Diastereoselective Ireland-Claisen rearrangements of substituted allyl β-amino esters: Applications in the asymmetric synthesis of C(5)-substituted transpentacins

Article abstract of DOI:10.1039/c4ob00274a

The diastereoselective Ireland-Claisen rearrangement of a range of substituted allyl β-amino esters gave the corresponding enantiopure α-substituted-β-amino esters with good diastereoselectivity. The application of this methodology in the asymmetric synthesis of a range of C(5)-substituted 1,2-anti-1,5-syn-transpentacins was demonstrated by the rearrangement of a range of β-amino esters derived from sorbic acid, followed by esterification, ring-closing metathesis, hydrogenolytic deprotection/reduction, and hydrolysis, which gave the C(5)-substituted transpentacins in only 9 steps from commercially available starting materials. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00274a

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PAPER
Diastereoselective Ireland–Claisen rearrangements
of substituted allyl β-amino esters: applications in
the asymmetric synthesis of C(5)-substituted
transpentacins†
Cite this: Org. Biomol. Chem., 2014,
12, 2702
Stephen G. Davies,* Ai M. Fletcher, James A. Lee, Paul M. Roberts,
Myriam Y. Souleymanou, James E. Thomson and Charlotte M. Zammit
The diastereoselective Ireland–Claisen rearrangement of a range of substituted allyl β-amino esters gave
the corresponding enantiopure α-substituted-β-amino esters with good diastereoselectivity. The appli-
cation of this methodology in the asymmetric synthesis of a range of C(5)-substituted 1,2-anti-1,5-syn-
transpentacins was demonstrated by the rearrangement of a range of β-amino esters derived from sorbic
acid, followed by esterification, ring-closing metathesis, hydrogenolytic deprotection/reduction, and
hydrolysis, which gave the C(5)-substituted transpentacins in only 9 steps from commercially available
starting materials.
Received 6th February 2014,
Accepted 11th March 2014
DOI: 10.1039/c4ob00274a
www.rsc.org/obc
using this methodology, would create up to two new stereo-
genic centres within the β-amino acid scaffold and provide
Introduction
Since its introduction in 1972, the Ireland–Claisen rearrange- access to substrates that are not accessible by enolate alkyl-
ment1 of allyl esters (as the corresponding silyl ketene acetals) ation. It was envisaged that the requisite substrates 3 could
has shown considerable utility in synthesis. Its popularity is either be prepared by conjugate addition of lithium amide
principally due to the high levels of diastereoselectivity which (S)-6 to an α,β-unsaturated allyl ester 4, or by transesterification
are typically observed during this reaction, in which two adja- of the known tert-butyl β-amino esters 2 (Fig. 1). Part of this
cent stereogenic centers are produced in a single step. This work has been communicated previously.10
methodology has been extensively reviewed,2 and several asym-
metric variants have been developed.3,4
Previous investigations from our laboratory have demon-
strated that the conjugate addition of enantiopure secondary
lithium amides (derived from α-methylbenzylamines) to
α,β-unsaturated esters represents a general and efficient syn-
Results and discussion
Ireland–Claisen rearrangement of allyl β-amino esters: model
studies
thetic protocol for the synthesis of β-amino esters and their Allyl β-amino esters 10, 11 and 13 were selected as model sub-
derivatives.5 This methodology has found numerous appli- strates with which to optimise the conditions for an Ireland–
cations, including the total syntheses of natural products,6 Claisen rearrangement. Unfortunately, attempted conjugate
molecular recognition phenomena7 and resolution protocols,8 addition of lithium amide reagents to simple allyl α,β-unsatu-
and has been reviewed.9 As part of our ongoing research pro- rated esters [i.e., those lacking substitution at the C(1′) posi-
gramme to extend the scope and utility of this methodology, tion] resulted the competitive formation of amide products
we envisaged that the diastereoselective Ireland–Claisen resulting from 1,2-addition of the lithium amide reagent.
rearrangement of enantiopure allyl β-amino esters, prepared Compounds 10, 11 and 13 were therefore prepared via
transesterification of the corresponding tert-butyl β-amino
esters 8, 9 and 12. Conjugate addition of lithium N,N-dibenzyl-
amide and lithium N-isopropyl-N-benzylamide to tert-butyl
cinnamate 7 gave racemic β-amino esters 8 and 9 in 73
and 80% yield, respectively.11 Similarly, conjugate addition
of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide 6 to 7 gave
enantiopure β-amino ester 12 in 82% yield and >99 : 1 dr.11
Transesterification of all three substrates upon treatment with
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
Mansfield Road, Oxford, OX1 3TA, UK. E-mail: steve.davies@chem.ox.ac.uk;
Fax: +44 (0)1865 275633; Tel: +44 (0)1865 275695
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterisation data, copies of 1H and 13C NMR spectra, and crystallo-
graphic data. CCDC 982697–982706. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c4ob00274a
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Scheme 2 Reagents and conditions: (i) TMSCl, PhMe, −78 °C, 10 min
then LiHMDS, −78 °C, 30 min then reflux, 1 h; (ii) SOCl2, MeOH, 50 °C,
48 h; (iii) H2 (1 atm), Pd(OH)2/C, MeOH–acetone (9 : 1), rt, 16 h.
Fig. 1 Ireland–Claisen rearrangement of substituted allyl β-amino
esters.
Fig. 2 X-ray crystal structures of (RS,SR)-16 [left] and (RS,SR)-18 [right]
(selected H-atoms are omitted for clarity).
with LiHMDS followed by reaction of the resultant lithium
(E)-β-amino enolate12 with TMSCl produced the corresponding
silyl ketene acetal which was heated at reflux in PhMe to give
β-amino acid 14 in 83 : 17 dr. Subsequent esterification of 14
(for ease of handling and isolation) upon treatment with
SOCl2 in MeOH produced β-amino ester 16 in 40% yield (from
10) and 83 : 17 dr (Scheme 2).13 The relative configuration
within the major diastereoisomer 16 was unambiguously
determined by single crystal X-ray diffraction analysis
(Fig. 2);14 this analysis also secured the relative configuration
within β-amino acid 14. Ireland–Claisen rearrangement of 11
Scheme 1 Reagents and conditions: (i) LiNiPrBn or LiNBn2, THF,
−78 °C, 2 h; (ii) lithium (S)-N-benzyl-N-(α-methylbenzyl)amide 6, THF,
−78 °C, 2 h; (iii) SOCl2, allyl alcohol, 50 °C, 3 h.
i
(R = Pr) following an identical procedure produced β-amino
acid 15 in 91 : 9 dr, which was converted into β-amino ester 17
upon treatment with SOCl2 and MeOH; after purification 17
was isolated in 62% yield and 88 : 12 dr.13 The configurations
within 15 and 17 were assigned by chemical correlation: hydro-
genolysis of 16 (83 : 17 dr) in the presence of acetone effected
removal of the N-benzyl groups and in situ reductive alkylation
to give N-isopropyl substituted β-amino ester 18 in 85% yield
SOCl2 in allyl alcohol gave 10, 11 and 13 in good yield
(Scheme 1).
Following a screen of different reaction conditions (varying
the temperature, solvent, base, equivalents of reagents, etc.), a
reproducible procedure for the Ireland–Claisen rearrangement
of 10, 11 and 13 was developed: deprotonation of 10 (R = Bn)
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Fig. 3 X-ray crystal structures of (2S,3R,αS)-19 [left] and (2S,3R,αS)-20
[right] (selected H-atoms are omitted for clarity).
known (S)-configuration of the α-methylbenzyl fragment and
were confirmed by determination of Flack x parameters17 of
−0.02(18) and −0.02(15), respectively.
The rearrangement of isoprenyl β-amino ester 25 was investi-
gated next. As 1,2-addition of the lithium amide reagent was
not expected to present a problem upon conjugate addition to
isoprenyl cinnamate 24, β-amino ester 25 was prepared from
2418 upon conjugate addition of enantiopure lithium amide
(S)-6, which gave 25 as the only reaction product in 73% iso-
lated yield and >99 : 1 dr after chromatographic purification
(Scheme 4).19 The relative configuration within 25 was
assigned unambiguously via single crystal X-ray diffraction
analysis and the absolute (3R,αS)-configuration within 25 was
assigned relative to the known (S)-configuration of the
α-methylbenzyl fragment (Fig. 4); furthermore, the determi-
nation of a Flack x parameter17 of −0.09(10) confirmed this
assignment.14 Ireland–Claisen rearrangement of 25 gave
β-amino acid 26 in 93 : 7 dr. Subsequent esterification of 26,
upon treatment with DBU and MeI,20,21 gave β-amino ester 27
in 93 : 7 dr, which was isolated in 66% yield and >99 : 1 dr. The
relative configuration within 27 was then established by X-ray
diffraction analysis of a derivative: hydrogenolysis of 27 fol-
lowed by reductive N-alkylation of 28 gave 29 in 55% yield and
>99 : 1 dr. Alternatively, 29 was accessed directly from 25 in 3
steps and 48% overall yield (Scheme 4). Subsequent single
crystal X-ray diffraction analysis of 29 allowed the relative con-
figurations within 26–28 to be established unambiguously
(Fig. 4).14
Scheme 3 Reagents and conditions: (i) TMSCl, PhMe, −78 °C, 10 min
then LiHMDS, −78 °C, 30 min then reflux, 1 h; (ii) SOCl2, MeOH, 50 °C,
48 h; (iii) LiHMDS, THF, −78 °C, 2 h then allyl bromide, −78 °C to rt, 16 h;
(iv) CAN, MeCN–H2O (5 : 1), rt, 16 h; (v) MeMgBr, Et2O, 0 °C, 30 min.
and 83 : 17 dr. Hydrogenolysis of 17 (88 : 12 dr), under identi-
cal conditions, gave 18 in 66% yield and 88 : 12 dr
(Scheme 2).15 The relative configuration within 18 was sub-
sequently confirmed unambiguously via single crystal X-ray
diffraction analysis (Fig. 2).14
Ireland–Claisen rearrangement of the corresponding enantio-
pure substrate 13 [derived from conjugate addition of enantio-
pure lithium amide (S)-6 to α,β-unsaturated ester 7, followed
by transesterification] produced β-amino acid 19 in 92 : 8 dr.
Esterification of 19 upon treatment with SOCl2 in MeOH gave
β-amino ester 20 in 92 : 8 dr, which was then isolated in 50%
yield and >99 : 1 dr. An authentic sample of 20 was prepared
upon alkylation of the known5b β-amino ester 21 with allyl
bromide, which gave 20 in 87 : 13 dr, and 67% yield and >99 : 1
dr after chromatographic purification. β-Amino ester 20 was
subsequently converted into the corresponding β-lactam 23 via
(i) oxidative monodebenzylation with CAN, and (ii) MeMgBr-
mediated cyclisation of 22 to give β-lactam 23 in 76% overall
yield for the two step procedure (Scheme 3). The relative con-
figuration within 23 (and therefore also those within 19, 20
The Ireland–Claisen rearrangement of prenyl β-amino ester
30 [which was expected to generate a quaternary centre at the
C(1′)-position upon rearrangement] was investigated next.
β-Amino ester 30 was prepared by hydrolysis of tert-butyl
ester 12 followed by treatment of the resultant β-amino
acid with prenyl bromide in the presence of DBU. Ireland–
Claisen rearrangement of 30 produced β-amino acid 31 in
90 : 10 dr, and esterification with DBU and MeI gave methyl
ester 32 in 90 : 10 dr, which was isolated in 50% yield and
>99 : 1 dr (Scheme 5). The stereochemical outcome of this
1
3
and 22) was assigned from the value of the H NMR J coup-
ling constant observed between the C(3)H and C(4)H protons
(3J3,4 = 2.1 Hz), which is known to be diagnostic of the relative
stereochemical configuration within β-lactams.16 These assign-
ments were all confirmed unambiguously by subsequent
single crystal X-ray diffraction analyses of both 19 and 20
(Fig. 3);14 in both cases the absolute configurations within
(2S,3R,αS)-19 and (2S,3R,αS)-20 were assigned relative to the
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Scheme 5 Reagents and conditions: (i) TFA, CH2Cl2, rt, 16 h; (ii) prenyl
bromide, DBU, MeCN, rt, 17 h; (iii) TMSCl, PhMe, −78 °C then LiHMDS,
−78 °C, 30 min then reflux, 1 h; (iv) DBU, MeCN, MeI, rt, 8 h.
Ireland–Claisen rearrangement of cis- and trans-configured
allyl β-amino esters: asymmetric synthesis of β-amino acids
bearing chiral C(2)-substituents
As the Ireland–Claisen rearrangement of stereodefined allyl
esters bearing only one substituent at the C(3′)-position would
create an additional stereogenic centre at the C(1′)-position of
the product, representative substrates derived from cis- or
trans-crotyl and cinnamyl alcohols were evaluated in this reac-
tion manifold; the rearrangement of the trans-configured sub-
strates 33 and 34 were investigated first. Both substrates were
again prepared by transesterification of tert-butyl ester 12. In
the case of trans-crotyl alcohol derived substrate 33 (R = Me),
the Ireland–Claisen rearrangement proceeded with poor
diastereoselectivity to give a 54 : 46 mixture of diastereo-
isomeric β-amino acids 35.22 Improved diastereoselectivity was
observed upon rearrangement of the trans-cinnamyl alcohol
derived substrate 34 (R = Ph), which gave a 70 : 30 mixture of
diastereoisomeric β-amino acids 37 and 38, respectively. The
configuration within the major diastereoisomer 37 was deter-
mined unambiguously by single crystal X-ray diffraction ana-
lysis (Fig. 5),14 and the absolute (2S,3R,1′S,αS)-configuration
within 37 was assigned relative to the known configuration of
the (S)-α-methylbenzyl fragment; furthermore, the determi-
nation of a Flack x parameter17 of 0.02(16) for the crystal
structure of 37 confirmed this assignment. Subsequent esteri-
fication gave β-amino esters 39 and 40 in 38 and 13% yield,
respectively, and >99 : 1 dr in both cases (Scheme 6).
Scheme 4 Reagents and conditions: (i) lithium (S)-N-benzyl-N-
(α-methylbenzyl)amide 6, THF, −78 °C, 2 h; (ii) TMSCl, PhMe, −78 °C,
10 min then LiHMDS, −78 °C, 30 min then reflux, 1 h; (iii) DBU, MeCN,
MeI, rt, 4 h; (iv) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 15 h; (v) acetone,
NaBH3CN, MeOH, rt, 22 h; (vi) H2 (1 atm), Pd(OH)2/C, MeOH–acetone
(9 : 1), rt, 22 h; (vii) SOCl2, MeOH, 50 °C, 48 h.
Ireland–Claisen rearrangement of the corresponding cis-
configured substrates 41 and 42 (derived from transesterifica-
tion of tert-butyl ester 12 with either cis-crotyl alcohol or cis-
cinnamyl alcohol, respectively) proceeded with far greater
diastereoselectivity than the trans-configured substrates 33 and
34, giving β-amino acids 43 and 37 in 96 : 4 and 90 : 10 dr,
respectively. Conversion of 43 and 37 to the corresponding
methyl esters gave 44 in 85% yield (from 41) and 96 : 4 dr, and
39 in 48% yield (from 42) and >99 : 1 dr. It is interesting
to note that the major diastereoisomer resulting from the
Fig. 4 X-ray crystal structures of (3R,αS)-25 [left] and (2S,3R)-29 [right]
(selected H-atoms are omitted for clarity).
rearrangement was assigned by analogy to the stereochemical
outcomes observed upon rearrangement of substrates 10, 11,
13 and 25.
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Fig. 5 X-ray crystal structure of (2S,3R,1’S,αS)-37 (selected H-atoms are
omitted for clarity).
Scheme 7 Reagents and conditions: (i) TFA, CH2Cl2, rt, 16 h;
(ii) (COCl)2, CH2Cl2, DMF, 0 °C to rt, 1 h then crotyl alcohol [>99 : 1 dr
(Z):(E)] or cinnamyl alcohol [>99 : 1 dr (Z):(E)], CH2Cl2, 0 °C to rt, 16 h;
(iii) LiHMDS, TMSCl, PhMe, −78 °C then reflux, 1 h; (iv) DBU, MeI, MeCN, rt,
16 h; (v) Pd(OH)2/C, H2 (1 atm), MeOH, rt, 24 h; (vi) HCl (6.0 M aq), reflux,
5 days then DOWEX 50WX8.
Ireland–Claisen rearrangement of the cis-cinnamyl alcohol
derived substrate 42 is identical to the major diastereoisomer
resulting from the rearrangement of the trans-cinnamyl
alcohol derived substrate 34. The configurations within 43 and
44 were assigned by analogy to those within 37 and 39.
Tandem hydrogenation/hydrogenolysis of both 44 and 39, and
subsequent hydrolysis of 45 and 46 gave β-amino acids 47 and
48 in good overall yield after purification on DOWEX 50WX8
ion exchange resin (Scheme 7).
The origin of diastereoselectivity in the Ireland–Claisen
rearrangement of allyl β-amino esters
The levels of diastereoselectivity observed upon Ireland–
Claisen rearrangement of this range of allyl β-amino esters
have proven to be somewhat variable, with the substrates
lacking substitution on the allyl fragment, and the cis-config-
ured substrates bearing a substituent on the allyl fragment,
displaying superior levels of diastereoselectivity to the corres-
ponding trans-configured substrates. It is also curious that the
formation of β-amino acid 37 occurs as the major diastereo-
isomer resulting from Ireland–Claisen rearrangement of both
β-amino esters trans-34 (giving 37 in 70 : 30 dr) and cis-42
(giving 37 in 90 : 10 dr).23 These data can be explained by con-
sidering the possible transition states for rearrangement: it
can be expected that rearrangement of the cis-configured
substrates, such as 42 (R1 = H, R2 = Ph), would proceed via
Scheme 6 Reagents and conditions: (i) TFA, CH2Cl2, rt, 16 h; (ii)
(COCl)2, CH2Cl2, DMF, 0 °C to rt, 1 h then crotyl alcohol [96 : 4 dr (E):(Z)]
or cinnamyl alcohol [>99 : 1 dr (E):(Z)], CH2Cl2, 0 °C to rt, 16 h; (iii)
LiHMDS, TMSCl, PhMe, −78 °C then reflux, 1 h; (iv) DBU, MeI, MeCN, rt,
16 h.
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Fig. 7 Proposed asymmetric synthesis of enantiopure 1,2-anti-1,5-syn-
transpentacins 63.
Fig. 6 Proposed transition state models for rearrangement.
logues 54–56,27 and subsequently investigated the secondary
structural characteristics of some of their oligomers.28 It was
therefore envisaged that an alternative procedure for the syn-
theses of 1,2-anti-1,5-syn-diastereoisomers 61, which are not
accessible using the PKR protocol, could be developed employ-
ing the diastereoselective Ireland–Claisen rearrangement of
enantiopure cis-substituted allyl esters 57. The resultant α-sub-
stituted β-amino acid products 58 could then be elaborated to
the corresponding C(5)-substituted transpentacins 61 via a
three step protocol involving ring-closing metathesis, hydrogeno-
lytic deprotection/reduction, and finally hydrolysis (Fig. 7).
Esterification of commercially available sorbic acid 62
upon treatment with isobutylene in the presence of H2SO4
gave α,β-unsaturated ester 63 in 80% isolated yield. Conjugate
addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide 6 to
63 produced the known19,29 β-amino ester 64 as a single dia-
stereoisomer (>99 : 1 dr), which was isolated in 89% yield and
>99 : 1 dr. Hydrolysis of 64 upon treatment with TFA, conver-
sion of the resultant carboxylic acid to the corresponding acid
chloride, and treatment with the requisite cis-allylic alcohols
chair-like transition state 50 in which 1,3-allylic strain between
the C(3)-substituents and the C(1)–O bond is minimised and
the reaction occurs on the face opposite the bulky N-benzyl-N-
(α-methylbenzyl) group. A chair-like transition state is dis-
favoured for substrates such as 34 (R1 = Ph, R2 = H) when signifi-
cant steric interactions between R1 and the C(3)-phenyl group
are encountered; in this case a boat-like transition state 52,24
in which 1,3-allylic strain between the C(3)-substituents and
the C(1)–O bond is minimised and the reaction occurs on the
face opposite the bulky N-benzyl-N-(α-methylbenzyl) group,
would be favoured as the R1 substituent occupies a far less
sterically congested position (Fig. 6). This analysis is also con-
sistent with the rearrangement of 41 (R1 = H, R2 = Me; 96 : 4
dr) being more highly diastereoselective than that of 42 (R1 =
H, R2 = Ph; 90 : 10 dr), and the rearrangement of 33 (R1 = Me,
R2 = H; 54 : 46 dr) being essentially non-selective.
Application to the asymmetric synthesis of C(5)-substituted
transpentacins
i
(R = Me, Et, Bn, Pr, Ph) gave β-amino esters 65–69 in good
yield (Scheme 8).
The development of routes to access enantiopure substituted
derivatives of the cyclic β-amino acid transpentacin (trans-2-
aminocyclopentanecarboxylic acid) is of considerable impor-
tance as oligomers of these β-amino acids display interesting
secondary structural characteristics.25,26 In order to enhance
the structural diversity of enantiopure monomeric cispentacin
and transpentacin derivatives available we have previously
developed efficient parallel kinetic resolution (PKR) procedures
for the asymmetric syntheses of C(3)- and C(5)-substituted ana-
In each case, Ireland–Claisen rearrangement of 65–69 pro-
duced the corresponding β-amino acids 70–79 in ∼80 : 20 dr.
Following esterification of 70–79, upon treatment with DBU
and MeI, and chromatographic purification, the major diastereo-
isomers 80–84 were isolated in 38–69% yield, and the minor
diastereoisomers 85–89 were isolated in 7–16% yield,30 as
single diastereoisomers (>99 : 1 dr) in each case (Scheme 9).
The configurations within 84, 86, 87 and 89 were established
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Fig. 8 X-ray crystal structures of (S,S,S,E)-86·HBF4 [left] and
(2R,3S,1’-R,αS,E)-87 [right] (the BF4 counterion and selected H-atoms
are omitted for clarity).
−
Scheme 8 Reagents and conditions: (i) isobutylene, H2SO4, CH2Cl2,
0 °C to rt, 48 h; (ii) lithium (S)-N-benzyl-N-(α-methylbenzyl)amide (S)-6,
THF, −78 °C, 2 h; (iii) CH2Cl2–TFA (2 : 1), rt, 16 h; (iv) (COCl)2, CH2Cl2,
DMF, 0 °C to rt, 1 h then cis-RCHvCHCH2OH [>99 : 1 dr (E) : (Z)], CH2Cl2,
0 °C to rt, 16 h.
Scheme 10 Reagents and conditions: (i) Grubbs I, CH2Cl2, 40 °C, 24–48 h;
(ii) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 24 h; (iii) HCl (6.0 M aq), reflux, 16 h
then DOWEX 50WX8.
65–69) gave the corresponding cyclic β-amino esters 90–94 in
38–96% yield. Subsequent tandem hydrogenation/hydrogeno-
lysis of 90–94 gave primary β-amino esters 95–99 as single
diastereoisomers (>99 : 1 dr) in 40–87% yield (Scheme 10).
The configurations within 95, 96 and 99 were established
by single crystal X-ray diffraction analyses (Fig. 9),14,31 and
the configurations within 97 and 98 were then assigned by
Scheme 9 Reagents and conditions: (i) LiHMDS, TMSCl, PhMe, −78 °C,
15 min, then reflux, 1 h; (ii) DBU, MeI, MeCN, rt, 16 h.
by single crystal X-ray diffraction analyses (Fig. 8),14,31 and the analogy. Finally, hydrolysis of the methyl ester functionalities
configurations within 80–83, 85 and 88 were then assigned by within 95–99, upon treatment with 6.0 M aq. HCl at reflux for
analogy.
16 h, gave β-amino acids 100–104 which were isolated in 84%
Ring-closing metathesis of 80–84 (the major diastereo- to quantitative yield and >99 : 1 dr after purification on Dowex
isomers resulting from Ireland–Claisen rearrangement of 50WX8 ion exchange resin (Scheme 10).
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teristic peaks are reported in cm−1. NMR spectra were recorded
in the deuterated solvent stated. Spectra were recorded at rt
unless otherwise stated. The field was locked by external refer-
encing to the relevant deuteron resonance. 1H–1H COSY,
1H–13C HMQC, and 1H–13C HMBC analyses were used to estab-
lish atom connectivity. Accurate mass measurements were run
on a TOF spectrometer internally calibrated with polyalanine.
Prop-2′-en-1′-yl (RS)-3-(N,N-dibenzylamino)-3-phenyl-
propanoate 10
Fig. 9 X-ray crystal structure of (S,S,S)-96·HCl (selected H-atoms are
omitted for clarity).
