Utilizing the asymmetric amino-cope rearrangement as a novel approach to enantiomerically enriched 3-substituted aldehydes

Article abstract of DOI:10.1080/00397910903318666

We report the asymmetric amino-Cope rearrangement of some novel 3-amino-1,5-diene substrates to yield enantiomerically enriched 3-alkyl and 3-aryl aldehyde products. We have developed a system that gives excellent and comparable levels of product enantiomeric excess (ee) for both alkyl-and aryl-substituted products. Our results have implications for the control of the mechanistic pathway of the amino-Cope rearrangement and thus its potential utility in asymmetric synthesis.

Full text of DOI:10.1080/00397910903318666

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Utilizing the Asymmetric Amino-Cope
Rearrangement as a Novel Approach to
Enantiomerically Enriched 3-Substituted
Aldehydes
Steven M. Allin a , Catarina Horro-Pita b , Munira Essat b , Ian
Aspinall c & Pritom Shah d
a School of Chemical and Geographical Sciences, Keele University ,
Keele, United Kingdom
b Department of Chemistry , Loughborough University ,
Loughborough, United Kingdom
c Syngenta, Jealott's Hill Research Centre , Bracknell, United
Kingdom
d GlaxoSmithKline , Stevenage, United Kingdom
Published online: 09 Aug 2010.
To cite this article: Steven M. Allin , Catarina Horro-Pita , Munira Essat , Ian Aspinall & Pritom Shah
(2010) Utilizing the Asymmetric Amino-Cope Rearrangement as a Novel Approach to Enantiomerically
Enriched 3-Substituted Aldehydes, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:18, 2696-2711, DOI: 10.1080/00397910903318666
To link to this article: http://dx.doi.org/10.1080/00397910903318666
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Synthetic Communications1, 40: 2696–2711, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903318666
UTILIZING THE ASYMMETRIC AMINO-COPE
REARRANGEMENT AS A NOVEL APPROACH TO
ENANTIOMERICALLY ENRICHED 3-SUBSTITUTED
ALDEHYDES
Steven M. Allin,1 Catarina Horro-Pita,2 Munira Essat,2
Ian Aspinall,3 and Pritom Shah4
1School of Chemical and Geographical Sciences, Keele University, Keele,
United Kingdom
2Department of Chemistry, Loughborough University, Loughborough,
United Kingdom
3Syngenta, Jealott’s Hill Research Centre, Bracknell, United Kingdom
4GlaxoSmithKline, Stevenage, United Kingdom
We report the asymmetric amino-Cope rearrangement of some novel 3-amino-1,5-diene
substrates to yield enantiomerically enriched 3-alkyl and 3-aryl aldehyde products. We have
developed a system that gives excellent and comparable levels of product enantiomeric
excess (ee) for both alkyl- and aryl-substituted products. Our results have implications
for the control of the mechanistic pathway of the amino-Cope rearrangement and thus its
potential utility in asymmetric synthesis.
Keywords: Aldehyde; aminoalcohol; amino-Cope; asymmetric; rearrangement
There is considerable interest in asymmetric variants of sigmatropic rearrange-
ments,[1] and we have pioneered the amino-Cope rearrangement as a new synthetic
protocol. Scheme 1 summarizes our ultimate goal: the one-pot asymmetric synthesis
of acyclic aldehyde targets containing up to three contiguous chiral centres via
amino-Cope rearrangement (step 1) and subsequent enamine derivatization and
hydrolysis (step 2).
Our group has pioneered the key steps of this protocol, including a successful
tandem amino-Cope rearrangement–enamine derivatization reaction.[2] We have
established that an anionic variant of the amino-Cope rearrangement is possible
and that high asymmetric induction can be achieved at an asymmetric center created
during the rearrangement of a diastereoisomerically pure substrate.[3] We have also
reported applications of our methodology in the synthesis of enantiomerically
enriched heterocyclic targets.[4]
Received June 5, 2009.
Address correspondence to Steven M. Allin, School of Chemical and Geographical Sciences, Keele
University, Keele, ST5 5BG, UK. E-mail: s.m.allin@chem.keele.ac.uk
2696

ASYMMETRIC AMINO-COPE REARRANGEMENT
2697
Scheme 1. Synthetic potential of the amino-Cope rearrangement.
Given our own work in this area, and that of Dobson et al.[5] and Yoo et al.,[6]
there remains a question over the mechanisms involved in the anionic amino-Cope
rearrangement. Whereas Yoo et al. have suggested a dissociation=recombination
mechanism rather than a concerted [3,3]-rearrangement,[6] Dobson et al. prefer a
competitive [1,3]-, not [3,3]-, rearrangement mechanism.[5] In our own work, a
methyl group marker within the 3-amino-1,5-diene substrate gave further evidence
of a competing mechanism to the expected [3,3]-rearrangement.[7]
So far we have only reported the asymmetric rearrangement of substrates bear-
ing a phenyl substituent at the 1-position of the 3-amino-1,5-diene system (i.e., com-
=
pound 2a, R Ph). High enantiomeric excess (ee) values can be obtained on
rearrangement of this substrate,[3b] but clearly the same product is achieved on
rearrangement of this substrate by any of the suggested mechanisms (Scheme 2).
We have proposed the chairlike transition-state conformation, 4, to rationalize the
observed stereochemical outcome of the rearrangement; indeed we have shown that
the absolute stereochemistry of the product aldehyde 3a can be predicted using this
rule of thumb, if one knows the absolute stereochemistry of the amine stereocenter in
the 1,3-diene unit.[3]
Clearly, our overall proposal outlined in Scheme 1 relies heavily upon the
control of the reaction mechanism, with the [3,3]-route being highly desirable. One
would expect to observe higher ee values in reactions that proceed by a concerted
[3,3]-rearrangement mechanism than one in which competitive dissociation played
a major role, because dissociation of the substrate could lead to some loss of
stereochemical information from within the diene unit. One would then be left with
a remote chiral auxiliary as sole contributor to stereochemical induction in this pro-
cess. A competing [1,3]-shift mechanism would also prove problematic for us because
our proposal calls for the creation of neighboring stereocenters during amino-Cope
rearrangement (at positions X and Y in Scheme 1). The work of Dobson et al.
has suggested that the identity of the solvent can play an important role in
Scheme 2. Asymmetric amino-Cope rearrangement.

