Towards the synthesis of [15]-membered stevastelins through the 2,3-epoxy analogues

Article abstract of DOI:10.1016/j.tetlet.2003.08.013

A synthetic approach to the [15]-membered stevastelins, a novel class of immunosuppressant agents, is reported based on a macrolactamization route to the 2,3-epoxy derivative 6. The synthesis of this compound was achieved via a stereoselective epoxidation

Full text of DOI:10.1016/j.tetlet.2003.08.013

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7671–7675
Towards the synthesis of [15]-membered stevastelins through the
2,3-epoxy analogues
Francisco Sarabia,* Samy Chammaa, Antonio Sa´nchez Ruiz and F. Jorge Lo´pez-Herrera†
Departamento de Bioqu´ımica, Biolog´ıa Molecular y Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Ma´laga,
29071 Ma´laga, Spain
Received 1 July 2003; revised 18 July 2003; accepted 6 August 2003
Abstract—A synthetic approach to the [15]-membered stevastelins, a novel class of immunosuppressant agents, is reported based
on a macrolactamization route to the 2,3-epoxy derivative 6. The synthesis of this compound was achieved via a stereoselective
epoxidation of the allylic alcohol 13, followed by a coupling reaction with a variety of peptide derivatives to give the epoxy
peptides 7–10. After an extensive study of cyclizations with these precursors, the best result was achieved with the macrolactamiza-
tion of 8 in the presence of DEPC, to obtain the epoxy cyclic depsipeptide 6 in 42% yield. From this product, an epoxy analogue
of stevastelin B, compound 27, was prepared. Finally, the synthesis of the natural product was attempted through the opening of
the oxirane ring contained in 6 and 26, with a variety of methyl cuprate reagents, but without success.
© 2003 Elsevier Ltd. All rights reserved.
The stevastelins, isolated from the culture broths of
Penicillium sp. NK374186,1 comprise a family of [13]-
and [15]-membered cyclic depsipeptides with outstand-
ing immunosuppressive properties (Fig. 1).2 The partic-
ular mechanism of action exhibited by this novel class
of cyclic depsipeptides, which is shared with the natural
product sanglifehrin A,3 is characterized by the inhibi-
tion of T-cell proliferation without affecting the phos-
phatase activity of calcineurin,4 and is in contrast with
the action displayed by the well-known immunosup-
pressant agents cyclosporin A5 and FK506.6
Due to the biological relevance of this class of naturally
occurring products, not only as potential therapeutics
in transplantation surgery, but also as biochemical
probes for the investigation of new signal transduction
pathways,7 the stevastelins have elicited a flurry of
synthetic interest culminating with the total syntheses
of stevastelin B (2)8,9 and stevastelin C3 (5),10 together
with various synthetic approaches11 and analogue syn-
theses.3 We recently initiated a research program
directed towards the syntheses of such compounds
based on a macrolactonization approach which suc-
Figure 1. Structures of stevastelins A (1), B (2), A3 (3), B3 (4) and C3 (5).
Keywords: stevastelin; immunosuppressant; natural products; cyclic depsipeptide; stereoselective synthesis; macrolactamization.
* Corresponding author. Tel.: +34-952134258; fax: +34-952131941; e-mail: frsarabia@uma.es
† With the utmost respect and sadness, we regret to inform the scientific community of Professor Lo´pez Herrera’s passing.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.013

