An approach to the stereoselective synthesis of enantiopure dihydropyrroles and aziridines from a common sulfinyl-sulfinamide intermediate

Article

pubs.acs.org/joc

An Approach to the Stereoselective Synthesis of Enantiopure

Dihydropyrroles and Aziridines from a Common Sulfinyl-Sulfinamide

Intermediate

́

Alma Viso,* Roberto Fernandez de la Pradilla, Mercedes Urena, Robert H. Bates, Miguel A. del Aguila,

́

̃

and Ignacio Colomer

́

Instituto de Química Organica, IQOG−CSIC, Juan de la Cierva, 3, 28006 Madrid, Spain

S

* Supporting Information

ABSTRACT: The diastereoselective addition of lithiated vinyl

sulfoxides to enantiopure sulfinimines provides direct access to

a wide assortment of allylic sulfinamides in good yields and

excellent selectivities. These adducts are key precursors to

differently functionalized cis- and trans-dihydropyrroles.

Modulation of the protecting group on nitrogen prior to

cyclization has a significant impact on the stereochemical

outcome, allowing for the selective preparation of 2,5-cis- or

2,5-trans-3-sulfinyl disubstituted dihydropyrroles from a

common sulfinamide intermediate. Further research on

halocyclization conditions has also yielded a stereoselective synthesis of trisubstituted vinyl aziridines from these chiral

sulfinamides, simply by changing the halogenating agent.

As part of our continuing program in chiral sulfur chemistry,⁹

we recently reported the synthesis of 3-sulfinyl and 3-sulfonyl

cis-2,5-disubstituted dihydropyrroles E from chiral N-sulfinimines

A (Scheme 1).¹⁰This route involves the diastereoselective

INTRODUCTION

■

Nitrogen heterocycles are versatile building blocks, and their use

in organic synthesis has been extensively explored. In particular,

dihydropyrroles constitute an interesting class because they

allow for direct access to pyrroles and pyrrolidines.¹Currently,

there is growing interest focused on the synthesis of poly-

substituted pyrrolidines, and the stereocontrolled entry to

different diastereomers from a common starting material is

regarded as an important synthetic challenge.²Additionally, very

few efficient methods for obtaining enantiopure trans-2,5-

disubstituted pyrrolidines have been reported.³Among the

different strategies, one straightforward route to five-membered

N-heterocycles is the amino cyclization of chiral γ,δ-unsaturated

amines, and substantial research has been devoted to this

subject.⁴

Scheme 1. Diastereoselective Synthesis of 2,5-cis-

Dihydropyrroles

Similarly, enantiomerically pure aziridines are another

important class of targets in organic chemistry for their many

interesting applications and biological activities.⁵Aziridines can

also be converted into functionalized α-substituted (O, N, S, P)

amino derivatives or into other heterocycles.⁶In order to obtain

these strained rings, several efficient approaches have been

developed in recent years, mainly based on intramolecular

substitution reactions of amines or transformations of imines

and alkenes.⁷Most diastereoselective routes found in the

literature lead to mono- and disubstituted aziridines, with the tri-

and tetrasubstituted variants being less accessible. Moreover,

vinyl aziridines are useful synthetic intermediates; however,

problems associated with the control of regioselectivity and

lability under acidic conditions could arise.⁸

addition of lithiated vinyl and dienyl sulfoxides B to enantio-

pure sulfinimines A, a plausible alternative to the aza-Morita−

Baylis−Hillman reaction (Aza-MBH).¹¹Although nonracemic

N-sulfinimines have proven to be efficient chiral auxiliaries for

this reaction, the loss of selectivity for trisubstituted double

bonds and the long reaction times are still drawbacks to be

Received: October 17, 2011

Published: November 16, 2011

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The Journal of Organic Chemistry

Article

overcome. Our preliminary results showed poor stereocontrol for

the addition of B to aldehydes and sulfonimines; however, the

additional chiral sulfur of sulfinimines A provides a double

diastereoselection scenario based on two chiral sulfur atoms that

gives sulfinamides C with high stereoselectivity.

Table 1. Addition of Lithio Vinyl and Dienyl Sulfoxides to

N-Sulfinimines (R)-1 and (S)-1

In this article, we will describe a full study of the

development of this recent methodology: synthesis of new

allylic sulfinamides C (different R, R¹, and R²), preparation of a

variety of N-protected amines D, and examination of the effect

of the protecting group (P) on the cyclization step (R¹= CH

CH₂). Furthermore, we have examined the synthesis of new

enantiopure heterocycles under diverse cyclization conditions

(MCPBA/CSA, TBATB, I₂, NIS, and NBS), and we have

described some examples of their reactivity as it contributes to

expanding the scope of the initial report.^10a

a

b

entry

1

1 (R)

2 (R¹)

R-2a

3/4 (%)

dr (3:3′/4:4′)

RESULTS AND DISCUSSION

■

R-1a

(Ph)

R-1a

(Ph)

S-1a

(Ph)

R-1a

(Ph)

S-1a

(Ph)

3a

99:1

Synthesis of Enantiopure Sulfonamides. Our synthetic

approach starts by submitting a number of optically pure

sulfinimines (R)-1 and (S)-1¹²to treatment with (R_S,E)-lithio

vinyl sulfoxides (generated from (R)-2 and LDA),¹³obtaining in

all cases good to excellent yields (55−91%) and moderate to high

diastereoselectivities of allylic sulfinamides 3 and 4 (Table 1).

The scope of the reaction was examined by varying not only

the absolute configuration of the sulfinimine sulfur (R or S), but

also the nature of the R group, including aryls, linear and

branched alkyls, alkenyls, and quaternary centers from sulfinyl

ketimines (Table 1, (R)-1a−k, (S)-1a−n). In addition, aryl,

alkyl, and alkenyl substitutions at vinyl sulfoxide (R)-2a−c gave

outstanding yields and selectivities (91:9−99:1) for the

matched pair. These results highlight the crucial role of the

absolute configuration of the sulfinimine in the process because

both the yields and selectivities increased when aldimines (R)-1

were employed (Table 1, entries 1, 2, 4, 6−10, and 13−16,

matched pairs). Table 1 clearly illustrates the broad substrate

scope under these general conditions. Also, with the aim of

improving the outcome for the mismatched pair, bulkier mesityl

sulfinimine (S)-1g was synthesized, and a slight increase in the

selectivity to 85:15 was observed (compare Table 1 entries 11

and 12).

(Ph)

(55)

3b

2

R-2b

(ⁿBu)

91:9

82:18

99:1

87:13

99:1

94:6

99:1

75:25

85:15

99:1

1:99

c

(90)

4b

3

R-2b

(ⁿBu)

(69)

3c

4

R-2c

(CHCH₂)

(95)

4c

5

R-2c

(CHCH₂)

R-2c

(91)

3d

6

R-1b

(1-naphth)

R-1c

(CHCH₂)

(70)

3e

7

R-2c

(p-MeOC₆H₄)

R-1d

(CHCH₂)

R-2c

(70)

3f

8

(3,4-(MeO)₂C₆H₃)

R-1e

(CHCH₂)

(75)

3g

9

R-2c

(p-CF₃C₆H₄)

R-1f

(CHCH₂)

R-2c

(86)

3h

10

11

12

13

14

15

16

17

18

19

(ⁱPr)

(CHCH₂)

(93)

4h

S-1f

(ⁱPr)

R-2c

(CHCH₂)

R-2c

(69)

4i

S-1g

(ⁱPr)

d

(CHCH₂)

(72)

3j

In contrast with these results, when sulfinyl ketimine (S)-1l

was submitted to the addition of lithiated dienyl sulfoxide

(R)-2c, we observed a high diastereoselectivity (1:99, 4n:4n′,

Table 1, entry 17), although a significant amount of starting

material was also recovered, probably because of the

competitive deprotonation of the ketimine. However, we did

not find a similar result for the enantiomeric ketimine (R)-1l, as

only complex crude mixtures containing starting material and

various byproducts were obtained.¹⁴This observation suggests

an inversion in the matched/mismatched pair for sulfinyl

ketimines.¹⁵More electron-deficient sulfinyl ketimines (S)-1m

and (S)-1n were employed and provided the same high

diastereoselectivity. In the case of (S)-1n, a slight increase in

reactivity was also observed (Table 1, entries 18 and 19).

As we described previously, the observed stereochemical out-

come can be explained in terms of the preferred S-cis conforma-

tion of N-sulfinyl aldimine and through a rigid transition state

in which lithium coordinates to the oxygens of both the

sulfoxide and the sulfinimine (Figure 1). Thus, the two chiral

sulfinyl groups are each positioned to influence the stereo-

chemical outcome, providing the high selectivities.^10aHence,

the nucleophilic addition takes place mostly anti to the p-tolyl

group of the sulfinyl aldimine onto the re-face of (R)-1 for the

R-1h

(ⁿBu)

R-2c

(CHCH₂)

R-2c

(98)

3k

R-1i

(Cy)

(CHCH₂)

(68)

3l

R-1j

R-2c

(Ph(CH₂)₂)

R-1k

(CHCH₂)

R-2c

(68)

3m

(62)

4n′

(E-Ph(CHCH))

(CHCH₂)

S-1l

R-2c

e

f

(Ph, Me)

(CHCH₂)

R-2c

(50)

S-1m

4o′

e

f

(p-NO₂Ph, Me)

(CHCH₂)

(51)

S-1n

R-2c

4p′

1:99

e

f

(p-CNPh, Me)

(CHCH₂)

(48)

a

b

c

1

Combined yield. Ratio determined by H NMR analysis. 3.0 equiv

of LDA and 1 were employed. S-1g: (+)-(S)-2,4,6-trimethyl-N-[(1E)-

2-methylpropylidene] benzenesulfinamide. A sulfinyl ketimine was

employed as starting material. Starting material R-2c was always

d

e

f

recovered in these experiments (S-1l: 40%, S-1m: 45%, S-1n: 35%).

matched pair or the si-face of (S)-1 for the mismatched pair.

Interestingly, in terms of facial discrimination, sulfinimines

behave similarly to the addition of α-sulfinyl carbanions,¹⁵

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Scheme 3. One-Pot Preparation of Hydroxymethyl

Dihydropyrroles 9 and 10 from 3

Figure 1. Stereochemical outcome of the addition of (R)-2 to N-

sulfinimines (R)-1 and (S)-1.

vinylaluminum reagents,^11gand α-imino enolates^9fbut opposite

to Baylis−Hillman nucleophiles^11c,dand other enolates.^10b

Subsequent cleavage of sulfinamides 3 and 4 under acidic

conditions¹⁶provided allylic amines 5 and 6, respectively

(Scheme 2). Also, desulfinylation of mixtures of 4h:4h′ to give

mixtures of oxiranes with camphorsulfonic acid (CSA) led to an

identical ratio of cyclized products.¹⁹Nevertheless, in situ

cyclization by reaction with a catalytic amount of CSA provided

9 and 10 in moderate yields and diastereoselectivities, with the

2,5-cis dihydropyrroles 9c and 9h being predominant. The

stereochemical assignment was based on an X-ray analysis of

the dihydropyrroles (see the Supporting Information).

Scheme 2. Synthesis of Diastereomeric Amines 5 and 6 and

Their Protected Derivatives 7 and 8

Hoping to preserve the sulfoxide moiety and after

considerable experimentation, we attempted the halocyclization

with tetrabutylammonium tribromide (TBATB) and K₂CO₃

(Scheme 4). In the cases of 3c, 7a (R = Ph, P = Boc), and 8a,b

Scheme 4. Stereochemical Outcome for Bromomethyl

Dihydropyrroles with TBATB

i

6h:5h (R = Pr, R¹= CH₂CH) allowed us to establish that

each pair of sulfinamides (3:3′ and 4:4′) were diastereomers at

C-1. It should be noted that 5h obtained by this method was

identical to the amine obtained by desulfinylation of 3h.

The major allylic amines 5 and 6 were further protected

using different sulfonyl chlorides and Boc₂O to afford products

7 and 8 in good yields (Scheme 2). Our efforts to synthesize

sulfonamides in a single step by selective oxidation of the

sulfinamide in the presence of the sulfoxide moiety failed.¹⁷

Synthesis of cis- and trans-2,5-Substituted Dihydro-

pyrroles. In order to obtain hydroxymethyl dihydropyrroles 9

and 10, sulfinamides 3c and 3h were treated with m-CPBA¹⁸in

toluene (Scheme 3). We observed a fast oxidation of both

sulfinyl groups followed by slow epoxidation at the distal

double bond. We determined that the epoxidation controls the

selectivity of the process because the cyclization of isolated

(R = Ph, P = Boc, Ts), complex mixtures were obtained. In

contrast, we could obtain the desired 3-sulfinyl bromomethyl

dihydropyrroles 2,5-cis-11 and 2,5-trans-12 by installing a more

acidic sulfonamido group onto the nitrogen of diastereomers

7.²⁰Moreover, we were delighted to detect the formation of a

major product 2,5-cis-11 for aryl and alkyl p-tolylsulfonamides

7b,c,d (Table 2, entries 1−3). The absolute configuration of the

bromomethyl pyrroles was unequivocally assigned by X-ray

analysis of 12a.^10aInterestingly, moderately fast disappearance

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Table 2. Stereoselective Synthesis of 2,5-cis- and 2,5-trans-Halomethyl Dihydropyrroles

a

entry

1

compd

R

P

conditions

ratio cis:trans

cis (%)

trans (%)

7b

Ph

ⁱPr

ⁿBu

Ph

Ts

TBATB/K₂CO₃

CH₂Cl₂

80:20

11a

(56)

11b

(48)

11c

(57)

11d

(41)

11e

(49)

11f

12a

(15)

12b

(9)

2

7c

7d

7e

7f

TBATB/K₂CO₃

CH₂Cl₂

87:13

90:10

80:20

20:80

10:90

56:44

78:22

73:27

35:65

42:58

56:44

b

3

TBATB/K₂CO₃

CH₂Cl₂

12c

4

o-NO₂C₆H₄SO₂

2,4,6-ⁱPr₃C₆H₂SO₂

8-quinolylSO₂

1-naphthSO₂

2-pyridylSO₂

Ts

TBATB/K₂CO₃

CH₂Cl₂

12d

(17)

12e

(8)

5

TBATB/K₂CO₃

CH₂Cl₂

6

7g

7h

7i

TBATB/K₂CO₃

CH₂Cl₂

12f

(14)

11g

(9)

(49)

12g

(65)

12h

7

3,4-(MeO)₂C₆H₃

TBATB/K₂CO₃

CH₂Cl₂

8

ⁱPr

TBATB/K₂CO₃

CH₂Cl₂

11h

c

(57)

9

7j

Ph

TBATB/K₂CO₃

CH₂Cl₂

11i

12i

c

(50)

10

11

12

13

14

7k

Ph

TBATB/K₂CO₃

CH₂Cl₂

11j

12j

(46)

(16)

d

b

e

7l

Ph/Me

Ph

TBATB/K₂CO₃

CH₂Cl₂

11k

12k

(43)

14a

7b

Ts

I₂/K₂CO₃

13a

(23)

13a

(39)

13a

(8)

CH₃CN−H₂O

NIS/K₂CO₃

CH₂Cl₂

(43)

14a

Ph

Ts

(32)

14a

Ph

Ts

NIS/K₂CO₃

21:79

toluene

(65)

a

b

c

d

Room temperature while stirring for 2−7 days was employed in all experiments. Not isolated. Combined yield of both isomers. 7l (S-

e

configuration in C-2) was prepared from 4n′ in two steps. The sulfonamido moiety is attached to a quaternary center. 12k is assigned as (2S,5R).

i

of the starting material (1−2 days) does not provide the

dihydropyrroles, but instead leads to mixtures of dibromo

adducts (Scheme 4, 15′). Then, these intermediates slowly

cyclize (1−5 days) into the final products. Other solvents

(CHCl₃, CH₃CN, THF), bases (Et₃N, DBU, KO^tBu), and

bromine sources (Br₂, PhMe₃NBr₃, BnMe₃Br₃, DMAPHBr₃)

were tried to increase the reaction rate, but no significant

improvements in rate, yield, or selectivity could be obtained.

At this point, the influence of the sulfonyl substituent on the

cyclization step was explored, and thus we tested different

sulfonamides 7e−g (R = Ph, Table 2, entries 4−6). Although

electronic and steric factors in 7e and 7f did not appreciably

affect the ratio of 11 and 12, the overall yield was slightly

reduced. More surprising for us was the inversion in ratio

observed upon changing from p-tolyl (7b) to 8-quinolyl

sulfonamide (7g and 7h), leading to the 2,5-trans isomers 12f

and 12g as the major products (Table 2, entries 1 vs 6 and 7).

The absolute configuration of the new stereogenic carbon and

the configurational stability of the sulfinyl group under the

reaction conditions were confirmed by X-ray crystallography of

12f. Unfortunately, the effect of the 8-quinolyl sulfonamido

group is limited to aromatic substrates (R = Ar), as the reaction

with 7i (R = Pr) is virtually nonselective, providing a 56:44

cis:trans ratio (Table 2, entry 8). The unique behavior of the

8-quinolyl sulfonamido group is evidenced by the ratios found

for 7j (P = 1-naphthSO₂) and 7k (P = 2-pyridylSO₂) because

2,5-cis-dihydropyrroles 11i and 11j were obtained as major

products (Table 2, entries 9−10). The above results indicate

that along with possible π-stacking effects (R = Ar/P = 8-

quinolylSO₂), the position of the nitrogen in the quinoline ring

could determine the diastereomeric outcome of the reaction.

Sulfonamide 7l, with an additional methyl group at the

sulfonamido position (C-2, 2S), was also submitted to the

bromocyclization reaction, giving a slightly lower yield of a

35:65 mixture of dihydropyrroles. The major product was

tentatively assigned as 2,5-trans-12k (Ph trans to CH₂Br) by

comparison of the ¹H NMR data with other compounds of the

series (Table 2, entry 11).

Finally, iodine was examined as an alternative halogen source

in the synthesis of dihydropyrroles (Table 2, entries 12−14).

Molecular iodine provides a modest selectivity for the 2,5-trans-

14a (42:58) that is reversed toward 2,5-cis-13a by using NIS in

CH₂Cl₂(56:44). However, the nature of the solvent is crucial

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because changing to toluene resulted in a 21:79 mixture of

iodomethyl dihydropyrroles 13a and 14a.

should be mentioned that the pure heterocycles are stable and

can be stored at room temperature without isomerization.

A thorough inspection of the ¹H NMR data of the

dihydropyrroles shows, in general, a remarkable difference in

the value of J_H2−H5values of the 2,5-cis (0−2.6 Hz) versus the

2,5-trans series (4.6−5.9 Hz). Also, the shifts of the methylene

protons (CH₂X) are higher in the 2,5-trans- than in the 2,5-cis-

dihydropyrroles (Δδ = 0.4−0.5 ppm for each methylenic

proton). In addition, along with the X-ray analysis, some

transformations were performed to extend the stereochemical

assignments to the iodomethyl and the hydroxymethyl

dihydropyrroles. Thus, treatment of cis-iodomethyl dihydro-

pyrrole 13a with tributyltin hydride/AIBN led to the 5-methyl

pyrroline 16a in good yield, and NOE experiments on this

derivative confirmed a 2,5-cis arrangement (Scheme 6).

As mentioned above, when the bromocyclizations were

quenched at short reaction times, primarily mixtures of

dibromo intermediates 15′ were isolated in variable ratios

(Scheme 4). Interestingly, we found that the diastereomeric

ratios of these dibromo intermediates did not correspond to the

final cis:trans ratios of the cyclized products (e.g., a 56:44

mixture of dibromo adducts from 7b (R = Ph, P = Ts) led to an

80:20 mixture of 11a:12a). This disparity between intermedi-

ates and products along with the isolation of trace amounts of

vinyl bromide 15 led us to speculate about the possibility of

equilibrium between dibromo diastereomers under the reaction

conditions.²¹The nature of the sulfonamido group (P) would

then determine which dibromo adduct cyclizes faster to the

dihydropyrrole. Thus, although transition states I are favored

from a steric point of view (Ph, P, CH₂Br in anti relative

arrangement), it is possible that by modifying the nature of P,

transition states II become more stabilized, thus providing

2,5-trans-12 as the major product. In the latter case, π,π-

stacking between the quinolyl and phenyl groups and chelation

of K cations to both nitrogen atoms (quinoline and

sulfonamide) could contribute to this outcome.

Scheme 6. Structural Correlation of Dihydropyrroles

In addition, we have evidenced that TBATB has a relevant

impact on the efficiency and rate of the cyclization as treatment

of the dibromo intermediates (from 7b) with K₂CO₃gave only

complex mixtures of products. Other bases such as DBU or

DABCO produced only small amounts of 11 and 12.

Alternatively, when 7b was treated with I₂or NIS iodomethyl

pyrrolidines 13a and 14a were isolated. The best diastereo-

selectivity was achieved using NIS/K₂CO₃in toluene (21:79)

to provide 2,5-trans-14a as the major dihydropyrrole (Table 2,

entry 14). Since diiodo intermediates were not detected under

these conditions, a common iodonium mechanism could be

operating in this case. Scheme 5 depicts the approach of iodine

Moreover, 11a and 14a were oxidized with m-CPBA to yield

3-sulfonyl dihydropyrroles 17 and 18 in moderate to good

yields (Scheme 6), whereas reaction of hydroxymethyl

dihydropyrroles 9c and 10c with CBr₄and I₂, respectively,

also led to the corresponding halocycloadducts 17 and 18, thus

correlating the stereochemistry of both the cis (9, 11, 13) and

trans products (10, 12, 14).

Scheme 5. Reaction Course for Iodocyclization

Synthesis of N-Sulfinyl Aziridines. While probing the

use of other halogenating reagents, we examined the reaction of

sulfinyl sulfonamide 7b with NBS/K₂CO₃(Scheme 7). To our

Scheme 7. Diastereoselective Synthesis of Trisubstituted

Aziridines

to the distal double bond. Coordination of the sulfoxide

(oxygen) and the sulfonamide (proton) in a nonpolar solvent

such as toluene could determine the reactive conformer of the

substrate. A possible epimerization from cis (13a) to trans

product (14a) under the reaction/isolation conditions is ruled

out. Equilibration between the diastereoisomers only occurs

after refluxing in toluene for 2 days, and the thermodynamic

ratio for 13a:14a was determined to be 62:38.²²In addition, it

surprise, sulfinyl aziridine 19a was isolated as a single

diastereoisomer (55%) along with minor amounts of 2,5-cis- and

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2,5-trans-dihydropyrroles 11a and 12a (45:55, 16%) (Scheme 7).²³

The relative configuration of the new stereogenic center

was assigned by NOE experiments. Alkyl derivatives 7c and

7d were also submitted to the reaction conditions with

N-bromosuccinimide; however, an 80:20 mixture of aziridines

19b,c and 20b,c, diastereomers at the sulfur atom, were isolated

after chromatographic purification.²⁴The epimerization at sulfur

through the process was confirmed by oxidation of mixtures of

19 and 20 with magnesium monoperoxyphthalate (MMPP) to

afford 21b and 21c as single diastereoisomers. The synthesis of

sulfinyl vinyl aziridines under these conditions is a notable

achievement; however, it should be mentioned that both the

purity of the starting material and the source of NBS appear to

be crucial requirements for the reaction to succeed.²⁵The

aziridine cyclization could be understood by the absence of an

effective bromide source that would allow for the sulfonamide

cyclization onto the bromonium intermediate at the distal double

bond.⁷ⁱStrict stereoelectronic requirements would lead primarily

to the formation of the aziridine ring (S_N2′ cyclization) as a

single diastereoisomer along with small amounts of dihydro-

pyrroles (S_N2 cyclization). Interestingly, the aziridine cyclization

does not take place on the simple allylic sulfonamide 7a, derived

from 3a where a single double bond instead of a diene moiety is

present. Although sulfonamides are known to react with NBS to

form N−Br compounds, we could not detect any sign of N−Br

intermediates whose presence might slow down the rate of

cyclization.^4c,26

In conclusion, we have extended the scope of the methodo-

logy for the preparation of enantiopure 2-sulfinyl allylic

sulfinamides from readily available sulfinimines and α-metalated

vinyl and dienyl sulfoxides, evidencing the generality of the

process that allows for the synthesis of allylic amines and

sulfonamides for a broad number of substrates with high yields

and diastereoselectivities. In addition, we have studied in depth

different protocols for aminocyclizations to afford sulfinyl and

sulfonyl dihydropyrroles. Importantly, we have found that the

sulfonamido group has a significant influence on the stereo-

chemical outcome of the bromocyclization, allowing for the

selective preparation of 2,5-cis- or 2,5-trans-3-sulfinyl disub-

stituted dihydropyrroles from a common sulfinamide inter-

mediate. On the other hand, a highly diastereoselective route

for the synthesis of trisubstituted vinyl aziridines has been

found using NBS as source of bromine. Further applications of

these cyclizations to the synthesis of bioactive products are

currently under exploration in our laboratory.

