Diastereoselective Friedel-Crafts alkylation of hydronaphthalenes

Article abstract of DOI:10.1021/jo201781x

An efficient and versatile synthesis of chiral tetralins has been developed using both inter- and intramolecular Friedel-Crafts alkylation as a key step. The readily available hydronaphthalene substrates were prepared via a highly enantioselective metal-c

Full text of DOI:10.1021/jo201781x

Article
pubs.acs.org/joc
Diastereoselective Friedel−Crafts Alkylation of Hydronaphthalenes
Jennifer Tsoung, Katja Kramer, Adam Zajdlik, Clemence Liebert, and Mark Lautens*
́
̈
Davenport Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S3H6, Canada
S
* Supporting Information
ABSTRACT: An efficient and versatile synthesis of chiral
tetralins has been developed using both inter- and intra-
molecular Friedel−Crafts alkylation as a key step. The readily
available hydronaphthalene substrates were prepared via a
highly enantioselective metal-catalyzed ring opening of meso-
oxabicyclic alkenes followed by hydrogenation. A wide variety
of complex tetracyclic compounds have been isolated with
high levels of regio-, diastereo-, and enantioselectivity.
report the inter- and intramolecular diastereoselective FC
alkylations of tetralin 11 to efficiently and selectively access
chiral carbocycles.
INTRODUCTION
■
Aryltetralin lignans, a subclass of the large lignan family of
secondary metabolites, display a substantial range of biological
activity.1 Selected examples include lasofoxifene for the
treatment of osteoporosis and podophyllotoxin as an anticancer
agent (Figure 1).2,3 Structurally, they are characterized by a
substituted 1,2,3,4-tetrahydronaphthalene core with up to four
contiguous chiral centers. Their challenging structures and
important biological roles have led to interest in developing an
efficient stereocontrolled synthesis of this class of natural
products.4
Our group has had a long-standing interest in the asymmetric
Pd(II)- or Rh(I)-catalyzed ring-opening reactions (ARO) of
meso-oxabiyclic alkenes to produce both trans- and cis-1,2-
disubstituted dihydronaphthalenols. High yields and excellent
enantioselectivities can be achieved using a wide variety of
nucleophiles such as dialkylzincs, aryl and vinylboronic acids,
thiols, alcohols, amines, and hydrides (Scheme 1).5−8 This
reaction may be performed in a racemic fashion or enantio-
selectively using a Josiphos-type ligand (PPF-PtBu2) or with
Tol-BINAP.
Our group has recently investigated the combination of the
ARO methodology with a diastereoselective Friedel−Crafts
(FC) alkylation of the resulting benzylic alcohol to readily
synthesize chiral aryltetralin products. Within the field of FC
alkylation, there is growing interest in the utilization of
π-activated alcohols instead of the less available and more
toxic organo-halides.9 Recent advances in this area have shown
that these substrates can display facial preferentiality, resulting
in a formal diastereoselective Friedel−Crafts alkylation of
benzylic alcohols.10 In particular, Bach and co-workers have
reported a highly diastereoselective Friedel−Crafts alkylation
of 1-arylalkanoles via the formation of chiral benzylic carbo-
cations.11 More recently, we have demonstrated that the
derivatization of amine ring-opened products 10 with inter-12
and intramolecular13 Friedel−Crafts alkylations can proceed
with high yield and diastereoselectivity (Scheme 2) and most
importantly with retention of the enantioselectivity. Herein, we
RESULTS AND DISCUSSION
■
We first investigated the conversion of the tetrahydronaph-
thalenol 12 to the arylated product 13. Substrate 12 is readily
prepared by performing an asymmetric Pd(II)-catalyzed ring
opening of meso-oxabicyclic alkene 4 followed by hydro-
genation. A wide variety of Lewis acids (LA) have been tested,
and Al(III) chloride proved to be the most effective (Table 1).
Treatment of substrate 12 with 10 equiv of anisole in the
presence of a stoichiometric amount of AlCl3 in nitromethane
(MeNO2)14 at room temperature delivered the desired trans-
alkylated product 13 in 98% yield and good diastereoselectivity
(Table 1, entries 1 and 2). The high level of trans-selectivity
obtained is noteworthy, and the change in selectivity as a
function of the nucleophile suggests that the reaction suggests
that the reaction may proceed through the formation of an
intermediate benzylic carbocation species. Performing the
reaction with a catalytic amount of Lewis acid did not lead to
the formation of the desired product 13, generating instead
unidentified side products (Table 1, entry 4). Additionally,
varying the temperature of the reaction was found to have little
influence on the selectivity (Table 1, entry 5). Finally, carrying
out the reaction according to Bach’s protocol also resulted in
the formation of trans-alkylated product 13 in good yield and
selectivity (Table 1, entry 7). However, this procedure was
found to be limited to the use of activated nucleophiles, the
eliminated product 14 being otherwise predominantly formed.
Having optimized the conditions, we then went on to explore
the substrate scope for intermolecular FC alkylation of the
chiral benzylic alcohol 12 (Scheme 3).
The use of heteroaromatics such as thiophene, pyrrole,
and indole as nucleophiles resulted in the formation of the
Received: August 26, 2011
Published: September 27, 2011
© 2011 American Chemical Society
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Figure 1. Examples of aryltetralin lignans.
2-position of the hydronaphthalenes. This can be easily
achieved by altering the boronic esters used in the asymmetric
Rh(I)-catalyzed ring-opening step (Scheme 4).
Scheme 1. Asymmetric Ring Opening of meso-Oxabicycle 4
As previously reported, ring opening of meso-oxabicyclic
alkenes using sterically hindered boronic esters proceeds in
reasonable yields only at elevated temperatures, causing a
reduction in the enantioselectivity of the reaction.6b However,
to our delight, the use of bulky aryltetralins 22 did lead to an
improvement of the diastereoselectivity for the Friedel−Crafts
alkylation (Scheme 5).
Treatment of tetrahydronaphthalenol 22a with anisole in the
presence of AlCl3 afforded the desired tetralin 23a in 90% yield
and with a 6.7:1 trans:cis diastereomeric ratio. Introducing
substituents at the 2- and 5-position on the phenyl ring further
increased the trans:cis diastereomeric ratio up to 13.3:1 (Scheme 5,
compound 23e). Single-crystal X-ray analysis of tetralin 23d
confirmed the trans arrangement of substituents.
We next investigated the intramolecular variant of the
Friedel−Crafts alkylation (Scheme 6). As shown in Scheme 6,
readily accessible aryl and alkenylboronic esters can be fixed
onto the hydronaphthalene during the asymmetric Pd(II)- or
Rh(I)-catalyzed ring-opening step of the synthetic sequence.
We first examined the conversion of the biphenyl tetralin 26
into the hexahyrophenanthrene 30a (Scheme 7).16
Intramolecular Friedel−Crafts arylation of biphenyl tetralin
26a afforded exclusively the cis product in quantitative yield.
This observation complements results published previously by
our group and others.11,17 Introduction of substituents on the
tetralin and nucleophile continued to give the Friedel−Crafts
arylated product 30b,c in good yields and cis-diastereoselectiv-
ity. Single-crystal X-ray analysis of tetralin 30a confirmed the cis
arrangement of substituents.
corresponding tetralins 15, 16, and 17 in excellent yields albeit
with lower diastereoselectivities. While electron-rich nucleo-
philes such as veratrole, anisole, and phenol led to the formation
of the tetralins 13, 18, and 19 almost quantitatively and with
high diastereoselectivity, less nucleophilic aromatics such as
toluene and xylenes failed to deliver the desired products,
instead forming predominantly the eliminated byproduct 14.
Additionally, no reaction of tetrahydronaphthalenol 12 with
furan derivatives, silyl enol ethers, or acetylacetonates occurred
under these conditions.15 It is important to note that the high
enantioselectivity established in the Pd(II)-catalyzed ring-
opening step is maintained throughout the entire synthetic
sequence, suggesting that 14 is not an intermediate in the
pathway leading to the FC product.
We next attempted to enhance the diastereoselectivity of
the reaction by introducing a more bulky aryl group at the
Scheme 2. Inter- and Intramolecular Friedel−Crafts Alkylation
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Table 1. Optimization of Friedel−Crafts Alkylation
a
b
entry
acid
AlCl3
equiv
temp (°C)
time (h)
yield 13 (%), (dr, rr)
c
yield 14 (%)
1
2
3
4
5
6
1
rt
15
1
98 (dr 6.3:1, rr 6:1)
c
AlCl3
1
rt
94 (dr 6.5:1, rr 10:1)
93 (dr 6.7:1, rr 7:1)
no product
AlCl3
2
rt
0.25
24
15
15
0.25
15
15
24
24
48
15
24
AlCl3
0.1
1
rt
AlCl3
0
68 (dr 4.5:1, rr 10:1)
88 (dr 4.2:1, rr 8:1)
FeCl3
1
rt
d
c
7
HBF4·OEt2
BF3·OEt2
pTsOH
TFA
1.2
1
−78
rt
99 (dr 9:1)
8
9
39 (dr 4.6:1)
22 (dr 4.2:1)
11 (dr 4.6:1, rr 9:1)
6 (dr 3.1:1)
32
77
61
94
1
rt
10
11
12
13
14
1
60
60
60
rt
Zn(OTf)2
Cu(OTf)2
Bi(OTf)3
AuCl3
0.1
0.1
0.1
0.1
no product
98
60
no product
a
1
Yield determined by analysis of the H NMR spectrum of the crude reaction mixture, in the presence of p-nitroacetophenone as an internal
b
c
d
standard. The dr for trans:cis products, rr for para:ortho products. Isolated yield Reaction was performed in CH2Cl2, warmed from −78 °C to rt
(ref 3).
Scheme 3. Intermolecular Friedel−Crafts Alkylation Scope
a
Crude yield, no purification required.
We next investigated the intramolecular Friedel−Crafts
alkylation of styryl tetralin 29. Friedel−Crafts alkylation yields
almost exclusively the cis tetracyclic product with high yields
with a variety of tethered nucleophiles (Scheme 8).18
A wide range of substitution patterns are tolerated with this
protocol, with ortho- and para-methoxy-substituted phenyls
giving high yields of the corresponding tetralins 31d and 31e
and meta-methoxy-substituted phenyls giving a slightly
lower yield of tetralin 31f. Surprisingly, having a disubstituted
phenyl nucleophile as seen in tetracyclic product 31d also
lowered the diastereoselectivity to 1.8:1 of the cis:trans
products. This may be due to the enhanced nucleophilicity of
the veratrole or due to the introduction of an ortho substituent.
The intramolecular variant of this protocol can also allow
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Scheme 4. Synthetic Sequence for Intermolecular Friedel−Crafts Alkylation
Scheme 5. Improving Diastereoselectivity
a
b
No ee determined as no suitable conditions could be found to achieve peak separation. Yield averaged over ARO and hydrogenation step.
Scheme 6. Synthetic Sequence for Intramolecular Friedel−Crafts Alkylation
Friedel−Crafts alkylation to occur with more electron-poor
nucleophiles such as the para-fluoro-substituted phenyl in 31b,
which is a challenging and rarely used nucleophile in diastereo-
selective Friedel−Crafts methodologies. Heteroaromatic
nucleophiles are also tolerated in this protocol, as seen in
product 31c.
Attempts to increase the ring size of the resulting tetracyclic
structure by increasing the length of the tether yielded the
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Scheme 7. Intramolecular Friedel−Crafts Arylation with Biphenyl Tetralin 26
a
b
Yield averaged over ARO and hydrogenation step; ee determined from hydrogenated product 26c. No ee determined as no suitable conditions
were found to achieve peak separation.
Scheme 8. Intramolecular Friedel−Crafts Alkylation of Styryl Tetralin 29
a
Yield based on recovered starting material.
unexpected spirocyclic product 36 as a racemic mixture in 75%
yield (Scheme 9). A possible pathway might be a Wagner−
Meerwein-type hydrogen shift to form the more stabilized
carbocation. Further attempts to increase the ring size using
2-phenoxyphenylboronic acid or 2-(3-methoxyphenoxy)-
phenylboronic acid resulted predominantly in the elimination
product though traces of the desired arylated product could be
seen using FC method B.
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Scheme 9. Increasing Ring Size
for C12H14O [M+] 174.1045; found 174.1043; [α]D = +97.0 (c 1.0,
CHCl3) for 88% ee, as determined by HPLC analysis (Chiralcel ODH,
2% iPrOH/hexane, 1.00 mL/min, 254 nm); tR = 12.99 min [minor],
tR = 13.57 min [major].
28
CONCLUSION
■
We have shown that asymmetric transition-metal-catalyzed ring
opening and diastereoselective Friedel−Crafts methodologies
can be tied in order to rapidly synthesize a wide variety of
aryltetralins in high yield and enantioselectivity. The initial
metal-catalyzed asymmetric ring-opening step establishes the
regiochemistry and the absolute stereochemistry with excellent
selectivities. Intermolecular Friedel−Crafts reaction of the
resulting products lead to the trans product with moderate
diastereoselectivity, which can be enhanced by adding steric
bulk around the hydronaphthalene core. The intramolecular
variant leads to almost exclusively the cis product. Numerous
aryltetracyclic products with various substitution patterns have
been synthesized, showing that this methodology is very useful
for the rapid synthesis of analogues. Future work will focus on
utilizing this methodology in the synthesis of aryltetralin lignans
and other similar natural products.
Representative Procedure 1 for the Hydrogenation of Ring-
Opened Substrate (1R,2R)-2-Ethyl-1,2-dihydronaphthalen-1-
ol: (1S,2S)-2-Ethyl-1,2,3,4-tetrahydronaphthalen-1-ol (12). A
magnetically stirred solution of (1R,2R)-2-ethyl-1,2-dihydronaphtha-
len-1-ol (482 mg, 2.77 mmol) in THF (20 mL) and H2O (20 mL) was
treated with tosylhydrazine (2.57 g, 13.9 mmol) and sodium acetate
(2.27 g, 27.7 mmol), and the resulting mixture was heated to reflux for
15 h. The mixture was then cooled to rt, treated with saturated K2CO3
solution, and the separated aqueous phase extracted with ether (3×).
The combined organic layers were then dried (MgSO4) and
concentrated under reduced pressure and the ensuing residue
subjected to flash chromatography (hexane/EtOAc 9:1, Rf = 0.23 in
hexane/EtOAc 85:15) to afford the title compound (577 mg, 99%) as
1
a colorless oil: H NMR (400 MHz, CDCl3) δ 7.39−7.32 (m, 1H),
7.25−7.17 (m, 2H), 7.16−7.10 (m, 1H), 4.67 (s, 1H), 2.88 (dt,
J = 17.1, 4.1 Hz, 1H), 2.82−2.71 (m, 1H), 1.80−1.54 (m, 5H), 1.53−
1.36 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 138.9, 137.3, 130.2, 129.2, 128.1, 126.2, 69.9, 41.6, 29.4, 24.6, 22.9,
11.8; IR (NaCl) 3364, 3061, 3020, 2958, 2031, 2874, 1605, 1455,
1432, 1273, 1130, 1072, 1033, 1008, 953, 931, 902, 853, 822, 774, 738
cm−1; HRMS (EI) calcd for C12H16O [M+] 176.1201; found 176.1204;
EXPERIMENTAL SECTION
For general experimental methods see Supporting Information.
Characterization data and experimental methods for 4, 5−11, 12,
21a, 22a, and 24a were reported previously.5−7,17−20
■
28
(1R,2R)-2-Ethyl-1,2-dihydronaphthalen-1-ol. Pd(MeCN)2Cl2
(46 mg, 0.18 mmol) and (R)-Tol-BINAP (119 mg, 0.18 mmol) were
dissolved in dry CH2Cl2 (20 mL) under argon, and the mixture was
stirred for 1 h at rt. The catalyst solution was then transferred via
canula to a solution of oxabicyclic alkene 4 (500 mg, 3.50 mmol) in
dry CH2Cl2 (50 mL). The mixture was cooled to −20 °C, and ZnEt2
(1.0 M in hexane, 5.3 mL, 5.25 mmol) was added dropwise. The
resulting red solution was stirred for 6 h over which time it reached
room temperature. The mixture was quenched by the addition of
saturated NH4Cl solution, and the aqueous phase was extracted with
CH2Cl2 (3×). The combined organic layers were dried (Na2SO4), and
the solvent was evaporated. The crude product was purified by flash
column chromatography (hexane/Et2O 85:15, Rf = 0.43 in hexane/
EtOAc 7:3) to afford the title compound (590 mg, 97%) as a colorless
oil. The characterization data were fully concordant with that already
reported in the literature:6a 1H NMR (400 MHz, CDCl3) δ 7.33 (dd,
J = 7.2, 1.0 Hz, 1H), 7.30−7.19 (m, 2H), 7.12 (dd, J = 7.2, 1.3 Hz,
1H), 6.54 (dd, J = 9.6, 2.7 Hz, 1H), 5.83 (ddd, J = 9.6, 2.7, 1.1 Hz,
1H), 4.61 (dd, J = 7.2, 4.7 Hz, 1H), 2.37 (dtt, J = 10.5, 5.1, 2.7 Hz,
1H), 1.90−1.76 (m, 1H), 1.70−1.56 (m, 1H), 1.53 (d, J = 7.7 Hz,
1H), 1.09 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 136.9,
132.9, 131.2, 128.7, 127.8, 127.7, 126.9, 126.6, 70.1, 42.4, 22.3, 12.0; IR
(NaCl) 3395, 3031, 2960, 2931, 2874, 2361, 2341, 1487, 1454, 1379,
1201, 1119, 1069, 1052, 941, 786, 768, 695 cm−1; HRMS (EI) calcd
[α]D = −57.7 (c 1.0, CHCl3) for 88% ee.
