Synthesis of β-Amino-Substituted Enones by Addition of Substituted Methyl Enones to Sulfinimines: Application to the Total Synthesis of Alkaloids (+)-Lasubine II and (+)-241D and the Formal Total Synthesis of (-)-Lasubine i

Article abstract of DOI:10.1021/acs.joc.6b01541

Addition of silyl enol ethers obtained from substituted methyl enones to chiral sulfinimines afforded the β-amino-substituted enones with excellent selectivity. Utility of the obtained N-sulfinyl β-amino ketones possessing α,β-unsaturation is exemplified

Full text of DOI:10.1021/acs.joc.6b01541

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Note
Synthesis of beta-Amino Substitued Enones by Addition of Substituted
Methyl Enones to Sulfinimines: Application to the Total Synthesis of alkaloids
(+)-Lasubine II, (+)-241D and Formal Total Synthesis of (-)-Lasubine I
Arava Amaranadha Reddy, Polimera Obula Reddy, and Kavirayani R. Prasad
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01541 • Publication Date (Web): 12 Oct 2016
Downloaded from http://pubs.acs.org on October 13, 2016
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The Journal of Organic Chemistry
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Synthesis of βꢀAmino Substitued Enones by Addition of
Substituted Methyl Enones to Sulfinimines: Application
to the Total Synthesis of alkaloids (+)ꢀLasubine II, (+)ꢀ
241D and Formal Total Synthesis of (−)ꢀLasubine I
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Arava Amaranadha Reddy, Polimera Obula 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: Addition of silyl enol ethers obtained from substituted methyl enones to chiral sulfinimines
afforded the βꢀamino substitued enones with excellent selectivity. Utility of the obtained Nꢀsulfinyl βꢀ
amino ketones possessing α, βꢀunsaturation is exemplified in the total synthesis of the quinolizidine
alkaloid natural products (−)ꢀlasubine I, (+)ꢀlasubine II and substituted piperidine alkaloid (+)ꢀ241ꢀD.
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Quinolizidines, indolizidines and substituted piperidines are ubiquitous structural units present in a
number of diverse alkaloids possessing simple to complex structural framework exhibiting varied bioꢀ
activity profiles.1 Some of the simple quinolizidine, indolizidine and piperidine alkaloids include the
lasubines 1 and 2, indolizidines 167 B 3 and 241ꢀD 4, while complex alkaloids comprising these
frameworks include vallesamidine 5 and aspidospermidine 6 (fig. 1).
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Fig. 1 Natural products possessing the quinolizidine and indolizidine framework
Over the years, impressive strategies were developed for the synthesis of substituted piperidines,
pyrrolidines which were further extended to the quinolizidine and indolidizine alkaloids. Extensively
used building blocks for the synthesis of the quinolizidine alkaloids include the δꢀaminoꢀβꢀketo esters 7
developed by Davis’ group2 by addition of excess sodium enolate of methyl acetate to nonꢀracemic
sulfinimines, which was also obtained by vinylogous MukaiyamaꢀMannich reaction of sulfinimines with
dioxinoneꢀderived silyloxydiene.3 Recently, the same building block was synthesized by employing
chiral Bronsted acid catalyzed enantioselective addition of dioxinoneꢀderived silyloxydiene to imines.4
Another useful building block for the synthesis of quinolizidine and indolizidine alkaloids is the γꢀ
aminoꢀα, βꢀunsaturated esters 8 derived from the vinylogous MukaiyamaꢀMannich addition of
vinylketene silyl acetals to imines developed by Schneider’s group.5 One of the direct syntheses of
quinolizidines inter alia is the intraꢀmolecular Michael reaction of βꢀamino enones 9, generally obtained
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in a multiꢀstep sequence from protected βꢀamino ester.6 While the above strategies are useful, they have
drawbacks in terms of generality and the multiꢀstep sequences involved. We reasoned that the addition
of silyloxy dienes or metal enolates derived from substituted methyl enones to imines7 would offer a
straightforward single step access to the building block 9 (scheme 1). To accomplish this challenge, we
relied on the direct addition of enolates/ silyl enol ethers derived from the enones 12 to nonꢀracemic
sulfinimines 11. The reliable and predictable selectivities observed in the nucleophilic addition reactions
of sulfinimines8 should yield the Nꢀsulfinamido βꢀamino enones 10 structurally similar to the building
block 9. The ease in the removal of the sulfinyl auxiliary in 10 and the simultaneous intramolecular
Michael addition reaction of the resultant βꢀamino enones should lead to functionalized piperidinone.
Interestingly in spite of a variety of nucleophilic addition reactions of sulfinimines reported, the direct
addition of substituted enones to sulfinimines was never examined.
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Scheme-1 Chiral building blocks 7-9 commonly utilized in the synthesis of quinolizidine and piperidine
alkaloids (Pg= protecting group).
At the outset, the study commenced with the addition of α, βꢀunsaturated phenyl methyl ketone 12a to
sulfinimine 11a using LHMDS as base. The reaction proceeded smoothly and afforded a 75:25
separable mixture of diastereomers 10a:13a in 90% yield with the major isomer 10a isolated in 65%
yield by column chromatography. Performing the reaction with NaHMDS as base did not improve the
diastereomeric ratio of the products, while the use of KHMDS as base improved the diastereomeric ratio
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of the products 10a:13a to 90:10 (92% yield) and the major isomer 10a was isolated in 73% yield.
Interestingly, addition of the trimethylsilyl enol ether derived from 12a furnished the products 13a:10a
in >99:1 diastereomeric ratio, with 13a as the major diastereomer isolated in 80% yield (scheme 2). The
intriguing outcome can be tentatively explained by the Davis chelation and open chain models TS-I and
TS-II respectively proposed earlier9 for the reaction of metal enolates with sulfinimines and Lewis acid
catalyzed addition of organometallics.
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Scheme-2 Addition of metal enolate/ silylenol ether derived from α, βꢀunsaturated aryl methyl ketone
12a to sulfinimine 11a.
Generality of the procedure was further exemplified by employing various silyl enol ethers 14a-l
derived from structurally different βꢀsubstituted enones in the reaction with sulfinimine 11a. As evident
from chartꢀ1, addition of silyl enol ethers obtained from βꢀaryl enones 12b-e as well as βꢀarylꢀαꢀmethyl
enones 12f-g proceeded smoothly to afford the products 13b-g in up to >99:1 diastereomeric ratio and
in good yields. Silyl enol ether prepared from enone 12i possessing βꢀbenzyloxy methyl substitution
afforded the product with >99:1 diastereoselectivity. Reaction of silyl enol ether 14k having βꢀester
substitution furnished the product 13k with excellent selectivity (>99:1) albeit in poor 12% yield. A
quick examination of the effect of substitution on the sulfinimine in the reaction outcome was also
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investigated. Thus, addition of silyl enol ether 14a to the sulfinimine 11b derived from acetaldehyde
proceeded with good dr 90:10 (81% yield), while employing the sulfinimine 11c obtained from
isobutyraldehyde afforded the product 13m in 22% yield (dr >99:1). It is interesting to note that the
sulfinimines 11d, 11e, 11f prepared from benzaldehyde, cyclohexanecarbaxaldehyde and pivalaldehyde
did not furnish the product at all. However, reaction of the potassium enolate of the enone 12a with
sulfinimines 11d and 11e furnished the products 10n and 10o in 75% and 48% yield with 90:10 and
96:4 diastereomeric ratios respectively.
