Synthesis of lactate derivatives via reductive radical addition to α-oxyacrylates

Article abstract of DOI:10.1016/j.tet.2019.05.002

Lactate derivatives are important synthetic precursors to a variety of pharmaceutical products. Previously reported methods to prepare lactates require multiple steps or have limited scopes. Herein, we report a Ni-catalyzed reductive addition of a variety

Full text of DOI:10.1016/j.tet.2019.05.002

Accepted Manuscript
Synthesis of lactate derivatives via reductive radical addition to α-oxyacrylates
Justin B. Diccianni, Mason Chin, Tianning Diao
PII:
S0040-4020(19)30509-5
https://doi.org/10.1016/j.tet.2019.05.002
TET 30323
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 23 February 2019
Revised Date: 26 April 2019
Accepted Date: 1 May 2019
Please cite this article as: Diccianni JB, Chin M, Diao T, Synthesis of lactate derivatives via reductive
radical addition to α-oxyacrylates, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.05.002.
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ACCEPTED MANUSCRIPT
Synthesis of Lactate Derivatives via Reductive
Radical Addition to α-Oxyacrylates
Justin B. Diccianni, Mason Chin, and Tianning Diao*
Department of Chemistry, New York University, 100 Washington Square East
New York, NY 10003
E-Mail: diao@nyu.edu
Graphical Abstract
ABSTRACT
Lactate derivatives are important synthetic precursors to a variety of pharmaceutical
products. Previously reported methods to prepare lactates require multiple steps or have limited
scopes. Herein, we report a Ni-catalyzed reductive addition of a variety of alkyl iodides to α-
oxyacrylates to afford substituted lactates. Exploring the scope of radical acceptors reveals that
electron-deficient alkenes, ranging from cyclohexenone to para-caboxystyrene, undergo efficient
coupling with alkyl iodides. This method represents an alternative strategy access lactate
derivatives.
1
. Introduction
1
Lactic acid and its derivatives are synthons to a large variety of pharmaceutical products.
For instance, cyclohexyl lactic acid is a building block for selective E-selectin inhibitor 1
2
(
Scheme 1). Phenyllactic acid is a precursor to the natural product sattabacin 2, which shows
1

ACCEPTED MANUSCRIPT
3
antiviral activity. While lactic acid is manufactured by microbial fermentation, accessing its
substituted variants requires multiple steps. With some methods, the scope of accessible lactate
variants is dependent on available amino acids. Previous methods for preparing substituted
4
5
lactates include α-hydroxylation of acids, diazotization of amino acids, nucleophilic addition of
2
6
7
cyanide to aldehydes, C–H activation of lactic acid, hydrogenation of the β-ketoacids, and
2
dihydroxylation of acrylic acids followed by reduction (Scheme 1).
Scheme 1. Strategies for Preparing Lactate Derivatives
CO H
2
R
NH2
CO H
2
HNO2
R
R
CHO
1
2
. HCN
+
. H
[O]
CO H
CO Et
2
2
CO H
R
this work
radical addition
2
R–X
Pd]
OH
OPG
R–I
[
OH
+
-
-
synthons
drugs
[
H]
1
. OsO4
2
CO H
2. H /Pd
2
R
O
CO H
2
R
The addition of radicals to alkenes represents a widely applied approach for preparing
8
-11
complex molecules from simple precursors.
Conventional radical initiators include peroxides,
However, by-products generated from these
1
2
2
azo compounds, tin hydrides, and SmI .
1
3
14
stoichiometric reagents restrict scale-up processes. Transition metal catalysts, such as Fe, Ti
1
5
and Cu, could enable sustainable catalytical radical addition to alkenes. Ni has been
2

