Formation, Alkylation, and Hydrolysis of Chiral Nonracemic N-Amino Cyclic Carbamate Hydrazones: An Approach to the Enantioselective α-Alkylation of Ketones

Article abstract of DOI:10.1021/acs.joc.8b00655

The α-alkylation of ketones is a fundamental synthetic transformation. The development of asymmetric variants of this reaction is important given that numerous natural products, drugs, and related compounds exist as α-functionalized ketones or derivatives thereof. We previously reported our preliminary studies on the development of a new enantioselective ketone α-alkylation procedure using N-amino cyclic carbamate (ACC) auxiliaries. In comparison to other auxiliary-based methods, ACC alkylation offers a number of advantages and is both highly enantioselective and high yielding. Herein, we provide a full account of our studies on the enantioselective ACC ketone α-alkylation method.

Full text of DOI:10.1021/acs.joc.8b00655

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Featured Article
Formation, Alkylation and Hydrolysis of Chiral Nonracemic
N-Amino Cyclic Carbamate Hydrazones: An Approach
to the Enantioselective #-Alkylation of Ketones
Uyen Huynh, Stacey L. McDonald, Daniel Lim, Md. Nasir
Uddin, Sarah E. Wengryniuk, Sumit Dey, and Don M Coltart
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00655 • Publication Date (Web): 10 Sep 2018
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Formation, Alkylation and Hydrolysis of Chiral Nonracemic N-Amino Cyclic
Carbamate Hydrazones: An Approach to the Enantioselective α-Alkylation of
Ketones
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†
‡
Uyen Huynh, Stacey L. McDonald, Daniel Lim, Md. Nasir Uddin, Sarah E.
§
*
Wengryniuk, , Sumit Dey, and Don M. Coltart
Department of Chemistry, University of Houston, Houston, TX, 77204
Abstract: The α-alkylation of ketones is a fundamental synthetic transformation.
The development of asymmetric variants of this reaction is important given that
numerous natural products, drugs, and related compounds exist as α-functionalized
ketones or derivatives thereof. We previously reported our preliminary studies on
the development of a new enantioselective ketone α-alkylation procedure using N-
amino cyclic carbamate (ACC) auxiliaries. In comparison to other auxiliary-based
†
Current address: Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel
Hill, NC 27599.
Current address: Department of Chemistry, Yeshiva University, New York, NY 10033.
Current address: Department of Chemistry, Temple University, Philadelphia, PA 19122.
‡
§
*
dcoltart@central.uh.edu
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methods, ACC alkylation offers a number of advantages and is both highly
enantioselective and high yielding. Herein, we provide a full account of our studies
on the enantioselective ACC ketone α-alkylation method.
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Introduction
The asymmetric α-alkylation of ketones is an important yet challenging
transformation. Remarkably, despite its importance only three methods are
available for ketone α-alkylation that have been used in the asymmetric total
1
synthesis of natural products. The use of derived azaenolates has proven more
effective in alkylation reactions than enolates in terms of reactivity, product yield,
and regioselectivity (C vs. O/N). Azaenolates also provide a means of effecting
asymmetric induction through the use of amine-based chiral auxiliaries. In 1969,
Yamada provided the first such demonstration along these lines, albeit with an
enamine rather than an azaenolate species. In that work, proline-derived enamines
were shown to undergo asymmetric conjugate addition to methyl acrylate and
2
acrylonitrile with low yield and asymmetric induction. While the results of these
studies left considerable room for improvement, they are highly important in
adumbrating not only future work in the context of azaenolate-based ketone
3
alkylation, but also that in the area of enamine-based organocatalysis. With regard
4
5
to the former, Koga and Meyer subsequently and independently reported the use
of acyclic amino acid-derived auxiliaries in the asymmetric α-alkylation of ketones
via derived imines, with good to very good diastereoselectivity in the case of cyclic
ketones, but poor selectivity for acyclic ketones. SAMP/RAMP dialkyl hydrazones
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were introduced by Enders in the late 1970s and were found to undergo alkylation
with moderate to excellent diastereoselectivity, and modest to very good yield.1a,b,6
The introduction of SAMP/RAMP chemistry marked a key advance in the field of
asymmetric synthesis. This method has been employed in asymmetric ketone α-
alkylation, but is most well established for aldehyde α-alkylation. In the early
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000s, Tunge, Stoltz, and Trost independently reported non-azaenolate-based
methods for the catalytic asymmetric α-allylation of ketones, with the Stoltz method
finding impressive applications in the synthesis of natural products.1c-p These
catalytic, asymmetric Tsuji-Trost-based approaches provided the first major
advance in the field of asymmetric ketone α-alkylation since the introduction of the
SAMP/RAMP auxiliaries, but are each limited to the incorporation of allyl-based
substituents.
Scheme 1. Enantioselective α-alkylation of ketones using ACC auxiliaries.
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In 2008, we reported our initial studies on the development of a method for
the enantioselective α-alkylation of ketones using N-amino cyclic carbamate (ACC)
auxiliaries (Scheme 1, 1 → 6).10,11 In contrast to other methods, ACC auxiliaries are
both easily introduced into and removed from ketones, with near quantitative
recovery. A key design feature of ACC auxiliaries is the placement of a carbonyl
group adjacent to the hydrazone moiety. This serves three purposes: 1) it enhances
the α-proton acidity leading to rapid deprotonation, even at low temperature, 2) it
enables the formation of a rigid five-membered chelate (cf. 4, 9) such that highly
diastereoselective alkylation is possible even at elevated temperature, and, 3) it
allows for regioselective deprotonation via complex-induced syn-deprotonation
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(
CIS-D) (vide infra). The latter effect, which is able to override the inherent
selectivity of LDA for removal of the least sterically hindered proton, makes possible
1
2, 13
the α,α-bisalkylation of ketones having both acidic α-, and α’-protons,
a
previously unattainable transformation. In what follows, we provide a full account
of the development of the enantioselective ACC ketone α-alkylation method.
