Synthetic studies on stevastelins. 1. Total synthesis of stevastelins B and B3

Article abstract of DOI:10.1021/jo050625l

The synthesis of stevastelin B3 (2) and B (5) are described. In a first approach, epoxy cyclodepsipeptide 8 was considered as a promising candidate for the synthesis of the [15]-membered ring members of the stevastelins; however, the oxirane ring opening,

Full text of DOI:10.1021/jo050625l

Synthetic Studies on Stevastelins. 1.
Total Synthesis of Stevastelins B and B3
Francisco Sarabia* and Samy Chammaa
Department of Biochemistry, Molecular Biology and Organic Chemistry, Faculty of Sciences,
University of Malaga, Campus de Teatinos s/n, 29071, Malaga, Spain
frsarabia@uma.es
Received March 31, 2005
The synthesis of stevastelin B3 (2) and B (5) are described. In a first approach, epoxy cyclodepsi-
peptide 8 was considered as a promising candidate for the synthesis of the [15]-membered ring
members of the stevastelins; however, the oxirane ring opening, required for the completion of the
natural stevastelin synthesis, failed. Thus, we synthesized stevastelin B (5), carrying out the oxirane
ring opening earlier in the synthesis and following a synthetic scheme capable of delivering
analogues. On the other hand, a translactonization reaction of the [15]-membered ring derivative
59 led to the total synthesis of the natural [13]-membered ring component of the stevastelins family,
stevastelin B3 (2).
Introduction
gests a novel mechanism of action for these cyclic
depsipeptides, different from the above-mentioned im-
munosuppressants. These interesting biological findings
demand further investigations to gain insights into the
biology of these natural cyclic depsipeptides. To this aim,
it was deemed of importance to develop strategies not
only for the total synthesis of these natural substances
but also of designed stevastelins for structure-activity
The isolation of the stevastelins (1-5) from culture
broths of Penicillium sp. NK374186,1 their structural
elucidation,2 and recognition as a new class of immuno-
suppressant agents3 with intriguing biological properties
prompted us to engage in a research program directed
toward the total synthesis of these naturally occurring
cyclic depsipeptides.4 Biological investigations have re-
vealed5 that the action displayed by the stevastelins
against OKT3-stimulated human T-cell proliferation is
due to their inhibition of IL-2 and IL-6 gene expressions
in a way similar to that of cyclosporin A,6 FK506,7 and
sanglifehrin A.8 The disclosure that the stevastelins do
not inhibit the phosphatase activity of calcineurin sug-
(6) (a) Dreyfuss, M.; Harri, E.; Hofmann, H. Eur. J. Appl. Microbiol.
1976, 3, 125-133. (b) Sta¨helin, H. F. Experientia 1996, 52, 5-13. (c)
Elliott, J. F.; Lin, Y.; Mizel, S. B.; Bleackley, R. C.; Harnish, D. G.;
Paetkau, V. Science 1984, 226, 1439-1441. (d) Bickel, M.; Amstad,
P.; Evequoz, V.; Mergenhagen, S. E.; Pluznik, D. H.; Tsuda, H.; Wahl,
S. M. Proc. Natl. Acad. Sci. U.S.A. 1987, 84, 3274-3277.
(7) (a) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino,
T.; Goto, T.; Hashimoto, M.; Taga, T. J. Am. Chem. Soc. 1987, 109,
5031-5033. (b) Tocci, M. J.; Matkovich, D. A.; Collier, K. A.; Kwok,
P.; Dumont, F.; Lin, S.; Degudicibus, S.; Siekerka, J. J.; Chin, J.;
Hutchinson, N. I. J. Immunol. 1989, 143, 718-726. (c) Harding, M.
W.; Golat, A.; Uehling, D. E.; Schreiber, S. L. Nature 1989, 341, 758-
760. (d) Lin, C. S.; Boltz, R. C.; Siekierka, J. J.; Sigal, N. H. Cell.
Immunol. 1991, 133, 269-284. (e) Bierer, B. E. Curr. Opin. Hematol.
1993, 1, 149-159. (f) Schreiber, S. L. Science 1991, 251, 283-287.
(8) (a) Sanglier, J.-J.; Quesniaux, V.; Fehr, T.; Hofmann, H.;
Mahnke, M.; Memmert, K.; Schuler, W.; Zenke, G.; Gschwind, L.;
Maurer, C.; Schilling, W. J. Antibiot. 1999, 52, 474-479. (b) Sedrani,
R.; Kallen, J.; Mart´ın Cabrejas, L. M.; Papageorgiou, C. D.; Senia, F.;
Rohrbach, S.; Wagner, D.; Thai, B.; Jutzi Eme, A.-M.; France, J.;
Oberer, L.; Rihs, G.; Zenke, G.; Wagner, J. J. Am. Chem. Soc. 2003,
125, 3849-3859.
* Corresponding author. Fax: 34-952 131941.
(1) Morino, T.; Masuda, A.; Yamada, M.; Nishimoto, M.; Nishikiori,
T.; Saito, S.; Shimada, N. J. Antibiot. 1994, 47, 1341-1343.
(2) 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.; Nish-
imoto, 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.
(4) Sarabia, F.; Chammaa, S.; Sa´nchez-Ruiz, A.; Mart´ın-Ortiz, L.;
Lo´pez-Herrera, F. J. Curr. Med. Chem. 2004, 11, 1309-1332.
(5) Hamaguchi, T.; Masuda, A.; Morino, T.; Osada, H. Chem. Biol.
1997, 4, 279-286.
10.1021/jo050625l CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/30/2005
7846
J. Org. Chem. 2005, 70, 7846-7857

Total Synthesis of Stevastelins B and B3
SCHEME 1. Synthetic Approaches to [13]- and
[15]-Membered Ring Stevastelins and
Retrosynthetic Analysis of Stevastelin B (5)
FIGURE 1. Structures of stevastelins A3 (1), B3 (2), C3 (3),
A (4), and B (5).
relationship studies. A number of recent publications
have reported upon the total syntheses of stevastelin B
(5),9,10 stevastelin B3 (2),11 and the recently structurally
revised stevastelin C3 (3),11a together with different
synthetic approaches12 and various analogue syntheses,5
indicating the great interest for this class of products in
the scientific community.
Structurally, the stevastelins contain two main frame-
works: (a) a stearic acid unit with a typical tetrade
fragment derived from the polypropionate biosynthetic
pathway and (b) a peptidic chain comprised of L-serine,
L-threonine, and L-valine amino acids residues, connected
by an ester and amide linkages to constitute two families
of [13]- and [15]-membered ring components (Figure 1).
Our preliminary synthetic studies utilizing a macrolac-
tonization-based strategy13 led to the synthesis of the
[13]-membered ring containing stevastelin C3 (3) from
the acyclic precursor 6; unfortunately, preparation of the
[15]-membered ring compound was found to be impossible
using this strategy. Similarly, the 3-O-benzyl protected
acyclic derivative 7 proved to be an unsuitable precursor
for the synthesis of the coveted [15]-membered cyclic
depsipetides.12 As an alternative that would permit
access to the targeted [15]-membered ring stevastelins,
we devised the epoxy-peptide 8 as a suitable precursor
for the macrocyclic depsipeptides, by which an oxirane
ring opening reaction would provide the corresponding
natural stevastelin. In addition, the precursor offers the
opportunity of incorporating structural modifications for
the preparation of 2-C-alkyl stevastelin analogues by
opening of the oxirane with different nucleophiles. To-
ward this aim, the synthesis of epoxy peptide 8 could be
efficiently achieved through a macrocyclization process,
via macrolactamizations a, b, or c or by a macrolacton-
ization reaction. This extensive macrocyclizations study
should require the preparation of the corresponding
acyclic epoxy amino acids,14 representing epoxy acid 9
as a common intermediate for the delivery of all of these
acyclic precursors (Scheme 1).
Results and Discussion
Toward the Synthesis of Stevastelin B (5) through
the 2,3-Epoxy Analogue 8. The synthesis of 2,3-epoxy-
stevastelin 8 commenced with the preparation of the
subtarget compound 9 as described in Scheme 2. Accord-
ingly, reaction of tetradecanal 11 with the boron enolate
of oxazolidinone 1015 furnished compound 12 in an 85%
yield. The conversion of this compound to the diol 13 was
achieved by treatment with lithium borohydride16 and,
after a sequence of selective protection and deprotection
(9) Kurosawa, K.; Nagase, T.; Chida, N. Chem. Commun. 2002,
1280-1281.
(14) Related to preliminary studies: Sarabia, F.; Chammaa, S.;
Sa´nchez-Ruiz, A.; Lo´pez-Herrera, F. J. Tetrahedron Lett. 2003, 44,
7671-7675.
(10) Kohyama, N.; Yamamoto, Y. Synlett 2001, 694-696.
(11) (a) Kurosawa, K.; Matsuura, K.; Chida, N. Tetrahedron Lett.
2005, 46, 389-392. (b) Chakraborty, T. K.; Ghosh, S.; Laxman, P.;
Dutta, S.; Samanta, R. Tetrahedron Lett. 2005, 46, 5447-5450.
(12) Chakraborty, T. K.; Ghosh, S.; Dutta, S. Tetrahedron Lett. 2001,
42, 5085-5088.
(15) (a) Evans, D. A. Aldrichimica Acta 1982, 15, 318-327. (b)
Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127-2129. (c) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem.
Soc. 1982, 104, 1737-1739. (d) Evans, D. A.; Mathre, D. J.; Scott, W.
L. J. Org. Chem. 1985, 50, 1830-1835. (e) Evans, D. A.; Scott, J. M.;
Ennis, M. D. J. Org. Chem. 1993, 58, 471-485.
(13) Sarabia, F.; Chammaa, S.; Lo´pez-Herrera, F. J. Tetrahedron
Lett. 2002, 43, 2961-2965.
(16) Smith, A. B., III; Lodise, S. A. Org. Lett. 1999, 1, 1249-1252.
J. Org. Chem, Vol. 70, No. 20, 2005 7847

Sarabia and Chammaa
SCHEME 2. Synthesis of the Stearic Acid
Derivative (9)a
FIGURE 2. Structures of amino acids and peptidic deriva-
tives.
chemistry.22 Thus, the precursor for the macrolactoniza-
tion reaction, epoxy peptide 29, was efficiently prepared
by coupling of acid 9 with tripeptide 26 by the action of
EDCI, to obtain epoxy peptide 27 in a 74% yield. The
transformation of the silyl ether 27 to the alcohol 28, by
the action of HF‚pyridine, was followed by the allyl ester
cleavage under the influence of Pd[PPh3]4 and morpho-
line23 to obtain the acyclic precursor 29. In a similar way,
the coupling of 9 with dipeptide 24 was undertaken under
identical conditions as for 27, to furnish epoxy peptide
30 in a 70% yield, which was subjected to the action of
HF‚pyridine to yield alcohol 31. The coupling of 31 with
the L-serine derivative 21 was accomplished, according
to the Yamaguchi protocol,24 to afford acyclic depsipeptide
32 in an 86% yield and with no detection of appreciable
epimerization as determined by NMR analysis. The
elaboration of this compound to the second acyclic
precursor 34 was carried out in two steps, involving allyl
ester and Boc cleavages by the action of Pd[PPh3]4 and
TFA, respectively, (Scheme 3).
The preparation of the acyclic precursor 41 was per-
formed according to a synthetic course similar to that for
the preparation of 34, with the introduction of the
L-valine derivative 23, with the formation of epoxy amide
35 in a 66% yield, followed by the linkage of the L-serine
residue via esterification of 36 with 21 by the Yamaguchi
methodology, to obtain ester 37 (90%), and subsequent
coupling of the resulting amine 38, obtained by Boc
cleavage of 37, with the L-threonine derivative 22 to
obtain epoxy peptide 39 in a poor 41% yield, which,
finally was prepared for the macrocyclization reaction via
a similar sequence of cleavage reactions as described
before for 34, to obtain epoxy peptide 41. The synthesis
of the fourth precursor, epoxy peptide 48, proceeded in a
slightly different synthetic sequence, requiring the previ-
ous formation of the allyl ester 42, from epoxy acid 9,
and subsequent TBAF treatment to obtain alcohol 43.
a Reagents and Conditions: (a) 1.1 equiv of n-Bu2BOTf, 1.1
equiv of Et3N, CH2Cl2, 0 °C, 0.5 h, then 1.1 equiv of 12, -78 °C,
12 h, 85%. (b) 8.8 equiv of LiBH4, THF, -20 f 0 °C, 2 h, 92%. (c)
1.3 equiv of PivCl, CH2Cl2, pyridine, -20 °C, 0.5 h, 94%. (d) 1.5
equiv of TBSCl, 2.0 equiv of imidazole, DMF, 25 °C, 12 h, 96%. (e)
2.2 equiv of DIBAL-H, CH2Cl2, -78 °C, 0.5 h, 98%. (f) 2.0 equiv of
(COCl)2, 4.0 equiv of DMSO, 6.0 equiv of Et3N, CH2Cl2, -78 °C,
0.5 h, 94%. (g) 2.0 equiv of Ph3PCHCO2Me, C6H6, 80 °C, 12 h,
92%. (h) 2.2 equiv of DIBAL-H, CH2Cl2, -78 °C, 0.5 h, 98%. (i)
0.4 equiv of D-(-)-DET, 0.4 equiv of Ti(Oi-Pr)4, 3.6 equiv of TBHP,
CH2Cl2, -20 °C, 24 h, 91% (de 84%). (j) 0.01 equiv of RuCl3, 4.2
equiv of NaIO4, CH3CN/CCl4/H2O (1:1:1), 0 °C, 0.5 h, 64%.
steps, was transformed into the alcohol 16. Alcohol 16
was then subjected to a Swern oxidation,17 and the
resulting aldehyde 17 was reacted with methyl (triph-
enylphosphoranylidene)acetate to give the E alkene 18
in a 92% yield. The DIBAL-H reduction of 18 afforded
allylic alcohol 19, which was subjected to a Sharpless
asymmetric epoxidation,18 using (-)-DET, to obtain the
epoxy alcohol 20 in very good yield (91%), although in a
modest 85% diastereomeric excess.19 The exposure of
epoxy alcohol 20 to the action of catalytic amounts of
ruthenium trichloride and sodium periodate as cooxi-
dant20 furnished epoxy acid 9 in a 64% yield.
The macrocyclization studies directed toward the syn-
thesis of the key cyclic precursor of stevastelins, the epoxy
analogue 8, required the coupling of epoxy acid 9 with
different amino acids (21-23) and peptide derivatives
(24-26), depicted in Figure 2, which were either com-
mercially available21 or prepared by conventional peptide
(17) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978,
43, 2480-2482.
(18) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974-5976. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic Asym-
metric Synthesis; Ojima, I., Ed.; VCH: Weinheim, New York, 1993;
pp 103-158.
(21) Amino acid derivatives 21 and 22 were purchased from Nova-
Biochem.
(22) Amino acid derivative 23 and peptides 24-26 were prepared
according to conventional chemistry of peptides, following general
procedures as described by: Jones, J. In Amino Acid and Peptide
Synthesis; Oxford Chemistry Primers Series 7; Oxford University
Press: New York, 1992.
(23) Kogen, H.; Kiho, T.; Nakayama, M.; Furukawa, Y.; Kinoshita,
T.; Inukai, M. J. Am. Chem. Soc. 2000, 122, 10214-10215.
(24) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989-1993.
(19) The low degree of diastereoselectivity found on this asymmetric
epoxidation was attributed to the fact that the pairing of substrate 19
with (-)-DET constitutes a mismatched case due to the opposite
stereofacial preference that both components display. See : Masamune,
S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl.
1985, 24, 1-30.
(20) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J. Org. Chem. 1981, 46, 3936-3938.
7848 J. Org. Chem., Vol. 70, No. 20, 2005

