Synthesis of β-Amino Ketones by Addition of Aryl Methyl Ketones to Sulfinimines: Application to the Total Synthesis of HPA-12, Norsedamine, and Sedamine

Article abstract of DOI:10.1021/acs.joc.7b02611

Synthesis of β-sulfinamido ketones was accomplished by the addition of silyl enol ethers derived from arylmethyl ketones to chiral sulfinimines in excellent yield and selectivity. Application of the formed β-amino substituted ketones is exemplified in the total synthesis of sphingolipid HPA-12 and the sedamine alkaloids.

Full text of DOI:10.1021/acs.joc.7b02611

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Article
Synthesis of #-Amino Ketones by Addition of Aryl
Methyl Ketones to Sulfinimines: Application to the
Total Synthesis of HPA-12, Norsedamine and Sedamine
Arava Amaranadha Reddy, and Kavirayani R Prasad
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02611 • Publication Date (Web): 21 Nov 2017
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The Journal of Organic Chemistry
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Synthesis of βꢀAmino Ketones by Addition of Aryl
Methyl Ketones to Sulfinimines: Application to the
Total Synthesis of HPAꢀ12, Norsedamine and Sedamine
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Arava Amaranadha Reddy and Kavirayani R. Prasad*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
Eꢀmail: prasad@orgchem.iisc.ernet.in; FAX: +918023600529
Abstract: Synthesis of
derived from arylmethyl ketones to chiral sulfinimines in excellent yield and selectivity. Application of
the formed ꢀamino substituted ketones is exemplified in the total synthesis of sphingolipid HPAꢀ12 and
the sedamine alkaloids.
βꢀsulfinamido ketones is accomplished by the addition of silyl enol ethers
β
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Introduction
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The pioneering work of Davis and Ellman concerning the nucleophilic addition reactions of chiral
sulfinimines has revolutionized the synthesis of amine containing compounds.1 The ability of chiral
sulfinimines to exert excellent stereoselectivity in nucleophilic reactions, coupled with the ease of
deprotection of the sulfinyl group stabilized the sulfinimines as the most frequently used compounds for
an alleviated synthesis of chiral amines. Although a number of nucleophilic addition reactions of
sulfinimines were documented in literature, the direct addition of ketones to sulfinimines to access the
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β
ꢀsulfinamido ketones, a building block with potential application in the synthesis of a number of
natural products, is scantily addressed. Prior to our efforts Davis and Yang reported the addition of
potassium enolates of ketones to benzylidine paraꢀtoluenesulfinamide2 while Han’s group documented
the addition of indanone derived lithium enolates to sulfinimines.3a Han’s group also reported the
addition of lithium enolate of acetophenone to trifluoro acetaldehyde derived sulfinimine.3b Herein, we
report a systematic study in developing an optimized protocol for the addition of different aryl methyl
ketones to functionalized and nonꢀfunctionalized sulfinimines and their application to the total synthesis
of simple sedamine alkaloids and ceramide trafficking inhibitor sphingolipid HPAꢀ12.
Results and Discussion
We commenced our study with the addition of acetophenone to the N-tertꢀbutylsulfinylimine 1a
(prepared from tertꢀbutyldiphenylsilyloxy acetaldehyde) using KHDMS as base. The reaction afforded
the diastereomeric sulfinamido ketones 3a:2a in 80:20 diastereomeric ratio in 71% yield. Interestingly,
when the addition of the silyl enol ether derived from acetophenone to the sulfinimine 1a was carried
out, the reaction furnished the product sulfinamido ketones 2a:3a in 96:4 ratio and the major
diastereomer 2a was isolated in 83% yield (Scheme 1). Similar outcome was observed in our earlier
work concerning the addition of metal enolates/ silyl enol ethers derived from enones to sulfinimines.4
The reversal of diastereoselectivity in the addition of potassium enolate versus silyl enol ether can be
explained using a chelation controlled chair transition state TS-l and Cram’s open transition state TS-ll
as described earlier.2,4
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Scheme 1: Addition of potassium enolate/silyl enol ether derived from acetophenone to sulfinimine 1a
After having established that the addition of silyl enol ether derived from acetophenone to the
sulfinimine 1a proceeds with good diastereoselectivity, we generalized the reaction with several silyl
enol ethers derived from various arylmethyl ketones. In all cases, the reaction furnished the products
with excellent diastereoselecitvity and in good yields. Addition of ortho aryl substituted acetophenones
such as orthoꢀflouro, bromo acetophenone afforded the product
βꢀsulfinamido ketones 2d-2e in
excellent selectivity and yields, while the reaction of silyl enol ethers derived from 2ꢀacetyl thiophene
and 2ꢀacetyl furan furnished the corresponding products 2j-2k in good yield and with excellent
selectivity. Addition of silyl enol ether derived from acetophenone to the sulfinimine 1b prepared from
acetaldehyde afforded the product 2l in a separable 85:15 ratio with 2l being the major diastereomer
isolated in 67% yield. Structure and absolute stereochemistry of 2l was confirmed by single crystal Xꢀ
ray analysis. Reaction of silyl enol ether derived from acetophenone to the sulfinimine 1c prepared from
isobutyraldehyde afforded the product 2m in mere 6% yield5 although the selectivity is >99:1. The
addition of neither the silyl enol ether nor the potassium enolate derived from acetophenone to
sulfinimine 1g prepared from pivalaldehyde furnished the required product. Formation of the product 2o
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was observed in 90% yield with excellent diastereoselectivity in the reaction of silyl enol ether derived
from acetophenone and sulfinimine 1e derived from ethylglyoxalate. Addition of silyl enol ether derived
from 3ꢀpentanone to the sulfinimine 1a afforded the product 2p6 as a nonꢀseparable 82:18
diastereomeric ratio in 62% yield. All the above results are summarized in Chart 1.
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Chart 1: Addition of silyl enol ethers derived from arylmethyl ketones to sulfiniminesa-c
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b
aUnless indicated all reactions were carried out with the silyl enol ethers derived from arylmethyl ketones. Diastereomeric
ratios were determined based on 1H NMR. cYield refer to isolated yield after column purification. dNonꢀseparable mixture of
diastereomers. eSeparable mixture of diastereomers.
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After successful addition of the silyl enol ethers derived from arylmethyl ketones to sulfinimines,
generalization of the procedure for the addition of potassium enolates derived from arylmethyl ketones
to various sulfinimines was under taken. It was found that the addition of paraꢀmethyl, paraꢀ methoxy,
paraꢀnitro acetophenones to the sulfinimine 1a afforded the products 3c-3f with very good selectivity
and yields. Reaction of potassium enolates of 2ꢀacetylnapthalene and 9ꢀacetylanthracene with the
sulfinimine 1a furnished the products 3i and 3q in 80:20 and 78:22 diastereomeric ratios respectively
with moderate yields. The formation of products 3j and 3r-3s were observed in excellent selectivity and
yields in the addition of potassium enolates of hetero arylmethyl ketones such as 2ꢀacetylthiophene, 2ꢀ
actylpyridine and 3ꢀacetylꢀN-benzyl indole to sulfinimine 1a. Addition of acetophenone to sulfinimines
1bꢀ1c, 1f (prepared from cyclohexylcarboxaldehyde) yielded the products 3l-3m, 3t in excellent
diastereoselectivity and in moderate yields. The addition of acetophenone to sulfinimine 3u derived
from benzaldehyde furnished the product in 97% yield as a single diastereomer, both the physical and
spectral properties were good in agreement with that reported in literature.3c Further, this addition was
extended to sulfinimines derived from 4ꢀmethoxy benzaldehyde, 4ꢀnitro benzaldehyde and furfural to
afford the products 3v-x in excellent diastereoselectivity and yields. All the results are summarized in
Chartꢀ2.
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As observed earlier (vide supra) addition of potassium enolate derived from acetophenone to
sulfinimine 1a afforded the diastereomer 3a as the major product. To check the generality of the
diastereomeric switch and to explore the reactivity towards other sulfinimines, addition of a number of
potassium enolates derived from arylmethyl ketones to various sulfinimines was undertaken.
