Diastereoselective multicomponent cascade reaction leading to [3.2.0]-heterobicyclic compounds

Article abstract of DOI:10.1021/jo3019413

A general three-component triple cascade reaction through an iminiuma-enaminea-iminium sequential activation initiated by a hetero-Michael addition to α,β-unsaturated aldehydes affords [3.2.0]heterobicycles in high diastereoselectivity. The rate and diastereoselectivity of the reaction depended on the (E)-4-heterocrotonate and size of the secondary amine. The enantiomers of the major diastereoisomer of oxa-and azabicyclo[3.2.0]heptane derivatives were separated by enzymatic kinetic resolution with immobilized Candida antarctica Lipase B (CALB), with E values up to 153. The absolute configuration of the nonacylated enantiomer of oxabicyclo[3.2.0]heptane was determined by single crystal X-ray analysis.

Full text of DOI:10.1021/jo3019413

Article
pubs.acs.org/joc
Diastereoselective Multicomponent Cascade Reaction Leading to
[3.2.0]-Heterobicyclic Compounds
Kerti Ausmees,† Kadri Kriis,† Tonis Pehk,‡ Franz Werner,† Ivar Jarving,† Margus Lopp,†
̈
̃
and Tonis Kanger*,†
̃
†Faculty of Science, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia
‡National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, Estonia
S
* Supporting Information
ABSTRACT: A general three-component triple cascade reaction through an iminium−enamine−iminium sequential activation
initiated by a hetero-Michael addition to α,β-unsaturated aldehydes affords [3.2.0]heterobicycles in high diastereoselectivity. The
rate and diastereoselectivity of the reaction depended on the (E)-4-heterocrotonate and size of the secondary amine. The
enantiomers of the major diastereoisomer of oxa- and azabicyclo[3.2.0]heptane derivatives were separated by enzymatic kinetic
resolution with immobilized Candida antarctica Lipase B (CALB), with E values up to 153. The absolute configuration of the
nonacylated enantiomer of oxabicyclo[3.2.0]heptane was determined by single crystal X-ray analysis.
aliphatic unsaturated aldehydes 1 can be used as Michael
acceptors, and various cyclic or acyclic secondary amines 3 are
tolerated.
INTRODUCTION
■
Synthetic organic chemistry has reached a crucial point in
which a new paradigm has been generated.1 An increasing
interest in multicomponent or cascade reactions reflects that
tendency, making these reactions superior over a traditional
single-step procedure, where only one or two new chemical
bonds are formed.2−12 In multicomponent cascade or domino
reactions, three or more reagents in multiple transformations
lead to the formation of complex structures with several new
C−C or C−heteroatom bonds in a single operation. This new
strategy has several advantages over the classical approach, such
as lower cost, decreased time and energy consumption,
therefore being environmentally benign.
In the course of our ongoing investigations in the field of
aminocatalysis,13−16 we recently discovered a new multi-
component cascade reaction (Scheme 1).17 The reaction of
α,β-unsaturated aldehyde 1, N-benzyl-(E)-4-aminocrotonate 2,
and secondary amine 3 afforded the racemic bicyclic ester with
general formula 4, together with a certain amount of the
byproduct, which contains a pyrrolidine ring. The formation of
the byproduct was suppressed by using a 2-fold excess of the
α,β-unsaturated aldehyde and secondary amine in respect to
aminocrotonate in methylene chloride, in the presence of
molecular sieves. The obtained ester 4 was reduced in situ,
because of its instability, into the corresponding alcohol 5. The
reaction was highly diastereoselective, affording mainly one
diastereoisomer of 4 (dr up to 65:1; isolated and characterized
by a wide substrate scope as alcohol 5). Both aromatic and
The mechanism of the reaction can be rationalized by
assuming that the reaction proceeds via a cascade that consists
of an aza-Michael addition to an iminium ion derived from α,β-
unsaturated aldehyde 1 and secondary amine 3, followed by a
second, intramolecular Michael addition. The last step of the
cascade is the formation of a four-membered ring via an ester
enolate attack on the newly formed iminium ion. (Scheme 1)17
The obtained bicyclic scaffold can be found in several
pharmacophores with different biological activities. For
example, the similar structures are known to be present in
the modulating agents of the dopamine D3 receptor18,19 (the
treatment of schizophrenia, depression, and Parkinson’s disease
(belaperidone),20 in antibacterial agents (ecenofloxacin),21 and
in antitumor drugs (mitindomide)).22 The strained
bicyclo[3.2.0]heptane skeleton is an interesting object for
further modifications for synthetic chemists engaged in the
synthesis of natural products.23 Therefore, the scope of the
reaction needs to be broadened with other heteroatom
substituted crotonates.
Domino reactions involving initiation by a hetero-Michael
addition of amines,24 thiols25−27 and phenols28−31 to α,β-
unsaturated aldehydes are relatively well documented, but few
Received: September 14, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo3019413 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Reaction between α,β-Unsaturated Aldehyde 1, N-Benzyl-(E)-4-aminocrotonate 2, and Secondary Amine 3
Scheme 2. Reaction Between α,β-Unsaturated Aldehyde 1, (E)-4-Hydroxycrotonate 6, and Secondary Amine 3
examples are available for the application of aliphatic alcohols in
oxa-Michael reactions.32,33 This is probably due to the low
nucleophilicity of alcohols, the reversibility of the reaction and
the competing acetal formation, making the oxa-Michael
reaction, especially intermolecular, challenging.34,35 At the
same time 3-oxabicyclo[3.2.0]heptane derivatives are valuable
synthetic intermediates, and they have been used in the
synthesis of cyclobutane-fused nucleoside analogues.36,37 This
heterobicyclic skeleton has previously been synthesized via
metal-catalyzed [2 + 2] cycloaddition.38,39
RESULTS AND DISCUSSION
■
We envisioned that by using hydroxycrotonate instead of
aminocrotonate it might also be possible to synthesize a 3-
oxabicyclo[3.2.0]heptane skeleton via the multicomponent
cascade reaction. When the reaction between cinnamic
aldehyde 1a (2 equiv), ethyl (E)-4-hydroxycrotonate 6 (1
equiv) and diethyl amine (2 equiv) was run under the same
optimum conditions as in our previous work (CH2Cl2, rt,
presence of molecular sieves), an oxabicyclic compound 7 and a
tetrahydrofurane derivative 8 were obtained in a 96:4 ratio
(Scheme 2, Figure 1). The reaction was moderately
diastereoselective, affording only [3.2.0]-oxabicyclo heptane 2-
Figure 1. Reaction progress profile for the reaction in Scheme 2,
obtained using H NMR spectroscopy. Molecular sieves were added,
and CDCl3 was used as a reaction medium.
exo and 2-endo diastereoisomers 7 and 7a in a 5:1 ratio,
respectively. The relative configuration of the product was
determined by NMR.17 The diastereoselectivity and the rate of
the reaction could not be increased by changing the solvent or
adding basic or acidic additives (see the Supporting
Information).
