Stereoselective synthesis of the C1-C12 segment of iriomoteolide-1a: a very potent macrolide antitumor agent

Article abstract of DOI:10.1016/j.tetlet.2009.01.043

A stereoselective synthesis of the C₁-C₁₂ segment of the potent cytotoxic macrolide, iriomoteolide 1a, has been accomplished. The key steps involve an enzymatic kinetic resolution of a β-hydroxy amide, a Pd-catalyzed cross-coupling t

Full text of DOI:10.1016/j.tetlet.2009.01.043

Tetrahedron Letters 50 (2009) 1416–1418
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of the C1–C12 segment of iriomoteolide-1a:
a very potent macrolide antitumor agent
*
Arun K. Ghosh , Hao Yuan
Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective synthesis of the C1–C12 segment of the potent cytotoxic macrolide, iriomoteolide 1a, has
been accomplished. The key steps involve an enzymatic kinetic resolution of a b-hydroxy amide, a Pd-cat-
alyzed cross-coupling to construct a substituted allylsilane, a highly and stereoselective conjugate addi-
Received 5 November 2008
Revised 24 December 2008
Accepted 9 January 2009
Available online 14 January 2009
tion of lithium dimethylcopper to an
a,b-acetylenic ester and an elaboration of the C6–C7 trans-olefin
geometry by a Julia-Kocienski olefination.
Ó 2009 Elsevier Ltd. All rights reserved.
Macrocyclic marine natural products are a rich source of potent
and structurally novel anticancer agents with clinical potential.1
Over the years, Kobayashi and co-workers have reported isolation
of a variety of structurally diverse macrolides known as amphidino-
lides from marine dinoflagellates, Amphidinium Sp.2 Recently, Tsuda
and co-workers isolated iriomoteolide-1a (1), a 20-membered mac-
rolide from Amphidinium Sp. from benthic sea sand collected off Irio-
mote island in Japan.3 Iriomoteolide-1a displayed remarkably
potent cytotoxicity against human B lymphocyte DG-75 cells with
an IC50 value of 2 ng/mL. Furthermore, it has shown cytotoxicity
against Epstein-Barr virus—infected human B lymphocyte Raji cells
with IC50 value of 3 ng/mL. Despite its potent activity, the biological
mechanism of action of iriomoteolide-1a is currently unknown. The
gross structure of 1 was established by extensive mass spectroscopy
and NMR studies.3 The unique structural features of iriomoteo-
lide-1a coupled with its potent antitumor activity attracted our
interest in its synthesis and structure-activity studies. Herein, we re-
port synthesis of the C1–C12 segment of iriomoteolide 1a in which
the key steps involve lipase-catalyzed kinetic resolution of a b-hy-
droxy amide, a highly stereoselective conjugate addition, and a Ju-
lia-Kocienski olefination to install the C6–C7 trans-olefin geometry.
Thus far, only Yang and co-workers have reported the synthesis of
C1–C12 fragment of iriomoteolide 1a, and the total synthesis of iri-
omoteolide has not yet been achieved.4
The synthesis of sulfone 4 was carried out as shown in Scheme 1.
Deprotonation of N-methoxy-N-methylacetamide by lithium diiso-
propylamide followed by reaction of the resulting enolate with
acrolein at À78 °C gave racemic alcohol 6 in 91% yield. The racemic
alcohol 6 was then exposed to an enzymatic acylation reaction using
lipase PS-30 in pentane in the presence of excess vinyl acetate at
25 °C for 30 h to provide enantio-enriched acetate derivative 7 in
49% yield and alcohol (R)-(+)-6 in 45% yield.7 The alcohol was
OH
HO
12
18
OH
1
O
O
O
8
H
4
Iriomoteolide 1a (1)
OH
TMS
12
MEMO
TBS
OTBS
O
HO
O
1
H
+
As shown in Figure 1, our synthetic strategy of iriomoteolide 1a
is convergent, and involves the assembly of fragments 2 (C1–C12
segment) and 3 (C13–C23 segment) by a Sakurai reaction5 and sub-
sequent macrolactonization between the C19-hydroxyl group and
the C1-carboxylic acid. Segment 2 was can be synthesized by a Ju-
lia-Kocienski olefination reaction6 between sulfone 4 and aldehyde
5. This reaction is expected to establish the C6–C7 trans-olefin
geometry.
