General methodologies toward cis-fused quinone sesquiterpenoids. enantiospecific synthesis of the epi-Ilimaquinone core featuring Sc-catalyzed ring expansion

Article abstract of DOI:10.3390/molecules22071041

A stereocontrolled approach to the cis-decalin framework of clerodane diterpenes and biologically active quinone sesquiterpenes is reported. Starting from an inexpensive optically pure tetrahydroindanone, Birch reductive alkylation builds two new contiguous chiral centers—one of which is quaternary and all-carbon-substituted. Also featured is a highly regioselective diazoalkane—carbonyl homologation reaction to prepare the 6,6-bicyclic skeleton. Therein, the utility of Sc(OTf)₃ as a mild catalyst for formal 1C insertion in complex settings is demonstrated.

Full text of DOI:10.3390/molecules22071041

molecules
Article
General Methodologies Toward cis-Fused Quinone
Sesquiterpenoids. Enantiospecific Synthesis of the
epi-Ilimaquinone Core Featuring Sc-Catalyzed
Ring Expansion
Hilan Z. Kaplan 1, Victor L. Rendina 1 and Jason S. Kingsbury 2,
*
1
Eugene F. Merkert Chemistry Center, Boston College, 2609 Beacon Street, Chestnut Hill, MA 02467, USA;
hilan.kaplan@gmail.com (H.Z.K.); vrendina@gmail.com (V.L.R.)
Ahmanson Science Center, California Lutheran University, 60 West Olsen Rd.,
Thousand Oaks, CA 91360, USA
2
*
Correspondence: jkingsbu@callutheran.edu; Tel.: +11-805-493-3026
Received: 1 June 2017; Accepted: 21 June 2017; Published: 24 June 2017
Abstract: A stereocontrolled approach to the cis-decalin framework of clerodane diterpenes
and biologically active quinone sesquiterpenes is reported. Starting from an inexpensive
optically pure tetrahydroindanone, Birch reductive alkylation builds two new contiguous chiral
centers—one of which is quaternary and all-carbon-substituted. Also featured is a highly
regioselective diazoalkane—carbonyl homologation reaction to prepare the 6,6-bicyclic skeleton.
Therein, the utility of Sc(OTf)3 as a mild catalyst for formal 1C insertion in complex settings
is demonstrated.
Keywords: quinone natural products; quaternary carbon synthesis; cis-decalin; scandium
triflate; catalytic ring expansion; homologation; (trimethylsilyl)diazomethane; hexahydroindanones;
5-epi-ilimaquinone; 5-epi-isospongiaquinone
1. Introduction
Earth’s biodiverse oceans remain a prolific source of small-molecule natural products [
The medicinal profile for the sea sponge metabolite ilimaquinone [ ] ( , Figure 1) includes antiviral,
anti-inflammatory, antimicrobial, and antitumor activities [ ] as well as the ability to protect the cell
against ricin and diptheria toxins [ ]. Efforts to understand how ilimaquinone causes a reversible
breakdown of the Golgi apparatus [ ] have been facilitated by total synthesis [ 10] and point to its
1].
2
1
3,4
5
6
7–
influence on cellular methylation [11]. Well over a hundred sesquiterpenes with avarane frameworks
fused to electrophilic quinone subunits are known [12], including those that bear an epimeric cis ring
fusion in the decalin core (Figure 1). It is fascinating that this and other seemingly minor structural
changes can translate to pharmacological effects that are unique to each natural product [13].
For instance, 5-epi-ilimaquinone and its amine-based variants
production of interleukin-8 (IL-8), a key cytokine in tumor progression and metastasis, but only
5-epi-smenospongine ( ) raises the production of TNF- in murine leukemia cells [14]. This data,
along with the fact that popolohuanone E ( ) is a potent nanomolar inhibitor of topoisomerase II with
2–4 are more active than 1 in the
4
α
7
efficacy against human non-small-cell lung cancer [15], suggests that a flexible synthesis of the cis-fused
clerodane core structure would be valuable. The ability to target entire families of bioactive natural
products rests upon the availability of inexpensive reagent or catalyst systems that are convenient,
reliable, and stereodiscriminating. Herein, we report on a widely applicable synthesis of complex
cis-decalins by a concise and scalable route featuring catalytic ring expansion methodology.
Molecules 2017, 22, 1041; doi:10.3390/molecules22071041
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Molecules 2017, 22, 1041
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H
N
O
OMe
O
O
O
OMe
O
R
HO
H
HO
H
O
HO
H
Me
Me
Me
Me
Me
Me
5
Me
Me
-smenospongorine (R = i-Bu)
Me
5
1
2–4
5-epi:
ilimaquinone
5-epi-isospongiaquinone
-smenospongidine (R = (CH2)2Ph)
-smenospongine (R = H)
HO
O
H
Me
O
HO
6'
Me
O
6
O
Me
OH
Me
Me
H
H
Me
Me
O
7
Me
arenarone
Me
popolohuanone E
Figure 1. Bioactive cis-fused sesquiterpene quinones and their relationship to (−)-ilimaquinone.