Total Synthesis of Stevastelins B and B3
SCHEME 3. Synthesis of Acyclic Precursors of
Epoxy-Stevastelins 29 and 34a
SCHEME 4. Synthesis of Acyclic Precursors of
Epoxy-Stevastelins 41 and 48a
a Reagents and Conditions: (a) 1.0 equiv of 9, 1.0 equiv of HOBt,
1.4 equiv of EDCI, 1.6 equiv of 26, DCM, 25 °C, 0.5 h, 74%. (b)
HF‚pyridine (70% w/v), THF, 25 °C, 12 h, 96%. (c) 0.15 equiv of
Pd[PPh3]4, 10.0 equiv of morpholine, THF, 25 °C, 1 h, 89%. (d) 1.0
equiv of 9, 1.1 equiv of HOBt, 1.4 equiv of EDCI, 1.2 equiv of 24,
DCM, 25 °C, 1 h, 70%. (e) HF‚pyridine (70% w/v), THF, 25 °C, 8
h, 95%. (f) 1.5 equiv of 21, 3.0 equiv of TEA, 2.3 equiv of 2,4,6-
Cl3C6H2COCl, THF, 0 °C, 2 h, then added over 1.0 equiv of 31,
1.3 equiv of 4-DMAP, toluene, 25 °C, 15 min, 86%. (g) 0.1 equiv of
Pd[PPh3]4, 5.0 equiv of morpholine, THF, 25 °C, 0.5 h, 94%. (h)
TFA (excess), DCM, 25 °C, 0.5 h, 100%.
a Reagents and Conditions: (a) 1.0 equiv of 9, 1.1 equiv of HOBt,
1.4 equiv of EDCI, 1.1 equiv of 23, DCM, 25 °C, 1.0 h, 66%. (b)
HF‚pyridine (70% w/v), THF, 25 °C, 7 h, 99%. (c) 1.4 equiv of 21,
2.7 equiv of TEA, 2.2 equiv of 2,4,6-Cl3C6H2COCl, THF, 0 °C, 2 h,
then added over 1.0 equiv of 36, 0.4 equiv of 4-DMAP, toluene, 25
°C, 0.5 h, 90%. (d) TFA (excess), DCM, 25 °C, 0.5 h, 100% for 38,
41, 45, and 48. (e) 1.0 equiv of 38, 1.2 equiv of 22, 1.3 equiv of
HOBt, 1.7 equiv of EDCI, DCM, 25 °C, 0.5 h, 41%. (f) 0.1 equiv of
Pd[PPh3]4, 5.0 equiv of morpholine, THF, 25 °C, 0.5 h, 95% for 40
and 47. (g) 4.0 equiv of allylic alcohol, 1.5 equiv of EDCI, 0.1 equiv
of 4-DMAP, DCM, 25 °C, 3 h, 75%. (h) HF‚pyridine (70% w/v),
THF, 25 °C, 12 h, 95%. (i) 1.5 equiv of 21, 2.0 equiv of EDCI, 0.1
equiv of 4-DMAP, DCM, 25 °C, 40 min, 85%. (j) 1.6 equiv of 25,
1.6 equiv of HOBt, 2.6 equiv of EDCI, DCM, 25 °C, 1 h, 60%.
The coupling with the L-serine derivative 21 was ac-
complished in a similar manner as for 32 to furnish epoxy
peptide 44 in an 85% yield, which was reacted with TFA
to yield amine 45, prior to the coupling with dipeptide
25 that afforded epoxy peptide 46 in a moderate 60%
yield. The two final deprotection steps were conducted
under similar conditions as those described in previous
schemes for the other acyclic precursors, to obtain
precursor 48 (Scheme 4).
With the delivery of acyclic epoxy amino acids 29, 34,
41, and 48 from the previous synthetic schemes, we
initiated the macrocyclization studies to determine which
of these compounds represented the most appropriate
precursor for the coveted epoxy cyclodepsipeptide 8. With
the exception of epoxy peptide 29, which was subjected
to macrolactonization reaction conditions, following
Yamaguchi methodology,25 the other precursors (34, 41,
and 48) were exposed, under high dilution conditions, to
a variety of coupling reagents,26 including diethyl cyano-
phosphonate (DEPC), diphenyl phosphoryl azide (DPPA),
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroni-
um hexafluorophosphate/1-hydroxybenzotriazole (HATU/
HOBt), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluro-
nium hexafluorophosphate/HOBt (HBTU/HOBt), EDCI/
HOBt, and pentafluorophenol/EDCI (PFP/EDCI), in
different solvents (DCM, THF, DMF, MeCN). The results
from these studies revealed that, whereas the macrolac-
tonization did not work at all for compound 29, resulting
in a complex mixture of decomposition products, the
macrolactamizations provided more positive results,
especially with the epoxy peptide 34, which afforded the
best yields for the desired macrocycle 8 when it was
treated with DPPA27 or DEPC28 as coupling reagents and
DMF as solvent. The epoxy peptide that was obtained
(25) (a) 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. (b) Nicolaou, K. C.; King, N. P.; Finlay, M. R. V.; He,
Y.; Roschangar, F.; Vourloumis, D.; Vallberg, H.; Sarabia, F.; Ninkovic,
S.; Hepworth, D. Bioorg. Med. Chem. 1999, 7, 665-697.
(26) 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.
(27) Li, W.-R.; Ewing, W. R.; Harris, B. D.; Joullie´, M. M. J. Am.
Chem. Soc. 1990, 112, 7659-7672.
(28) (a) Yamada, S.; Kasai, Y.; Shioiri, T. Tetrahedron Lett. 1973,
1595-1598. (b) Takuma, S.; Hamada, Y.; Shioiri, T. Chem. Pharm.
Bull. 1982, 30, 3147-3153. (c) Jeremic, T.; Linden, A.; Heimgartner,
H. Helv. Chim. Acta 2004, 87, 3056-3079.
J. Org. Chem, Vol. 70, No. 20, 2005 7849

Sarabia and Chammaa
SCHEME 5. Synthesis of Epoxy-Stevastelin B
Analogue 50a
52, of Chida’s synthesis, proceeding in a similar synthetic
sequence as they described.9 To support our ongoing
research involving the search for new stevastelin-type
immunosuppressive agents with the objective of gaining
insight into the structural elements that play an essential
role in their biological properties, we decided to under-
take the preparation of the natural substance. Thus,
epoxy alcohol 20 was treated with lithium dimethyl
cuprate,30 to yield the oxirane ring opening product 52
in an 88% yield. Protection of the 1,3-diol as the acetal,
followed by TBS deprotection, provided the corresponding
alcohol 54 in good yield (69%). The coupling of 54 with
the serine derivative 55 was accomplished by use of the
Yamaguchi protocol, to furnish the ester 56 in an 84%
average yield, but with 5-8% epimerization at C-2 of the
serine residue, which was anticipated based on observa-
tions by Chida’s group.9 Other reagents, including EDCI/
4-DMAP,31 which worked well for the epoxy analogue in
the synthesis of epoxy peptide 8 and with a lower degree
of epimerization, failed on this occasion. After incorpora-
tion of the serine amino acid residue, the introduction of
the rest of the peptidic chain was undertaken without
further problems, through free amino derivative 57,
followed by coupling with the dipeptide Boc-Val-Thr-
OH.32 The preparation of the resulting coupling product
for the key macrocyclization reaction was followed ac-
cording to the synthesis described by Chida, initiated
with the acetal cleavage by the action of acetic acid,
selective oxidation of the primary hydroxyl group by the
sequential action of TEMPO/NaClO33 and NaClO2 to
34
a Reagents and Conditions: (a) 2.7 equiv of TEA, 2.2 equiv of
2,4,6-Cl3C6H2COCl, THF, 0 °C, 2 h, then 2.2 equiv of 4-DMAP,
toluene, 70 °C, 0.5 h, decomposition. (b) See Table 1. (c) Pd-C
(10%), MeOH/EtOAc, 45 min, 92%. (d) 6.0 equiv of Ac2O, pyridine,
0 °C, 3 h, 70%. (e) 10.0 equiv of Me2CuLi, THF, 0 f 25 °C, 12 h,
or 20.0 equiv of Me4AlLi, THF, 0 °C, 1 h, no reaction in both cases.
the corresponding acid, macrocyclization reaction by
treatment of the resulting seco amino acid with diethyl
cyanophosphonate (DECP), debenzylation,35 and final
selective monoacetylation to yield stevastelin B (5)
(Scheme 6).36
Total Synthesis of Stevastelin B3 (2). We surmised
that a translactonization reaction37 would be possible
from the corresponding [15]-membered ring derivatives
to access the [13]-membered ring components of stevas-
telins. In this sense, [15]-cyclodepsipeptide 58 was pre-
represents an interesting compound for the preparation
of the 2,3-epoxy analogue of stevastelin B, as well as
representing the direct precursor for the natural com-
pound. Thus, compound 8 was subjected to catalytic
hydrogenation to provide diol 49, which was treated with
acetic anhydride to obtain stevastelin analogue 50 in a
64% overall yield from 8. The final key opening reaction
was then attempted. Unfortunately, the desired oxirane
ring opening did not take place under the influence of
various nucleophiles, including organocopper reagents,
in order to introduce the methyl group contained in
natural stevastelins (Scheme 5).
In light of this rather unexpected outcome, presumably
due to a conformational disposition of the oxirane ring
that prevented the attack of the nucleophile, as was
revealed later from the minimized structures of epoxy
stevastelins 8 and 49,29 we altered our synthetic strategy
to overcome the synthetic difficulties arising from the
epoxide opening step, opting to undertake the opening
of the oxirane ring with an earlier intermediate, epoxide
20, as we describe in the following section.
(30) (a) Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952,
17, 1630-1634. (b) Chakraborty, T. K.; Jayaprakash, S.; Laxman, P.
Tetrahedron 2001, 57, 9461-9467.
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47, 1962-1965.
(32) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207-
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1992, 33, 5029-5032.
(34) (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.
(35) (a) Hartung, W. H.; Simonoff, C. Org. React. 1953, 7, 263-326.
(b) Heathcock, C. H.; Ratcliffe, R. J. Am. Chem. Soc. 1971, 93, 1746-
1757.
(36) See the Supporting Information for experimental details.
(37) Representative examples of natural products synthesis based
on a translactonization reaction: (a) Corey, E. J.; Brunelle, D. J.;
Nicolaou, K. C. J. Am. Chem. Soc. 1977, 99, 7359-7360. (b) Corey, E.
J.; Kim, S.; Yoo, S.; Nicolaou, K. C.; Melvin, L. S., Jr.; Brunelle, D. J.;
Falck, J. R.; Trybulski, E. J.; Lett, R.; Sheldrake, P. W. J. Am. Chem.
Soc. 1978, 100, 4620-4622. (c) Nagel, A. A.; Celmer, W. D.; Jefferson,
M. T.; Vincent L. A.; Whipple, E. B.; Schulte, G. J. Org. Chem. 1986,
51, 5397-5400. (d) Kirst, H. A.; Wind, J. A.; Paschal, J. W. J. Org.
Chem. 1987, 52, 4359-4362. (e) Kibwage, I. O.; Busson, R.; Janssen,
G.; Hoogmartens, J.; Vanderhaeghe, H.; Bracke, J. J. Org. Chem. 1987,
52, 990-996. (f) Adachi, T. J. Org. Chem. 1989, 54, 3507-3510. (g)
Kretzschmar, G.; Krause, M.; Radics, L. Tetrahedron 1997, 53, 971-
986. (h) Ohara, T.; Kume, M.; Narukawa, Y.; Motokawa, K.; Uotani,
K.; Nakai, H. J. Org. Chem. 2002, 67, 9146-9152. (i) Trost, B. M.;
Papillon, J. P. N. J. Am. Chem. Soc. 2004, 126, 13618-13619.
Total Synthesis of Stevastelin B (5). This new route
for the synthesis of the stevastelins would lead us to the
same synthetic intermediate, represented by compound
(29) Theoretical calculations were performed with HyperChem 5.0,
using OPLS as the force field with a gradient limit of 0.001 kcal/(Å
mol). See Supporting Information for more details.
7850 J. Org. Chem., Vol. 70, No. 20, 2005