2698
S. M. ALLIN ET AL.
determining which mechanistic pathway is followed ([1,3] vs. [3,3]) on rearrangement
of certain substrates. Tetrahydrofuran (THF) as solvent appears to promote
the [1,3]-rearrangement, whereas the [3,3]-route can be favored by a solvent such
as hexane.[5]
In this article, we report our own work in this area. It is important at the outset
to note the differences between our substrates in this study, which lack any
additional substituent at the 4-position of the 3-amino-1,5-diene substrates
(Scheme 2, R1 ¼ H), and those of Dobson et al. that bear a thiophenol group in this
position (R1 ¼ SPh). Interestingly, it is known in anionic oxy-Cope rearrangement
chemistry that the presence of a sulfur-based substituent in this critical position
(i.e., a Dobson-type substrate) promotes the dissociative heterolytic cleavage path-
way as a result of the strong stabilizing effect of the divalent sulfur.[8]
Preparation of the 3-amino-1,5-diene substrates was accomplished through a
previously reported route.[3b] A series of imines derived from phenylalaninol and
unsaturated aldehydes were reacted with allyl magnesium bromide to yield the
desired amino-dienes 2a–f (Scheme 3). Rearrangement of substrates 2a–f was per-
formed on treatment with 2.5 eq. BuLi in the appropriate solvent system at
ꢀ78 ꢁC, followed by warming to ambient temperature before aqueous workup and
product isolation by column chromatography (Scheme 2). The ee and absolute
stereochemistry of the target aldehydes 3a–f (Table 1) were determined by conver-
sion to the corresponding diastereoisomeric oxazolidine derived from 1R,2S-
(–)-ephedrine, as described by Agami et al.[9]
As can be appreciated from Table 1, THF remains the solvent of choice, with
toluene and hexanes generally giving lesser yields and product ee values (in five out
of the six cases). In THF, the lowest ee is observed with substrate 2d, with arguably
the least sterically demanding substituent (a 3-carbon unit). As the chain length of
the substituent increases (i.e., in substrates 2e and 2f), the ee increases above that
of substrate 2d. The observation that the ee is slightly lower with the longer chain
substituent 2f (a 7-carbon unit) than with 2e, the 6-carbon unit, is perhaps due to
an increase in effective steric bulk of the 6-carbon alkyl substituent on removing
the conjugating (planar) alkene moiety present in 2f; thereby 2e may have slightly
Scheme 3. Preparation of 3-amino-1,5-diene substrates.

ASYMMETRIC AMINO-COPE REARRANGEMENT
2699
Table 1. Asymmetric anionic amino-Cope rearrangement of substrates 2a–f
THF
Yield (%)
Toluene
Yield (%)
Hexanes
Product
R
ee (%)
ee (%)
Yield (%)
ee (%)
3a
3b
3c
3d
3e
3f
Ph
-2-Furyl
-Ph-4-N(Me)2
=
-CH CHMe
-(CH2) 4Me
69
53
65
35
21
54
82 (R)
67 (R)
75 (R)
44 (R)
89 (R)
70 (R)
69
32
59
16
22
37
60
56
60
36
87
66
44
19
53
8
39
52
65
55
77
63
8
12
=
-CH CH(CH2)4Me
more degrees of freedom as a substituent, and its influence on the transition state of
the rearrangement may be more keenly felt. The cyclic aromatic substituents present
in substrates 2a–c give comparable levels of ee in THF, with furan being lowest of
all, perhaps because of its slightly smaller steric bulk. These arguments could be
applied to rationalize the observed ee values if one continued to apply the chairlike
conformational model, 4, noted previously, with the bulkier substituents expected to
occupy a pseudo-equatorial orientation. In all cases, the induced product stereo-
chemistry was as predicted by our usual model, 4.
Since the ee varied significantly in THF across the range of substrates, we
decided to investigate the addition of a cosolvent. In the Dobson study, the use
of a cosolvent such as N,N,N0,N0-tetramethylethylenediamine (TMEDA) or hexa-
methylphosphoramide (HMPA) gave an increase in the [3,3]- to [1,3]-product ratio
in toluene and hexanes, but with THF the use of a cosolvent actually favored the
[1,3]-process.[5] We chose to investigate the rearrangement of three of the substrates
noted earlier: our previously favored model 2a, the furan derivative 2b (because
this gave the lowest ee of the aryl substituents), and 2d (the substrate giving the
lowest ee of all, 8% ee, in hexanes). We chose to use 1,3-dimethyl-3,4,5,6-tetrahy-
dro-2-(1H)-pyrimidinone (DMPU) as a cosolvent (in varying amounts) in our
study, as a replacement for HMPA, and THF as the main solvent because hexanes
and toluene had given inferior yields in our initial screen of solvents. Our results
are presented in Table 2.
The addition of DMPU as a cosolvent reduced product yield in all cases, but
this was accompanied by significant increases in the ee of the product aldehydes.
The method of choice is to reduce the amount of cosolvent to just 2.5 equivalents
in THF solvent. Under these conditions, we observed an excellent increase in ee
from 35% in THF alone to 83% ee in THF-DMPU with substrate 2d. Although
the product yields have been sacrificed somewhat, we do observe an increase in
the product yield with all substrates as the amount of cosolvent is decreased to
2.5 equivalents in THF.

2700
S. M. ALLIN ET AL.
Table 2. Effect of DMPU as a cosolvent in the amino-Cope rearrangement in THF
10 eq. DMPU
5 eq. DMPU
Yield (%) ee (%)
2.5 eq. DMPU
Yield (%) ee (%)
Product
R
Yield (%)
ee (%)
3a
3b
3d
-Ph
-2-Furyl
=
-CH CHMe
6
84
75
72
29
32
10
86
82
81
50
41
18
89
82
83
11
8
As noted in Scheme 2, the possibility exists of competing rearrangement
mechanisms, leading to the formation of products 3a–f via alternative, non-[3,3]-
routes. We reasoned that the presence of a methyl group marker at position 4 of
the 3-amino-1,5-diene (Scheme 4) would allow us to detect the involvement of alter-
native reaction pathways during rearrangement in the now favored THF-DMPU
solvent system. Amino-diene 5 was prepared as previously described by us.[7] Clearly,
a concerted [3,3]-rearrangement of substrate 5 would lead to product 7, with the
methyl group marker ultimately located at the terminal alkene position. Formation
of isomeric product 6 would indicate the involvement of alternative mechanistic
pathways for rearrangement.
Previous work with the corresponding amino-diene derivative of valinol had
shown that rearrangement in THF alone proceeded to give a 1:1 mixture (57% yield)
of the available isomeric products, confirming that in THF alone the rearrangement
could not proceed solely by a [3,3]-mechanism.[7] However, on treating amino-diene
substrate 5 under typical rearrangement conditions in THF-DMPU, we observed a
yield of 49% for the reaction, with preferential formation of the [3,3]-product 7. The
observed ratio of 7:6, at >9:1, clearly demonstrates the enhanced control of the reac-
tion that is attainable in this mixed solvent system.
In summary, we have investigated a range of solvent systems for the asymmet-
ric amino-Cope rearrangement of some novel 3-amino-1,5-diene substrates and have
developed a new route for the asymmetric synthesis of 3-alkyl and 3-aryl aldehydes.
We have discovered that a solvent system of THF-DMPU (2.5 equivalents) produces
Scheme 4. Marker experiment with the THF-DMPU solvent system.

