Chelation-controlled reduction: An enantioselective synthesis of (-)-tarchonanthuslactone

Article abstract of DOI:10.1016/j.tetlet.2005.07.075

The total synthesis of tarchonanthuslactone (1) has been achieved by two different routes. In the first approach, LiAlH₄-LiI reduction and RCM protocols, and in the second approach, Wacker oxidation and LiAlH ₄-LiI reduction were use

Full text of DOI:10.1016/j.tetlet.2005.07.075

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6567–6570
Chelation-controlled reduction: an enantioselective synthesis
of (ꢀ)-tarchonanthuslactoneI
Gowravaram Sabitha,* K. Sudhakar, N. Mallikarjuna Reddy,
M. Rajkumar and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 19 May 2005; revised 23 June 2005; accepted 15 July 2005
Abstract—The total synthesis of tarchonanthuslactone (1) has been achieved by two different routes. In the first approach, LiAlH4–
LiI reduction and RCM protocols, and in the second approach, Wacker oxidation and LiAlH4–LiI reduction were used as key steps.
Ó 2005 Elsevier Ltd. All rights reserved.
Many natural products possessing the a,b-unsaturated
d-lactone moiety exhibit biological activities such as
antitumor, antibacterial, antifungal, and immunosup-
pressive properties. Tarchonanthuslactone (1), an a,b-
unsaturated d-lactone was isolated in 1979 by Bohlmann
from the leaves of a tree called Tarchonanthus trilobus.1
Later, its absolute configuration was established by
Nakata et al.2 by asymmetric synthesis. The basic struc-
ture of tarchonanthuslactone (a dihydrocaffeic acid
ester) consists of a syn-1,3-diol unit with one hydroxyl
group involved in an unsaturated lactone and the other
esterified with 3,4-dihydroxyhydrocinnamic acid. Caffeic
acid has been established as an active principle that
lowers the plasma glucose levels in diabetic rats3a and
several lactones from the Compositae family show
significant medicinal properties.3b Consequently, several
approaches have been reported for the synthesis of this
molecule. Mori and co-workers4 synthesized from a chi-
ral dithiane using a 16 step sequence. Solladie and Gres-
sot-Kempt5 utilized a chiral sulfoxide in their synthesis
of 1. Apart from these above asymmetric substrate-con-
trolled synthetic methodologies there have been reagent-
controlled6 and other syntheses7 reported. Herein, we
report two different protocols for the synthesis of tarcho-
nanthuslactone (1) based on reagent controlled
synthesis. Our retrosynthetic pathway is outlined in
Scheme 1.
In route a, the known alcohol 68 derived from L-malic
acid, was treated with IBX in DMSO to give aldehyde
7, which on further treatment with allyl bromide and
activated zinc in THF–aq NH4Cl at 0 °C, under Barbier
reaction conditions, gave carbinol 8 as a diastereomeric
mixture. Oxidation of carbinol 8 with IBX in DMSO
O
O
HO
HO
O
O
O
O
CHO
4
Tarchonanthuslactone
route a
(1)
route b
OPMB
OH
OH
5
2
OH
COOH
Keywords: Chelation-controlled reduction; Tarchonanthuslactone;
RCM; Wacker oxidation.
HOOC
3
q IICT Communication No. 050505.
L-malic acid
*
Corresponding author. Tel./fax: +91 40 27160512; e-mail:
sabitha@iictnet.org
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.075

