Formal Total Synthesis of (+)-C9-Deoxyomuralide from l -Leucine Using a Double Sacrificial Chirality Transfer Approach

Article abstract of DOI:10.1021/acs.joc.7b02078

Formal stereocontrolled syntheses of (±)- and (+)-C9-deoxyomuralide is reported, constituting one of the shortest routes to the full carbon skeleton reported to date.

Full text of DOI:10.1021/acs.joc.7b02078

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Article
Formal Total Synthesis of (+)-C9-Deoxyomuralide from L-
Leucine Using a Double Sacrificial Chirality Transfer Approach
Philip C. Bulman Page, Ross L. Goodyear, Alexandra E. Horton, Yohan Chan, rehana karim, Maria A.
O'Connell, Christopher Hamilton, Alexandra M. Z. Slawin, Benjamin R Buckley, and Steven Mark Allin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02078 • Publication Date (Web): 07 Nov 2017
Downloaded from http://pubs.acs.org on November 10, 2017
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Page 1 of 33
The Journal of Organic Chemistry
Formal Total Synthesis of (+)-C9-Deoxyomuralide from L-Leucine Using a Double Sacrificial
Chirality Transfer Approach
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Philip C. Bulman Page,a* Ross L. Goodyear,a Alexandra E. Horton,a Yohan Chan,a Rehana Karim,a Maria A.
O’Connell,b Christopher Hamilton,b Alexandra M. Z. Slawin,c Benjamin R. Buckley,d Steven M. Allin.e
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a School of Chemistry and b School of Pharmacy, University of East Anglia, Norwich Research Park,
Norwich, Norfolk NR4 7TJ, UK
c School of Chemistry, University of St Andrews, St Andrews, KY16 9ST, Scotland
d Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
e School of Science & Technology, Nottingham Trent University, Clifton, Nottingham NG11 8NS
p.page@uea.ac.uk
Me
HO
HO2C
CO2Me
O
N
NH2,HCl
H
Abstract: Formal stereocontrolled syntheses of (±)- and (+)-C9-deoxyomuralide is reported,
constituting one of the shortest routes to the full carbon skeleton reported to date.
Introduction
The proteasome is a 28 protein complex responsible for the normal turnover of cellular proteins, the removal
of damaged proteins, and control of cell growth and metabolism. It comprises a 20S catalytic core with
additional subunits.1 Selective proteasome inhibitors have great therapeutic potential for the treatment of
inflammatory diseases and cancer.2 In 1991 Omura reported the isolation of (+)-lactacystin 1, a novel amino
acid metabolite from Streptomyces sp. OM-6519.3 The compound, and the corresponding β-lactone
omuralide 2, inhibit cancer cell growth and vascular smooth muscle cell proliferation,4 suggesting that it
may have therapeutic potential in vascular diseases and diabetes.5 Several β-lactone-derived natural
products (e.g. lactacystin 1,1 omuralide 2, salinosporamides such as 3 6 and cinnabaramides such as 4 7) have
been identified with similar modes of activity as potent covalent inhibitors of the 20S proteasome (Figure 1).
Due to the unique ability of compounds 1 and 2 to inhibit the activity of the 20S proteasome, several
research groups have targeted this important biologically active structure,8 and the area has been reviewed.9
Retrosynthetic disconnection at the thiol ester linkage leads to the substituted pyroglutamic acid 5. Corey
has shown that this may be coupled with a suitably protected (R)-N-acetylcysteine in one step without
hydroxyl group protection (Figure 1).8 The convoluted chemical syntheses of such molecules, however,
render them costly and limit accessibility to improved analogues.8,9
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AcHN
HO2C
1
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6
Me
O
O
HO
S
R
OH
OH
O
O
HO
O
HO
HO2C
HO
H
HN
Me
Me
Me
O
HN
HN
HN
7
O
O
O
8
9
5
Lactacystin 1
Omuralide 2
R= CH2CH2Cl Salinosporamide A 3
R= -(CH2)5CH3 Cinnabaramide A 4
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Figure 1. Omuralide and related structures
Our approach was informed by our original finding that the carbon framework of the (±)-
lactacystin/omuralide nucleus could be achieved in as few as five steps from N-benzylglycine;10 in this
route, key steps were a Dieckmann cyclization,11 followed by enolate functionalization, hydrogenolysis, and
concomitant decarboxylation (Scheme 1).
O
CO2Bn
(i)
(ii)
CO2Et
(iii)
O
N-Benzylglycine
BnN
CO2Bn
BnN
O
O
O
MeO2C
BnN
MeO2C
BnN
O
MeO2C
BnN
(v)
CO2Bn
(iv)
CO2Bn
O
O
O
Reagents and conditions: (i) BnOCOCH2COCl, pyridine, DMAP, CH2Cl2, rt, 24 h, 83%; (ii) a) TBAF, Et2O, rt; b) MeI, THF, rt,
24 h, 53% over 2 steps; (iii) LiHMDS, NCCO2Me, DMPU, THF, –78 °C, 2 h, 75%; (iv) NaH, CH2=C(CH3)CH2Br, DMF, rt, 24 h,
75%; (v) H2, Pd/C, 90%.
Scheme 1. Early approach to omuralide skeleton
We have now devised a stereocontrolled formal synthesis of (+)-C9-deoxyomuralide from L-leucine, using a
double internal sacrificial chirality transfer approach (Scheme 2). This strategy hinges on preparation of the
key fully functionalized intermediate 6 from protected leucine 8 through a tandem Dieckmann
cyclisation/alkylation process to afford pyroglutamate 9, and subsequent acylation using Mander’s reagent.
Reduction, decarboxylation and protecting group removal sequence would lead to known intermediate 7.12
Stereochemistry is derived ultimately from L-leucine. The isobutyl group stereochemistry controls the
asymmetric induction during the enolate methylation step to give 9, but is then itself sacrificed during the
subsequent enolization; the stereochemistry at this centre is then re-introduced under the control of the
methylated centre, the stereochemistry of which is also subsequently sacrificed during decarboxylation.
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23
24
CO2Me
NH2
Me
CO2Bn
O
O
CO2Bn
O
CO2Me
O
N
OH
O
CO2Bn
N
PMB
N
O
O
O
PMB
PMB
8
9
Key tandem Dieckmann cyclisation/alkylation
OBn
Me
OMe
Me
Me
CO2Bn
HO
HO2C
Me
O
O
O
CO2Bn
7
4
MeO2C
5
O
O
O
O
O
N
N
N
N
9
H
H
PMB
PMB
6
7
Scheme 2. Synthetic approach towards (+)-C9-deoxyomuralide
Results and Discussion
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The synthesis began with the reductive amination of L-leucine methyl ester with 4-anisaldehyde and sodium
cyanoborohydride under reflux to afford amine (±)-10 as a racemic mixture in 96% yield (Scheme 2). It is
known that complete racemization of amino acids can occur at high temperature in the presence of an
aldehyde and acetic acid.13 In this racemic series, coupling of (±)-10 with the potassium salts of carboxylic
acids (±)-11 and (±)-12 using EDAC·HCl afforded the corresponding amides (±)-13 and (±)-8 in 75% and
78% yields, respectively (Scheme 3).
O
CO2Me
K
O
O
N
O
CO2Me
PMB
PMB
CO2Me
(i)
(ii)
O
O
O
HN
NH2,HCl
R
R
(±)-10
11: R= NO2
12: R= H
(±)-13: R= NO2, 75%
(±)-8: R= H, 78%
Reagents and conditions: (i) CH3CO2H, 4-methoxybenzaldehyde, toluene, reflux under Dean-Stark trap, 12 h; then CH3CO2H,
NaBH3CN (2 equiv.), MeOH, 0 ºC to r.t., 5 h, 96%; (ii) NMM, EDAC·HCl, DMAP, CH2Cl2, r.t., 20 h.
Scheme 3. Preparation of Dieckmann cyclization substrates
The key Dieckmann cyclization step was initially studied using 4-nitrobenzyl ester (±)-13. Treatment of
amide (±)-13 with 2.5 equivalents of TBAF in diethyl ether induced cyclization followed by deprotonation
to afford the cyclized enolate tetrabutylammonium salt. Removal of the solvent and dissolution of the
residue in THF followed by addition of methyl iodide produced the two methylated pyroglutamate
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1
diastereoisomers (±)-14a and (±)-14b in an approximately 1:1 ratio, assessed by analysis of the H NMR
spectrum of the reaction mixture. Column chromatography on silica gel afforded the first eluting
diastereoisomer (±)-14a and the second eluting diastereoisomer (±)-14b in 37% and 25% yields,
respectively. Compound (±)-14a was submitted to attempted enolate C-acylation α to the nitrogen atom
using Mander’s reagent,14 and two products, (±)-15 and (±)-16, were obtained in 36% and 28% yield,
respectively (Scheme 4). Structural assignment of these two products and of (±)-14a was achieved through
single crystal X-ray crystallography (Figure 2).
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NO2
NO2
CO2Me
N
O
(i)
PMB
O
O
Me
Me
O
O
O
O
O
O
O
O
N
N
NO2
PMB
PMB
(±)-14b
(±)-13
(±)-14a
(ii)
O2N
O
O
Me
O
RO
N
PMB
(±)-15 R=H, 36%
(±)-16 R= CO2Me, 28%
Reagents and conditions: (i) TBAF in THF, Et2O, r.t., overnight; then MeI, THF, 0 ºC to r.t., 16 h, 37% of (±)-14a and 25% of
(±)-14b,; (ii) n-BuLi, Hexamethyldisilazane, DMPU, THF, −78 °C, 0.5 h, then NCCO2Me, −78 °C 4h.
Scheme 4. Dieckmann cyclization and attempted acylation of (±)-13
The structure of (±)-14a indicates that the compound has the methyl and iso-butyl groups in a cis
relationship. The structure of (±)-15 and (±)-16 indicate the formation of a 5-membered ring lactone rather
than the desired C-acylated material, presumably through deprotonation at the benzylic position of the 4-
nitrobenzyl group followed by attack at the ketone moiety, giving the corresponding bicyclic alkoxide.
Quench with a proton source or reaction with Mander’s reagent would then yield (±)-15 or (±)-16,
respectively.
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(±)-14a
(±)-15
(±)-16
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Figure 2: Single crystal X-ray structures of compound (±)-14a, (±)-15 and (±)-16 (hydrogen atoms have
been omitted for clarity)
Starting from benzyl ester (±)-8, however, the two methylated pyroglutamate diastereoisomers (±)-9a and
(±)-9b were obtained, also in an approximately 1:1 ratio as assessed by analysis of the 1H NMR spectrum of
the reaction mixture. Column chromatography allowed the separation of these diastereoisomers, which were
obtained in 30% and 29% yield, respectively, (±)-9a being the first eluting isomer. The two diastereoisomers
were separately treated with base followed by Mander’s reagent. Pleasingly, the desired acylation took place
and was completely stereoselective; the same racemic diastereoisomer (±)-6 was isolated after column
chromatography when (±)-9a and (±)-9b were used separately, or in a mixture of (±)-9a and (±)-9b, as
substrates, the approach of the reagent having occurred towards the opposite face of the five-membered ring
to that bearing the benzyl ester group (Scheme 5). No competing cyclization to γ-lactone was observed,
presumably due to reduced acidity at the benzylic position.
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Me
O
Me
O
CO2Me
CO2Bn
CO2Bn
O
1
2
3
4
5
6
(i) or (ii)
N
PMB
CO2Bn
O
N
N
O
PMB
(±)-9a
PMB
(±)-9b
(±)-8
7
8
9
(iii)
(iii)
10
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Me
O
CO2Bn
O
MeO2C
N
PMB
(±)-6
Reagents and conditions: (i) TBAF in THF, Et2O, r.t., 16 h; then MeI, THF, 0 ºC to r.t., 16 h, 30% of (±)-9a and 29% of (±)-9b;
(ii) TBAF in THF, THF, r.t., 0.5 h, then MeI, r.t., 16 h, (±)-9a, 9b (1:1) 57% (iii) LiHMDS, DMPU, THF, −78 °C, 0.5 h, then
NCCO2Me, −78 °C, 4 h, 88%.
Scheme 5. Dieckmann cyclization and acylation of (±)-8
Two possible two-step pathways were now available to obtain target compound (±)-18: ketone reduction
followed by decarboxylation, or decarboxylation followed by ketone reduction. Sodium borohydride
reduction of the ketone moiety in compound (±)-6 afforded alcohol (±)-17 as a single diastereoisomer
1
13
according to analysis of the H and C NMR spectra (Scheme 6). Optimization of the reduction conditions
led to the isolation of the desired product in 52% yield with 31% of starting material recovered. Other
reducing agents such as sodium cyanoborohydride, sodium triacetoxyborohydride, DIBAL, and aluminium
triisopropoxide/isopropanol only led to complete recovery of the starting material, perhaps due to the steric
hindrance around the ketone moiety. Single crystal X-ray crystallography carried out on (±)-17 showed that
the relative stereochemistry is as desired with the methyl group, the hydroxyl group and the ester group in
an all cis relationship (Figure 3). Subsequent hydrogenolysis was expected to proceed with concomitant
decarboxylation of the resulting α-amidoacid, but only the corresponding carboxylic acid (±)-18 could be
isolated, most efficiently by treatment with palladium hydroxide and hydrogen.