Previous synthetic studies within the cis-fused series have focused on arenarol [16
since its 6’-hydroxy variant is a biosynthetic precursor of the cytotoxic dimer (Figure 1) [19].
Common strategies for accessing the cis ring juncture include bicyclization through intramolecular
Hosomi-Sakurai reactions [18 20] and the substrate-controlled hydrogenation of ene-decalin derivatives
that are readily prepared by Robinson annulation [16 17]. A comparable excess of syntheses have been
recorded for the trans-fused class of targets [21 25], including ilimaquinone [ 10]. These cases also
–18],
7
,
,
–
7–
rely on Wieland–Miescher-type starting materials, where Birch reduction–alkylation serves well to
install a thermodynamically favored trans ring juncture [26,27].
In designing our approach (Scheme 1), two cases [28,29] of dissolving metal reduction with
tetrahydroindanone ([4.3.0]-bicyclic) substrates were found showing a kinetic preference [30] for cis
stereochemistry. However, in neither case was the potential for diastereoselective alkylation of the
metal enolate explored. We reasoned that upon hydrogen atom abstraction by the radical anion to
give a, face-selective quaternization of the α-carbon would be facilitated by the cup-shaped nature
of the intermediate (a → b). After methylenation, stereoselective hydrogenation, and oxidation
(b → c), we planned to apply our Sc-catalyzed method [31] for regioselective ring expansion (c → d)
with (trimethylsilyl)diazomethane (TMSD). The ring-enlarged enolsilane
d
could then diverge to
both exocyclic and endocyclic alkenes (→ e, compare 5-epi-
1 vs. 5, Figure 1). Additional end-game
manipulations would involve unmasking of the bioactive quinone subunits in each target molecule.
Aryl
Me
H
Me
Li
O
O
O
Birch
9
H
LiO
Me Aryl
X
Me
Me
HO
HO
a
8
b
FGI
Aryl
Aryl
Aryl
Sc-catalyzed
1–C
homologation
Me
Me
Me
H
H
H
Me
Me
Me
FGI
9
Me
Me
Me
O
e
c
d
TMSO
Scheme 1. Entry to complex cis-decalins based on retrosynthetic simplification to a tetrahydroindanone.

Molecules 2017, 22, 1041
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2. Results and Discussion
2.1. Diastereochemical Control at the C9 Quaternary Carbon by Birch Alkylation
Our investigation began with multigram synthesis and enantioenrichment of reduced
Hajos-Parrish ketone according to a modified literature protocol. The efficiency of a known [32
8
]
D-Phe-catalyzed synthesis of C4-alkylated tetrahydroindandiones has been improved by minimizing
solvent and sonicating the reaction mixture [33]. Complete separation of the minor enantiomer
(
92 → >98% ee) was achieved through a single recrystallization of
α carbinol 8, itself obtained by
stereoselective borohydride reduction of the diketone. As shown below in Scheme 2, dissolution of
this material in Li-NH3/THF at
and trapping with excess 2-chloro-3,5-dimethoxybenzyl iodide affords hexahydroindanone
−
78 ◦C, followed by brief warming to
−
33 ◦C, re-cooling to −78 ◦C
,
9 as a
single diastereomer in 81% yield after aqueous ammonium chloride workup and chromatography.
The only detectable byproducts stem from protonation or O-alkylation of the putative Li enolate.
The scope of this convergent reductive C–C coupling process includes both doubly ortho-substituted
benzylic and allylic bromides or iodides and was communicated previously by our laboratory [34].
3 equiv Li/NH3
THF, –78 °C;
H
H
Li
MeO
H
OMe
Me
O
then –78 °C, THF
N
O
H
H
Cl
9
Me
then –33 °C, 1 h
O
MeO
OMe
O
Me
>98% ee
HO
Me
9
8
(81% yield)
radical anion intermediate
Cl
Me
I
HO
Scheme 2. Dissolving metal reduction–alkylation of tetrahydroindanone builds contiguous stereocenters.
Of interest are the perfect levels of relative configurational control imparted by the existing
secondary hydroxyl and angular methyl groups. Alcoholic additives such as methanol, t-butanol,
and even water have long been known [35] to improve efficiency and yield in dissolving metal
reductions, presumably by acting as H atom sources for high energy radical anion (or even dianion)
intermediates. That the chosen substrate [
proton source may be enabling. For example, an attempt to reproduce the above data with cyclopentyl
ethylene ketal (derived from the dione of ) or the t-butyl dimethylsilyl (TBS) ether of delivers
cis-fused products but with noticeable reductions (>15–20%) in chemical yield. At this point, we do not
rule out the possibility [34] that the more efficient transformations observed for tetrahydroindanol
7] contains an unprotected alcohol as a stoichiometric, built-in
8
8
8
benefit from intramolecular H atom abstraction within a radical anion intermediate formed by a
kinetically favored, single-electron reduction of the enone. Molecular models do not convincingly
demonstrate that the cyclopentyl hydroxyl is close enough in proximity to the
β carbon to permit
internal delivery, but with the potential for participation by a solvent molecule (NH3, Scheme 2) the
suggested process is likely more facile than intermolecular alternatives. Once a cis ring fusion is
established, stereochemical induction during formation of the congested C9 quaternary carbon is likely
the result of electrophilic approach being restricted to the convex side of the intermediate.
