Ready access to functionally embellished cis -hydrindanes and cis -decalins: Protecting group-free total syntheses of (±)-nootkatone and (±)-Noreremophilane

Article abstract of DOI:10.1021/jo401033j

A simple and efficient synthesis of functionalized cis-hydrindanes and cis-decalins was achieved using a sequential Diels-Alder/aldol approach in a highly diastereoselective manner. The scope of this method was tested with a variety of substrates and was successfully applied to the synthesis of two natural products in racemic form. The highlights of the present work provide ready access to 13 new cis-hydrindanes/cis-decalins, a protecting group-free total synthesis of an insect repellent Nootkatone, and the first synthesis of a Noreremophilane using the shortest sequence.

Full text of DOI:10.1021/jo401033j

Note
pubs.acs.org/joc
Ready Access to Functionally Embellished cis-Hydrindanes and cis-
Decalins: Protecting Group-Free Total Syntheses of ( )-Nootkatone
and ( )-Noreremophilane†
Kishor L. Handore, B. Seetharamsingh, and D. Srinivasa Reddy*
CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411008, India
S
* Supporting Information
ABSTRACT: A simple and efficient synthesis of function-
alized cis-hydrindanes and cis-decalins was achieved using a
sequential Diels−Alder/aldol approach in a highly diaster-
eoselective manner. The scope of this method was tested with
a variety of substrates and was successfully applied to the
synthesis of two natural products in racemic form. The
highlights of the present work provide ready access to 13 new cis-hydrindanes/cis-decalins, a protecting group-free total synthesis
of an insect repellent Nootkatone, and the first synthesis of a Noreremophilane using the shortest sequence.
atural products based entirely on the cis-hydrindane/cis-
from tiglic aldehyde by reacting with diene 1 and 2,
Ndecalin skeleton or embodying this system as the core respectively. The diastereomeric ratio was found to be ∼95:5
in both cases. This methodology was successfully applied for
the construction of various cis-hydrindanes/cis-decalins, and the
details are compiled in Scheme 2. The observed diastereo- and
regioselectivity can be explained on the basis of secondary
orbital interactions and atomic coefficient preferences,
respectively.7 Accordingly, the stereochemistry was assigned
to major isomers of all the hydrindanes (3, 5, 7, 9, 11, 13, 15)
and decalins (4, 6, 8, 10, 12, 14, 16), as shown in drawings
(Scheme 2).8 The assigned cis-stereochemistry of the ring
junction in compounds 7, 8, 9, and 10 was further confirmed by
2D-NMR analysis to exclude any possibility of epimerization
before the aldol condensation.8 In the majority of hydrindane
cases, the observed diastereoselectivity was high compared with
that of decalin cases. In the case of hydrindanes 13 and 15, low
diastereoselectivity was observed, which may be explained by
the presence of bulky substitution at α- and β-positions of the
dienophile. It is worth mentioning that all of these compounds
can be subjected to selective functional group transformations
and stereoselective manipulations as they possess chemically
differentiated double bonds present in two different rings and a
rigid framework.
To enhance the utility of this simple method, we have taken
up the protecting group-free total synthesis of Nootkatone, a
popular natural product for several years. (+)-Nootkatone is a
sesquiterpene first isolated from the heartwood of Alaskan
yellow cedar (Chamaecyparis nootkatensis) and was later found
in trace amounts in grapefruit (Citrus paradise), pummelo
(Citrus grandis), and vetiver oil (Vetiveria zizanioides).9 In
addition to its applications in the flavor and fragrance fields,
(+)-Nootkatone possesses very impressive insect repellent and/
or insecticidal activity against various ticks, mosquitos, termites,
unit in their gross structures are frequently encountered in the
literature. Many of these compounds exhibit interesting
biological activities and are endowed with various function-
alities and stereochemical patterns. All of these features aroused
considerable interest in the synthetic community (Figure 1).1
Along these lines, one of us (D.S.R.) recorded a simple method
to access the cis-hydrindane skeleton using a Diels−Alder/aldol
sequence in a highly diastereoselective manner and applied it to
the synthesis of bakkenolide A in the year 2004.2 Later, it was
used for the synthesis of other natural products.3 Here, we
would like to report a fresh extension of this work to access
several new cis-hydrindanes/cis-decalins and a short synthesis of
two natural products starting from readily accessible materials.
Retrosynthetically, natural products based on the cis-
hydrindane/cis-decalin skeleton could be constructed from
the key intermediates, such as cis-hydrindane (A) or cis-decalin
(B), which possess chemically differentiated double bonds. The
intermediates A and B could be prepared by reacting
appropriate dienophiles C with dienes 1 and 2, respectively,
using a previously developed Diels−Alder/aldol sequence,
(Scheme 1). The starting components 1, 2, and C are
commercially available or can be prepared using known
literature procedures.
