3850
Y.-X. Yang et al. / Tetrahedron Letters 51 (2010) 3848–3851
Scheme 3. Reagents and conditions: (i) TBSCl, imidazole, THF, 0 °C, 8 h, 80%; (ii) Dess–Martin reagent, CH2Cl2, overnight, 98%; (iii) CH2@CHMgBr, THF, ꢀ78 °C, 94%; (iv) (a)
5 mol % 2nd Gen. Grubbs’ cat., CH2Cl2, rt, overnight; (b) Ac2O, Et3N, DMAP, two steps, 85%; (v) p-benzoquinone, PdCl2(MeCN)2, THF, 86%; (vi) (a) 1% NaOH, MeOH; (b) CH2I2,
Et2Zn, CH2Cl2, 82% (over two steps).
yielded no desired product probably due to the steric hindrance of
TBS group. Deprotection of the silyl group of 11 with TBAF gave the
corresponding alcohol 12, which subsequently underwent the
above-mentioned conditions also failed to get the target cyclized
compound. Finally, we found that the improvement of catalyst
up to 10 mol % together with CHCl3 as a solvent under reflux was
favored to form cyclopentene derivative 13 (Scheme 2).
necessary stereocenters. Meanwhile the double bond remaining in
10 and 13 possesses a useful reaction site so that polyhydroxylic
groups were elaborated either by substrate-controlled diastereose-
lective epoxidation/epoxide opening or by direct dihydroxylation.
Furthermore, we have finished the formal synthesis of N-MCT by
preparing the key carbobicyclic intermediate 19 over nine steps
in 25% overall yield under conditions that are ecologically friend-
lier than previous methods.
After successful construction of the five-membered ring scaf-
fold, we further applied this method for the formal synthesis of
N-MCT 1. As shown in Scheme 3, the primary hydroxy group of
the diol 5 was selectively protected using equal equivalent TBSCl
in the presence of imidazole in THF at lower temperature and then
Dess–Martin oxidation of the secondary alcohol 14 to the ketone
15 was almost quantitative and no purification was necessary at
this stage. An analogue of ketone 15 has been synthesized by Ludek
Acknowledgment
This work was supported by National Science & Technology Ma-
jor Project ‘Key New Drug Creation and Manufacturing Program’,
China (No.: 2009ZX09102-026).
and Marquez23 starting from 2-deoxy-
D-ribose. They also indicated
References and notes
that this compound did not show any signs of epimerization/race-
mization caused by a possible keto–enol tautomerism. Ketone 15
can also be considered as an erythrulose analogue and nucleophilic
additions of organometallic compounds to the carbonyl group of
this carbohydrate have been investigated in detail.24 According to
1. (a) Marquez, V. E.; Lim, M. Med. Res. Rev. 1986, 6, 1–40; (b) Huryn, D. M.; Okabe,
M. Chem. Rev. 1992, 92, 1745–1768.
2. For a recent synthesis, see: Burlina, F.; Favre, A.; Fourrey, J.; Thomas, M. Bioorg.
Med. Chem. Lett. 1997, 7, 247–250.
3. For a recent synthesis, see: Trost, B. M.; Madsen, R.; Guile, S. G.; Elia, A. E.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1569–1572.
these studies, both benzyl-protected hydroxyl groups in
a and
4. King, S. B.; Ganem, B. J. Am. Chem. Soc. 1994, 116, 562–570.
5. Goering, B. K.; Ganem, B. Tetrahedron Lett. 1994, 35, 6997–7000. and references
cited therein.
6. Uchida, C.; Yamagishi, T.; Kitahashi, H.; Iwaisaki, Y.; Ogawa, S. Bioorg. Med.
Chem. 1995, 3, 1605–1624.
7. Farr, R. A.; Peet, N. P.; Kang, M. S. Tetrahedron Lett. 1990, 31, 7109–7112.
8. For review articles on carbasugars, see: (a) Suami, T. Top. Curr. Chem. 1990, 154,
257–283; (b) Suami, T. Pure Appl. Chem. 1987, 59, 1509–1520; (c) Agrofoglio, L.;
Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.; Earl, R. A.; Guedj, R.
Tetrahedron 1994, 50, 10611–10670.
9. For reviews, see: (a) Ogawa, S. In Carbohydrate Mimics: Concepts and Methods;
Chapleur, Y., Ed.; Wiley-VCH: Weinheim, 1998; (b) Berecibar, A.; Grandjean, C.;
Siriwardena, A. Chem. Rev. 1999, 99, 779–844.
10. (a) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A. J. Med. Chem. 1996, 39, 3739;
(b) Marquez, V. E.; Hughes, S. H.; Sei, S.; Agbaria, R. Antiviral Res. 2006, 71, 268.
11. McCasland, G. E.; Furuta, S.; Durham, L. J. J. Org. Chem. 1966, 31, 1516–1521.
12. Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779–2831 (Review on the
synthesis of carbocycles from carbohydrates).
13. (a) Marschner, C.; Baumgartner, J.; Griengl, H. J. Org. Chem. 1995, 60, 5224–
5235; (b) Marschner, C.; Penn, G.; Griengl, H. Tetrahedron 1993, 49, 5067–5078.
14. (a) Shoberu, K.; Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 1992, 2419–2425; (b)
Parry, R. J.; Haridas, K.; de Jong, R.; Johnson, C. J. Tetrahedron Lett. 1990, 31,
7549–7552.
a
’-position competing in chelation of the metal and the carbonyl
group usually lead to poor diastereoselectivities.25 Fortunately,
subsequent Grignard reaction with vinylmagnesium bromide in
our approach showed exclusive stereoselectivity. We presumed
that the steric hindrance of TBS group in 15 in accordance with
the Felkin–Anh model favored the anti-addition of the Grignard re-
agent to the carbonyl group, affording diene 16 as a major product.
After RCM conversion to the cyclopentenol with Grubbs’ second
generation catalyst and acetylation of the tertiary hydroxyl, com-
pound 17 could be purified by column chromatography (85%,
two steps). Finally, a palladium (II)-catalyzed rearrangement of
the resulting allylic system 18,26 followed by a hydroxy-directed
cyclopropanation under Simmons-Smith conditions gave the key
carbobicyclic intermediate 1927 according to the published proce-
dure,28 providing the antiviral agent North-methanocarbathymi-
dine (N-MCT, 1) precursor in high yield.
In summary, we have presented a simple and efficient approach
toward cyclopentene derivative 10 and 13, containing the prere-
quisite five-membered ring framework presented in many potent
bioactivity agents, such as N-MCT 1. Utilizing cheap and plentiful
(R)-2,3-O-isopropylidene glyceraldehyde 2 as starting material,
we were able to introduce the desired S-configuration chiral cen-
ter, which serves as an anchor for the stepwise buildup of the other
15. MacKeith, R. A.; McCague, R.; Olivo, H. F.; Roberts, S. M.; Taylor, S. J. C.; Xiong,
H. Bioorg. Med. Chem. 1994, 2, 387–394.
16. Burlina, F.; Clivio, P.; Fourrey, J.; Riche, C.; Thomas, M. Tetrahedron Lett. 1994,
35, 8151–8152.
17. Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K. Synthesis 1986, 403–406.
18. (a) Yadav, J. S.; Srinivas, Ch. Tetrahedron Lett. 2002, 43, 3837–3839; (b)
Chattopadhyay, A. J. Org. Chem. 1996, 61, 6104–6107.