2.2. Further Elaboration of the Stereotriad Gives a Lower Homologue of the epi-Ilimaquinone Core
Gratifyingly, further transformation of the hexahydroindanone adduct
successful despite steric crowding imposed by the new quaternary center. These studies commenced
with a standard TBS protection of the free cyclopentanol (step 1, Scheme 3). Unprotected does
9 described above is
9
furnish an ene-carbinol under the forcing and precedented [2◦1] Wittig conditions shown in step 2
(methyltriphenylphosphonium bromide, dimsyl sodium, 75 C), but it is the exclusive result of a
formal 1,5-hydride shift and subsequent cyclopentanone methylenation [34]. Avoiding Na alkoxide
formation prevents this transannular, acyloin-like rearrangement [36] and leads to the desired exocyclic

Molecules 2017, 22, 1041
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methylene cyclohexane 10 in good yield. Unfortunately, the features that led to high stereoselectivity
in the convergent Birch alkylation did not translate to alkene saturation. All efforts to hydrogenate
10 (or its free alcohol) to establish the C8
β methyl stereocenter were met with low conversion or
predominant formation of the unnatural diastereomer.
Judging that the adjacent quaternary carbon was discouraging metal hydride approach overall
yet allowing it syn to the smaller (methyl) group, migration of the alkene into the bicycle and farther
from the site of steric congestion was pursued. Rhodium(III)-mediated isomerization [23] with
concomitant silyl ether cleavage, followed by pyridinium chlorochromate (PCC) oxidation, provided
cyclopentanone 11 in 91% yield over two steps (Scheme 3). A range of heterogeneous hydrogenation
reactions were then tested for this alternative substrate. A favorable outcome is observed with Adams’
catalyst at ambient temperature and pressure, delivering epimeric hexahydroindanones 12a and
b
in near quantitative yield and an unoptimized 2:3 dr slightly favoring the desired methyl isomer.
β
The compounds proved chromatographically separable and crystalline, allowing for rigorous structure
proof by X-ray diffraction (Scheme 3). At this stage, our attention turned to the key catalytic ring
expansion with two advanced substrates in hand (11 and 12b). Before embarking on this goal,
we sought to establish a benchmark for reactivity and regioselectivity using a suitable model system.
MeO
OMe
Cl
MeO
OMe
Cl
MeO
OMe
Cl
1) TBSOTf, Et3N
CH2Cl2, –78 °C
3) RhCl3 H2O
EtOH, CHCl3, 80 °C
Me
Me
Me
H
H
H
2) Ph3PCH3Br, NaH
DMSO, 75 °C
4) PCC, CH2Cl2,
23 °C
O
(78%, two steps)
(91%, two steps)
11
9
10
Me
Me
Me
O
HO
TBSO
MeO
H
OMe
Cl
MeO
H
OMe
5) catalytic PtO2
1 atm H2 (g)
Cl
Me
Me
+
Me
Me
CH2Cl2, 23 °C
(98% combined)
Me
Me
2:3 dr (α:β) unoptimized
12a
12b
O
O
Scheme 3. Forward synthesis before ring expansion, including Oak Ridge Thermal Ellipsoid Plot
(ORTEP) plots for hexahydroindanones 12.
2.3. A Steroidal Model System for Catalysis of α-Quaternary Cyclopentanone Ring Enlargements
The accepted order of reactivity for ring expansion of cycloalkanones with diazoalkanes is
cyclobutanone
findings and literature precedent [37]. A previous report from our laboratory [31] on Sc-catalyzed
homologation focused on -quaternary cyclobutanones, whose reactions benefit from 4C ring strain.
≈
cyclohexanone > cycloheptanone > cyclopentanone on the basis of both empirical
α
We thus found ourselves at the opposite end of this spectrum of reactivity, seeking to ring expand very
hindered, neopentylic cyclic ketones lacking much angle strain. In order to ensure that our former
reaction conditions would be effective in the case of more reluctant substrates, we carried out initial
experimental optimization with commercially available estrone 3-methyl ether (13).
As shown below in Scheme 4, exposure of 13 to 2 equivalents of TMSD and 5 mol % Sc(OTf)3 at 23
C in chloroform for 24 h gave full conversion of starting material and a 72% NMR yield of the expected
◦
cyclohexenyl silyl ether iii. Subsequent workup of the reaction mixture with tetrabutylammonium
fluoride (TBAF) and purification by silica gel chromatography afforded the major regioisomer
14 in an acceptable 68% yield along with 22% of 15. The modest (~3:1) level of regiochemical
control in this reaction can be explained by a preferred approach of the diazoalkane nucleophile.

Molecules 2017, 22, 1041
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Carbonyl 1,2-addition with the bulky silicon group oriented away from the quaternary
α
carbon
situates the methylene substituent anti-coplanar to the dinitrogen leaving group (
i, Scheme 4).
