Enantioselective addition of organozinc reagents to carbonyl compounds catalyzed by a camphor derived chiral γ-amino thiol ligand

Article abstract of DOI:10.1016/j.tet.2015.07.038

In this article, the design and synthesis of the chiral camphor derived γ-amino thiol ligand 17 and its application in catalytic enantioselective carbon-carbon forming reactions through the addition of organozinc reagents to carbonyl compounds is described. The catalytic activity and enantioselectivity of ligand 17 is demonstrated in the enantioselective addition of various organozinc reagents to aldehydes and ketoesters, offering the corresponding alcohols in high yields and enantioselectivities. The role of the mercapto group in the highly enantioselective 1,2-addition reaction of organozincs to aldehyde is also discussed.

Full text of DOI:10.1016/j.tet.2015.07.038

Tetrahedron xxx (2015) 1e10
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Tetrahedron
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Enantioselective addition of organozinc reagents to carbonyl
compounds catalyzed by a camphor derived chiral
ligand
g
-amino thiol
,
Hsyueh-Liang Wu a, Ping-Yu Wu b, Ying-Ni Cheng b, Biing-Jiun Uang b
*
a Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
b Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this article, the design and synthesis of the chiral camphor derived g-amino thiol ligand 17 and its
Received 30 October 2014
Received in revised form 2 July 2015
Accepted 13 July 2015
Available online xxx
application in catalytic enantioselective carbon-carbon forming reactions through the addition of or-
ganozinc reagents to carbonyl compounds is described. The catalytic activity and enantioselectivity of
ligand 17 is demonstrated in the enantioselective addition of various organozinc reagents to aldehydes
and ketoesters, offering the corresponding alcohols in high yields and enantioselectivities. The role of the
mercapto group in the highly enantioselective 1,2-addition reaction of organozincs to aldehyde is also
discussed.
Keywords:
Chiral amino thiol ligand
Chiral alcohols
Ó 2015 Elsevier Ltd. All rights reserved.
Organozinc reagents
Catalytic asymmetric 1,2-addition reaction
1. Introduction
(Dimethylamino)isoborneol (DAIB, 3), a camphor derived beamino
alcohol with a tertiary amino group, exhibited high enantio-
induction in the addition reaction of dialkylzincs to aromatic al-
dehydes. Following these preliminary examples, and given that the
reactions employing organozinc reagents were conducted under
mild reaction conditions with high degree of functional group
compatibility and low metal toxicity of zinc, it has attracted tre-
mendous interest in the design and synthesis of chiral ligands,
primarily based on naturally occurring chiral scaffolds, for the
enantioselective addition of organozincs to aldehydes.5
Chiral alcohols are not only pivotal synthetic building blocks but
they are also common components in natural products as well as in
biologically active compounds. Given their importance, tremen-
dous effort has been focused on the efficient synthesis of chiral
alcohols. As compared with the enantioselective reduction of car-
bonyl compounds,1 enantioselective addition of organometallic
reagents to carbonyl compounds is a more practical route to the
synthesis of optically active alcohols.2 In the pioneering work of
Oguni and Omi, the enantioselective addition reaction of Et2Zn to
benzaldehyde (1a) in the presence of (S)-leucinol offered (R)-1-
phenylpropanol (2a) in moderate ee (Eq. 1).3
ð2Þ
ð1Þ
2. The development of camphor derived ligands for catalytic
CeC bond formation reactions
Noyori and co-workers subsequently reported the first highly
enantioselective addition of dialkylzincs to aryl aldehydes cata-
-amino alcohol (Eq. 2).4 (ꢀ)-3-exo-
2.1. Camphor derived g-amino alcohol as ligands
lyzed by
a
chiral
b
In our efforts on the development of camphor derived ligands
for asymmetric catalysis,6aee bis-sulfonamide ligand
was
* Corresponding author. E-mail address: bjuang@mx.nthu.edu.tw (B.-J. Uang).
4
http://dx.doi.org/10.1016/j.tet.2015.07.038
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
H.-L. Wu et al. / Tetrahedron xxx (2015) 1e10
Table 1
prepared and applied to the Ti(IV)-catalyzed enantioselective ad-
dition of Et2Zn to aldehydes (Eq. 3).6a The corresponding adducts
were isolated in high yields (91e99%), however, with only moder-
ate to good enantioselectivities (59e90% ee). Although it was re-
ported later by Walsh6f that bis-sulfonamide 4 was able to induce
higher enantioselectivities in a similar catalytic system, the use of
stoichiometric amount of Ti(OiPr)4 may not be ideal for the scale up
purpose.
Enantioselective addition reaction of benzaldehyde (1a) with Et2Zn catalyzed by
amino alcohols 8
g
-
Entry
Ligand
Solvent
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8a
8b
8c
8d
8e
8f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Hexanes
95
94
95
93
95
90
93
57
71
30
31
61
30
80
8b
a
Isolated yield.
Determined by chiral HPLC.
ð3Þ
b
ð4Þ
The development of a catalytic system that is not merely re-
quired of high catalytic activity and enantioselectivity but also
could be prepared concisely. It had been shown that the use of
chiral g-amino alcohol 5, bearing an isonorborneol scaffold derived
from ketopinic acid, in the catalytic enantioselective addition of
Et2Zn to benzaldehyde (1a) could give the addition product 2a in
35% yield and in 82% ee (Eq. 4).7a We anticipated that optimization
of the substituents on the nitrogen atom based on ligand 5 might
While amino alcohol ligands are prevalent in the realm of cata-
lytic enantioselective organozinc addition to carbonyl compounds,
amino thiol ligands5d,9 have also received considerable attention
owing to: 1) higher polarizability of a sulfur atom than an oxygen
atom; 2) better binding affinity of thiols and thiolates with metals,
zinc in particular; and 3) lower Lewis acidity of metal alcoholates
than metal thiolates.9f Having achieved moderately good enantio-
provide enhanced selectivity. Hence, a series of g-amino alcohols 8
were prepared from (1S)-ketopinic acid 68 via amidation with
various amines followed with a one-pot selective ketone reduction
at ꢀ40 ꢁC and subsequent amide reduction under refluxing tem-
perature with LAH in THF (Scheme 1). Each of 8aef was obtained as
a single diastereomer. Reaction of benzaldehyde (1a) with Et2Zn in
toluene at 0 ꢁC was conducted in the presence of ligand 8 to un-
derstand the effect of amino substituent on stereocontrol (Table 1).
selectivity using
reaction of Et2Zn and benzaldehyde (1a), we envisaged that new
-amino thiol 9 might exhibit improved selectivity (Scheme 2). In
g-amino alcohol 8b in the enantioselectiveaddition
g
Among the six ligands, the less bulky substituted g-amino alcohol
8b turned out to be the best ligand that gave 71% ee and 94% yield in
the catalytic addition reaction when the reaction was conducted in
toluene (entry 2). The enantioselectivity could be improved to
80% ee when the reaction was conducted in hexanes (entry 7). This
observation contradicted both Oppozler’s result and our anticipa-
tion that bulkier N-substituents would give higher asymmetric
induction.7b
Scheme 2. A proposed synthesis of g-amino thiol 9 from g-amino alcohol 8.
Scheme 1. Synthesis of g-amino alcohols 8 bearing an isonorborneol backbone.
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H.-L. Wu et al. / Tetrahedron xxx (2015) 1e10
3
principle, aminothiol 9 could be prepared from
converting the hydroxyl group into the corresponding thiol group.
g
-amino alcohol 8 by
thiol 17 catalyzed the addition reactions of Me2Zn or Et2Zn with
aldehydes to give the corresponding secondary alcohols with high
enantioselectivities.14 While the enantioselective addition reaction
of Me2Zn to benzaldehyde (1a) in the presence of 0.1 mol % of 17
offer alcohol 18a in 68% yield and 92% ee after 96 h (Table 2, entry
1), the reaction was accelerated and completed in 48 h to provide
89% yield of compound 18a with 94% ee when using 0.5 mol % of 17
(entry 2). An extended reaction time was necessary at these low
ligand loadings, but good yield and enantioselectivity were gener-
ally obtained when the reaction was carried out in the presence of
0.5 mol % of chiral ligand 17. Moderate levels of enantio-induction
2.2. Camphor derived
g-amino thiol ligands
In an attempt to synthesize
g-amino thiol 9, oxidation of com-
pound 8f was carried out with CrO3 under acidic conditions to
provide amino ketone 10 in 92% yield; however, thionation of 10
with Lawesson’s reagent10 failed to give the corresponding thione
compound (Scheme 3).
