Stereocontrolled Synthesis of Harzialactone A and Its Three Stereoisomers by Use of Standardized Polyketide Building Blocks

Article abstract of DOI:10.1002/ejoc.202001046

In this paper, we present a short and convenient synthesis of the natural product Harzialactone A and its three stereoisomers. In a three-step synthesis starting from cheap and commercially available benzaldehyde, we created the small polyketidic compound with full control over its two stereogenic centers. To this end, we employed a chiral building block previously described by us, introducing the first stereogenic center through a Horner–Wittig reaction. The second stereogenic center was installed via stereocontrolled syn- or anti-reduction with the corresponding β-hydroxy ketone intermediates. Upon ozonolysis followed by oxidation the natural product and its stereovariants were produced with excellent enantio- and diastereopurities.

Full text of DOI:10.1002/ejoc.202001046

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Polyketide Synthesis | Very Important Paper |
Stereocontrolled Synthesis of Harzialactone A and Its Three
Stereoisomers by Use of Standardized Polyketide Building
Blocks
Frederic Ballaschk,[a] Yasemin Özkaya,[a] and Stefan F. Kirsch*[a]
Abstract: In this paper, we present a short and convenient through a Horner–Wittig reaction. The second stereogenic cen-
synthesis of the natural product Harzialactone A and its three ter was installed via stereocontrolled syn- or anti-reduction with
stereoisomers. In a three-step synthesis starting from cheap and the corresponding ꢀ-hydroxy ketone intermediates. Upon
commercially available benzaldehyde, we created the small ozonolysis followed by oxidation the natural product and its
polyketidic compound with full control over its two stereogenic stereovariants were produced with excellent enantio- and dia-
centers. To this end, we employed a chiral building block previ- stereopurities.
ously described by us, introducing the first stereogenic center
The term “polyketides” encompasses a wide range of natu-
rally occurring compounds with a broad structural diversity that
ranges from very simple molecules, such as 6-methyl salicylic
acid[1] or Harzialactone A[2] (1, Scheme 1), to the highly complex
structures of, for example, Butyrolactol A[3] or Discodermolide.[4]
With their striking array of biological properties, polyketides are
prime synthetic targets for chemists, and the 1,3-polyol motif is
a distinguishing structural feature for many of them. Nature
creates this characteristic unit via iterative polyketide synthases
that linearly assemble polyketide intermediates from smaller
malonyl-CoA or methylmalonyl-CoA units, involving subse-
quent chain alterations.[1,5]
Mimicking the biosynthetic pathway toward natural polyket-
ides is a challenging but sublime task for synthetic chemists
since nature's pure efficacy in forming carbon–carbon bonds
and performing stereoselective carbonyl reductions and regio-
selective dehydratizations is simply unmatched. In the course
of time, a multitude of elegant but individual solutions were
developed to accomplish the formation of specific molecules
with 1,3-polyols,[6,7] utilizing chiral ligands or catalysts,[8] or by
Scheme 1. Structure of (+)-Harzialactone A (1) and its stereoisomers (2–4).
starting with enantiomerically pure building blocks (i.e., chiral
pool).[9] General strategies that adopt nature's iterative assem-
most natural polyketides consist of molecules with an inherent
bly of simple building blocks in natural product synthesis are
modularity, and thus they may be efficiently synthesized by the
less frequent. This shortcoming is even more surprising since
repeated succession of similar reaction sequences.[7,10]
[a] F. Ballaschk, Y. Özkaya, Prof. Dr. S. F. Kirsch
A classic in the bioinspired iterative synthesis of 1,3-polyol
arrays is the repetitive allylation of aldehydes (consisting of only
three steps including stereoselective allylation with chiral rea-
gents, protection and oxidative aldehyde regeneration).[11] Par-
ticularly, the use of catalytic allylation methods is attractive,[12]
and the arguably most advanced sequence is the one devel-
oped by Krische and co-workers[13] where Iridium-catalyzed
carbonyl allylation was accomplished from both the alcohol or
aldehyde oxidation level.[14] Other powerful concepts include
the iterative stereoselective alkylation of cyanohydrin aceton-
Organic Chemistry, Bergische Universität Wuppertal
Gaußstraße 20, 42119 Wuppertal, Germany
E-mail: sfkirsch@uni-wuppertal.de
https://www.oc.uni-wuppertal.de/prof-dr-stefan-f-kirsch.html
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202001046.
