Synthesis of iriomoteolide-1a C13-C23 fragment via asymmetric conjugate addition and Julia-Kocienski coupling reaction

Article abstract of DOI:10.1021/ol901480s

Image Presented The key C13-C23 fragment toward the total synthesis of iriomoteolide-1a (1) has been constructed from an 1,2-acetonide containing aldehyde 5 via a Julia-Kocienski olefination with the C16-C23 segment 6. The key step involves stereoselectiv

Full text of DOI:10.1021/ol901480s

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3674-3676
Synthesis of Iriomoteolide-1a C13-C23
Fragment via Asymmetric Conjugate
Addition and Julia-Kocienski Coupling
Reaction
Yen-Jin Chin, Shun-Yi Wang, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
teckpeng@ntu.edu.sg
Received June 30, 2009
ABSTRACT
The key C13-C23 fragment toward the total synthesis of iriomoteolide-1a (1) has been constructed from an 1,2-acetonide containing aldehyde
5 via a Julia-Kocienski olefination with the C16-C23 segment 6. The key step involves stereoselective introduction of the C29 methyl group
by a highly efficient CuI-Tol-BINAP-catalyzed asymmetric conjugate addition of methylmagnesium bromide to an r,ꢀ-unsaturated ester.
Recently, Tsuda and co-workers have reported isolation of
a series of macrolides named iriomoteolides from marine
dinoflagellates, Amphidinium sp., collected off the Iriomote
Island of Japan.1 Among them, iriomoteolide-1a (1) exhibited
potent cytotoxicity against human B lymphocyte DG-75 cells
with an IC50 of 2 ng/mL and Epstein-Barr virus (EBV)-
infected human B lymphocyte Raji cells with an IC50 of 3
ng/mL.1b To date, this natural product has yet to surrender
itself to any total synthesis. Nevertheless, Yang’s group and
Ghosh’s group have reported synthesis of the C1-C12
fragment.2 Moreover, Horne et al. lately has described the
synthetic route of the cyclic hemiketal core of the molecule.3
Its unique molecular structure and potent cytotoxicity have
also attracted our interest in its synthesis. Herein, we report
the synthesis of C13-C23 fragment of iriomoteolide-1a (1).
Our approach to the development of an efficient method
for the construction of iriomoteolide-1a (1) is as shown in
Scheme 1. The strategy involves stereoselective allylations
of 3 (C1-C9 segment) and 4 (C13-C23 segment) by
fragment 2 (C10-C12 segment), followed by a Yamaguchi
macrolactonization between the C1-carbonyl and C19-
hydroxyl group for construction of the macrolide ring.
Fragment 4 in turn, can be obtained via Julia-Kocienski
olefination between aldehyde 5 and sulfone 6, with E-alkene
geometry at C15-C16.
(1) The investigation of the Amphidinium strain HYA024 led to isolation
of iriomoteolide-1a (1), -1b, and -1c. (a) Isolation and structural elucidation
of iriomoteolide-1a (1): Tsuda, M.; Oguchi, K.; Iwamoto, R.; Okamoto,
Y.; Kobayashi, J.; Fukushi, E.; Kawabata, J.; Ozawa, T.; Masuda, A.; Kitaya,
Y.; Omasa, K. J. Org. Chem. 2007, 72, 4469. (b) Isolation and structural
elucidation of iriomoteolide-1b and -1c: Tsuda, M.; Oguchi, K.; Iwanmoto,
R.; Okamoto, Y.; Fukushi, E.; Kawabata, J.; Ozawa, T.; Masuda, A. J.
Nat. Prod. 2007, 70, 1661.
(4) The diastereoselectivity and enantioselectivity were determined by
comparison with the NMR spectroscopic and HPLC analytical results of
diastereomers obtained from this paper: Nots, W.; List, B. J. Am. Chem.
Soc. 2000, 122, 7386.
(5) Nicolaou, K. C.; Li, H.-M.; Nold, A. L.; Pappo, D.; Lenzen, A. J. Am.
Chem. Soc. 2007, 129, 10356.
(6) Compound 11a has also been used in an alternative synthesis of the
C13-C23 fragment (results submitted for publication).
(7) Nishikawa, T.; Urabe, D.; Isobe, M. Angew. Chem., Int. Ed. 2004,
43, 4785.
(2) (a) Fang, L. J.; Xue, H. R.; Yang, J. Org. Lett. 2008, 10, 4645. (b)
Ghosh, A. K.; Yuan, H. Tetrahedron Lett. 2009, 50, 1416.
(3) Xie, J.; Horne, D. A. Tetrahedron Lett. 2009, 50, 4485.
(8) Lum, T. K.; Wang, S. Y.; Loh, T. P. Org. Lett. 2008, 10, 761.
10.1021/ol901480s CCC: $40.75
Published on Web 07/23/2009
 2009 American Chemical Society