Subsequent 1,2-migration generates a stereodefined -trimethylsilyl cyclohexanone ii. However,
α
our previous results [31] confirm that the regenerated Sc(OTf)3 goes on to catalyze secondary 1,3-Brook
rearrangement [38], affording iii as the major product prior to desilylation. Noteworthy is the fact
that no unwanted hydrolysis of enol silane iii occurs under the reaction conditions: this prevents
overhomologation of the more reactive products. The simple regiochemical model based on a need to
minimize non-bonding interactions during diazoalkyl 1,2-addition is in accord with other literature
reports [39].
O
O
2 equiv TMSD
Me
H
Me
H
Me
O
5 mol % Sc(OTf)3
+
H
H
H
CHCl3, 23 °C, 24 h;
then TBAF, THF
H
H
H
H
13
14
15
MeO
MeO
MeO
(68% yield)
(22% yield)
ScLn
N2
O
OTMS
O
Me
Me
Me
H
TMS
TMS
H
i
ii
iii
H
72% NMR yield
H
Scheme 4. Catalytic regioselective homologation of an estrone by formal (trimethylsilyl)methine insertion.
Over the course of experimentation that led to the above conditions for effective preparation
of homoestrone 14, a number of important observations were made that we wish to summarize:
(1) Consumption of 13 is prohibitively slow at temperatures of 0 ◦C or below, and solvent screening
pointed to toluene, CH2Cl2, and CHCl3 as media that promote smooth conversion and high
levels of regioselectivity. Coordinating solvents, such as Et2O and THF, suppress catalyst efficiency.
The halogenated solvents also improve homogeneity, and thus CHCl3 was chosen due to its lower
volatility and a preference to monitor reaction progress by 1H-NMR spectroscopy; (2) Other Sc(III)
salts and other lanthanide triflates were examined, but Sc(OTf)3 remained the optimal catalyst.
A regioisomeric ratio as high as 55:1 was recorded for Yb(OTf)3 with a monocyclic α-quaternary
substrate, suggesting that the larger Lewis acid leads to a more selective addition of the diazoalkane.
Unfortunately, conversion was not as high relative to Sc(OTf)3, and attempts to use the stronger
Yb(NTf2)3 resulted in steady decomposition of the nucleophile; (3) Finally, trials performed with
the commercial hydrate of Sc(OTf)3 or unpurified reagent and solvent gave irreproducible results.
Trace amounts of adventitious water were previously found to have a profound impact on both
the rate and enantioselectivity of asymmetric ring expansion reactions with chiral Sc catalysts [40].
Control experiments have shown that although TMSD itself is stable to both water and Sc(OTf)3
separately, the combination of all three leads to rapid destruction of TMSD, with a measured t1/2
of only 20 min. Sc(OTf)3 is a water-tolerant trication and is prepared from aqueous TfOH [41],
but hydration of its coordination sphere creates an equilibrium generating the free Brønsted acid.
This, in turn, allows net OH insertion by TMSD, giving TMSCH2OH (or CH3OTMS after 1,2-Brook
rearrangement). All variables considered, the complex cyclopentanone homologations reported in the
next section were set up in a glovebox with only rigorously dried Sc(OTf)3, TMSD, and CHCl3.
2.4. Advancement of Synthetic Bicyclopentanones to the epi-Ilimaquinone Core by Ring Expansion
We were pleased to find that the conditions optimized for steroidal model 13 tracked quite well
to our first synthetic cyclopentanone 11 with very little modification (Scheme 5). Exposure of 11 to
10 mol % Sc(OTf)3 and 1.5 equivalents of TMSD in CHCl3 showed only 33% conversion after 18 h at
23 ◦C in a J Young NMR tube. However, by simply heating the solution to 50 ◦C, >98% conversion

Molecules 2017, 22, 1041
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was reached in 18 additional hours. Upon dilute acid hydrolysis, the regioselectivity by 1H-NMR
analysis was approximately 6:1 favoring the desired regioisomer 16. By dropping the catalyst loading to
5 mol %, increasing concentration, and heating the reaction from the outset, the desired cis-decalone (16
was isolated in an 89% purified yield after just 16 h. Integration of the mixture before protodesilylation
in the latter case showed 8:1 regioselectivity (Scheme 5).
)
MeO
OMe
Cl
MeO
OMe
Cl
5 mol % Sc(OTf)3
Me
Me
H
H
TMSD, CHCl3, 50 °C, 16 h;
(89% yield)
> 8:1 regioselectivity
then 1 N HCl, THF
Me
11
Me
16
O
O
◦
Scheme 5. Successful ring expansion of synthetic bicyclopentanone 11 by gentle warming to 50 C.
Notwithstanding this successful opening result, we were curious to know if the regioisomeric
ratio (8:1) could be further enhanced by recourse to a more hindered (trialkylsilyl)diazomethane.
(Phenyldimethylsilyl)diazomethane (PDMSD) was prepared in our prior study [31] by adapting the
known protocol for TMSD [42] in order to allow Fleming–Tamao oxidation [43] of
β-keto silane
products (see ii, Scheme 4) that are stable to Brook rearrangement if Sc(hfac)3 is used as catalyst.