1
ion or oxa-Michael addition product, were observed. The
conversion pathway of the starting material 6 and the formation
of 2-exo-[3.2.0]oxabicyclo heptane ester 7, its diastereoisomer
7a, and aldehyde 8 in the reaction is presented in Figure 1. The
formation of a monocycle and bicycle are competing reactions.
It was assumed that the reaction would follow a similar pathway
as with an aza-nucleophile (Scheme 1). However, it was not
clear if the monocyclic structure was in equilibrium with the
bicyclic product 7. Since the diastereoisomeric ratio of 2-exo
1
To obtain a mechanistic insight, a H NMR study of the
multicomponent reaction was conducted and the kinetics of the
process was monitored. The determination of the reaction
products and limiting starting material (ethyl (E)-4-hydrox-
ycrotonate 6) was straightforward on the basis of their
characteristic resonances in one-dimensional 1H spectrum
(Figure 2). Neither of the crucial intermediates, an iminium
B
dx.doi.org/10.1021/jo3019413 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
Figure 2. H NMR spectrum of the reaction mixture after 25 h.
a
Table 1. Scope of the Multicomponent Reaction
b
c
d
entry
compound
R1
amine 3
time (h)
ratio of 6/7/8
dr
isolated yield 9
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
Ph
Ph
Ph
Ph
Et2NH
48
72
48
72
48
48
48
96
96
0/96/4
5:1
4:1
76
pyrrolidine
piperidine
Me2NH
Et2NH
0/64/36
8/44/48
21/79/0
16/74/10
8/84/8
43
e
f
1:1:4
20 (43)
51
g
6:1
p-MeO-Ph
p-Br-Ph
p-NO2-Ph
Me
5:1
5:1
8:1
37
Et2NH
55
9g
9h
9i
Et2NH
12/82/6
n.d.
51
h
i
Et2NH
n.d.
−
h
i
diMe
Et2NH
n.d.
−
52
a
α,β-Unsaturated aldehyde (2 equiv), amine (2 equiv), and hydroxycrotonate (1 equiv) were stirred in CH2Cl2 at rt for the appropriate time in the
b
c
1
presence of MS. Ratios were determined by H NMR from the crude reaction mixture before reduction with LiAlH4. Ratio of (2-exo:2-endo)
d
e
diastereoisomers was determined by 1H NMR. Isolated yield of the major diastereoisomer. Ratio of 2-exo-6-endo-7-exo:2-endo-6-endo-7-exo:2-exo-
f
g
6-exo-7-endo diastereoisomers. Yield stated accordingly for 2-exo-6-endo-7-exo and 2-exo-6-exo-7-endo diastereoisomers. Major diastereoisomer in 2-
exo-6-exo-7-exo-configuration. 1 M Me2NH in THF was used for the reaction. Ratio was not determined because of overlapping of signals in H
NMR. Only one diastereoisomer was detected.
h
1
i
and 2-endo isomers changed over time (from 5:1 at 48 h to
2.5:1 at 215 h to 1.3:1 in 22 days), the cascade was reversible.
The reduction of the ester group excluded that equilibrium, so
in the following reactions a one-pot procedure was employed.
Next, the scope of the multicomponent reaction was assessed
under standard conditions. The summarized results in Table 1
show that the reaction has broad applicability, as various
secondary amines 3 and α,β-unsaturated aldehydes 1 can be
used. The diastereoisomeric ratio of the obtained bicycles was
generally high, and it was determined from the crude mixture
before the reduction of the ester by 1H NMR. The
predominant diastereoisomer of compound 7 was formed in
a 2-exo-6-endo-7-exo configuration as depicted in the heading of
Table 1. Exceptions to this general tendency were the
compounds 9c in 2-exo-6-exo-7-endo and 9d in 2-exo-6-exo-7-
exo configuration (Table 1, entries 3 and 4). The sterical
hindrance of the secondary amine 3 had a strong influence on
the chemoselectivity of the reaction, as pyrrolidine and
piperidine (entries 2 and 3) gave a close to 1:1 mixture of
the bicyclic product 7 and the tetrahydrofurane derivative 8. On
the other hand, sterically less demanding dimethyl amine gave
no monocyclic product and resulted in the formation of a
different diastereoisomer of bicycle 7 (entry 4). The reaction
proceeded efficiently with different α,β-unsaturated aldehydes,
not only with electron-rich aromatic substituents such as p-
methoxyphenyl, but also with those that are electron-deficient,
such as p-bromophenyl and p-nitrophenyl (entries 5−7). The
reactions with aliphatic aldehydes did not proceed to
completion, giving quite a lot of monocyclic product, and
only one diastereomer of bicyclic product 7 was detected and
isolated (entries 8, 9).
