Stereoselective formation of quaternary stereogenic centers via alkylation of α-substituted malonate-imidazolidinones

Article abstract of DOI:10.1021/jo502140d

A new stereoselective alkylation methodology is presented for formation of chiral, nonracemic quaternary centers via a chiral auxiliary protocol involving α-alkylated malonate imidazolidinones. Based on two X-ray structures of quaternized products, the diastereoselectivity observed may be rationalized via a transition-state involving an s-trans_C-N conformation of the C-N bond of the auxiliary, with the metal cation (K⁺) chelated into the malonate six-membered hole as a Z-enolate. A deprotection protocol involving ethanethiolate exchange of the imide to the corresponding thioester, followed by a standard Fukuyama reduction and a borohydride reduction, furnishes α,α-quaternized-hydroxypropionates in high ee overall.

Full text of DOI:10.1021/jo502140d

Article
pubs.acs.org/joc
Stereoselective Formation of Quaternary Stereogenic Centers via
Alkylation of α‑Substituted Malonate-Imidazolidinones
Thobela Bixa, Roger Hunter,* Ana Andrijevic, Wade Petersen, Hong Su, and Francis Dhoro
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
S
* Supporting Information
ABSTRACT: A new stereoselective alkylation methodology is presented for formation of chiral, nonracemic quaternary centers
via a chiral auxiliary protocol involving α-alkylated malonate imidazolidinones. Based on two X-ray structures of quaternized
products, the diastereoselectivity observed may be rationalized via a transition-state involving an s-transC−N conformation of the
C−N bond of the auxiliary, with the metal cation (K+) chelated into the malonate six-membered hole as a Z-enolate. A
deprotection protocol involving ethanethiolate exchange of the imide to the corresponding thioester, followed by a standard
Fukuyama reduction and a borohydride reduction, furnishes α,α′-quaternized β-hydroxypropionates in high ee overall.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The choice to pursue malonate as the template was influenced
not only by its well-behaved alkylation credentials together with
the possibility of chelation within the enolate for fixing enolate
geometry but also by the presence of C-1 ester groups for
further elaboration postalkylation and carbonyl chemodiffer-
entiation.6e To date, to the best of our knowledge, only one
asymmetric diastereoselective alkylation of an α-substituted
malonate has been reported, and that involved using a menthol
ester auxiliary on a half-acid ester (2 equiv of LDA were needed
for alkylation),9a in which the range of alkyl groups was limited
and dr’s were relatively modest. Enantioselective malonate
alkylation via PTC catalysis has recently been reported,6e while
asymmetric malonate fluorination has been achieved via both
diastereoselective9b and enantioselective9c protocols. Similarly,
acetoacetate has been used as a template for diastereoselective
Michael additions in modest de using triphenylphosphine as
catalyst.10 Another attractive feature for choosing malonate was
the ease of generation of the α-alkylated malonate imidazoli-
dinones, which were readily available from malonate half-acid
ester11 2, as depicted in Scheme 1. Initial screening with Evans’
auxiliary in the diastereoselective quaternization step revealed
that warming the solution to 0 °C in order to achieve a high
conversion in the alkylation resulted in a significant degree of
elimination of the auxiliary, particularly with R groups larger
than ethyl, whereas switching to the well-known auxiliary
(4S,5R)-1,5-dimethyl-4-phenylimidazolidin-2-one 312 (referred
to as the “down/down” enantiomer in the text) based on
(1S,2R)-ephedrine avoided this problem, allowing alkylations to
The construction of acyclic stereogenic quaternary centers in
nonracemic form1 is seen to be a challenging problem that has
seen an explosion of interest from the organic synthesis
community over the last 10 years or so in terms of the
relevance of this structural motif to both natural product
synthesis as well as medicinal chemistry programs. Method-
ologies reported for this purpose have covered the complete
gamut of asymmetric synthesis strategies ranging from the
classical diastereoselective auxiliary-controlled type to modern
approaches centered in enantioselective catalysis, and in which
four key reaction types stand out as (i) allylic substitution,2 (ii)
conjugate addition,3 (iii) nucleophilic allylation,4 and (iv)
alkylation in which aldol and Mannich reactions will not be
reviewed here. The alkylation option covers a plethora of
options of nucleophiles based on single-5 and double-stabilizing
functionalities,6 and is the most historical as it has blossomed
out of traditional carbonyl chemistry. While a solution to the
asymmetric formation of acyclic tertiary stereogenic centers in
nonracemic form using an auxiliary-control methodology has
been provided by the seminal work of Evans and others,7 by
comparison, the equivalent asymmetric production of acyclic
quaternary centers poses the challenge of controlling the
enolate geometry of the disubstituted (terminus) enolate
intermediate.5a,b,f,j Recently, an elegant methodology has been
reported8 that addresses this issue via a stereoselective
carbometalation-oxidation protocol. In this article, we report
on the use of a highly diastereoselective auxiliary-controlled
quaternization methodology that addresses the issue of
stereodefined disubstituted enolate generation.
Received: September 17, 2014
© XXXX American Chemical Society
A
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Scheme 1. Synthesis of the Auxiliary-Malonates 4a−f Using the Down/Down Auxiliary
Table 1. Diastereoselectivity of Quaternization of 4
a
b
entry
Cpd
R
R1
yield
dr (data)
c
1
2
5a
5a
5b
5c
5d
5e
5f
Me
allyl
Me
Me
allyl
Bn
60:40
95:5
allyl
Et
83
95
92
89
88
85
84
90
87
82
3
95:5
d
d
d
4
Et
96:4
5
Et
96:4
6
n-Bu
n-Bu
n-Bu
n-Hex
n-Hex
n-Hex
Me
allyl
Bn
95:5
7
96:4
8
5g
5h
5i
93:7
9
Me
allyl
Bn
99:1
10
11
>99:1
>99:1
5j
a
b
c
After chromatography on the “down/down” series. By chiral HPLC using a Chiralcel OD column on the “up/up” series. From allyl bromide; allyl
d
iodide gave the same diastereoselectivity. From allyl iodide.
proceed at ambient temperature to achieve full conversion and
without auxiliary elimination.13 Regarding the timing of
introduction of the α-substituent R to generate the α-
substituted auxiliary-malonates 4, it was found to be more
practical to prepare a large quantity of auxiliary-malonate 4a (R
= H) and introduce the α-substituents individually via
alkylation rather than converting α-substituted diethyl
malonates individually. In this sequence, the starting material
4a could be most conveniently prepared in around 90% yield
by activating half-acid ester 2 with pivaloyl chloride in THF
with N-methylmorpholine as base, followed by reaction with
the 2-imidazolidinone auxiliary 3. 4a was a crystalline solid that
could be crystallized to high purity. Other methodologies that
could be used included DCC (with BtOH in which the yield
was around 80%, but the isolation was complicated by the
formation of the urea byproduct), using the acid chloride
(prepared with SOCl2, but with losses due to volatility), and
using PPh3/BtCl14 (troublesome to separate the product from
BtH), the latter two reactions returning lower yields of around
65%. Thereafter, various R groups could be introduced using
alkylation of 4a with KHMDS as base, and the relevant alkyl
bromide or iodide (see the Experimental Section) to form
auxiliary-malonates 4b−f in high yield (>85%) after chroma-
tography (Scheme 1). Compounds 4b−f were prepared using
both enantiomers of the auxiliary 3 (referred to as “down/
down” or “up/up” accordingly), which were both taken through
quaternization.
Monosubstituted products 4b−f were produced in a
nonstereoselective manner as a 50:50 mixture of diastereomers
according to both NMR and chiral HPLC analysis, and this
result was considered to be significant regarding diastereose-
lectivity, and will be commented on later in the discussion
concerning the origin of stereoselectivity in the quaternized
products. In this regard, reaction of 4a with less than a
stoichiometric amount of base (0.4 equiv to the malonate),
reacting with benzyl bromide and quenching the reaction at
−20 °C (with full conversion of the enolate), still resulted in an
approximately 50:50 ratio of benzylated diastereomers, strongly
suggesting that the dr of ∼50:50 observed in the mono-
alkylation of 4a reflects formation of the kinetic product.
