Total synthesis of stevastelin B3

Article abstract of DOI:10.1016/j.tetlet.2005.06.073

The total synthesis of stevastelin B3 was achieved using, as a key step, a method developed by us for the synthesis of 2-methyl-1,3-diols by Ti(III)-mediated diastereo- and regioselective opening of trisubstituted 2,3-epoxy alcohols, to carry out the ster

Full text of DOI:10.1016/j.tetlet.2005.06.073

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5447–5450
Total synthesis of stevastelin B3I
Tushar Kanti Chakraborty,* Subhash Ghosh, Pasunoori Laxman,
Shantanu Dutta and Rajarshi Samanta
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 19April 2005; revised 8 June 2005; accepted 15 June 2005
Available online 1 July 2005
Abstract—The total synthesis of stevastelin B3 was achieved using, as a key step, a method developed by us for the synthesis of
2-methyl-1,3-diols by Ti(III)-mediated diastereo- and regioselective opening of trisubstituted 2,3-epoxy alcohols, to carry out the
stereoselective construction of its propionate-derived fatty acid segment.
Ó 2005 Elsevier Ltd. All rights reserved.
Stevastelins A (1), B (2), B3 (3) and C3 (4) belong to a
family of novel depsipeptide immunosuppressants, iso-
lated from a culture of a Penicillium sp. NK374186,
and inhibit the dual specificity phosphatase, VHR.1–3
Three more stevastelin congeners, named A3, D3 and
E3, were subsequently isolated from the same source.4
While the sulfated derivative stevastelin A (1) exhibits
potent inhibitory activities against VHR in extracellular
Me Me
Me Me
5
3
5
3
Me(CH2)12
O
Me(CH2)12
O
Me
Me
Me
Me
OH
O
HN
OH HN
O
O
O
O
O
O
O
NH
NH
N
H
Me
N
OR2
OR2
H
OR1
Me
OR1
1: stevastelin A: R1 = SO3H, R2 = Ac
2: stevastelin B: R1 = H, R2 = Ac
3: stevastelin B3: R1 = H, R2 = Ac
4: stevastelin C3 (earlier proposed): R1 = H, R2 = H
5: stevastelin C3 (corrected; ref 7a): 5-deoxy-4
Me Me
Me(CH2)12
O
Me
Me
Me
Me
OBn
OH OH HN
HO2C
Me Me
O
H
N
O
O
Me(CH2)12
CO2H+ BocHN
N
H
CO2Me
NH
N
H
O
O
O
BnO
Me
OBn
Me
OBn
7
8
6
Keywords: Stevastelins; Epoxide opening; 2-Methyl-1,3-diol; Immunosuppressants; Depsipeptide.
q IICT Communication No. 050410.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193108/27160757; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.073

