Stereoselective 1,4-addition of Grignard reagents to α,β-enamides using a combined chiral auxiliary-catalyst approach

Article abstract of DOI:10.1016/j.tetasy.2008.06.017

A catalyst composed of (R,R)-MeDuphos and CuBr·SMe₂ catalyzes the addition of RMgBr (R = Et, C₅H₁₁, Ph) to simple enamides (E)-Me₂NCOCH{double bond, long}CHR¹ (R¹ = Me, C₅H₁

Full text of DOI:10.1016/j.tetasy.2008.06.017

Tetrahedron: Asymmetry 19 (2008) 1702–1708
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Tetrahedron: Asymmetry
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Stereoselective 1,4-addition of Grignard reagents to
a combined chiral auxiliary-catalyst approach
a,b-enamides using
*
Kallolmay Biswas, Simon Woodward
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalyst composed of (R,R)-MeDuphos and CuBrꢀSMe2 catalyzes the addition of RMgBr (R = Et, C5H11
,
Ph) to simple enamides (E)-Me2NCOCH@CHR1 (R1 = Me, C5H11) in acceptable yields (50–78%), but with
poor to modest enantioselectivities (0–74% ee). By changing the enamide acceptor to the (E)-(Aux)N-
COCH@CHMe [Aux = from commercial pseudoephedrine, (R,R)-NMeCHMeCHPhOH] a stereochemically
enhanced regime could be attained. Structurally diverse RMgBr (R = C5H11, vinyl, allyl, Ph) underwent
1,4-additions in 57–89% de and 88–93% yield. In one case, the resulting enolate could be trapped with
allyl bromide.
Received 29 May 2008
Accepted 13 June 2008
Available online 14 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
latter is simply prepared from the commercially available acid.
Screening reactions were typically carried out using EtMgBr at
We recently described some preliminary studies concerning the
ꢁ50 °C in the presence of a 2–5 mol % catalyst attained by in situ
mixing of the copper source and LA. Out of a library of 10 CuX or
CuX2 species and five phosphine ligands, CuBrꢀSMe2 and (R,R)-
MeDuphos (LA, R = Me) proved optimal at ligand loadings of
5 mol %. Selected results using 2 are presented in Table 1. In all
cases, conversions were >80%. All enantiomeric excesses were
determined by chiral GC and have been assumed to give addition
to the Si (top) face of 1 and 2 (Scheme 1) by analogy with our pre-
vious stereochemical correlation.1
catalytic asymmetric 1,4-addition of Grignard reagents to
a,b-
unsaturated amides via the intermediacy of A.1 Although normally
disregarded in favor of more reactive Michael acceptors (e.g., enon-
es and
a
,b-unsaturated esters and thioesters)2 it was discovered
that the use of Duphos-based ligands LA afforded up to 57% ee
for the addition of EtMgBr. In order to define the scope of this reac-
tion, further experiments probing the generality of the reaction
have been carried out with the aim of attempting to identify reac-
tion conditions that favor highly selective 1,4-addition processes
for a range of Grignard reagents.
O
O
1.25 equiv. RMgX
-50 oC Et2O
NMe2
R2
NMe2
R1
XMg
O
CuI or CuII
R1
R2
R1
R
(R4)(R3)N
LA (R = Me)
R
P
P
R1
Me
(S)-4 C5H11
2-5 mol%
R1
R
R2
1
2
Me
R
LA
Cu
Et
Et
(R)-3
C5H11
LA DialkylDuphos
A
C5H11
Ph
(R)-5
( )-6
Me
Me
2. Results and discussion
Scheme 1. Asymmetric 1,4-additions of RMgX to 1–2.
2.1. CuI–DuPhos-catalyzed 1,4 RMgX additions
Polar solvents were of little use in attaining an enantioselective
reaction (Table 1, runs 1–2). In diethyl ether, CuBr.SMe2 consis-
tently provided the highest chemical yield as well as moderate ste-
reoselectivity (>5:1 er, run 4), while CuCN with the identical ligand
gave only low yields of racemic material (run 9). Other copper
sources offered behavior between these extremes. As we had noted
Further optimization studies on the addition of Grignard re-
agents were carried out using enamides 1 and 2 (Scheme 1). The
* Corresponding author. Fax: +44 115 951 3564.
E-mail address: simon.woodward@nottingham.ac.uk (S. Woodward).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.017

K. Biswas, S. Woodward / Tetrahedron: Asymmetry 19 (2008) 1702–1708
1703
Table 1
was unknown how changing from RLi to Grignard reagents would
affect the chemistry of Badía. It is known that the identity of metal
alkoxides in such auxiliaries can cause a dramatic change in such
delicate transition states. Thus, it could not be assured that the
use of Grignard reagents would be appropriate.
The required Michael acceptor 7 could easily be prepared from
crotylchloride and (R,R)-(ꢁ)-pseudoephedrine (Scheme 3). The
compound exists as a mixture of s-cis and s-trans rotamers in a
65:45 ratio at ambient temperatures. Coalescence in the 1H NMR
spectrum occurred at 70 °C (in C6D6), reaching a sharp high-tem-
perature limit at 90 °C. Using standard forms of the Eyring equa-
tion,4 it was estimated that the barrier to rotation was
17.2 kcal molꢁ1. Compound 7 was found to react with EtMgR in
the presence of (R,R)-MeDuphos and CuBrꢀSMe2 to give a mixture
of the two diastereoisomers 8a and 8b in good combined yield
(75%). Due to the poor solubility of 7 in Et2O, dichloromethane
alone was used for this initial study.
Optimization studies of EtMgBr to enamides 2a
Run
Solvent
Cu-source
Yield (%)
ee (%) (enantiomer)
1
2
3
4
5
6
7
8
9
THF
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
CuBrꢀSMe2
Cu(OTf)2
Cu(TC)
45
49
70
76
69
50
30
25
42
50
30 (S)
36 (S)
64 (S)
68 (S)
68 (S)
50 (S)
32 (S)
26 (S)
<5
CH2Cl2
ButOMe
Et2O
Et2O
Et2O
Et2O
CuBr
Et2O
CuCl
Et2O
CuCN
10
Et2O
CuBrꢀSMe2
38 (S)b
a
Ratio of enamide/EtMgBr/CuX/(R,R)-MeDuphos 1.25:0.05:0.05:1.0, unless
otherwise noted. All yields by isolation.
b
Using (R,R)-EtDuphos (LA, R = Et) 5 mol %.
before,1 the scope for modifying the nature of the Duphos ligand
was rather limited, as even (R,R)-EtDuphos resulted in a very sig-
nificant loss of stereoselectivity (run 10).
