Pd-catalyzed asymmetric allylic etherification using chiral biphenol-based diphosphinite ligands and its application for the formal total synthesis of (-)-galanthamine

Article abstract of DOI:10.1021/jo400355j

A library of novel chiral biphenol-based diphosphinite (BOP) ligands was designed and created. These BOP ligands were applied to a Pd-catalyzed intermolecular allylic etherification reaction, which provided a key intermediate for the formal total synthesis of (-)-galanthamine with 97% ee in 97% yield.

Full text of DOI:10.1021/jo400355j

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Article
Pd-catalyzed Asymmetric Allylic Etherification Using
Chiral Biphenol-based Diphosphonite Ligands and Its
Application for The Formal Total Synthesis of (-)-Galanthamine
Yang Zang, and Iwao Ojima
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400355j • Publication Date (Web): 11 Mar 2013
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Pd-catalyzed
Asymmetric
Allylic
Etherification
Using
Chiral
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Biphenol-based Diphosphonite Ligands and Its Application for The
Formal Total Synthesis of (-)-Galanthamine
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Yang Zang and Iwao Ojima*
Department of Chemistry, Stony Brook University, Stony Brook, NY 11794-3400
Email: Iwao.ojima@stonybrook.edu
ABSTRACT: A library of novel chiral biphenol-based diphosphonite (BOP) ligands
was designed and created. These BOP ligands were applied to a Pd-catalyzed
intermolecular allylic etherification reaction, which provided a key intermediate for
the formal total synthesis of (-)-galanthamine with 97% ee in 97% yield.
OTBDPS
OHC
OMe
[Pd(allyl)Cl]2/L*
OH
OMe
CHO
O
O
*
Br
OTBDPS
MeO
+
DMF
CN
CHO
Br
97% yield
97% ee
O
O
(-)-galanthamine
O
L* = BOP ligand
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INTRODUCTION
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Galanthamine (Figure 1), an amaryllidaceae alkaloid,1,2 has been used for the
treatment of mild to moderate Alzheimer’s disease and other memory impairments.3
Galanthamine reversibly inhibits acetylcholine esterase (Ache).4,5 Because the
isolation from nature sources is tedious, expensive and insufficient for clinical use, a
good number of chemical syntheses have been reported.6-14 Also, a biomimetic
synthesis through phenol coupling followed by dynamic resolution has been
performed in a pilot scale.15 However, only a few approaches to the asymmetric total
synthesis of (-)-galanthamine have been reported.16-20 One of the most efficient
methods was repored by Trost et al., wherein the critical chiral centers were created
by Pd-catalyzed intermolecular asymmetric allylic etherification.16-18 The best result
achieved so far in the key step using his “modular” diphosphine ligand, DPPBA, was
88% ee and 72% yield, and recrystallization was required in the subsequent step to
afford the key intermediate 6 (96% ee), bearing a tricyclic benzofuran skeleton with a
chiral quaternary carbon (Scheme 1).18 In addition, 6 is a versatile intermediate for the
syntheses of (-)-morphine and its derivatives, (-)-codeine and (-)-thebaine (Figure
1).18 Accordingly, this useful process to provide 6 still needs substantial improvement
in its enantioselectivity and chemical yield to be more practical.
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OMe
OH
OMe
5
MeN
6
O
O
O
7
8
9
MeN
MeN
H
H
OH
OR
OH
(-)-galanthamine
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(-)-morphine
R=H: (-)-codenine
R=Me: (-)-thebaine
Figure 1. (-)-Galanthamine, (-)-morphine and its derivatives
Scheme 1. Trost’s Total Synthesis of (-)-Galanthamine
Ph
Ph
MeO2C
O
O
NH HN
OH
O
CO2Me
OTroc
DPPBA
MeO
Br
MeO
Br
+
PPh2 Ph2P
CHO
CHO
[Pd(allyl)Cl]2, Et3N, CH2Cl2
72%
3 (88% ee)
1
2
1) CH(OMe)3
TsOH (5%)
2) DIBAL-H/
toluene
85%
CN
HOH2C
1) ACH, Ph3P
DIAD, Et2O
Pd(OAc)2
dppp
O
O
O
MeO
MeO
Br
2) TsOH (20%) MeO
THF, H2O
3) recrystallization
Br
Ag2CO3
91%
CN
CHO
CHO
CH(OCH3)2
76%,
5 (96% ee)
6
4
(ACH = acetonecyanohydrin)
We have been developing a library of novel chiral biphenol-based
monodentate phosphites and phosphoramidites as well as bidentate diphosphonite
ligands (BOP ligands) for a variety of catalytic asymmetric reactions.21-28 As
compared to common 1,1’-binaphthol-based diphosphonite (BINAPO) ligands,29,30
the novel BOP ligands have exhibited much higher efficiency in intramolecular and
intermolecular palladium-catalyzed asymmetric allylic amination (AAA) reaction (up
27,28
to 96% ee).
One of the salient features of BOP ligands is their fine-tuning
capability through modification of the substituents at the 3,3’-positions of the
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biphenyl moiety as well as the aromatic groups attached to the phosphorus atoms
(Figure 2). Thus, we have examined the efficacy of the BOP ligands (reported and
new) in the intermolecular asymmteric allylic etherification (AAE) reaction by
following up Trost’s approach to (-)-galanthamine and optimizing the
enantioselectivity and chemical yield for the synthesis of the key intermediate 6.
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R
OPPh2
OPPh2
OPAr2
R
OPAr2
(S)-L1a R = Ph
(S)-L1b R = 4-biphenyl
(S)-L1c R = 3,5-t-Bu2C6H3
(S)-L1d R = 2,6-Et2C6H3
(S)-L1e R = 2,4,6-Me3C6H2
(S)-L1f R = 1-Np
(S)-L1g R = 1-(2-MeNp)
(S)-L1h R = 1-(2-i-PrNp)
(S)-L2e Ar = tolyl
(S)-L3e Ar = m-xylyl
Figure 2. BOP ligand library (only S configuration is shown for simplicity)
Results and Disscusion
We investigated the AAE reaction of phenol 1 and allylic carbonates 7 instead
of 2 in Trost’s synthesis. Since the ester moiety of 2 was reduced to a hyroxymethyl
group later in Trost’s synthesis, we decided to use a protected hydroxymethyl group
in the allylic carbonate 7 from the beginning. It was reported that the methyl ester
moiety at the 2-position of 2 was essential for the reaction to take place under the
Trost conditions, and no reactions took place when other substrates bearing non-ester
moieties at the 2-position. We have recently used 7a and 7b for the successful
intermolecular AAA reaction.27 Initial screening of the allylic carbonates 7a-7c was
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performed using the BOP ligand, (R)-L1f, under the conditions almost the same as
those used for the previously reported intermolecular Pd-catalyzed AAA reaction.27
Thus, the reactions were carried out in DMF at the substrate concentration of 0.025 M
with a Pd/(R)-L1f ratio of 1:1.5. Results are summarized in Table 1.
