Improved enantioselective synthesis of natural striatenic acid and its methyl ester

Article abstract of DOI:10.1016/j.tetlet.2006.03.147

This letter describes the improved and efficient enantioselective synthesis of natural striatenic acid, isolated from Cheilolejeunea serpentina, and its methyl ester starting from a readily available enantiopure building block.

Full text of DOI:10.1016/j.tetlet.2006.03.147

Tetrahedron Letters 47 (2006) 3669–3671
Improved enantioselective synthesis of natural striatenic acid
and its methyl ester
*
*
´
´
Yoann Aubin, Gerard Audran and Honore Monti
Laboratoire de Re´activite´ Organique Se´lective, U.M.R. 6180 ‘Chirotechnologies: catalyse et biocatalyse’,
Universite´ Paul Ce´zanne, Aix-Marseille III, 13397 Marseille Cedex 20, France
Received 1 February 2006; revised 15 March 2006; accepted 22 March 2006
Available online 12 April 2006
Abstract—This letter describes the improved and efficient enantioselective synthesis of natural striatenic acid, isolated from
Cheilolejeunea serpentina, and its methyl ester starting from a readily available enantiopure building block.
ꢀ 2006 Elsevier Ltd. All rights reserved.
In 2000, Tori and his collaborators reported the isolation
of striatenic acid (+)-1, which was obtained from the liver-
wort Cheilolejeunea serpentina collected in Malaysia.1
They determined the structure and absolute configura-
tion of this striatane-type sesquiterpene by the synthesis
of the corresponding optically active methyl ester (+)-2
(Fig. 1). However, though this synthesis is suitable for
the characterization of the natural product, it suffers
from low yields at crucial steps and requires the use of
AgNO3-impregnated silica gel column chromatography
for the separation of undesired stereoisomers.
sane scaffold is considerably more efficient than the pre-
vious one and avoids the stereochemical problem of that
route. Our synthetic plan is outlined in Scheme 1. The
starting material is the readily available3 enone (+)-3.
Conjugate addition of organocopper reagents to 3,4-di-
methyl cyclohexenones is well documented and proceeds
with the generation of cis-vicinal methyls.4 Thus, expo-
sure of (+)-3 to the 1,4-addition of magnesium vinylcup-
rate, followed by quenching with methyl cyanoformate5
in hexamethylphosphoric triamide afforded 4 as a mix-
ture of highly enolizable b-keto esters in 74% yield.
Among four possible diastereomers, reduction of crude
4 with NaBH4 afforded, for the most part, the separable
diastereomeric carbomethoxy alcohols 5a/5b (3:2) in
85% yield.6 Since the stereochemistry of the two newly
generated stereogenic centres in 5a/5b is of no signifi-
cance for the final goal and will be extinguished later,
a convenient three-step procedure was then carried out
directly on 5a/5b mixture to furnish the key carbo-
methoxy aldehyde (+)-6 in 56% overall yield through
sequential mesylation of the hydroxyl functionality,
ozonolysis of the terminal olefin and DBU-promoted
elimination.7,8
As part of our research program on the total synthesis of
cyclofarnesane skeleton sesquiterpenoids,2 we describe
here an improved enantioselective synthesis of natural
striatenic acid (+)-1 and its methyl ester (+)-2. Our
straightforward approach of this rearranged cyclofarne-
CO2R
Wittig olefination of (+)-6 with the a-methoxy substi-
tuted ylid, obtained by reacting methoxymethyltri-
phenyl-phosphonium chloride9 with tert-BuOK in THF,
provided 7 as a mixture of stereoisomers in 62% yield.
Subsequently, hydrolysis at 0 ꢁC with 1 M HCl (THF/
H2O) afforded carbomethoxy aldehyde (+)-8 in
91% yield.7 Exposure of (+)-8 to the commercially
available 2-(triphenyl-phosphoranylidene) propionalde-
hyde stereoselectively gave the extended carbon chain
(+)-1 R = H
(+)-2 R = Me
Figure 1.
