Total synthesis of (-)-Apicularen A

Article abstract of DOI:10.1021/ol101753y

A convergent total synthesis of (-)-apicularen A, a highly cytostatic 12-membered macrolide, has been accomplished. The key steps include assembling of iodoalkene 8 and aldehyde 9 by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. Introduction of the (2Z,4Z)-heptadienamide moiety in the side chain by an efficient Cu(I)-mediated coupling completed the total synthesis.

Full text of DOI:10.1021/ol101753y

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4160-4163
Total Synthesis of (-)-Apicularen A
Sanjay S. Palimkar and Jun’ichi Uenishi*
Kyoto Pharmaceutical UniVersity, Misasagi Yamashina, Kyoto 607-8412, Japan
juenishi@mb.kyoto-phu.ac.jp
Received July 27, 2010
ABSTRACT
A convergent total synthesis of (-)-apicularen A, a highly cytostatic 12-membered macrolide, has been accomplished. The key steps include
assembling of iodoalkene 8 and aldehyde 9 by Nozaki-Hiyama-Kishi (NHK) coupling, stereospecific construction of 2,6-trans-disubstituted
dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reaction, and Yamaguchi macrolactonization. Introduction of the (2Z,4Z)-heptadienamide
moiety in the side chain by an efficient Cu(I)-mediated coupling completed the total synthesis.
Kunze et al. reported the isolation of (-)-apicularen A (1)
from a variety of strains of the myxobacterial genus Chondro-
myces in 1998.1 Subsequently, the gross structure of 1 including
the relative and absolute stereochemistry was determined.2
Biological studies revealed 1 to be highly cytostatic to a wide
range of human cancer cell lines such as ovarian, prostate, lung,
kidney, cervix, leukemia, and histiocytic cells with IC50 values
in the range of 0.23-6.79 nM.1 In addition, recent reports
indicated that 1 exhibited antiangiogenesis properties,3a induced
Figure 1. Structure of (-)-Apicularen A.
apoptosis,3b,c produced nitric oxide,3d acted as a novel specific
V-ATPase inhibitor,3e,f and was a promising new microtu-
bule-targeting compound.3g
embedded in a 12-membered salicylate macrolactone and
four stereogenic centers within the macrolactone core which
bears a highly unsaturated N-acylenamine side chain.
Because of its fascinating molecular architecture and potent
biological activity, 1 has been targeted by a number of
synthetic research groups. To date, four total syntheses of
14 have been achieved along with four formal total synthe-
ses.5 A number of synthetic efforts6 as well as syntheses of
analogues7 have also been reported.
From a structural point of view, 1 is characterized by a
number of motifs such as a 2,6-trans-tetrahydropyran ring
(1) Kunze, B.; Jansen, R.; Sasse, F.; Hofle, G.; Reichenbach, H. J.
Antibiot. 1998, 51, 1075–1080.
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2000, 913–919.
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Biotechnol. 2002, 12, 702–705. (b) Hong, J.; Yamaki, K.; Ishihara, K.; Ahn,
J.-W.; Zee, O.; Ohuchi, K. J. Pharm. Pharmacol. 2003, 55, 1299–1306.
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312. (d) Hong, J.; Yokomakura, A.; Nakano, Y.; Ban, H. S.; Ishihara, K.;
Ahn, J.-W.; Zee, O.; Ohuchi, K. J. Pharmacol. Exp. Ther. 2005, 312, 968–
977. (e) Hong, J.; Yokomakura, A.; Nakano, Y.; Ishihara, K.; Kaneda, M.;
Onodera, M.; Nakahama, K.; Morita, I.; Niikura, K.; Ahn, J.-W.; Zee, O.;
Ohuchi, K. FEBS Lett. 2006, 580, 2723–2730. (f) Huss, M.; Sasse, F.;
Kunze, B.; Jansen, R.; Steinmetz, H.; Ingenhorst, G.; Zeeck, A.; Wieczorek,
H. BMC Biochem. 2005, 6, 13. (g) Kim, J.-S.; Lee, Y.-C.; Nam, H.-T.; Li,
G.; Yun, E.-J.; Song, K.-S.; Seo, K.-S.; Park, J.-H.; Ahn, J.-W.; Zee, O.;
Park, J.-I.; Yoon, W.-H.; Lim, K.; Hwang, B.-D. Clin. Cancer Res. 2007,
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Lett. 2001, 42, 1217–1220. (b) Nicolaou, K. C.; Kim, D. W.; Baati, R.
Angew. Chem., Int. Ed. 2002, 41, 3701–3704. (c) Su, Q.; Panek, J. S. J. Am.
Chem. Soc. 2004, 126, 2425–2430. (d) Petri, A. F.; Bayer, A.; Maier, M. E.
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10.1021/ol101753y  2010 American Chemical Society
Published on Web 08/13/2010