Procedure for Optimization Studies of Friedel−Crafts
Alkylation of 12. A magnetically stirred solution of benzylic alcohol
12 (26.4 mg, 0.15 mmol) and anisole (163 μL, 1.50 mmol) was treated
with the desired Lewis or Brønsted acid catalyst in either
stoichiometric (0.15 mmol) or catalytic amounts (0.015 mmol) and
stirred under N2 for 16 h. The mixture was then treated with
p-nitroacetophenone (1.14 M in MeNO2, 131.6 μL, 0.15 mmol) as an
internal standard in CH2Cl2 (1.5 mL), diluted with CH2Cl2 (3 mL),
quenched with H2O, the aqueous phase then extracted with CH2Cl2
(3×). The combined organic layers were dried (Na2SO4), and the
solvent was evaporated. Product yield was then determined by analysis
1
of the H NMR spectrum of the crude reaction mixture.
Representative Procedure 2 for the AlCl3-Catalyzed Frie-
del−Crafts Alkylation of 12: (1S,2S)-2-Ethyl-1-(4-methoxyphen-
yl)-1,2,3,4-tetrahydronaphthalene (13). To a solution of alcohol 12
(53 mg, 0.30 mmol) and anisole (0.33 mL, 3.00 mmol) in CH2Cl2
(1 mL) was added AlCl3 (40 mg, 0.30 mmol), and the resulting
mixture was stirred for 16 h at rt. The mixture was then diluted with
CH2Cl2 (10 mL) and poured into saturated NaHCO3 solution
(10 mL). The separated aqueous phase was then extracted with
CH2Cl2 (2 × 15 mL), and the combined organic layers were dried
(MgSO4) and concentrated under reduced pressure. The ensuing
residue was subjected to flash chromatography (hexanes/EtOAc 98:2
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to 85:15, Rf = 0.49 in hexanes/EtOAc 9:1) to afford a ca. 6.3:1 mixture
of diastereomers (rr 6:1) of the title compound (78 mg, 98%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) major diastereomer δ 7.19−
6.87 (m, 5H), 6.82 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 7.7 Hz, 1H), 3.79
(s, 3H), 3.69 (d, J = 8.5 Hz, 1H), 2.98−2.77 (m, 2H), 2.10−1.99 (m,
1H), 1.78−1.67 (m, 1H), 1.54−1.40 (m, 2H), 1.23−1.07 (m, 1H),
0.89 (t, J = 7.4 Hz, 3H); minor diastereomer (selected signals) δ 4.11
(d, J = 4.9 Hz, 1H), 0.95 (t, J = 7.1 Hz, 3H); regioisomer (selected
signals) δ 4.30 (d, J = 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3)
major diastereomer δ 156.0, 140.3, 139.1, 137.3, 130.7, 130.4, 128.7,
125.8, 125.7, 113.7, 55.3, 51.0, 43.8, 28.9, 26.3, 26.0, 11.4; minor
diastereomer (selected signals) δ 131.3, 113.1, 12.2; IR (NaCl) 3058,
2997, 2958, 2931, 2874, 2836, 2361, 1611, 1583, 1511, 1491, 1462,
1011, 807, 756, 739, 580 cm−1; HRMS (EI) calcd for C20H22N [M +
H]+ 276.1752; found 276.1752.
Procedure 2 with Indole: Column chromatography (hexanes/
EtOAc 9:1, Rf = 0.77 in hexanes/EtOAc 9:1) yielded a ca. 2.2:1 mixture
of diastereomers (rr > 95:5) of the title compound (24.1 mg, 78%) as a
brown oil; [α]D29 = +17.1 (c 1.0, CHCl3) for 90% ee, as determined by
HPLC analysis (Chiralcel ODH, 2% iPrOH/hexane, 1.00 mL/min,
254 nm); tR = 15.34 min [major], tR = 20.78 min [minor].
Procedure 3 with Indole: Column chromatography (hexanes/
EtOAc 9:1) yielded a ca. 2.4:1 mixture of diastereomers (rr > 95:5) of
the title compound (85.9 mg, quant) as a brown oil; HPLC analysis
(Chiralcel ODH, 2% iPrOH/hexane, 1.00 mL/min, 254 nm); 89% ee,
tR = 15.43 min [minor], tR = 21.28 min [major].
Ethyl 5-((1R,2S)-2-ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-
pyrrole-2-carboxylate (17): 1H NMR (400 MHz, CDCl3) major
diastereomer δ 7.17−6.98 (m, 4H), 6.86−6.84 (m, 1H), 6.03−6.01 (m,
1H), 4.27 (q, J = 7.0 Hz, 2H), 3.85 (d, J = 8.2 Hz, 1H), 2.86 (t, J = 6.6
Hz, 2H), 2.05−1.98 (m, 1H), 1.86−1.77 (m, 2H), 1.57−1.44 (m, 2H),
1.32 (t, J = 7.0 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); minor diastereomer
(selected signals) δ 6.81−6.79 (m, 1H), 5.90−5.89 (m, 1H), 4.20 (d,
J = 5.5 Hz, 1H), 3.00−2.89 (m, 2H), 1.27 −1.17 (m, 4H), 1.14−1.04
(m, 2H), 0.98 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) major
diastereomer δ 161.52, 141.85, 139.63, 137.14, 130.11, 129.23, 126.66,
126.25, 121.93, 115.74, 110.26, 44.98, 42.40, 28.30, 26.34, 25.96; minor
diastereomer (selected signals) δ 136.93, 130.64, 129.57, 126.93,
121.78. 115.57, 110.65, 42.97, 40.72, 29.36, 26.64, 24.37; IR (NaCl)
3441, 2961, 2932, 2874, 1670, 1484, 1438, 1318, 1205, 1142, 1206,
796, 764, 739 cm−1; HRMS (EI) calcd for C19H24NO2 [M + H]+
298.1809; found 298.1807.
1378, 1301, 1245, 1177, 1108, 1037, 945, 823, 783, 741 cm−1; HRMS
(EI) calcd for C19H22O [M+] 266.1671; found 266.1674; [α]D
=
27
+23.0 (c 1.0, CHCl3) for 92% ee, as determined by HPLC analysis
(Chiralcel ODH, 0.5% iPrOH/hexanes, 0.80 mL/min, 254 nm); tR =
6.43 min [minor], tR = 9.97 min [major].
Representative Procedure 3 for the HBF4·OEt2-Catalyzed
Friedel−Crafts Alkylation of 12 (13): To a solution of alcohol 12
(53 mg, 0.30 mmol) and anisole (0.33 mL, 3.00 mmol) in CH2Cl2
(1 mL) was added HBF4·OEt2 (45 μL, 0.33 mmol) at −78 °C. The
mixture was stirred for 5 min at −78 °C and then for 15 min at rt. The
mixture was then treated with saturated NaHCO3 solution. The
separated aqueous phase was then extracted with Et2O. The combined
organic phases were washed sequentially with saturated NaHCO3
solution and brine, dried (MgSO4), and then concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (hexanes/EtOAc 9:1) to afford a ca. 9:1 mixture of
diastereomers (rr > 95:5) of the title compound (80 mg, quant) as a
colorless oil.
2-((1S,2R)-2-Ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-5-methyl-
thiophene (15): 1H NMR (400 MHz, CDCl3) major diastereomer δ
7.17−7.04 (m, 4H), 6.53 (m, 2H), 3.99 (d, J = 7.8 Hz, 1H), 2.91−2.87
(m, 2H), 2.41 (s, 3H), 2.14−2.07 (m, 1H), 1.90−1.78 (m, 2H), 1.64−
1.51 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); minor diastereomer (selected
signals) δ 6.50 (d, J = 3.5 Hz, 1H), 4.31 (d, J = 3.5 Hz, 1H), 1.48−1.39
(m, 2H), 1.22−1.09 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) major diastereomer δ 148.2, 140.1, 138.9, 138.0, 126.5,
130.3, 128.6, 126.0, 125.6, 124.1, 46.68, 44.0, 28.1, 25.5, 23.8, 15.4,
11.3; minor diastereomer (selected signals) δ 144.7, 136.1, 130.5, 129.0,
126.4, 125.6, 124.1, 44.4, 40.5, 29.3, 26.7, 23.8, 15.2, 12.0; IR (NaCl)
3059, 3017, 2959, 2872, 2860, 1491, 1450, 1435, 796, 741, 426, 421,
415, 402 cm−1; HRMS (EI) calcd for C17H20S [M+] 256.1286; found
256.1286.
Procedure 2 with Ethyl Pyrrole-2-carboxylate: Column chroma-
tography (hexanes/EtOAc 9:1) yielded a ca. 1.9:1 mixture of diastereo-
mers (rr > 95:5) of the title compound (21.7 mg, 44%) as a colorless
oil; [α]D29 = −18.2 (c 1.0, CHCl3) for 92% ee, as determined by HPLC
analysis (Chiralcel ADH, 2% iPrOH/hexane, 1.00 mL/min, 254 nm);
tR = 9.10 min [major], tR = 12.18 min [minor].
Procedure 3 with Ethyl Pyrrole-2-carboxylate: Column chroma-
tography (hexanes/EtOAc 9:1) yielded a ca. 1.6:1 mixture of diastereo-
mers (rr > 95:5) of the title compound (34.3 mg, 92%) as a colorless
oil; HPLC analysis (Chiralcel ADH, 2% iPrOH/hexane, 1.00 mL/min,
254 nm); 92% ee, tR = 9.11 min [minor], tR = 11.86 min [major].
(1S,2S)-1-(3,4-Dimethoxyphenyl)-2-ethyl-1,2,3,4-tetrahydro-
naphthalene (18): 1H NMR (400 MHz, CDCl3) major diastereomer δ
7.21−6.88 (m, 3H), 6.78 (t, J = 7.6 Hz, 2H), 6.68−6.53 (m, 2H), 3.87
(s, 3H), 3.81 (s, 3H), 3.68 (d, J = 8.8 Hz, 1H), 3.01−2.81 (m, 2H),
2.12−1.99 (m, 1H), 1.81−1.70 (m, 1H), 1.55−1.39 (m, 2H), 1.25−
1.09 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H); minor diastereomer (selected
signals) δ 4.12 (d, J = 5.0 Hz, 1H), 0.97 (t, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) major diastereomer δ 149.0, 147.4, 140.1, 139.4,
137.2, 130.6, 128.7, 125.8, 125.7, 121.8, 112.5, 111.0, 56.0, 56.0, 51.6,
43.6, 29.0, 26.4, 26.2, 11.3; minor diastereomer (selected signals) δ 140.4,
136.9, 136.5, 130.8, 128.9, 126.0, 122.7, 114.1, 110.5, 48.9, 40.9, 29.3,
23.2, 12.2; IR (NaCl) 2997, 2957, 2932, 2873, 2836, 2361, 1590, 1515,
1490, 1463, 1417, 1342, 1258, 1231, 1186, 1141, 1030, 806, 768, 740
cm−1; HRMS (EI) calcd for C20H24O2 [M+] 296.1776; found 296.1781.
Procedure 2 with Veratrole: Column chromatography (hexanes/
EtOAc 98:2 to 85:15, Rf = 0.30 in hexane/EtOAc 85:15) yielded a ca.
88:12 mixture of diastereomers of the title compound (62 mg, 70%) as
a colorless oil.
Procedure 2 with 2-methylthiophene: Column chromatography
(hexanes/EtOAc 98:2) yielded a ca. 2.3:1 mixture of diastereomers
(rr > 95:5) of the title compound (24.9 mg, 54%) as a colorless oil;
HPLC analysis (Chiralcel ODH, 1% iPrOH/hexanes, 1.00 mL/min,
254 nm); 86% ee, tR = 5.07 min [minor], tR = 5.64 min [major].
Procedure 3 with 2-methylthiophene: Column chromatography
(hexanes/EtOAc 98:2) yielded a ca. 1.6:1 mixture of diastereomers
(rr > 95:5) of the title compound (112.7 mg, 95%) as a colorless oil;
28
[α]D = +74.6 (c 1.0, CHCl3) for 88% ee, as determined by HPLC
analysis (Chiralcel ODH, 1% iPrOH/hexane, 1.00 mL/min, 254 nm);
tR = 5.08 min [major], tR = 5.66 min [minor].
3-((1S,2R)-2-Ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-indole
(16): 1H NMR (400 MHz, CDCl3) major diastereomer δ 7.88 (s, br,
1H), 7.42 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.22−7.04 (m,
6H), 6.77 (d, J = 2.4 Hz, 1H), 4.11 (d, J = 7.3 Hz, 1H), 2.97−2.94 (m,
2H), 2.12−2.05 (m, 1H), 1.62−1.51 (m, 2H), 1.37−1.26 (m, 2H),
0.98 (t, J = 7.4 Hz, 3H); minor diastereomer (selected signals) δ 7.91 (s,
br, 1H), 7.61 (d, J = 3.5 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 4.54 (d,
J = 4.8 Hz, 1H), 3.10−3.00 (m, 2H); 13C NMR (100 MHz, CDCl3)
major diastereomer δ 139.7, 137.1, 136.9, 130.7, 129.7, 126.7, 125.9,
125.7, 123.5, 122.0, 121.7, 119.9, 119.4, 111.4, 42.4, 41.0, 28.0, 26.2,
25.5, 11.5; minor diastereomer (selected signals) δ 141.6, 136.6, 126.1,
130.7, 129.0, 124.2, 121.8, 119.5, 119.5, 41.4, 29.5, 26.5, 23.6, 12.1; IR
(NaCl) 3419, 3056, 3015, 2958, 2926, 2872, 2859, 1600, 1488, 1454,
1417, 1377, 1350, 1338, 1265, 1350, 1338, 126, 1245, 1222, 1093,
Procedure 3 with Veratrole: Kugelrohr distillation (118 °C at
55 mmHg) yielded a ca. 9.3:1 mixture of diastereomers of the title
27
compund (41.0 mg, 84%) as a colorless oil; [α]D = +25.3 (c 0.5,
CHCl3) for 81% ee, as determined by HPLC analysis (Chiralcel ODH,
0.5% iPrOH/hexane, 0.80 mL/min, 254 nm); tR = 6.43 min [major],
tR = 7.13 min [minor].
4-((1S,2S)-2-Ethyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol
(19): 1H NMR (400 MHz, CDCl3) major diastereomer δ 7.15−6.91
(m, 5H), 6.75−6.73 (m, 1H), 4.77 (s, br, 1H), 3.69 (d, J = 8.6 Hz,
1H), 2.91−2.28 (m 2H), 2.06−2.00 (m, 1H), 1.74−1.71 (m, 2H),
1.51−1.41 (m, 2H), 1.21−1.14 (m, 1H), 0.90 (t, J = 7.4 Hz, 3H);
minor diastereomer (selected signals) δ 6.85−6.73 (m, 2H), 6.68−6.66
9037
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The Journal of Organic Chemistry
Article
(m, 1H), 4.11 (d, J = 5.1 Hz, 1H), 1.64−1.62 (m, 1H), 1.07 (t, J = 6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) major diastereomer δ 153.56,
140.06, 139.09, 137.16, 130.55, 130.39, 128.52, 125.59, 125.51, 115.02,
50.76, 43.60, 28.73, 26.07, 25.82, 11.18; minor diastereomer (selected
signals) δ 155.44, 131.34, 130.60, 129.63, 126.79, 125.82, 120.73,
115.29, 114.38, 48.24, 40.84, 29.17, 26.22, 22.74, 12.00; IR (NaCl)
3346, 2959, 2928, 2872, 1612, 1511, 1455, 1241, 1172, 824, 741, 407
cm−1; HRMS (EI) calcd for C18H24NO [M + NH4]+ 270.1858; found
270.1858.
