Molecular Iodine-Mediated α-C-H Oxidation of Pyrrolidines to N,O-Acetals: Synthesis of (±)-Preussin by Late-Stage 2,5-Difunctionalizations of Pyrrolidine

Article abstract of DOI:10.1021/acs.joc.7b00361

We previously reported an iterative synthesis of unsymmetrical 2,5-disubstituted pyrrolidines from pyrrolidine by two rounds of redox-triggered α-C-H functionalization. Although this approach can be used to introduce substituents at the 2- and 5-positions, it is lengthy because the redox auxiliary must be removed and then reinstalled. Therefore, we sought to develop a method to oxidize 2-functionalized pyrrolidine to cyclic N,O-acetal which could then react with a nucleophile for introduction of the 5-substituent. In this work, we found that molecular iodine can mediate the preferential oxidation of secondary over tertiary α-C-H bonds of α-substituted pyrrolidines to form cyclic N,O-acetals, improving the step economy of our previously reported method. With this strategy, (±)-preussin and its C(3) epimer were synthesized from (±)-pyrrolidin-3-ol.

Full text of DOI:10.1021/acs.joc.7b00361

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Article
Molecular Iodine–Mediated #-C–H Oxidation of Pyrrolidines to N,O-Acetals:
Synthesis of (±)-Preussin by Late-Stage 2,5-Difunctionalizations of Pyrrolidine
Hao-Jie Rong, Jun-Jun Yao, Ji-Kun Li, and Jin Qu
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 May 2017
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The Journal of Organic Chemistry
Molecular Iodine–Mediated αꢀC–H Oxidation of Pyrrolidines to N,OꢀAcetals: Synthesis of (±)ꢀPreussin
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by LateꢀStage 2,5ꢀDifunctionalizations of Pyrrolidine
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HaoꢀJie Rong, JunꢀJun Yao, JiꢀKun Li and Jin Qu*
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The State Key Laboratory and Institute of Elemento-organic Chemistry, Collaborative Innovation Center of Chemical Sci-
ence and Engineering (Tianjin), Nankai University, Tianjin 300071, China
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OH
R2M
R1
O
R1
N
N
R2
I2, K2CO3
TFE:CH2Cl2
(9:1)
O
OH
R1
Ph
O
O
N
C9H19
H
R1
N
CH3
(±)-preussin
N
H
R2
two round of late-stage
pyrrolidine -C H
functionalization
OH
N
R3
[O]
R2
N
R1
H
R2
OH
O
R3
R1
R1
N
N
R3M
R2
R2
ABSTRACT: We previously reported an iterative synthesis of unsymmetrical 2,5ꢀdisubstituted pyrrolidines from pyrrolidine by
two rounds of redoxꢀtriggered αꢀC–H functionalization. Although this approach can be used to introduce substituents at the 2ꢀ and
5ꢀpositions, it is lengthy because the redox auxiliary must be removed and then reinstalled. Therefore, we sought to develop a
method to oxidize 2ꢀfunctionalized pyrrolidine to cyclic N,Oꢀacetal which could then react with a nucleophile for introduction of
the 5ꢀsubstituent. In this work, we found that molecular iodine can mediate the preferential oxidation of secondary over tertiary αꢀ
C–H bonds of αꢀsubstituted pyrrolidines to form cyclic N,Oꢀacetals, improving the step economy of our previously reported methꢀ
od. With this strategy, (±)ꢀpreussin and its C(3) epimer were synthesized from (±)ꢀpyrrolidineꢀ3ꢀol.
Introduction
N,OꢀAcetals are analogues of acetals in which one oxygen atom in acetal is replaced by a nitrogen atom. N,OꢀAcetals are present in
many bioactive natural products.1 In addition, N,Oꢀacetals are synthetically useful because they act as masked iminium ions that are
stable under aerobic conditions but can be activated toward nucleophilic addition2 or oxidation.3 Chiral N,Oꢀacetal synthons have
been used in enantioselective syntheses of pyrrolidine and piperidine alkaloids.2a, 2b, 4 In analogy to the synthesis of acetals by reacꢀ
tions of aldehydes and diols, N,Oꢀacetals can be synthesized by addition of αꢀamino alcohols to aldehydes, as well as by other
methods.4ꢀ5 Recently, N,Oꢀacetal construction by direct oxidative C–O bond formation has become a focus of research (Figure 1).
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The reaction often begins with oxidation of the αꢀC–H bond of an amine by an intermolecular oxidant to produce an iminium ion,
which is attacked by an intraꢀ or intermolecular hydroxy group to generate the N,Oꢀacetal. Previously reported methods have used
the following oxidation pathways for iminium ion formation: oxidation by metalꢀbased oxidants combined with an inexpensive
terminal oxidant6 (e.g., Cu(OAc)2/O2,6d Ag2O/O26f); oxidation by hypervalent iodine reagents7 (e.g., PIDA, PIFA7c, 7e); redoxꢀneutral
type of amine αꢀoxygenation;2cꢀe, 8 anodic oxidation;9 and photoinduced oxidation.10 However, most of the previous work involved
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αꢀunsubstituted tertiary amines, and more research is necessary to enhance the regioselectivity of the oxidation of αꢀsubstituted
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tertiary amines.
Figure 1. N,O-Acetal Synthesis by Direct Oxidative C–O Bond Formation
We previously reported an iterative synthesis of unsymmetrical 2,5ꢀdisubstituted pyrrolidines from pyrrolidine by two rounds of
redoxꢀtriggered αꢀC–H functionalization (Scheme 1).2e In the first round, pyrrolidine reacts with oꢀbenzoquinone to generate an
N,Oꢀacetal, which then undergoes ring opening by a Grignard or organolithium reagent to introduce the first substituent at the αꢀ
position of pyrrolidine. The redox auxiliary is oxidatively removed to give a 2ꢀsubstituted pyrrolidine. In the second round, the 2ꢀ
substituted pyrrolidine reacts with oꢀbenzoquinone again to reinstall the N,Oꢀacetal in 2, which also undergoes ring opening by a
Grignard or organolithium reagent. Again, the redox auxiliary is removed to give the 2,5ꢀdisubstituted pyrrolidine. Although this
approach can be used to selectively introduce substituents at the 2ꢀ and 5ꢀpositions (with the trans product predominating), it is
lengthy because the redox auxiliary must be removed and then reinstalled. Therefore, we sought to develop a method to oxidize 2ꢀ
functionalized pyrrolidine 1, obtained from the first ringꢀopening step, to cyclic N,Oꢀacetal 2, which could then react with a nucleoꢀ
phile for introduction of the 5ꢀsubstituent (Scheme 1). The challenge was to control the regioselectivity of N,Oꢀacetal formation
because oxidation of the tertiary αꢀC–H, which gives the 2,2ꢀsubstituted N,Oꢀacetal, proceeds via an iminium ion intermediate that
is more thermodynamically stable than the intermediate from oxidation of the secondary αꢀC–H, which gives the 2,5ꢀsubstituted
N,Oꢀacetal. Herein, we report that with I2 as the oxidant, the secondary αꢀC–H of the αꢀsubstituted pyrrolidine could be selectively
oxidized in the presence of 3 equiv of K2CO3 to form a cyclic N,Oꢀacetal. This more stepꢀeconomical method was then used to synꢀ
thesize the natural product (±)ꢀpreussin and its C(3) epimer.