Total Synthesis of Stevastelins B and B3
SCHEME 6. Total Synthesis of Stevastelin B (5)a
SCHEME 7. Total Synthesis of Stevastelin B3 (2)a
a Reagents and Conditions: (a) 10.0 equiv of CuI, 20.0 equiv of
1.6 M MeLi, THF, 0 °C, 4.0 h, 88%. (b) 3.0 equiv of Me2C(OMe)2,
0.05 equiv of CSA, DMF, 0 °C, 2 h, 95%. (c) 3.0 equiv of TBAF,
THF, 25 °C, 4 days, 69%. (d) 6.4 equiv of 55, 9.0 equiv of 2,4,6-
Cl3C6H2COCl, 9.0 equiv of Et3N, THF/toluene, 0 °C, 1.5 h, then
0.5 equiv of 4-DMAP, 0 °C, 2.5 h, 84% (6:1 epimeric mixture). (e)
0.1 equiv of 10% Pd/C-ethylenediamine complex, H2, MeOH, 25
°C, 0.5 h.
a Reagents and Conditions: (a) 2.0 equiv of 2,6-lutidine, 1.5
equiv of TBSOTf, DCM, 0 °C, 15 min, 86%. (b) 2.0 equiv of
NaHMDS, THF, 0 °C, 15 min, 50%. (c) Pd-C (10%), MeOH, 25
°C, 15 min. (d) 10.0 equiv of Ac2O, 0.01 equiv of 4-DMAP, pyridine,
0 °C, 5 h. (e) HF‚pyridine (70% w/v), THF, 25 °C, 3 h, 55% from
60.
pared for this reaction by the protection of the secondary
hydroxyl group, located at the L-threonine residue, as the
silyl ether 59. The treatment of 59 with sodium hexa-
methyldisilylamide (NaHMDS) at 0 °C revealed the
formation of a new product, which, after purification by
flash column chromatography, was identified as the [13]-
membered ring derivative 60, obtained in 50% yield with
recovered starting compound 59 in a 48% yield. Attempts
to improve the degree of conversion by employing differ-
ent bases or reaction conditions were unsuccessful. On
the other hand, we tried to promote the translactoniza-
adequate to reach the [15]-membered ring stevastelins,
after failure with our attempt to reach this kind of cyclic
depsipeptides through the 2,3-epoxy analogue 8. In the
case of stevastelin B3 (2), a new synthesis was estab-
lished via a translactonization process from the corre-
sponding [15]-membered stevastelins. This new conver-
gent approach to the [13]-membered ring components
represents a highly convergent route for this family of
stevastelins from their corresponding [15]-membered ring
counterparts and provides a new direction in the design
of new potentially bioactive analogues,41 especially taking
into account that the [13]-membered stevastelins possess
greater potency than the [15]-membered congeners.
38
tion reaction by use of acidic conditions (Ti(Oi-Pr)4 or
Otera’s catalyst39), but again, the results were unsuc-
cessful with the recovery of starting [15]-membered
lactone. Finally, as shown in Scheme 7, compound 60 was
converted to stevastelin B3 (2) through the sequential
steps involving debenzylation of 60, acetylation of the
resulting alcohol 61, and final desilylation of 62 to
provide stevastelin B3 (2), whose physical and spectro-
scopic properties were identical to those reported in the
literature.40
Experimental Section
Compound 12. To a solution of oxazolidinone 10 (2.74 g,
14.8 mmol, 1.0 equiv) in anhydrous CH2Cl2 (55 mL) was added
a freshly distilled solution of di-n-butylboron triflate (0.93 M
in CH2Cl2, 17.5 mL, 16.3 mmol, 1.1 equiv) and anhydrous TEA
(2.3 mL, 16.3 mmol, 1.1 equiv) at 0 °C. After 30 min at this
temperature, the solution was cooled to -78 °C, and then, a
solution of tetradecanal 1142 (3.5 g, 16.3 mmol, 1.1 equiv) in
anhydrous CH2Cl2 (55 mL) was added dropwise. After 12 h at
-78 °C, methanol (30 mL) and 30% H2O2 (20 mL) were
sequentially added, and the resulting mixture was allowed to
warm to ambient temperature. The solvents were removed by
concentration under vacuum, and the crude mixture was
diluted with diethyl ether, methanol, and a small amount of
water to obtain a homogeneous solution which was left at
ambient temperature for 2 h. The resulting mixture was
diluted with CH2Cl2 and washed with water, and after separa-
tion of the phases, the aqueous phase was extracted with CH2-
Conclusions
In conclusion, we have described the synthesis of the
natural products stevastelin B (5) and stevastelin B3 (2).
In the first case, we have demonstrated that the route
designed by the Chida group proved to be the most
(38) Seebach, D.; Hungerbu¨hler, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zu¨ger, M. Synthesis 1982, 138-141.
(39) (a) Otera, J.; Ioka, S.; Nozaki, H. J. Org. Chem. 1989, 54, 4013-
4014. (b) Trost, B. M.; Papillon, J. P. N. J. Am. Chem. Soc. 2004, 126,
13618-13619.
(40) Synthetic stevastelins B3 (2) and B (5) exhibited identical
properties (TLC, [R]D, 1H and 13C NMR, and HRMS) with those
reported for the natural compounds, matching 1H and 13C NMR spectra
by direct comparison with spectra of natural substances: Morino, T.;
Nishimoto, M.; Nishide, M. U.; Masuda, A.; Yamada, M.; Kawano, E.;
Nishikiori, T.; Saito, S. EP0525361, 1993.
(41) See the following paper in this series: Sarabia, F.; Chammaa,
S.; Garc´ıa-Castro, M. J. Org. Chem. 2005, 70, 7858-7865.
(42) Tetradecanal 11 was prepared from commercially available
1-tetradecanol by oxidation according to the SO3‚pyr method: Parikh,
J. R.; Von Doering, W. E. J. Am. Chem. Soc. 1967, 89, 5505-5507.
J. Org. Chem, Vol. 70, No. 20, 2005 7851

