One-pot synthesis of [6-5-6] tricyclic products via a double Diels-Alder/Nazarov tandem reaction of unsymmetrically substituted cross-conjugated diynones

Article abstract of DOI:10.1016/j.tet.2016.11.047

A highly concise one-pot method towards biologically pertinent compounds having a [6-5-6] tricyclic framework has been established. The multicomponent reaction utilizes a tandem, double Diels-Alder cycloaddition followed by a Nazarov reaction to furnish the [6-5-6] backbone. This method produces three fused rings evolving from the construction of five new carbon-carbon bonds, a quaternary carbon, and stereogenic centers in a one-pot reaction. The products are produced with excellent regio- and diastereocontrol.

Full text of DOI:10.1016/j.tet.2016.11.047

Accepted Manuscript
One-pot synthesis of [6-5-6] tricyclic products via a Double Diels-Alder/Nazarov
tandem reaction of unsymmetrically substituted cross-conjugated diynones
Rachael A. Carmichael, Wesley A. Chalifoux
PII:
S0040-4020(16)31202-9
10.1016/j.tet.2016.11.047
TET 28261
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 August 2016
Revised Date: 4 November 2016
Accepted Date: 16 November 2016
Please cite this article as: Carmichael RA, Chalifoux WA, One-pot synthesis of [6-5-6] tricyclic products
via a Double Diels-Alder/Nazarov tandem reaction of unsymmetrically substituted cross-conjugated
diynones, Tetrahedron (2016), doi: 10.1016/j.tet.2016.11.047.
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ACCEPTED MANUSCRIPT
Graphical Abstract:
1

ACCEPTED MANUSCRIPT
One-pot Synthesis of [6-5-6] Tricyclic Products via a Double Diels-Alder/Nazarov Tandem
Reaction of Unsymmetrically Substituted Cross-conjugated Diynones
Rachael A. Carmichael and Wesley A. Chalifoux*
Department of Chemistry, University of Nevada-Reno, 1664 N. Virginia Street, Reno, NV
89557, USA
Abstract: A highly concise one-pot method towards biologically pertinent compounds having a
[6-5-6] tricyclic framework has been established. The multicomponent reaction utilizes a
tandem, double Diels-Alder cycloaddition followed by a Nazarov reaction to furnish the [6-5-6]
backbone. This method produces three fused rings evolving from the construction of five new
carbon-carbon bonds, a quaternary carbon, and stereogenic centers in a one-pot reaction. The
products are produced with excellent regio- and diastereocontrol.
Keywords: Diels-Alder cycloaddition; Nazarov reaction; multicomponent reaction; tandem
reaction; terpenes
1.
Introduction
Pharmaceutical endeavors toward biologically important molecules rely heavily on cost-
effective and economical synthetic methodologies.1 The use of relatively high-energy starting
materials to achieve multiple carbon-carbon bond formation in a single pot reaction is a highly
efficient technique to rapidly access advanced intermediates.2,3 A number of efficacious
examples targeting useful polycyclic substructures have recently been reported in the literature.4–
6
Five- and six-membered rings are highly prevalent in biologically active compounds, therefore
routes towards these polycyclic structures receive considerable attention.7,8 Cycloaddition
reactions are one of the most innovative and influential strategies for synthesizing desirable
cyclic target molecules. Since its discovery in 1928, the Diels-Alder reaction has been modified
to meet current needs in chemistry, particularly by increasing functionality in the products.9–11
The Nazarov cyclization is perhaps one of the most effective routes for the stereoselective
formation of cyclopentenones.12–16 Utilizing the Nazarov and Diels-Alder reactions in a cascade
process to generate multiple rings in a one-pot reaction is a very pragmatic approach towards
important biological scaffolds.17,18 A number of biologically germane molecules: Hirsutellone B,
taiwaniaquinol D, and gibberellic acid are characterized by a [6-5-6]-carbotricyclic skeleton, all
of which involve numerous steps to construct (Figure 1).19–22 Hirsutellone B displays potent
activity against tuberculosis,19 taiwaniaquinol D was found to exhibit potent cytotoxic activity
against KB epidermoid carcinoma cancer cells,23 and gibberellic acid is an important plant
hormone. Therefore, the development of efficient methods to obtain the [6-5-6]-tricyclic core
shared by these molecules is of value.
* Corresponding author. E-mail address: wchalifoux@unr.edu
2

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Figure 1. Biologically pertinent, naturally occurring compounds bearing a [6-5-6]-carbotricyclic
skeleton.
2.
Results and Discussion
We recently reported the multicomponent double Diels-Alder/Nazarov tandem reaction
of symmetric cross-conjugated diynones 1 that could be conducted within a single reaction pot
(Figure 2a).17 When 1,5-bis(TMS)-1,4-diyn-3-one is employed as a substrate, desilylation of one
TMS group occurs to ultimately provide product 2 with excellent regio- and diastereoselectivity.
If the TMS groups in the substrate are exchanged for other groups (R1 = aryl, alkyl) then
products 3, which contain vicinal quaternary centers, are produced. Unfortunately, the scope of
products 2 that contain a single quaternary center is limited to trialkylsilyl-substituted adducts.
To mend this limitation, we envisioned using unsymmetrically substituted TMS-substituted
diynones 4 as substrates, where the TMS will be cleaved during the reaction and the R4 group
retained in the product (Figure 2b). Intermediate 5 can undergo a second cyclization with a
second equivalent of the same diene to give product 6 where various substituents (R4) can be
envisioned at the quaternary center. An added advantage of this method is that one can also
utilize a second equivalent of a different diene to afford an even broader scope of products such
as 7. Herein, we report a one-pot double Diels-Alder/Nazarov tandem reaction of
unsymmetrically substituted diynones to produce [6-5-6]-tricyclic products with excellent regio-
and diastereoselectivity.
3

