The synthesis of carbohydrate-derived acylsilanes and their intramolecular
free radical cyclizations with the formation of polyoxygenated cyclopentanes
Che-Chien Chang, Yu-Hsien Kuo, Yeun-Min Tsai
*Department of Chemistry, National Taiwan University, Taipei, Taiwan 106, ROC
a r t i c l e
i n f o
Article history: Received 6 January 2009 Revised 14 March 2009 Accepted 6 April 2009 Available online 14 April 2009 Keywords:
Acylsilane Radical cyclization
Polyoxygenated cyclopentanes
a b s t r a c t
A convenient way for the synthesis of acylsilanes from arabinose, lyxose, and ribose is developed. All the chiral centers of the carbohydrate templates are conserved, and only the reducing end is transformed into the acylsilane functional group. The non-reducing end of the templates can be converted into a bromide. These bromo acylsilanes undergo efficient intramolecular radical cyclizations to give polyoxygenated cyclopentanes.
Ó 2009 Elsevier Ltd. All rights reserved.
Acylsilane is a useful functionality which has attracted the attentions of synthetic chemists.1The presence of silyl group on
the carbonyl not only enhances the reactivity of a carbonyl but also becomes a useful handle for additional transformations.
Several years ago we have initiated a project to study the intra-molecular radical cyclizations involving acylsilanes.2As shown in
Scheme 1, intramolecular radical cyclization of acylsilane 1 gives a cyclized alkoxy radical intermediate 2 with a silyl group attached at the b-position of the radical. A facile radical-Brook rearrange-ment3,4successfully drives the reaction toward the formation of
a silyloxy-substituted radical 3. In contrast, similar radical cycliza-tions involving formyl group are known to be reversible processes in favor of the acyclic radicals.5Therefore, the special feature of the
radical cyclizations of acylsilanes made this type of reaction a use-ful method in the preparation of cyclic alcohols.6
OO O Ph R I OMe O H Br H O OBn OMe OBn OMe Br SiR3 O RO OO O Ph R OMe HO H n Bu3SnH, AIBN 75−85% R = vinyl or OMe 4 5 n = 3 or 4 ð1Þ
Carbohydrates are unique sources of chirality in nature and have been extensively used as building blocks for the synthesis of enantiomerically pure and highly oxygenated derivatives.7 In
particular, the conversion of carbohydrates to carbocycles is an area that has been extensively studied.8Fraiser-Reid and
co-work-ers demonstrated several successful carbohydrate-based free radi-cal cyclizations in which aldehyde groups served as the radiradi-cal acceptor (Eq.1).9In these cyclizations, the
x
-formylalkyl radicalsare immobilized by fusing with a pyranoside ring. However, alde-hydes that carry carbohydrate skeleton, such as bromide 4, are not good substrates for radical cyclizations.9fThus there is a need to
examine whether acylsilane 5 can be suitable substrate for this purpose. Herein we wish to report our synthesis of some pen-tose-derived acylsilanes and the study of their intramolecular rad-ical cyclizations.
Preparation of carbohydrate-derived acylsilanes has been reported by Plantier-Royon and Portella10 using the 2-silylated-1,3-dithiane approach developed by Brook11and Corey.12In this
approach, all the chiral centers of the carbohydrate substrates are retained and the carbon skeleton is extended by one. However, the
a
-position of the resulting acylsilanes cannot have a hydroxyl or alkoxy substituent. Although several reports about the construction0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.04.032
* Corresponding author. Tel.: +886 2 33661651; fax: +886 2 23636359. E-mail address:ymtsai@ntu.edu.tw(Y.-M. Tsai).
R3Si O O SiR3 OSiR3 n 1 n = 1, 2 n 2 radical-Brook rearrangement n 3 Scheme 1. Tetrahedron Letters 50 (2009) 3805–3808
Contents lists available atScienceDirect
Tetrahedron Letters
of
a
-oxy acylsilanes were known, none of these methods employed carbohydrate starting material directly.13 We decided to explorethe possibility of adding a silyl anion to the carbonyl end of a car-bohydrate to generate an
a
-silyl alcohol.14 The resultinga
-silylalcohol can then be oxidized to give an acylsilane with the desired carbohydrate skeleton.
