Benzothiazines in organic synthesis, an approach to the synthesis of seco-pseudopteroxazole

Article abstract of DOI:10.3987/COM-08-S(F)9

As part of our approach to the synthesis of seco-pseudopteroxazole, we have succeeded in establishing the stereochemistry of the methyl-bearing stereocenter (C-11 ) with good diastereoselectivity. Though seemingly straightforward, the process was not simp

Full text of DOI:10.3987/COM-08-S(F)9

HETEROCYCLES, Vol. 77, No. 1, 2009
279
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 279 - 291. © The Japan Institute of Heterocyclic Chemistry
Received, 9th April, 2008, Accepted, 18th August, 2008, Published online, 21st August, 2008.
DOI: 10.3987/COM-08-S(F)9
BENZOTHIAZINES IN ORGANIC SYNTHESIS. AN APPROACH TO
THE SYNTHESIS OF SECO-PSEUDOPTEROXAZOLE
Michael Harmata* and Pinguan Zheng
Department of Chemistry, University of Missouri-Columbia, Columbia, Missouri
65211, U. S. A.; E-mail: HarmataM@Missouri.edu
Abstract – As part of our approach to the synthesis of seco-pseudopteroxazole,
we have succeeded in establishing the stereochemistry of the methyl-bearing
stereocenter (C-11) with good diastereoselectivity. Though seemingly
straightforward, the process was not simple and revealed some interesting aspects
of benzothiazine chemistry.
INTRODUCTION
We recently reported the synthesis of the antitubercular agent pseudopteroxazole (1)1 using benzothiazine
chemistry developed in our laboratories.2 One difficulty in that process was establishing the configuration
Me
Me
Me
Me
Me
Me
Me
H
Me
H
N
N
O
Me
O
Me
1, pseudopteroxazole
2, seco-pseudopteroxazole
Figure 1
of the C-11stereocenter in 1. The reaction of enantiomerically pure 3 with LDA afforded 4 as a 10:1
mixture of diastereomers, unfortunately in the direction opposite to that desired (Scheme 1).
While steps could be taken to amerliorate this situation so that 1 could be synthesized, we wanted to
develop one or more routes that would avoid this complication. We chose to do that in the context of the
synthesis of the natural product seco-pseudopteroxazole (2).
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 1, 2009
Me
CO2Me
11
MeO2C
Me
H
4
Me
Me
LDA (2.0), -78 oC
Me
88%, dr 10:1
S O
S O
Ph
N
N
Ph
OMe
OMe
3
4
Scheme 1
Seco-pseudopteroxazole (2) was isolated by Rodriguez and coworkers from Pseudopterogorgia
elisabethae.3 Like pseudopteroxazole, it showed antituberculosis activity, though its potency was less
than that of pseudopteroxazole. No synthesis of seco-pseudopteroxazole has been reported, and this target
appeared to be one through which we could demonstrate new strategies for establishing the common
stereochemical centers at C-4 and C-11 of both pseudopteroxazole and seco-pseudopteroxazole.
While several approaches can be conceived for the establishment of the appropriate C-4/ C-11
relationship, we chose to simply reverse the roles of the substituents on the α,β-unsaturated ester of the
benzothiazine precursor, relative to how those were used in the synthesis of pseudopteroxazole.
RESULTS AND DISCUSSION
We began with aldehyde 5, which is readily prepared from 3,5-dimethylanisole in a 4-step sequence.4 A
Horner-Emmons reaction with known phosphonate 65 using the modification introduced by Roush and
Me
Me
O
CO2Me
Me
6 (1.2) LiCl (1.2), DBU (1.0)
MeCN, RT, 4 hr
H
Me
Br
83% E+ 10% Z
Br
OMe
OMe
5
7
Me
Me
Me
CO2Me
Pd(OAc)2 (5%), BINAP (7.5%)
(R)-8 (1.2), Cs2CO3 (1.4)
Tol, reflux, 50 hr, 99%
Me
S
O
N
Ph
OMe
9
Me
CO2Me
P(O)(OMe)2
Me
O
S
HN
(R)-8
Me
Ph
6
Scheme 2. Synthesis of sulfoximine 9