Table 2
Enantioselective addition reaction of aldehyde 1 with Me2Zn catalyzed by
g-amino
thiol 17a
Scheme 3. An attempt to synthesize g-amino thiol 9 from g-amino alcohol 8f.
Entry
R
17 (mol %)
Time (h)
Yieldb (%)
eec (%)
Since the preparation of
g
-amino thiol ligands from
g
-amino
1
2
3
4
5
6
7
8
C6H5 (1a)
C6H5 (1a)
0.1
0.5
0.5
0.5
2.0
0.5
2.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2.0
0.5
0.5
0.5
0.5
0.5
96
48
48
48
48
72
48
48
48
48
48
48
48
48
48
48
48
72
48
48
68 (18a)
89 (18a)
82 (18b)
80 (18c)
89 (18d)
82 (18e)
91 (18f)
83 (18g)
86 (18h)
77 (18i)
70 (18j)
82 (18k)
77 (18l)
82 (18m)
90 (18n)
86 (18o)
95 (18p)
65 (18q)
83 (18r)
70 (18s)
92
94
90
90
96
85
78
84
90
93
89
92
78
83
93
92
64
83
42
86
alcohols 8 seemed infeasible, the installment of thiol group at an
early stage of ligand synthesis was sought. According Oae’s pro-
tocol,11 ketothiol 12 was synthesized from the reduction of cam-
phorsulfonyl chloride 11 with PPh3 in 87% yield (Scheme 4). After
benzylation of primary thiol, compound 13 was efficiently trans-
formed into oxime 14 by the condensation with hydroxylamine.
Oxime 14 was reduced with tBuNH2$BH3 in conjunction with TiCl3
to offer primary amine 15 as the sole diastereomer. Subsequent
N,N-dialkylation of amine 15 with 2-bromoethyl ether under basic
condition furnished compound 16 in 77% yield. (ꢀ)-2-Exo-mor-
pholino-isobornane-10-thiol (MITH) (17) was obtained in 64% yield
after removing the benzyl group of compound 16 by reduction
reaction with sodium in liquid ammonia at ꢀ78 ꢁC.12
2-Me-C6H4 (1b)
3-Me-C6H4 (1c)
4-Me-C6H4 (1d)
4-MeO-C6H4 (1e)
4-CF3-C6H4 (1f)
2-Cl-C6H4 (1g)
3-Cl-C6H4 (1h)
4-Cl-C6H4 (1i)
4-Br-C6H4 (1j)
2-Thienyl (1k)
2-Furyl (1l)
9
10
11
12
13
14
15
16
17
18
19
20
3-Furyl (1m)
1-Naphthyl (1n)
2-Naphthyl (1o)
Cinnamyl (1p)
2-Me-Cinnamyl (1q)
Hydrocinnamyl (1r)
Cyclohexyl (1s)
3. Catalytic enantioselective Et2Zn and Me2Zn addition to
aldehydes
a
A 0.73 M solution of Me2Zn in hexanes was used.13
Isolated yield.
Determined by chiral HPLC.
b
c
Although the position of amino and thiol functional groups are
reversed in the new ligand, compared to the original plan, g-amino
Scheme 4. Synthesis of g-amino thiol 17.
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4
H.-L. Wu et al. / Tetrahedron xxx (2015) 1e10
Table 4
were observed for 4-trifluoromethylbenzaldehyde (1f) (entry 7), 2-
furaldehyde (1l) and 3-furaldehyde (1m) (entries 13e14), and
cinnamaldehydes 1pe1r (entries 17e19) when 0.5 mol % of ligand
17 was used. In addition, the reaction of 4-methylbenzaldehyde
(1d) (entry 5) and 1-naphthaldehyde (1n) (entry 15) provided
good yields and enantioselectivities when conducted in the pres-
ence of 2 mol % of ligand 17.
Enantioselective addition reaction of aldehyde 1 with alkenylzinc reagents catalyzed
by -amino thiol 17
g
The catalytic enantioselective addition of Et2Zn to aldehydes 1
conducted in the presence of 0.1 mol % of chiral ligand 17 at 0 ꢁC
afforded the corresponding secondary alcohols 2 in excellent
enantioselectivities (92e99% ee) regardless of the aromatic sub-
stituent pattern of the aryl aldehydes (Table 3, entries 1e11) except
for 4-chlorobenzaldehyde (1i) (86% ee, entry 9). Under similar re-
action conditions, cinnamaldehydes (1p, 1q, and 1r) and cyclo-
hexanecarboxaldehyde (1s) were good electrophiles provided the
corresponding addition adducts in moderate to good yields
(56e95% yield) and enantioselectivities (64e90% ee) (entries
12e15).
Entry
R
R1
R2
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
C6H5 (1a)
H
H
H
H
H
H
H
H
H
H
H
H
C2H5
H
H
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C6H13
C4H9
85 (19a)
83 (19b)
83 (19d)
90 (19f)
87 (19t)
85 (19g)
88 (19h)
90 (19i)
88 (19u)
81 (19v)
83 (20a)
82 (20t)
89 (21a)
91 (22a)
80 (23s)
96
96
95
>99.5
98
95
97
96
96
95
2-Me-C6H4 (1b)
4-Me-C6H4 (1d)
4-CF3-C6H4 (1f)
3-CF3-C6H4 (1t)
2-Cl-C6H4 (1g)
3-Cl-C6H4 (1h)
4-Cl-C6H4 (1i)
3-F-C6H4 (1u)
3-MeO-C6H4 (1v)
C6H5 (1a)
Table 3
9
Enantioselective addition reaction of aldehyde 1 with Et2Zn catalyzed by
g-amino
10
11
12
13
14
15
thiol 17a
97
98
96
96
3-CF3-C6H4 (1t)
C6H5 (1a)
C6H5 (1a)
C4H9
C2H5
tBu
C6H5(CH2)3
Cyclohexyl (1s)
97
a
Isolated yield.
Determined by chiral HPLC.
b
Entry
R
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
C6H5 (1a)
24
24
24
24
48
24
24
24
48
24
24
24
48
24
24
95 (2a)
95 (2b)
94 (2c)
95 (2d)
94 (2e)
96 (2f)
88 (2g)
92 (2h)
80 (2i)
85 (2j)
94 (2o)
95 (2p)
77 (2q)
83 (2r)
56 (2s)
96
94
94
97
93
97
99
96
86
96
95
71
90
64
82
2-Me-C6H4 (1b)
3-Me-C6H4 (1c)
4-Me-C6H4 (1d)
4-MeO-C6H4 (1e)
4-CF3-C6H4 (1f)
2-Cl-C6H4 (1g)
3-Cl-C6H4 (1h)
4-Cl-C6H4 (1i)
4-Br-C6H4 (1j)
2-Naphthyl (1o)
Cinnamyl (1p)
2-Me-Cinnamyl (1q)
Hydrocinnamyl (1r)
Cyclohexyl (1s)
were suitable, offered chiral allylic alcohols 19 in 81e90% yield and
95e>99.5% ee under similar reaction conditions (entries 2e10).
The addition of 1-hexenylzinc reagent (R1¼H, R2¼C4H9) to benz-
aldehyde (1a) and 3-trifluoromethylbenzaldehyde (1t) gave alco-
hols 20a and 20t in 83% and 82% yields with 97% and 98% ee’s,
respectively (entries 11 and 12). Notably, alkenylzinc reagents with
a bulky substituent (R1¼H, R2¼tBu) or two ethyl substituents
(R1¼C2H5, R2¼C2H5) were good nucleophiles producing vinylic al-
cohols 21a and 22a both in excellent yields and ee’s (entries 13 and
14). A wide substrate scope in the enantioselective alkenylzincs
addition catalyzed by chiral amino thiol 17 was tolerated including
9
10
11
12
13
14
15
aromatic and a-branched aliphatic aldehydes and internal or ter-
minal alkenylzinc reagents.
a
A 1.0 M solution of Et2Zn in hexanes was used.
Isolated yield.