As shown inScheme 2, aldehyde 6a15 derived from arabinose
with all the secondary hydroxyl groups protected by benzyl groups did not react with methyldiphenylsilyl lithium or the correspond-ing silyl cuprate. With the hypothesis that this aldehyde is quite sterically hindered due to the presence of adjacent bulky substitu-ents, we switched to the methylated analog 6b.16Indeed, aldehyde
6b reacted with methyldiphenylsilyl lithium and gave
a
-silyl alco-hol 7 in 46% yield. By using the less basic lithium bis(methyldi-phenylsilyl)cuprate, the yield ofa
-silyl alcohol 7 was improved to 62%.The trityl group in alcohol 7 was removed in a mixture of THF and methanol in the presence of p-toluenesulfonic acid. The pri-mary hydroxyl group of the resulting diol 8a was converted to a methanesulfonate 8b. This material was then oxidized using the Swern method17to give acylsilane 8c in 45% yield over these three
steps. Treatment of 8c with lithium bromide in DMF afforded bro-moacylsilane 9 in a 91% yield.
Free radical cyclization of acylsilane 9 using the standard tribu-tyltin hydride method in refluxing benzene2gave successfully the
cyclized silyl ether 10 as a mixture of two epimers (10a/10b = 2.4/ 1) in a combined yield of 77%. For the sake of separation, this epi-meric mixture was desilylated in a mixture of THF and methanol with catalytic amount of p-toluenesulfonic acid. The resulting alco-hols were converted to the p-bromobenzoates and were separated to afford benzoates 10c (62%) and 10d (37%). Difference NOE experiments showed that irradiation of H(1) at d 5.14 (CDCl3) in
the major isomer 10c resulted in a 4% enhancement of H(2) at d 4.03. In contrast, irradiation of H(1) in benzoate 10d at d 5.435.48 did not show any enhancement of H(2) at d 3.833.89. We therefore assigned the structure of 10c as having a 1,2-cis relationship of the two substituents. This stereochemical outcome indicated that in the radical cyclization step the
corre-sponding
a
-silyloxy cyclopentyl radical preferred to abstract a hydrogen from the face opposite to the C(2) methoxy group.As mentioned above, we attributed the lack of reactivity of alco-hol 6a toward silyl anion to the steric environment around the car-bonyl group. Trying to understand the origin of this steric effect, we analyzed the conformation of aldehyde 6a. As shown inScheme 3, among the three staggered conformations of 6a, the carbonyl group in conformers AI and AII is gauche to the large group RL.
Con-former AIII has an all gauche relationship and presumably also made the carbonyl quite sterically encumbered. Based on this analysis, we felt that the lyxose-derived aldehyde 1115having a
C(2)–C(3) anti stereo-relationship would contain a low energy con-former LI.18In which, the two benzyloxy dipoles are anti to each other, and the carbonyl group is anti to the large group RL but
gauche to the smaller benzyloxy group. We therefore hypothesized that the carbonyl group in aldehyde 11 might be less sterically hin-dered in comparison with aldehyde 6a.
Indeed, aldehyde 11 (Scheme 4) successfully coupled with the silyl cuprate and afforded diol 12 in 79% yield after removal of the trityl group. Diol 12 was converted to mesylate 13 followed by Swern oxidation17to give acylsilane 14 in 51% over two steps.
Replacing the mesylate group in 14 with bromide using lithium bromide in DMF met with failure. However, this task was accom-plished by the reaction of acylsilane 14 with tetrabutylammonium bromide in refluxing benzene19 and yielded bromo acylsilane 15
(77%). TrO H O OR OR OR Br Σ O OMe MeO OMe X Y OMe MeO MeO X Σ OMe MeO OMe Y Z TrO Σ OH OMe MeO OMe 6a R = Bn 6b R = Me
(a) MePh2SiLi/THF/−78 oC
(b) (MePh2Si)2CuLi/THF/−78 oC
or 7 Σ = SiMePh2 46% via (a) 62% via (b) 1) TsOH, THF/MeOH (77%) 2) MsCl, Et3N, CH2Cl2, 0 oC (92%) 3) Swern oxidation (64%) 8a X = OH, Y = H, Z = OH 8b X = OMs, Y = H, Z = OH 8c X = OMs, Y = Z = O LiBr, DMF, 90 oC 9 91%
Bu3SnH, AIBN (cat. amt.)
