Asymmetric syntheses of the homalium alkaloids (-)-(S, S)-homaline and (-)-(R, R)-hopromine

Article abstract of DOI:10.1021/jo3012732

The highly diastereoselective conjugate additions of the novel lithium amide reagents lithium (R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amide and lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to α,β-unsaturated esters were used as the key steps in syntheses of the homalium alkaloids (-)-(S,S)-homaline and (-)-(R,R)-hopromine. The asymmetric synthesis of (-)-(S,S)-homaline was achieved in 8 steps and 18% overall yield, and the asymmetric synthesis of (-)-(R,R)-hopromine was achieved in 9 steps and 23% overall yield, from commercially available starting materials in each case. These syntheses therefore represent by far the most efficient total asymmetric syntheses of these alkaloids reported to date. A sample of the (4′R,4′′S)-epimer of hopromine was also produced using this approach, which provided the first unambiguous confirmation of its absolute configuration and therefore that of natural (-)-(R,R)-hopromine.

Full text of DOI:10.1021/jo3012732

Article
pubs.acs.org/joc
Asymmetric Syntheses of the Homalium Alkaloids (−)‑(S,S)‑Homaline
and (−)‑(R,R)‑Hopromine
Stephen G. Davies,†,* James A. Lee,† Paul M. Roberts,† Jeffrey P. Stonehouse,‡ and James E. Thomson†
†Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
‡Novartis Institutes for Biomedical Research, Horsham, West Sussex RH12 5AB, U.K.
S
* Supporting Information
ABSTRACT: The highly diastereoselective conjugate additions of the novel lithium amide
reagents lithium (R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amide and lithium (R)-N-(3-
chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to α,β-unsaturated esters were used as
the key steps in syntheses of the homalium alkaloids (−)-(S,S)-homaline and (−)-(R,R)-
hopromine. The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps and
18% overall yield, and the asymmetric synthesis of (−)-(R,R)-hopromine was achieved in 9
steps and 23% overall yield, from commercially available starting materials in each case.
These syntheses therefore represent by far the most efficient total asymmetric syntheses of
these alkaloids reported to date. A sample of the (4′R,4′′S)-epimer of hopromine was also
produced using this approach, which provided the first unambiguous confirmation of its
absolute configuration and therefore that of natural (−)-(R,R)-hopromine.
have unique bis-eight-membered azalactam structures, and it
has been postulated that they are biogenetically based on a
combination of two α,β-unsaturated carboxylic acid residues
combined with a spermine structural backbone.7
INTRODUCTION
■
The family of homalium alkaloids, comprising (−)-(S,S)-
homaline 1, (−)-(R,R)-hopromine 2, (−)-hoprominol 3, and
(−)-hopromalinol 4, were first isolated in the early 1970s from
the leaves of an African Homalium species and Homalium
pronyense Guillaum (a member of the Flacourtiacae family)
found in the forests of New Caledonia (Figure 1).1−6 They
(−)-(S,S)-Homaline 1 is the only member of this family of
alkaloids whose structure and relative configuration has since
been unambiguously confirmed by single crystal X-ray
diffraction analysis,8 and because of the inherent symmetry
within this compound it has received significantly more interest
from synthetic chemists than the other homalium alkaloids. For
example, in 1982 Wasserman and Berger reported the
transamidation of enantiopure β-lactam precursors for their
synthesis of the eight-membered azalactam units within
(−)-(S,S)-homaline 1.9,10 In this synthesis methyl (RS)-3-
amino-3-phenylpropanoate was resolved by recrystallization of
its L-tartrate salt11 and after a further 14 steps enantiopure
(−)-(S,S)-homaline 1 was isolated in 0.07% overall yield. In
1983 Crombie et al. first reported their enantiospecific
synthesis of (−)-(S,S)-homaline 1, which proceeded via an
Arndt−Eistert homologation of (R)-phenylglycine.12 Ten years
later they reported their full investigations within this area,
which revealed that (−)-(S,S)-homaline 1 was produced in 10
steps and 1.4% overall yield from (R)-phenylglycine.13 An
enantiospecific synthesis of the unsymmetrical dialkylsubsti-
tuted analogue (−)-(R,R)-hopromine 2 was reported by Ensch
and Hesse in 2002.7,14 In this synthesis N-tosyl protected β-
amino esters 5 and 6 (which were both prepared from
L-aspartic acid via seven-step procedures) were treated with
Sb(OEt)3 to give azalactams 7 and 8 in good yield. Subsequent
Received: June 19, 2012
Published: July 24, 2012
Figure 1. Homalium alkaloids 1−4.
© 2012 American Chemical Society
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alkylation of C(4)-pentyl substituted azalactam 7 with 1,4-
dibromobutane gave 9 in 82% yield, and then treatment of
bromide 9 with C(4)-heptyl substituted azalactam 8 gave 10 in
71% yield. Further elaboration of 10 gave (−)-(R,R)-
hopromine 2, which was isolated in 7% overall yield (from L-
aspartic acid) for this 12-step procedure (Scheme 1).
amide 12] to α,β-unsaturated esters 13, followed by functional
group interconversion of the resultant β-amino esters and
cyclization (in a manner analogous to that used by Ensch and
Hesse)7 could be used to produce all the azalactam units 14
within the homalium alkaloids 1−4 (Figure 2). We report
herein our full investigations concerning the syntheses of
(−)-(S,S)-homaline 1 and (−)-(R,R)-hopromine 2; part of this
work has been communicated previously.23
a
Scheme 1
Figure 2. Conjugate addition of 3-chloropropyl substituted lithium
amides 12 to α,β-unsaturated esters 13 in the asymmetric synthesis of
the homalium alkaloid skeleton 15.
RESULTS AND DISCUSSION
■
a
Reagents and conditions: (i) Sb(OEt)3, dry benzene, 4 Å sieves,
Asymmetric Synthesis of (−)-(S,S)-Homaline 1. Follow-
ing Ensch and Hesse’s Sb(OEt)3 mediated cyclization strategy
for the formation of the desired azalactam units, we set out to
establish the structural requirements of this reaction manifold
by attempting the cyclization of substrates 20−22 that
incorporate either a primary or secondary amino substituent
and either a methyl or tert-butyl ester. These substrates were
prepared via the conjugate addition of lithium (R)-N-(3-
chloropropyl)-N-(α-methylbenzyl)amide (R)-1724 to tert-butyl
cinnamate 16,25 which gave β-amino ester 18 in 84% yield as a
single diastereoisomer (>99:1 dr). The stereochemical outcome
of this transformation was assigned by reference to the well
established transition state mnemonic developed by us to
rationalize the diastereoselectivity observed upon conjugate
addition of lithium amides derived from α-methylbenzyl-
amine.26 Subsequent elaboration of 18 via displacement of
the primary chloride functionality with NaN3 under Finkelstein
conditions (i.e., in the presence of NaI) gave 19 in 79% yield,
and then Staudinger reduction of the azide moiety within 19
gave primary amine 20 in 88% yield. Similarly, displacement of
the chloride functionality within 18 with allylamine (also in the
presence of NaI) gave 21 in 86% yield, and transesterification
of 21 upon treatment with SOCl2 in MeOH produced the
corresponding methyl ester 22 in 72% yield. Unfortunately,
attempted formation of the azalactam scaffolds derived from
either 20, 21, or 22 via Sb(OEt)3 mediated cyclization7,14 was
in each case unsuccessful, confirming that an unhindered ester
and a primary amino group are both required to achieve this
transformation (Scheme 2).
reflux, 16 h; (ii) Br(CH2)4Br (2.2 equiv), KOH, DMSO, rt, overnight;
(iii) 8, KOH, DMSO, 0 °C to rt, overnight; (iv) electrolysis, Me4NCl,
aq EtOH, 5 °C; (v) 37% aq CH2O, AcOH, 0 °C, 15 min, then
NaBH3CN, MeOH, 0 °C to rt, 4 h.
Comparison of the specific rotation of this synthetic sample
with that of the sample of (−)-hopromine 2 isolated from the
natural source established the absolute (R,R)-configuration
within this alkaloid.7 However, it is noteworthy that only one of
the two possible diastereoisomers was synthesized in this study,
and the possibility that the epimer could also display a specific
rotation of comparable magnitude should not be discounted;
these data do not therefore provide unambiguous proof of the
absolute configuration within (−)-hopromine 2. The assigned
absolute configuration within (−)-(S,S)-homaline 1 is, however,
secure as the epimer is a meso structure. Several other methods
for the synthesis of the homalium alkaloids 1−4 have also been
investigated, although inseparable mixtures of stereoisomers
were formed in each case.15−17 As such, the relative and
absolute configurations within (−)-hoprominol 3 and
(−)-hopromalinol 4 are unknown.
Previous investigations from our laboratory have demon-
strated that the conjugate addition of numerous enantiopure
secondary lithium amides (derived from α-methylbenzylamine)
to α,β-unsaturated esters represents a general and efficient
protocol for the synthesis of β-amino esters and their
derivatives.18 This methodology has found many applications,
including the total syntheses of natural products,19 molecular
recognition phenomena,20 and resolution protocols,21 and has
been reviewed.22 As part of our ongoing research program in
this area we became interested in the application of this
methodology for the preparation of the homalium alkaloids 1−
4 and envisaged that the conjugate addition of functionalized
lithium amides [such as N-(3-chloropropyl) substituted lithium
The corresponding substrate containing both a primary
amino substituent and a methyl ester moiety was therefore
prepared via conjugate addition of lithium (R)-N-(3-chlor-
opropyl)-N-(α-methylbenzyl)amide (R)-1724 to methyl cinna-
mate 23, which gave β-amino ester 24 in quantitative yield as a
single diastereoisomer (>99:1 dr); the stereochemical outcome
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a
a
Scheme 2
Scheme 3
a
Reagents and conditions: (i) (R)-17, THF, −78 °C, 2 h; (ii) NaN3,
NaI, DMSO, 50 °C, 48 h; (iii) PPh3, THF/H2O (v/v 7:3), 50 °C, 2 h;
(iv) allylamine, NaI, 65 °C, 24 h; (v) SOCl2, MeOH, reflux, 4 h.
of this transformation was initially assigned by reference to our
well established transition state mnemonic26 and was later
confirmed by chemical correlation. Displacement of the
primary chloride functionality within 24 with NaN3 gave 25
in 78% yield, and then Staudinger reduction of 25 followed by
Sb(OEt)3 mediated cyclization7,14 of 26 gave azalactam 27 in
77% overall yield for the two-step procedure. Upon scale-up,
without purification of any intermediates, the overall yield of
azalactam 27 was improved further, giving 27 in 69% overall
yield from methyl cinnamate 23. Alkylation of the N(1) atom
within 27 with a range of electrophiles under different
conditions proved to be somewhat problematic, consistent
with the reported difficulties encountered upon attempted
alkylation of similar substrates.7,12−17 After extensive optimiza-
tion it was found that reacting 27 with allyl bromide in the
presence of K2CO3, NaOH, and triethylbenzylammonium
chloride (TEBAC) in THF at 75 °C gave 28 in 96% yield.
Homodimerization of 28 upon treatment with Grubbs II
catalyst then gave 29 in 82% isolated yield. The configuration of
the newly formed CC double bond within 29 was established
by the preparation of an authentic sample of (E)-29 in 66%
yield via the alkylation of azalactam 27 with trans-1,4-
dibromobut-2-ene in the presence of K2CO3, KOH, and
TEBAC. Attempted tandem hydrogenation/hydrogenolysis of
29 under our standard conditions for removal of N-α-
methylbenzyl groups [i.e., H2 (5 atm), Pd(OH)2/C, MeOH,
rt, 1 h]22 did not result in N-debenzylation and gave only 30,
which was isolated in quantitative yield. It was found that
alkylation of 27 with 1,4-dibromobutane in the presence of
K2CO3, KOH, and tetrabutylammonium chloride (TBAC) in
PhMe at 160 °C in a microwave reactor gave 30 directly in 83%
isolated yield. Exhaustive attempts at removal of the N-α-
methylbenzyl groups within 30 gave inseparable mixtures of
products, and procedures for N-debenzylation and in situ N-
methylation of either 29 or 30 also gave inseparable mixtures of
compounds, including (−)-(S,S)-homaline 1 as well as other
products arising from incomplete N-debenzylation (Scheme 3).
An alternative protecting group strategy was therefore
investigated that employed the acid-labile N-α-methyl-p-
methoxybenzyl group, negating the requirement for a hydro-
genolysis step. Accordingly, conjugate addition of lithium (R)-
N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide (R)-
3127 to methyl cinnamate 23 proceeded to full conversion to
give β-amino ester 32 as a single diastereoisomer (>99:1 dr);
a
Reagents and conditions: (i) (R)-17, THF, −78 °C, 2 h; (ii) NaN3,
NaI, DMSO, 50 °C, 24 h; (iii) PPh3, THF/H2O (v/v 7:3), 50 °C, 2 h;
(iv) Sb(OEt)3, PhMe, reflux, 18 h; (v) allyl bromide, K2CO3, NaOH,
TEBAC, THF, 75 °C, 18 h; (vi) Grubbs II, CH2Cl2, 40 °C, 18 h; (vii)
trans-1,4-dibromobut-2-ene, K2CO3, KOH, TEBAC, DMSO, rt, 72 h;
(viii) H2 (5 atm), Pd(OH)2/C, MeOH, rt, 1 h; (ix) 1,4-
dibromobutane, K2CO3, KOH, TBAC, PhMe, 160 °C, microwave,
15 min; (x) H2 (5 atm), Pd(OH)2/C, MeOH/formalin/AcOH (v/v/v
1:2:3), rt, 48 h.
b
Crude and isolated.
again, the stereochemical outcome of this transformation was
initially assigned by reference to our well established transition
state mnemonic,26 and this assignment was latter confirmed by
chemical correlation. Displacement of the primary chloride
functionality within 32 with NaN3 followed by Staudinger
reduction of 33 and Sb(OEt)3 mediated cyclization7,14 of 34
gave azalactam 35 in 53% overall yield from methyl cinnamate
23. Subsequent alkylation of 35 with 1,4-dibromobutane in the
presence of K2CO3, KOH, and TBAC at 160 °C in a microwave
reactor gave 36 in 67% yield, and then N-debenzylation was
achieved upon treatment of 36 with TFA, giving 37 in 30%
yield. Finally, treatment of 37 with NaBH3CN in the presence
of formalin (37% formaldehyde in water with 12% MeOH
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stabilizer) effected reductive N-methylation of both secondary
amino groups within 37 to give a sample of (−)-(S,S)-homaline
1 in >99:1 dr. Attempted purification of the crude reaction
mixture gave (−)-(S,S)-homaline 1 in approximately 30% yield,
although it could not be separated from trace quantities of
unidentified impurites.28 However, reaction of 36 under
Eschweiler−Clarke conditions (i.e., heating 36 in a mixture of
formic acid and formalin at reflux) effected both N-
debenzylation and N-methylation to give (−)-(S,S)-homaline
1 directly in 39% isolated yield and >99:1 dr (Scheme 4). The
synthesis. Attempted deprotection of either N-α-methylbenzyl
protected azalactam 27 or N-α-methyl-p-methoxybenzyl
protected azalactam 35 gave either returned starting material,
poor mass return, or a complex mixture of unidentifiable
products. Procedures involving attempted in situ N-methylation
were also attempted in the hope that methylation of the N(5)
atom would aid with isolation of the desired product; in the
case of N-α-methyl-p-methoxybenzyl protected azalactam 35
this again gave a complex mixture of products. Hydrogenolysis
of N-α-methylbenzyl protected azalactam 27 in the presence of
formalin, however, gave a complex mixture of products from
which only 39 and 40 were isolated in 13% and 28% yield,
respectively (Scheme 5). Comparison of the specific rotation
a
Scheme 4
a
Scheme 5
a
Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, AcOH, rt, 18
h; (ii) H2 (5 atm), Pd(OH)2/C, MeOH, rt, 24 h; (iii) TFA, 60 °C, 2.5
h; (iv) H2 (5 atm), Pd(OH)2/C, MeOH/formalin/AcOH (v/v/v
1:2:3), rt, 72 h; (v) formalin, HCO2H, reflux, 2.5 h. PMP = p-
methoxyphenyl.
value for this sample of 39 with that of the previously
reported17 sample confirmed the absolute configuration within
(S)-39, as well as the absolute configurations within 24−30.
The identities of both 39 and 40 were also unambiguously
confirmed via single crystal X-ray diffraction analyses,29 and the
determination of a Flack x parameter30 of 0.19(19) for the
crystal structure of 39 allowed the absolute (S)-configuration
within 39 to be confirmed.
It was therefore decided that N-debenzylation of β-amino
esters 24 and 32 (i.e., the products arising from conjugate
addition of lithium amides (R)-17 and (R)-31 to methyl
cinnamate 23) and N-methylation of the resultant secondary β-
amino ester 41 would be investigated. Thus, hydrogenolytic
removal of the N-α-methylbenzyl group from within β-amino
ester 24 (in the presence of HCl)31 gave 41 in 70% yield, and
N-debenzylation of N-α-methyl-p-methoxybenzyl protected β-
amino ester 32 upon treatment with TFA gave 41 in 92% yield.
Subsequent reductive N-methylation of 41 upon treatment with
(CH2O)n and NaBH3CN gave 42 in 75% isolated yield.
Displacement of the primary chloride functionality within 42
with NaN3 gave 43, and Staudinger reduction of 43 followed by
Sb(OEt)3 mediated cyclization7,14 of 44 gave azalactam 39 in
62% yield over the three-step procedure (Scheme 6).
a
Reagents and conditions: (i) (R)-31, THF, −78 °C, 2 h; (ii) NaN3,
NaI, DMSO, 50 °C, 24 h; (iii) PPh3, THF/H2O (v/v 7:3), 50 °C, 2 h;
(iv) Sb(OEt)3, PhMe, reflux, 18 h; (v) 1,4-dibromobutane, K2CO3,
KOH, TBAI, PhMe, 160 °C, microwave, 15 min; (vi) TFA, 60 °C, 2.5
h; (vii) NaBH3CN, formalin, AcOH, MeOH, 0 °C to rt, 3.5 h; (viii)
HCO2H/formalin (v/v 5:6), reflux, 2.5 h. Not isolated. [PMP = p-
methoxyphenyl].
b
overall yield of this synthesis was therefore 10% in 7 steps from
commercially available starting materials. The specific rotation
of this sample of (−)-(S,S)-homaline 1 {[α]2D4 −29.2 (c 1.0 in
CHCl3)} was in excellent agreement with that of the sample
isolated from the natural source {lit.6 [α]D20 −34 (c 1.0 in
CHCl3)}.
In an effort to improve the overall yield of (−)-(S,S)-
homaline 1, a further strategy was investigated in which the
chiral N-protecting group was removed at an earlier stage in the
Two strategies for the homodimerization of azalactam 39
were then explored. In the first of these strategies, N-allylation
of 39 upon treatment with allyl bromide, K2CO3, NaOH, and
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a
a
Scheme 6
Scheme 7
a
Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, HCl (1.0 M,
aq), rt, 18 h; (ii) TFA, 60 °C, 2.5 h; (iii) (CH2O)n, NaBH3CN,
MeOH, rt, 18 h; (iv) NaN3, NaI, DMSO, 50 °C, 24 h; (v) PPh3,
THF/H2O (v/v 7:3), 50 °C, 2 h; (vi) Sb(OEt)3, PhMe, reflux, 18 h.
[PMP = p-methoxyphenyl].
a
Reagents and conditions: (i) allyl bromide, K2CO3, NaOH, TEBAC,
THF, 75 °C, 18 h; (ii) Grubbs II, CH2Cl2, 40 °C, 40 h; (iii) trans-1,4-
dibromobut-2-ene, K2CO3, KOH, TEBAC, DMSO, rt, 96 h; (iv) H2 (1
atm), Pd(OH)2/C, EtOAc, rt, 2 h; (v) 1,4-dibromobutane, KOH,
DMSO, rt, 96 h.
TEBAC gave 45 in 94% yield. Homodimerization of 45 using
Grubbs II catalyst gave a complex mixture of olefinic products
from which 46 and 47 were isolated in 42% and 11% yield,
respectively, after purification by flash column chromatography.
The configuration of the newly formed CC double bond
within 46 was established by the preparation of an authentic
sample of (E)-46 via the alkylation of azalactam 39 with trans-
1,4-dibromobut-2-ene.32 Unfortunately, resubjection of 47 to
the reaction conditions did not produce 46, and all attempts to
suppress the formation of 47 failed. Hydrogenation of 46 gave a
pure sample of (−)-(S,S)-homaline 1 {[α]2D4 −32.5 (c 1.0 in
CHCl3)} in 44% yield, concluding the synthesis in 10 steps and
5.3% overall yield from commercially available starting
materials. In the second strategy for the conversion of
azalactam 39 into (−)-(S,S)-homaline 1, direct alkylation of
39 with 1,4-dibromobutane and KOH in DMSO was found to
give (−)-(S,S)-homaline 1 {[α]2D1 −28.1 (c 1.0 in CHCl3)} as a
single diastereoisomer in 60% yield (Scheme 7). The overall
yield for this synthesis of (−)-(S,S)-homaline 1 (in 8 steps from
commercially available starting materials) was 18%, represent-
ing by far the most efficient synthesis of this natural product
reported to date (vide supra). The spectroscopic data obtained
for these samples of (−)-(S,S)-homaline 1 were again in
excellent agreement with those for the sample isolated from the
natural source,6 and other samples obtained by total syn-
thesis.33
Asymmetric Synthesis of (−)-(R,R)-Hopromine 2. We
envisaged that this methodology would also be readily
applicable to the asymmetric synthesis of the C(4)-alkyl
substituted azalactam units within (−)-(R,R)-hopromine 2,
and then a stepwise alkylation strategy could be used to couple
the differentially substituted azalactam scaffolds. Substrates 58
and 59 were therefore prepared in a similar manner as the
C(4)-phenyl substituted azalactam 27. α,β-Unsaturated esters
48 and 49 were prepared in >99:1 dr by our MeMgBr mediated
Wadswoth−Emmons olefination of the corresponding alde-
hydes.25,34 Conjugate addition of lithium (R)-N-(3-chloroprop-
yl)-N-(α-methylbenzyl)amide (R)-1724 to either 48 or 49 gave
the corresponding β-amino esters 50 and 51 as single
diastereoisomers (>99:1 dr) in 81% and 73% isolated yield,
respectively.35 Transesterification of 50 and 51 upon treatment
with SOCl2 in MeOH gave methyl esters 52 and 53 in 80% and
61% yield, and subsequent treatment of 52 and 53 with NaN3
(again under Finkelstein conditions) gave 54 and 55 in 94%
and 87% yield, respectively. Staudinger reduction of azides 54
and 55 followed by Sb(OEt)3 mediated cyclization7,14 of 56
and 57 gave the corresponding azalactams 58 and 59 in 98%
and 52% yield over the two-step procedures. Upon scale-up of
this process, it was found that the overall yields of azalactams
58 and 59 could be significantly improved if the intermediate
compounds 48−57 were used without purification; this gave 58
and 59 in 72% and 40% overall yield from the corresponding
aldehydes (Scheme 8). The relative configuration within 58 was
unambiguously established via single crystal X-ray diffraction
analysis of the corresponding hydrochloride salt 58·HCl,36 with
the absolute (R,R)-configuration within 58 being assigned from
the known configuration of the (R)-α-methylbenzyl fragment.