The optimized conditions (ꢁ50 °C, Et2O) were then applied to a
range of catalytic additions (Table 2). In all cases, good conversions
(88–98%) of the starting enamides 1 and 2 were attained. Unfortu-
nately, both the isolated yields and the induced stereochemistry
proved modest (4.6–6.7:1 er; runs 1–3). Furthermore, the system
could not be used for asymmetric addition of PhMgBr at all (run
4). While some of our results were encouraging, the system was
resistant to further optimization leading us to reconsider our
strategy.
O
3 EtMgBr
-30 oC
O
Ph
OH
Ph
OH
N
N
Me
Me
CuBr SMe2
(R,R)-LA
2 mol%
Et
7
major
(3R)-8a
+
O
O
Y
4 M NaOH
Ph
N
Table 2
Me
Catalytic asymmetric addition of RMgBr to enamides 1–2a
OH
Et
THF Δ
Et
Run
Enamide
Grignard
Yield (%)
ee (%) (enantiomer)
Y = OH
3 Y = NMe2
i, CO2Cl2
ii, HNMe2
minor
(3S)-8b
1
2
3
4
1
2
1
1
EtMgBr
EtMgBr
C5H11MgBr
PhMgBr
66
78
68
50
64 (R)
68 (S)
74 (R)
<5
Scheme 3. Diastereoselective 1,4-additions of EtMgBr.
a
Ratio of enamide/RMgBr/CuBrꢀSMe2/(R,R)-MeDuphos 3.0:0.05:0.05:1.0, unless
Comparative integration of two diastereomeric related 1H NMR
signals is normally an effective method for the determination of a
reaction’s de. Unfortunately both products 8a and 8b exist as ꢂ3:1
mixture of rotameric conformers that are appreciably exchange
broadened at room temperature. Extracting the relevant ‘de’ ratio
from the resultant morass of broadened signals is problematic.
The diastereoselectivity of 8 was easily measured by HPLC on a
Daicel-OD column (as suggested by Badía,3), giving a ratio of
77:23 for a run carried out in THF. To confirm the HPLC analysis
and to verify the proposed facial selectivity, the 8a–b mixture
was hydrolyzed and reconverted to 3 with oxalyl chloride and
methylamine. Chiral GC analysis revealed the presence of (R)-3
with an ee value equivalent to the original diastereoselectivity to-
ward 8a. These studies thus revealed that HPLC analysis was effec-
tive and unaffected by the rotamer population observed in the 1H
and 13C NMR spectra. Therefore, all subsequent de values were
determined by chiral HPLC. Additional screening reactions using
7 and EtMgBr revealed a significant solvent dependence (Table 3).
otherwise stated. All yields by isolation; ee by chiral GC.1
2.2. Auxiliary-supported 1,4 RMgX additions
As we had not been able to realize a synthetically useful regime
(>80% ee) for (R,R)-MeDuphos/CuI additions to simple
a,b-unsatu-
rated enamides, we decided to bolster the stereoselectivity of the
1,4-Grignard addition by the use of an appropriate chiral auxiliary.
While conceptually less elegant, such an approach is justifiable if:
(i) high levels of stereoinduction are achieved, and (ii) the resultant
chiral enolate can be trapped selectively allowing clean generation
of two contiguous stereogenic centers. The beautiful work of Badí-
a,3 who had described highly diastereoselective 1,4-additions of
RLi to (S,S)-(+)-pseudoephedrine-derived species (Scheme 2),
seemed to offer a strategy to support the stereoinduction of our
chiral catalyst.
O
O
R2Li
LiCl
Ph
OH
Ph
OH
N
N
Me
Me
THF
Table 3
R1
R1 R2
-105 oC
Solvent effects on the addition of EtMgBr to enamides 7a
80-97% de on workup
Run
Solvent
Yield (%)
de (%)
1
2
3
CH2Cl2
THF
4:1 Et2O/CH2Cl2
55
55
94
48
54
84
Scheme 2. Badía’s diastereoselective 1,4-additions of RLi.
In our case (S,S)-(+)-pseudoephedrine was not available, only its
(R,R)-enantiomer. It was initially unclear to us if the latter would
constitute a ‘matched’ or ‘miss-matched’ pairing in the presence
of the (R,R)-MeDuphos/CuI catalyst. Much more importantly, it
a
Ratio of enamide/EtMgBr/CuBrꢀSMe2/(R,R)-MeDuphos 3.0:0.05:0.05:1.0, unless
otherwise stated. All yields by isolation; de by HPLC on a Daicel-OD column;
selectivity favors 8a.

1704
K. Biswas, S. Woodward / Tetrahedron: Asymmetry 19 (2008) 1702–1708
The reaction of EtMgBr with 7, in 4:1 CH2Cl2:Et2O, in both the
presence and absence of a range of catalysts was then studied (Ta-
ble 4).
ilarity of compounds 9–12, separation of their stereoisomers by
chiral HPLC can be nontrivial in some cases. After an extensive
screen of conditions and columns, we could identify various assays
for direct HPLC measurement of 9–12 that correlated with GC mea-
surements on the derived dimethylamides. In some cases, how-
ever, the use of such conditions resulted in inversion of the
enantiomer elution order. Again, 1H NMR spectroscopy was not
useful as only the rotamers of compounds 9–12 were observed in
broadened partially overlapping spectra. The dispersion was better
in the 13C NMR spectra, but only rotameric signals of the major dia-
stereomer could be detected easily. Assignment of the minor dia-
stereomers was not attempted due to their very low signal
intensity. It is worth noting that the 13C NMR signals due to two
NR pseudoephedrine substituents in 9–12 are especially problem-
atic as they are appreciably broadened at ambient temperature
(NMe at ꢂ32 ppm and N-10CH at ꢂ58 ppm) due to amide rotation.
Good signal-to-noise spectra are required for confident assign-
ment. Finally, we note that even under copper catalysis, inade-
quate reactivity was observed for MeMgBr addition (<5% yield in
all substrates trialed). While the stereoselectivities given in Table
4 are in a modest range (57–89% de) an ability to add allyl Grig-
nard-noteworthy. Almost no processes for stereoselective 1,4-
additions of allyl organometallics are known. The only publication
we are aware of is the allyl additions of Pourcelot who used a re-
lated auxillary.7 However, no detailed experimental details appear
in his preliminary note and the auxiliary itself has to be prepared
rather than being commercially available.
Although many highly enantioselective catalytic procedures
have appeared in recent years,8 selective alkylation of the resulting
metal enolates remains the exception,9 rather than the norm. Typ-
ically, aluminum and zinc enolates are too unreactive to participate
in such procedures. Myers has described that lithium enolates con-
taining (S,S)-(+)-pseudoephedrine can be alkylated highly selec-
tively;10 an enhanced variant has been described by Tietze very
recently.11 Equivalent reactions using Mg-enolates resulting from
conjugate addition have not been described to the best of our
knowledge. We probed the reactivity of 8 with allylbromide as a
simple representative electrophile (Scheme 5).