SOCl2 (2.15 mL, 29.9 mmol) was added dropwise to a stirred
solution of 811 (4.00 g, 9.96 mmol) in allyl alcohol (40 mL) at
0 °C and the resultant mixture was stirred at 50 °C for 3 h. The
reaction mixture was then allowed to cool to rt and concen-
trated in vacuo, the residue was dissolved in CH2Cl2 (150 mL),
and the resultant solution was washed with satd aq. NaHCO3
(3 × 150 mL), then dried and concentrated in vacuo. Purifi-
cation via flash column chromatography (eluent 30–40 °C
petrol–Et2O, 98 : 2) gave 10 as a colourless oil (3.30 g, 86%);
νmax (ATR) 2934 (C–H), 1735 (CvO), 1602 (CvC); δH (400 MHz,
CDCl3) 2.69 (1H, dd, J 14.4, 7.3, C(2)HA), 3.07 (1H, dd, J 14.4,
7.3, C(2)HB), 3.11 (2H, d, J 13.9, N(CHAHBPh)2), 3.69 (2H, d,
J 13.9, N(CHAHBPh)2), 4.25 (1H, t, J 7.3, C(3)H), 4.38–4.55 (2H,
m, C(1′)H2), 5.09–5.17 (2H, m, C(3′)H2), 5.69–5.79 (1H, m,
C(2′)H), 7.12–7.31 (15H, m, Ph); δC (100 MHz, CDCl3) 36.6 (C(2)),
53.7 (N(CH2Ph)2), 58.9 (C(3)), 65.3 (C(1′)), 118.3 (C(3′)), 126.9,
127.5, 128.1, 128.2, 128.6, 128.8 (o,m,p-Ph), 132.1 (C(2′)), 137.4,
139.5 (i-Ph), 171.3 (C(1)); m/z (ESI+) 408 ([M + Na]+, 100%), 386
Conclusions
In conclusion, a diastereoselective Ireland–Claisen rearrange-
ment protocol has been developed for the asymmetric syn-
thesis of α-substituted-β-amino acids. The rearrangement
precursors were typically prepared upon conjugate addition of
enantiopure lithium amides to tert-butyl α,β-unsaturated
esters, followed by transesterification to give the requisite allyl
β-amino ester substrates. Subsequent Ireland–Claisen
rearrangement gave the corresponding enantiopure β-amino
acids in good yield. The stereochemical outcomes of these
reactions were considered and transition state models to
account for this diastereoselectivity were proposed. The appli-
cation of this methodology in the asymmetric synthesis of a
range of C(5)-substituted 1,2-anti-1,5-syn-transpentacins was
demonstrated by the rearrangement of β-amino esters derived
from sorbic acid, followed by esterification of the rearrange-
ment products, ring-closing metathesis, hydrogenolytic depro-
tection/reduction, and hydrolysis which provided access to the
C(5)-substituted transpentacins in only 9 steps from commer-
cially available starting materials. Further applications of this
methodology are under investigation within our laboratory.
+
([M + H]+, 70%); HRMS (ESI+) C26H28NO2 ([M + H]+) requires
386.2115; found 386.2101.
Prop-2′-en-1′-yl (RS)-3-(N-isopropyl-N-benzylamino)-
3-phenylpropanoate 11
SOCl2 (2.44 mL, 33.9 mmol) was added dropwise to a stirred
solution of 911 (4.00 g, 11.3 mmol) in allyl alcohol (40 mL) at
0 °C and the resultant mixture was stirred at 50 °C for 3 h. The
reaction mixture was then allowed to cool to rt and concen-
trated in vacuo, the residue was dissolved in CH2Cl2 (150 mL),
Experimental
General experimental details
All reactions involving organometallic or other moisture-sensi- and the resultant solution was washed with satd aq. NaHCO3
tive reagents were carried out under a nitrogen atmosphere (3 × 150 mL), then dried and concentrated in vacuo. Purifi-
using standard vacuum line techniques and glassware that was cation via flash column chromatography (eluent 30–40 °C
flame dried and cooled under nitrogen before use. Solvents petrol–Et2O, 98 : 2) gave 11 as a colourless oil (2.94 g, 77%);
were dried according to the procedure outlined by Grubbs and νmax (ATR) 2965, 2934 (C–H), 1735 (CvO), 1601 (CvC); δH
co-workers.32 BuLi was purchased as a solution in hexanes and (400 MHz, CDCl3) 0.71 (3H, d, J 6.6, CHMeAMeB), 0.98 (3H, d,
titrated against diphenylacetic acid before use. Pd(OH)2/C J 6.6, CHMeAMeB), 2.55 (1H, dd, J 14.4, 8.5, C(2)HA), 2.87 (1H,
(20 wt % dry basis) was used for all hydrogenolysis reactions. dd, J 14.4, 6.9, C(2)HB), 3.01 (1H, septet, J 6.6, CHMe2), 3.61
All other reagents were used as supplied without prior purifi- (2H, d, J 15.1, NCH2Ph), 4.25 (1H, dd, J 8.5, 6.9, C(3)H),
cation. Organic layers were dried over MgSO4. Thin layer 4.29–4.40 (2H, m, C(1′)H2), 5.04–5.10 (2H, m, C(3′)H2),
chromatography was performed on aluminium plates coated 5.62–5.71 (1H, m, C(2′)H), 7.12–7.31 (10H, m, Ph); δC
with 60 F254 silica. Plates were visualised using UV light (100 MHz, CDCl3) 18.4, 21.4 (CHMe2), 38.9 (C(2)), 47.9
(254 nm), 1% aq. KMnO4 or Dragendorff’s reagent. Flash (CHMe2), 49.3 (NCH2Ph), 60.0 (C(3)), 65.0 (C(1′)), 118.0 (C(3′)),
column chromatography was performed on Kieselgel 60 silica. 126.5, 127.1, 128.0, 128.1 (o,m,p-Ph), 132.1 (C(2′)), 141.3, 141.8
Melting points are uncorrected. Specific rotations are reported (i-Ph), 171.5 (C(1)); m/z (ESI+) 360 ([M + Na]+, 100%), 338
in 10−1 deg cm2 g−1 and concentrations in g per 100 mL. IR ([M + H]+, 90%); HRMS (ESI+) C22H28NO2 ([M + H]+) requires
+
spectra were recorded using an ATR module. Selected charac- 338.2115; found 338.2104.
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Prop-2′-en-1′-yl (3R,αS)-3-[N-benzyl-N-(α-methylbenzyl)-amino]- 116.6 (C(3′)), 126.9, 127.7, 128.1, 128.2, 128.9, 129.4 (o,m,p-Ph),
3-phenylpropanoate 13
133.9 (i-Ph), 135.0 (C(2′)), 139.3 (i-Ph), 174.0 (C(1)). Data for
minor diastereoisomer: δH (400 MHz, CDCl3) 2.22 (1H, ddd,
J 14.0, 10.9, 8.1, C(1′)HA), 2.93 (2H, d, J 13.4, N(CHAHBPh)2),
3.08–3.12 (1H, m, C(1′)HB), 3.14 (3H, s, OMe), 3.24 (1H, td,
J 10.9, 3.5, C(2)H), 3.75–3.82 (3H, m, C(3)H, N(CHAHBPh)2),
4.91–5.02 (2H, m, C(3′)H2), 5.64–5.74 (1H, m, C(2′)H),
7.07–7.35 (15H, m, Ph); δC (100 MHz, CDCl3) 35.0 (C(1′)), 48.1
(C(2)), 51.0 (OMe), 53.8 (N(CH2Ph)2), 63.4 (C(3)), 116.6 (C(3′)),
127.0, 127.8, 128.0, 128.4, 128.8, 129.4 (o,m,p-Ph), 134.7 (i-Ph),
135.6 (C(2′)), 139.4 (i-Ph), 174.0 (C(1)). Data for mixture: νmax
(ATR) 2948, 2839 (C–H), 1738 (CvO), 1603 (CvC); m/z (ESI+)
422 ([M + Na]+, 40%), 400 ([M + H]+, 100%); HRMS (ESI+)
C27H30NO2+ ([M + H]+) requires 400.2271; found 400.2253.
Method B. LiHMDS (1.0 M in THF, 3.56 mL, 3.56 mmol)
was added dropwise to a solution of methyl (RS)-3-(N,N-dibenzyl-
amino)-3-phenylpropanoate33 (508 mg, 1.19 mmol) in THF
(5 mL) at −78 °C, and the resultant solution was stirred at
−78 °C for 2 h. Allyl bromide (465 μL, 5.35 mmol) was then
added dropwise, and the resultant solution was allowed to
warm to rt over 16 h. Satd aq. NH4Cl (0.5 mL) was then added
and the aqueous layer was extracted with Et2O (2 × 10 mL). The
combined organic extracts were washed with brine (20 mL),
then dried and concentrated in vacuo to give 16 in 54 : 46 dr.
Purification via flash column chromatography (eluent
30–40 °C petrol–Et2O, 93 : 7) gave 16 as a colourless oil (72 mg,
15%, 98 : 2 dr).
SOCl2 (0.94 mL, 13.1 mmol) was added dropwise to a solution
of 1211 (1.82 g, 4.38 mmol, >99 : 1 dr) in allyl alcohol (18 mL)
at 0 °C and the resultant mixture was stirred at 50 °C for 3 h.
The reaction mixture was then allowed to cool to rt and con-
centrated in vacuo. The residue was dissolved in CH2Cl2
(100 mL) and the resultant solution was washed with satd aq.
NaHCO3 (3 × 150 mL), then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent
30–40 °C petrol–Et2O, 98 : 2) gave 13 as a colourless oil (1.39 g,
79%, >99 : 1 dr); [α]D20 −4.9 (c 1.0 in CHCl3); νmax (ATR) 2971,
2935 (C–H), 1733 (CvO), 1601 (CvC); δH (400 MHz, CDCl3)
1.14 (3H, d, J 6.8, C(α)Me), 2.52 (1H, dd, J 14.6, 9.6, C(2)HA),
2.61 (1H, dd, J 14.6, 5.4, C(2)HB), 3.58 (1H, d, J 14.6,
NCHAHBPh), 3.65 (1H, d, J 14.6, NCHAHBPh), 3.92 (1H, q,
J 6.8, C(α)H), 4.24–4.32 (2H, m, C(1′)H2), 4.38 (1H, dd, J 9.6, 5.4,
C(3)H), 5.00–5.04 (2H, m, C(3′)H2), 5.56–5.66 (1H, m, C(2′)H),
7.07–7.32 (15H, m, Ph); δC (100 MHz, CDCl3) 15.8 (C(α)Me),
37.5 (C(2)), 50.7 (NCH2Ph), 56.7 (C(α)), 59.3 (C(3)), 64.9 (C(1′)),
118.0 (C(3′)), 126.6, 126.8, 127.2, 127.8, 128.0, 128.0, 128.1,
128.1, 128.2 (o,m,p-Ph), 132.0 (C(2′)), 141.3, 141.6, 143.9 (i-Ph),
171.4 (C(1)); m/z (ESI+) 422 ([M + Na]+, 100%), 400 ([M + H]+,
+
90%); HRMS (ESI+) C27H29NNaO2 ([M
+
Na]+) requires
422.2091; found 422.2091.
Methyl (RS,SR)-2-(prop-2′-en-1′-yl)-3-(N,N-dibenzylamino)-
3-phenylpropanoate 16
X-ray crystal structure determination for 16
Method A. TMSCl (0.9 mL, 7.8 mmol) was added dropwise Data were collected using a Nonius κ-CCD diffractometer with
to a solution of 10 (1.00 g, 2.59 mmol) in PhMe (10 mL) at graphite monochromated Mo-Kα radiation, using standard
−78 °C, and the resultant solution was stirred at −78 °C for procedures at 150 K. The structure was solved by direct
10 min. LiHMDS (1.0 M in THF, 7.8 mL, 7.8 mmol) was added methods (SIR92); all non-hydrogen atoms were refined with
dropwise and the resultant solution was stirred at −78 °C for anisotropic thermal parameters. Hydrogen atoms were added
30 min. The reaction mixture was heated at reflux for 1 h, then at idealised positions.
allowed to cool to rt and concentrated in vacuo. The residue
X-ray crystal structure data for 16 [C27H29NO2]: M = 399.53,
ˉ
was then partitioned between CH2Cl2 (100 mL) and 1.0 M aq. triclinic, P1, a = 10.0503(2) Å, b = 10.9520(2) Å, c = 11.2054(3)
HCl (100 mL), and the aqueous layer was extracted with Å, α = 74.3842(8)°, β = 68.6115(8)°, γ = 80.1552(12)°, V =
CH2Cl2 (2 × 50 mL). The combined organic extracts were 1102.40(4) Å3, Z = 2, μ = 0.075 mm−1, colourless block, crystal
washed with brine (150 mL), then dried and concentrated in vacuo. dimensions = 0.17 × 0.22 × 0.27 mm3. A total of 5018 unique
The residue was then dissolved in MeOH (20 mL), the resultant reflections were measured for 5 < θ < 27 and 3448 reflections
solution was cooled to 0 °C, and SOCl2 (5.6 mL, 77.8 mmol) were used in the refinement. The final parameters were wR2 =
was added dropwise. The reaction mixture was heated at 50 °C 0.109 and R1 = 0.053 [I > −3.0σ(I)]. CCDC 982697.†
for 48 h, then allowed to cool to rt and concentrated in vacuo.
Methyl (RS,SR)-2-(prop-2′-en-1′-yl)-3-(N-isopropyl-N-benzyl-
amino)-3-phenylpropanoate 17
The residue was dissolved in CH2Cl2 (100 mL) and the resul-
tant solution was washed with satd aq. NaHCO3 (3 × 100 mL).
The organic extract was then dried and concentrated in vacuo.
Method A. TMSCl (1.12 mL, 8.89 mmol) was added drop-
Purification via flash column chromatography (eluent wise to a solution of 11 (1.00 g, 2.96 mmol) in PhMe (10 mL)
30–40 °C petrol–Et2O, 99 : 1) gave 16 as a pale yellow oil at −78 °C, and the resultant solution was stirred at −78 °C for
(51 mg, 40%, 83 : 17 dr). Data for major diastereoisomer: δH 10 min. LiHMDS (1.0 M in THF, 8.89 mL, 8.89 mmol) was
(400 MHz, CDCl3) 1.69–1.73 (1H, m, C(1′)HA), 1.90–1.99 (1H, added dropwise and the resultant solution was stirred at
m, C(1′)HB), 2.86 (2H, d, J 13.6, N(CHAHBPh)2), 3.33 (1H, app −78 °C for 30 min. The reaction mixture was allowed to warm
td, J 11.5, 3.3, C(2)H), 3.67 (3H, s, OMe), 3.83–3.89 (3H, m, C(3)H, to rt then heated at reflux for 1 h, before being allowed to cool
N(CHAHBPh)2), 4.79–4.82 (2H, m, C(3′)H2), 5.47–5.57 (1H, to rt and concentrated in vacuo. The residue was then parti-
m, C(2′)H), 7.08–7.36 (15H, m, Ph); δC (100 MHz, CDCl3) 34.8 tioned between CH2Cl2 (100 mL) and 1.0 M aq. HCl (100 mL),
(C(1′)), 48.4 (C(2)), 51.4 (OMe), 53.7 (N(CH2Ph)2), 64.5 (C(3)), and the aqueous layer was extracted with CH2Cl2 (2 × 50 mL).
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The combined organic extracts were washed with brine
Method B – step 2. LiHMDS (1.0 M in THF, 2.27 mL,
(150 mL), then dried and concentrated in vacuo. The residue 2.27 mmol) was added dropwise to a solution of methyl (RS)-3-
was then dissolved in MeOH (10 mL), the resultant solution (N-isopropyl-N-benzylamino)-3-phenylpropanoate (236 mg,
was cooled to 0 °C, and SOCl2 (6.39 mL, 88.9 mmol) was 0.76 mmol) in THF (2.5 mL) at −78 °C, and the resultant solu-
added dropwise. The reaction mixture was then heated at tion was stirred at −78 °C for 2 h. Allyl bromide (198 μL,
50 °C for 48 h, then allowed to cool to rt and concentrated 2.27 mmol) was then added dropwise, and the resultant solu-
in vacuo. The residue was dissolved in CH2Cl2 (100 mL), the resul- tion was allowed to warm to rt over 16 h. Satd aq. NH4Cl
tant solution was washed with satd aq. NaHCO3 (3 × 100 mL), (0.5 mL) was then added and the aqueous layer was extracted
then dried and concentrated in vacuo. Purification via flash with Et2O (2 × 10 mL). The combined organic extracts were
column chromatography (eluent 30–40 °C petrol–Et2O, 99 : 1) washed with brine (20 mL), then dried and concentrated
gave 17 as a pale yellow oil (640 mg, 62%, 88 : 12 dr). Data for in vacuo to give 17 in 81 : 19 dr. Purification via flash column
major diastereoisomer: δH (400 MHz, CDCl3) 0.42 (3H, d, J 6.6, chromatography (eluent, 30–40 °C petrol–Et2O, 98 : 2) gave 17
CHMeAMeB), 1.01 (3H, d, J 6.6, CHMeAMeB), 1.70–1.74 (1H, m, as a colourless oil (30 mg, 11%, >99 : 1 dr).
C(1′)HA), 1.87–1.95 (1H, m, C(1′)HB), 3.22–3.30 (2H, m, C(2)H,
CHMe2), 3.28 (1H, d, J 14.2, NCHAHBPh), 3.60 (3H, s, OMe),
3.80 (1H, d, J 14.2, NCHAHBPh), 3.84 (1H, d, J 11.6, C(3)H),
Methyl (RS,SR)-2-propyl-3-(N-isopropylamino)-3-phenyl-
propanoate 18
4.78–4.82 (2H, m, C(3′)H2), 5.47–5.57 (1H, m, C(2′)H),
Method A. Pd(OH)2/C (50 mg, 50% w/w) was added to a
7.17–7.30 (10H, m, Ph); δC (100 MHz, CDCl3) 17.8, 22.7 degassed solution of 16 (100 mg, 0.25 mmol, 83 : 17 dr) in
(CHMe2), 34.7 (C(1′)), 47.4 (C(2)), 49.2 (CHMe2), 49.5 MeOH–acetone (9 : 1, 2.5 mL) at rt. The resultant suspension
(NCH2Ph), 51.2 (OMe), 64.3 (C(3)), 116.4 (C(3′)), 126.7, 127.4, was stirred vigorously under H2 (1 atm) at rt for 16 h. The reac-
127.9, 128.3, 129.0, 129.1 (o,m,p-Ph), 135.2 (C(2′)), 137.8, 140.4 tion mixture was then filtered through Celite® (eluent EtOAc)
(i-Ph), 174.4 (C(1)). Data for minor diastereoisomer: δH and the filtrate was washed with satd aq. NaHCO3 (10 mL),
(400 MHz, CDCl3) 0.46 (3H, d, J 6.7, CHMeAMeB), 1.06 (3H, d, then dried and concentrated in vacuo to give 18 in 83 : 17 dr.
J 6.7, CHMeAMeB), 2.00–2.06 (1H, m, C(1′)HA), 2.86–2.92 (1H, Purification via flash column chromatography (eluent,
m, C(1′)HB), 3.08 (1H, dt, J 11.2, 3.4, C(2)H), 3.14–3.19 (1H, m, 30–40 °C petrol–Et2O, 93 : 7) gave 18 as a colourless oil (56 mg,
CHMe2), 3.15 (3H, s, OMe), 3.34 (1H, d, J 14.2, NCHAHBPh), 85%, 83 : 17 dr). Data for major diastereoisomer: δH (400 MHz,
3.72–3.76 (2H, m, NCHAHBPh, C(3)H), 4.87–4.96 (2H, m, CDCl3) 0.67 (3H, t, J 7.2, C(3′)H3), 0.81 (3H, d, J 6.2, CHMeAMeB),
C(3′)H2), 5.58–5.68 (1H, m, C(2′)H), 7.15–7.34 (10H, m, Ph); δC 0.86 (3H, d, J 6.2, CHMeAMeB), 0.91–1.18 (3H, m, C(1′)HA,
(100 MHz, CDCl3) 18.4, 22.8 (CHMe2), 35.5 (C(1′)), 47.7 (C(2)), C(2′)H2), 1.32–1.42 (1H, m, C(1′)HB), 1.51 (1H, br s, NH),
48.8 (CHMe2), 49.2 (NCH2Ph), 50.9 (OMe), 63.3 (C(3)), 116.2 2.40 (1H, dt, J 12.4, 6.2, CHMe2), 2.51 (1H, dt, J 10.1, 3.5,
(C(3′)), 126.8, 127.2, 127.8, 128.2, 128.9 (o,m,p-Ph), 136.0 (C(2′)), C(2)H), 3.64 (3H, s, OMe), 3.70 (1H, d, J 10.1, C(3)H), 7.13–7.19
138.4, 140.6 (i-Ph), 174.4 (C(1)). Data for mixture: νmax (ATR) (3H, m, Ph), 7.24–7.27 (2H, m, Ph); δC (100 MHz, CDCl3) 13.7
2964 (C–H), 1738 (CvO), 1602 (CvC); m/z (ESI+) 374 (C(3′)), 20.6 (C(1′)), 21.6, 24.2 (CHMe2), 32.1 (C(2′)), 45.2
([M + Na]+, 50%), 352 ([M + H]+, 100%); HRMS (ESI+) (CHMe2), 51.3 (OMe), 53.6 (C(2)), 62.4 (C(3)), 127.2, 127.3,
C23H30NO2+ ([M + H]+) requires 352.2271; found 352.2260.
128.4 (o,m,p-Ph), 142.3 (i-Ph), 175.7 (C(1)). Data for minor
Method B – step 1. SOCl2 (0.31 mL, 4.24 mmol) was added diastereoisomer: δH (400 MHz, CDCl3) [selected peaks]
dropwise to a solution of 9 (500 mg, 9.96 mmol) in MeOH 1.57–1.65 (2H, m, C(1′)H2), 3.34 (3H, s, OMe), 3.79 (1H, d, J 7.8,
(12 mL) at 0 °C and the reaction mixture was then stirred at C(3)H); δC (100 MHz, CDCl3) [selected peaks] 13.9 (C(3′)), 20.9
50 °C for 16 h. The resultant mixture was concentrated (C(1′)), 21.7 (CHMeAMeB), 30.8 (C(2′)), 45.5 (CHMe2), 51.0
in vacuo, and the residue was dissolved in CH2Cl2 (20 mL). The (OMe), 53.4 (C(2)), 61.8 (C(3)), 127.0, 128.0 (o,m,p-Ph), 142.2
resultant solution was washed with satd aq. NaHCO3 (3 × (i-Ph), 174.8 (C(1)). Data for mixture: νmax (ATR) 3326 (N–H),
25 mL), then dried and concentrated in vacuo. Purification via 2960, 2872 (C–H), 1735 (CvO), 1602 (CvC); m/z (ESI+) 286
flash column chromatography (eluent 30–40 °C petrol–Et2O, ([M + Na]+, 5%), 264 ([M + H]+, 100%); HRMS (ESI+)
99 : 1) gave methyl (RS)-3-(N-isopropyl-N-benzylamino)-3-phenyl- C16H26NO2+ ([M + H]+) requires 264.1958; found 264.1956.
propanoate as a colourless oil (330 mg, 75%); νmax (ATR)
Method B. Pd(OH)2/C (120 mg, 50% w/w) was added to a
2964 (C–H), 1738 (CvO); δH (400 MHz, CDCl3) 0.68 (3H, d, degassed solution of 17 (240 mg, 0.68 mmol, 88 : 12 dr) in
J 6.6, CHMeA), 0.98 (3H, d, J 6.6, CHMeB), 2.51 (1H, dd, J 14.5, MeOH–acetone (9 : 1, 6 mL) at rt. The resultant suspension
7.7, C(2)HA), 2.86 (1H, dd, J 14.5, 7.7, C(2)HB), 3.02 (1H, septet, was stirred vigorously under H2 (1 atm) at rt for 17 h. The reac-
J 6.6, CHMe2), 3.43 (3H, s, OMe), 3.59 (2H, app d, J 15.2, tion mixture was then filtered through Celite® (eluent EtOAc)
NCH2Ph), 4.22 (1H, app t, J 7.7, C(3)H), 7.12–7.30 (10H, m, Ph); and the filtrate was washed with satd aq. NaHCO3 (10 mL),
δC (100 MHz, CDCl3) 18.4, 21.5 (CHMe2), 38.7 (C(2)), 47.7 then dried and concentrated in vacuo to give 18 in 88 : 12 dr.
(CHMe2), 49.3 (NCH2Ph), 51.4 (OMe), 59.8 (C(3)), 126.5, 127.1, Purification via flash column chromatography (eluent,
128.0, 128.1, 128.1, 128.1 (o,m,p-Ph), 141.2, 141.7 (i-Ph), 30–40 °C petrol–Et2O, 93 : 7) gave 18 as a colourless oil
172.2 (C(1)); m/z (ESI+) 312 ([M
+
H]+, 100%); HRMS (101 mg, 66%, 88 : 12 dr).
(ESI+) C20H26NO2 ([M
312.1949.
+
H]+) requires 312.1958; found
Method C. Pd(OH)2/C (87 mg, 50% w/w by substrate) was
added to a degassed solution of 20 (173 mg, 0.42 mmol,
+
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>99 : 1 dr) in MeOH–acetone (4 mL, 9 : 1) at rt. The resultant 3.14 (3H, s, OMe), 3.54 (1H, d, J 13.8, NCHAHBPh), 3.83 (1H, d,
suspension was stirred vigorously under H2 (1 atm) at rt for J 11.4, C(3)H), 3.87 (1H, d, J 13.8, NCHAHBPh), 4.06–4.11 (1H,
16 h. The reaction mixture was then filtered through Celite® m, C(α)H), 4.86–4.91 (2H, m, C(3′)H2), 5.56 (1H, ddt, J 17.1,
(eluent EtOAc) and the filtrate was washed with satd aq. 10.0, 7.1, C(2′)H), 7.14–7.32 (15H, m, Ph); δC (100 MHz, CDCl3)
NaHCO3 (10 mL), then dried and concentrated in vacuo. Purifi- 14.9 (C(α)Me), 35.3 (C(1′)), 49.3 (C(2)), 50.6 (NCH2Ph), 50.9
cation via flash column chromatography (eluent, 30–40 °C (OMe), 55.9 (C(α)), 62.5 (C(3)), 116.3 (C(3′)), 126.7, 127.0, 127.3,
petrol–Et2O, 93 : 7) gave 18 as a colourless oil which solidified 127.8, 128.0, 128.2, 128.3, 128.9, 129.1 (o,m,p-Ph), 135.9 (C(2′)),
upon standing (75 mg, 68%, >99 : 1 dr); mp 47–50 °C; [α]2D0 138.8, 140.0, 144.5 (i-Ph), 174.3 (C(1)).
+23.4 (c 1.0 in CHCl3).