Sarabia and Chammaa
Cl2. The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The crude product was purified by flash column
chromatography (silica gel, 15% EtOAc in hexanes) to obtain
12 (5.0 g, 85%) as a pale yellow liquid: Rf ) 0.62 (silica gel,
30% EtOAc in hexanes). [R]25D ) +51.1° (c ) 1.4, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ ) 0.85 (t, J ) 7.0 Hz, 3 H, CH3-
CH2), 0.86 (d, J ) 7.0 Hz, 3 H, CH(CH3)2), 0.90 (d, J ) 7.0 Hz,
3 H, CH(CH3)2), 1.32-1.21 (m, 27 H, 12 × CH2, CH(CH3)), 2.33
(dsept, J ) 7.0, 4.1 Hz, 1 H, CH(CH3)2), 2.98 (d, J ) 2.3 Hz, 1
H, OH), 3.74 (dq, J ) 7.0, 2.3 Hz, 1 H, CH(CH3)), 3.94-3.88
(m, 1 H, CH(OH)), 4.20 (dd, J ) 9.4, 3.5 Hz, 1 H, CH2OC-
(dO)), 4.27 (dd, J ) 9.4, 8.2 Hz, 1 H, CH2OC(dO)), 4.45 (ddd,
J ) 8.2, 7.0, 3.5 Hz, 1 H, CHN). 13C NMR (100 MHz, CDCl3):
δ ) 10.6, 14.0, 14.6, 17.8, 22.6, 25.9, 28.2, 29.2, 29.47, 29.49,
29.50, 29.55, 29.58, 31.8, 33.7, 41.9, 58.1, 63.2, 71.1, 153.4,
177.8. FAB HRMS (NBA): m/e 398.3272, M + H+; calcd for
C23H43NO4 398.3270.
by flash column chromatography (silica gel, 3% EtOAc in
hexanes) to afford silyl ether 15 (1.08 g, 96%) as a colorless
oil: Rf ) 0.40 (silica gel, 3% EtOAc in hexanes). [R]25D ) -12.7°
(c ) 0.64, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ ) 0.01 (s, 3
H, CH3Si), 0.02 (s, 3 H, CH3Si), 0.84 (d, J ) 7.0 Hz, 3 H, CH-
(CH3)), 0.84-0.88 (m, 12 H, SiC(CH3)3, CH3CH2), 1.18 (s, 9 H,
C(CH3)3), 1.20-1.30 (m, 22 H, 11 × CH2), 1.34-1.53 (m, 2 H,
CH2CH(OTBS)), 1.87 (dddq, J ) 7.0, 2.9 Hz, 1 H, CH(CH3)),
3.69 (ddd, J ) 7.0, 5.9, 2.9 Hz, 1 H, CH(OTBS)), 3.92 (dd, J )
10.6, 7.6 Hz, 1 H, CH2OCOC(CH3)3), 3.96 (dd, J ) 10.6, 6.5
Hz, 1 H, CH2OCOC(CH3)3). 13C NMR (100 MHz, CDCl3): δ )
-4.7, -4.1, 10.3, 14.1, 18.1, 22.7, 25.7, 25.9, 27.2, 29.4, 29.59,
29.63, 29.66, 29.71, 31.9, 34.3, 36.7, 38.8, 66.6, 71.9, 178.5.
Alcohol 16. A solution of the pivaloyl ester 15 (1.03 g, 2.19
mmol, 1.0 equiv) in CH2Cl2 (20 mL) was cooled to -78 °C and
subjected to the action of DIBAL-H (1 M in CH2Cl2, 4.8 mL,
4.8 mmol, 2.2 equiv). After stirring for 30 min at -78 °C, the
resulting mixture was diluted with ethyl acetate at the same
temperature and allowed to warm to 25 °C. Then, a saturated
aqueous Na/K tartrate solution was added, and the mixture
was vigorously stirred for 30 min. After this time, the phases
were separated, the aqueous phase was extracted with ethyl
acetate, and the final organic layer was sequentially washed
with saturated aqueous Na/K tartrate solution, water, and
brine. After treatment with MgSO4, the organic solution was
filtered and concentrated under reduced pressure, and the
crude product was purified by flash column chromatography
(silica gel, 5% EtOAc in hexanes) to obtain alcohol 16 (762 mg,
98%) as a colorless oil: Rf ) 0.44 (silica gel, 10% EtOAc in
hexanes). [R]25D ) +1.2° (c ) 0.6, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ ) 0.05 (s, 3 H, CH3Si), 0.07 (s, 3 H, CH3Si), 0.78 (d,
J ) 7.0 Hz, 3 H, CH(CH3)), 0.86 (t, J ) 7.0 Hz, 3 H, CH3CH2),
0.87 (s, 9 H, (CH3)3CSi), 1.21-1.31 (m, 22 H, 11 × CH2), 1.38-
1.48 (m, 2 H, CH2CH(OTBS)), 1.89-1.99 (m, 1 H, CH(CH3)),
2.66 (dd, J ) 6.5, 3.5 Hz, 1 H, CH2OH), 3.50 (ddd, J ) 11.2,
6.5, 5.9 Hz, 1 H, CH2OH), 3.64-3.75 (m, 2 H, CH2OH,
CH(OTBS)). 13C NMR (100 MHz, CDCl3): δ ) -4.5, -4.4, 12.0,
14.1, 22.7, 25.8, 26.3, 29.4, 29.59, 29.63, 29.67, 29.8, 31.9, 32.2,
39.5, 66.1, 76.0. FAB HRMS (NBA): m/e 387.3655, M + H+;
calcd for C23H50O2Si 387.3658.
Aldehyde 17. To a solution of oxalyl chloride (0.46 mL, 5.18
mmol, 2.0 equiv) in CH2Cl2 (15 mL) was added dropwise
DMSO (0.75 mL, 10.36 mmol, 4.0 equiv) at -78 °C. After the
mixture was stirred for 15 min, a solution of alcohol 16 (1.0 g,
2.59 mmol, 1.0 equiv) in CH2Cl2 (15 mL) was added dropwise
at -78 °C over a 10 min period. The solution was stirred for
a further 30 min at -78 °C, and TEA (2.5 mL, 15.54 mmol,
6.0 equiv) was added at the same temperature. The reaction
mixture was allowed to warm to 0 °C over 30 min, and then
diethyl ether was added, followed by saturated aqueous NH4-
Cl solution. The organic phase was separated, and the aqueous
phase was extracted with diethyl ether. The combined organic
solution was sequentially washed with water and brine, dried
(MgSO4), filtered, and concentrated under reduced pressure.
Purification by flash column chromatography (silica gel, 2%
EtOAc in hexanes) provided aldehyde 17 (952 mg, 94%) as a
colorless oil: Rf ) 0.69 (silica gel, 40% CH2Cl2 in hexanes).
[R]25D ) +40.4° (c ) 1.2, CH2Cl2). 1H NMR (400 MHz, CDCl3):
δ ) 0.01 (s, 3 H, CH3Si), 0.04 (s, 3 H, CH3Si), 0.84 (s, 9 H,
(CH3)3CSi), 0.86 (t, J ) 7.0 Hz, 3 H, CH3CH2), 1.03 (d, J ) 7.0
Hz, 3 H, CH(CH3)), 1.20-1.31 (m, 22 H, 11 × CH2), 1.38-1.52
(m, 2 H, CH2CH(OTBS)), 2.42 (ddq, J ) 7.0, 3.5, 1.2 Hz, 1 H,
CH(CH3)CHO), 4.07 (dt, J ) 6.5, 3.5 Hz, 1 H, CH(OTBS)), 9.75
(d, J ) 1.2 Hz, 1 H, CHO). 13C NMR (100 MHz, CDCl3): δ )
-4.7, -4.2, 7.6, 14.1, 18.0, 22.7, 25.72, 29.3, 29.54, 29.59, 29.61,
29.63, 29.66, 31.9, 34.5, 51.2, 72.1, 205.6.
Diol 13. To a solution of the aldol product 12 (3.64 g, 9.17
mmol, 1.0 equiv) in THF (42 mL) at -20 °C was added LiBH4
(2 M in THF, 10.1 mL, 20.17 mmol, 8.8 equiv). The reaction
mixture was allowed to warm to 0 °C and, after 2 h, was
carefully treated with water and saturated aqueous NH4Cl
solution. The organic phase was separated, the aqueous layer
was extracted with CH2Cl2, and the combined organic phase
was washed with water and brine, dried (MgSO4), and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (silica gel, 35%
EtOAc in hexanes) to obtain 13 (2.29 g, 92%) as a white solid:
Rf ) 0.27 (silica gel, 30% EtOAc in hexanes). [R]25 ) +14.3°
D
1
(c ) 0.8, CH2Cl2). H NMR (400 MHz, CDCl3): δ ) 0.86 (t, J
) 7.0 Hz, 3 H, CH3CH2), 0.90 (d, J ) 7.0 Hz, 3 H, CH(CH3)),
1.22-1.32 (m, 22 H, 11 × CH2), 1.37-1.51 (m, 2 H, CH2CH-
(OH)), 1.70-1.85 (m, 1 H, CH(CH3)), 3.70 (d, J ) 4.7 Hz, 2 H,
CH2OH), 3.78-3.83 (m, 1 H, CH(OH)). 13C NMR (100 MHz,
CDCl3): δ ) 10.0, 14.1, 22.7, 26.2, 29.3, 29.59, 29.61, 29.65,
31.9, 34.1, 39.0, 67.2, 74.6. FAB HRMS (NBA): m/e 295.2612,
M + Na+; calcd for C17H36O2 295.2613.
Pivaloyl Ester 14. To a solution of the diol 13 (1.55 g, 5.69
mmol, 1.0 equiv) in pyridine (8.0 mL) and CH2Cl2 (4.0 mL) at
-20 °C was added pivaloyl chloride (0.9 mL, 7.30 mmol, 1.3
equiv). After 30 min at this temperature, 0.2 mL more of
pivaloyl chloride was added to complete the reaction. After
additional 10 min, the reaction mixture was diluted with CH2-
Cl2 and treated with saturated aqueous NaHCO3 solution. The
organic phase was separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic layers were
washed with brine, separated, dried (MgSO4), and concen-
trated under vacuum. The crude product was purified by flash
column chromatography (silica gel, 10% EtOAc in hexanes)
to obtain monopivaloyl ester 14 (1.91 g, 94%) as a colorless
oil: Rf ) 0.35 (silica gel, 10% EtOAc in hexanes). [R]25D ) +7.5°
1
(c ) 1.3, CH2Cl2). H NMR (400 MHz, CDCl3): δ ) 0.86 (t, J
) 7.0 Hz, 3 H, CH3CH2), 0.89 (d, J ) 7.0 Hz, 3 H, CH(CH3)),
1.19 (s, 9 H, C(CH3)3), 1.32-1.21 (m, 22 H, 11 × CH2), 1.35-
1.46 (m, 1 H, CH2CH(OH)), 1.53-1.36 (m, 2 H, CH2CH(OH)),
1.89-1.80 (m, 1 H, CH(CH3)), 3.55-3.61 (m, 1 H, CH(OH)),
3.91 (dd, J ) 11.2, 5.9 Hz, 1 H, CH2OCOC(CH3)3), 4.18 (dd, J
) 11.2, 7.6 Hz, 1 H, CH2OCOC(CH3)3). 13C NMR (100 MHz,
CDCl3): δ ) 10.0, 14.1, 22.6, 26.2, 27.2, 29.3, 29.57, 29.62, 31.9,
34.3, 37.7, 38.8, 66.8, 71.4, 178.9. FAB HRMS (NBA): m/e
357.3372, M + H+; calcd for C22H44O3 357.3369.
Silyl Ether 15. A solution of the pivaloyl ester 14 (866 mg,
2.29 mmol, 1.0 equiv) in DMF (5 mL) was treated with
imidazole (313 mg, 4.6 mmol, 2.0 equiv) and tert-butyldi-
methylsilyl chloride (544 mg, 3.5 mmol, 1.5 equiv) at 0 °C.
After 24 h, the reaction mixture was treated with methanol
(1.0 mL), diluted with diethyl ether, and washed with satu-
rated aqueous NH4Cl solution. After decantation, the aqueous
phase was extracted with diethyl ether, and the combined
organic solution was washed with water and brine, dried
(MgSO4), and concentrated. The resulting crude was purified
r,â-Unsaturated Ester 18. Aldehyde 17 (713 mg, 1.86
mmol, 1.0 equiv) was dissolved in benzene (12 mL), and
(carbomethoxymetilen)triphenylphosphorane (1.24 g, 3.72 mmol,
2.0 equiv) was added at room temperature. The reaction
mixture was heated at reflux until the reaction was complete
as judged by TLC (ca. 12 h). The solvents were removed by
7852 J. Org. Chem., Vol. 70, No. 20, 2005