As shown in Scheme 6, heating of the same ketone with 5 mol % Sc(OTf)3 and the bulkier PDMSD
resulted in steady ring expansion, and only a single regioisomer was detectable after 24 h by 1H-NMR
spectroscopy. Regrettably, the conversion had only reached 75% during this time period. As expected,
the larger silyl substituent ensures a complete preference for the addition mode that places it opposite
the quaternary center (Scheme 4). This can be useful in cases where regioisomers are not otherwise
separable by column chromatography. However, we remained content with the utilization of TMSD as
a commercial 1C source that clearly promotes the most efficient reactions.
MeO
OMe
Cl
MeO
OMe
Cl
5 mol % Sc(OTf)3
Me
Me
H
H
PDMSD, CHCl3, 50 °C, 24 h;
(75% conv)
then TBAF, THF
single regioisomer
by 1H NMR
Me
11
Me
16
O
O
Scheme 6. Complete regiochemical control but lower efficiency with (phenyldimethylsilyl)diazomethane.
Surprisingly, when the saturated
β-methyl bicyclopentanone 12b was subjected to identical
homologation conditions that had cleanly transformed 11, we were disappointed to see complete
◦
lack of reactivity. Prolonged heating of the reaction mixture at 50 C did nothing to drive a ring
expansion, and the starting material was returned unchanged. In a more forceful experiment with
six equivalents of TMSD, heating to 70 ◦C led to extensive decomposition of both the diazoalkane
and substrate. Not even trace amounts of the characteristic cyclohexyl enol silane could be found.
Eventually, an experiment performed on a mixture of the
with two equivalents of TMSD and 5 mol % Sc(OTf)3 at 50 ◦C overnight provided insight. Complete
conversion of the epimer remained totally untouched.
epimer was visible by 1H-NMR, but the
α- and β-methyl cyclopentanones (12a,b)
α
β
This control indicated that our reaction was working properly, yet something particular about the
β
isomer 12b was preventing diazoalkane–carbonyl homologation from occurring.
Close scrutiny of the X-ray structure of 12b (Scheme 3) reveals a sound rationale for why this
substrate fails to undergo catalytic homologation even under strongly forcing conditions. Access to
the
The
π
* orbital of the carbonyl is completely blocked by methyl groups on both sides of the bicycle.
face is effectively shielded by the adjacent methyl, and the face is even more encumbered
α
β

Molecules 2017, 22, 1041
7 of 13
by the axial methyl group at the C9 quaternary center. In contrast, the solid-state structure for 12a
represents the ‘chair-flip’ conformer, with each quaternary methyl group falling nearly in plane
with the cyclopentanone ring and orthogonal to the π* orbital. Though each representation of the
solid state may not accurately represent conformations accessible in solution—especially at higher
temperatures—these structural features shed light on why 12a readily homologates, whereas 12b is
completely inert.
With a success rate for ring expansion involving just two out of three substrates, we sought to
devise a second-generation strategy that would address some of the deficiencies in our approach to
the natural products. Foremost among these were the low degree of stereocontrol in hydrogenation
with PtO2 and our inability to transform 12b to a fully saturated avarane core with the correct C8
configuration for the tertiary methyl group. Specifically, we wanted to incorporate functionality into the
Birch trapping agent that could be selectively unmasked and provide a means to direct a homogeneous
hydrogenation catalyst to the
α face of either unsaturated bicyclopentanone (see 10 or 11, Scheme 3).
Thus, 2-benzyloxy-6-chloro-3-methoxybenzyl iodide [34] was secured, containing an orthogonally
protected phenol that we planned to later test as a directing group and functional handle for quinone
oxidation. Under precisely the same conditions of Scheme 2, Birch alkylation with the new electrophile
gave the desired keto-alcohol in 79% yield. Analogous TBS protection and Wittig olefination then
delivered compound 17 (see Scheme 7) in 85% yield over two steps.
OMe
OBn
OMe
OBn
OMe
OBn
1) TBAF H2O
THF, 55 °C, ))))
1) RhCl3 H2O
Cl
H
Cl
H
Cl
Me
EtOH, CHCl3, 55 °C
Me
Me
H
2) DMP, CH2Cl2,
23 °C
2) DMP, CH2Cl2,
23 °C
(>98%, two steps)
(98%, two steps)
Me
Me
Me
18
17
19
O
O
TBSO
Scheme 7. Divergent entry to new ring expansion substrates with orthogonal phenolic protecting groups.
At this point in the original route, we had isomerized the exocyclic alkene to help facilitate a
modestly selective hydrogenation over Adams’ catalyst. By diverging our material and bringing
forward both the 1,1-disubstituted and trisubstituted olefins, we would have two more substrates
to showcase the generality of the Sc-catalyzed ring enlargement. As illustrated above in Scheme 7,
direct deprotection of 17 with TBAF followed by Dess–Martin oxidation furnished the exocyclic
ene-bicyclopentanone 18 in quantitative yield. In parallel, rhodium-mediated isomerization and
desilylation of 17 followed again by periodinane oxidation afforded its endocyclic constitutional
isomer 19 in 98% yield over two steps.
We then returned to an exploration of catalytic ring expansion with two additional complex
cyclopentanone substrates in hand (18 and 19). Both structures readily underwent 1C homologation
with mild warming under the optimum conditions, reaching full conversion in less than 24 h. Still,
as structural isomers likely having innate conformational preferences, it was not surprising to find
measurable differences in efficiency and regiochemistry.