Method B – step 1. TMSCl (1.3 mL, 10.4 mmol) was added
dropwise to a solution of 13 (1.39 g, 3.48 mmol, >99 : 1 dr) in
PhMe (14 mL) at −78 °C, and the resultant mixture was stirred
X-ray crystal structure determination for 18
Data were collected using an Oxford Diffraction SuperNova at −78 °C for 10 min. LiHMDS (1.0 M in THF, 10.4 mL,
diffractometer with graphite monochromated Cu-Kα radiation, 10.4 mmol) was then added dropwise and the resultant solu-
using standard procedures at 150 K. The structure was solved tion was stirred at −78 °C for 30 min. The reaction mixture was
by direct methods (SIR92); all non-hydrogen atoms were stirred at reflux for 1 h, then allowed to cool to rt and concen-
refined with anisotropic thermal parameters. Hydrogen atoms trated in vacuo. The residue was partitioned between CH2Cl2
were added at idealised positions.
(100 mL) and 1.0 M aq. HCl (100 mL), and the aqueous layer
X-ray crystal structure data for 18 [C16H25NO2]: M = 263.38, was extracted with CH2Cl2 (2 × 50 mL). The combined organic
orthorhombic, P212121, a = 8.66504(13) Å, b = 9.9818(2) Å, c = extracts were washed with brine (150 mL), then dried and con-
18.4067(4) Å, V = 1592.04(5) Å3, Z = 4, μ = 0.562 mm−1, colour- centrated in vacuo to give 19 as an orange oil (1.39 g, 92 : 8 dr).
less plate, crystal dimensions = 0.05 × 0.19 × 0.21 mm3. A total Purification of an aliquot via flash column chromatography
of 1913 unique reflections were measured for 5 < θ < 76 and (eluent, 30–40 °C petrol–acetone, 93 : 7) gave 19 as a white solid;
7067 reflections were used in the refinement. The final para- [α]2D0 +73.3 (c 1.0 in CHCl3); νmax (ATR) 3100–2600 (O–H), 2934,
meters were wR2 = 0.083 and R1 = 0.034 [I > −3.0σ(I)]. CCDC 2849 (C–H), 1708 (CvO), 1603 (CvC); δH (400 MHz, CDCl3)
982698.†
1.05 (3H, d, J 7.1, C(α)Me), 1.62–1.69 (1H, m, C(1′)HA),
2.31–2.35 (1H, m, C(1′)HB), 3.04 (1H, ddd, J 11.3, 6.8, 3.8,
C(2)H), 3.60 (1H, d, J 13.5, NCHAHBPh), 4.07 (1H, app q, J 6.8,
C(3)H), 4.16–4.20 (1H, m, C(α)H), 4.18 (1H, d, J 13.5, NCHAHBPh),
Methyl (2S,3R,αS)-2-(prop-2′-en-1′-yl)-3-[N-benzyl-N-
(α-methylbenzyl)amino]-3-phenylpropanoate 20
Method A. LiHMDS (1.0 M in THF, 4.0 mL, 4.0 mmol) was 4.57–4.76 (2H, m, C(3′)H2), 5.38–5.48 (1H, m, C(2′)H),
added dropwise to a solution of 2112a (500 mg, 1.34 mmol, 7.16–7.41 (15H, m, Ph); δC (100 MHz, CDCl3) 13.9 (C(α)Me),
>99 : 1 dr) in THF (5 mL) at −78 °C, and the resultant solution 32.9 (C(1′)), 44.5 (C(2)), 51.0 (NCH2Ph), 57.6 (C(3)), 61.6 (C(α)),
was stirred at −78 °C for 2 h. Allyl bromide (525 μL, 117.4 (C(3′)), 127.7, 127.8, 128.4, 128.4, 128.6, 128.7, 129.4,
6.03 mmol) was then added dropwise, and the resultant solu- 129.7 (o,m,p-Ph), 134.1 (C(2′)), 135.8, 136.3, 140.2 (i-Ph), 175.9
tion was allowed to warm to rt over 16 h. Satd aq. NH4Cl (C(1)); m/z (ESI+) 422 ([M + Na]+, 100%), 400 ([M + H]+, 30%);
(0.5 mL) was added and the aqueous layer was extracted with m/z (ESI–) 398 ([M − H]−, 40%); HRMS (ESI+) C27H30NO2
+
Et2O (2 × 10 mL). The combined organic extracts were washed ([M + H]+) requires 400.2271; found 400.2268.
with brine (20 mL), then dried and concentrated in vacuo to
Method B – step 2. The residue of 19 (92 : 8 dr) was dis-
give 20 in 83 : 17 dr. Purification via flash column chromato- solved in MeOH (15 mL) and the resultant solution was cooled
graphy (eluent, 30–40 °C petrol–Et2O, 98 : 2) gave 20 as a col- to 0 °C. SOCl2 (7.5 mL, 104 mmol) was then added dropwise
ourless oil which solidified upon standing (370 mg, 67%, and the reaction mixture was allowed to warm to rt, then
>99 : 1 dr); mp 79–81 °C; [α]2D0 +27.4 (c 1.0 in CHCl3); νmax (ATR) heated at 50 °C for 48 h, then allowed to cool to rt and concen-
2977 (C–H), 1737 (CvO), 1642 (CvC); δH (400 MHz, CDCl3) trated in vacuo. The residue was dissolved in CH2Cl2 (100 mL)
0.83 (3H, d, J 7.0, C(α)Me), 1.60–1.64 (1H, m, C(1′)HA), and the resultant solution was washed with satd aq. NaHCO3
1.80–1.88 (1H, m, C(1′)HB), 3.21 (1H, dt, J 11.3, 3.4, C(2)H), (3 × 100 mL), then dried and concentrated in vacuo. Purifi-
3.45 (3H, s, OMe), 3.56 (1H, d, J 13.7, NCHAHBPh), 3.92 (1H, d, cation via flash column chromatography (eluent, 30–40 °C
J 11.3, C(3)H), 4.07–4.14 (1H, m, C(α)H), 4.12 (1H, d, J 13.7, petrol–Et2O, 98 : 2) gave 20 as a colourless oil which solidified
NCHAHBPh), 4.73–4.78 (2H, m, C(3′)H2), 5.39–5.49 (1H, m, upon standing (718 mg, 50%, >99 : 1 dr); [α]2D0 +26.1 (c 1.0 in
C(2′)H), 7.13–7.32 (15H, m, Ph); δC (100 MHz, CDCl3) 13.9 (C(α)Me), CHCl3). Further elution gave second (44 mg, 3%, 62 : 38 dr)
34.8 (C(1′)), 49.3 (C(2)), 50.7 (NCH2Ph), 51.2 (OMe), 55.3 and third (30 mg, 5%, 58 : 42 dr) fractions of 20 as colourless
(C(α)), 63.4 (C(3)), 116.4 (C(3′)), 126.4, 126.8, 127.5, 127.7, oils.
128.0, 128.2, 128.4, 129.0, 129.1 (o,m,p-Ph), 135.0 (C(2′)), 138.8,
X-ray crystal structure determination for 19
139.8, 144.0 (i-Ph), 174.0 (C(1)); m/z (ESI+) 436 ([M + Na]+,
100%), 414 ([M + H]+, 80%); HRMS (ESI+) C28H31NNaO2 ([M + Data were collected using an Oxford Diffraction SuperNova
+
Na]+) requires 436.2247; found 436.2234. Data for minor dia- diffractometer with graphite monochromated Cu-Kα radiation,
stereoisomer: δH (400 MHz, CDCl3) 0.88 (3H, d, J 6.8, C(α)Me), using standard procedures at 150 K. The structure was solved
1.80–1.91 (2H, m, C(1′)H2), 3.09 (1H, td, J 11.2, 3.2, C(2)H), by direct methods (SIR92); all non-hydrogen atoms were
2712 | Org. Biomol. Chem., 2014, 12, 2702–2728
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refined with anisotropic thermal parameters. Hydrogen atoms 0 °C for 30 min. Satd aq. NH4Cl (2 mL) was then added and
were added at idealised positions. the aqueous layer was extracted with Et2O (2 × 5 mL). The com-
X-ray crystal structure data for 19 [C27H29NO2]: M = 399.53, bined organic extracts were then dried and concentrated
trigonal, P312, a = b = 11.2376(1) Å, c = 31.9939(3) Å, V = in vacuo. Purification via flash column chromatography
3498.98(6) Å3, Z = 6, μ = 0.553 mm−1, colourless block, crystal (eluent, 30–40 °C petrol–Et2O, 80 : 20) gave 23 as a colourless
dimensions = 0.23 × 0.24 × 0.27 mm3. A total of 4879 unique oil (30 mg, 83%, >99 : 1 dr); [α]2D0 +34.8 (c 1.0 in CHCl3); νmax
reflections were measured for 5 < θ < 77 and 4158 reflections (ATR) 2979, 2934 (C–H), 1746 (CvO), 1603 (CvC); δH
were used in the refinement. The final parameters were wR2 = (400 MHz, CDCl3) 1.22 (3H, d, J 7.3, C(α)Me), 2.20–2.29 (1H, m,
0.085 and R1 = 0.034 [I > −3.0σ(I)])], with Flack enantiopole = C(1′)HA), 2.38–2.45 (1H, m, C(1′)HB), 3.00 (1H, ddd, J 8.8, 5.1,
−0.02(18).17 CCDC 982699.†
2.0, C(3)H), 3.87 (1H, d, J 2.0, C(4)H), 4.85–4.90 (2H, m,
C(3′)H2), 4.97 (1H, q, J 7.3, C(α)H), 5.57–5.67 (1H, m, C(2′)H),
7.14–7.27 (10H, m, Ph); δC (100 MHz, CDCl3) 18.6 (C(α)Me),
X-ray crystal structure determination for 20
Data were collected using an Oxford Diffraction SuperNova 32.3 (C(1′)), 51.9 (C(α)), 58.4 (C(3)), 59.8 (C(4)), 117.1 (C(3′)),
diffractometer with graphite monochromated Cu-Kα radiation, 127.3, 127.7, 128.3, 128.5, 128.6, 128.8 (o,m,p-Ph), 134.1 (C(2′)),
using standard procedures at 150 K. The structure was solved 139.5, 140.0 (i-Ph), 170.0 (C(2)); m/z (ESI+) 314 ([M + Na]+,
by direct methods (SIR92); all non-hydrogen atoms were 100%), 292 ([M + H]+, 40%); HRMS (ESI+) C20H21NNaO+
refined with anisotropic thermal parameters. Hydrogen atoms ([M + Na]+) requires 314.1515; found 314.1509.
were added at idealised positions.
2′-Methylbut-3′-en-2′-yl (3R,αS)-3-[N-benzyl-N-(α-methyl-
benzyl)amino]-3-phenylpropanoate 25
X-ray crystal structure data for 20 [C28H31NO2]: M = 413.56,
monoclinic, P21, a = 9.7215(3) Å, b = 13.5384(2) Å, c = 10.1187(3)
Å, β = 116.959(3)°, V = 1187.05(6) Å3, Z = 2, μ = 0.559 mm−1
,
BuLi (2.0 M in hexanes, 14.3 mL, 28.7 mmol) was added drop-
colourless block, crystal dimensions = 0.25 × 0.31 × 0.40 mm3. wise to a solution of (S)-N-benzyl-N-(α-methylbenzyl)amine
A total of 2574 unique reflections were measured for 5 < θ < 77 (6.25 g, 29.6 mmol) in THF (132 mL) at −78 °C, and the resul-
and 9573 reflections were used in the refinement. The final tant mixture was stirred at −78 °C for 30 min. A solution of 24
parameters were wR2 = 0.101 and R1 = 0.038 [I > −3.0σ(I)], with (4.00 g, 18.5 mmol, >99 : 1 dr) in THF (52 mL) at −78 °C was
Flack enantiopole = −0.02(15).17 CCDC 982700.†
then added dropwise via cannula, and the resultant mixture
was stirred at −78 °C for 2 h. Satd aq. NH4Cl (20 mL) was then
added and the reaction mixture was allowed to warm to rt. The
aqueous layer was extracted with Et2O (3 × 100 mL) and the
Methyl (2S,3R,αS)-2-(prop-2′-en-1′-yl)-3-[N-(α-methyl-benzyl)-
amino]-3-phenylpropanoate 22
CAN (696 mg, 1.27 mmol) was added to a stirred solution of 20 combined organic extracts were washed sequentially with 10%
(250 mg, 0.60 mmol, >99 : 1 dr) in MeCN–H2O (5 : 1, 7 mL) at rt aq. citric acid (100 mL), satd aq. NaHCO3 (100 mL) and brine
and the resultant mixture was stirred at rt for 16 h. Satd aq. (100 mL), then dried and concentrated in vacuo to give 25 in
NaHCO3 (15 mL) and Et2O (20 mL) were then added and the >95 : 5 dr. Purification via flash column chromatography
aqueous layer was extracted with Et2O (2 × 20 mL). The com- (eluent 30–40 °C petrol–Et2O, 99 : 1) gave 25 as a colourless oil
bined organic extracts were washed with brine (50 mL), then which solidified upon standing (5.78 g, 73%, >99 : 1 dr); mp
dried and concentrated in vacuo. Purification via flash column 60–62 °C; [α]2D0 −8.2 (c 1.0 in CHCl3); νmax (ATR) 2976, 2934
chromatography (eluent, 30–40 °C petrol–Et2O, 95 : 5) gave 22 (C–H), 1728 (CvO), 1602 (CvC); δH (400 MHz, CDCl3) 1.34
as a colourless oil (179 mg, 91%, >99 : 1 dr); [α]2D0 −5.3 (c 1.0 in (3H, d, J 7.0, C(α)Me), 1.35 (3H, s, C(2′)MeA), 1.37 (3H, s, C(2′)MeB),
CHCl3); νmax (ATR) 3320 (N–H), 2970, 2949 (C–H), 1735 (CvO), 2.61–2.64 (2H, m, C(2)H2), 3.76 (2H, app s, NCH2Ph),
1642, 1603 (CvC); δH (400 MHz, CDCl3) 1.16 (3H, d, J 6.3, C(α)Me), 4.07 (1H, q, J 7.0, C(α)H), 4.51 (1H, dd, J 8.3, 6.6, C(3)H),
1.74 (1H, br s, NH), 1.83–1.88 (1H, m, C(1′)HA), 2.10–2.17 4.98–5.04 (2H, m, C(4′)H2), 5.87 (1H, dd, J 17.4, 10.9, C(3′)H),
(1H, m, C(1′)HB), 2.62 (1H, app td, J 9.9, 6.9, C(2)H), 3.43 (1H, 7.22–7.42 (11H, m, Ph), 7.49–7.51 (4H, m, Ph); δC (100 MHz,
q, J 6.3, C(α)H), 3.63 (3H, s, OMe), 3.83 (1H, d, J 9.9, C(3)H), CDCl3) 16.2 (C(α)Me), 26.1 (C(2′)Me2), 38.2 (C(2)), 50.8
4.83–4.88 (2H, m, C(3′)H2), 5.49–5.59 (1H, m, C(2′)H), (NCH2Ph), 57.0 (C(α)), 59.6 (C(3)), 80.5 (C(2′)), 112.2 (C(4′)),
7.08–7.25 (10H, m, Ph); δC (125 MHz, CDCl3) 21.8 (C(α)Me), 126.5, 126.8, 127.1, 127.8, 127.9, 128.1, 128.2 (o,m,p-Ph), 141.6,
34.2 (C(1′)), 51.3 (OMe), 53.3 (C(2)), 54.4 (C(α)), 61.9 (C(3)), 141.6 (i-Ph), 142.4 (C(3′)), 144.0 (i-Ph), 170.6 (C(1)); m/z (ESI+)
116.6 (C(3′)), 126.5, 126.8, 127.3, 127.4, 128.2, 128.5 (o,m,p-Ph), 428 ([M + H]+, 100%); HRMS (ESI+) C29H34NO2 ([M + H]+)
+
135.0 (C(2′)), 141.3, 146.2 (i-Ph), 174.7 (C(1)); m/z (ESI+) 346 requires 428.2584; found 428.2569.
([M + Na]+, 100%), 324 ([M + H]+, 100%); HRMS (ESI+)
X-ray crystal structure determination for 25
C21H26NO2+ ([M + H]+) requires 324.1958; found 324.1949.
Data were collected using an Oxford Diffraction SuperNova
diffractometer with graphite monochromated Cu-Kα radiation,
using standard procedures at 150 K. The structure was solved
(3S,4R,αS)-N(1)-(α-Methylbenzyl)-3-(prop-2′-en-1′-yl)-4-
phenylazetidin-2-one 23
MeMgBr (90 μL, 2.0 M in Et2O, 0.18 mmol) was added drop- by direct methods (SIR92); all non-hydrogen atoms were
wise to a solution of 22 (50.0 mg, 0.15 mmol, >99 : 1 dr) in refined with anisotropic thermal parameters. Hydrogen atoms
Et2O (2 mL) at 0 °C and the resultant mixture was stirred at were added at idealised positions.
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X-ray crystal structure data for 25 [C29H33NO2]: M = 427.59, 3.53 (1H, d, J 13.9, NCHAHBPh), 3.91 (1H, d, J 11.3, C(3)H),
monoclinic, P21, a = 10.27494(11) Å, b = 10.27815(10) Å, c = 4.06–4.11 (1H, m, C(α)H), 4.09 (1H, d, J 13.9, NCHAHBPh),
12.21513(16) Å, β = 107.2702(13)°, V = 1231.85(3) Å3, Z = 2, μ = 4.76–4.80 (1H, m, C(2′)H), 7.09–7.30 (15H, m, Ph); δC
0.554 mm−1, colourless block, crystal dimensions = 0.15 × 0.18 (100 MHz, CDCl3) 14.0 (C(α)Me), 17.4 (C(3′)MeA), 25.6 (C(3′)MeB),
× 0.19 mm3. A total of 2711 unique reflections were measured 29.3 (C(1′)), 49.7 (C(2)), 50.6 (NCH2Ph), 51.1 (OMe), 55.2
for 4 < θ < 77 and 10 142 reflections were used in the refinement. (C(α)), 63.3 (C(3)), 120.6 (C(2′)), 126.3, 126.8, 127.4, 127.7,
The final parameters were wR2 = 0.076 and R1 = 0.029 [I > −3.0σ(I)], 127.9, 128.1, 128.3, 128.9, 129.0 (o,m,p-Ph), 133.4 (C(3′)), 139.0,
with Flack enantiopole = −0.09(10).17 CCDC 982701.†
139.8, 144.1 (i-Ph), 174.4 (C(1)); m/z (ESI+) 464 ([M + Na]+,
+
H]+, 100%); HRMS (ESI+) C30H36NO2
+
40%), 442 ([M
Methyl (2S,3R,αS)-2-(3′-methylbut-2′-en-1′-yl)-3-[N-benzyl-
N-(α-methylbenzyl)amino]-3-phenylpropanoate 27
([M + H]+) requires 442.2741; found 442.2734. Further elution
gave 27 as a colourless oil (6 mg, 12% from 25, 43 : 57 dr). Data
Step 1. TMSCl (89 μL, 0.70 mmol) was added dropwise to a for minor diastereoisomer: δH (400 MHz, CDCl3) 0.85 (3H, d,
solution of 25 (100 mg, 0.23 mmol, >99 : 1 dr) in PhMe (1 mL) J 6.9, C(α)Me), 1.41 (3H, s, C(3′)MeA), 1.57 (3H, s, C(3′)MeB),
at −78 °C, and the resultant mixture was stirred at −78 °C for 1.79–1.87 (1H, m, C(1′)HA), 2.70–2.73 (1H, m, C(1′)HB), 3.01
10 min. LiHMDS (1.0 M in THF, 0.70 mL, 0.70 mmol) was then (1H, app td, J 11.1, 3.6, C(2)H), 3.13 (3H, s, OMe), 3.54 (1H, d,
added dropwise and the resultant mixture was stirred at J 13.9, NCHAHBPh), 3.83 (1H, d, J 11.1, C(3)H), 3.89 (1H, d,
−78 °C for 30 min. The reaction mixture was then allowed to J 13.9, NCHAHBPh), 4.07–4.10 (1H, m, C(α)H), 4.86–4.89 (1H,
warm to rt, then heated at reflux for 1 h, then allowed to cool m, C(2′)H), 7.12–7.33 (15H, m, Ph); δC (100 MHz, CDCl3) 14.6
to rt and concentrated in vacuo. The residue was partitioned (C(α)Me), 17.6 (C(3′)MeA), 25.8 (C(3′)MeB), 29.8 (C(1′)), 49.5
between CH2Cl2 (10 mL) and 1.0 M aq. HCl (10 mL), and the (C(2)), 50.6 (NCH2Ph), 51.0 (OMe), 55.6 (C(α)), 62.6 (C(3)), 121.2
aqueous layer was extracted with CH2Cl2 (2 × 10 mL). The com- (C(2′)), 126.7, 127.0, 127.2, 127.9, 128.0, 128.1, 128.3, 129.0,
bined organic extracts were washed with brine (25 mL), then dried 129.2 (o,m,p-Ph), 133.3 (C(3′)), 139.1, 140.1, 144.6 (i-Ph), 174.7
and concentrated in vacuo to give 26 as a pale orange solid (C(1)). Data for mixture: νmax (ATR) 2929, 2853 (C–H), 1736
(100 mg, 93 : 7 dr). Purification of an aliquot via flash column (CvO), 1603 (CvC); m/z (ESI+) 464 ([M + Na]+, 60%), 442
+
chromatography (eluent 30–40 °C petrol–acetone, 93 : 7) gave ([M + H]+, 100%); HRMS (ESI+) C30H36NO2 ([M + H]+) requires
26 as a white solid (>99 : 1 dr); mp 146–148 °C; [α]2D0 +58.9 442.2741; found 442.2742.
(c 1.0 in CHCl3); νmax (ATR) 2969, 2929 (C–H), 1706 (CvO),
Methyl (2S,3R)-2-(3′-methylbutyl)-3-(N-isopropylamino)-
3-phenylpropanoate 29
1602 (CvC); δH (400 MHz, CDCl3) 1.03 (3H, d, J 7.0, C(α)Me),
1.05 (3H, s, C(3′)MeA), 1.42 (3H, s, C(3′)MeB), 1.68–1.75 (1H, m,
C(1′)HA), 2.16 (1H, app d, J 14.4, C(1′)HB), 2.98–3.04 (1H, m,
Method A – step 1. Pd(OH)2/C (75 mg, 50% w/w) was added
C(2)H), 3.60 (1H, d, J 13.2, NCHAHBPh), 4.08 (1H, q, J 7.0, to a degassed solution of 27 (150 mg, 0.34 mmol, >99 : 1 dr) in
C(α)H), 4.15 (1H, d, J 11.6, C(3)H), 4.17 (1H, d, J 13.2, NCHAHBPh), MeOH (3.4 mL) at rt. The resultant mixture was stirred vigor-
4.69–4.72 (1H, m, C(2′)H), 7.16–7.27 (10H, m, Ph), 7.31–7.38 (5H, ously under H2 (1 atm) at rt for 15 h. The reaction mixture was
m, Ph); δC (100 MHz, CDCl3) 13.8 (C(α)Me), 17.6 (C(3′)MeA), 25.6 then filtered through Celite® (eluent EtOAc) and the filtrate
(C(3′)MeB), 27.4 (C(1′)), 45.2 (C(2)), 50.9 (NCH2Ph), 57.4 (C(α)), was washed with satd aq. NaHCO3 (10 mL), then dried and con-
61.7 (C(3)), 119.9 (C(2′)), 127.7, 127.7, 128.3, 128.3, 128.5, centrated in vacuo to give 28 as a yellow solid (76 mg, >99 : 1 dr).
128.6, 129.4, 129.8 (o,m,p-Ph), 133.8 (C(3′)), 136.2, 136.4, 140.3
Method A – step 2. Acetone (44 μL, 0.61 mmol) and
(i-Ph), 176.6 (C(1)); m/z (ESI+) 450 ([M + Na]+, 10%), 428 NaBH3CN (77 mg, 1.22 mmol) were added sequentially to a
([M + H]+, 100%); m/z (ESI–) 426 ([M − H]− 100%); HRMS (ESI+) solution of the residue of 28 (76 mg, >99 : 1 dr) in MeOH
C29H34NO2+ ([M + H]+) requires 428.2584; found 428.2573.
(4 mL) at rt, and the resultant mixture was stirred at rt for
Step 2. The residue of 26 (50 mg, 93 : 7 dr) was dissolved in 22 h. The reaction mixture was then concentrated in vacuo, the
MeCN (500 μL) and the resultant solution was treated sequen- residue was partitioned between CH2Cl2 (10 mL) and H2O
tially with DBU (18 μL, 0.12 mmol) and MeI (9 μL, 0.14 mmol), (10 mL), and the aqueous layer was extracted with CH2Cl2
and the resultant mixture was stirred at rt for 4 h, then concen- (3 × 10 mL). The combined organic extracts were then dried
trated in vacuo. The residue was partitioned between CH2Cl2 and concentrated in vacuo. Purification via flash column
(5 mL) and 2.0 M aq. HCl (5 mL), and the aqueous layer was chromatography (eluent 30–40 °C petrol–Et2O, 93 : 7) gave 29
extracted with CH2Cl2 (3 × 5 mL). The combined organic as a colourless oil which solidified upon standing (49 mg, 55%
extracts were then washed sequentially with satd aq. NaHCO3 from 27, >99 : 1 dr); mp 47–49 °C; [α]2D0 +12.2 (c 1.0 in CHCl3);
(15 mL) and brine (15 mL), then dried and concentrated νmax (ATR) 3324 (N–H), 2956, 2870 (C–H), 1735 (CvO); δH
in vacuo. Purification via flash column chromatography (eluent (400 MHz, CDCl3) 0.63 (3H, d, J 6.7, C(3′)MeA), 0.66 (3H, d,
30–40 °C petrol–Et2O, 98 : 2) gave 27 as a colourless oil (34 mg, J 6.7, C(3′)MeB), 0.81 (3H, d, J 6.2, NHCHMeAMeB), 0.86 (3H, d,
66% from 25, >99 : 1 dr); [α]2D0 +4.3 (c 1.0 in CHCl3); νmax (ATR) J 6.2, NHCHMeAMeB), 0.90–0.96 (2H, m, C(2′)H2), 0.97–1.06
2969, 2946 (C–H), 1737 (CvO), 1602 (CvC); δH (400 MHz, (1H, m, C(1′)HA), 1.24–1.32 (1H, m, C(3′)H), 1.33–1.41 (1H, m,
CDCl3) 0.81 (3H, d, J 7.1, C(α)Me), 1.23 (3H, s, C(3′)MeA), 1.46 C(1′)HB), 2.44–2.51 (1H, m, NHCHMe2), 2.46 (1H, td, J 10.0,
(3H, s, C(3′)MeB), 1.49–1.55 (1H, m, C(1′)HA), 1.77–1.86 (1H, m, 3.4, C(2)H), 3.64 (3H, s, OMe), 3.71 (1H, d, J 10.0, C(3)H),
C(1′)HB), 3.11 (1H, app td, J 11.3, 3.4, C(2)H), 3.42 (3H, s, OMe), 7.17–7.20 (3H, m, Ph), 7.24–7.27 (2H, m, Ph); δC (100 MHz,
2714 | Org. Biomol. Chem., 2014, 12, 2702–2728
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CDCl3) 21.6, 21.9, 22.7, 24.2 (C(3′)Me2, NHCHMe2), 27.7 (C(3′)), 3′-Methylbut-2′-en-1′-yl (3R,αS)-3-[N-benzyl-N-(α-methyl-
27.8 (C(1′)), 36.4 (C(2′)), 45.2 (NHCHMe2), 51.4 (OMe), 53.9 benzyl)amino]-3-phenylpropanoate 30
(C(2)), 62.3 (C(3)), 127.2, 127.3, 128.4 (o,m,p-Ph), 142.3 (i-Ph),
Step 1. TFA (0.9 mL) was added to a stirred solution of 1211
175.7 (C(1)); m/z (ESI+) 314 ([M + Na]+, 10%), 292 ([M + H]+,
(200 mg, 0.48 mmol, >99 : 1 dr) in CH2Cl2 (1.9 mL) at rt, and
+
100%); HRMS (ESI+) C18H30NO2 ([M + H]+) requires 292.2271;
found 292.2263.
