Metathesis-based synthesis of 3-methoxy α,β-unsaturated lactones: total synthesis of (R)-kavain and of the C1-C6 fragment of jerangolid D

Article abstract of DOI:10.1016/j.tetlet.2007.12.113

The total synthesis of (R)-kavain and of the C1-C6 fragment of jerangolid D has been achieved in nine and seven steps, respectively, from commercially available dimethyl d-malate. A metathesis reaction of vinyl ethers and a sulfoxide-modified Julia olefination have been employed as the key steps.

Full text of DOI:10.1016/j.tetlet.2007.12.113

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1523–1526
Metathesis-based synthesis of 3-methoxy a,b-unsaturated lactones:
total synthesis of (R)-kavain and of the C1–C6 fragment of jerangolid D
*
ˇ´
´ˇ
´
´
Jirı Pospısil, Istvan E. Marko
ˆ
Universite´ Catholique de Louvain, De´partement de Chimie, Batiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
Received 24 October 2007; revised 19 December 2007; accepted 20 December 2007
Available online 25 December 2007
Abstract
The total synthesis of (R)-kavain and of the C1–C6 fragment of jerangolid D has been achieved in nine and seven steps, respectively,
from commercially available dimethyl D-malate. A metathesis reaction of vinyl ethers and a sulfoxide-modified Julia olefination have
been employed as the key steps.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Kavain; Jerangolid D; Metathesis; Julia olefination; Sulfoxide-modified Julia olefination
A wide variety of natural products contain a lactone
core in their structures. In many cases, these compounds
display antitumor activities and the presence of an endo-
or exo-cyclic a,b-unsaturated lactone1 typically confers to
the molecule some antineoplastic activities (among
others).2
As a part of our ongoing research program toward the
efficient synthesis of natural products possessing anticancer
and antifungal properties, we became interested in the
development of novel approaches for the assembly of var-
ious lactone-bearing subunits. Our initial efforts in this field
culminated recently in the establishment of two novel
strategies leading to exo-methylenelactones. More recently,
the synthesis of 3-methoxy a,b-unsaturated lactones of the
general structure 1 was targeted.3
We became attracted by this particular class of lactones
because of their presence in various natural products, such
as kavain 2 and jerangolid D 3 (Scheme 1).
Kavain 2 belongs to the group of styryl lactone-deriva-
tives and it can be found in the Kava plant (Piper methys-
ticum). The Kava plant has a long and colorful history
spanning several thousand years.4 Kava has been used by
O
R
O
O
MeO
1
Sulfoxide-modified
Julia reaction
Kocienski-Julia
olefination
O
O
O
Me
O
O
MeO
MeO
Ph
H
H
Me
Jerangolid D (3)
(R)-Kavain (2)
Scheme 1. Retrosynthesis of kavain (2) and jerangolid D (3).
Pacific Island societies to prepare an intoxicating ceremo-
nial beverage renowned for its relaxing effects and ability
to promote sociability. Modern use of Kava root, com-
monly available in dietary supplements labeled ‘Kava
Kava’, is mostly reported for its purported anxiolytic5
and soporific qualities. Analgesic,6 anesthetic, antifungal,
antithrombotic,7 anticonvulsive,8 and muscle-relaxing9
properties have also been reported.4
Jerangolid D10 is a secondary metabolite produced by
the myxobacterium Sorangium cellulosum (strain So ce
307), a myxobacterium isolated in 1987 in the soil of Jeru-
salem. In vitro tests suggested that jerangolid D might be a
*
Corresponding author. Tel.: +32 10 472 740; fax: +32 10 472 788.