PMBO
MOMO
2
3
Ph
OTBS
H
N
N
OTBS
N
+
O
N
S
MOMO
O
O
TMS
4
5
* Corresponding author. Tel.: +1 765 494 5323; fax: +1 765 496 1612.
E-mail address: akghosh@purdue.edu (A.K. Ghosh).
Figure 1. Retrosynthetic analysis of iriomoteolide 1a.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.043

A. K. Ghosh, H. Yuan / Tetrahedron Letters 50 (2009) 1416–1418
OAc
1417
OtBu
OtBu
OtBu
O
OH
O
Lipase PS-30
Lipase PS-30
Me
Me
OAc
Pentane
N
N
OH
OAc
15
O
O
OAc
OMe
OMe
_
_ 6
(+)-
7
+
( )-14
Pentane
+
+
CH3
R
O
OTBS
O
OR
1. TBSCl,
Imid.
MeMgBr
THF, -20 °C
96%
OH
18
Me
N
2. DIBAL-H,
9
OTBS
OH
O
OMe
CH2Cl2
1. BH3.Me2S,
6,
R (+)- R = H
82%
LDA, MeI
1. Swern
16
, R = H
17
aq sodium perborate
2. TBSCl, Imid.
3. Swern
65%
TBSCl, Imid.
2. CBr4, PPh3
8
, R = TBS
, R = Me
90%
97%
3. nBuLi, ClCO2Me
73%
TMS
O
OMe
HA
1. KHMDS,
PhNTf2
O
OTBS
OTBS
CH3
CH3
MeLi, CuI
THF
2. Pd(PPh3)4 (cat),
LiCl, Et2O,
MOMO
10
OR
CO2Me
11
96%
OTBS
OTBS
HB
HB
TMSCH2MgCl
HB
1. DIBAL-H
2. TBSCl, Imid.
NOE
21
N
19, R = TBS
20, R = MOM
1. HF.Py
1. PPTS, MeOH
2. 12, PPh3, DIAD
N
69%
N
2. MOMCl,
84%
N
HS
DIPEA
61%
95%
Ph
12
OTBS
OTBS
CH3
OTBS
OTBS
H
CH3
(NH4)6Mo7O24
.4H2O
1. OsO4, NMO
N
N
N
N
O
N
N
2. Pb(OAc)4, Py
62%
MOMO
H2O2, EtOH
MOMO
22
N
N
S
S
5
O
O
Ph
Ph
52%
TMS
TMS
4
13
Scheme 2. Synthesis of aldehyde 5.
Scheme 1. Synthesis of sulfone 4.
converted to its corresponding Mosher’s ester, and an optical purity
of 97% ee was determined by 19F NMR analysis.8 Protection of alco-
hol R(+)-6 with tert-butyldimethylsilyl chloride and imidazole pro-
vided silyl ether 8. Reaction of 8 with methylmagnesium bromide
furnished methyl ketone 9 in 96% yield. Treatment of 9 with borane
dimethylsulfide complex resulted in hydroboration of the olefin as
well as in the reduction of the ketone providing a diol. The resulting
diol was selectively protected to give the bis-silyl ether. Swern oxi-
dation of the resulting alcohol furnished methyl ketone 10. Treat-
ment of methyl ketone 10 with KHMDS and phenyl triflimide in
THF from À100 °C to À78 °C gave the corresponding vinyl triflate.
Cross-coupling9 of the triflate and trimethylsilylmethylmagnesium
chloride in the presence of a catalytic amount of Pd(PPh3)4 (7 mol %)
afforded the allyl silane 11 in 69% yield in two steps. Treatment of
silyl ether 11 with pyridinium p-toluenesulfonate in methanol at
23 °C for 4 h resulted in the deprotection of the primary silyl ether
to provide the corresponding alcohol. A Mitsunobu reaction of the
alcohol with 1-phenyl-1H-tetrazole-5-thiol furnished the sulfide
13. It was oxidized by hydrogen peroxide in the presence of ammo-
nium molybdate to furnish sulfone 4, as one of the Julia-Kocienski
olefination precursors.
