Directed addition of sulfur-stabilised carbanions to 1,2,3-trisubstituted aziridines

Article abstract of DOI:10.1016/j.tet.2010.04.096

Thioether and sulfone-stabilised carbanions possessing varying functional groups enter into highly regioselective, stereospecific ring-opening reactions with vinyl- and hydroxymethyl-substituted aziridines. Some derivatisation reactions of the adducts are

Full text of DOI:10.1016/j.tet.2010.04.096

Tetrahedron 66 (2010) 6376e6382
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Directed addition of sulfur-stabilised carbanions to 1,2,3-trisubstituted aziridines
*
Donald Craig , Pengfei Lu, Tanya Mathie, Niels T.H. Tholen
Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 March 2010
Received in revised form 19 April 2010
Accepted 22 April 2010
Available online 29 April 2010
Thioether and sulfone-stabilised carbanions possessing varying functional groups enter into highly re-
gioselective, stereospecific ring-opening reactions with vinyl- and hydroxymethyl-substituted aziridines.
Some derivatisation reactions of the adducts are reported.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Aziridine
Cyclisation
Directed addition
Regioselective
Sulfur-stabilised Carbanion
1. Introduction
NR1
R2
HNR1
R2
R1N
+
Nu
Nu
Nu
Aziridines are valuable intermediates for the synthesis of ni-
trogen-containing molecules. Combining electrophilic reactivity
with ease of synthesis, they are readily available from a variety of
sources, most notably by cyclisation reactions of aminoalcohol
derivatives, and by nitrenoid insertion into alkenes, and carbenoid
insertion into the CeN double bonds of imines. Aziridine reactivity
towards nucleophiles may be modified by variation of the N-sub-
stituent, and in general, aziridines substituted on nitrogen and on
one of the ring carbon atoms suffer attack by anionic nucleophiles
at the less substituted 3-position. When both carbon atoms are
substituted, steric and electronic effects may compete, such that
mixtures of products of attack at both electrophilic ring positions
are obtained (Scheme 1).1,2
Nu
Nu
R2
1,2-disubstituted
aziridine
NR1
R2
HNR1
R2
Nu
R1N
+
R3
1,2,3-trisubstituted
aziridine
R3
R3
R3
R2
R2
R2
H
R1N
R1N
Nu
Nu
R3
We reported recently3 a series of reactions in which sulfur-sta-
bilised (arylsulfenyl, arylsulfonyl) carbanions combined with 1,2,3-
trisubstituted aziridines to give the products of stereospecific and
completely regioselective ring-opening. These reactions proceeded
with inversion of configuration at the aziridine carbon atom un-
dergoing nucleophilic attack. We ascribed the observed complete
regioselectivity in the vinylaziridine reactions to the directing ef-
fects of unsaturation, which causes selective weakening through
Scheme 1.
type mechanisms.4e9 The same regioselectivity has been reported
for sulfur ylides10,11 and organometallic reagents.12 In contrast, re-
action of vinylaziridines with organomagnesium13 and organo-
copper14e16 reagents frequently gives predominantly the products
of SN20-type ring-opening. In the case of the hydroxyaziridine re-
actions, the directing group is the lithiated oxygen atom, through
attractive interaction with the incoming lithiated carbanionic spe-
cies (Scheme 2).17 This paper describes further examples of these
highly selective processes, and documents derivatisation reactions
of the ring-opened products, which illustrate their potential in
synthesis.
pes overlap of the breaking aziridine CeN bond. Aryl groups have
*
been reported to show analogous directing effects, in ring-opening
reactions of electron-rich arenes with arylaziridines involving SEAr-
* Corresponding author. E-mail address: d.craig@imperial.ac.uk (D. Craig).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.096

D. Craig et al. / Tetrahedron 66 (2010) 6376e6382
6377
sufficiently basic to abstract reversibly the thioether
a
-proton in the
adduct, thereby causing double bond migration to the thermody-
namically favoured position. Finally, reaction of the potassium
enolate of ester 8 with 3 gave in good yield a 3:1 diastereoisomeric
mixture of adducts 9. This behaviour again contrasted with that of
the analogous sulfone-containing nucleophile, which in our earlier
work had been shown to give the corresponding N-tosyl lactam, by
spontaneous 5-exo-trig additioneelimination of the initially formed
adduct. The reactions of 3 with thioether-stabilised carbanionic
species are depicted in Scheme 3.
2.2. Derivatisation reactions of vinylaziridine ring-opening
adducts
One of the goals of this study was the identification of synthesis
sequences, which would enable access to prepare thioether-
substituted cyclic eneesulfonamides, such as 10 (Scheme 4). These
are less highly oxidised congeners of sulfones 11, which we had
demonstrated previously to be effective substrates for oxaphilic
Lewis acid-mediated SN1 and SN10 CeC bond forming processes.18,19
Scheme 3 shows an unsuccessful attempt to prepare 10 using the
sequence 2þ3/4/5, which was unviable because of the low ef-
ficiency of combination of lithio-2 and 3, and the unwanted cycli-
sation of 4 to give 5 on treatment with BF3$OEt2. Our earlier report3
described the formation of 11 from the corresponding tosyl-
substituted vinylaziridine ring-opened adduct 12 using the same
conditions (Scheme 4).
Scheme 2. Ref. 3.
2. Results and discussion
2.1. Olefin-directed nucleophilic ring-opening of
a vinylaziridine: thioether-stabilised carbanions
Our earlier work had established that both sulfone- and thio-
ether-stabilised carbanions reacted with a trans-1,2,3-trisubstituted
vinylaziridine in a highly selective manner. Further experimenta-
tion sought to extend the range of thioether-containing nucleophilic
partners in these coupling reactions, and vinylaziridine 33 was se-
lected as the electrophile to enable valid comparisons to be made
with the reactions studied previously. In contrast with the sulfone
derivative 1 (Scheme 2), the lithio-anion of thioethereacetal 2
combined poorly with 3, providing a 5:1 diastereoisomeric mixture
of adducts 4 in just 12% yield; the structure of the major isomer was
not assigned. Exposure of the isomeric mixture of 4 to BF3$OEt2
resulted in cyclisation to give the benzo-fused 9-azabicyclo[3.3.1]
nonane 5, in good yield. Attempts to improve the yield of the ring-
opening reaction of 1-phenylthio-2-propene 6 with 3 studied pre-
viously,3 by raising the reaction temperature instead gave the
vinylic thioether 7 in good yield, predominantly as the E-isomer.
Presumably the N-centred anion formed on ring-opening of 3 is
Scheme 4.
In the event, two routes to 10 were uncovered. The first of these
employed thioether 13, the ring-opened adduct of 1-phenylthio-2-
propyne and 3.3 Treatment of 13 with mCPBA gave in 52% yield the
E-enal 14; likely this is formed by S-oxidation, followed by [2,3]-
sigmatropic rearrangement of the propargylic sulfoxide20 and
hydrolysis of the resultant allenyl sulfenate. Reaction of 14 with
thiophenoleEt3N, and subsequent treatment of the resulting cyclic
N-tosylhemiaminal with methanesulfonyl chloride in situ gave
ene-sulfonamide 10 in 66% yield for the one-pot process starting
from 14.21 Alternatively, simple exposure of 11 to Me2AlSPh22 gave
10 in 89% yield. This transformation was subsequently adapted to
enable incorporation of 2-pyridylthio (from Me2AlSPy,23 to give 15)
and methylthio (from Me2AlSMe,24 to give 16) groups into the
eneesulfonamide ring, although the latter reaction gave pre-
dominantly the allylically transposed product 17 (Scheme 5).
2.3. Alkoxide-directed nucleophilic ring-opening of
hydroxyaziridines: sulfone-stabilised carbanions
The last part of this investigation focussed on hydroxyaziridines
as electrophiles. Following the successful combination of sulfony-
lacetal 1 with the lithiated indolic hydroxyaziridine depicted in
Scheme 1, we became interested in the analogous reaction of the
Scheme 3.

6378
D. Craig et al. / Tetrahedron 66 (2010) 6376e6382
However, this reactivity could be modified by functionalisation of
the primary alcohol prior to acid treatment. Thus, reaction of ad-
duct 21 with diketene, and treatment of the product with TMSI
gave in 44% yield over two steps the tetracyclic b-ketoester 22, as
a single diastereoisomer (Scheme 6). We have reported pre-
viously28 a related intramolecular PicteteSpengler reaction of
a structurally simpler indolic aziridine ring-opened adduct.
