Total synthesis of the proposed structure of heronamide C

Article abstract of DOI:10.1002/ejoc.201301487

The total synthesis of the proposed structure of heronamide C was accomplished through a Sato-Micalizio reductive alkyne-alkyne coupling strategy and remote-amine controlled stannylcupration. However, the physical data for the synthetic and natural samples differ from each other, which suggests that the proposed structure should be reinvestigated. The total synthesis of the proposed structure of heronamide C is accomplished by using a Sato-Micalizio reductive alkyne-alkyne coupling strategy and remote-amine-controlled stannylcupration. However, the physical data for the synthetic and natural samples differ from each other, which suggests that the proposed structure should be reinvestigated. Copyright

Full text of DOI:10.1002/ejoc.201301487

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301487
Total Synthesis of the Proposed Structure of Heronamide C
Kohei Sakanishi,[a] Shunya Itoh,[a] Ryosuke Sugiyama,[b] Shinichi Nishimura,[b]
Hideaki Kakeya,[b] Yoshiharu Iwabuchi,[a] and Naoki Kanoh*[a]
Keywords: Total synthesis / Natural products / Macrocycles / Alkynes / Cross-coupling
The total synthesis of the proposed structure of heron-
the synthetic and natural samples differ from each other,
amide C was accomplished through a Sato–Micalizio re- which suggests that the proposed structure should be re-
ductive alkyne–alkyne coupling strategy and remote-amine
controlled stannylcupration. However, the physical data for
investigated.
Introduction
Heronamide C (1) was discovered together with heron-
amides A (2) and B (3) from the culture broth of Strepto-
myces sp. CMB-M0406, which was isolated from a shallow
water sediment sample collected off Heron Island, Australia
(Figure 1).[1] All three heronamides have a highly unsatu-
rated macrocyclic or polycyclic system having a vicinal diol
functionality. Indeed, this class of natural products has
been widely found in nature[2] and is currently known to
consist of a growing number of polyene macrocyclic lactam
classes of natural products. Among the heronamide conge-
ners, only heronamide C (1) is reported to have a pro-
nounced and unique effect on the morphology of cultured
cells.
Raju et al. postulated in their report on the isolation and
structure determination that there is a plausible biosyn-
thetic relationship among the heronamides.[1] They pro-
posed that heronamide C (1) is a pivotal polyene precursor
that is capable of undergoing either 6π+6π tandem electro-
cyclization to generate heronamide B (3) or selective epox-
idation and macrolactam pyrrolidine formation followed by
4π+6π tandem electrocyclization to generate heronamide A
(2).[3] Indeed, they took these possible transformations into
Figure 1. Reported and revised structures of the heronamides.
We are interested in the chemistry and biology of polyene
consideration when proposing the structure of heron- macrolactams.[5] As part of our program aimed at synthe-
amide C (1) on the basis of the structure of heronamide A sizing biologically active polyene macrolactams, we em-
(2). However, recent studies showed that the structure of barked on synthetic studies of heronamides. In this com-
heronamide A is not as originally proposed in 2 but instead munication, we describe a total synthesis of the proposed
is that in 4.[4]
structure of heronamide C (1) featuring a Sato–Micalizio
reductive alkyne–alkyne coupling strategy[6] and remote-
amine-controlled stannylcupration. The NMR spectro-
scopic data of the synthetic sample, however, does not
match those of heronamide C, which indicates that the
structure of heronamide C needs to be reinvestigated.
[a] Graduate School of Pharmaceutical Sciences, Tohoku
University,
6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
E-mail: nkanoh@m.tohoku.ac.jp
http://www.pharm.tohoku.ac.jp/~gousei/synthetic/index.html
[b] Department of System Chemotherapy and Molecular Sciences,
Division of Bioinformatics and Chemical Genomics, Graduate
School of Pharmaceutical Sciences, Kyoto University,
Kyoto 606-8501, Japan
Results and Discussion
Our retrosynthetic analysis is shown in Scheme 1. We en-
visioned that the C10–C17 tetraene moiety of the reported
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301487.
1376
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1376–1380

Total Synthesis of the Proposed Structure of Heronamide C
structure of heronamide C (1) would be unstable and therefore retrosynthetically disconnected the C11–C12
should be constructed in the late stage of the synthesis. We bond and planned to construct this through intramolecular
Stille coupling. Further disconnection of the amide linkage
led to C12–C27 amine fragment A and C1–C11 carboxylic
acid fragment B. Amine fragment A was further discon-
nected, as shown, to chiral homoallylamine C. We then en-
visioned that C1–C11 carboxylic acid fragment B could be
constructed through a reductive alkyne–alkyne cross-cou-
pling procedure: disconnection between the C5–C6 bond
leads to internal alkyne fragment D and terminal alkyne
fragment E, which could be synthesized from d-ribose and
methyl propiolate, respectively.