ASYMMETRIC AMINO-COPE REARRANGEMENT
2701
better and comparable levels of ee for the 3-aryl or 3-alkyl substituted aldehyde
products. The consistency of the product ee across the substrate types, the predictive
capacity of the conformational model used by us, and our results obtained when
using a methyl group marker support the premise that the rearrangement is proceed-
ing predominantly through a [3,3]-mechanism in the THF-DMPU cosolvent system
developed herein.
EXPERIMENTAL
General Experimental Details
˚
All solvents were dried, distilled, and stored over 4-A molecular sieves prior
to use. Analytical thin layer chromatography (TLC) was carried out using
aluminium-backed plates coated with 0.2 mm silica. Plates were visualized under
ultraviolet (UV) light (at 254 nm) or by staining with either potassium permanga-
nate solution or PMA (phosphomolybdic acid). Flash-column chromatography
was carried out using Merck Kieselgel (70–230 mesh ASTM). Samples were
applied as saturated solutions in an appropriate solvent or pre-adsorbed onto
the minimum quantity of silica. Hand bellows were used to apply pressure when
required at the column. Infrared (IR) spectra were recorded in the range from
4000 to 600 cmꢀ1. Solid samples were run as nujol mull, and liquids were run
as thin films. Nuclear magnetic resonance (NMR) spectra (1H and 13C) were
recorded using either Bruker AC-250 or DPX-400 instruments. Multiplicities were
recorded as broad peaks (br), singlets (s), doublets (d), triplets (t), and multiplets
(m). All NMR samples were made up in deuterated chloroform with all values
quoted in parts per million relative to tetramethylsilane (TMS) as internal refer-
ence, unless otherwise stated. Coupling constants (J values) are reported in hertz
(Hz). Diastereoisomer ratios were calculated from the integration of suitable
peaks in the proton NMR.
(S,2E)-2-((E)-3-Phenylallylideneamino)-3-phenylpropan-1-ol 1a
trans-Cinnamaldehyde (1.66 mL, 13.2 mmol) was added dropwise to a stirred
solution of (S)-2-amino-3-phenylpropan-1-ol (2.0 g, 13.2 mmol) in dicholoromethane
(DCM; 50 mL) at room temperature. The solution was stirred for 10 min, anhydrous
magnesium sulfate was added, and the reaction mixture was stirred for an additional
10 min. Filtration and removal of solvent under reduced pressure produced the tar-
get compound as a yellow solid (3.48 g, 99%), a sample of which was recrystallized
25
from DCM=hexanes to yield white crystals: mp 115–116 ꢁC; ½aꢂD ¼ ꢀ220 (c 1.0,
CHCl3); IR (nujol) 3220, 3026, 2921, 2856, 1635, 1450, 749 cmꢀ1; 1H NMR (CDCl3,
400 MHz) 2.78 (1H, dd, J 13.6, 8.8), 2.92 (1H, dd, J 13.6, 5.2), 3.40–3.44 (1H, m),
3.78 (1H, dd, J 11.2, 3.6), 3.85 (1H, dd, J 11.2, 7.6), 6.64 (1H, d, J 16.0), 6.77
(1H, dd, J 16.0, 8.8), 7.12–7.37 (10H, m), 7.63 (1H, d, J 8.8); 13C NMR (CDCl3,
100 MHz) 39.4, 66.2, 74.9, 126.6, 127.5, 127.6 (2), 128.8 (2), 129.1 (2), 129.5, 129.9
(2), 135.9, 138.9, 142.8, 164.4; HRMS (EI) 265 (Mþ, 7%), 174 (100%). Calcd for
C18H19NO: 265.1467; found: 265.1468.

2702
S. M. ALLIN ET AL.
(S,2E)-2-((E)-3-(Furan-2-yl)allylideneamino)-3-phenylpropan-1-ol 1b
3-(2-Furyl)acrolein (1.62 g, 13.2 mmol) was added to a stirred solution of (S)-2-
-amino-3-phenylpropan-1-ol (2.0 g, 13.2 mmol) in DCM (50 mL) at room tempera-
ture. The solution was stirred for 10 min, anhydrous magnesium sulfate was
added, and the reaction mixture was stirred for an additional 10 min. Filtration
and removal of solvent under reduced pressure produced the target compound as
a yellow solid (3.31 g, 98%), a sample of which was recrystallized from diethyl
25
ether=hexanes to yield yellow crystals: mp 75–78 ꢁC; ½aꢂD ¼ꢀ245.6 (c 1.4, CHCl3);
1
IR (nujol) 3227, 2855, 1628, 1016, 745, 701 cmꢀ1; H NMR (CDCl3, 400 MHz)
2.78 (1H, dd, J 13.4, 8.6), 2.92 (1H, dd, J 13.4, 8.4), 3.38–3.41 (1H, m), 3.76 (1H,
dd, J 11.3, 3.5), 3.83 (1H, dd, J 11.3, 7.5), 6.38–6.41 (2H, m), 6.50 (1H, d, J 15.9),
6.67 (1H, dd, J 15.9, 9.1), 7.11–7.26 (5H, m), 7.41 (1H, s), 7.58 (1H, d, J 9.1); 13C
NMR (CDCl3, 100 MHz) 38.9, 65.8, 74.3, 111.9 (2), 125.4, 126.1, 128.2 (2), 129.0,
129.6 (2), 138.5, 143.8, 151.7, 163.6; HRMS (EI) 255 (Mþ, 18%), 164 (100%). Calcd
for C16H17NO2: 255.1259; found: 255.1258.
(S,2E)-2-((E)-3-(4-(Dimethylamino)phenyl)allylideneamino)-
3-phenylpropan-1-ol 1c
4-Dimethylaminocinnamaldehyde (2.32 g, 13.2 mmol) was added to a stirred
solution of (S)-2-amino-3-phenylpropan-1-ol (2.0 g, 13.2 mmol) in DCM (50 mL)
at room temperature. The solution was stirred for 10 min, anhydrous magnesium sul-
fate was added, and the reaction mixture was stirred for an additional 10 min. Fil-
tration and removal of solvent under reduced pressure produced the target
compound as a yellow solid (3.96 g, 97%), a sample of which was recrystallized from
25
diethyl ether=hexanes to yield yellow crystals: mp 161–164 ꢁC; ½aꢂD ¼ꢀ217.0 (c 1.1,
CHCl3). C20H24N2O requires C, 77.89; H, 7.84; N, 9.08%; found: C, 77.61; H,
1
7.86; N, 9.07. IR (nujol) 3156, 2922, 2843, 1631, 1603, 1367, 981, 814 cmꢀ1; H
NMR (CDCl3, 400 MHz) 2.79 (1H, dd, J 13.4, 8.0), 2.92 (1H, dd, J 13.4, 5.6),
3.00 (6H, s), 3.37–3.42 (1H, m), 3.74–3.83 (2H, m), 6.63–6.70 (4H, m), 7.15–7.34
(7H, m), 7.68 (1H, d, J 7.6); 13C NMR (CDCl3, 100 MHz) 39.6, 40.7 (2), 66.4,
74.8, 112.3 (2), 123.0, 124.0, 126.5, 128.7 (2), 129.2 (2), 130.1 (2), 139.2, 143.6,
151.4, 165.2; HRMS (EI) 308 (Mþ, 42%), 217 (100%). Calcd. for C20H24N2O:
308.1889; found: 308.1893.
(S,2E)-2-((2E,4E)-Hexa-2,4-dienylideneamino)-
3-phenylpropan-1-ol 1d
trans,trans-2,4-Hexadienal (1.46 mL, 13.2 mmol, containing a trace of the
minor trans, cis isomer) was added dropwise to a stirred solution of (S)-2-amino-3-
phenylpropan-1-ol (2.0 g, 13.2 mmol) in DCM (50 mL) at room temperature. The
solution was stirred for 10 min, anhydrous magnesium sulfate was added, and the
reaction mixture was stirred for an additional 10 min. Filtration and removal of sol-
vent under reduced pressure produced the target compound as a yellow oil (2.86 g,
25
94%), which was used without further purification: ½aꢂD ¼ ꢀ146.8 (c 0.9, CHCl3);
IR (neat) 3244, 3025, 2914, 2856, 1628, 1453, 995, 737, 701 cmꢀ1; 1H NMR (CDCl3,

