321.1461, found: 321.1416.

3.49. tert-butyl((6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalen-

2-yl)methoxy)diphenylsilane (84)

To aluminum chloride (133ꢀmg, 1.00ꢀmmol, 3.00ꢀequiv) in an

oven dried Schlenk flask was added dry toluene (1.0ꢀmL) and

3.48. 8-methoxy-4,5,5-trimethyl-3a,4,5,9b-tetrahydro-4,1-

prop[1]enonaphtho[1,2-c]furan-3,12(1H)-dione (94a)

ethyl magnesium bromide solution (3ꢀ

M in diethylether, 1.00ꢀmL,

3.00ꢀmmol, 12.0ꢀequiv). The suspension was irradiated in an

ultrasonic bath for 15ꢀmin. To a second Schlenk flask equipped

To a solution of allylic alcohol 93a (50.0ꢀmg, 0.168ꢀmmol,

1ꢀequiv) in 1,2-dichloroethane (4.4ꢀmL) was added pivalaldehyde

(0.09ꢀmL, 0.8ꢀmmol, 5ꢀequiv) and copper(II) acetate monohydrate

(33.5ꢀmg, 0.168ꢀmmol, 1.00ꢀequiv). The flask was capped with a

septum and sparged with oxygen gas from a balloon for 2ꢀmin.

The solution was stirred under oxygen at 23ꢀ°C until monitoring

by thin layer chromatography indicated full conversion of the

starting material (1.5ꢀh). Sodium bicarbonate (70.4ꢀmg,

0.838ꢀmmol, 5.00ꢀequiv) and Dess–Martin periodinane (142ꢀmg,

0.335ꢀmmol, 2.00ꢀequiv) were added and the reaction was stirred

at 23ꢀ°C. After 1ꢀh, an additional portion of Dess-Martin

periodinane (142ꢀmg, 0.335ꢀmmol, 2.00ꢀequiv) was added and the

reaction was stirred at 23ꢀ°C for 1ꢀh. Excess Dess–Martin

periodinane was quenched by addition of saturated aqueous

sodium bicarbonate solution (9ꢀmL) and saturated aqueous

sodium thiosulfate solution (4.5ꢀmL). The mixture was extracted

with dichloromethane (3ꢀ×ꢀ25ꢀmL). The combined organic layers

were dried over sodium sulfate. The dried solution was filtered

and the filtrate was concentrated under reduced pressure.

Purification by flash column chromatography on silica gel (10%

ethyl acetate in cyclohexane initially, grading to 25% ethyl

acetate in cyclohexane) afforded a mixture of lactones 94a and

95a. Separation by slow flash column chromatography on silica

gel (5% ethyl acetate in cyclohexane initially, grading to 10%

ethyl acetate in cyclohexane) afforded lactone 94a (34ꢀmg, 64%)

and lactone 95a (13ꢀmg, 25%) as both colorless crystalline solids.

Analytical Data for 94a: TLC (25% ethyl acetate in

cyclohexane) R_f= 0.27 (UV, CAM) ¹H NMR (400ꢀMHz, CDCl₃)

δ: 7.21 (d, J = 8.8ꢀHz, 1H), 6.78 (ddd, J = 8.9, 2.8, 0.6ꢀHz, 1H),

6.61 (dd, J = 2.8, 0.8ꢀHz, 1H), 6.10 (dd, J = 13.1, 1.5ꢀHz, 1H),

5.63 (dd, J = 13.1, 1.9ꢀHz, 1H), 5.03 (dd, J = 8.6, 2.0ꢀHz, 1H),

4.05 (t, J = 8.7ꢀHz, 1H), 3.75 (s, 3H), 3.15 (dd, J = 8.7, 1.5ꢀHz,

1H), 1.58 (s, 3H), 1.42 (s, 3H), 1.21 (s, 3H). ¹³C NMR

(101ꢀMHz, CDCl₃) δ: 195.8, 176.9, 158.2, 148.2, 135.7, 128.4,

127.6, 126.2, 114.9, 113.0, 84.6, 55.4, 45.7, 43.7, 42.3, 39.6,

with

a

magnetic stirring bar was added bis(1,5-

cyclooctadiene)nickel(0) (5.8ꢀmg, 21ꢀµmol, 25ꢀmol%) and 1,2-

bis(dicyclohexylphosphino)ethane (8.9ꢀmg, 21ꢀµmol, 25ꢀmol%)