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Chart 2: Addition of potassium enolates derived from arylmethyl ketones to sulfiniminesa-c
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aUnless indicated all reactions were carried out with the potassium enolates derived from arylmethyl ketones.
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bDiastereomeric ratios were determined based on H NMR. Yield refer to isolated yield after column purification. Nonꢀ
separable mixture of diastereomers. eSeparable mixture of diastereomers.
The utility of formed
βꢀsulfinamido ketones 2a-x/3a-x are exemplified in short synthesis of the
alkaloids norsedamine and sedamine as shown below. Reduction of the ketone in 2n (86:14
diastereomeric mixture) afforded the alcohol 4 in 58% yield as a major diastereomer after column
purification. Treatment of 4 with NaH furnished the cyclized product 5 in almost quantitative yield.
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Deprotection of the sulfinamide in 5 yielded norsedamine 6 in 99% yield, the physical and spectral
properties of which is identical in all aspects with that reported in literature.7 Reductive alkylation of the
6 with aq. formaldehyde in the presence of sodium cyanoborohydride yielded sedamine 7, the physical
characteristics of which were in good agreement with that reported in literature.7 (Schemeꢀ2)
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Scheme 2: Total synthesis of norsedamine 6 and sedamine 7
Similarly, reduction of the ketone in 2a' (enantiomer of 2a) with NaBH4 furnished a mixture of
separable diastereomeric alcohols 8a and 8b in 44% and 46% yields respectively. After separation of the
diastereomers, individually they were subjected to deprotection of the sulfinyl group followed by amide
formation with dodecanoic acid to afford the corresponding amide 9a in 64% yield. Deprotection of the
TBDPS group completed the synthesis of the reported structure of HPAꢀ12 10a (Scheme 3). Following
a similar sequence, the other isomer 8b was transformed to the revised structure of HPAꢀ12 10b. Both
physical and spectral data of compounds 10a and 10b were in good agreement with that reported in
literature.8 In an alternate route for the synthesis of HPAꢀ12 the sulfinamido group in the keto ester 2o'
(enantiomer of 2o) was deprotected which on reaction with dodecanoic acid afforded the keto amide 11
in 90% yield. Diastereoselectivity reduction of the keto group as well as reduction of the ester in 11 is a
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procedure reported by Kobayashi et al.9 This route constitutes a formal synthesis of HPAꢀ12 (Scheme
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Scheme 3: Total synthesis of 3ꢀepiꢀHPAꢀ12 10a and HPAꢀ12 10b
Scheme 4: Formal synthesis of HPAꢀ12 10b
In conclusion, an efficient synthesis of βꢀamino ketones was accomplished by the addition of silyl enol
ethers derived from arylmethyl ketones to chiral sulfinimines. High diastereoselctivity and
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enantioselectivities were observed in the reaction. Application of the strategy is demonstrated in a short
synthesis of HPAꢀ12, norsedamine and sedamine.
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Experimental:
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General Procedures: Column chromatography was performed on silica gel, Acme grade 100ꢀ200
mesh. TLC plates were visualized either with UV, in an iodine chamber, or with phosphomolybdic acid
spray, unless noted otherwise. All reagents were purchased from commercial sources and used without
additional purification. THF was freshly distilled over Naꢀbenzophenone ketyl. Melting points were
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uncorrected. Unless stated otherwise, H NMR and C NMR spectra were recorded either on a 400
machine in CDCl3 as solvent with TMS as reference unless otherwise indicated. Highꢀresolution mass
spectra (HRMS) were recorded on a QꢀTOF micromass spectrometer using electron spray ionization
mode. Sulfinimine 1a and 1d were prepared according to the procedure described by us earlier.4 All
other sulfinimines were prepared according to the procedure described by Ellman et al.10a and Morgas et
al.10b
General procedure A for the addition of pottasium enolate derived from the arylmethyl ketones to
the sulfinimine 1a: The following preparation of 3a is representative.
(R)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-phenylbutan-
1-one (3a): To a preꢀcooled (−78 °C) stirred solution of acetophenone (0.08 g, 0.67 mmol) in dry THF
(10 mL) under argon atmosphere at −78 °C was added KHMDS (0.5 M solution in toluene 1.34 mL,
0.67 mmol). The reaction mixture was stirred for 1 h at the same temperature and the sulfinimine 1a
(0.1 g, 0.25 mmol) dissolved in 5 mL dry THF was added at −78 °C. The reaction mixture was stirred at
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the same temperature for additional 2 hours which was quenched by addition of saturated NH4Cl
solution (20 mL) and was extracted with EtOAc (2 × 20 mL). The organic layer was washed with brine
(20 mL) and dried over Na2SO4. Evaporation of solvent followed by silica gel column chromatography
of the resulting crude residue with petroleum ether/EtOAc as eluent afforded the sulfinamide 3a in 93%
yield (0.121 g) as a 80:20 diastereomeric mixture. Major isomer was separated using silica gel column
chromatography in 71% yield (0.092 g) as a gummy mass. [α]D24 +19.6 (c 0.5, CHCl3). IR (Neat): νmax
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3582, 2930, 2857, 1682, 1110, 1069 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.85 (d, J = 7.6 Hz, 2H), 7.57
(dd, J = 16.4, 7.2 Hz, 5H), 7.46 (t, J = 7.6 Hz, 2H), 7.42ꢀ7.24 (m, 6H), 4.22 (d, J = 9.2 Hz, 1H), 4.03ꢀ
3.89 (m, 1H), 3.85 (dd, J = 10, 3.6 Hz, 1H), 3.80 (dd, J = 10, 4.8 Hz, 1H), 3.55 (m, 2H), 1.19 (s, 9H),
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1.03 (s, 9H). C NMR (100 MHz, CDCl3):
δ 198.9, 136.8, 135.45 (2C), 135.41 (2C), 133.3, 133.0,
132.9, 129.8 (2C), 128.6 (2C), 128.1 (2C), 127.7 (4C), 65.8, 55.9, 54.9, 40.6, 26.8 (3C), 22.5 (3C), 19.2.
HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C30H39NO3SSi+Na 544.2318.; found 544.2314.
General procedure B for the addition of silyl enol ether derived from the arylmethyl ketones to
the sulfinimines 1a-1e: The following preparation of 2a is representative:
(S)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-phenylbutan-
1-one (2a): To a preꢀcooled solution of acetophenone (0.06 g, 0.5 mmol) in dry CH2Cl2 (5 mL) at 0 °C
under argon atmosphere was added Et3N (0.19 mL, 1.4 mmol) followed by TMSOTf (0.18 mL, 1
mmol). The reaction mixture was stirred for 1 h at the same temperature. After completion of the
reaction (TLC) it was quenched by addition of saturated NaHCO3 solution (20 mL). The reaction
mixture was diluted with petroleum ether (30 mL) and was stirred for 5 minutes. The organic layer was
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separated and was washed with water (20 mL), brine (20 mL) and was dried over Na2SO4. Evaporation
of solvent gave the silyl enol ether which was used in the next step without further purification.
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A solution of the crude silyl enol ether (obtained above) in dry CH2Cl2 (5 mL) under argon atmosphere
was cooled to −78 °C and sulfinimine 1a (0.1 g, 0.25 mmol) dissolved in dry CH2Cl2 (5 mL) was added.
TMSOTf (0.09 mL, 0.5 mmol) was introduced into the reaction mixture and was stirred for 0.5h at −78
°C. After completion of the reaction (TLC), it was quenched by addition of saturated NaHCO3 solution
(20 mL) and was extracted with EtOAc (2 × 20 mL). The organic layer was washed with brine and dried
over Na2SO4. Evaporation of solvent followed by silica gel column chromatography of the resulting
crude residue with petroleum ether/EtOAc as eluent afforded the product 2a as a 94:6 diastereomeric
mixture). Major isomer was separated using silica gel column chromatography in 83% yield (0.108 g) as
a gummy mass. [α]D24 +8.0 (c 1.0, CHCl3). IR (Neat) 3416, 2930, 2858, 1682, 1590, 1111, 1065 cm−1.