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F. Sarabia et al. / Tetrahedron Letters 44 (2003) 7671–7675
degree of diastereoselectivity was attributed to the fact
that the pairing of substrate 13 with (−)-DET consti-
tutes a mismatched case due to the opposite stereofacial
preference that both components display.14 In fact,
epoxidation of 13 with m-CPBA furnished epoxy alco-
hol 15 as the sole product in 90% yield. Both epoxy
alcohols were transformed into the corresponding acids
by treatment with ruthenium tetraoxide15 to furnish the
epoxy acids 16 and 17, respectively (Scheme 2). Subse-
quently, the acid 16 was transformed into the allyl ester
19 in order to obtain the corresponding precursors for
the macrolactamization reactions.
ceeded with the synthesis of the [13]-membered ring
component, stevastelin C3.10 Unfortunately, this syn-
thetic strategy proved to be completely ineffective for
the construction of the [15]-membered ring contained in
stevastelin A (1) and B (2). Consequently, an alternative
synthetic strategy was required for these members, that
would permit: (a) an efficient and rapid construction of
the [15]-membered ring, and (b) access to analogues of
biological and mechanistic interest. Among a wide vari-
ety of structural and synthetic possibilities, the 2,3-
epoxyamide analogue of the [15]-membered stevestalin,
compound 6, was identified as an excellent candidate
that would satisfy both requisites indicated above. For
the synthesis of this target compound, we decided to
explore all the macrocyclization possibilities including
the three possible macrolactamizations (a, b and c) and
the macrolactonization of the corresponding epoxy-
amino acids (8–10) and epoxy-hydroxy acid 7 (Scheme
1).
Initially, we began with the epoxy-acid with the correct
configuration, 19, which was submitted to a variety of
coupling reactions with different peptide derivatives
depending on the desired final macrocyclization to be
executed. Scheme 3 outlines the synthesis of the key
precursor 8. Thus, the coupling of the epoxy ester 19
with the serine derivative 20 was accomplished by treat-
ment with EDCI/DMAP to provide ester 21 in 85%
yield with <2% epimerization. It is worthy to mention
that other procedures such as the Yamaguchi proto-
col,16 provided the desired ester 21 in 75% yield but
with a 5–8% epimerization degree, most likely located
at C-2 of the serine residue, whereas the Corey–Nico-
The synthesis commenced with the reaction of aldehyde
1110,12 with methyl (triphenylphosphoranylidene)acetate
to give the E alkene 12 in a 92% yield. The DIBAL-H
reduction of 12 was followed by an asymmetric Sharp-
less epoxidation13 employing (−)-DET to provide epox-
ide alcohol 14 in very good yield (91%) but with a
modest d.e. (diastereomeric excess) of 85%. This low
Scheme 2. Reagents and conditions: (a) 1.5 equiv.
Ph3PCHCO2Me, C6H6, 80°C, 12 h, 92%. (b) 2.2 equiv.
DIBAL-H, CH2Cl2, −78°C, 0.5 h, 98%. (c) 1.0 equiv.
D-(−)-
DET, 1.0 equiv. Ti(Oi-Pr)4, 2.0 equiv. TBHP, CH2Cl2, −20°C,
24 h, 91% (d.e. 85%). (d) 2.0 equiv. mCPBA, CH2Cl2, 0°C,
0.5 h, 90%. (e) 4.2 equiv. NaIO4, 0.05 equiv. RuCl3, CCl4,
CH3CN, H2O, 0°C, 0.5 h, 65% for 16 and 65% for 17. (f) 4.0
equiv. CH2ꢀCH-CH2OH, 1.5 equiv. EDCI, 0.1 equiv. DMAP,
CH2Cl2, 25°C, 2 h, 85% (d.e. 85%). (g) HF·Pyr, THF, 25°C,
12 h, 99% (d.e. 85%).
Scheme 1. Retrosynthetic analysis of stevastelin B (2).