Procedure 2 with Phenol: Column chromatography (hexanes/
EtOAc 9:1) yielded a ca. 6.7:1 mixture of diastereomers (rr 3.9:1) of
the title compound (126.0 mg, quant) as a white solid, mp = 48−54 °C.
Procedure 3 with Phenol: Column chromatography (hexanes/
EtOAc 9:1) yielded a ca. 6.6:1 mixture of diastereomers (rr 7.2:1) of
the title compound (100.9 mg, quant) as a white solid; [α]D29 = +16.8
(c 0.3, CHCl3) for 88% ee, as determined by HPLC analysis (Chiralcel
ODH, 2% iPrOH/hexane, 1.00 mL/min, 254 nm); tR = 13.64 min
[minor], tR = 20.13 min [major].
130.5, 129.9, 128.6, 127.9, 127.7, 127.2, 125.9, 125.6, 120.7, 111.1,
55.6, 48.1, 30.1, 29.7; HRMS (EI) calcd for C23H22O [M+] 314.1671;
found 314.1668; [α]D = −46.8 (c 1.0, CHCl3) for 81% ee, as
27
determined by HPLC analysis (Chiralcel ODH, 1% iPrOH/hexane,
1 mL/min, 254 nm); tR = 4.96 min [minor], tR = 8.92 min [major].
Representative Procedure 5 for the Protection of Boronic
Acids as Boronic Ethylene Glycol Esters: 2-(2,5-Difluorophen-
yl)-1,3,2-dioxaborolane (20b). (2,5-Difluorophenyl)boronic acid
(800 mg, 5.07 mmol) was dissolved in toluene (80 mL), and ethylene
glycol (314 mg, 5.07 mmol) was added. The mixture was heated to
150 °C with magnetic stirring under Dean−Stark and reflux for 24 h.
The mixture was allowed to cool to rt, and the solvent was removed
under reduced pressure to afford the title compound (933 mg, quant)
1
as a white solid: mp 45−46 °C; H NMR (400 MHz, CDCl3) δ 7.41
(d, J = 3.7 Hz, 1H), 7.16−7.10 (m, 1H), 7.02 (td, J = 8.8, 4.0 Hz, 1H),
4.42 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 22.5, 122.4, 122.3,
122.2, 120.3, 120.2, 120.1, 120.0, 116.9, 116.8, 116.6, 116.6, 66.2; IR
(NaCl) 3468, 2959, 1640, 1485, 1435, 1420, 1400, 1343, 1254, 1188,
1115, 1084, 1022, 895, 818, 764 cm−1; HRMS (EI) calcd for
C8H7BF2O2 [M+] 184.0507; found 184.0507.
Representative Procedure 4 for the Rh-Catalyzed Asym-
metric Ring Opening of Substrate 4: (1R,2S)-2-phenyl-1,2-
dihydronaphthalen-1-ol (21a). A 100 mL flask was charged with
[Rh(COD)Cl]2 (43 mg, 0.086 mmol), (R)-(S)-PPF-P(t-Bu)2 (95 mg,
0.175 mmol), and oxabicyclic alkene 4 (506 mg, 3.50 mmol). A stir bar
was added and the flask was sealed and flushed with argon before
distilled THF (20 mL) was added. Phenylboronic acid ethylene glycol
ester (609 mg, 4.20 mmol) was then added by syringe as a THF
solution (3 mL), followed by Cs2CO3 (5M) in H2O (0.35 mL). The
reaction was stirred for 16 h at rt. The reaction mixture was filtered on
a short silica gel pad, washing with CH2Cl2. The filtrate was
concentrated under reduced pressure and the crude product purified
by column chromatography (hexanes/EtOAc 9:1) to afford the title
compound (507 mg, 65%) as a colorless oil. The characterization data
were fully concordant with that already reported in the literature:6g 1H
NMR (400 MHz, CDCl3) δ 7.38−7.21 (m, 8H), 7.17 (dd, J = 7.2, 1.2
Hz, 1H), 6.71 (dd, J = 9.6, 2.0 Hz, 1H), 6.13 (dd, J = 9.6, 4.0 Hz, 1H),
4.94 (dd, J = 7.7, 6.2 Hz, 1H), 3.88 (ddd, J = 6.0, 4.0, 2.1 Hz, 1H), 1.46
(1R,2S)-2-(2,5-Difluorophenyl)-1,2-dihydronaphthalen-1-ol
(21b). Procedure 4 from 4: Column chromatography (pentane/
Et2O 98:2 to 95:5) yielded the title compound (128.5 mg, 78%) as an
off-white oil; 1H NMR (400 MHz, CDCl3) δ 7.36−7.25 (m, 3H), 7.19
(dd, J = 7.2, 1.4 Hz, 1H), 7.06−6.98 (m, 2H), 6.95−6.89 (m, 1H),
6.75 (dd, J = 9.6, 2.5 Hz, 1H), 6.00 (dd, J = 9.6, 3.4 Hz, 1H), 4.88 (t,
J = 6.0, 1H), 4.25 (dt, J = 5.3, 2.8 Hz, 1H), 1.67 (d, J = 7.1, 1H); 13
C
NMR (100 MHz, CDCl3) δ 160.1, 160.1, 158.4, 158.4, 157.7, 157.7,
156.0, 156.0, 135.5, 132.1, 129.2, 129.0, 128.5, 128.0, 127.6, 127.0,
117.7, 117.7, 117.5, 117.4, 116.5, 116.4, 116.3, 116.2, 115.4, 115.3,
115.2, 115.1, 70.4, 40.2, 40.2; IR (NaCl) 3391, 3071, 3040, 2924,
2855, 2361, 1628, 1593, 1493, 1454, 1424, 1277, 1238, 1177, 1142,
1072, 995, 980, 945, 876, 826, 768, 741, 694, 629 cm−1; HRMS (EI)
calcd for C16H12F2O [M+] 258.0856; found 258.0856; [α]D28 = +189.0
(c = 1.0, CHCl3) for 78% ee, as determined by HPLC analysis
(Chiralcel ODH, 2% iPrOH/hexane, 1.00 mL/min, 254 nm); tR
10.60 min [minor], tR = 13.88 min [major].
=
28
(d, J = 8.0 Hz, 1H); [α]D = −76.7 (c 1.2, CHCl3) for 85% ee, as
(1R,2S)-2-(2,5-Difluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-
ol (22b). Procedure 1 from 21b: Column chromatography
(pentanes/EtOAc 8:2) yielded the title compound (695 mg, 89%)
as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 7.3, 1.5
Hz, 1H), 7.30−7.23 (m, 2H), 7.21−7.19 (m, 1H), 7.11 (m, 1H), 7.03
(td, J = 9.2, 4.6 Hz, 1H), 6.96−6.90 (m, 1H), 4.86 (t, J = 3.5 Hz, 1H),
3.05 (ddd, J = 17.1, 5.7, 2.0 Hz, 1H), 2.99−2.91 (m, 1H), 2.41 (qd,
J = 12.5 Hz, 5.6 Hz, 1H), 1.91−1.85 (m, 1H), 1.54 (d, J = 4.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 160.0, 160.0, 157.9, 157.8, 157.6,
157.6, 155.5, 155.4, 137.6, 136.2, 131.7, 131.6, 131.5, 131.4, 130.3,
129.2, 128.4, 126.4, 116.5, 116.4, 116.2, 116.2, 116.1, 116.0, 115.9,
115.8, 114.4, 114.3, 114.2, 114.1, 100.0, 69.5, 69.5, 38.7, 38.7, 29.4,
21.1; IR (NaCl) 3314, 3078, 3063, 3024, 2916, 2839, 2361, 2342,
1628, 1593, 1493, 1454, 1424, 1377, 1316, 1278, 1246, 1173, 1142,
1080, 1053, 1010, 957, 907, 872, 814, 779, 745 cm−1; HRMS (EI)
calcd for C16H14F2O [M+] 260.1013; found 260.1013; [α]D28 = +189.0
(c = 1.0, CHCl3).
(1R,2R)-2-(2,5-Difluorophenyl)-1-(4-methoxyphenyl)-1,2,3,4-tet-
rahydronaphthalene (23b). Procedure 2 from 22b: Preparative
thin layer chromatography (hexanes/EtOAc 9:1) yielded a ca. 8.1:1
mixture of diastereomers (rr 13.3:1) of the title compound (89 mg,
94%) as an off-white oil; 1H NMR (400 MHz, CDCl3) major
diastereomer δ 7.18−7.11 (m, 2H), 7.03 (t, J = 8.1 Hz, 1H), 6.88−6.85
(m, 2H), 6.84−6.73 (m, 4H), 6.72−6.68 (m, 2H), 4.17 (d, J = 10.1
Hz, 1H), 3.74 (s, 3H), 3.40 (td, J = 9.8, 3.7 Hz, 1H), 3.15−3.07 (m,
1H), 2.93 (dt, J = 16.8, 4.3 Hz, 1H), 2.19−2.07 (m, 2H) ppm; minor
diastereomer (selected signals) δ 7.25−7.18 (m, 2H), 7.00−6.94 (m,
3H), 6.58−6.55 (m, 2H), 6.43−6.40 (m, 2H), 6.10−6.05 (m, 1H),
4.51 (d, J = 5.0 Hz, 1H), 3.70 (s, 3H), 1.79−1.75 (m, 1H), 0.89−0.87
(m, 1H); regioisomer (selected signals) δ 4.74 (d, J = 5.8 Hz, 1H), 3.61
(s, 3H); 13C NMR (100 MHz, CDCl3) major diastereomer δ 158.0,
139.7, 136.9, 136.5, 131.1, 130.1, 130.1,128.7, 126.0, 125.9, 116.4,
116.3, 116.1, 116.0, 115.2, 115.2, 115.0, 114.9, 113.9, 113.8, 113.7,
determined by HPLC analysis (Chiralcel ODH, 2% iPrOH/hexane, 1.00
mL/min, 210 nm); tR = 16.41 min [major], tR = 31.53 min [minor].
(1R,2S)-2-Phenyl-1,2,3,4-tetrahydronaphthalen-1-ol (22a). Pro-
cedure 1 from 21a: Column chromatography (hexanes/EtOAc
85:15, Rf = 0.18 in 85:15 EtOAc/hexanes) yielded the title compound
(462 mg, 99%) as a white solid. The characterization data were fully
concordant with that already reported in the literature:19 1H NMR
(400 MHz, CDCl3) δ 7.43−7.33 (m, 5H), 7.32−7.17 (m, 4H), 4.80 (t,
J = 2.8 Hz, 1H), 3.13 (dt, J = 12.9, 2.8 Hz, 1H), 3.05 (ddd, J = 17.1,
5.5, 2.1 Hz, 1H), 2.95 (dd, J = 12.0, 5.7 Hz, 1H), 2.46 (ddd, J = 25.1,
12.7, 5.6 Hz, 1H), 2.04−1.92 (m, 1H), 1.56 (d, J = 3.6 Hz, 1H);
28
[α]D = +126 (c 1.2, CHCl3) for 93% ee, as determined by HPLC
analysis (Chiralcel ODH, 2% iPrOH/hexane, 1.00 mL/min, 210 nm);
tR = 20.41 min [major], tR = 30.96 min [minor].
(1S,2S)-1-(4-Methoxyphenyl)-2-phenyl-1,2,3,4-tetrahydronaph-
thalene (23a). Procedure 2 from 22a: Column chromatography
(hexanes/EtOAc 95:5, Rf = 0.63 in hexanes/EtOAc 9:1) to afford a
ca. 6.7:1 mixture of diastereomers (rr 5.7:1) of the title compound
(84 mg, 90%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
p-regioisomer, major diastereomer δ 7.21−7.07 (m, 6H), 7.07−6.98 (m,
3H), 6.87−6.76 (m, 2H), 6.69 (d, J = 8.6 Hz, 2H), 4.14 (d, J = 9.7 Hz,
1H), 3.74 (s, 3H), 3.18−2.98 (m, 2H), 2.93 (dt, J = 16.6, 4.2 Hz, 1H),
2.19−2.08 (m, 2H); minor diastereomer (selected signals) δ 6.54 (d,
J = 8.6 Hz, 2H), 6.33 (d, J = 8.6 Hz, 2H), 4.30 (d, J = 4.9 Hz, 1H);
o-regioisomer, major diastereomer δ 7.19−7.07 (m, 1H), 7.07−6.98 (m,
1H), 6.86−6.76 (m, 1H), 6.74 (d, J = 8.2 Hz, 1H), 4.70 (d, J = 8.9 Hz,
1H), 3.49 (s, 1H), 3.17 (td, J = 9.1, 4.5 Hz, 1H), 3.13−3.02 (m, 1H),
2.90 (dt, J = 16.6, 4.6 Hz, 1H), 2.15 (d, J = 4.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) p-regioisomer, major diastereomer δ 157.9, 145.4,
140.4, 138.2, 137.2, 130.5, 130.3, 128.8, 128.2, 127.7, 126.1, 126.0,
125.9, 113.5, 55.3, 52.6, 50.4, 30.3, 30.1; minor diastereomer (selected
signals) δ 131.6, 128.4, 127.9, 126.3, 112.5, 30.0; o-regioisomer, major
diastereomer (selected signals) δ 157.7, 145.7, 140.4, 137.3, 134.7,
9038
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The Journal of Organic Chemistry
Article
113.6, 113.5, 112.6, 77.4, 77.0, 76.7, 55.1, 51.0, 51.0, 43.0, 29.8, 29.0,
29.0; minor diastereomer (selected signals) δ 159.9, 159.9, 157.8, 157.7,
157.5, 157.5,155.4, 155.4, 133.9, 133.8, 133.7, 133.7, 131.1, 130.8,
128.9, 126.3, 53.4, 48.0, 37.8, 29.6, 21.5; IR (NaCl) 3731, 3445, 3422,
2932, 2839, 2361, 2334, 2064, 1643, 1616, 1501, 1462, 1427, 1387,
1366, 1339, 1300, 1246, 1207, 1178, 1146, 1107, 1038, 976, 868, 818,
745 cm−1; HRMS (EI) calcd for C23H20F2O [M+] 350.1482; found
350.1482; [α]D28 = −78.6 (c = 1.0, CHCl3) for 77% ee, as determined
by HPLC analysis (Chiralcel ODH, 2% iPrOH/hexanes, 1.00 mL/min,
269 nm); tR = 4.69 min [minor], tR = 5.30 min [major].
2361, 2064, 1613, 1586, 1508, 1454, 1300, 1246, 1215, 1177, 1107,
1038, 818, 779, 748 cm−1; HRMS (EI) calcd for C24H23FO [M+]
346.1733; found 346.1733; [α]D28 = +42.6 (c = 1.0, CHCl 3) for 73% ee,
as determined by HPLC analysis (Chiralcel ODH, 2% iPrOH/hexane,
1.00 mL/min, 269 nm); tR = 4.29 min [minor], tR = 4.49 min [major].
2-(2,5-Dimethylphenyl)-1,3,2-dioxaborolane (20d). Procedure
5 from (2,5-Dimethylphenyl)boronic Acid: The title compound
1
(586 mg, quant) was isolated as a colorless oil; H NMR (400 MHz,
CDCl3) δ 7.62 (s, 1H), 7.15 (dd, J = 1.5, 7.7 Hz, 2H), 7.07 (d, J = 7.7
Hz, 1H), 4.33 (s, 4H), 2.49 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 142.0, 136.9, 134.0, 132.0, 130.0, 65.8, 21.8, 20.8; IR (NaCl)
3013, 2974, 2909, 2862, 1609, 1574, 1497, 1481, 1385, 1367, 1331,
2-(2-Fluoro-5-methylphenyl)-1,3,2-dioxaborolane (20c). Proce-
dure 5 from 2-Fluoro-5-methylphenyl)boronic acid: The title
1
1277, 1207, 1146, 1076, 1007, 945, 876, 817, 783, 733, 671, 656 cm−1
HRMS (EI) calcd for C10H13BO2 [M+] 176.1009; found 176.1006.