and protected dehydrotetraline 81 (45.0ꢀmg, 95.6ꢀµmol, 1ꢀequiv)

in a glovebox. Toluene (0.5ꢀmL) and diisopropyl ether (0.5ꢀmL)

were added. The suspension of aluminum chloride and ethyl

magnesium bromide (0.50ꢀmL, 0.50ꢀmmol AlEt₃, 5.2ꢀequiv) was

transferred to this solution. The resulting bright yellow

suspension was heated to 100ꢀ°C for 19ꢀh and then cooled to

23ꢀ°C. Excess ethyl metal species were quenched by slow

addition of saturated aqueous potassium sodium tartrate solution

(5ꢀmL) and the biphasic mixture was stirred for 2ꢀh at 23ꢀ°C. The

aqueous phase was separated and extracted with ethyl acetate

(3ꢀ×ꢀ5ꢀmL). The combined organic phases were washed with

saturated aqueous sodium chloride solution (5ꢀmL) and dried

over sodium sulfate. The dried solution was filtered and

concentrated. The crude product was purified by flash column

chromatography on silica gel (20% ethyl acetate in hexanes) to

provide ethyl tetraline 84 (3.1ꢀmg, 7%) as a colorless oil.

Analytical Data for 84: The physical data were identical in all

respects to those previously reported [54].

3.50. tert-butyl((6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalen-

2-yl)methoxy)diphenylsilane (84)

To a solution of triflate 83 (15.0ꢀg, 25.5ꢀmmol, 1ꢀequiv) in dry

dioxane

bis(diphenylphosphino)ferrocene]dichloropalladium(II) (250ꢀmg,

0.34ꢀmmol, 1.3ꢀmol%). The orange suspension was cooled to

0ꢀ°C causing partial crystallization of the solvent. Diethylzinc

(130ꢀꢀmL)

was

added

[1,1′-

(1ꢀ

M in hexanes, 38.2ꢀmL, 38.2ꢀmmol, 1.50ꢀequiv) was added and

the ice bath was removed. When all dioxane was melted again, a

yellow clear solution was formed. The reaction mixture was

heated at 70ꢀ°C for 1ꢀh and was then cooled to 0ꢀ°C. Excess

diethylzinc of the brownish solution was quenched by addition of

methanol (20ꢀmL), water (100ꢀmL) and saturated aqueous

ammonium chloride solution (100ꢀmL). The mixture was

extracted with ethyl acetate (3ꢀ×ꢀ150ꢀmL). The combined organic

layers were washed with saturated aqueous sodium chloride

solution (100ꢀmL) and the washed solution was dried over

sodium sulfate. The filtrate was concentrated under reduced

pressure, passed through a plug of silica (5% ethyl acetate in

cyclohexane) and used without further purification in the next

step. Analytical Data for 84: The physical data were identical in

all respects to those previously reported [54].

28.6, 22.2, 21.4. IR (ATR, CDCl₃) ν_max: 2978 (w), 2838 (w),

̃

1776 (s), 1680 (s), 1612 (m), 1579 (w), 1503 (m), 1479 (w), 1466

(m), 1427 (w), 1392 (w), 1377 (w), 1368 (w), 1331 (w), 1314 (m),

1284 (m), 1258 (s), 1242 (s), 1206 (m), 1180 (m), 1155 (s), 1109

(m), 1090 (w), 1065 (w), 1028 (s), 992 (w), 958 (w), 923 (w), 905

(w), 877 (w), 825 (s), 753 (m), 722 (w), 704 (w), 692 (w), 666

(w), 602 (w), 563 (w), 547 (w), 498 (w), 457 (w), 432 (w)ꢀcm^-1.

