Catalytic asymmetric petasis reactions of vinylboronates

Article abstract of DOI:10.1021/jo4016425

Binaphthol-catalyzed asymmetric Petasis reactions of salicylaldehydes with dibutyl vinylboronates and secondary amines in the presence of 4 A molecular sieves (MS) afforded products with up to 99% ee in isolated yields of 39-94%. The 99% ee of the product indicated that the reaction by the binaphthol-catalyzed pathway was roughly 500 times faster than the uncatalyzed pathway. NMR experiments (¹H and ¹¹B) showed that the amine component played a role in triggering the reaction between the binaphthol catalyst and the vinylboronate in the catalytic reaction sequence. The 4 A MS enhanced both the rate and enantioselectivity by effective removal of water from the reaction system. A novel rearrangement reaction of the unconjugated allylic amine Petasis reaction product to a conjugated allylic amine was also observed.

Full text of DOI:10.1021/jo4016425

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Article
Catalytic Asymmetric Petasis Reactions of Vinylboronates
Xianglin Shi, William F Kiesman, Anna Levina, and Zhili Xin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4016425 • Publication Date (Web): 23 Aug 2013
Downloaded from http://pubs.acs.org on August 28, 2013
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Catalytic Asymmetric Petasis Reactions of Vinylboronates
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Xianglin Shi,* William F. Kiesman, Anna Levina, Zhili Xin
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Chemical Process Research and Development, Biogen Idec, 14 Cambridge Center, Cambridge,
MA 02142, USA;
Email: xianglin.shi@biogenidec.com
Table of Contents Graphic
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Abstract: Binaphthol catalyzed asymmetric Petasis reactions of salicylaldehydes with dibutyl
vinylboronates and secondary amines in the presence of 4Å molecular sieves (MS) afforded
products in up to 99% ee and 39−94% isolated yields. The 99% ee of product indicated that the
reaction by the binaphthol catalyzed pathway was roughly five hundred times faster than the
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uncatalyzed pathway. NMR experiments (1H and B) showed the amine component played a
role in triggering the reaction between the binaphthol catalyst and the vinylboronate in the
catalytic reaction sequence. 4Å MS enhanced both the rate and enantioselectivity by effective
removal of water from the reaction system. A novel rearrangement reaction of the unconjugated
allylic amine Petasis reaction product to a conjugated allylic amine was also observed.
Introduction
Multiple component Petasis reactions of boronic acids or their esters with amines and
aldehydes/ketones afford diverse complex structures in a single step from simple and readily
available starting materials.1 The reaction has been used in the synthesis of amino acids and
alcohols,2 iminocyclitols,3 natural products,4 and a drug recently approved for the treatment of
multiple sclerosis (Gilenya).5 The main characteristic of the Petasis reaction is the presence of a
hydroxyl or carboxylic acid group proximate to the reacting aldehyde or ketone carbonyl group.
This characteristic has been elegantly applied to diastereoselective syntheses of a variety of
compounds of interest by taking advantage of directing effect of the α–hydroxyl group of chiral
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aldehydes and ketones.1,3,4 Diastereoselective syntheses have also been demonstrated using
readily available chiral amines and boronates of chiral alcohols.1 These approaches, however,
have limited use for the Petasis reactions of salicylaldehydes due to lack of chirality in
salicylaldehydes and their lower reactivity.6
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Despite their potential versatility, few catalytic asymmetric Petasis reactions have been
reported.1 Lou and Schaus reported the first catalytic asymmetric Petasis reaction of glyoxylates
with boronates using organocatalyst7 binaphthols.8 Later Takemoto and coꢀworkers reported a
thioureaꢀalcohol conjugate catalyzed asymmetric Petasis reaction of Nꢀarylꢀαꢀimino amides with
vinylboronates.9 Yuan and coꢀworkers recently described catalytic asymmetric Petasis reactions
of salicylaldehydes with boronic acids using thioureaꢀbinaphthol conjugates10 and binaphthols11
as the catalysts. Unfortunately, in addition to the modest ee afforded by the more readily
available binaphthol catalysts, both catalytic systems showed low reactivity, with reactions
typically taking 1−5 days. The substrate scope of reaction partner amines was also limited to
cyclic secondary amines.10,11 The poor activity of these reaction systems may be due to either
the low reactivity of the intermediates formed from the reactions between boronic acids and
binaphthol catalysts or poor catalyst turnover rates.
In contrast to the boronic acids, the corresponding methyl, ethyl, isopropyl, and butyl esters
showed significantly higher reactivity and enantioselectivity in a variety of reactions in the
presence of binaphthol catalysts. Besides the Petasis reaction with glyoxylates,8 arylꢀ, alkenylꢀ,
and acetylenylboronates have shown good reactivity in asymmetric reactions with conjugated
ketones,1212,13 hemiacetals,14 and acylimines,15 as well as allylboronates with acyl imines,16 and
ketones17 in the presence of binaphthol catalysts to afford products in good ee and yields. The
reactions were usually very slow in the absence of the binaphthol catalysts. To explain the high
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ee obtained acyclic8,14−17 or cyclic12,18 binaphtholꢀboronate intermediates formed from reactions
between binaphthols and boronates were proposed. These results suggested interactions between
binaphthols and the boronates not only imparted stereoselectivity, but also enhanced reaction
rates. Low catalyst loading required for some reactions suggested that the binaphthol catalysts
readily decoupled from the products once formed and reentered the catalytic cycle.
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We have employed a nonꢀstereoselective Petasis reaction of substituted salicylaldehydes with
amines and boronic acids in the synthesis of a compound of biologic interest.19 During the
development of enantioselective Petasis reaction conditions for synthesis of the core structure of
the compound, we found that binaphthols dramatically increased the rate of Petasis reactions of
salicylaldehydes with vinylboronates to afford the chiral amines in high ee and good isolated
yields. Herein we disclose the results of this study, which represents the first example of
binaphthol catalyzed asymmetric reactions of salicylaldehydes with vinylboronates and amines.
Results and discussion
The investigation began by examining the reactions of salicylaldehyde with commercially
available phenyl and vinylboronates in the presence of a binaphthol catalyst (catꢀA*) in CH2Cl2
at 22 oC (Table 1). For PhB(OH)2 pinacol ester (entry 1), < 5% product was observed after 24 h.
Increased conversion (27%) was observed when molecular sieves (MS) 4Å were added, similar
to a previous account for the Petasis reaction of boronic acids.19 The screening data from Table
1 indicated that vinylboronates were more reactive than the corresponding phenylboronates and
the 76% ee for vinylB(OBu)2 (entry 4), although modest, was worthy of additional investigation.
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Therefore, the reaction of vinylB(OBu)2 was studied further with a goal to improve the
enantioselectivity of the transformation.
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Table 1. Reactions of Salicylaldehyde with Commercially Available Aryl and Vinylboronatesa
entry
1
R1B(OR2)2
conversion (%)
<5
ee (%)
ndc
2
3
27 b
ndc
26
92 (48 h)
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5
69b
ndc
76
100
a. Conditions: salicylaldehyde (0.2 mmol), catꢀA* (0.2 equiv), piperidine (1.2 equiv),
boronate (1.2 equiv), CH2Cl2 (0.8 mL), 22 oC, 24 h. The conversions and ee were determined by
HPLC. b. Reactions done at 0.8 mmol scale with 4Å MS (200 mg) added. c. not determined.
