Enantioselective desymmetrization of diesters

Article abstract of DOI:10.1021/jo402853v

The desymmetrization of prochiral diesters with a chiral phosphoric acid catalyst to produce highly enantioenriched lactones in excellent yield is reported. The process is easily scaled and accommodates a variety of substitution patterns, many of which result in the generation of an enantioenriched all-carbon quaternary center. Manipulation of lactone product to useful small building blocks is also described.

Full text of DOI:10.1021/jo402853v

Note
pubs.acs.org/joc
Enantioselective Desymmetrization of Diesters
Jennifer Wilent and Kimberly S. Petersen*
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina 27402, United
States
S
* Supporting Information
ABSTRACT: The desymmetrization of prochiral diesters
with a chiral phosphoric acid catalyst to produce highly
enantioenriched lactones in excellent yield is reported. The
process is easily scaled and accommodates a variety of
substitution patterns, many of which result in the generation
of an enantioenriched all-carbon quaternary center. Manipu-
lation of lactone product to useful small building blocks is also described.
Scheme 1. Previously Reported Desymmetrization of Diester
he desymmetrization of prochiral molecules to yield
enantioenriched products is a powerful tool in asymmetric
T
synthesis.1 In particular, the desymmetrization of diesters
through an enzyme-mediated partial hydrolysis is a strategy that
has been widely used.2 However, biocatalyzed reactions are
often hampered by poor selectivity and catalyst instability as
well as difficulties with recovery and reuse.
The lactone motif is seen in many biologically active
molecules, and in particular, enantiopure lactones with a fully
substituted carbon α to the carbonyl are common. (+)-Hope-
ahainol A (1),3 which has proven to be an acetylcholinesterase
inhibitor that is associated with Alzheimer’s disease, and (S)-
camptothecin (2),4 which exhibits anticancer activity through
topoisomerase I inhibition, are two examples (Figure 1).
of silyl ketene acetals has been accomplished with chiral DMAP
derivatives,6 isothiourea,7 or thiourea catalysts;8 however,
results are limited to aryl R groups and/or a need for
disubstitution of the γ-carbon. Diastereoselective conjugate
addition of an enolate equivalent is another strategy that has
yielded some promising results, yet the scope of acceptable
Michael acceptors is limited.9 A recent desymmetrization of
diynoic acids via bromolactonization has yielded interesting
bromoenol lactones; however, scope of the reaction is again
limited.10 Most recently, a method for the enantioselective α-
alkylation of α-tert-butoxycarbonyllactones through phase-
transfer catalysis was revealed; however, substitution was
limited to benzylic or allylic groups.11 The methodology
described here, whereby a chiral Brønsted acid 5 catalyzes the
cyclization of a symmetric substrate to deliver an enantio-
enriched lactone, takes advantage of our previously established
ester activation by a chiral acid and thus differentiation of the
two enantiotopic groups. The lactone products obtained
through variation of the methyl group to other substitution
patterns are valuable compounds potentially carrying a
challenging all-carbon quaternary center (when R ≠ H).
The synthesis of diester substrates such as 3a begins with the
monoalkylation of di-tert-butyl malonate (6) with sodium
hydride and methyl iodide. A second alkylation with 2-
Figure 1. Lactone natural products with an α-chiral center.
Due to our ongoing interest in the development of
enantioselective cyclizations, we have previously disclosed the
desymmetrization of hydroxy diester 3a to lactone 4a in the
presence of chiral Brønsted acid 5 in high yield and excellent
enantioselectivity (Scheme 1).5 Presumably, the reaction
proceeds through selective activation of one of the esters
with the chiral phosphoric acid followed by an intramolecular
transesterification. On the basis of this encouraging initial
result, we set out to explore the full scope of the
desymmetrization process and the utilization of the lactone
product.
Construction of enantioenriched α-carboxy-γ-lactones such
as 4a containing a quaternary center has been previously
explored due to the high utility of such compounds. Acylation
Received: January 8, 2014
Published: February 7, 2014
© 2014 American Chemical Society
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bromoethyl acetate and subsequent hydrolysis yields hydroxy
diester 3a in three short steps and 52% overall yield (Scheme
2).
3a, but using the appropriate alkyl halide in the first alkylation
step. Gratifyingly, modification of the original methyl group in
3a with larger groups such as ethyl 3c, isopropyl 3d, allyl 3e,
and benzyl 3f yielded enantioenriched lactones containing an
all-carbon quaternary stereocenter that would be difficult to
install using other methodologies in good to excellent yields
(67−97%) and enantiopurity greater than 90%. Replacement of
the methyl group with a proton 3b generated lactone 4b in
excellent yield and good enantiopurity (93% yield and ee =
91%).