ASYMMETRIC AMINO-COPE REARRANGEMENT
2703
400 MHz) 1.81 (3H, d, J 8.0), 2.75 (1H, dd, J 13.5, 8.2), 2.89 (1H, dd, J 13.5, 5.4),
3.31–3.37 (1H, m), 3.69–3.78 (2H, m), 5.88–5.94 (1H, m), 6.10–6.20 (2H, m), 6.43
(1H, dd, J 10.7, 5.3), 7.11–7.27 (5H, m), 7.56 (1H, d, J 9.1); 13C NMR (CDCl3,
100 MHz) 18.5, 39.0, 65.9, 74.0, 126.1, 128.2 (2), 128.5, 129.6 (2), 130.8, 135.7,
138.5, 142.9, 164.3; HRMS (EI) 230 [(M þ 1)þ, 100%]. Calcd. for C15H20NO:
230.1545; found: 230.1540.
(S, 2E)-2-((E)-Oct-2-enylideneamino)-3-phenylpropan-1-ol 1e
trans-2-Octenal (1.97 mL, 13.2 mmol) was added dropwise to a stirred solution
of (S)-2-amino-3-phenylpropan-1-ol (2.0 g, 13.2 mmol) in DCM (50 mL) at room
temperature. The solution was stirred for 10 min, anhydrous magnesium sulfate
was added, and the reaction mixture was stirred for an additional 10 min. Filtration
and removal of solvent under reduced pressure produced the target compound as a
25
yellow oil (3.25 g, 95%), which was used without further purification: ½aꢂD ¼ꢀ102.5
(c 1.5, CHCl3); IR (neat) 3237, 2953, 2925, 2856, 1653, 1495, 1453, 1080, 1046,
747 cmꢀ1 1H NMR (CDCl3, 400 MHz) 0.88 (3H, t, J 7.2), 1.23–1.50 (6H, m),
;
2.03–2.14 (2H, m), 2.73 (1H, dd, J 13.5, 8.4), 2.89 (1H, dd, J 13.5, 5.3), 3.27–3.37
(1H, m), 3.71 (1H, dd, J 11.4, 3.6), 3.79 (1H, dd, J 11.4, 7.6), 5.97–6.04 (1H, m),
6.11 (1H, dd, J 15.6, 8.5), 7.10–7.28 (5H, m), 7.44–7.48 (1H, m); 13C NMR (CDCl3,
100 MHz) 14.0 (CH3), 22.4, 28.1, 31.3, 32.5, 39.0, 65.6, 74.1, 126.4, 128.2 (2), 129.7
(2), 129.8, 138.6, 146.8, 164.3; HRMS (EI) 259 (Mþ, 3%), 168 (100%). Calcd. for
C17H25NO: 259.1936; found: 259.1932.
(S,2E)-2-((2E,4E)-Deca-2,4-dienylideneamino)-3-
phenylpropan-1-ol 1f
trans,trans-2,4-Decadienal (2.30 mL, 13.2 mmol) was added dropwise to a stir-
red solution of (S)-2-amino-3-phenylpropan-1-ol (2.0 g, 13.2 mmol) in DCM (50 mL)
at room temperature. The solution was stirred for 10 min, anhydrous magnesium sul-
fate was added, and the reaction mixture was stirred for an additional 10 min. Fil-
tration and removal of solvent under reduced pressure produced the target
compound as a yellow oil (3.74 g, 99%), which was used without further purification:
25
½aꢂD ¼ꢀ101.6 (c 1.2, CHCl3); IR (neat) 3276, 2924, 2855, 1629, 1453, 1046, 995,
700 cmꢀ1 1H NMR (CDCl3, 400 MHz) 0.88 (3H, t, J 7.2), 1.25–1.41 (6H, m),
;
2.08–2.13 (2H, m), 2.73 (1H, dd, J 13.4, 8.3), 2.88 (1H, dd, J 13.4, 5.1), 3.29–3.36
(1H, m), 3.70–3.81 (2H, m), 5.82–5.90 (1H, m), 6.04–6.23 (2H, m), 6.37 (1H, dd, J
16.0, 8.0), 7.10–7.26 (5H, m), 7.49 (1H, d, J 9.1); 13C NMR (CDCl3, 100 MHz)
14.0, 22.4, 28.5, 31.3, 32.8, 38.9, 65.7, 74.3, 126.1, 128.2 (2), 128.4, 129.3, 129.5
(2), 138.5, 141.2, 143.1, 164.2; HRMS (EI) 286 [(M þ 1)þ, 100%]. Calcd. for
C19H28NO: 286.2171; found: 286.2170.
(S)-2-((S,E)-1-Phenylhexa-1,5-dien-3-ylamino)-3-
phenylpropan-1-ol 2a
(S,2E)-2-((E)-3-Phenylallylideneamino)-3-phenylpropan-1-ol (3.0 g, 11.3mmol)
was dissolved in a 4:1 mixture of dry toluene=diethyl ether (75 mL) under a nitrogen