Products 4b,c with small products 4b,c with small R groups
were crystalline solids that could be crystallized to a single
diastereomer, while the products with longer-chain substituents
(4d−f) were oils that were characterized as a diastereoisomeric
mixture by NMR spectroscopy, HRMS, and chiral HPLC.
Moving on to the all-important quaternization step, we were
surprised to find that the use of LDA as base (1.3 equiv) at −78
°C in dry THF, followed by addition of the electrophile and
allowing the solution to warm up to room temperature, gave
back mainly starting material with minimal conversion to the
B
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Figure 1. X-ray structure of 5d.
alkylated product (<10%). Switching to LiHMDS gave the
same result. Eventually, it was discovered that full conversion
could only be attained using KHMDS as base, with NaHMDS
giving only a moderate conversion (∼50%) under the
conditions described. Furthermore, in keeping with other
quaternizations, good results could only be achieved with
reactive SN2-type electrophiles (MeI, allylBr/I, BnBr) in which
full conversion could be achieved in each case without a
cosolvent by allowing the reaction to warm and stir for a
number of hours at room temperature. For R > Me, allylations
were carried out with allyl iodide. Table 1 summarizes the
results for the “down/down” series varying the two alkyl
substituents to afford products 5a−j.
The diastereoselectivity (reported as a dr) in the quaternized
products 5 was measured by chiral HPLC on the “up/up” series
(see the Supporting Information), which revealed a healthy
separation between the two diastereomers. These results were
corroborated by 1H NMR spectroscopy, which was less
accurate for calculating the dr but nevertheless supported the
formation of one diastereomer predominantly. The results in
Table 1 reveal that, apart from R as Me, which gave no
diastereoselectivity at all in allylation (entry 1), all other
combinations where R was C-2 or larger and R1 was anything in
size from C-1 upward gave a dr equal to or in excess of 95:5
(93:7 for 5g), with larger groups giving effectively complete
diastereoselectivity. Yields were good to excellent in each case.
A single-crystal X-ray structure determination for each of the
products 5d and 5f derived from the “down/down” auxiliary
(shown in the Supporting Information) revealed absolute
configurations at the new quaternary stereogenic centers to be
S in each case. Figure 1 shows the structure for 5d, which is
redrawn in the customary all-cis-carbonyl conformation.
imidazolidinone moiety as is well-known for Evans’ enolates
with oxazolidinone as the auxiliary and the cation as lithium.7
The proposed transition state is depicted in Figure 2.
Importantly, such a transition state allows the R group to
position into a relatively uncrowded area facing the
imidazolidinone carbonyl oxygen. Support for this comes
from the classical literature on boron enolate aldol reactions
involving oxazolidinone auxiliaries.7,15 Here, an s-cisC−N
conformation is also preferred when the boron (metal) is
chelated to the aldehyde carbonyl. Furthermore, the fact that
the reaction only worked with potassium as the cation suggests
the importance of having the latter close to the site of
electrophile attack, and this aspect effectively offers a solution
to the enolate geometry control problem pertaining to
terminally disubstituted enolates, except, in this case, one of
the groups is an ester. In addition, the unselective result (see
entry 1 in Table 1) involving a dr of 60:40 from the allylation
with the much smaller Me group (as R) presumably arises as a
result of both s-cis and s-transC−N conformers being populated
(reaction occurs from around 0 °C onward), which leads to
opposite facial selectivities in the alkylation. Similarly, this
interpretation can be extended to R = H in the monoalkylation
of 4a to afford derivatives 4b−f (Scheme 1), in which there was
also effectively no diastereoselectivity observed. High diaster-
eoselectivities in quaternization are possible with Me so long as
it is introduced as R1 (to afford cpds 5a, 5b, 5e, 5h), effectively
offering a workable solution to achieving a high diastereose-
lectivity for any combination of R and R1 provided R1 is an SN2-
reactive electrophile.
Removal of the auxiliary to complete the methodology as a
means of synthesizing quaternary centers in high enantioen-
riched form proved to be challenging and was carried out in the
“up/up” series. The standard methods involving metal
hydroperoxide or hydroxide to promote acyl-oxygen fission
showed no chemoselectivity between the two carboxyl
functions. Similarly, reaction with LiBH4, which was thought
would result in preferential complexation of the lithium cation
into the auxiliary hole, also gave mixtures of carbonyl-group
reduction products. Fortunately, it was eventually established
that chemoselective auxiliary removal could be achieved using a
Fukuyama reduction protocol16 with minimal dithioester
formation by heating with LiSEt (10 equiv) in THF at 45
°C. Presumably the high lipophilicity and crowded nature of
the substrate repels the reagent, making for the slightly more
stringent conditions than normal. In such a way, four selected
quaternized products (5d, 5e, 5i, and 5j) could each be
transformed into thioesters 6a−d in 77−89% yield after
chromatography, and with auxiliary recovery (>80%) (Table 2).
Thereafter, reduction with Et3SiH on Pd−C in THF
furnished the aldehydes 7a−d (not shown), which appeared
to be somewhat unstable toward isolation and so were isolated
A major clue as to the origin of the diastereoselectivity was
given by the X-ray structures (see the Supporting Information),
which showed a preference for the auxiliary to adopt an s-
transC−N conformation, as shown in Figure 2 for 5d. Invoking
this in the transition state in conjunction with the customary
electrophile attack anti- to the phenyl and methyl groups on the
auxiliary leads one to conclude that reaction proceeds via a Z-
enolate from the si-face. Such an enolate geometry would be
promoted by potassium chelation into the six-membered
malonate hole rather than the alternative involving the
Figure 2. Proposed transition state of quaternization.
C
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Table 2. Auxiliary Exchange by LiSEt
a
compound
product
R-group
R1-group
reaction time (h)
yield (%)
5d
5e
5i
6a
6b
6c
6d
Et
Bn
5
2
4
7
82
77
89
70
n-Bu
n-Hex
n-Hex
Me
allyl
Bn
5j
a
Carried out on the “up/up” series.
distilled from phosphorus pentoxide. Reagents were obtained from
commercial sources and used as obtained unless stated. All reactions
were carried out in oven-dried glassware with a magnetic stirrer, and
performed under a nitrogen atmosphere unless otherwise stated.
Reaction temperatures were achieved with heat/silicone oil (for >25
°C), ice/NH4Cl salt (for 0 °C), and acetone/liquid nitrogen (<−20
°C). Aqueous solutions were prepared using deionized water. All
reactions were monitored by TLC using aluminum-backed silica gel 60
F254 plates, while column chromatography was carried out using
Kieselgel 60 silica gel. Active compounds were observed under a UV
lamp (ultraviolet), while non-UV-active compounds were sprayed with
a 2.5% solution of p-anisaldehyde in a mixture of sulfuric acid and
ethanol (1:10 v/v), iodine vapor, or ceric ammonium sulfate solution
and then heated. Nuclear magnetic resonance (NMR) spectra were
as their primary alcohols 8a−d following a standard
borohydride reduction (Table 3). Yields overall for these last
Table 3. Fukuyama Protocol To Afford α,α′-Dialkylated, β-
Hydroxy Esters 8
a
compound product R-group R1-group yields (%)
ee (%) (data)
6a
6b
6c
6d
8a
8b
Et
Bn
65
55
54
60
94
1
recorded at 399.95 or 300.08 MHz for H, and 100.6 MHz for 13C.
b
n-Bu
n-Hex
Me
Chemical shifts (δ) and J-coupling values are reported in units of ppm
c
d
e
1
and Hz, respectively. Chemical shifts for H and 13C were recorded
8c
Pr
94
8d
n-Hex
Bn
>99
relative to residual chloroform, at 7.26 and 77.16 ppm, respectively.
High-resolution mass spectra (HRMS) were recorded in electrospray
positive mode with a quadrupole time-of-flight analyzer system. Infra-
red (IR) spectroscopy absorptions were measured in units of cm−1.