Keywords: Striatenic acid; Natural products; Enantioselective synthe-
sis; (+)-(2R,5R)-trans-Dihydrocarvone.
Corresponding authors. Tel./fax: +33 (0)4 9128 8862; e-mail:
g.audran@univ.u-3mrs.fr
*
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.147

3670
Y. Aubin et al. / Tetrahedron Letters 47 (2006) 3669–3671
CO2Me
CO2Me
CO2Me
OH
R
a
b
+
3 : 2
O
OH
O
(+)-5a
(
—)-5b
4
(+)-
3
OMe
CO2Me
CHO
CO2Me
CHO
CO2Me
d
c
e
7
(+)-6
(+)-8
CHO
CO2Me
CO2Me
CO2H
S
g
f
R
h
(+)-9
(+)-2
(+)-1
Scheme 1. Reagents and conditions: (a) CH2@CHMgBr, CuBrÆSMe2, THF, ꢁ78 ꢁC then HMPA and NCCO2Me, ꢁ78 ꢁC to rt, 74%; (b) NaBH4,
MeOH, ꢁ40 ꢁC to rt, 85%; (c) (i) MsCl, pyridine; (ii) O3, CH2Cl2, ꢁ78 ꢁC; SMe2; (iii) DBU, benzene, reflux, 56% for three steps; (d)
Ph3P+CH2OMeClꢁ, tert-BuOK, THF, rt, 62%; (e) 1 M HCl/THF 1:2, 0 ꢁC, 91%; (f) Ph3P@C(CH3)CHO, toluene, reflux, 84%; (g) Ph3P+MeIꢁ, tert-
BuOK, toluene, rt, 93%; (h) 1 M KOH/MeOH 1:1, 65 ꢁC, 85%.
´
E-a,b-unsaturated carbomethoxy aldehyde (+)-9 as a
single stereoisomer in 84% yield.7 At this stage, methyl-
enation of (+)-9 with the salt-free Wittig reagent, pre-
pared from methyltriphenyl-phosphonium iodide and
tert-BuOK, provided the methyl ester of striatenic acid
(+)-2 in 93% yield. The spectroscopic data (1H and
13C NMR) of (+)-2 matched those reported in the liter-
ature1,7 and the specific rotation10 was the same in
mique et chiralite, Pr. C. Roussel) for chiral HPLC anal-
yses. We thank P. Fournier for the English language
revision of the manuscript.
References and notes
1. Tori, M.; Aiba, A.; Koyama, H.; Hashimoto, T.; Naka-
shima, K.; Sono, M.; Asakawa, Y. Tetrahedron 2000, 56,
1655–1659.
magnitude and in sign [a2D5 +51.0 (c 1, CHCl3)/lit.1
20
½aꢀD +49.9 (c 0.8, CHCl3)]. Finally, saponification of
2. (a) Audran, G.; Galano, J.-M.; Monti, H. Eur. J. Org.
Chem. 2001, 2293–2296; (b) Uttaro, J.-P.; Audran, G.;
Palombo, E.; Monti, H. J. Org. Chem. 2003, 68, 5407–
5410; (c) Palombo, E.; Audran, G.; Monti, H. Tetrahedron
Lett. 2003, 44, 6463–6464; (d) Palombo, E.; Audran, G.;
Monti, H. Synlett 2005, 2104–2106; (e) Palombo, E.;
Audran, G.; Monti, H. Tetrahedron 2005, 61, 9545–
9549.
3. Obtained in two steps from (+)-(2R,5R)-trans-dihydro-
carvone, conveniently separated by column chromato-
graphy from its minor cis-isomer starting from the
commercial Aldrich mixture (hexane/ether 6:1). Eq. 1 (a)
Ozonolysis in methanol and then treatment with
Cu(OAc)2/FeSO4 led to (+)-(R)-6-methylcyclohex-2-en-1-
(+)-2 using 1 M KOH/MeOH at 65 ꢁC afforded the
crystalline target molecule (+)-1 (mp 106 ꢁC) in 85%
1
yield. The H and 13C NMR spectra of our synthetic
sample were in complete agreement with those of the
25
literature, but the specific rotation [½aꢀD +36.0 (c 1,
20
CHCl3)] was slightly different in magnitude [lit.1 ½aꢀD
+43.5 (c 2.7, CHCl3)], probably due to the high purity
of our sample. The crystalline nature of natural striate-
nic acid has not been reported in the original isolation
from the liverwort C. serpentina.
