Construction of chiral α-amino quaternary stereogenic centers via phase-transfer catalyzed enantioselective α-alkylation of α-amidomalonates

Article abstract of DOI:10.1021/jo502791d

An efficient enantioselective synthetic method for α-amido-α-alkylmalonates via phase-transfer catalytic α-alkylation was successfully developed. The α-alkylation of α-amidomalonates under phase-transfer catalytic conditions (50% KOH, toluene, 40 °C) in the presence of (S,S)-3,4,5-trifluorophenyl-NAS bromide afforded the corresponding α-amido-α-alkylmalonates in high chemical yields (up to 99%) and optical yields (up to 97% ee), which could be readily converted to versatile chiral intermediates bearing α-amino quaternary stereogenic centers. The synthetic potential of this methodology was demonstrated via the synthesis of chiral azlactone, oxazoline, and unnatural α-amino acid.

Full text of DOI:10.1021/jo502791d

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Note
Construction of Chiral alpha-Amino quaternary
Stereogenic Centers via Phase-transfer Catalyzed
Enantioselective alpha-Alkylation of alpha-Amidomalonates
Min Woo Ha, Myungmo Lee, Sujee Choi, Seek Kim, Suckchang Hong, Yohan Park,
Mi-hyun Kim, Taek-Soo Kim, Jihoon Lee, Jae Kyun Lee, and Hyeung-Geun Park
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502791d • Publication Date (Web): 12 Feb 2015
Downloaded from http://pubs.acs.org on February 18, 2015
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Construction of Chiral αꢀAmino quaternary Stereogenic Centers via
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Phaseꢀtransfer
Catalyzed Enantioselective αꢀAlkylation of αꢀ
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Amidomalonates
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Min Woo Ha,† Myungmo Lee,† Sujee Choi,† Seek Kim,† Suckchang Hong,† Yohan Park,‡ Miꢀhyun Kim,§ Taekꢀ
Soo Kim,§ Jihoon Lee,† Jae Kyun Leeǁ and Hyeungꢀgeun Park†,*
†Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151ꢀ
742, Korea.
‡College of Pharmacy, Inje University, 607 Obangꢀdong, Gimhae, Gyeongnam 621ꢀ749, Korea.
§College of Pharmacy, Gachon University, 191 Hambakmoero, Yeonsuꢀgu, Incheon 406ꢀ799, Korea.
ǁNeuroꢀMedicine Center, Korea Institute of Science and Technology, PO Box 131, Cheongyang, Seoul 130ꢀ650,
Republic of Korea.
Corresponding author
Hyeungꢀgeun Park, Tel: +82ꢀ2ꢀ880ꢀ7821, 8264, Fax: +82ꢀ2ꢀ872ꢀ9129, eꢀmail: hgpark@snu.ac.kr
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F
F
(S,S)-NAS (5 mol %)
E+ (5.0 equiv)
O
O
O
O
F
F
*
R1O
R3HN
OR2
OR2
NHR3
R1O
N Br
50% KOH (5.0 equiv)
E
toluene, -40 o
C
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R1, R2 = Bn, Ph2CH, Et, t-Bu
up to 99%, 97% ee
22 samples
R3 = Ac, Bz, Boc, Cbz, Alloc
F
F
Abstract
Efficient enantioselective synthetic method for αꢀamidoꢀαꢀalkylmalonates via phaseꢀtransfer catalytic αꢀ
alkylation was successfully developed. The αꢀalkylation of αꢀamidomalonates under phaseꢀtransfer catalytic
conditions (50% KOH, toluene, –40 °C) in the presence of (S,S)ꢀ3,4,5ꢀtrifluorophenylꢀNAS bromide afforded
the corresponding αꢀamidoꢀαꢀalkylmalonates in high chemical yields (up to 99%) and optical yields (up to 97%
ee), which could be readily converted to versatile chiral intermediates bearing αꢀamino quaternary stereogenic
centers. The synthetic potential of this methodology was demonstrated via the synthesis of chiral azlactone,
oxazoline and unnatural αꢀamino acid.
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The synthesis of optically active nitrogenꢀcontaining organic compounds is very important inorganic
chemistry and medicinal chemistry due to their versatile biological activities and pharmaceutical applications.1
Alkaloids are a class of nitrogenꢀcontaining natural products, showing various biological activities, and also
molecules of most pharmaceutics contain nitrogen. During the last decade, significant progress has enabled the
construction of αꢀamino quaternary stereogenic centers with impressive levels of enantioselectivity, using either
organometallic catalysis or organocatalysis.2 There have been a lot of enantioselective synthetic methods
developed for the αꢀaminoꢀβꢀketo esters via electrophilic αꢀamination of βꢀketo esters (Scheme 1, A).3 However,
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the enantioselective synthetic methods for the αꢀaminomalonates have mostly been achieved by the enzymatic
desymmetrization4 of prochiral αꢀaminomalonates, and there are only two cases as part of study via chemical
synthesis (each one malonate sample).3u,5
Scheme 1. Synthetic strategy for chiral αꢀaminomalonates.
Recently, we reported new synthetic methods for producing αꢀmonosubstituted chiral malonates or
α,αꢀdisubstituted chiral malonates with high chemical yields and enantioselectivities via phaseꢀtransfer catalytic
(PTC)6 αꢀalkylation of malonates in the presence of catalytic amounts of chiral quaternary ammonium salts, and
successfully proved their usefulness by application to the synthesis of various chiral building blocks bearing
quaternary stereogenic centers.7 We planned to develop a new method for the synthesis of chiral tertiary αꢀ
aminomalonates via the wellꢀestablished enantioselective phaseꢀtransfer catalytic αꢀalkylation of malonates.
Incorporation of an amino group into the αꢀposition of malonates, followed by enantioselective αꢀalkylation
under phaseꢀtransfer catalysis conditions as the key step for asymmetric induction would produce chiral αꢀ
aminomalonates (Scheme 1, B). This is an alternative strategy to the direct αꢀamination process (Scheme 1, A).
Although the direct electrophilic αꢀaminations of carbonyl compounds can afford amines or protected amines
directly in a single step, there is a limited availability of electrophilic nitrogen sources. In terms of diversity, the
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advantage of the reverse strategy compared to the direct electrophilic αꢀamination is that a variety of chiral
compounds can be easily prepared simply by changing the alkylating reagent. Herein, we report a new and
highly efficient enantioselective synthetic method for αꢀaminoꢀαꢀalkylmalonates, which can be converted to
valuable chiral building blocks bearing αꢀamino quaternary stereogenic centers (Scheme 2).
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Scheme 2. Versatile chiral building blocks from chiral αꢀaminoꢀαꢀalkylmalonates.7b,8
First, we needed to design enantiotopic unsymmetrical αꢀaminomalonates, possessing non
nucleophilic nitrogen as substrates for PTC αꢀalkylation. Seven of αꢀamidomalonates were prepared from
various malonates 1 in 2 steps (Scheme 3). Diazotization of 1 by using pꢀacetamidobenzenesulfonyl azide (pꢀ
ABSA) in the presence of triethylamine under acetonitrile afforded αꢀdiazomalonates 2.9 Subsequent NꢀH
insertion of 2 into acetamide, benzamide or carbamates via carbenoid in the presence of rhodium (II) acetate
[Rh2(OAc)4] successfully provided the corresponding αꢀamidomalonates 3–9 (30 – 50 %).10
O
O
O
O
p-ABSA, Et3N
R1O
OR2
CH3CN
0 oC - rt, 12 h
92 - 98%
R1O
OR2
N2
1
2
O
O
R3NH2, Rh2(OAc)4
R1O
OR2
NHR3
ClCH2CH2Cl, reflux, 12 h
30 - 50%
3
R1 = Ph2CH R2 = t-Bu R3 = Ac
R1 = PhCH2 R2 = t-Bu R3 = Ac
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R1 = Ph2CH R2 = Et
R3 = Ac
R1 = Ph2CH R2 = t-Bu R3 = Bz
R1 = Ph2CH R2 = t-Bu R3 = Boc
R1 = Ph2CH R2 = t-Bu R3 = Cbz
R1 = Ph2CH R2 = t-Bu R3 = Alloc
Scheme 3. Preparation of αꢀamidomalonates.
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For preliminary study, the substrate efficiency of the prepared αꢀamidomalonates was examined by αꢀ
benzylation under typical PTC conditions, based on the previous reports.7a The enantioselective PTC
benzylation of 3–9 were performed in the presence of the representative chiral quaternary ammonium salts (10–
14)11 (Figure 1), along with benzyl bromide (5.0 equiv.) and 50% KOH (aq., 5.0 equiv.) at room temperature in
toluene (Table 1). As shown in Table 1, all substrates successfully gave the corresponding αꢀbenzylated
products in high chemical yields with variable enantioselectivities in the presence of Maruoka’s catalyst, (S,S)ꢀ
3,4,5ꢀtrifluorophenylꢀNAS bromide (10) (entries 1 – 7). Diphenylmethyl ester and tertꢀbutyl ester group (3)
showed quite higher enantioselectivity than those of benzyl ester and ethyl ester group, respectively (4 and 5),
which is in accord with the previous report for the synthesis of chiral quaternary α,αꢀdisubstituted malonates.7a
In the case of amide groups, acetyl group (3) gave better enantioselectivity than those of benzoyl (6), Boc (7).
The Cbz (8) and Alloc (9) groups afforded the same enantioselectivity with a lower chemical yield than those of
acetyl group. Optimization of catalyst was then performed with substrate 3.
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Figure1. Representative chiral phaseꢀtransfer catalysts.
Table 1. Enantioselective PTC αꢀalkylation of αꢀamidomalonates.a
O
O
O
O
cat (5 mol%), BnBr (5 eq)
50% KOH (5 eq), toluene
*
R1O
R3NH
OR2
Bn
R1O
OR2
NHR3
entry
sub.