;
compound (435 mg, 93%) was isolated as a colorless oil; H NMR
(400 MHz, CDCl3) δ 7.54 (dd, J = 1.7, 5.4 Hz, 1H), 7.26−7.22 (m,
1H), 6.94 (t, J = 8.9 Hz, 1H), 4.40 (s, 4H), 2.32 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 166.9, 164.4, 137.2, 137.1, 134.2, 134.2, 133.0, 133.0,
115.2, 115.0, 66.0, 20.5; IR (NaCl) 2982, 2913, 2361, 1616, 1493, 1416,
1335, 1285, 1219, 1126, 1076, 1003, 945, 818, 736, 648 cm−1; HRMS
(EI) calcd for C9H10BFO2 [M+] 180.0758; found 180.0758.
(1S,2R)-2-(2,5-Dimethylphenyl)-1,2-dihydronaphthalen-1-ol
(21d). Procedure 4 from 20d: Flash chromatography (pentanes/
Et2O 95:5) yielded the title compound (94 mg, 65%) as a white,
viscous oil; 1H NMR (400 MHz, CDCl3) δ 7.34−7.29 (m, 2H), 7.27−
7.23 (m, 1H), 7.19−7.17 (m, 1H), 7.12−7.08 (m, 2H), 7.01−6.99 (m,
1H), 6.71 (dd, J = 9.6, 2.6 Hz, 1H), 6.06 (dd, J = 9.6, 2.3 Hz, 1H), 4.74
(t, J = 4.6 Hz, 1H), 4.16 (dt, J = 5.1, 9.2 Hz, 1H), 2.36 (s, 3H), 2.27 (s,
3H), 1.54 (d, J = 5.1, 1H); 13C NMR (100 MHz, CDCl3) δ 136.7,
135.8, 135.3, 133.4, 132.5, 130.6, 130.5, 130.1, 128.7, 128.0, 127.9,
127.8, 127.8, 126.6, 69.5, 43.4, 21.1, 19.3; IR (NaCl) 3522, 3422, 3032,
2920, 2731, 1613, 1501, 1451, 1377, 1288, 1192, 1157, 1072, 1034,
991, 945, 92, 872, 806, 768, 690, 667, 629 cm−1; HRMS (EI) calcd for
(1R,2S)-2-(2-Fluoro-5-methylphenyl)-1,2-dihydronaphthalen-1-ol
(21c). Procedure 4 from 20c: Flash chromatography (pentanes/
EtOAc 95:5 to 9:1) to afford the title compound (335 mg, 95%) as an
1
off-white oil; H NMR (400 MHz, CDCl3) δ 7.36−7.33 (m, 1H),
7.36−7.24 (m, 2H), 7.19−7.18 (m, 1H), 7.11 (dd, J = 7.1, 1.9 Hz,
1H), 7.06−7.02 (m, 1H), 6.99−6.95 (m, 1H), 6.74 (dd, J = 9.6, 2.6
Hz, 1H), 6.04 (dd, J = 9.6, 2.6 Hz, 1H), 4.82 (s, 1H), 4.26 (dt, J = 5.1,
2.9 Hz, 1H), 2.29 (s, 3H), 1.62 (d, J = 4.6, 1H); 13C NMR (100 MHz,
CDCl3) δ 160.5, 158.1, 135.5, 133.6, 133.6, 132.2, 131.2, 131.1, 129.3,
129.2, 128.7, 128.6, 128.5, 128.1, 127.8, 126.7, 125.7, 125.5, 115.1,
114.9, 70.2, 40.2, 40.2, 20.8; IR (NaCl) 3553, 3430, 3036, 2924, 2859,
2361, 1497, 1454, 1381, 1281, 1238, 1204, 1072, 991, 880, 818, 764
cm−1; HRMS (EI) calcd for C17H15FO [M+] 254.1107; found
254.1107; [α]D28 = −56.5 (c = 1.0, CHCl3) for 74% ee, as determined
by HPLC analysis (Chiralcel ODH, 2% iPrOH/hexane, 1.00 mL/min,
254 nm); tR = 8.88 min [minor], tR = 14.27 min [major].
C18H18O [M+] 250.1358; found 250.1358; [α]D = −7.4 (c = 1.0,
28
CHCl3).
(1S,2R)-2-(2,5-Dimethylphenyl)-1,2,3,4-tetrahydronaphthalen-1-
ol (22d). Procedure 1 from 21d: Column chromatography
(pentanes/EtOAc 95:5 to 9:1) to afford the title compound (396
mg, 87%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 7.35−7.33
(m, 1H), 7.29−7.25 (m, 1H), 7.23−7.19 (m, 2H), 7.13−7.10 (m, 2H),
7.01−6.99 (m, 1H), 4.74 (bs, 1H), 3.30 (dt, J = 12.9, 2.6 Hz, 1H), 3.05
(ddd, J = 19.0, 5.4, 1.8 Hz, 1H), 2.98−2.89 (m, 1H), 2.52 (qd, J = 12.7,
5.4, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 4.26 (dt, J = 5.2, 3.0 Hz, 1H), 3.68
(s, 3H), 1.83 (dqt, J = 12.87, 2.2, 1.2 Hz, 1H), 1.60 (d, J = 3.1, 1H);
13C NMR (100 MHz, CDCl3) δ 140.1, 137.7, 136.9, 135.6, 132.8,
(1R,2S)-2-(2-Fluoro-5-methylphenyl)-1,2,3,4-tetrahydronaphtha-
len-1-ol (22c). Procedure 1 from 21c: Flash chromatography
(hexanes/EtOAc 8:2) yielded the title compound (265 mg, 92%) as
1
a colorless oil; H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 7.3, 1.3
130.7, 130.6, 129.1, 128.5, 128.1, 127.3, 126.1, 68.8, 42.0, 30.2, 22.0,
21.3, 19.1; IR (NaCl) 3530, 3329, 3021, 2920, 2874, 2835, 1609, 1501,
Hz, 1H), 7.29−7.22 (m, 2H), 7.20−7.18 (m, 1H), 7.16 (dd, J = 7.1,
1.8 Hz, 1H), 7.06−7.02 (m, 1H), 6.98−6.93 (m, 1H), 4.85 (s, 1H),
3.44 (dt, J = 13.2, 2.5 Hz, 1H), 3.05 (ddd, J = 17.1, 5.5, 1.8 Hz, 1H),
2.99 - 2.90 (m, 1H), 2.45 (qd, J = 12.7, 5.8 Hz, 1H), 2.35 (s, 3H),
1.90−1.84 (m, 1H), 1.53 (d, J = 4.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 160.2, 157.8, 137.7, 136.5, 133.5, 133.4, 130.5, 129.9, 129.8,
129.1, 129.0, 128.9, 128.5, 128.5, 128.2, 126.2, 114.9, 114.7, 69.6, 69.6,
53.4, 38.7, 38.7, 30.9, 29.7, 21.0, 21.0; IR (NaCl) 3538, 3318, 3024,
2928, 2839, 2338, 1605, 1497, 1454, 1435, 1381, 1242, 1207, 1088,
1053, 961, 941, 810, 775, 741 cm−1; HRMS (EI) calcd for C17H17FO
1454 m 1381, 1157, 1084, 967, 941, 903, 810, 771, 737 cm−1; HRMS
(EI) calcd for C18H20O [M+] 252.1514; found 252.1514; [α]D
−50.0 (c = 1.0, CHCl3)
=
28
(1S,2S)-2-(2,5-Dimethylphenyl)-1-(4-methoxyphenyl)-1,2,3,4-tet-
rahydronaphthalene (23d). Procedure 2 from 22d: Preparatory
thin layer chromatography (hexanes/EtOAc 9:1, Rf = 0.73 in hexanes/
EtOAc 9:1) yielded a ca. 8.1:1 mixture of diastereomers (rr > 95:5) of
1
the title compound (122 mg, 97%) as a colorless oil; H NMR (400
MHz, CDCl3) major diastereomer δ 7.19−7.10 (m, 3H), 7.06−7.02 (m,
1H), 6.86−6.82 (m, 3H), 6.79−6.75 (m, 2H), 6.67−6.63 (m, 2H),
4.19 (d, J = 10.0 Hz, 1H), 3.72 (s, 3H), 3.27 (td, J = 10.4, 3.9 Hz, 1H),
3.09 (m, 1H), 2.92 (dt, J = 16.5, 3.9, 1H), 2.30 (s, 3H), 2.05−2.00 (m,
2H), 1.79 (m, 3H); minor diastereomer (selected signals) δ 6.98−6.96
(m, 1H), 6.56−6.53 (m, 2H), 6.28−6.25 (m, 2H), 4.27 (d, J = 4.8 Hz,
1H), 3.70 (s, 3H), 3.54 - 3.50 (m, 1H), 2.41 (s, 3H), 2.27 (s, 1H), 2.11
(d, J = 4.6 Hz, 1H), 1.25 (s, 3H), 0.90−0.81 (m, 2H); 13C NMR (100
MHz, CDCl3) major diastereomer δ 157.7, 143.5, 140.6, 138.1, 137.3,
135.2, 132.8, 130.3, 130.2, 129.8, 128.6, 126.9, 126.4, 125.8, 125.6,
113.2, 55.1, 52.4, 45.0, 30.6, 30.4, 21.3, 19.0; minor diastereomer
(selected signals) δ 131.5, 130.8, 129.5, 128.9, 128.7, 126.3, 126.2, 125.8,
112.1, 109.5, 55.2, 47.9, 40.9, 30.2, 22.7, 20.9, 19.0; IR (NaCl) 3473,
3013, 2928, 2862, 2839, 2334, 1640, 1613, 1586, 1508, 1458, 1300,
1246, 1177, 1107, 1038, 814, 745 cm−1; HRMS (EI) calcd for C25H26O
[M+] 256.1263; found 256.1263; [α]D = −20.9 (c = 0.5, CHCl3).
28
(1R,2R)-2-(2-Fluoro-5-methylphenyl)-1-(4-methoxyphenyl)-
1,2,3,4-tetrahydronaphthalene (23c). Procedure 2 from 22c:
Column chromatography (pentanes/EtOAc 98:2) yielded a ca. 8.1:1
mixture of diastereomers of the title compound (62 mg, 76%) as a
pink oil; 1H NMR (400 MHz, CDCl3) major diastereomer δ 7.16−7.10
(m, 2H), 7.02 (t, J = 8.0 Hz,1H), 6.92−6.88 (m, 2H), 6.86−6.83 (m,
2H), 6.79 (d, J = 7.8 Hz, 1H), 6.76−6.72 (m, 1H), 6.70−6.66 (m,
2H), 4.22 (d, J = 10.2 Hz, 1H), 3.73 (s, 3H), 3.36 (td, J = 10.8, 2.9 Hz,
1H), 3.14−3.06 (m, 1H), 2.92 (dt, J = 16.6, 3.1, 1H), 2.23 (s, 3H),
2.21−2.07 (m, 2H); minor diastereomer (selected signals) δ 7.19−7.17
(m, 1H), 7.08−7.06 (m, 1H), 6.98−6.95 (m, 2H), 6.57−6.53 (m, 2H),
6.39−6.36 (m, 2H), 6.11 (d, J = 7.5 Hz, 1H), 4.38 (d, J = 5.0 Hz, 1H),
3.69 (s, 3H), 1.78−1.74 (m, 1H), 1.53 (s, 3H), 0.90−0.83 (m, 2H);
13C NMR (100 MHz, CDCl3) major diastereomer δ 160.0, 157.8, 157.6,
[M+] 342.1984; found 342.1984; [α]D = 35.5 (c = 1.0, CHCl3).
28
140.2, 137.5, 136.8, 133.1, 133.0, 131.5, 131.3, 131.3, 130.2, 130.1,
129.2, 129.2, 128.6, 127.8, 127.7, 125.8, 125.8, 115.0, 114.7, 113.3,
112.3, 55.1, 51.0, 51.0, 43.2, 30.1, 29.3, 29.3, 20.8; minor diastereomer
(selected signals) δ 139.6, 136.4, 134.8, 130.8, 129.7, 129.6, 128.9,
128.5, 127.6, 127.5, 127.1, 126.2, 125.9, 114.2, 113.9, 112.3, 55.1, 48.3,
37.6, 29.8, 29.7, 21.6, 20.6; IR (NaCl) 3441, 2059, 2017, 2928, 2835,
2-(2-Fluoro-5-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane
(20e). Procedure 5 from (2-Fluoro-5-(trifluoromethyl)phenyl)-
boronic Acid: The title compound (881 mg, 98%) was isolated as a
colorless oil; 1H NMR (400 MHz, CDCl3) δ 8.05 (dd, J = 5.1, 2.2 Hz,
1H), 7.72 (septet of doublets, J = 2.5, 0.5 Hz, 1H), 7.16 (t, J = 8.7 Hz,
1H), 4.43 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 170.2, 170.2,
9039
dx.doi.org/10.1021/jo201781x|J. Org. Chem. 2011, 76, 9031−9045

The Journal of Organic Chemistry
Article
167.6, 167.6, 134.5, 134.5, 130.9, 130.9, 130.8, 130.8, 122.5, 116.2,
116.0, 66.2; IR (NaCl) 3422, 2990, 2920, 1624, 1597, 1497, 1435, 1400,
1373, 1350, 1311, 1231, 1165, 1123, 1084, 995, 945, 833, 748 cm−1;
HRMS (EI) calcd for C9H7BF4O2 [M+] 235.0475; found 235.0475.
(1R,2S)-2-(2-Fluoro-5-(trifluoromethyl)phenyl)-1,2-dihydronaph-
thalen-1-ol (21e). Procedure 4 from 20e: Flash chromatography
(pentanes/EtOAc 98:2 to 7:3) yielded the title compound as a mixture
(dd, J = 9.6, 3.4 Hz, 1H), 4.89 (t, J = 6.0, 1H), 4.26 (dt, J = 5.2, 3.0 Hz,
1H), 3.68 (s, 3H), 1.68 (d, J = 6.8, 1H); 13C NMR (100 MHz, CDCl3)
δ 156.7, 155.7, 155.7, 154.3, 135.5, 132.2, 128.7, 128.7, 128.5, 128.2,
127.4, 126.7, 126.6, 126.5, 115.9, 115.7, 115.7, 115.6, 113.5, 113.4,
77.4, 77.1, 76.7, 70.3, 55.7, 40.2, 40.2; IR (NaCl) 3422, 2835, 1640,
1505, 1107, 1076, 1042, 1076, 1042, 991, 945, 860, 725 cm−1; HRMS
(EI) calcd for C17H15FO2 [M+] 270.1056; found 270.1056; [α]D
=
28
1
with some oxabenzonorbornadiene starting material (identified by H
+226.5 (c = 0.5, CHCl3) for 73% ee, as determined by HPLC analysis
NMR). Separation of the starting material from the desired product
was not further attempted. Rather, the crude was continued to the
hydrogenation step.
(Chiralcel ODH, 2% iPrOH/hexane, 1.00 mL/min, 269 nm); tR
13.84 min [minor], tR = 20.97 min [major].
=
(1R,2S)-2-(2-Fluoro-5-methoxyphenyl)-1,2,3,4-tetrahydronaph-
thalen-1-ol (22f). Procedure 1 from 21f: Flash chromatography
(pentanes/EtOAc 95:5) yielded the title compound (598 mg, 83%) as
(1R,2S)-2-(2-Fluoro-5-(trifluoromethyl)phenyl)-1,2,3,4-tetrahy-
dronaphthalen-1-ol (22e). Procedure 1 from 21e: Flash chroma-
tography (pentanes/EtOAc 95:5) to afford the title compound
(177 mg, 61% (over 2 steps)) as a colorless oil; 1H NMR (400
MHz, CDCl3) δ 7.70 (dd, J = 6.6, 2.0 Hz, 1H), 7.54 (m, 1H), 7.33 (dd,
J = 7.2, 1.2 Hz, 1H), 7.31−7.27 (m, 1H), 7.26−7.15 (m, 3H), 4.86
(t, J = 3.3 Hz, 1H), 3.48 (dt, J = 13.2, 2.5 Hz, 1H), 3.08 (ddd, J = 17.1,
5.6, 1.7 Hz, 1H), 3.01−2.92 (m, 1H), 2.49 (qd, J = 12.7, 5.7 Hz, 1H),
1.95−1.86 (m, 1H), 1.53 (d, J = 4.9, 1H); 13C NMR (100 MHz,
CDCl3) δ 137.6, 136.2, 131.0, 130.9, 130.3, 129.3, 128.5, 127.4, 127.4,
127.4 127.3, 126.4, 125.6, 125.5, 125.5,, 125.5, 115.8, 115.5, 69.4, 69.4,
38.6, 29.5, 21.2; IR (NaCl) 3376, 2924, 2851, 1640, 1605, 1501, 1424,
1
a colorless oil; H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 7.3, 1.5
Hz, 1H), 7.29−7.18 (m, 3H), 7.00 (t, J = 9.3 Hz, 1H), 6.91 (dd, J =
5.9, 3.1 Hz, 1H), 6.76 (dt, J = 8.9, 3.6 Hz, 1H), 4.86 (t, J = 3.2 Hz,
1H), 3.79 (s, 3H), 3.45 (dt, J = 13.2, 2.8 Hz, 1H), 3.04 (ddd, J = 17.0,
5.5, 1.9 Hz, 1H), 2.99−2.90 (m, 1H), 2.43 (qd, J = 12.6, 5.6 Hz, 1H),
1.92−1.85 (m, 1H), 1.55 (d, J = 4.2, 1H); 13C NMR (100 MHz,
CDCl3) δ 156.4, 155.7, 137.6, 136.4, 130.5, 130.5, 129.1, 128.2, 126.3,
115.6, 115.4, 115.2, 115.2, 112.2, 112.2, 100.0, 69.6, 69.6, 55.7, 38.9,
29.6, 21.1; IR (NaCl) 3445, 3422, 2936, 2835, 2357, 2087, 1640, 1497,
1454, 1427, 1296, 1204, 1150, 1088, 1057, 1038, 945, 806, 775, 741
cm−1; HRMS (EI) calcd for C17H17FO2 [M+] 272.1213; found
1331, 1269, 1169, 1126, 1088, 1053, 961, 907, 829, 779, 741 cm−1
;
HRMS (EI) calcd for C17H14F4O [M+] 310.0981; found 310.0981;
28
272.1213; [α]D = −62.8 (c = 1.0, CHCl3).
