Syntheses of arabinose-derived pyrrolidine catalysts and their applications in intramolecular Diels-Alder reactions

Article abstract of DOI:10.1039/c4ob02219j

Six chiral hydroxylated pyrrolidine catalysts were synthesized from commercially available D-arabinose in seven steps. Various aromatic substituents α to the amine can be introduced readily by a Grignard reaction, which enables facile optimization of the catalyst performance. The stereoselectivities of these catalysts have been assessed by comparing with those of MacMillan's imidazolidinone in a known intramolecular Diels-Alder (IMDA) reaction of a triene. Two additional IMDA reactions of symmetrical dienals with concomitant desymmetrisation further established the potential use of these novel amine catalysts. These pyrrolidines are valuable catalysts for other synthetic transformations.

Full text of DOI:10.1039/c4ob02219j

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Journal Name
RSCPublishing
ARTICLE
Syntheses of Arabinose-derived Pyrrolidine
Catalysts and Their Applications in
Intramolecular Diels-Alder Reactions
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Tony K. M. Shing, * Kwun W. Wu, Ho T. Wu, Qicai Xiao,
DOI: 10.1039/x0xx00000x
Six chiral hydroxylated pyrrolidine catalysts were synthesized from commercially available
D-arabinose
www.rsc.org/
in seven steps. Various aromatic substituents α to the amine can be introduced readily by a Grignard
reaction, which enables facile optimization of the catalyst performance. The stereoselectivities of these
catalysts have been assessed by comparing with those of MacMillan’s imidazolidinone on a known
intramolecular Diels-Alder (IMDA) reaction of a triene. Two additional IMDA reactions of symmetrical
dienals with concomitant desymmetrisation further established the potential use of these novel amine
catalysts. These pyrrolidines are valuable catalysts for other synthetic transformations.
Introduction
Enantioselective organocatalysis, which signifies the use of
small chiral organic molecules to promote different chemical
transformations in a stereoselective manner, is a research area
that has received widespread attention over the past decade.1
Nowadays, organocatalysis has become
a
vast and
interconnected field of catalysis, which produces a large
volume of research work with intriguing prospectives.
Organocatalysis has established itself as a vital role in
Fig. 1 Chiral amine catalysts.
asymmetric
catalysis,
complementing
enzymes
and
organometallic catalysis.2
Inspired by the powerful capabilities of aminocatalysis, our
group has initiated a project to develop new chiral pyrrolidines
with a monoꢀaryl group that would complement the existing
diarylprolinol ether and imidazolidinone catalysis. With a
glance of the aforementioned amine catalysts, we believe that
modification of MacMillan’s catalysts should not be easily
performed on the phenyl group of the amino acid; whereas
modification on proline was possible on the acid functionality
and afforded a series of diaryl prolinol derivatives. However,
reactions catalyzed by diaryl prolinols could be sluggish due to
the bulky diaryl substituents and the corresponding monoꢀaryl
prolinol derivatives are not readily accessible. As a result, the
feature in our catalyst design is that the aryl group can be easily
modified in adjusting the electronic or steric demand of the
blocking group, via different substituents on the phenyl ring.
Among the different classes of organocatalysis, aminocatalysis
was first reckoned to have a general catalysis concept. Two
representative classes of chiral amine catalysts are MacMillan’s
imidazolidinone organocatalysts
diarylprolinol silyl ether organocatalysts
MacMillan’s catalysts were synthesized from
(
1
)
and
J
ø
rgensen’s
(Figure 1).
ꢀphenylalanine3a
ꢀproline5; both
(
2)
L
and the diarylprolinol ethers were derived from
L
of these catalyst classes have demonstrated impressive results
in a large array of chemical transformations, including Dielsꢀ
Alder
reaction,3a,6,7
aldol
reaction,8a
epoxidation,9
cyclopropanation,10 enal hydrogenation,11 FriedelꢀCrafts
alkylation,12 Mannich reaction,8b Michael reaction,13 1,3ꢀ
dipolar cycloadddition,8c domino reaction14 and halogation.15
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DOI: 10.1039/C4OB02219J
Results and Discussion
D
ꢀArabinose was conveniently chosen as the starting material
because of its builtꢀin chirality and its ready commercial
availability in large quantities for both enantiomers. The
synthetic scheme is shown below (Scheme 1):
Scheme 1 Synthesis of hemiaminal 6.
Fig. 2 Proposed Grignard addition pathway.
The hydroxyl groups at Cꢀ3,4 of
D
ꢀarabinose (3) were first
selectively protected by kinetic acetonation. The 1,2ꢀdiol unit
underwent glycol cleavage oxidation and the subsequent basic
Finally, the
deprotected by hydrogenolysis in the presence of 10% Pdꢀonꢀ
charcoal to give the chiral pyrrolidine catalysts 19 23. Amine
18 on the other hand, underwent dehalogenation and an
alternative strategy using
ꢀchloroethyl chloroformate16 was
employed to obtain the desired amine catalyst 24 (Scheme 3).
Nꢀbenzyl group of the amines 13ꢀ17 was
hydrolysis smoothly generated 2,3ꢀ
erythrose ( ) with 60% overall yield in three steps. Lactol
was then converted into hemiaminal
O
ꢀisopropylideneꢀ
D
ꢀ
5
5
ꢀ
6
by reacting with
benzylamine in the presence of 3Å molecular sieves prior to
Grignard reaction. Such conversion was made because direct
α
Grignard reaction on lactol
diastereoselectively. In contrast, Grignard reaction of the
common intermediate hemiaminal smoothly furnished amines
12 regio and stereospecifically. Mesylation of the free
alcohol followed by facile intramolecular substitution reaction
gave tertiary amines 13 18 in good yields. (Scheme 2).
5 resulted in poor regioꢀ and
6
7
ꢀ
ꢀ
Scheme 3 Syntheses of pyrrolidine catalysts 19-24
.
With the chiral pyrrolidine catalysts in hand, we first compared
them with MacMillan’s imidazolidinone , following his
1
published enantioselective intramolecular DielsꢀAlder reaction
(IMDA) (Scheme 4).6 The results indicated that although the
enantioselectivities of our amine catalysts were not as superior
as those of MacMillan’s catalyst, satisfactory enantiocontrol
could be attained.
Scheme 2 Syntheses of protected pyrrolidines.
The stereochemical outcome of the Grignard addition can be
rationalized by an
chelated with the oxygen and nitrogen functionalities,
is more favourable to give amines 12 due to steric hindrance
αꢀchelation model, where the metal center is
β
attack
7
ꢀ
of the isopropylidene ring. Such a stereospecific addition on
imine not only provided the desired stereochemistry, but also a
more accessible and simple approach to introduce the monoꢀ
aryl group on the catalyst without any rearrangement problem
(Figure 2).
Scheme 4 Chiral amine catalysed asymmetric IMDA reactions.
2 | J. Name., 2012, 00, 1-3
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On the other hand, Hong17 and Christmann18 have applied chiral induction in both IMDA reactions, despite the generally
Jørgensen’s catalyst in enantioselective IMDA reaction of poor chemical yields. The low yields are attributed to the
dienals to create bicyclic ring systems. In view of the potential instability of both the starting material and the cycloadduct in
of functionalized bicyclic ring systems, we designed and the IMDA reactions, as both were found decomposing before
synthesized two hydroxylated dienals and applied our amine reaction completion.
catalysts in enantioselective IMDA reactions with concomitant
desymmetrization. Dienals 28 and 31 were prepared from ethyl Vinylogous enamine activated IMDA reactions are assumed
formate and ethyl glycolate via standard transformations, and the proposed catalytic cycle is illustrated in Figure 3 using
respectively (see Supporting Information for details). Several hydroxylated dienal 28 and amine 19 as an example. Amine 19
solvents and coꢀacids were evaluated and it was found that would condense with an aldehyde function in 28 to form
chloroform and oꢀnitrobenzoic acid gave the best results. The enamine 34, via a transꢀtrans iminium ion, with the carbon
results of the IMDA reactions are shown below:
chain pointing away from the bulky benzyl group in order to
minimize steric repulsion. It is expected that the π− system of
the enamine is relatively open at the α−face and thus is ready
for endoꢀapproach of the enol moiety from the bottom face by
steric control. β−Elimination of the cycloadduct 35 gives a
thermodynamically stable dienal system 29 and liberates amine
19. It is reasonable to rationalize that the amine catalyst would
assist this elimination via the formation of an iminium ion with
the remaining aldehyde group either before or after the IMDA
reaction.