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Table 1. Initial Screening of Allylic Substrates 7a-c
OR
OR
OMe
OR
OMe
OH
O
[Pd] (2.5 mol %)
(R)-L1f (7.5 mol %)
O
O
+
+
Br
O
Br
DMF, rt, 12 h
CHO
CHO
7a
R = TIPS
8a
8b
8c
9a
9b
9c
1
(+)-
(+)-
(+)-
R = TIPS
R = TBDMS
R = TBDPS
7b R = TBDMS
7c R = TBDPS
(1.1 eq.)
(+)-8 (%
entry substrate
catalyst
conv (%)a
(+)-8:9a
ee)b
1
2
3
4
7a
7b
7c
7c
Pd2(dba)3
Pd2(dba)3
>95
>95
>95
>95
54 (+)
62 (+)
72 (+)
80 (+)
80:20
79:21
82:18
85:15
Pd2(dba)3
[Pd(allyl)Cl]2
a Determined by 1H NMR. b Determined by HPLC using Chiralcel OJ after desilylation with TBAF.
As Table 1 shows, the aryl ethers (+)-8a-c were obtained in good yields in all
reactions, but together with byproduct 9a-c.27,31 It is of interest to note that the
formation of this type of byproduct was not reported by Trost et al, who used 2
instead of 7.16-18 An increase in enantioselectivity for the formation of (+)-8 was
observed as the size of the silyl group increased (Table 1, entries 1-3). Switching the
Pd-catalyst precursor Pd(0) (Pd2(dba)3) to Pd(II) ([Pd(allyl)Cl]2) increased the
enantioselectivity to 80% ee (Table 1, entry 4). All reactions completed within 12 h at
o
room temperature. Lowering the reaction temperature to 0 C slightly increased the
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enantioselectivity to 82% ee (see Table 2, entry1), but the reaction was naturally
slowed down.
8
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The effect of solvents on this reaction was also examined, using 7c as the
allylic substrate and [Pd(allyl)Cl]2 as the catalyst precursor, at 0 ºC for 24 h. As Table
2 shows, the reactions run in CH3CN and CH2Cl2 gave (+)-8c with 86% ee, but with
only 46-65% conversion (Table 2, entries 2 and 3). It was found that phenol 1
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o
precipitated out in these solvents at 0 C. Then, the addition of 1.1 equivalents of
triethylamine (TEA) was found to solve or improve this problem and the reactions
proceeded much more smoothly, especially in CH3CN (Table 2, entries 4 and 5).
Table 2. Effect of Solvents
OTBDPS
+
OTBDPS
OMe
OTBDPS
OMe
CHO
[Pd(allyl)Cl]2
(R)-L1f
OH
Br
O
O
O
+
solvent
0 oC, 24h
O
Br
CHO
1
(1.1 equiv)
7c
8c
9c
(+)-
entry solvent
conv (%)a
(+)-8c (% ee)b
(+)-8c:9ca
1
2
DMF
>95
65
82 (+)
86 (+)
86 (+)
84 (+)
84 (+)
90:10
92:8
CH3CN
CH2Cl2
CH3CN
CH2Cl2
3
46
93:7
4c
5c
>95
76
89:11
91:9
a,b See the footnote of Table 1. c 1.1 equiv of TEA was added.
Next, BOP ligands were screened using 7c as the allylic substrate, CH3CN as
o
the solvent and TEA (1.1 equiv) as the additive at 0 C for 24 h. The results are
summarized in Table 3. (The result on using (R)-L1f from Table 2 is included for
comparison). It should be noted that, at this point, we screened (S)-BOP ligands since
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the key intermediate 5 for (-)-galanthamine should have the (-)-(S) configuration, and
thus 8 should also have the (-)-(S) configuration, which was found to be achieved by
using (S)-BOP ligands based on the results shown above.
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Table 3. Screening of BOP ligandsa
entry
ligand
conv (%)b
8c (% ee)c
8c:9cb
1
2
3
4
5
6
7
8
(S)-L1a
(S)-L1b
(S)-L1c
(S)-L1d
(S)-L1e
(R)-L1f
(S)-L1g
(S)-L1h
>95
>95
78
79 (-)
78 (-)
69 (-)
90 (-)
91 (-)
84 (+)
90 (-)
90 (-)
92:8
92:8
87:13
90:10
92:8
90
>95
>95
89
89:11
89:11
88:12
83
a Reactions were run using 7c (0.025 M), [Pd(allyl)Cl2] (2.5 mol %) with a BOP ligand (5.0 mol %) and
1.1 equiv of TEA in CH3CN at 0 oC for 24 h. b, c See the footnote of Table 1
As Table 3 shows, (S)-L1b bearing a 4-phenylbenzyl group at the
3,3’-positions afforded (-)-8c with 78% ee (Table 3, entry 2), which was close to the
results using 3,3’-unsubustitued ligand (S)-L1a (Table 3, entry 1). However, the
introduction of a bulky substituent at the meta position, i.e., 3,5-di-tert-butylbenzyl
group at the 3,3’-positions, i.e., (S)-L1c, resulted in a substantial decrease in
enantioselectivity as well as conversion (Table 3, entry 3). In contrast to the para and
meta substitutions, a significant increase in enantioselectivity was observed when
ligands bearing an ortho-substituted benzyl group, including 2,6-disubstituted and
2,4,6-trisubsituted benzyl groups, was used at the 3,3’-positions, i.e., (S)-L1d-h
(Table 3, entries 4-8). It should be noted that the introduction of very bulky benzyl
groups, such as 2-Me-naphth-1-ylmethyl [(S)-L1g], and 2-i-Pr-naphth-1-ylmethyl
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[(S)-L1h], slightly reduced the reaction rate and product selectivity, but
enantioselectivity was not affected (Table 3, entries 7 and 8). Among the BOP ligands
screened, (S)-L1e gave the best result so far (Table 3, entry 5). Thus, (S)-L1e was
selected for further optimization. At this point, we also ran the reaction with (S)-L1e
in DMF and found that the same enantioselectivity (91% ee) was obtained without
addition of TEA, and the product selectivity was improved to 94:6 (see Table 4, entry
1).
