J. S. Yadav et al. / Tetrahedron Letters 53 (2012) 2504–2507
2507
O
OMOM
O
Tos
NC
OMOM
MeO
OMOM
LHMDS, THF:HMPA (4:1),
.
Tos
O
MeO
I
OMOM
.
+
O
CN
-78 oC-r.t, 10 h, 70%
O
O
O
O
O
32
31
3
O
O
O
O
HO
.
O
BBr3, CH2CI2, -78 oC-rt, 18h, 40%
HO
HO
O
2
Scheme 5. Synthesis of the C38–C54 segment (2) of halichondrin B.
3. (a) Hamel, E. H. Pharmac. Ther. 1992, 55, 31–51; (b) Luduena, R. F.; Roach, M. C.;
Prasad, V.; Pettit, G. R. Biochem. Pharmacol. 1993, 45, 421–427; (c) Pettit, G. R.
Pure Appl. Chem. 1994, 66, 2271–2281; (d) Paull, K. D.; Lin, C. M.; Malspeis, L.;
Hamel, E. Cancer Res. 1992, 52, 3892.
4. Aicher, T. D.; Buszek, K. R. G.; Fang, F. J.; Forsyth, C.; Jung, S. H.; Kishi, Y.;
Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114,
3162–3164.
5. (a) Austad, B. C.; Hart, A. C.; Burke, S. D. Tetrahedron 2002, 58, 2011–2026; (b)
Burke, S. D.; Austad, B. C.; Hart, A. C. J. Org. Chem. 1998, 63, 6770–6771; (c)
Burke, S. D.; Buchanan, J. L.; Rovin, J. D. Tetrahedron Lett. 1991, 32, 3961–3964;
(d) Burke, S. D.; Zhang, H.; Buchanan, J. L. Tetrahedron Lett. 1995, 36, 7023–
7026; (e) Cooper, A. J.; Pan, W.; Salomon, R. G. Tetrahedron Lett. 1993, 34, 8193–
8196; (f) Stamos, D. P.; Kishi, Y. Tetrahedron Lett. 1996, 37, 8643–8646; (g)
James, J.; Duan, W.; Kishi, Y. Tetrahedron Lett. 1993, 34, 7541–7544; (h) Aicher,
T. D.; Kishi, Y. Tetrahedron Lett. 1987, 28, 3463–3466; (i) Cooper, A. J.; Salomon,
R. G. Tetrahedron Lett. 1990, 31, 3813–3816; (j) Burke, S. D.; Jung, K. W.; Phillips,
J. R.; Perri, R. E. Tetrahedron Lett. 1994, 35, 703–706.
TPP, iodine, and imidazole in THF afforded yellow colored com-
pound 3 in 90% yield.
For the preparation of the other alkylated fragment 31, alde-
hyde 13 (prepared as shown in Scheme 2) was chosen as the start-
ing material. Thus, oxidation of aldehyde 13 with sodium chlorite
in DMSO under buffer conditions provided the corresponding car-
boxylic acid. Deprotection of the acetonide followed by cyclization
occurred in one-pot by using a catalytic amount of concentrated
HCl in methanol to furnish the five membered lactone 2816
(Scheme 4). The resulting secondary hydroxyl group in 28 was pro-
tected as its MOM ether by using MOM-Cl and DIPEA to furnish 29.
Removal of the benzyl group by Pd(OH)2 in benzene followed by
the treatment with iodine and TPP yielded iodo compound 5. The
crude alkyl iodide 5 on treatment with TosMIC 4 (tosyl methyl iso-
cyanide) in the presence of n-BuLi in a mixture of THF:HMPA (4:1)
afforded 3117 in 85% yield over two steps.
6. (a) Barry, M.; Trost; Yoshinori, K. Tetrahedron Lett. 1991, 32, 1613–1616; (b)
Yadav, J. S.; Sathaiah, K.; Srinivas, R. Tetrahedron 2009, 65, 3545–3552.