Determined by chiral HPLC.
b
c
5. Catalytic enantioselective arylzinc addition to aryl
aldehydes
4. Catalytic enantioselective alkenylzinc addition to
aldehydes
Optically active diarylmethanols are vital building blocks for the
synthesis of natural products and molecules of biological interest.22
In 1997, Fu and co-workers reported a catalytic enantioselective
addition of diphenylzinc to 4-chlorobenzaldehyde (1i), offering the
corresponding chiral diarylmethanol in 57% ee.23 Despite sub-
sequent work showing the enantioselective addition could proceed
in a highly enantioselective manner, the fact that only one of the
two phenyl groups was transferred during the course of the addi-
In 1992, Oppolzer and co-workers reported an efficient prepa-
ration of chiral (E)-allylic alcohols, which are versatile and invalu-
able synthetic intermediates, via
a catalytic enantioselective
addition of alkenylzinc reagents to aldehydes.15a This method in-
volved the in situ generation of nucleophilic alkenylzincs by
transmetalation of Et2Zn and the (E)-alkenylboron species, which
could be directly synthesized from hydroboration of dicyclohex-
ylborane and alkynes. The efficiency of this method has prompted
considerable focus to investigate the catalytic activities and enan-
tion reaction rendered the use of diphenylzinc uneconomic.5f,24
A
flexible solution came when Bolm and co-workers reported that
arylboronic acids could be transmetalated with Et2Zn, giving nu-
cleophilic arylzinc reagents useful for catalytic enantioselective
synthesis of diarylmethanols with not only high efficiency but also
improved reactivity.25 When chiral amino thiol 17 (10 mol %) was
employed in this catalytic enantioselective transformation, addi-
tion of the phenylethylzinc reagent, derived from the reaction of
phenylboronic acid and Et2Zn to 2-methylbenzaldehyde (1b) pro-
vided the corresponding (R)-alcohol 24b in 95% yield and
>99.5% ee (Table 5, entry 1).26 In contrast to Bolm’s findings that
a catalytic amount of additive (DiMPEG, 10 mol %) is required to
tioselectivities of various ligands including
ketimines of chiral [2,2]paracyclophane,17
-amino naphthols,19 and dipeptides.20
Taking advantage of Oppolzer’s protocol, the catalytic activity of
chiral -amino thiol 17 was tested in the enantioselective addition
b
-amino alcohols,15,16
-amino thiols,18
b
g
g
reaction of 1-octenylzinc and benzaldehyde (1a). The optimal result
was obtained when the reaction was carried out in the presence of
10 mol % of ligand 17 at ꢀ30 ꢁC, giving the corresponding product
(R)-21a in 85% yield with 96% ee (Table 4, entry 1).21 Aryl aldehydes,
either with electron-withdrawing or electron-donating groups
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H.-L. Wu et al. / Tetrahedron xxx (2015) 1e10
5
Table 5
Enantioselective addition reaction of aldehyde 1 with arylzinc reagents catalyzed by
-amino thiol 17a
Table 6
Enantioselective Me2Zn addition reaction of
thiol 17
a
-ketoesters 25 catalyzed by
g-amino
g
Entry
Ar
Time (h)
Yielda (%)
eeb (%)
Entry
Ar1
Ar2
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
C6H5 (25a)
22
72
27
24
96
12
41
22
18
96
23
24
85 (26a)
46c (26b)
76 (26c)
84 (26d)
54d (26e)
71 (26f)
79 (26i)
52e (26j)
87 (26k)
82 (26l)
70 (26o)
83 (26r)
79
76
84
85
89
16
59
55
85
75
82
19
1
2
3
4
5
6
7
8
2-Me-C6H4 (1b)
3-Me-C6H4 (1c)
4-Me-C6H4 (1d)
4-MeO-C6H4 (1e)
4-CF3-C6H4 (1f)
2-Cl-C6H4 (1g)
3-Cl-C6H4 (1h)
4-Cl-C6H4 (1i)
2-Naphthyl (1o)
4-CO2Me-C6H4 (1t)
C6H5 (1a)
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-Me-C6H4
4-Cl-C6H4
95 (24b)
90 (24c)
84 (24d)
73 (24e)
83 (24f)
90 (24g)
96 (24h)
96 (24i)
73 (24o)
84 (24t)
86 (24d)
98 (24i)
>99.5
97
97
97
97
98
95
96
95
2-Me-C6H4 (25b)
3-Me-C6H4 (25c)
4-Me-C6H4 (25d)
4-MeO-C6H4 (25e)
4-CF3-C6H4 (25f)
4-Cl-C6H4 (25i)
4-Br-C6H4 (25j)
2-Thienyl (25k)
2-Furyl (25l)
9
9e
10
11
12
10
11
12
96
97
96
2-Naphthyl (25o)
Hydrocinnamyl (25r)
C6H5 (1a)
a
Isolated yields.
Determined by chiral HPLC.
25b was recovered in 25% yield.
25e was recovered in 32% yield.
25j was recovered in 18% yield.
a
Conditions: PhB(OH)2 (2 equiv) and Et2Zn (6 equiv) were used with respect to
b
c
ArCHO.
b
Isolated yield.
Determined by chiral HPLC.
In entries 1e10, (R)-products were obtained, and in entries 11 and 12,
d
e
c
d
(S)-products were obtained.
e
27% of the ethylation product was isolated.
chiral ligand 17.30 Enantioselective reaction of compound 25b
(entry 2) having an ortho-tolyl group was less selective than meta-
and para-tolyl substituted substrates (25c and 25d, entries 3 and 4).
achieve high enantio excess, high enantioselectivity was achieved
without any additive in our study. Further investigation of reaction
scope showed that phenylation occurred smoothly with alkyl-
substituted, electron-donating and electron-withdrawing aryl
aldehydes, furnishing diarylmethanols 24 with high enantioin-
duction (95e>99.5% ee, entries 1e10). Catalytic addition of
4-methylphenylzinc and 4-chlorophenylzinc species to benzalde-
hyde (1a) gave (S)-24d (entry 11) and (S)-24i (entry 12) with similar
levels of selectivity, demonstrating the advantage of this method
for the synthesis of both (R)- and (S)-alcohols using chiral ligand 17
by aptly assigning the two aromatic groups to either the nucleo-
philic or electrophilic reaction components.
High levels of enantioselectivity were observed when a-ketoesters
bearing aromatic rings substituted with electron-donating groups
(entries 1e5), whereas analogues with electron-withdrawing
groups provided the corresponding products with moderate ee’s
(entries 6e8). While a-ketoesters substituted with 2-thienyl (25k,
entry 9), 2-furyl (25l, entry 10) and 2-naphthyl (25o, entry 11)
groups were good electrophiles in this enantioselective trans-
formation furnishing the corresponding alcohols in good yields and
ee’s, the reaction with an aliphatic
offered the corresponding -hydroxyester 26r with a less than
satisfactory enantioselectivity.
a-ketoester (25r, entry 12)
a
6. Catalytic enantioselective Me2Zn addition to
a-ketoesters
7. Catalytic enantioselective alkynylzincs addition to
aldehydes
Chiral quaternary substituted -hydroxy esters are key pre-
a
cursors for the preparation of natural products and pharmacolog-
ically active molecules. Although diastereoselective addition of
The enantioselective synthesis of propargylic alcohols, which
see wide application in the synthesis of enantioenriched pharma-
ceutical components as well as natural products, with high
optically purity is a particularly important enantioselective trans-
formation.31 Preparation of chiral propargylic alcohols from the
addition of nucleophilic Zn-acetylides, generated in situ from the
deprotonation of alkynes with Et2Zn or Me2Zn, to carbonyl com-
pounds is straightforward and operates under mild reaction con-
ditions, but usually requires high ligand loading to achieve high
ee.5e In the presence of 2.5 mol % of ligand 17, enantioselective
alkynylation of the zinc acetylide, prepared from 1-phenylethyne
(27a) and Me2Zn, with benzaldehyde (1a) at ꢀ20 ꢁC gave (S)-
28aa in 68% yield with 86% ee (Table 7, entry 1).32 Various
substituted aromatic aldehydes were tolerated by this catalytic
system, providing the corresponding propargylic alcohols with
80e87% ee (entries 2e9). While the enantioselective reaction of
cinnamaldehyde (1p) was less selective (61% ee, entry 10) than
organometallics to
cally active
-hydroxy esters,27 the employment of stoichiometric
amount of the chiral modifier renders the corresponding catalytic
enantioselective addition of nucleophiles to -ketoesters a more
a-ketoesters with chiral auxiliaries offers opti-
a
a
attractive route. On the contrary to the addition chemistry of
organozincs to aldehydes and ketones, coordination of organozincs
to
a-ketoesters promotes a non-selective addition process, giving
rise to a few applicable catalytic systems.28 In 2003, Shibasaki and
co-workers reported a highly enantioselective preparation of
hydroxy esters through a Me2Zn addition to
by an
-amino alcohol.28c Given the competence of our chiral
amino thiol 17, the catalytic addition of Me2Zn to
investigated. When -ketoesters with various ester groups were
tested, the corresponding -hydroxy esters 26 were isolated with
diminishing selectivity as the size of ester group increased; methyl
a
-
a
-ketoesters catalyzed
a
g-
a-ketoesters was
a
a
a
-ketoesters 25 were identified as optimal substrates in our study
(Table 6).29 Enantioselective addition of Me2Zn to methyl benzoyl
formate (25a), in the presence of ligand 17 (20 mol %), gave the
corresponding product 26a in 85% yield with 79% ee at ꢀ50 ꢁC
(entry 1). Notably, the addition of a catalytic amount of B(OEt)3
(25 mol %) enhanced the catalytic activity and enantioselectivity of
those of aryl aldehydes, the corresponding a-methyl substituted
congener 1q underwent a much more selective addition (entry 11).