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Chart 1. Addition of silyl enol ethers derived from substituted methyl enones to sulfinimines.a
aAll reactions were performed with freshly prepared silylenol ethers 14a-k from the ketones 12a-k.
bNonꢀseparable mixture of diastereomers.
Synthetic utility of the resultant βꢀNꢀsulfinamido ketones was demonstrated in the total synthesis of
quinolizidine alkaloids (−)ꢀlasubine I 1 and (+)ꢀlasubine II 210 and the piperidine alkaloid (+)ꢀ241ꢀD 4.
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Accordingly, treatment of silylenol ether 14d with the sulfinimine 11g (synthesized from 5ꢀ
bromopentenꢀ1ꢀal) afforded the product 13p in 63% yield with 85:15 diastereomeric ratio. Removal of
the sulfinyl group using HCl furnished the free amine hydrochloride salt which on treatment with DBU
furnished the diastereomerically pure cis and trans quinolizidinones 15 and 16 in 41% and 35% yield
respectively involving an in situ tandem Michael addition/ displacement of bromine. Reduction of the
ketone in 15 with LAH furnished 2ꢀepiꢀlasubine II, which on Mitsunobu inversion provided (+)ꢀlasubine
II 2 in 81% yield, the spectral and physical data of which are in complete agreement with that reported
in literature.10d Reduction of the ketone in transꢀ quinolidizinone 16 to (−)ꢀlasubine I 1 using Lꢀ
selectride is a procedure reported in literature (schemeꢀ3), thus constituting the formal synthesis.10d
Synthesis of lasubines I and II depicted in the present strategy is one of the shortest syntheses of
lasubine alkaloids.
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Scheme-3 Total synthesis of (−)ꢀ lasubine I 1 (+)ꢀ lasubine II 2
Synthesis of the alkaloid (+)ꢀ241ꢀD 4 was accomplished by the following sequence. The βꢀ
sulfinamido ketone 13q was synthesized by addition of silyl enol ether 14j to the sulfinimine 11b in
62% yield. Removal of the sulfinyl group in 13q with HCl in MeOH and neutralization with Et3N
resulted in the piperidinone 17 in 84% yield. Reduction of the ketone in 17 with NaBH4 as described in
literature2d,11 furnished the natural product (+)ꢀ241D 4 in 82% yield (scheme 4).
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Scheme 4 Total synthesis of (+)ꢀ241D 4
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In conclusion, addition of silylenol ethers obtained from substituted enones to chiral sulfinimines with
very high selectivity was presented. The reaction proceeds with excellent diastereoselectivity and
products were obtained in good yields. Application of the resultant βꢀ Nꢀsulfinamido ketones was
demonstrated in a concise enantioselective total synthesis of a collection of natural products such as
quinolizidine alkaloids lasubine I and lasubine II, the piperidine alkaloid 241D.
Experimental:
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 on a 400 MHz
machine in CDCl3 as solvent with TMS as reference unless otherwise indicated. High resolution mass
spectra (HRMS) were recorded on a QꢀTOF microꢀmass spectrometer using electron spray ionization
mode. Sulfinimines 11a-g were prepared according to the procedure described by Ellamn’s group.12
Aryl methyl enones 12b-d were synthesized according to the procedure described in literature.13
Compounds 12e-k were synthesized according to literature procedures.14
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Preparation
of
(SS,E)-N-(2-((tert-butyldiphenylsilyl)oxy)ethylidene)-2-methylpropane-1-
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sulfinamide (11a): To a stirred solution of ((tertꢀbutyldiphenylsilyl)oxy)acetaldehyde (1.054 g, 3.55
mmol) and (S)ꢀtꢀbutanesulfinamide (0.429 g, 3.5 mmol) in dry CH2Cl2 (11 mL) at room temperature was
added oven dried CuSO4 (1.58 g, 10.5 mmol) and the reaction mixture was stirred for 12 hours at the
same temperature. After completion of reaction (TLC), the reaction mixture was filtered through a short
pad of celite. Evaporation of solvent followed by silica gel column chromatography of the resulting
crude residue with petroleum ether:EtOAc as eluent afforded the sulfinimine 11a in 84% yield (1.2 g) as
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a colorless oil. [α]D +94.6 (c 0.5, CHCl3). IR (neat) 3359, 3070, 2857, 1630, 1427, 1083 cm−1. H
NMR (400 MHz, CDCl3):
δ
8.10 (t, J = 3.2 Hz, 1H), 7.67 (d, J = 6.8 Hz, 4H), 7.50ꢀ7.32 (m, 6H), 4.56
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(d, J = 2.8 Hz, 2H), 1.18 (s, 9H), 1.08 (s, 9H). C NMR (100 MHz, CDCl3):
δ 168.2, 135.5 (2 × C),
135.49 (2 × C), 132.8, 129.9, 127.82 (2 × C), 127.81 (2 × C), 66.1, 56.8, 26.7 (3 × C), 22.3 (3 × C),
19.2. HRMS: m/z calcd for C22H31NO2SSi+Na 424.1742; found: 424.1743.
Br
O
S
N
H
11g
Preparation of (SS,E)-N-(5-bromopentylidene)-2-methylpropane-2-sulfinamide (11g): To a stirred
solution of 5ꢀbromopentanal (1.65 g, 9.8 mmol) and (S)ꢀtꢀbutanesulfinamide (1.17 g, 9.7 mmol) in dry
CH2Cl2 (30 mL) at room temperature was added oven dried CuSO4 (4.4 g, 29.4 mmol) and was stirred
for 12 hours. After completion of reaction (by TLC), the reaction mixture was filtered through a short
pad of celite. Evaporation of solvent followed by silica gel column chromatography of the resulting
crude residue with petroleum ether:EtOAc as eluent afforded the sulfinimine 11g in 87% yield (2.18 g)
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as yellow oil. [α]D24 +186.5 (c 0.65, CHCl3). IR (neat) 1634, 1270, 1135, 1018 cm−1. H NMR (400
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MHz, CDCl3):
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8.11 (t, J = 4.0 Hz, 1H), 3.5 (dt, J = 6.4, 2.8 Hz, 2H), 2.79ꢀ2.65 (m, 2H), 2.31ꢀ2.14 (m,
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2H), 1.19 (s, 9H). C NMR (100 MHz, CDCl3):
δ 167.7, 56.6, 34.3, 32.5, 28.0, 22.3 (3 × C). HRMS:
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m/z calcd for C9H18BrNOS+Na 290.0190; found: 290.0193.