Me
Me
Me
O
HO
MeO2C
HO
MeO2C
CO2Bn
O
CO2Bn
O
CO2H
O
(i)
(ii)
MeO2C
N
N
N
PMB
(±)-6
PMB
PMB
(±)-17
(±)-18
Reagents and conditions: (i) NaBH4, EtOH, −10 °C, 30 min, 52% of (±)-17 and 31% of (±)-6; (ii) H2, Pd(OH)2/C, THF, quant.
Scheme 6. Reduction and hydrogenolysis of (±)-6
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8
9
10
11
12
13
14
15
16
17
18
19
20
Figure 3: Single crystal X-ray structure of (±)-17 (hydrogen atoms are omitted for clarity)
Decarboxylation of (±)-17 was attempted using Krapcho conditions (Scheme 7),15 but double
decarboxylation and elimination occurred to give products (±)-19 and (±)-20 in 49% and 38% yields,
respectively.
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22
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24
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Me
Me
Me
HO
MeO2C
CO2Bn
O
(i)
O
O
N
N
N
PMB
(±)-19
PMB
(±)-20
PMB
(±)-17
Reagents and conditions: (i) LiCl, DMF, 135°C, 4 h, (±)-19, 49% and (±)-20, 38%.
Scheme 7. Attempted decarboxylation of (±)-17
Radical-mediated decarbonylation of the corresponding acylselenide was also attempted (Scheme 8).
F3C
O
O
Me
Me
Me
HO
MeO2C
HO
MeO2C
CO2H
O
O
CO2H
O
(ii)
SePh
(iii)
MeO2C
O
N
N
N
PMB
PMB
PMB
(±)-18
(±)-23
(±)-24
(iv)
(i)
O
Me
Me
HO
MeO2C
HO
MeO2C
O
Me
O
MeO2C
O
O
N
N
N
PMB
PMB
PMB
(±)-22
(±)-21a
(±)-21b
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Reagents and conditions: (i) (SePh)2, Bu3P, CH2Cl2, 18 h, 43%; or oxalyl chloride, 2-mercaptopyridine N-oxide sodium salt,
DMF, CHCl3; or EDAC·HCl, NMM, DMAP, 2-mercaptopyridine N-oxide sodium salt, THF; (ii) TFAA, Pyridine, Et2O, −10 °C,
4 h, 81%; (iii) (SePh)2, Bu3P, CH2Cl2, 18 h, 31%; (iv) Bu3SnH, ABCN, toluene
1
2
3
4
Scheme 8. Attempted decarboxylation of (±)-18
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6
7
8
9
Carboxylic acid (±)-18 was dissolved in dichloromethane at 0 °C and tributylphosphine and diphenyl
diselenide were added. Data for the major product did not, however, match the expected acyl selenide. β-
Lactone (±)-22 was identified as the product using mass spectrometry (m/z = 376.1756, corresponding to
[M+H]+) and IR spectroscopy (β-lactone signal at 1842 cm-1), and its relative configuration was confirmed
using NOESY NMR spectroscopy (Figure 4). The Barton decarboxylation methodology was investigated, 16
but attempted preparation of the thiolester using EDAC or oxalyl chloride yielded only β-lactone (±)-22.
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O
O
Me
H
MeO2C
O
N
OMe
(±)-22
Figure 4: NOESY NMR spectrum analysis of (±)-22
The lactonization was partially circumvented by protection of the hydroxyl group; trifluoroacetylation
proceeded in 81% yield to give (±)-23 after an aqueous work-up. Trifluoroacetate (±)-23 was used without
further purification as it proved unstable to silica gel column chromatography. Treatment with diphenyl
diselenide and tributylphosphine afforded the desired acyl selenide (±)-24 in 31% yield alongside lactone
(±)-22 in 10% yield; the trifluoroacetate unit appears to be lost during the reaction process. Attempted
radical-mediated decarboxylation of (±)-24 using tributyltin hydride and ABCN (1,1’-
azobis(cyclohexanecarbonitrile)) as the initiator failed to yield the desired products 21a/21b.
Tributylgermanium hydride and tris(trimethylsilyl)silane were tested in the reaction in place of tributyltin
hydride, but both methods proved unsuccessful and resulted in complex mixtures, with neither the desired
compound nor the starting material being isolated.
As this first route was unsuccessful, we investigated initial decarboxylation of (±)-6: hydrogenolysis of β-
ketoamide (±)-6 induced concomitant decarboxylation as expected, leading to a mixture of inseparable
diastereoisomers (±)-25a and (±)-25b in a 1:1 ratio in quantitative yield (Scheme 9).
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Me
Me
Me
O
O
O
CO2Bn
1
2
3
4
(i)
MeO2C
MeO2C
MeO2C
O
O
O
N
N
N
PMB
PMB
PMB
5
6
7
(±)-6
(±)-25a
(±)-25b
Reagents and conditions: (i) H2, Pd(OH)2/C, THF, 30 °C, 12 h, 100%
8
9
Scheme 9. Decarboxylation of (±)-6
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The subsequent reduction of the ketone, however, proved much more challenging than expected. Attempted
reduction using sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, DIBAL,
and Red-Al all proved unsuccessful under a variety of reaction conditions, perhaps due to ready enolization.
These reactions all resulted in the recovery of the starting material, decomposition, or formation of complex
mixtures.
Noting that both Pattenden (Scheme 10) and Corey8 had prepared C-thiomethyl derivatives prior to ketone
reduction in related structures, we treated the mixture of (±)-25a and (±)-25b with S-methyl-p-
toluenethiosulfonate 2617 and triethylamine in dichloromethane solution to give the desired thiomethyl
product as an inseparable mixture of diastereoisomers (±)-27a and (±)-27b in 63% yield and a 1:2 ratio
(Scheme 11).
Me
Me
Me
Me
SMe
O
SMe
O
O
O
O
HO
(i)
(ii)
O
O
MeO2C
OTBS
MeO2C
OTBS
MeO2C
OTBS
MeO2C
N
N
N
N
H
H
H
H
OTBS
Reagents and conditions: (i) i) p-MePhSO2SMe, Et3N, CH2Cl2, r.t., 78%; (ii) Zn(BH4)2 (4.4 M in THF), THF, 0 °C, 79%.
Scheme 10. Approach to reduction in related systems
We also prepared the thiophenyl analogue using S-phenyl-p-toluenethiosulfonate 28.8 Despite a slightly
decreased overall yield, incorporation of the thiophenyl group increased the yield of the desired
diastereoisomer (±)-29a: the (±)-29a/(±)-29b mixture was obtained in 60% yield and 1:1 ratio; the
diastereoisomers were identified using NOESY spectroscopy (Figure 5).
SO2Na
SO2SR
(i)
RS SR
26 R=Me
28 R=Ph
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Me
SR
Me
SR
Me
Me
O
O
O
O
1
2
3
4
(ii) or (iii)
MeO2C
MeO2C
MeO2C
MeO2C
O
O
O
O
N
N
N
N
PMB
PMB
PMB
PMB
5
6
7
8
(±)-25a
(±)-25b
(±)-27a R=Me
(±)-29a R=Ph
(±)-27b R=Me
(±)-29b R=Ph
9
Reagents and conditions: i) Iodine, CH2Cl2, r.t., 26: 76%; 28: 67%; ii) 26, Et3N, CH2Cl2, r.t., (±)-27a and (±)-27b: 63%; iii) 28,
Et3N, CH2Cl2, r.t., (±)-29a and (±)-29b: 60%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
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45
46
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49
50
51
52
53
54
55
56
57
58
59
60
Scheme 11. Introduction of thioether groups
Me
SMe
Me
SMe
Me
SPh
O
O
O
O
O
O
O
O
O
MeO
MeO
MeO
N
N
N
PMB
PMB
PMB
(±)-27a
(±)-27b
(±)-29a
Figure 5: NOESY analysis of the relative configurations of (±)-27a, (±)-27b and (±)-29a
Reduction of the mixtures of diastereoisomers (±)-27a/b (thiomethyl) and (±)-29a/b (thiophenyl) using
sodium borohydride was successful and completely stereoselective (Scheme 12). Only diastereoisomers (±)-
30a and (±)-30b were isolated from the reaction of (±)-27a/b, in 17% and 25% yields, respectively,
alongside recovered starting material (23%). The ratio of (±)-27b to (±)-27a in the recovered starting
material increased from 2:1 to 6:1, suggesting a higher reactivity of isomer (±)-27a. Increased reaction times
led to lower yields, presumably due to the reduction of the ester moiety. Reduction of (±)-29a/b took place
to give only diastereoisomers (±)-31a and (±)-31b in 29% and 20% yields, respectively, alongside recovered
starting material (15%). Similarly to the reduction of (±)-27a/b, the ratio of (±)-29b to (±)-29a in the
recovered starting material increased from 0.9:1 to 6:1, suggesting a higher reactivity of isomer (±)-29a.
Reduction of the thiophenyl isomers (±)-29a/b provided a higher isolated yield of (±)-31a, the desired
product isomer, than was observed for (±)-30a in the reduction of the thiomethyl isomers (±)-27a/b.
Me
SR
Me
SR
Me
SR
Me
SR
O
O
HO
MeO2C
HO
MeO2C
(i)
MeO2C
MeO2C
O
O
O
O
N
N
N
N
PMB
PMB
PMB
PMB
(±)-27a, R=Me
(±)-29a, R=Ph
(±)-27b, R=Me
(±)-29b, R=Ph
(±)-30a, R=Me, 17%
(±)-31a, R=Ph, 29%
(±)-30b, R=Me, 25%
(±)-31b, R=Ph, 20%
Reagents and conditions: i) NaBH4, EtOH, −10 °C, 30 min.
Scheme 12. Carbonyl group reduction
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The Journal of Organic Chemistry
The relative configurations of compounds (±)-30a/b and (±)-31a/b were determined using NOESY
1
2
3
spectroscopy (Figure 6).
4
5
6
7
8
H
Me
H
Me
SPh
H
Me
SMe
H
Me
SPh
HO
MeO2C
HO
MeO2C
HO
MeO2C
HO
MeO2C
SMe
O
O
O
O
N
N
N
N
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
PMB
PMB
PMB
PMB
(±)-30a
(±)-30b
(±)-31a
(±)-31b
Figure 6: NOESY analysis of (±)-30a, (±)-30b, (±)-31a and (±)-31b
Treatment of (±)-30a with Raney nickel (Raney 2800) in ethanol at 0 °C did not induce desulfurization.8r
When the reaction mixture was heated, a 3:1 mixture of diastereoisomeric products (±)-21a/b was obtained
in just 7% yield. Similar treatment of (±)-31a led at best to a 3:1 mixture of (±)-21a/b in 42% yield (Scheme
13).
Me
SR
Me
Me
HO
MeO2C
HO
MeO2C
HO
MeO2C
(i), (ii), or (iii)
O
O
O
N
N
N
PMB
PMB
PMB
(±)-30a, R=Me
(±)-31a, R=Ph
(±)-21a
(±)-21b
Reagents and conditions: i) Starting from (±)-30a, Raney nickel, ethanol, reflux, 4 h, (±)-21a:(±)-21b 3:1, 7%; starting from (±)-
31a, Raney nickel, ethanol, reflux, 4 h, (±)-21a:(±)-21b 3:1, 42%; (ii) Starting from (±)-31a, tributyltin hydride, AIBN, acetone,
reflux, 16 h, (±)-21a:(±)-21b 1:2, 93%; (iii) Starting from (±)-31a, tris(trimethylsilyl)silane, AIBN, acetone, reflux, 16 h, (±)-
21a:(±)-21b 1:5, 88%.
Scheme 13. Desulfurization reactions
Inversion of the preferred stereochemical outcome in related desulfurization processes in an α-
thiophenylamide was previously observed under Raney nickel-mediated and AIBN/tributyltin hydride-
mediated reaction conditions.18 We were pleased to observe that desulfurization with tributyltin hydride
proceeded in 93% yield to give a 2:1 ratio in favour of the desired diastereoisomer (±)-21b. To our delight,
replacing the radical propagator with the bulkier tris(trimethylsilyl)silane further improved this selectivity to
5:1 in 88% yield, allowing the isomers to be separated by column chromatography.
Removal of the PMB protecting group of (±)-21b led to the formation of (±)-32 in 82% yield, the structure
of which was confirmed by NOESY spectroscopy and single crystal X-ray analysis (Figure 7).
Saponification of the methyl ester afforded (±)-7 in good yield (Scheme 14). Compound (±)-7 was
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previously lactonized to produce (±)-9-deoxyomuralide in one step with BOP.Cl by Mereddy.12 The formal
synthesis of (±)-9-deoxyomuralide was thus complete at this point.