Moderate to good enantioselectivities (66e84% ee) were obtained
for zinc acetylides with varied substituents, while unsatisfactory
chemical yields (15e55%) were observed (entries 13e16).
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6
H.-L. Wu et al. / Tetrahedron xxx (2015) 1e10
Table 7
to the high performance of ligand 17 in catalytic organozinc addi-
tion reactions, or whether instead the installment of an amino
group at 2-position of the [2.2.1]bornane scaffold was responsible.
Enantioselective alkynylzincs addition reaction of aldehydes 1 catalyzed by
thiol 17
g-amino
To elucidate this, synthesis of
g-amino alcohol 29, a hydroxy ana-
logue of -amino thiol 17 was conducted and its catalytic activity
g
and enantioselectivity was investigated. Based on Dallacker’s pro-
tocol, substitution of 10-iodocamphor (31),11 synthesized from
camphor sulfonic acid (30), with KOAc under acidic conditions,
Entry R1
R2
Time (h) Yielda (%) eeb (%)
ensued by
a basic saponification efficiently furnished 10-
hydroxylcamphor (32) (Scheme 5).33 Treatment of alcohol 32
with hydroxylamine gave oxime 33 in 93% yield, which was re-
duced by NiCl2/NaBH4 to provide amine 34 in 84% as a single di-
astereomer.34 Amine 34 underwent N,N-dialkylation reaction with
2-bromoethyl ether under basic conditions to provide compound
29 in 68% yield.
Shown in Table 8 are the results obtained from the catalytic
addition of Et2Zn to benzaldehyde (1a) carried out in the presence
of 10 mol % of ligands (17 and 29) at 0 ꢁC in hexanes. While com-
pound 2a was isolated in 95% yield with 97% ee (entry 1) when
ligand 17 was utilized, using ligand 29 produced alcohol 2a in a 66%
yield with 30% ee (entry 2). These results clearly demonstrated the
decisive influence of the thiol group for gaining high catalytic
activity and enantioselectivity.
1
C6H5 (1a)
C6H5 (27a)
C6H5 (27a)
C6H5 (27a)
C6H5 (27a)
C6H5 (27a)
C6H5 (27a)
C6H5 (27a)
C6H5 (27a)
C6H5 (27a)
C6H5 (27a)
48
72
72
72
72
48
48
48
48
48
48
48
68 (28aa) 86
79 (28ba) 86
88 (28ca) 85
70 (28da) 86
27c (28ea) 80
84 (28fa) 87
79 (28ga) 83
82 (28ha) 86
80 (28ia) 86
41 (28pa) 61
21d (28qa) 71
69 (28ra) 49
46 (28ab) 84
55 (28ac) 76
15 (28ad) 66
15 (28ae) 75
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2-Me-C6H4 (1b)
3-Me-C6H4 (1c)
4-Me-C6H4 (1d)
4-MeO-C6H4 (1e)
4-CF3-C6H4 (1f)
2-Cl-C6H4 (1g)
3-Cl-C6H4 (1h)
4-Cl-C6H4 (1i)
Cinnamyl (1p)
2-Me-Cinnamyl (1q) C6H5 (27a)
Hydrocinnamyl (1r) C6H5 (27a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
4-CF3-C6H4 (27b) 48
4-MeO-C6H4 (27c) 48
4-Cl-C6H4 (27d)
n-Bu (27e)
48
48
a
Isolated yields.
Determined by chiral HPLC.
1e was recovered in 68% yield.
1q was recovered in 59% yield.
b
c
Table 8
Enantioselective Et2Zn addition reaction of benzaldehyde catalyzed by
and -amino alcohols
g-amino thiol
d
g
8.
g-Amino thiol versus g-amino alcohol: catalytic activity
and enantioselectivity
Yielda (%)
eeb (%)
The unsuccessful synthesis of
g-amino thiol 9 from g-amino
Entry
Ligand
Time (h)
alcohol 8 instead resulted in the originally unintended design and
synthesis of ligand 17 from camphorsulfonyl chloride 11. The cat-
alytic activity and enantioselectivity of ligand 17 has been dem-
onstrated in this manuscript to be useful in the preparation of
a structurally diverse series of alcohols with high optical purity.
Although ligand 17 shares same bicyclo[2.2.1] framework as ligand
8, the corresponding amino group is situated at C2 instead of C10
and possesses a thiol group at C10 instead of a hydroxyl group at C2.
We questioned whether the presence of the thiol group attributed
1
2
17
29
24
48
95
66
97
30
a
Isolated yield.
b
Determined by chiral HPLC.
In conclusion, a series of camphor derived chiral
g-amino al-
cohols and -amino thiols were synthesized. The catalytic effi-
ciency and selectivity of these structurally similar ligands was
tested in the enantioselective addition of Et2Zn to benzaldehyde.
g
Scheme 5. Synthesis of g-amino alcohol 29.
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H.-L. Wu et al. / Tetrahedron xxx (2015) 1e10
7
Among them chiral
g
-amino thiol 17 was found to be an efficient
(400 MHz, CDCl3):
d
2.92 (s, 6H), 2.45 (ddd, J¼18.0, 5.1 2.7 Hz, 1H),
chiral modifier. Subsequent studies using ligand 17 in the catalytic
organozincs addition reactions were conducted giving chiral sec-
ondary alcohols, chiral allylic alcohols, chiral diarylmethanols,
2.26e2.14 (m, 1H), 2.10e1.96 (m, 2H), 1.96e1.80 (m, 2H), 1.86 (d,
J¼18.0 Hz, 1H), 1.39 (ddd, J¼12.7, 9.1, 3.6 Hz, 1H), 1.16 (s, 3H), 1.15 (s,
3H). 13C NMR (100 MHz, CDCl3):
d 212.3 (C]O), 168.9 (C]O), 67.4
chiral
a
-hydroxy esters with quaternary stereogenic centers, and
(C), 50.4 (C), 43.6 (CH2), 43.1 (CH), 38.0 (CH3), 36.5 (CH3), 27.1 (CH2),
26.9 (CH2), 21.3 (CH3), 20.7 (CH3). FTIR (neat): 2952, 2899, 1736,
1622, 1489, 1466 cmꢀ1. HRMS (EI): m/z calcd for [C12H19NO2]þ
209.1416, found 209.1416.
chiral propargylic alcohols with high levels of optical purity. Given
its wide application, several concise synthetic routes have been
devised,12 aside from the original synthesis, to access ligand 17 on
larger scales. While chiral ligand 17 has been proved to show high
stereocontrol based on a bicyclo[2.2.1]heptane skeleton, lowering
catalytic loading of catalyst and reducing reaction time remain
challenging. We are currently developing novel amino thiol ligands
with higher efficiency and applicability for the catalytic addition
reactions of organozinc reagents to carbonyl compounds.