Optical rotations were measured at 20 °C and are reported as [α]2D0 (c
g/mL, solvent). The determination of melting points was carried out
using a hot-stage microscope (HSM) and are uncorrected. HPLC
analyses were carried out with a Chiralcel OD column.
General Procedure for the Synthesis of α-Substituted
Auxiliary-Malonates 4b−f. To a solution of diethyl malonate (50
mmol) in EtOH (10 mL) at 0 °C was added dropwise a solution of aq.
KOH in H2O (60 mmol, 2.5 M), and the contents were allowed to
slowly warm up to rt. After 1 h, the EtOH was removed under reduced
pressure, and the concentrate was diluted with water (10 mL) and
extracted with DCM (3 × 20 mL) to remove unreacted diester. The
aqueous layer was then acidified with conc. HCl to pH = 2 and then
re-extracted with DCM (3 × 30 mL); the organic extracts combined,
dried over MgSO4, filtered under vacuum, and concentrated in vacuo
to obtain the half-acid ester 2 (5.9 g, 90%) as a colorless oil.
To a solution of 2 (5.61 g, 42.5 mmol, 1.62 equiv) and N-
methylmorpholine (4.25 g, 42.0 mmol, 1.60 equiv) in dry THF at −15
°C under an Ar atmosphere was added dropwise a solution of freshly
distilled pivaloyl chloride in dry THF (36.8 mmol, 1.4 equiv, 0.5 M),
and the reaction was allowed to stir at this temperature for 30 min.
Thereafter, (4S,5R)-1,5-dimethyl-4-phenylimidazolidin-2-one (5.00 g,
26.3 mmol) 3 was added over a period of 5 min and the contents
slowly warmed to rt and left to stir overnight at 30 °C. After 12 h, the
organic solvent was removed in vacuo, and EtOAc (150 mL) was
added to the crude residue to dissolve the organic product, which was
subsequently washed with 1 M HCl (3 × 75 mL), followed by sat.
NaHCO3 (3 × 75 mL). The organic extract was then dried with
MgSO4, and the product was purified by column chromatography after
removal of the organic solvent to afford ethyl 3-((4R,5S)-3,4-dimethyl-
2-oxo-5-phenylimidazolidin-1-yl)-3-oxopropanoate (4a), (7.36 g, 92%
yield) as a colorless solid, which was recrystallized from EtOAc/
hexane. mp 84 °C; [α]2D0 = −6.2, (c = 1.0, DCM); IR νmax (cm−1)
3008, 2860, 1736, 1687; 1H NMR (300 MHz, CDCl3) δ 7.35 (m, 3H),
a
b
c
Over the two steps. No UV chromophore. 8c isolated as its
d
benzoate (9). Reduction of the allyl group double bond occurred.
e
Over three steps.
two steps on a small scale (0.1−0.2 mmol scale) were about
60%, while final ee’s were ∼95% according to chiral HPLC. In
the case of 6c, reduction of the allyl group double bond
occurred as mentioned in Fukuyama’s original article
(monosubstituted olefins), to afford 8c containing hexyl and
propyl as the two R groups, which was isolated and
characterized as its benzoate derivative (9) in order to obtain
an ee measurement.
CONCLUSION
■
In conclusion, we have discovered a means of controlling the
geometry of a chiral terminally disubstituted enolate derived
from an α-substituted malonate-imidazolidinone, based on a
preference for the potassium cation to chelate to the malonate
part of the anion. High diastereoselectivities in alkylation to
afford quaternary centers were achieved in which a transition
state is proposed involving the auxiliary adopting an s-transC−N
conformation, as suggested by X-ray analysis of two quaternized
products. The auxiliary removal of such adducts with lithium
ethanethiolate can be achieved chemoselectively to afford the
corresponding thioesters, which undergo Fukuyama reduction
to afford quaternized chirons in high ee overall of relevance to
natural product synthesis and medicinal chemistry scaffolds.
EXPERIMENTAL SECTION
General Information. All reaction solvents were freshly distilled
under nitrogen, in which THF was distilled from sodium wire with
benzophenone, MeCN distilled from calcium hydride, and DCM
■
D
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7.18 (m, 2H), 5.32 (d, J = 8.7 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.02
(s, 1H), 3.97 (s, 1H), 3.93 (dq, J = 8.7, 6.6 Hz, 1H), 2.81 (s, 3H), 1.26
(t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 167.7, 165.1, 155.6, 136.1, 128.6, 128.3, 127.2, 61.3, 59.5,
54.2, 43.5, 28.3, 15.1, 14.2; Anal. Calc. for C16H20N2O4 (%): C, 63.14;
H, 6.61; N, 9.20. Found (%): C, 63.19; H, 6.57; N, 9.24.
To a solution of 4a (0.40 g, 1.31 mmol) in THF (3.5 mL) at −78
°C was added KHMDS (3.15 mL, 0.5M, 1.58 mmol, 1.2 equiv), and
the contents were allowed to stir at this temperature for 30 min.
Thereafter, the alkylating agent (3.0 equiv) was added at −78 °C and
the contents were allowed to slowly warm up to rt and left to stir at the
appropriate temperature. After 14 h, the reaction was quenched with
sat. NH4Cl/Na2S2O3 (25 mL) and extracted with DCM (3 × 25 mL),
the organic solvents were combined, dried over MgSO4, and filtered
under pressure, and the organic solvent was removed under reduced
pressure. The residue was purified by column chromatography (30%
EtOAc in hexane) to afford a mixture of diastereomers of products
4b−f.
Ethyl 3-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidin-1-yl)-
2-methyl-3-oxopropanoate (4b). Scale: 1.31 mmol (0.400 g), with
MeI (0.25 mL, 3.93 mmol) at room temperature. Yield: 0.375 g, 90%
as an off-white solid and as a mixture of diastereomers.
Recrystallization from EtOAc/hexane to a constant mp afforded one
single diastereomer: mp 152−153 °C; [α]2D0 = −31.9, (c = 1.0, DCM);
IR νmax (cm−1) 3010, 2863, 1732, 1689; 1H NMR (300 MHz, CDCl3)
δ 7.31 (m, 3H), 7.22 (m, 2H), 5.30 (d, J = 8.7 Hz, 1H), 4.65 (q, J = 7.5
Hz, 1H), 4.25−4.05 (m, 2H), 3.90 (dq, J = 8.7, 6.6 Hz, 1H), 2.81 (s,
3H), 1.39 (d, J = 7.5 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H), 0.80 (d, J = 6.6
Hz, 3H); 13C NMR (75.5 MHz, CDCl3) δ 171.1, 169.0, 155.7, 136.2,
128.5, 128.2, 127.3, 61.2, 59.8, 54.3, 45.9, 28.4, 15.2, 14.2, 13.5; Anal.
Cal. for C17H22N2O4 (%): C, 64.13; H, 6.97; N, 8.80. Found (%): C,
64.02; H, 7.04; N, 8.89.
mixture of diastereomers. IR νmax (cm−1) 3010, 2861, 1732, 1689;
HRMS (ES) m/z: [M + H]+ Calcd for C20H29N2O4 361.2125; Found
361. 2127.
Major Diastereomer. 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 3H),
7.23 (m, 1H), 7.12 (m, 1H), 5.31 (d, J = 8.6 Hz, 1H), 4.63 (dd, J = 5.3,
3.4 Hz, 1H), 4.24−4.19−4.09 (m, 2H), 3.96−3.88 (m, 1H), 2.82 (s,
3H), 2.00−1.75 (m, 2H), 1.35−1.28 (m, 2H), 1.25−1.18 (m, 2H),
1.20 (t, J = 7.2 Hz, 3H), 0.82 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.4 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 170.4, 168.4, 155.7, 136.2,
128.4, 128.2, 127.2, 61.1, 59.7, 54.0, 51.1, 29.2, 28.3, 27.6, 22.6, 15.1,
14.3, 14.2.