3
cat
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time (h) yield (%)b ee (%)c
T (°C)
1
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4
5
rt
rt
rt
rt
rt
0.5
0.5
0.5
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0.5
99
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aReactions were performed with 5.0 equiv. of benzyl bromide and 5.0 equiv. of 50% KOH(aq.) under the given
b
c
conditions. Isolated yields. Enantiopurity was determined by HPLC analysis using a chiral column (DAICEL
Chiralpak ADꢀH or DAICEL Chiralpak ODꢀH).
Among the employed catalysts, Maruoka’s catalyst, (S,S)ꢀ3,4,5ꢀtrifluorophenylꢀNAS bromide (10)
afforded the highest enantioselectivity in the PTC benzylation of 3 (entries 1 and 8 – 11). However, the other
N,Nꢀdibutylbinaphthyl derived catalyst 11 and the cinchona alkaloid derived catalysts (12 – 14) including
Lygo’s catalysts (12, 13) resulted in lower enantioselectivities than use of 10. It is also notable that Nꢀ
benzylation was not observed as a minor product, even in the presence of excess base and benzyl bromide under
PTC conditions.
Next, the best substrate 3 was chosen to optimize the reaction conditions. The PTC benzylation of 3
was performed in the presence of the best catalyst, (S,S)ꢀ10, under variable base, solvent, and temperature
conditions. Generally, the chemical yield and enantioseletivity were not significantly dependent on the base and
solvent conditions at room temperature (data were not shown). In the case of temperature conditions, lower
reaction temperatures clearly resulted in higher enantioselectivity (entry 1, entries 12 – 15). However, the
reaction time increased with a decrease in temperature, resulting in quite longer reaction time at –60 °C (entry
15). Finally, 50% KOH base under toluene at –40 °C was chosen as the optimized reaction conditions, in
consideration of enantioselectivity, chemical yield, and reaction time (entry 14; 97%, 95% ee).
The scope and limitations of enantioselective PTC alkylation of 3 with various electrophiles were
performed under the optimized reaction conditions (Table 1, entry 14). As shown in Table 2, most of the
alkylating agents showed very high enantioselectivities (3d, 3f–p, 91–97% ee). However, unactivated alkylating
reagent (3a, nꢀhexyl iodide) and three activated alkylating agents (3b–c, 3e, propargyl bromide, allyl bromide
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and tertꢀbutyl bromoacetate), resulted in relatively lower enantioselectivities due to possibly low reaction rate or
small molecular sizes, respectively. The very high enantioselectivities (up to 97% ee) indicate that this reaction
system is a very efficient enantioselective synthetic method for αꢀaminoꢀαꢀalkylmalonates.
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Table 2. Enantioselective synthesis of αꢀacetamidoꢀαꢀalkylmalonates via PTC αꢀalkylationa
10
RX (5 eq)
(S,S)- (5 mol%)
Ph
O
O
Ph
O
O
Ph
O
Ot-Bu
Ph
O
AcHN
Ot-Bu
50% KOH (5 eq)
toluene, -40 oC, 4 h
R
NHAc
3a-p
3
aReactions were performed with 5.0 equiv. of benzyl bromide and 5.0 equiv. of 50% KOH(aq.) under the given
b
c
conditions except 3a (reaction time, 75 h). Isolated yields. Enantiopurity was determined by HPLC analysis
using a chiral column (DAICEL Chiralpak ADꢀH). dAbsolute configuration of 3f was determined by the
comparison of specific optical rotation value of αꢀbenzylserine, prepared from 3f with the reported (S)ꢀαꢀ
benzylserine12, and by Xꢀray crystallography of 19 (Figure 2).13
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Figure 2. Xꢀray Crystallographic Structure of 19.13
The synthetic potential of this method was demonstrated via the synthesis of an unnatural amino acid,
αꢀbenzylserine, from optically active αꢀacetamidoꢀαꢀbenzylmalonate (3e), as exemplified in Scheme 4.
Catalytic hydrogenation of 3e with Pd/CꢀH2 in methanol afforded the corresponding mono acid 15. The
activation of 15 via mixed anhydride by using ethyl chloroformate in the presence of Nꢀmethylmorphorine
(NMM) gave azlactone 16 via intramolecular cyclization. The reduction of 16 using NaBH4 provided the
corresponding alcohol 17. Finally, the acidic hydrolysis of 17 using 6NꢀHCl afforded (R)ꢀαꢀbenzylserine
20
20
{[α]D = –15.5 (c 1.0, H2O); lit12 (S)ꢀαꢀbenzylserine, [α]D = 16.4 (c 0.80, H2O), 98% ee}. The mesylation of
17, followed by intramolecular cyclization in the presence of triethylamine under methylene chloride afforded
oxazoline 20. Also, opening of the ring of azlactone 16 was attempted via nucleophilic substitution of amine.
The treatment of (R)ꢀmethylbenzylamine with azlactone 16 in the presence of DMAP under methylene chloride
successfully afforded amide 19.
Scheme 4. Conversion of 3f to 19, 20, and (R)ꢀαꢀbenzylserine.
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In conclusion, an enantioselective synthetic method for αꢀamidoꢀαꢀalkylmalonates via PTC αꢀ
alkylation was successfully developed. The asymmetric PTC αꢀalkylations of diphenylmethylꢀtertꢀbutyl αꢀ
acetamidomalonate afforded thecorresponding αꢀacetamidoꢀαꢀalkylmalonates in high chemical yields (up to
99%) and optical yields (up to 97% ee). Our new catalytic system provides an attractive synthetic method for
versatile chiral building blocks, which could be readily converted to chiral target molecules involving αꢀamino
quaternary stereeogenic centers. We are now extending our synthetic method to βꢀketo ester system.
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Experimental Section
General Methods
All reagents bought from commercial sources were used without further purification. Commercially available
KOH pellet (99%) was grinded to prepare Solid KOH as powder form. 50% w/v aqueous KOH was used as
stock solution. Phaseꢀtransfer catalyst (12, 14) was prepared according to the reported procedure. Phaseꢀtransfer
catalysts (10, 11, 13) were purchased from the commercial source. TLC analyses were performed using
precoated TLC plate (silica gel 60 GF254, 0.25 mm). Flash column chromatography was performed on flash
silica gel 230~400 mesh size. The values of enantiomeric excess (ee) of chiral products were determined by
HPLC using 4.6 mm × 250 mm Daicel Chiralpak ADꢀH. Infrared analyses (KBr pellet) were performed by FTꢀ
1
IR. HꢀNMR spectra was recorded at 300MHz, 400MHz, or 500MHz with reference to CHCl3 (δ 7.24) or
CH3OH (δ 3.31). 13CꢀNMR spectra was obtained by 100 MHz, 125 MHz, or 150MHz spectrometer relative to
1
the central CDCl3 (δ 77.0) or CD3OD (δ 49.0) resonance. Coupling constants (J) in HꢀNMR are in Hz. Lowꢀ
resolution mass spectra (LRMS) and highꢀresolution mass spectra (HRMS) were measured on positiveꢀion FAB,
CI, or QꢀTOF (ESI) spectrometer. Melting points were measured on melting point apparatus and were
uncorrected. Optical rotations were measured on polarimeter and calibrated with pure solvent as blank.
Procedure for the preparation of malonate substrates
Triethylamine (1.28 mL, 9.19 mmol) was added to a stirred solution of benzhydryl tertꢀbutyl malonate (1a, 1.0 g,
3.06 mmol) and pꢀ(acetamido)benzenesulfonyl azide (pꢀABSA) (795 mg, 3.31 mmol) in acetonitrile (15 mL) at
0 °C under argon atmosphere. The reaction was gradually warmed to room temperature overnight. Unexpectedly,
the product spot had the same Rf value with the substrate spot on TLC. Therefore the reaction was stirred during
12 hours for complete conversion of the substrate into the product. The expected duration of the reaction might
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have been shorter than the actual reaction time. The reaction mixture was then filtered through a pad of celite
and washed with EtOAc, and the filtrate was purified by flash column chromatography on silica gel eluting with
hexaneꢀEtOAc (15:1) to afford 2a (1.058 g, 98% yield) as a yellow solid. A solution of acetamide (101 mg, 1.70
mmol) and rhodium (II) acetate (2.5 mol%) in 1,2ꢀdichloroethane (10 mL) was heated to reflux. To this solution
was added a solution of the diazo compound 2a (500 mg, 1.42 mmol) in 1,2ꢀdichloroethane(5 mL) drop wise
over 1 hour. The reaction was stirred for a further 12 hours until the reaction was complete. The mixture was
evaporated and concentrated for loading on flash column chromatography without further workꢀup procedure.
Eluting with hexaneꢀEtOAc (5:1) afforded purified αꢀacetamidomalonate 3 (272 mg, 50% yield) as a white solid.
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Typical experimental procedure for enantioselective phaseꢀtransfer catalytic alkylation.
Benzyl bromide (46.5 ꢁL, 0.39 mmol) was added to a solution of 1ꢀbenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀ
acetamidomalonate (3, 30 mg, 0.078 mmol) and (S,S)ꢀ3,4,5ꢀtrifluorophenylꢀNAS bromide (10, 3.6 mg, 0.004
mmol) in toluene (261 ꢁL) at room temperature. At the designated low temperature, aqueous 50% w/v aqueous
KOH (44 ꢁL, 0.39 mmol) was added to the reaction mixture and stirred until the starting material disappeared.
After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20 mL), washed with brine
(10 mL × 2), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by
flash column chromatography on silica gel eluting with hexaneꢀEtOAc solution (7:1) to afford 3e (36 mg, 97%
yield) as a white solid.
