Total synthesis of apratoxin A and B using Matteson's homologation approach

Article abstract of DOI:10.1039/d1ob00713k

Apratoxin A and B, two members of an interesting class of marine cyclodepsipeptides are synthesized in a straightforward mannerviaMatteson homologation. Starting from a chiral boronic ester, the polyketide fragment of the apratoxins was obtainedviafive su

Full text of DOI:10.1039/d1ob00713k

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Total synthesis of apratoxin A and B using
Matteson’s homologation approach†
Cite this: Org. Biomol. Chem., 2021,
19, 4866
Oliver Andler and Uli Kazmaier
*
Received 12th April 2021,
Accepted 30th April 2021
DOI: 10.1039/d1ob00713k
rsc.li/obc
Apratoxin A and B, two members of an interesting class of marine
cyclodepsipeptides are synthesized in a straightforward manner via
Matteson homologation. Starting from a chiral boronic ester, the
polyketide fragment of the apratoxins was obtained via five suc-
cessive homologation steps in an overall yield of 27% and very
good diastereoselectivity. This approach is highly flexible and
should allow modification also of this part of the natural products,
while previous modifications have been carried out mainly in the
peptide fragment.
Introduction
The apratoxins are a class of cyclodepsipeptides produced by
cyanobacteria.1 The first described member of this group,
apratoxin A, was isolated by Moore and Paul et al. from the
marine cyanobacterium Lyngbya majuscula in 2001.2 It showed
potent cytotoxicity towards a range of tumor cell lines in the
sub nanomolar range,3 acting as a broad-spectrum Sec61
inhibitor4 targeting HER/ErbB family proteins.5 Over the fol-
lowing years, a wide range of further apratoxins have been iso-
lated.6 Some of these structures are shown in Fig. 1.
The apratoxins form a 25-membered ring consisting of a
pentapeptide and a rather unusual polyketide fragment, con-
taining, in most cases, a terminal t-butyl group. The apratoxins
differ mainly in their methylation pattern (apratoxins A–D) or
in the composition of the peptide fragment. While most apra-
toxins embody an unusual unsaturated prolonged cysteine
unit, in some of the members of the apratoxin S family, artifi-
cial derivatives obtained by a medicinal chemistry campaign,
this unit is (structurally) reduced.7 The unusual polyketide
fragment is common to most family members. In case of apra-
toxin D, its carbon chain is even one carbon longer. Detailed
Fig. 1 Selected apratoxins.
studies indicate that an iron-dependent methyltransferase
directs the tert-butyl group formation by initiating the assem-
bly of the apratoxin A polyketide starter unit.8
Not surprisingly, the excellent cytotoxicities in the low
nanomolar range, and the interesting mode of action initiated
synthetic investigations for the synthesis of the polyketide frag-
ment of the apratoxins,9 the apratoxins themselves10 as well as
derivatives for SAR studies.11 Common to all syntheses of apra-
toxin A is the late-stage assembly of the thiazoline moiety,
which is oxidatively sensitive and potentially prone to
unwanted side reactions, e.g. epimerization of the adjacent
stereogenic centre. To synthesise the polyketide fragment,
asymmetric cuprate additions or allyl isomerisations are used
to introduce the internal methyl group, while the two stereo-
genic centres adjacent to the thiazoline ring are generated via
different versions of aldol reactions.
Organic Chemistry, Saarland University, P.O. Box 151150, 66041 Saarbrücken,
Germany. E-mail: u.kazmaier@mx.uni-saarland.de
Results and discussion
†Electronic supplementary information (ESI) available: Experimental details,
compound characterization, copies of 1H and 13C NMR spectra and HPLC chro-
matograms. See DOI: 10.1039/d1ob00713k
Since a couple of years our group is involved in the synthesis
of natural products,12 especially cyclic peptides with interest-
4866 | Org. Biomol. Chem., 2021, 19, 4866–4870
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ing biological activities.13 Recently, we have become interested to nucleophilic substitution under SN2-conditions with a wide
in the synthesis of peptide/polyketide hybrids14 such as the range of nucleophiles such as Grignard reagents, alkoxides or
apratoxins, with a focus on aldol-free polyketide synthesis. The certain enolates.20 Continual application of this procedure
aldol reaction,15 or alternatively an allylation/ozonolysis allows the stepwise stereoselective incorporation of a wide
sequence,16 is perfectly suited to generating the 3, 5, 7, …-poly- range of substituents and functionalities into a growing
hydroxylated carboxylic acids found in many natural products, carbon chain.