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(Ss)-N-((R,E)-1-((tert-butyldiphenylsilyl)oxy)-4-oxo-6-phenylhex-5-en-2-yl)-2-methylpropane-2-
sulfinamide (10a): To a preꢀcooled (−78 °C) stirred solution of benzylideneacetone 12a (0.08 g, 0.55
mmol) in dry THF (14 mL) under argon atmosphere at −78 °C was added KHMDS (0.5 M solution in
toluene 1.64 mL, 0.82 mmol). The reaction mixture was stirred for 1 h at the same temperature and the
sulfinimine 11a (0.1 g, 0.25 mmol) dissolved in 5 mL dry THF was added at −78 °C. Then the reaction
mixture was stirred at 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 10a in 92% yield (0.125 g) as a 90:10 diastereomeric mixture). Major isomer was
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separated using silica gel column chromatography in 73% yield (0.102 g) as a gummy mass. [α]D
–
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25.8 (c 0.9, CHCl3). IR (Neat): νmax 3290, 2957, 1660, 1609, 1110, 1067 cm−1. H NMR (400 MHz,
CDCl3):
δ
7.68ꢀ7.47 (m, 7H), 7.48ꢀ7.27 (m, 9H), 6.70 (d, J = 16.4 Hz, 1H), 4.20 (d, J = 8.8 Hz, 1H),
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3.94ꢀ3.69 (m, 3H), 3.25 (m, 2H), 1.19 (s, 9H), 1.06 (s, 9H). C NMR (100 MHz, CDCl3):
δ 198.8,
143.3, 135.49 (2 × C), 135.47 (2 × C), 134.3, 133.0, 132.9, 130.6, 129.8, 128.9 (2 × C), 128.4 (2 × C),
127.76 (2 × C), 127.74 (2 × C), 126.5, 65.9, 55.9, 54.8, 42.5, 26.8 (3 × C), 22.5 (3 × C), 19.3. HRMS:
m/z calcd for C32H41NO3SSi+Na570.2474.; found 570.2475.
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General procedure for the addition of silyl enol ethers 14a-l derived from enones 12a-l to the
sulfinimines 11a-g: The following preparation of 13a is representative:
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Procedure A: To a preꢀcooled solution of benzylideneacetone 12a (0.1 g, 0.68 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
separated and was washed with water (20 mL), brine (20 mL) and was dried over Na2SO4. Evaporation
of solvent gave the silylenolether which was used in the next step without further purification.
A solution of the crude silylenolether (obtained above) in dry CH2Cl2 (5 mL) under argon atmosphere
was cooled to −78 °C and sulfinimine 11a (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 0.5
h 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 13a in 80% yield
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(0.11 g) as a colorless solid. mp: 98ꢀ102 °C. [α]D +10.6 (c 0.9, CHCl3). IR (KBr) 3290, 2957, 1660,
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1609, 1110, 1067 cm−1. H NMR (400 MHz, CDCl3):
δ 7.72ꢀ7.62 (m, 4H), 7.55ꢀ7.50 (m, 3H), 7.43ꢀ
7.32 (m, 9H), 6.69 (d, J = 16.4 Hz, 1H), 4.08 (d, J = 7.2 Hz, 1H), 4.02ꢀ3.90 (m, 2H), 3.83 (dd, J = 10.0,
4.4 Hz, 1H), 3.06 (dd, J = 16.4, 6.4 Hz, 1H), 2.86 (dd, J= 16.4, 5.2 Hz 1H), 1.18 (s, 9H), 1.09 (s, 9H).
13C NMR (100 MHz, CDCl3):
δ
197.9, 143.1, 135.6 (2 × C), 135.5 (2 × C), 134.3, 133.1, 132.7, 130.6,
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129.8, 128.9 (2 × C), 128.3 (2 × C)127.8 (5 × C), 126.2, 66.3, 55.8, 54.2, 43.3, 26.9 (3 × C), 22.5 (3 ×
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C), 19.3. HRMS: m/z calcd for C32H41NO3SSi+Na 570.2474; found: 570.2476.
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Procedure B: To a preꢀcooled solution of benzylideneacetone 12a (0.1 g, 0.68 mmol) in dry CH2Cl2 (5
mL) at 0 °C was added Et3N (0.19 mL, 1.4 mmol) followed by TMSOTf (0.18 mL, 1 mmol) under
argon atmosphere. The reaction mixture was stirred for 1 h at the same temperature, cooled to −78 °C
and sulfinimine 11a (0.1 g, 0.25 mmol) dissolved in 5 mL CH2Cl2 was added at −78 °C, followed by
addition of 2nd portion of TMSOTf (0.09 ml, 0.5 mmol). The reaction mixture was stirred for 0.5 h at
−78 °C. After completion of the reaction (TLC), it was quenched by addition of saturated NaHCO3
solution (20 mL) and extracted with EtOAc (2 × 20 mL). The organic layer was washed with water,
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
product 13a in 78% yield (0.11 g) as a colorless solid. The spectral data is same as described above.
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Compound 13b was prepared from 4ꢀmethyl benzylideneacetone 12b (0.1 g, 0.62 mmol) and
sulfinimine 11a (0.1 g, 0.25 mmol) using the procedure A described above in 70% yield (0.097 g) as a
gummy mass. [α]D24 +7.7 (c 0.66, CHCl3). IR (neat) 3709, 2958, 2855, 1659, 1425, 1111 cm−1. 1H NMR
(400 MHz, CDCl3):
δ 7.71ꢀ7.58 (m, 4H), 7.49 (d, J = 16.4 Hz, 1H), 7.48ꢀ7.29 (m, 8H), 7.21 (d, J = 8.0
Hz, 2H), 6.67 (d, J = 16.0 Hz, 1H), 4.09 (d, J = 7.2 Hz, 1H), 4.05ꢀ3.86 (m, 2H), 3.83 (dd, J = 10.0, 4.4
Hz, 1H), 3.05 (dd, J = 16.4, 6.8 Hz, 1H), 2.85 (dd, J = 16.4, 5.6 Hz, 1H), 2.39 (s, 3H), 1.18 (s, 9H), 1.09
(s, 9H). 13C NMR (100 MHz, CDCl3):
δ 198.0, 143.2, 141.2, 135.6 (2 × C), 135.5 (2 × C), 133.1, 132.8,
131.5, 129.8, 129.7 (2 × C), 128.4 (2 × C), 127.8 (5 × C), 125.3, 66.4, 55.8, 54.3, 43.2, 26.9 (3 × C),
22.5 (3 × C), 21.5, 19.3. HRMS: m/z calcd for C33H43NO3SSi+Na 584.2631; found: 584.2631.
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Compound 13c was prepared from 4ꢀmethoxy benzylideneacetone 12c (0.1 g, 0.57 mmol) and
sulfinimine 11a (0.1 g, 0.25 mmol) using the procedure A described above in 69% yield (0.09 g) as an
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inseparable mixture (91:9) of diastereomers as a gummy mass. [α]D24 +6.4 (c 1.09, CHCl3). IR (neat)
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3069, 2839, 1683, 1600, 1250, 1111, 1027 cm−1. H NMR (400 MHz, CDCl3):
δ 7.72ꢀ7.58 (m, 4.5H),
7.54ꢀ7.45 (m, 3.4H), 7.44ꢀ7.29 (m, 6.5H), 6.92 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 16.4 Hz, 1H, major),
6.05 (d, J = 12.8 Hz, 0.1H, minor), 4.09 (d, J = 7.2 Hz, 1H), 4.03ꢀ3.85 (m, 2H), 3.85 (s, 3H), 3.84ꢀ3.81
(m, 1H), 3.80ꢀ3.69 (m, 1H), 3.03 (dd, J = 16.4, 6.8 Hz, 1H), 2.83 (dd, J= 16.0, 5.2 Hz, 1H), 1.2 (s, 9H,
major), 1.16 (s 1H, minor), 1.08 (s, 9H, major) , 1.04 (s, 1H, minor). 13C NMR (100 MHz, CDCl3):
δ
197.9, 161.7, 142.9, 135.6 (2 × C), 135.5 (2 × C), 133.1, 132.8, 130.1(2 × C), 129.8, 127.8 (5 × C),
126.96, 124.0, 114.4 (2 × C), 66.4, 55.8, 55.4, 43.2, 26.9 (3 × C), 22.5 (3 × C), 19.3. HRMS: m/z calcd
for C33H43NO4 SSi+Na 600.2580; found: 600.2580.