Minor Diastereomer. 1H NMR (400 MHz, CDCl3) δ 7.29 (m,
3H), 7.23 (m, 1H), 7.12 (m, 1H), 5.36 (d, J = 8.6 Hz, 1H), 4.61 (dd, J
= 6.4, 1.2 Hz, 1H), 4.24−4.09 (m, 2H), 3.96−3.88 (m, 1H), 2.81 (s,
3H), 2.00−1.75 (m, 2H), 1.35−1.28 (m, 2H), 1.25−1.18 (m, 2H),
1.26 (t, J = 7.2 Hz, 3H), 0.87 (t, J = 7.2 Hz, 3H), 0.79 (d, J = 6.4 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 170.5, 168.8, 155.7, 136.7,
128.6, 128.3, 127.3, 61.1, 59.8, 54.2, 51.3, 29.3, 28.7, 27.9, 22.7, 15.1,
14.3, 14.2.
Ethyl 2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)octanoate (4f). Scale: 0.400 g (1.31 mmol) with 1-
bromohexane (0.55 mL, 3.93 mmol) and TBAI (0.241 g, 0.655
mmol, 0.5 equiv) at 65 °C. Yield: 0.458 g, 90% as a colorless oil and a
51:49 mixture of diastereomers.
IR νmax (cm−1) 3010, 2860, 1732, 1689; HRMS (ES) m/z: [M +
H]+ Calcd for C22H33N2O4 389.2443; Found 389.2440.
Major Diastereomer. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 3H),
7.20 (m, 1H), 7.17 (m, 1H), 5.31 (d, J = 8.8 Hz, 1H), 4.63 (dd, J = 4.6,
3.6 Hz, 1H), 4.24−4.24−4.08 (m, 2H), 3.97−3.88 (m, 1H), 2.82 (s,
3H), 1.95−1.86 (m, 2H), 1.35−1.17 (m, 8H), 1.20 (t, J = 7.2 Hz, 3H),
0.84 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 170.4, 168.4, 155.7, 136.2, 128.4, 128.2, 127.2, 61.1,
59.7, 54.2, 51.3, 29.3, 29.2, 28.9, 28.3, 27.6, 22.6, 15.1, 14.2, 14.2.
Minor Diastereomer. 1H NMR (400 MHz, CDCl3) δ 7.30 (m,
3H), 7.17 (m, 2H), 5.36 (d, J = 8.4 Hz, 1H), 4.79 (dd, J = 6.0, 2.4 Hz,
1H), 4.24−4.08 (m, 2H), 3.97−3.88 (m 1H), 2.82 (s, 3H), 1.95−1.86
(m, 2H), 1.35−1.17 (m, 8H), 1.25 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.2
Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ
170.5, 168.8, 155.7, 136.7, 128.6, 128.3, 127.3, 61.1, 59.8, 54.2, 51.3,
29.3, 29.2, 28.9, 28.7, 27.9, 22.7, 15.2, 14.2, 14.2.
Ethyl 2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)butanoate (4c). Scale: 1.31 mmol (0.400 g) with ethyl
iodide (0.32 mL, 3.93 mmol) at 65 °C for 12 h. Yield: 0.388 g, 89% as
a 51:49 colorless solid and a mixture of diastereomers. Recrystalliza-
tion from EtOAc/hexane to a constant mp afforded one single
diastereomer: mp 126−129 °C; [α]2D0 = −4.5, (c = 1.0, DCM); IR νmax
1
(cm−1) 3010, 2863, 1732, 1689; H NMR (400 MHz, CDCl3) δ 7.31
(m, 3H), 7.21 (m, 2H), 5.31 (d, J = 8.8 Hz, 1H), 4.59 (dd, J = 5.6, 2.8
Hz 1H), 4.25−4.08 (m, 2H), 3.91 (dq, J = 8.8, 6.8 Hz, 1H), 2.82 (s,
3H), 2.04−1.86 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 8.0 Hz,
3H), 0.80 (d, J = 6.8 Hz, 3H); 13C (100.6 MHz, CDCl3) δ 170.3,
168.1, 155.7, 136.2, 128.5, 128.2, 127.3, 61.0, 59.8, 54.2, 52.7, 28.3,
22.1, 15.2, 14.2, 12.2; Anal. Calcd for C18H24N2O4 (%): C, 65.04; H,
7.28; N, 8.43. Found (%): C, 64.85; H, 7.06; N, 8.36.
Ethyl 2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)pent-4-enoate (4d). Scale: 1.31 mmol (0.400 g) with allyl
bromide (0.34 mL, 3.93 mmol) at 20 °C. Yield: 0.393 g, 87% as an oil
and a 52:48 mixture of diastereomers. IR νmax (cm−1) 3010, 2959,
2863, 1732, 1689; HRMS (ES) m/z: [M + H]+ Calcd for C19H25N2O4
345.1813; Found 345.1814.
General Procedure for the Synthesis of α,α′-Disubstituted
Auxiliary-Malonates 5a−j. To a solution of the appropriate
derivative of 4 (0.6 mmol) in THF (2 mL) at −78 °C was added a
solution of KHMDS (1.56 mL, 0.78 mmol, 1.3 equiv, 0.5 M), and the
reaction contents were allowed to stir at this temperature for 30 min.
Thereafter, the appropriate alkylating agent (1.8 mmol, 3 equiv) was
slowly added, and the reaction contents were allowed to slowly warm
up to rt and left to stir overnight for 20 h. The reaction was quenched
with sat. NH4Cl (15 mL) and extracted with DCM (3 × 15 mL), the
organic extracts were dried over MgSO4 and filtered under vacuum,
and the organic solvent was removed in vacuo. The crude residue was
chromatographed using EtOAc/hexane mixtures to afford the
derivative 5, which was analyzed by chiral HPLC and 1H NMR
spectroscopy for diastereoselectivity.
Ethyl (R)-2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)-2-methylpent-4-enoate (5a). Scale: 0.200 g (0.581 mmol)
of 4d with MeI (0.11 mL, 1.77 mmol). Yield: 0.173 g, 83% as a
colorless oil and a 95:5 mixture of diastereomers.[α]2D01 = −33.3, (c =
1.0, DCM); IR νmax 3010, 2991, 2858, 1735, 1675; H NMR (400
MHz, CDCl3) δ 7.31 (m, 3H), 7.17 (m, 2H), 5.80−5.71 (m, 1H), 5.29
(d, J = 8.4 Hz, 1H), 5.04−4.98 (m, 1H), 4.97−4.89 (m, 1H), 4.25−
4.13 (m, 2H), 3.90 (dq, J = 8.4, 6.4 Hz, 1H), 2.79 (s, 3H), 2.78−2.63
(m, 2H), 1.45 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H), 0.79 (d, J = 6.4 Hz,
3H); 13C NMR (100.6 MHz, CDCl3) δ 173.1, 170.2, 155.9, 136.7,
133.8, 128.6, 128.2, 127.0, 118.2, 60.8, 60.5, 54.5, 54.5, 40.5, 28.3, 21.4,
15.1, 14.3; HRMS (ES) m/z: [M + H]+ Calcd for C20H27N2O4
359.1971; Found 359.1971.
Major Diastereomer. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 3H),
7.20 (m, 1H), 7.17 (m, 1H), 5.81−5.45 (m, 1H), 5.35 (d, J = 8.8 Hz,
1H), 5.12−5.02 (m, 1H), 5.01−4.92 (m, 1H), 4.91 (dd, J = 4.2, 2.6
Hz, 1H), 4.25−4.11 (m, 2H), 3.98−3.85 (m, 1H), 2.83 (s, 3H), 2.50−
2.21 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 171.6, 169.7, 155.1, 136.1, 135.0, 128.5,
128.2, 127.2, 117.1, 61.3, 58.8, 54.1, 50.9, 32.8, 28.3, 15.2, 14.3.
