(2-Bromoethyl)sulfonium Trifluoromethanesulfonates in Stereoselective Annulation Reactions for the Formation of Fused Bicyclic Epoxides and Aziridines

Article abstract of DOI:10.1002/hlca.201200455

A versatile and simple methodis reported for the synthesis of bicyclic epoxide and aziridine?￡?fused heterocycles (up to 98% yield, up to 96: 4 er or up to 15: 1 dr), using a tandem Michael addition/ Johnson?￡?Corey?￡?Chaykovsky annulation approach. A new

Full text of DOI:10.1002/hlca.201200455

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Helvetica Chimica Acta – Vol. 95 (2012)
(2-Bromoethyl)sulfonium Trifluoromethanesulfonates in Stereoselective
Annulation Reactions for the Formation of Fused Bicyclic Epoxides and
Aziridines
by Sven P. Fritza), Zulfiquar Alia), Matthew G. Unthanka), Eoghan M. McGarriglea)b), and
Varinder K. Aggarwal*a)
a) School of Chemistry, University of Bristol, Bristol, BS8 1TS, UK (phone: þ 44-117-9546315;
fax: þ 44-117-9298611; e-mail: V.Aggarwal@Bristol.ac.uk)
b) Centre for Synthesis and Chemical Biology, UCD School of Chemistry and Chemical Biology,
University College Dublin, Belfield, Dublin 4, Ireland
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
A versatile and simple method is reported for the synthesis of bicyclic epoxide and aziridineꢀfused
heterocycles (up to 98% yield, up to 96 :4 er or up to 15 :1 dr), using a tandem Michael addition/
JohnsonꢀCoreyꢀChaykovsky annulation approach. A new chiral (2-bromoethyl)sulfonium reagent is
described, based on an easily available chiral sulfide; it promotes or enhances stereoselectivity in the
reaction.
Introduction. – The asymmetric synthesis of heterocycles continues to be of
significant contemporary interest due to their prevalence in both natural products and
pharmaceutical agents [1]. Strained, fused bicyclic systems are ideal starting points for
the synthesis of functionalized heterocycles [2]. In particular, epoxide- and aziridine-
fused five- and six-membered rings can be easily modified towards a broad range of
more complex targets, as they are prone to ring-opening reactions [2][3]. Previous
syntheses of these systems mostly relied on cyclic, olefin precursors, but subsequent
asymmetric reactions (epoxidation [2c][2i][4], dihydroxylation [5], halogenation [6])
are often difficult to control.
We recently reported that bicyclic epoxide- or aziridine-fused heterocycles could be
prepared using vinylsulfonium salt 1 or its chiral variant 2 [3][7][8], and also explored
other modes of reactivity [9][10]. However, the diphenylvinylsulfonium salt 1 is a
reactive oil, and the chiral salt 2 requires a lengthy synthesis [11]. We, therefore,
decided to exploit recent advances in annulation reactions using (2-bromoethyl)sulfo-
nium salts as precursors for the in situ generation of vinylsulfonium salts [9g] with the
much more readily available chiral sulfonium salt 4 [12], which had the potential to
render this work more practical (Scheme 1).
Results and Discussion. – (2-Bromoethyl)sulfonium salt 3 is, in contrast to
vinylsulfonium salt 1, a commercially available, air-stable, and crystalline compound
that can be stored on the bench without precautions and weighed easily [9g].
Additionally, it often gives higher yields because the reactive vinylsulfonium salt
ꢀ 2012 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 1. Context of Present Work
2385
species is generated in situ, in lower concentrations. We also wanted to investigate the
use of a novel (2-bromoethyl)sulfonium salt 4, which in comparison to previously
reported chiral sulfonium salt 2 (6 steps), was expected to be easily available from
commercially sulfide 7 [12]. Indeed, chiral (2-bromoethyl)sulfonium salt 4 was readily
prepared by alkylation of the corresponding triflate 6 (Scheme 2).
Scheme 2. Synthesis of Sulfonium Salt 4
We first explored epoxy-annulation reactions, and inital results were promising,
showing that we could achieve higher yields in the epoxy annulation reaction by using
(2-bromoethyl)sulfonium salt 3 instead of vinylsulfonium salt 1 in almost every case
(compare conditions A with B, Table 1). Furthermore, use of chiral (2-bromoethyl)-
sulfonium salt 4 gave good yields with moderate to high enantioselectivity (Table 1,

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Table 1. Results and Scope of the Annulation Reactions Using Sulfonium Salts 1 – 4 (DBU ¼ 1,8-diaza-
bicylo[5.4.0]undec-7-ene)
Entry Substrate
R
n
Method Product Yield [%] (with 1 or 2)a) ee [%] (ee with 2)b)
1
2
3
4
5
8a
8b
8c
8d
8e
Me
1
A/B
C/D
9a
9b
9c
9d
9e
94/(90)
52/(76)
–
54/(97)
Et
Ph
H
1
1
2
2
A/B
C/D
99/(90)
87/(65)
–
72/(99)
A/B
C/D
98/(96)
88/(80)
–
68/(92)
A/B
C/D
71/(67)
68/(67)
–
54/(98)
Me
A/B
C/D
72/(77)
35/(30)
–
92/(86)
a) Isolated yields. Data in brackets are from [3]. b) Determined by chiral HPLC (for details, see Exper.
Part).
conditions C). It should be noted that the lower yields observed with b-amino ketones/
aldehydes 8d/8e compared to those with the corresponding a-amino ketones/aldehydes
8a – 8c are a result of competing elimination of TsNH2, leading to an enone (compare
Entries 4 and 5 with Entries 1 – 3, Table 1).
While higher yields were obtained with the new conditions employing the (2-
bromoethyl)sulfonium salt 3, the enantioselectivities using the new chiral (2-
bromoethyl)sulfonium salt 4 were generally lower than those we had obtained with
the less easily accessible sulfonium salt 2 [3]. Alternative solvents and additives were
explored, but no significant increase in enantioselectivity was observed (see Exper. Part
for details). The enantioselectivity in ylide epoxidations is determined in the reaction
of the ylide with the aldehyde to form a betaine [13]. We propose that the lower
enantioselectivity obtained using salt 4 vs. salt 2 as ylide precursors is due to differences