with methyl groups between the hydroxy functionalities, but
We attempted to prepare the polyketide fragment of apra-
these reactions are more or less restricted to this substitution toxin A and B using the above-mentioned Matteson homologa-
pattern. With the synthesis of lagunamide A,17 we could show tion approach. Starting from diisopropyl tert-butylboronate 121
that also other approaches, such as Matteson homologa- transesterification with (S,S)-DICHED (dicyclohexylethane-1,2-
tions,18 which are more flexible, are well suited to the synthesis diol)22 gave the chiral boronic ester 2 (Scheme 2). While homo-
of complex polyketides. This elegant stereoselective pro- logation of sterically demanding 2 to the α-chloroboronic ester
longation of chiral boronic esters was introduced by Donald proceeded smoothly under the usual conditions, the sub-
Matteson 40 years ago (Scheme 1).19
sequent substitution to the alkoxyboronic ester 3 was sluggish
A key step of this protocol is the highly stereoselective for- and incomplete when we used only a slight excess (1.3 eq.) of
mation of an α-chloro boronic ester A, which can be subjected NaOPMB. In contrast, with a larger excess (3.0 eq.) of alkoxide,
we observed full conversion and could isolate 3 in excellent
yield.
In the following step, we introduced a CH2 group by treat-
ing the intermediate α-chloroboronic ester with LiBHEt3. Next,
we used a methyl Grignard reagent as a nucleophile, which
cleanly yielded 5. Introduction of a second CH2 unit gave the
Scheme 1 Matteson homologation.
Scheme 2 Synthesis of the apratoxin polyketide fragment.
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prolonged boronic ester 6 in good yield. In the following
homologation step, we applied the lithium enolate of tert-butyl
propionate as a nucleophile. Similar reactions of simple
α-haloboronic esters with enolates have already been described
by Matteson et al.20a,b but, surprisingly, this method has not
been applied to the synthesis of more complex natural pro-
ducts so far. A reason for this may be that this reaction
requires the use of α-bromoboronic esters which are more reac-
tive, but also more prone to epimerization than their chloro-
analogues.23 Fortunately, we could completely suppress epi-
merization by quenching the formation of the α-bromoboronic
ester at low temperature (−55 °C) and immediately treated the
crude product with the enolate. While the homologations from
2 to 6 provided the products as single diastereomers, we
obtained 8 as a mixture of syn and anti isomers, but with good
anti selectivity (d.r. = 9 : 1 after oxidation of the boronic ester
to alcohol 8). O-Troc protection of 8 followed by oxidative clea-
vage of the PMB ether provided alcohol 10, which we reacted
with Fmoc-(S)-Pro-Cl24 to ester 11 in almost quantitative yield
and without epimerization of the α-stereogenic centre of
proline. Acidic cleavage of the tert-butyl ester gave access to
crude carboxylic acid 12. N-Boc deprotection of the modified
cysteine building block 13, followed by coupling with acid 12,
yielded amide 14, which is a known intermediate of the apra-
toxin A synthesis reported by Doi et al.10c,11c To convert 14 into
a thiazoline, we applied Kelly’s method using Tf2O and
Ph3PO.25 For the subsequent cleavage of the Troc carbamate,
we examined several conditions, e.g. with a Zn/Cu couple or
Me3SnOH26 as a deprotection reagent, but Doi’s protocol using
zinc dust and aqueous NH4OAc10c,11c gave 15 in the best
yield. Pd-catalysed cleavage of the allyl ester provided car-
boxylic acid 16.
