Absolute configuration assignment by asymmetric syntheses of the homalium alkaloids (?)-(R, R, R)-hoprominol and (?)-(4′ S,4″ R,2? R)-Hopromalinol

Article abstract of DOI:10.1021/jo301830j

The conjugate addition of lithium (R)-N-(3-chloropropyl)-N-(α- methylbenzyl)amide to α,β-unsaturated esters was used as the key step in the syntheses of all possible diastereoisomers of the homalium alkaloids hoprominol and hopromalinol. Comparison of the

Full text of DOI:10.1021/jo301830j

Article
pubs.acs.org/joc
Absolute Configuration Assignment by Asymmetric Syntheses of the
Homalium Alkaloids (−)‑(R,R,R)‑Hoprominol and
(−)-(4′S,4″R,2‴R)‑Hopromalinol
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, United
Kingdom
‡Novartis Institutes for Biomedical Research, Horsham, West Sussex RH12 5AB, United Kingdom
S
* Supporting Information
ABSTRACT: The conjugate addition of lithium (R)-N-(3-chloropropyl)-N-(α-
methylbenzyl)amide to α,β-unsaturated esters was used as the key step in the
syntheses of all possible diastereoisomers of the homalium alkaloids hoprominol and
hopromalinol. Comparison of the specific rotation data for these synthetic samples with
those of samples isolated from the natural source enabled the absolute configurations
within these alkaloids to be confidently assigned for the first time as (−)-(R,R,R)-
hoprominol and (−)-(4′S,4″R,2‴R)-hopromalinol. The asymmetric syntheses of
(−)-(R,R,R)-hoprominol (in 10 steps and 4.0% overall yield) and
(−)-(4′S,4″R,2‴R)-hopromalinol (in 10 steps and 9.3% overall yield), from
commercially available starting materials in each case, therefore represent the first
total asymmetric syntheses of these alkaloids to be reported.
membered lactam structure7 of these compounds has led to
various synthetic investigations, although to date only the
INTRODUCTION
■
(−)-(S,S)-Homaline 1, (−)-(R,R)-hopromine 2, (−)-hopromi-
simpler (−)-(S,S)-homaline 1 and (−)-(R,R)-hopromine 2
nol 3, and (−)-hopromalinol 4 constitute the family of
homalium alkaloids. All four alkaloids were isolated 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 The unique bis-eight-
have been synthesized in stereoisomerically pure form.8−15
Several other methods for the synthesis of the homalium
alkaloids have also been investigated, although inseparable
mixtures of stereoisomers were formed in each case.16−18
Despite being isolated over 40 years ago, (−)-hoprominol 3
and (−)-hopromalinol 4 are yet to acquiesce to total synthesis,
and so the relative and absolute configurations within these two
alkaloids are yet to be established.
As part of our ongoing research program concerning the
conjugate additions of chiral lithium amides to α,β-unsaturated
esters,19−21 we have recently reported total asymmetric
syntheses of (−)-(S,S)-homaline 1 and (−)-(R,R)-hopromine
2.14,15 For example, our strategy for the synthesis of the
unsymmetrical alkaloid (−)-(R,R)-hopromine 2 involved the
preparation of the monomeric 8-membered azalactam units 16
and 17, followed by their sequential alkylation with 1,4-
dibromobutane. Azalactams 16 and 17 were prepared via
conjugate addition of lithium (R)-N-(3-chloropropyl)-N-(α-
methylbenzyl)amide (R)-722 to α,β-unsaturated esters 5 and
6,23 transesterification of the resultant β-amino esters 8 and 9,
treatment of 10 and 11 with NaN3 (under Finkelstein24
conditions), Staudinger reduction of azides 12 and 13, followed
by Sb(OEt)3-mediated cyclization,12,13 which gave the corre-
sponding azalactams 14 and 15 in 60% and 20% overall yield
Received: August 27, 2012
Published: October 9, 2012
Figure 1. The homalium alkaloids 1−4.
© 2012 American Chemical Society
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for the five-step procedure. Upon scale-up of this process, it was
found that the overall yields of azalactams 14 and 15 could be
significantly improved if the intermediate compounds 8−13
were used without purification: this gave 14 and 15 in 72% and
40% overall yield, respectively. Tandem hydrogenolysis/N-
methylation of 14 and 15 gave the corresponding N(5)-methyl-
substituted azalactams 16 and 17 in quantitative and 98% yield.
Subsequent monoalkylation of azalactam 16 with 1,4-
dibromobutane (3.0 equiv) in the presence of triethylbenzy-
lammonium chloride (TEBAC) proved optimal, giving 18 in
51% isolated yield, and finally treatment of bromide 18 with
azalactam 17 gave (−)-(R,R)-hopromine 2 in 48% yield and
>99:1 dr (Scheme 1).
to the other alkaloids in this family, and possess (4′R,4″R)- and
(4′S,4″R)-configurations, respectively, as shown for 19 and 20.
This assumption was also advocated by Ensch and Hesse13 who
reported a synthesis of the protected “hoprominol derivative”
(R,R,R)-25 and speculated that “all the members of the
homalium family share the same three-dimensional orientation
of the residues at their corresponding stereogenic centers of the
lactam rings”, although 25 was not deprotected and correlated
with the natural product as part of their investigations. As only
very limited characterization data have previously been reported
for both (−)-hoprominol 3 and (−)-hopromalinol 4,6 we
envisaged that it would be necessary to prepare authentic
samples of all four possible diastereoisomers of each alkaloid so
that the magnitudes of their specific rotations could be
compared to the reported data for the samples of
(−)-hoprominol 3 and (−)-hopromalinol 4 isolated from the
natural source. A versatile synthetic strategy enabling the rapid
synthesis of all possible stereochemical permutations of 4-(2′-
hydroxyheptyl) or 4-(2′-benzyloxyheptyl)-substituted azalac-
tams 21 was therefore devised: it was envisaged that conjugate
addition of lithium (R)-N-(3-chloropropyl)-N-(α-
methylbenzyl)amide (R)-7 to a racemic δ-benzyloxy-α,β-
unsaturated ester 24 would proceed under the dominant
stereocontrol of the lithium amide reagent25 to give a mixture
of C(3)-epimeric β-amino ester conjugate addition products
23. Separation of these compounds, followed by functional
group manipulation and Sb(OEt)3-mediated cyclization12,13 of
22 (using our established protocols),14,15 would then provide
access to the corresponding azalactams 21; the antipodes would
then be accessed via an analogous approach starting with the
conjugate addition of lithium (S)-N-(3-chloropropyl)-N-(α-
methylbenzyl)amide (S)-7 to α,β-unsaturated ester 24 (Figure
2).
a
Scheme 1
Synthesis of the 2-Hydroxyheptyl-Substituted Aza-
lactam Units. Racemic samples of the requisite C(5)-
benzyloxy-substituted α,β-unsaturated esters (RS)-29 and
(RS)-30 were prepared via initial treatment of hexanal 26
with allylmagnesium bromide, which gave homoallylic alcohol
a
Reagents and conditions: (i) (R)-7, THF, −78 °C, 2 h; (ii) SOCl2,
MeOH, reflux, 3 h; (iii) NaN3, NaI, DMSO, 50 °C, 24 h; (iv) PBu3,
THF, rt, 30 min then H2O, 50 °C, 2 h; (v) Sb(OEt)3, PhMe, reflux, 18
h; (vi) H2 (1 atm), Pd(OH)2/C, (CH2O)n, MeOH, rt, 3 days; (vii)
1,4-dibromobutane (3.0 equiv), KOH, K2CO3, TEBAC, DMSO, rt, 24
b
c
h; (viii) 17, KOH, DMSO, rt, 96 h. Crude and isolated. Isolated as a
single diastereoisomer (>99:1 dr).
