Efficient synthesis of the C1-C9 fragment of 7,8-O-isopropylidene protected iriomoteolide 3a derivative

Article abstract of DOI:10.1002/jccs.201190054

An efficient and stereoselective synthesis of the C1-C9 moiety of the 7,8-O-isopropylidene protected iriomoteolide 3a derivative has been accomplished. In our strategy, we employed olefin cross-metathesis of the L-(+)-tartaric acid derivative (((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl) methoxy)(tert-butyl) diphenylsilane with a synthesized methyl (S)-3-methylhex-5-enate to successfully provide the correct olefin geometry of the desired fragment.

Full text of DOI:10.1002/jccs.201190054

Journal of the Chinese Chemical Society, 2011, 58, 31-34
31
Communication
Efficient Synthesis of the C1-C9 Fragment of 7,8-O-Isopropylidene
Protected Iriomoteolide 3a Derivative
Ching-Yao Chang
Department of Biotechnology, Asia University, Wufeng, Taichung, 413, Taiwan, R.O.C.
Received August 3, 2010; Accepted December 27, 2010; Published Online January 7, 2011
An efficient and stereoselective synthesis of the C1-C9 moiety of the 7,8-O-isopropylidene protected
iriomoteolide 3a derivative has been accomplished. In our strategy, we employed olefin cross-metathesis
of the L-(+)-tartaric acid derivative (((4S,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)methoxy)(tert-bu-
tyl)diphenylsilane with a synthesized methyl (S)-3-methylhex-5-enate to successfully provide the correct
olefin geometry of the desired fragment.
Keywords: Amphidinium sp.; Iriomoteolide 3a; Cytotoxic; Olefin cross-metathesis.
INTRODUCTION
Iriomoteolide 3a was isolated from the cultured algal
dene protected iriomoteolide 3a derivative. Following the
procedure of Akita,4 the commercially available L-(+)-tar-
taric acid is transformed to 4-O-(tert-butyldiphenylsilyl)-
2,3-O-isopropylidene-L-threitol (4), followed by Swern
oxidation to afford aldehyde 5. The crude aldehyde could
not be purified with silica chromatography due to its insta-
bility, 5 so it was used without purification in the Wittig
olefination to give the desired olefin 2 in 72% yield as a
colorless liquid (Scheme II).6
cells of a marine benthic dinoflagellate Amphidinium sp.
(strain HYA024), which was monoclonally separated from
sea sand collected from the Iriomote Island in Japan.
Iriomoteolide 3a and its 7,8-O-isopropylidene derivative
exhibit potent cytotoxicity against human B lymphocyte
DG-75 (IC50: 0.08 and 0.02 mg/mL, respectively) and also
against human B lymphocyte Raji cells infected with Ep-
stein-Barr virus (IC50: 0.05 and 0.02 mg/mL, respectively)
in vitro.1
The C1-C5 segment was developed from the com-
mercially available (S)-(-)-citronellic acid as shown in
Scheme III. Oxidative cleavage of (S)-(-)-citronellic acid
with OsO4/NaIO4 to give (S)-3-methyl-6-oxo-hexanoic
acid7 and subsequent reduction of the carbonyl group with
NaBH4 afforded (S)-6-hydroxy-3-methylhexanoic acid (6)
as a colorless liquid in 80% yield. A two-step sequence in-
volving iodination (NaI, TMSCl, CH3CN)8 and elimination
(t-BuOK, THF)9 produced (S)-3-methylhex-5-enoic acid
(7) in an excellent yield (98%). The spectral integration ra-
tio for the olefinic protons which appeared at d 5.82-5.72
(m, 1H) and d 5.06-5.02 (m, 2H) was 1:2, suggesting a ter-
minal alkenoid geometry in the double bond.
To the best of our knowledge, few examples have
been published on the synthesis of iriomoteolide 3a. In
2009, the successful total synthesis of iriomoteolide 3a and
various analogues was achieved by Nevado et al., and these
compounds were used for biological evaluation.2 More re-
cently, the synthesis of the macrocyclic core of iriomoteolide
3a was published by Reddy and co-workers. In this work,
the C1-C9 fragment was synthesized in eight steps in 34%
yield from (S)-(-)-citronellol.3 Herein, we report a conver-
gent and efficient synthesis of the C1-C9 fragment of the
7,8-O-isopropylidene protected iriomoteolide 3a deriva-
tive using (S)-(-)-citronellic acid as the starting material.
However, the key step in our strategy employed the
olefin cross-metathesis (CM) of olefin 2 with unsaturated
acid 7 using the 2nd generation Grubbs catalyst in CH2Cl2
under refluxing conditions.10 After 2 days, the expected
product could not be observed from the reaction mixture
RESULTS AND DISCUSSION
Scheme I illustrates our retrosynthetic strategy for the
synthesis of the C1-C9 fragment of the 7,8-O-isopropyli-
* Corresponding author. Tel: +886(4)23323456; Fax: +886(4)23316699; E-mail: cychang@asia.edu.tw