EXPERIMENTAL SECTION

■

1. Materials and Methods. ¹H and ¹³C NMR spectra were

recorded at 300, 400, or 500 MHz (¹H) using CDCl₃as solvent and

with the residual solvent signal as internal reference (CDCl₃, 7.24 and

77.0 ppm) unless otherwise noted. Optical rotations were measured at

20 °C in CHCl₃solution using a sodium lamp. Low- and high-

resolution mass spectra were recorded using the electronic impact

technique with ionization energy of 70 eV or using the electrospray

(ESI) chemical ionization techniques in its positive or negative

modes. Vinyl and dienyl sulfoxides were prepared as E/Z mixtures

that completely isomerized to the E isomer upon lithiation.¹³

N-Sulfinimines¹²and (S)-2,4,6-trimethylbenzenesulfinamide²⁹were

prepared as described in the literature. Compounds 3b,c,h,j, 5c,h,

4b,c,h, 6c,h, 9c, 10c, 7b−d, 8a, 11a−c, and 17 were already reported.^10a

2. General Procedure for the Synthesis of Vinyl Sulfina-

mides. A round-bottomed flask was charged with THF (3.5 mL/

mmol) and 2.1 equiv of freshly distilled i-Pr₂NH and cooled to −78

°C. To the above solution was added 2.0 equiv of n-BuLi, and the

resulting LDA solution was stirred at this temperature. After 10 min, a

solution of 1.0 equiv of a Z/E mixture of vinyl or dienyl sulfoxides in

THF (2 mL/mmol), previously dried over 4 Å sieves, was added

slowly dropwise (ca. 8 min/mmol of sulfoxide) to produce a pale

yellow solution. After stirring for an additional 10 min at −78 °C, 2.0

equiv of N-sulfinimine in THF (2 mL/mmol) was added dropwise,

and the resulting colorless solution was stirred at this temperature for

10 min. The reaction mixture was quenched with a saturated solution

of NH₄Cl (2 mL/mmol) and H₂O (2 mL/mmol) and diluted with

EtOAc (3 mL/mmol). The layers were separated, and the aqueous

layer was extracted with EtOAc (3 times, 4 mL/mmol). The combined

organic extracts were washed with a saturated solution of NaCl (4 mL/

mmol), dried over Na₂SO₄, and concentrated under reduced pressure

to give a crude product that was purified by column chromatography

using the appropriate mixture of eluents. In most cases, recovery of the

excess N-sulfinimine was straightforward.

Seeking to explore the chemoselective transformations of

these highly functionalized aziridines, we submitted 19a to

bromide displacement with piperidine to afford sulfinyl aziridine

22 in 71% yield (Scheme 8). Ozonolysis protocols were then

Scheme 8. Chemoselective Transformations of

Trisubstituted Aziridines

2.1. Synthesis of (−)-(R)-N-[(1S,2E)-2-((S)-p-Tolylsulfinyl)-1,3-

diphenyl-2-propen-1-yl]-4-methylbenzenesulfinamide, 3a. From

an E/Z mixture of vinyl sulfoxides R-2a (59 mg, 0.24 mmol, 1.0

equiv) with 2.0 equiv of LDA and sulfinimine R-1a (124 mg, 0.51

mmol, 2.0 equiv), following the general procedure, 3a was obtained as

a single isomer. Chromatographic purification (10−50% EtOAc/hex)

gave 3a (65 mg, 55%) as a colorless oil.

attempted on sulfonyl aziridines 21b and 21c with the aim of

transforming the allylic bromide into a carboxylic acid moiety.

However, ozonolysis at room temperature in acetone/H₂O led

to a 90:10 mixture of the aldehyde 23b and 2,3-cis-ditosyl

aziridine 24b, produced by decarboxylation of the carboxylic

acid (not shown). The value of 6.8 Hz for J_H2−H3in 24b

indicates that the stereochemistry of the aziridine is preserved.²⁷

The use of milder reaction conditions for 21c by lowering the

temperature (−78 °C) and quenching with SMe₂did not

influence the result. Mixtures of 23bc and 24bc were then fully

oxidized with TCCA²⁸(trichloroisocianuric acid) to afford

ditosyl aziridines 24b and 24c as single isomers in good yields.

Data for 3a: R_f0.10 (40% EtOAc/hex); [α]²⁰_D−57.8 (c = 1.17); ¹H

NMR (CDCl₃, 300 MHz) δ 2.33 (s, 3 H), 2.34 (s, 3 H), 5.13 (d, 1 H,

J = 6.3 Hz), 5.89 (d, 1 H, J = 6.3 Hz), 7.14−7.17 (m, 9 H), 7.27−7.36

(m, 6 H), 7.40 (dt, 2 H, J = 8.3, 1.8 Hz), 7.45 (dt, 2 H, J = 8.3, 1.8

Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.3, 21.4, 56.1, 125.4 (2 C),

126.2 (2 C), 126.8 (2 C), 127.6, 128.5 (2 C), 128.6, 128.7 (2 C),

129.0 (2 C), 129.4 (2 C), 129.9 (2 C), 133.4, 133.9, 138.5, 140.0,

141.1, 141.4, 142.1, 146.3; IR (film) 3191, 3056, 3020, 2920, 1594,

530

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1492, 1448, 1400, 1176, 1085, 1051, 1014, 810, 752, 697 cm⁻¹; MS

(ESI) 486 [M + 1]⁺(100%), 993 [2M + Na]⁺. Anal. Calcd for

C₂₉H₂₇NO₂S₂: C, 71.72; H, 5.60; N, 2.88; S, 13.20. Found: C, 71.85;

H, 5.25; N, 2.47; S, 13.02.

2.2. Synthesis of (−)-(R)-N-[(1S,2E)-2-((S)-p-Tolylsulfinyl)-1-(1-

naphthyl)-2,4-pentadien-1-yl]-4-methylbenzenesulfinamide, 3d. From

an E/Z mixture of dienyl sulfoxides (45 mg, 0.23 mmol, 1.0 equiv)

with 2.0 equiv of LDA and sulfinimine R-1b (184 mg, 0.46 mmol, 2.0

equiv), following the general procedure, 3d was obtained as a single

isomer. Chromatographic purification (20−50% EtOAc/hex) gave 3d

(78 mg, 70%) as a colorless oil.

Chromatographic purification (20−50% EtOAc/hex) provided major

diastereomer 3g (208 mg, 86%) as a colorless oil.

Data for 3g: R_f0.2 (50% EtOAc/hex); [α]²⁰_D−74.7 (c = 2.00); ¹H

NMR (CDCl₃, 300 MHz) δ 2.26 (s, 3 H), 2.29 (s, 3 H), 5.24 (d, 1 H,

J = 5.5 Hz), 5.53 (dd, 1 H, J = 9.8, 1.3 Hz), 5.61 (dd, 1 H, J = 16.5, 1.3

Hz), 5.73 (d, 1 H, J = 5.5 Hz), 6.77 (ddd, 1 H, J = 16.5, 11.3, 9.8 Hz),

6.95 (d, 1 H, J = 11.3 Hz), 7.03−7.14 (m, 6 H), 7.22−7.25 (m, 4 H),

7.45 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz) δ 21.1, 48.6, 53.7, 125.0

(q, J = 3.8 Hz), 125.3 (2 C), 125.8 (2 C), 126.3, 127.3 (q, J = 272 Hz),

127.5 (2 C), 129.6 (2 C, q, J = 39 Hz), 129.4 (2 C), 129.8 (2 C),

129.9, 133.7, 139.3, 141.2, 141.6, 142.1, 142.7, 144.5; IR (film) 3648,

3173, 2925, 2870, 1618, 1595, 1445, 1416, 1380, 1326, 1265, 1164,

1068, 932, 838, 736, 704 cm⁻¹; HRMS (ESI) m/z for C₂₆H₂₅F₃NO₂S₂

[M + H]⁺calcd 504.1279, observed 504.1280.

Data for 3d: R_f0.21 (60% EtOAc/hex); [α]²⁰_D−32.6 (c = 1.23); ¹H

NMR (CDCl₃, 300 MHz) δ 2.10 (s, 3 H), 2.92 (s, 3 H), 4.52 (d, 1 H,

J = 2.1 Hz), 5.70 (dd, 1 H, J = 9.7, 1.6 Hz), 5.80 (dd, 1 H, J = 16.3, 1.6

Hz), 6.40 (d, 1 H, J = 2.2 Hz), 6.71 (d, 2 H, J = 7.9 Hz), 6.96 (dt, 2 H,

J = 8.2, 1.9 Hz), 7.13−7.24 (m, 4 H), 7.24−7.42 (m, 4 H), 7.54−7.64

(m, 4 H), 7.72 (dd, 1 H, J = 7.9, 1.2 Hz); ¹³C NMR (CDCl₃, 75

MHz)-HSQC δ 21.1, 21.2, 49.9, 122.1, 124.6, 125.0 (2 C), 125.2 (2

C), 125.5 (2 C), 126.3, 126.6, 128.5, 128.9 (2 C), 129.2, 129.3 (2 C),

130.0, 130.2, 132.1, 133.4, 134.1, 138.5, 141.1 (2 C), 141.5, 143.1; IR

(film) 3050, 2949, 2924, 2849, 1594, 1491, 1458, 1376, 1085, 1049,

805, 776, 758 cm⁻¹; MS (ESI) 508 [M + Na]⁺(100%), 993 [2M +

Na]⁺; HRMS (ESI) m/z for C₂₉H₂₈NO₂S₂[M + H]⁺calcd 486.1561,

observed 486.1552.

2.6. Synthesis of (+)-(S)-N-[(1R,2E)-1-Isopropyl-2-((S)-p-tolylsul-

finyl)-2,4-pentadien-1-yl]-2,4,6-trimethylbenzenesulfinamide, 4i,

and (S)-N-[(1S,2E)-1-Isopropyl-2-((S)-p-tolylsulfinyl)-2,4-pentadien-

1-yl]-2,4,6-trimethylbenzenesulfinamide, 4i′. From an E/Z mixture

of dienyl sulfoxides 2c (80 mg, 0.42 mmol, 1.0 equiv) with 2.0 equiv of

LDA and sulfinimine S-1g (208 mg, 0.88 mmol, 2.0 equiv), following

the general procedure, an 85:15 mixture of 4i:4i′ was obtained.

Chromatographic purification (10−50% EtOAc/hex) gave the mixture

of isomers 4i:4i′ (128 mg, 72%) as a colorless oil. Crystallization (2:1

Et₂O/hex) of this fraction led to 4i as a white solid (102 mg, 57%).

Data for 4i: R_f0.21 (40% EtOAc/hex); mp 118 °C; [α]²⁰+194.7

D

2.3. Synthesis of (−)-(R)-N-[(1S,2E)-1-(4-Methoxyphenyl)-2-((S)-p-

tolylsulfinyl)-2,4-pentadien-1-yl]-4-methylbenzenesulfinamide,

3e. From an E/Z mixture of dienyl sulfoxides 2c (92 mg, 0.476 mmol,

1.0 equiv) with 2.0 equiv of LDA and sulfinimine R-1d (260 mg, 0.951

mmol, 2.0 equiv), following the general procedure, compound 3e was

obtained as a single diastereomer. Chromatographic purification (20−

55% EtOAc/hex) provided 3e (156 mg, 70%) as a white solid.

1

(c = 0.69); H NMR (CDCl₃, 500 MHz) δ 0.84 (d, 3 H, J = 6.6 Hz),

1.05 (d, 3 H, J = 6.6 Hz), 1.98 (m, 1 H), 2.25 (s, 3 H), 2.26 (s, 3 H),

2.31 (s, 6 H), 3.95 (d, 1 H, J = 6.8 Hz), 4.08 (dd, 1 H, J = 9.3, 7.2 Hz),

5.47 (d, 1 H, J = 10.0 Hz), 5.60 (d, 1 H, J = 16.6 Hz), 6.81 (m, 3 H),

7.00 (m, 3 H), 7.40 (d, 2 H, J = 8.1 Hz); ¹³C NMR (CDCl₃, 75 MHz)

δ 19.0 (2 C), 19.9, 20.0, 20.9, 21.3, 32.4, 60.3, 124.9, 125.5 (2 C),

127.2, 129.7 (2 C), 130.0, 130.4 (2 C), 132.3, 135.9, 138.4, 139.9,

140.2, 141.9, 145.6; IR (KBr) 3233, 2964, 2926, 2867, 1600, 1492,

1466, 1081, 1048, 927, 851, 810, 754, 664 cm⁻¹; MS (ESI) 430 [M +

1]⁺(100%), 452 [M + Na]⁺, 881 [2M + Na]⁺. Anal. Calcd for

C₂₄H₃₁NO₂S₂: C, 67.09; H, 7.27; N, 3.26; S, 14.93. Found: C, 66.86;

H, 7.04; N, 3.07; S, 14.81.

Data for 3e: R_f0.15 (50% EtOAc/hex); mp 155 °C; [α]²⁰−18.4

D

(c = 2.60); ¹H NMR (CDCl₃, 300 MHz) δ 2.32 (s, 3 H), 2.37 (s, 3 H),

3.71 (s, 3 H), 4.51 (br d, 1 H, J = 4.9 Hz), 5.49 (dd, 1 H, J = 9.9, 1.4

Hz), 5.57 (d, 1 H, J = 4.6 Hz), 5.59 (dd, 1 H, J = 16.6, 1.5 Hz), 6.64

(m, 2 H), 6.78 (ddd, 1 H, J = 16.6, 11.2, 9.9 Hz), 6.98 (d, 1 H, J = 11.2

Hz), 7.00 (m, 2 H), 7.15 (m, 2 H), 7.23 (m, 2 H), 7.37 (m, 2 H), 7.53

(m, 2 H); ¹³C NMR (CDCl₃, 75 MHz) δ 21.4, 21.5, 55.2, 55.3, 114.0

(2 C), 125.3 (2 C), 125.5, 126.1 (2 C), 129.6 (2 C), 129.9 (2 C),

130.5 (2 C), 130.7, 130.8, 132.9, 139.8, 141.8, 141.8, 142.0, 145.4,

159.2; IR (KBr) 3436, 3191, 2924, 1610, 1511, 1493, 1455, 1304,

1249, 1178, 1090, 1048, 1016, 931, 810, 705, 624, 533 cm⁻¹; HRMS

(ESI) m/z for C₂₆H₂₈NO₃S₂[M + H]⁺calcd 466.1511, observed

466.1532.

Partial data for 4i′: ¹H NMR (CDCl₃, 300 MHz) δ 4.39 (br s, 1 H),

7.66 (d, 2 H, J = 8.3 Hz).

2.7. Synthesis of (+)-(R)-N-[(1S,2E)-1-Cyclohexyl-2-((S)-p-tolylsul-

finyl)-2,4-pentadien-1-yl]-4-methylbenzenesulfinamide, 3k. From

an E/Z mixture of dienyl sulfoxides 2c (463 mg, 2.41 mmol, 1.0

equiv) with 2.0 equiv of LDA and sulfinimine R-1i (1.25 g, 4.81 mmol,

2.0 equiv), following the general procedure, compound 3k was

obtained as a single diastereomer. Chromatographic purification (25−

50% EtOAc/hex) provided 3k (729 mg, 69%) as a white solid.

2.4. Synthesis of (−)-(R)-N-[(1S,2E)-1-(3,4-Dimethoxyphenyl)-2-

((S)-p-tolylsulfinyl)-2,4-pentadien-1-yl]-4-methylbenzenesulfina-

mide, 3f. From an E/Z mixture of dienyl sulfoxides 2c (2.70 g, 14.2

mmol, 1.0 equiv) with 2.0 equiv of LDA and sulfinimine R-1d (8.56 g,

28.3 mmol, 2.0 equiv), following the general procedure, compound 3f

was obtained as a single diastereomer. Chromatographic purification

(20−55% EtOAc/hex) provided 3f (5.27 g, 75%) as a white solid.

Data for 3f: R_f0.10 (50% EtOAc/hex); mp 71−73 °C; [α]²⁰_D−24.2

(c = 0.95); ¹H NMR (CDCl₃, 300 MHz) δ 2.30 (s, 3 H), 2.36 (s, 3 H),

3.65 (s, 3 H), 3.78 (s, 3 H), 4.53 (br d, 1 H, J = 4.9 Hz), 5.47 (d, 1 H,

J = 9.9), 5.57 (d, 1 H, J = 4.7 Hz), 5.60 (d, 1 H, J = 14.1 Hz), 6.51 (d,

1 H, J = 0.8 Hz), 6.60 (d, 1 H, J = 8.4 Hz), 6.69 (dm, 1 H, J = 8.2 Hz),

6.70−6.80 (m, 1 H), 7.01 (d, 1 H, J = 11.3 Hz), 7.13 (d, 2 H, J = 8.4

Hz), 7.22 (d, 2 H, J = 8.5 Hz), 7.36 (d, 2 H, J = 8.2 Hz), 7.52 (d, 2 H,

J = 8.2 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.6, 27.1, 55.5, 55.9, 56.1,

110.6, 119.8, 125.5 (2 C), 125.8, 126.1 (2 C), 129.7 (2 C), 130.1 (2

C), 130.7, 131.4, 133.3, 140.1, 141.8, 142.0, 142.2, 145.5, 148.9, 149.1;

IR (KBr) 3436, 2925, 2851, 1594, 1516, 1464, 1264, 1144, 1089, 1048,

1029, 810, 625 cm⁻¹; HRMS (ESI) m/z for C₂₇H₃₀NO₄S₂[M + H]⁺

calcd 496.1616, observed 496.1620.

Data for 3k: R_f0.15 (50% EtOAc/hex); mp 85 °C; [α]²⁰+71.6

D

(c = 1.90); ¹H NMR (CDCl₃, 300 MHz) δ 0.69−0.88 (m, 3 H), 0.91−

1.04 (m, 2 H), 1.07−1.23 (m, 1 H), 1.44−1.69 (m, 4 H), 1.81 (br d, 1

H, J = 13.1 Hz), 2.36 (s, 3 H), 2.39 (s, 3 H), 4.03 (dd, 1 H, J = 9.2, 4.5

Hz), 4.18 (d, 1 H, J = 4.5 Hz), 5.46 (d, 1 H, J = 9.9 Hz), 5.56 (d, 1 H,

J = 16.6 Hz), 6.66 (ddd, 1 H, J = 16.6, 11.2, 9.9 Hz), 6.96 (d, 1 H, J =

11.3 Hz), 7.24−7.28 (m, 4 H), 7.50 (br d, 2 H, J = 8.1 Hz), 7.57 (br d,

2 H, J = 8.1 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.4, 21.5, 25.8, 25.8,

25.9, 30.1, 30.5, 41.9, 58.6, 124.4, 125.3 (2 C), 126.5 (2 C), 129.5

(2 C), 130.0 (2 C), 130.5, 132.0, 139.9, 141.5, 142.2, 142.5, 144.8; IR

(KBr) 3436, 2925, 2853, 1637, 1450, 1043, 811, 560 cm⁻¹; HRMS

(ESI) m/z for C₂₅H₃₂NO₂S₂[M + H]⁺calcd 442.1874, observed

442.1908.

2.8. Synthesis of (+)-(R)-N-[(1S,2E)-1-Phenyl-4-((S)-p-tolylsulfinyl)-

4,6-heptadien-3-yl]-4-methylbenzenesulfinamide, 3l. From an E/Z

mixture of dienyl sulfoxides 2c (106 mg, 0.553 mmol, 1.0 equiv) with

2.0 equiv of LDA and sulfinimine R-1j (300 mg, 1.11 mmol, 2.0

equiv), following the general procedure, compound 3l was obtained as

a single diastereomer. Chromatographic purification (25−45%

gradient EtOAc/hex) provided 3l (174 mg, 68%) as a white solid.

Data for 3l: R_f0.20 (50% EtOAc/hex); mp 60 °C; [α]²⁰_D+18.8 (c =

1.30); ¹H NMR (CDCl₃, 300 MHz) δ 1.61 (q, 2 H, J = 7.6 Hz), 2.33

(s, 3 H), 2.37 (s, 3 H), 2.37−2.52 (m, 2 H), 4.27 (d, 1 H, J = 4.9 Hz),

4.48 (td, 1 H, J = 7.1, 4.9 Hz), 5.41 (d, 1 H, J = 10.0 Hz), 5.55 (d, 1 H,

2.5. Synthesis of (−)-(R)-N-[(1S,2E)-2-((S)-p-Tolylsulfinyl)-1-(4-

(trifluoromethyl)phenyl)-2,4-pentadien-1-yl)]-4-methylbenzenesul-

finamide, 3g. From an E/Z mixture of dienyl sulfoxides 2c (93 mg,

0.482 mmol, 1.0 equiv) with 2.0 equiv of LDA and sulfinimine R-1e

(300 mg, 0.964 mmol, 2.0 equiv), following the general procedure,

compound 3g was obtained as a 94:6 mixture of diastereomers.

531

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J = 16.5 Hz), 6.44 (ddd, 1 H, J = 16.6, 11.3, 10.0 Hz), 6.90−6.93 (m,

3 H), 7.08−7.24 (m, 7 H), 7.46−7.49 (m, 4 H); ¹³C NMR (CDCl₃, 75

MHz) δ 21.21, 21.26, 31.9, 38.0, 52.5, 124.7, 125.1 (2 C), 125.9, 126.1

(2 C), 128.2 (2 C), 128.2 (2 C), 129.3 (2 C), 129.4, 129.8 (2 C),

129.9, 131.9, 140.1, 140.1, 141.3, 142.1, 145.6; IR (KBr) 3436, 3082,

3055, 3022, 2923, 1633, 1493, 1454, 1177, 1088, 1052, 1016, 935, 810,

752, 702, 624, 554, 508 cm⁻¹; HRMS (ESI) m/z for C₂₇H₃₀NO₂S₂

[M + H]⁺calcd 464.1718, observed 464.1712.