3. Conclusions
In conclusion, the results reported herein provide further
demonstration of the powerful directing effects of the vinyl and
lithiated hydroxymethyl groups on the regiochemistry of aziridine
ring-opening reactions. These stereospecific transformations allow
the rapid assembly of polyfunctionalised small molecules, which
possess mutually reactive functional motifs, which may participate
in subsequent transformations. We are presently applying some of
the chemistry described above to the synthesis of piperidine and
indole-containing natural products, and the results of these in-
vestigations will be reported in due course.
4. Experimental
4.1. General
Scheme 5.
1H and 13C NMR spectra were recorded in CDCl3 (unless other-
wise stated) on either Jeol GX-270a, DRX 300, DRX 400 or Aspect
500 spectrometers, using residual isotopic solvents as internal
reference. Infra-red spectra were measured on a Mattson 5000 FTIR
spectrometer. Mass spectra were recorded using VG 707E or VG
Autospec Q instruments. Accurate masses were determined using
the Autospec Q instrument at Imperial College. Elemental com-
bustion analyses were performed in the London Metropolitan
University microanalytical laboratory. Melting points were mea-
sured on a Stuart Scientific SMP1 melting point apparatus and are
uncorrected. Chromatography refers to flash chromatography on
sulfonyl-substituted orthoester 18. Compound 18 was best syn-
thesised starting from commercially available phenylthioethene
using the procedure of Parham and co-workers;25 despite repeated
attempts, we were unable to reproduce the method reported sub-
sequently by Ghosez and co-workers.26 Treatment of lithiated 18
with O-lithiated 19 again resulted in stereospecific, completely
regioselective aziridine ring-opening to give the methyl ester 20 as
a single diastereoisomer upon mildly acidic work-up. No products
corresponding to aza-Payne rearrangement27 of 19 were detected.
In contrast, the analogous acetal-containing product 21 of the
previously-reported3 reaction of lithio-1 with 19 underwent ready
cyclisation on brief treatment with acid, giving lactol ether 23.
BDH (40e63 mM) silica gel. Analytical thin layer chromatography
was performed using pre-coated aluminium-backed plates (Merck
Kieselgel 60 F254) and visualised with ultraviolet light and/or acidic
ammonium molybdate (IV), acidic vanillin, ethanolic potassium
permanganate or acidic 3,5-dinitrophenylhydrazine solutions.
Standard solvents were distilled under nitrogen; Et2O and THF from
sodiumebenzophenone ketyl, CH2Cl2 and MeCN from calcium hy-
dride and PhMe from sodium. Petrol refers to petroleum ether bp
40e60 ꢀC. Other solvents and reagents were used as received or
purified before use according to standard procedures. All reactions
were performed under an atmosphere of nitrogen unless stated
otherwise.
SO2Ph
OH
SO2Ph
18 + nBuLi, THF;
add O-Li-19
OH
+
TsN
MeO2C
HN
Ts
C(OMe)3
−78 °C→rt;
aq. NH4Cl
18
19
20
90%
MeN
MeN
Ts
Ts
OH
ref.3
4.1.1. 3-(Phenylthio)propanal29. To a solution of thiophenol (2.20 g,
20.0 mmol, 1.0 equiv), Et3N (0.28 mL, 2.0 mmol, 0.1 equiv) and
CH2Cl2 (20 mL) at 0 ꢀC was added acrolein (2.67 mL, 40 mmol,
2.0 equiv). After 30 min, concentration under reduced pressure and
drying under high vacuum gave 3-(phenylthio)propanal (3.32 g,
100%) as a colourless oil; Rf 0.59 (50% EtOAcepetrol); dH (400 MHz)
9.79 (1H, s, CHO), 7.39e7.25 (5H, m, Ph), 3.21 (2H, t, J 7.0 Hz,
CH2CHO), 2.80 (2H, t, J 7.0 Hz, PhSCH2); dC (125 MHz) 200.3 (CHO),
135.1 (ipso PhS),130.0 (ortho PhS),129.1 (meta PhS),126.7 (para PhS),
43.3 (CH2CHO), 26.4 (CH2PhS); m/z (CI) 184 [MþNH4]þ, 166, 52.
+
(MeO)2HC
19
21
CH(OMe)2
HN
Ts
83%
1
Ts
MeN
O
TFA ref. 3
1. diketene, DMAP
THF, rt, 2 h
N
O
O
OMe
O
Ts
2.TMSI, CH3CN
0 °C, 1 h
MeN
22
23
44%
Ts
MeN
4.1.2. ((3,3)-Dimethoxypropyl)(phenyl)sulfane (2)30. A solution of 3-
(phenylthio)propanal (2.90 g, 17.5 mmol, 1.0 equiv), CH(MeO)3
(3.71 g, 34.9 mmol, 2.0 equiv), p-TsOH$H2O (100 mg, 0.526 mmol,
0.03 equiv) and MeOH (35 mL) was heated to 50 ꢀC. Then, EtOH
(15 mL) was added to the crude, washed with satd aq NaHCO3
(3ꢁ30 mL), H2O (3ꢁ10 mL), brine (2ꢁ15 mL) and dried (Na2SO4).
H
NHTs
Scheme 6.

D. Craig et al. / Tetrahedron 66 (2010) 6376e6382
6379
Concentration under reduced pressure and column chromatogra-
phy (5% EtOAcepetrol containing 1% Et3N) gave ((3,3)-dimethox-
ypropyl)(phenyl)sulfone 2 (3.90 g, 96%) as a colourless oil; Rf 0.51
(23% Et2Oepetrol); nmax (film) 3057, 2933, 2830, 1944, 1870, 1724,
1686, 1583, 1400, 1438, 1382, 1366, 1281, 1192, 1160, 1123,
(q Ar)], 137.7 (3ꢀ), [137.2, 135.9 (q Ar)], 133.6 (3ꢀ), 131.8 (q Ar), [129.1,
129.0 (3ꢀ)],128.8 (3ꢀ), 127.7 (3ꢀ), 126.9 (3ꢀ), 125.5 (q Ar),119.2 (CH]
CH2), 113.5, 110.5, 55.4 (OMe), [53.8, 53.6 (CHNCH)], 50.1 (PhSCH),
41.1 (CHCH]CH2), 40.4 (CH2ArOMe), 25.4 (CH2CHS), 21.4 (Me of
Ts); m/z (EI) 491 [M]þ, 382, 314, 227, 160, 91 (found: [M]þ, 491.1583.
C28H29NO3S2 requires [M]þ, 491.1589).
1073 cmꢂ1
; dH (400 MHz) 7.38e7.19 (5H, m, Ph), 4.53 (1H, t, J 5.0 Hz,
CH), 3.35 (6H, s, OMe), 2.99 (2H, t, J 7.0 Hz, CH2SPh), 1.96 (2H, dt, J
7.0, 5.0 Hz, CH2CH); dC (125 MHz) 136.2 (ipso PhS), 129.2 (ortho
PhS), 128.9 (meta PhS), 125.9 (para PhS), 103.2 (CH), 53.2 (OMe),
32.3 (CH2PhS), 28.8 (CH2CH).
