Synthesis of silyloxy dienes by silylene transfer to divinyl ketones: Application to the asymmetric synthesis of substituted cyclohexanes

Article abstract of DOI:10.1021/jo202650k

Silver-catalyzed silylene transfer to divinyl ketones provided 2-silyloxy-1,3-dienes with control of stereochemistry and regioselectivity. The products participated in Diels-Alder reactions with electron-deficient alkenes and imines to form six-membered-ring products diastereoselectively. Cycloaddition reactions with alkenes bearing chiral auxiliaries provided access to chiral, nonracemic cyclohexenes. The methodology, therefore, represents a synthesis of diastereomerically and enantiomerically pure products in a single flask. The highly substituted cyclohexene products could be functionalized stereoselectively to provide cyclohexanols after oxidation of the carbon-silicon bond.

Full text of DOI:10.1021/jo202650k

Article
pubs.acs.org/joc
Synthesis of Silyloxy Dienes by Silylene Transfer to Divinyl Ketones:
Application to the Asymmetric Synthesis of Substituted
Cyclohexanes
Christian C. Ventocilla† and K. A. Woerpel*,‡
†Department of Chemistry, University of California, Irvine, California 92697-2025, United States
‡Department of Chemistry, New York University, New York, New York 10003, United States
S
* Supporting Information
ABSTRACT: Silver-catalyzed silylene transfer to divinyl ketones
provided 2-silyloxy-1,3-dienes with control of stereochemistry and
regioselectivity. The products participated in Diels−Alder reactions
with electron-deficient alkenes and imines to form six-membered-ring
products diastereoselectively. Cycloaddition reactions with alkenes
bearing chiral auxiliaries provided access to chiral, nonracemic
cyclohexenes. The methodology, therefore, represents a synthesis of
diastereomerically and enantiomerically pure products in a single
flask. The highly substituted cyclohexene products could be functionalized stereoselectively to provide cyclohexanols after
oxidation of the carbon−silicon bond.
5). The regioselectivity was further enhanced upon using THF
as the solvent as well as cooling the reaction mixture to −78 °C
(Table 1, entry 6).
INTRODUCTION
■
Conjugated dienes are important precursors to complex organic
products. In addition to the polymerization of 1,3-dienes, an
important industrial transformation,1 dienes have been used in
stereoselective synthesis, such as the vinylogous aldol
reaction.2,3 Among the most important transformations of
dienes is the Diels−Alder reaction because it enables the
synthesis of cyclohexenes with a high degree of control. The
importance of dienes has required the development of new
routes for their synthesis.4 In particular, the synthesis of highly
substituted 2-silyloxy-1,3-dienes, which are important inter-
mediates,5 has been difficult to achieve with control of
stereochemistry.6−8
In this Article, we report the synthesis of 2-silyloxy-1,3-dienes
from divinyl ketones by transfer of a silylene moiety (R2Si).
The resulting silyloxy dienes participated in stereoselective
Diels−Alder cycloaddition reactions. Treatment of these dienes
with chiral dienophiles allowed for kinetic resolution of the
chiral diene to afford enantiopure cyclohexene products.
The regioselectivity of this reaction can be understood by
considering the structure of the divinyl ketone. It is likely that
α-substitution blocks the lone pair of the carbonyl group’s
oxygen atom13 from forming the silacarbonyl ylide14−17
intermediate on that side of the divinyl ketone, whereas β-
substitution does little to block the oxygen lone pair (Figure 1).
It is also expected that α-substitution forces the alkene into the
s-trans configuration, or possibly even out of plane,18−22 thus
preventing formation of the silacarbonyl ylide on this side of
the carbonyl group.
The geometry of the alkene has a profound effect on the
regioselectivity of silylene transfer. The regioselectivity of
silylene transfer to ketone E-12 (eq 1) closely matched the
RESULTS AND DISCUSSION
■
Because silylene transfer to unsaturated carbonyl compounds
forms cyclic silyl enol ethers,9−11 initial experiments focused on
reactions of divinyl ketones with silylene intermediates. The
synthesis of silyloxy dienes was general for a range of substrates
(Table 1). The reaction was regioselective: silylene transfer
occurred to the side of the divinyl ketone bearing a β-
substituent over the side bearing an α-substituent. This
regioselectivity is consistent with the observed selectivity of
nucleophilic additions to divinyl ketones.12 Increasing the steric
bulk of the α-substituent further increased this regioselectivity
for transfer to the side bearing a β-substituent (Table 1, entry
regioselectivity found in silylene transfer to methyl-substituted
divinyl ketone (Table 1, entry 1). This result indicates the
significance of α-substitution for the observed selectivity. In
contrast, addition across a Z-double bond was highly
disfavored. Silylene transfer to ketone Z-12 favored transfer
across the CC bond that contained an α-methyl substituent
Received: January 8, 2012
Published: February 28, 2012
© 2012 American Chemical Society
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a
Table 1. Silylene Transfer to Divinyl Ketones
entry
ketone
R1
R2
product
α:β ratio
NMR yield
1
2
3
4
5
2
4
Me
Ph
Me
Me
Ph
3a:3b
5a:5b
25:75
27:73
26:74
37:63
15:85
7:93
100%
100%
97%
6
Me
Me
i-Pr
i-Pr
7a:7b
8
i-Pr
Me
Me
9a:9b
88%
10
11a:11b
100%
b
6
10
11a:11b
96%
a
b
1H NMR spectroscopic analysis was used to determine both regioisomeric ratios and yields relative to an internal standard (PhSiMe3). Transfer
was run in THF at −78 °C instead of tol-d8. Silyloxy dienes were carried onto cycloaddition reactions without further purification due to their
instability to isolation conditions.
Scheme 1. Synthesis of Cycloadduct
Figure 1. Possible conformations of divinyl ketones.
rather than the CC bond that contained an α-hydrogen and
Z-β-methyl substituent (eq 2). The high preference for the Z-
alkene to react at the α-substituted double bond may arise
cycloadduct showed both high endo-selectivity and a high π-
because only conformers Z-12a and Z-12b are populated
facial preference in which the dienophile approached the diene
from the face opposite to the methyl substituent of the silyloxy
diene 11b. No cycloadducts were observed from regioisomer
11a, presumably due to the high energy of the s-cis
conformation that is necessary for cycloaddition.23
because the conformers Z-12c and Z-12d are too sterically
crowded (Figure 2). For the conformers Z-12a and Z-12b, in
The highly substituted silyloxy diene also engaged in Diels−
Alder cycloadditions with other π-systems. Although other
Lewis acids decomposed the diene, the use of AlBr3 with AlMe3
acting as a proton scavenger and desiccant24 promoted Diels−
Alder cycloadditions with a variety of dienophiles (eqs 3 and 4).
Figure 2. Rationale for regioselective transfer to Z-12.
neither case can a silylene moiety approach the carbonyl group
from the side of the β-substituted double bond.