We envisaged that a similar strategy could be used for the
preparation of the more elaborate alkaloids (−)-hoprominol 3
and (−)-hopromalinol 4, and the results of these investigations,
which culminated in the assignment of the absolute
configurations within both (−)-hoprominol 3 and (−)-hopro-
malinol 4, are reported herein.
RESULTS AND DISCUSSION
■
At the onset of this project, the relative and absolute
configurations within (−)-hoprominol 3 and (−)-hopromalinol
4 had yet to be established, and as the structures of both
(−)-hoprominol 3 and (−)-hopromalinol 4 contain three
stereogenic centers, there were eight possible stereoisomers to
consider for each alkaloid. However, given the homochirality
between (−)-homaline 1 and (−)-hopromine 2 (i.e., both
substituents within 1 and 2 are pointing upward as drawn in
Figure 1), we predicted that (−)-hoprominol 3 and
(−)-hopromalinol 4 would also be homochiral with respect
Figure 2. Synthetic strategy to access the stereoisomers of hoprominol
3 and hopromalinol 4.
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a
(RS)-27 in 90% isolated yield; subsequent protection of the
hydroxyl group within (RS)-27 upon treatment with NaH and
BnBr gave (RS)-28 in quantitative yield, then cross metathesis
of (RS)-28 with either methyl acrylate or tert-butyl acrylate gave
(RS)-29 and (RS)-30 in 74% and 85% yield, respectively. When
investigating doubly diastereoselective26 conjugate additions of
lithium amide reagents to chiral α,β-unsaturated esters, we have
previously found that it is prudent to follow a strategy of first
investigating the levels of substrate control offered by the chiral
α,β-unsaturated ester upon conjugate addition of an achiral
lithium amide (such as lithium N-isopropyl-N-benzylamide),27
prior to attempting the conjugate addition reactions of chiral
secondary lithium amides derived from α-methylbenzylamine.
In both cases, conjugate addition of lithium N-isopropyl-N-
benzylamide to racemic α,β-unsaturated esters (RS)-29 and
(RS)-30 gave essentially 50:50 mixtures28 of the corresponding
diastereoisomeric products, which could not be separated and
were therefore isolated in 47% and 82% combined yield,
respectively, and 50:50 dr in each case. These reaction
outcomes established that there is effectively no substrate
control upon the conjugate addition of achiral lithium amide
reagent lithium N-isopropyl-N-benzylamide to 29 and 30, and
suggested that any diastereoisomeric excess arising from
conjugate addition of chiral lithium amide (R)-7 to α,β-
unsaturated esters 29 and 30 will be due to reagent control
alone. An enantiopure sample of α,β-unsaturated ester (R)-30
was prepared by Brown allylation of hexanal 26 in the presence
of (−)-B-chlorodiisopinocampheylborane [(−)-Ipc2BCl],
which gave homoallylic alcohol (R)-2729 in 77% yield and
96% ee.30 The absolute configuration within (R)-27 was
assigned by comparison of the specific rotation of this sample
with that of a sample of known configuration reported in the
literature {[α]24D +9.0 (c 1.0 in CHCl3); lit.31 [α]25D +8.9 (c 1.1
in CHCl3)}. O-Benzyl protection of (R)-27, followed by cross
metathesis of (R)-28 with tert-butyl acrylate, gave (R)-30 in
53% yield [from (R)-27]. Subsequent conjugate addition of
lithium (R)-N-(3-chloropropyl)-N-(α-methylbenzyl)amide
(R)-722 to enantiopure α,β-unsaturated ester (R)-30 gave 33
as a single diastereoisomer (>99:1 dr), which was isolated in
84% yield after purification (Scheme 2). Given the usually very
high reagent control and predictable sense of diastereoselectiv-
ity observed upon conjugate addition of secondary lithium
amides derived from α-methylbenzylamine to α,β-unsaturated
esters,21 and the extremely low substrate control observed upon
conjugate addition of lithium N-isopropyl-N-benzylamide to
(RS)-30, the (R)-configuration of the newly formed C(3)-
stereogenic center within 33 was confidently assigned by
reference to our well-established transition state mnemonic.32
A sample of the C(5)-epimeric β-amino ester 34 was then
accessed upon conjugate addition of lithium (R)-N-(3-
chloropropyl)-N-(α-methylbenzyl)amide (R)-722 to racemic
α,β-unsaturated ester (RS)-30, which gave a 50:50 mixture of
33 and 34; after chromatographic purification of the crude
reaction mixture, 33 and 34 were isolated as single
diastereoisomers (>99:1 dr) in 41% and 46% yield, respectively.
The absolute configuration within 34 was assigned by analogy
to the established configuration within 33, given very high
reagent control and predictable sense of diastereoselectivity
observed upon conjugate addition of secondary lithium amides
derived from α-methylbenzylamine to α,β-unsaturated esters,21
and the extremely low substrate control observed upon
conjugate addition of lithium N-isopropyl-N-benzylamide to
(RS)-30. Subsequent conversion of β-amino esters 33 and 34
Scheme 2
a
Reagents and conditions: (i) allylmagnesium bromide, THF, rt, 1 h;
(ii) NaH, THF, rt, 1 h, then BnBr, rt, 18 h; (iii) Grubbs II, methyl
acrylate, CH2Cl2, 40 °C, 24 h; (iv) Grubbs II, tert-butyl acrylate,
CH2Cl2, 40 °C, 24 h; (v) lithium N-isopropyl-N-benzylamide, THF,
−78 °C, 2 h; (vi) (−)-Ipc2BCl, allylmagnesium bromide, Et2O, −78
b
°C, 1 h; (vii) (R)-7, THF, −78 °C, 2 h. Crude and isolated.
into the corresponding azalactams 41 and 42 was then achieved
in 54% and 47% overall yield33 using our established four-step
sequence of reactions for azalactam formation: sequential
transesterification, displacement of the chloride functionality
with NaN3, Staudinger reduction of the resultant azide, and
Sb(OEt)3-mediated lactamization (Scheme 3).