Scheme 2. Preparation of Prochiral Substrates
Based on the successful generation of enantioenriched γ-
lactones, the desymmetrization was expanded to include
preparation of a δ-lactone. Lactonization of the one-carbon
homologated hydroxyl diester 3g, which was prepared through
hydroboration and oxidation of methyl, allyl di-tert-butyl
malonate, occurred with the Brønsted acid chiral catalyst 5 in
dichloromethane at room temperature to yield lactone 4g in
good yield (84%) and selectivity (86%).
Variuos substrates (Table 1, 3b−3g) were studied, ranging in
length and branching. Each substrate was prepared as substrate
a
Table 1. Substrate Scope
In order to fully exploit the desymmetrization process,
lactone 4a was prepared on a 1.3 g scale from 1.9 g of 3a and 20
mg of catalyst 5, yielding lactone 4a in 95% yield and 98% ee.
Lactones with enantioenriched all-carbon containing stereo-
centers such as 4a prepared from prochiral diesters in good
yield and enantioselectivity are prime candidates for incorpo-
ration into more complex molecules. The utility of these highly
enantioenriched lactone substrates was shown through the
transformation of lactone (−)-4a into a variety of highly
functionalized building blocks (Scheme 3). Successful reduction
of lactone (−)-4a with lithium tri-tert-butoxyaluminum hydride
yielded diol (−)-7 in 92% yield and without loss of
enantiopurity (ee = 98%).12 Amide ester (−)-8 was formed
upon treatment of lactone 4a with the benzyl amine in 76%
yield and retention of 98% ee.13 Cleavage of the tert-butyl ester
of lactone 4a with TFA followed by conversion of the resulting
carboxylic acid to the acyl azide and subsequent Curtius
rearrangement yielded amido lactone (+)-9 in 56% overall yield
and 98% ee.14 Treatment of lactone 4a with aqueous
ammonium hydroxide followed by acetylation of the resulting
alcohol yielded an amide ester that then underwent a Hofmann
a
Typical reaction conditions: 0.4 mmol 3, 0.02 mmol catalyst (S)-5, in
5 mL of CH2Cl2 at set temperature and time. Yields are isolated yields
and % ee’s determined by GC analysis with a chiral support unless
indicated otherwise. Enantiomeric excess determined by HPLC
analysis with a chiral support column. Reaction carried out on 1.9 g of
b
c
d
4a with 20 mg of catalyst (S)-5. Catalyst used was (R)-5.
Scheme 3. Transformations
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0 °C, phases were separated, and aqueous phase was extracted EtOAc
(2 × 15 mL). The combined organic phases were dried over MgSO4
and concentrated. The residue was purified by flash chromatography
on silica gel (5→15% EtOAc in hexanes) to afford dialkylated
malonate (yields up to 90%).
rearrangement with lead(IV) acetate and hydrolysis with
potassium carbonate to give α-amino ester (+)-10 in 65%
overall yield and 96% ee.15
The absolute configuration of lactone products 4a−4g was
assigned through comparison of a known optical rotation value.
Diol (+)-11 is readily prepared from lactone (+)-4f, and the
sign of rotation matches literature values for (R)-11 (Scheme
4).
To a solution of the dialkylated intermediate (1 equiv) in MeOH (7
mL) was added K2CO3, and the solution was stirred at rt until reaction
completion was determined by TLC analysis. The reaction mixture
was diluted with CH2Cl2 and was extracted with CH2Cl2 (2 × 15 mL)
and H2O (1 × 10 mL). The organic layer was dried over MgSO4 and
concentrated. The residue was purified by flash chromatography on
silica gel (20→40% EtOAc in hexanes with 0.1% TEA) to afford
hydroxyl diester (yields up to 87%).
Scheme 4. Determination of Absolute Configuration
1
Compound 3a: colorless oil (0.26 g, 78% yield); H NMR (300
MHz, CDCl3) δ 3.69 (t, J = 6.3 Hz, 2H), 2.07 (t, J = 6.3 Hz, 2H), 1.47
(s, 18 H), 1.39 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 171.9, 81.4,
58.8, 38.1, 27.8, 20.1; IR (neat) cm−1 3440, 2974, 2934, 1723, 1456,
1367, 1156, 1113, 847; HRMS (C14H26O5, ESI) calcd 297.1677 [M +
Na]+, found 297.1667.