HETEROCYCLES, Vol. 77, No. 1, 2009
281
Masamune6 afforded the ester 7 in 83% yield along with a 10% yield of the corresponding Z isomer.
Coupling of this compound with enantiomerically pure sulfoximine 8 under standard conditions led to
sulfoximine 9 in 99% yield (Scheme 2).7 We were thus prepared to develop an intramolecular conjugate
addition/protonation sequence that would be highly diastereoselective.
Based on earlier results,1 we knew that the key to selectivity would be the protic quench itself. A selection
of quenching procedures attempted are illustrated in Table 1.
Table 1. Optimization of intramolecular Michael reaction
Me
Me
Me
Me
Me
Me
11
CO2Me
Me
CO2Me
H
conditions
S
S
Ph
Ph
N
N
O
O
OMe
OMe
10
9
Yield
(%)
entry
base (2.0)
LDA
electrophilea
MeOH
d.r.b
1
2
3
4
5
6
3.8: 1.0
4.6: 1.0
5.8: 1.0
9.2: 1.0
4.4: 1.0
5.6: 1.0
85
LiHMDS
LDA
MeOH
95
NAc
99
1N HCl in MeOH
1N HCl in MeOH
LiHMDS
LDA
DIPA∙HCl in MeOH
98
LiHMDS
DIPA∙HCl in MeOH
80
aPre-cooled to -78 oC. bDetermined by 1H NMR of the crude reaction mixture
cAN = Not Available
Initial attempts utilizing cold methanol as quenching reagent afforded the desired product in good yield,
but with only fair diastereoselectivity. This might result from the rapid epimerization at C-11 position
during the protonation of enolate, due to the formation of methoxide. A stronger proton donor was
necessary to achieve better stereoselectivity. When the reaction was quenched by rapid addition of cold
o
1N HCl in methanol solution at –78 C, the product was obtained in quantitative yield with a
diastereomeric ratio of up to 9.2:1.0 (entry 4). Interestingly, a sterically-hindered proton donor
(diisopropylamine-HCl) afforded product with only moderate diastereoselectivity (entry 6). Further, the
reaction utilizing LDA as a base generally gave lower diastereoselectivity than LiHMDS, which might
suggest that the role of free amines (HMDS and DIPA) in the reaction mixture should not be overlooked
(entries 3 and 5). The stereochemical outcome of the reaction could be rationalized by a model analogous
to one developed by Kocienski (11, Figure 2).8 Protonation on the Re face of 11 avoids an untoward
interaction with the hydrogen on the aryl ring (Figure 2) and is thus favored.

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HETEROCYCLES, Vol. 77, No. 1, 2009
Me
MeO
H
H
OLi
N
O S
Ph
OMe
R
11
Figure 2. Model for diastereoselective enolate quench
After successfully establishing the stereocenters at carbons 4 and 11 (2 numbering), we set out to convert
the methyl ester in 10 to a methyl group. One step procedures were not successful.9 LAH reduction gave
only moderate yields (43-57%) of the corresponding alcohol after silica gel column chromatography,
despite the fact that relatively clean conversion was achieved on a 200 mg scale (entry 1, Table 2). The
low yield of this reaction might be attributed to the lability of alcohol 12, which was prone to undergo
decomposition under the reaction conditions and during silica gel chromatography.
Table 2. Reduction and subsequent functionalization of 10
Me
Me
Me
Me
Me
12 R1= OH
CO2Me
OH
Ph
13 R1= OMs (87% from 12)
14 R1= OSO2i-Pr (95% from 12)
15 R1= OTs (87% from 12)
16 R1= I (85% from 13 or 14)
H
conditions
Me
S
S
N
Ph
N
O
O
OMe
OMe
12-16
10
yield (%)
12 or 16
entry condition
1
2
3
4
5
LAH (1.5), THF, 0 oC, 0.5 h
43-57
Red-Al (3.0), 0 oC, 2 h, rt, 5 h
DIBAL (3.0), 0 oC, 1.5 h, rt
LiEt3BH (3.0), THF, 0 oC, 0.5 h
a
46b
Quant.
80-89c
1. LiEt3BH, THF; 2. I2, PPh3, imid.
aDecomposition of 10 was observed. b8% recovery of starting material. cIodide 16 was obtained in 80-89% yield.
Compound 10 afforded a complex mixture of products upon with the treatment of Red-Al (Table 2, entry
2). Attempted reduction with DIBAL afforded product in 46% yield along with a small amount of starting
material (Table 2, entry 3). LiEt3BH10 was found to work perfectly to give a quantitative yield of alcohol,
which was directly converted to iodide 16 in 80-89% yield (Table 2, entries 4 and 5).11 Other substrates
(13-15), bearing different sulfonate functionalities, were also prepared from 12 in good yields.