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G. Sabitha et al. / Tetrahedron Letters 46 (2005) 6567–6570
gave ketone 9. A highly syn-stereoselective 1,3-asymmet-
ric reduction was carried out using LiAlH4–LiI9 in ether
at ꢀ100 °C to provide the desired syn-diol 1010 in 94%
yield (syn:anti = 95:5). The hydroxy group was pro-
tected as the PMB ether 11 with PMBBr and subjected
to acid catalyzed hydrolysis in aq MeOH to give diol
12. Selective tosylation of the primary hydroxy group
and further reduction with LAH in THF afforded
monohydroxy compound 2. Treatment of 2 with
TBDMS-protected dihydrocaffeic acid 13 using DCC,
DMAP provided the corresponding ester 14 in 86%
yield. PMB deprotection using DDQ furnished homoal-
lylic alcohol 15 in 81% yield, which was esterified with
acryloyl chloride to provide the diester 16. The RCM
reaction in refluxing DCM using GrubbsÕ bis(tri-
cyclohexylphosphine)benzylidene ruthenium(IV) dichlo-
ride catalyst (17)11 furnished TBDMS-protected ester
1812 in 76% yield (Scheme 2). Finally, TBDMS depro-
tection was carried out using oxone in aq MeOH13 to
An alternative strategy has also been devised for the syn-
thesis of tarchonanthuslactone 1 (route b). Propargyl
alcohol 5 on alkylation with allyl bromide in the pres-
ence of Na2CO3/TBAI, CuI afforded the alkylated prod-
uct 19 in 82% yield, which was reduced to trans allylic
alcohol 20 under LAH/THF conditions. Allylic alcohol
20 was subjected to Sharpless asymmetric epoxidation
with (ꢀ)-DET, Ti(isopropoxide)4 and TBHP to afford
the epoxide 21 in 82% yield, which on reduction with
Red-Al yielded diol 22. The primary hydroxy group
was protected as the TBDPS ether 23 and this com-
pound, when subjected to Wacker oxidation, gave
ketone 24 in 65% yield. The key intermediate, syn-
1,3-diol 25 was prepared conveniently by reduction of
b-hydroxy ketone using a LiI/LiAlH4 protocol.9 This
reaction has been shown to proceed with high diastereo-
selectively (syn:anti selectivity up to >99:1). Com-
pound 25 was subsequently transformed into the
isopropylidene derivative 2615 with 2,2-dimethoxy pro-
pane and catalytic PPTS in CH2Cl2. In the 13C NMR
of 26, the acetonide methyl groups resonated at 19.8
and 30.3 ppm and the quaternary carbon resonated at
98.4 ppm thereby confirming the 1,3-syn relationship.16
Removal of the TBDPS group by treatment with TBAF
furnish the target molecule, tarchonanthuslactone 114
25
in 80% yield, ½aꢁD ¼ ꢀ80 (c 0.4, CHCl3). The 1H
NMR and 13C NMR spectral data and optical rotation
value of synthetic sample 1 were in good accord with
those of the natural product.5
O
OH
O
O
O
c
a
b
O
O
O
OH
O
8
6
7
OPMB
O
OH
O
O
O
f
d
e
O
O
10
11
9
O
TBSO
TBSO
OH
OPMB
OH
OPMB
OH
13
g, h
HO
i
12
2
O
O
O
TBSO
TBSO
TBSO
TBSO
k
O
OR
O
m
O
16
14 R = PMB
15 R = H
j
O
O
O
O
TBSO
TBSO
l
1
PCy3
Cl
Cl
Ph
Ru
17
PCy3
18
Scheme 2. Reagents and conditions: (a) IBX, DMSO, DCM, 3 h, 90%; (b) allyl bromide, Zn, THF, NH4Cl, 4 h, 92%; (c) IBX, DMSO, DCM, 3 h,
85%; (d) LiAlH4–LiI (3 equiv, 1:1), THF, ꢀ100 °C, ether, 94%; (e) NaH, PMBBr, THF, 87%; (f) PTSA, MeOH, 30 min, 0 °C, 90%; (g) TsCl, Et3N,
cat. DMAP, 3 h, DCM, 75%; (h) LiAlH4, THF, rt, 3 h, 72%; (i) DCC, DMAP, DCM, 0 °C to rt, 2 h, 86%; (j) DCM–H2O (9:1), DDQ, 2 equiv, rt, 2 h,
81%; (k) acryloyl chloride, Et3N, DMAP, 0 °C to rt, 2 h, 70%; (l) 10 mol % 17, DCM, rt, 3 h, 76%; (m) oxone, aq MeOH, rt, 24 h, 80%.