1
2
3
4
5
6
7
8
Me
Me
Me
Me
HO
MeO2C
HO
MeO2C
HO
HO2C
O
(i)
(ii)
O
O
O
O
O
N
N
N
N
9
H
H
PMB
PMB
(±)-9-deoxyomuralide
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(±)-21b
(±)-32
(±)-7
Reagents and conditions: i) CAN, MeCN/H2O (3:1), r.t., 82% (ii) NaOH (0.5M), 0-5 °C, 62%
Scheme 14. Generation of (±)-7 and formal total synthesis of (±)-9-deoxyomuralide
H
H
Me
O
HO
MeO2C
N
H
(±)-32
Figure 7: NOESY spectroscopy and single crystal X-ray structure of (±)-32 (hydrogen atoms have been
omitted for clarity)
With our methodology in place for the synthesis of (±)-7, we turned our attention to the corresponding
enantioselective route. To obtain amine 10 as a chiral non-racemic mixture, a milder one-pot reductive
amination procedure was attempted: p-methoxybenzaldehyde and L-leucine methyl ester hydrochloride were
stirred in methanol in the presence of triethylamine and sodium borohydride, affording amine (−)-10 in 71%
yield. Peptide coupling proceeded as described above to form (−)-8. Analysis of both products using HPLC
on chiral stationary phase confirmed that no racemization had occurred at this point. Compound (−)-8 was
subjected to the Dieckmann cyclization/alkylation reaction. Methylation in THF at 0 °C led to
pyroglutamate diastereoisomers (+)-9a and (−)-9b in an improved 1:2 ratio. Upon separation and HPLC
analysis, we found that both (+)-9a and (−)-9b had undergone partial epimerization; racemization has
previously been observed during Dieckmann cyclization reactions.19 Isomer (+)-9a was isolated in just 10%
ee. The desired major isomer (−)-9b, however, was isolated in 79% ee (and up to 86% ee on a small scale).
Isomer (−)-9b was then used to complete the synthesis as described above. The fully diastereoselective
acylation using Mander’s reagent led to the formation of (−)-6 in 70% yield and 79% ee. Decarboxylation of
(−)-6 followed by thiophenylation and reduction of the ketone moiety afforded (−)-31a and (−)-31b in 30%
and 35% yield over the three steps, respectively. Desulfurization of (−)-31a using the conditions described
above led to the formation of (−)-21b and (+)-21a in a 5:1 ratio (21b: 83% yield). Successive protecting
group removal on substrate (−)-21b gave compound (−)-7 in 53% yield over two steps, completing the first
synthesis of 7 in non-racemic form. The complete sequence is shown for clarity in Scheme 15.
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
CO2Bn
Me
Me
CO2Bn
O
O
CO2Me
CO2Me
(i)
(ii)
O
O
N
PMB
+
N
N
CO2Bn
NH2,HCl
PMB
PMB
O
(−)-10
(±)-9a
(−)-9b
10
11
12
13
14
15
16
17
18
19
20
21
22
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53
54
55
56
57
58
59
60
Me
CO2Bn
Me
O
O
Me
Me
SPh
HO
MeO2C
HO
MeO2C
CO2Bn
SPh
(iv)
(iii)
MeO2C
O
O
O
O
N
N
N
N
PMB
PMB
PMB
(−)-31a
PMB
(−)-31b
(−)-9b
(−)-6
Me
Me
Me
HO
MeO2C
HO
MeO2C
HO
MeO2C
SPh
(v)
O
O
O
N
PMB
N
N
PMB
PMB
(−)-31a
(+)-21a
(−)-21b
Me
HO
Me
O
HO
MeO2C
(vi)
HO2C
O
N
H
N
PMB
(−)-21b
(−)-7
Reagents and conditions: (i) 1) p-Methoxybenzaldehyde, Et3N, MeOH, NaBH4, 0 ° C to r.t., 71%; 2) 12, NMM, EDAC·HCl,
DMAP, CH2Cl2, r.t., 16 h, 93%; (ii) TBAF in THF, THF, r.t., 0.5 h, then MeI, 0 °C to r.t., 16 h, 9a/b 57%; (iii) LiHMDS, DMPU,
THF, −78 °C, 0.5 h, then NCCO2Me, −78 °C, 4 h, 70%; (iv) 1) H2, Pd(OH)2/C, THF, 30 °C, 12 h, quant.; 2) 28, Et3N, CH2Cl2, r.t.,
mixture of 29a-b, 67%; 3) NaBH4, EtOH, −10 °C, 0.5 h, 30% of (−)-31a and 35% of (−)-31b; (v) Acetone, reflux, AIBN, 16 h,
tris(trimethylsilyl)silane, 83% of 21b; (vi) 1) CAN, MeCN/H2O (3:1), r.t., 62%; 2) NaOH (0.5M), 0-5 °C, 86%.
Scheme 15. Synthesis of (–)-7 and formal total synthesis of (+)-9-deoxyomuralide
Experimental Detail
General experimental detail
Infrared spectra were acquired using a Perkin-Elmer Spectrum 100 FT-IR spectrophotometer. Solid samples
were run as thin films of their solution in CH2Cl2 on sodium chloride plates. Liquid samples were run neat.
1H and 13C NMR spectra were measured respectively at 500 and 126 MHz using a Bruker Ascend 500, or at
400 and 100 MHz using a Bruker Ultrashield 400 Plus instrument. The solvent used for NMR spectroscopy
was deuteriated chloroform unless stated otherwise, using tetramethylsilane as the internal reference.
Chemical shifts are given in parts per million (ppm) and J values are given in Hertz (Hz). Mass spectra were
recorded by the EPSRC Mass Spectrometry Service at the University of Swansea; ionization technique is
stated alongside the data. HPLC was carried out on a VWR Elite Lachrom instrument. Separation was
achieved by an AD-H Chiralpak column (4.6mm x 250mm 5μm) under the stated conditions. Melting points
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were recorded using a Büchi B-545 melting point instrument and are reported uncorrected. Optical rotation
values were measured with a Bellingham and Stanley ADP-440 instrument, operating at λ=589 nm,
corresponding to the sodium D line, at the temperatures indicated. Spectrophotometric grade chloroform
was used for these measurements unless otherwise stated; solutions for these measurements were prepared
in volumetric flasks for maximum accuracy of the volume of solvent used. Reactions requiring anhydrous
conditions were carried out under a nitrogen atmosphere unless otherwise stated, using flame dried
glassware. Reaction solvents were obtained commercially anhydrous, except for the following. Light
petroleum (b.p. 40-60 ºC) was distilled prior to use. Dichloromethane was distilled over calcium hydride.
Tetrahydrofuran and diethyl ether were distilled under an argon atmosphere from the sodium/benzophenone
ketyl radical. All chromatographic manipulations used silica gel as the adsorbent. Reactions were monitored
using thin layer chromatography (TLC) on aluminium-or glass-backed plates with Merck Kieselgel 60 F254
silica gel. TLC plates were visualized by UV radiation at a wavelength of 254 nm, or stained by exposure to
an ethanolic solution of phosphomolybdic acid or aqueous potassium permanganate, followed by charring
where appropriate. Purification by column chromatography used Material Harvest silica gel 60.
1
2
3
4
5
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7
8
9
10
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60
(±)-2-(N-(4-Methoxybenzylimino))-4-methylpentanoic acid methyl ester 20
L-Leucine methyl ester hydrochloride (5.0 g, 28 mmol), acetic acid (1.0 mL, 17 mmol, 0.6 equiv) and p-
anisaldehyde (3.4 mL, 28 mmol, 1 equiv) were heated under reflux in toluene (250 mL) using a Dean-Stark
apparatus for 24 h. The solvent was removed under reduced pressure and the corresponding racemized imine
was collected as a mustard coloured oil (7.3 g, quant.), which was used for the next experiment without
further purification. νmax (thin film)/cm−1 2956 and 1739. 1H NMR (CDCl3, 400 MHz) δH: 8.20 (s, 1H), 7.73
(d, 2H, J = 8.8 Hz), 6.92 (d, 2H, J = 8.8 Hz), 4.05 (dd, 1H, J = 8.7, 5.7 Hz), 3.84 (s, 3H), 3.73 (s, 3H), 1.77-
1.86 (m, 2H), 1.52-1.63 (m, 1H), 0.94 (d, 3H, J = 6.6 Hz), 0.89 (d, 3H, J = 6.6 Hz); 13C NMR (CDCl3, 100
MHz) δC: 173.3, 162.6, 162.2, 130.4, 128.8, 114.1, 71.7, 55.6, 52.3, 42.3, 24.6, 23.3, 21.6.
(±)-2-(4-Methoxybenzylamino)-4-methylpentanoic acid methyl ester (±)-10 20
(±)-2-(N-(4-Methoxybenzylimino))-4-methylpentanoic acid methyl ester (8.26 g, 31 mmol) was dissolved
in methanol (150 mL), followed by addition of acetic acid (2.0 mL, 35 mmol, 1.2 equiv). The mixture was
cooled to 0 °C, sodium cyanoborohydride (3.9 g, 62 mmol, 2 equiv) added in portion, and the mixture
stirred for 30 min at 0 °C, then allowed to reach room temperature while stirring for 20 h under an
atmosphere of nitrogen. The reaction was quenched with a few drops of water and the solvents removed
under reduced pressure to give a colourless residue that was suspended in water (25 mL) and washed with
dichloromethane (2 x 25 mL). The combined organic layers were washed with water (2 x 30 mL), brine (2 x
30 mL), and sodium carbonate (2 x 30 mL), and dried over magnesium sulfate. The solvent was removed
under reduced pressure, and the residue purified by column chromatography on silica gel using 10% ethyl
acetate in petroleum ether (40-60 °C) as eluent to give the product 10 as a pale yellow oil (8.2 g, 97%).
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1
2
3
(±)-2-(4-Methoxybenzylamino)-4-methylpentanoic acid methyl ester (±)-10
One step procedure: Leucine methyl ester hydrochloride (9.96 g, 55 mmol) and p-methoxybenzaldehyde
(7.4 ml, 61 mmol) were dissolved in toluene (100 mL). Acetic acid (2 mL, 35 mmol) was added, and the
solution vigorously refluxed with a well-insulated Dean-Stark apparatus overnight. The resulting solution
was evaporated to dryness to produce a thick red/brown oil, which was dissolved in methanol (130 mL).
Acetic acid was added (2.8 mL, 50 mmol, 0.9 equiv.) and the reaction mixture cooled to 0 °C. Sodium
cyanoborohydride (6.9 g, 110 mmol, 2 equiv.) was added in small portions and the reaction stirred for 30
min. The solution was allowed to reach room temperature and stirred for a further 5 h. A few drops of water
were added, and the solution was evaporated to dryness. The resulting oil was dissolved in dichloromethane
(150 mL) and washed twice each with equal amounts of water, brine and aqueous sodium carbonate. The
organic layer was then dried over magnesium sulfate, filtered, and evaporated to dryness to produce
compound ±10 as a red/brown oil (14g, 96%), which was used without further purification.
4
5
6
7
8
9
10
11
12
13
14
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17
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19
20
21
22
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60
(−)-2-(4-Methoxy-benzylamino)-4-methyl-pentanoic acid methyl ester (−)-10 20
Leucine methyl ester hydrochloride (0.19 g, 1.05 mmol) was dissolved in methanol (10 mL). Et3N (0.15 mL,
1.0 mmol), and p-methoxybenzaldehyde (0.15 mL, 1.2 mmol) added. The solution was stirred for 90 min,
cooled to 0 °C, and sodium borohydride (0.82 g, 2.0 mmol) added over 30 min. The mixture was stirred for
a further 30 min. The solvents were removed under reduced pressure and the resulting oil was dissolved in
ethyl acetate (50 mL). The organic solution was washed twice each with equal amounts of water, brine, and
aqueous sodium carbonate. The aqueous layer was washed with ethyl acetate, and the organic fractions were
combined, dried over magnesium sulfate, filtered and the solvents removed under reduced pressure. The
residue was purified by column chromatography on silica gel using petroluem ether-ethyl acetate (2:1) as
eluent to afforded (−)-10 as a colourless oil (0.212g, 76%). νmax (neat)/cm-1: 2953, 2869, 2836, 1733, 1612,
1511, 1244, 1170, 1149, 824; [α]D25 = −40.3 (c 1.3, CHCl3); 1H NMR (CDCl3, 400 MHz) δH: 0.82 (d, 3H, J=
6.6 Hz), 0.90 (d, 3H, J= 6.6 Hz), 1.46 (t, 2H, J= 7.2 Hz), 1.71-1.79 (m, 2H), 3.29 (t, 1H, J= 7.3 Hz), 3.54 (d,
1H, J= 12.6 Hz), 3.68 (d, 1H, J= 12.6 Hz), 3.71 (s, 3H), 3.78 (s, 3H), 6.84 (d, 2H, J= 8.6 Hz), 7.23 (d, 2H,
J= 8.3 Hz); 13C NMR (CDCl3, 100 MHz) δC: 176.7, 158.8, 132.2, 129.6, 113.9, 59.2, 55.4, 51.8, 51.7, 43.0,
25.0, 23.0, 22.3. HRMS (ESI-FTMS) m/z: [M+H]+ Calcd for [C15H24NO3]+ 266.1751; Found 266.1745.