Furthermore, the determination of a Flack x parameter30 of
0.03(4) for the crystal structure of 58·HCl allowed the absolute
(R,R)-configuration within 58 to be confirmed, and the
absolute (R,R)-configuration within 59 was therefore assigned
by analogy.
The compatibility of these substrates with N-α-methylbenzyl
deprotection and N-methylation procedures was established
next: hydrogenolysis of 58 and 59 in the presence of
Pd(OH)2/C gave 60 and 61 in 95% and quantitative yield,
respectively. Subsequent reductive methylation of the N(5)
atoms within both 60 and 61 gave the corresponding N-methyl
substituted azalactams 62 and 63 in 36% and 83% yield. The
overall yield of this process was improved further by conducting
a one-pot hydrogenolysis/N-methylation procedure, which
gave 62 and 63 in quantitative and 98% yield from 58 and
59, respectively (Scheme 9).
As C(4)-alkyl substitution was compatible with the N-α-
methylbenzyl deprotection and N-methylation procedures,
coupling of N(5)-(R)-α-methylbenzyl substituted azalactams
58 and 59 was attempted first. Monoalkylation of C(4)-pentyl
substituted azalactam 58 with 1,4-dibromobutane (3.0 equiv) in
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a
a
Scheme 8
Scheme 10
a
Reagents and conditions: (i) 1,4-dibromobutane (3.0 equiv), K2CO3,
KOH, TEBAC, DMSO, rt, 24 h; (ii) 59, KOH, DMSO, rt, 96 h; (iii)
1,4-dibromobutane (3.0 equiv), KOH, K2CO3, TBAC, DMSO, rt, 24
h; (iv) 58, KOH, K2CO3, TBAC, DMSO, rt, 24 h; (v) H2 (1 atm),
Pd(OH)2/C, (CH2O)n, MeOH, rt, 72 h.
a
Reagents and conditions: (i) (R)-17, THF, −78 °C, 2 h; (ii) SOCl2,
MeOH, reflux, 3 h; (iii) NaN3, NaI, DMSO, 50 °C, 24 h; (iv) PBu3,
THF/H2O (v/v 7:3), 50 °C, 2 h; (v) Sb(OEt)3, PhMe, reflux, 18 h.
bCrude and isolated.
a
Scheme 9
C(4)-pentyl substituted azalactam 62 with 1,4-dibromobutane
was achieved under a range of conditions; however, it was
found that treatment of 62 with 1,4-dibromobutane (3.0 equiv),
KOH, K2CO3, and TEBAC in DMSO at rt for 24 h proved
optimal, giving 67 in 66% isolated yield. Subsequent treatment
of bromide 67 with C(4)-heptyl substituted azalactam 63 gave
(−)-(R,R)-hopromine 2 {[α]2D4 −13.8 (c 1.0 in CHCl3)} in 48%
yield and >99:1 dr. This strategy was found to be superior to
alkylation of the C(4)-heptyl substituted azalactam 63 with 1,4-
dibromobutane, which gave 68 in 35% isolated yield, followed
by treatment of bromide 68 with C(4)-pentyl substituted
azalactam 62, which gave (−)-(R,R)-hopromine 2 {[α]2D4 −11.2
(c 0.3 in CHCl3)} in 7% yield and >99:1 dr (Scheme 11).
Under the former, optimized set of conditions, (−)-(R,R)-
hopromine 2 was produced in 9 steps and 23% overall yield
from commercially available starting materials, representing the
most efficient synthesis of this natural product to date.
In order to unambiguously confirm the assigned absolute
(R,R)-configuration within (−)-hopromine 2 we sought to use
this synthetic strategy to produce an authentic sample of the
epimer 69 so that its specific rotation could also be compared
with the sample of (−)-hopromine 2 isolated from the natural
source. A sample of the C(4)-heptyl substituted azalactam ent-
63 was therefore prepared in six steps and 31% overall yield
from α,β-unsaturated ester 49 under identical conditions to
those used previously. Coupling of this azalactam unit with
bromide 67 then produced a sample of (4′R,4′′S)-69 in 17%
isolated yield (Scheme 12). Comparison of the specific rotation
value for this sample {[α]D24 +2.3 (c 0.8 in CHCl3)} with that of
the sample of (−)-hopromine 2 isolated from the natural
source {lit.6 [α]D20 −10 (c 3.0 in CHCl3) unambiguously
confirmed the assigned absolute (R,R)-configuration within
(−)-hopromine 2.
a
Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 24
h; (ii) NaBH3CN, (CH2O)n, MeOH, rt, 18 h; (iii) H2 (1 atm),
Pd(OH)2/C, (CH2O)n, MeOH, rt, 72 h.
the presence of KOH in DMSO gave 64 in 66% yield, and then
treatment of bromide 64 with C(4)-heptyl substituted
azalactam 59 and KOH in DMSO over an extended reaction
time of 96 h gave 65 in 29% yield. Subsequent tandem
hydrogenolysis/N-methylation of 65 gave (−)-(R,R)-hopro-
mine 2 in 32% yield and >99:1 dr (Scheme 10). The
spectroscopic data obtained for this sample of (−)-(R,R)-
hopromine 2 were in excellent agreement with those for the
sample isolated from the natural source {[α]2D0 −12.1 (c 0.1 in
CHCl3); lit.6 [α]D20 −10 (c 3.0 in CHCl3)}, and also a sample
obtained by total synthesis {lit.7 [α]D20 −14.4 (c 2.1 in CHCl3)}.
(−)-(R,R)-Hopromine 2 was therefore produced in 9 steps and
4% overall yield from commercially available starting materials
via this route. Conversely, alkylation of the C(4)-heptyl
substituted azalactam 59 with 1,4-dibromobutane gave 66 in
31% isolated yield, although repeated attempts at the treatment
of bromide 66 with azalactam 58 failed to give 65 (Scheme 10).
Coupling of the corresponding N(5)-methyl substituted
azalactams 62 and 63 was found to give significantly improved
overall yields of (−)-(R,R)-hopromine 2. Monoalkylation of
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a
were used as the key steps in the total asymmetric syntheses of
(−)-(S,S)-homaline and (−)-(R,R)-hopromine. (−)-(S,S)-
Homaline was produced in 8 steps and 18% overall yield,
and (−)-(R,R)-hopromine was produced in 9 steps and 23%
overall yield, from commercially available starting materials in
each case. These syntheses therefore represent by far the most
efficient total asymmetric syntheses of these alkaloids reported
to date. A sample of the (4′R,4′′S)-epimer of hopromine was
also produced using this approach, which allowed the assigned
absolute configuration within (−)-(R,R)-hopromine to be
unambiguously confirmed.
Scheme 11
EXPERIMENTAL SECTION
■
General Experimental Details. All reactions involving organo-
metallic or other moisture-sensitive reagents were carried out under a
nitrogen atmosphere using standard vacuum line techniques and
glassware that was flame-dried and cooled under vacuum before use.
Solvents were dried according to the procedure outlined by Grubbs
and co-workers.37 BuLi was purchased as a solution in hexanes and
titrated against diphenylacetic acid before use. MeMgBr was purchased
as
a solution in Et2O and titrated against (E)-2-(2′-
phenylhydrazonomethyl)phenol before use.38 1,4-Dibromobutane
was distilled from CaCl2 before use. Formalin was purchased as a
37% aq solution of formaldehyde, stabilized with 12% MeOH. All
other reagents were used as supplied without prior purification.
Organic layers were dried over MgSO4. Thin layer chromatography
was performed on aluminum plates coated with 60 F254 silica. Plates
were visualized using UV light (254 nm), 1% aq KMnO4, or
Dragendorff′s reagent. Flash column chromatography was performed
on Kieselgel 60 silica.
a
Reagents and conditions: (i) 1,4-dibromobutane (3.0 equiv), K2CO3,
KOH, TEBAC, DMSO, rt, 24 h; (ii) 63, KOH, DMSO, rt, 96 h; (iii)
62, KOH, DMSO, rt, 96 h.
a
Scheme 12
Melting points are uncorrected. Specific rotations are reported in
10−1 deg cm2 g−1 and concentrations in g 100 mL−1. IR spectra were
recorded as either a thin film on NaCl plates (film) or using an ATR
module (ATR), as stated. Selected characteristic 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 referencing to the relevant deuteron resonance.
Resonances in the 13C NMR spectra which are broad have their
corresponding chemical shifts italicized in the list of assignments.
1
1
1H−1H COSY, H−13C HMQC, and H−13C HMBC analyses were
used to establish atom connectivity. Accurate mass measurements were
run on a TOF spectrometer internally calibrated with polyalanine.
General Procedure 1: Lithium Amide Conjugate Addition.
BuLi was added to a solution of the requisite amine in THF at −78 °C,
and the resultant mixture was stirred at −78 °C for 15 min. A solution
of the requisite α,β-unsaturated ester in THF at −78 °C was then
added via cannula, and the resultant mixture was stirred at −78 °C for
2 h. Saturated aq NH4Cl was then added, and the reaction mixture was
allowed to warm to rt and then concentrated in vacuo. The residue was
partitioned between CH2Cl2 and 10% aq citric acid, and the aqueous
layer was extracted with two portions of CH2Cl2. The combined
organic extracts were washed with satd aq NaHCO3 and brine, dried,
and concentrated in vacuo.
General Procedure 2: NaN3 Displacement. NaN3 and NaI were
added to a stirred solution of the requisite amine in DMSO, and the
resultant mixture was heated at 50 °C for either 24 or 48 h. The
reaction mixture was then allowed to cool to rt and partitioned
between Et2O and H2O. The aqueous layer was extracted with two
portions of Et2O, and the combined organic extracts were washed
sequentially with two portions of H2O and brine, dried, and
concentrated in vacuo.
a
Reagents and conditions: (i) (S)-17, THF, −78 °C, 2 h; (ii) SOCl2,
MeOH, reflux, 3 h; (iii) NaN3, NaI, DMSO, 50 °C, 24 h; (iv) PBu3,
THF/H2O (v/v 7:3), 50 °C, 2 h; (v) Sb(OEt)3, PhMe, reflux, 18 h;
(vi) H2 (1 atm), Pd(OH)2/C, (CH2O)n, MeOH, rt, 72 h; (vii) ent-63,
K2CO3, KOH, TEBAC, DMSO, rt, 96 h.
General Procedure 3: Staudinger Reduction. PPh3 or PBu3
was added to a solution of the requisite amine in THF, and the
resultant mixture was stirred at rt for 30 min. H2O was then added,
and the reaction mixture was heated at 50 °C for 2 h before being
allowed to cool to rt and concentrated in vacuo.
General Procedure 4: Transesterification. SOCl2 was added to
MeOH at 0 °C, and the resultant mixture was stirred for 1 min and
CONCLUSION
■
The highly diastereoselective conjugate additions of the novel
lithium amide reagents lithium (R)-N-(3-chloropropyl)-N-(α-
methylbenzyl)amide and lithium (R)-N-(3-chloropropyl)-N-
(α-methyl-p-methoxybenzyl)amide to α,β-unsaturated esters
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then allowed to warm to rt. A solution of the requisite tert-butyl ester
in MeOH was then added, and the resultant mixture was heated at
reflux for 4 h. The reaction mixture was then allowed to cool to rt and
concentrated in vacuo. The residue was partitioned between satd aq
NaHCO3 and CH2Cl2, the aqueous layer was extracted with two
portions of CH2Cl2, and then the combined organic extracts were
dried and concentrated in vacuo.
General Procedure 5: Sb(OEt)3 Mediated Macrolactamiza-
tion. A solution of the requisite amine in PhMe was added to a two-
necked round bottomed flask fitted with an open pressure equalizing
dropping funnel part filled with activated 4 Å molecular sieves and a
condenser attached to the top of the dropping funnel. A glass stopper
was placed in the second neck, and the solution was heated at reflux so
that the PhMe vapor condensed above the level of the molecular sieves
for a period of 2 h. The resultant solution was allowed to cool for 5
min, and then Sb(OEt)3 was added. The resultant mixture was heated
at reflux for 18 h and then allowed to cool to rt. Saturated aq NH4Cl
was then added, and the reaction mixture was stirred at rt for 15 min
before being filtered through Celite (eluent EtOAc). The aqueous
layer was extracted with EtOAc, and the combined organic extracts
were dried and concentrated in vacuo.
tert-Butyl (3S,αR)-3-[N-(3′-Chloropropyl)-N-(α-
methylbenzyl)amino]-3-phenylpropanoate 18. Following Gen-
eral Procedure 1, (R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amine
(1.55 g, 7.83 mmol), BuLi (2.5 M, 3.04 mL, 7.59 mmol), and 16 (1.00
mL, 4.90 mmol) were reacted in THF (40 mL) to give 18 in >99:1 dr.
Purification via flash column chromatography (gradient elution, 0% →
8% Et2O in 30−40 °C petrol) gave 18 as a yellow oil (1.65 g, 84%,
>99:1 dr); [α]2D0 −4.2 (c 1.0 in CHCl3); vmax (ATR) 1728 (CO); δH
(400 MHz, CDCl3) 1.22 (3H, s, C(α)Me), 1.35 (9H, s, CMe3), 1.71−
1.84 (2H, m, C(2′)H2), 2.65−2.71 (3H, m, C(2)HA, C(1′)H2), 2.83
(1H, app dd, J 14.7, 6.6, C(2)HB), 3.22−3.32 (2H, m, C(3′)H2), 4.02
(1H, q, J 6.7, C(α)H), 4.44 (1H, dd, J 8.6, 6.6, C(3)H), 7.25−7.43
(10H, m, Ph); δC (100 MHz, CDCl3) 16.7 (C(α)Me), 27.9 (CMe3),
33.1 (C(2′)), 38.5 (C(2)), 43.3 (C(3′)), 43.9 (C(1′)), 57.1 (C(α)),
58.7 (C(3)), 80.3 (CMe3), 126.8, 127.2, 127.7, 128.1, 128.2 (o,m,p-
Ph), 141.4, 144.8 (i-Ph), 171.2 (C(1)); m/z (ESI+) 426 ([M(37Cl) +
Na]+, 24%), 424 ([M(35Cl) + Na]+, 58%), 404 ([M(37Cl) + H]+,
+
55%), 402 ([M(35Cl) + H, 100%); HRMS (ESI+) C24H3337ClNO2
([M(37Cl)
+
H]+) requires 404.2165, found 404.2163;
+
C24H3335ClNO2 ([M(35Cl) + H]+) requires 402.2194, found
402.2182.
General Procedure 6: N-Alkylation of Amide. Method A:
Powdered KOH, K2CO3, and TEBAC were added to a solution of the
requisite amide and alkyl bromide in DMSO, and the resultant mixture
was stirred at rt for either 24, 72, or 96 h (as stated). The reaction
mixture was then partitioned between H2O and CHCl3, and the
aqueous layer was extracted with two portions of CHCl3. The
combined organic extracts were sequentially washed with two portions
of H2O and brine, dried, and concentrated in vacuo.
Method B: Powdered KOH was added to a solution of the requisite
amide and alkyl bromide in DMSO, and the resultant mixture was
stirred at rt for either 24 or 96 h (as stated). The reaction mixture was
then partitioned between H2O and CHCl3, and the aqueous layer was
extracted with two portions of CHCl3. The combined organic extracts
were sequentially washed with two portions of H2O and brine, dried,
and concentrated in vacuo.
General Procedure 7: Hydrogenolysis. Pd(OH)2/C (20% w/
w) was added to a solution of the requisite substrate (in some cases
with (CH2O)n also added, if specified) in degassed solvent (either
MeOH, EtOAc or 1.0 M aq HCl, as stated), and the resultant mixture
was stirred under H2 (1 atm) at rt for either 1, 2, 18, 24, or 72 h (as
stated). The reaction mixture was then degassed, filtered through
Celite (eluent EtOAc then MeOH), and concentrated in vacuo.
General Procedure 8: Reductive N-Methylation. NaBH3CN
was added to a stirred solution of the requisite amine and (CH2O)n in
MeOH, and the resultant mixture was stirred at rt for 18 h before
being concentrated in vacuo. The residue was partitioned between
CH2Cl2 and H2O, the aqueous layer was extracted with two portions
of CH2Cl2, and the combined organic extracts were washed with brine,
dried, and concentrated in vacuo.
(R)-N-(3-Chloropropyl)-N-(α-methylbenzyl)amine. (R)-α-
Methylbenzylamine (32.2 mL, 253 mmol) was added to a solution
of 1-bromo-3-chloropropane (10.0 mL, 101 mmol) in MeCN (80
mL), and the resultant mixture was stirred for 16 h at rt. The reaction
mixture was basified to pH 9 with satd aq NaHCO3 and then extracted
with EtOAc (3 × 100 mL). The combined organic extracts were then
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30−40 °C petrol/Et2O, 3:7) gave (R)-N-
(3-chloropropyl)-N-(α-methylbenzyl)amine as a yellow oil (13.9 g,
70%, >99:1 er); [α]D24 +59.8 (c 1.0 in CHCl3); vmax (film) 3337 (N−
H); δH (400 MHz, CDCl3) 1.37 (3H, d, J 6.7, C(α)Me), 1.91 (2H, app
quintet, J 6.6, C(2)H2), 2.58 (1H, dt, J 11.9, 6.8, C(1)HA), 2.68 (1H,
dt, J 11.9, 6.6, C(1)HB), 3.55−3.66 (2H, m, C(3)H2), 3.78 (1H, q, J
6.7, C(α)H), 7.24−7.28 (1H, m, Ph), 7.31−7.37 (4H, m, Ph); δC (100
MHz, CDCl3) 24.5 (C(α)Me), 33.2 (C(2)), 43.2 (C(3)), 44.8 (C(1)),
58.3 (C(α)), 126.5, 126.9, 128.5 (o,m,p-Ph), 145.6 (i-Ph); m/z (ESI+)
200 ([M(37Cl) + H]+, 19%), 198 ([M(35Cl) + H]+, 47%), 162 ([M −
Cl]+, 100%); HRMS (ESI+) C11H1737ClN+ ([M(37Cl) + H]+) requires
200.1015, found 200.1013; C11H1735ClN+ ([M(35Cl) + H]+) requires
198.1044, found 198.1045.
tert-Butyl (3S,αR)-3-[N-(3′-Azidopropyl)-N-(α-methylbenzyl)-
amino]-3-phenylpropanoate 19. Following General Procedure 2,
NaN3 (129 mg, 1.99 mmol), NaI (298 mg, 1.99 mmol) and 18 (400
mg, 995 μmol, >99:1 dr) in DMSO (2 mL) were reacted for 48 h.
Purification via flash column chromatography (gradient elution, 3% →
9% Et2O in 30−40 °C petrol) gave 19 as a yellow oil (323 mg, 79%,
>99:1 dr); [α]2D4 −0.3 (c 1.0 in CHCl3); vmax (film) 2095 (NN),
1728 (CO); δH (400 MHz, CDCl3) 1.18 (3H, d, J 6.8, C(α)Me),
1.32 (9H, s, CMe3), 1.48−1.62 (2H, m, C(2′)H2), 2.58 (2H, t, J 7.1,
C(1′)H2), 2.64 (1H, dd, J 14.7, 8.5, C(2)HA), 2.79 (1H, dd, J 14.7, 6.6,
C(2)HB), 2.91−3.03 (2H, m, C(3′)H2), 3.98 (1H, q, J 6.8, C(α)H),
4.39 (1H, dd, J 8.5, 6.6, C(3)H), 7.22−7.41 (10H, m, Ph); δC (100
MHz, CDCl3) 16.6 (C(α)Me), 27.9 (CMe3), 29.1 (C(2′)), 38.4
(C(2)), 43.5 (C(1′)), 49.4 (C(3′)), 57.0 (C(α)), 59.6 (C(3)), 80.4
(CMe3), 126.8, 127.2, 127.7, 128.0, 128.1, 128.2 (o,m,p-Ph), 141.3,
144.8 (i-Ph), 171.2 (C(1)); m/z (ESI+) 431 ([M + Na]+, 46%), 409
([M + H]+, 100%); HRMS (ESI+) C24H33N4O2+ ([M + H]+) requires
409.2598, found 409.2600.
tert-Butyl (3S,αR)-3-[N-(3′-Aminopropyl)-N-(α-
methylbenzyl)amino]-3-phenylpropanoate 20. Following Gen-
eral Procedure 3, 19 (270 mg, 660 μmol, >99:1 dr) and PPh3 (192 mg,
730 μmol) in THF (1.3 mL) and H2O (0.27 mL) were reacted. The
residue was partitioned between CH2Cl2 (10 mL) and 2.0 M aq HCl
(5 mL). The organic layer was extracted with 2.0 M aq HCl (2 × 5
mL) and the combined aqueous layers washed with CH2Cl2 (15 mL).
