Three-component glycolate michael reactions of enolates, silyl glyoxylates, and α,β-enones

Article abstract of DOI:10.1021/jo202679u

Silyl glyoxylates react with enolates and enones to afford either glycolate aldol or Michael adducts. Product identity is controlled by the countercation associated with the enolate. Reformatsky nucleophiles in the presence of additional Zn(OTf)₂

Full text of DOI:10.1021/jo202679u

Article
pubs.acs.org/joc
Three-Component Glycolate Michael Reactions of Enolates, Silyl
Glyoxylates, and α,β-Enones
Daniel C. Schmitt, Ericka J. Malow, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: Silyl glyoxylates react with enolates and enones
to afford either glycolate aldol or Michael adducts. Product
identity is controlled by the countercation associated with the
enolate. Reformatsky nucleophiles in the presence of addi-
tional Zn(OTf)2 result in aldol coupling (A), while lithium
enolates provide the Michael coupling (B). Deprotonation of
the aldol product A with LDA induces equilibration to form
the minor diastereomer of Michael product B. This
observation suggests that formation of the major diastereomer
of Michael product B does not occur via an aldol/retro-aldol/
Michael sequence.
Scheme 1. Michael Acceptors as Terminal Electrophiles
INTRODUCTION
■
Chiral glycolic acids are common subunits of biologically active
molecules such as zaragozic acid, trachyspic acid, and
echinosporin (Figure 1);1 therefore, the development of new
(Scheme 1).20,21 Reagent design hinges on a nucleophile-
triggered [1,2]-Brook rearrangement to achieve umpolung
reactivity at the silyl ketone carbon.22 The resulting enolate 2
may then react with various carbonyl electrophiles to provide
glycolate aldol21 or Claisen23 products. While there are several
examples of enolate 2 participating in 1,2-addition with
carbonyl24 or imine25 electrophiles, reactions with πCC
electrophiles have been less studied. To date, only vinylogous
trapping of enolate 2 with nitroolefins to provide chiral
enolsilanes has been reported.26 In contrast to nitroolefins,
enone electrophiles may exhibit ambident behavior, with both
aldol addition and Michael addition pathways possible.
Reactions with enone electrophiles would therefore need to
be controlled regioselectively. This report describes the
development of a three-component glycolate Michael reaction
Figure 1. Biologically active δ-oxygenated glycolic acids.
methods that produce α-substituted glycolic acids and esters
remains an important goal. Glycolate aldol2,3/alkylation4,5
reactions, nucleophilic additions to α-ketoesters,6,7 and ester
enolate oxygenations8 are among the most reliable means to
generate chiral α-hydroxy esters.9 On the other hand, syntheses
of δ-oxygenated glycolic acid derivatives are most directly
achieved via glycolate Michael reactions.10−18
Chemical reactions that generate multiple C−C bonds in a
single operation are valuable transformations as they provide
time- and cost-effective alternatives to multistep routes.19 Silyl
glyoxylate 1 has been utilized in such cascade reactions
Received: December 28, 2011
Published: March 6, 2012
© 2012 American Chemical Society
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Table 1. Three-Component Coupling: Influence of Counterions
entry
M
salt
solvent
4:5
dr (5)
1
ZnBr
ZnBr
ZnBr
ZnBr
Cu
Et2O
Et2O
Et2O
Et2O
THF
THF
THF
THF
Et2O
THF
THF
4.2:1.0
ND
ND
ND
2
ZnCl2
1.0:1.2
3
ZnBr2
1.0:1.0
4
Zn(OTf)2
>20:1
5
decomp
decomp
decomp
decomp
1.0:>20
1.0:>20
1.0:>20
6
CuCl
TiCl3
K
7
8
9
Li
1:1.5
2.1:1
3.5:1
10
11
Li
Li
LiCl
that displays counterion-dependent regioselectivity for 1,4-
versus 1,2-addition to α,β-unsaturated ketones.
glyoxylate (R = trans-2-phenylcyclohexanol,32,33 entry 9)
underwent three-component coupling with moderate diaster-
eoselectivity (13:Σothers = 4.8:1), demonstrating the potential
viability of chiral auxiliary-mediated glycolate Michael reactions.
Ineffective Michael acceptors included those with sterically
hindered β-positions (R2 = t-Bu or 2-substituted phenyl) and
α,β-unsaturated aldehydes, both of which favored three-
component 1,2-addition. Enolizable aliphatic enones did
undergo the desired three-component coupling but usually
suffered from low conversion, probably due to quenching of
enolate 2 via proton transfer. α,β-Unsaturated esters and
lactones were unreactive terminal electrophiles.
