- Email: [email protected]
Benzothiazines in synthesis. Eight-membered ring formation in an intramolecular Friedel–Crafts reaction
Tetrahedron Letters 50 (2009) 2326–2328
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Benzothiazines in synthesis. Eight-membered ring formation in an intramolecular Friedel–Crafts reaction Michael Harmata *, Weijiang Ying, Charles L. Barnes Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
a r t i c l e
i n f o
Article history: Received 6 February 2009 Revised 23 February 2009 Accepted 26 February 2009 Available online 9 March 2009
a b s t r a c t Treatment of certain benzothiazines bearing allylic bromides side chains with indium tribromide resulted in the formation of eight-membered rings in addition to the expected six-membered rings. Ó 2009 Elsevier Ltd. All rights reserved.
Elisapterosin B (1) is a complex natural product isolated by Rodriguez and co-workers.1 The compound is not only structurally intriguing, but biologically as well, as it possesses significant antitubercular activity, inhibiting the growth of M. tuberculosis H37Rv. These factors have stimulated interest in the compound in the synthetic community and a number of syntheses have been reported.2–6 Our approach to this compound is centered on benzothiazine chemistry, with which we have had success in the synthesis of a number of natural products.7,13 Our plan in the synthesis of elisapterosin B depends on the stereoselective synthesis of 2, which we anticipate can be converted to the natural product in short order (Scheme 1). One approach to 2 involves a stereoselective intramolecular Friedel–Crafts reaction of an allylic cation (3) or its equivalent. This Letter describes several approaches to 2 and the interesting observation of the formation of an eight-membered ring product in the Friedel–Crafts reaction of one of the precursors. Our approach to precursors to 3 consisted of generating benzothiazines via the stereoselective conjugate addition of sulfoximine carbanions to alkenes bearing an electron-withdrawing group.8 These electron-withdrawing groups would be removed at some point during the synthesis to afford 2, which could be carried forward to the natural product. The N-aryl sulfoximine needed for this study was prepared as shown in Scheme 2. The commercially available benzoic acid 4 was reduced with LAH, brominated with NBS, and oxidized to the corresponding aldehyde 5 in 93% overall yield. Protection of the aldehyde afforded acetal 6 quantitatively. A Buchwald–Hartwig reaction with (S)-8,9 followed by hydrolysis gave aldehyde 7 in 67% overall yield. Sulfoximine 7 was used as a substrate for the generation of two cyclization precursors. These were synthesized via a Horner–Em-
Me HO
O O C
steps
Me
H
MeO
H
Me
Me Me 1, elisapterosin B
N OMe 2
H
MeO Me
N OMe
Ph S O
3
Scheme 1. Partial retrosynthesis of elisapterosin B.
MeO
CO2H
MeO
1. LAH
CHO CH(OMe)3
2. NBS Me
Me
3. Swern OMe
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.02.227
100%
OMe
93%
4
Br 5
OMe MeO
OMe
Me
BINAP, Cs2CO3
Br OMe
1. (S )-8, Pd(OAc)2,
6
MeO Me
2. HCl 67%
HN
Me + Ph S O_
(S)-8 * Corresponding author. Tel.: +1 573 882 1097; fax: +1 573 882 2754. E-mail address: [email protected] (M. Harmata).
Ph S O
Scheme 2. Synthesis of sulfoximine.