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1
6
17 , 18
characterized to catalytically initiate radical formation from aryl
and alkyl halides.
1
9
20
21
22,23,24,25,26
Recently, reports from Shenvi, Weix , our group , and others
reveal that radicals
initiated by Ni catalysts can undergo addition to alkenes. Herein, we demonstrate that Ni-
catalyzed radical addition can be applied to the preparation of lactate derivatives via reductive
coupling of alkyl iodides to α-oxyacrylates. The use of reducing conditions with alkyl halides as
the coupling partners avoids stoichiometric organometallic reagents in conventional cross-
2
7
coupling reactions and improves functional group tolerance.
. Results and Discussion
We examined reaction conditions for the postulated reductive addition reaction using α-
acetoxyacrylate ester 3 as the model substrate and iodocyclohexane as the coupling partner
Table 1). α-Acetoxyacrylate ester 3 could be readily prepared by refluxing ethyl pyruvate in
acetic anhydride in the presence of catalytic acid. With a common catalyst precursor, NiBr-
2
(
2
8
2
⋅DME, we explored various ligands in the presence of HFIP (hexafluoroisopropanol) as the
proton source. While the monodentate triphenylphosphine gave trace product 4 (entry 1),
bidentate ligands, including dppe (1,2-bis(diphenylphosphino)ethane), dppp (1,3-
bis(diphenylphosphino)propane), dppb (1,4-bis(diphenylphosphino)propane, dpppe (1,5-
bis(diphenylphosphino)pentane), and dppf (1,1’-bis(diphenylphosphino)ferrocene) led to good
2
9
conversions (entries 2-6). In particular, ligands with large bite angles, such as dppb and dppf,
gave the highest yields. N-ligands are commonly used in Ni catalysis. The use of bpy (bipyridine)
afforded 4 in 40% yield (entry 7). Proton sources with higher pK s than HFIP decreased the
a
yields (entries 8-10). The use of Mn as the reductant led to formation of 4 in 38% yield (entry
1
1), but other reductants, including In, Mg, and Fe, led to trace product. It is noteworthy that the
3

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reaction does not require air-free conditions. Repeating the standard reaction in air generated 4 in
7
0% NMR yield and 69% isolated yield (Table S3).
Table 1. Catalyst Optimization
a
Entry Ligand Proton Source Yield (%)
1
2
3
4
5
6
7
8
9
1
1
PPh3
dppe
dppp
dppb
dpppe
dppf
bpy
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
tBuOH
iPrOH
1
62
65
78 (73)
62
79 (76)
40
42
31
24
b
b
dppf
dppf
dppf
0
1
H O
2
c
dppf
HFIP
38
a
b
c
GC yield with mesitylene as the internal standard.
Isolated yields in parenthesis.
Mn was used as the reductant in place of Zn.
With the optimized conditions, NiBr ⋅DME in combination with dppf and Zn, we explored
2
the scope of alkyl iodides (Table 2). A vareity of secondary alkyl iodides undergo addition to 3,
as well as primary and tertiary alkyl iodides, to afford lactate derivatives 4-14. The success of
different electrophiles suggests that the conditions are relatively insensitive to the sterics of the
alkyl group. In the formation of 13, tBuI could be replaced by tBuBr to generate 13 in
comparable yields, but other alkyl bromides are inactive under these conditions. When both a
chloride and an iodide are present in the substrate, the iodide reacts preferentially, leaving the
chloride intact in the formation of 11.
4

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Subsequently, we evaluated different alkene acceptors. Replacing the acetate of 3 with the
bulkier pivalate led to formation of 15 in lower yield. A methyl protected α-oxyacrylate
underwent efficient addition with CyI to give 16 in 86% yield. The α-oxy group, despite
3
0
providing a captodative effect, is not essential for obtaining reactivity. Iodocyclohexane added
to cyclohexanone and benzyl acrylate to give 18 and 19, respectively. Methyl 4-vinylbenzoate
underwent cyclohexyl addition to afford 20 in 74% yield, but parent styrene produced the
addition product in 23% yield with dicyclohexylation as the major-byproduct. These results are
consistent with the preference of the nucleophilic alkyl radicals to add to electron-deficient
alkenes.
a
Table 2. Scopes of Alkyl Iodides and Alkene Acceptors
5