Relative stereochemistry was determined by glycolate
Michael addition to enone 14, followed by elaboration to
trachyspic acid trimethyl ester (Scheme 2).34 Further evidence
was obtained by crystallization and X-ray analysis of ketone 7,
which confirmed the syn-relationship between 2-furyl and silyl
ether substituents (Figure 2).35,36 The stereochemical result is
consistent with (Z)-enolate geometry37 according to Heath-
cock’s model for Michael addition of ester enolates to enones.38
A closed eight-membered transition state, in which steric
interactions between the enolate’s O-tert-butyl group and the
enone’s phenyl substituent are minimized, may be operative
(Figure 3).
The origin of the observed inversion of regioselectivity upon
switching from Zn to Li acetate enolates was of interest (Table
1). In general, additions to a C−C double bond are more
exergonic than additions to a C−O double bond;39 therefore, a
hypothesis that required evaluation was that the observed
selectivity reversal arose from kinetic (1,2-addition) versus
thermodynamic (1,4-addition) control. By this rationale, the
Zn(OTf)2-mediated reaction would proceed irreversibly to
afford the observed aldol product. On the other hand, the Li-
mediated reaction would involve an initial aldol addition,
followed by retro-aldol fragmentation, and finally 1,4-addition
to provide the observed Michael addition product.
To test the proposed retro-aldol/Michael sequence, aldol
product 4 was deprotonated with LDA in the presence of LiCl
(Scheme 3). The glycolate Michael product was indeed
obtained, but it favored the diastereomeric Michael adduct 5-
anti rather than adduct 5-syn that was obtained in the three-
component coupling of the lithium acetate enolate, silyl
RESULTS AND DISCUSSION
■
Preliminary experiments utilized the Reformatsky reagent of
tert-butyl bromoacetate,23 TBS-tert-butyl silyl glyoxylate,20 and
difurylideneacetone27 (dfa), which resulted in a mixture of
glycolate aldol and Michael three-component coupling
products with <75% conversion (Table 1). In an effort to
increase conversion by Lewis acid activation of the enone, a
number of zinc salts were screened as additives. No significant
improvement in conversion was observed, but the ratio of 1,4-
addition to 1,2-addition was influenced. While ZnCl2 and ZnBr2
additives provided no selectivity for Michael versus aldol
products, zinc triflate produced exclusively the aldol 1,2-
addition product 4. Examples of highly selective 1,2-addition to
sterically unbiased α,β-enones by Reformatsky reagents are
scarce.28,29
Noting the influence of counterion on regioselectivity and
aiming to access the complementary glycolate Michael addition
products, we tested a series of cationic counterions. After
various metal enolates proved ineffective as nucleophilic
triggers (entries 5−8, Table 1), lithium enolates provided
exclusively the desired 1,4-addition (entries 9−11). The
addition of superstoichiometric lithium chloride provided
optimal conversion and diastereoselectivity, which may be
due to altered aggregation of the glycolate enolate or an
increased degree of chelation during Michael addition.30,31
Reaction optimization revealed that the order of reagent
addition influenced the diastereoselectivity. Addition of silyl
glyoxylate to a solution of acetate enolate at −78 °C and
warming to 0 °C, followed by addition of the enone, resulted in
modest diastereoselection (2.1:1 dr for both dfa and chalcone).
However, an increase in diastereoselectivity was observed when
the enone and silyl glyoxylate were added simultaneously to a
solution of the acetate enolate (3.5:1 dr for dfa, 4.0:1 dr for
chalcone). Simultaneous reagent addition is possible due to the
lithium enolate nucleophile’s high selectivity for the silyl
glyoxylate over the enone electrophile, providing the desired
three-component coupling products.
Effective enones possessed electron-rich aromatic, electron-
poor aromatic, or heteroaromatic substituents. A chiral silyl
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a b
,
Table 2. Scope of 1,4-Addition
Figure 2. X-ray structure of ketone 7 (some hydrogens have been
omitted for clarity).
Figure 3. Proposed transition states.
glyoxylate, and dfa. Diastereoselectivity in the addition of ester
enolates to enones is believed to stem from enolate geometry.38
Therefore, retro-aldol fragmentation may provide (E)-enolate
2E,40 whereas Brook rearrangement following the addition of
lithium acetate enolate to silyl glyoxylate has previously been
shown to produce the (Z)-enolate 2Z.37
Since the retro-aldol/Michael sequence provides the
opposite diastereomer from the three-component coupling
reaction, it is unlikely that the three-component Michael
addition products 5−13 result from reversible aldol addition
followed by Michael addition. To the extent that the aldol/
retro-aldol/Michael addition pathway is operative, it likely
results in formation of 5-anti and a net erosion of
diastereoselectivity in the Michael-terminated Li+-based three-
component couplings.
a
Reagents: LiCl (8.0 equiv), enolate (1.9 equiv), 1 (2.1 equiv), enone
b
(1.0 equiv). See the Supporting Information for detailed procedures.
c
PMP: 4-methoxy-phenyl.