The effect of solvents on enantioselectivity of the reaction was explored first. Table 2 shows
the ee of 2 obtained from the reaction in six different solvents in the presence of 20ꢀmol% catꢀA*.
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As the data show, increase of ee from 76% in CH2Cl2 to 86% in toluene and trifluoromethyl
benzene was obtained. Decrease of ee to 46% was observed in EtOH.
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Table 2. Solvent Effect on the Enantioselectivity of the Binaphthol Catalyzed Petasis Reaction
solvent
CH2Cl2
76
PhMe
86
EtOAc
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PhCF3
86
EtOH
46
ee (%)
*Conditions: salicylaldehyde (0.2 mmol), catꢀA* (0.2 equiv), piperidine (1.2 equiv),
o
vinylB(OBu)2 (1.2 equiv), solvent (0.8 mL), 22 C, 24 h. The ee were determined by chiral
HPLC and the conversions were 91−100%.20
The reaction was accelerated by catꢀA* in all solvents. The reactions in the presence of the
catalyst were completed in 24 h with the exception in toluene (91% conversion). Uncatalyzed
reactions had significantly lower conversions; only the reaction in CH2Cl2 completed. Figure 1
shows the conversion rates of salicylaldehyde in three representative solvents. The observed ee
can be qualitatively explained by the differences between rates of the catalyzed (in solid lines)
and uncatalyzed (in dotted lines) reactions. The low ee (46%) obtained in EtOH was thought to
be due to loss of catalytic activity during the reaction, as indicated by diminishing difference in
conversions between the catalyzed (solid line) and the uncatalyzed (dotted line) reactions. The
data also showed that the background reaction was significant in all solvents, indicating a
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potential difficulty in achieving high ee. For prior binaphthol catalyzed reactions that achieved
high ee, the rates of the background reactions seemed negligible under the conditions.8,13
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Figure 1. Conversions of Salicylaldehyde in Three Representative Solvents in the Presence and
Absence of catꢀA*
The influence of the structures of the catalysts on the enantioselectivity was then examined in
the two best reaction solvents, CH2Cl2 and toluene, and the results are shown in Table 3. As the
data show, in CH2Cl2, the methyl group of catꢀA* provided the optimal size of 3 and 3’
substituents on the binaphthol while smaller hydrogen of catꢀB* or larger triphenylsilyl of catꢀD*
substituents provided poorer selectivity. In CH2Cl2, catꢀF* was less effective than catꢀA* and
catꢀE*, but in toluene it was as effective as catꢀA* and catꢀE*. In general, however, higher ee
was obtained in toluene than in CH2Cl2 regardless of the catalysts. Therefore, toluene was
chosen as the standard solvent for further exploration of the reactions. In toluene, catꢀE*, F*,
and A* provided highest but similar ee; therefore, the reaction was further investigated with only
catꢀA* and E*.
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Table 3. Effect of Catalyst Structures on Enantioselectivity of the Petasis Reaction in CH2Cl2
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and Toluenea
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cat*
ee (%)
cat-B*b
cat-D*b
cat-A*
cat-C*
cat-E* cat-F*
in CH2Cl2
in PhMe
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85
ꢀ63
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90
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a. Conditions: salicylaldehyde (0.2 mmol), catꢀA* (0.2 equiv), piperidine (1.2 equiv),
o
vinylB(OBu)2 (1.2 equiv), solvent (0.8 mL), 22 C, 26 h. The conversions were determined by
HPLC. The ee were determined by chiral HPLC and the conversions were 91ꢀ100%. b. The
major product obtained with (R) configuration catalysts was the enantiomer of 2.
Molecular sieves were used in many binaphthol catalyzed reaction of boronates and their
enhancement of reaction enantioselectivity was reported for binaphthol catalyzed allylboration of
acyl imines.16 The positive effect of 4Å MS on the rate and enantioselectivity of the reaction is
shown in Fig. 2. Similar results were observed for the reaction using catꢀE*. With the same
amount of 4Å MS, however, slightly higher ee were obtained with catꢀA*. Therefore, catꢀA*
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was considered as the better catalyst for this substrate and was used as the catalyst for additional
studies. As the data show, the 4Å MS not only accelerated the rate (Fig. 2a), but also increased
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Figure 2. Enhancement of both Conversion Rates (a) and Enantioselectivity (b) by 4Å MS*
20 mol% cat-A*, 4Å MS
OH
OH
+
+
OBu
NH
B
O
H
N
OBu
toluene, 22 oC, 3 h
1.2 equiv
1.2 equiv
2
* Conditions: salicylaldehyde (0.2 mmol), catꢀA* (0.2 equiv), piperidine (1.2 equiv),
vinylB(OBu)2 (1.2 equiv), 4Å MS, toluene (0.8 mL), 22 oC, 3 h. The conversions and ee were
determined by HPLC.
the ee of the product 2 (Fig. 2b). Further experiments showed use of 100−600 wt% 4Å MS
relative to the weight of salicylaldehyde was acceptable and afforded product 2 in about 99% ee
consistently. The ee increase from 87% to 99% due to addition of the 4Å MS has practical
significance because the resulting higher ee may be sufficient for most applications without the
need for further enrichment. Aldrich 3Å MS showed comparable effects. Drying agent MgCl2
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also enhanced the rate and the enantioselectivity of the reaction, but was less effective than the
4Å MS. Na2SO4 showed no effect, however.
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These results are in agreement with earlier work describing the beneficial effects of 4Å MS
ascribed to their efficient removal of H2O.19 The MS may also diminish hydrolysis of the
moisture sensitive boronates to form the corresponding boronic acids, which had slower reaction
rates in the presence of catꢀA* and afforded products in low ee.
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The Petasis reaction of salicylaldehydes with boronic acids in the presence of binaphthol
catalysts was slow and provided products in 0−87% ee.11 Our data indicated rate of the Petasis
reaction of salicylaldehyde with boronic acid, styrenylB(OH)2, in the presence of catꢀA* and 4Å
MS was actually slower than in the absence of the catalyst (Scheme 1) and provided lower
Scheme 1. Petasis Reactions of Boronic Acid in the Presence and Absence of catꢀA*
enantioselectivity (<40% ee) than its dibutyl ester (52% ee). HPLC monitoring revealed that the
reaction of the boronic acid reached 91% conversion in 30 min and completed in 2 h without catꢀ
A*. In the presence of the catalyst, the reaction stalled after 30 min. In contrast, the catalytic
reaction of dibutyl ester of the boronic acid was significantly faster than the uncatalyzed and
completed in less than 30 min. These results suggested the 4Å MS also eliminated the negative
effect of the boronic acid by preventing its formation from hydrolysis of the corresponding
boronate.