Benzhydryl tertꢀbutyl malonate (1a)
Commercially available hydrogen tertꢀbutyl malonate (1 g, 6.24 mmol) was dissolved in acetonitrile (20 mL)
and heated to reflux. To this solution was added αꢀbromodiphenylmethane (1.7 g, 6.87 mmol) and triethylamine
(960 ꢁL, 6.87 mmol) in sequence. The reaction was stirred until the TLC analysis showed that the reaction was
complete. Water mixable solvent was evaporated and diluted with dichloromethane. Quenching with ammonium
chloride (200 mL), washing with brine (150 mL × 2), drying over anhydrous MgSO4, filtration, and purifying by
flash column chromatography (silica gel, hexane : EtOAc solution = 15 : 1) afforded 1a (1.73 g, 85% yield) as a
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yellow oil. HꢀNMR (300 MHz, CDCl3) δ 7.34 ~ 7.18 (m, 10H), 6.89 (s, 1H), 3.33 (s, 2H), 1.36 (s, 9H) ppm;
13CꢀNMR (100 MHz, CDCl3) δ 165.8, 165.3, 139.6, 128.4, 127.9, 127.1, 82.0, 77.6, 43.2, 27.7 ppm; IR (KBr)
2960, 2924, 2853, 1732, 1680, 1462, 1377, 1021, 773 cmꢀ1; HRMS (ESI) calcd for [C20H22O4Na]+ ([M+Na]+)
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349.1410, found: 349.1422.
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Benzyl tertꢀbutyl malonate (1b)
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Commercially available hydrogen tertꢀbutyl malonate (1 g, 6.24 mmol) was dissolved in acetonitrile (20 mL)
and heated to reflux. To this solution was added benzyl bromide (816 mg, 6.87 mmol) and triethylamine (960
ꢁL, 6.87 mmol) in sequence. The reaction was stirred until the TLC analysis showed that the reaction was
complete. Water mixable solvent was evaporated and diluted with dichloromethane. Quenching with ammonium
chloride (200 mL), washing with brine (150 mL x 2), drying over anhydrous MgSO4, filtration, and purifying by
flash column chromatography (silica gel, hexane : EtOAc solution = 20 : 1) afforded 1b (1.27 g, 81% yield) as a
pale yellow oil. 1HꢀNMR (300MHz, CDCl3) δ 7.36 ~ 7.28 (m, 5H), 5.15 (s, 2H), 3.31 (s, 2H), 1.41 (s, 9H) ppm;
13CꢀNMR (125MHz, CDCl3) δ 166.7, 165.5, 135.4, 128.5, 128.3, 128.3, 82.0, 66.9, 42.8, 27.8 ppm; IR (KBr)
2979, 1750, 1731, 1369, 1333, 1280, 1143, 1001, 772, 698 cmꢀ1; HRMS (FAB) calcd for [C14H19O4]+ ([M+H]+)
251.1283, found: 251.1282.
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Benzhydryl ethyl malonate (1c)
Commercially available monoꢀethyl malonate (1 g, 7.57 mmol) was dissolved in acetonitrile (25 mL) and heated
to reflux. To this solution was added αꢀbromodiphenylmethane (2.06 g, 8.33 mmol) and triethylamine (1.16 mL,
8.33 mmol) in sequence. The reaction was stirred until the TLC analysis showed that the reaction was completed.
Water mixable solvent was evaporated and diluted with dichloromethane. Quenching with ammonium chloride
(200 mL), washing with brine (150 mL x 2), drying over anhydrous MgSO4, filtration, and purifying by flash
column chromatography (silica gel, hexane : EtOAc solution = 10 : 1) afforded 1c (1.72 g, 76% yield) as a
yellow oil. 1HꢀNMR (300 MHz, CDCl3) δ 7.34 ~ 7.24 (m, 10H), 6.93 ~ 6.92 (d, 1H, J = 1.65Hz), 4.24 ~ 4.14 (p,
2H, J = 7.1Hz), 3.46 (s, 2H), 1.25 ~ 1.19 (t, 3H, J = 7.1Hz) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 166.3, 165.5,
165.3, 139.6, 139.5, 128.5, 128.0, 128.0, 127.1, 127.1, 127.0, 139.6, 139.5, 128.5, 128.0, 128.0, 127.1, 127.1,
127.0, 78.0, 61.6, 41.9, 14.0 ppm; IR (KBr) 3033, 1751, 1734, 1220, 1148, 1032, 772, 699 cmꢀ1 ; HRMS (CI)
calcd for [C18H17O4]+ ([MꢀH]+) 297.1127, found: 297.1125.
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀdiazomalonate (2a)
Following the procedure (A) from 1a, 2a was obtained quantitatively as a yellow solid (98% yield). mp 68.8 °C;
1HꢀNMR (300 MHz, CDCl3) δ 7.37 ~ 7.20 (m, 10H), 7.03 (s, 1H), 1.50 (s, 9H) ppm; 13CꢀNMR (100 MHz,
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CDCl3) δ 160.3, 159.3, 139.5, 128.3, 127.8, 126.8, 82.8, 77.3, 65.9, 28.0 ppm; IR (KBr) 2979, 2139, 1954, 1755,
1727, 1687, 1325, 1276, 1166, 1097, 760, 700 cmꢀ1; HRMS (FAB) calcd for [C20H20N2NaO4]+ ([M+Na]+)
375.1321, found: 375.1316.
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1ꢀBenzyl 3ꢀ(tertꢀbutyl) 2ꢀdiazomalonate (2b)
Following the procedure (A) from 1b, 2b was obtained quantitatively as a pale yellow oil (95% yield). 1HꢀNMR
(300 MHz, CDCl3) δ 7.37 ~ 7.27 (m, 5H), 5.24 (s, 2H), 1.49 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 161.2,
159.7, 135.4, 128.5, 128.3, 128.2, 83.1, 66.7, 28.2 ppm; IR (KBr) 2979, 2137, 1757, 1731, 1687, 1370, 1328,
1276, 1165, 1095, 772, 697 cmꢀ1; HRMS (FAB) calcd for [C14H17N2O4]+ ([M+H]+) 277.1188, found: 277.1180.
1ꢀBenzhydryl 3ꢀethyl 2ꢀdiazomalonate (2c)
Following the procedure (A) from 1c, 2c was obtained quantitatively as a pale yellow oil (92% yield). 1HꢀNMR
(300 MHz, CDCl3) δ 7.40 ~ 7.24 (m, 10H), 7.01 (s, 1H), 4.37 ~ 4.28 (q, 2H, J = 7.1 Hz), 1.34 ~ 1.30(t, 3H, J =
7.1 Hz); 13CꢀNMR (125 MHz, CDCl3) δ 160.8, 160.5, 139.7, 128.5, 128.0, 127.0, 77.9, 66.2, 61.7, 14.3 ppm; IR
(KBr) 2941, 2143, 1759, 1733, 1692, 1372, 1320, 1307, 1269, 1098, 1076, 772, 701 cmꢀ1; HRMS (CI) calcd for
[C18H15N2O4]+ ([MꢀH]+) 323.1032, found: 323.1036.
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀacetamidomalonate (3)
Following the procedure (A) on regitzꢀdiazo transfer and NꢀH insertion via rhodium carbenoid, the title
compound 3 was obtained as a white solid (50% yield). mp 120.3 °C; 1HꢀNMR (400 MHz, CDCl3) δ 7.33 ~ 7.25
(m, 10H), 6.92 (s, 1H), 6.56 ~ 6.54 (d, 1H, J = 6.7 Hz), 5.20 ~ 5.18 (d, 1H, J = 7.0Hz), 2.01 (s, 3H), 1.33 (s, 9H)
ppm; 13CꢀNMR (125 MHz, CDCl3) δ 169.6, 165.9, 164.9, 139.2, 139.0, 128.5, 128.4, 128.2, 128.1, 127.3, 127.0,
83.8, 78.7, 57.2, 27.6, 22.6 ppm; IR (KBr) 3299, 2980, 1756, 1666, 1371, 772, 700 cmꢀ1; HRMS (FAB) calcd
for [C22H26NO5]+ ([M+H]+): 384.1811, found: 384.1803.
1ꢀBenzyl 3ꢀ(tertꢀbutyl) 2ꢀacetamidomalonate (4)
Following the procedure (A) from 2b using acetamide, the title compound 4 was obtained as a colorless oil (49%
yield). 1HꢀNMR (500 MHz, CDCl3) δ 7.33 ~ 7.29 (m, 5H), 6.54 ~ 6.53 (d, 1H, J = 5.8 Hz), 5.28 ~ 5.26 (d,1H, J
= 12.1 Hz), 5.13 ~ 5.10 (d, 1H, J = 12.1 Hz), 5.09 ~ 5.08 (d, 1H, J = 7.0 Hz), 2.03 (s, 3H), 1.33 (s, 9H) ppm;
13CꢀNMR (125 MHz, CDCl3) δ 169.7, 166.6, 165.0, 134.9, 128.5, 128.4, 83.8, 67.8, 57.0, 27.6, 22.7 ppm; IR
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(KBr) 3286, 2980, 2939, 1756, 1666, 1524, 1500, 1371, 1149, 1003, 770, 754, 699 cmꢀ1; HRMS (FAB) calcd for
[C16H22NO5]+ ([M+H]+) 308.1498, found: 308.1494.
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1ꢀBenzhydryl 3ꢀethyl 2ꢀacetamidomalonate (5)
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Following the procedure (A) from 2c using acetamide, the title compound 5 was obtained as a white solid (46%
yield). mp 106.1 °C; 1HꢀNMR (300 MHz, CDCl3) δ 7.36 ~ 7.24 (m, 10H), 6.90 (s, 1H), 6.60 ~ 6.57 (d, 1H, J =
7.0 Hz), 5.31 ~ 5.29 (d, 1H, J = 7.0 Hz), 4.21 ~ 4.14 (q, 2H, J = 7.2 Hz), 2.02 (s, 3H), 1.19 ~ 1.14 (t, 3H, J = 7.2
Hz) ppm; 13CꢀNMR (150 MHz, CDCl3) δ 169.7, 166.1, 165.5, 139.1, 138.9, 128.5, 128.4, 128.2, 128.2, 127.0,
127.0, 79.0, 62.7, 56.6, 22.6, 13.8 ppm; IR (KBr) 3284, 3063, 3033, 2983, 1760, 1743, 1666, 1221, 1158, 1028,
771, 700 cmꢀ1; HRMS (FAB) calcd for [C20H22NO5]+ ([M+H]+) 356.1498, found: 356.1489.