F. Sarabia et al. / Tetrahedron Letters 44 (2003) 7671–7675
7673
With the acyclic epoxy acids 7, 8, 9 and 10 in hand, we
proceeded with the macrocyclization studies. Due to the
chemical lability of the oxirane function, we deemed it
of prime importance to scan a wide array of different
coupling reagents and reaction conditions to optimize
the production of the targeted epoxy cyclic depsipeptide
6. In contrast to the macrolactonization reaction of 7,
in which only the Yamaguchi protocol was investi-
gated, for epoxy amino acids 8, 9 and 10 a variety of
reagents, solvents and conditions were surveyed for the
macrolactamization reactions. From these studies, the
best results were obtained when the acyclic precursor 8
was treated with pentafluorophenyl diphenylphosphi-
nate (FDPP),19 diphenyl phosphorazidate (DPPA)20 or
diethyl cyanophosphonate (DEPC)9 under high dilution
conditions to give the desired macrocycle 621 in 35, 40
and 42% yields, respectively. The use of other coupling
reagents22 such as BOP, HATU, HBTU, EDCI-HOBt
or EDCI-PFP led to yields lower than 10% accompa-
nied by a complex mixture of decomposition products,
including elimination compounds. Additionally, simi-
larly disappointing results were obtained from 9 and 10
by using this set of reagents, including FDPP, DPPA or
DEPC, or from 7 by the Yamaguchi procedure. The
cyclic depsipeptide 6 was then subjected to catalytic
hydrogenation with palladium on charcoal to give diol
26 in good yield (75%), which was monoacetylated to
compound 27.23 This product represents an interesting
analogue of stevastelin B (2) for biological evaluation.
In a similar synthetic sequence, epoxy aminoacid 28
was prepared and subjected to the macrolactamization
reaction by the action of DEPC to furnish the epoxide
analogue 29 in 40% yield. This compound represents an
interesting analogue to probe the influence of the
configurations at C-2 and C-3 on the immunosuppres-
sant activity of this class of compounds. On the other
hand, in order to obtain an improved yield of the
epoxide 6, we decided to synthesize it via the alkene
analogue of stevastelin B followed by a final epoxida-
tion step. Thus, the a,b-unsaturated ester 12 was sub-
jected to a transesterification reaction mediated by
dibutyltin oxide24 to give the allyl ester 30 followed by
treatment with HF·pyridine to afford the alcohol 31.
The reaction of 31 with the serine derivative 20, in the
presence of EDCI/DMAP, provided the diester 32,
which was then reacted with Pd[PPh3]4 and morpholine
to give the deprotected derivative 33. The subsequent
coupling of 33 with dipeptide 23 afforded the acyclic
precursor 34 in 81% yield, which was sequentially
treated with Pd(0)/morpholine and TFA to furnish the
seco amino acid 36. This amino acid was subjected to
the macrocyclization reaction mediated by EDCI–
HOBt, to give the macrocycle 37 in 18% yield (Scheme
4). The attempted improvement of the macrocyclization
yield through the use of other coupling reagents was
unsuccessful. Similarly discouraging was the epoxida-
tion of 37, which proved to be elusive using a variety of
reagents such as H2O2–urea and TBHP–DIPEA.25
Scheme 3. Reagents and conditions: (a) 1.4 equiv. of 20, 1.5
equiv. EDCI, 0.1 equiv. DMAP, CH2Cl2, 25°C, 2 h, 85%. (b)
0.1 equiv. Pd(PPh3)4, 5.0 equiv. morpholine, THF, 25°C, 0.5
h, 98%. (c) 1.1 equiv. of 23, 1.5 equiv. EDCI, 1.1 equiv.
HOBt, CH2Cl2, 25°C, 0.5 h, 89%. (d) 0.1 equiv. Pd(PPh3)4,
5.0 equiv. morpholine, THF, 25°C, 0.5 h, 97%. (e) TFA,
CH2Cl2, 25°C, 0.5 h, 99%. (f) 2.0 equiv. DEPC, 2.0 equiv.
DIPEA, DMF (2.0 mM based on 8), 25°C, 12 h, 42%. (g) H2,
Pd–C, EtOAc/MeOH (1/1), 25°C, 2 h, 75%. (h) 6.0 equiv.
Ac2O, pyr., 0°C, 1.5 h, 60%.
laou method17 produced a complex mixture of decom-
position products. We therefore continued with com-
pound 21, expecting to increase the diastereomeric
purity of the following compounds through successive
chromatographic purifications. Compound 21 repre-
sented the common intermediate for the synthesis of the
other three epoxy amino acids. Thus, conversion to the
acid 22 by the action of Pd[PPh3]4 and morpholine,18
followed by coupling with dipeptide 23 by treatment
with EDCI and 1-hydroxybenzotriazole (HOBt),
afforded compound 24 in 89% yield, which was trans-
formed into the key precursor 8 by the conventional
cleavage reaction. In a similar manner the other key
precursors, compounds 7, 9 and 10, were prepared
following conventional methods as described before,
without significant difficulty.
Despite the previous results, we continued the study
with the epoxide 6. Preliminary studies directed towards
the synthesis of stevastelin B 2 led us to believe that the
reaction of 6 with lithium dimethylcuprate would