Our fresh exploration began with a BF3·Et2O mediated
intermolecular Diels−Alder reaction4 between diene 12 and 2.5
equiv of dienophile methacrolein. Although the reaction works
well with MeAlCl2, we preferred using BF3·Et2O because of
availability and safety. The crude Diels−Alder adduct was
subjected to an intramolecular aldol condensation reaction with
15% aq KOH in MeOH to furnish cis-hydrindane 3 in a highly
diastereoselective fashion (dr ∼ 98:2) with a moderate yield of
53%. Similarly, cis-decalin 4 was prepared by the reaction
between 25 and methacrolein in 50% yield with a dr ∼ 98:2
ratio.6 The cis-hydrindane 5 and cis-decalin 6 were prepared
Received: May 11, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401033j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 2
Figure 1. Structures of selected natural products based on the cis-
hydrindane/cis-decalin motif and a previous approach to the synthesis
of bakkenolide A from our group.
Scheme 1
made us take up the synthesis of this interesting molecule. In
this context, it is worth highlighting that the recent synthesis of
(+)-Nootkatone from Laine’s group starting from pinene is
capable of meeting industrial needs.14 A short synthesis of
( )-Nootkatone is reported here using a novel route.
Ultimately, our goal in this project is to generate a focused
library of compounds around the Nootkatone scaffold toward
identifying improved and safe candidates of AMPK modulators
and insect repellents/insecticides.
The cis-decalin 6 prepared using the present methodology
was utilized for the construction of ( )-Nootkatone. The
enone double bond present in 6 was chemoselectively reduced
using Na/liq. NH3 conditions to give an ∼1:1 mixture of
diastereomers, which, on exposure to K2CO3 in MeOH,
furnished the single diastereomer 17 in 73% isolated yield.
Allylic oxidation of 17 using the Chandrasekharan protocol15
bed bugs, etc.10 The mechanism of action of Nootkatone is
believed to be by blocking the octopamine receptor, a
neurotransmitter found in insects.11 As humans do not have
these receptors, compounds like Nootkatone are safe for
human beings. Recently, it was found that Nootkatone acts as
an AMP activated protein kinase (AMPK) activator, a serine/
threonine kinase that is implicated in the control of energy
metabolism and is considered to be a molecular target for the
treatment of metabolic syndrome. Nootkatone induced the
phosphorylation of AMPK and the downstream target acetyl-
CoA carboxylase (ACC), and enhanced AMPK activities in
vitro and in vivo.12 Although several syntheses of Nootkatone
were documented in the literature,13,14 the recent findings
B
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The Journal of Organic Chemistry
Note
(tBuOOH, PDC) produced the compound 18 as a major
product with an enone moiety in the right place as that of the
target molecule. In addition to the desired compound 18, an
undesired enone 19 was also isolated as a minor product (10%
with respect to 18).16 Although, compound 19 is not the
required intermediate in Nootkatone synthesis, the motif is
present in related natural products. In addition, it can be used
for the preparation of potential Nootkatone analogues. Both
the compounds 18 and 19 were cleanly separated using silica
gel column chromatography as they are well-separated on a tlc
plate. Compound 18 on single carbon Wittig olefination
furnished the target compound ( )-Nootkatone 20 in 65%
yield (Scheme 3). All the spectral data (IR, 1H and 13C NMR)
aldol sequence. The synthesized hydrindanes and decalins
loaded with orthogonal functional groups can serve as key
intermediates in the synthesis of complex molecules.
Considering the renewed interest in Nootkatone, we have
synthesized the same in the shortest route using the modern
concept of “protecting group-free total synthesis”. In addition,
we have accomplished the first total synthesis of a
Noreremophilane, which confirmed the previously assigned
structure based on NMR. All the compounds disclosed in this
letter can serve as potential Nootkatone analogues. Our next
focus on this project will be a systematic understanding of
structure activity relationships (SARs) with respect to mosquito
repellent activity and AMPK activity of these compounds. The
results will be the subject of a full article from this group.
Scheme 3
EXPERIMENTAL SECTION
■
General. All reactions were carried out in oven-dried glassware
under a positive pressure of argon or nitrogen, unless otherwise
mentioned, with magnetic stirring. Air-sensitive reagents and solutions
were transferred via syringe or cannula and were introduced to the
apparatus via rubber septa. All reagents, starting materials, and solvents
were obtained from commercial suppliers and used as such without
further purification. Reactions were monitored by thin-layer
chromatography (TLC) with 0.25 mm precoated silica gel plates
(60 F254). Visualization was accomplished either with UV light or by
immersion in an ethanolic solution of phosphomolybdic acid (PMA),
para-anisaldehyde, 2,4-DNP, KMnO4, Ninhydrin solution, or iodine
adsorbed on silica gel, followed by heating with a heat gun for ∼15 s.