Helvetica Chimica Acta – Vol. 95 (2012)
2387
in the populations of ylide conformers Y1/Y2 vs. Z1/Z2 (Scheme 3), which in turn leads
to different enantiomers of the product being formed. In the case of ylide Y, conformer
Y1 is strongly favored over Y2 due to the steric interactions between the bridgehead H-
atoms and the ylide substitutents. Similar steric interactions are present in ylide
conformer Z2, but conformer Z1 suffers from gauche interactions from the neighboring
geminal dimethyl moiety, not present in Y, making it less strongly favored. As a result
lower enantioselectivity was observed (Scheme 3).
Use of enantiomerically enriched a-substituted aldehydes/ketones 10a – 10g was
also explored with the two new sets of conditions [8b]. Use of the achiral (2-
bromoethyl)sulfonium salt 3 gave the epoxides in high yield and moderate diaster-
Scheme 3. Proposed Reaction Pathway for Annulations Using Chiral Sulfur Ylides

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Helvetica Chimica Acta – Vol. 95 (2012)
eoselectivity. Using the chiral sulfonium salt 4, enhanced diastereoselectivity was
observed, with the reagent contributing a ca. 2.5-fold increase (matched case) in
selectivity (Table 2).
The issue of matched vs. mismatched double stereodifferentiation was explored
with (þ)- and (ꢀ)-amino ketone 10d/12. Using the achiral salt 3, a 4.2 :1 ratio of
epoxides syn-11b/anti-11b was obtained (Scheme 4), reflecting the extent of substrate
Table 2. Results and Scope for a-Substituted Substrates
Entry Substrate
R
H
R’ Method Product
Yield [%]a) d.r.b)
1
2
3
4
5
6
10a
10b
10c
10d
10e
H
A
E
11a
11b
11c
11d
11e
47c)
No reaction
1 : 1.2
–
Me H
Et
A
E
98
60
4.2 : 1
10 : 1
H
A
E
89
66
3.8 : 1
9.5 : 1
Me Ph A
88
64
6.6 : 1
15 : 1
E
Et Ph A
98
66
7.2 : 1
15 : 1
E
A
99
3.2 : 1
E
A
No reaction –
7
56
10 : 1
E
No reaction
b
a) Isolated yields. ) Determined from crude H-NMR spectrum. c) From polymeric starting material.
1

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2389
Scheme 4. Proposed Rationalization for Diastereoselectivity in the Annulation Reaction of 8b with 3
control. Using chiral sulfonium salt 4, a 10 :1 ratio was observed (matched), whereas,
using the enantiomeric substrate 12 and the same chiral sulfonium salt 4, a 1:1.4 ratio of
diastereoisomers 13 was obtained (mismatched; Scheme 5). In the latter case, the
major diastereoisomer is favored by the reagent (sulfide stereochemistry dominates)
but disfavored by the substrate (pseudo-axial substituent, anti-FelkinꢀAnh-like),
whereas the minor diastereoisomer is favored by the substrate (pseudo-equatorial
substituent, FelkinꢀAnh-like) but disfavored by the reagent.
We were also able to expand this methodology to indole-derived amino aldehydes
and imines as substrates [7]. In the case of the aldehyde 14, good yields were observed
using salts 1 or 3 (Scheme 6).
Experiments with chiral sulfonium salts and indole 14 were limited by low yield and
enantioselectivity [3][7]. However, the reaction of (2-bromoethyl)sulfonium salt 3
with the Ellman [14] sulfinimine 16 gave high diastereoselectivity for the fused
aziridine 17. This represents a short asymmetric route to the basic core of the mitomycin
class of antibiotics [7][15] (Scheme 7).
Conclusions. – We have shown that the use of (2-bromoethyl)sulfonium salt 3
provides significantly improved yields and operational simplicity in epoxy-annulation
reactions of a- and b-amino carbonyl compounds in the synthesis of epoxy-pyrrolidines
and epoxy-piperidines. In the case of chiral a-substituted amino aldehydes and ketones,
moderate diastereoselectivity was observed, which is easily enhanced using the chiral
sulfonium salt 4. The use of indole-derived imines in the annulation process leads to the
core of mitomycins in good yield and high diastereoselectivity.

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Scheme 5. Proposed Rationalization for Diastereoselective Annulation with 4
Scheme 6. Reaction of Indole-2-aldehyde 14 with 3
S. P. F. thanks the Engineering and Physical Sciences Research Council (EPSRC). Z. A. thanks the
Higher Education Commission of Pakistan (HEC). V. K. A. thanks the EPSRC for a Senior Research
Fellowship.
Experimental Part
1. General. All reagents and solvents were used as received. Anh. solvents (CH2Cl2, MeCN, THF)
were obtained from a purification column composed of activated alumina (A-2) [7b][16]. Flash
chromatography (FC): silica gel (Merck Kieselgel 60 F254, 230 – 400 mesh). TLC: Aluminium backed
silica-gel plates (0.2 mm, 60 F254); standard visualising agents: UV fluorescence (254 & 366 nm), I2. M.p.:
Kofler hotstage; uncorrected. Enantioselectivity: Agilent 1100 series HPLC instrument using the
described columns and solvent systems. All ratios of diastereoisomers were determined from the NMR of

