Highly enantioselective aldol reactions using a tropos dibenz[c,e]azepine organocatalyst

Article abstract of DOI:10.1016/j.tet.2011.09.101

The four-step synthesis of a chiral primary tertiary diamine salt, possessing a tropos dibenz[c,e]azepine ring is described. It is shown that 3.5-5 mol % of this salt is capable of promoting highly enantioselective crossed-aldol reactions between cyclohexanone and a series of aromatic aldehydes. In all cases, the aldol reactions proceed with high diastereoselectivity for the anti-aldol product. The outcome of crossed-aldol reactions involving other cyclic ketones and acyclic ketones are also described. All examples involving cyclic ketones result in selectivity for the anti-aldol products, whereas acyclic ketones were found to favour the syn-aldol products. A discussion on the role of the chiral primary tertiary diamine salt in the catalysis of the aldol reactions is also presented.

Full text of DOI:10.1016/j.tet.2011.09.101

Tetrahedron 67 (2011) 10164e10170
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Highly enantioselective aldol reactions using a tropos dibenz[c,e]azepine
organocatalyst
,
a
a
a
b
a
Barry Lygo a , Christopher Davison , Timothy Evans , James A.R. Gilks , John Leonard , Claude-Eric Roy
*
a School of Chemistry, University of Nottingham, Nottingham NG7 2RD, UK
b AstraZeneca, Silk Business Park, Macclesfield, Cheshire SK10 2NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2011
Received in revised form 19 September 2011
Accepted 21 September 2011
Available online 4 October 2011
The four-step synthesis of a chiral primary tertiary diamine salt, possessing a tropos dibenz[c,e]azepine
ring is described. It is shown that 3.5e5 mol % of this salt is capable of promoting highly enantioselective
crossed-aldol reactions between cyclohexanone and a series of aromatic aldehydes. In all cases, the aldol
reactions proceed with high diastereoselectivity for the anti-aldol product. The outcome of crossed-aldol
reactions involving other cyclic ketones and acyclic ketones are also described. All examples involving
cyclic ketones result in selectivity for the anti-aldol products, whereas acyclic ketones were found to
favour the syn-aldol products. A discussion on the role of the chiral primary tertiary diamine salt in the
catalysis of the aldol reactions is also presented.
Dedicated to Professor Gilbert Stork on the
occasion of his 90th birthday
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Aldol
Organocatalysis
Diamine
Stereoselective
1. Introduction
For a number of years our research group has been investigating
the potential of asymmetric organocatalysts based on tropos dibenz
[c,e]azepines derived from simple chiral amines. This has led to the
development of a range of chiral dibenz[c,e]azepinium salts that have
proved highly effective in asymmetric phase-transfer alkylation re-
actions.1 During the course of these studies we have acquired in-
creasing evidence to suggest that a stereogenic centre external to the
dibenz[c,e]azepine ring is capable of generating a catalyst that be-
havesasif itwere a single atropisomer. Forexample, thetropos dibenz
[c,e]azepinium salt 1, derived from (R)-a-methylbenzylamine, gives
high enantioselectivity in the PTC alkylation of glycine imines.1a The
magnitudeandsenseofenantioselectivityobtainedinthesereactions
is consistent with the active catalyst adopting an (aS)-conformation
about the arylearyl bond during PTC alkylation reactions (Fig. 1).
These observations led us to wonder if a similar phenomenon
might be possible using tertiary ammonium salts derived from
tropos dibenz[c,e]azepines. With this in mind we were attracted to
a recent publication identifying amine salt 2 as a highly effective
bifunctional organocatalyst for asymmetric aldol reactions.2 In this
study it was shown that atropos dibenz[c,e]azepinium salt (R,R,aR)-
Fig. 1. Tropos dibenz[c,e]azepinium salt 1.
2 was capable of generating the anti-aldol product from cyclohex-
anone and 4-nitrobenzaldehyde in 98% ee and >98:2 dr. In contrast,
the corresponding (S,S,aR)-diastereoisomer of the catalyst was re-
ported to give the anti-aldol product 85% ee and 79:21 dr. These
observations suggest that the axial chiral element in catalyst 2 is
having a significant influence on the stereochemical outcome of the
reaction. This led us to ask the question, what would happen if the
binaphthyl group was replaced by a conformationally-labile biaryl
group? To probe this we investigated the potential of dibenz[c,e]
azepinium salt 3 (Fig. 2) as a catalyst for asymmetric aldol reactions.
* Corresponding author. E-mail address: b.lygo@nottingham.ac.uk (B. Lygo).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.101

B. Lygo et al. / Tetrahedron 67 (2011) 10164e10170
10165
Table 1
Comparison of catalysts 2e6
In this paper we describe our preliminary findings, along with
a discussion as to the possible role of the biaryl group in influencing
the stereochemical outcome of aldol reactions involving catalyst 3.
O
OH
O
OHC
+
2-6 (3.5 mol%)
H O, 12 h, RT
2
NO
2
NO
2
13a
11
12a
Catalyst
Conversion (%)
dra
eeb (%)
2
3
4
100
100
14
18
ꢃ2
98:22
98:2
90:10
90:10
36:64
982
98 (47)c
97
95
d
5
6d
a
Determined by 1H NMR spectroscopy.
ee of anti-diastereoisomer.
ee in parentheses is for syn-aldol product.
A 1:1 mixture of cyclohexylamine and salt 6.
b
c
d
N,N-dibenzyl analogue 4 generated the same aldol product, but with
significantly reduced rate and diastereoselectivity. The lower dia-
stereoselectivity obtained with this catalyst is in line with that re-
ported for other primary-tertiary trans-1,2-diaminocyclohexane
salts possessing alkyl substituents on the tertiary amine group.6 It
was also found that the N,N-dimethyl analogue 5 was a poor catalyst
for this process, a result, that is, also in agreement with previous
observations.2,6 Under the conditions employed, cyclohexylamine
salt 6 did not catalyze the reaction at all. However, a 1:1 mixture of
cyclohexylamine and salt 6 did lead to ca. 2% conversion after 12 h,
and gave a slight preference for the syn-aldol product.
These initial findings show that catalyst 3 is as effective as cat-
alyst 2 for this aldol process, and suggest that the biphenyl group
may play an important role in maximizing the diastereoselectivity.