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Figure 2. a) A double Diels-Alder/Nazarov reaction of symmetric diynones to produce [6-5-6]
products with a quaternary (2) or vicinal quaternary (3) centers.17 b) Proposed use of
unsymmetrically substituted diynones 4 and various dienes to broaden the scope of this reaction.
Regiochemical control is a common obstacle that plagues the utility of the Nazarov
reaction.24 The utilization of the β-silyl effect in the Nazarov reaction to elicit high regiocontrol
of the products has proven to be an exceedingly valuable tool.17,25–27 The incorporation of a
TMS-substituent in substrate 4 not only stabilizes the oxyallyl cation intermediate 8 through the
β-silyl effect but also results in a very regioselective elimination of the TMS group to provide
product 6 (Figure 3). Using this as the foundation for this work, we set out to survey
unsymmetrically substituted cross-conjugated diynones in a one-pot double Diels-Alder/Nazarov
tandem reaction.
Figure 3. Nazarov cyclization and stabilization of the carbocation intermediate via the β-silyl
effect.
We chose to explore the cyclization reaction of bulky diynone 4a due to its stability and
ease of handling. Use of this diynone also allowed for a direct comparison of the double Diels-
Alder cycloaddition with respect to substituents of similar size (TMS vs tert-butyl). We initially
attempted to use our previously reported conditions to invoke the tandem cyclization reaction.17
Unfortunately, compound 4a only produced monocyclized product 5a in the presence of
ethylaluminum dichloride with no detection of 6a, even at elevated temperatures (Scheme 1).
The high regioselectivity of the single Diels-Alder reaction product was interesting as we
envisioned that this might prove useful for mixed Diels-Alder reactions (vide infra). Nonetheless,
it seemed that ethylaluminum dichloride was not sufficiently strong enough for this one-pot
reaction. Thus, we turned to using boron trichloride since we have recently reported the
successful use of this catalyst for the cyclization of challenging symmetric diynones.17 Indeed,
boron trichloride worked well to provide 6a in 43% yield (Scheme 1). One should note that this
modest overall yield is the product of two separate Diels-Alder reactions and a Nazarov
cyclization that equates to roughly 75% yield per reaction accompanied by the formation of five
new carbon-carbon bonds, three new rings, and vicinal quaternary centers. As we had predicted,
the elimination of the TMS group provided excellent regioselectivity for the newly formed
double bond in compound 6b (shown in red). The major diastereomer contains a syn relationship
between the methine hydrogen and the tert-butyl group and was assigned based on NOESY
NMR experiments. This result is also consistent with what was reported for compound 2 (Figure
2).17
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Scheme 1. Double Diels-Alder/Nazarov tandem reaction of sterically hindered diynone 4a and
2,3-dimethyl-1,3-butadiene to generate [6-5-6]-carbotricyclic product 6a catalyzed by BCl3.
We synthesized a variety of TMS-substituted diynones 4 to establish the scope of the
unsymmetrically substituted diynone system and its applicability for targeting a wide range of
[6-5-6]-carbotricyclic derivatives (Table 1). Interestingly, we determined that the product with
the larger tert-butyl substituent (6a, entry 1) was actually obtained in higher yield versus the
smaller methyl-substituted derivative (6b, entry 2). Diynone 4c provided product 6c in a
moderate 32% yield (entry 3). Not surprisingly, electron-rich aryl groups on substrates 4d and 4e
proved to be more difficult for the Diels-Alder cycloaddition but nevertheless generated the
desired tricyclic products 6d and 6e in modest yields of 24% and 32%, respectively (entries 4
and 5). It should be noted that the skipped cyclohexadiene moiety in product 6d (entry 4) had
partially oxidized to an aromatic ring over the course of the reaction and this side-product was
separated and isolated in 6% yield (see supporting information for details). The bromine-
substituted aryl derivatives 4f and 4g (entries 6 and 7) underwent the tandem double Diels-
Alder/Nazarov reaction rapidly to generate the corresponding products 6f and 6g in relatively
good yields of 29% and 42%, respectively. The fluorine-substituted aryl derivatives 4h and 4i
(entries 8 and 9) also performed well to give 6h and 6i in 38% and 43% yield, respectively. All
of the tricyclic products 6a-i were generated with excellent regio- and diastereoselectivity. As is
common with cyclic “skipped dienes”, we observed that products 6a-i would begin to oxidize if
exposed to air under the reaction conditions or if left under an air atmosphere for an extended
period of time.10,11 For many of the reactions, only the two expected diastereomeric products
were detected by GC-MS analysis. However, in entries 1 and 2 we observed an additional minor
isomer (uncharacterized) that is possibly the result of double bond migration.17
Table 1. Substrate scope of diynone 4.
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Entry Substrate
R4
t-butyl
Me
C6H5
Product Yield [%][a] Isomeric ratio[b]
43
17
15:2:1[c]
15:1:1[c]
>20:1
>20:1
>20:1
12:1
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
6a
6b
6c
6d
6e
6f
6g
6h
6i
32
o-MeO-C6H4
p-MeO-C6H4
o-Br-C6H4
p-Br-C6H4
o-F-C6H4
p-F-C6H4
24[d,e]
32
29[e]
42
>20:1
>20:1
>20:1
38[e]
43
[a] Isolated yield of major isomer. [b] Crude diastereomeric ratio of products determined by GC-
MS analysis. [c] An uncharacterized third minor isomer was detected possibly due to double
bond migration in the product. [d] Oxidized/aromatized side-product (S10) was also isolated in
6% yield. [e] The NOESY data was ambiguous; therefore, the stereochemistry was assigned by
analogy.
In a previous study, we noted that at low temperatures we could selectively form the
monocyclized product 2a in good yield, even in the presence of excess diene (Scheme 2a).17
With this result we imagined that we could employ a timed double Diels-Alder reaction between
compound 4 and two different dienes to arrive at highly functionalized [6-5-6]-tricyclic products
with excellent regiocontrol. We were thrilled to find that by carrying out the reaction between
unsymmetrically substituted diynone 4a and 1.1 equivalents of 2,3-dimethyl-1,3-butadiene at
low temperature, the Diels-Alder cycloaddition occurred exclusively with the silyl-substituted
alkyne to generate the monocyclic intermediate 5a (Scheme 2b). Corey and coworker have also
observed that silyl-substituted alkynes react faster as dienophiles than alkyl-substituted alkynes
in an analogous Diels-Alder reaction.28 After the formation of 5a, the addition of an excess
amount of a second diene (1,3-butadiene) in the same reaction pot, followed by warming to room
temperature, provided asymmetric product 7a in a modest 21% yield with excellent regio- and
diastereoselectivity. We could also change the order of diene addition to provide 7b in 23% yield
with excellent regio- and diastereoselectivity. We should point out that the expected side-product
from the double cycloaddition of 1,3-butadiene was not detected upon workup. Presumably, this
is because the relative rate of cycloaddition is much higher for 2,3-dimethyl-1,3-butadiene during
the second Diels-Alder reaction. This proof-of-concept demonstrates that we can indeed arrive at
a host of [6-5-6]-tricyclic products using this timed double Diels-Alder method with a high level
of regiocontrol.
6

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Scheme 2. a) Formation and isolation of monocyclized product 2a at low temperatures
suggesting a timed double Diels-Alder reaction is possible.17 b) Demonstration of a timed double
Diels-Alder cycloaddition with two different dienes followed by a Nazarov cyclization to
generate 7a and 7b as the major isomers along with a small amount of oxidized products 9a and
9b.
3.
Conclusions
In summary, we have demonstrated a double Diels-Alder/Nazarov tandem reaction of
unsymmetrically substituted diynones to yield biologically important [6-5-6] tricyclic scaffolds
in a one-pot reaction. Additionally, we have demonstrated that a controlled, multicomponent
diene system can undergo a timed double Diels-Alder cycloaddition to generate highly
functionalized [6-5-6]-carbotricyclic products in a single reaction pot. The one-pot double Diels-
Alder/Nazarov tandem reaction is highly regioselective and diastereoselective, providing very
concise and efficient access to important molecules, while also imparting useful functional
handles (isolated and conjugated double bonds and a ketone) for further chemical elaboration.
4.
Experimental
4.1. General Methods
Reagents were purchased reagent grade from commercial suppliers and used without further
purification unless otherwise noted. CH2Cl2 and THF were purified using a PureSolv MD 5
solvent purification system. Ethynyltrimethylsilane was distilled before use. Evaporation and
concentration in vacuo by rotary evaporation. Where appropriate, reactions were performed in
standard, dry glassware under an inert atmosphere of N2. Column chromatography: Silica gel
7