9.1.1.3. N,N-diisobutyl-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-
1-carbox-amide (7c). Yield: 78%, white solid [Eluting with (EtOAc:
Hexanes¼1:10)]. Mp 93.4e93.9 ꢁC. ½a D22
ꢃ
þ8.5 (c 1.3, CHCl3). 1H NMR
(500 MHz, CDCl3):
d
3.60 (dd, J¼13.3, 7.5 Hz, 1H), 3.16e2.98 (m, 2H),
2.85 (dd, J¼13.3, 7.5 Hz, 1H), 2.45 (ddd, J¼18.3, 5.0, 2.7, 1H),
2.28e2.16 (m, 1H), 2.12e1.82 (m, 6H), 1.48e1.38 (m, 1H), 1.20 (s,
3H), 1.17 (s, 3H), 0.98e0.76 (m, 12H). 13C NMR (125 MHz, CDCl3):
9. Experimental section
d
212.1 (C]O), 169.6 (C]O), 67.8 (C), 54.1 (CH2), 50.9 (CH2), 43.7
General information. All commercial chemicals and solvents
were reagent grade and were used without further treatment un-
less otherwise noted. All reactions were carried out under an at-
mosphere of argon gas. Reactions were monitored by TLC using
Merck 60 F 254 silica gel plates; zones were detected visually under
ultraviolet irradiation (254 nm) or by spraying with 2,4-
dinitrophenylhydrazine solution (Aldrich) followed by heating.
Flash column chromatography was done using silica gel. 1H NMR
spectra were obtained on 400 MHz and 500 MHz spectrometers.
13C NMR spectra were obtained on 100 MHz and 125 MHz spec-
trometers. Chemical shifts were recorded in parts per million (ppm,
(CH2), 42.8 (CH), 28.6 (CH2), 27.3 (CH2), 26.4 (CH), 25.6 (CH), 21.4
(CH3), 21.1 (CH3), 20.2 (CH3), 19.9 (CH3), 19.6(CH3). FTIR (neat):
2961, 2928, 2872, 1737, 1624, 1456, 1418 cmꢀ1. HRMS (EI): m/z calcd
for [C18H31NO2]þ 293.2355, found 293.2357.
9.1.1.4. 7,7-Dimethyl-1-(pyrrolidine-1-carbonyl)-bicyclo[2.2.1]
heptane-2-one (7d). Yield: 77%, white solid [Eluting with (EtOAc:
Hexanes¼1:6)]. Mp 116.4e117.4 ꢁC. ½a D25
ꢃ
ꢀ42.3 (c 2.2, CHCl3). 1H
NMR (400 MHz, CDCl3):
d
3.71 (dt, J¼11.6, 5.8 Hz,1H), 3.58e3.42 (m,
2H), 3.24e3.12 (m,1H), 2.48 (ddd, J¼18.4, 5.0, 2.4 Hz,1H), 2.28e2.14
(m, 1H), 2.12e1.98 (m, 2H), 1.98e1.82 (m, 5H), 1.80e1.64 (m, 1H),
1.48e1.36 (m, 1H), 1.23 (s, 3H), 1.17 (s, 3H). 13C NMR (100 MHz,
d) and were reported relative to the solvent peak. High-resolution
mass spectra were obtained using EI method. Optical purities of
the final compounds were determined using chiral HPLC. Optical
rotations were measured on a polarimeter.
CDCl3): d 212.3 (C]O), 167.9 (C]O), 67.7 (C), 50.0 (C), 46.9 (CH2),
46.7 (CH2), 43.9 (CH2), 43.4 (CH), 28.9 (CH2), 26.7 (CH2), 23.4 (CH2),
21.6 (CH3), 20.4 (CH3). FTIR (neat): 2978, 2942, 2878, 1742, 1615,
1451, 1416 cmꢀ1. HRMS (EI): m/z calcd for [C14H21NO2]þ 235.1572,
found 235.1581.
9.1. General procedures for the preparation of chiral ligands
9.1.1. Synthesis of ketoamide compound 7. In a 50 mL round-bottom
flask was added ketopinic acid (6) (5.0 g, 27.4 mmol), SOCl2
(41.1 mmol), the whole was heated to reflux for 2 h. After removal
of the remaining SOCl2, the thus-obtained acylchloride was dis-
solved in CH2Cl2 (50 mL) and was slowly added to a mixture of NEt3
(5.8 mL, 41.6 mmol) and amine (41.2 mmol) in CH2Cl2 (50 mL) at
0 ꢁC. It was warmed up to room temperature 10 min later, and H2O
(20 mL) was added after being stirred at ambient temperature for
10 h. The aqueous layer was separated, extracted with CH2Cl2
(20 mLꢂ3) and the combined organic layer was washed with brine
(25 mL), dried over anhydrous Na2SO4, filtered and evaporated at
reduced pressure to give a brown crude solid compound, which
was purified column chromatography to give a white solid.
9.1.1.5. 7,7-Dimethyl-1-(piperidine-1-carbonyl)-bicyclo[2.2.1]
heptane-2-one (7e). Yield: 61%, white solid [Eluting with (EtOAc:
Hexanes¼1:6)]. Mp 89.2e90.0 ꢁC. ½a D25
ꢃ
ꢀ21.5 (c 1.1, CHCl3). 1H NMR
(400 MHz, CDCl3):
d
3.60e3.24 (m, 4H), 2.47 (ddd, J¼18.3, 4.8,
2.8 Hz,1H), 2.34e2.20 (m, 1H), 2.14e1.94 (m, 3H),1.88 (d, J¼18.4 Hz,
1H), 1.74e1.46 (m, 6H), 1.46e1.34 (m, 1H), 1.20 (s, 3H), 1.18 (s, 3H).
13C NMR (100 MHz, CDCl3):
d 212.3 (C]O), 167.2 (C]O), 67.3 (C),
50.4 (C), 47.3 (CH2), 43.5 (CH2), 43.0 (CH), 27.3 (CH2), 26.9 (CH2),
26.0 (CH2), 24.4 (CH2), 21.2 (CH3), 20.9 (CH3). FTIR (neat): 2932,
2854, 1739, 1618, 1452, 1435 cmꢀ1. HRMS (EI): m/z calcd for
[C15H23NO2]þ 249.1729, found 249.1745.
9.1.1.6. 7,7-Dimethyl-1-(morpholine-1-carbonyl)-bicyclo[2.2.1]
heptane-2-one (7f). Yield: 73%, white solid [Eluting with (EtOAc:
9.1.1.1. N,N-dicyclohexyl-7,7-dimethyl-2-oxobicyclo[2.2.1]hep-
Hexanes¼1:15)]. Mp 107.5e108.4 ꢁC. ½a D25
ꢃ
ꢀ27.4 (c 1.2, CHCl3). 1H
tane-1-car-boxamide (7a). Yield: 7.1 g, 75%, white solid [Eluting
NMR (400 MHz, CDCl3):
d
3.72 (ddd, J¼11.5, 6.0, 3.6 Hz, 2H), 3.63
with (EtOAc: Hexanes¼1:10)]. Mp 208.3e209.0 ꢁC. ½a D25
ꢃ
ꢀ13.9 (c
(ddd, J¼11.5, 6.0, 3.6 Hz, 2H), 3.54e3.24 (m, 4H), 2.48 (ddd, J¼18.0,
4.8, 3.2 Hz, 1H), 2.30e2.16 (m, 1H), 2.12e1.92 (m, 3H), 1.87 (d,
J¼18.8 Hz, 1H), 1.42 (ddd, J¼12.4, 8.8, 3.2 Hz, 1H), 1.19 (s, 3H), 1.18 (s,
1.5, CHCl3). 1H NMR (400 MHz, CDCl3):
d
3.33 (tt, J¼11.6, 3.4 Hz, 1H),
2.82 (tt, J¼11.8, 3.4 Hz, 1H), 2.56e2.38 (m, 4H), 2.24e2.16 (m, 1H),
2.12e1.97 (m, 2H), 1.95e1.83 (m, 3H), 1.82e1.66 (m, 6H), 1.63e1.49
(m, 5H), 1.47e1.28 (m, 6H), 1.18 (s, 3H), 1.16 (s, 3H). 13C NMR
3H). 1H NMR (100 MHz, CDCl3):
d 212.5 (C]O), 167.7 (C]O), 67.3
(C), 67.1 (CH2), 50.6 (C), 43.7 (CH2), 43.1 (CH), 27.2 (CH2), 27.0 (CH2),
21.3 (CH3), 20.9 (CH3). FTIR (neat): 2967, 2917, 2895, 1740, 1615,
1432, cmꢀ1. HRMS (EI): m/z calcd for [C14H21NO3]þ 251.1521, found
251.1521.