In general, the multicomponent cascade reaction of aromatic
unsaturated aldehydes with (E)-4-hydroxycrotonate was less
diastereo- and chemoselective than the corresponding reaction
with N-benzyl-(E)-4-aminocrotonate.17
Our attempts to apply asymmetric organocatalytic ap-
proaches, such as iminium catalysis with chiral secondary
amines (such as diaryl prolinol derivatives) or hydrogen
C
dx.doi.org/10.1021/jo3019413 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 2. Enzymatic Kinetic Resolution of Aza- and Oxa[3.2.0]bicyclic Compounds
D
dx.doi.org/10.1021/jo3019413 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 2. continued
a
b
For the synthesis of N-benzyl azabicyclo[3.2.0]heptane derivatives, see ref 17. K2CO3 was used as an additive to remove acid from the reaction
media
bonding catalysts (quinidine, cinchonine, (R)-TRIP and chiral
thiourea derivatives) to the oxa- or aza-Michael cascade
reaction in order to generate enantiomeric aza- or
oxabicyclo[3.2.0]heptane derivatives were unsuccessful, and
racemic compounds were always obtained. As catalytic chemical
methods failed to yield enantiopure bicyclic products, we
looked into enzymatic kinetic resolution options. Lipases are
widely used for the acylation of secondary and primary
alcohols.40,41 We chose immobilized lipase B of Candida
antarctica (Novozym 435) as the catalyst and ethyl acetate as an
acyl donor and reaction medium. A kinetic resolution of
enantiomers of certain [3.2.0]heterobicycles 9 and 10
derivatives was run at room temperature (Table 2). The
process was monitored by Chiral HPLC, which allows for the
direct determination of the enzyme enantioselectivity E. The
acylated enantiomer 11 and nonacylated enantiomer of 9 were
separated by column chromatography, affording both enan-
tiomers needed for biological assays. The enantiomeric purity
of the acylated enantiomer was determined after hydrolysis of
the ester.
The enzyme enantioselectivity E value greatly depended on
the structure of the diastereoisomer of the bicyclic substrate
(Table 2). It was found that the selectivity was slightly higher
for N-benzyl bicycles (entries 2, 4, 9) than oxa-bicyclic
compounds (entries 1, 3, 8). For the major diastereoisomer
of N-benzylazabicyclo[3.2.0]heptanes, the kinetic resolution
resulted in 90% ee for both enantiomers after the first resolution
(entries 2, 4). To obtain substrates in high ee for biological
activity testing, repeated resolutions were needed. The spatial
arrangement around the chiral centers adjacent to the hydroxy
E
dx.doi.org/10.1021/jo3019413 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
on silica gel affording alcohol 9 (A-enantiomer) and ester 11. As the
enantiomeric excess of ester 11 could not be determined by chiral
HPLC, it was hydrolyzed to 9 (B-enantiomer), with 4 M NaOH in
MeOH by stirring 3 h at room temperature.
group is the most important factor in stereoselectivity. The
kinetic resolution of compounds in 6-exo configuration was
slower and gave poorer selectivities (entries 7, 11). N-
Tosylazabicyclo[3.2.0]heptanes 1042 did not provide a good
fit with the enzyme, and the resolution slowed down drastically
from 5 h to 3 days (entries 11, 12).
The absolute configuration of nonacylated enantiomer of 9f
was determined to be in (1R,2S,5R,6S,7R)-configuration by
single crystal X-ray diffraction (see the Supporting Informa-
tion). It is assumed that all 2-exo-6-endo-7-exo configuration
enantiomers of oxabicyclo[3.2.0]heptane derivatives that have
been acylated by Novozym 435 possess the same configuration
as shown in the heading of Table 2. The absolute configuration
of the azabicyclo[3.2.0]heptane derivatives was determined by
us previously,42 and enantiopreference of the enzyme was the
same.
(7-exo-(Diethylamino)-2-exo-phenyl-3-oxabicyclo[3.2.0]-
heptan-6-endo-yl)methanol 9a. 40.4 mg, yield 76%. Light yellow
oil: dr (2-exo:2-endo) 5:1; 1H NMR (400 MHz, CDCl3) δ 1.02 (t, J =
7.1 Hz, 6H), 2.14 (s, 1H), 2.44−2.55 (m, 1H), 2.57−2.69 (m, 4H),
2.78−2.84 (m, 1H), 2.97−3.06 (m, 1H), 3.09 (dd, J = 8.1, 5.0 Hz,
1H), 3.67−3.83 (m, 3H), 4.09 (dd, J = 10.2, 1.4 Hz, 1H), 4.94 (s, 1H),
7.23−7.30 (m, 3H), 7.30−7.38 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 10.5 (2C), 35.3, 39.6, 41.8 (2C), 47.2, 61.9, 62.4, 66.2, 84.3,
125.9 (2C), 127.4, 128.5 (2C), 140.9; IR (KBr, neat), ν (cm−1) 3085,
2960, 1454, 1062, 765; m/z (EI+) 275 (M+, 0.62%), 188 (43), 129
(100), 98 (47); HRMS (ESI+) calculated for (C17H26NO2)+ 276.1958
[M + H+], found 276.1960.
HPLC: (Chiralcel Lux Amylose-2 column, hexanes/2-propanol =
96/4, 0.1% Et2NH in hexane, flow rate = 1.0 mL/min, λ = 230 nm)
t(+)‑A = 8.6 min, t(−)‑B = 13.1 min. [α]25D +57.6 (c 0.82 in CHCl3, ee =
96%), [α]25 −63.6 (c 0.86 in CHCl3, ee > 99%).
CONCLUSIONS
D
■
(7-exo-(Diethylamino)-2-endo-phenyl-3-oxabicyclo[3.2.0]-
heptan-6-endo-yl)methanol 9a-2-endo diastereoisomer. 9.7
In summary, we have shown that a one-step multicomponent
hetero-Michael/Michael/Mannich-type reaction is a general
reaction that can be used for the synthesis of tetrasubstituted 3-
oxabicyclo[3.2.0]heptane derivatives as well as 3-
azabicyclo[3.2.0]heptane derivatives. This chemistry provides
quick access to important pharmacophores, and could be used
for the synthesis of starting materials for other heterocycles
with more complicated structures. A method to obtain both
enantiomers of the major diastereomer via enzymatic kinetic
resolution immobilized lipase B of Candida antarctica
(Novozym 435) was developed. The absolute configuration
of resolved bicyclic compounds was unambiguously assigned by
single crystal X-ray diffraction.