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irregular 60 Å (40-60 micron) from VWR International. The bulb-to-bulb distillation was
performed using a kugelrohr apparatus, Büchi GKR-51. Thin-layer chromatography (TLC): glass
sheets covered with silica gel 60 F254 from Millipore a Corporation; visualization by UV light,
anisaldehyde stain or KMnO4 stain. Mp: Mel-Temp apparatus; uncorrected. IR spectra (cm–1):
1
Thermo Nicolet 6700 FT-IR (diamond ATR), data are reported as cm–1. H and 13C NMR:
Varian NMR 400 MHz, 500 MHz at r.t. in CDCl3; solvent peaks (7.26 ppm and 77.16 ppm for
13
1
13
1H and C, respectively) or C6D6; solvent peaks (7.16 ppm and 128.06 ppm for H and C,
respectively) as reference. GCMS (EI): Agilent 7890A with a 5970C mass spectrometer with
triple axis detector using a 122-5532UI DB-5MS Ui column (30m x 0.25mm). ESI-TOF and
APCI-TOF MS: Agilent G6230A instrument with purine and HP-Ø921 as internal calibrants.
4.2. General experimental procedure for 1,4-pentadiyn-3-ols (S1-S9)
General procedure A:29 To a solution of n-butyllithium (1.0 equiv.) in tetrahydrofuran (15 mL)
at –78 ºC under N2 atmosphere was added terminal alkyne (1.0 equiv.). After 15 minutes of
stirring 3-(trimethylsilyl)-2-propynal (1.1 equiv.) was added slowly and the reaction was slowly
warmed to r.t. and stirred until complete by TLC. The reaction was quenched at –78 ºC through
the addition of saturated aqueous NH4Cl and extracted with Et2O. The layers were separated, the
organic phase washed with H2O, brine, and dried over Na2SO4. The mixture was filtered and the
solvent was removed in vacuo to provide the crude product.
General procedure B: To a solution of n-butyllithium (1.1 equiv.) in tetrahydrofuran (15 mL) at
–78 ºC under N2 atmosphere was added ethynyltrimethylsilane (1.1 equiv.). After 15 minutes of
stirring the 3-aryl-2-propynal30,31 (1.0 equiv.) was added dropwise and the reaction was slowly
warmed to r.t. and stirred until complete by TLC. The reaction was quenched at –78 ºC through
the addition of saturated aqueous NH4Cl and extracted with Et2O. The layers were separated, the
organic phase washed with H2O, brine, and dried over Na2SO4. The mixture was filtered and the
solvent was removed in vacuo to provide the crude product.
4.2.1. 1-(4-methoxyphenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-ol (S1). This reaction was
performed according to general procedure A.29 4-Ethynylanisole (954 mg, 7.20 mmol) in THF
(20 mL). Crude alcohol S1 was isolated (1.51 g, 81%) as a light brown oil and was used without
1
purification: Rf = 0.3 (EtOAc:hexanes, 1:10); H NMR (400 MHz, C6D6): δ = 7.25 – 7.19 (m,
2H), 6.48 – 6.42 (m, 2H), 5.18 (d, J = 6.6 Hz, 1H), 3.07 (s, 3H), 1.72 (d, J = 6.8 Hz, 1H), 0.07 (s,
13
9H); C NMR (100 MHz, C6D6): δ = 160.4, 133.7, 114.7, 114.3, 103.5, 89.0, 85.8, 84.8, 54.7,
53.5, –0.3; IR (film): 3414, 2961, 2224, 1610, 1511, 1252 cm–1; HRMS (APCI-TOF) m/z calcd
for [C15H18O2Si – OH)]+ 241.1043; found 241.1034.
4.2.2. 1-(2-methoxyphenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-ol (S2). This reaction was
performed according to general procedure A.29 2-Ethynylanisole (954 mg, 7.20 mmol) in THF
(20 mL). Crude alcohol S2 was purified by column chromatography [pH 7 buffered phosphate
silica gel; EtOAc/ CH2Cl2/hexanes (1:29:70)] to yield S2 (1.53 g, 82 %) as a yellow-orange oil:
1
Rf = 0.2 (CH2Cl2:hexanes, 2:3); H NMR (400 MHz, CDCl3): δ = 7.42 – 7.39 (m, 1H), 7.34 –
7.25 (m, 1H), 6.94 – 6.79 (m, 2H), 5.41 (d, J = 5.2 Hz, 1H), 3.87 (s, 3H), 2.88 (d, J = 6.1 Hz,
13
1H), 0.19 (s, 9H); C NMR (100 MHz, CDCl3): δ = 160.3 133.9, 130.4, 120.5, 111.3, 110.8,
8

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102.1, 90.2, 89.5, 80.9, 55.9, 53.3, –0.2; IR (film): 3411, 2952, 2236, 1594, 1492, 1261 cm–1;
HRMS (APCI-TOF) m/z calcd for [C15H18O2Si – OH]+ 241.1043; found 241.1034.
4.2.3. 1-(4-bromophenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-ol (S3). This reaction was
performed according to general procedure B. 3-(4-Bromophenyl)-2-propynal30,31 (553 mg, 2.65
mmol) in THF (30 mL). Crude alcohol S3 was isolated (770 mg, 95%) as a light brown oil and
1
was used without purification: Rf = 0.4 (EtOAc:hexanes, 1:10); H NMR (500 MHz, CDCl3): δ
13
= 7.44 – 7.42 (m, 2H), 7.32 – 7.29 (m, 2H), 5.34 (s, 1H), 2.67 (s, 1H), 0.20 (s, 9H); C NMR
(100 MHz, CDCl3): δ = 133.4, 131.7, 123.3, 121.0, 101.6, 90.1, 87.1, 83.5, 53.1, –0.2; IR (film):
3294, 2955, 2236, 2179, 1483, 1245 cm–1; HRMS (APCI-TOF) m/z calcd for [C14H15BrOSi –
OH]+ 289.0043; found 289.0033.
4.2.4. 1-(2-bromophenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-ol (S4). This reaction was
performed according to general procedure B. 3-(2-Bromophenyl)-2-propynal29,30 (986 mg, 4.72
mmol) in THF (20 mL). Crude alcohol S4 was isolated (1.51 g, 81%) as a brown oil and was
1
used without purification: Rf = 0.4 (EtOAc:hexanes, 1:10); H NMR (400 MHz, CDCl3): δ =
7.59 – 7.54 (m, 1H), 7.51 – 7.44 (m, 1H), 7.27 – 7.21 (m, 1H), 7.19 – 7.13 (m, 1H), 5.39 (s, 1H),
13
2.68 (s, 1H), 0.20 (s, 9H); C NMR (100 MHz, CDCl3): δ = 133.7, 132.5, 130.1, 127.1, 125.9,
124.2, 101.5, 90.4, 90.1, 83.1, 53.2, –0.2; IR (film): 3348, 2961, 2895, 2173, 2097, 1632, 1470
cm–1; HRMS (ESI-TOF) m/z calcd for [C14H15BrOSi – OH]+ 289.0043; found 289.0036.
4.2.5. 1-phenyl-5-(trimethylsilyl)-1,4-pentadiyn-3-ol (S5). This compound was synthesized
following a known procedure.32 1H NMR (400 MHz, CDCl3): δ = 7.52 – 7.42 (m, 2H), 7.37 –
7.26 (m, 3H), 5.37 (d, J = 5.5 Hz, 1H), 2.73 (s, 1H), 0.22 (s, 9H); 13C NMR (100 MHz, CDCl3):
δ = 131.9, 128.9, 128.4, 122.0, 101.9, 89.8, 86.0, 84.5, 53.1, –0.2.
4.2.6. 1-(4-fluorophenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-ol (S6). This reaction was
performed according to general procedure B. 3-(4-Fluorophenyl)-2-propynal29,31 (1.08 g, 7.30
mmol) in THF (20 mL). Crude alcohol S6 was isolated (1.49 g, 83%) as a yellow oil and was
1
used without purification: Rf = 0.4 (EtOAc:hexanes, 1:10); H NMR (400 MHz, CDCl3): δ =
7.46 – 7.39 (m, 2H), 7.02 – 6.92 (m, 2H), 5.35 (s, 1H), 2.86 (s, 1H), 0.20 (s, 9H); 13C NMR (100
MHz, CDCl3): δ = 162.8 (d, J = 250.2 Hz), 133.9 (d, J = 8.7 Hz), 118.1 (d, J = 3.6 Hz), 115.7 (d,
J = 22.3 Hz), 101.8, 89.9, 85.8 (d, J = 1.6 Hz), 83.5, 53.0, –0.2; 19F NMR (376 MHz, CDCl3) δ =
–110.0; IR (film): 3335, 2961, 2901, 2230, 2179, 1600, 1505 cm–1; HRMS (APCI-TOF) m/z
calcd for [C14H15FOSi+H]+ 247.0949; found 247.0942.
4.2.7. 1-(2-fluorophenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-ol (S7). This reaction was
performed according to general procedure A.29 2-fluorophenylacetylene (239 mg, 1.99 mmol) in
THF (10 mL). Crude alcohol S7 was isolated (188 mg, 38%) as a yellow oil by fractional
1
distillation: Rf = 0.4 (EtOAc:hexanes, 1:10); H NMR (100 MHz, C6D6): δ = 7.16 – 7.10 (m,
1H), 6.77 – 6.68 (m, 1H), 6.67 – 6.61 (m, 1H), 6.60 – 6.53 (m, 1H), 5.22 (s, 1H), 2.29 (s, 1H),
13
0.10 (s, 9H); C NMR (125 MHz, C6D6): δ = 163.3 (d, J = 251.7 Hz), 133.9 (d, J = 1.2 Hz),
130.6 (d, J = 7.9 Hz), 124.0 (d, J = 3.9 Hz), 115.6 (d, J = 20.9 Hz), 111.2 (d, J = 15.6 Hz), 102.8,
19
92.3 (d, J = 3.0 Hz), 89.5, 78.1, 53.3, –0.3; F NMR (376 MHz, C6D6) δ = –109.6; IR (film):
3408, 2961, 2278, 1689, 1644, 1492 cm–1; HRMS (APCI-TOF) m/z calcd for [C14H15FOSi+H]+
247.0949; found 247.0945.
9

