Asymmetric synthesis of dihydroartemisinic acid through intramolecular Stetter reaction

Article abstract of DOI:10.1016/j.tet.2016.06.066

A short and concise formal synthesis of enantiopure dihydroartemisinic acid from (R)-citronellal is described in this article. Intramolecular version of asymmetric Stetter reaction using Rovis aminoindane based NHC catalyst was explored to access the core

Full text of DOI:10.1016/j.tet.2016.06.066

Accepted Manuscript
Asymmetric synthesis of dihydroartemisinic acid through intramolecular Stetter
reaction
Rohan Kalyan Rej, Ranjan Kumar Acharyya, Samik Nanda
PII:
S0040-4020(16)30598-1
10.1016/j.tet.2016.06.066
TET 27880
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 May 2016
Revised Date: 13 June 2016
Accepted Date: 25 June 2016
Please cite this article as: Rej RK, Acharyya RK, Nanda S, Asymmetric synthesis of dihydroartemisinic
acid through intramolecular Stetter reaction, Tetrahedron (2016), doi: 10.1016/j.tet.2016.06.066.
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ACCEPTED MANUSCRIPT
Asymmetric synthesis of dihydroartemisinic acid through
intramolecular Stetter reaction
Rohan Kalyan Rej, Ranjan Kumar Acharyya and Samik Nanda*
Department of Chemistry, Indian Institute of Technology, Kharagpur, 721302, India
H
H
RCM
a) CM
CHO
H
H
b) Stetter
O
H
H
H
HO2C
BnO
BnO
(R)-Citronellal
Dihydroartemisinic acid

ACCEPTED MANUSCRIPT
Asymmetric synthesis of dihydroartemisinic acid through
intramolecular Stetter reaction
Rohan Kalyan Rej, Ranjan Kumar Acharyya and Samik Nanda*
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur, 721302,
snanda@chem.iitkgp.ernet.in
Abstract: A short and concise formal synthesis of enantiopure dihydroartemisinic acid from (R)-
citronellal is described in this article. Intramolecular version of asymmetric Stetter reaction using
Rovis aminoindane based NHC catalyst was explored to access the core substituted
cyclohexanone framework which on functional group manipulation and late stage ring closing
metathesis (RCM) reaction afforded an advanced intermediate for dihydroartemisinic acid.
Introduction
Artemisinin (1), also called qinghaosu is the most promising and significant anti-malarial agent
discovered in the last 50 years.1 Artemisinin, a sesquiterpene lactone (made up of three isoprene
units bound to cyclic organic esters) was distilled from the dried leaves or flower clusters of
2
Artemisia annua. The antipyretic properties of that specific plant were first documented in the
4th century by Chinese physicians, who named the plant qinghao and recommended it as a
natural remedy in the form of qinghao tea. The active ingredient from this plant was isolated in
1970 by Tu Youyou who was awarded the prestigious Nobel Prize in Medicine (2015) for her
excellent work on artemisinin (1) and dihydroartemisinin. Malaria is widely known lethal
infectious disease caused by four protozoan species of the genus Plasmodium (Plasmodium
falciparum, Plasmodium malariae, Plasmodium ovale, and Plasmodium vivax). In the majority
of the cases death of the infected people (malaria kills 1-2 million people each year) are caused
by P. falciparum. According to World Health Organization (WHO), the eradication of malaria
from developing countries is a long-term goal that will depend on the success of sustainable
research effort to deliver a more robust arsenal of tools than those available today. The growing
resistance to existing antimalarial drugs could nullify efforts to eliminate this deadly disease.
Unfortunately, there are still very few drugs available that are active against malaria (artemisinin,
3
atovaquone, and chloroquine analogues) and vaccines against malaria are not yet available.
Artemisinin (1) is effective against all the malaria-causing protozoal organisms of the genus
1

ACCEPTED MANUSCRIPT
Plasmodium. The drug is particularly useful in the treatment of infections involving chloroquine-
4
resistant parasites and infections involving multidrug-resistant P. falciparum, which is the
deadliest of the malaria protozoans. The WHO has recommended artemisinin combination
therapies (ACT) to be the first-line therapy for P. falciparum malaria worldwide.
Dihydroartemisinic acid (2) another natural product isolated from the same species and a
metabolite of artemisinin was also known for several years and structurally much simpler.
Dihydroartemisinic acid was regarded as one of the potential biogenetic precursor for
artemisinin, as researchers shown that spontaneous auto-oxidation of compound 2 yields 1.5 In
addition artemisinin (1) and, dihydroartemisinic acid (2) (Figure 1), can also be useful as
anticancer agents,6 as it disrupts the growth of various types of cancer cells in laboratory
research.
Me
H
Me
H
O
O
O
H
H
H
O
H
Me
Me
HOOC
O
Dihydroartemisinic acid (2)
Artemisinin (1)
Figure 1. Structure of artemisinin (1) and dihydroartemisinic acid (2)
After its disclosure in 1979, artemisinin and dihydroartemisinic acid has been the subject of
7
several elegant syntheses. In pursuit of potentially novel and efficient synthetic strategies for
artemisinin and analogues, we would like to report here a short and stereoselective asymmetric
synthesis of dihydroartemisinic acid (2).
Results and Discussion
We envisioned that a late stage RCM (ring closing metathesis) reaction of a bis-olefinic
precursor (3) might be an alternative option to construct the bicyclic ring of dihydroartemisinic
acid, as it was never attempted before. The bis-olefinic precursor was planned to be accessed by
double Wittig reaction of a properly functionalized cyclohexanone (4), which in turn can be
2