7
OMe
CHO Me S Ph N O
2327
M. Harmata et al. / Tetrahedron Letters 50 (2009) 2326–2328
OH 9
n-BuLi, t-BuLi
TMS
2. NBS, Ph3P
11
OH
Br +
O EtO P EtO
MeO
R
NaH
OMe
TMS
O
R
1. 2 equiv LiHMDS Me S Ph 2. NH4Cl N O
15b', R = SO2Ph(β) (86%, α:β = 1:4.1)
TMS
Me OMe 7
R
13a/b, LiHMDS LiCl, THF
MeO Me OMe
OMe
15b, R = SO2Ph(α)
13b, R = SO2Ph, 52% from 10
mons reaction. The preparation of the appropriate reagents is shown in Scheme 3. The conversion of 2-butyn-1-ol (9) into 10,10 followed by hydrogenation with P2-nickel,11 afforded alcohol 12 in good yield. Alcohol 12 was converted into the corresponding allylic bromide 11, which served as an electrophile to furnish phosphonates 13a and 13b. Benzothiazines were prepared by coupling 13a/b with 7 followed by intramolecular conjugate addition. The coupling sequence is shown in Scheme 4. Stereoselectivity in the formation of 14a and 14b was acceptable.12 The E and Z isomers of each compound were separable and only the E isomers were taken forward. Diastereomeric mixtures were obtained when 14a and 14b were treated with base (Scheme 5). All of our results to date demonstrate that diastereomers result from non-selective protonation of the anions that arise from the intramolecular conjugate addition. We have had success in achieving relatively high diastereoselectivity in some cases,13 but the selectivity in this study was low. Stereochemical assignments of the individual stereoisomers were based on several factors, including the idea that the major stereoisomers would bear the stereochemistry of similar compounds prepared in other studies. Treatment of the individual benzothiazine diastereomers with NBS resulted in the formation of the corresponding secondary allylic bromides in low to good diastereoselectivities.14 The exact stereochemistry of the bromide-bearing carbon was not ascertained. Rather, the compounds were treated with InBr3 in refluxing CH2Cl2 in the presence of molecular sieves (Scheme 6).15 The stereochemistry of the major isomer 17b in the cyclization of 16a was assigned by NOESY, a correlation being seen between the methylene group of the ethyl ester and one hydrogen on the methylene of the vinyl group. The major isomer obtained from the cyclization of 16a0 was crystalline and the stereochemistry was established by X-ray analysis. These data imply the stereochemistry of the other products and of the starting materials as well. It is interesting to note that there is a close correlation between the diastereomeric ratios of the bromides and the corresponding
CHO Me S Ph N O
S Ph O
N
(80%, α:β = 1:2.5)
Scheme 3. Preparation of phosphonates 13a and 13b.
MeO
Me
15a', R = CO2Et(β)
14b, R = SO2Ph
13a, R = CO2Et, 47% from 10
H
MeO
15a, R = CO2Et(α)
14a, R = CO2Et
OEt P
Me
12a, R = CO2Et 12b, R = SO2Ph
EtO
R
R
10
66%
1. P2-Ni, H2
TMS
TMS
TMS
then TMSCl
Me S Ph N O
14a, R = CO2Et, 86%, dr = 8:1 14b, R =SO2Ph, 83%. dr = 8:1 Scheme 4. Horner–Wadsworth–Emmons reactions of 7.
NBS, -10 oC
MeO
Br
MeCN Me
N OMe
16a, R = CO2Et(α)
R
(83%, dr = 7.7:1)
H
16a', R = CO2Et(β)
(84%, dr = 2.5:1) S Ph O 16b', R = SO2Ph(β) (82%, dr = 5.8:1)
Scheme 5. Synthesis of allylic bromides.
Br
CO2Et H
MeO N
Me
S Ph O
OMe
InBr3, CH2Cl2
CO2Et H
MeO
reflux, 24 h 82%
Me
S
N
O
OMe
16a, dr = 7.7:1
Ph
17a, β-vinyl 17b, α-vinyl β:α, 1:6.7
Br
CO2Et H
MeO
Me
N
S Ph O
OMe
16a', dr = 2.5:1
InBr3, CH2Cl2
CO2Et H
MeO
reflux, 24 h 86%
Me
N OMe
Ph S O
17a', β-vinyl 17b', α-vinyl β:α, 2.5:1
Scheme 6. Intramolecular Friedel–Crafts reaction of 16 and 16a0 .