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a
b
c
d
Isolated yields. Reaction conditions: 0.2 mmol olefin, 0.3 mL THF, 0.2 mL HFIP, 25 °C, 12 hrs.
1
equiv iodide.
tBuBr instead of tBuI.
NMR yield with mesitylene as the internal standard.
We then carried out experiments to probe whether a radical intermediate is formed. Addition
of one equivalent TEMPO to the coupling of 3 with iodocyclohexane under standard conditions
completely inhibited the reactivity. The addition of 6-iodo-1-hexene to 3 led to a mxiture of 23,
1
2
4, and 25 in the ratio of 1:1:0.9 (eq 1). The internal alkene product 25 was characterized by H
NMR spectroscopy, but the precise position of the internal double bond was not determined. The
formation of 23 may suggest a hexenyl radical intermediate that underwent cyclization at the rate
6

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5
-1 31
of 10 s , but a Ni-mediated insertion pathway cannot be ruled out. Even though a radical is
formed, Ni may only serve as an initiator and the reaction may proceed through a radical chain
3
2
mechanism via S 2 iodide atom transfer.
H
(1)
3
. Conclusion
In summary, we have developed a Ni-catalyzed reductive coupling of alkyl iodides with
electron-deficient alkenes, including α-oxyacrylates. This reaction can be readily applied to
preparing lactate derivatives. Based on previous studies of Ni-catalyzed cross-coupling reactions,
it is reasonable to propose that Ni initiates radical formation from the alkyl iodide, which then
adds to the electron-deficient alkenes. However, current data is insufficient to distinguish radical
pathways from Ni-mediated addition.
4
. Experimental Section
All reactions were carried out under dry nitrogen. Solvents (free of inhibitors) were dried and
deoxygenated by passing through alumina in a solvent purification system, other than HFIP
which was used as received. Chloroform-d was purchased from Cambridge Isotope Laboratories.
Ethyl 2-acetoxyacrylate (3) and ethyl 2-methoxyacrylate were synthesized according to literature
3
3 , 34 1
13
procedures.
H and C NMR spectra were recorded on a Bruker 400 MHz Avance
spectrometer. The chemical shifts (δ) are given in parts per million and referenced to residual
solvent peaks. The following abbreviations were used to describe multiplicities: s = singlet, d =
7

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doublet, t = triplet, q = quartet, sept = septet, m = multiplet, br = broad. IR spectra were recorded
on a Nicolet 6700 FT-IR spectrometer. High resolution mass spectra (HRMS) were collected on
an Agilent 6224 TOF LC/MS. Reactions were monitored by thin-layer chromatography (TLC)
on Merck TLC silica gel 60 F254 plates and compounds were visualized by UV light (254 nm)
or KMnO4 staining. Column chromatography was performed on Merck silica gel 60 (0.015−
0
.040 mm).
4
.1. General Procedure for the Alkylation Reaction
A 2 mL crimp-top GC vial was charged with NiBr2(DME) (6.2 mg, 0.02 mmol, 0.1 equiv),
3
5
dppf (11 mg, 0.02 mmol, 0.1 equiv), and activated Zn powder (26.2 mg, 0.4 mmol, 2 equiv).
The vial was crimped shut and the olefin (0.2 mmol, 1 equiv) was injected through the septum as
a solution in 0.3 mL THF followed by 0.2 mL HFIP. The iodide (1-2 equiv) was then added (as a
solution in THF, if solid) and the vial was shaken at 1000 rpm for 12 hours at 25 °C. The
reaction was diluted with EtOAc and quenched by the addition of 1 M HCl (aq). The aqueous
phase was extracted with three portions of EtOAc. The combined organic phase was then passed
through a plug of silica. An aliquot of the organic phase was used for GC or GC/MS analysis
with mesitylene as an internal standard. Solvent was removed and the mixture was purified by
chromatography on silica gel with EtOAc/hexane as the eluent to give the products as colorless
oils.
4
.2. Preparation of NiBr ⋅DME
2
The thimble of a 250 mL Soxhlet apparatus was charged with 10 g anhydrous NiBr . The
2
apparatus was flushed with N
condensor was attached. The solvent was heated to reflux and the solid was extracted for 1 week,
under N . Occasionally, the solid mass of NiBr was broken up with a spatula. Excess solvent
2
, the boiling flask was charged with 150 mL 1,2-DME, and the
2
2
8