HETEROCYCLES, Vol. 77, No. 1, 2009
283
Table 3. Reductions of sulfonate esters and iodides
Me
Me
Me
Me
Me
H
R1
Ph
H
conditions
Me
Me
S
S
Ph
N
N
O
O
OMe
OMe
17
13-16
Yield
(%) 17
Yield (%)
18 or 19
entry educt
conditions
LAH (3.0), Et2O
-25 oC, 12 h
1
2
13
13
13
13
13
14
14
15
15
15
15
16
16
16
45 (60a)
15 (18)
NA
LiEt3BH (3.0), THF
0 oC, 12 h
b
LiAlH(OMe)3, CuI
THF, 0 oC, 12 h
3
b
NA
LiH3BNMe2, Et3B
THF, 65 oC, 12 h
4
c
NA
NaBH4, DMSO
50 oC, 24 h
5
71, <40d
NA
LAH (3.0), Et2O
0 oC, 1 h; rt, 1 h
6
e
e
NA
LiEt3BH (3.0), THF rt,
12 h
7
NA
LAH (3.0), Et2O
0 oC, 3 h
24 (18)
4 (19)
8
50
LAH (3.0), Et2O
-25 oC, 12 h
9
53
NA
LAH (1.2), Et2O
0 oC, 12 h
5 (18)
2 (19)
10
11
12
13
14
35 (62a)
23e
38f
LiEt3BH (3.0), THF rt,
24 h
NA
NA
5% Pd/C (20%) EtOAc,
12 h
NaBH4, DMSO, 50oC
24 h
e
NA
LiEt3BH (3.0), THF
0 oC, 2 h
80-91
5-12 (20)
aYield was calculated based on recovered starting material. bOnly starting material was recovered. cComplex mixture. d900 mg scale.
eDecomposition observed. fThe yield was calculated based on 1H NMR analysis of the crude reaction mixture; see text.
Substrates 13-16 were subjected to different conditions of reductive cleavage of the C-X bond (Table 3).
When 13 was first exposed to 3.0 equivalents of LAH at –25 oC, compound 17 was obtained in 45% yield
(60% based on recorvered starting material). A 15% yield of overreduction product 18 was isolated (entry
1). Compound 13 reacted very slowly upon treatment of LiEt3BH or LiAlH(OMe)3 combined with CuI12
(entries 2 and 3). An unidentified complex mixture was obtained when 13 was treated with lithium
dimethylaminoborohydride and 20% Et3B13 (entry 4). NaBH4 dissolved in DMSO14 was also applied to
the deoxygenation of 13. A 71% yield of 17 was obtained in a small-scale reaction, but the yield dropped
precipitously on a larger scale. When sulfonate 1415 was treated with either LAH or LiBHEt3, only
decomposition of starting material was observed (entries 6 and 7). When tosylate 15 was subjected to

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HETEROCYCLES, Vol. 77, No. 1, 2009
reaction with LAH at 0 oC, significant amounts of over-reduction products 18 and 19 were isolated (entry
o
8).16 A lower temperature (-25 C) and lower loading of LAH suppressed the side reactions leading to
these compounds (entries 9 and 10), but the yield of 17 was still not satisfactory. Decomposition of 15
was observed when it was reacted with LiEt3BH (entry 11).
Me
Me
Me
Me
Me
Me
SPh
Me
H
Me
H
Me
Me
Me
SPh
N
S
H
N
O
NH2
OMe
H
OMe
OMe
19
18
20
Figure 3
Alkyl iodide 16 was first subjected to catalytic hydrogenolysis.17 Only a 38% conversion to product was
observed through 1H NMR analysis of crude reaction mixtures (entry 12). Heating 16 in the presence of
Me
Me
Me
Me
Me
Me
OTs
H
OTs
Li
H
H
-H2
LAH
H AlH3
Ph
S
S
Ph
N
N
O
O
OMe
OMe AlH3
15
21
Me
Me
Me
Me
Me
Me
OTs
Me
H
O
S
H
1. tosylate reduction
2. sulfoxide reduction
SPh
Ph
NH2
NLi
OMe
OMe AlH2
18
22
SPh
Me
1. intramolecular cyclization
2. sulfoxide reduction
Me
Me
N
H
OMe
19
Scheme 3. Formation of 18 and 19

HETEROCYCLES, Vol. 77, No. 1, 2009
285
NaBH4 in DMSO resulted in the decomposition of starting material (entry 13). However, treatment with
o
3.0 equivalents of LiEt3BH at 0 C for 2 h afforded 17 in up to 91% yield, together with 5-12% of
sulfinamide 20.18 This reaction was generally very clean and was easily scaled up to gram-scale.
A possible mechanism for the formation of byproducts 18 and 19 is shown in Scheme 3. Based on
proposed mechanisms for the LAH reduction of sulfones and sulfoxides,19 we suggest that reduction
might occur through initial S-N bond cleavage to afford 22. Tosylate reduction followed by sulfoxide
reduction would afford 18. If displacement of the leaving group at the nascent C-11 methyl group has not
yet occurred, cyclization is possible and subsequent sulfoxide reduction would give 19. The exact timing
of tosylate reduction is open to question, but formation of an anilide must presumably precede reduction
during the formation of 19.
If reagents and reaction conditions could be manipulated to selectively produce 18 or 19, a powerful
methodology for the synthesis of such compounds would be available.
CONCLUSION
We have developed a reliable 6-step sequence to benzothiazine 17, a key intermediate in our projected
total synthesis of seco-pseudopteroxazole (2), featuring our completely stereoselective benzothiazine
chemistry. Enolate protonation provided high levels of diastereoselectivity in setting the C-11
stereochemistry of 2. The total synthesis of seco-pseudopteroxazole is still in progress and the results will
be reported in due course.
EXPERIMENTAL
General. All reactions were carried out under an atmosphere of nitrogen or argon in flamed-dried
glassware. All commercial grade reagents and solvents were used as supplied with the following
exceptions. Ethyl ether (Et2O), tetrahydrofuran (THF) and toluene were freshly distilled from
sodium-benzophenone before use. Triethylamine, dichloromethane and acetonitrile were distilled from
calcium hydride. Chromatographic separations were carried out using Silicycle ultra pure silica gel
(230-400 mesh). Analytical thin layer chromatography was performed on EM reagent 0.25 nm silica gel
60-F plates with F-254 indicator. Melting points were measured with a Fisher-Johns melting point
apparatus. Infrared spectra were recorded on a Thermo Nicolet NEXUS 670 FT-IR spectrometer. Optical
rotations were measured on a Jasco DIP-370 digital polarimeter with a sodium lamp and are reported as
follows: [α]25 (c g/100 mL, solvent). High-resolution mass was measured on a Bruker 12 Tesla
D
FRICR-MS with an Apollo II ion source in Old Dominion University. Elemental analysis was performed
1
13
by the MHW laboratories, Phoenix, AZ. H and C-NMR spectra were recorded on a Bruker ARX-250
(250 MHz), DRX-300 (300 MHz), DRX-500 (500 MHz) spectrometer. Chemical shifts were reported in
ppm using tetramethylsilane (TMS: δ 0.0 ppm) as an internal standard. Data are reported as follows:

