Total synthesis of iejimalide B. An application of the Shiina macrolactonization

Article abstract of DOI:10.1021/ol702129w

(Chemical Equation Presented) The potent anticancer compound iejimalide B (1) was prepared by a total synthesis through a strategy that features Julia olefinations, Wittig olefinations, a Carreira enantioselective alkynylation, a Heck reaction, a Marshall

Full text of DOI:10.1021/ol702129w

ORGANIC
LETTERS
2
007
Vol. 9, No. 22
619-4622
Total Synthesis of Iejimalide B.
An Application of the Shiina
Macrolactonization
4
†
†
†
‡
Dirk Schweitzer, John J. Kane, Daniel Strand, Peter McHenry,
‡
,†
Martin Tenniswood, and Paul Helquist*
Department of Chemistry and Biochemistry and Walther Cancer Research Center
and Department of Biological Sciences, UniVersity of Notre Dame,
Notre Dame, Indiana 46556
helquist.1@nd.edu
Received August 30, 2007
ABSTRACT
The potent anticancer compound iejimalide B (1) was prepared by a total synthesis through a strategy that features Julia olefinations, Wittig
olefinations, a Carreira enantioselective alkynylation, a Heck reaction, a Marshall propargylation reaction, a Stille coupling, and a Shiina
macrolactonization.
The iejimalides1,2 are a class of marine microbial secondary
metabolites that were originally isolated from tunicate species
native to the coral reefs in the vicinity of Ie Island (Iejima)
Their structures consist of a 24-membered lactone ring,
containing five chiral centers and four dienes, one of which
is a skipped triene, to which an N-formyl (S)-serine termi-
nated diene side chain is attached (Figure 1). In the initially
assigned structure, the absolute configurations of the chiral
carbons within the macrolactone remained unspecified. It was
at this point that we commenced the total synthesis of one
1
3
near Okinawa, Japan. Work by Kobayashi and us has
shown that the iejimalides possess potent growth inhibitory
activity against a wide range of human tumor cell lines.
Especially potent is iejimalide B (1). For example, it is
cytostatic (GI50) at <5 nM against 40 of the 56 cell lines
7
-10
of its diastereomers.
However, a follow-up study, by the
4
tested in the NCI screen. Recently, novel modes of
anticancer activity were shown to be exhibited by the
(5) Davisson, V. J.; Anadu, N.; Zhu, J.; Tenniswood, M.; McHenry, P.
R.; Higa, T.; Tanaka, J.; Schweitzer, D.; Helquist, P. Chemical, Biochemical,
and Biological Studies of the Iejimalides, PacifiChem, Honolulu, HI, Dec
iejimalides.5,6
1
7-19, 2005.
†
Department of Chemistry and Biochemistry and Walther Cancer
(6) (a) Kazami, S.; Muroi, M.; Kawatani, M.; Kubota, T.; Usui, T.;
Research Center.
Kobayashi, J.; Osada, H. Biosci. Biotechnol. Biochem. 2006, 70, 1364. (b)
McHenry, P.; Wang, W. L.; Jeffrey, R.; Devitt, E.; Kluesner, N.; Schweitzer,
D.; Helquist, P.; Tenniswood, M. Iejimalide A and Iejimalide B Induce
S-phase Arrest or Apoptosis Through a Potentially p53-independent Pathway
(Poster 791.7), Experimental Biology, Washington, DC, April 28-May 2,
2007.
‡
Department of Biological Sciences.
1) (a) Kobayashi, J.; Cheng, J.; Ohta, T.; Nakamura, H.; Nozoe, S.;
(
Hirata, Y.; Ohizumi, Y.; Sasaki, T. J. Org. Chem. 1988, 53, 6147. (b)
Kikuchi, Y.; Ishibashi, M.; Sasaki, T.; Kobayashi, J. Tetrahedron Lett. 1991,
3
2, 797. (c) Nozawa, K.; Tsuda, M.; Ishiyama, H.; Sasaki, T.; Tsuruo, T.;
Kobayashi, J. Bioorg. Med. Chem. 2006, 14, 1063.