Scheme 2. Stereochemical Proof
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Hz, 1H), 2.64 (d, J = 17.6 Hz, 1H), 1.46 (s, 9H), 1.42 (s, 9H), 0.93 (s,
9H), 0.25 (s, 3H), 0.16 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
171.7, 169.7, 152.9, 142.0, 128.5, 127.6, 118.1, 117.5, 111.2, 108.0 (2
peaks), 83.1, 82.7, 80.6, 78.8, 41.4, 28.1, 27.9, 26.2, 19.0, −2.5, −2.8;
TLC (10:90 EtOAc/petroleum ether) Rf 0.50; HRMS (ESI) calculated
for C31H46O8SiCs 707.2016, found 707.2040.
Scheme 3. LDA-Induced Rearrangement of Aldol Product
General Procedure A for Aldol/Michael Three-Component
Couplings. To a solution of LiCl (8.0 equiv, 1.9 M) in THF was
added iPr2NH (2.1 equiv). The solution was cooled to 0 °C, and nBuLi
(1.4 M in hexanes, 2.0 equiv) was added. The solution was stirred at 0
°C for 10 min and then stirred at room temperature for 10 min. The
solution was cooled to −78 °C, and a solution of tBuOAc (1.9 equiv)
in THF (1.1 M) was added. The solution was stirred at −78 °C for 1
h. A solution of α,β-unsaturated ketone (1.0 equiv, 0.2 M) and tert-
butyl tert-butyldimethylsilyl glyoxylate20 (2.1 equiv) in THF was
added. The solution was allowed to slowly warm to room temperature
over 3 h and then stirred at room temperature for 14−24 h. The
reaction was diluted with Et2O (15 mL) and quenched with saturated
NH4Cl (5 mL). The layers were separated, and the aqueous layer was
extracted with Et2O (3 × 20 mL). The organic extracts were
combined, washed with brine (15 mL), dried with MgSO4, and
concentrated under reduced pressure. The resulting oil was purified as
indicated.
Di-tert-butyl 2-((tert-Butyldimethylsilyl)oxy)-2-(3-oxo-1,3-
diphenylpropyl)succinate (6). General procedure A was performed
using trans-chalcone (42 mg, 0.200 mmol, 1.0 equiv). 1H NMR
analysis of the crude mixture revealed a diastereomeric ratio of 4.0:1.
Purification by flash chromatography (97:3 petroleum ether/Et2O)
furnished 6 (67 mg, 0.118 mmol, 59% yield) as a colorless oil.
Analytical data for 6: IR (thin film, cm−1) 2929, 2855, 2360, 2124,
1
1739, 1691, 1607, 1578, 1495, 1017; H NMR (600 MHz, CDCl3) δ
7.86 (d, J = 6.6 Hz, 2H), 7.51−7.49 (m 1H), 7.49−7.36 (m, 4H),
7.25−7.19 (m, 3H), 3.79 (d, J = 10.2 Hz, 1H), 3.60 (dd, J = 10.2, 18.0
Hz, 1H), 3.47 (d, J = 18.0 Hz, 1H), 2.70 (d, J = 16.8 Hz, 1H), 2.24 (d,
J = 17.4 Hz, 1H), 1.40 (s, 9H), 1.39 (s, 9H), 0.92 (s, 9H), 0.39 (s,
3H), 0.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 198.0, 172.3,
169.0, 140.0, 137.2, 132.8, 130.2, 130.0, 128.5, 128.0, 127.9, 127.5,
126.9, 81.7, 80.5, 80.3, 49.1, 44.4, 40.6, 28.1 (2 peaks), 27.8, 26.5, 26.3,
19.2, −2.1, −2.6; TLC (10:90 EtOAc/petroleum ether) Rf 0.52;
LRMS (ESI) calculated for C33H48O6SiNa 591.31, found 591.33;
HRMS (ESI) calculated for C33H48O6SiCs 701.2274, found 701.2262.
Di-tert-butyl 2-((tert-Butyldimethylsilyl)oxy)-2-(1-(furan-2-
yl)-3-oxo-3-phenylpropyl)succinate (7). General procedure A
was performed using (E)-3-(furan-2-yl)-1-phenylprop-2-en-1-one (29
CONCLUSION
■
In summary, we have developed a chemoselective and
regioselective three-component coupling reaction of lithium
enolates, silyl glyoxylates, and α,β-unsaturated ketones. The
products possess two contiguous stereogenic centers, including
a protected tertiary alcohol, with potential for synthetic
elaboration (Scheme 2). The regioselectivity of glycolate
enolate addition to the α,β-unsaturated ketone may be switched
to favor exclusively aldol addition simply by modifying the
counterion.