The silyloxy diene obtained by silylene transfer to a divinyl
ketone participated in a thermal Diels−Alder cycloaddition
with high diastereoselectivity and chemoselectivity (Scheme 1).
Silylene transfer to 10, for example, produced diene 11b along
with small amounts (7%) of its regioisomer 11a. Heating this
mixture with diethyl fumarate produced cycloadduct 14, which
is the result of cycloaddition with regioisomer 11b. The
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The cyclic silyloxy dienes also could be used for the synthesis
of enantiomerically enriched cyclohexenes. We considered that
the high π-facial selectivity of the silyloxy diene could be
combined with the high facial selectivity of a chiral N-
acyloxazolidinone25 to enable a Diels−Alder/kinetic resolution
reaction.26,27 Upon treatment with an excess of a chiral,
nonracemic dienophile, the enantiomer of the silyloxy diene
with a stereochemical preference matched to the dienophile
should react to form a nonracemic cycloadduct with high
diastereoselectivity, leaving behind the opposite enantiomer of
the diene. Treating chiral dienophile 17 with an excess (3
equiv) of silyloxy diene 11b allowed for selective cycloaddition
to one enantiomer of the racemic diene, affording cycloadduct
18 with 99:1 diastereoselectivity (eq 5). Because of the high
Scheme 2. Functionalization of Cycloadducts
functionalization of these cycloadducts led to cyclohexanes
containing multiple contiguous stereocenters.
EXPERIMENTAL SECTION
■
(E)-2-Methylhexa-1,4-dien-3-one (2). Representative Proce-
dure for the Synthesis of Divinyl Ketones. To a solution of
isopropenyl magnesium bromide (100 mL, 0.5 M, 50 mmol) in THF
cooled to 0 °C was added crotonaldehyde (4.54 mL, 55.0 mmol)
dropwise. The mixture was allowed to warm to rt and stir overnight.
To the mixture was added a saturated aqueous solution of NH4Cl
(50.0 mL), and the layers were allowed to separate. The aqueous layer
was extracted with 3 × 15 mL of ether. The organic layers were
combined, washed with brine (15 mL), and dried over MgSO4. The
mixture was filtered and concentrated in vacuo. The resulting residue
was diluted with CH2Cl2 (250 mL), and activated MnO2 (43.4 g, 500
mmol) was added. The slurry was allowed to stir at rt for 7 days. The
slurry was filtered over a layer of Celite on top of a layer of SiO2, and
the filtrate was concentrated in vacuo to afford a yellow oil. The oil
was purified by flash chromatography (10:90 ether/pentane) to afford
sensitivity of the silyloxy diene 11b to even mild acids, such as
silica gel, the selectivity with respect to this component could
not be determined. 1H NOE spectroscopic correlation revealed
that cycloadduct 18 was the endo-product, but the relative
configuration of the auxiliary to the cyclohexene ring could not
be determined. The chiral, nonracemic dienophile28 19
kinetically resolved the phenyl-substituted silyloxy diene 5b
(albeit with lower selectivity). The cycloadduct 20, however,
was crystalline, so its configuration was determined by X-ray
crystallography (eq 6). The relative configuration of this
1
(E)-2-methylhexa-1,4-dien-3-one (3.024 g, 55%) as a colorless oil: H
NMR (400 MHz, CDCl3) δ 6.92 (dq, J = 15.3, 6.9 Hz, 1H), 6.67 (d, J
= 15.3 Hz, 1H), 5.91 (s, 1H), 5.76 (s, 1H), 1.93 (dd, J = 1.6, 0.8 Hz,
3H), 1.91 (d, J = 1.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.3,
145.3, 143.6, 126.8, 124.4, 18.6, 18.2; IR (thin film) 2971, 1668, 1622,
1446, 1348, 966 cm−1; HRMS (ESI) m/z calcd for C7H11O (M + H)+
111.0810, found 111.0813.
(E)-2-Phenylhexa-1,4-dien-3-one (4). The representative proce-
dure for the synthesis of divinyl ketones was followed using a Grignard
prepared from α-bromostyrene (91.0 mL, 0.3 M, 30 mmol),
crotonaldehyde (2.47 mL, 30.0 mmol), and MnO2 (23.7 g, 273
mmol) to afford (E)-2-phenylhexa-1,4-dien-3-one (2.34 g, 50%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.44−7.33 (m, 5H), 7.03
(dq, J = 15.4, 6.9 Hz, 1H), 6.52 (dq, J = 15.4, 1.6 Hz, 1H), 5.93 (q, J =
0.7 Hz, 2H), 1.95 (dd, J = 6.9, 1.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 193.6, 149.3, 145.7, 137.2, 129.9, 128.5, 128.3, 127.8, 122.0,
18.5; IR (thin film) 3057, 1884, 1670, 1621, 1443, 937 cm−1; HRMS
(ESI) m/z calcd for C12H13O (M + H)+ 173.0966, found 173.0966.
(E)-4-Methyl-1-phenylpenta-1,4-dien-3-one (6). The represen-
tative procedure for the synthesis of divinyl ketones was followed using
isopropenyl magnesium bromide (100 mL, 0.5 M, 50 mmol),
cinnamaldehyde (6.29 mL, 50 mmol), and MnO2 (43.4 g, 500
mmol) to afford (E)-4-methyl-1-phenylpenta-1,4-dien-3-one (8.13 g,
95%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J =
15.7 Hz, 1H), 7.58 (dt, J = 5.4, 3.4 Hz, 2H), 7.42−7.36 (m, 3H), 7.30
(d, J = 15.6 Hz, 1H), 6.04 (s, 1H), 5.84 (d, J = 0.9 Hz, 1H), 2.02−1.98
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 192.1, 145.8, 143.8, 135.2,
130.5, 129.1, 128.5, 124.5, 121.6, 18.4. 1H NMR and 13C NMR
spectroscopic data match those previously reported.38
product was used to assign the three-dimensional structure of
cycloadduct 18. This kinetic resolution is an example of double
stereoinduction29,30 for which there are few examples using the
Diels−Alder cycloaddition.26,29
Further functionalization of the Diels−Alder adducts
demonstrates the utility of these silyloxy dienes (Scheme 2).