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Optimal amount of catꢀA* for the reaction of salicylaldehyde with vinylB(OBu)2 and
piperidine in toluene in the presence of 4Å MS was determined experimentally. The results
showed that the ee of 2 reached a plateau around 98% ee with ~20 mol% catꢀA* (Fig. 3).
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Figure 3. Effect of Catalyst Loading on Product ee*
*Conditions: salicylaldehyde (0.2 mmol), catꢀA* (0.2 equiv), piperidine (1.2 equiv),
vinylB(OBu)2 (1.2 equiv), 4Å MS, toluene (0.8 mL), 22 oC, 3 h. The conversions (95ꢀ100%)
and ee were determined by HPLC.
The substrate scope of the reaction was explored with a variety of reaction partners and the
results are shown in Table 4. The data were obtained using the reaction conditions optimized for
compound 2 and the yields were not optimized. Cyclic and acyclic secondary amines, except
HNCy2, participated in the reaction providing the products (6−11) in good yields and ee. To our
delight, participation of acyclic secondary amines showed the reaction had broader generality for
amine reaction partner compared to the binaphtholꢀthiourea and binaphthol catalyzed reactions
of boronic acids systems, where only cyclic secondary amines participated in the reaction.10,11
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Table 4. Scope of the Catalytic Asymmetric Petasis Reactiona
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Br
OMe
O2N
OH
OH
OH
OH
OH
N
N
N
N
N
O
2
4
3
5
6
92% yield
85 %c
70% yield
92% ee
94% yield
92% ee
92% yield
99% ee
99.8% ee (98.5% ee)b
7% ee
OH
OH
OH
OH
OH
Cy
N
N
N
N
N
Cy
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10
11
43% yield
80% ee
39% yield
96% ee
62 % yield
91 % ee
68 % yield
52% ee
0% yieldd
OH
OH
OH
OH
HN
N
N
N
HN
Cy
OMe
Cl
15
12
13
45% yield
84% ee (81% ee)
14
71 % yield
0% yieldd
0% yieldd
0% yieldd
96% ee (87% ee)
a. Representative conditions for 2: salicylaldehyde (1.6 mmol), catꢀA* (0.2 equiv), piperidine
o
(1.2 equiv), vinylB(OBu)2 (1.2 equiv), toluene (6 mL), 4Å MS (1.6 g), 22 C, 1.5 h. The yields
were for isolated products. b. Values in parentheses are for isolated products. c. Yield of crude
product after subtracting residual catꢀA*. d. No Petasis reaction products were observed.
Two reactions run using primary amines, cyclohexylamine and isopropylamine, respectively,
however did not provide the desired products (14 and 15). HPLC analysis showed that >75% of
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the starting salicylaldehyde remained after 3 days for both reactions. This result was consistent
with the observation that primary amines did not participate in the Petasis reaction of
salicylaldehydes with either boronic acids21 or boronates.22 The vinylboronates with electron
deficient, neutral, and rich aryl substituents on the 2ꢀposition of the vinyl also reacted to afford
products 11−13. The reaction worked well for electron neutral and deficient salicylaldehydes to
give products 2–4 in good yields and ee.
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With the electron donating group MeOꢀ on salicylaldehyde, the Petasis reaction went to
completion in < 30 min; however, analysis showed the chiral purity of 5 was ~7% ee. In
addition, purification of 5 by silica gel column chromatography was hampered by an apparent
lack of stability. A 1HꢀNMR spectrum of crude 5 obtained after aqueous workꢀup showed fairly
pure 5 containing ~20 mol% catꢀA*. However, chromatographic isolation gave 5 in very low
yield (the yield in Table 4 was based on crude 5 after subtracting residual catꢀA*content). In a
separate experiment, pure 5 was obtained from the unꢀcatalyzed reaction without a
chromatographic purification. These results indicated the reaction of 4ꢀMeOꢀsalicylaldehyde
was fast and clean. The observed low ee was either due to the low stereoselectivity of the
reaction or instability of the stereogenic center of 5.
Discrepancies in the ee determined in situ and after isolation, for examples compounds 11–13
(Table 4), indicated partial racemization of the stereogenic center occurred during isolation.
Erosion of the ee was also observed upon holding samples of isolated products, for instance a
o
change of ee for 2 from 98.5% to 96.9% was observed after holding it in a vial at 22 C for 4
days. Adding NEtiPr2 had no effect upon the ee erosion of 2, but adding TFA did accelerate the
o
ee erosion. The racemization of compound 2 in the reaction mixture at 22 C without isolation
was relatively slow, however. No change of ee in 48 h and a slight decrease (~ 0.2%) after 5
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days were observed. At lower temperature (0−5 C) 2 was chemically stable for at least 4
5
6
months based on NMR analysis.
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Racemic product 5 (oil) obtained from the unꢀcatalyzed reaction cleanly converted into a new
solid compound (16) at 22 oC in 2 days. An NMR sample of 5 in DMSOꢀd6 also converted into
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16 and the 1HꢀNMR spectrum showed 16 was the only product. Hꢀ and 13CꢀNMR, HRMS data
indicated 16 was a rearrangement product of 5 (Scheme 2).
Scheme 2. Rearrangement Reaction of Compound 5
OMe
OMe
neat or in DMSO-d6
OH
OH
22 oC
N
N
16
5
The rearrangement of 5 and racemization of the compounds discussed above may occur
through a quinone methide intermediate (Scheme 3), which was suggested23 as an intermediate in
the formation of 2Hꢀchromenes from aryl allylic amines.24 The quinone methide can react with
the amine eliminated during its formation resulting in racemization (pathway a) and the linear
rearrangement products (pathway b), such as 16. It may also undergo an electrocyclization25
(pathway c) to give the 2Hꢀchromenes, which may alternatively be formed through an anionic
cyclization mechanism as proposed previously.24 The mechanism, substrate scope, and
application of this rearrangement reaction are under investigation and will be reported separately.
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Scheme 3. Possible Mechanism for the Racemization, Rearrangement, and Cyclization
5
6
Reactions
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The (S) configuration of 2 obtained using (S)ꢀcatꢀA* was determined by using vibrational
circular dichroism (VCD)26 and that of 11 was determined on the basis of chiral HPLC analysis
and its sign of optical rotation comparing with literature data.10 The (R) enantiomer of 2 was
obtained in 98% ee with (R) enantiomer of catꢀA* based on chiral HPLC analysis. The absolute
configurations of the other compounds in Table 5 were assigned by analogy.
The mechanism for the rate acceleration27 of this catalytic Petasis reaction is not entirely
clear. Acyclic (III) and cyclic (IV) types of structures formed from reactions between
binaphthols and boronates were proposed to explain the observed enantioselectivity of many
reactions (Scheme 4).12ꢀ18 Formation of III with a vinylboronate was reported based on NMR
and MS studies.14 Our 1Hꢀ and 11B ꢀNMR experiments showed that the reaction between cat-A*
and vinylB(OBu)2 in CD2Cl2 in the presence of 4Å MS (a, Fig. 4) to generate either acyclic III
or cyclic IV was very slow28 compared with the overall rate of the catalytic Petasis reaction,
which was complete in < 20 min in a NMR tube under the same conditions. Addition of
salicylaldehyde did not affect the reaction between the catꢀA* and vinylB(OBu)2 in 24 h.29
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Scheme 4. Ligand Exchange Reaction between Binaphthols and Boronates
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However, addition of HNEt2 resulted in immediate appearance of new 1H signals in the aromatic
region (6.8−8.0 ppm) (b, Fig. 4). The spectra of the mixture remained the same over 24 h.