Method B – step 1. TMSCl (443 μL, 3.51 mmol) was added
dropwise to a solution of 25 (500 mg, 1.17 mmol, >99 : 1 dr) in
PhMe (5 mL) at −78 °C, and the resultant mixture was stirred
at −78 °C for 10 min. LiHMDS (1.0 M in THF, 3.5 mL,
3.51 mmol) was then added dropwise and the resultant
the resultant mixture was stirred at rt for 16 h. Satd aq.
NaHCO3 (10 mL) and CH2Cl2 (10 mL) were then added and the
aqueous layer was extracted with CH2Cl2 (10 mL). The com-
bined organic extracts were then concentrated in vacuo to give
an orange oil (109 mg, >99 : 1 dr).
Step 2. A solution of the residue (109 mg, >99 : 1 dr) in
MeCN (2 mL) was treated sequentially with DBU (144 μL,
mixture was stirred at −78 °C for 30 min. The reaction mixture
0.96 mmol) and 3,3-dimethylallyl bromide (134 μL,
was then allowed to warm to rt, then heated at reflux for 1 h,
1.16 mmol) at rt. The resultant mixture was stirred at rt for
then allowed to cool to rt and concentrated in vacuo. The
17 h, then concentrated in vacuo. The residue was partitioned
residue was partitioned between CH2Cl2 (10 mL) and 1.0 M aq.
between CH2Cl2 (20 mL) and 2.0 M aq. HCl (20 mL), and the
HCl (10 mL), and the aqueous layer was extracted with CH2Cl2
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The com-
(2 × 10 mL). The combined organic extracts were washed with
bined organic extracts were then washed sequentially with satd
aq. NaHCO3 (30 mL) and brine (30 mL), then dried and con-
centrated in vacuo. Purification via flash column chromato-
graphy (eluent 30–40 °C petrol–Et2O, 99 : 1) gave 30 as a
brine (25 mL), then dried and concentrated in vacuo to give 26
as a pale orange solid (63 mg, 93 : 7 dr).
Method B – step 2. Pd(OH)2/C (32 mg, 50% w/w) was added
colourless oil (115 mg, 56% from 12, >99 : 1 dr); [α]2D0 −9.7
to a degassed solution of the residue of 26 (63 mg, 93 : 7 dr) in
MeOH–acetone (9 : 1, 1.6 mL) at rt. The resultant suspension
(c 1.0 in CHCl3); νmax (ATR) 2971, 2933 (C–H), 1731 (CvO); δH
(400 MHz, CDCl3) 1.15 (3H, d, J 6.7, C(α)Me), 1.51 (3H, s,
C(3′)MeA), 1.61 (3H, s, C(3′)MeB), 2.48 (1H, dd, J 14.8, 9.6, C(2)HA),
2.58 (1H, dd, J 14.8, 5.4, C(2)HB), 3.56–3.66 (2H, m, NCH2Ph),
3.92 (1H, q, J 6.7, C(α)H), 4.24–4.34 (2H, m, C(1′)H2), 4.37 (1H,
dd, J 9.6, 5.4, C(3)H), 5.02–5.06 (1H, m, C(2′)H), 7.07–7.26
was stirred vigorously under H2 (1 atm) at rt for 22 h. The reac-
tion mixture was then filtered through Celite® (eluent EtOAc)
and the filtrate was washed with satd aq. NaHCO3 (10 mL),
then dried and concentrated in vacuo to give a yellow oil
(39 mg).
Method B – step 3. The residue (39 mg) was dissolved in
(11H, m, Ph), 7.31–7.34 (4H, m, Ph); δC (100 MHz, CDCl3) 15.8
MeOH (0.4 mL), and the resultant solution was cooled to 0 °C
then SOCl2 (300 μL, 4.25 mmol) was added dropwise. The
resultant mixture was allowed to warm to rt then heated at
50 °C for 48 h, then allowed to cool to rt and concentrated
in vacuo. The residue was then dissolved in CH2Cl2 (10 mL)
and the resultant solution was washed with satd aq. NaHCO3
(3 × 10 mL), then dried and concentrated in vacuo. Purification
(C(α)Me), 17.9 (C(3′)MeA), 25.7 (C(3′)MeB), 37.7 (C(2)), 50.7
(NCH2Ph), 56.8 (C(α)), 59.5 (C(3)), 61.1 (C(1′)), 118.5 (C(2′)),
126.5, 126.8, 127.1, 127.8, 128.0, 128.1, 128.1, 128.2 (o,m,p-Ph),
138.7 (C(3′)), 141.4, 141.7, 144.0 (i-Ph), 171.8 (C(1)); m/z (ESI+)
450 ([M + Na]+, 10%), 428 ([M + H]+, 100%); HRMS (ESI+)
C29H34NO2+ ([M + H]+) requires 428.2584; found 428.2567.
Methyl (2S,3R,αS)-2-(2′-methylbut-3′-en-2′-yl)-3-[N-benzyl-
N-(α-methylbenzyl)amino]-3-phenylpropanoate 32
via flash column chromatography (eluent, 30–40 °C petrol–
Et2O, 92 : 8) gave 29 as a colourless oil (20 mg, 48% from 25,
>99 : 1 dr); [α]2D0 +11.1 (c 1.0 in CHCl3).
Step 1. TMSCl (101 μL, 0.81 mmol) was added dropwise to a
solution of 30 (115 mg, 0.27 mmol, >99 : 1 dr) in PhMe (1 mL)
at −78 °C, and the resultant mixture was stirred at −78 °C for
10 min. LiHMDS (1.0 M in THF, 0.8 mL, 0.80 mmol) was then
X-ray crystal structure determination for 29
added dropwise and the resultant mixture was stirred at
Data were collected using a Nonius κ-CCD diffractometer with
graphite monochromated Mo-Kα radiation, using standard
procedures at 150 K. The structure was solved by direct
methods (SIR92); all non-hydrogen atoms were refined with
anisotropic thermal parameters. Hydrogen atoms were added
at idealised positions.
−78 °C for 30 min. The reaction mixture was heated at reflux
for 1 h, then allowed to cool to rt and concentrated in vacuo.
The residue was partitioned between CH2Cl2 (10 mL) and 1.0
M aq. HCl (10 mL), and the aqueous layer was extracted with
CH2Cl2 (2 × 10 mL). The combined organic extracts were
washed with brine (25 mL), then dried and concentrated
in vacuo to give 31 as a pale orange solid (117 mg, 90 : 10 dr).
Purification of an aliquot via flash column chromatography
(eluent 30–40 °C petrol–acetone, 95 : 5) gave 31 as a white solid
(>99 : 1 dr); νmax (ATR) 2969 (C–H), 1737 (CvO), 1638, 1602
(CvC); δH (400 MHz, CDCl3) 0.74 (3H, s, C(2′)MeA), 0.75 (3H, s,
X-ray crystal structure data for 29 [C18H29NO2]: M = 291.43,
monoclinic, P21, a = 12.4852(2) Å, b = 9.9345(2) Å, c = 15.0329(3)
Å,
β = 100.0163(9)°, V = Z = 4, μ =
1836.17(6) Å3,
0.067 mm−1, colourless block, crystal dimensions = 0.27 × 0.33
× 0.38 mm3. A total of 4416 unique reflections were measured
for 5 < θ < 27 and 4002 reflections were used in the refinement. C(2′)MeB), 0.82 (3H, d, J 7.1, C(α)Me), 3.21 (1H, d, J 11.1, C(2)H),
The final parameters were wR2 = 0.109 and R1 = 0.049 3.64 (1H, d, J 13.1, NCHAHBPh), 3.95–4.01 (1H, m, C(α)H), 4.14
[I > −3.0σ(I)]. CCDC 982702.†
(1H, d, J 11.1, C(3)H), 4.38 (1H, d, J 13.1, NCHAHBPh),
This journal is © The Royal Society of Chemistry 2014
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4.42–4.46 (2H, m, C(4′)H2), 5.47 (1H, dd, J 17.2, 11.1, C(3′)H), (c 0.5 in CHCl3); νmax (ATR) 3028 (C–H), 1732 (CvO), 1493
7.12–7.41 (15H, m, Ph); δC (100 MHz, CDCl3) 12.1 (C(α)Me), (CvC); δH (400 MHz, CDCl3) 1.14 (3H, d, J 6.8, C(α)Me), 1.56
24.9, 26.3 (C(2′)Me2), 38.3 (C(2′)), 51.3 (NCH2Ph), 56.4 (C(α)), (3H, d, J 6.8, C(4′)H3), 2.48 (1H, dd, J 14.6, 9.4, C(2)HA), 2.59
58.5 (C(2)), 59.9 (C(3)), 110.7 (C(4′)), 127.0, 127.1, 127.7, (1H, dd, J 14.6, 5.4, C(2)HB), 3.57 (1H, d, J 14.6, NCHAHBPh),
127.7, 128.3, 129.1, 129.3 (o,m,p-Ph), 138.7, 139.1, 141.5 (i-Ph), 3.65 (1H, d, J 14.6, NCHAHBPh), 3.92 (1H, q, J 6.8, C(α)H),
145.5 (C(3′)), 178.3 (C(1)); m/z (ESI+) 450 ([M + Na]+, 5%), 428 4.19–4.24 (2H, m, C(1′)H2), 4.36 (1H, dd, J 9.4, 5.4, C(3)H),
([M + H]+, 100%); m/z (ESI−) 426 ([M − H]−, 100%); HRMS (ESI+) 5.23–5.30 (1H, m, C(2′)H), 5.47–5.55 (1H, m, C(3′)H), 7.06–7.26
C29H34NO2+ ([M + H]+) requires 428.2584; found 428.2570.
(11H, m, Ph), 7.31–7.34 (4H, m, Ph); δC (100 MHz, CDCl3) 15.7
Step 2. A solution of the residue of 31 (117 mg, 90 : 10 dr) in (C(α)Me), 17.7 (C(4′)), 37.7 (C(2)), 50.7 (NCH2Ph), 56.7 (C(α)),
MeCN (1.2 mL) was treated sequentially with DBU (40 μl, 59.4 (C(3)), 64.9 (C(1′)), 124.9 (C(2′)), 126.5, 126.8, 127.2, 127.8,
0.27 mmol) and MeI (40 μL, 0.64 mmol) at rt. The reaction 128.0, 128.1, 128.1, 128.1, 128.2 (o,m,p-Ph), 130.9 (C(3′)), 141.4,
mixture was stirred at rt for 8 h, then concentrated in vacuo. 141.7, 144.0 (i-Ph), 171.5 (C(1)); m/z (ESI+) 414 ([M + H]+,
+
The residue was partitioned between CH2Cl2 (5 mL) and 2.0 M 100%); HRMS (ESI+) C28H32NO2 ([M + H]+) requires 414.2428;
aq. HCl (5 mL) and the aqueous layer was extracted with found 414.2418.
CH2Cl2 (3 × 5 mL). The combined organic extracts were then
(E)-3′-Phenylprop-2′-en-1′-yl (3R,αS)-3-[N-benzyl-N-
(α-methylbenzyl)amino]-3-phenylpropanoate 34
Step 1. TFA (8 mL) was added to a solution of 1211 (1.70 g,
washed sequentially with satd aq. NaHCO3 (15 mL) and brine
(15 mL), then dried and concentrated in vacuo. Purification via
flash column chromatography (eluent 30–40 °C petrol–Et2O,
4.09 mmol, >99 : 1 dr) in CH2Cl2 (16 mL) at rt and the resultant
mixture was stirred at rt for 16 h. The reaction mixture was
diluted with CH2Cl2 (100 mL) and washed with NaHCO3
(100 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
100 mL) and the combined organic extracts were then dried
and concentrated in vacuo to give a yellow oil (1.75 g, >99 : 1 dr).
Step 2. A solution of the residue (1.75 g, >99 : 1 dr) in
CH2Cl2 (18 mL) was treated sequentially with (COCl)2 (0.37 μL,
4.29 mmol) and DMF (14 μL, 0.18 μmol) at 0 °C. The reaction
mixture was allowed to warm to rt over 1 h then concentrated
in vacuo. A solution of (E)-3-phenylprop-2-en-1-ol (770 mg,
5.73 mmol, >99 : 1 dr) was then added to a solution of the
residue in CH2Cl2 (18 mL) at 0 °C. The reaction mixture was
allowed to warm to rt and stirred at rt for 16 h. Satd aq.
NaHCO3 (100 mL) was then added and the resultant mixture
was extracted with CH2Cl2 (3 × 100 mL). The combined organic
extracts were washed with brine (300 mL), then dried and con-
centrated in vacuo. Purification via flash column chromato-
graphy (gradient elution, 0% → 6% Et2O in 30–40 °C petrol)
gave 34 as a colourless oil (1.47 g, 76%, >99 : 1 dr); [α]2D0 −14.6
(c 1.0 in CHCl3); νmax (ATR) 3027, 2935 (C–H), 1732 (CvO),
1494 (CvC); δH (400 MHz, CDCl3) 1.33 (3H, d, J 6.9, C(α)Me),
2.72 (1H, dd, J 14.6, 9.6, C(2)HA), 2.82 (1H, dd, J 14.6, 5.8,
C(2)HB), 3.77 (1H, d, J 14.6, NCHAHBPh), 3.85 (1H, d, J 14.6,
NCHAHBPh), 4.12 (1H, q, J 6.9, C(α)H), 4.57–4.67 (3H, m, C(3)H,
C(1′)H2), 6.09–6.16 (1H, dt, J 15.8, 6.4, C(2′)H), 6.56 (1H, d,
J 15.8, C(3′)H), 7.25–7.44 (16H, m, Ph), 7.52–7.54 (4H, m, Ph);
δC (100 MHz, CDCl3) 15.8 (C(α)Me), 37.7 (C(2)), 50.7 (NCH2Ph),
56.7 (C(α)), 59.4 (C(3)), 64.8 (C(1′)), 123.1 (C(2′)), 126.5, 126.6,
126.8, 127.2, 127.8, 127.9, 128.0, 128.0, 128.1, 128.1, 128.2,
128.5, (o,m,p-Ph), 133.8 (C(3′)), 136.2, 141.3, 141.6, 144.0 (i-Ph),
171.5 (C(1)); m/z (ESI+) 476 ([M + H]+, 100%); HRMS (ESI+)
C33H33NNaO2+ ([M + Na]+) requires 498.2404; found 498.2388.
98 : 2) gave 32 as a colourless oil (60 mg, 50% from 30, >99 : 1
dr); [α]2D0 +21.4 (c 1.0 in CHCl3); νmax (ATR) 3027, 2969 (C–H),
1737 (CvO), 1494 (CvC); δH (400 MHz, CDCl3) 0.58 (3H, s,
C(2′)MeA), 0.65 (3H, s, C(2′)MeB), 0.78 (3H, d, J 7.1, C(α)Me),
3.21 (1H, d, J 11.4, C(2)H), 3.27 (3H, br s, OMe), 3.53 (1H, d,
J 13.6, NCHAHBPh), 4.10 (1H, d, J 11.4, C(3)H), 4.11–4.16 (2H,
m, NCHAHBPh, C(α)H), 4.34–4.41 (2H, m, C(4′)H2), 5.48 (1H,
dd, J 17.3, 10.7, C(3′)H), 7.10–7.40 (15H, m, Ph); δC (100 MHz,
CDCl3) 25.5 (C(α)Me), 25.7 (C(2′)Me2), 38.5 (C(2′)), 50.6 (OMe),
51.0 (NCH2Ph), 53.4 (C(α)), 55.5 (C(2)), 60.1 (C(3)), 110.3 (C(4′)),
126.2, 126.7, 127.4, 127.6, 127.8, 128.2, 128.9 (o,m,p-Ph), 139.1,
139.6 (i-Ph), 145.7 (C(3′)), 173.0 (C(1)); m/z (ESI+) 464
([M + Na]+, 20%), 442 ([M + H]+, 100%); HRMS (ESI+)
C30H36NO2+ ([M + H]+) requires 442.2741; found 442.2724.
(E)-But-2′-en-1′-yl (3R,αS)-3-[N-benzyl-N-(α-methylbenzyl)-
amino]-3-phenylpropanoate 33
Step 1. TFA (4.6 mL) was added to a solution of 1211 (1.00 g,
2.41 mmol, >99 : 1 dr) in CH2Cl2 (9.3 mL) at rt, and the resul-
tant mixture was stirred at rt for 16 h. Satd aq. NaHCO3
(100 mL) and CH2Cl2 (100 mL) were then added and the
aqueous layer was extracted with CH2Cl2 (3 × 100 mL). The
combined organic extracts were then dried and concentrated
in vacuo to give a yellow oil (1.05 g, >99 : 1 dr).
Step 2. A solution of the residue (1.05 g, >99 : 1 dr) in
CH2Cl2 (10 mL) was treated sequentially with (COCl)2
(0.22 mL, 2.53 mmol) and DMF (8 μL, 0.10 μmol) at 0 °C. The
reaction mixture was allowed to warm to rt over 1 h then con-
centrated in vacuo. A solution of (E)-but-2-en-1-ol (240 mg,
3.37 mmol, 96 : 4 dr) was then added to a solution of the
residue in CH2Cl2 (10 mL) at 0 °C. The reaction mixture was
allowed to warm to rt and stirred at rt for 16 h. Satd aq.
NaHCO3 (100 mL) was then added and the resultant mixture
was extracted with CH2Cl2 (3 × 100 mL). The combined organic
extracts were washed with brine (300 mL), then dried and con-
centrated in vacuo. Purification via flash column chromato-
graphy (gradient elution, 0% → 6% Et2O in 30–40 °C petrol)
Methyl (2S,3R,1′S,αS)-2-(1′-phenylprop-2′-en-1′-yl)-3-[N-benzyl-
N-(α-methylbenzyl)amino]-3-phenylpropanoate 39
Method A (from 42) – step 1. TMSCl (780 μL, 6.18 mmol)
gave 33 as a colourless oil (613 mg, 62%, 93 : 7 dr); [α]2D0 −16.1 was added dropwise to a solution of 42 (980 mg, 2.06 mmol,
2716 | Org. Biomol. Chem., 2014, 12, 2702–2728
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Paper
>99 : 1 dr) in PhMe (9.8 mL) at −78 °C, and the resultant 4.07 (1H, q, J 7.0, C(α)H), 4.19 (1H, d, J 13.5, NCHAHBPh), 4.23
mixture was stirred at −78 °C for 10 min. LiHMDS (1.0 M in (1H, d, J 11.7, C(3)H), 4.52 (1H, dd, J 17.1, 1.8, C(3′)HA), 4.87
THF, 6.31 mL, 6.31 mmol) was added dropwise at −78 °C and (1H, dd, J 9.9, 1.8, C(3′)HB), 6.09 (1H, app dt, J 17.1, 9.9,
the resultant mixture was stirred at −78 °C for 15 min. The C(2′)H), 6.98–7.01 (3H, m, Ph), 7.06–7.14 (5H, m, Ph), 7.16–7.21
reaction mixture was then heated at reflux for 1 h, then (3H, m, Ph), 7.36–7.39 (9H, m, Ph); δC (100 MHz, CDCl3) 13.5
allowed to cool to rt and concentrated in vacuo. The residue (C(α)Me), 48.6 (C(1′)), 51.0 (NCH2Ph), 52.3 (C(2)), 56.9 (C(α)),
was partitioned between CH2Cl2 (200 mL) and 1.0 M aq. HCl 61.5 (C(3)), 118.0 (C(3′)), 126.3, 127.3, 127.3, 127.4, 128.0,
(150 mL), and the aqueous layer was extracted with CH2Cl2 128.1, 128.3, 128.5, 128.5, 128.6, 129.2, 129.9 (o,m,p-Ph), 135.9
(2 × 200 mL). The combined organic extracts were washed with (C(2′)), 136.8, 137.5, 141.2, 142.6 (i-Ph), 176.1 (C(1)); m/z (ESI+)
+
brine (150 mL), then dried and concentrated in vacuo to give 476 ([M + H]+, 100%); HRMS (ESI+) C33H34NO2 ([M + H]+)
37 as an off-white solid (962 mg, 90 : 10 dr).
requires 476.2584; found 476.2571. Further elution (eluent
Method A – step 2 (for 37). A solution of the residue of 37 30–40 °C petrol–acetone, 92 : 8) gave 38 as a yellow oil (175 mg,
(962 mg, 90 : 10 dr) in MeCN (9.8 mL) was treated sequentially >99 : 1 dr); [α]2D0 +39.2 (c 1.0 in CHCl3); νmax (ATR) 3029, 2928
with DBU (0.62 mL, 4.12 mmol) and MeI (0.28 mL, (C–H), 1707 (CvO), 1494 (CvC); δH (400 MHz, CDCl3) 0.96
4.53 mmol) at rt. The resultant mixture was stirred at rt for (3H, d, J 7.0, C(α)Me), 3.05 (1H, dd, J 7.7, 3.6, C(1′)H), 3.33 (1H,
16 h, then concentrated in vacuo. The residue was partitioned dd, J 11.4, 3.6, C(2)H), 3.55 (1H, d, J 13.2, NCHAHBPh), 4.03
between CH2Cl2 (50 mL) and 2.0 M aq. HCl (50 mL), and the (1H, q, J 7.0, C(α)H), 4.12 (1H, d, J 13.2, NCHAHBPh), 4.16 (1H,
aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The com- app d, J 11.4, C(3)H), 4.55 (1H, app d, J 17.1, C(3′)HA), 4.77 (1H,
bined organic extracts were then washed sequentially with satd d, J 10.0, C(3′)HB), 6.30–6.38 (1H, m, C(2′)H), 6.75–6.78 (2H, m,
aq. NaHCO3 (100 mL) and brine (100 mL), then dried and con- Ph), 6.94–7.02 (3H, m, Ph), 7.09–7.28 (12H, m, Ph), 7.35–7.41
centrated in vacuo. Purification via flash column chromato- (3H, m, Ph); δC (100 MHz, CDCl3) 13.7 (C(α)Me), 49.5 (C(1′)),
graphy (eluent 30–40 °C petrol–Et2O, 98 : 2) gave 39 as a 50.5 (C(2)), 51.1 (NCH2Ph), 57.9 (C(α)), 60.9 (C(3)), 113.9 (C(3′)),
colourless oil (487 mg, 48% from 42, >99 : 1 dr); [α]2D0 +28.9 126.4, 128.0, 128.0, 128.1, 128.4, 128.6, 128.6, 128.8, 128.8,
(c 1.0 in CHCl3); νmax (ATR) 3027, 2946 (C–H), 1736 (CvO), 128.8, 129.5, 130.1 (o,m,p-Ph), 135.0, 135.2, 138.9, 139.5 (i-Ph),
1494 (CvC); δH (400 MHz, CDCl3) 0.83 (3H, d, J 6.9, C(α)Me), 141.2 (C(2′)), 174.0 (C(1)); m/z (ESI+) 476 ([M + H]+, 100%);
2.96 (1H, dd, J 9.6, 4.4, C(1′)H), 3.20 (3H, s, OMe), 3.49 (1H, d, HRMS (ESI+) C33H34NO2 ([M + H]+) requires 476.2584; found
+
J 14.0, NCHAHBPh), 3.53 (1H, dd, J 11.7, 4.4, C(2)H), 4.01 (1H, 476.2579.
d, J 14.0, NCHAHBPh), 4.15 (1H, d, J 11.7, C(3)H), 4.16 (1H, q,
Method B – step 2 (for 37). A solution of 37 (472 mg) in
J 6.9, C(α)H), 4.36 (1H, dd, J 16.9, 1.7, C(3′)HA), 4.80 (1H, dd, MeCN (4.7 mL) was treated sequentially with DBU (296 μL,
J 10.0, 1.7, C(3′)HB), 6.22 (1H, app dt, J 16.9, 10.0, C(2′)H), 1.98 mmol) and MeI (135 μL, 2.18 mmol) at rt. The reaction
6.87–6.89 (2H, m, Ph), 6.99–7.33 (18H, m, Ph); δC (100 MHz, mixture was stirred at rt for 16 h, then concentrated in vacuo.