Deprotection of 4-(2′-benzyloxyheptyl)-substituted azalac-
tams 41 and 42 via hydrogenolysis gave 43 and 44 in 63% and
81% yield, respectively, and then N-methylation of these
substrates upon treatment with (CH2O)n and NaBH3CN gave
45 and 46 in 45% and 40% isolated yield (Scheme 4).
Attempted tandem hydrogenolysis/N-methylation of 41
produced an 85:15 mixture of 45 and 47, which were isolated
in 29% and 14% yield, respectively, after chromatographic
purification. Upon changing the solvent used for this reaction
from MeOH to AcOH, it was possible to completely suppress
the formation of 47, giving 45 as the sole reaction product in
90% isolated yield. Treatment of the epimeric compound 42
under identical conditions gave 46 in quantitative yield
(Scheme 5).
The enantiomeric azalactams ent-45 and ent-46 were
prepared via an analogous sequence of reactions: conjugate
addition of lithium (S)-N-(3-chloropropyl)-N-(α-
methylbenzyl)amide (S)-734 to racemic α,β-unsaturated ester
(RS)-30 gave a 50:50 mixture of diastereoisomeric conjugate
addition products ent-33 and ent-34, which were isolated as
single diastereoisomers (>99:1 dr) in 36% and 40% yield,
respectively. Subsequent conversion of β-amino esters ent-33
and ent-34 into the corresponding azalactams ent-41 and ent-42
was then achieved in 60% and 69% overall yield using our
standard four-step sequence of reactions for azalactam
formation. Finally, tandem hydrogenolysis/N-methylation of
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a
a
Scheme 3
Scheme 5
a
Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, (CH2O)n,
MeOH, rt, 72 h; (ii) H2 (1 atm), Pd(OH)2/C, (CH2O)n, AcOH, rt, 24
h.
a
Scheme 6
a
Reagents and conditions: (i) (R)-7, THF, −78 °C, 2 h; (ii) SOCl2,
MeOH, reflux, 4 h; (iii) NaN3, NaI, DMSO, 50 °C, 24 h; (iv) PBu3,
THF, rt, 30 min, then H2O, 50 °C, 2 h; (v) Sb(OEt)3, PhMe, reflux,
18 h.
a
Scheme 4
a
Reagents and conditions: (i) H2 (1 atm), Pd(OH)2/C, MeOH, rt, 24
h; (ii) NaBH3CN, (CH2O)n, MeOH, rt, 18 h.
both ent-41 and ent-42 gave samples of ent-45 and ent-46 in
quantitative and 85% yield, respectively (Scheme 6).
Asymmetric Synthesis of (−)-Hoprominol. Reaction of
the known bromide 18 [an intermediate in our synthesis of
(−)-(R,R)-hopromine 2]15 with 4-(2′-benzyloxyheptyl)-sub-
stituted azalactam 42 gave 48 in 21% isolated yield. Tandem
hydrogenolysis/N-methylation of 48 gave (4′R,4″R,2‴S)-49
{[α]24D −18.4 (c 1.0 in CHCl3)} in 38% yield after purification.
However, treatment of bromide 18 with the corresponding 4-
(2′-hydroxyheptyl)-substituted azalactam 46 was found to
a
Reagents and conditions: (i) (S)-7, THF, −78 °C, 2 h; (ii) SOCl2,
MeOH, reflux, 4 h; (iii) NaN3, NaI, DMSO, 50 °C, 24 h; (iv) PBu3,
THF, rt, 30 min, then H2O, 50 °C, 2 h; (v) Sb(OEt)3, PhMe, reflux,
18 h; (vi) H2 (1 atm), Pd(OH)2/C, (CH2O)n, AcOH, rt, 24 h. Not
b
isolated.
proceed with superior yield, giving (4′R,4″R,2‴S)-49 {[α]24
D
−18.4 (c 1.0 in CHCl3)} directly in 26% isolated yield. This
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a
procedure was therefore repeated using the epimeric 2-
Scheme 8
hydroxyheptyl-substituted azalactam 45, which gave (R,R,R)-
50 {[α]24 −17.5 (c 1.0 in CHCl3)} in 24% isolated yield
D
(Scheme 7).
a
Scheme 7
a
Reagents and conditions: (i) ent-46, KOH, K2CO3, TEBAC, DMSO,
rt, 60 h; (ii) ent-45, KOH, K2CO3, TEBAC, DMSO, rt, 60 h.
a
Scheme 9
a
Reagents and conditions: (i) 42, KOH, DMSO, rt, 96 h; (ii) H2 (1
atm), Pd(OH)2/C, (CH2O)n, AcOH, rt, 24 h; (iii) 46, KOH, K2CO3,
TEBAC, DMSO, rt, 48 h; (iv) 45, KOH, K2CO3, TEBAC, DMSO, rt,
48 h.
The same strategy was then followed for the synthesis of the
remaining diastereoisomers of (−)-hoprominol via alkylation of
azalactams ent-45 and ent-46 with bromide 18. Reaction of
bromide 18 with 4-(2′-hyrdoxyheptyl)-substituted azalactam
ent-46 gave (4′R,4″S,2‴R)-51 {[α]24 −2.4 (c 1.0 in CHCl3)}
D
in 26% yield and >99:1 dr after chromatographic purification,
and treatment of 18 with the epimeric 4-(2′-hydroxyheptyl)-
substituted azalactam ent-45 gave (4′R,4″S,2‴S)-52 {[α]24
a
Reagents and conditions: (i) 1,4-dibromobutane (3.0 equiv), KOH,
D
DMSO, rt, 18 h; (ii) 46, KOH, K2CO3, TEBAC, DMSO, rt, 48 h; (iii)
45, KOH, K2CO3, TEBAC, DMSO, rt, 48 h.
+5.8 (c 1.0 in CHCl3)} in 4% isolated yield and >99:1 dr
(Scheme 8).
Asymmetric Synthesis of (−)-Hopromalinol. Alkylation
of 4-phenyl-substituted azalactam 53 [an intermediate in our
synthesis of (−)-(R,R)-homaline 1]14,15 with 3.0 equiv of 1,4-
dibromobutane gave 54 in 59% yield. Subsequent treatment of
bromide 54 with 4-(2′-hydroxyheptyl)-substituted azalactam 46
1.0 in CHCl3)} in 59% isolated yield and >99:1 dr (Scheme
10).
Comparison with Literature Data. Unfortunately, only
very limited NMR data for both (−)-hoprominol and
(−)-hopromalinol are available in the literature,6 and, despite
exhaustive enquiries, we have been unable to acquire authentic
samples of either of these alkaloids, or more extensive
characterization data. The specific rotations for our synthetic
samples of the possible diastereoisomers of (−)-hoprominol
and (−)-hopromalinol were therefore compared to the
originally reported values: considering the four diaster-
eoisomers of hopromalinol (i.e., the authentic synthetic samples
gave (4′S,4″R,2‴S)-55 {[α]24 −9.3 (c 1.0 in CHCl3)} in 36%
D
isolated yield, and analogous alkylation of 54 with the epimeric
2-hydroxyheptyl-substituted azalactam 45 gave (4′S,4″R,2‴R)-
56 {[α]24 −16.8 (c 1.0 in CHCl3)} in 56% isolated yield
D
(Scheme 9).