Column chromatography was performed on silica gel (100−200 or
230−400 mesh size). Deuterated solvents for NMR spectroscopic
analyses were used as received. The aldehydes (E)-2-methylpent-2-
enal and (E)-2-ethylhex-2-enal used in the present work were prepared
from the known literature procedure (see: Abate, A.; Brenna, E.;
Fregosi, G. Tetrahedron: Asymmetry 2005, 16, 1997). All 1H NMR and
13C NMR spectra were obtained using a 400 or 500 MHz
spectrometer. Coupling constants were measured in Hertz. All
chemical shifts were quoted in parts per million, relative to TMS,
using the residual solvent peak as a reference standard. The following
abbreviations were used to explain the multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, b = broad. HRMS (ESI)
were recorded on on ORBITRAP mass analyzer (QExactive). Mass
spectra were measured with ESI ionization in an MSQ LCMS mass
spectrometer. Infrared (IR) spectra were recorded on a FT-IR
spectrometer as a thin film. Chemical nomenclature was generated
using Chem Bio Draw Ultra 13.0.
are found to be identical to those reported in the literature.14
Thus, we have achieved the protecting group-free total
synthesis of ( )-Nootkatone 20 in just five steps.
To increase the utility of the developed method further, the
first synthesis of a ( )-Noreremophilane 2117 sesquiterpene
isolated from the roots of Ligularia macrophylla and Ligularia
virgaurea was accomplished starting from hydrindane inter-
mediate 5 through exclusive chemoselective reduction of the
isolated double bond using Wilkinson’s catalyst in 82% yield
(E/Z)-Nona-6,8-dien-2-one (2). A stream of ozone was bubbled
through a solution of 1-methylcyclopentene (5.0 g, 60.8 mmol) in
CH2Cl2 (300 mL) at −78 °C until the solution turned into a pale blue
color. Triphenylphosphine (16.6 g, 63.3 mmol) was added
portionwise, allowed to warm room temperature, and stirred for 10
h. The solution was concentrated in vacuo. Purification by flash
chromatography over silica gel (3:7; EtOAc−hexane) afforded the
ketoaldehyde as a colorless oil (5.4 g, 78% yield).
(Scheme 4).18 All the spectral data (IR, H and 13C NMR)
1
Scheme 4
To a solution of allyltriphenylphosphonium bromide (19.9 g. 52.1
mmol) in THF (80 mL) was added n-BuLi (26 mL, 52.1 mmol)
dropwise at −78 °C. The reaction mixture was stirred at −78 °C for 30
min and then was added to the above ketoaldehyde (5.4 g, 47.36
mmol) in THF (50 mL) dropwise at the same temperature. After
completion of the starting material by TLC, the reaction was quenched
by adding saturated NH4Cl (30 mL) and extracted with diethyl ether
(2 × 50 mL). The combined organic layer was washed with brine (50
mL) and dried over anhydrous Na2SO4. Purification by flash
chromatography over silica gel (0.5:9.5; EtOAc−hexane) afforded
compound 2 (4.8 g, 73%, ∼1:1 E,Z mixture) as a colorless oil.
IRυmax(film) 1715, 1648, 1365, 1005 cm−1; 1H NMR (400 MHz,
CDCl3) δ 6.61−6.55 (m, 1 H), 6.31−6.24 (m, 1 H), 6.06−5.99 (m, 2
H), 5.66−5.60 (m, 1 H), 5.41−5.36 (m, 1 H), 5.19−4.94 (m, 4 H),
2.43−2.39 (m, 4 H), 2.20−2.16 (m, 2 H), 2.11 (s, 6 H), 2.08−2.05
were found to be identical to those reported in the literature,
which further confirmed the previously assigned structure.17
Noreremophilane-related compounds are reported to have
antibacterial and cytotoxicity activities.
In summary, we have developed a facile and simple method
for the practical preparation of cis-decalins and cis-hydrindanes
in a highly diastereoselective manner using the Diels−Alder/
C
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The Journal of Organic Chemistry
Note
(m, 2 H), 1.77−1.64 (m, 4 H); 13C NMR (100 MHz, CDCl3) δ 208.9
(2C), 137.1, 134.2, 132.1, 131.9, 131.6, 130.2, 117.4, 115.3, 42.9, 42.8,
31.8, 30.0 (2C), 26.9, 23.5, 23.2.
1-((3aS*,4R*,7aR*)-4-Methyl-3a,4,5,7a-tetrahydro-1H-inden-
1
2-yl)ethan-1-one (7). IRυmax(film) 2962, 1669,1461 cm−1; H NMR
(500 MHz, CDCl3) δ 6.82 (d, J = 3.2 Hz, 1 H), 5.71−5.67 (m, 2 H),
2.81−2.72 (m, 2 H), 2.51−2.49 (m, 1 H), 2.30 (s, 3 H), 2.25−2.20
(m, 1 H), 2.06−2.01 (m, 1 H), 1.71−1.66 (m, 1 H), 1.59−1.53 (m, 1
H), 1.02 (d, J = 6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 197.2,
147.5, 145.2, 129.3, 126.1, 51.6, 38.1, 36.5, 32.5, 31.0, 26.6, 19.7;
HRMS (ESI) calcd for C12H17O [M + H]+ 177.1274, found 177.1274.