© 2020 The Authors published by Wiley-VCH GmbH · This is an open access
article under the terms of the Creative Commons Attribution-NonCommer-
cial-NoDerivs License, which permits use, distribution and reproduction in
any medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
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ides,[15] or rely on the repetitive use of Aldol chemistry.[16] More-
Harzialactone A was first isolated by Numata and co-workers
over, iterative syntheses based on asymmetric epoxidations and from a strain of Trichoderma harzianum OUPS-N1115, among
subsequent reductive epoxide-openings were successfully util- several other secondary metabolites and lactones in 1998.[2] It
ized.[17]
was found to have potential antitumor and cytotoxic activity
against cultured P388 cells[2] as well as leishmanicidal activity
against Leishmania amazonensis.[22] Due to the biological prop-
erties, Harzialactone A (and its stereoisomers and derivatives)
became an interesting target compound for synthetic endeav-
ors. Numerous groups reported synthetic approaches toward
racemic product mixtures[23] or enantioenriched material, start-
ing from readily available carbohydrates[24] and enantiomeri-
cally pure epoxides,[25] or by using asymmetric catalysis[26] or
kinetic resolution.[27]
We became involved in the field when embedding the asym-
metric Overman rearrangement[18] as key step of a iterative se-
quence toward 1,3-polyols, which we then applied for several
polyketide syntheses.[19] However, the multistep character of
our repetitive sequence rendered this concept unattractive for
the synthesis of more complex structures. Therefore, we then
focused on the development of a chiral building block that is
easily attached onto a growing carbon chain. In order to be-
come effective as a standardized polyketide building block, its
defining feature shall be that it possesses a pre-installed stereo-
We began the synthesis with the connection between build-
genic secondary alcohol prone for stereocontrolled follow-up ing block 5, the manufacturing of which was described else-
chemistry, and no challenging enantioselective reaction will be where,[20] and inexpensive benzaldehyde (6), thus installing the
involved in the build-up of the polyketidic chain. To this end, first of the two stereogenic centers (Scheme 2). The Horner–
we developed the acetonide 5 shown in Scheme 1, a reagent Wittig reaction[28] proceeded in good yields without loss of
that is readily available in both enantiomeric forms[20] and thus enantiomeric excess: ꢀ-hydroxy ketone 7 having the R-configu-
became the ideal building block, in our hands: we already dem- ration was obtained with the R-configured building block 5 in
onstrated its simple use in a short four step iteration sequence 71 % yield, upon acidic work-up. Its enantiomer 8 was produced
(consisting of Horner–Wittig reaction, reduction, protection and in 83 % yield. The second stereogenic center was created by
ozonolysis).[21] We now present the total synthesis of the use of standard methods for the directed reduction: (1) The
polyketidic Harzialactone A and its three diastereomers using Narasaka–Prasad reaction[29] gave the corresponding syn-1,3-
this standardized 1,3-diol precursor. The target compounds diols 9 and 11 when using diethylmethoxyborane and sodium
were obtained in high overall yields, in only three synthetic borohydride. This conversion was successful with excellent dia-
steps when starting with enantiomerically pure 5.
