<figure><img src="image_1.png" /></figure>

HAL
open science

# Asymmetric synthesis of a stereopentade fragment toward latrunculins

Benjamin Joyeux, Antoine Gamet, Nicolas Casaretto, Bastien Nay

► To cite this version:

Benjamin Joyeux, Antoine Gamet, Nicolas Casaretto, Bastien Nay. Asymmetric synthesis of a stereopentade fragment toward latrunculins. Beilstein Journal of Organic Chemistry, 2023, 19, pp.428-433. 10.3762/bjoc.19.32. hal-04060528

HAL Id: hal-04060528

https://hal.science/hal-04060528

Submitted on 6 Apr 2023

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_3.png" /></figure>

# Asymmetric synthesis of a stereopentade fragment toward latrunculins

Benjamin Joyeux<sup>†1</sup>, Antoine Gamet<sup>†1</sup>, Nicolas Casaretto<sup>2</sup> and Bastien Nay<sup>*1</sup>

## Letter

Open Access

Address:
¹Laboratoire de Synthèse Organique, Ecole Polytechnique, CNRS, ENSTA, Institut Polytechnique de Paris, 91128 Palaiseau, France and
²Laboratoire de Chimie Moléculaire, Ecole Polytechnique, CNRS, Institut Polytechnique de Paris, 91128 Palaiseau, France

Email:
Bastien Nay* - bastien.nay@polytechnique.edu

* Corresponding author ‡ Equal contributors

Keywords:
allylation; aldol reaction; latrunculins; stereocontrol; total synthesis

Beilstein J. Org. Chem. **2023**, *19*, 428–433.
https://doi.org/10.3762/bjoc.19.32

Received: 15 December 2022
Accepted: 27 March 2023
Published: 03 April 2023

This article is part of the thematic issue "Total synthesis: an enabling science".

Associate Editor: D. Y.-K. Chen

© 2023 Joyeux et al.; licensee Beilstein-Institut.
License and terms: see end of document.

## Abstract

Latrunculins are marine toxins used in cell biology to block actin polymerization. The development of new synthetic strategies and methods for their synthesis is thus important in order to improve, modulate or control this biological value. The total syntheses found in the literature all target similar disconnections, especially an aldol strategy involving a recurrent 4-acetyl-1,3-thiazolidin-2-one ketone partner. Herein, we describe an alternative disconnection and subsequent stereoselective transformations to construct a stereopentade amenable to latrunculin and analogue synthesis, starting from (+)-β-citronellene. Key stereoselective transformations involve an asymmetric Krische allylation, an aldol reaction under 1,5-*anti* stereocontrol, and a Tishchenko–Evans reduction accompanied by a peculiar ester transposition, allowing to install key stereogenic centers of the natural products.

## Introduction

Latrunculins constitute a class of marine polyketide natural products isolated from Sponges like *Negombata* (= *Latrunculia*) *magnifica* [1,2]. They are characterized by the presence of an unsaturated fourteen- or sixteen-membered macrolactone decorated by an L-cysteine-derived 2-oxo-1,3-thiazolidin-4-yl substituent, and the presence of five stereogenic centers forming a 1,2,4,6,9-stereopentade (Figure 1). In latrunculins A (1) and B (2) three of them are embedded in a lactol ring, while latrunculin C (3) lacks this ring due to the reduction of C-15. The bio-

logical activities of latrunculins A and B have early been reported [3]. These compounds induce important but reversible morphological changes on mouse neuroblastoma and fibroblast cells at low concentrations such as 50 ng/ mL [2]. It was rapidly demonstrated that the toxins target the cytoskeleton and inhibit the actin polymerization by specifically sequestering the G-actin monomers with a high affinity [4], unlike cytochalasin D that targets the actin filament [5]. Structure–activity relationships have also been demonstrated thanks to the synthesis of an-
alogues, which hardly superseded the natural product proper-
ties, highlighting the importance of the macrocycle and of the
lactol ring for this biological activity (3 is inactive) [6,7].