Scheme 1. Synthesis of 2,5-Disubstituted Pyrrolidines by Two-Round Functionalization of Pyrrolidine
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Results and Discussion
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First, we oxidized 2,4ꢀdiꢀtertꢀbutylꢀ6ꢀ(2ꢀcyclopropylpyrrolidinꢀ1ꢀyl)phenol (1a) by various previously reported methods. Specificalꢀ
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ly, Cu(OAc)2/O2 oxidized the tertiary αꢀC–H in 1a to afford 2,2ꢀdisubstituted N,Oꢀacetal 2a′ in 29% yield (Table 1, entry 1). In
contrast, CuCl2/O26g provided desired transꢀ 2,5ꢀdisubstituted N,Oꢀacetal 2a in 49% yield (entry 2). The use of a hypervalent iodine
reagent, PIDA or PIFA, in 2,2,2ꢀtrifluoroethanol (TFE)7c resulted in good chemical yields but gave a mixture of two regioisomers in
almost equal amounts (entries 3 and 4). Reaction with I2, a mild, readily available oxidant,11 in TFE gave a complicated reaction
mixture (entry 5). However, when K2CO3 was added, the reaction cleanly gave transꢀ product 2a in 75% yield as a single isomer
(entry 6). Owing to the poor solubility of 1a in TFE, we switched to 9:1 TFE/DCM, which improved the yield to 96% (entries 7 and
8). We also evaluated various concentrations and found that the yield dropped at concentrations higher than 0.03 M (entries 8–9).
Table 1. Oxidation and Cyclization of o-Pyrrolidine-Substituted Phenol 1aa
b
aReaction conditions: 1a (0.3 mmol) and oxidant in solvent (10 mL) were stirred at rt. Determined by NMR spectroscopy, with
1,3,5ꢀtrimethoxylbenzene as the internal standard. c1a (0.3 mmol) and copper (II) salt (0.06 mmol) in mꢀxylene (10 mL) were heatꢀ
ed at 130 °C in air. dIsolated yield.
Various alkyl groups are present in 2,5ꢀdisubstituted pyrrolidine natural products,12 so we investigated the reactions of 1 with difꢀ
ferent alkyl substituents at the αꢀposition of the pyrrolidine ring (Table 2). Within 0.5 h, reactions of 1b–1k exclusively gave deꢀ
sired N,Oꢀacetals 2b–2k, respectively. Previously, we found that reinstallation of the N,Oꢀacetal by the reaction between oꢀ
benzoquinone and pyrrolidines with a bulky αꢀsubstituent (n-heptyl or nꢀnonyl) required at least 48 h.2e With the current method,
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these reactions could be completed within 0.5 h at room temperature. Note that vinylꢀ and arylꢀsubstituted substrates 1l–1n were
unstable, so they were utilized immediately after purification. By using this procedure, we obtained target products 2l–2n in 53% to
70% yield over two steps. We also tested 2,3ꢀdisubstituted pyrrolidines 1o and 1p and were delighted to find that the oxidationꢀ
sensitive hydroxyl group was compatible with the reaction conditions, and the desired products 2o and 2p were obtained in good
yields at 0 °C.
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Table 2. Regioselective Oxidative Formation of N,OꢀAcetals 2a
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aReaction conditions: 1 (0.3 mmol), I2 (0.36 mmol), and K2CO3 (0.9 mmol) were stirred in 9:1 TFE/DCM (10 mL) at rt. bThe reacꢀ
tion was carried out at 0 °C overnight.
We carried out several experiments to elucidate the reaction mechanism (Scheme 2). Reaction of 1a in the presence of 3 equiv of
TEMPO gave 2a in 43% yield together with a 56% yield of the amide (2q) as the TEMPO oxidation product (Scheme 2, eq 1),
showing that the reaction did not go through a free radical mechanism. If the phenoxy group in 1a was converted to a methyl ether,
the resulting substrate did not react and was fully recovered after the reaction (data not shown). This suggested that the reaction
began with the oxidation of the phenoxy group. Oxidation of the phenoxy group by I2 initially gave iminium ion A. When H2O was
added to the reaction mixture as a coꢀsolvent, 2ꢀcyclopropylpyrrolidine (3a) and 3,5ꢀdiꢀtertꢀbutylꢀ1,2ꢀbenzoquinone (4), which are
the products of hydrolysis of A, were obtained (Scheme 2, eq 2). Similarly, the addition of pyrrolidine to the reaction mixture led to
the formation of amine exchange product 2r (Scheme 2, eq 3). Intermediate A tautomerized to intermediate B through a 1,5ꢀproton
shift. Then the cyclization of iminium B gave the transꢀ N,Oꢀacetal 2 exclusively. The 2,5ꢀregioselectivity was due to steric repulꢀ
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sion between the 2ꢀsubstituent and the carbonyl group during the 1,5ꢀproton shift involved in the transformation of A to B. When
the reaction was carried out in CF3CH2OD/DCM/D2O, no deuterium was found in the αꢀC–H bond of 3a (eq 4, Scheme 2), showing
that B could not be converted to A (the conversion of B to A is unfavorable because of the loss of aromaticity). This result suggests
that A formed first and then tautomerized to B, rather than the other way around (it has been reported that B can be produced by
direct oxidation of tertiary amines6d, 7c). However, when PIDA or PIFA was used as the oxidant, the reaction should generate iminiꢀ
um ion B and its conformational isomer B′ in almost equal amount; 7c, 7e the cyclizations of B and B′ afforded equal amounts of 2,5ꢀ
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and 2,2ꢀsubstituted N,Oꢀacetals 2 and 2′. The reaction also gave 2 equiv. of HI, the addition of K2CO3 can neutralize the acid generꢀ
ated.
Scheme 2. Proposed Pathway of the Oxidation Reaction
We used the method reported herein to synthesize (+)ꢀpreussin, which was first isolated in 1988 as a potent antifungal agent13 and
later revealed to have antitumor and antiviral activities.14 These bioactivities and its unique allꢀcis structure make it a popular target
for total synthesis. More than 30 routes to preussin and (+)ꢀpreussin B15 (a heptylꢀsubstituted analogue) have been reported to date,
five of the total syntheses were reported since 2014.15aꢀc, 15e, 15f Syntheses of all eight possible stereoisomers of preussin have also
been reported.15h, 15i, 15l, 16 Most of these syntheses start with (L)ꢀphenylalanine derived precursors; after installation of all the subꢀ
stituents in the correct configurations, the linear molecule is then cyclized to form the final pyrrolidine structure.15d, 15f, 15h, 17 We
hypothesized that we could use our lateꢀstage twoꢀround αꢀC–H functionalization protocol for a moreꢀflexible approach to preussin
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analogues. By employing proper Grignard reagents, other alkyl or aryl substitutions can also be easily introduced at the 2ꢀ, and 5ꢀ
positions of pyrrolidine.