1
mg, yield 18%. Light yellow transparent oil: H NMR (400 MHz,
CDCl3) δ 0.55 (t, J = 7.1 Hz, 6H), 1.97−2.09 (m, 2H), 2.12−2.28 (m,
2H), 2.44 (tt, J = 9.2, 6.0 Hz, 1H), 2.58 (t, J = 5.5 Hz, 1H), 2.88−2.98
(m, 1H), 3.06−313 (m, 1H), 3.66−3.83 (m, 3H), 4.29 (d, J = 10.2 Hz,
1H), 4.77 (d, J = 5.0 Hz, 1H), 7.17−7.27 (m, 1H), 7.28−7.42 (m,
4H); 13C NMR (101 MHz, CDCl3) δ 9.9, 35.7, 39.8, 41.0, 45.76, 55.5,
61.5, 68.2, 82.5, 126.3, 127.2, 128.0, 137.8; HRMS (ESI+) calculated
for (C17H26NO2)+ 276.1958 [M + H+], found 276.1954.
7-exo-(Diethylamino)-2-endo-phenyl-3-oxabicyclo[3.2.0]-
heptane-6-endo-carboxylate 7 (9a-2-exo diethyl ester). 25 mg,
yield 41%. Yellow oil: Column chromatography petroleum
1
ether:EtOAc 10−50%; H NMR (400 MHz, CDCl3) δ 0.99 (t, J =
7.2 Hz, 6H), 1.21 (t, J = 7.1 Hz, 3H), 2.60 (q, J = 7.2 Hz, 4H), 3.02−
3.19 (m, 3H), 3.46 (dd, J = 7.0, 5.7 Hz, 1H), 3.74 (dd, J = 10.3, 6.4 Hz,
1H), 3.84 (dd, J = 10.2, 2.0 Hz, 1H), 4.04−4.19 (m, 2H), 4.92 (s, 1H),
7.16−7.22 (m, 4H), 7.22−7.34 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 10.2, 14.4, 36.6, 41.5, 42.6, 47.4, 60.6, 60.9, 67.8, 84.3, 125.8,
127.5, 128.5, 140.6, 172.1; HRMS (ESI+) calculated for (C19H28NO3)+
318.2064 [M + H+], found 318.2062.
EXPERIMENTAL SECTION
■
Full assignment of 1H and 13C chemical shifts is based on the 1D and
2D FT NMR spectra 400 MHz instrument. Chemical shifts are
reported in ppm with internal reference to TMS, and J values are given
in Hertz. Mass spectra were obtained in GC−MS mode (EI, 70 eV).
High resolution mass spectra were recorded on Accurate-Mass Q-TOF
LC−MS spectrometer recorded by using AJ-ESI ionization. All HPLC
analysis were done using Chiralcel AS-H or Lux Amylose-2 columns.
Precoated silica gel 60 F254 plates were used for TLC.
(2-exo-Phenyl-7-exo-(pyrrolidin-1-yl)-3-oxabicyclo[3.2.0]-
heptan-6-endo-yl)methanol 9b. 182.7 mg, yield 43%. Yellow oil, dr
(2-exo:2-endo) 4:1. After 24 and 48 h, additional 3 equiv of
1
cinnamaldehyde and pyrrolidine were added: H NMR (400 MHz,
CDCl3) δ 1.78−1.86 (m, 4H), 2.42−2.63 (m, 7H), 2.99−3.15 (m,
2H), 3.64−3.78 (m, 3H), 4.09 (d, J = 10.2 Hz, 1H), 4.94 (s, 1H), 7.24
(d, J = 8.7 Hz, 2H), 7.29−7.38 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 23.3 (2C), 36.0, 39.9, 47.1, 51.3 (2C), 61.4, 65.8, 66.3, 84.1,
125.8 (2C), 127.3, 128.5 (2C), 140.9; IR (KBr, neat), ν (cm−1) 3385,
2957, 1012, 729; m/z (EI+) 273 (M+, 0.40%), 186 (35), 127 (100), 96
(36); HRMS (ESI+) calculated for (C17H24NO2)+ 274.1802 [M + H+],
found 274.1802.
Reactions sensitive to oxygen or moisture were conducted under Ar
atmosphere in flame-dried glassware. Dichloromethane was freshly
distilled from P2O5 and stored on K2CO3 and anhydrous
tetrahydrofuran from LiAlH4. Commercial reagents were used as
received. Petroleum ether used had bp 40−60 °C.
General Procedure for the Synthesis of Racemic Compound
9. To a solution of the corresponding aldehyde 1 (3.0 mmol) in
anhydrous CH2Cl2 (10 mL) in the presence of molecular sieves (4 Å),
secondary amine 3 (3.0 mmol) and (E)-4-hydroxycrotonate 6 (1.5
mmol) were added. The mixture was stirred at room temperature for
20−96 h. The mixture was concentrated in a vacuum, and the crude
bicyclic ester 7 was reduced with LiAlH4 (10.8 mmol) in anhydrous
THF (20 mL). After 16 h, the reaction mixture was cooled to 0 °C,
and the reaction was quenched by the addition of water and an
aqueous solution of 4 M aq NaOH. The mixture was dried over
K2CO3. The crude product was purified by chromatography on silica
gel (CH2Cl2:MeOH/NH3 eluent system) affording bicyclic alcohol 9.
General Procedure for Enzymatic Kinetic Resolution of 9
and 10. Immobilized lipase B of Candida antarctica (Novozym 435)
(50 mg) was added to a solution of the racemic compound 9 or 10 (50
mg) in EtOAc (1.0 mL). The resulting mixture was stirred occasionally
at room temperature and monitored by TLC. Reaction was stopped
when about 50% conversion was achieved, typically after 2.5−5 h.
Immobilized lipase was filtered off, and the filtrate was concentrated
under reduced pressure. This mixture was purified by chromatography
HPLC: (Chiralcel Lux Amylose-2 column, hexanes/2-propanol =
80/20, 0.1% Et2NH in hexane, flow rate = 1.0 mL/min, λ = 230 nm)
t(+)‑A = 6.8 min, t(−)‑B = 10.8 min. [α]25 +60° (c 0.74 in CHCl3, ee =
D
95.3%), [α]25 −55° (c 0.72 in CHCl3, ee = 80.4%).
