Synthesis of [13]-membered macrocyclic stevastelins via a transesterification reaction as the key step: Total synthesis of stevastelin C3

Article abstract of DOI:10.1016/j.tetlet.2005.09.037

A new synthesis of stevastelin C3 (3), a [13]-membered ring component of the stevastelin family, whose structure was recently revised, is reported. Initially, a macrolactonization approach was attempted to generate the [13]-membered macrolactone but this

Full text of DOI:10.1016/j.tetlet.2005.09.037

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7695–7699
Synthesis of [13]-membered macrocyclic stevastelins via a
transesterification reaction as the key step: total synthesis of
stevastelin C3
*
´
Francisco Sarabia, Miguel Garcıa-Castro and Samy Chammaa
Department of Biochemistry, Molecular Biology and Organic Chemistry, Faculty of Sciences,
University of Malaga, 29071 Malaga, Spain
Received 25 August 2005; revised 6 September 2005; accepted 7 September 2005
Available online 26 September 2005
Abstract—A new synthesis of stevastelin C3 (3), a [13]-membered ring component of the stevastelin family, whose structure was
recently revised, is reported. Initially, a macrolactonization approach was attempted to generate the [13]-membered macrolactone
but this met with failure, so a translactonization reaction was tried to obtain the targeted stevastelin C3 (3) from the corresponding
[15]-membered ring counterpart. Unfortunately, this strategy did not prove successful, and, consequently, we opted to undertake a
transesterification reaction from 23, as a means to accommodate the requisite aminoacid moiety at the correct position, to obtain 24.
From 24, and through intermediates 25–28, the acyclic precursor of the [13]-membered ring macrolactone, compound 30, was effi-
ciently prepared. By utilizing the synthetic course developed by Chida, we took 30 forward and completed the total synthesis of
stevastelin C3 (3).
Ó 2005 Elsevier Ltd. All rights reserved.
The discovery of novel natural products with unprece-
dented molecular architectures and intriguing biological
modes of action has always represented a stimulating
and attractive landmark to initiate a research pro-
gramme directed towards their chemistry and biology.1
Presently, the stevastelins, a family of cyclic depsipep-
tides isolated from the culture broths of Penicillium sp.
NK374186,2 fulfil the features mentioned above. In par-
ticular, they exhibit interesting immunosuppressive
properties,3 characterized by their inhibition of T-cell
proliferation without affecting the phosphatase activity
of calcineurin, in contrast to other related immunosup-
pressive agents.4 The use of the stevastelins as potential
probes to gain insights into new signal transduction
pathways,5 as well as their potential as therapeutics in
transplantation surgery and their interesting molecular
structures, drew our attention and encouraged us to ini-
tiate a program directed towards the total synthesis of
the [15]- and [13]-membered ring stevastelins. As part
of this research, we recently completed the total syn-
theses of stevastelins B, B3 (2)6 and a set of analogues
modified at the lipidic and peptidic regions,7 and have
published synthetic studies towards the [13]-8 and the
[15]-membered ring macrolactones.9 In a similar direc-
tion, other research groups have been engaged in the to-
tal syntheses of stevastelin B,10,11 stevastelin B3 (2),12,13
and the recently revised stevastelin C3 (3),12 as an indi-
cator of the increasing interest for this class of products
in the scientific community.14,15 Inspired by our initial
macrolactonization approach,8 that gave access to the
[13]-membered ring congeners of the stevastelins, we de-
vised a synthesis of stevastelin C3 (3) based on this strat-
egy. Accordingly, and after disassembly of the peptidic
chain, the hydroxy acid 4 represents the targeted lipidic
fragment to be constructed. As is depicted in the retro-
synthetic Scheme 1, the synthesis of hydroxy acid 4
would be planned from the chiral aldehyde 5, involving
a sequence composed of a Wittig reaction, ester reduc-
tion, Sharpless epoxidation and an oxirane ring opening
reaction as a means for the stereoselective construction
of the C-2/C-3 system. The chiral aldehyde 5 then would
be readily accessible by an Enders alkylation of SAMP-
hydrazone 6 with alkyl iodide 7 (Scheme 1).
Keywords: Cyclic depsipeptide; Immunosuppressant; Stevastelin C3;
Total synthesis; Transesterification.
