Enantioselective syntheses of spiroketals via a tandem reaction of Cu(I)-catalyzed cycloetherification and hydrogen-bond-induced [4 + 2] cyclization

Article abstract of DOI:10.1021/acs.joc.5b00384

A tandem reaction consisting of a copper(I)-catalyzed cycloetherification and a hydrogen-bond-induced inverse-electron-demand oxa-Diels-Alder cycloaddition was performed from chiral propargyl alcohol, generating several kinds of optically pure [5, 6] spir

Full text of DOI:10.1021/acs.joc.5b00384

Note
pubs.acs.org/joc
Enantioselective Syntheses of Spiroketals via a Tandem Reaction of
Cu(I)-Catalyzed Cycloetherification and Hydrogen-Bond-Induced
[4 + 2] Cyclization
Tian Tian, Liqi Li, Jijun Xue,* Jie Zhang, and Ying Li*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, Gansu P. R. China
S
* Supporting Information
ABSTRACT: A tandem reaction consisting of a copper(I)-catalyzed cycloetherification and a hydrogen-bond-induced inverse-
electron-demand oxa-Diels−Alder cycloaddition was performed from chiral propargyl alcohol, generating several kinds of
optically pure [5, 6] spiroketals in excellent stereoselectivities and yields. The investigation on mechanism found that the
cyclization prompted by a hydrogen bond not only improved the efficiency but also determined the diastereoselectivity.
(o-QM) with a chiral enol ether.6 Our group has focused on
piroketal moieties are found in a variety of natural
Sproducts, such as rubromycins, berkelic acids, virgatolides,
this field and found a series of efficient methods for the
and papulacandins, and have demonstrated compelling
bioactivity (Figure 1).1
syntheses of racemic spiroketals.7 Although significant progress
has been made in recent years, great demand remains for the
development of efficient methods for the synthesis of chiral
spiroketal centers, especially chiral bisbenzannulated [5, 6] and
[6, 6] spiroketals in natural products.8 In accordance with our
interest in developing synthetic tools for the synthesis of
natural products, we wanted to determine a new and efficient
method for the stereocontrolled synthesis of spiroketals.
Copper, which is a cheap and green catalyst that has been
used to catalyze intramolecular alkyne hydroalkoxylation, was
regarded as one of the most attractive approaches due to its
high atom economy and mild reaction conditions,9 and the
inverse-electron-demand Diels−Alder reaction (IEDDAR), one
of the most useful organic synthesis tools, has attracted
continuous interests from chemists and has been studied
extensively.10 On the basis of these two advantages, we have
previously developed a tandem approach to spiroketals using
copper(I)-catalyzed cycloetherification and IEDDAR cyclo-
addition.11 However, this procedure could only provide racemic
bisbenzannulated spiroketals. To address this problem, we
envisioned an improved entry to chiral spiroketal from chiral
propargyl alcohol. Two to three stereocenters were built in a
Figure 1. Selected natural products containing spiroketal cores
(*configuration unknown).
As spiroketal cores are essential for bioactivity in natural
products and pharmacophores in drug discovery,1,2 construct-
ing spiroketals, especially those with optically pure cores, would
be very useful for the syntheses of natural compounds and
characterization of their chiral centers. Thus, construction of
chiral spiroketals has been widely investigated. Tan and co-
workers reported a systematic stereocontrolled synthesis of
spiroketals using a kinetic spirocyclization reaction of glycal
epoxides.3 Groundbreaking investigations have identified
Brønsted acid-catalyzed asymmetric spiroacetalizations.4 Ding
and co-workers synthesized chiral benzannulated spiroketals
using precious metal Ir as a catalyst.5 Pettus and co-workers
reported the diastereoselective formal synthesis of Berkelic acid
using a hetero Diels−Alder reaction of an o-quinone methide
Received: February 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
one pot reaction, which will be beneficial for natural product
synthesis and derivatization.
Scheme 2. Substrate Scope of Syntheses Compound 4
Our work was initiated with the syntheses of chiral substrate
2a and analogues. Using asymmetric (S)-Me-CBS-catalyzed
reduction, 2a and its analogues could be prepared in excellent
ee values and good yields; configurations were also confirmed
according to the literature.12 Fortunately, when 2b and 3a were
heated in the presence of 5 mol % CuI and 5 mol % PPh3,
desired product 4a formed in more than 97% ee, >20:1 dr ratio,
and 90% yield after a 24 h reaction (Scheme 1). A similar result
Scheme 1. Initial Examination of Enantioselective
a
Spiroketalization in Optimal Conditions
a
Reaction conditions: substrate (0.1 mmol), CuI catalyst (5 mol %),
a
Reaction conditions: substrate (0.1 mmol), CuI catalyst (5 mol %),
PPh3 (5 mol %), CHCl3 (2 mL), 100 °C in a sealed tube for 24 h.
Isolated yields are shown. dr = syn/anti determined via 1H NMR
spectroscopy and HPLC. The ee value was determined via HPLC.
PPh3 (5 mol %), CHCl3 (2 mL), 100 °C in a sealed tube for 24 h.
1
Isolated yields are shown. dr = syn/anti determined via H NMR
b
spectroscopy and HPLC. The ee value was determined via HPLC. 2a:
R1 = H, >99% ee; 2b: R1 = 4-Br, >99% ee; 2c: R1 = 6-OMe, >99% ee.
was found in the reaction of 2a with 5a, which gave 6a in more
than 99% ee, >20:1 dr ratio, and 77% yield (Scheme 1). X-ray
crystallography showed that the relative structures of 4a and 6a
both have syn configurations between the hydroxyl groups and
C−O bond of the pyran ring.13 Because the substrates 2a and
2b have the R-configuration, the spiroketal center was
confirmed accordingly (Scheme 1).
group on the phenyl ring of 2 did not have obvious effect on
the yields, enantio-, or diastereoselectivities (6a and 6b, 6j; 6c
and 6d, Scheme 3). However, when R5 in 5 was 2-OMe, the ee
value was slightly decreased (6c, Scheme 3). More interestingly,
the yield increased when R1 in compound 2 was 4-Br (6f,
Scheme 3); however, compared with 6a, the yield decreased
when R5 was 4-Br (6g, 6h, Scheme 3). Comparing 6d and 6e in
Scheme 3, the position of the methoxyl group shows an effect
on the yield, which may be due to steric hindrance from the
methoxyl group. Similar to 6k, the methyl group on the phenyl
ring of compound 5 also caused the yield to decrease (6m,
Scheme 3). In addition, 6n, the enantiomer of 6a, was
generated from (S)-2a in >20:1 dr with >99% ee,
demonstrating that the reaction could proceed with high
efficiency regardless of whether (R)- or (S)-alcohol 2 was
utilized. Notably, compounds 2 with methoxymethyl group at
R4 could participate in the cycloaddition to afford the desired
three stereo center products in 81 to over 99% ee and 15:1 to
20:1 dr (6o−s, Scheme 3). The yields of 6o−s were controlled
by the steric environment and electronic effects. Compared
with 6t (5% yield), compounds 6o−s have an electron-
donating methoxymethyl group that induces the reaction more
efficiently in the same steric environment. When changing the
substituent from n-pentyl to cyclohexyl, cyclo-etherification
occurred without cycloaddition (6u, Scheme 3). Unfortunately,
when R1 and R5 were 4-Br, the ee value of 6s decreased to
provide only 81% ee. Meanwhile, the crystal structure of 7f was
characterized via X-ray crystallography analysis, and the
structure showed that the methoxymethyl group was in the
cis position to the C−O bond of the furan ring (Scheme 3).15
Thus, on the basis of our hydrogen-bond-induced strategy and
the Alder−Stein principle, the configurations of 6o−u were
With the optimal reaction condition in hand, we con-
sequently investigated the substrate scope. At first, three
propargyl alcohols 2 were explored in reactions with β,γ-
unsaturated-α-keto-ester 3b. In comparison with the results of
4b, the 4e and 4h electron-donating groups with 2 slightly
decreased the yield. When α,β-unsaturated ketone (3a, 3c)
reacted with phenol 2 in optimal conditions, the corresponding
spiroketals were produced in high yields with excellent dr and
ee values; meanwhile, different substituents on alcohol 2 had
little influence on the yield.14 However, the electronic influence
of substrates 3 should be responsible for the difference in yields.
When R2 is COOMe (4b, 4e, 4h, Scheme 2), the reactions are
obviously less efficient and gave lower yields than others. The
configuration of the 4′-position was determined by substrate 3.
When phenyl group and R3 in substrate 3 are in the cis-
configuration, the phenyl group at the 4′-position of product 4
stretched to the back of ground (4a, 4b, 4d, 4e, 4g, 4h, Scheme
2). Otherwise, it stretched to the front of ground (4c, 4f, 4i,
Scheme 2).
Inspired by the excellent result for spiroketal 6a, we
examined the generality of this method. A number of chiral
propargyl alcohols 2 and o-methyleneacetoxyphenols 5 were
utilized in the spiroketalization to afford the corresponding
optical active benzannulated spiroketals in excellent diastereo-
and enantioselectivities (>20:1 dr and >81% ee, Scheme 3),
which indicated high adaptability to variations in the
substituents of the substrates. Compared with 2a, the methoxyl
B
DOI: 10.1021/acs.joc.5b00384
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The Journal of Organic Chemistry
Note
Scheme 3. Substrate Scope of Syntheses Compound 6 and
Structure of Compound 7f
Scheme 4. Overall Approach for the Stereocontrolled
Syntheses of Benzannulated Spiroketals
a
alcohol 2a determined the configuration of the spiroketal chiral
center.
To demonstrate the proposed mechanism, a controlled
experiment was designed and performed under the same
conditions. Using compound ( )-9a with a protected hydroxyl
group as the substrate, a reaction with compound 5b generated
spiroketal 6v in very low yield (5%). After removing the TBS
group of 6v, compound 6w was formed and compared with
1
compound 6c by H NMR and 13C NMR spectra. We found
that 6w is the anti diastereoisomer of 6c, which reflects a
reaction proceeding through an endo orientation on the face
opposite of the TBS group that met the result of another
group.8g The yield is also affected if the hydrogen-bond-
induced process is prevented. Meanwhile, the relative
configuration of 6a showed that the hydroxyl group was in
the syn position to the oxygen atom of the pyran ring. These
results indicate that a hydrogen-bond is a key factor to the
cyclization, which not only induced the syn stereoselectivity,
but also improved the yield (Scheme 5).18
a
Reaction conditions: substrate (0.1 mmol), CuI catalyst (5 mol %),
PPh3 (5 mol %), CHCl3 (2 mL), 100 °C in a sealed tube for 24 h.
Isolated yields are shown. dr = syn/anti determined via 1H NMR
spectroscopy and HPLC. The ee value was determined via HPLC.
b
2a: R1 = H, R4 = H, >99% ee; 2b: R1 = 4-Br, R4 = H, >99% ee; 2c: R1
Scheme 5. Carrying the Reaction with Protected Secondary
Propargyl Alcohol
= 6-OMe, R4 = H, >99% ee; 2d: R1 = H, R4 = CH2OCH3, 98% ee; 2e:
R1 = 6-OMe, R4 = CH2OCH3, >99% ee; 2f: R1 = 4-Br, R4
=
CH2OCH3, 93% ee; 2g: R1 = H, R4 = H, >99% ee; 2h: R1 = 4-OMe,
R4 = H, >99% ee; 2i: R1 = 4-Me, R4 = H, >99% ee.
determined as shown in Scheme 3. It can also be observed that
electronic effects have little influence on the stereoselectivities;
thus, all cases gave excellent ee and dr values.
On the basis of these results, a mechanism was proposed.
Similar to the previous report, the CuI-catalyzed hydro-
alkoxylation formed exocyclic enol ether 7a, which was
subsequently captured by 3a or 8a to form the spiroketal 4d
or 6a.16 Because of the high syn configuration diastereose-
lectivity obtained, we propose that the reaction should proceed
through transition state I or II (Scheme 4).17 Because the
hydrogen-bond interaction between the hydroxy group of 7a
and the carbonyl of 3a or 8a may be responsible for the
stereoselectivity of the IEDDAR stage, the optically pure
CONCLUSION
■
In conclusion, an enantio- and diastereoselective approach
toward various spiroketals was developed that combined Cu(I)-
catalyzed cycloetherification of chiral propargyl alcohols and
hydrogen-bond-induced inverse-electron-demand hetero-
Diels−Alder cycloaddition reaction in one pot. The method
could construct two or three chiral centers in one sequence,
and gave a series of [5, 6] spiroketal cores in excellent
enantioselectivities, diastereoselectivities, and good yields. This
C
DOI: 10.1021/acs.joc.5b00384
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The Journal of Organic Chemistry
Note
is the first method to provide optically pure bisbenzannulated
spiroketal cores of natural products and will be helpful for the
syntheses of rubromycin natural products and other spiroketal
compounds.
concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel to afford 2.