Table 1. Chiral Pyrrolidine catalysed Intramolecular DielsꢀAlder Reactions
of dienal 28 with concomitant desymmetrization.
Entry Catalyst
R
Temp Reaction Yield
ee
(%)c
90
a
Time
20 h
21 h
(%)b
11
10
1
2
19
20
benzyl
biphenylmethyl
rt
rt
86
3
21
2ꢀ
rt
16 h
9
90
naphthylmethyl
pꢀMeꢀbenzyl
4
5
6
22
23
24
rt
rt
rt
20 h
20 h
20 h
13
9
87
88
87
pꢀOMeꢀbenzyl
pꢀClꢀbenzyl
12
a All IMDA reactions were carried out at 0.1M.
b Isolated yield.
c Enantioselectivity was determined by HPLC using a chiral column.
Table 2. Chiral Pyrrolidine catalysed Intramolecular DielsꢀAlder Reactions
of dienal 31 with concomitant desymmetrization .
Fig. 3. Proposed catalytic cycle of
asymmetric IMDA reaction of 28
.
Entrya
Catalyst
R
Temp Reaction Yield
ee
(%)b
82
77
81
Time
(%)a
16
1
2
3
19
20
21
benzyl
biphenylmethyl
2ꢀ
rt
rt
rt
9 h
9 h
9 h
16
15
Conclusion
naphthylmethyl
pꢀMeꢀbenzyl
pꢀOMeꢀbenzyl
pꢀClꢀbenzyl
To summarize, the extraordinary potential of the new
pyrrolidine catalysts 19 24 should not be dismissed just because
4
5
6
22
23
24
rt
rt
rt
16 h
8 h
8 h
20
17
18
80
77
78
ꢀ
of the low yields obtained from the current IMDA reactions of
dienals. Facile modification of the aromatic unit and the ready
availability of both enantiomers of the pyrrolidine catalysts
provide a very flexible and practical platform to tackle amine
catalyzed reactions. Application of our amine catalysts to
different reaction types involving enamine and iminium ion
activation modes is underway.
a All IMDA reactions were carried out at 0.1M.
b Isolated yield.
c Enantioselectivity was determined by HPLC using chiral column.
Among the six amine catalysts screened, amines 19 (R= benzyl)
and 21 (R= 2ꢀnaphthylmethyl) displayed comparatively better
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DOI: 10.1039/C4OB02219J
after being stirred at room temperature for 15 min. The
resultant solution was stirred at room temperature for another
18 h. The reaction was quenched by dropwise addition of Et3N
until pH~7 (test by pH paper). The solution was concentrated
Experimental section
General Information
under reduced pressure to afford the crude
4
. Following by the
Melting points were measured with a Reichert apparatus in glycol cleavage procedure, the crude
4 was converted to
Celsius degrees and are uncorrected. Optical rotations were colourless oil. The powdered K2CO3 (2.66 g, 19.2 mmol) was
obtained operating at 589nm. Infrared (IR) spectra were added to the solution of crude mixture in MeOH (50 mL). The
recorded as thin films on potassium bromide discs. Nuclear mixture was stirred at room temperature for 24 h. The resultant
magnetic resonance (NMR) spectra were measured with at mixture was filtered through a pad of silica gel that was eluted
400.19 MHz (1H) or at 100.62 MHz (13C) in CDCl3 solutions, with Et2O. Concentration of the filtrate followed by flash
unless stated otherwise. All chemical shifts were recorded in chromatography (Hexane: Et2O, 3:2) yielded lactol
5 (3.54 g,
ppm relative to tetramethylsilane (δ = 0.0). Spinꢀspin coupling 60%) as a colourless oil: [α]20 –59.4 (c 2.45, CHCl3) {lit.43 [α]25
D
D
constants (J value) recorded in Hz were measured directly from –79.3 (c 0.925, CHCl3)}; Rf 0.3 (Hexane:Et2O, 1:2); IR (thin
1
the spectra. MS and HRMS were measured on a ESIꢀMS film) 3438, 2986, 2940, 1378, 1214, 1071, 989, 856 cmꢀ1; H
instrument with a magnetic sector analyzer. All reactions were NMR (major anomer) δ 1.30 (3H, s), 1.45 (3H, s), 3.37 (1H, br
monitored by analytical thinꢀlayer chromatography (TLC) on s), 3.98–4.06 (2H, m), 4.55 (1H, d,
J = 5.9 Hz), 4.82 (1H, dd, J
aluminiumꢀprecoated plates of silica gel 60 F254 with detection = 5.8, 3.7 Hz), 5.39 (1H, s); 13C NMR δ 25.0, 26.5, 72.2, 80.2,
by spraying with 5% (w/v) dodecamolybdophosphoric acid in 85.4, 102.1, 112.6; MS (ESI) m/z (relative intensity) 183 ([M+
ethanol or 5% (w/v) ninhydrin in ethanol, and subsequent Na]+, 100); HRMS (ESI) calcd for C7H12O4 [M+Na]+ 183.0628,
heating. Silica gel 60 (230ꢀ400 mesh) was used for flash found 183.0831.
chromatography. All reagents and solvents were general
reagent grade unless otherwise stated. DMF was dried by Imine 6. To a solution of lactol
5 (5.74 g, 35.8 mmol) in
magnesium sulfate, filtered, and the filtrate was then distilled CH2Cl2 (10 mL) were added BnNH2 (39 mL. 358 mmol) and
under reduced pressure. THF was freshly distilled from 3Å molecular sieves (ca. 22 g) at room temperature. The
Na/benzophenone ketyl under nitrogen. Et2O was freshly reaction mixture was stirred at room temperature for 24 h until
distilled from K/benzophenone ketyl under nitrogen. the disappearance of the starting material as shown on TLC.
Dichloromethane and chloroform were freshly distilled from The mixture was filtered and the residue was washed with
P2O5 under nitrogen. Other reagents were purchased from EtOAc. Concentration of the filtrate followed by flash column
commercial suppliers and were used without purification.
chromatography (hexane:EtOAc, 3:1) produced imine
6 (8.60
g, 96%) as a white solid: mp 58–59 °C; [α]2D0 –34.0 (c 2.22,
General procedure for glycol cleavage reaction. NaIO4 (3 CHCl3); Rf 0.33 (hexane:EtOAc, 1:1); IR (thin film) 3673,
eq.) was dissolved in a minimum amount of hot water (~80 °C) 3456, 3269, 3028, 2932, 2858, 1461, 1376, 1270, 1209, 1102,
and to this solution was added silica gel (230–400 mesh, 10
weight of diol) with vigorous swirling and shaking. The s), 1.5 (3.8H, s), 3.42 (1H, dd,
mixture was suspended in CH2Cl2 and then a solution of diol (1 = 13.3 Hz), 3.89 (0.29H, d,
= 13.3 Hz), 3.93–3.99 (2.58H, m),
eq.) in CH2Cl2 was added. After vigorous stirring at room 4.15 (1H, d,
= 13.3 Hz), 4.29 (1H, d, = 3.3 Hz), 4.40 (0.29
temperature for 1 h, the mixture was filtered. The filtrate was H, d,
= 6 Hz), 4.50 (1H, dd, = 6, 3.5 Hz), 4.68 (1H, dd,
concentrated under reduced pressure to give the aldehyde 6, 3.6 Hz), 4.77–4.82 (0.58 H, m), 7.23–7.41 (6.45H, m); 13C
×
1057, 992, 859, 702 cmꢀ1; 1H NMR δ 1.31 (0.87H, s), 1.33 (3H,
J
= 11, 3.2 Hz), 3.77 (0.29H, d, J
J
J
J
J
J
J =
product.