Scheme 4 Synthesis of apratoxin A and B.
which we cyclised to the natural products after cleavage of the
allyl and Fmoc protecting groups (Scheme 4). As reported in pre-
vious syntheses,10c,d,11c,d we observed partial epimerization of
the stereogenic center adjacent to the thiazoline moiety during
the steps from 15 to 21, and we obtained the cyclisation pro-
ducts as mixtures of two diastereomers 21a/b and epi-21a/b.
Interestingly, no water elimination to the α,β-unsaturated thiaz-
oline occurred under these conditions. In both cases, we were
able to separate the isomers via preparative HPLC to isolate the
diastereomerically pure natural products.
We were also interested in preparing apratoxin B27 for
which, to our knowledge, there has not yet been a total syn-
thesis reported. Starting from Boc-(S)-Ile-OAllyl (17b),28 we syn-
thesised the tripeptide building block 19b in two HATU-
mediated peptide couplings, achieving excellent overall yield
(Scheme 3). The corresponding apratoxin A tripeptide 19a, in
which (S)-Ile is replaced by N-Me-(S)-Ile, was prepared accord-
ing to known procedures.10c,11c
Coupling of the polyketide fragment 16 with Fmoc-depro-
tected 19a or 19b yielded the linear precursors 20a and 20b,
Conclusions
In conclusion: we have shown that the Matteson homologation
is perfectly suited to generating the unusual polyketide frag-
ment of the apratoxins. Starting from a chiral boronic ester (2),
we were able to prepare the desired building block 8 of apra-
toxin A and B via five successive Matteson homologations and
subsequent oxidation, achieving an overall yield of 27% and
very good diastereoselectivity. Obviously, even a sterically
demanding tert-butyl group is well accepted in the boronic
ester and, therefore, this protocol should also be perfectly
suited for the synthesis of libraries of derivatives for SAR
studies, simply by changing the nucleophilic coupling partners
in the homologation steps. Further applications are currently
under investigation.
Scheme 3 Synthesis of the apratoxin B tripeptide.
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8 (a) M. A. Skiba, A. P. Sikkema, N. A. Moss, C. L. Tran,
R. M. Sturgis, L. Gerwick, W. H. Gerwick, D. H. Sherman
and J. L. Smith, ACS Chem. Biol., 2017, 12, 3039–3048;
(b) M. A. Skiba, A. P. Sikkema, N. A. Moss, A. N. Lowell,
M. Su, R. M. Sturgis, L. Gerwick, W. H. Gerwick,
D. H. Sherman and J. L. Smith, ACS Chem. Biol., 2018, 13,
1640–1650.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
9 (a) J. Chen and C. J. Forsyth, Org. Lett., 2003, 5, 1281–1283;
(b) Z. Xu, Z. Chen and T. Ye, Tetrahedron: Asymmetry, 2004,
15, 355–363; (c) A. Gilles, J. Martinez and F. Cavelier,
C. R. Chim., 2011, 14, 437–440; (d) S. Dey, S. E. Wengryniuk,
E. M. Tarsis, B. D. Robertson, G. Zhou and D. M. Coltart,
Tetrahedron Lett., 2015, 56, 2927–2929.
10 (a) J. Chen and C. J. Forsyth, J. Am. Chem. Soc., 2003, 125,
8734–8735; (b) J. Chen and C. J. Forsyth, Proc. Natl. Acad.
Sci. U. S. A., 2004, 101, 12067–12072; (c) T. Doi, Y. Numajiri,
A. Munakata and T. Takahashi, Org. Lett., 2006, 8, 531–534;
(d) T. Doi, Yo. Numajiri, T. Takahashi, M. Takagi and
Financial support from Saarland University and the DFG
(Grant Ka 880/13-1) is gratefully acknowledged.