2.12. Synthesis of (+)-N-[(2S,3E)-2-(4-Cyanophenyl)-3-((S)-p-

tolylsulfinyl)-3,5-hexadien-2-yl]-4-methylbenzenesulfonamide,

4p′. From an E/Z mixture of dienyl sulfoxides 2c (39 mg, 0.20 mmol,

1.0 equiv) with 2.0 equiv of LDA and sulfinimine S-1n (113 mg, 0.40

mmol, 2.0 equiv), following the general procedure, compound 4p′ was

obtained as a single diastereomer (65%) along with 35% of starting

1

material (ratio measured in the H NMR of the crude). Chromato-

graphic purification (0−50% gradient EtOAc/hex) provided 4p′ (46 mg,

48%) as a yellow solid.

2.9. Synthesis of (−)-(R)-N-([3S,1E,4E)-1-Phenyl-4-((S)-p-tolylsul-

finyl)-1,4,6-heptatrien-3-yl]-4-methylbenzenesulfinamide, 3m. From

an E/Z mixture of dienyl sulfoxides 2c (272 mg, 1.42 mmol, 1.0 equiv)

with 2.0 equiv of LDA and sulfinimine R-1k (763 mg,

2.83 mmol, 2.0 equiv), following the general procedure, compound

3m was obtained as a single diastereomer. Chromatographic

purification (0−50% EtOAc/hex) provided 3m (408 mg, 62%) as a

white solid.

Data for 4p′: R_f0.10 (50% EtOAc/hex); mp 140−142 °C; [α]²⁰

D

1

+87.9 (c = 2.10); H NMR (CDCl₃, 300 MHz) δ 2.11 (s, 3 H), 2.45

(s, 6 H), 4.89 (br s, 1 H), 5.34 (dm, 1 H, J = 10.7 Hz), 5.52 (dm, 1 H,

J = 15.9 Hz), 5.97−6.03 (m, 1 H), 7.03 (d, 1 H, J = 11.5 Hz), 7.26−

7.29 (m, 9 H), 7.43 (d, 2 H, J = 9.1 Hz), 7.49 (d, 2 H, J = 8.9 Hz), 7.65

(d, 2 H, J = 8.8 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.4, 21.6, 30.2,

65.6, 112.1, 118.3, 124.9 (2 C), 125.3, 126.6 (2 C), 127.0, 128.5 (2 C),

129.7 (2 C), 130.3 (2 C), 132.4 (2 C), 133.7, 139.7, 141.9 (2 C), 142.4,

147.5, 148.2; IR (KBr) 3411, 2927, 2232, 1596, 1404, 1091, 929, 810,

669 cm⁻¹; HRMS (ESI) m/z for C₂₇H₂₇N₂O₂S₂[M + H]⁺calcd

475.1514, observed 475.1516. Anal. Calcd for C₂₇H₂₆N₂O₂S₂: C, 68.32;

H, 5.52; N, 5.90; S, 13.51. Found: C, 68.12; H, 5.75; N, 5.53; S, 13.32.

3. General Procedure for the Synthesis of Amines. To a

solution of 1.0 equiv of N-sulfinamides 3 or 4 in MeOH (18 mL/

mmol) was added 4.0 equiv of H₃PO₄(85% aqueous solution). The

mixture was stirred from 0 °C to rt until the disappearance of 3 or 4

(aliquots for TLC were neutralized with solid K₂CO₃). The solvent

was evaporated, and the crude was diluted with water (10 mL/mmol).

After basifying with solid K₂CO₃to pH = 10−11, it was extracted with

CHCl₃(3 × 8 mL/mmol). The combined organic extracts were dried

over Na₂SO₄and concentrated under vacuum to afford the

corresponding amines 5 or 6 that were purified by chromatography

on silica gel using the appropriate mixture of eluents.

Data for 3m: R_f0.25 (50% EtOAc/hex); mp 53 °C; [α]²⁰−1.4

D

(c = 0.70); ¹H NMR (CDCl₃, 300 MHz) δ 2.23 (s, 3 H), 2.34 (s, 3 H),

4.17 (br s, 1 H), 5.28 (dd, 1 H, J = 7.5, 3.3 Hz), 5.52 (dd, 1 H, J = 15.7,

7.5 Hz), 5.58 (d, 1 H, J = 9.9 Hz), 5.69 (d, 1 H, 16.6 Hz), 6.13 (d, 1 H,

J = 15.7 Hz), 6.83 (ddd, 1 H, J = 16.6, 11.2, 9.9 Hz), 6.92 (m, 2 H),

7.05 (d, 1 H, J = 11.3 Hz), 7.14−7.26 (m, 7 H), 7.51−7.57 (m, 4 H);

¹³C NMR (CDCl₃, 75 MHz) δ 21.32, 21.35, 53.4, 125.2 (2 C), 125.6,

126.3 (2 C), 126.4 (2 C), 126.7, 128.0, 128.3 (2 C), 129.5 (2 C),

130.0 (2 C), 130.2, 132.6, 133.0, 135.6, 139.8, 141.6, 141.8, 142.2,

144.2; IR (KBr) 3437, 3174, 3049, 3022, 2920, 2862, 1628, 1597,

1493, 1448, 1304, 1177, 1090, 1052, 1016, 987, 967, 930, 837, 809,

752, 695, 623, 594, 557, 511, 484 cm⁻¹; HRMS (ESI) m/z for

C₂₇H₂₈NO₂S₂[M + H]⁺calcd 462.1561, observed 462.1562.

2.10. Synthesis of (+)-(S)-N-[(2S,3E)-2-Phenyl-3-((S)-p-tolylsulfin-

yl)-3,5-hexadien-2-yl]-4-methylbenzenesulfinamide, 4n′. From an

E/Z mixture of dienyl sulfoxides 2c (200 mg, 1.04 mmol, 1.0 equiv)

with 2.0 equiv of LDA and sulfinimine S-1l (540 mg, 2.08 mmol, 2.0

equiv), following the general procedure, compound 4n′ was obtained

as a single diastereomer (60%) along with 40% of starting material

(ratio measured in the ¹H NMR of the crude). Chromatographic

purification (0−50% gradient EtOAc/hex) provided 4n′ (234 mg,

50%) as a white solid.

Data for 4n′: R_f0.10 (50% EtOAc/hex); mp 135−137 °C;

[α]²⁰_D−108 (c = 0.62); ¹H NMR (CDCl₃, 300 MHz) δ 2.11 (s, 3 H),

2.41 (s, 6 H), 4.83 (brs, 1 H), 5.25 (dd, 1 H, J = 10.0, 1.5 Hz), 5.45

(dd, 1 H, J = 6.6, 0.9 Hz), 6.00−6.13 (m, 1 H), 7.01 (d, 1 H, J = 11.5

Hz), 7.20−7.36 (m, 9 H), 7.40 (d, 2 H, J = 8.3 Hz), 7.62 (d, 2 H, J =

8.3 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.7, 21.8, 30.5, 65.8, 125.2 (2

C), 125.9, 127.1 (2 C), 128.1 (2 C), 128.6, 128.9 (2 C), 129.8 (2 C),

130,1 (2 C), 130.4 (2 C), 132.4, 140.5, 141.8, 142.3, 142.4, 149.2; IR

(KBr) 3436, 3191, 3054, 2926, 1595, 1494, 1445, 1191, 1078, 1060,

820, 811, 701 cm⁻¹; HRMS (ESI) m/z for C₂₆H₂₈NO₂S₂[M + H]⁺

calcd 450.1561, observed 450.1600.

2.11. Synthesis of (+)-(S)-N-[(2S,3E)-2-(4-Nitrophenyl)-3-((S)-p-

tolylsulfinyl)-3,5-hexadien-2-yl]-4-methylbenzenesulfinamide,

4o′. From an E/Z mixture of dienyl sulfoxides (37 mg, 0.19 mmol,

1.0 equiv) with 2.0 equiv of LDA and sulfinimine S-1m (116 mg,

0.38 mmol, 2.0 equiv), following the general procedure, compound 4o′

was obtained as a single diastereomer (55%) along with 45% of

starting material (ratio measured in the ¹H NMR of the crude).

Chromatographic purification (0−50% gradient EtOAc/hex) provided

4o′ (49 mg, 51%) as a yellow solid.

Data for 4o′: R_f0.10 (50% EtOAc/hex); mp 103−105 °C;

[α]²⁰_D+57.9 (c = 1.60); ¹H NMR (CDCl₃, 300 MHz) δ 2.11 (s, 3 H),

2.41 (s, 6 H), 4.83 (br s, 1 H), 5.25 (dd, 1 H, J = 10.0, 1.5 Hz), 5.45

(dd, 1 H, J = 6.6, 0.9 Hz), 6.00−6.13 (m, 1 H), 7.01 (d, 1 H, J = 11.5

Hz), 7.20−7.36 (m, 9 H), 7.40 (d, 2 H, J = 8.3 Hz), 7.62 (d, 2 H, J =

8.3 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.4, 21.5, 30.4, 65.5, 123.8 (2

C), 124.6 (2 C), 126.6 (2 C), 127.1, 128.7 (2 C), 129.6, 129.7 (2 C),

130.1 (2 C), 133.6, 139.7, 142.0 (2 C), 142.5, 147.4, 147.5, 150.1; IR

(KBr) 3436, 2924, 1644, 1606, 1596, 1519, 1492, 1347, 1049, 855, 810

cm⁻¹; HRMS (ESI) m/z for C₂₆H₂₇N₂O₄S₂[M + H]⁺calcd 495.1412,

observed 495.1411. Anal. Calcd for C₂₆H₂₆N₂O₄S₂: C, 63.13; H, 5.30;

N, 5.66; S, 12.97. Found: C, 63.01; H, 5.15; N, 5.75; S, 12.77.

3.1. Synthesis of (−)-(1S,2E)-1,3-Diphenyl-2-((S)-p-tolylsulfinyl)-2-

propen-1-amine, 5a. From sulfinamide 3a (58 mg, 0.12 mmol, 1.0

equiv) and 4.0 equiv of H₃PO₄, according to the standard procedure

(5 h), 5a was obtained after purification by chromatography (40−80%

Et₂O/CH₂Cl₂) as a white solid (36 mg, 87%).

Data for 5a: R_f0.21 (80% Et₂O/CH₂Cl₂× 2); mp 125 °C; [α]²⁰

−37.6 (c = 0.46); H NMR (CDCl₃, 300 MHz) δ 1.86 (br s, 2 H),

D

1

2.32 (s, 3 H), 5.25 (s, 1 H), 7.09−7.13 (m, 7 H), 7.25−7.37 (m, 7 H),

7.50 (s, 1 H); ¹³C NMR (CDCl₃, 75 MHz) δ 21.4, 52.9, 125.7 (2 C),

126.6 (2 C), 127.0, 128.2 (2 C), 128.5 (3 C), 129.2 (2 C), 129.7 (2 C),

132.1, 134.1, 140.5 (2 C), 141.6, 150.0; IR (KBr) 3370, 3297, 3073,

3050, 3020, 2861, 1594, 1490, 1445, 1394, 1376, 1082, 1043, 931, 805,

753, 700, 640, 617, 505 cm⁻¹; MS (ESI) 717 [2M + Na]⁺, 370 [M +

Na]⁺, 348 [M + 1]⁺(100%). Anal. Calcd for C₂₂H₂₁NOS: C, 76.04; H,

6.09; N, 4.03; S, 9.23. Found: C, 75.86; H, 5.88; N, 4.10; S, 8.95.

3.2. Synthesis of (−)-(1S,2E)-1-Phenyl-2-((S)-p-tolylsulfinyl)-2-

hepten-1-amine, 5b. From 3b^10a(41 mg, 0.09 mmol, 1.0 equiv)

and 4.0 equiv of H₃PO₄, according to the standard procedure (6 h), 5b

was obtained after purification by chromatography (30% Et₂O/

CH₂Cl₂−Et₂O) as a colorless oil (29 mg, 99%).

Data for 5b: R_f0.07 (80% Et₂O/CH₂Cl₂); [α]²⁰_D−63.7 (c = 1.14);

¹H NMR (CDCl₃, 400 MHz) δ 0.75 (t, 3 H, J = 7.1 Hz), 1.10−1.19

(m, 3 H), 1.23−1.30 (m, 1 H), 1.69 (s, 2 H), 1.91−2.11 (m, 2 H), 2.37

(s, 3 H), 4.82 (s, 1 H), 6.41 (t, 1 H, J = 7.6 Hz), 6.97−7.00 (m, 2 H),

7.10−7.16 (m, 3 H), 7.24 (d, 2 H, J = 7.9 Hz), 6.45 (d, 2 H, J = 8.2

Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 13.7, 21.4, 22.3, 28.4, 30.6, 51.3,

125.2 (2 C), 126.0 (2 C), 126.7, 128.1 (2 C), 129.8 (2 C), 138.1,

140.1, 141.4, 142.1, 148.4; IR (film) 3362, 3292, 3056, 3026, 2955,

2927, 2855, 1676, 1594, 1492, 1450, 1082, 1042, 809, 698 cm⁻¹; MS

(ESI) 328 [M + 1]⁺(100%); HRMS (ESI) m/z for C₂₀H₂₆NOS [M +

H]⁺calcd 328.1735, observed 328.1753.

3.3. Synthesis of (+)-(1R,2E)-1-Phenyl-2-((S)-p-tolylsulfinyl)-2-

hepten-1-amine, 6b. From 4b^10a(32 mg, 0.07 mmol, 1.0 equiv)

and 4.0 equiv of H₃PO₄, according to the standard procedure (6 h), 6b

was obtained after purification by chromatography (30−60% Et₂O/

CH₂Cl₂) as a colorless oil (19 mg, 84%).

Data for 6b: R_f0.21 (80% Et₂O/CH₂Cl₂); [α]²⁰_D+108.7 (c = 0.98);

¹H NMR (CDCl₃, 400 MHz) δ 0.76 (t, 3 H, J = 7.1 Hz), 1.11−1.18

532

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(m, 2 H), 1.21−1.36 (m, 2 H), 2.03−2.09 (m, 4 H), 2.38 (s, 3 H), 4.94

(s, 1 H), 6.46 (t, 1 H, J = 7.3 Hz), 7.15−7.28 (m, 5 H), 7.33 (m, 2 H),

7.52 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz) 13.7, 21.4, 22.3, 28.3,

30.5, 50.2, 125.1 (2 C), 126.3 (2 C), 126.7, 128.1 (2 C), 129.9 (2 C),

138.7, 140.7, 141.3, 142.5, 148.8; IR (film) 3368, 3292, 3056, 2927,

2855, 1597, 1493, 1450, 1161, 1082, 1042, 1014, 811 cm⁻¹; MS (ESI)

328 [M + 1]⁺(100%); HRMS (ESI) m/z for C₂₀H₂₆NOS [M + H]⁺

calcd 328.1735, observed 328.1740.

3.4. Synthesis of (+)-(1S,2E)-1-(4-Methoxyphenyl)-2-((S)-p-tolyl-

sulfinyl)-2,4-pentadien-1-amine, 5e. From 3e (24 mg, 0.052 mmol,

1.0 equiv) and 4.0 equiv of H₃PO₄, according to the standard pro-

cedure (6 h), amine 5e was obtained after purification by chromato-

graphy (0−5% EtOH/CH₂Cl₂) as a colorless oil (13 mg, 76%).

Data for 5e: R_f0.25 (10% EtOH/CH₂Cl₂); [α]²⁰_D+25.3 (c = 1.80);

¹H NMR (CDCl₃, 300 MHz) δ 1.60 (br s, 2 H), 2.34 (s, 3 H), 3.71 (s,

3 H), 4.86 (s, 1 H), 5.33 (dd, 1 H, J = 9.9, 1.6 Hz), 5.48 (dd, 1 H, J =

16.7, 1.6, Hz), 6.60 (ddd, 1 H, J = 16.7, 11.3, 9.9 Hz), 6.66 (m, 2 H),

6.90 (d, 1 H, J = 11.3 Hz), 6.95 (d, 2 H, J = 8.9 Hz), 7.19 (d, 2 H, J =

8.4 Hz), 7.42 (d, 2 H, J = 8.2 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ

21.3, 51.5, 55.1, 113.6 (2 C), 124.4, 125.5 (2 C), 127.3 (2 C), 129.8

(2 C), 130.8, 132.3, 133.9, 139.9, 141.6, 149.5, 158.4; IR (film) 3369,

3291, 3000, 2926, 2836, 1608, 1510, 1492, 1463, 1417, 1303, 1249,

1177, 1113, 1081, 1036, 928, 835, 809, 735, 704 cm⁻¹; HRMS (ESI)

m/z for C₁₉H₂₂NO₂S [M + H]⁺calcd 328.1371, observed 328.1373.

3.5. Synthesis of (−)-(1S,2E)-1-(3,4-Dimethoxyphenyl)-2-((S)-p-

tolylsulfinyl)-2,4-pentadien-1-amine, 5f. From 3f (2.6 g, 5.25

mmol, 1.0 equiv) and 4.0 equiv of H₃PO₄, according to the standard

procedure (2 h), amine 5f was obtained after purification by chromato-

graphy (0−10% EtOH/Et₂O) as an orange oil (1.22 g, 65%).

Data for 5f: R_f0.20 (10% EtOH/Et₂O); [α]²⁰_D−8.7 (c = 0.58); ¹H

NMR (CDCl₃, 300 MHz) δ 1.61 (br s, 2 H), 2.25 (s, 3 H), 3.52 (s, 3

H), 3.70 (s, 3 H), 4.83 (br s, 1 H), 5.24 (d, 1 H, J = 10.0 Hz), 5.41

(d, 1 H, J = 16.8 Hz), 6.56−6.66 (m, 3 H, H-4), 6.83 (m, 2 H), 6.83

(d, 1 H, J = 11.2 Hz), 7.11 (d, 2 H, J = 8.1 Hz), 7.35 (d, 2 H, J = 8.1

Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 20.9, 51.2, 55.3, 55.5, 109.6,

110.8, 118.6, 124.0, 125.1 (2 C), 129.4 (2 C), 130.5, 132.1, 134.2,

140.0, 141.1, 147.8, 148.6, 149.7; IR (film) 3435, 2936, 1596, 1514,

1464, 1264, 1141, 1027, 810, 765 cm⁻¹; HRMS (ESI) m/z for

C₂₀H₂₄NO₃S [M + H]⁺calcd 358.1477, observed 358.1484.

1181, 1084, 1041, 1016, 995, 928, 879, 788, 707 cm⁻¹; HRMS (ESI)

m/z for C₁₈H₂₆NOS [M + H]⁺calcd 304.1735, observed 304.1727.

3.8. Synthesis of (+)-(3S,4E)-1-Phenyl-4-((S)-p-tolylsulfinyl)-4,6-

heptadien-3-amine, 5l. From 3l (171 mg, 0.369 mmol, 1.0 equiv)

and 4.0 equiv of H₃PO₄, according to the standard procedure (18 h),

amine 5l was obtained after purification by chromatography (0−5%

EtOH/CH₂Cl₂) as an orange solid (93 mg, 77%).

Data for 5l: R_f0.35 (10% EtOH/CH₂Cl₂); mp < 30 °C; [α]²⁰

D

1

+146.1 (c = 0.90); H NMR (CDCl₃, 300 MHz) δ 1.27 (br s, 2 H),

1.44 (m, 1 H), 1.65 (m, 1 H), 2.33 (m, 1 H), 2.34 (s, 3 H), 2.47 (ddd,

1 H, J = 13.7, 10.0, 5.6 Hz), 3.64 (dd, 1 H, J = 8.2, 5.9 Hz), 5.37 (dd, 1

H, J = 9.8, 1.6 Hz), 5.49 (dd, 1 H, J = 16.4, 1.6 Hz), 6.75 (ddd, 1 H, J =

16.4, 11.3, 9.8 Hz), 6.85 (d, 1 H, J = 11.3 Hz), 6.92 (m, 2 H), 7.07−

7.22 (m, 5 H), 7.45 (app d, 2 H, J = 8.1 Hz); ¹³C NMR (CDCl₃, 75

MHz) δ 21.3, 32.8, 39.1, 49.4, 123.6, 125.8, 125.9, 128.2, 128.3, 129.8,

129.9, 130.1, 131.4, 140.7, 141.1, 141.7 (some peaks overlap); IR

(KBr) 3435, 3055, 2922, 2856, 1630, 1596, 1454, 1398, 1302, 1209,

1178, 1043, 1015, 925, 810, 749, 700, 636, 624 cm⁻¹; HRMS (ESI)

m/z for C₂₀H₂₄NOS [M + H]⁺calcd 326.1573, observed 326.1588.

3.9. Synthesis of (+)-(2S,3E)-2-Phenyl-3-((S)-p-tolylsulfinyl)hexa-

3,5-dien-2-amine, 5n. From 4n′ (408 mg, 0.91 mmol, 1.0 equiv) and

5.0 equiv of H₃PO₄, according to the standard procedure (48 h),

amine 5n was obtained after purification by chromatography (0−5%

EtOH/CH₂Cl₂) as an orange oil (230 mg, 81%).

Data for 5n: R_f0.34 (4% EtOH/CH₂Cl₂); [α]²⁰_D+218.1 (c = 5.02);

¹H NMR (CDCl₃, 300 MHz) δ 1.61 (br s, 2H, NH), 1.81 (s, 3 H),

2.41 (s, 3 H), 5.14 (ddd, 1 H, J = 9.8, 1.9, 0.4 Hz), 5.88 (ddd, 1 H, J =

15.6, 1.9, 0.7 Hz), 5.88 (ddd, 1 H, J = 16.6, 11.4, 9.9 Hz), 7.06−7.13

(m, 3 H), 7.20−7.70 (m, 5 H), 7.72 (d, 2 H, J = 8.1 Hz); ¹³C NMR

(CDCl₃, 75 MHz) δ 21.4, 29.7, 58.8, 123.6, 125.2 (2 C), 126.9 (2 C),

127.0, 128.7 (2 C), 129.8 (2 C), 129.9, 130.3, 141.5, 142.6, 148.1,

152.0; IR (film) 3435, 3056, 2924, 1597, 1492, 1445, 1318, 1302,

1084, 1041, 811, 702 cm⁻¹; HRMS (ESI) m/z for C₁₉H₂₂NOS [M +

H]⁺calcd 312.1422, observed 312.1413.

4. General Procedure for the Synthesis of Sulfonamides 7/

8. To a solution of 1.0 equiv of amines 5 or 6 in anhydrous CH₂Cl₂

(3 mL/mmol) were added 1.3−3.0 equiv of RSO₂Cl and 2.7−3.5

equiv of Et₃N. The mixture was stirred from 0 °C to rt and monitored

by TLC until completion. Then, it was hydrolyzed with a 50:50

mixture of a saturated aqueous solution of K₂CO₃and H₂O (10 mL/

mmol) and extracted with CH₂Cl₂(3 × 10 mL/mmol). The combined

organic phases were washed with a saturated solution of NaCl

(10 mL/mmol), dried over Na₂SO₄, and filtered, and the solvent was

evaporated under reduced pressure to give sulfonamides 7 or 8, which

were purified by chromatography on silica gel using the appropriate

mixture of eluents.

