Synthesis of the macrocyclic core of iriomoteolide 3a

Article abstract of DOI:10.1021/ol9025183

[Chemical Equation Presented] The asymmetric synthesis of the fully functionalized macrocyclic core of iriomoteolide 3a, a cytotoxic 15-membered macrolide, is disclosed. The key steps involve Sharpless asymmetric dihydroxylation, Sharpless asymmetric epox

Full text of DOI:10.1021/ol9025183

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5730-5733
Synthesis of the Macrocyclic Core of
Iriomoteolide 3a
Chada Raji Reddy,* Gajula Dharmapuri, and Nagavaram Narsimha Rao
Organic DiVision-I, Indian Institute of Chemical Technology,
Hyderabad, India 500 007
rajireddy@iict.res.in
Received October 31, 2009
ABSTRACT
The asymmetric synthesis of the fully functionalized macrocyclic core of iriomoteolide 3a, a cytotoxic 15-membered macrolide, is disclosed.
The key steps involve Sharpless asymmetric dihydroxylation, Sharpless asymmetric epoxidation, olefin cross-metathesis, Yamaguchi esterification,
and a ring-closing metathesis reaction for macrocyclization.
Recently, Tusda and co-workers have reported the isolation
of a cytotoxic macrolide iriomoteolide 3a (1, Figure 1) from
a marine dinoflagellate Amphidinium sp. (strain HYA024),
collected off the Iriomote Island of Japan.1 Prior to isolation
of this macrolide they have also found iriomoteolides 1a-c
(20-membered macrolides) from the same strain.2 However,
iriomoteolide 3a is a 15-membered macrolide having an
allylic epoxide, three hydroxyl groups, two methyl branches
and with a new carbon skeleton compared to the known 15-
membered macrolides.3 Iriomoteolide 3a (1) and its 7,8-O-
isopropylidene derivative (2) displayed a potent cytotoxicity
against human B lymphocyte DG-75 cells (IC50 ) 0.08 and
0.02 µg/mL, respectively) and Raji cells (IC50 ) 0.05 and
0.02 µg/mL, respectively). The distinctive structural features
and biological activities together with our interest on
macrolides4 have driven us to the synthesis of iriomoteolide
3a. Recently, various synthetic approaches toward the
synthesis of iriomoteolide 1a have been reported.5 The first
total synthesis of iriomoteolide 3a has appeared while this
paper was under review.6 Herein, we report an asymmetric
approach to the fully functionalized macrocyclic core of
iriomoteolide 3a.
From a retrosynthetic perspective, we planned that the side
chain installation onto macrocyclic core 3 would be the late
stage reaction. The 15-membered macrolide 3 in turn can
be achieved from two fragments, 4 and 5, via esterification
followed by a ring-closing metathesis reaction. The synthesis
of fragment 4 was envisioned from a subunit 6, using
stereoselective methylation and Sharpless asymmetric ep-
oxidation as the key steps. Further analysis of 5 revealed
two subunits 7 and 8, which could be coupled by olefin cross-
(1) Oguchi, K.; Tsuda, M.; Iwamoto, R.; Okamoto, Y.; Kobayashi, J.;
Fukushi, E.; Kawabata, J.; Ozawa, T.; Masuda, A.; Kitaya, Y.; Omasa, K.
J. Org. Chem. 2008, 73, 1567–1570.
(4) (a) Reddy, Ch. R.; Rao, N. N. Tetrahedron Lett. 2009, 50, 2478–
2480. (b) Chandrasekhar, S.; Vijeender, K.; Chandrashekar, G.; Reddy, Ch.
R. Tetrahedron: Asymmetry 2007, 20, 2473–2478.
(2) (a) 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, 4469–4474. (b) Tsuda, M.; Oguchi, K.; Iwamoto,
R.; Okamoto, Y.; Fukushi, E.; Kawabata, J.; Ozawa, T.; Masuda, A. J.
Nat. Prod. 2007, 70, 1661–1663.
(5) (a) Wang, S.-Y.; Chin, Y.-J.; Loh, T.-P. Synthesis 2009, 3557–3564.
(b) Chin, Y.-J.; Wang, S.-Y.; Loh, T.-P. Org. Lett. 2009, 11, 3674–3676.
(c) Xie, J.; Horne, D. A. Tetrahedron Lett. 2009, 50, 4485–4487. (d) Ghosh,
A. K.; Yuan, H. Tetrahedron Lett. 2009, 50, 1416–1418. (e) Ye, Z.; Deng,
L.; Qian, S.; Gang, Z. Synlett 2009, 2469–2472. (f) Fang, L.; Xue, H.; Yang,
J. Org. Lett. 2008, 10, 4645–4648.
(3) (a) Kobayashi, J.; Sato, M.; Ishibashi, M. J. Org. Chem. 1993, 58,
2645–2646. (b) Ishibashi, M.; Takahashi, M.; Kobayashi, J. Tetrahedron
1997, 53, 7827–7832.
(6) Cribiu, R.; Jager, C.; Nevado, C. Angew. Chem., Int. Ed. 2009, 48,
8780–8783.
10.1021/ol9025183  2009 American Chemical Society
Published on Web 11/20/2009