Signals of HNEt2 in the 1HꢀNMR spectra were broad suggesting coordination of HNEt2 to
1
Figure 4. H− and 11B−NMR Spectra of the Reaction Mixtures of catꢀA* and VinylB(OBu)2
and HNEt2
1
a. Partial H NMR and 11B NMR spectrum of the reaction mixture of catꢀA* (1.0 equiv),
vinylB(OBu)2 (1.0 equiv), and 4Å MS in CD2Cl2 at 22 oC taken after the mixing was completed.
1
b. Partial H NMR and 11B NMR spectrum of the reaction mixture of catꢀA* (1.0 equiv),
o
vinylB(OBu)2 (1.0 Equiv), HNEt2 (1.0 equiv), and 4Å MS in CD2Cl2 at 22 C taken after the
1
mixing was completed. Note the H NMR spectra of both reaction mixtures remained
unchanged over 24 h except appearance of similar weak new signals.
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vinylB(OBu)2. New 11B signals at 10.1 and 8.8 ppm in addition to the peak of vinylB(OBu)2 at
28.6 ppm were also detected from the mixture (b, Fig. 4). These data indicated formation of
tetrahedral boron complexes30 from the reaction. 1H and 11B NMR experiments showed there
was no change in spectrum between vinylB(OBu)2 and HNEt2 in CD2Cl2 in the presence of 4Å
MS at 22 oC in 24 h.31
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These NMR observations prompted us to propose a reaction mechanism shown in Scheme 5.
In this mechanism, HNEt2 reacts with salicylaldehyde to form iminium II, a proposed key
intermediate for Petasis reaction,19 through aminal I. HNEt2 also activates and participates in the
Scheme 5. Proposed Mechanism
reaction between catꢀA* and vinylB(OBu)2 to form reactive intermediates V or VI, which then
lead to the cyclic (VII) or acyclic (VIII) intermediates, respectively. Migration of the vinyl
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group in VII and VIII affords the Petasis product boron complex, which gives the final product
after aqueous workup. Each step of this catalytic reaction sequence is faster than the rate
limiting step of the uncatalyzed pathway and results in the overall rate acceleration. The
criticality of the −OH group of salicylaldehyde indicated in the mechanism was confirmed when
PhCHO did not react under the same conditions. The structures of V−VIII and the mechanism
for the rate acceleration of this catalytic Petasis reaction, particularly the role of the amine
components, are the subject of further studies and will be reported on in due course.
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In conclusion, a novel and highly enantioselective catalytic asymmetric Petasis reaction of
salicylaldehydes with secondary amines and vinylboronates has been achieved using
binaphthol−molecular sieves catalytic system. The amine component of the reaction also played
a role in activating the reaction between catꢀA* and vinylB(OBu)2.
Experimental Section
General. All reagents, catalysts, and solvents were purchased from commercial sources
and used as received. Both (S)ꢀ and (R)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol catalysts
were purchased from Astar Pharma. Molecular sieves (4Å, activated, 2.5 ꢁm, powdered) were
purchased from Aldrich. NMR spectra were recorded for 1H NMR at 400 MHz, for 13C NMR at
100 MHz. Chemical shifts are expressed as δ (ppm) values using TMS or the residual signals of
the solvents as the internal standard. High resolution mass spectra were acquired using FT ICR.
HPLC data were collected with UV detection at 214 nm or as specified using Sunfire column
(C18, 3.5 ꢁm, 150 x 4.6 mm) and mobile phase A: water with 0.1% TFA and B: acetonitrile with
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0.1% TFA; a linear gradient from 30ꢀ70% B in 15 min; flow rate 1 mL per minute. The products
were isolated by flash chromatography with CH2Cl2ꢀIPA gradient eluent.
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Representative procedure for preparation of racemic samples. Preparation of racemic
5-methoxy-2-(1-(piperidin-1-yl)allyl)phenol (5). To a magnetically stirred mixture of 4ꢀmethoxyꢀ
2ꢀhydroxyꢀbenzaldehyde (121 mg, 0.8 mmol), molecular sieves 4Å (0.8 g), and dibutyl
vinylboronate (211 ꢁL, 0.96 mmol, 1.2 equiv) in toluene (6 mL) was added piperidine (96 uL,
0.97 mmol, 1.2 equiv). The mixture was stirred at 22 ºC for 20 h (until completion by HPLC
analysis), and filtered through a Celite® bed. The Celite® bed was washed with toluene. The
combined filtrates were washed with dilute brine (3 times) and dried over anhydrous Na2SO4,
filtered and concentrated on a rotary evaporator to give product 5 as an oil (166 mg, 84% yield).
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The purity and structure of 5 were verified by HꢀNMR analysis. All other racemic samples
1
prepared by this procedure were confirmed by HꢀNMR and used for the development of the
chiral HPLC methods without further purification. 1H NMR (400 MHz, CDCl3) δ 11.77 (br.,
1H), 6.74 (d, J = 8.28 Hz, 1H), 6.30 (d, J = 2.26 Hz, 1H), 6.24 (dd, J = 2.51, 8.28 Hz, 1H), 5.80 ꢀ
5.96 (m, 1H), 5.06 ꢀ 5.22 (m, 2H), 3.84 (d, J = 9.54 Hz, 1H), 3.65 (s, 3H), 2.22 ꢀ 2.78 (m, 4H),
13
1.44 ꢀ 1.65 (m, 4H), 1.28 – 1.43 (m, 2H); C NMR (101 MHz, CDCl3) δ 158.6, 156.8, 133.2,
127.0, 116.7, 115.3, 103.2, 100.1, 71.7, 53.4, 49.2, 24.3, 22.5
(M + H)+ 248.16541, found 248.16438.