Helvetica Chimica Acta – Vol. 95 (2012)
Scheme 7. Reaction of Sulfinimine 16 with 3
2391
the crude reaction material, prior to isolation. Absolute configuration of the enantiomer was determined
by comparison with previously reported literature data (same major, same minor, similar [a]D), for which
X-ray crystallography was used [3]. Configuration of diastereoisomers (syn/anti) was determined by
comparison with previously reported literature data (same 1H- and 13C-NMR), for which X-ray
crystallography was used [8b]. IR Spectra: ATR sampling accessory on a PerkinꢀElmer Spectrum One
1
FT-IR spectrometer, neat compounds, only strong and selected absorbances (˜nmax) reported. H-NMR
Spectra: 300 or 400 MHz on JEOL Delta GX or Eclipse ECP/400 instruments, resp.; d(H) in ppm rel. to
Me4Si and/or the appropriate NMR solvent peak(s), J in Hz. 13C-NMR Spectra: 100 MHz on JEOL
Delta GX or Eclipse ECP/400 instruments, resp.; d(C) in ppm rel. to the appropriate solvent peak(s) and
are assigned C, CH, CH2, and Me. DEPT, COSY, HMBC and HMQC/HSQC were used where necessary
in assigning NMR spectra. LR-MS: VG Autospec (CI) and a Bruker Daltronics Apex 4e 7.0T FT-MS
(ESI), with only molecular ions (Mþ or [M þ H]þ) and major peaks being reported; in m/z. HR-MS: VG
Autospec (CI) and a Bruker Daltronics Apex 4e 7.0T FT-MS (ESI) spectrometer; in m/z.
2. Synthesis of Precursors and Reagents. (2-Bromoethyl)(diphenyl)sulfonium trifluoromethanesulfo-
nate (3) [9g], 4-methyl-N-(3-oxopropyl)benzenesulfonamide [3], 4-methyl-N-(2-oxoethyl)benzenesul-
fonamide [3], 4-methyl-N-(2-oxopropyl)benzenesulfonamide [3], 4-methyl-N-(2-oxobutyl)benzenesul-
fonamide [3], 4-methyl-N-(2-oxo-2-phenylethyl)benzenesulfonamide [17], 4-methyl-N-(3-oxobutyl)-
benzenesulfonamide [18], 4-methyl-N-[(2R)-1-methyl-2-oxopropyl]benzenesulfonamide [8b], 4-methyl-
N-[(2R)-1-methyl-2-oxobutyl]benzenesulfonamide [8b], 4-methyl-N-(1-methyl-2-oxoethyl)benzenesul-
fonamide [8b], 4-methyl-N-[(2R)-3-oxo-1-phenylbutan-2-yl]benzenesulfonamide [19], and a-hydroxy-
propiophenone [20] were synthesized according to previously published procedures.
(1R,4R,5R,6R)-6-(2-Bromoethyl)-4,7,7-trimethyl-6-thiabicyclo[3.2.1]octan-6-ium Trifluoromethane-
sulfonate (4). A soln. of 2-bromoethyl trifluoromethanesulfonate (6) [9e] (5.00 g, 19.5 mmol, 1 equiv.) in
CH2Cl2 was treated with (1R,4R,5R)-4,7,7-trimethyl-6-thiabicyclo[3.2.1]octane [12] (4.00 g, 23.4 mmol,
1.2 equiv.; er 99 :1) at r.t. and stirred for 3 d under N2. The mixture was concentrated in vacuo, Et2O was
added to the crude oil, and the mixture was stirred vigorously until precipitation of a gray salt was
complete. The salt was decanted from Et2O and washed with additional Et2O (3 ꢁ 50 ml), then dried in
vacuo to afford pure 4 (6.73 g, 81%). White-to-pink salt. M.p. 68 – 718 (CH2Cl2/Et2O). Rf (10% MeOH/
CH2Cl2) 0.3. [a]2D3 ¼ ꢀ45 (c ¼ 4.2, CHCl3). IR (neat): 2932 – 2871, 1469, 1266, 1252, 1221, 1151, 1135, 1025.
1H-NMR (400 MHz, CDCl3): 4.30 – 4.22 (m, SꢀCH); 3.99 – 3.77 (m, 4 H); 2.56 – 2.31 (m, 4 H); 1.91 – 1.52
(m, 10 H); 1.17 (d, J ¼ 7.1, Me ) . 13C-NMR (100 MHz, CDCl3): 120.4 (q, J ¼ 322, CF3); 73.2 (C); 68.1
(CH); 49.7 (CH); 41.5 (CH2); 32.5 (CH2); 31.7 (CH); 27.4 (CH2); 26.4 (Me); 25.1 (CH2); 23.0 (Me); 22.1

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Helvetica Chimica Acta – Vol. 95 (2012)
(CH2); 17.7 (Me). ESI-MS: 277.1 (Mþ(79Br)), 279.1 (Mþ(81Br)). HR-ESI-MS: 277.0620 (Mþ, C12H22BrSþ;
calc. 277.0613).