3.6. Synthesis of (−)-(1S,2E)-2-((S)-p-Tolylsulfinyl)-1-(4-

(trifluoromethyl)phenyl)-2,4-pentadien-1-amine, 5g. From 3g

(160 mg, 0.318 mmol, 1.0 equiv) and 4.0 equiv of H₃PO₄, according

to the standard procedure (18 h), amine 5g was obtained after

purification by chromatography (0−5% EtOH/CH₂Cl₂) as an orange

solid (92 mg, 79%).

Data for 5g: R_f0.25 (10% EtOH/CH₂Cl₂); mp 38 °C; [α]²⁰_D−10.5

(c = 1.30); ¹H NMR (CDCl₃, 300 MHz) δ 1.67 (s, 2 H), 2.32 (s, 3 H),

5.01 (s, 1 H), 5.39 (ddd, 1 H, J = 10.0, 1.6, 0.7 Hz), 5.54 (ddd, 1 H, J =

16.7, 1.6, 0.8 Hz), 6.54 (ddd, 1 H, J = 16.7, 11.3, 10.0 Hz), 6.96 (dt, 1

H, J = 11.3, 0.7 Hz), 7.07−7.16 (m, 4 H), 7.31−7.39 (m, 4 H); ¹³C

NMR (CDCl₃, 75 MHz) δ 21.7, 51.7, 124.5 (q, J = 274 Hz), 125.5 (q,

J = 3.5 Hz), 125.9 (2 C), 126.0, 126.9 (2 C), 129.5 (2 C, q, J = 37 Hz),

130.1 (2 C), 130.6, 133.6, 139.6, 142.1, 146.1, 149.1; IR (KBr) 3368,

3292, 3052, 2926, 2856, 2237, 1595, 1493, 1412, 1380, 1123, 1069,

1043, 1017, 929, 849, 756, 733 cm⁻¹; HRMS (ESI) m/z for

C₁₉H₁₉F₃NOS [M + H]⁺calcd 366.1139, observed 366.1140.

3.7. Synthesis of (+)-(1S,2E)-1-Cyclohexyl-2-((S)-p-tolylsulfinyl)-

2,4-pentadien-1-amine, 5k. From 3k (600 mg, 1.36 mmol, 1.0

equiv) and 5.0 equiv of H₃PO₄, according to the standard procedure

(22 h), amine 5k was obtained after purification by chromatography

(0−5% EtOH/CH₂Cl₂) as an orange solid (346 mg, 84%).

Alternatively, 7l was synthesized using Na₂CO₃in CH₂Cl₂/H₂O as

described in section 4.9.

4.1. Synthesis of (+)-N-[(1R,2E)-2-((S)-p-Tolylsulfinyl)-1,3-diphe-

nylprop-2-en-1-yl]-4-methylbenzenesulfonamide, 7a. From amine

5a (28 mg, 0.08 mmol, 1.0 equiv), TsCl (23 mg, 0.12 mmol, 1.5

equiv), and Et₃N (30 μL, 0.20 mmol, 2.5 equiv), following the general

procedure (24 h) and after chromatographic purification (10−50%

EtOAc/hex), 7a was obtained as a colorless oil (26 mg, 65%).

Data for 7a: R_f0.43 (60% EtOAc/hex); [α]²⁰_D+14.8 (c = 2.40); ¹H

NMR (CDCl₃, 500 MHz)-COSY δ 2.35 (s, 3 H, Me p-Tol), 2.36 (s, 3

H, Me p-Tol), 6.07 (d, 1 H, J = 9.3 Hz), 6.50 (dd, 1 H, J = 9.3, 1.5

Hz), 6.87 (s, 1 H, H-3), 7.04 (d, 2 H, J = 9.3 Hz), 7.12−7.16 (m, 5 H,

ArH), 7.16−7.19 (m, 4 H, ArH), 7.31 (m, 3 H, ArH), 7.34−7.38 (m, 4

H, ArH); ¹³C NMR (CDCl₃, 100 MHz) δ 21.4 (2 C), 55.9, 126.0 (2

C), 126.8 (2 C), 127.0 (2 C), 127.6, 128.5 (2 C), 128.6 (2 C), 128.9

(2 C), 129.0, 129.2 (2 C), 130.0 (2 C), 133.4 (2 C), 137.6 (2 C),

139.5, 142.3, 142.9, 144.9; IR (film) 3271, 1597, 1493, 1450, 1332,

1160, 1086, 1056, 811, 756 cm⁻¹; HMRS (ESI) m/z for

C₂₉H₂₇NNaO₃S₂[M + Na]⁺calcd 524.1330, observed 524.1327.

4.2. Synthesis of (+)-N-[(1S,2E)-1-Phenyl-2-((S)-p-tolylsulfinyl)-2,4-

pentadien-1-yl]-2-nitrobenzenesulfonamide, 7e. From amine 5c^10a(78

mg, 0.26 mmol, 1.0 equiv), 2-nitrobenzenesulfonyl chloride (76 mg,

0.34 mmol, 1.3 equiv), and Et₃N (0.07 mL, 0.52 mmol, 2.0 equiv),

following the standard procedure (24 h) and after chromatographic

Data for 5k: R_f0.30 (10% EtOH/CH₂Cl₂); mp 128 °C; [α]²⁰

+328.3 (c = 1.43); H NMR (CDCl₃, 300 MHz) δ 0.65−0.85 (m, 2

D

1

H), 0.92−1.18 (m, 5 H), 1.29−1.44 (m, 1 H), 1.50−1.72 (m, 4 H),

1.91 (br d, 1 H, J = 12.2 Hz), 2.38 (s, 3 H), 3.05 (d, 1 H, J = 9.2 Hz),

5.41 (m, 1 H), 5.53 (m, 1 H), 6.91 (m, 1 H), 6.96 (d, 1 H, J = 11.3

Hz), 7.26 (d, 2 H, J = 8.6 Hz), 7.55 (d, 2 H, J = 8.1 Hz); ¹³C NMR

(CDCl₃, 75 MHz) δ 21.9, 26.3, 26.4, 26.6, 30.6, 30.7, 43.8, 56.5, 123.6,

126.8 (2 C), 130.4 (2 C), 130.7, 131.9, 140.7, 142.6, 148.3; IR (KBr)

3436, 3376, 2954, 2806, 1592, 1493, 1448, 1399, 1307, 1262, 1209,

533

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purification (10−60% EtOAc/hex), 7e was obtained as a colorless oil

(94 mg, 74%).

J = 7.8 Hz), 7.60 (td, 1 H, J = 7.1, 0.9 Hz), 7.67 (td, 1 H, J = 7.1, 1.3

Hz), 7.90 (d, 1 H, J = 7.8 Hz), 7.95 (d, 1 H, J = 8.1 Hz), 8.05 (dd, 1 H,

J = 7.3, 1.2 Hz), 8.59 (d, 1 H, J = 8.5 Hz); ¹³C NMR (CDCl₃, 100

MHz) δ 21.7, 56.9, 124.2, 124.9, 126.3, 126.4 (2 C), 127.1 (3 C),

127.9, 128.2, 128.6 (3 C), 129.1, 129.6, 129.7, 130.1, 133.5, 134.2,

134.4, 135.7, 137.2, 138.8, 142.4, 143.7 (2 C); IR (KBr) 3467, 3059,

2868, 1595, 1493, 1451, 1330, 1162, 1135, 1052, 805, 772 cm⁻¹;

HRMS (ESI) m/z for C₂₈H₂₅NO₃S₂[M]⁺calcd 487.1276, observed

487.1245. Anal. Calcd for C₂₈H₂₅NO₃S₂: C, 68.97; H, 5.17; N, 2.87; S,

13.15. Found: C, 68.75; H, 5.20; N, 2.65; S, 12.93.

Data for 7e: R_f0.25 (40% EtOAc/hex); [α]²⁰_D+19.5 (c = 1.10); ¹H

NMR (CDCl₃, 500 MHz) δ 2.32 (s, 3 H), 5.49 (d, 1 H, J = 9.8 Hz),

5.53 (d, 1 H, J = 15.6 Hz), 5.84 (d, 1 H, J = 8.1 Hz), 6.64 (ddd, 1 H,

J = 15.7, 11.3, 9.8 Hz), 6.67 (d, 1 H, J = 10.8 Hz), 6.96 (d, 1 H, J = 8.3

Hz), 7.03−7.08 (m, 5 H), 7.14 (d, 2 H, J = 7.8 Hz), 7.32 (d, 2 H, J =

8.3 Hz), 7.55 (td, 1 H, J = 7.8, 1.2 Hz), 7.60 (td, 1 H, J = 7.6, 1.5 Hz),

7.78 (dd, 1 H, J = 7.8, 1.2 Hz), 7.81 (dd, 1 H, J = 7.8, 1.2 Hz); ¹³C

NMR (CDCl₃, 100 MHz) δ 21.3, 56.1, 125.0, 125.3 (2 C), 126.8,

126.9 (2 C), 127.7, 128.4 (2 C), 129.6, 129.8 (2 C), 130.8, 132.5,

133.2, 134.2, 134.3, 137.4, 139.0, 141.8, 143.4, 147.4; IR (film) 3435,

1540, 1451, 1355, 1168, 1051, 742, 700, 591 cm⁻¹; MS (ESI) 483 [M

+ 1]⁺(100%), 987 [2M + Na]⁺; HRMS (ESI) m/z for C₂₄H₂₂N₂O₅S₂

[M]⁺calcd 482.0970, observed 482.0965.

4.6. Synthesis of (+)-N-[(1S,2E)-1-Phenyl-2-((S)-p-tolylsulfinyl)-

2,4-pentadien-1-yl]pyridine-2-sulfonamide, 7k. From amine 5c^10a

(70 mg, 0.24 mmol, 1.0 equiv), 2-pyridinesulfonyl chloride (70 mg,

0.31 mmol, 1.3 equiv), and Et₃N (67 μL, 0.48 mmol, 2.0 equiv),

following the standard procedure (20 h) and after chromatographic

purification (5−60% EtOAc/CH₂Cl₂), 7k was obtained as a white

solid (84 mg, 80%).

4.3. Synthesis of (+)-N-[(1S,2E)-1-Phenyl-2-((S)-p-tolylsulfinyl)-

2,4-pentadien-1-yl]-2,4,6-triisopropylbenzenesulfonamide, 7f. From

amine 5c^10a(74 mg, 0.25 mmol, 1.0 equiv), 2,4,6-triisopro-

pylbenzenesulfonyl chloride (204 mg, 0.67 mmol, 2.7 equiv), and

Et₃N (0.14 mL, 1.0 mmol, 4.0 equiv), following the standard

procedure (48 h) and after chromatographic purification (10−40%

EtOAc/hex), 7f was obtained as a colorless oil (72 mg, 51%).

Data for 7f: R_f0.28 (30% EtOAc/hex); [α]²⁰_D+14.1 (c = 0.59); ¹H

NMR (CDCl₃, 500 MHz) δ 1.13 (t, 12 H, J = 6.8 Hz), 1.22 (d, 6 H,

J = 6.8 Hz), 2.36 (s, 3 H), 2.85 (m, 1 H), 3.95 (m, 2 H), 5.40 (dd, 1 H,

J = 10.0, 1.0 Hz), 5.44 (dd, 1 H, J = 16.6, 1.0 Hz), 5.85 (d, 1 H, J = 7.3

Hz), 6.14 (d, 1 H, J = 7.3 Hz), 6.43 (d, 1 H, J = 11.2 Hz), 6.55 (ddd,

1 H, J = 16.4, 11.0, 10.0 Hz), 6.99 (d, 2 H, J = 7.1 Hz), 7.05−7.12

(m, 5 H), 7.20 (d, 2 H, J = 7.8 Hz), 7.40 (d, 2 H, J = 8.1 Hz); ¹³C

NMR (CDCl₃, 100 MHz) δ 21.4, 23.6 (2 C), 24.7 (2 C), 24.8 (2 C),

29.8 (2 C), 34.1, 56.1, 123.5 (2 C), 125.9, 126.3 (2 C), 127.0 (2 C),

127.7, 128.4 (2 C), 129.5, 129.9 (2 C), 132.8, 133.9, 138.0, 139.2,

142.1, 144.4, 149.7, 152.6; IR (film) 3435, 2959, 2927, 1629, 1455,

1324, 1153, 1040, 667 cm⁻¹; MS (ESI) 564 [M + 1]⁺(100%), 1149

[2M + Na]⁺; HRMS (ESI) m/z for C₃₃H₄₁NO₃S₂[M]⁺calcd

563.2528, observed 563.2502.

Data for 7k: R_f0.22 (60% EtOAc/hex); mp 139−141 °C; [α]²⁰

D

+107.4 (c = 3.80); ¹H NMR (CDCl₃, 300 MHz) δ 2.35 (s, 3 H), 5.48

(d, 1 H, J = 16.8 Hz), 5.50 (m, 1 H, J = 9.5 Hz), 5.95 (d, 1 H, J = 8.5

Hz), 6.48 (d, 1 H, J = 11.7 Hz), 6.63 (d, 1 H, J = 10.0 Hz), 6.68 (ddd,

1 H, J = 16.3, 11.0, 10.0 Hz), 7.13−7.20 (m, 7 H), 7.33 (d, 2 H, J = 8.1

Hz), 7.60 (m, 1 H), 7.77 (m, 2 H), 8.54 (ddd, 1 H, J = 4.6, 2.3, 1.0

Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.6, 56.6, 121.9, 125.9 (2 C),

126.2, 126.5, 127.0 (2 C), 127.8, 128.6 (2 C), 130.0 (2 C), 133.4,

133.5, 137.7, 138.1, 139.5, 142.0, 144.0, 150.0, 157.9; IR (KBr) 3436,

3233, 2975, 1577, 1492, 1428, 1344, 1172, 1121, 1011, 954, 808, 782

cm⁻¹; HRMS (ESI) m/z for C₂₃H₂₂N₂O₃S₂[M]⁺calcd 438.1072,

observed 438.1059.

4.7. Synthesis of (+)-N-[(1S,2E)-1-(3,4-Dimethoxyphenyl)-2-((S)-p-

tolylsulfinyl)-2,4-pentadien-1-yl]quinoline-8-sulfonamide, 7h.

From amine 5f (1100 mg, 3.08 mmol, 1.0 equiv), 8-quinolinesulfonyl

chloride (1050 mg, 4.62 mmol, 1.5 equiv), and Et₃N (1.50 mL, 10.78

mmol, 3.5 equiv), following the general procedure (20 h) and after

chromatographic purification (25−40% EtOAc/hex), 7h was obtained

as a white solid (1569 mg, 93%).

Data for 7h: R_f0.20 (80% Et₂O/CH₂Cl₂); mp 68−70 °C; [α]²⁰

4.4. Synthesis of (+)-N-[(1S,2E)-1-Phenyl-2-((S)-p-tolylsulfinyl)-

2,4-pentadien-1-yl]-8-quinolinesulfonamide, 7g. From amine 5c^10a

(97 mg, 0.33 mmol, 1.0 equiv), 8-quinolinesulfonyl chloride (96 mg,

0.42 mmol, 1.3 equiv), and Et₃N (0.09 mL, 0.65 mmol, 2.0 equiv),

following the standard procedure (4 h) and after chromatographic

purification (5−40% EtOAc/CH₂Cl₂), 7g was obtained as a white

solid (104 mg, 65%).

D

+58.5 (c = 0.53); ¹H NMR (CDCl₃, 300 MHz)-COSY δ 2.29 (s, 3 H,

Me p-Tol), 3.40 (s, 3 H, OMe), 3.68 (s, 3 H, OMe), 5.34 (d, 1 H, J =

9.8 Hz, H-5 trans), 5.38 (d, 1 H, J = 16.6 Hz, H-5 cis), 5.63 (d, 1 H, J =

8.1 Hz, H-1 HMBC(H−N)), 6.18 (s, 1 H, ArH), 6.28 (d, 1 H, J = 8.3

Hz, ArH), 6.39 (d, 1 H, J = 8.3 Hz, ArH), 6.55 (m, 1 H, H-4), 6.63 (d,

1 H, J = 11.2 Hz, H-3), 7.04 (d, 2 H, J = 8.1, ArH), 7.19 (d, 2 H, J =

8.1, ArH), 7.38 (br d, 1 H, J = 8.6 Hz, NH HMBC(H−N)), 7.46 (dd,

1 H, J = 8.1, 4.2 Hz, ArH), 7.49 (dd, 1 H, J = 7.3, 8.1 Hz, ArH), 7.93

(d, 1 H, J = 8.3 Hz, ArH), 8.16 (d, 1 H, J = 8.3 Hz, ArH), 8.21 (d, 1 H,

J = 7.3 Hz, ArH), 8.90 (d, 1 H, J = 4.2 Hz, CH=N HMBC(H−N)); ¹³C

NMR (CDCl₃, 75 MHz)-HSQC δ 21.3, 55.4, 55.8, 56.2, 110.2, 110.4,

119.5, 122.0, 125.3, 125.5 (2 C), 128.6, 129.5 (2 C), 129.8, 130.0, 130.4

132.4, 132.9, 136.6, 137.0, 140.3, 141.4, 143.0, 144.8, 148.3, 148.6,

151.0 (2 C); IR (KBr) 3259, 2931, 1595, 1515, 1492, 1335, 1246, 1165,

1144, 1029, 911, 839, 810, 790, 762, 732 cm⁻¹; HRMS (ESI) m/z for

C₂₉H₂₈N₂O₅S₂[M]⁺calcd 548.1440, observed 548.1434.

Data for 7g: R_f0.22 (60% EtOAc/hex); mp 195 °C; [α]²⁰+94.4

D

1

(c = 0.75); H NMR (CDCl₃, 500 MHz) δ 2.28 (s, 3 H), 5.35 (m,

1 H), 5.40 (m, 1 H), 5.68 (d, 1 H, J = 8.1 Hz), 6.57 (m, 1 H), 6.60 (d,

1 H, J = 11.0 Hz), 6.80−6.84 (m, 4 H), 6.88−6.91 (m, 1 H), 7.00 (d,

2 H, J = 8.1 Hz), 7.13 (d, 2 H, J = 8.1 Hz), 7.45 (d, 1 H, J = 9.5 Hz),

7.47 (dd, 1 H, J = 8.3, 4.4 Hz), 7.51 (dd, 1 H, J = 8.1, 7.51 Hz), 7.93

(dd, 1 H, J = 8.3, 1.5 Hz), 8.17 (dd, 1 H, J = 8.3, 1.7 Hz), 8.22 (dd, 1

H, J = 7.3, 1.5 Hz), 8.90 (dd, 1 H, J = 4.4, 1.7 Hz); ¹³C NMR (CDCl₃,

100 MHz) δ 21.3, 56.1, 122.1, 125.3, 125.5 (2 C), 126.8 (2 C), 127.3,

127.9 (2 C), 128.6, 129.5 (2 C), 129.9, 130.4, 132.4, 133.1, 136.6,

136.7, 137.6, 139.8, 141.4, 142.9, 144.5, 151.0 (2 C); IR (KBr) 3435,

1493, 1333, 1166, 1146, 1082, 1049, 790, 701 cm⁻¹; MS (ESI) 489

[M + 1]⁺(100%), 511 [M + Na]⁺. Anal. Calcd for C₂₇H₂₄N₂O₃S₂: C,

66.37; H, 4.95; N, 5.73; S, 13.12. Found: C, 66.09; H, 5.20; N, 5.65; S,

12.98.

4.8. Synthesis of (+)-N-[(1S,2E)-1-Isopropyl-2-((S)-p-tolylsulfinyl)-

2,4-pentadien-1-yl]quinoline-8-sulfonamide, 7i. From amine 5h^10a

(125 mg, 0.48 mmol, 1.0 equiv), 8-quinolinesulfonyl chloride (141 mg,

0.62 mmol, 1.3 equiv), and Et₃N (1.34 mL, 0.96 mmol, 2.0 equiv),

following the standard procedure (4 h) and after chromatographic

purification (1−30% EtOH/CH₂Cl₂), 7i was obtained as a solid (159 mg,

73%).

4.5. Synthesis of (−)-N-[(1S,2E)-1-Phenyl-2-((S)-p-tolylsulfinyl)-

2,4-pentadien-1-yl]naphthalene-1-sulfonamide, 7j. From amine

5c^10a(70 mg, 0.24 mmol, 1.0 equiv), 1-naphthalenesulfonyl chloride

(70 mg, 0.31 mmol, 1.3 equiv), and Et₃N (67 μL, 0.48 mmol, 2.0

equiv), following the standard procedure (24 h) and after chromato-

graphic purification (5−40% EtOAc/CH₂Cl₂), 7j was obtained as a

white solid (101 mg, 87%).

Data for 7i: R_f0.20 (5% EtOH/CH₂Cl₂); mp 49−51 °C; [α]²⁰

D

+239 (c = 0.53); ¹H NMR (CDCl₃, 300 MHz) δ 0.45 (d, 3 H, J = 6.6

Hz), 1.01 (d, 3 H, J = 6.6 Hz), 1.72 (m, 1 H), 2.28 (s, 3 H), 4.24 (t, 1

H, J = 8.8 Hz), 5.28 (d, 1 H, J = 16.6 Hz), 5.31 (d, 1 H, J = 9.8 Hz),

6.25 (d, 1 H, J = 11.5 Hz), 6.59 (ddd, 1 H, J = 16.6, 11.0, 10.0 Hz),

6.95 (d, 1 H, J = 8.8 Hz), 7.00 (d, 2 H, J = 8.1 Hz), 7.13 (d, 2 H, J =

8.1 Hz), 7.46 (dd, 1 H, J = 8.3, 7.3 Hz), 7.51 (dd, 1 H, J = 8.3, 4.2 Hz),

7.94 (dd, 1 H, J = 8.3, 1.5 Hz), 8.13 (dd, 1 H, J = 7.3, 1.5 Hz,), 8.21

(dd, 1 H, J = 8.3, 1.7 Hz), 9.02 (dd, 1 H, J = 8.3, 1.7 Hz); ¹³C NMR

(CDCl₃, 75 MHz) δ 19.2, 19.8, 21.4, 32.6, 59.2, 122.3, 124.3, 125.3,

Data for 7j: R_f0.22 (40% EtOAc/hex); mp 76−78 °C; [α]²⁰_D−9.60

(c = 1.60); ¹H NMR (CDCl₃, 300 MHz) δ 2.36 (s, 3 H), 5.30 (d, 1 H,

J = 16.6 Hz), 5.36 (m, 1 H, J = 10.0 Hz), 5.80 (d, 1 H, J = 8.1 Hz),

6.04 (dd, 1 H, J = 11.0, 0.9 Hz), 6.52 (ddd, 1 H, J = 16.5, 11.0, 10.0

Hz), 6.88 (d, 1 H, J = 8.0 Hz), 7.03−7.14 (m, 9 H), 7.35 (t, 1 H,

534

dx.doi.org/10.1021/jo202144k | J. Org. Chem. 2012, 77, 525−542

The Journal of Organic Chemistry

Article

125.9 (2 C), 128.7, 129.7 (2 C), 129.8, 130.1, 131.4, 132.8, 136.7

(2 C), 140.0, 141.9, 143.1, 144.7, 151.2; IR (KBr) 3268, 3063, 2960,

2937, 2873, 1596, 1568, 1494, 1172, 1045, 987, 833, 792, 719 cm⁻¹;

HRMS (ESI) m/z for C₂₄H₂₆N₂O₃S₂[M]⁺calcd 454.1385, observed

454.1394.

