Formal synthesis of fostriecin by a carbohydrate-based approach

Article abstract of DOI:10.1016/j.tetlet.2006.03.116

The formal synthesis of fostriecin starting from d-glucose, involves chelation-controlled addition, Wittig rearrangement, ring closing metathesis and iodomethylenation, as described.

Full text of DOI:10.1016/j.tetlet.2006.03.116

Tetrahedron Letters 47 (2006) 3773–3776
Formal synthesis of fostriecin by a carbohydrate-based approachI
J. S. Yadav,* I. Prathap and Bulli Padmaja Tadi
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 21 December 2005; revised 8 March 2006; accepted 17 March 2006
Available online 17 April 2006
Abstract—The formal synthesis of fostriecin starting from D-glucose, involves chelation-controlled addition, Wittig rearrangement,
ring closing metathesis and iodomethylenation, as described.
Ó 2006 Elsevier Ltd. All rights reserved.
OH
14
Fostriecin (CI-920) 1, a cytotoxic phosphate ester natu-
ral product isolated from Streptomyces pulveraceus, pos-
sesses potent anticancer activity against leukaemia and
many other cell lines.1,2 The cytotoxic properties of 1
are attributed to its selective inhibition of protein phos-
phatase 2A (PP2A).3 The relative and absolute stereo-
chemistry of 1 was established by Boger,4 who also
disclosed the first synthesis of the natural product,5 as
well as by preliminary SAR studies.6 A number of total
syntheses7 as well as synthetic approaches to fostriecin
have been reported in the literature.8 However, it contin-
ues to be a challenging endeavor to synthesize this
molecule using inexpensive and readily available raw
materials via shorter routes.
2
O
9
OH
11
H2O3P
18
8
13
O
O
5
12
HO CH3
Fostriecin ( CI - 920 ) 1
OH OH
I
O
O
HO CH3
Key intermediate 2
Figure 1.
rearrangement.11 Asymmetric allylation and generation
of the Z-olefin by iodomethylenation12 completed the
synthesis of 2 (Scheme 2).
Herein, we disclose a chiral pool approach to the C1–
C13 fragment 2, a key intermediate in the Imanishi syn-
thesis of fostriecin (Fig. 1).7d The C14–C18 fragment has
been prepared in a straightforward fashion,9 and has
also been attached to the C1–C13 fragment.7a,f,d
Elimination of the triflate derived from glucose diaceto-
nide 313a by treatment with DBU afforded olefin 4.14
Subsequent hydrogenation of 4 in the presence of
Raney-Ni in ethanol at 40 psi gave 5, whose spectral
and analytical data were in agreement with the assigned
structure.15a
Our approach to 2 is illustrated in Scheme 1, in which
the key fragment 8 obtained from D-glucose, plays a
central role, serving not only as the source of the C-9
and C-11 stereocentres, but also sets the stage for intro-
ducing the C-8 and C-5 stereocentres through chelation-
controlled addition10 of anion 9 (M = MgBr) and Wittig
Selective deprotection of the 5,6-O-isopropylidene
group, followed by sodium periodate mediated oxidative
cleavage of diol 6 and Grignard reaction of the resulting
aldehyde with methylmagnesium iodide in ether at 0 °C,
gave a diastereomeric mixture of alcohol 7, which was
oxidized using PCC and NaOAc in CH2Cl2 to give the
ketone 8.15b Following the above sequence, a higher
overall yield of ketone 8 (59%) was obtained from 3 as
compared to earlier routes (44%) using the same starting
material.13
Keywords: D-Glucose; Raney-Ni; Chelation-controlled addition; Wit-
tig rearrangement; Wittig olefination; Chiral allylation; Ring closing
metathesis, Iodomethylenation.
q IICT Communication No. 051213.
*
Corresponding author. Tel.: +91 40 27193434; fax: +91 40
27160512; e-mail: yadavpub@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.116