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4.2.8. 1-tert-butyl-5-(trimethylsilyl)-1,4-pentadiyn-3-ol (S8).29 To a solution of n-butyllithium
(4.00 mL, 10.0 mmol, 2.50 M in hexanes) in tetrahydrofuran (15 mL) at –78 ºC under N2
atmosphere was added ethynyltrimethylsilane (1.10 g, 11.2 mmol). After 45 minutes of stirring
S8 (1.0 g, 9.0 mmol) was added dropwise and the reaction was slowly warmed to r.t. and stirred
until complete by TLC. The reaction was quenched at –78 ºC through the addition of saturated
aqueous NH4Cl and extracted with Et2O. The layers were separated, the organic phase washed
with H2O, brine, and dried over Na2SO4. The solvent was removed in vacuo to yield S8 (88%) as
1
a light yellow solid: M.p.: 39–41 ˚C; Rf = 0.5, (EtOAc:hexanes, 1:5); H NMR (400 MHz,
CDCl3): δ = 5.01 (s, 1H), 3.02 (s, 1H), 1.14 (s, 9H), 0.09 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
= 103.2, 93.0, 88.2, 76.2, 52.4, 30.6, 27.2, –0.3; IR (film): 3326, 2965, 2243, 2173 cm–1; HRMS
(APCI-TOF) m/z calcd for [C12H20OSi – OH]+ 191.1251; found 191.1253.
4.2.9. 1-(trimethylsilyl)-1,4-hexadiyn-3-ol (S9). This compound was synthesized following a
known procedure.33
4.3. General experimental procedure for 1,4-pentadiyn-3-one (4a-i)
Dichloromethane was added to a mixture of sieves (2 wt. equiv.), celite (2 wt. equiv.), and
pyridinium chlorochromate (2 equiv.). A dilute solution of 1,4-pentadiyn-3-ol (4a, 4c, 4e, 4h) (1
equiv.) in dichloromethane was added slowly to the reaction mixture and stirred overnight or
until complete by TLC. The resulting mixture was filtered through a celite/silica gel plug. The
solvent was removed in vacuo and the crude product used without further purification. BaMnO4
(4 equiv.) in dichloromethane was used for 1,4-pentadiyn-3-ol (4b, 4d, 4f, 4g, and 4i) (1 equiv.)
and stirred overnight or until complete by TLC. The resulting mixture was purified by filtering
through a celite/silica gel plug.
4.3.1 1-tert-butyl-5-(trimethylsilyl)-1,4-pentadiyn-3-one (4a). Alcohol S8 (5.24 g, 25.2
mmol). The crude product used without further purification, 4a (59%) as a pale brown solid:
1
M.p.: 37–40 ˚C; Rf = 0.6, (EtOAc:hexanes, 1:10); H NMR (500 MHz, CDCl3): 1.25 (s, 9H),
13
0.20 (s, 9H); C NMR (100 MHz, CDCl3): δ = 160.9, 102.9, 102.5, 97.6, 80.8, 29.8, 27.9, –0.9;
IR (film): 2975, 2219, 1614 cm–1; HRMS (APCI-TOF) m/z calcd for [C12H18SiO+H]+ 207.1200;
found 207.1198.
4.3.2 1-(trimethylsilyl)-1,4-hexadiyn-3-one (4b). This compound was synthesized from S9
following a known procedure.33
4.3.3 1-phenyl-5-(trimethylsilyl)-1,4-pentadiyn-3-one (4c).32 1H NMR (500 MHz, CDCl3): δ
13
= 7.65 – 7.60 (m, 2H), 7.51 – 7.46 (m, 1H), 7.44 – 7.36 (m, 2H), 0.29 (m, 9H); C NMR (100
MHz, CDCl3): δ = 160.6, 133.5, 131.4, 128.8, 119.5, 102.8, 99.4, 91.8, 89.4, –0.7.
4.3.4 1-(2-methoxyphenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-one (4d). Alcohol S2 (1.53 g,
5.90 mmol). Crude ketone 4d was isolated (860 mg, 57 %) as a yellow oil and was used without
1
purification: Rf = 0.3 (EtOAc:hexanes, 1:10); H NMR (400 MHz, CDCl3): δ = 7.53 – 7.47 (m,
13
1H), 7.41 (ddd, J = 9.1, 7.6, 1.8 Hz, 1H), 6.96 – 6.85 (m, 2H), 3.86 (s, 3H), 0.25 (s, 9H); C
NMR (100 MHz, CDCl3): δ = 162.0, 160.5, 135.2, 133.2, 120.6, 111.0, 108.5, 102.8, 98.8, 93.5,
10

