Enantiospecific Entry to a Common Decalin Intermediate for the Syntheses of Highly Oxygenated Terpenoids

Article abstract of DOI:10.1021/acs.joc.9b01937

Herein, we describe an enantiospecific route to one enantiomer of a common decalin core that is present in numerous highly oxygenated terpenoids. This intermediate is accessed in eight steps from (R)-carvone, an inexpensive, enantioenriched building block, which can be elaborated to the desired bicycle through sequential Fe(III)-catalyzed reductive olefin coupling and Dieckmann condensation. The same synthetic route may be applied to (S)-carvone to afford the enantiomer of this common intermediate for other applications.

Full text of DOI:10.1021/acs.joc.9b01937

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Note
Enantiospecific Entry to a Common Decalin Intermediate
for the Syntheses of Highly Oxygenated Terpenoids
Shota Nagasawa, Kerry E Jones, and Richmond Sarpong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01937 • Publication Date (Web): 27 Aug 2019
Downloaded from pubs.acs.org on August 27, 2019
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Enantiospecific Entry to a Common Decalin Intermediate for the
Syntheses of Highly Oxygenated Terpenoids
Shota Nagasawa,† Kerry E. Jones, Richmond Sarpong*
Department of Chemistry, University of California, Berkeley, California, 94720, United States
*rsarpong@berkeley.edu
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Abstract:
Herein, we describe an enantiospecific route to one enantiomer of a common decalin core
that is present in numerous highly oxygenated terpenoids. This intermediate is accessed in eight
steps from (R)-carvone, an inexpensive, enantioenriched building block, which can be elaborated
to the desired bicycle through sequential Fe(III)-catalyzed reductive olefin coupling and
Dieckmann condensation. The same synthetic route may be applied to (S)-carvone to afford the
enantiomer of this common intermediate for other applications.
Main text:
Terpenoids possessing decalin scaffolds are found in many families of natural products,1
some of which express significant biological activity.2 The structural features and biological
function of decalin-containing secondary metabolites have made them attractive synthetic targets.
Noteworthy examples of decalin-containing molecules that possess interesting structure and
function include jungermatrobrunin A (1), an ent-kaurene diterpenoid, which showcases a rare
endoperoxide bridge3a, and isodrimanial (2), a drimane sesquiterpenoid that displays significant
cytotoxicity against the KB tumor cell line with an IC50 of 0.30 µM.3b These intriguing attributes
have resulted in many synthetic studies aimed at the preparation of these decalin containing
molecules.
Several naturally occurring terpenoids including the labdane, ent-kaurene, drimane,
cleistanthane, and isoprimarane terpenoid natural products, which possess highly oxygenated
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decalin cores, are highlighted in Figure 1.3 The highly functionalized core in each of these
compounds spurred us to identify a common intermediate such as decalin 3 and ent-3, which could
provide access to each of these compounds. Indeed, racemic 3 has been elaborated to (±)-erigerol
(4) by Kienzle and coworkers4 and has also been taken forward to (±)-forskolin (5) in a synthesis
by Švenda and coworkers.5 In light of this previously demonstrated synthetic utility of 3, we sought
to prepare this decalin derivative in enantioenriched form as part of a broad campaign to access a
diverse array of enantioenriched terpenoids.
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O
O
OH
O
H
O
HO
OAc
Me
OAc
Me
OH
O
Me
Me
Me
O
O
O
O
OH Me
O
OAc
MeO
H
H
H
H
Me Me
OAc
Me Me
Me Me
OH
OH
Me Me
OAc
1α,6α-diacetoxy-ent-kaura-
9(11),16-dien-12,15-dione (6)
forskolin (5)
isodrimanial (2)
jungermatrobrunin A (1)
labdane diterpenoids
drimane sesquiterpenoids
ent-kaurane diterpenoids
TBSO
O
Me
TBSO
O
O
Me
Me
Me
H
H
Me Me
3
Me Me
ent-3
O
potential
common intermediate
potential
common intermediate
cleistanthane/isoprimarane
labdane diterpenoids
diterpenoids
O
Me
Me
Me
Me
OH
Me
OH
Me
O
OH
Me
H
Me
O
Me
OH
O
O
H
H
H
Me Me
Me Me
OH
OH
Me Me
OH
erigerol (4)
aspergiloid D (8)
aspergiloid C (7)
Figure 1: Selected terpenoids containing a highly oxygenated decalin core traced back to a plausible
common intermediate
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As noted above, racemic 3 has been prepared previously by Kienzle and coworkers and
was utilized in several natural product syntheses.4 Specifically, from diene 10 and quinone 11, a
Diels–Alder cycloaddition constructed the decalin scaffold (Scheme 1a). Similar decalin
derivatives have been prepared in enantioenriched form by exploiting a kinetic resolution, as
demonstrated by Sih and coworkers6 (see (±)-12®(+)-13; Scheme 1b). In principle, intermediate
3 could be obtained in enantioenriched form using porcine pancreatic lipase to effect a lipase ester
hydrolysis of a decalin ester. However, enzymatic resolution provides a maximum yield of 50%
and would necessitate several manipulations (e.g., an acylation or dehydrogenation) in order to
obtain intermediate 3. During the time when our studies were initiated, there had been no reported
route to decalin 3 in enantioenriched form.7 Given the synthetic utility of decalin 3 in complex
molecule synthesis, we sought to develop an efficient and enantiospecific route for its preparation.