NMR δ 24.5, 24.8, 25.9, 26.3, 49.2, 50.1, 68.7, 70.5, 79.2, 79.8,
80.5, 85.2, 91.3, 94.4, 111.9, 112.3, 128.2, 128.2, 128.2, 128.4,
Generation of benzylmagnesium bromide/chloride. To a 139.6, 139.9; MS (ESI) m/z (relative intensity) 250 ([M]+, 100),
suspension of magnesium powder (150 mmol) in THF (50 mL) 251 (23), 252 (2); HRMS (ESI) calcd for C14H19NO3 [M]+
was added 1,2ꢀdibromoethane (0.36 mL) and the mixture was 250.1438, found 250.1440.
stirred at room temperature for 15 min. A solution of benzyl
halide (50.0 mmol) in THF (50 mL) was added dropwise to the Amine 7 (R=benzyl). To a stirred solution of a 0.5M THF
mixture at a rate to maintain a gentle reflux of the THF. After solution of benzylmagnesium bromide (4.7 mL, 2.34 mmol)
the addition of the benzyl halide solution, the mixture was was added imine
heated under reflux for 2h and then cooled down for use. The dropwise at –20 C under N2. After the addition, the mixture
concentration of the benzylmagnesium bromide/ chloride was allowed to rise to room temperature and stirred for a
6 (56.2 mg, 0.225 mmol) in dry THF (4.3 mL)
o
solution generated was around 0.5
M
.
further 13 h. The mixture was quenched with saturated NH4Cl
solution and the aqueous phase was extracted with EtOAc (3
ꢀarabinose 3 (5.55 g, 20 mL). The combined organic extracts were dried over
×
Lactol 5. To a milky suspension of dry
D
37.0 mmol) in DMF (50 mL) were added 2,2ꢀ anhydrous MgSO4, and filtered. The filtrate was concentrated
dimethoxypropane (13.6 mL, 110 mmol) and TsOH (629 mg, under reduced pressure and the residue was purified by flash
3.70 mmol) at room temperature. The solution became clear chromatography (hexane:Et2O, 1:1) to afford amine
7 (44.5 mg,
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58%) as a colourless oil: [α]20 –34.6 (c 1.98, CHCl3); Rf 0.22 concentrated under reduced pressure and the residue was
D
(hexane:Et2O, 1:2); IR (thin film) 3678, 3653, 3457, 3270, purified by flash chromatography (hexane:Et2O, 1:1) to afford
3063, 3028, 2985, 2930 1495, 1455, 1214, 1061, 745 cmꢀ1; H amine
9 –
(816 mg, 57%) as a white solid: mp 98–99 °C; [α]2D0
1
NMR δ 1.34 (3H, s), 1.53 (3H, s), 2.77 (1H, dd,
Hz), 3.03 (1H, ddd, = 9.6, 4.6, 1.4 Hz), 3.35 (1H, dd,
4.6 Hz), 3.56 (1H, dd, = 12.8, 2.2 Hz), 3.73 (1H, dd,
4.9 Hz), 3.88 (1H, d,
(1H, d, = 12.3 Hz), 4.15 (1H, dd,
(10H, m); 13C NMR δ 24.7 (CH3), 26.7 (CH3), 37.3 (CH2), 50.5 3.74 (1H, dd,
J = 13.1, 9.7 46.6 (c 1.28, CHCl3); Rf 0.15 (hexane:Et2O, 1:2); IR (thin film)
J
J
J
= 13.1, 3666, 3642, 2983, 2928, 1453, 1375, 1248, 1214, 1139, 1053,
1
J
J
= 12.8, 817, 748, 701 cmꢀ1; H NMR δ 1.33 (3H, s), 1.55 (3H, s), 2.93
= 12.3 Hz), 3.96–4.00 (1H, m), 4.06 (1H, dd,
J
= 13.0, 9.7 Hz), 3.13 (1H, ddd,
J
= 9.6, 4.6, 1.4 Hz),
= 13.0, 4.6 Hz), 3.57 (1H, dd, = 12.8, 2.1 Hz),
= 12.8, 4.9 Hz), 3.91 (1H, d, = 12.3 Hz), 3.94–
= 12.3 Hz), 4.18 (1H, dd, = 7.2,
J
J
= 7.2, 1.5 Hz), 7.19–7.38 3.51 (1H, dd,
J
J
J
J
(CH2), 56.5 (CH), 60.6 (CH2), 76.3 (CH), 77.7 (CH), 107.5 (C), 3.96 (1H, m), 4.10 (1H, d,
J
J
126.5 (CH), 127.6 (CH), 128.6 (CH), 128.7 (CH), 128.7 (CH), 1.6 Hz), 7.30–7.52 (8H, m), 7.65 (1H, s), 7.79–7.85 (3H, m);
129.2 (CH), 138.1 (C), 138.6 (C); MS (ESI) m/z (relative 13C NMR δ 24.8 (CH3), 26.7 (CH3), 37.5 (CH2), 50.7 (CH2),
intensity) 342 ([M+H]+, 100), 343 (24), 344 (4); HRMS (ESI) 56.6 (CH), 60.6 (CH2), 76.4 (CH), 77.8 (CH), 107.6 (C), 125.6
calcd for C21H27NO3 [M+H]+ 342.2064, found 342.2059.
(CH), 126.3 (CH), 127.4 (CH), 127.5 (CH), 127.6 (CH), 127.7
(CH), 127.8 (CH), 128.4 (CH), 128.7 (CH), 128.7 (CH), 132.2
Amine (R=biphenylmethyl).
8
Following the general (C), 133.6 (C), 136.1 (C), 138.2 (C); MS (ESI) m/z (relative
procedure for generation of benzylic zinc reagent, the 4ꢀ intensity) 392 ([M+H]+, 100), 393 (27), 394 (5); HRMS (ESI)
(bromomethyl)biphenyl (850 mg, 3.44 mmol) was converted calcd for C25H29NO3 [M+H]+ 392.2220, found 392.2214.
o
into the biphenylmethyl zinc reagent at 25 C in 2h. To a
stirred solution of a 0.31M THF solution of biphenylmethyl Amine 10 (R=
zinc bromide (11.1 mL, 3.44 mmol) was added imine (87.7 THF solution of
mg, 0.336 mmol) in dry THF (29 mL) dropwise at –20 oC 3.33 mmol) was added imine
under N2. After the addition, the mixture was allowed to rise to THF (2 mL) dropwise at –20 C under N2. After the addition,
room temperature and stirred for a further 24 h. The mixture the mixture was allowed to rise to room temperature and stirred
was quenched with saturated NH4Cl solution and the aqueous for a further 17 h. The mixture was quenched with saturated
p
-Me-benzyl). To a stirred solution of a 0.5M
ꢀmethylbenzylmagnesium bromide (7.0 mL,
(52.7 mg, 0.211 mmol) in dry
6
p
6
o
phase was extracted with EtOAc (3
organic extracts were dried over anhydrous MgSO4, and EtOAc (3
filtered. The filtrate was concentrated under reduced pressure over anhydrous MgSO4, and filtered.
and the residue was purified by flash chromatography concentrated under reduced pressure and the residue was
(hexane:Et2O, 1:1) to afford amine (102 mg, 73%) as a purified by flash chromatography (hexane:Et2O, 1:1) to afford
2.11, CHCl3); Rf 0.15 amine 10 (27.3 mg, 50%) as a colourless oil: [α]2D0 –33.0 (c 1.13,
×
20 mL). The combined NH4Cl solution and the aqueous phase was extracted with
20 mL). The combined organic extracts were dried
The filtrate was
×
8
20
colourless oil: [α]
–48.6 (c
D
(hexane:Et2O, 1:2); IR (thin film) 3677, 3653, 3423, 3205, CHCl3); Rf 0.18 (hexane:Et2O, 1:2); IR (thin film) 3415, 3335,
3026, 2984, 2931, 1486, 1451, 1375, 1248, 1214, 1137, 1055, 2984, 2926, 1701, 1513, 1456, 1375, 1214, 1046, 808, 746 cmꢀ
754 cmꢀ1; 1H NMR δ 1.36 (3H, s), 1.55 (3H, s), 2.81 (1H, dd,
= 13.0, 9.8 Hz), 3.06 (1H, ddd, = 9.7, 4.6, 1.2 Hz), 3.39 (1H, dd,
= 13.1, 4.5 Hz), 3.58 (1H, dd, = 12.8, 2.0 Hz), 3.75 (1H, (1H, dd,
= 12.3 Hz), 3.99–4.02 (1H, (1H, dd,
J
1; 1H NMR δ 1.31 (3H, s), 1.51 (3H, s), 2.34 (3H, s), 2.70 (1H,
= 13.1, 9.8 Hz), 2.97 (1H, ddd, = 9.7, 4.6, 1.6 Hz), 3.30
= 13.1, 4.6 Hz), 3.53 (1H, dd, = 12.8, 2.1 Hz), 3.70
= 12.8, 4.8 Hz), 3.85 (1H, d, = 12.3 Hz), 3.94–3.97
= 12.3 Hz), 4.14 (1H, dd, = 7.2, 1.6
= 8.0 Hz), 7.12 (2H, d, = 7.8 Hz), 7.27–
J
J
J
dd,
dd,
J
J
J
J
J
J
J
= 12.8, 4.9 Hz), 3.90 (1H, d,
J
m), 4.09 (1H, d,
J
= 12.3 Hz), 4.20 (1H, dd,
J
= 7.2, 1.4 Hz), (1H, m), 4.05 (1H, d,
J
J
7.28–7.39 (8H, m), 7.44–7.48 (2H, m), 7.56–7.62 (4H, m); 13C Hz), 7.06 (2H, d,
J
J
NMR δ 24.8 (CH3), 26.7 (CH3), 37.0 (CH2), 50.6 (CH2), 56.6 7.35 (5H, m); 13C NMR δ 21.1 (CH3), 24.8 (CH3), 26.7 (CH3),
(CH), 60.6 (CH2), 76.4 (CH), 77.8 (CH), 107.6 (C), 126.9 36.9 (CH2), 50.6 (CH2), 56.7 (CH), 60.6 (CH2), 76.4 (CH), 77.8
(CH), 127.3 (CH), 127.4 (CH), 127.6 (CH), 128.7 (CH), 128.7 (CH), 107.5 (C), 127.6 (CH), 128.7 (CH), 128.7 (CH), 129.2
(CH), 128.8 (CH), 129.7 (CH), 137.7 (C), 138.2 (C), 139.4 (C), (CH), 129.4 (CH), 135.5 (C), 136.1 (C), 138.2 (C); MS (ESI)
140.7 (C); MS (ESI) m/z (relative intensity) 418 ([M+H]+, 100), m/z (relative intensity) 356 ([M+H]+, 100), 357 (25), 358 (4);
419 (35), 420 (5); HRMS (ESI) calcd for C27H31NO3 [M+H]+ HRMS (ESI) calcd for C22H29NO3 [M+H]+ 356.2220, found
418.2377, found 418.2369.