The aqueous layer was then basified to pH 12 by addition of solid
KOH and extracted with CH2Cl2 (3 × 10 mL). The combined organic
extracts were then dried and concentrated in vacuo to give 20 as a
colorless oil (222 mg, 88%, >99:1 dr); [α]2D4 −3.3 (c 1.0 in CHCl3);
vmax (film) 1725 (CO); δH (400 MHz, CDCl3) 1.17 (3H, d, J 6.8,
C(α)Me), 1.29 (9H, s, CMe3), 1.48 (2H, app quintet, J 6.8, C(2′)H2),
2.39−2.46 (2H, m, C(1′)H2), 2.53 (2H, app td, J 6.8, 2.5, C(3′)H2),
2.63 (1H, dd, J 14.6, 8.8, C(2)HA), 2.71 (1H, dd, J 14.6, 6.2, C(2)HB),
3.98 (1H, q, J 6.8, C(α)H), 4.39 (1H, dd, J 8.8, 6.2, C(3)H), 7.20−
7.40 (10H, m, Ph); δC (100 MHz, CDCl3) 16.4 (C(α)Me), 27.9
(CMe3), 33.2 (C(2′)), 38.3 (C(2)), 39.7 (C(1′)), 43.4 (C(3′)), 56.7
(C(α)), 59.4 (C(3)), 80.3 (CMe3), 126.7, 127.1, 127.8, 128.0, 128.1,
128.2 (o,m,p-Ph), 141.6, 144.8 (i-Ph), 171.3 (C(1)); m/z (ESI+) 405
([M + Na]+, 18%), 383 ([M + H]+, 100%); HRMS (ESI+)
+
C24H35N2O2 ([M + H]+) requires 383.2693, found 383.2682.
tert-Butyl (3S,αR)-3-{N-[3′-(N′-Allylamino)propyl]-N-[α-
methylbenzyl]amino}-3-phenylpropanoate 21. NaI (182 mg,
1.21 mmol) was added to a solution of 18 (163 mg, 405 μmol, >99:1
dr) in allyl amine (1.22 mL, 16.3 mmol) and the resultant mixture was
heated at 65 °C for 24 h before being concentrated in vacuo. The
residue was partitioned between CH2Cl2 (25 mL) and satd aq
NaHCO3 (25 mL) and the aqueous layer was extracted with CH2Cl2
(2 × 25 mL). The combined organic extracts were washed with brine
(75 mL), then dried and concentrated in vacuo. Purification via flash
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column chromatography (eluent CH2Cl2/MeOH, 19:1) gave 21 as a
yellow oil (147 mg, 86%, >99:1 dr); C27H38N2O2 requires C, 76.7; H,
9.1; N, 6.6%, found C, 76.7; H, 9.0; N, 6.7%; [α]2D4 −4.5 (c 1.0 in
CHCl3); vmax (film) 1727 (CO); δH (400 MHz, CDCl3) 1.21 (3H,
d, J 6.8, C(α)Me), 1.27 (9H, s, CMe3), 1.52−1.64 (2H, m, C(2′)H2),
2.28−2.50 (3H, m, C(1′)H2, NH), 2.56 (2H, app t, J 6.8, C(3′)H2),
2.64−2.67 (2H, m, C(2)H2), 3.02 (2H, d, J 6.0, NCH2CHCH2),
3.98 (1H, q, J 6.8, C(α)H), 4.38 (1H, dd, J 8.6, 6.6, C(3)H), 5.06−
5.14 (2H, m, CHCH2), 5.75−5.85 (1H, m, CHCH2), 7.20−7.40
(10H, m, Ph); δC (100 MHz, CDCl3) 16.6 (C(α)Me), 28.0 (CMe3),
29.4 (C(2′)), 38.0 (C(2)), 44.0 (C(3′)), 47.0 (C(1′)), 52.0
(NCH2CHCH2), 56.8 (C(α)), 59.4 (C(3)), 80.3 (CMe3), 116.4
(CHCH2), 126.7, 127.1, 127.7, 128.1, 128.2 (o,m,p-Ph), 135.9
(CHCH2), 141.7, 144.6 (i-Ph), 171.2 (C(1)); m/z (ESI+) 423
([M + H]+, 100%); HRMS (ESI+) C27H39N2O2+ ([M + H]+) requires
423.3006, found 423.3008.
MHz, CDCl3) 16.8 (C(α)Me), 30.0 (C(2′)), 37.1 (C(2)), 43.5
(C(1′)), 49.4 (C(3′)), 51.6 (OMe), 57.0 (C(α)), 59.3 (C(3)), 126.9,
127.4, 127.6, 127.9, 128.2, 128.4 (o,m,p-Ph), 141.2, 144.7 (i-Ph), 172.3
(C(1)); m/z (ESI+) 389 ([M + Na]+, 100%), 367 ([M + H]+, 74%);
+
HRMS (ESI+) C21H27N4O2 ([M + H]+) requires 367.2129, found
367.2129.
Methyl (3S,αR)-3-[N-(3′-Aminopropyl)-N-(α-methylbenzyl)-
amino]-3-phenylpropanoate 26. Following General Procedure 3,
25 (1.20 g, 3.24 mmol, >99:1 dr) and PPh3 (948 mg, 3.60 mmol) in
THF (6.6 mL) and H2O (1.2 mL) were reacted. The residue was
partitioned between CH2Cl2 (40 mL) and 2.0 M aq HCl (25 mL).
The organic layer was extracted with 2.0 M aq HCl (2 × 25 mL), and
the combined aqueous layers were washed with CH2Cl2 (50 mL). The
aqueous layer was then basified to pH 12 by the addition of solid KOH
and extracted with CH2Cl2 (3 × 50 mL). The combined organic
extracts were then dried and concentrated in vacuo to give 26 as a
colorless oil (1.19 g, 90%, >99:1 dr); [α]2D0 −9.9 (c 1.0 in CHCl3); vmax
(film) 1736 (CO); δH (400 MHz, CDCl3) 1.17 (3H, d, J 6.8, C(α)
Me), 1.52 (2H, app t, J 7.0, C(2′)H2), 2.44−2.48 (2H, m, C(3′)H2),
2.57 (2H, t, J 7.3, C(1′)H2), 2.71 (1H, dd, J 14.9, 8.5, C(2)HA), 2.82
(1H, dd, J 14.9, 6.7, C(2)HB), 3.56 (3H, s, OMe), 4.02 (1H, q, J 6.8,
C(α)H), 4.46 (1H, dd, J 8.5, 6.7, C(3)H), 7.21−7.42 (10H, m, Ph); δC
(100 MHz, CDCl3) 16.5 (C(α)Me), 33.4 (C(2′)), 37.0 (C(2)), 39.8
(C(3′)), 43.3 (C(1′)), 51.5 (OMe), 56.5 (C(α)), 58.9 (C(3)), 126.7,
127.2, 127.7, 127.9, 128.1, 128.3 (o,m,p-Ph), 141.6, 144.7 (i-Ph), 172.4
(C(1)); m/z (ESI+) 363 ([M + Na]+, 76%), 341 ([M + H]+, 100%);
Methyl (3S,αR)-3-{N-[3′-(N′-Allylamino)propyl]-N-[α-
methylbenzyl]amino}-3-phenylpropanoate 22. Following Gen-
eral Procedure 4, 21 (900 mg, 1.19 mmol, >99:1 dr) and SOCl2 (0.90
mL, 12.4 mmol) in MeOH (9 mL) were reacted. Purification via flash
column chromatography (gradient elution, 1% → 5% MeOH in
CH2Cl2) gave 22 as a yellow oil (585 mg, 72%, >99:1 dr);
C27H38N2O2 requires C, 76.7; H, 9.0; N, 6.6%, found C, 76.7; H,
9.0; N, 6.7%; [α]2D4 −1.1 (c 1.0 in CHCl3); vmax (film) 1739 (CO);
δH (400 MHz, CDCl3) 1.17 (3H, d, J 6.8, C(α)Me), 1.56 (2H, app
quintet, J 7.1, C(2′)H2), 2.28−2.39 (2H, m, C(1′)H2), 2.56 (2H, t, J
7.1, C(3′)H2), 2.70 (1H, dd, J 14.9, 8.6, C(2)HA), 2.79 (1H, dd, J 14.9,
6.3, C(2)HB), 3.03 (2H, app d, J 6.1, NCH2CHCH2), 3.52 (3H, s,
OMe), 4.00 (1H, q, J 6.8, C(α)H), 4.44−4.48 (1H, m, C(3)H), 5.03−
5.12 (2H, m, CHCH2), 5.75−5.85 (1H, m, CHCH2), 7.18−7.38
(10H, m, Ph); δC (100 MHz, CDCl3) 16.7 (C(α)Me), 29.5 (C(2′)),
36.8 (C(2)), 43.9 (C(3′)), 46.9 (C(1′)), 51.5 (OMe), 52.2
(NCH2CHCH2), 56.7 (C(α)), 58.9 (C(3)), 116.0 (CHCH2),
126.8, 127.2, 127.7, 127.9, 128.1, 128.3 (o,m,p-Ph), 136.4 (CHCH2),
141.5, 144.6 (i-Ph), 172.4 (C(1)); m/z (ESI+) 381 ([M + H]+, 100%);
+
HRMS (ESI+) C21H29N2O2 ([M + H]+) requires 341.2224, found
341.2213.
(4S,αR)-4-Phenyl-N(5)-(α-methylbenzyl)-1,5-diazocan-2-one
27. Following General Procedure 5, 26 (1.19 g, 3.50 mmol, >99:1 dr)
and Sb(OEt)3 (0.72 mL, 4.18 mmol) in PhMe (350 mL) were reacted.
Purification via flash column chromatography (gradient elution, 50%
→ 100% EtOAc in 30−40 °C petrol) gave 27 as a white solid (915 mg,
85%, >99:1 dr); mp 46−48 °C; [α]2D4 +22.4 (c 1.0 in CHCl3); vmax
(film) 1662 (CO); δH (400 MHz, CDCl3) 1.00−1.07 (1H, m,
C(7)HA), 1.16−1.30 (4H, m, C(7)HB, C(α)Me), 2.57−2.70 (2H, m,
C(6)H2), 3.04−3.16 (3H, m, C(8)HA, C(3)H2), 3.46−3.58 (1H, m,
C(8)HB), 3.99 (1H, q, J 6.8, C(α)H), 4.55 (1H, br s, C(4)H), 6.59
(1H, br t, J 7.1, NH), 7.18−7.44 (10H, m, Ph); δH (500 MHz, PhMe-
d8, 363 K) 0.74−0.81 (1H, m, C(7)HA), 1.03−1.11 (1H, m, C(7)HB),
1.18 (3H, d, J 6.6, C(α)Me), 2.48−2.56 (2H, m, C(3)HA, C(6)HA),
2.59−2.65 (1H, m, C(8)HA), 2.79 (1H, app t, J 11.7, C(3)HB), 2.92
(1H, ddd, J 15.8, 8.5, 2.8, C(6)HB), 3.05−3.14 (1H, m, C(8)HB), 3.96
(1H, q, J 6.6, C(α)H), 4.51 (1H, dd, J 11.0, 3.8, C(4)H), 5.94 (1H, br
s, NH), 7.04−7.11 (2H, m, Ph), 7.14−7.21 (4H, m, Ph), 7.24−7.28
(2H, m, Ph), 7.30−7.34 (2H, m, Ph); δC (100 MHz, CDCl3) 33.2
(C(7)), 41.2 (C(3)), 46.8 (C(8)), 60.7 (C(α)), 62.8 (C(4)), 126.8,
127.0, 127.2, 128.0, 128.1, 128.6 (o,m,p-Ph), 143.1, 145.5 (i-Ph), 176.7
(C(2));39 δC (125 MHz, PhMe-d8, 363 K) 16.5 (C(α)Me), 33.8
(C(7)), 41.8 (C(6)), 41.9 (C(3)), 46.7 (C(8)), 61.2 (C(α)), 63.5
(C(4)), 126.9, 127.0, 127.6, 128.1, 128.4, 128.6 (o,m,p-Ph), 144.3,
146.0 (i-Ph), 175.0 (C(2)); m/z (ESI+) 948 ([3M + Na]+, 46%), 639
([2M + Na]+, 100%), 331 ([M + Na]+, 82%), 309 ([M + H]+, 66%);
HRMS (ESI+) C20H25N2O+ ([M + H]+) requires 309.1961, found
309.1960.
(4S,αR)-N(1)-Allyl-4-phenyl-N(5)-(α-methylbenzyl)-1,5-diazo-
can-2-one 28. Allyl bromide (17 μL, 196 μmol) was added to a
mixture of 27 (51 mg, 165 μmol, >99:1 dr), K2CO3 (28 mg, 203
μmol), NaOH (28 mg, 700 μmol), and TEBAC (5 mg, 22.0 μmol) in
THF (1 mL). The resultant mixture was heated at 75 °C for 18 h, then
filtered through Celite (eluent EtOAc), and concentrated in vacuo.
Purification via column chromatography (gradient elution, 10% →
65% EtOAc in 30−40 °C petrol) gave 28 as a yellow oil (55 mg, 96%,
>99:1 dr); C23H28N2O requires C, 79.3; H, 8.1; N, 8.0%, found C,
79.4; H, 7.9; N, 7.9%; [α]2D4 −4.5 (c 1.0 in CHCl3); vmax (film) 1635
(CO); δH (400 MHz, CDCl3) 0.92−0.99 (1H, m, C(7)HA), 1.20−
1.32 (1H, m, C(7)HB), 1.24 (3H, d, J 6.6, C(α)Me), 2.52 (1H, br s,
C(6)HA), 2.67 (1H, dd, J 12.9, 3.8, C(3)HA), 3.04−3.19 (3H, m, C(3)
HB, C(6)HB, C(8)HA), 3.49 (1H, dd, J 15.2, 7.1, CHAHBCHCH2),
3.75 (1H, app br t, J 13.6, C(8)HB), 3.95 (1H, q, J 6.6, C(α)H), 4.52−
+
HRMS (ESI+) C24H33N2O2 ([M + H]+) requires 381.2537, found
381.2526.
Methyl (3S,αR)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)-
amino]-3-phenylpropanoate 24. Following General Procedure 1,
(R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amine (5.00 g, 25.3
mmol), BuLi (2.2 M in hexanes, 9.8 mL, 24.5 mmol) and 23 (2.56
g, 15.8 mmol) in THF (250 mL) were reacted to give 24 as a yellow
oil (5.68 g, quant, >99:1 dr); C21H26ClNO2 requires C, 70.1; H, 7.3;
N, 3.9%, found C, 70.2; H, 7.2; N, 3.8%; [α]2D4 −7.0 (c 1.0 in CHCl3);
vmax (film) 1738 (CO); δH (400 MHz, CDCl3) 1.18 (3H, d, J 6.8,
C(α)Me), 1.69−1.81 (2H, m, C(2′)H2), 2.67 (2H, t, J 6.8, C(1′)H2),
2.71 (1H, dd, J 14.9, 8.2, C(2)HA), 2.87 (1H, dd, J 14.9, 6.8, C(2)HB),
3.21−3.31 (2H, m, C(3′)H2), 3.58 (3H, s, OMe), 3.99 (1H, q, J 6.8,
C(α)H), 4.45 (1H, dd, J 8.2, 6.8, C(3)H), 7.22−7.38 (10H, m, Ph); δC
(100 MHz, CDCl3) 16.9 (C(α)Me), 32.8 (C(2′)), 37.2 (C(2)), 43.2
(C(3′)), 43.8 (C(1′)), 51.6 (OMe), 57.1 (C(α)), 59.3 (C(3)), 126.9,
127.4, 127.7, 128.0, 128.2, 128.4 (o,m,p-Ph), 141.2, 144.7 (i-Ph), 172.3
(C(1)); m/z (ESI+) 384 ([M(37Cl) + Na], 66%), 382 ([M(35Cl) +
Na]+, 100%), 362 ([M(37Cl) + H], 44%), 360 ([M(35Cl) + H]+, 72%);
+
HRMS (ESI+) C21H2737ClNO2 ([M(37Cl) + H]+) requires 362.1695,
+
found 362.1697; C21H2735ClNO2 ([M(35Cl) + H]+) requires
360.1725, found 360.1721.
Methyl (3S,αR)-3-[(N-3′-Azidopropyl)-N-(α-methylbenzyl)-
amino]-3-phenylpropanoate 25. Following General Procedure 2,
NaN3 (1.08 g, 16.7 mmol, >99:1 dr), NaI (2.49 g, 16.7 mmol) and 24
(3.00 g, 8.36 mmol, >99:1 dr) in DMSO (15 mL) were reacted for 24
h. Purification via column chromatography (eluent 30−40 °C petrol/
Et2O, 8:2) gave 25 as a yellow oil (2.38 g, 78%, >99:1 dr);
C21H26N4O2 requires C, 68.8; H, 7.15; N, 15.3%, found C, 68.9; H,
7.1; N, 15.2%; [α]2D4 −9.3 (c 1.0 in CHCl3); vmax (film) 2096 (NN),
1738 (CO); δH (400 MHz, CDCl3) 1.20 (3H, d, J 6.8, C(α)Me),
1.50−1.66 (2H, m, C(2′)H2), 2.62 (2H, t, J 6.8, C(1′)H2), 2.73 (1H,
dd, J 14.8, 8.1, C(2)HA), 2.90 (1H, dd, J 14.8, 6.8, C(2)HB), 2.95−3.06
(2H, m, C(3′)H2), 3.61 (3H, s, OMe), 4.02 (1H, q, J 6.8, C(α)H),
4.49 (1H, app t, J 7.6, C(3)H), 7.24−7.41 (10H, m, Ph); δC (100
7036
dx.doi.org/10.1021/jo3012732 | J. Org. Chem. 2012, 77, 7028−7045

The Journal of Organic Chemistry
Article
4.61 (2H, m, C(4)H, CHAHBCHCH2), 5.12−5.18 (2H, m,
CH2CHCH2), 5.76−5.87 (1H, m, CH2CHCH2), 7.17−7.31
(4H, m, Ph), 7.33−7.38 (4H, m, Ph), 7.40−7.45 (2H, m, Ph); δC (100
MHz, CDCl3) 30.3 (C(7)), 43.1 (C(3)), 46.7 (C(8)), 48.3
(CH2CHCH2), 60.7 (C(α)), 63.5 (C(4)), 117.2 (CH2CHCH2),
126.8, 127.0, 127.2, 127.9, 128.0, 128.6 (o,m,p-Ph), 143.4, 145.6 (i-Ph),
173.2 (C(2));40 m/z (ESI+) 371 ([M + Na]+, 38%), 349 ([M + H]+,
100%); HRMS (ESI+) C23H29N2O+ ([M + H]+) requires 349.2274,
found 349.2266.
(o,m,p-Ph), 145.0, 146.5 (i-Ph), 172.5 (2 × C(2′)); m/z (ESI+) 693
([M + Na]+, 41%), 671 ([M + H]+, 100%); HRMS (ESI+)
+
C44H55N4O2 ([M + H]+) requires 671.4320, found 671.4312.
Method B: Following General Procedure 7, 29 (20 mg, 29.9 μmol)
and Pd(OH)2/C (10 mg) in MeOH (1.0 mL) were reacted in the
presence of H2 (5 atm) for 1 h. The residue was partitioned between
CH2Cl2 (5 mL) and satd aq NaHCO3 (5 mL), the aqueous layer was
extracted with CH2Cl2 (2 × 5 mL), and the combined organic extracts
were dried and concentrated in vacuo to give 30 as a yellow oil (21 mg,
quant, >99:1 dr); [α]2D4 +4.2 (c 1.0 in CHCl3).
(4′S,αR,E)-1,4-Di[2′-oxo-4′-phenyl-N(5′)-α-methylbenzyl-
1′,5′-diazocan-N(1′)-yl]but-2-ene 29. Method A: Grubbs II catalyst
(120 mg, 143 μmol) was added to a degassed solution of 28 (500 mg,
1.43 μmol, >99:1 dr) in CH2Cl2 (7 mL, EtOH stabilized), and the
reaction mixture was heated at 40 °C for 18 h. The reaction mixture
was then concentrated in vacuo. Purification via column chromatog-
raphy (gradient elution, 0% → 7% MeOH in CH2Cl2) gave 29 as a
yellow solid (394 mg, 82%, >99:1 dr); mp 64−67 °C; [α]2D0 −7.1 (c 1.0
in CHCl3); vmax (ATR) 1637 (CO); δH (400 MHz, CDCl3) 0.91−
1.01 (2H, m, 2 × C(7′)HA), 1.19−1.28 (2H, m, 2 × C(7′)HB)
overlapping 1.24 (6H, d, J 6.6, 2 × C(α)Me), 2.42−2.57 (2H, m, 2 ×
C(6′)HA), 2.65 (2H, dd, J 12.6, 3.3, 2 × C(8′)HA), 3.03−3.18 (6H, m,
2 × C(3′)HA, 2 × C(6′)HB, 2 × C(8′)HB), 3.44 (2H, br d, J 12.1,
C(1)HA, C(4)HA), 3.74 (2H, br t, J 11.9, 2 × C(3′)HB), 3.95 (2H, br
q, J 6.6, 2 × C(α)H), 4.40−4.66 (4H, m, C(1)HB, C(4)HB, 2 × C(4′)
H), 5.54−5.59 (2H, m, C(2)H, C(3)H), 7.19−7.45 (20H, m, Ph); δC
(100 MHz, CDCl3) 30.2 (2 × C(7′)), 46.9 (2 × C(3′)), 126.8, 127.0,
127.1, 127.9, 128.0, 128.6 (o,m,p-Ph), 143.3 (i-Ph), 172.2 (2 ×
C(2′));41 m/z (ESI+) 691 ([M + Na]+, 95%), 669 ([M + H]+, 100%);
(R)-N-3-(Chloropropyl)-N-(α-methyl-4′-methoxybenzyl)-
amine. (R)-N-α-Methyl-4-methoxybenzyl amine (5.00 g, 33.1 mmol)
was added to a solution of 1-bromo-3-chloropropane (1.81 mL, 18.3
mmol) in MeCN (10 mL), and the resultant mixture was stirred for 16
h at rt. The reaction mixture was basified to pH 9 with satd aq
NaHCO3 and then extracted with EtOAc (3 × 100 mL). The
combined organic extracts were then dried and concentrated in vacuo.