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synthesized from a 1,5-diketosystem (5). The diketo compound was synthesized from a vinyl
silane derivative (6) which was prepared by alkylation of corresponding cyclohexanone (7). The
required cyclohexanone was thought to be synthesized by intramolecular asymmetric Stetter
reaction from an acyclic precursor (8). To the best of our knowledge intramolecular Stetter
reaction and ring closing metathesis (RCM) reaction was never used for the synthesis of
artemisinin and its analogues (Scheme 1).
O
H
H
H
H
double Wittig
Wittig
RCM
O
PgO
O
PgO
H
H
H
H
H
H
PgO
HO2C
4
5
Dihydroartemisinic acid (2)
3
Pg = Protection group
TMS
H
Stetter
CHO
CM
CHO
O
O
PgO
H
H
PgO
EtO2C
8
7
6
Scheme 1. Retrosynthetic analysis of dihydroartemisinic acid
Compound 8 was earlier synthesized in four steps by a reported procedure starting from (R)-
citronellal.8 We have prepared compound 8 from (R)-(+)-citronellal via a Ru-catalyzed E-
selective olefin cross-metathesis (CM) with ethyl methacrylate in 70% yield using G-II catalyst
9
in single step (Scheme 2). With the required α,β-unsaturated ester (8) in our hand, the model
10
version of intramolecular Stetter reaction
was attempted with the thiazolium catalyst in
anhydrous toluene as a solvent as reported by Trost and co-workers for their synthesis of hirsutic
acid.11 To our delight, the reaction proceeded smoothly and furnished compound 9 with overall
good diastereoselectivity (12:1) in favour of the conformationally more favourable diastereomer
(desired one for our synthetic exercise). The minor diastereomer was also separated and well
characterized by standard analytic method (see the ESI for more detail). Inspired by the initial
result, next we switched our attention to the enantioselective version of the same reaction. Thus
when compound 8 was exposed to Rovis’s aminoindane based NHC catalyst (20 mol%) in
presence of KHMDS as a base, the intramolecular Stetter reaction went smoothly and furnished
compound 9 with excellent diastereoselection and enantioselection (ee ≥ 98 %; see the HPLC
3

ACCEPTED MANUSCRIPT
chromatogram in supporting information). The absolute configuration of compound 9 was
assigned based on the known model for similar NHC catalyzed Stetter reaction.10c It has been
speculated that attack from the Si-face of the Breslow intermediate (formed between Rovis NHC
catalyst and R- citronellal) to the more accessible Si-face of the α,β-unsatuarated carbonyl system
yielded the desired stereoisomer (The Re-face of the α,β-unsatuarated carbonyl system seems to
be blocked by the bulky aminoindane moiety of the NHC catalyst, which seems to position itself
just above the double bond of the α,β-unsatuarated carbonyl system through probably a π- π
stacking type of interaction). It was also hypothesized that the transition state for such
intramolecular Stetter reaction which seem to be occur through 6-exo-trig pathway and is
favoured by Baldwin’s rule of cyclization. The transition state is further stabilized by bridged H-
bonding between carbonyl “O” (from CO2Et group) and the –OH moiety of the Breslow
intermediate as predicted by Enders et al and which was later supported by Houk and co-
workers.10e Similarly a π- π stacking type of interaction also was predicted for intermolecular
asymmetric benzoin condensation reaction with NHC. Eventually such π- π stacking type of
interaction might also take place in our case, hence the relative positioning of the aminoindane
framework with the olefinic unsaturation has a predictive role to block one face of the substrate.
In our case we do believe that the Re-face (top face or the β-face of the electrophilic carbon
where the umpolung attacks) of the α,β-unsatuarated carbonyl system seems to be blocked by the
bulky aminoindane moiety of the NHC catalyst and thus making the Si-face (bottom face or α-
face) more accessible for attacking of the nucleophile generated from the Breslow intermediate.
In addition the starting substrate 8, derived from (R)-citronellal has its own conformational bias
and once it reacts with the Rovis-NHC, the generated Breslow intermediate adopts a more
flexible chair like conformational orientation (Scheme 2). The existing stereocenter in substrate
8, seems to not play any predictive role in the final outcome of the reaction due to its remote
location from the reaction center. The intarmolecular asymmetric version of Stetter reaction was
also attempted with ent-8 (prepared from S-citronellal as described in Scheme 2) by using ent-
Rovis aminoindane based NHC catalyst, to afford ent-9 with excellent enantioselection (refer to
ESI for HPLC chromatogram).
Reduction of both the ester and keto functionality of compound 9 was achieved by using LiAlH4
in ether to afford the diol 10, which on selective benzylation of the primary hydroxyl group
forms compound 11 7b in 90% overall yield over two steps (Scheme 2). The crystal structure of
4

ACCEPTED MANUSCRIPT
diol 10 (CCDC-1469107) was presented in Figure 2, which also confirms the relative
stereochemistry of the two newly formed stereocenters in compound 9 after intramolecular
Stetter reaction with Rovis’s aminoindane based NHC catalyst. Dess-Martin periodinane
oxidation of compound 11 afforded the known ketone 7 in 91% yield (Scheme 2). Spectral data
as well as optical rotation value was also in good agreement with the literature value reported by
7b, 7c
Zhou’s group in their respective synthesis of Arteannuin and deoxyarteannuin,
which also
established the absolute configuration of compound 9 obtained after asymmetric intramolecular
Stetter reaction. We have also observed that presence of an “E” olefinic geometry in the parent
α,β-unsaturated ester (8) was essential for overall good yield and stereoselection in the final
product, which was also noticed by Rovis and co-workers for similar intramolecular Stetter
reaction.10
5