1
mg, 0.145 mmol, 1.0 equiv). H NMR analysis of the crude mixture
revealed a diastereomeric ratio of 4.9:1. Purification by flash
chromatography (97:3 hexanes/Et2O) furnished 35e (53 mg, 0.0948
mmol, 65% yield) as a clear oil (the major diastereomer could be
isolated as a pale yellow solid (mp 71−77 °C)). Analytical data for
35e: IR (thin film, cm−1) 2930, 2855, 1741, 1692, 1598, 1472, 1393,
1368, 1251, 1149, 1106, 1012; 1H NMR (500 MHz, CDCl3) δ 7.90 (d,
J = Hz, 2H), 7.53 (t, J = 7 Hz, 1H), 7.44−7.40 (m, 2H), 7.28 (s, 1H),
6.24 (d, J = 2 Hz, 1H), 6.14 (d, J = 3.5 Hz, 1H), 3.95 (dd, J = 2, 10.5
Hz, 1H), 3.66 (dd, J = 10.5, 17.5 Hz, 1H), 3.31 (dd, J = 2, 17 Hz, 1H),
2.92 (d, J = 16.5 Hz, 1H), 2.45 (d, J = 17 Hz, 1H), 1.43 (s, 9H), 1.39
(s, 9H), 0.87 (s, 9H), 0.33 (s, 3H), 0.14 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 197.7, 171.9, 168.9, 153.1, 141.4, 137.0, 132.9, 128.5, 128.0,
110.2, 108.5, 81.7, 80.3, 79.8, 43.6, 43.3, 28.1, 27.7, 26.2, 19.0, −2.4,
−2.9; TLC (10:90 EtOAc/petroleum ether) Rf 0.45; LRMS (ESI)
calculated for C31H46O7SiNa 581.29, found 581.31; HRMS (ESI)
calculated for C31H46O7SiCs 691.2067, found 691.2061.
EXPERIMENTAL SECTION
■
Di-tert-butyl 2-((tert-Butyldimethylsilyl)oxy)-2-((1E,4E)-1,5-
di(furan-2-yl)-3-hydroxypenta-1,4-dien-3-yl)succinate (4). To
the Reformatsky reagent of tert-butyl bromoacetate23 (0.39 M in
Et2O, 1.5 mL, 0.583 mmol, 2.5 equiv) was added 0.9 mL Et2O. The
solution was cooled to −30 °C, and a solution of tert-butyl tert-
butyldimethylsilyl glyoxylate20 (142 mg, 0.583 mmol, 2.5 equiv) in
Et2O (1.5 mL) was added. The solution was slowly warmed to 0 °C
over 30 min before a solution of Zn(OTf)2 (85 mg, 0.233 mmol, 1.0
equiv) and difurylideneacetone (50 mg, 0.233 mmol, 1.0 equiv) in
Et2O (3.0 mL) was added. (Some Zn(OTf)2 would not dissolve and
was not transferred.) The solution was slowly warmed to room
temperature over 15 h, and then saturated NH4Cl (5 mL) was added.
The layers were separated, and the aqueous layer was extracted with
Et2O (3 × 20 mL). The organic extracts were combined, washed with
brine (15 mL), dried with MgSO4, and concentrated under reduced
pressure. Purification by flash chromatography (97:3 to 95:5
petroleum ether/EtOAc gradient) furnished 4 (56 mg, 0.0974
mmol, 42% yield) as a colorless oil. Analytical data for 4: IR (thin
film, cm−1) 3437, 2930, 2856, 1734, 1472, 1394, 1369, 1253, 1013; 1H
NMR (400 MHz, CDCl3) δ 7.33 (s, 2H), 6.59−6.52 (m, 3H), 6.38−
6.33 (m, 3H), 6.21 (t, J = 4.4 Hz, 2H), 3.83 (brs, 1H), 3.17 (d, J = 17.6
Di-tert-butyl 2-((tert-Butyldimethylsilyl)oxy)-2-(1-(4-chloro-
phenyl)-3-oxo-3-phenylpropyl)succinate (8). General procedure
A was performed using 4-chlorochalcone (49 mg, 0.200 mmol, 1.0
equiv). 1H NMR analysis of the crude mixture revealed a
diastereomeric ratio of 3.8:1. Purification by flash chromatography
(97:3 petroleum ether/Et2O) furnished 8 (83 mg, 0.138 mmol, 69%
yield) as a clear oil. Analytical data for 8: IR (thin film, cm−1) 2954,
1
2856, 2360, 1739, 1597, 1580, 1449, 1393, 1015; H NMR (major
diastereomer) (300 MHz, CDCl3) δ 7.84 (d, J = 7.5 Hz, 2H), 7.55−
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7.20 (m, 7H), 3.77 (dd, J = 3.0, 9.9 Hz, 1H), 3.55 (dd, J = 10.2, 18 Hz,
1H), 3.44 (dd, J = 3.0, 17.7 Hz, 1H), 2.62 (d, J = 17.1 Hz, 1H), 2.20
(d, J = 16.8 Hz, 1H), 1.42 (s, 9H), 1.39 (s, 9H), 0.92 (s, 9H), 0.39 (s,
3H), 0.17 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 198.2, 172.1,
168.8, 138.5, 136.8, 133.1, 132.8, 132.1, 131.2, 128.6, 128.1, 127.9,
121.0, 82.0, 80.5, 80.3, 48.3, 44.4, 40.6, 32.4, 28.0, 27.7, 26.4, 24.9,
19.2, −2.2, −2.6; TLC (10:90 EtOAc/petroleum ether) Rf 0.45;
HRMS (ESI) calculated for C33H47ClO6SiCs 735.1884, found
735.1892.