Total Synthesis of Stevastelins B and B3
concentration under reduced pressure, and the resulting crude
product was purified by flash column chromatography (silica
gel, 30% CH2Cl2 in hexanes) to obtain the R,â-unsaturated
ester 18 (740 mg, 92%) as a colorless oil: Rf ) 0.58 (silica gel,
equiv) at 0 °C. After vigorous stirring for 30 min, a saturated
aqueous NaHSO3 solution was added, and after decantation,
the aqueous phase was extracted with EtOAc. The combined
organic extracts were dried (MgSO4), filtered, and concentrated
under reduced pressure. The obtained crude product was
purified by flash column chromatography (silica gel, 25%
EtOAc and 5% MeOH in hexanes) to obtain epoxy acid 9 (692
mg, 64%) as colorless liquid: Rf ) 0.27 (silica gel, 20% EtOAc
10% EtOAc in hexanes). [R]25 ) +31.0° (c ) 1.02, CH2Cl2).
D
1H NMR (400 MHz, CDCl3): δ ) 0.01 (s, 3 H, CH3Si), 0.02 (s,
3 H, CH3Si), 0.86 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.87 (s, 9 H,
(CH3)3CSi), 0.99 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 1.19-1.41 (m,
24 H, 12 × CH2), 2.38-2.48 (m, 1 H, CH(CH3)), 3.55-3.61 (m,
1 H, CH(OTBS)), 3.71 (s, 3 H, CH3O), 5.78 (dd, J ) 15.8, 1.2
Hz, 1 H, CHdCHCO2CH3), 7.00 (dd, J ) 15.8, 7.0 Hz, 1 H,
CHdCHCO2CH3). 13C NMR (100 MHz, CDCl3): δ ) -4.5,
-4.4, 14.0, 14.1, 18.1, 22.7, 25.3, 25.9, 29.4, 29.58, 29.62, 29.64,
29.67, 29.74, 31.9, 34.0, 41.7, 51.4, 75.2, 120.2, 152.5, 167.2.
1
and 10% methanol in hexanes). H NMR (400 MHz, CDCl3):
δ ) -0.02 (s, 3 H, CH3Si), 0.03 (s, 3 H, CH3Si), 0.81-0.88 (m,
12 H, (CH3)3CSi, CH3CH2), 0.97 (d, J ) 7.0 Hz, 3 H, CH(CH3)),
1.12-1.31 (m, 22 H, 11 × CH2), 1.37-1.58 (m, 2 H, CH2CH-
(OTBS)), 2.33-2.45 (m, 1H, CH(CH3)), 3.20 (dd, J ) 7.0, 1.8
Hz, 1 H, CH(O)CH), 3.31 (d, J ) 1.8 Hz, 1 H, CH(O)CO2H),
3.66 (dt, J ) 6.5, 3.5 Hz, 1 H, CH(OTBS)). 13C NMR (100 MHz,
CDCl3): δ ) -4.7, -4.3, 11.0, 14.1, 25.8, 29.3, 29.55, 29.63,
29.65, 29.69, 40.6, 52.1, 61.5, 74.0, 174.6. FAB HRMS (NBA):
m/e 443.3536, M+H+; calcd for C25H50O4Si 443.3557.
Allylic Alcohol 19. To a solution of ester 18 (1.07 g, 2.44
mmol, 1.0 equiv) in CH2Cl2 (30 mL) was added DIBAL-H (1
M in CH2Cl2, 5.4 mL, 5.4 mmol, 2.2 equiv) at -78 °C. After 30
min at this temperature, EtOAc was added, and the reaction
mixture was allowed to warm to ambient temperature. Then,
saturated aqueous Na/K tartrate solution was added, and the
resulting mixture was vigorously stirred for 30 min at ambient
temperature. The organic phase was separated, the aqueous
layer was extracted with ethyl acetate, and the combined
organic solution was washed with water and brine. After
drying with MgSO4, the solvents were evaporated, and the
crude product was purified by flash column chromatography
(silica gel, 8% EtOAc in hexanes) to obtain the allylic alcohol
19 (923 mg, 98%) as a colorless oil: Rf ) 0.27 (silica gel, 10%
EtOAc in hexanes). [R]25D ) +22.7° (c ) 0.5, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ ) 0.00 (s, 3 H, CH3Si), 0.01 (s, 3 H, CH3-
Si), 0.86 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.87 (s, 9 H, (CH3)3-
CSi), 0.94 (d, J ) 6.5 Hz, 3 H, CH(CH3)), 1.17-1.42 (m, 24 H,
12 × CH2), 2.24-2.34 (m, 1 H, CH(CH3)), 3.47-3.52 (m, 1 H,
CH(OTBS)), 4.09 (dd, J ) 5.9, 5.3 Hz, 2 H, CH2OH), 5.59 (ddt,
J ) 15.8, 5.9, 1.2 Hz, 1 H, CHdCHCH2OH), 5.70 (ddt, J )
15.8, 7.0, 1.2 Hz, 1 H, CHdCHCH2OH). 13C NMR (100 MHz,
CDCl3): δ ) -4.4, -4.3, 14.1, 15.0, 18.2, 22.7, 25.3, 25.9, 29.4,
29.61, 29.64, 29.68, 29.8, 31.9, 33.7, 41.3, 64.1, 75.9, 128.3,
136.1. FAB HRMS (NBA): m/e 435.3627, M + Na+; calcd for
C25H52O3Si 435.3634.
Epoxy Peptide 30. A solution of epoxy acid 9 (676 mg, 1.53
mmol, 1.0 equiv) in CH2Cl2 (9.0 mL) was treated with HOBt
(240 mg, 1.68 mmol, 1.1 equiv) and EDCI (419 mg, 2.14 mmol,
1.4 equiv) at 25 °C. After stirring for 10 min, a solution of
dipeptide 24 (642 mg, 1.84 mmol, 1.2 equiv) in CH2Cl2 (10 mL)
was added. After 1 h at room temperature, the depletion of
starting epoxyacid was detected by TLC, and a 30% aqueous
NH3 solution was added, before addition of a saturated
aqueous NH4Cl solution. After decantation of both phases, the
aqueous layer was extracted with CH2Cl2, and the resulting
organic solution was washed with water and brine, dried
(MgSO4), filtered, and concentrated under reduced pressure.
The obtained crude product was purified by flash column
chromatography (silica gel, 20% EtOAc in hexanes) to afford
epoxy peptide 30 (817 mg, 70%) as a white solid: Rf ) 0.45
(silica gel, 20% EtOAc in hexanes). [R]25 ) +10.4° (c ) 0.23,
D
CH2Cl2). 1H NMR (400 MHz, CDCl3) δ: -0.02 (s, 3 H, CH3Si),
0.03 (s, 3 H, CH3Si), 0.83-0.96 (m, 21 H, (CH3)3CSi, CH3CH2,
CH(CH3), CH(CH3)2), 1.20 (d, J ) 6.4 Hz, 3 H, (CH3)CH(OBn)),
1.20-1.29 (m, 22 H, 11 × CH2), 1.39-1.47 (m, 2 H, CH2CH-
(OTBS)), 1.51-1.59 (m, 1 H, CH(CH3)), 2.03-2.13 (m, 1 H,
CH(CH3)2), 3.03 (dd, J ) 5.9, 2.1 Hz, 1 H, CH(O)CH), 3.24 (d,
J ) 2.1 Hz, 1 H, CH(O)CON), 3.72 (dt, J ) 6.4, 3.2 Hz, 1 H,
CH(OTBS)), 4.17 (dq, J ) 6.4, 2.1 Hz, 1 H, (CH3)CH(OBn)),
4.25 (dd, J ) 9.1, 6.4 Hz, 1 H, CHNH-Val), 4.35 (d, J ) 11.8
Hz, 1 H, CH2Ph), 4.47-4.60 (m, 3 H, CH2Ph, CO2CH2CHd
CH2), 4.62 (dd, J ) 9.1, 2.1 Hz, 1 H, CHNH-Thr), 5.17-5.29
(m, 2 H, CO2CH2CHdCH2), 5.74-5.85 (m, 1 H, CO2CH2CHd
CH2), 6.34 (d, J ) 8.6 Hz, 1 H, NH), 6.70 (d, J ) 8.6 Hz, 1 H,
NH), 7.20-7.34 (m, 5 H, Ph). 13C NMR (100 MHz, CDCl3) δ:
-4.7, -4.2, 9.9, 14.1, 16.2, 18.0, 19.1, 22.7, 25.8, 29.3, 29.56,
29.59, 29.63, 29.66, 29.7, 31.3, 31.9, 34.0, 40.2, 54.3, 56.8, 57.6,
62.1, 66.1, 70.8, 73.84, 73.85, 119.1, 127.8, 128.4, 131.5, 137.7,
168.7, 169.9, 170.9. FAB HRMS (NBA): m/e 795.5341, M+Na+;
calcd for C44H76N2O7Si 795.5320.
Epoxy Alcohol 20. To a cooled suspension of 4 Å molecular
sieves (1.4 g) in CH2Cl2 (48 mL) was sequentially added at
-20 °C, titanium tetraisopropoxide (0.73 mL, 2.41 mmol, 0.4
equiv), d-(-)-DET (0.42 mL, 2.41 mmol, 0.4 equiv), and a
solution of the allylic alcohol 19 (2.48 g, 6.03 mmol, 1.0 equiv)
in CH2Cl2 (50 mL). After 30 min at this temperature, TBHP
(5.5 M in decane, 3.0 mL, 21.5 mmol, 3.6 equiv) was added.
The reaction mixture was stirred at -20 °C, and after 24 h,
the reaction was quenched by addition of dimethyl sulfide (2.1
mL) at 0 °C. After 30 min, the crude mixture was filtered, the
solvents were evaporated, and the resulting crude product was
purified by flash column chromatography (silica gel, 15%
EtOAc in hexanes) to afford epoxy alcohol 20 together with
its â-epoxide epimer (2.41 g, 91% total yield) as an inseparable
Epoxy Peptide 31. To a solution of silyl ether 30 (817 mg,
1.06 mmol, 1.0 equiv) in THF (15.0 mL) was added HF‚
pyridine (4 mL, 70% w/v) at 25 °C. After stirring for 12 h at
25 °C, a saturated aqueous NaHCO3 solution was added until
release of CO2 ceased. The resulting crude mixture was
extracted with CH2Cl2, and the organic phase was washed with
water and brine. After separation of both phases, the organic
solution was dried (MgSO4), filtered, and concentrated under
reduced pressure. The obtained crude product corresponded
to epoxy peptide 31 (660 mg, 95%), which was used in the next
step without further purification: Rf ) 0.53 (silica gel, 50%
EtOAc in hexanes). [R]25D ) +3.8° (c ) 0.95, CH2Cl2). 1H NMR
(400 MHz, CDCl3) δ: 0.85 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.90
(d, J ) 6.4 Hz, 3 H, CH(CH3)2), 0.94 (d, J ) 6.4 Hz, 3 H, CH-
(CH3)2), 0.98 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 1.19 (d, J ) 6.4
Hz, 3 H, (CH3)CH(OBn)), 1.20-1.30 (m, 22 H, 11 × CH2),
1.40-1.48 (m, 2 H, CH2CH(OH)), 1.51-1.60 (m, 1 H, CH(CH3)),
1.84 (bs, 1 H, CH(OH)), 2.05-2.15 (m, 1 H, CH(CH3)2), 3.00
(dd, J ) 6.4, 2.1 Hz, 1 H, CH(O)CH), 3.31 (d, J ) 2.1 Hz, 1 H,
1
mixture in an approximately 92:8 proportion by H NMR (de
1
85%): Rf ) 0.47 (silica gel, 20% EtOAc in hexanes). H NMR
(400 MHz, CDCl3): δ ) 0.00 (s, 3 H, CH3Si), 0.03 (s, 3 H, CH3-
Si), 0.86 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.87 (s, 9 H, (CH3)3-
CSi), 0.97 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 1.15-1.31 (m, 23 H,
11 × CH2, CH2CH(OTBS)), 1.37-1.53 (m, 2 H, CH(CH3), CH2-
CH(OTBS)), 2.92 (dd, J ) 7.6, 2.3 Hz, 1 H, CH(O)CHCH2OH),
2.98 (ddt, J ) 4.7, 2.3 Hz, 1 H, CH(O)CHCH2OH), 3.57 (dd, J
) 12.6, 4.7 Hz, 1 H, CH2OH), 3.59-3.64 (m, 1 H, CH(OTBS)),
3.91 (dd, J ) 12.3, 2.3 Hz, 1 H, CH2OH). 13C NMR (100 MHz,
CDCl3): δ ) -4.6, -4.3, 11.7, 14.1, 18.0, 22.6, 25.7, 25.8, 29.3,
29.55, 29.56, 29.60, 29.64, 29.7, 31.9, 33.9, 40.7, 58.2, 58.5, 61.8,
74.4. FAB HRMS (NBA): m/e 451.3599, M + Na+; calcd for
C25H52O3Si 451.3583.
Epoxy Acid 9. A solution of epoxy alcohol 20 (1.08 g, 2.45
mmol, 1.0 equiv) in a system formed by CCl4 (12 mL), CH3CN
(12 mL), and H2O (12 mL) was treated with NaIO4 (2.22 g,
10.36 mmol, 4.2 equiv) and RuCl3 (5 mg, 0.0245 mmol, 0.01
J. Org. Chem, Vol. 70, No. 20, 2005 7853