ACCEPTED MANUSCRIPT
CHO
f
a
b or c
e
d
CHO
O
HO
HO
HO
O
H
H
H
H
BnO
BnO
EtO2C
Me
F
EtO2C
(R)-citronellal
10
11
8
7
9, dr = 12:1 (ee >98% for Rovis NHC)
F
N
O
H3C
Bn
N
N
Compound 7: [α]D25 = -10.7 (c = 1.3, CHCl3)
Reported Value: [α]D = -10.8 (c = 1.3, CHCl3) 7c
N
F
25
S
HO
F
F
BF4
Thiazolium catalyst
Rovis catalyst
Nu
H
The top face is shielded by the bulky aminoindane group of NHC catalyst,
which positions itself on the top of the π-bond of the unsaturated ester, hence
the bottom face seems to be more accessible. The Si-face of the Breslow
intermediate attacks to the Si face of the unstaurated ester.
CO2Et
Me
Nu
β
Top face ( ) is Re
α
Bottom face ( ) is Si
Ar
Ar
Ar
N
N
Me
N
N
N
N
Me
O
H
N
H-bridge
N
X
N
Y
O
Me
O
Me
EtO2C
OH
O
Me
O
O
H
9
CO2Et
OEt
X = CO2Et; Y = OH
π π
-
stacking
Transition state for
Stetter reaction
major interactions to stabilize the TS
π π
* - stacking interaction with the aminoindane Ph ring and unstauration present at the substrate
* H-bonded bridge between carbonyl oxygen of unsaturated ester with -OH of Breslow intermediate
Scheme 2. Intramolecular asymmetric Stetter reaction; Reagents and conditions: (a) G-II
catalyst, ethylmethacrylate, 70%; (b) Thiazolium Catalyst (20 mol%), KHMDS (20 mol%),
Toluene, 24 h, 85%;(c) Rovis catalyst (20 mol%), KHMDS (20 mol%), Toluene, 24 h, 87%; (d)
LAH, dry ether, 0 °C, 1 h, (e) NaH, dry DMF, BnBr, 0 °C, 3 h, 90% for two steps; (f) DMP,
DCM, 2 h, 91%.
6

ACCEPTED MANUSCRIPT
Figure 2: ORTEP diagram of compound 10 (50% probbality, H-atoms are omitted for clarity)
To install the required α-homoallyl appendage in compound 7, we have relied upon the selective
alkylation which was more challenging than may be apparent at first glance.12 Initial trial with
allyl bromide or allyl iodide resulted in the desired compound with poor yield, whereas 4-iodo-2-
methylbut-1-ene did not yield any desired alkylated product. Finally kinetic enolate formation of
compound 7 was achieved using LDA as base and Et2Zn as additive, and treatment of the
14
resulting enolate with (E)-(3-iodo-l-methyl-1-propenyl)-trimethylsilane (Stork-Jung iodide)
(12) provided the alkylated product 6 in 75% overall yield (Scheme 3) as a sole product. Similar
yield was also obtained on using three equivalent of HMPA instead of diethyl zinc keeping the
other reaction conditions similar. 13 The vinylsilane 6 on treatment with m-CPBA afforded 1,5
diketone compound 5 in one pot in 60% yield over two steps. At first the epoxide was formed,
which upon in-situ Tamao-Fleming oxidation resulted the diketone 5 (Scheme 3). Diketone 5 on
regioselective Wittig olefination with Ph3P+CH3I-, afforded the olefin 4 in 80% yield. The keto-
olefin 4 was then subjected to Wittig reaction15a with methoxymethyltriphenylphosphonium
chloride (MeOCH2Ph3P+Cl-) and KHMDS at room temperature afforded a mixture of enone
15b
ethers which was subjected to hydrolysis with trichloroacetic acid in DCM
to afford the
aldehyde 13 in 60% yield for two steps. Compound 13 was then immediately treated with
Ph3P+CH3I-, to furnish the bis-olefin 3, which on RCM using Grubbs-II metathesis catalyst in dry
dichloromethane furnished the required functionalized bicyclic core of dihydroartemisinic acid,
(14; Scheme 3) in 72% yield.16 The synthesis of dihydroartemisinic acid (2) was reported from
compound 14 by Zhou et al. 7b
7

ACCEPTED MANUSCRIPT
H
H
H
a
b
c
d
Me3Si
O
O
O
O
O
H
H
H
H
BnO
BnO
BnO
BnO
4
7
5
TMS
I
6
12
H
H
H
H
H
H
f
e
Zhou. et.al
OHC
BnO
H
H
H
H
H
BnO
BnO
HOOC
13
3
2
14
Overall yield 6% for 10 steps starting from (R)-citronellal
Scheme 3. Formal synthesis of dihydroartemisinic acid; Reagents and conditions: (a) LDA,
Et2Zn, compound 12, 75%; (b) mCPBA, Dry DCM, 8 h, 60%; (c) Ph3P+CH3I-, LiHMDS, THF, 0
°C, 80%, 4h; (d) i) methoxymethyl triphenylphosphonium chloride, KHMDS, room temperature,
24 h; ii) CCl3CO2H, Dry DCM, 60% (for two steps); (e) Ph3P+CH3I-, LiHMDS, THF, 0 °C, 72%;
(f) G-II, DCM, reflux, 12 h, 72%.
Conclusions
In summary an intramolecular asymmetric version of Stetter reaction using Rovis aminoindane
based NHC catalyst was employed to access the fully functionalized enantiopure cyclohexanone
from an acyclic precursor. Finally substrate directed alkylation and RCM reaction was
successfully exploited to access the required fully functionalized bicyclic core of
dihydroartemisinic acid.
Experimental Section
General. Unless otherwise stated, materials were obtained from commercial suppliers and used
without further purification. THF and diethylether were distilled from sodiumbenzophenone
ketyl. Dichloromethane (CH2Cl2), dimethylformamide (DMF) and dimethylsulfoxide (DMSO)
were distilled from CaH2. Rovis’s aminoindane based NHC catalyst (both the enantiomers) was
purchased from commercial supplier and used as obtained. Reactions were monitored by thin-
8

