A stereoselective synthesis of the C13-C19 fragment of sanglifehrin A

Article abstract of DOI:10.1016/S0040-4039(02)00191-0

A stereo-controlled radical C-C bond formation involving a 5-chloro-5-deoxy-L-idofurano-6,3-lactone derivative and allyltri-n-butyltin/AIBN is described. Further elaboration led to the synthesis of the C13-C19 segment of sanglifehrin A.

Full text of DOI:10.1016/S0040-4039(02)00191-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2435–2438
A stereoselective synthesis of the C13ꢀC19 fragment of
sanglifehrin A
Mukund K. Gurjar* and Siddhartha Ray Chaudhuri
National Chemical Laboratory, Pune 411008, India
Received 6 November 2001; revised 17 January 2002; accepted 24 January 2002
Abstract—A stereo-controlled radical CꢀC bond formation involving a 5-chloro-5-deoxy-L-idofurano-6,3-lactone derivative and
allyltri-n-butyltin/AIBN is described. Further elaboration led to the synthesis of the C13ꢀC19 segment of sanglifehrin A. © 2002
Published by Elsevier Science Ltd.
A large number of immunosuppressive agents repre-
sented by cyclosporin A, FK- 506, ISP-1, pironetin, etc
have become focal points of investigations.1 These com-
pounds, except pironetin, are involved in T-lymphocyte
inhibition. However, there is a demand to discover
immunosuppressants such as pironetin,2 which can
inhibit both T- and B-lymphocytes simultaneously. But,
pironetin is associated with cytotoxicity. The recently
isolated3 natural product sanglifehrin A (1) showed
immunosuppressive activity against both T- and B-
lymphocytes. This bio-activity coupled with the struc-
tural ingenuity of 1 has attracted much attention4
towards synthetic investigations leading to its total
synthesis. As a part of our long standing interest5 in
immunosuppressive agents, the synthesis of sanglifehrin
A (1) was chosen for investigation and this report
communicates a synthesis of the C13ꢀC19 segment
Our strategy to the above segment of sanglifehrin A (1)
was founded on the study of stereoselective CꢀC bond
formation through a radical mediated reaction of the
5-chloro-5-deoxy-glucurono-6,3-lactone derivative (2)
with carbon electrophiles. This step was envisaged to
stereochemically control the installation of the crucial
side-chain present at C-14 of 1. The stereochemical
correlation of the remaining C2ꢀC4 segment of 2 with
C15ꢀC17 of the natural product should be amenable by
the virtue of well-defined transformations of carbohy-
drate chemistry. More importantly, the 1,2-acetonide
backbone of 2 inherently blocked non-participating
hydroxy groups, thus circumventing to a large extent,
protection–deprotection protocols.
The synthesis started with the radical CꢀC bond forma-
tion of the known6 5-chloro-5-deoxy-1,2-O-isopropy-
starting from 1,2-O-isopropylidene-a-
D
-glucurono-6,3-
lidine-a-
L
-idofurano-6,3-lactone (2) with various
lactone.
electrophiles7 shown in Table 1. Surprisingly, methyl
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00191-0

2436
M. K. Gurjar, S. R. Chaudhuri / Tetrahedron Letters 43 (2002) 2435–2438
Table 1.
vinyl ketone (entry 1), was found to be a poor elec-
trophile, the reaction generating predominantly the
hydrodechlorination product (4). The reaction with
ethyl acrylate (entry 2) gave the desired product (3) in
only 25% yield. The most promising results were
obtained from the reaction of 2 with allyltri-n-butyltin
in the presence of AIBN in refluxing benzene.
In another sequence, compound 5 was reduced with
LAH in THF and then subjected to a hydroboration–
oxidation sequence to afford 7 which had already been
transformed into 8. The conversion of 8 into the corre-
sponding 3-ulose derivative (10) via 9 was accomplished
in three high yielding steps (Scheme 1).
Our next concern was to introduce the methyl group at
C-3 with concomitant epimerization at C-4 via the
intermediate 12. Grignard reaction of 10 with MeMgI
furnished the carbinol derivative (11). We believe based
on literature precedents9 that the methyl group
approaches from the top face leading to 11 as the
exclusive product.
From these observations it was apparent that the com-
petitive dechlorination reaction, due to the presence of
Bu3SnH (entries 1–2), was a major stumbling block.