Compound 13d was prepared from 3,4ꢀdimethoxy benzylideneacetone 12d (0.1 g, 0.48 mmol) and
sulfinimine 11a (0.1 g, 0.25 mmol) using the procedure A described above in 75% yield (0.12 g) as an
inseparable mixture (87:13) of diastereomers as a gummy mass. [α]D24 +4.7 (c 4.9, CHCl3). IR (neat)
3198, 2929, 2819, 1678, 1456, 1085 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.77ꢀ7.55 (m, 4.5H), 7.46 (d,
J = 16 Hz, 1H), 7.48ꢀ7.29 (m, 6.7H), 7.16 (dd, J = 8.4, 2.0 Hz, 0.13H, minor), 7.11 (dd, J = 8.0, 1.6 Hz,
1H, major), 7.05 (d, J = 2 Hz, 1H), 6.88 (d, J = 8.0 Hz, major), 6.81 (d, J = 8.4 Hz, minor) (1 H), 6.58
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(d, J = 16.4 Hz, major), 6.08 (d, J = 12.8 Hz, minor) (1 H), 4.10 (d, J = 7.2 Hz, 1H), 4.07ꢀ3.93 (m, 9H),
3.83 (dd, J = 9.6, 4.4 Hz, 1H), 3.06 (dd, J = 16.4, 6.8 Hz, 1H), 2.86 (dd, J = 16.0, 5.2 Hz, major), 2.71
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(dd, J = 16.8, 5.6 Hz, minor) (1 H), 1.18 (s, major), 1.16 (s, minor) (9 H), 1.09 (s, major), 1.05 (s,
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minor) (9 H). C NMR (100 MHz, CDCl3):
δ 197.8, 151.4, 149.2, 143.2, 135.6 (2 × C), 133.1, 132.8,
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129.8, 129.7, 127.7 (3 × C), 127.2, 124.2, 123.2, 111.0, 109.7, 66.3, 56.0, 55.9, 55.8, 54.3, 43.1, 26.9 (3
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× C), 22.5 (3 × C), 16.3. HRMS: m/z calcd for C34H45NO5SSi+Na 630.2685.; found 630.2687.
Compound 13e was prepared from 4ꢀNitro benzylideneacetone 12e (0.1 g, 0.5 mmol) and sulfinimine
11a (0.1 g, 0.25 mmol) using the procedure A described above in 76% yield (0.112 g) as an inseperable
mixture (94:6) of diastereomeric ratio as a gummy mass. [α]D24 +12.6 (c 1.63, CHCl3). IR (neat) 3419,
2929, 2856, 1656, 1600, 1344, 1112 cm−1. 1H NMR (400 MHz, CDCl3):
δ 8.25 (d, J = 8.4 Hz, 1.84H,
major), 8.15 (d, J = 8.4 Hz, 0.12H, minor), 7.70ꢀ7.60 (m, 6H), 7.52 (d, J = 16.4 Hz, 1H), 7.47ꢀ7.31 (m,
6H), 6.78 (d, J = 16.0 Hz, 1H, major), 6.34 (d, J = 12.8 Hz 0.06H, minor), 4.12 (d, J = 6.8 Hz, 1H),
4.07ꢀ3.86 (m, 2H), 3.84 (dd, J = 9.6, 4.4 Hz, 1H), 3.11 (dd, J = 16.8, 6.8 Hz, 1H), 2.90 (dd, J = 16.8, 5.2
Hz, 1H), 1.18 (s, 9H, major), 1.16 (s, 0.7H, minor), 1.08 (s, 9H, major), 1.05 (s, 0.6H, minor). 13C NMR
(100 MHz, CDCl3):
δ 197.3, 148.6, 140.5, 139.8, 135.6 (2 × C), 135.5 (2 × C), 133.0, 132.7, 129.9,
129.4, 128.8 (2 × C), 127.8 (5 × C), 124.1, 66.2, 55.9, 53.9, 43.9, 26.8 (3 × C), 22.5 (3 × C), 19.3.
HRMS: m/z calcd for C32H40N2O5SSi+Na 615.2325; found: 615.2318.
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Compound 13f was prepared from (E)ꢀ3ꢀmethylꢀ4ꢀphenylbutꢀ3ꢀenꢀ2 one 12f (0.15 g, 0.94 mmol) and
sulfinimine 11a (0.1 g, 0.25 mmol) using the procedure A described above in 85% yield (0.12 g) as a
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gummy mass. [α]D +14.9 (c 0.7, CHCl3). IR (neat) 3062, 2956, 2858, 1663, 1111, 1067 cm−1. H
NMR (400 MHz, CDCl3): 7.71ꢀ7.58 (m, 4H), 7.51ꢀ7.31 (m, 12H), 4.09 (d, J = 7.6 Hz, 1H), 4.04ꢀ3.87
δ
(m, 2H), 3.84 (d, J = 6.4 Hz, 1H), 3.19 (dd, J = 16.8, 6.8 Hz, 1H), 2.98 (dd, J = 16.8, 5.2 Hz, 1H), 2.01
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(s, 3H), 1.18 (s, 9H), 1.09 (s, 9H). C NMR (100 MHz, CDCl3):
δ 200.1, 139.2, 137.5, 135.7, 135.6 (2
× C), 135.5 (2 × C), 133.2, 132.8, 129.8, 129.7 (2 × C), 128.6, 128.5 (2 × C), 127.8 (5 × C), 66.4, 55.8,
54.8, 40.2, 26.9 (3 × C), 22.5 (3 × C), 19.3, 13.0. HRMS: m/z calcd for C33H43NO3SSi+Na 584.2631;
found 584.2631.
Compound 13g was prepared from (E)ꢀ4ꢀ(furanꢀ2ꢀyl)ꢀ3ꢀmetylbutꢀ3ꢀenꢀ2 one 12g (0.1 g, 0.625 mmol)
and sulfinimine 11a (0.1 g, 0.25 mmol) using the procedure A described above in 87% yield (0.119 g)
as a yellow gummy mass. [α]D24 +8.1 (c 2.25, CHCl3). IR (neat) 3068, 2932, 2860, 1659, 147, 1111,
1068 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.70ꢀ7.60 (m, 4H), 7.59 (s, 1H), 7.48ꢀ7.29 (m, 6H), 7.22 (s,
1H), 6.67 (d, J = 3.6 Hz, 1H), 6.54 (dd, J = 3.2, 2.0 Hz, 1H), 4.06 (d, J = 7.2 Hz, 1H), 4.01ꢀ3.85 (m,
2H), 3.82 (dd, J = 9.6, 4.0 Hz, 1H), 3.12 (dd, J = 16.4, 6.8 Hz, 1H), 2.91 (dd, J = 16.8, 5.6 Hz, 1H),
2.09 (s, 3H), 1.17 (s, 9H), 1.08 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 199.0, 151.6, 144.5, 135.5 (2 ×
C), 135.4 (2 × C), 133.6, 133.1, 132.8, 129.8, 127.7 (5 × C), 126.1, 115.5, 112.3, 66.3, 55.7, 54.7, 39.8,
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26.8 (3 × C), 22.4 (3 × C), 19.2, 12.8. HRMS: m/z calcd for C31H41NO4SSi+Na 574.2423.; found
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Compound 13h was prepared from mesityl oxide 12h (0.15 g, 1.53 mmol) and sulfinimine 11a (0.1 g,
0.25 mmol) using the procedure A described above in 55% yield (0.068 g as an inseparable 85:15
mixture of diastereomers) as a pale yellow liquid. [α]D24 +18.4 (c 0.83, CHCl3). IR (neat) 3437, 2931,
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1685, 1621, 1427, 1110, 1068 cm−1. H NMR (400 MHz, CDCl3):
δ 7.71ꢀ7.57 (m, 4H), 7.49ꢀ7.30 (m,
6H), 6.15 (s, minor), 6.03 (s, major) (1 H), 4.26 (d, J = 8.4 Hz, minor), 4.03 (d, J = 7.2 Hz, major) (1H),
3.95ꢀ3.84 (m, 2H), 3.83ꢀ3.69 (m, 1H), 2.78 (dd, J = 16.4, 6.8 Hz, 1H), 2.62 (dd, J = 16.4, 5.2 Hz, 1H,
major), 2.54 (dd, J = 12.8, 4.8 Hz, 0.15H, minor), 2.13 (s, 0.42H), 2.10 (s, 3H), 1.88 (s, 3H, major), 1.85
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(s, 0.47H), 1.17 (s, major), 1.14 (s, minor) (9H), 1.08 (s, minor), 1.07 (s, major) (9H). C NMR (100
MHz, CDCl3):
δ 198.3, 156.0, 135.6 (2 × C), 135.5 (2 × C), 133.2, 132.8, 129.77, 129.76, 127.74 (2 ×
C), 127.73 (2 × C), 123.8, 66.4, 55.7, 54.2, 46.7, 27.7, 26.8 (3 × C), 22.5 (3 × C), 20.8, 19.3. HRMS:
m/z calcd for C28H41NO3SSi+Na 522.2474.; found 522.2474.