stereomeric ratios of > 99:1 and high yields (98 % for 7 → 9
Scheme 2. Synthetic pathway for all four stereoisomers. a) i) DIPA (2 equiv.), nBuLi (2 equiv.), –78 °C, 15 min; ii) (R)-5 (1 equiv.), –78 °C, 60 min; iii) 6 (3 equiv.),
–78 °C to r.t., 90 min; iv) KOtBu (1.3 equiv.), (THF), r.t., 60 min, 71 % b) i) DIPA (1 equiv.), nBuLi (1 equiv.), –78 °C, 15 min; ii) (S)-5 (1 equiv.), –78 °C, 60 min;
iii) 6 (1.3 equiv.), –78 °C to r.t., 90 min; iv) KOtBu (1.3 equiv.), (THF), r.t., 60 min, 83 % c) i) Et2BOMe (1.2 equiv.), –78 °C, 20 min; ii) NaBH4 (1.1 equiv.), –78 °C,
–
2 h; iii) 2
N
NaOH (13 equiv.), H2O2 (40 equiv.), (THF/methanol), r.t., 60 min; 98 %, d.r. > 99:1 (9); 93 %, d.r. > 99:1 (11); d) Me4N+HB(OAc)3 (5 equiv.), –20 °C,
16 h, (MeCN/AcOH); 92 %, d.r. 95:5 (10); 92 %, d.r. 95:5 (12); e) i) O3, NEt3 (1 equiv.), (DCM/MeOH), –78 °C, 10 min then Me2S (7.8 equiv.), –78 °C to r.t., 1.5 h;
ii) Ag2CO3/Celite (1.2 equiv. or 5 equiv.), (benzene/DMF), reflux, 1 h; 56 % (1), 68 % (2), 57 % (3), 51 % (4).
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M. Engqvist, E. Reyes, Chem. Eur. J. 2005, 11, 4772–4784; c) L. Lin, K.
Yamamoto, H. Mitsunuma, Y. Kanzaki, S. Matsunaga, M. Kanai, J. Am.
Chem. Soc. 2015, 137, 15418–15421; d) Y. Shimoda, S. Kotani, M. Sugiura,
M. Nakajima, Chem. Eur. J. 2011, 17, 7992–7995; e) A. Genoni, M. Ben-
aglia, S. Rossi, G. Celentano, Chirality 2013, 25, 643–647; f) F. Maier, O.
Trapp, Angew. Chem. Int. Ed. 2014, 53, 8756–8760; Angew. Chem. 2014,
126, 8901.
and 93 % for 8 → 11). (2) The creation of the anti-1,3-diols 10
and 12 was realized with the established Evans–Saksena reac-
tion.[30] With tetramethylammonium triacetoxyborohydride at
–20 °C, the reduction yielded a high diastereomeric ratio of 95:5
and a good yield of 92 % for 10 (from 7). In a similar manner,
the (S)-enantiomer 8 was converted under these conditions to
provide the respective anti-diol 12 in 92 % yield and 95:5 dia-
stereomeric ratio. The synthesis of all four stereovariants was
thus completed. Finally, we chose to generate the lactone
through a two-step sequence consisting of a lactol-forming
ozonolysis followed by a selective oxidation to produce the de-
sired target compounds 1–4. While the ozonolysis of diols 9–
12 was unproblematic in all cases, isolation of the correspond-
ing lactols that formed upon cyclization of the primarily gener-
ated aldehydes proved difficult and low-yielding. As a result, we
decided to directly convert the crude mixtures of olefin ozonol-
ysis into the lactones through oxidation with Fétizon′s rea-
gent.[31] Of note, protection of the secondary alcohol was not
required under those conditions. Gratifyingly, we were then
able to produce the desired natural substance 1 and its three
stereoisomers 2–4 in yields ranging from 51 % to 68 % over the
two steps. Based on spectroscopic data,[2] the synthetic material
was identical to natural Harzialactone A, and the optical rota-
tion confirmed the absolute configuration we expected from
our synthetic route.
[9] a) A. B. Smith, S. M. Pitram, A. M. Boldi, M. J. Gaunt, C. Sfouggatakis,
W. H. Moser, J. Am. Chem. Soc. 2003, 125, 14435–14445; b) A. B. Smith,
S. M. Pitram, M. J. Fuertes, Org. Lett. 2003, 5, 2751–2754; c) Y. Mori, Y.
Kohchi, M. Suzuki, H. Furukawa, Chem. Pharm. Bull. 1992, 40, 1934–1936.
[10] D. Mohapatra, P. Krishnarao, E. Bhimireddy, J. Yadav, Synthesis 2014, 46,
1639–1647.