Moreover, as the (S,S,aR) diastereoisomer of 2 has been shown to be
substantially less stereoselective, it suggests that catalyst 3 might
preferentially adopt an aR-axis during the CeC bond forming step
of the aldol process. If this were the case, it would represent an-
other example of the power of induced atropisomerism in asym-
metric catalysis.8
To probe this further, we investigated the effect of the reaction
medium on the outcome of the aldol process. Cyclohexanone 11 and
4-nitrobenzaldehyde 12a have low water solubility. As a conse-
quence, the reaction conditions employed in Table 1 are heteroge-
neous. Switching from water to dichloromethane resulted in similar
levels of stereoselectivity, but appeared to slow the reaction. As the
reaction mixture in dichloromethane is homogeneous we sought to
optimize the conditions before investigating a wider range of sol-
vents. Using 5 mol % catalyst, it was found that varying ketone con-
centration between 0.5 M and 4 M had a dramatic effecton the rate of
reaction (Fig. 3). At concentrations below 0.5 M the aldol took ca. 58 h
to reach completion, whereas concentrations of 4 M and above gave
complete conversion within 3 h. In neat cyclohexanone (9.7 M ke-
tone) the reaction was complete within 2 h. This latter observation is
interesting because the aldol reaction performed in the presence of
water also has cyclohexanone in excess. In all cases the anti-aldol
product 13a was obtained with ꢀ97:3 dr and 97ꢁ1% ee.
Fig. 2. Ammonium salts 2e6.
2. Results and discussion
Diamine salt
3 was prepared as outlined in Scheme 1.
Commercially-available diol 7 was converted into dibromide 8, and
then reacted with the known cyclohexane diamine derivative 9.3
Removal of the DAB-group followed by treatment with triflic acid
then gave the desired salt 3 in 69% overall yield.
NH
2
NHDAB
Br
Br
OH
OH
HBr, AcOH
9
K CO , CH CN
2
3
3
o
60 C
8
7
80%
.HOTf
N
1. KOH, EtOH
2. TfOH, CH Cl
N
2
2
NH
NHDAB
10
2
3
96%
90%
Scheme 1. Synthesis of ammonium salt 3.
A slight modification of this route was also employed for the
preparation of salts 4 and 5. These additional diamine derivatives
were prepared in order to aid evaluation of the role of the arylearyl
bond in structure 3.
Amine salts 3e5 were then tested as catalysts for the aldol re-
action between cyclohexanone 11 and 4-nitrobenzaldehyde 12a.4
Cyclohexylamine salt 6 was also included in an effort to probe
the influence of the tertiary amino group on the diastereoselectivity
of these aldol processes. The reaction conditions initially employed
were identical to those previously reported using catalyst 2.2 The
results obtained are shown in Table 1.
As 5 mol % catalyst and a ketone concentration of 4.6 M resulted
in complete conversion within 3 h at 20 ꢂC, we employed these
conditions to investigate the effect of varying the solvent (Table 2).
The results in Table 2 show that the process is tolerant of a wide
range of solvents. In all cases the anti-aldol product 13a was ob-
tained as the major product. Diastereoisomeric ratios typically
ranged from 95:5e98:2 and ees for the anti-aldol 13a were typi-
cally 96e99%. Intriguingly, the stereoselectivity observed in di-
methyl carbonate (94:6 dr, 93% ee) was significantly lower than in
all the other solvents investigated. Sampling the reaction mixtures
over time indicated that the stereoselectivity is maintained
throughout the course of the reaction. This suggests that a well-
It was found that the tropos-diamine salt 3 generated the anti-
aldol product 13a with high stereoselectivity.5 The rate of reaction,
diastereoselectivity and enantioselectivity observed were all almost
identical tothose reported for the atropos-diamine salt 2. In contrast,

10166
B. Lygo et al. / Tetrahedron 67 (2011) 10164e10170
-
O
TfO
.HOTf
N
H
N+
NH
NH
3
14
2
O
OH
Ar
Ar-CHO
12a
13a
-
+
-
TfO
TfO
N
N
H
H
+
O
NH
O
NH
Ar
Ar
16
15
Scheme 2. Possible catalytic cycle for aldol reaction involving tropos-ammonium
salt 3.
Fig. 3. Effect of ketone concentration on rate of reaction.
that TS-1 and TS-2 (Fig. 4) were the two most viable transition
states that could lead to the anti-aldol precursor 16. Both of these
have an antiperiplanar conformation about the enamine CeN bond,
which is consistent with the high enantioselectivity observed in
this reaction. Both transition states also have the aldehyde in the
same orientation. The only difference between the two is the
conformation of the azepinium ring, TS-1 having an (aS)-confor-
mation about the biaryl axis, and TS-2 having an (aR)-conforma-
tion. In the gas phase, these two transition states were predicted to
be almost identical in energy (TS-1 being favoured by 0.1 kcal/mol).
Table 2
Effect of solvent on stereoselectivity
O
OH
O
OHC
+
3 (5 mol%)
o
20 C
(4.6 M ketone)
NO
2
NO
2
13a
11
12a
Solvent
3
Time (h)c
drd
eee (%)
PhMe
2.4
3.1
4.5
6.0
7.0
3
3
3
3
3
3
3
3
3
8
15
8
15
8
96:4
94:6
97:3
97:3
97:3
97:3
96:4
98:2
97:3
96:4
95:5
95:5
98:2
97:3
96
93
97
96
96
96
96
99
98
96
98
97
98
98
(MeO)2CO
t-BuOMe
EtOAc
2-MeTHF
THF
CH2Cl2
Cyclohexanonea
i-PrOH
EtOH
7.6
8.9
16.1
19.9
24.6
32.7
35.9
36.7
78.3
MeOH
CH3CN
DMF
H2Ob
Fig. 4. Predictedtransition state structures(B3LYP/6-31G**) for theconversion of15 to 16.
a
Ketone (9.7 M).
b
Heterogeneous reaction mixture.
Time required for ꢀ97% conversion.
Determined by 1H NMR spectroscopy.
ee of anti-diastereoisomer.
Inspection of the two transition state structures reveals that in
TS-2, one of the aryl rings in the dibenz[c,e]azepinium fragment
projects over the cyclohexene ring (indicated by an arrow in Fig. 4).
This hinders alternative orientations of the aldehyde, and so is
consistent with high anti-diastereoselectivity observed. In TS-1, this
aryl ring is twisted away from the region above the cyclohexene
ring and this may allow the aldehyde to approach in orientations
that would lead to the minor syn-aldol product.
c
d
e
defined transition state is involved in the CeC bond forming step,
and that solvent has a small but significant impact on both dia-
stereoselectivity and enantioselectivity. Interestingly there also
appears to be a significant reduction in the overall rate of reaction
The two transition state structures shown are consistent with
the proposal that the high diastereo- and enantioselectivities re-
ported in Table 2 are a consequence of the dibenz[c,e]azepinium
salt 3 acting as a bifunctional catalyst. They are also consistent with
earlier observations that the corresponding (R,R,aR)-atropos dibenz
[c,e]azepinium salt 2 also delivers high diastereo- and enantiose-
lectivity, whereas its (S,S,aR)-diastereoisomer (which would lead to
a transition state analogous to TS-1) results in significantly lower
diastereoselectivity.2 However, as TS-1 and TS-2 are predicted to be
close in energy,9 it may be that the high diastereoselectivity ob-
tained using catalyst 3 is not a consequence of induced atropiso-
merism. Instead it may simply be the dynamic nature of the tropos
with more polar solvents ( >20). It is possible that these solvents
better stabilize polar reaction intermediates, and in this way retard
the catalytic cycle (see below).