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1H NMR (400 MHz, CDCl3):
δ 7.89 (d, J = 7.2 Hz, 2H), 7.70ꢀ7.51 (m, 5H), 7.50ꢀ7.26 (m, 8H), 4.15ꢀ
4.00 (m, 2H), 3.98 (dd, J = 10, 3.6 Hz, 1H), 3.35 (dd, J = 17.2, 6.4 Hz, 1H), 3.14 (dd, J = 17.2, 5.2 Hz,
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1H), 1.15 (s, 9H), 1.07 (s, 9H). C NMR (100 MHz, CDCl3):
δ 198.1, 136.8, 135.6 (2C), 135.5 (2C),
133.2, 133.1, 132.7, 129.8 (2 C), 128.6 (3C), 128.1 (3C), 127.8 (4C), 66.3, 55.8, 54.4, 41.2, 26.9 (3C),
22.5 (3C), 19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C30H39NO3SSi+Na 544.2318; found:
544.2321.
(S)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(4-
nitrophenyl)butan-1-one (2b): Compound 2b was prepared from 4ꢀnitro acetophenone (0.1 g, 0.60
mmol) and sulfinimine 1a (0.10 g, 0.25 mmol) using the general procedure B described above in 74%
yield (0.104 g) as a gummy mass. [α]D24 +7.3 (c 1.8, CHCl3). IR (Neat) 3380, 2929, 2856, 1691, 1527,
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1346, 1111, 1014 cm−1. H NMR (400 MHz, CDCl3):
δ 8.29 (d, J = 9.2 Hz, 2H), 8.01 (d, J = 9.2 Hz,
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2H), 7.69ꢀ7.56 (m, 4H), 7.47ꢀ7.29 (m, 6H), 4.13ꢀ4.00 (m, 2H), 3.98 (dd, J = 10, 5.2 Hz, 1H), 3.88 (dd, J
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= 10, 4 Hz, 1H), 3.38 (dd, J = 16.8, 6.8 Hz, 1H), 3.15 (dd, J = 17.2, 5.2 Hz, 1H), 1.16 (s, 9H), 1.08 (s,
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9H). C NMR (100 MHz, CDCl3):
δ 196.6, 150.4, 141.2, 135.6 (2C), 135.5 (2C), 133.0, 132.6, 129.9,
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129.1 (3C), 127.8 (3C), 123.8 (4C), 66.2, 55.9, 53.9, 41.8, 26.9 (3C), 22.5 (3C), 19.3. HRMS (ESIꢀ
TOF) m/z: [M+Na]+ calcd for C30H38N2O5SSi+Na 589.2168; found: 589.2170.
(R)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(4-
nitrophenyl)butan-1-one (3b): Compound 3b was prepared from 4ꢀnitro acetophenone (0.123 g, 0.74
mmol) and sulfinimine 1a (0.15 g, 0.37 mmol) using the general procedure A described above in 71%
yield (0.150 g) as a gummy mass. [α]D24 +37.9 (c 1.0, CHCl3). IR (Neat) 3380, 2929, 2856, 1691, 1527,
1
1346, 1111, 1014 cm−1. H NMR (400 MHz, CDCl3):
δ 8.29 (d, J = 8.8 Hz, 2H), 8.07 (d, J = 9.2 Hz,
2H), 7.64ꢀ7.49 (m, 4H), 7.48ꢀ7.23 (m, 6H), 4.09 (d, J = 9.6 Hz, 1H), 4.02ꢀ3.90 (m, 1H), 3.90ꢀ3.76 (m,
13
2H), 3.66ꢀ3.45 (m, 2H), 1.19 (s, 9H), 1.03 (s, 9H). C NMR (100 MHz, CDCl3):
δ 197.2, 160.9, 150.4,
141.1, 135.43 (2C), 135.40 (2C), 132.8, 129.9 (2C), 129.1 (2C), 127.8 (4C), 123.8 (2C), 65.8, 56.0,
54.6, 41.4, 26.8 (3C), 22.5 (3C), 19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C30H38N2O5SSi+Na
589.2168; found: 589.2170.
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(S)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(p-tolyl)butan-
1-one (2c): Compound 2c was prepared from 4ꢀmethyl acetophenone (0.04 g, 0.30 mmol) and
sulfinimine 1a (0.060 g, 0.15 mmol) using the general procedure B described above in 76% yield (0.061
g) as a gummy mass. [α]D24 +5.1 (c 1.7, CHCl3). IR (Neat) 3583, 2934, 2857, 1679, 1108, 1017 cm−1.
1
2
3
4
5
6
7
8
9
1H NMR (400 MHz, CDCl3):
δ 7.79 (d, J = 8 Hz, 2H), 7.70ꢀ7.56 (m, 4H), 7.46ꢀ7.28 (m, 6H), 7.25 (d, J
10
11
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= 8 Hz, 2H), 4.15ꢀ3.99 (m, 2H), 3.97 (dd, J = 10, 5.2 Hz, 1H), 3.86 (dd, J = 10, 4 Hz, 1H), 3.32 (dd, J =
13
16.8, 6.8 Hz, 1H), 3.12 (dd, J = 16.8, 5.6 Hz, 1H), 1.15 (s, 9H), 1.07 (s, 9H). C NMR (100 MHz,
CDCl3):
δ 197.7, 144.0, 135.6 (2C), 135.5 (2C), 134.5, 133.1, 132.8, 129.79, 127.77, 129.2 (2C), 128.2
(2C), 127.74 (2C), 127.73 (2C), 66.4, 55.8, 54.5, 41.1, 26.9 (3C), 22.5 (3C), 19.2. HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd for C31H41NO3SSi+Na 558.2474; found: 558.2479.
(R)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(p-
tolyl)butan-1-one (3c): Compound 3c was prepared from 4ꢀmethyl acetophenone (0.1 g, 0.75 mmol)
and sulfinimine 1a (0.15 g, 0.37 mmol) using the general procedure A described above in 72% yield
(0.130 g) as a gummy mass. [α]D24 +16.7 (c 1.4, CHCl3). IR (Neat) 3583, 2934, 2857, 1679, 1108, 1017
cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.93 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6
Hz, 2H), 7.48ꢀ7.20 (m, 8H), 4.25 (d, J = 8.8 Hz, 1H), 3.94 (m, 1H), 3.84 (dd, J = 10.4, 4.0 Hz, 1H), 3.79
13
(dd, J = 10.0, 5.2 Hz, 1H), 3.64ꢀ3.42 (m, 2H), 2.42 (s, 3H), 1.19 (s, 9H), 1.03 (s, 9H). C NMR (100
MHz, CDCl3):
δ 198.5, 144.1, 135.44 (2C), 135,41 (2C), 134.4, 133.0, 132.9, 129.8 (2C), 129.2 (2C),
128.3 (2C), 127.7 (4C), 65.8, 55.9, 54.9, 40.4, 26.8 (3C), 22.5 (3C), 21.6, 19.2. HRMS (ESIꢀTOF) m/z:
[M+Na]+ calcd for C31H41NO3SSi+Na 558.2474; found: 558.2479.
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1
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(S)-1-(2-bromophenyl)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-
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butyldiphenylsilyl)oxy)butan-1-one (2d): Compound 2d was prepared from 2ꢀbromo acetophenone
(0.075 g, 0.38 mmol) and sulfinimine 1a (0.1 g, 0.25 mmol) using the general procedure B described
above in 86% yield (0.128 g) as a white solid. Mp: 104ꢀ106 °C. [α]D24 +15.4 (c 0.5, CHCl3). IR (Neat)
3253, 2930, 2856, 1703, 1110, 1037 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.66 (t, J = 6.4 Hz, 4H), 7.60
(d, J = 8 Hz, 1H), 7.47ꢀ7.22 (m, 9H), 4.07ꢀ3.90 (m, 3H), 3.83 (d, J = 6.8 Hz, 1H), 3.37 (dd, J = 17.2, 6.8
Hz, 1H), 3.17 (dd, J = 17.6, 4 Hz, 1H), 1.19 (s, 9H), 1.07 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ
201.6,
141.1, 135.6 (2C), 135.5 (2C), 133.8, 133.1, 132.8, 131.8, 139.9, 129.0, 127.8 (5C), 127.5, 118.8, 66.4,
55.8, 54.0, 45.6, 26.9 (3C), 22.6 (3C), 19.3. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C30H38BrNO3SSi+Na 622.1423; found: 622.1424.