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was removed by distillation under vacuum and the resulting orange solid was dried under
vacuum overnight. The NiBr ⋅DME (8.5 g, 63%) was stored in a N -filled glovebox. A higher
2
2
yield can be obtained by allowing the extraction to run for a longer period of time, as some NiBr2
remains in the thimble after one week.
4
.3. Substrate Synthesis
4
.3.1. Ethyl 2-(pivaloyloxy)acrylate
A 100 mL RBF was charged with pivalyl chloride (2.2 mL, 18 mmol, 4 equiv), Et N (2.5 mL,
3
1
8 mmol, 4 equiv), and 20 mL of DCM under N . The solution was cooled to 0 °C and ethyl
2
pyruvate (0.5 mL, 4.5 mmol, 1 equiv) was added dropwise. The reaction was stirred at 0 °C for
one hour, then at room temperature overnight. The mixture was quenched with H O and the
2
phases were separated. The aqueous phase was extracted with three portions of DCM. The
combined organic phase was washed with 1 M HCl (aq), then saturated NaHCO3 (aq), then brine,
4
then dried over MgSO . Solvent was removed and the residue was purified via column
chromatography on silica gel with 10:1 hexane:EtOAc as the eluent. The product was obtained
1
as a colorless oil (760 mg, 84%). H NMR (400 MHz, Chloroform-d) δ 6.03 (d, J = 1.6 Hz, 1H),
1
3
5
.41 (d, J = 1.6 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 1.26 (s, 9H). C
NMR (101 MHz, Chloroform-d) δ 176.8, 161.7, 145.3, 113.5, 61.8, 39.0, 26.7, 14.2. TLC: R =
f
+
0
.42 (10:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+H] calcd for C H O 201.1121,
1
0
17
4
found 201.1130.
4
.3.2. Ethyl 2-(naphthalen-2-yloxy)acrylate
A 25 mL RBF was charged with naphthalen-2-yl 2-oxopropanoate (1.00 g, 4.67 mmol, 1
equiv), TsOH-H O (80 mg, 0.46 mmol, 0.1 equiv), and 12 mL of Ac O under N . The solution
2
2
2
was heated to reflux for 48 hours. The reaction was cooled to room temperature and quenched
9