Purification via flash column chromatography (eluent Et2O) gave (R)-
N-3-(chloropropyl)-N-(α-methyl-4′-methoxybenzyl)amine as a yellow
oil (2.90 g, 70%, >99:1 er); C12H18ClNO requires C, 63.3; H, 8.0; N,
6.15%, found C, 63.5; H, 7.9; N, 6.1%; [α]2D4 +28.6 (c 1.0 in CHCl3);
vmax (ATR) 3323 (N−H); δH (400 MHz, CDCl3) 1.34 (3H, d, J 6.7,
C(α)Me), 1.89 (2H, app quintet, J 6.8, C(2)H2), 2.56 (1H, dt, J 11.9,
6.8, C(1)HA), 2.66 (1H, dt, J 11.9, 6.6, C(1)HB), 3.54−3.65 (2H, m,
C(3)H2), 3.73 (1H, q, J 6.7, C(α)H), 3.80 (3H, s, OMe), 6.86−6.89
(2H, m, C(3′)H, C(5′)H), 7.22−7.25 (2H, m, C(2′)H, C(6′)H); δC
(100 MHz, CDCl3) 24.4 (C(α)Me), 33.1 (C(2)), 43.2 (C(3)), 44.7
(C(1)), 55.2 (OMe), 57.6 (C(α)), 113.8 (C(3′), C(5′)), 127.5 (C(2′),
C(6′)), 137.7 (C(1′)), 158.5 (C(4′)); m/z (ESI+) 252 ([M(37Cl) +
Na]+, 4%), 250 ([M(35Cl) + Na]+, 10%), 230 ([M(37Cl) + H]+, 40%),
228 ([M(35Cl) + H]+, 100%); HRMS (ESI+) C12H1937ClNO+
+
HRMS (ESI+) C44H53N4O2 ([M + H]+) requires 669.4163, found
669.4161.
Method B: Following General Procedure 6A, 27 (244 mg, 791
μmol), trans-1,4-dibromobutane (85 mg, 397 μmol), K2CO3 (132 mg,
955 μmol), KOH (177 mg, 3.15 mmol), and TEBAC (22 mg, 98.3
μmol) in DMSO (4.0 mL) were reacted for 72 h. Purification via
column chromatography (gradient elution, 0% → 2% MeOH in
CHCl3) gave 29 as a white solid (175 mg, 66%, >99:1 dr); mp 67−69
°C; [α]2D0 −7.9 (c 1.0 in CHCl3).
([M(37Cl)
+
H]+) requires 230.1120, found 230.1119;
C12H1935ClNO+ ([M(35Cl) + H]+) requires 228.1150, found 228.1145.
(4S,αR)-4-Phenyl-N(5)-(α-methyl-4′-methoxybenzyl)-1,5-di-
azocan-2-one 35. Step 1: Following General Procedure 1, (R)-N-3-
(chloropropyl)-N-(α-methyl-4′-methoxybenzyl)amine (3.00 g, 13.2
mmol), BuLi (2.5 M, 5.12 mL, 12.8 mmol), and 23 (1.33 g, 8.23
mmol) in THF (75 mL) were reacted to give 32 (3.37 g, >99:1 dr).
Purification of an aliquot via flash column chromatography (gradient
elution, 2% → 20% Et2O in 30−40 °C petrol) gave 32 as a colorless
oil; C22H28ClNO3 requires C, 67.8; H, 7.2; N, 3.6%, found C, 67.9; H,
7.0; N, 3.3%; [α]2D4 −3.0 (c 1.0 in CHCl3); vmax (ATR) 1737 (CO);
δH (400 MHz, CDCl3) 1.18 (3H, d, J 6.8, C(α)Me), 1.69−1.85 (2H,
m, C(2′)H2), 2.68 (2H, t, J 7.1, C(1′)H2), 2.73 (1H, dd, J 14.9, 8.2,
C(2)HA), 2.90 (1H, dd, J 14.9, 6.7, C(2)HB), 3.23−3.33 (2H, m,
C(3′)H2), 3.59 (3H, s, CO2Me), 3.81 (3H, s, ArOMe), 3.98 (1H, q, J
6.8, C(α)H), 4.48 (1H, dd, J 8.2, 6.7, C(3)H), 6.87−6.91 (2H, m,
C(3′′)H, C(5′′)H), 7.27−7.32 (3H, m, C(2′′)H, C(6′′)H, Ph), 7.33−
7.39 (4H, m, Ph); δC (100 MHz, CDCl3) 16.9 (C(α)Me), 32.9
(C(2′)), 37.1 (C(2)), 43.2 (C(3′)), 43.6 (C(1′)), 51.5 (CO2Me), 55.2
(ArOMe), 56.4 (C(α)), 59.2 (C(3)), 113.5 (C(3′′), C(5′′)), 127.3
(C(2′′), C(6′′)), 128.0, 128.4, 128.7 (o,m,p-Ph), 136.6 (C(1′′)), 141.4
(i-Ph), 158.5 (C(4′′)), 172.3 (C(1)); m/z (ESI+) 414 ([M(37Cl) +
Na]+, 35%), 412 ([M(35Cl) + Na]+, 100%), 392 ([M(37Cl) + H]+,
(4′S,αR)-1,4-Di[2′-oxo-4′-phenyl-N(5′)-α-methylbenzyl-1′,5′-
diazocan-1′-yl]butane 30. Method A: 1,4-Dibromobutane (0.29 mL,
2.43 mmol) was added to a mixture of 27 (1.50 g, 4.86 mmol, >99:1
dr), K2CO3 (2.69 g, 19.5 mmol), KOH (1.10 g, 19.5 mmol), and
TBAC (135 mg, 486 μmol) in PhMe (16 mL) under N2 and sealed in
a tube. The resultant mixture was heated at 160 °C in a microwave
reactor for 15 min before being cooled to rt and partitioned between
H2O (20 mL) and EtOAc (20 mL). The aqueous layer was extracted
with EtOAc (2 × 30 mL), and the combined organic extracts were
washed with brine (40 mL), then dried, and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 40%
→ 100% EtOAc in 30−40 °C petrol) gave 30 as a yellow oil (1.36 g,
83%, >99:1 dr); [α]D24 +4.5 (c 1.0 in CHCl3); vmax (ATR) 1614
(CO); δH (400 MHz, CDCl3) 0.95−1.04 (2H, m, 2 × C(7′)HA),
1.20−1.33 (8H, m, 2 × C(α)Me, 2 × C(7′)HB), 1.53−1.59 (4H, m,
C(2)H2, C(3)H2), 2.57−2.65 (2H, m, 2 × C(6′)HA), 2.78−2.86 (2H,
m, C(1)HA, C(4)HA), 3.02−3.19 (8H, m, 2 × C(3′)HA, 2 × C(8′)H2,
2 × C(6′)HB), 3.80 (2H, br t, J 11.9, 2 × C(3′)HB), 3.90−4.01 (4H,
m, 2 × C(α)H, C(1)HB, C(4)HB), 4.42−4.60 (2H, m, 2 × C(4′)H),
7.17−7.47 (20H, m, Ph); δH (500 MHz, PhMe-d8, 363 K) 0.74−0.80
(2H, m, 2 × C(7′)HA), 1.13 (6H, d, J 6.6, 2 × C(α)Me), 1.17−1.27
(2H, m, 2 × C(7′)HB), 1.51−1.57 (4H, m, C(2)H2, C(3)H2), 2.40−
2.47 (2H, m, 2 × C(6′)HA), 2.56 (2H, dd, J 12.6, 3.8, C(1)HA, C(4)
HA), 2.77−2.94 (8H, m, 2 × C(3′)HA, 2 × C(6′)HB, 2 × C(8′)H2),
3.45 (2H, t, J 13.6, 2 × C(3′)HB), 3.89−3.98 (4H, m, 2 × C(α)H,
C(1)HB, C(4)HB), 4.47 (2H, dd, J 11.0, 3.5, 2 × C(4′)H), 7.02−7.08
(4H, m, Ph), 7.15 (8H, app t, J 7.9, Ph), 7.22−7.29 (8H, m, Ph); δC
(100 MHz, CDCl3) 25.3 (C(2), C(3)), 30.5 (2 × C(7′)), 45.5 (C(1),
C(4)), 126.7, 127.0, 127.1, 127.2, 127.9, 128.0, 128.1, 128.6, 128.7
(o,m,p-Ph), 173.3 (2 × C(2′));42 δC (125 MHz, PhMe-d8, 363 K) 16.5
(2 × C(α)Me), 26.3 (C(2), C(3)), 31.4 (2 × C(7′)), 43.7 (2 × C(3′)),
46.1 (C(1), C(4)), 46.9 (2 × C(8′)), 47.9 (2 × C(6′)), 61.2 (2 ×
C(α)), 64.3 (2 × C(4′)), 127.3, 127.4, 128.0, 128.6, 128.9, 129.1
+
21%), 390 ([M(35Cl) + H]+, 84%); HRMS (ESI+) C22H2937ClNO3
([M(37Cl)
+
H]+) requires 392.1801, found 392.1804;
C22H2935ClNO3 ([M(35Cl) + H]+) requires 390.1830, found
+
390.1819.
Step 2: Following General Procedure 2, NaN3 (1.07 g, 16.5 mmol),
NaI (2.47 g, 16.5 mmol), and 32 (3.00 g, >99:1 dr) in DMSO (20
mL) were reacted for 24 h to give 33 (2.93 g, >99:1 dr). Purification of
an aliquot via flash column chromatography (gradient elution, 2% →
20% Et2O in 30−40 °C petrol) gave 33 as a yellow oil; [α]2D4 −3.4 (c
1.0 in CHCl3); vmax (film) 2096 (NN), 1738 (CO); δH (400
MHz, CDCl3) 1.17 (3H, d, J 6.8, C(α)Me), 1.48−1.64 (2H, m, C(2′)
H2), 2.59 (2H, t, J 6.8, C(1′)H2), 2.73 (1H, dd, J 14.9, 8.1, C(2)HA),
2.89 (1H, dd, J 14.9, 6.8, C(2)HB), 2.95−3.05 (2H, m, C(3′)H2), 3.60
(3H, s, CO2Me), 3.82 (3H, s, ArOMe), 3.97 (1H, q, J 6.8, C(α)H),
4.45−4.49 (1H, m, C(3)H), 6.87−6.90 (2H, m, C(3′′)H, C(5′′)H),
7.28−7.31 (2H, m, C(2′′)H, C(6′′)H), 7.34−7.38 (5H, m, Ph); δC
7037
dx.doi.org/10.1021/jo3012732 | J. Org. Chem. 2012, 77, 7028−7045

The Journal of Organic Chemistry
Article
(100 MHz, CDCl3) 16.8 (C(α)Me), 29.0 (C(2′)), 37.1 (C(2)), 43.3
(C(1′)), 49.4 (C(3′)), 51.6 (CO2Me), 55.2 (ArOMe), 56.3 (C(α)),
59.2 (C(3)), 113.5 (C(3′′), C(5′′)), 127.3 (C(2′′), C(6′′)), 127.9,
128.4, 128.7 (o,m,p-Ph), 136.6 (C(1′′)), 141.3 (i-Ph), 158.4 (C(4′′)),
172.3 (C(1)); m/z (ESI+) 419 ([M + Na]+, 100%), 397 ([M + H]+,
HRMS (ESI+) C46H58N4NaO4+ ([M + Na]+) requires 753.4350, found
753.4358.
(S,S)-1,4-Di[2′-oxo-4′-phenyl-1′,5′-diazocan-N(1′)-yl]butane
37. A mixture of TFA (1.00 mL) and 36 (50 mg, 78.1 μmol, >99:1 dr)
was heated at 60 °C for 2.5 h, then allowed to cool to rt, and
concentrated in vacuo. The residue was partitioned between EtOAc (5
mL) and satd aq NaHCO3 (5 mL), and then the aqueous layer was
extracted with EtOAc (2 × 5 mL). The combined organic extracts
were washed with brine (10 mL), then dried, and concentrated in
vacuo. Purification via column chromatography (gradient elution, 0%
→ 10% MeOH in CHCl3) gave 37 as a colorless oil (11 mg, 30%,
>99:1 dr);10 [α]D24 −32.5 (c 0.5 in CHCl3); {lit.10 [α]2D0 −30 (c 1.3 in
CHCl3)}; δH (400 MHz, CDCl3) 1.59−1.68 (2H, m, 2 × C(7′)HA),
1.76−1.84 (6H, m, C(2)H2, C(3)H2, 2 × C(7′)HB), 2.38 (2H, dd, J
12.3, 8.9, 2 × C(3′)HA), 2.50 (2H, dd, J 12.3, 1.7, 2 × C(3′)HB),
2.89−3.04 (4H, m, 2 × C(6′)H2), 3.13−3.32 (4H, m, C(1)H2, C(4)
H2), 3.83−3.92 (2H, m, 2 × C(8′)HA), 3.95−4.23 (4H, m, 2 × C(4′)
H, 2 × C(8′)HB), 7.23−7.43 (10H, m, Ph).
+
94%); HRMS (ESI+) C22H29N4O3 ([M + H]+) requires 397.2234,
found 397.2232.
Step 3: Following General Procedure 3, 33 (2.69 g, >99:1 dr) and
PPh3 (1.78 g, 6.77 mmol) in THF (10 mL) and H2O (2.7 mL) were
reacted. The residue was partitioned between CH2Cl2 (100 mL) and
2.0 M aq HCl (25 mL). The organic layer was extracted with 2.0 M aq
HCl (2 × 25 mL), and the combined aqueous layers were washed with
CH2Cl2 (50 mL). The aqueous layer was then basified to pH 12 by the
addition of solid KOH and extracted with CH2Cl2 (3 × 30 mL). The
combined organic extracts were then dried and concentrated in vacuo
to give 34 as a colorless oil (1.95 g, >99:1 dr); δH (400 MHz, CDCl3)
1.15 (3H, d, J 6.8, C(α)Me), 1.50 (2H, app quintet, J 6.9, C(2′)H2),
2.46 (2H, td, J 6.9, 2.7, C(3′)H2), 2.54 (2H, t, J 7.9, C(1′)H2), 2.70
(1H, dd, J 14.9, 8.7, C(2)HA), 2.81 (1H, dd, J 14.9, 6.5, C(2)HB), 3.57
(3H, s, CO2Me), 3.81 (3H, s, ArOMe), 3.96 (1H, q, J 6.8, C(α)H),
4.45 (1H, dd, J 8.7, 6.5, C(3)H), 6.86 (2H, d, J 8.5, C(3′′)H, C(5′′)
H), 7.24−7.36 (7H, m, Ph, C(2′′)H, C(6′′)H).
(S)-N(1)-(Hydroxymethyl)-4-phenyl-N(5)-methyl-1,5-diazo-
can-2-one 40. Pd(OH)2/C (200 mg) was added to a degassed
solution of 27 (200 mg, 648 μmol, >99:1 dr) in MeOH (3.4 mL),
formalin (6.4 mL), and AcOH (10 mL), and the resultant mixture was
stirred under H2 (5 atm) for 72 h. The reaction mixture was degassed,
filtered through Celite (eluent MeOH), and concentrated in vacuo.
The residue was partitioned between EtOAc (15 mL) and satd aq
NaHCO3 (15 mL). The aqueous layer was extracted with EtOAc (2 ×
15 mL), and the combined organic extracts were dried and
concentrated in vacuo. Purification via flash column chromatography
(eluent CH2Cl2/MeOH, 19:1) gave 40 as a white solid (45 mg, 28%);
mp 94−97 °C; [α]2D4 −5.3 (c 1.0 in CHCl3); vmax (ATR) 3357 (O−H),
1631 (CO); δH (400 MHz, CDCl3) 1.67−1.75 (1H, m, C(7)HA),
1.85−1.96 (1H, m, C(7)HB), 2.25 (3H, s, NMe), 2.51−2.57 (2H, m,
C(6)HA, C(3)HA), 2.97 (1H, ddd, J 15.4, 7.1, 3.3, C(6)HB), 3.14 (1H,
app t, J 11.9, C(3)HB), 3.49 (1H, dt, J 15.4, 3.8, C(8)HA), 3.88−4.00
(2H, m, C(4)H, C(8)HB), 4.11 (1H, br s, OH), 4.77 (1H, d, J 10.3,
N(1)CHAHBOH), 5.02 (1H, d, J 10.3, N(1)CHAHBOH), 7.23−7.35
(5H, m, Ph); δC (100 MHz, CDCl3) 31.1 (C(7)), 41.5 (C(3)), 43.8
(NMe), 48.6 (C(8)), 51.5 (C(6)), 68.4 (C(4)), 72.9 (N(1)CH2OH),
127.3, 127.5, 128.4 (o,m,p-Ph), 141.8 (i-Ph), 175.5 (C(2)); m/z (ESI+)
271 ([M + Na]+, 100%), 249 ([M + H]+, 41%); HRMS (ESI+)
C14H21N2O2+ ([M + H]+) requires 249.1598, found 249.1599. Further
elution gave 39 as a white solid (18 mg, 13%, >99:1 dr).
Step 4: Following General Procedure 5, 34 (1.95 g, >99:1 dr) and
Sb(OEt)3 (1.07 mL, 6.31 mmol) in PhMe (600 mL) were reacted.
Purification via flash column chromatography (eluent EtOAc) gave 35
as a colorless oil (1.31 g, 53% over 4 steps, >99:1 dr); C21H26N2O2
requires C, 74.5; H, 7.7; N, 8.3%, found C, 74.4; H, 7.6; N, 8.2%; [α]D20
+21.4 (c 1.0 in CHCl3); vmax (ATR) 1663 (CO); δH (400 MHz,
CDCl3) 0.99−1.08 (1H, m, C(7)HA), 1.20−1.30 (1H, m, C(7)HB)
overlapping 1.21 (3H, d, J 6.3, C(α)Me), 2.51−2.66 (2H, m, C(2)HA,
C(6)HA), 2.98−3.17 (3H, m, C(2)HB, C(6)HB, C(8)HA), 3.49 (1H,
app br q, J 9.9, C(8)HB), 3.74 (3H, s, OMe), 3.93 (1H, q, J 6.3, C(α)
H), 4.49 (1H, br s, C(4)H), 6.81 (2H, d, J 8.3, C(3′)H, C(5′)H), 7.02
(1H, br t, J 6.8, NH), 7.21−7.41 (7H, m, C(2′)H, C(6′)H, Ph); δC
(125 MHz, PhMe-d8, 363 K) 16.8 (C(α)Me), 33.8 (C(7)), 41.9
(C(6)), 42.0 (C(3)), 46.6 (C(8)), 54.9 (OMe), 60.4 (C(α)), 63.4
(C(4)), 114.0 (C(3′), C(5′)), 127.0, 127.6, 128.6, 129.4 (o,m,p-Ph,
C(2′), C(6′)), 138.0, 144.4 (i-Ph), 159.3 (C(4′)), 175.7 (C(2));43 m/z
(ESI+) 699 ([2M + Na]+, 100%), 361 ([M + Na]+, 79%), 339 ([M +
+
H]+, 76%); HRMS (ESI+) C21H26N2NaO2 ([M + Na]+) requires
361.1886, found 361.1880.
X-ray Crystal Structure Determination for 40.29 Data were
collected using 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
idealized positions. The structure was refined using CRYSTALS.46 X-
ray crystal structure data for 40 [C14H20N2O2]: M = 248.32,
monoclinic, space group P21, a = 6.0224(3) Å, b = 6.8706(3) Å, c =
15.3642(6) Å, β = 93.565(2)°, V = 634.50(5) Å3, Z = 2, μ = 0.088
mm−1, colorless plate, crystal dimensions = 0.08 × 0.19 × 0.22 mm3. A
total of 1545 unique reflections were measured for 5 < θ < 27, and
1545 reflections were used in the refinement. The final parameters
were wR2 = 0.105 and R1 = 0.058 [I > −3.0σ(I)].