The next objective was to ascertain the stereochemistry
1
at C-5. For example, the H NMR spectrum of com-
pound 3 (entry 2) was amenable to first order splitting
which clearly revealed signals due to H-1, H-2, H-3 and
H-4 as doublets at l 6.00 (J=3.4 Hz), 4.83 (J=3.4 Hz),
4.84 (J=3.2 Hz) and 4.71 (J=3.2 Hz). The lack of any
coupling between H-4/H-5 confirmed the trans relation-
ship and the structure as 3. In addition, the triplet due
The elimination step was carried out by reacting 11
1
with triflic anhydride in Py/CH2Cl2 at −15°C. The H
NMR spectrum of the newly formed product did not
correspond to the expected structure 12. However,
1
1
based on the H and 13C NMR spectroscopic data, the
to H-5 appeared at l 2.76 (J=8.7 Hz). Similarly the H
NMR spectrum of 5 was useful proving its structure
beyond any doubt.
presence of an exo-methylene group was noted and
structure 13 is proposed. The structure was further
supported when 13 was hydrogenated over Pd/C to
1
The lithium aluminium hydride (LAH) reduction of 3
in THF gave a triol which was protected as its seven-
membered acetonide derivative (7) whose successive
oxidation, Grignard reaction with MeMgI and benzyla-
tion gave 8.8
produce 14 whose H NMR spectrum was consistent
with the assigned structure (Scheme 2).
In order to circumvent the above problem, we revised
our initial strategy according to which 9 was subjected

M. K. Gurjar, S. R. Chaudhuri / Tetrahedron Letters 43 (2002) 2435–2438
2437
Scheme 1. Reagents and conditions: (a) LAH, THF, 0°C–rt, 2 h (90%); (b) 2,2-dimethoxypropane, PTSA, CH2Cl2, 3 h (70%); (c)
BH3:DMS, NaOAc, H2O2 (75%); (d) (COCl)2, DMSO, ET3N, CH2Cl2, −78°C; (e) CH3MgI, Et2O, THF, rt, 2 h (75%, two steps);
(f) BnBr, NaH, DMF, rt (80%); (g) 0.8% H2SO4, MeOH (85%); (h) TBS-Cl, imidazole, CH2Cl2, rt (90%).
Scheme 2. Reagents and conditions: (a) CH3MgI, Et2O, THF, 0–rt, 2 h (75%, from 10); (b) TF2O, Py, CH2Cl2, 1.5 h, −15°C; (c)
DBU, Et2O; 12 h (75%, two steps); (d) 10% Pd/C, H2, MeOH, 3 h (95%).
Scheme 3. Reagents and conditions: (a) TF2O, Py, CH2Cl2, −15°C, 1.5 h; (b) DBU, Et2O; rt, 12 h (75%, two steps); (c) BH3:DMS,
NaOAc, H2O2 (75%); (d) (COCl)2, DMSO, ET3N, CH2Cl2, −78°C; (e) PhP3ꢁCH2, THF, −15°C–rt (80%, two steps); (f) BH3:DMS,
NaOAc, H2O2, THF; (g) NaH, THF, 0–rt, CS2, rt, MeI; Bu3SnH, AIBN, toluene, reflux, 3 h (50%, three steps); (h) TBAF, THF,
rt, 1 h; (i) RuCl3·H2O, CH3CN:CCl4:H2O, NaIO4, 2 h (50%).

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M. K. Gurjar, S. R. Chaudhuri / Tetrahedron Letters 43 (2002) 2435–2438
to an elimination reaction to give 15 which on hydro-
boration–oxidation gave the alcohol 16 in which the
stereochemistry at C-4 had been reversed. The 1H NMR
spectrum of 16 when compared with 9 supported the
assigned structure. The derived exo-methylene derivative
(17) was transformed into the C-3 methyl derivative (18)
in two steps involving hydroboration–oxidation and
Barton-radical deoxygenation reactions.10,11 The stereo-
centres at C-3 and C-4 of 18 were compatible with C16
and C15 of 1, respectively. Removal of the silyl protect-
ing group and oxidation with RuCl3/NaIO4 in CH3CN–
CCl4–H2O gave 19 in which the benzyl group was also
oxidised to the benzoate.