3774
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 3773–3776
H
O
H
O
O
O
b
d,e
OH
O
a
EtO
O
O
HOH2C
O
O
8
c
b
O
O
a
O
O
O
O
D-Glucose
O
14
13
O
O
O
HO
4
3
f
c
HOH2C
HO
O
O
O
O
O
O
d
e,f
O
O
O
HO CH3
O
O
O
HO
O
16
15
OH
O
O
O
7
5
6
O
g
O
HO
h
O
O
O
O
HO CH3
O
O
h
g
O
HO CH3
O
HO CH3
+
O
O
OH
18
17
H3C
O
i
O
8
10a (73%)
10b (18%)
O
i
j, k
OHC
O
O
O
HO
O
j
HO CH3
O
O
10a
O
O
HO CH3
O
HO
19
HO
12a
O
HO CH3
HO CH3
O
O
11
12a (50%)
l
O
O
OH
OH
+
O
O
O
O
O
M
O
HO CH3
HO CH3
O
HO
O
21
20
HO CH3
O
9
m
12b (25%)
Imanishi
OH OH
1
I
O
O
synthesis
Scheme 1. Reagents and conditions: (a) Ref. 12a; (b) Tf2O, pyridine,
CH2Cl2, 0 °C, 0.5 h, then DBU, rt, 16 h, 94%; (c) Raney-Ni, H2,
ethanol, 40 psi, 6 h, 98%; (d) 40% AcOH, rt, 6 h, 83%; (e) NaIO4 on
silica gel, CH2Cl2/H2O (8:2), 1 h; (f) MeMgI, ether, 0 °C, 2 h, 88% (for
two steps); (g) PCC, NaOAc, CH2Cl2, rt, 12 h, 89%; (h) 9, ꢀ78 to
ꢀ50 °C, 3 h, 91% (9a alone 73%); (i) n-BuLi (5 equiv), THF, ꢀ100 °C,
3 h; (j) LiAlH4, THF, 0 °C to rt, 2 h; 75% (for two steps, 12a alone 50%).
HO CH3
key intermediate 2
(Z : E ratio 3 : 1)
Scheme 2. Reagents and conditions: (a) Ph3PCHCOOEt (3 equiv),
C6H5COOH (cat), toluene, reflux, 16 h, 91% (E-isomer alone 83%); (b)
DIBAL-H, THF, ꢀ78–0 °C, 2 h, 92%; (c) (+)-DIPT, Ti(O-i-Pr)4,
˚
TBHP, 4 A molecular sieves, CH2Cl2, ꢀ23 °C, 24 h, 90%; (d) TPP,
CCl4, reflux, 6 h; (e) n-BuLi, THF, ꢀ23 °C, 84% (two steps, 76%, 16);
(f) EtMgBr, THF, 0 °C, 1 h then (CH2O)n, reflux, 3 h, 79%; (g)
LiAlH4, THF, 0 °C to rt, 2 h, 91%; (h) Dess–Martin periodinane,
NaHCO3, CH2Cl2, rt, 94%; (i) (+)-Ipc2BOMe, allylmagnesium
bromide, Et2O, ꢀ100 to 23 °C, 1.5 h; 30% H2O2, pH 7 buffer, 23 °C,
12 h, 79%; (j) acryloyl chloride, DIPEA, CH2Cl2, 0 °C, 2 h; (k)
(PCy3)2RuCl2(@CHPh) (0.1 equiv), Ti(O-i-Pr)4 (0.3 equiv), CH2Cl2,
reflux, 12 h, 92% (for two steps); (l) 30% AcOH, 50 °C, 2 h, 92%;
(m) Ph3P+CHI Iꢀ, NaHMDS, HMPT, ꢀ78 °C to rt, 2 h, 63% (Z:E
ratio = 3:1).
The stereocentre at C-8 of fostriecin was introduced by
the chelation-controlled addition10 of 9 (M = MgBr),
generated from allyl propargyl ether and EtMgBr in
THF at 0 °C to ketone 8 in THF at ꢀ78 to ꢀ50 °C
for 3 h to afford a chromatographically separable mix-
ture of diastereomers 10a and 10b in 91% yield in a ratio
of 8:2. Additionally, the reaction of the lithium anion of
9 (M = Li) with ketone 8 was also examined under the
same reaction conditions, which gave a mixture of 10a
and 10b in a 3:7 ratio.
Compound 10a was subjected to Wittig rearrangement11
by treatment with excess n-BuLi at ꢀ100 °C for 3 h to
afford 11. Reduction of the triple bond using LiAlH4
in THF afforded a separable mixture of diastereomers
12a and 12b in a 2:1 ratio (Scheme 1).
not separated at this stage, transformation by our meth-
odology17 furnished acetylenic alcohol 16 in 76% yield
after chromatography on silica gel, without contamina-
tion by the other diastereomer. Compound 16 when
subjected to formylation gave 17 in 79% yield, which
upon protection as its allyl ether, gave spectral and ana-
lytical data in agreement with the assigned structure of
10a.18a
The stereocentres at C-8 and C-5 were also confirmed by
establishing another route, for which ketone 8 was sub-
jected to Wittig olefination with (carboethoxymethyl-
idene)triphenylphosphorane and catalytic benzoic acid
in refluxing toluene to afford E-ester 13 in 83% yield.
The ester was reduced to allylic alcohol 14 using DI-
BAL-H in THF. Sharpless asymmetric epoxidation16
of 14 proceeded efficiently to produce epoxide 15 in
90% yield in a 10:1 ratio. Although the mixture was
Triple bond reduction of 17 with LiAlH4 in THF
provided allylic alcohol 18. Oxidation of 18 with Dess–
Martin periodinane gave aldehyde 19, which underwent
asymmetric allylation19 using (+)-b-methoxydiisopino-
camphenyl borane and allylmagnesium bromide at low
temperature to afford 12a in 79% yield.