Notes and references
1 (a) M. Gutiérrez, T. L. Suyama, N. Engene, J. S. Wingerd,
T. Matainaho and W. H. Gerwick, J. Nat. Prod., 2008, 71,
1099–1103; (b) S. Matthew, P. J. Schupp and H. Luesch,
J. Nat. Prod., 2008, 71, 1113–1116 (correction: J. Nat.
Prod. 2018, 81, 217–217);
(c) C. C. Thornburg,
K. Shin-ya, Chem.
–
Asian J., 2011, 6, 180–188;
E. S. Cowley, J. Sikorska, L. A. Shaala, J. E. Ishmael,
D. T. A. Youssef and K. L. McPhail, J. Nat. Prod., 2013, 76,
1781–1788; (d) E. M. Tarsis, E. J. Rastelli,
S. E. Wengryniuk and D. M. Coltart, Tetrahedron, 2015,
71, 5029–5044.
(e) B. D. Robertson, S. E. Wengryniuk and D. M. Coltart,
Org. Lett., 2012, 14, 5192–5195; (f) Y. Masuda, J. Suzuki,
Y. Onda, Y. Fujino, M. Yoshida and T. Doi, J. Org. Chem.,
2014, 79, 8000–8009; (g) P. Wu, W. Cai, Q.-Y. Chen, S. Xu,
R. Yin, Y. Li, W. Zhang and H. Luesch, Org. Lett., 2016, 18,
5400–5403; (h) T. Doi, Y. Masuda and M. Yoshida, J. Synth.
Org. Chem., Jpn., 2018, 76, 1170–1175.
2 H. Luesch, W. Y. Yoshida, R. E. Moore, V. J. Paul and
T. H. Corbett, J. Am. Chem. Soc., 2001, 123, 5418–5423.
3 (a) Y. Liu, B. K. Law and H. Luesch, Mol. Pharmacol., 2009, 11 (a) B. Zou, J. Wei, G. Cai and D. Ma, Org. Lett., 2003, 5,
76, 91–104; (b) H. Luesch, S. K. Chanda, R. M. Raya,
P. D. DeJesus, A. P. Orth, J. R. Walker, J. C. Izpisúa
Belmonte and P. G. Schultz, Nat. Chem. Biol., 2006, 2, 158–
167; (c) X. Wan, J. D. Serrill, I. R. Humphreys, M. Tan,
K. L. McPhail, I. G. Ganley and J. E. Ishmael, Mar. Drugs,
2018, 16, 77.
4 (a) K.-C. Huang, Z. Chen, Y. Jiang, S. Akare, D. Kolber-
Simonds, K. Condon, S. Agoulnik, K. Tendyke, Y. Shen,
K.-M. Wu, S. Mathieu, H.-W. Choi, X. Zhu, H. Shimizu,
Y. Kotake, W. H. Gerwick, T. Uenaka, M. Woodall-Jappe
and K. Nomoto, Mol. Cancer Ther., 2016, 15, 1208–1216;
(b) A. O. Paatero, J. Kellosalo, B. M. Dunyak, J. Almaliti,
J. E. Gestwicki, W. H. Gerwick, J. Taunton and
V. O. Paavilainen, Cell Chem. Biol., 2016, 23, 561–566.
5 S. Kazemi, S. Kawaguchi, C. E. Badr, D. R. Mattos, A. Ruiz-
Saenz, J. D. Serrill, M. M. Moasser, B. P. Dolan,
V. O. Paavilainen, S. Oishi, K. L. McPhail and J. E. Ishmael,
Biochem. Pharmacol., 2021, 183, 114317.
