Application of the diastereoselective photodeconjugation of α,β-unsaturated esters to the synthesis of gymnastatin H

Article abstract of DOI:10.3762/bjoc.7.21

The asymmetric synthesis of gymnastatin H has been achieved by using the photoisomerisation of a conjugated ester to its β,γ-unsaturated isomer through the protonation of a in situ generated dienol as key step. Thanks to diacetone D-glucose used as a chiral alkoxy group, the protonation occurred well onto one of the two diastereotopic faces with very high yields and selectivities. Moreover, by this way the configuration of the C-6 centre of the target molecule was controlled.

Full text of DOI:10.3762/bjoc.7.21

Application of the diastereoselective
photodeconjugation of α,β-unsaturated esters
to the synthesis of gymnastatin H
Ludovic Raffier and Olivier Piva*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 151–155.
Université Lyon 1, UMR 5246 CNRS, Institut de Chimie et de
Biochimie Moléculaire et Supramoléculaire, 69622 Villeurbanne,
France
doi:10.3762/bjoc.7.21
Received: 31 October 2010
Accepted: 04 January 2011
Published: 02 February 2011
Email:
Olivier Piva* - piva@univ-lyon1.fr
This article is part of the Thematic Series "Photocycloadditions and
photorearrangements"
* Corresponding author
Keywords:
Guest Editor: A. G. Griesbeck
amide; diastereoselective protonation; dienol; isomerisation; Wittig
reaction
© 2011 Raffier and Piva; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The asymmetric synthesis of gymnastatin H has been achieved by using the photoisomerisation of a conjugated ester to its β,γ-
unsaturated isomer through the protonation of a in situ generated dienol as key step. Thanks to diacetone D-glucose used as a chiral
alkoxy group, the protonation occurred well onto one of the two diastereotopic faces with very high yields and selectivities.
Moreover, by this way the configuration of the C-6 centre of the target molecule was controlled.
Introduction
The photodeconjugation of α,β-unsaturated esters 1 – which Despite the potential interest in β,γ-unsaturated acid derivatives,
bear at least one hydrogen atom on γ-position – allows a until recently only a few applications of this photochemical
straightforward access to β,γ-unsaturated isomers 2 [1]. This transformation in total synthesis appeared in the literature.
reaction was first reported by Jorgenson [2,3] and has been
extensively studied by different groups in a mechanistical point However, the scope of the photochemical isomerisation has
of view. For example, Weedon et al. were able to trap an inter- been greatly enhanced thanks to the development of diastereo-
mediate species identified as a photodienol (its formation and enantioselective versions. Starting from α-substituted esters
resulting from a [1,5]-sigmatropic rearrangement). It was shown 3 in the presence of a catalytic amount of an enantiomerically
that the efficiency of the isomerisation process is highly pure bicyclic amino alcohol 4 – derived from camphor –, the
dependent on the nature of the solvent and on the presence of protonation of the prochiral photodienol can be achieved with
various additives (e.g., amines) which could catalyse the an ee up to 91% [5]. This value is one of the highest values
reketonisation of the transient dienol [4] (Scheme 1).
observed for an enantioselective protonation transformation
151

Beilstein J. Org. Chem. 2011, 7, 151–155.
Figure 1: Natural products prepared by photodeconjugation.
Filamentous fungi are the source of a wide range of secondary
metabolites which possess very promising biological activities.
Among them, gymnastatins 10 constitute a family of com-
pounds isolated from Gymnascella dankaliensis which grows in
symbiosis with the marine sponge Halichondria japonica [10]
(Figure 2).
Scheme 1: Principle of the photodeconjugation process.
reaction. However, as the selectivities were highly dependent on Gymnastatins 10 possess a common unsaturated fatty acid
the substrate, an alternative diastereoselective version has been residue connected to a tyrosine subunit. These compounds have
developed. By using cheap and commercially available been reported to exhibit antibacterial activity and cytotoxities
diacetone D-glucose (DAG-OH) as chiral alkoxy group and di- against cultured P388 cancer cells. Interestingly, the same acid
methylamino alcohol as additive, a selective protonation of one chain with an R-configuration has been identified in other struc-
of the two diastereotopic faces of the transient dienol was tures like dankastatins [11] isolated from the same source,
achieved which lead to esters 7 with a d.r. better than 97.5:2.5 aranorosin (11) isolated from Pseudoarachniotus roseus [12]
[6] (Scheme 2). This transformation allowed the formation of a and manumycin C (12) isolated from Streptomyces parvulus
new allylic stereogenic centre and found already a direct appli- [13]. Different groups have investigated the synthesis of
cation to the asymmetric synthesis of different natural products gymnastatins 10a–c [14-16], compounds 11 [17] and 12 [18]. In
including (R)-lavandulol (8), (R)-arundic acid (9) and most cases, the lateral acid chain was prepared starting from
2-fluoroacids or lactones [7-9] (Figure 1).
(R)-2-methyloctanal by iterative Wittig reactions to build the
Scheme 2: Enantio- and diastereoselective photodeconjugation reactions.
152