<figure><img src="image_4.png" /><figcaption>**Figure 1:** Structure of latrunculins (the red dots show the natural product stereopentade).</figcaption></figure>

Considering the structural features of these toxins and their
valuable biological properties (1 and 2 are nowadays commer-
cially available as tools for cell biology), latrunculins have been
appealing targets for synthetic studies. Several total syntheses
of latrunculins were reported by Smith III [8-10], White [11],
Fürstner [6,12] and Watson [13]. These syntheses involved sim-
ilar disconnection strategies for the macrocycle or the lactol for-
mation (Figure 2, left), and for the aldol reaction leading to 4,

using a 4-acetyl-1,3-thiazolidin-2-one 5 as ketone partner (Figure 2, route A). Strikingly, this last disconnection was adopted in all previous syntheses to form the (15,16)- or the (13,14)-bond of 1 and 2, respectively. Conversely, we envisaged an alternative disconnection to form the (16,17)- or the (14,15)-bond of 1 and 2, through an aldol reaction of aldehyde 8 readily available from L-cysteine, leading to aldol adduct 7 (Figure 2, route B). The methyl ketone partner 9 could be formed by the oxidation of an allyl moiety introduced by the asymmetric allylation of an aldehyde derived from (+)-β-citronellene. At this stage, we can speculate that the stereocontrol of this reaction could either follow a polar Felkin–Anh model [14-16] based on chiral aldehyde partner 8 [17], or a 1,5-anti induction of the aldol reaction [18-20] based on chiral alkoxy partner 9. Furthermore, it could be envisaged to reduce the resulting β-hydroxyketone 7 in a diastereoselective manner to obtain a 1,3-diol.

This synthetic strategy could thus bring new stereochemical op-
portunities to synthesize latrunculin analogues for chemical
biology studies. In particular, our initial goal was to protect an
inactive lactol-opened form of latrunculins, which could cyclize
in vivo upon deprotection under a specific stimulus (light or en-
zyme, for instance) for biological applications. This challenge
precluded the installation of the pyran ring – and the use of its
well-known isomerization to set up important stereocenters

<figure><img src="image_5.png" /><figcaption>**Figure 2:** General strategy for latrunculin cycle disconnections (left), previous works towards linear precursor 4 (A), and our alternative disconnection of 7 through the aldol reaction (B).</figcaption></figure>
[6,9] –, thus imposing the anticipated construction of key asym-
metric centers. The following discussion will deal with the
stereoselective synthesis of a stereopentade amenable to such
latrunculin synthesis and the encountered difficulties thereof.

**Results and Discussion**

Our synthesis started from commercially available (+)-β-citronellene (10). The ozonolysis of the trisubstituted double bond followed by a reductive treatment with NaBH4 chemoselectively afforded primary alcohol 11 in 78% yield (Scheme 1). Due to easier purification, this alcohol was preferred to the aldehyde in our synthetic route, allowing a key stereoselective Krische allylation [21,22] to be envisaged. Applying reported conditions for this allylation – in presence of allyl acetate (10 equiv), [Ir(COD)Cl]2 (2.5 mol %), (S)-SEGPHOS (5 mol %), 3-nitrobenzoic acid (10 mol %), Cs2CO3 (20 mol %) in THF at 100 °C for 24 hours – we obtained homoallylic alcohol 12 in a good 86% yield, with a diastereomeric ratio (dr) of 93:7 deduced from the NMR analysis of the methyl substituent signals in CD3OD (NMR spectra compared to those of a 50:50 mixture of diastereoisomers, obtained from the addition of allylmagnesium bromide onto the corresponding aldehyde). The stereochemistry of the resulting secondary alcohol was expected to be (R) according to Krische's studies involving (S)-SEGPHOS [22]. This result was secured by the NMR analysis of Mosher's esters made from (R)-(+)- and (S)-(-)-α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) (see Supporting Information File 1) [23-25], confirming the installation of the C-11 stereocenter of latrunculins.

The next steps consisted in the functionalization of **12**, in view
of its coupling to **8**. We first relied the chemoselective epoxida-

tion of the homoallylic alcohol, done in presence of VO(OiPr)3
(20 mol %) and t-BuOOH to afford epoxide **13**, in 86% yield
and a dr of 75:25 (measured by NMR, presumably resulting
from the major diastereoisomer of **13**; minor isomers were not
identified), when the reaction was performed at room tempera-
ture during 6 hours. This vanadium catalyst superseded
VO(acac)2 in terms of yields [26,27]. Additional epoxidation
attempts allowed to improve the dr to 82:18 (82% yield) when
the reaction was left at -30 °C for 6 days. Unfortunately, it was
not possible to set up an appropriate nucleophile through the
umpolung of aldehyde **8** to react with this epoxide, which led us
to envisage the following aldol strategy through ketone **15**.
Attempts of Wacker reactions to produce **15** were unsuccessful
on **12**, presumably due to a competition between the two
olefinic parts. After protection of the secondary alcohol as a
para-methoxybenzyl (PMB) ether (78% yield of **14**), the ke-
tone (**15**) was installed in two steps from the epoxide (direct re-
arrangement attempts of the epoxide to form the ketone were
unsuccessful). Thus, the epoxide was first reduced on its prima-
ry carbon in presence of LiAlH4, and the resulting secondary
alcohol was oxidized in presence of Dess–Martin periodinane
(DMP), giving ketone **15** in 78% yield over the two steps. This
six-step sequence to **15** was performed in a 35% overall yield
from starting material **10**.