CDCl3) 15.1 (C(α)Me), 49.3 (C(1′)), 50.8 (OMe), 50.9 (NCH2Ph), The residue was partitioned between CH2Cl2 (50 mL) and 2.0
54.5 (C(2)), 55.5 (C(α)), 61.7 (C(3)), 117.7 (C(3′)), 126.3, 126.4, M aq. HCl (50 mL), and the aqueous layer was extracted with
126.8, 127.3, 127.6, 127.7, 127.9, 128.1, 128.3, 128.3, 129.0, CH2Cl2 (3 × 50 mL). The combined organic extracts were then
129.6 (o,m,p-Ph), 135.5 (C(2′)), 137.4, 139.6, 142.7, 144.3 (i-Ph), washed sequentially with satd aq. NaHCO3 (100 mL) and brine
172.6 (C(1)); m/z (ESI+) 490 ([M + H]+, 100%); HRMS (ESI+) (100 mL), then dried and concentrated in vacuo. Purification
C34H35NNaO2+ ([M + Na]+) requires 512.2560; found 512.2541.
via flash column chromatography (eluent 30–40 °C petrol–
Method B (from 34) – step 1. TMSCl (956 μL, 7.57 mmol) Et2O, 98 : 2) gave 39 as a colourless oil (350 mg, 38% from 34,
was added dropwise to a solution of 34 (1.20 g, 2.52 mmol, >99 : 1 dr).
>99 : 1 dr) in PhMe (12 mL) at −78 °C, and the resultant
Method B – step 2 (for 38). A solution of 38 (150 mg) in
mixture was stirred at −78 °C for 10 min. LiHMDS (1.0 M in MeCN (1.5 mL) was treated sequentially with DBU (94 μL,
THF, 7.57 mL, 7.57 mmol) was added dropwise at −78 °C and 0.63 mmol) and MeI (43 μL, 0.69 mmol) at rt. The reaction
the resultant mixture was stirred at −78 °C for 15 min. The mixture was stirred at rt for 16 h, then concentrated in vacuo.
reaction mixture was heated at reflux for 1 h, then allowed to The residue was partitioned between CH2Cl2 (10 mL) and 2.0
cool to rt and concentrated in vacuo. The residue was then par- M aq. HCl (10 mL), and the aqueous layer was extracted with
titioned between CH2Cl2 (200 mL) and 1.0 M aq. HCl CH2Cl2 (3 × 10 mL). The combined organic extracts were then
(150 mL), and the aqueous layer was extracted with CH2Cl2 washed sequentially with satd aq. NaHCO3 (40 mL) and brine
(2 × 200 mL). The combined organic extracts were washed with (40 mL), then dried and concentrated in vacuo. Purification via
brine (150 mL), then dried and concentrated in vacuo to give a flash column chromatography (eluent 30–40 °C petrol–Et2O,
70 : 30 mixture of 37 and 38. Purification via flash column 98 : 2) gave 40 as a colourless oil (133 mg, 13% from 34, >99 : 1
chromatography (gradient elution, 0% → 8% acetone in dr); [α]2D0 +33.1 (c 1.0 in CHCl3); νmax (ATR) 3028, 2946 (C–H),
30–40 °C petrol) gave 37 as a white solid (632 mg, >99 : 1 dr); 1739 (CvO), 1494 (CvC); δH (400 MHz, CDCl3) 0.98 (3H, d,
mp 77–79 °C; [α]2D0 +57.5 (c 1.0 in CHCl3); νmax (ATR) 3028, J 6.9, C(α)Me), 3.28 (3H, s, OMe), 3.38 (1H, app t, J 8.1, C(1′)H),
2971 (C–H), 1704 (CvO), 1494 (CvC); δH (400 MHz, CDCl3) 3.67 (1H, d, J 13.9, NCHAHBPh), 3.83 (1H, dd, J 11.2, 8.1, C(2)H),
0.95 (3H, d, J 7.0, C(α)Me), 3.03 (1H, dd, J 9.9, 3.4, C(1′)H), 3.51 4.18 (1H, d, J 13.9, NCHAHBPh), 4.24 (1H, d, J 11.2, C(3)H),
(1H, dd, J 11.7, 3.4, C(2)H), 3.58 (1H, d, J 13.5, NCHAHBPh), 4.32 (1H, q, J 6.9, C(α)H), 4.58–4.68 (2H, m, C(3′)H2), 5.55–5.64
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(1H, m, C(2′)H), 7.01–7.03 (2H, m, Ph), 7.15–7.47 (18H, m, Ph); 7.41–7.45 (4H, m, Ph); δC (100 MHz, CDCl3) 13.0 (C(4′)), 15.8
δC (100 MHz, CDCl3) 15.4 (C(α)Me), 50.8 (OMe), 50.9 (NCH2Ph), (C(α)Me), 37.6 (C(2)), 50.7 (NCH2Ph), 56.7 (C(α)), 59.4 (C(3)),
51.4 (C(1′)), 54.0 (C(2)), 55.9 (C(α)), 62.3 (C(3)), 114.4 (C(3′)), 59.9 (C(1′)), 124.1 (C(2′)), 126.5, 126.8, 127.1, 127.8, 128.0,
126.2, 126.3, 126.6, 127.4, 127.7, 127.7, 127.8, 128.0, 128.1, 128.0, 128.1, 128.1, 128.2 (o,m,p-Ph), 129.3 (C(3′)), 141.4, 141.7,
128.4, 128.9, 129.9 (o,m,p-Ph), 138.2, 139.0, 139.6 (i-Ph), 141.1 144.0 (i-Ph), 171.6 (C(1)); m/z (ESI+) 414 ([M + H]+, 100%);
+
(C(2′)), 144.4 (i-Ph), 172.6 (C(1)); m/z (ESI+) 490 ([M + H]+, HRMS (ESI+) C28H31NNaO2 ([M + Na]+) requires 436.2247;
+
100%); HRMS (ESI+) C34H36NO2 ([M + H]+) requires 490.2741; found 436.2234.
found 490.2750.
(Z)-3′-Phenylprop-2′-en-1′-yl (3R,αS)-3-[N-benzyl-N-
X-ray crystal structure determination for 37
(α-methylbenzyl)amino]-3-phenylpropanoate 42
Data were collected using an Oxford Diffraction SuperNova
Step 1. TFA (2 mL) was added to a solution of 1211 (500 mg,
diffractometer with graphite monochromated Cu-Kα radiation, 1.20 mmol, >99 : 1 dr) in CH2Cl2 (4 mL) at rt and the resultant
using standard procedures at 150 K. The structures was solved mixture was stirred at rt for 16 h. The reaction mixture was
by direct methods (SIR92); all non-hydrogen atoms were then diluted with CH2Cl2 (50 mL) and washed with NaHCO3
refined with anisotropic thermal parameters. Hydrogen atoms (50 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
were added at idealised positions.
50 mL) and the combined organic extracts were then dried and
X-ray crystal structure data for 37 [C34.5H36NO2.5]: M = concentrated in vacuo to give a yellow oil (475 mg, >99 : 1 dr).
504.67, orthorhombic, P212121, a = 12.3150(1) Å, b = 15.4817(2)
Å, c = 29.8308(3) Å, V = 5687.45(10) Å3, Z = 8, μ = 0.571 mm−1
Step 2. A solution of the residue (475 mg, >99 : 1 dr) in
CH2Cl2 (5 mL) was treated sequentially with (COCl)2 (108 μL,
,
colourless plate, crystal dimensions = 0.15 × 0.21 × 0.26 mm3. 1.26 mmol) and DMF (4 μL, 0.05 μmol) at 0 °C. The reaction
A total of 11 951 unique reflections were measured for 3 < θ < mixture was allowed to warm to rt over 1 h then concentrated
77 and 11 907 reflections were used in the refinement. The in vacuo.
A
solution of (Z)-3-phenylprop-2-en-1-ol10,35,36
final parameters were wR2 = 0.118 and R1 = 0.045 [I > −3.0σ(I)], (226 mg, 1.69 mmol, >99 : 1 dr) was then added to a solution
with Flack enantiopole = 0.02(16).17 CCDC 982703.†
of the residue in CH2Cl2 (5 mL) at 0 °C. The reaction mixture
was allowed to warm to rt and stirred at this temperature for
16 h. Sat aq. NaHCO3 (50 mL) was then added and the resul-
tant mixture was extracted with CH2Cl2 (3 × 50 mL). The com-
(Z)-But-2′-en-1′-yl (3R,αS)-3-[N-benzyl-N-(α-methylbenzyl)-
amino]-3-phenylpropanoate 41
Step 1. TFA (7 mL) was added to a solution of 1211 (1.60 g, bined organic extracts were washed with brine (150 mL), then
3.85 mmol, >99 : 1 dr) in CH2Cl2 (15 mL) at rt and the resultant dried and concentrated in vacuo. Purification via flash column
mixture was stirred at rt for 16 h. The reaction mixture was chromatography (gradient elution, 0%
→ 10% Et2O in
diluted with CH2Cl2 (100 mL) and washed with NaHCO3 30–40 °C petrol) gave 42 as a colourless oil (342 mg, 60%,
(100 mL). The aqueous layer was extracted with CH2Cl2 (3 × >99 : 1 dr); [α]2D0 −12.1 (c 1.0 in CHCl3); νmax (ATR) 3027, 2969
100 mL) and the combined organic extracts were then dried (C–H), 1733 (CvO), 1494 (CvC); δH (400 MHz, CDCl3) 1.12
and concentrated in vacuo to give a yellow oil (1.58 g, >99 : 1 (3H, d, J 6.9, C(α)Me), 2.51 (1H, dd, J 14.7, 9.4, C(2)HA), 2.60
dr).
(1H, dd, J 14.7, 5.6, C(2)HB), 3.57 (1H, d, J 14.8, NCHAHBPh),
Step 2. A solution of the residue (1.58 g, >99 : 1 dr) in 3.64 (1H, d, J 14.8, NCHAHBPh), 3.91 (1H, q, J 6.9, C(α)H), 4.37
CH2Cl2 (16 mL) was treated sequentially with (COCl)2 (1H, dd, J 9.4, 5.6, C(3)H), 4.51–4.60 (2H, m, C(1′)H2), 5.45 (1H,
(0.35 mL, 4.05 mmol) and DMF (13 μL, 0.17 μmol) at 0 °C. The dt, J 11.7, 6.6, C(2′)H), 6.44–6.47 (1H, m, C(3′)H), 7.02–7.25
reaction mixture was allowed to warm to rt over 1 h then con- (16H, m, Ph), 7.31–7.33 (4H, m, Ph); δC (100 MHz, CDCl3) 15.9
centrated in vacuo. A solution of (Z)-but-2-en-1-ol10,34 (0.39 g, (C(α)Me), 37.5 (C(2)), 50.7 (NCH2Ph), 56.7 (C(α)), 59.3 (C(3)),
5.39 mmol, >99 : 1 dr) was then added to a solution of the 61.3 (C(1′)), 125.7 (C(2′)), 126.6, 126.8, 127.2, 127.4, 127.8,
residue in CH2Cl2 (16 mL) at 0 °C. The reaction mixture was 128.0, 128.0, 128.1, 128.1, 128.2, 128.3, 128.6 (o,m,p-Ph), 132.6
allowed to warm to rt and stirred at rt for 16 h. Satd aq. (C(3′)), 135.9, 141.3, 141.6, 143.9 (i-Ph), 171.5 (C(1)); m/z (ESI+)
+
NaHCO3 (100 mL) was then added and the resultant mixture 476 ([M + H]+, 100%); HRMS (ESI+) C33H33NNaO2 ([M + Na]+)
was extracted with CH2Cl2 (3 × 100 mL). The combined organic requires 498.2404; found 498.2382.
extracts were washed with brine (300 mL), then dried and con-
Methyl (2S,3R,1′S,αS)-2-(but-3′-en-2′-yl)-3-[N-benzyl-N-
(α-methylbenzyl)amino]-3-phenylpropanoate 44
centrated in vacuo. Purification via flash column chromato-
graphy (gradient elution, 0% → 7% Et2O in 30–40 °C petrol)
gave 41 as a colourless oil (960 mg, 60%, >99 : 1 dr); [α]2D0 −8.0
Step 1. TMSCl (541 μL, 5.08 mmol) was added dropwise to a
(c 1.0 in CHCl3); νmax (ATR) 3028 (C–H), 1732 (CvO), 1493 solution of 41 (590 mg, 1.69 mmol, >99 : 1 dr) in PhMe (7 mL)
(CvC); δH (400 MHz, CDCl3) 1.25 (3H, d, J 6.8, C(α)Me), at −78 °C, and the resultant mixture was stirred at −78 °C for
1.61–1.63 (3H, m, C(4′)H3), 2.59 (1H, dd, J 14.6, 9.4, C(2)HA), 10 min. LiHMDS (1.0 M in THF, 4.28 mL, 4.28 mmol) was
2.69 (1H, dd, J 14.6, 5.6, C(2)HB), 3.68 (1H, d, J 14.8, added dropwise at −78 °C and the resultant mixture was
NCHAHBPh), 3.75 (1H, d, J 14.8, NCHAHBPh), 4.02 (1H, q, J 6.8, stirred at −78 °C for 15 min. The reaction mixture was then
C(α)H), 4.40–4.51 (3H, m, C(3)H, C(1′)H2), 5.31–5.38 (1H, m, heated at reflux for 1 h, then allowed to cool to rt and concen-
C(2′)H), 5.61–5.70 (1H, m, C(3′)H), 7.17–7.37 (11H, m, Ph), trated in vacuo. The residue was partitioned between CH2Cl2
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Paper
(200 mL) and 1.0 M aq. HCl (150 mL), and the aqueous layer 76%, 96 : 4 dr); [α]2D0 +33.7 (c 1.0 in CHCl3); νmax (ATR) 3386
was extracted with CH2Cl2 (2 × 200 mL). The combined organic (N–H), 2963 (C–H), 1727 (CvO), 1154; δH (400 MHz, CDCl3)
extracts were washed with brine (150 mL), then dried and con- 0.81 (3H, t, J 7.4, C(4′)H3), 0.96 (3H, d, J 6.7, C(1′)H3), 0.99–1.07
centrated in vacuo to give 43 as an orange oil (582 mg, 96 : 4 (1H, m, C(3′)HA), 1.45–1.60 (2H, m, C(2′)H, C(3′)HB), 1.70 (2H,
dr); [α]2D0 +59.4 (c 1.0 in CHCl3); νmax (ATR) 3029, 2965 (C–H), br s, NH2), 2.57 (1H, dd, J 7.8, 6.7, C(2)H), 3.59 (3H, s, OMe),
1704 (CvO), 1494 (CvC); δH (400 MHz, CDCl3) 1.13–1.19 (6H, 4.26 (1H, d, J 7.8, C(3)H), 7.24–7.28 (3H, m, Ph), 7.30–7.36 (2H,
m, C(1′)H3, C(α)Me), 1.94–2.02 (1H, m, C(2′)H), 3.11 (1H, dd, m, Ph); δC (100 MHz, CDCl3) 11.6 (C(4′)), 17.2 (C(1′)), 25.8
J 11.6, 2.5, C(2)H), 3.66 (1H, d, J 13.4, NCHAHBPh), 4.16 (1H, q, (C(3′)), 34.2 (C(2′)), 51.0 (OMe), 55.1 (C(3)), 59.4 (C(2)), 126.3,
J 6.9, C(α)H), 4.23–4.28 (2H, m, NCHAHBPh, C(3)H), 4.47–4.51 127.1, 128.4 (o,m,p-Ph), 144.2 (i-Ph), 174.6 (C(1)); m/z (ESI+) 236
+
(1H, m, C(4′)HA), 4.70–4.73 (1H, m, C(4′)HB), 5.58–5.67 (1H, m, ([M + H]+, 100%); HRMS (ESI+) C14H22NO2 ([M + H]+) requires
C(3′)H), 7.25–7.49 (15H, m, Ph); δC (125 MHz, CDCl3) 13.9 236.1645; found 236.1643.
(C(α)Me), 20.1 (C(1′)), 38.1 (C(2′)), 50.8 (C(2)), 51.1 (NCH2Ph),
57.5 (C(α)), 61.4 (C(3)), 115.5 (C(4′)), 127.6, 128.2, 128.3, 128.6,
128.7, 129.4, 130.0 (o,m,p-Ph), 136.4, 136.6 (i-Ph), 139.2 (C(3′)),
140.4 (i-Ph), 175.5 (C(1)); m/z (ESI+) 414 ([M + H]+, 100%);
Methyl (2S,3R,1′S)-2-(1′-phenylpropyl)-3-amino-3-phenyl-
propanoate 46
Pd(OH)2/C (200 mg, 50% w/w by substrate) was added to a
degassed solution of 39 (400 mg, 0.82 mmol, >99 : 1 dr) in
MeOH (12 mL) at rt. The resultant suspension was stirred vig-
orously under H2 (1 atm) at rt for 24 h. The reaction mixture
was then filtered through Celite® (eluent MeOH) and the fil-
trate was concentrated in vacuo. The residue was dissolved in
CH2Cl2 (15 mL) and the resultant solution was washed with
satd aq. NaHCO3 (15 mL). The aqueous layer was extracted
with CH2Cl2 (3 × 15 mL), then the combined organic extracts
were dried and concentrated in vacuo. Purification via flash
column chromatography (eluent CHCl3–iPrOH, 99 : 1) gave 46
as a pale yellow oil (184 mg, 76%, >99 : 1 dr); [α]2D0 +4.2 (c 1.0 in
CHCl3); νmax (ATR) 3397 (N–H), 3027, 2962 (C–H), 1725 (CvO);
δH (400 MHz, CDCl3) 0.59 (3H, t, J 7.3, C(3′)H3), 1.44–1.56 (2H,
m, C(2′)H2), 1.66 (2H, br s, NH2), 2.89 (1H, app td, J 10.0, 4.4,
C(2)H), 2.91–2.97 (1H, m, C(1′)H), 3.39 (3H, s, OMe), 3.66 (1H,
d, J 4.4, C(3)H), 7.02–7.05 (2H, m, Ph), 7.08–7.12 (1H, m, Ph),
7.15–7.20 (5H, m, Ph), 7.25–7.29 (2H, m, Ph); δC (100 MHz,
CDCl3) 12.0 (C(3′)), 27.2 (C(2′)), 47.3 (C(1′)), 51.0 (OMe), 54.8
(C(3)), 59.4 (C(2)), 125.8, 126.7, 126.8, 128.0, 128.2, 128.6
(o,m,p-Ph), 141.7, 144.3 (i-Ph), 174.4 (C(1)); m/z (ESI+) 298
+
HRMS (ESI+) C28H32NO2 ([M + H]+) requires 414.2428; found
414.2432.
Step 2. A solution of the residue of 43 (582 mg, 96 : 4 dr) in
MeCN (5.9 mL) was treated sequentially with DBU (0.51 mL,
3.39 mmol) and MeI (0.23 mL, 3.73 mmol) at rt. The resultant
mixture was stirred at rt for 16 h, then concentrated in vacuo.
The residue was partitioned between CH2Cl2 (50 mL) and
2.0 M aq. HCl (50 mL), and the aqueous layer was extracted
with CH2Cl2 (3 × 50 mL). The combined organic extracts were
then washed sequentially with satd aq. NaHCO3 (100 mL) and
brine (100 mL), then dried and concentrated in vacuo. Purifi-
cation via flash column chromatography (eluent 30–40 °C
petrol–Et2O, 98 : 2) gave 44 as a colourless oil (517 mg, 85%,
96 : 4 dr); [α]2D0 +98.2 (c 1.0 in CHCl3); νmax (ATR) 3027, 2968
(C–H), 1736 (CvO), 1494 (CvC); δH (400 MHz, CDCl3) 0.78 (3H,
d, J 7.1, C(1′)H3), 0.85 (3H, d, J 6.9, C(α)Me), 1.79–1.88 (1H, m,
C(2′)H), 3.22 (1H, dd, J 12.0, 4.2, C(2)H), 3.43 (3H, s, OMe), 3.46
(1H, d, J 14.2, NCHAHBPh), 3.98 (1H, d, J 14.2, NCHAHBPh),
4.06 (1H, d, J 12.0, C(3)H), 4.13 (1H, q, J 6.9, C(α)H), 4.22–4.27
(1H, m, C(4′)HA), 4.62 (1H, dd, J 10.0, 2.0, C(4′)HB), 5.62 (1H,
app dt, J 17.2, 10.0, C(3′)H), 7.08–7.17 (4H, m, Ph), 7.19–7.29
(11H, m, Ph); δC (100 MHz, CDCl3) 15.2 (C(α)Me), 19.6 (C(1′)),
37.5 (C(2′)), 50.7 (NCH2Ph), 50.8 (OMe), 53.4 (C(2)), 55.8 (C(α)),
61.5 (C(3)), 115.2 (C(4′)), 126.3, 126.6, 127.3, 127.6, 127.9,
128.0, 128.1, 128.9, 129.5 (o,m,p-Ph), 137.7 (i-Ph), 138.8 (C(3′)),
+
([M + H]+, 100%); HRMS (ESI+) C19H23NNaO2 ([M + Na]+)
requires 320.1621; found 320.1611.
(2S,3R,1′S)-2-(But-2′-yl)-3-amino-3-phenylpropanoic acid 47
139.8, 144.3 (i-Ph), 172.9 (C(1)); m/z (ESI+) 428 ([M + H]+, A solution of 45 (63 mg, 0.27 mmol, 96 : 4 dr) in 6.0 M aq. HCl
+
100%); HRMS (ESI+) C29H34NO2 ([M + H]+) requires 428.2584; (8.8 mL) was heated at reflux for 5 days. The reaction mixture
found 428.2583.
was then allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in H2O (2 mL) and purified on DOWEX
50WX8 ion exchange resin (hydrogen form, 100–200 mesh,
Methyl (2S,3R,1′S)-2-(but-2′-yl)-3-amino-3-phenylpropanoate 45
Pd(OH)2/C (100 mg, 50% w/w by substrate) was added to a eluent 1.0 M aq. NH4OH) to give 47 as a white solid (54 mg,
degassed solution of 44 (200 mg, 0.47 mmol, 96 : 4 dr) in 91%, 96 : 4 dr); mp 190–192 °C; [α]2D0 +27.1 (c 0.3 in H2O); νmax
MeOH (6 mL) at rt. The resultant suspension was stirred vigor- (ATR) 3604, 2965 (C–H), 1649 (CvO), 1498 (CvC); δH
ously under H2 (1 atm) at rt for 24 h. The reaction mixture was (400 MHz, MeOH-d4) 0.88 (3H, t, J 7.2, C(4′)H3), 1.10 (3H, d,
then filtered through Celite® (eluent MeOH) and concentrated J 6.8, C(1′)H3), 1.06–1.17 (1H, m, C(3′)HA), 1.50–1.64 (2H, m,
in vacuo. The residue was dissolved in CH2Cl2 (15 mL) and the C(2′)H, C(3′)HB), 2.49–2.52 (1H, m, C(2)H), 4.51 (1H, d, J 6.4,
resultant solution was washed with satd aq. NaHCO3 (15 mL). C(3)H), 7.38–7.52 (5H, m, Ph); δC (100 MHz, MeOH-d4) 12.3
The aqueous layer was extracted with CH2Cl2 (3 × 15 mL) and (C(4′)), 17.7 (C(1′)), 27.7 (C(3′)), 36.1 (C(2′)), 56.1 (C(3)), 59.1
the combined organic extracts were then dried and concen- (C(2)), 128.5, 130.0, 130.3 (o,m,p-Ph), 139.0 (i-Ph), 179.4 (C(1));
trated in vacuo. Purification via flash column chromatography m/z (ESI+) 222 ([M + H]+, 100%); HRMS (ESI+) C13H19NNaO2
+
(eluent CHCl3–MeOH, 99 : 1) gave 45 as a colourless oil (83 mg, ([M + Na]+) requires 244.1308; found 244.1314.
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(2S,3R,1′S)-2-(1′-Phenylpropyl)-3-amino-3-phenylpropanoic
acid 48
56.7 (C(3)), 56.8 (C(α)), 60.0 (C(1′)), 122.9 (C(2′)), 126.5, 126.6
(o,m,p-Ph), 127.1 (C(5)), 127.8, 127.9, 128.0, 128.3 (o,m,p-Ph),
131.1 (C(4)), 136.5 (C(3′)), 141.3, 144.3 (i-Ph), 171.7 (C(1)); m/z
A solution of 46 (73 mg, 0.24 mmol, >99 : 1 dr) in 6.0 M aq.
HCl (10 mL) was heated at reflux for 5 days. The reaction
mixture was then allowed to cool to rt and concentrated
in vacuo. The residue was dissolved in H2O (2 mL) and purified
on DOWEX 50WX8 ion exchange resin (hydrogen form,
100–200 mesh, eluent 1.0 M aq. NH4OH) to give 48 as a white
solid (61 mg, 88%, >99 : 1 dr); mp 209–211 °C (sub); [α]D20
−19.6 (c 0.2 in H2O); νmax (ATR) 2957 (C–H), 1613, 1571, 1496;
δH (500 MHz, D2O) 0.57 (3H, t, J 7.3, C(3′)H3), 1.47–1.56 (1H,
m, C(2′)HA), 1.60–1.67 (1H, m, C(2′)HB), 2.71 (1H, td, J 10.8,
3.7, C(1′)H), 2.84 (1H, dd, J 10.8, 3.7, C(2)H), 4.05 (1H, d, J 3.7,
C(3)H), 7.10–7.12 (2H, m, Ph), 7.27–7.34 (6H, m, Ph), 7.36–7.39
(2H, m, Ph); δC (125 MHz, D2O) 11.1 (C(3′)), 27.1 (C(2′)), 47.1
(C(1′)), 54.1 (C(3)), 58.6 (C(2)), 126.0, 127.1, 128.5, 128.8, 129.0,
129.1 (o,m,p-Ph), 136.3, 141.3 (i-Ph), 179.1 (C(1)); m/z (ESI+) 284
+
(ESI+) 392 ([M
+
H]+, 100%); HRMS (ESI+) C26H34NO2
([M + H]+) requires 392.2584; found 392.2584.