5l (57 mg, 0.156 mmol, 1.0 equiv), TsCl (59 mg, 0.312 mmol, 2.0

equiv), and Et₃N (65 μL, 0.468 mmol, 3.0 equiv), following the

general procedure (4 h) and after chromatographic purification (20−

40% EtOAc/hex), 7o was obtained as a white solid (74 mg, 99%).

Data for 7o: R_f0.25 (50% EtOAc/hex); mp 136 °C; [α]²⁰+74.4

D

(c = 1.80); ¹H NMR (CDCl₃, 300 MHz) δ 1.73 (m, 1 H), 1.87 (m, 1

H), 2.34−2.57 (m, 2 H), 2.38 (s, 3 H), 2.39 (s, 3 H), 4.50 (td, 1 H, J =

6.5, 8.1 Hz), 5.35−5.46 (m, 2 H), 5.66 (d, 1 H, J = 7.9 Hz), 6.26−6.40

(m, 2 H), 6.92 (m, 2 H), 7.11−7.22 (m, 7 H), 7.39 (m, 2 H), 7.64 (m,

2 H); ¹³C NMR (CDCl₃, 75 MHz) δ 21.5, 21.5, 31.9, 37.5, 52.3, 125.3,

126.0 (2 C), 126.1 (2 C), 127.2 (2 C), 128.3 (4 C), 128.4 (2 C),

129.4, 130.1, 132.2, 137.5, 139.4, 140.0, 142.4, 143.2, 144.1; IR (KBr)

3436, 3182, 3061, 3026, 2924, 2860, 1633, 1597, 1493, 1453, 1398,

1333, 1291, 1209, 1182, 1162, 1088, 1042, 1026, 1014, 994, 963, 949,

911, 886, 813, 751, 700, 668, 637, 619, 570, 549, 501 cm⁻¹; HRMS

(ESI) m/z for C₂₇H₃₀NO₃S₂[M + H]⁺calcd 480.1667, observed

480.1679.

4.9. Synthesis of (+)-N-[(2S,3E)-2-Phenyl-3-((S)-p-tolylsulfinyl)-

3,5-hexadien-2-yl]-4-methylbenzenesulfonamide, 7l. Amine 5n

(25 mg, 0.084 mmol, 1.0 equiv), TsCl (19 mg, 0.1 mmol, 1.2 equiv),

and Na₂CO₃(19 mg, 0.18 mmol, 2.1 equiv) in 1 mL of CH₂Cl₂and

1 mL of H₂O as solvents were stirred 4 days at room temperature. The

organic layer was separated, washed with brine, and evaporated. After

chromatographic purification (25−40% EtOAc/hex) 7l was obtained as

a yellow oil (25 mg, 63%).

1

Data for 7l: R_f0.30 (50% EtOAc/hex); [α]²⁰+1.3 (c = 1.30); H

D

NMR (CDCl₃, 300 MHz)-COSY δ 1.80 (s, 3 H, Me), 2.31 (s, 3 H, Me

p-Tol), 2.45 (s, 3 H, Me p-Tol), 5.21 (dd, 1 H, J = 9.9, 1.5 Hz, H-6

cis), 5.42 (dd, 1 H, J = 16.7, 0.7 Hz, H-6 trans), 5.81 (ddd, 1 H, J =

16.7, 11.3, 9.9 Hz, H-5), 6.83 (d, 1 H, J = 11.3 Hz, H-4), 6.91 (d, 2 H,

J = 8.0 Hz, ArH), 6.96−7.07 (m, 5 H, ArH), 7.13 (d, 2 H, J = 8.2 Hz,

ArH), 7.36 (d, 2 H, J = 8.1 Hz, ArH), 7.46 (br s, 1 H, NH), 7.63 (d, 2

H, J = 8.1 Hz, ArH); 2D NOESY between H-5/H-6, H-4-ArH

(sulfox), NH/ArH (Ts); ¹³C NMR (CDCl₃, 75 MHz)-HSQC δ 21.4,

21.5, 26.0, 66.8, 125.8 (2 C), 126.5 (2C), 126.8, 127.2 (2 C), 127.4,

128.0 (2 C), 128.9 (2 C), 130.0, 130.1 (2 C), 136.4, 138.6, 139.1,

141.8, 142.0, 142.2, 147.2; IR (film) 3435, 3153, 2922, 1598, 1446,

1331, 1246, 1161, 1092, 1028, 911, 811, 702, 666 cm⁻¹; HRMS (ESI)

m/z for C₂₆H₂₈NO₃S₂[M + H]⁺calcd 466.1511, observed [M + H]⁺

466.1504.

4.13. Synthesis of (+)-N-[(1S,2E)-1-Cyclohexyl-2-((S)-p-tolylsulfin-

yl)-2,4-pentadien-1-yl]-4-methylbenzenesulfonamide, 7p. From

amine 5k (88 mg, 0.290 mmol, 1.0 equiv), TsCl (111 mg, 0.580

mmol, 2.0 equiv), and Et₃N (120 μL, 0.870 mmol, 3.0 equiv),

following the general procedure (4 h) and after chromatographic

purification (20−40% EtOAc/hex), 7p was obtained as a white solid

(116 mg, 87%).

Data for 7p: R_f0.25 (50% EtOAc/hex); mp 58 °C; [α]²⁰+103.3

D

(c = 3.80); ¹H NMR (CDCl₃, 300 MHz) δ 0.69−1.22 (m, 5 H), 1.46−

1.75 (m, 5 H), 2.08 (app d, 1 H, J = 12.7 Hz), 2.37 (s, 6 H), 4.33 (t, 1

H, J = 9.5 Hz), 5.28 (d, 1 H, J = 16.6), 5.37 (d, 1 H, J = 10.3 Hz), 5.93

(d, 1 H, J = 11.0 Hz), 6.02 (d, 1 H, J = 8.9 Hz), 6.53 (ddd, 1 H, J =

16.6, 11.0, 10.3 Hz), 7.15 (app d, 2 H, J = 8.0 Hz), 7.17 (d, 2 H, J = 8.0

Hz), 7.26 (d, 2 H, J = 8.2 Hz), 7.57 (d, 2 H, J = 8.2 Hz); ¹³C NMR

(CDCl₃, 75 MHz) δ 21.5, 21.5, 25.6, 25.7, 26.0, 30.1, 40.9, 58.9, 124.8,

126.6 (2 C), 127.0 (2 C), 129.2 (2 C), 129.8 (2 C), 129.9, 132.7,

138.3, 139.2, 142.6, 142.8, 142.8; IR (KBr) 3436, 2926, 2853, 1632,

1494, 1450, 1334, 1161, 1088, 1046, 931, 813, 668, 569, 551 cm⁻¹;

HRMS (ESI) m/z for C₂₅H₃₂NO₃S₂[M + H]⁺calcd 458.1824,

observed 458.1813.

4.10. Synthesis of (+)-N-[(1S,2E)-1-(4-Methoxyphenyl)-2-((S)-p-

tolylsulfinyl)-2,4-pentadien-1-yl]-4-methylbenzenesulfonamide,

7m. From amine 5e (42 mg, 0.128 mmol, 1.0 equiv), TsCl (49 mg,

0.256 mmol, 2.0 equiv), and Et₃N (60 μL, 0.385 mmol, 3.0 equiv),

following the general procedure (20 h) and after chromatographic

purification (20−40% EtOAc/hex) 7m was obtained as a white solid

(59 mg, 96%).

Data for 7m: R_f0.25 (50% EtOAc/hex); mp 48 °C; [α]²⁰+27.8

D

(c = 2.80); ¹H NMR (CDCl₃, 300 MHz) δ 2.36 (s, 3 H), 2.37 (s, 3 H),

3.72 (s, 3 H), 5.43 (d, 1 H, J = 10.8 Hz), 5.44 (d, 1 H, J = 15.8 Hz),

5.65 (d, 1 H, J = 7.8 Hz), 6.11 (d, 1 H, J = 7.7 Hz), 6.38 (d, 1 H, J =

11.2 Hz), 6.62 (ddd, 1 H, J = 10.8, 11.2, 15.8 Hz), 6.64 (app d, 2 H,

J = 8.7 Hz), 6.96 (app d, 2 H, J = 8.7 Hz), 7.14 (app d, 2 H, J = 5.9

Hz), 7.17 (app d, 2 H, J = 5.9 Hz), 7.27 (app d, 2 H, J = 8.2 Hz), 7.54

(app d, 2 H, J = 8.2 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.9, 22.0,

55.7, 56.2, 114.3 (2 C), 126.4 (2 C), 126.5 (2 C), 127.7 (2 C), 128.7

(2 C), 129.8 (2 C), 130.2, 130.3, 130.4, 133.5, 138.1, 139.6, 142.5,

143.5, 144.3, 159.6; IR (KBr) 3437, 2924, 2854, 1610, 1511, 1458,

1334, 1305, 1251, 1160, 1080, 1033, 927, 811, 705, 665, 624, 549

cm⁻¹; HRMS (ESI) m/z for C₂₆H₂₈NO₄S₂[M + H]⁺calcd 482.1460,

observed 482.1468.

5. Synthesis of (+)-tert-Butyl N-[(1R,2E)-1-phenyl-2-((S)-p-

tolylsulfinyl)-2,4-pentadien-1-yl] Carbamate, 8b. To amine 6c

(38 mg, 0.13 mmol, 1 equiv) in CH₂Cl₂(20 mL/mmol) at 0 °C were

added sequentially 1 N NaOH (0.3 + 0.3 + 0.2 mL, 6 equiv) and 0.5 M

Boc₂O in CH₂Cl₂(0.3 + 0.3 + 0.2 mL, 3.2 equiv). The mixture was

stirred from 0 °C to rt (24 h) until disappearance of the starting

material. Then, CH₂Cl₂was evaporated under vacuum, and the residue

was extracted with CHCl₃. The organic extracts were washed with

brine, dried (Na₂SO₄), and evaporated under vacuum. After

chromatographic purification (10−40% EtOAc/hex), 8b was obtained

as a white solid (40 mg, 79%).

Data for 8b: R_f0.28 (30% EtOAc/hex); mp 155 °C; [α]²⁰_D+181.6

(c = 0.64); ¹H NMR (CDCl₃, 300 MHz) δ 1.35 (s, 9 H), 2.33 (s, 3 H),

5.22 (d, 1 H, J = 8.8 Hz), 5.43 (d, 1 H, J = 10.0 Hz), 5.60 (d, 1 H, J =

16.6 Hz), 5.93 (d, 1 H, J = 8.8 Hz), 6.51 (ddd, 1 H, J = 16.6, 10.8, 10.6

Hz), 7.03 (d, 3 H, J = 10.9 Hz), 7.15 (d, 5 H, J = 7.6 Hz), 7.38 (d, 2 H,

J = 8.1 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.3, 28.2 (3 C), 51.2,

79.8, 125.4 (2 C), 125.7, 126.1 (2 C), 127.1, 128.3 (2 C), 129.8 (2 C),

129.9, 133.5, 138.7, 139.3, 141.6, 145.3, 154.6; IR (KBr) 3427, 3337,

3020, 2973, 2920, 1709, 1629, 1508, 1491, 1450, 1365, 1282, 1249,

1170, 1082, 1049, 981, 937, 806 cm⁻¹; MS (ESI) 817 [2M + Na]⁺

(100%), 420 [M + Na]⁺. Anal. Calcd for C₂₃H₂₇NO₃S: C, 69.49; H,

6.85; N, 3.52; S, 8.07. Found: C, 69.71; H, 6.67; N, 3.76; S, 7.93.

6. General Procedure for the Synthesis of Hydroxymethyl 2-

Sulfonyldihydropyrroles. To a solution of 1.0 equiv of 3 in toluene

(10 mL/mmol) was added 3.5 equiv of solid m-CPBA (70%). The

mixture was stirred until the disappearance by TLC of the bis-tosylated

compound generated at the initial stage. Then, 0.2 equiv of CSA was

added, and the reaction was stirred until no epoxides were observed by

TLC. After that, the reaction was hydrolyzed with 1 M solution of

Na₂S₂O₄(5 mL/mmol) and extracted with EtOAc (3 × 5 mL/mmol).

The organic phases were washed with saturated aqueous solution of

NaHCO₃(5 mL/mmol), H₂O (5 mL/mmol), and brine (5 mL/mmol).

4.11. Synthesis of (+)-N-[(1S,2E)-2-((S)-p-Tolylsulfinyl)-1-(4-

(trifluoromethyl)phenyl)-2,4-pentadien-1-yl]-4-methylbenzenesul-

fonamide, 7n. From amine 5g (61 mg, 0.167 mmol, 1.0 equiv), TsCl

(64 mg, 0.334 mmol, 2.0 equiv), and Et₃N (70 μL, 0.501 mmol, 3.0

equiv), following the general procedure (5 h) and after chromato-

graphic purification (25−40% gradient EtOAc/hex), 7n was obtained

as a white solid (56 mg, 65%).

Data for 7n: R_f0.25 (50% EtOAc/hex); mp 68 °C; [α]²⁰+17.0

D

(c = 3.00); ¹H NMR (CDCl₃, 300 MHz) δ 2.33 (s, 3 H), 2.36 (s, 3 H),

5.48 (br s, 1 H), 5.52 (dd, 1 H, J = 8.4, 1.5 Hz), 6.47 (d, 1 H, J = 11.2

Hz), 6.52−6.64 (m, 2 H), 7.12 (br d, 4 H, J = 7.7 Hz), 7.20 (m, 4 H),

7.31 (br d, 2 H, J = 8.1 Hz), 7.54 (m, 2 H); ¹³C NMR (CDCl₃, 75

MHz) δ 21.8, 21.9, 56.0, 124.2 (q, J = 272 Hz), 125.7 (2 C, q, J = 3.7

Hz), 126.3, 127.4, 127.6, 127.8, 129.7, 129.9, 130.2 (2 C, q, J = 33 Hz),

130.4, 134.5, 138.0, 139.2, 142.2 142.8, 143.3, 143.8 (some signals

overlap); IR (KBr) 3435, 2927, 2868, 1620, 1597, 1493, 1450, 1419,

1327, 1163, 1123, 1069, 1018, 935, 868, 810, 706, 669, 549 cm⁻¹;

HRMS (ESI) m/z for C₂₆H₂₅F₃NO₃S₂[M + H]⁺calcd 520.1228,

observed 520.1198.

4.12. Synthesis of (+)-N-[(3S,4E)-1-Phenyl-4-((S)-p-tolylsulfinyl)-

4,6-heptadien-3-yl]-4-methylbenzenesulfonamide, 7o. From amine

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It was dried over Na₂SO₄and concentrated under reduced pressure to

give a mixture of 2,5-cis 9 and 2,5-trans-dihydropyrroles 10, which were

separated by chromatography on silica gel using the appropriate mixture

of eluents.

(TBATB) and 2.5 equiv of solid K₂CO₃at rt. The mixture was

stirred until the disappearance of 7 and no further evolution was

detected by TLC. It was quenched with a 1 M solution of Na₂S₂O₄

(10 mL/mmol), extracted with CH₂Cl₂(3 × 10 mL/mmol), washed

with a saturated solution of NaCl (10 mL/mmol), dried over Na₂SO₄,

and filtered, and the solvent was evaporated under reduced pressure to

give a mixture of 2,5-cis 11 and 2,5-trans-dihydropyrroles 12, which

were separated by chromatography on silica gel using the appropriate

mixture of eluents.

6.1. Synthesis of (+)-N-[(1S,2E)-1-Isopropyl-2-[(4-methylphenyl)-

sulfonyl]-3-[(2S)-2-oxiranyl]-2-propen-1-yl]-4-methylbenzenesulfo-

namide, (+)-[(2S,5S)-5-Isopropyl-1,4-bis[(4-methylphenyl)sulfonyl]-

2,5-dihydro-1H-pyrrol-2-yl]methanol, 9h, and (+)-[(2R,5S)-5-Iso-

propyl-1,4-bis[(4-methylphenyl)sulfonyl]-2,5-dihydro-1H-pyrrol-2-

yl]methanol, 10h. From sulfinamide 3h^10a(70 mg, 0.2 mmol, 1.0

equiv), m-CPBA 70% (171 mg, 0.7 mmol, 3.5 equiv), and CSA (8 mg,

0.04 mmol, 0.2 equiv), following the standard procedure (7 days), a

70:30 cis:trans mixture of dihydropyrroles was obtained. After

chromatographic purification (CH₂Cl₂-5% EtOAc/CH₂Cl₂), 9h (26

mg, 34%, colorless oil) and 10h (16 mg, 20%, white solid) were

obtained. When quenching the reaction at shorter times (5−6 days),

small amounts of a monoepoxide (10%) were obtained. Monoepoxide

(8 mg) was further treated with CSA to afford 9h as a single isomer

(6 mg, 74%).

7.1. Synthesis of (+)-(2S,5S)-5-(Bromomethyl)-1-[(2-nitrophenyl)-

sulfonyl]-2-phenyl-3-((S)-tolylsulfinyl)-2,5-dihydro-1H-pyrrole,

11d, and (+)-(2S,5R)-5-(Bromomethyl)-1-[(2-nitrophenyl)-

sulfonyl]-2-phenyl-3-((S)-tolylsulfinyl)-2,5-dihydro-1H-pyrrole,

12d. From sulfonamide 7e (25 mg, 0.05 mmol, 1.0 equiv), TBATB

(50 mg, 0.1 mmol, 2.0 equiv), and K₂CO₃(18 mg, 0.13 mmol, 2.5

equiv), following the standard procedure (6 days), a crude mixture of

80:20 cis:trans isomers was obtained, and after chromatographic

purification (20−80% EtOAc/hex), 11d (12 mg, 41%, colorless oil)

and 12d (5 mg, 17%, colorless oil) were obtained.

Data for cis-11d: R_f0.27 (60% EtOAc/hex); [α]²⁰+102.7 (c =

Data for cis-9h: R_f0.29 (10% EtOAc/CH₂Cl₂); [α]²⁰+62.4 (c =

D

0.44); ¹H NMR (CDCl₃, 300 MHz) δ 2.40 (s, 3 H), 3.51 (dd, 1 H, J =

10.0, 9.0 Hz), 3.89 (dd, 1 H, J = 10.2, 3.8 Hz), 5.11 (ddt, 1 H, J = 9.0,

3.9, 2.2 Hz), 5.19 (t, 1 H, J = 1.9 Hz), 6.85 (t, 1 H, J = 1.9 Hz), 7.16−

7.23 (m, 6 H), 7.25−7.27 (m, 3 H), 7.40 (ddd, 1 H, J = 7.8, 7.3, 1.2

Hz), 7.47 (dd, 1 H, J = 7.8, 1.2 Hz), 7.51 (dd, 1 H, J = 8.1, 1.2 Hz),

7.60 (ddd, 1 H, J = 7.8, 7.1, 1.5 Hz); ¹³C NMR (CDCl₃, 75 MHz)-

HSQC 21.6 (Me p-Tol), 33.9 (CH₂), 67.5 (C-5), 69.8 (C-2), 121.4,

125.3 (2 C), 128.5 (2 C), 128.9 (2 C), 129.3, 129.5, 130.3 (2 C),

130.4, 130.9, 131.4, 134.0 (2 C), 136.1, 137.5, 143.0, 149.6; IR (film)

2923, 1544, 1372, 1171, 1057, 756 cm⁻¹; MS (ESI) 561 [M + H]⁺,

583 [M + Na]⁺; HRMS (ESI) m/z for C₂₄H₂₂BrN₂O₅S₂[M + H]⁺

calcd 561.0154, observed 561.0133.

0.58); ¹H NMR (CDCl₃, 400 MHz)-COSY δ 0.81 (d, 3 H, J = 6.9 Hz,

Me i-Pr), 1.11 (d, 3 H, J = 7.1 Hz, Me i-Pr), 2.25 (m, 1 H, CH i-Pr),

2.42 (s, 3 H, Me p-Tol), 2.49 (s, 3 H, Me p-Tol), 2.64 (dd, 1 H, J =

8.6, 2.9 Hz, OH), 3.67 (ddd, 1 H, J = 11.1, 8.8, 5.3 Hz, CH₂), 3.80

(ddd, 1 H, J = 11.1, 7.1, 3.1 Hz, CH₂), 4.33 (dddd, 1 H, J = 7.5, 5.1,

2.6, 1.1 Hz, H-2), 4.55 (dt, 1 H, J = 2.6, 1.2 Hz, H-5), 6.35 (dd, 1 H,

J = 2.7, 1.3 Hz, H-3), 7.14 (dd, 2 H, J = 8.6, 0.6 Hz, ArH), 7.31 (dd, 2

H, J = 8.6, 0.5 Hz, ArH), 7.44 (dt, 2 H, J = 8.4, 2.0 Hz, ArH), 7.54 (dt,

2 H, J = 8.2, 2.2 Hz, ArH); 1D-NOE CH₂(3.80 ppm)/2 Me i-Pr

(2.6%); CH₂(3.67 ppm)/Me i-Pr (0.81 ppm) (1.2%); Me i-Pr (0.81

ppm)/CH₂(1.5%); ¹³C NMR (CDCl₃, 125 MHz)-HSQC δ 17.1 (Me

i-Pr), 20.2 (Me i-Pr), 21.7 (2 C, Me p-Tol), 31.5 (CH i-Pr), 64.4

(CH₂), 69.1 (C-2), 72.8 (C-5), 127.7 (2 C), 128.1 (2 C), 129.9 (2 C),

130.0 (2 C), 132.7, 135.8, 137.0, 137.1, 144.3, 145.2; IR (film) 3523,

2965, 2928, 1597, 1350, 1319, 1160, 1084, 757 cm⁻¹; MS (ESI) 450

[M + H]⁺; HRMS (ESI) m/z for C₂₂H₂₇NO₅S₂[M]⁺calcd 449.1331,

observed 449.1325.

Data for trans-12d: R_f0.38 (60% EtOAc/hex); [α]²⁰+180.6 (c =

D

0.33); ¹H NMR (CDCl₃, 300 MHz) δ 2.44 (s, 3 H), 3.80 (dd, 1 H, J =

10.7, 1.7 Hz), 4.23 (dd, 1 H, J = 10.9, 4.6 Hz), 5.13 (dd, 1 H, J = 5.1,

1.7 Hz), 5.65 (tt, 1 H, J = 4.6, 2.0 Hz), 6.62 (t, 1 H, J = 2.2 Hz), 6.75

(dd, 1 H, J = 8.1, 1.5 Hz), 6.91−7.21 (m, 6 H), 7.27−7.39 (m, 4 H),

7.44 (m, 2 H); ¹³C NMR (CDCl₃, 75 MHz) δ 21.6, 31.8, 68.0, 70.0,

123.4, 125.3, 126.7 (2 C), 128.6 (2 C), 128.9, 129.3 (2 C), 129.4,

130.3 (2 C), 131.0, 131.1, 132.6, 137.2, 142.9, 143.7, 150.3; IR (film)

2924, 1542, 1368, 1164, 1083, 1049, 758 cm⁻¹; MS (ESI) 561 [M +

H]⁺, 583 [M + Na]⁺.