Shown below (Scheme 8), the exocyclic ene-cyclopentanone 18 transformed with a 7:1 ratio of
cyclic enol silanes detectable by NMR prior to hydrolysis with fluoride. Upon workup and column
chromatography, 69% of the major ene-decalone 20 was isolated along with 8% of its regioisomer.
By contrast, the isomerized cyclopentanone 19 bearing an additional sp2 hybrid carbon in its core
afforded a much higher 93% isolated yield of the target homologated product 21, as shown below
in Scheme 9. The latter outcome tracks well with the result obtained earlier for the trisubstituted
alkene 11, differing only in the substitution and pattern on the arene that is removed from the site
of reaction (89% yield, >8:1 rr, Scheme 5). Overall, this direct comparison of ring expansion data
underscores how seemingly subtle changes in molecular structure and solution-phase conformations

Molecules 2017, 22, 1041
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have a fairly striking effect on the efficiency with which the ketone acceptor, the diazoalkane reagent,
and perhaps even the Lewis acidic catalyst approach one another and engage in reaction.
OMe
OBn
OMe
OBn
OMe
OBn
Cl
H
Cl
H
Cl
H
5 mol % Sc(OTf)3
Me
Me
Me
TMSD, CHCl3, 50 °C;
+
then TBAF, THF
18
20
O
>98% conv., < 24 hrs
Me
Me
Me
O
(69% yield)
(8% yield)
O
Scheme 8. Homologating the 1,1-disubstituted exocyclic olefin 18 gives a diminished selectivity and yield.
OMe
OBn
OMe
Cl
H
Cl
H
OBn
5 mol % Sc(OTf)3
Me
Me
TMSD, CHCl3, 50 °C;
(93% yield)
then TBAF, THF
>98% conv., < 24 hrs
Me
Me
19
21
O
O
Scheme 9. Excellent yield and >10:1 regiochemical control for ring expansion of 19.
The above conclusion begs a question of whether everyday practitioners of organic synthesis could
gain some predictive power over how different kinds of ring systems and their unique shapes will
behave in this classic and strategically useful reaction. Modeling of complex cyclopentanones 18
and 19 in silico confirms that the positioning of the olefin greatly impacts the preferred chair
conformation. Optimized geometries were calculated with Guassian ’09–B3LYP 3-21G/Avogadro 1.03.
The exocyclic alkene bicyclopentanone 18 (left, Figure 2) prefers a twist-boat conformation in which
both quaternary methyl groups are pseudoaxial and more effectively block Bürgi–Dunitz approach
to the carbonyl. Though not as prohibitive a situation, this picture resembles the X-ray conformation
that was characteristic of the totally unreactive saturated hexahydroindanone 12b, and to an extent
explains the less selective and efficient result recorded in Scheme 8. On the other hand, endocyclic
alkene bicyclopentanone 19 adopts a half-chair structure with the arene subunit and angular methyl
group in a distorted 1,3-diaxial orientation (right, Figure 2). Note that in each case, the molecules
are using rotational freedom as a way to avoid a severe syn pentane interaction that is incurred for
any perfect chair conformer given the 1,3-relationship of the fully substituted quaternary carbons.
The predicted conformation for 19 reveals a more favorable and less congested environment about the
ketone that, in turn, positively affects the outcome of methylene insertion.
18
19
Figure 2. Computational models for complex cyclopentanones 18 and 19 suggest distinct chair conformers.

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3. Materials and Methods
3.1. General Remarks
All reactions were carried out in flame-dried glassware under an atmosphere of argon in dry,
degassed solvents using standard Schlenk and vacuum-line techniques. Particularly air-sensitive
manipulations were performed in an MBraun Unilab nitrogen atmosphere glove box (MBraun USA,
Stratham, NH, USA). Commercial reagents were used as received unless otherwise noted. Flash column
chromatography was driven by compressed air and performed with ZEOPrep 60 Eco 40–63 µm silica
gel (AICMA, Framingham, MA, USA). Analytical thin-layer chromatography (TLC) was conducted
with 0.25 mm silica gel 60 F254 plates purchased from EMD Chemicals (Gibbstown, NJ, USA). Sc(OTf)3
(99%, Sigma-Aldrich, St. Louis, MO, USA) was finely powdered, dried at 200 ◦C over P2O5 for 24 h
under high vacuum (0.1 mm of Hg), and recovered in the glovebox. (Trimethylsilyl)diazomethane
(TMSD) and (phenyldimethylsilyl)diazomethane (PDMSD) were prepared according to a known
procedure [41] and stored over freshly activated 3 Å molecular sieves at
Note: TMSD is both non-explosive and non-mutagenic; however, it is extremely toxic and should be
handled with suitable precautions. A representative homologation protocol and characterization for
−
40 ◦C in glovebox freezer.
compounds 14 and 15 are provided. Experimental procedures for structures
precursor to 17 are omitted since they have been reported elsewhere [34]. Additional details for
synthesis and identification of total synthesis intermediates 11 12a 12b 16 17 18 19 20 and 21
9, 10, and the ketone
8
,
,
,
,
,
,
,
,
were compiled from a previous source [44] and have been included as Supplementary Material.