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with H
2
O. The reaction mixture was extracted three times with EtOAc. The combined organic
phase was washed with water then brine and dried over Na SO . Solvent was removed and the
2
4
residue was purified via column chromatography on silica gel with 10:1 hexane:EtOAc as the
1
eluent. The product was obtained as a colorless oil (915 mg, 77%). H NMR (400 MHz,
Chloroform-d): δ 7.87 (d, J = 8.3 Hz, 1H, overlap), 7.83 (ddd, J = 12.9 ,8.3, 2.3 Hz, 2H, overlap),
7
.62 (d, J = 2.3 Hz, 1H), 7.55 – 7.45 (m, 2H), 7.35 – 7.21 (dd, J = 8.3, 2.3 Hz 1H, overlap), 6.32
1
3
(
d, J = 2.0 Hz, 1H), 5.68 (d, J = 2.0 Hz, 1H), 2.29 (s, 1H). C NMR (101 MHz, CDCl
3
): δ 169.2,
1
60.4, 148.1, 144.4, 133.8, 131.8, 129.7, 127.9, 127.9, 126.8, 126.1, 120.8, 118.7, 115.6, 20.6.
+
f 13 4
TLC: R = 0.24 (10:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+H] calcd for C15H O
2
57.0808, found 257.0808.
4
.4. Characterization
4
.4.1. Ethyl 2-acetoxy-3-cyclohexylpropanoate (4)
1
H NMR (400 MHz, Chloroform-d): δ 5.03 (dd, J = 9.5, 4.2 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H),
.14 (s, 3H), 1.84 – 1.59 (m, 7H), 1.51 – 1.36 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.24 – 1.05 (m,
2
1
3
3
3
H), 0.94 (m, 2H). C NMR (101 MHz, Chloroform-d): δ 171.1, 170.8, 70.8, 61.4, 38.6, 34.0,
f
3.8, 32.4, 26.5, 26.3, 26.1, 20.9, 14.3. TLC: R = 0.33 (8:1 hexane:EtOAc). HRMS (APCI-TOF)
+
m/z: [M+H] calcd for C H O 243.1591, found 243.1601.
1
3
23
4
4
.4.2. Naphthalen-2-yl 2-acetoxy-4-methylpentanoate (5)
1
H NMR (400 MHz, Chloroform-d) δ 7.86 (d, J = 8.3 Hz, 1H, overlap), 7.86 – 7.80 (ddd, J =
1
2.4, 7.3, 2.3 Hz, 2H, overlap), 7.58 (d, J = 2.3 Hz, 1H), 7.54 – 7.45 (m, J = 12.4, 2.3 Hz, 2H),
.26 – 7.24 (dd, J = 7.3, 2.3 Hz, 1H, overlap), 5.27 (dd, J = 9.5, 4.0 Hz, 1H), 2.20 (s, 3H), 2.07 –
7
1
1
1
3
.79 (m, 3H), 1.05 (dd, J = 12.5, 6.2 Hz, 6H). C NMR (101 MHz, CDCl
3
) δ 170.9, 169.8, 148.0,
33.8, 131.7, 129.7, 127.9, 127.8, 126.8, 126.0, 120.9, 118.5, 71.4, 39.9, 24.9, 23.2, 21.8, 20.8.
1
0

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+
TLC: R
f
4 4
= 0.23 (8:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+NH ] calcd for C18H24NO
3
18.1700, found 318.1711.
.4.3. Ethyl 2-acetoxy-3-cyclopentylpropanoate (6)
4
1
H NMR (400 MHz, Chloroform-d) δ 4.98 (dd, J = 8.7, 4.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H),
.14 (s, 3H), 2.13 – 1.84 (m, 2H), 1.85 – 1.76 (m, 2H), 1.67 – 1.60 (m, 2H), 1.60 – 1.47 (m, 2H),
2
1
3
1
.38 – 1.14 (t, J = 7.1 Hz, 3H), 1.19 – 1.07 (m, 2H), 0.88 (m, J = 1.2 Hz, 1H). C NMR (101
MHz, CDCl
3
) δ 170.8, 170.8, 72.4, 61.4, 37.3, 36.6, 33.0, 32.4, 25.3, 25.0, 20.9, 14.3. TLC: 0.27
+
R
f = 0.27 (20:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+Na] calcd for C12
H20NaO
4
2
51.1254, found 251.1263.
4
.4.4. Ethyl 2-acetoxy-3-(1-tosylpiperidin-4-yl)propanoate (7)
1
H NMR (400 MHz, Chloroform-d): δ 7.63 (d, J = 7.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 4.98
dd, J = 8.9, 3.7 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.77 (d, J = 11.0 Hz, 2H), 2.43 (s, 3H), 2.21
q, J = 10.3 Hz, 2H), 2.08 (s, 3H), 1.87 – 1.63 (m, 4H), 1.34 (m, 3H), 1.24 (t, J = 7.1 Hz, 3H).
(
(
1
3
C NMR (101 MHz, Chloroform-d): δ 170.5, 170.3, 143.6, 133.2, 129.7, 127.9, 70.3, 61.6, 46.4,
4
f
6.3, 37.2, 31.9, 31.8, 30.9, 21.7, 20.8, 14.2. TLC: R = 0.33 (6:1 hexane:EtOAc). HRMS (APCI-
+
TOF) m/z: [M+H] calcd for C19
H28NO
6
S 398.1632, found 398.1629.
4
.4.5. Ethyl 2-acetoxy-5,5-dimethylhexanoate (8)
1
H NMR (400 MHz, Chloroform-d): δ 4.97 – 4.89 (dd, J = 6.5, 5.5 Hz 1H), 4.20 (qd, J = 7.2, 3.1
13
Hz, 2H), 2.13 (s, 3H), 1.88 – 1.69 (m, 2H), 1.27 (td, J = 7.2, 3.1 Hz, 5H), 0.88 (s, 9H). C NMR
(101 MHz, Chloroform-d): δ 170.8, 170.5, 73.1, 61.4, 39.1, 30.2, 29.3, 26.7, 20.8, 14.3. TLC: Rf
+
=
0.33 (10:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+H] calcd for C H O 231.1591,
1
2
23
4
found 231.1602.
4
.4.6. Ethyl 2-acetoxy-5,5,5-trifluoropentanoate (9)
1
1