1
Minor Diastereomer. H NMR (400 MHz, CDCl3) δ 7.30 (m,
3H), 7.20 (m, 1H), 7.17 (m, 1H), 5.81−5.45 (m, 1H), 5.30 (d, J = 8.8
Hz, 1H), 5.12−5.02 (m, 1H), 5.01−4.92 (m, 1H), 4.80 (dd, J = 5.4,
3.6 Hz, 1H), 4.25−4.11 (m, 2H), 3.98−3.85 (m, 1H), 2.82 (s, 3H),
2.50−2.21 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H);
13C NMR (100.6 MHz, CDCl3) δ 171.6, 170.7, 155.1, 136.7, 135.4,
128.6, 128.3, 127.3, 117.1, 61.3, 58.8, 54.2, 51.1, 32.8, 28.3, 15.2, 14.3.
Ethyl 2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)hexanoate (4e). Scale: 0.400 g (1.31 mmol) with 1-
bromobutane (0.42 mL, 3.93 mmol) and TBAI (0.241 g, 0.655 mmol,
0.5 equiv) at 65 °C. Yield: 0.411 g, 87% as a colorless oil and a 51:49
Ethyl (R)-2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)-2-methylbutanoate (5b). Scale: 0.200 g (0.602 mmol) of
E
dx.doi.org/10.1021/jo502140d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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4c with MeI (0.11 mL, 1.77 mmol). Yield: 0.198 g, 95%, as a colorless
oil and as a 95:5 mixture of diastereomers.
= 2.3, DCM); IR νmax (cm−1) 3011, 3009, 2861, 1737, 1674; 1H NMR
(400 MHz, CDCl3) δ 7.34 (m, 3H), 7.26 (m, 2H), 7.07 (m, 1H), 6.99
(m, 2H), 6.82 (m, 2H), 5.36 (d, J = 8.4 Hz, 1H), 4.04 (q, J = 7.2 Hz,
2H), 3.95 (dq, J = 8.4, 6.8 Hz, 1H), 3.38 (bs, 2H), 2.81 (s, 3H), 1.87−
1.77 (m, 2H), 1.42−1.30 (m, 1H), 1.29−1.20 (m, 2H), 1.12 (t, J = 7.2
Hz, 3H), 1.10−1.05 (m, 1H), 0.87 (t, J = 6.8 Hz, 3H), 0.85 (d, J = 7.2
Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 171.6, 170.1, 155.5, 137.0,
136.6, 130.6, 128.5, 128.2, 127.8, 127.8, 126.4, 60.8, 60.5, 59.9, 54.5,
39.7, 33.1, 28.4, 26.7, 23.1, 15.1, 14.1, 14.1; HRMS (ES) m/z: [M +
H]+ Calcd for C27H35N2O4 451. 2593; Found 451.2590.
[α]2D0 = −32.6, (c = 0.65, DCM); IR νmax 3012, 2863, 1737, 1676;
1H NMR (400 MHz, CDCl3) δ 7.29 (m, 3H), 7.16 (m, 2H), 5.28 (d, J
= 8.4 Hz, 1H), 4.25−4.11 (m, 2H), 3.89 (dq, J = 8.4, 6.4 Hz, 1H), 2.76
(s, 3H), 2.02−1.90 (m, 2H), 1.42 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H),
0.82 (t, J = 7.2 Hz, 3H), 0.76 (d, J = 6.4 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 172.9, 170.8, 155.4, 136.9, 128.6, 128.2, 127.1, 60.6,
60.5, 55.5, 54.4, 29.0, 28.3, 21.0, 15.1, 14.3, 9.1; HRMS (ES) m/z: [M
+ H]+ Calcd for C19H27N2O4 347.1967; Found 347.1971.
Ethyl (R)-2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)-2-methyloctanoate (5h). Scale: 0.200 g (0.515 mmol) of
4f with methyl iodide (0.10 mL, 1.61 mmol). Yield: 0.187 g, 90%, as a
colorless oil and a 99:1 mixture of diastereomers.[α]2D01 = −47.0, (c =
1.0, DCM); IR νmax (cm−1) 3011, 2865, 1735, 1675; H NMR (400
MHz, CDCl3) δ 7.30 (m, 3H), 7.17 (m, 2H), 5.29 (d, J = 8.4 Hz, 1H),
4.26−4.12 (m, 2H), 3.90 (dq, J = 8.4, 6.4 Hz, 1H), 2.78 (s, 3H), 1.98−
1.85 (m, 2H), 1.45 (s, 3H), 1.38−1.31 (m, 1H), 1.27 (t, J = 7.2 Hz,
3H), 1.26−1.22 (m, 6H), 1.13−0.98 (m, 1H), 0.85 (t, J = 6.8 Hz, 3H),
0.78 (d, J = 6.4 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 173.1,
170.9, 155.3, 136.8, 128.6, 128.2, 127.0, 60.7, 60.5, 55.1, 54.4, 36.0,
31.7, 29.7, 28.3, 24.4, 22.7, 21.6, 15.1, 14.3, 14.2; HRMS (ES) m/z: [M
+ H]+ Calcd for C23H35N2O4 403.2590; Found 403.2587.
Ethyl (S)-2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)-2-ethylpent-4-enoate (5c). Scale: 0.200 g (0.602 mmol) of
4c with allyl iodide (0.17 mL, 1.86 mmol). Yield: 0.203 g, 92%, as a
colorless oil and a 96:4 mixture of diastereomers.0
[α]D20 = −23.6, (c = 1.0, DCM); IR νmax (cm−1) 3010, 2987, 2860,
1
1737, 1675; H NMR (400 MHz, CDCl3) δ 7.30 (m, 3H), 7.19 (m,
2H), 5.49−5.37 (m, 1H), 5.32 (d, J = 8.4 Hz, 1H), 5.00−4.94 (m,
1H), 4.91−4.85 (m, 1H), 4.25−4.11 (m, 2H), 3.91 (dq, J = 8.4, 6.4
Hz, 1H), 2.93−2.85 (m, 1H), 2.78 (s, 3H), 2.74−2.68 (m, 1H), 2.00
(q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 0.81 (t, J = 7.6 Hz, 3H),
0.79 (d, J = 7.6 Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 171.5,
169.8, 155.3, 136.7, 133.3, 128.5, 128.2, 127.3, 118.0, 60.6, 60.5, 58.8,
54.4, 37.5, 28.3, 26.0, 15.1, 14.4, 8.7; HRMS (ES) m/z: [M + H]+
Calcd for C21H29N2O4 373.2126; Found 373.2127.
Ethyl (S)-2-Benzyl-2-((4R,5S)-3,4-dimethyl-2-oxo-5-phenylimida-
zolidine-1-carbonyl)butanoate (5d). Scale: 0.200 g, (0.602 mmol)
of 4c with benzyl bromide (0.21 mL, 1.77 mmol). Yield: 0.219 g, 89%,
as a colorless solid and as a 96:4 mixture of diastereomers. mp 107−
110 °C; [α]2D0 = −42.0, (c = 0.8, DCM); IR νmax (cm−1) 3010, 3009,
2863, 1739, 1635; 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 3H), 7.25
(m, 2H), 7.07 (m, 1H), 6.98 (m, 2H), 6.84 (m, 2H), 5.37 (d, J = 8.5
Hz, 1H), 4.04 (q, J = 9.6 Hz, 2H), 3.95 (dq, J = 8.5, 6.6 Hz, 1H), 3.37
(bs, 2H), 2.81 (s, 3H), 1.98−1.89 (m, 2H), 1.12 (t, J = 9.6 Hz, 3H),
0.87 (t, J = 7.5 Hz, 3H), 0.86 (d, J = 6.6 Hz, 3H); 13C NMR (100.6
MHz, CDCl3) δ 171.5, 169.9, 155.6, 137.1, 136.7, 130.7, 128.6, 128.2,
128.0, 127.8, 126.4, 61.0, 60.5, 55.4, 54.7, 39.5, 28.4, 26.7, 15.1, 14.1,
9.1; Anal. Calcd for C25H30N2O4 (%): C, 71.07; H, 7.16; N, 6.63.
Found (%): C, 70.81; H, 6.99; N, 6.67.