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HETEROCYCLES, Vol. 77, No. 1, 2009
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constants (Hz) and integration.
Preparation of (E)-methyl 2-(2-bromo-3-methoxy-5-methylbenzylidene)-6-methylhept-5-enoate 7
To a stirred suspension of LiCl (2.21g, 52.3 mmol) in dry MeCN (170 mL) under N2 atmosphere at rt,
were sequentially added phosphonate 6 (13.8 g, 52.3 mmol), DBU (6.5 mL, 43.6 mmol) and aldehyde 5
(10 g, 43.6 mmol). The resulting mixture was stirred for overnight (12 h) before it was diluted with
EtO2C. The organic solution was washed with water and brine, then dried over MgSO4. Concentration of
the solvent in vacuo afforded the crude product. NMR analysis of crude reaction mixture showed the ratio
of E: Z isomer is 10: 1.0. Flash column chromatography (5% EtOAc/hexanes) gave 13.3 g (83%) of E-7
and 1.6 g (10%) of an E/Z mixture. E-7: Yellow liquid; IR: ν 2945, 2851, 1715, 1572, 1425, 1323, 1258,
1090, 1029, 833 cm-1; 1H-NMR (250 MHz, CDCl3): δ 7.60 (s, 1H), 6.68 (s, 1H), 6.64 (s, 1H), 5.03 (t, J =
7.5 Hz, 1H), 3.84 (d, J = 1.9 Hz, 3H), 3.79 (d, J = 1.6 Hz, 3H), 2.32-2.39 (m, 2H), 2.29 (s, 3H), 2.10-2.16
13
(m, 2H), 1.61 (s, 3H), 1.51 (s, 3H); C-NMR (62.5 MHz, CDCl3): δ 168.1, 155.7, 139.0, 137.7, 137.5,
134.0, 132.1, 123.4, 122.4, 112.0, 109.6, 56.1, 51.8, 27.7, 27.4, 25.5, 21.3, 17.4; HRMS caclcd for
C18H23BrO3Na+ [M+ Na]+ 389.0722, found 389.0716.
Procedure for Buchwald-Hartwig coupling reaction
To a 500 mL round bottomed flask equipped with a reflux condenser under N2 atmosphere were
sequentially added bromoester 7 (10 g, 27.2 mmol), R-sulfoximine 8 (5.0 g, 32.6 mmol), Pd(OAc)2 (312
mg, 1.36 mmol), rac-BINAP (1.31 g, 2.04 mmol), Cs2CO3 (12.4 g, 38.0 mmol) and then toluene (270
mL). The reaction mixture was heated in an oil bath at 110-115 oC for 50 hr. The solution was cooled to rt
and diluted with CH2Cl2. The organic solution was filtered through a pad of Celite. Concentration of
solvent in vacuo afforded the crude product as brown oil. Purification of the product was carried out by
flash chromatography (30% EtOAc/hexane) afforded 9 as a pale yellow semi-solid 12.0 g (99%). IR: ν
2929, 1703, 1462, 1335, 1258, 1204, 1160, 1090, 739 cm-1; 1H-NMR (250 MHz, CDCl3): δ 8.06 (s, 1H),
8.00-8.04 (m, 2H), 7.47-7.57 (m, 3H), 6.77 (s, 1H), 6.60 (d, J = 1.3 Hz, 1H), 5.17 (tt, J = 7.3, 1.3 Hz, 1H),
3.82 (s, 3H), 3.58 (s, 3H), 3.12 (s, 3H), 2.46-2.52 (m, 2H), 2.28 (s, 3H), 2.22-2.25 (m, 2H), 1.68 (s, 3H),
1.62 (s, 3H); 13C-NMR (62.5 MHz, CDCl3): δ 169.0, 151.9, 142.6, 139.1, 132.3, 131.9, 131.8, 131.5,
130.0, 128.8, 127.4, 123.8, 122.0, 112.9, 55.4, 51.6, 46.0, 28.0, 27.8, 25.6, 21.2, 17.6; HRMS caclcd for
C25H31NO4SNa+ [M+ Na]+ 464.1849, found 464.1849; [α]25D +15.66 (c 1.66, acetone).
Procedure for the intramolecular Michael reaction
To a 1 L round bottom flask under N2 atmosphere were added 9 (9.6 g, 21.7 mmol) and THF (430 mL).