4.2.1. 4-Methyl-N-((2R
*
,3S ,E)-1-(4-methoxyphenyl)-4-(phenylthio)-
*
3-vinylhex-4-en-2-yl)benzenesulfonamide (7). To a solution of thi-
oether 6 (81.4 mg, 0.542 mmol, 1.4 equiv) in THF (0.3 ml) at ꢂ78 ꢀC
was added nBuLi (62
mL of a 9.4 M solution in hexanes, 0.581 mmol,
4.1.3. N-((2R
*
,3S
*
)-6,6-Dimethoxy-1-phenyl-4-(phenylthio)-3-vinyl-
1.5 equiv). After 15 min, the mixture was warmed to ꢂ30 ꢀC, and
then to 0 ꢀC. After 15 min, it was re-cooled to ꢂ20 ꢀC then a solution
of aziridine 3 (100 mg, 0.387 mmol, 1.0 equiv) in THF (0.2 ml) was
added. The resulting solution was warmed to rt. After 16 h the so-
lution was quenched with satd aq NH4Cl (2 mL), diluted with H2O
(5 mL) and the aqueous phase extracted with EtOAc (2ꢁ5 ml). The
combined organic layers were washed with brine (2ꢁ5 ml) and
dried (Na2SO4). Concentration under reduced pressure and column
chromatography (5/15% EtOAcepetrol) gave a 12:1 E/Z mixture of
hexan-2-yl)-4-methylbenzenesulfonamide (4). To a solution of ace-
tal 2 (403 mg, 1.90 mmol, 1.3 equiv) in THF (0.7 mL) at ꢂ78 ꢀC was
added nBuLi (905
mL of a 2.1 M solution in hexanes, 1.90 mmol,
1.3 equiv). After 20 min, the mixture was warmed to 0 ꢀC and
stirred during 20 min. The mixture was re-cooled to ꢂ78 ꢀC and
a solution of vinylaziridine 3 (500 mg, 1.46 mmol, 1.0 equiv) in THF
(0.7 mL) was added. The resulting solution was allowed to warm to
rt. After 16 h, the reaction was quenched with satd aq NaHCO3
(10 mL) and the aqueous phase extracted with EtOAc (3ꢁ7 mL). The
combined organic layers were washed with brine (3ꢁ5 mL) and
dried (Na2SO4). Concentration under reduced pressure and column
chromatography (10%/25% EtOAcepetrol) gave a 5:1 diaster-
4-methyl-N-[(2R
*
,3S )-1-(4-methoxyphenyl)-4-(phenylthio)-3-vinyl-
*
hex-4-en-2-yl]-4-methylbenzenesulfonamide 7 (97.0 mg, 67%) as
a solid; data for E-isomer only: Rf 0.33 (15% EtOAcepetrol); nmax
(film) 3287, 1612, 1513, 1439, 1326, 1247, 1158, 1093, 1036, 813, 741,
eoisomeric mixture of N-[(2R
*
,3S
*
)-6,6-dimethoxy-1-(4-methox-
690, 663 cmꢂ1
; dH (400 MHz) 7.66 (2H, d, J 8.5 Hz, ortho Ts), 7.30
yphenyl)-4-(phenylthio)-3-vinylhexan-2-yl]-4-methylbenzenesulfon-
amide 4 (100 mg, 12%) as a gum; data for major diastereomer only:
Rf 0.21 (25% EtOAcepetrol); nmax (film) 3277, 2938, 2833, 1161,1583,
(2H, d, J 8.5 Hz, meta Ts), 7.25 (2H, d, J 8.0 Hz, ortho PhS), 7.13e7.09
(1H, m, para PhS), 6.98e6.96 (2H, m, meta PhS), 6.85 (2H, d, J 8.5 Hz,
meta ArOMe), 6.63 (2H, d, J 8.5 Hz, ortho ArOMe), 6.03 (1H, q, J
6.5 Hz, CH3CH]C), 5.75 (1H, ddd, J 17.0, 10.0, 8.5 Hz, CH2]CH), 5.16
(1H, dd, J 10.0, 1.5 Hz, trans CHH]CH), 4.91 (1H, dd, J 17.0, 1.5 Hz, cis
CHH]CH), 4.44 (1H, d, J 8.0 Hz, NH), 3.80e3.78 (4H, m, OMe and
NCH), 2.85e2.81 (1H, m, CHCH]CH2), 2.74 (1H, dd, J 14.0, 5.0 Hz,
CHH), 2.63e2.58 (1H, m, CHH), 2.43 (3H, s, Me of Ts), 1.79 (3H, d, J
6.5 Hz, CH3CH]C); dC (125 MHz) [158.0, 143.1, 137.5 (q Ar)], [134.9,
134.8, 133.8 (CH]C and para PhS)], [129.9, 129.6 (q Ar)], [130.1,
129.5, 128.9, 128.7, 127.2 (ortho and meta Ar)], 125.8 (CH]CH2),
119.2 (CH]CH2), 113.6 (ortho or meta Ar), 56.9, 55.1, 52.1, 38.5, 21.5,
15.9; m/z (ESI) 516 [MþNa]þ, 494 [MþH]þ, 304, 214 (found:
[MþNa]þ, 516.1642. C28H31NO3S2 requires [MþNa]þ, 516.1643).
1513, 1439, 1324, 1302, 1248, 1178, 1157, 1124 cmꢂ1
; dH (400 MHz)
7.69 (2H, d, J 8.0 Hz, ortho Ts), 7.65e7.14 (7H, m, SPh and meta Ts),
6.95 (2H, d, J 8.5 Hz, meta ArOMe), 6.73 (2H, d, J 8.5 Hz, ortho
ArOMe), 5.47 (1H, dt, J 17.0, 10.0 Hz, CH]CH2), 5.18 (1H, dd, J 10.0,
1.5 Hz, trans CH]CHH), 5.01 (1H, dd, J 17.0, 1.5 Hz, cis CH]CHH),
4.54 [1H, t, J 5.5 Hz, CH(OMe)2], 4.42 (1H, d, J 7.5 Hz, NH), 3.92e3.89
(1H, m, CHN), 3.79 (3H, s, ArOMe), 3.54 (1H, dt, J 7.0, 4.0 Hz, CHS),
3.25 (3H, s, MeOCHOMe), 3.23 (3H, s, MeOCHOMe), 2.76 (1H, dd, J
14.0, 6.0 Hz, CHHArOMe), 2.55 (1H, dd, J 14.0, 4.5 Hz, CHHArOMe),
2.44 (3H, s, Me of Ts), 2.30e2.25 (1H, m, CHCH]CH2), 1.85 (2H, dd, J
7.0, 5.5 Hz, CH2CHS); dC (100.7 MHz) [158.3, 143.2, 137.6, 135.6 (q
Ar)], 134.9 (3ꢀ Ar), [131.4, 130.9, 129.6, 128.9 (3ꢀ Ar)], 128.1 (q Ar),
127.2 (3ꢀ Ar), 126.9 (CH]CH2), 120.8 (CH]CH2), 113.8 (3ꢀ Ar), 102.5
[CH(OMe)2], 55.3 [CH(OMe)2], 53.1 (ArOMe), 50.7 (CHN), 47.1
(CHSPh), [37.6, 37.4 (CH2)], 23.9 (Me of Ts), 21.6 (CHCH]CH2); m/z
(ESI) 578 [MþNa]þ, 556 [MþH]þ, 554, 492 (found: [MþNH4]þ,
578.1995. C30H37NO5S2 requires [MþNH4]þ. 578.2011) (found: C,
65.00; H, 6.71; N, 2.58. C30H37NO5S2 requires C, 64.84; H, 6.71; N,
2.52%).
4.2.2. (R
*
)-Methyl 3-[(S) -2-(4-methoxyphenyl)-1-(4-methylphenyl-
*
sulfonamido)ethyl]-2-(phenylthio)pent-4-enoate (9). A solution of
thioether 8 (64.0 mg, 0.35 mmol, 1.3 equiv) in DMF (0.2 mL) was
added dropwise to KH (27 mg, from a 35% mixture in oil washed
with petrol three times, 0.673 mmol, 2.6 equiv) at 0 ꢀC. After
30 min, a solution of aziridine 3 in DMF (0.8 mL) was added. After
2 h at that temperature, the reaction mixture was heated to 60 ꢀC.
After 16 h, the reaction was quenched with MeOH (2 mL). The
resulting mixture was concentrated under reduced pressure to
remove the excess MeOH, then diluted with EtOAc (3 mL) and brine
(5 mL). The organic phase was separated and aqueous phase
extracted with EtOAc (2ꢁ5 mL). The combined organic layers were
washed with brine (3ꢁ5 mL) and dried (MgSO4). Concentration
under reduced pressure and column chromatography (10/25%
4.2. Cyclisation of acetal 4
To a solution of tosamide 4 (16.0 mg, 0.029 mmol, 1.0 equiv) in
CH2Cl2 (0.6 mL) at ꢂ78 ꢀC was added BF3$Et2O (0.06 mL,
0.44 mmol, 15.0 equiv). The solution was warmed to rt slowly. After
16 h, satd aq NaHCO3 (1.0 mL) was added. The mixture was
extracted with CH2Cl2 (2ꢁ2 mL). The combined organic layers were
washed with brine and dried (Na2SO4). Concentration under re-
duced pressure and purification by preparative TLC gave the major
diastereomer of the tricycle 5 (10.0 mg, 73%) as a gum; Rf 0.74 (30%
EtOAcepetrol); dH (400 MHz) 7.50 (2H, d, J 8.5 Hz, ortho Ts),
7.26e7.23 (5H, m, SPh), 7.05 (2H, d, J 8.5 Hz, meta Ts), 6.75 (1H, d, J
8.5 Hz, meta ArOMe), 6.67 (1H, dd, J 8.5, 2.5 Hz, ortho MeOAr), 6.50
(1H, d, J 2.5 Hz, ortho MeOAr), 5.76 (1H, ddd, J 17.0, 10.5, 8.5 Hz,
CH]CH2), 5.34e5.27 (2H, m, CH]CH2), 5.07 (1H, m, ArCHN),
4.29e4.27 (1H, m, CHCHN), 3.79 (3H, s, OMe), 2.91e2.84 (1H, m,
CHSPh), 2.69e2.56 (3H, m, CH2ArOMe and CHCH]CH), 2.33 (3H, s,
Me of Ts), 2.07e2.00 (2H, m, CH2CHS); dC (100.7 MHz) [157.9, 143.0
EtOAcepetrol) gave a separable 3:1 diastereomeric of (R
3-[(S) -2-(4-methoxyphenyl)-1-(4-methylphenylsulfonamido)ethyl]-
2-(phenylthio)pent-4-enoate 9 (93.0 mg, 68%) as gums.