HRMS (ESI) calcd for C₁₉H₂₀NaO₄[M+Na]⁺: 335.1254, found:

335.1194. Analytical Data for 95a: TLC (25% ethyl acetate in

1

cyclohexane) R_f= 0.20 (UV) H NMR (400ꢀMHz, CDCl₃) δ:

7.18 (d, J = 8.8ꢀHz, 1H), 6.78 (dd, J = 8.8, 2.7ꢀHz, 1H), 6.59 (dd,

J = 2.8, 0.8ꢀHz, 1H), 6.04 (dd, J = 13.2, 1.8ꢀHz, 1H), 5.70 (dd, J =

13.2, 1.7ꢀHz, 1H), 5.10 (dd, J = 8.2, 1.8ꢀHz, 1H), 4.18 (t, J =

8.5ꢀHz, 1H), 3.90 (dd, J = 8.8, 1.7ꢀHz, 1H), 3.75 (s, 3H), 1.49 (s,

3H), 1.43 (s, 3H), 1.25 (s, 3H). ¹³C NMR (101ꢀMHz, CDCl₃) δ:

192.2, 171.6, 158.3, 148.0, 135.6, 130.8, 127.9, 127.3, 114.9,

113.6, 81.5, 60.1, 55.4, 49.2, 43.2, 40.6, 28.6, 23.2, 19.0. IR

3.51. (6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalen-2-

yl)methanol (58b)

To a stirred solution of protected alcohol 84 (ca. 25.5ꢀmmol,

1ꢀequiv) in tetrahydrofuran (130ꢀmL) was added a solution of

tetrabutylammonium fluoride (1ꢀ

M in THF, 35ꢀmL, 35ꢀmmol,

1.4ꢀequiv) at 0ꢀ°C. The ice bath was removed after 15ꢀmin and the

(ATR, CDCl₃) ν_max: 2977 (w), 2927 (w), 1774 (s), 1673 (m), 1612

̃

18

reaction was stirred at 23ꢀ°C for 18ꢀh. Excess fluoride was

on silica gel (50% ethyl acetate in cyclohexane) afforded the title

compound 87b (7.5ꢀg, 99%) as a pale-yellow oil. Analytical

Data for 87b: The physical data were identical in all respects to

those previously reported [54].

ACCEPTED MANUSCRIPT

quenched by addition of water (50ꢀmL). The reaction was

extracted with ethyl acetate (3ꢀ×ꢀ50ꢀmL). The combined organic

layers were washed with saturated aqueous sodium chloride

solution (50ꢀmL) and the washed solution was dried over sodium

sulfate. The filtrate was concentrated under reduced pressure.

Purification by flash column chromatography (1% ethyl acetate

in cyclohexane initially, grading to 5% ethyl acetate in

cyclohexane) afforded the title compound 58b (5.9ꢀg, 99%) as a

colorless viscous oil. Analytical Data for 58b: The physical data

were identical in all respects to those previously reported [54].

3.55. 7-ethyl-3,4,4-trimethyl-2a,3,4,8b-tetrahydro-3,1-

prop[1]enocyclobuta[a]- naphthalen-2(1H)-one (90b)