Data for trans-10h: R_f0.39 (10% EtOAc/CH₂Cl₂); mp 165 °C

1

[α]²⁰+51.3 (c = 0.76); H NMR (CDCl₃, 400 MHz)-COSY δ 0.69

D

(d, 3 H, J = 6.9 Hz, Me i-Pr), 1.08 (d, 3 H, J = 7.3 Hz, Me i-Pr), 1.23

(br s, 1 H, OH), 2.41 (s, 3 H, Me p-Tol), 2.46 (s, 3 H, Me p-Tol), 2.57

(m, 1 H, CH i-Pr), 3.70 (dd, 1 H, J = 12.8, 3.1 Hz, CH₂), 4.06 (dd, 1

H, J = 12.8, 3.1 Hz, CH₂), 4.34 (ddt, 1 H, J = 4.9, 3.1, 1.6 Hz, H-2),

4.81 (ddd, 1 H, J = 4.9, 2.2, 0.9 Hz, H-5), 6.50 (dd, 1 H, J = 1.5, 0.9

Hz, H-3), 7.28 (dd, 2 H, J = 8.6, 0.5 Hz, ArH), 7.35 (dd, 2 H, J = 8.4,

0.6 Hz, ArH), 7.65 (dt, 2 H, J = 8.4, 2.0 Hz, ArH), 7.76 (dt, 2 H, J =

8.2, 2.0 Hz, ArH); 1D-NOE H-2/Me i-Pr (1.5%); Me i-Pr (1.08

ppm)/H-2 (0.1%); Me i-Pr (0.69 ppm)/H-2 (0.5%); ¹³C NMR

(CDCl₃, 100 MHz)-HSQC δ 16.5 (Me i-Pr), 18.1 (Me i-Pr), 21.5 (Me

p-Tol), 21.7 (Me p-Tol), 32.3 (CH i-Pr), 62.5 (CH₂), 68.3 (C-2), 73.9

(C-5), 126.7 (2 C), 128.3 (2 C), 129.9 (2 C), 130.1 (2 C), 135.6,

137.2, 141.4, 143.4, 143.9, 145.3; IR (KBr) 3435, 2959, 2926, 1596,

1335, 1319, 1159, 1090, 812 cm⁻¹; MS (ESI) 450 [M + H]⁺. Anal.

Calcd for C₂₂H₂₇NO₅S₂: C, 58.77; H, 6.05; N, 3.12; S, 14.26. Found:

C, 59.01; H, 6.12; N, 2.98; S, 14.05.

7.2. Synthesis of (−)-(2S,5S)-5-(Bromomethyl)-2-phenyl-3-((S)-

tolylsulfinyl)-1-[(2,4,6-triisopropylphenyl)sulfonyl]-2,5-dihydro-1H-

pyrrole, 11e, and (2S,5R)-5-(Bromomethyl)-2-phenyl-3-((S)-tolylsul-

finyl)-1-[(2,4,6-triisopropylphenyl)sulfonyl]-2,5-dihydro-1H-pyrrole,

12e. From sulfonamide 7f (20 mg, 0.04 mmol, 1.0 equiv), TBATB

(34 mg, 0.07 mmol, 2.0 equiv), and K₂CO₃(12 mg, 0.09 mmol, 2.5

equiv), following the standard procedure (6 days), a crude of 80:20

cis:trans isomers was obtained. Chromatographic purification (10−

50% EtOAc/hex) gave 11e (11 mg, 49%, colorless oil) and 12e (2 mg,

8%, colorless oil).

Data for cis-11e: R_f0.42 (40% EtOAc/hex); [α]²⁰_D−5.9 (c = 0.44);

¹H NMR (CDCl₃, 300 MHz)-COSY δ 0.90 (d, 6 H, J = 6.8 Hz, Me

Ar × 2), 0.93 (d, 6 H, J = 6.8 Hz, Me Ar × 2), 1.18 (d, 6 H, J = 6.8 Hz,

Me Ar × 2), 2.42 (s, 3 H, Me p-Tol), 2.81 (m, 1 H, CH Ar), 3.20 (m, 2

H, CH₂), 3.76 (m, 2 H, CH Ar × 2), 5.03 (t, 1 H, J = 1.7 Hz, H-2),

5.14 (ddt, 1 H, J = 7.8, 6.3, 1.9 Hz, H-5), 6.90 (m, 2 H, ArH), 6.97 (m,

3 H, ArH), 7.15−7.23 (m, 3 H, ArH), 7.26−7.35 (m, 4 H, ArH); ¹³C

NMR (CDCl₃, 125 MHz)-HSQC 21.6 (Me p-Tol), 23.5 (Me Ar),

23.6 (Me Ar), 24.3 (2 C, Me Ar), 24.7 (2 C, Me Ar), 29.1 (2 C, Me

Ar), 33.6 (CH₂), 34.2 (CH Ar), 66.2 (C-5), 68.8 (C-2), 124.0 (2 C),

126.0 (2 C), 128.5 (2 C), 128.6 (2 C), 128.8, 129.7, 130.4 (2 C),

130.6, 137.1, 137.4, 143.3, 149.6, 151.9 (2 C), 154.6; IR (film) 2961,

2927, 1599, 1457, 1314, 1260, 1152, 1084, 1057, 807, 679 cm⁻¹; MS

(ESI) 642 [M + H]⁺, 664 [M + Na]⁺; HRMS (ESI) m/z for

C₃₃H₄₁BrNO₃S₂[M + H]⁺calcd 642.1711, observed 642.1730.

Partial data for trans-12e: R_f0.27 (40% EtOAc/hex); ¹H NMR

(CDCl₃, 300 MHz) δ 1.05 (d, 6 H, J = 6.8 Hz), 1.13 (d, 12 H, J = 6.6

Hz), 2.43 (s, 3 H), 2.72 (m, 1 H), 3.76 (m, 2 H), 3.86 (dd, 1 H,

J = 10.5, 2.4 Hz), 4.00 (dd, 1 H, J = 10.5, 6.2 Hz), 5.03 (dd, 1 H, J =

Data for monoepoxide: R_f0.71 (10% EtOAc/CH₂Cl₂); [α]²⁰

+79.2 (c = 0.80); H NMR (CDCl₃, 300 MHz) δ 0.46 (d, 3 H, J =

D

1

6.6 Hz), 0.95 (d, 3 H, J = 6.6 Hz), 1.95 (m, 1 H), 2.40 (s, 3 H), 2.41

(m, 1 H), 2.42 (s, 3 H), 2.95 (dd, 1 H, J = 5.4, 4.1 Hz), 3.47 (ddd, 1 H,

J = 7.8, 3.9, 2.4 Hz), 4.09 (t, 1 H, J = 10.4 Hz), 6.01 (d, 1 H, J = 8.3

Hz), 6.05 (m, 1 H), 7.25 (d, 2 H, J = 8.1 Hz, ArH), 7.29 (d, 2 H, J =

8.1 Hz), 7.66 (dt, 4 H, J = 8.5, 2.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ

19.4, 19.9, 21.5, 21.7, 31.2, 47.4, 48.5, 59.1, 127.1 (2 C), 128.1 (2 C),

129.5 (2 C), 130.0 (2 C), 133.7, 137.3, 142.3, 143.4, 144.9, 145.0; IR

(film) 3306, 2924, 1722, 1431, 1318, 1303, 1286, 1161, 1144, 1085,

814 cm⁻¹; MS (ESI) 450 [M + H]⁺.

7. General Procedure for the Synthesis of Bromomethyl 3-

Sulfinyl-2,5-dihydro-1H-pyrroles, 11 and 12. To a solution of

sulfonamides 7 in anhydrous CH₂Cl₂(7 mL/mmol) protected from

light were added 2.0 equiv of solid tetrabutylammonium tribromide

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4.6, 2.2 Hz), 5.34 (m, 1 H), 6.73 (t, 1 H, J = 2.2 Hz), 6.77 (m, 3 H),

6.98 (m, 4 H), 7.26 (d, 1 H, J = 8.5 Hz), 7.36 (d, 2 H, J = 8.1 Hz).

7.3. Synthesis of (−)-8-[(2S,5R)-5-(Bromomethyl)-3-((S)-tolylsul-

finyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]sulfonylquinoline, 12f,

and 8-[(2S,5S)-5-(Bromomethyl)-3-((S)-tolylsulfinyl)-2-phenyl-2,5-

dihydro-1H-pyrrol-1-yl]sulfonylquinoline, 11f. From sulfonamide

7g (48 mg, 0.10 mmol, 1.0 equiv), TBATB (95 mg, 0.20 mmol, 2.0

equiv), and K₂CO₃(34 mg, 0.24 mmol, 2.5 equiv), following the

standard procedure (7 days), an 80:20 mixture of 12f and 11f was

obtained, and after chromatographic purification (CH₂Cl₂-10%

EtOAc/CH₂Cl₂), 12f (28 mg, 49%, white solid) and 11f (8 mg,

14%, colorless oil) were obtained.

HRMS (ESI) m/z for C₂₃H₂₂BrN₂O₃S₂[M + 1]⁺calcd 517.0255,

observed 517.0237.

7.5. Synthesis of (2S,5S)-5-(Bromomethyl)-1-(naphthalen-1-ylsul-

fonyl)-2-phenyl-3-((S)-p-tolylsulfinyl)-2,5-dihydro-1H-pyrrole,

11i, and (2S,5R)-5-(Bromomethyl)-1-(naphthalen-1-ylsulfonyl)-2-

phenyl-3-((S)-p-tolylsulfinyl)-2,5-dihydro-1H-pyrrole, 12i. From

sulfonamide 7j (49 mg, 0.1 mmol, 1.0 equiv), TBATB (55 mg, 0.11

mmol, 1.10 equiv), and K₂CO₃(20 mg, 0.15 mmol, 1.5 equiv),

following the standard procedure (6 days), 50% (23 mg) of an

inseparable 78:22 mixture of 2,5-cis 11i and 2,5-trans 12i was obtained.

Data for 2,5-cis 11i from the mixture: R_f0.40 (5% EtOAc/CH₂Cl₂);

¹H NMR (CDCl₃, 300 MHz) δ 2.43 (s, 3 H), 3.48 (t, 1 H, J = 9.3 Hz),

Data for 12f: R_f0.23 (5% EtOAc/CH₂Cl₂); mp 148 °C; [α]²⁰

3.70 (dd, 1 H, J = 10.1, 3.5 Hz), 5.09 (m, 1 H), 5.16 (dm, 1 H, J = 9.0

Hz), 6.82 (t, 1 H, J = 2.0 Hz); HRMS (ESI) m/z for C₂₈H₂₅BrNO₃S₂

[M + H]⁺calcd 566.0459, observed 566.0476.

D

−26.1 (c = 0.72); ¹H NMR (CDCl₃, 500 MHz)-COSY δ 2.42 (s, 3 H,

Me p-Tol), 4.04 (dd, 1 H, J = 10.5, 2.1 Hz, CH₂), 4.32 (dd, 1 H, J =

10.3, 5.1 Hz, CH₂), 5.09 (dd, 1 H, J = 5.1, 2.0 Hz, H-2), 6.51−6.59 (br

s, 4 H, ArH), 6.64 (ddt, 1 H, J = 5.1, 2.0 Hz, H-5), 6.69 (t, 1 H, J = 2.0

Hz, H-4), 6.82 (tt, 1 H, J = 7.3, 1.2 Hz, ArH), 7.01 (dd, 1 H, J = 8.1,

7.6 Hz, ArH), 7.26 (d, 2 H, J = 7.8 Hz, ArH), 7.37 (dt, 2 H, J = 8.1, 1.8

Hz, ArH), 7.44 (dd, 1 H, J = 7.6, 1.3 Hz, ArH), 7.52 (dd, 1 H, J = 8.3,

4.4 Hz, ArH), 7.70 (dd, 1 H, J = 8.1, 1.5 Hz, ArH), 8.14 (dd, 1 H, J =

8.1, 1.8 Hz, ArH), 9.04 (dd, 1 H, J = 4.2, 1.7 Hz, ArH); NOE-1D H-2/

2 CH₂(0.18%); CH₂(4.32 ppm)/H-2 (0.27%); ¹³C NMR (CDCl₃,

125 MHz)-HSQC δ 21.6 (Me p-Tol), 38.9 (CH₂), 68.0 (C-5), 69.5

(C-2), 121.8, 125.3, 126.4 (2 C), 127.5 (2 C), 128.3, 128.8, 130.1

(C-4), 130.2 (2 C), 131.2, 132.2, 133.1, 136.5, 137.3, 139.4, 143.4,

149.5, 150.8 (2 C) (some signals overlap); IR (KBr) 2961, 2927, 1599,

1457, 1314, 1260, 1152, 1084, 1057, 807, 679 cm⁻¹; MS (ESI) 567

[M + H]⁺. Anal. Calcd for C₂₇H₂₃BrN₂O₃S₂: C, 57.14; H, 4.08; N,

4.94; S, 11.30. Found: C, 56.89; H, 4.00; N, 5.08; S, 11.46.

Data for the minor product 2,5-trans 12i from the mixture: R_f0.40

1

(5% EtOAc/CH₂Cl₂); H NMR (CDCl₃, 300 MHz) δ 2.44 (s, 3 H,

Me p-Tol), 4.13 (dd, 1 H, J = 10.4, 2.2 Hz, CH₂), 4.29 (dd, 1 H, J =

10.5, 5.9 Hz, CH₂), 5.08 (m, 1 H, H-2), 5.59 (ddm, 1 H, J = 5.3, 2.2

Hz, H-5), 6.51 (dm, 2 H, J = 8.3 Hz, ArH), 6.68 (t, 1 H, J = 2.1 Hz,

H-4), 6.72 (br t, 2 H, J = 7.6 Hz, ArH).

7.6. Synthesis of (−)-8-[(2S,5R)-5-(Bromomethyl)-2-(3,4-dime-

thoxyphenyl)-3-((S)-p-tolylsulfinyl)-2,5-dihydro-1H-pyrrol-1-yl]-

sulfonylquinoline, 12g, and 8-[(2S,5S)-5-(Bromomethyl)-2-(3,4-

dimethoxyphenyl)-3-((S)-p-tolylsulfinyl)-2,5-dihydro-1H-pyrrol-1-

yl]sulfonylquinoline, 11g. From sulfonamide 7h (45 mg, 0.082 mmol,

1.0 equiv), TBATB (80 mg, 0.164 mmol, 2.0 equiv), and K₂CO₃(29

mg, 0.205 mmol, 1.5 equiv), following the standard procedure (7 days),

a 90:10 mixture of 2,5-trans and 2,5-cis was obtained, and after

chromatographic purification (CH₂Cl₂-10% EtOAc/CH₂Cl₂), 12g (33

mg, 65%, yellow solid) and 11g (5 mg, 9%, colorless oil) were obtained.

Data for 2,5-trans 12g: R_f0.20 (10% EtOAc/CH₂Cl₂); mp 98−

100 °C; [α]²⁰_D−95.0 (c = 0.57); ¹H NMR (CDCl₃, 300 MHz) δ 2.43

(s, 3 H), 2.92 (brs, 3 H), 3.73 (s, 3 H), 4.04 (dd, 1H, J = 10.4, 2.0 Hz),

4.33 (dd, 1 H, J = 10.4, 5.2 Hz), 5.06 (dd, 1 H, J = 5.0, 2.2 Hz), 5.76

(br s, 1 H), 6.34 (m, 2 H), 6.64 (ddm, 1 H, J = 4.2, 1.9 Hz), 6.71 (t, 1

H, J = 1.8 Hz), 7.07 (t, 1 H, J = 7.7 Hz), 7.27 (dm, 2 H, J = 8.5 Hz),

7.39 (dm, 2 H, J = 8.2 Hz), 7.52 (dd, 1 H, J = 3.1, 1.5 Hz), 7.55 (m, 1

H), 7.75 (dd, 1 H, J = 5.0, 1.4 Hz), 8.18 (dd, 1 H, J = 8.4, 2.2 Hz), 9.06

(dd, 1 H, J = 4.2, 1.8 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.8, 39.1,

55.1, 55.9, 68.1, 69.3, 109.7, 121.8, 123.1, 125.0, 125.8, 126.4 (2 C),

128.4, 130.3 (3 C), 130.5, 132.0, 132.3, 136.8, 137.5, 139.4, 143.5,

148.1, 149.3, 149.5, 150.8 (2 C); IR (KBr) 3049, 2932, 1515, 1338,

1261, 1162, 1144, 790, 678 cm⁻¹; HRMS (ESI) m/z for

C₂₉H₂₈BrN₂O₅S₂[M + H]⁺calcd 627.0623, observed 627.0644.

Partial data for the minor product 2,5-cis 11g: R_f= 0.30 (10%

Partial data for the minor product 11f: ¹H NMR (CDCl₃, 300

MHz) δ 3.59 (dd, 1 H, J = 10.2, 9.8 Hz), 4.13 (dd, 1 H, J = 9.8, 3.9

Hz), 5.45 (t, 1 H, J = 1.8 Hz), 5.52 (ddt, 1 H, J = 10.2, 3.9, 2.2 Hz),

8.00 (dd, 1 H, J = 8.3, 1.6 Hz), 8.22 (dd, 1 H, J = 8.5, 1.8 Hz), 8.36

(dd, 1 H, J = 7.6, 1.5 Hz), 8.54 (dd, 1 H, J = 4.1, 1.7 Hz).

7.4. Synthesis of (+)-2-[(2S,5S)-5-(Bromomethyl)-2-phenyl-3-((S)-

p-tolylsulfinyl)-2,5-dihydro-1H-pyrrol-1-yl]sulfonylpyridine, 11j, and

2-[(2S,5R)-5-(Bromomethyl)-2-phenyl-3-((S)-p-tolylsulfinyl)-2,5-di-

hydro-1H-pyrrol-1-yl]sulfonylpyridine, 12j. From sulfonamide 7k

(41 mg, 0.097 mmol, 1.0 equiv), TBATB (52 mg, 0.11 mmol, 1.10

equiv), and K₂CO₃(20 mg, 0.15 mmol, 1.5 equiv), following the

standard procedure (7 days), a 73:27 mixture of 2,5-cis 11j and 2,5-trans

12j was obtained, and after chromatographic purification (CH₂Cl₂-10%

EtOAc/CH₂Cl₂), 11j (23 mg, 46%, white solid) and 12j (8 mg, 16%,

colorless oil) were obtained.

Data for 2,5-cis 11j: R_f0.30 (10% EtOAc/CH₂Cl₂); mp 154−156

1

EtOAc/CH₂Cl₂); H NMR (CDCl₃, 300 MHz) δ 2.39 (s, 3 H), 3.74

1

°C; [α]²⁰+37.0 (c = 0.39); H NMR (CDCl₃, 400 MHz)-COSY δ

D

(s, 3 H), 3.77 (dd, 1 H, J = 10.1, 8.9 Hz), 3.86 (s, 3 H), 4.15 (dd, 1 H,

J = 10.1, 3.7 Hz), 5.47 (m, 1 H), 5.51 (dm, 1 H, J = 8.5 Hz), 6.65−6.78

(m, 4 H), 7.03 (m, 4 H), 7.46−7.55 (m, 2 H), 8.01 (dm, 1 H, J = 8.1

Hz), 8.23 (dm, 1 H, J = 8.4 Hz), 8.34 (dm, 1 H, J = 7.5 Hz), 8.60 (dm,

1 H, J = 4.2 Hz).

2.43 (s, 3 H, Me p-Tol), 3.53 (t, 1 H, J = 9.9 Hz, CH₂), 4.01 (dd, 1 H,

J = 9.7, 3.8 Hz, CH₂), 5.04 (ddt, 1 H, J = 10.1, 4.0, 2.2 Hz, H-5), 5.33

(t, 1 H, J = 2.0 Hz, H-2), 6.88 (t, 1 H, J = 1.8 Hz, H-4), 7.19−7.32 (m,

9 H, ArH), 7.44 (ddd, 1 H, J = 7.5, 4.7, 1.3 Hz, ArH), 7.69 (d, 1 H, J =

7.9 Hz, ArH), 7.77 (td, 1 H, J = 7.8, 1.6 Hz, ArH), 8.43 (dm, 1 H, J =

4.8 Hz, ArH); NOESY-2D H-5/2 CH₂; H-5/H-4; H-4/ArH. ¹³C

NMR (CDCl₃, 125 MHz)-HSQC δ 21.6 (Me p-Tol), 34.4 (CH₂),

68.2 (C-5), 70.7 (C-2), 123.1, 125.7 (2 C), 126.8, 128.3 (2 C), 128.8

(2 C), 129.0, 129.7 (C-4), 130.1 (2 C), 137.1, 137.8, 142.8, 149.4,

149.8 (2 C), 156.4; IR (KBr) 3082, 2923, 1580. 1425, 1343, 1171,

1129, 1060, 1050, 808, 744, 657, 607 cm⁻¹; HRMS (ESI) m/z for

C₂₃H₂₂BrN₂O₃S₂[M + H]⁺calcd 517.0255, observed 517.0221.

Partial data for the minor product 2,5-trans 12j: R_f0.10 (10%

EtOAc/CH₂Cl₂); ¹H NMR (CDCl₃, 400 MHz)-COSY δ 2.44 (s, 3 H,

Me p-Tol), 3.98 (dd, 1 H, J = 10.4, 2.2 Hz, CH₂), 4.19 (dd, 1 H, J =

10.4, 5.5 Hz, CH₂), 5.90 (dd, 1 H, J = 5.1, 1.6 Hz, H-5), 5.90 (ddm, 1

H, J = 4.4, 2.0 Hz, H-5), 6.70 (t, 1 H, J = 1.8 Hz, H-4), 6.78 (dm, 2 H,

J = 7.5 Hz, ArH), 6.91 (br t, 2 H, J = 7.5 Hz, ArH), 7.06 (tm, 1 H, J =

7.3 ArH), 7.23−7.32 (m, 5 H, ArH), 7.40 (d, 2 H, J = 8.2 Hz, ArH),

8.53 (dm, 1 H, J = 4.6 Hz, ArH); ¹³C NMR (CDCl₃, 125 MHz)-

HSQC δ 21.6 (Me p-Tol), 37.6 (CH₂), 68.4 (C-5), 70.0 (C-2), 121.1,

125.8, 126.2 (2 C), 128.0 (2 C), 128.7 (2 C), 129.4, 129.9 (C-4),

130.1 (2 C), 133.8, 137.1, 143.5, 149.3, 149.8 (2 C), 150.0, 159.2;

7.7. Synthesis of 8-[(2S,5S)-5-(Bromomethyl)-2-isopropyl-3-(p-

tolylsulfinyl)-2,5-dihydro-1H-pyrrol-1-yl]sulfonylquinoline, 11h,

and 8-[(2S,5R)-5-(Bromomethyl)-2-isopropyl-3-(p-tolylsulfinyl)-2,5-

dihydro-1H-pyrrol-1-yl]sulfonylquinoline, 12h. From sulfonamide

7i (25 mg, 0.055 mmol, 1.0 equiv), TBATB (53 mg, 0.11 mmol, 2.0

equiv), and K₂CO₃(19 mg, 0.14 mmol, 2.5 equiv), following the

standard procedure (7 days), a 56:44 mixture of cis and trans isomers

was obtained. Chromatographic purification (1−10% EtOAc/CH₂Cl₂)

gave the mixture of both compounds (16 mg, 57%, colorless oil).