D
(2-exo-Phenyl-7-endo-(piperidin-1-yl)-3-oxabicyclo[3.2.0]-
heptan-6-exo-yl)methanol 9c 2-exo-7-endo-6-exo diaster-
eomer (major). 190 mg, yield 43%. Yellow amorphous solid, mp
52−58 °C. After 24 h, additional 3 equiv of cinnamaldehyde and
1
pyrrolidine were added: H NMR (400 MHz, CDCl3) δ 1.39−1.52
(m, 2H), 1.55−1.66 (m, 4H), 2.19 (d, J = 7.6 Hz, 1H), 2.23−2.68 (m,
4H), 2.86−2.94 (m, 1H), 2.98 (t, J = 7.0 Hz, 1H), 3.15−3.28 (m, 1H),
3.69 (dd, J = 11.9, 1.5 Hz, 1H), 3.91 (dd, J = 9.5, 2.4 Hz, 1H), 4.00
(dd, J = 9.4, 7.3 Hz, 1H), 4.15 (dd, J = 11.9, 3.0 Hz, 1H), 4.88 (s, 1H),
5.29 (s, 1H), 7.22−7.28 (m, 3H), 7.29−7.35 (m, 2H); 13C NMR (101
MHz, CDCl3) δ 23.7, 25.1 (2C)37.8, 40.7, 48.7, 51.6 ((2C, bs), 63.6,
64.4, 71.8, 84.6, 125.3 (2C), 126.7, 127.8 (2C), 140.3; IR (KBr, neat),
ν (cm−1) 3373, 2935, 1452, 1036, 732; m/z (EI+) 287 (M+, 0.48%),
F
dx.doi.org/10.1021/jo3019413 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
200 (37), 141 (100), 110 (53); HRMS (ESI+) calculated for
(C18H26NO2)+ 288.1958 [M + H+], found 288.1862.
(7-exo-(Diethylamino)-2,2-dimethyl-3-oxabicyclo[3.2.0]-
1
heptan-6-endo-yl)methanol 9i. 181 mg, yield 52%. Yellow oil: H
NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.1 Hz, 6H), 1.09 (s, 3H), 1.30
(s, 3H), 2.34−2.45 (m, 2H), 2.47−2.62 (m, 5H), 2.78 (t, J = 5.9 Hz,
1H), 2.94−3.05 (m, 1H), 3.60−3.78 (m, 3H), 3.97 (d, J = 10.4 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ 10.6 (2C), 22.2, 24.8, 35.4, 38.7,
41.6 (2C), 50.0, 57.6, 61.8, 64.8, 81.0; m/z (EI+) 227 (M+, 0.31%) 140
(67), 129 (100), 112 (24), 98 (54); IR (KBr, neat), ν (cm−1) 3245,
2969, 1378, 1183, 1014; HRMS (ESI+) calculated for (C13H26NO2)+
228.1958 [M + H+], found 228.1959.
(2-exo-Phenyl-7-exo-(piperidin-1-yl)-3-oxabicyclo[3.2.0]-
heptan-6-endo-yl)methanol 9c 2-exo-7-exo-6-endo dia-
1
streoisomer. 89 mg, yield 20%. Yellow oil: H NMR (400 MHz,
CDCl3) δ 1.42−1.53 (m, 2H), 1.57−1.66 (m, 4H), 2.26−2.31 (m,
1H), 2.32−2.41 (m, 4H), 2.46−2.55 (m, 2H), 3.00−3.07 (m, 1H),
3.10 (dd, J = 7.9, 4.9 Hz, 1H), 3.66−3.71 (m, 1H), 3.71−3.75 (m,
2H), 4.09 (dd, J = 10.2, 0.9 Hz, 1H) 4.90 (s, 1H), 7.23−7.26 (m, 2H),
7.30−7.36 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 24.3, 25.5 (2C),
35.4, 39.0, 46.6, 51.3 (2C), 61.8, 66.2, 67.0, 84.4. 125.9 (2C), 127.3,
128.5 (2C), 140.8; HRMS (ESI+) calculated for (C18H26NO2)+
288.1958 [M + H+], found 288.1857.
(3-Benzyl-7-exo-diethylamino-2-exo-phenyl-3-azabicyclo-
[3.2.0]hept-6-endo-yl)methanol 9j. HPLC: (Chiralcel AS-H
column, hexanes/2-propanol = 98/2, 0.05% Et2NH in hexane, flow
rate = 1.0 mL/min, λ = 254 nm) t(+)‑A = 11.3 min, t(−)‑B = 16.6 min.
[α]25 +10 (c 0.82 in CH2Cl2, ee = 99%), [α]25 −10 (c 0.47 in
(7-exo-(Dimethylamino)-2-exo-phenyl-3-oxabicyclo[3.2.0]-
heptan-6-exo-yl)methanol 9d. 96.5 mg, yield 51%. Light yellow oil:
1H NMR (400 MHz, CDCl3) δ 2.15−2.20 (m, 1H), 2.24 (s, 6H),
D
D
CH2Cl2, ee = 95%).
(3-Benzyl-2-exo-phenyl-7-exo-pyrrolidin-1-yl-3-azabicyclo-
[3.2.0]hept-6-endo-yl) methanol 9k. HPLC: (Chiralcel AS-H
column, hexanes/2-propanol = 98/2, 0.1% Et2NH in hexane, flow
rate = 1.0 mL/min, λ = 254 nm) t(+)‑A = 18.3 min, t(−)‑B = 24.8 min.
[α]25 +10 (c 1.22 in CH2Cl2, ee = 96%), [α]25 −11 (c 1.46 in
2.85−2.94 (m, 2H), 3.12−3.23 (m, 1H), 3.70 (dd, J = 11.9, 1.8 Hz,
1H), 3.91 (dd, J = 9.5, 2.4 Hz, 1H), 3.99 (dd, J = 9.4, 7.2 Hz, 1H), 4.17
(dd, J = 11.9, 3.1 Hz, 1H), 4.91 (s, 1H), 5.14 (s, 1H), 7.22−7.26 (m,
1H), 7.26−7.29 (m, 2H), 7.29−7.37 (m, 2H); 13C NMR (101 MHz,
CDCl3) δ 37.9, 41.5, 43.2 (2C), 49.9, 64.1, 66.7, 72.4, 85.2, 125.9
(2C), 127.4, 128.4 (2C), 140.9; IR (KBr, neat), ν (cm−1) 3181, 2905,
1497, 1057, 729; m/z (EI+) 273 (M++H, 0.11%), 160 (57), 101 (100);
HRMS (ESI+) calculated for (C15H22NO2)+ 248.1645 [M+], found
248.1646.