Our interest in the synthesis of (-)-apicularen A stemmed
from its molecular architecture of a bridged 2,6-trans-
tetrahydropyran located in a 12-membered macrolactone ring.
Recent work in our laboratory has provided a facile access
to stereodefined either 2,6-cis- or trans-disubstituted dihy-
dropyran and tetrahydropyran rings by using Pd(II)-catalyzed
1,3-chirality transfer reactions.8,9 We sought to apply our
Pd(II)-catalyzed cyclization strategy to the synthesis of 1.
Herein, we report the total synthesis of (-)-apicularen A
using the Pd(II)-catalyzed cyclization for the construction
of the core 2,6-trans-tetrahydropyran ring.
by Buchwald et al.11 Thus, Cu(I)-catalyzed coupling of io-
doalkene 2 with (2Z,4Z)-hepta-2,4-dienamide 3 could be
expected at a late stage by this improved protocol. Further, the
disconnection of macrolactone indicates that it could be realized
by classical Yamaguchi macrolactonization.12 We envisioned that
the 2,6-trans-disubstituted 2,5-dihydro-2H-pyran ring system in 6
could be constructed by a regio- and stereospecific Pd(II)-catalyzed
cyclization in conjunction with a 1,3-chirality transfer.8 We planned
to synthesize allylic alcohol 7, the precursor of the Pd(II)-catalyzed
cyclization, by Nozaki-Hiyama-Kishi (NHK) coupling,13 and
the alcohol 7 would be derived from two advanced fragments,
iodoalkene 8 and aldehyde 9. The fragments 8 and 9 could be
prepared from their respective starting materials.
Our retrosynthetic plan is outlined in Scheme 1. Nicolaou et
al.4b introduced a conjugated (Z,Z)-dienamide moiety by Cu(I)-
Scheme 1. Retrosynthetic Plan of (-)-Apicularen A
Scheme 2. Synthesis of Iodoalkene 8
In the synthesis of aromatic fragment 8 (Scheme 2), the Stille
coupling of 1014 with allyltributyltin in the presence of cat.
[Pd(PPh3)4] gave terminal alkene 11 in 90% yield.
Ozonolysis of 11 provided aldehyde 12 in 96%, which was
subjected to Takai iodoolefination15 to give 8 in 75% yield with
high selectivity (E:Z ) 9:1). Synthesis of fragment 9 com-
Scheme 3. Synthesis of Aldehyde 9
catalyzed coupling of iodoalkene with (2Z,4Z)-heptadienamide
3 under Shen and Proco’s conditions10 before the macrolac-
tonization because the poor result was obtained in the coupling
after the macrolactonization.7a,5a Although Panek et al. suc-
cessfully attached the side chain amide,4c the coupling was
performed only in 40% yield after the macrolactonization.
However, we anticipated that formation of 1 could be
achieved by using the mild and efficient procedure developed
(6) (a) Bhattacharjee, A.; De Brabander, J. K. Tetrahedron Lett. 2000,
41, 8069–8073. (b) Ku¨hnert, S.; Maier, M. E. Org. Lett. 2002, 4, 643–646.
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1178. (e) Poniatowski, A. J.; Floreancig, P. E. Synthesis 2007, 2291–2296.
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kakou, P. Chem.sEur. J. 2003, 9, 6177–6191. (b) Petri, A. F.; Sasse, F.;
Maier, M. E. Eur. J. Org. Chem. 2005, 1865–1875. (c) Jundt, L.; Ho¨fle, G.
J. Nat. Prod. 2007, 70, 1377–1379. (d) Lewis, A.; Stefanuti, I.; Swain,
S. A.; Smith, S. A.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 5549–
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Org. Lett., Vol. 12, No. 18, 2010
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menced with aldehyde 1316 (Scheme 3). The Horner-
Wadsworth-Emmons reaction of 13 with triethyl phosphonate
ester 1417 afforded (2E,4E)-dienoate 15 in 55% yield (E:Z >
30:1). Sharpless asymmetric dihydroxylation of 15 afforded a
diol, which was converted to cyclic carbonate 16 by treatment
with carbonyldiimidazole (CDI) in 73% overall yield. Reduction
of cyclic carbonate in the presence of Pd catalyst with formic
acid provided δ-hydroxy-R,ꢀ-unsaturated ester 17 in 82% yield.
The δ-hydroxy enoate 17 was transformed into the benzylidene
acetal 18 in 65% yield by using the Evans protocol.18 Finally,
reduction of the ester by DIBALH gave 9 in 90% yield.
For the synthesis of macrolactone core 4 (Scheme 4), the
fragments 8 and 9 were assembled by NHK coupling13 to
oxidation19 followed by diastereofacial selective reduction