sequence.7 The addition of lithiated ethyl propiolate to
aldehyde 9 provided the propargylic alcohol 10 (82%),8
which underwent Ph3P-mediated “allene”-type rearrangement
to give (E,E)-diene 11 in 74% yield.9 A stereo- and
regioselective dihydroxylation of 11 was achieved via
Sharpless asymmetric dihydroxylation, using ADmix-R to
obtain diol 12 in 80% yield with 96% enantioselectivity.10
Hydrogenation of 12 (Pd-C in EtOAc) followed by K2CO3-
mediated cyclization8b and subsequent protection of the free
secondary hydroxyl group as tert-butyldimethyl silyl (TBS)
ether provided the fully protected lactone 6 in 76% yield
for the two steps.
Scheme 2. Synthesis of Fragment 4
Figure 1. Structures of iriomoteolide 3a (1) and acetonide (2) and
their retrosynthetic analysis.
metathesis (Figure 1). The protective group in subunit 7 was
chosen as ketal for vicinal 7,8-diol, which is based on the
precedence that the isopropylidene derivative 2 showed
activity comparable with that of the natural product.
Scheme 1. Synthesis of Fragment 6
The subunit 6 was transformed to the desired key fragment
4 as shown in Scheme 2. Initially, the introduction of the
(7) Jung, H. H.; Floreancig, P. E. Org. Lett. 2006, 8, 1949–1951.
(8) (a) Chandrasekhar, S.; Sultana, S. S. Tetrahedron Lett. 2006, 47,
7255–7258. (b) Chandrasekhar, S.; Parida, B. B.; Rambabu, C. Tetrahedron
Lett. 2009, 50, 3294–3295.
(9) Guo, C.; Lu, X. J. Chem. Soc., Chem. Commun. 1993, 394–395.
(10) (a) Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc.
1992, 114, 7570–7571. (b) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001,
3, 1049–1052.
The synthesis of fragment 6 is outlined in Scheme 1. This
was commenced from the known aldehyde 9, derived from
commercially available 1,4-butane diol using a two step
Org. Lett., Vol. 11, No. 24, 2009
5731