356.2210.
Amine 9 (R=2-naphthylmethyl). To a stirred solution of a Amine 11 (R=
0.25M Et2O solution of 2ꢀnaphthylmethylmagnesium bromide THF solution of
(146 mL, 36.5 mmol) was added imine (910 mg, 3.65 mmol) 5.01 mmol) was added imine
in dry THF (20 mL) dropwise at –20 C under N2. After the THF (1 mL) dropwise at –20 C under N2. After the addition,
addition, the mixture was allowed to rise to room temperature the mixture was allowed to rise to room temperature and stirred
and stirred for a further 24 h. The mixture was quenched with for a further 17 h. The mixture was quenched with saturated
saturated NH4Cl solution and the aqueous phase was extracted NH4Cl solution and the aqueous phase was extracted with
p
-OMe-benzyl). To a stirred solution of a 0.5M
ꢀmethoxybenzylmagnesium chloride (5.0 mL,
(53.5 mg, 0.214 mmol) in dry
p
6
6
o
o
with EtOAc (3
×
50 mL). The combined organic extracts were EtOAc (3
×
20 mL). The combined organic extracts were dried
The filtrate was
dried over anhydrous MgSO4, and filtered. The filtrate was over anhydrous MgSO4, and filtered.
This journal is © The Royal Society of Chemistry 2012
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Organic & Biomolecular Chemistry
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VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C4OB02219J
concentrated under reduced pressure and the residue was (hexane:Et2O, 6:1); IR (thin film) 3027, 2982, 2932, 2787,
purified by flash chromatography (hexane:Et2O, 1:1) to afford 1451, 1373, 1210, 1133, 1102, 1033, 739, 700 cmꢀ1; 1H NMR δ
amine 11 (21.1 mg, 26%) as a colourless oil: [α]2D0 –35.9 (c 3.17, 1.42 (3H, s), 1.73 (3H, s), 2.08 (1H, dd,
J
= 11.2, 4.7 Hz), 2.41
= 13.2, 3.6 Hz), 3.14–
= 13.5 Hz), 4.28 (1H, d, = 13.5
= 6.4, 4.5 Hz), 4.57 (1H, dd, = 6.4, 4.8
CHCl3); Rf 0.13 (hexane:Et2O, 1:2); IR (thin film) 3312, 2985, (1H, dt,
2929, 1612, 1512, 1457, 1247, 1037, 747 cmꢀ1; 1H NMR δ 1.32 3.22 (2H, m), 3.27 (1H, d,
(3H, s), 1.51 (3H, s), 2.69 (1H, dd, J = 13.2, 9.7 Hz), 2.95 (1H, Hz), 4.45 (1H, dd,
J = 10.1, 4.0 Hz), 3.01 (1H, dd, J
J
J
J
J
ddd,
(1H, dd,
(3H, s), 3.84 (1H, d,
d, = 12.3 Hz), 4.14 (1H, dd,
8.6 Hz), 7.09 (2H, d,
J
= 9.6, 4.6, 1.4 Hz), 3.26 (1H, dd,
J
J
= 13.2, 4.6 Hz), 3.54 Hz), 7.28–7.46 (10H, m); 13C NMR δ 25.8 (CH3), 26.5 (CH3),
= 12.8, 4.8 Hz), 3.79 33.3 (CH2), 57.1 (CH2), 59.9 (CH2), 70.2 (CH), 77.5 (CH),
J
= 12.8, 2.1 Hz), 3.70 (1H, dd,
J
= 12.3 Hz), 3.94–3.98 (1H, m), 4.04 (1H, 80.4 (CH), 111.0 (C), 125.9 (CH), 126.8 (CH), 128.2 (CH),
= 7.2, 1.5 Hz), 6.85 (2H, d, 128.5 (CH), 129.5 (CH), 138.6 (C), 139.6 (C); MS (ESI) m/z
J
J
J =
J
= 8.5 Hz), 7.28–7.36 (5H, m); 13C NMR (relative intensity) 324 ([M+H]+, 100), 325 (20), 326 (3);
δ 24.8 (CH3), 26.7 (CH3), 36.4 (CH2), 50.6 (CH2), 55.2 (CH3), HRMS (ESI) calcd for C21H25NO2 [M+H]+ 324.1958, found
56.6 (CH), 60.6 (CH2), 76.3 (CH), 77.8 (CH), 107.5 (C), 114.1 324.1962.
(CH), 127.5 (CH), 128.6 (CH), 128.7 (CH), 130.2 (CH), 130.5
(C), 138.2 (C), 158.2 (C); MS (ESI) m/z (relative intensity) 372 Amine 14 (R=biphenylmethyl). To a solution of amine
8
([M+H]+, 100), 373 (25), 374 (5); HRMS (ESI) calcd for (1.24 g, 2.98 mmol) in CH2Cl2 (40 mL) and then triethylamine
C22H29NO4 [M+H]+ 372.2169, found 372.2173.
(1.8 mL, 13.1 mmol) and methanesulfonyl chloride (0.51 mL,
6.55 mmol) were added under N2 at 0 oC. The reaction mixture
Amine 12 (R=
THF solution of
2.08 mmol) was added imine
p
-Cl-benzyl). To a stirred solution of a 0.5M was stirred for 1 h and quenched with saturated NaHCO3
ꢀchlorobenzyl magnesium bromide (4.2 mL, solution. The aqueous phase was extracted with Et2O (3 30
(52 mg, 0.206 mmol) in dry mL). The combined organic extracts were washed with brine,
p
×
6
o
THF (4 mL) dropwise at –20 C under N2. After the addition, dried over anhydrous MgSO4, and filtered. The filtrate was
the mixture was allowed to rise to room temperature and stirred concentrated under reduced pressure and the residue was
for a further 24 h. The mixture was quenched with saturated purified by flash chromatography (hexane:Et2O, 1:1) to afford
NH4Cl solution and the aqueous phase was extracted with amine 14 (1.06 g, 88%) as a white solid: mp 120–121 °C; [α]2D0
EtOAc (3
over anhydrous MgSO4, and filtered.