2) Tsuda, M.; Nozawa, K.; Shimbo, K.; Ishiyama, H.; Fukushi, E.;
Kawabata, J.; Kobayashi, J. Tetrahedron Lett. 2003, 44, 1395.
3) Schweitzer, D.; Zhu, J.; Jarori, G.; Tanaka, J.; Higa, T.; Davisson,
V. J.; Helquist, P. Bioorg. Med. Chem. 2007, 15, 3208.
4) National Cancer Institute Developmental Therapeutics Program,
(7) Cottard, M.; Kann, N.; Rein, T.; A° kermark, B.; Helquist, P.
Tetrahedron Lett. 1995, 36, 3115.
(
(8) Mendlik, M. T.; Cottard, M.; Rein, T.; Helquist, P. Tetrahedron Lett.
1997, 38, 6375.
(9) Pedersen, T. M.; Hansen, E. L.; Kane, J.; Rein, T.; Helquist, P.;
Norrby, P.-O.; Tanner, D. J. Am. Chem. Soc. 2001, 123, 9738.
(10) Kane, J. J. Ph.D. Dissertation, University of Notre Dame, Notre
Dame, IN, 2003.
(
(
NSC: 727699, Test Date: July 21, 2003, http://www.dtp.nci.nih.gov/docs/
dtp_search.html.
1
0.1021/ol702129w CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/04/2007

Scheme 1. Synthesis of the C(1)-C(11) Subunit
Figure 1. Key bond formations and key starting materials in the
construction of iejimalide B (1).
Hydroxyl deprotection, Mitsunobu reaction, and oxidation
yielded the completed C(1)-C(11) subunit (4) ready for the
4
second Julia olefination. The mild conditions of NH F/MeOH
same group that had originally isolated the iejimalides,
assigned the absolute configuration of all of the stereocenters
15,16
allowed clean deprotection of the TBDPS group
without
epimerization of the C(4) stereocenter, which was caused
by TBAF/THF or HF/Py.
(
4R,9S,17S,22S,23S,32S) and revised the configuration of the
2
C(13)-C(14) double bond from E to Z. These changes led
The Z olefin, within the C(12)-C(19) subunit, was formed
us to modify our synthesis.
We have previously reported a basic strategy and the
17
by a Wittig reaction between the phosphonium salt (5) of
18
THF-derived 4-iodo-1-silyloxybutane and TBDPS-protect-
synthesis and assembly of several of the subunits of the
1
9
ed acetol (6) using a substoichiometric amount of n-BuLi
iejimalides.5
,7-10
Recently, a total synthesis was published
2
0
as the base (Scheme 2). An excess of this base or the use
1
1
by F u¨ rstner, employing much of the same strategy and
many of the same subunits, but differing most importantly
in the macrocyclic ring formation method. F u¨ rstner used an
elegant ring-closing alkene metathesis when macrolacton-
ization failed. However, we now wish to report that the
synthesis of iejimalide B can be completed successfully
utilizing an appropriate macrolactonization procedure despite
F u¨ rstner’s report of difficulty with this transformation.
Scheme 2. Preparation of the C(12)-C(19) Intermediate rac-8
In order to have the greatest flexibility in controlling the
absolute configurations of the chiral centers, our strategy was
based upon the use of fragments carrying individual stereo-
chemical elements (Figure 1). Since the Julia olefination has
12
been well precedented in challenging structures, we decided
to employ it for two of the diene constructions along with
organometallic couplings for the formation of the other two
dienes.
of other bases resulted in lower selectivity and decomposi-
tion. Selective deprotection followed by oxidation yielded
2
1
aldehyde 7. Addition of TMS-acetylene produced racemic
2
2
propargylic alcohol rac-8.
As we have reported earlier, both the C(1)-C(5) and the
C(6)-C(11) subunits were prepared from the chiral pool.