Hydrogenation of cycloadduct 21, formed in 62% from divinyl
ketone 4 in a one-flask synthesis as a single diastereomer after
purification, established two new stereocenters diastereoselec-
tively. Oxidation31,32 of intermediate 23 produced diol 24
containing six contiguous stereocenters. The synthesis of highly
substituted cyclohexanes33 is important for the preparation of
natural products.34−37
CONCLUSION
■
Silylene transfer to divinyl ketones afforded silyloxy dienes
regioselectively. Subsequent Diels−Alder cycloadditions of
these silyloxy dienes afforded cyclohexene products chemo-
and diastereoselectively. In addition, treatment with chiral
dienophiles afforded enantioenriched cyclohexenes. Further
(E)-2,6-Dimethylhepta-1,4-dien-3-one (8). The representative
procedure for the synthesis of divinyl ketone was followed using
isopropenyl magnesium bromide (25.0 mL, 0.5 M, 13 mmol), (E)-4-
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methylpent-2-enal (1.45 mL, 12.5 mmol), and MnO2 (10.9 g, 125
6.23 (dq, J = 15.5, 1.5 Hz, 1H), 1.06 (s, 18H). Representative peaks for
the β-regioisomer (5b): 1H NMR (500 MHz, tol-d8) δ 5.94−5.89 (m,
1H), 5.16 (ddd, J = 2.4, 1.1, 0.7 Hz, 1H), 4.99 (d, J = 3.3 Hz, 1H), 1.12
(s, 9H), 1.05 (s, 9H).
mmol) to afford (E)-2,6-dimethylhepta-1,4-dien-3-one (0.88 g, 51%)
1
as a colorless oil: H NMR (400 MHz, CDCl3) δ 6.87 (dd, J = 15.5,
6.8 Hz, 1H), 6.58 (dd, J = 15.5, 1.2 Hz, 1H), 5.91 (d, J = 0.5 Hz, 1H),
5.78−5.74 (m, 1H), 2.54−2.43 (m, 1H), 1.93 (s, 3H), 1.09 (dd, J =
6.8, 2.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 192.8, 154.6, 145.5,
124.3, 122.3, 31.5, 21.6, 18.3; IR (thin film) 2962, 1668, 1622, 1359,
1083, 984 cm−1; HRMS (ESI) m/z calcd for C9H14NaO (M + Na)+
161.0942, found 161.0940. Anal. Calcd for C9H14O: C, 78.21; H,
10.21. Found: C, 77.98; H, 10.50.
(E)-6-Methyl-5-methylenehept-2-en-4-one (10). The represen-
tative procedure for the synthesis of divinyl ketone was followed using
propenyl magnesium bromide (100.0 mL, 0.5 M, 50 mmol), 3-methyl-
2-methylenebutanal (7.01 g, 50.0 mmol) prepared using the method
described by Breit,39 and MnO2 (43.5 g, 500 mmol) to afford 6-
methyl-5-methylenehept-2-en-4-one (3.17 g, 46%) as a 2:1 E/Z
mixture of isomers that were separated by flash chromatography.
Spectroscopic data for E isomer: 1H NMR (400 MHz, CDCl3) δ 6.88
(dq, J = 15.3, 6.9 Hz, 1H), 6.57 (dq, J = 15.3, 1.5 Hz, 1H), 5.80 (s,
1H), 5.63 (d, J = 1.2 Hz, 1H), 3.00−2.87 (m, 1H), 1.94−1.89 (m,
3H), 1.05 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 194.6,
156.7, 141.7, 126.2, 121.1, 27.9, 21.9, 15.9; IR (thin film) 2964, 1668,
1622, 1444, 1292, 939 cm−1; HRMS (ESI) m/z calcd for C9H14NaO
(M + Na)+ 161.0942, found 161.0937. Anal. Calcd for C9H14O: C,
78.21; H, 10.21. Found: C, 78.24; H, 10.26.
Silyloxy Dienes 7a and 7b. The representative procedure for the
silylene transfer to divinyl ketones was followed using (E)-4-methyl-1-
phenylpenta-1,4-dien-3-one (6) (0.017 g, 0.10 mmol). The α/β
1
regioisomeric ratio was found to be 26:74 by H NMR spectroscopy,
1
and the yield was determined by H NMR spectroscopy to be 97%
relative to the internal standard. Representative peaks for the α-
regioisomer (7a): 1H NMR (500 MHz, tol-d8) δ 2.09 (qn, J = 2.2 Hz,
1H), 1.05 (s, 18H). Representative peaks for the β-regioisomer (7b):
1H NMR (500 MHz, tol-d8) δ 5.79 (t, J = 1.5 Hz, 1H), 5.28 (d, J = 3.2
Hz, 1H), 5.01 (s, 1H), 3.59 (d, J = 3.0 Hz, 1H), 1.88 (s, 3H), 1.11 (s,
9H), 0.82 (s, 9H).
Silyloxy Dienes 9a and 9b. The representative procedure for the
silylene transfer to divinyl ketones was followed using (E)-2,6-
dimethylhepta-1,4-dien-3-one (8) (0.014 g, 0.10 mmol). The α/β
1
regioisomeric ratio was found to be 37:63 by H NMR spectroscopy,
1
and the yield was determined by H NMR spectroscopy to be 88%
relative to the internal standard. Representative peaks for the α-
regioisomer (9a): 1H NMR (400 MHz, tol-d8) δ 6.37 (dd, J = 15.2, 6.7
Hz, 1H), 6.24 (d, J = 15.2 Hz, 1H), 1.77 (s, 3H), 1.08 (s, 18H).
Representative peaks for the β-regioisomer (9b): 1H NMR (400 MHz,
tol-d8) δ 5.81 (dd, J = 1.8, 0.8 Hz, 1H), 5.33 (d, J = 2.9 Hz, 1H), 5.01
(d, J = 0.7 Hz, 1H), 2.33 (dq, J = 13.6, 6.8 Hz, 1H), 1.83 (s, 3H), 1.14
(s, 9H), 1.04 (s, 9H).
(2E,5E)-3-Methylhepta-2,5-dien-4-one (E-12) and (2E,5Z)-3-
Methylhepta-2,5-dien-4-one (Z-12). The representative procedure
for the synthesis of divinyl ketone was followed using propenyl
magnesium bromide (50.0 mL, 0.5 M, 25 mmol), tiglic aldehyde (2.42
mL, 25 mmol), and MnO2 (21.7 g, 250 mmol) to afford 3-
methylhepta-2,5-dien-4-one (1.92 g, 62%) as a 1:1 E/Z mixture of
isomers that were separated by flash chromatography. Spectroscopic
Silyloxy Dienes 11a and 11b. The representative procedure for
the silylene transfer to divinyl ketones was followed using 6-methyl-5-
methylenehept-2-en-4-one (10) (0.014 g, 0.10 mmol). The α/β
1
regioisomeric ratio was found to be 15:85 by H NMR spectroscopy,
1
and the yield was determined by H NMR spectroscopy to be 100%
1
data for E isomer: H NMR (500 MHz, CDCl3) δ 6.85 (dq, J = 15.2,
relative to the internal standard. Representative peaks for the α-
regioisomer (11a): 1H NMR (500 MHz, tol-d8) δ 6.39−6.25 (m, 1H),
6.23 (d, J = 15.3 Hz, 1H), 2.81 (sept, J = 6.8 Hz, 1H), 1.70 (d, J = 6.2
Hz, 3H), 1.04 (s, 18H). Representative peaks for the β-regioisomer
(11b): 1H NMR (500 MHz, tol-d8) δ 5.76 (s, 1H), 5.11 (d, J = 3.2 Hz,
1H), 5.02 (s, 1H), 2.60−2.50 (m, 1H), 1.09 (s, 9H), 1.02 (s, 9H).