5448
T. K. Chakraborty et al. /Tetrahedron Letters 46 (2005) 5447–5450
enzyme preparations, it has little effect in cellular prepa-
rations.5,6 The opposite is true for stevastelin B (2). The
free threonyl hydroxyl group in 2 enables it to penetrate
cells much better than its sulfated version 1. Once inside,
it is converted to an active form by intracellular sulfa-
tion or phosphorylation of its hydroxyl function. The
pronounced biological activities of stevastelin molecules
and their structures have attracted the attention of
organic chemists.7,8 The structure of stevastelin C3 was
recently corrected to the 5-deoxy derivative 5 by Chida
and co-workers through chemical synthesis of the mole-
cule.7a In our earlier paper,8b we reported an attempt to
synthesize stevastelin B following a macrolactonization
route that involved reaction between the C5–OH and
the Ser-carboxyl function having the C3–OH protected
as a PMB–ether. The failure encountered in that ap-
proach forced us to alter our strategy and adopt a cycli-
zation reaction keeping both C3– and C5–OH
unprotected. Herein we report the results of that work,
which led to the synthesis of the 13-membered macrolac-
tone stevastelin B3.
Retrosynthetically, stevastelin B3 (3) could be obtained
by macrolactonization of the acyclic hydroxy acid 6
which, in turn, could be prepared by coupling the two
key intermediates 7 and 8, the former with the long
n-BuLi, THF, –78 oC to rt;
(EtO)2P(O)Et (10), n-BuLi,
Me Me
Me
THF, –78 oC; then 9, 2 h
then CH3(CH2)12CHO (12)
OTBDPS
OTBDPS
(EtO)2P
MeO2C
at –78 oC; –78 oC to rt, 3 h
O
O
11
65%
9
75%
DIBAL-H, toluene,
mCPBA, 0 oC
to rt, 0.5 h
Me Me
Me Me
–78 oC, 0.5 h
CH3(CH2)12
OTBDPS
OTBDPS
CH3(CH2)12
OTBDPS
O
OH
85%
90%
14
13
Cp2TiCl, cyclohexa-1,4-diene,
THF, –20 oC to rt, 8 h
Me Me
Me Me
OTBDPS
O
CH3(CH2)12
CH3(CH2)12
OH
OH OH
75%
15
16
1. 2,2-dimethoxypropane,
CSA (cat.), 0 oC to rt, 1 h
Me Me
Me(CH2)12
O
EDCI, HOBt, CH2Cl2, 0 oC,
Me
2. TBAF, THF, 0 oC to rt, 2 h
O
O
HN
Me
O
7
O
then 17, DIPEA, 0 oC to rt, 12 h
MeO2C
3. RuCl3.3H2O, NaIO4,
CH3CN-CCl4-H2O, 0 oC, 0.5 h
65% (in 3 steps)
NH
N
65%
Me
Me
OBn
CO2Me
H
OBn
O
H
Me
18
OBn
TFA,
N
TFA.H2N
N
H
Me
8
O
CH2Cl2, 0 o
C
BnO
17
Me Me
1. LiOH, THF-MeOH-H2O
1. CSA (cat.), CH2Cl2
0 oC to rt, 2 h
Me(CH2)12
O
0 oC, 1 h
Me
Me
O
O
HN
6
O
O
2. allyl alcohol, DCC,
DMAP (cat.), CH2Cl2, 0 oC, 2 h
78% (in 2 steps)
AllO2C
2. Pd(Ph3P)4, morpholine, THF
80% (in 2 steps)
NH
N
H
OBn
Me
OBn
19
Me Me
O
Me(CH2)12
Me
ref. 7a,c
2,4,6-Trichlorobenzoyl chloride, Et3N, THF, 0 oC, 1 h;
OH
HN
Me
3
then added to 6 and DMAP in toluene (0.005 M), 0 oC to rt
O
O
O
O
NH
N
H
45%
OBn
Me
OBn
20
Scheme 1.