cyclization products. The implication is that the substitution process occurs in an SN2 fashion, though we have by no means rigorously established this. Interestingly, when 16b0 was treated with excess indium bromide in CH2Cl2 for 24 h at room temperature, an eight-membered ring product (18) was obtained, in addition to the two expected six-membered ring diastereomers. A brief investigation of reaction conditions demonstrated some variability in product distribution as a function of temperature. Thus, the ratio of the three products formed changed from 8.5:4.7:1 (18:19a0 :19b0 ) at room temperature to 9.1:4.8:1 in refluxing dichloroethane. In a reaction run at 78 °C to room temperature, the product ratio was 5.1:5.5:1.16 Exposure of the product mixture from a low temperature experiment to reagent and heat did not result in equilibration to a new product mixture. This suggests a larger entropy of activation (less negative) for the formation of 18 vis-à-vis the six-membered ring regioisomer (Scheme 7). Interestingly, the formation of the six-membered ring products from 16a0 proceeded with moderate diastereoselectivity in the direction desired for the synthesis of elisapterosin B, but also clo-
2328
M. Harmata et al. / Tetrahedron Letters 50 (2009) 2326–2328
Br
Supplementary data
SO2Ph
MeO
H
Me
S Ph N O OMe
16b', dr = 5.8:1
SO2Ph InBr3, CH2Cl2 rt, 24 h, 87%
Me OMe 19a'
Me
8.5:4.7:1
N OMe
18:19a':19b' SO2Ph H
MeO
H
MeO
Ph S N O
+
Ph S O
+
18 SO2Ph H
MeO Me
N OMe
Ph S O
19b'
Scheme 7. Intramolecular Friedel–Crafts reaction of 16b0 .
sely reflected the diastereomer ratio of the precursor allylic bromides. In conclusion, we have discovered that it is possible to prepare potential precursors to elisapterosin B as well as a unique cyclooctanoid via an intramolecular Friedel–Crafts alkylation process. The basis of substituent effects on this process with respect to both regiochemistry and stereochemistry is presently not clear and further work is necessary to determine it. Such studies and application of the method to the synthesis of various targets will be reported in due course.17 Acknowledgment This work was supported by the NIH (1R01-AI59000-01A1) to whom we are grateful.
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2009.02.227. References and notes 1. Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Barnes, C. L. J. Org. Chem. 2000, 65, 1390–1398. 2. Kim, A. I.; Rychnovsy, S. D. Angew. Chem., Int. Ed. 2003, 42, 1267–1270. 3. Waizumi, N.; Stankovic, A. R.; Rawal, V. H. J. Am. Chem. Soc. 2003, 125, 13022– 13023. 4. Boezio, A. A.; Jarvo, E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6046–6060. 5. Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485–2490. 6. Werle, S.; Fey, T.; Neudorfl, J. M.; Schmalz, H. Org. Lett. 2007, 7, 3555–3558. 7. (a) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581–3583; (b) Harmata, M.; Hong, X.; Schreiner, P. R. J. Org. Chem. 2008, 73, 1290–1296; (c) Harmata, M.; Hong, X. Tetrahedron Lett. 2005, 46, 3847–3849; (d) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44, 7261–7264. 8. Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754–5756. 9. (a) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419–2422; (b) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731–5734. 10. Tong, R.; Valentine, J. C.; McDonald, F. E.; Cao, R.; Fang, X.; Hardcastle, K. I. J. Am. Chem. Soc. 2007, 129, 1050–1051. 11. (a) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226–2230; (b) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796–16797; (c) Dussault, P. H.; Eary, C. T.; Lee, R. J.; Zope, U. R. J. Chem. Soc., Perkin Trans. 1 1999, 2189–2204. 12. Diastereomer ratios were determined by analysis of the 1H NMR data for crude reaction products. 13. Harmata, M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201–2203. 14. We did not explore the bromination of benzothiazine 15b as we could not obtain it in large amounts in pure form. 15. Hayashi, R.; Cook, G. R. Org. Lett. 2007, 9, 1311–1314. 16. Other experiments we have performed show that the reaction does not take place to any significant extent at 10 °C. 17. Crystallographic data (excluding structure factors) for some structures reported in this Letter have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 716164 (17a0 ) and 716143 (18). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44(1223)336033; Email: [email protected]].