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀbenzamidomalonate (6)
Following the procedure (A) from 2a using benzamide, the title compound 6 was obtained as a colorless oil (37%
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yield). HꢀNMR (300 MHz, CDCl3) δ 7.84 ~ 7.81 (m, 2H), 7.55 ~ 7.20 (m, 13H), 7.13 ~ 7.11 (d, 1H, J = 6.6
Hz), 6.97 (s, 1H), 5.38 ~ 5.36 (d, 1H, J = 6.8Hz), 1.37(s, 1H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 166.8, 165.8,
164.9, 139.2, 139.0, 133.1, 132.0, 128.5, 128.5, 128.4, 128.2, 128.1, 127.3, 127.2, 127.0, 84.1, 78.9, 57.6, 27.6
ppm; IR (KBr) 3430, 2980, 1755, 1667, 1483, 1369, 1339, 1220, 1148, 772, 699 cmꢀ1; HRMS (FAB) calcd for
[C27H28NO5]+ ([M+H]+) 446.1967, found: 446.1967.
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀ[(tertꢀbutoxycarbonyl)amino]malonate (7)
Following the procedure (A) from 2a using tertꢀbutyloxycarboxamide, the title compound 7 was isolated as a
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pale yellow oil (30% yield). HꢀNMR (300 MHz, CDCl3) δ 7.30 ~ 7.21 (m, 10H), 6.89 (s, 1H), 5.52 ~ 5.49 (d,
1H, J = 7.3 Hz), 4.93 ~ 4.90 (d, 1H, J = 7.7Hz), 1.39 (s, 9H), 1.29 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ
166.1, 165.1, 154.7, 139.3, 139.2, 128.5, 128.4, 128.2, 128.1, 127.3, 127.1, 83.6, 80.4, 78.6, 58.4, 28.2, 27.6
ppm; IR (KBr) 3440, 2979, 2932, 1759, 1720, 1496, 1368, 1220, 1161, 772 cmꢀ1; HRMS (CI) calcd for
[C25H32NO6]+ ([M+H]+) 442.2230, found: 442.2229.
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀ{[(benzyloxy)carbonyl]amino}malonate (8)
Following the procedure (A) from 2a using benzyl carbamate, the title compound 8 was isolated as a colorless
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oil (32% yield). HꢀNMR (300 MHz, CDCl3) δ 7.33 ~ 7.24 (m, 15H), 6.93 (s, 1H), 5.81 ~ 5.78 (d, 1H, J = 7.5
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Hz), 5.10 (s, 2H), 5.06 ~ 5.01 (d, 1H, J = 7.53 Hz), 1.33 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 165.8,
164.8, 155.3, 139.2, 139.1, 136.01, 128.5, 128.5, 128.5, 128.2, 128.2, 128.1, 127.3, 127.1, 83.9, 78.8, 67.3, 58.6,
27.6 ppm; IR (KBr) 1759, 1730, 1622, 1497, 1339, 1220, 1148, 840, 772 cmꢀ1; HRMS (CI) calcd for
[C28H30NO6]+ ([M+H]+) 476.2073, found: 476.2071.
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀ{[(allyloxy)carbonyl]amino}malonate (9)
Following the procedure (A) from 2a using allylcarbamate, the title compound 9 was isolated as a colorless oil
(33% yield). 1HꢀNMR (500 MHz, CDCl3) δ 7.33 ~ 7.26 (m, 10H), 6.94 (s, 1H), 5.92 ~ 5.83 (m, 1H), 5.79 ~ 5.78
(d, 1H, J = 7.4 Hz), 5.31 ~ 5.28 (d, 1H, J = 17.2 Hz), 5.20 ~ 5.18(d, 1H, J = 10.4 Hz), 5.03 ~ 5.01(d, 1H, J =
7.7 Hz), 4.57 ~ 4.56(d, 2H, J = 5.4 Hz), 1.34(s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 165.8, 164.8, 155.2,
139.2, 139.0, 132.3, 128.5, 128.4, 128.2, 128.1, 127.3, 127.0, 83.9, 78.7, 66.1, 58.5, 27.6 ppm; IR (KBr) 2980,
1759, 1731, 1648, 1497, 1220, 1148, 1059, 772, 700 cmꢀ1; HRMS (FAB) calcd for [C24H28NO6]+ ([M+H]+)
426.1917, found: 426.1931.
1ꢀBenzyl 3ꢀ(tertꢀbutyl) 2ꢀacetamidoꢀ2ꢀbenzylmalonate (4e)
Following the procedure (B) from 4, the title compound 4e was obtained as a colorless oil (92% yield). 1HꢀNMR
(300 MHz, CDCl3) δ 7.40 ~ 7.30 (m, 5H), 7.21 ~ 7.18 (m, 3H), 7.00 ~ 6.94 (m, 2H), 6.50 (s, 1H), 5.29 ~ 5.25
(d,1H, J = 12.0 Hz), 5.17 ~ 5.13 (d, 1H, J = 12.0 Hz), 3.68 ~ 3.63 (d, 1H, J = 14.0 Hz), 3.58 ~ 3.53 (d, 1H,
J=14.0Hz), 1.99 (s, 3H), 1.32 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 169.0, 167.6, 166.1, 135.3, 135.0,
123.0, 128.9, 128.5, 128.5, 128.1, 127.0, 83.9, 67.9, 67.4, 37.6, 27.6, 23.0 ppm; IR (KBr) 3412, 2979, 2933,
1739, 1681, 1496, 1370, 1217, 1198, 1150, 1048, 771, 701 cmꢀ1; HRMS (FAB) calcd for [C23H28NO5]+ ([M+H]+)
398.1967, found: 398.1966; The enantioselectivity was determined by chiral HPLC analysis (DAICEL
Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time;
minor isomer 6.99 min, major isomer 8.03 min, 47% ee, [α]25D = +6.92 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀethyl 2ꢀacetamidoꢀ2ꢀbenzylmalonate (5e)
Following the procedure (B) from 5, the title compound 5e was obtained as a white solid (95% yield). mp
120.0 °C; 1HꢀNMR (300 MHz, CDCl3) δ 7.39 ~ 7.21 (m, 10H), 7.21 ~ 7.10 (m, 3H), 6.96 ~ 6.92 (s, 1H), 6.82 ~
6.79(d, 2H, J = 6.4 Hz), 6.53 (s, 1H), 4.16 ~ 4.08 (q, 2H, J = 7.1 Hz), 3.73 ~ 3.63 (m, 2H), 1.99 (s. 3H), 1.13 ~
1.08 (t, 3H, J = 7.1 Hz) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 169.0, 167.3, 166.6, 139.1, 138.9, 135.0, 129.8,
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128.6, 128.4, 128.4, 128.2, 128.1, 127.7, 127.1, 126.9, 78.9, 67.3, 62.7, 37.7, 22.9, 13.8 ppm; IR (KBr) 3411,
3032, 2983, 1742, 1680, 1496, 1281, 1218, 1196, 771, 701 cmꢀ1; HRMS (FAB) calcd for [C27H28NO5]+ ([M+H]+)
446.1967, found: 446.1976; The enantioselectivity was determined by chiral HPLC analysis (DAICEL
Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time;
minor isomer 16.38 min, major isomer 32.22 min, 59% ee, [α]25D = +16.8 (c 1.0, CHCl3).
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀbenzamidoꢀ2ꢀbenzylmalonate (6e)
Following the procedure (B) from 6, the title compound 6e was obtained as a white solid (94% yield). mp
101.9 °C; 1HꢀNMR (300 MHz, CDCl3) δ 7.70 ~ 7.67 (m, 2H), 7.58 ~ 7.49 (m, 1H), 7.49 ~ 7.29 (m, 7H), 7.29 ~
7.20 (m, 6H), 7.19 ~ 7.09 (m, 3H), 7.05 (s, 1H), 6.93 ~ 6.91 (d, 2H, J = 6.6 Hz), 3.88 ~ 3.83 (d,1H, J = 14.1 Hz),
3.76 ~ 3.71 (d, 1H, J = 14.1 Hz), 1.28 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 166.9, 166.2, 166.2, 139.2,
139.1, 135.2, 133.8, 131.8, 130.1, 128.5, 128.5, 128.3, 128.2, 128.2, 128.1, 128.0, 127.8, 127.0, 127.0, 84.2,
78.5, 67.7, 37.6, 27.6 ppm; IR (KBr) 3415, 3032, 3006, 2979, 1734, 1667, 1508, 1479, 1287, 1219, 1201, 1150,
839, 772, 700 cmꢀ1; HRMS (FAB) calcd for [C34H34NO5]+ ([M+H]+) 536.2437, found: 536.2439; The
enantioselectivity was determined by chiral HPLC analysis (DAICEL Chiralcel ODꢀH, hexane : 2ꢀpropanol =
99 : 1, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 9.85 min, major isomer 11.26
min, 82% ee, [α]25D = + 15.03 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀbenzylꢀ2ꢀ((tertꢀbutoxycarbonyl)amino)malonate (7e)
Following the procedure (B) from 7, the title compound 7e was obtained as a white solid (98% yield). mp
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104.0 °C; HꢀNMR (300 MHz, CDCl3) δ 7.34 ~ 7.18 (m, 10H), 7.11 ~ 7.05 (m, 3H), 6.93 (s, 1H), 6.82 ~ 6.80
(m, 2H), 5.56 (s, 1H), 3.63 ~ 3.58 (d,1H, J = 14.0 Hz), 3.52 ~ 3.47 (d, 1H, J = 14.0 Hz), 1.35 (s, 9H), 1.19 (s,
9H); 13CꢀNMR (125 MHz, CDCl3) δ 167.2, 166.2, 153.8, 139.3, 135.4, 130.1, 128.6, 128.3, 128.1, 128.0, 127.1,
83.6, 80.0, 78.5, 67.3, 38.2, 28.36, 27.6 ppm; IR (KBr) 3410, 2927, 1736, 1682, 1370, 1219, 772, 700 cmꢀ1,
HRMS (CI) calcd for [C32H38NO6]+ ([M+H]+) 532.2699, found: 532.2703; The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 85 : 15, flow rate = 1.0
mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 8.55 min, major isomer 10.16 min, 80% ee, [α]25
+11.67 (c 1.0, CHCl3).