ACCEPTED MANUSCRIPT
1
H NMR (400 MHz, Chloroform-d) δ 5.04 (dd, J = 7.4, 4.2 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H),
1
3
2
1
1
.36 – 2.02 (m, 4H), 2.17 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, Chloroform-d) δ
70.3, 169.3, 126.5 (q, J = 276 Hz), 70.7, 61.9, 30.0 (q, J = 30 Hz), 24.0 (q, J = 3.3 Hz), 20.7,
+
4.2. TLC: R = 0.36 (10:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M-H O] calcd for
f
2
C H F O 224.0655, found 224.0648.
9
11
3
3
4
.4.7. Ethyl 2-acetoxydecanoate (10)
1
H NMR (400 MHz, Chloroform-d) δ 4.95 (t, J = 6.4 Hz, 1H), 4.20 (qd, J = 7.1, 1.1 Hz, 2H),
.13 (s, 3H), 1.85 – 1.74 (m, 2H), 1.41 (s, 2H), 1.27 (t, J = 7.1 Hz, 13H), 0.87 (t, J = 6.7 Hz, 3H).
2
1
3
C NMR (101 MHz, Chloroform-d) δ 170.8, 170.6, 72.6, 61.4, 32.0, 31.2, 29.5, 29.3, 29.3, 25.2,
+
2
2.8, 20.8, 14.3, 14.2. TLC: R = 0.50 (10:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+H]
f
calcd for C H O 259.1904, found 259.1913.
1
4
27
4
4
.4.8. Ethyl 2-acetoxy-8-chlorooctanoate (11)
1
H NMR (400 MHz, Chloroform-d): δ 4.96 (t, J = 6.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.53 (t,
J = 6.7 Hz, 2H), 2.13 (s, 3H), 1.85 – 1.73 (m, 4H), 1.49 – 1.32 (m, 6H), 1.27 (t, J = 7.1 Hz, 3H).
1
3
C NMR (101 MHz, Chloroform-d) δ 170.7, 170.4, 72.4, 61.4, 45.1, 32.6, 31.1, 28.5, 26.7, 25.1,
+
2
0.8, 14.3. TLC: R
f
= 0.23 (10:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+H] calcd for
C H ClO 265.1207, found 265.1203.
12
22
4
4
.4.9. Ethyl 2-acetoxy-4,4,5,5,6,6,6-heptafluorohexanoate (12)
1
H NMR (400 MHz, Chloroform-d) δ 5.46 (dd, J = 8.5, 3.7 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H),
1
3
2
1
0
.85 – 2.59 (m, 2H), 2.16 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). C NMR (101 MHz, Chloroform-d) δ
69.8, 168.3, 116.5 (m), 113.9 (m), 65.6, 62.5, 32.4 (t, J = 21.7 Hz), 30.4, 20.6, 14.1. TLC: R =
f
+
.63 (20:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [(M+H)] calcd for C10
H
12
F
7
O
4
329.0624,
found 329.0635.
1
2