HETEROCYCLES, Vol. 77, No. 1, 2009
287
o
The mixture was cooled to –78 C before it was added dropwise LiHMDS (1.0 M in THF, 43 mL, 43.4
mmol). The stirring was continued for 1 h. The mixture was vigorously stirring with the rapid addition of
a cold 1N HCl in MeOH solution, which was precooled to -78 oC. The resulting mixture was warmed to rt
and diluted with EtOAc and H2O. The organic layer was separated and the aqueous layer was extracted
with EtOAc. The combined organic layer was washed with brine and dried over MgSO4. Concentration of
solvent in vacuo afforded crude product (d.r. 9.2: 1.0). Purification was carried out using column
chromatography (30% EtOAc/hexane) to afford 9.5 g of 10 (> 99%). 10: Yellow foam; IR: ν 2929, 1732,
1458, 1254, 1159, 1012, 747 cm-1; major isomer: 1H-NMR (250 MHz, CDCl3): δ 8.11 (d, J = 7.8 Hz, 2H),
7.50-7.65 (m, 3H), 6.68 (s, 1H), 6.60 (s, 1H), 4.96 (t, J = 7.0 Hz, 1H), 3.86 (s, 3H), 3.52-3.58 (m, 2H),
3.37 (s, 3H), 3.29-3.37 (m, 1H), 3.11-3.20 (m, 1H), 2.30 (s, 3H), 1.85-1.91 (m, 2H), 1.65 (s, 3H),
1.56-1.62 (m, 1H), 1.52 (s, 3H), 1.45-1.52 (m, 1H); 13C-NMR (62.5 MHz, CDCl3): δ 174.9, 152.7, 139.5,
133.3, 132.6, 131.4, 130.2, 129.1, 129.0, 125.3, 122.7, 120.1, 111.9, 55.9, 52.4, 51.2, 44.3, 38.5, 31.4,
25.6, 21.3, 17.5; HRMS caclcd for C25H31NO4SNa+ [M+ Na]+ 464.1866, found 464.1853.
Procedure for LiEt3BH reduction of ester 10
o
In a 300 mL flask were placed 10 (3.6 g, 8.15 mmol) and THF (160 mL). The flask was cooled to 0 C
with ice cooling. LiEt3BH (1.0 M in THF, 24.4 mL, 24.4 mmol) was added dropwise in 30 min with
vigorous stirring. The stirring was continued for an additional 30 min. The reaction was quenched by
sequential addition of MeOH, 1 N NaOH and 30% H2O2. The resulting mixture was extracted with
CH2Cl2. The combined organic extract was washed with H2O and brine. The organic extract was dried
over MgSO4. Concentration of solvent in vacuo afforded 12 (3.4 g, >99% yield), which was pure enough
to carry out next step without further purification. 12: Yellow semi-solid; IR: ν 3440, 2925, 1470, 1249
1
cm-1; major isomer: H-NMR (250 MHz, CDCl3): δ 8.01 (d, J =7.2 Hz, 2H), 7.43-7.59 (m, 3H), 6.64 (s,
1H), 6.59 (s, 1H), 5.03 (t, J = 7.1 Hz, 1H), 3.82 (s, 3H), 3.48-3.54 (m, 1H), 3.30-3.43 (m, 3H), 3.15-3.21
(m, 1H), 2.28 (s, 3H), 2.24-2.33 (m, 2H), 1.94-2.03 (m, 2H), 1.66 (s, 3H), 1.54 (s, 3H), 1.24-1.36 (m,
2H); 13C-NMR (62.5 MHz, CDCl3): δ 152.3, 139.1, 133.4, 132.1, 131.9, 129.6, 129.0, 129.0, 126.1, 123.8,
118.9, 111.1, 61.4, 55.8, 49.9, 38.4, 29.3, 25.6, 21.4, 17.6; HRMS caclcd for C24H32NO3S+ M+ 414.2097,
found 414.2097.
Procedure for the preparation of sulfonate ester 13, 14 and 15
To the dichloromethane solution (17 mL) of alcohol 12 (360 mg, 0.87 mmol) were successively added
sulfonyl chloride (1.30 mmol), DMAP (10.6 mg, 0.09 mmol) and TEA (365 μL, 2.60 mmol). The
resulting mixture was stirred at rt for a few hours before it was diluted with water. The organic layer was
washed with brine and dried over MgSO4. Flash chromatography (50% EtOAc/hexane) provided the

