Enantioselective synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a

Article abstract of DOI:10.1021/ol300785c

Synthesis of the C1-C6 and C7-C23 fragments of the proposed structure of iriomoteolide 1a has been accomplished. Key steps include a cross metathesis to form the C15-C16 E olefin and a chelation controlled Grignard addition to form the tertiary alcohol at C14. Notably, 7 of the 9 stereocenters of the proposed structure have been set using various aldol reactions employing metallo enolates of thiazolidinethiones.

Full text of DOI:10.1021/ol300785c

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2366–2369
Enantioselective Synthesis of the C1ÀC6
and C7ÀC23 Fragments of the Proposed
Structure of Iriomoteolide 1a
Michael T. Crimmins* and Anne-Marie R. Dechert
Kenan, Caudill, Venable and Murray Laboratories of Chemistry, University of North
Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
crimmins@email.unc.edu
Received March 27, 2012
ABSTRACT
Synthesis of the C1ÀC6 and C7ÀC23 fragments of the proposed structure of iriomoteolide 1a has been accomplished. Key steps include a cross
metathesis to form the C15ÀC16 E olefin and a chelation controlled Grignard addition to form the tertiary alcohol at C14. Notably, 7 of the 9
stereocenters of the proposed structure have been set using various aldol reactions employing metallo enolates of thiazolidinethiones.
In 2007, Tsuda and co-workers isolated a novel macro-
lide from the dinoflagellate sp. Amphdinium strain HYA024,
identified as iriomoteolide 1a (1).1 The natural product
exhibits potent cytotoxicity against the human B lympho-
cyte DG-75 cells (IC50 = 0.002 mg/mL), which is 20 times
more potent than doxorubicin (IC50 = 0.04 mg/mL), a
common chemotherapy agent.1 Additionally, iriomoteolide 1a
also displays activity against EpsteinÀBarr virus (EBV) in-
fected human B-lymphocyte Raji cells (IC50 = 0.003 mg/mL).1
Because of the attractive biological profile and the unique
Figure 1. Iriomoteolide 1a proposed structure.
structural attributes of iriomoteolide 1a, several labo-
ratories have undertaken the total synthesis of 1. The
groups of Loh,2 Paterson,3 Zhao,4 Li,5 and Dai6 have
reported creative approaches to complex fragments of 1,
while Horne,7 Ghosh,8 and Yang9 have completed the total
synthesis of macrolactone 1. During the course of their
synthetic studies, Horne,7 Ghosh,8 and Yang9 indepen-
dently ascertained that the proposed structure of iriomo-
teolide 1a had been misassigned (Figure 1).
Our interest in the total synthesis of iriomoteolide 1a
stems from the inherent ability of the thiazolidinethione
chiral auxiliary to access all possible polyketide subunits
using simplevariationsofaldolreaction conditions. Oncea
(1) Tsuda, M.; Oguchi, K.; Iwamoto, R.; Kobayashi, J.; Fukushi, E.;
Kawabata, J.; Ozawa, T.; Masuda, A.; Kitaya, Y.; Omasa, K. J. Org.
Chem. 2007, 72, 4469.
(2) (a) Chin, Y.; Wang, S.; Loh, T. Org. Lett. 2009, 11, 3674.
(b) Wang, S.; Chin, Y.; Loh, T. Synthesis 2009, 3557.
(3) Patterson, I.; Rubenbauer, P. Synlett 2010, 571.
(4) Ye, Z.; Deng, L.; Quian, S.; Zhao, G. Synlett 2009, 2469.
(5) Li, S.; Cheng, Z.; Xu, Z.; Ye, T. Chem. Commun. 2010, 46, 4773.
(6) Liu, Y.; Wang, J.; Li, H.; Wu, J.; Feng, G.; Dai, W. Synlett 2010,
2184.
(8) (a) Ghosh, A. K.; Yuan, H. Org. Lett. 2010, 12, 3120. (b) Ghosh,
A. K.; Yuan, H. Tetrahedron Lett. 2009, 50, 1416.
(9) (a) Fang, L.; Yang, J.; Yang, F. Org. Lett. 2010, 12, 3124.
(b) Fang, L.; Xue, H.; Yang, J. Org. Lett. 2008, 10, 4495.
(7) (a) Xie, J; Ma, Y; Horne, D. Chem. Commun. 2010, 46, 4770. (b)
Xie, J.; Ma, Y.; Horne, D. A. Org. Lett. 2009, 11, 5082. (c) Xie, J.; Horne,
D. A. Tetrahedron Lett. 2009, 50, 4485.
r
10.1021/ol300785c
Published on Web 04/18/2012
2012 American Chemical Society

