Studies directed towards the synthesis of antascomicin A: stereoselective synthesis of the C1-C21 fragment of the molecule

Article abstract of DOI:10.1016/j.tetlet.2006.05.113

A stereoselective synthesis of the C1-C21 fragment of the non-immunosuppressive immunophilin-binding natural product, antascomicin A was achieved using, as key steps, highly stereoselective Aldol reactions to build the C1-C17 fragment and a Nozaki-Hiyama-

Full text of DOI:10.1016/j.tetlet.2006.05.113

Tetrahedron Letters 47 (2006) 4999–5002
Studies directed towards the synthesis of antascomicin A:
stereoselective synthesis of the C1–C21 fragment of the moleculeI
Tushar Kanti Chakraborty* and Bajjuri Krishna Mohan
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 C1–C21 fragment of the non-immunosuppressive immunophilin-binding natural prod-
uct, antascomicin A was achieved using, as key steps, highly stereoselective Aldol reactions to build the C1–C17 fragment and a
Nozaki–Hiyama–Kishi reaction to couple it with the remaining C18–C21 moiety.
Ó 2006 Elsevier Ltd. All rights reserved.
Antascomicins are produced by fermenting a strain of
the genus Micromonospora isolated from a soil sample
collected in China.1 The binding affinity of antascomic-
ins to FKBP12 (IC50 = 2 nm, for antascomicin A, 1) is
very similar to that of FK506 or rapamycin (1.1 and
0.6 nm, respectively) in the same binding assay, but
antascomicins do not show any immunosuppressive
activity. Non-immunosuppressive immunophilin bind-
ing ligands such as antascomicins hold a lot of promise
for the treatment of various neuro-degenerative disor-
ders like Alzheimer’s and Parkinson’s diseases.2 We
envisaged that the total synthesis of these molecules
would not only provide an access to larger quantities
necessary for further biological studies, but also help
to design and build more potent synthetic analogues.
The total syntheses of antascomicin B3 and the C18–
C34 fragment of antascomicin A4 have been reported.
As part of our ongoing studies directed towards the syn-
thesis of various immunosuppressants, we investigated
the total synthesis of antascomicin A.
In this letter, we describe the stereoselective synthesis of
the C1–C21 fragment of antascomicin A.6 Schemes 2–4
outline the details of the synthesis of this desired frag-
ment. Asymmetric Aldol addition of the titanium eno-
late derived from N-propanoyl oxazolidinethione 57
(Scheme 1) to aldehyde 6, prepared by oxidation of
mono benzyl-protected pentane-1,5-diol, gave the
‘non-Evans’ syn Aldol product 7 as the only isolable dia-
stereomer in 78% yield. The relative and absolute stereo-
chemistry of the product was assigned on the basis of an
HO
HO
TBSO
TBSO
RCM
reaction
O
O
N
O
N
O
O
O
O
O
O
O
HO
TMSO
An RCM5 approach was contemplated to construct the
macrocyclic ring of antascomicin A. Retrosynthetic ana-
lysis (Scheme 1) reveals that an acyclic precursor such as
2 was ideally suited to carry out the planned RCM reac-
tion. Triene 2 could be easily assembled by coupling the
C1–C21 unit 3 with the C22–C34 fragment 4.
O
O
1
2
1
OH
N
O
O
O
TMSO
21
TBSO
TBSO
34
O
+
Keywords: Antascomicin; Immunosuppressant; FKBP12 binding
ligand; Takai reaction.
q IICT Communication No. 060413.
22
OH
3
O
4
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193108/
27160757; e-mail: chakraborty@iict.res.in
Scheme 1. Retrosynthetic analysis of antascomicin A (1).
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.113