T. K. Chakraborty et al. /Tetrahedron Letters 46 (2005) 5447–5450
5449
chain fatty acid moiety and the latter possessing the tri-
peptide component. For scale-up purposes, we had to
devise an alternative, more efficient route than that used
by us earlier8b for constructing the C1–C18 fragment 7
that carries four contiguous chiral centres. The salient
feature of the new scheme described here for synthesiz-
ing 7 is the successful application, as a key step, of a very
efficient method developed by us earlier for the synthesis
of 2-methyl-1,3-diols via radical-mediated regioselective
opening of trisubstituted 2,3-epoxy alcohols at the more
substituted centre using Cp2TiCl.9,10 The excellent dia-
stereoselectivities observed in these reactions prompted
us to employ it in our present study for the stereoselec-
tive construction of the propionate-derived fatty acid
component 7.
oxidation of the primary hydroxyl group to the carboxyl
function. Synthesis of the peptide 8 and its coupling with
7 were carried out in the same way as described earlier
by us8b following the standard solution phase peptide
synthesis conditions. Thus peptide 8 was treated with
trifluoroacetic acid (TFA) in CH2Cl2 to deprotect the
N-terminus to afford 17 which was then coupled with
7 in dry CH2Cl2 using 1-ethyl-3-(3-(dimethylamino)pro-
pyl)carbodiimide hydrochloride (EDCI) and 1-hydr-
oxybenzotriazole (HOBt) as coupling agents to give
the coupled product 18 in 65% yield.17 At this stage, it
became necessary to replace the methyl ester with an
allyl ester in order to avoid a saponification step before
the crucial macrolactonization reaction, an unsuccessful
sequence also encountered by others.7c Accordingly, 18
was converted to the allyl ester 19 in two steps—sapon-
ification using LiOH, followed by esterification of the
acid with allyl alcohol using DCC and DMAP (cat.).
Acid hydrolysis of the acetonide protection in 19 was
followed by Pd-catalyzed deprotection of the allyl ester
to provide the acid 6 in 80% yield.
Scheme 1 outlines the details of the total synthesis. Silyl-
ation of commercially available methyl (S)-3-hydroxy-2-
methylpropionate provided the starting material 9
for our synthesis. The ester function of 9 was reacted
with the Li-anion derived from diethyl ethylphospho-
nate (10) to give the ketophosphonate 11 in 65% yield.
Horner–Wadsworth–Emmons olefination11,12 of tetra-
decanal (12) with the Li-enolate generated from keto-
phosphonate 11 provided exclusively the E-enone 13 in
75% yield. Next, diastereoselective 1,2-reduction of the
enone moiety of 13 using DIBAL-H13 led to the forma-
tion of 14 with (S)-C3 configuration in 85% yield. Desi-
lylation of 14 and acetonide protection of the resulting
diol allowed us to unambiguously establish the stereo-
chemistry of the product whose 1H NMR showed a
With the requisite intermediate 6 in hand the stage was
now set to carry out the crucial macrolactonization reac-
tion. Compound 6 was subjected to Yamaguchi macro-
lactonization,18 which furnished the 13-membered
macrolactone 20 in 45% yield.19 There was no trace of
the other possible product, that is, the 15-membered
macrolactone framework of stevastelins A and B.
Whether this can be attributed to an inherent structural
feature of the cyclization intermediate 6, which possibly
could not attain the required conformation for 15-mem-
bered lactone formation, or to some other steric effects,
is not yet clear. Debenzylation of 20 and selective acyl-
ation of the primary hydroxyl of Ser to stevastelin B3
(3) have already been reported.7a,c Efforts are now in
progress to try the cyclization reactions under different
conditions in order to achieve the synthesis of other
members of the stevastelin family.
3
large J coupling of 11.6 Hz between C2–H and C3–H
indicating their diaxial dispositions in a chair-type con-
formation with the C2-methyl and C3-alkenyl groups
occupying equatorial positions. The minor isomer could
be easily removed by silica gel column chromatography.
Treatment of 14 with mCPBA gave the syn epoxy alco-
hol 15 as the only diastereomer in 90% yield.14 The
assigned stereochemistry of 15 was proved after the
epoxide ring opening step.
Acknowledgements
The stage was now set to carry out our radical-mediated
ring opening reaction. It has been well established by us
that syn epoxy alcohols produce syn,syn-isomers of the
2-methyl-1,3-diol stereotriad as the major product in
these reactions. Indeed, reaction of 15 with Cp2TiCl,
generated in situ from Cp2TiCl2 using Zn dust and
freshly fused anhydrous ZnCl2, led to a clean transfor-
mation with excellent diastereoselectivity (>90% de)
and the major product 16 possessing the requisite
syn,syn 2-methyl-1,3-diol moiety was obtained in 75%
isolated yield. The stereochemistry of the product
The authors wish to thank CSIR, New Delhi for
research fellowships (S.G., P.L., S.D. and R.S.).
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´
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