ACCEPTED MANUSCRIPT
89.5, 55.9, –0.8; IR (film): 2968, 2202, 1616, 1489, 1464, 1277, 1245 cm–1; HRMS (APCI-TOF)
m/z calcd for [C15H16O2Si+H]+ 257.0992; found 257.0986.
4.3.5 1-(4-methoxyphenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-one (4e). Alcohol S1 (1.51 g,
5.84 mmol). Crude ketone 4e was isolated (308 mg, 21%) as a yellow solid and was used without
1
purification: Rf = 0.3 (EtOAc:hexanes, 1:10); H NMR (400 MHz, CDCl3): δ = 7.55 – 7.49 (m,
13
2H), 6.89 – 6.83 (m, 2H), 3.80 (s, 3H), 0.25 (s, 9H); C NMR (100 MHz, CDCl3): δ = 162.2,
160.4, 135.5, 114.5, 110.9, 102.8, 98.4, 93.2, 89.6, 55.4, –0.8; IR (film): 2968, 2838, 2195, 1619,
1596, 1515 cm–1; HRMS (ESI-TOF) m/z calcd for [C15H16O2Si+H]+ 257.0992; found 257.0989.
4.3.6 1-(2-bromophenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-one (4f). Alcohol S4 (1.34 g,
4.36 mmol). Crude alcohol 4f was isolated (1.01 g, 76%) as a burnt orange oil and was used
1
without purification: Rf = 0.5 (EtOAc:hexanes, 1:10); H NMR (500 MHz, CDCl3): δ = 7.63 –
7.53 (m, 2H), 7.35 – 7.22 (m, 2H), 0.26 (s, 9H); 13C NMR (100 MHz, CDCl3): δ = 160.1, 135.0,
132.9, 132.3, 127.4, 127.2, 121.9, 102.6, 100.1, 92.2, 89.6, –0.9; IR (film): 2958, 2202, 2145,
1625, 1461, 1426, 1255 cm–1; HRMS (APCI-TOF) m/z calcd for [C14H13 BrOSi+H]+ 304.9992;
found 304.9986.
4.3.7 1-(4-bromophenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-one (4g). Alcohol S3 (770 mg,
2.51 mmol). Crude ketone 4g was isolated (598 mg, 78%) as a yellow oil and was used without
purification: Rf = 0.4 (EtOAc:hexanes, 1:10); 1H NMR (400 MHz, CDCl3): δ = 7.53 (dd, J = 8.6,
13
1.9 Hz, 2H), 7.46 (dd, J = 8.5, 2.0 Hz, 2H), 0.27 (s, 9H); C NMR (100 MHz, CDCl3): δ =
160.3, 134.7, 132.2, 126.3, 118.4, 102.6, 99.8, 90.1, 90.0, –0.8; IR (film): 2965, 2208, 2145,
1616, 1584, 1480, 1274 cm–1; HRMS (APCI-TOF) m/z calcd for [C14H13 BrOSi+H]+ 304.9992;
found 304.9981.
4.3.8 1-(2-fluorophenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-one (4h). Alcohol S7 (188 mg,
0.763 mmol). Crude ketone 4h was isolated (126 mg, 68%) as a yellow oil and was used without
1
purification: Rf = 0.5 (EtOAc:hexanes, 1:10); H NMR (400 MHz, C6D6): δ = 6.97 – 6.93 (m,
13
1H), 6.76 – 6.70 (m, 1H), 6.57 – 6.41 (m, 2H), 0.00 (s, 9H); C NMR (125 MHz, C6D6): δ =
164.02 (d, J = 256.3 Hz), 159.77, 134.9, 133.16 (d, J = 8.2 Hz), 124.3 (d, J = 4.0 Hz), 115.9 (d, J
19
= 20.2 Hz), 108.6 (d, J = 15.2 Hz), 103.4, 99.0, 94.1 (d, J = 3.4 Hz), 84.3, –1.2; F NMR (376
MHz, C6D6) δ = –107.0; IR (film): 2958, 2211, 1622, 1489, 1258, 1128 cm–1; HRMS (APCI-
TOF) m/z calcd for [C14H13FOSi+H]+ 245.0792; found 245.0807.
4.3.9 1-(4-fluorophenyl)-5-(trimethylsilyl)-1,4-pentadiyn-3-one (4i). Alcohol S6 (1.49 g,
6.05 mmol). Crude ketone 4i was isolated (1.16 g, 78%) as a brown oil and was used without
1
purification: Rf = 0.6 (EtOAc:hexanes, 1:10); H NMR (400 MHz, CDCl3): δ = 7.63 – 7.56 (m,
13
2H), 7.11 – 7.03 (m, 2H), 0.26 (s, 9H); C NMR (100 MHz, CDCl3): δ = 164.3 (d, J = 254.9
Hz), 160.3, 135.8 (d, J = 9.0 Hz), 116.4 (d, J = 22.5 Hz), 115.6 (d, J = 3.5 Hz), 102.6, 99.4, 90.5,
89.2 (d, J = 1.5 Hz), –0.8; 19F NMR (376 MHz, CDCl3): δ = –105.1; IR (film): 2965, 2211, 2148,
1622, 1594, 1502 cm–1; HRMS (APCI-TOF) m/z calcd for [C14H13FOSi+H]+ 245.0792; found
245.0788.
4.4. Experimental procedure for 9H-fluoren-9-ones (6a-i)
11

ACCEPTED MANUSCRIPT
4.4.1. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(tert-butyl)-9H-fluoren-9-one
(6a).
To a solution of 4a (124 mg, 0.600 mmol) in CH2Cl2 (9 mL) under N2 at 0 ˚C was added boron
trichloride (0.59 mL, 0.59 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-butadiene
(240 mg, 2.96 mmol). The reaction was stirred until complete by TLC (1.5 h). The reaction was
quenched at 0 ˚C with saturated aqueous NaHCO3 and extracted with Et2O. The layers were
separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The solvent was
removed in vacuo and the crude product purified by column chromatography [pH 7 buffered
phosphate silica gel; EtOAc/hexanes (1:30)] to yield 6a (76 mg, 43%) as a white solid. The
isomeric ratio of the crude product was determined to be 15:2:1 by GC analysis (GC-MS
method: flow = 1 mL/min.; inlet = 250 °C; 200 ˚C for 5 min., ramp at 2 ˚C/min. to 250 ˚C and
hold for 10 min.). The isomeric ratio of the purified product 6a to all other isomers was
1
1
determined to be >20:1 by H NMR analysis: Rf = 0.4 (EtOAc:hexanes, 1:10); H NMR (400
MHz, CDCl3): δ = 2.93 (dd, J = 15.0, 7.5 Hz, 2H), 2.70 – 2.61 (m, 2H), 2.44 (dd, J = 5.7, 2.5 Hz,
1H), 2.37 (dd, J = 14.4, 2.6 Hz, 1H), 2.24 (dd, J = 13.9, 2.8 Hz, 1H), 2.11 – 1.97 (m, 2H), 1.69
13
(s, 3H), 1.67 (s, 3H), 1.54 (s, 3H), 1.49 (s, 3H), 0.95 (s, 9H); C NMR (100 MHz, CDCl3): δ =
209.6, 173.0, 139.5, 126.8, 125.8, 123.3, 121.7, 56.5, 49.8, 36.4, 35.1, 33.8, 32.9, 28.6, 27.3,
19.5, 19.2, 18.9, 18.6; IR (film): 2965, 2908, 1701, 1644, 1432, 1369 cm–1; HRMS (ESI-TOF)
m/z calcd for [C21H30O+H]+ 299.2369; found 299.2374.
4.4.2. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(methyl)-9H-fluoren-9-one (6b). To a
solution of 4b (72 mg, 0.44 mmol) in CH2Cl2 (8 mL) under N2 at 0 °C was added boron
trichloride (0.44 mL, 0.44 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-butadiene
(181 mg, 2.20 mmol). The reaction was stirred until complete by TLC (40 min). The reaction
was quenched at 0 °C with saturated aqueous NaHCO3 and extracted with Et2O. The layers were
separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The solvent was
removed in vacuo and the crude product purified by column chromatography [pH 7 buffered
phosphate silica gel; EtOAc/hexanes (1:30)] to yield 6b (19 mg, 17 %) as an off-white solid. The
isomeric ratio of the crude product was determined to be 15:1:1 by GC analysis (GC-MS
method: flow = 1 mL/min.; inlet = 250 °C; 200 ˚C for 5 min., ramp at 1 ˚C/min. to 250 ˚C and
hold for 10 min.). The isomeric ratio of the purified product 6b to all other isomers was
1
1
determined to be >20:1 by H NMR analysis: Rf = 0.5 (EtOAc:hexanes, 1:10); H NMR (400
MHz, C6D6): δ = 2.81 – 2.72 (m, 2H), 2.56 – 2.50 (m, 3H), 2.13 (dd, J = 14.6, 6.4 Hz, 1H), 2.03
(dd, J = 6.6, 3.6 Hz, 1H), 1.80 – 1.70 (m, 2H), 1.63 (s, 3H), 1.52 (s, 3H), 1.45 (s, 3H), 1.43 (s,
13
3H), 0.88 (s, 3H); C NMR (100 MHz, C6D6): δ = 206.7, 172.3, 137.3, 127.5, 126.1, 124.1,
121.4, 53.9, 45.6, 40.5, 31.9, 30.8, 29.3, 25.0, 19.4, 19.2, 18.8, 18.5; IR (film): 2908, 2851, 1701,
1654, 1442, 1378, 1302 cm–1; HRMS (APCI-TOF) m/z calcd for [C18H24O+H]+ 257.1900; found
257.1904.
4.4.3. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(phenyl)-9H-fluoren-9-one (6c). To a
solution of 4c (153 mg, 0.676 mmol) in CH2Cl2 (10 mL) at 0 ˚C under N2 was added boron
trichloride (0.68 mL, 0.68 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-butadiene
(276 mg, 3.36 mmol). The reaction was stirred until complete by TLC (2 h). The reaction was
quenched at 0 ˚C with saturated aqueous NaHCO3 and extracted with Et2O. The layers were
separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The solvent was
removed in vacuo and the crude product purified by recrystallization from hexanes at 0 ˚C to
yield 4c (68 mg, 32%) as an off-white solid. The diastereomeric ratio of the crude product was
12