32 J. Chin. Chem. Soc., Vol. 58, No. 2, 2011
Chang
Scheme I Retrosynthetic analysis for the C1-C9 fragment of 7,8-O-isopropylidene protected iriomoteolide 3a
Scheme II
Reagents and conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, -84 °C; (b) Ph3P+CH3I-,
n-BuLi, THF, -84 °C to 0 °C, 72% over two steps
Scheme III
Reagents and conditions: (a) OsO4, NalO4, dioxane-H2O (1:1), rt, 16 h, then NaBH4,
MeOH, rt, overnight, 80%; (b) TMSCl/Nal, CH3CN, rt, 6 d, then t-BuOK, THF, rt, over-
night, 98%; (c) H2SO4, MeOH, rt, 16 h, 98%; (d) 2, Grubbs catalyst 2nd generation,
CH2Cl2, 50 °C, 24 h, 91%

Grubbs Catalyst, Cross-metathesis, Wittig Olefination
J. Chin. Chem. Soc., Vol. 58, No. 2, 2011 33
and instead the reaction resulted in recovery of the starting
materials. Next, the CM reaction was carried out in toluene
either at room temperature or under refluxing conditions,
but again only the starting materials could be recovered.11
Subsequently, the unsaturated acid 7 was esterified to
give methyl (3S)-3-methylhex-5-enate (3) in good yield
(98%). We then performed CM with compound 2 in CH2Cl2
in a sealed-tube at 50 ºC. The desired C1-C9 fragment 1
was successfully obtained after 24 hours in 91% yield. A
large coupling constant (15.2 Hz) for the olefinic protons
confirmed a transoid geometry of the double bond that is
consistent with the predicted structure of the C1-C9 frag-
ment of the 7,8-O-isopropylidene protected iriomoteolide
3a derivative. The physical and spectral data of these com-
pounds were in agreement with those reported in the litera-
ture.4-5,12
39.3, 30.0, 27.1, 26.9, 29.7, 19.5, 19.2; MS (FAB): m/z 509
(M-H)+; Anal. calcd for C30H42O5Si: C, 70.75; H, 8.19.
Found: C, 71.05; H, 8.07.
ACKNOWLEDGMENTS
We would like to thank the National Science Council
of the Republic of China (NSC 99-2113-M-468-001) and
Asia University for financial support. We thank the Depart-
ment of Chemistry, National Chung-Hsing University, Tai-
chung, Taiwan, R.O.C. for analyzing the NMR spectra.
REFERENCES AND NOTES
1. Oguchi, K.; Tsuda, M.; Iwamoto, R.; Okamoto, Y.; Kobayashi,
J.; Fukushi, E.; Kawabata, J.; Ozawa, T.; Masuda, A.;
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2. Cribiu, R.; Jager, C.; Nevado, C. Angew. Chem. Int. Ed.
2009, 48, 8780-8783.
3. Reddy, C. R.; Dharmapuri, G.; Rao, N. N. Org. Lett. 2009,
11, 5730-5733.
CONCLUSION
In summary, a short and efficient route is presented
for the stereoselective synthesis of the (5E)-(3S,7S,8S)-
C1-C9 fragment of the 7,8-O-isopropylidene protected
iriomoteolide 3a derivative in six steps with 70% overall
yield from commercially available (S)-(-)-citronellic acid.
We are actively pursuing the synthesis of other fragments
of iriomoteolide 3a, which will be reported in due course.
4. Uchida, K.; Kato, K.; Akita, H. Synthesis 1999, 1678-1686.
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EXPERIMENTAL
Olefin cross-metathesis of alkene 2 and methyl ester
3
7. Demuth, M.; Ritterskamp, P.; Weigt, E.; Schaffner, K. J. Am.
Chem. Soc. 1986, 108, 4149-4154.
The Grubbs 2nd generation catalyst (0.086 g, 10
mol%) was added to a pressure-resistant glass tube contain-
ing alkene 2 (0.396 g, 1 mmol) and methyl ester 3 (0.142 g,
1 mmol) in CH2Cl2 (3 mL). The reaction tube was purged
with N2 for 5 min. The tube was then sealed and heated to
50 ºC for 24 h. After cooling to room temperature, the sol-
vent was removed in vacuo to obtain a yellowish liquid
(0.74 g). The product was purified by flash column chro-
matography eluting with hexane/EtOAc (10:1) to afford 1
(0.462 g, 91%) as a colorless liquid. [a]D = -9.14 (c 1.28,
CHCl3); IR (neat) 2985, 2956, 2931, 2858, 1738, 1589,
1459, 1429, 1369, 1112 cm-1; 1H NMR (400 MHz, CDCl3)
d 7.70-7.66 (m, 4H), 7.41-7.26 (m, 6H), 5.71-5.64 (m, 1H),
5.45 (dd, J = 15.2, 7.6 Hz, 1H), 4.44 (t, J = 7.8 Hz, 1H),
3.84-3.61 (m, 3H), 3.67 (s, 3H), 2.33-2.31 (m, 1H), 2.12-
1.93 (m, 4H), 1.44 (s, 6H), 1.06 (s, 9H), 0.90 (d, J = 6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 173.3, 135.5, 133.1,
129.6, 129.4, 127.6, 108.7, 81.3, 78.5, 62.5, 51.3, 40.8,
8. Olah, G. A.; Narang, S. C.; Balaram Gupta, B. G.; Malhotra,
R. J. Org. Chem. 1979, 44, 1247-1251.
9. Mandel, A. L.; Bellosta, V.; Curran, D. P.; Cossy, J. Org.
Lett. 2009, 11, 3282-3285.
10. (a) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 11360-11370. (b) Chang,
Y.-K.; Lo, H.-J.; Yan, T.-H. Org. Lett. 2009, 11, 4278-4281.
(c) Chang, Y.-K.; Lo, H.-J.; Yan, T.-H. J. Chin. Chem. Soc.
2010, 57, 24-27.
11. Chang, C.-W.; Chen, Y.-N.; Adak, A. K.; Lin, K.-H.; Tzou,
D. M.; Lin, C.-C. Tetrahedron 2007, 63, 4310-4318.
12. (((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)meth-
oxy)(tert-butyl)diphenylsilane (2): [a]D = +1.05 (c 1.14,
CHCl3); IR (neat) 3071, 2932, 2858, 1647, 1471, 1427, 1371,
1
1241, 1138 cm-1; H NMR (400 MHz, CDCl3) d 7.71-7.67
(m, 4H), 7.45-7.37 (m, 6H), 5.89-5.80 (m, 1H), 5.34 (dd, J =
17.2, 1.6 Hz, 1H), 5.22 (dd, J = 7.6, 1.6 Hz, 1H), 4.47-4.44
(m, 1H), 3.85-3.73 (m, 3H), 1.44 (s, 6H), 1.06 (s, 9H); 13C
NMR (100 MHz, CDCl3) d 135.6, 133.2, 129.7, 129.6,
127.6, 118.1, 109.0, 81.2, 79.1, 62.9, 27.0, 26.9, 26.7, 19.2;