; ESIꢀHRMS: calcd. for C15H22NO2
Representative procedure for the catalytic asymmetric Petasis reactions. Preparation of
(S)-2-(1-(piperidin-1-yl)allyl)phenol (2). To a magnetically stirred mixture of 2ꢀhydroxyꢀ
benzaldehyde (195.4 mg, 1.6 mmol), (S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (100.6 mg,
0.32 mmol, 0.2 equiv), molecular sieves 4Å (1.60 g), dibutyl vinylboronate (423 ꢁL, 1.92 mmol,
1.2 equiv) in toluene (6 mL) was added piperidine (192 uL, 1.94 mmol, 1.2 equiv). The mixture
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was stirred at 22 ºC for 1.5 h and filtered through a Celite® bed (Note: The reaction was first
monitored by HPLC at 30 min reaction time and the data showed the reaction was complete. For
some reactions below the first HPLC analysis was done after 24 h). The Celite® bed was
washed with toluene. The product in the filtrate had 99% ee by HPLC analysis (Chiralcel ODꢀH
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column, eluent nꢀhexane containing 0.1% HNEt2, flow rate 0.8 mL/min, 35 C, signal detection
at 280 nm), tmajor =12.1 min, 99.4%; tminor = 16.8 min, 0.6%. The combined filtrates were washed
with dilute brine (3 times) and dried over anhydrous Na2SO4, filtered and concentrated on a
rotary evaporator. The residue was isolated by flash chromatography and the fractions
containing product 2 were combined and concentrated on rotary evaporator to give 2 as a
colorless oil (317 mg, 91% yield). The (S) configuration of 2 was determined by using VCD
(see next section of this experimental below). 98.4% ee by HPLC (same method as above),
tmajor=11.8 min, 99.2%; tminor = 16.0 min, 0.8%. [α]546 = +248o (c = 0.10, MeOH); 1H NMR
26
(400 MHz, DMSOꢀd6) δ 11.48 (brs., 1H), 7.04 ꢀ 7.13 (m, 1H), 7.00 (dd, J = 1.25, 7.53 Hz, 1H),
6.65 ꢀ 6.78 (m, 2H), 5.94 (td, J = 9.69, 17.00 Hz, 1H), 5.30 (dd, J = 1.63, 16.94 Hz, 1H), 5.21 (dd,
J = 2.01, 10.04 Hz, 1H), 4.08 (d, J = 9.54 Hz, 1H), 2.27 ꢀ 2.53 (m, 4H), 1.47 ꢀ 1.64 (m, 4H), 1.34
ꢀ 1.46 (m, 2H); 13C NMR (101 MHz, DMSOꢀd6) δ 156.7, 135.6, 128.2, 128.2, 125.0, 118.8,
118.4, 115.8, 71.9, 50.7, 25.6, 23.8; ESIꢀHRMS: calcd. for C14H20NO (M + H)+ 218.15394,
found 218.15401.
The enantiomer of 2, (R)-2-(1-(piperidin-1-yl)allyl)phenol, was made with (R)ꢀcatꢀA*
using the same procedure. The enantiomeric excess was 98% based on chiral HPLC analysis
tmajor=14.6 min, 99.3%; tminor = 11.2 min, 0.7%.
(S)-5-Bromo-2-(1-(piperidin-1-yl)allyl)phenol
(3).
4ꢀBromoꢀ2ꢀhydroxyꢀbenzaldehyde
(321.6 mg, 1.6 mmol), (S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (100.6 mg, 0.32 mmol, 0.2
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equiv), molecular sieves 4Å (1.60 g), dibutyl vinylboronate (423 ꢁL, 1.92 mmol, 1.2 equiv) in
toluene (6 mL), piperidine (192 uL, 1.94 mmol, 1.2 equiv), 22 ºC, 24 h. er: 92% ee by HPLC
analysis (Chiralcel ODꢀH column, eluent nꢀhexane containing 0.1% HNEt2, flow rate 0.8
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o
mL/min, 35 C, signal detection at 280 nm), tmajor = 10.1 min, 96%; tminor = 11.9 min, 4%. Oil
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(330 mg, 70% yield). [α]546 = +239o (c = 0.054, MeOH); H NMR (400 MHz, DMSOꢀd6) δ
6.83 ꢀ 7.00 (m, 3H), 5.90 (td, J = 9.60, 16.94 Hz, 1H), 5.32 (dd, J = 1.63, 16.94 Hz, 1H), 5.25 (dd,
J = 1.76, 10.04 Hz, 1H), 4.12 (d, J = 9.29 Hz, 1H), 2.29 ꢀ 2.52 (m, 4H), 1.47 ꢀ 1.61 (m, 4H), 1.32
ꢀ 1.45 (m, 2H); 13C NMR (101 MHz, DMSOꢀd6) δ 158.2, 135.0, 129.9, 124.7, 121.5, 120.6,
119.0, 118.4, 70.8, 50.5, 25.5, 23.7; ESIꢀHRMS: calcd. for C14H19BrNO (M + H)+ 296.06445,
found 296.06453.
(S)-4-Nitro-2-(1-(piperidin-1-yl)allyl)phenol (4). 4ꢀNitroꢀ2ꢀhydroxyꢀbenzaldehyde (267.4
mg, 1.6 mmol), (S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (100.6 mg, 0.32 mmol, 0.2 equiv),
molecular sieves 4Å (1.60 g), dibutyl vinylboronate (423 ꢁL, 1.92 mmol, 1.2 equiv) in toluene (6
mL), piperidine (192 uL, 1.94 mmol, 1.2 equiv), 22 ºC, 24 h. 92% ee by HPLC (Chiralcel ODꢀH
o
column, eluent hexanes/IPA/HNEt2 (99/1/0.1), flow rate 0.8 mL/min, 35 C, signal detection at
280 nm), tmajor = 12.4 min, 96%; tminor = 13.9 min, 4%. Oil (393 mg, 94%). [α]546 = +183o (c =
26
0.093, MeOH); 1H NMR (400 MHz, DMSOꢀd6) δ 8.02 (dd, J = 2.76, 9.04 Hz, 1H), 7.93 (d, J =
2.76 Hz, 1H), 6.78 (d, J = 9.04 Hz, 1H), 6.00 (td, J = 9.73, 16.94 Hz, 1H), 5.32 ꢀ 5.53 (m, 2H),
13
4.47 (d, J = 9.29 Hz, 1H), 2.48 ꢀ 2.68 (m, 4H), 1.51 ꢀ 1.66 (m, 4H), 1.34 ꢀ 1.48 (m, 1H); C
NMR (101 MHz, DMSOꢀd6) δ 166.4, 137.9, 133.1, 125.2, 124.7, 124.4, 121.2, 116.8, 70.1, 50.0,
25.0, 23.2; ESIꢀHRMS: calcd. for C14H19N2O3 (M + H)+ 263.13902, found 263.13906.
(S)-5-Methoxy-2-(1-(piperidin-1-yl)allyl)phenol (5). 4ꢀMethoxyꢀ2ꢀhydroxyꢀbenzaldehyde
(243 mg, 1.6 mmol), (S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (100.6 mg, 0.32 mmol, 0.2
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equiv), molecular sieves 4Å (1.60 g), dibutyl vinylboronate (423 ꢁL, 1.92 mmol, 1.2 equiv) in
toluene (6 mL), piperidine (192 uL, 1.94 mmol, 1.2 equiv), 22 ºC, 1 h. 7% ee by HPLC
(Chiralcel ODꢀH column, eluent hexanes/isopropanol/diethylamine (99/1/0.1), flow rate 0.8
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mL/min, 35 C, signal detection at 280 nm), tmajor = 10.6 min, 54%; tminor = 11.3 min, 46%. Oil
(183 mg, crude, containing 20 mol%, 85% yield after subtracting residual catalyst based on
NMR analysis). The characterization data of this compound were obtained with a racemic
sample immediately after it was made (see data above in procedure for preparation of racemic
samples).
o
Compound 5 is not stable (0 − 22 C) and cleanly converted into a new solid compound
14, (E)ꢀ5ꢀmethoxyꢀ2ꢀ(3ꢀ(piperidinꢀ1ꢀyl)propꢀ1ꢀenꢀ1ꢀyl)phenol, at 22 oC in
Characterization data of 14 are provided below.