The aldehyde partner (8) for the aldol reaction brings the thiazolinone heterocycle of the natural product. It was synthesized in four steps from L-cysteine ester derivative 16, first reacting with carbonyldiimidazole (CDI) to afford thiazolidinone 17 in 85% yield (Scheme 2). The nitrogen atom was protected with a PMB group in 72% yield (18), after deprotonation with NaH and reaction with PMBBr. The ester moiety of 18 was then

<figure><img src="image_6.png" /></figure>
chemoselectively reduced into alcohol **19** in 90% yield, in presence of LiBH₄ to avoid the reduction of the thiazolidinone part. Finally, the aldehyde (**8**) was generated in 78% yield by oxidation in presence of DMP.

<figure><img src="image_7.png" /><figcaption>**Scheme 2:** Synthesis of fragment **8** from L-cysteine ethyl ester hydrochloride (**16**).</figcaption></figure>

The assembly of aldehyde **8** and methyl ketone **15** was envisaged through a stereoselective aldol reaction. After unsuccessful attempts of Mukaiyama aldol reactions with silyl enol ethers [28], we found that dicyclohexylboron enolate **20**, made in situ from ketone **15** and Cy₂BCl in presence of DIPEA, performed well in the aldol reaction to furnish product **21** in 55% yield with a good dr of 91:9 (Scheme 3).

The stereocontrol of the reaction could be envisaged through two principal mechanisms. A remote stereocontrol by the nucleophile could first be expected [29], through a 1,5-*anti*-induction of the aldol stereocenter by β-alkoxy ketone **9**, leading to an (*S*)-configuration [18-20]. This control is supposed to follow a boat transition state **A** stabilized by a formyl hydrogen bond [30]. It is known to be dependent on the nature of the β-alkoxy substituent, being particularly favoured by the PMB and other aromatic groups, while being disfavoured by silyl protecting groups. Alternatively, an (*R*)-configuration of C-15 could result from a polar Felkin–Anh model controlled by aldehyde **8** through chair-transition state **B** [14-16]. To determine the configuration of C-15, we initially relied on the comparative NMR analysis of Mosher's esters [23]. Despite clear ¹H NMR spectra, irregular values of ΔδS⁻R precluded the unambiguous determination of the C-15 stereocenter [24]. These difficulties were attributed to the hindered character of this secondary alcohol, substituted by the thiazolidinone ring, possibly leading to a strong conformational distortion of Mosher's model. The question of the resulting stereoselectivity was thus left open for later resolution.

<figure><img src="image_8.png" /><figcaption>**21** (1,5-*anti* product, dr 91:9)
see later discussion for the
determination of the configuration</figcaption></figure>

**Hypothesis 1: stereocontrol by the ketone**
remote 1,5-*anti* induction

* stabilizing formyl
hydrogen bond

* boat TS with
minimized steric
effect

<figure><img src="image_9.png" /></figure>

**Hypothesis 2: stereocontrol by the aldehyde**
polar Felkin–Anh model, affording the 1,5-syn diol

<figure><img src="image_10.png" /></figure>

* hyperconjugative effects

* chair-like TS with minimized steric effect

<caption>**Scheme 3:** Synthesis of fragment **21** through a stereoselective aldol reaction.</caption>
<figure><img src="image_11.png" /><figcaption>**Scheme 4:** 1,3-*Anti*-diastereoselective reduction of **21** with PNBz transposition, and final determination of the relative stereochemistry by NOESY experiment on **25**.</figcaption></figure>

To complete this study, the 1,3-*anti*-diastereoselective reduction of β-hydroxyketone **21** was undertaken through the Evans-Tishchenko method [31,32], in presence of SmI₂ and an aldehyde (Scheme 4). *para*-Nitrobenzaldehyde was used [33] to introduce a labile *para*-nitrobenzoate on the product, planning an easy deprotection of the alcohol. This would also pave the way to an orthogonal manipulation of protecting groups on the stereopentade, in view of designing molecular tools for biological purpose. The reduction took place in 76% yield with complete stereoselectivity. However, a mixture of two inseparable products was obtained, containing the expected but minor alcohol **22** (10%), and more surprisingly the major isomer **23** (66%). This compound results from the transposition of the *para*-nitrobenzoyl (PNBz) group onto the 13-OH, which could be favoured by the steric hindrance of C-15 and a possible π-π stacking with the OPMB group.