(S)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(2-
fluorophenyl)butan-1-one (2e): Compound 2e was prepared from 2ꢀfluoro acetophenone (0.042 g, 0.30
mmol) and sulfinimine 1a (0.015 g, 0.15 mmol) using the general procedure B described above in 74%
yield (62% g) as a gummy mass. [α]D24 +12.3 (c 0.6, CHCl3). IR (Neat) 3402, 2927, 2857, 1686, 1455,
1111 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.79 (dt, J = 7.6, 1.6 Hz, 1H), 7.65 (dt, J = 8.0, 1.2 Hz, 4H),
7.60ꢀ7.46 (m, 1H), 7.47ꢀ7.27 (m. 6H), 4.10ꢀ4.0 (m, 2H), 3.97 (dd, J = 10, 4.8 Hz, 1H), 3.82 (dd, J =
10.4, 3.6 Hz, 1H), 3.39 (ddd, J = 29.6, 7.2, 3.2 Hz, 1H), 3.19 (ddd, J = 17.2, 4.0, 2.8 Hz, 1H), 1.16 (s,
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9H), 1.07 (s, 9H). C NMR (100 MHz, CDCl3):
δ 196.2, 135.6 (2C), 135.5 (2C), 134.8, 134.7, 133.1,
1
2
3
4
5
6
7
8
132.8, 130.6 (d, J = 2.5 Hz), 129.8, 127.8 (3C), 127.7 (3C), 124.5 (d, J = 3.3 Hz), 116.8, 116.6, 66.5,
55.8, 54.3 (d, J = 2 Hz), 46.4 (d, J = 7.3 Hz), 26.8 (3C), 22.5 (3C), 19.3. HRMS (ESIꢀTOF) m/z:
[M+Na]+ calcd for C30H38FNO3SSi+Na 562.2223; found: 562.2226.
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(S)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(4-
methoxyphenyl)butan-1-one (2f): Compound 2f was prepared from 4ꢀmethoxy acetophenone (0.045 g,
0.30 mmol) and sulfinimine 1a (0.045 g, 0.15 mmol) using the general procedure B described above in
80% yield (0.067 g) as a gummy mass. [α]D24 +4.5 (c 2.2, CHCl3). IR (Neat) 3434, 2957, 2857, 1674,
1
1600, 1172, 1111 cm−1. H NMR (400 MHz, CDCl3):
δ 7.88 (d, J = 8.8 Hz, 1H), 7.70ꢀ7.56 (m, 4H),
7.46ꢀ7.26 (m, 6H), 6.92 (d, J = 8.8 Hz, 2H), 4.12 (d, J = 7.2 Hz, 1H), 4.09ꢀ4.00 (m, 2H), 3.96 (dd, J =
10, 5.6 Hz, 1H), 3.90ꢀ3.80 (m, 4H), 3.31 (dd, J = 16.8, 6.8 Hz, 1H), 3.10 (dd, J = 16.4, 5.6 Hz, 1H), 1.15
13
(s, 9H), 1.07 (s, 9H). C NMR (100 MHz, CDCl3):
δ 196.6, 163.5, 135.5 (2C), 133.1, 132.8, 130.3
(2C), 130.0, 129.76, 129.74, 127.72 (2C), 127.71 (2C), 113.7 (2C), 66.4, 55.7, 55.4, 54.5, 40.8, 26.8
(3C), 22.5 (3C), 19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C31H41NO4SSi+Na 574.2423; found:
574.2423.
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(R)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(4-
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methoxyphenyl)butan-1-one (3f): Compound 3f was prepared from 4ꢀmethoxy acetophenone (0.112 g,
0.74 mmol) and sulfinimine 1a (0.150 g, 0.37 mmol) using the general procedure A described above in
79% yield (0.163 g) as a major diastereomer along with the minor diastereomer in 11% yield as a
gummy mass. [α]D24 +33.4 (c 0.85, CHCl3). IR (Neat) 3434, 2957, 2857, 1674, 1600, 1172, 1111 cm−1.
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1H NMR (400 MHz, CDCl3):
δ 7.94 (d, J = 8.8 Hz, 2H), 7.65ꢀ7.50 (m, 4H), 7.49ꢀ7.21 (m, 6H), 6.93 (d,
J = 9.2 Hz, 2H), 4.27 (d, J = 8.8 Hz, 1H), 3.93 (m, 1H), 3.88 (s, 3H), 3.87ꢀ3.71 (m, 2H), 3.61ꢀ3.39 (m,
2H), 1.19 (s, 9H), 1.03 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ
197.4, 163.7, 135.46 (2C), 135.43 (2C),
133.0, 132.9, 130.5 (2C), 130.0, 129.8 (2C), 127.7 (4C), 113.7 (2C), 65.9, 55.8, 55.5, 40.1, 26.8 (3C),
22.5 (3C), 19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C31H41NO4SSi+Na 574.2423; found:
574.2423.
(S)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(3,4-
dimethoxyphenyl)butan-1-one (2g): Compound 2g was prepared from 3,4ꢀdimethoxy acetophenone
(0.067 g, 0.37 mmol) and sulfinimine 1a (0.075 g, 0.19 mmol) using the general procedure B described
above in 72% yield (0.79 g) as a gummy mass. [α]D24 +4.6 (c 0.5, CHCl3). IR (Neat) 3286, 2955, 2862,
1660, 1590, 1266, 1019 cm−1. H NMR (400 MHz, CDCl3):
δ 7.69ꢀ7.56 (m, 4H), 7.53 (dd, J = 8.4, 2
1
Hz, 1H), 7.46 (d, J = 2 Hz, 1H), 7.45ꢀ7.26 (m, 6H), 6.87 (d, J = 8.4 Hz, 1H), 4.11 (d, J = 7.6 Hz, 1H),
4.09ꢀ4.00 (m, 1H), 3.96 (m, 4H), 3.92 (s, 3H), 3.85 (dd, J = 10, 4.4 Hz, 1H), 3.33 (dd, J = 16.8, 6.8 Hz,
13
1H), 3.09 (dd, J = 16.4, 5.6 Hz, 1H), 1.16 (s, 9H), 1.07 (s, 9H). C NMR (100 MHz, CDCl3):
δ 196.7,
153.4, 149.0, 135.6 (2C), 135.5 (2C), 133.1, 132.8, 130.2, 129.8, 129.78, 127.74 (2C), 127.73 (2C),
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122.9, 110.0, 109.9, 66.4, 56.1, 55.9, 55.8, 54.6, 40.6, 28.7 (3C), 22.5 (3C), 19.3. HRMS (ESIꢀTOF)
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2
3
4
m/z: [M+Na]+ calcd for C32H43NO5SSi+Na 604.2529; found: 604.2531.
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(S)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(napthalen-2-
yl)butan-1-one (2h): Compound 2h was prepared from 2ꢀacetyl napthalene (0.08 g, 0.47 mmol) and
sulfinimine 1a (0.1 g, 0.25 mmol) using the general procedure B described above in 91% yield (0.13 g)
1
as a gummy mass. [α]D24 +3.5 (c 0.9, CHCl3). IR (Neat) 3672, 2993, 2813, 1703, 1491, 1141cm−1. H
NMR (400 MHz, CDCl3):
δ 8.40 (s, 1H), 7.95 (t, J = 8.8 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.70ꢀ7.50
(m, 6H), 4.17ꢀ4.04 (m, 2H), 4.01 (dd, J = 10.4, 4.8 Hz, 1H), 3.91 (dd, J = 10, 3.2 Hz, 1H), 3.48 (dd, J =
13
16.4, 6 Hz), 3.28 (17.2, 5.2 Hz, 1H), 1.16 (s, 9H), 1.09 (s, 9H). C NMR (100 MHz, CDCl3):
δ 198.1,
135.6, 135.59 (2C), 135.5 (2C), 134.2, 133.1, 132.8, 132.4, 129.9, 129.83, 129.82, 129.6, 128.5, 127.7
(5C), 126.8, 123.7, 66.4, 55.8, 54.6, 41.2, 26.9 (3C), 22.5 (3C), 19.3. HRMS (ESIꢀTOF) m/z: [M+Na]+
calcd for C34H41NO3SSi+Na 594.2474; found: 594.2476.