7. Kolb, H. C.; Nieuwenhze, M. S. V.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483–
2547.
8. The diastereomeric excess of the product was determined using a Shimadzu
Further alkylation of the anion generated from 31 using LHMDS
in THF/HMPA (4:1) with iodo compound 3 gave di alkylated prod-
high-performance liquid-chromatography (HPLC) system equipped with
chiral HPLC column (Chiralcel OD) and a UV detector at an absorbance of
(column) and a solvent system of
a
uct 3217 (70%), which upon treatment with BBr3 in CH2Cl2 affor-
18
225 nm. ATLANTIS DC18 150 ꢂ 4.6 mm, 5
l
acetonitrile and water (6:4) at a flow rate of 1.0 ml/min were used. tR: 6.8 and
7.5 min.
ded the targeted spiroketal 2 comprising the K, L, M, and N rings as
well as ten out of the 32 stereogenic centers of the natural product
(Scheme 5). The spectroscopic (1H NMR, 13C NMR, IR, Mass) and
9. Liu, J. H.; Long, Y. Q. Tetrahedron Lett. 2009, 50, 4592–4594.
10. (a) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2002, 4, 2605–2606; (b)
Strand, D.; Rein, T. Org. Lett. 2005, 7, 199–202; (c) Georges, Y.; Ariza, X.; Garcia,
J. J. Org. Chem. 2009, 74, 2008–2012.
physical data (½a D25
ꢁ
) of the synthetic fragment 2 were in good
agreement with the reported data of Burke5a et al.
11. The diastereomeric excess of the product was determined using a Shimadzu
In summary, the double alkylation TosMIC strategy was used to
construct the C38–C54 spiroketal segment of halichondrin B com-
prising the KLM N ring system including 10 stereogenic centers.
Other salient features of the synthesis are the use of Carreira’s
addition, Sharpless asymmetric dihydroxylation, and double vinyl
coupling reactions.
high-performance liquid-chromatography (HPLC) system equipped with
chiral HPLC column (Chiralcel OD) and a UV detector at an absorbance of
(column) and a solvent system of
acetonitrile and water (3:7) at a flow rate of 1.0 ml/min were used. tR: 15.9 and
17.2 min.
a
225 nm. ZORBAX SBC 18 250 ꢂ 4.6 mm, 5
l
12. (a) Sabitha, G.; Reddy, C. N.; Raju, A.; Yadav, J. S. Tetrahedron: Asymmetry 2011,
22, 493–498; (b) S. Chandrasekhar, A. Sudhakar, Org. Lett. 2010, 12, 236–238.
The diastereomeric excess of the product was determined using a Shimadzu
high-performance liquid-chromatography (HPLC) system equipped with
chiral HPLC column (Chiralcel OD) and a UV detector at an absorbance of
(column) and a solvent system of
acetonitrile and water (4:6) at a flow rate of 1.0 ml/min were used. tR: 6.4 and
7.1 min.
a
Acknowledgments
225 nm. ZORBAX SBC 18 250 ꢂ 4.6 mm, 5
l
C.N.R. thanks UGC-New Delhi for the award of fellowship. J.S.Y.
acknowledges the partial support by the King Saud University for
Global Research Network for Organic Synthesis (GRNOS).
13. Kashman, Y. J. Org. Chem. 1972, 37, 912–914.
14. Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765–766.
15. Sabitha, G.; Reddy, C. N.; Gopal, P.; Yadav, J. S. Tetrahedron Lett. 2010, 51, 5736–
5739. The diastereomeric excess of the product was determined using
Shimadzu high-performance liquid-chromatography (HPLC) system equipped
with a chiral HPLC column (Chiralcel OD) and a UV detector at an absorbance of
a
References and notes
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225 nm. WATERS ATLANTIS 150 ꢂ 4.6 mm, 5
l (column) and a solvent system
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