1-((4aR*,8R*,8aS*)-8-Methyl-3,4,4a,7,8,8a-hexahydronaph-
thalen-2-yl)ethan-1-one (8). IRυmax(film) 2962, 1667, 1461, cm−1;
1H NMR (500 MHz, CDCl3) δ 6.88 (d, J = 3.6 Hz, 1 H), 5.64−5.52
1-((3aS*,7aR*)-3a-Methyl-3a,4,5,7a-tetrahydro-1H-inden-2-
yl)ethan-1-one (3). To a solution of diene 1 (200 mg, 1.61 mmol)
and methacrolein (0.34 mL, 4.03 mmol) in dry CH2Cl2 (10 mL) was
added BF3·OEt2 (0.39 mL, 3.22 mmol) dropwise at −78 °C. The
mixture was allowed to warm to room temperature and was stirred for
8 h at the same temperature. The reaction mixture was diluted with
CH2Cl2 and washed with saturated aqueous NaHCO3 (3 × 5.0 mL),
followed by H2O (10 mL) and brine (10 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. The crude material obtained after
the removal of solvent was dissolved in methanol (5.0 mL), cooled to
0 °C, and treated with 15% aqueous KOH (5.0 mL). After stirring for
1 h at room temperature, the reaction mass was diluted with petroleum
ether (30 mL), washed with water (10 mL), 1 N HCl (10 mL), and
brine (10 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo. Purification by flash chromatography over silica gel (0.5:9.5;
EtOAc−petroleum ether) afforded dienone 3 (150 mg, 53%) as a light
yellow oil. IRυmax(film) 1663, 1637, 1216, cm−1; 1H NMR (400 MHz,
CDCl3) δ 6.49 (s, 1 H), 5.73−5.61 (m, 2 H), 2.87−2.81 (m, 1 H),
2.35−2.32 (m, 1 H), 2.29 (s, 3 H), 2.27−2.21 (m, 1 H), 2.01−1.97
(m, 2 H), 1.54−1.51 (m, 2 H), 1.11 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 197.6, 153.1, 143.2, 129.8, 126.0, 47.2, 44.4, 36.6, 30.7, 26.5,
(m, 2 H), 2.35−2.27 (m, 1 H), 2.29 (s, 3 H), 2.26−2.20 (m, 2 H),
2.14−2.06 (m, 2 H), 1.77−1.68 (m, 3 H), 1.47−1.41 (m, 1 H), 1.09
(d, J = 6.3 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 199.5, 143.7,
139.8, 130.3, 126.3, 41.2, 33.0, 32.8, 31.1, 26.3, 25.5, 22.6, 19.3; HRMS
(ESI) calcd for C13H19O [M + H]+ 191.1430, found 191.1431
1-((3aS*,4R*,7aR*)-4-Ethyl-3a,4,5,7a-tetrahydro-1H-inden-2-
1
yl)ethan-1-one (9). IRυmax(film) 2962, 1669, 1461, 1373 cm−1; H
NMR (500 MHz, CDCl3) δ 6.80 (d, J = 3.3 Hz, 1 H), 5.69−5.65 (m, 2
H), 2.78−2.72 (m, 2 H), 2.63−2.63 (m, 1 H), 2.30 (s, 3 H), 2.27−2.23
(m, 1 H), 2.15−2.09 (m, 1 H), 1.76−1.64 (m, 1 H), 1.59−1.54 (m, 1
H), 1.47−1.42 (m, 1 H), 1.29−1.26 (m, 1 H), 0.91 (t, J = 7.2 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 197.2, 147.9, 145.1, 129.4, 125.9,
49.7, 37.8, 37.2, 36.5, 28.5, 26.6, 26.4, 11.5; HRMS (ESI) calcd for
C13H19O [M + H]+ 191.1430, found 191.1430.
+
24.6, 22.0; HRMS (ESI) calcd for C12H17O [M + H] 177.1274,
1-((4aR*,8R*,8aS*)-8-Ethyl-3,4,4a,7,8,8a-hexahydronaphtha-
len-2-yl)ethan-1-one (10). IRυmax(film) 2962, 1667, 1461, 1373
cm−1; 1H NMR (500 MHz, CDCl3) δ 6.80 (d, J = 3.7 Hz, 1 H), 5.64−
5.44 (m, 2 H), 2.38−2.35 (m, 1 H), 2.29−2.28 (m, 1 H), 2.27 (s, 3 H),
2.26−2.15 (m, 2 H), 2.13−2.05 (m, 1 H), 1.78−1.72 (m, 1 H), 1.67−
1.52 (m, 4 H), 1.41−1.33 (m, 1 H), 0.94 (t, J = 7.2 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ 199.5, 144.3, 139.8, 129.9, 126.4, 39.1,
38.0, 31.9, 28.7, 26.3, 25.6, 25.5, 21.8, 11.7; HRMS (ESI) calcd for
C14H21O [M + H]+ 205.1587, found 205.1586.
found 177.1274.