Beilstein J. Org. Chem. 2011, 7, 151–155.
Figure 2: Natural amides possessing the same (6R)-fatty acid side chain.
dienoate chain. The configuration at the C-2 carbon atom of this aldehydes [20]. The reduction of the ethyl ester into the corres-
precursor was controlled by using a diastereoselective alkyl- ponding allylic alcohol 22 followed by the oxidation with
ation of an acyl oxazolidinone. In some cases, a Claisen con- Dess–Martin periodinane (DMP) [21] afforded aldehyde 23
densation took place and afforded a β-ketoamide in noticeable which was converted into the known ethyl ester (E,E)-24 by a
amounts diminishing the overall yield of the sequence [15]. In subsequent Wittig–Horner reaction. The comparison of the
this context, we have considered an alternative synthetic route optical rotation with literature data confirmed the (R) configur-
to the fatty acid common to all gymnastatins according to a ation at the C-6 carbon. By saponification under mild condi-
photoisomerisation–diastereoselective protonation sequence tions, 24 was converted into carboxylic acid 25 which was im-
involving catalytic amounts of an achiral organocatalyst (e.g., plicated into a free-epimerising amidation procedure with HOBt
amino alcohol 4b). Our goal was to describe the first de novo [22] and the readily available O-protected tyrosine derivative
total synthesis of gymnastatin H (10c).
26. Finally, the TBS group of the amino ester moiety was
removed under standard conditions to deliver compound 10c.
The measured spectroscopic data were identical to those
Results and Discussion
Ethyl ester 14, readily prepared from hexanal by a reported for gymnastatin H [10]. Interestingly, the optical rota-
Wittig–Horner reaction, was saponified and esterified under tion of the synthetic product showed a higher value ([α]D25 =
DCC activation with commercially available diacetone +104 (0.3, CHCl3)) than those measured for the isolated natural
D-glucose (Scheme 3). Irradiation of 16 at 254 nm in methylene product ([α]D25 = +42.3 (0.76, CHCl3)). Similar discordances
chloride at −60 °C delivered the β,γ-unsaturated ester 17 in 90% have been already observed in the case of gymnastatin N and
yield as an inseparable mixture of E- and Z-isomers. Hydrogen- were shown to be a consequence of a partial epimerisation at
ation of the double bond lead to the saturated ester 18 for which the C-2’ carbon of the natural compound's amino ester subunit
a 95:5 diastereomeric ratio was measured by 1H NMR spectro- [15].
scopy. Next, a two-step sequence delivered 2-methyloctanal
(20) in 58% overall yield. The configuration of the newly Conclusion
created centre was first assigned as R by applying a model we In conclusion, we have achieved the total synthesis of (6R)-
disclosed earlier and was confirmed by comparison with optical gymnastatin H in 14 steps and 4.3% overall yield by using a
rotation values published in the literature [19]. Aldehyde 20 was highly diastereoselective photodeconjugation of a diacetone
submitted to a Wittig condensation with phosphorane 13b at D-glucose ester as key step (de >95%). Now, work is underway
reflux of toluene to deliver ester 21 only as the E-isomer. It to prepare parent structures that either possess an opposite con-
should be pointed out that the Wadsworth–Emmons variant figuration on the stereogenic centre or a modified geometry of
using 2-phosphonatoester 13a led mainly to the Z-isomer, a the two double bonds. Furthermore, the biological activities of
phenomenon which was already observed with α-substituted these novel structures are going to be studied.
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Beilstein J. Org. Chem. 2011, 7, 151–155.
Scheme 3: Reagents and conditions: (a) NaH, 13a, THF, 25 °C, 83%. (b) KOH, EtOH/H2O (95/5), Δ, 97% (E/Z: 90/10). (c) DAG-OH, DCC, DMAP,
CH2Cl2, 0 °C then rt, 76%. (d) hν (254 nm), 4b (0.3 equiv), CH2Cl2, −60 °C, 90%. (e) H2 (1 atm), PtO2 (cat.), Et2O, 99%. (f) LiAlH4, Et2O, 0 °C, 83%.
(g) DMP, CH2Cl2, 0 °C, 70%. (h) 13b, PhMe, 80 °C, 80% (E-only). (i) Dibal-H (2 equiv), THF, 0 °C, 99%. (j) DMP, CH2Cl2, 0 °C, 75%. (k) 13c, NaH,
THF, rt, 60%. (l) LiOH, MeOH, THF, H2O, 70%. (m) 26, DCC, HOBt, CH2Cl2, 57%. (n) TBAF, THF, 0 °C, 96%.
Lyon 1, CNRS and “Région Rhône-Alpes“ for financial support
Supporting Information
(programme Cible).
Supporting Information File 1
Full experimental and spectral data for compounds 10c,
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