+
Compound 3b: colorless oil (0.28 g, 54% yield); H NMR (500
MHz, CDCl3) δ 3.71 (m, 2H), 3.34 (t, J = 15.6 Hz, 1H), 2.07 (m, 2
H), 1.96 (bs, 1H), 1.45 (s, 18H); 13C NMR (126 MHz, CDCl3) δ
169.1, 81.8, 60.7, 51.3, 31.5, 28.0; IR (neat) cm−1 3441, 2977, 2933,
1723, 1456, 1367, 1137, 843; HRMS (C13H24O5, ESI) calcd 283.1521
[M + Na]+, found 283.1523.
CONCLUSIONS
■
1
In summary, we have developed a highly generalized and
scalable desymmetrization of hydroxy di-tert-butyl esters to
produce enantioenriched lactones in high yields and
selectivities, many of which contain a challenging all-carbon
quaternary center that are difficult to prepare using other
methods. The lactone products readily undergo transforma-
tions to generate highly functionalized small molecules that are
potentially valuable intermediates in the synthesis of bioactive
molecules.
Compound 3c: a white crystal (0.31 g, 87% yield); H NMR (500
MHz, CDCl3) δ 3.65 (m, 2H), 2.07 (t, J = 6.6 Hz, 2H), 1.88 (m, q, J =
7.5 Hz, 2H), 1.44 (s, 18 H), 0.83 (t, J = 7.6 Hz, 3H); 13C NMR (126
MHz, CDCl3) δ 171.4, 81.3, 59.1, 57.7, 34.7, 27.9, 25.9, 8.6; IR (neat)
cm−1 3434, 2975, 2934, 1745, 1474, 1365, 1154, 1117, 851; HRMS
(C15H28O5, ESI) calcd 311.1834 [M + Na]+, found 311.1835.
1
Compound 3d: colorless oil (0.09 g, 46% yield); H NMR (500
MHz, CDCl3) δ 3.74 (m, 2H), 2.23 (m, 1H), 2.01 (t, J = 6.5 Hz, 2H),
1.46 (s, 18 H), 0.96 (d, J = 6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3)
δ 170.6, 82.1, 61.5, 59.5, 36.3, 33.3, 28.3, 18.2; IR (neat) cm−1 3004,
2936, 2356, 1712, 1475, 1365, 1147, 1066, 852; HRMS (C16H30O5,
ESI) calcd 325.1990 [M + Na]+, found 325.2001.
EXPERIMENTAL SECTION
■
1
Compound 3e: colorless oil (38 mg, 74% yield); H NMR (500
General Methods. Unless noted, all solvents and reagents were
obtained from commercial sources and used without further
purification; anhydrous solvents were dried following standard
procedures. The 1H and 13C nuclear magnetic resonance (NMR)
spectra were plotted on 400 and 500 MHz spectrometers using CDCl3
as a solvent at rt. The NMR chemical shifts (δ) are reported in parts
MHz, CDCl3) δ 5.63 (m, 1H), 5.08 (m, 2H), 3.67 (t, J = 6.6 Hz, 2H),
2.58 (d, J = 7.4 Hz, 2H), 2.05 (t, J = 6.6 Hz, 2H), 1.43 (s, 18 H); 13C
NMR (126 MHz, CDCl3) δ 170.1, 132.4, 118.8, 81.6, 59.0, 56.9, 37.8,
35.3, 27.3; IR (neat) cm−1 3010, 2943, 1736, 1477, 1364, 1260, 1142,
1074; HRMS (C16H28O5, ESI) calcd 323.1834 [M + Na]+, found
323.1826.
1
per million. Abbreviations for H NMR: s = singlet, d = doublet, m =
1
Compound 3f: colorless oil (0.24 g, 42% yield); H NMR (500
multiplet, b = broad, t = triplet, q = quartet, p = pentet. The reactions
were monitored by TLC using silica G F254 precoated plates. Flash
chromatography was performed using flash grade silica gel (particle
size: 40−63 μm, 230 × 400 mesh). Enantiomeric excess was
determined by GC analysis and HPLC analysis. IR data were obtained
with a FTIR spectrometer with frequencies reported in cm−1. High-
resolution mass spectra were acquired on an Orbitrap XL MS system.
The specific rotations were acquired on an analytical polarimeter.
Typical Procedure for Alkylations of Di-tert-butylmalonate.
To a solution of sodium hydride (60% in mineral oil, 1 equiv) in THF
(7 mL) was added di-tert-butyl malonate (1 equiv), and the solution
was stirred until gas evolution was complete. To the reaction mixture
was added alkyl halide (1 equiv), and the solution was stirred until
reaction completion was determined by TLC analysis.16 The reaction
was quenched with saturated NH4Cl (6 mL) at 0 °C, phases were
separated, and aqueous phase was extracted EtOAc (2 × 15 mL). The
combined organic phases were dried over MgSO4 and concentrated.