(Z)-4′-Phenylbut-2′-en-1′-yl (3R,αS,E)-3-[N-benzyl-N-
(α-methylbenzyl)amino]hex-4-enoate 67
Step 1. TFA (18 mL) was added to a solution of 6429a (4.13 g,
10.9 mmol, >99 : 1 dr) in CH2Cl2 (33 mL) at rt and the resultant
mixture was stirred at rt for 16 h. The reaction mixture was
then diluted with CH2Cl2 (100 mL) and washed with NaHCO3
(100 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
100 mL) and the combined organic extracts were then dried
and concentrated in vacuo to give a yellow oil (4.31 g, >99 : 1
dr).
Step 2. A solution of the residue (4.31 g, >99 : 1 dr) in
CH2Cl2 (43 mL) was treated sequentially with (COCl)2
(0.98 mL, 11.4 mmol) and DMF (33 μL, 0.43 μmol) at 0 °C. The
reaction mixture was allowed to warm to rt over 1 h then con-
centrated in vacuo. A solution of (Z)-4-phenylbut-2-en-1-ol38
(2.26 g, 15.3 mmol, >99 : 1 dr) was then added to a solution of
the residue in CH2Cl2 (43 mL) at 0 °C. The reaction mixture
was allowed to warm to rt and stirred at rt for 16 h. Satd aq.
NaHCO3 (100 mL) was then added and the resultant mixture
was extracted with CH2Cl2 (3 × 100 mL). The combined organic
extracts were washed with brine (300 mL), then dried and con-
centrated in vacuo. Purification via flash column chromato-
graphy (gradient elution, 0% → 5% Et2O in 30–40 °C petrol)
gave 67 as a colourless oil (3.04 g, 62%, >99 : 1 dr); [α]2D0 +7.0
(c 1.0 in CHCl3); νmax (ATR) 3027, 2935 (C–H), 1733 (CvO),
1494 (CvC); δH (400 MHz, CDCl3) 1.31 (3H, d, J 6.8, C(α)Me),
1.62 (3H, d, J 5.2, C(6)H3), 2.26 (1H, dd, J 14.2, 8.1 C(2)HA),
2.41 (1H, dd, J 14.2, 6.6, C(2)HB), 3.35 (2H, d, J 7.6, C(4′)H2),
([M + H]+, 100%); HRMS (ESI+) C18H22NO2 ([M + H]+) requires
+
284.1645; found 284.1645.
(Z)-Pent-2′-en-1′-yl (3R,αS,E)-3-[N-benzyl-N-(α-methyl-benzyl)-
amino]hex-4-enoate 66
Step 1. TFA (8 mL) was added to a solution of 6429a (2.00 g,
5.27 mmol, >99 : 1 dr) in CH2Cl2 (16 mL) at rt and the resultant
mixture was stirred at rt for 16 h. The reaction mixture was
diluted with CH2Cl2 (100 mL) and washed with NaHCO3
(100 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
100 mL) and the combined organic extracts were then dried
and concentrated in vacuo to give a yellow oil (1.97 g, >99 : 1
dr).
Step 2. A solution of the residue (1.97 g, >99 : 1 dr) in
CH2Cl2 (21 mL) was treated sequentially with (COCl)2
(0.53 mL, 6.18 mmol) and DMF (18 μL, 0.24 μmol) at 0 °C. The
reaction mixture was allowed to warm to rt over 1 h then con-
centrated in vacuo. A solution of (Z)-pent-2-en-1-ol37 (0.72 g,
8.41 mmol, >99 : 1 dr) in CH2Cl2 (2 mL) was then added to a
solution of the residue in CH2Cl2 (21 mL) at 0 °C. The reaction
mixture was allowed to warm to rt and stirred at rt for 16 h.
Satd aq. NaHCO3 (100 mL) was then added and the resultant
mixture was extracted with CH2Cl2 (3 × 100 mL). The combined
organic extracts were washed with brine (300 mL), then dried
and concentrated in vacuo. Purification via flash column
chromatography (eluent 30–40 °C petrol–Et2O, 98 : 2) gave 66
as a colourless oil (1.30 g, 54%, >99 : 1 dr); [α]2D0 +5.8 (c 1.0 in
CHCl3); νmax (ATR) 2966 (C–H), 1733 (CvO), 1494 (CvC); δH
(400 MHz, CDCl3) 0.89 (3H, t, J 7.5, C(5′)H3), 1.29 (3H, d, J 6.9,
C(α)Me), 1.61 (3H, d, J 5.4, C(6)H3), 1.99 (2H, qdd, J 7.5, 7.5,
1.3, C(4′)H2), 2.23 (1H, dd, J 14.2, 8.2, C(2)HA), 2.38 (1H, dd,
J 14.2, 6.6, C(2)HB), 3.57 (1H, d, J 14.6, NCHAHBPh), 3.62 (1H,
d, J 14.6, NCHAHBPh), 3.69–3.74 (1H, m, C(3)H), 3.92 (1H, q,
3.58 (1H, d,
J 14.6, NCHAHBPh), 3.64 (1H, d, J 14.6,
NCHAHBPh), 3.71–3.76 (1H, m, C(3)H), 3.94 (1H, q, J 6.8, C(α)H),
4.47 (1H, dd, J 12.8, 6.8, C(1′)HA), 4.58 (1H, dd, J 12.8, 7.2,
C(1′)HB), 5.41–5.54 (3H, m, C(5)H, C(2′)H, C(4)H), 5.66–5.74
(1H, m, C(3′)H), 7.08–7.15 (5H, m, Ph), 7.19–7.24 (6H, m, Ph),
7.26–7.30 (4H, m, Ph); δC (100 MHz, CDCl3) 16.8 (C(α)Me), 18.0
(C(6)), 33.7 (C(4′)), 38.6 (C(2)), 50.3 (NCH2Ph), 56.7 (C(3)), 56.8
(C(α)), 59.9 (C(1′)), 124.4 (C(2′)), 126.1, 126.5, 126.6, 127.8,
127.9, 128.0, 128.3, 128.3, 128.5 (o,m,p-Ph), 127.1 (C(5)), 131.0
(C(4)), 132.9 (C(3′)), 139.8, 141.3, 144.3 (i-Ph), 171.6 (C(1)); m/z
+
(ESI+) 454 ([M
+
H]+, 100%); HRMS (ESI+) C31H36NO2
([M + H]+) requires 454.2741; found 454.2741.
(Z)-4′-Methylpent-2′-en-1′-yl (3R,αS,E)-3-[N-benzyl-N-
(α-methylbenzyl)amino]hex-4-enoate 68
Step 1. TFA (4 mL) was added to a solution of 6429a (0.95 g,
J 6.9, C(α)H), 4.34–4.39 (1H, m, C(1′)HA), 4.44–4.49 (1H, m, 2.50 mmol, >99 : 1 dr) in CH2Cl2 (8 mL) at rt and the resultant
C(1′)HB), 5.26–5.33 (1H, m, C(2′)H), 5.39–5.55 (3H, m, C(4)H, mixture was stirred at rt for 16 h. The reaction mixture was
C(5)H, C(3′)H), 7.09–7.14 (2H, m, Ph), 7.17–7.22 (4H, m, Ph), diluted with CH2Cl2 (100 mL) and washed with NaHCO3
7.24–7.29 (4H, m, Ph); δC (100 MHz, CDCl3) 14.0 (C(5′)), 16.8 (100 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
(C(α)Me), 18.0 (C(6)), 20.8 (C(4′)), 38.6 (C(2)), 50.3 (NCH2Ph), 100 mL) and the combined organic extracts were then dried
2720 | Org. Biomol. Chem., 2014, 12, 2702–2728
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and concentrated in vacuo to give a yellow oil (900 mg, >99 : 1 t, J 6.5, C(2)H), 3.47 (1H, dd, J 8.4, 7.5, C(3)H), 3.53 (1H, d,
dr). J 14.2, NCHAHBPh), 3.74 (1H, d, J 14.2, NCHAHBPh), 4.06 (1H,
Step 2. A solution of the residue (900 mg, >99 : 1 dr) in q, J 6.8, C(α)H), 4.65 (1H, dd, J 17.1, 1.7, C(1′)HA), 4.83 (1H, dd,
CH2Cl2 (9 mL) was treated sequentially with (COCl)2 (0.2 mL, J 10.3, 1.7, C(1′)HB), 5.38–5.45 (1H, m, C(2′)H), 5.47–5.56 (2H,
2.62 mmol) and DMF (8 μL, 0.10 μmol) at 0 °C. The reaction m, C(4)H, C(5)H), 7.08–7.12 (3H, m, Ph), 7.14–7.18 (3H, m, Ph),
mixture was allowed to warm to rt over 1 h then concentrated 7.23–7.31 (4H, m, Ph); δC (100 MHz, CDCl3) 11.7 (C(5′)), 15.0
in vacuo. A solution of (Z)-4-methylpent-2-en-1-ol29a (350 mg, (C(α)Me), 18.0 (C(6)), 25.0 (C(4′)), 43.7 (C(3′)), 51.7 (NCH2Ph), 52.0
3.49 mmol, >99 : 1 dr) was then added to a solution of the (C(2)), 57.7 (C(α)), 62.0 (C(3)), 116.0 (C(1′)), 126.9, 127.1 (o,m,p-
residue in CH2Cl2 (9 mL) at 0 °C. The reaction mixture was Ph), 127.5 (C(4)), 128.2, 128.2, 128.3, 128.8 (o,m,p-Ph), 130.6
allowed to warm to rt and stirred at rt for 16 h. Satd aq. (C(5)), 139.0 (C(2′)), 140.0, 143.0 (i-Ph), 177.3 (C(1)); m/z (ESI+)
+
NaHCO3 (100 mL) was then added and the resultant mixture 392 ([M + H]+, 100%); HRMS (ESI+) C26H33NNaO2 ([M + Na]+)
was extracted with CH2Cl2 (3 × 100 mL). The combined organic requires 414.2404; found 414.2404. Further elution (eluent
extracts were washed with brine (300 mL), then dried and con- 30–40 °C petrol–acetone, 95 : 5) gave 71 as a yellow oil (1.11 g,
centrated in vacuo. Purification via flash column chromato- >99 : 1 dr); [α]2D0 +26.8 (c 1.0 in CHCl3); νmax (ATR) 2964 (C–H),
graphy (gradient elution, 0% → 5% Et2O in 30–40 °C petrol) 1703 (CvO), 1495 (CvC); δH (400 MHz, CDCl3) 0.64 (3H, t,
gave 68 as a colourless oil (510 mg, 50%, >99 : 1 dr); [α]D20 +12.1 J 7.5, C(5′)H3), 1.41–1.55 (1H, m, C(4′)HA), 1.47 (3H, d, J 7.0,
(c 1.0 in CHCl3); νmax (ATR) 2962 (C–H), 1734 (CvO), 1494 C(α)Me), 1.63–1.75 (1H, m, C(4′)HB), 1.81 (3H, dd, J 6.5, 1.5,
(CvC); δH (400 MHz, CDCl3) 0.87 (6H, app d, J 6.8, C(5′)H3, C(6)H3), 1.86–1.93 (1H, m, C(3′)H), 2.13 (1H, dd, J 11.1, 1.8, C(2)H),
C(4′)Me), 1.29 (3H, d, J 6.9, C(α)Me), 1.61–1.62 (3H, m, C(6)H3), 3.64 (1H, d, J 13.5, NCHAHBPh), 3.72 (1H, app t, J 10.0, C(3)H),
2.23 (1H, dd, J 14.3, 6.6, C(2)HA), 2.38 (1H, dd, J 14.3, 8.0, C(2)HB), 3.85 (1H, d, J 13.5, NCHAHBPh), 3.96 (1H, q, J 7.0, C(α)H), 4.65
2.47–2.56 (1H, m, C(4′)H), 3.57 (1H, d, J 14.4, NCHAHBPh), (1H, dd, J 17.2, 2.1, C(1′)HA), 4.78 (1H, dd, J 10.1, 2.1, C(1′)HB),
3.62 (1H, d, J 14.4, NCHAHBPh), 3.69–3.74 (1H, m, C(3)H), 3.92 5.38 (1H, app ddd, J 15.4, 10.0, 1.5, C(4)H), 5.51 (1H, app dt,
(1H, q, J 6.9, C(α)H), 4.37 (1H, ddd, J 12.7, 6.8, 1.2, C(1′)HA), J 17.2, 10.1, C(2′)H), 5.67 (1H, dq, J 15.4, 6.5, C(5)H), 7.15–7.25
4.47 (1H, ddd, J 12.7, 6.8, 1.2, C(1′)HB), 5.17–5.23 (1H, m, C(2′)H), (10H, m, Ph); δC (100 MHz, CDCl3) 12.3 (C(5′)), 17.2 (C(α)Me),
5.31–5.37 (1H, m, C(3′)H), 5.39–5.46 (1H, m, C(5)H), 18.3 (C(6)), 26.5 (C(4′)), 46.0 (C(3′)), 47.1 (C(2)), 51.1 (NCH2Ph),
5.46–5.52 (1H, m, C(4)H), 7.09–7.15 (2H, m, Ph), 7.17–7.31 (8H, 59.9 (C(α)), 60.6 (C(3)), 116.6 (C(1′)), 126.0 (C(4)), 128.0, 128.1,
m, Ph); δC (100 MHz, CDCl3) 16.8 (C(α)Me), 18.0 (C(6)), 128.3, 128.6, 128.6, 129.6 (o,m,p-Ph), 133.9 (C(5)), 135.2 (i-Ph),
23.0 (C(5′), C(4′)Me), 26.9 (C(4′)), 38.6 (C(2)), 50.3 (NCH2Ph), 138.8 (C(4′)), 140.0 (i-Ph), 174.0 (C(1)); m/z (ESI+) 392 ([M + H]+,
+
56.7 (C(3)), 56.8 (C(α)), 60.2 (C(1′)), 121.1 (C(2′)), 126.5, 100%); HRMS (ESI+) C26H33NNaO2 ([M + Na]+) requires
126.6 (o,m,p-Ph), 127.1 (C(5)), 127.8, 127.9, 128.0, 128.3 (o,m,p- 414.2404; found 414.2404.
Ph), 131.0 (C(4)), 141.3 (i-Ph), 142.2 (C(3′)), 144.3 (i-Ph),
Step 2 (for 71). A solution of 71 (906 mg) in MeCN (4 mL)
171.7 (C(1)); m/z (ESI+) 406 ([M
+
H]+, 100%); HRMS was treated sequentially with DBU (692 μl, 4.63 mmol) and
(ESI+) C27H36NO2 ([M
406.2745.
+
H]+) requires 406.2741; found MeI (317 μL, 5.09 mmol) at rt. The reaction mixture was stirred
at rt for 16 h, then concentrated in vacuo. The residue was par-
+
titioned between CH2Cl2 (80 mL) and 2.0 M aq. HCl (80 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 50 mL) and
the combined organic extracts were then washed sequentially
Methyl (S,S,S,S,E)-2-(pent-1′-en-3′-yl)-3-[N-benzyl-N-
(α-methylbenzyl)amino]hex-4-enoate 81
Step 1. TMSCl (1.94 mL, 15.3 mmol) was added dropwise to with satd aq. NaHCO3 (150 mL) and brine (150 mL), then
a solution of 66 (2.00 g, 5.11 mmol, >99 : 1 dr) in PhMe dried and concentrated in vacuo. Purification via flash column
(20 mL) at −78 °C, and the resultant solution was stirred at chromatography (eluent 30–40 °C petrol–Et2O, 98 : 2) gave 81
−78 °C for 10 min. LiHMDS (1.0 M in THF, 15.3 mL, as a colourless oil (791 mg, 38% from 66, >99 : 1 dr); [α]2D0 +4.7
15.3 mmol) was added dropwise at −78 °C and the resultant (c 1.0 in CHCl3); νmax (ATR) 2967 (C–H), 1733 (CvO), 1495
mixture was stirred at −78 °C for 15 min. The reaction mixture (CvC); δH (400 MHz, CDCl3) 0.70 (3H, t, J 7.3, C(5′)H3),
was stirred at reflux for 1 h, then allowed to cool to rt and con- 0.98–1.09 (1H, m, C(4′)HA), 1.18–1.28 (1H, m, C(4′)HB), 1.31
centrated in vacuo. The residue was then partitioned between (3H, d, J 6.9, C(α)Me), 1.68–1.70 (3H, m, C(6)H3), 1.84 (1H, m,
CH2Cl2 (200 mL) and 1.0 M aq. HCl (150 mL). The aqueous C(3′)H), 2.68 (1H, dd, J 11.5, 4.5, C(2)H), 3.35 (3H, s, OMe),
layer was extracted with CH2Cl2 (2 × 200 mL) and the com- 3.43–3.48 (1H, m, C(3)H), 3.47 (1H, d, J 14.2, NCHAHBPh), 3.71
bined organic extracts were washed with brine (150 mL), then (1H, d, J 14.2, NCHAHBPh), 4.03 (1H, q, J 6.9, C(α)H), 4.63 (1H,
dried and concentrated in vacuo to give a 85 : 15 mixture of 71 dd, J 17.1, 2.1, C(1′)HA), 4.81 (1H, dd, J 10.1, 2.1, C(1′)HB),
and 76. Purification via flash column chromatography (gradi- 5.22–5.28 (1H, m, C(4)H), 5.34–5.42 (1H, m, C(5)H), 5.50 (1H,
ent elution, 0% → 5% acetone in 30–40 °C petrol) gave 76 as a dt, J 17.1, 10.1, C(2′)H) 7.05–7.13 (2H, m, Ph), 7.14–7.22 (8H,
yellow oil (308 mg, >99 : 1 dr); [α]2D0 −7.9 (c 1.0 in CHCl3); νmax m, Ph); δC (100 MHz, CDCl3) 11.9 (C(5′)), 16.9 (C(α)Me), 18.0
(ATR) 2965 (C–H), 1702 (CvO), 1494 (CvC); δH (400 MHz, (C(6)), 26.4 (C(4′)), 45.6 (C(3′)), 50.3 (NCH2Ph), 50.6 (OMe), 52.3
CDCl3) 0.61 (3H, t, J 7.3, C(5′)H3), 0.97–1.08 (1H, m, C(4′)HA), (C(2)), 56.3 (C(α)), 60.4 (C(3)), 116.4 (C(1′)), 127.9 (C(4)), 126.2,
1.09–1.16 (1H, m, C(4′)HB), 1.34 (3H, d, J 6.8, C(α)Me), 1.61 126.4, 127.6, 127.8, 128.1, 128.9 (o,m,p-Ph), 130.1 (C(5)), 137.5
(3H, d, J 4.9, C(6)H3), 2.17–2.24 (1H, m, C(3′)H), 2.39 (1H, app (C(2′)), 140.3, 144.7 (i-Ph), 173.2 (C(1)); m/z (ESI+) 406 ([M + H]+,
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100%); HRMS (ESI+) C27H36NO2 ([M + H]+) requires 406.2741; was allowed to warm to rt then heated at reflux for 1 h, then
found 406.2746. allowed to cool to rt and concentrated in vacuo. The residue
+
Step 2 (for 76). A solution of 76 (256 mg) in MeCN (1.0 mL) was then partitioned between CH2Cl2 (150 mL) and 1.0 M aq.
was treated sequentially with DBU (196 μL, 1.31 mmol) and HCl (100 mL), and the aqueous layer was extracted with
MeI (90 μL, 1.44 mmol) at rt. The reaction mixture was stirred CH2Cl2 (2 × 150 mL). The combined organic extracts were
at rt for 16 h, then concentrated in vacuo. The residue was par- washed with brine (150 mL), then dried and concentrated
titioned between CH2Cl2 (50 mL) and 2.0 M aq. HCl (50 mL), in vacuo to give a 76 : 24 mixture of 72 and 77. Purification via
and the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). flash column chromatography (gradient elution, 0% → 12%
The combined organic extracts were then washed sequentially acetone in 30–40 °C petrol) gave 77 as a yellow oil (360 mg,
with satd aq. NaHCO3 (150 mL) and brine (150 mL), then >99 : 1 dr); [α]2D0 −21.3 (c 0.8 in CHCl3); νmax (ATR) 2928 (C–H),
dried and concentrated in vacuo. Purification via flash column 1704 (CvO), 1494 (CvC); δH (400 MHz, CDCl3) 1.38 (3H, d,
chromatography (eluent 30–40 °C petrol–Et2O, 98 : 2) gave 86 J 6.6, C(α)Me), 1.58–1.59 (3H, m, C(6)H3), 2.42–2.47 (1H, m,
as a white solid (179 mg, 9% from 66, >99 : 1 dr); [α]2D0 −19.2 C(1′)HA), 2.49–2.57 (1H, m, C(2′)H), 2.67–2.69 (1H, m, C(2)H), 2.78
(c 1.0 in CHCl3); νmax (ATR) 2966 (C–H), 1732 (CvO), 1494 (1H, dd, J 12.8, 6.5, C(1′)HB), 3.40 (1H, dd, J 10.0, 5.9, C(3)H),
(CvC); δH (400 MHz, CDCl3) 0.55 (3H, t, J 7.5, C(5′)H3), 3.55 (1H, d,
J 14.0, NCHAHBPh), 3.63 (1H, d, J 14.0,
0.84–0.95 (1H, m, C(4′)HA), 0.97–1.06 (1H, m, C(4′)HB), 1.30 NCHAHBPh), 4.11 (1H, q, J 6.6, C(α)H), 4.54 (1H, app d, J 17.5,
(3H, d, J 6.9, C(α)Me), 1.63 (3H, dd, J 6.4, 1.5, C(6)H3), C(4′)HA), 4.82 (1H, app d, J 10.2, C(4′)HB), 5.25–5.32 (1H, m,
2.18–2.25 (1H, m, C(3′)H), 2.45 (1H, dd, J 8.6, 6.1, C(2)H), C(4)H), 5.48–5.57 (1H, m, C(5)H), 5.67 (1H, ddd, J 17.5, 10.2, 8.2,
3.39–3.42 (1H, m, C(3)H), 3.44 (3H, s, OMe), 3.57 (1H, d, J 14.0, C(3′)H), 6.91–6.93 (2H, m, Ph), 7.04–7.28 (13H, m, Ph); δC
NCHAHBPh), 3.65 (1H, d, J 14.0, NCHAHBPh), 3.90 (1H, q, J 6.9, (100 MHz, CDCl3) 15.2 (C(α)Me), 17.9 (C(6)), 39.3 (C(1′)), 44.2
C(α)H), 4.64 (1H, dd, J 17.1, 2.0, C(1′)HA), 4.80 (1H, dd, J 10.3, (C(2)), 50.2 (C(2′)), 51.2 (NCH2Ph), 56.9 (C(α)), 62.4 (C(3)), 116.1
2.0, C(1′)HB), 5.34–5.40 (1H, m, C(2′)H), 5.40–5.47 (1H, m, C(5)H), (C(4′)), 125.9, 126.9, 127.2 (o,m,p-Ph), 127.9 (C(4)), 128.1, 128.2,
5.55–5.61 (1H, m, C(4)H), 7.09–7.14 (2H, m, Ph), 7.17–7.24 128.2, 128.3, 128.8, 129.4 (o,m,p-Ph), 130.8 (C(5)), 138.5 (C(3′)),
(6H, m, Ph), 7.30–7.31 (2H, m, Ph); δC (100 MHz, CDCl3) 11.4 139.4, 140.2, 142.0 (i-Ph), 176.6 (C(1)); m/z (ESI+) 454 ([M + H]+,
+
(C(5′)), 16.6 (C(α)Me), 18.1 (C(6)), 24.9 (C(4′)), 44.0 (C(3′)), 50.7 100%); HRMS (ESI+) C31H36NO2 ([M + H]+) requires 454.2741;
(OMe), 50.9 (NCH2Ph), 53.6 (C(2)), 57.9 (C(α)), 59.9 (C(3)), 116.1 found 454.2754. Further elution (eluent 30–40 °C petrol–
(C(1′)), 127.9 (C(4)), 126.5, 126.6, 128.0, 128.0, 128.1, 128.8 acetone, 88 : 12) gave 72 as a yellow oil (1.15 g, >99 : 1 dr); [α]D20
(o,m,p-Ph), 129.3 (C(5)), 138.7 (C(2′)), 141.3, 144.6 (i-Ph), 173.9 +13.7 (c 1.0 in CHCl3); νmax (ATR) 3027, 2933 (C–H), 1704
(C(1)); m/z (ESI+) 406 ([M
+
H]+, 100%); HRMS (ESI+) (CvO), 1495 (CvC); δH (400 MHz, CDCl3) 1.43 (3H, d, J 6.9,
C27H36NO2+ ([M + H]+) requires 406.2741; found 406.2745.
C(α)Me), 1.76 (3H, dd, J 6.4, 0.9, C(6)H3), 2.02 (1H, app d, J 11.0,
C(2)H), 2.29 (1H, app q, J 8.0, C(2′)H), 2.79 (1H, dd, J 13.4, 6.6,
C(1′)HA), 3.14 (1H, dd, J 13.4, 9.3, C(1′)HB), 3.54 (1H, d, J 13.6,
X-ray crystal structure determination for 86·HBF4
Data were collected using an Oxford Diffraction SuperNova NCHAHBPh), 3.65–3.70 (2H, m, NCHAHBPh, C(3)H), 3.89 (1H,
diffractometer with graphite monochromated Cu-Kα radiation, q, J 6.9, C(α)H), 4.64 (1H, app d, J 17.1, C(4′)HA), 4.77 (1H, dd,
using standard procedures at 150 K. The structure was solved J 10.2, 1.7, C(4′)HB), 5.07 (1H, dd, J 14.8, 10.1, C(4)H), 5.53–5.61
by direct methods (SIR92); all non-hydrogen atoms were (1H, m, C(5)H), 5.61–5.70 (1H, m, C(3′)H), 7.02–7.03 (2H, m,
refined with anisotropic thermal parameters. Hydrogen atoms Ph), 7.07–7.11 (3H, m, Ph), 7.14–7.25 (10H, m, Ph); δC
were added at idealised positions.
