Total synthesis of (±)-elegansidiol, (±)-farnesiferol B, and (±)-farnesiferol D

Article abstract of DOI:10.1016/j.bmcl.2010.04.030

The racemic total synthesis of elegansidiol, farnesiferol B, and farnesiferol D has been obtained following a Diels-Alder approach. Gillman addition, cross metathesis reaction are the other key steps involved in the target synthesis.

Full text of DOI:10.1016/j.bmcl.2010.04.030

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3814–3817
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Total synthesis of ( )-elegansidiol, ( )-farnesiferol B, and ( )-farnesiferol D
a
a
a
b
Jhillu Singh Yadav a, , Kamani Satyanarayana , Pamu Sreedhar , Pabbaraja Srihari , Thokhir Basha Shaik ,
*
Shasi Vardhan Kalivendi b
a Organic Chemistry Division—I, Indian Institute of Chemical Technology, Council of Scientific and Industrial Research, Hyderabad 500 607, India
b Chemical Biology, Indian Institute of Chemical Technology, Council of Scientific and Industrial Research, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The racemic total synthesis of elegansidiol, farnesiferol B, and farnesiferol D has been obtained following
a Diels–Alder approach. Gillman addition, cross metathesis reaction are the other key steps involved in
the target synthesis.
Received 18 January 2010
Revised 23 March 2010
Accepted 9 April 2010
Available online 21 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Terpene
Intermolecular Diels–Alder
Reduction
Wittig
Metathesis
Monocarbocyclic terpenoids continue to attract significant
interest due to their continuous appearance as constituent in nat-
ural products with interesting biological properties.1 Elegansidiol
(5), an oxygenated monocyclic sesquiterpenoid which has been
isolated a decade back2 has a 3-substituted 2,2-dimethyl-4-meth-
ylene cyclohexanol unit. This unit is being frequently isolated as
a structural motif in several other naturally occurring products.
Few examples include achilleol A (1), achilleol B (2),3 cordiaqui-
none C (6)4 and also in biologically active derivatives farnesiferol
B and D (3 and 4)5 (Fig. 1). Achilleol A displayed antifeedent activ-
ity and farnesiferol B and C showed potent anticancer activity. As
the scarcity of the natural material becomes the barrier for further
evaluation of biological activity, total synthesis becomes an attrac-
tive solution for getting these natural materials in sufficient
amounts. The interesting biological activity of farnesiferol B has
stimulated us to take up its total synthesis along with its isomer
farnesiferol D. As farnesiferol B can be easily achieved from ele-
gansidiol, we started initially with the synthesis of elegansidiol.
The earlier strategies to build the building block with 2,2-di-
methyl-4-methylene cyclohexanol unit comprised an intramolecu-
lar epoxy-ene cyclization2 or the recently developed biomimetic
approach.6 Several other strategies are also reported for elegansidi-
ol and their derivatives.7 In continuation to our efforts toward total
synthesis of biologically active natural products, recently we have
accomplished the synthesis of a key intermediate for fumagillin,
TNP-470, and ovalicin (anti angiogenesis) using an intermolecular
Diels–Alder approach.8 We herein extend our investigation with
the Diels–Alder adduct obtained earlier to synthesize the oxygen-
ated monocarbocyclic elegansidiol, and its further derivatives far-
nesiferol B and farnesiferol D.
Retrosynthetically, the three molecules, farnesiferol B (3), D (4),
and elegansidiol (5) can be obtained from a key intermediate 8 in
OH
OH
OH
Elegansidiol (5)
Achilleol A (1)
O
H
CH3
O
O
Achilleol B (2)
OH
O
Cordiaquinonel-C (6)
O
O
O
R
R'
R = H, R' = OH, Farnesiferol-B (3)
R = OH, R' = H, Farnesiferol-D (4)
Farnesiferol-C (7)
* Corresponding author. Tel.: +91 40 27193535; fax: +91 40 27160512.
E-mail address: yadavpub@iict.res.in (J.S. Yadav).