The model that we have developed to rationalize the stereochemical outcome
of the ACC alkylation reaction is outlined in Scheme 2.10,11 Conformational
equilibrium favors what we term the carbonyl front form of the hydrazone (8) to
2
minimize steric interactions between R and the auxiliary. As indicated above,
azaenolate formation occurs upon treatment with LDA via CIS-D, which leads to
regioselective deprotonation of the front-facing proton on the same side of the
carbon-nitrogen double bond as the auxiliary (8→9). This results in the formation
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of an azaenolate having the E-geometry about the C–C bond and the Z-geometry
about the C–N bond (9). The azaenolate exists as a five-membered chelate involving
+
the nitrogen-centered anion, the auxiliary carbonyl, and Li , and is configurationally
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stable at the reaction temperature. In this form, the bottom face of the azaenolate is
blocked, causing the electrophile to approach from the top face to give the α-
alkylated hydrazone (9→10). Auxiliary cleavage then provides the desired ketone
(11) in enantiomerically enriched form.
Scheme 2. Proposed stereochemical model of ACC alkylation.
Results and Discussion
Our initial report on ACC alkylation centered on auxiliaries 13-16 (Table
).10 Of these, 13 proved to be the most effective in terms of asymmetric induction,
1
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Table 1. Allylation of 3-Pentanone using ACC Auxiliaries 13-16.
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ACC
13
hydrazone
allylated hydrazone alkylation yield (%)
(R)-12:(S)-12* hydrolysis yield (%)
1
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4
17
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21
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24
98
92
93
82
96:4
96
90
93
82
14
76:24
91:9
15
16
86:14
*Determined by chiral GC analysis.
14
giving an er of 96:4 for the α-allylation of 17. The synthesis of auxiliary 13 is
shown in Scheme 3, and begins with readily accessible and inexpensive camphor
sulfonic acid (25). Sulfonyl chloride 26 is also commercially available and can be
used as a starting point for the synthesis of 13. However, given the simplicity of the
conversion of 25 to 26 (vide infra), along with the lower cost of the former, we
prefer to begin from the sulfonic acid. 25 is converted into ketopinic acid (27) by
treatment with thionyl chloride to produce 26, which is then used in crude form and
1
5
oxidized by KMnO . The conversion of 26 to 27 has been described previously and
4
involves the treatment of 26 with an aqueous solution of KMnO , producing 27 in
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8–43% yield. We were able to improve this procedure through the simple
modification of adding acetonitrile as a co-solvent to the reaction mixture. This gave
consistently high yields (~80%) of 27 at various reaction scales. 27 was used
without purification to generate acid chloride 28, which was used in crude form to
prepare the corresponding acyl azide. Curtius rearrangement then led to isocyanate
29, which was also used without purification to produce oxazolidinone 30 upon
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treatment with NaBH
converted into the required ACC (13) by treatment with NH
desired, pure 30 could be obtained in 81% yield by recrystallization of the crude
4
in the presence of CeCl
3
∙7H O. The crude oxazolidinone was
2
1
6
2
Cl and t-BuOK. (If
1
7
amination mixture from EtOAc.) The amination method we used was developed by
chemists at the Bristol-Myers Squibb Company as a safe approach for the amination
of various nitrogen heterocycles, even in the large scale (75 g) amination of 1H-
pyrrole-2,4-dicarboxylic acid, 3-methyl-, 2,4-diethyl ester. Conveniently, in both
small and large scale applications, the required ACC hydrazones could be obtained
in pure form directly from the crude amination mixture [30 → 13 (crude)] by
condensation with the ketone in the presence of p-TsOH·H
2
O and CH
2
Cl at reflux
2
temperature [e.g., 13 (crude) → 17], followed by silica gel chromatography. At first
glance the synthesis of 13 appears rather long. However, since at all stages the
1
8
crude material generated is very clean and is used directly in the subsequent step,
along with the fact that all the transformations are easy to conduct and are complete
in a reasonably short time, large amounts of 13 can easily be generated in two days.
An alternative approach to the formation of the ACC hydrazones begins with
the acidification of 13 to produce 31 (the HCl salt of 13) in crude form, which could
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be recrystallized to give pure 31 in 82% yield over the two steps. Pure 31 could be
condensed directly with the required ketone by combining it in a 1:1 molar ratio at
reflux for 12 h using a Dean-Stark trap (e.g., 13 → 17), or by condensing it with an
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excess (10 equiv.) of the required ketone for 12 h at room temperature in CH
2
Cl . If
2
desired, pure 13 can be obtained by conversion to the corresponding acetone
OH⋅HCl and silica gel chromatography.10
hydrazone, followed by treatment with NH
2
Pure 13 can then be condensed with the appropriate ketone in a 1:10 molar ratio,
respectively, in the presence of p-TsOH·H O and CH Cl at reflux to produce the
2
2
2
desired hydrazone in excellent yield (not shown in Scheme 3).
Scheme 3. Synthesis of ACC auxiliary 13.
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As indicated above (Table 1), our original study of the α-alkylation of 17 gave
ers of up to 96:4.10 However, subsequent theoretical calculations conducted in
collaboration with the Houk group11 in an effort to confirm our proposed
stereochemical model,10 suggested that the level of asymmetric induction in the
alkylation of 17 should have been even greater than we had originally observed.
Consequently, we reinvestigated the allylation reaction for auxiliaries 13-16 and
found that, indeed, in each case the selectivity was better than we had initially
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19
found. To do this, we analyzed the level of diastereoselectivity of the allylation
products (21-24) of each ACC hydrazone (17-20, respectively), and compared that
to the level of enantioselectivity of the allylated ketone product (12), following
20
hydrolysis of the auxiliary. As it turned out, epimerization at the new stereogenic
center was occurring during auxiliary removal. To address this problem, we carried
out a survey of auxiliary cleavage conditions using 32 (prepared in the same
manner as 21, but using benzyl bromide), in the hope of being able to remove the
2
1
auxiliary without causing epimerization (Table 2). After some experimentation we
were able to find suitable conditions [p-TsOH⋅H O, acetone-H O (4:1)] that did not
2
2
compromise the new stereogenic center, yet gave the desired ketone in excellent
yield.