´
E-mail address: istvan.marko@uclouvain.be (I. E. Marko).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.113

1524
J. Pospı´sˇil, I. E. Marko´ / Tetrahedron Letters 49 (2008) 1523–1526
potentially useful antifungal agent, since it exhibits inter-
esting activities against the developing cells of Hansenula
anomala and Mucor hiemalis (ꢀ70 ng/mL); Pichia membra-
naefaciens, Debaryomyces hansenii, and Trichosporon ter-
restre (0.1–0.4 lg/mL); and Trichoderma hamata, Botritis
cinerea, and Candida albicans (4–7 lg/mL). The mechanism
of its action is believed to be similar to that of ambruti-
cin,11 another well-known myxobacterium isolate, for
which the mode of action is still unclear.
Having established an easy access to the desired interme-
diate 4, our first key step, the Grubbs’ metathesis, could be
challenged. From the literature precedents, it is known that
the metathesis reaction of electron-rich olefins,16 in parti-
cular enol ethers, is rather difficult and requires harsh con-
ditions, for example, prolonged reaction times, high
temperatures and high catalyst loading. For this reason,
the use of Schrock’s more reactive, though more sensitive,
catalyst17 is generally preferred.
Our retrosynthesis of lactone 1 was designed to use the
metathesis reaction as a key step (Scheme 2). As a conse-
quence, lactone 1 was disconnected at the C2–C3 positions,
leading to acrylate 4. The required vinyl ether function
present in 4 could then be prepared from ester 5 via tita-
nium alkylidenation of the C3 carbonyl group.
The sensitivity of the Schrock carbene prompted us to
perform our reactions using the 2nd generation Grubbs’
catalyst (GC-2) in a non-polar solvent.16a Thus, ester 4
was treated with GC-2 in deuterated toluene and the influ-
ence of the reaction conditions on the conversion was
monitored (Table 1).
The synthesis began with the selective reduction of the
C6 ester of (R)-dimethyl malate 6 to the corresponding pri-
mary alcohol,12 followed by the transformation of the
resulting C6 alcohol13 into a TBS ether (Scheme 3). The
remaining C5 alcohol was masked as a TMS ether and
the resulting compound 8 was reacted with titanium alkyl-
idene reagents. In our hands, Rainer’s modification of the
Takai–Utimoto reaction14 gave the best results,15 affording
the desired enol ether 9 in 74% yield.
It was observed that the metathesis reaction proceeded
somewhat better at 50 °C (Table 1, entry 1) than at higher
temperatures. In all cases, the catalyst was fully decom-
posed under the reaction conditions within 4–7 h. There-
fore, constant addition of the catalyst over a period of
66 h (5 mol % of GC-2 every 6 h) was performed. The start-
ing material 4 gradually disappeared, yielding the desired
lactone 10 in 88% yield (Table 1, entry 5). Unfortunately,
up to 55 mol % of GC-2 was consumed in this single
experiment.
These results, though rather encouraging, could not be
reconciled with our idea of a useful synthetic transforma-
tion. It was suggested that the low reactivity of 4 could
be due, among other potential problems, to its difficulty
in adopting an (S)-cis conformation and hence, enabling
the two alkene termini to reach a proper distance for the
reaction to occur.18 To overcome this problem and to
reduce the catalyst loading, it was decided to use the
modified metathesis precursor 11 (Fig. 1).19
Finally, a selective one pot TMS group removal/base
mediated esterification of the resulting C5 alkoxide accom-
plished the synthesis of the metathesis precursor 4.
O
O
1
R
1
2
R
O
2
O
OPG
4
4
5
6
3
5
6
MeO
3
4
1
O
OMe
The synthesis of 11 began with the monoprotected diol
7, which was transformed into acetals 12a and 12b via
O
OH
O
OH
4
6
OMe
OPG
3
5
3
5
MeO
MeO
4
6
6
O
5
Table 1
Scheme 2. Retrosynthesis of lactone 1.