In conclusion, we have presented a highly efficient syn-
thetic route to striatenic acid via the corresponding
methyl ester. The target molecule (+)-1 was prepared
from a versatile enantiopure building block by a 10-step
sequence in 14% overall yield (9-step sequence in 16%
overall yield for (+)-2). We believe that our strategy
compares favourably with the one described1 as far as
stereoselectivity, chemical yields and high purity of the
crystalline target molecule are concerned. The applica-
tion of this methodology to the synthesis of other rear-
ranged cyclofarnesane skeleton sesquiterpeno¨ıds is in
progress and will be given in due course.
´
one (Solladie, G.; Hutt, J. J. Org. Chem. 1987, 52, 3560–
3566); (b) Treatment of this ketone with methyllithium,
followed by oxidation with pyridinium chlorochromate
(PCC), afforded (+)-3 (Iio, H.; Monden, M.; Okada, K.;
Tokoroyama, T. J. Chem. Soc., Chem. Commun. 1987,
358–359; See also: Dauben, W. G.; Michno, D. M. J. Org.
Chem. 1977, 42, 682–685).
O
O
b
a
R
(1)
R
R
R
O
(+)-
3
Acknowledgements
4. (a) Ziegler, F. E.; Wender, P. A. Tetrahedron Lett. 1974,
449–452; (b) Ziegler, F. E.; Reid, G. R.; Studt, W. L.;
Wender, P. A. J. Org. Chem. 1977, 42, 1991–2001; (c)
We are thankful to Dr. R. Faure for NOESY and COSY
´ ´
experiments and Dr. N. Vanthuyne (Stereochimie dyna-

Y. Aubin et al. / Tetrahedron Letters 47 (2006) 3669–3671
3671
Cory, R. M.; Burton, L. P. J.; Chan, D. M. T.; McLaren,
F. R.; Rastall, M. H.; Renneboog, R. M. Can. J. Chem.
1984, 62, 1908–1921; (d) Safaryn, J. E.; Chiarello, J.;
Chen, K. M.; Joullie, M. M. Tetrahedron 1986, 42, 2635–
2642.
J = 16.0, 4.1, 1.5 Hz, 2H), 2.24–2.17 (m, 2H), 1.70 (dqd,
J = 10.8, 6.8, 3.0 Hz, 1H), 1.58–1.40 (m, 2H), 1.16 (s, 3H),
0.94 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): d
203.4 (CH), 167.4 (C), 141.9 (CH), 135.8 (C), 51.5 (CH3),
50.0 (CH2), 38.3 (C), 36.7 (CH), 25.7 (CH2), 25.6 (CH2),
20.9 (CH3), 15.4 (CH3). Anal. Calcd for C12H18O3: C,
68.54; H, 8.63. Found: C, 68.35; H, 8.68. Compound (+)-
5. Mander, L. N.; Sethi, P. Tetrahedron Lett. 1983, 24, 5425–
5428.
25
1
6. At this stage, and before the next three-step sequence, an
aliquot of the 5a/5b mixture was carefully separated by
column chromatography on silica gel and analyzed in
order to confirm the expected gross structures. Assignment
of the complete stereochemistry as showed in Scheme 1
was deduced on the basis of the connectivities observed in
9. ½aꢀD +44.0 (c 1, CHCl3), H NMR (300 MHz, CDCl3):
d 9.31 (s, 1H), 7.00 (t, J = 3.9 Hz, 1H), 6.27 (ddq, J = 8.4,
6.2, 1.3 Hz, 1H), 3.66 (s, 3H), 3.03 (ddq, J = 16.3, 6.2,
1.1 Hz, 1H), 2.60 (dd, J = 16.3, 8.4 Hz, 1H), 2.21–2.13 (m,
2H), 1.71 (br s, 3H), 1.64–1.39 (m, 3H), 1.19 (s, 3H), 0.90
(d, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 195.2
(CH), 167.4 (C), 152.1 (CH), 142.2 (CH), 140.4 (C), 136.2
(C), 51.4 (CH3), 40.0 (C), 35.8 (CH2), 35.3 (CH), 25.7
(CH2), 25.6 (CH2), 20.9 (CH3), 15.6 (CH3), 9.4 (CH3).