We first synthesized the C12–C27 amine fragment
(Scheme 2). Starting from amine 5, which was obtained
with 95%ee by using a Kobayashi transfer aminoallylation
protocol,[7] two-step protection of the amine gave carb-
amate 6 in 94% yield. Oxidative cleavage of the olefin in 6
and the following (E)-selective Wittig reaction with the use
of phosphonium salt 7[8] generated diene 8 as an inseparable
10:1 mixture of (E)/(Z) isomers. Double tert-butoxycarb-
onyl (Boc) protection of the amine was necessary for the
high (E) selectivity.[9] Protecting group exchange and the
following Horner–Wadsworth–Emmons (HWE) reaction
with phosphonate 10[10] gave (2E)/(2Z)-12 in a 3:1 ratio,
Scheme 1. Retrosynthetic analysis.
Scheme 2. Synthesis of C12–C27 amine fragments 15 and 16. Reagents and conditions: (a) Boc2O, Et3N, DMAP, CH2Cl2, r.t., 13 h;
(b) BuLi, Boc2O, THF, –78 to 0 °C, 1 h, 94% (2 steps); (c) OsO4, NaIO4, 2,6-lutidine, dioxane/H2O (3:1), r.t., 1.5 h; (d) Wittig reagent 7,
NaHMDS, THF, –78 °C, 30 min, 78% (2 steps); (e) TFA, CH2Cl2, 0 °C to r.t., 1.5 h; (f) FmocCl, K2CO3, THF, 0 °C to r.t., 1 h, 86%
(2 steps); (g) BCl3, CH2Cl2, –78 to 0 °C, 20 min; (h) IBX, DMSO, r.t., 1 h, 93% (2 steps); (i) phosphonate 10, BuLi, THF, –78 °C, then
9, 0 °C, 30 min; (j) FmocCl, NaHCO3, THF/H2O (1:1), r.t., 30 min, 93% (2 steps); (k) DIBALH, CH2Cl2, –78 °C, 30 min, then separation,
61%; (l) MnO2, CH2Cl2, r.t., 30 min, 95%; (m) trimethylsilyldiazomethane, BuLi, THF, –78 to 0 °C, 10 min, 77%; (n) FmocCl, NaHCO3,
THF/H2O (1:1), r.t., 30 min, 52%. DMAP = 4-dimethylaminopyridine, NaHMDS = sodium hexamethyldisilazide, TFA = trifluoroacetic
acid, IBX = 2-iodoxybenzoic acid, DIBALH = diisobutylaluminum hydride.
Eur. J. Org. Chem. 2014, 1376–1380
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1377

N. Kanoh et al.
SHORT COMMUNICATION
along with 9-fluorenylmethoxycarbonyl (Fmoc)-depro-
We then focused on the preparation of C1–C11 carbox-
tected product 11. Reprotection of 11 and diisobutylalumi- ylic acid fragment B (Scheme 3). After numerous attempts,
num hydride (DIBALH) reduction of 12 gave allyl alcohol we found that internal alkyne 22 and alkyne 26 were suit-
13. Fortunately, desired (E,E,E,E) isomer 13 could be sepa- able for the necessary coupling reaction. Compounds 22
rated from the other isomers at this point. MnO2 oxidation and 26 were prepared from known alcohols 21[15] and 25,[16]
and Colvin rearrangement afforded desired tetraenyne 15 in respectively. Thus, internal alkyne 22 was treated with
good yield. Treatment of 15 with FmocCl gave 16 in 52% in situ generated low-valent titanium complex 23 under
yield.
