Organolithium-mediated conversion of β-alkoxy aziridines into allylic sulfonamides: Effect of the N-sulfonyl group and a formal synthesis of (±)-perhydrohistrionicotoxin

Article abstract of DOI:10.1021/jo801586h

(Chemical Equation Presented) In 18 out of 20 examples of the organolithium-mediated conversion of β-alkoxy aziridines into substituted allylic sulfonamides, use of a Bus (Bus = t-BuSO₂) substituent on the nitrogen gave higher yields compared t

Full text of DOI:10.1021/jo801586h

SCHEME 1. Lithiated Aziridines in Action: Synthesis of the
Spirocyclic Core of Cephalotaxine
Organolithium-Mediated Conversion of ꢀ-Alkoxy
Aziridines into Allylic Sulfonamides: Effect of the
N-Sulfonyl Group and a Formal Synthesis of
(()-Perhydrohistrionicotoxin†
Susannah C. Coote,‡ Stephen P. Moore,‡ Peter O’Brien,‡,*
Adrian C. Whitwood,‡ and John Gilday§
Department of Chemistry, UniVersity of York, Heslington,
York YO10 5DD, U.K., and Process R & D, AstraZeneca
AVlon Works, SeVern Road, Hallen, Bristol BS10 7ZE, U.K.
paob1@york.ac.uk
ReceiVed July 17, 2008
SCHEME 2. Low-Yielding Reaction of a
Cyclohexene-Derived ꢀ-Methoxy Aziridine with n-BuLi
In 18 out of 20 examples of the organolithium-mediated
conversion of ꢀ-alkoxy aziridines into substituted allylic
sulfonamides, use of a Bus (Bus ) t-BuSO2) substituent on
the nitrogen gave higher yields compared to the analogous
N-Ts compounds. The success with the N-Bus aziridines
facilitated the development of a new route to the spirocyclic
core of the histrionicotoxins and completion of a formal
synthesis of (()-perhydrohistrionicotoxin.
members of the histrionicotoxin family,4 we were especially
keen to extend our methodology to reactions of 3-substituted
cyclohexene-derived ꢀ-methoxy aziridines. Unfortunately, in our
earlier work5 we had found that reactions of such aziridines
with organolithium reagents gave low yields of cyclohexenyl
sulfonamides due, in part, to the competing formation of an
enesulfonamide. An example is shown in Scheme 2. Reaction
of aziridine cis-7a with 2.5 equiv of n-BuLi gave allylic
sulfonamide 8a in 22% yield and enesulfonamide 9a in 25%
yield. Note that we had originally proposed5 the regioisomeric
structure 10 (in which a 1,2-alkyl shift had occurred) as the
enesulfonamide generated from this process. However, in light
of the results presented in this paper (vide infra), we are
confident that enesulfonamide 9a is the correct structure, and
we now wish to correct our previous erroneous report.
Our planned synthetic efforts toward the histrionicotoxins
required the preparation of azaspiro[5.5]undecanes, and this
necessitated higher yielding transformation of ꢀ-methoxy aziri-
dines such as cis-7a into substituted allylic sulfonamides such
as 8a. We elected to evaluate the use of N-Bus-substituted
aziridines (Bus ) t-BuSO2) in place of the N-Ts aziridines used
in our previous studies2,3,5 for two reasons: (i) we were
concerned that ortho-lithiation6 of the N-Ts group might be a
deleterious competing process and (ii) we wondered whether
the different electronic properties of the N-sulfonyl substituent
might affect the efficiency of the carbenoid insertion into the
organolithium reagent. With this in mind, we directly compared
As part of our ongoing studies into the synthetic opportunities
offered by lithiated aziridine intermediates,1,2 we recently
reported a new route to azaspirocycles such as the core of
cephalotaxine (Scheme 1).3 Thus, treatment of ꢀ-methoxy
aziridine cis-1 with 3 equiv of functionalized aryllithium 2
(prepared by bromine-lithium exchange) gave, after aqueous
workup, allylic sulfonamide 5 in 43% yield. It is likely that
this transformation proceeds via lithiated aziridine 3 from which
carbenoid insertion into the aryllithium 2 to give 4 is followed
by elimination of lithium methoxide. A five-step sequence was
then used to convert 5 into the azaspirocycle 6.