Silyloxy Dienes 11a and 11b. To a solution of 6-methyl-5-
methylenehept-2-en-4-one (10) (0.014 g, 0.10 mmol) and AgO2CCF3
(0.002 g, 0.01 mmol) in THF (0.25 mL) cooled to −78 °C was added
a solution containing cyclohexene silacyclopropane 1 (0.028 g, 0.12
mmol) and PhSiMe3 (internal standard, 0.008 g, 0.05 mmol) in THF
(0.25 mL). The mixture was allowed to warm slowly to rt over 5 h.
The THF was removed in vacuo, and the resulting residue was
dissolved in C6D6 for 1H NMR spectroscopic analysis. The α/β
6.8 Hz, 1H), 6.74−6.69 (m, 1H), 6.67 (dq, J = 15.2, 1.6 Hz, 1H), 1.91
(dd, J = 6.8, 1.6 Hz, 3H), 1.87 (dq, J = 6.9, 1.1 Hz, 3H), 1.84 (qn, J =
1.2 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 192.3, 142.3, 139.0,
137.4, 127.0, 18.6, 15.0, 11.7; IR (thin film) 2918, 1666, 1444, 1296,
1080, 966 cm−1; HRMS (ES) m/z calcd for C8H12NaO (M + Na)+
147.0786; found, 147.0782. Spectroscopic data for Z isomer: 1H NMR
(500 MHz, CDCl3) δ 6.73 (qq, J = 6.9, 1.4 Hz, 1H), 6.47 (dq, J = 11.7,
1.8 Hz, 1H), 6.16 (dq, J = 11.7, 7.2 Hz, 1H), 1.97 (dd, J = 7.2, 1.8 Hz,
3H), 1.87−1.85 (m, 3H), 1.83−1.82 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 194.9, 140.0, 139.8, 138.5, 126.1, 16.0, 15.0, 11.1; IR (thin
film) 2927, 1664, 1444, 1296, 1080, 966 cm−1; HRMS (ESI) m/z calcd
for C8H12NaO (M + Na)+ 147.0786, found 147.0779.
Silyloxy Dienes 3a and 3b. Representative Procedure for
Silylene Transfer to Divinyl Ketones for the Synthesis of
Silyloxy Dienes. To an NMR tube was added a solution of (E)-2-
methylhexa-1,4-dien-3-one (2) (0.011 g, 0.10 mmol) and AgO2CCF3
(0.002 g, 0.01 mmol) in tol-d8 (0.25 mL). The solution was cooled to
−22 °C, and a solution containing cyclohexene silacyclopropane 1
(0.028 g, 0.12 mmol)40 and PhSiMe3 (internal standard, 0.008 g, 0.05
mmol) in tol-d8 (0.25 mL), also cooled to −22 °C, was added to the
NMR tube. The mixture was allowed to warm to rt. The α/β
1
regioisomeric ratio was found to be 7:93 by H NMR spectroscopy,
1
and the yield was determined by H NMR spectroscopy to be 96%
relative to the internal standard. Representative peaks matched those
above.
Silyloxy Dienes 13a and E-13b. The representative procedure
for silylene transfer to divinyl ketones was followed using (2E,5E)-3-
methylhepta-2,5-dien-4-one (E-12) (0.012 g, 0.10 mmol) at rt. The
1
13a/E-13b regioisomeric ratio was found to be 77:23 by H NMR
1
spectroscopy, and the yield was determined by 1H NMR spectroscopy
to be 93% relative to the internal standard. Representative peaks for
regioisomeric ratio was found to be 25:75 by H NMR spectroscopy,
1
and the yield was determined by H NMR spectroscopy to be 100%
1
relative to the internal standard. Representative peaks for the α-
oxasilacyclopentene 13a: H NMR (400 MHz, C6D6) δ 6.35 (q, J =
1
regioisomer (3a): H NMR (400 MHz, tol-d8) δ 6.33−6.25 (m, 1H),
7.0 Hz, 1H), 4.98 (d, J = 3.2 Hz, 1H), 1.27 (d, J = 7.7 Hz, 3H), 1.10 (s,
9H), 1.03 (s, 9H). Representative peaks for oxasilacyclopentene E-
13b: 1H NMR (400 MHz, C6D6) δ 6.38−6.29 (m, 1H), 6.23 (dd, J =
15.0, 1.4 Hz, 1H), 2.20−2.12 (m, 1H), 1.71 (d, J = 6.6 Hz, 3H), 1.13
(s, 9H), 1.05 (s, 9H).
6.22 (d, J = 12.0 Hz, 1H), 1.74 (s, 3H), 1.70 (d, J = 6.5 Hz, 3H), 1.05
1
(s, 18H). Representative peaks for the β-regioisomer (3b): H NMR
(400 MHz, tol-d8) δ 5.81 (d, J = 1.9 Hz, 1H), 5.08 (d, J = 3.2 Hz, 1H),
5.01 (s, 1H), 2.13 (qd, J = 7.7, 3.3 Hz, 1H), 1.82 (s, 3H), 1.11 (s, 9H),
1.04 (s, 9H).
Oxasilacyclopentenes 13a and Z-13b. The representative
procedure for silylene transfer to divinyl ketones was followed using
(2E,5Z)-3-methylhepta-2,5-dien-4-one (Z-12) (0.012 g, 0.10 mmol) at
Silyloxy Dienes 5a and 5b. The representative procedure for the
silylene transfer to divinyl ketones was followed using (E)-2-
phenylhexa-1,4-dien-3-one (4) (0.017 g, 0.10 mmol). The α/β
1
rt. The 13a/Z-13b regioisomeric ratio was found to be 9:91 by H
1
NMR spectroscopy, and the yield was determined by 1H NMR
spectroscopy to be 71% relative to the internal standard.
Representative peaks for oxasilacyclopentene 13a are the same as
regioisomeric ratio was found to be 27:73 by H NMR spectroscopy,
1
and the yield was determined by H NMR spectroscopy to be 100%
relative to the internal standard. Representative peaks for the α-
1
1
regioisomer (5a): H NMR (500 MHz, tol-d8) δ 6.43−6.30 (m, 1H),
above. Representative peaks for oxasilacyclopentene Z-13b: H NMR
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(400 MHz, C6D6) δ 6.01−5.97 (m, 1H), 5.47 (dqq, J = 11.7, 7.2, 0.5
Hz, 1H), 1.61−1.60 (m, 3H), 1.08 (s, 9H), 1.00 (s, 9H).