Herein, we report an enantiospecific synthesis of one enantiomer of 3 from (R)-carvone (14), a
cheap and commercially available “chiral pool” terpene that can be purchased in both enantiomeric
forms (Scheme 1c). We envisioned a synthetic route that would employ three C–C bond forming
transformations (radical coupling, Dieckmann condensation and methylation) and one C–H
oxidation step (g-oxidation of enone).
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Scheme 1: Access to the intermediate 3
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Previous work
a) racemic entry of intermediate 3 (Kienzle, 1989 and 1990)
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8
O
TBSO
O
O
OEt
OEt
OEt
OEt
Me
H
6 steps
2 steps
Me
Me
Me
EtO
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Me
Me
O
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(±)-3
b) enzymatic kinetic resolution of similar substrates (Sih, 1987)
O
O
porcine
O
O
O
OH
Me
O
O
O
O
Me
H
pancreatic
lipase
Cl
Me
Me
Cl
Me
+
H
H
Me Me
Me Me
Me Me
O
(±)-12
(+)-13
12 (remaining)
This work
c) enantiospecific entry of intermediate 3
methylation
O
TBSO
O
Dieckmann
condensation
Me
Me
Me
widely available
chiral building block
radical coupling
via HAT
γ-oxidation
H
Me
Me Me
O
(R)-carvone (14)
3
Our initial attempts toward the synthesis of enantioenriched 3 began with an Fe(III)-
catalyzed reductive olefin coupling, adapted from the work of Baran and co-workers,7 between
(R)-carvone (14) and methyl acrylate, which would install all the carbons necessary for the decalin
scaffold (Scheme 2). However, under the reported reaction conditions, desired coupling product
15 was not obtained; rather, bicyclo[3.3.1]nonane 16 was formed in low yield,8 likely arising
through sequential 1,4-additions (see brackets in Scheme 2).
Scheme 2: Formation of bridged bicycle 16
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Fe(acac)3 (cat.)
PhSiH3
methyl acrylate
Na2HPO4
O
via
O
O
O
MeO2C
Me
Me
Me
Me
Me
CO2Me
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7
8
9
DCE:(CH2OH)2 (5:1)
60 °C
Me
Me Me
Me
(R)-carvone (14)
Me
Me
CO2Me
16
27%
15
not observed
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We recognized that masking of the double bond of the enone functional group in (R)-
carvone (14) could circumvent this undesired Giese-type addition. While protection of the enone
through the conjugate addition of thiophenol was successful, subsequent reactions failed.
Therefore, in our revised synthetic scheme, we began our synthesis with the Weitz–Scheffer9
nucleophilic epoxidation of (R)-carvone (14) to yield epoxide 17 (Scheme 3). Subsequent Fe(III)-
catalyzed intermolecular reductive olefin coupling with methyl acrylate afforded the desired
ketoester (18) in good yield. Dieckmann condensation of ketoester 18 delivered the expected 1,3-
diketone in the keto-enol form (19), and subsequent methylation of the alpha position of 19 with
methyl iodide gave cis-fused bicycle 20. The cis-configuration at the ring junction of 20 was
confirmed by nOe correlations. Of note, the addition of tetrabutylammonium bromide was
important in order to consistently achieve high conversion.
Scheme 3: Synthesis of cis-fused decalin compound 20
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With diketone 20 in hand, we focused on the functionalizations required to advance the
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decalin core to
3
(Scheme 4). Reductive deoxygenation of the epoxide with
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bis(cyclopentadienyl)titanium(III) chloride (Cp2TiCl), generated in situ from Cp2TiCl2 and zinc
dust, afforded enone 21.10 Subsequent oxidation of the gamma methylene of enone 21 was
investigated with an array of transition metal catalysts and t-butyl hydroperoxide,11 which yielded
a mixture of C-4 and C-2 oxidation products in a 1.5-1.6:1 ratio. To our delight, oxidation of 21
using chromium trioxide and 3,5-dimethylpyrazole gave dienone 22 in moderate yield as the sole
product.12 Selective reduction of the C-8 carbonyl of enedione 22 was achieved with sodium
borohydride in a dichloromethane-methanol solvent mixture13 to provide alcohol 23, which was
subsequently protected to yield the desired silyl ether (i.e., 3). Spectroscopic data for
enantioenriched 3 was fully consistent with the previously reported data.4,5 The synthetic sequence
reported here is amenable to the multi-gram scale preparation of this compound.
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Scheme 4: Completion of the synthesis of intermediate 3
O
O
O
O
O
O
Me
Me
CrO3
Me
H
Cp2TiCl2
Zn
Me
O
2
Me
Me
3,5-dimethylpyrazole
8
1
4
DCE, 50 °C
THF
87%
H
H
4
Me Me
Me Me
Me Me
O
21
20
22
HO
O
O
TBSO
O
Me
Me
H
TBSOTf
2,6-lutidine
Me
Me
NaBH4
DCM:MeOH (1:1)
–78 °C
DCM, –78 °C
57% for 3 steps
H
Me Me
Me Me
O
3
23
We note that both enantiomers of 3 are accessible using this sequence, starting from either
(R)- or (S)-carvone (14). Additionally, cis-decalin 3 can be epimerized to the corresponding trans-
decalin (24) through treatment with basic aluminum oxide, according to Kienzle’s protocol
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(Scheme 5).4 Thus, all 4 diastereomers with respect to the decalin ring junctions are accessible
through this synthetic route.