The synthesis of aldehyde is outlined in Scheme 2. Enolization
of tert-butylacetate using lithium diisopropylamide followed by
reaction of the resulting enolate with acrolein at À78 °C gave
racemic alcohol 14 in 90% yield.10 The racemic alcohol 14 was
then exposed to lipase PS-30 in pentane in the presence of ex-
cess vinyl acetate at 30 °C for 19 h to provide acetate derivative
15 and enantio-enriched alcohol 16 in 47% and 44% yields,
respectively.11 The alcohol was converted to the corresponding
Mosher ester, and 19F NMR analysis revealed optical purity to
be 98% ee.8 Treatment of alcohol 16 with lithium diisopropyl-
amide followed by reaction of the resulting dianion with methyl
iodide as described by Seebach and co-workers afforded the
anti-alcohol 17 as a single isomer by 1H-NMR analysis.12 Protec-
tion of alcohol as TBS-ether followed by DIBAL-H reduction
afforded alcohol 18. Swern oxidation of 18 followed by subjec-
tion of the resulting aldehyde to Corey-Fuchs’ homologation13
aldehyde 5. Using carbon tetrabromide and triphenyl-phosphine
in dichloromethane at 0 °C to 23 °C for 30 min afforded the cor-
responding dibromo olefin in 90% yield for two steps. Treatment
of the dibromide with butyl lithium followed by reaction of the
derived alkynyl anion with methyl chloroformate furnished the
alkynyl ester 19 in near quantitative yield. Removal of the
TBS-ether by exposure to HFÁpyridine followed by protection of
the alcohol as a MOM-ether with MOMCl and diisopropylethyl-
amine afforded 20 in 95% yield. Alkynyl ester 20 was treated
with freshly prepared Me2CuLi14 to provide the Z-olefin 21 as
a single product in 96% isolated yield. The observed NOESY
among the protons is consistent with the assigned Z-olefin
geometry in ester 21. DIBAL-H reduction followed by protection
with tert-butyldimethylsilyl chloride furnished the silyl ether 22.
Selective oxidative cleavage of the terminal olefin provided the
other Julia-Kocienski olefination precursor, aldehyde 5.
With the aldehyde and sulfone in hand, we then carried out
Julia-Kocienski olefination as shown in Scheme 3. Thus, treat-
ment of sulfone 4 with KHMDS in THF followed by addition of
aldehyde 5 provided 2 (C1–C12 segment) in 71% isolated yield.15
To test the feasibility of the Sakurai reaction, we have investi-
gated reaction of allyl silane 2 with isobutylaldehyde as a model.
As shown, the reaction of 2 with 1.5 equiv of isobutylaldehyde in
the presence of 1.5 equiv of SnCl4 and 0.5 equiv of Et3N at
À78 °C for 10 min in CH2Cl2 afforded alcohol 23 as a mixture
(1:1.5) of diastereoisomers in 43% yield. Dess–Martin Period-
inane oxidization of the alcohol mixture furnished ketone 24 in
85% yield.15
In summary, a highly stereocontrolled synthesis of the C1–C12
fragment of iriomoteolide 1a has been achieved. Lipase-catalyzed
kinetic resolution of b-hydroxy amide provided the key starting
material for the synthesis. Other important steps involve a Pd-cat-
alyzed cross-coupling reaction, a highly stereoselective conjugate
addition of methylcuprate to an
a,b-acetylenic ester, and elabora-
tion of the C6–C7 trans-olefin geometry by a Julia-Kocienski olefin-

1418
A. K. Ghosh, H. Yuan / Tetrahedron Letters 50 (2009) 1416–1418
TMS
References and notes
TBS
1. Harris, C. R.; Danishefsky, S. J. J. Org. Chem. 1999, 64, 8434.
2. Kobayashi, J.; Kubota, T. J. Nat. Prod. 2007, 70, 451.
KHMDS, THF
OTBS
O
4
3. 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.