Similarly, alkylation of bromide 54 with 4-(2′-hydroxyhep-
tyl)-substituted azalactam ent-46 gave (4′S,4″S,2‴R)-57 {[α]24
D
−7.1 (c 1.0 in CHCl3)} in >99:1 dr and 22% isolated yield, and
alkylation of 54 with the epimeric 4-(2′-hydroxyheptyl)-
of 55−58), the (4′S,4″R,2‴R)-stereoisomer 56 {[α]24 −16.8
D
substituted azalactam ent-45 gave (S,S,S)-58 {[α]24 +2.1 (c
(c 1.0 in CHCl3)} is the only one of these possibilities that
D
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a
position, (4′R,4″R,2‴S)-49 {[α]24 −18.4 (c 1.0 in CHCl3)}
Scheme 10
D
and (R,R,R)-50 {[α]24 −17.5 (c 1.0 in CHCl3)}, which have
D
comparable specific rotation values (both sign and magnitude)
with that of the sample isolated from the natural source {lit.6
[α]20 −19 (c 2.0 in CHCl3)}; the other two diastereoisomers
D
51 and 52 have specific rotations that are far too small to be
consistent with either antipode of the natural product. This
confirms that all four homalium alkaloids are homochiral with
respect to the configurations of the azalactam rings, and it is
only the configuration of the C(2‴) position within
hoprominol that cannot be unambiguously assigned given the
comparable specific rotation values observed for the C(2‴)-
epimers 49 and 50. However, given the homochirality observed
between all four homalium alkaloids with respect to the
configurations of the azalactam rings, it seems reasonable that
the configurations at the C(2‴) positions within both
(−)-hoprominol and (−)-hopromalinol are identical. On the
basis of this analysis, we have therefore confidently assigned the
absolute (R,R,R)-configuration to (−)-hoprominol 50 (Figure
3).
This study represents the first reported total asymmetric
syntheses of these alkaloids: (−)-(R,R,R)-hoprominol 50 was
produced in 10 steps and 4.0% overall yield, and
(−)-(4′S,4″R,2‴R)-hopromalinol 56 was produced in 10
steps and 9.3% overall yield, from commercially available
starting materials in each case.
a
Reagents and conditions: (i) ent-46, KOH, K2CO3, TEBAC, DMSO,
rt, 60 h; (ii) ent-45, KOH, K2CO3, TEBAC, DMSO, rt, 60 h.
shows good agreement between its specific rotation value and
that reported for the natural product {lit.6 [α]20D −17 (c 2.5 in
CHCl3)}, in terms of both sign and magnitude; the other three
diastereoisomers 55, 57, and 58 all have specific rotations that
are far too small to be consistent with either antipode of the
natural product. This analysis has therefore enabled the
absolute (4′S,4″R,2‴R)-configuration within (−)-hopromalinol
56 to be unambiguously assigned. For hoprominol, however,
there are two possible stereoisomers, epimeric at the C(2‴)
CONCLUSION
■
The conjugate addition of lithium (R)- or (S)-N-(3-
chloropropyl)-N-(α-methylbenzyl)amide to an α,β-unsaturated
ester was used as the key step in the syntheses of all possible
diastereoisomers of the homalium alkaloids hoprominol and
hopromalinol. Comparison of the specific rotation data for
Figure 3. Comparison of specific rotation data for the synthetic samples of all possible diastereoisomers of (−)-hoprominol and (−)-hopromalinol
[red = configuration unambiguously secured; blue = proposed configuration].
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NaHCO3 and CH2Cl2, the aqueous layer was extracted with two
portions of CH2Cl2, then the combined organic extracts were dried
and concentrated in vacuo.
these synthetic samples with those of samples isolated from the
natural source enabled the absolute configurations within these
alkaloids to be confidently assigned for the first time as
(−)-(R,R,R)-hoprominol and (−)-(4′S,4″R,2‴R)-hopromali-
nol. The asymmetric syntheses of (−)-(R,R,R)-hoprominol
(in 10 steps and 4.0% overall yield) and (−)-(4′S,4″R,2‴R)-
hopromalinol (in 10 steps and 9.3% overall yield), from
commercially available starting materials in each case, represent
the first total asymmetric syntheses of these alkaloids to be
reported.
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 to rt
over 5 min, then Sb(OEt)3 was added. The resultant mixture was
heated at reflux for 18 h 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.
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 48 or 60 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,
then 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 18 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, then
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 or AcOH, as stated), and the resultant mixture was stirred at rt
under H2 (1 atm) for either 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,
then dried and concentrated in vacuo.
(RS)-Non-1-en-4-ol 27. Allylmagnesium bromide (1.0 M, 50 mL,
50 mmol) was added to a stirred solution of 26 (5.70 mL, 4.75 mmol)
in THF (125 mL) at 0 °C. The resultant mixture was allowed to warm
to rt over 1 h. Saturated aq NH4Cl (50 mL) was then added, and the
aqueous layer was extracted with Et2O (2 × 50 mL). The combined
organic extracts were washed with brine (100 mL), then dried and
concentrated in vacuo to give (RS)-27 as a colorless oil (6.02 g,
90%);37 δH (400 MHz, CDCl3) 0.90 (3H, t, J 7.1, C(9)H3), 1.26−1.52
(8H, m, C(5)H2, C(6)H2, C(7)H2, C(8)H2), 2.14 (1H, dt, J 14.0, 7.9,
C(3)HA), 2.29−2.35 (1H, m, C(3)HB), 3.62−3.69 (1H, m, C(4)H),
5.12−5.18 (2H, m, C(1)H2), 5.79−5.89 (1H, m, C(2)H).
(R)-Non-1-en-4-ol 27. Allylmagnesium bromide (1.0 M, 11 mL,
11.0 mmol) was added to a stirred solution of (−)-Ipc2BCl (4.24 g,
13.2 mmol) in Et2O (60 mL) at −78 °C, and the resultant mixture was
warmed to 0 °C over 1 h. The stirring was ceased, and the mother
liquor was carefully transferred to another flask via cannula such that
the white precipitate remained. The resultant solution was cooled to
−78 °C, and a solution of 26 (1.08 mL, 8.79 mmol) in Et2O (30 mL)
was added. The resultant solution was stirred at −78 °C for 1 h, then
phosphate pH 7 buffer (60 mL), MeOH (60 mL), and 30% aq H2O2
(30 mL) were added sequentially, and the resultant mixture was
allowed to warm to rt. The reaction mixture was then stirred at rt for
30 min and poured into satd aq NaHCO3 (100 mL). The aqueous
layer was extracted with Et2O (2 × 100 mL), and the combined
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.35 BuLi was purchased as a solution in hexanes, and
titrated against diphenylacetic acid before use. Allylmagnesium
bromide was purchased as a solution in Et2O, and titrated against
(E)-2-(2′-phenylhydrazonomethyl)phenol before use.36 1,4-Dibromo-
butane was distilled from CaCl2 before use. All other reagents were
used as supplied without prior purification. Organic layers were dried
over MgSO4 unless otherwise stated. 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.