FT-IR spectra were recorded on a Bruker Alpha-p spectrometer (Bruker Optics Inc., Billerica, MA,
USA). Bands are reported as strong (s), medium (m), weak (w), broad strong (bs), broad medium
(bm), and broad weak (bw). Optical rotation data was recorded on a Rudolph research Autopol
IV automatic polarimeter (Rudolph Research Analytical, Hackettstown, NJ, USA) and is given as
the average of five readings. Melting points were recorded on a Digimelt MPA160 SRS (Stanford
Research Systems Inc., Sunnyvale, CA, USA) and are uncorrected. Sonication was performed with a
Misonix Sonicator 3000 (Misonix Inc., Farmingdale, NY, USA) linked to a Laude external circulator
1
for temperature control. H-NMR spectra were collected on Varian VNMRS (500 MHz) or INOVA
(500 MHz) (Agilent Technologies, Santa Clara, CA, USA) spectrometers. Chemical shifts are reported
in ppm from tetramethylsilane with the solvent resonance as the internal standard (CHCl3:
δ 7.26).
Data are reported as follows: chemical shift, multiplicities (s = singlet, d = doublet, dd = doublet of
doublets, ddd = doublet of doublet of doublets, dddd = doublet of doublet of doublet of doublets,
t = triplet, m = multiplet), coupling constants (Hz), and integration. 13C-NMR spectra were recorded
on Varian VNMRS (125 MHz) or INOVA (125 MHz) spectrometers with complete proton decoupling.
Chemical shifts are reported in ppm from tetramethylsilane with the solvent as the internal reference
(CDCl3:
δ 77.16). High-resolution mass spectra were collected at the Boston College Mass Spectrometry
Facility (Merkert Chemistry Center, Chestnut Hill, MA, USA). Supercritical fluid chromatography
(SFC) data were obtained on a Berger Instruments system (Waters Corp., Milford, MA, USA) using a
Daicel CHIRALPAK AS-H column (φ 4.6 mm, 25 cm length).
3.2. Representative Procedure for Regioselective Sc-Catalyzed Ring Expansion with Estrone Model
Homologous estrone 3-methyl ether—Major (14). In a drybox, Sc(OTf)3 (3.7 mg, 0.0075 mmol, 0.05 equiv.)
was weighed directly into a 1.5 mL vial equipped with a magnetic stirbar. A solution of estrone
3-methyl ether (13, 42.6 mg, 0.15 mmol, 1.0 equiv.) in CDCl3 (0.53 mL) was transferred directly to the
solid Sc(OTf)3. The resulting cloudy gray suspension was stirred for 15 min, at which point TMSD
(121 µL, 0.30 mmol, 2.0 equiv., 2.47 M in hexanes) was introduced dropwise. The entire reaction
mixture (including any residual solids) was transferred with a glass pipette to a J. Young NMR tube,
and the vial was rinsed with an additional 0.2 mL of CDCl3. The reaction◦tube was removed from the
drybox, connected to a nitrogen manifold, and allowed to stand 24 h at 23 C. 1,3,5-trimethoxybenzene
(11.0 mg, 0.65 mmol, 4.3 equiv.) was added as an internal standard, and 1H-NMR integrals indicated a

Molecules 2017, 22, 1041
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72% yield of the major cyclic enol silane. The reaction mixture was poured into H2O (5 mL), and the
product was extracted with CH2Cl2 (3 10 mL). The combined organic layer was dried over Na2SO4,
filtered, and concentrated. The unpurified residue was then dissolved in 1 mL of THF, TBAF xH2O
×
·
(168 mg, 0.60 mmol, 4.0 equiv.) was added as a solid, and the reaction mixture was stirred for 30 min
at 23 ◦C. The reaction mixture was then poured into H2O (5 mL) and the product was extracted with
Et2O (3
×
5 mL). The combined organic layer was then passed through a short plug of silica gel rinsed
with ethyl acetate (10 mL) and concentrated. Purification by column chromatography over silica gel
(15% ethyl acetate in hexanes) delivered the desired homologated estrone derivative 14 as a white
solid (30.4 mg, 68%), m.p. = 136–138 ◦C.
Rf = 0.30 (15% Ethyl acetate in hexanes); 1H-NMR (CDCl3, 500 MHz)
δ 7.22 (dd, J = 8.8, 0.5 Hz, 1H),
6.72 (dd, J = 8.9, 2.9 Hz, 1H), 6.63 (d, 2.9 Hz, 1H), 3.78 (s, 3H), 2.88–2.83 (m, 2H), 2.67 (ddd, J = 14.2,
14.2, 6.8 Hz, 1H), 2.38 (dddd, 11.5, 4.2, 4.2, 4.2 Hz, 1H), 2.28–2.21 (m, 2H), 2.16–2.05 (m, 2H), 1.99–1.93
(m, 1H), 1.89 (ddd, J = 13.9, 3.4, 3.4 Hz, 1H), 1.73 (ddd, J = 13.7, 13.7, 3.9 Hz, 1H), 1.69–1.58 (m, 1H),
1.55–1.39 (m, 4H), 1.34–1.25 (m, 1H), 1.13 (s, 3H); 13C-NMR (CDCl3, 125 MHz)
δ 216.45, 157.69, 137.76,
132.60, 126.48, 113.59, 111.77, 55.33, 50.44, 48.54, 43.17, 38.99, 37.32, 32.66, 30.24, 26.78, 26.07, 26.03,
23.08, 17.02; IR (neat) 2930 (bs), 2863 (bm), 1703 (s), 1610 (w), 1502 (m), 1429 (bm), 1254 (m), 1237 (m),
1040 (w) cm−1; HRMS (ESI+) Calcd. for C20H27O2 [M + H]+: 299.2011; Found 299.1999.