Since there are a number of biologically interesting azaspi-
rocycles equipped with an azaspiro[5.5]undecane motif such as
† This paper is dedicated to the memory of Professor C. Mioskowski for his
numerous pioneering contributions to organic chemistry and lithiated epoxide
methodology in particular.
‡ University of York.
§ AstraZeneca.
(1) For reviews on lithiated aziridines, see: (a) Satoh, T. Chem. ReV. 1996,
96, 3303. (b) Hodgson, D. M.; Bray, C. D.; Humphreys, P. G. Synlett 2006, 1.
(c) For a special issue of Tetrahedron on “oxiranyl and aziridinyl anions”, see:
Tetrahedron 2003, 59, 9693-9847.
(2) For our most recent paper on lithiated aziridines, see: Moore, S. P.;
O’Brien, P.; Whitwood, A. C.; Gilday, J. Synlett 2008, 237.
(3) Moore, S. P.; Coote, S. C.; O’Brien, P.; Gilday, J. Org. Lett. 2006, 8,
5145.
(4) For an excellent and comprehensive review on the synthesis of the
histrionicotoxins, see: Stockman, R. A.; Sinclair, A. Nat. Prod. Rep. 2007, 24,
298.
(5) Rosser, C. M.; Coote, S. C.; Kirby, J. P.; O’Brien, P.; Caine, D. Org.
Lett. 2004, 6, 4817.
7852 J. Org. Chem. 2008, 73, 7852–7855
10.1021/jo801586h CCC: $40.75 2008 American Chemical Society
Published on Web 09/09/2008

TABLE 1. Comparison of N-Bus and N-Ts for the
Organolitihium-Mediated Reactions of ꢀ-Methoxy Aziridines
TABLE 2. Comparison of N-Bus and N-Ts for the
Organolitihum-Mediated Reactions of 3-Substituted
Cyclohexene-Derived ꢀ-Methoxy Aziridines
a: P ) Ts prod, b: P ) Bus prod,
yield (%) yield (%)
a: P ) Ts b: P ) Bus
entry SM
R1
R2
n-Bu
s-Bu
t-Bu
entry SM
n
R1
R2
n-Bu
Me3SiCH2 16
prod yield (%)
yield (%)
1
2
3
4
5
6
7
7
7
7
7
Me
Me
Me
Me
Me
8a, 22 9a, 25 8b, 69 9b, 19
1
11
11
11
12
12
12
13
13
13
13
13
14
14
14
1
1
1
1
1
1
1
1
1
1
1
2
2
2
H
H
H
Me
Me
Me
15
53
67
58
76
67
66
80
84
76
82
63
34
67
47
67
71
75
87
75
76
82
84
80
84
75
81
76
81
30a, 32 9a, 27 30b, 86
31a, 72 9a, 0 31b, 65
9b, 0
9b, 0
2
3
4
5
Ph
n-Bu
17
18
Me3SiCH2 32a, 47 9a, 19 32b, 53 9b, 30
Ph
33a, 12 9a, 34 33b, 23 9b, 49
34a, 18 35a, 42 34b, 44 35b, 35
Me3SiCH2 19
29 homoallyl n-Bu
7a 29 homoallyl n-Bu
-
-
34b, 73 35b, 24
6
7
8
9
Ph
20
21
22
23
homoallyl n-Bu
homoallyl s-Bu
homoallyl t-Bu
homoallyl Me3SiCH2 24
homoallyl Ph
a Reaction carried out in THF on 3.0 mmol scale.