5000
T. K. Chakraborty, B. K. Mohan / Tetrahedron Letters 47 (2006) 4999–5002
TiCl4, DIPEA, CH2Cl2,
−78 oC, 15 min, then 6,
NaBH4, EtOH,
0 oC, 10 min
Bn
Bn
−78 to 0 oC, 3 h (78%)
O
N
O
N
OBn
HO
OBn
BnO
H
(90%)
O
O
OH
OH
S
S
6
O
7
8
5
1. Swern oxidation
2. NaClO2, NaH2PO4,
1. TBDMSCl, imidazole, DMAP (cat)
DMF, 0 oC to rt, 24 h
TBSO
OH
2-methyl-2-butene, tBuOH
0
95% in two steps
2. H2, Pd/C, EtOAc
74% in two steps
OTBS
oC to rt
9
Piv-Cl, Et3N, THF
then 11, LiCl, THF,
−20 oC to rt, 4 h
Bn
1. NaHMDS, THF,
then MeI, −78 oC, 2 h
TBSO
TBSO
OH
OH
TBSO
N
O
Bn
85%
2. LiBH4, Et2O, H2O
0 oC, 10 min
46% in two steps
OTBS
O
OTBS
O
O
11
O
HN
10
12
O
1. Swern oxidation
TBSO
CO2Et
2. LDA, CH3CO2Et, THF
−78 to 0 oC, 30 min
85% in two steps
OTBS
OTBS
OH
13
14
1. DMP, py, CH2Cl2,
rt, 2 h
1. LiOH, THF-MeOH-H2O (3:1:1)
oC to rt, 4 h
0
TBSO
N
2. HF, CH3CN, 3 h
60% in two steps
OTBS
OH
O
CO2Me
2. L-Pip-OMe, EDCI, HOBt, DIPEA
CH2Cl2, 0 oC to rt, 3 h
67% in two steps
15
OMe
N
OMe
N
OMe
N
O
O
O
1. TMSOTf, 2,6-lutidine,
CH2Cl2, 0 oC to rt, 2 h
SO3-py, DMSO
Et3N, CH2Cl2,
0
O
O
O
O
O
TMSO
O
O
HO
TMSO
oC, 1 h
O
2. 0.1(N) HCl, THF, rt,
15 min
70% in two steps
O
H
96%
OH
OH
O
16
17
18
Scheme 2. Stereoselective synthesis of the C1–C16 fragment 18.
CSA, CH2Cl2, MeOH
oC, 30 min
1. Swern oxidation
2. CHI3, CrCl2, THF,
I
0
TBSO
OH
TBSO
81%
oC to rt, 1 h
19
20
0
73% in two steps
1. TsCl, Et3N, DMAP (cat),
CH2Cl2, 0 oC to rt, 10 h
I
I
PhSe
HO
2. PhSeSePh, NaBH4, EtOH,
THF, 0 oC to rt, 4 h
22
21
78% in two steps
1.
m
CPBA, CH2Cl2, −20 oC, 2 h
I
2. DIPA, CCl4, reflux, 4 h
71% in two steps
23
Scheme 3. Synthesis of the C17–C21 fragment 23.
earlier reported work.8 The syn-relationship between the
newly generated chiral centres was supported by the rel-
atively small value of the corresponding vicinal coupling
constant of 2.97 Hz.
ation to furnish the di-TBS ether and finally debenzyl-
ation by hydrogenation gave 9 in 68% yield from 8. A
two-step oxidation protocol was followed to oxidize the
alcohol 9 to acid 10 in 95% overall yield. Compound 10
was used to carry out N-acylation of the chiral oxazolid-
inone 11, derived from D-Phe, under the mixed anhydride
method9 to furnish 12 in 85% yield. Diastereoselective
Reductive removal of the chiral auxiliary using NaBH4
gave an intermediate diol 8 that was subjected to disilyl-