Table 4
Catalyst effects on the addition of EtMgBr to enamides 7a
Run
Catalyst
Yield (%)
de (%)
b
b
1
2
3
4
5
6
7
None
CuBrꢀSMe2
—
—
—
—
b
b
P(OPh)3/CuBrꢀSMe2
(R,S,S)-Feringac/CuBrꢀSMe2
(S,S)-MeDuphos/CuBrꢀSMe2
(R,R)-EtDuphos/CuBrꢀSMe2
(R,R)-MeDuphos/CuBrꢀSMe2
20
88
78
75
94
20
84
83
82
84
a
Ratio of enamide/EtMgBr/CuBrꢀSMe2/(R,R)-MeDuphos 3.0:0.05:0.05:1.0, unless
otherwise stated. All reactions in 4:1 Et2O/CH2Cl2. All yields by isolation; de by
HPLC on a Daicel-OD column; selectivity favors 8a.
b
No reaction.
c
Feringa’s phosphoramidite [see Ref. 5 for ligand structure].
It was worthwhile determining if the observed facial selectivity
arose solely from the auxiliary or from a combination of auxiliary
and catalyst effects. From Table 4, it is clear that the (R,R)-(ꢁ)-
pseudoephedrine auxiliary dominates the stereocontrol. However,
the presence of a copper catalyst is vital if acceptable chemical
yields are to be attained. Species of the type CuI/‘L’ are particularly
effective in this role if the ligand ‘L’ shows a strong ligand acceler-
ation effect6 (runs 4–7). In the absence of such effects, either a poor
(run 3) or no yield (runs 1 and 2) was realized. Very little difference
was observed in the behavior of (R,R)- and (S,S)-MeDuphos (runs 5
and 7). As the former had very slightly superior characteristics, it
was used in all further studies. The generality of the reaction was
tested with a range of Grignard reagents (Scheme 4, Table 5).
Table 5
Effects on the addition of RMgBr to enamides 7a
Run
RMgX
Yield (%)
de (%)
1
2
3
4
C5H11
Ph
CH2CH@CH2
CH@CH2
93
88
92
88
74b
89c
76d
57d
BrMgO
3 EtMgBr
-30 oC
O
Ph
a
Ph
Ratio of enamide/RMgBr/CuBrꢀSMe2/(R,R)-MeDuphos 3.0:0.05:0.05:1.0, unless
N
N
Me
otherwise stated. All yields by isolation.
Me
4:1 Et2O:CH2Cl2
OMgBr
b
OH
De by HPLC analysis on a Daicel OJ-H column.
De by HPLC analysis on a Daicel OD column.
De by HPLC analysis on a Daicel AD-H column.
Et
c
7
CuBr SMe2
(R,R)-LA
2 mol%
d
allylbromide
The diastereomers of 9 and 11–12 could not be split on a Daicel-
OD column, only single peaks were observed. As a control, a sample
of 9 was converted to 5 to allow its independent assay by chiral GC.
This study revealed (R)-5 in 74% ee indicating that despite the sim-
O
Ph
N
Me
OH
Et
O
R
3 RMgBr
-30 oC
O
13
Ph
OH
Ph
N
N
Me
Scheme 5. Diastereoselective alkylation studies.
Me
4:1 Et2O:CH2Cl2
OH
Reaction of this representative Mg-enolate with allylbromide
resulted in formation of the expected product in good chemical
yield (88% for 13). The stereochemistry of 13 and 14 has been as-
signed on the basis of the models of Myers10 and Badía,3 where
the (R,R)-(ꢁ)-pseudoephedrine auxiliary is expected to engender
the formation of the (R)-stereochemistry at the C(2) alkylation site
(if priority Ralkylating < RMichaelSide Chain). Our alkylation is quite slow
and apparently some kinetic resolution of the stereoisomeric eno-
lates takes place resulting in an enrichment of the final product to
CuBr SMe2
(R,R)-LA
2 mol%
7
R
9
10
11
C5H11
Ph
CH2CH=CH2
12 CH=CH2
Scheme 4. Diastereoselective 1,4-additions of RMgBr.

K. Biswas, S. Woodward / Tetrahedron: Asymmetry 19 (2008) 1702–1708
1705
92% de. Attempts to further extend the reactivity of the Mg-enolate
with PhCHO were not successful. While the desired aldol products
were formed in good yield, the diastereoselectivity was very poor.
and N,N-dimethylamine (21.9 mL of 2.0 M THF solution,
43.8 mmol) in THF was added. Dry triethylamine (6.7 mL,
48.2 mmol) was added and stirring was continued at ambient tem-
perature (6 h). The solvent was removed under reduced pressure
and the residue was extracted with dichloromethane (100 mL).
The organic phase was washed with dilute hydrochloric acid
(2 M, 20 mL ꢃ 2), water (25 mL ꢃ 2), and brine (30 mL), and dried
over sodium sulfate. After removal of the solvent, the resulting
crude product was purified by flash chromatography (petrol/ethyl
acetate 7:1) to afford 2 as a colorless liquid (5.5 g, 89%). IR 3001,
3. Conclusion
In conclusion we have developed a methodology for a catalyst-
assisted 1,4-addition of a wide variety of Grignard reagents to a,b-
unsaturated amides. Those Michael acceptors bearing a (R,R)-(ꢁ)-
pseudoephedrine-derived auxiliary allow the attainment of higher
stereoselectivities than those attained with a chiral catalyst alone.
Unusually, allylMgBr can be used in a 1,4-stereoselective addition
(76% de). In one case, opportunities to intercept the intermediate
enolates with allylbromide exist.
2959, 2931, 2873, 1659, 1607, 1497, 1467, 1399, 1155 cmꢁ1 1H
;
NMR (400.1 MHz, CDCl3) d 0.89 (t, J = 7.3 Hz, CH3), 1.29–1.36 (m,
4H, CH2CH2), 1.42–1.50 (m, 2H, CH2), 2.20 (dq, J = 1.5, 7.2 Hz, 2H,
CH2CH), 3.00 (s, 3H, NCH3), 3.07 (s, 3H, NCH3), 6.24 (dt, J = 16.0,
1.5 Hz, 1H, COCH), 6.57 (dt, J = 16.0, 7.2 Hz, 1H, CHCH2); 13C NMR
(100.6 MHz) d 14.0, 22.6, 28.1, 31.4, 32.5, 35.6, 37.3, 120.1, 146.4,
167.0; HRMS (M++Na) requires m/z, 192.13589; found, 192.13630.