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Scheme 5: Epimerization of cis-decalin 3 to trans-decalin 24
TBSO
O
O
TBSO
O
Me
H
Me
Me
Me
basic Al2O3
toluene, 100 °C
80%
H
Me Me
Me Me
O
24
3
OTBS
Me
OTBS
O
Me
H
O
Me
Me
O
H
O
Me
Me
Me
Me
cis-decalin
trans-decalin
In summary, we have developed an eight step sequence from (R)- or (S)-carvone (14) that
provides access to an enantioenriched, highly oxygenated decalin structural motif using an Fe(III)-
catalyzed reductive olefin coupling followed by a Dieckmann condensation. The resultant bicycle
is a highly versatile intermediate that has been employed previously in the syntheses of labdane
diterpenoids and may form the basis for the synthesis of other highly oxygenated terpenoids.
Efforts in our laboratory that employ decalin 3 and ent-3 in the synthesis of terpenoid natural
products are currently ongoing.
EXPERIMENTAL SECTION
General: Unless otherwise stated, all reactions were performed in flame-dried or oven-dried
glassware under an atmosphere of nitrogen using Teflon coated stir bars. Reactions ran above room
temperature were heated in an oil bath, room temperature is defined as 23 °C. All commercially
available reagents were used without purification. Tetrahydrofuran (THF), methanol (MeOH),
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acetonitrile (MeCN), and triethylamine (Et3N) were dried by passage through an activated alumina
column under argon. Dichloromethane (DCM) was distilled over calcium hydride under nitrogen.
Flash column chromatography was performed on Silicycle SiliaFlash® P60 silica gel (230–400
mesh, 40–63 µm particle size). Automated flash chromatography was performed on Yamazen
Flash EPCLC W-Prep 2XY (dual channel) automated flash chromatography systems with
premium grade universal columns. Thin layer chromatography (TLC) and preparative TLC were
performed on glass-backed Silicycle SiliaPlate 250 µm thickness, 60 Å porosity F-254 precoated
plates. Compounds were visualized with UV light (254 nm) and stained with p-anisaldehyde and
heat, or potassium permanganate (KMnO4) and heat. Nuclear magnetic resonance (NMR) spectra
were obtained on Bruker AV-300 (NSF grant CHE-0130862 and NSF grant CHE-911557), AVQ-
400 (NSF grant CHE-0130862), AVB-400 (NSF grant CHE-0130862, NIH grant S10 RR 03353-
01, and NSF grant CHE-8703048), AV-500 (NIH grant 1S10RR016634-01), and AV-600 (NIH
grant SRR023679A) instruments at UC Berkeley’s College of Chemistry NMR Facility. Residual
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chloroform (CHCl3) was used as an internal reference for H (δ = 7.26 ppm) and C (δ = 77.1
ppm). The following abbreviations were used to describe the NMR multiplicities: br = broad, s =
singlet, d = doublet, t = triplet, q = quartet, q = quintet, m = multiplet. Coupling constants J are
given in Hertz. Infrared (IR) spectroscopy were obtained on Bruker ALPHA FT-IR
spectrophotometer using a diamond attenuated total reflectance (ATR) accessory. Substances were
dissolved in chloroform prior to direct application on the ATR unit. Frequency of absorption is
given in cm-1. High-resolution mass spectra (HRMS) were obtained on a Perkin-Elmer AxION 2
UHPLC-TOF Instrument (ESI) or an AutoSpec Premier mass spectrometer (Waters, Manchester,
UK), equipped with an electron impact (EI). Optical rotations were measured on a Perkin-Elmer
241 Polarimeter. Melting points were measured on a Laboratory Devices Mel-Temp II.
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Experimental procedures: Methyl (1R,5S,8R)-4,4,8-trimethyl-7-oxobicyclo[3.3.1]nonane-2-
carboxylate (16). Prepared according to a modification of the procedure by Baran and coworkers:
7 (R)-carvone (14, 50. mg, 0.33 mmol, 1.0 equiv) was dissolved in a mixture of 1,2-dichloroethane
(1.5 mL) and ethylene glycol (0.3 mL) in a flask open to the atmosphere. Iron(III) acetylacetonate
(10.6 mg, 30.0 µmol, 0.1 equiv), methyl acrylate (0.11 mL, 0.99 mmol, 3.0 equiv), anhydrous
sodium phosphate dibasic (47 mg, 0.33 mmol, 1.0 equiv) were added to the rapidly stirring
mixture. Phenylsilane (0.06 mL, 0.66 mmol, 2.0 equiv) was added dropwise. (CAUTION: rapid
evolution of gas is observed). The flask was fitted with a water jacketed reflux condenser and the
mixture was heated to 60 °C for 1 h, and then additional phenylsilane (0.06 mL, 0.66 mmol, 2.0
equiv) was added and stirred 1 h. Upon observed completion by TLC the reaction mixture was
cooled to room temperature and diluted with saturated aqueous sodium chloride (5 mL). The
organic layer was separated, and the aqueous layer was extracted with diethyl ether (3 x 8 mL).