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We started our synthesis from racemic Bocꢀprotected pyrrolidineꢀ3ꢀol (Scheme 3, $9/g, Bocꢀprotected (R)ꢀ and (S)ꢀpyrrolidineꢀ3ꢀol
are also commercially available). The acetate of pyrrolidineꢀ3ꢀol (5) reacted with quinone 4 to give desired N,Oꢀacetal 6. The regiꢀ
oselective oxidation of Cꢀ2 hydrogen was because of the higher acidity of this hydrogen due to the nearby hydroxy group. Ring
opening of 6 with a benzyl Grignard reagent gave transꢀ1o as the only product. The trans diastereoselectivity may have resulted
from the transient nucleophilic addition to the iminium by the neighboring acetyl carbonyl before the addition of the Grignard reaꢀ
gent (the acetyl group was removed during the treatment of excess amount of Grignard reagent).18 The ring opening reaction with
the hydroxy group unprotected 6 gave both transꢀ and cisꢀ products in almost equal amount. Then 1o was oxidized with I2/K2CO3 in
9:1 TFE/DCM to reinstall the N,Oꢀacetal moiety, and the resulting compound (2o) underwent ring opening by a nonyl Grignard
reagent from the opposite side of the C−O bond. Trans diastereoisomer 7 (relative to the hydroxy group) was the major product of
the second nucleophilic addition reaction of the N,Oꢀacetal. Transꢀproduct 7 and cisꢀproduct 7’ were inseparable mixture, also the
dr ratio of 7 and 7’ cannot be read out from the crude 1H NMR spectrum because product 7’ exists as an equilibrium mixture of one
major conformer and one minor conformer owing to the restricted rotation of the transꢀ 2,5ꢀdisubstituted pyrrolidine moiety. The
transꢀ major conclusion was deduced from the ratio of products 8 and 8’, which were produced from the mixture of 7 and 7’. Nꢀ
Dearylation of 7 followed by reductive amination gave the C(3) epimer of (±)ꢀpreussin (9). Oxidation and reduction of 915i gave
(±)ꢀpreussin (10), the spectroscopic data of which agreed with the literature.
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Scheme 3. Synthesis of (±)-Preussin and Its C(3) Epimer by Late-Stage Functionalizations of Pyrrolidine-3-ol
OH
OAc
1. AcCl, Et3N, DMAP(cat.)
CH2Cl2, 0 oC-rt
t-Bu
N
O
4, Et3N/TFE, rt
OAc
N
N
2. TFA/CH2Cl2, rt
99%
92%
H
TFA
Boc
t-Bu
5
6
trans:cis = 5:1
Ph
OH
OH
t-Bu
N
BnMgCl (4.0 equiv)/DCE
I2, K2CO3
t-Bu
N
O
0 °C-rt
98%
TFE/CH2Cl2(9:1)
0 °C-rt
Ph
OH
t-Bu
1o
OH
2o
t-Bu
OH
Ph
MgBr
HCHO,NaBH3CN
AcOH
(5.0 equiv)
8
I2, NaOH
Ph
t-Bu
N
CH2Cl2, 78 °C
CH3CN/H2O(2:1)
82%
N
8
8
H
71% for two steps
0 °C
83%
OH
trans:cis = 3.6:1
8 and 8'
t-Bu
trans major
7 and 7'
OH
Ph
OH
LiAlH4/THF, 40 °C
DMSO, (COCl)2, Et3N
Ph
N
8
THF, 78 °C
72%
dr = 9:1
100%
N
8
CH3
CH3
(±)-preussin 10
C(3)-epi-(±)-preussin 9
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Conclusion
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In summary, we found that I2 mediates regioꢀ and diastereoselective oxidation of the αꢀC–H bonds of pyrrolidines to form cyclic
N,Oꢀacetals, thus improving the step economy of our previously reported strategy for synthesizing unsymmetrically 2,5ꢀ
disubstituted pyrrolidines from pyrrolidine. (±)ꢀPreussin and its C(3) epimer were synthesized by two rounds of functionalization of
commercially available (±)ꢀBoc pyrrolidineꢀ3ꢀol (9 steps, 22% overall yield). Our practical, adaptable strategy for (±)ꢀpreussin synꢀ
thesis is potentially useful for the rapid construction of a library of preussin analogues.
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Experimental Section
General Information. Unless otherwise noted, all reagents were used without further purification. DCM was distilled from CaH2
before used. Flash column chromatographies were performed on Qingdao silica gel (200–300 mesh). 1H, 13C spectra were measured
on a NMR instrument (400 MHz for 1H NMR; 100 MHz for 13C NMR). Chemical shifts of 1H NMR spectra were recorded relative
to internal standard (TMS δ 0.00). The following abbreviations were used to express the multiplicities: s = singlet; d = doublet; t =
triplet; q = quartet; m = multiplet; br = broad. Chemical shifts of 13C NMR spectra were recorded relative to solvent resonance
(CDCl3: δ 77.0). Highꢀresolution mass spectral analyses were performed on a high resolution ESIꢀFTICR mass spectrometer.
Preparation and Characterization of Substrates
Substrates (1a −1k) were synthesized according to our previously reported method.2e
2,4-di-tert-butyl-6-(2-cyclopropylpyrrolidin-1-yl)phenol (1a) A solution of cyclopropylmagnesium bromide (0.5 M in THF, 3
mL, 1.5 mmol) was added dropwise to a solution of 5,7ꢀdiꢀtertꢀbutylꢀ1,2,3,3aꢀtetrahydrobenzo[d]pyrrolo[2,1ꢀb]oxazole2e (137 mg,
o
0.5 mmol) in DCE (10 mL) at 0 C under Ar. When the reaction completed, the reaction was quenched with saturated aqueous
NH4Cl, extracted with DCM (3x) and dried over MgSO4. The reaction mixture was concentrated and the residue was purified by
column chromatography (PE/EA = 50:1) to afford the title compound (149 mg, 95% yield) as colorless oil; Rf = 0.30 (PE/EA =
50/1);1H NMR (400 MHz, CDCl3) δ 8.26 (brs, 0.9H), 7.09 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 3.23 (ddd, J = 9.4, 7.3, 3.8
Hz, 1H), 2.99–2.87 (m, 1H), 2.41–2.30 (m, 1H), 2.17–2.03 (m, 1H), 2.01–1.87 (m, 2H), 1.82–1.60 (m, 1H) 1.41 (s, 9H), 1.27 (s,
9H), 0.66 (ddt, J = 13.1, 8.3, 4.1 Hz, 1H), 0.32–0.20 (m, 1H), 0.20–0.05 (m, 1H), 0.05 (dq, J = 9.8, 4.9 Hz, 1H), 0.40 (dq, J = 10.1,
5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 150.3, 140.7, 135.9, 133.3, 120.3, 116.9, 70.8, 55.3, 34.8, 34.5, 31.7, 30.8, 29.4, 23.4,
14.5, 3.3, 0.5; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H34NO: 316.2635; found: 316.2640.
2,4-di-tert-butyl-6-(2-methylpyrrolidin-1-yl)phenol (1b) Following the synthetic procedure of 1a, methylmagnesium bromide
(3.0 M in Et2O) was used and the title compound was obtained in 94% yield as a colorless oil; Rf = 0. 50 (PE/EA = 50/1); 1H NMR
(400 MHz, CDCl3) δ 8.06 (brs, 0.8H), 7.10 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 3.24 (ddd, J = 9.5, 7.3, 3.9 Hz, 1H), 3.20–
3.08 (m, 1H), 2.83 (q, J = 8.7 Hz, 1H), 2.21–2.09 (m, 1H), 2.02–1.83 (m, 2H), 1.63–1.48 (m, 1H), 1.41 (s, 9H), 1.29 (s, 9H), 0.96 (d,
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J = 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.2, 140.9, 135.0, 133.5, 120.5, 116.4, 60.4, 55.5, 34.8, 34.6, 33.0, 31.8, 29.5,
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2,4-di-tert-butyl-6-(2-nonylpyrrolidin-1-yl)phenol (1f) Following the synthetic procedure of 1a, nonyl magnesium bromide (1.0
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M in Et2O) was used and the title compound was obtained in 96% yield as a viscous colorless oil; Rf = 0.55 (PE/EA = 50/1); H
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NMR (400 MHz, CDCl3) δ 8.06 (brs, 0.9H), 7.10 (s, 0.9H), 7.05 (s, 1H), 3.27–3.16 (m, 1H), 3.04 (d, J = 7.9 Hz, 1H), 2.83–2.68 (m,
1H), 2.22–2.05 (m, 1H), 1.97–1.85 (m, 2H), 1.57 (q, J = 8.4 Hz, 2H), 1.41 (s, 9H), 1.30 (s, 9H), 1.28–1.09 (m, 15H), 0.86 (t, J = 7.0
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 150.1, 140.8, 135.5, 133.5, 120.4, 116.6, 64.9, 55.8, 34.8, 34.5, 34.2, 31.9, 31.7, 30.8,
29.65, 29.56, 29.48, 29.46, 29.3, 26.5, 23.3, 22.7, 14.1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C27H48NO: 402.3730; found:
402.3735.