ACCEPTED MANUSCRIPT
determined to be >20:1 by GC analysis (GC-MS method: flow = 1 mL/min.; inlet = 250 °C; 220
˚C for 5 min., ramp at 1 ˚C/min. to 260 ˚C and hold for 10 min.). The diastereomeric ratio of the
purified product was determined to be >20:1 by GC analysis: Rf = 0.3 (EtOAc:hexanes, 1:20); 1H
NMR (400 MHz, C6D6): δ = 7.22 – 7.16 (m, 4H), 7.13 – 7.05 (m, 1H), 2.95 – 2.87 (m, 2H), 2.68
(dd, J = 6.7, 3.1 Hz, 1H), 2.64 – 2.49 (m, 3H), 2.44 – 2.30 (m, 1H), 2.21 (d, J = 14.6 Hz, 1H),
13
2.18 – 2.10 (m, 1H), 1.65 (s, 3H), 1.59 (s, 3H), 1.46 (s, 3H), 1.37 (s, 3H); C NMR (125 MHz,
C6D6): δ = 207.5, 172.0, 145.5, 138.6, 129.0, 127.7, 126.8, 126.7, 125.4, 123.6, 121.7, 57.0, 53.7,
36.2, 32.3, 31.6, 29.4, 19.4, 19.1, 18.6, 18.5; IR (film): 2984, 2917, 2854, 1698, 1651 cm–1;
HRMS (APCI-TOF) m/z calcd for [C23H26O+H]+ 319.2056; found 319.2063.
4.4.4. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(2-methoxyphenyl)-9H-fluoren-9-one
(6d). To a solution of 4d (138 mg, 0.538 mmol) in CH2Cl2 (10 mL) under N2 at 0 °C was added
boron trichloride (0.54 mL, 0.54 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-
butadiene (222 mg, 2.70 mmol). The reaction was stirred until complete by TLC (2-2.5 h). The
reaction was quenched at 0 °C with saturated aqueous NaHCO3 and extracted with Et2O. The
layers were separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The
solvent was removed in vacuo and the crude product purified by column chromatography [pH 7
buffered phosphate silica gel; EtOAc/hexanes (1:20)] to yield 6d (45 mg, 24%) as a white solid.
The diastereomeric ratio of the crude product was determined to be >20:1 by GC analysis (GC-
MS method: flow = 1 mL/min.; inlet = 250 °C; 220 ˚C for 5 min., ramp at 1 ˚C/min. to 250 ˚C
and hold for 10 min.). The diastereomeric ratio of the purified product was determined to be
1
>20:1 by 1H NMR analysis: Rf = 0.4 (EtOAc:hexanes, 1:10); H NMR (400 MHz, CDCl3): δ =
7.30 – 7.20 (m, 2H), 6.97 – 6.93 (m, 1H), 6.85 – 6.83 (m, 1H), 3.65 (s, 3H), 2.87 (dd, J = 7.1, 3.0
Hz, 1H), 2.83 – 2.62 (m, 4H), 2.46 (dt, J = 22.8, 7.2 Hz, 1H), 2.35 (dd, J = 15.1, 3.1 Hz, 1H),
2.26 (d, J = 14.1 Hz, 1H), 2.28 – 2.20 (m, 1H), 1.71 (s, 3H), 1.67 (s, 3H), 1.63 (s, 3H);13C NMR
(100 MHz, CDCl3): δ = 209.8, 172.4, 158.2, 137.2, 132.1, 128.1, 128.0, 127.2, 124.9, 123.5,
121.8, 120.5, 111.8, 55.3, 53.2, 52.2, 37.4, 32.5, 32.1, 29.0, 19.5, 19.0, 18.8, 18.8; IR (film):
2984, 2917, 2854, 1689, 1654, 1486, 1426 cm–1; HRMS (ESI-TOF) m/z calcd for [C24H28O2+H]+
349.2162; found 349.2159.
4.4.5. 1,4,4a,9a-tetrahydro-2,3,6,7-tetramethyl-4a-(2-methoxyphenyl)-9H-fluoren-9-one
1
(S10). Rf = 0.4 (EtOAc:hexanes, 1:10); H NMR (400 MHz, CDCl3): δ = 7.45 (s, 1H), 7.31 –
7.29 (m, 1H), 7.24 – 7.20 (m, 1H), 7.03 (s, 1H), 6.93 – 6.90 (m, 1H), 6.83 – 6.81 (m, 1H), 3.54
(s, 3H), 3.07 (t, J = 4.9 Hz, 1H), 2.98 (d, J = 14.0 Hz, 1H), 2.45 (d, J = 4.8 Hz, 2H), 2.37 (d, J =
13.9 Hz, 1H), 2.28 (s, 6H), 1.56 (s, 3H), 1.41 (s, 3H);13C NMR (100 MHz, CDCl3): δ = 209.5,
158.9, 157.8, 144.0, 136.5, 135.8, 134.8, 128.0, 127.6, 127.0, 126.5, 125.6, 123.1, 120.3, 112.1,
55.7, 55.1, 50.3, 40.9, 33.5, 21.0, 19.9, 19.6, 19.2; IR (film): 2927, 2851, 1701, 1613, 1486,
1454, 1245 cm–1; HRMS (ESI-TOF) m/z calcd for [C24H26O2+H]+ 347.2006; found 347.2008.
4.4.6. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(4-methoxyphenyl)-9H-fluoren-9-one
(6e). To a solution of 4e (89 mg, 0.35 mmol) in CH2Cl2 (11 mL) under N2 at r.t. was added boron
trichloride (0.35 mL, 0.35 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-butadiene
(145 mg, 1.77 mmol). The reaction was stirred until complete by TLC (1.5 h). The reaction was
quenched at r.t. with saturated aqueous NaHCO3 and extracted with Et2O. The layers were
separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The solvent was
removed in vacuo and the crude product purified by column chromatography [pH 7 buffered
13