(S)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(napthalen-1-
yl)butan-1-one (2i): Compound 2i was prepared from 1ꢀacetyl naphthalene (0.08 g, 0.47 mmol) and
sulfinimine 1a (0.1 g, 0.25 mmol) using the general procedure B described above in 74% yield (0.106 g)
1
as a gummy mass. [α]D24 −1.0 (c 1.2, CHCl3). IR (Neat) 3298, 2934, 2859, 1676, 1109, 1069 cm−1. H
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NMR (400 MHz, CDCl3):
δ 8.56 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.93ꢀ7.78 (m, 2H), 7.64
1
2
3
(dt, J = 8, 1.2 Hz, 4H), 7.60ꢀ7.43 (m, 3H), 7.43ꢀ7.26 (m, 6H), 4.12 (m, 2H), 4.02 (dd, J = 10.4, 4.8 Hz,
4
5
6
1H), 3.90 (dd, J = 10.4, 3.6 Hz, 1H), 3.45 (dd, J = 16.8, 6.8 Hz, 1H), 3.25 (dd, J = 16.8, 4.8 Hz, 1H),
7
8
13
1.16 (s, 9H), 1.07 (s, 9H). C NMR (100 MHz, CDCl3):
δ 201.9, 135.6 (2C), 135.53, 135.50 (2C),
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10
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133.9, 133.1, 132.9, 132.7, 130.1, 129.8 (2C), 128.4, 127.9 (2C), 127.8 (4C), 126.5, 125.8, 124.3, 66.5,
55.8, 54.6, 44.6, 26.9 (3C), 22.5 (3C), 19.3. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C34H41NO3SSi+Na 594.2474; found: 594.2478.
(R)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(napthalen-1-
yl)butan-1-one (3i): Compound 3i was prepared from 1ꢀacetyl naphthalene (0.127 g, 0.75 mmol) and
sulfinimine 1a (0.15 g, 0.37 mmol) using the general procedure A as a separable 80:20 diastereomeric
mixture. The major isomer XX was isolated in 52% yield (0.110 g) as a gummy mass. [α]D24 −8.9 (c 0.8,
CHCl3). IR (Neat) 3298, 2934, 2859, 1676, 1109, 1069 cm−1. 1H NMR (400 MHz, CDCl3):
δ 8.56 (d, J
= 8.4 Hz, 1H), 7.99 (t, J = 8.0 Hz, 2H), 7.89 (d, J = 7.2 Hz, 1H), 7.68ꢀ7.42 (m, 7H), 7.42ꢀ7.25 (m, 6H),
4.26 (d, J = 9.2 Hz, 1H), 4.02 (m, 1H), 3.97ꢀ3.79 (m, 2H), 3.78ꢀ3.57 (m, 2H), 1.21 (s, 9H), 1.02 (s, 9H).
13C NMR (100 MHz, CDCl3):
δ 202.9, 135.5 (2C), 135.4 (2C), 133.9, 133.0, 132.9, 132.8, 130.1, 129.8
(2C), 128.4, 128.3, 128.0, 127.7 (5C), 126.4, 125.7, 124.4, 65.9, 55.9, 55.2, 44.0, 26.8 (3C), 22.5 (3C),
19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C34H41NO3SSi+Na 594.2474; found: 594.2478.
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(S)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(thiophen-2-
yl)butan-1-one (2j): Compound 2j was prepared from 2ꢀacetyl thiophene (0.037 g, 0.3 mmol) and
sulfinimine 1a (0.06 g, 0.15 mmol) using the general procedure B described above in 84% yield (0.065
g) as a gummy mass. [α]D24 −1.7 (c 0.9, CHCl3). IR (Neat) 3382, 2930, 2856, 1659, 1416, 1111 cm−1. 1H
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4
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NMR (400 MHz, CDCl3):
δ 7.72ꢀ7.57 (m, 6H), 7.48ꢀ7.27 (m, 6H), 7.12 (dd, J = 4.8, 4 Hz, 1H), 4.06 (d,
J = 7.6 Hz, 1H), 4.06ꢀ4.00 (m, 1H), 3.96 (dd, J = 10.4, 5.6 Hz, 1H), 3.86 (dd, J = 10.0, 4.0 Hz, 1H), 3.30
(dd, J = 16.0, 6.8 Hz, 1H), 3.06 (dd, J = 16.0, 5.2 Hz, 1H), 1.14 (s, 9H), 1.08 (s, 9H). 13C NMR (100
MHz, CDCl3):
δ 190.84, 144.3, 135.5 (2C), 135.4 (2C), 133.9, 133.0, 132.6, 132.1, 128.9, 128.1, 127.7
(5C), 66.3, 55.8, 54.7, 41.9, 26.8 (3C), 22.4 (3C), 19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C28H37NO3S2Si+Na 550.1882; found: 550.1882.
(R)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(thiophen-2-
yl)butan-1-one (3j): Compound 3j was prepared from 2ꢀacetyl thiophene (0.094 g, 0.74 mmol) and
sulfinimine 1a (0.15 g, 0.37 mmol) using the general procedure A described above in 74% yield (0.146
g) as a gummy mass. [α]D24 +16.9 (c 1.05, CHCl3). IR (Neat) 3382, 2930, 2856, 1659, 1416, 1111 cm−1.
1H NMR (400 MHz, CDCl3):
δ 7.75 (d, J = 3.6 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.60ꢀ7.50 (m, 4H),
7.48ꢀ7.24 (m, 6H), 7.13 (t, J = 4.8 Hz, 1H), 4.27 (d, J = 9.2 Hz, 1H), 3.99ꢀ3.86 (m, 1H), 3.83 (dd, J =
10.0, 4.0 Hz, 1H), 3.77 (dd, J = 10.0, 5.6 Hz, 1H), 3.52 (dd, J = 16.8, 6.4 Hz, 1H), 3.48 (dd, J = 16.4,
13
5.6 Hz, 1H), 1.19 (s, 9H), 1.03 (s, 9H). C NMR (100 MHz, CDCl3):
δ 191.6, 144.2, 135.43 (2C),
135.40 (2C), 134.1, 132.9, 132.8, 132.5, 129.8 (2C), 128.2, 127.7 (4C), 65.7, 55.9, 55.0, 41.1, 26.8 (3C),
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22.5 (3C), 19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C28H37NO3S2Si+Na 550.1882; found:
1
2
3
550.1882.
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6
7
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(S)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(furan-2-
yl)butan-1-one (2k): Compound 2k was prepared from 2ꢀacetyl furan (0.1 g, 0.9 mmol) and
sulfinimine 1a (0.08 g, 0.20 mmol) using the general procedure B described above in 83% yield (0.081
g) as a gummy mass. [α]D24 +4.1 (c 2.8, CHCl3). IR (Neat) 3403, 2929, 2859, 1671, 1468, 1111, 1017
cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.64 (t, J = 6.4 Hz, 4H), 7.57 (s, 1H), 7.48ꢀ7.29 (m, 6H), 7.16 (d, J
= 3.6 Hz, 1H), 6.53 (d, J = 3.6 Hz, 1H), 4.01ꢀ3.93 (m, 2H), 3.94 (dd, J = 10.0, 4.8 Hz, 1H), 3.84 (dd, J =
10.0, 3.6 Hz, 1H), 3.25 (dd, J = 16.0, 6.8 Hz, 1H), 2.98 (dd, J = 16.4, 5.2 Hz, 1H), 1.13 (s, 9H), 1.08 (s,
1H). 13C NMR (100 MHz, CDCl3):
δ 187.1, 152.8, 146.4, 135.6 (2C), 135.5 (2C), 133.0, 132.7, 129.8,
129.78, 127.73 (2C), 127.72 (2C), 117.2, 112.3, 66.4, 55.8, 54.5, 41.2, 26.8 (3C), 22.4 (3C), 19.2.
HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C28H37NO4SSi+Na 534.2110; found: 534.2112.
(R)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-1-phenylbutan-1-one (2l): Compound 2l was
prepared from acetophenone (0.110 g, 0.74 mmol) and sulfinimine 1b (0.110 g, 0.74 mmol) using the
general procedure B as a separable 85:15 diastereomeric mixture. The major isomer XX was isolated in
24
67% yield (0.134 g) as a white solid. Mp: 75ꢀ80 °C. [α]D +62.5, (c 0.55, CHCl3). IR (Neat) 3421,
2973, 2923, 1680, 1452, 1044 cm−1. 1H NMR (400 MHz, CDCl3):
δ
7.94 (d, J = 8 Hz, 2H), 7.57 (t, J =
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7.2 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 4.11ꢀ3.94 (m, 1H), 3.80 (d, J = 6.4 Hz, 1H), 3.40 (dd, J = 17.2, 7.6
1
2
3
13
Hz, 1H), 3.06 (dd, J = 16.8, 4.8 Hz, 1H), 1.44 (d, J = 6.4 Hz, 3H), 1.16 (s, 9H). C NMR (100 MHz,
4
5
6
CDCl3):
δ 198.7, 136.9, 133.3, 128.6 (2C), 128.0 (2C), 55.6, 49.2, 46.4, 22.5 (3C), 22.1. HRMS (ESIꢀ
7
8
TOF) m/z: [M+Na]+ calcd for C14H21NO2S+Na 290.1191; found: 290.1189.
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(S)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-1-phenylbutan-1-one (3l): Compound 3l was
prepared from acetophenone (0.245 g, 2.0 mmol) and sulfinimine 1b (0.15 g, 1.0 mmol) using the
general procedure A described above in 55% yield (0.150 g) as a gummy mass. [α]D24 +87.3, (c 1.2,
CHCl3). IR (Neat) 3421, 2973, 2923, 1680, 1452, 1044 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.94 (d, J
= 8.4 Hz, 2H), 7.56 (t, J = 6.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 4.18 (d, J = 6.0 Hz, 1H), 3.96 (sep, J =
13
6.4 Hz, 1H), 3.28 (d, J = 5.6 Hz, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.20 (s, 9H). C NMR (100 MHz,
CDCl3):
δ 198.9, 136.8, 133.4, 128.6 (2C), 128.0 (2C), 55.4, 48.4, 46.0, 22.6 (3C), 21.5. HRMS (ESIꢀ
TOF) m/z: [M+Na]+ calcd for C14H21NO2S+Na 290.1191; found: 290.1190, m/z: [M+H]+ calcd for
C14H21NO2S+H 268.1374; found: 268.1371.
(S)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-methyl-1-phenylpentan-1-one
(2m):
Compound 2m was prepared from acetophenone (0.136 g, 1.14 mmol) and sulfinimine 1c (0.1 g, 0.57
24
mmol) using the general procedure B described above in 6% yield (0.01 g) as a colorless liquid. [α]D
1
+25.6, (c 0.45, CHCl3). IR (Neat) 3299, 2922, 2853, 1680, 1020 cm−1. H NMR (400 MHz, CDCl3):
δ
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7.94 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.47 (d, J = 7.6 Hz, 2H), 3.82ꢀ3.70 (m, 1H), 3.68 (d, J
1
2
3
= 7.2 Hz, 1H), 3.32 (dd, J = 16.4, 8.8 Hz, 1H), 3.06 (dd, J = 16.4, 3.6 Hz, 1H), 2.15 (m, 1H), 1.13 (s,
4
5
6
13
9H), 1.04 (t, J = 7.2 Hz, 6H). C NMR (100 MHz, CDCl3):
δ 199.0, 137.1, 133.2, 128.6 (2C), 128.1
7
8
(2C), 58.9, 56.0, 41.4, 32.1, 22.5 (3C), 19.3, 18.6. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
9
10
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C16H25NO2S+Na 318.1504; found: 318.1503.
(R)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-methyl-1-phenylpentan-1-one
(3m):
Compound 3m was prepared from acetophenone (0.16 g, 1.4 mmol) and sulfinimine 1c (0.12 g, 0.69
mmol) using the general procedure A described above in 69% yield (0.14 g) as a white solid. Mp: 61ꢀ66
°C. [α]D24 +74.1, (c 1.5, CHCl3). IR (Neat) 3299, 2922, 2853, 1680, 1020 cm−1. H NMR (400 MHz,
1
CDCl3):
δ 7.944 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 4.09 (d, J = 8.8
Hz, 1H), 3.61ꢀ3.45 (m, 1H), 3.42 (dd, J = 17.2, 4.8 Hz, 1H), 3.34 (dd, J = 17.2, 6.0 Hz, 1H), 2.13ꢀ1.95
(m, 1H), 1.23 (s, 9H), 0.96 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ
199.5, 136.9, 133.3, 128.6 (2C), 128.1 (2C), 59.5, 56.1, 41.3, 31.6, 22.7 (3C), 19.4, 18.5. HRMS (ESIꢀ
TOF) m/z: [M+Na]+ calcd for C16H25NO2S+Na 318.1504; found: 318.1503.
(R)-7-bromo-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)
-1-phenylpentan-1-one
(2n):
Compound 2n was prepared from acetophenone (0.537 g, 0.47 mmol) and sulfinimine 1d (0.6 g, 2.24
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mmol) using the general procedure B described above in 81% yield (0.7 g) as a nonseparable 86:14
1
2
3
4
5
24
diastereomeric mixture. [α]D +56.0, (c 0.4, CHCl3). IR (Neat) 3220, 2949, 2864, 1680, 1450, 1053
cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.94 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6
6
7
8
Hz, 2H), 4.17ꢀ4.09 (m, 0.23H, minor), 3.94ꢀ3.80 (m, 2H, major), 3.55ꢀ3.35 (m, 3H), 3.09 (dd, J = 17.6,
9
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59
60
4 Hz, 1H), 2.00ꢀ1.77 (m, 4H), 1.77ꢀ1.63 (m, 2H), 1.60ꢀ1.48 (m, 1H), 1.23 (s, 1.3H, minor), 1.16 (s, 9H).
13C NMR (100 MHz, CDCl3):
δ 198.9, 136.9, 133.3, 128.6 (2C), 128.0 (2C), 55.8, 53.1, 44.7, 34.1,
33.5, 32.2, 24.7 (3C), 22.5 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C17H26BrNO2S+Na
410.0765; found: 410.0764.
Ethyl (S)-2-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-4-oxo-4-phenylbutanoate (2o): Compound
2o was prepared from acetophenone (0.116 g, 0.97 mmol) and sulfinimine 1e (0.1 g, 0.48 mmol) using
the general procedure B described above 79% yield (0.125 g) as a gummy mass. [α]D24 +40.8, (c 1.3,
CHCl3). IR (Neat) 3228, 2976, 1738, 1684, 1175, 1066 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.94 (d, J
= 7.6 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 4.48 (q, J = 5.2 Hz, 2H), 4.40 (d, J = 6
13
Hz, 1H), 4.26 (q, J = 7.2 Hz, 1), 3.55 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H). C NMR (100
MHz, CDCl3):
δ 196.3, 172.0, 136.3, 133.5, 128.7 (2C), 128.0 (2C), 62.0, 56.0, 53.6, 41.9, 22.4 (3C),
14.0. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C16H23NO4S+Na 348.1245; found: 348.1249.