[11] a) J. García-Fortanet, J. Murga, M. Carda, J. A. Marco, Org. Lett. 2003, 5,
1447–1449; b) S. BouzBouz, J. Cossy, Org. Lett. 2003, 5, 1995–1997.
[12] Z. Zhang, S. Aubry, Y. Kishi, Org. Lett. 2008, 10, 3077–3080.
[13] a) S. B. Han, A. Hassan, I. S. Kim, M. J. Krische, J. Am. Chem. Soc. 2010,
132, 15559–15561; b) I. S. Kim, M.-Y. Ngai, M. J. Krische, J. Am. Chem. Soc.
2008, 130, 6340–6341.
[14] A. Hassan, Y. Lu, M. J. Krische, Org. Lett. 2009, 11, 3112–3115.
[15] S. D. Rychnovsky, G. Griesgraber, J. Org. Chem. 1992, 57, 1559–1563.
[16] a) B. J. Albert, H. Yamamoto, Angew. Chem. Int. Ed. 2010, 49, 2747–2749;
Angew. Chem. 2010, 122, 2807; b) B. J. Albert, Y. Yamaoka, H. Yamamoto,
Angew. Chem. Int. Ed. 2011, 50, 2610–2612; Angew. Chem. 2011, 123,
2658.
[17] a) T. Katsuki, Lee, A. W. M., P. Ma, V. S. Martin, S. Masamune, K. B. Sharp-
less, D. Tuddenham, F. J. Walker, J. Org. Chem. 1982, 47, 1373–1378;
b) K. C. Nicolaou, R. A. Daines, T. K. Chakraborty, Y. Ogawa, J. Am. Chem.
Soc. 1987, 109, 2821–2822; c) S.-y. Tosaki, Y. Horiuchi, T. Nemoto, T. Oh-
shima, M. Shibasaki, Chem. Eur. J. 2004, 10, 1527–1544.
[18] a) S. F. Kirsch, L. E. Overman, N. S. White, Org. Lett. 2007, 9, 911–913;
b) S. F. Kirsch, L. E. Overman, J. Am. Chem. Soc. 2005, 127, 2866–2867;
c) J. S. Cannon, S. F. Kirsch, L. E. Overman, H. F. Sneddon, J. Am. Chem.
Soc. 2010, 132, 15192–15203.
[19] a) S. Kirsch, P. Klahn, H. Menz, Synthesis 2011, 2011, 3592–3603; b) J. T.
Binder, S. F. Kirsch, Chem. Commun. 2007, 4164–4166; c) H. Menz, S. F.
Kirsch, Org. Lett. 2009, 11, 5634–5637.
[20] A. Bredenkamp, Z.-B. Zhu, S. F. Kirsch, Eur. J. Org. Chem. 2016, 2016, 252–
254.
[21] A. Bredenkamp, M. Wegener, S. Hummel, A. P. Häring, S. F. Kirsch, Chem.
Commun. 2016, 52, 1875–1878.
In conclusion, we produced all four stereoisomers of Harzial-
actone A starting from benzaldehyde in a short three-step syn-
thesis. The creation of all stereogenic centers was fully con-
trolled, by using our standardized chiral building blocks for 1,3-
polyol syntheses in combination with established syn- or anti-
reduction protocols. The synthetic route is protective group-
free, and only two intermediates were isolated by chromatogra-
phy on the route from (6 + 5) to 1(or 2,3,4). We will continue
to use building block 5, and variants thereof, for the synthesis
of more complex polyketidic structures.
[22] G. H. Braun, H. P. Ramos, C. Candido, B. B. Ana, C. Pedroso, N. Rita, K. A.
Siqueira, M. A. Soares, G. M. Dias, L. G. Magalhães, S. R. Ambrósio, A. H.
Januário, et al., Nat. Prod. Res. 2019, 1–4.
[23] M. Sá, M. Peterle, M. Marques, J. Braz. Chem. Soc. 2019, 30, 1779–1787.
