Studies directed towards the synthesis of antascomicin A: stereoselective synthesis of the C22-C34 fragment of the molecule

Article abstract of DOI:10.1016/j.tetlet.2006.05.115

A stereoselective synthesis of the C22-C34 fragment of the non-immunosuppressive immunophilin-binding natural product, antascomicin A was achieved using d-quinic acid as the starting material and highly stereoselective aldol reactions were employed, as ke

Full text of DOI:10.1016/j.tetlet.2006.05.115

Tetrahedron Letters 47 (2006) 5003–5005
Studies directed towards the synthesis of antascomicin A:
stereoselective synthesis of the C22–C34 fragment of the
moleculeq
Tushar Kanti Chakraborty,* Bajjuri Krishna Mohan and Midde Sreekanth
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 13 April 2006; revised 10 May 2006; accepted 18 May 2006
Abstract—A stereoselective synthesis of the C22–C34 fragment of the non-immunosuppressive immunophilin-binding natural prod-
uct, antascomicin A was achieved using D-quinic acid as the starting material and highly stereoselective aldol reactions were
employed, as key steps, to build the remaining stereocentres at C23, C26 and C27.
Ó 2006 Elsevier Ltd. All rights reserved.
Although the binding affinities of antascomicins1 to
FKBP12 (IC50 = 2 nm, for antascomicin A, 1) are very
similar to that of FK506 or rapamycin (1.1 and
0.6 nm, respectively, in the same binding assay), they
do not show any immunosuppressive activity. Such
non-immunosuppressive immunophilin binding ligands
as antascomicins, produced by fermenting a strain of
the genus Micromonospora isolated from a soil sample
collected in China,1 hold much promise for the treat-
ment of various neuro-degenerative disorders like Alz-
heimer’s and Parkinson’s diseases.2 The biological
activities of these molecules and their structural features
have attracted the attention of synthetic organic chem-
ists leading to the total syntheses of antascomicin B3
and the C18–C34 fragment of antascomicin A.4 As part
of our studies directed towards the total synthesis of
antascomicin A, we report here the stereoselective syn-
thesis of the C22–C34 fragment of the molecule.5
HO
HO
TBSO
TBSO
RCM
reaction
O
O
N
O
N
O
O
O
O
O
O
O
HO
TMSO
O
O
1
2
1
OH
N
O
O
O
TMSO
21
TBSO
TBSO
34
O
+
22
Retrosynthetic analysis of antascomicin A (1) (Scheme
1) reveals that an acyclic precursor such as 2 was ideally
suited to build the macrocyclic ring of the molecule
using an RCM reaction.6 Compound 2 could be easily
assembled by coupling the C1–C21 unit 3 with the
C22–C34 fragment 4 through an esterification reaction.
OH
3
O
4
Scheme 1. Retrosynthetic analysis of antascomicin A (1).
For the synthesis of the C22–C34 fragment 4 of antasco-
micin A, D-quinic acid was chosen as the starting
material. Scheme 2 outlines the details of the synthesis.
D-(ꢀ)-Quinic acid 5 was transformed into the intermedi-
ate 6 in six steps and in 33% overall yield following the
procedure reported earlier.7 Silylation of 6 was followed
by reduction to furnish the diol 7 in 76% yield. Selective
Keywords: Antascomicin; Immunosuppressant; FKBP12 binding ligand;
Aldol reaction.
q IICT Communication No. 060414.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193108/
27160757; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.115