4. Experimental
4.1. General methods
4.4. General procedure for the 1,4-addition to a,b-enamides 1–2
Optical rotations were measured using a JASCO DIP370 digital
polarimeter and are quoted as 10ꢁ1 deg cm2 gꢁ1. Concentration
(c) is given in units of g/100 cm3 solvent. Proton and 13C NMR spec-
tra were recorded on a Bruker AV400 in CDCl3. Chemical shifts are
reported as d values in ppm relative to CHCl3 (7.27 ppm for 1H;
77.0 ppm for 13C) in CDCl3. IR spectra were measured on a Bruker
Tensor 27 FT-IR spectrometer. Mass spectra (MS) were recorded
at high resolution (HRMS) on a micromass LCT or VG micromass
70E mass spectrometers using electrospray ionization (ESI) or elec-
tron impact (EI). Chiral HPLC analysis was performed on a Hewlett
Packard 1100LC chromatograph using Daicel Chiracel (250 mm)
stationary phase columns. GC analyses were carried out on Varian
3380 instruments using the columns indicated. Preparative chro-
matography was performed with Fluorochem Davisil silica gel
In a typical procedure, solutions of the Cu-salt (2–5 mol %) and
chiral ligand (2–5 mol %) in 4 mL of freshly distilled Et2O were stir-
red at room temperature (20 min) and then cooled to ꢁ50 °C. A
solution of Grignard reagent (EtMgBr, pentyl MgBr or phenyl MgBr;
2–3 M in Et2O, 1.25 equiv) was added dropwise and the resulting
solution was stirred for a further 5 min before a solution of ena-
mide (1 mmol) in Et2O (2 mL) was added dropwise. The reaction
mixture was stirred at ꢁ50 °C for further 2 h, then quenched with
0.5 mL of 2 M HCl. Undecane (25 lL) was then added as an internal
standard, and the organic layer filtered through a plug of silica.
Yields and enantiomeric excesses were measured by GC.
4.5. (R)-N,N-Dimethyl-3-methyl-pentanamide 3
(35–70 lm) using mixtures of ethyl acetate and petrol (40–60 °C)
The compound was prepared using the procedure described in
Section 4.4 with CuBrꢀSMe2 (22.6 mg, 0.11 mmol), (R,R)-MeDuphos
(33.7 mg, 0.11 mmol), EtMgBr (0.96 mL, 3.0 M in Et2O, 2.86 mmol),
and a solution of 1 (250 mg, 2.20 mmol) in Et2O (2 mL). Usual work
as eluents. Diethyl ether (Et2O), and tetrahydrofuran (THF) were
freshly distilled from sodium/benzophenone under argon. Dichlo-
romethane (CH2Cl2) was freshly distilled from calcium hydride un-
der argon. Commercially available compounds were used without
further purification.
up afforded a colorless liquid 3 (260 mg, 82%, 64% ee). [
(c 1.5, CHCl3); IR 3003, 2964, 2932, 2876, 1630, 1498, 1461,
1400 cmꢁ1 1H NMR (400.1 MHz, CDCl3) d 0.91 (t, J = 7.2 Hz, 3H,
CH2CH3), 0.94 (d, J = 6.5 Hz, 3H, CHCH3), 1.18–1.25 (m, 1H,
CH2 CH3), 1.38–1.47 (m, 1H, CH2bCH3), 1.90–1.99 (m, 1H. CHCH3),
a]
D = ꢁ5.6
;
4.2. N,N-Dimethyl-trans-crotonamide 1
a
The compound was prepared by a literature procedure.12
A
2.13 (dd, J = 14.7 and 8.0 Hz, 1H, COCH2 ), 2.32 (dd, J = 14.7 and
a
6.5 Hz, 1H, COCH2b), 2.96 (s, 3H, NCH3), 3.02 (s, 3H, NCH3); 13C
NMR (100.6 MHz) d 11.5, 19.5, 29.7, 31.9, 35.4, 37.5, 40.3, 172.8.
HRMS (M++Na) requires m/z, 166.1208; found, 166.1192. The data
were concurrent with literature values.1 The ee value was deter-
mined by chiral GC using an octakis(2,6-di-O-methyl-3-O-pen-
solution of crotonyl chloride (5.00 g, 47.9 mmol) in 30 mL dry
Et2O was cooled to 0 °C in an ice-bath. Anhydrous dimethylamine
(48.0 mL of a 2.0 M THF solution, 95.8 mmol) was added for over
5 min and the reaction mixture was allowed to warm to room tem-
perature (12 h). The solvents were evaporated under reduced pres-
sure. Kugerohl distillation of the reaction mixture (110 °C,
9 mmHg) afforded 1 as the colorless liquid (4.90 g, 90%) with liter-
ature properties.13 IR 3001, 1661, 1610, 1493, 1445, 1399, 1278,
tyl)-c-cyclodextrin column, 0.25 lm i.d. (50% in OV1701, w/w)
using the programme: 80 °C (isothermal). Retention times: 1
16.1, R-3 22.6, S-3 23.8 min.
1241, 1156, 1100, 995 cmꢁ1 1H NMR (400.1 MHz, CDCl3) d 1.86
;
(dd, J = 6.9 and 1.6 Hz, 3H, CHCH3), 3.01 (br, s, 2 ꢃ NCH3), 6.26
(dq, J = 15.0, 1.7 Hz, 1H, COCH), 6.84 (dq, J = 15.0, 6.9 Hz, 1H,
CHCH3); 13C NMR (100.6 MHz) d 15.3, 35.4, 37.3, 121.7, 141.2,
166.9.