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2,4-di-tert-butyl-6-(2-cyclopentylpyrrolidin-1-yl)phenol (1g) Following the synthetic procedure of 1a, cyclopentylmagnesium
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bromide (1.0 M in Et2O) was used, the title compound was obtained in 99% yield as colorless oil; Rf = 0.60 (PE/EA = 50/1); H
NMR (400 MHz, CDCl3) δ 8.18 (brs, 0.8H), 7.10 (d, J = 2.3 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 3.32–3.11 (m, 2H), 2.87–2.73 (m,
1H), 2.11–1.99 (m, 1H), 1.97–1.77 (m, 3H), 1.74–1.32 (m, 8H), 1.41 (s, 9H), 1.29 (s, 9H), 0.93–0.74 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 150.0, 140.8, 136.2, 133.3, 120.3, 117.1, 68.5, 56.8, 43.6, 34.8, 34.5, 31.7, 30.3, 29.4, 28.3, 28.1, 25.9, 25.4, 23.8; HRMS
(ESIꢀTOF) m/z: [M+H]+ Calcd for C23H38NO: 344.2948; found: 344.2952.
2,4-di-tert-butyl-6-(2-(4-methoxybenzyl)pyrrolidin-1-yl)phenol (1i) Following the synthetic procedure of 1a, (4ꢀ
methoxybenzyl)magnesium chloride (0.05 M in Et2O)19 was used, the title compound was obtained in 40% yield as colorless oil; Rf
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= 0.55 (PE/EA = 50/1); H NMR (400 MHz, CDCl3) δ 7.90 (brs, 0.8H), 7.16–7.04 (m, 2H), 6.97–6.90 (m, 2H), 6.78–6.70 (m, 2H),
3.75 (s, 3H), 3.36–3.23 (m, 2H), 2.85–2.72 (m, 1H), 2.72–2.61 (m, 1H), 2.47–2.31 (m, 1H) 2.02–1.81 (m, 3H), 1.75–1.59 (m, 1H),
1.42 (s, 9H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 157.8, 149.9, 141.1, 135.0, 133.8, 131.5, 129.9, 120.6, 116.3, 113.6, 66.2,
55.7, 55.2, 39.5, 34.9, 34.6, 31.8, 30.5, 29.5, 22.8; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C26H38NO2: 396.2897; found:
396.2899.
2,4-di-tert-butyl-6-(2-(4-fluorobenzyl)pyrrolidin-1-yl)phenol (1k) Following the synthetic procedure of 1a, 4ꢀ
fluorobenzylmagnesium (0.25 M in Et2O) was used, the title compound was obtained in 85% yield as colorless oil; Rf = 0.50
(PE/EA = 50/1); 1H NMR (400 MHz, CDCl3) δ 7.87 (brs, 0.8H), 7.11 (d, J = 2.3 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.99–6.92 (m,
2H), 6.91–6.83 (m, 2H), 3.40–3.23 (m, 2H), 2.84–2.72 (m, 1H), 2.69 (dd, J = 13.4, 4.3 Hz, 1H), 2.44 (dd, J = 13.4, 8.6 Hz, 1H),
2.05–1.81 (m, 3H), 1.71–1.60 (m, 1H), 1.42 (s, 9H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ161.3 (d, J = 244.2 Hz), 149.8,
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141.2, 135.0 (d, J = 3.1 Hz), 134.8, 133.8, 130.3 (d, J = 7.6 Hz), 120.6, 116.3, 114.9 (d, J = 21.6 Hz). 65.9, 55.8, 39.6, 34.8, 34.5,
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2-benzyl-1-(3,5-di-tert-butyl-2-hydroxyphenyl)pyrrolidin-3-ol (1o) To
a solution of tertꢀbutylꢀ3ꢀhydroxypyrrolidineꢀ1ꢀ
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carboxylate (337 mg, 1.8 mmol) in DCM (20 mL) at 0 C was added NEt3 (283 mg, 389 ꢀL, 2.8 mmol) and DMAP (24 mg, 0.2
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mmol) sequentially under Ar. AcCl (188 mg, 171 ꢀL,2.4 mmol) was added dropwise and the reaction was stirred at 0 C. Upon
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completion, the reaction was quenched by H2O, extracted with DCM (50 mL) three times. The combined organic layer was dried
with MgSO4 and concentrated. The residue was purified by chromatography using EA/PE (1:20) to give the double protected pyrꢀ
rolidineꢀ3ꢀo1. The protected pyrrolidineꢀ3ꢀo1was stirred in a mixed solvent of DCM (10 mL) and TFA (2 mL). When the reaction
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completed, the reaction mixture was concentrated to give 5 (403 mg, 99% yield). H NMR (400 MHz, CDCl3) δ 8.94 (brs, 1H),
8.78 (brs, 1H), 5.47–5.36 (m, 1H), 3.61–3.44 (m, 4H), 2.34–2.22 (m, 2H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 170.6, 72.2,
51.2, 44.5, 30.6, 20.6; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C6H12NO2 : 130.0863; found: 130.0865.
To the solution of 5 (403 mg, 1.8 mmol) in TFE (60 mL) was added NEt3 (546 mg, 0.75 mL, 5.4 mmol). Next, 3,5ꢀdiꢀtertꢀbutylꢀ1,2ꢀ
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benzoquinone 4 (436 mg, 1.98 mmol) was added portion wise at 0 C. Then reaction was stirred at room temperature. TFE was
evaporated when the reaction was completed. The residue was purified by chromatography using EA/PE (1:9) to afford 5,7ꢀdiꢀtertꢀ
butylꢀ1,2,3,3aꢀtetrahydrobenzo[d]pyrrolo[2,1ꢀb]oxazolꢀ3ꢀyl acetate 6 as the mixture of trans/cis diastereoisomers (602 mg, 92%
yield, trans/cis = 5:1, both trans and cis isomers were used in the next step). Trans isomer: 1H NMR (400 MHz, CDCl3) δ 6.83 (d, J
= 1.9 Hz, 1H), 6.74 (d, J = 1.9 Hz, 1H), 5.69 (s, 1H), 5.39–5.25 (m, 1H), 3.64–3.44 (m, 1H), 3.36–3.15 (m, 1H), 2.13 (s, 3H), 2.10–
2.00 (m, 1H), 1.92–1.82 (m, 1H), 1.33 (s, 9H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 170.3, 146.8, 144.2, 140.8, 131.0, 117.1,
109.6, 104.4, 78.2, 55.1, 34.7, 34.1, 31.8, 29.4, 29.2, 21.1.