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HETEROCYCLES, Vol. 77, No. 1, 2009
desired sulfonate ester.
1
13: Yellow oil, 87% yield; IR: ν 2929, 1462, 1254, 1168 cm-1; major isomer: H-NMR (250 MHz,
CDCl3): δ 8.11 (d, J = 8.0 Hz, 2H), 7.53-7.69 (m, 3H), 6.70 (s, 1H), 6.59 (s, 1H), 5.04 (t, J = 6.5 Hz, 1H),
4.17-4.21 (m, 1H), 3.85-3.93 (m, 1H), 3.88 (s, 3H), 3.42-3.46 (m, 2H), 3.14 (dd, J = 13.7, 9.5 Hz, 1H),
2.87 (s, 3H), 2.65-2.67 (m, 1H), 2.33 (s, 3H), 2.03-2.10 (2H), 1.70 (s, 3H), 1.44-1.70 (m, 2H), 1.59 (s,
3H); 13C-NMR (62.5 MHz, CDCl3): δ 152.7, 138.8, 133.8, 132.8, 132.0, 130.1, 129.3, 129.1, 124.7, 122.8,
118.7, 111.5, 68.7, 55.9, 49.4, 37.0, 36.4, 36.1, 29.1, 25.6, 25.2, 21.4, 17.7; HRMS caclcd for
C25H33NO5S2Na+ [M+Na]+ 514.1692, found 514.1695.
o
14: Yellow solid, 95% yield, mp 103-4 C; IR: ν 2929, 1462, 1331, 1254, 1151 cm-1; major isomer:
1H-NMR (300 MHz, CDCl3): δ 8.08-8.11 (m, 2H), 7.54-7.66 (m, 3H), 6.70 (d, J = 1.2 Hz, 1H), 6.59 (s,
1H), 5.04 (td, J = 7.0, 1.5 Hz, 1H), 4.14-4.19 (m, 1H), 3.89-3.92 (m, 1H), 3.89 (s, 3H), 3.41-3.47 (m, 2H),
13
3.12-3.21 (m, 2H), 2.60-2.70 (m, 1H), 2.33 (s, 3H), 2.02-2.15 (m, 2H), C-NMR (75 MHz, CDCl3): δ
152.7, 138.9, 133.8, 132.8, 132.0, 130.1, 129.3, 129.0, 124.9, 122.9, 118.8, 111.5, 67.7, 56.0, 52.0, 49.5,
36.4, 36.2, 29.3, 25.7, 25.3, 21.4, 17.7, 16.5, 16.4; HRMS caclcd for C27H37NO5S2Na+ [M+Na]+ 542.2005,
found 524.2004.
1
15: Yellow foam, 87% yield. IR: ν 2913, 1450, 1168, 1086 cm-1; major isomer: H-NMR (250 MHz,
CDCl3): δ 8.02 (d, J = 7.4 Hz, 2H), 7.48-7.65 (m, 5H), 7.24 (d, J = 8.1 Hz, 2H), 6.65 (s, 1H), 6.46 (s, 1H),
4.91 (t, J = 6.7 Hz, 1H), 3.90 (dd, J = 10.3, 3.0 Hz, 1H), 3.85 (s, 3H), 3.63 (dd, J = 10.0, 4.3 Hz, 1H),
3.28-3.38 (m, 2H), 2.99-3.09 (m, 1H), 2.42-2.50 (m, 1H), 2.39 (s, 3H), 2.26 (s, 3H), 1.83-1.89 (m, 2H),
1.64 (s, 3H), 1.47 (s, 3H), 1.22-1.55 (m, 2H); 13C-NMR (62.5 MHz, CDCl3): δ 152.6, 144.9, 138.9, 133.7,
132.5, 132.2, 131.8, 130.1, 129.8, 129.2, 129.0, 127.6, 124.9, 122.9, 119.0, 111.5, 69.0, 55.9, 49.8, 36.5,
36.0, 28.9, 25.6, 25.1, 21.5, 21.3, 17.6.
Procedure for the preparation of iodide 16
To a stirred, cooled (0 oC) MeCN (30 mL) and Et2O (30 mL) mixture were successively added 12 (3.30 g,
8.15 mmol), triphenylphosphine (4.27 g, 16.3 mmol) and imidazole (1.11 g, 16.3 mmol). Iodine (4.10 g,
16.3 mmol) was slowly added. After the resulting pale yellow suspension was stirred for 5 hr (monitored
by TLC), the reaction mixture was diluted with ether and sequentially washed with saturated aqueous
Na2S2O3, saturated aqueous CuSO4 and water. The organic layer was dried over MgSO4 and concentrated
in vacuo to afford crude iodide. Flash chromatography (30% EtOAc/hexanes) gave 3.79 g of desired
iodide 16 (89% over the two steps). Yellow seimi-solid; IR: ν 2921, 1462, 1254, 1151, 1017, 747 cm-1;
1
major isomer: H-NMR (250 MHz, CDCl3): δ 8.12 (d, J = 7.9 Hz, 2H), 7.51-7.67 (m, 3H), 6.70 (s, 1H),
6.55 (s, 1H), 4.97 (t, J = 7.0 Hz, 1H), 3.88 (s, 3H), 3.42 (d, J = 5.3 Hz, 2H), 3.09-3.14 (m, 2H), 2.51 (dd, J
= 10.4, 5.7 Hz, 1H), 2.33 (s, 3H), 1.80-1.96 (m, 3H), 1.68 (s, 3H), 1.55 (s, 3H), 1.23-1.52 (m, 2H);

