Stereoselective synthesis of premisakinolide A, the monomeric counterpart of the marine 40-membered dimeric macrolide misakinolide A

Article abstract of DOI:10.1021/ol050864v

(Chemical Equation Presented) The first synthesis of premisakinolide A, the monomeric counterpart of misakinolide A, the marine 40-membered macrolide displaying potent activity against a variety of human carcinoma cell lines, has been reported. The strate

Full text of DOI:10.1021/ol050864v

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2929-2932
Stereoselective Synthesis of
Premisakinolide A, the Monomeric
Counterpart of the Marine 40-Membered
Dimeric Macrolide Misakinolide A
Ryoichi Nakamura, Keiji Tanino, and Masaaki Miyashita*
DiVision of Chemistry, Graduate School of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
miyasita@sci.hokudai.ac.jp
Received April 20, 2005
ABSTRACT
The first synthesis of premisakinolide A, the monomeric counterpart of misakinolide A, the marine 40-membered macrolide displaying potent
activity against a variety of human carcinoma cell lines, has been reported. The strategy was highlighted by a crucial coupling of a tetrahydropyran
fragment and an alkynylaluminum reagent having a polypropionate chain, the highly stereoselective cross aldol reaction of segment A and
segment B, and the stereospecific construction of the polypropionate structure based on original acyclic stereocontrol.
The marine natural products swinholides,1 44-membered
dimeric macrolides, isolated from the Okinawan marine
sponge Theonella swinhoei, and misakinolide A2a-c (1)
(bistheonellide A),2b,d a 40-membered dimeric macrolide,
isolated from another Okinawan marine sponge Theonella,
have been revealed to exhibit potent cytotoxicity against a
variety of human carcinoma cell lines, as well as a broad
spectrum of antifungal activity.1-3 The stereostructures of
the monomeric units of swinholide A and misakinolide A
(termed preswinholide A and premisakinolide A (2), respec-
tively), are remarkably similar, and only the number of
double bonds connected to a carboxyl group is different.
Also, the polypropionate structures of these monomeric
counterparts are similar to that of scytophycin C, the 22-
membered macrolide isolated from the terrestrial blue-green
alga, Scytonema pseudohofmanni,4 which also exhibits
significant activity against a variety of human carcinoma cell
lines, including solid tumors.5 The structures of the swin-
holide and misakinolide families are characterized by the
C2-symmetrical dimeric macrolides in which two polypro-
pionate-derived chains, including a gigantic lactone ring, are
axially oriented on a tetrahydropyran ring. Their unique
structures as well as potent anticancer activities have elicited
much attention from synthetic chemists.6 However, total
synthesis of misakinolide A (1) has not been achieved yet,
(1) (a) Carmely, S.; Cashman, Y. Tetrahedron Lett. 1985, 26, 511. (b)
Kobayashi, M.; Tanaka, J.; Katori, T.; Matsuura, M.; Kitagawa, I.
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10.1021/ol050864v CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/10/2005