Compound 13i was prepared from (E)ꢀ5ꢀ(benzyloxy)pentꢀ3ꢀenꢀ2ꢀone 12i (0.1 g, 0.5 mmol) and
sulfinimine 11a (0.1 g, 0.25 mmol) using the procedure A described above in 79% yield (0.12 g) as a
gummy mass. [α]D24 + 23.5 (c 1.0, CHCl3). IR (neat) 3359, 3060, 2954, 1669, 1684, 1256, 1070 cm−1.
1H NMR (400 MHz, CDCl3):
δ
7.70ꢀ7.57 (m, 3H), 7.48ꢀ7.25 (m, 11H), 6.79 (dt, J = 16.0, 4.0 Hz, 1H),
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6.36 (d, J = 16.0 Hz, 1H), 4.56 (s, 2H), 4.18 (dd, J = 4.0, 1.6 Hz, 2H), 4.01 (d, J = 6.8 Hz, 1H), 3.99ꢀ
3.38 (m, 2H), 3.82ꢀ3.71 (m, 1H), 2.95 (dd, J = 16.8, 6.4 Hz, 1H), 2.75 (dd, J = 16.8, 5.2 Hz, 1H), 1.17
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(s, 9H), 1.07 (s, 9H). 13C NMR (100 MHz, CDCl3):
δ 197.7, 142.7, 137.5, 135.6 (2 × C), 135.5 (2 × C),
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133.1, 132.8, 129.8, 129.3, 128.5 (2 × C), 127.9, 127.8 (5 × C), 127.6 (2 × C), 72.9, 68.7, 66.3, 55.8,
53.9, 43.1, 26.9 (3 × C), 22.5 (3 × C), 19.2. HRMS: m/z calcd for C34H45NO4SSi+Na .614.2736.; found
614.2735.
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Compound 13j was prepared from (E)ꢀtridecꢀ3ꢀenꢀ2ꢀone 12j (0.098 g, 0.5 mmol) and sulfinimine 11a
(0.1 g, 0.25 mmol) using the procedure A described above in 73% yield (0.107 g) as a gummy mass.
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[α]D24 +18.2 (c 1.0, CHCl3). IR (neat) 3406, 2989, 1647, 1015 cm−1. H NMR (400 MHz, CDCl3):
δ
7.70ꢀ7.57 (m, 4H), 7.49ꢀ7.31 (m, 6H), 6.79 (dt, J = 16.0, 6.8 Hz, 1H), 6.05 (d, J = 16.0 Hz, 1H), 4.02 (d,
J = 6.8 Hz, 1H), 3.98ꢀ3.82 (m, 2H), 3.81ꢀ3.71 (m, 1H), 2.93 (dd, J = 16.4, 5.2 Hz, 1H), 2.72 (dd, J =
16.8, 5.2 Hz, 1H), 2.19 (q, J = 7.2 Hz, 2H), 1.51ꢀ1.38 (m, 2H), 1.27 (m, 12H), 1.17 (s, 9H), 1.07 (s, 9H),
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0.88 (t, J = 7.2 Hz, 3H). C NMR (100 MHz, CDCl3):
δ 198.2, 148.3, 135.6 (2 × C), 135.5 (2 × C),
133.2, 132.8, 130.4, 129.8, 127.8 (5 × C), 66.4, 55.8, 54.2, 42.5, 32.5, 31.8, 29.5, 29.4, 29.3, 29.2, 28.0,
26.9 (3 × C), 22.6, 22.5 (2 × C), 19.3, 14.1. HRMS: m/z calcd for C35H55NO3SSi+Na 620.3570.; found
620.3571.
O
S
NH
O
OEt
OTBDPS
O
13k
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Compound 13k was prepared from (E)ꢀethyl 4ꢀoxopentꢀ2ꢀenoate 12k (0.08 g, 0.56 mmol) and
sulfinimine 11a (0.09 g, 0.22 mmol) using the procedure A described above in 12% yield (0.015 g) as a
gummy mass. [α]D24 +8.7 (c 0.765, CHCl3). IR (neat) 3726, 2928, 2861, 2313, 1727, 1644, 1018 cm−1.
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1H NMR (400 MHz, CDCl3):
δ 7.70ꢀ7.56 (m, 3H), 7.50ꢀ7.31 (m, 6H), 6.99 (d, J = 16.0 Hz, 1H), 6.58
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(d, J = 16.0 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.98 (d, J = 7.2 Hz, 1H), 3.95ꢀ3.83 (m, 2H), 3.82ꢀ3.71 (m,
1H), 2.99 (dd, J = 17.2, 6.8 Hz, 1H), 2.80 (dd, J = 17.2, 4.8 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.17 (s,
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9H), 1.07 (s, 9H). C NMR (100 MHz, CDCl3):
δ 197.5, 165.3, 139.1, 135.9 (2 × C), 135.5 (2 × C),
132.9, 132.6, 131.2, 129.9 (2 × C), 127.8 (4 × C), 66.2, 61.5, 55.9, 53.7, 44.1, 26.9 (3 × C), 19.2, 14.1.
HRMS: m/z calcd for C29H41NO5SSi+Na 566.2372.; found 566.2372.