4-Methyl-N-[(2R)-3-oxo-1-phenylpentan-2-yl]benzenesulfonamide (10e). The title compound was
prepared from the corresponding Weinreb amide (300 mg, 0.82 mmol) [20], following literature
procedure for similar compounds [8b] (182 mg, 68%). M.p. 94 – 968 (CH2Cl2/pentane). Rf (AcOEt/PE
1:1) 0.6. [a]2D4 ¼ ꢀ30 (c ¼ 2.66, CHCl3). IR (film): 3270 (arom. CꢀH), 3035 (CꢀH), 2941 (CꢀH), 1717
(C¼O). 1H-NMR (400 MHz, CDCl3): 7.53 – 7.65 (m, 2 arom. H); 7.17 – 7.26 (m, 5 arom. H); 6.98 – 7.07 (m,
2 arom. H); 5.37 (d, J ¼ 8.0, NH); 4.06 – 4.19 (m, COCH); 2.95 (dd, J ¼ 14.0, 6.5, 1 H, PhCH2); 2.87 (dd,
J ¼ 14.0, 6.5, 1 H, PhCH2); 2.40 (s, ArMe); 2.33 (dq, J ¼ 18.4, 7.2, 1 H, MeCH2); 2.18 (dq, J ¼ 18.4, 7.2, 1 H,
MeCH2); 0.85 (t, J ¼ 7.2, MeCH2). 13C-NMR (100 MHz, CDCl3): 208.8 (C¼O); 143.5 (C); 136.5 (C);
135.1 (C); 129.6 (CH); 129.1 (CH); 128.6 (CH); 127.1 (CH); 127.0 (CH); 61.8 (CH); 38.7 (CH2); 33.8
(CH2); 21.4 (ArMe); 7.1 (Me). ESI-MS: 354.1 ([M þ H]þ). HR-ESI-MS: 354.1134 ([M þ Na]þ,
C18H21NNaO3Sþ; calc. 354.1130).
3. Racemic and Enantioselective Epoxy-annulation Reactions. Method A (optimal achiral sulfonium
salt conditions). A soln. of amino ketone (0.13 mmol, 1 equiv.) in anh. CH2Cl2 (1.5 ml) was treated with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.45 mmol, 3.5 equiv.) at 08 under inert atmosphere with
stirring. (2-Bromoethyl)(diphenyl)sulfonium triflate (3; 0.16 mmol. 1.2 equiv.) was added, and the
mixture was stirred for 2 – 4 h until complete consumption of starting material (HPLC or TLC). The
reaction was then quenched with 10% aq. citric acid soln. (10 ml), and the aq. phase was extracted with
CH2Cl2 (3 ꢁ 10 ml). The combined org. layers washed with brine (1 ꢁ 10 ml) and dried (MgSO4). The
crude mixture was purified by FC (AcOEt/petroleum ether (PE) or AcOEt/pentane) to give the desired
epoxide after concentration under reduced pressure.
Method B (optimal chiral sulfonium salt conditions). A soln. of amino ketone or aldehyde
(0.13 mmol, 1 equiv.) in CH2Cl2 (8.5 ml) was cooled to ꢀ 208 by means of an ice/acetone/dry ice bath,
under Ar with stirring. The mixture was then treated with DBU (0.45 mmol, 3.5 equiv.), followed by
chiral (2-bromoethyl)sulfonium triflate (0.16 mmol. 1.2 equiv.). The mixture was placed in the freezer at
ꢀ 208 for 2 – 3 d until complete consumption of starting material was detected by HPLC or TLC, after
which time the reaction was quenched with 10% aq. citric acid soln. (10 ml). The aq. phase was extracted
with CH2Cl2 (3 ꢁ 10 ml), the combined org. layers washed with brine (1 ꢁ 10 ml), dried (MgSO4), and
concentrated in vacuo. The crude mixture was purified by FC (AcOEt/PE or AcOEt/pentane) to give the
desired epoxide after concentration under reduced pressure. The ee was determined by chiral HPLC,
with comparison to a racemic sample prepared by Method A.
Initial Screening of Conditions for the Enantioselective Reaction. Changes in conditions from
standard Method B, using 4-methyl-N-(2-oxobutyl)benzenesulfonamide to prepare (1S,5R)-1-ethyl-3-
[(4-methylphenyl)sulfonyl)]-6-oxa-3-azabicyclo[3.1.0]hexane:
Entry
Condition change
ee [%]
1
2
3
4
5
6
7
8
9
CH2Cl2
MeCN
THF
MeCN/LiCl (1 equiv.)
MeCN/LiOTf (1 equiv.)
MeCN/tBuOH (9 : 1)
CH2Cl2/LiCl (1 equiv.)
CH2Cl2/LiOTf (1 equiv.)
CH2Cl2, 08, 8 h
72
70
71
71
70
72
70
69
63
72
10
CH2Cl2, ꢀ 408, 5 d
We found the ee obtained in the reaction was not significantly affected by any of these changes,
except that an increase of temp. eroded the ee. Further cooling of the reaction to ꢀ 408 did not enhance
enantioselectivity.