4.6. (S)-N,N-Dimethyl-3-ethyl-octanamide 4
The compound was prepared in an identical fashion to that
described in Section 4.4 using CuBrꢀSMe2 (15.2 mg, 0.074 mmol),
(R,R)-MeDuphos (22.7 mg, 0.074 mmol), EtMgBr (0.65 mL, 3.0 M
in Et2O, 1.95 mmol), and a solution of 2 (250 mg, 1.48 mmol) in
Et2O (2 mL). Usual work up afforded a colorless liquid 4 (252 mg,
4.3. N,N-Dimethyl-trans-oct-2-enmide 2
To a cold (0 °C) solution of octenoic acid (5.5 mL, 36.5 mmol) in
dichloromethane (30 mL) were added oxalyl chloride (9.5 mL,
85%, 68% ee). [
a]
D = +1.1 (c 1.1, CHCl3); IR 3003, 2961, 2930,
2858, 1630, 1497, 1461, 1399, 1380 cmꢁ1
;
1H NMR (400.1 MHz,
109.5) and dry DMF (100 lL). The solution was then stirred at
CDCl3) d 0.86 (t, J = 7.2 Hz, 3H, CH2CH3) overlapped by 0.87 (t,
J = 7.2 Hz, 3H, CH2CH3), 1.27–1.36 (m, 10H, 5 ꢃ CH2), 1.85–1.89
(m, 1H, CHCH2), 2.22 (app. d, J = 8 Hz, 2H, CH2CO), 2.94 (s, 3H,
NCH3), 3.01 (s, 3H, NCH3); 13C NMR (100.6 MHz) d 10.8, 14.1,
room temperature (1 h) and concentrated under reduced pressure
to remove residual oxalyl chloride. The resulting pale yellow resi-
due was re-dissolved in dichloromethane (20 mL), cooled (0 °C)

1706
K. Biswas, S. Woodward / Tetrahedron: Asymmetry 19 (2008) 1702–1708
22.7, 23.9, 26.5, 32.2, 33.4, 35.4, 36.2, 37.5, 37.7, 177.0; HRMS
(M+H+) requires m/z, 200.2014; found, 200.1996. The ee value
was determined by chiral GC using an octakis(2,6-di-O-methyl-3-
(d, J = 6.9 Hz, 3H, 3-CHCH3), 2.89 (s, 3H, NCH3), 2.95* (s, 3H,
NCH3), 4.49–4.51* (m, 2H, 10,20-CH), 4.51–4.53 (m, 2H, 10,20-CH),
6.21 (d, J = 15.0 Hz, 1H, 2-CH), 6.37* (d, J = 15.0 Hz, 1H, 2-CH),
6.82* (dq, J = 15.0, 7.2 Hz, 1H, 3-CH), 6.95 (dq, 1H, J = 15.0, 7.2 Hz,
1H, 3-CH), 7.31–7.44 (m, 5H, Ph both rotamers); 13C NMR
(100.6 MHz) d 14.5, 15.5*, 18.3 (both rotamers), 27.2*, 32.7, 58.6*,
58.7, 75.5, 76.5*, 122.4, 122.7*, 126.2*, 226.5, 127.0*, 127.7, 128.4,
128.6, 140.8, 141.2, 142.5*, 142.6, 168.5*, 169.1 (CO both rota-
mers); HRMS (M++Na) requires m/z, 256.1313; found, 256.1261.
O-pentyl)-c-cyclodextrin column, 0.25 lm i.d. (50% in OV1701,
w/w) using the programme: 110 °C (isothermal). Retention times:
2 48.4, R-4 38.6, S-4 41.6 min. The structural assignments are by
analogy with 3.
4.7. (S)-N,N-Dimethyl-3-methyl-octanamide 5
The compound was prepared using the procedure described in
Section 4.4 with CuBrꢀSMe2 (15.2 mg, 0.074 mmol), (R,R)-MeDu-
phos (22.7 mg, 0.074 mmol), MeMgBr (0.65 mL, 3.0 M in Et2O,
1.95 mmol), and a solution of 2 (250 mg, 1.48 mmol) in Et2O
(2 mL). Usual work up afforded a colorless liquid 5 (240 mg, 87%,
4.10. (3R)- and (3S)-(10R,20R)-N-methyl-N-(20-phenyl-20-
hydroxy-10-methyethyl)-3-methylpentanamide 8a and 8b
Solid CuBrꢀSMe2 (10.2 mg, 0.05 mmol) and (R,R)-MeDuphos
(15.2 mg, 0.05 mmol) were dissolved in 3 mL of freshly distilled
Et2O. The solution was stirred at room temperature for 20 min
and then cooled to ꢁ30 °C. A solution of EtMgBr (1.0 mL, 3.0 M in
Et2O, 3.0 mmol) was added dropwise, and the resulting solution
was stirred for further 5 min before a solution of 7 (233.3 mg,
1.00 mmol) in Et2O:CH2Cl2 (1:1; 2 mL) was added dropwise. The
reaction mixture was kept under stirring at that temperature for
further 6 h. The reaction mixture was then quenched with 5 mL
of 2 M HCl and extracted with ethyl acetate. Usual workup and
purification by column chromatography (petrol/ethyl acetate 3:1)
gave a 92:8 mixture of diastereomers 8a–b as a colorless oil
74% ee). [
a
]
D = +1.0 (c 1.1, CHCl3); IR 2995, 2951, 2887, 2841,
1628, 1497, 1461, 1399, 1380 cmꢁ1
;
1H NMR (400.1 MHz, CDCl3)
d 0.88 (t, J = 6.8 Hz, 3H, CH2CH3), 0.93 (d, J = 6.6 Hz, 3H, CHCH3),
1.16–1.34 (m, 8H, 4 ꢃ CH2), 1.99–2.04 (m, 1H, CHCH2), 2.12 (dd,
J = 14.6, 7.6 Hz, 1H, COCH2 ), 2.30 (dd, J = 14.6, 5.6 Hz, 1H, COCH2b),
a
2.95 (s, 3H, NCH3), 3.01 (s, 3H, NCH3); 13C NMR (100.6 MHz) d 14.1,
19.9, 22.7, 26.7, 30.3, 32.0, 35.4, 37.1, 37.5, 40.7, 172.8; HRMS
(M+H+) requires m/z, 186.1858; found, 186.1846. The ee value
was determined by chiral GC using an octakis(2,6-di-O-methyl-3-
O-pentyl)-c-cyclodextrin column, 0.25 lm i.d. (50% in OV1701,
w/w) using the programme: 110 °C (isothermal). Retention times:
1 10.9, R-5 31.7, S-5 34.6 min. The structural assignments are by
analogy with 3.
(250 mg, 95%, 84% de). [
a
]
D = ꢁ101 (c 1.26, CHCl3) for 84% de mate-
rial. IR 3609, 3065, 3010, 2965, 2877, 1618, 1488, 1406, 1380,
1242, 1047, 1021 cmꢁ1; both diastereomers exist as a 3.7:1 mix-
tures of rotamers (ꢄ indicates minor rotamer resonances), due to
its low population full assignment of 8b could not be attained.