*
Thus, using the general strategy outlined in Scheme 1,
Corresponding author. Tel.: +34 952 134258; fax: +34 952 131941;
e-mail: frsarabia@uma.es
the SAMP hydrazone 616 was sequentially treated with
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.037

7696
F. Sarabia et al. / Tetrahedron Letters 46 (2005) 7695–7699
according to the Yamaguchi method24 (2,4,6-trichloro-
b. Peptidic Coupling
benzoyl chloride, Et3N, 4-DMAP) at various tempera-
tures, ranging from 25 up to 80 °C. Unfortunately, in
no case, the desired macrocyclic derivative 17 was
obtained, yielding a complex mixture of decomposition
products (Scheme 2).
O
H
X
O
O
N
a. Macrolactonization
NH HN
O
R1O
OR2
O
Stevastelin A3 (1): R1 = Ac, R2 = SO3H, X = OH
Stevastelin B3 (2): R1 = Ac, R2 = H, X = OH
Stevastelin C3 (3): R1 = R2 = H, X = OH (proposed)
R1 = R2 = X = H (revised)
c. Epoxide
Opening
(X = H)
b, a
OH
O
OH
4
d. Sharpless Epoxidation
OMe
+
N
N
Wittig Reaction
H
d, c
6
+
O
I
12
12
5
7
Enders Alkylation
Scheme 1. Structures of [13]-membered stevastelins and retrosynthetic
analysis for stevastelin C3 (3).
LDA and 1-iodotetradecane (7) to afford compound 8 in
87% yield and >98% de. Cleavage of the hydrazone moi-
ety by exposure to ozone,17 followed by Wittig reaction
of the resulting aldehyde 5 provided the a,b-unsaturated
ester 9 in 93% yield and complete stereoselectivity. After
treatment of ester 9 with DIBAL-H, the resulting allylic
alcohol 10 was subjected to an asymmetric Sharpless
epoxidation (TBHP, Ti(Oi-Pr)4, D-(ꢀ)-DET)18 to afford
epoxy alcohol 11 in 86% yield and 92% de, according to
1
its H NMR spectra. The reaction of 11 with the Gill-
Scheme 2. Reagents and conditions: (a) 1.0 equiv 8, 1.0 equiv LDA,
THF, ꢀ78 °C, 12 h, then 1.0 equiv 7, ꢀ78 °C, 6 h, 87%, > 98% ee; (b)
O3, CH2Cl2, ꢀ78 °C, 1 h, 76%; (c) 2.0 equiv Ph3P@CHCO2Me,
CH2Cl2, 25 °C, 4 h, 93%; (d) 2.4 equiv DIBAL-H, CH2Cl2, ꢀ78 °C,
0.5 h, 81%; (e) 0.25 equiv D-(ꢀ)-DET, 0.23 equiv Ti(Oi-Pr)4, 2.1 equiv
TBHP, CH2Cl2, ꢀ20 °C, 24 h, 86% (de 92%); (f) 3.0 equiv Me2CuLi,
THF, 0 °C, 4 h, 77%; (g) 0.01 equiv TEMPO, 0.1 equiv KBr,
15.0 equiv NaHCO3, 2.4 equiv NaClO, CH2Cl2/H2O, 0 °C, 15 min;
(h) 3.0 equiv NaClO2, 2.4 equiv NaH2PO4, 87.0 equiv 2-methyl-2-
man reagent (Me2CuLi)19 was followed by a sequential
oxidation of the resulting diol 12 that involved oxidation
of the primary alcohol to aldehyde 13 by the selective ac-
21
tion of TEMPO,20 followed by treatment with NaClO2
to yield hydroxy acid 4, which was used in the subse-
quent step without further purification. The coupling
of 4 with tripeptide 14 was accomplished under conven-
tional conditions (EDCI, HOBt)22 providing the corre-
sponding coupled product 15 in 47% overall yield
from diol 12. The preparation of the key seco acid 16
required the transformation of the allyl ester functional
group to the corresponding acid, which was achieved by
the action of Pd[PPh3]4 and morpholine.23 The key
macrolactonization reaction of 16 was carried out
t
butene, BuOH/H2O (4/1), 25 °C, 10 min; (i) 1.2 equiv 15, 1.5 equiv
EDCI, 1.1 equiv HOBt, CH2Cl2, 25 °C, 2 h, 47% overall yield from 13;
(j) 0.15 equiv Pd[PPh3]4, 10.0 equiv morpholine, THF, 25 °C, 0.5 h,
60%; (k) 5.0 equiv 2,4,6-trichlorobenzoyl chloride, 6.0 equiv Et3N,
THF, 0 °C, 20 min; then slow addition to a solution of 4-DMAP
(10.0 equiv) in toluene (0.002 M based on 4), 25 ! 80 °C, 8 h,
decomposition products.