ACCEPTED MANUSCRIPT
phosphate silica gel; EtOAc/hexanes (1:20)] to yield 6e (39 mg, 32%) as an off-white solid. The
diastereomeric ratio of the crude product was determined to be >20:1 by GC analysis (GC-MS
method: flow = 1 mL/min.; inlet = 250 °C; 220 ˚C for 35 min., ramp at 1 ˚C/min. to 260 ˚C and
hold for 10 min.). The diastereomeric ratio of the purified product was determined to be >20:1 by
1
1H NMR analysis: Rf = 0.3 (EtOAc:hexanes, 1:10); H NMR (400 MHz, C6D6): δ = 7.07 – 7.01
(m, 2H), 6.79 – 6.73 (m, 2H), 3.34 (s, 3H), 2.93 – 2.86 (m, 2H), 2.68 (dd, J = 6.6, 3.1 Hz, 1H),
2.61 – 2.50 (m, 3H), 2.46 – 2.33 (m, 1H), 2.23 – 2.11 (m, 2H), 1.63 (s, 3H), 1.57 (s, 3H), 1.43 (s,
13
3H), 1.38 (s, 3H); C NMR (125 MHz, C6D6): δ = 207.7, 172.3, 158.8, 138.3, 137.2, 127.8,
127.7, 125.5, 123.7, 121.8, 114.4, 57.0, 54.9, 53.1, 36.5, 32.3, 31.6, 29.4, 19.4, 19.1, 18.6, 18.5;
IR (film): 2984, 2923, 2857, 1692, 1651, 1515 cm–1; HRMS (APCI-TOF) m/z calcd for
[C24H28O2+H]+ 349.2162; found 349.2169.
4.4.7. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(2-bromophenyl)-9H-fluoren-9-one
(6f). To a solution of 4f (162 mg, 0.531 mmol) in CH2Cl2 (10 mL) under N2 at 0 °C was added
boron trichloride (0.53 mL, 0.53 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-
butadiene (218 mg, 2.70 mmol). The reaction was stirred until complete by TLC (2 h). The
reaction was quenched at 0 °C with saturated aqueous NaHCO3 and extracted with Et2O. The
layers were separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The
solvent was removed in vacuo and the crude product purified by column chromatography [pH 7
buffered phosphate silica gel; EtOAc/hexanes (1:25)] to yield 6f (62 mg, 29 %) as an off-white
solid. The diastereomeric ratio of the crude product was determined to be 12:1 by GC analysis
(GC-MS method: flow = 1 mL/min.; inlet = 250 °C; 220 ˚C for 5 min., ramp at 1 ˚C/min. to 260
˚C and hold for 10 min.). The diastereomeric ratio of the purified product was determined to be
1
>20:1 by 1H NMR analysis: Rf = 0.4 (EtOAc:hexanes, 1:10); H NMR (400 MHz, CDCl3): δ =
7.60 – 7.54 (m, 1H), 7.37 – 7.27 (m, 2H), 7.12 – 7.08 (m, 1H), 3.12 (dd, J = 7.5, 2.5 Hz, 1H),
2.88 (d, J = 15.2 Hz, 1H), 2.81 – 2.77 (d, 2H), 2.78 – 2.51 (m, 2H), 2.50 (d, J = 16.5 Hz, 1H),
2.28 – 2.19 (m, 1H), 2.22 (d, J = 15.2 Hz, 1H), 1.73 (s, 3H), 1.68 (s, 3H), 1.66 (s, 3H), 1.65 (s,
13
3H); C NMR (100 MHz, CDCl3): δ = 208.4, 172.8, 141.4, 138.4, 135.8, 130.1, 128.5, 127.5,
127.2, 123.8, 123.5, 123.4, 121.5, 53.7, 52.5, 39.4, 32.5, 31.1, 29.0, 19.3, 19.0, 18.8, 18.8; IR
(film): 2909, 2847, 1701, 1416 cm–1; HRMS (APCI-TOF) m/z calcd for [C23H25BrO+H]+
397.1162; found 397.1139.
4.4.8. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(4-bromophenyl)-9H-fluoren-9-one
(6g). To a solution of 4g (154 mg, 0.505 mmol) in CH2Cl2 (10 mL) at 0 ˚C under N2 was added
boron trichloride (0.50 mL, 0.50 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-
butadiene (203 mg, 2.47 mmol). The reaction was stirred until complete by TLC (1.5 h). The
reaction was quenched at 0 ˚C with saturated aqueous NaHCO3 and extracted with Et2O. The
layers were separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The
solvent was removed in vacuo and the crude product purified by recrystallization from hexanes
to yield 6g (83 mg, 42%) as an off-white solid. The diastereomeric ratio of the crude product was
determined to be >20:1 by GC analysis (GC-MS method: flow = 1 mL/min.; inlet = 250 °C; 230
˚C for 5 min., ramp at 1 ˚C/min. to 260 ˚C and hold for 10 min.). The diastereomeric ratio of the
1
purified product was determined to be >20:1 by H NMR analysis: Rf = 0.5 (EtOAc:hexanes,
1
1:10); H NMR (400 MHz, CDCl3): δ = 7.44 – 7.42 (m, 2H), 7.11 – 7.03 (m, 2H), 2.89 – 2.79
(m, 2H), 2.73 – 2.64 (m, 2H), 2.56 (dd, J = 6.7, 3.6 Hz, 1H), 2.46 – 2.17 (m, 4H), 1.71 (s, 3H),
13
1.70 (s, 3H), 1.64 (s, 3H), 1.62 (s, 3H); C NMR (100 MHz, CDCl3): δ = 209.2, 173.3, 144.0,
14

ACCEPTED MANUSCRIPT
138.4, 131.8, 128.3, 127.4, 125.2, 123.4, 121.6, 120.5, 56.6, 53.5, 36.1, 32.2, 31.5, 28.8, 19.5,
19.0, 18.7, 18.7; IR (film): 2980, 2917, 2854, 2243, 1698, 1685, 1647, 1483, 1429 cm–1; HRMS
(ESI-TOF) m/z calcd for [C23H25BrO+H]+ 397.1162; found 397.1162.
4.4.9. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(2-fluorophenyl)-9H-fluoren-9-one
(6h). To a solution of 4h (95 mg, 0.39 mmol) in CH2Cl2 (7 mL) at 0 ˚C under N2 was added
boron trichloride (0.39 mL, 0.39 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-
butadiene (160 mg, 1.95 mmol). The reaction was stirred until complete by TLC (< 1 h). The
reaction was quenched at 0 ˚C with saturated aqueous NaHCO3 and extracted with Et2O. The
layers were separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The
solvent was removed in vacuo and the crude product purified by recrystallization from hexanes
at 0 ˚C to yield 6h (50 mg, 38%) as a white solid. The diastereomeric ratio of the crude product
was determined to be >20:1 by GC analysis (GC-MS method: flow = 1 mL/min.; inlet = 250 °C;
220 ˚C for 5 min., ramp at 1 ˚C/min. to 260 ˚C and hold for 10 min.). The diastereomeric ratio of
the purified product was determined to be >20:1 by GC analysis: Rf = 0.4 (EtOAc:hexanes,
1:10); 1H NMR (400 MHz, C6D6): δ = 7.15 – 7.09 (m, 1H), 6.89 – 6.82 (m, 2H), 6.78 – 6.70 (m,
1H), 2.94 – 2.83 (m, 3H), 2.65 – 2.49 (m, 3H), 2.49 – 2.35 (m, 1H), 2.11 (d, J = 14.3 Hz, 1H),
13
2.16 – 2.07 (m, 1H), 1.60 (s, 3H), 1.52 (s, 3H), 1.39 (s, 3H), 1.37 (s, 3H); C NMR (125 MHz,
C6D6): δ = 206.6, 169.2, 162.0 (d, J = 248.4 Hz), 138.6 (d, J = 2.3 Hz), 132.2 (d, J = 9.5 Hz),
128.8, 128.7 (d, J = 1.5 Hz), 128.7, 128.0, 124.3 (d, J = 59.3 Hz), 124.3 (d, J = 3.5 Hz), 121.4,
19
116.8 (d, J = 23.3 Hz), 54.3, 51.6, 37.0, 32.3, 31.9, 29.4, 19.3, 19.1, 18.6, 18.5; F NMR (376
MHz, C6D6): δ = –109.3; IR (film): 2984, 2920, 2851, 1704, 1654 cm–1; HRMS (ESI-TOF) m/z
calcd for [C23H25FO+H]+ 337.1962; found 337.1960.
4.4.10. 1,4,4a,5,8,9a-hexahydro-2,3,6,7-tetramethyl-4a-(4-fluorophenyl)-9H-fluoren-9-one
(6i). To a solution of 4i (135 mg, 0.553 mmol) in CH2Cl2 (10 mL) at 0 ˚C under N2 was added
boron trichloride (0.55 mL, 0.55 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-
butadiene (225 mg, 2.74 mmol). The reaction was stirred until complete by TLC (2.5 h). The
reaction was quenched at 0 ˚C with saturated aqueous NaHCO3 and extracted with Et2O. The
layers were separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The
solvent was removed in vacuo and the crude product purified by recrystallization from hexanes
to yield 6i (79 mg, 43%) as an off-white solid. The diastereomeric ratio of the crude product was
determined to be >20:1 by GC analysis (GC-MS method: flow = 1 mL/min.; inlet = 250 °C; 220
˚C for 5 min., ramp at 1 ˚C/min. to 260 ˚C and hold for 10 min.). The diastereomeric ratio of the
1
purified product was determined to be >20:1 by H NMR analysis: Rf = 0.5 (EtOAc:hexanes,
1:10); 1H NMR (400 MHz, C6D6): δ = 6.91 – 6.83 (m, 2H), 6.83 – 6.75 (m, 2H), 2.86 (t, J = 7.3
Hz, 2H), 2.56 – 2.43 (m, 3H), 2.40 (d, J = 14.3 Hz, 1H), 2.25 (dt, J = 23.2, 7.3 Hz, 1H), 2.11 –
2.06 (m, 2H), 1.61 (s, 3H), 1.53 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H); 13C NMR (125 MHz, C6D6): δ
= 207.2, 171.6, 161.9 (d, J = 245.1 Hz), 141.1 (d, J = 3.2 Hz), 138.7, 128.4 (d, J = 7.7 Hz),
127.8, 125.3, 123.7, 121.7, 115.6 (d, J = 21.1 Hz), 56.9, 53.2, 36.4, 32.2, 31.5, 29.4, 19.4, 19.1,
19
18.6, 18.5; F NMR (376 MHz, C6D6): δ = –116.5; IR (film): 2917, 2857, 1689, 1651, 1603,
1505, 1439, 1400 cm–1; HRMS (ESI-TOF) m/z calcd for [C23H25FO+H]+ 337.1962; found
337.1969.
15