The residue was purified by flash chromatography on silica gel (5→
15% EtOAc in hexanes) to afford monoalkylated malonate (yields up
to 82%).
MHz, CDCl3) δ 5.03 (m, 5H), 3.75 (t, J = 6.6 Hz, 2H), 3.21 (s, 2H),
2.00 (t, J = 6.6 Hz, 2H), 1.47 (s, 18 H); 13C NMR (126 MHz, CDCl3)
δ 170.8, 138.4 130.3, 128.2, 126.9, 82.1, 59.3, 30.1, 35.5, 28.0; IR
(neat) cm−1 3321, 2971, 2963, 1758, 1471, 1330, 1116, 1045, 879;
HRMS (C20H30O5, ESI) calcd 373.1990 [M + Na]+, found 373.1987.
Compound 3g: To a solution of sodium hydride (60% in mineral
oil, 1.5 g, 38.2 mmol) in THF (10 mL) was added di-tert-butyl 2-
methylmalonate intermediate dropwise (4.4 g, 19.1 mmol), and the
solution was stirred for 10 min at rt. To the reaction mixture was
added allyl bromide (4.2 mL, 47.8 mmol) dropwise, and the solution
was stirred for 24 h at rt. The reaction was quenched with saturated
NH4Cl (7 mL) at 0 °C, phases were separated, and aqueous phase was
extracted EtOAc (2 × 15 mL). The combined organic phases were
dried over MgSO4 and concentrated to afford the di-tert-butyl 2-allyl-2-
1
methylmalonate intermediate): H NMR (500 MHz, CDCl3) δ 5.66
(m, 1H), 5.07 (m, 2H), 2.52 (m, 2H), 1.43 (s, 18H), 1.29 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 171.3, 133.1, 118.7, 81.1, 54.3, 40.1, 36.5,
27.9, 19.6.
The BH3-THF (1 M in THF, 0.74 mmol) was diluted with THF
(0.11 mL). To the solution was added di-tert-butyl 2-allyl-2-
methylmalonate intermediate (0.4 g) at 0 °C and allowed to warm
to rt. After 2.5 h, a NaOH solution (3 M, 0.89 mL) was added
followed by hydrogen peroxide (30 wt % in water, 0.3 mL, 2.87 mmol)
at 0 °C. The reaction mixture was stirred at 50 °C overnight. The
reaction mixture was extracted with Et2O (2 × 10 mL) and H2O (1 ×
To a solution of sodium hydride (60% mineral oil, 2 equiv) in THF
(7 mL) was added monoalkylated malonate intermediate, and the
solution was stirred until gas evolution was complete. To the reaction
mixture was added 2-bromoethyl acetate (2.5 equiv) at 0 °C, and the
solution was stirred until reaction completion was determined by TLC
analysis. The reaction was quenched with saturated NH4Cl (6 mL) at
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10 mL). The organic layer was dried over MgSO4 and concentrated.
The residue was purified by flash chromatography on silica gel (20→
40% EtOAc in hexanes with 0.1% TEA) to afford compound 3g as a
colorless oil (0.13 g, 31% yield): 1H NMR (500 MHz, CDCl3) δ 3.62
(m, 2H), 1.79 (m, 2H), 1.51 (m, 2H), 1.42 (s, 18H), 1.29 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 171.8, 81.1, 62.9, 54.34, 31.6, 27.9, 19.9;
IR (neat) cm−1 3442, 2970, 2929, 1720, 1457, 1366, 1150, 1112, 851;
HRMS (C15H28O5, ESI) calcd 311.1834 [M + Na]+, found 311.1825.
Typical Procedure for Enantioselective Lactonization of
Hydroxy Diester. To a solution of chiral acid catalyst 5 (0.05 mmol)
in CH2Cl2 (5 mL) was added hydroxy diester (1.0 mmol), and the
solution was stirred for the allocated time and temperature. The
reaction was extracted with EtOAc (2 × 10 mL) and H2O (1 × 10
mL). The organic phase was dried over MgSO4 and concentrated.
The residue was purified by flash chromatography on silica gel
(10→20% EtOAc in hexanes) to afford enantioenriched lactone
(yields up to 97%).