10
11
12
13
14
25
26
yield improvement was dramatic: N-Bus 26b was formed in
81% yield, whereas N-Ts 26a was obtained in only 34% yield
(entry 12). Thus, there is a significant improvement on using
the N-Bus aziridines in these reactions. Hodgson and co-workers
have noted a similar positive effect in a number of reactions of
aziridines.10
H
H
H
n-Bu
Me3SiCH2 27
Ph
28
20 examples of organolithium-mediated reactions of N-Bus and
N-Ts cyclopentene- and cyclohexene-derived ꢀ-methoxy aziri-
dines. As part of this study, two X-ray structures of enesulfona-
mides like 9a were obtained, establishing the structures of the
enesulfonamide byproduct. Ultimately, the results enabled us
to carry out a formal synthesis of (()-perhydrohistrionicotoxin.
Twelve different ꢀ-methoxy aziridines (cis-7a/b,11-14a/b,
and 29a/b, Tables 1 and 2) were prepared by standard
methylation (KHMDS, THF, MeI or Ag2O, MeCN, MeI; see
Supporting Information) of the corresponding hydroxy aziri-
dines. The hydroxy aziridines were in turn prepared by cis-
stereoselective Sharpless aziridination of the allylic alcohols
using Chloramine-T (TsNClNa)7 or BusNClNa,8 the details of
which are described elsewhere.9 The following standard pro-
cedure was adopted for the ꢀ-methoxy aziridine f allylic
sulfonamide reactions: 2.5 equiv of the organolithium reagent
was reacted with the aziridine in Et2O at -78 °C for 5 min,
and then the reaction was allowed to warm to room temperature
over 1 h before quenching. The reactions of ꢀ-methoxy
aziridines cis-11-14a/b yielded allylic sulfonamides (15a/
b-28a/b) as the only isolable products after chromatography;
the results are shown in Table 1.
Next, we determined whether a similar yield improvement
would be found with the more troublesome 3-substituted
aziridines cis-7a/b and cis-29a/b (Table 2). Pleasingly, use of
the N-Bus-substituted aziridines led to significant increases in
the yields of the allylic sulfonamides 8b and 30-34b. These
are the highest yields we have ever obtained for the organo-
lithium-mediated transformations of 3-substituted cyclohexene-
derived aziridines. The reaction of N-Bus homoallyl-substituted
aziridine cis-29b (entries 6 and 7) required some further
optimization, and it was found that the best reproducible yield
(73%, entry 7) could be obtained using THF as the solvent.
In addition, we have now unequivocally established the
structure of the enesulfonamide byproduct from these reactions
as 9a/b and 35a/b with X-ray crystal structures of enesulfona-
mides 9b and 35a (see Supporting Information). It is likely that
the enesulfonamides form from a lithiated aziridine (analogous
to 3, Scheme 1) and subsequent elimination in which the ring-
CH2 and the 3-substituent (R1) can stabilize a developing
positive charge as the C-N bond breaks. Such a mechanistic
pathway occurs for 3-substituted cyclohexene-derived aziridines
such as cis-7a/b and 29a/b (as well as for structurally related
acyclic analogues2) but not for the corresponding 3-substituted
cyclopentene aziridines cis-12a/b and 13a/b and cyclohexene
aziridines cis-14a/b, which lack a 3-substituent.
In all but one (entry 8) of the examples in Table 1, the N-Bus-
substituted aziridines gave higher yields of the allylic sulfona-
mides than the corresponding N-Ts aziridine. In one case, the
Finally, having established that the use of N-Bus-substituted
aziridines enabled high yields of allylic sulfonamides to be
obtained from 3-substituted cyclohexene-derived ꢀ-methoxy
aziridines, we then applied our methodology to the synthesis
of the azaspiro[5.5]undecane motif of the histrionicotoxins
(Scheme 3).4 N-Bus aziridine cis-29b was reacted with excess
n-BuLi to give allylic sulfonamide 34b in 73% yield. Then,
(6) (a) Huang, J.; O’Brien, P. Tetrahedron Lett. 2005, 46, 3253. (b)
Chamberlin, A. R.; Stemke, J. E.; Bond, F. T. J. Org. Chem. 1978, 43, 147. (c)
Hellwinkel, D.; Supp, M. Tetrahedron Lett. 1975, 1499. (d) Schafer, S. J.;
Closson, W. D. J. Org. Chem. 1975, 40, 889. (e) Lombardino, J. G. J. Org.