ACCEPTED MANUSCRIPT
4.4.11. 1,4,4a,5,8,9a-hexahydro-6,7-dimethyl-4a-(tert-butyl)-9H-fluoren-9-one (7a). To a
solution of 4a (177 mg, 0.858 mmol) in CH2Cl2 (8 mL) at –40 ˚C under N2 was added boron
trichloride (0.86 mL, 0.86 mmol, 1.0 M in hexanes) followed by 2,3-dimethyl-1,3-butadiene (78
mg, 0.95 mmol). The reaction was kept between –40 ˚C and –10 ˚C until the ketone was fully
converted to monocyclized (3 h) after which 1,3-butadiene was bubbled into the solution for 3
minutes. The reaction was warmed to r.t. and stirred until complete by TLC (5-6 h). The reaction
was quenched at 0 ˚C with saturated aqueous NaHCO3 and extracted with Et2O. The layers were
separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The solvent was
removed in vacuo and the crude product purified by column chromatography [pH 7 buffered
phosphate silica gel; EtOAc/hexanes (1:30)] to yield 7a (48 mg, 21%) as a pale yellow oil. The
diastereomeric and regioisomeric ratio of the crude product were both determined to be >20:1 by
GC analysis (GC-MS method: flow = 1 mL/min.; inlet = 250 °C; 190 ˚C for 5 min., ramp at 1
˚C/min. to 260 ˚C and hold for 10 min.). The isomeric ratio of the purified product 7a to all other
1
1
isomers was determined to be >20:1 by H NMR analysis: Rf = 0.4 (EtOAc:hexanes, 1:10); H
NMR (400 MHz, C6D6): δ = 5.82 – 5.72 (m, 1H), 5.53 (ddt, J = 10.0, 7.3, 2.9 Hz, 1H), 2.93 –
2.59 (m, 5H), 2.42 (dd, J = 6.5, 2.1 Hz, 1H), 1.97 (dd, J = 15.1, 6.9 Hz, 1H), 1.93 – 1.83 (m, 2H),
13
1.49 (s, 3H), 1.42 (s, 3H), 0.74 (s, 9H); C NMR (125 MHz, C6D6): δ = 207.2, 171.0, 140.0,
128.7, 127.6, 123.7, 121.7, 55.9, 49.3, 36.6, 35.1, 29.2, 27.1, 26.6, 26.4, 18.8, 18.4; IR (film):
3044, 2965, 2892, 1695, 1644, 1435, 1366, 1302 cm–1; HRMS (ESI-TOF) m/z calcd for
[C19H26O+H]+ 271.2056; found 271.2057.
4.4.12. 1,4,4a,9a-tetrahydro-6,7-tetramethyl-4a-(tert-butyl)-9H-fluoren-9-one (9a). Rf = 0.5
(EtOAc:hexanes, 1:10); 1H NMR (400 MHz, C6D6): δ = 7.61 (s, 1H), 7.15 (s, 1H), 5.70 (ddt, J =
9.6, 6.7, 3.3 Hz, 1H), 5.56 (ddt, J = 9.7, 6.7, 3.2 Hz, 1H), 2.86 – 2.74 (m, 2H), 2.32 (dd, J = 14.7,
6.8 Hz, 1H), 2.19 (dq, J = 14.6, 2.8 Hz, 1H), 2.11 – 2.00 (m, 1H), 1.92 (s, 3H), 1.84 (s, 3H), 0.78
(s, 9H); 13C NMR (125 MHz, C6D6): δ = 207.1, 158.3, 143.6, 138.0, 136.4, 129.0, 128.2, 126.8,
123.9, 53.8, 51.4, 37.6, 30.0, 27.5, 26.7, 20.8, 19.3; IR (film): 3037, 2965, 1704, 1613, 1454,
1407, 1363, 1302 cm–1; HRMS (ESI-TOF) m/z calcd for [C19H24O+H]+ 269.1900; found
269.1900.
4.4.13. 1,4,4a,5,8,9a-hexahydro-2,3-dimethyl-4a-(tert-butyl)-9H-fluoren-9-one (7b). To a
solution of 4a (90 mg, 0.44 mmol) in CH2Cl2 (6 mL) at –78 ˚C under N2 was added boron
trichloride (0.48 mL, 0.48 mmol, 1.0 M in hexanes). 1,3-Butadiene was bubbled into the solution
for 3 minutes. The reaction was kept at –78 ˚C until the ketone was fully converted to the
monocyclized 5b intermediate (3 h) after which 2,3-dimethyl-1,3-butadiene (excess) was added
and the reaction warmed to 0 ˚C and stirred until complete by TLC (1 h). The reaction was
quenched at 0 ˚C with saturated aqueous NaHCO3 and extracted with Et2O. The layers were
separated, the organic phase washed with H2O, brine, and dried over Na2SO4. The solvent was
removed in vacuo and the crude product purified by column chromatography [pH 7 buffered
phosphate silica gel; EtOAc/hexanes (1:30)] to yield 7b (27 mg, 23%) as a white solid. The
diastereomeric and regioisomeric ratio of the crude product were both determined to be >20:1 by
GC analysis (GC-MS method: flow = 1 mL/min.; inlet = 250 °C; 190 ˚C for 5 min., ramp at 1
˚C/min. to 250 ˚C and hold for 10 min.). The isomeric ratio of the purified major product 7b to
1
all other isomers was determined to be >20:1 by H NMR analysis: Rf = 0.3 (EtOAc:hexanes,
1:10); 1H NMR (500 MHz, C6D6): δ = 5.56 – 5.50 (m, 1H), 5.48 – 5.43 (m, 1H), 2.97 – 2.88 (m,
1H), 2.78 – 2.72 (m, 1H), 2.72 – 2.64 (m, 2H), 2.62 (d, J = 2.6 Hz, 1H), 2.37 (dd, J = 5.6, 2.6 Hz,
16

ACCEPTED MANUSCRIPT
1H), 2.05 – 1.98 (m, 1H), 1.95 (dddd, J = 15.8, 3.9, 2.6, 1.3 Hz, 1H), 1.77 (d, J = 14.5 Hz, 1H),
13
1.63 (dt, J = 2.3, 1.2 Hz, 3H), 1.44 (dt, J = 2.3, 1.2 Hz, 3H), 0.71 (s, 9H); C NMR (125 MHz,
C6D6): δ = 207.4, 170.3, 139.3, 127.4, 125.7, 124.7, 122.9, 56.5, 49.5, 36.2, 33.8, 33.0, 28.2,
27.0, 22.7, 19.4, 19.3; IR (film): 3022, 2957, 2909, 1691, 1672, 1626, 1424, 1401, 1366 cm–1;
HRMS (APCI-TOF) m/z calcd for [C19H26O+H]+ 271.2056; found 271.2061.
Acknowledgements
This work was supported by startup funds from the University of Nevada, Reno. We also thank
the National Science Foundation for supporting this work through a CAREER Award (CHE-
1555218). We would also like to thank Dr. Steven Spain and Casey Philbin for assisting in NMR
and mass spectra collection and training.
Supplementary data
13
Supplementary data (1H and C NMR spectra) associated with this article can be found in the
online version, at…
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