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For further optimization of (S)-L1e, two new BOP ligands bearing p-tolyl
[(S)-L2e] and m-xylyl [(S)-L3e] groups in the diarylphosphorus moieties were
designed and prepared. Their efficacy was evaluated under the same conditions as
those employed for ligand (S)-L1e. As Table 4 shows, the introduction of a p-tolyl
group [(S)-L2e] slightly decreased the enantioselectivity (88% ee) and reaction rate
(Table 4, entry 2), while that of a m-xylyl group [(S)-L3e] considerably increased the
enantioselectivity to 97% ee with very good product selectivity (93:7), but slowed
down the reaction (Table 4, entry 3). Accordingly, the reaction was run at higher
concentration of 7c (0.1 M), which gave a moderate increase in conversion (Table 4,
entry 4). Thus, this substrate concentration was used in the subsequent reactions as
1
well. To our delight, 97% ee with full conversion (>95% by H NMR analysis
wherein no 7c was observed) after 36 h was achieved by increasing the Pd catalyst
precursor loading to 5 mol % (Table 4, entry5). When the reaction was run at room
temperature, the reaction was complete within 12 h and (-)-8c was obtained with 94%
o
ee (Table 4, entry 6). Addition of TEA at 0 C accelerated the reaction, but
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enantioselectivity was 94% ee (Table 4, entry 7).
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Table 4. Optimization of BOP ligands and conditionsa
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OTBDPS
OTBDPS
OMe
OTBDPS
OMe
[Pd(allyl)Cl]2
(S)-L
OH
Br
O
O
O
ne
+
+
DMF 0 o
C
O
Br
CHO
CHO
1
(1.1 equiv)
7c
8c
(-)-
9c
entry
ligand
time (h)
conv (%)b (-)-8c (% ee)c (-)-8c:9cb
1
(S)-L1e
(S)-L2e
(S)-L3e
(S)-L3e
24
24
24
24
36
12
12
>95
85
91 (-)
88 (-)
97 (-)
97 (-)
97 (-)
94 (-)
94 (-)
94:6
95:5
2
3
4d
41
93:7
51
89:11
91:9
5d,e (S)-L3e
6d,f (S)-L3e
7d,g (S)-L3e
>95
>95
>95
83:17
83:17
a Reactions were run using 7c (0.025 M), [Pd(allyl)Cl2] (2.5 mol %) with a BOP ligand (5.0 mol %) in
DMF at 0 C. b, c See the footnote of Table 1. d At 0.1 M concentration of 7c. e 5 mol % [Pd(allyl)Cl]2
and 15 mol % (S)-L3e. f At room temperature. g 1.1 equiv TEA was added.
o
With the optimized condition for the asymmetric allylic etherification, we
prepared (-)-8c with 97% ee and 97% isolated yield using a little excess of 2c (1.2
equiv) to increase the product yield, i.e, phenol 1 became the limiting reactant under
these conditions (Scheme 2). Deprotection of (-)-8c with TBAF afforded allylic
alcohol 10 in 99% yield. The key intermediate, nitrile 5, was prepared in good yield
(71% for two steps) by treatment of 10 with MsCl/TEA and then NaCN in DMSO.
The crucial tricylic key intermediate 6 for the total synthesis of (-)-galanthamine was
obtained in 90% yield through intramolecular Heck reaction. Thus, the critical
intermediate 6 was obtained via 5 steps in 61% overall yield from 1. As compared to
Trost’s original work (42 % yield for 6 steps from 1),18 our synthesis of 6 has made
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significant improvement, in that substantial enhancement of enantioselectivity (97%
ee vs 88% ee) was achieved in the AAE step so that recrystallization of 5 is not
necessary and the protection and deprotection of aldehyde (-)-8c is not required.
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Scheme 2. Synthesis of the key intermediate 6
OTBDPS
OTBDPS
OMe
OMe
CHO
[Pd(allyl)Cl]2
(S)-L3e
OH
Br
O
O
O
+
O
DMF, 0 o
97%
C
Br
8c
CHO
7c
1
(-)- (97% ee)
(1.2 equiv)
TBAF
99%
CN
O
HOH2C
1) MsCl
TEA
Pd(OAc)2
dppp
O
O
MeO
MeO
Br
Ag2CO3
MeO
Br
2) NaCN
71 %
CN
CHO
90%
CHO
CHO
6
10
5
CONCLUSIONS
A new series of BOP ligands have been developed, which exhibit excellent
efficacy when applied to the Pd-catalyzed AAE reaction, leading to the formal total
synthesis of (-)-galanthamine. The results presented here further demonstrate the
advantages of readily fine-tuning capability of our BOP ligands for a specific process
in a variety of catalytic asymmetric reactions, including the AAE reaction. Further
applications of BOP ligands as well as other biphenol-based chiral phosphorus ligands
are currently underway in our laboratory.
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EXPERIMENTAL SECTION
6
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1
General Methods. H, 13C, and 31P NMR were measured on a 500 MHz (500
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MHz for H; 125 MHz for C), 400 MHz (400 MHz for 1H; 100 MHz for C; 162
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MHz for P), or a 300 MHz (300 MHz for H; 75 MHz for C; 121.5 MHz for P)
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NMR spectrometer in a deuterated solvent using residual protons (CHCl3: H, 7.26
ppm; 13C, 77.0 ppm) as the internal standard or phosphoric acid as the external
reference (31P 0.00 ppm). Analytical HPLC in normal phase was carried out using a
Chiralcel OJ analytical column. Melting points were measured on a capillary melting
point apparatus and are uncorrected. Optical rotations were measured on a digital
polarimeter. TLC analyses were performed using aluminum pre-coated silica gel
plates. Flash column chromatography was carried out using silica gel (particle size
40~63 µm). High-resolution mass data were obtained using an electron impact (EI+)
or a time-of-flight (TOF) mass spectrometry. Unless otherwise noted all reactions
were carried out under argon or nitrogen atmosphere in oven-dried glassware using
standard Schlenck techniques.