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F. Sarabia et al. / Tetrahedron Letters 44 (2003) 7671–7675
tunately the same results were observed. Similarly, the
action of these nucleophiles on epoxide 29 did not
result in the successful formation of the desired ring-
opened products (Scheme 5).
In conclusion, we have designed an approach to the
[15]-membered stevastelins26 with the aim of delivering
not only the natural compounds but also analogues
thereof. Initial results have proved the convergence and
efficiency of our synthetic approach conducted through
the epoxide 8, which was cyclized to the desired macro-
cyclic derivative 6. Initial attempts to utilize these stev-
astelin analogues to reach the natural members and
analogues through the opening of the epoxide at C-2
with different nucleophiles proved to be elusive. Pre-
sumably, according to molecular modelling studies,27
the preferred conformation of epoxide 6 leads to a
conformational disposition of the oxirane ring that
hinders the entrance and subsequent attack of nucle-
ophiles, preventing the opening of the oxirane ring.
Currently, we are considering two different strategies to
overcome these important hurdles: (1) the use of cata-
lysts capable of enhancing the reactivity of the epoxide,
and (2) the nucleophilic opening of the oxirane ring
prior to the key macrocyclization. Both strategies are
currently being investigated and are expected to provide
access to a broad family of stevastelin analogues for
further biological evaluations.
Scheme 4. Reagents and conditions: (a) 2.0 equiv. DEPC, 2.0
equiv. DIPEA, DMF (2.0 mM based on 28), 25°C, 12 h, 40%.
(b) Allyl alcohol, nBu2SnO, 98°C, 12 h, 99%. (c) HF·Pyr,
THF, 25°C, 12 h, 99%. (d) 1.4 equiv. of 20, 1.5 equiv. EDCI,
0.1 equiv. DMAP, CH2Cl2, 25°C, 2 h, 82%. (e) 0.1 equiv.
Pd(PPh3)4, 5.0 equiv. morpholine, THF, 25°C, 0.5 h, 98%. (f)
1.1 equiv. of 23, 1.5 equiv. EDCI, 1.1 equiv. HOBt, CH2Cl2,
25°C, 0.5 h, 81%. (g) 0.1 equiv. Pd(PPh3)4, 5.0 equiv. morpho-
line, THF, 25°C, 0.5 h, 96%. (h) 1. TFA, CH2Cl2, 25°C, 0.5 h.
2. NaHCO3, Na2CO3, 99%. (i) 1.5 equiv. EDCI, 1.1 equiv.
HOBt, CH2Cl2 (2.0 mM based on 36), 0.5 h, 18%. (j) 4.0
equiv. H2O2, 4.0 equiv. urea, THF, 25°C, 72 h or 1.5 equiv.
TBHP, 1.5 equiv. DIPEA, THF, 25°C, 72 h (starting material
recovered in both cases).
provide the desired product. However, the desired ring
opening reaction did not occur, giving only recovered
starting material with a high degree of epimerization. In
fact, reaction of 6 with different nucleophiles such as
halides, azide or thiolates proved unsuccessful resulting
in the recovery of starting material or the formation of
a product derived from the elimination of the benzyl-
oxy group located on the serine residue with the oxi-
rane ring functionality intact. Consequently, we decided
to test the diol 26 in reactions with different nucle-
ophiles, including lithium dimethylcuprate, fluoride,
chloride, bromide, azide and phenylthiolate, but unfor-
Scheme 5. Reagents and conditions: (a) 4.0 equiv. Me2CuLi,
or Me4AlLi, or Me2CuCNLi2/BF3, THF, −25“0°C, 48 h. (b)
5.0 equiv. LiCl, THF/AcOH, 70°C, 72 h. (c) 5.0 equiv. LiBr,
THF/AcOH, 70°C, 72 h. (d) 10.0 equiv. NaN3, DMF/AcOH,
100°C, 72 h (starting materials recovered for a, b, c and d). (e)
2.0 equiv. MeSNa, THF, 0°C, 48 h (elimination of benzyl
ether on serine residue).

F. Sarabia et al. / Tetrahedron Letters 44 (2003) 7671–7675
7675
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This work was financially supported by Fundacio´n
Ramo´n Areces, the Direccio´n General de Investigacio´n
(ref. BQU2001-1576), the Direccio´n General de Univer-
sidades e Investigacio´n (Junta de Andaluc´ıa. FQM
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for assistance in the preparation of this manuscript. We
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