(±)-2-{N-(4-Methoxybenzyl)-[2-(4-nitrobenzyloxycarbonyl)-acetyl]-amino}-4-methyl-pentanoic
methyl ester (±)-13
acid
Amine (±)-10 (4.36 g, 16 mmol), N-methylmorpholine (2 mL, 18 mmol), p-nitrobenzyl malonic half ester
11 (4.31 g, 18 mmol), EDAC.HCl (4.60 g, 24 mmol) and 4-dimethylaminopyridine (0.39 g, 3 mmol) were
stirred in dichloromethane (100 mL) for 20 h under a nitrogen atmosphere. Aqueous HCl (1M, 5 mL) was
added, and the reaction mixture stirred for a further 30 min. The reaction mixture was washed with water (2
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x 50 mL), and the organic layer dried over magnesium sulfate. The solvent was removed under reduced
pressure, and the residue purified by column chromatography on silica gel using 30% ethyl acetate in
petroleum ether (40-60 ºC) as eluent to give the product 12 as a dark brown oil (5.65 g, 75%). νmax (neat)/cm-
1
2
3
4
5
6
1
1: 2957, 1747, 1651, 1611, 1515, 1435, 1348, 1252, 1176, 1033; Major conformation: H NMR (500 MHz,
7
8
9
CDCl3) δ 8.22 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz,
2H), 5.33 – 5.24 (m, 2H), 4.89 (t, J = 6.9 Hz, 1H), 4.59 (d, J = 17.2 Hz, 1H), 4.45 (d, J = 17.3 Hz, 1H), 3.80
(s, 3H), 3.62 (s, 3H), 3.51 (d, J = 5.6 Hz, 2H), 1.90 – 1.80 (m, 1H), 1.65 – 1.52 (m, 2H), 0.89 (d, J = 6.4 Hz,
3H), 0.81 (d, J = 6.4 Hz, 3H).13C NMR (126 MHz, CDCl3) δ 171.8, 167.3, 167.1, 159.4, 147.9, 142.9, 129.6,
128.5, 127.9, 123.9, 114.4, 65.6, 56.4, 55.5, 52.3, 50.1, 41.7, 38.5, 25.3, 22.7, 22.4; HRMS (ESI-FTMS)
m/z: [M+H]+ Calcd for [C25H31N2O8]+ 487.2075; Found 487.2066.
10
11
12
13
14
15
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17
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20
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60
trans and cis (±)-5-Isobutyl-1-(4-methoxybenzyl)-3-methyl-2,4-dioxopyrrolidine-3-carboxylic acid 4-
nitrobenzyl ester (±)-14a and (±)-14b
tert-Butylammonium fluoride (1 M solution in THF, 19.0 mL, 19 mmol) was added to a solution of the
ester-amide (±)-13 (3.65 g, 7.5 mmol) in diethyl ether (80 mL) at room temperature under a nitrogen
atmosphere, and the reaction mixture stirred overnight. The solvents were removed under reduced pressure,
and the residue was suspended in THF (80 mL) and cooled to 0 °C. Methyl iodide (1.44 mL, 23 mmol) was
added, and the mixture stirred at room temperature overnight under a nitrogen atmosphere. The solvent was
removed under reduced pressure and the residue dissolved in dichloromethane (50 mL) and washed with
water (50 mL). The organic layer was dried over magnesium sulfate, and the solvents removed under
removed pressure. The residue was purified by column chromatography on silica gel using 20% acetone in
petroleum ether (40-60 °C) as eluent to afford (±)-14a as colourless crystals (1.3 g, 2.8 mmol, 37%) and (±)-
14b as a pale yellow oil (0.9 g, 1.9 mmol, 25 %).
First eluting diastereoisomer (±)-14a: νmax (solid)/cm-1: 2959, 1780, 1749, 1696, 1610, 1348, 1248, 1123;
1H NMR (CDCl3, 400 MHz) δH: 0.82 (3H, d, J= 8.0 Hz), 0.92 (3H, d, J= 8.0 Hz), 1.60 (3H, s), 1.64-1.86
(3H, m), 3.74 (3H, s), 3.85 (1H, d J= 16.0 Hz), 3.90 (1H, dd, J= 8.0, 7.92 Hz), 5.19 (1H, d J= 14.0 Hz), 5.26
(1H, d J= 14.0 Hz), 5.40 (1H, d J= 16.0 Hz), 6.69 (2H, d, J=8.0 Hz), 7.11 (2H, d, J= 8.0 Hz), 7.33 (2H, d,
J= 8.0 Hz), 8.19 (2H, d, J= 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δC: 16.4, 22.6, 23.5, 24.8, 38.2, 43.5, 55.4,
58.8, 62.8, 66.5, 114.3, 124.1, 126.5, 128.3, 129.8, 142.1, 148.0, 159.6, 165.6, 169.4, 205.9; HRMS (ESI-
FTMS) m/z: [M+H]+ Calcd for [C25H29N2O7]+ 469.1969; Found 469.1966.
Second eluting diastereoisomer(±)-14b: νmax (neat)/cm-1: 2959, 1778, 1748, 1694, 1610, 1515, 1454,
1416, 1347, 1248, 1177, 1124, 1034; 1H NMR (CDCl3, 400 MHz) δH: 0.76-0.82 (6H, m), 1.56 (3H, s), 1.51-
1.60 (2H, m), 1.77-1.85 (1H, m), 3.72-3.77 (1H, dd, J= 8.0, 4.0 Hz), 3.80 (3H, s), 4.0 (1H, d J= 16.0 Hz),
5.20-5.30 (2H, m), 5.32 (1H, d J= 16.0 Hz), 6.86 (2H, d, J= 8.0 Hz), 7.16 (2H, d, J= 8.0 Hz), 7.45 (2H, d, J=
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8.0 Hz), 8.22 (2H, d, J= 8.0 Hz); C NMR (CDCl3, 100 MHz) δC: 17.0, 22.1, 23.4, 24.6, 39.0, 43.7, 55.5,
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58.7, 62.4, 66.5, 114.6, 124.1, 127.0, 128.5, 129.7, 142.2, 148.0, 159.7, 165.7, 169.3, 205.6; HRMS (ESI-
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FTMS) m/z: [M+H]+ Calcd for [C25H29N2O7]+ 469.1969; Found 469.1965.
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(±)-(3R,3aS,4S,6aS)-3a-Hydroxy-4-isobutyl-5-(4-methoxybenzyl)-6a-methyl-3-(4-nitro
phenyl)-
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tetrahydro-1H-furo[3,4-c]pyrrole-1,6(6aH)-dione (±)-15 and (±)- (3R,3aS,4S, 6aS)-4-isobutyl-5-(4-
methoxybenzyl)-6a-methyl-3-(4-nitrophenyl)-1,6-dioxohexahydro-1H-furo[3,4-c]pyrrol-3a-yl methyl
carbonate (±)-16
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Hexamethyldisilazane (0.27 mL, 1.3 mmol) was dissolved in anhydrous THF (20 mL) and the solution
cooled to –78 °C. n-Butyllithium (2.5 M in THF, 0.51 mL, 1.3 mmol) was added. The solution was a stirred
for 30 min and DMPU (0.08 mL, 0.6 mmol) added. Lactam (±)-14a (0.20 g, 0.4 mmol) was dissolved in
anhydrous THF (5 mL), the resulting solution cooled to –78 °C, and DMPU (0.08 mL, 0.6 mmol) added.
The solution of LHMDS was added dropwise using a cannula to the solution of the lactam. The mixture was
stirred at –78 °C for 30 min. Methyl cyanoformate (0.17 mL, 2.13 mmol) was added and the reaction stirred
for a further 4 h at –78 °C. A saturated aqueous solution of ammonium chloride was added at –78 °C. The
mixture was allowed to reach room temperature and the solvents were removed under reduced pressure. The
residue was dissolved in ethyl acetate and the solution washed with water (50 mL) and brine (50 mL). The
organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced
pressure. The residue was purified using column chromatography on silica gel using petroleum ether (40-60
°C)/ethyl acetate (4:1) as eluent to yield (±)-15 as an off-white solid (0.08 g, 36%) together with the methyl
carbonate (±)-16 (0.06g, 28%).
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Compound (±)-15: νmax (neat)/cm-1 (thin film) 3390, 2958, 1791, 1679; H NMR (CDCl3, 400 MHz) δH:
8.21 (d, 2H, J= 8.8 Hz), 7.28 (d, 2H, J= 8.8 Hz), 7.18 (d, 2H, J= 8.8 Hz), 6.97 (d, 2H, J= 8.8 Hz), 5.29 (d,
1H, J= 14.4 Hz), 4.82 (s, 1H), 3.84 (s, 3H), 3.77 (d, 1H, J= 14.4 Hz), 3.34 (dd, 1H, J= 8.6, 3.0 Hz), 1.68-
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1.74 (m, 1H), 1.58 (s, 3H), 1.37-1.47 (m, 2H), 0.84 (d, 6H, J= 6.0 Hz); C NMR (CDCl3, 100 MHz) δC:
167.4, 160.1, 148.9, 139.7, 130.4, 127.8, 127.6, 124.3, 114.8, 84.6, 83.0, 58.3, 57.3, 55.5, 44.6, 37.3, 27.3,
26.3, 23.1, 22.0, 15.2; HRMS (NSI-FTMS) m/z: [M+NH4]+ Calcd for [C25H32 N3O7]+ 486.2224; Found
486.2235.
Compound (±)-16: 1H NMR (CDCl3, 400 MHz) δH: 8.18 (d, 2H, J= 8.8 Hz), 7.28 (d, 2H, J= 8.8 Hz), 7.26
(d, 2H, J= 8.8 Hz), 6.93 (d, 2H, J= 8.8 Hz), 5.29 (d, 1H, J= 14.8 Hz), 4.96 (s, 1H), 3.85 (d, 1H, J= 14.8 Hz),
3.80 (s, 3H), 3.66-3.72 (m, 1 H), 3.47 (s, 3H), 1.70-1.82 (m, 2H), 1.62 (s, 3H), 1.46-1.50 (m, 1H), 0.97 (d,
3H, J= 6.4 Hz), 0.96 (d, 3H, J= 6.4 Hz); 13C NMR (CDCl3, 100 MHz) δC: 171.5, 167.1, 160.1, 153.5, 148.3,
139.9, 130.2, 127.13, 127.09, 123.6, 114.8, 88.8, 83.7, 59.8, 56.4, 55.7, 55.4, 44.6, 38.5, 25.9, 23.1, 22.0,
15.9; HRMS (NSI-FTMS) m/z: [M+NH4]+ Calcd for [C27H34N3O9]+ 544.2290; Found 544.2282.
(±)-2-{(4-Methoxybenzyl)-[2-(benzyloxycarbonyl)-acetyl]-amino}-4-methylpentanoic acid methyl ester
(±)-8
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Compound (±)-10 (11.0 g, 41.5 mmol), N-methylmorpholine (5 mL, 45.7 mmol), benzyl malonic half ester
(10.6 g, 45.7 mmol), EDAC.HCl (11.9 g, 62.3 mmol) and 4-dimethylaminopyridine (1.0 g, 8.3 mmol) were
dissolved in dichloromethane (500 mL), and the mixture stirred for 20 h under a nitrogen atmosphere.
Aqueous HCl (1M, 20 mL) was added and the reaction mixture stirred for further 30 minutes, washed with
water (2 x 50 mL) and the organic layer dried over magnesium sulfate. The solvent was removed under
reduced pressure, and the residue purified by column chromatography on silica gel using 30% ethyl acetate
in petroleum ether (40-60 ºC) as eluent to give the product as a yellow oil (14.5 g, 79%).
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)-8
Compound (–)-10 (1.38 g, 5.19 mmol), N-methylmorpholine (1.3 mL, 11.82 mmol), benzyl malonic half
ester (2.54 g, 10.95 mmol), EDAC.HCl (2.63 g, 13.75 mmol) and 4-dimethylaminopyridine (0.16 g, 1.3
mmol) were dissolved in dichloromethane (40 mL), and the mixture stirred for 20 h under a nitrogen
atmosphere. Aqueous HCl (1M, 1.5 mL) was added, and the reaction mixture stirred for a further 30 min,
washed with water (2 x 50 mL), and the organic layer dried over magnesium sulfate. The solvent was
removed under reduced pressure, and the residue purified by column chromatography on silica gel using
30% ethyl acetate in petroleum ether (40-60 ºC) as eluent to give the product as a yellow oil (2.128 g, 93%).