Anal. Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C,
25
COSY and NOESY experiments. Compound (+)-5a. ½aꢀD
1
+43.0 (c 1, CHCl3), H NMR (500 MHz, CDCl3): d 5.58
(dd, J = 17.4, 10.7 Hz, 1H), 4.99 (dd, J = 10.7, 1.1 Hz,
1H), 4.86 (dd, J = 17.4, 1.1 Hz, 1H), 4.14 (q, J = 2.3 Hz,
1H), 3.91 (d, J = 2.3 Hz, 1H), 3.59 (s, 3H), 2.33 (d,
J = 2.3 Hz, 1H), 1.90 (dq, J = 14.0, 3.5 Hz, 1H), 1.68 (qd,
J = 13.5, 3.6 Hz, 1H), 1.44 (tt, J = 13.7, 3.6 Hz, 1H), 1.39–
1.32 (m, 2H), 1.13 (s, 3H), 0.75 (d, J = 6.8 Hz, 3H). 13C
NMR (75 MHz, CDCl3): d 175.6 (C), 147.5 (CH), 112.6
(CH2), 66.8 (CH), 54.6 (CH), 51.0 (CH3), 42.9 (C), 40.1
(CH), 31.6 (CH2), 24.2 (CH2), 16.3 (CH3), 12.3 (CH3).
Anal. Calcd for C12H20O3: C, 67.89; H, 9.50. Found: C,
25
72.31; H, 8.89. Compound (+)-2. ½aꢀD +51.0 (c 1, CHCl3),
1H NMR (300 MHz, CDCl3): d 6.90 (t, J = 3.9 Hz, 1H),
6.32 (dd, J = 17.4, 10.8 Hz, 1H), 5.24 (br t, J = 7.2 Hz,
1H), 5.03 (d, J = 17.4 Hz, 1H), 4.88 (d, J = 10.8 Hz, 1H),
3.66 (s, 3H), 2.73 and 2.40 (ABX, J = 15.5, 8.3, 6.1 Hz,
2H), 2.18–2.09 (m, 2H), 1.71 (s, 3H), 1.69–1.61 (m, 1H),
1.55–1.46 (m, 1H), 1.39–1.35 (m, 1H), 1.15 (s, 3H), 0.89 (d,
J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 167.9 (C),
141.8 (CH), 140.8 (CH), 137.3 (C), 135.1 (C), 130.0 (CH),
110.2 (CH2), 51.2 (CH3), 40.0 (C), 34.9 (CH2), 34.5 (CH),
25.9 (CH2), 25.6 (CH2), 20.9 (CH3), 15.7 (CH3), 11.9
(CH3). Anal. Calcd for C16H24O2: C, 77.38; H, 9.74.
Found: C, 77.09; H, 9.78. Compound (+)-1. Mp = 106 ꢁC,
25
68.12; H, 9.47. Compound (ꢁ)-5b. Mp = 62 ꢁC, ½aꢀD
1
ꢁ17.0 (c 1, CHCl3), H NMR (500 MHz, CDCl3): d 6.25
(dd, J = 17.4, 11.1 Hz, 1H), 5.02 (dd, J = 11.1, 0.8 Hz,
1H), 4.98 (dd J = 17.4, 0.8 Hz, 1 Hz, 1H), 4.09 (td,
J = 10.4, 4.8 Hz, 1H), 3.69 (s, 3H), 2.48 (d, J = 10.4 Hz,
1H), 1.90 (tt, J = 13.8, 4.3 Hz, 1H), 1.85–1.76 (m, 2H),
1.62 (br s, 1H), 1.51 (tdd, J = 13.1, 11.0, 4.1 Hz, 1H), 1.39
(dq, J = 13.8, 3.2 Hz, 1H), 1.05 (s, 3H), 1.01 (d,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 174.2
