Stereoselective synthesis of iriomoteolide-1a hemiketal core

Article abstract of DOI:10.1016/j.tetlet.2009.05.092

A stereoselective synthesis of the cyclic hemiketal core of iriometeolide-1a (1) is described. The key step involves a Sakurai reaction of allylsilane 4 and aldehyde 5, which bears a chiral α-tertiary center. Mild TES deprotection of β,γ-unsaturated keton

Full text of DOI:10.1016/j.tetlet.2009.05.092

Tetrahedron Letters 50 (2009) 4485–4487
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Stereoselective synthesis of iriomoteolide-1a hemiketal core
*
Jun Xie, David A. Horne
Department of Molecular Medicine, Beckman Research Institute and Graduate School of Biological Sciences at City of Hope, Duarte, CA 91010, 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 cyclic hemiketal core of iriometeolide-1a (1) is described. The key step
Received 21 March 2009
Revised 13 May 2009
Accepted 18 May 2009
Available online 29 May 2009
involves a Sakurai reaction of allylsilane 4 and aldehyde 5, which bears a chiral
a-tertiary center. Mild
TES deprotection of b,
hemiketal core 2.
c
-unsaturated ketone 23 led to concomitant cyclization to produce the fully intact
Ó 2009 Elsevier Ltd. All rights reserved.
In 2007, Tsuda’s group reported the isolation and structure
determination of the remarkably potent cytotoxic 20-membered
ring macrolide, iriomoteolide-1a (1) from the Amphidinium sp.
strain HYA024.1 IC50 values against human B lymphocyte DG-75
cells and Epstein-Barr virus infected human B lymphocyte Raji cells
were measured at 2 and 3 ng/mL, respectively. The structure of 1
was elucidated primarily by 2-D NMR analysis. Contained within
this natural product is a cyclic hemiketal core that bears an exocy-
clic methylene unit and a tertiary chiral center that is vicinal to the
hemiketal functionality. These distinguishing structural features
make this system unique among related systems, such as the one
found in amphidinolide-P.2
Recently, papers have begun to emerge that describe various
synthetic efforts toward 1 but none have reported the synthesis
of the fully intact six-membered ring hemiketal core.3 Herein, we
describe a relatively short stereoselective synthesis of core struc-
ture 2 which bears all the essential structural elements found in
the natural product. These include the six-membered hemiketal
ring possessing the exocyclic methylene unit as well as the adja-
cent chiral tertiary allylic alcohol appendage.
OH
OH
OH
13
O
O
O
9
H
OH
iriomoteolide-1a (1)
OH
OH
O
OR
O
+
H
PMBO
H
5
SiMe3
2
3 R=TBS
4
R=TES
The retrosynthesis of 2 is depicted in Figure 1. A key step in the
Figure 1. Retrosynthetic analysis of core structure 2.
synthetic scheme centers on a Sakurai reaction4 between an allylsi-
lane and aldehyde that bears an a-chiral tertiary center. While this
work was in progress, a strategically similar approach outlined by
Ghosh has appeared.3b Subsequent oxidation of the resulting alco-
hol and deprotection facilitates concomitant cyclization to the de-
sired hemiketal functionality.
Preparation of allylsilane 3 commenced with ring opening of
epoxide 75 with commercially available 6 in the presence of t-BuLi
and CuI to provide allylsilane 8 in excellent yield.6 The resulting
alcohol was protected with either TBS or TES to generate coupling
precursors 3 and 4, respectively (Scheme 1).
SiMe3
H
O
b
a
OR
OH
+
Br
SiMe3
SiMe3
6
7
8
3
R=TBS
4 R=TES
Scheme 1. Synthesis of allyltrimethylsilanes 3 and 4. Reagents and conditions: (a)
6, t-BuLi, CuI, À78 °C then 7, À45 °C, 84%; (b) TBSOTf, 2,6-lutidine, CH2Cl2, 99% or
TESOTf, 2,6-lutidine, CH2Cl2, 91%.
* Corresponding author. Tel.: +1 626 256 4673; fax: +1 626 930 5410.