1-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-3-(trimethylsilyl)-
prop-2-yn-1-ol (s1-a). Purified by flash chromatography
(petroleum ether/EtOAc = 16:1). Yield: 2.74 g, 82%, as a
colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.20 (s, 9H), 0.29
(s, 3H), 0.31 (s, 3H), 1.05 (s, 9H), 2.76 (d, J = 5.6, 1H), 5.72
(d, J = 5.6, 1H), 6.84 (d, J = 6, 1H), 7.00 (t, J = 7.6, 1H), 7.22
(td, J = 7.6, 1.6, 1H), 7.59 (dd, J = 7.6, 1.6, 1H). 13C NMR (100
MHz, CDCl3): δ −4.2, −0.2, 18.2, 25.8, 61.2, 90.7, 104.9, 118.3,
121.3, 128.0, 129.3, 130.8, 153.0. IR [vmax, cm−1]: 3434, 2957,
2930, 2858, 1638, 1488, 1252, 917, 841, 757, 663. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C18H30O2Si2Na, 357.1677;
found, 357.1683.
Experimental Section. General Experimental Meth-
ods. All manipulations were conducted with a round-bottom
flask in dry air. All reactions under standard conditions were
monitored by thin-layer chromatography (TLC) on GF254
plates. Silica gel (200−300 meshes) was used for column
chromatography. Unless otherwise noted, commercially avail-
able reagents and solvents were used without any purification.
The distillation range of petro ether was 60−90 °C. DCM was
freshly distilled from CaH2, and THF was dried by distillation
1
over Na/K. H and 13C NMR spectra were recorded at 400/
1-(5-Bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s1-b). Purified by flash chro-
matography (petroleum ether/EtOAc = 16:1). Yield: 3.43 g,
83%, as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.20 (s,
9H), 0.28 (d, J = 6.4, 6H), 1.03 (s, 9H), 2.67 (d, J = 5.6, 1H),
5.64 (d, J = 5.6, 1H), 6.71 (d, J = 8.8, 1H), 7.29−7.32 (dd, J =
8.8, 2.8, 1H), 7.70 (d, J = 2.8, 1H). 13C NMR (100 MHz,
CDCl3 ): δ −4.2, −0.2, 18.2, 25.8, 60.6, 91.4, 104.1, 113.6,
120.0, 130.9, 132.0, 133.0, 152.1. IR [vmax, cm−1]: 3431, 2956,
2929, 2858, 2360, 1479, 1273, 1254, 915, 842, 818, 782, 760,
670, 568. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C18H29BrO2Si2Na, 435.0782; found, 435.0784.
600 (100/150) MHz instruments, respectively, and spectral
data were reported in ppm relative to tetramethylsilane (TMS)
as the internal standard. High-resolution mass spectra (HRMS)
were obtained on a mass spectrometer using electrospray
ionization (ESI) analyzed by quadrupole time-of-flight
(QToF). IR spectra were recorded on an FT-IR spectrometer,
and major peaks were reported in cm−1. Enantiomeric excesses
(ee) were determined by HPLC analysis using the correspond-
ing commercial chiral column as stated. Melting points were
determined on a microscopic apparatus and were uncorrected.
The following abbreviations are used for the multiplicities: s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad
singlet for proton spectra. Coupling constants (J) are reported
in hertz (Hz).
General Procedure for the Syntheses of Propargyl
Alcohols 2. To a solution of corresponding alkyne (11 mmol)
in dry THF (25 mL) was slowly added n-BuLi (12.1 mmol, 2.5
M in THF) at −78 °C under argon. The reaction mixture was
heated to −40 °C and then cooled to −78 °C. A solution of the
corresponding salicylaldehyde (10 mmol in 15 mL of THF)
was added dropwise. The reaction mixture was stirred at −78
°C for 4 h and was then quenched with saturated NH4Cl
solution. The aqueous phase was extracted with EtOAc.
Combined organic layers were washed with brine, dried over
Na2SO4, and evaporated. The residue was purified by flash
chromatography on silica gel to give intermediate product s1
for the next step.
Alcohol s1 (3 mmol) was dissolved in CH2Cl2 (50 mL) at
room temperature (rt); MnO2 (30 mmol) was added, and the
mixture was stirred at rt overnight. Then, the reaction mixture
was filtered through a neutral SiO2 column and washed with
CH2Cl2 (100 mL). The combined organic solution was
concentrated in vacuo to obtain ketone s2 for the next step.
Me-(S)-CBS (1 M in toluene, 0.4 mL, 0.4 mmol) was added
to the solution of ketone s2 (0.8 mmol) in THF (15 mL) at
−30 °C under an argon atmosphere. After the mixture was
stirred for 10 min, BH3·Me2S (2.0 M in THF, 0.96 mmol) was
added dropwise and stirred at −30 °C under an argon
atmosphere for 40 min. CH3OH (0.6 mL) was added followed
by aq NaHCO3. The mixture was extracted by EtOAc, and the
combined extracts were dried (Na2SO4) and concentrated. The
crude product obtained was purified by flash column
chromatography to afford alcohol s3.
1-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxyphenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s1-c). Purified by flash chroma-
tography (petroleum ether/EtOAc = 8:1). Yield: 3.06 g, 84%,
1
as a brown oil. H NMR (400 MHz, CDCl3): δ 0.20 (s, 9H),
0.26 (s, 6H), 1.03 (s, 9H), 3.80 (s, 3H), 5.84 (d, J = 4, 1H),
6.85 (dd, J = 8, 1.6, 1H), 6.96 (t, J = 8, 1H), 7.26 (dd, J = 7.6,
1.6, 1H). 13C NMR (100 MHz, CDCl3 ): δ −4.0, −0.2, 18.9,
26.2, 54.9, 60.5, 91.0, 104.8, 111.6, 119.6, 121.2, 131.6, 142.4,
149.6. IR [vmax, cm−1]: 3423, 2956, 2929, 2857, 1637, 1482,
1252, 912, 841, 782. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C19H32O3Si2Na, 387.1782; found, 387.1786.
1-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-4-methoxybut-
2-yn-1-ol (s1-d). Purified by flash chromatography (petroleum
1
ether/EtOAc = 8:1). Yield 2.45 g, 80%, as a colorless oil. H
NMR (400 MHz, CDCl3): δ 0.30 (d, J = 6.0, 6H), 1.05 (s, 9H),
3.40 (s, 3H), 4.19 (d, J = 1.6, 2H), 5.79 (s, 1H), 6.84 (dd, J =
8.4, 0.8, 1H), 6.97−7.01 (td, J = 7.2, 0.8, 1H), 7.19−7.24 (td, J
= 8, 1.6, 1H), 7.70 (dd, J = 7.6, 2, 1H). 13C NMR (100 MHz,
CDCl3): δ −4.2, 18.2, 25.8, 57.6, 60.0, 60.8, 81.9, 86.1, 118.5,
121.4, 128.0, 129.4, 130.8, 152.9. IR [vmax, cm−1]: 3409, 2955,
2930, 2895, 2858, 1600, 1489, 1454, 1279, 1258, 1097, 921,
840, 807, 783. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C17H26O3SiNa, 329.1543; found, 329.1542.
1-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxyphenyl)-4-
methoxybut-2-yn-1-ol (s1-e). Purified by flash chromatog-
raphy (petroleum ether/EtOAc = 8:1). Yield 2.69 g, 80%, as a
colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.21 (s, 3H), 0.25
(s, 3H), 1.03 (s, 9H), 2.64 (d, J = 4.4, 1H), 3.39 (s, 3H), 3.80
(s, 3H), 4.19 (s, 2H), 5.91 (t, J = 4.4, 1H), 6.84 (dd, J = 8.0, 1.6,
1H), 6.95 (t, J = 8.0, 1H), 7.25 (dd, J = 8, 0.8, 1H). 13C NMR
(100 MHz, CDCl3): δ −3.9, 18.9, 26.1, 54.9, 57.6, 60.0, 81.9,
86.1, 111.6, 119.5, 121.3, 131.7, 142.2, 149.7. IR [vmax, cm−1]:
3417, 2954, 2930, 2900, 2857, 1484, 1301, 1256, 1227, 1086,
918, 840, 783. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C18H28O4SiNa, 359.1649; found, 359.1647.
To a solution of the alcohol s3 (0.5 mmol) in 20 mL dry
THF was added a solution of tetrabutylammonium fluoride
(1.05 mmol, 2.1 equiv) in 5 mL of dry THF at 0 °C. After 1 h,
water (5 mL) was added to the reaction mixture; the aqueous
phase was extracted with ethyl acetate, and the extract was
1-(5-Bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)-4-me-
thoxybut-2-yn-1-ol (s1-f). Purified by flash chromatography
D
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Note
(petroleum ether/EtOAc = 8:1). Yield: 2.92 g, 76%, as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ 0.27 (s, 3H), 0.28 (s, 3H),
1.03 (s, 9H), 2.66 (d, J = 4.2, 1H), 3.40 (s, 3H), 4.18 (s, 2H),
5.72 (d, J = 4.2, 1H), 6.71 (d, J = 8.4, 1H), 7.29−7.32 (dd, J =
8.8, 2.4, 1H), 7.70 (d, J = 2.4, 1H). 13C NMR (100 MHz,
CDCl3): δ −4.2, −4.2, 18.2, 25.7, 57.7, 59.9, 60.0, 82.3, 85.4,
113.6, 120.1, 130.8, 132.1, 133.0, 152.0. IR [vmax, cm−1]: 3406,
2954, 2930, 2893, 2858, 1481, 1272, 1259, 1104, 919, 842, 783.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H25BrO3SiNa,
409.0628; found, 409.0624.
102.7, 115.8, 120.6, 123.8, 129.8, 145.5, 151.3, 177.5. IR [vmax,
cm−1]: 2957, 2851, 2359, 1645, 1457, 1384, 1317, 1254, 1222,
1068, 1027, 905. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C19H31O3Si2, 363.1806; found, 363.1810.
1-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-4-methoxybut-
2-yn-1-one (s2-d). Purified by flash chromatography (petro-
leum ether/EtOAc = 16:1). Yield: 802 mg, 88%, as a colorless
oil. 1H NMR (400 MHz, CDCl3): δ 0.24 (s, 6H), 1.02 (s, 9H),
3.44 (s, 3H), 4.32 (s, 2H), 6.89 (d, J = 8, 1H), 7.02 (t, J = 7.6,
1H), 7.39−7.43 (m, 1H), 7.92−7.95 (dd, J = 8, 2, 1H). 13C
NMR (100 MHz, CDCl3): δ −4.3, 18.4, 25.7, 58.0, 59.8, 86.1,
1-(2-((tert-Butyldimethylsilyl)oxy)-5-methoxyphenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s1-g). Purified by flash chro-
matography (petroleum ether/EtOAc = 8:1). Yield: 3.1 g, 85%,
88.2, 120.9, 121.4, 128.8, 132.7, 134.4, 155.8, 176.7. IR [vmax
,
cm−1]: 2957, 2930, 2900, 2858, 1651, 1597, 1568, 1478, 1287,
1254, 1223, 1157, 1011, 914, 844, 759. HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C17H24O3SiNa, 327.1387; found,
327.1388.
1
as a yellow oil. H NMR (400 MHz, CDCl3): δ 0.20 (s, 9H),
0.27 (d, J = 10, 6H), 1.04 (s, 9H), 2.85 (t, J = 5.2, 1H), 3.79 (s,
3H), 5.68 (d, J = 5.2, 1H), 6.75 (d, J = 1.6, 2H), 7.18 (t, J = 1.6,
1H). 13C NMR (100 MHz, CDCl3): δ −4.2, −0.2, 18.1, 25.8,
55.5, 61.2, 90.9, 104.7, 113.0, 114.7, 119.1, 131.4, 146.7, 153.8.
IR [vmax, cm−1]: 3432, 2360, 1636, 1491, 1275, 1152, 1025.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H33O3Si2,
365.1963; found, 365.1951.
1-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxyphenyl)-4-
methoxybut-2-yn-1-one (s2-e). Purified by flash chromatog-
raphy (petroleum ether/EtOAc = 16:1). Yield: 912 mg, 91%, as
a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.17 (s, 6H), 0.99
(s, 9H), 3.43 (s, 3H), 3.80 (s, 3H), 4.31 (s, 2H), 6.95 (t, J = 8,
1H), 7.00−7.03 (dd, J = 8, 1.6, 1H), 7.44−7.46 (dd, J = 7.6, 1.6,
1H). 13C NMR (100 MHz, CDCl3): δ −4.1, 18.8, 25.7, 55.2,
58.0, 59.8, 86.2, 88.2, 115.9, 120.7, 123.3, 129.8, 145.4, 151.3,
177.1. IR [vmax, cm−1]: 3417, 2954, 2930, 2900, 2857, 1651,
1597, 1568, 1478, 1287, 1254, 1223, 1157, 1011, 918, 840, 783.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C18H26O4SiNa,
357.1493; found, 357.1492.