5. (a) Gurjar, M. K.; Henri, J. T., Jr.; Bose, D. S.; Rama Rao,
A. V. Tetrahedron Lett. 1996, 37, 6615; (b) Rama Rao, A.
V.; Murali Dhar, T. G.; Bose, D. S.; Chakraborty, T. K.;
Gurjar, M. K. Tetrahedron 1989, 45, 7361.
6. Gurjar, M. K.; Pawar, S. M. Tetrahedron Lett. 1987, 28,
1327.
7. Keck, G. E.; Enholm, E. J; Yates, J. B.; Wiley, M. R.
Tetrahedron 1985, 41, 4079.
8. The Grignard reaction gave predominantly (>95%) of a
single diastereomer based on its 1H and 13C NMR spectro-
scopic data. The newly formed stereo-centre of 8 is of no
consequence as it will finally be transformed into a ketone
functionality.
9. Vasella, A. In Modern Synthetic Methods; Schoffold, R.,
Ed.; Verlag, O. S: Frankfurt, 1980; Vol. 2, p. 173.
10. Barton, D. H. R.; Motherwell, B. Pure Appl. Chem. 1981,
53, 15.
1
In the H NMR spectrum of 19, signals due to H-8
appeared at 5.12 ppm as a multiplet indicating the
presence of a benzoate group at this carbon. The
double-doublet (J=2.0, 4.8 Hz) due to H-2 appeared at
4.57 ppm and was indicative of its coupling with H-1 and
H-3 and therefore the syn relation between H-2/H-3. In
addition H-4 revealed a double–doublet (J=8.0, 10.0 Hz)
at 4.13 ppm. The MS, 13C NMR and elemental analysis
of 19 were in support of the assigned structure (Scheme
3).12
11. PdꢀC-catalysed hydrogenation of 17 even at 250 psi was
found to be very sluggish perhaps due to steric reasons.
12. Spectroscopic data of some selected compounds: 3: 1H
NMR (500 MHz, CDCl3): 1.27 (t, 3 H, J=7.6 Hz), 1.35
(s, 3 H), 1.54 (s, 3 H), 1.94 (m, 2 H), 2.52 (m, 2 H), 2.76
(t, 1 H, J=8.7 Hz), 4.18 (q, 2 H, J=7.6 Hz), 4.71 (d, 1
H, J=3.2 Hz), 4.83 (d, 1 H, J=3.4 Hz), 4.84 (d, 1 H, J=3.2
Hz), 6.0 (d, 1 H, J=3.4 Hz); 13C NMR (125 MHz, CDCl3):
14.3, 23.2, 26.5, 27.0, 31.3, 46.5, 60.8, 82.3, 82.9, 84.2,
106.0, 112.7, 172.0, 175.9; MS: 285 (M+−15). Compound
In conclusion, this communication reports a highly
stereo-controlled radical CꢀC bond formation on glu-
curono-6,3-lactone and elegant synthetic manoeuvering
to complete the C-13 to C-19 segment of sanglifehrin A
(1). Our next strategy is to couple the peptide segment
with the carboxylic acid portion of 19 followed by
synthetic elaboration at C-1.
1
5: H NMR (200 MHz, CDCl3): 1.34 (s, 3 H), 1.50 (s, 3
H), 2.32 (dt, 1 H, J=8.0, 14.0 Hz), 2.49 (dt, 1 H, J=6.0,
14.0 Hz), 2.81 (dd, 1 H, J=6.0, 8.0 Hz), 4.71 (d, 1 H, J=2.0
Hz), 4.75 (d, 1 H, J=4.0 Hz), 4.81 (d, 1 H, J=4.0 Hz),
5.20 (m, 2 H), 5.78 (m, 1 H), 5.94 (d, 1 H, J=4.0 Hz); 13
C
NMR (50 MHz, CDCl3): 25.9, 26.0, 31.6, 46.4, 81.7, 82.0,
83.7, 105.4, 111.8, 118.0, 132.8, 175.7; MS: 225 (M+−15).