34 J. Chin. Chem. Soc., Vol. 58, No. 2, 2011
Chang
MS (FAB): m/z 396 (M+); Anal. calcd for C24H32O3Si: C,
72.88; H, 8.00. Found: C, 72.90; H, 8.25.
5.06-5.02 (m, 2H), 2.43-2.38 (m, 1H), 2.17-2.00 (m, 4H),
0.99 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
179.6, 136.1, 116.7, 40.8, 40.7, 29.8, 19.4; MS (EI): m/z 128
(M+); HRMS (EI) m/z calcd for C7H12O2 128.0837, found
128.0844.
(S)-6-Hydroxy-3-methylhexanoic acid (6): [a]D = -8.37 (c
1.23, CHCl3); IR (neat) 3360, 2958, 1708, 1407, 1170, 1055
cm-1; 1H NMR (400 MHz, CDCl3) d 3.66 (t, J = 6.6 Hz, 2H),
2.38-2.33 (m, 1H), 2.25-2.17 (m, 1H), 2.02-1.95 (m, 1H),
1.68-1.53 (m, 2H), 1.48-1.42 (m, 1H), 1.32-1.24 (m, 1H),
0.99 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
178.8, 62.9, 41.7, 32.7, 30.1, 29.9, 19.9; MS (EI): m/z 147
(M+H)+; Anal. calcd for C7H14O3: C, 57.53; H, 9.59. Found:
C, 57.19; H, 9.67.
Methyl (S)-3-methylhex-5-enate (3): [a]D = -2.00 (c 1.25,
CHCl3); IR (neat) 3078, 2957, 1740, 1641, 1437, 1221, 1174
1
cm-1; H NMR (400 MHz, CDCl3) d 5.81-5.71 (m, 1H),
5.03-5.00 (m, 2H), 3.67 (s, 3H), 2.36-2.33 (m, 1H), 2.14-
1.98 (m, 4H), 0.95 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 173.3, 136.2, 116.4, 51.2, 40.8, 40.6, 29.9, 19.4;
MS (EI): m/z 142 (M+); HRMS (EI) m/z calcd for C8H14O2
142.0994, found 142.0990.
(S)-3-Methylhex-5-enoic acid (7): [a]D = -0.71 (c 1.13,
CHCl3); IR (neat) 3078, 2962, 1709, 1641, 1413, 1297, 914
1
cm-1; H NMR (400 MHz, CDCl3) d 5.82-5.72 (m, 1H),