*
)-methyl
*
Data for minor diastereoisomer: 22 mg, 16%; Rf 0.73 (40%
EtOAcepetrol); nmax (film) 3522, 3275, 3061, 2988, 2958, 2836,
1728, 1612, 1584, 1513, 1438, 1326, 1248, 1159, 1091, 1036, 998, 928,
814, 738, 665 cmꢂ1
; dH (400 MHz) 7.55 (2H, d, J 8.0 Hz, ortho Ts),
7.38e7.36 (2H, m, meta SPh), 7.27e7.25 (3H, m, ortho and para SPh),
7.17 (2H, d, J 8.0 Hz, meta Ts), 6.81 (2H, d, J 8.5 Hz, meta ArOMe),
6.67 (2H, d, J 8.5 Hz, ortho ArOMe), 5.66 (1H, td, J 17.0, 10.0 Hz, CH]
CH2), 5.40 (1H, dd, J 10.0, 1.5 Hz, trans CH]CHH), 5.14 (1H, dd, J 17.0,
1.5 Hz, cis CH]CHH), 4.57 (1H, d, J 8.5 Hz, NH), 3.96 (1H, d, J 11.0 Hz,

6380
D. Craig et al. / Tetrahedron 66 (2010) 6376e6382
CHSPh), 3.77 (3H, s, CH3OOC), 3.70 (1H, m, NCH), 3.64 (3H, s,
CH3OAr), 2.66 (1H, ddd, J 11.5, 11.5, 2.0 Hz, CHCH]CH2), 2.55 (1H,
dd, J 14.0, 8.5 Hz, CHHArOMe), 2.42e2.37 (4H, m, Me of Ts and
CHHArOMe); dC (125 MHz) 171.9 (COO), [158.3, 143.2, 137.3 (q Ar)],
[133.2, 133.0 (3ꢀ)], 132.9 (q Ar), [130.1, 129.9, 128.8 (3ꢀ)], 128.4(q Ar),
[127.9, 126.9 (3ꢀ)], 121.7 (CH]CH2), 113.8 (3ꢀ), 55.3, 55.1, 52.1, 51.2,
47.0, 39.2 (CH2), 21.5; m/z (ESI) 548.1555 [MþNa]þ, 526.1734
[MþH]þ, 469.3163, 208.0410 (found: [MþNa]þ, 526.1734.
C28H31O5S2 requires [MþNa]þ, 526.1722).
815, 749, 675 cmꢂ1
; dH (400 MHz) 7.57 (2H, d, J 8.5 Hz, ortho Ts,
minor diast.), 7.48 (2H, d, J 8.5 Hz, ortho Ts, major diast.), 7.41e7.24
[(2ꢁ5H, m, SPh, 2ꢁdiast.) and (2H, meta Ts, minor diast.)], 7.19 (2H,
d, J 8.5 Hz, meta Ts, major diast.), 7.14 (2H, d, J 8.5 Hz, meta ArOMe,
minor diast.), 7.08 (2H, d, J 8.5 Hz, meta ArOMe, major diast.),
6.88e6.82 (2ꢁ2H, d, J 8.5 Hz, ortho ArOMe, 2ꢁdiast.), 6.65e6.12
(2ꢁ1H, m, CH]CHNTs, 2ꢁdiast.), 5.70 (1H, ddd, J 17.5, 10.5, 8.0 Hz,
CH]CH2, major diast.), 5.49e5.43 (1H, m, CH]CH2, minor diast.),
5.28e5.22 [(2ꢁ1H, m, CH]CHNTs, 2ꢁdiast.) and (1H, m, trans CH]
CHH, major diast.)], 5.16 (1H, dd, J 10.5, 1.5 Hz, trans CH]CHH,
minor diast.), 4.99e4.92 (2ꢁ1H, m, cis CH]CHH, 2ꢁdiast.),
4.09e4.03 (2ꢁ1H, m, NTsCHCH2, 2ꢁdiast.), 3.83 (3H, s, OMe, minor
diast.), 3.82 (3H, s, OMe, major diast.), 3.55e3.48 (2ꢁ1H, m, CHSPh,
2ꢁdiast.), [2.98e2.85 and 2.78e2.65 (2ꢁ2H, m, CH2ArOMe,
2ꢁdiast.), 2.44 (3H, s, Me of Ts, major diast.), 2.43 (3H, s, Me of Ts,
minor diast.), 1.73e1.68 (2ꢁ1H, m, CHCH]CH2, 2ꢁdiast.); dC
(125 MHz) (major diast.) [158.3, 143.4 (q Ar)], 137.4, 135.7 (q Ar),
133.7 (3ꢀ Ar), 132.0 (q Ar), [130.6, 129.7 (3ꢀ Ar)], 129.6 (q Ar), 128.7
(3ꢀ Ar), 127.7, 126.8 (3ꢀ Ar), 124.2, 118.7 (CH]CH2), 113.6 (3ꢀ Ar),
112.1, 60.9, 55.1, 43.9, 42.9, 32.4 (CH2ArOMe), 21.6; m/z (ESI)
555.1768, 530.1248, 514.1501 [MþNa]þ, 509.1948, 492.1668
[MþH]þ, 382.1476 (found: [MþH]þ, 514.1668. C28H29NO3S2 re-
quires [MþH]þ, 492.1667).
Data for major diastereoisomer: 71 mg, 52%; Rf 0.65 (40%
EtOAcepetrol); nmax (film) 3510, 3273, 3060, 2951, 2837,1732, 1612,
1513, 1439, 1326, 1248, 1159, 1048, 1035, 931, 815, 737, 664 cmꢂ1
; dH
(400 MHz) 7.78 (2H, d, J 8.0 Hz, ortho Ts), 7.29e7.19 (7H, SPh and
meta Ts), 6.87 (2H, d, J 8.5 Hz, meta ArOMe), 6.76 (2H, d, J 8.5 Hz,
ortho ArOMe), 5.70 (1H, td, J 17.0, 10.0 Hz, CH]CH2), 5.29 (1H, dd, J
10.5, 1.0 Hz, trans CH]CHH), 5.14 (1H, dd, J 17.0, 1.0 Hz, cis CH]
CHH), 4.81 (1H, d, J 9.0 Hz, NH), 4.27e4.21 (1H, m, NCH), 3.99 (1H, d,
J 11.0 Hz, CHSPh), 3.80 (3H, s, CH3OOC), 3.48 (3H, s, CH3OAr),
2.51e2.39 (6H, m, CHCH]CH2 and CH2ArOMe and Me of Ts); dC
(125 MHz) 171.7 (COO), [158.4, 143.5, 137.3 (q Ar)], [133.5, 132.6
(3ꢀ)], 131.9 (q Ar), [130.1, 129.7 (3ꢀ)], 129.4 (q Ar), [128.7, 128.1, 127.2
(3ꢀ)], 121.8 (CH]CH2), 114.1 (3ꢀ), 55.2, 54.6, 52.0, 51.7, 45.6, 39.2
(CH2), 21.5; m/z (ESI) 548.1540 [MþNa]þ, 526.1730 [MþH]þ,
494.1479, 344.1046 (found: [MþNa]þ, 526.1730. C28H31O5S2 re-
quires [MþNa]þ, 526.1722).