General procedure A was performed using (1E,4E)-1,5-bis(3,5-
dimethoxyphenyl)-1,4-pentadien-3-one (60 mg, 0.169 mmol, 1.0
equiv). 1H NMR analysis of the crude mixture revealed a
diastereomeric ratio of 1.6:1. Purification by flash chromatography
(85:15 petroleum ether/Et2O) furnished 12 (50 mg, 0.0699 mmol,
41% yield) as a clear oil. Analytical data for 12: IR (thin film, cm−1)
2929, 2850, 1740, 1651, 1595, 1463, 1428, 1368, 1067; 1H NMR (400
MHz, CDCl3) δ 7.37−7.33 (m, 1H), 6.61−6.47 (m, 6H) 6.28 (d, J =
18.4 Hz, 1H), 3.80 (s, 6H), 3.75 (s, 6H), 3.48 (d, J = 7.2 Hz, 1H),
3.26−3.14 (m, 2H), 2.71 (d, J = 17.2 Hz, 1H), 2.35 (d, J = 17.2 Hz,
1H), 1.42 (s, 9H), 1.40 (s, 9H), 0.95 (s, 9H), 0.36 (s, 3H), 0.16 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 198.1, 172.1, 169.0, 160.9,
160.3, 142.3 (2 peaks), 136.4, 126.9, 108.2, 106.0, 102.6, 98.8, 81.7,
80.3 (2 peaks), 55.4 (2 peaks), 49.7, 43.9, 42.6, 28.1, 27.7, 26.5, 19.2,
−2.3, −2.6; TLC (10:90 EtOAc/petroleum ether) Rf 0.11; LRMS
(ESI) calculated for C39H58O10SiNa 737.37, found 737.39; HRMS
(ESI) calculated for C39H58O10SiCs 847.2853, found 847.2825.
(E)-Di-tert-butyl 2-((tert-Butyldimethylsilyl)oxy)-2-(1,5-di-
(furan-2-yl)-3-oxopent-4-en-1-yl)succinate (5-syn). General pro-
cedure A was performed using difurylideneacetone (29 mg, 0.136
Di-tert-butyl 2-((tert-Butyldimethylsilyl)oxy)-2-(3-oxo-3-phe-
nyl-1-(4-(trifluoromethyl)phenyl)propyl)succinate (9). General
procedure
A was performed using (E)-1-phenyl-3-(4-
(trifluoromethyl)phenyl)prop-2-en-1-one (40 mg, 0.145 mmol, 1.0
equiv). 1H NMR analysis of the crude mixture revealed a
diastereomeric ratio of 2.7:1. Purification by flash chromatography
(97:3 hexanes/Et2O) furnished 9 (49 mg, 0.0769 mmol, 53% yield) as
a clear oil. Analytical data for 9: IR (thin film, cm−1) 2931, 2359, 1741,
1618, 1472, 1394, 1325, 1255, 1222, 1164, 1069, 1019; 1H NMR (600
MHz, CDCl3) δ 7.85 (d, J = 8.4 Hz, 2H), 7.53−7.50 (m, 5H), 7.44−
7.40 (m, 2H), 3.88 (dd, J = 2.4, 10.2 Hz), 3.58 (t, J = 10.2 Hz, 1H),
3.51 (dd, J = 3, 18 Hz, 1H), 2.63 (d, J = 17.4 Hz, 1H), 2.22 (d, J = 17.4
Hz, 1H), 1.42 (s, 9H), 1.40 (s, 9H), 0.93 (s, 9H), 0.39 (s, 3H), 0.18 (s,
3H); 13C NMR (150 MHz, CDCl3) δ 197.5, 171.8, 168.6, 136.8,
133.1, 130.3, 128.6, 127.8, 124.9, 82.1, 80.6, 80.2, 48.6, 44.4, 40.6, 28.1,
27.7, 26.5, 19.2, −2.2, −2.6; TLC (10:90 EtOAc/petroleum ether) Rf
0.45; LRMS (ESI) calculated for C34H47F3O6SiNa 659.30, found
659.32; HRMS (ESI) calculated for C34H47F3O6SiCs 769.2148, found
769.2175.