Roche ester contributed chiral carbon C(4), while malic acid
Three methods to access enantiomerically enriched pro-
pargylic alcohol (S)-8 were successfully employed (Scheme
3). First, a kinetic resolution of racemic propargylic alcohol
8 by Amano AK Lipase, which catalyzes only the formation
of the (R)-acetate, was achieved. Second, the enantio-
selective reduction of the corresponding alkynyl ketone 10
8
provided C(9). Initially, we formed the C(5)-C(6) double
8
23
bond between C(1)-C(5) sulfone 2 and C(6)-C(11) alde-
hyde 3 employing the traditional, three-step M. Julia ole-
13
fination protocol. However, we subsequently found that the
(
15) Munakata, R.; Katakai, H.; Ueki, T.; Kurosaka, J.; Takao, K.-I.;
Tadano, K.-I. J. Am. Chem. Soc. 2004, 126, 11254.
16) Zhang, W.; Robins, M. J. Tetrahedron Lett. 1992, 33, 1177.
modified, one-step S. Julia-Kocie n´ ski olefination proto-
12,14
col
using an excess of base under Barbier conditions
(
proceeded in excellent yield and selectivity (Scheme 1).
(17) Merlic, C. A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian,
A.; Mammen, J. J. Org. Chem. 2001, 66, 1297.
(
18) Nystr o¨ m, J.-E.; McCanna, T. D.; Helquist, P.; Amouroux, R.
(11) (a) F u¨ rstner, A.; A ¨ı ssa, C.; Chevrier, C.; Tepl y´ , F.; Nevado, C.;
Synthesis 1988, 56.
Tremblay, M. Angew. Chem., Int. Ed. 2006, 45, 5832. (b) F u¨ rstner, A.;
Nevado, C.; Tremblay, M.; Chevrier, C.; Tepl y´ , F.; A ¨ı ssa, C.; Waser, M.
Angew. Chem., Int. Ed. 2006, 45, 5837. (c) F u¨ rstner, A.; Nevado, C.; Waser,
M.; Tremblay, M.; Chevrier, C.; Tepl y´ , F.; A ¨ı ssa, C.; Moulin, E.; M u¨ ller,
O. J. Am. Chem. Soc. 2007, 129, 9150.
(19) Kim, D.-K.; Kim, G.; Gam, J.; Cho, Y.-B.; Kim, H.-T.; Tai, J.-H.;
Kim, K. H.; Hong, W.-S.; Park, J.-G. J. Med. Chem. 1994, 37, 1471.
(20) Sreekumar, C.; Darst, K. P.; Still, W. C. J. Org. Chem. 1980, 45,
4260.
(21) Hayashi, N.; Noguchi, H.; Tsuboi, S. Tetrahedron 2000, 56, 7123.
(22) Chakraborty, T. K.; Reddy, V. R.; Reddy, T. J. Tetrahedron 2003,
59, 8613.
(12) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
(13) Julia, M.; Paris, J.-M. Tetrahedron Lett. 1973, 49, 4833.
(14) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett.
(23) Marshall, J. A.; Chobanian, H. R.; Yanik, M. M. Org. Lett. 2001,
3, 3369.
1
991, 32, 1175.
4620
Org. Lett., Vol. 9, No. 22, 2007

Scheme 3. Completion of C(12)-C(19) Subunita
Scheme 4. Completion of the C(1)-C(19) Fragment
7
previously reported use of a Heck reaction. We have
alternatively synthesized this subunit through use of an
10
alkenyl-alkenyl Suzuki-Miyaura coupling reaction. Fol-
lowing conversion of the methyl ester in 17 to the aldehyde
Scheme 5. Preparation of the C(20)-C(34) Vinylstannane
was performed. Most important, however, is the result of
extensive investigation of the Carreira-style enantioselective
addition of TMS-acetylene to aldehyde 7. It was found that
TMS-acetylene adds enantioselectively to aldehyde 7 if the
reaction is performed employing an excess of TMS-acetylene
at elevated temperature at a high concentration. Albeit
moderate yielding,24 this protocol represents a significant
achievement considering that the attempted Carreira enan-
tioselective addition of a terminal alkyne to an R-unsubsti-
tuted aldehyde has failed previously.25
Employing very efficient phase-transfer catalysis, alcohol
1
8, Marshall’s diastereoselective addition of an enantio-
8
was methylated and the alkenyl TMS group was removed
2
6
27
enriched allenylindium reagent derived from (R)-4-trimeth-
ylsilylbut-3-yn-2-yl mesylate was performed.