1-(2-((tert-Butyldimethylsilyl)oxy)-5-methylphenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s1-h). Purified by flash chro-
matography (petroleum ether/EtOAc = 16:1). Yield: 2.96 g,
1
85%, as a brown oil. H NMR (400 MHz, CDCl3): δ 0.20 (s,
9H), 0.29 (d, J = 8.4, 6H), 1.04 (s, 9H), 2.31 (s, 3H), 2.80 (d, J
= 5.6, 1H), 5.67 (d, J = 5.6, 1H), 6.73 (d, J = 8.4, 1H), 6.99−
7.02 (dd, J = 8, 1.2, 1H), 7.32 (d, J = 1.2, 1H). 13C NMR (100
MHz, CDCl3): δ −4.2, −0.2, 18.2, 20.6, 25.8, 61.4, 90.6, 105.0,
118.2, 128.6, 129.7, 130.4, 130.6, 150.7. IR [vmax, cm−1]: 3451,
2957, 2924, 2854, 2360, 1648, 1488, 1252, 1020, 918, 842, 669.
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H33O2Si2,
349.2014; found, 349.2021.
1-(5-Bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)-4-me-
thoxybut-2-yn-1-one (s2-f). Purified by flash chromatography
(petroleum ether/EtOAc = 16:1). Yield: 974 mg, 85%, as a
1
yellow oil. H NMR (400 MHz, CDCl3): δ 0.23 (s, 6H), 1.00
(s, 9H), 3.45 (s, 3H), 4.33 (s, 2H), 6.78 (d, J = 8.8, 1H), 7.48−
7.50 (dd, J = 8.8, 2.4, 1H), 8.00 (d, J = 2.4, 1H). 13C NMR (100
MHz, CDCl3): δ −4.3, 18.4, 25.7, 58.1, 59.8, 85.6, 89.2, 113.0,
123.2, 130.2, 134.8, 137.0, 154.8, 175.3. IR [vmax, cm−1]: 2954,
2930, 2894, 2858, 1657, 1597, 1589, 1471, 1283, 1255, 1217,
1106, 842, 824, 809, 784. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C17H24BrO3Si, 383.0673; found, 383.0669.
1-(2-((tert-Butyldimethylsilyl)oxy)-5-methoxyphenyl)-3-
(trimethylsilyl)prop-2-yn-1-one (s2-g). Purified by flash
chromatography (petroleum ether/EtOAc = 16:1). Yield: 989
mg, 91%, as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.19
(s, 6H), 0.27 (s, 9H), 1.01 (s, 9H), 3.80 (s, 3H), 6.82 (d, J =
8.8, 1H), 6.97−7.00 (dd, J = 8.8, 3.2, 1H), 7.46 (d, J = 3.2, 1H).
13C NMR (100 MHz, CDCl3): δ −4.3, −0.7, 18.4, 25.9, 55.6,
98.6, 102.5, 116.0, 121.1, 122.6, 128.9, 149.7, 153.3, 176.9. IR
[vmax, cm−1]: 2956, 2931, 2900, 2858, 2360, 2149, 1653, 1567,
1489, 1413, 1278, 1253, 1197, 1176, 1042, 1013, 921, 846, 782,
763, 739, 626. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C19H31O3Si2, 363.1806; found, 363.1809.
1-(2-((tert-Butyldimethylsilyl)oxy)-5-methylphenyl)-3-
(trimethylsilyl)prop-2-yn-1-one (s2-h). Purified by flash
chromatography (petroleum ether/EtOAc = 32:1). Yield: 935
mg, 90%, as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.21
(s, 6H), 0.28 (s, 9H), 1.02 (s, 9H), 2.33 (s, 3H), 6.78 (d, J =
8.4, 1H), 7.19−7.22 (td, J = 8.4, 2.0, 1H), 7.73 (d, J = 2.0, 1H).
13C NMR (100 MHz, CDCl3): δ −4.3, −0.7, 18.4, 20.4, 25.8,
98.3, 102.7, 121.3, 128.6, 130.2, 133.0, 135.0, 153.6, 177.3. IR
[vmax, cm−1]: 2957, 2930, 2898, 2858, 2360, 2148, 1651, 1607,
1565, 1490, 1405, 1287, 1254, 1181, 1020, 920, 845, 782, 689,
627, 534. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C19H31O2Si2, 347.1857; found, 347.1862.
1-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-3-(trimethylsilyl)-
prop-2-yn-1-one (s2-a). Purified by flash chromatography
(petroleum ether/EtOAc = 32:1). Yield: 897 mg, 90%, as a
1
brown oil. H NMR (400 MHz, CDCl3): δ 0.24 (s, 6H), 0.28
(s, 9H), 1.03 (s, 9H), 6.89 (d, J = 7.6, 1H), 7.05 (d, J = 7.2,
1H), 7.44 (d, J = 7.6, 1H), 7.97 (d, J = 7.2, 1H). 13C NMR (100
MHz, CDCl3): δ −4.2, −0.7, 18.4, 25.8, 98.3, 102.6, 120.9,
121.5, 129.0, 133.1, 134.2, 155.8, 177.1. IR [vmax, cm−1]: 2957,
2930, 2900, 2858, 1651, 1597, 1568, 1478, 1287, 1254, 1223,
1157, 1011, 914, 844, 759, 697, 625, 548. HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H29O2Si2, 333.1701; found,
333.1713.
1-(5-Bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)-3-
(trimethylsilyl)prop-2-yn-1-one (s2-b). Purified by flash
chromatography (petroleum ether/EtOAc = 32:1). Yield:
1
1.14 g, 92%, as a brown oil. H NMR (400 MHz, CDCl3): δ
0.23 (s, 6H), 0.29 (s, 9H), 1.01 (s, 9H), 6.78 (d, J = 8.8, 1H),
7.48−7.51 (dd, J = 8.8, 2.4, 1H), 8.03 (d, J = 2.4, 1H). 13C
NMR (100 MHz, CDCl3): δ −4.3, −0.8, 18.4, 25.7, 99.7, 102.0,
112.9, 123.2, 130.5, 135.3, 136.8, 154.8, 175.7. IR [vmax, cm−1]:
2955, 2925, 2854, 1656, 1621, 1587, 1466, 1379, 1283, 1253,
1195, 1017, 911, 845, 821, 759, 675. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C18H28BrO2Si2, 411.0806; found, 411.0812.
1-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxyphenyl)-3-
(trimethylsilyl)prop-2-yn-1-one (s2-c). Purified by flash
chromatography (petroleum ether/EtOAc = 16:1). Yield: 989
1
mg, 91%, as a brown oil. H NMR (400 MHz, CDCl3): δ 0.18
(s, 6H), 0.27 (s, 9H), 1.00 (s, 9H), 3.82 (s, 3H), 6.97 (t, J = 8,
1H), 7.02 (dd, J = 8, 1.6, 1H), 7.50 (dd, J = 8, 1.6, 1H). 13C
NMR (100 MHz, CDCl3): δ −4.0, −0.7, 18.9, 25.8, 55.3, 98.4,
E
DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(S)-1-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s3-a). Purified by flash chro-
matography (petroleum ether/EtOAc = 16:1). Yield: 265 mg,
99%, as a colorless oil. [α]2D7 +3 (c 1, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 100:1, 1 mL/min, λ = 254 nm, t
(major) = 16.57 min. All spectroscopic data were consistent
with the racemic compound.
(S)-1-(5-Bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s3-b). Purified by flash chro-
matography (petroleum ether/EtOAc = 8:1). Yield: 307 mg,
93%, as a colorless oil. [α]D27 −18 (c 1, CHCl3). All
spectroscopic data were consistent with the racemic compound.
(S)-1-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxyphenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s3-c). Purified by flash chroma-
tography (petroleum ether/EtOAc = 4:1). Yield: 288 mg, 99%,
as a brown oil. [α]2D6 +12 (c 0.5, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 98:2, 1 mL/min, λ = 254 nm, t
(major) = 8.65 min. All spectroscopic data were consistent with
the racemic compound.
(R)-1-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-4-methoxy-
but-2-yn-1-ol (s3-d). Purified by flash chromatography
(petroleum ether/EtOAc = 4:1). Yield: 235 mg, 96%, as a
colorless oil. [α]D26 −15 (c 1, CHCl3, 98% ee). The
enantiomeric ratio was determined by Daicel Chiralcel OD-H
(25 cm), hexanes/IPA = 98:2, 1 mL/min, λ = 273 nm, t
(major) = 11.56 min, t (minor) = 8.49 min. All spectroscopic
data were consistent with the racemic compound.
(R)-1-(2-((tert-Butyldimethylsilyl)oxy)-3-methoxyphenyl)-
4-methoxybut-2-yn-1-ol (s3-e). Purified by flash chromatog-
raphy (petroleum ether/EtOAc = 4:1). Yield: 263 mg, 98%, as a
colorless oil. [α]2D6 +8 (c 1, CHCl3, >99% ee). The enantiomeric
ratio was determined by Daicel Chiralcel OD-H (25 cm),
hexanes/IPA = 98:2, 1 mL/min, λ = 273 nm, t (major) = 12.97
min. All spectroscopic data were consistent with the racemic
compound.
(R)-1-(5-Bromo-2-((tert-butyldimethylsilyl)oxy)phenyl)-4-
methoxybut-2-yn-1-ol (s3-f). Purified by flash chromatography
(petroleum ether/EtOAc = 8:1). Yield: 295 mg, 96%, as a
colorless oil. [α]1D8 −6 (c 1, CHCl3, 93% ee). The enantiomeric
ratio was determined by Daicel Chiralcel OD-H (25 cm),
hexanes/IPA = 99:1, 0.8 mL/min, λ = 230 nm, t (major) =
21.03 min, t (minor) = 15.19. All spectroscopic data were
consistent with the racemic compound.
(R)-1-(2-((tert-Butyldimethylsilyl)oxy)phenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s3-g). Me-(R)-CBS (1 M in
toluene, 0.4 mL, 0.4 mmol) was added to the solution of ketone
s2-a (0.8 mmol) in THF (15 mL) at −30 °C under an argon
atmosphere. After the mixture was stirred for 10 min, BH3·
Me2S (2.0 M in THF, 0.96 mmol) was added dropwise and
stirred at −30 °C under an argon atmosphere for 40 min.
CH3OH (0.6 mL) was added followed by aq NaHCO3. The
mixture was extracted by EtOAc, and the combined extracts
were dried (Na2SO4) and concentrated. The crude product
obtained was purified by flash column chromatography to
afford alcohol s3-g. Purified by flash chromatography
(petroleum ether/EtOAc = 8:1). Yield: 265 mg, 99%, as a
colorless oil. [α]2D5 −0.77 (c 1.3, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 100:1, 1 mL/min, λ = 254 nm, t
(major) = 18.83 min. All spectroscopic data were consistent
with the racemic compound.
(S)-1-(2-((tert-Butyldimethylsilyl)oxy)-5-methoxyphenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s3-h). Purified by flash chro-
matography (petroleum ether/EtOAc = 8:1). Yield: 277 mg,
95%, as a yellow oil. [α]D26 −5.9 (c 0.17, CHCl3). All
spectroscopic data were consistent with the racemic compound.
(S)-1-(2-((tert-Butyldimethylsilyl)oxy)-5-methylphenyl)-3-
(trimethylsilyl)prop-2-yn-1-ol (s3-i). Purified by flash chroma-
tography (petroleum ether/EtOAc = 8:1). Yield: 276 mg, 99%,
as a brown oil. [α]2D7 −14 (c 1, CHCl3). All spectroscopic data
were consistent with the racemic compound.
(R)-2-(1-Hydroxyprop-2-yn-1-yl)phenol (2a). Purified by
flash chromatography (petroleum ether/EtOAc = 2:1). Yield:
73 mg, 99%, as a colorless oil. 1H NMR (400 MHz, CDCl3): δ
2.77 (d, J = 2, 1H), 5.69 (d, J = 2, 1H), 6.90−6.94 (m, 2H),
7.23−7.25 (dd, J = 7.6, 1.2, 1H), 7.38−7.40 (dd, J = 7.6, 1.2,
1H). [α]2D7 −44 (c 1, CHCl3). All spectroscopic data were
consistent with our previously reported data.11
(R)-4-Bromo-2-(1-hydroxyprop-2-yn-1-yl)phenol (2b). Pu-
rified by flash chromatography (petroleum ether/EtOAc = 2:1).