Chem. 1971, 36, 1843. (f) Watanabe, H.; Schwarz, R. A.; Hauser, C. R.; Lewis,
J.; Slocum, D. W. Can. J. Chem. 1969, 47, 1543. (g) Hodgson, D. M.; Cameron,
I. D.; Christlieb, M.; Green, R.; Lee, G. P.; Robinson, L. A. J. Chem. Soc.,
Perkin Trans. 1 2001, 2161. (h) Florio, S.; Aggarwal, V.; Salomone, A. Org.
Lett. 2004, 6, 4191. (i) Luisi, R.; Capriatti, V.; Florio, S.; Ranaldo, R. Tetrahedron
Lett. 2003, 44, 2677.
(7) Jeong, J. U.; Tao, B.; Sagasser, I.; Henniges, H.; Sharpless, K. B. J. Am.
Chem. Soc. 1998, 120, 6844.
(8) Gontcharov, A. V.; Liu, H.; Sharpless, K. B. Org. Lett. 1999, 1, 783.
(9) Coote, S. C.; O’Brien, P. Whitwood, A. C. Org. Biomol. Chem. 2008,
DOI: 10.1039, B811137E.
(10) (a) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2005, 7,
1153. (b) Hodgson, D. M.; Humphreys, P. G.; Ward, J. G. Org. Lett. 2006, 8,
995. (c) Hodgson, D. M.; Stefane, B.; Miles, T. J.; Witherington, J. J. Org.
Chem. 2006, 71, 8510. (d) Hodgson, D. M.; Hughes, S. P.; Thompson, A. L.;
Heightman, T. D. Org. Lett. 2008, 10, 3453.
J. Org. Chem. Vol. 73, No. 19, 2008 7853

SCHEME 3. Formal Synthesis of
(()-Perhydrohistrionicotoxin
into allylic sulfonamides. In particular, reaction of n-BuLi with
N-Bus cyclohexene-derived aziridine cis-29b generated 34b in
73% yield, which enabled a formal synthesis of (()-perhydro-
histrionicotoxin to be completed. As part of this study, a useful
method for N-Bus deprotection (sodium in liquid ammonia) has
been identified.
Experimental Section
General Procedure for the Organolithium-Mediated Reac-
tions of ꢀ-Methoxy Aziridines. Organolithium reagent (2.5 equiv)
was added dropwise to a stirred solution of methoxy aziridine (0.5
mmol) in Et2O (5 mL) at -78 °C under argon. After stirring at
-78 °C for 5 min, the resulting solution was allowed to warm to
room temperature over 1 h. Then saturated NH4Cl(aq) (10 mL) was
added. The layers were separated, and the aqueous layer was
extracted with Et2O (3 × 10 mL). The combined organic layers
were dried (MgSO4) and evaporated under reduced pressure to give
the crude product.
N-(2-Butyl-1-methyl-2-cyclopenten-1-yl)-2-methyl-2-propane-
sulfonamide 18b. Using the general procedure, n-butyllithium (0.8
mL of a 1.20 M solution in hexanes, 1.0 mmol) and methoxy
aziridine cis-12b (99 mg, 0.4 mmol) in Et2O (5 mL) gave the crude
product. Purification by flash column chromatography on silica with
petrol-Et2O (7:3) as eluent gave allylic sulfonamide 18b (95 mg,
87%) as a white solid, mp 52-55 °C (petrol-Et2O); Rf (7:3
petrol-Et2O) 0.2; IR (Nujol mull) 3269 (NH), 1305 (SO2), 1128
hydroboration of the least sterically hindered alkene in 34b was
accomplished using BH3 ·Me2S and oxidative workup; alcohol
36 was generated in 70% yield. In our previously reported
azaspirocycle syntheses,3 Mitsunobu conditions (DEAD or
DIAD, PPh3) were used to form the piperidine ring. However,
in model studies, we found that the N-Bus sulfonamides gave
e52% yield for cyclization using Mitsunobu conditions. Hence,
mesylation of the hydroxyl group and base-mediated cyclization
(in refluxing MeCN) were utilized for the conversion of 36 into
azaspirocycle 37 (82% yield).