The combined organic layers were washed with saturated aqueous sodium chloride (5 mL), dried
over magnesium sulfate, and concentrated in vacuo. The crude oil was then purified via gradient
flash chromatography (Yamazen, eluting with 8-29% ethyl acetate in hexanes) to give the title
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compound 16 (21.5 mg, 0.090 mmol, 27%). The H NMR and C NMR spectra are consistent
with that reported in the literature.8 1H NMR (400 MHz, CDCl3) δ 3.64 (s, 3H), 2.94 – 2.88 (m,
1H), 2.73 – 2.62 (m, 2H), 2.47 (qdd, J = 6.9, 6.4, 0.9 Hz, 1H), 2.32 (ddd, J = 15.7, 5.7, 0.9 Hz,
1H), 2.20 (dq, J = 13.6, 3.3 Hz, 1H), 1.96 (dt, J = 13.6, 3.1 Hz, 1H), 1.88 – 1.83 (m, 1H), 1.48 (dd,
J = 14.8, 3.8 Hz, 1H), 1.32 (d, J = 14.8 Hz, 1H), 1.00 (s, 3H), 0.97 (s, 3H), 0.94 (d, J = 7.0 Hz,
13
3H). C NMR (101 MHz, CDCl3) δ 212.8, 175.4, 51.6, 48.8, 44.6, 41.9, 41.8, 40.1, 34.0, 33.4,
33.1, 29.2, 27.5, 12.0.
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(1R,4R,6R)-1-Methyl-4-(prop-1-en-2-yl)-7-oxabicyclo[4.1.0]heptan-2-one (carvone oxide,
17). Prepared according to a modification of the procedure outlined by Mulzer and coworkers:14
(R)-(–)-Carvone (14, 5.0 g, 33 mmol, 1.0 equiv) was added to HPLC grade methanol (83 mL) in a
flask open to the environment and the mixture was cooled to –20 °C. A 4.0 M solution of sodium
hydroxide (2.5 mL, 9.9 mmol, 0.3 equiv) and a 35% aqueous hydrogen peroxide solution (3.7 mL,
43 mmol, 1.3 equiv) were added sequentially in a dropwise fashion. The solution was warmed to
0 °C within 1.5 h, and then additional 35% aqueous hydrogen peroxide solution (1.8 mL, 21 mmol,
0.6 equiv) was added and the reaction mixture was stirred for 1 h. The excess hydrogen peroxide
was quenched with 2N hydrochloric acid (4 mL) and sodium thiosulfate (3.0 g, 0.5 equiv) and
allowed to stir at room temperature for 30 min before the addition of water (100 mL) was added,
and the aqueous layer was extracted with diethyl ether (3 x 100 mL). The combined organic layers
were dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified via
column chromatography (20:1 hexanes:ethyl acetate) to yield carvone oxide 17 as a colorless oil
(5.0 g, 30. mmol, 90% yield). Full characterization has been reported by Cao and coworkers. The
1H NMR spectrum is consistent with that reported in the literature.15 1H NMR (400 MHz, CDCl3)
δ 4.79 (s, 1H), 4.72 (s, 1H), 3.45 (dd, J = 3.2, 1.2 Hz, 1H), 2.71 (tt, J = 11.2, 4.8 Hz, 1H), 2.59
(ddd, J = 17.7, 4.7, 1.4 Hz, 1H), 2.37 (dt, J = 14.8, 3.3 Hz, 1H), 2.03 (dd, J = 17.6, 11.6 Hz, 1H),
1.90 (ddd, J = 14.8, 11.1, 1.2 Hz, 1H), 1.71 (s, 3H), 1.41 (s, 3H).
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Methyl 4-methyl-4-((1R,3R,6R)-6-methyl-5-oxo-7-oxabicyclo[4.1.0]heptan-3-yl)pentanoate
(18). Prepared according to a modification of the procedure by Baran and coworkers:7 Epoxide 17
(1.0 g, 6.0 mmol, 1.0 equiv) was dissolved in a mixture of 1,2-dichloroethane (25 mL) and ethylene
glycol (5 mL) in a flask open to the atmosphere. Iron(III) acetylacetonate (0.21 g, 0.59 mmol, 0.1
equiv), methyl acrylate (2.0 mL, 22 mmol, 3.0 equiv), and anhydrous sodium phosphate dibasic
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(0.85 g, 5.9 mmol, 1.0 equiv) were added to the rapidly stirring mixture. Phenylsilane (1.2 mL, 12
mmol, 2.0 equiv) was added dropwise. (CAUTION: rapid evolution of gas is observed). The
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equiv) was added and the reaction mixture was stirred 30 min. Upon observed completion by TLC
the reaction mixture was cooled to room temperature and diluted with saturated aqueous sodium
chloride (100 mL). The organic layer was separated, and the aqueous layer was extracted with
diethyl ether (3 x 75 mL). The combined organic layers were washed with saturated aqueous
sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. Purification of the
crude residue via column chromatography (10:1 hexanes:ethyl acetate) yielded methyl ester 18 as
a colorless oil (0.94 g, 3.7 mmol, 62% yield). 1H NMR (300 MHz, CDCl3) δ 3.67 (s, 3H), 3.43 (d,
J = 3.6 Hz, 1H), 2.52 – 2.41 (m, 1H), 2.36 – 2.22 (m, 3H), 2.02 – 1.95 (m, 1H), 1.89 (dd, J = 17.4,
11.8 Hz, 1H), 1.69 (dd, J = 14.4, 11.6 Hz, 1H), 1.62 – 1.53 (m, 2H), 1.40 (s, 3H), 0.84 (s, 3H),
0.83 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 206.2, 174.2, 61.1, 58.7, 51.6, 38.5, 34.7, 34.4, 33.8,
28.8, 24.3, 23.8, 23.7, 15.2. IR: ṽ = 2954, 2874, 1736, 1706, 1437, 1371, 1304, 1197, 1171, 1116
cm-1. [a]20D = +69.2° (c 0.93, CHCl3). HRMS (ESI): calcd for ([M+H], C14H23O4)+: m/z = 255.1591
found 255.1594. Rf = 0.26 (4:1 hexanes:ethyl acetate), red spot (p-anisaldehyde).