1
Yield: 109 mg, 96%, as a brown oil. H NMR (400 MHz,
CDCl3): δ 2.81−2.83 (m, 2H), 5.67 (d, J = 4, 1H), 6.81 (d, J =
8, 1H), 7.12 (s, 1H), 7.34−7.37 (dd, J = 8, 4, 1H), 7.52 (d, J =
4, 1H). [α]2D6 +9.2 (c 0.65, CHCl3, >99% ee). The enantiomeric
ratio was determined by Daicel Chiralpak IC (25 cm), hexanes/
IPA = 100:0, 31 min, 99:1, 11 min, 98:2, 10 min. 1 mL/min, λ
= 254 nm, t (major) = 34.57 min. All spectroscopic data were
consistent with our previously reported data.11
(R)-2-(1-Hydroxyprop-2-yn-1-yl)-6-methoxyphenol (2c).
Purified by flash chromatography (petroleum ether/EtOAc =
2:1). Yield: 86 mg, 97%, as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 2.65 (d, J = 2.4, 1H), 3.90 (s, 3H), 5.74 (d, J = 2.4,
1H), 6.86−6.91 (m, 2H), 7.13−7.15 (dd, J = 6.8, 2.4, 1H).
[α]D25 +10 (c 0.2, CHCl3). All spectroscopic data were
consistent with our previously reported data.11
(R)-2-(1-Hydroxy-4-methoxybut-2-yn-1-yl)phenol (2d). To
a solution of the intermediate product (0.5 mmol) in 20 mL
dry THF was added a solution of tetrabutylammonium fluoride
(1.1 equiv) in 5 mL dry THF. After 1 h, water (5 mL) was
added to the reaction mixture; the aqueous phase was extracted
with ethyl acetate, and the extract was concentrated under
reduced pressure. The residue was purified by flash
chromatography on silica gel to afford 2d. Purified by flash
chromatography (petroleum ether/EtOAc = 4:1). Yield: 95 mg,
99%, as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 3.40 (s,
3H), 4.19 (d, J = 1.6, 2H), 5.72 (s, 1H), 6.87−6.91 (m, 2H),
7.20−7.24 (td, J = 7.6, 1.6, 1H), 7.33−7.35 (m, 1H), 7.56 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 57.7, 59.9, 63.5, 83.3,
84.8, 116.9, 120.2, 124.6, 127.6, 130.0, 155.0. IR [vmax, cm−1]:
3322, 2954, 2928, 2852, 1459, 1279, 1238, 1092, 756, 737.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C11H12O3Na,
215.0679; found, 215.0680. [α]2D6 −77 (c 1, CHCl3).
(R)-2-(1-Hydroxy-4-methoxybut-2-yn-1-yl)-6-methoxyphe-
nol (2e). To a solution of the intermediate product (0.5 mmol)
in 20 mL dry THF was added a solution of tetrabutylammo-
nium fluoride (1.1 equiv) in 5 mL dry THF. After 1 h, water (5
mL) was added to the reaction mixture; the aqueous phase was
extracted with ethyl acetate, and the extract was concentrated
under reduced pressure. The residue was purified by flash
chromatography (petroleum ether/EtOAc = 4:1) on silica gel
1
to afford 2e. Yield: 110 mg, 99%, as a colorless oil. H NMR
(400 MHz, CDCl3): δ 3.00 (d, J = 5.6, 1H), 3.41 (s, 3H), 3.90
(s, 3H), 4.20 (d, J = 1.6, 2H), 5.79 (d, J = 3.6, 1H), 6.13 (s,
1H), 6.85−6.90 (m, 2H), 7.12−7.14 (dd, J = 9.6, 3.6, 1H). 13
C
F
DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
NMR (100 MHz, CDCl3): δ 56.0, 57.5, 59.8, 60.8, 81.7, 85.6,
110.9, 119.6, 119.7, 126.1, 143.2, 146.7. IR [vmax, cm−1]: 3382,
2926, 1483, 1275, 1225, 1093, 735. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C12H14O4Na, 245.0784; found, 245.0782.
[α]2D6 −23 (c 1, CHCl3).
(Z)-4-Benzylidene-5-methyl-2-phenyl-2,4-dihydro-3H-pyr-
azol-3-one (3c). Purified by flash chromatography (petroleum
ether/EtOAc = 8:1). Yield: 55%, as a red solid, mp 105−107
°C. 1H NMR (400 MHz, CDCl3): δ 2.36 (s, 3H), 7.20 (t, J = 8,
1H), 7.40−7.45 (m, 3H), 7.50−7.56 (m, 3H), 7.97 (d, J = 8,
2H), 8.50 (d, J = 8, 2H). All spectroscopic data were consistent
with previously reported data.14c
General Procedure for the Syntheses of 5,6-Spiroke-
tals (4). A reaction tube was charged with 2-(1-hydroxyprop-2-
ynyl)phenol 2 (0.1 mmol), α,β-unsaturated keto 3 (0.12
mmol), CuI (0.005 mmol), PPh3 (0.005 mmol), and CHCl3 (2
mL). The tube was filled with argon was then sealed and heated
at 100 °C for 24 h in a drying oven. The resulting reaction
mixture was cooled to ambient temperature; then the solvent
evaporated, and the residue was purified by flash silica gel
chromatography giving the desired spiroketal 4.
(R)-4-Bromo-2-(1-hydroxy-4-methoxybut-2-yn-1-yl)phenol
(2f). To a solution of the intermediate product (0.5 mmol) in
20 mL dry THF was added a solution of tetrabutylammonium
fluoride (1.1 equiv) in 5 mL dry THF. After 1 h, water (5 mL)
was added to the reaction mixture; the aqueous phase was
extracted with ethyl acetate, and the extract was concentrated
under reduced pressure. The residue was purified by flash
chromatography (petroleum ether/EtOAc = 8:1) on silica gel
1
to afford 2f. Yield: 132 mg, 98%, as a colorless oil. H NMR
(400 MHz, CDCl3): δ 3.40 (s, 3H), 4.20 (d, J = 1.6, 2H), 5.67
(s, 1H), 6.75 (d, J = 8.8, 1H), 7.28−7.31 (dd, J = 8.8, 2.4, 1H),
7.44 (d, J = 2.4, 1H). 13C NMR (100 MHz, CDCl3): δ 57.8,
59.9, 62.8, 83.7, 84.1, 111.9, 118.7, 126.5, 130.2, 132.6, 154.3.
IR [vmax, cm−1]: 3304, 2955, 2927, 2853, 1713, 1510, 1420,
1360, 1276, 1223, 1104, 1023, 1002. HRMS (ESI-TOF) m/z:
[M + Na]+ calcd for C11H11BrO3Na, 292.9784; found,
292.9780. [α]1D8 +20 (c 1, CHCl3).
(2S,3S,4′S)-5-Bromo-3-hydroxy-4′,6′-diphenyl-3′,4′-dihy-
dro-3H-spiro[benzofuran-2,2′-pyran]-5′-carbonitrile (4a).
Purified by flash chromatography (petroleum ether/EtOAc =
1
4:1). Yield: 35 mg, 76%, as a white solid, mp 198−200 °C. H
NMR (400 MHz, CDCl3): δ 2.50 (d, J = 10.6, 1H), 2.55−2.60
(dd, J = 14, 6.8, 1H), 2.65−2.71 (dd, J = 14, 6.8, 1H), 4.10 (t, J
= 6.8, 1H), 5.23 (d, J = 10.6, 1H), 6.70 (d, J = 8.8, 1H), 7.31−
7.35 (m, 1H), 7.40−7.70 (m, 9H), 7.71−7.72 (m, 2H). 13C
NMR (150 MHz, DMSO- d6): δ 36.8, 37.9, 76.1, 88.5, 110.5,
112.3, 113.4, 119.1, 127.5, 128.0, 128.2, 128.3, 128.4, 128.9,
130.9, 131.2, 132.5, 132.7, 140.8, 155.3, 164.5. IR[vmax, cm−1]:
3397, 3062, 2956, 2925, 2852, 2210, 1615, 1599, 1469, 1340,
1251, 1184, 1162, 1145, 1049, 1024, 1001, 968, 816, 766, 737,
698. [α]1D9 −85 (c 1, CHCl3, 97% ee). The enantiomeric ratio
was determined by Daicel Chiralpak AD-H (25 cm), hexanes/
IPA = 86:14, 1 mL/min, λ = 273 nm, t (major) = 37.11 min, t
(minor) = 33.46 min. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C25H19BrNO3, 460.0543; found, 460.0536.
(S)-2-(1-Hydroxyprop-2-yn-1-yl)phenol (2g). Purified by
flash chromatography (petroleum ether/EtOAc = 2:1). Yield:
1
73 mg, 99%, as a colorless oil. H NMR (400 MHz, CDCl3):
δ2.78 (d, J = 2.4, 1H), 2.82 (d, J = 6, 1H), 5.69−5.70 (m, 1H),
6.90−6.94 (m, 2H), 7.01 (s, 1H), 7.24−7.28 (m, 1H), 7.37−
7.40 (dd, J = 8, 1.2, 1H). [α]2D5 +47 (c 1, CHCl3). All
spectroscopic data were consistent with our previously reported
data.11
(R)-2-(1-Hydroxyprop-2-yn-1-yl)-4-methoxyphenol (2h).
Purified by flash chromatography (petroleum ether/EtOAc =
1
2:1). Yield: 87 mg, 98%, as a yellow oil. H NMR (400 MHz,
CDCl3): δ 2.75 (d, J = 2, 1H), 3.76 (s, 3H), 5.63 (d, J = 1.6,
1H), 6.75−6.79 (m, 2H), 6.81 (s, 1H), 6.91−6.96 (m, 1H).
[α]2D7 −15 (c 1, CHCl3, >99% ee). The enantiomeric ratio was
determined by Daicel Chiralcel OD-H (25 cm), hexanes/IPA =
90:10, 1 mL/min, λ = 254 nm, t (major) = 18.02 min. All
spectroscopic data were consistent with our previously reported
data.11
(2S,3S,4′R)-Methyl 5-Bromo-3-hydroxy-4′-phenyl-3′,4′-di-
hydro-3H-spiro[benzofuran-2,2′-pyran]-6′-carboxylate (4b).
Purified by flash chromatography (petroleum ether/EtOAc =
1
4:1). Yield: 25 mg, 60%, as a white solid, mp 198−200 °C. H
NMR (400 MHz, CDCl3): δ 2.38−2.44 (dd, J = 14, 7.2, 1H),
2.49−2.54 (dd, J = 14, 7.2, 1H), 3.25 (d, J = 9.6, 1H), 3.79 (s,
3H), 3.88−3.93 (td, J = 7.2, 3.6, 1H), 5.09 (d, J = 8, 1H), 6.38
(d, J = 3.6, 1H), 6.64 (d, J = 8.4, 1H), 7.28−7.38 (m, 6H), 7.48
(d, J = 0.8, 1H). 13C NMR (100 MHz, CDCl3): δ 35.7, 36.7,
52.4, 78.1, 108.2, 112.3, 114.0, 114.9, 127.1, 127.7, 128.3, 128.6,
129.5, 133.1, 141.8, 142.1, 155.8, 162.5. IR [vmax, cm−1]: 3361,
2970, 2928, 1722, 1654, 1467, 1379, 1299, 1256, 1161, 1128,
1106, 952, 816, 701. [α]1D9 −20 (c 1, CHCl3, 99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 94:6, 1 mL/min, λ = 254 nm, t
(major) = 32.26 min, t (minor) = 29.51 min. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C20H17BrO5Na, 439.0152;
found, 439.0149.
(R)-2-(1-Hydroxyprop-2-yn-1-yl)-4-methylphenol (2i). Pu-
rified by flash chromatography (petroleum ether/EtOAc = 2:1).