C-17 methyl stereocenter was accomplished through a
stereoselective methylation of 6 with use of LiHMDS/MeI
at -78 °C to afford exclusively 13 in 87% yield,11 which
was confirmed by NOE studies. The reduction of lactone 13
with LiBH4 provided the diol 14 in 96% yield. A three-step
protection-deprotection sequence involving selective protec-
tion of the primary hydroxyl group in 14 as tert-butyldiphenyl
silyl (TBDPS) ether (imidazole, TBDPSCl), secondary
hydroxyl as methoxy methyl (MOM) ether (DIPEA, MO-
MCl), and selective deprotection of primary TBS ether
(pTSA, MeOH) produced the alcohol 15 in 78% yield over
three steps. The free alcohol was then oxidized by using
Parikh-Doering oxidation (SO3·Py, DMSO)12 to the corre-
sponding aldehyde followed by a Wittig two-carbon ho-
mologation (Ph3PdCHCOOEt) and gave R,ꢀ-unsaturated
ester 16 (86%) as the (E)-isomer (>98%). The ester 16 was
reduced with DIBAL-H at -78 °C to allylic alcohol 17 in
92% yield. The requisite chiral epoxide was introduced at
this stage via a Sharpless asymmetric epoxidation reaction,13
using (+)-diisopropylethyl tartrate to yield epoxide 18 in 88%
with good stereoselectivity. The conversion of epoxy alcohol
18 to allylic epoxide 19 was accomplished via SO3·Py
mediated oxidation followed by one-carbon Wittig methyl-
enation (78% yield over two steps). To make the epoxide
19 ready for the esterification reaction with fragment 5, we
needed to deprotect the TBS ether to obtain a free hydroxyl
group. Consequently, we have chosen a two-step protecting
group manipulation involving deprotection of both the silyl
groups in 19 (TBAF) followed by selective protection of the
resulting primary hydroxyl group as a TBS ether to produce
fragment 4 in 92% yield.
Scheme 3. Synthesis of Fragment 5
successfully accomplished by the deprotection of the TBDPS
group with TBAF in THF followed by BAIB/TEMPO-
mediated oxidation17 of the resulting alcohol to carboxylic
acid in 73% yield over two steps.
The synthesis of fragment 5 started with the known
aldehyde 20 (Scheme 3), derived from commercially avail-
able (S)-citronellol.14 Sodium borohydride reduction of
aldehyde 20 followed by the iodination of the resulting
alcohol (I2/Ph3P) and subsequent elimination under t-BuOK
conditions afforded the subunit 8 in 75% yield over three
steps. At this point, compound 8 was coupled with the known
fragment 7 (obtained from (+)-diethyl tartrate)15 under olefin
cross-metathesis conditions, using second generation Grubbs
catalyst16 to obtain the desired alkene 21 in 72% yield as
Scheme 4. Construction of Macrocycle 3
1
the (E)-isomer (observed by H NMR). Parikh-Doering
oxidation of 21 followed by Wittig methylenation of the
resulting aldehyde afforded the alkene 22 (71%). The
conversion of alkene 22 to the desired fragment 5 was
(11) Mohapatra, D. K.; Sahoo, G.; Sankar, K.; Gurjar, M. K. Tetrahe-
dron: Asymmetry 2008, 19, 2123–2129.
(12) Parikh, J. R.; Doering, W. V. E. J. Am. Chem. Soc. 1967, 89, 5505–
5507.
(13) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974–5976. (b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765–5780.
(14) (a) Stuart, P.; Romeril, S. P.; Lee, L.; Baldwin, J. E. Tetrahedron
Lett. 2004, 45, 3273–3277. (b) Chandrasekhar, S.; Yaragorla, S. R.;
Sreelakshmi, L.; Reddy, Ch. R. Tetrahedron 2008, 64, 5174–5183.
(15) Andre, V.; Lahrache, H.; Robin, S.; Rousseau, G. Tetrahedron 2007,
63, 10059–10066.
Having both the desired fragments 4 and 5 in hand, we
turned to fasten these together to obtain the 15-membered
macrocycle 3 (Scheme 4). Thus, the esterification of alcohol
4 with carboxylic acid 5 was carried out under Yamaguchi
conditions18 to produce compound 23 in 93% yield. This
(16) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953–956. (b) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 3783–3784. (c) Chatterjee, A. K.; Choi, T.-
L; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–
11370.
(17) Miyaoka, H.; Yamanishi, M.; Hoshino, A.; Kinbara, A. Tetrahedron
2006, 62, 4103–4109.
(18) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
5732
Org. Lett., Vol. 11, No. 24, 2009

set the stage for the macrocyclization by ring-closing
metathesis. Reaction of 23 with second-generation Grubbs
catalyst in refluxing dichloromethane provided the separable
mixture of E/Z-isomers (8:2) in 71% yield.19 Finally, the
major required (E)-isomer 24 was subjected to desilylation
under TBAF conditions to give the macrocyclic core 3 in
89% yield. The structure of macrolactone 3 was fully
characterized by 1H NMR, 13C NMR, and mass spectral data.
and a cross-metathesis reaction were efficiently used for the
preparation of key intermediates. The salient features of the
approach include an efficient and scalable synthesis of two
fragments, 4 and 5, in a stereoselective manner and the use
of ring-closing metathesis for macrocyclization. We believe
that this approach sets the stage for total synthesis as well
as entry to a diversity of analogues through the installation
of various side chains. Studies in this direction are underway.
In conclusion, a convergent synthesis of the 15-membered
macrocyclic core of iriomoteolide 3a has been demonstrated.
Both Sharpless reactions (epoxidation and dihydroxylation)
Acknowledgment:G.D. and N.N.R. thank CSIR-New
Delhi for the award of research fellowships.
Supporting Information Available: Spectroscopic and
analytical data and expeimental details. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) (a) Fu¨rstner, A.; Nevado, C.; Waser, M.; Tremblay, M.; Chevrier,
C.; Teply´, F.; As¨sa, C.; Moulin, E.; Mu¨ller, O. J. Am. Chem. Soc. 2007,
129, 9150–9161. (b) Garbaccio, R. M.; Danishefsky, S. J. Org. Lett. 2000,
20, 3127–3129.
OL9025183
Org. Lett., Vol. 11, No. 24, 2009
5733