THF, 2 mL, 2.0 mmol) at −78 °C. The solution was allowed to warm
to rt and react for 24 h. The reaction was quenched with saturated
potassium sodium tartrate, phases were separated, and aqueous phase
was extracted with EtOAc (2 × 10 mL). The combined organic phases
were dried over MgSO4 and concentrated. The residue was purified by
flash chromatography on silica gel (20→40% EtOAc in hexanes) to
1
afford compound 7 as a colorless oil (94 mg, 92% yield): H NMR
(500 MHz, CDCl3) δ 4.23 (m, 2H), 3.48 (d, J = 8.6 Hz, 1H), 3.23 (d,
J = 8.0 Hz, 1H), 2.43 (m, 1H), 1.99 (m, 1H), 1.17 (s, 3H) 1.12 (s, 9
H); 13C NMR (126 MHz, CDCl3) δ 181.5, 73.6, 67.3, 65.9, 43.8, 32.8,
27.0, 20.3; IR (neat) cm−1 3436, 2976, 2930, 1722, 1456, 1367, 1146,
1103, 846; HRMS (C10H20O4, ESI) calcd 227.1259 [M + Na]+, found
23
227.1250; [α]D = −0.6 (c = 1.0, CHCl3).
Compound 8: To a solution of compound 4a (100 mg, 0.5 mmol)
in THF (5.0 mL) was added benzyl amine (0.27 mL, 2.5 mmol) at rt.
The solution was allowed to react under reflux for 4 days. The reaction
was acidified with 1 M HCl at 0 °C and extracted with Et2O (2 × 10
mL) and H2O (1 × 10 mL). The combined organic phases were dried
over MgSO4 and concentrated. The residue was purified by flash
chromatography on silica gel (15→30% EtOAc in hexanes) to afford
Compound 4a: Reaction was carried out at rt for 120 h to yield a
1
white crystal (184 mg, 97% yield); H NMR (300 MHz, CDCl3) δ
4.35 (m, 2H), 2.64 (m, 1H), 2.13 (m, 1H), 1.47 (s, 9 H), 1.46 (s, 3H);
13C NMR (126 MHz, CDCl3) δ 176.4, 169.5, 83.0, 65.9, 50.6, 35.2,
1
compound 8 as a colorless oil (90 mg, 77% yield): H NMR (500
27.8, 20.1; IR (neat) cm−1 2980, 1735, 1448, 1372, 1235, 1043; HRMS
MHz, CDCl3) δ 7.27 (m, 5H), 4.44 (d, J = 5.7 Hz, 2H), 3.7 (m, 2H),
2.15 (m, 2H), 1.46 (m, 3H) 1.44 (s, 9 H); 13C NMR (126 MHz,
CDCl3) δ 174.0, 172.2, 138.1, 128.7, 127.7, 127.5, 82.3, 59.4, 52.9,
43.6, 39.2, 27.7, 22.1; IR (neat) cm−1 3358, 2980, 2359, 1726, 1369,
1242, 1045; HRMS (C17H25NO4, ESI) calcd 308.1861 [M + H]+,
23
(C10H16O4, ESI) calcd 223.0946 [M + Na]+, found 223.0934; [α]D
−3.6 (c = 0.5, CHCl3).
=
Compound 4b: Reaction was carried out at 5 °C for 72 h to yield a
colorless oil (188 mg, 93% yield); 1H NMR (500 MHz, CDCl3) δ 4.43
(m, 1H) 4.30 (m, 1H), 3.42 (m, 1H), 2.59 (m, 1H), 2.46 (m, 1H),
1.48 (s, 9 H); 13C NMR (126 MHz, CDCl3) δ 172.9, 166.9, 83.1, 67.3,
47.0, 27.9, 26.5; IR (neat) cm−1 2980, 1772, 1725, 1369, 1138, 1016;
HRMS (C9H14O4, ESI) calcd 185.0813, [M − H]−, found 185.0807;
23
found 308.1866; [α]D = −3.3 (c = 1.5, CHCl3).
Compound 9: To a solution of compound 4a (45 mg, 0.22 mmol)
was added trifluoroacetic acid (9 mL) at rt. The solution was allowed
to react at rt overnight. The reaction mixture was then concentrated.
To the reaction residue were added NaN3 (18 mg, 0.27 mmol) and
PPh3 (0.12 g, 0.44 mmol) at rt. MeCN (10 mL) was then added to the
reaction mixture at 0 °C and stirred until homologous. Cl3CCN (0.08
mL, 0.44 mmol) was added at 0 °C, and the solution was allowed to
warm to rt and react for 30 h. The reaction mixture was partially
concentrated and the residue dissolved in CH2Cl2 (5 mL) and
extracted with CH2Cl2 (2 × 10 mL) and H2O (1 × 10 mL). The
combined organic phases were dried over MgSO4 and concentrated to
yield a yellow clear oil (43 mg).
23
[α]D = +3.6 (c = 2.8, CHCl3).