concentrated under reduced pressure and the residue was NMR δ 1.38 (3H, s), 1.68 (3H, s), 2.06 (1H, dd,
purified by flash chromatography (hexane:Et2O, 1:1) to afford Hz), 2.40 (1H, dt, = 10.2, 4.0 Hz), 3.00 (1H, dd,
amine 12 (35.8 mg, 46%) as a colourless oil: [α]2D0 –33.8 (c 2.59, Hz), 3.12 (1H, d,
= 11.2 Hz), 3.18 (1H, dd,
= 13.5 Hz), 4.25 (1H, d, = 13.5 Hz), 4.44–4.47
×
20 mL). The combined organic extracts were dried –153.6 (
c 1.30, CHCl3); Rf 0.20 (hexane:Et2O, 6:1); IR (thin
1
The filtrate was film) 3659, 3471, 2943, 2767, 1439, 1375, 1211, 746 cmꢀ1; H
J
= 11.1, 4.7
J
J = 13.2, 3.5
J
J = 13.0, 10.5 Hz),
CHCl3); Rf 0.13 (hexane:Et2O, 1:2); IR (thin film) 3316, 3028, 3.24 (1H, d,
J
J
2983, 2927, 1491, 1452, 1376, 1247, 1214, 1087, 1051, 813 (1H, m), 4.54–4.57 (1H, m), 7.27–7.64 (14H, m); 13C NMR δ
1
cmꢀ1; H NMR δ 1.29 (3H, s), 1.49 (3H, s), 2.71 (1H, dd,
J
=
25.9 (CH3), 26.6 (CH3), 33.1 (CH2), 57.2 (CH2), 59.9 (CH2),
= 9.6, 4.6, 1.5 Hz), 3.28 (1H, dd, 70.2 (CH), 77.6 (CH), 80.5 (CH), 111.2 (C), 126.9 (CH), 127.0
= 13.2, 4.6 Hz), 3.53 (1H, dd, = 12.8, 2.1 Hz), 3.71 (1H, dd, (CH), 127.1 (CH), 128.3 (CH), 128.6 (CH), 128.7 (CH), 130.0
= 12.8, 4.9 Hz), 3.84 (1H, d, = 12.3 Hz), 3.94–3.98 (1H, (CH), 138.8 (C), 138.9 (C), 141.1 (C); MS (ESI) m/z (relative
13.2, 9.8 Hz), 2.96 (1H, ddd,
J
J
J
J
J
m), 4.02–4.07 (2H, m), 7.09 (2H, d,
J
= 8.3 Hz), 7.25–7.37 (7H, intensity) 400 ([M+H]+, 100), 401 (32), 402 (7); HRMS (ESI)
m); 13C NMR δ 24.7 (CH3), 26.7 (CH3), 36.7 (CH2), 50.6 calcd for C27H29NO2 [M+H]+ 400.2271, found 400.2271.
(CH2), 56.5 (CH), 60.6 (CH2), 76.3 (CH), 77.7 (CH), 107.7 (C),
127.7 (CH), 128.6 (CH), 128.8 (CH), 128.9 (CH), 130.6 (CH), Amine 15 (R=2-naphthylmethyl). To a solution of amine
9
132.4 (C), 137.1 (C), 138.0 (C); MS (ESI) m/z (relative (745 mg, 1.90 mmol) in CH2Cl2 (25 mL) and then triethylamine
intensity) 376 ([M+H]+, 100), 377 (25), 378 (36), 379 (8), 380 (1.16 mL, 8.37 mmol) and methanesulfonyl chloride (0.32 mL,
(2); HRMS (ESI) calcd for C21H26NO3Cl [M+H]+ 376.1674, 4.19 mmol) were added under N2 at 0 oC. The reaction mixture
found 376.1680.
was stirred at 0 oC for 1 h and quenched with saturated
NaHCO3 solution. The aqueous phase was extracted with Et2O
Amine 13 (R=benzyl). To a solution of amine
7 (1.37 g, 4.00 (3 × 30 mL). The combined organic extracts were washed with
mmol) in CH2Cl2 (53 mL) and then triethylamine (2.4 mL, 17.6 brine, dried over anhydrous MgSO4, and filtered. The filtrate
mmol) and methanesulfonyl chloride (0.68 mL, 8.81 mmol) was concentrated under reduced pressure and the residue was
o
were added under N2 at 0 C. The reaction mixture was stirred purified by flash chromatography (hexane:Et2O, 12:1) to afford
for 1 h and quenched with saturated NaHCO3 solution. The amine 15 (695 mg, 98%) as a colourless oil; [α]2D0 –153.5 (c
aqueous phase was extracted with Et2O (3
× 30 mL). The 2.99, CHCl3); Rf 0.33 (hexane:Et2O, 6:1); IR (thin film) 3054,
combined organic extracts were washed with brine, dried over 2980, 2932, 2787, 1601, 1449, 1372, 1271, 1209, 1131, 1093,
1
anhydrous MgSO4, and filtered. The filtrate was concentrated 859, 748 cmꢀ1; H NMR δ 1.43 (3H, s), 1.78 (3H, s), 2.08 (1H,
under reduced pressure and the residue was purified by flash dd,
J
= 11.2, 4.7 Hz), 2.49 (1H, dt,
= 13.5 Hz), 3.36 (1H, dd,
= 13.5 Hz), 4.44 (1H, dd, = 6.3, 4.5 Hz),
J
= 10.2, 4.0 Hz), 3.16–3.20
chromatography (hexane:Et2O, 1:1) to afford amine 13 (1.06 g, (2H, m), 3.29 (1H, d,
J
J
= 13.2, 10.2
82%) as a colourless oil: [α]20 –156.4 (c 1.94, CHCl3); Rf 0.23 Hz), 4.33 (1H, d,
J
J
D
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 10
Journal Name
Organic & Biomolecular Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4OB02219J
4.56 (1H, dd,
J = 6.4, 4.8 Hz), 7.34–7.61 (8H, m), 7.87–7.92 (CH3), 57.1 (CH2), 60.0 (CH2), 70.4 (CH), 77.5 (CH), 80.5
(4H, m); 13C NMR δ 25.8 (CH3), 26.5 (CH3), 33.5 (CH2), 57.1 (CH), 111.0 (C), 113.6 (CH), 126.8 (CH), 128.2 (CH), 128.6
(CH2), 59.9 (CH2), 70.2 (CH), 77.5 (CH), 80.4 (CH), 111.0 (C), (CH), 130.4 (CH), 131.6 (C), 138.7 (C), 157.9 (C); MS (ESI)
125.2 (CH), 125.8 (CH), 126.8 (CH), 127.5 (CH), 127.6 (CH), m/z (relative intensity) 354 ([M+H]+, 100), 355 (22), 356 (4);
127.7 (CH), 127.7 (CH), 128.2 (CH), 128.2 (CH), 128.5 (CH), HRMS (ESI) calcd for C22H27NO3 [M+H]+ 342.2064, found
132.0 (C), 133.5 (C), 137.2 (C), 138.7 (C); MS (ESI) m/z 342.2058.
(relative intensity) 374 ([M+H]+, 100), 375 (94), 376 (5);
HRMS (ESI) calcd for C25H27NO2 [M+H]+ 374.2115, found Amine 18 (R=p-Cl-benzyl). To a solution of amine 12 (32.7
274.2121.