28
[α]D = −40.7 (c = 1.0, CHCl3).
(1R,2R)-2-(2-Fluoro-5-methoxyphenyl)-1-(4-methoxyphenyl)-
1,2,3,4-tetrahydronaphthalene (23f). Procedure 2 from 22f:
Preparative thin layer chromatography (hexanes/EtOAc 8:2) yielded
a ca. 7.1:1 mixture of diastereomers (rr 13.3:1) of the title compound
(118 mg, 89%) as an off-white oil; 1H NMR (400 MHz, CDCl3) major
diastereomer δ 7.16−7.10 (m, 2H), 7.03 (t, J = 7.3 Hz, 1H), 6.89−6.86
(m, 2H), 6.81−6.76 (m, 2H), 6.70−6.66 (m, 2H), 6.65−6.64 (m, 1H),
6.62−6.58 (m, 1H), 4.21 (d, J = 10.0 Hz, 1H), 3.73 (s, 3H), 3.69 (s,
3H), 3.38 (td, J = 10.3, 3.5 Hz, 1H), 3.14−3.06 (m, 1H), 2.92 (dt,
J = 16.7, 4.3, 1H), 2.15−2.06 (m, 2H); minor diastereomer (selected
signals) δ 7.20−7.14 (m, 1H), 7.08−7.06 (m, 1H), 6.58−6.55 (m,
2H), 6.44−6.40 (m, 2H), 5.85 (dd, J = 5.9, 3.1 Hz, 1H), 4.39 (d,
J = 5.0 , 1H), 3.48 (s, 3H), 1.21−1.20 (m, 1H); regioisomer (selected
signals) δ 4.77 (d, J = 9.4 Hz, 1H), 3.66 (s, 3H), 3.60 (s, 3H), 3.50 (d,
J = 2.4 Hz, 1H), 2.85 (t, J = 4.8 Hz, 1H), 1.80−1.75 (m, 2H);
regioisomer; minor diastereomer (selected signals) δ 3.91 (s, 3H), 3.86
(s, 3H); 13C NMR (100 MHz, CDCl3) major diastereomer δ 158.1,
140.2, 137.5, 137.0, 130.4, 130.3, 128.9, 126.1, 126.1, 115.9, 115.7,
114.4, 114.3, 113.6, 112.7, 112.1, 112.0, 77.6, 77.3, 77.2, 77.0, 76.9
55.8, 55.3, 51.1, 51.1, 43.5, 30.1, 29.3, 29.3; minor diastereomer (selected
signals): δ 156.5, 155.7, 154.2, 133.0, 132.8, 131.4, 131.0, 114.4, 112.7,
29.9; IR (NaCl) 3449, 3001, 2932, 2835, 2361, 2334, 1609, 1589,
(1R,2R)-2-(2-Fluoro-5-(trifluoromethyl)phenyl)-1-(4-methoxy-
phenyl)-1,2,3,4- tetrahydronaphthalene (23e). Procedure 2 from
22e: Preparative thin layer chromatography (hexanes/EtOAc 8:2)
yielded a ca. 13.3:1 mixture of diastereomers (rr 7:1) of the title
1
compound (91 mg, quant) as an off-white oil; H NMR (400 MHz,
CDCl3) major diastereomer δ 7.43 (dd, J = 6.4, 1.9 Hz, 1H), 7.39−7.35
(m, 1H), 7.17−7.11 (m, 2H), 7.03, (t, J = 8.1 Hz, 1H), 6.96 (t, J = 9.2
Hz, 1H), 6.85−6.81 (m, 2H), 6.78 (d, J = 7.8 Hz, 1H), 6.70−6.67 (m,
2H), 4.19 (d, J = 10.6 Hz, 1H), 3.73 (s, 3H), 3.46 (td, J = 11.1, 2.9 Hz,
1H), 3.19−3.10 (m, 1H), 2.97 (dt, J = 16.5, 4.0, 1H), 2.22 (qd,
J = 12.1, 4.8 Hz, 1H), 2.15−2.18 (m, 1H); minor diastereomer (selected
signals) δ 7.56 (dd, J = 6.7, 2.0 Hz, 1H), 7.20 (dd, J = 7.3, 1.1 Hz, 1H),
7.10−7.08 (m, 2H), 6.91−6.90 (m, 1H), 6.57−6.53 (m, 2H), 6.51 (dd,
J = 6.6, 1.7 Hz, 1H), 6.37−6.33 (m, 2H), 4.35 (d, J = 5.0, 1H), 3.68 (s,
3H), 1.80−1.75 (m, 1H), 0.94−0.90 (m, 2H); regioisomer (selected
signals) δ 7.72−7.70 (m, 1H), 7.54−7.52 (m, 1H), 4.85 (d, J = 10.2
Hz, 1H), 3.55 (s, 3H), 1.68 (q, J = 5.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) major diastereomer δ 158.0, 139.7, 136.5, 136.4, 133.1, 132.9,
131.0, 130.0, 130.0, 128.7, 126.4, 126.4, 126.3, 126.3, 126.3, 126.0,
125.9, 125.0, 124.9, 124.9, 124.8, 116.0, 115.7, 113.5, 112.7, 77.3, 77.0,
76.7, 55.1, 51.3, 51.3, 43.2, 30.0, 29.3, 29.3; minor diastereomer
(selected signals) δ 163.6, 163.6, 161.1, 161.1, 133.1, 132.9, 131.0,
130.8, 130.0, 130.0, 128.9, 128.5, 127.9, 127.4, 126.7, 126.6, 126.4,
126.4, 126.3, 126.3, 125.7, 125.2, 125.0, 125.0, 124.9, 124.9, 124.8,
124.8, 124.8, 122.5, 120.7, 114.9, 112.7, 48.2, 38.7, 37.5, 21.6, 11.0; IR
(NaCl) 3433, 3422, 3067, 3021, 2932, 2839, 1728, 1609, 1508, 1458,
1331, 1242, 1169, 1126, 1076, 1038, 903, 826, 745 cm−1; HRMS (EI)
calcd for C24H20F4O [M+] 400.1450; found 400.1450; [α]D28 = +26.2
(c = 1.0, CHCl3).
1500, 1458, 1296, 1246, 1296, 1211, 1180, 1107, 1038, 818, 745 cm−1
;
HRMS (EI) calcd for C24H23FO2 [M+] 362.1682; found 362.1682;
[α]D28 = +70.2 (c = 1.0, CHCl3) for 70% ee, as determined by HPLC
analysis (Chiralcel ODH, 2% iPrOH/hexane, 1.00 mL/min, 269 nm);
tR = 4.58 min [minor], tR = 5.20 min [major].
2-(2-Biphenyl)-1,3,2-dioxaborolane (24a). Procedure 5 from 2-
(2-Biphenyl)boronic Acid: The title compound (2.77 g, 98%) was
isolated as a colorless oil. The characterization data were fully
concordant with that already reported in the literature:20 1H NMR
(400 MHz, CDCl3) δ 7.82 (dd, J = 7.4, 0.9 Hz, 1H), 7.53−7.46 (m,
1H), 7.44−7.31 (m, 7H), 4.21 (s, 4H).
2-(2-Fluoro-5-methoxyphenyl)-1,3,2-dioxaborolane (20f). Pro-
cedure 5 from (2-Fluoro-5-methoxyphenyl)boronic Acid: The title
1
compound (937 mg, quant) was isolated as a colorless oil; H NMR
(400 MHz, CDCl3) δ 7.22−7.21 (m, 1H), 6.99−6.98 (m, 1H), 6.97
(d, J = 1.8 Hz, 1H), 4.41 (s, 4H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 163.0, 160.6, 119.9, 119.8, 116.4, 116.1, 100.0, 66.1, 55.8; IR
(NaCl) 3445, 3422, 2963, 2916, 2839, 1640, 1420, 1335, 1292, 1207,
1126, 1069, 1038, 995, 945, 880, 818, 733 cm−1; HRMS (EI) calcd for
C9H10BFO3 [M+] 196.0707; found 196.0707.
(1R,2S)-2-(2-Biphenyl)-1,2-dihydronaphthalen-1-ol (25a). Pro-
cedure 4 from 24a: Flash chromatography (hexanes/EtOAc 9:1 to
85:15, Rf = 0.28 in hexanes/EtOAc 85:15) yielded the title compound
1
(264 mg, 60%) as a colorless oil; H NMR (400 MHz, CDCl3) δ
7.45−7.17 (m, 12H), 7.13 (d, J = 7.5 Hz, 1H), 6.64 (dd, J = 9.6, 2.5
Hz, 1H), 6.05 (dd, J = 9.6, 3.3 Hz, 1H), 4.61 (dd, J = 6.8, 6.2 Hz, 1H),
4.20−4.10 (m, 1H), 1.48 (d, J = 6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 143.0, 141.6, 136.5, 135.7, 132.4, 131.0, 130.5, 129.6, 129.4,
128.6, 128.4, 128.1, 127.9, 127.6, 127.6, 127.3, 127.1, 126.6, 70.5, 43.3;
IR (NaCl) 3534, 3424, 3056, 3025, 2361, 2338, 1735, 1452, 1244
cm−1; HRMS (EI) calcd for C22H16 [M−H2O]+: 280.1252; found
280.1254; [α]D28 = −163 (c 0.4, CHCl3) for 74% ee, as determined by
(1R,2S)-2-(2-Fluoro-5-methoxyphenyl)-1,2-dihydronaphthalen-1-
ol (21f). Procedure 4 from 20f: Flash chromatography (pentanes/
EtOAc 9:1) yielded the title compound (747 mg, 69%) as an off-white
1
oil; H NMR (400 MHz, CDCl3) δ 7.37−7.35 (m, 1H), 7.32−7.24
(m, 2H), 7.18 (dd, J = 7.2, 1.3 Hz, 1H), 7.00 (t, J = 9.2 Hz, 1H), 6.83−
6.80 (m, 1H), 6.77−7.75 (m, 1H), 6.73 (dd, J = 7.4, 2.2 Hz, 1H), 6.04
9040
dx.doi.org/10.1021/jo201781x|J. Org. Chem. 2011, 76, 9031−9045

The Journal of Organic Chemistry
Article
HPLC analysis (Chiralcel ODH, 10% iPrOH/hexane, 1.00 mL/min,
254 nm); tR = 5.99 min [minor], tR = 11.59 min [major].
added aq NaOH (1 N, 3 mL, 3 mmol) at rt. The mixture was stirred
vigorously for 15 min. Mixture was diluted with pH 7 sodium
phosphate buffer, then extracted with Et2O (3×). The organic phase
was dried (MgSO4) and evaporated under vacuum, leaving the boronic
acid (898 mg, quant) as a brown oil. Procedure 5 was then followed to
produce the title compound (687 mg, 85%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 7.4, 1.0 Hz, 1H), 7.51−7.46
(m, 1H), 7.42−7.34 (m, 2H), 7.31 (t, J = 7.9 Hz, 1H), 7.01−6.94 (m,
2H), 6.90 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 4.22 (s, 4H), 3.84 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 288.4, 277.0, 274.0, 264.3, 259.7,
258.4, 258.1, 255.7, 250.7, 249.9, 243.6, 242.0, 195.2, 184.5; IR (NaCl)
3056, 2963, 2907, 2834, 1596, 1584, 1560, 1478, 1437, 1388, 1366,
1333, 1258, 1212, 1178, 1119, 1082, 1048, 1019, 987, 942, 864, 801,
787, 764 cm−1; HRMS (EI) calcd for C15H15O3B [M+] 254.1114;
found 254.1112.
(1R,2S)-2-(2-Biphenyl)-1,2,3,4-tetrahydronaphthalen-1-ol
(26a). Procedure 1 from 25a: Flash chromatography (hexanes/
EtOAc 95:5, Rf = 0.20 in hexanes/EtOAc 85:15) yielded the title
1
compound (471 mg, 98%) as a colorless oil; H NMR (400 MHz,
CDCl3) δ 7.52 (dd, J = 7.8, 1.1 Hz, 1H), 7.44−7.05 (m, 12H), 4.46 (d,
J = 2.7 Hz, 1H), 3.30 (dt, J = 12.8, 2.8 Hz, 1H), 2.95 (ddd, J = 16.9,
5.1, 2.0 Hz, 1H), 2.84−2.68 (m, 1H), 2.43 (qd, J = 12.7, 5.2 Hz, 1H),
1.92−1.79 (m, 1H), 1.59 (s, br, 1H); 13C NMR (100 MHz, CDCl3) δ
142.6, 141.8, 140.0, 138.0, 136.7, 130.6, 130.5, 129.3, 129.1, 128.5,
128.3, 128.0, 127.7, 127.1, 126.5, 126.2, 70.0, 41.8, 29.9, 23.0; IR
(NaCl) 3317, 3057, 3023, 2931, 2361, 2338, 1598, 1575, 1480, 1450,
1453, 1383, 1272, 1242, 1216, 1088, 1050 cm−1; HRMS (EI) calcd for
C22H20O [M+] 300.1514; found 300.1507; [α]D = −94.9 (c 1.0,
28
CHCl3) for 74% ee, as determined by HPLC analysis (Chiralcel ODH,
10% iPrOH/hexane, 1.00 mL/min, 254 nm); tR = 5.45 min [minor],
tR = 8.26 [major].
(1R,2S)-2-(3′-Methoxy-[1,1′-biphenyl]-2-yl)-1,2-dihydronaphtha-
len-1-ol (25b). To a mixture of oxabicyclic akene 4 (40 mg, 0.281
mmol) and 24b (72 mg, 0.283 mmol) in MeOH (3 mL) was added
a premixed solution of Pd(CH3CN)2Cl2 (3.6 mg, 0.014 mmol) and
(S)-Tol-BINAP (10.4 mg, 0.015 mmol) under an argon atmosphere.
The vial was sealed, and Cs2CO3 in H2O (5 M) was syringed in. The
reaction was stirred at 60 °C for 16 h. After cooling to rt, the mixture
was filtered through a pad of silica gel. Evaporation of the volatile
material under vacuum followed by flash column chromatography
(hexanes/EtOAc 4:1) afforded the title compound as a brown oil
(4bR,10bR)-4b,5,6,10b-Tetrahydrobenzo[g]chrysene (30a). Pro-
cedure 2 from 26a: Flash chromatography (hexanes to hexanes/
EtOAC 95:5, Rf = 0.59 in hexanes/EtOAc 95:5) to afford the title
compound (56 mg, quant) as a white solid, mp 114−115 °C; 1H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.7 Hz,
1H), 7.38−7.09 (m, 9H), 6.85 (d, J = 7.6 Hz, 1H), 3.17 (dt, J = 11.5,
4.1 Hz, 1H), 2.96 (ddd, J = 17.7, 10.1, 7.8 Hz, 1H), 2.83 (dd, J = 17.3,
5.3 Hz, 1H), 1.99−1.71 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
140.8, 138.7, 136.6, 136.5, 133.6, 133.5, 131.6, 129.8, 128.8, 128.1,
128.1, 127.7, 127.4, 126.9, 125.4, 124.0, 124.0, 42.8, 39.6, 28.5, 24.6; IR
(NaCl) 3342, 3062, 3017, 2886, 2927, 1917, 1597, 1493, 1451, 1090,
772, 749, 756, 738, 621 cm−1; HRMS (EI) calcd for C22H18 [M+]
282.1409; found 282.1404; [α]D28 = +161 (c 1.0, CHCl3) for 74% ee,
as determined by HPLC analysis (Chiralcel ADH, 1% iPrOH/hexane,
1.00 mL/min, 254 nm); tR = 5.42 min [major], tR = 6.61 min [minor].