5004
T. K. Chakraborty et al. / Tetrahedron Letters 47 (2006) 5003–5005
OH
1. TBSOTf, 2,6-lutidine
CH2Cl2, 0 oC, 10 min
6 steps, 33%
overall yield
HO
HO
BzO
HO
HO
OH
OH
OMe
OH
2. DIBAL-H, CH2Cl2,
−78 to 0 oC, 2 h
76% in two steps
(ref. 6)
TBSO
O
O
6
7
5
1. AcCl, 2,4,6-collidine, CH2Cl2, −78 oC, 3 h
Swern
oxidation
TBSO
TBSO
TBSO
TBSO
2. TBSOTf, 2,6-lutidine, CH2Cl2, 0 oC, 5 min
O
OH
3. K2CO3, MeOH, 0 oC to rt, 1 h
78% in three steps
95%
H
9
8
O
O
H
OBn
O
N
P(O)(OEt)2
10
1. 10, LiCl, DIPEA, CH3CN, rt, 6 h
12
O
Ph
Me
1. Bu2BOTf, Et3N, CH2Cl2, −78 oC
O
O
N
then 12, −78 oC to rt, 12 h
OTBS
OTBS
O
2. H2, Pd-C, EtOAc,
rt, 1 h
2. TESOTf, 2,6-lutidine, CH2Cl2,
0 oC, 5 min
Ph
Me
71% in two steps
11
3. LiEt3BH, Et2O, 0 oC, 30 min
40% in three steps
OTES
OTES
OTBS
1. TsCl, Et3N, DMAP (cat)
CH2Cl2, 0 oC to rt, 24 h
OTBS
OTBS
BnO
BnO
2. LiEt3BH, THF, −20 to
0 oC, 5 h
OTBS
13 OH
14
70% in two steps
1. H2, Pd-C, EtOAc, rt, 1 h
OH
2. SO3-py, Et3N, DMSO, CH2Cl2, 0 oC, 1 h
OTBS
OTBS
3. (Ph3P-CH3)I, NaNH2, Et2O, 0 oC, 10 min
4. CSA (cat), MeOH, CH2Cl2, 0 oC, 5 min
75% in four steps
4
Scheme 2. Stereoselective synthesis of C22–C34 fragment 4.
acylation of the primary hydroxyl group, silylation of
the secondary hydroxyl and deprotection of the acetate
gave the disilylated intermediate 8 in 78% yield in three
steps. Finally Swern oxidation8 of 8 furnished the alde-
hyde 9 in 95% yield.
14 in 70% yield.11 Debenzylation of 14 by catalytic
hydrogenation, oxidation of the resulting primary
hydroxyl group, one-carbon Wittig olefination and
finally an acid-catalyzed desilylation step furnished the
target fragment 4 in 75% yield.13 Further work is now
in progress to couple 4 with the C1–C21 fragment 3
and complete the total synthesis of the molecule.
Horner–Wadsworth–Emmons olefination of 9 with the
(1S,2R)-(+)-norephedrine-derived
keto-phosphonate
109 using LiCl–DIPEA10 provided an a,b-unsaturated
amide intermediate, which was hydrogenated to furnish
the N-acylated chiral auxiliary 11.11 The enolate of 11
was reacted with the aldehyde 1212 to furnish the aldol
product as a single isomer. The stereochemistries of
the newly generated chiral centres were assigned on
the basis of an earlier reported work.11 The aldol adduct
was then silylated and the chiral auxiliary was removed
by reduction with lithium triethylborohydride to furnish
13 in 40% yield in three steps. A two-step protocol was
followed to convert the hydroxymethyl group of 13 to a
methyl group—tosylation followed by nucleophilic sub-
stitution of the tosylate group with hydride—to furnish
Acknowledgements
The authors wish to thank CSIR, New Delhi, for
research fellowships (B.K.M., M.S.).
References and notes
1. Fehr, T.; Sanglier, J.-J.; Schuler, W.; Gschwind, L.;
Ponelle, M.; Schilling, W.; Wioland, C. J. Antibiot. 1996,
49, 230–234.
2. (a) Snyder, S. H.; Sabatini, D. M.; Lai, M. M.; Steiner, J.
P.; Hamilton, G. S.; Suzdak, P. D. Trends Pharmacol. Sci.