PhH, 80 oC, 2 h 77% 10a X = OSiMePh2, Y = H 10b X = H, Y = OSiMePh2 10a/10b = 2.4/1
1) TsOH (cat. amt.) MeOH/THF 2) 4-BrPhCOCl DMAP (cat. amt.) Et3N, CH2Cl2 10c X = OCOPhBr, Y = H (62%) 10d X = H, Y = OCOPhBr (37%) Tr = trityl 2 3 4 Scheme 2. BnO H RL CHO H OBn H RL OBn CHO H OBn RL OBn H CHO H OBn RL H OBn CHO H OBn H OBn RL CHO H OBn BnO RL H CHO H OBn O BnO OBn OBn TrO H H O BnO OBn OBn TrO AI AII AIII LI LII LIII RL = Arabinose-type 6a Lyxose-type 11 Scheme 3. MsO Σ OBn BnO OBn X Y
Bu3SnH, AIBN (cat. amt.), PhH, 80 o C Bu4NBr HO Σ OH OBn BnO OBn Br Σ O OBn BnO OBn X Y OBn BnO BnO 1) (MePh2Si)2CuLi
THF, −78 o C 12 (79%) Σ = SiMePh2 13 X = OH, Y = H 14 X = Y = O 15 16a X = OSiMePh2, Y = H 16b X = H, Y = OSiMePh2 TsOH (cat. amt.) MeOH/THF 11
2) TsOH (cat. amt.) THF/MeOH 1) MsCl, Et3N CH2Cl2 (74%) 2) Swern oxid. (70%) PhH 80 oC (77%) (76%) 17a X = OH, Y = H 17b X = H, Y = OH (77%) Scheme 4.
The tin-mediated cyclization of 15 was carried out successfully to give the cyclization products 16 in a 76% yield with a stereoiso-meric ratio of 2.8/1 (16a/16b). The inseparable mixture of 16 was desilylated to afford partially separable alcohols 17 (77%). The ste-reochemistry of 17 was determined by difference NOE experi-ments. Specifically, irradiation of H(2) in cyclopentanol 17a at d 3.943.99 (CDCl3) resulted in a 16% enhancement of H(1) at d
4.264.37. On the contrary, irradiation of H(2) in 17b at d 3.75 only resulted in a 4% enhancement of H(1) at d 4.164.23. These results indicated that the major isomer 17a exhibited a C(1)–C(2) cis-rela-tionship. Similar selectivity was also observed for the cyclization of acylsilane 9 as mentioned above.
Ribose is another pentose that exhibits a C(2)–C(3) anti stereo-relationship. Using similar methods we synthesized theD
-ribose-derived acylsilane 1820(Scheme 5). Radical cyclization of 18 with tributyltin hydride gave a 76% yield of an inseparable mixture of cyclized products 19a and 19b (19a/19b = 1.6/1). Removal of the silyl group then afforded alcohols 19c (43%) and 19d (28%). Differ-ence NOE experiments of 19d showed that irradiation of H(1) at d 4.04–4.11 (CDCl3) resulted in a 6% enhancement of H(2) at d 3.43.
Conversely, irradiation of H(2) resulted in a 14% enhancement of H(1). We therefore assigned 19d as having a C(1)–C(2) cis-relationship.
Surprisingly, the preference of stereochemical outcome in this system showed that the corresponding
a
-silyloxy cyclopentyl rad-ical abstracted a hydrogen atom from the same face relative to the benzyloxy group at C(2) on the cyclopentane ring. We suspected that intramolecular hydrogen abstraction might be the cause of this preference. To confirm this suspicion, the cyclization of acylsi-lane 18 was carried out using tributyltin deuteride followed by desilylation, and we were able to isolate alcohols 19f (24%) and a mixture (31%) of 19c-D and 19e (19c-D/19e = 45/55).The complete deuteration at C(1) in the all-cis isomer 19f is obvious in the1H NMR spectrum for the disappearance of the
pro-ton signal at C(1) (d 4.10 in CD3OD). The13C signal of C(1) also
diminished into a very small triplet of equal intensity centered at d69.5 (in CDCl3; JC–D= 23 Hz). In contrast, in the1H NMR spectrum
of the trans–cis–cis isomer mixture 19c-D and 19e, the proton sig-nal at C(1) (d 4.36 in CD3OD) only partially disappeared. The13C
signal of C(1) of 19e appeared as a small triplet centered at d 74.1 (in CDCl3; JC–D= 23 Hz) coexisted with a signal at d 74.4
belonging to C(1) of 19c-D. The13C signal of the benzylic carbon
(d 73.0 in CDCl3on the C(3)-side chain also appeared as a singlet
overlapped with a triplet indicating the incorporation of a deute-rium atom at this carbon.21
Therefore, the incorporation of1H at C(1) in 19c-D is most likely
occurred through an intramolecular 1,5-hydrogen transfer process from the benzylic position of the C(3)-benzyloxy group. We sug-gest that the C(3)-substituent is located at a pseudo-axial position (A) and is more accessible to deliver the benzylic hydrogen to the radical at C(1). Whereas the C(4)-benzyloxy group adopts a pseu-do-equatorial position, it is difficult to reach the corresponding benzylic hydrogen for the radical.