E-mail address: dhorne@coh.org (D.A. Horne).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.092

4486
J. Xie, D. A. Horne / Tetrahedron Letters 50 (2009) 4485–4487
The preparation of aldehyde 5 began with known diol 97, which
since the chirality at this center disappears upon subsequent oxidi-
zation to the ketone. Using BF3ÁEt2O, the allylation yield was
slightly improved to 37% overall but a different stereoisomer at
the alcohol center is produced. While awaiting confirmation, the
allylation products from the use of SnCl4 and BF3ÁEt2O are antici-
pated to result from chelation controlled and Felkin-Ahn type
selectivities, respectively. As expected, similar results were seen
with TBS or TES protected alcohols. The intermolecular addition
of an allylsilane to a relatively hindered aldehyde bearing an a-chi-
ral tertiary center represents a new example that expands the
scope of the Sakurai reaction.
At this stage, we chose to delay oxidation of alcohols 16/17 over
concerns regarding a potentially undesirable double bond migra-
was protected as its PMP acetal to afford 10 (Scheme 2). Cleavage
of the PMBz ester with MeONa followed by Dess–Martin period-
inane oxidation of the resulting alcohol gave aldehyde 12, which
was used in the next step without chromatographic purification.
In our model study, sulfone 13 was prepared from 1-bromopen-
tane and utilized in a Julia-Kocienski olefination8 with aldehyde
12. The sole E-olefin 14 was obtained in 78% yield for the two steps.
Treatment of 14 with DIBAL-H yielded primary alcohol 15. Oxida-
tion of this alcohol with Dess–Martin periodinane furnished cou-
pling precursor 5, which was used directly in the next step.
With allyltrimethylsilane 3 and aldehyde 5 in hand, several Le-
wis acids were explored in the Sakurai reaction (Scheme 3). Using
TiCl4, only trace amounts of product were observed. On the other
hand, when SnCl4 was utilized, alcohol 169 was produced as a sin-
gle diastereomer in 30% yield over two steps. The stereochemistry
of the newly formed chiral center was not determined at this time
tion in subsequent steps yielding the corresponding
a,b-unsatu-
rated ketone. Additional concerns regarding vicinal hydroxyl
participation upon deprotection of the PMB moiety of 16 led us
to protect the newly formed hydroxyl group in 16 with AcCl to give
18. Removal of the PMB group proceeded smoothly by DDQ oxida-
tion (Scheme 4). Cleavage of the acetyl group using LiAlH4 pro-
duced diol 20 in nearly quantitative yield. The desired b,c-
unsaturated ketone 2110 was obtained in excellent yield upon oxi-
dation of alcohol 20 with SO3ÁPy.
OMe
With cyclization precursor 21 in hand, all that remained was
deprotection of the TBS group and cyclization. Several conditions
were attempted which had previously proven successful in related
systems.11 These included TBAF, TBAF plus HOAc, TASF
(tris(dimethylamino)sulfonium difluorotrimethylsilicate), and
TBAT (tetrabutylammonium triphenyldifluorosilicate), but in our
case, no cyclization products were obtained. Only double bond
OH
O
a
b
PMBzO
HO
OH
O
PMBzO
O
9
10
PMP
PMP
O
O
migration of b,c-unsaturated ketone 21 to the corresponding a,b-
c
O
O
unsaturated system was observed. When HFÁPy was tried, how-
ever, an interesting observation was noted. Neither cyclization
nor isomerization products were detected. The bulk of the reaction
mixture comprised unreacted starting material. This suggests that
H
12
11
N
N
N
O
N
the b,
c
-enone system of 21 is stable to HFÁPy and replacing the TBS
Br
e
g
d
S
group with the more labile TES moiety might facilitate deprotec-
Ph
O
tion and cyclization.
Thus, allylsilane 8 was retooled as its TES ether by treatment
with TESOTf, which afforded 4. Addition of allylsilane 4 to aldehyde
5 occurred in the presence of BF3ÁEt2O to provide compound 17 in
34% over two steps.