Figure 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.030

J. S. Yadav et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3814–3817
3815
Farnesiferol B (3)
functionality in 11 was reduced to alcohol 16 and then oxidized to
aldehyde 17. The aldehyde 17 obtained was treated with 1 equiv of
dimethyl-copper lithium to get the dimethyl substituent 18 and
then subjected to a Wittig reaction with 1-(triphenylphosphorany-
I
CO2Et
Elegansidiol (5)
Farnesiferol-D (4)
OPMB
CO2Et
O
lidene)-2-propanone to get the a,b-unsaturated ketone 10. One pot
9
8
O
olefin reduction and PMB deprotection of 10 with Pd/C in methanol
afforded alcohol 19 in good yield. The ketone was subjected to 2-C
Wittig reaction with stable ylide (carbethoxymethylene) triphenyl-
OPMB
OPMB
O
CO2R
CO2R
O
O
O
phosphorane in tolueneunderrefluxconditions to getthe a,b-unsat-
Br
10
11
12
urated ester 20. The primary alcohol was converted to iodide 9 with
I2, triphenylphosphine, and imidazole and then treated with zinc in
ethanol at reflux temperature to get monocyclic ring with free sec-
ondary alcohol 21.12 Oxidation of the secondary alcohol 21 with
PCC gave the key intermediate 8 and was then reduced with DI-
BAL-H to yield the desired target elegansidiol (5) along with its other
diastereomer22 in 4:2 ratio (Scheme 2). While elegansidiol (5) could
be carried forward for the synthesis of farnesiferol B (3), the other
diastereomer 22 can be utilized for the total synthesis of farnesiferol
D (4).
Initial attempts to do a cross metathesis reaction with either
Grubbs’ 1st generation catalyst or 2nd generation catalyst between
elegansidiol (5) and 7-O-allyl umbelliferone 23 did not succeed and
resulted in recovery of the starting materials. However, when ele-
gansidiol was mono protected as its corresponding acetate and
then exposed to Grubbs 2nd generation catalyst13 with 7-O-allyl
umbelliferone in CH2Cl2 at reflux temperature, a mixture of diaste-
reomers E:Z (3:2) of farnesiferol B (3)was obtained.
OPMB
Br
CO2R
14
+
O
13
Scheme 1. Retrosynthesis.
three to four steps, and elegansidiol (5) can be converted to farne-
siferol B (3) in two steps. The intermediate 8 is in turn obtained by
a ring opening reaction of iodide 9 followed by an oxidation. The
iodo compound 9 is obtained from 10 in three steps (PMB depro-
tection, alcohol to iodide conversion and 2C-Wittig reaction). The
compound 10 is synthesized from 11 in four steps which in turn
can be obtained from compound 12 by 1,4-Gillman addition reac-
tion. The adduct 12 is readily synthesized by a Diels–Alder reaction
of PMB protected furfuryl alcohol and ethyl bromopropiolate
(Scheme 1).
Thus, our synthesis starts with a Diels–Alder reaction of PMB pro-
tected furfuryl ether 13 and ethyl bromopropiolate9 14 to result in
adduct 12 in 70% yield with the desired regioselectivity as reported
earlierfrom our group.10 This adductwas reduced with Pd/Cto result
in saturation of the isolated double bond yielding compound 15. 1,4-
Gillman addition with dimethyl-copper lithium gave 11.11 The ester
Similarly, the compound 22 was also selectively monoprotected
as acetate and subjected to cross metathesis with Grubbs 2nd gener-
ation catalyst in CH2Cl2 under reflux temperature to get farnesiferol
D(4)(E:Z)in3:2ratio(Scheme3). As thediastereomers werenoteas-
ily separable, both farnesiferol B and D were also synthesized start-
ing from the corresponding alcohols 5 and 22 following the earlier
OPMB
CO2Et
OPMB
CO2Et
benzene, reflux
24 h, 70%
10%Pd-C, H , MeOH
2
OPMB
Br
CO2Et
+
O
O
rt, 15 min, 98%
O
Br
Br
14
OPMB
CO2Et
13
12
OPMB
15
OPMB
O
(CH3)2CuLi,THF
0 oC, 20 min, 67%
DIBAL-H, DCM
PCC, DCM
H
OH
O
O
O
-78 ºC, 20 min, 95%
30 min, 96%
O
11
16
OPMB
PPh3
17
OPMB
O
10% Pd-C, H2, MeOH
rt, 6 h, 98%
(CH3)2CuLi,THF
O
O
H
benzene, reflux,
0 ºC, 15 min, 65%
O
72 h, 81%
10
100% E isomer
18
I
HO
HO
O
CO2Et
C2 Wittig
toluene, reflux, 81%
CO2Et TPP, imadazole
I2, toluene, reflux,
72%
O
O
O
20
(7:3 E/Z isomers)
19
9
CO2Et
CO2Et
DIBAL-H, DCM
-78 ºC, 2 h, 95%
Zn, EtOH
reflux, 6 h, 92%
PCC, DCM,
rt, 1 h, 98%
OH
+
21
O
8
OH
OH
OH
OH
Elegansidiol (5)
(4:2)
22
Scheme 2. Synthesis of elegansidiol (5) and its diastereomer 22.