D
D
CH2Cl2, ee = 99%).
(3-Benzyl-2-exo-phenyl-7-exo-piperidin-1-yl-3-azabicyclo-
[3.2.0]hept-6-endo-yl) methanol 9l. HPLC: (Chiralcel AS-H
column, hexanes/2-propanol = 97/3, 0.1% Et2NH in hexane, flow
rate = 1.0 mL/min, λ = 254 nm) t(+)‑A = 10.2 min, t(−)‑B = 14.8 min.
[α]25 +19 (c 0.37 in CH2Cl2, ee = 95%), [α]25 −20 (c 0.37 in
(7-exo-(Diethylamino)-2-exo-(4-methoxyphenyl)-3-oxa-
D
D
bicyclo[3.2.0]heptan-6-endo-yl)methanol 9e. 174 mg, yield 37%.
1
CH2Cl2, ee = 99%).
Light yellow solid: mp 62−65 °C; dr (2-exo:2-endo) 5:1; H NMR
(3-Benzyl-7-exo-dimethylamino-2-exo-phenyl-3-azabicyclo-
[3.2.0]hept-6-exo-yl)methanol 9m. HPLC: (Chiralcel Lux Amy-
lose-2 column, hexanes/2-propanol = 98/2, 0.05% Et2NH in hexane,
flow rate = 1.0 mL/min, λ = 254 nm) t(A) = 17.8 min, t(B) = 13.5 min.
(3-Benzyl-7-exo-diethylamino-2-exo-p-bromophenyl-3-
azabicyclo[3.2.0]hept-6-endo-yl) methanol 9o. HPLC: (Chiralcel
AS-H column, hexanes/2-propanol = 98/2, 0.1% Et2NH in hexane,
flow rate = 1.0 mL/min, λ = 254 nm) t(−)‑A = 14.5 min, t(+)‑B = 18.9
min. [α]25D −2.4 (c 0.90 in CH2Cl2, ee = 96%), [α]25D +4.8 (c 2.94 in
CH2Cl2, ee = 99%).
(400 MHz, CDCl3) δ 1.01 (t, J = 7.2 Hz, 6H), 2.04 (s, 1H), 2.44−2.55
(m, 1H), 2.56−2.68 (m, 4H), 2.79 (dd, J = 6.8, 4.5 Hz, 1H), 2.97−
3.10 (m, 2H), 3.66 (dd, J = 10.2, 6.1 Hz, 1H), 3.80 (s, 3H) 3.71−3.79
(m, 2H), 4.05 (d, J = 10.0 Hz, 1H), 4.89 (s, 1H), 6.83−6.91 (m, 2H),
7.14−7.23 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 10.4 (2C), 35.3,
39.6, 41.8 (2C), 46.8, 55.3, 61.9, 62.3, 65.8, 83.9, 113.8 (2C), 127.4,
132.9 (2C), 158.9; IR (KBr, neat), ν (cm−1) 2975, 2859, 1611, 1513,
1251, 1184, 1031, 825; m/z (EI+) 273 (M++H, 1%), 218 (52), 129
(100), 98 (39); HRMS (ESI+) calculated for (C18H28NO3)+ 306. 2064
[M + H+], found 306.2066.
(3-Benzyl-7-exo-diethylamino-2-exo-methyl-3-azabicyclo-
[3.2.0]hept-6-endo-yl)methanol 9r. HPLC: (Chiralcel Lux Amy-
lose-2 column, hexanes/2-propanol = 98/2, 0.1% Et2NH in hexane,
flow rate = 1.0 mL/min, λ = 254 nm) t(+)‑A = 22.2 min, t(−)‑B = 20.9
min. [α]25 +31 (c 0.16 in CH2Cl2, ee = 99%), [α]25 −28 (c 0.61 in
(2-exo-(4-Bromophenyl)-7-exo-(diethylamino)-3-oxabicyclo-
[3.2.0]heptan-6-endo-yl)methanol 9f. 117.3 mg, yield 55%.
Colorless sticky oil (rac). (+)-A-enantiomer was crystallized from
1
EtOAc, resulting in white crystals: mp 94 °C; H NMR (400 MHz,
D
D
CDCl3) δ 1.02 (t, J = 7.2 Hz, 6H), 2.02 (bs, 1H), 2.44−2.54 (m, 1H),
2.55−2.69 (m, 4H), 2.80 (dd, J = 6.9, 4.5 Hz, 1H), 2.94−3.06 (m,
2H), 3.67 (dd, J = 10.2, 6.2 Hz, 1H), 3.70−3.82 (m, 2H), 4.05−4.12
(m, 1H), 4.88 (s, 1H), 7.12−7.17 (m, 2H), 7.40−7.50 (m, 2H); 13C
NMR (101 MHz, CDCl3) δ 10.5 (2C), 35.2, 39.4, 41.9 (2C), 47.2,
61.9, 62.3, 66.4, 83.6, 121.2, 127.6 (2C), 131.6 (2C), 139.9; IR (KBr,
neat), ν (cm−1) 3145, 2975, 1458, 1062, 1010; m/z (EI+) 355 (M+,
0.05%), 268 (19), 266 (19), 129 (100), 98 (53); HRMS (ESI+)
calculated for (C17H25BrNO2)+ 354.1063 [M + H+], found 354.1062.
HPLC: (Chiralcel Lux Amylose-2 column, hexanes/2-propanol =
90/10, 0.1% Et2NH in hexane, flow rate = 1.0 mL/min, λ = 230 nm)
CH2Cl2, ee = 94%).