2704
S. M. ALLIN ET AL.
atmosphere. Magnesium turnings (0.91 g, 37.3 mmol) and a catalytic amount of
iodine were added to the solution. Allyl bromide (3.16 mL, 37.3 mmol) was cau-
tiously added, and the mixture was stirred for 18 h. The reaction was quenched with
water until a gelatinous precipitate formed. The organic layer was decanted, and the
gelatinous residue was rinsed with diethyl ether (2 ꢃ 50 mL). The combined organic
layers were washed with a saturated solution of NaHCO3(2 ꢃ 75 mL), dried over
anhydrous sodium sulfate, and filtered. The solvent was removed under reduced
pressure, and a yellow solid was obtained, which was recrystallized from diethyl
ether=hexanes to yield the target compound 2a as white crystals (2.74 g, 79%): mp
25
73–74 ꢁC; ½aꢂD ꢀ43.3 (c 1.6, CHCl3); IR (nujol) 3320, 3024, 2924, 1494, 1453,
1030, 967, 748, 700 cmꢀ1 1H NMR (400 MHz, CDCl3) 2.22–2.25 (2H, m),
;
2.71–2.81 (2H, m), 2.99–3.04 (1H, m), 3.22–3.27 (1H, m), 3.34 (1H, dd, J 10.6,
3.5), 3.63 (1H, dd, J 10.6, 3.5), 5.04–5.10 (2H, m), 5.68 (1H, dd, J 15.9, 8.3),
5.73–5.81 (1H, m), 6.28 (1H, d, J 15.9), 7.13–7.33 (10H, m); 13C NMR (100 MHz,
CDCl3) 38.9, 40.9, 56.4, 57.7, 62.0, 117.5, 126.3 (2C), 126.4, 127.4, 128.49 (2C),
128.52 (2C), 129.2 (2C), 130.7, 132.0, 134.8, 136.7, 138.6; HRMS (EI) 308
([M þ 1]þ, 100%). Calcd. for C21H26NO: 308.2014; found: 308.2012.
(S)-2-((S,E)-1-(Furan-2-yl)hexA-1,5-dien-3-ylamino)-
3-phenylpropan-1-ol 2b
(S)-2(E)-2-((E)-3-(Furan-2-yl)allylideneamino)-3-phenylpropan-1-ol
(3.0 g,
11.8 mmol) was dissolved in a 4:1 mixture of dry toluene=diethyl ether (75 mL)
under a nitrogen atmosphere. Magnesium turnings (0.94 g, 38.8 mmol) and a cata-
lytic amount of iodine were added to the solution. Allyl bromide (3.28 mL,
38.8 mmol) was cautiously added, and the mixture was stirred for 18 h. The reac-
tion was quenched with water until a gelatinous precipitate formed. The organic
layer was decanted, and the gelatinous residue was rinsed with diethyl ether
(2 ꢃ 50 mL). The combined organic layers were washed twice with a saturated sol-
ution of NaHCO3 (2 ꢃ 75 mL), dried over anhydrous sodium sulfate, and filtered.
The solvent was removed under reduced pressure, and a brown solid was obtained,
which was recrystallized from diethyl ether=hexanes to yield the target compound
25
2b as yellow crystals (2.56 g, 78%); mp 88–90 ꢁC; ½aꢂD ꢀ103.2 (c 1.0, CHCl3); IR
(nujol) 3386, 2923, 1453, 736 cmꢀ1 1H NMR (400 MHz, CDCl3) 2.22 (2H, m),
;
2.70–2.81 (2H, m), 2.97–3.03 (1H, m), 3.20–3.25 (1H, m), 3.32 (1H, dd, J 10.7,
3.5), 3.60 (1H, dd, J 10.7, 3.8), 5.04–5.10 (2H, m), 5.69–5.81 (2H, m), 6.03 (1H,
d, J 16.1), 6.13 (1H, d, J 3.2), 6.36 (1H, d, J 3.2), 7.15–7.28 (5H, m), 7.33 (1H,
s); 13C NMR (100 MHz, CDCl3) 38.8, 40.9, 56.5, 57.4, 61.9, 107.5, 111.2, 117.6,
119.1, 126.4, 128.5 (2C), 129.2 (2C), 130.7, 134.8, 138.5, 141.7, 152.3; HRMS
(EI) 298 ([M þ 1]þ, 83%), 147 (100%). Calcd. for C19H24NO2: 298.1807; found
298.1818.
(S)-2-(S,E)-1-(4-(Dimethylamino)phenyl)hexa-1,5-dien-3-ylamino)-
3-phenylpropan-1-ol 2c
(S,2E)-2-((E)-3-(4-(Dimethylamino)phenyl)allylideneamino)-3-phenylpropan-
1-ol (3.0 g, 9.7 mmol) was dissolved in a 4:1 mixture of dry toluene=Et2O

ASYMMETRIC AMINO-COPE REARRANGEMENT
2705
(75 mL) under a nitrogen atmosphere. Magnesium turnings (0.78 g, 32.1 mmol)
and a catalytic amount of iodine were added to the solution. Allyl bromide
(2.72 mL, 32.1 mmol) was cautiously added, and the mixture was stirred for
18 h. The reaction was quenched with water, and a gelatinous precipitate
formed. The organic layer was decanted, and the gelatinous residue was rinsed
with diethyl ether (2 ꢃ 50 mL). The combined organic layers were washed with a
saturated solution of NaHCO3(2 ꢃ 75 mL), dried over anhydrous sodium sul-
fate, and filtered. The solvent was removed under reduced pressure, and a yel-
low solid was obtained, which was recrystallized from diethyl ether=hexanes to
yield the target compound 2c as orange crystals (3.04 g, 89%); mp 116–118 ꢁC;
25
½aꢂD –65.7 (c 1.0, CHCl3); IR (nujol) 2891, 1611, 1523, 1354, 965, 804, 700 cmꢀ1
;
1H NMR (400 MHz, CDCl3) 2.24–2.29 (2H, m), 2.79–2.81 (2H, m), 2.99 (6H,
s), 3.02–3.08 (1H, m), 3.24–3.26 (1H, m), 3.36 (1H, dd, J 10.4, 3.2), 3.66
(1H, dd, J 10.4, 4.0), 5.06–5.09 (2H, m), 5.53 (1H, dd, J 15.8, 8.4), 5.78–5.84
(1H, m), 6.23 (1H, d, J 15.8), 6.72 (2H, d, J 4.8), 7.18–7.31 (7H, m); 13C
NMR (100 MHz, CDCl3) 39.3, 41.0 (2C), 41.6, 56.7, 58.5, 62.3, 112.9 (2C),
117.7, 125.6, 126.8, 127.7 (2C), 128.1, 129.0 (2C), 129.8 (2C), 131.2, 135.7,
139.1, 150.5; HRMS (EI) 350 (Mþ, 1%), 309 (100%). Calcd. for C23H30N2O:
350.2358; found: 350.2365.
(S)-2-((S,5E,7E)-Nona-1,5,7-trien-4-ylamino)-3-phenylpropan-1-ol 2d
(S,2E)-2-((2E,4E)-Hexa-2,4-dienylideneamino)-3-phenylpropan-1-ol (2.50 g,
10.9 mmol) was dissolved in a 4:1 mixture of dry toluene=diethyl ether (75 mL)
under a nitrogen atmosphere. Magnesium turnings (0.87 g, 36.0 mmol) and a
catalytic amount of iodine were added to the solution. Allyl bromide
(3.04 mL, 36.0 mmol) was cautiously added, and the mixture was stirred for
18 h. The reaction was quenched with water until a gelatinous precipitate
formed. The organic layer was decanted, and the gelatinous residue was rinsed
with Et2O (2 ꢃ 50 mL). The combined organic layers were washed with a satu-
rated solution of NaHCO3 (2 ꢃ 75 mL), dried over anhydrous sodium sulfate,
and filtered. The solvent was removed under reduced pressure, and a yellow solid
was obtained, which was adsorbed onto silica and purified by flash-column chro-
matography (4:1, hexanes=EtOAc) to produce a yellow solid. Traces of a minor
isomer, resulting from the presence of traces of trans,cis-2,4-hexadienal in the
original commercial reagents, were partially removed by recrystallization from
hexanes, yielding the target compound 2d as white crystals (1.91 g, 65%); mp
25
74–75 ꢁC; ½aꢂD ꢀ35.8 (c 1.6, CHCl3). Calcd. for C18H25NO: C, 79.66; H, 9.28;
N, 5.16; found: C, 79.67; H, 9.29; N, 5.09. IR (nujol) 3403, 3023, 2927, 1639,
1
1495, 1453, 1265, 1030, 990, 739, 701 cmꢀ1; H NMR (400 MHz, CDCl3) 1.75
(3H, dd, J 6.7, 1.7), 2.13–2.17 (2H, m), 2.68–2.78 (2H, m), 2.93–2.98 (1H, m),
3.07–3.12 (1H, m), 3.28 (1H, dd, J 10.7, 3.5), 3.51 (1H, dd, J 10.7, 3.8),
5.02–5.09 (3H, m), 5.59–5.75 (2H, m), 5.84–5.98 (2H, m), 7.15–7.31 (5H, m);
13C NMR (100 MHz, CDCl3) 18.1, 38.8, 40.9, 56.3, 57.3, 61.7, 117.3, 126.4,
128.5 (2C), 129.1, 129.3 (2C), 130.8, 131.2, 132.8, 135.0, 138.5; HRMS (FAB)
272 ([M þ 1]þ, 37%), 92 (100%). Calcd. for C18H26NO: 272.2014; found:
272.2012.