Metathesis reaction of the precursor 4
MesN
NMes
1) BH3.SMe2
NaBH4, THF
O
OH
O
2
OH
MeO2C3
5
Cl
Cl
OTBS
Ru
PCy3
GC-2
3
MeO
2
O
O
OTBS
O
5
CO2Me
Ph
2) TBSCl, Et3N
7
6
OTBS
cat. DMAP, CH2Cl2
3
5
3
5
MeO
MeO
81%
TMSCl, Et3N
CH2Cl2
10a
4
Conversiona (%) Yielda (%)
98%
Entry Conditions
TiCl4, Zn, PbCl2,
CH2Br2, TMEDA,
O
OTMS
1
5 mol %, toluene-d8, 12 h, 50 °C
5 mol %, toluene-d8, 12 h, 60 °C
5 mol %, toluene-d8, 12 h, 70 °C
5 mol %, toluene-d8, 12 h, 80 °C
55 mol %, toluene-d8, 66 h, 50 °C 91
10 mol %, toluene-d8, 72 h, rt
20
18
10
5
20
18
10
5
88e
<5
OTMS
2b
3b
4c
5d
6
OTBS
OTBS
5
3
MeO
MeO
5
3
MeO
THF, CH2Cl2, 65 °C
74%
8
9
2
8
1) MeLi, THF, 0 °Cto r.t.
O
O
OTBS
Based on 1H NMR spectra.
Conversion stopped after 5–7 h.
Conversion stopped after 4 h.
5 mol % of GC-2 was added every 6 h.
Isolated yield.
a
CO Me
2)
, THF, r.t., 12 h
(exces2s)
b
c
3
5
92%
4
d
e
Scheme 3. Synthesis of metathesis precursor 4.

J. Pospı´sˇil, I. E. Marko´ / Tetrahedron Letters 49 (2008) 1523–1526
1525
compared to substrate 4, were observed (Table 2, entries
1–3).
R
2
σ
-bonds = free rotation
O
OEt
OTBS
The reaction proceeded with a slightly higher conver-
sion, but the decomposition of the catalyst under the reac-
tion conditions was still significant.
3
5
MeO
11
To avoid this decomposition, the reaction was
attempted at rt. in the presence of 50 mol % of GC-2 (Table
2, entry 4). After 24 h, a 39% conversion of 11a to cyclic
acetal 13a was reached. Allowing the cyclization to proceed
longer led to improved conversions.
Under the optimized conditions, only 10 mol % of GC-2
was required to fully transform 11 to 13 (Table 2, entries 5
and 6).21 The oxidation of acetals 13 with PCC then affor-
ded the desired lactones 10a and 10b in 56% and 51%
yields, respectively, over two steps.
Fig. 1. Alternative metathesis precursor 11.
PPTS-catalyzed trans-acylation of acrolein diethyl acetal
and methacrolein diethyl acetal,20 respectively (Scheme
4). Acetals 12a and 12b were then submitted to the
Takai–Utimoto olefination yielding the desired precursors
11a and 11b in 80% and 85% yields.
With the desired substrates in hand, the crucial ring clos-
ing metathesis could be tested again (Table 2). To our sur-
prise, no important changes in the reactivity of 11a, as
Removal of the TBS group of 10b furnished alcohol 14b,
the left-hand fragment of jerangolid D (3), in 81% yield
(Scheme 5).22
The C2 desmethyl lactone 10a was also deprotected
(82% yield) and the resulting alcohol 14a was then used
in the synthesis of (R)-kavain23 2 (Scheme 6). Thus, alcohol
14a was transformed into aldehyde 1a via Swern oxidation.
Lactone 1a was immediately reacted with benzyl phenyl
sulfoxide under our sulfoxide-Julia olefination conditions24
(Scheme 6), affording (R)-kavain 2 in 65% yield and with
an excellent E/Z selectivity.