T. K. Chakraborty, B. K. Mohan / Tetrahedron Letters 47 (2006) 4999–5002
5001
OMe
OMe
N
O
N
O
DMP, py, CH2Cl2,
rt, 2 h
CrCl2, NiCl2 (0.1%)
DMSO, rt, 5 h
O
O
O
O
O
O
18
23
+
TMSO
TMSO
85%
62%
25
24
O
HO
Scheme 4. Coupling of the C1–C16 (18) and C17–C21 (23) fragments.
alkylation of the Na-enolate of 12 with MeI was followed
by reductive removal of the chiral auxiliary to give alco-
hol 13 as the only isomer in 46% overall yield. Swern oxi-
dation10 of 13 gave an intermediate aldehyde, which was
reacted with the Li-enolate of ethyl acetate to give the b-
hydroxy ester 14 as a mixture of diastereoisomers in 85%
yield. Saponification of 14 and subsequent coupling with
L-pipecolic acid methyl ester furnished the amide 15 in
67% overall yield.
References and notes
1. Fehr, T.; Sanglier, J.-J.; Schuler, W.; Gschwind, L.;
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Bioorg. Med. Chem. Lett. 1997, 7, 1785–1790.
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Yasuda, K.; Ley, S. V. Angew. Chem., Int. Ed. 2005, 44,
2732–2737.
Oxidation of the b-hydroxy amide 15 with Dess–Martin
periodinane (DMP)11 gave a ‘1,2,3-triketo’ intermedi-
ate,12 which was subjected to desilylation resulting in
the spontaneous formation of the hemiketal 16 in 60%
yield. Disilylation of 16 gave a di-TMS–ether intermedi-
ate. Brief exposure of this intermediate di-TMS–ether to
mild acid selectively deprotected the primary hydroxyl
group to furnish the TMS–ether of the hemiketal 17 in
70% yield. Finally oxidation of 17 gave the aldehyde
18 in 96% yield.
4. Fuwa, H.; Okamura, Y.; Natsugari, H. Tetrahedron 2004,
60, 5341–5352.
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Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490–4527.
6. For our synthesis of the C22–C34 fragment of antascom-
icin A see the following paper.
7. (a) Crimmins, M. T.; King, B. W.; Tabet, E. A. J. Am.
Chem. Soc. 1997, 119, 7883–7884; For some earlier leading
references of the oxazolidinethione based Aldol reactions
giving ‘non-Evans’ syn products see: (b) Fujita, E.; Nagao,
Y. Adv. Heterocycl. Chem. 1989, 45, 1–36; (c) Mukaiyama,
T.; Kobayashi, S. Org. React. 1994, 46, 1–103.
8. (a) Chakraborty, T. K.; Jayaprakash, S.; Laxman, P.
Tetrahedron 2001, 57, 9461–9467; (b) Delaunay, D.;
Toupet, L.; Le Corre, M. J. Org. Chem. 1995, 60, 6604–
6607.
Synthesis of the C19–C21 fragment started with the
mono-TBS ether of pentane-1,5-diol 19 (Scheme 3).
Swern oxidation of 19 followed by a Takai reaction13
furnished the vinyl iodide 20 in 73% yield. Acid-cata-
lyzed desilylation of 20 gave 21 in 81% yield. Tosylation
of 21 was followed by nucleophilic substitution of the
tosylate group by PhSeꢀ, generated in situ by sodium
borohydride reduction of diphenyl diselenide,14 giving
the phenylselenide 22, in 78% overall yield, which was
then subjected to an oxidation–elimination process.
Oxidation of selenide 22 using mCPBA and subsequent
b-elimination of the resulting selenoxide furnished the
diene 23 in 71% yield.
9. Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998,
39, 7775–7778.
10. Mancuso, A. J.; Swern, D. Tetrahedron Lett. 1981, 35,
2473–2476.
11. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277.
12. Batchelor, M. J.; Gillespie, R. J.; Golec, J. M. C.;
Hedgecock, C. J. R. Tetrahedron Lett. 1993, 34, 167–170.
13. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986,
108, 7408–7410.
14. (a) Reich, H. J.; Wollowitz, S.; Trend, J. E.; Chow, F.;
Wendelborn, D. F. J. Org. Chem. 1978, 43, 1697–1705; (b)
Clark, R. D.; Heathcock, C. H. J. Org. Chem. 1976, 41,
1396–1403.
15. (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.;
Nozaki, H. Tetrahedron Lett. 1983, 24, 5281–5284; (b) Jin,
H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644–5646; For reviews, see: (c) Cintas, P.
Synthesis 1992, 248–257; (d) Hashmi, A. S. K. J. Prakt.
Chem. 1996, 338, 491–495; (e) Wessjohann, L. A.; Scheid,
G. Synthesis 1999, 1–36; (f) Fu¨rstner, A. Chem. Rev. 1999,
Coupling of the C1–C16 (18) and C17–C21 (23) frag-
ments to build the target C1–C21 moiety is shown in
Scheme 4. A Nozaki–Hiyama–Kishi coupling15 was em-
ployed to carry out the coupling, giving the coupled
product 24 in 62% yield as a mixture of isomers. Finally,
Dess–Martin oxidation11 of 24 furnished dienone 25,16
the target C1–C21 fragment of antascomicin A, in
85% yield.
Further work is now in progress to complete the total
synthesis of antascomicin A (1).
Acknowledgements
The authors wish to thank CSIR, New Delhi, for a
research fellowship (B.K.M.).

5002
T. K. Chakraborty, B. K. Mohan / Tetrahedron Letters 47 (2006) 4999–5002
99, 991–1045; (g) Furstner, A. Chem. Eur. J. 1998, 4, 567–
11.5, 2.9, 1H, C6–Hb), 2.88 (m, 1H, C15–H), 2.36–2.25 (m,
4H, C19–H2, C20–H2), 2.25–2.20 (m, 2H, C5–H2), 1.85–
1.40 (m, 9H, C3–H2, C4–H2, C11–H, C12–H2, C13–H2),
1.16 (d, J = 6.9 Hz, 3H, C15–CH3), 0.77 (d, J = 6.5 Hz,
3H, C11–CH3), 0.17 (s, 9H, Si(CH3)3); 13C NMR (CDCl3,
75 MHz): d 201.16, 197.18, 170.55, 166.74, 146.67, 136.86,
129.66, 115.50, 102.23, 76.57, 71.66, 56.00, 52.07, 51.60,
48.64, 44.34, 36.03, 32.00, 29.36, 26.57, 24.70, 21.15, 15.43,
12.39, 1.66; Mass (ESIMS): m/z 544 [M+Na]+; HRMS
(ESIMS): calcd for C27H43NO7SiNa [M+Na]+: 544.2706,
found: 544.2718.
¨
570.
16. Data of 25 Rf = 0.55 (SiO2, 20% EtOAc in petroleum
27
ether); ½aꢁD ꢀ 4:0 (c 0.058, CHCl3); IR (KBr): mmax 2930,
1741, 1646, 1448, 1249, 1039, 845 and 758 cmꢀ1; 1H NMR
(CDCl3, 400 MHz): d 6.89 (m, 1H, C18–H), 6.19 (d,
J = 15.7, 1H, C17–H), 5.80 (m, 1H, C23–H), 5.27 (d,
J = 5.4 Hz, 1H, C2–H), 5.05 (dd, J = 15.6, 1.7 Hz, 1H,
C24–Ha), 5.01 (dd, J = 10.2, 1.5 Hz, 1H, C24–Hb), 4.04
(m, 1H, C14–H), 3.78 (s, 3H, –CO2CH3), 3.44 (ddd,
J = 14.4, 2.9, 1.2 Hz, 1H, C6–Ha), 3.28 (ddd, J = 14.4,