although total syntheses of swinholide A have been reported
by two groups, those of Paterson7a-e and Nicolaou.7f
Recently, we reported a stereoselective total synthesis of
scytophycin C based on new acyclic stereocontrol.8,9 As part
of our synthetic program toward the polypropionate-derived
natural products,6e,8,10 we report herein the first synthesis of
premisakinolide A (2), the monomeric counterpart of mis-
akinolide A (1),2 which involves a crucial coupling of a
tetrahydropyran fragment and an alkynylaluminum reagent
having a polypropionate chain bearing five consecutive
stereogenic centers, the highly stereoselective cross aldol
reaction of segment A and segment B, and the stereospecific
construction of the polypropionate structures in these seg-
ments as the key steps.
Scheme 1. Synthetic Strategy of Misakinolide A (1)
Our retrosynthesis of premisakinolide A (2) is shown in
Scheme 1. Namely, 2 was divided into the C(1)-C(16)
segment (segment A) and the C(17)-C(30) segment (seg-
ment B), and both segments were designed to connect by
an aldol reaction at the C16 and C17 positions under Felkin-
Anh control similarly to the synthesis of scytophycin C.8,9
Segment A, including a dihydropyran ring bearing trans-
substituted side chains, could be straightforwardly synthe-
sized from the intermediate 3 used in our total synthesis of
scytophycin C.8 On the other hand, to construct segment B
containing a tetrahydropyran ring and eight asymmetric
carbon atoms, we envisaged the coupling reaction of the
tetrahydropyran derivative 4 and the alkynyl segment 5
having five consecutive stereogenic centers.
Segment A was straightforwardly synthesized starting from
the intermediate 3 in the synthesis of scytophycin C8
according to Scheme 2, which involves the Grubbs olefin
metathesis and chemoselective reduction of epoxy aldehyde
as the key steps.
(5) (a) Moore, R. E.; Patterson, G. M. L.; Mynderse, J. S.; Barchi, J.,
Jr.; Norton, T. R.; Furusawa, E.; Furusawa, S. Pure. Appl. Chem. 1986,
58, 263. (b) Moore, R. E.; Banarjee, S.; Bornemann, V.; Caplan, F. R.;
Chen, J. L.; Corley, D. E.; Larsen, L. K.; Moore, B. S.; Patterson, G. M.
L.; Paul, V. J.; Stewart, J. B.; Williams, D. E. Pure. Appl. Chem. 1989, 61,
521. (c) Valeriote, F. A.; Moore, R. E.; Patterson, G. M. L.; Paul, V. J.;
Sheuer, P. J.; Corbett, T. H. In Anticancer Drug DiscoVery and DeVelop-
ment: Natural Products and New Molecular Models; Valeriote, F. A.,
Corbett, T. H., Baker, L. H., Eds.; Kluwer Academic Publishers: Norwell,
MA, 1994; pp 1-25.
(6) (a) Patron, A. P.; Richter, P. K.; Tomaszewski, M. J.; Miller, R. A.;
Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1994, 1147. (b) Richter,
P. K.; Tomaszewski, M. J.; Miller, R. A.; Patron, A. P.; Nicolaou, K. C. J.
Chem. Soc., Chem. Commun. 1994, 1151. (c) Nakata, T.; Komatsu, T.;
Nagasawa, K.; Yamada, H.; Takahashi, T. Tetrahedron Lett. 1994, 35, 8225.
(d) Nakata, T.; Komatsu, T.; Nagasawa, K. Chem. Pharm. Bull. 1994, 42,
2403. (e) Hayakawa, H.; Miyashita, M. J. Chem. Soc., Perkin Trans. 1
1999, 3399. (f) Yeung, K.-S.; Paterson, I. Angew. Chem., Int. Ed. 2002,
41, 4632.
(7) (a) Paterson, I.; Yeung, K.-S.; Ward, R. A.; Cumming, J. G.; Smith,
J. D. J. Am. Chem. Soc. 1994, 116, 9391. (b) Paterson, I.; Cumming, J. G.;
Ward, R. A.; Lamboley, S. Tetrahedron 1995, 51, 9393. (c) Paterson, I.;
Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51, 9413. (d) Paterson, I.;
Ward, R. A.; Smith, J. D.; Cumming, J. G.; Yeung, K.-S. Tetrahedron 1995,
51, 9437. (e) Paterson, I.; Yeung, K.-S.; Ward, R. A.; Smith, J. D.;
Cumming, J. G.; Lamboley, S. Tetrahedron 1995, 51, 9467. (f) Nicolaou,
K. C.; Patron, A. P.; Ajito, K.; Richter, P. K.; Khatuya, H.; Bertinato, P.
Miller, R. A.; Tomaszewski, M. J. Chem. Eur. J. 1996, 2, 847.
(8) (a) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2003, 5, 3579.
(b) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2003, 5, 3583.
(9) Total synthesis of scytophycin C by Patterson et al.: (a) Paterson,
I.; Watson, C.; Yeung, K.-S.; Wallace, P. A.; Ward, R. A. J. Org. Chem.
1997, 62, 452. (b) Paterson, I.; Yeung, K.-S.; Watson, C.; Ward, R. A.;
Wallace, P. A. Tetrahedron 1998, 54, 11935. (c) Paterson, I.; Watson, C.;
Yeung, K.-S.; Ward, R. A.; Wallace, P. A. Tetrahedron 1998, 54, 11955.
(d) Ref 6f.
Thus, treatment of 3 with the second-generation Grubbs’
catalyst11 (2 mol %) and crotonaldehyde in CH2Cl2 at reflux
gave unsaturated aldehyde 6 in 78% yield. The product was
then converted to â-epoxy alcohol 7 in two steps in 90%
yield: (1) reduction with DIBAH in THF (92%) and (2) the
Katsuki-Sharpless asymmetric epoxidation12 (98%). Oxida-
tion of the epoxy diol 7 with Dess-Martin periodinane13
followed by treatment of the resulting epoxy aldehyde with
Na[PhSeB(OEt)3]14 and AcOH in EtOH furnished hydroxy
aldehyde 8, which was then subjected to a Wittig reaction
with Ph3PdC(CH3)CO2Me in toluene to give rise to the (E)-
unsaturated ester in 69% yield for three steps. Notably,
chemoselective reduction of the epoxide functionality in the
epoxy aldehyde cleanly occurred with the use of benzene-
(10) (a) Shiratani, T.; Kimura, K.; Yoshihara, K.; Hatakeyama, S.; Irie,
H.; Miyashita, M. Chem. Commun. 1996, 21. (b) Komatsu, K.; Tanino, K.;
Miyashita, M. Angew. Chem., Int. Ed. 2004, 43, 4341. (c) Iwata, Y.;
Maekawara, N.; Tanino, K.; Miyashita, M. Angew. Chem., Int. Ed. 2005,
44, 1532.
(11) Chatterjee, A. K.; Choi, T.-L.; Sanders, A. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360.
2930
Org. Lett., Vol. 7, No. 14, 2005