mg, 0.0869 mmol) in CH2Cl2 (1.1 mL) and then triethylamine
(0.05 mL, 0.382 mmol) and methanesulfonyl chloride (0.015
o
Amine 16 (R=
p
-Me-benzyl). To a solution of amine 10 (17.7 mL, 0.191 mmol) were added under N2 at 0 C. The reaction
o
mg, 0.05 mmol) in CH2Cl2 (0.7 mL) and then triethylamine mixture was stirred at 0 C for 1 h and quenched with saturated
(0.03 mL, 0.22 mmol) and methanesulfonyl chloride (0.0085 NaHCO3 solution. The aqueous phase was extracted with Et2O
o
mL, 0.11 mmol) were added under N2 at 0 C. The reaction (3
× 30 mL). The combined organic extracts were washed with
mixture was stirred at 0 oC for 1.5 h and quenched with brine, dried over anhydrous MgSO4, and filtered. The filtrate
saturated NaHCO3 solution. The aqueous phase was extracted was concentrated under reduced pressure and the residue was
with Et2O (3
× 30 mL). The combined organic extracts were purified by flash chromatography (hexane:Et2O, 12:1) to afford
washed with brine, dried over anhydrous MgSO4, and filtered. amine 18 (28.1 mg, 90%) as a colourless oil; [α]2D0 –159.2 (
c
The filtrate was concentrated under reduced pressure and the 1.82, CHCl3); Rf 0.17 (hexane:Et2O, 12:1); IR (thin film) 3027,
residue was purified by flash chromatography (hexane:Et2O, 2980. 2932, 2787, 1491, 1451, 1373, 1210, 1133, 1089, 862,
12:1) to afford amine 16 (14.3 mg, 85%) as a colourless oil: 743 cmꢀ1; 1H NMR δ 1.32 (3H, s), 1.61 (3H, s), 2.03 (1H, dd,
J
J
[α]2D0 –149.3 (c 1.79, CHCl3); Rf 0.27 (hexane:Et2O, 6:1); IR = 11.2, 4.8 Hz), 2.29 (1H, dt,
(thin film) 3676, 3651, 3629, 3211, 3022, 2983, 2932, 2863, = 13.2, 3.8 Hz), 3.01–3.08 (2H, m), 3.21 (1H, d,
J = 10.4, 4.1 Hz), 2.89 (1H, dd,
J
= 13.6 Hz),
= 6.4, 4.6 Hz), 4.51
= 6.4, 4.7 Hz), 7.24–7.37 (9H, m); 13C NMR δ 25.8
= 13.2, 3.7 Hz), 3.06–3.12 (2H, m), 3.20 (CH3), 26.5 (CH3), 32.9 (CH2), 57.1 (CH2), 59.9 (CH2), 70.1
= 13.5 Hz), 4.22 (1H, d, = 13.5 Hz), 4.41 (1H, dd, (CH), 77.5 (CH), 80.3 (CH), 111.2 (C), 126.9 (CH), 128.3
= 6.4, 4.5 Hz), 4.53 (1H, dd, = 6.4, 4.8 Hz), 7.13–7.40 (9H, (CH), 128.4 (CH), 128.6 (CH), 130.9 (CH), 131.8 (C), 138.0
1
2787, 1514, 1451, 1372, 1209, 942 cmꢀ1; H NMR δ 1.35 (3H, 4.16 (1H, d,
s), 1.65 (3H, s), 2.02 (1H, dd, = 11.2, 4.8 Hz), 2.31–2.36 (4H, (1H, dd,
m), 2.92 (1H, dd,
(1H, d,
J = 13.6 Hz), 4.33 (1H, dd, J
J
J
J
J
J
J
J
m); 13C NMR δ 21.1 (CH3), 25.90 (CH3), 26.5 (CH3), 32.9 (C), 138.6 (C); MS (ESI) m/z (relative intensity) 358 ([M+H]+,
(CH2), 57.2 (CH2), 60.0 (CH2), 70.4 (CH), 77.6 (CH), 80.5 100), 359 (24), 360 (34), 361 (9); HRMS (ESI) calcd for
(CH), 111.1 (C), 126.8 (CH), 128.2 (CH), 128.6 (CH), 129.0 C21H24NO3Cl [M+H]+ 358.1568, found 358.1571.
(CH), 129.4 (CH), 135.4 (C), 136.6 (C), 138.8 (C); MS (ESI)
m/z (relative intensity) 338 ([M+H]+, 100), 339 (26), 340 (4); Amine 19 (R=benzyl). To a solution of amine 13 (444 mg,
HRMS (ESI) calcd for C22H27NO2 [M+H]+ 338.2115, found 1.38 mmol) in
tꢀBuOH (23 mL) and water (4.5 mL) was added
338.2118.
10% Pdꢀonꢀcharcoal (147 mg, 0.138 mmol) The mixture was
activated with an atmosphere of H2 (balloon) by three times
Amine 17 (R=p-OMe-benzyl). To a solution of amine 11 followed by stirring under the same H2 atmosphere at room
(13.0 mg, 0.0349 mmol) in CH2Cl2 (0.5 mL) and then temperature for another 48 h. The mixture was filtered and
triethylamine (0.02 mL, 0.153 mmol) and methanesulfonyl washed with EtOAc. The filtrate was concentrated under
chloride (0.0059 mL, 0.0767 mmol) were added under N2 at 0 reduced pressure and the residue was purified by flash
oC. The reaction mixture was stirred at 0 oC for 1 h and chromatography (CHCl3:MeOH, 20:1) to afford amine 19 (293
quenched with saturated NaHCO3 solution. The aqueous phase mg, 91%) as a colourless oil: [α]2D0 –93.4 (
c
1.75, CHCl3); Rf
1
was extracted with Et2O (3
×
30 mL). The combined organic 0.40 (CHCl3:MeOH, 20:1); H NMR δ 1.32 (3H, s), 1.51 (3H,
extracts were washed with brine, dried over anhydrous MgSO4, s), 1.93 (1H, br s), 2.60 (1H, dd,
and filtered. The filtrate was concentrated under reduced (2H, m), 2.95–3.01 (1H, m), 3.06 (1H, d,
J
= 13.3, 4 Hz), 2.81–2.89
= 13.3 Hz), 4.40
J =5.5, 3.5 Hz), 4.62 (1H, dd, J = 5.5, 4.0 Hz), 7.18–
J
pressure and the residue was purified by flash chromatography (1H, dd,
(hexane:Et2O, 12:1) to afford amine 17 (10.3 mg, 83%) as a 7.32 (5H, m); 13C NMR δ 23.9 (CH3), 25.8 (CH3), 34.7 (CH2),
20
colourless oil; [α]
–145.7 (c 2.58, CHCl3); Rf 0.13 53.1 (CH2), 65.5 (CH), 81.1 (CH), 81.8 (CH), 110.3 (C), 126.0
D
(hexane:Et2O, 6:1); IR (thin film) 3027, 2983, 2933, 2830, (CH), 128.2 (CH), 129.0 (CH), 139.5 (C); MS (ESI) m/z
1
2787, 1611, 1512, 1452, 1372, 1244, 1036, 835 cmꢀ1; H NMR (relative intensity) 234 ([M+H]+, 100), 235 (15), 236 (2);
δ 1.34 (3H, s), 1.64 (3H, s), 2.02 (1H, dd,
2.30 (1H, dt, = 10.3, 4.0 Hz), 2.89 (1H, dd,
3.02–3.09 (2H, m), 3.20 (1H, d,
(1H, d, = 13.6 Hz), 4.39 (1H, dd,
dd, = 6.4, 4.7 Hz), 6.87 (2H, d,
m); 13C NMR δ 25.9 (CH3), 26.5 (CH3), 32.4 (CH2), 55.2 was added 10% Pdꢀonꢀcharcoal (97.6 mg, 0.0917 mmol) The
J
= 11.2, 4.8 Hz), HRMS (ESI) calcd for C14H19NO2 [M+H]+ 234.1489, found
J = 13.3, 3.7 Hz), 234.1489.
J
J
= 13.6 Hz), 3.81 (3H, s), 4.21
= 6.4, 4.5 Hz), 4.52 (1H, Amine 20 (R=biphenylmethyl). To a solution of amine 14
= 8.6 Hz), 7.24–7.37 (7H, (367 mg, 0.917 mmol) in ꢀBuOH (30 mL) and water (6 mL)
J
J
J
J
t
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Organic & Biomolecular Chemistry
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ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4OB02219J
mixture was activated with an atmosphere of H2 (balloon) by br s), 2.31 (3H, s), 2.58 (1H, dd,
J
= 13.3, 4.0 Hz), 2.78–2.85
three times followed by stirring under the same H2 atmosphere (2H, m), 2.91–2.97 (1H, m), 3.06 (1H, d,
at room temperature for another 72 h. The mixture was filtered (1H, dd, J =5.5, 3.3 Hz), 4.62 (1H, dd,
and washed with EtOAc. The filtrate was concentrated under (2H, d, = 7.8 Hz), 7.19 (2H, d,
= 8.0 Hz); 13C NMR δ 21.0
J
= 13.3 Hz), 4.41
J
= 5.5, 4.1 Hz), 7.10
J
J
reduced pressure and the residue was purified by flash (CH3), 23.9 (CH3), 25.9 (CH3), 34.2 (CH2), 53.1 (CH2), 65.7
chromatography (CHCl3:MeOH, 20:1) to afford amine 20 (250 (CH), 81.2 (CH), 81.9 (CH), 110.3 (C), 128.9 (CH), 129.0
mg, 88%) as a white solid: mp 89–90 °C; [α]2D0 –92.9 (
c 1.10, (CH), 135.5 (C), 136.4 (C); MS (ESI) m/z (relative intensity)
CHCl3); Rf 0.33 (CHCl3:MeOH, 20:1); IR (thin film) 3671, 248 ([M+H]+, 100), 249 (18), 250 (2); HRMS (ESI) calcd for
3648, 3027, 2982, 2927, 2860, 1488, 1376, 1269, 1207, 1080, C15H21NO2 [M+H]+ 248.1645, found 248.1647.