Cycloadduct 18. To AgO2CCF3 (0.066 g, 0.30 mmol) was added
a solution of (E)-6-methyl-5-methylenehept-2-en-4-one (10) (0.415 g,
3.00 mmol) in CH2Cl2 (10.0 mL). The mixture was cooled to −78 °C,
and a solution of cyclohexene silacyclopropane 1 (0.842, 3.75 mmol)
in CH2Cl2 (5.0 mL) was added dropwise. The mixture was allowed to
warm to rt and transferred to a flask containing (S,E)-4-benzyl-3-but-2-
enoyloxazolidin-2-one (0.245 g, 1.00 mmol). The mixture was cooled
to −100 °C, and AlMe3 (0.50 mL, 2.0 M, 1.0 mmol) was added. The
mixture was allowed to stir for 5 min, and AlMe2Cl (1.50 mL, 1.0 M,
1.5 mmol) was added. The mixture was allowed to warm slowly to rt
over 18 h, then was treated with a saturated aqueous solution of
sodium potassium tartrate (20.0 mL). The mixture was extracted with
3 × 10 mL of CH2Cl2. The organic layers were combined, washed with
brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo
to afford a yellow oil. GCMS analysis of the oil showed a mixture of
diastereomers (99:1 dr). The oil was purified by flash chromatography
(20:80 EtOAc/hexanes) to afford a colorless solid (0.405 g, 77%): mp
Cycloadduct 14. To AgO2CCF3 (0.079 g, 0.36 mmol) was added
a solution of (E)-6-methyl-5-methylenehept-2-en-4-one (10) (0.500 g,
3.62 mmol) in THF (9.0 mL), and the mixture was cooled to −78 °C.
A solution of cyclohexene silacyclopropane 1 (0.898 g, 4.00 mmol) in
THF (9.0 mL) was added, and the mixture was allowed to warm to
room temperature. The solvent was removed in vacuo, and the residue
was diluted with toluene (18.0 mL). Diethyl fumarate (2.16 mL, 10.8
mmol) was added, and the mixture was heated to 100 °C for 3 days.
The mixture was cooled to rt and concentrated in vacuo to afford a
brown oil. GCMS analysis of the unpurified reaction mixture revealed
that two diastereomers were formed (97:3 dr). The oil was purified by
flash chromatography (20:80 EtOAc/hexanes) to afford a yellow oil
1
(1.076 g, 66%): H NMR (400 MHz, CDCl3) δ 4.23−4.05 (m, 4H),
3.08 (sept, J = 7.1 Hz, 1H), 2.86 (td, J = 11.4, 5.8 Hz, 1H), 2.51 (dd, J
= 16.8, 5.9 Hz, 1H), 2.47−2.40 (m, 1H), 2.34 (ddd, J = 16.3, 5.8, 1.8
Hz, 1H), 2.15−2.05 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.28−1.22 (m,
4H), 1.16 (d, J = 7.1 Hz, 3H), 1.08 (s, 9H), 1.00 (s, 9H), 0.97 (d, J =
7.0 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
175.2, 174.7, 147.1, 112.0, 60.9, 60.7, 50.6, 47.6, 44.3, 28.0, 27.9, 26.5,
25.8, 22.6, 21.5, 21.2, 21.1, 20.4, 14.4, 14.3, 13.7; IR (thin film) 2964,
2862, 1728, 1647, 1471, 1300 cm−1; HRMS (ESI) m/z calcd for
C25H44NaO5Si (M + Na)+ 475.2856, found 475.2850. Anal. Calcd for
C25H44O5Si: C, 66.33; H, 9.80. Found: C, 66.44; H, 9.89.
60−62 °C; [α]D25 + 114° (c 1.00, CH2Cl2); H NMR (400 MHz,
1
CDCl3) δ 7.41−7.19 (m, 5H), 4.78 (td, J = 7.1, 3.7 Hz, 1H), 4.30−
4.13 (m, 2H), 3.84 (td, J = 10.6, 5.7 Hz, 1H), 3.29 (dd, J = 13.3, 2.8
Hz, 1H), 3.15 (dt, J = 13.8, 6.9 Hz, 1H), 2.88 (dd, J = 13.3, 9.3 Hz,
1H), 2.36 (dd, J = 15.1, 5.0 Hz, 1H), 2.20−2.13 (m, 1H), 2.08 (d, J =
8.3 Hz, 1H), 1.99 (dt, J = 16.0, 8.2 Hz, 1H), 1.44 (d, J = 7.4 Hz, 3H),
1.37−1.20 (m, 1H), 1.15 (s, 12H), 1.06 (s, 9H), 1.03 (d, J = 6.8 Hz,
3H), 0.98 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.9,
153.2, 148.0, 135.4, 129.6, 129.4, 129.0, 127.4, 111.6, 66.1, 55.3, 51.0,
45.8, 40.2, 38.1, 28.1, 27.9, 27.2, 26.7, 26.4, 23.0, 21.4, 20.9, 19.2, 16.3;
IR (thin film) 2937, 2860, 1782, 1697, 1471, 1389 cm−1; HRMS (ESI)
m/z calcd for C31H47NNaO4Si (M + Na)+ 548.3172, found 548.3165.
Anal. Calcd for C31H47NO4Si: C, 70.81; H, 9.01. Found: C, 70.58; H,
9.11.
Cycloadduct 15. To silyloxy diene 11b (0.028 g, 0.10 mmol) and
methyl acrylate (0.027 mL, 0.30 mmol), diluted with CH2Cl2 (1.0 mL)
and cooled to −78 °C, was added AlMe3 (0.015 mL, 2.0 M, 0.030
mmol). The mixture was allowed to stir for 5 min. AlBr3 (0.15 mL, 1.0
M, 0.15 mmol) was added, and the mixture was allowed to warm to
−45 °C and stir for 2 h. Pyridine (1.0 mL) was added, and the mixture
was allowed to warm to rt. The resulting slurry was filtered through a
pad of SiO2. GCMS analysis of the filtrate showed a mixture of
diastereomers (85:10:5 dr). The filtrate was concentrated in vacuo,
and the resulting residue was purified by flash chromatography (10:90
EtOAc/hexanes) to afford a colorless oil (0.020 g, 55%) as an
inseparable mixture of diastereomers. Representative peaks for the
major diastereomer: 1H NMR (400 MHz, CDCl3) δ 3.70 (s, 3H), 3.09
(sept, J = 7.0 Hz, 1H), 2.53 (tdd, J = 12.0, 5.6, 2.6 Hz, 1H), 2.46−2.35
(m, 1H), 2.27−2.08 (m, 3H), 1.26−1.22 (m, 1H), 1.24 (d, J = 7.4 Hz,
3H), 1.08 (s, 9H), 1.00 (s, 9H), 0.97 (d, J = 6.9 Hz, 3H), 0.92 (d, J =
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 176.9, 148.7, 111.9, 51.9,
45.0, 40.4, 33.1, 28.0, 26.4, 25.5, 24.1, 23.9, 21.6, 21.1, 20.6, 13.3; IR
(thin film) 2957, 2860, 1739, 1471, 1165, 824 cm−1; HRMS (ESI) m/z
calcd for C21H38NaO3Si (M + Na)+ 389.2488, found 389.2488. Anal.