Ethyl (S)-2-Allyl-2-((4R,5S)-3,4-dimethyl-2-oxo-5-phenylimida-
zolidine-1-carbonyl)octanoate (5i). Scale: 0.200 g (0.515 mmol) of
4f with allyl iodide (0.14 mL, 1.53 mmol). Yield: 0.192 g, 87%, as a
colorless oil and a >99:1 mixture of diastereomers.[α]2D0 = −27.2, (c =
1
1.0, DCM); IR νmax (cm−1) 3010, 2988, 2860, 1735, 1674; H NMR
(400 MHz, CDCl3) δ 7.30 (m, 3H), 7.18 (m, 2H), 5.50−5.41 (m,
1H), 5.31 (d, J = 8.4 Hz, 1H), 5.00−4.96 (m, 1H), 4.91−4.87 (m,
1H), 4.24−4.11 (m, 2H), 3.91 (dq, J = 8.4, 6.4 Hz, 1H), 2.96−2.88
(m, 1H), 2.79 (s, 3H), 2.76−2.69 (m, 1H), 1.97−1.88 (m, 2H), 1.28−
1.22 (m, 7H), 1.26 (t, J = 7.2 Hz, 3H), 1.19−1.00 (m, 1H), 0.85 (t, J =
6.8 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 171.6, 170.0, 155.3, 136.7, 133.4, 128.5, 128.2, 127.3, 118.0, 60.6,
60.5, 58.4, 54.4, 38.1, 33.0, 31.7, 29.6, 28.3, 24.0, 22.7, 15.1, 14.4, 14.2;
HRMS (ES) m/z: [M + H]+ Calcd for C25H37N2O4 429.2762; Found
429.2753.
Ethyl (S)-2-Benzyl-2-((4R,5S)-3,4-dimethyl-2-oxo-5-phenylimida-
zolidine-1-carbonyl)octanoate (5j). Scale: 0.200 g (0.515 mmol) of
4f with benzyl bromide (0.18 mL, 1.52 mmol). Yield: 0.202 g, 82%, as
a colorless oil and a >99:1 mixture of diastereomers. [α]2D0 = −10.8, (c
= 1.0, DCM); IR νmax (cm−1) 3013, 3010, 2863, 1739, 1677; 1H NMR
(400 MHz, CDCl3) δ 7.34 (m, 3H), 7.26 (m, 2H), 7.07 (m, 1H), 6.99
(m, 2H), 6.82 (m, 2H), 5.36 (d, J = 8.4 Hz, 1H), 4.04 (q, J = 7.2 Hz,
2H), 3.94 (dq, J = 8.4, 6.6 Hz, 1H), 3.38 (bs, 2H), 2.81 (s, 3H), 1.90−
1.80 (m, 2H), 1.42−1.35 (m, 1H), 1.30−1.20 (m, 6H), 1.11 (t, J = 7.2
Hz, 3H), 1.16−1.08 (m, 1H), 0.86 (d, J = 6.6 Hz, 3H), 0.85 (t, J = 6.8
Hz, 3H); 13C NMR (100.6 MHz, CDCl3) δ 171.6, 170.0, 155.5, 137.0,
136.6, 130.6, 128.5, 128.2, 127.8, 127.8, 126.4, 60.8, 60.5, 60.0, 54.5,
39.7, 33.2, 31.8, 29.6, 28.4, 24.4, 22.7, 15.1, 14.2, 14.1; HRMS (ES) m/
z: [M + H]+ Calcd for C29H39N2O4 479.2916; Found 479.2910.
General Procedure for Converting Quaternized Products 5
to Hydroxyesters 8. To a solution of ethanethiol (0.19 mL, 2.63
mmol, 10.5 equiv) in THF (2.0 mL) at −78 °C was slowly added n-
BuLi (1.00 mL, 2.50 mmol, 10 eq, 2.5 M). After 30 min, a solution of 5
(100 mg, 0.25 mmol) in the “up/up” series in THF (1.5 mL) was
slowly added to the reaction mixture at −78 °C, and the contents were
allowed to gradually warm up to rt over 1 h. Thereafter, the reaction
mixture was warmed to 40 °C and stirred at this temperature until
TLC indicated the complete conversion of starting material (see Table
2 for durations). Thereafter, the contents were cooled to rt and
quenched with sat. NaHCO3 (15 mL) and extracted with DCM (3 ×
20 mL), and the organic extracts were combined and dried over
MgSO4. Following the removal of organic solvent under reduced
pressure, the crude residue was purified by column chromatography
using (5% EtOAc in hexane) to afford thioester 6.
Ethyl (R)-2-((4R,5S)-3,4-Dimethyl-2-oxo-5-phenylimidazolidine-1-
carbonyl)-2-methylhexanoate (5e). Scale: 0.200g (0.555 mmol) of
4e with methyl iodide (0.10 mL, 1.61 mmol). Yield: 0.283 g, 88%, as a
colorless oil and a 95:5 mixture of diastereomers. [α]2D01 = −40.5, (c =
1.0, DCM); IR νmax (cm−1) 3010, 2859, 1739, 1677; H NMR (400
MHz, CDCl3) δ 7.30 (m, 3H), 7.17 (m, 2H), 5.30 (d, J = 8.4 Hz, 1H),
4.20 (m, 2H), 3.91 (dq, J = 8.4, 6.4 Hz, 1H), 2.78 (s, 3H), 1.92 (m,
2H), 1.45 (s, 3H), 1.37−1.80 (m, 3H), 1.27 (t, J = 6.8 Hz, 3H), 1.10−
1.00 (m, 1H), 0.86 (t, J = 7.2 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H); 13C
NMR (100.6 MHz, CDCl3) δ 173.1, 170.9, 155.3, 136.8, 128.6, 128.2,
127.0, 60.7, 60.5, 55.0, 54.4, 35.8, 28.3, 26.7, 23.2, 21.6, 15.1, 14.3,
14.1; HRMS (ES) m/z: [M + H]+ Calcd for C21H31N2O4 375.2286;
Found 375.2284.
Ethyl (S)-2-Allyl-2-((4R,5S)-3,4-dimethyl-2-oxo-5-phenylimida-
zolidine-1-carbonyl)hexanoate (5f). Scale: 0.200 g (0.555 mmol) of
4e with allyl iodide (0.15 mL, 1.64 mmol). Yield: 0.189 g, 85%, as a
colorless solid and a 96:4 mixture of diastereomers. mp 88−90 °C;
[α]D20 = −30.2, (c = 0.8, DCM); IR νmax (cm−1) 3009, 2989, 2861,
1
1738, 1674; H NMR (400 MHz, CDCl3) δ 7.30 (m, 3H), 7.20 (m,
2H), 5.49−5.40 (m, 1H), 5.31 (d, J = 8.4 Hz, 1H), 5.00−4.95 (m,
1H), 4.90−4.87 (m, 1H), 4.25−4.09 (m, 2H), 3.91 (dq, J = 8.4, 6.4
Hz, 1H), 2.90−2.89 (m, 1H), 2.79 (s, 3H), 2.75−2.69 (m, 1H), 2.00−
1.92 (m, 2H), 1.35−1.19 (m, 3H), 1.26 (t, J = 7.2 Hz, 3H), 1.08−0.98
(m, 1H), 0.86 (t, J = 7.2 Hz, 3H), 0.79 (d, J = 6.4 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3) δ 171.6, 170.0, 155.3, 136.7, 133.4, 128.5, 128.2,