[α]D = –46.42 (c 1.12, CHCl3) νmax (neat)/cm-1: 2956, 2870, 2838, 1740, 1655, 1613, 1515, 1456, 1249,
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1176, 1033, 824, 699; δH H NMR (500 MHz, CDCl3) Major conformation: δ 7.41 – 7.30 (m, 5H), 7.15 (d, J
= 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.23 – 5.15 (m, 2H), 4.82 (t, J = 6.9 Hz, 1H), 4.55 (d, J = 17.1 Hz,
1H), 4.42 (d, J = 17.2 Hz, 1H), 3.79 (s, 3H), 3.58 (s, 3H), 3.50 – 3.46 (m, 2H), 1.90 – 1.79 (m, 1H), 1.61 –
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1.50 (m, 2H), 0.88 (d, J = 6.4 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H). C NMR (126 MHz, CDCl3) δ 171.8,
167.3, 159.3, 135.5, 128.7, 128.5, 128.1, 114.3, 67.3, 56.2, 55.5, 52.2, 50.1, 41.8, 38.4, 25.2, 22.7, 22.4;
HRMS (ESI-FTMS) m/z: [M–H]+ Calcd for [C25H31NO6]+ 442.2224; Found 442.2226.
(±)-(3S,5S)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-pyrrolidin-2,4-dione-3-carboxylic
acid benzyl ester (±)-9a and (±)-(3R,5S)-N-(4’-methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-
pyrrolidin-2,4-dione-3-carboxylic acid benzyl ester (±)-9b
Two-step synthesis: Diester (±)-8 (8.86 g, 0.02 mol) was dissolved in diethyl ether (50 mL) under a
nitrogen atmosphere. Tetrabutylammonium fluoride (1 M solution in THF, 50 mL, 0.05 mol) was added and
the reaction mixture was stirred overnight. The solvents were removed under reduced pressure and the
residue dissolved in THF (50 mL) under an atmosphere of nitrogen. The solution was cooled to 0 °C,
iodomethane (5.00 mL, 0.08 mol) added, and the mixture stirred overnight. The solvents were removed
under reduced pressure and the residue dissolved in dichloromethane (50 mL). The solution was washed
with water (2 x 50 mL), dried over anhydrous magnesium sulfate, filtered, and solvents removed under
reduced pressure. The residue was purified by column chromatography on silica gel using 20% ethyl acetate
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in light petroleum ether as eluent. The first eluting diastereoisomer (±)-9a was obtained as a pale yellow oil
(2.59 g, 30%), and the second eluting diastereoisomer (±)-9b as a darker yellow oil (2.47 g, 29%).
One-pot synthesis: Diester (±)-8 (4.915 g, 11.14 mmol) was dissolved in THF (250 mL).
Tetrabutylammonium fluoride (1M in THF, 39 mL, 39 mmol) was added, and the solution stirred at room
temperature for 0.5 h under static pressure of nitrogen. Iodomethane (2.9 mL, 46.58 mmol) was added, and
the solution stirred overnight. Water (5 mL) was added, and the solvent removed under reduced pressure.
The residue was dissolved in dichloromethane, and the mixture washed with water (2 x 50 mL) and brine (2
x 50 mL), dried over magnesium sulphate, filtered, and the solvent removed under reduced pressure. The
residue was purified using column chromatography on silica gel using 20% ethyl acetate in petroleum ether
(40-60 °C) as eluent to obtain the diastereoisomers (±)-9a and (±)-9b in a 1:1 ratio (2.69 g, 57%).
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(+)-(3S,5S)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-pyrrolidin-2,4-dione-3-carboxylic
acid benzyl ester (+)-9a and (–)-(3R,5S)-N-(4’-methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-
pyrrolidin-2,4-dione-3-carboxylic acid benzyl ester (–)-9b
Tetrabutylammonium fluoride (1 M solution in THF, 11.5 mL, 11.5 mmol,) was added to a solution of the
diester (–)-8 (1.442 g, 3.2 mmol) in THF (72 mL) at room temperature under a nitrogen atmosphere. The
mixture was stirred for 30 min and cooled to 0 °C using an ice bath. Iodomethane (0.81 mL, 13 mmol) was
added, and the reaction mixture stirred overnight. Water (4 mL) was added, and the solvent was removed
under reduced pressure and the residue dissolved in dichloromethane (50 mL) and washed with water (50
mL). The organic layer was dried over magnesium sulfate and the solvent removed under reduced pressure.
The residue was purified and partially separated by silica gel column chromatography using 10% ethyl
acetate in petroleum ether (40-60°C) as eluent to afford the diastereoisomers in a 1:2 ratio (0.78 g, 57%).
For (+)-(3S,5S)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-pyrrolidin-2,4-dione-3-carboxylic
acid benzyl ester (+)-9a: [α]D26 = +14.54 (c 0.44, CHCl3); νmax (thin film)/cm−1 2958, 1778, 1747, 1697; 1H
NMR (500 MHz, CDCl3) δ 7.35 (dd, 3H, J = 5.0, 1.9 Hz), 7.24 – 7.21 (m, 2H, Ar), 7.02 (d, 2H, J = 8.6 Hz),
6.59 (d, 2H, J = 8.6 Hz), 5.42 (d, 1H, J = 15.0 Hz), 5.19 (d, 1H, J = 12.3 Hz), 5.09 (d, 1H, J = 12.3 Hz), 3.85
(dd, 1H, J = 7.8, 3.9 Hz), 3.80 (d, 1H, J = 15.0 Hz), 3.73 (s, 3H), 1.82 – 1.73 (m, 1H), 1.67 – 1.61 (m, 1H),
13
1.58 (s, 3H), 1.56 – 1.48 (m, 1H), 0.87 (d, 3H, J = 6.6 Hz), 0.76 (d, 3H, J = 6.5 Hz); C NMR (126 MHz,
CDCl3) δC: 205.9, 169.6, 165.6, 159.2, 134.8, 129.4, 128.7, 128.5, 128.2, 126.2, 114.1, 68.1, 62.4, 58.6,
55.2, 43.2, 37.9, 24.6, 23.2, 22.4, 16.1; HRMS (NSI-FTMS) m/z: [M+H]+ Calcd for [C25H30NO5]+ 424.2124;
Found 424.2110. Determined by HPLC to be 13% ee.
For (–)-(3R,5S)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-pyrrolidin-2,4-dione-3-carboxylic
acid benzyl ester (−)-9b: [α]D26 = −17.14 (c 0.98, CHCl3); νmax (thin film)/cm−1 2927, 1775, 1746, 1696; 1H
NMR (500 MHz, CDCl3) δ 7.38 – 7.26 (m, 5H), 7.13 (d, 2H, J = 8.6 Hz), 6.83 (d, 2H, J = 8.6 Hz), 5.26 (d,
1H, J = 12.1 Hz), 5.19 (d, 1H, J = 14.9 Hz), 5.08 (d, 1H, J = 12.1 Hz), 4.01 (d, 1H, J = 14.9 Hz), 3.79 (s,
3H), 3.67 (t, 1H, J = 6.8 Hz, H5), 1.77 – 1.72 (m, 1H), 1.54 (s, 3H), 1.50 (dd, 2H, J = 7.4, 6.5 Hz), 0.73 (d,
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3H, J = 6.5 Hz), 0.70 (d, 3H, J = 6.5 Hz); 13C NMR (126 MHz, CDCl3) δ: 205.6, 169.3, 165.6, 159.4, 134.7,
129.4, 128.7, 128.6, 128.4, 127.1, 114.3, 68.2, 62.4, 58.6, 55.3, 43.5, 38.9, 24.4, 23.0, 21.9, 16.6; HRMS
(NSI-FTMS) m/z: [M+H]+ Calcd for [C25H30NO5]+ 424.2124; Found 424.2108. Determined by HPLC to be
79% ee.
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(±)-(3R,5R)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-pyrrolidin-2,4-dione-3,5-
dicarboxylic acid-3-benzyl ester-5-methyl ester (±)-6
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From the first eluting diastereoisomer (±)-9a. Hexamethyldisilazane (0.24 mL, 1.1 mmol) was dissolved
in anhydrous THF (10 mL) and the solution cooled to –78 °C. n-Butyllithium (2.5 M in THF, 0.46 mL, 1.1
mmol) was added. The mixture was stirred for 30 min and DMPU (0.07 mL, 0.5 mmol) added. Compound
(±)-9a (0.16 g, 0.3 mmol) was dissolved in anhydrous THF (5 mL), the solution was cooled to –78 °C, and
DMPU (0.07 mL, 0.5 mmol) added. The solution of LHMDS was added dropwise using a cannula to the
solution of the lactam. The mixture was stirred at –78 °C for 30 min. Methyl cyanoformate (0.15 mL, 1.9
mmol) was added, and the mixture was stirred for a further 4 h at –78 °C. Saturated aqueous ammonium
chloride was added (0.2 mL), the mixture was allowed to reach room temperature, and the organic solvents
were removed under reduced pressure. The residue was dissolved in ethyl acetate and the solution washed
with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered,
and the solvents were removed under reduced pressure. The residue was purified by column
chromatography on silica gel using light petroleum ether (40-60 °C)/ethyl acetate (2:1) as eluent to yield
(±)-6 as an off-white solid (0.13 g, 73%).
From the second eluting diastereoisomer (±)-9b: Hexamethyldisilazane (0.32 mL, 1.5 mmol) was
dissolved in anhydrous THF (10 mL) and the solution cooled to –78 °C. n-Butyllithium (2.5 M in THF, 0.62
mL, 1.5 mmol) was added. The mixture was stirred for 30 min and DMPU (0.06 mL, 0.75 mmol) added.
Compound (±)-9b (0.22 g, 0.5 mmol) was dissolved in anhydrous THF (5 mL), the solution was cooled to –
78 °C, and DMPU (0.06 mL, 0.75 mmol) added. The solution of LHMDS was added dropwise using a
cannula to the solution of the lactam. The mixture was stirred at –78 °C for 30 min. Methyl cyanoformate
(0.20 mL, 2.6 mmol) was added, and the mixture stirred for a further 4 h at –78 °C. Saturated aqueous
ammonium chloride (0.2 mL) was added, the mixture allowed to reach room temperature, and the solvents
were removed under reduced pressure. The residue was dissolved in ethyl acetate and the solution was
washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate,
filtered, and the organic solvents were removed under reduced pressure. The residue was purified by column
chromatography on silica gel using light petroleum ether (40-60 °C)/ethyl acetate (2:1) as eluent to yield
(±)-6 as an off-white solid (0.19 g, 79%).
From a mixture of diastereoisomers (±)-9a and (±)-9b: A mixture of (±)-9a-b (0.34 g, 0.8 mmol) was
dissolved in anhydrous THF (15 mL) and the solution cooled to –78 °C. DPMU (1.10 mL, 9.2 mmol) was
added followed by LHMDS (1M in THF, 6.1 mL, 6.13 mmol), and the mixture stirred at –78 °C for 30 min.
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Methyl cyanoformate (0.78 mL, 9.2 mmol) was added, and the mixture stirred for a further 4 h at –78 °C.
Saturated aqueous ammonium chloride was added (0.4 mL) at –78 °C, the mixture allowed to reach room
temperature, and the organic solvents were removed under reduced pressure. The residue was dissolved in
ethyl acetate and the solution washed with water (30 mL) and brine (30 mL). The organic layer was dried
over anhydrous sodium sulfate, filtered, and the solvents were removed under reduced pressure. The residue
was purified by column chromatography on silica gel using light petroleum ether/ethyl acetate (2:1) as
eluent to yield (±)-6 as an off-white solid (1.26 g, 86%).
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(–)-(3R,5R)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-pyrrolidin-2,4-dione-3,5-dicarboxylic
acid-3-benzyl ester-5-methyl ester (−)-6
Compound (−)-9b (1.747 g, 4.125 mmol.) was dissolved in anhydrous THF (70 mL) and the solution cooled
to –78 °C. DPMU (1.5 mL, 9.2 mmol) was added followed by LiHMDS (1M in THF, 8.5 mL, 8.5 mmol),
and the mixture stirred at –78 °C for 30 min. Methyl cyanoformate (1.1 mL, 13 mmol) was added, and the
mixture stirred for a further 4 h at –78 °C. Saturated aqueous ammonium chloride was added (2 mL) at –78
°C, the mixture allowed to reach room temperature, and the organic solvents were removed under reduced
pressure. The residue was dissolved in ethyl acetate and the solution washed with water (2 x 100 mL) and
brine (2 x 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents
were removed under reduced pressure. The residue was purified by column chromatography on silica gel
using light petroleum ether (40-60 C)/ethyl acetate (4:1) to yield (−)-6 as an off-white solid (1.985 g, 70%).