4.3. Preparation of 10 from 11
4.2.3. N-((2R
*
,3R
*
,E)-1-(4-Methoxyphenyl)-6-oxo-3-vinylhex-4-en-
To a solution of PhSH (924 mg, 8.38 mmol, 4.5 equiv) in CH2Cl2
at rt was added AlMe3 (4.20 mL of a 3 M solution in hexanes,
8.38 mmol, 4.5 equiv). After 30 min, the resulting solution was
added to a solution of tetrahydropyridines 11 in CH2Cl2 via cannula.
After 1 h, the solution was cooled to 0 ꢀC and satd Na/K aq tartrate
(15 mL) added dropwise, followed by H2O (10 mL) and EtOAc
(10 mL). The organic phase was separated and aqueous phase
extracted with EtOAc (3ꢁ10 mL). The combined organic layers were
washed with brine (2ꢁ10 mL), dried (Na2SO4) and concentrated
under reduced pressure. Purification by column chromatography
(5/10% EtOAcepetrol) followed by recrystallisation gave a 2:1
diastereoisomeric mixture of 11 (810 mg, 89%) as a solid; data were
in agreement with those listed above.
2-yl)-4-methylbenzenesulfonamide (14). To a solution of thioethers
133 (1.47 g, 2.99 mmol, 1.0 equiv) in CH2Cl2 (3 mL) at rt was added
a solution of mCPBA (1.07 g of a 53% mixture of m-chlorobenzoic acid
and H2O, 3.29 mmol, 1.1 equiv) in CH2Cl2 (5 mL). After 16 h, Con-
centration under reduced pressure and column chromatography
(20% EtOAcepetrol) gave N-[(2R
*
,3R ,E)-1-(4-methoxyphenyl)-6-oxo-
*
3-vinylhex-4-en-2-yl]-4-methylbenzene-sulfonamide 14 (622 mg,
52%) as a gum; Rf 0.21 (25% EtOAcepetrol); nmax (film) 3275, 2923,
1687, 1612, 1513, 1442, 1324, 1303, 1248, 1158, 1093, 1034, 814 cmꢂ1
;
dH (400 MHz) 9.37 (1H, d, J 8.0 Hz, CHO), 7.60 (2H, d, J 8.0 Hz, ortho
Ts), 7.23 (2H, d, J 8.0 Hz, meta Ts), 6.89 (2H, d, J 8.5 Hz, meta ArOMe),
6.75e6.69 (3H, m, ortho ArOMe and CHOCH]CH), 6.03 (1H, ddd, J
16.0, 8.0,1.5 Hz, CHOCH]CH), 5.77 (1H, ddd, J 17.0,10.5, 8.0 Hz, CH]
CH2), 5.37 (1H, d, J 10.5 Hz, trans CH]CHH), 5.21 (1H, d, J 17.0 Hz, cis
CH]CHH), 4.43 (1H, d, J 8.0 Hz, NH), 3.80 (3H, s, OMe), 3.59e3.53
(1H, m, NCH), 3.28e3.24 (1H, m, CHCH]CH2), 2.73 (1H, dd, J 14.0,
7.5 Hz, CHHArOMe), 2.54 (1H, dd, J 14.0, 7.0 Hz, CHHArOMe), 2.44
(3H, s, Me of Ts); dC (125 MHz) 193.4 (CHO),158.6 (q Ar),155.7, [143.6,
139.9 (q Ar)],134.1,132.9,129.9,129.6,128.2 (q Ar),128.1,121.3 (CH]
CH2), 114.1, 58.5, 55.1, 48.9, 37.9 (CH2), 21.5, 15.3; m/z (ESI) 422.1422
[MþNa]þ, 417.1865, 400.1585 [MþH]þ, 382.1478, 338.3427, 245.0269
(found: [MþH]þ, 400.1585. C22H25NO4S requires [MþH]þ, 400.1583)
(found: C, 66.20; H, 6.30; N, 3.50. C22H25NO4S requires C, 66.14; H,
6.31; N, 3.51%).
4.3.1. 2-[(2R
*
,3S )-2-(4-Methoxybenzyl)-1-tosyl-3-vinyl-1,2,3,4-tet-
*
rahydropyridin-4-ylthio]pyridine (15). To a solution of 2-mercapto-
pyridine (207 mg, 1.86 mmol, 5.0 equiv) in CH2Cl2 (2 mL) at rt was
added AlMe3 (930 mL of a 2 M solution in hexane, 1.86 mmol,
5.0 equiv). After 45 min, it was added to a solution of a 2:1 di-
astereoisomeric mixture of tetrahydropyridines 11 (200 mg,
0.372 mmol, 1.0 equiv) in CH2Cl2 (0.7 mL) at rt. After 16 h, the re-
action was quenched with satd Na/K aq tartrate and stirred for
5 min. The organic phase was separated and the aqueous phase
extracted with EtOAc (3ꢁ10 mL). The combined organic layers were
washed with brine (2ꢁ10 mL), dried (Na2SO4) and concentrated
under reduced pressure. Purification by column chromatography
(5/10% EtOAcepetrol) followed by recrystallisation gave a 2.5:1
4.2.4. (2R
nyl-1,2,3,4-tetrahydropyridine (10). To
(244 mg, 0.561 mmol, 1.0 equiv) in CH2Cl2 (2.3 mL) at 0 ꢀC were
added thiophenol (173 L, 1.68 mmol, 3.0 equiv) and Et3N (391 L,
*
,3S
*
)-2-(4-Methoxybenzyl)-4-(phenylthio)-1-tosyl-3-vi-
a
solution of enal 14
diastereoisomeric mixture of 2-[(2R
*
,3S )-2-(4-methoxybenzyl)-1-
*
tosyl-3-vinyl-1,2,3,4-tetrahydropyridin-4-ylthio]pyridine 15 (125 mg,
68%) as a solid; Rf 0.69 (30% EtOAcepetrol); nmax (film) 3044, 2922,
2850,1637, 1613, 1597, 1577, 1558, 1512, 1453, 1416,1354, 1302, 1247,
m
m
2.80 mmol, 5.0 equiv). The solution was then warmed to rt gradu-
ally. After 16 h, TLC analysis showed complete consumption of 14.
The mixture was cooled to ꢂ20 ꢀC followed by addition of Et3N
1165, 1122, 1091, 1035, 986, 927, 891, 815, 760, 684 cmꢂ1
; dH
(400 MHz) 8.42 (1H, ddd, J 4.0, 1.5, 1.0 Hz, 2-pyH, minor diast.), 8.35
(1H, ddd, J 4.0, 1.5, 1.0 Hz, 2-pyH, major diast.), 7.61e7.57 (2ꢁ2H, m,
ortho Ts, 2ꢁdiast.), 7.48e7.43 (2ꢁ1H, m, 6-pyH, 2ꢁdiast.), 7.29e7.26
(2ꢁ2H, m, meta Ts, 2ꢁdiast.), 7.16e7.09 (2ꢁ3H, m, meta ArOMe and
1-pyH, both diast.), 6.98e6.95 (2ꢁ1H, m, 5-pyH, 2ꢁdiast.),
6.86e6.82 (2ꢁ2H, m, ortho ArOMe, 2ꢁdiast.), 6.67 (1H, ddd, J 6.5,1.5,
1.0 Hz, CH]CHNTs, major diast.), 6.60 (1H, ddd, J 6.5, 1.5, 1.0 Hz,
minor diast.), 5.99 (1H, ddd, J 14.0, 8.5, 6.0 Hz, CH]CH2, major
(391 mL, 2.80 mmol, 5.0 equiv) and mesyl chloride (434 mL,
5.61 mmol, 10.0 equiv). After 2 h, Concentration under reduced
pressure and column chromatography (5% EtOAcepetrol) gave
a 2:1 diastereomeric mixture of (2R
(phenylthio)-1-tosyl-3-vinyl-1,2,3,4-tetrahydropyridine 10 (182 mg,
66%) as a solid; Rf 0.47 (18% EtOAcepetrol); nmax (film) 2930, 1721,
1640, 1612, 1512, 1440, 1353, 1302, 1247, 1165, 1091, 1035, 991, 927,
*
,3S )-2-(4-methoxybenzyl)-4-
*

D. Craig et al. / Tetrahedron 66 (2010) 6376e6382
6381
diast.), 5.63 (1H, ddd, J 14.5, 8.5, 6.5 Hz, CH]CH2, minor diast.), 5.46
(1H, dd, J 6.5, 4.0 Hz, CH]CHH, major diast.), 5.38e5.36 (1H, dd, J
6.5, 2.0 Hz, CH]CHH, minor diast.), 5.11e5.09 (1H, m, CH]CHH,
minor diast.), 5.06e5.04 (1H, m, CH]CHH, major diast.), 4.97e4.92
(2ꢁ1H, m, CH]CHNTs, 2ꢁdiast.), 4.83e4.81 (1H, m, CHNTs, major
diast.), 4.62e4.59 (1H, m, CHNTs, minor diast.), [3.80, 3.79 (2ꢁ3H,
2ꢁs, OMe, 2ꢁdiast.)], 2.88e2.76 (2ꢁ2H, m, CH2ArOMe, 2ꢁdiast.),
[2.43, 2.42 (2ꢁ3H, 2ꢁs, Me of Ts, 2ꢁdiast.)], 2.39e2.36 (1H, m,
CHCH]CH2, major diast.), 2.87e2.82 (1H, m, CHCH]CH2, minor
diast.); dC (100 MHz) 157.9, 157.9, 149.6, 149.4, 149.1, 143.7, 137.4,
137.1,136.1,135.9,135.8,130.8,130.6, 130.5,130.4,129.8, 129.7,129.7,
127.0, 126.9, 123.9, 123.6, 122.8, 122.6, 121.1, 119.7, 118.5, 117.5, 113.8,
113.6,113.3, 60.9, 59.9, 55.1, 44.4, 38.6, 38.2, 33.7, 31.9, 29.7, 21.6; m/z
(ESI) 531.1200, 515.1447, 493.1632 [MþNa]þ, 382.1485, 221.0214
(found: [MþNa]þ, 493.1632. C27H28N2O3S2 requires [MþNa]þ,
493.1620).