ACCEPTED MANUSCRIPT
layer chromatography (TLC) carried out on 0.25 mm silica gel plates with UV light, ethanolic
anisaldehyde and phosphomolybdic acid/heat as developing agents. Silicagel 100-200 mesh was
used for column chromatography. Yields refer to chromatographically and spectroscopically
homogeneous materials unless otherwise stated. Proton nuclear magnetic resonance (1H-NMR)
and carbon nuclear magnetic resonance (13C-NMR) spectra were acquired in CDCl3 unless
otherwise mentioned. Chemical shifts are reported in parts per million (ppm, δ), downfield from
tetramethylsilane (TMS, δ = 0.00 ppm), and are referenced to residual solvent [CDCl3, δ = 7.26
ppm (1H), 77.16 ppm (13C)]. Data are presented in the form: chemical shift (multiplicity,
1
coupling constants, and integration). H data are reported as though they were first order. The
errors between the coupling constants for two coupled protons were less than 0.5 Hz, and the
average number was reported. Coupling constants (J) are reported in hertz (Hz) and the
resonance multiplicity abbreviations used are: s, singlet; d, doublet; t, triplet; q, quartet; dt,
doublet of triplets; dd, doublet of doublets; ddd, doublet of doublet of doublets; m, multiplet;
comp, overlapping multiplets of magnetically non-equivalent protons. Optical rotations were
measured on a digital polarimeter. Mass spectrometric analysis was performed in the CRF, IIT-
Kharagpur (TOF analyzer). X-ray crystallographic analysis was performed at IACS, Kolkata.
(R,E)-ethyl 2,6-dimethyl-8-oxooct-2-enoate (8):
To a solution of (R)-(+)-citronellal (1.45 mL, 1.23 g, 8.0 mmol) in DCM (150 mL) was added
ethyl methacrylate (1.7 mL, 1.6 g, 16.0 mmol) and G-II catalyst (340 mg, 0.4 mmol). The
reaction mixture was refluxed for 24 h under argon atmosphere. The reaction mixture was then
allowed to cool to room temperature and concentrated under vacuum. The residue was then
purified via silica column chromatography (EtOAc:hexane = 1:20) to afford compound 8 (1.18 g,
5.6 mmol, 70%) as a pale yellow oil.
Rf = 0.4 (EtOAc:hexane = 1:20); [α]
28 = +14.7 (c = 0.5, CHCl3); 1H NMR (200 MHz, CDCl3)
D
δH: 9.80 (s, 1H), 6.76 (t, J = 7.2 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 2.49-2.29 (m, 5H), 1.61 (s,
3H), 1.50-1.40 (m, 2H), 1.33 (t, J = 7.0 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H); 13C NMR (50 MHz,
CDCl3), δC: 202.2, 168.0, 141.3, 127.9, 60.3, 50.6, 35.4, 27.7, 25.9, 19.4, 14.0, 12.0; HRMS
(ESI) m/z: calcd. for C12H20O3Na [M + Na]+, calculated: 235.1309; found: 235.1302.
[α]
28 = -14.5 (c = 0.5, CHCl3) for ent-8.
D
9

ACCEPTED MANUSCRIPT
(R
)-ethyl 2-((1
S,4
R
)-4-methyl-2-oxocyclohexyl)propanoate (9):
General procedure for the asymmetric intramolecular Stetter reaction of aliphatic
substrates: A flame-dried round bottom flask was charged with Rovis aminoindane based NHC
catalyst (0.02 mmol, 0.2 equiv) and toluene (1 mL) under argon atmosphere. To this solution was
added KHMDS (0.5 M in toluene) (0.02 mmol, 0.2 equiv) via syringe and the solution was
stirred at ambient temperature for 5 min. Substrate 8 (0.1 mmol, 1 equiv) was added in toluene (1
mL) via syringe and allowed to stirred for 24 h at room temperature. The residue was then
purified via silica column chromatography (EtOAc:hexane = 1:10) to afford compound 9 in 85%
yield.
28
D
1
Rf = 0.4 (EtOAc:hexane = 1:10); [
α]
= +27.1 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3)
δH: 4.10 (q, J = 7.2 Hz, 2H), 2.73 (quint, J = 6.8 Hz, 1H), 2.58-2.52 (m, 1H), 2.36 (dd, J = 2.4,
13.2 Hz, 1H), 2.04-1.96 (m, 2H), 1.89-1.85 (m, 2H), 1.55 (dq, J = 3.2, 12.8 Hz, 1H), 1.39 (dq, J
= 3.2, 12.8 Hz, 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H);
13C NMR (50 MHz, CDCl3) δC: 210.2, 175.4, 60.2, 52.4, 50.5, 39.1, 35.3, 33.8, 30.1, 22.3, 14.8,
14.2; HRMS (ESI) m/z: calcd. for C12H21O3 [M + H]+, calculated: 213.1491; found: 213.1491.
(S)-ethyl 2-((1R,4S)-4-methyl-2-oxocyclohexyl)propanoate (ent-9): The compound was
synthesised as described earlier by using the enantiomeric Rovis aminoindane based NHC
catalyst to furnish ent-9 in 83% yield.
[α]
28 = -26.8 (c = 1.0, CHCl3) for ent-9.
D
(2S,5R)-2-((R)-1-(benzyloxy)propan-2-yl)-5-methylcyclohexanol (11):
LAH (0.5 g, 12 mmol) was taken in 250 mL dry ether followed by addition of the keto ester 9
(2.12 g, 10.0 mmol) at 0 °C. After 1 h saturated solution of Na2SO4 was added to quench the
reaction mixture. Then the reaction solution was filtered by washing with hot Et2O for several
times and then it was concentrated in vacuo. The product was then purified by flash
chromatography (1:1; EtOAc/hexane) to afford the diol compound 10 as a thick liquid, which
was crystallized from EtOAc (1.85 g, 87.2 % yield) to furnish the diol as long needles. Rf = 0.2
(EtOAc:hexane = 1:1).
To a suspension of NaH (520 mg, 60%, 13.0 mmol) in DMF (20 mL) was added drop wise a
solution of compound 10 (1.6 g, 9.3 mmol) in DMF (16 mL) and further stirred for 45 min. Then
PhCH2Br (1.2 mL, 10.22 mmol) in DMF (5 mL) was added drop wise and stirring was continued
for 3 h. The temperature of the reaction solution was kept at 0 °C. The reaction mixture was then
10