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mp 79-82 °C; [α]D = –20.35 (c 1.12, CHCl3); νmax (thin film)/cm-1 2958, 1782, 1751, 1699; H NMR (400
MHz, CDCl3) δ 7.39 – 7.28 (m, 5H), 7.19 (d, 2H, J = 8.7 Hz), 6.77 (d, 2H, J = 8.7 Hz), 5.20 (d, 1H, J = 12.1
Hz), 5.14 (d, 1H, J = 12.1 Hz), 4.89 (d, 1H, J = 15.0 Hz), 4.15 (d, 1H, J = 15.0 Hz), 3.77 (s, 3H), 3.23 (s,
3H), 2.15 (dd, 1H, J = 15.2, 5.4 Hz), 1.86 (dd, 1H, J = 15.2, 6.3 Hz), 1.72 (s, 3H), 1.47 – 1.41 (m, 1H), 0.65
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(d, 3H, J = 6.6 Hz), 0.52 (d, 3H, J = 6.6 Hz); C NMR (126 MHz, CDCl3) δ 201.8, 170.8, 167.6, 165.2,
159.23, 134.5, 130.3, 128.7, 128.61, 128.64, 127.6, 113.8, 76.1, 68.5, 58.4, 55.3, 52.9, 43.9, 38.7, 24.2, 23.4,
23.1, 18.9; HRMS (NSI-FTMS) m/z: [M+Na]+ Calcd for [C27H31NO7Na]+ 504.1993; Found 504.1979.
Determined by HPLC to be 79% ee.
(±)-(3R,4R,5R)-N-(4’-Methoxybenzyl)-3-methyl-4-hydroxy-5-(2’-methylpropyl)-pyrrolidin-2-one-3,5-
dicarboxylic acid-3-benzyl ester-5-methyl ester (±)-17
Compound (±)-6 (0.21 g, 0.44 mmol) was dissolved in EtOH (10 mL). The mixture was cooled to –10 °C,
and sodium borohydride (0.01 g, 0.22 mmol) added. The mixture was stirred at –10 °C for 30 min, and
water added. The solvent was removed under reduced pressure and the residue was dissolved in ethyl
acetate (10 mL). The mixture was washed with water (2 x 30 mL) and brine (2 x 30 mL), the organic layer
dried over anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure. The residue
was purified by column chromatography on silica gel using light petroleum ether (40-60 °C)/ethyl acetate
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(2:1) as eluent to afford (±)-17 was isolated as a colourless foam (0.11 g, 52%). nmax (thin film)/cm-1 3373,
1735, 1676; 1H NMR (500 MHz, CDCl3) δ 7.41-7.33 (m, 5H), 7.11 (d, 2H, J = 8.7 Hz), 6.68 (d, 2H, J = 8.7
Hz), 5.25 (d, 2H, J = 1.5 Hz), 4.94 (d, 1H, J = 16.1 Hz), 4.69 (d, 1H, J = 8.4 Hz), 4.39 (d, 1H, J = 16.1 Hz),
3.75 (s, 3H), 3.70 (s, 3H), 3.14 (d, 1H, J = 8.4 Hz), 1.71-1.67 (m, 2H), 1.67-1.62 (m, 1H), 1.48 (s, 3H), 0.83
1
2
3
4
5
6
7
8
13
(d, 3H, J = 6.2 Hz), 0.70 (d, 3H, J = 6.2 Hz); C NMR (126 MHz, CDCl3) δ 172.8, 172.18, 170.8, 158.5,
9
135.1, 130.3, 128.7, 128.4, 128.3, 127.9, 113.8, 77.5, 72.1, 67.7, 56.2, 55.3, 52.5, 45.1, 40.3, 24.1, 24.1,
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23.4, 19.2; HRMS (NSI-FTMS) m/z: [M+Na]+ Calcd for [C27H33NO7Na]+ 506.2149; Found 506.2134.
(±)-(3R,4R,5R)-N-(4’-Methoxybenzyl)-3-methyl-4-hydroxy-5-(2’-methylpropyl)-pyrrolidin-2-one-3,5-
dicarboxylic acid 5-methyl ester (±)-18
Compound (±)-17 (1.29 g, 2.67 mmol) was dissolved in anhydrous THF (20 mL) and Pd(OH)2/C (0.65 g, 10
mol%) added. The mixture was purged with nitrogen, and treated with hydrogen under balloon pressure
overnight at room temperature. The mixture was filtered through celite, and the solvent removed under
reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-
petroleum ether (40-60°C) (1:2) as eluent to afford (±)-18 as a colourless solid (0.89 g, 86%), mp 108-111
°C; νmax (thin film)/cm-1 3343, 1741, 1673; 1H NMR (500 MHz, CDCl3) δ: 7.14 (d, 2H, J= 8.6 Hz), 6.85 (d, 2
H, J= 8.7 Hz), 4.98 (d, 1H, J= 16.2 Hz), 4.91 (s, 1H), 4.54 (d, 1H, J= 16.2 Hz), 3.79 (s, 3H), 3.77 (s, 3H),
13
1.89-1.84 (m, 1H), 1.70-1.64 (m, 2H), 1.44 (s, 3H), 0.90 (d, 3H, J= 6.4 Hz), 0.75 (d, 3H, J= 6.2 Hz); C
NMR (126 MHz, CDCl3) δ 176.3, 172.3, 172.2, 158.8, 129.0, 127.9, 114.1, 74.4, 72.3, 55.6, 55.3, 52.7,
45.4, 39.4, 24.2, 24.0, 23.3, 20.9; HRMS (NSI-FTMS) m/z: [M–H]+ Calcd for [C20H26NO7]+ 392.1715;
Found 392.1704.
(±)-(3R,4S,5R)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-3-azabicyclo[3.2.0] heptane-2,7-
dione-5-carboxylic acid methyl ester (±)-22
Compound (±)-18 (0.13 g, 0.3 mmol) was dissolved in anhydrous dichloromethane (5 mL) under a nitrogen
atmosphere, and diphenyldiselenide (0.16 g, 0.5 mmol) added. The mixture was cooled to 0 °C and
tributylphosphine (0.16 mL, 0.7 mmol) added. The mixture was allowed to reach room temperature with
stirring overnight, diluted with dichloromethane (2 mL), and washed with water (2 mL). The aqueous layer
was extracted with dichloromethane (2ml), and the combined organic layers were washed with brine (2 mL),
dried over anhydrous magnesium sulphate, and the solvents removed under reduced pressure. The residue
was purified by column chromatography on silica gel using ethyl acetate-petroleum ether (40-60 °C) (1:2) to
yield (±)-22 as an off-white solid (0.05 g, 43%), mp 104-109 °C; νmax (thin film)/cm-1 1842, 1731, 1702. 1H
NMR (500 MHz, CDCl3) δ 7.12 (d, 2H, J = 8.7 Hz), 6.83 (d, 2H, J = 8.7 Hz), 5.15 (s, 1H), 4.51 (d, 2H, J =
1.8 Hz), 3.78 (s, 3H), 3.52 (s, 3H), 2.11 (dd, 1H, J = 13.4, 7.7 Hz), 1.77 – 1.71 (m, 1H), 1.67 (s, 3H), 1.62
(dd, 1H, J = 13.4, 5.5 Hz), 0.93 (d, 3H, J = 6.6 Hz), 0.86 (d, 3H, J = 6.6 Hz); 13C NMR (126 MHz, CDCl3) δ
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169.7, 168.4, 165.8, 159.0, 128.84, 128.82, 114.0, 76.0, 68.6, 64.9, 55.3, 52.7, 43.9, 37.3, 24.6, 23.8, 22.8,
1
2
3
11.7; HRMS (NSI-FTMS) m/z: [M+H]+ Calcd for [C20H26NO6]+ 376.1755; Found 376.1756.
4
5
6
7
8
(±)-(3R,4R,5R)-N-(4’-Methoxybenzyl)-3-methyl-4-trifluoroacetoxy-5-(2’-methylpropyl)-pyrrolidin-2-
one-3,5-dicarboxylic acid 5-methyl ester (±)-23
9
Compound (±)-17 (0.30 g, 0.75 mmol) was dissolved in anhydrous diethyl ether (5 mL), and the solution
cooled to 0 °C. Pyridine (0.15 mL, 1.88 mmol) and trifluoroacetic anhydride (0.26 mL, 1.88 mmol) were
added. On completion of the reaction (TLC), pentane (3 mL) was added and the mixture filtered through
celite to remove the pyridinium trifluoroacetate by-product. The solvent was removed under reduced
pressure, the residue dissolved in dichloromethane (3 mL), and the solution washed with water (2 x 10 mL)
and brine (2 x 10 mL), and dried over anhydrous magnesium sulfate. The solvent was removed under
reduced pressure to yield the product as a yellow oil (0.30 g, 81%), used without further purification. νmax
(thin film)/cm−1 1799, 1742, 1707 and 1676. 1H NMR (500 MHz, CDCl3) δ 7.11 (d, 2H, J = 8.6 Hz), 6.87 (d,
2H, J = 8.7 Hz), 6.35 (s, 1H), 5.08 (d, 1H, J = 16.2 Hz), 4.57 (d, 1H, J = 16.2 Hz), 3.82 (s, 3H), 3.80 (s, 3H),
1.74 (dd, 1H, J = 13.9, 6.6 Hz), 1.56 (s, 3H), 1.54-1.48 (m, 2H), 0.72 (d, 3H, J = 6.5 Hz), 0.68 (d, 3H, J =
6.3 Hz); 13C NMR (126 MHz, CDCl3) δ 175.1, 170.7, 168.6, 159.1, 129.1, 128.4, 127.7, 114.6, 114.2, 77.9,
70.8, 55.3, 53.8, 53.3, 45.5, 40.3, 23.9, 23.3, 23.2, 21.1; HRMS (NSI-FTMS) m/z: [M–COCF3]+ Calcd for
[C20H26NO7]+ 392.1709; Found 392.1701.
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(±)-(3R,4R,5R)-N-(4’-Methoxybenzyl)-3-methyl-4-hydroxy-5-(2’-methylpropyl)-pyrrolidin-2-one-3-
phenylseleno ester-5-carboxylic acid methyl ester (±)-24
Compound (±)-23 (0.36 g, 0.7 mmol) was dissolved in anhydrous dichloromethane (5 mL) under a nitrogen
atmosphere, and diphenyldiselenide (0.35 g, 1.0 mmol) added. The mixture was cooled to 0 °C and
tributylphosphine (0.36 mL, 0.7 mmol) added. The mixture was allowed to reach room temperature and
stirred overnight, and diluted with dichloromethane (3 mL) and water (3 mL). The aqueous layer was
extracted with dichloromethane (3 mL). The combined organic layers were washed with brine (2 mL), dried
over anhydrous magnesium sulphate, and the solvent removed under reduced pressure. The residue was
purified by column chromatography on silica gel using ethyl acetate-petroleum ether (40-60 °C) (1:4) as
eluent to yield the desired compound (±)-24, isolated as a yellow oil (0.12 g, 31%). Compound (±)-22 was
also isolated (0.03 g, 10%).
1
For compound (±)-24: νmax (thin film)/cm-1 3423, 1736, 1690; H NMR (500 MHz, CDCl3) δ 7.55 – 7.51
(m, 2H), 7.44 – 7.37 (m, 3H), 7.22 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H, J = 8.7 Hz), 4.98 (d, 1H, J = 16.1 Hz),
4.84 (d, 1H, J = 5.2 Hz), 4.49 (d, 1H, J = 16.1 Hz), 3.79 (s, 3H), 3.73 (s, 3H), 2.94 (d, 1H, J = 5.3 Hz), 1.85
13
– 1.77 (m, 1H), 1.72 – 1.64 (m, 2H), 1.51 (s, 3H), 0.87 (d, 3H, J = 6.4 Hz), 0.75 (d, 3H, J = 6.3 Hz); C
NMR (126 MHz, CDCl3) δ 204.9, 172.6, 172.5, 158.6, 136.3, 136.2, 130.2, 129.3, 129.1, 128.1, 126.6,
113.9, 76.9, 71.5, 64.3, 55.3, 52.5, 45.0, 40.3, 24.1, 23.5, 21.4; 77Se NMR (95 MHz, CDCl3) δ 700.24.
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HRMS (NSI-FTMS) m/z: [M–HSePh]+ Calcd for [C20H25NO6]+ 376.1760; Found 376.1758.
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8
9
(±)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-3,4-dehydropyrrolidin-2-one (±)-20 and (±)-
N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-4,5-dehydropyrrolidin-2-one (±)-19
Compound (±)-18 (0.18 g, 0.4 mmol) was dissolved in DMF (5 mL), and lithium chloride (0.05 g, 1.1
mmol) added. The mixture was heated at 135 °C for 4 h, allowed to reach room temperature, and aqueous
ammonium hydroxide (5%) added. The aqueous phase was extracted with diethyl ether (3 x 10 mL). The
organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous magnesium sulfate,
filtered, and the solvent removed under reduced pressure. The residue was purified by silica gel column
chromatography using 20% ethyl acetate in petroleum ether (40-60 °C) as eluent to give the first eluting
compound (±)-20 as a colourless oil (0.05 g, 49%) and the second eluting compound (±)-19 as a colourless
oil (0.04 g, 38%).