3816
J. S. Yadav et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3814–3817
23
O
O
O
OH
O
O
O
Grubbs 1st gen. catalyst
or
OH
Farnesiferol-B (3)
OH
Grubbs 2nd gen. catalyst
CH2Cl2, reflux 10-48 h.
Elegansidiol (5)
AC2O,Py,DMAP
DCM, -5 ºC,
20 min, 89%
OAc
23
O
Grubbs 2nd gen. catalyst
CH2Cl2, reflux 48 h, 19%
O
O
O
O
O
OH
Farnesiferol-B (3)
(3:2 E/Z isomers)
OH
24
AC2O,Py,DMAP
DCM, -5 ºC, 20 min, 89%
O
O
O
OAc
OH
O
Grubbs 2nd gen. catalyst
CH2Cl2, reflux 48 h, 19%
OH
OH
25
22
O
O
OH
Farnesiferol-D (4)
(3:2 E/Z isomers)
Scheme 3. Synthesis of farnesiferol B and D via metathesis.
products were compared with the earlier literature analytical
data.6,7b
The compounds 3, 4, 5, 10, 11, 18, and 21 were screened for
their effects on growth inhibition and cytotoxicity in two different
human cancer cell lines viz., human lung cancer (A549) and neuro-
blastoma (SK-N-SH) employing sulforhodamine B assay as per the
published protocol.14,15 We observed that the compound 21 dem-
1) PBr3, Et2O, 0 ºC
2)
O
O
O
5
OH
HO
O
O
Farnesiferol-B (3)
K2CO3, acetone, rt,
18 h, 85% (overall for 2 steps)
onstrated a GI50 of 6.9 and 4.75
as compared with the reference compound nocodozole, which dis-
played a GI50 of 0.5 and 0.65 M, respectively (Table 1).
lM in A549 and SK-N-SH cell lines
1) PBr3, Et2O, 0 ºC
O
O
O
22
2)
l
OH
In conclusion, we have accomplished the total synthesis of ( )-
elegansidiol, ( )-farnesiferol B, and ( )-farnesiferol D.16 Intermo-
lecular Diels–Alder cyclization, zinc mediated ring opening and
olefin metathesis are the key steps involved. Interesting activity
from one of the intermediate has stimulated us to further investi-
gate the synthesis of the chiral version of the key intermediate and
the target molecules for further biological evaluation studies which
are currently underway.
HO
O
O
Farnesiferol-D (4)
K2CO3, acetone, rt,
18 h, 85% (overall for 2 steps)
Scheme 4. Synthesis of farnesiferol B and D.
Table 1
Biological activity data of compounds screened
Acknowledgment
Substrate
A549 (Human lung cancer
cell)
SK-N-SH (Human
neuroblastoma)
One of us (K.S.) thanks UGC, New Delhi for financial assistance.
GI50
(lM)
LC50
(lM)
GI50
(l
M)
LC50 (lM)
Supplementary data
3
4
5
10
11
18
21
Not active
25
Not active
46
Not active
Not active
Not active
Not active
Not active
4.5
Not active
Not active
Not active
Not active
Not active
20
Not active
Not active
Not active
Not active
6.9
Not active
Not active
Not active
Not active
14.5
Supplementary data (full experimental details and analytical
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.bmcl.2010.04.030.
4.75
15.2
Nocodozole 0.5
1.0
0.65
2.8
References and notes
Values are indicated.
1. Fraga, B. M. Nat. Prod. Rep. 2008, 25, 1180. and references cited there in.
2. Barrero, A. F.; Manzaneda, E. A.; Herrador, M. M.; Manzaneda, R. A.; QuõÑlez, J.;
Chahboun, R.; Linares, P.; Rivas, A. Tetrahedron Lett. 1999, 40, 8273.
3. (a) Barrero, A. F.; Manzaneda, E. A.; Manzaneda, R. Tetrahedron Lett. 1989, 30,
3351; (b) Barrero, A. F.; Alvarez-Manzaneda, E.; Alvarez-Manzaneda, R.;
Arseniyadis, S.; Guittet, E. Tetrahedron 1990, 46, 8161; (c) Arteaga, J. F.;
Domingo, V.; Quilez del Moral, J. F.; Barrero, A. F. Org. Lett. 2008, 10, 1723.