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Table 2. Studies on the hydrolysis of ACC hydrazone 32.
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conditions
p-TsOH•H
p-TsOH•H
p-TsOH•H
equiv.
solvent
time (h)
0.25
3
conversion (%)
(R)-33:(S)-33*
97:3
>99:1
98:2
>99:1
na
1
2
3
4
5
6
7
8
9
2
2
2
O
O
O
2
acetone
2
acetone-H O (4:1)
>99
>99
81
>99
0
2
2
THF-H
2
O (4:1)
24
BF
CuCl
Cu(OAc)
HO CCO
NH PO
3
•OEt
2
2
acetone-H
2
O (4:1)
12
2
1.2
2
THF-H
THF-H
THF-H
THF-H
2
2
2
2
O (4:1)
O (4:1)
O (4:1)
O (4:1)
24
2
24
0
na
2
2
H
2
24
0
na
H
4 2
4
20
2
24
0
na
10% HCl
10% HCl
AcOH
acetone
THF
24
>99
88
>99
95:5
98:2
98:2
10
2
3
11
2
acetone-H
2
O (4:1)
24
*
Determined by chiral HPLC analysis.
Using these new auxiliary cleavage conditions, the α-allylated ketone (12)
formed using auxiliaries 13-16 could be obtained with ers that were a true
reflection of the asymmetric induction of each auxiliary (Table 3).21 In all cases, the
level of asymmetric induction was greater than in our original analysis, and was
uniformly very high.
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Table 3. Allylation and hydrolysis of ACC hydrazones 17-20 using epimerization-
free hydrolysis conditions.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
entry
ACC
hydrazone
allylated hydrazone
alkylation yield (%) (R)-12:(S)-12*
hydrolysis
conversion (%)
>99
1
2
3
4
13
14
15
16
17
18
19
20
21
22
23
24
98
92
93
82
99:1
93:7
97:3
93:7
>99
>99
>99
*
Determined by chiral GC analysis.
We next examined the effect of temperature on the alkylation selectivity
using ACC hydrazone 17 (Table 4). To do this, 17 was treated with LDA at either –
8, –40, –20, or 0 °C for 1 h, followed by addition of allyl bromide. After 5 min the
7
cooling bath was removed and the mixture was allowed to stir for 30 min.
Following work up, the ratio of allylated hydrazone diasteroemers [(R)-21–(S)-21]
was determined by HPLC. In comparison to the result as –78 °C, the level of
asymmetric induction was not diminished by increasing the reaction temperature
up to –20 °C. However, the selectivity was comprised to a small extent when the
reaction was carried out at 0 °C. We attribute the high diasteroselectivity at
elevated temperatures to the stability of the five-membered chelate (cf. 4, 9) that
forms following deprotonation of the hydrazone. The structure of this species bears
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2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a strong resemblance to deprotonated hydroxamic acids and related compounds,
2
2
which are well established as very strong cation chelators. The ability to conduct
the transformation with ACC hydrazones at elevated temperature is significant, as it
creates the possibility of conducting large-scale enantioselective ketone α-
alkylations for the first time. As a preliminary test of this, the allylation of 17 was
carried out on a five gram scale at –20 °C, as described above, followed by
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
hydrolysis using p-TsOH⋅H
2
O, acetone-H
2
O (4:1). This resulted in the production of
12 in 92% yield (over the two steps) with an er of >99:1.
Table 4. Effect of temperature on the allylation of 17.
entry
temperature (ºC)
(R)-21: (S)-21*
>99:1
1
2
3
–78
–40
–20
0
>99:1
>99:1
4
97:3
*Determined by HPLC analysis.
With suitable conditions available for the alkylation procedure, we set out to
10
further refine the data from our preliminary study and extend it to include new
alkylating agents. We began by conducting a series of three alkylation reactions in a
way that allowed us to further test that the new hydrolysis conditions established
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Synthesis of racemic 12, 33, and 36.
above did not lead to epimerization during auxiliary removal. To do this, racemic 2-
allyl-3-pentanone [(±)-12], 2-benzyl-3-pentanone [(±)-33], and 2-ethyl-3-
pentanone [(±)-36] were prepared as outlined in Scheme 4. Each of these was
condensed with 13 (Scheme 5), which generated a mixture of the four possible
diastereomers (21a-d, 32a-d, and 37a-d, respectively). The chromatographically
purified mixtures of diastereomers were analyzed by HPLC under conditions that
gave near baseline resolution of the four diastereomers contained within each
mixture. Next, 17 was allylated, benzylated, and ethylated using our standard
conditions, and the crude reaction mixtures were analyzed under the same HPLC
conditions (Table 5). In each instance, the ratio of α-alkylated diastereomers was
>
99:1, and the α'-alkylated diastereomers were not observed. The alkylated
hydrazones were hydrolyzed and the enanitomer ratio of the resulting ketones was
determined by either chiral GC or HPLC analysis.21 In all cases the enantiomer ratio
corresponded to the diastereomer ratio of the alkylated hydrazones. This further
established that no appreciable epimerization was occurring during auxiliary
cleavage. On the basis of these results, for subsequent alkylations the level of
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
asymmetric induction was determined only from the enantiomer ratio of the
ketones produced, thereby simplifying the analysis process.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5. Synthesis of diastereomers 21a-d, 32a-d, 37a-d.
We continued exploring the scope of the transformation using hydrazone 17
and several different alkylating agents (Table 6). The electrophiles used varied from
simple primary alkyl halides with or without bulky substituents, to a secondary
alkyl halide. In addition, alkyl halides bearing other functional groups, such as
protected alcohols, an epoxide, and an ester, were employed. In all cases, the
alkylated hydrazones were obtained in very good to excellent yield. Hydrolysis
21
produced the corresponding ketones with very good to excellent conversion, and
with generally excellent ers. The only complications that we encountered was
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1
2
3
4
5
6
7
8
9
during the hydrolysis of 45 and 46. Under the acidic conditions the silyl ether of
compound 45 was also hydrolyzed, leading to hydroxy ketone 56. Furthermore, the
epoxide moiety of hydrazone 46 did not survive the hydrolysis step, and a complex
mixture of products resulted.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 5. Diastereoselectivity and enantioselectivity for the alkylation of 17.