Helvetica Chimica Acta – Vol. 95 (2012)
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(1S,5R)-1-Methyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane (9a). The title
compound was synthesized from 4-methyl-N-(2-oxopropyl)benzenesulfonamide. Method A (racemic):
9a as a white solid (34 mg, 94% yield); Method B (asymmetric): 9a as a white solid (23 mg,72% yield,
54% ee) after 3 d. M.p. 94 – 968 (AcOEt/PE). Rf (MeOH/CH2Cl2 1:99) 0.4. Chiral HPLC (OD-H, 0.9 ml/
min, 238, 8% iPrOH/hexane): major (shown) tR 27.2 min, minor tR 31.30 min, 54% ee. 1H-NMR
(400 MHz, CDCl3): 7.58 (d, J ¼ 8.0, 2 arom. H); 7.24 (d, J ¼ 8.0, 2 arom. H); 3.60 (d, J ¼ 12.0, 1 H, NCH2);
3.50 (d, J ¼ 12.0, 1 H, NCH2); 3.21 – 3.38 (m, 1 H, NCH2, OꢀCH); 3.21 (d, J ¼ 12.0, 1 H, NCH2); 2.34 (s,
ArMe); 1.38 (s, MeC(O)CH). 13C-NMR (100 MHz, CDCl3): 143.6 (C); 135.0 (C); 129.7 (CH); 127.5
(CH); 63.1 (C); 60.8 (CH); 51.8 (CH2); 49.3 (CH2); 21.6 (ArMe); 15.3 (Me). Spectroscopic data are in
accordance with those reported in [3].
(1S,5R)-1-Ethyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane (9b). The title com-
pound was synthesized from 4-methyl-N-(2-oxobutyl)benzenesulfonamide; Method A (racemic): 9b as a
white solid (42 mg, 99% yield) after 5 h; Method B (asymmetric): 9b as a white solid (38 mg, 87% yield,
72% ee) after 3 d. M.p. 79 – 818 (AcOEt/PE). Rf (AcOEt/PE 3 :7) 0.3. Chiral HPLC (OD-H, 0.8 ml/min,
i
1
238, 8% PrOH/hexane): major (shown) tR 42.8 min, minor tR 52.5 min; 72% ee. H-NMR (400 MHz,
CDCl3): 7.64 (d, J ¼ 8.0, 2 arom. H); 7.21 (d, J ¼ 8.0, 2 arom. H); 3.61 (d, J ¼ 12.0, 1 H, NCH2C(Et)); 3.54
(d, J ¼ 12.0, 1 H, NCH2C(Et)); 3.33 (br. d, J ¼ 1.5, OꢀCH); 3.32 (dd, J ¼ 12.0, 1.5, 1 H, NCH2C(O)H);
3.23 (d, J ¼ 12.0, 1 H, NCH2); 2.38 (s, ArMe); 1.78 (dq, J ¼ 14.5, 7.5, 1 H, MeCH2); 1.65 (dq, J ¼ 14.5, 7.5,
1 H of MeCH2); 0.83 (t, J ¼ 7.5, MeCH2). 13C-NMR (100 MHz, CDCl3): 143.4 (C); 134.8 (C); 129.5 (CH);
127.4 (CH); 67.1 (C); 59.0 (CH); 50.5 (CH2); 49.0 (CH2); 22.1 (CH2); 21.5 (ArMe); 9.0 (Me).
Spectroscopic data are in accordance with those reported in [3].
(1S,5R)-1-Phenyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane (9c). The title
compound was synthesized from 4-methyl-N-(2-oxo-2-phenylethyl)benzenesulfonamide (8c). Method A
(racemic): 9c as a white solid (45 mg, 98% yield); Method B (asymmetric): 9c as a white solid (41 mg,
88% yield, 68% ee) after 3 d. M.p. 77 – 808 (AcOEt/PE). Chiral HPLC (OD-H, 0.9 ml/min, 238, 8%
iPrOH/hexane): major (shown) tR 38.9 min, minor tR 47.5 min; 68 % ee. 1H-NMR (400 MHz, CDCl3): 7.64
(d, J ¼ 8.0, 2 arom. H); 7.10 – 7.33 (m, 7 arom. H); 3.86 (d, J ¼ 12.0, 1 H, NCH2C(Ph)); 3.81 (d, J ¼ 12.0,
1 H, NCH2C(Ph)); 3.71 (d, J ¼ 12.0, 1 H, NCH2CH(O)); 3.60 (d, J ¼ 1.2, OꢀCH); 3.45 (dd, J ¼ 12.0, 1.2,
1 H, NCH2CH(O)); 2.31 (s, ArMe). 13C-NMR (100 MHz, CDCl3): 143.7 (C); 134.6 (C); 131.0 (C); 129.7
(CH); 128.8 (CH); 128.7 (CH); 127.5 (CH); 126.0 (CH); 65.8 (C); 63.2 (CH); 50.1 (CH2); 49.4 (CH2);
21.6 (ArMe). Spectroscopic data are in accordance with those reported in [3].
(1R,6S)-3-[(4-Methylphenyl)sulfonyl]-7-oxa-3-azabicyclo[4.1.0]heptane (9d). The title compound
was synthesized from 4-methyl-N-(3-oxopropyl)benzenesulfonamide (8d). Method A (racemic): 9d as a
white solid (33 mg, 71% yield); Method B (asymmetric): 9d as a white solid (31 mg, 68% yield, 54% ee)
after 3 d. Rf (CH2Cl2) 0.2. Chiral HPLC (OD-H, 0.9 ml/min, 238, 2% iPrOH/hexane): major (shown) tR
61.6 min, minor tR 72.3 min; 54 % ee. 1H-NMR (400 MHz, CDCl3): 7.64 (d, J ¼ 8.0, 2 arom. H); 7.31 (d,
J ¼ 8.0, 2 arom. H); 3.81 (ddd, J ¼ 13.5, 4.0, 1.5, 1 H, NCH2); 3.32 (dtd, J ¼ 11.5, 4.5, 1.5, 1 H, NCH2);
3.22 – 3.25 (m, 2 OꢀCH); 3.10 (d, J ¼ 13.5, 1 H, NCH2); 2.53 (m, 1 H, 1 H, NCH2CH2); 2.41 (s, ArMe);
2.11 (m, NCH2CH2CH). 13C-NMR (100 MHz, CDCl3): 143.7 (C); 132.8 (C); 129.8 (CH); 127.6 (CH);
50.4 (CH); 49.8 (CH); 44.2 (CH2); 39.2 (CH2); 25.3 (CH2); 21.5 (ArMe). Spectroscopic data are in
accordance with those reported in [3].
(1R,6S)-6-Methyl-3-[(4-methylphenyl)sulfonyl]-7-oxa-3-azabicyclo[4.1.0]heptane (9e). The title
compound was synthesized from 4-methyl-N-(3-oxobutyl)benzenesulfonamide (8e). Method A (race-
mic): 9e as a white solid (35 mg, 72% yield); Method B (asymmetric): 9e as a white solid (17 mg, 35%
yield, 92% ee) after 3 d. M.p. 95 – 978 (from AcOEt/hexane). Chiral HPLC (IB column, 0.7 ml/min, 238,
i
15% PrOH/hexane): major (shown) tR 20.0 min, minor tR 21.8 min, 92% ee. 1H-NMR (400 MHz,
CDCl3): 7.52 (d, J ¼ 8.0, 2 arom. H); 7.21 (d, J ¼ 8.0, 2 arom. H); 3.82 (ddd, J ¼ 13.5, 4.5, 1.5, 1 H, NCH2);
3.34 – 3.37 (m, 1 H, NCH2); 3.03 (d, J ¼ 4.5, OꢀCH); 2.87 (d, J ¼ 13.5, 1 H, NCH2); 2.38 (td, J ¼ 11.0, 3.0,
1 H, NCH2); 2.31 (s, ArMe); 1.97 (ddd, J ¼ 14.5, 11.0, 5.0, 1 H of NCH2CH2); 1.88 (dt, J ¼ 14.5, 3.0, 1 H,
NCH2CH2); 1.26 (s, MeC(O)). 13C-NMR (100 MHz, CDCl3): 143.6 (C); 133.7 (C); 129.7 (CH); 127.6
(CH); 56.7 (C); 56.6 (CH); 44.4 (CH2); 40.1 (CH2); 30.4 (CH2); 22.4 (Me); 21.6 (Me). Spectroscopic
data are in accordance with those reported in [3].