To demonstrate the synthetic usefulness of the N-Bus aziridine
methodology and to complete a formal synthesis of (()-
perhydrohistrionicotoxin, it was crucial to show that the N-Bus
group could be deprotected. Disappointingly, use of TFA or
TfOH (in the presence of anisole), conditions reported by
Weinreb,11 led only to decomposition of spirocycle 37. At-
tempted deprotection of the N-Bus group in 37 using Red-Al
in refluxing toluene (or xylenes)12 or lithium naphthalenide13
each returned recovered starting material. Finally, it was found
that N-Bus deprotection could be effected by treating 37 with
excess sodium in liquid ammonia and THF at -40 °C. The free
amine was generated in quantitative yield and subsequent
N-benzylation using benzyl bromide also proceeded quantita-
tively to give N-Bn azaspirocycle 38. A combination of
Husson’s14 and Corey’s15 syntheses can then be used to convert
38 into (()-perhydrohistrionicotoxin. We also briefly explored
intercepting Corey’s route to (()-perhydrohistrionicotoxin more
directly by hydroboration of the alkene in 37 using BH3 ·Me2S
in refluxing THF. However, as expected, hydroboration occurred
opposite to the sterically bulky N-Bus group to give a 50% yield
of a diastereomer of the compound required for perhydrohis-
trionicotoxin (incorrect relative stereochemistry between the OH,
n-Bu, and N-Bus groups).
1
(SO2); H NMR (400 MHz, C6D6) δ 5.22 (app. quintet, J ) 2.0,
1H, dCH), 3.70 (s, 1H, NH), 2.63-2.55 (m, 1H, CH), 2.29-2.19
(m, 1H, CH), 2.05-1.80 (m, 4H, 4 × CH), 1.43-1.33 (m, 2H, 2
× CH), 1.38 (s, 3H, Me), 1.27 (app. sextet, J ) 7.5, 2H, CH2Me),
1.23 (s, 9H, CMe3), 0.89 (t, J ) 7.5, 3H, Me); 13C NMR (100.6
MHz, C6D6) δ 148.5 (dC), 125.5 (dCH), 70.6 (CN), 59.0 (SO2C),
40.1 (CH2), 30.3 (CH2), 29.3 (CH2), 26.0 (CH2), 24.7 (CH2), 24.4
(CMe3), 23.0 (CH2), 14.3 (Me); MS (CI, NH3) m/z 291 [(M +
NH4)+, 5], 155 (45), 137 (100); HRMS (CI, NH3) m/z: [M + NH4]+
calcd for C14H27NO2S, 291.2106; found, 291.2104.