Scheme 1. Retrosynthetic Analysis of Iriomoteolide-1a (1)
Figure 1. Stereochemical Determination of 11a
unsaturated ester previously developed in our group, the C29
methyl moiety was stereoselectively introduced into the
acyclic carbon chain 15 using (R)-Tol-BINAP, to give 16 in
94% de (Table 1).9,10 Subsequently, DIBAL-H reduction
followed by asymmetric Brown crotylation11 of aldehyde 17
furnished 18 with two new stereogenic centers. Next, the
secondary hydroxyl group in 18 was protected as the
triethylsilyl ether. Following oxidation of the terminal olefin
Our synthesis of the aldehyde 5, shown in Scheme 2,
commences with cyclohexanecarbaldehyde 7 and hydroxy-
acetone 8. The direct asymmetric aldol reaction catalyzed
Scheme 2. Synthesis of Aldehyde 5
Scheme 3. Synthesis of Sulfone 6
by D-proline provided anti-diol 9 in 60% yield, with a dr
>20:1 and ee >99%.4 Ensuing isoproylidene formation5 was
employed to protect the 1,2-diol. The Grignard derived from
vinyl bromide was added smoothly to intermediate 10 leading
ultimately to tertiary alcohol 11a,6 whose diastereomeric
1
purity (80% de) was determined by H NMR analysis.
Subsequent silylation7 followed by ozonolysis generated
aldehyde 5. The stereochemistries were further confirmed
by X-ray structural analysis of PMB ether protected 11a
(Figure 1).
Our synthesis of sulfone 6 is depicted in Scheme 3. Silyl
ether protection of (-)-methyl-L-lactate 13 followed by a
one-pot DIBAL-H reduction-Wittig olefination8 protocol
afforded the trans-enoate 15 in 69% yield. By means of an
asymmetric conjugate addition of Grignard reagents to R,ꢀ-
Org. Lett., Vol. 11, No. 16, 2009
3675

Table 1. 1,4-Michael Addition of MeMgBr to 15a
Table 2. Julia-Kocienski Olefination
yield (%) anti:synb
entry
R
base (soln)
product (yield, %) E:Za
entry
ester
catalyst
1
2
3
TES KHMDS (in toluene)
TES KHMDS (in THF)
PMB KHMDS (in toluene)
4a (29)
4a (27)
4b (trace)
60:40
>99:1
1
2
trans-15 10 mol % CuI
trans-15 2 mol % CuI +
64
60
95:5
>99:1
3 mol % (S)-Tol-BINAP
trans-15 2 mol % CuI +
3 mol % (R)-Tol-BINAP
10 mol % CuI
a The E/Z ratios were determined by 1H NMR analysis of the crude
product mixtures.
3
4
63
0
3:97
cis-15
a All reactions were performed with 15 (0.5 mmol) and MeMgBr (2.5
mmol, 3 M in diethyl ether) in t-BuOMe (1 mL) at -20 °C. b Determined
by crude 13C NMR.
ingly, when KHMDS (in THF) was used, the desired product
was isolated as a single isomer, albeit in low yield (27%,
Table 2, entry 2). In addition, replacement of the TES ether
protecting group with a PMB ether proved detrimental,
suggesting steric effect from the adjacent tertiary protected
hydroxyl group in operation.
in 19 employing hydrogen peroxide as the oxidizing agent,12
the resulting primary alcohol 20 was subjected to Mitsunobu
protocol,13 affording the desired aryl sulfide 21 in good yield.
Finally, completion of the requisite sulfone 6 was achieved
by oxidation using ammonium molybdate and hydrogen
peroxide.13
With the aldehyde 5 and sulfone 6 in hand, we then carried
out Julia-Kocienski olefination14 (Table 2). The use of
KHMDS (in toluene) provided 4a (C13-C23 fragment) in
only 29% isolated yield with low regioselectivity. Interest-
In summary, we have developed an asymmetric synthesis
of the C13-C23 fragment of iriomoteolide-1a (1). Further
work toward the total synthesis of iriomoteolide-1a (1) is in
progress.
Acknowledgment. We gratefully acknowledge the Nan-
yang Technological University and Singapore of Education
Academic Research Fund Tier 2 (No. T206B1221 and
T207B1220RS) and Biomedical Research Council (05/1/22/
19/408) for the funding of this research.
(9) Diastereoselectivity was determined by 13C NMR by comparing an
average of carbon signals with respective diastereomeric mixtures of the
acyclic carbon chain. The stereochemistry was assigned on the basis of
enantiomeric Tol-BINAP ligands.
(10) (a) Wang, S. Y.; Ji, S. J.; Loh, T. P. J. Am. Chem. Soc. 2007, 129,
276. (b) Wang, S. Y.; Lum, T. K.; Ji, S. J.; Loh, T. P. AdV. Synth. Catal.
2008, 350, 673.
Supporting Information Available: Additional experi-
ment procedures, cif file of crystallographic data for com-
pound 12b, and NMR spectral data for reaction products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) (a) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 293.
(b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.
(12) Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org. Chem.
1989, 54, 5930.
(13) Paquette, L. A.; Chang, S. K. Org. Lett. 2005, 7, 3111.
(14) Esteban, J.; Costa, A. M.; Vilarrasa, J. Org. Lett. 2008, 10, 4843.
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