1
Yield: 79 mg, 98%, as a colorless oil. H NMR (400 MHz,
CDCl3): δ 2.28 (s, 3H), 2.75 (d, J = 2, 1H), 5.63 (d, J = 2, 1H),
6.78 (d, J = 8, 1H), 7.01−7.04 (dd, J = 8, 2, 1H), 7.17 (d, J =
1.2, 1H). [α]2D7 −16 (c 1, CHCl3, >99% ee). The enantiomeric
ratio was determined by Daicel Chiralpak IC (25 cm), hexanes/
IPA = 100:0, 31 min, 99:1, 11 min, 98:2, 10 min, 1 mL/min, λ
= 254 nm, t (major) = 54.79 min. All spectroscopic data were
consistent with our previously reported data.11
(E)-2-Benzoyl-3-phenylacrylonitrile (3a). Purified by flash
chromatography (petroleum ether/EtOAc = 8:1). Yield: 83%,
as a yellow solid, mp 67−69 °C. 1H NMR (400 MHz, CDCl3):
δ 7.52−7.56 (m, 4H), 7.59 (d, J = 7.2, 1H), 7.65 (t, J = 7.2,
1H), 7.90−7.92 (m, 2H), 8.04 (d, J = 7.6, 2H), 8.07 (s, 1H). All
spectroscopic data were consistent with previously reported
data.14a
(2S,3S,4′R)-5-Bromo-3′-methyl-1′,4′-diphenyl-4′,5′-dihy-
dro-1′H,3H-spiro[benzofuran-2,6′-pyrano[2,3-c]pyrazol]-3-ol
(4c). Purified by flash chromatography (petroleum ether/
EtOAc = 4:1). Yield: 43 mg, 88%, as a yellow solid, mp 196−
198 °C. 1H NMR (400 MHz, CDCl3): δ 1.89 (s, 3H), 2.08 (s,
1H), 2.49−2.54 (dd, J = 14, 5.6, 1H), 2.62−2.68 (dd, J = 14.4,
6.8, 1H), 4.22 (t, J = 6, 1H), 5.20 (s, 1H), 6.59 (d, J = 8.4, 1H),
7.20 (t, J = 7.2, 1H), 7.31−7.37 (m, 8H), 7.47 (d, J = 0.6, 1H),
7.60 (d, J = 0.4, 1H), 7.62 (d, J = 0.6, 1H). 13C NMR (100
MHz, CDCl3): δ 13.1, 33.7, 38.6, 77.4, 98.3, 111.4, 112.5,
114.3, 120.8, 126.0, 126.8, 127.9, 128.3, 128.5, 129.0, 129.1,
Methyl (E)-2-Oxo-4-phenylbut-3-enoate (3b). Purified by
flash chromatography (petroleum ether/EtOAc = 8:1). Yield:
1
45%, as a yellow solid, mp 67−69 °C. H NMR (400 MHz,
CDCl3): δ 3.93 (s, 3H), 7.34−7.47 (m, 4H), 7.61−7.63 (m,
2H), 7.87 (d, J = 16, 1H). All spectroscopic data were
consistent with previously reported data.14b
G
DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
133.4, 138.1, 142.2, 147.2, 148.2, 155.6. IR [vmax, cm−1]: 3375,
2922, 2854, 1598, 1460, 1384, 1257, 1152, 1095, 1026, 936,
808, 756, 698, 663. [α]1D9 −80 (c 1, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 80:20, 1 mL/min, λ = 273 nm, t
(major) = 50.73 min. HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C26H22BrN2O3, 489.0808; found, 489.0804.
Purified by flash chromatography (petroleum ether/EtOAc =
4:1). Yield: 36 mg, 89%, as a yellow solid, mp 198−200 °C. 1H
NMR (400 MHz, CDCl3): δ 2.56−2.69 (m, 3H), 3.85 (s, 3H),
4.08−4.11 (dd, J = 9.2, 2.4, 1H), 5.27 (d, J = 10.8, 1H), 6.88−
6.90 (m, 1H), 6.99−7.01 (m, 2H), 7.31−7.35 (m, 1H), 7.37−
7.44 (m, 7H), 7.75−7.77 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 37.1, 38.5, 56.4, 78.8, 89.1, 109.1, 114.3, 116.9,
118.7, 123.4, 127.8, 127.8, 128.0, 128.3, 128.4, 128.9, 130.9,
132.4, 139.9, 144.6, 145.0, 164.1. IR [vmax, cm−1]: 3358, 2957,
2923, 2854, 2215, 1615, 1494, 1458, 1264, 1162, 1064, 1045,
1023, 799, 740, 698. [α]1D8 −14 (c 1, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 86:14, 1 mL/min, λ = 273 nm, t
(major) = 37.90 min. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C26H21NO4Na, 434.1363; found, 434.1358.
(2S,3S,4′R)-Methyl 3-hydroxy-7-methoxy-4′-phenyl-3′,4′-
dihydro-3H-spiro[benzofuran-2,2′-pyran]-6′-carboxylate
(4h). Purified by flash chromatography (petroleum ether/
EtOAc = 4:1). Yield, 20 mg, 55%, as a white solid, mp 192−194
°C. 1H NMR (400 MHz, CDCl3): δ 2.48 (s, 1H), 2.50 (s, 1H),
2.94 (s, 1H), 3.78 (s, 3H), 3.81 (s, 3H), 3.91−3.95 (td, J = 7.6,
3.2, 1H), 5.14 (s, 1H), 6.31 (d, J = 2.8, 1H), 6.84 (d, J = 7.6,
1H), 6.95 (t, J = 8, 1H), 7.01 (d, J = 7.6, 1H), 7.28−7.38 (m,
5H). 13C NMR (100 MHz, CDCl3): δ 36.0, 37.2, 52.2, 56.3,
79.0, 108.4, 114.2, 114.8, 117.1, 122.8, 127.1, 127.6, 128.3,
128.7, 141.9, 142.4, 144.5, 145.3, 162.5. IR [vmax, cm−1]: 3368,
2923, 2856, 2367, 1594, 1459, 1260, 1157, 1118, 1046, 748.
[α]1D8 +24 (c 1, CHCl3, >99% ee). The enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
93:7, 1 mL/min, λ = 254 nm, t (major) = 34.67 min. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C21H20O6Na, 391.1152;
found, 391.1147.
(2S,3S,4′R)-7-Methoxy-3′-methyl-1′,4′-diphenyl-4′,5′-dihy-
dro-1′H,3H-spiro[benzofuran-2,6′-pyrano[2,3-c]pyrazol]-3-ol
(4i). Purified by flash chromatography (petroleum ether/EtOAc
= 4:1). Yield: 37 mg, 86%, as a yellow solid, mp 94−96 °C. 1H
NMR (400 MHz, CDCl3): δ 1.83 (s, 3H), 2.04 (s, 1H), 2.59
(dd, J = 3.2, 1H), 2.61 (d, J = 3.2, 1H), 3.76 (s, 3H), 4.22 (t, J =
6.4, 1H), 5.23 (s, 1H), 6.84 (d, J = 7.2, 1H), 6.93−7.00 (m,
2H), 7.17 (t, J = 7.6, 1H), 7.25−7.36 (m, 7H), 7.66−7.68 (m,
2H). 13C NMR (100 MHz, CDCl3): δ 13.2, 26.9, 34.1, 39.3,
56.4, 77.8, 98.7, 111.5, 114.5, 117.2, 120.8, 123.1, 125.7, 126.8,
127.9, 127.9, 128.5, 129.0, 138.2, 142.0, 144.5, 145.0, 146.9,
148.6. IR [vmax, cm−1]: 3325, 3061, 2958, 2925, 2853, 1718,
1599, 1518, 1496, 1456, 1282, 1260, 1058, 1035, 1019, 757,
739, 700. [α]1D9 −22 (c 1, CHCl3, 96% ee). The enantiomeric
ratio was determined by Daicel Chiralpak AD-H (25 cm),
hexanes/IPA = 80:20, 1 mL/min, λ = 254 nm, t (major) =
36.97 min, t (minor) = 12.40 min. HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C27H25N2O4, 441.1809; found, 441.1808.
General Procedure for the Syntheses of Bisbenzannu-
lated 5,6-Spiroketals (6). A reaction tube was charged with
phenol 2 (0.1 mmol), o-methyleneacetoxy-phenol 5 (0.12
mmol), CuI (0.005 mmol), PPh3 (0.005 mmol), and CHCl3 (2
mL). The tube was filled with argon and was then sealed and
heated at 100 °C for 24 h in a drying oven. The resulting
reaction mixture was cooled to ambient temperature; then, the
solvent evaporated, and the residue was purified by flash silica
gel chromatography giving desired spiroketal 6.
(2S,3S,4′S)-3-Hydroxy-4′,6′-diphenyl-3′,4′-dihydro-3H-
spiro[benzofuran-2,2′-pyran]-5′-carbonitrile (4d). Purified by
flash chromatography (petroleum ether/EtOAc = 4:1). Yield:
1
34 mg, 90%, as a white solid, mp 218−220 °C. H NMR (400
MHz, CDCl3): δ 2.46 (d, J = 9.6, 1H), 2.55−2.61 (dd, J = 14,
7.2, 1H), 2.63−2.68 (dd, J = 14, 7.2, 1H), 4.11 (t, J = 7.2, 1H),
5.25 (d, J = 9.6, 1H), 6.83 (d, J = 8, 1H), 7.05 (t, J = 8, 1H),
7.29−7.53 (m, 10H), 7.73−7.75 (m, 2H). 13C NMR (150
MHz, DMSO- d6): δ 37.6, 38.5, 76.9, 88.8, 110.4, 110.4, 119.6,
122.6, 125.9, 127.9, 128.5, 128.7, 128.9, 129.0, 129.3, 130.2,
131.2, 133.3, 141.4, 156.5, 165.2. IR [vmax, cm−1]: 3405, 3270,
3049, 2957, 2926, 2853, 2252, 2206, 1716, 1617, 1601, 1478,
1464, 1264, 1164, 1147, 1056, 1028, 1008, 821, 760, 732, 700.
[α]2D0 +9 (c 1, MeOH, >99% ee). The enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
88:12, 1 mL/min, λ = 273 nm, t (major) = 36.37 min. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C25H19NO3Na,
404.1257; found, 404.1267.
Methyl (2S,3S,4′R)-3-Hydroxy-4′-phenyl-3′,4′-dihydro-3H-
spiro[benzofuran-2,2′-pyran]-6′-carboxylate (4e). Purified by
flash chromatography (petroleum ether/EtOAc = 3:1). Yield:
22 mg, 65%, as a yellow solid, mp 141−143 °C. 1H NMR (400
MHz, CDCl3): δ 2.36−2.42 (dd, J = 13.6, 8, 1H), 2.44−2.49
(dd, J = 13.6, 7.2, 1H), 3.14 (d, J = 10.4, 1H), 3.75 (s, 3H),
3.88−3.92 (td, J = 7.2, 3.2, 1H), 5.10 (d, J = 8.4, 1H), 6.32 (d, J
= 3.2, 1H), 6.75 (d, J = 8, 1H), 6.96 (t, J = 7.6, 1H), 7.21 (t, J =
7.6, 1H), 7.25−7.36 (m, 6H). 13C NMR (100 MHz, CDCl3): δ
36.0, 37.1, 52.3, 78.5, 107.9, 110.6, 114.8, 122.0, 125.3, 127.0,
127.0, 127.7, 128.7, 130.4, 142.0, 142.4, 156.8, 162.5. IR [vmax
,
cm−1]: 3430, 2928, 2857, 2361, 1717, 1652, 1602, 1477, 1464,
1439, 1335, 1292, 1240, 1115, 1068, 1028, 914, 876, 754, 701.
[α]2D6 +2 (c 1, CHCl3, 97% ee). The enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
94:6, 1 mL/min, λ = 254 nm, t (major) = 18.08 min, t (minor)
= 16.19 min. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C20H18O5Na, 361.1046; found, 361.1050.
(2S,3S,4′R)-3′-Methyl-1′,4′-diphenyl-4′,5′-dihydro-1′H,3H-
spiro[benzofuran-2,6′-pyrano[2,3-c]pyrazol]-3-ol (4f). Puri-
fied by flash chromatography (petroleum ether/EtOAc = 4:1).
Yield: 34 mg, 83%, as a white solid, mp 118−120 °C. 1H NMR
(400 MHz, CDCl3): δ 1.89 (s, 3H), 2.47 (d, J = 11.2, 1H),
2.52−2.57 (dd, J = 14.4, 6, 1H), 2.63−2.69 (dd, J = 14.4, 6.8,
1H), 4.25 (t, J = 6, 1H), 5.24 (d, J = 11.2, 1H), 6.73 (d, J = 8,
1H), 7.01 (t, J = 7.2, 1H), 7.17−7.63 (m, 11H), 7.65 (d, J = 0.8,
2H). 13C NMR (100 MHz, CDCl3): δ 13.3, 33.9, 38.9, 77.3,
77.7, 98.5, 110.7, 111.0, 120.7, 122.3, 125.3, 125.7, 126.6, 126.8,
128.0, 128.4, 129.0, 130.6, 138.3, 142.3, 147.1, 148.4, 156.6. IR
[vmax, cm−1]: 3376, 2956, 2923, 2852, 2373, 1737, 1599, 1460,
1383, 1263, 1121, 1075, 1037, 857, 802, 751, 698, 667, 405.
[α]2D0 −35 (c 1, MeOH, 92% ee). The enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
80:20, 1 mL/min, λ = 254 nm, t (major) = 31.06 min, t (minor)
= 11.36 min. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C26H23N2O3, 411.1703; found, 411.1712.