Compound 4c: Reaction was carried out at rt for 120 h to yield a
white crystal (94 mg, 93% yield); 1H NMR (500 MHz, CDCl3) δ 4.32
(m, 2H), 2.63 (m, 1H), 2.21 (m, 1H), 2.04 (m, 1H), 1.81 (m, 1H),
1.46 (s, 9 H), 0.95 (t, J = 7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ
175.3, 168.7, 82.9, 66.1, 55.4, 31.3, 27.9, 27.1, 9.1; IR (neat) cm−1
2979, 1741, 1466, 1370, 1236, 1043; HRMS (C11H18O4, ESI) calcd
237.1102 [M + Na]+, found 237.1105; [α]D23 = +1.6 (c = 2.2, CHCl3).
Compound 4d: Reaction was carried out at 35 °C for 192 h to yield
1
a white crystal (39.2 mg, 89% yield); H NMR (400 MHz, CDCl3) δ
The crude acyl azide intermediate (43 mg, 0.26 mmol) was
dissolved in THF (1.5 mL) and heated to 100 °C for 20 min in a
microwave reactor. The observance of an isocyanate peak (2283 cm−1)
by IR spectroscopy confirmed that the rearrangement had occurred. A
mixture of K2CO3 (0.14 g, 1.02 mmol) in H2O (0.3 mL) was added to
the reaction mixture and allowed to stir for 20 min, and to it was added
benzoyl chloride (0.027 mL, 0.24 mmol). The solution was allowed to
react overnight at rt. The reaction was acidified with 1 M HCl, and the
reaction mixture was extracted with EtOAc (2 × 10 mL) and H2O (1
× 10 mL). The organic layer was dried over MgSO4 and concentrated.
The residue was purified by flash chromatography on silica gel (30→
60% acetone in hexanes) to afford compound 9 as a white crystal (31
4.32 (m, 2H), 2.61 (m, 2H), 2.17 (m, 1H), 1.47 (s, 9 H), 0.89 (m,
6H); 13C NMR (100 MHz, CDCl3) δ 174.5, 167.9, 82.8, 66.2, 59.8,
31.4, 27.7, 26.3, 17.9, 17.7; IR (neat) cm−1 2970, 1734, 1414, 1383,
1201, 1044; HRMS (C12H20O4, ESI) calcd 251.1259 [M + Na]+,
23
found 251.1259; [α]D = −5.6 (c = 1.1, CHCl3).
Compound 4e: Reaction was carried out at 35 °C for 168 h to yield
1
a white crystal (18 mg, 95% yield); H NMR (400 MHz, CDCl3) δ
5.72 (m, 1H), 5.22 (m, 2H), 4.31 (m, 2H), 2.73 (m, 1H), 2.51 (m, 2
H), 2.33 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
174.9, 168.2, 132.1, 120.0, 83.1, 66.2, 54.1, 37.9, 31.0, 27.7; IR (neat)
cm−1 2949, 1772, 1349, 1286, 1141, 1066; HRMS (C12H18O4, ESI)
23
1
calcd 249.1102 [M + Na]+, found 249.1093; [α]D = −4.7 (c = 0.5,
mg, 56% yield): H NMR (500 MHz, CDCl3) δ 7.78−7.42 (m, 5H),
CHCl3).
4.56 (m, 1H), 4.33 (m, 1H), 2.83 (m, 1H), 2.57 (m, 1H), 1.63 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 177.8, 166.8, 133.5, 132.3,
130.2, 128.8, 65.9, 56.2, 35.0, 22.3; IR (neat) cm−1 3296, 2982, 2361,
1763, 1632, 1527, 1319, 1107, 1023, 936; HRMS (C16H30O5, ESI)
Compound 4f: Reaction was carried out at 35 °C for 155 h to yield
1
a colorless oil (77 mg, 67% yield); H NMR (500 MHz, CDCl3) δ
7.25 (m, 5H), 4.25 (m, 1H), 3.85 (m, 1H), 3.25 (m, 2H), 2.54 (m,
1H), 2.25 (m, 1H), 1.47 (s, 9 H); 13C NMR (126 MHz, CDCl3) δ
175.3, 169.6, 135.7, 130.2, 128.7, 127.3, 83.3, 66.2, 56.1, 38.9, 30.6,
27.9; IR (neat) cm−1 2979, 2360, 1771, 1721, 1454, 1368, 1145, 1029;
HRMS (C16H20O4, ESI) calcd 299.1259 [M + Na]+, found 299.1261;
23
calcd 325.1990 [M + Na]+, found 325.2001; [α]D = +2.0 (c = 1.0,
CHCl3).