chiral centers were produced in good selectivity as compared
2 3
to 2-E-heptenal which gives only 2.4/1 selectivity. K CO
in MeOH selectively cleaved the alkynyl-TMS group to
provide free alkyne 20, whose hydrostannylation provided
the C(20)-C(34) vinylstannane 21, ready for the ensuing
Stille coupling. It was found that Pd(dppf)Cl
catalyst to Pd(PPh in the hydrostannylation. Attempted
in a one-pot reaction. Hydrozirconation-iodination, hy-
2
3,31
2
8
Thus, two
droxyl deprotection, and allylic alcohol oxidation using
TPAP/NMO provided the fully functionalized C(12)-C(19)
subunit (12). Other oxidizing agents such as MnO , SO ‚
2 3
Py, or even DMP/Py caused partial double-bond isomeriza-
tion.
Formation of the C(11)-C(12) double bond between
sulfone 4 and volatile aldehyde 12 proceeded smoothly again
using the Julia-Kocie n´ ski olefination (Scheme 4). Methyl
ester saponification provided the completed, fully function-
alized iejimalide C(1)-C(19) subunit 14.
32
2
is a far superior
3 4
)
hydroboration or hydrozirconation-iodination of 20 resulted
in decomposition.
The iejimalide side chain (Scheme 5) was completed by
Since the Stille coupling is compatible with a carboxylic
acid functionality, as was reported by Stille himself,33 we
proceeded to the reaction between C(1)-C(19) vinyl iodide
carboxylic acid 14 and C(20)-C(34) vinylstannane 21
amide formation between O-TBS-protected N-formylserine
(
15)29 and diene-amine 16 promoted by diethyl phospho-
30
rocyanidate (DEPC). The diene in 16 was formed by our
(
Scheme 6). By screening a number of catalytic systems,34
(
24) An inspection of the NMR spectrum of the reaction mixture taken
3 4
we found the conditions of Tadano [Pd(PPh ) and CuCl in
prior to workup indicates the presence of about 65% desired product and
no remaining aldehyde starting material.
(
(
(
25) L o´ pez, F.; Castedo, L.; Mascare n˜ as, J. L. Org. Lett. 2005, 7, 287.
26) Wipf, P.; Graham, T. H. J. Am. Chem. Soc. 2004, 126, 15346.
27) Kalish, V. J.; Shone, R. L.; Kramer, S. W.; Collins, P. W. Synth.
(30) Ando, A.; Shioiri, T. Tetrahedron 1989, 45, 4969.
(31) A similar reaction was employed by F u¨ rstner in ref 11.
(32) Marshall, J. A.; Grant, C. M. J. Org. Chem. 1999, 64, 696.
(33) Stille, J. K.; Sweet, M. P. Tetrahedron Lett. 1989, 30, 3645.
(34) Conditions screened: PdCl2(MeCN)2, PdCl2(BnCN)2, PdCl2(PPh3)2,
PdCl2(AsPh3)2, Pd(PPh3)4, Pd2(dba)3, CuTC, CuCl, CuI, AsPh3, P(o-Tol)3,
([(n-Bu)4N][Ph2PO2]), LiCl, CsF, OdPPh3, BHT, and/or i-Pr2NEt in various
solvents.
Commun. 1990, 20, 1641.
28) Alvarez, R.; Dom ´ı nguez, M.; Pazos, Y.; Sussman, F.; de Lera, A.
R. Chem. Eur. J. 2003, 9, 5821.
29) Hill, D. R.; Hsiao, C.-N.; Kurukulasuriya, R.; Wittenberger, S. J.
(
(
Org. Lett. 2002, 4, 111.
Org. Lett., Vol. 9, No. 22, 2007
4621

1
Synthetic iejimalide B is identical by HPLC, H NMR,
HRMS, and biological activity (within normal assay limits)
to natural iejimalide B, which was isolated in our laboratory
from the tunicate [LC50 (prostate cancer cell line LNCaP,
Scheme 6. Completion of the Total Synthesis
3
7
2 h) ) 5-8 nM (synthetic 1) and 20-30 nM (natural 1)],
2
and therefore, Kobayashi’s assignment of its structure and
absolute configuration is confirmed. In comparison, the
biological activity of O-TBS protected iejimalide B (22),
LC50 (LNCaP, 72 h) ) 160-225 nM, is reduced but falls
within the range of one of the iejimalide O-carbamate
3
derivatives previously studied by us.