To

a vigorously stirred solution of freshly distilled

trifluoromethanesulfonic anhydride (4.50ꢀmL, 26.8ꢀmmol,

1.30ꢀequiv) in dry 1,2-dichloroethane (270ꢀmL) at 80ꢀ°C was

added dropwise a solution of amide 87b (7.25ꢀg, 20.6ꢀmmol,

1ꢀequiv) and 2,4,6-collidine (3.54ꢀmL, 26.8ꢀmmol, 1.30ꢀequiv) in

1,2-dichloroethane (270ꢀmL) via a dropping funnel over a period

of 3.5ꢀh. The initial yellowish reaction mixture turned red-

brownish, stirring was continued at 80ꢀ°C for 20ꢀh and then the

reaction mixture was concentrated under reduced pressure. To the

crude iminium salt was added tetrachloromethane (100ꢀmL) and

water (100ꢀmL) and the dark brown mixture was heated at reflux

at 80ꢀ°C for 5ꢀh under an atmosphere of argon. The organic layer

was separated and the aqueous phase was extracted with

dichloromethane (3ꢀ×ꢀ50ꢀmL). The combined organic layers were

dried over sodium sulfate and the filtrate was concentrated under

reduced pressure. Purification by flash column chromatography

on silica gel (5% ethyl acetate in cyclohexane grading to 10%

ethyl acetate in cyclohexane) afforded cyclobutanone 90b (4.8ꢀg,

83%) as a pale yellowish oil that solidified upon storage.

Analytical Data for 90b: The physical data were identical in all

respects to those previously reported [54].

3.52. 6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalene-2-

carbaldehyde (85b)

To a solution of oxalyl chloride (4.4ꢀmL, 50ꢀmmol, 2.0ꢀequiv)

in dichloromethane (250ꢀmL) was added a solution of dimethyl

sulfoxide (4.4ꢀmL, 63ꢀmmol, 2.5ꢀequiv) in dichloromethane

dropwise at –78ꢀ°C. The mixture was stirred for 30ꢀmin before a

solution of alcohol 58b (5.8ꢀg, 25ꢀmmol, 1ꢀequiv) in

dichloromethane (25ꢀmL) was added dropwise. The reaction

mixture was stirred at –78ꢀ°C for 1ꢀh before triethylamine

(17ꢀmL, 0.13ꢀmol, 5.0ꢀequiv) was added. The reaction was stirred

for 30ꢀmin at –78ꢀ°C and 4ꢀh at 23ꢀ°C. Excess base was quenched

by the addition of saturated aqueous ammonium chloride solution

(100ꢀmL). The biphasic mixture was extracted with diethyl ether

(3ꢀ×ꢀ200ꢀmL). The combined organic layers were washed with

concentrated aqueous sodium chloride solution (200ꢀmL) and

dried over sodium sulfate. The dried solution was filtered and

concentrated under reduced pressure. Purification by flash

column chromatography on silica gel (5% ethyl acetate in

cyclohexane) afforded aldehyde 85b as colorless oil (5.7ꢀg, 99%).

Analytical Data for 85b: The physical data were identical in all

respects to those previously reported [54].

3.56. 7-ethyl-11-hydroxy-3,4,4-trimethyl-2a,3,4,8b-tetrahydro-

3,1- prop[1]enocyclobuta[a]naphthalen-2(1H)-one (93b)

To finely grinded selenium dioxide (21ꢀg, 0.19ꢀmol, 10ꢀequiv)

and oven-dried (100ꢀ°C) fine white quartz sand (21ꢀg, 0.35ꢀmol,

19ꢀeq, particle size >230ꢀmesh) in a flame-dried pressure tube

equipped with a magnetic stirring bar was added cyclobutanone

90b (5.2ꢀg, 19ꢀmmol, 1ꢀequiv). After sparging with nitrogen for

5ꢀmin, dry 1,4-dioxane (93ꢀmL) was added. The tube was sealed

and the vigorously stirred reaction mixture was heated at 120ꢀ°C

for 6ꢀh. The reaction mixture was cooled to 23ꢀ°C and filtered

through a pad of Celite®. The Celite® was washed with ethyl

acetate (200ꢀmL) and the filtrate was concentrated under reduced

pressure. Purification by flash column chromatography (1% ethyl

acetate in cyclohexane initially, grading to 10% ethyl acetate in

cyclohexane, grading to 25% ethyl acetate in cyclohexane,

grading to 50% ethyl acetate in cyclohexane) afforded slightly

impure 93b (1.21ꢀg) as an orange oil. Cyclobutanone 90b (3.38ꢀg,

65%) was recovered and used in the next cycle following the

same procedure. After four cycles, the product fractions were

combined and collectively purified by flash column

chromatography on silica gel (dichloromethane grading to 10%

ethyl acetate in dichloromethane) to afford the allylic alcohol 93b

(2.42ꢀg, 44%) as a slightly yellow wax. Analytical Data for 93b:

The physical data were identical in all respects to those

previously reported [54].