(7-exo-(Diethylamino)-2-exo-phenyl-3-tosyl-3-azabicyclo-
[3.2.0]heptan-6-exo-yl)methanol 10a.42 34 mg, yield 20.5%. Light
1
yellow sticky oil: H NMR (400 MHz, CDCl3) δ 1.00 (t, J = 7.2 Hz,
6H), 2.12 (d, J = 6.1 Hz, 1H), 2.34 (s, 3H), 2.40−2.59 (m, 4H), 2.87−
2.95 (m, 1H), 2.96−3.03 (m, 1H), 3.08 (t, J = 7.0 Hz, 1H), 3.61−3.72
(m, 3H), 4.03 (dd, J = 12.0, 3.1 Hz, 1H), 4.85 (s, 1H), 6.99−7.06 (m,
2H), 7.09 (d, J = 8.0 Hz, 2H), 7.16−7.22 (m, 3H), 7.38−7.43 (m,
2H); 13C NMR (101 MHz, CDCl3) δ 11.0, 21.4, 37.2, 42.5, 43.0, 51.4,
53.7, 61.3, 64.0, 69.6, 126.4 (2C), 127.0 (2C), 127.5, 128.5 (2C),
129.2 (2C), 136.4, 140.6, 142.9; HRMS (ESI+) calculated for
(C24H33N2O3S)+ 249.2206 [M + H+], found 249.2203.
t(+)‑A = 9.4 min, t(−)‑B = 13.9 min. [α]25 +66° (c 0.57 in CHCl3, ee =
D
89.7%), [α]25 −59° (c 0.84 in CHCl3, ee = 90.6%).
HPLC: (Chiralcel AS-H column, hexanes/ethanol = 92/8, 0.1%
Et2NH in hexane, flow rate = 1.0 mL/min, λ = 254 nm) t(−)‑A = 20.6
(7-exo-(DDiethylamino)-2-exo-methyl-3-oxabicyclo[3.2.0]-
heptan-6-endo-yl)methanol 9h. 166 mg, yield 51%. Light yellow
oil: 1H NMR (400 MHz, CDCl3) δ 0.98 (t, J = 7.2 Hz, 6H), 1.05 (d, J
= 6.6 Hz, 3H), 2.31 (bs, 1H) 2.41 (ddd, J = 12.4, 7.9, 5.1 Hz, 1H),
2.47 (dd, J = 8.0, 5.1 Hz, 1H), 2.50−2.58 (m, 4H), 2.58−2.65 (m,
1H), 2.92−3.03 (m, 1H), 3.61−3.76 (m, 3H), 4.00 (dd, J = 10.2, 1.0
Hz, 1H), 4.02−4.10 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 10.4
(2C), 18.6, 34.4, 39.1, 41.8 (2C), 47.7, 61.8, 62.0, 65.1, 79.4; m/z
(EI+) 213 (M+, 0.72%), 129 (100), 112 (55), 98 (59); IR (KBr, neat),
ν (cm−1) 3143, 2967, 1454, 1112, 1051; HRMS (ESI+) calculated for
(C12H24NO2)+ 214.1802 [M + H+], found 214.1801.
min, t(+)‑B = 14.4 min. [α]25D −52 (c 0.66 in CH2Cl2, ee = 88%), [α]25
+59 (c 0.51 in CH2Cl2, ee = 93%).
D
(7-exo-(Diethylamino)-2-exo-phenyl-3-tosyl-3-azabicyclo-
[3.2.0]heptan-6-endo-yl)methanol 10b. 37 mg, yield 22%. White
solid: mp 115−121 °C; 1H NMR (400 MHz, CDCl3) δ 0.95 (t, J = 7.1
Hz, 6H), 2.32 (s, 3H), 2.48−2.58 (m, 5H), 2.63−2.68 (m, 1H), 2.68−
2.73 (m, 1H), 3.06−3.16 (m, 1H), 3.36 (dd, J = 11.3, 8.3 Hz, 1H),
3.62−3.75 (m, 2H), 3.87 (dd, J = 11.3, 1.9 Hz, 1H), 4.83 (s, 1H),
6.98−7.08 (m, 4H), 7.14−7.23 (m, 3H), 7.32−7.36 (m, 2H); 13C
NMR (101 MHz, CDCl3) δ 10.2 (2C), 21.4, 34.5, 40.0, 41.7 (2C),
47.2, 49.3, 61.6, 62.5, 69.0, 126.7 (2C), 127.0 (2C), 127.5, 128.5 (2C),
129.1 (2C), 136.1, 140.4, 142.8; IR (KBr, neat), ν (cm−1) 2968, 2972,
1550, 1346, 1161; HRMS (ESI+) calculated for (C24H33N2O3S)+
249.2206 [M + H+], found 249.2206.
HPLC: (Chiracel Lux Amylose-2 column, hexanes/2-propanol/
ethanol = 94/5/1, 0.1% Et2NH in hexane, flow rate = 1.0 mL/min, λ =
230 nm) t(+)‑A = 10.5 min, t(−)‑B = 11.6 min. [α]25 +19° (c 0.71 in
D
CHCl3, ee = 81.6%), [α]25 −19° (c 0.19 in CHCl3, ee = 94.7%).
D
G
dx.doi.org/10.1021/jo3019413 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HPLC: (Chiralcel AS-H column, hexanes/ethanol = 92/8, 0.1%
(24) Enders, D.; Wang, C.; Liebich, J. X. Chem.Eur. J. 2009, 15,
11058−11076.
Et2NH in hexane, flow rate = 1.0 mL/min, λ = 254 nm) t(−)‑A = 19.5
min, t(+)‑B = 10.5 min. [α]25D −27 (c 0.29 in CH2Cl2, ee = 96%), [α]25
+26 (c 0.24 in CH2Cl2, ee = 98%).
(25) Bonne, D.; Constantieux, T.; Coquerel, Y.; Rodriguez, J. Org.
Biomol. Chem. 2012, 10, 3969−3973.
D
(26) Ling, J.-B.; Su, Y.; Zhu, H.-L.; Wang, G.-Y.; Xu, P.-F. Org. Lett.
2012, 14, 1090−1093.
ASSOCIATED CONTENT
■
(27) Enders, D.; Luttgen, K.; Narine, A. A. Synthesis 2007, 959−980.