3
It is generally thought that primary tertiary 1,2-diamine salts of
this type act as bifunctional catalysts in aldol reactions.2,6,7 A pos-
sible catalytic cycle for diamine 3 is shown in Scheme 2. The results
shown in Table 2 and Fig. 3 are entirely consistent with this, and the
observation that (R,R)-3 delivers similar stereoselectivity to
(R,R,aR)-2 suggests that the reaction may proceed preferentially
with the tropos-biaryl element in 3 in the (aR)-conformation.
To probe this further we examined potential transition states for
the transformation 15 to 16 using DFT calculations. These suggested

B. Lygo et al. / Tetrahedron 67 (2011) 10164e10170
10167
dibenz[c,e]azepinium ring that results in an effective steric barrier
to orientations of the aldehyde that would lead to the minor syn-
aldol product.
In order to probe this process further, we examined the effect of
varying the nature of the aldehyde (Table 3). As this study included
relatively unreactive aldehydes, all reactions were performed in
neat cyclohexanone as this was found to give the shortest reaction
times (see Fig. 3).
found to react at a similar rate to cyclohexanone, and gave the anti-
aldol product 18a in high ee. However, when the reaction was
performed using the same conditions as used for cyclohexanone,
substantial amounts of bis-aldol product (25e30%) was obtained.
Fortunately formation of this by-product could be suppressed
simply by lowering the concentration of aldehyde. Under optimized
conditions, the anti-aldol product 15a was isolated in 76% yield,
80:20 dr and 97% ee In contrast, cycloheptanone (17b) was found to
react at a much slower rate and no bis-aldol by-product was pro-
duced. In this case the reaction conditions used for cyclohexanone
gave the anti-aldol product 18b with good diastereoselectivity, but
relatively low ee (72% ee). It was found that addition of 2 equiv of
water to the reaction mixture increased the ee to 87% ee. Adding
more water simply led to a reduction in the rate of reaction.
Table 3
Effect of aryl aldehyde structure
O
O
OH
Ar
3 (5 mol%)
+
ArCHO
12
o
neat, 20 C
13
11
Table 4
Effect of ketone structure
Entry
Ar
Time (h)
Yield (%)a
drb
eec (%)
O
OH
O
a
b
c
d
e
f
g
h
i
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-NCC6H4
Ph
3
3
3
4
3
3
3
3
6
92
88
89
84
90
92
87
91
98:2
97:3
98:2
98:2
96:4
95:5
94:6
98:2
95:5
98:2
96:4
87:13
99
96
96
98
98
98
96
97
95
98
98
95
OHC
3 (5 mol%)
+
o
neat, 20
C
1
2
1
2
R
R
18
R
R
NO
2
NO
2
17
12a
R2
Entry
R1
Time (h)
Yield (%)a
anti:synb
eec (%)
ad
e(CH2)2e
e(CH2)4e
3.5
13
22
30
10
76e
99
80:20
90:10
d
97
87g
88
98
98
bf
61 (75)d
63 (86)d
65 (73)d
25 (93)d
ch,i
dh
ef,h
H
H
86j
93
j
k
l
2-Naphthyl
3-Furyl
4-MeOC6H4
5
15
30
CH3
H
CH3
OBn
20:80
17:83
92
a
a
Isolated yield after purification.
Determined by 1H NMR spectroscopy.
ee of major diastereoisomer.
Aldehyde added in three batches to minimize formation of bis-aldol adduct.
14% Bis-aldol product also obtained.
Ketone (3 equiv) was used.
Water (2 equiv) was added.
3-Nitrobenzoic acid (5 mol %) was added.
Reaction performed at 10 ꢂC.
Isolated yield after purification.
Determined by 1H NMR spectroscopy.
ee of anti-diastereoisomer.
b
c
d
e
f
b
c
d
Yield in parenthesis is based on consumed aldehyde.
g
h
i
Using 5 mol % catalyst, reactions involving electron-deficient
aromatic aldehydes (12aeh) were complete within 4 h at room
temperature. For these substrates the anti-aldol products 13 were
obtained as the major product and diastereoisomer ratios ranged
from 94:6 to 98:2. The ee of the anti-aldol products 13 were also
high in all cases (95e99% ee). Although some variation in dr and ee
was observed, this does not appear to correlate to the substitution
pattern in the aromatic ring. This latter observation is consistent
with the transition state structures depicted in Fig. 4, as both TS-1
and TS-2 can accommodate aldehydes substituted in the o-, m-, or
p-positions.
For electron-neutral and electron-rich aromatic aldehydes
(12iel) the outcome is more complicated. All give the anti-aldol
product 13 as the major isomer, and in all cases the ee of 13 is high
(95e98% ee). However, with these substrates the aldol process is
slower, and generally does not proceed to completion. The reaction
times quoted in Table 3 refer to the point at which the ratio of
starting material (aldehyde) to product remains constant. After this
point, the proportion of product does not increase, but the dr starts
to diminish. This is most pronounced for the electron-rich aromatic
aldehyde 12l, which after 6 h gives the anti-aldol product 13l in
93:7 dr, but after 30 h at 20 ꢂC this has fallen to 87:13. As the cat-
alyst and starting materials do not appear to degrade under the
reaction conditions, this is most likely a consequence of equilibra-
tion via retro-aldol reaction. It is known that diamine salts can
promote retro-aldol process and that aldol products derived from
electron-rich aldehydes react far faster that those derived from
electron-poor aldehydes.10 Low yields are often reported for amine-
catalysed aldol reactions involving electron-rich aldehydes,4 so this
may be a common facet of this chemistry.
j
6% Bis-aldol product also obtained.