(1aR,6aS,7aR)-3-Hydroxy-1a,6,6-trimethyl-4,5,6,6a,7,7a-hexahydronaphtho[2,3-b]oxiren-
2(1aH)-one (19). Methyl ester 18 (0.94 g, 3.7 mmol, 1.0 equiv) was dissolved in THF (37 mL) and
cooled to 0 °C. Potassium tert-butoxide (0.50 g, 4.4 mmol, 1.2 equiv) was added and the mixture
stirred for 30 min. Upon completion by TLC, saturated aqueous ammonium chloride (50 mL) was
added and the reaction mixture was warmed to room temperature. The aqueous layer was extracted
with ethyl acetate (3 x 50 mL), the combined organic layers were washed with saturated aqueous
sodium chloride (25 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue
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was purified by flash chromatography (10:1 hexanes:ethyl acetate) to give enol 19 as a white solid
(0.69 g, 3.1 mmol, 84% yield). 1H NMR (400 MHz, CDCl3) δ 15.81 (s, 1H), 3.49 (d, J = 3.5 Hz,
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1H), 2.48 – 2.24 (m, 4H), 1.64 – 1.42 (m, 6H), 1.01 (s, 3H), 0.78 (s, 3H). C NMR (101 MHz,
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CDCl3) δ 196.1, 182.3, 106.0, 62.4, 57.6, 37.6, 36.3, 31.0, 29.0, 28.1, 23.7, 19.8, 15.8. mp: 41–44
°C. IR: ṽ = 2927, 2868, 1601, 1416, 1379, 1367, 1355, 1290, 1260, 1183, 934, 406 cm-1. [a] 20
=
D
–45.4° (c 0.97, CHCl3). HRMS (ESI): calcd for ([M+H], C13H19O3)+ m/z = 223.1329 found
223.1322. Rf = 0.55 (4:1 hexanes:ethyl acetate), UV-active, orange spot (p-anisaldehyde).
(1aR,2aS,6aS,7aR)-1a,2a,6,6-Tetramethylhexahydronaphtho[2,3-b]oxirene-2,3(1aH,2aH)-
dione (20). Enol 19 (4.4 g, 20 mmol, 1.0 equiv) was dissolved in anhydrous dimethylformamide
(90 mL), followed by subsequent addition of potassium carbonate (12.3 g, 88.9 mmol, 4.5 equiv),
tetrabutylammonium bromide (64 mg, 0.2 mmol, 0.01 equiv), and iodomethane (6.15 mL, 98.7
mmol, 5.0 equiv). This mixture was stirred in a closed vessel for 4.5 h at room temperature. Excess
solid potassium carbonate removed by filtration through fritted glass and the filtrate was diluted
with water (300 mL) and extracted with diethyl ether (4 x 100 mL). The combined organic layers
were washed with saturated aqueous sodium chloride (50 mL), dried over magnesium sulfate, and
concentrated in vacuo. Purification via flash chromatography (9:1 hexanes:ethyl acetate) afforded
1,3-dione 20 (3.2 g, 13 mmol, 68% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 3.47 (d,
J = 5.2 Hz, 1H), 2.57 (td, J = 14.4, 6.0 Hz, 1H), 2.46 (dd, J = 16.4, 7.2 Hz, 1H), 2.30 (ddd, J =
14.3, 4.6, 3.1 Hz, 1H), 2.15 (ddd, J = 16.4, 5.2, 2.2 Hz, 1H), 1.92 (dt, J = 7.0, 1.6 Hz, 1H), 1.75
(ddd, J = 13.8, 6.2, 3.1 Hz, 1H), 1.59 (td, J = 14.0, 4.5 Hz, 1H), 1.48 (s, 3H), 1.40 (s, 3H), 1.00 (s,
13
6H). C NMR (101 MHz, CDCl3) δ 208.5, 208.5, 64.3, 59.9, 58.8, 56.4, 40.5, 36.6, 34.2, 30.7,
22.9, 22.7, 20.6, 15.9. mp: 128–131 °C. IR: ṽ = 2980, 2962, 2943, 2880, 1716, 1686, 1471, 1380,
20
1044, 1009, 851 cm-1. [a]
= +122.5° (c 1.13, CHCl3). HRMS (ESI): calcd for ([M+Na],
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C14H20NaO3)+ m/z = 259.1305 found 259.1308. Rf = 0.37 (4:1 hexanes:ethyl acetate), yellow-
orange spot (p-anisaldehyde).