2706
S. M. ALLIN ET AL.
(S)-2-((S,E)-Undeca-1,5-dien-4-ylamino)-3-phenylpropan-1-ol 2e
(S,2E)-2-((E)-Oct-2-enylideneamino)-3-phenylpropan-1-ol (3.0 g, 11.6 mmol)
was dissolved in a 4:1 mixture of dry toluene=Et2O (75 mL) under a nitrogen atmos-
phere. Magnesium turnings (0.93 g, 38.2 mmol) and a catalytic amount of iodine
were added to the solution. Allyl bromide (3.23 mL, 38.2 mmol) was cautiously
added, and the mixture was stirred for 18 h. The reaction was quenched with water
until a gelatinous precipitate formed. The organic layer was decanted, and the gelati-
nous residue was rinsed with diethyl ether (2 ꢃ 50 mL). The combined organic layers
were washed with a saturated solution of NaHCO3 (2 ꢃ 75 mL), dried over anhy-
drous sodium sulfate, and filtered. The solvent was removed under reduced pressure,
and a yellow oil was obtained, which was adsorbed onto silica and purified by
flash-column chromatography (9:1, hexanes=EtOAc). The target compound 2e was
isolated as yellow crystals (2.15 g, 62%), a portion of which was recrystallized from
25
diethyl ether=hexanes to yield pale yellow needles: mp 54–57 ꢁC; ½aꢂD ꢀ44.7 (c 1.6,
CHCl3). Calcd. for C20H31NO: C, 79.68; H, 10.36; N, 4.65; found: C, 79.58; H,
1
10.68; N, 4.67. IR (nujol) 3028, 2924, 1463, 1118, 967, 914, 701 cmꢀ1; H NMR
(400 MHz, CDCl3) 0.90 (3H, t, J 6.8), 1.24–1.34 (6H, m), 1.93–1.98 (2H, m),
2.04–2.17 (2H, m), 2.69–2.79 (2H, m), 2.94–2.98 (1H, m), 3.00–3.05 (1H, m), 3.28
(1H, dd, J 10.6, 3.6), 3.55 (1H, dd, J 10.6, 3.9), 4.93 (1H, dd, J 15.3, 8.4),
5.00–5.06 (2H, m), 5.31–5.38 (1H, m), 5.67–5.78 (1H, m), 7.15–7.30 (5H, m); 13C
NMR (100 MHz, CDCl3) 14.5, 22.9, 29.4, 31.8, 32.6, 39.7, 41.4, 56.6, 57.9, 62.1,
117.4, 126.8, 128.9 (2C), 129.7 (2C), 132.4, 132.7, 135.7, 139.0; HRMS (EI) 300
([M ꢀ 1]þ, 1%), 260 (100%). Calcd. for C20H30NO: 300.2327; found: 300.2323.
(S)-2-((S,5E,7E)-Trideca-1,5,7-trien-4-ylamino)-
3-phenylpropan-1-ol 2f
(S,2E)-2-((2E,4E)-Deca-2,4-dienylideneamino)-3-phenylpropan-1-ol
(3.5 g,
12.3 mmol) was dissolved in a 4:1 mixture of dry toluene=diethyl ether (100 mL)
under a nitrogen atmosphere. Magnesium turnings (0.98 g, 40.5 mmol) and a cata-
lytic amount of iodine were added to the solution. Allyl bromide (3.42 mL,
40.5 mmol) was cautiously added, and the mixture was stirred for 18 h. The reaction
was quenched with water until a gelatinous precipitate formed. The organic layer
was decanted, and the gelatinous residue was rinsed with diethyl ether (2 ꢃ 50 mL).
). The combined organic layers were washed with a saturated solution of NaH-
CO3(2 ꢃ 75 mL), dried over anhydrous sodium sulfate, and filtered. The solvent
was removed under reduced pressure, and a yellow solid was obtained, which was
adsorbed onto silica and purified by flash-column chromatography (4:1, hexanes=
EtOAc) followed by recrystallization from hexanes to yield the target compound
25
2f as white crystals (2.69 g, 67%): mp 62–63 ꢁC; ½aꢂD –32.1 (c 1.1, CHCl3). Calcd.
for C22H33NO: C, 80.68; H, 10.16; N, 4.28; found: C, 80.83; H, 9.98; N, 4.15. IR
1
(nujol) 3319, 2954, 2924, 1495, 1454, 989, 700 cmꢀ1; H NMR (400 MHz, CDCl3)
0.90 (3H, t, J 6.9), 1.24–1.43 (6H, m), 2.03–2.09 (2H, m), 2.12–2.17 (2H, m),
2.68–2.78 (2H, m), 2.93–2.98 (1H, m), 3.07–3.12 (1H, m), 3.28 (1H, dd, J 10.6,
3.5), 3.57 (1H, dd, J 10.6, 3.8), 5.02–5.11 (4H, m), 5.56–5.64 (1H, m), 5.67–5.78
(1H, m), 5.84–5.96 (2H, m), 7.15–7.31 (5H, m); 13C NMR (100 MHz, CDCl3,)