Next we examined three acyclic ketones 17cee possessing dif-
ferent levels of substitution. These substrates were found to react at
a significantly slower rate than cyclohexanone. It was found that
addition of 5 mol % of 3-nitrobenzoic acid6c increased the rate of
reaction for all three of these ketones. In contrast, addition of 3-
nitrobenzoic acid had no beneficial effect on reactions involving
cyclic ketones. When acetone (17c) was used, the bis-aldol by-
product was again formed. In this case it was more convenient to
suppress this by performing the reaction at 10 ꢂC. Under these
conditions, the aldol product 18c could be isolated in 86% yield and
88% ee. With diethylketone (17d), the syn-aldol product 18d was
obtained as the major diastereoisomer in high ee. syn-Selectivity
has also been reported for this reaction using a related primary-
tertiary diamine catalyst6c and presumably arises due to reaction
proceeding predominantly via the Z-enamine. Benzyloxyacetone
(17e) was also found to favour the syn-aldol product, again in high
ee. In this case only the branched aldol products (syn- and anti-18e)
could be detected by 1H NMR indicating that this reaction proceeds
with high regioselectivity. This is again consistent with observa-
tions reported for related primary-tertiary diamine catalysts.6c
Finally, in an effort to further investigate the utility of catalyst 3
we examined the aldol reactions between cyclohexanone 11 and
cyclopentanone 17a, and chloral hydrate 19. As far as we are aware,
there has only been one previous report of enantioselective amine-
catalyzed aldol reactions involving these ketones and chloral hy-
drate.11 In this study it was shown that reaction of cyclohexanone
11 with chloral hydrate 19 in the presence of a proline tetrazole
catalyst gave the anti-aldol product (92% de, 98% ee), whereas re-
action of cyclopentanone 17a with chloral hydrate 19 gave the syn-
To further probe the utility of catalyst 3 the aldol reaction be-
tween 4-nitrobenzaldehyde and a number of other ketones (17aee)
was investigated (Table 4). We started by examining the effect of
altering the ring size of the ketone. Cyclopentanone (17a) was

10168
B. Lygo et al. / Tetrahedron 67 (2011) 10164e10170
aldol product (76% de, 82% ee). Such a dramatic switch in diaster-
eoselectivity on going from cyclopentanone to cyclohexanone is
unusual. Consequently we were interested to see whether the same
switch would occur using catalyst 3. It was found that both aldol
reactions were complete within 3 h at 20 ꢂC (Scheme 3) and in both
cases the anti-aldol product (20 and 21) was obtained. For each
ketone, the enantioselectivity and diastereoselectivity observed
was in line with that obtained with other aldehydes, suggesting
that chloral hydrate does not behave in an anomalous fashion when
catalyst 3 is used.
detector. All ees were determined by HPLC comparison with race-
mates using Chiralcel OD-H or Chiralpak AD-H columns. HPLCs
were run in duplicate and the ratio of integrals checked for con-
sistency at four separate wavelengths (220 nm, 232 nm, 254 nm,
280 nm). All DFT calculations were performed using B3LYP/6-31G**
as implemented in Spartan’10 v1.1.0.12 Relative energies quoted are
based on total energies (gas phase) at 298 K and have ZPE correc-
tions applied. All transition states were verified by frequency cal-
culations and by confirming that the imaginary frequency vibration
was consistent with the CeC bond forming process depicted in
Scheme 2.
Salt 5 was prepared as previously reported. The absolute ste-
reochemistry of the anti-aldol products 13a,5 13d,13 and 13i,14 2111
was determined to be (2R,10S) by comparison of HPLC retention
times or sign of optical rotation with known compounds. The ab-
solute stereochemistry of anti-aldol products 13b,6a 13c,15 13e,6a
13f,16 13g,17 13h,6a 13j,18 13l,19 18a,18 18b20 is assumed to be
(2R,10S). These compounds all have HPLC retention times or sign of
optical rotation consistent with those previously reported for
compounds assumed to have this stereochemistry. The absolute
stereochemistry of syn-aldol products 18d,6c 18e6c is assumed to be
(1S,2S). These compounds all have HPLC retention times or sign of
optical rotation consistent with those previously reported for
compounds assumed to have this stereochemistry.
O
OH
CCl
O
3 (5 mol%)
HO
CCl
3
+
3
o
neat, 2 h, 20 C
OH
19
n
n
11 or 17a
20, n = 1; 70% (75:25 d.r., 94% e.e.)
21, n = 2; 91% (98:2 d.r., >99% e.e.)
Scheme 3. Aldol reactions involving chloral hydrate 19.
3. Conclusion
In conclusion, we have been able to demonstrate that a simple
tropos dibenz[c,e]azepinium salt
3
derived from trans-1,2-
4.2. 2,20-Bis-bromomethylbiphenyl, 8
diaminocyclohexane can be prepared in four steps and 69% over-
all yield. This salt is able to promote stereoselective cross-aldol
reactions between ketones and aldehydes. When cyclic ketones
are used, anti-aldol products are obtained with high diastereo- and
enantioselectivity. In contrast acyclic ketones were found to favour
syn-aldol products. These observations are consistent with cyclic
ketones reacting via an E-enamine intermediate and acyclic ketones
reacting preferentially via a Z-enamine intermediate. High conver-
sions and isolated yields are obtained when electron-deficient ar-
omatic aldehydes and chloral hydrate are used. With electron-
neutral and electron-deficient aromatic aldehydes the reactions
do not proceed to completion, but in most cases reasonable isolated
yields (60e65%) of the aldol products can be obtained.
Finely powdered 2,20-biphenyldimethanol (2.40 g, 11.2 mmol)
was dissolved in 33% HBr in acetic acid (30 ml) and the mixture was
heated at reflux for 30 min. The reaction was then allowed to cool to
room temperature and the precipitate collected by filtration. The
filtrate was dissolved in chloroform (50 ml) and washed sequen-
tially with saturated aqueous NaHCO3 (50 ml) and brine (50 ml).
The organic layer was dried (Na2SO4), then activated charcoal (1 g)
added. After standing for 5 min the solution was filtered through
a pad of CeliteÒ and then concentrated under reduced pressure to
give dibromide 8 (3.06 g, 80%) as a colourless solid, mp 85e86 ꢂC
(lit., mp 91e93 ꢂC21). Rf 0.6 (9:1, petroleum ether/diethyl ether);
nmax(CHCl3)/cmꢄ1 3067, 3022, 2990, 2933, 2878,1475; dH (400 MHz,
CDCl3) 7.57 (2H, dd, J 7.5, 1.5 Hz, ArH), 7.44 (2H, ddd, J 7.5, 7.5, 1.5 Hz,
ArH), 7.40 (2H, ddd, J 7.5, 7.5, 1.5 Hz, ArH), 7.30 (2H, dd, J 7.5, 1.5 Hz,
ArH), 4.37 (2H, d, J 10.0 Hz, CHaHb), 4.22 (2H, d, J 10.0 Hz, CHaHb); dC
(100 MHz, CDCl3) 139.4 (C), 135.9 (C), 130.7 (CH), 130.2 (CH), 128.7
(CH), 128.3 (CH), 32.0 (CH2); m/z (EI) 340 (Mþ, 79Br81Br, 6%), 261
4. Experimental
4.1. General information
All solvents and chemicals were used as provided by the sup-
plier. Reactions were monitored by thin layer chromatography us-
ing Merck silica gel 60 F254 pre-coated glass TLC plates, visualized
using UV light and then basic potassium permanganate solution.
Flash chromatography was performed using Merck silica gel
(230e400 mesh) as the stationary phase. Melting points were de-
termined using a Kopfler hot-stage apparatus and are uncorrected.