G. Sabitha et al. / Tetrahedron Letters 46 (2005) 6567–6570
6569
c
a
b
OH
OH
OH
OH
19
20
-5
O
OH
d
f
O
OR
OR
OH
24
R = H
R = TBDPS
21
22
23
e
O
O
O
OH
OH
O
O
j
g
h
CHO
OR
OR
4
25
R = TBDPS
R = H
26
27
i
TBSO
TBSO
O
O
O
OH
OMe
13
O
O
OH
l
k
m
29
30
O
O
TBSO
TBSO
n
O
O
1
18
Scheme 3. Reagents and conditions: (a) (1) allyl bromide, Na2CO3/TBAI; (2) CuI, DMF, rt, 82%; (b) LiAlH4, THF, rt, 75%; (c) (1) (ꢀ)-DET, Ti(O-i-
˚
Pr)4; (2) TBHP, 4 A MS; (3) DCM, ꢀ20 °C, 82%; (d) Red-Al, THF, ꢀ15 °C to rt, 90%; (e) imidazole, TBDPS–Cl, DCM 0 °C to rt, 1 h, 95%; (f)
PdCl2, CuCl, O2, THF–H2O (10:1) rt, 3–4 h, 65%; (g) LiAlH4, LiI (1:1), Et2O, ꢀ78 °C to rt, 1 h, 84%; (h) 2,2-DMP, PPTS, 12 h, 94%; (i) TBAF,
THF, 1 h, 90%; (j) (1) Dess–Martin periodinane; (2) DCM, rt, 1 h, 88%; (k) (CF3CH2O)2 P(O)CH2COOCH3, NaH, THF, ꢀ80 °C, 0.5 h, 78%; (l) (1)
0.1 N HCl, MeOH, 86%; (2) ZnCl2, THF, D, 80%; (m) DCC, DMAP, 82%; (n) oxone, aq MeOH, rt, 24 h, 80%.
in THF provided the alcohol 27, which was oxidized to
aldehyde 4. A modified Wadsworth–Emmons reaction
of 4 using methyl(bistrifluoroethyl)phosphonoacetate
in the presence of NaH in THF gave Z-unsaturated ester
29, exclusively. After hydrolyzing the acetonide with
dilute acid, lactonization of the hydroxy ester was
achieved by treatment with ZnCl2 in THF at reflux to
give hydroxylactone 30,17 which was identical to that
of the material prepared by Solladie and Gressot-
Kempt.5 Next, this was acylated with 13 following the
OÕDoherty procedure7a to provide protected tarchonan-
thuslactone 18 in 80% yield. The spectral data of 18 was
identical to those of the material prepared by us. Depro-
tection of TBS groups as before completed the total syn-
thesis of tarchonanthuslactone 1 (Scheme 3).14 The
spectral data and optical rotation were again in agree-
ment with those of the natural product.5
References and notes
1. Bohlmann, F.; Suwita, A. Phytochemistry 1979, 18,
677.
2. Nakata, T.; Hata, N.; Iida, K.; Qishi, T. Tetrahedron Lett.
1987, 46, 5661.
3. (a) Hsu, F.; Chem, Y. C.; Cheng, J. T. Planta Med. 2000,
66, 228; (b) Jodynis-Liebert, J.; Murias, M.; Bloszyk, E.
Planta Med. 2000, 66, 199.
4. (a) Mori, Y.; Suzuki, M. J. Chem. Soc., Perkin Trans. 1
1990, 1809; (b) Mori, Y.; Kageyama, H.; Suzuki, M.
Chem. Pharm. Bull. 1990, 38, 2574.
5. Solladie, G.; Gressot-Kempt, L. Tetrahedron: Asymmetry
1996, 7, 2371.
6. Reddy, M. V. R.; Yucel, A. J.; Ramachandran, P. V.
J. Org. Chem. 2001, 66, 2512.
7. (a) Garaas, S.-D.; Hunter, T. J.; OÕDoherty, G. A. J. Org.
Chem. 2002, 67, 2682; (b) Enders, D.; Steinbusch, D. Eur.
J. Org. Chem. 2003, 4550.
8. Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can. J.
Chem. 1984, 62, 2146.
In summary, the total synthesis of (ꢀ)-tarchonanthus-
lactone has been accomplished using chelation-con-
trolled reduction reaction as a key step via two
different approaches.
9. Ghosh, A. K.; Lei, H. J. Org. Chem. 2002, 67,
8783.
10. Spectral data of compound 10: 1H NMR (200 MHz,
CDCl3): d 1.30–1.60 (m, 10H), 1.60–1.70 (m, 2H), 2.20
(m, 2H), 3.54 (t, 1H, J = 7.3 Hz), 3.80–3.90 (m, 1H), 4.00
(dd, 1H, J = 8.1, 5.6 Hz), 4.20–4.30 (m, 1H), 5.00 (s, 1H),
5.12 (d, 1H, J = 3.2 Hz), 5.70–5.90 (m, 1H). EI Mass: m/z
Acknowledgements
25
226 (M+), ½aꢁD +1.54 (c 1.5, CHCl3).
K.S. thanks UGC, and N.M.R. and M.R. thank CSIR,
New Delhi, for the awards of fellowships.
11. For a review, see: Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413.