Material. Solvents were reagents grade and freshly dried, degassed and
distilled before use. Anhydrous N,N-dimethylformamide (DMF) and acetonitrile were
obtained commercially and used without further purification. Chemicals and reagents
were purchased from commercial sources and used without further purification unless
otherwise noted. 2-Bromo-3-hydroxy-4-methoxybenzaldehyde (1) was prepared
following the reported procedure.18 Chiral BOP ligands, (S)-L1a and (R)-L1f, were
synthesized according to the procedure previously reported by our laboratory.27,28
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2-Hydroxymethyl-2-cyclohexenol,30,31 allylic vinyl carbonates 7a27,30 and 7b27 were
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prepared by the literature methods.
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(S)-3,3’-Bis(2,4,6-trimethylbenzyl)-5,5’,6,6’-tetramethyl-1,1’-biphenyl-2,2’-diol
((S)-B1e)
A solution of mesitylmagnesium bromide in tetrahydrofuran (THF, 1 M, 3 mL)
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was added at 0 C to a solution of (S)-3,3’-bis(chloromethyl)-2,2’-dimethoxy-
5,5’,6,6’-tetramethyl-1,1’-biphenyl27 (366 mg, 1 mmol) in THF (10 mL) containing
CuI (48 mg, 0.125 mmol) over 30 min. The mixture was warmed up to room
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temperature and stirred for an additional 30 min and then at 50 C for 10 h. The
reaction was quenched with aqueous NH4Cl solution (20 mL) and the reaction
mixture was extracted with CH2Cl2 (20 mL x 3). The combined organic layers were
washed with water (40 mL) and brine (40 mL), dried over anhydrous MgSO4, and
concentrated in vacuo. The resulting oil was directly used for the next step without
further purification.
Boron tribromide (2.2 mL, 1 M solution in CH2Cl2) was added dropwise over
20 min to a stirred solution of the previous crude product in CH2Cl2 (20 mL) at 0 oC.
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The mixture was stirred at 0 C for 1.5 h. The reaction was quenched by the slow
addition of water. The aqueous layer was extracted with Et2O (20 mL x 3). The
combined organic layers were washed with water (40 mL) and brine (40 mL), dried
over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel (hexanes/AcOEt = 50:1 to 30:1) to afford
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(S)-B1e (476 mg, 94% over two steps) as a white foam: mp 185-186 C; [α]D -20.0
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(c 0.30, CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.87 (s, 6H), 2.12 (s, 6H), 2.25 (s,
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12H), 2.33 (s, 6H), 3.95 (d, J = 17 Hz, 2H), 4.00 (d, J = 17 Hz, 2H), 4.76 (s, 2H), 6.45
(s, 2H), 6.93 (s, 4H); 13C NMR (100 Hz, CDCl3) δ 16.0, 19.9, 20.0, 20.9, 28.2, 119.7,
123.5, 128.8, 128.8, 129.8, 133.6, 133.9, 135.4, 137.2, 149.5; HRMS (EI+) calcd for
C36H42O2 [M]+ 506.3185, found 506.3193 (Δ = 0.8 ppm).
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In the same manner, chiral biphenols, (S)-B1b-d and (S)-B1g-h were
synthesized.
(S)-3,3’-Bis(4-phenylbenzyl)-5,5’,6,6’-tetramethyl-1,1’-biphenyl-2,2’-diol
((S)-B1b)
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White foam; 534 mg; yield 93%; mp 141-142 C; [α]D +10.8 (c 0.65,
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CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.94 (s, 6H), 2.28 (s, 6H), 4.06 (d, J = 15.2
Hz, 2H), 4.11 (d, J = 15.2 Hz, 2H), 4.72 (s, 2H), 7.06 (s, 2H), 7.38 (m, 6H), 7.46 (m,
4H), 7.57 (d, J = 7.8 Hz, 4H), 7.63 (d, J = 7.8 Hz, 4H); 13C NMR (100 Hz, CDCl3) δ
16.3, 19.9, 35.6, 120.5, 124.7, 127.1, 127.1, 127.2, 128.8, 129.1, 129.2, 132.6, 134.9,
138.9, 140.3, 141.2, 149.7; HRMS (EI+) calcd for C42H38O2 [M]+ 574.2872, found
574.2869 (Δ = -0.3 ppm).
(S)-3,3’-Bis(3,5-di-tert-butylbenzyl)-5,5’,6,6’-tetramethyl-1,1’-biphenyl-2,2’-diol
((S)-B1c)
White foam; 575 mg; yield 89%; mp 80-81 oC; [α]D21 +40.0 (c 0.45, CH2Cl2);
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1H NMR (400 MHz, CDCl3) δ 1.29 (s, 36H), 1.88 (s, 6H), 2.21 (s, 6H), 3.92 (d, J =
15.2 Hz, 2H), 4.04 (d, J = 15.2 Hz, 2H), 4.62 (s, 2H), 6.97 (s, 2H), 7.10 (s, 4H), 7.26
(s, 2H); 13C NMR (100 Hz, CDCl3) δ 16.2, 19.8, 31.5, 34.8, 36.2, 119.9, 120.6, 122.9,
124.8, 128.8, 132.5, 134.4, 140.0, 149.5, 150.6; HRMS (EI+) calcd for C46H62O2 [M]+
646.4750, found 646.4743 (Δ = -0.7 ppm).
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(S)-3,3’-Bis(2,6-diethylbenzyl)-5,5’,6,6’-tetramethyl-1,1’-biphenyl-2,2’-diol
((S)-B1d)
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White foam; 449 mg; yield 84%; mp 170-171 C; [α]D -14.9 (c 0.47,
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CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.19 (t, J = 7.5 Hz, 12H), 1.90 (s, 6H), 2.12
(s, 6H), 2.65 (q, J=7.5 Hz, 8H), 4.05 (d, J = 17.2 Hz, 2H), 4.12 (d, J = 17.2 Hz, 2H),
4.81 (s, 2H), 6.45 (s, 2H), 7.17 (d, J = 7.5 Hz, 4H), 7.26 (t, J = 7.5 Hz, 2H); 13C NMR
(100 Hz, CDCl3) δ 15.4, 16.0, 19.8, 26.4, 27.1, 119.6, 124.4, 126.2, 126.6, 128.8,
130.3, 133.9, 135.2, 143.4, 149.2; HRMS (EI+) calcd for C38H46O2 [M]+ 534.3498,
found 534.3491 (Δ = -0.6 ppm).