1036, 853, 762 cmꢀ1; 1H NMR δ 1.34 (3H, s), 1.54 (3H, s), 2.06
(1H, br s), 2.62 (1H, dd,
3.00–3.06 (1H, m), 3.09 (1H, d,
5.4, 3.4 Hz), 4.66 (1H, dd, = 5.5, 4.0 Hz), 7.31–7.53 (9H, m); was added 10% Pdꢀonꢀcharcoal (12.5 mg, 0.0118 mmol) The
J
= 13.4, 4.0 Hz), 2.86–2.94 (2H, m), Amine 23 (R=p-OMe-benzyl). To a solution of amine 17
J
= 13.3 Hz), 4.47 (1H, dd, (41.5 mg, 0.118 mmol) in ꢀBuOH (1.7 mL) and water (0.3 mL)
J
=
t
J
13C NMR δ 24.0 (CH3), 25.9 (CH3), 34.4 (CH2), 53.3 (CH2), mixture was activated with an atmosphere of H2 (balloon) by
65.6 (CH), 81.3 (CH), 82.0 (CH), 110.4 (C), 127.0 (CH), 127.0 three times followed by stirring under the same H2 atmosphere
(CH), 127.1 (CH), 128.7 (CH), 129.5 (CH), 138.8 (C), 139.1 at room temperature for another 12 h. The mixture was filtered
(C), 141.1 (C); MS (ESI) m/z (relative intensity) 310 ([M+H]+, and washed with EtOAc. The filtrate was concentrated under
100), 311 (23), 312 (3); HRMS (ESI) calcd for C20H23NO2 reduced pressure and the residue was purified by flash
[M+H]+ 310.1802, found 310.1801.
chromatography (CHCl3:MeOH, 20:1) to afford amine 23 (27.3
mg, 88%) as a pale yellow oil: [α]20 –89.5 (c 1.06, CHCl3); Rf
D
Amine 21 (R=2-naphthylmethyl). To a solution of amine 15 0.27 (CHCl3:MeOH, 20:1); IR (thin film) 2983, 2929, 2831,
1
(41.4 mg, 0.111 mmol) in
was added 10% Pdꢀonꢀcharcoal (11.8 mg, 0.0111 mmol) The s), 1.50 (3H, s), 2.13 (1H, br s), 2.59 (1H, dd,
mixture was activated with an atmosphere of H2 (balloon) by 2.76–2.83 (2H, m), 2.88–2.95 (1H, m), 3.06 (1H, d,
three times followed by stirring under the same H2 atmosphere Hz), 3.78 (3H, s), 4.41 (1H, dd, =5.4, 3.3 Hz), 4.62 (1H, dd,
at room temperature for another 48 h. The mixture was filtered = 5.4, 4.1 Hz), 6.83 (2H, d, = 7.8 Hz), 7.21 (2H, d,
t
ꢀBuOH (1.6 mL) and water (0.4 mL) 1649, 1513, 1459, 1246, 1036, 833 cmꢀ1; H NMR δ 1.31 (3H,
= 13.3, 3.9 Hz),
= 13.3
J
J
J
J
J
J
= 8.6
and washed with EtOAc. The filtrate was concentrated under Hz); 13C NMR δ 24.0 (CH3), 25.9 (CH3), 33.8 (CH2), 53.2
reduced pressure and the residue was purified by flash (CH2), 55.2 (CH3), 65.8 (CH), 81.2 (CH), 81.9 (CH), 110.4 (C),
chromatography (CHCl3:MeOH, 20:1) to afford amine 21 (30.5 113.8 (CH), 130.0 (CH), 131.6 (C), 158.0 (C); MS (ESI) m/z
mg, 97%) as a colourless oil: [α]20 –102.3 (c 1.03, CHCl3); Rf (relative intensity) 264 ([M+H]+, 100), 265 (17), 266 (2);
D
0.33 (CHCl3:MeOH, 20:1); IR (thin film) 3051, 2981, 2929, HRMS (ESI) calcd for C15H21NO3 [M+H]+ 264.1594, found
2860, 1441, 1375, 1269, 1206, 1162, 1036, 985, 858, 819, 749 264.1600.
cmꢀ1; 1H NMR δ 1.33 (3H, s), 1.55 (3H, s), 2.26 (1H, br s),
2.61 (1H, dd,
J = 13.3, 3.8 Hz), 2.92–2.96 (1H, m), 3.02–3.18 Amine 24 (R=p-Cl-benzyl). To a solution of amine 18 (30 mg,
(3H, m), 4.42–4.45 (1H, m), 4.63–4.65 (1H, m), 7.40–7.79 (7H, 0.0838 mmol) in dry CH2Cl2 (0.6 mL) was added
m); 13C NMR δ 24.0 (CH3), 25.9 (CH3), 34.9 (CH2), 53.2 chloroethylchloroformate (0.0135 mL, 0.126 mmol) at 0 °C
(CH2), 65.3 (CH), 81.2 (CH), 81.9 (CH), 110.4 (C), 125.3 under N2. The solution was stirred at 0 °C for 13 h and the
(CH), 125.9 (CH), 127.4 (CH), 127.5 (CH), 127.6 (CH), 127.7 solvent was removed under reduced pressure. The residue was
(CH), 127.9 (CH), 132.2 (C), 133.6 (C), 137.1 (C); MS (ESI) redissolved in MeOH (1 mL) and the mixture was then heated
m/z (relative intensity) 284 ([M+H]+, 100), 285 (23), 286 (3); to reflux for 2 h. The reaction mixture was concentrated under
HRMS (ESI) calcd for C18H21NO2 [M+H]+ 284.1645, found reduced pressure and the crude residue was directly purified by
284.1641.
flash chromatography (CHCl3:MeOH, 20:1) to afford amine 24
(7.1 mg, 32%) as a colourless oil: [α]2D0 –95.2 (c 0.36, CHCl3);
Amine 22 (R=
p
-Me-benzyl). To a solution of amine 16 (46.9 Rf 0.33 (CHCl3:MeOH, 20:1); IR (thin film) 2982, 2929, 2845,
mg, 0.139 mmol) in
added 10% Pdꢀonꢀcharcoal (148 mg, 0.139 mmol) The mixture NMR δ 1.31 (3H, s), 1.50 (3H, s), 1.83 (1H, br s), 2.60 (1H, dd,
was activated with an atmosphere of H2 (balloon) by three = 13.4, 3.8 Hz), 2.77–2.86 (2H, m), 2.92–2.97 (1H, m), 3.07
times followed by stirring under the same H2 atmosphere at (1H, d, = 13.3 Hz), 4.39 (1H, dd, J =5.2, 3.6 Hz), 4.64 (1H,
room temperature for another 24 h. The mixture was filtered dd, = 5.2, 4.3 Hz), 7.20–7.25 (4H, m); 13C NMR δ 24.0
t
ꢀBuOH (3.3 mL) and water (0.7 mL) was 1491, 1376, 1270, 1207, 1165, 1080, 1036, 983, 856 cmꢀ1; 1H
J
J
J
and washed with EtOAc. The filtrate was concentrated under (CH3), 25.9 (CH3), 34.1 (CH2), 53.2 (CH2), 65.5 (CH), 81.1
reduced pressure and the residue was purified by flash (CH), 81.9 (CH), 110.5 (C), 128.5 (CH), 130.5 (CH), 132.0 (C),
chromatography (CHCl3:MeOH, 20:1) to afford amine 22 (33.5 138.0 (C); MS (ESI) m/z (relative intensity) 268 ([M+H]+,
mg, 97%) as a colourless oil: [α]20 –93.6 (c 1.51, CHCl3); Rf 100), 269 (16), 270 (30), 271 (6); HRMS (ESI) calcd for
D
0.36 (CHCl3:MeOH, 20:1); IR (thin film) 3671, 3270, 2982, C14H18NO3Cl [M+H]+ 268.1099, found 268.1105.