F. Sarabia et al. / Tetrahedron Letters 46 (2005) 7695–7699
7697
In an effort to find a direct route to the desired [13]-
membered ring macrolactone and taking advantage of
our previous experience with the synthesis of stevastelin
B3 (2),6 a second protocol involving a [15]- ! [13]-mem-
bered ring translactonization reaction was explored.
According to this new approach, the [15]-membered ring
macrodepsipeptide 20 was established as the suitable
precursor for the corresponding [13]-membered ring
derivative 19, through a translactonization reaction,
which would only require the appending of the appro-
priate lipidic chain through a suitable C–C-bond forma-
tion reaction. This new synthetic strategy would avoid
an important drawback found within the reported syn-
thesis by Chida and co-workers,12 which is the introduc-
tion of the serine residue by an esterification process that
results in a high degree of epimerization (60:40) at C-20
of compound 18 (Scheme 3).
2.0 equiv of LHMDS furnished the desired ester 24 in
approximately 50% yield, together with the recovered
starting material (ꢁ50%), which could be incorporated
into a recycling process. Other catalysts such as the
Otera catalyst proved to be similarly efficient in this
reaction, providing 24 in similar yields as the treatments
involving basic reagents. Prior to the introduction of the
peptidic fragment, we decided to incorporate the lipidic
Having successfully synthesized the cyclic depsipeptide
20 from acyclic precursor 21,7 prepared by esterification
of the corresponding alcohol25 with the commercially
available amino acid derivative Cbz–Ser(Bn)–OH,26 we
studied the translactonization reaction by exposing 20
to different reagents, which proved to be effective for
related derivatives. Thus, treatment of 20 with bases
(LHMDS or related bases) or with Lewis acids (Ti(Oi-
Pr)4 or Otera catalyst27) did not result in the formation
of the desired [13]-membered derivative 19, and pro-
vided only recovered starting material. In pursuit of
the targeted compound 20, we turned our attention to
a transesterification reaction as a potential entry into
the [13]-membered ring derivatives.28 To this end, ester
21 was transformed into hydroxy ester 23, through
dihydroxy ester 22. To our delight, treatment of 23 with
Scheme 4. Reagents and conditions: (a) See Ref. 10; (b) 2.0 equiv
NaHMDS, THF, 0 °C, 15 min, recovery of starting material; (c)
AcOH/H2O, THF, 25 °C, 12 h, 95%; (d) 1.2 equiv TBSCl, 1.5 equiv
imidazole, DMF, 25 °C, 15 min, 95%; (e) 2.0 equiv LHMDS, THF,
ꢀ40 °C, 10 min, 50%, recovering ꢁ50% of starting material; (f)
0.02 equiv TEMPO, 0.1 equiv KBr, 20.0 equiv NaHCO3, 3.0 equiv
NaClO, CH2Cl2/H2O, 0 °C, 45 min; (g) 2.0 equiv 26, 2.0 equiv
NaHMDS, THF, 0 °C, 10 min, then addition to a solution of 1.0 equiv
of 25, 15 min, 42% over two steps from 24; (h) 0.1 equiv 10% Pd/C-
ethylenediamine complex, H2, MeOH, 25 °C, 0.5 h; (i) 1.2 equiv 29,
1.0 equiv HOBt, 1.5 equiv EDCI, DMF, 25 °C, 0.5 h, 70% over two
steps from 27.
Scheme 3. New synthetic strategy for stevastelin C3 based on a
translactonization reaction.

7698
F. Sarabia et al. / Tetrahedron Letters 46 (2005) 7695–7699
chain, thus alcohol 24 was transformed into aldehyde 25
by the oxidative action of TEMPO and then reacted
with the in situ generated phosphorous ylide derived
from phosphonium salt 26 by treatment with NaH-
MDS, to afford the Z olefin 27 in 42% yield over two
steps from 24. The reduction of alkene 27 to the alkane
28 was followed by the coupling of dipeptide 29, which
was carried out with EDCI and HOBt to provide com-
pound 30 in a 70% overall yield from alkene 27 (Scheme
4).
ing our previously described strategy based on a
translactonization reaction that was employed for the
synthesis of stevastelin B3 (2).