Methyl (S)-3-(3′-Chloropropylamino)-3-phenylpropanoate
41. Method A: Following General Procedure 7, 24 (1.00 g, 2.78
mmol, >99:1 dr), and Pd(OH)2/C (500 mg) in 1.0 M aq HCl (10
mL) were reacted for 18 h. The residue was partitioned between
CH2Cl2 (20 mL) and satd aq NaHCO3 (20 mL), and the aqueous
layer was extracted with CH2Cl2 (2 × 25 mL). The combined organic
extracts were then dried and concentrated in vacuo to give 41 as a
yellow oil (496 mg, 70%); [α]2D4 −29.1 (c 1.0 in CHCl3); vmax (ATR)
3347 (N−H), 1735 (CO); δH (400 MHz, CDCl3) 1.83−1.95 (2H,
m, C(2′)H2), 2.54−2.67 (3H, m, C(1′)H2, C(2)HA), 2.72 (1H, dd, J
15.7, 8.7 C(2)HB), 3.54−3.64 (2H, m, C(3′)H2), 3.66 (3H, s, OMe),
4.09 (1H, dd, J 8.7, 5.3, C(3)H), 7.25−7.36 (5H, m, Ph); δC (100
MHz, CDCl3) 32.7 (C(2′)), 42.7 (C(2)), 42.9 (C(3′)), 44.2 (C(1′)),
51.7 (OMe), 59.4 (C(3)), 126.9, 127.6, 128.6 (o,m,p-Ph), 142.3 (i-Ph),
172.2 (C(1)); m/z (ESI+) 280 ([M(37Cl) + Na]+, 9%), 278 ([M(35Cl)
(4′S,αR)-1,4-Di[2′-oxo-4′-phenyl-N(5′)-(α-methyl-4′′-me-
thoxybenzyl)-1′,5′-diazocan-1′-yl]butane 36. 1,4-Dibromobu-
tane (88 μL, 739 μmol) was added to a suspension of 35 (500 mg,
1.48 mmol, >99:1 dr), K2CO3 (818 mg, 5.92 mmol), KOH (332 mg,
5.92 mmol), and TBAI (55 mg, 148 μmol) in PhMe (8 mL) under N2
and sealed in a tube. The resultant mixture was heated at 160 °C in a
microwave reactor for 15 min before being cooled to rt and partitioned
between H2O (5 mL) and EtOAc (5 mL). The aqueous layer was
extracted with EtOAc (2 × 10 mL), and the combined organic extracts
were washed with brine (20 mL), then dried, and concentrated in
vacuo. Purification via flash column chromatography (gradient elution,
70% → 100% EtOAc in 30−40 °C petrol) gave 36 as a white solid
(363 mg, 67%, >99:1 dr); mp 46−49 °C; [α]2D4 +20.1 (c 1.0 in
CHCl3); vmax (ATR) 1661 (CO); δH (500 MHz, CDCl3) 0.96−1.04
(2H, m, 2 × C(7′)HA), 1.19 (6H, d, J 6.5, 2 × C(α)Me), 1.27−1.37
(2H, m, 2 × C(7′)HB), 1.56 (4H, br s, C(2)H2, C(3)H2), 2.45 (2H, br
s, 2 × C(6′)HA), 2.78−2.86 (2H, m, C(1)HA, C(4)HA), 3.02 (2H, br s,
2 × C(3′)HA), 3.06−3.17 (4H, m, 2 × C(6′)HB, 2 × C(8′)HA), 3.78−
3.84 (8H, m, OMe, 2 × C(8′)HB), 3.88 (2H, q, J 6.5, 2 × C(α)H),
3.90−3.98 (2H, m, C(1)HB, C(4)HB), 4.44 (2H, br s, 2 × C(4′)H),
6.82 (4H, d, J 8.8, 2 × C(3′′)H, 2 × C(5′′)H), 7.22−7.28 (6H, m, 2 ×
C(2′′)H, 2 × C(6′′)H, Ph), 7.32−7.37 (4H, m, Ph), 7.38−7.44 (4H,
m, Ph);44 δC (125 MHz, CDCl3) 15.1 (2 × C(α)Me), 25.3 (C(2),
C(3)), 30.6 (2 × C(7′)), 43.4 (2 × C(3′)), 45.4 (C(1), C(4)), 47.5 (2
× (C(8′)), 55.2 (2 × OMe), 59.5 (2 × C(α)), 63.7 (2 × C(4′)), 113.2
(2 × C(3′′), 2 × (C(5′′)), 126.9, 127.1, 128.6, 129.0 (2 × C(2′′), 2 ×
C(6′′), o,m,p-Ph), 137.5 (2 × C(1′′)), 143.6 (i-Ph), 158.3 (2 ×
C(4′′)), 170.3 (2 × C(1′));45 m/z (ESI+) 753 ([M + Na]+, 100%);
7038
dx.doi.org/10.1021/jo3012732 | J. Org. Chem. 2012, 77, 7028−7045

The Journal of Organic Chemistry
Article
+ Na]+, 26%), 258 ([M(37Cl) + H]+, 47%), 256 ([M(35Cl) + H]+,
methods (SIR92); all non-hydrogen atoms were refined with
anisotropic thermal parameters. Hydrogen atoms were added at
idealized positions. The structure was refined using CRYSTALS.46 X-
ray crystal structure data for 39 [C13H18N2O]: M = 218.30,
monoclinic, space group P21, a = 6.0474(2) Å, b = 6.8974(2) Å, c =
13.9812(4) Å, β = 96.696(3)°, V = 579.19(3) Å3, Z = 2, μ = 0.632
mm−1, colorless plate, crystal dimensions =0.05 × 0.11 × 0.23 mm3. A
total of 6077 reflections were measured for 5 < θ < 77 and 5458
reflections were used in the refinement. The final parameters were wR2
= 0.084 and R1 = 0.034 [I > −3.0σ(I)].
(S)-N(1)-Allyl-4-phenyl-N(5)-methyl-1,5-diazocan-2-one 45.
Allyl bromide (0.24 mL, 2.80 mmol) was added to a mixture of 39
(500 mg, 2.29 mmol), K2CO3 (380 mg, 2.75 mmol), NaOH (387 mg,
9.68 mmol), and TEBAC (69 mg, 298 μmol) in THF (14 mL). The
resultant mixture was heated at 75 °C for 18 h, then filtered through
Celite (eluent EtOAc) and concentrated in vacuo. Purification via
column chromatography (gradient elution, 60% → 100% EtOAc in
30−40 °C petrol) gave 45 as a yellow oil (555 mg, 94%); [α]2D4 −31.1
(c 1.0 in CHCl3); vmax (ATR) 1633 (CO); δH (400 MHz, CDCl3)
1.55−1.64 (1H, m, C(7)HA), 1.77−1.88 (1H, m, C(7)HB), 2.28 (3H,
s, NMe), 2.52 (1H, ddd, J 15.4, 7.8, 3.0, C(6)HA), 2.58 (1H, dd, J 12.9,
3.3, C(3)HA), 2.98 (1H, ddd, J 15.4, 7.8, 3.0, C(6)HB), 3.19 (1H, app
t, J 12.1, C(3)HB), 3.33 (1H, dt, J 15.4, 3.8, C(8)HA), 3.68 (1H, dd, J
15.2, 6.8, CHAHBCHCH2), 3.79−3.86 (1H, m, C(8)HB), 4.03 (1H,
dd, J 11.6, 3.3, C(4)H), 4.45 (1H, dd, J 15.2, 5.3, CHAHBCHCH2),
5.16−5.24 (2H, m, CH2CHCH2), 5.79−5.89 (1H, m, CH2CH
CH2), 7.22−7.36 (5H, m, Ph); δC (100 MHz, CDCl3) 29.6 (C(7)),
41.1 (C(3)), 43.7 (NMe), 47.1 (C(8)), 48.5 (CH2CHCH2), 51.1
(C(6)), 68.1 (C(4)), 117.2 (CH2CHCH2), 127.1, 127.5, 128.3
(o,m,p-Ph), 133.9 (CH2CHCH2), 141.9 (i-Ph), 173.3 (C(2)); m/z
(ESI+) 539 ([2M + Na]+, 100%), 517 ([2M + H]+, 13%), 281 ([M +
Na]+, 96%) 259 ([M + H]+, 90%); HRMS (ESI+) C16H23N2O+ ([M +
H]+) requires 259.1805, found 259.1803.
(S,E)-1,4-Di[2′-oxo-4′-phenyl-N(5′)-methyl-1′,5′-diazocan-1′-
yl]but-2-ene 46 and (S,E)-1-(Prop-1′-en-1′-yl)-4-phenyl-N(5)-
methyl-1,5-diazocan-2-one 47. Grubbs II catalyst (75 mg, 88.6
μmol) was added to a degassed solution of 45 (229 mg, 886 μmol) in
CH2Cl2 (3 mL, EtOH stabilized), and the resultant mixture was heated
at 40 °C for 16 h. The reaction mixture was then concentrated in vacuo
to give a 78:22 mixture of 46 and 47. Purification via flash column
chromatography (gradient elution, 0% → 10% MeOH in CH2Cl2)
gave 47 as a brown oil (26 mg, 11%, >99:1 dr); [α]2D4 +14.4 (c 0.4 in
CHCl3); vmax (ATR) 1644 (CO); δH (400 MHz, CDCl3) 1.75 (3H,
dd, J 6.6, 1.5, C(3′)H3), 1.80−1.93 (2H, m, C(7)H2), 2.24 (3H, s,
NMe), 2.50 (1H, ddd, J 15.3, 8.3, 2.8, C(6)HA), 2.64 (1H, dd, J 13.1,
3.3, C(3)HA), 2.93 (1H, ddd, J 15.3, 6.8, 3.3, C(6)HB), 3.25 (1H, br t,
J 12.1, C(3)HB), 3.75 (1H, dt, J 15.4, 3.5, C(8)HA), 3.94−4.05 (2H, m,
C(4)H, C(8)HB), 5.11 (1H, dq, J 14.7, 6.6, C(2′)H), 7.19−7.37 (6H,
m, C(1′)H, Ph); δC (100 MHz, CDCl3) 15.5 (C(3′)), 28.6 (C(7)),
42.1 (C(3)), 43.8 (NMe), 44.3 (C(8)), 51.4 (C(6)), 68.9 (C(4)),
106.5 (C(2′)), 126.5, 127.5, 128.4 (o,m,p-Ph), 127.3 (C(1′)), 171.7
(C(2));48 m/z (ESI+) 539 ([2M + Na]+, 100%), 517 ([2M + H]+,
6%), 281 ([M + Na]+, 82%) 259 ([M + H]+, 71%); HRMS (ESI+)
C16H23N2O+ ([M + H]+) requires 259.1805, found 259.1805. Further
elution gave 46 as a brown oil (92 mg, 42%, >99:1 dr) [α]2D4 −29.2 (c
0.8 in CHCl3); vmax (ATR) 1631 (CO); δH (400 MHz, CDCl3)
1.55−1.68 (2H, m, 2 × C(7′)HA), 1.74−1.87 (2H, m, 2 × C(7′)HB),
2.27 (6H, s, 2 × NMe), 2.46−2.59 (4H, m, 2 × C(3′)HA, 2 × C(6′)
HA), 2.98 (2H, app ddd, J 15.2, 7.8, 2.8, 2 × C(6′)HB), 3.18 (2H, app
t, J 12.1, 2 × C(3′)HB), 3.31 (2H, app dt, J 15.4, 3.5, 2 × C(8′)HA),
3.68 (2H, dd, J 15.7, 3.3, C(1)HA, C(4)HA), 3.81 (2H, app t, J 13.4, 2
× C(8′)HB), 4.01 (2H, dd, J 11.6, 3.0, 2 × C(4′)H), 4.41 (2H, app d, J
13.4, C(1)HB, C(4)HB), 5.65 (2H, t, J 3.3, C(2)H, C(3)H), 7.23−7.35
(10H, m, Ph); δC (100 MHz, CDCl3) 29.6 (2 × C(7′)), 41.0 (2 ×
C(3′)), 43.7 (2 × NMe), 47.3 (2 × C(8′)), 47.4 (C(1), C(4)), 51.1 (2
× (C(6′)), 68.1 (2 × C(4′)), 127.2, 127.5, 128.3 (o,m,p-Ph), 128.5
(C(2), C(3)), 141.7 (i-Ph), 173.3 (2 × C(2′)); m/z (ESI+) 511 ([M +
Na]+, 69%), 489 ([M + H]+, 100%); HRMS (ESI+) C30H41N4O2+ ([M
+ H]+) requires 489.3224, found 489.3233.
+
100%); HRMS (ESI+) C13H1937ClNO2 ([M(37Cl) + H]+) requires
+
258.1069, found 256.1068; C13H1935ClNO2 ([M(35Cl) + H]+)
requires 256.1099, found 256.1096.
Method B: A mixture of 32 (958 mg, 2.66 mmol, >99:1 dr) and TFA
(9.6 mL) was heated at 60 °C for 2.5 h, then allowed to cool to rt, and
concentrated in vacuo. The residue was partitioned between EtOAc
(20 mL) and satd aq NaHCO3 (20 mL) and then the aqueous layer
was extracted with EtOAc (2 × 20 mL). The combined organic
extracts were washed with brine (30 mL), then dried, and
concentrated in vacuo. Purification via column chromatography
(eluent, 30−40 °C petrol/Et2O, 3:7) gave 41 as a yellow oil (581
mg, 92%); [α]2D4 −28.5 (c 1.0 in CHCl3).
Methyl (S)-3-[N-(3′-Chloropropyl)-N-methylamino]-3-phe-
nylpropanoate 42. Following General Procedure 8, 41 (675 mg,
2.64 mmol), (CH2O)n (159 mg, 5.28 mmol), and NaBH3CN (664 mg,
10.6 mmol) in MeOH (27 mL) were reacted. Purification via flash
column chromatography (gradient elution, 60% → 100% EtOAc in
30−40 °C petrol) gave 42 as a yellow oil (573 mg, 75%); [α]2D4 −5.3 (c
0.4 in CHCl3); vmax (ATR) 1737 (CO); δH (400 MHz, CDCl3)
1.85−1.93 (2H, m, C(2′)H2), 2.14 (3H, s, NMe), 2.38−2.45 (1H, m,
C(1′)HA), 2.49−2.55 (1H, m, C(1′)HB), 2.70 (1H, dd, J 14.8, 7.1,
C(2)HA), 3.00 (1H, dd, J 14.8, 8.3, C(2)HB), 3.57 (2H, t, J 6.3, C(3′)
H2), 3.64 (3H, s, OMe), 4.17 (1H, app t, J 7.8, C(3)H), 7.23−7.36
(5H, m, Ph); δC (100 MHz, CDCl3) 30.4 (C(2′)), 37.3 (NMe, C(2)),
42.9 (C(3′)), 50.7 (C(1′)), 51.6 (OMe), 64.5 (C(3)), 127.5, 128.1,
128.3 (o,m,p-Ph), 137.9 (i-Ph), 172.3 (C(1)); m/z (ESI+) 294
([M(37Cl) + Na]+, 11%), 292 ([M(35Cl) + Na]+, 31%), 272
([M(37Cl) + H]+, 53%), 270 ([M(35Cl) + H]+, 100%); HRMS
+
(ESI+) C14H2137ClNO2 ([M(37Cl) + H]+) requires 272.1226, found
272.1227; HRMS (ESI+) C14H2135ClNO2+ ([M(35Cl) + H]+) requires
270.1255, found 270.1250.
Methyl (S)-3-[N-(3′-Azidopropyl)-N-methylamino]-3-phenyl-
propanoate 43. Following General Procedure 2, NaN3 (1.21 g, 18.6
mmol), NaI (2.79 g, 18.6 mmol), and 42 (2.51 g, 9.31 mmol) in
DMSO (40 mL) were reacted for 24 h. Purification via flash column
chromatography (gradient elution, 10% → 50% Et2O in 30−40 °C
petrol) gave 43 as a yellow oil (2.57 g, quant); [α]2D4 −4.6 (c 1.0 in
CHCl3); vmax (ATR) 2096 (NN), 1739 (CO); δH (400 MHz,
CDCl3) 1.69−1.73 (2H, m, C(2′)H2), 2.14 (3H, s, NMe), 2.30−2.36
(1H, m, C(1′)HA), 2.41−2.48 (1H, m, C(1′)HB), 2.70 (1H, dd, J 14.9,
7.2, C(2)HA), 2.99 (1H, dd, J 14.9, 8.4, C(2)HB), 3.31 (2H, t, J 6.8,
C(3′)H2), 3.64 (3H, s, OMe), 4.16 (1H, app t, J 7.9, C(3)H), 7.21−
7.37 (5H, m, Ph); δC (100 MHz, CDCl3) 26.7 (C(2′)), 37.2 (C(2)),
37.3 (NMe), 49.2 (C(3′)), 50.7 (C(1′)), 51.6 (OMe), 64.3 (C(3)),
127.5, 128.1, 128.2 (o,m,p-Ph), 137.9 (i-Ph), 172.3 (C(1)); m/z (ESI+)
299 ([M + Na]+, 49%), 277 ([M + H]+, 100%); HRMS (ESI+)
+
C14H21N4O2 ([M + H]+) requires 277.1659, found 277.1654.
(S)-4-Phenyl-N(5)-methyl-1,5-diazocan-2-one 39. Step 1:
Following General Procedure 3, 43 (2.40 g, 8.69 mmol) and PPh3
(2.51 g, 9.55 mmol) in THF (25 mL) and H2O (7.2 mL) were reacted
to give 44 as a yellow oil (5.15 g);4,13 δH (400 MHz, CDCl3) [selected
peaks] 1.55−1.62 (2H, m, C(2′)H2), 2.15 (3H, s, NMe), 2.29−2.35
(1H, m, C(1′)HA), 2.39−2.46 (1H, m, C(1′)HB), 2.67−2.72 (3H, m,
C(2)HA, C(3′)H2), 3.00 (1H, app dd, J 14.9, 8.0, C(2)HB), 3.63 (3H,
s, OMe), 4.16 (1H, app t, J 7.9, C(3)H).
Step 2: Following General Procedure 5, 44 (5.15 g) and Sb(OEt)3
(1.49 mL, 8.77 mmol) in PhMe (750 mL) were reacted. Purification
via flash column chromatography (gradient elution, 0% → 10% MeOH
in EtOAc) gave 39 as a white solid (1.18 g, 62% over 2 steps); mp 97−
99 °C; [α]2D4 +6.7 (c 1.0 in CHCl3); {lit.47 for enantiomer [α]2D5 −6.2
(c 0.9 in CHCl3)}; δH (400 MHz, CDCl3) 1.54−1.64 (1H, m, C(7)
HA), 1.67−1.78 (1H, m, C(7)HB), 2.31 (3H, s, NMe), 2.46 (1H, dd, J
12.6, 3.8, C(3)HA), 2.53 (1H, ddd, J 15.4, 6.8, 2.8, C(6)HA), 2.99−
3.04 (1H, m, C(6)HB), 3.08 (1H, app t, J 12.1, C(3)HB), 3.24−3.34
(1H, m, C(8)HA), 3.46−3.57 (1H, m, C(8)HB), 4.05 (1H, dd, J 8.3,
3.5, C(4)H), 5.77 (1H, br s, NH), 7.21−7.35 (5H, m, Ph).
X-ray Crystal Structure Determination for 39.29 Data were
collected using graphite monochromated Cu Kα radiation using
standard procedures at 150 K. The structure was solved by direct
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Article
(S,S)-1,4-Di[2′-oxo-4′-phenyl-N(5′)-methyl-1′,5′-diazocan-
N(1′)-yl]butane [(−)-Homaline] 1. Method A: Formalin (2.71 mL)
was added to a stirred mixture of 36 (50 mg, 78.1 μmol, >99:1 dr) in
HCO2H (2.28 mL), and the resultant mixture was heated at reflux for
2.5 h and then allowed to cool to rt. Next 1.0 M aq NaOH was added
to the reaction mixture until pH >13 was achieved, and the aqueous
layer was extracted with CHCl3 (3 × 10 mL). The combined organic
extracts were then dried and concentrated in vacuo. Purification via
column chromatography (gradient elution, 0% → 13% MeOH in
Et2O) gave 1 as a white solid (15 mg, 39%, >99:1 dr); mp 113−116
°C; {lit.6 mp 132 °C (Et2O)}; [α]D24 −29.2 (c 1.0 in CHCl3); {lit.6
[α]2D0−34 (c 1.0 in CHCl3)}; vmax (film) 1630 (CO); δH (400 MHz,
CDCl3) 1.57−1.67 (6H, m, C(2)H2, C(3)H2, 2 × C(7′)HA), 1.76−
1.87 (2H, m, 2 × C(7′)HB), 2.26 (6H, s, 2 × NMe), 2.47−2.55 (4H,
m, 2 × C(3′)HA), 2 × C(6′)HA), 2.93−3.08 (4H, m, C(1)HA, C(4)
HA, 2 × C(6′)HB), 3.16 (2H, app t, J 12.1, 2 × C(3′)HB), 3.32 (2H,
app dt, J 15.4, 3.5, 2 × C(8′)HA), 3.77−3.90 (4H, m, C(1)HB, C(4)
HB, 2 × C(8′)HB), 4.00 (2H, dd, J 11.6, 3.0, 2 × C(4′)H), 7.23−7.34
(10H, m, Ph); δC (100 MHz, CDCl3) 25.4 (C(2), C(3)), 29.9 (2 ×
C(7′)), 41.2 (2 × C(3′)), 43.7 (2 × NMe), 45.7 (C(1), C(4)), 47.9 (2
× C(8′)), 51.0 (2 × C(6′)), 68.1 (2 × C(4′)), 127.1, 127.5, 128.3
(o,m,p-Ph), 142.0 (i-Ph), 173.5 (2 × C(2′)); m/z (ESI+) 982 ([2M +
H]+, 43%), 513 ([M + Na]+, 100%), 491 ([M + H]+, 96%); HRMS
(ESI+) C30H43N4O2+ ([M + H]+) requires 491.3381, found 491.3389.
Method B:7 Formalin (0.81 mL) was added to a solution of 37 (25
mg, 54 μmol, >99:1 dr) in AcOH (2.5 mL) at 0 °C, and the resultant
mixture was stirred for 15 min. NaBH3CN (65 mg, 1.03 mmol) in
MeOH (0.43 mL) was added, and the resultant mixture was allowed to
warm to rt over 3.5 h. The reaction mixture was cooled to 0 °C, 2.0 M
aq HCl (2 mL) was added, and the resultant mixture was concentrated
in vacuo. The residue was partitioned between CH2Cl2 (5 mL) and
satd aq Na2CO3 (5 mL), the aqueous layer was extracted with CH2Cl2
(2 × 5 mL), and the combined organic extracts were washed with
brine (10 mL), then dried, and concentrated in vacuo. Purification via
flash column chromatography (gradient elution, 0% → 4% MeOH in
CHCl3) gave (−)-homaline 1 as a white solid (8 mg, 30%, >99:1 dr);6
mp 115−117 °C; [α]2D1 −16.8 (c 0.4 in CHCl3).