13
PMP
O
O
OPMB
OH
f
5
Dess–Martin periodinane oxidation of homoallylic alcohol 17
produced b,c-unsaturated ketone 22 (Scheme 5). Selective removal
14
15
Scheme 2. Synthesis of aldehyde 5. Abbreviations: PMBz = p-methoxybenzoyl;
PMP = p-methoxyphenyl; PMB = p-methoxybenzyl. Reagents and conditions: (a)
4-methoxybenzaldehyde dimethyl acetal, PPTS (cat), CH2Cl2, 76%; (b) NaOMe,
MeOH, 95%; (c) Dess–Martin, NaHCO3, CH2Cl2; (d) (i) Na2CO3, acetone, reflux; (ii)
(NH4)6Mo7O24Á4H2O, H2O2, 95% for 2 steps; (e) 13, KHMDS, À78 °C then 12 to rt, 79%
from 11; (f) DIBAL-H, À78 °C, CH2Cl2, 82%; (g) Dess–Martin, NaHCO3, CH2Cl2.
OH
OPMB
AcO
AcO
a
b
16
OTBS
OTBS
OPMB
HO
5
18
19
OR
OR
condition
OH
OH
SiMe3
HO
c
O
d
2
16
3
R=TBS
R=TBS
OTBS
17 R=TES
OTBS
4 R=TES
Lewis Acid
TiCl4
SnCl4
Yield
trace
30% from 15
37% from 15
R=TBS
R=TBS
R=TBS
21
20
BF3·Et2O
Scheme 4. Attempted synthesis of core structure 2. Reagents: (a) AcCl, Py, CH2Cl2,
88%; (b) DDQ, CH2Cl2: pH 7 buffer = 1:1, 83%; (c) LiAlH4, THF, 99%; (d) SO3ÁPy,
i-Pr2NEt, DMSO, CH2Cl2, 99%.
Scheme 3. Sakurai reaction.

J. Xie, D. A. Horne / Tetrahedron Letters 50 (2009) 4485–4487
OPMB
4487
OPMB
Acknowledgments
O
HO
The authors thank Dr. Sangkil Nam for cytotoxicity testing. Sup-
port from Chugai Pharmaceutical Co. and the Caltech/City of Hope
Medical Research Fund is gratefully acknowledged. The authors
thank Professor Brian Stoltz (Caltech) for helpful discussions.
a
b
OTES
OTES
17
22
References and notes
OH
1. Tsuda, M.; Oguchi, K.; Iwamoto, R.; Okamoto, Y.; Kobayashi, J.; Fukushi, E.;
Kawabata, J.; Ozawa, T.; Masuda, A.; Kitay, Y.; Omasa, K. J. Org. Chem. 2007, 72,
4469.
O
2. Ishibashi, M.; Takahashi, M.; Kobayashi, J. J. Org. Chem. 1995, 60, 6062.
3. (a) Fang, L.; Xue, H.; Yang, J. Org. Lett. 2008, 10, 4645; (b) Ghosh, A. K.; Yuan, H.
Tetrahedron Lett. 2009, 50, 1416.
c
2
OTES
4. Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295.
5. Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2004, 126, 2495.
6. (a) Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.;
Reeves, J. T. Proc. Natl. Acad. Sci. 2004, 101, 12058; (b) Munoz-Torrero, D.;
Brückner, R. Eur. J. Org. Chem. 1998, 1998, 1031.
23
7. Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem. Soc. 1995, 117, 10805.
8. (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 26; (b)
Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002, 124, 9718.
Scheme 5. Synthesis of the core structure 2. Reagents: (a) Dess–Martin, NaHCO3,
CH2Cl2, 99%; (b) DDQ, CH2Cl2: pH 7 buffer = 1:1, 90% (c) HFÁPy, Py, THF, 74%.
9. Compound 16: 1H NMR (400 MHz, CDCl3): d 7.24 (d, 2H, J = 8.6 Hz), 6.85 (d, 2H,
J = 8.6 Hz), 5.78–5.85 (m, 1H), 5.70 (dt, 1H, J = 16 Hz, 6.4 Hz), 5.59 (d, 1H,
J = 16 Hz), 4.99–5.03 (m, 2H), 4.91 (s, 1H), 4.86 (s, 1H), 4.28–4.34 (m, 2H), 3.81–
3.85 (m, 1H), 3.79 (s, 3H), 3.63–3.66 (m, 1H), 2.53 (d, 1H, J = 1.9 Hz), 1.98–2.28
(m, 8H), 1.24–1.42 (m, 4H), 1.32 (s, 3H), 0.90 (t, 3H, J = 7 Hz), 0.86 (s, 9H), 0.02
(s, 3H), 0.01 (s, 3H); 13C NMR (400 MHz, CDCl3): d 159.1, 144.4, 135.6, 134.7,
131.8, 130.8, 129.1, 117.1, 114.7, 113.9, 80.4, 75.9, 71.1, 64.4, 55.5, 43.8, 41.6,
38.5, 32.6, 31.8, 26.1, 22.5, 18.4, 18.2, 14.2, À4.2, À4.3; HRMS (EI) calcd for
[M+H+ÀH2O]: 499.3608; found 499.3627.