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poured into ice water (40 mL) and extracted with ether. The ethereal solution was washed to
neutrality, dried and concentrated. The residue was then purified by silica gel chromatography
(EtOAc:hexane = 1:5) to afford 11 as colorless oil (2.19 g, 8.37 mmol, 90%).
Rf = 0.4 (EtOAc:hexane = 1:5); [α]
28 = -13.0 (c = 1.6, CHCl3); 1H NMR (200 MHz, CDCl3) δH:
D
7.34 (s, 5H), 4.53 (d, J = 2.6 Hz, 2H), 3.95 (brs, 1H), 3.52 (brs, 1H), 3.40-3.27 (m, 2H), 1.96-
1.80 (m, 5H), 1.50-1.40 (m, 4H), 0.97 (d, J = 7.2 Hz, 3H), 0.86 (d, J = 6.2 Hz, 3H); 13C NMR
(50 MHz, CDCl3) δC: 137.6, 128.4, 127.7, 73.3, 72.7, 69.6, 46.3, 42.4, 36.4, 35.3, 26.0, 22.3,
21.0, 17.4; HRMS (ESI) m/z: calcd. for C17H26O2Na [M + Na]+, calculated: 285.1830; found:
285.1831.
(2S,5R)-2-((R)-1-(benzyloxy)propan-2-yl)-5-methylcyclohexanone (7):
Alcohol 11 (930 mg, 3.54 mmol), was taken in dry DCM (10 mL) and cooled to 0 °C. Dess
Martin periodinane (DMP) (1.8 g, 4.25 mmol) was then added and warmed to room temperature
over 2 h. The reaction mixture was then quenched with Na2S2O3 and saturated NaHCO3 solution
successively and stirred for further 20 min. The organic solution was then dried with MgSO4,
filtered, and the solvent was removed in vacuo. The residue was then purified by silica gel
chromatography (EtOAc:hexane = 1:10) to furnish compound 7 as colorless oil (828 mg, 3.18
mmol, 91%).
28
D
1
Rf = 0.5 (EtOAc:hexane = 1:10); [
α]
= -10.7 (c = 1.3, CHCl3); H NMR (600 MHz, CDCl3)
δH: 7.37-7.33 (m, 4H), 7.30-7.28 (m, 1H), 4.50 (dd, J = 12.0, 18.0 Hz, 2H), 3.50 (dd, J = 5.4, 9.0
Hz, 1H), 3.40 (dd, J = 6.0, 9.0 Hz, 1H), 2.37-2.34 (m, 2H), 2.19-2.17 (m, 1H), 2.05-2.03 (m,
1H), 2.01 (dt, J = 1.2, 12.6 Hz, 1H), 1.90-1.85 (m, 2H), 1.46-1.38 (m, 2H), 1.04 (d, J = 2.4 Hz,
13
3H), 1.03 (d, J = 6.0 Hz, 3H); C NMR (50 MHz, CDCl3) δC: 211.9, 138.7, 128.2, 127.5, 73.0,
72.9, 52.2, 51.0, 35.5, 34.1, 32.6, 29.5, 22.3, 15.5; HRMS (ESI) m/z: calcd. for C17H25O2 [M +
H]+, calculated: 261.1855; found: 261.1851.
(2
S,3R,6S)-6-((R)-1-(benzyloxy)propan-2-yl)-3-methyl-2-((E)-3-(trimethylsilyl)but-2-en-1-
yl)cyclohexanone (6):
To a THF solution (6 mL) of n-BuLi (2.1 mL, 3.38 mmol, 1.6 M) was added diisopropylamine
(0.52 mL, 3.68 mmol) at -78 °C under an inert atmosphere. The reaction mixture was held at -78
°C for 15 min. then it was allowed to warm to room temperature and stirred for 30 min before
being recooled to -78 °C. Next, compound 7 (800 mg, 3.07 mmol) was added dropwise as a
solution in THF (2.0 mL). The reaction was held at -78 °C for 40 min. before being allowed to
11