2
days.
(E)-5-Methoxy-2-(3-(piperidin-1-yl)prop-1-en-1-yl)phenol (16). Pure compound 16
(solid) was obtained from racemic 5ꢀmethoxyꢀ2ꢀ(1ꢀ(piperidinꢀ1ꢀyl)allyl)phenol (5) when it was
o
1
left on bench at 22 C for ~2 days and then slurried in EtOAc and dried. H NMR (400 MHz,
CDCl3) δ 7.18 (d, J = 8.53 Hz, 1H), 6.55 ꢀ 6.69 (m, 1H), 6.29 ꢀ 6.52 (m, 3H), 3.75 (s, 3H), 3.17
(d, J = 6.78 Hz, 2H), 2.32 ꢀ 2.71 (m, 4H), 1.62 ꢀ 1.78 (m, 4H), 1.37 ꢀ 1.58 (m, 2H);
13C NMR
(101 MHz, CDCl3) δ 159.9, 155.9, 129.5, 129.4, 124.8, 117.7, 105.5, 102.2, 62.7, 55.2, 54.3,
ESIꢀHRMS: calcd. for C15H22NO2 (M + H)+ 248.16541, found 248.16430.
25.3, 24.2
.
(S)-2-(1-Morpholinoallyl)phenol (6). 2ꢀHydroxyꢀbenzaldehyde (195.0 mg, 1.6 mmol), (S)ꢀ
3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (100.6 mg, 0.32 mmol, 0.2 equiv), molecular sieves
4Å (1.60 g), dibutyl vinylboronate (423 ꢁL, 1.92 mmol, 1.2 equiv) in toluene (6 mL),
morpholine (168 uL, 1.92 mmol, 1.2 equiv), 22 ºC, 24 h. 99% ee by HPLC (Chiralcel ODꢀH
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280 nm), tmajor = 12.9 min, 99.5%; tminor = 14.2 min, 0.5%. Oil (324 mg, 92%). [α]546 = +212o
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(c = 0.11, MeOH); 1H NMR (400 MHz, DMSOꢀd6) δ 10.49 (s, 1H), 6.99 ꢀ 7.18 (m, 2H), 6.65 ꢀ
6.85 (m, 2H), 5.91 (td, J = 9.60, 16.94 Hz, 1H), 5.30 (dd, J = 1.51, 16.82 Hz, 1H), 5.17 (dd, J =
1.76, 10.04 Hz, 1H), 4.07 (d, J = 9.29 Hz, 1H), 3.60 (t, J = 4.64 Hz, 4H), 2.24 ꢀ 2.53 (m, 4H); 13C
NMR (101 MHz, DMSOꢀd6) δ 155.8, 136.7, 128.5, 128.2, 125.0, 119.2, 118.0, 115.7, 70.7, 66.2,
50.8; ESIꢀHRMS: calcd. for C13H18NO2 (M + H)+ 220.13325, found 220.13325.
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(S)-2-(1-(Diethylamino)allyl)phenol (7). 2ꢀHydroxyꢀbenzaldehyde (195.0 mg, 1.6 mmol),
(S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (100.6 mg, 0.32 mmol, 0.2 equiv), molecular
sieves 4Å (1.60 g), dibutyl vinylboronate (423 ꢁL, 1.92 mmol, 1.2 equiv) in toluene (6 mL),
diethylamine (199 uL, 1.92 mmol, 1.2 equiv), 22 ºC, 24 h. 80% ee by HPLC analysis (Chiralcel
o
ODꢀH column, eluent nꢀhexane containing 0.1% HNEt2, flow rate 0.8 mL/min, 35 C, signal
detection at 280 nm), tmajor = 10.7 min, 90.0%; tminor = 14.1 min, 10%. Oil (140 mg, 43%).
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[α]546 = ꢀ15o (c = 0.075, MeOH); 1H NMR (400 MHz, DMSOꢀd6) δ 7.06 ꢀ 7.14 (m, 1H), 7.00
(d, J = 6.78 Hz, 1H), 6.74 (dt, J = 0.88, 7.47 Hz, 1H), 6.69 (d, J = 8.03 Hz, 1H), 5.96 (td, J =
9.79, 17.07 Hz, 1H), 5.26 ꢀ 5.42 (m, 2H), 4.45 (d, J = 9.29 Hz, 1H), 2.59 ꢀ 2.73 (m, 2H), 2.45 ꢀ
2.56 (m, 2H), 1.02 (t, J = 7.15 Hz, 6H); 13C NMR (101 MHz, DMSOꢀd6) δ 157.2, 134.4, 128.2,
128.0, 125.3, 119.2, 118.7, 115.8, 66.9, 42.4, 11.5; ESIꢀHRMS: calcd. for C13H20NO (M + H)+
206.15394, found 206.15399.
(S)-2-(1-(Diallylamino)allyl)phenol (8). 2ꢀHydroxyꢀbenzaldehyde (195.0 mg, 1.6 mmol),
(S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (100.6 mg, 0.32 mmol, 0.2 equiv), molecular
sieves 4Å (1.60 g), dibutyl vinylboronate (423 ꢁL, 1.92 mmol, 1.2 equiv) in toluene (6 mL),
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diallylamine (239 uL, 1.94 mmol, 1.2 equiv), 22 ºC, 24 h. 96% ee by HPLC (Chiralcel ODꢀH
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o
column, eluent nꢀhexane containing 0.1% HNEt2, flow rate 0.8 mL/min, 35 C, signal detection
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at 280 nm), tmajor = 10.0 min, 98.0%; tminor = 13.3 min, 2%. Oil (144 mg, 39%). [α]546 = +3.7o
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(c = 0.054, MeOH); H NMR (400 MHz, DMSOꢀd6) δ 10.86 (s, 1H), 7.02 ꢀ 7.15 (m, 2H), 6.70 ꢀ
6.79 (m, 2H), 5.91 ꢀ 6.06 (m, 1H), 5.84 (tdd, J = 6.59, 10.32, 16.91 Hz, 2H), 5.25 ꢀ 5.36 (m, 2H),
5.10 ꢀ 5.24 (m, 4H), 4.49 (d, J = 9.29 Hz, 1H), 3.01 ꢀ 3.25 (m, 4H); 13C NMR (101 MHz,
DMSOꢀd6) δ 156.6, 134.9, 134.1, 128.3, 128.2, 125.2, 119.1, 119.0, 118.8, 115.8, 65.6, 51.7;
ESIꢀHRMS: calcd. for C15H20NO (M + H)+ 230.15394, found 230.15400.