Melting points are uncorrected. Specific rotations are reported in
10−1 deg cm2 g−1, and concentrations are in g/100 mL. IR spectra
were recorded on an ATR module. 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, then 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 24 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, then dried and concentrated in vacuo.
General Procedure 3: Staudinger Reduction. 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, 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
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Article
organic extracts were washed with satd aq Na2S2O3 (100 mL), then
dried and concentrated in vacuo. Purification via flash column
chromatography (gradient elution, 2% → 10% Et2O in 30−40 °C
was then concentrated in vacuo. Purification via flash column
chromatography (gradient elution, 0% → 5% Et2O in 30−40 °C
petrol) gave (R,E)-30 as a colorless oil (539 mg, 53% over two steps,
petrol) gave (R)-27 as a colorless oil (959 mg, 77%, 96% ee); [α]24
>99:1 dr); [α]20 +10.9 (c 1.0 in CHCl3).
D
D
+9.0 (c 1.0 in CHCl3); {lit.31 [α]25 +8.9 (c 1.1 in CHCl3)}.
Methyl (RS,RS)- and (RS,SR)-3-(N-Isopropyl-N-benzylamino)-
5-(benzyloxy)decanoate 31. Following general procedure 1, N-
isopropyl-N-benzylamine (0.34 mL, 2.06 mmol), BuLi (2.4 M, 0.83
mL, 2.00 mmol), and (RS,E)-29 (375 mg, 1.29 mmol, >99:1 dr) in
THF (10 mL) were reacted to give 31 in 50:50 dr. Purification via
flash column chromatography (gradient elution, 2% → 10% Et2O in
30−40 °C petrol) gave 31 as a colorless oil (266 mg, 47%, 50:50 dr);39
vmax (ATR) 1737 (CO); δH (400 MHz, CDCl3) 0.97 (6H, t, J 7.3, 2
× C(10)H3), 1.09−1.14 (12H, m, 2 × CHMe2), 1.25−1.68 (18H, m,
C(4)HA, C(4)HA, 2 × C(6)H2, 2 × C(7)H2, 2 × C(8)H2, 2 × C(9)
H2), 1.77 (1H, ddd, J 14.2, 7.3, 3.5, C(4)HB), 2.01 (1H, app dt, J 13.9,
6.3, C(4)HB), 2.40 (1H, dd, J 13.9, 6.8, C(2)HA), 2.46 (1H, dd, J 13.8,
7.6, C(2)HA), 2.63 (1H, dd, J 13.9, 7.1, C(2)HB), 2.71 (1H, dd, J 13.8,
6.1, C(2)HB), 3.05 (2H, app d, J 6.1, 2 × NCHMe2), 3.45−3.76 (8H,
m, 2 × C(3)H, 2 × C(5)H, 2 × NCH2Ph), 3.69 (3H, s, OMe), 3.69
(3H, s, OMe), 4.32 (1H, d, J 11.3, OCHAHBPh), 4.52 (1H, d, J 11.6,
OCHAHBPh), 4.53 (1H, d, J 11.3, OCHAHBPh), 4.57 (1H, d, J 11.6,
OCHAHBPh), 7.22−7.42 (20H, m, Ph); δC (100 MHz, CDCl3) 14.1
(2 × C(10)), 20.0, 20.6, 20.7, 21.2 (2 × NCHMe2), 22.7, 22.8, 24.8,
24.9, 32.1, 32.2, 33.7, 33.9 (2 × C(6), 2 × C(7), 2 × C(8), 2 × C(9)),
37.4, 38.7 (2 × C(2)), 38.1 (2 × C(4)), 47.5, 48.2 (2 × NCHMe2),
49.1, 49.3 (2 × NCH2Ph), 51.3, 51.4 (OMe), 51.4, 52.1 (2 × C(3)),
70.3, 71.0 (2 × OCH2Ph), 76.9, 77.2 (2 × C(5)), 126.6, 126.7, 127.3,
127.4, 127.6, 127.8, 128.1, 128.1, 128.2, 128.3, 128.5, 128.7 (o,m,p-Ph),
139.0, 139.2, 141.3, 141.5 (i-Ph), 173.1, 173.2 (2 × C(1)); m/z (ESI+)
902 ([2M + Na]+, 71%), 462 ([M + Na]+, 100%), 440 ([M + H]+,
(RS)-4-(Benzyloxy)non-1-ene D28. NaH (60% dispersion in
mineral oil, 1.55 g, 38.7 mmol) was added to a solution of (RS)-27
(5.00 g, 35.2 mmol) in THF (100 mL) at rt, and the resultant mixture
was stirred for 1 h. BnBr (4.39 mL, 36.9 mmol) was added, and the
resultant mixture was stirred at rt for 18 h. H2O (50 mL) was then
cautiously added, and the aqueous layer was extracted with Et2O (2 ×
50 mL). The combined organic extracts were then dried and
concentrated in vacuo to give (RS)-28 as a colorless oil (8.16 g,
quant);38 δH (400 MHz, CDCl3) 0.89 (3H, t, J 7.2, C(9)H3), 1.21−
1.57 (8H, m, C(5)H2, C(6)H2, C(7)H2, C(8)H2), 2.30−2.36 (2H, m,
C(3)H2), 3.44 (1H, app quintet, J 5.8, C(4)H), 4.50 (1H, d, J 11.6,
OCHAHBPh), 4.57 (1H, d, J 11.6, OCHAHBPh), 5.05−5.12 (2H, m,
C(1)H2), 5.81−5.92 (1H, m, C(2)H), 7.26−7.37 (5H, m, Ph).
Methyl (RS,E)-5-(Benzyloxy)dec-2-enoate 29. Grubbs II
catalyst (92 mg, 108 μmol) and methyl acrylate (0.48 mL, 3.28
mmol) were added to a degassed solution of (RS)-28 (500 mg, 2.15
mmol) in CH2Cl2 (6 mL, EtOH stabilized), and the resultant mixture
was heated at 40 °C for 24 h, then allowed to cool to rt and
concentrated in vacuo. Purification via flash column chromatography
(gradient elution, 0% → 10% Et2O in 30−40 °C petrol) gave (RS,E)-
29 as a colorless oil (461 mg, 74%, >99:1 dr); vmax (ATR) 1724 (C
O), 1658 (CC); δH (400 MHz, CDCl3) 0.90 (3H, t, J 7.1, C(10)
H3), 1.23−1.65 (8H, m, C(6)H2, C(7)H2, C(8)H2, C(9)H2), 2.46
(2H, app t, J 6.6, C(4)H2), 3.53 (1H, app quintet, J 5.8, C(5)H), 3.74
(3H, s, OMe), 4.51 (1H, d, J 11.6, OCHAHBPh), 4.56 (1H, d, J 11.6,
OCHAHBPh), 5.90 (1H, d, J 15.6, C(2)H), 7.02 (1H, dt, J 15.6, 7.6,
C(3)H), 7.26−7.37 (5H, m, Ph); δC (100 MHz, CDCl3) 14.0 (C(10)),
22.6, 25.0, 31.8, 34.0 (C(6), C(7), C(8), C(9)), 36.8 (C(4)), 51.4
(OMe), 71.1 (OCH2Ph), 77.7 (C(5)), 123.0 (C(2)), 127.6, 127.8,
128.4 (o,m,p-Ph), 138.5 (i-Ph), 145.9 (C(3)), 166.8 (C(1)); m/z
+
100%); HRMS (ESI+) C28H42NO3 ([M + H]+) requires 440.3159;
found 440.3166.