N-(2-Butyl-1-methyl-2-cyclohexen-1-yl)-2-methyl-2-propane-
sulfonamide 8b and N-(6-Methoxy-2-methyl-1-cyclohexen-1-yl)-
2-methyl-2-propanesulfonamide 9b. Using the general procedure,
n-butyllithium (0.8 mL of a 1.15 M solution in hexanes, 1.0 mmol)
and methoxy aziridine cis-7b (100 mg, 0.4 mmol) in Et2O (4 mL)
gave the crude product. Purification by flash column chromatog-
raphy on silica with petrol-Et2O (7:3) as eluent gave allylic
sulfonamide 8b (75 mg, 69%) as a colorless oil, Rf (7:3
petrol-Et2O) 0.3; IR (film) 3282 (NH), 2955, 2932, 2871, 1456,
1
1305 (SO2), 1129 (SO2), 1106, 951; H NMR (400 MHz, CDCl3)
δ 5.53-5.51 (m, 1H, dCH), 3.62 (s, 1H, NH), 2.46-2.40 (m, 1H,
CH), 2.15-1.93 (m, 4H, 4 × CH), 1.81-1.63 (m, 3H, 3 × CH),
1.49 (s, 3H, Me), 1.45-1.31 (m, 4H, 4 × CH), 1.41 (s, 9H, CMe3),
0.93 (t, J ) 7.5, 3H, Me); 13C NMR (100.6 MHz, CDCl3) δ 141.1
(dC), 125.0 (dCH), 59.9 and 59.8 (SO2C and CN), 37.9 (CH2),
31.1 (CH2), 30.4 (CH2), 25.4 (CH2), 24.6 (Me), 24.4 (CMe3), 22.8
(CH2), 18.6 (CH2), 14.1 (Me); MS (CI, NH3) m/z 288 [(M + H)+,
40], 272 (20), 168 (55), 151 (100); HRMS (CI, NH3) m/z: [M +
H]+ calcd for C15H29NO2S, 288.1997; found, 288.1997 and ene-
sulfonamide 9b (19 mg, 19%) as a white solid, mp 94-95 °C
(petrol-Et2O); Rf (8:2 petrol-Et2O) 0.1; IR (Nujol mull) 3213
(NH), 1297 (SO2), 1125 (SO2); 1H NMR (400 MHz, CDCl3) δ 5.37
(s, 1H, NH), 3.97-3.95 (m, 1H, CHO), 3.39 (s, 3H, OMe),
2.15-2.02 (m, 2H, 2 × CH), 1.81 (s, 3H, Me), 1.81-1.63 (m, 3H,
3 × CH), 1.58-1.49 (m, 1H, CH), 1.49 (s, 9H, CMe3); 13C NMR
(100.6 MHz, CDCl3) δ 135.7 (dC), 126.5 (dC), 76.1 (CHO), 59.9
(SO2C), 56.4 (OMe), 31.6 (CH2), 26.6 (CH2), 24.3 (CMe3), 19.2
(Me), 17.6 (CH2); MS (CI, NH3) m/z 279 [(M + NH4)+, 10], 262
(20), 261 (30), 247 (25), 230 (100), 141 (30), 110 (35); HRMS
(CI, NH3) m/z: [M + NH4]+ calcd for C12H23NO3S, 279.1742;
found, 279.1748.
In summary, with 18 examples, we have demonstrated that
N-Bus-substituted ꢀ-methoxy aziridines give higher yields than
their N-Ts analogues in their organolithium-mediated conversion
(11) Sun, P.; Weinreb, S. M. J. Org. Chem. 1997, 62, 8604.
(12) Gold, E. H.; Babad, E. J. Org. Chem. 1972, 37, 2208.
(13) Alonso, E.; Ramo´n, J.; Yus, M. Tetrahedron 1997, 53, 14355.
(14) Zhu, J.; Royer, J.; Quirion, J.-C.; Husson, H.-P. Tetrahedron Lett. 1991,
32, 2485.
(15) Corey, E. J.; Arnett, J. F.; Widiger, G. N. J. Am. Chem. Soc. 1975, 97,
430.
7854 J. Org. Chem. Vol. 73, No. 19, 2008

N-[1-(3-Butenyl)-2-butyl-2-cyclohexen-1-yl]-2-methyl-2-propane-
sulfonamide 34b and N-[2-(3-butenyl)-6-methoxy-1-cyclohexen-1-
yl]-2-methyl-2-propanesulfonamide 35b. n-Butyllithium (5.2 mL
of a 1.40 M solution in hexanes, 7.3 mmol) was added dropwise
to a stirred solution of methoxy aziridine cis-29b (880 mg, 2.9
mmol) in THF (40 mL) at -78 °C under argon (reaction carried
out in 500 mL flask). After stirring at -78 °C for 5 min, the
resulting solution was allowed to warm to room temperature over
1 h. Then saturated NH4Cl(aq) (10 mL) was added. The layers were
separated and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were dried (MgSO4) and
evaporated under reduced pressure to give the crude product.