Data for 1.2:1 diastereoisomeric mixture of (2R
*
,3R
*
)-2-(4-
methoxybenzyl)-6-(methylthio)-1-tosyl-3-vinyl-1,2,3,6-tetrahydro-
pyridine 17: Rf 0.76 (30% EtOAcepetrol); nmax (film) 3035, 2922,
2837, 1609, 1512, 1442, 1339, 1247, 1159, 1094, 1036, 914, 816 cmꢂ1
;
dH (400 MHz) 7.60 (2H, d, J 8.0 Hz, ortho Ts, major diast.), 7.55 (2H, d,
J 8.0 Hz, ortho Ts, minor diast.), 7.28e7.19 (2ꢁ4H, m, meta Ts and
meta ArOMe, 2ꢁdiast.), 6.87 (2H, d, J 8.5 Hz, ortho ArOMe, major
diast.), 6.77 (2H, d, J 8.5 Hz, ortho ArOMe, minor diast.), 5.89e5.63
(2ꢁ3H, m, CH]CH2 and CH]CH, 2ꢁdiast.), 5.19e5.02 (2ꢁ2H, m,
CH]CH2, 2ꢁdiast.), 4.57e4.52 (1H, m, NCHSMe, minor diast.),
4.39e4.34 (1H, m, NCHSMe, major diast.), 3.83 (3H, s, OMe, minor
diast.), 3.81 (3H, s, OMe, major diast.), 3.51e3.44 (1H, m, NCHCH2,
major diast.), 3.22 (1H, dd, J 15.0, 10.0 Hz, CHHArOMe, major diast.),
3.09 (1H, dd, J 14.5, 9.0 Hz, CHHArOMe, minor diast.), 2.76e2.68
(2ꢁ1H, m, CHHArOMe, 2ꢁdiast. and 1H, m, NCHCH2, minor diast.),
2.44e2.39 (2ꢁ4H, m, Me of Ts and CHCH]CH2, 2ꢁdiast.), 2.14 (3H, s,
SMe, major diast.), 1.66 (3H, s, SMe, minor diast.); dC (100 MHz)
158.2,157.8,143.6,143.4,137.3,136.9,134.8,130.9,130.8,130.6,130.5,
130.2, 129.6, 129.4, 129.3, 128.1, 127.7, 127.3, 125.3, 124.8, 118.4, 117.1,
113.8, 113.3, 64.0, 59.8, 58.8, 57.7, 57.1, 56.5, 55.3, 55.2, 43.8, 40.2,
35.2, 32.5, 21.5, 15.5; m/z (ESI) 425.1346 [MþNa]þ, 382.1488
[MþH]þ, 318.0591, 253.5798, 227.1316 (found: [MþNa]þ, 452.1346.
C23H27NO3S2 requires [MþNa]þ, 452.1330).
4.3.2. (2R
*
,3S
*
)-2-(4-Methoxybenzyl)-4-(methylthio)-1-tosyl-3-vi-
,3R )-2-(4-methox-
nyl-1,2,3,4-tetrahydropyridine (16) and (2R
*
*
ybenzyl)-6-(methylthio)-1-tosyl-3-vinyl-1,2,3,6-tetrahydropyridine
(17). To a mixture of sulfur powder (27.0 mg, 0.842 mmol, 4.5 equiv)
in toluene (1.3 mL) at rt was added AlMe3 (373 mL of a 2 M solution in
hexanes, 0.745 mmol, 4.0 equiv). The mixture was heated to reflux
for 2 h then cooled to rt. To the resulting mixture was added via
cannula a solution of 2:1 diastereoisomeric mixture of tetrahy-
dropyridines 11 (100 mg, 0.186 mmol, 1.0 equiv) in toluene (0.6 mL).
After 16 h, it was quenched with H2O (5 mL), diluted with satd aq Na/
K tartrate (5 mL) and EtOAc (5 mL). After stirring for 5 min, the or-
ganic phase was separated and the aqueous phase extracted with
EtOAc (2ꢁ5 mL). The combined organic layers were washed with
brine (3ꢁ5 mL) and dried (Na2SO4). Concentration under reduced
pressure and column chromatography (5/10% EtOAcepetrol) gave
4.3.3. (4R
*
,5S )-Methyl 4-(hydroxymethyl)-6-(1-methyl-1H-indol-3-
yl)-5-(4-methylphenylsul-fonamido)-3-(phenylsulfonyl)hexanoate
*
(20). To a solution of sulfonylorthoester 18 (108 mg, 0.39 mmol,
1.5 equiv) in THF (0.5 mL) at ꢂ78 ꢀC was added nBuLi (150
mL of
a 2.6 M solution in hexanes, 0.39 mmol, 1.5 equiv [1 equiv with re-
spect to 18]). The mixture was stirred for 30 min, and a solution of O-
lithio-19 (made by nBuLi (1 equiv) treatment of 19 (100 mg,
0.26 mmol,1.0 equiv)) inTHF (0.6 mL) at ꢂ78 ꢀC added dropwise. The
mixture was warmed to rt during 16 h, quenched with satd aq NH4Cl
(10 mL) and the aqueous layer extracted with EtOAc (3ꢁ15 mL). The
combined organic layers were dried (MgSO4) and concentrated un-
der reduced pressure. Chromatography (50% EtOAcepetrol) gave
a 2:1 diastereomeric mixture of (2R
(methylthio)-1-tosyl-3-vinyl-1,2,3,4-tetrahydropyridine 16 (11.1 mg,
14%) as a gum and a 1.2:1 diastereomeric mixture of (2R ,3R )-2-(4-
*
,3S )-2-(4-methoxybenzyl)-4-
*
*
*
methoxybenzyl)-6-(methylthio)-1-tosyl-3-vinyl-1,2,3,6-tetrahydropyr-
idine 17 (55.1 mg, 69%) as a gum.