Compound 6 (602 mg) obtained in the previous step was dissolved in DCE (40 mL) and PhCH2MgCl (7.2 mL, 1.0 M in Et2O, 7.2
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mmol) was added dropwise at 0 C under Ar. The reaction was diluted with DCM (50 mL) after 2 h, quenched with saturated
NH4Cl (20 mL), and extracted with DCM (50 mL) three times. The organic phase was concentrated and purified by chromatogꢀ
raphy using EA/PE = (1:9) to give the title compound 1o (613 mg, 98% yield) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3)
δ 7.59 (brs, 0.8H), 7.27–7.12 (m, 5H), 7.10–7.05 (m, 2H), 4.26–4.19 (m, 1H), 3.39–3.27 (m, 1H), 3.23–3.15 (m, 1H), 3.11–2.97 (m,
1H), 2.82 (dd, J = 13.5, 4.5 Hz, 1H), 2.61–2.47 (m, 1H), 2.31–2.17 (m, 1H), 1.90–1.77 (m, 1H), 1.42 (s, 9H), 1.30 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 149.6, 141.4, 138.1, 134.3, 134.0, 129.1, 128.5, 126.4, 120.9, 116.8, 75.5, 73.5, 53.4, 38.7, 34.8, 34.5,
33.0, 31.7, 29.4; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C25H36NO2: 382.2741; found: 382.2745.
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2-allyl-1-(3,5-di-tert-butyl-2-hydroxyphenyl)pyrrolidin-3-ol (1p) Following the synthetic procedure of 1o, allylmagnesium broꢀ
mide (1.0 M in Et2O) was used, the title compound was obtained in 97% yield as a colorless oil; Rf = 0.35 (PE/EA = 20/1); 1H NMR
(400 MHz, CDCl3) δ 7.73 (brs, 0.9H), 7.17 (s, 1H), 7.13 (s, 1H), 5.81–5.68 (m, 1H), 5.12–5.00 (m, 2H), 4.23 (s, 0.9H), 3.22–3.15
(m, 1H), 3.14–3.04 (m, 2H), 2.29–2.20 (m, 2H), 2.10–2.02 (m, 1H), 1.92–1.86 (m, 1H), 1.74 (brs, 0.9H), 1.40 (s, 9H), 1.29 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 149.8, 141.3, 134.7, 134.4, 133.9, 121.0, 117.7, 117.2, 75.6, 72.2, 53.6, 37.0, 34.8, 34.5, 33.6, 31.7,
29.4; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C21H34NO2: 332.2584; found: 332.2586.
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Preparation and Characterization of Products
Typical procedure for oxidative N,O-acetal formation (2a−2k, 2o, 2p):
5,7-di-tert-butyl-1-cyclopropyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2a) To a solution of 1a (95 mg, 0.3 mmol) in
10 mL of 9:1 (V/V) DCM/TFE was added K2CO3 (124 mg, 0.9 mmol), iodine (91 mg, 0.36 mmol) sequentially. Fifteen minutes
later, TFE and DCM was evaporated, the residue was dissolved in DCM (30 mL) and the organic phase was washed with aq.
Na2S2O3, H2O, and brine. After dried with MgSO4, the organic phase was concentrated and the residue was purified by chromatogꢀ
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raphy using EtOAc/PE (1/50) to give the desired compound 2a (87 mg, 93% yield) as a colorless oil; Rf = 0.35 (PE/EA = 50/1); H
NMR (400 MHz, CDCl3) δ 6.85 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 5.85 (dd, J = 5.3, 3.3 Hz, 1H), 2.69 (q, J = 6.7 Hz,
1H), 2.42–2.31 (m, 1H), 2.13–2.00 (m, 2H), 1.88–1.69 (m, 1H), 1.33 (s, 9H), 1.29 (s, 9H), 1.01–0.84 (m, 1H), 0.66–0.57 (m, 1H),
0.55–0.46 (m, 1H), 0.35 (dq, J = 9.5, 4.9 Hz, 1H), 0.23 (dq, J = 9.5, 4.9 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 147.8, 142.9, 141.1,
130.5, 116.9, 110.3, 102.6, 72.3, 34.5, 34.1, 31.8, 31.7, 30.2, 29.4, 16.3, 3.7, 1.9; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C21H32NO+H: 314.2478, found: 314.2481.
5,7-di-tert-butyl-3a-cyclopropyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2a’) The synthetic procedure followed was
the same as 2a, except that the I2 was replaced with [bis(trifluoroacetoxy)iodo]benzene (PIFA). Compound 2a was obtained in 32%
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yield and compound 2a’ was obtained in 36%yield. 2a’: Colorless oil; Rf = 0.40 (PE/EA = 50/1); H NMR (400 MHz, CDCl3) δ
6.76 (d, J = 2.0 Hz, 1H), 6.69 (d, J = 2.0 Hz, 1H), 3.37 (dt, J = 10.6, 7.1 Hz, 1H), 3.13 (dt, J = 11.1, 5.8 Hz, 1H), 2.23–2.10 (m, 2H),
1.85–1.73 (m, 2H), 1.32 (s, 9H), 1.27 (s, 9H), 0.56–0.48 (m, 1H), 0.44–0.33 (m, 3H), 0.07 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
147.8, 142.9, 142.0, 129.7, 116.2, 111.3, 109.6, 57.7, 37.9, 34.6, 34.0, 31.8, 29.3, 24.1, 19.3, 0.71, 0.69. HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C21H32NO: 314.2478, found: 314.2476.
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5,7-di-tert-butyl-1-methyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2b)2e Light yellow solid, mp = 50–51 C; 89%
yield; Rf = 0.40 (PE/EA = 50/1); 1H NMR (400 MHz, CDCl3) δ 6.84 (d, J = 2.1 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 5.87 (dd, J = 5.5,
3.4 Hz, 1H), 3.36–3.18 (m, 1H), 2.46–2.32 (m, 1H), 2.13–1.98 (m, 2H), 1.65–1.47 (m, 1H), 1.33 (s, 9H), 1.32 (d, J = 7.2 Hz, 3H),
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1.29 (s, 9H)；13C NMR (100 MHz, CDCl3) δ 147.7, 143.0, 141.2, 130.7, 117.2, 109.8, 102.6, 63.8, 34.6, 34.1, 31.9, 31.8, 31.7,
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5,7-di-tert-butyl-1-butyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2c)2e Colorless oil; 85% yield; Rf = 0.40 (PE/EA =
50/1); 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 1.9 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 5.84 (dd, J = 5.0, 3.0 Hz, 1H), 3.20–3.17 (m,
1H), 2.34–2.25 (m, 1H), 2.10–1.98 (m, 2H), 1.69–1.65 (m, 1H), 1.53–1.39 (m, 6H), 1.33 (s, 9H), 1.29 (s, 9H), 0.95 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 147.6, 143.1, 141.7, 130.5, 116.6, 109.3, 102.3, 68.8, 36.5, 34.6, 34.1, 31.8, 31.7, 29.4, 28.9,
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5,7-di-tert-butyl-1-isobutyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2d)2e Colorless oil; 83% yield; Rf = 0.35 (PE/EA
= 50/1); 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 2.0 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 5.84 (dd, J = 5.0, 2.8 Hz, 1H), 3.35–3.23
(m, 1H), 2.36–2.22 (m, 1H), 2.12–2.00 (m, 2H), 1.89–1.74 (m, 1H), 1.65–1.44 (m, 3H), 1.33 (s, 9H), 1.29 (s, 9H), 1.02 (d, J = 6.6
Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 147.7, 143.2, 141.8, 130.5, 116.6, 109.4, 102.3, 67.2, 46.5, 34.6,
34.1, 31.81, 31.78, 29.4, 29.2, 25.6, 23.1, 22.7; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C22H36NO: 330.2791; found: 330.2794.
