Total synthesis of (+)-conagenin

Article abstract of DOI:10.1016/j.tetlet.2006.06.087

The total synthesis of the immunomodulator, (+)-conagenin was achieved using, as a key step, a method developed by us for the synthesis of 2-methyl-1,3-diols via Ti(III)-mediated diastereo- and regioselective opening of trisubstituted 2,3-epoxy alcohols,

Full text of DOI:10.1016/j.tetlet.2006.06.087

Tetrahedron Letters 47 (2006) 5847–5849
Total synthesis of (+)-conageninI
Tushar Kanti Chakraborty* and Gangarajula Sudhakar
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 10 May 2006; revised 6 June 2006; accepted 15 June 2006
Available online 3 July 2006
Abstract—The total synthesis of the immunomodulator, (+)-conagenin was achieved using, as a key step, a method developed by us
for the synthesis of 2-methyl-1,3-diols via Ti(III)-mediated diastereo- and regioselective opening of trisubstituted 2,3-epoxy alcohols,
to carry out the stereoselective construction of its pentanoic acid segment.
Ó 2006 Elsevier Ltd. All rights reserved.
Conagenin (1) is a low molecular weight immunomodu-
lator isolated from the fermentation broth of Strepto-
myces roseosporus.1 This molecule exhibits wide-ranging
biological activity. It stimulates activated T cells, which
produce lymphokines and generate antitumor effector
cells.2 The antitumor efficacies of adriamycin and mito-
mycin C against murine leukemias are also enhanced by
1, making it a potential candidate for cancer chemother-
apy.3 It has a densely functionalized structure consisting
of a (2R,3S,4R)-2,4-dihydroxy-3-methylpentanoic acid
moiety with three contiguous chiral centers, coupled to
a (S)-a-methylserine possessing a quaternary chiral cen-
ter. The pronounced biological activities of conagenin
and its highly substituted structure make it an attractive
target to synthetic organic chemists.4
sary for further biological studies, but also help to
design and build more potent synthetic analogs. Retro-
synthetic analysis of 1 reveals that it can be made easily
from the two units 2 and 3. In this letter, we describe the
total synthesis of the conagenin (1) using 3-methyl-2-bu-
ten-1-ol (4) as a common starting material to build both
the fragments, 2 and 3.
The salient feature of our synthesis 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 ring open-
ing of trisubstituted 2,3-epoxy alcohols at the more
substituted center using Cp2TiCl.5 The excellent dia-
stereoselectivities observed in these reactions prompted
us to employ it in our present study for the stereose-
lective construction of the propionate-derived acid
component 2.
We envisaged that the total synthesis of this molecule
would not only provide access to larger quantities neces-
OAc OAc
CO2H
OH OH
H
N
CO2H
OH
2
OH
O
+
4
OH
1
BocHN
CO2Me
3
Keywords: Conagenin; Epoxide opening; 2-Methyl-1,3-diol; Immunomodulator.
q IICT Communication No. 060507.
*
Corresponding author. Tel.: +91 40 27193154; fax: +91 40 27193275/27193108; e-mail: chakraborty@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.087