(S)-2-(1-(Pyrrolidin-1-yl)allyl)phenol (9). 2ꢀHydroxyꢀbenzaldehyde (195.0 mg, 1.6 mmol),
(S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (100.6 mg, 0.32 mmol, 0.2 equiv), molecular
sieves 4Å (1.60 g), dibutyl vinylboronate (423 ꢁL, 1.92 mmol, 1.2 equiv) in toluene (6 mL),
pyrrolidine (162 uL, 1.94 mmol, 1.2 equiv), 22 ºC, 24 h. 91% ee by HPLC (Chiralcel ODꢀH
o
column, eluent nꢀhexane containing 0.1% HNEt2, flow rate 0.8 mL/min, 35 C, signal detection
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at 280 nm), tmajor = 11.9 min, 95.5%; tminor = 14.2 min, 4.5%. Oil (200 mg, 62%). [α]546
=
+228o (c = 0.054, MeOH); H NMR (400 MHz, DMSOꢀd6) δ 11.07 (br. s., 1H), 7.02 ꢀ 7.14 (m,
1
2H), 6.64 ꢀ 6.79 (m, 2H), 5.90 ꢀ 6.06 (m, 1H), 5.26 (dd, J = 1.38, 16.94 Hz, 1H), 5.07 (dd, J =
13
1.76, 10.04 Hz, 1H), 4.00 (d, J = 8.78 Hz, 1H), 2.35 ꢀ 2.62 (m, 4H), 1.63 ꢀ 1.84 (m, 4H); C
NMR (101 MHz, DMSOꢀd6) δ 156.1, 138.0, 128.1, 127.9, 126.2, 118.9, 116.3, 115.6, 70.9, 51.4,
23.0; ESIꢀHRMS: calcd. for C13H18NO (M + H)+ 204.13829, found 204.13831.
(S,E)-2-(3-Phenyl-1-(piperidin-1-yl)allyl)phenol (11). This compound is the enantiomer of
a known compound.10 2ꢀHydroxyꢀbenzaldehyde (195 mg, 1.6 mmol), (S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀ
binaphthaleneꢀ2,2’ꢀdiol (100.6 mg, 0.32 mmol, 0.2 equiv), molecular sieves 4Å (1.60 g), dibutyl
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phenylvinylboronate (499 mg, 1.92 mmol, 1.2 equiv) in toluene (6 mL), piperidine (192 uL, 1.94
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mmol, 1.2 equiv), 22 ºC, 24 h. 52% ee by HPLC (Chiralpak ADꢀH column, eluent nꢀ
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hexane/EtOH/diethylamine: 97/3/0.1, flow rate 0.8 mL/min, 35 C, signal detection at 280 nm),
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tmajor = 6.3 min, 76%; tminor = 6.9 min, 24%. Oil (321 mg, 68%) turned into a solid in refrigerator.
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[α]546 = +44o (c = 0.054, MeOH).
(S,E)-2-(3-(4-Chlorophenyl)-1-(piperidin-1-yl)allyl)phenol (12). 2ꢀHydroxyꢀbenzaldehyde
(69 mg, 0.0.56 mmol), (S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (35.5 mg, 0.11 mmol, 0.2
equiv), molecular sieves 4Å (0.2 g), dibutyl 4ꢀchlorophenylvinylboronate (200 mg, 0.68 mmol,
1.2 equiv) in toluene (2 mL), piperidine (68 uL, 0.68 mmol, 1.2 equiv), 22 ºC, 1.5 h. 96% ee by
o
(Chiralpak ADꢀH column, eluent nꢀhexane/EtOH/HNEt2: 97/3/0.1, flow rate 1.0 mL/min, 35 C,
signal detection at 280 nm), tmajor = 5.5 min, 98%; tminor = 9.7 min, 2%. Oil (169 mg, 91%)
turned into a solid in refrigerator. [α]546 = +50o (c = 0.046, MeOH); H NMR (400 MHz,
DMSOꢀd6) δ 7.50 (d, J = 8.53 Hz, 2H), 7.37 (d, J = 8.28 Hz, 2H), 7.02 ꢀ 7.14 (m, 2H), 6.62 ꢀ
6.81 (m, 3H), 6.44 (dd, J = 9.54, 15.81 Hz, 1H), 4.26 (d, J = 9.29 Hz, 1H), 2.35 ꢀ 2.58 (m, 4H),
1.48 ꢀ 1.66 (m, 4H), 1.32 ꢀ 1.46 (m, 2H); 13C NMR (101 MHz, DMSOꢀd6) δ 156.6, 135.1, 132.0,
131.2, 128.5, 128.3, 128.3, 128.2, 128.1, 125.1, 118.9, 115.8, 70.8, 50.8, 25.6, 23.7; ESIꢀHRMS:
calcd. for C20H22ClNO (M + H)+ 328.14627, found 328.14637.
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(S,E)-2-(3-(4-Methoxyphenyl)-1-(piperidin-1-yl)allyl)phenol (13). 2ꢀHydroxyꢀbenzaldehyde
(28 mg, 0.23 mmol), (S)ꢀ3,3’ꢀdimethylꢀ1,1’ꢀbinaphthaleneꢀ2,2’ꢀdiol (14.5 mg, 0.046 mmol, 0.2
equiv), molecular sieves 4Å (0.4 g), dibutyl 4ꢀmethoxyphenylvinylboronate (80 mg, 0.28 mmol,
1.2 equiv) in toluene (0.9 mL), piperidine (28 uL, 0.28 mmol, 1.2 equiv), 22 ºC, 1 h. er: 84 by
HPLC (Chiralcel ODꢀH column, eluent nꢀhexane/EtOH/HNEt2: 97/3/0.1, flow rate 0.7 mL/min,
35 oC, signal detection at 280 nm), tmajor = 7.2 min, 92% (area); tminor = 7.6min, 8%. Oil (40 mg,
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43%) turned into a solid in refrigerator. [α]546 = +0.85o (c = 0.117, MeOH); H NMR (400
MHz, DMSOꢀd6) δ 11.64 (br. s., 1H), 7.40 (d, J = 8.78 Hz, 2H), 7.07 (dq, J = 1.63, 7.74 Hz, 2H),
6.88 (d, J = 8.78 Hz, 2H), 6.68 ꢀ 6.76 (m, 2H), 6.60 (d, J = 15.81 Hz, 1H), 6.24 (dd, J = 9.54,
15.81 Hz, 1H), 4.22 (d, J = 9.54 Hz, 1H), 3.74 (s, 3H), 2.38 ꢀ 2.60 (m, 4H), 1.49 ꢀ 1.60 (m, 4H),
1.37 ꢀ 1.47 (m, 2H); 13C NMR (101 MHz, DMSOꢀd6) δ 158.9, 156.7, 132.2, 128.8, 128.2, 128.0,
127.6, 125.5, 124.5, 118.8, 115.7, 113.9, 71.2, 55.0, 50.7, 25.6, 23.7; ESIꢀHRMS: calcd. for
C21H26NO2 (M + H)+ 324.19581, found 324.19585.
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Acknowledgments. The authors thank Mr. Lloyd Franklin and Ms. Lauren Blair, Biogen Idec,
for preliminary studies on the reactions; Dr. Xiaoping Hronowski, Ms. Annie Raditsis and Dr.