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Helvetica Chimica Acta – Vol. 95 (2012)
4. Diastereoselective Epoxy-annulation Reactions. Method A (achiral reagent conditions). A soln. of
a-amino ketone (0.13 mmol, 1 equiv.) in anh. CH2Cl2 (0.09m) was treated with DBU (0.46 mmol,
3.5 equiv.) at 08 under Ar with stirring. Salt 3 (0.16 mmol, 1.2 equiv.) was added, and the mixture was
stirred for 2 – 4 h until complete consumption of starting material (HPLC or TLC). The reaction was
then quenched with 10% aq. citric acid soln. (10 ml), the aq. phase was extracted with CH2Cl2 (3 ꢁ
10 ml), and the combined org. layers were washed with brine (1 ꢁ 10 ml), dried (MgSO4), and
concentrated in vacuo. The crude mixture was then purified by FC (AcOEt/PE or AcOEt/pentane) to
give the desired epoxide after concentration under reduced pressure.
Method E (chiral reagent conditions). A soln. of a-amino ketone (0.13 mmol, 1 equiv.) in anh.
CH2Cl2 (0.015m) was treated with NaH (60% in mineral oil, 2.5 equiv.) at 08 under Ar with stirring. The
mixture was then treated with chiral salt 4 (1.4 equiv.) and stirred for 15 h until complete consumption of
starting material (HPLC or TLC). The reaction was then quenched with 10% aq. citric acid soln. (10 ml),
the aq. phase was extracted with CH2Cl2 (3 ꢁ 10 ml), and the combined org. layers were washed with
brine (1 ꢁ 10 ml) dried (MgSO4), and concentrated in vacuo. At this point, diastereoisomer ratio was
determined by crude NMR. The crude mixture was then purified by FC (AcOEt/PE or AcOEt/pentane)
to give the desired epoxide after concentration under reduced pressure.
(1S,2R,5R)-2-Methyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane (11a). The title
compound was synthesized from 4-methyl-N-[(2R)-1-oxopropan-2-yl]benzenesulfonamide (10a; poly-
meric). Method A yielded the 11a as a white gum (26 mg, 47% yield; dr 1.2 :1). Rf (AcOEt/PE 1:3) 0.3.
Reported as a mixture of two diastereoisomers: 1H-NMR (400 MHz, CDCl3): 7.70 (d, J ¼ 8.0, 2 arom. H);
7.65 (d, J ¼ 8.0, 2 arom. H); 7.32 (d, J ¼ 8.0, 2 arom. H); 7.29 (d, J ¼ 8.0, 2 arom. H); 3.98 (q, J ¼ 7.0,
MeCHN); 3.75 (d, J ¼ 11.5, 1 H, NCH2CH(O)); 3.47 – 3.67 (m, 6 H, NCH2CH(O), NCH2CH(O),
MeCHN, 1 H of NCH2CH(O), 1 H of NCH2CH(O), CH(O)CHCH2); 3.31 (dd, J ¼ 9.5, 1.5,
NCHCH(O)); 3.29 (br. s, CH(O)CHCH2); 2.43 (s, ArMe); 2.42 (s, ArMe); 1.50 (d, J ¼ 6.5, Me); 1.32
(d, J ¼ 7.0, Me). 13C-NMR (100 MHz, CDCl3): 143.6 (C); 143.3 (C); 135.7 (C); 135.5 (C); 129.7 (CH);
129.5 (CH); 127.5 (CH); 127.4 (CH); 60.4 (CH); 59.2 (CH); 56.5 (CH); 55.9 (CH); 54.8 (CH2); 54.2
(CH2); 50.6 (CH); 47.9 (CH); 21.7 (ArMe); 21.6 (ArMe); 18.0 (Me); 16.5 (Me). Spectroscopic data are in
accordance with those reported in [8b].
(1S,2R,5R)-1,2-Dimethyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane (11b): The
title compound was synthesized from 4-methyl-N-[(2R)-3-oxobutan-2-yl]benzenesulfonamide (10b).
Method A (achiral reagent): 11b as a white solid (98% yield; dr 4.2 :1 (syn/anti)); Method E (chiral
reagent): 11b as a white solid (60%; dr 10 :1, determined from MeC(O)). Rf (AcOEt/PE 3 :7) 0.3. Data
for major (syn) stereoisomer: 1H-NMR (400 MHz, CDCl3): 7.68 (d, J ¼ 8.0, 2 arom. H); 7.30 (d, J ¼ 8.0, 2
arom. H); 3.66 (d, J ¼ 12.0, 1 H, NCH2); 3.41 (d, J ¼ 1.5, OꢀCH); 3.40 (q, J ¼ 6.5, NCH(Me)); 3.27 (dd,
J ¼ 12.0, 1.5, 1 H, NCH2); 2.42 (s, ArMe); 1.42 (d, J ¼ 6.5, MeCHN); 1.36 (s, MeC(O)). 13C-NMR
(100 MHz, CDCl3): 143.5 (C); 134.9 (C); 129.6 (CH); 127.4 (CH); 66.5 (C); 60.1 (CH); 58.3 (CH2); 49.9
(CH); 21.5 (ArMe); 14.8 (Me); 14.7 (Me). Spectroscopic data are in accordance with those reported in
[8b].
(1S,2R,5R)-1-Ethyl-2-methyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane (11c).
The title compound was synthesized from 4-methyl-N-[(2R)-3-oxopentan-2-yl]benzenesulfonamide
(10c). Method A (achiral reagent): 11c as a white solid (33 mg, 89% yield, dr 3.8 :1 (syn/anti)); Method E
(chiral reagent): 11c as a white solid (37 mg, 66%, dr 9.5 :1, determined from MeCH2). Rf (AcOEt/PE
1
3 :7) 0.5. Data for major (syn) stereoisomer: H-NMR (400 MHz, CDCl3): 7.65 (d, J ¼ 8.0, 2 arom. H);
7.29 (d, J ¼ 8.0, 2 arom. H); 3.65 (d, J ¼ 11.5, 1 H of NCH2CH(O)); 3.45 (q, J ¼ 6.5, MeCHN); 3.43 (d, J ¼
2.0, OꢀCH); 3.23 (dd, J ¼ 11.5, 2.0, 1 H, NCH2CH(O)); 2.43 (s, ArMe); 1.72 (dq, J ¼ 15.0, 7.5, 1 H,
MeCH2); 1.64 (dq, J ¼ 15.0, 7.5, 1 H, MeCH2); 1.34 (d, J ¼ 6.5, MeCHN); 0.75 (t, J ¼ 7.5, MeCH2).
13C-NMR (100 MHz, CDCl3): 143.5 (C); 135.0 (C); 129.6 (CH); 127.4 (CH); 70.5 (C); 58.0 (CH); 57.4
(CH); 49.9 (CH2); 21.5 (ArMe); 20.9 (CH2); 15.0 (Me); 8.4 (Me). Spectroscopic data are in accordance
with those reported in [8b].
(1S,2R,5R)-2-Benzyl-1-methyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane
(11d). The title compound was synthesized from 4-methyl-N-[(2R)-3-oxo-1-phenylbutan-2-yl]benzene-
sulfonamide (10d); Method A (achiral reagent): 11d as a white solid (30 mg, 88% yield; dr 6.6 :1 (syn/
anti)); Method E (chiral reagent): 11d as a white solid (34 mg, 64%; dr 15 :1, determined from Me). M.p.