In conclusion, we have developed a convenient way for the syn-thesis of acylsilanes from carbohydrate templates. All the chiral centers of the templates were conserved, and only the reducing end was transformed into acylsilane. In the meantime, the non-reducing end of the templates can be converted into a bromide. We demonstrated that these bromo acylsilanes can undergo effi-cient intramolecular radical cyclizations to give polyoxygenated carbocycles with different stereochemical structures. One can ex-pect the silyloxy group to serve as a handle for the conversion of these cyclopentitols to potentially useful compounds such as aminopentitols22and carbocyclic nucleotides.23,24
Acknowledgments
Financial support of the National Science Council of the Repub-lic of China is gratefully acknowledged. We are also grateful to the National Center for High-performance Computing for the computer time and facilities.
Supplementary data
Supplementary data (compound characterization data of 9, 10c, d, 15, 17a, b, 18, 19c, and d) associated with this article can be found, in the online version, atdoi:10.1016/j.tetlet.2009.04.032.
References and notes
1. For recent reviews about acylsilanes, see: (a) Ricci, A.; Degl’Innocenti, A. Synthesis 1989, 647–660; (b) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147–195; (c) Cirillo, P. F.; Panek, J. S. Org. Prep. Proced. Int. 1992, 24, 553–582; (d) Page, P. C. B.; McKenzie, M. J.; Klair, S. S.; Rosenthal, S. In The Chemistry of Organic Silicon Compounds; Rappoport, Z., Apeloig, Y., Eds.; John Wiley & Sons: New York, 1998; Vol. 2, pp 1599–1665. Chapter 27; (e) Bonini, B. F.; Comes-Franchini, M.; Fochi, M.; Mazzanti, G.; Ricci, A. J. Organomet. Chem. 1998, 567, 181–189.
2. Huang, C.-H.; Chang, S.-Y.; Wang, N.-S.; Tsai, Y.-M. J. Org. Chem. 2001, 66, 8983– 8991. and references cited therein.
3. (a) Dalton, J. C.; Bourque, R. A. J. Am. Chem. Soc. 1981, 103, 699–700; (b) Harris, J. M.; MacInnes, I.; Walton, J. C.; Maillard, B. J. Organomet. Chem. 1991, 403, C25– C28; (c) Tsai, Y.-M.; Ke, B.-W. J. Chin. Chem. Soc. (Taipei) 1993, 40, 641–642; (d) Robertson, J.; Burrows, J. N. Tetrahedron Lett. 1994, 35, 3777–3780; (e) Schiesser, C. H.; Styles, M. L. J. Chem. Soc., Perkin Trans. 2 1997, 2335–2340; (f) Paredes, M. D.; Alonso, R. Tetrahedron Lett. 1999, 40, 3973–3976; (g) Paredes, M. D.; Alonso, R. J. Org. Chem. 2000, 65, 2292–2304.
4. For a recent review about Brook rearrangement, see: Moser, W. H. Tetrahedron 2001, 57, 2065–2084.
5. (a) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1989, 111, 230–234; (b) Beckwith, A. L. J.; Hay, B. P. J. Am. Chem. Soc. 1989, 111, 2674–2681; (c) Beckwith, A. L. J.; Raner, K. D. J. Org. Chem. 1992, 57, 4954–4962.
6. Chen, M.-J.; Tsai, Y.-M. Tetrahedron Lett. 2007, 48, 6271–6274.
7. (a) Hanessian, S. Total Synthesis of natural products: The Chiron Approach; Pergamon: New York, 1983; (b) Bols, M. Carbohydrate Building Blocks; Wiley: New York, 1996.
8. (a) Madsen, R. Eur. J. Org. Chem. 2007, 399–415; (b) Zhou, J.; Wang, G.; Zhang, L.-H.; Ye, X.-S. Curr. Org. Chem. 2006, 10, 625–642; (c) Ferrier, R. J.; Hoberg, J. O. Adv. Carbohydr. Chem. Biochem. 2003, 58, 55–119; (d) Ferrier, R. J. Top. Curr. Chem. 2001, 215, 277–291; (e) Dalko, P. I.; Sinaÿ, P. Angew. Chem., Int. Ed. 1999, 38, 773–777; (f) Marco-Contelles, J.; Alhambra, C.; Martínez-Grau, A. Synlett 1998, 693–699; (g) Martínez-Grau, A.; Marco-Contelles, J. Chem. Soc. Rev. 1998, 27, 155–162; (h) Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779–2831.