=
D
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀbenzylꢀ2ꢀ(((benzyloxy)carbonyl)amino)malonate (8e)
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Following the procedure (B) from 8, the title compound 8e was obtained as a colorless oil (85% yield). 1HꢀNMR
(300MHz, CDCl3) δ 7.37 ~ 7.24 (m, 15H), 7.17 ~ 7.04 (m, 3H), 6.98 (s, 1H), 6.81 ~ 6.79 (d, 2H, J = 6.96 Hz),
6.00 (s, 1H), 5.15 ~ 5.11 (d,1H, J = 12.3 Hz), 5.02 ~ 4.98 (d, 1H, J = 12.3 Hz), 3.68 ~ 3.63 (d,1H, J = 14.1 Hz),
3.60 ~ 3.55 (d, 1H, J = 14.1 Hz), 1.22 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 166.9, 165.9, 154.3, 139.2,
139.1, 136.4, 135.0, 130.0, 128.6, 128.5, 128.3, 128.1, 128.1, 128.0, 127.9, 127.1, 126.9, 83.9, 78.6, 67.7, 66.8,
38.0, 27.5 ppm; IR (KBr) 3421, 2979, 2932, 1727, 1496, 1286, 1261, 1219, 1150, 1023, 772, 699 cmꢀ1; HRMS
(CI) calcd for [C35H36NO6]+ ([M+H]+) 566.2543, found: 566.2548; The enantioselectivity was determined by
chiral HPLC analysis (DAICEL Chiralcel ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C,
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λ = 254 nm, retention time; minor isomer 13.42 min, major isomer 16.37 min, 87% ee, [α]25 = +15.63 (c 1.0,
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CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀ(((allyloxy)carbonyl)amino)ꢀ2ꢀbenzylmalonate (9e)
Following the procedure (B) from 9, the title compound 9e was obtained as a colorless oil (93% yield). 1HꢀNMR
(300 MHz, CDCl3) δ 7.37 ~ 7.26 (m, 10H), 7.20 ~ 7.10 (m, 3H), 6.98 (s, 1H), 6.92 ~ 6.89 (m, 2H), 6.00 (s, 1H),
5.94 ~ 5.81(m, 1H), 5.31 ~ 5.28 (d, 1H, J = 17.1 Hz), 5.22 ~ 5.18 (d, 1H, J = 11.0Hz), 4.60 ~ 4.45 (m, 2H), 3.70
~ 3.65 (d, 1H, J = 14.2 Hz), 3.61 ~ 3.56 (d, 1H, J=14.2Hz), 1.25 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ
166.9, 165.9, 154.2, 139.2, 139.2, 135.0, 132.6, 130.1, 128.6, 128.3, 128.1, 128.0, 127.9, 127.6, 127.1, 127.0,
117.8, 84.0, 78.5, 67.6, 65.6, 38.0, 27.5 ppm; IR (KBr) 3421, 2925, 2854, 1728, 1495, 1258, 1219, 1150, 1095,
1027, 772 cmꢀ1; HRMS (FAB) calcd for [C31H34NO6]+ ([M+H]+) 516.2386, found: 516.2396; The
enantioselectivity was determined by chiral HPLC analysis (DAICEL Chiralcel ADꢀH, hexane : 2ꢀpropanol =
80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 8.83 min, major isomer 13.71
min, 87% ee, [α]25D = +16.16 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) 2ꢀacetamidoꢀ2ꢀhexylmalonate (3a)
Following the procedure (B), the title compound 3a was obtained as a white solid (26% yield). mp 90.9 °C; 1Hꢀ
NMR (300 MHz, CDCl3) δ 7.27 ~ 7.17 (m, 10H), 6.87 (s, 1H), 6.70 (s, 1H), 2.38 ~ 2.15 (m, 2H), 1.92 (s, 3H),
1.20 ~ 1.11 (m, 15H), 0.95 ~ 0.90 (s, 2H), 0.79 ~ 0.74 (t, 3H, J = 6.9 Hz) ppm; 13CꢀNMR (125 MHz, CDCl3) δ
168.7, 167.5, 167.0, 139.4, 139.3, 128.5, 128.3, 128.2, 128.0, 127.6, 127.3, 83.5, 78.3, 67.1, 32.1, 31.6, 28.9,
27.5, 23.4, 23.0, 22.5, 14.0 ppm; IR (KBr) 2956, 2926, 2856, 1738, 1682, 1496, 1219, 1155, 772 cmꢀ1; HRMS
(FAB) calcd for [C28H38NO5]+ ([M+H]+) 468.2750, found: 468.2764; The enantioselectivity was determined by
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(propꢀ2ꢀynꢀ1ꢀyl)malonate (3b)
Following the procedure (B), the title compound 3b was obtained as a white solid (99% yield). mp 135.2 °C;
1HꢀNMR (300 MHz, CDCl3) δ 7.31 ~ 7.18 (m, 10H), 6.91 ~ 6.88 (m, 2H), 3.37 ~ 3.30 (dd,1H, J1 = 17.2 Hz, J2 =
2.8 Hz), 3.21 ~ 3.15 (dd,1H, J1 = 17.2 Hz, J2 = 2.8 Hz) 1.96 (m, 3H), 1.87 ~ 1.85 (t, 1H, J = 2.66 Hz), 1.23 (s,
9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 169.2, 165.9, 165.3, 139.0, 128.4, 128.3, 128.1, 128.1, 127.5, 127.4,
84.4, 78.8, 78.4, 71.3, 65.7, 27.4, 23.7, 22.8 ppm; IR (KBr) 3413, 3294, 2979, 2926, 2854, 2122, 1740, 1682,
1496, 1314, 1218, 1151, 963, 772, 699, 648 cmꢀ1; HRMS(FAB) calcd for [C25H28NO5]+ ([M+H]+) 422.1967,
found: 422.1977; The enantioselectivity was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH,
hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 10.46
min, major isomer 25.78 min, 54% ee, [α]25D = +5.39 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀallylmalonate (3c)
Following the procedure (B), the title compound 3c was obtained as a white solid (99% yield). mp 71.9 °C; 1Hꢀ
NMR (300 MHz, CDCl3) δ 7.30 ~ 7.22 (m, 10H), 6.90 (s, 1H), 6.71 (s, 1H), 5.53 ~ 5.39 (m, 1H), 5.01 ~ 4.94 (m,
2H), 3.19 ~ 3.12 (m, 1H), 3.02 ~ 2.94 (m, 1H), 1.95 (s, 3H), 1.22 (m, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ
168.8, 166.9, 166.4, 139.2, 131.2, 128.5, 128.3, 128.2, 128.0, 127.6, 127.3, 119.7, 83.9, 78.5, 66.5, 36.8, 27.6,
22.9 ppm; IR (KBr) 3408, 2926, 1736, 1683, 1496, 1219, 1154, 959, 772, 699 cmꢀ1; HRMS(FAB) calcd for
[C25H30NO5]+ ([M+H]+) 424.2124, found: 424.2111; The enantioselectivity was determined by chiral HPLC
analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm,
retention time; minor isomer 9.42 min, major isomer 19.04 min, 76% ee, [α]25D = +6.02 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(2ꢀmethylallyl)malonate (3d)
Following the procedure (B), the title compound 3d was obtained as a white solid (98% yield). mp 112.0 °C; 1Hꢀ
NMR (300 MHz, CDCl3) δ 7.32 ~ 7.20 (m, 10H), 6.90 (s, 1H), 6.76 (s, 1H), 4.74 (m, 1H), 4.56 (s, 1H), 3.19 ~
3.14 (d, 1H, J = 14.2 Hz), 3.04 ~ 2.99 (d, 1H, J = 14.2 Hz), 1.93 (s, 3H), 1.55 (s, 3H), 1.20 (s, 9H) ppm; 13Cꢀ
NMR (125 MHz, CDCl3) δ 168.8, 167.3, 166.7, 140.0, 139.3, 139.1, 128.4, 128.3, 128.2, 128.0, 127.7, 127.3,
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115.8, 83.9, 78.5, 66.6, 39.6, 27.5, 23.3, 22.9 ppm; IR (KBr) 3413, 2979, 1736, 1682, 1370, 1277, 1219, 841,
772 cmꢀ1; HRMS (FAB) calcd for [C26H32NO5]+ ([M+H]+) 438.2280, found: 438.2277; The enantioselectivity
was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate =
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= +8.16 (c 1.0, CHCl3).
1ꢀBenzhydryl 1,2ꢀdiꢀtertꢀbutyl (R)ꢀ1ꢀacetamidoethaneꢀ1,1,2ꢀtricarboxylate (3e)
Following the procedure (B), the title compound 3e was obtained as a white solid (67% yield). mp 120.5 °C; 1Hꢀ
NMR (300 MHz, CDCl3) δ 7.28 ~ 7.18 (m, 10H), 6.96 (s, 1H), 6.88 (s, 1H), 3.50 ~ 3.32 (dd, 2H, J1 = 36.7 Hz,
J2 = 17.3 Hz), 1.91 (s, 3H), 1.29 (s, 9H), 1.19 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 169.4, 169.2, 166.3,
165.4, 139.2, 139.1, 128.4, 128.4, 128.1, 128.1, 127.4, 127.4, 83.9, 81.3, 78.7, 64.5, 38.7, 27.9, 27.4, 28.9 ppm;
IR (KBr) 3413, 2979, 1682, 1153, 772, 2926, 1741, 1496, 1370, 1220, 961, 700 cmꢀ1; HRMS (FAB) calcd for
[C28H36NO7]+ ([M+H]+) 498.2492, found: 498.2483; The enantioselectivity was determined by chiral HPLC
analysis (DAICEL Chiralcel ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm,
retention time ; minor isomer 20.34 min, major isomer 41.45 min, 67% ee, [α]25D = –2.97 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀbenzylmalonate (3f)
Following the procedure (B), the title compound 3f was obtained as a white solid (97% yield). mp 164.5 °C; 1Hꢀ
NMR (400 MHz, CDCl3) δ 7.41 ~ 7.26 (m, 10H), 7.17 ~ 7.11 (m, 3H), 6.98 (s, 1H), 6.87 ~ 6.85 (d, 2H, J = 6.4
Hz), 6.53 (s, 1H), 3.73 ~ 3.69 (d, 1H, J = 14.0 Hz), 3.63 ~ 3.59 (d, 1H, J = 14.0 Hz), 1.96 (s, 3H), 1.28 (s, 9H)
ppm; 13CꢀNMR (125 MHz, CDCl3) δ 168.9, 167.0, 166.1, 139.2, 139.1, 135.3, 130.0, 128.6, 128.3, 128.1, 128.0,
128.0, 127.2, 127.0, 84.0, 78.7, 67.6, 37.6, 27.6, 23.0 ppm; IR (KBr) 3410, 2927, 1736, 1682, 1370, 1219, 772,
700 cmꢀ1; HRMS (CI) calcd for [C29H32NO5]+ ([M+H]+) 474.2280, found: 474.2277; The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0
mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 10.20 min, major isomer 17.04 min, 95% ee, [α]25
+23.06 (c 1.0, CHCl3).