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(R)-1-(anthracen-9-yl)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-
1
2
3
4
5
6
7
8
butyldiphenylsilyl)oxy)butan-1-one (3q): Compound 3q was prepared from 9ꢀacetyl anthracene (0.10
g, 0.45 mmol) and sulfinimine 1a (0.1 g, 0.25 mmol) using the general procedure A described above in
74% yield (0.106 g) as a gummy mass. [α]D24 +17.4 (c 2.0, CHCl3). IR (Neat) 3058, 2932, 2856, 2359,
9
1697, 1109−1. 1H NMR (400 MHz, CDCl3):
δ 8.49 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 9.2 Hz,
10
11
12
13
14
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0.4H minor), 7.84 (d, J = 8.4 Hz, 2H), 7.69ꢀ7.56 (m, 4.8H), 7.55ꢀ7.24 (m, 11.8H), 4.35 (d, J = 9.2 Hz,
0.2H minor), 4.25ꢀ4.20 (m, 1H), 4.14 (dd, J = 14.4, 8.0 Hz, 2H), 3.99 (dd, J = 10.0, 4.4 Hz, 1H), 3.80
(dd, J = 19.2, 6.4 Hz, 0.22H minor), 3.67 (dd, J = 19.2, 4.0 Hz, 0.22H minor), 3.53 (dd, J = 18.8, 6.8
Hz, 1H major), 3. 28 (dd, J = 18.8, 4.8 Hz, 1H major), 1.26 (s, 9H major), 1.21 (s, 1.8H minor), 1.06 (s,
13
10.7H). C NMR (100 MHz, CDCl3):
δ 208.1, 135.6 (2C), 135.5 (2C), 133.0, 132.7, 131.0, 129.8,
128.8 (2C), 128.5, 127.79 (2C), 127.77 (2C), 126.9, 126.8 (2C), 125.5 (2C), 124.1 (2C), 66.4, 55.9,
53.7, 48.8, 26.9 (3C), 22.6 (3C), 19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C38H43NO3SSi+Na
644.2631; found: 644.2634.
(R)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-butyldiphenylsilyl)oxy)-1-(pyridin-2-
yl)butan-1-one (3r): Compound 3r was prepared from 2ꢀacetyl pyridine (0.06 g, 0.5 mmol) and
sulfinimine 1a (0.085 g, 0.21 mmol) using the general procedure A described above in 71% yield (0.078
1
g) as a gummy mass. [α]D24 +32.8, (c 1.05, CHCl3). IR (Neat) 3296, 2926, 2854, 1647, 1111 cm−1. H
NMR (400 MHz, CDCl3):
δ 8.67 d, J = 4 Hz, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H),
7.61 (t, J = t, 8.4 Hz, 4H), 7.53ꢀ7.24 (m, 7H), 4.32 (d, J = 8.0 Hz, 1H), 4.06ꢀ3.92 (m, 1H), 3.82 (dd, J
13
=10, 4.4 Hz, 4H), 3.79ꢀ3.69 (m, 3H), 1.17 (s, 9H), 1.02 (s, 9H). C NMR (100 MHz, CDCl3):
δ 200,
153.2, 148.9, 136.8, 135.5 (3C), 133.1, 133.0, 129.7 (2C), 127.6 (5C), 127.2, 121.9, 66.4, 55.7, 54.7,
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40.2, 26.7 (3C), 22.5 (3C), 19.2. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C29H38N2O3SSi+Na
1
2
3
545.2270; found: 545.2274.
4
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6
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9
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(R)-1-(1-benzyl-1H-indol-3-yl)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-4-((tert-
butyldiphenylsilyl)oxy)butan-1-one (3s): Compound 3s was prepared from 3ꢀacetyl indole (0.075 g,
0.32 mmol) and sulfinimine 1a (0.08 g, 0.2 mmol) using the general procedure A as a separable 90:10
diastereomeric mixture. The major isomer XX was isolated in 58% yield (0.075 g) as a gummy mass.
[α]D24 +22.6, (c 1.2, CHCl3). IR (Neat) 3405, 2925, 2391, 2280, 1642, 1017 cm−1. 1H NMR (400 MHz,
CDCl3):
δ 8.39 (d, J = 7.2 Hz, 1H), 7.84 (s, 1H), 7.56 (t, J = 8 Hz, 4H), 7.46ꢀ7.15 (m, 12H), 7.11 (t, J =
3.2 Hz, 2H), 5.26 (s, 2H), 4.47 (d, J = 8.8 Hz, 1H), 3.95 (m, 1H), 3.89 (dd, J = 10, 3.6 Hz, 1H), 3.79 (dd,
13
J = 9.6, 5.2 Hz, 1H), 3.42 (m, 2H), 1.19 (s, 9H), 1.01 (s, 9H). C NMR (100 MHz, CDCl3):
δ 193.8,
137.0, 135.6, 135.4 (4C), 133.1, 133.0, 129.7 (2C), 129.0 (2C), 128.1, 127.7 (5C), 126.9 (2C), 126.4,
123.5, 122.8 (2C), 117.3, 110.2, 65.9, 55.8, 55.4, 50.8, 41.4, 26.8 (3C), 22.6 (3C), 19.2. HRMS (ESIꢀ
TOF) m/z: [M+Na]+ calcd for C39H46N2O3SSi+Na 673.2896; found: 673.2898.
(R)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-3-cyclohexyl-1-phenylpropan-1-one
(3t):
Compound 3t was prepared from acetophenone (0.167 g, 1.39 mmol) and sulfinimine 1f (0.15 g, 0.70
24
mmol) using the general procedure A described above in 54% yield (0.125 g) as a gummy mass. [α]D
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1
+47.5 (c 1.7, CHCl3). IR (Neat) 2924, 2854, 1680, 1448, 1055 cm−1. H NMR (400 MHz, CDCl3):
δ
1
2
3
7.93 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 4.16 (d, J = 8.8 Hz, 1H),
4
5
6
3.56ꢀ3.42 (m, 1H), 3.40 (dd, J = 9.6, 4.8 Hz, 2H), 1.92 (d, J = 11.6 Hz, 1H), 1.79ꢀ1.50 (m, 6H), 1.21 (s,
7
8
13
9H major), 1.15 (m, 1H), 1.10 (s, 1.5H minor), 1.08ꢀ0.80 (m, 3H). C NMR (100 MHz, CDCl3):
δ
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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199.6, 136.9, 133.3, 128.6 (2C), 128.0 (2C), 59.0, 56.0, 41.3, 41.0, 29.9, 29.3, 26.3, 26.0, 25.9, 22.7
(3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C19H29NO2S+Na 358.1817; found: 358.1817.
(R)-3-((tert-butyl(λ1-oxidanyl)-
λ3-sulfanyl)amino)-3-(4-methoxyphenyl)-1-phenylpropan-1-one
(3v): Compound 3v was prepared from acetophenone (0.10 g, 0.84 mmol) and sulfinimine 3h (0.1 g,
0.42 mmol) using the general procedure A described above in 33% yield (0.05 g) as a gummy mass.
[α]D +66.1 (c 1.1, CHCl3). IR (Neat) 3277, 2966, 1680, 1514, 1035 cm−1. H NMR (400 MHz,
24
1
CDCl3): 7.91 (d, J = 8.4 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 8.8 Hz,
δ
2H), 4.98ꢀ4.85 (m, 1H), 4.79 (d, J = 2.8 Hz, 1H), 3.80 (s, 3H), 3.56 (dd, J = 17.2, 4.0 Hz, 1H), 3.44 (dd,
13
J = 17.2, 8.0 Hz, 1H), 1.22 (s, 9H). C NMR (100 MHz, CDCl3):
δ 198.6, 159.2, 136.5, 133.5, 132.8,
128.7 (2C), 128.6 (2C), 128.1 (2C), 114.0 92C), 55.5, 55.2, 54.6, 46.0, 22.6 (3C). HRMS (ESIꢀTOF)
m/z: [M+Na]+ calcd for C20H25NO3S+Na 382.1453; found: 382.1455.