5848
T. K. Chakraborty, G. Sudhakar / Tetrahedron Letters 47 (2006) 5847–5849
OH OH
O
5 steps
Ac2O, Et3N, DMAP,
CH2Cl2
Cp2TiCl, Zn, ZnCl2,
BnO
OBn
4
(refs. 5,6)
THF, -20 oC to rt, 6 h
84%
OH
92%
5
6
2
1. H2, 10% Pd-C, EtOAc, rt, 1 h
2. SO3-Py, Et3N, CH2Cl2, DMSO, 0 oC
OAc OAc
OBn
3. NaClO2, NaH2PO4, 2-methyl-2-butene,
tBuOH, rt
81%
7
Scheme 1. Stereoselective synthesis of 2.
Scheme 1 outlines the details of the synthesis of 2. The
syn epoxy alcohol 5 was prepared from 4 in five steps
following the procedures reported earlier5,6—benzyl-
ation of the hydroxyl group, SeO2-mediated allylic oxi-
dation,7 Grignard addition to the resulting aldehyde
with MeMgI, Sharpless kinetic resolution8 of the allylic
alcohol and mCPBA epoxidation of the chiral allylic
alcohol. Ring opening of 5 with Cp2Ti(III)Cl, generated
in situ from Cp2TiCl2 following the reported procedure,5
gave the expected all syn product 6 almost exclusively as
a single isomer. The trace amount of the anti,anti isomer
could be easily removed by standard silica gel column
chromatography. The 13C NMR spectrum of the aceto-
nide of 6 showed the chemical shifts of the methyl car-
bons of the acetonide function at 19.6 and 29.9 ppm
and that of the ketal carbon at 98.8 ppm confirming it
ated 4 from Scheme 1 was reduced with NaBH4 to fur-
nish the allylic alcohol 8 in 60% yield in two steps.
Katsuki–Sharpless catalytic asymmetric epoxidation10
of 8 using D-(ꢀ)-tartrate gave the requisite chiral epoxy
alcohol 9 in 80% yield (>95% ee). The trichloroacetimi-
date 10 of this epoxy alcohol underwent facile intramo-
lecular SN2 opening of the epoxide ring under acidic
conditions4a,11 to furnish the oxazole 11 in 84% yield.
Acid hydrolysis of the oxazole ring gave an amino diol
which was protected in situ using Boc2O to furnish 12
in 92% yield. Debenzylation of 12 by catalytic hydroge-
nation gave a triol intermediate whose 1,2-diol moiety
was oxidatively cleaved using NaIO4. The resulting alde-
hyde was next oxidized to an acid and esterified using
CH2N2 to give Boc-(S)-a-methylserine methyl ester 3
in 72% yield in three steps from 13.
3
to be a ‘1,3-syn’ acetonide.9 Besides, the J couplings
of 2.4 Hz between 2H and 3H and 2.3 Hz between 3H
and 4H in the acetonide support the S-configuration
of the 3-Me substituent. Compound 6 was then trans-
formed into its diacetate 7 in 92% yield. Debenzylation
of 7 by catalytic hydrogenation was followed by a
two-step oxidation of the resulting primary hydroxyl
group to the acid 2 in 81% yield.
The coupling of the fragments 2 and 3 and the final
stages of the synthesis are shown in Scheme 3. Acid 2
was esterified with the alcohol 3 using DCC, HOBt,
and DMAP to furnish the ester 14 in 91% yield.4d
Deprotection of the Boc-group freed the amine, which
underwent a smooth ester to amide rearrangement on
4c,d
treatment with aqueous NaHCO3
to give 15 in 78%
The synthesis of fragment 3 is described in Scheme 2.
The aldehyde obtained by the SeO2 oxidation of benzyl-
yield. Finally saponification of 15 furnished the target
molecule 1 in 83% yield. The spectroscopic data,
D-(–)-DIPT, Ti(OiPr)4,
1. SeO2, TBHP,
Bn-ether CH2Cl2, 0 oC to rt, 16 h
HO
TBHP, CH2Cl2, –20 oC
O
HO
of 4
OBn
OBn
2. NaBH4, MeOH, 0 oC, 1 h
60%
(Scheme 1)
80%
9
8
1M HCl, THF,
CCl3CN, DBU,
CH2Cl2, −20 oC
Et2AlCl, CH2Cl2,
0 oC to rt, 4 h
NH
O
O
then NaHCO3, Boc2O
OBn
Cl3C
O
Cl3C
OBn
N
92%
84% (in 2 steps)
OH
10
11
1. NaIO4, CH2Cl2, aq NaHCO3
2. NaClO2, NaH2PO4
OH
OH
H2, 10% Pd-C,
EtOAc, rt
2-methyl-2-butene, tBuOH
BocHN
OBn
BocHN
OH
3
3. CH2N2, ether, 0 oC
72% (3 steps)
OH
12
OH
13
94%
Scheme 2. Stereoselective synthesis of 3.