1
5
In conclusion, this total synthesis of iejimalide B provides
access to the final product and potentially many possible
analogues. The overall yield is 3% for the longest linear
sequence of 13 steps starting from 5 or 6. Notable features
of this total synthesis include Julia couplings of elaborated
substrates, an application of Carreira’s enantioselective
alkyne addition to an R-unsubstituted aldehyde, a Marshall
DMSO/THF] to give the most reproducible results and the
highest yield for this Stille coupling at room temperature. A
maximum yield of 58% was achieved in simpler model
systems, with loss of material caused by protodestannylation.
Since the resulting O-TBS-protected iejimalide open-chain
carboxylic acid proved difficult to purify, we employed the
crude product in the subsequent macrocyclization step.
We realized that the formation of the macrolide ring would
be challenging in this system due to a combination of the
hindered nature of the secondary C(23) hydroxyl group, the
complex functionalization pattern of the substrate, and the
usual problems associated with large ring formation. We,
therefore, explored the use of selected methods of macro-
propargylation with good selectivity, the use of Pd(dppf)Cl
2
as a superior catalyst for hydrostannylation, a Stille coupling
of highly complex substrates, and a complex application of
the Shiina macrolactonization.
Acknowledgment. Financial support from the Depart-
ment of the Army, U.S. Army Research Office, and the
Walther Cancer Institute is greatly appreciated. We thank
Dr. M. Grand-Cottard, J. Zigterman, D. Miller, K. O’Leary,
Dr. T. M. Pedersen, M. Mendlik, and J. Ulager (University
of Notre Dame) for the synthesis of early intermediates, Prof.
J. Tanaka and Prof. T. Higa (University of the Ryukyus) for
assistance in the collection of natural material, and Prof. T.
Rein (KTH, Stockholm) for discussions.
35
36
lactonization, including those of Yamaguchi, Mukaiyama,
3
7
and Shiina. For our substrate, we found the Shiina
3
8
macrolactonization protocol to be the most effective;
a
solution of the intermediate seco-acid was slowly added to
a solution of DMAP and 2-methyl-6-nitrobenzoic anhydride
containing powdered molecular sieves. Although occurring
in modest yield, this is the first case of its application to
form such a richly functionalized large-ring system compared
39
to other recent applications. Desilylation completed the total
synthesis of iejimalide B (1).
Supporting Information Available: Experimental pro-
cedures and characterization data of all key reaction products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
35) (a) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. ReV. 2006,
1
06, 911. (b) Evans, D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc.
1
993, 115, 11446.
(36) Crosignani, S.; Gonzalez, J.; Swinnen, D. Org. Lett. 2004, 6, 4579.
37) (a) Shiina, I.; Kubota, M.; Oshiumi, H.; Hashizume, M. J. Org.
(
OL702129W
Chem. 2004, 69, 1822. (b) Wu, Y.; Yang, Y.-Q. J. Org. Chem. 2006, 71,
296.
38) In our hands, application of Mukaiyama conditions did not result
in macrolactonization. However, the Yamaguchi macrolactonization also
provided the desired product, but only in about half the yield of the Shiina
method. We did not observe aromatization to a phenol during the Yamaguchi
macrolactonization as was reported by F u¨ rstner in ref 11a.
4
(
(39) (a) Falck, J. R.; He, A.; Fukui, H.; Tsutsui, H.; Radha, A. Angew.
Chem., Int. Ed. 2007, 46, 4527. (b) Ito, T.; Ito, M.; Arimoto, H.; Takamura,
H.; Uemura, D. Tetrahedron Lett. 2007, 48, 5465. (c) Scheerer, J. R.;
Lawrence, J. F.; Wang, G. C.; Evans, D. A. J. Am. Chem. Soc. 2007, 129,
8968.
4622
Org. Lett., Vol. 9, No. 22, 2007