ASYMMETRIC AMINO-COPE REARRANGEMENT
2707
14.1, 22.5, 28.9, 31.4, 32.6, 38.9, 40.9, 56.3, 57.3, 61.8, 117.2, 126.4, 128.5 (2C),
129.28 (2C), 129.33, 131.3, 133.0, 134.8, 135.0, 138.6; HRMS (EI) 328 ([M þ 1]þ,
100%). Calcd. for C22H34NO: 328.2640; found: 328.2649.
(R)-3-Phenylhex-5-enal 3a
(S)-2-((S,E)-1-Phenylhexa-1,5-dien-3-ylamino)-3-phenylpropan-1-ol 2a (2.50 g,
8.1 mmol) was dried in vacuo for 1 h, dissolved in dry THF (40 mL) under a nitrogen
atmosphere, and cooled to ꢀ78 ꢁC. A 2.5 M solution of n-BuLi in hexanes (8.13 mL,
20.3 mmol) was added dropwise, and the mixture was stirred for 10 min before
warming to room temperature. The resultant solution was heated at reflux for 1 h,
quenched with water, dried over anhydrous sodium sulfate, and filtered through a
small pad of celite, eluting with DCM. The solvent was removed under reduced
pressure, and an orange oil was obtained, which was adsorbed onto silica and pur-
ified by flash-column chromatography (9:1, light petroleum=diethyl ether) to yield
25
the target compound 3a as a pale yellow oil (0.98 g, 69%): ½aꢂD ꢀ21.3 (c 1.7, CHCl3);
IR (neat) 3028, 2923, 1724, 1494, 1453, 915, 700 cmꢀ1; 1H NMR (400 MHz, CDCl3)
2.34–2.46 (2H, m), 2.68–2.81 (2H, m), 3.26–3.33 (1H, m), 4.93–5.04 (2H, m),
5.55–5.70 (1H, m), 7.18–7.32 (5H, m), 9.60 (1H, t, J 1.9); 13C NMR (100 MHz,
CDCl3) 40.13, 41.3, 49.7, 117.6, 126.7, 127.5 (2C), 128.5 (2C), 136.1, 143.8, 202.1;
HRMS (EI) 174 (Mþ, 8%), 105 (100%). Calcd for C12H14O: 174.1045; found:
174.1046.
Following rearrangements and isolation, the ee values of all aldehyde products
were immediately determined by conversion to the diastereoisomeric oxazolidine
derivative of 1R, 2S-(–)-ephedrine, as described by Agami et al.[9]
The same procedure was conducted separately in toluene, hexanes, and THF=
DMPU. In each case, the solvents were removed under reduced pressure, and the
crude orange oil was adsorbed onto silica and purified by flash-column chromato-
graphy (9:1, light petroleum=diethyl ether) to yield the target compound 3a as a
pale yellow oil. Spectroscopic data were identical to those previously obtained
for 3a.
(R)-3-(Furan-2-yl)hex-5-enal 3b
(S)-2-((S,E)-1-(Furan-2-yl)hexa-1,5-dien-3-ylamino)-3-phenylpropan-1-ol 2b
(1.0 g, 3.4 mmol) was dried in vacuo for 1 h, dissolved in dry THF (30 mL) under
a nitrogen atmosphere, and cooled to ꢀ78 ꢁC. A 2.5 M solution of n-BuLi in hexanes
(3.36 mL, 8.4 mmol) was added dropwise, and the mixture was stirred for 10 min
before warming to room temperature. The resultant solution was heated at reflux
for 1 h, quenched with water, dried over anhydrous sodium sulfate, and filtered
through a small pad of celite, eluting with DCM. The solvent was removed under
reduced pressure, and an orange oil was obtained, which was adsorbed onto silica
and purified by flash-column chromatography (9:1, light petroleum=diethyl ether)
25
to yield the target compound 3b as a pale yellow oil (0.29 g, 53%): ½aꢂD ꢀ13.6 (c
1.0, CHCl3); IR (neat) 2923, 1724, 1506, 1011, 920, 734 cmꢀ1
(400 MHz, CDCl3) 2.33–2.41 (1H, m), 2.46–2.54 (1H, m), 2.66–2.78 (2H, m),
;
1H NMR
3.39–3.46 (1H, m), 5.03–5.08 (2H, m), 5.64–5.75 (1H, m), 6.04 (1H, d, J 3.2), 6.28

2708
S. M. ALLIN ET AL.
(1H, dd, J 3.2, 1.8), 7.32 (1H, dd, J 1.8, 0.7), 9.73 (1H, t, J 1.9); 13C NMR (100 MHz,
CDCl3) 32.9, 38.0, 46.6, 105.4, 110.0, 117.5, 135.1, 141.3, 156.3, 201.3; HRMS (EI)
164 (Mþ, 11%), 95 (100%). Calcd. for C10H12O2: 164.0837; found: 164.0835.
The same procedure was conducted separately in toluene, hexane, and tetra-
hydrofuran=DMPU. In each case, the solvents were removed under reduced press-
ure, and the crude orange oil was adsorbed onto silica and purified by
flash-column chromatography (9:1, light petroleum=diethyl ether) to yield the target
compound 3b as a pale yellow oil. Spectroscopic data were identical to those pre-
viously obtained for 3b.
(R)-3-(4-(Dimethylamino)phenyl)hex-5-enal 3c
(S)-2-(S,E)-1-(4-(Dimethylamino)phenyl)hexa-1,5-dien-3-ylamino)-3-phenyl-
propan-1-ol 2c (1.0 g, 2.9 mmol) was dried in vacuo for 1 h, dissolved in dry THF
(20 mL) under a nitrogen atmosphere, and cooled to ꢀ78 ꢁC. A 2.5 M solution of
n-BuLi in hexanes (2.85 mL, 7.1 mmol) was added dropwise, and the mixture was
stirred for 10 min before warming to room temperature. The resultant solution
was heated at reflux for 1 h, quenched with water, dried over anhydrous sodium
sulfate, and filtered through a small pad of celite, eluting with DCM. The solvent
was removed under reduced pressure, and an orange oil was obtained, which was
adsorbed onto silica and purified by flash-column chromatography (9:1, light
petroleum=diethyl ether) to yield the target compound 3c as a pale yellow oil
25
(0.41 g, 65%): ½aꢂD ꢀ13.8 (c 1.4, CHCl3); IR (neat) 2921, 1721, 1614, 1518, 1444,
1348, 1164, 947, 816 cmꢀ1 1H NMR (400 MHz, CDCl3) 2.30–2.43 (2H, m),
;
2.62–2.75 (2H, m), 2.92 (6H, s), 3.16–3.24 (1H, m), 4.98–5.04 (2H, m), 5.63–5.73
(1H, m), 6.69 (2H, d, J 8.6), 7.06 (2H, d, J 8.6), 9.65 (1H, t, J 2.2); 13C NMR
(100 MHz, CDCl3) 38.9, 40.6 (2C), 41.2, 49.5, 112.8 (2C), 116.8, 128.0 (2C), 131.1,
136.2, 149.4, 202.5; HRMS (EI) 217 (Mþ, 23%), 176 (100%). Calcd. for
C14H19NO: 217.1467; found: 217.1467.
The same procedure was conducted separately in toluene and in hexane. In
each case, the solvent was removed under reduced pressure, and the crude orange
oil was adsorbed onto silica and purified by flash-column chromatography (9:1,
light petroleum=diethyl ether) to yield the target compound 3c as a pale yellow
oil. Spectroscopic data were identical to those previously obtained for 3c.
(R)-3-((E)-Prop-1-enyl)hex-5-enal 3d
(S)-2-((S,5E,7E)-Nona-1,5,7-trien-4-ylamino)-3-phenylpropan-1-ol 2d (1.5 g,
5.5 mmol) was dried in vacuo for 1 h, dissolved in dry THF (40 mL) under a nitrogen
atmosphere, and cooled to ꢀ78 ꢁC. A 2.5 M solution of n-BuLi in hexanes (5.53 mL,
13.8 mmol) was added dropwise, and the mixture was stirred for 10 min before
warming to room temperature. The resultant solution was heated at reflux for 1 h,
quenched with water, dried over anhydrous sodium sulfate, and filtered through a
small pad of celite, eluting with DCM. The solvent was removed under reduced
pressure, and an orange oil was obtained, which was adsorbed onto silica and pur-
ified by flash-column chromatography (9.5:1, light petroleum=diethyl ether) to yield
25
the target compound 3d as a pale yellow oil (0.27 g, 35%): ½aꢂD ꢀ15.7 (c 1.1, CHCl3);