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(4aS,8aS)-4,4,7,8a-Tetramethyl-3,4,4a,8a-tetrahydronaphthalene-1,8(2H,5H)-dione
(21).
Procedure adapted from Nugent.9 THF (25 mL) was added to a flask charged with zinc (4.2 g, 64
mmol, 6.6 equiv) and bis(cyclopentadienyl)titanium(IV) dichloride (5.33 g, 21.4 mmol, 2.2 equiv).
After 15 min, 1,3-dione 20 (2.3 g, 9.7 mmol, 1.0 equiv) was added dropwise in THF (25 mL).
After stirring the solution at room temperature for 1.5 h, saturated aqueous monosodium phosphate
(50 mL), saturated aqueous sodium chloride (50 mL), and ethyl acetate (50 mL) were added. After
1 h, the mixture was filtered through Celite® and the filtrate was extracted with ethyl acetate (3 x
75 mL). The combined organic layers were washed with saturated aqueous sodium chloride (25
mL), dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified
via flash chromatography (8:1 hexanes:ethyl acetate). This yielded 21 (1.87 g, 8.48 mmol, 87%
yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 6.58 – 6.55 (m, 1H), 2.71 – 2.56 (m, 2H),
2.39 (dd, J = 21.0, 4.8 Hz, 1H), 2.28 (dt, J = 13.9, 3.3 Hz, 1H), 1.99 (d, J = 6.7 Hz, 1H), 1.77 –
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1.69 (m, 4H), 1.61 (td, J = 13.9, 3.8 Hz, 1H), 1.33 (s, 3H), 0.97 (s, 3H), 0.90 (s, 3H). C NMR
(101 MHz, CDCl3) δ 209.5, 200.6, 142.4, 133.8, 59.2, 54.1, 41.8, 37.1, 34.4, 30.4, 24.8, 23.0, 20.7,
16.0. mp: 99–104 °C. IR: ṽ = 2958, 2928, 2874, 1713, 1653, 1455, 1424, 1372, 1361, 1030, 847,
754 cm-1. [a] 20 = +144.7° (c 1.14, CHCl3). HRMS (ESI): calcd for ([M+H], C14H21O2)+ m/z =
D
221.1536 found 221.1543.
Rf = 0.34 (4:1 hexanes:ethyl acetate), UV-active, yellow spot (p-anisaldehyde).
(4aS,8aS)-3,4a,8,8-Tetramethyl-6,7,8,8a-tetrahydronaphthalene-1,4,5(4aH)-trione
(22)
Diketone 21 (1.87 g, 8.49 mmol, 1.0 equiv) was dissolved in 1,2-dichloroethane (50 mL) in a flask
open to the environment. Chromium trioxide (17.0 g, 169 mmol, 20 equiv) and 3,5-
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dimethylpyrazole (16.2 g, 169 mmol, 20 equiv) were added sequentially at 0 °C, and after stirring
at 0 °C for 10 min the mixture was heated to 50 °C. After 20 h, slight starting material remined as
evident by TLC, the mixture was cooled to room temperature and filtered through a silica plug.
The silica was washed with 1:1 hexanes:ethyl acetate and the filtrate concentrated. The resultant
residue was subjected to flash chromatography (1:6 hexanes:ethyl acetate) resulting in triketone
22 (1.54 g) as a yellow solid, which contained minimal inseparable starting material. The mixture
was carried forward without further purification. NOTE: reaction goes to completion on small
scales, portion of product further purified for full characterization. 1H NMR (400 MHz, CDCl3):
δ 6.58 – 6.52 (m, 1H), 2.68 (s, 1H), 2.67 (td, J = 14.4, 6.0 Hz, 1H), 2.40 (dt, J = 14.8, 3.4 Hz, 1H),
2.01 (d, J = 1.6 Hz, 3H), 1.83 – 1.68 (m, 2H), 1.37 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 205.9, 200.1, 197.9, 148.2, 137.2, 68.5, 60.6, 41.1, 36.5, 35.2, 29.7, 24.3,
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23.7, 16.4. mp: 63–66 C. IR: ṽ = 2962, 2933, 2871, 1721, 1666, 1625, 1428, 1375, 1249, 1191,
1178, 1030, 978, 892 cm-1. [a] 20 = +178.9° (c 1.21, CHCl3). HRMS (ESI): calcd for ([M+Na],
D
C14H18NaO3)+ m/z = 257.1148 found 257.1144. Rf = 0.28 (4:1 hexanes:ethyl acetate), UV-active,
yellow spot (p-anisaldehyde).