These PNBz esters were readily hydrolyzed to furnish diol **24** in 97% yield. The oxydation of the PMB group, in presence of DDQ under anhydrous conditions [18], gratifyingly afforded acetal **25** in 74% yield, whose stereochemical assignment by NOESY NMR experiment showed the *syn* stereochemistry of the acetal. By deduction, it was confirmed that the asymmetric boron aldol reaction between **8** and **15** proceeded through a 1,5-*anti* induction by the ketone to form **21**. Most importantly, compounds **22–25** bear the (11*R*,13*R*) configuration of latrunculins (**1** and **2**).

## Conclusion

A straightforward synthesis of a stereopentade intermediate towards latrunculins and lactol-opened analogues was achieved with high stereoselectivity. Starting from the chiral pool bringing the 8-methyl substituent, the secondary alcohol on

C-11 was stereoselectively introduced by the Krische allylation of alcohol **11**. The next key step consisted in an aldol reaction of ketone **15** onto aldehyde **8**, which proceeded with a high stereocontrol resulting from a 1,5-*anti* induction by the nucleophile leading to product **21**, and excluding a Felkin-Anh control by the aldehyde. This reaction validates a unique disconnection among latrunculin synthetic strategies and avoids the construction of a 4-acetyl-1,3-thiazolidin-2-one. Finally, this β-hydroxyketone was submitted to the SmI₂-mediated Evans-Tishchenko reduction, which was performed with full 1,3-*anti*-stereocontrol but surprisingly resulted in the ester transposition to predominantly form alcohol **23** in good yields. This last reduction allowed to install the key (11*R*,13*R*) configuration of latrunculins.

## Supporting Information

Crystallographic data of compound **19** were deposited in the Cambridge Crystallographic Data Center under the CCDC number 2225628.

### Supporting Information File 1

Experimental procedures, compound characterizations and spectra.

[https://www.beilstein-journals.org/bjoc/content/supplementary/1860-5397-19-32-S1.pdf]

### Supporting Information File 2

Crystallographic Information File of compound **19**.

[https://www.beilstein-journals.org/bjoc/content/supplementary/1860-5397-19-32-S2.tif]
## Funding

We are grateful to CNRS, Ecole Polytechnique, and ANR (project N°ANR-22-CE44-0006) for financial supports. BJ and AG respectively acknowledge receipt of a Ph.D. grant from Ecole Polytechnique (2019-2022) and of a master internship grant from Labex CHARM3AT (2022).

## ORCID® iDs

Antoine Gamet - https://orcid.org/0009-0001-7919-4324

Nicolas Casaretto - https://orcid.org/0000-0003-0636-983X

Bastien Nay - https://orcid.org/0000-0002-1209-1830

## References

1. Kashman, Y.; Groweiss, A.; Shmueli, U. *Tetrahedron Lett.* **1980**, *21*, 3629–3632. doi:10.1016/0040-4039(80)80255-3

2. Groweiss, A.; Shmueli, U.; Kashman, Y. *J. Org. Chem.* **1983**, *48*, 3512–3516. doi:10.1021/jo00168a028

3. Spector, I.; Shochet, N. R.; Kashman, Y.; Groweiss, A. *Science* **1983**, *219*, 493–495. doi:10.1126/science.6681676

4. Coué, M.; Brenner, S. L.; Spector, I.; Korn, E. D. *FEBS Lett.* **1987**, *213*, 316–318. doi:10.1016/0014-5793(87)81513-2

5. Spector, I.; Shochet, N. R.; Blasberger, D.; Kashman, Y. *Cell Motil. Cytoskeleton* **1989**, *13*, 127–144. doi:10.1002/cm.970130302

6. Fürstner, A.; Kirk, D.; Fenster, M. D. B.; Aïssa, C.; De Souza, D.; Nevado, C.; Tuttle, T.; Thiel, W.; Müller, O. *Chem. – Eur. J.* **2007**, *13*, 135–149. doi:10.1002/chem.200601136

7. Amagata, T.; Johnson, T. A.; Cichewicz, R. H.; Tenney, K.; Mooberry, S. L.; Media, J.; Edelstein, M.; Valeriote, F. A.; Crews, P. *J. Med. Chem.* **2008**, *51*, 7234–7242. doi:10.1021/jm8008585

8. Zibuck, R.; Liverton, N. J.; Smith, A. B. *J. Am. Chem. Soc.* **1986**, *108*, 2451–2453. doi:10.1021/ja00269a056

9. Smith, A. B., III; Noda, I.; Remiszewski, S. W.; Liverton, N. J.; Zibuck, R. *J. Org. Chem.* **1990**, *55*, 3977–3979. doi:10.1021/jo00300a006