Method C: Following General Procedure 7, 46 (57 mg, 117 μmol,
>99:1 dr) and Pd(OH)2/C in EtOAc (1 mL) were reacted for 2 h.
Purification via column chromatography (gradient elution, 1% → 10%
MeOH in Et2O) gave (−)-homaline 1 as a white solid (25 mg, 44%,
>99:1 dr); mp 122−124 °C; [α]2D4 −32.5 (c 1.0 in CHCl3).
Method D: Following General Procedure 6B, 39 (100 mg, 458
μmol), 1,4-dibromobutane (28 μL, 234 μmol), and KOH (103 mg,
1.84 mmol) in DMSO (0.92 mL) were reacted for 96 h. Purification
via column chromatography (gradient elution, 0% → 2.5% MeOH in
CH2Cl2) gave (−)-homaline 1 as a white solid (67 mg, 60%, >99:1
dr); mp 115−117 °C; [α]2D1 −28.1 (c 1.0 in CHCl3).
tert-Butyl (E)-Oct-2-enoate 48. MeMgBr (2.5 M in Et2O, 17.5
mL, 43.7 mmol) was added to a solution of tert-butyl diethylphos-
phonoacetate (10.7 mL, 45.7 mmol) in THF (300 mL) at rt, and the
resultant mixture was stirred for 15 min. Hexanal (5 mL, 41.6 mmol)
was then added, and the resulatant mixture was heated at reflux for 2.5
h. The reaction mixture was allowed to cool to rt and partitioned
between satd aq NH4Cl (100 mL) and Et2O (100 mL). The aqueous
layer was extracted with Et2O (2 × 100 mL), and the combined
organic extracts were washed with brine (200 mL), then dried, and
concentrated in vacuo to give 48 in >99:1 dr. Purification via flash
column chromatography (eluent 30−40 °C petrol) gave 48 as a
colorless oil (4.18 g, 51%, >99:1 dr);49 δH (400 MHz, CDCl3) 0.89
(3H, t, J 6.8, C(8)H3), 1.25−1.60 (6H, m, C(5)H2, C(6)H2, C(7)H2)
overlapping 1.49 (9H, s, CMe3), 2.17 (2H, app q, J 7.0, C(4)H2), 5.74
(1H, dt, J 15.7, 1.6, C(2)H), 6.87 (1H, dt, J 15.7, 7.0, C(3)H).
tert-Butyl (E)-Dec-2-enoate 49. MeMgBr (2.5 M in Et2O, 17.5
mL, 43.7 mmol) was added to a solution of tert-butyl diethylphos-
phonoacetate (10.7 mL, 45.7 mmol) in THF (300 mL) at rt, and the
resultant mixture was stirred for 15 min. Octanal (6.5 mL, 41.6 mmol)
was then added, and the resulatant mixture was heated at reflux for 2.5
h. The reaction mixture was allowed to cool to rt and partitioned
between satd aq NH4Cl (100 mL) and Et2O (100 mL). The aqueous
layer was extracted with Et2O (2 × 100 mL), and the combined
organic extracts were washed with brine (200 mL), then dried, and
concentrated in vacuo to give 49 in >99:1 dr. Purification via flash
column chromatography (eluent 30−40 °C petrol) gave 49 as a
colorless oil (3.57 g, 38%, >99:1 dr);50 δH (400 MHz, CDCl3) 0.89
(3H, t, J 6.8, C(10)H3), 1.22−1.48 (10H, m, C(5)H2, C(6)H2, C(7)
H2, C(8)H2, C(9)H2), 1.49 (9H, s, CMe3), 2.17 (2H, app q, J 7.2,
C(4)H2), 5.74 (1H, dt, J 15.6, 1.5, C(2)H), 6.87 (1H, dt, J 15.6, 6.8,
C(3)H).
tert-Butyl (R,R)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)-
amino]octanoate 50. Following General Procedure 1, (R)-N-(3′-
chloropropyl)-N-(α-methylbenzyl)amine (6.67 g, 33.7 mmol), BuLi
(2.5 M, 13.1 mL, 32.7 mmol), and 48 (4.18 g, 21.1 mmol) in THF
(300 mL) were reacted to give 50 in >99:1 dr. Purification via flash
column chromatography (eluent 30−40 °C petrol/Et2O, 19:1) gave
50 as a yellow oil (6.75 g, 81%, >99:1 dr); [α]2D4 −13.6 (c 1.0 in
CHCl3); vmax (film) 1726 (CO); δH (400 MHz, CDCl3) 0.89 (3H, t,
J 7.3, C(8)H3), 1.17−1.35 (7H, m, C(4)HA, C(5)H2, C(6)H2, C(7)
H2), 1.40−1.48 (13H, m, CMe3, C(4)HB, C(α)Me), 1.85 (2H, app
quintet, J 6.6, C(2′)H2), 2.00 (1H, dd, J 14.7, 7.8, C(2)HA), 2.06 (1H,
dd, J 14.7, 5.3, C(2)HB), 2.55−2.68 (2H, m, C(1′)H2), 3.17−3.24
(1H, m, C(3)H), 3.50 (2H, td, J 6.3, 1.0, C(3′)H2), 3.87 (1H, q, J 6.8,
C(α)H), 7.19−7.25 (1H, m, Ph), 7.26−7.34 (4H, m, Ph); δC (100
MHz, CDCl3) 14.1 (C(8)), 20.6 (C(α)Me), 22.7, 26.6, 31.9, 32.6
(C(4), C(5), C(6), C(7)), 28.0 (CMe3), 33.1 (C(2′)), 38.1 (C(2)),
42.9 (C(1′)), 43.3 (C(3′)), 55.3 (C(3)), 58.7 (C(α)), 79.9 (CMe3),
126.8, 127.7, 128.1 (o,m,p-Ph), 144.5 (i-Ph), 172.3 (C(1)); m/z (ESI+)
420 ([M(37Cl) + Na]+, 67%), 418 ([M(35Cl) + Na]+, 100%), 398
([M(37Cl) + H]+, 77%), 396 ([M(35Cl) + H]+, 72%); HRMS (ESI+)
+
C23H3937ClNO2 ([M(37Cl) + H]+) requires 398.2634, found
398.2626; HRMS (ESI+) C23H3935ClNO2+ ([M(35Cl) + H]+) requires
396.2664, found 396.2664.
tert-Butyl (R,R)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)-
amino]decanoate 51. Following General Procedure 1, (R)-N-(3′-
chloropropyl)-N-(α-methylbenzyl)amine (4.99 g, 25.2 mmol), BuLi
(2.5 M, 9.72 mL, 24.3 mmol), and 49 (3.57 g, 15.7 mmol) in THF
(230 mL) were reacted to give 51 in >99:1 dr. Purification via flash
column chromatography (eluent 30−40 °C petrol/Et2O, 19:1) gave
51 as a yellow oil (4.85 g, 73%, >99:1 dr); [α]2D4 −13.6 (c 1.0 in
CHCl3); vmax (ATR) 1727 (CO); δH (400 MHz, CDCl3) 0.90 (3H,
t, J 6.6, C(10)H3), 1.20−1.35 (12H, m, C(4)H2, C(5)H2, C(6)H2,
C(7)H2, C(8)H2, C(9)H2), 1.40−1.44 (12H, m, CMe3, C(α)Me), 1.85
(2H, app quintet, J 6.6, C(2′)H2), 2.00 (1H, dd, J 14.6, 8.1, C(2)HA),
2.06 (1H, dd, J 14.6, 5.3, C(2)HB), 2.55−2.68 (2H, m, C(1′)H2),
3.17−3.24 (1H, m, C(3)H), 3.49 (2H, app td, J 8.6, 1.2, C(3′)H2),
3.87 (1H, q, J 7.1, C(α)H), 7.20−7.24 (1H, m, Ph), 7.26−7.34 (4H,
m, Ph); δC (100 MHz, CDCl3) 14.1 (C(10)), 20.6 (C(α)Me), 22.7,
27.0, 29.3, 29.6, 31.9, 32.6 (C(4), C(5), C(6), C(7), C(8), C(9)), 28.0
(CMe3), 33.1 (C(2′)), 38.1 (C(2)), 42.9 (C(1′)), 43.3 (C(3′)), 55.3
(C(3)), 58.7 (C(α)), 79.9 (CMe3), 126.8, 127.7, 128.1 (o,m,p-Ph),
144.5 (i-Ph), 172.2 (C(1)); m/z (ESI+) 448 ([M(37Cl) + Na]+, 12%),
446 ([M(35Cl) + Na]+, 34%), 426 ([M(37Cl) + H]+, 91%), 424
+
([M(35Cl) + H]+, 100%); HRMS (ESI+) C25H4337ClNO2 ([M(37Cl)
+
+ H]+) requires 426.2947, found 426.2951; C25H4335ClNO2 ([M-
(35Cl) + H]+) requires 424.2977, found 424.2969.
Methyl (R,R)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)-
amino]octanoate 52. Following General Procedure 4, 50 (1.00 g,
2.53 mmol, >99:1 dr) in MeOH (7.5 mL) and SOCl2 (0.25 mL, 3.45
mmol) in MeOH (7.5 mL) were reacted. Purification via flash column
chromatography (gradient elution, 0% → 6% Et2O in 30−40 °C
petrol) gave 52 as a yellow oil (717 mg, 80%, >99:1 dr); [α]2D4 −12.3
(c 1.0 in CHCl3); vmax (film) 1737 (CO); δH (400 MHz, CDCl3)
0.90 (3H, t, J 7.3, C(8)H3), 1.20−1.53 (8H, m, C(4)H2, C(5)H2, C(6)
H2, C(7)H2) overlapping 1.41 (3H, d, J 6.8, C(α)Me), 1.86 (2H, app
quintet, J 6.6, C(2′)H2), 2.10−2.19 (2H, m, C(2)H2), 2.59−2.72 (2H,
m, C(1′)H2), 3.23 (1H, app quintet, J 6.6, C(3)H), 3.51 (2H, t, J 6.1,
C(3′)H2), 3.57 (3H, s, OMe), 3.90 (1H, q, J 6.8, C(α)H), 7.20−7.26
(1H, m, Ph), 7.27−7.32 (4H, m, Ph); δC (100 MHz, CDCl3) 14.1
(C(8)), 20.0 (C(α)Me), 22.7, 26.8, 31.9, 32.8 (C(4), C(5), C(6),
C(7)), 32.9 (C(2′)), 37.0 (C(2)), 42.8 (C(1′)), 43.3 (C(3′)), 51.3
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The Journal of Organic Chemistry
Article
(OMe), 55.4 (C(3)), 58.3 (C(α)), 126.8, 127.7, 128.1 (o,m,p-Ph),
144.4 (i-Ph), 173.3 (C(1)); m/z (ESI+) 378 ([M(37Cl) + Na]+, 22%),
376 ([M(35Cl) + Na]+, 64%), 356 ([M(37Cl) + H]+, 59%), 354
MHz, CDCl3) 0.89 (3H, t, J 7.2, C(8)H3), 1.18−1.54 (8H, m, C(4)H2,
C(5)H2, C(6)H2, C(7)H2) overlapping 1.40 (3H, d, J 6.9, C(α)Me),
1.60 (2H, app quintet, J 6.8, C(2′)H2), 2.15 (2H, app dd, J 6.3, 2.1,
C(2)H2), 2.54 (2H, app q, J 7.7, C(3′)H2), 2.66 (2H, app td, J 7.0, 3.8,
C(1′)H2), 3.22 (1H, app quintet, J 6.7, C(3)H), 3.56 (3H, s, OMe),
3.93 (1H, q, J 6.9, C(α)H), 7.19−7.25 (1H, m, Ph), 7.28−7.33 (4H,
m, Ph); δC (100 MHz, CDCl3) 14.0 (C(8)), 19.7 (C(α)Me), 22.6,
26.7, 31.9, 32.8, 33.5 (C(4), C(5), C(6), C(7), C(2′)), 37.0 (C(2)),
40.0 (C(1′)), 42.9 (C(3′)), 51.3 (C(3)), 55.2 (OMe), 57.9 (C(α)),
126.6, 127.7, 128.0 (o,m,p-Ph), 144.6 (i-Ph), 173.4 (C(1)); m/z (ESI+)
+
([M(35Cl) + H]+, 100%); HRMS (ESI+) C20H3337ClNO2 ([M(37Cl)
+
+ H]+) requires 356.2165, found 356.2173; C20H3335ClNO2 ([M-
(35Cl) + H]+) requires 354.2194, found 354.2196.
Methyl (R,R)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)-
amino]decanoate 53. Following General Procedure 4, 51 (1.00 g,
2.36 mmol, >99:1 dr) in MeOH (7.5 mL) and SOCl2 (0.25 mL, 3.45
mmol) in MeOH (7.5 mL) were reacted. Purification via flash column
chromatography (gradient elution, 0% → 6% Et2O in 30−40 °C
petrol) gave 53 as a yellow oil (550 mg, 61%, >99:1 dr); [α]2D4 −15.8
(c 1.0 in CHCl3); vmax (film) 1737 (CO); δH (400 MHz, CDCl3)
0.90 (3H, t, J 6.8, C(10)H3), 1.21−1.63 (12H, m, C(4)H2, C(5)H2,
C(6)H2, C(7)H2, C(8)H2, C(9)H2), 1.41 (3H, d, J 7.0, C(α)Me), 1.86
(2H, app quintet, J 6.6, C(2′)H2), 2.09−2.19 (2H, m, C(2)H2), 2.58−
2.72 (2H, m, C(1′)H2), 3.23 (1H, app quintet, J 6.8, C(3)H), 3.51
(2H, t, J 6.3, C(3′)H2), 3.57 (3H, s, OMe), 3.89 (1H, q, J 7.0, C(α)H),
7.20−7.25 (1H, m, Ph), 7.29−7.30 (4H, m, Ph); δC (100 MHz,
CDCl3) 14.1 (C(10)), 20.0 (C(α)Me), 22.7, 29.2, 29.3, 29.6, 31.9, 32.8
(C(4), C(5), C(6), C(7), C(8), C(9)), 32.9 (C(2′)), 37.0 (C(2)), 42.8
(C(1′)), 43.3 (C(3′)), 51.3 (OMe), 55.4 (C(3)), 58.3 (C(α)), 126.8,
127.7, 128.1 (o,m,p-Ph), 144.4 (i-Ph), 173.3 (C(1)); m/z (ESI+) 406
([M(37Cl) + Na]+, 14%), 404 ([M(35Cl) + Na]+, 37%), 384 ([M(37Cl)
+ H]+, 61%), 382 ([M(35Cl) + H]+, 100%); HRMS (ESI+)
+
335 ([M + H]+, 100%); HRMS (ESI+) C20H35N2O2 ([M + H]+)
requires 335.2693, found 335.2692.
Step 2: Following General Procedure 5, 56 (158 mg, >99:1 dr) and
Sb(OEt)3 (57 μL, 333 μmol) in PhMe (20 mL) were reacted.
Purification via flash column chromatography (gradient elution, 10%
→ 100% EtOAc in 30−40 °C petrol) gave 58 as a colorless oil (82 mg,
98% over 2 steps, >99:1 dr); C19H30N2O requires C, 75.45; H, 10.0;
N, 9.3%, found C, 75.55; H, 10.0; N, 9.25%; [α]2D4 +3.7 (c 1.0 in
CHCl3); vmax (film) 1661 (CO); δH (400 MHz, CDCl3) 0.86 (3H, t,
J 6.8, C(5′)H3), 0.97−1.06 (1H, m, C(7)HA), 1.12−1.54 (9H, m, C(7)
HB, C(1′)H2, C(2′)H2, C(3′)H2, C(4′)H2) overlapping 1.27 (3H, d, J
6.4, C(α)Me), 2.43 (2H, d, J 7.1, C(3)H2), 2.46−2.55 (1H, m, C(6)
HA), 2.81 (1H, br t, J 12.9, C(6)HB), 3.20 (2H, br s, C(8)H2), 3.44
(1H, br s, C(4)H), 3.74 (1H, q, J 6.4, C(α)H), 6.83 (1H, br s, NH),
7.12−7.16 (1H, m, Ph), 7.22 (2H, app t, J 7.8, Ph), 7.29−7.33 (2H, m,
Ph); δC (100 MHz, CDCl3) 14.0 (C(5′)), 21.9 (C(α)Me), 22.6, 26.5,
28.2 (C(2′), C(3′), C(4′)), 32.1 (C(7)), 32.4 (C(1′)), 37.9 (C(3)),
42.6 (C(8)), 45.9 (C(6)), 56.5 (C(4)), 62.6 (C(α)), 126.8, 128.0
(o,m,p-Ph), 146.5 (i-Ph), 177.1 (C(2)); m/z (ESI+) 930 ([3M + Na]+,
36%), 627 ([2M + Na]+, 100%), 325 ([M + Na]+, 23%), 303 ([M +
H]+, 34%); HRMS (ESI+) C19H31N2O+ ([M + H]+) requires
303.2431, found 303.2435.
+
C22H3737ClNO2 ([M(37Cl) + H]+) requires 384.2478, found
+
384.2494; C22H3735ClNO2 ([M(35Cl) + H]+) requires 382.2507,
found 382.2506.
Methyl (R,R)-3-[N-(3′-Azidopropyl)-N-(α-methylbenzyl)-
amino]octanoate 54. Following General Procedure 2, NaN3 (367
mg, 5.65 mmol, >99:1 dr), NaI (847 mg, 5.65 mmol), and 52 (1.00 g,
2.83 mmol) in DMSO (6 mL) were reacted for 24 h. Purification via
flash column chromatography (eluent 30−40 °C petrol/Et2O, 30:1)
gave 54 as a yellow oil (959 mg, 94%, >99:1 dr); [α]2D5 −22.3 (c 1.0 in
CHCl3); vmax (film) 2096 (NN), 1737 (CO); δH (400 MHz,
CDCl3) 0.90 (3H, t, J 7.3, C(8)H3), 1.20−1.55 (8H, m, C(4)H2, C(5)
H2, C(6)H2, C(7)H2) overlapping 1.40 (3H, d, J 6.8, C(α)Me), 1.60−
1.72 (2H, m, C(2′)H2), 2.11−2.21 (2H, m, C(2)H2), 2.52−2.63 (2H,
m, C(1′)H2), 3.20−3.27 (3H, m, C(3)H, C(3′)H2), 3.58 (3H, s,
OMe), 3.89 (3H, q, J 6.8, C(α)H), 7.20−7.26 (1H, m, Ph), 7.28−7.30
(4H, m, Ph); δC (100 MHz, CDCl3) 14.1 (C(8)), 19.9 (C(α)Me),
22.7, 26.8, 31.9, 32.7 (C(4), C(5), C(6), C(7)), 29.2 (C(2′)), 37.0
(C(2)), 42.8 (C(1′)), 49.4 (C(3′)), 51.3 (OMe), 55.4 (C(3)), 58.3
(C(α)), 126.8, 127.7, 128.1 (o,m,p-Ph), 144.6 (i-Ph), 173.3 (C(1)); m/
z (ESI+) 383 ([M + Na]+, 28%), 361 ([M + H]+, 100%); HRMS
(ESI+) C20H33N4O2+ ([M + H]+) requires 361.2598, found 361.2597.
Methyl (R,R)-3-[(3′-Azidopropyl)(α-methylbenzyl)amino]-
decanoate 55. Following General Procedure 2, NaN3 (367 mg,
5.65 mmol), NaI (847 mg, 5.65 mmol) and 53 (1.08 g, 2.83 mmol,
>99:1 dr) in DMSO (6 mL) were reacted for 24 h. Purification via
flash column chromatography (eluent 30−40 °C petrol/Et2O, 30:1)
gave 55 as a yellow oil (958 mg, 87%, >99:1 dr); C22H36N4O2 requires
C, 68.0; H, 9.3; N, 14.4%, found C, 68.1; H, 9.1; N, 14.3%; [α]D24
−20.9 (c 1.0 in CHCl3); vmax (film) 2096 (NN), 1737 (CO); δH
(400 MHz, CDCl3) 0.90 (3H, t, J 7.1, C(10)H3), 1.22−1.53 (12H, m,
C(4)H2, C(5)H2, C(6)H2, C(7)H2, C(8)H2, C(9)H2) overlapping
1.40 (3H, d, J 6.8, C(α)Me), 1.61−1.69 (2H, m, C(2′)H2), 2.11−2.21
(2H, m, C(2)H2), 2.53−2.61 (2H, m, C(1′)H2), 3.20−3.26 (3H, m,
C(3)H, C(3′)H2), 3.58 (3H, s, OMe), 3.89 (1H, q, J 6.8, C(α)H),
7.20−7.26 (1H, m, Ph), 7.28−7.31 (4H, m, Ph); δC (100 MHz,
CDCl3) 14.1 (C(10)), 19.8 (C(α)Me), 22.7, 27.1, 29.3, 29.7, 31.9, 32.7
(C(4), C(5), C(6), C(7), C(8), C(9)), 29.2 (C(2′)), 37.1 (C(2)), 42.8
(C(1′)), 49.4 (C(3′)), 51.3 (OMe), 55.4 (C(3)), 58.3 (C(α)), 126.8,
127.7, 128.1 (o,m,p-Ph), 144.6 (i-Ph), 173.3 (C(1)); m/z (ESI+) 411
([M + Na]+, 15%), 389 ([M + H]+, 100%); HRMS (ESI+)
X-ray Crystal Structure Determination for 58·HCl.36 Data were
collected using 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
idealized positions. The structure was refined using CRYSTALS.46 X-
ray crystal structure data for 58·HCl [C19H31ClN2O]: M = 338.92,
triclinic, space group P1, a = 7.2921(4) Å, b = 7.3234(4) Å, c =
9.7967(6) Å, α = 102.695(3)°, β = 94.987(3)°, γ = 109.832(2)°, V =
472.62(5) Å3, Z = 1, μ = 0.209 mm−1, colorless block, crystal
dimensions =0.10 × 0.16 × 0.18 mm3. A total of 3477 unique
reflections were measured for 5 < θ < 27, and 3477 reflections were
used in the refinement. The final parameters were wR2 = 0.074 and R1
= 0.032 [I > −3.0σ(I)], with Flack enantiopole = 0.03(4).30
(R,R)-4-Heptyl-N(5)-(α-methylbenzyl)-1,5-diazocan-2-one
59. Step 1: Following General Procedure 3, 55 (7.66 g, 19.7 mmol,
>99:1 dr) and PBu3 (5.42 mL, 21.7 mmol) in THF (75 mL) and H2O
(22 mL) were reacted to give 57 as a yellow oil (11.2 g, >99:1 dr); δH
(400 MHz, CDCl3) 0.85 (3H, t, J 7.1, C(10)H2), 1.18−1.68 (14H, m,
C(4)H2, C(5)H2, C(6)H2, C(7)H2, C(8)H2, C(9)H2, C(2′)H2)
overlapping 1.39 (3H, d, J 7.2, C(α)Me), 2.11 (2H, app t, J 6.8,
C(2)H2), 2.49 (2H, app q, J 7.3, C(3′)H2), 2.61 (2H, td, J 7.1, 1.5,
C(1′)H2), 3.18 (1H, app quintet, J 6.6, C(3)H), 3.52 (3H, s, OMe),
3.88 (1H, q, J 7.2, C(α)H), 7.14−7.30 (5H, m, Ph); δC (100 MHz,
CDCl3) 14.1 (C(10)), 19.6 (C(α)Me), 22.6, 25.8, 29.2, 29.6, 31.8,
32.8, 33.4 (C(4), C(5), C(6), C(7), C(8), C(9), C(2′)), 37.0 (C(2)),
40.0 (C(1′)), 42.9 (C(3′)), 51.3 (C(3)), 55.2 (OMe), 57.9 (C(α)),
126.7, 127.7, 128.0 (o,m,p-Ph), 144.6 (i-Ph), 173.4 (C(1)); m/z (ESI+)
+
363 ([M + H]+, 100%); HRMS (ESI+) C22H39N2O2 ([M + H]+)
requires 363.3006, found 363.3006.