6-(2-Bromophenyl)-2-methyl-1,3,5,7,2,6-tetraoxazaborocane-
4,8-dione. The title compound was synthesized according to a
procedure of Burke and co-workers. A round-bottom flask equipped
with a stir bar was charged with 2-bromophenylboronic acid (2 g, 10
mmol), N-methyliminodiacetic acid (1.47 g, 10 mmol), and toluene/
DMSO (100 mL:40 mL). The flask was fitted with a Dean−Stark trap
and a reflux condenser, and the mixture was refluxed with stirring for
20 h. The reaction solution was allowed to cool to rt and the solvent
was removed in vacuo. The product was eluted with Et2O:MeCN 1:1.
The title compound was isolated as a white crystalline solid (3.05 g,
96%). The characterization data were fully concordant with that
already reported in literature:21 1H NMR (400 MHz, CDCl3) δ 7.74
(dd, J = 7.5, 2.0 Hz, 1H), 7.61 (dd, J = 8.0, 1.2 Hz, 1H), 7.36 (td,
J = 7.5, 1.2 Hz, 1H), 7.27 (td, J = 7.6, 1.9 Hz, 1H), 4.03 (d, J = 16.6
Hz, 2H), 3.96 (d, J = 16.8 Hz, 2H), 2.81 (s, 3H).
6-(3′-Methoxy-[1,1′-biphenyl]-2-yl)-2-methyl-1,3,5,7,2,6-tetraox-
azaborocane-4,8-dione. To a mixture of 6-(2-bromophenyl)-2-
methyl-1,3,5,7,2,6-tetraoxazaborocane-4,8-dione (664 mg, 2 mmol)),
3-methoxyboronic acid (365 mg, 2.4 mmol), and K3PO4 (1.27 g, 6
mmol) in THF (18 mL) was added a premixed solution of Pd(OAc)2
(67 mg, 0.1 mmol) and cyclohexyl-JohnPHOS (70 mg, 0.2 mmol)
under a nitrogen atmosphere. The mixture was stirred at 65 °C for
20 h. After cooling to room temperature, the mixture was filtered
through a pad of silica gel and Celite. Evaporation of the volatile
material under vacuum followed by purification by flash column
chromatography (Et2O to 3:1 Et2O/CH3CN) afforded the title
compound as a brown oil (452 mg, 56%): 1H NMR (400 MHz,
CDCl3) δ 7.91 (dd, J = 7.0, 2.0 Hz, 1H), 7.42 (m, 2H), 7.30 (m, 1H),
7.22 (dd, J = 7.4, 1.6 Hz, 1H), 6.89 (m, 2H), 3.85 (s, 3H), 2.48 (s, 3H),
2.01 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 157.2, 145.4, 142.8,
132.59, 129.0, 127.6, 127.5, 125.3, 119.9, 116.5, 113.8, 111.6, 53.4, 45.4;
IR (NaCl) 3007, 2956, 2917, 2837, 1767, 1489, 1476, 1336, 1297,
1211, 1196, 1113, 1029, 1005, 887, 863, 754, 705, 642 cm−1; HRMS
(EI) calcd for C18H22BN2O5 [M + NH4]+ 357.1622; found 357.1622.
2-(3′-Methoxy-[2-biphenyl]-2-yl)-1,3,2-dioxaborolane (24b). To
a solution of 6-(3′-methoxy-[1,1′-biphenyl]-2-yl)-2-methyl-1,3,5,7,2,6-
tetraoxazaborocane-4,8-dione (342 mg, 1 mmol) in THF (30 mL) was
1
(42 mg, 60% bsrm): H NMR (400 MHz, CDCl3) δ 7.40−7.36 (m,
1H), 7.31−3.17 (m, 7H), 7.11 (d, J = 7.6 Hz, 1H), 6.93−6.85 (m,
3H), 6.62 (dd, J = 9.6, 2.5 Hz, 1H), 6.03 (dd, J = 9.7, 3.3 Hz, 1H), 4.62
(m, 1H), 4.13 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.3, 142.8,
142.6, 136.3, 135.5, 132.3, 130.9, 130.1, 129.4, 129.2, 128.4, 127.9,
127.7, 126.4, 121.7, 112.6, 70.4, 55.2, 43.1 IR (NaCl) 3416, 3058,
3019, 2926, 2858, 2836, 1607, 1579 1498, 1451, 1254, 1212, 1043,
1021, 762, 745, 412, 403 cm−1. LRMS (ESI) calcd for C23H20O2 [M −
H2O]+ 210.14; found 311.1; [α]D27 = −1.3 (c 1.0, CHCl3) for 81% ee,
as determined by HPLC analysis (Chiralcel ADH, 8% iPrOH/hexane,
1.00 mL/min, 254 nm); tR = 4.04 min [minor], tR = 15.58 min [major].
(1R,2S)-2-(3′-Methoxy-[1,1′-biphenyl]-2-yl)-1,2,3,4-tetrahydro-
naphthalen-1-ol (26b). Procedure 1 from 25b: Flash chromatog-
raphy (hexane/EtOAc 95:5, Rf = 0.20 in hexane/EtOAc 85:15) yielded
1
the title compound (21 mg, 85%) as a colorless oil. H NMR (400
MHz, CDCl3) δ 7.52 (dd, J = 7.8, 1.4 Hz, 1H), 7.40 (td, J = 7.5, 1.7
Hz, 1H), 7.31 (td, J = 7.4, 1.4 Hz, 2H), 7.28−7.10 (m, 6H), 6.89 (t,
J = 1.3 Hz, 1 H), 6.87 (t, J = 1.2 Hz, 1H), 4.50 (m, 1H), 3.32 (dt,
J = 12.9, 2.9 Hz, 1H), 2.99−2.92 (m, 1H), 2.77 (ddd, J = 17.2, 12.0,
5.5 Hz, 1H), 2.51−2.38 (m, 1H), 1.81−1.89 (m, 1H), 1.59 (d, J = 3.7
Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 159.2, 143.0, 142.3, 139.8,
137.9, 126.6, 130.4, 130.3, 129.2, 129.0, 127.9, 128.4, 127.6, 126.3,
126.0, 121.6, 115.0, 112.4, 66.9, 55.2, 41.6, 29.8, 22.9; IR (NaCl) 3379,
2933, 1605, 1575, 1475, 1463, 1424, 1317, 1297, 1214, 1178, 1046,
1020, 959, 760, 739, 704 cm−1; HRMS (EI) calcd for C23H26NO2
[M + NH4]+: 348.1964; found 348.1964; [α]D26 = −1.2 (c 1.00, CHCl3).
(4bR,10bR)-13-Methoxy-4b,5,6,10b-tetrahydrobenzo[g]chrysene
(30b). Procedure 3 from 26b: Flash chromatography (hexanes/
Et2O 99:1) yielded the title compound (10 mg, 76%) as a colorless oil;
1H NMR (400 MHz, CDCl3) major regioisomer δ 7.78 (d, J = 7.4 Hz,
1H), 7.49−7.16 (m, 8H), 6.94−6.92 (m, 1H), 6.71 (d, J = 2.7 Hz,
1H), 4.21 (d, J = 5.1 Hz, 1H), 3.83 (s, 3H), 3.18−3.13 (m, 1H), 3.01−
2.84 (m, 2H), 1.92−1.75 (m, 2H); minor regioisomer (selected signals)
δ 7.67 (dd, J = 7.4, 1.6 Hz, 1H), 6.85 (td, J = 7.1, 7.1, 2.2 Hz, 1H), 6.68
(d, J = 2.3 Hz, 1H), 4.64 (d, J = 5.5 Hz, 1H), 3.93 (s, 3H), 3.40−3.37
(m, 1H), 2.82−2.73 (m, 2H), 2.44−2.39 (m, 1H); 13C NMR (100
MHz, CDCl3) major regioisomer δ 158.6, 136.4, 134.5, 131.4, 131.0,
129.7, 128.5, 128.1, 128.0, 128.0, 127.3, 126.7, 125.6, 125.3, 125.2,
123.1, 110.0, 109.3, 55.4, 35.7, 34.9, 28.5, 24.5; minor regioisomer
(selected signals) δ 117.3, 112.4, 55.7, 41.9, 39.6, 24.8, 23.7; IR (NaCl)
3418, 2926, 2849, 1642, 1490, 1464, 1253, 1218, 1044, 1023, 751, 741
cm−1; HRMS (EI) calcd for C23H24NO [M + NH4 ] 330.1858; found
+
330.1858.
(1R,2S)-2-([1,1′-Biphenyl]-2-yl)-6,7-dimethoxy-1,2-dihydronaph-
thalen-1-ol (25c). Procedure 4 from 24a: Flash chromatography
9041
dx.doi.org/10.1021/jo201781x|J. Org. Chem. 2011, 76, 9031−9045

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Article
(hexanes/EtOAc 7:3) yielded the title compound (141 mg, 20%) as a
colorless solid, mp 63−65 °C; H NMR (400 MHz, CDCl3) δ 7.47−
then dried (MgSO4) and concentrated under reduced pressure, and
the ensuing residue was subjected to flash chromatography (hexane/
EtOAc 9:1, Rf = 0.31 in EtOAc/hexane 85:15) to afford the title
1
7.24 (m, 9H), 6.80 (s, 1H), 6.67 (s, 1H), 6.55 (dd, J = 9.6, 2.4 Hz,
1H), 5.95 (dd, J = 9.6, 3.3 Hz, 1H), 4.52 (t, J = 5.8 Hz, 1H), 4.13−4.06
(m, 1H), 3.88 (s, 1H), 3.86 (s, 1H), 1.44 (d, J = 6.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 148.7, 143.0, 141.6, 136.7, 130.5, 129.7,
129.4, 129.1, 128.4, 127.9, 127.3, 127.2, 127.1, 125.5, 111.3, 110.1,
70.4, 56.2, 56.2, 43.3; IR (NaCl) 3515, 2001, 2956, 2935, 2835, 2359,
2340, 1605, 1512, 1478, 1463, 1452, 1288, 1266, 1211, 1168, 115,
1071, 1027, 909, 861, 775 cm−1; HRMS (EI) calcd for C24H20O2 [M−
H2O]+: 340.1463; found 340.1479.
1
compound (674 mg, quant) as a colorless solid, mp 48−50 °C: H
NMR (400 MHz, CDCl3) δ 7.39−7.08 (m, 9H), 4.68 (s, 1H), 2.94−
2.65 (m, 4H), 2.12−1.89 (m, 1H), 1.86−1.64 (m, 4H), 1.44 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 142.7, 138.7, 137.2, 130.2, 129.2,
128.6, 128.5, 128.1, 126.3, 125.9, 70.0, 39.1, 33.5, 33.4, 29.3, 23.1; IR
(NaCl) 3364, 3024, 2926, 2859, 2361, 2341, 1603, 1496, 1454, 1431,
1102, 1080, 968, 941, 902, 775, 739, 698, 668 cm-1; HRMS (EI) calcd
for C18H20O [M+] 252.1514; found 252.1507; [α]D = +57.0 (c 1.0,
28
(1R,2S)-2-([1,1′-Biphenyl]-2-yl)-6,7-dimethoxy-1,2,3,4-tetrahydro-
naphthalen-1-ol (26c). Procedure 1 from 25c: Flash chromatog-
raphy (hexane/EtOAc 7:3, Rf = 0.15 in EtOAc/hexane 7:3) to afford
the title compound (119 mg, quant) as a colorless solid, mp 63−
65 °C; 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 7.8, 1.3 Hz, 1H),
7.45−7.22 (m, 8H), 6.70 (s, 1H), 6.57 (s, 1H), 4.39 (s, 1H), 3.83 (d,
J = 1.4 Hz, 6H), 3.28 (dt, J = 12.8, 2.8 Hz, 1H), 2.85 (ddd, J = 16.5,
5.1, 2.2 Hz, 1H), 2.75−2.62 (m, 1H), 2.43−2.32 (m, 1H), 1.88−1.79
(m, 1H), 1.55 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 149.0, 142.7,
141.9, 140.0, 130.7, 130.0, 129.7, 129.3, 129.1, 128.5, 128.4, 128.3,
127.8, 127.2, 126.5, 113.0, 111.4, 77.6, 77.2, 76.9, 69.8, 56.2, 56.1, 42.0,
29.7, 23.2; IR (NaCl) 3441, 2921, 2851, 2361, 2341, 1643, 1515, 1463,
CHCl3) for 84% ee, as determined by HPLC analysis (Chiralcel ADH,
2% iPrOH/hexane, 1.00 mL/min, 210 nm); tR = 30.14 min [major],
tR = 31.75 min [minor].
(6aS,12bS)-5,6,6a,7,8,12b-Hexahydrobenzo[c]phenanthrene
(31a). Procedure 3 from 29a: Flash chromatography (pentane/
Et2O 99:1 to 98:2, Rf = 0.69 in hexanes/EtOAc 95:5) to afford the title
1
compound (68 mg, 97%) as a white solid, mp 52−53 °C; H NMR
(400 MHz, CDCl3) δ 7.22−7.05 (m, 8H), 3.99 (d, J = 5.2 Hz, 1H),
2.90−2.76 (m, 4H), 2.47−2.36 (m, 1H), 1.98 (td, J = 11.2, 5.6 Hz,
2H), 1.55 (dq, J = 13.0, 8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
139.0, 137.6, 130.0, 128.7, 126.1, 125.4, 43.0, 32.5, 28.2, 27.4; IR
(NaCl) 3059, 3016, 1924, 2858, 2361, 1489, 1449, 786, 748 cm−1
;
1338, 1230, 1164, 1122, 1019 756, 703, 679, 678, 659, 651 cm−1
;
HRMS (EI) calcd for C18H18 [M+] 234.1409; found 234.1411;
HRMS (ESI) calcd for C24H24O3Na [M + Na]+: 383.1617; found
363.1617; [α]D28 = −50.0 (c 1.0, CHCl3) for 84% ee, as determined by
HPLC analysis (Chiralcel ADH, 15% iPrOH/hexane, 1.00 mL/min,
254 nm); tR = 17.39 min [minor], tR = 31.00 min [major].
26
[α]D = +207.1 (c 0.5, CHCl3) for 80% ee, as determined by HPLC
analysis (Chiralcel ODH, 1% iPrOH/hexane, 1.00 mL/min, 254 nm);
tR = 6.47 min [major], tR = 7.14 min [minor].
(1S,2S)-2-((E)-3-Fluorostyryl)-1,2-dihydronaphthalen-1-ol
(28b). Procedure 4 from (E)-3-Fluorostyrylboronic Acid: Flash
chromatography (pentane/EtOAc 9:1) yielded the title compound
(4bR,10bR)-8,9-Dimethoxy-4b,5,6,10b-tetrahydrobenzo[g]-
chrysene (30c). Procedure 2 from 26c: Flash chromatography
(hexanes to hexanes/EtOAC 9:1, Rf = 0.37 in hexanes/EtOAc 95:5)
yielded the title compound (40 mg, 58%) as a white solid, mp 68−70
°C; 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H), 7.76 (dd,
J = 7.7, 1.2 Hz, 1H), 7.38−7.24 (m, 5H), 7.16 (td, J = 7.5, 1.2 Hz, 1H),
6.93 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 6.68 (s, 1H), 4.19 (d, J = 4.9
Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 3.19−3.10 (m, 1H), 2.90 (ddd,
J = 17.8, 10.6, 7.4 Hz, 1H), 2.75 (ddd, J = 17.1, 6.6, 2.3 Hz, 1H), 1.92−
1.69 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 148.1, 146.9, 139.0,
133.4, 128.7, 128.4, 128.1, 127.8, 127.4, 126.9, 124.0, 123.9, 114.2,
112.3, 56.2, 56.0, 42.4, 39.9, 28.3, 24.6; IR (NaCl) 2997, 2931, 2855,
2253, 1512, 1452, 1235 cm−1; HRMS (ESI) calcd for C24H23O2 [M +
H+] 343.1692; found 343.1702; [α]D28 = +153 (c 1.0, CHCl3) for 88%
ee, as determined by HPLC analysis (Chiralcel ADH, 1% iPrOH/
hexane, 1.00 mL/min, 254 nm); tR = 23.71 min [major], tR = 30.42
min [minor].