(C), 143.5 (CH), 112.6 (CH2), 68.6 (CH), 55.8 (CH), 51.2
(CH3), 42.7 (C), 37.1 (CH), 28.3 (CH2), 26.9 (CH2), 25.1
(CH3), 14.7 (CH3). Anal. Calcd for C12H20O3: C, 67.89; H,
9.50. Found: C, 68.07; H, 9.53.
25
1
½aꢀD +36.0 (c 1, CHCl3), H NMR (300 MHz, CDCl3): d
7.14 (t, J = 3.9 Hz, 1H), 6.31 (dd, J = 17.4, 10.6 Hz, 1H),
5.28 (br t, J = 7.5 Hz, 1H), 5.03 (d, J = 17.4 Hz, 1H), 4.88
(d, J = 10.6 Hz, 1H), 2.83 and 2.40 (ABX, J = 15.7, 8.8,
6.1 Hz, 2H), 2.21–2.15 (m, 2H), 1.75 (s, 3H), 1.73–1.61 (m,
1H), 1.55–1.36 (m, 2H), 1.15 (s, 3H), 0.89 (d, J = 6.8 Hz,
3H). 13C NMR (75 MHz, CDCl3): d 172.8 (C), 144.1
(CH), 141.8 (CH), 136.4 (C), 135.1 (C), 130.0 (CH), 110.3
(CH2), 39.9 (C), 34.7 (CH2), 34.6 (CH), 25.9 (CH2), 25.8
(CH2), 20.7 (CH3), 15.7 (CH3), 11.9 (CH3). Anal.
Calcd for C15H22O2: C, 76.88; H, 9.46. Found: C, 76.53;
H, 9.49.
7. All new compounds were fully characterized spectro-
scopically and had satisfactory microanalyses. Selected data:
25
Compound (+)-6. Mp = 54 ꢁC, ½aꢀD +41.0 (c 1, CHCl3),
1H NMR (300 MHz, CDCl3): d 9.32 (s, 1H), 7.22 (t,
J = 4.0 Hz, 1H), 3.69 (s, 3H), 2.32–2.25 (m, 2H), 1.76
(dqd, J = 12.2, 6.8, 3.0 Hz, 1H), 1.71–1.59 (m, 1H), 1.45–
1.34 (m, 1H), 1.12 (s, 3H), 0.80 (d, J = 6.9 Hz, 3H). 13C
NMR (75 MHz, CDCl3): d 201.5 (CH), 166.7 (C), 143.5
(CH), 133.2 (C), 51.8 (CH3), 51.0 (C), 31.6 (CH), 26.0
(CH2), 24.9 (CH2), 15.4 (CH3), 13.5 (CH3). Anal. Calcd
for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.56; H, 8.19.
8. Direct transformation of the b-ketoester into a,b-unsatu-
rated ester using Cp2ZrHCl (Schwartz reagent) was
unfitted for our synthetic sequence [Godfrey, A. G.;
Ganem, B. Tetrahedron Lett. 1992, 33, 7461–7464].
9. Soderquist, J. A.; Ramos-Veguilla, J. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; John
Wiley & Sons: Chichester, 1995; Vol. 5, pp 3363–3365.
10. The high enantiomeric purity of (+)-2 was verified by
chiral HPLC [>98% ee; Chiralpak AD (250 · 4.6 mm)
column, hexane, 1 mL/min].
25
Compound (+)-8. ½aꢀ +118 (c 1, CHCl3), 1H NMR
(300 MHz, CDCl3): d D9.59 (dd, J = 4.1, 1.5 Hz, 1H), 7.05
(t, J = 3.9 Hz, 1H), 3.70 (s, 3H), 3.18 and 2.55 (ABX,