Sarabia and Chammaa
CH(O)CON), 3.68-3.74 (m, 1 H, CH(OH)), 4.16 (dq, J ) 6.4,
2.1 Hz, 1 H, (CH3)CH(OBn)), 4.25 (dd, J ) 9.1, 6.4 Hz, 1 H,
CHNH-Val), 4.34 (d, J ) 11.8 Hz, 1 H, CH2Ph), 4.46-4.60
(m, 3 H, CH2Ph, CO2CH2CHdCH2), 4.62 (dd, J ) 9.1, 2.1 Hz,
1 H, CHNH-Thr), 5.17-5.29 (m, 2 H, CO2CH2CHdCH2),
5.74-5.84 (m, 1 H, CO2CH2CHdCH2), 6.46 (d, J ) 9.1 Hz, 1
H, NH(Thr)), 6.73 (d, J ) 8.6 Hz, 1 H, NH(Val)), 7.20-7.33
(m, 5 H, Ph). 13C NMR (100 MHz, CDCl3) δ: 9.9, 14.1, 16.2,
18.0, 19.1, 22.7, 26.0, 29.3, 29.52, 29.56, 29.58, 29.62, 29.64,
31.3, 31.9, 34.6, 40.5, 54.5, 56.8, 57.8, 62.2, 66.1, 70.8, 73.0,
73.8, 119.1, 127.8, 128.4, 131.4, 137.6, 168.7, 169.9, 170.9. FAB
HRMS (NBA): m/e 659.4621, M+H+; calcd for C38H62N2O7
659.4635.
MHz, CDCl3) δ: 12.8, 14.5, 16.8, 18.8, 19.8, 23.8, 27.0, 28.8,
30.4, 30.5, 30.7, 30.77, 30.81, 30.85, 31.1, 32.2, 33.1, 40.5, 55.5,
55.8, 58.1, 59.6, 60.7, 71.0, 72.3, 74.4, 76.0, 78.2, 80.9, 128.7,
128.9, 129.0, 129.3, 129.5, 139.1, 139.7, 158.2, 170.6, 172.4,
173.3, 173.7. FAB HRMS (NBA): m/e 918.5470, M + Na+;
calcd for C50H77N3O11 918.5456.
Epoxy Peptide 34. To a solution of epoxy peptide 33 (705
mg, 0.787 mmol) in anhydrous CH2Cl2 (20.0 mL) was added
TFA (14 mL) at 0 °C. The reaction mixture was stirred for 1
h at that temperature, and after that time, the solvents were
evaporated under reduced pressure and the crude product
diluted with toluene (20.0 mL) and concentrated again, repeat-
ing this operation twice. The resulting ammonium trifluoro-
acetate salt of 34 (727 mg, 100%) was used for the macro-
cyclization step without any purification.
Epoxy Cyclodepsipeptide 8. Macrolactamizations of
Acyclic Epoxy amino Acids 34, 41, and 48. A solution of
the trifluroacetate salt of amines 34, 41, or 48 (872 mg, 0.958
mmol, 1.0 equiv) in DMF (400 mL, 2.4 mM) was treated with
DEPC (0.32 mL, 1.92 mmol, 2.0 equiv) at 25 °C, and, after 30
min, with DIPEA (0.34 mL, 1.92 mmol, 2.0 equiv). The reaction
mixture was allowed to react at this temperature for 16 h, after
which DMF was removed by distillation under vacuum (0.5
mm of Hg) at 50 °C. The resulting crude product was purified
by flash column chromatography (silica gel, 3% MeOH and
27% EtOAc in hexanes) to obtain the macrocyclic epoxy peptide
8 (332 mg, 45%) as a white solid: Rf ) 0.54 (silica gel, 30%
EtOAc and 10% MeOH in hexanes). 1H NMR (400 MHz,
CDCl3) δ: 0.86 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.95 (d, J ) 6.5
Hz, 3 H, CH(CH3)2), 0.97 (d, J ) 6.5 Hz, 3 H, CH(CH3)2), 1.10
(d, J ) 7.0 Hz, 3 H, CH(CH3)), 1.14-1.30 (m, 25 H, 11 × CH2,
(CH3)CH(OBn)), 1.40-1.67 (m, 3 H, CH2CHOC(dO), CH(CH3)),
2.64-2.76 (m, 1 H, CH(CH3)2), 2.97 (dd, J ) 8.2, 2.4 Hz, 1 H,
CH(O)CH), 3.14 (d, J ) 2.4 Hz, 1 H, CH(O)CON), 3.30 (dd, J
) 11.2, 7.6 Hz, 1 H, CHNH-Val), 3.54 (dd, J ) 9.4, 6.5 Hz, 1
H, CH2OBn), 3.69 (dd, J ) 9.4, 5.3 Hz, 1 H, CH2OBn), 4.11
(dq, J ) 6.5, 3.5 Hz, 1 H, (CH3)CH(OBn)), 4.40 (s, 2 H, CH2-
Ph), 4.45 (d, J ) 11.7 Hz, 1 H, CH2Ph), 4.46-4.60 (m, 2 H),
4.60 (d, J ) 11.7 Hz, 1 H, CH2Ph), 5.22-5.29 (m, 1 H, CHOC-
(dO)), 6.57 (d, J ) 7.0 Hz, 1 H, CHNH(Val)), 7.20-7.32 (m,
11 H, 2 × Ph, CHNH), 7.43 (d, J ) 9.4 Hz, 1 H, CHNH(Ser)).
13C NMR (100 MHz, CDCl3) δ: 11.7, 14.1, 16.2, 19.6, 19.7, 22.7,
25.4, 27.4, 29.3, 29.34, 29.4, 29.56, 29.61, 29.63, 29.65, 29.68,
30.4, 31.9, 39.3, 53.5, 54.8, 57.7, 61.7, 66.5, 69.1, 71.0, 73.3,
73.9, 75.7, 127.6, 127.7, 127.8, 128.4, 128.5, 137.5, 137.6, 170.2,
170.25, 170.3, 172.0. FAB HRMS (NBA): m/e 800.4832,
M+Na+; calcd for C45H67N3O8 800.4826.
Epoxy Peptide 32. A solution of Boc-Ser(Bn)-H (436 mg,
1.48 mmol, 1.5 equiv) in THF (13 mL) was treated with
anhydrous TEA (0.41 mL, 2.96 mmol, 3.0 equiv) and 2,4,6-
trichlorobenzoyl chloride (0.35 mL, 2.22 mmol, 2.3 equiv) at 0
°C. After stirring for 2 h at this temperature, the resulting
crude mixture was added dropwise over a solution of epoxy
peptide 31 (648 mg, 0.98 mmol, 1.0 equiv) and 4-DMAP (157
mg, 1.27 mmol, 1.3 equiv) in toluene (20 mL) via cannula. The
reaction mixture was allowed to warm to ambient temperature
and stirred for 15 min, prior to the addition of a saturated
aqueous NH4Cl solution and CH2Cl2. After separation of both
phases, the aqueous layer was extracted with CH2Cl2, and the
combined organic solution was washed with water and brine
and then dried (MgSO4), filtered, and concentrated under
reduced pressure. Purification by flash column chromatogra-
phy (silica gel, 25% EtOAc in hexanes) of the resulting crude
product provided ester 32 (785 mg, 86%) as a colorless oil: Rf
) 0.42 (silica gel, 30% EtOAc in hexanes). 1H NMR (400 MHz,
CDCl3) δ: 0.86 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.92 (d, J ) 6.5
Hz, 3 H, CH(CH3)), 0.95 (d, J ) 7.0 Hz, 3 H, CH(CH3)2), 1.15-
1.27 (m, 28 H, 11 × CH2, CH(CH3)2, (CH3)CH(OBn)), 1.42 (s,
9 H, C(CH3)3), 1.52-1.69 (m, 3 H, CH2CHOC(dO), CH(CH3)),
2.03-2.13 (m, 1 H, CH(CH3)2), 2.87 (dd, J ) 7.6, 1.8 Hz, 1 H,
CH(O)CH), 3.28 (d, J ) 1.8 Hz, 1 H, CH(O)CON), 3.67 (dd, J
) 9.4, 3.5 Hz, 1 H, CH2OBn), 3.87 (dd, J ) 9.4, 2.9 Hz, 1 H,
CH2OBn), 4.16 (dq, J ) 6.5, 2.5 Hz, 1 H, (CH3)CH(OBn)), 4.27
(dd, J ) 8.8, 7.0 Hz, 1 H, CHNH-Val), 4.34 (d, J ) 11.7 Hz,
1 H, CH2Ph), 4.45-4.6 (m, 6 H), 4.62 (dd, J ) 9.4, 2.4 Hz, 1
H, CHNH-Thr), 4.84-4.91 (m, 1 H, CHOC(dO)), 5.17-5.29
(m, 2 H, CO2CH2CHdCH2), 5.69 (d, J ) 9.4 Hz, 1 H, NHBoc),
5.74-5.85 (m, 1 H, CO2CH2CHdCH2), 6.41 (d, J ) 8.8 Hz, 1
H, NH), 7.20-7.34 (m, 11 H, 2 × Ph, NH). 13C NMR (100 MHz,
CDCl3) δ: 12.5, 14.1, 16.1, 18.1, 19.2, 21.0, 22.7, 25.7, 28.3,
29.29, 29.33, 29.5, 29.62, 29.63, 29.66, 31.1, 31.9, 38.8, 54.2,
54.8, 56.7, 58.1, 59.7, 60.4, 66.1, 70.1, 70.7, 73.4, 73.8, 80.0,
119.0, 127.6, 127.8, 128.36, 128.37, 131.4, 137.3, 137.6, 156.1,
168.2, 169.9, 170.5, 171.1. FAB HRMS (NBA): m/e 958.5753,
M+Na+; calcd for C53H81N3O11 958.5769.
Epoxy Peptide 33. To a solution of allyl ester 32 (785 mg,
0.839 mmol, 1.0 equiv) in THF (10.0 mL) was added morpho-
line (0.37 mL, 4.28 mmol, 5.0 equiv) and Pd[PPh3]4 (100 mg,
0.084 mmol, 0.10 equiv) at 25 °C. After 30 min, the reaction
mixture was diluted with diethyl ether and treated with a 0.5
M aqueous solution of citric acid. Separation of both phases
was followed by extraction of the aqueous layer with diethyl
ether, and the combined organic extracts were washed with
water and brine, dried (MgSO4), filtered, and concentrated
under reduced pressure. The resulting crude product was
purified by flash column chromatography (silica gel, 38%
EtOAc and 2% AcOH in hexanes) to obtain epoxy acid 33 (705
mg, 94%) as a colorless oil: Rf ) 0.62 (silica gel, 36% EtOAc
and 4% AcOH in hexanes). 1H NMR (400 MHz, CDCl3) δ:
0.87-1.07 (m, 12 H, CH3CH2, CH(CH3), CH(CH3)2), 1.15-1.34
(m, 25 H, 11 × CH2, (CH3)CH(OBn)), 1.46 (s, 9 H, C(CH3)3),
1.56-1.78 (m, 3 H, CH2CHOC(dO), CH(CH3)), 2.05-2.16 (m,
1 H, CH(CH3)2), 2.95-3.01 (m, 1 H, CH(O)CH), 3.38-3.41 (bs,
1 H, CH(O)CH), 3.67-3.75 (m, 1 H), 3.82-3.89 (m, 1 H), 4.18-
4.25 (m, 1 H), 4.35-4.64 (m, 8 H), 7.23-7.36 (m, 10 H, 2 ×
Ph), 8.03 (bd, 1 H, NH), 8.24 (bd, 1 H, NH). 13C NMR (100
Epoxy Peptide 49. To a solution of cyclic depsipeptide 8
(333 mg, 0.427 mmol, 1.0 equiv) in EtOAc/MeOH (20 mL, 1:1)
was added 10% Pd/C (50 mg). The reaction was allowed to
proceed under an atmosphere of H2 at ambient temperature.
After 45 min, the suspension was filtered through a silica gel
pad, and the solid washed with MeOH and CH2Cl2. The
combined clear organic solution was concentrated under
reduced pressure to obtain crude product 49 (234 mg, 92%)
which was used in the next step without purification. [49]:
Colorless oil. Rf ) 0.39 (silica gel, 10% MeOH and 40% EtOAc
1
in hexanes). [R]25 ) -64.5° (c ) 0.4, DMSO). H NMR (400
D
MHz, DMSO-d6) δ: 0.85 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.91 (d,
J ) 7.0 Hz, 3 H, CH(CH3)), 0.94 (d, J ) 7.0 Hz, 3 H, CH(CH3)2),
0.97 (d, J ) 7.0 Hz, 3 H, CH(CH3)2), 1.00 (d, J ) 6.5 Hz, 3 H,
(CH3)CH(OH)), 1.15-1.29 (m, 22 H, 11 × CH2), 1.31-1.42 (m,
1 H, CH2CHOC(dO)), 1.48-1.62 (m, 1 H, CH2CHOC(dO)),
1.74-1.83 (m, 1 H, CH(CH3)), 2.00-2.12 (m, 1 H, CH(CH3)2),
2.82 (dd, J ) 5.9, 2.2 Hz, 1 H, CH(O)CH), 3.32 (d, J ) 2.2 Hz,
1 H, CH(O)CON), 3.61-3.76 (m, 2 H, CH2OH), 3.87 (dd, J )
9.7 Hz, 1 H, CHNH(Val)), 3.96-4.04 (m, 1 H, CH(OH)), 4.18
(dd, J ) 9.1, 2.7 Hz, 1 H, CHNH(Thr)), 4.25-4.32 (m, 1 H,
CHNH(Ser)), 4.89 (dt, J ) 10.2, 2.7 Hz, 1 H, CHOC(dO)), 4.97
(t, J ) 5.9 Hz, 1 H, CH2OH), 5.02 (d, J ) 4.8 Hz, 1 H, CH-
(OH)), 7.52 (d, J ) 9.1 Hz, 1 H, NH(Thr)), 8.12 (d, J ) 7.5 Hz,
1 H, NH(Ser)), 8.74 (d, J ) 9.1 Hz, 1 H, NH(Val)). 13C NMR
7854 J. Org. Chem., Vol. 70, No. 20, 2005