T. K. Chakraborty et al. / Tetrahedron Letters 47 (2006) 5003–5005
5005
1998, 19, 21–26; (b) Steiner, J. P.; Connolly, M. A.;
Valentine, H. I.; Hamilton, G. S.; Dawson, T. M.; Hester,
L.; Snyder, S. H. Nat. Med. 1997, 3, 421–428; (c)
Hamilton, G. S.; Huang, W.; Connolly, M. A.; Ross, D.
T.; Guo, H.; Valentine, H. L.; Suzdak, P. D.; Steiner, J. P.
Bioorg. Med. Chem. Lett. 1997, 7, 1785–1790.
12. Aldehyde 12 was synthesized from the mono-benzylated
chiral 2-methyl-propane-1,3-diol 15, which was prepared
from commercially available methyl (R)-3-hydroxy-2-
methylpropionate in two steps—benzylation with
O-benzyl trichloroacetimidate under acidic conditions
followed by reduction of the ester with lithium alumin-
ium hydride. Compound 15 was then transformed into
12 in four steps, as shown below, and in 65% overall
yield.
3. Brittain, D. E. A.; Griffiths-Jones, C. M.; Linder, M. R.;
Smith, M. D.; McCusker, C.; Barlow, J. S.; Akiyama, R.;
Yasuda, K.; Ley, S. V. Angew. Chem., Int. Ed. 2005, 44,
2732–2737.
4. Fuwa, H.; Okamura, Y.; Natsugari, H. Tetrahedron 2004,
60, 5341–5352.
5. For our synthesis of the C1–C21 fragment of antascomicin
A see the preceding paper, doi:10.1016/j.tetlet.2006.05.113.
6. (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–
1. Swern oxidation
Swern
2. Ph3P=CHCO2Et, CH2Cl2, rt, 12 h
oxidation
HO
OBn
HO
OBn
12
3. LiBH4, Et2O, 0 oC to rt, 48 h
68% in three steps
95%
15
16
4450; (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39,
¨
3013–3043; (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18–29; (d) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527.
7. Rao, A. V. R.; Chakraborty, T. K.; Sankaranarayanan,
D.; Purandare, A. V. Tetrahedron Lett. 1991, 32, 547–550.
8. Mancuso, A. J.; Swern, D. Tetrahedron Lett. 1981, 35,
2473–2476.
9. Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E.
Tetrahedron Lett. 1987, 28, 39–42.
10. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A.
P.; Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron
Lett. 1984, 25, 2183–2186.
11. (a) Nicolaou, K. C.; Bertinato, P.; Piscopio, A. D.;
Chakraborty, T. K.; Minowa, N. J. Chem. Soc., Chem.
Commun. 1993, 619–622; (b) Nicolaou, K. C.; Piscopio, A.
D.; Bertinato, P.; Chakraborty, T. K.; Minowa, N.;
Koide, K. Chem. Eur. J. 1995, 1, 318–333.
13. Data of 4. Rf = 0.5 (SiO2, 10% EtOAc in petroleum ether);
27
½aꢁD ꢀ23.1 (c 0.016, CHCl3); IR (KBr): mmax 3422, 2929,
2857, 1465, 1253, 835 and 774 cmꢀ1 1H NMR (CDCl3,
;
400 MHz): d 5.69 (ddd, J = 16.0, 10.0, 7.3 Hz, 1H, olefinic
proton), 4.97 (dd, J = 16.0, 1.7 Hz, 1H, olefinic proton),
4.92 (dd, J = 10.0, 1.7 Hz, 1H, olefinic proton), 3.42–3.32
(m, 3H, CH–O–), 2.11 (m, 1H, allylic CH), 1.89–1.82 (m,
2H, CH), 1.63–1.04 (m, 12H, CH2), 1.00 (d, J = 6.7 Hz,
3H, CH3), 0.893 (s, 9H, t-butyl), 0.888 (s, 9H, t-butyl) 0.87
(d, J = 6.8 Hz, 3H, CH3), 0.068 (s, 12H, 2Si(CH3)2); 13C
NMR (CDCl3, 75 MHz): d 144.55, 112.71, 76.47, 75.92,
40.49, 38.16, 37.90, 35.95, 34.04, 33.50, 33.19, 32.15, 31.09,
26.11, 20.19, 18.19, 15.57, ꢀ3.79, ꢀ4.63, ꢀ4.67; mass
(ESIMS): m/z 521 [M+Na]+, 522 [M+Na+H]+; HRMS
(ESIMS): calcd for C28H59O3Si2 [M+H]+: 499.4002,
found: 499.4004.