(2R,3S)-3H-Spiro[benzofuran-2,2′-chroman]-3-ol (6a). Pu-
rified by flash chromatography (petroleum ether/EtOAc = 8:1).
Yield: 20 mg, 77%, as a white solid, mp 142−144 °C. 1H NMR
(400 MHz, CDCl3): δ 2.30−2.34 (m, 2H), 2.84−2.92 (m, 2H),
(2R,3S,4′S)-3-Hydroxy-7-methoxy-4′,6′-diphenyl-3′,4′-di-
hydro-3H-spiro[benzofuran-2,2′-pyran]-5′-carbonitrile (4g).
H
DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3.20−3.29 (m, 1H), 5.19 (d, J = 10.8, 1H), 6.81 (d, J = 8, 1H),
6.84 (d, J = 8, 1H), 6.95−6.98 (m, 1H), 7.03 (t, J = 7.6, 1H),
7.13−7.17 (m, 2H), 7.24 (d, J = 8, 1H), 7.46 (d, J = 7.2, 1H).
13C NMR (100 MHz, CDCl3): δ 21.5, 28.5, 77.6, 106.7, 110.7,
117.0, 121.7, 121.8, 121.9, 125.2, 127.6, 128.2, 129.2, 130.1,
151.6, 156.8. [α]2D3 −201 (c 1, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 96:4, 1 mL/min, λ = 254 nm, t
(major) = 24.37 min. HRMS (ESI-TOF) m/z: [M + NH4]+
calcd for C16H18O3N, 272.1281; found, 272.1276.
= 8, 1H), 6.98 (t, J = 7.8, 1H), 7.07 (d, J = 7.2, 1H). 13C NMR
(100 MHz, CDCl3): δ 21.8, 28.7, 55.7, 56.1, 77.8, 107.2, 113.5,
113.7, 117.1, 117.5, 122.5, 122.6, 129.4, 144.7, 145.2, 145.7,
154.2. [α]2D6 −95 (c 1, CHCl3, >99% ee). The enantiomeric
ratio was determined by Daicel Chiralpak AD-H (25 cm),
hexanes/IPA = 90:10, 1 mL/min, λ = 254 nm, t (major) =
28.12 min. HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H19O5, 315.1227; found, 315.1224.
(2R,3S)-5-Bromo-3H-spiro[benzofuran-2,2′-chroman]-3-ol
(6f). Purified by flash chromatography (petroleum ether/EtOAc
= 8:1). Yield: 29 mg, 87%, as a white solid, mp 145−146 °C. 1H
NMR (400 MHz, CDCl3): δ 2.27−2.33 (m, 2H), 2.86−2.92
(m, 2H), 3.18−3.27 (m, 1H), 5.17 (d, J = 11.2, 1H), 6.68 (d, J
= 8.8, 1H), 6.83 (d, J = 8, 1H), 6.96−7.00 (m, 1H), 7.13−7.17
(m, 2H), 7.33−7.35 (dd, J = 8.4, 2, 1H), 7.56 (d, J = 0.8, 1H).
13C NMR (100 MHz, CDCl3): δ 21.4, 28.3, 77.3, 107.3, 112.4,
113.9, 116.9, 121.7, 121.9, 127.7, 128.3, 129.2, 130.6, 132.9,
151.4, 155.8. [α]2D5 −202.2 (c 0.92, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 96:4, 1 mL/min, λ = 254 nm, t
(major) = 31.76 min. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C16H13BrO3Na, 354.9940; found, 354.9939.
(2R,3S)-7-Methoxy-3H-spiro[benzofuran-2,2′-chroman]-3-
ol (6b). Purified by flash chromatography (petroleum ether/
EtOAc = 4:1). Yield: 22 mg, 80%, as a white solid, mp 135−137
1
°C. H NMR (400 MHz, CDCl3): δ 2.26−2.34 (td, J = 12.4,
5.6, 1H), 2.35−2.41 (ddd, J = 13.6, 6, 3.2, 1H), 2.85−2.90 (m,
2H), 3.24−3.33 (m, 1H), 3.83 (s, 3H), 5.19 (d, J = 10.4, 1H),
6.85 (t, J = 8.8, 2H), 6.94 (d, J = 7.6, 1H), 6.99 (t, J = 7.6, 1H),
7.08 (d, J = 7.2, 1H), 7.13 (t, J = 7.6, 2H). 13C NMR (100
MHz, CDCl3): δ 21.5, 28.7, 56.1, 77.9, 107.2, 113.5, 116.9,
117.1, 121.6, 121.9, 122.6, 127.6, 129.1, 129.4, 144.7, 145.2,
151.7. [α]2D6 −133 (c 1, CHCl3, >99% ee). The enantiomeric
ratio was determined by Daicel Chiralpak AD-H (25 cm),
hexanes/IPA = 94:6, 1 mL/min, λ = 254 nm, t (major) = 38.56
min. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H17O4,
285.1121; found, 285.1123.
(2R,3S)-5,6′-Dibromo-3H-spiro[benzofuran-2,2′-chro-
man]-3-ol (6g). Purified by flash chromatography (petroleum
ether/EtOAc = 8:1). Yield: 31 mg, 76%, as a yellow solid, mp
1
145−146 °C. H NMR (400 MHz, CDCl3): δ 2.27−2.32 (m,
(2S,3S)-8′-Methoxy-3H-spiro[benzofuran-2,2′-chroman]-
3-ol (6c). Purified by flash chromatography (petroleum ether/
EtOAc = 4:1). Yield: 20 mg, 71%, as a white solid, mp 136−137
°C. 1H NMR (400 MHz, CDCl3): δ 2.20−2.28 (td, J = 13, 5.6,
1H), 2.31−2.36 (ddd, J = 13.6, 6, 2.8, 1H), 2.83−2.89 (ddd, J =
16.2, 5.2, 2.8, 1H), 3.19−3.27 (m, 2H), 3.75 (s, 3H), 5.18 (d, J
= 10.4, 1H), 6.74−6.77 (m, 2H), 6.80 (d, J = 8, 1H), 6.90 (t, J
= 8, 1H), 6.99−7.03 (td, J = 7.4, 0.8, 1H), 7.23 (d, J = 7.2, 1H),
7.46 (d, J = 7.2, 1H). 13C NMR (100 MHz, CDCl3): δ 21.5,
28.8, 55.7, 77.5, 106.7, 110.1, 110.6, 120.9, 121.1, 121.8, 122.9,
125.3, 128.2, 130.0, 141.2, 148.4, 156.8. [α]2D5 −112.5 (c 0.4,
CHCl3, 96% ee). The enantiomeric ratio was determined by
Daicel Chiralpak AD-H (25 cm), hexanes/IPA = 92:8, 1 mL/
min, λ = 254 nm, t (major) = 14.53 min, t (minor) = 15.80.
HRMS (ESI-TOF) m/z: [M + NH4]+ calcd for C17H20O4N,
302.1387; found, 302.1390.
2H), 2.80 (d, J = 11.2, 1H), 2.83−2.89 (m, 1H), 3.15−3.24 (m,
1H), 5.17 (d, J = 11.2, 1H), 6.68 (d, J = 8.4, 1H), 6.71 (d, J =
8.4, 1H), 7.22−7.25 (dd, J = 8.8, 2.4, 1H), 7.29 (s, 1H), 7.33−
7.36 (dd, J = 8.4, 2, 1H), 7.55 (d, J = 0.4, 1H). 13C NMR (100
MHz, CDCl3): δ 21.3, 27.9, 77.3, 107.2, 112.4, 114.1, 114.1,
118.7, 123.9, 128.3, 130.4, 130.6, 131.8, 133.0, 150.5, 155.6.
[α]2D6 −112 (c 1, CHCl3, >99% ee). The enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
96:4, 1 mL/min, λ = 254 nm, t (major) = 41.34 min, t (minor)
= 44.12. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C16H12Br2O3Na, 432.9045; found, 432.9044.
(2R,3S)-6′-Bromo-3H-spiro[benzofuran-2,2′-chroman]-3-
ol (6h). Purified by flash chromatography (petroleum ether/
EtOAc = 8:1). Yield: 22 mg, 67%, as a white solid, mp 142−144
1
°C. H NMR (400 MHz, CDCl3): δ 2.28−2.33 (m, 2H), 2.74
(d, J = 10.8, 1H), 2.84−2.90 (m, 1H), 3.18−3.27 (m, 1H), 5.20
(d, J = 10.8, 1H), 6.72 (d, J = 8.8, 1H), 6.80 (d, J = 8, 1H), 7.04
(2R,3S)-7,8′-Dimethoxy-3H-spiro[benzofuran-2,2′-chro-
man]-3-ol (6d). Purified by flash chromatography (petroleum
ether/EtOAc = 4:1). Yield: 25 mg, 79%, as a yellow solid, mp
(t, J = 7.6, 1H), 7.22−7.32 (m, 3H), 7.45 (d, J = 7.2, 1H). 13
C
1
NMR (100 MHz, CDCl3): δ 21.4, 28.2, 77.6, 106.6, 110.7,
113.9, 118.8, 122.1, 124.0, 125.2, 128.0, 130.2, 130.5, 131.8,
150.9, 156.6. [α]2D5 −128.9 (c 0.52, CHCl3, 96% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 96:4, 1 mL/min, λ = 254 nm, t
(major) = 29.70 min, t (minor) = 34.12. HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C16H13BrO3Na, 354.9940; found,
354.9936.
152−153 °C. H NMR (400 MHz, CDCl3): δ 2.19−2.27 (m,
1H), 2.35−2.41 (ddd, J = 13.6, 5.6, 2.8, 1H), 2.81−2.87 (ddd, J
= 16, 5.2, 2.8, 1H), 3.23−3.38 (m, 2H), 3.74 (s, 3H), 3.83 (s,
3H), 5.17 (d, J = 10, 1H), 6.72−6.75 (m, 2H), 6.83−6.90 (m,
2H), 6.97 (t, J = 7.6, 1H), 7.08 (d, J = 7.2, 1H). 13C NMR (100
MHz, CDCl3): δ 21.5, 29.0, 55.7, 56.1, 77.8, 107.2, 110.0,
113.3, 117.2, 120.8, 121.0, 122.5, 123.1, 129.3, 141.2, 144.6,
145.2, 148.4. [α]2D6 −106 (c 1, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 95:5, 1 mL/min, λ = 254 nm, t
(major) = 22.70 min. HRMS (ESI-TOF) m/z: [M + NH4]+
calcd for C18H22O5N, 332.1492; found, 332.1495.
(2R,3S)-6′-Nitro-3H-spiro[benzofuran-2,2′-chroman]-3-ol
(6i). Purified by flash chromatography (petroleum ether/EtOAc
= 4:1). Yield: 23 mg, 76%, as a yellow solid, mp 160−161 °C.
1H NMR (400 MHz, CDCl3): δ 2.34−2.41 (m, 2H), 2.98−3.04
(m, 1H), 3.27−3.35 (m, 1H), 5.26 (s, 1H), 6.82 (d, J = 7.6,
1H), 6.92 (d, J = 8.8, 1H), 7.07 (t, J = 7.2, 1H), 7.29 (d, J = 7.6,
1H), 7.46 (d, J = 7.2, 1H), 8.03−8.06 (dd, J = 8.8, 2.4, 1H),
8.12 (d, J = 7.4, 1H). 13C NMR (100 MHz, CDCl3): δ 21.5,
27.9, 77.7, 107.2, 110.7, 117.6, 122.5, 122.7, 123.7, 125.2, 125.3,
127.5, 130.4, 142.1, 156.4, 157.1. [α]2D6 −151.7 (c 0.87, CHCl3,
>99% ee). The enantiomeric ratio was determined by Daicel
(2R,3S)-6′,7-Dimethoxy-3H-spiro[benzofuran-2,2′-chro-
man]-3-ol (6e). Purified by flash chromatography (petroleum
ether/EtOAc = 4:1). Yield: 27 mg, 87%, as a white solid, mp
194−195 °C. 1H NMR (400 MHz, CDCl3): δ 2.23−2.31 (td, J
= 13.2, 5.6, 1H), 2.32−2.38 (m, 1H), 2.81−2.89 (m, 2H),
3.22−3.31 (m, 1H), 3.77 (s, 3H), 3.83 (s, 3H), 5.17 (d, J =
10.8, 1H), 6.68−6.71 (m, 2H), 6.77 (d, J = 8.8, 1H), 6.86 (d, J
I
DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Chiralpak AD-H (25 cm), hexanes/IPA = 88:12, 1 mL/min, λ
= 254 nm, t (major) = 29.22 min, t (minor) = 27.43. HRMS
(ESI-TOF) m/z: [M + NH4]+ calcd for C16H17N2O5, 317.1132;
found, 317.1129.