tert-Butyl (RS,RS) and (RS,SR)-3-(N-Isopropyl-N-benzylami-
no)-5-(benzyloxy)decanoate 32. Following general procedure 1,
N-isopropyl-N-benzylamine (0.30 mL, 1.77 mmol), BuLi (2.5 M, 0.69
mL, 1.72 mmol), and (RS,E)-30 (369 mg, 1.11 mmol) in THF (5 mL)
were reacted to give 32 in 50:50 dr. Purification via flash column
chromatography (gradient elution, 1% → 9% Et2O in 30−40 °C
petrol) gave 32 as a colorless oil (411 mg, 82%, 50:50 dr);40 vmax
(ATR) 1723 (CO); δH (400 MHz, CDCl3) 0.95−1.00 (6H, m, 2 ×
C(10)H3), 1.11 (3H, app d, J 3.0, NCHMeA), 1.12 (3H, app d, J 3.0,
NCHMeB), 1.15 (6H, app t, J 6.7, NCHMe2), 1.23−1.66 (18H, m, 2 ×
C(4)HA, 2 × C(6)H2, 2 × C(7)H2, 2 × C(8)H2, 2 × C(9)H2), 1.50
(9H, s, CMe3), 1.54 (9H, s, CMe3), 1.73 (1H, ddd, J 14.4, 8.3, 3.5,
C(4)HB), 2.02 (1H, ddd, J 13.9, 8.1, 5.3, C(4)HB), 2.24−2.32 (2H, m,
C(2)H2), 2.66 (2H, app td, J 13.6, 5.6, C(2)H2), 2.99−3.14 (2H, m, 2
× NCHMe2), 3.35−3.43 (1H, m, C(3)H), 3.50−3.58 (2H, m, C(3)H,
C(5)H), 3.61 (1H, d, J 14.2, NCHAHBPh), 3.63−3.70 (1H, m, C(5)
H), 3.64 (1H, d, J 14.2, NCHAHBPh), 3.77 (2H, app d, J 14.2, 2 ×
NCHAHBPh), 4.27 (1H, d, J 11.1, OCHAHBPh), 4.50 (1H, d, J 11.1,
OCHAHBPh), 4.54 (1H, d, J 11.5, OCHAHBPh), 4.58 (1H, d, J 11.5,
OCHAHBPh), 7.22−7.47 (20H, m, Ph); δC (100 MHz, CDCl3) 14.1,
14.1 (2 × C(10)), 19.5, 19.8, 21.7, 21.8 (2 × NCHMe2), 22.7, 22.8,
24.8, 24.9, 32.1, 32.2, 33.7, 33.9 (2 × C(6), 2 × C(7), 2 × C(8), 2 ×
C(9)), 28.1, 28.2 (2 × CMe3), 37.4, 38.3 (2 × C(4)), 39.2, 39.9 (2 ×
C(2)), 47.5, 48.3 (2 × NCHMe2), 49.1, 49.3 (2 × NCH2Ph), 51.5,
52.1 (2 × C(3)), 70.3, 71.0 (2 × OCH2Ph), 76.9, 77.1 (2 × C(5)),
80.1, 80.1 (2 × CMe3), 128.6, 127.1, 127.4, 127.6, 127.8, 128.1, 128.1,
128.1, 128.3, 128.7, 128.9 (o,m,p-Ph), 139.2, 139.4, 141.4, 141.7 (i-Ph),
172.1, 172.3 (2 × C(1)); m/z (ESI+) 986 ([2M + Na]+, 75%), 504
([M + Na]+, 100%), 482 ([M + H]+, 78%); HRMS (ESI+)
+
(ESI+) 313 ([M + Na]+, 100%); HRMS (ESI+) C18H26NaO3 ([M +
Na]+) requires 313.1774; found 313.1764.
tert-Butyl (RS,E) 5-(Benzyloxy)dec-2-enoate 30. Grubbs II
catalyst (121 mg, 143 μmol) and tert-butyl acrylate (4.87 mL, 33.2
mmol) were added to a degassed solution of (RS)-28 (3.37 g, 14.5
mmol) in CH2Cl2 (33 mL, EtOH stabilized), and the resultant mixture
was heated at 40 °C for 24 h, then allowed to cool to rt and
concentrated in vacuo. Purification via flash column chromatography
(gradient elution, 0% → 5% Et2O in 30−40 °C petrol) gave (RS,E)-30
as a colorless oil (4.10 g, 85%, >99:1 dr); C21H32O3 requires C, 75.9%;
H, 9.7%; found C%, 75.9; H, 9.6%; vmax (ATR) 1713 (CO), 1653
(CC); δH (400 MHz, CDCl3) 0.89 (3H, t, J 7.1, C(10)H3), 1.22−
1.60 (8H, m, C(6)H2, C(7)H2, C(8)H2, C(9)H2), 1.50 (9H, s, CMe3),
2.41−2.46 (2H, m, C(4)H2), 3.51 (1H, app quintet, J 5.6, C(5)H),
4.50 (1H, d, J 11.5, OCHAHBPh), 4.56 (1H, d, J 11.5, OCHAHBPh),
5.81 (1H, dt, J 15.6, 1.3, C(2)H), 6.90 (1H, dt, J 15.6, 7.3, C(3)H),
7.26−7.41 (5H, m, Ph); δC (100 MHz, CDCl3) 14.0 (C(10)), 22.6,
25.0, 31.8, 34.0 (C(6), C(7), C(8), C(9)), 28.2 (CMe3), 36.7 (C(4)),
71.1 (OCH2Ph), 77.9 (C(5)), 80.1 (CMe3), 125.1 (C(2)), 127.6,
127.8, 128.3 (o,m,p-Ph), 138.6 (i-Ph), 144.2 (C(3)), 165.8 (C(1)); m/
z (ESI+) 687 ([2M + Na]+, 23%), 355 ([M + Na]+, 100%); HRMS
(ESI+) C21H32NaO3+ ([M + Na]+) requires 355.2244; found 355.2246.
tert-Butyl (R,E)-5-(Benzyloxy)dec-2-enoate 30. Step 1. NaH
(60% dispersion in mineral oil, 155 mg, 3.87 mmol) was added to a
solution of (R)-27 (500 mg, 3.52 mmol) in THF (5 mL) at rt, and the
resultant mixture was stirred at rt for 1 h. BnBr (0.44 mL, 3.69 mmol)
was then added, and the resultant mixture was stirred at rt for 18 h.