5,7-di-tert-butyl-1-heptyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2e) Colorless oil; 80% yield; Rf = 0.40 (PE/EA =
50/1); 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 2.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 5.85 (dd, J = 5.1, 3.0 Hz, 1H), 3.24–3.09 (m,
1H), 2.36–2.24 (m, 1H), 2.12–1.98 (m, 2H), 1.73–1.62 (m, 1H), 1.61–1.26 (m, 12H), 1.33 (s, 9H), 1.29 (s, 9H), 0.89 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 147.7, 143.2, 141.7, 130.6, 116.7, 109.4, 102.3, 68.9, 36.8, 34.6, 34.1, 31.9, 31.83, 31.77, 29.7,
29.4, 29.0, 26.8, 22.8, 14.2; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C25H42NO:372.3261; found: 372.3258.
5,7-di-tert-butyl-1-nonyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2f) Colorless oil; 78% yield; Rf = 0.45 (PE/EA =
50/1); 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 1.9 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 5.84 (dd, J = 5.1, 2.9 Hz, 1H), 3.24–3.13 (m,
1H), 2.36–2.25 (m, 1H), 2.12–1.99 (m, 2H), 1.75–1.62 (m, 1H), 1.56–1.23 (m, 16H), 1.33 (s, 9H), 1.29 (s, 9H), 0.89 (t, J = 6.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 147.6, 143.1, 141.7, 130.5, 116.6, 109.4, 102.3, 68.8, 36.8, 34.5, 34.1, 31.9, 31.82, 31.78,
31.72, 29.7, 29.6, 29.4, 28.9, 26.8, 22.7, 14.1; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C27H46NO: 400.3574, found: 400.3571.
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5,7-di-tert-butyl-1-cyclopentyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2g) White solid, mp = 60–62 C; 86% yield;
Rf = 0.40 (PE/EA = 50/1); 1H NMR (400 MHz, CDCl3) δ 6.77 (d, J = 2.0 Hz, 1H), 6.68 (d, J = 2.0 Hz, 1H), 5.84 (dd, J = 4.9, 2.8 Hz,
1H), 3.12 (td, J = 7.7, 3.7 Hz, 1H), 2.31–2.17 (m, 1H), 2.12–1.84 (m, 4H), 1.80–1.57 (m, 8H), 1.33 (s, 9H), 1.29 (s, 9H); 13C NMR
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(100 MHz, CDCl3) δ 147.3, 143.2, 142.0, 130.3, 116.1, 108.8, 102.2, 73.2, 45.9, 34.6, 34.0, 31.8, 31.6, 30.8, 29.6, 29.4, 27.0, 25.15,
25.12; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C23H36NO: 342.2791, found: 342.2789.
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1-allyl-5,7-di-tert-butyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2h)2e Light yellow solid; mp = 45–46 oC; 93% yield;
Rf = 0.35 (PE/EA = 50/1); 1H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 5.99–5.88 (m, 1H), 5.86
(dd, J = 5.2, 3.3 Hz, 1H), 5.19–5.08 (m, 2H), 3.36–3.20 (m, 1H), 2.54–2.39 (m, 1H), 2.38–2.22 (m, 2H), 2.13–1.93 (m, 2H), 1.69–
1.58 (m, 1H), 1.34 (s, 9H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 147.6, 143.2, 141.4, 135.9, 130.7, 117.0, 109.5, 102.4,
102.3, 68.4, 41.2, 34.6, 34.1, 31.8, 31.7, 29.4, 28.6.
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5,7-di-tert-butyl-1-(4-methoxybenzyl)-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2i) 83% yield; Colorless oil; Rf =
0.30 (PE/EA = 50/1); 1H NMR (400 MHz, CDCl3) δ 7.24–7.18 (m, 2H), 6.92–6.86 (m, 2H), 6.73 (d, J = 2.0 Hz, 1H), 5.89–5.81 (m,
2H), 3.80 (s, 3H), 3.44–3.32 (m, 1H), 2.85–2.71 (m, 2H), 2.35–2.20 (m, 1H), 2.15–1.98 (m, 2H), 1.69–1.59 (m, 1H), 1.31 (s, 9H),
1.15 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.1, 147.4, 143.1, 141.6, 132.0, 130.6, 130.3, 116.4, 113.8, 109.2, 102.3, 77.2 71.1,
55.2, 42.9, 34.5, 34.0, 31.6, 29.4, 28.9; HRMS (MALDIꢀTOF) m/z: [M+H]+ Calcd for C26H36NO2: 394.2741, found: 394.2746.
1-benzyl-5,7-di-tert-butyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2j) White solid; mp = 98−100 oC; 97% yield; Rf =
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0.35 (PE/EA = 50/1); H NMR (400 MHz, CDCl3) δ 7.37–7.16 (m, 5H), 6.73 (d, J = 2.0 Hz, 1H), 5.89 (d, J = 2.0 Hz, 1H), 5.86 (dd,
J = 4.9, 2.9 Hz, 1H), 3.72–3.25 (m, 1H), 2.86 (dd, J = 13.1, 8.4 Hz, 1H), 2.78 (dd, J = 13.0, 5.6 Hz, 1H), 2.35–2.22 (m, 1H), 2.14–
2.00 (m, 2H), 1.72–1.60 (m, 1H), 1.30 (s, 9H), 1.14 (s, 9H)；13C NMR (100 MHz, CDCl3) δ 147.4, 143.2, 141.5, 139.9, 130.4,
129.7, 128.4, 126.3, 116.5, 109.3, 102.3, 71.0, 43.8, 34.5, 34.0, 31.63, 31.56, 29.4, 28.9; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C25H34NO: 364.2635, found: 364.2630.
5,7-di-tert-butyl-1-(4-fluorobenzyl)-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2k) Colorless oil; 81% yield; Rf = 0.45
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(PE/EA = 50/1); H NMR (400 MHz, CDCl3) δ 7.29–7.19 (m, 2H), 7.09–6.98 (m, 2H), 6.74 (d, J = 2.0 Hz, 1H), 5.92–5.67 (m, 2H),
3.44–3.23 (m, 1H), 2.87–2.72 (m, 2H), 2.27 (dq, J = 11.4, 5.4 Hz, 1H), 2.14–2.00 (m, 2H), 1.69–1.57 (m, 1H), 1.30 (s, 9H), 1.15 (s,
9H); 13C NMR (100 MHz, CDCl3) δ161.6 (d, J = 244.4 Hz), 147.4, 143.2, 141.4, 135.6 (d, J = 3.2 Hz), 131.1 (d, J = 7.6 Hz), 130.5,
116.6, 115.2 (d, J = 20.9 Hz), 109.1, 102.2, 70.9, 42.9, 34.4, 34.1, 31.6, 31.5, 29.4, 28.9; HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C25H33FNO: 382.2541, found: 382.2545.
5,7-di-tert-butyl-1-vinyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2l)2e To a solution of 5,7ꢀdiꢀtertꢀbutylꢀ1,2,3,3aꢀ
tetrahydrobenzo[d]pyrrolo[2,1ꢀb]oxazole 1’2e (82 mg, 0.3 mmol) in DCE (30 mL) was added vinylmagnesium bromide (1.8 mL,
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0.5 M in THF, 0.9 mmol) at 0 C under Ar. When completed, the reaction was diluted with PE (30 mL), quenched with saturated
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NH4Cl (10 mL), and extracted with EtOAc (30 mL) for three times. The combined organic phase was concentrated and dissolved in
a mixed solvent of DCM/TFE (1 mL:9 mL), then K2CO3 (124 mg, 0.9 mmol) and I2 (91 mg, 0.36 mmol) was added sequentially at
room temperature. Fifteen minutes later, TFE and DCM were evaporated, the residue was dissolved in DCM (30 mL). The DCM
layer was washed with aq. Na2S2O3, H2O, and brine. After dried with MgSO4, the organic phase was concentrated and the residue
was purified by chromatography using EtOAc/PE (1/50) to give the desired compound 2l (63 mg, 70% yield) as a colorless oil; 1H
NMR (400 MHz, CDCl3): δ 6.84 (d, J = 1.8 Hz, 1H), 6.77 (d, J = 1.8 Hz, 1H), 5.98–5.89 (m, 2H), 5.32 (d, J = 17.0 Hz, 1H), 5.15 (d,
J = 10.2 Hz, 1H), 3.70–3.65 (m, 1H), 2.40–2.33 (m, 1H), 2.11–2.01 (m, 2H), 1.75–1.67 (m, 1H), 1.34 (s, 9H), 1.27 (s, 9H); 13C
NMR (100 MHz, CDCl3): δ 147.8, 143.1, 140.9, 140.7, 130.6, 117.0, 115.3, 109.8, 102.3, 70.6, 34.6, 34.1, 31.9, 31.7, 30.6, 29.4.