(100 MHz, CDCl3):
d 213.0 (C]O), 168.3 (C]O), 68.8 (C), 57.4 (CH),
57.0 (CH), 50.8 (C), 43.7 (CH2), 43.2 (CH2), 31.9 (CH), 31.4 (CH2), 30.1
(CH2), 29.5 (CH2), 27.6 (CH2), 27.0 (CH2), 26.7 (CH2), 26.6 (CH2), 26.0
(CH2), 25.8 (CH2), 25.3 (CH2), 25.2 (CH2), 21.6 (CH3), 21.1 (CH3). FTIR
(neat): 2968, 2929, 2849, 1733, 1635, 1521, 1507 cmꢀ1. HRMS (EI):
m/z calcd for [C22H35NO2]þ 345.2668, found 345.2675.
9.2. Synthesis of aminoalocohol 8
To a 50 mL round-bottom flask was charged with compound 7a
(0.5 g, 1.45 mmol) and THF (5 mL). At ꢀ78 ꢁC, a solution of LiAlH4
(1.0 M, 4.0 mL, 4 mmol) was slowly added to the above-mentioned
solution. It was warmed to ꢀ40 ꢁC 2 h later, and was gradually
9.1.1.2. N,N,7,7-tetramethyl-2-oxobicyclo[2.2.1]heptane-1-
carboxamide (7b). Yield: 65%, white solid [Eluting with (EtOAc:
Hexanes¼2:3)]. Mp 81.4e82.2 ꢁC. ½a D22
ꢃ
ꢀ67.4 (c 1.5, CHCl3). 1H NMR
Please cite this article in press as: Wu, H.-L.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.038

8
H.-L. Wu et al. / Tetrahedron xxx (2015) 1e10
warmed to ambient temperature after 2 h, and the whole mixture
was heated to reflux. After refluxing for another 12 h, the mixture
was cooled to 0 ꢁC and 3 N NaOH(aq) was slowly added to stop the
reaction. The solid material was filtered off on a pad of Celite and
the organic layer was dried over anhydrous Na2SO4, filtered, and
evaporated to give a yellow crude product, which was purified by
column chromatography.
(CH2), 50.6 (C), 47.8 (C), 44.7 (CH), 39.1 (CH2), 34.2 (CH2), 27.6 (CH2),
26.1 (CH), 23.9 (CH3), 20.4 (CH3). FTIR (neat): 3393, 2933, 2876,
2806, 1386, 1369, 1350 cmꢀ1. HRMS (EI): m/z calcd for [C15H27NO]þ
237.2093, found 237.2102.
9.2.6. 7,7-Dimethyl-1-morpholin-4-ylmethylbicyclo[2.2.1]heptane-2-
ol (8f). Yield: 89%, colorless oil [Eluting with (EtOAc:
Hexanes¼1:6)]. ½a D25
ꢃ
ꢀ64.8 (c 1.1, CHCl3).1H NMR (500 MHz, CDCl3):
9.2.1. 1-((Dicyclohexylamino)methyl)-7,7-dimethylbicyclo[2.2.1]hep-
d
3.91 (dd, J¼8.0, 4.0 Hz,1H), 3.67 (t, J¼4.5 Hz, 4H), 2.72 (d, J¼13.0 Hz,
tan-2-ol (8a). Yield: 73%, white solid [Eluting with (EtOAc:
1H), 2.68e2.54 (m, 2H), 2.46e2.32 (m, 2H), 2.25 (d, J¼13.0 Hz, 1H),
1.82e1.74 (m, 1H), 1.72e1.60 (m, 4H), 1.55e1.46 (m, 1H), 1.30e1.18
(m, 1H), 1.10 (s, 3H), 1.04e0.94 (m, 1H), 0.77 (s, 3H). 13C NMR
Hexanes¼1:2)]. Mp 129.8e130.5 ꢁC. ½a D25
ꢃ
ꢀ67.0 (c 1.0, CHCl3). 1H
NMR (400 MHz, CDCl3):
d
6.05 (br, 1H), 3.88 (dd, J¼8.0, 4.4 Hz, 1H),
2.80 (d, J¼12.8 Hz, 1H), 2.71 (d, J¼12.8 Hz, 1H), 2.62 (tt, J¼11.0,
3.3 Hz, 2H),1.88e1.70 (m, 8H),1.70e1.55 (m, 7H),1.52e1.20 (m, 6H),
1.16 (s, 3H), 1.14e0.97 (m, 6H), 0.80 (s, 3H). 13C NMR (100 MHz,
(125 MHz, CDCl3): d 78.1 (CH), 66.9 (CH2), 59.2 (CH2), 55.1 (CH2), 50.8
(C), 47.9 (C), 44.6 (CH), 38.9 (CH2), 34.0 (CH2), 27.6 (CH2), 20.4 (CH3),
20.3 (CH3). FTIR (neat): 3478, 2805, 2731, 1476, 1112 cmꢀ1. HRMS
(EI): m/z calcd for [C14H25NO2]þ 239.1885, found 239.1895.
CDCl3):
d 78.1 (CH), 58.1 (CH), 50.3 (C), 48.6 (C), 45.0 (CH2), 44.5
(CH), 39.2 (CH2), 35.1 (CH2), 33.0 (CH2), 28.9 (CH2), 27.8 (CH2), 26.8
(CH2), 26.4 (CH2), 26.1 (CH2), 20.6 (CH3), 20.4 (CH3). FTIR (neat):
3269, 2947, 2926, 2851, 1338, cmꢀ1. HRMS (EI): m/z calcd for
[C22H39NO]þ 333.3032, found 333.3035.
9.3. 1-Hydroxymethyl-7,7-dimethyl-bicyclo[2,2,1]heptan-2-
one (32)
A flask, equipped with a condenser, containing 10-iodocamphor
(31) (2.06 g, 7.4 mmol), glacial acetic acid (3.3 mL, 58 mmol) and
potassium acetate (5.09 g, 52 mmol) was heated at 180 ꢁC for 3 h.
After the flask was cooled to room temperature, the mixture was
added H2O (10 mL), and was extracted with EtOAc (20 mLꢂ3). The
combinedorganicsolutionwasconcentratedandthen evaporated in
vacuo. The residue was added 10% KOH/MeOH solution (35 mL). The
solution was stirred at room temperature for 12 h, and then neu-
tralized with aqueous 3 N NaOH solution. The solution was added
ethyl acetate (40 mL) and water (40 mL), and the layers were sepa-
rated. The organic layer was extracted with EtOAc (40 mLꢂ2). The
organic layers were combined, washed with brine, dried over an-
hydrous Na2SO4 and concentrated to afford the crude product. The
crude product was purified by column chromatography (EtOAc:n-
hexanes¼1:4) to yield 10-hydroxycamphor (32) as a white powder
9.2.2. 1-((Dimethylamino)methyl)-7,7-dimethylbicyclo[2.2.1]heptan-
2-ol (8b). Yield: 91%, colorless oil [Eluting with (MeOH:
CHCl3¼1:20)]. ½a D25
ꢃ
ꢀ62.3 (c 1.1, CHCl3). 1H NMR (400 MHz, CDCl3):
d
3.96 (dd, J¼8.0, 4.4 Hz,1H), 2.78 (d, J¼13.2 Hz,1H), 2.26 (s, 6H), 2.09
(d, J¼13.2 Hz, 1H), 1.84e1.72 (m, 1H), 1.72e1.58 (m, 4H), 1.52e1.42
(m,1H),1.38e1.26 (m,1H),1.10 (s, 3H),1.08e0.96 (m,1H), 0.76(s, 3H).
13C NMR (100 MHz, CDCl3):
d
78.1 (CH), 60.0 (CH2), 51.0 (C), 47.9 (C),
47.3 (CH3), 44.7 (CH), 39.0 (CH2), 33.5 (CH2), 27.6 (CH2), 20.4 (CH3),
20.3 (CH3). FTIR (neat): 3411, 2949, 2878, 2820, 1461, 1338, cmꢀ1
.
HRMS (EI): m/z calcd for [C12H23NO]þ 197.1780, found 197.1785.