Helvetica Chimica Acta – Vol. 95 (2012)
2395
134 – 1368 (CH2Cl2/pentane). Rf (Et2O/pentane 1:1) 0.6. [a]2D4 ¼ ꢀ70 (c ¼ 0.923, CHCl3; from 15 :1
mixture of diastereoisomers). IR (film): 3020 (arom. CꢀH), 2859 (aliph. CꢀH), 1337 (CꢀO). Data for
1
major (syn) stereoisomer: H-NMR (400 MHz, CDCl3): 7.76 (d, J ¼ 8.3, 2 arom. H); 7.20 – 7.39 (m, 7
arom. H); 3.79 (dd, J ¼ 10.5, 3.5, NCHC); 3.63 (d, J ¼ 11.5, 1 H, NCH2); 3.55 (dd, J ¼ 13.5, 3.5, 1 H,
PhCH2); 3.43 (dd, J ¼ 11.5, 2.0, 1 H, NCH2); 3.34 (d, J ¼ 2.0, OꢀCH); 2.96 (dd, J ¼ 13.5, 10.5, 1 H,
PhCH2); 2.45 (s, ArMe); 0.86 (s, Me). 13C-NMR (100 MHz, CDCl3): 143.7 (C); 137.8 (C); 135.3 (C);
129.8 (CH); 129.6 (CH); 128.5 (CH); 127.4 (CH); 126.6 (CH); 66.7 (C); 64.1 (CH); 61.9 (CH); 49.5
(CH2); 37.6 (CH2); 21.5 (ArMe); 17.1 (Me). ESI-MS: 366.1 ([M þ Na]þ). HR-ESI-MS: 366.1134 ([M þ
Na]þ, C19H21NNaO3Sþ; calc. 366.1145).
(1S,2R,5R)-2-Benzyl-1-ethyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane (11e).
The title compound was synthesised from 4-methyl-N-[(2R)-3-oxo-1-phenylpentan-2-yl]benzenesulfon-
amide (10e). Method A (achiral reagent): 11e as a white solid (35 mg, 98% yield; dr 7.2 :1 (syn/anti));
Method E (chiral reagent): 11e as a white solid (39 mg, 66%, dr 15 :1, determined from Me). M.p. 91 – 938
(CH2Cl2/pentane). Rf (Et2O/pentane 4 :6) 0.4. [a]2D4 ¼ ꢀ85.5 (c ¼ 0.72, CHCl3; syn/anti 15 :1). IR (film):
3020 (arom. CꢀH), 2972 (aliph. CꢀH), 1338 (CꢀO). Data for major (syn) stereoisomer: 1H-NMR
(400 MHz, CDCl3): 7.77 (d, J ¼ 8.3, 2 arom. H); 7.19 – 7.38 (m, 7 arom. H); 3.87 (dd, J ¼ 10.5, 3.5, NCH);
3.65 (d, J ¼ 12.2, 1 H, NCH2); 3.52 (dd, J ¼ 13.5, 3.5, 1 H, PhCH2); 3.37 – 3.43 (m, 1 H, NCH2, OꢀCH);
2.99 (dd, J ¼ 13.5, 10.5, 1 H, PhCH2); 2.44 (s, ArMe); 1.20 (dq, J ¼ 15.0, 7.5, 1 H of MeCH2); 1.03 (dq, J ¼
15.0, 7.5, 1 H, MeCH2); 0.50 (t, J ¼ 7.5, MeCH2). 13C-NMR (100 MHz, CDCl3): 143.7 (C); 137.9 (C); 135.2
(C); 129.7 (CH); 129.4 (CH); 128.4 (CH); 127.3 (CH); 126.6 (CH); 71.0 (C); 62.7 (CH); 59.4 (CH); 49.6
(CH2); 37.7 (CH2); 22.7 (CH2); 21.5 (Me); 8.5 (Me). ESI-MS: 380.1 ([M þ Na]þ). HR-ESI-MS: 380.1291
([M þ Na]þ, C20H23NNaO3Sþ; calc. 380.1301).
(ꢂ)-1,2-Diphenyl-3,6-dioxabicyclo[3.1.0]hexane (11f). The title compound was synthesized from 2-
hydroxy-1,2-diphenylethanone (10f). Method A (achiral reagent): 11f as a clear oil (101 mg, 98% yield;
dr 3.2 :1 (syn/anti)). Rf (AcOEt/pentane 1:4) 0.3. IR (neat): 3021 (arom. CꢀH), 2966 (aliph. CꢀH), 1354
1
(CꢀO). Data for major (syn) stereoisomer: H-NMR (400 MHz, CDCl3): 7.04 – 7.50 (m, 10 arom. H);
4.26 – 4.38 (m, 1 H, OCH2, OCHPh); 4.02 (dd, J ¼ 11.0, 0.5, 1 H, OCH2); 3.85 (d, J ¼ 0.5, OꢀCH).
13C-NMR (100 MHz, CDCl3): 135.9 (C); 133.2 (C); 128.4 (CH); 128.3 (CH); 128.2 (CH); 128.0 (CH);
127.9 (CH); 126.4 (CH); 80.1 (C); 68.8 (CH); 67.8 (CH); 64.5 (CH2). ESI-MS: 261.1 ([M þ Na]þ). HR-
ESI-MS: 261.0886 ([M þ Na]þ, C16H14NaO2þ ; calc. 261.0895).
(1S,4S,6R)-5,5-Dimethyl-4-(4-nitrophenyl)-3,7-dioxabicyclo[4.1.0]heptane (11g). Method A with
(3S)-3-hydroxy-2,2-dimethyl-3-(4-nitrophenyl)propanal (10g), prepared according to Ley et al. [9j]
[21], afforded 11g as a clear oil (32 mg, 58%; dr 10 :1). Rf (AcOEt/pentane 2 :8) 0.6. Data for major (syn)
stereoisomer: 1H-NMR (400 MHz, CDCl3): 8.17 (d, J ¼ 8.8, 2 arom. H); 7.40 (d, J ¼ 8.8, 2 arom. H); 4.37
(s, CHOCH2); 4.31 (d, J ¼ 13.5, 1 H, CH2); 4.07 (d, J ¼ 13.5, 1 H, CH2); 3.40 (d, J ¼ 4.0, CHOCHCH2);
3.10 (d, J ¼ 4.0, CHOCHCH2); 1.03 (s, Me); 0.86 (s, Me). 13C-NMR (100 MHz, CDCl3): 147.3 (C); 145.9
(C); 128.4 (CH); 122.7 (CH); 78.4 (CH); 65.4 (CH2); 60.9 (CH); 52.7 (CH); 35.3 (C); 22.9 (Me); 17.9
(Me). Spectroscopic data are in accordance with those reported in [9j].
(1S,2S,5R)-1,2-Dimethyl-3-[(4-methylphenyl)sulfonyl]-6-oxa-3-azabicyclo[3.1.0]hexane (13). The
title compound was synthesized from (S)-3-{[(4-methylphenyl)sulfonyl]amino}butan-2-one (12) using
Method E. White solid (46% yield, dr 1:1.4 (anti/syn)). Minor diastereoisomer (anti): 1H-NMR
(400 MHz, CDCl3): 7.64 (d, J ¼ 8.0, 2 arom. H); 7.29 (d, J ¼ 8.0, 2 arom. H); 3.82 (q, J ¼ 6.5, NCH(Me);
3.59 (d, J ¼ 12.0, 1 H, NCH2); 3.51 (d, J ¼ 12.0, 1 H, NCH2); 3.30 (s, OꢀCH); 2.41 (s, ArMe); 1.36 (s,
MeC(O)); 1.35 (d, J ¼ 6.5, Me). 13C-NMR (100 MHz, CDCl3): 143.2; 135.4; 129.4; 127.5; 65.6; 60.4; 59.1;
48.0; 21.0; 18.8; 14.2. Major diastereoisomer (syn) has identical data to those of enantiomeric 11b.
Spectroscopic data are in accordance with those reported in [8b].
2-Azido-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ol (15). Prepared according to the Method by
Jimenez and co-workers [7], using 1H-indole-2-carbaldehyde (14; 342 mg, 2.0 mmol). Orange oil
(316 mg, 74%). 1H-NMR (400 MHz, CDCl3): 7.65 (dt, J ¼ 8.0, 1.0); 7.27 (ddd, J ¼ 8.0, 2.0, 1.0, 1 H); 7.23
(ddd, J ¼ 8.0, 7.0, 1.0, 1 H); 7.13 (ddd, J ¼ 8.0, 7.0, 1.0, 1 H); 6.55 (s, 1 H); 4.88 (dd, J ¼ 3.0, 1.0, 1 H); 4.76 –
4.84 (m, 1 H); 4.42 (dd, J ¼ 11.0, 5.5, 1 H); 4.01 (dd, J ¼ 11.0, 3.0, 1 H); 2.34 (br. s, OH). 13C-NMR
(100 MHz, CDCl3): 137.0; 133.0; 132.0; 122.3; 121.6; 120.0; 109.9; 96.7; 80.1; 64.7; 50.4. Spectroscopic data
are in accordance with those reported in [7].