6 (a) Q. Chen, Y. Liu and H. Luesch, ACS Med. Chem. Lett.,
2011, 2, 861–865; (b) C. C. Thornburg, E. S. Cowley,
J. Sikorska, L. A. Shaala, J. E. Ishmael, D. T. A. Youssef and
K. L. McPhail, J. Nat. Prod., 2013, 76, 1781–1788.
7 (a) B. Qiu, A. Tan, A. B. Veluchamy, Y. Li, H. Murray,
W. Cheng, C. Liu, J. M. Busoy, Q.-Y. Chen, S. Sistla,
W. Hunziker, C. M. G. Cheung, T. Y. Wong, W. Hong,
H. Luesch and X. Wang, Invest. Ophthalmol. Visual Sci.,
3503–3506; (b) D. Ma, B. Zou, G. Cai, X. Hu and J. O. Liu,
Chem. – Eur. J., 2006, 12, 7615–7626; (c) Y. Numajiri,
T. Takahashi and T. Doi, Chem. – Asian J., 2009, 4, 111–125;
(d) T. Doi, Chem. Pharm. Bull., 2014, 62, 735–743;
(e) M. Yoshida, Y. Onda, Y. Masuda and T. Doi,
Biopolymers, 2016, 104, 404–414; (f) R. Yin, W. Zhang,
G. Liu, P. Wu, C. Lau and Y. Li, Tetrahedron, 2016, 72,
3823–3831; (g) P. Wu, H. Xu, Z. Li, Y. Zhou, Y. Li and
W. Zhang, Tetrahedron Lett., 2017, 58, 3333–3336;
(h) Y. Onda, Y. Masuda, M. Yoshida and T. Doi, J. Med.
Chem., 2017, 60, 6751–6765; (i) Z.-Y. Mao, C.-M. Si,
Y.-W. Liu, H.-Q. Dong, B.-G. Wie and G.-Q. Lin, J. Org.
Chem., 2017, 82, 10830–10845; ( j) E. J. Rastelli and
D. M. Coltart, Tetrahedron, 2018, 74, 2269–2290; (k) W. Cai,
R. Ratnayake, M. H. Gerber, Q.-Y. Chen, Y. Yu,
H. Derendorf, J. G. Trevino and H. Luesch, Invest. New
Drugs, 2019, 37, 364–374.
12 (a) A. Ullrich, Y. Chai, D. Pistorius, Y. A. Elnakady,
J. E. Herrmann, K. J. Weissman, U. Kazmaier and
R. Müller, Angew. Chem., Int. Ed., 2009, 48, 4422–4425,
(Angew. Chem., 2009, 121, 4486–4489); (b) A. Ullrich,
J. Herrmann, R. Müller and U. Kazmaier, Eur. J. Org.
Chem., 2009, 6367–6378; (c) P. Servatius, T. Stach and
U. Kazmaier, Eur. J. Org. Chem., 2019, 3163–3168;
(d) P. Servatius, L. Junk and U. Kazmaier, Synlett, 2019,
1289–1302.
2019, 60, 3254–3263; (b) W. Cai, Q.-Y. Chen, L. H. Dang and 13 (a) P. Barbie and U. Kazmaier, Org. Lett., 2016, 18, 204–207;
H. Luesch, ACS Med. Chem. Lett., 2017, 8, 1007–1012 (cor-
rection: ACS Med. Chem. Lett. 2017, 8, 1342). .
(b) L. Junk and U. Kazmaier, Angew. Chem., Int. Ed., 2018,
57, 11432–11435, (Angew. Chem., 2018, 130, 11602–11606);
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(c) L. Junk and U. Kazmaier, J. Org. Chem., 2019, 84, 2489– 18 Reviews: (a) D. S. Matteson, J. Org. Chem., 2013, 78, 10009–
2500; (d) A. Kiefer, C. D. Bader, J. Held, A. Esser,
J. Rybniker, M. Empting, R. Müller and U. Kazmaier, Chem.
– Eur. J., 2019, 25, 8894–8902.
10023;
(b)
S.
Kirupakaran,
H.-G.
Korth
and
C. Hirschhäuser, Synthesis, 2018, 50, 2307–2322.
19 (a) R. Ray and D. S. Matteson, Tetrahedron Lett., 1980, 21,
449–450; (b) D. S. Matteson and R. Ray, J. Am. Chem. Soc.,
1980, 102, 7590–7591.
14 (a) L. Karmann, K. Schultz, J. Herrmann, R. Müller and
U. Kazmaier, Angew. Chem., Int. Ed., 2015, 54, 4502–4507,
(Angew. Chem., 2015, 127, 4585–4590); (b) D. Becker and 20 (a) D. S. Matteson, K. M. Sadhu and M. L. Peterson, J. Am.