John Guzowski, Biogen Idec, for acquiring high resolution mass spectra and 11BꢀNMR data, for
help with chiral HPLC analysis, respectively; and Dr. Yanan He at Biotools for determining the
absolute configuration of compound 2 using VCD. The authors are also grateful for constructive
discussions with Dr. Donald Walker of Biogen Idec.
Supporting Information Available. Procedures, characterization data, H/13C NMR spectra,
1
chiral HPLC chromatograms of the new compounds; H/11B NMR spectra for mechanistic
1
studies. This material is available free of charge via the Internet at http://pubs.acs.org
1 For reviews, see: a) Candeias, N. R.; Montalbano, F.; Cal, P. M. S.D.; and Gois, P. M. P. Chem.
Rev. 2010, 110, 6169; b) Graaff, C. de; Ruijter, E.; Orru, R. V. A. Chem. Soc. Rev. 2012, 41,
3969 and references cited therein.
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2 (a) Petasis, N. A. and Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445; (b) Petasis, N. A.;
Goodman, A.; Zavialov, I. A. Tetrahedron Lett. 1997, 53, 16463; (c) Petasis, N. A. and Zavialov,
I. A. J. Am. Chem. Soc. 1998, 120, 11798.
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3 (a) Hong, Z.; Liu, L.; Hsu, C.ꢀC.; Wong, C.ꢀH. Angew. Chem. Int. Ed. 2006, 45, 7417; (b) Hong,
Z.; Liu, L.; Sugiyama, M.; Fu, Y.; Wong, C.ꢀH. J. Am. Chem. Soc. 2009, 131, 8352.
4 (a) Ritthiwigrom, T.; Willis, A.; Pyne, S. G. J. Org. Chem. 2010, 75, 815; (b) Ritthiwigrom, T.;
Pyne, S. G. Org. Lett. 2008, 10, 2769; (c) Davis, A. S.; Pyne, S. G.; Skelton, B. W.; White, A. H.
J. Org. Chem. 2004, 69, 3139.
5 Sugiyama, S.; Arai, S.; Kiriyama, M.; Ishii, K. Chem. Pharm. Bull. 2005, 53, 100.
6 Boronic acid diol esters, analog of the typically required chiral diol boronic acid esters for
diastereoselective reactions, showed low reactivity toward salicylaldehyde, see Jourdan, H.;
Gouhier, G.; Van Hijfte, L.; Angibaud, P.; Piettre, S. R. Tetrahedron Lett. 2005, 46, 8027.
7 For reviews on organocatalysis, see (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713ꢀ5743; (b) Cheong, P. H.ꢀY.; Legault,C. Y.; Um, J. M.; CelebiꢀOlcum, N.; Houk, K. N.
Chem. Rev. 2011, 111, 5042.
8 Lou, S. and Schaus, S. E. J. Am. Chem. Soc. 2008, 130, 6922.
9 Inokuma, T.; Suzuki,Y.; Sakaeda, T.; Takemoto, Y. Chem. Asian J. 2011, 6, 2902.
10 Han, W.ꢀY.; Wu, Z.ꢀJ.; Zhang, X.ꢀM.; Yuan, W.ꢀC. Org. Lett. 2012, 14, 976.
11 Han, W.ꢀY.; Zuo, J.; Zhang, X.ꢀM.; Yuan, W.ꢀC. Tetrahedron 2013, 69, 537.
12
Wu, T. R. and Chong, J. M. J. Am. Chem. Soc. 2005, 127, 3244.
13 Wu, T. R. and Chong, J. M. J. Am. Chem. Soc. 2007, 129, 4908.
14 Muncipinto, G.; Moquist, P. N.; Schreiber, S. L.; Schaus, S. E. Angew. Chem. Int. Ed. 2011,
50, 8172.
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15 Bishop, J. A.; Lou, S.; Schaus, S. C. Angew. Chem. Int. Ed. 2009, 48, 4337.
16 Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007, 129, 15398.
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Barnett, D. S.; Moquist, P.N.; Schaus, S. E. Angew. Chem. Int. Ed. 2009, 48, 8679 and
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references cited therein.
18 a) Paton, R. S.; Goodman, J. M.; Pellegrinet, S. C. Org. Lett. 2009, 11, 37; b) Sakata, K. and
Fujimoto, H. J. Am. Chem. Soc. 2008, 130, 12519.
19 Shi, X.; Hebrault, D.; Humora, D.; Kiesman, W. F.; Peng, H.; Talreja,T.; Wang, Z.; Xin, Z. J.
Org. Chem. 2012, 77, 1154.
20 Although the reaction in CH2Cl2 completed in 3 h, chiral HPLC monitoring showed there was
no racemization of product 2 in the reaction mixture at 22 oC in 24 h.
21
Candeias, N. R.; Cal, P. M.S.D.; Andre, V.; Duarte, M. T.; Veiros, L. F.; Gois, P M.
Tetrahedron 2010, 66, 2736.
22 Jourdan, H.; Gouhier, G.; Van Hijfte, L.; Angibaud, P.; Piettre, S. R. Tetrahedron Lett. 2005,
46, 8027.
23 Batey, R. A. in Boronic Acids, Preparation, Applications in Organic Synthesis and medicine;
Hall, D. G. Ed.; WileyꢀVCH Verglag GmbH & Co. KGaA, 2005; p 292.
24 Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063.
25 Smith, M. B.; March, J. March’s Advanced Organic Chemistry, Reactions, Mechanisms, and
Structure, 6th ed; John Wiley & Sons, Inc.: Hoboken, New Jersey, 2007; pp 1632ꢀ1633.
26
VCD has become a useful tool to determine absolute configuration of a variety of chiral
molecules including active pharmaceutical ingredients and natural products. For a review on
VCD, see (a) He, Y.; Wang, B.; Dukor, R. K.; Nafie, L. A. Appl. Spectrosc. 2011, 65, 699. For
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determination of absolute configuration using VCD without calculation, see (b) Taniguchi, T.;
Monde, K. J. Am. Chem. Soc. 2012, 134, 3695.
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27 Assuming the catalytic reaction followed the mechanism depicted in Scheme 5 and produced
only one enantiomer, the overall reaction rate via the catalyzed pathway was roughly 495 times
faster than the uncatalyzed reaction in order to provide product in 99% ee with 20 mol% catꢀA*.
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No new H signals were observed in the reaction mixture of catꢀA* and vinylB(OBu)2 in the
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presence of MS (4 Å) at 22 C in 1 h. Some very weak new H signals in the aromatic region
appeared in the spectrum of the reaction mixture after 19 h.
29 Electrophile acetophenone was reported to catalyze the reaction between 3,3ꢀBr2ꢀBINOL and
diisopropyl allylboronate, see ref. 16.
30 H. Nöth, B. Wrackmeyer, in Nuclear Magnetic Resonance Spectroscopy of Boron Compounds,
P. Diehl, E. Fluck, R. Kosfeld Ed, NMR Basic Principles and Progress Series 14, Springerꢀ
Verlag, Berlin, 1978; pp 300ꢀ305.
31 Boronic acids react with amines quickly. See Schlienger, N.; Bryce, M. R.; Hansen, T. K.
Tetrahedron 2000, 56,10023.
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