1
(88.8 mg, 75%) as white crystalline needles, mp 171−173 °C; H
NMR (400 MHz, CDCl3) δ 7.46−7.44 (m, 1H), 7.31−7.27 (m, 2H),
7.25−7.21 (m, 1H), 7.15−7.10 (m, 2H), 7.06−7.06 (m, 1H), 6.93−
6.88 (m, 1H), 6.61 (d, J = 15.8 Hz, 1H), 6.58 (dd, J = 9.4, 1.6 Hz, 1H),
6.19 (dd, J = 15.8, 8.6 Hz, 1H), 5.99 (dd, J = 9.4, 4.7 Hz, 1H), 4.92
(dd, J = 8.6, 5.5 Hz, 1H), 3.34 (ddd, J = 8.6, 5.5, 4.7 Hz, 1H), 1.76 (d,
J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 164.3, 136.8, 132.9,
132.4, 129.9, 128.6, 128.2, 128.1, 127.9, 237.7, 126.5, 114.5, 114.3,
112.9, 112.7, 70.8, 45.2; IR (NaCl) 3365, 3033, 1607, 1583, 1485,
1446, 1143, 779, 685 cm−1; HRMS (ESI) calcd for C18H15FO [M +
+
26
NH4 ] 284.1451; found 284.1451; [α]D = +117 (c 1.1, CHCl3) for
89% ee, as determined by HPLC analysis (Chiralcel ADH, 2% iPrOH/
hexane, 1.00 mL/min, 254 nm); tR = 4.53 min [major], tR = 7.61 min
[minor].
(1S,2S)-2-(3-Fluorophenethyl)-1,2,3,4-tetrahydronaphthalen-1-ol
(29b). Procedure 6 from 28b: Flash chromatography (pentane/
EtOAc 9:1, Rf = 0.55 in pentane/EtOAc 9:1) yielded the title
compound (61.8 mg, 82%) as a brown oil; 1H NMR (400 MHz,
CDCl3) δ 7.37−7.35 (m, 1H), 7.26−7.21 (m, 3H), 7.15−7.13 (m,
1H), 6.96 (dt, J = 10.1, 2.3 Hz, 1H), 6.88 (td, J = 8.5, 2.6 Hz, 1H),
4.69 (app. s, 1H), 2.92−2.73 (m, 4H), 2.02−1.97 (m, 1H), 1.82−1.72
(m, 4H); 13C NMR (100 MHz, CDCl3) δ 145.2, 138.5, 130.0, 129.7,
129.7, 129.1, 128.0, 126.2, 124.1, 115.3, 115.1, 112.5, 69.8, 38.9, 33.1,
33.0, 29.1, 22.9; IR (NaCl) 2927, 1588, 1488, 1452, 1254, 1159, 1139,
781, 75, 691, 590 cm−1; HRMS (ESI) calcd for C18H19FO [M+]
(1R,2R)-2-((E)-Styryl)-1,2-dihydronaphthalen-1-ol (28a). Proce-
dure 4 from (E)-Styrylboronic Acid: Flash chromatography (hexanes/
EtOAc 95:5 to 9:1) yielded the title compound (730 mg, 84%) as a
1
white solid, mp 93−97 °C; H NMR (400 MHz, CDCl3) δ 7.45 (dd,
J = 5.6, 3.0 Hz, 1H), 7.39−7.32 (m, 2H), 7.31−7.24 (m, 4H), 7.24−
7.18 (m, 1H), 7.13 (dd, J = 5.7, 3.1 Hz, 1H), 6.65 (d, J = 15.9 Hz, 1H),
6.58 (d, J = 9.6 Hz, 1H), 6.15 (dd, J = 15.9, 8.9 Hz, 1H), 6.01 (dd,
J = 9.5, 4.7 Hz, 1H), 4.92 (dd, J = 8.8, 5.8 Hz, 1H), 3.34 (dt, J = 9.2,
5.7 Hz, 1H), 1.81 (d, J = 8.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
137.1, 137.0, 134.4, 132.7, 129.1, 128.7, 128.2, 128.1, 127.9, 127.8,
126.6, 126.5, 126.1, 126.1, 70.9, 45.4; IR (NaCl) 3410, 3027, 2917,
2361, 2338, 1651, 1574, 1543, 1489, 1451, 1379, 1051, 966, 787, 748
cm−1; HRMS (EI) calcd for C18H16O [M+] 248.1201; found 248.1199;
26
270.1420; found 270.1420; [α]D = −66.0 (c 0.3, CHCl3).
(6aR,12bS)-3-Fluoro-5,6,6a,7,8,12b-hexahydrobenzo[c]-
phenanthrene (31b). Procedure 3 from 29b: Flash chromatog-
raphy (pentane/toluene 98:2, Rf = 0.63 in pentane/toluene 98:2)
yielded the title compound (29.3 mg, 61%) as a colorless oil; 1H NMR
(400 MHz, CDCl3) δ 7.21−7.11 (m, 3H), 7.05−6.99 (m, 2H), 6.88−
6.79 (m, 2H), 3.93 (d, J = 5.0 Hz, 1H), 2.84−2.78 (m, 4H), 2.43−2.34
(m, 1H), 2.02−1.90 (m, 2H), 1.58−1.46 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 162.7, 139.7, 138.9, 127.6, 124.7, 131.3, 129.9, 128.9,
126.4, 125.6, 115.2, 112.3, 42.5, 32.6, 28.4, 28.2, 27.3, 27.1; IR (NaCl)
28
[α]D = −35.5 (c 1.1, CHCl3) for 84% ee, as determined by HPLC
analysis (Chiralcel ADH, 2% iPrOH/hexane, 1.00 mL/min, 254 nm);
tR = 32.11 min [minor], tR = 33.64 min [major].
Representative Procedure 6 for the Reduction of Alkenyl-
boronic Acid Ring-Opened Products. (1R,2R)-2-Phenethyl-
1,2,3,4-tetrahydronaphthalen-1-ol (29a). A magnetically stirred
solution of the alkene 28a (638 mg, 2.57 mmol) in THF (44 mL)
and H2O (44 mL) was treated with tosylhydrazine (4.78 g, 25.7
mmol) and sodium acetate (4.21 g, 51.4 mmol), and the resulting
mixture was heated to reflux for 20 h. The mixture was then cooled to
rt, treated with saturated K2CO3 solution, and the separated aqueous
phase extracted with ether (3×). The combined organic layers were
2923. 2854, 2359, 2330, 2322, 2312, 1491, 867, 773, 742, 676 cm−1
;
HRMS (EI) calcd for C18H17F [M+] 252.1314; found 252.1309;
27
[α]D = −14.9 (c 1.0, CHCl3) for 92% ee, as determined by HPLC
analysis (Chiralcel ODH, 2% iPrOH/hexane, 1.00 mL/min, 254 nm);
tR = 3.41 min [minor], tR = 7.66 min [major].
9042
dx.doi.org/10.1021/jo201781x|J. Org. Chem. 2011, 76, 9031−9045

The Journal of Organic Chemistry
Article
(1R,2S)-2-((E)-2-(Thiophen-3-yl)vinyl)-1,2-dihydronaphthalen-1-
ol (28c). Procedure 4 from (E)-4,4,5,5-Tetramethyl-2-(2-(thio-
phen-3-yl)vinyl)-1,3,2-dioxaborolane: Column chromatography
(pentane/EtOAc 9:1, Rf = 0.45 in pentane/EtOAc 9:1) yielded the
740, 593, 584 cm−1; HRMS (ESI) calcd for C20H23O2 [M − OH]+
26
295.1698; found 295.1692; [α]D = +26.9 (c 0.3, CHCl3).
(6aS,12bR)-1,3-Dimethoxy-5,6,6a,7,8,12b-hexahydrobenzo[c]-
phenanthrene (31d). Procedure 3 from 29d: Column chromatog-
raphy (pentane/Et2O 95:5, Rf = 0.25 in pentane/Et2O 95:5) yielded
1
title compound (375 mg, quant) as a yellow oil; H NMR (400 MHz,
1
CDCl3) δ 7.47−7.42 (m, 1H), 7.29−7.26 (m, 1H), 7.24−7.22 (m,
1H), 7.17−7.15 (m, 1H), 7.14−7.12 (m, 1H), 6.66 (d, J = 15.8 Hz,
1H), 6.56 (dd, J = 9.5, 1.5 Hz, 1H), 6.03−5.95 (m, 2H), 4.90 (dd,
the title compound (20 mg, 97%) as a colorless oil; H NMR (400
MHz, CDCl3) major diastereomer δ 7.10−6.98 (m, 3H), 6.66 (d,
J = 7.4 Hz, 1H), 6.39 (d, J = 2.7 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H0,
4.16 (d, J = 5.5 Hz, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 2.85−2.76 (m,
3H), 2.73−2.66 (m, 1H), 2.33−2.19 (m, 2H), 1.55−1.37 (m, 3H);
minor diastereomer (selected signals) δ 7.15−6.98 (m, 3H), 6.67 (d,
J = 7.4, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 3.59
(d, J = 9.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) major diastereomer
δ 158.9, 139.8, 139.1, 137.4, 128.2, 127.5, 125.5, 125.3, 120.4, 104.5,
95.8, 55.3, 55.2, 36.1, 32.5, 30.0, 28.8, 26.7, 25.7; minor diastereomer
(selected signals) δ 140.5, 134.2, 130.9, 127.6, 123.4, 103.6, 33.4, 29.1,
28.6, 27.0; IR (NaCl) 3401, 2925, 2850, 2364, 2331, 1656, 1417, 1365,
1044, 850, 832, 668, 592, 577 cm−1; HRMS (ESI) calcd for C20H23O2
[M + H]+ 295.1704; found 295.1704; [α]D26 = +2.9 (c 1.0, CHCl3) for
81% ee, as determined by HPLC analysis (Chiralcel ODH, 1% iPrOH/
hexane, 0.80 mL/min, 254 nm); tR = 7.09 min [major], tR = 9.48 min
[minor].
J = 8.7, 5.8 Hz, 1H), 3.33−3.26 (m, 1H), 1.79 (d, J = 9.0 Hz, 1H); 13
C
NMR (100 MHz, CDCl3) δ 139.5, 136.9, 128.9, 128.4, 128.02, 127.94,
127.6, 126.7, 126.4, 126.0, 125.7, 125.0, 122.0, 119.3, 70.8, 45.1; IR
(NaCl) 3396, 3095, 3032, 1385, 1246, 1156, 1049, 963, 788, 766
cm−1; HRMS (ESI) calcd for C16H13S [M−H2O]+: 237.0738; found
28
237.0738; [α]D = −165 (c 1.0, CHCl3) for 93% ee, as determined
by HPLC analysis (Chiralcel ADH, 1% iPrOH/hexane, 1.00 mL/min,
254 nm); tR = 3.67 min [minor], tR = 12.51 min [major].
(1R,2S)-2-(2-(Thiophen-3-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-
1-ol (29c). Procedure 1 from 28c: Column chromatography
(hexanes/EtOAc 95:5 to 9:1, Rf = 0.62 in hexanes/EtOAc 9:1)
1
yielded the title compound (24.1 mg, 69%) as a yellow oil; H NMR
(400 MHz, CDCl3) δ 7.36−7.34 (m, 1H), 7.25−7.19 (m, 3H), 7.17−
7.16 (m, 1H), 4.69 (d, J = 5.9 Hz, 1H), 2.91−2.72 (m, 4H), 2.02−1.97
(m, 1H), 1.92−1.73 (m, 4H), 1.41 (d, J = 5.9 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 139.1, 133.3, 126.3, 125.4, 124.5, 124.3, 123.0, 122.5,
121.6, 116.3, 115.6, 66.2, 32.3, 25.4, 24.0, 19.2; IR (NaCl) 3408, 2926,
(1S,2S)-2-((E)-3-Methoxystyryl)-1,2-dihydronaphthalen-1-ol
(28e). Procedure 4 from (E)-3-Methoxystyrylboronic Acid: Flash
chromatography (pentane/EtOAc 4:1, Rf = 0.21 in pentane/EtOAc
9:1) yielded the title compound (214 mg, 96%) as yellow powder, mp
75−78 °C; 1H NMR (400 MHz, CDCl3) δ 7.73 −7.41 (m, 1H), 7.28−
7.22 (m, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.12−7.09 (m, 1H), 6.92 (d,
J = 7.4 Hz, 1H), 6.87−6.86 (m, 1H), 6.77 −6.75 (m, 1H), 6.61−6.54
(m, 2H), 6.14 (dd, J = 16.0, 9.0 Hz, 1H), 5.97 (dd, J = 9.6, 4.5 Hz,
1H), 4.88 (dd, J = 7.8, 5.9 Hz, 1H), 3.76 (s, 3H), 3.33−3.28 (m, 1H),
1.97 (s, br, 1H); 13C NMR (100 MHz, CDCl3) δ 159.7, 138.2, 136.8,
133.4, 132.4, 129.4, 128.8, 128.0, 127.9, 126.3, 125.9, 119.0, 113.2,
111.6, 70.6, 55.2, 45.1; IR (NaCl) 3433, 3061, 3029, 2956, 2915, 2834,
2360, 1597, 1579, 1486, 1262, 1155, 1046, 969, 788, 769 cm−1; HRMS
(ESI) calcd for C19H16O [M − H2O]+ 260.1201; found 261.1271;
2857, 1455, 1262, 1155, 1099, 1062, 942, 904, 773, 758, 740 cm−1
;
HRMS (ESI) calcd for C16H22NOS [M + NH4]+ 276.1422; found
27
276.1432; [α]D = −8.2 (c 0.5, CHCl3).
(5aS,11bR)-4,5,5a,6,7,11b-Hexahydrophenanthro[4,3-b]-
thiophene (31c). Procedure 3 from 30a: Flash chromatography
yielded the title compound (pentane/toluene 95:5) yielded the title
1
compound (12.3 mg, 87%) as a colorless oil; H NMR (400 MHz,
CDCl3) δ 7.45 (d, J = 7.0 Hz, 1H), 7.23−7.15 (m, 2H), 7.11−7.09 (m,
1H), 7.05 (dd, J = 5.1, 0.8 Hz, 1H), 6.76 (d, J = 5.1 Hz, 1H), 4.18 (d,
J = 4.7 Hz, 1H), 2.86−2.82 (m, 2H), 2.71−2.67 (m, 2H), 2.38 (ddd,
J = 10.0, 4.7, 3.3 Hz, 1H), 2.05−1.88 (m, 2H), 1.85−1.72 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 139.3, 138.5, 133.61, 129.5, 129.1,
127.7, 126.7, 126.6, 125.7, 122.6, 40.7, 33.6, 29.0, 28.0, 23.7, 22.3; IR
(NaCl) 2922, 2887, 2854, 2841, 2366, 2321, 1612, 1493, 1451, 1339,
742, 703 cm−1; HRMS (ESI) calcd for C16H17S [M + H]+ 241.1051;
29
[α]D = +271 (c 0.3, CHCl3) for 78% ee, as determined by HPLC
analysis (Chiralcel ADH, 5% iPrOH/hexane, 1.00 mL/min, 254 nm);
tR = 23.68 min [major], tR = 25.33 min [minor].
(1S,2S)-2-(3-Methoxyphenethyl)-1,2,3,4-tetrahydronaphthalen-
1-ol (29e). Procedure 1 from 28e: Column chromatography
(hexanes/EtOAc 9:1, Rf = 0.37 in hexanes/EtOAc 9:1) yielded the
28
found 241.1051; [α]D = +46 (c 0.5, CHCl3) for 97% ee, as
determined by HPLC analysis (Chiralcel ODH, 0.5% iPrOH/hexane,
1.00 mL/min, 254 nm); tR = 6.29 min [major], tR = 6.99 min [minor].