J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 3773–3776
3775
8. (a) Just, G.; O’Connor, B. Tetrahedron Lett. 1988, 29,
753–756; (b) Liu, S. Y.; Huang, D. F.; Huang, H. H.;
Huang, L. Chin. Chem. Lett. 2000, 11, 957–960; (c) Cossy,
J.; Pradaux, F.; BouzBouz, S. Org. Lett. 2001, 3, 2233–
2235; (d) Kiyotsuka, Y.; Igarashi, J.; Kobayashi, Y.
Tetrahedron Lett. 2002, 43, 2725–2729; (e) Marshall, J. A.;
Bourbeau, M. P. Org. Lett. 2003, 5, 3197–3199; (f)
Ramachandran, P. V.; Liu, H. P.; Reddy, M. V. R.;
Brown, H. C. Org. Lett. 2003, 5, 3755–3757.
9. Mapp, A. K.; Heathcock, C. H. J. Org. Chem. 1999, 64,
23–27.
Chemoselective esterification of diol 12a with acryloyl
chloride and DIPEA in CH2Cl2 at 0 °C gave an ester
alcohol, which was subjected to ring-closing metathe-
sis20 (RCM) with Grubbs’ 1st generation catalyst (0.1
equiv) in the presence of Ti(O-i-Pr)4 (0.3 equiv) in reflux-
ing CH2Cl2 for 12 h to afford lactone 20 in 92% yield.
Cleavage of the 1,2-O-isopropylidene group of 20 by
heating at 50 °C in 30% aq AcOH afforded the lactol
21. Iodomethylenation of lactol 21 gave the Z-isomer
of 2 as the major product (Z:E = 3:1; Scheme 2).
10. Still, W. C.; McDonald, J. H., III. Tetrahedron Lett. 1980,
21, 1031–1034.
11. Wittig, G.; Lohmann, L. Justus Liebigs Ann. Chem. 1942,
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12. (a) Seyferth, D.; Heeren, J. K.; Singh, G.; Grim, S. O.;
Hughes, W. B. J. Organomet. Chem. 1966, 5, 267–274; (b)
Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 2173–
2174.
In conclusion, we have disclosed the synthesis of the key
intermediate 2 in the formal synthesis of fostriecin using
a carbohydrate-based approach, which would be of
great use for the synthesis of various fostriecin
congeners.
13. (a) Schmidt, O. T. Methods Carbhydr. Chem. 1965, 2, 320–
324; (b) Wolfrom, M. L.; Hanessian, S. J. Org. Chem.
1962, 27, 1800–1804.
Acknowledgement
I.P. thanks CSIR, New Delhi, for the research
fellowship.
O
OH
O
d, e
O
b, c
a
8
3
O
O
O
O
HO
(Diacetone
glucose)
BnO
References and notes
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Reagents and conditions: (a) Ref. 12b; (b) PCC, NaOAc,
CH2Cl2, rt, 12 h, 89%; (c) Pd/C, H2, rt, 12 h, 98%; (d)
MsCl, Et3N, DMAP (cat), CH2Cl2, 0 °C–rt, 3 h, then
DBU, rt, 12 h, 94%; (e) Raney-Ni, H2, n-hexane, 98%.
14. Flechtner, T. W. Carbohydr. Res. 1979, 77, 262–266.
25
15. (a) Spectral data of compound 5: mp = 78–80 °C ½aꢁD
ꢀ28.4 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3): d 5.73
(d, J = 3.8 Hz, 1H), 4.70–4.65 (m, 1H), 4.42–4.32 (m, 1H),
4.11–4.05 (m, 1H), 4.00 (td, J = 7.7, 1.5 Hz, 1H), 3.60 (dd,
J = 8.5, 7.0 Hz, 1H), 2.24–2.09 (m, 1H), 1.82 (dd, J = 14.0,
3.8 Hz, 1H), 1.55 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.30 (s,
3H). 13C NMR (75 MHz, CDCl3): d 112.6, 109.8, 106.3,
81.3, 80.3, 77.5, 65.9, 33.4, 27.2, 26.6, 26.1, 25.2. Mass
(ESI-MS) m/z: 267 (M+Na)+. HRMS calcd for
C12H20O5Na: 267.1203 (M+Na)+. Found: 267.1208; (b)
25
Spectral data of compound 8: ½aꢁD +5.8 (c 3.2, CHCl3). 1H
NMR (300 MHz, CDCl3): d 5.82 (d, J = 4.5 Hz, 1H),
4.67–4.64 (m, 1H), 4.31 (dd, J = 9.8, 1.5 Hz, 1H), 2.69 (d,
J = 14.3 Hz, 1H), 2.32 (s, 3H), 2.11–2.02 (m, 1H), 1.37 (s,
3H), 1.25 (s, 3H). 13C NMR (75 MHz, CDCl3): d 208.8,
111.6, 106.5, 84.4, 79.5, 33.4, 26.5, 25.6, 25.3. Mass (ESI-
MS) m/z: 209 (M+Na)+. HRMS calcd for C9H14O4Na:
209.0734 (M+Na)+. Found: 209.0738.
7. (a) Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2001, 40, 3667–3670; (b) Reddy, Y. K.; Falck, J. R. Org.
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25
18. (a) Spectral data of compound 9a: ½aꢁD ꢀ28.5 (c 3.5,
CHCl3). 1H NMR (300 MHz, CDCl3): d 5.93–5.78 (m,
1H), 5.71 (d, J = 4.5 Hz, 1H), 5.29 (dd, J = 17.3, 1.5 Hz,
1H), 5.18 (dd, J = 10.5, 1.5 Hz, 1H), 4.77–4.71 (m, 1H),
4.15 (s, 2H), 4.07 (dd, J = 8.3, 7.5 Hz, 1H), 4.04–4.01 (m,
2H), 2.92 (br s, OH), 2.22 (dt, J = 13.5, 7.5 Hz 1H), 2.09
(ddd, J = 13.5, 11.3, 3.7 Hz, 1H), 1.56 (s, 3H), 1.40 (s, 3H),