6570
G. Sabitha et al. / Tetrahedron Letters 46 (2005) 6567–6570
12. Spectral data of compound 18: 1H NMR (300 MHz,
CDCl3): d 0.18 (s, 6H), 0.19 (s, 6H), 0.97 (s, 9H), 0.98
(s, 9H), 1.26 (d, J = 6.5 Hz, 3H), 1.80 (m, 1H), 2.15 (m,
1H), 2.26 (m, 1H), 2.35 (m, 1H), 2.55 (t, J = 8 Hz,
2H), 2.80 (t, J = 8 Hz, 2H), 4.40 (m, 1H), 5.10 (m, 1H,
6.01 (d, J = 9.6 Hz, 1H), 6.60–6.76 (m, 4H). 13C
NMR (75 MHz, CDCl3): ꢀ4.1, 18.4, 20.2, 25.9, 29.1,
30.2, 36.11, 40.8, 67.1, 74.8, 120.8, 121.1, 121.4, 133.4,
15. Spectral data of compound 26: 1H NMR (300 MHz,
CDCl3): d 1.04 (s, 9H), 1.12 (d, 3H, J = 6.0 Hz), 1.20–1.46
(m, 2H), 1.34 (s, 3H), 1.41 (s, 3H), 1.64 (m, 2H), 3.60–3.70
(m, 1H), 3.80–3.96 (m, 2H), 4.07 (m, 1H), 7.25–7.39 (6H,
ArH), 7.60–7.65 (4H, ArH). 13C NMR (75 MHz, CDCl3):
19.2, 19.8, 22.2, 27.1, 30.3, 39.3, 40.1, 60.1, 65.1, 65.6, 98.4,
127.62, 127.65, 129.50, 135.5; IR 3071, 2933, 1428,
25
1109 cmꢀ1. FAB Mass: 412 (M+); ½aꢁD ꢀ2.5 (c 0.2, CHCl3).
25
144.5, 145.2, 146.6, 163.9, 172.4. ½aꢁD ꢀ43.8 (c 1.2,
16. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett.
1990, 31, 945; (b) Evans, D. A.; Rieger, D. L.; Gage, J. R.
Tetrahedron Lett. 1990, 31, 7099.
CHCl3).
13. Sabitha, G.; Syamala, M.; Yadav, J. S. Org. Lett. 1999, 11,
1701.
17. Spectral data of compound 30: 1H NMR (200 MHz,
CDCl3): d 1.24 (d, 3H, J = 6 Hz), 1.80–1.88 (m, 2H),
2.30–2.50 (m, 2H), 4.07 (m, 1H), 4.60 (m, 1H), 6.10 (dt, 1H,
J = 10, 2 Hz), 6.90 (ddd, 1H, J = 10, 4.4, 3.8 Hz); 13C NMR
(75 MHz, CDCl3): 23.6, 30.2, 43.5, 65.0, 76.8, 121.1, 145.4,
164.2; EI Mass: m/z 156 (M+); IR: 3422, 2925, 1712, 1253,
14. Spectral data of compound 1: 1H NMR (200 MHz,
CDCl3): d 1.21 (d, J = 6.0 Hz, 3H) 1.78 (m, 1H) 2.10 (m,
1H) 2.15–2.35 (m, 2H) 2.62 (t, J = 6.9 Hz, 2H) 2.82 (t,
J = 6.9 Hz, 2H) 4.25 (m, 1H) 5.08 (m, 1H) 6.03 (d,
J = 10.3 Hz, 1H) 6.59 (m, 1H) 6.70–6.86 (m, 3H). EI
25
25
Mass: m/z 320 (M+), ½aꢁD ꢀ80 (c 0.4, CHCl3).
1117 cmꢀ1. ½aꢁD ꢀ110 (c 1, CHCl3), lit.5 ꢀ111 (c 1, CHCl3).