=
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(4ꢀmethylbenzyl)malonate (3g)
Following the procedure (B), the title compound 3g was obtained as a white solid (99% yield). mp 165.6 °C; 1Hꢀ
NMR (300 MHz, CDCl3) δ 7.35 ~ 7.18 (m, 10H), 6.91 ~ 6.86 (m, 3H), 6.69 ~ 6.66 (m, 2H), 6.46 (s, 1H), 3.63 ~
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3.58 (d, 1H, J = 14.0 Hz), 3.52 ~ 3.47 (d, 1H, J = 14.0 Hz), 2.19 (s, 3H), 1.90 (s, 3H), 1.21(m, 9H) ppm; 13Cꢀ
NMR (125 MHz, CDCl3) δ 168.9, 167.1, 168.2, 139.2, 139.1, 136.5, 132.1, 129.8, 128.8, 128.6, 128.3, 128.0,
127.9, 127.2, 83.9, 78.6, 67.6, 37.2, 27.6, 23.0, 21.0 ppm; IR (KBr) 3416, 2925, 1736, 1683, 1281, 1220, 1150,
772 cmꢀ1, HRMS (FAB) calcd for [C30H33NO5]+([M+H]+) 488.2437, found: 488.2441; The enantioselectivity
was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate =
1.0 mL/min, 23 °C, λ = 254 nm, retention time ; minor isomer 11.53 min, major isomer 17.09 min, 97% ee,
[α]25D = +22.59 (c 1.0, CHCl3).
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(4ꢀ(trifluoromethyl)benzyl)malonate (3h)
Following the procedure (B), the title compound 3h was obtained as a white solid (95% yield). mp 158.5 °C;
1HꢀNMR (300 MHz, CDCl3) δ 7.41 ~ 7.25 (m, 12H), 6.98 (s, 1H), 6.93 ~ 6.90 (d, 2H, J = 8.0 Hz), 6.53 (s, 1H),
3.77 ~ 3.65 (dd, 2H, J1 = 22.2 Hz, J2 = 14.0 Hz), 1.97 (s, 3H), 1.28 (s, 9H) ppm; 13CꢀNMR (100 MHz, CDCl3) δ
169.1, 166.8, 165.83 139.5, 138.9, 130.3, 129.3 (d, J = 32.4 Hz) 128.7, 128.4, 128.3 (d, J = 40.5 Hz), 128.0,
127.1, 125.0 (q, J = 3.5 Hz), 84.3, 78.9, 67.4, 37.4, 27.6, 22.9 ppm; IR (KBr) 3410, 3298, 2981, 1737, 1676,
1371, 1326, 1219, 1165, 772, 699 cmꢀ1; HRMS (FAB) calcd for [C30H31F3NO5]+ ([M+H]+) 542.2154, found:
542.2153; The enantioselectivity was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane :
2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 8.26 min, major
isomer 14.10 min, 95% ee, [α]25D = +25.74 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(4ꢀ(tertꢀbutyl)benzyl)malonate (3i)
Following the procedure (B), the title compound 3i was obtained as a white solid (99% yield). mp 156.5 °C;1Hꢀ
NMR (300 MHz, CDCl3) δ 7.53 ~ 7.34 (m, 10H), 7.27 ~ 7.23 (m, 2H), 7.09 (s, 1H), 6.92 ~ 6.90 (m, 2H), 6.66 (s,
1H), 3.81 ~ 3.76 (d, 1H, J = 14.1 Hz), 3.71 ~ 3.66 (d, 1H, J = 14.1 Hz), 2.08 (s, 3H), 1.38ꢀ1.36 (m, 18H) ppm;
13CꢀNMR (125 MHz, CDCl3) δ 168.9, 167.1, 166.2, 149.7, 139.3, 139.1, 132.1, 129.7, 128.6, 128.3, 128.3,
128.0, 127.9, 127.3, 125.0, 83.9, 78.6, 67.6, 37.1, 34.3, 31.3, 27.6, 23.0 ppm; IR (KBr) 3410, 2963, 2927, 1736,
1676, 1496, 1369, 1219, 772 cmꢀ1; HRMS (FAB) calcd for [C33H40NO5]+ ([M+H]+) 530.2906, found: 530.2902;
The enantioselectivity was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol
= 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 6.88 min, major isomer
11.26 min, 95% ee, [α]25D = +22.86 (c 1.0, CHCl3).
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(3ꢀmethoxybenzyl)malonate (3j)
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Following the procedure (B), the title compound 3j was obtained as a white solid (96% yield). mp 130.5 °C; 1Hꢀ
NMR (300 MHz, CDCl3) δ 7.41 ~ 7.29 (m, 10H), 7.07 ~ 7.02 (t, 1H, J = 7.9 Hz), 6.98 (s, 1H), 6.73 ~ 6.70 (m,
1H), 6.56 (s, 1H), 6.48 ~ 6.44 (m, 2H), 3.72 ~ 3.56 (m, 5H), 1.96 (s, 3H), 1.26 (s, 9H) ppm; 13CꢀNMR (125 MHz,
CDCl3) δ 168.9, 167.0, 166.1, 159.3, 139.2, 139.1, 136.8, 129.0, 128.6, 128.3, 128.3, 128.0, 127.7, 127.3, 122.3,
115.6, 112.6, 84.0, 78.6, 67.5, 54.9, 37.7, 27.6, 23.0 ppm; IR (KBr) 2984, 1736, 1676, 1370, 1220, 1151, 1043,
772 cmꢀ1; HRMS (FAB) calcd for [C30H34NO6]+ ([M+H]+) 504.2386, found: 504.2395; The enantioselectivity
was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate =
1.0 mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 11.56 min, major isomer 20.53 min, 94% ee,
[α]25D = +15.05 (c 1.0, CHCl3).
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(4ꢀ(trifluoromethoxy)benzyl)malonate (3k)
Following the procedure (B), the title compound 3k was obtained as a white solid (91% yield). mp 130.5 °C;
1HꢀNMR (300 MHz, CDCl3) δ 7.40 ~ 7.22 (m, 10H), 6.97 ~ 6.94 (d, 3H, J = 9.2 Hz), 6.84 ~ 6.81 (d, 2H, J = 8.8
Hz), 6.55 (s, 1H), 3.71 ~ 3.59 (dd, 2H, J1` = 22.4 Hz, J2 = 14.1 Hz), 1.97 (s, 3H), 1.27 (s, 9H) ppm; 13CꢀNMR
(100 MHz, CDCl3) δ 169.0, 166.8, 165.9, 148.3 (d, J = 1.6 Hz), 139.0, 134.0, 131.3, 128.6, 128.4, 128.3 (d, J =
38.5 Hz), 128.0, 127.1, 120.5, 84.2, 78.8, 67.5, 36.9, 27.6, 23.0 ppm; IR (KBr) 2925, 1739, 1508, 1262, 1153,
839, 3411, 1680, 1220, 699 cmꢀ1; HRMS (FAB) calcd for [C30H31F3NO6]+ ([M+H]+) 558.2103, found: 558.2093.
The enantioselectivity was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol
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= 80 : 20, flow rate = 1.0 mL/min, 23 C, λ = 254 nm, retention time ; minor isomer 7.28 min, major isomer
11.90 min, 95 % ee, [α]25D = +24.73 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(4ꢀnitrobenzyl)malonate (3l)
Following the procedure (B), the title compound 3l was obtained as a white solid (99% yield). mp 168.8 °C; 1Hꢀ
NMR(300 MHz, CDCl3) δ 7.92 ~ 7.89 (d, 2H, J = 8.6 Hz), 7.34 ~ 7.19 (m, 10H), 6.92 ~ 6.86 (t, 3H, J = 9.1 Hz),
6.47 (s, 1H), 3.75 ~ 3.65 (dd, 2H, J1 = 18.3 Hz, J2 = 14.1 Hz), 1.93 (s, 3H), 1.24 (s, 9H) ppm; 13CꢀNMR (125
MHz, CDCl3) δ 169.2, 166.6, 165.7, 147.1, 143.2, 138.8, 138.8, 130.8, 128.8, 128.7, 128.5, 128.2, 128.1, 127.7,
127.1, 123.8, 123.3, 84.5, 79.1, 67.3, 37.5, 31.9, 29.7, 29.4, 27.6, 23.0, 22.7, 14.1 ppm; IR (KBr) 2979, 2925,
1738, 1522, 1348, 1219, 1149 cmꢀ1; HRMS (FAB) calcd for [C29H31N2O7]+ ([M+H]+) 519.2131, found:
519.2131; The enantioselectivity was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane :
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2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 23.37 min, major
isomer 37.80 min, 96% ee, [α]25D = +25.54 (c 1.0, CHCl3).