Homologous estrone 3-methyl ether–minor (15). Isolated as a minor regioisomer in the above reaction of
compound 14. Purification by column chromatography (15% ethyl acetate in hexanes) afforded the
minor regioisomer 15 as a white solid (9.9 mg, 22%), m.p. = 176–180 ◦C.
Rf = 0.17 (15% ethyl acetate in hexanes); 1H-NMR (CDCl3, 500 MHz)
δ 7.22 (d J = 8.3 Hz, 1H), 6.73
(dd, J = 8.8, 2.9 Hz, 1H), 6.64 (d, J = 2.9 Hz, 1H), 3.78 (s, 3H), 2.89–2.83 (m, 2H), 2.47–2.21 (m, 5H),
2.23 (d, J = 13.7 Hz, 1H), 2.16–2.09 (m, 1H), 2.14 (d, J = 13.4, 2.4 Hz, 1H), 1.67–1.42 (m, 5H), 1.41–1.24
(m, 2H), 0.83 (s, 3H); 13C-NMR (CDCl3, 125 MHz)
δ 211.83, 157.74, 137.95, 132.58, 126.45, 113.64, 111.84,
56.93, 55.38, 48.12, 43.72, 41.38, 41.33, 39.66, 38.38, 30.20, 26.76, 26.50, 25.72, 17.88; IR (neat) 2922 (bs),
2861 (bm), 1709 (s), 1612 (w), 1501 (m), 1256 (s), 1038 (m), 810 (w), 79 (w) cm−1; HRMS (ESI+) Calcd.
for C20H27O2 [M + H]+: 299.2011; Found 299.2015.
4. Conclusions
In summary, we paired a known [34] stereoselective Birch reduction–alkylation of [4.3.0]-bicyclic
enones with catalytic diazoalkane–carbonyl homologation [45] as methods applicable to the synthesis
of a wide range of bioactive quinone sesquiterpenes. Our data constitutes the first examples of
Sc-catalyzed 1C homologation with α-quaternary cyclopentanones. In model systems, excellent levels
of regioselectivity can be obtained by either using Yb(OTf)3 as the catalyst or by employing the more
sterically demanding diazoalkane PDMSD (up to >50:1 rr). Rigorous control over environmental
variables and reagent purity allows our procedures to be carried out reliably on scale. When extending
the catalytic method to more complex substrates, high yields and good levels of regiochemical control
were observed (69–93% yield, >8:1 rr).
Methylene insertion is a very common synthetic objective that continues to be carried out with
diazomethane in protic solvents [46] or with TMSD in the presence of stoichiometric amounts of
BF3
the new reactions catalyzed by low loadings of Sc(OTf)3 are among the highest yielding and most
selective [31 45]. Also worthy of note is the stability of TMSD in the presence of catalyst at high
·
Et2O [47] and other Al-based promoters [48]. Compared to prior examples in the literature,
,
temperature and the 1,3-Brook access to enol silane products, which eliminates the possibility for
overhomologation. The inability of our most advanced intermediate 12b to react certainly implies that
unforeseen conformational effects may continue to complicate mainstream use of this reaction in total
synthesis. Nonetheless, we hope that our findings encourage other synthetic chemists to test the newly
developed catalytic conditions in other target-based applications in the future.

Molecules 2017, 22, 1041
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Supplementary Materials: Supplementary materials are available online. Additional experimental details for
11, 12a, 12b, 16, 17, 18, 19, 20 and 21, including copies of 1H- and 13C-NMR spectra for all new compounds.
8,
Acknowledgments: This work was carried out at Boston College before the principal investigator relocated.
We gratefully acknowledge Boston College for startup funds (2006–2012) and the ACS Petroleum Research Fund
for a Type G Award (# 5001009). We also wish to thank Bo Li for X-ray analyses and California Lutheran University
for sustained funding. CLU’s Department of Chemistry is part of an NSF-sponsored user consortium with access
to a high-field NMR laboratory at California State University, Channel Islands (VIA-CI; CCLI 0737081).
Author Contributions: J.S.K. conceived of the synthesis plan and directed this research. H.Z.K. performed the
majority of multi-step synthesis experiments, characterized new entities, and grew crystals for X-ray diffraction.
V.L.R. designed, optimized, and executed reactions involving α-quaternary cyclopentanone homologation. J.S.K.
authored the manuscript for publication; all authors discussed the results and commented on the manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).