Compounds 5, 7, 9, 11, 13, and 15 were prepared using the similar
experimental procedure as described above.
1-((4aR*,8aS*)-8a-Methyl-3,4,4a,7,8,8a-hexahydronaphtha-
len-2-yl)ethan-1-one (4). To a solution of diene 2 (200 mg, 1.44
mmol) and methacrolein (0.30 mL, 3.62 mmol) in dry CH2Cl2 (10
mL) was added BF3·OEt2 (0.35 mL, 2.89 mmol) dropwise at −78 °C.
The mixture was allowed to warm to room temperature and was
stirred for 8 h at room temperature. The reaction mixture was diluted
with CH2Cl2 and washed with saturated aqueous NaHCO3 (3 × 5.0
mL), followed by H2O (10 mL) and brine (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Crude material
obtained after the removal of solvent was dissolved in methanol (5.0
mL), cooled to 0 °C, and treated with 15% aqueous KOH (5.0 mL).
After stirring for 4 h at room temperature, the reaction mass was
diluted with petroleum ether (30 mL), washed with water (10 mL), 1
N HCl (10 mL), and brine (10 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo. Purification by flash chromatography over
silica gel (0.5:9.5; EtOAc−petroleum ether) afforded dienone 4 (137
mg, 50%) as a light yellow oil. IRυmax (film) 1669, 1640, 1452, 1236
cm−1; 1H NMR (400 MHz, CDCl3) δ 6.44 (s, 1 H), 5.69−5.64 (m, 1
H), 5.49−5.45 (m, 1 H), 2.29 (s, 3 H), 2.26−2.20 (m, 1 H), 2.16−2.10
(m, 1 H), 2.02−1.96 (m, 3 H), 1.84−1.79 (m, 1 H), 1.61−1.41 (m, 3
H), 1.10 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.8, 149.0, 138.3,
130.3, 126.7, 39.9, 34.9, 32.6, 26.6, 25.6, 25.4, 22.6, 21.3; HRMS (ESI)
calcd for C13H19O [M + H]+ 191.1430, found 191.1430.
1-((3aS*,7aR*)-3a,4,5,7a-Tetrahydro-1H-inden-2-yl)ethan-1-
1
one (11). IRυmax(film) 2962, 1669, 1461, 1380 cm−1; H NMR (400
MHz, CDCl3) δ 6.75−6.70 (m, 1 H), 5.70−5.53 (m, 2 H), 2.55−2.46
(m, 1 H), 2.30 (s, 3 H), 2.24−2.16 (m, 1 H), 2.06−2.00 (m, 2 H),
1.95−1.86 (m, 1 H), 1.79−1.68 (m, 1 H), 1.56−1.28 (m, 2 H), 13C
NMR (100 MHz, CDCl3) δ 199.6, 145.0, 143.3, 131.2, 127.0, 39.9,
33.3, 28.6, 25.8, 25.4, 22.1; HRMS (ESI) calcd for C11H15O [M + H]+
163.1117, found 163.1117.
1-((4aR*,8aS*)-3,4,4a,7,8,8a-Hexahydronaphthalen-2-yl)-
1
ethan-1-one (12). IRυmax(film) 2962, 1668, 1461 cm−1; H NMR
(400 MHz, CDCl3) δ 6.75−6.71 (m, 1 H), 5.73−5.56 (m, 2 H), 2.52−
2.46 (m, 1 H), 2.38−2.31 (m, 1 H), 2.30 (s, 3 H), 2.24−2.18 (m, 1 H),
2.14−2.08 (m, 1 H), 2.06−2.01 (m, 1 H), 1.93−1.89 (m, 1 H), 1.81−
1.70 (m, 1 H), 1.53−1.27 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ
199.8, 145.2, 139.6, 131.5, 127.3, 40.1, 33.5, 28.6, 26.0, 25.6, 24.5, 22.3;
HRMS (ESI) calcd for C12H17O [M + H]+ 177.1274, found 177.1273.
1-((3aS*,4R*,7aR*)-4-Ethyl-3a-methyl-3a,4,5,7a-tetrahydro-
1H-inden-2-yl)ethan-1-one (13). IRυmax(film) 2962, 1669,
1
1461,cm−1; H NMR (400 MHz, CDCl3) δ 6.73 (s, 1 H), 5.72−
Compounds 6, 8, 10, 12, 14 and 16 were prepared using the similar
experimental procedure as described above.
5.65 (m, 2 H), 2.82−2.78 (m, 1 H), 2.30 (s, 3 H), 2.25−2.13 (m, 2 H),
1.67−1.60 (m, 2 H), 1.49−1.35 (m, 2 H), 1.26−1.23 (m, 1 H), 1.00
(s, 3 H), 0.90 (t, J = 7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ
197.6, 153.6, 143.3, 128.2, 125.8, 49.9, 47.6, 40.6, 36.7, 27.2, 26.6, 23.3,
18.7, 12.8; HRMS (ESI) calcd for C14H21O [M + H]+ 205.1587, found
205.1587.