Yield: 20 mg, 78%, as a white solid, mp 142−144 °C. 1H NMR
(400 MHz, CDCl3): δ 2.30−2.34 (m, 2H), 2.83−2.92 (m, 2H),
3.20−3.29 (m, 1H), 5.19 (d, J = 10.8, 1H), 6.80 (d, J = 8, 1H),
6.84 (d, J = 8, 1H), 6.94−6.98 (td, J = 7.6, 0.8, 1H), 7.01−7.05
(td, J = 7.6, 0.8, 1H), 7.12−7.17 (m, 2H), 7.24 (d, J = 7.6, 1H),
7.46 (d, J = 7.2, 1H). 13C NMR (150 MHz, CDCl3): δ 21.5,
28.5, 77.6, 106.6, 110.7, 117.0, 121.7, 121.8, 121.9, 125.2, 127.6,
128.1, 129.2, 130.1, 151.6, 156.7. [α]2D5 +233.3 (c 0.3, CHCl3,
>99% ee). The enantiomeric ratio was determined by Daicel
Chiralpak AD-H (25 cm), hexanes/IPA = 96:4, 1 mL/min, λ =
254 nm, t (major) = 30.77 min. HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C16H15O3, 255.1016; found, 255.1019.
(2R,3S)-5-Methoxy-3H-spiro[benzofuran-2,2′-chroman]-3-
ol (6j). Purified by flash chromatography (petroleum ether/
EtOAc = 4:1). Yield: 21 mg, 75%, as a white solid, mp 176−177
°C. 1H NMR (400 MHz, CDCl3): δ 2.29−2.33 (m, 2H), 2.85−
2.94 (m, 2H), 3.19−3.27 (m, 1H), 3.81 (s, 3H), 5.17 (d, J =
10.8, 1H), 6.71 (d, J = 8.8, 1H), 6.78−6.80 (dd, J = 8.8, 2.4,
1H), 6.84 (d, J = 8, 1H), 6.96 (t, J = 7.2, 1H), 7.03 (d, J = 2,
1H), 7.12−7.16 (m, 2H). 13C NMR (100 MHz, CDCl3): δ
21.5, 28.5, 56.0, 78.0, 107.0, 110.4, 111.0, 115.8, 117.0, 121.7,
121.8, 127.6, 128.9, 129.2, 150.6, 151.7, 155.2. [α]2D5 −175 (c 1,
CHCl3, >99% ee). The enantiomeric ratio was determined by
Daicel Chiralpak AD-H (25 cm), hexanes/IPA = 92:8, 1 mL/
min, λ = 254 nm, t (major) = 25.14 min. HRMS (ESI-TOF) m/
z: [M + NH4]+ calcd for C17H20O4N, 302.1387; found,
302.1386.
(2R,3S,3′R)-3′-(Methoxymethyl)-3H-spiro[benzofuran-2,2′-
chroman]-3-ol (6o). Purified by flash chromatography
(petroleum ether/EtOAc = 4:1). Yield: 18 mg, 60%, as a
1
white solid, mp 102−104 °C. H NMR(400 MHz, CDCl3): δ
2.61−2.69 (m, 1H), 2.88−2.96 (m, 3H), 3.32 (s, 3H), 3.39−
3.43 (m, 1H), 3.66−3.70 (m, 1H), 5.73 (d, J = 10.8, 1H), 6.79
(d, J = 8, 1H), 6.82 (d, J = 8, 1H), 6.94−6.98 (td, J = 7.2, 1.2,
1H), 7.02−7.06 (td, J = 7.6, 0.8, 1H), 7.12−7.16 (m, 2H),
7.22−7.26 (m, 1H), 7.46 (d, J = 7.6, 1H). 13C NMR (100 MHz,
CDCl3): δ 25.7, 36.7, 58.9, 72.6, 74.9, 107.7, 110.6, 116.6,
121.3, 121.7, 122.0, 125.2, 127.6, 128.6, 129.0, 129.9, 151.0,
156.7. IR[vmax, cm−1]: 3393, 2955, 2925, 1477, 1460, 1226,
1172, 1110, 1076, 907, 754. [α]2D7 −146 (c 1, CHCl3, 97% ee).
The enantiomeric ratio was determined by Daicel Chiralcel
OD-H (25 cm), hexanes/IPA = 80:20, 1 mL/min, λ = 273 nm,
t (major) = 23.74 min, t (minor) = 41.30 min. HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C18H18O4Na, 321.1097;
found, 321.1093.
(2R,3S)-5-Methyl-3H-spiro[benzofuran-2,2′-chroman]-3-ol
(6k). Purified by flash chromatography (petroleum ether/
EtOAc = 8:1). Yield: 17 mg, 63%, as a white solid, mp 135−137
1
°C. H NMR (400 MHz, CDCl3): δ 2.26−2.30 (m, 2H), 2.33
(s, 3H), 2.83−2.89 (m, 2H), 3.17−3.26 (m, 1H), 5.14 (d, J =
10.8, 1H), 6.67 (d, J = 8.4, 1H), 6.82 (d, J = 8, 1H), 6.92−6.96
(m, 1H), 7.03 (d, J = 8.4, 1H), 7.09−7.14 (m,2H), 7.24 (s, 1H).
13C NMR (100 MHz, CDCl3): δ 20.8, 21.5, 28.5, 77.7, 106.8,
110.3, 117.0, 121.7, 121.8, 125.6, 127.6, 128.1, 129.2, 130.5,
131.4, 151.7, 154.7. [α]D26 −174.5 (c 0.98, CHCl3, >99% ee).
The enantiomeric ratio was determined by Daicel Chiralpak
AD-H (25 cm), hexanes/IPA = 95:5, 1 mL/min, λ = 254 nm, t
(major) = 27.99 min. HRMS (ESI-TOF) m/z: [M + NH4]+
calcd for C17H20O3N, 286.1438; found, 286.1433.
(2R,3S,3′R)-7-Methoxy-3′-(methoxymethyl)-3H-spiro-
[benzofuran-2,2′-chroman]-3-ol (6p). Purified by flash
chromatography (petroleum ether/EtOAc = 4:1). Yield: 18
1
mg, 55%, as a white solid, mp 114−116 °C. H NMR (400
(2R,3S)-6′-Methoxy-3H-spiro[benzofuran-2,2′-chroman]-
3-ol (6l). Purified by flash chromatography (petroleum ether/
EtOAc = 4:1). Yield: 21 mg, 75%, as a white solid, mp 148−150
°C. 1H NMR (400 MHz, CDCl3): δ 2.28−2.32 (m, 2H), 2.82−
2.89 (m, 2H), 3.19−3.28 (m, 1H), 3.78 (s, 3H), 5.17 (d, J =
10.8, 1H), 6.70−6.72 (m, 2H), 6.76−6.81 (m, 2H), 7.02 (t, J =
7.2, 1H), 7.24 (d, J = 8, 1H), 7.45 (d,J = 7.2, 1H). 13C NMR
(100 MHz, CDCl3): δ 21.8, 28.6, 55.7, 77.5, 106.6, 110.7,
113.6, 113.8, 117.6, 121.9, 122.4, 125.2, 128.2, 130.1, 145.6,
154.3, 156.8. [α]2D5 −220 (c 0.6, CHCl3, >99% ee). The
enantiomeric ratio was determined by Daicel Chiralpak AD-H
(25 cm), hexanes/IPA = 92:8, 1 mL/min, λ = 254 nm, t
(major) = 25.89 min. HRMS (ESI-TOF) m/z: [M + NH4]+
calcd for C17H20O4N, 302.1387; found, 302.1389.
MHz, CDCl3): δ 2.60−2.68 (td, J = 12.4, 6, 1H), 2.91−3.06
(m, 3H), 3.31 (s, 3H), 3.41−3.45 (dd, J = 10, 6, 1H), 3.70−
3.74 (dd, J = 9.6, 6.4, 1H), 3.81 (s, 3H), 5.72 (d, J = 10.4, 1H),
6.82 (d, J = 8, 1H), 6.85 (d, J = 8, 1H), 6.94 (t, J = 7.2, 1H),
6.99 (t, J = 8, 1H), 7.08−7.14 (m, 3H). 13C NMR (100 MHz,
CDCl3): δ 25.6, 36.9, 56.2, 58.8, 72.6, 75.2, 108.2, 113.5, 116.5,
117.1, 121.4, 121.7, 122.7, 127.6, 129.0, 129.9, 144.6, 145.1,
151.1. IR [vmax, cm−1]: 3396, 2955, 2925, 1492, 1458, 1283,
1224, 1171, 1054, 904, 754. [α]2D5 −158 (c 1, CHCl3, >99% ee).
The enantiomeric ratio was determined by Daicel Chiralcel
OD-H (25 cm), hexanes/IPA = 98:2, 1 mL/min, λ = 273 nm, t
(major) = 34.10 min. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C19H20O5Na, 351.1203; found, 351.1198.
(2R,3S,3′R)-6′-Methoxy-3′-(methoxymethyl)-3H-spiro-
[benzofuran-2,2′-chroman]-3-ol (6q). Purified by flash
chromatography (petroleum ether/EtOAc = 4:1). Yield: 23
mg, 70%, as a white solid, mp 94−96 °C. 1H NMR (400 MHz,
CDCl3): δ 2.59−2.67 (m, 1H), 2.91−2.94 (m, 3H), 3.31 (s,
3H), 3.37−3.41 (dd, J = 10, 6, 1H), 3.65−3.69 (dd, J = 10, 6.4,
1H), 3.77 (s, 3H), 5.70 (d, J = 11.2, 1H), 6.69−6.71 (m, 2H),
6.74−6.80 (m, 2H), 7.03 (t, J = 7.6, 1H), 7.23 (t, J = 8, 1H),
7.45 (d, J = 7.6, 1H). 13C NMR (100 MHz, CDCl3): δ 26.1,
36.8, 55.6, 58.8, 72.6, 74.8, 107.6, 110.6, 113.5, 113.6, 117.2,
(2R,3S)-6′-Methyl-3H-spiro[benzofuran-2,2′-chroman]-3-
ol (6m). Purified by flash chromatography (petroleum ether/
EtOAc = 8:1). Yield: 17 mg, 65%, as a white solid, mp 126−128
°C. 1H NMR (400 MHz, CDCl3): δ 2.28−2.32 (m, 5H), 2.81−
2.87 (m, 2H), 3.17−3.26 (m, 1H), 5.18 (d, J = 10.8, 1H), 6.74
(d, J = 8, 1H), 6.80 (d, J = 8, 1H), 6.94−6.97 (m, 2H), 7.00−
7.04 (td, J = 7.6, 0.8, 1H), 7.24 (d, J = 7.6, 1H), 7.45 (d, J = 7.6,
1H). 13C NMR (100 MHz, CDCl3): δ 20.5, 21.5, 28.7, 77.6,
106.7, 110.7, 116.7, 121.4, 121.8, 125.2, 128.2, 128.2, 129.5,
130.1, 131.0, 149.5, 156.8. [α]2D6 −103 (c 1, CHCl3, >99% ee).
The enantiomeric ratio was determined by Daicel Chiralpak
AD-H (25 cm), hexanes/IPA = 96:4, 1 mL/min, λ = 254 nm, t
(major) = 20.79 min. HRMS (ESI-TOF) m/z: [M + NH4]+
calcd for C17H20O3N, 286.1438; found, 286.1443.
121.9, 122.0, 125.2, 128.6, 129.8, 145.0, 154.3, 156.7. IR [vmax
,
cm−1]: 3399, 2924, 2852, 1498, 1477, 1463, 1213, 1152, 1117,
1076, 1024, 906. [α]D27 −152 (c 1, CHCl3, 90% ee). The
enantiomeric ratio was determined by Daicel Chiralcel OD-H
(25 cm), hexanes/IPA = 85:15, 1 mL/min, λ = 273 nm, t
(major) = 11.87 min, t (minor) = 9.07 min. HRMS (ESI-TOF)
(2S,3R)-3H-Spiro[benzofuran-2,2′-chroman]-3-ol (6n). Pu-
rified by flash chromatography (petroleum ether/EtOAc = 4:1).
J
DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
m/z: [M + Na]+ calcd for C19H20O5Na, 351.1203; found,
351.1199.
(ESI-TOF) m/z: [M + H]+ calcd for C22H29O3Si, 369.1880;
found, 369.1876.