convergent route to the proposed structure is developed,
appropriate diastereomers can be rapidly prepared in a
highly convergent fashion in an effort to elucidate the
actual structure of the natural product. The retrosynthetic
analysis is shown in Figure 2. It was envisioned that
iriomoteolide 1a would arise via a late stage Yamaguchi
esterification10 between acid 2 and secondary alcohol 3
followed by a ring closing metathesis to construct the
C6ÀC7 alkene and install the macrocyclic ring of 1. A
cross metathesis of enone 4 with PMB ether 5 would form
the C15ÀC16 E olefin, while a nonselective aldol between a
C12ÀC23 methyl ketone and aldehyde 6 would assemble
the C11ÀC12 bond.
primary alcohol, which underwent a one-carbon homo-
logation by first transforming the primary alcohol into
mesylate 9 followed by stirring with KCN. Isolation of the
nitrile proved difficult, so the crude mixture was reduced
directly with i-Bu2AlH, to provide aldehyde 10. Aldehyde
10 was then subjected to a second Evans syn aldol with
thioimide 11, generating secondaryalcohol 12in 86% yield
and >20:1 dr.12 Reductive cleavage of the chiral auxiliary
with LiBH4 provided a diol, which cleanly underwent an
acetal formationÀreduction sequence to regioselectively
mask the secondary alcohol as PMB ether 13. Exposure of
the resultant primaryalcohol tomesyl chloridefollowedby
LiEt3BH reduction generated PMB ether 5 in 12 steps and
18% overall yield.
The C12ÀC15 fragment was synthesized beginning with
commercially available (S)-ethyl lactate, which was trans-
formed in two steps via a known procedure to the benzyl
protected Weinreb amide 14 (Scheme 2).13 Exposure of
Weinreb amide 14 to excess vinyl Grignard reagent pro-
vided 4 (Figure 2), which was utilized in a cross metathesis
with PMB ether 5 to deliver exclusive formation of the E
isomer 15 in 67% yield over two steps. A chelation-
controlled addition of methyl magnesium bromide to
ketone 15 provided the tertiary alcohol 16 as the only
detectable diastereomer after reductive cleavage of the
benzyl ether with lithium 4,4-di-tert-butylbiphenylide
(LDBB).14 Oxidation of the secondary alcohol to the
ketone under ParikhÀDoering conditions15 produced
the ketone 17a. Protection of the tertiary alcohol as its TBS
ether provided the C12ÀC23 fragment 17b. The stereo-
chemistry of the tertiary alcohol at C14 was deduced by
forming the five-membered acetonide 18 from diol 16
(Scheme 3). The C14 stereochemistry was assigned as (R)
based on observed NOESY correlation between the C13
hydrogen and C14 methyl group as well as the C15
hydrogen and C13 methyl group.
With ketone fragment 17a in hand, attention turned to
the preparation of aldehyde 6. Beginning with an acetate
aldol utilizing mesityl substituted thiazolidinethione 1916
and 3-butenal,17 secondary alcohol 20 was generated in
70% yield and >20:1 dr (Scheme 4). Protection of the
resulting secondary alcohol as the TES ether and reductive
cleavage of the chiral auxiliary furnished aldehyde 6. A
nonselective aldol between ketone 17a and aldehyde 6
Figure 2. Retrosynthetic analysis of iriomoteolide 1a.
Preparation of the C16ÀC23 PMB ether 5 commenced
with an Evans syn aldol with thioimide 7 and acetaldehyde
toprovide the secondary alcohol8 in 80% yield and 20:1 dr
(Scheme 1).11 Protection of the secondary alcohol as the
TIPS ether and cleavage of the chiral auxiliary delivered a
Scheme 1. Preparation of the C16ÀC23 Fragment of Iriomoteolide 1a
Org. Lett., Vol. 14, No. 9, 2012
2367