3776
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 3773–3776
1.33 (s, 3H). 13C NMR (75 MHz, CDCl3): d 133.9, 117.6,
2H), 1.52 (s, 3H), 1.43 (s, 3H), 1.30 (s, 3H). 13C NMR
(75 MHz, CDCl3): d 133.8, 117.5, 113.5, 106.1, 87.4, 85.8,
80.5, 80.4, 70.3, 69.1, 57.2, 33.0, 27.1, 26.8, 26.5.
113.4, 105.7, 88.5, 86.0, 80.6, 80.3, 70.3, 68.3, 57.2, 32.0,
27.5, 26.8, 25.1. IR (Neat): 3417, 2987, 2936, 1619, 1445,
1376, 1218, 1164, 1082, 931, 860 cmꢀ1. Mass (ESI-MS) m/z:
305 (M+Na)+. HRMS calcd for C15H22O5Na: 305.1363
(M+Na)+. Found: 305.1364; (b) Spectral data of com-
19. (a) Jadav, P. K.; Brown, H. C. J. Am. Chem. Soc. 1983,
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Soc. 1996, 118, 100–110.
25
1
pound 9b: ½aꢁD +46 (c 3.5, CHCl3). H NMR (300 MHz,
CDCl3): d 5.92–5.77 (m, 1H), 5.70 (d, J = 3.77 Hz, 1H),
5.27 (dd, J = 16.8, 1.5 Hz, 1H), 5.19 (dd, J = 9.8, 1.5 Hz,
1H), 4.74–4.69 (m, 1H), 4.13 (s, 2H), 4.07 (t, J = 7.55 Hz,
1H), 4.01–3.99 (m, 2H), 3.06 (br s, OH), 2.34–2.30 (m,