Compound 13l was prepared from benzylideneacetone 12l (0.146 g, 1 mmol) and (SS,E)ꢀNꢀethylideneꢀ
2ꢀmethylpropaneꢀ2ꢀsulfinamide 11b (0.07 g, 0.5 mmol) using the procedure A described above in 81%
yield (0.12 g) as a 90:10 seperable mixture of diastereomers. Major diastereomer was isolated using
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silicagel column chromatography in 63% yield (0.087 g) as a gummy mass. [α]D + 22.4 (c 1.0,
CHCl3).IR (neat) 3386, 2957, 2924, 2854, 1714, 1243, 1017 cmꢀ1.1H NMR (400 MHz, CDCl3) δ 7.59ꢀ
7.49 (m, 3H), 7.43ꢀ7.34 (m, 3H), 6.71 (d, J = 16.2 Hz, 1H), 4.0ꢀ3.84 (m, 1H), 3.71 (d, J = 6.2 Hz, 1H),
3.06 (dd, J = 16.6, 7.6 Hz, 1H), 2.78 (dd, J = 16.6, 5.2 Hz, 1H), 1.94 (s, 1H), 1.39 (d, J = 6.7 Hz, 3H),
1.21 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 198.4, 143.2, 134.2, 130.6, 128.9, 128.3, 126.2, 55.6, 49.1,
48.5, 22.5, 22.0. HRMS: m/z for C16H23NO2S+Na, calcd: 316.1347; found: 316.1351.
O
S
NH
O
13m
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Compound 13m was prepared from benzylideneacetone 12a (0.15 g, 1.0 mmol) and sulfinimine 11d
(0.09 g, 0.5 mmol) using the procedure A described above in 22% yield (0.036 g) as a colorless liquid.
[α]D24 +22.4 (c 0.25, CHCl3). IR (neat) 3410, 1651, 1602, 1458, 1130, 1018 cm−1. 1H NMR (400 MHz,
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CDCl3):
δ 7.62ꢀ7.45 (m, 3H), 7.44ꢀ7.34 (m, 3H), 6.76 (d, J = 16.0 Hz, 1H), 3.72ꢀ3.60 (m, 2H), 3.07ꢀ
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2.91 (m, 1H), 2.80 (dd, J = 16.0, 3.2 Hz, 1H), 2.22ꢀ1.99 (m, 1H), 1.17 (s, 9H), 1.02 (t, J = 6.0 Hz, 6H).
13C NMR (100 MHz, CDCl3):
δ
198.7, 143.0, 134.3, 130.6, 128.9, 128.4, 126.2, 58.9, 56.1, 43.8, 32.1,
22.6, 16.3, 18.5. HRMS: m/z calcd for C18H27NO2S+Na 344.1660; found: 344.1657.
Compound 10n was synthesized using procedure B as follows: To a preꢀcooled stirred solution (−78 °C)
of benzylideneacetone 12a (0.14 g, 0.96 mmol) in dry THF (14 mL) under argon atmosphere at −78 °C
was added KHMDS (2.88 mL of 0.5M solution in toluene, 1.44 mmol). The reaction mixture was stirred
for 1 h at the same temperature. A solution of (E)ꢀNꢀbenzylideneꢀ2ꢀmethylpropaneꢀ2ꢀsulfinamide 11c
(0.1 g, 0.25 mmol) dissolved in 5 mL dry THF was introduced at −78 °C and the reaction mixture was
stirred 2 h at the same temperature. After completion of the reaction (TLC), it was quenched by
addition of saturated NH4Cl (20 mL) and was extracted with EtOAc (2 × 20 mL). The organic layer was
separated and 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 product 10n in 96% yield (0.163 g in 90:10 diastreomeric ratio). Major isomer was
24
separated using silica gel column chromatography in 75% yield (0.127 g) as a gummy mass. [α]D
+89.8 (c 0.215, CHCl3). IR (neat) 3446, 3270, 2868, 1680, 1048 cm −1. 1H NMR (400 MHz, CDCl3):
δ
7.59ꢀ7.44 (m, 3H), 7.45ꢀ7.28 (m, 8H), 6.68 (d, J = 16.4 Hz, 1H), 4.96ꢀ4.85 (pen, J = 3.6 Hz, 1H), 4.83
(d, J = 4.0 Hz, 1H), 3.28 (dd, J = 16.8, 4.4 Hz, 1H), 3.19 (dd, J = 16.8, 7.6 Hz, 1H), 1.23 (s, 9H). 13C
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NMR (100 MHz, CDCl3):
δ
198.5, 143.9, 140.95, 134.1, 130.8, 128.96 (2 × C), 128.6 (2 × C) 128.4, (2
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3
× C), 127.9, 127.5 (2 × C), 125.96, 55.6, 55.3, 47.3, 22.6 (3 × C). HRMS: m/z calcd for
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C21H25NO2S+Na 378.1504.; found 378.1504.
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To a preꢀcooled stirred solution (−78 °C) of benzylideneacetone 12a (0.12 g, 0.8 mmol) in dry THF (14
mL) under argon atmosphere at −78 °C was added KHMDS (2.5 mL of 0.5M solution in toluene, 1.2
mmol). The reaction mixture was stirred for 1 h at the same temperature. A solution of sulfinimine 11e
(0.1 g, 0.47 mmol) dissolved in 5 mL dry THF was introduced at −78 °C and the reaction mixture was
stirred 2 h at the same temperature. After completion of the reaction (TLC), it was quenched by
addition of saturated NH4Cl (20 mL) and was extracted with EtOAc (2 × 20 mL). The organic layer was
separated and 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
24
afforded the product 10o in 48% yield (0.08 g in 96:4 inseperable diastreomeric ratio). [α]D +36.7 (c
1.4, CHCl3). IR (neat) 3406, 2926, 2856, 1735, 1643, 1132, 1018 cm −1. 1H NMR (400 MHz, CDCl3):
δ
7.64ꢀ7.49 (m 3H), 7.45ꢀ7.35 (m, 3H), 6.72 (d, J = 16.4 Hz, 1H), 4.19 (d, J = 8.8 Hz, 1H), 3.51ꢀ3.34 (m,
13
1H), 3.12 (d, J = 4.8 Hz, 2H), 1.93 (d, J = 12.4 Hz, 1H), 1.82ꢀ1.57 (m, 5H), 1.32ꢀ1.05 (m, 14H). C
NMR (100 MHz, CDCl3):
δ 199.5, 143.2, 134.2, 130.6, 128.9, 128.4, 126.4, 59.0, 56.0, 43.2, 41.4, 29.9,
29.4, 26.3, 26.1, 26.0, 22.7. HRMS: m/z calcd for C21H31NO2S+Na 384.1973.; found 384.1973.
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Compound 13p was prepared from 3,4 dimethoxy benzylideneacetone 12d (0.17 g, 0.8 mmol) and
sulfinimine 11g (0.1 g, 0.37 mmol) using the procedure A described above in 63% yield (0.12 g as an
inseparable mixture of diastereomers) as a green yellow oil. [α]D24 +46.7 (c 2.4, CHCl3). IR (neat) 3442,
2931, 2856, 1650, 1513, 1023 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.51 (d, J = 16.0 Hz, 1H), 7.20 (dd,
J = 8.4, 1.6 Hz, 0.15H, minor), 7.13 (dd, J = 8.4, 1.6 Hz, 1H, major), 7.07 (d, J = 2.0 Hz, 1H), 6.87 (d, J
= 8.4 Hz, 1H), 6.61 (d, J = 16.0 Hz, major), 6.11 (d, J = 12.8 Hz, minor) (1H), 3.98ꢀ3.82 (m, 8.8H), 3.43
(t, J = 6.8, 2H), 3.14 (dd, J = 16.8, 8 Hz, 1H), 2.82 (dd, J = 16.8, 4.4 Hz, 1H), 1.99ꢀ1.78 (m, 3H), 1.74ꢀ
13
1.59 (m 3H), 1.19 (s, major), 1.16 (s, minor) (9H). C NMR (100 MHz, CDCl3):
δ 198.4, 151.4, 149.2,
143.3, 127.2, 124.3, 123.2, 111.0, 109.7, 55.9, 55.8, 55.7, 53.0, 46.6, 34.0, 33.5, 32.2, 24.6, 22.5 (3 ×
C). HRMS: m/z calcd for C21H32BrNO4S+Na 496.1133 found: 496.1131.