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1
(±)-20: νmax (thin film)/cm−1: 1713, 1671; H NMR (500 MHz, CDCl3) δ 7.15 (d, 2H, J = 8.6 Hz), 6.82 (d,
2H, J = 8.6 Hz), 4.57 (d, 2H, J = 2.0 Hz), 4.51 (dt, 1H, J = 9.5, 2.2 Hz), 3.78 (s, 3H), 2.91 (ddd, 1H, J =
16.1, 9.7, 2.0 Hz), 2.72 – 2.61 (m, 1H), 2.39 – 2.31 (m, 1H), 2.22 (ddd, 1H, J = 16.1, 6.3, 2.4 Hz), 1.29 (d,
13
3H, J = 7.2 Hz), 0.92 (d, 3H, J = 4.9 Hz), 0.91 (d, 3H, J = 4.9 Hz); C NMR (126 MHz, CDCl3) δ 178.3,
158.7, 135.8, 128.7, 128.5, 113.8, 109.7, 55.2, 43.1, 35.1, 30.3, 26.8, 23.6, 23.5, 17.3; HRMS (NSI-FTMS)
m/z: [M+H]+ Calcd for [C17H24NO2]+ 274.1807; Found 274.1794.
(±)-19: νmax (thin film)/cm−1: 1675; 1H NMR (500 MHz, CDCl3) δ 7.15 (d, 2H, J = 8.6 Hz), 6.83 (d, 2H, J =
8.6 Hz), 6.70 – 6.66 (m, 1H), 5.09 (d, 1H, J = 15.0 Hz), 4.01 (d, 1H, J = 15.0 Hz), 3.78 (s, 4H), 1.92 (t, 3H,
J = 1.7 Hz), 1.68 – 1.60 (m, 1H), 1.65 (d, 1H, J = 9.7 Hz), 1.25 (d, 1H J = 9.7 Hz), 0.89 (d, 3H, J = 6.1 Hz),
13
0.85 (d, 3H, J = 6.1 Hz); C NMR (126 MHz, CDCl3) δ 171.7, 158.9, 140.6, 134.5, 129.9, 129.3, 114.0,
58.1, 55.3, 43.3, 39.8, 25.1, 23.9, 22.3, 11.3; HRMS (NSI-FTMS) m/z: [M+H]+ Calcd for [C17H24NO2]+
274.1807; Found 274.1794.
(±)-(3S,5R)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-pyrrolidin-2-one-5-carboxylic acid
methyl ester (±)- 25a and (±)-(3R,5R)-N-(4’-Methoxybenzyl)-3-methyl-5-(2’-methylpropyl)-pyrrolidin-
2-one-5-carboxylic acid methyl ester (±)-25b
Compound (±)-6 (0.33 g, 0.70 mmol) was dissolved in anhydrous THF (1.65 mL) Pd(OH)2/C (0.17 g) was
added, and the mixture stirred under a static pressure of hydrogen at 35 °C overnight. The mixture was
filtered through celite, and the solvent removed under reduced pressure. (±)-25a and (±)-25b were obtained
as an inseparable mixture of diastereoisomers in a 1:1 ratio as a colourless oil (0.26 g, quant.). No further
purification was carried out.
νmax (thin film)/cm−1: 2955, 1743, 1638; 1H NMR (500 MHz, CDCl3) δ 7.25 (d, 4H, J = 8.7 Hz), 6.82 (d, 4H,
J = 8.7 Hz), 5.22 (d, 1H, J = 14.8 Hz), 4.97 (d, 1H, J = 14.8 Hz), 4.02 (d, 1H, J = 14.8 Hz), 3.84 (d, 1H, J =
14.8 Hz), 3.78 (s, 6H), 3.20 – 3.18 (m, 1H), 3.17 (s, 3H), 3.14 (s, 3H), 2.89 (q, 1H, J = 7.4 Hz), 2.17 – 2.08
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(m, 4H), 1.45 (d, 3H, J = 7.6 Hz), 1.45 – 1.37 (m, 2H) 1.37 (d, 3H, J = 7.6 Hz), 0.92 (d, 3H, J = 6.8 Hz),
0.86 (d, 3H, J = 6.8 Hz), 0.78 (d, 3H, J = 6.6 Hz), 0.76 (d, 3H, J = 6.6 Hz); 13C NMR (126 MHz, CDCl3) δ
207.4, 206.0, 173.6, 173.2, 168.1, 167.9, 159.3, 159.3, 130.84, 130.81, 127.7, 127.5 113.8, 113.7, 75.7, 75.2,
55.3, 52.8, 44.5, 44.2, 43.7, 43.7, 38.1, 36.9, 23.9, 23.8, 23.7, 23.65, 23.62, 23.5, 12.5, 10.0;
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HRMS (NSI-FTMS) m/z: [M+H]+ Calcd for [C19H26NO5]+ 348.1085; Found 348.1806.
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S-Methyl 4-methylbenzene-1-sulfonothioate 26 17
Sodium p-toluenesulfinate (3.23 g, 18.13 mmol) was dissolved in dichloromethane (50 mL), and dimethyl
disulfide (0.50 mL, 5.7 mmol) was added. Iodine (2.81 g, 11.33 mmol) was added with vigorous stirring.
The mixture was stirred and monitored by TLC until the dimethyl disulfide was consumed. The mixture was
diluted with dichloromethane (30 mL) followed by the addition of aqueous sodium thiosulfate (1M) with
stirring until the iodine colour disappeared. The organic layer was washed with water (2 x 50 mL), dried
over anhydrous sodium sulfate, filtered, and the solvents removed under reduced pressure to yield 26 as an
off-white solid (1.15 g, quant.), mp 56-57 °C; νmax (thin film)/cm−1: 2926, 1594; 1H NMR (500 MHz, CDCl3)
δ 7.80 (d, 2H, J = 8.3 Hz), 7.36 (d, 2H, J = 8.3 Hz), 2.50 (s, 3H), 2.46 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 144.9, 140.9, 129.9, 127.2, 21.7, 18.1. The product was sufficiently pure to be used without further
purification.
S-Phenyl 4-methylbenzene-1-sulfonothioate 28 22
Sodium p-toluenesulfinate (1.20 g, 6.7 mmol) and iodine (0.74 g, 2.9 mmol) were dissolved in CH2Cl2 (15
mL). Diphenyldisulfide (0.55 g, 2.9 mmol) was added with vigorous stirring, and the mixture stirred
overnight. Aqueous sodium thiosulphate (1M) was added until the iodine colour was removed. The mixture
was washed with water (100 mL) twice, dried over anhydrous sodium sulphate, filtered, and the solvents
removed under reduced pressure to give an oil that crystallized on cooling to afford 28 as a colourless solid
(1.0 g, 67%) mp 71-75 °C νmax (thin film)/cm−1: 3063, 1594; H NMR (500 MHz, CDCl3) δ 7.50-7.30 (m,
1
7H), 7.20 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H).13C NMR (126 MHz, CDCl3) δ 144.8, 140.5, 136.7, 131.4, 129.5,
129.5, 128.2, 127.8, 21.8. The product was sufficiently pure to be used without further purification.
(±)-(3R,5R)-N-(4’-Methoxybenzyl)-3-methyl-3-methylsulfanyl-5-(2’-methylpropyl)-pyrrolidin-2,4-
dione-5-carboxylic acid methyl ester (±)-27a and (±)-(3S,5R)-N-(4’-Methoxybenzyl)-3-methyl-3-
methylsulfanyl-5-(2’-methylpropyl)-pyrrolidin-2,4-dione-5-carboxylic acid methyl ester (±)-27b
A mixture of (±)-25a-b (0.30 g, 0.86 mmol) was dissolved in dichloromethane (5 mL) at room temperature
under a nitrogen atmosphere. Triethylamine (0.2 mL, 1 mmol) and S-methyl p-toluenethiosulfonate (0.18 g,
0.8 mmol) were added. The mixture was stirred overnight at room temperature. The solvent was removed
under reduced pressure and the residue purified by column chromatography on silica gel using 10% ethyl
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acetate in petroleum ether (40-60 °C) as eluent to yield diastereoisomers (±)-27a and (±)-27b as an
inseparable mixture in a 1:2 ratio (0.16 g, 47%).
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For the mixture (±)-27a-b: νmax (thin film)/cm−1: 2960, 1769, 1745, 1698; HRMS (NSI-FTMS) m/z:
[M+H]+ Calcd for [C20H28NO5S]+ 394.1683; Found 394.1682.
7
8
9
For (±)-(3R,5R)-N-(4’-Methoxybenzyl)-3-methyl-3-methylsulfanyl-5-(2’-methylpropyl)-pyrrolidin-2,4-
dione-5-carboxylic acid methyl ester (±)-27a
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1H NMR (500 MHz, CDCl3) δ 7.27 (d, 2H, J = 8.7 Hz), 6.83 (d, 2H, J = 8.7 Hz), 4.80 (d, 1H, J = 15.2 Hz),
4.43 (d, 1H, J = 15.2 Hz), 3.78 (s, 3H), 3.45 (s, 3H), 2.25 (dd, 1H, J = 15.2, 6.8 Hz), 2.15 (s, 3H), 1.96 (dd,
1H, J = 15.2, 5.7 Hz), 1.58 (s, 3H), 1.38 – 1.29 (m, 1H), 0.75 (d, 3H, J = 4.5 Hz), 0.74 (d, 3H, J = 4.5 Hz);
13C NMR (126 MHz, CDCl3) δ 200.2, 171.7, 167.9, 159.0, 129.8, 128.5, 113.8, 75.4, 55.3, 52.9, 49.3, 44.9,
40.0, 24.0, 23.9, 23.5, 16.9, 12.3.
For (±)-(3S,5R)-N-(4’-Methoxybenzyl)-3-methyl-3-methylsulfanyl-5-(2’-methylpropyl)-pyrrolidin-2,4-
dione-5-carboxylic acid methyl ester (±)-27b
1H NMR (500 MHz, CDCl3) δ 7.24 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 4.96 (d, 1H, J = 14.9 Hz),
4.03 (d, 1H, J = 14.9 Hz), 3.77 (s, 3H), 3.16 (s, 3H), 2.28 (s, 3H), 2.24 (dd, 1H, J = 15.25, 5.39 Hz), 1.98
(dd, 1H, J = 15.25, 6.15 Hz), 1.74 (dtd, 1H, J = 13.1, 6.6, 1.2 Hz), 1.67 (s, 3H), 0.93 (d, 3H, J = 6.6 Hz),
13
0.87 (d, 3H, J = 6.6 Hz); C NMR (126 MHz, CDCl3) δ 202.6, 172.4, 168.0, 159.3, 130.7, 127.5, 113.8,
75.2, 55.3, 52.8, 48.2, 43.7, 38.3, 24.6, 23.9, 23.7, 18.5, 11.6.
(±)-(2S,4S)-methyl 2-isobutyl-1-(4-methoxybenzyl)-4-methyl-3,5-dioxo-4-(phenylthio)-pyrrolidine-2-
carboxylate (±)-29a and (±)-(2S,4R)-methyl 2-isobutyl-1-(4-methoxybenzyl)-4-methyl-3,5-dioxo-4-
(phenylthio)-pyrrolidine-2-carboxylate (±)-29b
(±)-25a/b (0.21 g, 0.61 mmol) was dissolved in anhydrous dichloromethane (15 mL). Triethylamine (0.1
mL, 0.73 mmol) and S-phenyl 4-methylbenzene-1-sulfonothioate 28 (0.16 g, 0.67 mmol) were added. The
mixture was stirred at room temperature for 6 h. The solvents were removed under reduced pressure, and the
residue was purified by silica gel column chromatography using 10% ethyl acetate in petroleum ether (40-60
°C) as eluent to afford diastereoisomers (±)-29a-b as an inseparable mixture in a 0.95:1 ratio as an off-white
solid (0.17 g, 60%).
(2S,4S)-Methyl
2-isobutyl-1-(4-methoxybenzyl)-4-methyl-3,5-dioxo-4-(phenylthio)-pyrrolidine-2-
and (2S,4R)-methyl 2-isobutyl-1-(4-methoxybenzyl)-4-methyl-3,5-dioxo-4-
carboxylate
29a
(phenylthio)-pyrrolidine-2-carboxylate 29b
(–)-6 (0.4377 g, 0.70 mmol) was dissolved in THF (2.2 mL). A catalytic amount of Pd(OH)2/C was added
the mixture was stirred overnight under a static pressure of hydrogen at 35 °C, filtered through celite, and
the solvents removed under reduced pressure. The resulting oil was dissolved in anhydrous dichloromethane
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The Journal of Organic Chemistry
(3.1 mL), and S-phenyl 4-methylbenzene-1-sulfonothioate 28 (0.481 g, 2 mmol) and triethylamine (0.15
mL, 1.1 mmol) added. The mixture was stirred under an atmosphere of nitrogen for 5 h, the solvents
removed under reduced pressure, and the residue purified by column chromatography using petroleum ether
(40-60 °C/ethyl acetate (9:1) as eluent, yielding diastereoisomers (2S,4S)-29a and (2S,4R)-29b as an
inseparable mixture in 1:1 ratio as a pale yellow oil. (0.281 g, 67% over the two steps).
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For the mixture 29a-b: νmax (thin film)/cm−1: 2957, 1771, 1745, 1700; HRMS (ASAP-TOF) m/z: [M+H]+
Calcd for [C25H30NO5S]+ 456.1845; Found 456.1854.