HETEROCYCLES, Vol. 77, No. 1, 2009
289
13C-NMR (62.5 MHz, CDCl3): δ 152.9, 139.4, 133.7, 132.4, 131.6, 130.5, 129.3, 129.0, 125.7, 123.0,
120.3, 111.7, 56.0, 50.7, 40.6, 36.5, 31.8, 25.7, 25.1, 21.3, 17.7, 11.1; HRMS caclcd for C24H31INO2S+ M+
524.1114, found 524.1109.
Procedure for the preparation of 17
In a 300 mL flask were placed iodide 16 (4.62 g, 8.82 mmol) and THF (175 mL). The flask was
o
immersed into an ice bath (0 C). LiEt3BH (1.0 M in THF, 26.3 mL, 26.3 mmol) was added dropwise in
50 mins using syringe pump (0.49 mL/min) with vigorous stirring. After addition was complete, stirring
was continued for an additional 1 hr. The reaction was quenched by sequential addition of MeOH, 1 N
NaOH and 30% H2O2. The reaction mixture was extracted with CH2Cl2. The combined organic layers
were washed with H2O and brine. The combined organic layer was dried over MgSO4. Concentration of
solvent in vacuo afforded crude 17. Flash chromatography (30% EtOAc/Hexane) afforded 3.19 g of 17
(91% yield) and 260 mg of 20 (ca. 10% yield). 17: Yellow semi-solid; IR: ν 2913, 1458, 1241, 1012 cm-1;
major isomer: 1H-NMR (250 MHz, CDCl3): δ 8.08-8.12 (m, 2H), 7.52-7.67 (m, 3H), 6.68 (s, 2H), 5.12 (tt,
J = 7.1, 1.3 Hz, 1H), 3.89 (s, 3H), 3.30-3.44 (m, 2H), 2.85 (t, J = 12.0 Hz, 1H), 2.49-2.56 (m, 1H), 2.34 (s,
3H), 2.03-2.09 (m, 2H), 1.71 (s, 3H), 1.62 (s, 3H), 1.27-1.51 (m, 2H), 0.80 (d, J = 6.7 Hz, 3H); 13C-NMR
(62.5 MHz, CDCl3): δ 152.2, 139.2, 133.5, 132.3, 131.9, 129.4, 129.1, 125.7, 123.8, 118.3, 110.9, 55.9,
47.9, 40.2, 38.0, 35.2, 31.4, 25.8, 25.6, 21.4, 17.6, 14.7; HRMS caclcd for C24H31NO2SNa+ [M+Na]+
420.1967, found 420.1958.
Byproduct 18: Red oil; d.r.: 3.3: 1.0; IR: ν 3444, 3366, 2913, 1585, 1486, 1290, 1160, 735 cm-1; major
isomer: 1H-NMR (500 MHz, CDCl3): δ 7.25-7.32 (m, 4H), 7.16 (t, J = 7.0 Hz, 1H), 6.53 (s, 2H), 5.02 (t, J
= 6.8 Hz, 1H), 3.86 (s, 3H), 3.64 (s, 2H, NH2), 3.43 (dd, J = 12.2, 4.2 Hz, 1H), 3.20 (dd, J = 12.5, 10.5 Hz,
1H), 2.89 (ddd, J = 10.6, 6.8, 3.8 Hz, 1H), 2.29 (s, 3H), 1.85-2.0 (m, 5H), 1.68 (s, 3H), 1.56 (s, 3H),
13
1.38-1.40 (m, 1H), 1.13-1.17 (m, 1H), 1.03 (d, J = 6.5 Hz, 3H); C-NMR (75 MHz, CDCl3): δ 147.4,
137.4, 132.0, 131.4, 128.8, 128.7, 127.9, 127.0, 125.5, 124.5, 119.6, 109.0, 55.3, 43.5, 36.5, 36.4, 34.3,
25.6, 25.4, 21.3, 17.5, 16.8; HRMS caclcd for C24H33NOSNa+ [M+Na]+ 406.2175, found 406.2165.
The presence of NH2 group was clearly shown in IR spectrum (doublet: 3444, 3366 cm–1). A peak of
doublet at 1.03 ppm with coupling constant of 6.5 Hz indicated that the tosylate group was cleaved.
Furthermore, a careful comparison of proton NMR of desired product 17, a lower chemical shift of
S-phenyl group (7.15-7.32 ppm in 18, as compared 7.52-8.12 ppm in 17) suggested the more shielding
from sulfur atom, and thus low valence of sulfur in the molecule, which was later confirmed to be
thiophenyl ether by the high resolution mass spectrum. Thus, the structure of 18 was assigned.