Purification by flash column chromatography on silica with
petrol-Et2O (7:3) as eluent gave allylic sulfonamide 34b (699 mg,
73%) as a colorless oil, RF (7:3 petrol-Et2O) 0.3; IR (Nujol mull)
3288 (NH), 2956, 2931, 2872, 1454, 1309 (SO2), 1127 (SO2), 973,
328 [(M + H)+, 5], 272 (20), 191 (100); HRMS (CI, NH3) m/z:
[M + H]+ calcd for C18H33NO2S, 328.2310; found, 328.2320 and
enesulfonamide 35b (216 mg, 24%) as a white solid, mp 111-113
°C (petrol-Et2O); Rf (7:3 petrol-Et2O) 0.1; IR (Nujol mull) 3226
(NH), 1298 (SO2), 1124 (SO2), 1079, 911, 890; 1H NMR (400 MHz,
CDCl3) δ 5.81 (ddt, J ) 17.0, 10.0, 6.5, 1H, dCH), 5.36 (s, 1H,
NH), 5.03 (dq, J ) 17.0, 1.5, 1H, CHdCHAHB), 4.95 (ddt, J )
10.0, 2.0, 1.0, 1H, CHdCHAHB), 3.94 (t, J ) 4.0, 1H, CHO), 3.37
(s, 3H, OMe), 2.36 (ddd, J ) 13.0, 9.0, 7.5, 1H, CH), 2.29-2.07
(m, 5H, 5 × CH), 1.85-1.78 (m, 1H, CH), 1.76-1.50 (m, 3H, 3
× CH), 1.46 (s, 9H, CMe3); 13C NMR (100.6 MHz, CDCl3) δ 139.1
(dC), 138.0 (dCH), 126.7 (dC), 115.0 (dCH2), 76.2 (CHO), 59.9
(SO2C), 56.4 (CN), 31.8 (CH2), 31.4 (CH2), 29.2 (CH2), 26.5 (CH2),
24.2 (CMe3), 17.6 (CH2); MS (CI, NH3) m/z 302 [(M + H)+, 25],
287 (20), 270 (100), 150 (20), 140 (20); HRMS (CI, NH3) m/z: [M
+ H]+ calcd for C15H27NO3S, 302.1790; found, 302.1788.
1
907; H NMR (400 MHz, C6D6) δ 5.80 (ddt, J ) 17.0, 10.0, 6.5,
Acknowledgment. We thank the EPSRC for a DTA award
(to S.C.C.) and the EPSRC and AstraZeneca for an Industrial
CASE award (to S.P.M.).
1H, CH ) CH2), 5.66-5.63 (m, 1H,dCH), 5.01 (app. dq, J ) 17.0,
1.5, 1H, CHdCHACHB), 4.95 (app. dq, J ) 10.0, 1.5, 1H,
CHdCHACHB), 3.69 (s, 1H, NH), 2.44-2.38 (m, 1H, CH),
2.32-2.24 (m, 1H, CH), 2.16-1.91 (m, 5H, 5 × CH), 1.88-1.67
(m, 5H, 5 × CH), 1.51-1.37 (m, 2H, 2 × CH), 1.41 (s, 9H, CMe3),
1.35 (app. sextet, J ) 7.5, 2H, CH2Me), 0.93 (t, J ) 7.5, 3H, Me);
13C NMR (100.6 MHz, C6D6) δ 139.5 (dC), 138.3 (dCHCH2),
126.9 (dCH), 114.6 (dCH2), 63.2 (CN), 60.0 (SO2C), 35.3 (CH2),
32.7 (CH2), 30.8 (CH2), 30.1 (CH2), 29.2 (CH2), 25.5 (CH2), 24.4
(CMe3), 22.8 (CH2), 18.4 (CH2), 14.1 (Me); MS (CI, NH3) m/z
Supporting Information Available: Full experimental pro-
cedures, characterization data and copies of 1H/13C NMR spectra
of novel compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO801586H
J. Org. Chem. Vol. 73, No. 19, 2008 7855