Preparation of compounds 15 and 16: To a preꢀcooled stirred solution of 13p (0.1 g, 0.21 mmol) in
MeOH (5 mL) at 0 °C was added a saturated solution of HCl in MeOH (0.5 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 solid was dissolved in MeOH (12 mL), DBU (0.125 mL, 0.84 mmol)
was added. The reaction mixture was stirred for 4 days at rt. The solvent was evaporated off and the
residue was diluted with water (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
products 15 in 41% yield (0.025 g) as a greenish yellow oil and 16 in 35% yield (0.021 g) as a greenish
yellow oil.
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[α]D24 +70.0 (c 2.5, CHCl3) [lit.15 +71 (c 0.25, CHCl3)]. IR (neat) 2930, 2855, 1721, 1513, 1261, 1138,
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1027 cm−1. H NMR (400 MHz, CDCl3):
δ 6.92 (s, 1H), 6.90ꢀ6.75 (m, 2H), 3.90 (s, 3H), 3.87 (s, 3H),
3.20 (dd, J = 12.0, 2.8 Hz, 1H), 2.79 (m, 1H), 2.68 (t, J = 13.2 Hz, 1H), 2.58ꢀ2.19 (m, 4H), 1.80ꢀ1.19
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(m, 7H). C NMR (100 MHz, CDCl3):
δ 207.7, 149.3, 148.3, 135.1, 119.5, 111.0, 109.8, 69.9, 62.4,
55.9, 55.8, 52.7, 50.8, 48.7, 34.3, 25.8, 24.1. HRMS: m/z calcd for C17H23NO3+H 290.1756; found:
290.1756.
[α]D24 +11.3 (c 1.0, CHCl3) [lit16 +10.8 (c 1.31, CHCl3); IR (neat) 2930, 2855, 1721, 1513, 1261, 1138,
1027 cm−1. 1H NMR (400 MHz, CDCl3):
δ 6.81 (d, J = 8.8 Hz, 1 H), 6.74ꢀ6.62 (m, 2 H), 4.24 (dd, J =
6.4, 4.4 Hz, 1 H), 3.87 (s, 3H), 3.86 (s, 3H), 2.98ꢀ2.81 (m, 3H), 2.60 (m, 2H), 2.38 (dd, J = 14.8, 8.4 Hz
1H), 2.20 (dt, J = 11.6, 2.8 Hz, 1H), 1.75ꢀ1.12 (m, 6H). 13C NMR:
δ
209.5, 148.7, 148.4, 131.4, 120.9,
111.8, 110.6, 63.8, 55.9, 55.8, 54.3, 51.3, 47.5, 46.7, 31.8, 23.9, 23.3. HRMS: m/z calcd for
C17H23NO3+H 290.1756; found: 290.1760.
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Compound 13q was prepared from (E)ꢀtridecꢀ3ꢀenꢀ2ꢀone 12j (0.190 g, 1.0 mmol) and sulfinimine 11b
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(0.074 g, 0.5 mmol) using the procedure A described above in 62% yield (0.106 g) as a colorless oil.
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[α]D +59.4 (c 0.75, CHCl3). IR (neat) 3403, 3269, 2926, 2855, 1736, 1666, 1629, 1462, 1369, 1243,
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1050 cmꢀ1. H NMR (400 MHz, CDCl3): δ 6.83 (dt, J = 16.0, 6.9 Hz, 1H), 6.07 (d, J = 16.0 Hz, 1H),
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3.9ꢀ3.78 (m, 1H), 3.66 (d, J = 6.2 Hz, 1H), 2.92 (dd, J = 16.7, 7.6 Hz, 1H), 2.66 (dd, J = 16.7, 5.2 Hz,
1H), 2.19 (dt, J = 8.0, 4.0 Hz, 2H), 1.72 (s, 1H), 1.51ꢀ1.39 (m, 2H), 1.35 (d, J = 6.8 Hz, 3H), 1.25 (s,
12H), 1.16 (s, 9H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ. 198.7, 148.5, 130.4, 55.6,
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49.1, 47.7, 32.4, 31.8, 29.4, 29.3, 29.2, 29.2, 28.0, 22.6, 22.5, 22.0, 14.1.
C19H37NO2S+Na, calcd: 366.2447; found: 366.2443.
HRMS: m/z for
Preparation of (2R,4R,9aR)-4-(3,4-dimethoxyphenyl)octahydro-1H-quinolizin-2-ol (2): To a preꢀ
cooled stirred solution of 15 (0.045 g, 0.16 mmol) in dry THF (2 mL) under argon atmosphere at 0 °C
was added LiAlH4 (8.8 mg, 0.23 mmol). The reaction mixture was stirred for 0.5 h. After completion of
reaction (by TLC) it was quenched with MeOH (0.5 mL) and it was stirred for 2 h. The resultant
reaction mixture was filtered through a celite pad. Evaporation of solvent gave the crude alcohol which
was taken to further reaction without purification.
To a pre−cooled (0 °C) solution of crude alcohol in dry toluene (5.2 mL) was added triphenyl phosphine
(0.086 g, 0.31 mmol) and pꢀnitrobenzoic acid (0.052 g, 0.31 mmol) under argon atmosphere and
allowed to stirred for 10 min. DEAD (0.026 mL, 0.16 mmol) was introduced into the reaction mixture
over period of 10 min at the same temperature. The reaction mixture was warmed up to room
temperature and was stirred for 1 h. After the reaction was complete (TLC), the volatiles were removed
under reduced pressure and the crude residue thus obtained was subjected to next reaction without
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further purification. To a solution of the pꢀnitrobenzoate (obtained above) in MeOH (3 mL) was added
K2CO3 (0.038 g, 0.28 mmol) at room temperature and stirred for 1.5 h. After completion of the reaction
to it was added saturated NaHCO3 solution (5 mL) and extracted with EtOAc (15 mL) and washed with
brine (5 mL). Evaporation of solvent followed by neutral alumina column chromatography of the
resulting crude residue with petroleum ether:EtOAc as eluent afforded the alcohol 2 (0.035 g, 81% for 2
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steps) as a yellow oil. [α]D +47.9 (c 1.1, CHCl3) [lit.17a +43.4 (c 1.0, CHCl3). IR (neat) 2928, 1594,
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1513, 1460, 1261, 1139, 1062cm−1. H NMR (400 MHz, CDCl3):
δ 6.97ꢀ6.73 (m, 3H), 4.20ꢀ4.08 (m,
1H), 3.88 (s, 3H), 3.86 (s, 3H), 3.32 (dd, J = 11.6, 3.2 Hz, 1H), 2.75ꢀ2.62 (m, 1H), 2.48ꢀ2.30 (m, 1H),
13
1.96ꢀ1.21 (m, 12H). C NMR (100 MHz, CDCl3):
δ 148.9, 147.8, 137.2, 119.6, 110.9, 110.4, 64.9,
63.4, 56.4, 55.9, 55.8, 53.2, 42.8, 40.3, 33.6, 26.1, 24.8. HRMS: m/z calcd for C17H25NO3H 292.1913.;
found 292.1918.