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Compound 29a 1H NMR (500 MHz, CDCl3) δ 7.50 (dd, J = 8.2, 1.3 Hz, 2H), 7.48-7.31 (m, 3H), 7.28 (d, J
= 8.7 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 4.85 (d, J = 15.2 Hz, 2H), 4.41 (d, J = 15.2 Hz, 1H), 3.79 (s, 3H),
3.44 (s, 3H), 2.26 (dd, J = 15.2, 6.8 Hz, 1H), 1.95 (dd, J = 15.2, 5.6 Hz, 1H), 1.45 (s, 3H), 1.29 (d, J = 6.7
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Hz, 1H), 0.73 (d, J = 6.7 Hz, 3H), 0.70 (d, J = 6.6 Hz, 3H); C NMR (126 MHz, CDCl3) δ 200.4, 171.8,
168, 159.2, 137.9, 130.6, 130.1, 129., 128.6, 128.2, 113.9, 75.7, 55.4, 53.1, 53, 45, 40.1, 24, 23.7, 18.3.
Compound 29b 1H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 7.0 Hz, 2H), 7.47-7.31 (m, 3H), 7.22 (d, J = 8.7
Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 4.96 (d, J = 15.0 Hz, 1H), 4.04 (d, J = 15.0 Hz, 1H), 3.77 (s, 3H), 3.15 (s,
3H), 2.14 (dd, J = 15.0, 5.7 Hz, 1H), 1.74 (d, J = 6.5 Hz, 1H), 1.60 (dd, J = 15.0, 6.5 Hz, 1H), 1.54 (s, 3H),
0.95 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 204.2, 172.6, 168, 159.4,
137.8, 130.8, 130.4, 129, 128.3, 127.8, 113.9, 74.9, 55.4, 53.2, 52.9, 43, 38.4, 24.6, 23.9, 20.8.
(±)-(3S,4S,5R)-N-(4’-Methoxybenzyl)-3-methyl-3-methylsulfanyl-4-hydroxy-5-(2’-methylpropyl)-
pyrrolidin-2-one-5-carboxylic acid methyl ester (±)-30a and (±)-(3R,4R,5R)-N-(4’-Methoxybenzyl)-3-
methyl-3-methylsulfanyl-4-hydroxy-5-(2’-
methylpropyl)-pyrrolidin-2-one-5-carboxylic acid methyl ester (±)-30b
A mixture of compounds (±)-27a-b (0.088 g, 0.22 mmol) was dissolved in ethanol (4.6 mL). Sodium
borohydride (0.004 g, 0.11 mmol) was added and the mixture stirred at –10 °C for 30 min. Water (1 mL)
was added, and the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate (5
mL), washed with water (2 x 5 mL) and brine (2 x 5 mL), and the organic layer dried over sodium sulfate,
filtered, and the solvents removed under reduced pressure. The residue was purified by column
chromatography on silica gel using petroleum ether (40-60 °C/ethyl acetate (3:1) as eluent. The first eluting
diastereoisomer (±)-30a was obtained as a yellow oil (0.015 g, 17%), and the second eluting diastereoisomer
(±)-30b was obtained as a dark yellow oil (0.023 g, 25%). An inseparable mixture of compounds (±)-27a-b
in a 1:6 ratio was recovered (0.020 g, 23%).
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For (±)-30a: νmax (thin film)/cm−1: 3432, 2957, 2927, 1741, 1698; H NMR (500 MHz, CDCl3) δ 7.15 (d,
2H, J = 8.7 Hz), 6.82 (d 2H, J = 8.7 Hz), 4.84 (d, 1H, J = 15.9 Hz), 4.47 (d, 1H, J = 10.0 Hz), 4.36 (d, 1H, J
= 15.9 Hz), 4.03 (d, 1H, J = 10.0 Hz), 3.78 (s, 3H), 3.66 (s, 3H), 2.14 (s, 3H), 1.85 (dd, 1H, J = 14.5, 6.0
Hz), 1.77 – 1.72 (m, 1H), 1.65 (dd, 1H, J = 14.5, 4.5 Hz), 1.63 (s, 3H), 0.82 (d, 3H, J = 6.6 Hz), 0.71 (d, 3H,
J = 6.6 Hz); 13C NMR (126 MHz, CDCl3) δ 174.6, 173.1, 158.7, 130.2, 128.7, 113.8, 81.3, 67.4, 55.3, 52.7,
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51.5, 44.8, 44.0, 24.4, 23.9, 23.5, 21.8, 11.5; HRMS (NSI-FTMS) m/z: [M+H]+ Calcd for [C20H30NO5S]+
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396.1839; Found 396.1830.
For (±)-30b: νmax (thin film)/cm−1: 3484, 2957, 2928, 1738; 1682; H NMR (500 MHz, CDCl3) δ 7.15 (d,
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2H, J = 8.7 Hz), 6.82 (d, 2H, J = 8.7 Hz), 4.89 (d, 1H, J = 16.0 Hz), 4.47 (d, 1H, J = 3.3 Hz), 4.43 (d, 1H, J
= 16.0 Hz), 3.78 (s, 3H), 3.70 (s, 3H), 3.20 (d, 1H, J = 3.3 Hz), 2.15 (s, 3H), 1.88 (dd 1H, J = 13.7, 6.3 Hz),
1.80 (dd, 1H, J = 13.7, 5.3 Hz), 1.76 – 1.71 (m, 1H), 1.50 (s, 3H), 0.91 (d, 3H, J = 6.6 Hz), 0.77 (d, 3H, J =
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6.6 Hz); C NMR (126 MHz, CDCl3) δ 173.2, 173.1, 158.5, 130.5, 128.2, 113.8, 75.9, 71.6, 57.5, 55.3,
52.4, 45.2, 40.7, 24.23, 24.20, 23.5, 21.9, 12.6; HRMS (NSI-FTMS) m/z: [M+H]+ Calcd for [C20H30NO5S]+
396.1839; Found 396.1832.
(±)-(2S,3S,4S)-Methyl
3-hydroxy-2-isobutyl-1-(4-methoxybenzyl)-4-methyl-5-oxo-4-
(phenylthio)pyrrolidine-2-carboxylate (±)-31a and (±)-(2S,3R,4R)-methyl 3-hydroxy-2-isobutyl-1-(4-
methoxybenzyl)-4-methyl-5-oxo-4-(phenylthio)pyrrolidine-2-carboxylate (±)-31b
A mixture of (±)-29a-b (0.36 g, 0.8 mmol) was dissolved in ethanol (16 mL), and the solution cooled to −10
°C. Sodium borohydride (0.02 g, 0.45 mmol) was added, and the mixture stirred for 30 min. Water (1 mL)
was added, and the mixture allowed to reach room temperature. The solvents were removed under reduced
pressure, and the residue dissolved in dichloromethane. The solution was washed twice with water (20 mL)
and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvents
were removed under reduced pressure. The residue was purified by silica gel column chromatography using
petroleum ether (40-60 °C)/ethyl acetate (6:1) as eluent, to give (±)-31a (0.11 g, 29%) and (±)-31b (0.075 g,
20%) as colourless oils.
(−)-(2S,3S,4S)-Methyl
3-hydroxy-2-isobutyl-1-(4-methoxybenzyl)-4-methyl-5-oxo-4-
(phenylthio)pyrrolidine-2-carboxylate (±)-31a and (±)-(2S,3R,4R)-methyl 3-hydroxy-2-isobutyl-1-(4-
methoxybenzyl)-4-methyl-5-oxo-4-(phenylthio)pyrrolidine-2-carboxylate (−)-31b
A mixture of (2S,4S)-29a and (2S,4R)-29b (0.2059, 0.45mmol) was dissolved in ethanol (9mL) and the
solution cooled to −10 °C. Sodium borohydride (0.012g, 0.3mol) was added, and the mixture stirred for 30
min before being quenched by addition of water (1 mL). The solvents were removed under reduced
pressure, and the residue dissolved in dichloromethane. The organic layer was washed with twice each with
water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered, and
the solvents were removed under reduced pressure. The residue was purified by column chromatography
using petroleum ether (40-60 °C)/ethyl acetate (6:1) as eluent to give (−)-31a and (−)-31b as colourless oils.
The first eluting diastereoisomer (−)-31a: (0.063 g, 30%); νmax (thin film)/cm−1: 3423, 2957, 1740, 1701;
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[α]D = - 60.00 (c 0.34, CHCl3); H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 6.9 Hz, 2H), 7.40 – 7.28 (m,
3H), 7.18 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 4.71 (d, J = 15.7 Hz, 1H), 4.52 – 4.45 (m, 2H), 4.09
(d, J = 10.3 Hz, 1H), 3.78 (s, 3H), 3.66 (s, 3H), 1.95 (dd, J = 14.6, 6.1 Hz, 1H), 1.78 (d, J = 6.4 Hz, 1H),
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The Journal of Organic Chemistry
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1.66 (dd, J = 14.6, 5.0 Hz, 1H), 1.44 (s, 3H), 0.87 (d, J = 6.6 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H). C NMR
(126 MHz, CDCl3) 13C NMR (126 MHz, CDCl3) δ 174.1, 173.6, 158.8, 137.5, 130.0, 129.5, 129.15, 129.09,
128.8, 113.8, 80.3, 68.0, 56.0, 55.4, 52.7, 44.8, 43.7, 24.5, 24.1, 23.6, 23.2; HRMS (ASAP-TOF) m/z:
[M+H]+ Calcd for [C25H32NO5S]+ 458.2001; Found 458.2003. Determined by HPLC to be 77% ee.
The second eluting diastereoisomer (−)-31b: (0.073 g, 35%); νmax (thin film)/cm−1: 3405, 2957, 2930,
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1736, 1683; [α]D = - 5.8 (c 13.1, CHCl3); H NMR (500 MHz, CDCl3) δ 7.63 (d, J = 6.7 Hz, 2H), 7.42 –
7.33 (m, 3H), 7.15 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 4.92 (d, J = 16.1 Hz, 1H), 4.44 (d, J = 16.1
Hz, 1H), 4.41 (d, J = 3.8 Hz, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 3.65 (d, J = 3.9 Hz, 1H), 1.93 – 1.86 (m, 1H),
1.81 – 1.72 (m, 2H), 1.29 (s, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.76 (d, J = 6.3 Hz, 3H).13C NMR (126 MHz,
CDCl3) δ 173.4, 173.2, 158.6, 136.4, 130.5, 129.5, 129.3, 128.7, 128.3, 113.9, 75.4, 71.8, 62.3, 55.4, 52.5,
45.4, 41.3, 24.3, 24.2, 23.7, 22.4; HRMS (ASAP-TOF) m/z: [M–SPh]+ Calcd for [C19H26NO5]+ 348.1811;
Found 348.1821.
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(±)-(2S,3R,4S)-Methyl
3-hydroxy-2-isobutyl-1-(4-methoxybenzyl)-4-methyl-5-oxopyrrolidine-2-
carboxylate (±)-21a and (±)-(2S,3R,4R)-methyl 3-hydroxy-2-isobutyl-1-(4-methoxybenzyl)-4-methyl-5-
oxopyrrolidine-2-carboxylate (±)-21b
Raney Nickel method: Raney nickel 2800 grade was washed using ethanol and dried under an atmosphere
of nitrogen. A catalytic quantity was added to a solution of (±)-30a (0.02 g, 0.05 mmol) in ethanol (2.3 mL).
The mixture was heated under reflux for 4 h. After removal of the Raney nickel by filtration, the solvent was
removed under reduced pressure. The residue was purified by column chromatography on silica gel using
petroleum ether (40-60 °C)/ethyl acetate (3:1) as eluent to give (±)-21a and (±)-21b as a 3:1 mixture of
diastereoisomers (5.7 mg, 7%).
AIBN method: (±)-31a (0.064 g, 0.14 mmol) and AIBN (0.007 g, 0.043 mmol) were dissolved in
anhydrous acetone (1 mL). Tris(trimethylsilyl)silane (0.14 mL, 0.45 mmol) was added and the mixture was
heated under reflux under a nitrogen atmosphere overnight. The solvents were removed under reduced
pressure, and the residue purified by column chromatography using ethyl acetate/petroleum ether (40-60 °C)
(1:1) as eluent to afford (±)-21a as a colourless oil (0.007 g, 14%) and (±)-21b as a colourless oil (0.036 g,
74%).
(+)-(2S,3R,4S)-Methyl
3-hydroxy-2-isobutyl-1-(4-methoxybenzyl)-4-methyl-5-oxopyrrolidine-2-
carboxylate (+)-21a and (−)-(2S,3R,4R)-methyl 3-hydroxy-2-isobutyl-1-(4-methoxybenzyl)-4-methyl-5-
oxopyrrolidine-2-carboxylate (−)-21b
Raney Nickel method: Raney nickel 2800 grade was washed using ethanol and dried under an atmosphere
of nitrogen. A catalytic quantity was added to a solution of (−)-31a (0.0237 g, 0.05 mmol) in ethanol (1
mL). The mixture was heated under reflux for 4 h. After removal of the Raney nickel by filtration, the
solvent was removed under reduced pressure. The residue was purified by column chromatography on silica
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