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HETEROCYCLES, Vol. 77, No. 1, 2009
Byproduct 19: Red liquid; single diastereomer; IR: 3423, 2908, 1585, 1507, 1262, 1102, 833, 735, 690
cm-1; 1H-NMR (500 MHz, CDCl3): δ 7.13-7.37 (m, 5H), 6.55 (s, 1H), 6.49 (d, J = 1.4 Hz, 1H), 5.10 (td, J
= 7.0, 1.3 Hz, 1H), 4.17 (s, 1H), 3.81 (s, 3H), 3.36 (ddd, J = 11.5, 4.2, 1.2 Hz, 1H), 3.22 (dd, J = 11.8,
10.3 Hz, 1H), 3.21 (dd, J = 12.0, 4.7 Hz, 1H), 3.05-3.09 (m, 1H), 3.02-3.05 (m, 1H), 2.25 (s, 3H),
13
2.02-2.10 (m, 3H), 1.67 (s, 3H), 1.60 (s, 3H), 1.25-1.55 (m, 2H); C-NMR (75 MHz, CDCl3): δ 145.9,
137.3, 131.8, 130.6, 129.0, 128.7, 125.6, 124.2, 124.0, 123.2, 121.6, 109.1, 55.3, 42.9, 39.4, 35.3, 34.9,
29.5, 25.7, 25.6, 20.9, 17.6; HRMS caclcd for C24H31NOSNa+ [M+Na]+ 404.2018, found 404.2014.
H10a
H10b
H5
Me
SPh
H7
Me
Me
H8
H
N
H9a
MeO
H9b
Figure 4. Key NOE Correlations of 19
The structure of minor byproduct 19 was assigned based on the extensive NMR studies. Coupling
1
constants of H9 and H10 were calculated based on 2D J-resolved NMR spectrum. As shown in H-NMR,
the sulfoximine moiety was reduced as clearly indicated by the lower chemical shift of S-phenyl group.
The absence of tosylate group and no distinct doublet around 1.00 ppm (methyl group), together with the
evidence of free NH group, suggested the presence of tetrahydroquinoline moiety in the molecule. The
1
attempts to calculate the coupling constants of H7 based on the H-NMR turned out to be fruitless,
because H7 overlapped with H10a and the spectrum turned into second-order spectrum (Δδ/J: 1.87). Thus,
the stereochemistry of H7 and H8 were assigned based on the stereochemistry of the starting material. The
structural assignment was also supported by NOESY experiment (Figure 4).
ACKNOWLEDGEMENTS
We are grateful to the National Institutes of Health (1R01-AI59000-01A1).
REFERENCES
1. (a) M. Harmata, X. Hong, and C. L. Barnes, Org. Lett., 2004, 6, 2201. (b) M. Harmata and X. Hong,
Org. Lett., 2005, 7, 3581.
2. M. Harmata and X. Hong, J. Am. Chem. Soc., 2003, 125, 5754.
3. A. D. Rodriguez, C. Ramirez, I. I. Rodriguez, and E. Gonzalez, Org. Lett., 1999, 1, 527.
4. G. Qabaja and G. B. Jones, J. Org. Chem., 2000, 65, 7187.

HETEROCYCLES, Vol. 77, No. 1, 2009
291
5. (a) W. Biernacki and A. Gdula, Synthesis, 1979, 37. (b) Z. Liu, W. Z. Li, L. Peng, Y. Li, and Y. Li, J.
Chem. Soc., Perkin Trans. 1, 2000, 4250.
6. M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune, W. R. Roush, and T. Sakai,
Tetrahedron Lett., 1984, 25, 2183.
7. (a) C. Bolm and J. P. Hildebrand, Tetrahedron Lett., 1998, 39, 5731. (b) C. Bolm and J. P.
Hildebrand, J. Org. Chem., 2000, 65, 169. (c) M. Harmata and N. Pavri, Angew. Chem. Int. Ed., 1999,
38, 2419.
8. R. Chow, P. J. Kocienski, A. Kuhl, J.-Y. LeBrazidec, K. Muir, and P. Fish, J. Chem. Soc., Perkin
Trans. 1, 2001, 2344.
9. V. Gevorgyan, M. Rubin, J. X. Liu, and Y. Yamamoto, J. Org. Chem., 2001, 66, 1672.
10. S. Krishnamurthy and H. C. Brown, J. Org. Chem., 1976, 41, 3064.
11. J. A. Marshall and D. G. Cleary, J. Org. Chem., 1986, 51, 858.
12. S. Masamune, P. A. Rossy, and G. S. Bates, J. Am. Chem. Soc., 1973, 95, 6452.
13. S. Thomas, T. Huynh, V. Enriquez-Rios, and B. Singaram, Org. Lett., 2001, 3, 3915.
14. H. M. Bell, C. W. Vanderslice, and A. Spehar, J. Org. Chem., 1969, 34, 3923.
15. D. H. Hua, G. Sinai-Zingde, and S. Venkataraman, J. Am. Chem. Soc., 1985, 107, 4088.
16. The structures of these side products were assigned on the basis of one and two-dimensional NMR
data. See experimental section.
17. A. H. G. Siebum, W. S. Woo, and J. Lugtenburg, Eur. J. Org. Chem., 2003, 4664.
18. M. Harmata and P. Zheng, Org. Lett., 2007, 9, 5251.
19. (a) T. A. Whitney and D. J. Cram, J. Org. Chem., 1970, 35, 3964. (b) F. G. Bordwell and W. H.
McKellin, J. Am. Chem. Soc., 1951, 73, 2251.