1-((3aS*,4R*,7aR*)-3a,4-Dimethyl-3a,4,5,7a-tetrahydro-1H-
inden-2-yl)ethan-1-one (5). IRυmax(film) 1669, 1637, 1452, 1237
cm−1; 1H NMR (500 MHz, CDCl3) δ 6.68 (s, 1 H), 5.67−5.66 (m, 2
H), 2.78 (dd, J = 15.5, 8.2 Hz, 1 H), 2.33−2.30 (m, 1 H), 2.28 (s, 3
H), 2.24−2.17 (m, 1 H), 1.96−1.89 (m, 1 H), 1.79−1.61 (m, 2 H),
0.98 (s, 3 H), 0.91 (d, J = 6.4 Hz, 3 H); 13C NMR (125 MHz, CDCl3)
δ 197.5, 153.4, 143.3, 128.4, 125.9, 49.8, 46.9, 36.6, 33.2, 30.6, 26.5,
18.1, 15.9.
1-((4aR*,8R*,8aS*)-8-Ethyl-8a-methyl-3,4,4a,7,8,8a-hexahy-
dronaphthalen-2-yl)ethan-1-one (14). IRυmax(film) 2962, 1669,
1
1233 cm−1; H NMR (400 MHz, CDCl3) δ 6.69 (s, 1 H), 5.63−5.50
1-((4aR*,8R*,8aS*)-8,8a-Dimethyl-3,4,4a,7,8,8a-hexahydro-
(m, 2 H), 2.36−2.32 (m, 1 H), 2.29 (s, 3 H), 2.19−2.04 (m, 2 H),
1.87−1.84 (m, 1 H), 1.81−1.68 (m, 2 H), 1.63−1.58 (m, 1 H), 1.51−
1.39 (m, 2 H), 1.22−1.16 (m, 1 H), 1.0 (s, 3 H), 0.90 (t, J = 7.32 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ 199.9, 149.6, 137.6, 130.2, 125.4,
41.4, 40.9, 37.6, 27.6, 25.6, 25.5, 22.6, 21.5, 21.4, 12.8; HRMS (ESI)
calcd for C15H23O [M + H]+ 219.1743, found 219.1743.
naphthalen-2-yl)ethanone (6). IRυmax(film) 1665, 1637, 1452,
1
1237 cm−1; H NMR (500 MHz, CDCl3) δ 6.64 (s, 1 H), 5.60−5.56
(m, 1 H), 5.53−5.48 (m, 1 H), 2.28 (s, 3 H), 2.12−2.00 (m, 2 H),
1.93−1.88 (m, 2 H), 1.90−1.63 (m, 3 H), 1.43 (ddd, J = 18.9, 9.15,
5.49 Hz, 1 H), 1.00 (s, 3 H), 0.96 (d, J = 6.4 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 198.0, 149.3, 137.8, 130.1, 125.5, 40.4, 37.3, 34.2,
31.6, 25.6, 25.5, 22.6, 21.1, 15.1; HRMS (ESI) calcd for C14H21O [M +
H]+ 205.1587, found 205.1586.
1-((3aS*,4R*,7aR*)-3a-Ethyl-4-propyl-3a,4,5,7a-tetrahydro-
1H-inden-2-yl)ethan-1-one (15). IRυmax(film) 2962, 1667, 1461
cm−1; 1H NMR (400 MHz, CDCl3) δ 6.74 (s, 1 H), 5.68−5.67 (m, 2
D
dx.doi.org/10.1021/jo401033j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
H), 2.88−2.75 (m, 1 H), 2.60−2.52 (m, 1 H), 2.31 (s, 3 H), 2.26−2.17
(m, 1 H), 2.12−2.04 (m, 1 H), 1.80−1.62 (m, 2 H), 1.42−1.38 (m, 1
H), 1.38−1.23 (m, 3 H), 0.93−0.85 (m, 5 H), 0.77 (t, J = 7.32 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ 197.3, 152.8, 149.1, 131.5, 125.5,
55.5, 41.2, 36.5, 32.3, 28.2, 27.3, 26.6, 21.1, 14.5, 9.2, 8.9; HRMS (ESI)
calcd for C16H25O [M + H]+ 233.1900, found 233.1899.