8′-Methoxy-3H-spiro[benzofuran-2,2′-chroman]-3-ol
(6w). To a solution of the 6v (0.005 mmol) in 2 mL of THF
was added a solution of tetrabutylammonium fluoride (1.1
equiv) in 2 mL THF. After 0.5 h, water (2 mL) was added to
the reaction mixture; the aqueous phase was extracted with
ethyl acetate, and the extract was concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel to afford 6w. Purified by flash chromatography
(petroleum ether/EtOAc = 8:1). Yield: 1.5 mg, 95%, as a
yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.87 (d, J = 8, 1H),
2.16−2.24 (td, J = 13.2, 6, 1H), 2.36−2.41 (m, 1H), 2.90−2.96
(m, 1H), 3.15−3.24 (m, 1H), 3.75 (s, 3H), 5.31 (d, J = 8, 1H),
6.74 (d, J = 8, 1H), 6.78 (d, J = 8, 1H), 6.84−6.91 (m, 2H),
7.01 (t, J = 7.2, 1H), 7.30 (d, J = 7.6, 1H), 7.47 (d, J = 7.6, 1H).
13C NMR (150 MHz, CDCl3): δ 21.4, 29.7, 56.1, 78.1, 110.2,
110.9, 110.9, 120.9, 121.2, 121.7, 123.0, 125.9, 127.6, 130.9,
141.8, 148.5, 158.5. IR [vmax, cm−1]: 3400, 2926, 1615, 1480,
1465, 1377, 1266, 1200, 1175, 1122, 1046, 916, 880, 752, 732.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H14O3Na,
277.0835; found, 277.0833.
(Z)-5-Bromo-2-(2-methoxyethylidene)-2,3-dihydrobenzo-
furan-3-ol (7f). CuI (0.05 mmol, 10 mg) and PPh3 (0.05 mol,
13 mg) were added to a solution of compound 2f (1 mmol, 270
mg) in CHCl3 (3 mL). The tube was filled with argon and was
then sealed and heated at 100 °C for 24 h in a drying oven. The
resulting reaction mixture was cooled to ambient temperature;
then, the solvent evaporated, and the residue was purified by
flash silica gel chromatography (petroleum ether/EtOAc = 4:1)
giving 7f. Yield: 189 mg, 70%, as a white solid;, mp 70−72 °C.
1H NMR (400 MHz, CDCl3): δ 3.39 (s, 3H), 4.21 (d, J = 8,
2H), 5.29−5.33 (td, J = 8, 1.6, 1H), 5.63 (s, 1H), 6.86 (d, J = 8,
1H), 7.40−7.43 (dd, J = 8, 2, 1H), 7.57 (d, J = 2, 1H). 13C
NMR (150 MHz, CDCl3): δ 58.1, 66.1, 70.7, 103.0, 112.0,
114.7, 128.7, 129.5, 133.5, 156.3, 159.2. HRMS (ESI-TOF) m/
z: [M + Na]+ calcd for C11H11BrO3Na, 292.9784; found,
292.9788.
(2R,3S,3′R)-6′,7-Dimethoxy-3′-(methoxymethyl)-3H-spiro-
[benzofuran-2,2′-chroman]-3-ol (6r). Purified by flash chro-
matography (petroleum ether/EtOAc = 4:1). Yield: 23 mg,
1
65%, as a yellow solid, mp 128−130 °C. H NMR (400 MHz,
CDCl3): δ 2.58−2.66 (td, J = 12, 6, 1H), 2.88−3.03 (m, 3H),
3.31 (s, 3H), 3.410−3.43 (dd, J = 10, 6, 1H), 3.70−3.72 (dd, J
= 10, 6.4, 1H), 3.76 (S, 1h), 3.81 (s, 3H), 5.69 (d, J = 10.8,
1H), 6.67−6.70 (m, 2H), 6.74−6.76 (m, 1H), 6.85 (d, J = 8,
1H), 6.98 (t, J = 8, 1H), 7.07 (d, J = 8, 1H). 13C NMR (100
MHz, CDCl3): δ 26.0, 37.0, 55.6, 56.2, 58.8, 72.6, 75.1, 108.1,
113.4, 113.5, 113.6, 117.1, 122.0, 122.6, 129.9, 144.6, 145.0,
145.1, 154.2. IR [vmax, cm−1]: 3414, 2955, 2922, 2852, 1494,
1460, 1435, 1291, 1275, 1220, 1117, 1053, 1008, 903, 801, 748.
[α]2D7 −163 (c 1, CHCl3, 91% ee). The enantiomeric ratio was
determined by Daicel Chiralcel OD-H (25 cm), hexanes/IPA =
90:10, 1 mL/min, λ = 273 nm, t (major) = 12.79 min, t (minor)
= 8.17 min. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C20H22O6Na, 381.1309; found, 381.1304.
(2R,3S,3′R)-5,6′-Dibromo-3′-(methoxymethyl)-3H-spiro-
[benzofuran-2,2′-chroman]-3-ol (6s). Purified by flash
chromatography (petroleum ether/EtOAc = 4:1). Yield: 28
mg, 62%, as a white solid, mp 86−88 °C. 1H NMR (400 MHz,
CDCl3): δ 2.57−2.65 (m, 1H), 2.83−2.89 (m, 3H), 3.32 (s,
3H), 3.37−3.41 (dd, J = 10, 5.2, 1H), 3.61−3.66 (dd, J = 10,
7.2, 1H), 5.75 (d, J = 11.2, 1H), 6.66−6.70 (m, 2H), 7.22−7.24
(m, 1H), 7.32−7.35 (m, 1H), 7.55 (t, J = 0.8, 2H). 13C NMR
(100 MHz, CDCl3): δ 25.3, 36.2, 58.9, 72.3, 74.6, 108.4, 112.4,
114.2, 114.2, 118.4, 123.4, 128.3, 130.6, 130.9, 131.6, 132.8,
150.0, 155.5. IR[vmax, cm−1]: 3395, 2925, 2850, 1480, 1467,
1250, 1256, 1172, 1120, 1080, 1022, 909,814, 738, 660. [α]D18
−
166 (c 1, CHCl3, 81% ee). The enantiomeric ratio was
determined by Daicel Chiralpak AD-H (25 cm), hexanes/IPA =
80:20, 1 mL/min, λ = 280 nm, t (major) = 15.07 min, t (minor)
= 27.43 min. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C18H16Br2O4Na, 476.9308; found, 476.9309.
3′-Pentyl-3H-spiro[benzofuran-2,2′-chroman]-3-ol (6t).
tert-Butyldimethyl((2-methylene-2,3-dihydrobenzofuran-
3-yl)oxy)silane (9a). To a solution of intermediate 2-
methylene-2,3-dihydrobenzofuran-3-ol (1 mmol, 148 mg) in
dry THF (8 mL) was slowly added NaH (70%, 1.1 mmol, 38
mg) at rt. A solution of TBSCl (1.1 mmol in 2 mL of THF)
was then added dropwise. The reaction mixture was stirred at rt
overnight and was then quenched with saturated NH4Cl
solution. The aqueous phase was extracted with EtOAc.
Combined organic layers were washed with brine, dried over
Na2SO4, and evaporated. The residue was purified by flash
chromatography (petroleum ether/EtOAc = 16:1) on silica gel
Purified by flash chromatography (petroleum ether/EtOAc =
1
4:1). Yield: 2 mg, 5%, as a white solid, mp 98−100 °C. H
NMR (400 MHz, CDCl3): δ 0.92 (t, J = 6.8, 3H), 1.27−1.38
(m, 7H), 1.65−1.68 (m, 1H), 2.20−2.28 (m, 1H), 2.85−3.04
(m, 3H), 5.51 (d, J = 11.2, 1H), 6.78−6.83 (m, 2H), 6.93−6.97
(td, J = 7.6, 0.8, 1H), 7.02 (t, J = 7.2, 1H), 7.11−7.15 (m, 2H),
7.24 (t, J = 8, 1H), 7.46 (d, J = 7.6, 1H). 13C NMR (150 MHz,
CDCl3): δ 14.0, 22.6, 26.6, 27.3, 29.6, 31.8, 36.3, 74.2, 108.9,
110.6, 116.5, 121.6, 121.9, 121.9, 125.3, 127.5, 128.3, 129.0,
130.1, 151.1, 157.0. HRMS (ESI-TOF) m/z: [M + Na]+ calcd
for C21H24O3Na, 347.1618; found, 347.1619.
1
to give the product 9a. Yield: 130 mg, 50%, as a brown oil. H
tert-Butyl((8′-methoxy-3H-spiro[benzofuran-2,2′-chro-
man]-3-yl)oxy)dimethylsilane (6v). Purified by flash chroma-
tography (petroleum ether/EtOAc = 16:1). Yield: 2 mg, 5%, as
a white solid, mp 110−112 °C. 1H NMR (400 MHz, CDCl3): δ
0.20 (s, 3H), 0.21 (s, 3H), 0.92 (s, 9H), 1.98−2.06 (td, J = 13.6,
6, 1H), 2.37−2.43 (m, 1H), 2.84−2.89 (m, 1H), 3.16−3.24 (m,
1H), 3.75 (s, 3H), 5.37 (s, 1H), 6.73−6.81 (m, 3H), 6.88 (t, J =
7.6, 1H), 6.96 (t, J = 7.6, 1H), 7.21−7.25 (m, 1H), 7.33−7.35
(m, 1H). 13C NMR (150 MHz, CDCl3): δ −4.4, −4.1, 21.4,
24.9, 25.8, 29.7, 56.2, 78.7, 110.4, 110.7, 111.2, 120.8, 121.2,
NMR (400 MHz, CDCl3): δ 0.13 (s, 3H), 0.19 (s, 3H), 0.94 (s,
9H), 4.60−4.61 (m, 1H), 4.91−4.92 (t, J = 2, 1H), 5.78 (s,
1H), 6.92 (d, J = 8, 1H), 7.00−7.04 (td, J = 8, 0.8, 1H), 7.25−
7.29 (m, 1H), 7.34 (d, J = 8, 1H). 13C NMR (100 MHz,
CDCl3): δ −4.1, −3.9, 18.0, 25.7, 71.4, 89.0, 110.1, 122.1,
125.5, 128.0, 130.1, 157.4, 164.1. HRMS (ESI-TOF) m/z: [M
+ Na]+ calcd for C15H22O2SiNa, 285.1281; found, 285.1286.
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray crystallographic data and copies of H, 13C, and HPLC
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
121.3, 123.3, 125.8, 128.3, 130.0, 142.1, 148.6, 158.3. IR [vmax
,
cm−1]: 2926, 1600, 1479, 1464, 1381, 1301, 1257, 1213, 1198,
1175, 1123, 1086, 1063, 1048, 921, 838, 798, 776, 750. HRMS
K
DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
K.; Fushimi, M.; Akakura, M. Acc. Chem. Res. 2007, 40, 1049.
(c) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: xuejj@lzu.edu.cn.
*E-mail: liying@lzu.edu.cn.
(11) Li, X.; Xue, J.; Huang, C.; Li, Y. Chem.−Asian J. 2012, 7, 903.
(12) (a) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc.
1996, 118, 10938. (b) Matsuya, Y.; Ihara, D.; Fukuchi, M.; Honma, D.;
Itoh, K.; Tabuchi, A.; Nemoto, H.; Tsuda, M. Bioorg. Med. Chem.
2012, 20, 2564. For syntheses details and structures of s1−s3, see the
Experimental Section and Supporting Information.
Notes
The authors declare no competing financial interest.
(13) For details of the X-ray report, see the Supporting Information.
(14) For synthesis details of 3a: (a) Deshpande, S. J.; Leger, P. R.;
Sieck, S. R. Tetrahedron Lett. 2012, 53, 1772. For synthesis details of
3b: (b) Evans, D. A.; Olhava, E. J.; Johnson, J. S.; Janey, J. M. Angew.
Chem., Int. Ed. 1998, 37, 3372. For synthesis details of 3c: (c) Chen,
Q.; Liang, J.; Wang, S.; Wang, D.; Wang, R. Chem. Commun. 2013, 49,
1657.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (NFSC No. 21372107, 21272099, and
21202069) is gratefully acknowledged.
(15) For details of the X-ray report, see the Supporting Information.
(16) Selected example of [4 + 2] cycloaddition using o-quinone
methide: (a) Arduini, A.; Bosi, A.; Pochini, A.; Ungaro, R. Tetrahedron
1985, 41, 3095. (b) Chambers, J. D.; Crawford, J.; Williams, H. W. R.;
Dufresne, C.; Scheigetz, J.; Bernstein, M. A.; Lau, C. K. Can. J. Chem.
1992, 70, 1717. (c) Chiba, K.; Hirano, T.; Kitano, Y.; Tada, M. J.
Chem. Soc., Chem. Commun. 1999, 691. (d) Van De Water, R. W.;
Pettus, T. R. R. Tetrahedron 2002, 58, 5367. (e) Jones, R. M.; Selenski,
C.; Pettus, T. R. R. J. Org. Chem. 2002, 67, 6911.
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DOI: 10.1021/acs.joc.5b00384
J. Org. Chem. XXXX, XXX, XXX−XXX