Step 2: Following General Procedure 5, 57 (11.2 g, >99:1 dr) and
Sb(OEt)3 (4.02 mL, 23.7 mmol) in PhMe (2.00 L) were reacted.
Purification via flash column chromatography (gradient elution, 60%
→ 100% EtOAc in 30−40 °C petrol) gave 59 as a white solid (3.38 g,
52% over 2 steps, >99:1 dr); mp 47−49 °C; [α]2D4 +3.3 (c 1.0 in
CHCl3); vmax (ATR) 1658 (CO); δH (400 MHz, CDCl3) 0.87 (3H,
t, J 7.1, C(7′)H3), 0.99−1.07 (1H, m, C(7)HA), 1.12−1.54 (13H, m,
C(7)HB, C(1′)H2, C(2′)H2, C(3′)H2, C(4′)H2, C(5′)H2, C(6′)H2)
+
C22H37N4O2 ([M + H]+) requires 389.2911, found 389.2914.
(R,R)-4-Pentyl-N(5)-(α-methylbenzyl)-1,5-diazocan-2-one 58.
Step 1: Following General Procedure 3, 54 (100 mg, 277 μmol, >99:1
dr) and PBu3 (74 μL, 297 μmol) in THF (1 mL) and H2O (0.3 mL)
were reacted to give 56 as a yellow oil (158 mg, >99:1 dr); δH (400
7041
dx.doi.org/10.1021/jo3012732 | J. Org. Chem. 2012, 77, 7028−7045

The Journal of Organic Chemistry
Article
overlapping 1.29 (3H, d, J 6.6, C(α)Me), 2.45 (2H, d, J 7.3, C(3)H2),
2.52 (1H, dt, J 15.4, 3.0, C(6)HA), 2.79−2.82 (1H, m, C(6)HB), 3.22
(2H, br s, C(8)H2), 3.45 (1H, br s, C(4)H), 3.75 (1H, q, J 6.6, C(α)
H), 6.60 (1H, t, J 7.1, NH), 7.15−7.18 (1H, m, Ph), 7.22−7.26 (2H,
m, Ph), 7.32−7.34 (2H, m, Ph); δC (100 MHz, CDCl3) 14.1 (C(7′)),
21.9 (C(α)Me), 22.6, 26.9, 28.3, 29.3, 30.0, 31.8, 32.4 (C(7), C(1′),
C(2′), C(3′), C(4′), C(5′), C(6′)), 37.9 (C(3)), 42.6 (C(8)), 45.9
(C(6)), 56.5 (C(4)), 62.7 (C(α)), 126.8, 128.0, 128.1 (o,m,p-Ph),
146.5 (i-Ph), 177.0 (C(2)); m/z (ESI+) 683 ([2M + Na]+, 100%), 353
([M + Na]+, 25%), 331 ([M + H]+, 49%); HRMS (ESI+) C21H35N2O+
([M + H]+) requires 331.2744, found 331.2742.
(R)-4-Pentyl-1,5-diazocan-2-one 60. Following General Proce-
dure 7, 58 (200 mg, 661 μmol, >99:1 dr) and Pd(OH)2/C (100 mg)
in MeOH (3 mL) were reacted for 24 h to give 60 as a colorless oil
(125 mg, 95%);16 [α]D24 +39.3 (c 1.0 in CHCl3); δH (400 MHz,
CDCl3) 0.75 (3H, t, J 6.9, C(5′)H3), 1.11−1.27 (6H, m, C(2′)H2,
C(3′)H2, C(4′)H2), 1.34−1.40 (2H, m, C(1′)H2), 1.47−1.59 (2H, m,
C(7)H2), 2.25 (1H, app d, J 12.3, C(3)HA), 2.32−2.43 (2H, m, C(3)
HB, C(6)HA), 2.79−2.85 (1H, m, C(4)H), 3.01 (1H, dt, J 14.8, 4.1,
C(6)HB), 3.10−3.17 (1H, m, C(8)HA), 3.40−3.53 (2H, m, C(8)HB,
N(5)H), 7.06 (1H, br s, N(1)H).
(R)-4-Heptyl-1,5-diazocan-2-one 61. Following General Proce-
dure 7, 59 (100 mg, 303 μmol, >99:1 dr) and Pd(OH)2/C (50 mg) in
MeOH (3.0 mL) were reacted for 24 h to give 61 as a colorless oil (69
mg, quant);16 [α]D24 +34.7 (c 1.0 in CHCl3); δH (400 MHz, CDCl3)
0.83 (3H, t, J 6.7, C(7′)H3), 1.16−1.35 (10H, m, C(2′)H2, C(3′)H2,
C(4′)H2, C(5′)H2, C(6′)H2), 1.39−1.47 (2H, m, C(1′)H2), 1.49−
1.67 (2H, m, C(7)H2), 2.29−2.57 (4H, m, C(3)H2, N(5)H, C(6)HA),
2.83−2.92 (1H, m, C(4)H), 3.08 (1H, dt, J 14.9, 4.0, C(6)HB), 3.15−
3.25 (1H, m, C(8)HA), 3.50−3.61 (1H, m, C(8)HB), 6.64 (1H, br s,
N(1)H).
(R)-4-Pentyl-N(5)-methyl-1,5-diazocan-2-one 62. Method A:
Following General Procedure 7, 58 (100 mg, 331 μmol, >99:1 dr),
(CH2O)n (20 mg, 666 μmol) and Pd(OH)2/C (50 mg) in MeOH
(1.3 mL) were reacted for 72 h to give 62 as a colorless oil (71 mg,
quant);16 [α]D24 −0.3 (c 1.0 in CHCl3); δH (400 MHz, CDCl3) 0.89
(3H, t, J 6.8, C(5′)H3), 1.26−1.41 (7H, m, C(1′)HA, C(2′)H2, C(3′)
H2, C(4′)H2), 1.47−1.60 (2H, m, C(7)HA, C(1′)HB), 1.68−1.80 (1H,
m, C(7)HB), 2.43 (2H, d, J 7.2, C(3)H2), 2.46 (3H, s, NMe), 2.54
(1H, app dt, J 15.4, 4.3, C(6)HA), 2.90−3.04 (2H, m, C(4)H, C(6)
HB), 3.29−3.33 (2H, m, C(8)H2), 5.60 (1H, br s, NH).
Method B: Following General Procedure 8, 60 (965 mg, 4.87
mmol), (CH2O)n (231 mg, 7.69 mmol) and NaBH3CN (970 mg, 29.5
mmol) in MeOH (40 mL) were reacted. Purification via flash column
chromatography (gradient elution, 0% → 5% MeOH in CH2Cl2) gave
62 as a colorless oil (373 mg, 36%); [α]2D4 −0.5 (c 1.0 in CHCl3).
(R)-4-Heptyl-5-methyl-1,5-diazocan-2-one 63. Method A:
Following General Procedure 7, 59 (109 mg, 331 μmol, >99:1 dr),
(CH2O)n (20 mg, 666 μmol), and Pd(OH)2/C (50 mg) in MeOH
(1.3 mL) were reacted for 72 h to give 63 as a colorless oil (78 mg,
98%);16 [α]D24 −0.5 (c 1.0 in CHCl3); δH (400 MHz, CDCl3) 0.89
(3H, t, J 7.3,C(7′)H3), 1.22−1.41 (11H, m, C(1′)HA, C(2′)H2, C(3′)
H2, C(4′)H2, C(5′)H2, C(6′)H2), 1.47−1.67 (2H, m, C(1′)HB, C(7)
HA), 1.68−1.79 (1H, m, C(7)HB), 2.42 (2H, d, J 7.0, C(3)H2), 2.46
(3H, s, NMe), 2.54 (1H, dt, J 15.2, 4.1, C(6)HA), 2.90−3.04 (2H, m,
C(4)H, C(6)HB), 3.28−3.34 (2H, m, C(8)H2), 6.54 (1H, br s, NH).
Method B: Following General Procedure 8, 61 (989 mg, 4.37
mmol), (CH2O)n (231 mg, 7.69 mmol) and NaBH3CN (970 mg, 29.5
mmol) in MeOH (40 mL) were reacted. Purification via flash column
chromatography (gradient elution, 0% → 5% MeOH in CH2Cl2) gave
63 as a colorless oil (875 mg, 83%); [α]2D4 −0.4 (c 1.0 in CHCl3).
(R,R)-N(1)-(4′-Bromobutyl)-4-pentyl-N(5)-(α-methylbenzyl)-
1,5-diazocan-2-one 64. Following General Procedure 6A, 58 (150
mg, 496 μmol, >99:1 dr), 1,4-dibromobutane (0.18 mL, 1.48 mmol),
K2CO3 (83 mg, 600 μmol), KOH (111 mg, 1.97 mmol), and TEBAC
(14 mg, 61.8 μmol) in DMSO (1.0 mL) were reacted for 24 h.
Purification via flash column chromatography (gradient elution, 20%
→ 50% Et2O in 30−40 °C petrol) gave 64 as a yellow oil (143 mg,
66%, >99:1 dr); [α]D24 −16.5 (c 1.0 in CHCl3); vmax (ATR) 1636 (C
O); δH (500 MHz, PhMe-d8, 363 K) 0.81−0.91 (1H, m, C(7)HA),
0.92 (3H, t, J 7.3, C(5′′)H3), 1.11−1.20 (1H, m, C(7)HB), 1.24−1.61
(8H, m, C(1′′)H2, C(2′′)H2, C(3′′)H2, C(4′′)H2), 1.27 (3H, d, J 6.5,
C(α)Me), 1.53 (2H, app quintet, J 7.6, C(2′)H2), 1.67 (2H, app
quintet, J 7.6, C(3′)H2), 2.34 (1H, dd, J 12.3, 8.8, C(3)HA), 2.41−2.52
(2H, m, C(3)HB, C(6)HA), 2.57−2.67 (1H, m, C(6)HB), 2.97−3.15
(3H, m, C(8)H2, C(1′)HA), 3.15 (2H, t, J 6.9, C(4′)H2), 3.32−3.48
(2H, m, C(4)H, C(1′)HB), 3.71 (1H, q, J 6.5, C(α)H), 7.06−7.12
(1H, m, Ph), 7.18 (2H, app t, J 7.6, Ph), 7.23−7.29 (2H, m, Ph); δC
(125 MHz, PhMe-d8, 363 K) 13.9 (C(5′′)), 21.3 (C(α)Me), 22.9,
26.9, 27.2, 29.3, 30.7, 32.5 (C(7), C(2′), C(3′), C(2′′), C(3′′), C(4′′)),
30.5 (C(1′′)), 33.0 (C(4′)), 39.3 (C(3)), 45.0 (C(1′), C(6)), 47.8
(C(8)), 57.5 (C(4)), 62.8 (C(α)), 127.1, 128.2 (o,m,p-Ph), 146.8 (i-
Ph), 172.4 (C(2)); m/z (ESI+) 461 ([M(81Br) + Na]+, 83%), 459
([M(79Br) + Na]+, 82%), 439 ([M(81Br) + H]+, 100%), 437
([M(79Br) + H]+, 93%); HRMS (ESI+) C23H3881BrN2O+ ([M(81Br)
+ H]+) requires 439.2142, found 439.2155; C23H3879BrN2O+ ([M-
(79Br) + H]+) requires 437.2162, found 437.2174.
(R,R)-1-(4′-Bromobutyl)-4-heptyl-5-(α-methylbenzyl)-1,5-di-
azocan-2-one 66. Following General Procedure 6A, 59 (233 mg,
706 μmol, >99:1 dr), 1,4-dibromobutane (0.25 mL, 2.12 mmol),
K2CO3 (118 mg, 854 μmol), KOH (158 mg, 2.81 mmol), and TEBAC
(20 mg, 88.0 μmol) in DMSO (2.0 mL) were reacted for 24 h.
Purification via flash column chromatography (gradient elution, 25%
→ 60% Et2O in 30−40 °C petrol) gave 66 as a yellow oil (101 mg,
31%, >99:1 dr); [α]D24 −11.1 (c 1.0 in CHCl3); vmax (ATR) 1628 (C
O); δH (500 MHz, PhMe-d8, 363 K) 0.83−0.90 (1H, m, C(7)HA),
0.92 (3H, t, J 7.3, C(7′′)H3), 1.12−1.22 (1H, m, C(7)HB), 1.23−1.48
(12H, m, C(1′′)H2, C(2′′)H2, C(3′′)H2, C(4′′)H2, C(5′′)H2, C(6′′)
H2), 1.27 (3H, d, J 6.6, C(α)Me), 1.53 (2H, app quintet, J 7.6, C(2′)
H2), 1.66 (2H, app quintet, J 7.6, C(3′)H2), 2.35 (1H, dd, J 12.3, 8.8,
C(3)HA), 2.43−2.52 (2H, m, C(3)HB, C(6)HA), 2.63 (1H, app dt, J
12.6, 2.5, C(6)HB), 2.98−3.14 (2H, m, C(8)H2, C(1′)HA), 3.15 (2H,
t, J 6.6, C(4′)H2), 3.33−3.47 (2H, m, C(4)H, C(1′)HB), 3.72 (1H, q, J
6.6, C(α)H), 7.07−7.12 (1H, m, Ph), 7.18 (2H, t, J 7.6, Ph), 7.24−7.29
(2H, m, Ph); δC (125 MHz, PhMe-d8, 363 K) 14.0 (C(7′′)), 21.3
(C(α)Me), 22.9, 27.2, 27.3, 29.4, 29.6, 30.3, 30.5, 30.7, 32.2 (C(7),
C(2′), C(3′), C(1′′), C(2′′), C(3′′), C(4′′), C(5′′), C(6′′)), 33.0
(C(4′)), 39.3 (C(3)), 45.0 (C(1′), C(6)), 47.8 (C(8)), 57.5 (C(4)),
62.8 (C(α)), 127.1, 128.3 (o,m,p-Ph), 146.8 (i-Ph), 172.3 (C(2)); m/z
(ESI+) 489 ([M(81Br) + Na]+, 40%), 487 ([M(79Br) + Na]+, 47%),
467 ([M(81Br) + H]+, 100%), 465 ([M(79Br) + H]+, 95%); HRMS
(ESI+) C25H4281BrN2O+ ([M(81Br) + H]+) requires 467.2455, found
467.2464; C25H4279BrN2O+ ([M(79Br) + H]+) requires 465.2475,
found 465.2483.
(R,R,R,R)-1-[2′-Oxo-4′-pentyl-N(5′)-(α-methylbenzyl)-1′,5′-
diazocan-N(1′)-yl]-4-[2′′-oxo-4′′-heptyl-N(5′′)-(α′-methylben-
zyl)-1′′,5′′-diazocan-N(1′′)-yl]butane 65. Following General
Procedure 6B, 59 (91 mg, 275 μmol, >99:1 dr), 64 (109 mg, 249
μmol, >99:1 dr), and KOH (62 mg, 1.10 mmol) in DMSO (1.0 mL)
were reacted for 96 h. Purification via flash column chromatography
(gradient elution, 0% → 2% MeOH in CH2Cl2) gave 65 as a yellow oil
(50 mg, 29%, >99:1 dr); [α]2D4 −23.5 (c 1.0 in CHCl3); vmax (ATR)
1630 (CO); δH (500 MHz, PhMe-d8, 363 K) 0.89−0.98 (6H, br m,
C(4′)(CH2)4CH3, C(4′′)(CH2)6CH3), 1.20−1.53 (30H, br m, C(7′)
H2, C(7′′)H2, C(α)Me, C(α′)Me, C(4′)(CH2)4CH3, C(4′′)-
(CH2)6CH3), 1.57−1.65 (4H, br m, C(2)H2, C(3)H2), 2.35−2.44
(2H, br m, C(3′)HA, C(3′′)HA), 2.46−2.58 (4H, br m, C(3′)HB,
C(3′′)HB, C(6′)HA, C(6′′)HA), 2.63−2.73 (2H, br m, C(6′)HB,
C(6′′)HB), 3.07−3.18 (2H, br m, C(8′)HA, C(8′′)HA), 3.24 (4H, br s,
C(8′)HB, C(8′′)HB, C(1)HA, C(4)HA), 3.38 (2H, br s, C(4′)H, C(4′′)
H), 3.59 (2H, br s, C(1)HB, C(4)HB), 3.72−3.79 (2H, br m, C(α)H,
C(α′)H), 7.08−7.14 (2H, br m, Ph), 7.18−7.24 (4H, br m, Ph), 7.27−
7.33 (4H, br m, Ph); δC (125 MHz, PhMe-d8, 363 K) 13.9, 14.0
(C(4′)(CH2)4CH3, C(4′′)(CH2)6CH3), 21.3 (C(α)Me, C(α′)Me),
22.9, 22.9, 26.9, 27.3, 29.5, 29.5, 29.6, 30.3, 30.6, 30.6, 32.2, 32.5
(C(7′), C(7′′), C(4′)(CH2)4CH3, C(4′′)(CH2)6CH3), 26.2 (C(2),
C(3)), 39.4 (C(3′), C(3′′)), 45.0 (C(6′), C(6′′)), 46.0 (C(1), C(4)),
47.9 (C(8′), C(8′′)), 57.5, 57.5 (C(4′), C(4′′)), 62.7 (C(α), C(α′)),
127.1, 128.3, 128.3 (o,m,p-Ph), 146.9 (i-Ph), 172.3 (C(2′), C(2′′)); m/
7042
dx.doi.org/10.1021/jo3012732 | J. Org. Chem. 2012, 77, 7028−7045

The Journal of Organic Chemistry
Article
z (ESI+) 710 ([M + Na]+, 100%), 688 ([M + H]+, 94%); HRMS
(ESI+) C44H71N4O2+ ([M + H]+) requires 687.5572, found 687.5591.
(R)-N(1)-(4′-Bromobutyl)-4-pentyl-N(5)-methyl-1,5-diazo-
can-2-one 67. Following General Procedure 6A, 62 (423 mg, 1.99
mmol), 1,4-dibromobutane (0.71 mL, 6.00 mmol), K2CO3 (333 mg,
2.41 mmol), KOH (446 mg, 7.94 mmol), and TEBAC (56 mg, 248
μmol) in DMSO (6 mL) were reacted for 24 h. Purification via flash
column chromatography (eluent Et2O) gave 67 as a colorless oil (456
mg, 66%); [α]2D4 −8.1 (c 1.0 in CHCl3); vmax (ATR) 1634 (CO); δH
(400 MHz, CDCl3) 0.89 (3H, t, J 7.0, C(5′′)H3), 1.23−1.92 (14H, m,
C(7)H2, C(2′)H2, C(3′)H2, C(1′′)H2, C(2′′)H2, C(3′′)H2, C(4′′)
H2), 2.42 (3H, s, NMe), 2.46−2.56 (3H, m, C(3)H2, C(6)HA), 2.83−
3.00 (2H, m, C(4)H, C(6)HB), 3.26−3.51 (6H, m, C(8)H2, C(1′)H2,
C(4′)H2); δC (100 MHz, CDCl3) 14.0 (C(5′′)), 22.6, 26.5, 26.6, 28.8,
29.9, 31.9 (C(2′), C(3′), C(1′′), C(2′′), C(3′′), C(4′′)), 30.5 (C(7))
33.7 (C(4′)), 38.4 (C(3)), 40.0 (NMe), 44.8 (C(8)), 47.1 (C(6)), 47.7
(C(1′)), 63.2 (C(4)), 173.8 (C(2)); m/z (ESI+) 349 ([M(81Br) + H]+,
100%), 347 ([M(79Br) + H]+, 94%); HRMS (ESI+) C16H3281BrN2O+
Method C: Following General Procedure 6B, 62 (32 mg, 149 μmol),
68 (51 mg, 136 μmol) and KOH (34 mg, 598 μmol) in DMSO (0.6
mL) were reacted for 96 h. Purification via column chromatography
(gradient elution, 0% → 2.5% MeOH in CHCl3) gave 2 as a colorless
oil (5 mg, 7%, >99:1 dr); [α]2D4 −11.2 (c 0.3 in CHCl3).