For 8a: 1H NMR (400.1 MHz, CDCl3) d 0.91 (t, J = 7.2 Hz, 3H,
CH2CH3), 0.93* (t, J = 7.2 Hz, 3H, CH2CH3), overlapped by 0.94 (d,
J = 6.9 Hz, 3H, 10-CHCH3), 0.95* (d, J = 6.9 Hz, 3H, 10-CHCH3), 1.01*
(d, J = 6.9 Hz, 3H, 3-CHCH3), 1.15 (d, J = 6.9 Hz, 3H, 3-CHCH3), over-
lapped by 1.01-1.28 (m, 3H, CH2CH3 and 3-CH both rotamers),
1.34-1.45 (m, 3H, CH2CH3 and 3-CH both rotamers), 1.72 (s, br,
4.8. (S)-N,N-Dimethyl-3-phenyl-butanamide 6
The compound was prepared using the procedure described in
Section 4.4 with CuBrꢀSMe2 (22.6 mg, 0.11 mmol), (R,R)-MeDuphos
(33.7 mg, 0.11 mmol), PhMgBr (0.95 mL, 3.0 M in Et2O, 2.85 mmol),
and a solution of 1 (250 mg, 2.21 mmol) in Et2O (2 mL). Usual work
up afforded a colorless liquid 6 (230 mg, 54%, of near racemic
material). IR 3085, 3009, 2935, 1633, 1494, 1453, 1401,
1H, OH both rotamers), 2.13 (dd, J = 15.0, 7.7 Hz, 1H, COCH2 ),
a
1241 cmꢁ1
;
1H NMR (400.1 MHz, CDCl3) d 1.36 (d, J = 7.1 Hz, 3H,
2.28 (dd, J = 15.0, 6.5 Hz, 1H, COCH2b), 2.29* (dd, J = 14.9, 6.5 Hz,
CHCH3), 2.54 (dd, J = 7.9, 15.1 Hz, 1H, CH2 CH), 2.64 (dd, J = 6.0,
1H, COCH2 ), 2.42 (dd, J = 14.9, 5.9 Hz, 1H, COCH2b), 2.84 (s, 3H,
a
a
15.1 Hz, 1H, CH2bCH), 2.89 (s, 3H, NCH3), 2.93 (s, 3H, NCH3), 3.39
(ddq, J = 6.0, 7.9, 7.1 Hz, 1H, CHCH3), 7.25–7.34 (m, 5H, Ph); 13C
NMR (100.6 MHz) d 21.6, 35.4, 36.5, 37.3, 41.9, 126.3, 126.9,
128.5, 146.6, 171.8; HRMS (M++Na) requires m/z, 214.1208; found,
214.1195. These data were concurrent with published values.13
NCH3), 2.94* (s, 3H, NCH3), 4.44–4.64 (m, 1H, CHOH both rotom-
ers), 7.26–7.45 (m, 5H, Ph both rotamers); 13C NMR (100.6 MHz)
d 11.4, 11.5*, 14.5, 15.4*, 19.4, 19.6*, 29.5, 29.6*, 31.8, 31.9*, 32.0
(br, NMe), 41.3, 40.7*, 58.5 (br 10-CH both rotamers), 75.6*, 76.7,
126.3, 126.3*, 126.9*, 127.6, 128.4, 128.8*, 141.2*, 142.6, 173.9*,
175.3. For 8b: 1H NMR (400.1 MHz, CDCl3) d 0.86 (t, J = 7.0 Hz,
3H, CH2CH3), 0.87* (t, J = 7.0 Hz, 3H, CH2CH3), 2.90 (s, 3H, NCH3),
4.05-4.08 (m, 1H, 10-CH), 4.17–4.20* (m, 1H, 20-CH0), other signal
were overlapped by 8a signals and could not be asigned; HRMS
(M++Na) requires m/z, 286.1783; found, 286.1725. The diastereose-
lectivity was determined by HPLC on a Daicel-OD column. 98:2
Hexane/PriOH, 0.8 ml/min; t(3R,10R,20R) = 62.6 min for 8a,
t(3S,10R,20R) = 72.9 min for 8b.
Analysis on an octakis(2,6-di-O-methyl-3-O-pentyl)-
c-cyclodex-
trin column, 0.25 m i.d. (50% in OV1701, w/w) using the pro-
l
gramme: 110 °C (isothermal) showed the presence of the
racemate: 1 10.9, enantiomer1 45.2, enantiomer2 46.0 min.
4.9. (E)-(ꢁ)-(10R,20R)-N-Methyl-N-(20-phenyl-20-hydroxy-10-
methyethyl)-but-2-enemide 7
Crotonyl chloride (6.10 mL, 58.85 mmol) in THF (25 mL) was
slowly added to a solution of (R,R)-(ꢁ)-pseudoephedrine (10.00 g,
58.85 mmol) and Et3N (9.95 mL, 71.5 mmol) in dry THF (150 mL)
at ꢁ20 °C. The reaction mixture was stirred at this temperature
for 90 min, after which it was quenched with a saturated NaHCO3
solution (100 mL). The mixture was extracted with AcOEt
(3 ꢃ 100 mL) and the combined organic fractions were dried over
Na2SO4, filtered, and the solvent was removed under reduced pres-
sure affording 7 as a colorless crystalline solid (13.5 g, 92%), mp
4.11. (ꢁ)-(3R,10R, 20R)-N-Methyl-N-(20-phenyl-20-hydroxy-10-
methyethyl)-3-methyloctanamide 9
Compound 9 was obtained according to the procedure de-
scribed in Section 4.10 from 7 (233.3 mg, 1.00 mmol) using
CuBrꢀSMe2 (10.2 mg, 0.05 mmol), (R,R)-MeDuphos (15.2 mg,
0.05 mmol), freshly distilled Et2O (4 mL) and CH2Cl2 (1 mL), and
C5H11MgBr (1.5 mL, 2.0 M in Et2O, 3.0 mmol) as a colorless oil
100 °C. [
1481, 1452, 1406, 1302, 1240, 1101, 1046, 965 cmꢁ1
(400.1 MHz, CDCl3) (3:1 rotamer ratio; ꢄ indicates minor rotamer
resonances)
1.00* (d, J = 6.9 Hz, 3H, 10-CHCH3), 1.16 (d,
J = 7.0 Hz, 3H, 10-CHCH3), 1.90 (d, J = 6.9 Hz, 3H, 3-CHCH3), 1.98*
a
]
D = ꢁ162 (c 1.0 CHCl3); IR 3610, 3008, 1658, 1599,
(283 mg, 93%, 76% de). [
a
]
D = ꢁ88 (c 1.13, CHCl3). IR 3608, 3006,
;
1H NMR
2959, 2873, 2858, 1617, 1456, 1406, 1379, 1244, 1140, 1047,
1021 cmꢁ1
;
1H NMR (400.1 MHz, CDCl3) (3.4:1 rotamer ratio; ꢄ
d
indicates minor rotamer resonances; minor diastereomer not
assigned) d 0.90 (t, J = 7.0 Hz, 3H, CH2CH3 both rotamers), 0.94 (d,

K. Biswas, S. Woodward / Tetrahedron: Asymmetry 19 (2008) 1702–1708
1707
J = 6.8 Hz, 3H, 10-CHCH3), 0.95* (d, J = 6.7 Hz, 3H, 10-CHCH3), 1.00*
(d, J = 6.9 Hz, 3H, 3-CHCH3), 1.14 (d, J = 6.8 Hz, 3H, 3-CHCH3),
1.23–1.44 (m, 8H, (CH2)4 both rotamers), 1.92–2.05 (m, 1H, 3-
(m, 1H, 10-CH), 4.38–4.52 (m, 1H, 10-CH and 20-CH minor rotamer),
4.55–4.58 (m, 1H, 20-CH), 5.00–5.08 (m, 2H, @CH2 both rotamers),
5.75–5.84 (m, 1H, @CH both rotamers), 7.26–7.42 (m, 5H, Ph both
13
CHCH3 both rotamers), 2.13 (dd, J = 14.6, 7.1 Hz, 1H, COCH2 ),
rotamers); C NMR (100.6 MHz) d 14.5, 15.4*, 19.8, 20.0*, 29.9,
a
2.27 (dd, J = 14.6, 6.1 Hz, 1H, COCH2b) overlapped by 2.21–2.23*
30.1*, 33.2 (both rotamers NMe), 40.2*, 40.6, 41.1, 41.3*, 58.4*,
58.8, 75.5*, 76.6, 116.2*, 116.4, 126.4, 126.9, 127.6*, 128.4, 128.4*,
128.7*, 136.7, 137.1*, 141.2*, 142.5, 173.6*, 174.9; HRMS (M++Na):
m/z, 298.17775; found, 298.1497. The diastereoselectivity was
determined by HPLC on a Daicel AD-H column. 98:2 Hexane/PriOH,
1 ml/min; t(3R,10R,20R) = 43.0 min for 11a, t(3S,10R,20R) = 47.1 min
for 11b.