4. Arkoudis, E.; Stratakis, M. J. Org. Chem. 2008, 73, 4484.
known procedures6 by converting them to bromide with PBr3 and
then treating with umbelliferone in acetone at room temperature
to yield the corresponding products in good yields (Scheme 4). The

J. S. Yadav et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3814–3817
3817
5. Caglioti, L.; Naef, H.; Arigoni, D.; Jeger, O. Helv. Chim. Acta 1959, 42, 2557.
6. Tsangarakis, C.; Arkoudis, E.; Raptis, C.; Stratakis, M. Org. Lett. 2007, 9, 583.
7. (a) Audran, G.; Galano, J. M.; Monti, H. Eur. J. Org. Chem. 2001, 2293; (b) Cao, L.;
Sun, J.; Wang, X.; Zhu, R.; shi, H.; Hu, Y. Tetrahedron 2007, 63, 5036; (c)
Demnitz, F. W. J.; Philippini, C.; Raphael, R. A. J. Org. Chem. 1995, 60, 5114; (d)
Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chahboun, R.; Rivas, A. R.; Palomino, P.
L. Tetrahedron 2000, 56, 6099.
8. Yadav, J. S.; Sreedhar, P.; Srihari, P.; Dattatreya Sarma, G.; Jagadeesh, B.
Synthesis 2008, 1460.
9. Leroy, J. Synth. Commun. 1992, 22, 567.
10. Regiospecificity was studied by comparing the reactions of different protective
group bearing furfuryl alcohols and their stereochemistry was identified by
NMR analysis. When TBS protection was used, mixture of isomers was formed,
but for PMB protective group, only one regioisomer was formed. Also see:
Nelson, W. L.; Allen, D. R. Heterocycl. Chem. 1972, 9, 561.
11. (a) Piers, E.; Nagakura, I. J. Org. Chem. 1975, 40, 2694; (b) Clark, R. D.;
Heathcock, C. H. J. Org. Chem. 1976, 41, 636; (c) Piers, E.; Cheng, K. F.; Nagakura,
I. Can. J. Chem. 1982, 60, 1256.
acetic acid. The plates were air-dried. Bound stain was subsequently eluted
with 10 mM trizma base, and the absorbance was read on an ELISA plate reader
at
a wavelength of 540 nm with 690 nm reference wavelengths. Percent
growth was calculated on a plate-by-plate basis for test wells relative to
control wells. The above determinations were repeated three times. Percentage
growth was expressed as the (ratio of average absorbance of the test well to the
average absorbance of the control wells) Â 100. Growth inhibition of 50% (GI50
)
was calculated from [(Ti À Tz)/(C À Tz)] Â 100 = 50, which is the drug
concentration resulting in a 50% reduction in the net protein increase (as
measured by SRB staining) in control cells during the drug incubation. Where,
Tz = Optical density at time zero, OD of control = C, and OD of test growth in the
presence of drug = Ti.
16. Analytical data of selected compounds: Compound 3: IR (neat):
mmax 3441, 2924,
2844, 1696, 1608, 1230, 1126 cmÀ1 1H NMR (300 MHz, CDCl3): d 7.64 (d,
;
J = 9.4 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.86 (dd, J = 8.5, 2.5 Hz, 1H), 6.83 (t,
J = 2.6 Hz, 1H), 6.25 (d, J = 9.4 Hz, 1H), 5.45 (t, J = 6.8 Hz, 1H), 4.88 (s, 1H), 4.61
(d, J = 7.2 Hz, 2H) 4.59 (s, 1H), 3.39 (dd, J = 9.6, 4.1 Hz, 1H), 2.33 (td, J = 13.0,
4.9 Hz, 1H), 2.25–2.13 (m, 1H), 2.02–1.79 (m, 3H), 1.76 (s, 3H), 1.73–1.44 (m,
4H), 1.02 (s, 3H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3): d 162.1, 161.3, 155.8,
147.0, 143.5, 142.8, 128.7, 118.4, 113.3, 113.0, 112.4, 108.5, 101.5, 77.2, 65.5,
51.0, 40.5, 38.4, 32.7, 32.1, 25.9, 23.4, 16.5, 15.8; MS (ESI): m/z 383 [M+H]+, 405
[M+Na]+; HRMS (ESI): calcd for C24H30O4 Na: 405.2041; found: m/z 405.2044.