1
mmol, 1.0 equiv). H NMR analysis of the crude mixture revealed a
diastereomeric ratio of 3.5:1. Purification by flash chromatography
(97:3 hexanes/Et2O) furnished 5 (41 mg, 0.0713 mmol, 52% yield) as
a clear oil. Analytical data for 5: IR (thin film, cm−1) 2855, 1739, 1614,
1
1555, 1473, 1369, 1150, 1107, 1017; H NMR (300 MHz, CDCl3) δ
7.48 (s, 1H), 7.30 (d, J = 1.2 Hz, 1H), 7.23 (d, J = 15.9 Hz, 1H), 6.62
(d, J = 3.3 Hz, 1H), 6.54 (d, J = 15.9 Hz, 1H), 6.46 (dd, J = 1.8, 3.6
Hz, 1H), 6.25 (dd, J = 1.8, 3.0 Hz, 1H), 6.13 (d, J = 3.0 Hz, 1H), 3.81
(dd, J = 2.7, 11.1 Hz, 1H), 3.23−3.15 (m, 1H), 2.97 (dd, J = 2.4, 16.5
Hz, 1H), 2.89 (d, J = 16.8 Hz, 1H), 2.42 (d, J = 16.8 Hz, 1H), 1.44 (s,
9H), 1.42 (s, 9H), 0.87 (s, 9H), 0.30 (s, 3H), 0.12 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 197.3, 171.8, 168.9, 152.9, 151.1, 144.8, 141.4,
128.6, 123.2, 115.6, 112.5, 110.2, 108.6, 81.7, 80.3, 79.7, 43.6, 43.4,
40.5, 28.1, 28.0, 27.9, 27.8, 27.7, 26.2, 19.0, −2.5, −2.9; TLC (10:90
EtOAc/petroleum ether) Rf 0.44; LRMS (ESI) calculated for
C31H46O8SiNa 597.29, found 597.30; HRMS (ESI) calculated for
C31H46O8SiCs 707.2016, found 707.2075.
(E)-Di-tert-butyl 2-((tert-Butyldimethylsilyl)oxy)-2-(3-oxo-
1,5-diphenylpent-4-en-1-yl)succinate (10). General procedure A
was performed using dibenzylideneacetone (62 mg, 0.265 mmol, 1.0
equiv). 1H NMR analysis of the crude mixture revealed a
diastereomeric ratio of 2.4:1. Purification by flash chromatography
(60:40 petroleum ether/CH2Cl2 to 0:100 petroleum ether/CH2Cl2
linear gradient) furnished 10 (66 mg, 0.111 mmol, 42% yield) as a
clear oil. Analytical data for 10: IR (thin film, cm−1) 2930, 2855, 1740,
1
1613, 1496, 1455, 1393, 1368, 1254, 1152, 1104; H NMR (major
diastereomer) (600 MHz, CDCl3) δ 7.47−7.34 (m, 9H), 7.27−7.20
(m, 2H), 6.56 (d, J = 16.2 Hz, 1H), 3.67, (dd, J = 3.0, 10.8 Hz, 1H),
3.26 (dd, J = 10.8, 16.8 Hz, 1H), 3.14 (dd, J = 3.0, 16.8 Hz, 1H), 2.68
(d, J = 16.8 Hz, 1H), 2.25 (d, J = 16.8 Hz, 1H), 1.42 (s, 9H), 1.39 (s,
9H), 0.93 (s, 9H), 0.37 (s, 3H), 0.17 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 198.1, 172.1, 168.9, 142.3, 139.8, 134.5, 130.3, 130.0, 128.9,
128.8, 128.2, 128.0, 127.0, 126.4, 81.7, 80.5, 80.2, 49.4, 44.2, 42.7, 28.1,
27.8, 27.4, 26.5, 25.7, 25.6, 19.2, −2.2, −2.6; TLC (10:90 EtOAc/
petroleum ether) Rf 0.39; LRMS (ESI) calculated for C35H50O6SiCs
727.25, found 727.27; HRMS (ESI) calculated for C35H50O6SiCs
727.2431, found 727.2432.