Compound 10: To a solution of compound 4a (88.1 mg, 0.44
mmol) in dioxane (1.5 mL) was added concentrated NH4OH (5 mL)
at rt. The solution was allowed to react at rt overnight. The reaction
mixture was then concentrated. The reaction mixture was dissolved in
TEA (0.10 mL, 0.66 mmol) in CH2Cl2 (2 mL). DMAP (11 mg, 0.09
mmol) was added followed by Ac2O (0.06 mL, 0.66 mmol) at rt, and
the solution was allowed to react for 40 h. The reaction mixture was
concentrated, and the residue dissolved in EtOAc (5 mL) and
extracted with EtOAc (2 × 10 mL) and H2O (10 mL). The combined
organic phases were dried over MgSO4 and concentrated. The residue
was purified by flash chromatography on silica gel (15→30% acetone
in hexanes) to afford amide ester intermediate as a colorless oil (47
23
[α]D = +25.1 (c = 1.1, CHCl3).
Compound 4g: Reaction was carried out at rt for 144 h to yield a
1
colorless oil (29.1 mg, 85% yield); H NMR (500 MHz, CDCl3) δ
4.32 (m, 1H), 2.42 (m, 1H), 1.91 (m, 2H), 1.63 (m, 1H), 1.46 (s,
12H); 13C NMR (126 MHz, CDCl3) δ 171.5, 171.1, 82.7, 68.7, 51.1,
30.8, 27.8, 23.1, 20.5; IR (neat) cm−1; 2983, 1730, 1446, 1370, 1229,
1042; HRMS (C11H18O4, ESI) calcd 237.1102 [M + Na]+, found
23
237.1095; [α]D +14.1 (c = 1.0, CHCl3).
Compound 7: To a solution of compound 4a (110 mg, 0.5 mmol)
in THF (5.0 mL) was added a solution of LiAl(OtBu)3H (1.0 M in
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The Journal of Organic Chemistry
Note
mg, 41% yield): 1H NMR (500 MHz, CDCl3) δ 4.1 (m, 2H), 2.25 (m,
1H), 2.15 (m, 1H), 2.00 (s, 3H), 1.46 (s, 9H) 1.44 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 173.8, 173.3, 171.1, 82.6, 61.0, 52.2, 35.4, 27.7,
21.9, 20.9; IR (neat) cm−1 3348, 2979, 2358, 1745, 1669, 1364, 1227,
1121, 1037; HRMS (C12H21NO5, ESI) calcd 282.1317 [M + Na]+,
found 282.1326.
(3) (a) Snyder, S. A.; Thomas, S. B.; Mayer, A. C.; Breazzano, S. P.
Angew. Chem., Int. Ed. 2012, 51, 4080−4084. (b) Nicolaou, K. C.; Wu,
T. R.; Kang, Q.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2009, 48, 3440−
3443. (c) Ge, H. M.; Zhu, C. H.; Shi, D. H.; Zhang, L. D.; Xie, D. Q.;
Yang, J.; Ng, S. W.; Tan, R. X. Chem.Eur. J. 2008, 14, 376−381.
(d) Ge, H. M.; Xu, C.; Wang, X. T.; Huang, B.; Tan, R. X. Eur. J. Org.
Chem. 2006, 5551−5554.
To a solution of the amide ester intermediate (28 mg, 0.108 mmol)
in tBuOH (0.55 mL) was added Pb(OAc)4 (95.9 mg, 0.216 mmol) at
70 °C. The solution was allowed to react overnight. To the reaction
mixture were added Et2O (4 mL) and NaHCO3 (0.11 g) and allowed
to stir for 10 min. The reaction mixture was filtered through SiO2 and
concentrated. The residue was purified by flash chromatography on
silica gel (20→40% acetone in hexanes) to afford the amide
(4) (a) Yu, S.; Huang, Q.-Q.; Luo, Y.; Lu, W. J. Org. Chem. 2012, 77,
713−717. (b) Stead, D.; Carbone, G.; O’Brien, P.; Campos, K. R.;
Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010, 132, 7260−7261.
(c) Adams, D. J.; Wahl, M. L.; Flowers, J. L.; Sen, B.; Colvin, M.;
Dewhirst, M. W.; Manikumar, G.; Wani, M. C. Cancer Chemother.
Pharmacol. 2006, 57, 145−154. (d) Comins, D. L.; Nolan, J. M. Org.
Lett. 2001, 3, 4255−4257. (e) Fang, F. G.; Xie, S.; Lowery, M. W. J.
Org. Chem. 1994, 59, 6142−6143. (f) Corey, E. J.; Crouse, D. N.;
Anderson, J. E. J. Org. Chem. 1975, 40, 2140−2141. (g) Wall, M. E.;
Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim, G. A. J.
Am. Chem. Soc. 1966, 88, 3888−3890.