(100 MHz, CDCl3) 16.9 (C(α)Me), 18.4 (C(6)), 40.0 (C(1′)), 44.4
X-ray crystal structure data for 86·HBF4 [C27H36BF4NO2]: (C(2)), 46.1 (C(2′)), 51.0 (NCH2Ph), 59.9 (C(α)), 60.4 (C(3)), 116.9
M = 493.39, monoclinic, P21, a = 8.93933(11) Å, b = 14.19427(18) (C(4′)), 125.7 (C(4)), 125.9, 128.1, 128.2, 128.3, 128.4, 128.8,
Å, c = 10.40085(16) Å, β = 98.8420(13)°, V = 1304.05(3) Å3, Z = 2, 128.9, 129.5, 129.6 (o,m,p-Ph), 134.3 (C(5)), 134.6 (i-Ph), 138.5
μ = 0.808 mm−1, colourless block, crystal dimensions = 0.08 × (C(3′)), 139.6, 140.6 (i-Ph), 174.0 (C(1)); m/z (ESI+) 454 ([M + H]+,
0.10 × 0.19 mm3. A total of 5399 unique reflections were 100%); HRMS (ESI+) C31H36NO2 ([M + H]+) requires 454.2741;
+
measured for 4 < θ < 76 and 5377 reflections were used in the found 454.2763.
refinement. The final parameters were wR2 = 0.070 and R1
=
Step 2 (for 72). A solution of 72 (1.15 g, >99 : 1 dr) in MeCN
0.029 [I > −3.0σ(I)], with Flack enantiopole = 0.03(9).17 CCDC (12 mL) was treated sequentially with DBU (758 μl, 5.07 mmol)
982704.†
and MeI (347 μL, 5.58 mmol) at rt. The resultant mixture was
stirred at rt for 16 h, then concentrated in vacuo. The residue
was partitioned between CH2Cl2 (80 mL) and 2.0 M aq. HCl
(80 mL), and the aqueous layer was extracted with CH2Cl2 (3 ×
Methyl (S,S,S,S,E)-2-(1′-phenylbut-3′-en-2′-yl)-3-[N-benzyl-N-
(α-methylbenzyl)amino]hex-4-enoate 82
Step 1. TMSCl (1.11 mL, 8.80 mmol) was added dropwise to 50 mL). The combined organic extracts were then washed
a solution of 67 (1.33 g, 2.93 mmol, >99 : 1 dr) in PhMe sequentially with satd aq. NaHCO3 (150 mL) and brine
(13 mL) at −78 °C, and the resultant mixture was stirred at (150 mL), then dried and concentrated in vacuo. Purification
−78 °C for 10 min. LiHMDS (1.0 M in THF, 8.80 mL, via flash column chromatography (eluent 30–40 °C petrol–
8.80 mmol) was then added dropwise and the resultant Et2O, 98 : 2) gave 82 as a pale yellow oil (777 mg, 57% from 67,
mixture was stirred at −78 °C for 15 min. The reaction mixture >99 : 1 dr); [α]2D0 −12.6 (c 1.0 in CHCl3); νmax (ATR) 3027, 2935
2722 | Org. Biomol. Chem., 2014, 12, 2702–2728
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(C–H), 1734 (CvO), 1495 (CvC); δH (400 MHz, CDCl3) 1.28 less prism, crystal dimensions = 0.08 × 0.11 × 0.19 mm3.
(3H, d, J 6.9, C(α)Me), 1.67 (3H, dd, J 6.4, 1.5, C(6)H3), A total of 5681 unique reflections were measured for 3 < θ < 77
2.26–2.33 (1H, m, C(2′)H), 2.38 (1H, dd, J 13.4, 8.2, C(1′)HA), and 5154 reflections were used in the refinement. The final
2.55 (1H, dd, J 13.4, 6.6, C(1′)HB), 2.72 (1H, dd, J 11.4, 3.8, parameters were wR2 = 0.205 and R1 = 0.079 [I > −3.0σ(I)], with
C(2)H), 3.42 (3H, s, OMe), 3.45 (1H, d, J 14.0, NCHAHBPh), Flack enantiopole = −0.7(4).17 CCDC 982705.†
3.46–3.52 (1H, m, C(3)H), 3.66 (1H, d, J 14.0, NCHAHBPh), 3.98
(1H, q, J 6.9, C(α)H), 4.50 (1H, dd, J 17.1, 2.1, C(4′)HA), 4.74
Methyl (S,S,S,S,E)-2-(4′-methylpent-1′-en-3′-yl)-3-[N-benzyl-N-
(1H, dd, J 10.2, 2.1, C(4′)HB), 5.15–5.22 (1H, m, C(4)H), 5.36
(α-methylbenzyl)amino]hex-4-enoate 83
(1H, app dq, J 15.3, 6.4, C(5)H), 5.57–5.66 (1H, m, C(3′)H),
6.98–7.01 (2H, m, Ph), 7.06–7.22 (13H, m, Ph); δC (100 MHz,
Step 1. TMSCl (476 μL, 3.77 mmol) was added dropwise to a
CDCl3) 16.9 (C(α)Me), 18.0 (C(6)), 40.1 (C(1′)), 45.6 (C(2′)), 50.3 solution of 68 (509 mg, 1.26 mmol, >99 : 1 dr) in PhMe (5 mL)
(NCH2Ph), 50.7 (OMe), 51.6 (C(2)), 56.3 (C(α)), 60.4 (C(3)), 116.6 at −78 °C, and the resultant mixture was stirred at −78 °C for
(C(4′)), 125.8, 126.2, 126.4, 127.6, 127.8, 127.9 (o,m,p-Ph), 127.9 10 min. LiHMDS (1.0 M in THF, 3.76 mL, 3.76 mmol) was
(C(4)), 128.0, 128.9, 129.2 (o,m,p-Ph), 130.3 (C(5)), 137.0 (C(3′)), added dropwise at −78 °C and the resultant mixture was
139.9, 140.2, 144.6 (i-Ph), 173.0 (C(1)); m/z (ESI+) 468 ([M + H]+, stirred at −78 °C for 15 min. The reaction mixture was then
+
100%); HRMS (ESI+) C32H38NO2 ([M + H]+) requires 468.2897; stirred at reflux for 1 h, then allowed to cool to rt and concen-
found 468.2907.
trated in vacuo. The residue was then partitioned between
Step 2 (for 77). A solution of 77 (359 mg, >99 : 1 dr) in CH2Cl2 (200 mL) and 1.0 M aq. HCl (150 mL). The aqueous
MeCN (3.6 mL) was treated sequentially with DBU (237 μL, layer was extracted with CH2Cl2 (2 × 200 mL) and the com-
1.58 mmol) and MeI (108 μL, 1.74 mmol) at rt. The resultant bined organic extracts were washed with brine (150 mL), then
mixture was stirred at rt for 16 h, then concentrated in vacuo. dried and concentrated in vacuo to give an 85 : 15 mixture of 73
The residue was partitioned between CH2Cl2 (50 mL) and 2.0 and 78. Purification via flash column chromatography (gradi-
M aq. HCl (50 mL), and the aqueous layer was extracted with ent elution, 0% → 6% acetone in 30–40 °C petrol) gave 78 as a
CH2Cl2 (3 × 50 mL). The combined organic extracts were then yellow oil (81 mg, >99 : 1 dr); [α]2D0 −9.7 (c 1.0 in CHCl3); νmax
washed sequentially with satd aq. NaHCO3 (150 mL) and brine (ATR) 2962 (C–H), 1701 (CvO), 1494 (CvC); δH (400 MHz,
(150 mL), then dried and concentrated in vacuo. Purification CDCl3) 0.34 (3H, d, J 6.7, C(4′)MeA), 0.54 (3H, d, J 6.7,
via flash column chromatography (gradient elution, 2% Et2O C(4′)MeB), 1.25 (3H, d, J 6.8, C(α)Me), 1.33–1.43 (1H, m, C(4′)H),
in 30–40 °C petrol) gave 87 as a yellow oil (221 mg, 16% from 1.57 (3H, d, J 6.4, C(6)H3), 1.91–1.97 (1H, m, C(3′)H), 2.47 (1H,
67, >99 : 1 dr); [α]D20 +15.7 (c 1.0 in CHCl3); νmax (ATR) 3028, app t, J 7.0, C(2)H), 3.34 (1H, dd, J 9.4, 7.0, C(3)H), 3.47 (1H, d,
2950 (C–H), 1732 (CvO), 1496 (CvC); δH (400 MHz, CDCl3) J 14.4, NCHAHBPh), 3.69 (1H, d, J 14.4, NCHAHBPh), 3.93 (1H,
1.27 (3H, d, J 7.0, C(α)Me), 1.63–1.65 (3H, m, C(6)H3), 2.25 (1H, q, J 6.8, C(α)H), 4.51–4.56 (1H, m, C(1′)HA), 4.74–4.77 (1H, m,
dd, J 13.7, 8.8, C(1′)HA), 2.39 (1H, dd, J 13.7, 6.4, C(1′)HB), 2.56 C(1′)HB), 5.38–5.47 (2H, m, C(5)H, C(2′)H), 5.54–5.61 (1H, m,
(1H, dd, J 8.8, 5.4, C(2)H), 2.63–2.70 (1H, m, C(2′)H), 3.43–3.49 C(4)H), 7.03–7.20 (8H, m, Ph), 7.27–7.29 (2H, m, Ph); δC
(1H, m, C(3)H), 3.48 (3H, s, OMe), 3.51 (1H, d, J 14.4, (100 MHz, CDCl3) 14.6 (C(α)Me), 17.6 (C(4′)MeA), 17.9 (C(6)),
NCHAHBPh), 3.58 (1H, d, J 14.4, NCHAHBPh), 3.85 (1H, q, J 7.0, 21.2 (C(4′)MeB), 27.6 (C(4′)), 49.0 (C(3′)), 51.1 (C(2)), 51.5
C(α)H), 4.35–4.40 (1H, m, C(4′)HA), 4.66 (1H, dd, J 10.4, 2.1, (NCH2Ph), 57.3 (C(α)), 61.0 (C(3)), 117.5 (C(1′)), 126.7, 126.8
C(4′)HB), 5.37–5.45 (1H, m, C(3′)H), 5.40–5.48 (1H, m, C(5)H), (o,m,p-Ph), 127.6 (C(4)), 128.0, 128.1, 128.3, 128.8 (o,m,p-Ph),
5.51–5.57 (1H, m, C(4)H), 6.87–6.89 (2H, m, Ph), 7.02–7.27 130.2 (C(5)), 136.1 (C(2′)) 140.6, 143.7 (i-Ph), 179.2 (C(1));
(13H, m, Ph); δC (100 MHz, CDCl3) 16.0 (C(α)Me), 18.1 (C(6)), m/z (ESI+) 406 ([M + H]+, 100%); HRMS (ESI+) C27H36NO2
+
38.7 (C(1′)), 43.8 (C(2′)), 50.7 (NCH2Ph), 50.8 (OMe), 53.0 (C(2)), ([M + H]+) requires 406.2741; found 406.2748. Further elution
57.0 (C(α)), 59.6 (C(3)), 116.1 (C(4′)), 125.8 (C(4)), 126.6 (C(5)), (eluent 30–40 °C petrol–acetone, 94 : 6) gave 73 as a yellow oil
127.9, 128.0, 128.0, 128.1, 128.1, 128.3, 129.0, 129.3, 129.3 (382 mg, >99 : 1 dr); [α]2D0 +5.0 (c 1.0 in CHCl3); νmax (ATR) 2960
(o,m,p-Ph), 138.0 (C(3′)), 140.0, 140.9, 144.4 (i-Ph), 173.4 (C(1)); (C–H), 1702 (CvO), 1495 (CvC); δH (400 MHz, CDCl3) 0.57
+
m/z (ESI+) 468 ([M + H]+, 100%); HRMS (ESI+) C32H38NO2
(3H, d, J 6.7, C(4′)MeA), 0.64 (3H, d, J 6.7, C(4′)MeB), 1.40 (1H,
app td, J 10.0, 1.7, C(3′)H), 1.48 (3H, d, J 7.1, C(α)Me), 1.83 (3H,
dd, J 6.5, 1.8, C(6)H3), 2.14–2.24 (C(2)H, C(4′)H), 3.67 (1H, d,
J 13.4, NCHAHBPh), 3.74–3.79 (1H, m, C(3)H), 3.78 (1H, d, J 13.4,
([M + H]+) requires 468.2897; found 468.2904.
X-ray crystal structure determination for 87
Data were collected using an Oxford Diffraction SuperNova NCHAHBPh), 3.91 (1H, q, J 7.1, C(α)H), 4.59 (1H, dd, J 17.3, 2.5,
diffractometer with graphite monochromated Cu-Kα radiation, C(1′)HA), 4.79 (1H, dd, J 10.0, 2.5, C(1′)HB), 5.33 (1H, app ddd,
using standard procedures at 150 K. The structure was solved J 15.5, 9.6, 1.8, C(4)H), 5.52 (1H, ddd, J 17.3, 10.2, 10.0, C(2′)H),
by direct methods (SIR92); all non-hydrogen atoms were 5.66 (1H, dq, J 15.5, 6.5, C(5)H), 7.15–7.27 (10H, m, Ph);
refined with anisotropic thermal parameters. Hydrogen atoms δC (100 MHz, CDCl3) 17.9 (C(α)Me), 18.3 (C(6)), 20.6, 22.1
were added at idealised positions.
(C(4′)Me2), 28.4 (C(4′)), 43.9 (C(2)), 51.4 (NCH2Ph), 52.2 (C(3′)), 60.6
X-ray crystal structure data for 87 [C31H35NO2]: M = 453.62, (C(α)), 60.6 (C(3)), 117.0 (C(1′)), 125.7 (C(4)), 128.0, 128.1,
orthorhombic, P22121, a = 10.7026(7) Å, b = 15.0868(9) Å, c = 128.1, 128.7, 128.7, 129.6 (o,m,p-Ph), 134.2 (C(5)), 135.1 (i-Ph),
16.8872(8) Å, V = 2726.8(3) Å3, Z = 4, μ = 0.527 mm−1, colour- 138.5 (C(2′)), 140.3 (i-Ph), 174.0 (C(1)); m/z (ESI+) 406 ([M + H]+,
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100%); HRMS (ESI+) C27H36NO2 ([M + H]+) requires 406.2741; 128.0, 128.1, 128.2, 128.8 (o,m,p-Ph), 129.5 (C(5)), 136.1 (C(2′)),
+
found 406.2747.
141.3, 144.5 (i-Ph), 174.5 (C(1)); m/z (ESI+) 420 ([M + H]+,
Step 2 (for 73). A solution of 73 (382 mg, >99 : 1 dr) in 100%); HRMS (ESI+) C28H38NO2 ([M + H]+) requires 420.2897;
MeCN (3.9 mL) was treated sequentially with DBU (281 μL, found 420.2898.
1.88 mmol) and MeI (129 μL, 2.07 mmol) at rt. The reaction
+
mixture was stirred at rt for 16 h, then concentrated in vacuo.
The residue was partitioned between CH2Cl2 (50 mL) and 2.0
M aq. HCl (50 mL). The aqueous layer was extracted with
CH2Cl2 (3 × 50 mL) and the combined organic extracts were
Methyl (S,S,S,S)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-
ethylcyclopent-3-ene-1-carboxylate 91
then washed sequentially with satd aq. NaHCO3 (150 mL) and Grubbs I catalyst (292 mg, 0.36 mmol) was added to a
brine (150 mL), then dried and concentrated in vacuo. Purifi- degassed solution of 81 (360 mg, 0.89 mmol, >99 : 1 dr) in
cation via flash column chromatography (eluent 30–40 °C CH2Cl2 (36 mL) at rt and the resultant mixture was heated at
petrol–Et2O, 98 : 2) gave 83 as a colourless oil (272 mg, 52% 40 °C for 24 h. The reaction mixture was then allowed to cool
from 68, >99 : 1 dr); [α]2D0 +1.2 (c 1.0 in CHCl3); νmax (ATR) 2958 to rt and concentrated in vacuo. Purification via flash column
(C–H), 1737 (CvO), 1495 (CvC); δH (400 MHz, CDCl3) 0.65 chromatography (eluent 30–40 °C petrol–Et2O, 98 : 2) gave 91
(3H, d, J 6.6, C(4′)MeA), 0.80 (3H, d, J 6.6, C(4′)MeB), 1.22–1.29 as a colourless oil (200 mg, 62%, >99 : 1 dr); [α]2D0 +198.8 (c 1.0
(1H, m, C(4′)H), 1.31 (3H, d, J 6.9, C(α)Me), 1.58 (1H, app td, in CHCl3); νmax (ATR) 2965 (C–H), 1729 (CvO), 1493 (CvC); δH
J 9.5, 3.8, C(3′)H), 1.69 (3H, dd, J 6.4, 1.2, C(6)H3), 2.83 (1H, dd, (400 MHz, CDCl3) 0.75 (3H, t, J 7.3, C(2′)H3), 0.97–1.08 (1H, m,
J 11.4, 3.8, C(2)H), 3.34 (3H, s, OMe), 3.42–3.48 (1H, m, C(3)H), C(1′)HA), 1.18–1.29 (1H, m, C(1′)HB), 1.27 (3H, d, J 7.0, C(α)Me),
3.48 (1H, d,
J 13.9, NCHAHBPh), 3.71 (1H, d, J 13.9, 2.67–2.75 (1H, m, C(5)H), 2.89 (1H, dd, J 9.4, 6.0, C(1)H), 3.37
NCHAHBPh), 4.03 (1H, q, J 6.9, C(α)H), 4.58 (1H, dd, J 17.1, 2.5, (3H, s, OMe), 3.58 (1H, d, J 15.4, NCHAHBPh), 3.62 (1H, d,
C(1′)HA), 4.80 (1H, dd, J 10.2, 2.5, C(1′)HB), 5.17–5.24 (1H, m, J 15.4, NCHAHBPh), 3.77 (1H, q, J 7.0, C(α)H), 4.35–4.38 (1H,
C(4)H), 5.31–5.40 (1H, m, C(5)H), 5.51 (1H, dt, J 17.1, 10.2, C(2′)H), m, C(2)H), 5.64–5.66 (1H, m, C(4)H), 5.70–5.73 (1H, m, C(3)H),
7.05–7.12 (2H, m, Ph), 7.13–7.23 (8H, m, Ph); δC (100 MHz, 7.09–7.25 (8H, m, Ph), 7.31–7.33 (2H, m, Ph); δC (100 MHz,
CDCl3) 17.2 (C(α)Me), 18.1 (C(6)), 21.0 (C(4′)MeB), 21.3 (C(4′)MeA), CDCl3) 12.5 (C(2′)), 16.3 (C(α)Me), 24.5 (C(1′), 48.4 (C(5)), 50.1
30.0 (C(4′)), 49.6 (C(2)), 50.5 (NCH2Ph), 50.6 (OMe), 51.2 (NCH2Ph), 50.6 (C(1)), 51.1 (OMe), 57.8 (C(α)), 67.5 (C(2)),
(C(3′)), 56.5 (C(α)), 60.7 (C(3)), 116.8 (C(1′)), 126.1, 126.4, 127.6, 126.5, 126.5, 127.7, 127.8, 128.1, 128.1 (o,m,p-Ph), 132.5 (C(4)),
127.8, 127.9, 129.0 (o,m,p-Ph), 128.1 (C(4)), 130.2 (C(5)), 136.9 134.8 (C(3)), 141.7, 144.0 (i-Ph), 174.1 (CO2Me); m/z (ESI+) 364
+
(C(2′)), 140.3, 144.8 (i-Ph), 173.3 (C(1)); m/z (ESI+) 420 ([M + H]+, ([M + H]+, 100%); HRMS (ESI+) C24H30NO2 ([M + H]+) requires
100%); HRMS (ESI+) C28H38NO2 ([M + H]+) requires 420.2897; 364.2271; found 364.2275.
+
found 420.2900.
Step 2 (for 78). A solution of 78 (72 mg, >99 : 1 dr) in MeCN
(0.7 mL) was treated sequentially with DBU (53 μL, 0.36 mmol)
and MeI (24 μL, 0.39 mmol) at rt. The reaction mixture was
stirred at rt for 16 h, then concentrated in vacuo. The residue
Methyl (S,S,S,S)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-
benzylcyclopent-3-ene-1-carboxylate 92
was partitioned between CH2Cl2 (10 mL) and 2.0 M aq. HCl Grubbs I catalyst (282 mg, 0.34 mmol) was added to a
(10 mL), and the aqueous layer was extracted with CH2Cl2 (3 × degassed solution of 82 (400 mg, 0.86 mmol, >99 : 1 dr) in
10 mL). The combined organic extracts were then washed CH2Cl2 (40 mL) at rt and the resultant mixture was heated at
sequentially with satd aq. NaHCO3 (40 mL) and brine (40 mL), 40 °C for 48 h. The reaction mixture was then allowed to cool
then dried and concentrated in vacuo. Purification via flash to rt and concentrated in vacuo. Purification via flash column
column chromatography (eluent 30–40 °C petrol–Et2O, 98 : 2) chromatography (eluent 30–40 °C petrol–Et2O, 98 : 2) gave 92
gave 88 as a white solid (44 mg, 7% from 68, >99 : 1 dr); [α]2D0 as a colourless oil (349 mg, 96%, >99 : 1 dr); [α]2D0 +185.6 (c 1.0
−27.1 (c 1.0 in CHCl3); νmax (ATR) 2960 (C–H), 1731 (CvO), in CHCl3); νmax (ATR) 3027, 2946 (C–H), 1730 (CvO), 1494
1494 (CvC); δH (400 MHz, CDCl3) 0.30 (3H, d, J 6.7, C(4′)MeA), (CvC); δH (400 MHz, CDCl3) 1.28 (3H, d, J 6.9, C(α)Me), 2.23
0.57 (3H, d, J 6.7, C(4′)MeB), 1.28 (3H, d, J 6.7, C(α)Me), 1.34 (1H, dd, J 13.2, 10.6, C(1′)HA), 2.58 (1H, dd, J 13.2, 5.6, C(1′)HB),
(1H, dd, J 11.9, 6.7, C(4′)H), 1.65 (3H, dd, J 6.4, 1.5, C(6)H3), 2.95 (1H, dd, J 9.4, 5.6, C(1)H), 3.11–3.19 (1H, m, C(5)H),
2.00 (1H, ddd, J 9.9, 7.6, 5.2, C(3′)H), 2.56 (1H, app t, J 7.6, C(2)H), 3.34 (3H, s, OMe), 3.60 (2H, app s, NCH2Ph), 3.78 (1H, q, J 6.9,
3.36 (1H, dd, J 9.9, 7.6, C(3)H), 3.44 (3H, s, OMe), 3.56 (1H, C(α)H), 4.43–4.46 (1H, m, C(2)H) 5.45 (1H, app dt, J 5.6, 2.1,
d, J 14.2, NCHAHBPh), 3.69 (1H, d, J 14.2, NCHAHBPh), 3.90 C(4)H), 5.66 (1H, app dt, J 5.6, 2.1, C(3)H), 6.98–7.01 (2H, m, Ph),
(1H, q, J 6.7, C(α)H), 4.61 (1H, dd, J 17.1, 2.3, C(1′)HA), 4.84 7.05–7.25 (11H, m, Ph), 7.30–7.33 (2H, m, Ph); δC (100 MHz,
(1H, dd, J 9.9, 2.3, C(1′)HB), 5.40–5.52 (2H, m, C(5)H, C(2′)H), CDCl3) 16.2 (C(α)Me), 37.7 (C(1′)), 47.9 (C(5)), 50.1 (NCH2Ph),
5.68–5.75 (1H, m, C(4)H), 7.10–7.13 (2H, m, Ph), 7.17–7.27 (6H, m, 50.3 (C(1)), 51.2 (OMe), 57.7 (C(α)), 67.8 (C(2)), 126.0, 126.6,
Ph), 7.33–7.35 (2H, m, Ph); δC (100 MHz, CDCl3) 15.2 (C(α)Me), 126.6, 127.7, 127.9, 128.1, 128.1, 128.2, 128.8 (o,m,p-Ph), 132.6
17.2 (C(4′)MeA), 18.1 (C(6)), 21.2 (C(4′)MeB), 27.5 (C(4′)), (C(3)), 134.6 (C(4)), 140.1, 141.6, 144.0 (i-Ph), 174.0 (CO2Me);
49.3 (C(3′)), 50.8 (OMe), 51.1 (NCH2Ph), 52.1 (C(2)), 57.2 (C(α)), m/z (ESI+) 426 ([M + H]+, 100%); HRMS (ESI+) C29H32NO2
+
59.8 (C(3)), 117.4 (C(1′)), 126.6, 126.6 (o,m,p-Ph), 127.9 (C(4)), ([M + H]+) requires 426.2428; found 426.2439.
2724 | Org. Biomol. Chem., 2014, 12, 2702–2728
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Methyl (S,S,S,S)-2-[N-benzyl-N-(α-methylbenzyl)amino]-5-
isopropylcyclopent-3-ene-1-carboxylate 93
methods (SIR92); all non-hydrogen atoms were refined with
anisotropic thermal parameters. Hydrogen atoms were added
at idealised positions.