Calcd for C21H38O3Si: C, 68.80; H, 10.45. Found: C, 69.01; H, 10.55.
Cycloadduct 16. To silyloxy diene 11b (0.028 g, 0.10 mmol) was
added (E)-N-benzylidene-4-methylaniline (0.060 g, 0.30 mmol). The
mixture was diluted with CH2Cl2 (1.0 mL) and cooled to −78 °C.
AlMe3 (0.015 mL, 2.0 M, 0.030 mmol) was added, and the mixture
was allowed to stir for 5 min. AlBr3 (0.15 mL, 1.0 M, 0.15 mmol) was
added, and the mixture was allowed to warm to rt over 16 h. Pyridine
(1.0 mL) was added, and the resulting slurry was filtered through a pad
of SiO2. GCMS analysis of the filtrate showed a mixture of
diastereomers (85:15 dr). The filtrate was concentrated in vacuo,
and the resulting residue was purified by flash chromatography (10:90
EtOAc/hexanes) to afford a colorless solid (0.027 g, 57%) as a single
diastereomer. The minor diastereomer is presumed unstable to
chromatography conditions. Characteristic data for major diaster-
Cycloadduct 20. To AgO2CCF3 (0.066 g, 0.30 mmol) was added
a solution of (E)-2-phenylhexa-1,4-dien-3-one (4) (0.517 g, 3.00
mmol) in CH2Cl2 (10.0 mL). The mixture was cooled to −78 °C, and
a solution of cyclohexene silacyclopropane 1 (0.842, 3.75 mmol) in
CH2Cl2 (5.0 mL) was added dropwise. The mixture was allowed to
warm to rt and transferred to a flask containing (S,E)-3-but-2-enoyl-4-
isopropyl-5,5-diphenyloxazolidin-2-one28 (0.349 g, 1.00 mmol). The
mixture was cooled to −100 °C, and AlMe3 (0.50 mL, 2.0 M, 1.0
mmol) was added. The mixture was allowed to stir for 5 min, and
AlMe2Cl (1.50 mL, 1.0 M, 1.5 mmol) was added. The mixture was
allowed to warm slowly to rt over 18 h, and then, it was treated with a
saturated aqueous solution of sodium potassium tartrate (20.0 mL).
The mixture was extracted with 3 × 10 mL of CH2Cl2. The organic
layers were combined, washed with brine (10 mL), dried over MgSO4,
filtered, and concentrated in vacuo to afford a yellow oil. GCMS
analysis of the oil showed two diastereomers (80:20 dr). The oil was
purified by flash chromatography (20:80 EtOAc/hexanes) to afford a
colorless solid (0.564 g, 77%) as a mixture of diastereomers. A small
amount (0.060 g) of the major diastereomer was isolated by flash
chromatography for the purpose of X-ray crystallographic analysis.
Characteristic data for the major diastereomer: [α]D25 − 18.8° (c 1.00,
1
CH2Cl2); H NMR (500 MHz, CDCl3) δ 7.67−6.98 (m, 15H), 5.47
(d, J = 3.6 Hz, 1H), 3.89 (td, J = 10.5, 5.8 Hz, 1H), 2.83−2.74 (m,
1H), 2.70 (dd, J = 15.3, 5.5 Hz, 1H), 2.16 (t, J = 10.0 Hz, 1H), 2.09−
1.91 (m, 2H), 1.33 (d, J = 7.4 Hz, 3H), 1.29−1.21 (m, 1H), 1.10 (s,
9H), 0.90 (s, 9H), 0.86 (d, J = 7.0 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H),
0.59 (d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 176.2, 152.9,
152.8, 142.6, 139.9, 138.0, 129.0, 128.9, 128.6, 128.5, 128.1, 127.5,
127.3, 127.2, 125.9, 125.7, 125.1, 106.1, 89.3, 64.9, 52.3, 45.7, 40.0,
32.4, 29.9, 28.6, 28.1, 28.0, 27.7, 27.6, 22.2, 21.8, 21.4, 21.0, 18.2, 16.5.
Characteristic data for the mixture of diastereomers: mp 123−125 °C;
IR (thin film) 2962, 2933, 1786, 1701, 1209, 1173 cm−1; HRMS (ESI)
m/z calcd for C42H53NNaO4Si (M + Na)+ 686.3641, found 686.3657.
Anal. Calcd for C42H53NO4Si: C, 75.98; H, 8.05. Found: C, 76.08; H,
8.10.
1
eomer: mp 163−166 °C; H NMR (400 MHz, CDCl3) δ 7.27−7.21
(m, 2H), 7.12 (dd, J = 10.1, 4.6 Hz, 2H), 7.05 (ddd, J = 7.4, 3.7, 1.3
Hz, 1H), 6.93−6.84 (m, 4H), 3.91 (d, J = 8.0 Hz, 1H), 3.69 (dd, J =
15.2, 2.2 Hz, 1H), 3.46 (dd, J = 15.2, 3.2 Hz, 1H), 3.07 (sept, J = 6.9
Hz, 1H), 2.69 (ddt, J = 10.9, 8.0, 2.6 Hz, 1H), 2.15 (s, 3H), 1.30−1.18
(m, 1H), 1.07 (s, 9H), 1.06 (d, J = 8.0 Hz, 3H), 1.04 (s, 9H), 0.99 (d, J
= 7.1 Hz, 3H), 0.43 (d, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 149.8, 148.1, 142.3, 132.6, 129.3, 129.2, 128.1, 127.0, 125.3, 112.2,
70.6, 54.8, 52.5, 28.1, 26.3, 21.6, 21.3, 21.2, 21.0, 20.5, 13.9; IR (thin
film) 2958, 2933, 2859, 1511, 1472, 1153 cm−1; HRMS (ESI) m/z
calcd for C31H46NOSi (M + H)+ 476.3349, found 476.3350.