12. Bernet, B.; Vasella, A. Helv. Chim. Acta 1979, 62, 1990.
13. Chatarjee, A. K.; Choi, T. L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125(37), 11360.
14. Vichai, V.; Kirthikara, K. Nat. Protoc. 2006, 1, 1112.
15. Evaluation of anticancer activity: The synthesized compounds (3, 4, 5, 10, 11, 18,
and 21) have been evaluated for their in vitro cytotoxicity in two different
human cancer cell lines (A549 and SK-N-SH). A protocol of 48 h continuous
drug exposure has been used and a sulforhodamine B (SRB) protein assay has
been employed to estimate cell viability or growth. The cell lines were grown
in Dulbecco’s modified eagles medium containing 10% fetal bovine serum and
Compound 4: IR (neat): mmax 3441, 2924, 2844, 1696, 1608, 1230, 1126 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 7.64 (d, J = 9.6 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H),
6.85 (dd, J = 8.5, 2.4 Hz, 1H), 6.83 (t, J = 2.0 Hz, 1H), 6.25 (d, J = 9.4 Hz, 1H), 5.45
(t, J = 6.6 Hz, 1H), 4.81 (s, 1H), 4.60 (d, J = 7.2 Hz, 2H), 4.59 (s, 1H), 3.67 (dd,
J = 10.0, 4.3 Hz, 1H), 2.32–2.12 (m, 2H), 2.12–1.97 (m, 1H), 1.94–1.77 (m, 3H),
1.75 (s, 3H), 1.72–1.57 (m, 2H), 1.57–1.38 (m, 2H), 0.98 (s, 3H), 0.89 (s, 3H); 13C
NMR (75 MHz, CDCl3): d 162.1, 161.4, 155.8, 147.1, 143.5, 142.6, 128.7, 118.3,
113.3, 113.0, 112.4, 110.7, 101.5, 73.9, 65.5, 53.3, 39.0, 38.0, 31.4, 29.9, 24.5,
24.0, 21.5, 16.9; MS (ESI): m/z 383 [M+H]+, 405 [M+Na]+; HRMS (ESI): calcd for
C24H30O4 Na: 405.2041; found: m/z 405.2044. 5: IR (neat): mmax 3433, 2922,
2 mM L-glutamine and were seeded into 96-well microtiter plates in 100 lL at
plating densities depending on the doubling time of individual cell lines. The
microtiter plates were incubated at 37 °C, 5% CO2, 95% air, and 100% relative
humidity for 24 h prior to addition of experimental drugs. Aliquots of 3
the drug dilutions were added to cells resulting in the required final drug
concentrations. For each compound three concentrations (0.1, 1 and 10 M)
were evaluated, and each were done in triplicate wells. Plates were incubated
further for 48 h and assay was terminated by the addition of 50 L of cold
lL of
2852, 1640, 1560, 1415, 1336, 1019 cmÀ1 1H NMR (300 MHz, CDCl3): d 5.40
;
l
(dt, J = 6.8, 1.1 Hz, 1H), 4.88 (s, 1H), 4.60 (s,1H), 4.16 (d, J = 6.8 Hz, 2H), 3.42 (dd,
J = 9.6, 4.3 Hz, 1H), 2.34 (td, J = 13.0, 5.0 Hz, 1H), 2.20–2.07 (m, 1H), 2.07–1.92
(m, 1H), 1.92–1.74 (m, 2H), 1.68 (s, 3H), 1.66–1.55 (m, 2H), 1.55–1.43 (m, 2H),
1.03 (s, 3H), 0.73 (s, 3H); 13C NMR (75 MHz, CDCl3): d 147.1, 140.1, 123.1,
108.4, 77.1, 59.3, 51.1, 40.5, 38.5, 32.8, 32.1, 25.9, 23.6, 16.3, 15.7; MS (ESI): m/z
239 [M+H]+, 261 [M+Na]+; HRMS (ESI): calcd for C15H26O2 Na: 261.1830;
found: m/z 261.1836.
l
trichloro acetic acid (TCA) (final concentration, 10% TCA) and incubated for
60 min at 4 °C. The plates were washed five times with water and air-dried.
Sulforhodamine B (SRB) solution (50 lL) at 0.4% (w/v) in 1% acetic acid was
added to each of the wells, and plates were incubated for 20 min at room
temperature. The residual dye was removed by washing five times with 1%