10. Williams, B. D.; Smith, A. B., III. *J. Org. Chem.* **2014**, *79*, 9284–9296. doi:10.1021/jo501733m

11. White, J. D.; Kawasaki, M. *J. Am. Chem. Soc.* **1990**, *112*, 4991–4993. doi:10.1021/ja00168a071

12. Fürstner, A.; De Souza, D.; Parra-Rapado, L.; Jensen, J. T. *Angew. Chem., Int. Ed.* **2003**, *42*, 5358–5360. doi:10.1002/anie.200352413

13. She, J.; Lampe, J. W.; Polianski, A. B.; Watson, P. S. *Tetrahedron Lett.* **2009**, *50*, 298–301. doi:10.1016/j.tetlet.2008.10.144

14. Chérest, M.; Felkin, H.; Prudent, N. *Tetrahedron Lett.* **1968**, *9*, 2199–2204. doi:10.1016/s0040-4039(00)89719-1

15. Anh, N. T.; Eisenstein, O. *Nouv. J. Chim.* **1977**, *1*, 61–70.

16. Mengel, A.; Reiser, O. *Chem. Rev.* **1999**, *99*, 1191–1224. doi:10.1021/cr980379w

17. Cee, V. J.; Cramer, C. J.; Evans, D. A. *J. Am. Chem. Soc.* **2006**, *128*, 2920–2930. doi:10.1021/ja0555670

18. Paterson, I.; Gibson, K. R.; Oballa, R. M. *Tetrahedron Lett.* **1996**, *37*, 8585–8588. doi:10.1016/0040-4039(96)01962-4

19. Evans, D. A.; Coleman, P. J.; Côté, B. *J. Org. Chem.* **1997**, *62*, 788–789. doi:10.1021/jo962417m

20. Dias, L. C.; Aguilar, A. *M. Chem. Soc. Rev.* **2008**, *37*, 451–469. doi:10.1039/b701081h

21. Kim, I. S.; Ngai, M.-Y.; Krische, M. J. *J. Am. Chem. Soc.* **2008**, *130*, 6340–6341. doi:10.1021/ja802001b

22. Kim, I. S.; Ngai, M.-Y.; Krische, M. J. *J. Am. Chem. Soc.* **2008**, *130*, 14891–14899. doi:10.1021/ja805722e

23. Dale, J. A.; Mosher, H. S. *J. Am. Chem. Soc.* **1973**, *95*, 512–519. doi:10.1021/ja00783a034

24. Seco, J. M.; Quiñoá, E.; Riguera, R. *Chem. Rev.* **2004**, *104*, 17–118. doi:10.1021/cr000665j

25. Hoye, T. R.; Jeffrey, C. S.; Shao, F. *Nat. Protoc.* **2007**, *2*, 2451–2458. doi:10.1038/nprot.2007.354

26. Mihelich, E. D.; Daniels, K.; Eickhoff, D. J. *J. Am. Chem. Soc.* **1981**, *103*, 7690–7692. doi:10.1021/ja00415a067

27. Zhang, W.; Yamamoto, H. *J. Am. Chem. Soc.* **2007**, *129*, 286–287. doi:10.1021/ja067495y

28. Matsuo, J.-i.; Murakami, M. *Angew. Chem., Int. Ed.* **2013**, *52*, 9109–9118. doi:10.1002/anie.201303192

29. Roush, W. R. *J. Org. Chem.* **1991**, *56*, 4151–4157. doi:10.1021/jo00013a015

30. Paton, R. S.; Goodman, J. M. *Org. Lett.* **2006**, *8*, 4299–4302. doi:10.1021/ol061671q

31. Evans, D. A.; Hoveyda, A. H. *J. Am. Chem. Soc.* **1990**, *112*, 6447–6449. doi:10.1021/ja00173a071

32. Ralston, K. J.; Hulme, A. N. *Synthesis* **2012**, *44*, 2310–2324. doi:10.1055/s-0032-1316544

33. Jiang, Y.; Hong, J.; Burke, S. D. *Org. Lett.* **2004**, *6*, 1445–1448. doi:10.1021/ol049701h

## License and Terms

This is an open access article licensed under the terms of the Beilstein-Institut Open Access License Agreement (https://www.beilstein-journals.org/bjoc/terms), which is identical to the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0). The reuse of material under this license requires that the author(s), source and license are credited. Third-party material in this article could be subject to other licenses (typically indicated in the credit line), and in this case, users are required to obtain permission from the license holder to reuse the material.

The definitive version of this article is the electronic one which can be found at: https://doi.org/10.3762/bjoc.19.32