Partial data for 2,5-cis-11h: R_f0.15 (5% EtOAc/CH₂Cl₂); ¹H NMR

(CDCl₃, 300 MHz) δ 0.94 (d, 3 H, J = 7.5 Hz), 1.06 (d, 3 H, J = 7.4

Hz), 2.27 (m, 1 H), 2.33 (s, 3 H), 3.44 (dd, 1 H, J = 11.2, 9.0 Hz),

4.04 (dd, 1 H, J = 9.2, 4.2 Hz), 4.21 (m, 1 H), 5.84 (ddm, 1 H, J =

11.5, 4.1 Hz), 6.80 (d, 2 H, J = 7.0 Hz), 6.85 (br s, 1 H), 6.92 (d, 2 H,

J = 7.0 Hz), 7.50 (dd, 1 H, J = 8.3, 4.1 Hz), 7.55 (t, 1 H, J = 7.8 Hz),

8.03 (dd, 1 H, J = 8.1, 1.2 Hz), 8.25 (dd, 1 H, J = 8.3, 1.9 Hz), 8.35

(dd, 1 H, J = 7.4, 1.5 Hz), 8.64 (dd, 1 H, J = 4.2, 1.6 Hz); HRMS

(ESI) m/z for C₂₄H₂₆BrN₂O₃S₂[M + H]⁺calcd 533.0568, observed

533.0583.

537

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Partial data for 2,5-trans-12h: R_f0.10 (5% EtOAc/CH₂Cl₂); ¹H

NMR (CDCl₃, 300 MHz) δ 0.26 (d, 3 H, J = 7.4 Hz), 0.87 (d, 3 H, J =

7.4 Hz), 2.46 (m, 1 H), 2.47 (s, 3 H), 4.02 (dd, 1 H, J = 10.5, 2.5 Hz),

4.12 (m, 1 H), 4.80 (m, 1 H), 6.00 (m, 1 H), 6.69 (br s, 1 H), 7.30 (d,

2 H, J = 7.8 Hz), 7.48 (dd, 1 H, J = 8.3, 4.2 Hz), 7.60 (dd, 1 H, J = 8.0,

7.3 Hz), 7.66 (d, 2 H, J = 8.1 Hz), 8.01 (dd, 1 H, J = 8.3, 1.5 Hz), 8.23

(dd, 1 H, J = 8.6, 2.0 Hz), 8.43 (dd, 1 H, J = 7.6, 1.5 Hz), 8.75 (dm,

1 H, J = 1.9 Hz).

2.45 (s, 3 H, Me p-Tol), 3.21 (dd, 1 H, J = 10.5, 9.5 Hz, CH₂), 3.68

(dd, 1 H, J = 9.5, 3.9 Hz, CH₂), 4.74 (ddt, 1 H, J = 10.5, 3.9, 2.0 Hz,

H-5), 4.86 (t, 1 H, J = 2.0 Hz, H-2), 6.80 (t, 1 H, J = 2.0 Hz, H-4),

7.11 (d, 2 H, J = 8.1 Hz, ArH), 7.17 (m, 4 H, ArH), 7.20 (d, 2 H, J =

7.8 Hz, ArH), 7.29 (m, 3 H, ArH), 7.34 (dt, 2 H, J = 8.3, 1.8 Hz, ArH);

1D-NOE (C₆D₆) between H-2/Ar−H (6.88−7.08 ppm) (6.2%); H-5/

CH₂(2.2%); CH₂(3.55 ppm)/H-5 (2.1%); CH₂(2.97 ppm)/Ar−H

(6.88−7.08 ppm) (1.5%); ¹³C NMR (CDCl₃, 75 MHz)-HSQC δ 7.7

(CH₂), 21.5 (2 C), 68.1, 70.2, 125.6 (2 C), 127.3 (2 C), 128.3 (2 C),

128.8 (2 C), 129.0, 129.7 (2 C), 130.2 (2 C), 130.7, 134.3, 137.1,

137.7, 142.9, 144.0, 149.4; IR (film) 3436, 3032, 2922, 1596, 1493,

1455, 1353, 1306, 1164, 1087, 1056, 865, 810, 756, 700, 667, 587, 549

cm⁻¹; MS (ESI) 578 [M + H]⁺(100%), 1177 [2M + Na]⁺. Anal.

Calcd for C₂₅H₂₄INO₃S₂: C, 51.99; H, 4.19; N, 2.43; S, 11.10. Found:

C, 52.04; H, 4.31; N, 2.21; S, 11.01.

7.8. Synthesis of (2S,5S)-5-(Bromomethyl)-2-methyl-2-phenyl-3-

(p-tolylsulfinyl)-1-(p-tolylsulfonyl)-2,5-dihydro-1H-pyrrole, 11k, and

(+)-(2S,5R)-5-(Bromomethyl)-2-methyl-2-phenyl-3-(p-tolylsulfinyl)-

1-(p-tolylsulfonyl)-2,5-dihydro-1H-pyrrole, 12k. From sulfonamide

7l (30 mg, 0.06 mmol, 1.0 equiv), TBATB (58 mg, 0.12 mmol, 2.0

equiv), and K₂CO₃(21 mg, 0.15 mmol, 2.5 equiv), following the

standard procedure (3 days), a 35:65 mixture of cis and trans isomers

was obtained. Chromatographic purification (10−50% EtOAc/hex) gave

a pure fraction of the major isomer 12k (14 mg, 43%, yellow solid).

Data for trans-12k: R_f₁0.30 (40% EtOAc/hex); mp 111−113 °C;

Data for 2,5-trans-14a: R_f0.17 (40% EtOAc/hex); mp 205 °C;

1

[α]²⁰+84.2 (c = 0.99); H NMR-COSY (CDCl₃, 300 MHz) δ 2.28

D

(s, 3 H, Me p-Tol), 2.43 (s, 3 H, Me p-Tol), 3.83 (dd, 1 H, J = 10.2,

2.3 Hz, CH₂), 3.90 (dd, 1 H, J = 10.1, 6.1 Hz, CH₂), 4.80 (ddt, 1 H,

J = 5.9, 2.0 Hz, H-5), 5.04 (dd, 1 H, J = 5.1, 1.5 Hz, H-2), 6.57 (t, 1 H,

J = 1.7 Hz, H-4), 6.85 (m, 6 H, ArH), 7.06 (t, 2 H, J = 7.6 Hz, ArH),

7.22 (m, 1 H, ArH), 7.29 (d, 2 H, J = 7.8 Hz, ArH), 7.42 (d, 2 H, J =

7.8 Hz, ArH); ¹³C NMR (CDCl₃, 75 MHz)-HSQC δ 12.9 (CH₂), 21.4

(Me p-Tol), 21.6 (Me p-Tol), 66.2 (C-5), 70.2 (C-2), 126.3 (2 C),

126.4 (2 C), 128.4 (2 C), 128.9, 129.0 (2 C), 129.5 (2 C), 130.3 (2

C), 130.5, 133.8, 137.2, 137.6, 142.7, 143.5, 150.6; IR (KBr) 3435,

2920, 1595, 1455, 1344, 1309, 1160, 1092, 1058, 814, 704, 675, 597,

549, 506 cm⁻¹; MS (ESI) 578 [M + H]⁺(100%), 1177 [2M + Na]⁺.

Anal. Calcd for C₂₅H₂₄INO₃S₂: C, 51.99; H, 4.19; N, 2.43; S, 11.10.

Found: C, 52.13; H, 4.25; N, 2.37; S, 11.12.

9. Synthesis of (+)-(2S,5R)-5-Methyl-2-phenyl-3-((S)-p-tolyl-

sulfinyl)-1-(p-tolylsulfonyl)-2,5-dihydro-1H-pyrrole, 16a. To a

solution of 13a (13 mg, 0.02 mmol, 1.0 equiv) in anhydrous toluene

(10 mL/mmol) were added Bu₃SnH (0.007 mL, 0.02 mmol, 1.1 equiv)

and AIBN (0.5 equiv). The solution was heated at 80 °C for 16 h. The

solvent was removed under reduced pressure, and 16a was obtained as a

colorless oil (8 mg, 81%) after chromatography (10−40% EtOAc/hex).

Data for 16a: R_f0.12 (40% EtOAc/hex); [α]²⁰_D+129.1 (c = 0.33);

¹H NMR (CDCl₃, 500 MHz)-COSY δ 1.53 (d, 3 H, J = 6.6 Hz, Me),

2.38 (s, 3 H, Me p-Tol), 2.45 (s, 3 H, Me p-Tol), 4.71 (qt, 1 H, J = 6.6,

2.1 Hz, H-5), 4.92 (t, 1 H, J = 1.7 Hz, H-2), 6.46 (t, 1 H, J = 2.0 Hz,

H-4), 7.08 (d, 2 H, J = 8.1 Hz, ArH), 7.15 (m, 2 H, ArH), 7.21 (m, 4

H, ArH), 7.30 (m, 5 H, ArH); ¹³C NMR (CDCl₃, 75 MHz)-HSQC δ

21.5 (Me p-Tol), 21.6 (Me p-Tol), 22.9 (Me), 63.6 (C-5), 69.3 (C-2),

125.7 (2 C), 127.2 (2 C), 128.1 (2 C), 128.7, 128.8 (2 C), 129.5

(2 C), 130.2 (2 C), 132.7, 135.3 (2 C), 137.9, 142.9, 143.4, 146.8; 1D-

NOE between H-4/H-5 (1.7%); H-4/Me (1.1%); H-2/Ar−H (7.15−

7.21 ppm) (5.2%); H-5/H-4 (2.0%); Me/Ar−H (1.2%); Me/H-4

(0.8%); Me/H-5 (2.0%), Me/Ph (7.15−7.21 ppm) (1.0%); IR (film)

3031, 2926, 1597, 1493, 1455, 1350, 1305, 1163, 1083, 1053, 1014,

810, 752, 699, 666, 607 cm⁻¹; MS (ESI) 452 [M + H]⁺(100%), 474

[M + Na]⁺; HRMS (ESI) m/z for C₂₅H₂₆NO₃S₂[M + H]⁺calcd

452.1354, observed 452.1322.

10. Synthesis of (+)-(2S,5R)-5-(Iodomethyl)-2-phenyl-1,3-

bis(p-tolylsulfonyl)-2,5-dihydro-1H-pyrrole, 18. To a stirred

solution of 10c^10a(5.0 mg, 0.01 mmol, 1.0 equiv), triphenylphosphine

(11 mg, 0.04 mmol, 4.0 equiv), and imidazole (3 mg, 0.04 mmol, 4.0

equiv) in dry toluene (0.5 mL) was added iodine (8 mg, 0.03 mmol,

3.0 equiv), and the resulting mixture was refluxed for 2 h. After

cooling, the solution was treated with saturated aqueous NaHCO₃

(10 mL/mmol), and after stirring for 10 min, it was diluted with

EtOAc (10 mL/mmol). The phases were separated; the organic phase

was washed with saturated aqueous Na₂S₂O₄(2 × 10 mL/mmol) and

dried over Na₂SO₄. Filtration, evaporation under reduced pressure,

and further purification of the crude (10−40% EtOAc/hex) yielded

the desired product 18 as a colorless oil (3.2 mg, 54%).

[α]²⁰+68.4 (c = 0.68); H NMR (CDCl₃, 300 MHz)-COSY δ 1.63

D

(s, 3 H, Me), 2.33 (s, 3 H, Me p-Tol), 2.42 (s, 3 H, Me p-Tol), 3.84

(dd, 1 H, J = 10.3, 7.1 Hz, CH₂), 4.11 (dm, 1 H, J = 10.0 Hz, CH₂),

4.96 (dt, 1 H, J = 7.1, 2.7 Hz, H-5), 6.82 (d, 2 H, J = 8.3 Hz, ArH

sulfoxide), 6.87 (d, 2 H, J = 2.4 Hz, H-4), 6.93 (d, 2 H, J = 7.2 Hz,

ArH sulfoxide), 7.03−7.12 (m, 4 H, ArH, Ph), 7.21−7.28 (m, 3 H,

ArH Ph, sulfonamide), 7.46 (d, 2 H, J = 8.0 Hz, ArH, sulfonamide);

1D NOESY between Me/H-Ph (7.03−7.12 ppm) (5%); CH₂(3.84

ppm)/Me (1.8%); CH₂(3.84 ppm)/H-5 (2%); CH₂(3.84 ppm)/CH₂

(4.11 ppm) (21%); CH₂(4.11 ppm)/H-5 (3.0%); CH₂(4.11 ppm)/

H-4 (0.5%); H-5/2 × CH₂(3.5%); H-5/H-4 (3%); ¹³C NMR

(CDCl₃, 75 MHz) δ 21.4, 21.6, 26.8, 36.4, 65.8, 75.4, 126.7 (2 C),

126.8 (2 C), 128.1, 128.2 (2 C), 128.3, 129.0 (2 C), 130.2, 136.7,

136.8, 139.2, 142.8, 143.5, 154.0 (some signals overlap); IR (film)

2926, 1597, 1494, 1448, 1340, 1036 cm⁻¹; HRMS (ESI) m/z for

C₂₆H₂₇BrNO₃S₂[M + H]⁺calcd 544.0616, observed 544.0606.

Partial data for the minor isomer 11k: R_f0.40 (40% EtOAc/hex);

¹H NMR (CDCl₃, 300 MHz) δ 1.63 (s, 3 H, Me), 2.37 (s, 3 H, Me

p-Tol), 2.39 (s, 3 H, Me p-Tol), 3.43 (dd, 1 H, J = 10.0, 8.5 Hz, CH₂),

4.11 (dd, 1 H, J = 10.3, 3.2 Hz, CH₂), 4.96 (dm, 1 H, J = 8.5 Hz, H-5),

6.78 (d, 1 H, J = 1.9 Hz, H-4), 7.12−7.39 (m, 13 H, ArH).

8. Synthesis of (+)-(2S,5S)-5-(Iodomethyl)-2-phenyl-3-((S)-

tolylsulfinyl)-1-(p-tolylsulfonyl)-2,5-dihydro-1H-pyrrole, 13a,

and (+)-(2S,5R)-5-(Iodomethyl)-2-phenyl-3-((S)-tolylsulfinyl)-1-

(p-tolylsulfonyl)-2,5-dihydro-1H-pyrrole, 14a. To a solution of

sulfonamide 7b^10a(43 mg, 0.10 mmol, 1.0 equiv) in a 10:1 mixture of

CH₃CN/H₂O (10 mL/mmol) protected from light were added

K₂CO₃(40 mg, 0.29 mmol, 3.0 equiv) and I₂(73 mg, 0.29 mmol, 3.0

equiv) at rt. The mixture was stirred until the disappearance of 7b

by TLC. Then, it was quenched with a saturated solution of Na₂S₂O₄

(10 mL/mmol), extracted with CH₂Cl₂(3 × 10 mL/mmol), and

washed with a saturated solution of NaCl (10 mL/mmol). It was dried

over Na₂SO₄and filtered, and the solvent was evaporated under

reduced pressure to give a 42:58 mixture of 2,5-cis and 2,5-trans

dihydropyrroles. Chromatographic purification (10−50% EtOAc/hex)

gave cis (13 mg, 23%, colorless oil) and trans (25 mg, 43%, white

solid).

Alternatively, a solution of 7b (48 mg, 0.11 mmol, 1.0 equiv) in

CH₂Cl₂(7 mL/mmol) protected from light, with solid K₂CO₃(88 mg,

0.64 mmol, 6.0 equiv) and NIS (105 mg, 0.48 mmol, 4.4 equiv), at rt

was stirred for 4 days. A similar workup gave a crude mixture of 56:44

cis:trans isomers. Chromatographic purification (10−50% EtOAc/hex)

gave cis (25 mg, 39%, colorless oil) and trans (20 mg, 32%, white

solid).

Also, a solution of 7b (19 mg, 0.04 mmol, 1.0 equiv) in toluene

(14 mL/mmol) protected from light, with solid K₂CO₃(26 mg, 0.19

mmol, 4.5 equiv) and NIS (26 mg, 0.19 mmol, 4.5 equiv), at rt was

stirred for 4 days. A similar workup gave a crude mixture of 21:79

cis:trans isomers. Chromatographic purification (10−50% EtOAc/hex)

gave cis (2 mg, 8%, colorless oil) and trans (15 mg, 65%, white solid).

Alternatively, from dihydropyrrole 14a (4 mg, 0.01 mmol, 1.0

equiv) and m-CPBA (5 mg, 0.02 mmol, 2.0 equiv) in CH₂Cl₂(5 h at

rt), and after an aqueous workup and chromatographic purification

Data for 2,5-cis-13a: R_f0.24 (40% EtOAc/hex); [α]²⁰+76.4 (c =

D

0.47); ¹H NMR (CDCl₃, 500 MHz)-COSY δ 2.40 (s, 3 H, Me p-Tol),

538

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Article

(CH₂Cl₂-5% EtOAc/CH₂Cl₂), an identical product was obtained

(2 mg, 46%).

2′/H-3 (1.8%); H-3/H-1′+H-2′ (1.5%); ¹³C NMR (CDCl₃, 75 MHz)-

HSQC δ 19.9, 21.0, 21.6, 21.7, 25.3, 30.0, 57.9, 68.9, 124.0, 125.4,

126.6 (2 C), 128.3 (2 C), 129.6 (2 C), 129.7 (2 C), 135.9, 137.0,

143.0, 144.8; MS (ESI) 1015 [2M + 2 + Na]⁺(100%), 527 [M +

MeOH]⁺.

Data for 18: R_f0.13 (20% EtOAc/hex); [α]²⁰_D+28.1 (c = 0.21); ¹H

NMR (CDCl₃, 500 MHz)-COSY δ 2.26 (s, 3 H, Me p-Tol), 2.33 (s, 3

H, Me p-Tol), 3.76 (dd, 1 H, J = 10.0, 7.4 Hz, CH₂), 3.95 (dd, 1 H, J =

10.0, 2.4 Hz, CH₂), 4.83 (ddt, 1 H, J = 7.4, 5.4, 2.4 Hz, H-5), 5.67 (dd,

1 H, J = 5.4, 1.2 Hz, H-2), 6.70 (d, 2 H, J = 6.6 Hz, ArH), 6.83−6.88

(m, 7 H, ArH), 7.03 (d, 2 H, J = 7.8 Hz, ArH), 7.08 (t, 1 H, J = 7.3 Hz,

ArH), 7.29 (d, 2 H, J = 8.3 Hz, ArH); ¹³C NMR (CDCl₃, 75 MHz)-

HSQC δ 10.4 (CH₂), 21.4 (Me p-Tol), 21.6 (Me p-Tol), 66.0 (C-5),

70.8 (C-2), 121.7, 126.5 (2 C), 128.0 (2 C), 128.2 (2 C), 128.4, 129.0

(2 C), 129.4, 129.6 (2 C), 139.6 (some signals overlap); IR (film)

2923, 1735, 1596, 1456, 1326, 1156, 1088, 811, 759, 698 cm⁻¹; MS

(ESI) 594 [M + H]⁺, 616 [M + Na]⁺; HRMS (ESI) m/z for

C₂₅H₂₅INO₄S₂[M + H]⁺calcd 594.0270, observed 594.0265.

11. General Procedure for the Synthesis of Sulfinyl

Aziridines, 19. To a solution of sulfonamide 7 in CH₂Cl₂(7 mL/

mmol) protected from light were added 4.5−6.0 equiv of solid K₂CO₃

and 1.0−4.0 equiv of NBS (in fractions of 1.5 equiv of K₂CO₃and 1.0

equiv of NBS) at rt. The mixture was stirred until the disappearance

of 7 as monitored by TLC. It was quenched with a 1 M solution of

Na₂S₂O₄(20 mL/mmol), extracted with CH₂Cl₂(3 × 15 mL/mmol),

and washed with a saturated solution of NaCl (10 mL/mmol). Then, it

was dried over Na₂SO₄and filtered, and the solvent was evaporated

under reduced pressure to give a crude product that was purified by

chromatography on deactivated silica gel using the appropriate mixture

of eluents.

Partial data for 20b: R_f0.52 (5% EtOAc/CH₂Cl₂); ¹H NMR

(CDCl₃, 500 MHz)-COSY δ 0.79 (d, 3 H, J = 6.8 Hz, Me i-Pr), 1.16

(d, 3 H, J = 6.8 Hz, Me i-Pr), 2.10 (m, 1 H, CH i-Pr), 2.42 (s, 3 H, Me

p-Tol), 2.45 (s, 3 H, Me p-Tol), 2.92 (d, 1 H, J = 10.0 Hz, H-3), 3.90

(ddd, 1 H, J = 9.8, 8.1, 1.0 Hz, CH₂Br), 3.98 (ddd, 1 H, J = 10.8, 6.8,

1.2 Hz, CH₂Br), 5.64 (d, 1 H, J = 15.2 Hz, H-1′), 6.13 (ddd, 1 H, J =

14.9, 7.8, 6.8 Hz, H-2′), 7.28 (d, 2 H, J = 7.8 Hz, ArH), 7.32 (d, 2 H,

J = 7.8 Hz, ArH), 7.50 (d, 2 H, J = 8.1 Hz, ArH), 7.73 (d, 2 H, J = 8.3

Hz, ArH); 1D-NOE between H-3/H-1′ (0.61%); H-3/H-2′ (0.85%);

H-3/CH i-Pr (0.52%); H-3/Me (1.16 ppm) (1.7%); H-3/Me (0.79

ppm); 1.6%; H-1′/H-3: 0.14%; H-1′/CH₂(1.6%); H-2′/H-3 (1.2%);

H-2′/CH₂(1.9%).

11.3. Synthesis of (2R,3S)-[2-((1E)-3-Bromo-1-propen-1-yl)-3-

butyl-2-((S)-p-tolylsulfinyl)-1-(p-tolylsulfonyl)]aziridine, 19c, and

(2R,3S)-[2-((1E)-3-Bromo-1-propen-1-yl)-3-butyl-2-((R)-p-tolylsulfin-

yl)-1-(p-tolylsulfonyl)]aziridine, 20c. From sulfonamide 7d (42 mg,

0.10 mmol, 1.0 equiv), K₂CO₃(100 mg, 0.72 mmol, 7.5 equiv), and

NBS (95 mg, 0.54 mmol, 5.0 equiv), following the general procedure (5

days), an 80:20 mixture of 19c and 20c was obtained. Chromatographic

purification (10−50% EtOAc/hex) yielded a fraction of 70:30 mixture

of aziridines 19c and 20c (28 mg, 56%) as a colorless oil.