̈
S
* Supporting Information
́ ́
(28) Sunden, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Cordova, A.
Chiral-phase HPLC chromatograms and crystallographic data
(CIF files), NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Chem.Eur. J. 2007, 13, 574−581.
(29) Lingen, H. L.; van; Zhuang, W.; Hansen, T.; Rutjes, F. P. J. T.;
Jørgensen, K. A. Org. Biomol. Chem. 2003, 1, 1953−1958.
(30) Zhang, X.; Zhang, S.; Wang, W. Angew. Chem., Int. Ed. 2010, 49,
1481−1484.
AUTHOR INFORMATION
■
(31) Zu, L.; Zhang, S.; Xie, H.; Wang, W. Org. Lett. 2009, 11, 1627−
1630.
Corresponding Author
*E-mail: kanger@chemnet.ee.
(32) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2012, 41, 988−999.
̈
(33) Nising, C. F.; Brase, S. Chem. Soc. Rev. 2008, 37, 1218−1228.
̈
Notes
(34) Kano, T.; Tanaka, Y.; Maruoka, K. Tetrahedron Lett. 2006, 47,
The authors declare no competing financial interest.
3039−3041.
(35) Kano, T.; Tanaka, Y.; Maruoka, K. Tetrahedron 2007, 63, 8658−
ACKNOWLEDGMENTS
8664.
■
(36) Figueras, A.; Miralles-Lluma,
Busque, F.; Figueredo, M.; Font, J.; Alibes
ChemMedChem 2012, 7, 1044−1056.
́
R.; Flores, R.; Rustullet, A.;
The authors thank the Estonian Science Foundation (Grants
No. 8289 and 8880), the Ministry of Education and Research
(Grant No. SF0140060s12) and the EU European Regional
Development Fund (3.2.0101.08-0017) for financial support.
́
́
, R.; Marechal, J.-D.
́
(37) Alibes, R.; Alvarez-Larena, A.; de March, P.; Figueredo, M.;
Font, J.; Parella, T.; Rustullet, A. Org. Lett. 2006, 8, 491−494.
(38) Sarkar, N.; Nayek, A.; Ghosh, S. Org. Lett. 2004, 6, 1903−1905.
(39) Baik, T.-G.; Luis, A. L.; Wang, L.-C.; Krische, M. J. J. Am. Chem.
Soc. 2001, 123, 6716−6717.
(40) Faber, K. Biotransformations in Organic Chemistry; Springer:
Heidelberg, 2004.
(41) Oger, C.; Marton, Z.; Brinkmann, Y.; Bultel-Ponce, V.; Durand,
T.; Graber, M.; Galano, J. M. J. Org. Chem. 2010, 75, 1892−1897.
(42) Reinart-Okugbeni, R.; Ausmees, K.; Kriis, K.; Werner, F.;
Rinken, A.; Kanger, T. Eur. J. Med. Chem. 2012, 55, 255−261.
We are grateful to Dr. A.-M. Muurisepp for MS analysis and to
̈
̈
Mrs. T. Kailas for IR analysis.
REFERENCES
■
(1) Marek, I. Chem.Eur. J. 2008, 14, 7460−7468.
(2) Ruijter, E.; Scheffelaar, R.; Orru, R. V. Angew. Chem., Int. Ed.
2011, 50, 6234−6246.
(3) Sunderhaus, J. D.; Martin, S. F. Chem.Eur. J. 2009, 15, 1300−
1308.
(4) Ganem, B. Acc. Chem. Res. 2009, 42, 463−472.
(5) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42,
367−378.
(6) Ramon
1634.
́
, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602−
(7) Domling, A. Chem. Rev. 2006, 106, 17−89.
̈
(8) Pellissier, H. Adv. Synth. Catal. 2012, 354, 237−294.
(9) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167−
178.
(10) Enders, D.; Narine, A. A. J. Org. Chem. 2008, 73, 7857−7870.
(11) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
̈
2007, 46, 1570−1581.
(12) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341−5378.
(13) Laars, M.; Ausmees, K.; Uudsemaa, M.; Tamm, T.; Kanger, T.;
Lopp, M. J. Org. Chem. 2009, 74, 3772−3775.
(14) Laars, M.; Kriis, K.; Kailas, T.; Muurisepp, A.-M.; Pehk, T.;
̈
̈
Kanger, T.; Lopp, M. Tetrahedron: Asymmetry 2008, 19, 641−645.
(15) Kanger, T.; Kriis, K.; Laars, M.; Kailas, T.; Muurisepp, A.-M.;
̈
̈
Pehk, T.; Lopp, M. J. Org. Chem. 2007, 72, 5168−5173.
(16) Mosse, S.; Laars, M.; Kriis, K.; Kanger, T.; Alexakis, A. Org. Lett.
́
2006, 8, 2559−2562.
(17) Kriis, K.; Ausmees, K.; Pehk, T.; Lopp, M.; Kanger, T. Org. Lett.
2010, 12, 2230−2233.
(18) Drescher, K.; Haupt, A.; Unger, L.; Turner, S. C.; Braje, W.;
Grandel, R. Chem. Abstr. 2006, 144, 390732.
(19) Drescher, K.; Haupt, A.; Unger, L.; Turner, S. C.; Braje, W.;
Grandel, R. PCT Int. Appl. WO 2006040176.
(20) Sosunov, E. A.; Gainullin, R. Z.; Danilo, P., Jr.; Anyukhovsky, E.
P.; Kirchengast, M.; Rosen, M. R. J. Pharm. Exp. Ther. 1999, 290, 146−
152.
(21) Graul, A.; Castaner, J. Drugs Future 1998, 23, 370−373.
(22) Hasinoff, B. B.; Creighton, A. M.; Kozlowska, H.; Thampatty,
P.; Allan, W. P.; Yalowich, J. C. Mol. Pharmacol. 1997, 52, 839−845.
(23) Miesch, M. Curr. Org. Synth. 2006, 3, 327−340.
H
dx.doi.org/10.1021/jo3019413 | J. Org. Chem. XXXX, XXX, XXX−XXX