Infrared spectra were recorded using either a PerkineElmer FT
1600 or a Nicolet Avatar 360 FT-IR infrared spectrophotometer. 1H
NMR and 13C NMR spectra were recorded on a Bruker AV3400 or
DPX400 spectrometer at ambient temperature. Chemical shifts are
quoted relative to residual solvent and J values are given in hertz.
Multiplicities are designated by the following abbreviations: s,
singlet; d, doublet; t, triplet; q, quartet; br, broad; m, multiplet.
Diastereoisomer ratios (dr) were measured by integration of the
CHOH proton signals on expanded spectra. Mass spectra were ob-
tained on a Micromass Autospec or Micromass LCT instruments
using electron impact (EI) or electrospray (ES) ionization. Specific
rotations were measured using a Bellingham and Stanley ADP440
polarimeter at ambient conditions and are given in units of
(35), 259 (37), 179 (100), 178 (44), 76 (39), 51 (32); m/z (EI) found
79
[M, 79Br81Br]þ 339.9282, C14
H
12
Br81Br requires 339.9285.
4.3. DAB protected amine, 93
A solution of (R,R)-1,2-diaminocyclohexane (0.69 g, 6.0 mmol) in
dry tetrahydrofuran (120 ml) was placed under an argon atmo-
sphere. 1,3-Dimethyl-5-acetylbarbituric acid (1.19 g, 6.0 mmol) was
added and the reaction stirred at room temperature for 5 h over
which time a white precipitate formed. The precipitate was col-
lected by filtration and dried in air to afford amine 9 (1.71 g, 97%) as
a colourless solid, mp 231e233 ꢂC. ½a D24
ꢄ63.0 (c 0.9, CHCl3); Rf 0.3
ꢅ
(1:9 methanol/dichloromethane); nmax(CHCl3)/cmꢄ1 3675, 3378,
3009, 2942, 2863, 1702, 1638, 1593, 1523, 1478, 1382; dH (400 MHz,
CDCl3) 12.76 (1H, br d, J 7.5 Hz, NH), 3.48e3.37 (1H, m, NHCH), 3.33
(3H, s, NCH3), 3.32 (3H, s, NCH3), 2.87e2.79 (1H, m, NH2CH), 2.75
(3H, s, CCH3), 2.04e1.91 (2H, m, NHCHCH2), 1.87e1.73 (2H, m,
NH2CHCH2), 1.56 (2H, br s, NH2), 1.48e1.15 (4H, m, 2ꢆ CH2); dC
(100 MHz, CDCl3) 173.9 (C), 166.7 (C), 163.1 (C), 151.5 (C), 90.3 (C),
60.7 (CH), 54.9 (CH), 34.8 (CH2), 32.4 (CH2), 27.9 (CH3), 27.6 (CH3),
24.6 (CH2), 24.5 (CH2), 18.4 (CH3); m/z (ES) 295 (MþHþ, 100%); m/z
(ES) found [MþH]þ 295.1769. C14H23N4Oþ3 requires 295.1765.
deg cm2
g
ꢄ1; c is in g/100 ml of solvent. HPLC analysis was per-
formed on a Varian Pro-Star 210 machine fitted with a diode array

B. Lygo et al. / Tetrahedron 67 (2011) 10164e10170
10169
4.4. DAB protected (10R, 20R)-6-(20-aminocyclohexyl)-6,7-
dihydro-5H-dibenzo[c,e]azepine, 10
1.86e1.73 (2H, m, CH2), 1.71e1.53 (1H, m, CHaHb), 1.52e1.22 (3H, m,
CHaHb and CH2); dC (100 MHz, CDCl3) 140.8 (C), 135.0 (C), 129.9
(CH), 128.2 (2ꢆ CH), 127.6 (CH), 120.2 (q, J 319 Hz, CF3), 66.9 (CH),
52.4 (CH), 51.7 (br, 2ꢆ CH2), 29.9 (CH2), 26.6 (CH2), 25.1 (CH2), 24.1
(CH2); m/z (ES) 293 (MꢄTfOꢄ, 100%), 242 (54); m/z (ES) found
[MꢄTfOꢄ] 293.2002. C20H25Nþ2 requires 293.2012.
A solution of amine 93 (1.73 g, 5.88 mmol) and dibromide 8
(2.00 g, 5.88 mmol) in acetonitrile (150 ml) was placed under an
argon atmosphere. Anhydrous K2CO3 (5.36 g, 38.8 mmol) was
added and the mixture stirred at 60 ꢂC for 24 h. The mixture was
allowed to cool to room temperature, then filtered, washing
through with dichloromethane (100 ml). The filtrand was concen-
trated under reduced pressure and the residue purified by chro-
matography on silica gel to give amine 10 (2.67 g, 96%) as
4.7. DAB protected (1R,2R)-N,N-dibenzyldiaminocyclohexane
A solution of benzaldehyde (309 mg, 2.91 mmol) and amine 9
(171 mg, 0.58 mmol) in acetonitrile (4 ml) and water (0.2 ml) was
stirred for 45 min until the reaction was homogeneous. NaCNBH3
(76.8 mg, 1.22 mmol) was added and the reaction stirred for a fur-
ther 30 min. Acetic acid (0.2 ml) was then added and the mixture
concentrated under reduced pressure. The residue was dissolved in
chloroform (10 ml), washed with 1 M aqueous NaOH (2ꢆ5 ml),
dried (Na2SO4) and concentrated under reduced pressure. The
residue was purified by chromatography on silica gel to give the
a colourless solid, mp 106e108 ꢂC. ½a D22
ꢅ
ꢄ177.6 (c 0.8, CHCl3); Rf 0.2
(69:30:1,
petroleum
ether/ethyl
acetate/triethylamine);
nmax(CHCl3)/cmꢄ1 3692, 3676, 3606, 3067, 3009, 2941, 2862, 2813,
1731,1700,1637,1597,1478,1383; dH (400 MHz, CDCl3) 12.90 (1H, br
d, J 7.0 Hz, NH), 7.48e7.44 (2H, m, ArH), 7.44e7.38 (2H, m, ArH),
7.38e7.31 (4H, m, ArH), 3.81e3.71 (1H, m, CHN), 3.60 (2H, d, J
12.5 Hz, NCHaHb), 3.48 (2H, d, J 12.5 Hz, NCHaHb), 3.37 (3H, s, NCH3),
3.31 (3H, s, NCH3), 2.90e2.81 (1H, m, CHN), 2.73 (3H, s, CCH3),
2.22e2.14 (1H, m, CHaHb), 2.01e1.93 (1H, m, CHaHb), 1.89e1.78 (2H,
m, CH2), 1.60e1.23 (4H, m, 2ꢆ CH2); dC (100 MHz, CDCl3) 172.8 (C),
166.4 (C), 163.2 (C), 151.6 (C), 140.8 (C), 135.9 (C), 129.6 (CH), 128.0
(CH), 127.8 (CH), 127.6 (CH), 90.0 (C), 68.5 (CH), 55.6 (CH), 52.4
(CH2), 33.5 (CH2), 27.8 (CH3), 27.8 (CH2), 27.6 (CH3), 25.4 (CH2), 24.6
(CH2), 18.6 (CH3); m/z (ES) 473 (MþHþ, 100%); m/z (ES) found
[MþH]þ 473.2537. C28H33N4Oþ3 requires 473.2547.