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(4ꢀfluorobenzyl)malonate (3m)
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Following the procedure (B), the title compound 3m was obtained as a white solid (99% yield). mp 154.4 °C;
1HꢀNMR (300 MHz, CDCl3) δ 7.40 ~ 7.24 (m, 10H), 6.96 (s, 1H), 6.84 ~ 6.74 (m, 4H), 6.52 (s, 1H), 3.69 ~ 3.56
(dd, 2H, J1 = 25.3 Hz, J2 = 14.3 Hz), 1.96 (s, 3H), 1.27 (m, 9H) ppm; 13CꢀNMR (100 MHz, CDCl3) δ 169.0,
166.9, 166.0, 162.0 (d, J = 243.8 Hz), 139.1, 139.0, 131.4 (d, J = 7.9 Hz), 131.0 (d, J = 3.1 Hz), 128.6, 128.4,
128.4, 128.1, 128.0, 127.2, 115.0 (d, J = 21.0 Hz), 114.9, 84.1, 78.8, 67.6, 36.8, 27.6, 23.0 ppm; IR (KBr) 3408,
2926, 1736, 1676, 1510, 1220, 1150, 841, 772 cmꢀ1; HRMS (FAB) calcd for [C29H31FNO5]+ ([M+H]+) 492.2186,
found: 492.2195. The enantio selectivity was determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH,
hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C, λ = 254 nm, retention time ; minor isomer 10.77
min, major isomer 16.01 min, 96 % ee, [α]25D = +23.41 (c 1.0, CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(4ꢀchlorobenzyl)malonate (3n)
Following the procedure (B), the title compound 3n was obtained as a white solid (86% yield). mp 158.9 °C;
1HꢀNMR (300 MHz, CDCl3) δ 7.39 ~ 7.26 (m, 10H), 7.09 ~ 7.06 (m, 2H), 6.96 (s, 1H), 6.74ꢀ6.72 (m, 2H), 6.52
(s, 1H), 3.68 ~ 3.55 (dd, 2H, J1 = 24.0 Hz, J2 = 14.1 Hz), 1.96 (s, 3H), 1.27 (s, 9H) ppm; 13CꢀNMR (125 MHz,
CDCl3) δ 169.0, 166.9, 165.9, 139.0, 139.0, 133.8, 133.0, 131.2, 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.1,
84.1, 78.8, 67.5, 37.0, 27.6, 23.0 ppm; IR (KBr) 3410, 2926, 1738, 1219, 1150, 1092, 2854, 1680, 1493, 772 cmꢀ
1 ; HRMS (FAB) calcd for [C29H31ClNO5]+ ([M+H]+) 508.1891, found: 508.1901. The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0
mL/min, 23 °C, λ = 254 nm, retention time ; minor isomer 11.76 min, major isomer 18.48 min, 97 % ee, [α]25
+ 20.33 (c 1.0, CHCl3).
=
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1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(4ꢀbromobenzyl)malonate (3o)
Following the procedure (B), the title compound 3o was obtained as a white solid (98% yield). mp 182.5°C; 1Hꢀ
NMR (300 MHz, CDCl3) δ 7.40 ~ 7.20 (m, 12H), 6.96 (s, 1H), 6.68 ~ 6.65 (m, 2H), 6.51 (s, 1H), 3.66 ~ 3.54
(dd, 2H, J1 = 23.3 Hz, J2 = 14.0 Hz), 1.95 (s, 3H), 1.27 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 169.0, 166.8,
165.9, 138.98, 138.96, 134.3, 131.6, 131.2, 128.6, 128.5, 128.4, 128.1, 128.0, 127.1, 121.1, 84.1, 78.8, 67.4,
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37.0, 27.6, 23.0 ppm; IR (KBr) 3408, 2924, 1736, 1676, 1491, 1370, 1219, 1149, 1012, 772 cmꢀ1; HRMS (FAB)
calcd for [C29H31BrNO5]+ ([M+H]+) 552.1386, found: 552.1381; The enantioselectivity was determined by
chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0 mL/min, 23 °C,
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λ = 254 nm, retention time; minor isomer 11.86 min, major isomer 19.32 min, 97% ee, [α]25 = +29.97 (c 1.0,
D
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CHCl3).
1ꢀBenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ(naphthalenꢀ2ꢀylmethyl)malonate (3p)
Following the procedure (B), the title compound 3p was obtained as a white solid (98% yield). mp 162.4 °C;
1HꢀNMR (300 MHz, CDCl3) δ 7.78 ~ 7.73 (m, 1H), 7.64 ~ 7.61 (d, 1H, J = 8.6 Hz), 7.56 ~ 7.52 (m, 1H), 7.46 ~
7.24 (m, 13H), 7.01 ~ 6.98 (m, 2H), 6.53 (s, 1H), 3.91 ~ 3.86 (d, 1H, J = 14.1 Hz), 3.81 ~ 3.76 (d, 1H, J = 14.1
Hz), 1.98 (s, 3H), 1.30 (s, 9H) ppm; 13CꢀNMR (125 MHz, CDCl3) δ 169.1, 167.0, 166.1, 139.2, 139.2, 133.2,
132.9, 132.4, 128.8, 128.7, 128.4, 128.4, 128.1, 128.1, 127.9, 127.6, 127.5, 127.5, 127.2, 125.9, 125.6, 84.0,
78.7, 67.8, 37.7, 27.6, 23.0, ppm; IR (KBr) 3331, 2978, 1736, 1667, 1496, 1298, 1219, 1151, 772, 700 cmꢀ1,
HRMS (FAB) calcd for [C33H34NO5]+ ([M+H]+) 524.2437, found: 524.2424; The enantioselectivity was
determined by chiral HPLC analysis (DAICEL Chiralpak ADꢀH, hexane : 2ꢀpropanol = 80 : 20, flow rate = 1.0
mL/min, 23 °C, λ = 254 nm, retention time; minor isomer 12.11 min, major isomer 19.45 min, 91% ee, [α]25
+29.48 (c 1.0, CHCl3).
=
D
(R)ꢀ2ꢀAcetamidoꢀ2ꢀbenzylꢀ3ꢀ(tertꢀbutoxy)ꢀ3ꢀoxopropanoic acid (15)
Palladium carbon (5 mol%) was added to a stirred solution of 1ꢀbenzhydryl 3ꢀ(tertꢀbutyl) (R)ꢀ2ꢀacetamidoꢀ2ꢀ
benzylmalonate (3f, 300 mg, 0.63 mmol) in methanol (20 mL) under hydrogen gas. After being stirred for 2 ~ 4
hours, the substrate spot disappeared on TLC. The reaction mixture was filtered through a pad of celite and the
filtrate was concentrated. The residue was purified by flash column chromatography on silica gel eluting with
hexane/ EtOAc (3:1 ~ only EtOAc) to afford mono acid 15 as a white solid (98% yield). mp 135.7 °C; 1HꢀNMR
(500 MHz, CD3OD) 7.25 ~ 7.18 (m, 3H), 7.07 ~ 7.06 (d, 2H, J = 6.8 Hz), 3.57 ~ 3.49 (dd, 2H, J1 = 26.4 Hz, J2 =
13.9 Hz), 1.98 (s, 3H), 1.46 (s, 9H) ppm ; 13CꢀNMR (125 MHz, CD3OD) δ 173.1, 171.0, 168. 8, 137.9, 131.9,
130.0, 128.8, 84.8, 70.0, 39.4, 28.8, 23.3 ppm; IR (KBr) 3378, 3351, 2979, 2490, 1738, 1370, 1216, 1152, 757
cmꢀ1; HRMS (FAB) calcd for [C16H22NO5]+ ([M+H]+): 308.1498, found: 308.1497; [α]20 = –20.50 (c 1.0,
D
MeOH).
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The mono acid 15 (660 mg, 2.15 mmol) was dissolved in dry THF (9 mL) under argon atmosphere under ꢀ10 °C
which was maintained by acetone/ice (1:1) mixture. Then Nꢀmethylmorpholine (354 ꢁL, 3.22 mmol) and ethyl
chloroformate (307 ꢁL, 3.22 mmol) was added sequentially. Formation of azlactone 16 took less than 15
minutes on TLC analysis. The reaction mixture was filtered for removal of NMM•HCl salt precipitate. All
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volatile were also removed under reduced pressure to afford 16 as a colorless oil. The H NMR spectroscopy
and high resolution mass spectrometry of the crude 16 could be obtained as soon as isolation. However, the 13
C
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NMR spectroscopy of 16 could not be obtained due to its low stability. HꢀNMR (300 MHz, CDCl3) δ 7.26 ~
7.23 (m, 3H), 7.17 ~ 7.14 (m, 2H), 3.45 ~ 3.32 (dd, 2H, J1 = 25.4 Hz, J2 = 13.7 Hz), 2.02 (s, 3H), 1.48 (s, 9H)
ppm; HRMS (FAB) calcd for [C16H20NO4]+ ([M+H]+) 290.1392, found: 290.1392.