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5,7-di-tert-butyl-1-(4-chlorophenyl)-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2m) Following the synthetic procedure
of 2l, 4ꢀchlorophenylmagnesium bromide (1.0 M in THF) was used, the title compound was obtained in 53% yield as a colorless oil;
Rf = 0.40 (PE/EA = 50/1); 1H NMR (400 MHz, CDCl3) δ 7.43–7.31 (m, 4H), 6.84 (s, 1H), 6.43 (s, 1H), 6.04 (t, J = 4.5 Hz, 1H),
4.34–4.23 (m, 1H), 2.52–2.23 (m, 2H), 2.21–2.07 (m, 1H), 1.90–1.71 (m, 1H), 1.36 (s, 9H), 1.20 (s, 9H)；13C NMR (100 MHz,
CDCl3) δ 147.7, 143.4, 142.4, 140.7, 132.7, 130.8, 128.5, 127.9, 117.1, 109.2, 102.2, 70.9, 34.5, 34.2, 33.7, 32.3, 31.7, 29.4；
HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for C24H31ClNO+H: 384.2089, found: 384.2087.
5,7-di-tert-butyl-1-(4-fluorophenyl)-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazole (2n) Following the synthetic procedure
of 2l, 4ꢀfluorophenylmagnesium bromide (1.0 M in THF) was used and the title compound was obtained in 61% yield as a colorless
oil; Rf = 0.35 (PE/EA = 50/1); 1H NMR (400 MHz, CDCl3) δ 7.47–7.34 (m, 2H), 7.11–6.99 (m, 2H), 6.84 (s, 1H), 6.41 (s, 1H),
6.12–5.96 (m, 1H), 4.28 (t, J = 7.0 Hz, 1H), 2.45–2.26 (m, 2H), 2.20–2.08 (m, 1H), 1.92–1.79 (m, 1H), 1.36 (d, J = 1.8 Hz, 9H),
1.19 (d, J = 1.9 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ162.0 (d, J = 244.7 Hz), 147.7, 143.3, 140.8, 139.5 (d, J = 3.1 Hz), 130.9,
128.1 (d, J = 7.6 Hz), 117.2, 115.22 (d, J = 21.5 Hz), 109.3, 102.2, 70.9, 34.5, 34.2, 33.9, 32.4, 31.7, 29.4; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C24H31FNO: 368.2384, found:368.2381.
1-benzyl-5,7-di-tert-butyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazol-2-ol (2o) The synthetic procedure was the same as
o
2a, except that the reaction was carried out at 0 C for 14 h; light yellow solid; mp = 111−113 oC; 84% yield; Rf = 0.35 (PE/EA =
1
20/1); H NMR (400 MHz, CDCl3) δ 7.39–7.28 (m, 5H), 6.76 (d, J = 1.7 Hz, 1H), 5.86–5.82 (m, 1H), 5.77 (d, J = 1.6 Hz, 1H),
4.28–4.16 (m, 1H), 3.44 (dd, J = 10.2, 4.7 Hz, 1H), 2.88 (dd, J = 13.0, 4.7 Hz, 1H), 2.62 (dd, J = 12.9, 9.9 Hz, 1H), 2.54–2.41 (m,
2H), 2.01 (d, J = 8.7 Hz, 0.8H), 1.29 (s, 9H), 1.12 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 146.8, 144.0, 142.4, 139.0, 131.2, 129.8,
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128.5, 126.5, 117.3, 110.5, 101.8, 80.0, 77.0, 41.7, 39.3, 34.5, 34.1, 31.6, 29.4. HRMS (ESIꢀTOF) m/z: [M+H]+ Calcd for
C25H34NO2: 380.2584, found: 380.2586.
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1-allyl-5,7-di-tert-butyl-1,2,3,3a-tetrahydrobenzo[d]pyrrolo[2,1-b]oxazol-2-ol (2p) The synthetic procedure was the same as 2o.
Colorless oil; 94% yield; Rf = 0.40 (PE/EA = 20/1); 1H NMR (400 MHz, CDCl3) δ 6.85 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H),
5.98 (ddt, J = 16.9, 10.9, 7.1 Hz, 1H), 5.83 (dd, J = 5.0, 1.7 Hz, 1H), 5.22–5.18 (m, 1H), 5.17 (s, 1H), 4.22–4.11 (m, 1H), 3.37–3.25
(m, 1H), 2.63–2.50 (m, 1H), 2.43–2.21 (m, 3H), 1.93 (d, J = 7.9 Hz, 0.9H), 1.33 (s, 9H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 146.9, 143.9, 142.1, 135.2, 131.4, 117.6, 117.5, 110.4, 101.5, 76.6, 76.4, 39.5, 39.4, 34.6, 34.1, 31.7, 29.4; HRMS (ESIꢀTOF) m/z:
[M+H]+ Calcd for C21H32NO2 : 330.2428; found: 330.2432
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5-cyclopropyl-1-(3,5-di-tert-butyl-2-hydroxyphenyl)pyrrolidin-2-one (2q)3a The synthetic procedure followed was the same as
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2a, except that TEMPO was added before the addition of iodine. Light yellow solid; m.p. = 153–154 C; 35% yield; Rf = 0.25
(PE/EA = 9/1); 1H NMR (400 MHz, CDCl3): δ 7.24 (d, J = 2.2 Hz, 1H), 7.11 (s, 0.9H), 6.92 (d, J = 2.3 Hz, 1H), 3.64 (td, J = 8.1,
5.5 Hz, 1H), 2.89–2.56 (m, 2H), 2.46–2.37 (m, 1H), 2.16–1.97 (m, 1H), 1.43 (s, 9H), 1.28 (s, 9H), 0.87–0.85 (m, 1H), 0.41–0.33 (m,
2H), 0.14–0.05 (m, 1H), 0.02−0.00 (m, 1H); 13C NMR (101 MHz, CDCl3): δ 175.2, 148.3, 141.5, 139.2, 126.2, 122.2, 118.9, 66.4,
35.0, 34.4, 34.0, 31.2, 30.6, 29.5, 25.4, 14.8, 4.8.