(m, 1H, COCH2 ), 2.39* (dd, J = 14.9, 6.1, 1H, COCH2b), 2.85 (s, 3H,
a
NCH3), 2.95* (s, 3H, NCH3), 4.03–4.07* (m, 1H, 10-CH), 4.44–4.47
(br, m, 1H, 20-CH) overlapped by 4.44–4.47* (br, m, 1H, 20-CH),
4.58–4.62 (m, 1H, 20-CH), 7.31–7.44 (m, 5H, Ph both rotamers);
13C NMR (100.6 MHz) d 14.1 (both rotamers), 14.5, 15.4*, 19.9,
20.1*, 22.7 (both rotamers), 26.7, 26.8*, 30.2, 30.4*, 32.0 (both rota-
mers), 33.5 (br, NMe both rotamers), 37.0, 37.1*, 41.1*, 59.0 (br, 10-
CH both rotamers), 75.6*, 76.6, 126.3 (Ph-m major and Ph-p minor
rotamers), 126.9*, 127.6, 128.3, 128.7*, 141.2*, 142.6, 173.9*, 175.3;
HRMS (M++Na): m/z, 328.2247; found, 328.2254. The diastereose-
lectivity was determined by HPLC on a Daicel OJ-H column. 98:2
4.14. (3R,10R,20R)-N-Methyl-N-(20-phenyl-20-hydroxy-10-
methyethyl)-3-methylpent-4-enamide 12
Compound 12 was obtained according to the procedure de-
scribed in Section 4.10 from 7 (233.3 mg, 1.00 mmol) using
CuBrꢀSMe2 (10.2 mg, 0.05 mmol), (R,R)-MeDuphos (15.2 mg,
0.05 mmol), freshly distilled Et2O (4 mL), CH2Cl2 (1 mL), and vinyl-
magnesiumbromide (3.0 mL, 1.0 M in THF, 3.0 mmol) as a colorless
Hexane/PriOH,
t(3S,10R,20R) = 24.6 min for 9b.
1 ml/min;
t(3R,10R,20R) = 21.8 min
for
9a,
4.12. (ꢁ)-(10R,20R)-N-Methyl-N-(20-phenyl-20-hydroxy-10-
methyethyl)-3-phenylbutanamide 10
oil (235 mg, 90%, 57% de). [
a]
D = ꢁ93 (c 1.05, CHCl3). IR 3691, 3010,
1621, 1483, 1407, 1375, 1240, 1047, 1020, 920 cmꢁ1
;
1H NMR
Compound 10 was obtained according to the procedure de-
scribed in Section 4.10 from
0.05 mmol), (R,R)-MeDuphos (15.2 mg, 0.05 mmol), freshly dis-
(400.1 MHz, CDCl3) (3.09:1 rotamer ratio; ꢄ indicates minor rot-
amer resonances; minor diastereomer not assigned) d 1.00* (d,
J = 6.9 Hz, 3H, 10-CHCH3), 1.07 (d, J = 6.9 Hz, 3H, 10-CHCH3) over-
lapped by 1.08* (d, J = 6.9 Hz, 3H, 30-CHCH3) 1.11 (d, J = 6.9 Hz, 3H,
3-CHCH3), 2.24–2.45 (m, 2H, COCH2 both rotamers), 2.71–2.77 (m,
1H, 3-CHCH3 both rotamers), 2.84 (s, 3H, NCH3), 2.93* (s, 3H,
NCH3), 4.00–4.07* (m, 1H, 10-CH), 4.29 (br, 1H, 10-CH), 4.45–4.53
(m, 1H, 20-CH), 4.55–4.64 (m, 1 H, 20-CH both rotamers), 4.93–
5.08 (m, 2H, @CH2 both rotamers), 5.77–5.89 (m, 1H, @CH both
rotamers), 7.26–7.41 (m, 5H, Ph); 13C NMR (100.6 MHz) d 14.6,
15.4*, 19.6*, 19.8, 33.0 br (both rotamers NMe), 34.2, 34.3*, 40.3*,
40.9, 58.3 br (both rotamers 1-CH), 75.5*, 76.5, 112.9*, 113.0,
126.4, 126.9*, 127.7, 128.4 (Ph-o major and Ph-p minor rotamers),
128.7*, 141.2*, 142.4, 143.1, 143.6*, 172.9*, 174.3; HRMS (M++Na):
m/z, 284.16210; found, 284.1336. The diastereoselectivity was
determined by HPLC on a Daicel AD-H column. 98:2 Hexane/PriOH,
1 ml/min; t(3R,10R,20R) = 42.0 min for 12a, t(3S,10R,20R) = 45.1 min
for 12b.
7
using CuBrꢀSMe2 (10.2 mg,
tilled Et2O (4 mL), CH2Cl2 (1 mL), and PhMgBr (1.0 mL, 3.0 M in
Et2O, 3 mmol) as a colorless oil (275 mg, 88%, 89% de). [
a
]
D = ꢁ77
(c 1.25, CHCl3). IR 3610, 3009, 2936, 2877, 1622, 1493, 1454,
1406, 1378, 1313, 1239, 1134, 1019; 1H NMR (400.1 MHz, CDCl3)
(2.77:1 rotamer ratio; ꢄ indicates minor rotamer resonances; min-
or diastereomer not assigned) d 0.89* (d, J = 6.8 Hz, 3H, 10-CHCH3),
1.02 (d, J = 6.8 Hz, 3H, 10-CHCH3), 1.34 (d, J = 7.0 Hz, 3H, both rota-
mers 3-CHCH3), 2.54 (dd, J = 15.4, 7.6 Hz, 1H, COCH2 ), 2.62 (dd,
a
J = 15.4, 7.1 Hz, 1H, COCH2b) overlapped by COCH2 of minor rot-
amer, 2.74 (s, NCH3), 2.91* (s, NCH3), 3.36 (ddq, J = 7.6, 7.1,
6.8 Hz, 1H, PhCH), 3.49–3.51* (m, 1H, PhCH), 4.35–4.49 (br m, 1H,
10 and 20-CH both rotamers), 4.50–4.60 (br m, 1H, 10 and 20-CH both
rotamers), 7.18–7.46 (m, 10H, Ph both rotamers), OH not detected
due to exchange with water at 1.56 ppm; 13C NMR (100.6 MHz) d
14.5, 15.4*, 21.8, 21.9*, 32.8 br (both rotamers NMe), 36.4*, 36.6,
41.8*, 42.7, 58.4 (br, both rotamers 10-CH), 75.4*, 76.6, 126.3,
126.4, 126.9, 127.6, 128.5, 128.9, 142.4, 146.3 172.8*, 174.2, com-
plete assignment of the minor aryl rotamer signals could not be
made due to overlaps except for the Ph-i signals at 141.1* and
146.8*; HRMS (M++Na): m/z, 334.17775; found, 334.1783. These
data are comparable to those of the enantiomeric compound
isolated by Badía.3 The diastereoselectivity was determined by
HPLC on a Daicel-OD column. 98:2 Hexane/PriOH, 1 ml/min;
t(3R,10R,20R) = 62.1 min for 10a, t(3S,10R,20R) = 70.7 min for 10b.