(S)-3,3’-Bis(2-methylnaphthalen-1-ylmethyl)-5,5’,6,6’-tetramethyl-1,1’-biphenyl-
2,2’-diol ((S)-B1g)
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White foam; 484 mg; yield 88%; mp 127-128 C; [α]D -12.2 (c 0.74,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.89 (s, 6H), 2.02 (s, 6H), 2.54 (s, 6H), 4.47
(s, 4H), 4.94 (s, 2H), 6.42 (s, 2H), 7.43 (m, 6H), 7.76 (d, J = 8.4 Hz, 2H), 7.85 (d, J =
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6.9 Hz, 2H), 8.00 (d, J = 8.4 Hz, 2H); C NMR (100 Hz, CDCl3) δ 16.1, 19.8, 20.5,
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27.4, 119.8, 123.8, 124.3, 124.6, 126.0, 126.7, 128.4, 129.0, 129.2, 130.5, 132.6,
133.1, 133.4, 134.2, 134.5, 149.2; HRMS (EI+) calcd for C40H38O2 [M]+ 550.2872,
found 550.2863 (Δ = -0.8 ppm).
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(S)-3,3’-Bis(2-isopropylnaphthalen-1-ylmethyl)-5,5’,6,6’-tetramethyl-1,1’-biphen
yl-2,2’-diol ((S)-B1h)
White foam; 527 mg; yield 87%; mp 125-126 oC; [α]D21 -12.9 (c 0.3, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 1.32 (t, J = 7.7 Hz, 12H), 1.89 (s, 6H), 2.02 (s, 6H),
3.46 (m, 2H),
4.49 (d, J = 18.6 Hz, 2H), 4.54 (d, J = 18.6 Hz, 2H), 4.94 (s, 2H),
6.45 (s, 2H), 7.43 (m, 4H), 7.57 (d, J = 8.8 Hz, 2H), 7.82 (m 4H), 7.99 (d, J = 8.8 Hz,
2H); 13C NMR (100 Hz, CDCl3) δ 16.1, 19.8, 23.9, 23.9, 26.6, 29.8, 119.7, 123.9,
124.5, 124.7, 124.9, 126.1, 127.3, 128.3, 128.9, 130.8, 131.4, 132.4, 133.1, 134.1,
144.8, 149.0; HRMS (EI+) calcd for C44H46O2 [M]+ 606.3498, found 606.3507 (Δ =
0.9 ppm).
(S)-2,2’-Bisdiphenylphosphinoxy-3,3’-bis(2,4,6-trimethylbenzyl)-5,5’,6,6’-tetrame
thyl-1,1’-biphenyl ((S)-L1e)
A solution of chlorodiphenylphosphine (221 mg, 1 mmol) in CH2Cl2 (2 mL)
was added slowly over 20 min to a solution of an enantiopure biphenol (S)-B1e (202
mg, 0.4 mmol), 4-N,N-di- methylaminopyridine (DMAP) (5 mg, 0.04 mmol), and
triethyl- amine (TEA) (0.3 ml, 2.5 mmol) in CH2Cl2 (4 mL) at 0 oC. The mixture was
stirred at the same temperature for additional 2 h. The reaction mixture was then
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concentrated in vacuo. The residue was dissolved in ether (4 mL) and filtered through
a pad of Celite. The filtrate was concentrated again and the crude product was purified
on a silical gel column pretreated with TEA by using hexanes/ AcOEt (50:1) as the
eluent to afford (S)-L1e (248 mg, 71%), as a white foam. mp 95-97 oC; [α]D21 +127.6
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(c 0.29, CH2Cl2); H NMR (400 MHz, CDCl3) δ 1.79 (s, 6H), 1.83 (s, 6H), 2.03 (s,
12H), 2.28 (s, 6H), 3.49 (d, J = 16.8 Hz, 2H), 3.66 (d, J = 16.8 Hz, 2H), 6.06 (s, 2H),
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6.82 (s, 4H), 7.18 (m, 12H), 7.38 (m, 8H); C NMR (100 Hz, CDCl3) δ 16.7, 20.0,
20.9, 29.9, 127.7, 127.9, 128.2, 128.5, 129.0, 129.2, 130.2, 130.3, 131.4, 134.1, 134.2,
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135.1, 137.2, 151.9; P NMR (121.5 Hz, CDCl3) δ 108.75; HRMS (ESI+) calcd for
C60H61O2P2 [M + H]+ 875.4147, found 875.4165 (Δ = 1.8 ppm).
In the same manner, BOP ligands, (S)-B1b-d, (S)-B1g-h and (S)-B2-3e were
synthesized.
(S)-2,2’-Bisdiphenylphosphinoxy-3,3’-bis(4-phenylbenzyl)-5,5’,6,6’-tetramethyl-1
,1’-biphenyl ((S)-L1b)
White foam; 264 mg; yield 70%; mp 85-87 oC; [α]D21 +130.0 (c 0.29, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 1.80 (s, 6H), 1.90 (s, 6H), 3.55 (d, J = 15.9 Hz, 2H),
3.72 (d, J=15.9 Hz, 2H), 6.48 (s, 2H), 7.02 (d, J = 8.0 Hz, 4H), 7.16 (m, 12H), 7.39
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(m, 18H), 7. 58 (d, J = 8.0 Hz, 4H); C NMR (100 Hz, CDCl3) δ 17.0, 19.9, 36.0,
126.7, 126.9, 127.7, 127.8, 128.7, 128.7, 128.8, 128.9, 129.5, 129.8, 130.6, 131.1,
131.6, 134.9, 138.3, 140.3, 141.2, 151.8; 13P NMR (121.5 Hz, CDCl3) δ 110.63;
HRMS (ESI+) calcd for C66H57O2P2 [M + H]+ 943.3834, found 943.3858 (Δ = 2.4
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(S)-2,2’-Bisdiphenylphosphinoxy-3,3’-bis(3,5-di-tert-butylbenzyl)-5,5’,6,6’-tetram
ethyl-1,1’-biphenyl ((S)-L1c)
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White foam; 329 mg; yield 81%; mp 81-83 oC; [α]D21 +77.1 (c 0.48, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 1.33 (s, 36H), 1.75 (s, 6H), 1.82 (s, 6H), 3.57 (d, J =
15.4 Hz, 2H), 3.69 (d, J = 15.4 Hz, 2H), 6.48 (s, 2H), 6.94 (m, 4H), 6.99 (s, 4H), 7.10
(m, 2H), 7.21 (m, 6H), 7.29 (m, 6H), 7. 42 (m, 4H); 13C NMR (100 Hz, CDCl3) δ 16.9,
19.8, 31.5, 34.7, 36.8, 119.4, 123.4, 127.5, 127.7, 128.2, 128.7, 129.1, 129.8, 130.4,
130.9, 131.3, 134.3, 140.2, 150.1; 13P NMR (121.5 Hz, CDCl3) δ 109.45; HRMS
(ESI+) calcd for C70H81O2P2 [M + H]+ 1015.5712, found 1015.5728 (Δ = 1.6 ppm).