9. (a) Tsang, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1986, 108, 2116–2117; (b) Tsang, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1986, 108, 8102–8104; (c) Tsang, R.; Dickson, J. K., Jr.; Pak, H.; Walton, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1987, 109, 3484–3486; (d) Fraser-Reid, B.; Vite, G. D.; Yeung, B.-W. A.; Tsang, R. Tetrahedron Lett. 1988, 29, 1645–1648; (e) Dickson, J. K., Jr.; Tsang, R.; Llera, J. M.; Fraser-Reid, B. J. Org. Chem. 1989, 54, 5350–
Bu3SnD Br Σ O OBn BnO OBn Bu 3SnH AIBN BnO OO Bn OΣ H Ph A X Y OBn BnO BnO BnO OOBn Ph H OΣ 18 TsOH (cat. amt.) (76%) 19a X = OΣ, Y = H 19b X = H, Y = OΣ Σ = SiMePh2 MeOH/THF 19c X = OH, Y = H 19d X = H, Y = OH (cat. amt.) PhH, 80 oC
AIBN (cat. amt.) PhH, 80 oC
TsOH (cat. amt.) MeOH/THF
(71%)
19c-D (with D at C(3)-benzylic position) + 19e (X = OH, Y = D) + 19f (X = D, Y = OH) 1 4 19c-D 1,5-H transfer Scheme 5.
5356; (f) Yeung, B. A.; Alonso, R.; Vite, G. D.; Fraser-Reid, B. J. Carbohydr. Chem. 1989, 8, 413–427; (g) Walton, R.; Fraser-Reid, B. J. Am. Chem. Soc. 1991, 113, 5791–5799.
10. (a) Plantier-Royon, R.; Portella, C. Tetrahedron Lett. 1996, 37, 61136114; (b) Plantier-Royon, R.; Portella, C. Synlett 1994, 527–529.
11. Brook, A. G.; Duff, J. M.; Jones, P. F.; Davis, N. R. J. Am. Chem. Soc. 1967, 89, 431– 434.
12. Corey, E. J.; Seebach, D.; Freedman, R. J. Am. Chem. Soc. 1967, 89, 434–436. 13. (a) Raobo, P.; Wicha, J. J. Org. Chem. 1994, 59, 4355–4356; (b) Cirilla, P. F.;
Panek, J. S. J. Org. Chem. 1994, 59, 3055–3063; (c) Cirillo, P. F.; Panek, J. S. J. Org. Chem. 1990, 55, 6071–6073.
14. Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. J. Am. Chem. Soc. 1986, 108, 7791–7800.
15. Dubost, E.; Le Nouën, D.; Streith, J.; Tarnus, C.; Tschamber, T. Eur. J. Org. Chem. 2006, 610–626.
16. Miljkovic´, M.; Dropkin, D.; Hagel, P.; Habash-Marino, M. Carbohydr. Res. 1984, 128, 11–20.
17. (a) Mancuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482; (b) Mancuso, A. J.; Swern, D. Synthesis 1981, 165–185.
18. For the conformational analysis of 2,3-dihalobutanes and related compounds, see: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley & Sons: New York, 1994.
19. Brooks, G.; Edwards, P. D.; Hatto, J. D. I.; Smale, T. C.; Sonthgate, R. Tetrahedron 1995, 51, 7999–8014.
20. This acylsilane was synthesized from the corresponding aldehyde: Garegg, P. J.; Samuelsson, B. Carbohydr. Res. 1978, 67, 267–270.
21. The13
C signals of the benzylic carbons were identified through the techniques of HMQC and HMBC.
22. (a) Delgado, A. Eur. J. Org. Chem. 2008, 3893–3906; (b) Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837.
23. (a) Ferrero, M.; Gotor, V. Chem. Rev. 2000, 100, 4319–4347; (b) Crimmins, M. T. Tetrahedron 1998, 54, 9229–9272.
24. (a) Ando, T.; Iwata, M.; Zulfiqar, F.; Miyamoto, T.; Nakanishi, M.; Kitade, Y. Bioorg. Med. Chem. 2008, 3809–3815; (b) Ando, T.; Kojima, K.; Chahota, P.; Kozaki, A.; Milind, N. D.; Kitade, Y. Bioorg. Med. Chem. 2008, 2615–2618; (c) Siddiqi, S. M.; Jacobson, K. A.; Esker, J. L.; Olah, M. E.; Ji, X.; Melman, N.; Tiwari, K. N.; Secrist, J. A., III; Schneller, S. W.; Cristalli, G.; Stiles, G. L.; Johnson, C. R.; IJzerman, A. P. J. Med. Chem. 1995, 38, 1174–1188.