1
entry R
X
alkylated
alkylation
alkylated
alkylation ketone ketone hydrolysis
†
hydrazone
regioselectivity
α:α‘ [(a+b):[c+d)]
hydrazone dr yield (%)
R:S
conversion
(%)
(a:b)*
1
2
Br 21
Br 32
>99:1
>99:1
>99:1
98
97
18
40
99:1
99:1
>99
99:1
>99
3
I
37
99:1
>99:1
92
41
99:1
>99
†
*
Determined by HPLC analysis. Determined by chiral GC or HPLC analysis.
We also tested the alkylation of cyclohexanone using ACC auxiliary 13 (Table
). 2-Allyl cyclohexanone (38) was obtained in excellent yield and er (>99:1) from
6
this process (Table 6, entry 10). The corresponding benzylation procedure gave a
slightly lower er (96:4), but also good yield (entry 11).
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 6. Alkylation of 17 and 38.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
entry
1
R
hydrazone
R
X
alkylated
alkylation ketone ketone R:S* hydrolysis
conversion (%)
hydrazone yield (%)
Me
17
Br
39
92
50
>99:1
>99
2
3
4
Me
Me
Me
17
17
17
I
I
I
40
41
42
91
98
89
51
52
53
98:2
99:1
95:5
>99
>99
>99
5
Me
17
I
43
81
54
97:3
>99
6
7
8
Me
Me
Me
17
17
17
I
44
45
46
90
90
97
55
56
57
>99:1
>99:1
n/a
>99
>99*
n/a
†
†
I
Cl
9
Me
17
Br
47
99
58
99:1
61
1
0
1
-(CH ) - 38
Br
Br
48
49
94
95
59
60
>99:1
96:4
87
92
2
3
1
-(CH ) - 38
2
3
†
*
Determined by chiral GC or HPLC analysis. The silyl ether hydrolyzed during auxiliary cleavage to give 56.
In our original ACC alkylation study, we had investigated phenylalanine-
derived auxiliary 14 in the allyaltion of 3-pentanone, but found that it gave
relatively poor selectivity (er = 76:24) in comparison to auxiliary 13 (er = 96:4).
However, as indicated in Table 3, using the new hydrolysis conditions we developed
(
vide supra), the enantioselectivity for auxiliary 14 was found to be significantly
higher (er = 97:3).19 As part of that study we also found that the phenylglycine-
derived auxiliary (61) gave even higher levels of asymmetric induction (er = 3:97) in
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the allylation of 3-pentanone (Table 7, entry 5). Given the relatively simple
structure of auxiliaries 14 and 61, along with their corresponding ease of
1
6
accessibility in comparison to 13, we wanted to determine if one or both of them
might prove to be a viable alternative to the use of 13. As such, 3-pentanone was
alkylated using both 14 and 61, along with three different alkylating agents (Table
7). For each alkylation tried, the phenylglycine-derived hydrazone (62) gave
excellent levels of asymmetric induction (er = 3:97 to 2:98). The phenylalanine-
derived auxiliary produced enantiomer ratios of 95:5 to 93:7. The allylation
reaction was also tried at –20 and 0 °C using both 18 and 62 (Table 7, entries 8–11),
as had been done previously for hydrazone 17 (Table 4). As with 17, for both 18
and 62 the selectivity remained equally high at –20 °C, but dropped off slightly at 0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
°
C. Conveniently, both the R and S forms of the phenylglycine- and phenylalanine-
2
3
derived oxazolidinones are commercially available and inexpensive. So, while
neither auxiliary 14 or 61 outperformed 13 in the alkylations, given the ease and
low cost of their production, they are likely to prove useful in certain synthetic
applications.
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8
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table 7. Enantioselectivity for the alkylation of 18 and 62.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
entry ACC ACC
hydrazone
18
R
X
temp (ºC) alkylated
alkylation ketone ketone R:S* hydrolysis
hydrazone yield (%)
conversion (%)
>99
1
14
Br –78
22
92
12
93:7
2
3
14
14
18
18
Br –78
Br –78
63
64
98
95
52
33
95:5
93:7
>99
>99
5
61
62
Br –78
65
93
12
3:97
>99
6
7
61
61
62
62
I
–78
66
67
94
97
52
33
3:97
2:98
>99
>99
Br –78
8
9
1
14
61
14
61
18
62
18
62
Br –20
Br –20
22
65
22
65
95
94
92
93
12
12
12
12
94:6
4:96
91:9
7:93
>99
>99
>99
>99
0
1
Br
Br
0
0
1
*
Determined by chiral GC or HPLC analysis.
Conclusion
In conclusion, we have established that ACC auxiliaries 13, 14, and 61 are
capable of effecting asymmetric α-alkylation with excellent enantioselectivity and
yield. The transformations are highly reliable and easy to carry out. For each
auxiliary the allylation reaction can be conducted at temperatures up to –20 °C
without compromising asymmetric induction. While auxiliary 13 is clearly superior
to all other auxiliaries we have tested, both auxiliary 14 and 61 also deliver
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1
2
3
4
5
6
7
8
9
synthetically useful levels of asymmetric induction, and have the advantage of being
relatively easy and inexpensive to produce in comparison to 13.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
General Considerations. Unless stated to the contrary, where applicable, the
following considerations apply. Reactions were carried out using dried solvents (see
below) under a slight static pressure of Ar (pre-purified quality) that had been
passed through a column (5 x 20 cm) of Drierite. Glassware was dried in an oven at
120 °C for at least 12 hours prior to use and then either cooled in a desiccator
cabinet over Drierite or assembled quickly while hot, sealed with rubber septa, and
allowed to cool under a stream of Ar. Reactions were stirred magnetically using
Teflon-coated magnetic stirring bars. Teflon-coated magnetic stirring bars and
syringe needles were dried in an oven at 120 °C for at least 12 h prior to use then
cooled in a desiccator cabinet over Drierite. Hamilton microsyringes were dried in
an oven at 60 °C for at least 24 h prior to used and cooled in the same manner.