of the PMB ether group without enone migration was accom-
plished by treatment of 22 with DDQ in a 1:1 mixture of CH2Cl2
and pH 7 buffer. This resulted in the generation of ketone 23 in
excellent yield. Finally, deprotection of the TES group by HFÁPy
led to concomitant cyclization to afford the desired product 212
as a single stereoisomer. Positive ROSEY interactions seen between
H9 and OH13 support the configuration of the newly form stereo-
center as indicated.
10. Compound 21: 1H NMR (400 MHz, CDCl3): d 5.74–5.90 (m, 2H), 5.50 (d, 1H,
J = 15.5 Hz), 5.01–5.06 (m, 2H), 5.00 (s, 1H), 4.89 (s, 1H), 3.94 (s, 1H), 3.77–3.83
(m, 1H), 3.26–3.36 (m, 2H), 2.04–2.26 (m, 6H), 1.45 (s, 3H), 1.28–1.41 (m, 4H),
0.89 (t, 3H, J = 7 Hz), 0.87 (s, 9H), 0.05 (s, 3H), 0.02 (s, 3H); 13C NMR (400 MHz,
CDCl3): d 210.1, 139.9, 135.0, 133.5, 130.7, 117.5, 117.4, 79.2, 71.3, 43.8, 43.4,
41.9, 32.2, 31.3, 26.1, 24.8, 22.5, 18.3, 14.1, À4.2, À4.3; HRMS (EI) calcd for
[M+H+]: 395.2982; found 395.2971.
Cyclic ketal 2 was examined for cytotoxic activity against mel-
anoma (A2058) and prostate (DU145) cell lines. At the highest dose
examined (20 lM), viability (as measured by MTS assay) in both
11. (a) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett. 2000, 2, 945; (b) Savall, B.
M.; Blanchard, N.; Roush, W. R. Org. Lett. 2003, 5, 377; (c) Trost, B. M.; Yang,
H.; Probst, G. D. J. Am. Chem. Soc. 2004, 126, 48; (d) Breitfelder, S.;
Schuemacher, A. C.; Rolle, T.; Kikuchi, M.; Hoffmann, R. W. Helv. Chim. Acta
2004, 87, 1202.
cell lines was approximately 70% of the control. These results indi-
cate that the cyclic hemiketal alone is not responsible for the
remarkable cytotoxicity observed in the natural product.
In summary, the synthesis of the six-membered ring hemiketal
core of iriomoteolide-1a (1) has been achieved in a relatively effi-
cient manner. Noteworthy is the application of the Sakurai reaction
12. Compound 2: 1H NMR (400 MHz, CDCl3): d 5.66–5.84 (m, 3H), 5.04–5.10 (m,
2H), 4.86 (s, 1H), 4.83 (s, 1H), 3.88–3.94 (m, 1H), 3.03 (s, 1H), 2.37 (s, 1H),
2.22–2.32 (m, 5H), 2.05–2.10 (m, 2H), 1.86–1.93 (m, 1H), 1.33–1.47 (m, 4H),
1.30 (s, 3H), 0.90 (t, 3H, J = 7.2 Hz); 13C NMR (400 MHz, CDCl3): d 141.9,
134.7, 132.3, 131.3, 117.3, 111.4, 99.4, 77.3, 70.7, 40.4, 39.5, 37.9, 32.4, 31.6,
22.4, 21.0, 14.1; HRMS (EI) calcd for [M+H+ÀH2O]: 263.2011; found
263.2020.
involving an aldehyde bearing an a-chiral tertiary center. Further-
more, the use of TES/HFÁPy for the protection/deprotection se-
quence was found to be a viable solution for cyclization and
hemiketal formation.