Micalizio conditions to give presumed Ti–alkyne complex
We next examined the hydrostannylation reaction of 24.[6b] Addition of enyne 26 to titanium complex 24 fol-
tetraenyne 16 (Table 1). First, we attempted a palladium- lowed by acidic hydrolysis and tetrabutylammonium
catalyzed hydrostannylation reaction (Table 1, entries 1 and fluoride (TBAF) treatment afforded triene 27 and its re-
2[11]). However, neither the yield nor the regioselectivity gioisomer in 64% yield as a 12:1 inseparable mixture. The
(i.e., 19 vs. 20) of these reactions was satisfactory. We next same type of propargylic ether has been reported to un-
examined a stannylcupration/protonation sequence[12] by dergo β-elimination under these reaction conditions to gen-
using 16 as a substrate (Table 1, entry 3). In this case, a erate an allene product,[17] and this suggests the importance
high yield was obtained for the hydrostannylation product, of the choice of the protecting group in 22. The mixture was
although the regioselectivity was still unsatisfactory. After treated with MnO2 and KCN in MeOH,[18] and removal of
extensive investigation of this reaction, we finally found that the acetonide and chromatographic separation gave methyl
the reaction temperature, reaction time, and nonprotected ester 28. Finally, protection of the C8–C9 diol moiety fol-
amine in the substrate (i.e., 15) were critical for the high
selectivity; that is, treatment of tetraenyne 15 with in situ
[13]
generated Bu3Sn(Bu)Cu(CN)Li2 at –25 °C for 2 min fol-
lowed by the addition of MeOH delivered desired (E)-vinyl-
stannane 17 in 80% yield along with undesired exometh-
ylene compound 18 (2%; Table 1, entry 4). It should be em-
phasized that upon treating 16 under exactly the same con-
ditions, 19 and 20 were obtained in a 2:1 ratio (Table 1,
entry 5). We reasoned that the formation of a transiently
stable Cu–amine coordinating dimer was the key to the high
regioselectivity.[14]
Table 1. Hydrostannylation of tetraenynes 15 and 16.
Scheme 3. Synthesis of C1–C11 carboxylic acid fragment 30. Rea-
gents and conditions: (a) PMBCl, NaH, DMF, 0 °C to r.t., 3 h,
Entry Substrate Conditions[a] Temp. Time Products[b]
99%; (b) BuLi, HMPA, THF, –78 °C, 30 min, then MeI, –78 °C to
r.t., 2 h; (c) ClTi(OiPr)3, c-C5H9MgCl, toluene, –78 to –30 °C, 2 h,
then 26, –78 to –50 °C, 3 h, then satd. aq. NH4Cl; (d) TBAF, THF,
r.t., 2 h, 64% from 26 (27/regioisomer = 12:1); (e) TBDPSCl, imid-
azole, THF, r.t., 1 h, 88%; (f) MnO2, KCN, MeOH, r.t., 32 h, 90%;
(g) Amberlyst 15, MeOH/H2O (21:1), r.t., 6 h, 75%; (h) TESOTf,
2,6-lutidine, CH2Cl2, 0 °C, 10 min, 99%; (i) DDQ, CH2Cl2/pH 7
phosphate buffer (1:1), 0 °C, 1.5 h, 88%; (j) Dess–Martin
periodinane, pyridine, CH2Cl2, 0 °C to r.t. 10 min, 93%;
(k) (Ph3P+CH2I)I–, NaHMDS, HMPA, THF, –98 °C, 15 min, 77%;
(l) TMSOK, THF, 0 °C to r.t., 1 h, 51% (100% brsm). PMB = p-
methoxybenzyl, DMF = N,N-dimethylformamide, HMPA = hexa-
methylphosphoramide, TBDPS = tert-butyldiphenylsilyl, Tf = tri-
[°C]
[min]
1
2
3
4
5
16
16
16
15
16
A
B
C
C
C
r.t.
0
–25
–25
–25
60
120
19 (28), 20 (19)
19 (19), 20 (2)
10[c] 19 (54), 20 (24)
2[c]
2[c]
17 (80), 18 (2)
19 (53), 20 (25)
[a] Conditions A: PdCl2(PPh3)2,
Bu3SnH,
CH2Cl2;
condi-
tions B: Pd2(dba)3·CHCl3, Cy3P·HBF4, iPr2NEt, Bu3SnH, CH2Cl2;
conditions C: BuLi, CuCN, Bu3SnH, THF. dba = dibenzylidene-
acetone, Cy = cyclohexyl. [b] These isomers were inseparable.
Numbers in parentheses are yields calculated on the basis of
1H NMR integration. [c] The reaction was quenched by the ad-
dition of MeOH.
fluoromethanesulfonyl, DDQ
=
2,3-dichloro-5,6-dicyano-1,4-
benzoquinone, brsm = based on recovered starting material.
1378
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1376–1380

Total Synthesis of the Proposed Structure of Heronamide C
lowed by the construction of C10–C11 (Z)-iodoolefin and tion of the triethylsilyl (TES) group by using TBAF and
hydrolysis of the methyl ester moiety in 29 furnished C1– acetic acid afforded the proposed structure of heron-
C11 carboxylic acid fragment 30.
amide C (1) in 69% yield.