T. K. Chakraborty, G. Sudhakar / Tetrahedron Letters 47 (2006) 5847–5849
5849
OAc OAc
OAc OAc
CO2Me
NHBoc
H
N
1. TFA, CH2Cl2, rt, 4 h
DCC, HOBt, DMAP,
CH2Cl2, rt, 1.5 h
91%
CO2Me
OH
O
2 + 3
2. aq NaHCO3, THF, rt, 10 h
78%
O
O
14
15
1M K2CO3, MeOH (1:3), rt, 2 h
1
83%
Scheme 3. Synthesis of (+)-conagenin 1.
sink, J. Synthesis 1999, 243–248; For syntheses of diaste-
namely, IR, NMR, mass spectra as well as the rotation
of our synthetic products, 15 and 1,12 were in confor-
mity with those reported earlier.1,4
´
´
reomers see: (f) Kovacs-Kulyassa, A.; Herczegh, P.;
Sztaricskai, F. J. Tetrahedron Lett. 1996, 37, 2499–2502;
´
´
(g) Kovacs-Kulyassa, A.; Herczegh, P.; Sztaricskai, F.
Tetrahedron 1997, 53, 13883–13896; For a synthetic study
see: (h) Rodrigues, J. A. R.; Moran, P. J. S.; Milagre, C.
D. F.; Ursini, C. V. Tetrahedron Lett. 2004, 45, 3579–3582.
5. (a) Chakraborty, T. K.; Das, S. Tetrahedron Lett. 2002,
43, 2313–2315; (b) Chakraborty, T. K.; Dutta, S. J. Chem.
Soc., Perkin Trans. 1 1997, 1257–1259.
Acknowledgments
The authors wish to thank CSIR, New Delhi, for a
research fellowship (G.S.).
6. Chakraborty, T. K.; Thippeswamy, D.; Suresh, V. R.;
Jayaprakash, S. Chem. Lett. 1997, 563–564.
7. Bhalerao, U. T.; Rapoport, H. J. Am. Chem. Soc. 1971,
93, 5311–5313.
References and notes
1. Yamashita, T.; Iijima, M.; Nakamura, H.; Isshiki, K.;
Naganawa, H.; Hattori, S.; Hamada, M.; Ishizuka, M.;
Takeuchi, T.; Iitaka, Y. J. Antibiot. 1991, 44, 557–559.
2. (a) Kawatsu, M.; Yamashita, T.; Osono, M.; Ishizuka, M.;
Takeuchi, T. J. Antibiot. 1993, 46, 1687–1691; (b) Kawa-
tsu, M.; Yamashita, T.; Osono, M.; Ishizuka, M.; Takeu-
chi, T. J. Antibiot. 1993, 46, 1692–1698; (c) Kawatsu, M.;
Yamashita, T.; Ishizuka, M.; Takeuchi, T. J. Antibiot.
1994, 47, 1123–1129; (d) Ishizuka, M.; Kawatsu, M.;
Yamashita, T.; Ueno, M.; Takeuchi, T. Int. J. Immuno-
pharmacol. 1995, 17, 133–139.
3. (a) Kawatsu, M.; Yamashita, T.; Ishizuka, M.; Takeuchi,
T. J. Antibiot. 1995, 48, 222–225; (b) Hamada, M.;
Yamamoto, S.; Moriguchi, S.; Kishino, Y. J. Antibiot.
2001, 54, 349–353; (c) Hamada, M.; Sonotake, E.;
Yamamoto, S.; Moriguchi, S. J. Antibiot. 1999, 53, 548–
551.
4. For total syntheses of the molecule see: (a) Hatakeyama,
S.; Fukuyama, H.; Mukugi, Y.; Irie, H. Tetrahedron Lett.
1996, 37, 4047–4050; (b) Sano, S.; Miwa, T.; Hayashi, K.;
Nozaki, K.; Ozaki, Y.; Nagao, Y. Tetrahedron Lett. 2001,
42, 4029–4031; (c) Matsukawa, Y.; Isobe, M.; Kotsuki, H.;
Ichikawa, Y. J. Org. Chem. 2005, 70, 5339–5341; (d)
Yakura, T.; Yoshimoto, Y.; Ishida, C.; Mabuchi, S.
Synlett 2006, 930–932; For a formal asymmetric synthesis
of (+)-conagenin see: (e) Enders, D.; Bartsch, M.; Run-
8. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780.
9. (a) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I.
Acc. Chem. Res. 1998, 31, 9–17; (b) Evans, D. A.; Rieger,
D. L.; Gage, J. R. Tetrahedron Lett. 1990, 31, 7099–7102.
10. Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1–299.
11. Hatakeyama, S.; Matsumoto, H.; Fukuyama, H.;
Mukugi, Y.; Irie, H. J. Org. Chem. 1997, 62, 2275–2279.
12. Data for diacetylconagenin methyl ester 15: Rf = 0.4
29
(silica gel 70% EtOAc in petroleum ether); ½aꢁD +33.0 (c
0.51, CHCl3); IR (neat) mmax 3400, 3020, 1737, 1682 cmꢀ1
;
1H NMR (CDCl3, 200 MHz): d 7.15 (s, 1H, NH), 5.09–
5.89 (m, 2H), 4.15 (dd, J = 10.9, 3.1 Hz, 1H), 3.83 (dd,
J = 10.9, 5.4 Hz, 1H), 3.80 (s, 3H, CO2Me), 2.29 (qt,
J = 7, 5.4 Hz, 1H), 2.19 (s, 3H, CH3CO–), 2.07 (s, 3H,
CH3CO), 1.55 (s, 3H), 1.26 (d, J = 6.2 Hz, 3H) 1.02 (d,
J = 7 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d 173.4,
170.8, 170.2, 168.8, 75.1, 71.0, 65.4, 62.4, 53.0, 39.7, 21.1,
20.6, 19.6, 18.0, 9.6; MS (LSIMS): m/z (%) 348 (5)
[M+H]+, 370 (72) [M+Na]+.
31
Data for (+)-conagenin (1): ½aꢁD +50.2 (c 0.38, MeOH);
1H NMR (CD3OD, 500 MHz): d 4.16 (d, J = 2.4 Hz, 1H),
4.10 (d, J = 11 Hz, 1H), 3.93–3.82 (m, 2H), 1.93 (m, 1H),
1.50 (s, 3H), 1.23 (d, J = 6.1 Hz, 3H), 0.94 (d, J = 7.3 Hz,
3H); MS (LSIMS): m/z (%) 272 (18) [M+Na]+.