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Helvetica Chimica Acta – Vol. 95 (2012)
(R)-N-[(E)-1H-Indol-2-ylmethylidene]-2-methylpropane-2-sulfinamide (16). A stirred soln. of
indole-2-carboxaldehyde (0.44 g, 3.0 mmol, 1 equiv.) in anh. CH2Cl2 (50 ml) was treated with (EtO)4Ti
(ca. 20% soln. in EtOH; 7.0 ml; ca. 6.1 mmol, 2 equiv.) under Ar at r.t. The soln. was then treated with
(R)-2-methylpropane-2-sulfinamide (0.40 g, 3.3 mmol, 1.1 equiv.) in a single portion. The mixture was
heated to reflux for 4 h under Ar, then allowed to cool to r.t. before quenching the reaction with an equal
volume of brine (ca. 50 ml). The resulting slurry was filtered through Celiteꢂ, washed with an excess of
CH2Cl2 (300 ml), and the filtrate was partitioned between brine and CH2Cl2. The aq. phase was further
extracted with CH2Cl2 (3 ꢁ 75 ml), and the combined org. layers were dried (MgSO4) and concentrated
under reduced pressure to give 16 as a yellow solid (0.73 g, 98%) of sufficient purity to be used in the next
step. M.p. 140 – 1428 (directly from procedure). Rf (AcOEt/PE 3 :7) 0.2. [a]2D0 ¼ þ12 (c ¼ 1.0, CH2Cl2). IR
(film): 3251 (NH), 1586 (HC¼N), 1063 (S ¼ O). 1H-NMR (400 MHz, CDCl3): 8.87 (br. d, J ¼ 1.5, NH);
8.53 (s, CH ¼ N); 7.62 (dd, J ¼ 8.0, 1.0, HꢀC(4)); 7.35 (dd, J ¼ 8.5, 1.0, HꢀC(7)); 7.26 (ddd, J ¼ 8.5, 7.0, 1.0,
HꢀC(6)); 7.08 (ddd, J ¼ 8.0, 7.0, 1.0, HꢀC(5)); 6.98 (d, J ¼ 1.5, HꢀC(3)); 1.21 (s, tBu). 13C-NMR
(100 MHz, CDCl3): 153.0 (N ¼ CH); 137.8 (C); 133.4 (C); 128.0 (C); 126.0 (CH); 122.6 (CH); 120.9
(CH); 111.9 (CH); 111.6 (CH); 57.9 (C); 22.5 (3 Me). CI-MS: 249 (100, [M þ H]þ), 192 (52, [M þ H ꢀ
tBu]þ). HR-CI-MS: 249.1055 ([M þ H]þ, C13H17N2OSþ; calc. 249.1062).
(1aR,8bR)-1-[(R)-(tert-Butyl)sulfinyl]-1,1a,2,8b-tetrahydroazireno[2’,3’:3,4]pyrrolo[1,2-a]indole
(17): A soln. of 16 (200 mg, 0.81 mmol) in anh. THF (9 ml, 0.09m) was cooled to ꢀ 208 and treated with
NaH (60% in mineral oil; 64 mg, 1.7 mmol, 2.05 equiv.). The mixture was then treated with a soln. of
3 (377 mg, 0.85 mmol, 1.05 equiv.) in THF (3 ml) dropwise over 10 min, then allowed to stir for 2 h at
ꢀ 208. The mixture was poured onto sat. NH4Cl soln. (200 ml) and extracted with Et2O (3 ꢁ 50 ml), then
the org. layers were combined, washed with H2O (3 ꢁ 75 ml), and dried (MgSO4). After concentration
under reduced pressure, the crude product was obtained as a yellow oil as a 7:1 mixture of
1
diastereoisomers (major shown) containing Ph2S as the only impurity detected by H-NMR spectrum.
The crude mixture was triturated with hexane (4ꢁ) to give 17 (160 mg, 72; > 20 :1 diastereoselectivity).
Pale-yellow solid. M.p. 139 – 1418 (dec.). Rf (AcOEt/PE 3 :7) 0.3. [a]2D0 ¼ þ8 (c ¼ 1.00, CH2Cl2). IR
1
(film): 3053 (arom. CꢀH), 2954 (aliph. CꢀH), 1072 (S ¼ O). H-NMR (400 MHz, CDCl3): 7.56 (d, J ¼
8.0, HꢀC(4)); 7.13 – 7.20 (m, HꢀC(6,7)); 7.06 (ddd, J ¼ 8.0, 6.0, 2.0, HꢀC(5)); 6.41 (s, HꢀC(3)); 4.25 (d,
J ¼ 5.5, CH(NSOtBu)CHCH2N); 4.24 (d, J ¼ 11.0, 1 H, NCH2CH); 4.19 (dd, J ¼ 11.0, 3.5, 1 H,
t
NCH2CH); 3.75 (dd, J ¼ 5.5, 3.5, NCH2CH(N-SOtBu)CH); 1.23 (s, Bu). 13C-NMR (100 MHz, CDCl3):
139.2 (C); 133.9 (C); 132.2 (CH); 121.9 (CH); 121.5 (CH); 119.7 (CH); 109.3 (CH); 95.4 (C); 57.9 (C);
t
46.5 (CH); 42.9 (CH); 32.9 (CH2); 22.8 (3 Me). CI-MS: 275 (60, [M þ H]þ), 217 (100, [M ꢀ Bu]þ). HR-
CI-MS: 275.1207 ([M þ Hþ], C15H19N2OSþ; calc. 275.1218). Anal. calc. for C15H18N2OS (274.38): C 65.66,
H 6.61, N 10.21; found: C 65.27, H 6.37, N 10.00.
Personal Reminiscences
I first met Dieter Seebach at Sheffield University in 1992, where he received one of the highest
honours the University has to offer, the ꢃFirth Lectureship and Medalꢄ. As a young lecturer, I discussed
with him about our work on the synthesis and reactions of 1,3-dithiane-1,3-dioxide. I related some of the
issues we had with this compound, and the first question Dieter asked me was ꢃWhat is the melting point
of the bis-sulfoxide?ꢄ Well, we had measured it of course, but I could not recall what it was because I had
not attached any importance to the number. Dieter did. He told me that in discussions with his group he
would ask a co-worker about the compound with a melting point of (say) 1288. They would not remember
which one he was talking about so would have to look up the relevant compound to continue the
discussion. The co-workers were astonished that he could remember everyoneꢄs melting points but often,
they could not remember their own. Dieter taught me a valuable lesson, as melting points have an impact
on solubility, an issue we were struggling with at the time. Obvious, when you think about it. I learnt not
only from this exchange but also from his many papers, which have been an important source of teaching
for me.
Thank you Dieter for your help and insight. I wish you a very happy birthday.

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Received August 12, 2012