Scheme 2. Synthesis of the C12ÀC23 Fragment 17
Scheme 3. Stereochemical Proof for the Absolute Stereochem-
istry of the C14 Tertiary Alcohol
to install the C11 exocyclic olefin under standard methy-
lenation conditions (Wittig, Tebbe,20 Tour,21 TakaiÀ
Nozaki22) in the presence of the free tertiary alcohol at
C14 (21) resulted in either elimination or no reaction, likely
due to the presence of the free alcohol at C14. Attempts to
protect the free alcohol of 21 directly with TESOTf,
TMSOTf, or TMSCl resulted in formation of the C11
mixed silyl ketal, wherein the silyl triflate or silyl chloride
behaved as Lewis acids due to the crowded steric environ-
ment, rather than silylating agents as in similar systems.23
Fortunately, the C14 tertiary alcohol of 17a could be
protected as the TBS ether prior to the aldol addition to
form 17b. Aldol reaction of ketone 17b and aldehyde 6
followed by treatment as before generated mixed ketal 22.
The exocyclic methylene was then successfully installed in
77% yield employing the Tebbe reagent.20 Cleavage of the
PMB ether was accomplished with DDQ, which also
cleaved the mixed methyl ketal to deliver hemiketal 3.
Synthesis of the C1ÀC6 fragment 2 began with a known
Evans anti aldol with thioimide 23 and cinnamaldehyde24
followed by a HoveydaÀGrubbs catalyzed ethylene cross
metathesis to install terminal olefin 24 (Scheme 5). Protec-
tionofthe secondaryalcohol astheTBS ether and cleavage
of the chiral auxiliary afforded aldehyde 25, which was
subjected to a CoreyÀFuchs homologation25 to deliver
ynoate 26. Methyl cuprate addition was used to form
enoate 27, and the olefin geometry was confirmed by
observed NOESY correlations between the C2 hydrogen
and C3 methyl group. Cleavage of the methyl ester to the
acid was accomplished with LiOH and MeOH to provide
delivered the secondary alcohol as an inconsequential
ca. 1:1 mixture of diastereomers at C11.
Cleavage of the TES ether and spontaneous ketalization
to form a mixed methyl ketal was accomplished under mild
conditions utilizing catalytic triphenyl phosphonium hy-
drobromide salt to deliver an unstable mixed methyl
ketal.18 The resultant alcohol was used directly in the
subsequent Ley oxidation19 to afford ketone 21. The C11
exocyclic methylene proved challenging toinstall: attempts
(10) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(11) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. (b)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894. (c) Crimmins, M. T.; She, J. Synlett 2004, 1371.
(12) (a) Crimmins, M. T.; Slade, D. J. Org. Lett. 2006, 8, 2191.
(b) Crimmins, M. T.; Dechert, A. M. R. Org. Lett. 2009, 11, 1635.
(13) (a) Itso, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.;
Terashima, S. Tetrahedron 1989, 45, 5767. (b) Tomooka, K.; Kikuchi,
M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem., Int. Ed.
2000, 39, 4502. (c) Shang, S.; Iwandare, H.; Macks, D. E.; Ambrosin, L. M.;
Tan, D. S. Org. Lett. 2007, 9, 1895.
(14) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45,
1924. (b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854.
(15) Parikh, J. R.; Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505.
(16) Crimmins, M. T.; Shamszad, M. Org. Lett. 2007, 9, 149.
(17) Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L.
Synth. Commun. 1998, 28, 3675.
(21) Tour, J. M.; Bedworth, P. V.; Wu, R. Tetrahedron Lett. 1989, 30,
3927.
(22) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1978, 19, 2417. Hibino, J.-I.; Okazoe, T.; Takai, K.; Nozaki, H. Tetra-
hedron Lett. 1985, 26, 5579. Okazoe, T.; Hibino, J.-I.; Takai, K.; Nozaki,
H. Tetrahedron Lett. 1985, 26, 5581.
(18) Smith, A. B.; Fox, R. J.; Vanecko, J. A. Org. Lett. 2005, 7, 3099.
(19) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(20) (a) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 1980, 102, 3270. (b) Tebbe, F. N.; Parshall, G. W.; Reddy,
G. S. J. Am. Chem. Soc. 1978, 100, 3611.
(23) (a) Braje, W.; Frackenpohl, J.; Langer, P.; Hoffman, H. M. R.
Tetrahedron 1998, 54, 3495. (b) Chrobok, A.; Gossinger, E.; Kalb, R.;
Orglmeister, E.; Schwaiger, J. Tetrahedron 2007, 63, 8326.
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Lett. 2002, 4, 1127.
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Org. Lett., Vol. 14, No. 9, 2012

Scheme 4. Preparation of the C7ÀC23 Fragment 3
by RCM to generate the proposed structure of iriomo-
teolide 1a, in a similar strategy to that employed by
Horne.7
Scheme 5. Preparation of the C1ÀC6 Fragment 2 and Proposed
Completion of 1
In summary, a concise and convergent approach to the
proposed structure of iriomoteolide 1a has been devel-
oped. Key steps include a cross metathesis to form the
C15ÀC16 bond and an acetate aldol to form the C21ÀC22
bond. Thethiazolidinethione chiralauxiliary wasexploited
to create seven of the nine stereocenters of iriomoteolide
1a through various aldol additions. Importantly, simple
changes in the reagents utilized in these aldol additions
can facilitate access to other possible stereoisomers. Since
the proposed structure of the natural product has been
incorrectly assigned, our current efforts are directed to-
ward utilizing our approach to prepare diastereomers of
the reported structure in an effort to elucidate the correct
structure of the natural product.
Acknowledgment. Financial support from the National
Institute of General Medical Sciences (GM60567) is grate-
fully acknowledged.
Supporting Information Available. Experimental de-
tails and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
acid 2 in 63% yield over two steps. Completion of
the synthesis of 1 would require esterification of acid 2
with alcohol 3 and deprotection of the silyl ethers followed
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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