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Benzothiazines in synthesis. Eight-membered ring formation in an intramolecular Friedel–Crafts reaction Michael Harmata *, Weijiang Ying, Charles L. Barnes Department of Chemistry, University of Missouri-Columbia, Columbia, MO 65211, USA
a r t i c l e
i n f o
Article history: Received 6 February 2009 Revised 23 February 2009 Accepted 26 February 2009 Available online 9 March 2009
a b s t r a c t Treatment of certain benzothiazines bearing allylic bromides side chains with indium tribromide resulted in the formation of eight-membered rings in addition to the expected six-membered rings. Ó 2009 Elsevier Ltd. All rights reserved.
Elisapterosin B (1) is a complex natural product isolated by Rodriguez and co-workers.1 The compound is not only structurally intriguing, but biologically as well, as it possesses significant antitubercular activity, inhibiting the growth of M. tuberculosis H37Rv. These factors have stimulated interest in the compound in the synthetic community and a number of syntheses have been reported.2–6 Our approach to this compound is centered on benzothiazine chemistry, with which we have had success in the synthesis of a number of natural products.7,13 Our plan in the synthesis of elisapterosin B depends on the stereoselective synthesis of 2, which we anticipate can be converted to the natural product in short order (Scheme 1). One approach to 2 involves a stereoselective intramolecular Friedel–Crafts reaction of an allylic cation (3) or its equivalent. This Letter describes several approaches to 2 and the interesting observation of the formation of an eight-membered ring product in the Friedel–Crafts reaction of one of the precursors. Our approach to precursors to 3 consisted of generating benzothiazines via the stereoselective conjugate addition of sulfoximine carbanions to alkenes bearing an electron-withdrawing group.8 These electron-withdrawing groups would be removed at some point during the synthesis to afford 2, which could be carried forward to the natural product. The N-aryl sulfoximine needed for this study was prepared as shown in Scheme 2. The commercially available benzoic acid 4 was reduced with LAH, brominated with NBS, and oxidized to the corresponding aldehyde 5 in 93% overall yield. Protection of the aldehyde afforded acetal 6 quantitatively. A Buchwald–Hartwig reaction with (S)-8,9 followed by hydrolysis gave aldehyde 7 in 67% overall yield. Sulfoximine 7 was used as a substrate for the generation of two cyclization precursors. These were synthesized via a Horner–Em-
Me HO
O O C
steps
Me
H
MeO
H
Me
Me Me 1, elisapterosin B
N OMe 2
H
MeO Me
N OMe
Ph S O
3
Scheme 1. Partial retrosynthesis of elisapterosin B.
MeO
CO2H
MeO
1. LAH
CHO CH(OMe)3
2. NBS Me
Me
3. Swern OMe
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.02.227
100%
OMe
93%
4
Br 5
OMe MeO
OMe
Me
BINAP, Cs2CO3
Br OMe
1. (S )-8, Pd(OAc)2,
6
MeO Me
2. HCl 67%
HN
Me + Ph S O_
(S)-8 * Corresponding author. Tel.: +1 573 882 1097; fax: +1 573 882 2754. E-mail address: [email protected] (M. Harmata).
Ph S O
Scheme 2. Synthesis of sulfoximine.