Preparation of (2S,6R)-2-methyl-6-nonylpiperidin-4-one (17): To a pre−cooled stirred solution of
13q (0.068 g, 0.2 mmol) in MeOH (5 mL) at 0 °C was added saturated HCl in MeOH (0.5 mL). The
reaction mixture was stirred for 1 h at the same temperature. After completion of reaction (TLC) solvent
was evaporated and the resultant residue was dissolved in MeOH (6 mL), Et3N (0.04 mL, 0.27 mmol)
was added and was stirred for 12 h at rt. Most of the solvent was evaporated off and diluted with water
(10 mL) and extracted with EtOAc (2 × 20 mL). Solvent was evaporated and product was purified using
24
silica gel column chromatography to yield 17 as a colorless oil in 84% (0.039 g) yield. [α]D −1.4 (c
0.5, CHCl3) [lit11a −1.1 (c 1.56, CHCl3) IR (neat) 3386, 2957, 2924, 2854, 1714, 1243, 1017 cmꢀ1. 1H
NMR (400 MHz, CDCl3): δ 3.43 (dd, J = 12.0, 6.7 Hz, 1H), 3.28 (dt, J = 12.2, 6.2 Hz, 1H), 2.54ꢀ2.42
(m, 2H), 2.14 (td, J = 12.7, 6.7 Hz, 2H), 1.61 (s, 2H), 1.25 (s, 15H), 1.16 (d, J = 6.5 Hz, 3H), 0.87 (t, J =
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6.7 Hz, 3H). C NMR (100 MHz, CDCl3): δ 209.9, 52.6, 49.6, 47.8, 47.7, 34.7, 31.8, 29.6, 29.5, 29.2,
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26.1, 22.6, 21.6, 14.1. HRMS: m/z for C15H29NO+H, calcd: 240.2327; found: 240.2326.
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Preparation of (2S,4R,6R)-2-methyl-6-nonylpiperidin-4-ol (4): To a stirred solution of 17 (0.023 g
0.1 mmol) in ethanol (2 mL) at 0 °C was added NaBH4 (0.01 g, 0.25 mmol) and stirring was continued
for 1 h at 0 °C. After completion of reaction (TLC) the solvent was removed under reduced pressure and
the crude residue was taken up with a 15% ammonia solution (1 mL) and extracted with diethyl ether (2
× 3 mL). The combined organic layers were dried over NaSO4. Evaporation of solvent followed by
silica gel column chromatography of the resulting crude residue with EtOAc/MeOH as eluent afforded
the product 4 in 82% yield (0.019 g). [α]D24 +5.4 (c 0.5, MeOH) [lit18 +5.66 (c 0.60, MeOH)]. IR (neat)
1
3359, 2924, 2853, 1655, 1461, 1026 cmꢀ1. H NMR (400 MHz, CDCl3): δ 3.66 (td, J = 11.1, 5.5 Hz,
1H), 2.7ꢀ2.65 (m, 1H), 2.54 (dd, J = 9.1, 6.1 Hz, 1H), 2.00ꢀ1.92 (m, 2H), 1.40 (d, J = 8.0 Hz, 2H), 1.26
(s, 15H), 1.12 (d, J = 6.4 Hz, 3H), 1.00 (dd, J = 19.1, 11.5 Hz, 2H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 69.5, 54.8, 50.2, 43.9, 41.7, 36.8, 31.9, 29.7, 29.6, 29.5, 29.3, 26.0, 22.7, 22.4,
14.1. HRMS: m/z for C15H31NO+H, calcd: 242.2484; found: 242.2495.
Acknowledgements: A. A. R. and P. O. R. thank the Council of Scientific and Industrial Research
(CSIR), and University Grants Commission (UGC), New Delhi for a junior research fellowship and Dr.
D. S. Kothari postdoctoral fellowship respectively.
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Supporting information: Supporting information containing H and C NMR spectra of all the new
compounds is provided. “This material is available free of charge via the Internet at http://pubs.acs.org.”
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References:
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1) Michael, J. P. Nat. Prod. Rev. 2008, 25, 139.
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2) a) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett. 2000, 2, 1041. b) Davis, F. A.;
Chao, B. Org. Lett. 2000, 2, 2623. c) Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000,
2016. d) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169. e) Davis, F. A.; Rao, A.; Carroll,P. J.
Org. Lett. 2003, 5, 3855. f) Davis, F. A.; Zhang, Y.; Anilkumar, G. J. Org. Chem. 2003, 68, 8061.
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3) Gu, C. –L.; Liu, L. Wang, D.; Chen, Y. –J. J. Org. Chem. 2009, 74, 5754ꢀ5757.
4) Wang, Q.; Gemmeren, M. Van.; List, B. Angew. Chem. Int. Ed Eng, 2014, 53, 13592.
5) a) Sickert, M.; Schneider, C. Angew. Chem. Int. Ed. 2008, 47, 3631. b) Sickert , M.; Abels, F.;
Lang, M.; Sieler, J.; Birkemeyer, C.; Schneider.C Chem. –Eur. J. 2010, 16, 2806. For a recent account
see: c) Lindeman, C.; Schneider,C. Synthesis, 2016, 48, 828.
6) a) AbrunhosaꢀThomas, I.; Plas, A.; Vogrig, A.; Kandepedu, N.; Chalard, P.; Troin. Y. J. Org.
Chem. 2013, 78, 2511. b) AbrunhosaꢀThomas, I.; Plas, A.; Kandepedu, N.; Chalard, P.; Troin, Y.
Beilstein J. Org. Chem. 2013, 9, 486 and references cited therein.
7) While there has been a plethora of publications concerning the catalytic/ diastereoselective
addition of silyl enol ethers and silyloxy dienes obtained from various enolizable esters and unsaturated
esters to imines, the direct addition of either enolates or silyloxy dienes derived from substituted methyl
enones to imines was not explored in the literature. For a report concerning the addition of unsaturated
enone to chiral Nꢀphosphonyl imine See: a) Xiong, Y.; Mei, H.; Han, J.; Li, G.; Pan,Y. Tetrahedron
Lett, 2014, 55, 2476. An example of the enolate derived from αꢀarylmethylideneꢀ βꢀketo ester to 2ꢀArylꢀ
Nꢀsulfinylaldimines was also recorded. b) M. K. Ghorai, S. Halder, R. K. Das, J. Org. Chem. 2010, 75,
7061ꢀ7072. Addition of Danishesfky’s diene to sulfinimines c) Andreassen, T.; Haland, T.; Hansen, K.
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L.; Gautun, O. R. Tetrahedron Lett. 2007, 48, 8413ꢀ8415. d) Addition of Rawal’s diene to sulfinimines:
Kawecki, R. Tetrahedron: Asymmetry 2006, 17, 1420ꢀ1423.
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8) For reviews on the chemistry of sulfinimines: see a) Robak, M. T.; Herbage, M. A.; Ellman, J.
A. Chem. Rev. 2010, 110, 3600. b) Ferreira, F.; Botuha, C.; Chemla, F.; PérezꢀLuna, A. Chem. Soc. Rev.
2009, 38, 1162. c) Davis, F. A. J. Org. Chem. 2006, 71, 8993. d) Morton, D.; Stockman, R. A.
Tetrahedron, 2006, 62, 8869. e) Zhou, P.; –C, B.; Davis, F. A. Tetrahedron 2004, 60, 8003.
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9) For the chelation controlled addition of metal enolates of esters to sulfinimines a) Davis, F. A,;
Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992, 57, 6387ꢀ6389. b) Davis, F. A.; Reddy, R. E.;
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