Data for major isomer 19c from the mixture: R_f0.35 (40% EtOAc/

hex); ¹H NMR (CDCl₃, 300 MHz)-COSY δ 0.81 (d, 3 H, J = 7.0 Hz,

Me n-Bu), 1.16−1.35 (m, 4 H, CH₂n-Bu), 1.82 (q, 2 H, J = 6.8 Hz,

CH₂n-Bu), 2.40 (s, 3 H, Me p-Tol), 2.45 (s, 3 H, Me p-Tol), 3.22 (dd,

1 H, J = 7.6, 6.1 Hz, H-3), 3.77−3.90 (m, 2 H, CH₂Br), 5.86 (ddd, 1

H, J = 15.6, 7.8, 5.9 Hz, H-2′), 5.96 (d, 1 H, J = 15.6 Hz, H-1′), 7.30

(m, 4 H, ArH), 7.49 (d, 2 H, J = 8.3 Hz, ArH), 7.86 (d, 2 H, J = 8.3

Hz, ArH); ¹³C NMR (CDCl₃, 75 MHz)-HSQC δ 13.8, 21.5, 21.7,

22.0, 27.0, 29.8 (CH₂n-Bu), 30.2 (CH₂Br), 50.7 (C-3), 69.4 (C-2),

122.3 (C-1′), 125.8 (2 C), 128.1 (2 C), 129.6 (2 C), 129.8 (2 C),

136.2 (C-2′), 137.0, 137.8, 142.7, 144.8; IR (film) 2956, 2927, 1596,

1454, 1335, 1163, 1089, 1059, 811 cm⁻¹; HMRS (ESI) m/z for

C₂₃H₂₈BrNNaO₃S₂[M + Na]⁺calcd 532.0592, observed 532.0596.

Partial data for 20c from the mixture: ¹H NMR (CDCl₃, 300

MHz)-COSY δ 2.42 (s, 3 H, Me p-Tol), 2.46 (s, 3 H, Me p-Tol),

3.89−4.01 (m, 2 H, CH₂Br), 5.64 (d, 1 H, J = 15.4 Hz, H-1′), 6.17 (m,

1 H, H-2′), 7.49 (d, 2 H, J = 8.3 Hz, ArH), 7.73 (d, 2 H, J = 8.3 Hz,

ArH).

11.1. Synthesis of (−)-(2R,3S)-[2-((1E)-3-Bromo-1-propen-1-yl)-3-

phenyl-2-((S)-p-tolylsulfinyl)-1-(p-tolylsulfonyl)]aziridine, 19a.

From sulfonamide 7b^10a(86 mg, 0.19 mmol, 1.0 equiv), K₂CO₃

(120 mg, 0.87 mmol, 4.5 equiv), and NBS (102 mg, 0.57 mmol, 3.0

equiv), following the general procedure (2 days) and after chromato-

graphic purification (10−50% EtOAc/hex), aziridine 19a (55 mg,

55%) was obtained as a single diastereomer (colorless oil) with minor

amounts of dihydropyrroles 11a:12a, (45:55, 16 mg, 16%).

Data for 19a: R_f0.31 (40% EtOAc/hex); [α]²⁰−27.1 (c = 0.70);

D

¹H NMR (CDCl₃, 500 MHz)-selective decouplings δ 2.30 (s, 3 H, Me

p-Tol), 2.43 (s, 3 H, Me p-Tol), 3.93 (m, 2 H, CH₂Br), 4.36 (s, 1 H,

H-3), 5.88 (ddd, 1 H, J = 15.2, 8.6, 6.6 Hz, H-2′), 6.32 (d, 1 H, J = 15.4

Hz, H-1′), 6.67 (dd, 2 H, J = 6.6, 1.7 Hz, ArH), 7.05 (d, 2 H, J = 8.1

Hz, ArH), 7.25 (m, 2 H, ArH), 7.34 (m, 5 H, ArH), 7.91 (dt, 2 H, J =

8.3, 1.7 Hz, ArH); 1D-NOE between H-3/H-1′ (0.8%); H-3/H-2′

(2.6%); H-2′/H-3 (2.3%); H-1′/H-3 (0.5%); ¹³C NMR (CDCl₃, 75

MHz)-HSQC δ 21.4 (Me p-Tol), 21.7 (Me p-Tol), 30.2 (CH₂), 50.1

(C-3), 71.2 (C-2), 120.0, 125.3 (2 C), 127.9 (3 C), 128.6 (2 C), 129.1,

129.4 (2 C), 129.8 (2 C), 130.4, 136.0, 136.1, 137.3 (2 C), 142.4,

145.0; IR (film) 3030, 2923, 1596, 1492, 1452, 1402, 1331, 1163,

1089, 1032, 811, 755, 700, 666 cm⁻¹; HRMS (ESI) m/z for

C₂₅H₂₅BrNO₃S₂[M + H]⁺calcd 530.0459, observed 530.0460.

11.2. Synthesis of (2R,3S)-[2-((1E)-3-Bromo-1-propen-1-yl)-3-

isopropyl-2-((S)-p-tolylsulfinyl)-1-(p-tolylsulfonyl)]aziridine, 19b,

and (2R,3S)-[2-((1E)-3-Bromo-1-propen-1-yl)-3-isopropyl-2-((R)-p-

tolylsulfinyl)-1-(p-tolylsulfonyl)]aziridine, 20b. From sulfonamide

7c^10a(39 mg, 0.09 mmol, 1.0 equiv), K₂CO₃(57 mg, 0.42 mmol,

4.5 equiv), and NBS (48 mg, 0.27 mmol, 3.0 equiv), following the

general procedure (1.5 days), an 80:20 mixture of 19b and 20b was

obtained. Chromatographic purification (10−50% EtOAc/hex, deacti-

vated silica) yielded an 80:20 mixture of aziridines 19b and 20b

(38 mg, 83%) as a colorless oil. Further purification on silica gel

allowed us to isolate small amounts of both pure products; however,

they were unstable under these conditions.

12. General Procedure for the Oxidation of Sulfinyl

Aziridines with MMPP, 21. To a cold (0 °C) solution of aziridines

19 and 20 in MeOH (5 mL/mmol), solid MMPP was added, and after

5 min it was allowed to warm to rt. The reaction was stirred at this

temperature until disappearance of the starting material (monitored

by TLC). Then, it was quenched with saturated aqueous NaHCO₃

(0.3 mL/mmol), and the solvent was evaporated under reduced

pressure. The crude was purified with deactivated silica gel to give

sulfonyl aziridines 21 using the appropriate mixture of eluents.

12.1. Synthesis of (−)-(2R,3S)-[2-((1E)-3-Bromo-1-propen-1-yl)-3-

isopropyl-1,2-bis(p-tolylsulfonyl)]aziridine, 21b. From an 80:20

mixture of aziridines 19b:20b (26 mg, 0.05 mmol, 1.0 equiv) and

MMPP (49 mg, 0.08 mmol, 1.5 equiv), following the general procedure

(18 h) and after chromatographic purification of the crude (10−40%

EtOAc/hex), 21b was obtained as a colorless oil (20 mg, 75%).

Data for 21b: R_f0.20 (20% EtOAc/hex); [α]²⁰−43.2 (c = 0.34);

D

¹H NMR (CDCl₃, 500 MHz)-COSY δ 0.68 (d, 3 H, J = 6.6 Hz, Me

i-Pr), 1.12 (d, 3 H, J = 6.8 Hz, Me i-Pr), 2.44 (m, 1 H, CH i-Pr), 2.45

(s, 6 H, Me p-Tol), 2.92 (d, 1 H, J = 10.3 Hz, H-3), 3.88 (m, 2 H,

CH₂Br), 5.79 (d, 1 H, J = 15.2 Hz, H-1′), 6.21 (ddd, 1 H, J = 15.2, 8.1,

7.1 Hz, H-2′), 7.34 (t, 4 H, J = 7.7 Hz, ArH), 7.76 (dt, 2 H, J = 8.3, 1.7

Hz, ArH), 7.81 (dt, 2 H, J = 8.6, 1.9 Hz, ArH); 1D-NOE between

H-1′/H-3 (0.25%); H-1′/CH₂(2.3%); H-2′/CH₂(2%); H-2′/H-3

(2%); ¹³C NMR (CDCl₃, 75 MHz)-HSQC δ 19.8, 21.1, 21.7 (2 C),

26.0, 29.8 (CH₂), 59.1 (C-3), 67.6, 123.3, 125.6, 128.3 (4 C), 129.7

(4 C), 137.7 (2 C), 145.2, 145.6; IR (film) 2967, 2926, 1597, 1332,

Data for 19b: R_f0.42 (5% EtOAc/CH₂Cl₂); ¹H NMR (CDCl₃, 300

MHz)-COSY δ 0.71 (d, 3 H, J = 6.6 Hz, Me i-Pr), 1.03 (d, 3 H, J = 6.8

Hz, Me i-Pr), 2.24 (m, 1 H, CH i-Pr), 2.41 (s, 3 H, Me p-Tol), 2.44 (s,

3 H, Me p-Tol), 2.90 (d, 1 H, J = 10.0 Hz, H-3), 3.82 (dd, 1 H, J =

10.5, 8.5 Hz, CH₂Br), 3.90 (dd, 1 H, J = 10.5, 6.1 Hz, CH₂Br), 5.84 (d,

1 H, J = 15.4 Hz, H-1′), 5.98 (ddd, 1 H, J = 14.9, 8.8, 6.1 Hz, H-2′),

7.28 (d, 2 H, J = 8.1 Hz, ArH), 7.32 (d, 2 H, J = 8.3 Hz, ArH), 7.58 (d,

2 H, J = 8.1 Hz, ArH), 7.86 (d, 2 H, J = 8.3 Hz, ArH); 1D-NOE

between H-1′/CH₂(2.6%); H-1′/H-3 (0.6%); H-2′/CH₂(2.7%); H-

539

dx.doi.org/10.1021/jo202144k | J. Org. Chem. 2012, 77, 525−542

The Journal of Organic Chemistry

Article

1163, 1082, 965, 814, 745, 708, 677 cm⁻¹; MS (ESI) 1047 [2M + 2 +

Na]⁺, 512 [M + 1]⁺; HRMS (ESI) m/z for C₂₂H₂₇BrNO₄S₂[M + H]⁺

calcd 512.0565, observed 512.0577.

12.2. Synthesis of (−)-(2R,3S)-[2-((1E)-3-Bromo-1-propen-1-yl)-3-

butyl-1,2-bis(p-tolylsulfonyl)]aziridine, 21c. From a 70:30 mixture of

aziridines 19c:20c (30 mg, 0.06 mmol, 1.0 equiv) and MMPP (54 mg,

0.088 mmol, 1.5 equiv), following the general procedure (17 h) and

after chromatographic purification of the crude (10−40% EtOAc/hex),

21c was obtained as a colorless oil (21 mg, 68%).

14.1. Synthesis of (2S,3S)-3-Isopropyl-1,2-bis-(p-tolylsulfonyl)-

aziridine-2-carbaldehyde, 23b, and (+)-(2R,3S)-3-Isopropyl-1,2-bis-

(p-tolylsulfonyl)aziridine, 24b. From sulfonamide 21b (20 mg, 0.04

mmol, 1.0 equiv), following general procedure A for ozonolysis (50

min), a 90:10 mixture of 23b:24b was obtained (10 mg, 61%).

Oxidation of the mixture (9 days) using TCCA (70 mg, 0.3 mmol, 10

equiv), 15% NaHCO₃aqueous solution (0.9 mL), and NaBr afforded

a pure fraction of 24b as a white oil (8.1 mg, 86%).

Data for 23b from the mixture: ¹H NMR (CDCl₃, 300 MHz) δ 0.91

(d, 3 H, J = 6.7 Hz, Me i-Pr), 1.12 (d, 3 H, J = 6.8 Hz, Me i-Pr), 2.45

(s, 3 H, Me p-Tol), 2.48 (s, 3 H, Me p-Tol), 2.52−2.60 (m, 1 H, CH

i-Pr), 3.41 (d, 1 H, J = 10.0 Hz, H-3), 7.34 (d, 2 H, J = 9.0 Hz, ArH),

7.37 (d, 2 H, J = 8.9 Hz, ArH), 7.78 (dt, 2 H, J = 8.4, 1.8 Hz, ArH),

7.87 (dt, 2 H, J = 8.4, 1.8 Hz, ArH), 9.42 (s, 1 H, CHO).

Data for 21c: R_f0.43 (70% Et₂O/hex); [α]²⁰_D−61.0 (c = 0.29); ¹H

NMR (CDCl₃, 500 MHz) δ 0.79 (t, 3 H, J = 7.0 Hz, Me n-Bu), 1.15−

1.30 (m, 4 H, CH₂n-Bu), 1.98 (m, 2 H, CH₂n-Bu), 2.45 (s, 6 H, Me

p-Tol), 3.21 (dd, 1 H, J = 8.3, 5.6 Hz, H-3), 3.83−3.90 (m, 2 H,

CH₂Br), 5.84 (d, 1 H, J = 15.1 Hz, H-1′), 6.20 (ddd, 1 H, J = 15.1, 8.3,

6.8 Hz, H-2′), 7.33 (d, 4 H, J = 7.8 Hz, ArH), 7.74 (dt, 2 H, J = 8.3, 1.9

Hz, ArH), 7.81 (dt, 2 H, J = 8.3, 1.5 Hz, ArH); ¹³C NMR (CDCl₃, 75

MHz)-HSQC δ 13.8 (Me n-Bu), 21.7 (Me p-Tol), 21.8 (Me p-Tol),

22.1 (CH₂n-Bu), 26.1 (CH₂n-Bu), 29.7 (CH₂), 29.9 (CH₂), 52.4

(C-3), 67.2 (C-2), 123.2 (C-1′), 128.1 (2 C), 129.7 (6 C), 134.7,

135.8, 137.6 (C-2′), 145.0, 145.5; IR (film) 2958, 2928, 1597, 1455,

1332, 1163, 1083, 955, 814 cm⁻¹; HRMS (ESI) m/z for

C₂₃H₂₈BrNNaO₄S₂[M + Na]⁺calcd 548.0541, observed 548.0536.

13. Synthesis of (−)-1-[(E)-3-[(2R,3S)-3-Phenyl-2-(S)-p-tolyl-

sulfinyl-1-tolylsulfonylaziridin-2-yl]-2-propen-1-yl]piperidine,

22. To a solution of aziridine 19a (39 mg, 0.07 mmol, 1.0 equiv) in

toluene (0.7 mL) was added piperidine (2.0 equiv, 0.014 mL, 0.15

mmol), and it was stirred at rt until disappearance of the starting

material by TLC (2 h). The solvent was evaporated under reduced

pressure, and the crude was purified on deactivated silica (1−5% EtOH/

CH₂Cl₂) to yield a pure fraction of aziridine 22 as a colorless oil (28 mg,

71%).

Data for 24b: R_f0.25 (60% Et₂O/hex); [α]²⁰_D+52.6 (c = 0.81); ¹H

NMR (CDCl₃, 500 MHz)-COSY δ 0.92 (d, 3 H, J = 6.8 Hz, Me i-Pr),

1.13 (d, 3 H, J = 6.8 Hz, Me i-Pr), 2.37−2.48 (m, 1 H, CH i-Pr), 2.42

(s, 3 H, Me p-Tol), 2.44 (s, 3 H, Me p-Tol), 2.80 (dd, 1 H, J = 10.3,

6.8 Hz, H-3), 3.84 (d, 1 H, J = 6.8 Hz, H-2), 7.18 (d, 2 H, J = 7.8 Hz,

ArH), 7.20 (d, 2 H, J = 7.8 Hz, ArH), 7.60 (dt, 2 H, J = 8.3, 1.9 Hz,

ArH), 7.62 (dt, 2 H, J = 8.3, 1.9 Hz, ArH); 1D-NOE between H-3/H-

2 (2.0%); H-2/H-3 (3.0%); ¹³C NMR (CDCl₃, 125 MHz)-HSQC δ

19.7 (Me i-Pr), 21.2 (Me i-Pr), 21.7 (2 C, Me p-Tol), 26.2 (CH i-Pr),

53.0 (C-3), 57.4 (C-2), 128.3 (2 C), 128.4 (2 C), 129.6 (2 C), 129.8

(2 C), 133.6, 135.8, 145.2 (2 C); IR (film) 2969, 2928, 1597, 1466,

1336, 1303, 1162, 1086, 977, 891, 813, 759, 680 cm⁻¹; HRMS (ESI)

m/z for C₁₉H₂₇N₂O₄S₂[M+NH₄]⁺calcd 411.1412, observed

411.1421.

14.2. Synthesis of (2S,3S)-3-Butyl-1,2-bis-(p-tolylsulfonyl)-

aziridine-2-carbaldehyde, 23c, and (+)-(2R,3S)-3-Butyl-1,3-bis-(p-

tolylsulfonyl)aziridine, 24c. From sulfonamide 21c (15 mg, 0.03

mmol, 1.0 equiv), following general procedure B for ozonolysis

(30 min), a 90:10 mixture of 23c:24c was obtained (8 mg, 66%).

Oxidation of the mixture (4 days) with TCCA (42 mg, 0.18 mmol, 10

equiv), 15% NaHCO₃aqueous solution (0.54 mL), and NaBr afforded

a pure fraction of 24c as a colorless oil (4.6 mg, 63%).

Data for 22: R_f0.14 (10% EtOH/CH₂Cl₂); [α]²⁰_D−34.8 (c = 0.99);

¹H NMR (CDCl₃, 300 MHz) δ 1.43 (br s, 2 H), 1.59 (br s, 4 H), 2.20

(m, 2 H), 2.29 (s, 3 H), 2.42 (m, 2 H), 2.42 (s, 3 H), 3.08 (m, 2 H),

4.46 (s, 1 H), 5.82 (m, 1 H), 6.29 (d, 1 H, J = 15.6 Hz), 6.63 (dt, 2 H,

J = 8.3, 1.7 Hz), 7.03 (d, 2 H, J = 8.1 Hz), 7.24−7.34 (m, 7 H), 7.90

(dt, 2 H, J = 8.3, 1.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 21.4, 21.7,

23.6, 25.2, 50.1 (2 C), 54.2 (2 C), 60.4, 72.6, 124.9 (2 C), 127.8 (4 C),

127.8 (2 C), 128.6 (2 C), 129.0, 129.2 (2 C), 129.8 (2 C), 130.6,

136.4 (2 C), 142.1, 144.9; IR (film) 2933, 1597, 1494, 1453, 1340,

1164, 1090, 1056, 908, 812, 752 cm⁻¹; HRMS (ESI) m/z for

C₃₀H₃₅N₂O₃S₂[M + H]⁺calcd 535.2089, observed 535.2091.

14. Procedure for the Synthesis of Ditosyl Aziridines, 24.

Step 1: Ozonolysis.

1

Partial data for 23c: H NMR (CDCl₃, 300 MHz) δ 0.86 (m, 3 H,

Me n-Bu), 1.30−1.39 (m, 4 H, CH₂n-Bu), 1.99−2.19 (m, 2 H, CH₂

n-Bu), 2.42 (s, 3 H, Me p-Tol), 2.45 (s, 3 H, Me p-Tol), 3.08 (dd, 1 H,

J = 12.9, 7.3 Hz, H-3), 7.32 (d, 2 H, J = 8.5 Hz, ArH), 7.36 (d, 2 H, J =

8.5 Hz, ArH), 7.78 (d, 2 H, J = 8.3 Hz, ArH), 7.86 (d, 2 H, J = 8.3 Hz,

ArH), 9.43 (s, 1 H, CHO).

Data for 24c: R_f0.21 (50% Et₂O/hex); [α]²⁰_D+46.1 (c = 0.46); ¹H

NMR (CDCl₃, 500 MHz)-COSY δ 0.86 (t, 3 H, J = 7.0 Hz, Me n-Bu),

1.30−1.39 (m, 4 H, CH₂n-Bu), 1.95−2.06 (m, 2 H, CH₂n-Bu), 2.42

(s, 3 H, Me p-Tol), 2.44 (s, 3 H, Me p-Tol), 3.08 (ddd, 1 H, J = 8.3,

6.8, 5.4 Hz, H-3), 3.82 (d, 1 H, J = 7.3 Hz, H-2), 7.18 (d, 2 H, J = 7.8

Hz, ArH), 7.21 (d, 2 H, J = 7.8 Hz, ArH), 7.61 (d, 4 H, J = 8.3 Hz,

ArH); 1D-NOE between H-3/H-2 (2.8%); H-2/H-3 (2.9%); ¹³C

NMR (CDCl₃, 125 MHz)-HSQC δ 13.8 (Me n-Bu), 21.7 (2 C), 22.1,

25.9 (CH₂n-Bu), 29.6 (CH₂n-Bu), 46.7 (C-3), 57.1 (C-2), 128.3 (4

C), 129.7 (2 C), 129.8 (2 C), 133.7, 135.8, 145.2 (2 C); IR (film)

2958, 2927, 2860, 1597, 1456, 1335, 1162, 1086, 814, 717 cm⁻¹;

HRMS (ESI) m/z for C₂₀H₂₉N₂O₄S₂[M + NH₄]⁺calcd 425.1569,

observed 425.1556.

Procedure A: To a cold (0 °C) solution of aziridine 21 in a 95:5

acetone/H₂O solution (7 mL/mmol), O₂was bubbled for 10 min,

followed by a flow of O₃. The reaction was stirred at this temperature

until disappearance of the starting material by TLC. The reaction was

diluted with hexane (10 mL/mmol), quenched with a saturated

solution of NaCl (10 mL/mmol), and extracted with EtOAc (3 × 10

mL/mmol). The combined organic phases were washed with a

saturated solution of NaCl (10 mL/mmol), dried over Na₂SO₄, and

filtered, and the solvent was evaporated under reduced pressure. The

1

crude was analyzed by H NMR and submitted to further oxidation.

Procedure B: To a cold (−78 °C) solution of aziridine 21 in

CH₂Cl₂(19 mL/mmol), O₂was bubbled for 10 min, followed by a

flow of O₃. The reaction was allowed to reach −50 °C and was stirred

until the disappearance of the starting material by TLC. SMe₂was

added (5 equiv), and the reaction was warmed to rt. The solvent was

evaporated under reduced pressure, and the crude was analyzed by ¹H

NMR and submitted to further oxidation.

ASSOCIATED CONTENT

■

S

* Supporting Information

Spectral data (¹H NMR and ¹³C NMR) for new compounds

and X-ray data and structures. This material is available free of

charge via the Internet at http://pubs.acs.org.

Step 2: Oxidation with TCCA.

To a solution of the above mixtures in acetone (10 mL/mmol), a

15% NaHCO₃aqueous solution (30 mL/mmol) was added. The

reaction was cooled to 0 °C, and solid trichloroisocianuric acid

(TCCA, 10 equiv) and NaBr (0.2 equiv) were added. The reaction

was then stirred at rt for 4−10 days. The reaction was quenched with

ⁱPrOH (0.6 mL/mmol), and the crude was filtered through Celite.

Finally, the solvent was evaporated under reduced pressure, followed

by purification on deactivated silica gel.

AUTHOR INFORMATION

■

Corresponding Author

*Fax: (+34) 915644853. E-mail: iqov379@iqog.csic.es.

540

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The Journal of Organic Chemistry

Article

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ACKNOWLEDGMENTS

■

This research was supported by MICINN (CTQ2009-07752).

We thank Ms. Virginia de Elvira and Ms. Mercedes Zurro for

technical support. We also thank CM for additional support to

M.U., MEC for fellowships to I.C., MAA and CSIC for a

contract to R.H.B. (201080E101), and Cesar J. Pastor from X-

́

ray Laboratory of UAM.

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91. (e) Sweeney, J. Eur. J. Org. Chem. 2009, 4911−4919. For selected

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The Journal of Organic Chemistry

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Article Doi

An approach to the stereoselective synthesis of enantiopure dihydropyrroles and aziridines from a common sulfinyl-sulfinamide intermediate

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