(1R,2R)-2-((E)-3,5-Dimethoxystyryl)-1,2-dihydronaphthalen-1-ol
(28d). Procedure 4 from (E)-2-(3,5-Dimethoxystyryl)-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane: Column chromatography (pentane/
1
title compound (89 mg, 66%) as a yellow oil; H NMR (400 MHz,
CDCl3) δ 7.35−7.33 (m, 1H), 7.22−7.18 (m, 3H), 7.13−7.11 (m,
1H), 6.85 (d, J = 7.4 Hz, 1H), 6.79−6.78 (m, 1H), 6.73 (dt, J = 8.2, 1.4
Hz, 1H), 4.67 (d, J = 4.7 Hz, 1H), 3.86 (s, 3H), 2.91−2.71 (m, 4H),
2.98 (dt, J = 8.9, 6.7 Hz, 1H), 1.82−1.72 (m, 4H), 1.42 (d, J = 5.9 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 159.7, 144.26, 138.6, 137.0,
130.0, 129.3, 128.0, 126.2, 120.9, 114.2, 111.0, 69.9, 55.2, 38.9, 33.3,
29.2, 22.9; IR (NaCl) 3387, 2928, 2858, 2358, 1584, 1488, 1452, 1428,
1314, 1259, 1151, 1041, 969, 941, 871, 773, 738, 695 cm−1; HRMS
(ESI) calcd for C19H29NO2 [M + NH4]+ 300.1964; found 300.1964;
1
EtOAc 4:1, Rf = 0.45 in pentane/EtOAc 7:3); H NMR (400 MHz,
CDCl3) δ 7.46−7.44 (m, 1H), 7.30−7.25 (m, 2H), 7.14−7.12 (m,
1H), 6.60−6.56 (m, 2H), 6.50 (d, J = 2.0 Hz, 2H), 6.35 (t, J = 2.3 Hz,
1H), 6.15 (dd, J = 15.7, 9.0 Hz, 1H), 5.99 (dd, J = 9.4, 4.7 Hz, 1H),
4.90 (dd, J = 8.6, 5.9 Hz, 1H), 3.77 (s, 3H), 3.36−3.31 (m, 1H), 1.81
(d, J = 8.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 160.9, 138.8,
136.9, 134.2, 132.5, 128.8, 128.1, 128.0, 127.7, 126.6, 126.4, 126.0,
104.5, 99.9, 70.7, 55.4, 45.2; IR (NaCl) 3447, 2359, 2340, 1591, 1577,
1569, 1559, 1539, 1457, 1424, 1205, 1152, 1065, 800 cm−1; HRMS
(ESI) calcd for C20H21O3 [M + H+] 309.1503; found 309.1503;
26
[α]D = +57.3 (c 0.5, CHCl3).
(6aR,12bS)-3-Methoxy-5,6,6a,7,8,12b-hexahydrobenzo[c]-
phenanthrene (31e). Procedure 3 from 29e: Filtration through a
silica plug provided the title compound (41.1 mg, quant) as a colorless
1
oil; H NMR (400 MHz, CDCl3) δ 7.14−7.09 (m, 3H), 7.06−7.04
28
[α]D = −109 (c 0.3, CHCl3) for 80% ee, as determined by HPLC
(m, 1H), 6.99−6.97 (m, 1H), 6.70−6.68 (m, 2H), 3.90 (d, J = 5.1 Hz,
1H), 3.78 (s, 3H), 2.81−2.76 (m, 4H), 2.36 (tq, J = 8.3, 5.0 Hz, 1H),
1.99−1.87 (m, 2H), 1.57−1.48 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 158.0, 139.5, 138.8, 137.7, 131.1, 130.0, 128.7, 126.1, 125.5,
113.8, 111.4, 55.4, 42.3, 32.8, 28.6, 27.4; IR (NaCl) 3418, 2925, 2858,
1609, 1496, 1454, 1254, 1153, 1042, 743 cm−1; HRMS (ESI) calcd for
analysis (Chiralcel ADH, 8% iPrOH/hexane, 1.00 mL/min, 254 nm);
tR = 22.59 min [minor], tR = 32.34 min [major].
(1R,2R)-2-(3,5-Dimethoxyphenethyl)-1,2,3,4-tetrahydronaphtha-
len-1-ol (29d). Procedure 1 from 28d: Column chromatography
(pentane/EtOAc 9:1) yielded the title compound (45 mg, 49%) as a
brown oil; 1H NMR (400 MHz, CDCl3) δ 7.35−7.33 (m, 1H), 7.22−
7.19 (m, 2H), 7.13−7.11 (m, 1H), 6.40 (d, J = 2.3 Hz, 2H), 6.30 (t,
J = 2.2 Hz, 1H), 4.68 (d, J = 2.0 Hz, 1H), 3.78 (s, 6H), 2.91−2.67 (m,
4H), 2.02−1.91 (m, 1H), 1.76−1.73 (m, 4H), 1.65 (d, J = 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 160.8, 138.6, 137.0, 130.0,
129.1, 128.0, 126.2, 108.5, 97.7, 69.9, 55.3, 38.9, 33.6, 33.1, 29.1, 22.9;
IR (NaCl) 3400, 2931, 1606, 1595, 1459, 1428, 1205, 1151, 1058, 773,
C19H21O [M + H]+ 265.1589; found 265.1589; [α]D = −3 (c 0.5,
28
CHCl3) for 75% ee, as determined by HPLC analysis (Chiralcel ODH,
1% iPrOH/hexane, 1.00 mL/min, 254 nm); tR = 6.57 min [minor],
tR = 7.73 min [major].
(1S,2S)-2-((E)-4-Methoxystyryl)-1,2-dihydronaphthalen-1-ol
(28f). Procedure 4 from (E)-3-Methoxystyrylboronic Acid: Flash
chromatography (pentane/EtOAc 9:1, Rf = 0.35 in pentane/EtOAc
9043
dx.doi.org/10.1021/jo201781x|J. Org. Chem. 2011, 76, 9031−9045

The Journal of Organic Chemistry
Article
9:1) yielded the oxabicyclic alkene 4 starting material (18.2 mg, 0.122
7.22−7.12 (m, 3H), 7.09 (dd, J = 5.3, 3.5 Hz, 1H), 6.52 (dd, J = 9.6,
1.1 Hz, 1H), 5.94 (dd, J = 9.6, 4.6 Hz, 1H), 5.92−5.83 (m, 1H), 5.54
(dd, J = 15.3, 8.6 Hz, 1H), 4.81 (dd, J = 8.2, 5.8 Hz, 1H), 3.38 (d,
J = 6.9 Hz, 2H), 3.23−3.11 (m, 1H), 1.77 (d, J = 8.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 140.4, 137.1, 134.3, 132.7, 129.6, 128.6,
128.5, 128.2, 128.0, 127.6, 127.5, 126.5, 126.3, 126.3, 70.7, 44.8, 39.3;
IR (NaCl) 3548, 3426, 3060, 3028, 2900. 2836, 2360, 1602, 1440,
1281, 1189, 1157, 1115, 1075, 1050, 1011, 972, 945, 883, 786, 765,
747, 698 cm−1; HRMS (EI) calcd for C19H18O [M+] 262.1358; found
262.1354; [α]D28 = −72.6 (c 1.0, CHCl3) for 87% ee, as determined by
HPLC analysis (Chiralcel ADH, 2% iPrOH/hexane, 1.00 mL/min,
210 nm); tR = 25.82 min [major], tR = 29.03 min [minor].
mmol), and the title compound (49.7 mg, 0.179 mmol, 54% (92%
1
based on recovered starting material)) as a brown oil; H NMR (400
MHz, CDCl3) δ 7.47−7.45 (m, 1H), 7.29−7.25 (m, 4H), 7.13−7.11
(m, 1H), 6.83−6.81 (m, 2H), 6.62−6.55 (m, 2H), 6.03−5.94 (m, 2H),
4.91 (dd, J = 9.0, 5.9 Hz, 1H), 3.79 (s, 3H), 3.34−3.29 (m, 1H), 1.83
(d, J = 9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.2, 137.0,
133.79, 132.6, 129.6, 129.2, 127.9, 127.9, 127.5, 127.5, 127.4, 126.3,
125.8, 123.3, 114.1, 113.9, 70.6, 55.3, 45.3; IR (NaCl) 3451, 3031,
2955, 2925, 2853, 2836, 2361, 2324, 1615, 1511, 1455, 1377, 1250,
1175, 1035, 968, 823, 787, 675 cm−1; HRMS (ESI) calcd for C19H18O2
[M+] 278.1307; found 278.1313; [α]D = +111 (c 0.5, CHCl3) for
27
(1R,2R)-2-(3-Phenylpropyl)-1,2,3,4-tetrahydronaphthalen-1-ol
(34). Procedure 1 from 33: Flash chromatography (hexane/EtOAc
85:15, Rf = 0.25 in EtOAc/hexane 85:15) to afford the title compound
88% ee, as determined by HPLC analysis (Chiralcel ADH, 5% iPrOH/
hexane, 1.00 mL/min, 254 nm); tR = 4.49 min [minor], tR = 23.76 min
[major].
(1S,2S)-2-(4-Methoxyphenethyl)-1,2,3,4-tetrahydronaphthalen-
1-ol (29f). Procedure 1 from 28f: Flash chromatography (pentane/
EtOAc 9:1) yielded the title compound (67.5 mg, 87%) as a yellow oil;
1H NMR (400 MHz, CDCl3) δ 7.37−7.35 (m, 1H), 7.72−7.13 (m,
1
(128 mg, 92%) as a colorless oil; H NMR (400 MHz, CDCl3) δ
7.37−7.09 (m, 9H), 4.64 (s, 1H), 2.93−2.59 (m, 4H), 1.91−1.62 (m,
6H), 1.53−1.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 142.8,
138.8, 137.2, 130.2, 129.2, 128.6, 128.5, 128.1, 126.3, 125.8, 70.1, 39.7,
36.4, 31.47, 29.4, 29.2, 23.1; IR (NaCl) 3386, 3024, 2929, 2858, 2361,
2341, 1452, 114, 941, 773, 741 cm−1; HRMS (EI) calcd for C19H20
[M − H2O]+ 248.1565; found 248.1563; [α]D28 = +75.5 (c 1.1, CHCl3).
3,3′,4,4′-Tetrahydro-1H,2′H-1,2′-spirobi[naphthalene]
(36). Procedure 2 from 34: Flash chromatography (hexanes to
hexanes/EtOAC 98:2, Rf = 0.74 in hexane/EtOAc 95:5) to afford the
5H), 6.87−6.83 (m, 1H), 4.69 (s, 1H), 3.80 (s, 3H), 2.92−2.73 (m,
4H), 1.99−1.94 (m, 1H), 1.83−1.70 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 157.7, 138.6, 137.0, 124.6, 130.0, 129.2, 129.1, 127.9, 126.1,
113.5, 69.8, 55.2, 38.8, 33.4, 32.4, 29.1, 22.9; IR (NaCl) 3428, 2930,
2860, 1611, 1511, 1454, 1300, 1245, 1177, 1036, 941, 825, 739 cm−1
;
HRMS (ESI) calcd for: C19H21O [M − OH]+ 265.1600; found
1
title compound (38 mg, 75%) as a colorless oil; H NMR (400 MHz,
26
265.1600; [α]D = +57.3 (c 0.5, CHCl3).
CDCl3) δ 7.33 (d, J = 7.7 Hz, 1H), 7.22−7.02 (m, 6H), 3.12 -
(d, J = 16.7 Hz, 1H), 3.02−2.75 (m, 5H), 2.25 (ddd, J = 12.9, 11.7, 6.2
Hz, 1H), 1.88−1.70 (m, 4H), 1.70−1.57 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 145.3, 137.2, 136.7, 135.9, 129.6, 129.3, 128.9, 126.8,
126.2, 125.8, 125.7, 125.7, 43.0, 36.0, 35.7, 32.1, 30.9, 26.6, 19.3; IR
(NaCl) 3059, 3015, 2926, 2862, 2677, 2360, 2341, 1915, 1581, 1489,
1450, 1346, 1292, 1095, 786, 756, 746, 733 cm−1; HRMS (EI) calcd
for C19H20 [M+] 248.1565; found 248.1567. HPLC analysis (Chiralcel
ADH, 1% iPrOH/hexane, 1.00 mL/min, 254 nm); tR = 4.10 min, tR =
4.42 min.
(6aR,12bS)-2-Methoxy-5,6,6a,7,8,12b-hexahydrobenzo[c]-
phenanthrene (31f). Procedure 3 from 29f: Flash chromatography
(pentane/Et2O 99:1) yielded the title compound (10.8 mg, 80%) as a
yellow oil; H NMR (400 MHz, CDCl3) δ 7.17−7.05 (m, 5H), 6.74
1
(dd, J = 8.2, 2.7 Hz, 1H), 6.64 (d, J = 2.7 Hz, 1H), 3.94 (d, J = 5.5 Hz,
1H), 3.74 (s, 3H), 2.83−2.74 (m, 4H), 2.40−2.34 (m, 1H), 1.99−1.91
(m, 2H), 1.56−1.47 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 157.4,
140.1, 138.7, 137.5, 129.8, 129.5, 129.3, 128.6, 126.0, 125.3, 115.4,
111.5, 55.2, 43.1, 32.3, 29.7, 28.1, 27.6, 27.1; IR (NaCl) 2921, 2850,
2360, 2341, 1700, 1612, 1505, 1489, 1447, 1279, 1245, 1152, 1042,
772, 744, 668 cm−1; HRMS (ESI) calcd for: C19H21O [M + H]+
265.1592; found 265.1592; [α]D28 = −3 (c 0.5, CHCl3) for 86% ee, as
determined by HPLC analysis (Chiralcel ODH, 1% iPrOH/hexane,
1.00 mL/min, 254 nm); tR = 6.57 min [minor], tR = 7.73 min [major].
Prop-2-yn-1-ylbenzene. The title compound was synthesized
according to a procedure of Newton and co-workers. 1-Phenylpropyne
(7.55 g, 65.0 mmol) was added, under nitrogen athmosphere, to a
solution of BuLi (1.8 M in hexane, 85 mL, 152 mmol) in dry Et2O
(80 mL) at 0 °C. After stirring at rt for 3 days, the mixture was
quenched by slow addition of water (50 mL) and the separated
organic layer was dried (MgSO4) and concentrated. The residual oil
was purified by distillation in vacuo to afford the title compound
(5.04 g, 67%) as a colorless oil. The characterization data were fully
concordant with that already reported in the literature:22 1H NMR
(400 MHz, CDCl3) δ 7.43−7.18 (m, 5H), 3.61 (d, J = 2.7 Hz, 2H),
2.18 (t, J = 2.7 Hz, 1H).
2,4,6-Tris((E)-3-phenylprop-1-en-1-yl)boroxine (32). BHBr2·SMe2
(1.0 M in CH2Cl2, 12 mL, 12.0 mmol) was added to to a solution of
prop-2-yn-1-ylbenzene in CH2Cl2 (15 mL) at 0 °C. The mixture was
stirred for 2 days at rt, then for 4 h at 60 °C. After cooling to rt, the
mixture was slowly poured into mixture of Et2O (20 mL) and water
(10 mL) at 0 °C and stirred for 1 h. The phases were separated, and
the organic phase was washed with water and brine, dried (MgSO4),
and the solvent was evaporated. The residual oil was subjected to flash
column chromatography (CH2Cl2 to CH2Cl2/Et2O 95:5, Rf = 0.19 in
hexane/EtOAc 1:1) to afford the title compound (361 mg, 25%) as a
colorless oil. The compound could not be obtained in a pure form and
was used without further purification in the next step; HRMS (EI)
calcd for C27H27B3O3 [M+] 432.2239; found 432.2257.
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental methods, reaction procedures, complete
characterization data and copies of H NMR and 13C NMR
1
spectra for compounds 12−36. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mlautens@chem.utoronto.ca.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC), the
Merck and Merck Frosst Center for Therapeutic Research,
and the University of Toronto. We thank Solvias AG for the
generous gift of chiral Josiphos-type ligands as well as initial
support of this study. We also thank Dr. Alan Lough of the
University of Toronto for X-ray analysis. J.T. thanks NSERC
for a graduate scholarship. K.K. and C.L. thanks the Deutsche
Forschungsgemeinschaft (DFG) for a postdoctoral fellowship.
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9044
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The Journal of Organic Chemistry
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(14) Reaction was also tested in a variety of solvents. Performing the
reaction with the same conditions in CH2Cl2 and MeNO2 gave
comparable results (97% yield, 8:1 dr, 6.1 rr in CH2Cl2). However,
while doing concurrent studies in the intramolecular cases, we
discovered that the substrates did not dissolve well in CH2Cl2, hence
all reactions with AlCl3 were done in MeNO2. Performing the reaction
in acetonitrile gave poor selectivities (4.5:1 dr, 4.6:1 rr), and the
reaction did not yield any of the desired product when done in 1,4-
dioxane.
(15) Reaction with furan, 2-methylfuran, and benzofuran led to
unidentified products, whereas reaction with silyl enol ethers, 2,4-
pentanedione, and 1,3-cyclohexanedione led predominantly to the
elimination product.
(16) Asymmetric ring opening of oxabicyclic alkene 4 with ethylene
glycol protected boronic esters 24 required elevated temperatures to
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