R
OEt
2
OEt
O
OH
O
O
OEt
OTBS
R
OTBS
5
5
3
3
MeO
MeO
toluene, PPTS,
25 °C, 50-55 mbar
7
12a, R=H, 42%
12b
, R=Me, 49%
R
2
TiCl4, Zn, PbCl2,
CH2Br2, TMEDA,
The necessity to employ the sulfoxide version of the
Julia olefination reaction in this ultimate transformation
had been discussed previously.24c
O
OEt
11a
, R=H, 80%
11b, R=Me, 85%
OTBS
3
5
MeO
THF, CH2Cl2, 65 °C
In summary, the penultimate precursor of the left-hand
fragment of jerangolid D, alcohol 14b, was prepared in
seven steps and 16% overall yield from commercially avail-
able dimethyl D-malate 6. Similarly, (R)-kavain25 2 was
Scheme 4. Synthesis of precursor 11.
Table 2
RCM reaction of 11
R
OEt
O
O
2
R
Me
Me
2
O
2
TBAF
2
O
OEt
O
O
5
OTBS
3
MeO
OH
5
THF, 0 °C
81%
3
5
5
MeO
3
3
MeO
MeO
PCC,
CH2Cl2,
r.t., 4 h
OTBS
11a, R=H
OTBS
10b
13a, R=H
13b, R=Me
14b
jerangolid D C1-C6 fragment
11b, R=Me
O
Scheme 5. Synthesis of the C1–C6 fragment of jerangolid D.
R
2
O
3
5
MeO
OTBS
10a, R=H, 56% over
O
O
two steps (from entry 5)
2
2
O
O
TBAF
10b, R=Me, 51% over
OTBS
two steps (from entry 6)
3
5
3
5
MeO
MeO
THF, 0 °C
82%
14a
OH
10a
Entry
R
GC-2 loading Conditions
Yielda (%)
(mol %)
Swern
oxidation
1
2
3
4
5
6
H
H
H
H
H
Me
20b
30b
30b
50
10
10
Benzene, 50 °C, 4 h 21
Benzene, 70 °C, 6 h 26
Toluene, 50 °C, 6 h 21
1) PhS(O)Bn, LDA, THF, -78 °C
O
O
1a
2) , -78 °C, 2 h
3) BzCl, -78 °C to r.t.
4) SmI2, HMPA, THF, -78 °C
2
O
2
Benzene, rt, 24 h
Benzene, rt, 72 h
Benzene rt, 84 h
39
93
95
O
5
3
MeO
Ph
5
3
MeO
14a
, E/Z = >95:1
65% from
O
1a
(R)-Kavain 2
Based on the 1H NMR spectra.
a
b
10 mol % of GC-2 was added every 2 h.
Scheme 6. Total synthesis of (R)-kavain 2.

1526
J. Pospı´sˇil, I. E. Marko´ / Tetrahedron Letters 49 (2008) 1523–1526
10. (a) Reichenbach, H.; Ho¨fle, G.; Gerth, K.; Washausen, P. PCT Int.
Appl. 1997, DE 19607702, CAN 127:219644; (b) Gerth, K.; Washau-
sen, P.; Ho¨fle, G.; Irschik, H.; Reichenbach, H. J. Antibiot. 1996, 49,
71–75.
11. (a) Ringel, S. M.; Greenough, R. C.; Roemer, S.; Connor, D.; Gutt,
A. L.; Blair, B.; Kanter, G.; von Strandmann, M. J. Antibiot. 1977,
30, 371–378; (b) Connor, D. T.; Greenough, R. C.; von Strandtmann,
M. J. Org. Chem. 1977, 42, 3664–3669; (c) Knauth, P.; Reichenbach,
H. J. Antibiot. 2000, 53, 1182–1190.
12. (a) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu,
S.; Moriwake, T. Chem. Lett. 1984, 1389–1392; (b) Saito, S.;
Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T. Tetrahedron
1992, 48, 4067–4086.
13. Alcohol 7 was obtained as a 12:1 mixture of the C6 and C5
monosilylated diols. See Table S-1 (Supplementary information).
14. (a) Okazoe, T.; Takai, K.; Oshima, K.; Utimoto, K. J. Org. Chem.