2925, 2862, 1647, 1515, 1450, 1376, 1269, 1208, 1163, 1081,
1036, 818 cmꢀ1; 1H NMR δ 1.31 (3H, s), 1.51 (3H, s), 2.16 (1H,
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 9 of 10
Journal Name
Organic & Biomolecular Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4OB02219J
Dienol 30. To a solution of the anime 19 (9.3 mg, 0.04 mmol) This research has been supported by a Hong Kong RGC GRF
and ꢀNO2ꢀbenzoic acid (6.7 mg, 0.04 mmol) in a CHCl3 (0.5 grant (ref. number 403510).
o
mL) was added dienal 28 (62.4 mg, 0.201 mmol) in CHCl3 (1.5
mL) at room temperature and stirred at same temperature for 20
h until the disappearance of the starting material as shown on
TLC. The reaction mixture was filtered through a thin pad of
silica gel and the filtrate was concentrated under reduced
pressure. The residue was redissolved in EtOH (2 mL) and
NaBH4 (6.3 mg, 0.168 mmol) was added to crude product at 0
°C for 1 h. The mixture was quenched with saturated NH4Cl
Notes and references
a
Department of Chemistry and Center of Novel Functional Molecules,
The Chinese University of Hong Kong, Shatin, Hong Kong, China. Email:
tonyshing@cuhk.edu.hk
†
Electronic Supplementary Information (ESI) available: [Experimental
solution and the aqueous phase was extracted with EtOAc (3
×
data, detailed synthetic schemes, procedures and chemical
characterization data (1H, 13C NMR, HPLC spectra)]. See
DOI: 10.1039/b000000x/
10 mL). The combined organic extracts were dried over
anhydrous MgSO4, and filtered. The filtrate was concentrated
under reduced pressure and the residue was purified by flash
chromatography (hexane:EtOAc, 10:1) gave dienol 30 (6.4 mg,
11%) as a colourless oil: Rf 0.40 (hexane:EtOAc, 3:1); IR (thin
film) 3357, 3028, 2928, 2857, 1464, 1367, 1252, 1105, 1037,
1
2
Z. G. Hajos and D. R. Parrish, J. Org. Chem. 1974, 39, 1615.
Comprehensive Asymmetric Catalysis, E.N. Jacobsen, A. Pfaltz and
H. Yamamoto, Eds; Springer: Hiedelberg, 1999.; Asymmetric
Organocatalysis. Top. Curr.Chem. vol 291, B. List, Ed; Springer:
Berlin, 2009.
1
835, 773 cmꢀ1; H NMR δ 0.02–0.03 (6H, m), 0.87 (9H, s),
1.35–1.50 (2H, m), 1.62–1.83 (5H, m), 1.99–2.07 (1H, m),
2.48–2.56 (1H, m), 4.08–4.09 (1H, m), 4.18–4.26 (2H, m), 5.58
J
= 7.0 Hz), 5.59–5.94 (2H, m); 13C NMR (MeOD) δ –
3
4
K. A. Ahrendt, C. J. Broths and D. W. C. MacMillan, J. Am. Chem.
(1H, d,
Soc. 2000
MacMillan, J. Am. Chem. Soc. 2000
D. W. C. MacMillan, Nature. 2008 455, 304; S. Bertelsen and K. A.
Jørgensen, Chem. Soc. Rev. 2009
Angew. Chem. In. Ed. 2008 47
Alessandro, Angew. Chem. In. Ed. 2008
J. Franzén, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjærsgaard
and K. A. Jørgensen, J. Am. Chem. Soc. 2005 127, 18296.
R. M. Wilson, W. S. Jen and D. W. C. MacMillan, J. Am. Chem. Soc.
2005 127, 11616.
Z. Jia, H. Jiang, J. L. Li, B. Gschwend, Q. Z. Li, X. Yin, J. Grouleff,
Y. C. Chen and K. A. Jørgensen, J. Am. Chem. Soc. 2011 133, 5056.
B. List, R. A. Lerner and C. F. Barbas, J. Am. Chem. Soc. 2000 122
2395.; B. List, J. Am. Chem. Soc. 2000 122, 9336.; W. Notz and B.
List, J. Am. Chem. Soc. 2000 122, 7386.
M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang and K. A.
Jørgensen, J. Am. Chem. Soc. 2005 127, 6964.
,
122, 4243; W. S. Jen, J. J. M. Wiener and D. W. C.
4.73 (CH3), 18.9 (C), 23.9 (CH2), 26.3 (CH3), 34.9 (CH2), 35.2
(CH), 41.1 (CH2), 42.4 (CH), 63.8 (CH2), 68.5 (CH), 121.8
(CH), 125.2 (CH), 133.8 (CH), 142.6 (C); MS (EI) m/z (relative
intensity) 294 ([M]+, 100); HRMS (EI) calcd for C17H30O2Si
[M]+ 294.2010, found 294.2009.
,
122, 9874.
,
,
38, 2178.; C. F. Barbas III,
,
,
42.; A. Dondoni and M.
,
47, 4638.
5
6
7
8
Dienol 33. To a solution of the anime 19 (6.8 mg, 0.029 mmol)
and oꢀNO2ꢀbenzoic acid (4.9 mg, 0.029 mmol) in a CHCl3 (0.5
,
mL) was added dienal 31 (39.4 mg, 0.148 mmol) in CHCl3 (1
mL) at room temperature and stirred at same temperature for 9
h until the disappearance of the starting material as shown on
TLC. The reaction mixture was filtered through a thin pad of
silica gel and the filtrate was concentrated under reduced
pressure. The residue was redissolved in EtOH (1.5 mL) and
NaBH4 (6.3 mg, 0.168 mmol) was added to crude product at 0
°C for 1 h. The mixture was quenched with saturated NH4Cl
,
,
,
,
,
,
9
,
solution and the aqueous phase was extracted with EtOAc (3
×
10 R. K. Kunz and D. W. C. MacMillan, J. Am. Chem. Soc. 2005, 127,
10 mL). The combined organic extracts were dried over
anhydrous MgSO4, and filtered. The filtrate was concentrated
under reduced pressure and the residue was purified by flash
chromatography (hexane:EtOAc, 5:1) gave dienol 33 (5.9 mg,
16%) as a white solid: mp 61–62 °C; Rf 0.26 (hexane:EtOAc,
4:1); IR (thin film) 3284, 3025, 2983, 2918, 2857, 1437, 1374,
3240.
11 S. G. Ouellet, J. B. Tuttle and D. W. C. MacMillan, J. Am. Chem.
Soc. 2005 127, 32.; J. W. Yang, M. T. Hechavarria Fonseca and B.
List, Angew. Chem. In. Ed. 2005 44, 108.
,
,
12 S. Lee and D. W. C. MacMillan, J. Am. Chem. Soc. 2007
,
129
67
2006
,
,
,
1
1257, 1206, 1164, 1049, 1001, 874, 713 cmꢀ1; H NMR δ 1.38
15438.
13 A. Córdova, W. Notz and C. F. Barbas III, J. Org. Chem. 2002
,
(6H, s), 1.59–1.70 (3H, m), 1.85–1.92 (2H, m), 1.99–2.06 (2H,
m), 2.43–2.51 (1H, m), 3.74 (2H, s), 4.17–4.26 (2H, m), 5.58–
5.61 (1H, m), 5.93–5.95 (2H, m); 13C NMR δ 24.5 (CH2), 27.4
(CH3), 27.5 (CH3), 36.1 (CH2), 36.2 (CH), 40.5 (CH), 41.9
(CH2), 64.1 (CH2), 74.8 (CH2), 80.5 (C), 109.4 (C), 121.4
(CH), 124.1 (CH), 132.9 (CH), 141.1 (C); MS (EI) m/z (relative
intensity) 250 ([M]+, 100); HRMS (EI) calcd for C15H22O3 [M]+
250.1563, found 250.1563.
301.
14 D. Enders, M. R. M. Hüttl, C. Grondal and G. Raabe, Nature
.
441, 861.; A. Carlone, S. Cabrera, M. Marigo and K. A. Jørgensen,
Angew. Chem. In. Ed. 2007 46, 1101.
15 M. P. Brochu, S. P. Brown and D. W. C. MacMillan, J. Am. Chem.
Soc. 2004 126, 4108.; N. Halland, A. Braunton, S. Bechmann, M.
Marigo and K.. A. Jørgensen, J. Am. Chem. Soc. 2004 126, 4790.; T.
D. Beeson and D. W. C. MacMillan, J. Am. Chem. Soc. 2005 127
8826.; M. Marigo, D. Fielenbach, A. Braunton, A. Kjærsgaard and
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,
,
,
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,
,
Acknowledgements
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9

Organic & Biomolecular Chemistry
Page 10 of 10
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4OB02219J
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10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012