(R)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-3-(4-nitrophenyl)-1-phenylpropan-1-one (3w):
Compound 3w was prepared from acetophenone (0.094 g, 0.79 mmol) and sulfinimine 3i (0.12 g, 0.47
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24
mmol) using the general procedure A described above in 79% yield (0.133 g) as a gummy mass. [α]D
1
2
3
4
1
+66.0 (c 0.7, CHCl3). IR (Neat) 3275, 2966, 2358, 2316, 1681, 1519, 1346, 1056 cm−1. H NMR (400
5
6
MHz, CDCl3):
δ 8.21 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 7.2 Hz, 2H), 7.72ꢀ7.52 (m, 3H), 7.45 (t, J = 8.0
7
8
9
Hz, 2H), 5.15ꢀ5.0 (m, 1H), 4.89 (d, J = 4.4 Hz, 1H), 3.66 (dd, J = 17.6, 4.8 Hz, 1H), 3.55 (dd, J = 17.6,
7.6 Hz, 1H), 1.24 (s, 9H). 13C NMR (100 MHz, CDCl3):
10
11
12
13
14
15
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δ
197.7, 148.5, 147.4, 136.1, 133.9, 128.8 (2C),
128.4 (2C), 128.1 (2C), 123.9 (2C), 56.0, 55.0, 45.3, 22.6 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd
for C19H22N2O4S+Na 397.1198; found: 397.1198.
(R)-3-((tert-butyl(λ1-oxidanyl)- λ3-sulfanyl)amino)-3-(furan-2-yl)-1-phenylpropan-1-one (3x):
Compound 3x was prepared from acetophenone (0.12 g, 1.o mmol) and sulfinimine 1j (0.1 g, 0.5 mmol)
using the general procedure A described above in 56% yield (0.09 g) as a gummy mass. [α]D24 +75.3 (c
1
0.8, CHCl3). IR (Neat) 2970, 2380, 2312, 1681, 1516, 1062 cm−1. H NMR (400 MHz, CDCl3):
δ 7.94
(d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.34 (s, 1H), 6.31 (t, J = 2.4 Hz,
2H), 5.05 (q, J = 5.2 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 3.74 (dd, J = 17.6, 6.4 Hz, 1H), 3.63 (dd, J =
17.6, 4.8 Hz, 1H), 1.21 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 198.1, 153.4, 142.1, 136.4, 133.5, 128.6
(2C), 128.1 (2C), 110.3, 107.7, 55.8, 50.4, 42.9, 22.5 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
C17H21NO3S+Na 342.1140; found: 342.1141.
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Preparation of (1R, 3R)ꢀ7ꢀbromoꢀ3ꢀ((tert-butyl(λ1-oxidanyl)-λ3-sulfanyl)amino)ꢀ1ꢀphenylheptan-1-
ol (4): To a stirred solution of 2q (0.74 g 1.9 mmol) in MeOH (20 mL) at 0 °C was added NaBH4 (0.145
g, 3.8 mmol), and stirring was continued for 0.5 h at 0 °C. After completion of the reaction (TLC), the
solvent was removed under reduced pressure and the crude residue was diluted with water (20 mL) and
extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over anhyd. Na2SO4.
Evaporation of solvent followed by careful separation of resultant crude using silica gel column
chromatography with petroleum ether/EtOAc as eluent afforded the product 4 in 58% yield (0.39 g). Mp
80ꢀ85 °C. [α]D24 +34.51, (c 1.33, CHCl3). IR (Neat) 3296, 2928, 1646, 1452, 1020 cm−1. 1H NMR (400
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MHz, CDCl3):
δ 7.41ꢀ7.19 (m, 5H), 4.81 (dd, J = 8.8, 4.0 Hz, 1H), 3.90 (d, J = 6.0 Hz, 1H), 3.71 (bs,
1H), 3.39 (m, 3H), 2.13 (dt, J = 19.2, 9.6 Hz, 1H), 1.94ꢀ1.75 (m, 4H), 1.69ꢀ1.49 (m, 3H), 1.24 (s, 9H).
13C NMR (100 MHz, CDCl3):
δ
144.8, 128.5 (2C), 127.5, 125.6 (2C), 73.9, 56.1, 56.0, 45.1, 34.8, 33.6,
32.3, 24.3, 22.6 (3C). HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for C17H28BrNO2S+Na 412.0922; found:
412.0921 .
Preparation of (R)ꢀ2ꢀ((R)ꢀ1ꢀ(tert-butyl(λ1ꢀoxidanyl)ꢀλ3ꢀsulfanyl)piperidinꢀ2ꢀyl)ꢀ1ꢀphenylethanꢀ1ꢀol
(5): To a stirred solution of 4 (0.39 g, 1.0 mmol) in dry THF (35 mL) at 0 °C was added NaH (0.12 g,
5.0 mmol). The reaction mixture was stirred for 1 h at 0 °C. After completion of reaction (TLC) it was
quenched with ice cold water and extracted with EtOAc (2 × 40 mL). The organic layer was washed
with brine (30 mL) and dried over Na2SO4. Evaporation of solvent afforded the 5 in 99% yield (0.309
1
g). Mp: 108ꢀ110 °C. [α]D24 +60.5, (c 0.7, CHCl3). IR (KBr) 3396, 2923, 2859, 1451, 1046 cm−1. H
NMR (400 MHz, CDCl3):
δ 7.43ꢀ7.18 (m, 5H), 4.69 (d, J = 10.8 Hz, 1H), 4.13 (bs, 1H), 3.94 (m, 1H),
3.28ꢀ3.07 (m, 2H), 2.15 (ddd, J = 14.4, 10.8, 4.0 Hz, 1H), 1.95 (ddd, J = 14.0, 10.4, 2.8, 1H), 1.90ꢀ1.73
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(m, 1H), 1.71ꢀ1.54 (m, 5H), 1.21 (s, 9H).13C NMR (100 MHz, CDCl3):
δ 145.5, 128.4 (2C), 127.2,
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2
3
4
125.5 (2C), 73.0, 58.6, 42.0, 29.1, 23.2 (3C), 19.3. HRMS (ESIꢀTOF) m/z: [M+Na]+ calcd for
5
6
C17H27NO2S+Na 332.1660; found: 332.1662.
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Preparation of (R)-1-phenyl-2-((R)-piperidin-2-yl) ethan-1-ol (6): To a precooled stirred solution of
5 (0.1 g, 0.3 mmol) in MeOH (7 mL) at 0 °C was added a saturated solution of HCl in MeOH (0.8 mL).
The reaction mixture was stirred for 1 h at the same temperature. After completion of the reaction
(TLC), the solvent was evaporated off, and the resultant residue was dissolved in THF (10 mL), solid
NaHCO3 (0.25 g, 3 mmol) was added. The reaction mixture was stirred for 2h at rt. The reaction
mixture was filtered on a short celite pad. Evaporation of solvent followed by silica gel column
chromatography of the resulting crude residue with petroleum EtOAc/MeOH as eluent afforded the
products 6 in 99% yield (0.025 g) as a light brownish solid. Mp: 85ꢀ90 °C, [lit.9 82ꢀ84°C]. [α]D24 +33.2,
1
(c 1.25, MeOH), [lit.7 +24.6, c 1.0, MeOH]. IR (KBr) 3383, 3299, 2929, 2854, 1443, 1064 cm−1. H
NMR (400 MHz, CDCl3):
δ
7.42ꢀ7.16 (m, 5H), 4.92 (d, J = 6.8 Hz, 1H), 4.55 (bs, 2H), 3.13 (d, J = 13.2,
13
1H), 3.06ꢀ2.90 (m, 1H), 2.69 (m, 1H), 1.90ꢀ1.35 (m, 7H), 1.34ꢀ1.15 (m, 1H). C NMR (100 MHz,
CDCl3):
δ 145.0, 128.3 (2C), 127.1, 125.6 (2C), 75.0, 58.1, 45.6, 44.3, 33.2, 26.1, 24.0. HRMS (ESIꢀ
TOF) m/z: [M+H]+ calcd for C13H19NO+H 206.1545; found: 206.1546.
Preparation of (R)-2-((R)-1-methylpiperidin-2-yl)-1-phenylethan-1-ol (7): To a precooled stirred
solution of 5 (0.06 g, 0.2 mmol) in MeOH (5 mL) at 0 °C was added a saturated solution of HCl in
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