3.53. ethyl (Z)-5-(6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalen-

2-yl)pent-4-enoate (86b

)

To stirred

a

suspension

of

[3-

(ethoxycarbonyl)propyl]triphenylphosphonium bromide (17ꢀg,

38ꢀmmol, 1.50ꢀequiv) in tetrahydrofuran (150ꢀmL) was added

sodium bis(trimethylsilyl)amide (1.0ꢀ

M

in THF, 12.6ꢀmL,

12.6ꢀmmol, 1.70ꢀequiv) at 0ꢀ°C. The yellow-orange mixture was

stirred for 30ꢀmin at 0ꢀ°C and was then cooled to −78ꢀ°C. A

solution of aldehyde 85b (5.7ꢀg, 25ꢀmmol, 1ꢀequiv) in

tetrahydrofuran (20ꢀmL) was added slowly. After 15ꢀmin, the

reaction was allowed to warm to 23ꢀ°C and stirred at 23ꢀ°C for

5ꢀh. Excess amide was quenched by addition of saturated aqueous

ammonium chloride solution (100ꢀmL). The mixture was

extracted with diethyl ether (3ꢀ×ꢀ300ꢀmL). The combined organic

layers were washed with saturated aqueous sodium chloride

solution (200ꢀmL) and the washed solution was dried over

sodium sulfate. The filtrate was concentrated under reduced

pressure and the crude product was purified by flash column

chromatography on silica gel (5% ethyl acetate in cyclohexane)

to afford the title compound 86b (7.0ꢀg, 86%) as a colorless oil.

Analytical Data for 86b: The physical data were identical in all

respects to those previously reported [54].

3.57. 8-ethyl-4,5,5-trimethyl-3a,4,5,9b-tetrahydro-4,1-

prop[1]enonaphtho[1,2- c]furan-3,12(1H)-dione (94b)

3.54. (Z)-5-(6-ethyl-1,1,2-trimethyl-1,2-dihydronaphthalen-2-yl)-

1-(pyrrolidin-1-yl)pent-4-en-1-one (87b)

A flask charged with allylic alcohol 93b (1.27ꢀg, 4.29ꢀmmol,

1ꢀequiv) and copper(I) thiophene-2-carboxylate (82ꢀmg,

0.43ꢀmmol, 0.10ꢀequiv) was sparged with oxygen for 5ꢀmin.

Water saturated benzene (11ꢀmL) was added and the suspension

was stirred till the allylic alcohol was solved completely.

Pivaldehyde (3.26ꢀmL, 30.0ꢀmmol, 7ꢀequiv) was added in seven

portions (1 equivalent/hour). The green-blueish reaction mixture

was stirred after complete addition at 23ꢀ°C for 18ꢀh. Another

The ester 86b (7.0ꢀg, 21ꢀmmol, 1ꢀequiv) was dissolved in dry

and colorless pyrrolidine (26ꢀmL, 0.32ꢀmol, 15ꢀequiv) in a

pressure tube under argon. The tube was sealed and heated at

100ꢀ°C. The reaction mixture was stirred for 60ꢀh and then

allowed to cool to 23ꢀ°C. Excess pyrrolidine was removed under

reduced pressure. Purification by flash column chromatography

19

portion of copper(I) thiophene-2-carboxylate (82ꢀmg, 0.43ꢀmmol,

0.10ꢀequiv) was added and the mixture was stirred for 5ꢀh. Excess

Reference and notes

ACCEPTED MANUSCRIPT

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Acknowledgments

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European Union's Horizon 2020 research and innovation

program (grant agreement No 714049), the Austrian Science

Fund (FWF) [P31023-NBL] and the Center for Molecular

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ACCEPTED MANUSCRIPT

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21

Article Doi

Ring-expansion approaches for the total synthesis of salimabromide

DOI: 10.1016/j.tet.2019.03.010

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