4.15. (ꢁ)-(2R,3R,10R,20R)-N-Methyl-N-(20-phenyl-20-hydroxy-10-
methyethyl)-2-allyl-3-methylpentanamide 13
Compound 13 was obtained using a modification of procedure
described in Section 4.10 from 7 (233.3 mg, 1.00 mmol) using
CuBrꢀSMe2 (10.2 mg, 0.05 mmol), (R,R)-MeDuphos (15.2 mg,
0.05 mmol), freshly distilled Et2O (4 mL), CH2Cl2 (1 mL), and
EtMgBr (3.0 mL, 3.0 M in Et2O, 3 mmol). After 3 h at ꢁ30 °C neat
allyl bromide (0.13 mL, 1.5 mmol) was added at this temperature.
After 6 h at ꢁ30 °C, the mixture was allowed to come to room
temperature overnight. Usual workup followed by column chro-
matography (petrol/ethyl acetate 5:1) afforded 13 as a colorless
4.13. (3R,10R,20R)-N-Methyl-N-(20-phenyl-20-hydroxy-10-
methyethyl)-3-methylhex-5-enamide 11
Compound 11 was obtained according to the procedure de-
scribed in Section 4.10 from 7 (233.3 mg, 1.00 mmol) using
CuBrꢀSMe2 (10.2 mg, 0.05 mmol), (R,R)-MeDuphos (15.2 mg,
0.05 mmol), freshly distilled Et2O (4 mL), CH2Cl2 (1 mL), and ally-
lmagnesiumbromide (3.0 mL, 1.0 M in Et2O, 3 mmol) as a colorless
oil (268 mg, 88%, 92% de by HPLC). [
3691, 3008, 2968, 2935, 2877, 1710, 1611, 1482, 1455, 1414,
1363, 1240, 1047 cmꢁ1 1H NMR (400.1 MHz, CDCl3) (3.09:1 rot-
a
]
D = ꢁ73 (c 1.05, CHCl3). IR
;
amer ratio; ꢄ indicates minor rotamer resonances; minor diaste-
reomer not fully assigned) d 0.86* (t, J = 7.1 Hz, 3H, CH2CH3), 0.90
(t, J = 7.1 Hz, 3H, CH2CH3), overlapped by 0.92 (d, J = 6.9 Hz, 3H,
10-CHCH3) and 0.93* (d, J = 6.9 Hz, 3H, 10-CHCH3), 0.99* (d,
J = 6.9 Hz, 3H, 3-CHCH3), 1.12 (d, J = 6.9 Hz, 3H, 3-CHCH3), over-
lapped by 1.00–1.31 (m, 3H, CH2CH3 and 3-CH both rotamers),
1.53–1.76 (m, 3H, CH2CH3 and 3-CH both rotamers) overlapped
by 1.71 (s, br, 1H, OH both rotamers), 2.22–2.63 (m, 3H, @CHCH2
and COCH2 both rotamers), 2.83 (s, 3H, NCH3), 2.92* (s, 3H,
NCH3), 4.41–4.71 (m, 1H, CHOH both rotamers), 4.92–5.19 (m,
oil (255 mg, 92%, 76% de). [
a
]
D = ꢁ94 (c 0.84, CHCl3). IR 3741, 3011,
1618, 1454, 1407, 1264, 1240, 1047, 1021, 918 cmꢁ1
;
1H NMR
(400.1 MHz, CDCl3) (3.33:1 rotamer ratio; ꢄ indicates minor rot-
amer resonances; minor diastereomer not assigned) d 0.96 (d,
J = 6.6 Hz, 3H, 10-CHCH3), 1.00* 96 (d, J = 6.8 Hz, 3H, 10-CHCH3),
1.13 (d, J = 7.1 Hz, 3H, 3-CHCH3) overlapped by 1.14* (d,
J = 7.1 Hz, 3H, 3-CHCH3), 1.94–2.48 (m, 4H, COCH2 and CH2 allyl
both rotamers), 2.83 (s, 3H, NCH3), 2.93* (s, 3H, NCH3), 3.99–4.06*

1708
K. Biswas, S. Woodward / Tetrahedron: Asymmetry 19 (2008) 1702–1708
2H, @CH2 both rotamers), 5.59–5.67* (m, 1H, @CH), 5.82–5.96 (m,
1H, @CH2 minor diastereomer), 5.72–5.82 (m, 1H, @CH2), 7.26–
7.45 (m, 5H, Ph both rotamers); 13C NMR (100.6 MHz) d 11.0,
11.7*, 14.7, 15.4*, 17.0 (both rotamers CHCH3), 25.8, 27.5*, 33.9*,
33.8 (both rotamers NMe), 34.6, 36.9, 37.2*, 47.5, 47.6*, 59.0 (both
rotamers 10-CH), 75.5*, 76.4, 116.3, 116.6*, 126.4, 127.1, 127.5*,
128.3, 128.4*, 128.7*, 136.3, 136.4*, 141.3*, 142.5, 177.7 (both rota-
mers CO).; HRMS (M++Na): m/z, 326.20905; found, 326.2114. The
diastereoselectivity was determined by HPLC on a Daicel-OJ-H col-
umn; 98:2 Hexane/PriOH, 0.5 ml/min; t(3R,10R,20R) = 18.2 min for
13a, t(3S,10R,20R) = 19.8 min for 13b (2R,3S enantiomer of 13a).
Chem., Int. Ed. 2005, 44, 5560–5562. See also the extensive literature cited in
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Acknowledgments
We thank the EPSRC (Grant EP/E030092/1) for their financial
support of this work. We are indebted to DowPharma and the COST
D40 programme for generous gifts of Duphos and related ligands.
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