H2O (5 mL) was cautiously added, and the aqueous layer was
extracted with Et2O (2 × 5 mL). The combined organic extracts were
then dried and concentrated in vacuo to give (R)-28 as a colorless oil
(707 mg).
+
C31H48NO3 ([M + H]+) requires 482.3629; found 482.3614.
tert-Butyl (R,R,R)-3-[N-(3′-Chloropropyl)-N-(α-
methylbenzyl)amino]-5-(benzyloxy)decanoate 33 and tert-
Butyl (3R,5S,αR)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)-
amino]-5-(benzyloxy)decanoate 34. Method A. Following general
procedure 1, (R)-N-(3′-chloropropyl)-N-(α-methylbenzyl)amine15
(6.60 g, 33.4 mmol), BuLi (2.5 M, 12.9 mL, 32.4 mmol), and
(RS,E)-30 (6.95 g, 20.9 mmol, >99:1 dr) in THF (190 mL) were
reacted to give a 50:50 mixture of 33 and 34. Purification via flash
Step 2. Grubbs II catalyst (22 mg, 25.9 μmol) and tert-butyl acrylate
(0.89 mL, 6.08 mmol) were added to a degassed solution of (R)-28
(615 mg, 2.65 mmol) in CH2Cl2 (6 mL, EtOH stabilized), and the
resultant mixture was heated at 40 °C for 24 h. The reaction mixture
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column chromatography (gradient elution, 5% → 6.25% Et2O in 30−
40 °C petrol) gave 34 as a colorless oil (5.11 g, 46%, >99:1 dr);
C32H48ClNO3 requires C, 72.5%; H, 9.1%; N, 2.6%; found C, 72.4%;
HB), 2.22 (1H, dd, J 14.4, 6.3, C(2)HA), 2.29 (1H, dd, J 14.4, 7.3, C(2)
HB), 2.63−2.75 (2H, m, C(1′)H2), 3.41−3.47 (1H, m, C(5)H), 3.51
(2H, app t, J 6.3, C(3)H, C(3′)H2), 3.54 (3H, s, OMe), 3.90 (1H, q, J
6.8, C(α)H), 4.49 (1H, d, J 11.5, OCHAHBPh), 4.59 (1H, d, J 11.5,
OCHAHBPh), 7.21−7.26 (1H, m, Ph), 7.26−7.33 (5H, m, Ph), 7.34−
7.40 (4H, m, Ph); δC (100 MHz, CDCl3) 14.1 (C(10)), 19.0 (C(α)
Me), 22.7, 24.7, 32.1, 33.7 (C(6), C(7), C(8), C(9)), 33.0 (C(2′)),
37.3 (C(4)), 37.4 (C(2)), 43.1 (C(1′)), 43.3 (C(3′)), 51.4 (OMe),
52.3 (C(3)), 58.4 (C(α)), 71.0 (OCH2Ph), 76.7 (C(5)), 126.8, 127.5,
127.8, 127.8, 128.1, 128.3 (o,m,p-Ph), 144.7, 138.9 (i-Ph), 172.9
(C(1)); m/z (ESI+) 512 ([M(37Cl) + Na]+, 34%), 510 ([M(35Cl) +
Na]+, 81%), 490 ([M(37Cl) + H]+, 44%), 488 ([M(35Cl) + H]+,
H, 9.2%; N, 2.65%; [α]24 −11.6 (c 1.0 in CHCl3); vmax (ATR) 1718
D
(CO); δH (500 MHz, CDCl3) 0.91 (3H, t, J 7.3, C(10)H3), 1.25−
1.46 (6H, m, C(7)H2, C(8)H2, C(9)H2), 1.38 (9H, s, CMe3), 1.40
(3H, d, J 6.9, C(α)Me), 1.54−1.62 (4H, m, C(4)H2, C(6)H2), 1.85
(2H, app quintet, J 6.3, C(2′)H2), 2.03−2.06 (2H, m, C(2)H2), 2.56−
2.68 (2H, m, C(1′)H2), 3.44−3.55 (3H, m, C(3)H, C(3′)H2), 3.56−
3.61 (1H, m, C(5)H), 3.88 (1H, q, J 6.9, C(α)H), 4.31 (1H, d, J 11.2,
OCHAHBPh), 4.52 (1H, d, J 11.2, OCHAHBPh), 7.18−7.35 (10H, m,
Ph); δC (125 MHz, CDCl3) 14.1 (C(10)), 20.4 (C(α)Me), 22.7, 24.5,
32.2 (C(7), C(8), C(9)), 28.0 (CMe3), 32.9 (C(2′)), 33.5, 37.5 (C(4),
C(6)), 38.6 (C(2)), 42.8 (C(1′)), 43.2 (C(3′)), 52.8 (C(3)), 58.5
(C(α)), 69.8 (OCH2Ph), 76.6 (C(5)), 80.0 (CMe3), 126.9, 127.1,
127.5, 127.9, 128.1, 128.2 (o,m,p-Ph), 139.2, 144.0 (i-Ph), 172.0
(C(1)); m/z (ESI+) 554 ([M(37Cl) + Na]+, 11%), 552 ([M(35Cl) +
Na]+, 26%), 532 ([M(37Cl) + H]+, 97%), 530 ([M(35Cl) + H]+,
+
100%); HRMS (ESI+) C29H4337ClNO3 ([M(37Cl) + H]+) requires
+
490.2896; found 490.2905; C29H4335ClNO3 ([M(35Cl) + H]+)
requires 488.2926; found 488.2921.