With the two fragments in hand, the remaining objective
Although we accomplished the total synthesis, the physi-
was to assemble a macrocyclic lactam skeleton and depro- cal data for the synthetic sample did not match that of the
tection (Scheme 4). To couple the two fragments, we first natural product (see the Supporting Information). To verify
examined intermolecular Stille coupling of vinyl iodide 29 the structure of our synthetic sample, we performed exten-
and vinylstannane 19. Although we were able to identify sive NMR spectroscopy experiments. The synthetic sample
1
reaction conditions that gave coupling product 31 (condi- gave a H NMR spectrum containing broad and severely
tions not shown), the yield was quite low (≈8%), and prod- overlapping olefinic proton signals at room temperature
uct 31 was found to be very unstable and easily decomposed and at 40 °C in [D5]pyridine, whereas a spectrum with re-
upon standing. We therefore decided first to construct the solved signals was obtained at –30 °C (see the Supporting
amide linkage and examined the coupling of carboxylic acid Information). After a series of NMR spectroscopy experi-
30 and amine 17. Among the several coupling reagents ex- ments under these conditions, we successfully characterized
amined, the combination of O-(7-azabenzotriazol-1-yl)- the 1H NMR signals of the synthetic sample and confirmed
N,N,NЈ,NЈ-tetramethyluronium
hexafluorophosphate the planar structure, including the geometry of every double
(HATU) and diisopropylethylamine gave the best result: bond, as shown in 1 (see the Supporting Information). Con-
coupling of 30 and 17 in the presence of these reagents gave fidence in the stereochemical assignment in our synthetic
amide 32 in 87% yield.
sample was founded upon extensive NMR spectroscopy
analysis stated above and through the stereochemistry of
the C8–C9 diol from d-ribose, which indicates that the
structure of heronamide C should be revisited.
Conclusions
We accomplished the total synthesis of the proposed
structure of heronamide C (1) in a highly convergent man-
ner. The physical data for the synthetic and natural samples
differ from each other, however, which suggests that pro-
posed structure 1 should be reinvestigated. Further studies
towards the elucidation of the correct structure of heronam-
ide C are currently ongoing and will be reported in due
course.
Supporting Information (see footnote on the first page of this arti-
1
cle): Full experimental details and copies of the H NMR and 13C
NMR spectra for all intermediates and final products.
Acknowledgments
This work was financially supported by the Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan (Grant-
in-Aid for Scientific Research on Innovative Areas “Chemical Bio-
logy of Natural Products”) and by the Japan Society for the Pro-
motion of Science.
[1] R. Raju, A. M. Piggott, M. M. Conte, R. J. Capon, Org. Bio-
mol. Chem. 2010, 8, 4682.
Scheme 4. Total synthesis of the proposed structure of heron-
amide C (1). Reagents and conditions: (a) HATU, iPr2NEt, DMF,
r.t., dark, 20 min, 87%; (b) Pd2(dba)3·CHCl3, iPr2NEt, DMF, r.t.,
dark, 4 h, 48%; (c) TBAF, AcOH, THF, r.t., dark, 2 h, 69%. TMS
= trimethylsilyl.
[2] a) K. Kojiri, S. Nakajima, H. Suzuki, H. Kondo, H. Suda, J.
Antibiot. 1992, 45, 868; b) K. Shindo, M. Kamishohara, A.
Odagawa, M. Matsuoka, H. Kawai, J. Antibiot. 1993, 46, 1076;
c) I. Takahashi, Y. Oda, Y. Nishiie, K. Ochiai, T. Mizukami, J.
Antibiot. 1997, 50, 186; d) S. S. Mitchell, B. Nicholson, S. Tei-
san, K. S. Lam, B. C. M. Potts, J. Nat. Prod. 2004, 67, 1400; e)
D. W. Udwary, L. Zeigler, R. N. Asolkar, V. Singan, A. Lap-
idus, W. Fenical, P. R. Jensen, B. S. Moore, Proc. Natl. Acad.