9.2.3. 1-((Diisobutylamino)methyl)-7,7-dimethylbicyclo[2.2.1]hep-
tan-2-ol (8c). Yield: 89%, colorless oil [Eluting with (MeOH:
CHCl3¼1:20)]. ½a D25
ꢃ
ꢀ151.7 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
d
5.35 (br, 1H), 3.92 (dd, J¼8.0, 3.6 Hz, 1H), 2.86 (d, J¼13.2 Hz, 1H),
(1.08 g, 87%). 1H NMR (400 MHz, CDCl3):
d
3.86 (d, J¼12.0 Hz, 1H),
2.28 (dd, J¼12.8, 10.8 Hz, 2H), 2.06 (d, J¼12.8 Hz, 1H), 1.91 (dd,
J¼12.8, 3.4 Hz, 2H), 1.82e1.70 (m, 3H), 1.70e1.58 (m, 3H), 1.56e1.42
(m, 1H), 1.40e1.28 (m, 1H), 1.12 (s, 3H), 1.08e0.96 (m, 1H), 0.95 (d,
J¼6.4 Hz, 6H), 0.84 (d, J¼6.4 Hz, 6H), 0.77 (s, 3H). 13C NMR
3.63 (d, J¼12.0 Hz,1H), 2.40 (d, J¼18.4 Hz,1H), 2.06 (t, J¼4.6 Hz,1H),
2.03e1.94 (m,1H),1.85 (d, J¼18.4 Hz,1H),1.82 (td, J¼12.6, 4.0 Hz,1H),
1.62e1.55 (m, 1H), 1.41e1.35 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H).
(100 MHz, CDCl3):
d
77.7 (CH), 65.4 (CH2), 56.9 (CH2), 50.7 (C), 48.4
9.4. 1-Hydroxymethyl-7,7-dimethyl-bicyclo[2.2.1]heptan-2-
one oxime (33)
(C), 44.5 (CH), 38.9 (CH2), 34.7 (CH2), 27.8 (CH2), 26.2 (CH), 21.6
(CH3), 20.9 (CH3), 20.5 (CH3), 20.4 (CH3). FTIR (neat): 3300, 2949,
2870, 2806, 1461, 1393, cmꢀ1. HRMS (EI): m/z calcd for [C18H35NO]þ
281.2719, found 281.2704.
A mixture of 10-hydroxycamphor (32) (0.29 g, 1.7 mmol),
NH2OH$HCl (0.24 g, 3.4 mmol), NaOAc (0.28 g, 3.4 mmol), EtOH
(6.0 mL), and H2O (2.5 mL) in a 25 mL flask was heated to reflux for
24 h. After cooling to room temperature, the mixture was extracted
with EtOAc (20 mLꢂ3). The organic extracts were combined,
washed with brine, dried over anhydrous Na2SO4, and concentrated
to yield the crude product. The crude product was purified by
column chromatography (EtOAc:n-hexanes¼1:3 as an eluent) to
afford oxime 33 as colorless crystals (0.294 g, 93%). Mp 140e145 ꢁC.
9.2.4. 7,7-Dimethyl-1-pyrrolidin-1-ylmethylbicyclo[2.2.1]heptane-2-
ol (8d). Yield: 88%, colorless oil [Eluting with (MeOH:
CHCl3¼1:20)]. ½a D24
ꢃ
ꢀ67.7 (c 1.4, CHCl3). 1H NMR (500 MHz, CDCl3):
d
3.91 (dd, J¼7.8, 3.8 Hz, 1H), 3.08 (d, J¼12.5 Hz, 1H), 2.70e2.56 (m,
2H), 2.52e2.40 (m, 2H), 2.10 (d, J¼12.5 Hz, 1H), 1.82e1.70 (m, 6H),
1.70e1.60 (m, 3H), 1.42e1.32 (m, 1H), 1.34e1.24 (m, 1H), 1.10 (s, 3H),
1.00 (ddd, J¼12.5, 9.0, 4.3 Hz, 1H), 0.77 (s, 3H). 13C NMR (125 MHz,
½
a 2D7
ꢃ
ꢀ57.4 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3):
d 3.90 (d,
CDCl3):
d
78.5 (CH), 55.9 (CH2), 55.8 (CH2), 51.2 (C), 47.5 (C), 44.9
J¼11.6 Hz, 1H), 3.63 (d, J¼11.6 Hz, 1H), 2.56 (dt, J¼18.0, 3.6 Hz, 1H),
2.04 (d, J¼18.0 Hz, 1H), 1.90e1.76 (m, 3H), 1.68e1.62 (m, 1H),
1.30e1.24 (m, 1H), 0.94 (s, 3H), 0.90 (s, 3H). 13C NMR (100 MHz,
(CH), 38.9 (CH2), 33.3 (CH2), 27.5 (CH2), 23.9 (CH2), 20.5 (CH3), 20.4
(CH3). FTIR (neat): 3441, 2952, 2875, 2800, 1473, 1455, cmꢀ1. HRMS
(EI): m/z calcd for [C14H25NO]þ 223.1936, found 223.1929.
CDCl3):
d 169.6 (C), 61.5 (CH2), 56.2 (C), 48.1 (C), 44.5 (CH), 33.0
(CH2), 28.8 (CH2), 26.9 (CH2), 20.3 (CH3), 18.8 (CH3). FTIR (neat):
3390, 2948, 2878, 2249,1680,1451,1424 cmꢀ1. HRMS (EI): m/z calcd
for [C10H17NO2]þ 183.1259, found 183.1274.
9.2.5. 7,7-Dimethyl-1-pyrrolidin-1-ylmethylbicyclo[2.2.1]heptane-2-
ol (8e). Yield: 91%, colorless oil [Eluting with (MeOH:
CHCl3¼1:20)]. ½a D24
ꢃ
ꢀ68.2 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3):
d
3.92 (dd, J¼8.5, 3.5 Hz, 1H), 2.66 (d, J¼13.5 Hz, 1H), 2.62e2.42 (m,
9.5. (2R)-(2-Amino-7,7-dimethyl-bicyclo[2,2,1]hept-1-yl)-
methanol (34)
2H), 2.40e2.24 (m, 2H), 2.21 (d, J¼13.5 Hz, 1H), 1.77 (ddd, J¼12.9,
7.6, 4.0 Hz, 1H), 1.69e1.60 (m, 4H), 1.57e1.49 (m, 6H), 1.49e1.41 (m,
1H), 1.35 (br, 1H), 1.32e1.20 (m, 1H), 1.10 (s, 3H), 1.02e0.94 (m, 1H),
Oxime 33 (0.579 g, 3.2 mmol) and NiCl2$6H2O (4.5 g, 19 mmol)
were dissolved in MeOH (15 mL), and the mixture was cooled
0.76 (s, 3H). 13C NMR (125 MHz, CDCl3):
d
78.3 (CH), 59.5 (CH2), 56.1
Please cite this article in press as: Wu, H.-L.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.07.038

H.-L. Wu et al. / Tetrahedron xxx (2015) 1e10
9
toꢀ30 ꢁC. After 30 min, NaBH4 (3.6 g, 95 mmol) was added in
portions in 30 min. After stirring for another 30 min, the mixture
was slowly warmed to room temperature in 2 h. The mixture was
stirred at room temperature for 12 h and was diluted with Et2O
(15 mL). The mixture was slowly added concentrated ammonia
water (10 mL, 28%). The suspended mixture was filtrated through
a pad of Celite. The filtrate was diluted with aqueous 3 N NaOH
(20 mL), and the mixture was extracted with EtOAc (20 mLꢂ3). The
organic extracts were combined, washed with brine, dried over
anhydrous Na2SO4, and concentrated to yield the crude product.
The crude product was purified by column chromatography (elu-
ent: chloroform then methanol) to afford amine 34 as colorless
Asymmetric Catalysis in Organic Synthesis; Wiley: New York, NY, 1994, Chapter
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3. Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823e2824.
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5. (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49e69; (b) Soai,
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Acc. Chem. Res. 2014, 47, 1523e1535.
6. (a) Hwang, C.-D.; Uang, B.-J. Tetrahedron: Asymmetry 1998, 9, 3979e3984; (b)
Hwang, C.-D.; Hwang, D.-R.; Uang, B.-J. J. Org. Chem. 1998, 63, 6762e6763; (c)
Chang, C.-W.; Yang, C.-T.; Hwang, C.-D.; Uang, B.-J. Chem. Commun. 2002,
54e55; (d) Wu, H.-L.; Uang, B.-J. Tetrahedron: Asymmetry 2002, 13, 2625e2628;
(e) Uang, B.-J.; Fu, I.-P.; Hwang, C.-D.; Chang, C.-W.; Yang, C.-T.; Hwang, D.-R.