(E)-Di-tert-butyl 2-((tert-Butyldimethylsilyl)oxy)-2-(1,5-di-
(furan-2-yl)-3-oxopent-4-en-1-yl)succinate (5-anti). To a sol-
ution of LiCl (37 mg, 0.88 mmol, 8.0 equiv, 0.67 M) in THF was
added iPr2NH (20 μL, 0.14 mmol, 1.3 equiv). The solution was cooled
to 0 °C, and nBuLi (80 μL, 0.13 mmol, 1.654 M in hexanes, 1.2 equiv)
was added. The solution was stirred at 0 °C for 10 min and then
stirred at room temperature for 10 min. The solution was cooled to
−78 °C, and a solution of 4 (63 mg, 0.110 mmol, 1.0 equiv) in THF
(0.1 M) was added. The solution was allowed to slowly warm to room
temperature over 3 h and then stirred at room temperature for 14−24
h. The reaction was diluted with Et2O (15 mL) and quenched with
saturated NH4Cl (5 mL). The layers were separated, and the aqueous
layer was extracted with Et2O (3 × 20 mL). The organic extracts were
combined, washed with brine (15 mL), dried with MgSO4, and
concentrated under reduced pressure. Purification by flash chromatog-
raphy (97:3 hexanes/diethyl ether) furnished 5-anti (20 mg, 0.0348
mmol, 32% yield) as a yellow oil in a 5.5:1 dr. Analytical data for 5-
anti: IR (thin film, cm−1) 3420, 2920, 1733, 1635, 1507, 1265,1149,
1017; 1H NMR (400 MHz, CDCl3); 7.48 (d, J = 1.6 Hz, 1H), 7.27 (d,
J = 16.0 Hz, 1H), 6.63 (d, J = 3.6 Hz, 1H), 6.59 (d, J = 15.6 Hz, 1H),
6.47 (dd, J = 1.6, 2.0 Hz, 1H), 6.23 (dd, J = 1.2, 2.0 Hz, 1H), 6.01 (d, J
= 3.2 Hz, 1H), 3.92 (dd, J = 4.0, 10.0 Hz, 1H), 3.24−3.13 (m, 2H),
3.17 (d, J = 2.8 Hz, 1H), 2.88 (d, J = 16.0 Hz, 1H), 2.63 (d, J = 16.4
Hz, 1H), 1.44 (s, 9H), 1.41 (s, 9H), 0.89 (s, 9H), 0.14 (s, 3H), 0.12 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 197.5, 170.9, 168.5, 153.2,
151.1, 144.8, 140.9, 128.6, 123.3, 115.6, 112.5, 110.2, 108.4, 81.8, 80.6,
79.6, 44.5, 43.3, 39.9, 28.1, 27.8, 26.1, 18.9, −2.6, −2.8; TLC (10:90
EtOAc/petroleum ether) Rf 0.31; HRMS (ESI) calculated for
C31H46O8SiNa 597.2962, found 597.2866.
(E)-Di-tert-butyl 2-(1,5-Bis(4-methoxyphenyl)-3-oxopent-4-
en-1-yl)-2-((tert-butyldimethylsilyl)oxy)succinate (11). General
procedure A was performed using dianisylideneacetone (59 mg, 0.200
1
mmol, 1.0 equiv). H NMR analysis of the crude mixture revealed a
diastereomeric ratio of 1.9:1. Purification by flash chromatography
(95:5 to 85:15 petroleum ether/Et2O gradient) furnished 11 (52 mg,
0.0794 mmol, 40% yield) as a clear oil. Analytical data for 11: IR (thin
film, cm−1) 2930, 2854, 1740, 1658, 1602, 1513, 1463, 1422, 1393,
1107, 1036; 1H NMR (400 MHz, CDCl3) δ 7.43−7.37(m, 3H), 7.27−
7.25 (m, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 6.45
(d, J = 16.4 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 3.61 (dd, J = 2.4, 10.4
Hz, 1H), 3.20 (dd, J = 10.8, 16.8 Hz, 1H), 3.06 (dd, J = 2.8, 16.8 Hz,
1H), 2.65 (d, J = 17.2 Hz, 1H), 2.22 (d, J = 16.8 Hz, 1H), 1.43 (s, 9H),
1.39 (s, 9H), 0.93 (s, 9H), 0.37 (s, 3H), 0.16 (s, 0.16); 13C NMR (150
MHz, CDCl3) δ 198.3, 172.3, 169.0, 161.5, 158.5, 142.1, 131.8, 130.9,
130.0, 127.2, 124.3, 114.3, 113.4, 81.6, 80.6, 80.2, 55.4, 55.2, 48.8, 44.3,
42.6, 28.1, 27.8, 26.5, 19.2, −2.1, −2.6; TLC (10:90 EtOAc/petroleum
ether) Rf 0.18; LRMS (ESI) calculated for C37H54O8SiNa 677.35,
found 677.37; HRMS (ESI) calculated for C37H54O8SiCs 787.2642,
found 787.2623.