mg, 0.40 mmol) in dry THF (5.0 mL) was added potassium tert-
butoxide (40 mg, 0.34 mmol) at 0 °C. After 5 min, the solution
became canary yellow color, and to that, diketone compound 18 (30
mg, 0.136 mmol) in THF (5.0 mL) was added and allowed to stirred
at 0 °C for 1 h. The reaction was quenched with H2O (5.0 mL) and
extracted with ether (2 × 25 mL). The combined organic layer was
washed with water (5.0 mL) and brine (5.0 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification by flash chromatog-
raphy over silica gel (1:9; EtOAc−hexanes) afforded ( )-Nootkatone
1-((4aR*,8R*,8aS*)-8a-Ethyl-8-propyl-3,4,4a,7,8,8a-hexahy-
dronaphthalen-2-yl)ethan-1-one (16). IRυmax(film) 2962, 1669,
1
1461 cm−1; H NMR (400 MHz, CDCl3) δ 6.71 (s, 1 H), 5.61−5.47
1
(m, 2 H), 2.34−2.33 (m, 1 H), 2.30 (s, 3 H), 2.16−2.13 (m, 1 H), 2.09
−2.04 (m, 3 H), 1.83−1.78 (m, 1 H), 1.74−1.71 (m, 1 H), 1.60−1.49
(m, 2 H), 1.47−1.41 (m, 2 H), 1.21−1.16 (m, 1 H), 0.96−0.85 (m, 5
H), 0.76 (t, J = 7.3 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.6,
148.9, 139.3, 130.2, 125.7, 43.9, 40.6, 38.2, 36.3, 30.6, 27.6, 25.6, 25.5,
21.4, 14.6, 8.3 (2C) ; HRMS (ESI) calcd for C17H27O [M + H]+
247.2056, found 247.2054.
20 (19 mg, 65%). IRυmax(film) 2923, 1668, 1606, 1459 cm−1; H
NMR (400 MHz, CDCl3) δ 5.77 (s, 1 H), 4.74 (s, 1 H), 4.72(s, 1 H),
2.50 (ddt, J = 15.3, 5.0, 1.8 Hz, 1 H), 2.40−2.24 (m, 4 H), 2.04−1.89
(m, 3 H),1.74 (s, 3 H), 1.40−1.29 (m, 2 H), 1.11 (s, 3 H), 0.96 (d, J =
6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 199.9, 170.7, 149.3,
124.8, 109.4, 44.0, 42.2, 40.6, 40.5, 39.5, 33.2, 31.7, 21.0, 17.0, 15.0.
1-((3aS*,4R*,7aS*)-3a,4-Dimethyl-3a,4,5,6,7,7a-hexahydro-
1H-inden-2-yl)ethan-1-one (( )-Noreremophilane 21). The
compound 5 (30 mg, 0.16 mmol) and Wilkinson’s catalyst
[(PPh3)3RhCl] (29 mg, 0.03 mmol) were placed in an oven-dried
round-bottom flask. Dry benzene (5.0 mL) was added via syringe, the
flask was then flushed with hydrogen gas to expel the argon. The
reaction was allowed to proceed at room temperature under hydrogen
balloon pressure for 12 h. Upon completion of reaction (monitored by
TLC), the mixture was passed through an alumina column and
concentrated. Purification by flash chromatography over silica gel
(0.5:9.5; EtOAc−petroleum ether) afforded ( )-Noreremophilane 21
(25 mg, 82% yield) as a colorless liquid. IRυmax(film) 1668, 1606, 1367
1-((2R*,4aR*,8R*,8aS*)-8,8a-Dimethyl-1,2,3,4,4a,7,8,8a-octa-
hydronaphthalen-2-yl)ethan-1-one (17). A solution of α,β-
unsaturated ketone 6 (0.5 g, 2.45 mmol) in THF (20 mL) was
added to liquid ammonia (20 mL) at −78 °C. Sodium (0.67 g, 29.4
mmol) was added in small pieces, and the reaction mixture was stirred
at −78 °C for 1 h. After consumption of starting material (by TLC),
solid NH4Cl (1.0 g) was added and ammonia was allowed to evaporate
at room temperature. Water (10 mL) was added, and the reaction
mixture was extracted with EtOAc (3 × 20 mL). The combined
organic layer was washed with brine (20 mL) and dried over Na2SO4,
and the solvent was concentrated to afford the ketone as a 1:1 mixture
of diastereomers. The crude material was treated with K2CO3 (1.35 g,
9.80 mmol) in MeOH (20 mL) and refluxed for 2 h. The solvent was
removed under vacuum, and the crude residue was diluted with water
(10 mL) and extracted with ether (2 × 30 mL). The combined organic
layer was washed with brine (20 mL) and dried over anhydrous
Na2SO4. Purification by flash chromatography over silica gel (0.5:9.5;
EtOAc−hexanes) afforded 17 (368 mg, 73%) as a colorless oil.
1
cm−1; H NMR (400 MHz, C6D6) δ 6.30 (d, J = 2.0 Hz, 1 H), 2.57
(dd, J = 16.1, 8.3 Hz 1 H), 2.43 (ddd, J = 16.1, 11.3, 2.26 Hz, 1 H),
1.97 (s, 3 H), 1.78−1.73 (m, 1 H), 1.44−1.41 (m, 1 H), 1.38−1.35
(m, 1 H), 1.34−1.31 (m, 1 H), 1.22−1.17 (m, 1 H), 1.13−1.11 (m, 1
H), 1.10−1.08 (m, 1 H), 0.86−0.85 (m, 1 H), 0.84 (s, 3 H), 0.67 (d, J
= 6.7 Hz, 3 H); 13C NMR (100 MHz, C6D6) δ 195.6, 153.1, 143.9,
49.6, 46.5, 36.9, 33.6, 29.3, 25.9, 24.4, 22.2, 17.3 (2C). HRMS (ESI)
calcd for C13H21O [M + H]+ 193.1587, found 193.1589.