127.3, 118.0, 60.6, 60.5, 58.4, 54.4, 38.1, 32.8, 28.3, 26.3, 23.1, 15.1,
14.4, 14.1; Anal. Calcd for C23H32N2O4 (%): C, 68.97; H, 8.05; N,
6.99. Found (%): C, 68.53; H, 7.89; N, 7.00.
Ethyl (S)-2-Benzyl-2-((4R,5S)-3,4-dimethyl-2-oxo-5-phenylimida-
zolidine-1-carbonyl)hexanoate (5g). Scale: 0.200 g (0.555 mmol)
of 4e with benzyl bromide (0.20 mL, 1.68 mmol). Yield: 0.163 g, 84%,
as a colorless oil and a 93:7 mixture of diastereomers.[α]2D0 = −10.7, (c
A reaction flask with Pd/C (5.4 mg, 0.051 mmol, 0.30 equiv) was
purged with argon for 10 min, and dry THF (1.0 mL) was added. To
this suspension was slowly added a solution of thioester 6 (0.170
F
dx.doi.org/10.1021/jo502140d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
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mmol) in THF (1.5 mL), followed by triethylsilane (0.081 mL, 0.51
mmol, 3.0 equiv), and the contents were allowed to stir at rt. After 2 h,
the contents were diluted with EtOAc (10 mL), filtered through Celite
under reduced pressure, and washed with EtOAc (2 × 20 mL), and the
organic extracts were concentrated in vacuo. Aldehyde 7 was pure
enough by 1H NMR spectroscopy to be used without further
purification in the next step. NaBH4 (32 mg, 0.85 mmol, 5.0 equiv)
was suspended in dry THF (1.0 mL) at 0 °C under nitrogen. To this
solution was slowly added the crude mixture of 7 (0.170 mmol) in
THF (1.5 mL) at the same temperature. After 2 h, the reaction
mixture was slowly quenched with HCl (1.0 M, 10 mL) and extracted
with DCM (3 × 15 mL), and the organic extracts were dried over
MgSO4, which were filtered under reduced pressure and concentrated
in vacuo. The crude residue was purified by column chromatography
(20% EtOAc in hexane) to afford the alcohol 8.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra and HPLC traces of all compounds,
and X-ray data for 5d and 5f are presented. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: +27 21 650 5195. E-mail: Roger.Hunter@uct.ac.za
(R.H.).
■
Notes
The authors declare no competing financial interest.
Ethyl (2R)-2-Benzyl-2-(hydroxymethyl)butanoate (8a). Scale:
0.100 g (0.237 mmol) of 5d; yield of 6a, 0.060 g, 82% as a pale-
yellow oil. Scale: 0.050 g (0.170 mmol) of 6a; yield of 8a over two
steps, 0.026 g, 65% as a clear oil and in 94% ee. [α]2D0 = −21.9, (c = 0.9,
ACKNOWLEDGMENTS
■
We thank the South African National Research Foundation, the
UCT Chemistry Equity Development Program, and Sasol Ltd.
for financial support toward this project.
1
DCM); IR vmax (cm−1) 3339, 3012, 2855, 1730; H NMR (400 MHz,
CDCl3) δ 7.23 (m, 5H), 4.24−4.12 (m, 2H), 3.71 (m, 1H), 3.51 (m,
1H), 3.08 (d, J = 13.4 Hz, 1H), 2.86 (d, J = 13.4 Hz, 1H), 2.15 (bs,
1H), 1.75−1.65 (m, 1H), 1.51−1.42 (m, 1H), 1.27 (t, J = 7.2 Hz, 3H),
0.91 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.3, 137.2,
130.5, 128.3, 126.7, 63.6, 60.7, 52.6, 39.0, 26.5, 14.3, 8.9; HRMS (ES)
m/z: [M + H]+ Calcd for C14H21O3 237.1485; Found 237.1483.
Ethyl (2S)-2-(Hydroxymethyl)-2-methylhexanoate (8b). Scale:
0.100 g (0.267 mmol) of 5e; yield of 6b, 0.053 g, 77% as a clear
liquid. Scale: 0.050 g (0.202 mmol) of 6b; yield of 8b over two steps,
0.021 g, 55% as a clear oil. [α]2D0 = −2.6, (c = 1.3, DCM); IR vmax
(cm−1) 3337, 2853, 1732; 1H NMR (400 MHz, CDCl3) δ 4.17 (q, J =
7.2 Hz, 2H), 3.71 (d, J = 11.2 Hz, 1H), 3.47 (d, J = 11.2 Hz, 1H), 2.16
(bs, 1H), 1.65−1.51 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.29−1.18 (m,
4H), 1.17 (s, 3H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 177.4, 68.5, 60.7, 47.8, 35.8, 26.5, 23.3, 19.8, 14.4, 14.0;
HRMS (ES) m/z: [M + H]+ Calcd for C10H21O3 189.1496; Found
189.1491.
REFERENCES
■
(1) For recent reviews, see: (a) Bella, M.; Casperi, T. Synthesis 2009,
1583. (b) Hawner, C.; Alexakis, A. Chem. Commun. 2010, 46, 7295.
(c) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593.
(2) A selection of recent papers include: (a) Jung, B.; Hoveyda, A. H.
J. Am. Chem. Soc. 2012, 134, 1490. (b) Evans, P. A.; Oliver, S.; Chae, J.
J. Am. Chem. Soc. 2012, 134, 19314. (c) Fournier, F.; Lozano, O.;
Menozzi, C.; Arseniyadis, S.; Cossy, J. Angew. Chem., Int. Ed. 2013, 52,
1257. (d) Mingat, G.; McDouall, J. J. W.; Clayden, J. Chem. Commun.
2014, 50, 6754. (e) Hojoh, K.; Shido, Y.; Ohmiya, H.; Sawamura, M.
Angew. Chem., Int. Ed. 2014, 53, 4954.
(3) A selection of recent papers include: (a) Wang, B.; Wu, F.; Wang,
Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2007, 129, 768−769. (b) Wang,
J.-J.; Dong, X.-J.; Wei, W.-T.; Yan, M. Tetrahedron: Asymmetry 2011,
22, 690. (c) Nugent, T. C.; Shoaib, M.; Shoaib, A. Org. Biomol. Chem.
2011, 9, 52. (d) Kastl, R.; Wennemers, H. Angew. Chem., Int. Ed. 2013,
52, 7228. (e) Dabrowski, J. A.; Villaume, M. T.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2013, 52, 8156. (f) Muller, D.; Alexakis, A. Chem.Eur.
J. 2013, 19, 15226. (g) Ma, C.-H.; Kang, T.-R.; He, L.; Liu, Q.-Z. Eur.
J. Org. Chem. 2014, 2014, 3981. (h) Hayashi, Y.; Kawamoto, Y.;
Honda, M.; Okamura, D.; Umemiya, S.; Noguchi, Y.; Mukaiyama, T.;
Sato, I. Chem.Eur. J. 2014, 20, 12072.
Ethyl (2R)-2-Benzyl-2-(hydroxymethyl)octanoate (8d). Scale:
0.100 g (0.209 mmol) of 5j; yield of 6d, 0.051 g, 70% as a yellow
liquid. Scale: 0.040 g (0.114 mmol) of 6d; yield of 8d over two steps,
0.020 g, 60% as a clear oil in >99% ee. [α]2D0 = −1.4, (c = 0.85, DCM);
IR vmax (cm−1) 3341, 3009, 2856, 1733; 1H NMR (400 MHz, CDCl3)
δ 7.29−7.17 (m, 5H), 4.24−4.11 (m, 2H), 3.71 (d, J = 11.5 Hz, 1H),
3.50 (d, J = 11.5 Hz, 1H), 3.09 (d, J = 13.4 Hz, 1H), 2.86 (d, J = 13.4
Hz, 1H), 2.12 (bs, 1H), 1.67−1.59 (m, 2H), 1.47−1.39 (m, 1H), 1.25
(t, J = 6.8 Hz, 3H), 1.29−1.24 (m, 7H), 0.88 (t, J = 6.8 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 176.5, 137.2, 130.5, 128.3, 126.7, 64.0,
60.7, 52.3, 39.4, 33.8, 31.8, 30.0, 24.5, 22.7, 14.3, 14.2; HRMS (ES) m/
z: [M + H]+ Calcd for C18H29O3 293.2111; Found 293.2108.