Tetrahedron 2004, 60, 10479e10486; (f) Balsells, J.; Walsh, P. J. J. Am. Chem. Soc.
2000, 122, 3250e3251.
7. (a) Radinov, R.; Oppolzer, W. Tetrahedron Lett. 1988, 29, 5645e5648; (b) It was
reported later by Aoyama that the enantioselectivity could be enhanced to 95%
if the catalyst bore an 9-azabicyclo[3.3.1]nonane group; see Hari, Y.; Aoyama, T.
Synthesis 2005, 583e587.
8. Yan, T.-H.; Chu, V.-V.; Lin, T.-C.; Wu, C.-H.; Liu, L.-H. Tetrahedron Lett. 1991, 32,
4959e4962.
9. (a) Poelert, M. A.; Hof, R. P.; Peper, N. C. M. W.; Kellogg, R. M. Heterocycles 1994,
37, 461e475; (b) Hof, R. P.; Poelert, M. A.; Peper, N. C. M. W.; Kellogg, R. M.
Tetrahedron: Asymmetry 1994, 5, 31e34; (c) Fitzpatrick, K.; Hulst, R.; Kellogg, R.
M. Tetrahedron: Asymmetry 1995, 6, 1861e1864; (d) Kang, J.; Kim, J. W.; Lee, J.
W.; Kim, D. S.; Kim, J. I. Bull. Korean Chem. Soc. 1996, 17, 1135e1142; (e) Kang, J.;
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Asymmetry 1999, 10, 1551e1561; (j) Jimeno, C.; Moyano, A.; Riera, A.; Pericas,
M. A. Synlett 2001, 1155e1157; (k) Rijnberg, E.; Jastrzebski, J. T. B. H.; Janssen,
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1978, 87, 223e228.
11. Oae, S.; Togo, H. Bull. Chem. Soc. Jpn. 1983, 56, 3802e3812.
12. Ligand 17 can be synthesized via alternative routes, see: (a) Uang, B.-J.; Tsao, Y.-
H.; Wu, P.-Y. U.S. Pat. Appl. 2011/0269955, 2011; (b) Wu, P.-Y.; Henschke, J. P. U.
S. Patent 8,859,765 (B2), 2013.
13. Krasovskiy, A.; Knochel, P. Synthesis 2006, 890e891.
14. Cheng, Y.-N.; Wu, H.-L.; Wu, P.-Y.; Shen, Y.-Y.; Uang, B.-J. Chem.dAsian J. 2012, 7,
2921e2924.
15. (a) Oppolzer, W.; Radinov, R. N. Helv. Chim. Acta 1992, 75, 170e173; (b) Op-
polzer, W.; Radinov, R. N. J. Am. Chem. Soc. 1993, 115, 1593e1594; (c) Oppolzer,
W.; Radinov, R. N.; De Brabander, J. Tetrahedron Lett. 1995, 36, 2607e2610; (d)
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16. (a) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124,
12225e12231; (b) Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125,
10677e10683; (c) Lurain, A. E.; Maestri, A.; Kelly, A. R.; Carroll, P. J.; Walsh, P. J. J.
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crystals (0.449 g, 84%). Mp>200 ꢁC. ½a D27
ꢃ
þ35.3 (c 1.0, CHCl3). 1H
NMR (500 MHz, CDCl3):
d
3.82 (d, J¼11.5 Hz, 1H), 3.77 (d, J¼11.5 Hz,
1H), 3.03 (dd, J¼8.5, 5.0 Hz, 1H), 2.63 (br, 3H), 1.82 (dd, J¼13.3,
8.8 Hz, 1H), 1.70e1.62 (m, 2H), 1.56e1.51 (m, 1H), 1.41e1.35 (m, 1H),
1.14 (s, 3H), 1.02 (td, J¼7.0, 3.0 Hz, 2H), 0.88 (s, 3H). 13C NMR
(125 MHz, CDCl3):
d 63.9 (CH2), 59.4 (CH), 51.5 (C), 46.7 (C), 46.1
(CH), 42.6 (CH2), 32.5 (CH2), 26.7 (CH2), 21.7 (CH3), 20.7 (CH3). FTIR
(neat): 3381, 3306, 2987, 2951, 2878, 1588, 1479, 1458 cmꢀ1. HRMS
(EI): m/z calcd for [C10H19NO]þ 169.1467, found 169.1471.
9.6. (2R)-(7,7-Dimethyl-2-morpholin-4-yl-bicylco[2,2,1]hept-
1-yl)-methanol (29)
Amine 34 (0.155 g, 0.92 mmol) and K2CO3 (0.25 g, 1.8 mmol)
were dissolved in CH3CN (4.6 mL). The mixture was added dibro-
moethyl ether (0.17 mL, 1.4 mmol) and heated to reflux for 12 h.
After cooling to room temperature, the mixture was extracted with
CH2Cl2 (10 mLꢂ3). The organic extracts were combined, washed
with brine, dried over anhydrous Na2SO4, and concentrated to yield
the crude product. The crude product was purified by column
chromatography (EtOAc:hexanes¼1:2 as an eluent) to afford amino
alcohol 29 as a colorless oil (0.149 g, 68%). ½a D26
ꢀ88.8 (c 1.0, CHCl3).
ꢃ
1H NMR (400 MHz, CDCl3):
d
5.29 (br, 1H), 3.97 (d, J¼12.0 Hz, 1H),
3.77 (d, J¼12.0 Hz, 1H), 3.73e3.70 (m, 2H), 3.66e3.60 (m, 2H),
2.65e2.56 (m, 4H), 2.07e2.01 (m, 1H), 1.75e1.66 (m, 2H), 1.62 (t,
J¼4.4 Hz, 1H), 1.39 (dd, J¼12.8, 9.6 Hz, 1H), 1.28 (td, J¼12.2, 4.8 Hz,
1H), 1.10 (s, 3H), 1.08e1.03 (m, 1H), 0.96e0.88 (m, 1H), 0.92 (s, 3H).
13C NMR (125 MHz, CDCl3):
d 74.2 (CH), 67.6 (CH2), 67.6 (CH2), 64.4
(CH2), 51.9 (C), 47.0 (C), 45.8 (CH), 33.0 (CH2), 31.5 (CH2), 26.7 (CH2),
22.1 (CH3), 20.2 (CH3). FTIR (neat): 3445, 2954, 2879, 2852, 1454,
1260, 1115 cmꢀ1. HRMS (EI): m/z calcd for [C14H25NO2]þ calculated
239.1885, found 239.1884.
€
€
17. (a) Dahmen, S.; Brase, S. Org. Lett. 2001, 3, 4119e4122; (b) Brase, S.; Dahmen, S.;
€
Hofener, S.; Lauterwasser, F.; Kreis, M.; Ziegert, R. E. Synlett 2004, 2647e2669;
(c) Lauterwasser, F.; Gall, J.; Hofener, S.; Brase, S. Adv. Synth. Catal. 2006, 348,
Acknowledgements
€
€
2068e2074.
18. (a) Tseng, S.-L.; Yang, T.-K. Tetrahedron: Asymmetry 2005, 16, 773e782; (b) Ko,
D. H.; Kang, S. W.; Kim, K. H.; Chung, Y.; Ha, D. C. Bull. Korean Chem. Soc. 2004,
25, 35e36.
Financial support provided by the Ministry of Science and
Technology (NSC-99-2113-M-007-010-MY3 and 102-2113-M-007-
009-MY3) is gratefully acknowledged.
19. Ji, J.-X.; Qiu, L.-Q.; Yip, C. W.; Chan, A. S. C. J. Org. Chem. 2003, 68, 1589e1590.
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Bull. 1985, 33, 3787e3797; (b) Toda, F.; Tanaka, K.; Koshiro, K. Tetrahedron:
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Supplementary data
Supplementary data (Copies of 1H and 13C NMR spectra for all
products) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2015.07.038. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
23. Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444e445.
24. Bolm, C.; Hildebrand, J. P.; Muniz, K.; Hermanns, N. Angew. Chem., Int. Ed. 2001,
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