(S)-2,2’-Bisdiphenylphosphinoxy-3,3’-bis(2,6-diethylbenzyl)-5,5’,6,6’-tetramethyl
-1,1’-biphenyl ((S)-L1d)
White foam; 267 mg; yield 74%; mp 80-82 oC; [α]D21 +125.8 (c 0.31, CH2Cl2);
1H NMR (400 MHz, CDCl3) δ 1.07 (t, J = 7.5 Hz, 12H), 1.81 (s, 6H), 1.84 (s, 6H),
2.45 (q, J = 7.5 Hz, 8H), 3.58 (d, J = 16.9 Hz, 2H), 3.81 (d, J = 16.9 Hz, 2H), 6.08 (s,
2H), 7.07 (d, J = 7.6 Hz, 4H), 7.21 (s, 14H), 7.41 (m, 8H); 13C NMR (100 Hz, CDCl3)
δ 15.3, 16.6, 20.0, 26.3, 29.0, 126.0, 126.3, 127.7, 127.9, 128.4, 128.7, 129.0, 130.2,
130.3, 131.4, 134.0, 135.8, 143.2, 151.6; 13P NMR (121.5 Hz, CDCl3) δ 108.84;
HRMS (ESI+) calcd for C62H65O2P2 [M + H]+ 903.4460, found 903.4478 (Δ = 1.8
ppm).
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(S)-2,2’-Bisdiphenylphosphinoxy-3,3’-bis(2-methylnaphthalen-1-ylmethyl)-5,5’,6,
6’-tetramethyl-1,1’-biphenyl ((S)-L1g)
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White foam; 287 mg; yield 78%; mp 109-111 C; [α]D +106.2 (c 0.65,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.68 (s, 6H), 1.75 (s, 6H), 2.31 (s, 6H), 4.06
(d, J = 16.8 Hz, 2H), 4.17 (d, J = 16.8 Hz, 2H), 6.04 (s, 2H), 7.06 (m, 4H), 7.13 (m,
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2H), 7.35 (m, 16H), 7.52 (m, 4H), 7.68 (d, J = 8.4 Hz, 2H), 7.82 (m, 4H); C NMR
(100 Hz, CDCl3) δ 16.8, 19.9, 20.5, 29.4, 124.5, 124.7, 125.9, 126.4, 127.9, 128.2,
128.8, 129.0, 129.7, 129.8, 130.3, 130.4, 131.6, 132.4, 133.0, 133.8, 134.4, 134.5,
143.2, 151.5; 13P NMR (121.5 Hz, CDCl3) δ 110.15; HRMS (ESI+) calcd for
C64H57O2P2 [M + H]+ 919.3834, found 919.3842 (Δ = 0.8 ppm).
(S)-2,2’-Bisdiphenylphosphinoxy-3,3’-bis(2-isopropylnaphthalen-1-ylmethyl)-5,5’
,6,6’-tetramethyl-1,1’-biphenyl ((S)-L1h)
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White foam; 277 mg; yield 71%; mp 106-108 C; [α]D +162.2 (c 0.37,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.20 (d, J = 6.8 Hz, 6H), 1.27 (d, J = 6.8 Hz,
6H), 1.73 (s, 6H), 1.78 (s, 6H), 3.26 (m, 2H), 4.12 (d, J = 17.1 Hz, 2H), 4.26 (d, J =
17.1 Hz, 2H), 6.13 (s, 2H), 7.09 (m, 4H), 7.16 (m, 2H), 7.29 (m, 6H), 7.39 (m, 4H),
7.52 (m, 10H), 7.81 (m, 4 H), 7.88 (d, J = 7.6 Hz, 2H); 13C NMR (100 Hz, CDCl3) δ
16.7, 19.9, 23.8, 23.9, 28.6, 29.6, 123.8, 124.6, 125.3, 125.9, 127.0, 127.9, 128.1,
128.7, 129.0, 129.4, 129.7, 130.3, 131.5, 131.9, 132.2, 133.0, 134.4, 143.2, 144.5,
151.2; 13P NMR (121.5 Hz, CDCl3) δ 109.95; HRMS (ESI+) calcd for C68H65O2P2 [M
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+ H]+ 975.4460, found 975.4490 (Δ = 3.0 ppm).
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(S)-2,2’-Bis[bis(p-tolyl)phosphinoxy]-3,3’-bis(2,4,6-trimethylbenzyl)-5,5’,6,6’-tetr
amethyl-1,1’-biphenyl ((S)-L2e)
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White foam; 290 mg; yield 78%; mp 110-112 C; [α]D +119.4 (c 0.31,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.82 (s, 6H), 1.87 (s, 6H), 2.07 (s, 12H), 2.28
(s, 6H), 2.32 (s, 6H), 2.33 (s, 6H), 3.54 (d, J = 16.8 Hz, 2H), 3.70 (d, J = 16.8 Hz, 2H),
6.12 (s, 2H), 6.87 (s, 4H), 7.01 (d, J = 7.8 Hz, 4H), 7.06 (d, J = 7.8 Hz, 4H), 7.32 (m,
8H); 13C NMR (100 Hz, CDCl3) δ 16.7, 19.9, 20.9, 21.3, 21.3, 29.9, 128.0, 128.5,
128.6, 129.4, 130.3, 130.5, 131.2, 134.1, 134.5, 135.0, 137.2, 138.2, 138.6, 152.0; 13P
NMR (121.5 Hz, CDCl3) δ 110.40; HRMS (ESI+) calcd for C64H69O2P2 [M + H]+
931.4773, found 931.4798 (Δ = 2.5 ppm).
(S)-2,2’-Bis[bis(m-xylyl)phosphinoxy]-3,3’-bis(2,4,6-trimethylbenzyl)-5,5’,6,6’-tet
ramethyl-1,1’-biphenyl ((S)-L3e)
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White foam; 296 mg; yield 75%; mp 114-116 C; [α]D +104.8 (c 0.21,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.72 (s, 6H), 1.83 (s, 6H), 2.03 (s, 12H), 2.20
(s, 12H), 2.22 (s, 12H), 2.27 (s, 6H), 3.43 (d, J = 16.6 Hz, 2H), 3.71 (d, J = 16.4 Hz,
2H), 6.10 (s, 2H), 6.82 (s, 4H), 6.83 (s, 4H), 7.04 (s, 4H), 7.08 (s, 4H); 13C NMR (100
Hz, CDCl3) δ 16.6, 19.9, 20.8, 21.3, 21.4, 29.6, 126.8, 127.8, 128.2, 128.5, 130.3,
130.5, 130.9, 133.9, 134.8, 135.0, 136.8, 136.9, 137.1, 151.9; 13P NMR (121.5 Hz,
CDCl3) δ 111.25; HRMS (ESI+) calcd for C68H77O2P2 [M + H]+ 987.5399, found
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987.5406 (Δ = 0.7 ppm).