Commercially available Norm-Jet disposable syringes were used. Dry THF was
obtained using an Innovative Technologies solvent purification system. Commercial
grade solvents were used for routine purposes without further purification. i-Pr
2
NH
was distilled from CaH under a N atmosphere prior to use. Flash column
2
2
1
13
chromatography was performed using silica gel 60 (230-400 mesh). H and C NMR
spectra were recorded on a JEOL ECA-500 or ECX-400P spectrometer at ambient
1
temperature. All H chemical shifts are reported in ppm (δ) relative to TMS (0.00),
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0
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
13C shifts are reported in ppm (δ) relative to CDCl
(77.16). High-resolution Mass
3
Spectrometry was acquired using an Agilent Technologies 6530 Accurate Mass Q-
Tof LC/MS for electrospray ionization (ESI), or a Micromass Autospec Ultima for
chemical ionization (CI). Chiral HPLC was performed on a 4.6 x 250 mm Chiralcel
OD-H column (Chiral Technologies) using UV detection. Chiral GC was performed on
a 20 m x 0.25 mm Chiraldex G-TA column (Advanced Separation Technologies), 40
m x 0.25 mm Chiraldex G-TA column (Advanced Separation Technologies), or 25 m x
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
0
.25mm CP-Cyclodextrin-β-2,3,6-M-19 column (Agilent).
Synthesis of ACC auxiliaries
(
1S)-(+)-Camphorsulfonyl chloride (26). Thionyl chloride (4.10g, 34.4mmol) was
added dropwise with vigorous stirring to a flask containing l-10-camphor sulfonic
acid (2.01g, 8.61mmol). The resulting mixture was stirred at reflux for 30 min and
then allowed to cool and poured over ice. The slurry was partitioned between Et
and water and the aqueous phase was extracted with Et O (2 x 25 mL), dried
(MgSO ), and concentrated in vacuo to yield 26 as a white solid (2.07g; 96%). H
NMR (400 MHz, CDCl ) δ 4.30 (d, J = 14.7 Hz, 1H), 3.72 (d, J = 14.7, 1H), 2.49-2.40
m, 2H), 2.17-2.12 (t, J = 4.6 Hz, 1H), 2.12-2.05 (m, 1H), 1.99 (d, J = 18.8 Hz, 1H),
2
O
2
1
4
3
(
1
3
1.80-1.73 (m, 1H), 1.51-1.42 (m, 1H), 1.13 (s, 3H), 0.92 (s, 3H). C NMR (CDCl
3
, 100
MHz) δ 212.9, 64.3, 59.8, 48.3, 42.9, 42.4, 27.0, 25.4, 19.9, 19.8. Spectroscopic data
2
4
was consistent with that previously reported.
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1
2
3
4
5
6
7
8
9
(
+)-10-Chlorocamphor-10-sulfine (27). A solution of tosyl chloride (186.2 g, .975
mol) in pyridine (216 mL, 2.66 mol) was heated to 100 °C and a solution of l-10-
camphor sulfonyl chloride (222.2 g, 0.89 mol) in 1,2-dichloroethane (250 mL) was
added dropwise over ca. 30 min. Upon completion of addition, the reaction was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
refluxed for 45 min then allowed to cool before being poured into Et
resulting dark brown precipitate was then isolated (Et O solution saved) and
washed with Et O (500 mL). The combined organic solutions were then
2
O (2 L). The
2
2
concentrated in vacuo to yield a dark-brown oil. Recrystallization from hexanes
1
yielded 27 as tan crystals (161.6 g; 78%). H NMR (400 MHz, CDCl
3
) δ 2.63-2.59 (d, J
=
18.3 Hz, 1H), 2.53-2.48 (t, J = 13.8 Hz, 1H), 2.25-2.24 (t, J = 4.6 Hz, 1H), 2.17-2.12
(m, 1H), 2.06 (d, J = 18.9 Hz, 1H), 1.75-1.70 (m, 1h), 1.54 (td, J = 9.7, 2.3 Hz, 1H),
13
1
.13 (s, 3H), 1.1 (s, 3H). C NMR (CDCl , 125 MHz) δ 209.3, 181.7, 66.8, 52.0, 44.1,
3
43.6, 27.6, 27.0, 21.7, 20.1. Spectroscopic data was consistent with that previously
2
5
reported.
(
+)-Ketopinic acid chloride (28). A solution of (+)-10-chlorocamphor-10-sulfine
(49.8 g, 211 mmol) in CH Cl (625 mL) and pyridine (22.0 mL, 221 mmol) was
cooled to –78 °C and treated with ozone until a pale blue solution was observed. The
reaction mixture was then partitioned between Et O and water, and the aqueous
layer was extracted with Et O (2 x 100 mL), dried (MgSO ), and concentrated in
vacuo to yield 28 as a brown oil. Thionyl chloride (15.4 mL, 211 mmol) and pyridine
0.3 mL, 4 mmol) were then added and the resulting mixture was refluxed for 2h. It
2
2
2
2
4
(
was then allowed to cool before benzene was added and the solution concentrated
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2
1
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3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
in vacuo to yield (+)-ketopinic acid chloride (28) as a brown solid (39.4 g; 93%). H
NMR (400 MHz, CDCl
3
) δ 2.61-2.53 (m, 1H), 2.52-2.45 (m, 1H), 2.16-1.97 (m, 4H),
1
3
1.51-1.41 (m, 1H), 1.17 (d, J = 9.6 Hz, 6H). C NMR (CDCl
3
, 125 MHz) δ 207.6, 172.1,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
6.0, 50.5, 44.3, 43.9, 28.5, 26.4, 21.1, 19.7. Spectroscopic data was consistent with
that previously reported.25
(
+)-1-Isocyanato-7,7-dimethylbicyclo[2.2.1]heptan-2-one (29). A solution of
(
+)-ketopinic acid chloride (28) (4.832g, 24.1 mmol) in acetone (100 mL) was
added dropwise over ca. 60 min to a stirred solution of sodium azide (4.684 g, 72.1
mmol) in water (100 mL) that was cooled to 0 °C. The reaction was warmed to rt
and stirred for 3 h. The solution was then partially concentrated in vacuo, diluted
with H
2
O, and extracted with Et
2
O (3 x 50 mL). The combined organic layers were
then washed with 5 % NaHCO
3
(2 x 50 mL), dried (MgSO ), and concentrated in
4
vacuo to yield the crude acyl azide. The acyl azide was dissolved in toluene (50 mL),
refluxed for 3 h, and then concentrated to yield 29 as a brown solid (4.31 g; >99%).