Acknowledgements
This work was financially supported by Fundacio´n Ra-
mo´n Areces and the Direccio´n General de Investigacio´n
y Cientı´fica Te´cnica (ref. CTQ2004-08141) and fellow-
´
´
ship from Fundacion Ramon Areces (S.C.). We thank
Dr. J. I. Trujillo for assistance in the preparation of this
The completion of the synthesis of stevastelin C3 (3)
was achieved according to Scheme 5 and following the
route reported by Chida. Compound 30 was prepared
for the macrocyclization reaction through a synthetic
sequence that included silyl ether deprotection (AcOH,
H2O, 31, 90%), oxidation (TEMPO and NaClO2, 32)
and Boc-cleavage (TFA) to give amino acid 33, which
was subjected to the action of DEPC under high dilution
conditions to afford the macrocyclic derivative 17 in
42% overall yield from alcohol 31. Finally, the deprotec-
tion of the benzyl ether group delivered Stevastelin C3
(3)29 in 84% yield, whose physical and spectroscopic
properties were identical to those reported for the
natural product.30
´
manuscript. We thank Unidad de Espectroscopıa de
Masas de la Universidad de Granada for mass spectro-
scopic assistance.
References and notes
´
´
1. Sarabia, F.; Chammaa, S.; Sanchez-Ruiz, A.; Martın-
´
Ortiz, L.; Lopez-Herrera, F. J. Curr. Med. Chem. 2004, 11,
1309–1332.
2. (a) Morino, T.; Masuda, A.; Yamada, M.; Nishimoto, M.;
Nishikiori, T.; Saito, S.; Shimada, N. J. Antibiot. 1994, 47,
1341–1343; (b) Morino, T.; Shimada, K.-I.; Masuda, A.;
Nishimoto, M.; Saito, S. J. Antibiot. 1996, 49, 1049–
1051.
3. (a) Morino, T.; Shimada, K.-I.; Masuda, A.; Noriyuki, Y.;
Nishimoto, M.; Nishikiori, T.; Saito, S. J. Antibiot. 1996,
49, 564–568; (b) Shimada, K.-I.; Morino, T.; Masuda, A.;
Sato, M.; Kitagawa, M.; Saito, S. J. Antibiot. 1996, 49,
569–574.
In conclusion, the chemistry described in this article pre-
sents a concise strategy for the construction of the [13]-
membered stevastelins based on transesterification and
macrolactamization processes as the key reactions, giv-
ing efficient access to stevastelin C3 (3) and complement-
4. Hamaguchi, T.; Masuda, A.; Morino, T.; Osada, H.
Chem. Biol. 1997, 4, 279–286.
5. (a) Fischer, G. In Drug Discovery from Nature; Grabley,
S., Thiericke, R., Eds.; Springer, 2000; pp 257–280,
Chapter 14; (b) Fischer, G. Angew. Chem., Int. Ed. Engl.
1994, 33, 1415–1436.
6. Sarabia, F.; Chammaa, S. J. Org. Chem. 2005, 70, ASAP
(JO0506251).
´
7. Sarabia, F.; Chammaa, S.; Garcıa-Castro, M. J. Org.
Chem. 2005, 70, ASAP (JO050628y).
´
8. Sarabia, F.; Chammaa, S.; Lopez-Herrera, F. J. Tetrahe-
dron Lett. 2002, 43, 2961–2965.
´
´
9. Sarabia, F.; Chammaa, S.; Sanchez-Ruiz, A.; Lopez-
Herrera, F. J. Tetrahedron Lett. 2003, 44, 7671–7675.
10. Kurosawa, K.; Nagase, T.; Chida, N. Chem. Commun.
2002, 1280–1281.
11. Kohyama, N.; Yamamoto, Y. Synlett 2001, 694–696.
12. Kurosawa, K.; Matsuura, K.; Chida, N. Tetrahedron Lett.
2005, 46, 389–392.
13. Chakraborty, T. K.; Ghosh, S.; Laxman, P.; Dutta, S.;
Samanta, R. Tetrahedron Lett. 2005, 46, 5447–5450.
14. Chakraborty, T. K.; Ghosh, S.; Dutta, S. Tetrahedron
Lett. 2001, 42, 5085–5088.
15. Manger, M.; Scheck, M.; Prinz, H.; von Kries, J.-P.;
Langer, T.; Saxena, K.; Schwalbe, H.; Furstner, A.;
¨
Rademann, J.; Waldmann, H. ChemBiochem, in press.
16. Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933–
2960.
17. (a) Enders, D.; Tiebes, J.; De Kimpe, N.; Keppens, M.;
Stevens, C.; Smagghe, G.; Betz, O. J. Org. Chem. 1993, 58,
4881–4884; (b) Enders, D.; Plant, A.; Backhaus, D.;
Reinhold, U. Tetrahedron 1995, 51, 10699–10714.
18. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980,
102, 5974–5976; (b) Johnson, R. A.; Sharpless, K. B. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH:
Weinheim, New York, 1993; pp 103–158.
Scheme 5. Reagents and conditions: (a) AcOH/H2O, THF, 25 °C,
18 h, 90%; (b) i. 0.02 equiv TEMPO, 0.1 equiv KBr, 20.0 equiv
NaHCO3, 3.0 equiv NaClO, CH2Cl2, 0 °C, 1 h. ii. 2.5 equiv NaClO2,
2.0 equiv NaH2PO4, 100.0 equiv 2-methyl-2-butene, tBuOH/THF/
H2O, 25 °C, 1 h; (c) TFA (excess), CH2Cl2, 0 °C, 1 h; (d) 5.0 equiv
DEPC, 5.5 equiv Et3N, DMF (1.0 mM based on diol 31), 0 ! 25 °C,
42% for 17 from 31; (e) H2, 10% Pd(OH)2/C, MeOH, 25 °C, 2 h, 84%.

F. Sarabia et al. / Tetrahedron Letters 46 (2005) 7695–7699
7699
19. (a) Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem.
1952, 17, 1630–1634; (b) Chakraborty, T. K.; Jayaprak-
ash, S.; Laxman, P. Tetrahedron 2001, 57, 9461–9467.
20. Leanna, M. R.; Sowin, T. J.; Morton, H. E. Tetrahedron
Lett. 1992, 33, 5029–5032.
21. (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973,
27, 888–890; (b) Bal, B. S.; Childers, W. E., Jr.; Pinnick,
H. W. Tetrahedron 1981, 37, 2091–2096.
25. (a) Horita, K.; Oikawa, Y.; Yonemitsu, O. Chem. Pharm.
Bull. 1989, 37, 1698–1704; (b) Ziegler, F. E.; Kneisley, A.;
Thottathil, J. K.; Wester, R. T. J. Am. Chem. Soc. 1988,
110, 5434–5442.
26. Aminoacid derivative Cbz–Ser(Bn)–OH was purchased
from NovaBiochem.
27. (a) Seebach, D.; Hungerbuhler, E.; Naef, R.; Schnurren-
¨
berger, P.; Weidmann, B.; Zuger, M. Synthesis 1982, 138–
¨
22. (a) Jones, J. Amino Acid and Peptide Synthesis In Oxford
Chemistry Primers Serie, 7; Oxford University Press: New
York, 1992; (b) Hale, K. J.; Bhatia, G. S.; Frigerio, M. In
The Chemical Synthesis of Natural Products; Hale, K. J.,
Ed.; Sheffield Academic Press: Sheffield, 2000; pp 349–415.
23. Kogen, H.; Kiho, T.; Nakayama, M.; Furukawa, Y.;
Kinoshita, T.; Inukai, M. J. Am. Chem. Soc. 2000, 122,
10214–10215.
24. (a) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–
1993; (b) Nicolaou, K. C.; Patron, A. P.; Ajito, K.;
Richter, P. K.; Khatuya, H.; Bertinato, P.; Miller, R. A.;
Tomaszewski, M. J. Chem. Eur. J. 1996, 2, 847–868; (c)
Nicolaou, K. C.; Ninkovic, S.; Sarabia, F.; Vourloumis,
D.; He, Y.; Vallberg, H.; Finlay, M. R. V.; Yang, Z. J.
Am. Chem. Soc. 1997, 119, 7974–7991.
141; (b) Otera, J.; Ioka, S.; Nozaki, H. J. Org. Chem. 1989,
54, 4013–4014; (c) Trost, B. M.; Papillon, J. P. N. J. Am.
Chem. Soc. 2004, 126, 13618–13619.
28. (a) Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991,
56, 5307–5311; (b) Orita, A.; Sakamoto, K.; Hamada, Y.;
Mitsutome, A.; Otera, J. Tetrahedron 1999, 55, 2899–
2910.
29. All new compounds exhibited satisfactory spectroscopic
and analytical and/or accurate mass data.
30. Synthetic Stevastelin C3 (3) exhibited identical properties
(TLC, [a]D, 1H and 13C NMR and HRMS) with those
1
reported for the natural compound, matching H and 13C
NMR spectra by direct comparison with spectra of natural
substance: Morino, T.; Nishimoto, M.; Nishide, M. U.;
Masuda, A.; Yamada, M.; Kawano, E.; Nishikiori, T.;
Saito, S. EP0525361, 1993.