1
intermediate as a colorless oil (20 mg, 57% yield): H NMR (400
MHz, CDCl3) δ 4.12 (t, J = 6.6 Hz, 2H), 2.2 (m, 1H), 2.15 (m, 1H),
2.00 (s, 3H) 1.50 (s, 3H), 1.46 (s, 9 H), 1.41 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 173.4, 171.0, 154.2, 82.1, 79.4, 60.9, 58.1, 34.5, 28.4,
27.9, 24.2, 21.0; IR (neat) cm−1 3358, 2980, 2359, 1726, 1369, 1242,
1045; HRMS (C16H29NO6, ESI) calcd 354.1892 [M + Na]+, found
354.1882.
(5) Qabaja, G.; Wilent, J. E.; Benavides, A. R.; Bullard, G. E.;
Petersen, K. S. Org. Lett. 2013, 15, 1266−1269.
To a solution of the amide intermediate (20 mg, 0.061 mmol) in
MeOH (1.5 mL) was added K2CO3 (41 mg) at rt. The solution was
allowed to react for 20 min. The reaction mixture was diluted with
CH2Cl2 (5 mL) and extracted with H2O (1 × 5 mL). The organic
layer was washed with brine (5 mL) and dried over MgSO4. The
solution was concentrated to yield compound 10 as a colorless oil (14
mg, 80% yield): 1H NMR (500 MHz, CDCl3) δ 3.7 (m, 2H), 2.2 (m,
1H), 2.15 (m, 1H), 1.52 (s, 3H), 1.46 (s, 9 H), 1.41 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 173.4, 154.7, 81.8, 79.4, 59.2, 58.5, 39.1, 28.4,
28.0, 23.8; HRMS (C14H27NO5, ESI) calcd 312.1786 [M + Na]+,
(6) (a) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
5604−5607. (b) Mermerian, A. H.; Fu, G. C. J. Am. Chem. Soc. 2003,
125, 4050−4051.
(7) Woods, P. A.; Morrill, L. C.; Bragg, R. A.; Smith, A. D. Chem.
Eur. J. 2011, 17, 11060−11067.
(8) Birrell, J. A.; Desrosiers, J.-N.; Jacobsen, E. N. J. Am. Chem. Soc.
2011, 133, 13872−13875.
(9) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B.
M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105−108.
(10) Wilking, M.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Hennecke,
̈
23
found 312.1776; [α]D = +10.0 (c = 0.9, CHCl3).
Compound 11: colorless oil (100 mg, 57% yield); H NMR (500
U. J. Am. Chem. Soc. 2013, 135, 8133−8136.
1
(11) Ha, M. W.; Lee, H.; Yi, H. Y.; Park, Y.; Kim, S.; Hong, S.; Lee,
M.; Kim, M.; Kim, T.; Park, H. Adv. Synth. Catal. 2013, 355, 637−642.
(12) Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.;
Kanemasa, S. Angew. Chem., Int. Ed. 2008, 47, 164−168.
(13) Suzuki, T.; Goto, T.; Hamashima, Y.; Sodeoka, M. J. Org. Chem.
2007, 72, 246−250.
MHz, CDCl3) δ 7.25 (m, 2H), 3.84 (d, J = 12.0 Hz, 1H), 3.69 (m,
2H), 3.54 (d, J = 12.0 Hz, 1H), 3.17 (b, 2H), 2.95 (d, J = 13.7 Hz,
1H), 2.78 (d, J = 13.7 Hz, 1H), 2.10 (m, 1H), 1.73 (m, 1H), 1.44 (s,
9H); 13C NMR (126 MHz, CDCl3) δ 175.0, 136.5, 130.5, 127.9,
126.8, 82.0, 65.4, 59.2, 51.7, 41.9, 38.9, 27.9; IR (neat) cm−1 3433,
2974, 2932, 1773, 1725, 1453, 1369, 1145, 1104, 844; [α]D23 = +4.1 (c
= 1.3, CHCl3).
(14) Volp, K. A.; Johnson, D. M.; Harned, A. M. Org. Lett. 2011, 13,
4486−4489.
(15) Burgess, K.; Lim, D. Y. Tetrahedron Lett. 1995, 36, 7815−7818.
(16) Todd, R. C.; Hossain, M. M.; Josyula, K. V.; Goa, P.; Kuo, J.;
Tan, C. T. Tetrahedron Lett. 2007, 48, 2335−2337.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C spectra of new compounds and traces of
enantioenriched products are available. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kspeters@uncg.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of North Carolina at Greensboro for
financial support, and Dr. Franklin J. Moy and Dr. Brandie M.
Ehrman for assistance with NMR and mass spectrometry data
analysis.
REFERENCES
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