ASYMMETRIC AMINO-COPE REARRANGEMENT
2709
1
IR (neat) 2916, 1724, 1686, 1439, 967 cmꢀ1; H NMR (400 MHz, CDCl3) 1.65 (3H,
d, J 4), 2.05–2.20 (2H, m), 2.28–2.38 (1H, m), 2.43–2.52 (1H, m), 2.64–2.73 (1H, m),
4.99–5.07 (2H, m), 5.28–5.35 (1H, m), 5.44–5.57 (1H, m), 5.68–5.79 (1H, m), 9.70
(1H, t, J 2); 13C NMR (100 MHz, CDCl3) 17.9, 36.9, 39.6, 48.0, 116.9, 126.0,
133.1, 135.9, 202.8.
Traces of a minor aldehyde isomer were present, resulting from the presence of
traces of substrate analogs produced from the minor amounts of trans, cis-2,4-hex-
adienal present in the original commercial reagents used in the preparation of the
parent amino-diene substrate 2d.
The same procedure was conducted separately in toluene, hexane, and tetra-
hydrofuran=DMPU. The solvents were removed under reduced pressure, and the
crude orange oil was adsorbed onto silica and purified by flash-column chromato-
graphy (9.5:1, light petroleum=diethyl ether) to yield the target compound 3d as a
pale yellow oil. Spectroscopic data were identical to those previously obtained for
3d. Because of problems of instability of the product aldehyde, we were unable to
obtain high-resolution mass spectral (HRMS) data.
(R)-3-Allyloctanal 3e
(S)-2-((S,E)-Undeca-1,5-dien-4-ylamino)-3-phenylpropan-1-ol 2e(1.5 g, 5.0 mmol)
was dried in vacuo for 1 h, dissolved in dry THF (40 mL) under a nitrogen atmos-
phere, and cooled to ꢀ78ꢁC. A 2.5 M solution of n-BuLi in hexanes (5.0 mL,
12.4 mmol) was added dropwise, and the mixture was stirred for 10 min before
warming to room temperature. The resultant solution was heated at reflux for
1 h, quenched with water, dried over anhydrous sodium sulfate, and filtered
through a small pad of celite, eluting with DCM. The solvent was removed under
reduced pressure, and a yellow oil was obtained, which was adsorbed onto silica
and purified by flash-column chromatography (9.5:1, light petroleum=diethyl ether)
25
to yield the target compound 3e as a pale yellow oil (0.17 g, 21%): ½aꢂD ꢀ10.7 (c
1.3, CHCl3); IR (neat) 2955, 2925, 2856, 1725, 913 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) 0.88 (3H, t, J 7.0), 1.27–1.32 (8H, m), 1.99–2.10 (2H, m), 2.13–2.19 (1H,
m), 2.36 (2H, m), 5.01–5.06 (2H, m), 5.70–5.77 (1H, m), 9.76 (1H, t, J 2.3); 13C
NMR (100 MHz, CDCl3) 14.1, 22.6, 26.4, 31.9, 32.8, 34.0, 38.5, 48.1, 117.1,
136.2, 203.1.
The same procedure was conducted separately in toluene and in hexane. In
each case, the solvent was removed under reduced pressure, and the crude yellow
oil was adsorbed onto silica and purified by flash-column chromatography (9.5:1,
light petroleum=diethyl ether) to yield the target compound 3e as a pale yellow
oil. Spectroscopic data were identical to those previously obtained for 3e. Because
problems of instability of the aldehyde, we were unable to obtain HRMS data.
(R,E)-3-Allyldec-4-enal 3f
(S)-2-((S,5E,7E)-Trideca-1,5,7-trien-4-ylamino)-3-phenylpropan-1-ol 2f (0.70 g,
2.1 mmol) was dried in vacuo for 1 h, dissolved in dry THF (30 mL) under a nitrogen
atmosphere, and cooled to ꢀ78ꢁC. A 2.5 M solution of n-BuLi in hexanes (2.14 mL,
5.3 mmol) was added dropwise, and the mixture was stirred for 10 min before

2710
S. M. ALLIN ET AL.
warming to room temperature. The resultant solution was heated at reflux for 1 h,
quenched with water, dried over anhydrous sodium sulfate, and filtered through a
small pad of celite, eluting with DCM. The solvent was removed under reduced
pressure, and a yellow oil was obtained, which was adsorbed onto silica and purified
by flash-column chromatography (9.5:1, light petroleum=diethyl ether) to yield the
25
target compound 3f as a pale yellow oil (0.23 g, 54%): ½aꢂD ꢀ20.8 (c 1.2, CHCl3);
IR (neat) 2955, 2925, 2855, 1726, 1440, 971, 914 cmꢀ1; 1H NMR (400 MHz, CDCl3)
0.88 (3H, t, J 7), 1.20–1.37 (6H, m), 1.95–2.00 (2H, m), 2.10–2.18 (2H, m), 2.35 (1H,
m), 2.46 (1H, m), 2.65–2.71 (1H, m), 5.01–5.05 (2H, m), 5.25–5.31 (1H, m), 5.42–5.49
(1H, m), 5.68–5.79 (1H, m), 9.70 (1H, t, J 3); 13C NMR (100 MHz, CDCl3) 14.1,
22.5, 29.1, 31.3, 32.4, 37.0, 39.7, 48.1, 116.9, 131.7, 131.8, 135.9, 202.7; HRMS
(EI) 194 (Mþ, 2%), 109 (100%). Calcd. for C13H22O: 194.1671; found: 194.1675.
The same procedure was conducted separately in toluene and in hexane. In
each case, the solvent was removed under reduced pressure, and the crude yellow
oil was adsorbed onto silica and purified by flash-column chromatography (9.5:1,
light petroleum=diethyl ether) to yield the target compound 3f as a pale yellow oil.
Spectroscopic data were identical to those previously obtained for 3f.
ACKNOWLEDGMENTS
We thank Syngenta (joint studentship support to C. H. P.), GlaxoSmithKline
(joint studentship to M. E.), and the University of Loughborough for facilities and
financial support.
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ASYMMETRIC AMINO-COPE REARRANGEMENT
2711
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