Ethyl (2S)-2-Benzoyloxymethyl-2-propyloctanoate (9). Scale:
0.100 g (0.233 mmol) of 5i; yield of 6c, 0.062 g, 89% as a yellow
liquid. Scale: 0.037 g (0.123 mmol) of 6c gave crude alcohol 8c, to
which in DCM (1.0 mL) at 0 °C was added benzoyl chloride (29.0 μL,
0.246 mmol, 2.0 equiv), and the contents were allowed to warm to rt.
After 2 h, the contents were quenched with sat. NaHCO3 (10 mL) and
extracted with EtOAc (3 × 15 mL), the organic extracts were dried
over MgSO4 and filtered under vacuum, and the organic solvent was
removed in vacuo. The crude residue was chromatographed using
EtOAc/hexane mixtures to afford benzoate 9 (yield 0.023 g, 54% over
three steps from 6c) as a colorless oil in 94% ee. [α]2D0 = −8.0, (c =
(4) (a) Marek, I.; Sklute, G. Chem. Commun. 2007, 1683. (b) Dutta,
B.; Gilboa, N.; Marek, I. J. Am. Chem. Soc. 2010, 132, 5588. (c) Yus,
́ ́
M.; Gonzalez-Gomez, J.-C.; Foubelo, F. Chem. Rev. 2011, 111, 7774.
(5) (a) Abe, T.; Suzuki, T.; Sekiguchi, K.; Hosokawa, S.; Kobayashi,
S. Tetrahedron Lett. 2003, 44, 9303. (b) Arpin, A.; Manthorpe, J. M.;
Gleason, J. L. Org. Lett. 2006, 8, 1539. (c) Doyle, A. G.; Jacobsen, E.
N. Angew. Chem., Int. Ed. 2007, 46, 3701. (d) Mukherjee, S.; List, B. J.
Am. Chem. Soc. 2007, 129, 11336. (e) Zhang, K.; Peng, Q.; Hou, X.-L.;
Wu, Y.-D. Angew. Chem., Int. Ed. 2008, 47, 1741. (f) Kummer, D. A.;
Chain, W. J.; Morales, M. R.; Quiroga, O.; Myers, A. G. J. Am. Chem.
Soc. 2008, 130, 13231. (g) Fleming, F. F.; Liu, W.; Ghosh, S.; Steward,
O. W. J. Org. Chem. 2008, 73, 2803. (h) Hashimoto, T.; Sakata, K.;
Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 5014. (i) Mycka, R. J.;
Steward, O. W.; Fleming, F. F. Org. Lett. 2010, 12, 3030. (j) Gu, Z.;
Herrmann, A. T.; Stivala, C. E.; Zakarian, A. Synlett 2010, 1717.
(k) Yoshida, M.; Terumine, T.; Masaki, E.; Hara, S. J. Org. Chem.
2013, 78, 10853. (l) Xu, Q.-Q.; Zhao, Q.; Shan, G.-S.; Yang, X.-C.; Shi,
Q.-Y.; Lei, X. Tetrahedron 2013, 69, 10739.
1
0.65, DCM); IR vmax (cm−1) 3013, 2855, 1733, 1720; H NMR (400
(6) (a) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.;
Maruoka, K. Angew. Chem. 2003, 115, 3926. (b) Fujimoto, T.; Endo,
K.; Tsuji, H.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008,
130, 4492. (c) Nagata, K.; Sano, D.; Shimizu, Y.; Miyazaki, M.;
Kanemitsu, T.; Itoh, T. Tetrahedron: Asymmetry 2009, 20, 2530.
(d) Akashi, Y.; Takao, K-i.; Tadano, K-i. Tetrahedron Lett. 2009, 50,
1139. (e) Ha, M. W.; Hong, S.; Park, C.; Park, Y.; Lee, J.; Kim, M-h.;
Lee, J.; Park, H-g. Org. Biomol. Chem. 2013, 11, 4030−4039.
MHz, CDCl3) δ 8.00 (m, 2H), 7.56 (m, 1H), 7.44 (m, 2H), 4.44 (s,
2H), 4.17 (q, J = 7.1 Hz, 2H), 1.71−1.65 (m, 4H), 1.27 (m, 10H),
1.24 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 6.8 Hz,
3H); 13C NMR (101 MHz, CDCl3) δ 175.0, 166.4, 133.1, 130.4,
129.7, 128.6 65.8, 60.7, 49.7, 36.0, 33.7, 31.7, 29.8, 24.0, 22.7, 17.5,
14.7, 14.4, 14.1; HRMS (ES) m/z: [M + H]+ Calcd for C21H33O4
349.2373; Found 349.2377.
G
dx.doi.org/10.1021/jo502140d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(7) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737. (b) Evans, D. A.; Helmchen, G.; Ruping, M.;
Wolfgang, J. In Asymmetric Synthesis, 2nd ed.; Christmann, M. S. B.,
Ed.; Wiley-VCH: Weinheim, 2007; pp 3−9.
(8) (a) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I.
Nature 2012, 490, 522. (b) Minko, Y.; Pasco, M.; Lercher, L.; Marek, I.
Nat. Protoc. 2013, 8, 749.
(9) (a) Ihara, M.; Takahashi, M.; Niitsuma, H.; Taniguchi, N.; Yasui,
K.; Fukumoto, K. J. Org. Chem. 1989, 54, 5413. (b) Ihara, M.; Tanaka,
Y.; Takahashi, N.; Okunaga, Y.; Fukumoto, K. J. Chem. Soc., Perkin
Trans. 1 1997, 3043. (c) Reddy, D. S.; Shibata, N.; Nagai, J.;
Nakamura, S.; Toru, T.; Kanemasa, S. Angew. Chem., Int. Ed. 2008, 47,
164.
́
(10) (a) Lumbierres, M.; Marchi, C.; Moreno-Manas, M.; Sebastian,
̃
R. M.; Vallribera, A.; Lago, E.; Molins, E. Eur. J. Org. Chem. 2001,
2321. (b) Gimbert, C.; Lumbierres, M.; Marchi, C.; Moreno-Manas,
̃
́
M.; Sebastian, R. M.; Vallribera, A. Tetrahedron 2005, 61, 8598.
(11) Niwayama, S.; Cho, H.; Lin, C. Tetrahedron Lett. 2008, 49, 4434.
(12) (a) Roder, H.; Helmchen, G.; Peters, E. M.; von Schnering, H.
G. Angew. Chem., Int. Ed. Engl. 1984, 23, 898−899. (b) Drewes, S. E.;
Malissar, D. G. S.; Roos, G. H. P. Chem. Ber. 1993, 126, 2663−2673.
́
(c) Guillena, G.; Najera, C. Tetrahedron: Asymmetry 1998, 9, 1125.
(d) Shirali, S.; Zhang, A. Synth. Commun. 2004, 34, 3435.
(e) Treweeke, N. R.; Hitchcock, P. B.; Pardoeb, D. A.; Caddick, S.
Chem. Commun. 2005, 1868. (f) MacNevin, C. J.; Moore, R. L.; Liotta,
D. C. J. Org. Chem. 2008, 73, 1264−1269.
(13) (a) Cuifen, L.; Lei, H.; Guichun, Y.; Zuxing, C. Curr. Org. Chem.
2012, 16, 2802. (b) Khatik, G. L.; Kumar, V.; Nair, V. A. Org. Lett.
2012, 14, 2442.
(14) (a) Katritzky, A. R.; Hayden, A. E.; Kirichenko, K.; Pelphrey, P.;
Ji, Y. J. Org. Chem. 2004, 69, 5108. (b) Hunter, R.; Msutu, A.; Dwyer,
C. L.; Emslie, N. D.; Hunt, R. C.; Bezuidenhoudt, B. C. B. Synlett
2011, 16, 2335.
(15) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1. (b) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org.
Chem. 1990, 55, 173−181.
(16) (a) Fukuyama, T.; Lin, S.-C.; Li, L. J. Am. Chem. Soc. 1990, 112,
7050. (b) Fukuyama, T.; Tokuyama, H. Aldrichimica Acta 2004, 37,
87.
H
dx.doi.org/10.1021/jo502140d | J. Org. Chem. XXXX, XXX, XXX−XXX