Anal. calcd for C12H16O5: C, 59.99; H, 6.71. Found: C,
59.52; H, 6.75. Compound 16: 1H NMR (200 MHz,
CDCl3): 0.06 (s, 6 H), 0.90 (s, 9 H), 1.19 (d, 3 H, J=6.5
Hz), 1.33 (s, 3 H), 1.49 (s, 3 H), 1.55 (m, 4 H), 1.85 (m,
1 H), 3.49 (m, 1 H), 3.76 (m, 3 H), 4.08 (m, 1 H), 4.44,
4.57 (ABq, 2 H), 4.51 (dd, 1 H, J=2.0, 4.0 Hz), 5.75 (d,
1 H, J=4.0 Hz), 7.3 (m, 5 H); 13C NMR (50 MHz, CDCl3):
−5.5, 18.3, 19.7, 21.5, 25.9, 26.8, 27.6, 29.7, 34.0, 42.3,
62.2, 70.3, 74.9, 76.8, 87.0, 87.7, 104.2, 113.1, 127.4, 128.3,
138.9. Anal. calcd for C26H44O6Si: C, 64.95; H, 9.23.
References
1. (a) Rosen, K. M.; Schreiber, S. L. Angew. Chem., Int. Ed.
Engl. 1992, 31, 384; (b) Schreiber, S. L.; Albers, M. W.;
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S. L.; Liu, J.; Albers, M. W.; Rosen, M. K.; Standadaert,
R. F.; Wandless, T. J.; Somers, P. K. Tetrahedron 1992,
48, 2545.
2. (a) Kobayashi, S.; Tsochiya, K.; Harada, T.; Nishide, M.;
Kurokawa, T.; Nakagawa, T.; Shimada, N.; Kobayashi,
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K.; Kurokawa, T.; Nakagawa, T.; Shimada, N.; Iitaka, T.
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Mahnke, M.; Memmert, K.; Schuler, W.; Zenke, G.;
Gschwind, L.; Maurer, C.; Schilling, W. J. Antibiot. 1999,
52, 466; (b) Fehr, T.; Kallen, J.; Oberer, L.; Sanglier, J. J.;
Schilling, W. J. Antibiot. 1999, 52, 474.
4. (a) Nicolaou, K. C.; Xu, J.; Murphy, F.; Barluenga, S.;
Baudin, O.; Wei, H.-X.; Gray, D. L. F.; Ohshima, T.
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1
Found: C, 64.87; H, 9.66. Compound 17: H NMR (200
MHz, CDCl3): 0.06 (s, 6 H), 0.89 (s, 9 H), 1.21 (d, 3 H,
J=6.5 Hz), 1.33 (s, 3 H), 1.50 (s, 3 H), 1.51–1.71 (m, 4 H),
1.77 (m, 1 H), 3.49 (m, 1 H), 3.78 (m, 2 H), 4.50 (m, 3 H),
4.85 (d, 1 H, J=4.0 Hz), 5.16 (br. s, 1 H), 5.42 (br. s, 1
H), 5.77 (d, 1 H, J=4.0 Hz), 7.3 (m, 5 H); 13C NMR (50
MHz, CDCl3): −5.6, 18.1, 19.3, 19.5, 22.6, 25.8, 26.8, 33.5,
44.7, 60.9, 69.9, 74.8, 81.6, 82.5, 104.7, 112.4, 113.3, 127.0,
128.0, 139.0, 146.4; MS: 461 (M+−15). Anal. calcd for
C27H44O5Si: C, 68.01; H, 9.31. Found: C, 67.56; H, 9.03.
1
Compound 19: H NMR (200 MHz, CDCl3): 1.0–2.0 (m,
10 H), 1.34 (s, 3 H), 1.65 (s, 3 H), 2.43 (m, 1 H), 3.10 (m,
1 H), 4.13 (dd, 1 H, J=8.0, 10.0 Hz), 4.57 (dd, 1 H, J=2.0,
4.8 Hz), 5.12 (m, 1 H), 5.76 (d 1 H, J=2.0 Hz), 7.43 (m,
3 H), 8.02 (d, 2 H, J=7.0 Hz); 13C NMR (50 MHz, CDCl3):
9.7, 20.1, 25.6, 25.8, 33.6, 39.5, 48.8, 70.9, 71.4, 83.2, 105.2,
112.6, 128.3, 129.5, 130.7, 132.8, 166.2, 177.0, MS: 377
(M+−15). Anal. calcd for C21H28O7: C, 64.26; H, 7.20.
Found: C, 65.42; H, 7.99.