of the resulting ketone using (R)-CBS reagent20 in 72% yield
of 19 along with 7% of 19′ for the two steps.
Deprotection of the benzylidene group of 19 under the mild
acidic conditions gave triol 7 in 77% yield. When compound 7
was subjected to the Pd(II)-catalyzed cyclization, gratifyingly the
reaction proceeded smoothly in the presence of PdCl2(CH3CN)2
in THF to give the desired 2,6-trans-dihydropyran 6 in 72% yield
as a single diastereomer. Hydrolysis of the methyl ester using LiOH
gave seco acid 20 in 95% yield.
Further important goals of our synthetic procedure were to install
the macrolactone ring and an R-hydroxy group at the C-11 position
regio- and stereoselectively. Yamaguchi macrolactonization of 20
proceeded to give core macrolactone 5 in 80% yield. Electrophilic
reaction occurred from the ꢀ-face on the dihydropyran ring in this
case. An oxymercuration and successive reductive demercuration
installed the desired stereoinduction of the C-11 hydroxy group
from the R-face. Treatment of 5 with Hg(OCOCF3)2 in THF and
water followed by reductive demercuration with NaBH4 gave the
desired C-11 R-hydroxy product 4 preferentially as a mixture with
the corresponding ꢀ-hydroxy isomer in a 3:1 ratio.
Scheme 4. Synthesis of Core Structure
Scheme 5. Silylation of 4 and X-ray Crystal Structure of 21
(12) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
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provide a mixture of diastereomeric allyllic alcohols 19 and
19′ (dr ) 1.3:1) in 43 and 32% yields, respectively. The
undesired isomer 19′ was converted to 19 via Dess-Martin
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16, 1299–1303. (b) Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J.
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These diastereomers were separated after leading to silyl
ethers 21 and 21′. Silylation of 4 with TBSOTf gave the desired
21 along with undesired 21′ in 69% and 22% yields, respec-
tively. The stereochemistry of the major diastereomer 21 was
confirmed by the X-ray crystallographic analysis (Scheme 5).
The remaining task for completion of the synthesis addressed
the functionalization of the side chain, which is outlined in
Scheme 6. Hydrogenolysis of both O-benzyl groups gave 22
primary alcohol gave aldehyde 23 in 84% overall yield. Takai
iodoolefination15 of 23 gave (E)-iodoalkene 2 in 65% yield after
the separation of (Z)-isomer (21% yield). Initially, we attempted
to couple the key intermediate 2 with 3, in THF at 60 °C under
Buchwald’s conditions,11 but only a trace amount of the desired
product 24 was isolated. However, when this coupling reaction
was conducted with an excess of CuI (2 equiv) in DMF at room
temperature, the reaction improved dramatically, and the
chemical yield increased to 90%. Fortunately, the acetate was
removed under the coupling conditions. Finally, desilylation of
24 with TBAF provided (-)-apicularen A (1) in 96% yield.
Scheme 6. Synthesis of (-)-Apicularen A
The physical and spectroscopic data (1H, 13C, IR, HRMS)
as well as specific rotation were fully identical with those
reported for the naturally occurring (-)-1.2
In summary, the total synthesis of (-)-apicularen A has
been accomplished in 19 linear steps from aldehyde 13. The
key features of this total synthesis included: (i) assembly of
(E)-iodoalkene and substituted heptanal by NHK coupling;
(ii) stereospecific construction of 2,6-trans-disubstituted
dihydropyran by Pd(II)-catalyzed 1,3-chirality transfer reac-
tion; (iii) Yamaguchi macrolactonization to construct the 12-
membered lactone ring with dihydropyran bridge; (iv) regio-
and stereoselective introduction of the R-hydroxy group at
the C-11 position by oxymercuration and reductive demer-
curation; and (v) highly efficient Cu(I)-mediated coupling
of the iodoalkene with the dienamide under mild conditions.
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures and copies of NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
in 99% yield. The chemoselective protection of the phenol with
acetic anhydride followed by Dess-Martin oxidation of the
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