4. Fang, L.; Xue, H.; Yang, J. Org. Lett. 2008, 10, 4645.
5. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 1295.
then 5
71%
2
MOMO
6. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26.
7. Enzymatic resolution of b-hydroxy amide, particularly with Weinreb amide,
has not been reported. For enzymatic resolution of b-hydroxy ester, see:
Vrielynck, S.; Vandewalle, M.; García, A. M.; Mascareñas, J. L.; Mouriño, A.
Tetrahderon Lett. 1995, 36, 9023.
SnCl4, Et3N
Me2CHCHO
43%
OH
O
8. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543.
9. Enev, V. S.; Kachlig, H.; Mulzer, J. J. Am. Chem. Soc. 2001, 123, 10764.
10. Ghosh, A. K.; Kulkarni, S. Org. Lett. 2008, 10, 3907.
11. Pollini, G. P.; Risi, C. D.; Lumento, F.; Marchetti, P.; Zanirato, V. Synlett 2005,
164.
TBS
O
TBS
O
DMP,
NaHCO3
OTBS
OTBS
12. (a) Seebach, D.; Aebi, J.; Wasmuth, D. Organic Synthesis; John Wiley and Sons:
New York, 1990. Collect. Vol. III. pp 153–159; (b) Hermann, J. L.; Schlessinger,
R. A. Tetrahedron Lett. 1973, 14, 2429.
85%
24
23
MOMO
MOMO
13. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
14. Corey, E. J.; Katzenel, J. J. Am. Chem. Soc. 1969, 91, 1851.
15. All new compounds gave satisfactory spectroscopic and analytical results.
Compound 2: 1H NMR (CDCl3): d 5.66 (dt, J = 15.5, 7.0 Hz, 1H), 5.38 (t, J = 5 Hz,
1H), 5.25 (dd, J = 15.5, 9.0 Hz, 1H), 4.65 (d, J = 7.0 Hz, 1H), 4.60 (d, J = 2.5 Hz,
1H), 4.57 (d, J = 2.5 Hz, 1H), 4.37 (d, J = 7.0 Hz, 1H), 4.31 (dd, J = 7.2, 13.0 Hz
1H), 4.23–4.16 (m, 1H), 3.85–3.79 (m, 1H), 3.31 (s, 3H), 2.67–2.64 (m, 1H),
2.31–2.20 (m, 2H), 1.68 (br s, 3H), 0.92 (d, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.88 (s,
9H), 0.06–0.01 (m, 21H). Compound 24: 1H NMR (CDCl3): d 5.67 (dt, J = 15,
7.0 Hz, 1H), 5.42 (t, J = 4.5 Hz, 1H), 5.28 (dd, J = 15, 8.0 Hz, 1H), 5.00 (s, 1H), 4.94
(s, 1H), 4.67 (d, J = 7.0 Hz, 1H), 4.41 (d, J = 7.0 Hz, 1H), 4.33 (dd, J = 13.0, 5 Hz,
1H), 4.20 (dd, J = 13.0 Hz, 1H), 3.87 (t, J = 5.0 Hz, 1H), 3.83 (t, J = 9.0 Hz, 1H),
Scheme 3. Synthesis of ketone 24.
ation reaction. Sakurai reaction of 2 with isobutylaldehyde fol-
lowed by oxidation of the resulting alcohol provided ketone 24
in modest yield. Further work toward the total synthesis of iriomo-
teolide-1a is in progress.
Acknowledgment
3.34 (s, 3H), 3.24 (AB, JAB = 16.0 Hz,
DVAB = 32.5 Hz, 2H), 2.75–2.71 (m, 1H),
2.72–2.67 (m, 1H), 2.33–2.26 (m, 2H), 2.25–2.20 (m, 2H), 1.72 (br s, 3H), 1.13
(s, 3H), 1.12 (s, 3H), 0.92 (d, J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.06–0.01
(m, 12H); MS (EI), m/z = 619 (M+Na)+.
This research is supported in part by the National Institutes of
Health.