Cycloadduct 21. To AgO2CCF3 (0.027 g, 0.12 mmol) was added
a solution of (E)-2-phenylhexa-1,4-dien-3-one (4) (0.211 g, 1.22
mmol) in toluene (2.4 mL). The mixture was cooled to −22 °C, and a
solution of cyclohexene silacyclopropane 1 (0.322 g, 1.44 mmol) in
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toluene (2.4 mL) was added. The mixture was allowed to warm to
room temperature. Diethyl fumarate (0.59 mL, 3.6 mmol) was added,
and the mixture was heated to 100 °C for 3 days. The mixture was
concentrated in vacuo to afford a brown oil. GCMS analysis of the oil
showed a mixture of diastereomers (90:10 dr). The oil was purified by
flash chromatography (20:80 EtOAc/hexanes) to afford a colorless
solid (0.368 g, 62%) as a single diastereomer: mp 90−92 °C; 1H NMR
(500 MHz, CDCl3) δ 7.67−7.62 (m, 2H), 7.29 (t, J = 7.8 Hz, 2H),
7.15 (dd, J = 10.6, 4.1 Hz, 1H), 4.28−4.09 (m, 4H), 3.06 (ddd, J =
11.1, 9.8, 7.5 Hz, 1H), 2.83−2.76 (m, 1H), 2.75−2.71 (m, 2H), 2.65
(t, J = 10.7 Hz, 1H), 1.40−1.33 (m, 1H), 1.32 (dd, J = 7.6, 6.8 Hz,
3H), 1.26 (dd, J = 7.6, 6.7 Hz, 3H), 1.22 (d, J = 7.4 Hz, 3H), 1.14 (s,
9H), 0.95 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 174.7, 174.1,
151.7, 139.2, 127.8, 127.5, 125.6, 105.9, 61.0, 60.9, 50.4, 48.9, 44.5,
31.1, 28.0, 27.7, 21.9, 21.6, 21.1, 14.4, 14.3, 13.6; IR (thin film) 2935,
2860, 1738, 1659, 1471, 1171 cm−1; HRMS (ESI) m/z calcd for
C28H42NaO5Si (M + Na)+ 509.2699, found 509.2691. Anal. Calcd for
C28H42O5Si: C, 69.10; H, 8.70. Found: C, 68.94; H, 8.70.
(0.368 g, 85%): 1H NMR (400 MHz, CDCl3) δ 7.44−7.18 (m, 15H),
4.55−4.44 (m, 4H), 4.38−4.34 (m, 1H), 3.62 (ddd, J = 9.2, 4.6, 3.0
Hz, 2H), 3.54 (dd, J = 9.6, 3.0 Hz, 1H), 3.48 (dd, J = 9.3, 5.7 Hz, 1H),
2.81 (dd, J = 12.4, 2.9 Hz, 1H), 2.01 (dt, J = 19.5, 9.8 Hz, 2H), 1.90
(dd, J = 11.2, 4.7 Hz, 1H), 1.78 (dd, J = 13.2, 10.3 Hz, 2H), 1.30 (s,
4H), 1.09 (s, 9H), 0.99 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
145.0, 139.1, 139.0, 138.0, 129.2, 129.0, 128.6, 128.0, 127.8, 127.4,
125.8, 122.2, 78.0, 73.7, 73.4, 72.3, 69.5, 50.7, 47.4, 40.0, 39.7, 33.7,
29.5, 29.3, 24.3, 23.3, 20.4, 18.3; IR (thin film) 3029, 2933, 2860, 1454,
1363, 1097 cm−1; HRMS (ESI) m/z calcd for C38H52NaO3Si (M +
Na)+ 607.3583, found 607.3592. Anal. Calcd for C38H52O3Si: C, 78.03;
H, 8.96. Found: C, 77.73; H, 8.88.
Diol 24. To KH (0.135 g, 3.36 mmol) in THF (6.0 mL) was added
18-crown-6 (0.888 g, 3.36 mmol), and the slurry was cooled to 0 °C.
PhMe2COOH (0.49 mL, 88%, 3.36 mmol) was added slowly, and the
mixture was allowed to warm to rt. Cyclohexane 23 (0.328 g, 0.560
mmol) in THF (6.0 mL) was added, followed by a solution of TBAF
(3.36 mL, 1.0 M, 3.4 mmol). The mixture was heated to 50 °C for 24
h. The mixture was allowed to cool to rt and was diluted with saturated
aqueous Na2S2O3 solution (20 mL). The mixture was extracted with 3
× 10 mL of MTBE. The combined organic layers were washed with
brine (10 mL), dried over MgSO4, and concentrated in vacuo to afford
an oil. The oil was purified by flash chromatography (40:60 EtOAc/
hexanes) to afford a colorless oil (0.235 g, 91%): 1H NMR (400 MHz,
CDCl3) δ 7.38−7.26 (m, 15H), 4.54−4.44 (m, 4H), 4.37 (s, 1H), 3.79
(dd, J = 9.9, 1.5 Hz, 1H), 3.59−3.54 (m, 2H), 3.49 (dd, J = 9.3, 5.6 Hz,
1H), 2.75 (d, J = 12.7 Hz, 1H), 2.19 (dtd, J = 18.3, 6.6, 5.2 Hz, 2H),
2.02−1.95 (m, 1H), 1.85 (d, J = 12.6 Hz, 1H), 1.74 (d, J = 11.6 Hz,
1H), 1.31 (d, J = 5.7 Hz, 4H), 1.06 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 143.1, 138.8, 138.6, 128.7, 128.51, 128.46, 128.1, 127.9,
127.81, 127.79, 127.6, 126.8, 73.43, 73.39, 73.3, 71.3, 67.6, 67.2, 48.1,
47.1, 38.4, 35.2, 28.8, 27.4; IR (thin film) 3408, 3030, 2864, 1495,
1095, 737 cm−1; HRMS (ESI) m/z calcd for C30H36NaO4 (M + Na)+
483.2511, found 483.2515.
Confirmation of the Structure of Diol 24: Preparation of Its
p-Nitrobenzaldehyde Acetal. To diol 24 (0.088 g, 0.19 mmol) in
benzene (10.0 mL) were added p-nitrobenzaldehyde (0.033 g, 0.22
mmol) and p-toluenesulfonic acid (0.0008 g, 0.004 mmol). The
solution was heated at reflux for 1 h. The mixture was allowed to cool
to rt and was treated with a saturated solution of NaHCO3 (10.0 mL).