tertꢀButyl (R)ꢀ2ꢀacetamidoꢀ2ꢀbenzylꢀ3ꢀhydroxypropanoate (17)
The title compound 17 was prepared by consecutive two reaction steps from 15. A solution of (R)ꢀ2ꢀacetamidoꢀ
2ꢀbenzylꢀ3ꢀ(tertꢀbutoxy)ꢀ3ꢀoxopropanoic acid (15, 500 mg, 1.63 mmol) in dry THF (7 mL) at –10 °C was stirred
for 15 minutes with Nꢀmethylmorpholine (268 ꢁL, 2.44 mmol) and ethyl chloroformate (232 ꢁL, 2.44 mmol).Nꢀ
methylmorpholine hydrochloride was removed by filtration and the clear organic solution containing the
intermediate 16 was added over a period of 10 minutes to vigorously stirred suspension of sodium borohydride
(215 mg, 5.70 mmol) in H2O (2.5 mL) at 5 °C. The reaction was maintained for a further 3 hours at room
temperature until the TLC analysis showed that the reaction was completed. The mixture was then cooled to 0
oC, acidified to pH 2 with conc. HCl, diluted with water and extracted with diethyl ether (100mL x 2). The
organic phase was collected, dried over MgSO4, filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel eluting hexane/ EtOAc (1:2) to afford primary alcohol 17 as a white solid
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(398.8 mg, 84% yield). mp 142.7 °C; HꢀNMR (600 MHz, CDCl3) 7.24 ~ 7.19 (m, 3H), 7.09 ~ 7.07 (m, 2H),
6.38 (s, 1H), 4.31 ~ 4.29 (d,1H, J = 11.2 Hz), 3.86 ~ 3.84 (d, 1H, J = 11.2 Hz), 3.50 ~ 3.47 (d,1H, J = 13.7 Hz),
3.03 ~ 3.01 (d, 1H, J = 13.7 Hz), 1.96 (s, 3H), 1.45 (s, 9H) ppm; 13CꢀNMR (150 MHz, CDCl3) δ 170.8, 135.6,
129.8, 128.2, 127.0, 83.4, 67.6, 66.1, 36.6, 27.8, 24.0 ppm; IR (KBr) 3400, 2978, 1731, 1659, 1514, 1370, 1248,
1157, 741 cmꢀ1; HRMS (FAB) calcd for [C16H24NO4]+ ([M+H]+) 294.1705, found: 294.1706; [α]20D = +119.39 (c
1.0, CHCl3).
tertꢀButyl (R)ꢀ2ꢀacetamidoꢀ2ꢀbenzylꢀ3ꢀ((methylsulfonyl)oxy)propanoate (18)
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The title compound 18 was prepared by mesylation of primary alcohol 17. A solution of tertꢀbutyl (R)ꢀ2ꢀ
acetamidoꢀ2ꢀbenzylꢀ3ꢀhydroxypropanoate (17, 100 mg, 0.34 mmol) in dichloromethane (3 mL) at 0 °C was
stirred for 30 minutes with triethylamine (119 ꢁL, 0.85 mmol) and methanesulfonyl chloride (66 ꢁL, 0.85
mmol). The mixture was then diluted with dichloromethane and washed with saturated NH4Cl solution (25 mL)
and brine (25 mL). The organic phase was collected, dried over MgSO4, filtered, and concentrated. The residue
was purified by flash column chromatography on silica gel eluting hexane/ EtOAc (2:1) to afford mesylated
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compound 18 as a white solid (115 mg, 91% yield). mp 117.5 °C; HꢀNMR (400 MHz, CDCl3) 8.27 (bs, 1H),
7.30 ~ 7.27 (m, 5H), 4.57 ~ 4.48 (dd, 2H, J1 = 22.2 Hz, J2 = 11.8 Hz), 3.35 ~ 3.25 (dd, 2H, J1 = 24.1 Hz, J2 =
14.1Hz), 2.69 (s, 3H), 2.10 (s, 3H), 1.36 (s, 9H) ppm; 13CꢀNMR (100 MHz, CDCl3) δ 170.4, 166.7, 132.1,
130.5,. 128.8, 128.0, 85.1, 64.7, 63.7, 39.3, 38.5, 27.7, 20.6 ppm; IR (KBr) 3398, 3279, 2979, 2935, 1737, 1674,
1497, 1370, 1360, 1177, 1154, 989, 964, 838, 740, 704cmꢀ1; LRMS (FAB) calcd for [C17H26NO6S]+ ([M+H]+)
372, found: 372;[α]20D = +14.41 (c 1.0, CHCl3).
tertꢀButyl (R)ꢀ2ꢀacetamidoꢀ2ꢀbenzylꢀ3ꢀoxoꢀ3ꢀ{[(S)ꢀ1ꢀphenylethyl]amino}propanoate (19)
To the crude tertꢀbutyl (S)ꢀ4ꢀbenzylꢀ2ꢀmethylꢀ5ꢀoxoꢀ4,5ꢀdihydrooxazoleꢀ4ꢀcarboxylate (16, 95 mg, 0.33 mmol)
synthesized according to the method mentioned above were added catalytic amount of 4ꢀmethylamino pyridine
(10 mol%) and anhydrous dichloromethane (1 mL). An excess of (S)ꢀ(ꢀ)ꢀαꢀmethylbenzylamine (2 mL, 16 mmol)
was added to open the azlactone ring structure. After being stirred for 1hour at room temperature, the reaction
mixture was acidified with 6N HCl in ice bath. The crude residue was purified by column chromatography on
silica gel (Hexane : EtOAc = 5:1 as eluent) and subsequent recrystallization (Hexane : EtOAc = 6:1 solvent
system at room temperature) yielded stereochemically pure amide 19 as a white solid (129.6 mg, 96% yield).
For your information; In case of reaction starting from racemic mixture of 15, the diastereomer bearing the
different αꢀconfiguration appeared right below the title isomer 19 on TLC analysis. mp 122.5 °C; 1HꢀNMR (300
MHz, CDCl3) δ 7.35 ~ 7.25 (m, 8H), 7.10 ~ 7.07 (m, 2H), 6.78 (s, 1H), 6.52 ~ 6.49 (d, 1H, J = 7.9 Hz), 5.14 ~
5.04 (p, 1H, J = 7.2 Hz), 3.82 ~ 3.78 (d, 1H, J = 14.0 Hz), 3.51 ~ 3.46 (d, 1H, J = 14.0 Hz), 1.98 (s, 3H). 1.57 ~
1.55 (d, 3H, J = 7.2 Hz), 1.37 (s, 9H) ppm; 13CꢀNMR (150 MHz, CDCl3) δ 169.0, 169.0, 165.4, 142.3, 135.3,
129.9, 128.6, 128.1, 127.5, 127.1, 125.9, 83.5, 67.4, 49.3, 38.6, 27.5, 23.1, 21.3 ppm; IR (KBr) 3353, 2978,
2927, 1731, 1496, 1155, 772 cmꢀ1; HRMS (FAB) calcd for [C24H31N2O4]+ ([M+H]+) 411.2284, found: 411.2285;
[α]25D = –35.86 (c 1.0, CHCl3).
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(R)ꢀαꢀBenzylserine
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tertꢀButyl (R)ꢀ2ꢀacetamidoꢀ2ꢀbenzylꢀ3ꢀhydroxypropanoate (17, 235 mg, 0.80 mmol) was dispersed in 6N HCl
(12 mL) and methanol (3 mL) and refluxed for 2 days. The mixture was diluted with water (50 mL) and washed
with EtOAc (50 mL x 2). The aqueous layer was concentrated and purified by ionꢀexchange column
chromatography through DOWEX® 50WX8ꢀ100 column eluting with 15% aqueous NH4OH to afford (R)ꢀαꢀ
benzylserine as a white solid (143.5 mg, 92% yield, decomposed around at 230 °C). 1HꢀNMR (500 MHz, D2O)
7.34 ~ 7.27 (m, 3H), 7.20 ~ 7.18 (m, 2H), 3.98 ~ 3.95 (d, 1H, J = 12.0 Hz), 3.71 ~ 3.69 (d, 1H, J = 12.0 Hz),
3.19 ~ 3.16 (d, 1H, J = 14.3 Hz), 2.90 ~ 2.87 (d, 1H, J = 14.3 Hz) ppm; 13CꢀNMR (125 MHz, D2O) δ 174.0,
133.9, 130.3, 129.4, 128.3, 67.4, 64.5, 38.2 ppm; IR (ATR) 3240, 3141, 2844, 2771, 1593, 1492, 1389, 1055,
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697 cmꢀ1; HRMS (FAB) calcd for [C10H14NO3]+ ([M+H]+) 196.0974, found: 196.0978. [α]20 = –15.50 (c 1.0,
D
H2O) {lit S3 (S)ꢀαꢀbenzylserine, [α]D20 = +16.4 (c 0.80, H2O), 98% ee}.
tertꢀButyl (R)ꢀ4ꢀbenzylꢀ2ꢀmethylꢀ4,5ꢀdihydrooxazoleꢀ4ꢀcarboxylate (20)
The methanesulfonate 18 (100 mg, 0.27 mmol) was dissolved in dichloromethane (20 mL) and stirred for over 3
hours with silica gel under reflux. The mixture was then evaporated and then yielded silica gel powder coated
with organic compounds including desired product 20, which silica gel was loaded into column chromatography
directly. Eluting solvent (Hexane : EtOAc = 1: 1), the cyclized product from 18 was obtained successfully. (71%
yield). 1HꢀNMR (300 MHz, CDCl3) 7.30 ~ 7.19 (m, 5H), 4.50 ~ 4.47 (d, J = 9.0 Hz), 4.14 ~ 4.11 (d, J = 9.0 Hz),
3.11 (s, 2H), 1.92 (s, 3H), 1.46 (s, 9H) ppm; 13CꢀNMR (100 MHz, CDCl3) δ 171.5, 166.0, 135.6, 130.3, 128.1,
126.9, 82.1, 78.4, 72.7, 43.1, 27.9, 13.8 ppm; IR (KBr) 3433, 2979, 2931, 1726, 1670, 1369, 1256, 1163, 1096,
994, 915, 703, 618 cmꢀ1; HRMS (FAB) calcd for [C16H22NO3]+ ([M+H]+) 276.1600, found: 276.1609; [α]20D = –
47.28 (c 1.0, CHCl3).
Acknowledgements
This work was supported by grants from the National Research Foundation of Korea (No. 2012ꢀ002956 &No.
201000017).
Supporting Information
Spectral data of all new compounds as well as an Xꢀray crystallographic analysis of (R,S)ꢀ19 and copies of
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NMR and HPLC analysis graph of optimized conditions. This material is available free of charge via the
Internet at http://pubs.acs.org.
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References
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BelleminꢀLaponnaz, S.; Wadepohl, H.; Gade, L. H. Chem. Eur. J. 2007, 13, 9912; m) Comelles, J.; Pericas, À.;
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(13) CCDC 1045693 contain the supplementary crystallographic data for compound 19. The data can be
obtained
free
of
charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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