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2-tert-Butyldiphenylsiloxymethylcyclohex-2-enyl ethenyl carbonate (7c)
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A solution of 2-hydroxymethyl-2-cyclohexenol30 (1.28 g, 10 mmol),
tert-butyldiphenylsilyl chloride (2.8 g, 10 mmol) and imidazole (2 g, 30 mmol) in
o
THF (16 mL) was stirred at 0 C for 1.5 h. Then AcOEt (50 mL) was added and the
organic layer was washed with water (20 mL), dried over Na2SO4, and concentrated
in vacuo. The residue was purified by column chromatography on silica gel
(hexane/AcOEt = 6:1) to afford 2-tert-butyldiphenylsiloxymethyl-2-cyclohexenol
(3.29 g, 90%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 1.10 (s, 9H), 1.58 (m,
1H), 1.78 (m, 4H), 2.08 (m, 1H), 2.86 (s, 1H), 4.20 (d, J = 11.9 Hz, 1H), 4.31 (m, 2H),
13
5.70 (brs, 1H), 7.42 (m, 6H), 7.73 (d, J = 7.4 Hz, 4H); C NMR (100 Hz, CDCl3) δ
17.8, 19.1, 25.2, 26.8, 31.0, 66.0, 68.3, 127.2, 127.7, 127.7, 129.7, 129.7, 133.0, 133.0,
135.6, 135.6, 137.2; HRMS (ESI+) calcd for C23H31O2Si [M + H]+ 367.2093, found
367.2103 (Δ = 1.0 ppm).
To a solution of 2-tert-butyldiphenylsiloxymethyl-2-cyclohexenol (2.9 g, 8.0
mmol) and pyridine (7 mL) in CH2Cl2 (24 mL) was added vinyl chloroformate (0.7
o
o
mL, 8.0 mmol) at 0 C. The resulting solution was stirred at 0 C for 1 h. After
removal of the solvent, the residue was purified by column chromatography on silica
gel (hexanes/AcOEt = 30:1) to afford 7c (3.2 g, 91%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 1.06 (s, 9H), 1.74 (m, 3H), 2.08 (m, 3H), 4.10 (d, J = 12.8 Hz, 1H),
4.23 (d, J = 12.8 Hz, 1H), 4.56 (dd, J = 1.9, 6.2 Hz, 1H), 4.90 (dd, J = 1.9, 13.9 Hz,
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1H), 5.37 (brs, 1H), 5.97 (brs, 1H), 7.10 (dd, J = 6.2, 13.9 Hz, 1H), 7.40 (m, 6H), 7.67
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(d, J = 7.0 Hz, 4H); C NMR (100 Hz, CDCl3) δ 17.6, 19.1, 24.7, 26.7, 28.2, 64.9,
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71.7, 97.3, 127.5, 127.6, 129.5, 129.5, 129.5, 133.3, 133.4, 133.5, 135.4, 135.5, 142.6,
154.3; HRMS (ESI+) calcd for C26H32O4SiNa [M + Na]+ 459.1968, found 459.1971
(Δ = 0.3 ppm).
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(-)-2-Bromo-3-(2-(tert-butyldiphenylsiloxymethyl)cyclohex-2-enyloxy)-4-methoxy
benzaldehyde ((-)-8c)
A solution of 7c (105 mg, 0.24 mmol) in DMF (1 mL) was added to a solution
of 1 (46 mg, 0.20 mmol), [Pd(allyl)Cl]2 (3.6 mg 5 mol%) and (S)-L3e (30 mg, 15
mol%) in DMF (1 mL) at 0 oC, which was preincubated for 15 min. The solution was
kept stirred at the same temperature for 36 h. The reaction mixture was diluted with
diethyl ether and washed with water (3 x 10 mL). The aqueous layer was extracted
with diethyl ether (3 x 10 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash
chromatography on silica gel (hexanes/AcOEt = 20: 1) to afford (-)-8c (112 mg, 97%)
as a colorless oil: [α]D21 -59.8 (c 0.28, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 1.06 (s,
9H), 1.56 (m, 2H), 2.12 (m, 4H), 3.66 (s, 3H), 4.35 (d, J = 13.8 Hz, 1H), 4.43 (d, J =
13.8 Hz, 1H), 4.81 (brs, 1H), 6.10 (brs, 1H), 6.85 (d, J = 8.4, 1H), 7.37 (m, 6H), 7.67
(m, 5H), 10.25 (s, 1H); 13C NMR (100 Hz, CDCl3) δ 18.1, 19.3, 25.1, 26.9, 28.3, 55.7,
65.4, 75.7, 110.7, 123.5, 125.7, 127.3, 127.5, 127.6, 127.6, 129.5, 129.5, 133.7, 133.9,
135.5, 135.6, 135.6, 144.8, 158.4, 191.4; HRMS (ESI+) calcd for C31H36O4SiBr [M +
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H]+ 579.1566, found 579.1561 (Δ = -0.5 ppm).
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In a similar manner, allylic etherification products, (+)-8a, (+)-8b, were
obtained using (R)-L1f as the chiral ligand.
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(+)-2-Bromo-3-(2-(tert-butyldimethylsiloxymethyl)cyclohex-2-enyloxy)-4-methox
ybenzaldehyde ((+)-8a)
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Colorless oil; H NMR (500 MHz, CDCl3) δ 0.04 (s, 6H), 0.90 (s, 9H), 1.55 (m, 2H),
2.08 (m, 4H), 3.92 (s, 3H), 4.35 (brs, 2H), 4.88 (brs, 1H), 6.03 (brs, 1H), 6.93 (d, J = 8.7
13
Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 10.27 (s, 1H); C NMR (125 MHz, CDCl3) δ -5.4,
-5.2, 18.1, 18.4, 25.1, 25.9, 28.2, 56.0, 64.5, 75.6, 110.7, 123.6, 125.7, 127.1, 127.5,
136.2, 144.7, 158.5, 191.5; HRMS (ESI+) calcd for C21H31O4SiBr [M]+ 454.1175,
found 454.1179 (Δ = 0.8 ppm).