1H NMR (400 MHz, CDCl
(m, 1H), 1.47-1.45 (m, 1H), 1.04 (s, 3H), 0.90 (s, 3H); C NMR (CDCl
) δ 2.45 (d, J = 18.4 Hz, 1H), 2.12-1.95 (m, 4H), 1.67-1.65
3
1
3
3
, 100 MHz) δ
2
11.6, 128.6, 76.2, 47.3, 41.6, 40.2, 28.5, 26.8, 18.9, 18.7. Spectroscopic data was
2
6
consistent with that previously reported.
(
(
6R,7aR)-8,8-Dimethylhexahydro-2H-3a,6-methanobenz-o[d]oxazol-2-one
30). CeCl ·7H O (0.7 g, 1.84 mmol) was added to a solution of isocyanate 29 (3.3 g,
3
2
18.4 mmol) in MeOH (135 mL) that was cooled to 0 °C. The solution was stirred at 0
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1
2
3
4
5
6
7
8
9
°
C for 10 min, and then cooled to –78 °C. NaBH (0.99 g, 25.76 mmol) was then
4
added in four portions over a period of ca. 20 min. The reaction was warmed to –40
°C and stirred for 2.5 h. After warming to rt, the solvent was evaporated to remove
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
the majority of MeOH and the resulting mixture was diluted with H O (110 mL),
2
extracted with EtOAc (3 x 250 mL), dried (MgSO4), and concentrated in vacuo to
yield a tan powder. Recrystallization from EtOAc/hexanes yielded 30 as tan crystals
1
(
3.07 g; 92%). H NMR (CDCl
3
, 400 MHz) δ 5.67 (bs, 1H), 4.31 (dd, J = 8.1, 4.2 Hz,
1
3
1
2
H), 2.30-2.25 (m, 1H), 2.01-1.83 (m, 4H), 1.32-1.21 (m, 2H), 1.03 (s, 3H), 0.97 (s,
13
H); C NMR (CDCl
3
, 100 MHz) δ 161.1, 86.7, 69.6, 47.0, 42.2, 35.5, 27.2, 25.6, 19.3,
+
9.2. HRMS (ESI-TOF) m/z: [M+Na] Calcd for C10
H
15NO Na 204.09950; Found
2
04.09970.
(
6R,7aR)-3-Amino-8,8-dimethylhexahydro-2H-3a,6-methanobenzo[d]oxazol-
-one (13). KOtBu (0.727 g, 6.48 mmol) was added to a stirred solution of 30
0.587 g, 3.24 mmol) in THF (32.4 mL). The mixture was stirred at rt for 3.5 h.
2
(
16
Freshly prepared NH Cl (32.4 mL, 4.86 mmol) was then added dropwise over ca.
2
10 min, and the reaction mixture was stirred for 3 h. The reaction was quenched
with 1M Na (7 mL). The aqueous phase was extracted with Et O (2 x 25 mL),
and the combined organic layers were dried (MgSO
2
S
O
2 3
2
4
), and concentrated in vacuo to
1
yield crude 13 (0.642g, 93% conversion) as a yellow oil. H NMR (CDCl
3
, 500 MHz)
δ 4.15 (dd, J = 8.1, 4.1 Hz, 1H), 3.81 (s, 2H), 2.25-2.16 (m, 2H), 1.95-1.75 (m, 4H),
1
.29-1.25 (m, 1H), 1.67 (s, 3H), 1.00 (s, 3H); 13C NMR (CDCl
, 125 MHz) δ 159.7,
3
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4
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7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
8
2.9, 72.0, 47.2, 42.4, 34.8, 25.5, 25.0, 20.5, 19.1. Spectroscopic data was consistent
with that previously reported.10
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
6R,7aR)-8,8-Dimethyl-3-(pentan-3-ylideneamino)hexahy-dro-2H-3a,6-
methanobenzo[d]oxazol-2-one (17). Crude 13 (0.642g, approx. 3.24 mmol) was
dissolved in CH Cl (11 mL). 3-pentanone (2.4 mL, 32.4 mmol) and p-TsOH⋅H
0.04g, 0.194 mmol) were then added and the reaction mixture was stirred for 12 h.