(4R
*
,5S )-methyl 4-(hydroxymethyl)-6-(1-methyl-1H-indol-3-yl)-5-
*
Data for 2:1 diastereoisomeric mixture of (2R
*
,3S
*
)-2-(4-
(4-methylphenylsulfonamido)-3-(phenylsulfonyl)hexanoate 20 as an
off-white solid (140 mg, 90%); Rf 0.35 (66% EtOAcepetrol); mp
90e92 ꢀC; nmax (film) 3301, 2924, 1739, 1601, 1475, 1427, 1305, 1155,
methoxybenzyl)-4-(methylthio)-1-tosyl-3-vinyl-1,2,3,4-tetrahydro-
pyridine 16: Rf 0.71 (30% EtOAcepetrol); nmax (film) 3034, 2920,
2835, 1636, 1611, 1598, 1584, 1513, 1464, 1440, 1420, 1347, 1303, 1247,
1090, 1072, 954, 726 cmꢂ1
; dH (400 MHz, CDCl3) 7.94 (2H, d, J 8.0 Hz,
1161, 1092, 1036, 913, 814 cmꢂ1
;
dH (400 MHz) 7.61 (2H, d, J 8.0 Hz,
ortho-Ts), 7.69 (1H, m, ArH), 7.59 (3H, m, meta-TsþArH), 7.25 (2H, m,
2ꢁArH), 7.20 (2H, d, J 7.5 Hz, 2ꢁArH) 7.10 (2H, d, J 7.5 Hz, 2ꢁArH), 7.04
(1H, m, ArH), 6.80 (1H, s, CHNMe), 5.84 (1H, d, J 9.0 Hz, NHTs), 4.32
(1H, dt, J 3.0, 6.0 Hz, PhSO2CH), 4.10 (1H, dt, J 8.5 Hz, TsNHCH), 4.01
(2H, ddd, J 6.5 Hz, CH2OH), 3.64 (3H, s, NMe), 3.42 (3H, s, OMe),
3.10e2.90 (2H, dd, J 7.0 Hz, CH2CHNHTs), 2.36 (2H, d, J 5.0 Hz,
CH2CO2Me), 2.52(1H, m, CHCH2OH), 2.93 (3H, s, CH3Ts); dC (100 MHz,
CDCl3); 170.7 (CO), 142.9 (CSO2), 137.8 (CSO2), 137.6 (CH3C-Ts), 134.2
(para-PhSO2),129.8 (ArC),129.2 (ortho-Ts),129.3 (ortho-PhSO2),129.0
(meta-Ts), 128.8 (ArC), 127.7 (meta-PhSO2), 126.8 (meta-PhSO2), 121.7
(ArH), 119.1 (ArH), 118.5 (ArH), 109.0 (ArCH), 107.5 (CCHNCH3), 60.1
(CH2OH), 59.2 (OCH3), 53.2 (PhSO2CH), 52.2 (TsNHCH), 46.8
(CHCH2OH), 34.1 (CH2CO2CH3), 32.5 (NCH3), 29.0 (CH2C), 21.6
(TsCH3); m/z (ESI): 621.1710 [MþNa], 589.1450 [MþNaꢂHOCH3],
567.1626 [MeOCH3], 479.1616 [MþNaeHSO2Ph]þ, 457.1797
[MeSO2Ph]þ (found [M]þ, 599.1890. C30H34N2O7S2 requires [M]þ,
599.1886.) (found: C, 60.20; H, 5.74; N, 4.64. C30H34N2O7S2 requires C,
60.18; H, 5.72; N, 4.68%).
ortho Ts, major diast.), 7.57 (2H, d, J 8.0 Hz, ortho Ts, minor diast.),
7.30e7.26 (2ꢁ2H, m, meta Ts, 2ꢁdiast.), 7.12e7.09 (2ꢁ2H, m, meta
ArOMe, 2ꢁdiast.), 6.87e6.84 (2ꢁ2H, m, ortho ArOMe, 2ꢁdiast.), 6.69
(1H, d, J 8.0 Hz, NCH]CH, major diast.), 6.62 (1H, d, J 8.0 Hz, NCH]
CH, minor diast.), 6.18 (1H, ddd, J 17.5, 10.0, 8.0 Hz, CH]CHH, minor
diast.), 5.66 (1H, ddd, J 17.5,10.0, 8.0 Hz, CH]CHH, major diast.), 5.47
(1H, dd, J 8.0, 4.5 Hz, NCH]CH, minor diast.), 5.28e5.15 (2ꢁ1H, m,
CH]CHH, 2ꢁdiast. and 1H, m, NCH]CH, major diast.), 5.01e4.94
(2ꢁ1H, m, CH]CHH, 2ꢁdiast), 4.14e4.07 (2ꢁ1H, m, NCHCH2,
2ꢁdiast), 3.83 (2ꢁ3H, s, OMe, 2ꢁdiast), 3.14e3.11 (1H, m, CHSMe,
major diast.), 3.03e3.00 (1H, m, CHSMe, minor diast.), 2.92 (1H, dd, J
14.0, 4.0 Hz, CHHArOMe, minor diast.), 2.84 (1H, dd, J 14.0, 10.0 Hz,
CHHArOMe, minor diast.), 2.72 (1H, dd, J 14.0, 4.0 Hz, CHHArOMe,
major diast.), 2.65 (1H, dd, J 14.0, 10.0 Hz, CHHArOMe, major diast.),
2.43 (3H, s, Me of Ts, major diast.), 2.25e2.20 (1H, m, CHCH]CH2,
minor diast.), 2.18 (3H, s, Me of Ts, minor diast.), 1.77e1.72 (1H, m,
CHCH]CH2, major diast.), 1.59 (3H, s, SMe, minor diast.), 1.56 (3H, s,
SMe, major diast.); dC (100 MHz) 158.3, 158.1, 143.8, 143.6, 137.6,
136.5, 136.1, 135.6, 130.7, 130.5, 129.7, 129.6, 127.1, 127.0, 125.5, 125.4,
123.2, 118.4, 117.9, 113.7, 113.6, 113.1, 60.8, 60.1, 55.2, 45.7, 44.3,42.6,
39.5, 33.8, 32.1, 31.8, 29.7, 21.5, 18.4, 9.7; m/z (ESI) 452.1334
[MþNa]þ, 447.1773, 430.1506 [MþH]þ, 382.1479, 242.1179, 227.1312
(found: [MþNa]þ, 452.1334. C23H27NO3S2 requires [MþNa]þ,
452.1330).
4.3.4. (1R
*
,12R
*
,13S
*
,14S )-14,16-Ditosyl-3-methyl-3,16-diazate-
*
tracyclo[10.3.1.02,10.04,9]hexa-deca-2(10),4,6,8-tetraen-13-yl
3-ox-
obutanoate (22). To a solution of alcohol 213 (88 mg, 0.14 mmol,
1 equiv) and DMAP (1.7 mg, 0.0014 mmol, 10 mol %) in THF (1 mL) at
rt was added diketene (14
mL, 15 mg, 0.18 mmol, 1.26 equiv, freshly
distilled under vacuum). The reaction mixture was heated under

6382
D. Craig et al. / Tetrahedron 66 (2010) 6376e6382
F. V., Eds.; Pergamon: New York, NY, 1996; Vol. 1A, pp 1e60; (b) Murphree, S. S.;
Padwa, A. Prog. Heterocycl. Chem. 2001, 13, 52; (c) McCoull, W.; Davis, F. A.
Synthesis 2000, 1347; (d) Zwanenburg, B.; Holte, P. T. Top. Curr. Chem. 2001, 216,
93; (e) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247; (f) Hu, X. E. Tetrahedron
2004, 60, 2701; (g) Aziridines and Epoxides in Organic Synthesis; Yudin, A. K., Ed.;
Wiley-VCH: Weinheim, Germany, 2006; (h) Padwa, A. In Comprehensive Het-
erocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R.
J. K., Eds.; Elsevier: Oxford, 2008; Vol. 1, pp 1e104.
2. For a recent review of regioselective ring-opening reactions of aziridines, see:
Lu, P. Tetrahedron 2010, 66, 2549.
3. Carballares, S.; Craig, D.; Hyland, C. J. T.; Lu, P.; Mathie, T.; White, A. J. P. Chem.
Commun. 2009, 451.
reflux with stirring for 2 h, and then cooled and concentrated under
reduced pressure. Chromatography using gradient elution (50%/
75%/90% Et2Oepetrol, then Et2O, then 10% acetoneeEt2O) gave the
intermediate
solved in MeCN (0.73 mL) and NaI (60 mg, 0.43 mmol, 6 equiv) fol-
lowed by TMSCl (55 L, 49 mg, 0.43 mmol, 6 equiv) were added at
b-ketoester (51 mg, 0.072 mmol, 51%). This was dis-
m
0 ꢀC. The reaction mixture was stirred at 0 ꢀC for 1 h, satd aq NaHCO3
(5 ml) was added and the aqueous layer extracted with CH2Cl2
(3ꢁ10 ml). The combined organic layers were dried (MgSO4), filtered
and concentrated under reduced pressure. Chromatography using
gradient elution (50%/75%/90% Et2Oepetrol, then Et2O, then 10%
4. Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995.