The mixture was extracted with 3 × 5 mL of ether. The combined
organic layers were washed with brine (5 mL), dried over MgSO4, and
concentrated in vacuo to afford an oil. The oil was purified by flash
chromatography (20:80 EtOAc/hexanes) to afford the acetal as a pale
yellow oil (0.087 g, 77%): 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J =
8.9 Hz, 2H), 7.54 (d, J = 8.9 Hz, 2H), 7.37−7.20 (m, 16H), 4.51−4.37
(m, 6H), 3.65−3.57 (m, 2H), 3.55 (dd, J = 9.5, 3.4 Hz, 1H), 3.46 (dd,
J = 9.3, 5.7 Hz, 1H), 2.78 (dt, J = 12.7, 2.6 Hz, 1H), 2.23 (t, J = 9.6 Hz,
1H), 2.18 (t, J = 10.9 Hz, 1H), 2.13−2.05 (m, 1H), 1.87 (dt, J = 12.3,
3.1 Hz, 1H), 1.71 (dd, J = 11.3, 1.8 Hz, 1H), 1.46 (d, J = 6.9 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 148.1, 146.3, 143.6, 138.8, 138.7,
Cyclohexane 22. Cycloadduct 21 (0.100 g, 0.21 mmol) was
diluted with EtOH (9.5 mL). Pd(OH)2/C (0.029 g, 0.040 mmol) was
added, and the suspension was sparged with H2 for 15 min. The
suspension was allowed to stir for 18 h under 1 atm of H2. The
reaction mixture was filtered through a pad of SiO2, and the filtrate was
concentrated in vacuo to afford a yellow oil. GCMS analysis of the oil
showed a mixture of diastereomers (99:1 dr). The oil was purified by
flash chromatography (20:80 EtOAc/hexanes) to afford a colorless
1
solid (0.078 g, 76%): mp 93−95 °C; H NMR (500 MHz, CDCl3) δ
7.35 (d, J = 8.0 Hz, 2H), 7.30−7.17 (m, 3H), 4.35 (t, J = 3.2 Hz, 1H),
4.27−4.21 (m, 1H), 4.19−4.03 (m, 3H), 2.92 (t, J = 11.6 Hz, 1H),
2.81 (dt, J = 13.1, 3.1 Hz, 1H), 2.76 (td, J = 11.9, 3.2 Hz, 1H), 2.07 (q,
J = 12.8 Hz, 1H), 1.93 (dt, J = 8.1, 3.8 Hz, 2H), 1.59 (q, J = 8.0 Hz,
1H), 1.29 (td, J = 7.1, 0.7 Hz, 3H), 1.26 (d, J = 8.1 Hz, 3H), 1.22 (td, J
= 7.1, 0.8 Hz, 3H), 1.13 (s, 9H), 0.95 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 175.2, 174.2, 143.3, 128.5, 128.0, 126.4, 76.7, 60.8, 60.7,
51.9, 46.9, 46.1, 45.6, 29.4, 29.3, 28.0, 23.4, 23.2, 20.4, 17.7, 14.5, 14.3;
IR (thin film) 2937, 2860, 1736, 1475, 1250, 1180 cm−1; HRMS (ESI)
m/z calcd for C28H44NaO5Si (M + Na)+ 511.2856, found 511.2864.
Anal. Calcd for C28H44O5Si: C, 68.81; H, 9.07. Found: C, 69.02; H,
9.17.
Cyclohexane 23. To a slurry of LiAlH4 (0.075 g, 2.0 mmol) in
THF (5.0 mL) cooled to 0 °C was added a solution of cyclohexane 22
(0.485 g, 0.990 mmol) in THF (5.0 mL). The mixture was allowed to
stir at 0 °C for 2 h. To the mixture was added a saturated aqueous
solution of sodium potassium tartrate (10.0 mL), and the mixture was
allowed to warm to rt. The layers were separated, and the aqueous
layer was extracted with 3 × 5 mL of ether. The organic layers were
combined, washed with brine (5 mL), dried over MgSO4, and
concentrated in vacuo to afford an oil. The oil was purified by flash
chromatography (40:60 EtOAc/hexanes) to afford the diol as a
colorless solid (0.316 g, 79%): mp 125−127 °C; 1H NMR (400 MHz,
CDCl3) δ 7.36−7.18 (m, 5H), 4.46 (br s, 2H), 4.32 (t, J = 3.4 Hz,
1H), 3.91 (d, J = 10.9 Hz, 1H), 3.69 (dd, J = 10.9, 2.0 Hz, 1H), 3.59
(qn, J = 5.4 Hz, 2H), 2.78−2.74 (m, 1H), 1.83 (q, J = 12.2 Hz, 1H),
1.62−1.61 (m, 2H), 1.51 (d, J = 12.4 Hz, 1H), 1.45 (dd, J = 10.8, 4.3
Hz, 1H), 1.37 (s, 3H), 1.32−1.25 (m, 1H), 1.11 (s, 9H), 0.98 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 144.4, 128.4, 127.8, 126.0, 77.6, 68.0,
64.4, 51.1, 47.5, 45.5, 44.7, 29.4, 29.3, 28.9, 24.7, 23.3, 20.3, 18.7; IR
(thin film) 3317, 2860, 1471, 1363, 1055, 821 cm−1; HRMS (ESI) m/z
calcd for C24H40NaO3Si (M + Na)+ 427.2644, found 427.2649. Anal.
Calcd for C24H40O3Si: C, 71.23; H, 9.96. Found: C, 71.10; H, 10.14.
NaH (0.054 g, 2.2 mmol) in THF (1.0 mL) cooled to 0 °C was
added a solution of the diol prepared above (0.301 g, 0.74 mmol) in
THF (0.5 mL) dropwise. The mixture was allowed to stir at 0 °C for
10 min, then benzyl bromide (0.27 mL, 2.2 mmol) was added. The
mixture was allowed to warm to rt and stir for 3 days. The mixture was
poured into a separatory funnel containing water (10 mL), which was
extracted with 3 × 5 mL of ether. The organic layers were combined,
washed with brine (5 mL), dried over MgSO4, and concentrated in
vacuo to afford a cloudy oil. The oil was purified by flash
chromatography (10:90 EtOAc/hexanes) to afford a colorless oil
128.7, 128.6, 128.5, 128.2, 128.0, 127.9, 127.7, 127.4, 127.3, 126.7,
123.5, 92.8, 74.2, 73.4, 73.3, 70.3, 67.1, 47.6, 40.2, 38.2, 36.1, 30.1,
17.1; IR (thin film) 2922, 2868, 1524, 1348, 1097, 700 cm−1; HRMS
(ESI) m/z calcd for C37H39NNaO6 (M + Na)+ 616.2675, found
616.2659.
ASSOCIATED CONTENT
* Supporting Information
■
S
Spectroscopic and crystallographic data for the products (PDF,
CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kwoerpel@nyu.edu.
■
Notes
The authors declare no competing financial interest.
3282
dx.doi.org/10.1021/jo202650k | J. Org. Chem. 2012, 77, 3277−3283

The Journal of Organic Chemistry
Article
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ACKNOWLEDGMENTS
■
This project was supported by the National Institute of General
Medical Sciences of the National Institutes of Health (GM-
54909). C.C.V. thanks the NIGMS for a predoctoral fellowship
(F31GM080157) and Dr. Laura Anderson (University of
Illinois, Chicago) for her contributions to this project. K.A.W.
thanks Amgen and Lilly for awards to support the research. We
thank Dr. Phil Dennison (UCI) for assistance with NMR
spectroscopy, Dr. Joseph W. Ziller (UCI) for X-ray
crystallography, and Dr. John Greaves and Ms. Shirin
Sorooshian (UCI) for mass spectrometry.
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