Scheme 2. Stereoselective Synthesis of Segment A
selenol (PhSeH) generated from Na[PhSeB(OEt)3] in situ,14
as we expected. Protection of the secondary alcohol with
On the other hand, the tetrahydropyran fragment 4 was
also efficiently synthesized by using the new synthetic route
(Scheme 3). Namely, the Claisen condensation of the
commercially available methyl (S)-3-hydroxybutanoate (10)
with a lithium ester enolate of tert-butyl acetate15 in THF
afforded keto ester 11 in 93% yield, which was reduced with
tetramethylammonium triacetoxyborohydride16 and AcOH in
CH3CN to produce anti-diol 12 in a highly stereoselective
manner (ds > 98:2) in 97% yield.
Scheme 3. Chiral Synthesis of the Tetrahydropyran Moiety 4
Conversion of 12 to the hydroxy lactone by treatment with
PPTS17 and subsequent O-methylation of the secondary
hydroxyl group with MeI and Ag2O18 afforded the â-methoxy
lactone (86% yield for two steps), which was then converted
to the tetrahydropyran fragment 4 by reduction with DIBAH,
followed by acetylation in a one-pot operation in 80% yield.
Segment B containing a tetrahydropyran ring was ef-
ficiently and highly stereoselectively synthesized according
to Scheme 4, which involves a novel coupling reaction of
acetoxy tetrahydropyran 4 with an alkynylaluminum reagent,
including the polypropionate chain bearing five consecutive
stereogenic centers, as the key step.
TBSOTf and 2,6-lutidine in CH2Cl2 provided 9 (segment A)
in 88% yield. The present synthetic route enabled the
stereoselective introduction of the hydroxyl group at the C5
position without formation of any stereoisomers.
Scheme 4. Stereoselective Syntheses of Alkynyl Segment 5 and Segment B
Org. Lett., Vol. 7, No. 14, 2005
2931

Scheme 5. Stereoselective Synthesis of Premisakinolide (2)
Initially, the intermediate 13, which was used in our total
In turn, the adduct 15 was transformed into acetal 16 by
a three-step reaction sequence: (1) hydrogenation of the triple
bond and concomitant deprotection of the benzyl group (76%
yield), (2) removal of the silylene group with HF-Py, and
(3) acetalization of the resulting triol with 4-MeOC6H4CH-
(OMe)2 (87% yield for two steps). Protection of the second-
ary hydroxyl group in 16 with MOMCl followed by reductive
cleavage of the acetal with DIBAH in CH2Cl2 furnished the
primary alcohol in 88% yield, which was then subjected to
oxidation with Dess-Martin periodinane13 to produce 17
(segment B) in 93% yield.
synthesis of scytophycin C8, was routinely converted to
alcohol 14 in three steps: (1) removal of the TES group
with TBAF, 94% yield; (2) protection of the secondary
t
hydroxyl groups with Bu2Si(OTf)2, 74% yield; and (3)
reduction of the pivaloate with DIBAH, 92% yield. The
resulting alcohol 14 was readily transformed into the crucial
alkyne segment 5 by a Swern oxidation followed by a Wittig
reaction with (dibromomethylene)triphenylphosphorane19
(96% yield for two steps) and subsequent treatment with
BuLi in THF (90% yield).
The key coupling reaction of segments A and B was
performed by the aldol reaction of silyl enol ether 18 derived
from segment A and the aldehyde segment B by using
conditions similar to those employed in the synthesis of
scytophycin C8,9 resulting in the formation of an almost single
aldol 19 in 82% yield (Scheme 5). Then, the aldol was treated
with catecholborane8,9 to give the syn-diol exclusively in 64%
yield, which was eventually converted to the fully protected
premisakinolide A (2) by treatment with 2,2-dimethoxypro-
pane and a catalytic amount of CSA in 82% yield.
Thus, we have established a highly stereoselective syn-
thesis of the fully protected premisakinolide A (2) required
for the total synthesis of misakinolide A on the basis of the
original synthetic methodology.
With the requisite segments 4 and 5 in hand, we focused
on the coupling reaction of both segments leading to segment
B, the key step in the present synthesis. After a number of
experiments, we found that the coupling reaction of 4 and 5
successfully occurred with the use of the alkynylaluminum
reagent prepared from 5 in situ. Namely, initial treatment of
5 with BuLi in CH2Cl2 followed by treatment of the resulting
lithium acetylide with dimethylaluminum triflate produced
the requisite alkynyldimethylaluminum reagent, which was
reacted with 4 to give rise to the desired product 15 in 80%
yield. It should be noted that the quantity of Me2AlOTf was
of critical importance in this particular reaction and that the
use of 3.2 equiv of Me2AlOTf gave the best result. The
coupling reaction exclusively occurred from the opposite side
of two substituents on the tetrahydropyran ring, giving rise
to 15 as a single product.
Acknowledgment. Financial support from the Ministry
of Education, Culture, Sports, Science and Technology, Japan
(a Grant-in-Aid for Scientific Research (A) (No. 12304042)
and a Grant-in-Aid for Scientific Research (B) (No. 16350049)
is gratefully acknowledged. R.N. thanks JSPS for a predoc-
toral fellowship.
(12) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
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Supporting Information Available: Experimental details
and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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