ACCEPTED MANUSCRIPT
warm to 0 °C and stirred for 30 min after which the reaction was recooled to -78 °C.
Hexamethylphosphoramide (0.53 mL, 3.07 mmol) was then added and the reaction mixture was
stirred for 5 min, and then diethyl zinc (3.07 mL, 3.07 mmol) was added. A solution of 13 (1.19
g, 4.6 mmol) in 2 mL of THF was added drop wise and the reaction mixture was allowed to
warm to rt and stirred overnight. Saturated aqueous NH4Cl solution was added to quench the
reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with
water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over
MgSO4, filtered, and concentrated. The residue was purified using silica gel column
chromatography (EtOAc:hexane = 1:20) to furnish 6 as a colorless oil (890 mg, 2.30 mmol,
75%).
28
D
1
Rf = 0.6 (EtOAc:hexane = 1:10); [
α]
= -16.1 (c = 0.6, CHCl3); H NMR (600 MHz, CDCl3)
δH: 7.35 (s, 3H), 7.28 (s, 2H), 5.58 (tq, J = 1.8, 7.2 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.45 (d, J
= 12.0 Hz, 1H),3.45 (dd, J = 4.2, 9.0 Hz, 1H), 3.27 (t, J = 9.0 Hz, 1H), 2.54-2.51 (m, 1H), 2.41
(dd, J = 6.0, 15.6 Hz, 1H), 2.36-2.30 (m, 2H), 2.05 (dd, J = 10.8, 15.0 Hz, 1H), 1.77-1.75 (m,
1H), 1.67-1.65 (m, 1H), 1.65 (s, 3H), 1.60 (s, 2H), 1.49-1.45 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H),
13
0.88 (d, J = 6.6 Hz, 3H), 0.03 (s, 9H); C NMR (50 MHz, CDCl3), δC: 213.4, 138.7, 133.3,
128.2, 127.5 127.3, 73.2, 72.9, 52.1, 47.5, 35.2, 33.1, 32.5, 29.9, 29.1, 21.6, 14.6, 11.8, -2.13;
HRMS (ESI) m/z: calcd. for C24H39O2Si [M + H]+, calcutated: 387.2719; found: 387.2712.
(2S,3R,6S)-6-((R)-1-(benzyloxy)propan-2-yl)-3-methyl-2-(3-oxobutyl)cyclohexanone (5): To
a DCM solution (5.0 mL) of 6 (450 mg, 1.17 mmol) was added mCPBA (0.320 mg, 1.40 mmol)
at 0 °C under argon atmosphere. After 8 h the reaction was quenched with aqueous sodium
bicarbonate and extracted with DCM. The organic layer was dried over MgSO4, filtered, and
concentrated. The residue was purified using silica gel column chromatography (EtOAc:hexane
= 1:10) to afford 5 as a colorless oil (230 mg, 0.7 mmol, 60%).
Rf = 0.3 (EtOAc:hexane = 1:10); [α]
28 = -5.7 (c = 0.8, CHCl3); 1H NMR (600 MHz, CDCl3) δH:
D
7.35-7.32 (m, 4H), 7.29-7.27 (m, 1H), 4.52, 4.48 (ABq, JAB = 12.0 Hz, 2H), 3.47 (dd, J = 5.4, 9.0
Hz, 1H), 3.39 (dd, J = 6.0, 9.0 Hz, 1H), 2.56-2.52 (m, 1H), 2.43-2.40 (m, 1H), 2.37-2.32 (m,
1H), 2.14 (s, 3H), 2.08-2.01 (m, 2H), 1.87-1.70 (m, 4H), 1.53-1.50 (m, 2H), 1.39-1.37 (m, 1H),
1.07 (d, J = 6.0 Hz, 3H), 1.01 (d, J = 6.0 Hz, 3H); 13C NMR (50 MHz, CDCl3), δC: 213.0, 209.0,
138.6, 128.2, 127.4, 127.3, 72.9, 72.8, 56.9, 53.3, 41.3, 40.4, 34.7, 31.4, 30.5, 29.7, 20.4, 20.1,
12

ACCEPTED MANUSCRIPT
14.0; HRMS (ESI) m/z: calcd. for C21H30O3Na [M + Na]+, calcutated: 353.2092; found:
353.2093.
(2S,3R,6S)-6-((R)-1-(benzyloxy)propan-2-yl)-3-methyl-2-(3-methylbut-3-en-1-
yl)cyclohexanone (4):
To a suspension of methyltriphenylphosphonium iodide (242 mg, 0.6 mmol) in dry THF (2 mL)
was added LiHMDS (1.0 M solution in THF, 0.6 mL) at 0 °C. The yellow mixture was then
stirred at 0 °C for 15 min. A solution of the diketone 5 (132 mg, 0.4 mmol) in 2 mL of THF was
added to the reaction mixture. The yellow suspension was stirred at room temperature for further
4 h. After that the reaction solution was quenched with addition of water, and the layers were
separated and extracted with 25 mL of ether, washed with brine. It was then dried with MgSO4,
filtered, and the solvent was removed in vacuo. The crude residue was purified by flash column
chromatography (EtOAc:hexane = 1:30) to afford compound 4 (104 mg, 0.32 mmol) in 80%
yield.
28
D
1
Rf = 0.3 (EtOAc:hexane = 1:20); [
α]
= +1.2 (c = 0.8, CHCl3); H NMR (400 MHz, CDCl3)
δH: 7.32-7.21 (m, 5H), 4.58 (dd, J = 7.8, 15.6 Hz, 2H), 4.44-4.31 (m, 2H), 3.41-3.27 (m, 1H),
3.24 (dd, J = 2.1, 6.4 Hz, 1H), 2.46-2.25 (m, 2H), 2.12- 1.67(m, 5H), 1.63 (s, 3H), 1.50-1.42 (m,
5H), 0.96 (d, J = 6.1 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3), δC: 213.4,
146.2, 138.8, 128.4, 127.6, 127.5, 110.0, 73.5, 72.9, 57.4, 53.7, 40.9, 36.7, 35.7, 32.5, 31.2, 22.4,
20.7, 16.1, 13.4; HRMS (ESI) m/z: calcd. for C22H32O2Na [M + Na]+, calcutated: 351.2299;
found: 351.2303.
(2S,3R,6S)-6-((R)-1-(benzyloxy)propan-2-yl)-3-methyl-2-(3-methylbut-3-en-1-
yl)cyclohexanecarbaldehyde (13):
A solution of methoxymethyltriphenylphosponium chloride (296 mg, 0.86 mmol) in THF (1 mL)
o
and HMPA (1 mL) was stirred at 0 C for 20 min with a solution of 0.5 M potassium
bis(trimethylsilyl)amide (KHMDS) (0.86 mL, 0.86 mmol) in toluene. To this solution was
slowly added a solution of ketone 4 (94 mg, 0.289 mmol) in THF (1 mL) and the resulting
reaction mixture was allowed to warm to room temperature and stirred for 24 hours. The reaction
o
mixture was cooled to 0 C and saturated NH4Cl solution was added and extracted with diethyl
ether, the combined organic layers were washed with H2O, brine, dried over anhydrous Na2SO4
and evaporated under reduced pressure.
13