ACCEPTED MANUSCRIPT
4
.4.10. Ethyl 2-acetoxy-4,4-dimethylpentanoate (13)
1
H NMR (400 MHz, Chloroform-d) δ 5.04 (dd, J = 9.2, 3.0 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),
1
3
2
.12 (s, 3H), 1.85 – 1.66 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.96 (s, 9H). C NMR (101 MHz,
1
3
Chloroform-d) δ C NMR (101 MHz, Chloroform-d) δ 171.2, 170.7, 70.9, 61.5, 44.2, 30.6, 29.7,
+
2
0.9, 14.2. TLC: R = 0.33 (10:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+Na] calcd for
f
C H NaO 239.1254, found 239.1262.
11
20
4
4
.4.11. Ethyl 2-acetoxy-3-(adamantan-1-yl)propanoate (14)
1
H NMR (400 MHz, Chloroform-d) δ 5.08 (dd, J = 9.4, 2.5 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),
1
3
2
.12 (s, 3H), 2.07 – 1.89 (m, 3H), 1.83 – 1.44 (m, 14H), 1.27 (t, J = 7.1 Hz, 3H). C NMR (101
MHz, CDCl ) δ 171.5, 170.7, 69.5, 61.5, 45.0, 42.5, 37.0, 32.4, 28.7, 21.0, 14.3. TLC: R = 0.25
3
f
+
(
20:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M-(H O)+H] calcd for C H O 251.1642,
2 15 23 3
found 251.1639.
4
.4.12. 3-Cyclohexyl-1-ethoxy-1-oxopropan-2-yl pivalate (15)
1
H NMR (400 MHz, Chloroform-d): δ 5.00 (dd, J = 9.8, 4.2 Hz, 1H), 4.17 (qd, J = 7.1, 5.3 Hz,
H), 1.81 – 1.60 (m, 7H), 1.49 – 1.37 (m, 1H), 1.32 – 1.25 (m, 4H), 1.24 (s, 9H), 1.23 – 1.12 (m,
2
1
3
2
3
H), 1.04 – 0.85 (m, 2H). C NMR (101 MHz, Chloroform-d): δ 178.2, 171.1, 70.5, 61.3, 38.8,
8.4, 34.3, 33.8, 32.3, 27.2, 26.5, 26.4, 26.2, 14.3. TLC: R = 0.31 (20:1 hexane:EtOAc). HRMS
f
+
(
APCI-TOF) m/z: [M+H] calcd for C H O 285.2060, found 285.2069.
1
6
29
4
4
.4.13. Ethyl 3-cyclohexyl-2-methoxypropanoate (16)
1
H NMR (400 MHz, Chloroform-d): δ 4.22 (qq, J = 7.3, 3.7 Hz, 2H), 3.80 (dd, J = 9.0, 4.2 Hz,
H), 3.37 (s, 3H), 1.77 – 1.60 (m, 5H), 1.58 – 1.40 (m, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.27 – 1.06
1
1
3
(
m, 3H), 1.01 – 0.80 (m, 2H). C NMR (101 MHz, Chloroform-d): δ 173.5, 78.9, 60.9, 58.2,
1
3