7
OMe
CHO Me S Ph N O
2327
M. Harmata et al. / Tetrahedron Letters 50 (2009) 2326–2328
OH 9
n-BuLi, t-BuLi
TMS
2. NBS, Ph3P
11
OH
Br +
O EtO P EtO
MeO
R
NaH
OMe
TMS
O
R
1. 2 equiv LiHMDS Me S Ph 2. NH4Cl N O
15b', R = SO2Ph(β) (86%, α:β = 1:4.1)
TMS
Me OMe 7
R
13a/b, LiHMDS LiCl, THF
MeO Me OMe
OMe
15b, R = SO2Ph(α)
13b, R = SO2Ph, 52% from 10
mons reaction. The preparation of the appropriate reagents is shown in Scheme 3. The conversion of 2-butyn-1-ol (9) into 10,10 followed by hydrogenation with P2-nickel,11 afforded alcohol 12 in good yield. Alcohol 12 was converted into the corresponding allylic bromide 11, which served as an electrophile to furnish phosphonates 13a and 13b. Benzothiazines were prepared by coupling 13a/b with 7 followed by intramolecular conjugate addition. The coupling sequence is shown in Scheme 4. Stereoselectivity in the formation of 14a and 14b was acceptable.12 The E and Z isomers of each compound were separable and only the E isomers were taken forward. Diastereomeric mixtures were obtained when 14a and 14b were treated with base (Scheme 5). All of our results to date demonstrate that diastereomers result from non-selective protonation of the anions that arise from the intramolecular conjugate addition. We have had success in achieving relatively high diastereoselectivity in some cases,13 but the selectivity in this study was low. Stereochemical assignments of the individual stereoisomers were based on several factors, including the idea that the major stereoisomers would bear the stereochemistry of similar compounds prepared in other studies. Treatment of the individual benzothiazine diastereomers with NBS resulted in the formation of the corresponding secondary allylic bromides in low to good diastereoselectivities.14 The exact stereochemistry of the bromide-bearing carbon was not ascertained. Rather, the compounds were treated with InBr3 in refluxing CH2Cl2 in the presence of molecular sieves (Scheme 6).15 The stereochemistry of the major isomer 17b in the cyclization of 16a was assigned by NOESY, a correlation being seen between the methylene group of the ethyl ester and one hydrogen on the methylene of the vinyl group. The major isomer obtained from the cyclization of 16a0 was crystalline and the stereochemistry was established by X-ray analysis. These data imply the stereochemistry of the other products and of the starting materials as well. It is interesting to note that there is a close correlation between the diastereomeric ratios of the bromides and the corresponding
CHO Me S Ph N O
S Ph O
N
(80%, α:β = 1:2.5)
Scheme 3. Preparation of phosphonates 13a and 13b.
MeO
Me
15a', R = CO2Et(β)
14b, R = SO2Ph
13a, R = CO2Et, 47% from 10
H
MeO
15a, R = CO2Et(α)
14a, R = CO2Et
OEt P
Me
12a, R = CO2Et 12b, R = SO2Ph
EtO
R
R
10
66%
1. P2-Ni, H2
TMS
TMS
TMS
then TMSCl
Me S Ph N O
14a, R = CO2Et, 86%, dr = 8:1 14b, R =SO2Ph, 83%. dr = 8:1 Scheme 4. Horner–Wadsworth–Emmons reactions of 7.
NBS, -10 oC
MeO
Br
MeCN Me
N OMe
16a, R = CO2Et(α)
R
(83%, dr = 7.7:1)
H
16a', R = CO2Et(β)
(84%, dr = 2.5:1) S Ph O 16b', R = SO2Ph(β) (82%, dr = 5.8:1)
Scheme 5. Synthesis of allylic bromides.
Br
CO2Et H
MeO N
Me
S Ph O
OMe
InBr3, CH2Cl2
CO2Et H
MeO
reflux, 24 h 82%
Me
S
N
O
OMe
16a, dr = 7.7:1
Ph
17a, β-vinyl 17b, α-vinyl β:α, 1:6.7
Br
CO2Et H
MeO
Me
N
S Ph O
OMe
16a', dr = 2.5:1
InBr3, CH2Cl2
CO2Et H
MeO
reflux, 24 h 86%
Me
N OMe
Ph S O
17a', β-vinyl 17b', α-vinyl β:α, 2.5:1
Scheme 6. Intramolecular Friedel–Crafts reaction of 16 and 16a0 .