(4aS,8R,8aS)-8-Hydroxy-2,5,5,8a-tetramethyl-4a,5,6,7,8,8a-hexahydronaphthalene-1,4-dione
(23) Triketone 22 (1.54 g, 6.57 mmol, 1.0 equiv), with slight impurities, was dissolved in a mixture
of methanol (33 mL) and dichloromethane (33 mL) and the solution was cooled to –78°C. Sodium
borohydride (0.25 g, 6.6 mmol, 1.0 equiv) was added and stirred for 1.5 h, before the addition of
a second portion of sodium borohydride (0.25 g, 6.6 mmol, 1.0 equiv). After 1 h, acetone (50 mL)
and water (50 mL) were added to quench excess borohydride and the mixture was warmed to room
temperature. The mixture was diluted with water (50 mL) and extracted with dichloromethane (3
x 50 mL). The combined organic layers were washed with saturated aqueous sodium chloride (25
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mL), dried over magnesium sulfate, and concentrated in vacuo. The crude residue was subjected
to flash chromatography (1:8 hexanes:ethyl acetate) to yield alcohol 23 as a mixture with
remaining starting material (1.31 g) as a yellow solid. This was carried forward without further
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purification. Full characterization has been reported by Švenda and coworkers. The H NMR
spectrum is consistent with that reported in the literature.5 1H NMR (400 MHz, CDCl3): δ 6.50 –
6.48 (m, 1H), 3.98 (br s, 1H), 3.15 (dd, J = 12.0, 4.3 Hz, 1H), 2.35 (d, J = 1.3 Hz, 1H), 1.99 (d, J
= 1.5 Hz, 3H), 1.89 (dq, J = 13.4, 3.9 Hz, 1H), 1.77 (qd, J = 13.4, 3.5 Hz, 1H), 1.53 (dt, J = 13.7,
3.6 Hz, 1H), 1.46 (s, 3H), 1.48 – 1.39 (m, 1H), 0.96 (s, 3H), 0.72 (s, 3H).
(4aS,8R,8aS)-8-((Tert-butyldimethylsilyl)oxy)-2,5,5,8a-tetramethyl-4a,5,6,7,8,8a-hexahydro-
naphthalene-1,4-dione (3). Prepared according to a modification of the procedure outlined by
Švenda and coworkers.5 Alcohol 23 (1.31 g, 5.54 mmol, 1.0 equiv), with slight impurities, was
°
dissolved in dichloromethane (28 mL) and the solution was cooled to –78 C. 2,6-lutidine (0.97
mL, 8.3 mmol, 1.5 equiv) and tert-butyldimethylsilyl trifluoromethanesulfonate (1.27 mL, 5.54
°
mmol, 1.0 equiv.) were added sequentially. After 1 h of stirring at –78 C, additional tert-
butyldimethylsilyl trifluoromethanesulfonate (0.25 mL, 1.1 mmol, 0.2 equiv) was added. After
stirring for an additional 20 min, saturated aqueous sodium bicarbonate (30 mL) was added and
the reaction mixture was warmed to room temperature. The mixture was extracted with
dichloromethane (3 x 30 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude
residue was purified via flash chromatography in (20:1 → 8:1 hexanes:ethyl acetate) to yield 3
(1.70 g, 4.85 mmol, 57% over three steps) as a yellow solid. Full characterization has been reported
by Švenda and coworkers. The 1H NMR spectrum is consistent with that reported in the literature.5
1H NMR (400 MHz, CDCl3): δ 6.39 – 6.38 (m, 1H), 3.23 (dd, J = 11.8, 3.8 Hz, 1H), 2.29 (d, J =
1.4 Hz, 1H), 2.08 – 1.96 (m, 1H), 1.96 (d, J = 1.5 Hz, 3H), 1.63 (dq, J = 13.4, 3.7 Hz, 1H), 1.49
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(dt, J = 13.7, 3.6 Hz, 1H), 1.41 (td, J = 13.6, 3.7 Hz, 1H), 1.32 (s, 3H), 0.94 (s, 3H), 0.90 (s, 9H),
0.71 (s, 3H), 0.09 (s, 3H), 0.03 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 200.5, 200.0, 151.7, 135.5,
78.5, 67.7, 51.8, 40.9, 35.3, 30.8, 28.1, 27.0, 26.0, 24.6, 18.2, 16.8, –3.7, –4.8. [a] 20D = +29.5° (c
1.02, CHCl3).
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(4aR,8R,8aS)-8-((Tert-butyldimethylsilyl)oxy)-2,5,5,8a-tetramethyl-4a,5,6,7,8,8a-
hexahydronaphthalene-1,4-dione (24) Prepared according to a modification of the procedure
outlined by Švenda and coworkers, originally by Kienzle and coworkers.6,7 Cis-decalin 3 (10 mg,
28 µmol, 1.0 equiv) was dissolved in toluene (0.3 mL). Aluminum oxide (40.0 mg, 400 wt%) was
added and the heterogeneous mixture was heated to reflux at 100 °C and that temperature was held
for 24 h. The reaction mixture was cooled and filtered through a silica plug to remove solid
aluminum oxide. The silica plug was flushed with ethyl acetate. The filtrate was concentrated in
vacuo. The resultant crude product was purified via flash chromatography in (20:1 hexanes:ethyl
1
acetate) to yield trans-decalin 24 (7.8 mg, 22 µmol, 80%) as a white solid. H NMR (400 MHz,
CDCl3) δ 6.48 (m, 1H), 4.30 (m, 1H), 3.30 (s, 1H), 1.88 (d, J = 1.5 Hz, 3H), 1.86 – 1.66 (m, 2H),
1.59 – 1.49 (m, 1H), 1.24 (s, 3H), 1.14 (s, 6H), 1.10 (dt, J = 13.0, 3.1 Hz, 1H), 0.82 (s, 9H), 0.10
(s, 3H), 0.80 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 202.5, 201.2, 144.8, 138.7, 70.6, 55.9, 55.6,
35.1, 32.8, 32.4, 25.9, 24.9, 22.3, 21.3, 18.2, 15.9, –4.2, –5.1. mp: 43–44 °C. IR: ṽ = 2936, 2928,
2854, 1683, 1469, 1377, 1251, 1084, 836 cm-1. [a] 20 = –108.4° (c 1.02, CHCl3). HRMS (EI):
D
calcd for ([M-CH3], C19H31O3Si)+ m/z = 335.2037 found 335.2038. Rf = 0.61 (8:1 hexanes:ethyl
acetate), UV-active, blue spot (p-anisaldehyde).