1987, 52, 4410–4412; (b) Allwein, S. P.; Cox, J. M.; Howard, B. E.;
Johnson, H. W. B.; Rainier, J. D. Tetrahedron 2002, 58, 1997–
2009.
synthesized in nine steps and in 7.7% overall yield. To
achieve these goals, a simple approach toward 3-methoxy
a,b-unsaturated lactones of the general structure 1, based
upon the metathesis reaction of electron-rich alkenes, cou-
pled with our sulfoxide Julia olefination procedure was
employed.
Acknowledgments
´
Financial support of this work by the Universite catho-
lique de Louvain, Rhodia Ltd (studentship to J.P.), Merck
Sharp and Dohme (Merck Academic Development Award
to I.E.M.) is gratefully acknowledged.
Supplementary data
15. For the reaction optimization, see Table S-2 (Supplementary
information).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.12.113.
16. (a) Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2001, 42,
8023–8027; Use in total synthesis (b) Holson, E. B.; Roush, W. R.
Org. Lett. 2002, 4, 3719–3722; (c) Taillier, C.; Gille, B.; Bellosta, V.;
Cossy, J. J. Org. Chem. 2005, 70, 2097–2108; (d) Majumder, U.; Cox,
J. M.; Johnson, H. W. B.; Rainier, J. D. Chem. Eur. J. 2006, 12, 1736–
1746; (e) Johnson, H. W. B.; Majumder, U.; Rainier, J. D. Chem. Eur.
J. 2006, 12, 1747–1753.
References and notes
1. For a review see: Collins, I. J. Chem. Soc., Perkin Trans. 1 1999,
´ˇ
´
1377–1395; For recent examples see: (a) Pospısil, J.; Marko, I. E.
Tetrahedron Lett. 2006, 47, 5933–5937; (b) Gobbini, M.; Cerri, A.
Curr. Med. Chem. 2005, 12, 2343–2355; (c) de Fatima, A.; Pilli, R. A.
Tetrahedron Lett. 2003, 44, 8721–8724; (d) de Fatima, A.; Pilli, R. A.
ARKIVOC 2003, 10, 118–126; (e) Bruckner, R. Curr. Org. Chem.
2001, 5, 679–718; (f) Job, A.; Wolberg, M.; Muller, M.; Enders, D.
Synlett 2001, 1796–1798.
17. Schrock, R. R. Tetrahedron 1999, 55, 8141–8153.
18. Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29.
19. Stork, G.; Mook, R., Jr.; Biller, S. A.; Rychnovsky, S. D. J. Am.
Chem. Soc. 1983, 105, 3741–3742. Alternatively, initial reaction of
GC-2 with the enol ether function rather than the acrylate might lead
to a poorly active Fisher-type carbene. By shifting to an acetal,
preferential addition on C1–C2 takes place.
2. (a) Zhao, G.; Wu, B.; Wu, X. Y.; Zhang, Y. Z. Mini-Rev. Org. Chem.
2005, 2, 333–354; (b) Yet, L. Chem. Rev. 2003, 103, 4283–4306; (c)
Mereyala, H. B.; Joe, M. Curr. Med. Chem. – Anti-Cancer Agents
2001, 1, 293–300.
20. VanAllan, J. A. Org. Synth. 1952, 32, 5–8.
21. Interestingly, the same reaction conditions were applied to the
cyclization of 4, but only very low conversion (ꢀ20%) was observed.
22. For an alternative synthesis, leading to the jerangolid D C1–C6
´
3. (a) Leclercq, C.; Marko, I. E. Tetrahedron Lett. 2005, 46, 7229–7233;
´ˇ
´
fragment, see: Pospısil, J.; Marko, I. E. J. Am. Chem. Soc. 2007, 129,
´
(b) De Dobbeleer, C.; Ates, A.; Vanherk, J.-C.; Marko, I. E.