product (185 mg, 83%) as a colourless oil. ½a D24
ꢄ9.9 (c 1.0, CHCl3); Rf
ꢅ
0.3 (65:33:1 petroleum ether/ethyl acetate/triethylamine);
nmax(CHCl3)/cmꢄ1 3013, 2943, 1639, 1478, 1384; dH (400 MHz,
CDCl3) 12.81 (1H, d, J 7.0 Hz, NH), 7.37e7.35 (4H, m, ArH), 7.30e7.23
(6H, m, ArH), 3.79 (2H, d, J 14.0 Hz, 2ꢆ NCHaHb), 3.58 (2H, d, J
14.0 Hz, 2ꢆ NCHaHb), 3.56e3.51 (1H, m, CHN), 3.47 (3H, s, NCH3),
3.38 (3H, s, NCH3), 2.84 (1H, ddd, J 11.0, 11.0, 3.5 Hz, CHN), 2.40 (3H,
s, CCH3), 2.20e2.17 (1H, m, CHaHb), 1.98e1.95 (1H, m, CHaHb),
1.91e1.87 (1H, m, CHaHb), 1.76e1.72 (1H, m, CHaHb), 1.52e1.42 (1H,
m, CHaHb), 1.34e1.16 (3H, m, CHaHb and CH2); dC (100 MHz, CHCl3)
172.7 (C), 165.0 (C), 163.0 (C), 151.6 (C), 139.2 (C), 128.7 (CH), 128.3
(CH), 127.1 (CH), 89.8 (C), 63.0 (CH), 55.1 (CH), 54.5 (CH2), 34.1
(CH2), 27.8 (CH3), 27.5 (CH3), 25.0 (CH2), 24.7 (CH2), 23.6 (CH2), 18.0
(CH3); m/z (ES) 497 (MþNaþ, 100%), 304 (60); m/z (ES) found
[MþNa]þ 497.2524. C28H34N4O3Naþ requires 497.2523.
4.5. (10R,20R)-6-(20-Aminocyclohexyl)-6,7-dihydro-5H-
dibenzo[c,e]azepine22
A solution of the azepine 10 (2.67 g, 5.64 mmol) in ethanol
(100 ml) was placed under an argon atmosphere. Powdered KOH
(1.90 g, 33.9 mmol) was added and the mixture was stirred at 50 ꢂC
for 24 h. The resulting solution was allowed to cool to room tem-
perature, then diluted with water (150 ml) and dichloromethane
(150 ml). The aqueous layer extracted with dichloromethane
(2ꢆ150 ml), and the combined organics were then dried (MgSO4)
and concentrated under reduced pressure. The residue was purified
by chromatography on silica gel to give the product (1.49 g, 90%) as
4.8. (1R,2R)-N,N-dibenzyldiaminocyclohexane3
A solution of DAB protected (1R,2R)-N,N-dibenzyldiaminocy-
clohexane (132 mg, 0.26 mmol) in ethanol (4 ml) was placed under
an argon atmosphere. Finely ground KOH (72.7 mg, 1.30 mmol) was
added and the reaction heated to 50 ꢂC for 25 h. The mixture was
allowed to cool to room temperature, then diluted with water
(15 ml) and dichloromethane (15 ml). The aqueous layer was
extracted with dichloromethane (2ꢆ10 ml) and the combined or-
ganics were dried (MgSO4) and concentrated under reduced pres-
sure. The residue was purified by chromatography on silica gel to
a colourless oil. ½a D25
ꢄ39.8 (c 0.8, CHCl3); Rf 0.1 (97:2:1, dichloro-
ꢅ
methane/methanol/triethylamine); nmax(CHCl3)/cmꢄ1 3374, 2933,
2859, 1602, 1450, 1080; dH (400 MHz, CDCl3) 7.49e7.36 (8H, m,
ArH), 3.61 (2H, d, J 12.5 Hz, NCHaHb), 3.54 (2H, d, J 12.5 Hz, NCHaHb),
2.83 (1H, ddd, J 10.5, 10.5, 4.0 Hz, CHN), 2.47e2.38 (1H, m, CHNH2),
2.07e2.00 (3H, m, CHaHb and NH2), 1.82e1.68 (3H, m, CHaHb and
CH2), 1.39e1.14 (4H, m, 2ꢆ CH2); dC (100 MHz, CDCl3) 140.9 (C),
136.7 (C), 129.8 (CH), 127.9 (CH), 127.6 (CH), 127.5 (CH), 72.1 (CH),
52.1 (CH2), 52.0 (CH), 35.3 (CH2), 26.7 (CH2), 26.3 (CH2), 25.1 (CH2);
m/z (ES) 293 (MþHþ, 100%); m/z (ES) found [MþH]þ 293.1995.
C20H25Nþ2 requires 293.2012.
give the product (53.0 mg, 70%) as a pale orange oil. ½a D25
ꢄ61.3 (c
ꢅ
1.0, CHCl3); Rf 0.1 (97:2:1 dichloromethane/methanol/triethyl-
amine); nmax(CHCl3)/cmꢄ1 3373, 3352, 2933, 2859, 1452; dH
(400 MHz, CDCl3) 7.37e7.24 (10H, m ArH), 3.87 (2H, d, J 13.5 Hz, 2ꢆ
NCHaHb), 3.43 (2H, d, J 13.5 Hz, 2ꢆ NCHaHb), 2.73 (1H, ddd, J 10.5,
10.5, 4.0 Hz, CHN), 2.20 (1H, ddd, J 11.5, 10.5, 3.5 Hz, CHN),
2.04e2.00 (4H, m, NH2 and 2ꢆ CHaHb), 1.87e1.82 (1H, m, CHaHb),
1.69e1.65 (1H, m, CHaHb), 1.33e1.09 (3H, m, CHaHb and CH2),
1.03e0.92 (1H, m, CHaHb); dC (100 MHz, CHCl3) 140.1 (C), 128.8
(CH), 128.3 (CH), 126.8 (CH), 64.6 (CH), 53.7 (CH2), 51.1 (CH), 34.7
(CH2), 25.7 (CH2), 25.1 (CH2), 22.5 (CH2); m/z (ES) 295 (MþHþ,
100%); m/z (ES) found [MþH]þ 295.2172. C20H27N2þ requires
295.2169.