Sci. USA 2007, 104, 10376; f) Y. Futamura, R. Sawa, Y. Umez-
awa, M. Igarashi, H. Nakamura, K. Hasegawa, M. Yarnasaki,
E. Tashiro, Y. Takahashi, Y. Akarnatsu, M. Imoto, J. Am.
Chem. Soc. 2008, 130, 1822; g) H. Jorgensen, K. F. Degnes,
H. Sletta, E. Fjaervik, A. Dikiy, L. Herfindal, P. Bruheim, G.
The final task was intramolecular Stille coupling of 32
and deprotection. Fortunately, the reaction worked to give
macrocycle 33, although in 48% yield. In fact, we were con-
cerned about a possible intramolecular Heck reaction be-
tween the C10–C11 vinyl iodide and the C6–C7 double
bond, but no such product was observed. Finally, deprotec-
Eur. J. Org. Chem. 2014, 1376–1380
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1379

N. Kanoh et al.
SHORT COMMUNICATION
Klinkenberg, H. Bredholt, G. Nygard, S. O. Doskeland, T. E.
Ellingsen, S. B. Zotchev, Chem. Biol. 2009, 16, 1109; h) S. B.
Zotchev, H. Jorgensen, K. F. Degnes, A. Dikiy, E. Fjaervik, G.
Klinkenberg, Appl. Environ. Microbiol. 2010, 76, 283.
[3] We propose that the process that generates heronamides A and
B be termed a cycloaddition rather than an electrocyclization,
because the products possess two fewer double bonds and one
more ring than the reactants.
[4] R. Sugiyama, S. Nishimura, H. Kakeya, Tetrahedron Lett.
2013, 54, 1531.
[5] a) H. Fukuda, S. Nakamura, T. Eguchi, Y. Iwabuchi, N.
Kanoh, Synlett 2010, 2589; b) H. Fukuda, Y. Nishiyama, S.
Nakamura, Y. Ohno, T. Eguchi, Y. Iwabuchi, T. Usui, N.
Kanoh, Chem. Asian J. 2012, 7, 2872.
[12]
[13]
a) A. Barbero, F. J. Pulido, Chem. Soc. Rev. 2005, 34, 913; b)
V. Fargeas, P. LeMenez, I. Berque, J. Ardisson, A. Pancrazi,
Tetrahedron 1996, 52, 6613.
B. H. Lipshutz, E. L. Ellsworth, S. H. Dimock, D. C. Reuter,
Tetrahedron Lett. 1989, 30, 2065.
F. Suzenet, E. Blart, J. P. Quintard, Synlett 1998, 879.
Compound 21 was prepared from d-ribose in four steps, as
shown below: a) W. H. Kim, J. A. Kang, H. R. Lee, A. Y. Park,
P. Chun, B. Lee, J. Kim, J. A. Kim, L. S. Jeong, H. R. Moon,
Carbohydr. Res. 2009, 344, 2317; b) L. Nagarapu, S. Karnak-
anti, R. Bantu, Tetrahedron 2012, 68, 5829; c) A. G. Myers,
S. D. Goldberg, Angew. Chem. 2000, 112, 2844; Angew. Chem.
Int. Ed. 2000, 39, 2732. Note that Myers et al. (ref.[15c]) synthe-
sized ent-21 from ent-ii.
[14]
[15]
[6] a) T. Hamada, D. Suzuki, H. Urabe, F. Sato, J. Am. Chem.
Soc. 1999, 121, 7342; b) H. A. Reichard, M. McLaughlin,
M. Z. Chen, G. C. Micalizio, Eur. J. Org. Chem. 2010, 391.
[7] We utilized (1S)-camphorquinone-derived homoallylic amine i
to prepare homoallylic amine 5; thus, the absolute configura-
tion of 5 is (R), as shown in Schemes 1 and 2. For Kobayashi
transfer aminoallylation, see: M. Sugiura, C. Mori, S. Kobaya-
shi, J. Am. Chem. Soc. 2006, 128, 11038.
[8] R. Tamura, K. Saegusa, M. Kakihana, D. Oda, J. Org. Chem.
1988, 53, 2723.
[9] W. H. Li, J. G. Gan, D. W. Ma, Angew. Chem. 2009, 121, 9053;
Angew. Chem. Int. Ed. 2009, 48, 8891.
[16] S. Garrais, J. Turkington, W. P. D. Goldring, Tetrahedron 2009,
65, 8418.
[17] J. Wu, J. S. Panek, Angew. Chem. 2010, 122, 6301; Angew.
Chem. Int. Ed. 2010, 49, 6165.
[10] H. Albadri, E. Aboutjaudet, N. Collignon, Tetrahedron Lett.
1995, 36, 393.
[11] A. Darwish, A. Lang, T. Kim, J. M. Chong, Org. Lett. 2008,
10, 861.
[18] E. J. Corey, N. W. Gilman, B. E. Ganem, J. Am. Chem. Soc.
1968, 90, 5616.
Received: October 1, 2013
Published Online: January 28, 2014
1380
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1376–1380