(1S,2R)-2-Phenylcyclohexyl tert-Butyldimethylsilyl Glyoxy-
late. The standard protocol20 was followed using (1S,2R)-2-
phenylcyclohexanol.41 The silyl glyoxylate was obtained in 69% overall
yield. Analytical data: IR (thin film, cm−1): 3031, 2932, 2859,1736,
(E)-Di-tert-butyl 2-(1,5-Bis(3,5-dimethoxyphenyl)-3-oxo-
pent-4-en-1-yl)-2-((tert-butyldimethylsilyl)oxy)succinate (12).
3250
dx.doi.org/10.1021/jo202679u | J. Org. Chem. 2012, 77, 3246−3251

The Journal of Organic Chemistry
Article
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3H), 5.14 (dt, J = 10.2, 4.2 Hz, 1H), 2.76 (dt, J = 12, 3.6 Hz, 1H),
2.19−2.13 (m, 1H), 1.97−1.92 (m, 1H), 1.90−1.84 (m, 1H), 1.82−
1.77 (m, 1H), 1.62−1.45 (m, 3H), 1.42−1.32 (m, 1H), 0.78 (s, 9H),
0.03 (s, 3H), −0.01 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 231.9,
162.4, 142.4, 128.4, 127.5, 126.7, 77.6, 49.5, 34.1, 32.1, 26.2, 25.6, 24.7,
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0.108 mmol, 80% yield) as a clear oil. Analytical data for 13: IR (thin
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eche, G.; Johnson, J. S. Org. Synth. 2008,
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1254, 1151, 1105, 1015; H NMR (major diastereomer) (500 MHz,
CDCl3) δ 7.54 (s, 1H), 7.28−7.14 (m, 5H), 7.07−6.95 (m, 2H), 6.64
(d, J = 3.0 Hz, 1H), 6.52 (d, J = 1.5 Hz, 1H), 6.29 (d, J = 15.5 Hz,
1H), 6.22 (s, 1H), 6.01 (d, J = 3.0 Hz, 1H), 5.31−5.23 (m, 1H), 3.43
(dd, J = 2.5, 11.5 Hz, 1H), 2.89 (dd, J = 12, 17.5 Hz, 1H), 2.73−2.68
(m, 1H), 2.67 (d, J = 16.5 Hz, 1H), 2.32 (d, J = 16.5 Hz, 1H), 2.28
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Hz, 1H), 1.61−1.28 (m, 5H), 1.43 (s, 9H), 0.81 (s, 9H), 0.15 (s, 3H),
0.09 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.4, 172.0, 168.7,
153.1, 151.3, 144.6, 142.9, 128.6, 127.6, 127.4, 126.7, 124.0, 115.0,
112.4, 110.0, 108.1, 80.5, 79.6, 49.9, 45.2, 42.1, 39.8, 35.1, 31.8, 28.1,
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found 809.27; HRMS (ESI) calculated for C39H52O8SiCs 809.2485,
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ASSOCIATED CONTENT
■
S
* Supporting Information
(30) Hevia, E.; Mulvey, R. E. Angew. Chem., Int. Ed. 2011, 50, 6448−
6450.
1
Copies of H and 13C NMR spectra. This material is available
(31) Kolonko, K. J.; Wherritt, D. J.; Reich, H. J. J. Am. Chem. Soc.
2011, 133, 16774−16777.
(32) Giampietro, N. C.; Kampf, J. W.; Wolfe, J. P. J. Am. Chem. Soc.
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(35) CCDC 854999 contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request.cif.
(36) Stereochemistry of the remaining enones was assigned by
analogy. In each case the major diastereomer was less polar than the
minor diastereomer. In the 1H NMR spectra, the stereogenic methine
H was further upfield in the major diastereomer in all cases.
(37) For further evidence of (Z)-glycolate enolate generation from
silyl glyoxylates, see: Schmitt, D. C.; Johnson, J. S. Org. Lett. 2010, 12,
944−947.
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enolates such as 2 by chelation from the g-ester functionality:
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free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jsj@unc.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project described was supported by Award R01
GM084927 from the National Institute of General Medical
Sciences. Additional support was provided by Novartis (Early
Career Award to J.S.J.). Michael Slade (UNC) is acknowledged
for the preparation of trans-2-phenylcyclohexyl silyl glyoxylate.
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