4.6. Triflate salt of (10R,20R)-6-(20-aminocyclohexyl)-6,7-
dihydro-5H-dibenzo[c,e]azepine (3)
A solution of triflic acid (765 mg, 5.09 mmol) in dichloro-
methane (40 ml) was added to a solution of (10R,20R)-6-(20-ami-
nocyclohexyl)-6,7-dihydro-5H-dibenzo[c,e]azepine (1.49 g, 5.09
mmol) in dichloromethane (40 ml). The solution was stirred at
room temperature for 1 h, then concentrated under reduced
pressure to afford ammonium salt 3 (2.26 g, 100%) as an off-white
4.9. Triflate salt of (10R,20R)-N,N-dibenzyldiaminocyclohexane (4)
solid, mp 74e76 ꢂC. ½a D25
ꢅ
ꢄ6.0 (c 1.2, CHCl3); nmax(CHCl3)/cmꢄ1
3690, 3674, 3606, 3069, 3043, 2946, 2866, 1603, 1451, 1374, 1287,
1241, 1175, 1028; dH (400 MHz, CDCl3) 7.57e7.32 (8H, m, ArH), 5.48
(3H, br s, NHþ3 ), 3.63 (2H, d, J 12.5 Hz, 2ꢆ NCHaHb), 3.54 (2H, d, J
12.5 Hz, 2ꢆ NCHaHb), 3.24e3.13 (1H, m, CHN), 2.93e2.80 (1H, m,
CHNH2), 2.38e2.27 (1H, m, CHaHb), 1.95e1.86 (1H, m, CHaHb),
A solution of triflic acid (18.9 mg, 0.13 mmol) in dichloro-
methane (1 ml) was added to a solution of (1R,2R)-N,N-dibenzyl-
diaminocyclohexane (37.0 mg, 0.13 mmol) in dichloromethane
(1 ml). The solution was stirred at room temperature for 1 h, then
concentrated under reduced pressure. The residue was dissolved in

10170
B. Lygo et al. / Tetrahedron 67 (2011) 10164e10170
diethyl ether (0.5 ml) then petroleum ether (0.5 ml) was added and
the mixture filtered. The filtrand was concentrated under reduced
pressure to give 4 (46.3 mg, 83%) as a colourless solid, mp 49 ꢂC.
v); flow rate, 0.8 ml/min; retention times, 10.3 min (1.0%), 13.6 min
(99.0%), 98% ee.
½
a 2D2
ꢅ
ꢄ34.3 (c 1.0, CHCl3); nmax(CHCl3)/cmꢄ1 2941, 1603, 1454, 1240,
Acknowledgements
1028; dH (400 MHz, CDCl3) 7.37e7.24 (10H, m, ArH), 3.79 (2H, d, J
13.5 Hz, 2ꢆ NCHaHb), 3.47 (2H, d, J 13.5 Hz, 2ꢆ NCHaHb), 2.89 (1H,
ddd, J 11.0,11.0, 4.0 Hz, CHN), 2.49 (1H, ddd, J 11.5,11.0, 3.5 Hz, NCH),
2.16e2.13 (1H, m, CHaHb), 2.00e2.04 (1H, m, CHaHb), 1.86e1.84 (1H,
m, CHaHb), 1.74e1.71 (1H, m, CHaHb), 1.41e1.18 (4H, m, 2ꢆ CH2); dC
(100 MHz, CHCl3) 138.6 (C), 128.9 (CH), 128.7 (CH), 127.5 (C), 120.1
(q, J 319 Hz, CF3), 61.8 (CH), 53.9 (CH2), 51.3 (CH), 30.6 (CH2), 24.8
(CH2), 24.1 (CH2), 23.1 (CH2); m/z 295 (MꢄTfOꢄ, 100%); m/z (ES)
found [MꢄTfOꢄ] 295.2164. C20H27Nþ2 requires 295.2169.
Financial support for this work was provided by AstraZeneca,
EPSRC and the Leverhulme Trust.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.09.101.
References and notes
4.10. General procedure used to investigate effect of solvent
(Table 2)
1. (a) Lygo, B.; Allbutt, B.; Beaumont, D. J.; Butt, U.; Gilks, J. A. R. Synlett 2009,
675e680; (b) Lygo, B.; Beaumont, D. J. Chimia 2007, 61, 257e262; (c) Lygo, B.;
Allbutt, B.; Kirton, E. H. M. Tetrahedron Lett. 2005, 46, 4461e4464; (d) Melville,
J. L.; Lovelock, K. J. R.; Wilson, C.; Allbutt, B.; Burke, E. K.; Lygo, B.; Hirst, J. D. J.
Chem. Inf. Model 2005, 45, 971e981; (e) Lygo, B.; Humphreys, L. D. Synlett 2004,
2809e2811; (f) Lygo, B.; Allbutt, B. Synlett 2004, 326e328; (g) Lygo, B.; An-
drews, B. I. Acc. Chem. Res. 2004, 37, 518e525; (h) Lygo, B.; Allbutt, B.; James, S.
R. Tetrahedron Lett. 2003, 44, 5629e5632.
Cyclohexanone (0.60 ml, 6.4 mmol) was added to a solution of
diamine salt 3 (8.9 mg, 20 mmol) in the solvent (0.7 ml). A solution
of 4-nitrobenzaldehyde (60 mg, 0.40 mmol) in the solvent (0.7 ml)
was then added and the mixture stirred at 20 ꢂC. Aliquots (0.1 ml)
were taken after 1 h, 2 h, 3 h, 4 h, 8 h and 15 h. The catalyst was
removed by passing the aliquots through a short plug of silica, using
ethyl acetate (5 ml) to elute. They were then concentrated under
reduced pressure and immediately assayed by 1H NMR and
chiral HPLC. Reactions were stopped after >97% consumption of
4-nitrobenzaldehyde.
2. Peng, F.-Z.; Shao, Z.-H.; Pu, X.-W.; Zhang, H.-B. Adv. Synth. Catal. 2008, 350,
2199e2204.
3. Arai, T.; Watanabe, M.; Fujiwara, A.; Yokoyama, N.; Yanagisawa, A. Angew. Chem.
, Int. Ed. 2006, 45, 5978e5981.
4. For recent reviews on application of amine organocatalysis in aldol chemistry
see: Bhanushali, M.; Zhao, C.-G. Synthesis 2011, 1815e1830; Trost, B. M.; Brindle,
C. S. Chem. Soc. Rev. 2010, 39, 1600e1632; Zlotin, S. G.; Kucherenko, A. S.; Be-
letskaya, I. P. Russ. Chem. Rev. 2009, 78, 737e784.
5. The absolute stereochemistry of 13a was established by comparison of HPLC
retention times with those previously reported: Inoue, H.; Kikuchi, M.; Ito, J.-I.;
Nishiyama, H. Tetrahedron 2008, 64, 493e499.