The reaction was quenched with saturated aqueous NaHCO (5 mL), and the
aqueous phase was extracted with CH Cl (2 x 30 mL). The combined organic
extracts were washed with brine, dried (MgSO ), and concentrated in vacuo to yield
2
2
2
O
(
3
2
2
4
a yellow oil. Flash chromatography over silica gel using 20:80 EtOAc-hexanes gave
1
1
7 (0.789g, 92% over two steps) as a white solid. H NMR (CDCl
3
, 500 MHz) δ 4.25
(
dd, J = 8.1, 4.0 Hz, 1H), 2.50-2.19 (m, 5H), 2.11-1.79 (m, 3H), 1.73 (t, J = 4.3 Hz, 1H),
1
3
1.30-1.24 (m, 1H), 1.23 (s, 3H), 1.15-1.07 (m, 7H), 1.05 (t, J = 7.4 Hz, 3H); C NMR
(
CDCl , 125 MHz) δ 181.1, 155.4, 82.9, 73.3, 48.0, 42.9, 35.5, 29.0, 26.6, 25.7, 25.2,
3
2
1.3, 19.2, 10.7, 10.4. Spectroscopic data was consistent with that previously
reported.10
(
6R,7aR)-3-Amino-8,8-dimethylhexahydro-2H-3a,6-methanobenzo[d]oxazol-
2-onehydrochloride (31). Crude 13 (4.440 g) was dissolved in Et O (30 mL) and
2
cooled to 0 °C. Freshly generated HCl gas was bubbled through the solution and HCl
salt 31 immediately started to form as yellowish solid. This process was continued
for 15 min and then the reaction mixture was filtered and washed with cold Et O (3
2
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2
3
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5
6
7
8
9
x 5 mL). Recrystalization from EtOH gave pure 31 as white powder (4.35 g, 82%
1
yield over two steps). H NMR (CDCl
3
, 500 MHz) δ 9.85 (bs, 3H), 4.40 (dd, J = 8.0, 4.1
Hz, 1H), 2.74-2.67 (m, 1H), 2.31-2.64 (m, 1H), 2.02-1.97 (m, 1H), 1.88 (dd, J = 13.8,
.0 Hz, 1H), 1.83-1.81 (t, J = 4.1 Hz, 1H), 1.40-1.27 (m, 5H), 1.20 (s, 3H); 13C NMR
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
8
(
CDCl
3
, 125 MHz) δ 156.3, 85.5, 72.5, 47.1, 43.5, 34.9, 25.7, 25.3, 20.5, 19.2. HRMS
+
(ESI-TOF) m/z: [M+Na] Calcd for C10
H
16
N
2
O Na 219.11040; Found 219.1105.
2
(
6R,7aR)-8,8-Dimethyl-3-(pentan-3-ylideneamino)hexahy-dro-2H-3a,6-
methanobenzo[d]oxazol-2-one (17). To a suspension of 31 (0.506 g, 2.15 mmol)
in benzene was added 3-pentanone (0.225 mL, 2.15 mmol), and the solution was
heated to reflux for 12 h while attached to a Dean-Stark apparatus. The reaction was
quenched with saturated NaHCO
Et O (2 x 20 mL). The combined organic extracts were washed with brine (5 mL),
dried (MgSO ), and concentrated in vacuo to yield a yellow oil. Flash
3
(5 mL), and the aqueous phase was extracted with
2
4
chromatography over silica gel using 20:80 EtOAc-hexanes gave 17 (0.551 g, 97%)
1
as a white solid. H NMR (CDCl
3
, 500 MHz) δ 4.25 (dd, J = 8.1, 4.0 Hz, 1H), 2.50-2.19
(m, 5H), 2.11-1.79 (m, 3H), 1.73 (t, J = 4.3 Hz, 1H), 1.30-1.24 (m, 1H), 1.23 (s, 3H),
13
1
.15-1.07 (m, 7H), 1.05 (t, J = 7.4 Hz, 3H); C NMR (CDCl , 125 MHz) δ 181.1, 155.4,
3
8
2.9, 73.3, 48.0, 42.9, 35.5, 29.0, 26.6, 25.7, 25.2, 21.3, 19.2, 10.7, 10.4. Spectroscopic
data was consistent with that previously reported.10
(
6R,7aR)-8,8-Dimethyl-3-(pentan-3-ylideneamino)hexahy-dro-2H-3a,6-
methanobenzo[d]oxazol-2-one (17). 31 (0.567 g, 2.44 mmol) was dissolved in
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
CH
mixture was stirred for 12 h. The reaction was quenched with saturated aqueous
NaHCO (5 mL), and the aqueous phase was extracted with CH Cl (2 x 30 mL). The
combined organic extracts were washed with brine (10 mL), dried (MgSO ), and
2
Cl
2
(8 mL), 3-pentanone (2.6 mL, 24.4 mmol) was added, and the resulting
3
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
concentrated in vacuo to yield a yellow oil. Flash chromatography over silica gel
1
using 20:80 EtOAc-hexanes gave 17 (0.61 g, 93%) as a white solid. H NMR (CDCl
3
,
5
00 MHz) δ 4.25 (dd, J = 8.1, 4.0 Hz, 1H), 2.50-2.19 (m, 5H), 2.11-1.79 (m, 3H), 1.73
(
t, J = 4.3 Hz, 1H), 1.30-1.24 (m, 1H), 1.23 (s, 3H), 1.15-1.07 (m, 7H), 1.05 (t, J = 7.4
13
Hz, 3H); C NMR (CDCl , 125 MHz) δ 181.1, 155.4, 82.9, 73.3, 48.0, 42.9, 35.5, 29.0,
3
2
6.6, 25.7, 25.2, 21.3, 19.2, 10.7, 10.4. Spectroscopic data was consistent with that
previously reported.10
General procedure for the formation of hydrazones 18, 38, and 62
(
S)-4-Benzyl-3-(pentan-3-ylideneamino)oxazolidin-2-one
(18).
(5.2 mL). 3-pentanone
O (0.56, 2.94 mmol) were added, and the resulting mixture
was stirred for 14 h. The reaction was quenched with saturated aqueous NaHCO (5
mL), and the aqueous phase was extracted with CH Cl (2 x 20 mL). The combined
organic extracts were washed with brine, dried (MgSO ), and concentrated in vacuo
Crude
16
hydrazide 14, (0.26 g, 1.468 mmol) was dissolved in CH
(14.3 mL) and p-TsOH·H
Cl
2 2
2
3
2
2
4
to yield a yellow oil. Flash chromatography over silica gel using 20:80 EtOAc-
1
hexanes gave 18 (0.34 g, 88%) as a yellow oil. H NMR (CDCl
3
, 400 MHz): δ 7.30-
7.19 (m, 3H), 7.13-7.11 (m, 2H), 4.33- 4.25 (m, 1H), 4.22 (t, J = 8.2 Hz, 1H), 3.98 (t, J =
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8
.3 Hz, 1H), 3.09 (dd, J = 13.4, 4.3 Hz, 1H), 2.70 (dd, J = 13.6, 8.7 Hz, 1H), 2.49-2.30
1
3
(
m, 4H), 1.11 (q, J = 7.0 Hz, 6H); C NMR (CDCl , 400 MHz): δ 181.9, 154.9, 135.6,
3
128.9, 128.5, 126.7. Spectroscopic data was consistent with that previously
reported.16
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(6R,7aR)-3-(Cyclohexylideneamino)-8,8-dimethylhexahy-dro-2H-3a,6-
methanobenzo[d]oxazol-2-one (38). Crude hydrazide 13 and cyclohexanone
were used for formation of 38. Flash chromatography over silica gel using 20:80
1
EtOAc-hexanes gave 38 (0.195 g, 85%) as yellow oil. H NMR (CDCl
3
, 400 MHz): δ
4.23-4.21 (dd, J = 8.0, 4.0 Hz, 1H), 2.47-2.25 (m, 5H), 2.06-1.46 (m, 10H), 1.28-1.24
1
3
(
m, 1H), 1.22 (s, 3H), 1.16-1.14 (m, 1H), 1.12 (s, 3H); C NMR (CDCl
3
, 125 MHz): δ
178.4, 156.4, 83.0, 73.1, 48.0, 42.9, 35.8, 35.4, 30.1, 27.5, 26.7, 26.6, 25.7, 21.4, 19.2.