Total Synthesis of (±)-Preussin
2-benzyl-1-(3,5-di-tert-butyl-2-hydroxyphenyl)-5-heptylpyrrolidin-3-ol (7 + 7’)
To the solution of 1o (763 mg, 2 mmol) in the mixed solvent of DCM and TFE (60 mL, DCM/TFE = 1:9 (v/v)) was added K2CO3
(828 mg, 6 mmol) and iodine (559 mg, 2.2 mmol) at 0 oC sequentially. The reaction was stirred at 0 oC for overnight. Upon compleꢀ
tion, the solvent was evaporated and the residue was dissolved in DCM (50 mL) and the organic layer was washed with saturated
Na2S2O3, H2O, and brine. After dried with MgSO4, the organic phase was concentrated to give the crude 2o. The crude 2o was disꢀ
solved in the dry DCM (250 mL), n-C9H19MgCl (10.0 mL, 1.0 M in Et2O, 10 mmol) was added dropwise at −78 0C under Ar. The
reaction was quenched with saturated NH4Cl (200 mL) after 24 h and extracted with DCM (100 mL) for three times. The combined
organic phase was dried, concentrated, and the residue was purified by chromatography using EA/PE = (1:15) to give compound 720
1
and its diastereoisomer 7’ (because of the restricted rotation of the disubstituted pyrrolidine moiety, the H NMR spectra of 7’ apꢀ
pears as two conformers) as inseparable mixture (720 mg, 71% yield, trans isomer major). 1H NMR (400 MHz, CDCl3) δ 7.86 (brs,
0.6H), 7.57–6.70 (m, 7H), 4.24–4.11 (m, 1H), 3.69–3.40 (m, 0.42H, minor isomer), 3.28–3.24 (m, 1.57H, major isomer), 2.79 (dd,
J = 13.4, 4.5 Hz, 1H), 2.50 (dd, J = 13.4, 9.7 Hz, 1H), 2.35–2.11 (m, 0.2H, minor isomer), 2.03–1.97 (m, 0.8H, major isomer),
1.91–1.83 (m, 0.9H, major isomer), 1.67–1.05 (m, 34H), 0.86 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 150.8, 149.8,
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149.5, 141.4, 140.3, 140.2, 138.7, 138.4, 138.0, 134.2, 134.0, 133.8, 133.6, 130.9, 130.8, 129.3, 129.0, 128.6, 128.5, 126.4, 126.2,
121.0, 120.0, 119.9, 119.6, 119.2, 117.8, 76.5, 74.9, 74.7, 73.7, 71.6, 67.9, 65.2, 59.6, 58.4, 39.8, 39.5, 38.7, 38.5, 38.1, 34.95,
34.85, 34.8, 34.7, 34.5, 34.33, 34.25, 34.2, 32.0, 31.9, 31.84, 31.81, 31.7, 29.53, 29.47, 29.40, 29.38, 29.3, 26.33, 26.26, 26.0, 22.6,
14.1; HRMS (MALDIꢀTOF) m/z: [M+H]+ Calcd for C34H54NO2 : 508.4149; found: 508.4157.
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2-benzyl-5-heptylpyrrolidin-3-ol (8 + 8’) To the solution of mixed compounds 7 and 7’ (710 mg, 1.4 mmol) in the mixed solvent
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of aq. NaOH (1 M, 20 mL) and MeCN (40 mL) was added I2 (391 mg, 1.54 mmol) at 0 C. After 5 minutes, the reaction was exꢀ
tracted with DCM (40 mL) for three times. The combined organic phase was washed with saturated Na2S2O3 and brine. After dried
with Na2SO4, the reaction mixture was concentrated and purified by chromatography using MeOH/DCM(1:20) to afford compound
820 and 8’ which were inseparable (8:8’ = 3.6:1 from H NMR, 352 mg, 83% yield); 1H NMR (400 MHz, CDCl3) δ 7.48–6.95 (m,
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5H), 4.00 (dt, J = 7.7, 3.7 Hz, 1H), 3.33–3.26 (m, 0.23H, minor isomer), 3.24–3.08 (m, 1.73H, major isomer), 2.91–2.75 (m, 1.55H,
major isomer), 2.74–2.70 (m, 0.43H, minor isomer), 2.32 (brs, 2H), 1.84–1.77 (m, 1H),1.69–1.55 (m, 1H), 1.52–1.16 (m, 16H),
0.88 (t, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 139.1, 138.7, 129.0, 128.72, 128.66, 126.5, 126.4, 76.2, 76.1, 68.5, 66.6,
57.0, 55.6, 41.0, 40.7, 40.4, 39.3, 37.5, 36.6, 31.9, 29.75, 29.65, 29.61, 29.57, 29.3, 27.10, 27.06, 22.7, 14.1; HRMS ((MALDIꢀTOF)
m/z): [M+H]+ Calcd for C20H34NO: 304.2635; found: 304.2638.
2-benzyl-1-methyl-5-nonylpyrrolidin-3-ol (9+9’) By using previous reported method,17f the methylation of mixed compound 8
gave C(3)ꢀepiꢀ(+)ꢀpreusssin 9 (25 mg, 64% yield) and C(2)ꢀepiꢀ(+)ꢀpreusssin 9’(7 mg, 18% yield). C(3)ꢀepiꢀ(+)ꢀpreusssin 917b 1
H
NMR (400 MHz, CDCl3) δ 7.40–7.12 (m, 5H), 4.10–3.91 (m, 1H), 3.05 (dd, J = 13.2, 4.4 Hz, 1H), 2.54 (dd, J = 13.2, 9.6 Hz, 1H),
2.50–2.38 (m, 2H), 2.35 (s, 3H), 1.76 (ddd, J = 13.3, 6.7, 2.7 Hz, 1H), 1.71–1.57 (m, 2H), 1.37–1.05 (m, 16H), 0.88 (t, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 139.0, 129.3, 128.7, 126.4, 74.7, 64.9, 39.4, 39.2, 39.1, 33.9, 31.9, 30.0, 29.64, 29.60, 29.4,
26.4, 22.7, 14.2.
C(2)ꢀepiꢀ(+)ꢀpreusssin 9’21 1H NMR (400 MHz, CDCl3) δ 7.32–7.24 (m, 2H), 7.23–7.11 (m, 3H), 3.90 (d, J = 6.3 Hz, 1H), 3.15 (dd,
J = 10.8, 4.2 Hz, 1H), 2.97 (dd, J = 13.4, 4.2 Hz, 1H), 2.72–2.61 (m, 1H), 2.46 (s, 3H), 2.44–2.31 (m, 1H), 2.19 (dd, J = 13.4, 10.7
Hz, 1H), 2.06 (brs, 1H), 1.77–1.61 (m, 1H), 1.51 (dd, J = 14.2, 5.0 Hz, 1H), 1.43–1.14 (m, 15H), 0.88 (t, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 139.4, 129.0, 128.6, 126.1, 73.9, 73.3, 61.2, 38.9, 35.0, 33.6, 31.9, 31.4, 29.9, 29.7, 29.6, 29.3, 26.2, 22.7, 14.1.
2-benzyl-1-methyl-5-nonylpyrrolidin-3-ol (10)
Following the literature,17b 9 was firstly oxidized by Swern oxidation and then reduced by LiAlH4 to give (+)ꢀpreussin 10 (16 mg,
65% yield) whose spectra data matched with those reported.15g 1H NMR (400 MHz, CDCl3) δ 7.35–7.27 (m, 4H), 7.20 (m, 1H),
3.79 (m, 1H), 2.89–2.77 (m, 2H), 2.33 (s, 3H), 2.30–2.22 (m, 1H), 2.22–2.06 (m, 2H), 1.86 (d, J = 8.9 Hz, 1H), 1.72 (m, 1H), 1.41
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(dd, J = 13.6, 5.8 Hz, 1H), 1.26 (m, 15H), 0.88 (t, J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 139.5, 129.3, 128.4, 126.0, 73.5,
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Copies of NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: qujin@nankai.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was financially supported by the NSFC (21372119, 21572107) and by Tianjin Natural Science Foundation (14JCYBJC20200).
We thank Professor AnꢀXin Wu at Central China Normal University for helpful discussions.
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