6. (a) Lin, J.-H.; Zhang, C.-P.; Xiao, J.-C. Green Chem. 2009, 11, 1750e1753; (b) Luo,
S.; Li, J.; Zhang, L.; Xu, H.; Cheng, J.-P. Chem.dEur. J. 2008, 14, 1273e1281; (c)
Luo, S.; Xu, H.; Li, J.; Zhang, L.; Cheng, J.-P. J. Am. Chem. Soc. 2007, 129,
3074e3075.
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49, 7434e7437; Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58,
8167e8177; Saito, S.; Nakadai, M.; Yamamoto, H. Synlett 2001, 1245e1248.
8. Mikami, K.; Aikawa, K.; Yusa, Y.; Jodry, J. J.; Yamanaka, M. Synlett 2002,
1561e1578.
4.11. General procedure used to investigate effect of aldehyde
structure (Table 3)
Aldehyde (0.40 mmol) in cyclohexanone (118 mg, 1.20 mmol)
was added to a reaction tube containing diamine salt 3 (8.9 mg,
0.02 mmol). The mixture was stirred for 3e30 h at 20 ꢂC, then
purified by chromatography on silica gel to give the aldol products.
ees and drs were measured on unpurified samples.
9. For a discussion on the utility of B3LYP/6-31G** calculations for comparison of
relative transition state energies of organocatalysed aldol processes see: Alle-
mann, C.; Um, J. M.; Houk, K. N. J. Mol. Catal. A: Chem. 2010, 324, 31e38 and
references therein.
4.12. General procedure used to investigate effect of ketone
structure (Table 4)
10. Luo, S.; Zhou, P.; Li, J.; Cheng, J.-P. Chem.dEur. J. 2010, 16, 4457e4461.
11. Torii, H.; Masakazu, N.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew. Chem., Int.
Ed. 2004, 43, 1983e1986.
The appropriate ketone (4.0 mmol) was added to a reaction tube
containing diamine salt 3 (8.9 mg, 0.02 mmol) and any additives
specified. 4-Nitrobenzaldehyde (60.4 mg, 0.40 mmol) was then
added and the mixture stirred for 3e30 h at 20 ꢂC, then purified by
chromatography on silica gel to give the aldol products. drs were
measured on unpurified samples, ees were measured on both
unpurified and purified samples.
12. Shao, Y.; Molnar, L. F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.; Brown, S. T.; Gil-
bert, A. T. B.; Slipchenko, L. V.; Levchenko, S. V.; O’Neill, D. P.; DiStasio, R. A.;
Lochan, R. C.; Wang, T.; Beran, G. J. O.; Besley, N. A.; Herbert, J. M.; Lin, C. Y.; Van
Voorhis, T.; Chien, S. H.; Sodt, A.; Steele, R. P.; Rassolov, V. A.; Maslen, P. E.;
Korambath, P. P.; Adamson, R. D.; Austin, B.; Baker, J.; Byrd, E. F. C.; Dachsel, H.;
Doerksen, R. J.; Dreuw, A.; Dunietz, B. D.; Dutoi, A. D.; Furlani, T. R.; Gwaltney, S.
R.; Heyden, A.; Hirata, S.; Hsu, C. P.; Kedziora, G.; Khalliulin, R. Z.; Klunzinger, P.;
Lee, A. M.; Lee, M. S.; Liang, W.; Lotan, I.; Nair, N.; Peters, B.; Proynov, E. I.;
Pieniazek, P. A.; Rhee, Y. M.; Ritchie, J.; Rosta, E.; Sherrill, C. D.; Simmonett, A. C.;
Subotnik, J. E.; Woodcock, H. L.; Zhang, W.; Bell, A. T.; Chakraborty, A. K.;
Chipman, D. M.; Keil, F. J.; Warshel, A.; Hehre, W. J.; Schaefer, H. F.; Kong, J.;
Krylov, A. I.; Gill, P. M. W.; Head-Gordon, M. Phys. Chem. Chem. Phys. 2006, 8,
3172e3191.
13. Doherty, S.; Knight, J. G.; McRae, A.; Harrington, R. W.; Clegg, W. Eur. J. Org.
Chem. 2008, 1759e1766.
14. Denmark, S. E.; Stavenger, R. A.; Wong, K.-T.; Su, X. J. Am. Chem. Soc. 1999, 121,
4982e4991.
15. Lei, M.; Shi, L.; Li, G.; Chen, S.; Fang, W.; Ge, Z.; Cheng, T.; Li, R. Tetrahedron 2007,
63, 7892e7898.
16. Liu, Y.-X.; Sun, Y.-N.; Tan, H.-H.; Liu, W.; Tao, J.-C. Tetrahedron: Asymmetry 2007,
18, 2649e2656.
4.13. (2R,10S)-2-(10Hydroxy-10-(fur-3-yl)methyl)cyclohexan-1-
one 13k
Colourless oil; ½a D29
ꢄ11.4 (c 1.0, CHCl3, 98% ee); nmax (CHCl3)/
ꢅ
cmꢄ1 3528, 3009, 2944, 1697,1504,1450, 1239, 1023, 874; Rf 0.3 (1:4
ethyl acetate/petroleum ether); dH (400 MHz, CDCl3) 7.42e7.41 (2H,
m, ArH), 6.45e6.42 (1H, m, ArH), 4.83 (1H, dd, J 8.0, 3.0 Hz, CHOH),
3.86 (1H, d, J 3.0 Hz, OH), 2.63 (1H, dddd, J 13.0, 8.0, 5.0, 1.0 Hz,
CHCO), 2.52e2.47 (1H, m, CHaHb), 2.43e2.34 (1H, m, CHaHb),
2.17e2.10 (1H, m, CHaHb), 1.90e1.83 (1H, m, CHaHb), 1.74e1.60 (2H,
m), 1.41e1.30 (1H, m, CHaHb); dC (100 MHz, CDCl3) 215.3 (C), 143.4
(CH), 140.1 (CH), 125.6 (C), 108.7 (CH), 67.1 (CH), 56.5 (CH), 42.7
(CH2), 30.8 (CH2), 27.8 (CH2), 24.8 (CH2); m/z (ES) 217 (MþNaþ,
100%); m/z (ES) Found 217.0839. C11H14O3Naþ requires 217.0835;
HPLC: Chiralcel OD-H; mobile phase, hexane/2-propanol (90:10 v/
17. Chen, F.; Huang, S.; Zhang, H.; Liu, F.; Peng, Y. Tetrahedron 2008, 64, 9585e9591.
18. Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649e4652.
19. Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593e2595.
20. Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8, 4417e4420.
21. Hall, D. M.; Lesslie, M. S.; Turner, E. E. J. Chem. Soc. 1950, 711e713.
22. For an alternative approach to this compound see, Mitchell, J. M.; Finney, N. S.
Tetrahedron Lett. 2000, 41, 8431e8434.