ACCEPTED MANUSCRIPT
To a stirred solution of crude methylvinylether in dry DCM (3 mL) at 40 °C under N2 was added
trichloroacetic acid (0.16 g, 1.0 mmol) and stirring was continued for 15 min. After cooling to
room temperature, saturated aqueous NaHCO3 (7 mL) was added to the reaction mixture and the
organic layer separated. The aqueous layer was further extracted with DCM (20 mL) and the
combined organic phases washed with brine (5 mL), dried (MgSO4), and concentrated in vacuo
to provide as pale yellow oil 13 which was used immediately without further purification.
(((2R)-2-((1R,3S,4R)-4-methyl-3-(3-methylbut-3-en-1-yl)-2-
vinylcyclohexyl)propoxy)methyl)benzene (3):
To a suspension of methyltriphenylphosphonium iodide (121 mg, 0.3 mmol) in dry THF (1 mL)
was added LiHMDS (1.0 M solution in THF, 0.3 mL) at 0 °C. The yellow mixture was stirred at
0 °C for 15 min. A solution of compound 13 (68 mg, 0.2 mmol) in 1.0 mL of THF was added to
the reaction mixture. The yellow suspension was stirred at room temperature for further 4 h.
After that the reaction was quenched with addition of water, and the layers were separated and
extracted with 25 mL of ether, washed with brine. It was then dried with MgSO4, filtered, and
the solvent was removed in vacuo. The crude residue was purified by flash column
chromatography (EtOAc:hexane = 1:30) to afford compound 3 (48 mg, 0.15 mmol) in 72%
yield.
28
D
1
Rf = 0.6 (EtOAc:hexane = 1:40); [
α]
= -13.7 (c = 0.8, CHCl3); H NMR (400 MHz, CDCl3)
δH: 7.34-7.26 (m, 5H), 5.91-5.85 (m, 1H), 5.10-4.95 (m, 2H), 4.58 (m, 2H), 4.39 (s, 2H), 3.24
(dd, J = 4.4, 9.2 Hz, 1H), 3.12 (dd, J = 4.4, 9.2 Hz, 1H), 2.34-2.29 (m, 1H), 2.16-1.96 (m, 4H),
1.7 (s, 3H), 1.62-1.57 (m, 3H), 1.42-1.38 (m, 5H), 1.04 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.0 Hz,
13
3H); C NMR (100 MHz, CDCl3), δC: 145.8, 137.6, 137.5, 128.4, 127.6, 127.5, 117.6, 110.6,
74.4, 73.4, 46.9, 45.6, 40.1, 39.0, 38.1, 34.3, 30.8, 28.2, 22.5, 18.9, 15.5.
(1R,4R,4aS,8aR)-1-((R)-1-(benzyloxy)propan-2-yl)-4,7-dimethyl-1,2,3,4,4a,5,6,8a-
octahydronaphthalene (14):
Compound 3 (34 mg, 0.1 mmol) was taken in anhydrous degassed DCM (30 mL). Grubbs
second generation metathesis catalyst (G-II, 7 mg, 0.008 mmol) was added and the solution was
refluxed for 12 h. The solution was then evaporated and the content of the flask was directly
loaded on a silica gel column. Flash chromatography on silica (EtOAc:hexane = 1:50) afforded
the desired product 14 (22 mg, 0.072 mmol, 72%).
14