+
HRMS (ESI-TOF) m/z: [M+H] Calcd for C16
H
25
N
2
O 277.19110; Found 277.19160.
2
(
R)-3-(Pentan-3-ylideneamino)-4-phenyloxazolidin-2-one
(62).
Crude
hydrazide 6116 and 3-pentanone were used for formation of 62. Flash
chromatography over silica gel using 20:80 EtOAc-hexanes gave 62 (0.261 g, 86%)
1
as a yellow oil. H NMR (CDCl
3
, 500 MHz): δ 7.39-7.13 (m, 5H), 5.13 (dd, J = 10.3, 8.5
Hz, 1H), 4.32 (t, J = 8.7 Hz, 1H), 4.07 (dd, J = 10.1, 8.6 Hz, 1H), 2.51-2.69 (m, 4H),
1
.03-0.95 (m, 6H); 13C NMR (CDCl
3
, 125 MHz): δ 182.3, 155.1, 136.9, 128.6, 127.8,
127.1, 68.8, 64.1, 28.1, 24.9, 10.8, 10.1. Spectroscopic data was consistent with that
previously reported.16
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8
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
6
Methyl-2-methyl-3-oxopentanoate (35). K
2
CO (25.8 g, 0.187 mol) was added to a
3
solution of methyl-3-oxopentanoate (25 mL, 0.200 mol) in acetone (250 mL), and
the mixture was stirred for 5 min. Methyl iodide (60.0 mL, 0.964 mol) was added
dropwise over ca. 5 min, and stirring was continued for 10 min. The reaction
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mixture was refluxed for 12 h and allowed to cool to rt. Et
2
O (250 mL) was added,
the mixture was filtered, dried (MgSO ), and evaporated under reduced pressure to
4
give a yellow liquid (27.1 g, 94%). The crude material was used directly in the next
1
transformation. H NMR (CDCl
3
, 500 MHz): δ 3.61 (s, 3H), 3.46-3.41 (q, J = 7.3 Hz,
1
3
1
H), 2.51-2.39 (m, 2H), 1.22-1.19 (d, J = 6.9 Hz, 3H), 0.95-0.90 (t, J = 7.3 Hz, 3H). C
NMR (CDCl
3
, 125 MHz): δ 205.1, 169.9, 51.0, 49.8, 33.5, 11.7, 6.8. Spectroscopic data
27
was consistent with that previously reported.
General procedure for the synthesis of racemic mixtures of alkylated ketones
2
-Allyl-3-pentanone [(±)-12]. Step 1: NaH (0.099 g, 4.13 mmol) was added to a
cooled (ice-H O bath) and stirred solution of 35 (0.5 mL, 3.44 mmol) in THF (7.0
2
mL), and stirring was continued for 10 min. Allyl bromide (0.60 mL, 6.89 mmol) was
added dropwise over ca. 2 min. Stirring was continued for 3 h, the cold bath was
removed, and stirring was continued for an additional 12 h. The reaction mixture
was partitioned between saturated aqueous NH
aqueous phase was extracted with Et O (2 x 5 mL) and the combined organic
extracts were washed with brine (5 mL), dried (MgSO ), and concentrated in vacuo
4
Cl (5 mL) and Et
2
O (5 mL). The
2
4
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Page 29 of 58
The Journal of Organic Chemistry
2
9
1
2
3
4
5
6
7
8
9
to yield a colorless liquid (0.59 g, 93%) that was used in the next step without
further purification. Step 2: LiOH (0.35 g, 14.4 mmol) was added to a stirred
solution of the above crude material (0.59 g, approx. 3.19 mmol) in 3:1 THF-H
mL THF and 6 mL H O). The resulting suspension was stirred at reflux for 12 h, and
then allowed to cool to rt before acidifying with 1.0 M HCl to ~pH 1–2. The mixture
was then extracted with Et O (2 x 10 mL), dried (MgSO ), and evaporated under
weakly reduced pressure (400 torr) to give a pale-yellow liquid. Flash
chromatography over silica gel using 2:98 Et O-pentane gave (±)-12 as a colorless
2
O (18
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
4
2
liquid (0.36 g, 90%). Spectroscopic data was consistent with that obtained for 12
using the method described above corresponding to Table 5.
2
-Methyl-1-phenylpentan-3-one [(±)-33]. Flash chromatography over silica gel
using 5:95 Et O-pentane gave (±)-33 as a white solid (0.11 g, 81% over two steps).
2
Spectroscopic data was consistent with that obtained for 33 using the method
described in Table 5.
4-Methylhexan-3-one [(±)-36]. Flash chromatography over silica gel using 5:95
Et O-pentane gave (±)-36 as a colorless liquid (1.31 g, 75% over two steps).
2
Spectroscopic data was consistent with that obtained for 36 using the method
described in Table 5.
1
-(4-Bromophenyl)-2-methylpentan-3-one [(±)-50]. Flash chromatography over
silica gel using 5:95 Et
2
O-pentane gave (±)-50 as a white solid (0.46 g, 82% over two
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