ASSOCIATED CONTENT
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Supporting Information The Supporting Information is available free of charge via the Internet
at http://pubs.acs.org.
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1H and 13C NMR spectra for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: rsarpong@berkeley.edu
ORCID
Richmond Sarpong: 0000-0002-0028-6323
Shota Nagasawa: 0000-0002-9207-4423
Present Address
†Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku,
Sendai, 980-8578, Japan
ACKNOWLEDGEMENT
We thank College of Chemistry's NMR facility for resources provided and the staff for their assistance.
Instruments in CoC-NMR are supported in part by NIH S10OD024998 and the Catalysis Facility of
Lawrence Berkeley National Laboratory, which is supported by the Director, Office of Science, of the US
Department of Energy under contract no. DE-AC02-05CH11231.
REFERENCES
(1) Li, G.; Kusari, S.; Spiteller, M., Natural products containing 'decalin' motif in
microorganisms. Nat. Prod. Rep. 2014, 31, 1175–1201.
(2) reviews: a) Hanson, J. R., Diterpenoids of terrestrial origin. Nat. Prod. Rep. 2017, 34, 1233-
1243. b) Fraga, B. M., Natural sesquiterpenoids. Nat. Prod. Rep. 2013, 30, 1226–1264.
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(3) For publications detailing the isolation of the terpenoids in Figure 1, see: a) Qu, J. B.; Zhu,
R. L.; Zhang, Y. L.; Guo, H. F.; Wang, X. N.; Xie, C. F.; Yu, W. T.; Ji, M.; Lou, H. X.,
ent-Kaurane Diterpenoids from the Liverwort Jungermannia atrobrunnea. J. Nat. Prod.
2008, 71, 1418–1422. b) Fotsop, D. F.; Roussi, F.; Le Callonec, C.; Bousserouel, H.;
Litaudon, M.; Gueritte, F., Isolation and characterization of two new drimanes from
Zygogynum baillonii and synthesis of analogues. Tetrahedron 2008, 64, 2192–2197. c)
Waddell, T. G.; Osborne, C. B.; Collison, R.; Levine, M. J.; Cross, M. C.; Silverton, J. V.;
Fales, H. M.; Sokoloski, E. A., Erigerol, a New Labdane Diterpene from Erigeron
Philadelphicus. J. Org. Chem. 1983, 48, 4450–4453. d) Bhat, S. V.; Bajqw, B. S.;
Dornauer, H.; Scusa, N. J. d.; Fehlhaber, H.-W., Structures and stereochemistry of new
labdane diterpenoids from coleus forskohlii briq. Tetrahedron Lett. 1977, 18, 1669–1672.
e) Guo, Z. K.; Yan, T.; Guo, Y.; Song, Y. C.; Jiao, R. H.; Tan, R. X.; Ge, H. M., p-
Terphenyl and Diterpenoid Metabolites from Endophytic Aspergillus sp. YXf3. J. Nat.
Prod. 2012, 75, 15–21.
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(4) a) Kienzle, F.; Stadlwieser, J.; Rank, W.; Schonholzer, P., The Synthesis of the Labdane
Diterpenoid Erigerol and of Analogous Compounds. Helv. Chim. Acta. 1990, 73, 1108–
1139. b) Kienzle, F.; Stadlwieser, J.; Mergelsberg, I., Diels-Alder Reactions with 3-
Cyclopropylideneprop-1-enyl Ethyl Ether as 1,3-Diene. Helv. Chim. Acta. 1989, 72, 348–
352.
(5) Hylse, O.; Maier, L.; Kucera, R.; Perecko, T.; Svobodova, A.; Kubala, L.; Paruch, K.;
Svenda, J., A Concise Synthesis of Forskolin. Angew. Chem. Int. Ed. 2017, 56, 12586–
12589.
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(6) Bold, G.; Chao, S.; Bhide, R.; Wu, S. H.; Patel, D. V.; Sih, C. J.; Chidester, C., A Chiral
Bicyclic Intermediate for the Synthesis of Forskolin. Tetrahedron Lett. 1987, 28, 1973–
1976.
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TOC graphic
O
TBSO
O
O
Me
H
Me
Me
8 steps
Me Me
Me
carvone
• Versatile intermediate for
wide variety of terpenoid synthesis
• Both enantiomer can be available
widely available
chiral building block
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