ACCEPTED MANUSCRIPT
28
D
1
Rf = 0.3 (EtOAc:hexane = 1:40); [
α]
= -15.7 (c = 0.8, CHCl3); H NMR (400 MHz, CDCl3)
δH: 7.35-7.32 (m, 4H), 7.29-7.27 (m, 1H), 5.19 (s, 1H), 4.52, 4.48 (ABq, JAB = 12.0 Hz, 2H),
3.52 (dd, J = 3.2, 8.8 Hz, 1H), 3.30 (dd, J = 6.8, 8.8 Hz, 1H), 2.47 (brs, 1H), 1.93-1.90 (m, 2H),
1.80-1.73 (m, 2H), 1.64 (s, 3H), 1.53-1.50 (m, 4H), 1.27-1.21 (m, 4H), 1.00 (d, J = 6.4 Hz, 3H),
13
0.80 (d, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3), δC: 139.1, 135.1, 128.5, 127.7, 127.5,
121.0, 74.8, 73.2, 43.5, 42.3, 37.7, 35.9, 35.0, 27.9, 26.9, 26.6, 26.0, 24.0, 20.0, 16.0; HRMS
(ESI) m/z: calcd. for C22H32ONa [M + Na]+, calcutated: 335.235; found: 335.2351.
Acknowledgements
Financial support from IIT-Kharagpur is gratefully acknowledged (Grant: SGIRG). We are also
thankful to DST-India (IRPHA) for NMR instrument. Two of the authors RKR and RR are
thankful to CSIR-India and UGC for providing research fellowship.
Supplemantary data
13
Supplimentary data (1H, C and DEPT spectra for all new compounds, HPLC chromatogram
and X-ray crystallographic information for compound 10) associated with this article can be
found in the online version, at http://..........
1. (a) White, N. J. Antimicrob. Agents Chemother. 1997, 41, 1413-1422. (b) Miller, L. H.;
Su, X. Cell (CAMBRIDGE, MA 02139, USA: Cell Press), 2011, 146, 855-858.
2. Qinghaosu Antimalaria Coordinating Research Group. Chin. Med. J. 1979; 92, 811-816.
3. Nogueira, C. R.; Lopes, L. M. X. Molecules, 2011, 16, 2146-2190.
4. (a) Guidelines for the Treatment of Malaria. Geneva: World Health Organization. 2006,
ISBN 92-4-154694-8. (b) Douglas, N. M.; Anstey, N. M.; Angus, B. J.; Nosten, F.; Price.
:
R. N. Lancet. Infect. Dis. 2010, 10, 405-416. (c) White, N. J. J. Clin. Invest. 2004, 113,
1084-1092. (d) Dondorp, A.; Nosten, F.; Stepniewska, K.; Day, N.; White, N. Lancet
2005, 366, 717-275. (e) Taylor, W. R.; White, N. J.; Drug Saf. 2004, 27, 25-61. (f)
Krudsood, S.; Looareesuwan, S.; Tangpukdee, N.; Wilairatana, P.; Phumratanaprapin, W.;
Leowattana, W.; Chalermrut, K.; Ramanathan, S.; Navaratnam, V.; Olliaro, P. Antimicrob
Agents Chemother. 2010, 54, 3730-3737. (g) Cabello, C. M.; Lamore, S. D.; Bair, W. B.;
15

ACCEPTED MANUSCRIPT
Qiao. S.; Azimian, S.; Lesson, J. L.; Wondrak, G. T. Invest. New Drugs 2012, 30, 1289-
1301.
5. (a) Sy, L. K.; Brown, G. D.; Haynes, R. Tetrahedron, 1998, 54, 4345-4356. (b) L. K. Sy,
N. Y. Zhu, G. D. Brown, Tetrahedron, 2001, 57, 8495-8510. (c) N. C. Kim, S. U. Kim, J.
Korean Agric. Chem. Soc. 1992, 35, 106-109.
6. Lai, H.; Singh, N. P.; Sasaki, T. Invest. New Drugs. 2013, 31, 230-246.
7. (a) Cook, S. P. Synlett, 2014, 751-759 and reference cited therein. (b) Xu, X. X.; Zhu, J.;
Huang, D. Z.; Zhou, W. S.; Tetrahedron, 1986, 42, 819-828. (c) Moreira, J. A.; Correa, A.
G. Tetrahedron: Asymmetry 2003, 14, 3787-3795.
8. (a) Yin, J.; Wang, C.; Kong, L.; Cai, S.; Gao, S. Angew. Chem. Int. Ed. 2012, 51, 7786 -
7789. (b) Y. Nishikawa, M. Kitajima, N. Kogure, H. Takayama, Tetrahedron, 2009, 65,
1608-1617.
9. Xu, J.; Caro-Diaz, E. J. E.; L. Trzoss, L.; Theodorakis, E. A.; J. Am. Chem. Soc. 2012,
134, 5072-5075.
10. (a) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8877-8878. (b) Kerr, M. S.; Read
de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70, 5725-5728. (c) Read de Alaniz, J.; Rovis,
T. J. Am. Chem. Soc. 2005, 127, 6284-6289. (d) Kerr, M. S.; Read de Alaniz, J.; Rovis, T.
J. Am. Chem. Soc. 2002, 124, 10298-10299. (e) Kerr, M. S.; Rovis, T. Synlett, 2003, 12,
1934-1936. (f) Enders, D.; Niemeir, O.; Henseler, A. Chem. Rev., 2007, 107, 5606.
11. Trost, B. M.; Shuey, C. D.; DiNinno Jr, F.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101,
1284-1285.
12. Dudley, G. B.; Engel, D. A.; Ghiviriga, I.; Lam, H.; Poon, K. W. C.; Singletary, J. A. Org.
Lett. 2007, 9, 2839-2842.
13. Singletary, J. A.; Lam, H.; Dudley, G. B. J. Org. Chem. 2005, 70, 739-741.
14. (a) Stork, G.; Jung, M. E. J. Am. Chem. Soc. 1974, 96, 3682-3684. (b) G. Stork, G.; Jung,
M. E.; Colvin, E.; Noel, Y. J. Am. Chem. Soc. 1974, 96, 3684-3686.
15. (a) Liu, H. J.; Yeh, W. L.; Chew, S. Y. Tetrahedron Lett. 1993, 34, 4354-4438. (b) Corey,
E. J.; Tius, M. A. Tetrahedron Letters, 1980, 21, 3535-3538.
16. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.
16