(+)-2-Bromo-4-methoxy-3-(2-(triisopropylsiloxymethyl)cyclohex-2-enyloxy)benza
ldehyde ((+)-8b)
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Colorless oil; H NMR (500 MHz, CDCl3) δ 1.06 (d, J = 7.6 Hz 18H), 1.10 (m, 3H),
1.59 (m, 2H), 2.02 (m, 3H), 2.22 (m, 1H), 3.92 (s, 3H), 4.38 (d, J = 13.9 Hz, 1H), 4.48 (d,
J = 13.9 Hz, 1H), 4.85 (brs, 1H), 6.09 (brs, 1H), 6.94 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.6
Hz, 1H), 10.28 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 12.0, 17.7, 18.0, 25.1, 28.3,
55.9, 64.6, 75.8, 110.7, 123.7, 125.7, 126.4, 127.6, 136.1, 144.7, 158.5, 191.5; HRMS
(ESI+) calcd for C24H37O4SiBr [M]+ 496.1644, found 496.1645 (Δ = 0.2 ppm).
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(-)-2-Bromo-3-(2-hydroxymethylcyclohex-2-enyloxy)-4-methoxybenzaldehyde ((-)-10)
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To a solution of (-)-8c (90 mg, 0.16 mmol) in THF (1.6 mL) was added
tetra-n-butylammonium fluoride (1 M in THF, 0.2 mL) dropwise at room temperature.
The mixture was stirred at the same temperature for 1 h. After removal of the solvent,
the residue was purified by column chromatography on silica gel (hexanes/AcOEt =
2:1) to afford (-)-10 (54 mg, 99%) as a white solid: [α]D21 -106.5 (c 0.40, CH2Cl2); 1H
NMR (CDCl3, 400MHz): δ 1.50 (m, 2H), 2.03 (m, 3H), 2.24 (m, 1H), 3.98 (s, 3H),
4.27 (d, J = 12.4 Hz, 1H), 4.38 (d, J = 12.4 Hz, 1H), 4.95 (t, J = 4.1 Hz, 1H), 6.04 (brs,
1H), 6.99 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H), 10.29 (s, 1H); 13C NMR
(CDCl3, 100 MHz): δ 18.5, 25.2, 28.2, 56.3, 65.9, 77.3, 110.9, 124.0, 126.2, 127.8,
130.5, 136.3, 144.2, 158.1, 191.2. Enantiomers were separated by HPLC using
Chiralcel OJ column eluting with 95: 5 hexanes: isopropanol at 0.8 mL/min.
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Retention times: major enantiomer 55.1 min. and minor 66.8 min.1H NMR and C
NMR data are in agreement with the literature values.18
(-)-(S)-2-Bromo-3-(2-cyanomethylcyclohex-2-enyloxy)-4-methoxybenzaldehyde (5)
To a solution of (-)-10 (41 mg, 0.12 mmol) and TEA (0.04 mL, 0.29 mmol) in
DCM (1 mL) was added methanesulfonyl chloride (0.013 mL, 0.17 mmol), and the
solution was stirred at 0 oC for 15 min. The reaction mixture was then concentrated in
vacuo. The residue was dissolved in ether and filtered through a pad of Celite. The
filtrate was concentrated again. Because the crude product was unstable and prone to
decompose, it was immediately used for the next step without further purification.
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To a solution of the previous crude product in DMSO (1 mL) was added
NaCN (11.8 mg, 0.24 mmol), and the solution was stirred at room temperature for 1h.
Then EtOAc was added and the organic layer was washed with water, dried over
Na2SO4, and concentrated. The residue was purified by column chromatography on
silical gel (hexanes/AcOEt = 5:1) to afford 5 (30 mg, 71% over two steps) as a white
solid: [α]D21 -81.0 (c 0.30, CH2Cl2) (97% ee based on optical rotation; lit.18 [α]D -80.0
(c 3.05, CH2Cl2), 96%ee) ; 1H NMR (CDCl3, 400MHz): δ 1.60 (m, 2H), 2.01 (m, 3H),
2.25 (m, 1H), 3.35 (d, J = 18.1 Hz, 1H), 3.53 (d, J = 17.1 Hz, 1H), 3.99 (s, 3H), 4.82
(t, J = 3.5 Hz, 1H), 6.15 (brs, 1H), 6.98 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 8.7 Hz, 1H),
10.26 (s, 1H); 13C NMR (CDCl3, 100 MHz): δ 17.9, 22.7, 25.4, 28.0, 56.2, 76.1, 111.0,
118.4, 123.6, 126.4, 127.0, 127.6, 132.9, 143.9, 158.2, 191.1. All data are in
agreement with the literature values.18
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(-)-1-Formyl-4-methoxy-6,7-dihydro-5aH-9a-cyanomethyldibenzofuran (6)
To a 10 mL of flask was added 5 (30 mg, 0.08 mmol), Pd(OAc)2 (2.9 mg,
0.012 mmol), Ag2CO3 (70.9 mg, 0.24 mmol) and dppp (5.3 mg, 0.012 mmol).
Degassed toluene (1 mL) was added and the resulting suspension was heated at 107
0C for 24h. Direct column chromatography on silical gel (hexanes/AcOEt = 5:1)
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afford (-)-6 (19 mg, 90%) as a colorless liquid: [α]D -201.0 (c 0.30, CH2Cl2) (lit.18
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[α]D -199.0 (c 1.25, CH2Cl2); H NMR (CDCl3, 400MHz): δ 2.00 (m, 2H), 2.22 (m,
1H), 2.38 (m, 1H), 3.13 (d, J = 17.0 Hz, 1H), 3.45 (d, J = 17.0 Hz, 1H), 3.97 (s, 3H),
4.97 (t, J = 3.4 Hz, 1H), 5.98 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.4 Hz,
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1H), 9.79 (s, 1H); C NMR (CDCl3, 100 MHz): δ 18.8, 23.5, 26.1, 48.2, 56.2, 86.3,
111.0, 117.4, 126.0, 126.5, 130.5, 130.6, 132.0, 148.9, 150.3, 191.6. All data are in
agreement with the literature values.18
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Supporting Information. Copies of 1H, 13C, and 31P NMR spectra of new
compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
ACKNOWLEDGMENT
This work was supported by a grant from the National Science Foundation.
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