5. Manaka, T.; Nagayama, S.-I.; Desadee, W.; Yajima, N.; Kumamoto, T.; Watanabe,
T.; Ishikawa, T.; Kawahata, M.; Yamaguchi, K. Helv. Chim. Acta 2007, 90, 128.
6. Pineschi, M.; Bertolini, F.; Crotti, P.; Macchia, F. Org. Lett. 2006, 8, 2627.
7. Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J. J. Org. Chem. 2002, 67, 1399.
acetoneeEt2O) gave (1R
*
,12R
*
,13S
*
,14S )-14,16-ditosyl-3-methyl-3,16-
*
diazatetra-cyclo[10.3.1.02,10.04,9]hexadeca-2(10),4,6,8-tetraen-13-yl 3-
oxobutanoate 22 (40 mg, 0.062 mmol, 86%) as a colourless oil; Rf 0.27
€
€
8. Kaiser, H. M.; Zenz, I.; Lo, W. F.; Spannenberg, A.; Schroder, K.; Jiao, H.; Gordes,
D.; Beller, M.; Tse, M. K. J. Org. Chem. 2007, 72, 8847.
9. Bera, M.; Roy, S. Tetrahedron Lett. 2007, 48, 7144.
(Et2O); nmax (film) 1743, 1716, 1468, 1316, 1163, 1148, 674 cmꢂ1
; dH
(400 MHz, CDCl3) 7.65 (2H, d, J 8.0 Hz, 2ꢁTsH), 7.28 (4H, d, J 8.0 Hz,
4ꢁTsH), 7.22e7.15 (2H, m, 2ꢁArH), 7.07 (1H, d, J 8.0 Hz, ArH), 7.01 (1H,
t, J 7.0 Hz, ArH), 6.72 (2H, d, J 8.0 Hz, 2ꢁTsH), 5.43 (1H, app s,
NCHCNMe), 4.94 (1H, dd, J 11.5, 4.0 Hz, CHAHBO), 4.66 (1H, d, J 8.0 Hz,
NCHCH), 4.54 (1H, t, J 11.0, 3.5 Hz, CHAHBO), 3.58 (3H, s, NCH3), 3.56
(2H, d, J 5.5 Hz, CH2C]O), 3.38 (1H, dt, J 13.0, 4.0, CHTs), 2.87 (1H, dd, J
17.0, 8.5 Hz, CHAHBC), 2.57 (1H, td, J 13.0, 4.5 Hz, CHAHBCHTs),
2.48e2.27 (1H, m, CHCHN), 2.40 (3H, s, TsCH3), 2.36 (3H, s, TsCH3),
2.18 (1H, d, J 17.0 Hz, CHAHBC), 2.02e1.99 (1H, m, CHAHBCHTs), 1.93
(3H, s, CH3C]O); dC (100 MHz, CDCl3) 201.1 (C]O), 166.7 (C]O),
145.4 (TsC), 143.8 (TsC), 136.8 (ArC), 135.4 (TsC), 134.1 (TsC), 131.1
(ArC), 130.2 (2ꢁTsCH), 128.8 (2ꢁTsCH), 128.7 (2ꢁTsCH), 126.4
(2ꢁTsCH), 125.7 (ArC), 122.1 (ArCH), 119.4 (ArCH), 118.0 (ArCH), 109.1
(ArCH), 107.1 (ArC), 61.0 (CH2O), 57.2 (CHTs), 50.1 (CH2C]O), 48.8
(NCHCH2C), 47.2 (NCHCNMe), 41.1 (CHCHN), 30.4 (CH3C]O), 29.2
(NCH3), 26.4 (CH2CHTs), 24.2 (CH2C), 21.7 (TsCH3), 21.1 (TsCH3); m/z
(FAB) 648 ([M]þ), 391, 149, 71, 57 (found: [M]þ, 648.1976.
C34H36N2O7S2 requires [M]þ, 648.1964).
10. Mali, S.; Nadir, U. K. Synlett 2008, 108.
11. Hodgson, D. M.; Fleming, M. J.; Stanway, S. J. Org. Lett. 2005, 7, 3295.
12. (a) Medina, E.; Moyano, A.; Pericas, M. A.; Riera, A. J. Org. Chem. 1998, 63, 8574
(organocopper reagents); (b) Davis, F. A.; Liang, C.-H.; Liu, H. J. Org. Chem. 1997,
62, 3796 (organomagnesium reagents); (c) Bellos, K.; Stamm, H.; Speth, D. J.
Org. Chem. 1991, 56, 6846; Falkenstein, R.; Mall, T.; Speth, D.; Speth, H. J. Org.
Chem. 1993, 58, 7877 (organolithium reagents).
13. Cantrill, A. A.; Jarvis, A. N.; Osborn, H. M. I.; Ouadi, A.; Sweeney, J. B. Synlett
1996, 847.
14. Aoyama, H.; Mimura, N.; Ohno, H.; Ishii, K.; Toda, A.; Tamamura, H.; Otaka, A.;
Fujii, N.; Ibuka, T. Tetrahedron Lett. 1997, 38, 7383.
15. For a demonstration of the effect of aziridine stereochemistry on the re-
gioselectivity of ring-opening by organocopper reagents, see also: Wipf, P.;
Fritch, P. C. J. Org. Chem. 1994, 59, 4875.
16. Otaka, A.; Katagiri, F.; Kinoshita, T.; Odagaki, Y.; Oishi, S.; Tamamura, H.; Ha-
manaka, N.; Fujii, N. J. Org. Chem. 2002, 67, 6152.
17. For a single earlier report describing this directing effect, see: Fuji, K.; Kawabata,
T.; Kiryu, Y.; Sugiura, Y. Heterocycles 1996, 42, 701.
18. Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett 1998, 55.
19. Craig, D.; McCague, R.; Potter, G. A.; Williams, M. R. V. Synlett 1998, 58.
20. For [2,3]-sigmatropic rearrangements of alkynyl sulfoxides, see: (a) Baudin, J. B.;
Julia, S. A.; Lorne, R. Synlett 1991, 509; (b) Majumdar, K. C.; Ghosh, S. K. Tetra-
hedron Lett. 2002, 43, 2123; (c) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 4160.
21. Similar yields were obtained when the intermediate N-tosylhemiaminal was
isolated prior to the dehydration reaction.
22. (a) Itoh, A.; Ozawa, S.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21, 361; (b)
Berg, D. J.; Andersen, R. A. Organometallics 2003, 22, 627.
23. (a) Kumar, R.; de Mel, S. J.; Oliver, J. P. Organometallics 1989, 8, 2488; (b)
Newbold, R. C.; Shih, T. L.; Fisher, M. H. Tetrahedron Lett. 1993, 34, 3825.
24. (a) Maryanoff, B. E.; McComsey, D. F. J. Org. Chem. 1978, 43, 2735; (b) Kozi-
kowski, A. P.; Ames, A. Tetrahedron 1985, 41, 4821; (c) Murai, T.; Ogino, Y.;
Mizutani, T.; Kanda, T.; Kato, S. J. Org. Chem. 1995, 60, 2942.
25. Parham, W. E.; McKown, W. D.; Nelson, V.; Kajigaeshi, S.; Ishikawa, N. J. Org.
Chem. 1973, 38, 1361.
Acknowledgements
We thank EPSRC (responsive-mode grant GR/S10445; post-
doctoral associateship to T.M.) and Imperial College Chemistry
Department (Departmental Studentship to N.T.H.T.) for support.
Supplementary data
26. De Lombaert, S.; Nemery, I.; Roekens, B.; Carretero, J. C.; Kimmel, T.; Ghosez, L.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.04.096.
Tetrahedron Lett. 1986, 27, 5099.
27. For a review of the aza-Payne rearrangement, see: Ibuka, T. Chem. Soc. Rev. 1998,
27, 145.
28. Cox, P.; Craig, D.; Ioannidis, S.; Rahn, V. S. Tetrahedron Lett. 2005, 46, 4687.
29. Chang, Y.-H.; Pinnick, H. W. J. Org. Chem. 1978, 43, 373; (b) Ricci, A.; Danieli, R.;
Pirazzini, G. J. Chem. Soc., Perkin Trans. 1 1977, 1069.
References and notes
30. Watanabe, E.; Imai, N.; Inomata, K.; Kinoshita, H.; Kotake, H. Bull. Chem. Soc. Jpn.
1. For reviews on aziridines, see: (a) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In
1982, 55, 3225.
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E.