cyclization products. The implication is that the substitution process occurs in an SN2 fashion, though we have by no means rigorously established this. Interestingly, when 16b0 was treated with excess indium bromide in CH2Cl2 for 24 h at room temperature, an eight-membered ring product (18) was obtained, in addition to the two expected six-membered ring diastereomers. A brief investigation of reaction conditions demonstrated some variability in product distribution as a function of temperature. Thus, the ratio of the three products formed changed from 8.5:4.7:1 (18:19a0 :19b0 ) at room temperature to 9.1:4.8:1 in refluxing dichloroethane. In a reaction run at 78 °C to room temperature, the product ratio was 5.1:5.5:1.16 Exposure of the product mixture from a low temperature experiment to reagent and heat did not result in equilibration to a new product mixture. This suggests a larger entropy of activation (less negative) for the formation of 18 vis-à-vis the six-membered ring regioisomer (Scheme 7). Interestingly, the formation of the six-membered ring products from 16a0 proceeded with moderate diastereoselectivity in the direction desired for the synthesis of elisapterosin B, but also clo-
2328
M. Harmata et al. / Tetrahedron Letters 50 (2009) 2326–2328
Br
Supplementary data
SO2Ph
MeO
H
Me
S Ph N O OMe
16b', dr = 5.8:1
SO2Ph InBr3, CH2Cl2 rt, 24 h, 87%
Me OMe 19a'
Me
8.5:4.7:1
N OMe
18:19a':19b' SO2Ph H
MeO
H
MeO
Ph S N O
+
Ph S O
+
18 SO2Ph H
MeO Me
N OMe
Ph S O
19b'
Scheme 7. Intramolecular Friedel–Crafts reaction of 16b0 .
sely reflected the diastereomer ratio of the precursor allylic bromides. In conclusion, we have discovered that it is possible to prepare potential precursors to elisapterosin B as well as a unique cyclooctanoid via an intramolecular Friedel–Crafts alkylation process. The basis of substituent effects on this process with respect to both regiochemistry and stereochemistry is presently not clear and further work is necessary to determine it. Such studies and application of the method to the synthesis of various targets will be reported in due course.17 Acknowledgment This work was supported by the NIH (1R01-AI59000-01A1) to whom we are grateful.
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2009.02.227. References and notes 1. Rodriguez, A. D.; Ramirez, C.; Rodriguez, I. I.; Barnes, C. L. J. Org. Chem. 2000, 65, 1390–1398. 2. Kim, A. I.; Rychnovsy, S. D. Angew. Chem., Int. Ed. 2003, 42, 1267–1270. 3. Waizumi, N.; Stankovic, A. R.; Rawal, V. H. J. Am. Chem. Soc. 2003, 125, 13022– 13023. 4. Boezio, A. A.; Jarvo, E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 6046–6060. 5. Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc. 2006, 128, 2485–2490. 6. Werle, S.; Fey, T.; Neudorfl, J. M.; Schmalz, H. Org. Lett. 2007, 7, 3555–3558. 7. (a) Harmata, M.; Hong, X. Org. Lett. 2005, 7, 3581–3583; (b) Harmata, M.; Hong, X.; Schreiner, P. R. J. Org. Chem. 2008, 73, 1290–1296; (c) Harmata, M.; Hong, X. Tetrahedron Lett. 2005, 46, 3847–3849; (d) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron Lett. 2003, 44, 7261–7264. 8. Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125, 5754–5756. 9. (a) Harmata, M.; Pavri, N. Angew. Chem., Int. Ed. 1999, 38, 2419–2422; (b) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39, 5731–5734. 10. Tong, R.; Valentine, J. C.; McDonald, F. E.; Cao, R.; Fang, X.; Hardcastle, K. I. J. Am. Chem. Soc. 2007, 129, 1050–1051. 11. (a) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226–2230; (b) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796–16797; (c) Dussault, P. H.; Eary, C. T.; Lee, R. J.; Zope, U. R. J. Chem. Soc., Perkin Trans. 1 1999, 2189–2204. 12. Diastereomer ratios were determined by analysis of the 1H NMR data for crude reaction products. 13. Harmata, M.; Hong, X.; Barnes, C. L. Org. Lett. 2004, 6, 2201–2203. 14. We did not explore the bromination of benzothiazine 15b as we could not obtain it in large amounts in pure form. 15. Hayashi, R.; Cook, G. R. Org. Lett. 2007, 9, 1311–1314. 16. Other experiments we have performed show that the reaction does not take place to any significant extent at 10 °C. 17. Crystallographic data (excluding structure factors) for some structures reported in this Letter have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 716164 (17a0 ) and 716143 (18). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [Fax: +44(1223)336033; Email: [email protected]].