[24] a) H. B. Mereyala, M. Joe, R. R. Gadikota, Tetrahedron: Asymmetry 2000,
11, 4071–4081; b) V. U. Pawar, S. Ghosh, B. A. Chopade, V. S. Shinde,
Bioorg. Med. Chem. Lett. 2010, 20, 7243–7245.
Acknowledgments
Open access funding enabled and organized by Projekt DEAL.
[25] a) G. Sabitha, R. Srinivas, S. K. Das, J. S. Yadav, Beilstein J. Org. Chem.
2010, 6, 8; b) L. He, S. Zhang, Y. Wu, Y. Li, Chin. J. Chem. 2011, 29, 2664–
2668; c) S. Yamaguchi, T. Matsuo, K. Motokura, A. Miyaji, T. Baba, Chem.
Asian J. 2016, 11, 1731–1737.
Keywords: Harzialactone A · 1,3-Polyols · Polyketides ·
Natural products · Stereoselective synthesis
[26] a) S. P. Kotkar, G. S. Suryavanshi, A. Sudalai, Tetrahedron: Asymmetry 2007,
18, 1795–1798; b) D. Kumar, C. Reddy, B. Das, Synthesis 2011, 2011, 3190–
3194.
[27] B. Chen, H.-F. Yin, Z.-S. Wang, J.-H. Xu, Tetrahedron: Asymmetry 2010, 21,
237–240.
[1] J. Staunton, K. J. Weissman, Nat. Prod. Rep. 2001, 18, 380–416.
[2] T. Amagata, Y. Usami, K. Minoura, T. Ito, A. Numata, J. Antibiot. 1998, 51,
33–40.
[3] C. Kotake, T. Yamasaki, T. Moriyama, M. Shinoda, N. Komiyama, T. Furu-
mai, M. Konishi, T. Oki, J. Antibiot. 1992, 45, 1442–1450.
[4] S. P. Gunasekera, M. Gunasekera, R. E. Longley, G. K. Schulte, J. Org. Chem.
1990, 55, 4912–4915.
[5] a) B. Shen, Curr. Opin. Chem. Biol. 2003, 7, 285–295; b) H. Chen, L. Du,
Appl. Microbiol. Biotechnol. 2016, 100, 541–557; c) M. Cummings, R.
Breitling, E. Takano, FEMS Microbiol. Lett. 2014, 351, 116–125.
[6] a) C. Sperandio, J. Rodriguez, A. Quintard, Org. Biomol. Chem. 2020, 18,
1025–1035; b) S. E. Bode, M. Wolberg, M. Müller, Synthesis 2006, 2006,
557–588.
[28] L. Horner, H. Hoffmann, H. G. Wippel, Chem. Ber. 1958, 91, 61–63.
[29] a) K.-M. Chen, K. G. Gunderson, G. E. Hardtmann, K. Prasad, O. Repic,
M. J. Shapiro, Chem. Lett. 1987, 16, 1923–1926; b) K.-M. Chen, G. E.
Hardtmann, K. Prasad, O. Repič, M. J. Shapiro, Tetrahedron Lett. 1987, 28,
155–158; c) K. Narasaka, H. C. Pai, Chem. Lett. 1980, 9, 1415–1418; d) K.
Narasaka, F.-C. Pai, Tetrahedron 1984, 40, 2233–2238.
[30] a) D. A. Evans, K. T. Chapman, E. M. Carreira, J. Am. Chem. Soc. 1988, 110,
3560–3578; b) A. K. Saksena, P. Mangiaracina, Tetrahedron Lett. 1983, 24,
273–276.
[31] M. Fetizon, V. Balogh, M. Golfier, J. Org. Chem. 1971, 36, 1339–1341.
[7] K. Zheng, C. Xie, R. Hong, Front. Chem. 2015, 3, 32.
[8] a) N. S. Chowdari, D. B. Ramachary, A. Córdova, C. F. Barbas, Tetrahedron
Lett. 2002, 43, 9591–9595; b) A. Córdova, I. Ibrahem, J. Casas, H. Sundén,
Received: July 31, 2020
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