Grubbs I catalyst (197 mg, 0.24 mmol) was added to a
degassed solution of 83 (251 mg, 0.60 mmol, >99 : 1 dr) in
CH2Cl2 (25 mL) at rt and the resultant mixture was heated at
40 °C for 48 h then concentrated in vacuo. The residue was dis-
solved in degassed CH2Cl2 (25 mL) and Grubbs I catalyst
(197 mg, 0.24 mmol) was added to the resultant solution. The
reaction mixture was heated at 40 °C for 48 h then concen-
trated in vacuo. Purification via flash column chromatography
(eluent 30–40 °C petrol–Et2O, 98 : 2) gave 93 as a colourless oil
(85 mg, 38%, >99 : 1 dr); [α]2D0 +204.5 (c 1.0 in CHCl3); νmax
(ATR) 2958 (C–H), 1734 (CvO), 1494 (CvC); δH (400 MHz,
CDCl3) 0.68 (3H, d, J 6.6, C(1′)MeA), 0.75 (3H, d, J 6.6,
C(1′)MeB), 1.26 (3H, d, J 6.9, C(α)Me), 1.55–1.63 (1H, m, C(1′)H),
2.65 (1H, app t, J 8.0, C(5)H), 2.96 (1H, dd, J 9.2, 5.9, C(1)H),
3.38 (3H, s, OMe), 3.62 (2H, app s, NCH2Ph), 3.81 (1H, q, J 6.9,
C(α)H), 4.28 (1H, d, J 5.9, C(2)H), 5.68–5.71 (2H, m, C(3)H,
C(4)H), 7.10–7.15 (2H, m, Ph), 7.18–7.25 (6H, m, Ph), 7.31–7.33
(2H, m, Ph); δC (100 MHz, CDCl3) 16.5 (C(α)Me), 20.0 (C(1′)MeA),
22.7 (C(1′)MeB), 28.8 (C(1′)), 50.0 (NCH2Ph), 50.5 (C(1)),
51.2 (OMe), 54.1 (C(5)), 58.2 (C(α)), 68.3 (C(2)), 126.5, 127.7,
127.8, 128.0, 128.1 (o,m,p-Ph), 133.1 (C(3)), 133.4 (C(4)), 141.9,
144.3 (i-Ph), 174.4 (CO2Me); m/z (ESI+) 378 ([M + H]+, 100%);
X-ray crystal structure data for 96·HCl [C9H18ClNO2]: M =
207.70, monoclinic, P21, a = 5.4210(1) Å, b = 8.9375(3) Å, c =
11.4409(3) Å, β = 101.8270(12)°, V = 542.55(3) Å3, Z = 2, μ =
0.323 mm−1, colourless block, crystal dimensions = 0.21 × 0.23
× 0.24 mm3. A total of 2115 unique reflections were measured
for 5 < θ < 27 and 2115 reflections were used in the refinement.
The final parameters were wR2 = 0.056 and R1 = 0.025 [I >
−3.0σ(I)], with Flack enantiopole = 0.03(5).17 CCDC 982706.†
Methyl (1S,2S,5R)-2-amino-5-benzylcyclopentane-
1-carboxylate 97
Pd(OH)2/C (99 mg, 50% w/w by substrate) was added to a
degassed solution of 92 (197 mg, 0.46 mmol, >99 : 1 dr) in
MeOH (14 mL) at rt. The resultant suspension was stirred vig-
orously under H2 (1 atm) at rt for 24 h. The reaction mixture
was then filtered through Celite® (eluent MeOH) and concen-
trated in vacuo. The residue was dissolved in CH2Cl2 (15 mL)
and the resultant solution was washed with satd aq. NaHCO3
(15 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
15 mL) and the combined organic extracts were then dried and
concentrated in vacuo. Purification via flash column chromato-
graphy (eluent CHCl3–MeOH, 98 : 2) gave 97 as a white solid
(74 mg, 69%, >99 : 1 dr); mp 65–67 °C; [α]2D0 +32.4 (c 1.0 in
CHCl3); νmax (ATR) 3365 (N–H), 2950 (C–H), 1727 (CvO); δH
(400 MHz, CDCl3) 1.18–1.29 (1H, m, C(3)HA), 1.36–1.45 (3H, m,
C(4)HA, NH2), 1.64–1.72 (1H, m, C(4)HB), 2.02–2.09 (1H, m,
C(3)HB), 2.26–2.33 (1H, m, C(1′)HA), 2.52–2.58 (1H, m, C(1)H),
2.59–2.68 (2H, m, C(1′)HB, C(5)H), 3.59 (3H, s, OMe), 3.62–3.68
(1H, m, C(2)H), 7.06–7.12 (3H, m, Ph), 7.17–7.21 (2H, m, Ph);
δC (100 MHz, CDCl3) 29.4 (C(4)), 34.1 (C(3)), 37.7 (C(1′)), 42.5
(C(5)), 51.3 (OMe), 55.1 (C(2)), 57.5 (C(1)), 125.9, 128.2, 128.8
(o,m,p-Ph), 140.5 (i-Ph), 174.4 (CO2Me); m/z (ESI+) 234
+
HRMS (ESI+) C25H32NO2 ([M + H]+) requires 378.2428; found
378.2437.
Methyl (S,S,S)-2-amino-5-ethylcyclopentane-1-carboxylate 96
Pd(OH)2/C (87 mg, 50% w/w) was added to a degassed solution
of 91 (173 mg, 0.48 mmol, >99 : 1 dr) in MeOH (12 mL) at rt.
The resultant suspension was stirred vigorously under H2
(1 atm) at rt for 24 h. The reaction mixture was then filtered
through Celite® (eluent MeOH) and the filtrate was concen-
trated in vacuo. The residue was dissolved in CH2Cl2 (15 mL)
and the resultant solution was washed with satd aq. NaHCO3
(15 mL). The aqueous layer was extracted with CH2Cl2 (3 ×
15 mL) and the combined organic extracts were then dried and
+
([M + H]+, 100%); HRMS (ESI+) C14H20NO2 ([M + H]+) requires
234.1489; found 234.1495.
concentrated in vacuo. Purification via flash column chromato- Methyl (1S,2S,5R)-2-amino-5-isopropylcyclopentane-1-
graphy (eluent CHCl3–MeOH, 94 : 6) gave 96 as a white solid carboxylate 98
(55 mg, 67%, >99 : 1 dr); mp 64–66 °C; [α]2D0 +15.7 (c 0.5 in
CHCl3); νmax (ATR) 3344 (N–H), 2959, 2932 (C–H), 1730 (CvO);
δH (400 MHz, CDCl3) 0.80 (3H, t, J 7.3, C(2′)H3), 1.01–1.12 (1H,
m, C(1′)HA), 1.23–1.39 (3H, m, C(3)HA, C(4)HA, C(1′)HB),
1.81–1.91 (1H, m, C(4)HB), 2.00–2.09 (3H, m, C(3)HB, NH2),
2.13–2.23 (1H, m, C(5)H), 2.53 (1H, dd, J 9.1, 7.1, C(1)H),
3.54–3.65 (1H, m, C(2)H), 3.62 (3H, s, OMe); δC (100 MHz,
CDCl3) 12.4 (C(2′)), 24.7 (C(1′)), 29.2 (C(4)), 34.0 (C(3)), 42.9
Pd(OH)2/C (43 mg, 50% w/w by substrate) was added to a
degassed solution of 93 (85 mg, 0.23 mmol, >99 : 1 dr) in
MeOH (6 mL) at rt. The resultant suspension was stirred vigor-
ously under H2 (1 atm) at rt for 24 h. The reaction mixture was
then filtered through Celite® (eluent MeOH) and concentrated
in vacuo. The residue was dissolved in CH2Cl2 (15 mL) and the
resultant solution was washed with satd aq. NaHCO3 (15 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 15 mL) and
(C(5)), 51.2 (OMe), 54.9 (C(2)), 57.4 (C(1)), 174.5 (CO2Me); m/z
the combined organic extracts were then dried and concen-
trated in vacuo. Purification via flash column chromatography
(ESI+) 172 ([M + H]+, 100%); HRMS (ESI+) C9H18NO2+ ([M + H]+)
requires 172.1332; found 172.1336.
(eluent CHCl3–MeOH, 99 : 1) gave 98 as a colourless oil (17 mg,
40%, >99 : 1 dr); [α]D20 +16.1 (c 0.2 in CHCl3); νmax (ATR) 3392
X-ray crystal structure determination for 96·HCl
(N–H), 2956 (C–H), 1721 (CvO), 1477; δH (700 MHz, CDCl3)
Data were collected using a Nonius κ-CCD diffractometer with 0.81 (3H, d, J 3.6, C(1′)MeA), 0.85 (3H, d, J 3.6, C(1′)MeB),
graphite monochromated Mo-Kα radiation, using standard 1.24–1.30 (1H, m, C(3)HA), 1.44–1.53 (2H, m, C(4)HA, C(1′)H),
procedures at 150 K. The structure was solved by direct 1.71 (2H, br s, NH2), 1.79–1.83 (1H, m, C(4)HB), 1.93–1.98 (1H,
This journal is © The Royal Society of Chemistry 2014
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m, C(5)H), 2.15–2.19 (1H, m, C(3)HB), 2.59 (1H, dd, J 8.1, 3.2, (c 0.2 in H2O); νmax (ATR) 3419 (N–H), 2953 (C–H), 1634
C(1)H), 3.53–3.55 (1H, m, C(2)H), 3.59 (3H, s, OMe); δC (CvO), 1510; δH (700 MHz, D2O) 0.79 (3H, d, J 6.6, C(1′)MeA),
(176 MHz, CDCl3) 21.5 (C(1′)MeA), 22.3 (C(1′)MeB), 28.5 (C(4)), 0.87 (3H, d, J 6.6, C(1′)MeB), 1.48–1.58 (3H, m, C(3)HA, C(4)HA,
29.7 (C(1′)), 34.8 (C(3)), 49.9 (C(5)), 51.2 (OMe), 56.6 (C(2)), 56.8 C(1′)H), 1.83–1.87 (1H, m, C(4)HB), 1.92–1.97 (1H, m, C(5)H),
(C(1)), 175.0 (CO2Me); m/z (ESI+) 186 ([M + H]+, 100%); HRMS 2.21–2.25 (1H, m, C(3)HB), 2.73 (1H, dd, J 8.6, 4.4, C(1)H), 3.75
+
(ESI+) C10H20NO2 ([M
186.1493.
+
H]+) requires 186.1489; found (1H, app td, J 7.3, 4.4, C(2)H); δC (176 MHz, D2O) 20.3
(C(1′)MeA), 21.8 (C(1′)MeB), 27.4 (C(4)), 29.1 (C(1′)), 30.1 (C(3)),
49.4 (C(5)), 55.0 (C(1)), 55.2 (C(2)), 180.3 (CO2H); m/z (ESI+) 172
(S,S,S)-2-Amino-5-ethylcyclopentane-1-carboxylic acid 101
+
([M + H]+, 100%); HRMS (ESI+) C9H18NO2 ([M + H]+) requires
A solution of 96 (35 mg, 0.20 mmol, >99 : 1 dr) in 6.0 M aq. 172.1332; found 172.1335.
HCl (5 mL) was heated at reflux for 16 h. The reaction mixture
was then allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in H2O (2 mL) and purified on DOWEX
50WX8 ion exchange resin (hydrogen form, 100–200 mesh,
Notes and references
eluent 1.0 M aq. NH4OH) to give 101 as a white solid (27 mg,
85%, >99 : 1 dr); mp 202–204 °C; [α]2D0 +73.3 (c 1.0 in H2O); νmax
(ATR) 3399 (O–H, N–H), 2960 (C–H), 1629 (CvO), 1570; δH
(400 MHz, D2O) 0.75 (3H, t, J 7.3, C(2′)H3), 0.92–1.03 (1H, m,
C(1′)HA), 1.23–1.33 (1H, m, C(1′)HB), 1.35–1.43 (1H, m, C(4)HA),
1.44–1.53 (1H, m, C(3)HA), 1.81–1.89 (1H, m, C(4)HB),
2.08–2.17 (2H, m, C(3)HB, C(5)H), 2.65 (1H, dd, J 8.8, 7.7,
C(1)H), 3.71 (1H, app q, J 7.7, C(2)H); δC (100 MHz, D2O) 11.8
(C(2′)), 23.5 (C(1′)), 28.2 (C(4)), 28.9 (C(3)), 42.6 (C(5)), 53.8
(C(2)), 55.8 (C(1)), 179.5 (CO2H); m/z (ESI+) 158 ([M + H]+,
1 (a) R. E. Ireland and R. H. Mueller, J. Am. Chem. Soc., 1972,
94, 5897; (b) R. E. Ireland, R. H. Mueller and A. K. Willard,
J. Am. Chem. Soc., 1976, 98, 2868; (c) R. E. Ireland, P. Wipf
and J. D. Armstrong, J. Org. Chem., 1991, 56, 650;
(d) R. E. Ireland, P. Wipf and J.-N. Xiang, J. Org. Chem.,
1991, 56, 3572.
2 (a) D. Enders, M. Knopp and R. Schiffers, Tetrahedron:
Asymmetry, 1996, 7, 1847; (b) H. Ito and T. Taguchi, Chem.
Soc. Rev., 1999, 28, 43; (c) Y. Chai, S. Hong, H. A. Lindsay,
C. McFarland and M. C. McIntosh, Tetrahedron, 2002, 58,
2905; (d) A. G. O’Brien, Tetrahedron, 2011, 67, 9639;
(e) K. C. Majumdar and R. K. Nandi, Tetrahedron, 2013, 69,
6921.
+
100%); HRMS (ESI+) C8H16NO2 ([M + H]+) requires 158.1176;
found 158.1173.
(1S,2S,5R)-2-Amino-5-benzylcyclopentane-1-carboxylic acid 102
3 For example, see: (a) C. P. Dell, K. M. Khan and
D. W. Knight, J. Chem. Soc., Chem. Commun., 1989, 1812;
(b) D. W. Knight, A. C. Share and P. T. Gallagher, J. Chem.
Soc., Perkin Trans. 1, 1991, 1615; (c) C. Morley, D. W. Knight
and A. C. Share, J. Chem. Soc., Perkin Trans. 1, 1994, 2903;
(d) D. W. Knight, A. C. Share and P. T. Gallagher, J. Chem.
Soc., Perkin Trans. 1, 1997, 2089; (e) J. P. Tellam and
D. R. Carbery, Tetrahedron Lett., 2011, 52, 6027;
(f) N. W. G. Fairhurst, M. F. Mahon, R. H. Munday and
D. R. Carbery, Org. Lett., 2012, 14, 756; (g) W. R. R. Harker,
E. L. Carswell and D. R. Carbery, Org. Biomol. Chem., 2012,
10, 1406; (h) P. Barbie, L. Huo, R. Müller and U. Kazmaier,
Org. Lett., 2012, 14, 6064; (i) D. Becker and U. Kazmaier,
J. Org. Chem., 2013, 78, 59.
A solution of 97 (28 mg, 0.12 mmol, >99 : 1 dr) in 6.0 M aq.
HCl (4 mL) was heated at reflux for 16 h. The reaction mixture
was then allowed to cool to rt and concentrated in vacuo. The
residue was dissolved in H2O (2 mL) and purified on DOWEX
50WX8 ion exchange resin (hydrogen form, 100–200 mesh,
eluent 1.0 M aq. NH4OH) to give 102 as a white solid (26 mg,
quant, >99 : 1 dr); mp 213–215 °C; [α]2D0 +4.7 (c 1.0 in H2O);
νmax (ATR) 3363 (N–H), 3045 (C–H), 1571 (CvO), 1402; δH
(400 MHz, D2O) 1.35–1.45 (1H, m, C(4)HA), 1.45–1.54 (1H, m,
C(3)HA), 1.58–1.66 (1H, m, C(4)HB), 2.15–2.24 (2H, m, C(3)HB,
C(1′)HA), 2.52–2.61 (1H, m, C(5)H), 2.72 (1H, dd, J 13.2, 4.0,
C(1′)HB), 2.77 (1H, app t, J 7.9, C(1)H), 3.83 (1H, app q, J 7.9,
C(2)H), 7.15–7.21 (3H, m, Ph), 7.24–7.28 (2H, m, Ph); δC
(176 MHz, D2O) 27.8 (C(4)), 28.6 (C(3)), 36.2 (C(1′)), 42.5 (C(5)),
53.8 (C(2)), 55.8 (C(1)), 126.2, 128.6, 129.1 (o,m,p-Ph), 141.1
4 For reviews, see: ref. 2a and b.
5 (a) S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry,
1991, 2, 183; (b) S. G. Davies, N. M. Garrido, D. Kruchinin,
O. Ichihara, L. J. Kotchie, P. D. Price, A. J. Price Mortimer,
A. J. Russell and A. D. Smith, Tetrahedron: Asymmetry, 2006,
17, 1793; (c) S. G. Davies, R. L. Nicholson, P. D. Price,
P. M. Roberts, A. J. Russell, E. D. Savory, A. D. Smith and
J. E. Thomson, Tetrahedron: Asymmetry, 2009, 20, 758;
(d) S. G. Davies, A. C. Garner, R. L. Nicholson, J. Osborne,
P. M. Roberts, E. D. Savory, A. D. Smith and J. E. Thomson,
Org. Biomol. Chem., 2009, 7, 2604; (e) S. G. Davies,
N. Mujtaba, P. M. Roberts, A. D. Smith and J. E. Thomson,
Org. Lett., 2009, 11, 1959; (f) S. A. Bentley, S. G. Davies,
J. A. Lee, P. M. Roberts, A. J. Russell, J. E. Thomson and
S. M. Toms, Tetrahedron, 2010, 66, 4604; (g) E. A. Brock,
(i-Ph), 179.0 (CO2H); m/z (ESI+) 220 ([M + H]+, 100%); HRMS
+
(ESI+) C13H18NO2 ([M
+
H]+) requires 220.1332; found
220.1337.
(1S,2S,5R)-2-Amino-5-isopropylcyclopentane-1-carboxylic acid
103
A solution of 98 (20 mg, 0.11 mmol, >99 : 1 dr) in 6.0 M aq.
HCl (2.8 mL) was heated at reflux for 16 h. The reaction
mixture was then allowed to cool to rt and concentrated
in vacuo. The residue was dissolved in H2O (2 mL) and purified
on DOWEX 50WX8 ion exchange resin (hydrogen form,
100–200 mesh, eluent 1.0 M aq. NH4OH) to give 103 as a white
solid (17 mg, 94%, >99 : 1 dr); mp 200–204 °C (dec.); [α]2D0 +6.0
2726 | Org. Biomol. Chem., 2014, 12, 2702–2728
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Paper
S. G. Davies, J. A. Lee, P. M. Roberts and J. E. Thomson,
Org. Lett., 2011, 13, 1594; (h) S. K. Bagal, S. G. Davies,
A. M. Fletcher, J. A. Lee, P. M. Roberts, P. M. Scott and
J. E. Thomson, Tetrahedron Lett., 2011, 52, 2216;
(i) S. G. Davies, R. Huckvale, J. A. Lee, T. J. A. Lorkin,
P. M. Roberts and J. E. Thomson, Tetrahedron, 2012, 68,
3263.
6 For selected examples from this laboratory, see:
(a) S. G. Davies, K. Iwamoto, C. A. P. Smethurst, A. D. Smith
and H. Rodríguez-Solla, Synlett, 2002, 1146; (b) S. G. Davies,
R. J. Kelly and A. J. Price Mortimer, Chem. Commun., 2003,
2132; (c) S. G. Davies, A. J. Burke, A. C. Garner,
T. D. McCarthy, P. M. Roberts, A. D. Smith, H. Rodríguez-
Solla and R. J. Vickers, Org. Biomol. Chem., 2004, 2, 1387;
(d) S. G. Davies, J. R. Haggitt, O. Ichihara, R. J. Kelly,
M. A. Leech, A. J. Price Mortimer, P. M. Roberts and
A. D. Smith, Org. Biomol. Chem., 2004, 2, 2630;
(e) E. Abraham, J. I. Candela-Lena, S. G. Davies,
8 For selected examples from this laboratory, see:
(a) S. G. Davies, A. C. Garner, M. J. C. Long,
R. M. Morrison, P. M. Roberts, A. D. Smith, M. J. Sweet and
J. M. Withey, Org. Biomol. Chem., 2005, 3, 2762; (b) Y. Aye,
S. G. Davies, A. C. Garner, P. M. Roberts, A. D. Smith and
J. E. Thomson, Org. Biomol. Chem., 2008, 6, 2195;
(c) E. Abraham, S. G. Davies, A. J. Docherty, K. B. Ling,
P. M. Roberts, A. J. Russell, J. E. Thomson and S. M. Toms,
Tetrahedron: Asymmetry, 2008, 19, 1356; (d) S. G. Davies,
M. J. Durbin, S. J. S. Hartman, A. Matsuno, P. M. Roberts,
A. J. Russell, A. D. Smith, J. E. Thomson and S. M. Toms,
Tetrahedron: Asymmetry, 2008, 19, 2870; (e) S. G. Davies,
J. A. Lee, P. M. Roberts, J. E. Thomson and J. Yin, Org. Lett.,
2012, 14, 218.
9 (a) S. G. Davies, A. D. Smith and P. D. Price, Tetrahedron:
Asymmetry, 2005, 16, 2833; (b) S. G. Davies, A. M. Fletcher,
P. M. Roberts and J. E. Thomson, Tetrahedron: Asymmetry,
2012, 23, 1111.
M. Georgiou, R. L. Nicholson, P. M. Roberts, A. J. Russell, 10 S. G. Davies, A. M. Fletcher, P. M. Roberts, J. E. Thomson
E. M. Sánchez-Fernández, A. D. Smith and J. E. Thomson, and C. M. Zammit, Chem. Commun., 2013, 49, 7037.
Tetrahedron: Asymmetry, 2007, 18, 2510; (f) E. Abraham, 11 S. G. Davies, J. A. Lee, P. M. Roberts, J. E. Thomson and
S. G. Davies, N. L. Millican, R. L. Nicholson, P. M. Roberts J. Yin, Tetrahedron, 2011, 67, 6382.
and A. D. Smith, Org. Biomol. Chem., 2008, 6, 1655; 12 (a) S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin
(g) E. Abraham, E. A. Brock, J. I. Candela-Lena,
S. G. Davies, M. Georgiou, R. L. Nicholson, J. H. Perkins,
P. M. Roberts, A. J. Russell, E. M. Sánchez-Fernández,
P. M. Scott, A. D. Smith and J. E. Thomson, Org. Biomol.
Chem., 2008, 6, 1665; (h) S. G. Davies, A. M. Fletcher,
P. M. Roberts and A. D. Smith, Tetrahedron, 2009, 65,
Trans. 1, 1994, 1129; (b) S. G. Davies, A. M. Fletcher,
G. J. Hermann, G. Poce, P. M. Roberts, A. D. Smith,
M. J. Sweet and J. E. Thomson, Tetrahedron: Asymmetry,
2010, 21, 6135; (c) S. G. Davies, E. M. Foster,
C. R. McIntosh, P. M. Roberts, T. E. Rosser, A. D. Smith
and J. E. Thomson, Tetrahedron: Asymmetry, 2011, 22, 1035.
10192; (i) S. A. Bentley, S. G. Davies, J. A. Lee, P. M. Roberts 13 Authentic samples of 16 and 17 were also prepared via an
and J. E. Thomson, Org. Lett., 2011, 13, 2544;
( j) S. G. Davies, O. Ichihara, P. M. Roberts and
J. E. Thomson, Tetrahedron, 2011, 67, 216; (k) S. G. Davies,
A. M. Fletcher, D. G. Hughes, J. A. Lee, P. D. Price,
P. M. Roberts, A. J. Russell, A. D. Smith, J. E. Thomson and
O. M. H. Williams, Tetrahedron, 2011, 67, 9975;
(l) S. G. Davies, J. A. Lee, P. M. Roberts, J. E. Thomson and
C. J. West, Tetrahedron Lett., 2011, 52, 6477;
(m) S. G. Davies, J. A. Lee, P. M. Roberts, J. P. Stonehouse
alkylation strategy: transesterification of 8 upon treatment
with SOCl2 in MeOH, followed by alkylation of the resultant
methyl ester, upon sequential treatment with LiHMDS and
allyl bromide, gave 16 in 54 : 46 dr, from which the major
anti-diastereoisomer was isolated in 15% yield and 98 : 2
dr. Similarly, transesterification of 9, followed by alkylation
with allyl bromide gave 17 in 81 : 19 dr, from which the
major anti-diastereoisomer was isolated in 11% yield and
99 : 1 dr.
and J. E. Thomson, Tetrahedron Lett., 2012, 53, 1119; 14 Crystallographic data (excluding structure factors) for com-
(n) S. G. Davies, A. M. Fletcher, L. Lv, P. M. Roberts and
J. E. Thomson, Tetrahedron Lett., 2012, 53, 3052;
(o) S. G. Davies, A. M. Fletcher, J. A. Lee, P. M. Roberts,
A. J. Russell, R. J. Taylor, A. D. Thomson and
pounds 16, 18–20, 25, 29, 37, 86·HBF4, 87 and 96·HCl have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication numbers CCDC
982697–982706, respectively.
J. E. Thomson, Org. Lett., 2012, 14, 1672; (p) S. G. Davies, 15 An authentic sample of 18 was also prepared directly from
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7 For selected examples from this laboratory, see:
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the presence of acetone which gave 18 in 68% yield and
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P. M. Scott and A. D. Smith, Org. Biomol. Chem., 2009, 7, 19 The stereochemical outcome of this reaction is in accord-
761.
ance with our transition state mnemonic; see: J. F. Costello,
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 2702–2728 | 2727

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Organic & Biomolecular Chemistry
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22 The configurations of the products 35 and 36 were not
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23 This phenomenon has been noted previously; for example,
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30 Presumably, the formation of the minor diastereoisomers
75–79 is due to the rearrangement proceeding via an
alternative higher energy chair-like transition state in
which 1,3-allylic strain between the C(3)-substituents and
the C(1)–O bond is minimised and the reaction occurs on
the same face as the bulky N-benzyl-N-(α-methylbenzyl)-
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24 Boat-like transition states have previously been proposed to
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37 (Z)-Pent-2-en-1-ol was prepared in 75% yield upon
reduction of the corresponding alkynol with H2 (1 atm),
Ni(OAc)2, NaBH4 and (CH2NH2)2 in MeOH at rt for 8 h, fol-
26 For reviews, see: (a) F. Fülop, Chem. Rev., 2001, 101, 2181;
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27 (a) S. G. Davies, D. Díez, M. M. El Hammouni, A. C. Garner,
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M. J. Sweet and J. M. Withey, Chem. Commun., 2003, 2410;
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28 E. Abraham, T. D. W. Claridge, S. G. Davies, B. Odell,
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2728 | Org. Biomol. Chem., 2014, 12, 2702–2728
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