3516–3517.
´
Tetrahedron Lett. 2005, 46, 3889–3893; (c) Marko, I. E.; Dumeunier,
23. Previous total synthesis of (R)-kavain 2 (a) Smith, T. E.; Djang, M.;
Velander, A. J.; Downey, C. W.; Carroll, K. A.; Alphen, S. V. Org.
Lett. 2004, 6, 2317–2320; (b) Wang, F.-D.; Yue, J.-M. Synlett 2005,
2077–2079; (c) Sabitha, G.; Sudhakar, K.; Yadav, J. S. Tetrahedron
Lett. 2006, 47, 8599–8602.
R.; Leclercq, C.; Leroy, B.; Plancher, J.-M.; Mekhalfia, A.; Bayston,
D. J. Synthesis 2002, 958–972.
4. Lebot, V.; Merlin, M.; Lindstrom, L. Kava-the Pacific Elixir: The
Definitive Guide to its Ethnobotany, History, and Chemistry; Healing
Arts Press: Rochester, VT, 1997.
5. (a) Pittler, M. H.; Ernst, E. J. Clin. Psychopharm. 2000, 20, 84–89; (b)
Smith, K. K.; Dharmaratne, H. R. W.; Feltenstein, M. W.; Broom, S.
L.; Roach, J. T.; Nanayakkara, N. P. D.; Khan, I. A.; Sufka, K. J.
Psychopharmacology 2001, 155, 86–90.
6. (a) Jamieson, D. D.; Duffield, P. H. Clin. Exp. Pharmacol. Physiol.
1990, 17, 495–500; (b) Wu, D.; Yu, L.; Nair, M. G.; DeWitt, D. L.;
Ramsewak, R. S. Phytomedicine 2002, 9, 41–47.
7. Gleitz, J.; Beile, A.; Wilkens, P.; Ameri, A.; Peters, T. Planta Med.
1997, 63, 27–30.
8. Schmitz, D.; Zhang, C. L.; Chatterjee, S. S.; Heinemann, U. Arch.
Pharmacol. Toxicol. 1995, 351, 348–355.
9. Seitz, U.; Ameri, A.; Pelzer, H.; Gleitz, J.; Peters, T. Planta Med.
1997, 63, 303–306.
´ˇ
´ˇ
´
24. (a) Pospısil, J.; Pospısil, T.; Marko, I. E. Org. Lett. 2005, 7, 2373–
´ˇ ´ˇ
´
2376; (b) Pospısil, J.; Pospısil, T.; Marko, I. E. Collect. Czech Chem.
´ˇ
´
Commun. 2005, 70, 1953–1969; (c) Pospısil, J.; Marko, I. E.
Tetrahedron Lett. 2006, 47, 5933–5937.
25. Experimental data for (R)-(+)-kavain 2: 1H NMR (300 MHz, CDCl3)
d (ppm): 2.55 (dd, 1H, J = 17.1 Hz, J = 4.6 Hz), 2.68 (dd, 1H,
J = 17.1 Hz, J = 10.7 Hz), 3.77 (s, 3H), 5.06–5.09 (m, 1H), 5.20 (s,
1H), 6.27 (dd, 1H, J = 16.1 Hz, J = 6.3 Hz), 6.73 (d, 1H, J =
16.0 Hz), 7.29–7.41 (m, 5H). 13C NMR (75 MHz, CDCl3) d (ppm):
33.8, 56.5, 76.5, 91.1, 125.8, 133.2, 167.2, 127.0, 128.8, 129.2, 136.3,
172.6. Mp = 113–114 °C; lit. 112–113 °C.23a IR (KBr) m (cmꢁ1): 3063,
20
2967, 1703, 1626, 1394, 1248, 1233, 1063, 1024, 971, 747, 693. ½aꢂD
25
+120.3 (c 1.02, EtOH); lit. ½aꢂD +124.3 (c 1.00, EtOH).23a