Total Synthesis of Stevastelins B and B3
(100 MHz, DMSO-d6) δ: 12.3, 13.9, 19.2, 20.0, 22.0, 25.3, 27.8,
28.6, 28.7, 28.8, 28.87, 28.95, 28.98, 29.0, 29.02, 31.2, 37.4, 52.8,
54.8, 57.6, 58.2, 61.1, 62.5, 66.4, 76.3, 167.9, 169.7, 170.1, 170.9.
FAB HRMS (NBA): m/e 620.3885, M + Na+; calcd for
C31H55N3O8 620.3887.
purification: Rf ) 0.52 (silica gel, 5% AcOEt in hexanes). [R]25
D
1
) +20.8° (c ) 0.5, CH2Cl2). H NMR (400 MHz, CDCl3): δ )
0.01 (s, 3 H, CH3Si), 0.02 (s, 3 H, CH3Si), 0.66 (d, J ) 6.5 Hz,
3 H, CH(CH3)), 0.83-0.89 (m, 15 H, (CH3)3CSi, CH3CH2, CH-
(CH3)), 1.21-1.28 (m, 22 H, 11 × CH2), 1.31 (s, 3 H, C(CH3)2),
1.39 (s, 3 H, C(CH3)2), 1.38-1.47 (m, 2 H, CH2CH(OTBS)), 1.71
(dq, J ) 7.0, 1.6 Hz, 1 H, CH(CH3)), 1.75-1.86 (m, 1 H,
CH(CH3)), 3.48 (dd, J ) 11.3 Hz, 1 H, CH2O-), 3.53-3.58 (m,
1 H, CH(OTBS)), 3.63-3.69 (m, 2 H, CH2O, CH(O)). 13C NMR
(100 MHz, CDCl3): δ ) -4.3, 10.0, 12.6, 14.1, 18.1, 18.9, 22.7,
24.5, 26.0, 29.3, 29.58, 29.6, 29.65, 29.67, 29.69, 29.72, 30.0,
30.8, 31.9, 33.2, 38.4, 66.6, 73.4, 74.6, 97.7. FAB HRMS
(NBA): m/e 507.4213, M + Na+; calcd for C29H60O3Si 507.4209.
Epoxy Stevastelin B (50). To a solution of epoxy cyclo-
depsipeptide 49 (60 mg, 0.1 mmol, 1.0 equiv) in pyridine (8.0
mL) was added Ac2O (60 µL, 0.6 mmol, 6.0 equiv) at 0 °C. After
3 h at this temperature, MeOH was added, and the resulting
solution was concentrated under reduced pressure. The ob-
tained crude product was purified by flash column chroma-
tography (silica gel, 5% MeOH in CH2Cl2) to afford epoxy-
stevastelin B analogue 50 (45 mg, 70%) as a white solid: Rf )
0.59 (silica gel, 10% MeOH and 60% EtOAc in hexanes). [R]25
Alcohol 54. A solution of acetal 53 (1.43 g, 2.96 mmol 1.0
equiv) in THF (35 mL) was treated with TBAF (1 M in THF,
8.9 mL, 8.9 mmol, 3.0 equiv) at 25 °C. After being stirred for
4 days, the reaction mixture was diluted with diethyl ether
and washed with water. The aqueous solution was extracted
with diethyl ether, and the combined organic phase was
sequentially washed with water and brine, dried (MgSO4), and
concentrated under reduced pressure. The crude mixture was
purified by flash column chromatography (silica gel, 10% of
EtOAc in hexanes) to provide alcohol 54 (900 mg, 69% overall
yield for three steps from epoxyalcohol 9), as a colorless oil:
D
) -27° (c ) 0.2, DMSO). 1H NMR (400 MHz, DMSO-d6) δ:
0.76 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 0.85 (t, J ) 7.0 Hz, 3 H,
CH3CH2), 0.92 (d, J ) 7.0 Hz, 3 H, CH(CH3)2), 0.94 (d, J ) 6.5
Hz, 3 H, CH(CH3)2), 0.97 (d, J ) 6.5 Hz, 3 H, (CH3)CH(OH)),
1.19-1.31 (m, 23 H, 11 × CH2, CH2CHOC(dO)), 1.40-1.60
(m, 2 H, CH2CHOC(dO), CH(CH3)), 1.99 (s, 3 H, CH3C(dO)O-
), 1.96-2.02 (m, 1 H, CH(CH3)2), 2.15-2.23 (m, 1 H, CH(CH3)),
2.67 (bs, 1 H, CH(O)CH), 3.40 (d, J ) 1.6 Hz, 1 H, CH(O)-
CON), 3.73 (t, J ) 8.6 Hz, 1 H, CHNH(Val)), 3.86-3.94 (m, 1
H, CH(OH)), 4.13 (dd, J ) 8.1, 3.8 Hz, CHNH(Thr)), 4.17-
4.29 (m, 2 H, CH2OAc), 4.30-4.38 (m, 1 H, CHNH(Ser)), 4.85-
4.91 (m, 1 H, CHOC(dO)), 4.96 (d, J ) 4.8 Hz, 1 H, CH2OH),
7.13 (d, J ) 7.5 Hz, 1 H, NH(Ser)), 8.50 (d, J ) 7.0 Hz, 1 H,
NH(Thr)), 8.54 (d, J ) 8.1 Hz, 1 H, NH(Val)). 13C NMR (100
MHz, DMSO-d6) δ: 10.1, 13.9, 19.2, 19.4, 20.5, 22.0, 25.3, 27.5,
28.62, 28.67, 28.78, 28.87, 28.93, 28.96, 31.2, 35.4, 50.6, 51.0,
56.8, 57.6, 62.2, 62.7, 66.5, 77.1, 168.6, 169.0, 169.6, 170.1,
170.9. FAB HRMS (NBA): m/e 662.3941, M + Na+; calcd for
C33H57N3O9 662.3993.
Rf ) 0.34 (silica gel, 10% EtOAc in hexanes). [R]25 ) +19.8°
D
1
(c ) 0.5, CH2Cl2). H NMR (400 MHz, CDCl3): δ ) 0.69 (d, J
) 7.0 Hz, 3 H, CH(CH3)), 0.85 (t, J ) 7.0 Hz, 3 H, CH3CH2),
0.91 (d, J ) 7.5 Hz, 1 H, CH(CH3)), 1.21-1.30 (m, 22 H, 11 ×
CH2), 1.35 (s, 3 H, C(CH3)2), 1.35-1.45 (m, 1 H, CH2CH(OH)),
1.45 (s, 3 H, (CH3)2C), 1.49-1.58 (m, 1 H, CH2CH(OH)), 1.61-
1.70 (m, 1 H, CH(CH3)), 1.84-1.96 (m, 1 H, CH(CH3)), 3.51
(dd, J ) 11.3 Hz, 1 H, CH2O), 3.67 (dd, J ) 11.3, 4.8 Hz, 1 H,
CH2O), 3.71 (dd, J ) 10.2, 2.2 Hz, 1 H, CH(O)), 3.72-3.76 (m,
1 H, CH(OH)). 13C NMR (100 MHz, CDCl3): δ ) 4.8, 12.0, 14.1,
19.2, 22.7, 25.6, 26.2, 29.3, 29.59, 29.63, 29.66, 29.7, 30.0, 30.5,
31.9, 35.0, 36.8, 66.1, 76.7, 81.4, 98.2. FAB HRMS (NBA): m/e
393.3345, M + Na+; calcd for C23H46O3 393.3345.
Diol 52. To a suspension of CuI (6.811 g, 35.05 mmol, 10.0
equiv) in THF (23 mL) was added dropwise MeLi (1.6 M, 43.8
mL, 70 mmol, 20.0 equiv) at 0 °C. The resulting colorless
solution of Me2CuLi was added to a solution of epoxy alcohol
20 (1.5 g, 3.51 mmol, 1.0 equiv) in THF (23 mL) at 0 °C. The
reaction mixture was stirred for 4 h at this temperature and
quenched by careful addition of a minimal amount of aqueous
saturated NH4Cl solution. The resulting suspension was then
filtered, and the solids washed with diethyl ether several
times. The organic extracts were sequentially washed with
aqueous saturated NH4Cl solution, water, and brine. After
treatment with MgSO4, the solvents were removed by reduced
pressure to obtain a crude product, which was purified by flash
column chromatography (silica gel, 20% EtOAc in hexanes)
to afford diol 52 (1.34 g, 88%) as a colorless oil: Rf ) 0.33 (silica
Ester 56. A solution of the protected amino acid 55 (2.39 g,
7.27 mmol, 6.4 equiv) in THF (20 mL) was treated at 0 °C
with Et3N (1.53 mL, 10.9 mmol, 9.0 equiv) and 2,4,6-trichlo-
robenzoyl chloride (1.76 mL, 10.9 mmol, 9.0 equiv). The
reaction mixture was stirred at 0 °C for 1.5 h and then was
diluted with toluene (17 mL). The resulting suspension was
filtered through a silica gel pad, under Ar atmosphere, followed
by washing with toluene (10 mL) and THF (10 mL). The
resulting clear solution was then added to a solution of alcohol
54 (448 mg, 1.21 mmol, 1.0 equiv) in toluene (20 mL) at 0 °C,
and after 2.5 h, a solution of DMAP (0.06 M, 10.1 mL, 0.61
mmol, 0.5 equiv) in toluene was added at this temperature.
The reaction mixture was allowed to warm to room temper-
ature and stirred for one additional hour. After this time,
diethyl ether was added, and the resulting mixture was
sequentially washed with water and brine, and the organic
phase was separated, dried (MgSO4), filtered, and concentrated
under reduced pressure. Purification by flash column chro-
matography (silica gel, 13% EtOAc in hexanes) furnished ester
56 (518 mg, 84% based on a 75% conversion), as a 6:1 mixture
of epimers at C-R of the serine residue, recovering starting
alcohol 54 (113 mg, 25%). 56 (colorless oil): Rf ) 0.35 (silica
gel, 15% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3) (major
epimer): δ ) 0.66 (d, J ) 6.5 Hz, 3 H, CH(CH3)), 0.86 (t, J )
7.0 Hz, 3 H, CH3CH2), 0.88 (d, J ) 6.5 Hz, 3 H, CH(CH3)),
1.14-1.30 (m, 22 H, 11 × CH2), 1.29 (s, 3 H, C(CH3)2), 1.34 (s,
3 H, C(CH3)2), 1.48-1.58 (m, 2 H, CH2CHOC(dO)), 1.77-1.86
(m, 2 H, 2 × CH(CH3)), 3.46 (dd, J ) 11.3 Hz, 1 H, CH2O-),
3.56 (d, J ) 10.2 Hz, 1 H, CH(O-)), 3.65 (dd, J ) 11.3, 4.8 Hz,
1 H, CH2O-), 3.71 (dd, J ) 9.1, 2.7 Hz, 1 H, CH2OBn), 3.90
(dd, J ) 9.1, 2.7 Hz, 1 H, CH2OBn), 4.43-4.52 (m, 3 H, CH2-
Ph, CHNH), 4.98-5.05 (m, 1 H, CHOC(dO)), 5.10 (s, 2 H, CH2-
Ph(Cbz)), 5.66 (d, J ) 8.6 Hz, 1 H, NHCbz), 7.21-7.36 (m, 10
H, 2 × Ph). 13C NMR (100 MHz, CDCl3): δ ) 8.5, 12.2, 14.1,
18.6, 22.7, 24.9, 29.3, 29.45, 29.52, 29.53, 29.62, 29.65, 29.67,
gel, 20% EtOAc in hexanes). [R]25
) -2.2° (c ) 0.33, CH2Cl2).
D
1H NMR (400 MHz, CDCl3): δ ) 0.09 (s, 3 H, CH3Si), 0.10 (s,
3 H, CH3Si), 0.73 (d, J ) 6.5 Hz, 3 H, CH(CH3)), 0.84-0.88
(m, 15 H, (CH3)3CSi, CH3CH2, CH(CH3)), 1.20-1.30 (m, 22 H,
11 × CH2), 1.39-1.49 (m, 1 H, CH2CH(OTBS)), 1.50-1.60 (m,
1 H, CH2CH(OTBS)), 1.64-1.72 (m, 1 H, CH(CH3)), 1.81-1.90
(m, 1 H, CH(CH3)), 3.57-3.69 (m, 3 H, CH2OH, CH(OH)),
3.83-3.88 (m, 1 H, CH(OTBS)). 13C NMR (100 MHz, CDCl3):
δ ) -4.6, -3.5, 4.8, 13.7, 14.1, 18.0, 22.7, 25.5, 25.8, 29.3, 29.5,
29.59, 29.63, 29.65, 29.69, 31.9, 34.9, 36.3, 37.5, 68.9, 79.0, 82.6.
FAB HRMS (NBA): m/e 467.3901, M + Na+; calcd for
C26H56O3Si 467.3896.
Acetal 53. A solution of diol 52 (1.37 g, 3.07 mmol, 1.0
equiv) in DMF (30 mL) was cooled to 0 °C. 2,2-Dimethoxypro-
pane (1.14 mL, 9.21 mmol, 3.0 equiv) and CSA (35 mg, 0.15
mmol, 0.05 equiv) were sequentially added, and the reaction
mixture was stirred at 0 °C for 2 h. Then, TEA was added,
followed by diethyl ether, and the resulting mixture was
washed with a saturated aqueous solution of NH4Cl. After
separation of both layers, the aqueous phase was extracted
with diethyl ether, and the organic extracts were combined,
washed with water and brine, dried (MgSO4), filtered, and the
solvents were removed under reduced pressure to afford acetal
53 (1.43 g, 95%), which was used in the next step without
J. Org. Chem, Vol. 70, No. 20, 2005 7855