ACCEPTED MANUSCRIPT
4
0.6, 33.9, 32.7, 26.6, 26.4, 26.2, 14.4. TLC: R
f
= 0.18 (20:1 hexane:EtOAc). HRMS (APCI-
+
TOF) m/z: [M+Na] calcd for C H NaO 237.1467, found 237.1461.
1
2
22
3
4
.4.14. Naphthalen-2-yl 2-acetoxy-3-cyclohexylpropanoate (17)
1
H NMR (400 MHz, Chloroform-d): δ 7.90 – 7.74 (m, 3H), 7.57 (d, J = 2.1 Hz, 1H), 7.48 (ddd, J
7.2, 5.0, 1.6 Hz, 2H), 7.23 (dd, J = 8.9, 2.1 Hz, 1H), 5.29 (dd, J = 9.4, 4.5 Hz, 1H), 2.20 (s, 3H),
=
1
3
2
.04 – 1.65 (m, 7H), 1.63 – 1.57 (m, 1H), 1.39 – 1.14 (m, 3H), 1.13 – 0.95 (m, 2H). C NMR
(101 MHz, Chloroform-d): δ 171.0, 169.9, 148.1, 133.8, 131.7, 129.7, 127.9, 127.8, 126.8, 126.0,
1
f
20.9, 118.5, 70.9, 38.6, 34.2, 33.8, 32.5, 26.5, 26.4, 26.2, 20.9. TLC: R = 0.30 (10:1
+
hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+H] calcd for C21
H
25
O
4
341.1747, found 341.1747.
4
.4.15. [1,1'-Bi(cyclohexan)]-3-one (18)
1
H NMR (400 MHz, Chloroform-d): δ 2.42 – 2.29 (m, 2H), 2.29 – 2.16 (m, 1H), 2.08 (t, J = 12.9
Hz, 2H), 1.94 – 1.80 (m, 1H), 1.80 – 1.49 (m, 7H), 1.37 (qd, J = 12.6, 3.5 Hz, 1H), 1.29 – 1.04
1
3
(
m, 4H), 1.01 – 0.90 (m, 2H). C NMR (101 MHz, Chloroform-d): δ 212.9, 45.7, 44.8, 42.8,
4
1.7, 30.1, 30.0, 28.6, 26.7, 26.7, 26.7, 25.8. TLC: R = 0.36 (20:1 hexane:EtOAc). HRMS
f
+
(
APCI-TOF) m/z: [M+H] calcd for C12
H21O 181.1592, found 181.1587.
4
.4.16. Benzyl 3-cyclohexylpropanoate (19)
1
H NMR (400 MHz, Chloroform-d): δ 7.46 – 7.28 (m, 5H), 5.11 (s, 2H), 2.44 – 2.32 (m, 2H),
1
3
1
.74 – 1.59 (m, 5H), 1.58 – 1.49 (m, 2H), 1.32 – 1.06 (m, 4H), 1.00 – 0.77 (m, 2H). C NMR
(101 MHz, Chloroform-d): δ 174.1, 136.3, 128.7, 128.3, 128.3, 66.2, 37.3, 33.1, 32.5, 32.1, 26.7,
+
2
6.4. TLC: R = 0.38 (20:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+Na] calcd for
f
C H NaO 269.1512, found 269. 1518.
16
22
2
4
.4.17. Dimethyl 2-cyclohexylsuccinate (22)
1
4

ACCEPTED MANUSCRIPT
1
H NMR (400 MHz, Chloroform-d): δ 3.69 (s, 3H), 3.65 (s, 3H), 2.79 – 2.65 (m, 2H), 2.45 (dt, J
=
13.5, 8.9 Hz, 1H), 1.73 (br d, J = 13.5 Hz, 2H), 1.62 (br t, J = 13.5 Hz, 4H), 1.34 – 0.92 (m,
1
3
5
2
H). C NMR (101 MHz, Chloroform-d): δ 175.1, 173.1, 51.9, 51.7, 47.1, 40.1, 33.4, 30.8, 30.3,
+
6.4, 26.3. TLC: R = 0.29 (10:1 hexane:EtOAc). HRMS (APCI-TOF) m/z: [M+Na] calcd for
f
C H NaO 251.1254, found 251.1246.
12
20
4
ACKNOWLEDGMENTS
This work was supported by the National Science Foundation under Award Number DMR-
1
420073. J.D. is supported by the Margaret and Herman Sokol Fellowship and the Ted Keusseff
Fellowship. T.D. is a recipient of the Alfred P. Sloan Research Fellowship (FG-2018-10354).
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