(S)-N-(3-Chloropropyl)-N-(α-methylbenzyl)amine. (S)-α-
Methylbenzylamine (16.1 mL, 127 mmol) was added to a solution
of 1-bromo-3-chloropropane (5.00 mL, 50.5 mmol) in MeCN (40
mL), and the resultant mixture was stirred for 16 h at rt. The reaction
mixture was basified to pH 9 with satd aq NaHCO3 and then extracted
with EtOAc (3 × 50 mL). The combined organic extracts were then
dried and concentrated in vacuo. Purification via flash column
chromatography (eluent 30−40 °C petrol/Et2O, 3:7) gave (S)-N-(3-
chloropropyl)-N-(α-methylbenzyl)amine as a yellow oil (5.45 g, 55%,
>99:1 er); [α]2D4 −57.7 (c 1.0 in CHCl3).
(S,S)-4-Heptyl-N(5)-(α-methylbenzyl)-1,5-diazocan-2-one
ent-59. Step 1: Following General Procedure 1, (S)-N-(3-
chloropropyl)-N-(α-methylbenzyl)amine (5.25 g, 26.6 mmol), BuLi
(2.5 M, 10.2 mL, 25.6 mmol), and 49 (4.80 g, 21.2 mmol) were
reacted to give ent-51 as a yellow oil (5.41 g, >99:1 dr).
Step 2: Following General Procedure 4, ent-51 (5.41 g, >99:1 dr) in
MeOH (40 mL) and SOCl2 (1.35 mL, 18.6 mmol) in MeOH (40 mL)
were reacted to give ent-53 as a yellow oil (4.93 g, >99:1 dr).
Step 3: Following General Procedure 2, NaN3 (1.66 g, 25.5 mmol),
NaI (3.83 g, 25.6 mmol), and ent-53 (4.93 g, >99:1 dr) in DMSO (27
mL) were reacted for 24 h to give ent-55 as a yellow oil (4.74 g, >99:1
dr).
Step 4: Following General Procedure 3, ent-55 (4.74 g, >99:1 dr)
and PBu3 (3.50 mL, 14.0 mmol) in THF (50 mL) and H2O (14 mL)
were reacted to give ent-57 as a yellow oil (7.31 g, >99:1 dr).
Step 5: Following General Procedure 5, ent-57 (7.31 g, >99:1 dr)
and Sb(OEt)3 (2.28 mL, 13.4 mmol) in PhMe (1.10 L) were reacted.
Purification via flash column chromatography (gradient elution, 60%
→ 100% EtOAc in 30−40 °C petrol) gave ent-59 as a white solid (2.53
g, 36% over 5 steps, >99:1 dr); mp 45−47 °C; [α]2D4 −3.1 (c 1.0 in
CHCl3).
(S)-4-Heptyl-N(5)-methyl-1,5-diazocan-2-one ent-63. Follow-
ing General Procedure 7, ent-59 (2.50 g, 7.56 mmol, >99:1 dr),
(CH2O)n (459 mg, 15.3 mmol), and Pd(OH)2/C (1.15 g) in MeOH
(25 mL) were reacted for 72 h to give ent-63 as a colorless oil (1.58 g,
87%);16 [α]2D4 +0.4 (c 1.0 in CHCl3).
([M(81Br)
+
H]+) requires 349.1672, found 349.1678;
C16H3279BrN2O+ ([M(79Br) + H]+) requires 347.1693, found
347.1694.
(R)-1-(4′-Bromobutyl)-4-heptyl-5-methyl-1,5-diazocan-2-
one 68. Following General Procedure 6B, 63 (165 mg, 687 μmol),
1,4-dibromobutane (0.24 mL, 2.06 mmol), and KOH (155 mg, 2.76
mmol) in DMSO (1.4 mL) were reacted for 24 h. Purification via flash
column chromatography (gradient elution, 50% → 100% Et2O in 30−
40 °C petrol) gave 68 as a colorless oil (83 mg, 35%); [α]2D4 −10.4 (c
1.0 in CHCl3); vmax (ATR) 1631 (CO); δH (400 MHz, CDCl3) 0.86
(3H, t, J 6.8, C(7′′)H3), 1.20−1.90 (18H, m, C(7)H2, C(2′)H2, C(3′)
H2, C(1′′)H2, C(2′′)H2, C(3′′)H2, C(4′′)H2, C(5′′)H2, C(6′′)H2),
2.40 (3H, s, NMe), 2.44−2.54 (3H, m, C(3)H2, C(6)HA), 2.81−2.96
(2H, m, C(4)H, C(6)HB), 3.24−3.47 (6H, m, C(8)H2, C(1′)H2,
C(4′)H2); δC (100 MHz, CDCl3) 14.1 (C(7′′)), 22.6, 26.5, 27.0, 28.7,
29.3, 29.7, 29.9, 31.8 (C(2′), C(3′), C(1′′), C(2′′), C(3′′), C(4′′),
C(5′′), C(6′′)), 30.3 (C(7)), 33.7 (C(4′)), 38.3 (C(3)), 40.1 (NMe),
44.8 (C(8)), 47.3 (C(6)), 47.6 (C(1′)), 63.3 (C(4)), 173.7 (C(2)); m/
z (ESI+) 399 ([M(81Br) + Na]+, 39%), 397 ([M(79Br) + Na]+, 44%),
377 ([M(81Br) + H]+, 100%), 375 ([M(79Br) + H]+, 89%); HRMS
(ESI+) C18H3681BrN2O+ ([M(81Br) + H]+) requires 377.1985, found
377.1982, C18H3679BrN2O+ ([M(79Br) + H]+) requires 375.2006,
found 375.2002.
(4′R,4′′S)-1-[2′-Oxo-4′-pentyl-N(5′)-methyl-1′,5′-diazocan-
N(1′)-yl]-4-[2′′-oxo-4′′-heptyl-N(5′′)-methyl-1′′,5′′-diazocan-
N(1′′)-yl]butane 69. Following General Procedure 6A, ent-63 (30
mg, 127 μmol), 67 (40 mg, 115 μmol), KOH (26 mg, 457 μmol),
K2CO3 (19 mg, 138 μmol), and TEBAC (3 mg, 14.3 μmol) in DMSO
(0.75 mL) were reacted for 96 h. Purification via column
chromatography (gradient elution, 0% → 4% MeOH in CHCl3)
gave 69 as a yellow oil (10 mg, 17%, >99:1 dr); [α]2D4 +2.3 (c 0.8 in
CHCl3); vmax (ATR) 1636 (CO); δH (500 MHz, PhMe-d8, 363 K)
0.92 (6H, br s, C(4′)(CH2)4CH3, C(4′′)(CH2)6CH3), 1.22−1.60
(28H, m, C(2)H2, C(3)H2, C(7′)H2, C(7′′)H2, C(4′)(CH2)4)CH3,
C(4′′)(CH2)6CH3), 2.30−2.49 (12H, m, C(3′)H2, N(5′)Me, C(6′)
HA, C(3′′)H2, N(5′′)Me, C(6′′)HA), 2.68−2.77 (2H, m, C(6′)HB,
C(6′′)HB), 2.92 (2H, br s, C(4′)H, C(4′′)H), 3.07−3.22 (4H, m,
C(8′)H2, C(8′′)H2), 3.24−3.32 (2H, m, C(1)HA, C(4)HA), 3.35−3.43
(2H, m, C(1)HB, C(4)HB); δC (125 MHz, PhMe-d8, 363 K) 13.9, 14.0
(C(4′)(CH2)4CH3, C(4′′)(CH2)6CH3), 22.9, 26.0, 26.7, 27.4, 29.1,
29.6, 30.0, 30.1, 31.4, 31.5, 32.2, 32.3 (C(2), C(3), C(7′), C(7′′),
C(4′)(CH2)4CH3, C(4′′)(CH2)6CH3), 39.0 (N(5′)Me, N(5′′)Me),
39.9 (C(3′), C(3′′)), 45.8 (C(1), C(4)), 47.2 (C(6′), C(6′′)), 47.4
(C(8′), C(8′′)), 63.7 (C(4′), C(4′′)), 172.3 (C(2′), C(2′′)); m/z
(ESI+) 529 ([M + Na]+, 89%), 507 ([M + H]+, 100%); HRMS (ESI+)
(R,R)-1-[2′-Oxo-4′-pentyl-N(5′)-methyl-1′,5′-diazocan-N(1′)-
yl]-4-[2′′-oxo-4′′-heptyl-N(5′′)-methyl-1′′,5′′-diazocan-N(1′′)-
yl]butane [(−)-hopromine] 2. Method A: Following General
Procedure 7, 65 (17 mg, 24.7 μmol), (CH2O)n (3 mg, 99.0 μmol)
and Pd(OH)2/C (9 mg) in MeOH (1.0 mL) were reacted for 72 h.
Purification via column chromatography (gradient elution, 0% → 2.5%
MeOH in CHCl3) gave 2 as a colorless oil (4 mg, 32%, >99:1 dr);6
[α]D24 −12.1 (c 0.1 in CHCl3); {lit.6 [α]D20 −10 (c 3 in CHCl3)}; {lit.7
[α]2D0 −14.4 (c 2.1 in CHCl3)}; vmax (ATR) 1635 (CO); δH (500
MHz, PhMe-d8, 363 K) 0.91 (6H, t, J 7.25, C(4′)(CH2)4CH3,
C(4′′)(CH2)6CH3), 1.16−1.63 (28H, m, C(2)H2, C(3)H2, C(7′)H2,
C(7′′)H2, C(4′)(CH2)4CH3, C(4′′)(CH2)6CH3), 2.27−2.47 (12H, m,
C(3′)H2, N(5′)Me, C(6′)HA, C(3′′)H2, N(5′′)Me, C(6′′)HA), 2.66−
2.77 (2H, m, C(6′)HB, C(6′′)HB), 2.84−2.95 (2H, m, C(4′)H, C(4′′)
H), 3.04−3.22 (4H, m, C(8′)H2, C(8′′)H2), 3.22−3.43 (4H, m, C(1)
H2, C(4)H2); δC (125 MHz, PhMe-d8, 363 K) 14.0, 14.0 (C(4′)-
(CH2)4CH3, C(4′′)(CH2)6CH3), 22.9, 26.0, 27.0, 27.4, 29.1, 29.6,
30.0, 31.5, 31.6, 32.2, 32.3 (C(2), C(3), C(7′), C(7′′), C(4′)-
(CH2)4CH3, C(4′′)(CH2)6CH3), 39.0 (N(5′)Me, N(5′′)Me), 39.9
(C(3′), C(3′′)), 45.8 (C(1), C(4)), 47.2 (C(6′), C(6′′)), 47.4 (C(8′),
C(8′′)), 63.6 (C(4′), C(4′′)), 172.4 (C(2′), C(2′′)); m/z (ESI+) 529
([M + Na]+, 100%), 507 ([M + H]+, 66%); HRMS (ESI+)
+
C30H59N4O2 ([M + H]+) requires 507.4633, found 507.4617.
+
C30H59N4O2 ([M + H]+) requires 507.4633, found 507.4640.
Method B: Following General Procedure 6B, 63 (57 mg, 238 μmol),
67 (75 mg, 216 μmol) and KOH (48 mg, 864 μmol) in DMSO (0.5
mL) were reacted for 96 h. Purification via column chromatography
(gradient elution, 0% → 2.5% MeOH in CHCl3) gave 2 as a colorless
oil (53 mg, 48%, >99:1 dr); [α]2D4 −13.8 (c 1.0 in CHCl3).
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H, 13C NMR spectra, and crystallographic
information files (for structures CCDC 880488−880490).
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dx.doi.org/10.1021/jo3012732 | J. Org. Chem. 2012, 77, 7028−7045

The Journal of Organic Chemistry
Article
Smith, A. D.; Thomson, J. E.; Toms, S. M. Tetrahedron: Asymmetry
2008, 19, 2870.
(22) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron: Asymmetry
This material is available free of charge via the Internet at
http://pubs.acs.org.
2005, 16, 2833.
AUTHOR INFORMATION
Corresponding Author
*E-mail: steve.davies@chem.ox.ac.uk.
Notes
■
(23) Davies, S. G.; Lee, J. A.; Roberts, P. M.; Stonehouse, J. P.;
Thomson, J. E. Tetrahedron Lett. 2012, 53, 1119.
(24) Enantiopure (R)-α-methylbenzylamine (99% ee) is commer-
cially available. Alkylation of (R)-α-methylbenzylamine upon treat-
ment with 1-bromo-3-chloropropane gave (R)-(3-chloropropyl)-N-(α-
methylbenzyl)amine in 70% yield; subsequent deprotonation with
BuLi in THF generated a yellow solution of lithium (R)-N-(3-
chloropropyl)-N-(α-methylbenzyl)amide (R)-17.
(25) Claridge, T. D. W.; Davies, S. G.; Lee, J. A.; Nicholson, R. L.;
Roberts, P. M.; Russell, A. J.; Smith, A. D.; Toms, S. M. Org. Lett.
2008, 10, 5437.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors would like to thank the EPSRC−Pharma Synthesis
Network for a CASE award (J.A.L.).
■
REFERENCES
(26) Costello, J. F.; Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1994, 10, 1999.
■
(1) Païs, M.; Rattle, G.; Sarfati, R.; Jarreau, F. X. C. R. Seances Acad.
Sci., Ser. C 1968, 266, 37.
(2) Païs, M.; Rattle, G.; Sarfati, R.; Jarreau, F. X. C. R. Seances Acad.
Sci., Ser. C 1968, 267, 82.
(3) Païs, M.; Sarfati, R.; Jarreau, F. X.; Goutarel, R. C. R. Seances Acad.
Sci., Ser. C 1971, 272, 1728.
(4) Sarfati, R.; Païs, M.; Jarreau, F. X. Bull. Soc. Chim. Fr. 1971, 255.
(5) Païs, M.; Sarfati, R.; Jarreau, F. X. Bull. Soc. Chim. Fr. 1973, 331.
(6) Païs, M.; Sarfati, R.; Jarreau, F. X.; Goutarel, R. Tetrahedron 1973,
29, 1001.
(7) Ensch, C.; Hesse, M. Helv. Chim. Acta 2002, 85, 1659.
(8) Lefebvre-Soubeyran, O. Acta Crystallogr. B 1976, 32, 1305.
(9) Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron Lett.
1982, 23, 465.
(10) Wasserman, H. H.; Berger, G. D. Tetrahedron 1983, 39, 2459.
(11) Pietsch, H Tetrahedron Lett. 1972, 13, 2789.
(12) Crombie, L.; Jones, R. C. F.; Mat-Zin, A. R.; Osborne, S. J.
Chem. Soc., Chem. Commun. 1983, 961.
(13) Crombie, L.; Haigh, D.; Jones, R. C. F.; Mat-Zin, A. R. J. Chem.
Soc., Perkin Trans. 1 1993, 2047.
(14) The enantiospecific synthesis of an (R,R,R)-hoprominol
derivative from (S)-malic acid was also reported, see: Ensch, C.;
Hesse, M. Helv. Chim. Acta 2003, 86, 233.
(15) Crombie, L.; Jones, R. C. F.; Haigh, D. Tetrahedron Lett. 1986,
27, 5147.
(16) Crombie, L.; Haigh, D.; Jones, R. C. F.; Mat-Zin, A. R. J. Chem.
Soc., Perkin Trans. 1 1993, 2055.
(17) Itoh, N.; Matsuyama, H.; Yoshida, M.; Kamigata, N.; Iyoda, M.
Bull. Chem. Soc. Jpn. 1995, 68, 3121.
(27) Enantiopure (R)-α-methyl-p-methoxybenzylamine (99% ee) is
commercially available. Alkylation of (R)-α-methyl-p-methoxybenzyl-
amine upon treatment with 1-bromo-3-chloropropane gave (R)-(3-
chloropropyl)-N-(α-methylbenzyl)amine in 70% yield; subsequent
deprotonation with BuLi in THF generated a yellow solution of
lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide
(R)-31.
(28) This sample of (−)-(S,S)-homaline 1 was found to be
chromatographically identical to other samples of (−)-(S,S)-homaline
1
1 and displayed H and 13C NMR data consistent with those of the
natural product, although interestingly the value of the specific rotation
for this sample {[α]2D1−16.8 (c 0.4 in CHCl3)} did not show close
agreement with that of the sample isolated from the natural source
{lit.6 [α]2D0 −34 (c 1.0 in CHCl3)}; it is, however, in close agreement
with the value obtained by Wasserman and Berger for a sample of
(−)-(S,S)-homaline 1 obtained via the same Borch methylation
procedure {lit.10[α]D24 −15.4 (c 1.0 in CHCl3)}.
(29) Crystallographic data (excluding structure factors) for 39 and 40
have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication numbers CCDC 880488 and 880489,
respectively.
(30) (a) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
(b) Flack, H. D.; Bernardelli, G. Acta Crystallogr., Sect. A 1999, 55, 908.
(c) Flack, H. D.; Bernardinelli, G. J. Appl. Crystallogr. 2000, 33, 1143.
(31) Without acid present, cleavage of the N-C(3) bond also
occurred and methyl 3-phenylpropanate was the only observable
product of the reaction.
(32) Approximately 37% conversion to (E)-46 was observed under
these conditions, and the remaining starting material could not be
separated from the product so a pure sample of 46 was not isolated in
this case.
(18) For example, see: (a) Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1991, 2, 183. (b) Bentley, S. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S. M. Tetrahedron
2010, 66, 4604.
(19) For example, see: (a) Abraham, E.; Candela-Lena, J. I.; Davies,
S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.; Russell, A. J.;
(33) See: ref 9 [α]2D2−32 (c 0.95 in CHCl3); ref 10 [α]2D4−35 (c 0.9 in
CHCl3); ref 12 [α]2D2−32 (c 0.95 in CHCl3); ref 13 [α]2D2−32 (c 0.95
in CHCl3).
́ ́
Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J. E. Tetrahedron:
(34) Both reactions proceeded with excellent diastereoselectivity
(>99:1 dr), and following purification of the crude reaction mixtures
48 and 49 were isolated in 51% and 38% yield, respectively.
(35) Conjugate addition of (R)-17 to the corresponding α,β-
unsaturated methyl esters also proceeded in >99:1 dr, although in both
cases the crude reaction mixtures were contaminated with several
other species that could not be separated from the desired β-amino
esters; it was therefore far more practical to scale-up the reactions
using α,β-unsaturated tert-butyl esters 48 and 49 instead.
(36) Crystallographic data (excluding structure factors) for 58·HCl
have been deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 880490.
Asymmetry 2007, 18, 2510. (b) Bentley, S. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 2544. (c) Davies, S.
G.; Fletcher, A. M.; Hughes, D. G.; Lee, J. A.; Price, P. D.; Roberts, P.
M.; Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H.
Tetrahedron 2011, 67, 9975. (d) Davies, S. G.; Lee, J. A.; Roberts, P.
M.; Thomson, J. E.; West, C. J. Tetrahedron Lett. 2011, 52, 6477.
(20) For example, see: (a) Cailleau, T.; Cooke, J. W. B.; Davies, S.
G.; Ling, K. B.; Naylor, A.; Nicholson, R. L.; Price, P. D.; Roberts, P.
M.; Russell, A. J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem.
2007, 5, 3922. (b) Davies, S. G.; Durbin, M. J.; Goddard, E. C.; Kelly,
P. M.; Kurosawa, W.; Lee, J. A.; Nicholson, R. L.; Price, P. D.; Roberts,
P. M.; Russell, A. J.; Scott, P. M.; Smith, A. D. Org. Biomol. Chem.
2009, 7, 761.
(37) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(21) For example, see: (a) Abraham, E.; Davies, S. G.; Docherty, A.
J.; Ling, K. B.; Roberts, P. M.; Russell, A. J.; Thomson, J. E.; Toms, S.
M. Tetrahedron: Asymmetry 2008, 19, 1356. (b) Davies, S. G.; Durbin,
M. J.; Hartman, S. J. S.; Matsuno, A.; Roberts, P. M.; Russell, A. J.;
(38) Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64, 3755.
(39) Resonances corresponding to C(6) and C(α)Me were not
observed in the 100 MHz 13C NMR spectrum of 27 at rt.
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(40) Resonances corresponding to C(6), C(2′), and C(α)Me were
not observed in the 100 MHz 13C NMR spectrum of 28 at rt.
(41) No other resonances were observed in the 100 MHz 13C NMR
spectrum of 29 at rt.
(42) No other resonances were observed in the 100 MHz 13C NMR
spectrum of 30 at rt.
(43) A resonance corresponding to C(1′) was not observed in the
125 MHz 13C NMR spectrum of 35 at 363 K.
(44) A resonance corresponding to 2 × C(3′)HB was not observed in
1
the 500 MHz H NMR spectrum of 36 at rt.
(45) A resonance corresponding to 2 × C(6′) was not observed in
the 125 MHz 13C NMR spectrum of 36 at rt.
(46) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, C. K.;
Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487.
(47) The enantiopurity of ent-39 was not determined; however, the
enantiopurity of the precursor, (R)-4-phenyl-1,5-diazocan-2-one 38,
was assessed to be 91:9 er by chiral HPLC; see ref 17.
(48) A resonance corresponding to i-Ph was not observed in the 100
MHz 13C NMR spectrum of 47 at rt.
(49) Michael, J. P.; Gravestock, D. J. Chem. Soc., Perkin Trans. 2000,
12, 1919.
(50) Davies, S. G.; Mulvaney, A. W.; Russell, A. J.; Smith, A. D.
Tetrahedron: Asymmetry 2007, 18, 1554.
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