U. Kazmaier, Eur. J. Org. Chem., 2015, 2591–2602;
(c) S. Kappler, L. Karmann, C. Prudel, J. Herrmann,
G. Caddeu, R. Müller, A. Vollmar, S. Zahler and
U. Kazmaier, Eur. J. Org. Chem., 2018, 6952–6965.
Chem. Soc., 1986, 108, 810–819; (b) D. S. Matteson and
T. J. Michnick, Organometallics, 1990, 9, 3171–3177;
(c) D. S. Matteson and J.-J. Yang, Tetrahedron: Asymmetry,
1997, 8, 3855–3861; (d) H. W. Man, W. C. Hiscox and
D. S. Matteson, Org. Lett., 1999, 1, 379–382.
15 (a) G. Ehrlich, J. Hassfeld, U. Eggert and M. Kalesse, Chem.
– Eur. J., 2008, 14, 2232–2247; (b) H. Steinmetz, K. Gerth, 21 H. C. Brown, M. Srebnik and T. E. Cole, Organometallics,
R. Jansen, N. Schläger, R. Dehn, S. Reinecke, A. Kirschning 1986, 5, 2300–2303.
and R. Müller, Angew. Chem., Int. Ed., 2011, 50, 532–536, 22 W. C. Hiscox and D. S. Matteson, J. Org. Chem., 1996, 61,
(Angew. Chem., 2011, 123, 553–557); (c) I. Paterson and 8315–8316.
N. Y. S. Lam, J. Antibiot., 2018, 71, 215–233; (d) S. Scheeff 23 (a) D. S. Matteson and H.-W. Man, J. Org. Chem., 1994, 59,
and D. Menche, Org. Lett., 2019, 21, 271–274;
(e) N. Y. S. Lam and I. Paterson, Eur. J. Org. Chem., 2020,
2310–2320.
5734–5741; (b) D. S. Matteson, J. Organomet. Chem., 1999,
581, 51–65.
24 L. A. Carpino, B. J. Cohen, K. E. Stephens, S. Y. Sadat-
Aalaee, J. H. Tien and D. C. Langridge, J. Org. Chem., 1986,
51, 3732–3734.
16 (a) W. R. Roush, A. D. Palkowitz and K. Ando, J. Am. Chem.
Soc., 1990, 112, 6348–6359; (b) A. Arefolov and J. S. Panek,
J. Am. Chem. Soc., 2005, 127, 5596–5603; (c) A.-M. 25 S. You, H. Razavi and J. W. Kelly, Angew. Chem., Int. Ed.,
R. Dechert-Schmitt, D. C. Schmitt, X. Gao, T. Itoh and 2003, 42, 83–85, (Angew. Chem., 2003, 115, 87–89).
M. J. Krische, Nat. Prod. Rep., 2014, 31, 504–513; 26 B. M. Trost, C. A. Kalnmals, J. S. Tracy and W. Bai, Org.
(d) M. Pantin, J. G. Hubert, T. Söhnel, M. A. Brimble and Lett., 2018, 20, 8043–8046.
D. P. Furkert, J. Org. Chem., 2017, 82, 11225–11229; 27 H. Luesch, W. Y. Yoshida, R. E. Moore and V. J. Paul,
(e) K. Spielmann, G. Niel, R. M. de Figueiredo and
J.-M. Campagne, Chem. Soc. Rev., 2018, 47, 1159–1173.
17 (a) J. Gorges and U. Kazmaier, Org. Lett., 2018, 20, 2033–
2036; (b) O. Andler and U. Kazmaier, Chem. – Eur. J., 2021,
27, 949–953.
Bioorg. Med. Chem., 2002, 10, 1973–1978.
28 J. Hur, J. Jang, J. Sim, W. S. Son, H. Ahn, T. S. Kim, Y. Shin,
C. Lim, S. Lee, H. An, S. Kim, D.-C. Oh, E. Jo, J. Jang, J. Lee
and Y. Suh, Angew. Chem., Int. Ed., 2018, 57, 3069–3073,
(Angew. Chem., 2018, 130, 3123–3127).
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