Sarabia and Chammaa
30.5, 31.5, 31.9, 36.8, 54.6, 66.1, 66.9, 70.1, 73.4, 75.3, 78.4,
97.9, 127.5, 127.7, 128.0, 128.1, 128.3, 128.5, 137.4, 155.8,
169.9. FAB HRMS (NBA): m/e 682.4656, M + H+; calcd for
C41H63NO7 682.4683.
× CH3Si), 0.53 (d, J ) 6.4 Hz, 3 H, CH(CH3)), 0.85 (t, J ) 7.0
Hz, 3 H, CH3CH2), 0.85-0.89 (m, 12 H, CH(CH3), (CH3)3CSi),
0.91 (d, J ) 6.4 Hz, 3 H, CH(CH3)), 1.06 (d, J ) 5.9 Hz, 3 H,
CH(CH3)), 1.10 (d, J ) 7.0 Hz, 3 H, CH(CH3)), 1.19-1.40 (m,
24 H, 12 × CH2), 1.61-1.71 (m, 1 H, CH(CH3)), 1.97-2.09 (m,
1 H, CH(CH3)2), 2.87 (dq, J ) 7.0, 1.6 Hz, 1 H, CH(CH3)-
CONH), 3.58 (dd, J ) 9.7, 3.2 Hz, 1 H, CH2OBn), 3.82 (bs, 1
H, CH(OH)), 3.91 (dd, J ) 9.7, 4.3 Hz, 1 H, CH2OBn), 4.00
(bs, 1 H, CHNH(Val)), 4.15 (dq, J ) 5.9, 5.4 Hz, 1 H, (CH3)-
CH(OTBS)), 4.23 (dd, J ) 10.2, 5.4 Hz, 1 H, CHNH(Thr)), 4.47
(d, J ) 12.4 Hz, 1 H, CH2Ph), 4.57 (d, J ) 12.4 Hz, 1 H, CH2-
Ph), 4.79 (bs, 1 H, CHNH(Ser)), 4.96 (dd, J ) 10.2, 1.6 Hz, 1
H, CHOC(dO)), 7.24-7.37 (m, 6 H, Ph, NH(Val)), 7.70 (d, J )
9.7 Hz, 1 H, NH(Thr)), 7.93 (d, J ) 8.6 Hz, 1 H, NH(Ser)).
Dihydroxy Cyclodepsipeptide 61. To a solution of
macrocycle 60 (6 mg, 0.0073 mmol) in MeOH (2.0 mL) was
added 10% Pd-C (6 mg). The reaction was allowed to proceed
under an atmosphere of H2 at ambient temperature. After 15
min, the suspension was filtered and the solid washed with
methanol. The organic solution was concentrated under re-
duced pressure to afford diol 61 (5 mg) which was used in the
next step without any purification: Rf ) 0.58 (silica gel, 55%
EtOAc and 5% MeOH in hexanes). 1H NMR (400 MHz, DMSO-
d6) δ: 0.07 (s, 3 H, CH3Si), 0.07 (s, 3 H, CH3Si), 0.52 (d, J )
6.4 Hz, 3 H, CH(CH3)), 0.82-0.88 (m, 15 H, CH3CH2, CH(CH3),
SiC(CH3)3), 0.90 (d, J ) 6.4 Hz, 3 H, CH(CH3)), 1.08 (d, J )
5.9 Hz, 3 H, CH(CH3)), 1.13 (d, J ) 7.5 Hz, 3 H, CH(CH3)),
1.20-1.38 (m, 24 H, 12 × CH2), 1.53-1.66 (m, 1 H, CH(CH3)),
2.08-2.21 (m, 1 H, CH(CH3)2), 2.84 (dq, J ) 7.0, 2.1 Hz, 1 H,
CH(CH3)CONH), 3.52-3.59 (m, 1 H, CH2OH), 3.83 (bs, 1 H,
CH(OH)), 3.87-3.94 (m, 1 H, CH2OH), 3.97-4.07 (m, 1 H,
CHNH(Val)), 4.10-4.22 (m, 2 H, (CH3)CH(OTBS), CHNH-
(Thr)), 4.33 (d, J ) 5.9 Hz, 1 H, CH(OH)), 4.56-4.62 (m, 1 H,
CHNH(Ser)), 4.91 (dd, J ) 9.7, 2.1 Hz, 1 H, CHOC(dO)), 5.07-
5.12 (m, 1 H, CH2OH), 7.48 (bs, 1 H, CHNH), 8.03 (bs, 1 H,
CHNH), 8.24 (bs, 1 H, CHNH).
Amine 57. To a solution of N-Cbz amino ester 56 (70 mg,
1.0 equiv) in MeOH (0.01 M) was added 10% Pd/C-ethylen-
diamine complex43 (0.1 equiv). The reaction was allowed to
proceed under an atmosphere of H2 at 25 °C. After 30 min,
the suspension was filtered through Celite, and the solid was
washed with MeOH and CH2Cl2. The clear solution was
concentrated under reduced pressure, and the resulting crude
product was used in the next step without further purification.
[57]: 1H NMR (400 MHz, CDCl3): δ ) 0.64 (d, J ) 7.0 Hz, 3
H, CH(CH3)), 0.83-0.88 (m, 6 H, CH3CH2, CH(CH3)), 1.15-
1.32 (m, 22 H, 11 × CH2), 1.30 (s, 3 H, C(CH3)2), 1.36 (s, 3 H,
C(CH3)2), 1.45-1.63 (m, 2 H, CH2CHOC(dO)), 1.75-1.88 (m,
2 H, 2 × CH(CH3)), 3.00 (bs, 2 H, NH2), 3.45 (dd, J ) 11.3 Hz,
1 H, CH2O-), 3.54 (d, J ) 10.2 Hz, 1 H, CHO-), 3.56-3.63
(m, 1 H, CH(NH2)), 3.65 (dd, J ) 11.3, 4.8 Hz, 1 H, CH2O-),
3.83 (bs, 2 H, CH2OBn), 4.50 (s, 2 H, CH2Ph), 4.95-5.03 (m, 1
H, CHOC(dO)), 7.22-7.32 (m, 5 H, Ph). FAB HRMS (NBA):
m/e 548.4285, M + H+; calcd for C33H57NO5 548.4315.
Cyclic Depsipeptide 59. To a solution of diol 58 (50 mg,
0.0696 mmol, 1.0 equiv) in CH2Cl2 (4.0 mL) was added at 0
°C, 2,6-lutidine (16 µL, 0.139 mmol, 2.0 equiv) and TBSOTf
(24 µL, 0.104 mmol, 1.5 equiv). After stirring for 15 min, the
reaction crude was treated with MeOH and diluted with
diethyl ether. Then, the organic phase was sequentially
washed with saturated aqueous NH4Cl solution, water, and
brine. The combined organic solution was dried (MgSO4),
filtered, and concentrated under reduced pressure, to obtain
a crude product that was purified by flash column chroma-
tography (silica gel, 35% EtOAc and 5% methanol in hexanes)
to afford silyl ether 59 (50 mg, 86%) as a colorless oil: Rf )
1
0.38 (silica gel, 50% EtOAc in hexanes). H NMR (400 MHz,
CDCl3) δ: 0.06 (s, 3 H, CH3Si), 0.08 (s, 3 H, CH3Si), 0.85 (t, J
) 7.0 Hz, 3 H, CH3CH2), 0.86 (s, 9 H, (CH3)3CSi), 0.89 (d, J )
7.5 Hz, 3 H, CH(CH3)), 0.95 (d, J ) 7.5 Hz, 3 H, CH(CH3)),
1.00 (d, J ) 6.4 Hz, 3 H, CH(CH3)), 1.05 (d, J ) 6.4 Hz, 3 H,
CH(CH3)), 1.11 (d, J ) 6.4 Hz, 3 H, CH(CH3)), 1.16-1.30 (m,
22 H, 11 × CH2), 1.41-1.50 (m, 1 H, CH2CHOC(dO)), 1.64-
1.75 (m, 2 H, CH2CHOC(dO), CH(CH3)), 1.78-1.89 (m, 1 H,
CH(CH3)2), 2.25-2.34 (m, 1 H, CH(CH3)CONH), 3.43 (bs, 1
H, CH(OH)), 3.84 (bs, 1 H, CH2OBn), 4.09 (dd, J ) 9.1, 3.2
Hz, 1 H, CH2OBn), 4.23 (dd, J ) 9.1 Hz, 1 H, CHNH(Val)),
4.46 (s, 2 H, CH2Ph), 4.51 (dd, J ) 9.1, 1.1 Hz, 1 H, CHNH-
(Thr)), 4.65-4.75 (m, 2 H, CHNH(Ser), (CH3)CH(OTBS), 4.81-
4.86 (m, 1 H, CHOC(dO)), 6.20 (d, J ) 9.1 Hz, 1 H, NH(Thr)),
7.26-7.37 (m, 6 H, Ph, NH(Val)), 7.58 (d, J ) 8.1 Hz, 1 H,
NH(Ser)). 13C NMR (100 MHz, CDCl3) δ: -4.9, -4.7, 14.1, 17.1,
17.8, 19.0, 19.3, 20.9, 22.7, 25.6, 25.7, 26.0, 29.3, 29.47, 29.53,
29.63, 29.66, 31.4, 31.5, 31.9, 40.4, 45.5, 53.6, 57.5,61.5, 67.9,
71.1, 74.0, 77.2, 80.3, 128.2, 128.4, 128.7, 137.5, 169.5, 169.8,
171.6, 176.4. FAB HRMS (NBA): m/e 840.5531, M + Na+;
calcd for C45H79N3O8Si 840.5534.
Stevastelin B3 (2). To a solution of diol 61 (5 mg, 0.0068
mmol, 1.0 equiv) in pyridine (1.5 mL) was added Ac2O (7 µL,
0.068 mmol, 10.0 equiv) and 4-DMAP (7 µL, 0.01M, 0.01 equiv)
at 0 °C. After 5 h at this temperature, the reaction mixture
was treated with MeOH, and the resulting solution was
concentrated under reduced pressure. The resulting acetyl 62
was dissolved in THF (3.0 mL) at 25 °C and treated with HF‚
pyridine (70% w/v, 0.4 mL) at this temperature. After 3 h, a
saturated aqueous NaHCO3 solution was added until the
release of CO2 ceased. Then, the crude mixture was extracted
with CH2Cl2, and the organic phase was washed with water
and brine, dried (MgSO4), and filtered. After concentration
under reduced pressure, the resulting crude product was
purified by flash column chromatography (silica gel, 2%
methanol in CHCl3) to afford stevastelin B3 (2) (2.6 mg, 55%
over three steps from 60) as a colorless oil: Rf ) 0.17 (silica
gel, 3% MeOH in CHCl3). [R]25 ) -54.0° (c ) 0.05, CHCl3)
D
(natural stevastelin B3: [R]25D ) -53.0° (c ) 0.1, CHCl3)). 1H
NMR (400 MHz, DMSO-d6) δ: 0.54 (d, J ) 7.0 Hz, 3 H, CH-
(CH3)), 0.85 (t, J ) 7.0 Hz, 3 H, CH3CH2), 0.89 (d, J ) 6.4 Hz,
3 H, CH(CH3)), 0.93 (d, J ) 6.4 Hz, 3 H, CH(CH3)), 1.07 (d, J
) 6.4 Hz, 3 H, CH(CH3)), 1.11 (d, J ) 7.0 Hz, 3 H, CH(CH3)),
1.17-1.37 (m, 24 H, 12 × CH2), 1.67-1.77 (m, 1 H, CH(CH3)),
1.96-2.08 (m, 1 H, CH(CH3)2), 2.01 (s, 3 H, CH3C(dO)O-),
2.90 (dq, J ) 7.0, 1.6 Hz, 1 H, CH(CH3)CONH), 3.84 (m, 1 H,
CH(OH)), 3.98-4.06 (m, 2 H, (CH3)CH(OH), CHNH(Val)), 4.12
(dd, J ) 10.2, 2.7 Hz, 1 H, CHNH(Thr)), 4.18 (dd, J ) 11.3,
5.4 Hz, 1 H, CH2OAc), 4.35 (d, J ) 5.9 Hz, 1 H, CH(OH)), 4.38
(dd, J ) 11.3, 5.4 Hz, 1 H, CH2OAc), 4.89-4.95 (m, 1 H,
CHNH(Ser)), 4.91 (dd, J ) 9.7, 1.6 Hz, 1 H, CHOC(dO)), 5.24
(d, J ) 4.3 Hz, 1 H, (CH3)CH(OH)), 7.49 (bs, 1 H, NH(Val)),
7.67 (d, J ) 10.2 Hz, 1 H, NH(Thr)), 7.72 (d, J ) 9.1 Hz, 1 H,
NH(Ser)). 13C NMR (100 MHz, DMSO-d6) δ: 9.2, 13.8, 14.0,
19.0, 19.2, 20.7, 20.9, 22.1, 25.7, 28.7, 29.0, 31.3, 34.9, 41.1,
50.2, 59.4, 61.6, 63.3, 65.2, 69.0, 80.3, 168.8, 170.1, 170.5, 170.7,
170.8.
[13]-Cyclic Depsipeptide 60. To a solution of the cyclic
depsipeptide 59 (18 mg, 0.022 mmol, 1.0 equiv) in THF (2.0
mL) was added at 0 °C NaHDMS (0.25 mL, 0.1M, 0.025 mmol,
1.14 equiv). After 10 min at this temperature, the reaction
crude was diluted with diethyl ether and washed with a 0.5
M aqueous citric acid solution, followed by washings with
water and brine. After separation of both phases, the organic
layer was dried (MgSO4), filtered, and concentrated under
reduced pressure, to obtain a crude product which was
subjected to purification by flash column chromatography
(silica gel, 45% EtOAc in hexanes) to afford the [13]-membered
stevastelin derivative 60 (7 mg, 39%) together with starting
material 59 (7 mg, 39%). [60]: Rf ) 0.63 (silica gel, 50% EtOAc
in hexanes). 1H NMR (400 MHz, DMSO-d6) δ: 0.07 (s, 6 H, 2
(43) Sajiki, H.; Hattori, K.; Hirota, K. J. Org. Chem. 1998, 63, 7990-
7992.
7856 J. Org. Chem., Vol. 70, No. 20, 2005

Total Synthesis of Stevastelins B and B3
Acknowledgment. This work was financially sup-
ported by Fundacio´n Ramo´n Areces and the Direccio´n
General de Investigacio´n (BQU2001-1576) and fellow-
ships from Fundacio´n Ramo´n Areces (S.C.). We thank
Mr. A. Sa´nchez-Ruiz from the University of Malaga and
Dr. J. I. Trujillo from Pfizer (St. Louis, MO) for as-
sistance in molecular modeling studies and for the
preparation of this manuscript, respectively. We thank
Unidad de Espectroscop´ıa de Masas of Seville and
Granada Universities for exact mass spectroscopic as-
sistance.
Supporting Information Available: Table of macro-
lactamization results of epoxypeptides 34, 41, and 48, figures
of minimized structures of compounds 8 and 49, experimental
procedures and spectroscopic data for all other compounds, and
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO050625L
J. Org. Chem, Vol. 70, No. 20, 2005 7857