1
IRυmax(film) 1709, 1453, 1352 cm−1; H NMR (400 MHz, CDCl3) δ
5.59−5.48 (m, 2 H), 2.46−2.40 (m, 1 H), 2.13 (s, 3 H), 2.02−1.97
(m, 2 H), 1.88−1.84 (m, 1 H), 1.78−1.72 (m, 2 H), 1.63−1.53 (m, 1
H), 1.34−1.23 (m, 2 H), 1.06−1.00 (m, 2 H), 0.83−0.81 (m, 6 H);
13C NMR (100 MHz, CDCl3) δ 212.5, 131.1, 125.2, 46.4, 44.1, 38.2,
ASSOCIATED CONTENT
* Supporting Information
Copies of NMR spectra of all new compounds and 2D NMR
spectra of compounds 7, 8, 9, and 10. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
34.6, 32.6, 29.9, 28.7, 28.1, 27.2, 21.6, 14.6; HRMS (ESI) calcd for
C14H23O [M + H]+ 207.1743, found 207.1743.
(4R*,4aS*,6R*)-6-Acetyl-4,4a-dimethyl-4,4a,5,6,7,8-hexahy-
dronaphthalen-2(3H)-one (18). To a solution of the ketone 17
(250 mg, 1.21 mmol) in benzene (20 mL) at 15 °C were added PDC
(3.6 g, 9.70 mmol) and tBuOOH (2.5 mL). After the reaction mixture
stirred for 15 min, it was brought to ambient temperature and further
stirred for 12 h. The reaction mixture was diluted with ether (30 mL),
filtered through a Celite bed, and washed with ethyl acetate (2 × 10
mL).The filtrate was concentrated in vacuo. Purification by flash
chromatography over silica gel (2:8; EtOAc−hexanes) afforded 18
(170 mg, 63%) and 19 (20 mg, 8%) as colorless oils. IRυmax(film)
1708, 1665, 1354 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.77 (s, 1 H),
2.77−2.71(m, 1 H), 2.52−2.38 (m, 2 H), 2.28−2.25 (m, 2 H), 2.19 (s,
3 H), 2.10−2.01 (m, 3 H), 1.49−1.38 (m, 1 H), 1.25−1.21 (m, 1 H),
1.10 (s, 3 H), 0.97 (d, J = 6.7 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 210.7, 199.4, 168.7, 125.3, 48.8, 42.1, 40.3, 40.0, 38.9, 32.1, 28.6,
28.3, 16.8, 15.0.; HRMS (ESI) calcd for C14H21O2 [M + H]+ 221.1536,
found 221.1534.
(1S*,4aR*,7R*,8aR*)-7-Acetyl-1,8a-dimethyl-4a,5,6,7,8,8a-
hexahydronaphthalen-2(1H)-one (19). IRυmax(film) 1708, 1675,
1451, 1354 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.75 (dd, J = 5.7 Hz,
10.0 Hz, 1 H), 5.91 (d, J = 10.3 Hz, 1 H), 2.71 (m, 1 H), 2.46 (tt, J =
12.3 Hz, 2.7 Hz, 1 H), 2.16 (s, 3 H), 2.05−1.97 (m, 2 H), 1.94−1.86
(m, 2 H), 1.50−1.35 (m, 2 H), 1.17−1.08 (m, 1 H), 1.04 (d, J = 6.7
Hz, 3 H), 0.89 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 211.1, 201.6,
150.6, 127.8, 46.5, 45.0, 43.3, 38.8, 38.2, 28.3, 28.0, 27.2, 23.2, 6.7;
HRMS (ESI) calcd for C14H21O2 [M + H]+ 221.1536, found 221.1534.
(4R*,4aS*,6R*)-4,4a-Dimethyl-6-(prop-1-en-2-yl)-
4,4a,5,6,7,8-hexahydronaph thaen-2(3H)-one (( )-Nootkatone
20). To a suspension of methyl triphenylphosphonium bromide (148
AUTHOR INFORMATION
Corresponding Author
*E-mail: ds.reddy@ncl.res.in.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the Ministry of Earth Sciences, MoES, New
Delhi (Drugs from Sea program), and CSIR, New Delhi
(ORGIN program under XII Five Year Plan), for the financial
support and Dr. Roshan R. Kulakarni (NCL-Pune) and Mr.
Srikant M. Kunjir (NCL-Pune) for his help in 2D NMR
analysis. K.L.H. and B.S. thank CSIR for the award of research
fellowships.
DEDICATION
■
†In memory of Prof. A. Srikrishna, IISc, Banglore (1955−
2013), who made significant contributions to the field of
organic chemistry.
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dx.doi.org/10.1021/jo401033j | J. Org. Chem. XXXX, XXX, XXX−XXX