Methyl (3R,5S,αR)-3-[N-(3′-Chloropropyl)-N-(α-
methylbenzyl)amino]-5-(benzyloxy)decanoate 36. Following
general procedure 4, 34 (5.93 g, 11.2 mmol, >99:1 dr) and SOCl2
(1.36 mL, 18.6 mmol) in MeOH (90 mL) were reacted. Purification
via flash column chromatography (gradient elution, 0% → 6% Et2O in
30−40 °C petrol) gave 36 as a colorless oil (3.91 g, 72%, >99:1 dr);
C29H42ClNO3 requires C, 71.4%; H, 8.7%; N, 2.9%; found C, 71.4%;
+
100%); HRMS (ESI+) C32H4937ClNO3 ([M(37Cl) + H]+) requires
+
532.3366; found 532.3392; C32H4935ClNO3 ([M(35Cl) + H]+)
requires 530.3395; found 530.3400. Further elution gave 33 as a
colorless oil (4.57 g, 41%, >99:1 dr); C32H48ClNO3 requires C, 72.5%;
H, 8.7%; N, 2.8%; [α]24 −11.0 (c 1.0 in CHCl3); vmax (ATR) 1733
H, 9.1%; N, 2.6%; found C, 72.45%; H, 9.1%; N, 2.5%; [α]24 −16.2
D
D
(CO); δH (400 MHz, CDCl3) 0.95 (3H, t, J 7.1, C(10)H3), 1.29−
1.45 (6H, m, C(7)H2, C(8)H2, C(9)H2), 1.42 (3H, d, J 6.9, C(α)Me),
1.52−1.74 (4H, m, C(4)H2, C(6)H2), 1.84−1.93 (2H, m, C(2′)H2),
2.17 (1H, dd, J 14.5, 6.1, C(2)HA), 2.24 (1H, dd, J 14.5, 7.8, C(2)HB),
2.61−2.75 (2H, m, C(1′)H2), 3.47−3.63 (4H, m, C(3)H, C(5)H,
C(3′)H2), 3.57 (3H, s, OMe), 3.92 (1H, q, J 6.9, C(α)H), 4.36 (1H, d,
J 11.5, OCHAHBPh), 4.56 (1H, d, J 11.5, OCHAHBPh), 7.20−7.26
(1H, m, Ph), 7.26−7.33 (5H, m, Ph), 7.34−7.40 (4H, m, Ph); δC (100
MHz, CDCl3) 14.1 (C(10)), 19.9 (C(α)Me), 22.7, 24.7, 32.2 (C(7),
C(8), C(9)), 32.9 (C(2′)), 33.7, 37.8 (C(4), C(6)), 37.5 (C(2)), 42.8
(C(3′)), 43.2 (C(1′)), 51.4 (OMe), 52.8 (C(3)), 58.3 (C(α)), 69.8
(OCH2Ph), 76.9 (C(5)), 127.0, 127.3, 127.5, 127.8, 128.2, 128.3
(o,m,p-Ph), 139.1, 144.0 (i-Ph), 173.0 (C(1)); m/z (FI+) 489
([M(37Cl)]+, 32%), 487 ([M(35Cl)]+, 100%); HRMS (FI+)
(c 1.0 in CHCl3); vmax (ATR) 1724 (CO); δH (500 MHz, CDCl3)
0.91 (3H, t, J 7.3, C(10)H3), 1.20−1.47 (9H, m, C(4)HA, C(6)H2,
C(7)H2, C(8)H2, C(9)H2), 1.40 (3H, d, J 6.8, C(α)Me), 1.42 (9H, s,
CMe3), 1.71−1.80 (1H, m, C(2′)HA), 1.82−1.91 (2H, m, C(4)HB,
C(2′)HB), 2.09 (1H, dd, J 14.5, 7.3, C(2)HA), 2.19 (1H, dd, J 14.5, 6.3,
C(2)HB), 2.57−2.69 (2H, m, C(1′)H2), 3.37−3.50 (4H, m, C(3)H,
C(5)H, C(3′)H2), 3.85 (1H, q, J 6.8, C(α)H), 4.53 (2H, app s,
OCH2Ph), 7.20−7.25 (1H, m, Ph), 7.26−7.32 (5H, m, Ph), 7.32−7.40
(4H, m, Ph); δC (125 MHz, CDCl3) 13.1 (C(10)), 19.6 (C(α)Me),
21.7, 23.8, 31.1, 32.7 (C(6), C(7), C(8), C(9)), 27.1 (CMe3), 32.3
(C(2′)), 35.8 (C(4)), 37.1 (C(2)), 42.4, 42.4 (C(1′), C(3′)), 51.8
(C(3)), 57.9 (C(α)), 69.9 (OCH2Ph), 75.7 (C(5)), 79.1 (CMe3),
125.9, 126.4, 126.8, 126.8, 127.1, 127.3 (o,m,p-Ph), 137.9, 143.8 (i-Ph),
170.8 (C(1)); m/z (ESI+) 554 ([M(37Cl) + Na]+, 36%), 552
([M(35Cl) + Na]+, 94%), 532 ([M(37Cl) + H]+, 100%), 530
+
C29H4237ClNO3+ ([M(37Cl)]+) requires 489.2818; found 489.2833;
C29H4235ClNO3 ([M(35Cl)]+) requires 487.2848; found 487.2867.
Methyl (R,R,R)-3-[N-(3′-Azidopropyl)-N-(α-methylbenzyl)-
amino]-5-(benzyloxy)decanoate 37. Following general procedure
2, NaN3 (557 mg, 8.56 mmol), NaI (1.28 g, 8.56 mmol), and 35 (2.09
g, 4.28 mmol, >99:1 dr) in DMSO (8 mL) were reacted. Purification
via flash column chromatography (gradient elution, 0% → 6% Et2O in
30−40 °C petrol) gave 37 as a yellow oil (1.93 g, 91%, >99:1 dr);
C29H42N4O3 requires C, 70.4%; H, 8.6%; N, 11.3%; found C, 70.5%;
+
([M(35Cl) + H]+, 93%); HRMS (ESI+) C32H4937ClNO3 ([M(37Cl)
+
+ H]+) requires 532.3366; found 532.3389; C32H4935ClNO3 ([M-
(35Cl) + H]+) requires 530.3395; found 530.3399.
Method B. Following general procedure 1, (R)-N-(3′-chloroprop-
yl)-N-(α-methylbenzyl)amine15 (190 mg, 962 μmol), BuLi (2.3 M,
0.41 mL, 931 μmol), and (R,E)-30 (200 mg, 602 μmol) in THF (5
mL) were reacted to give 33 in >99:1 dr. Purification via flash column
chromatography (gradient elution, 2% → 10% Et2O in 30−40 °C
petrol) gave 33 as a colorless oil (267 mg, 84%, >99:1 dr).
H, 8.4%; N, 11.3%; [α]24 −33.4 (c 1.0 in CHCl3); vmax (ATR) 2095
D
(NN), 1737 (CO); δH (400 MHz, CDCl3) 0.94 (3H, t, J 7.3,
C(10)H3), 1.26−1.62 (10H, m, C(4)HA, C(6)H2, C(7)H2, C(8)H2,
C(9)H2, C(2′)HA), 1.41 (3H, d, J 6.8, C(α)Me), 1.64−1.73 (1H, m,
C(2′)HB), 1.84−1.91 (1H, m, C(4)HB), 2.23 (1H, dd, J 14.4, 6.3,
C(2)HA), 2.29 (1H, dd, J 14.4, 7.6, C(2)HB), 2.54−2.66 (2H, m,
C(1′)H2), 3.23 (2H, t, J 6.6, C(3′)H2), 3.39−3.46 (1H, m, C(5)H),
3.52−3.59 (1H, m, C(3)H), 3.55 (3H, s, OMe), 3.90 (1H, q, J 6.8,
C(α)H), 4.48 (1H, d, J 11.4, OCHAHBPh), 4.60 (1H, d, J 11.4,
OCHAHBPh), 7.21−7.26 (1H, m, Ph), 7.27−7.33 (5H, m, Ph), 7.34−
7.40 (4H, m, Ph); δC (100 MHz, CDCl3) 14.1 (C(10)), 18.9 (C(α)
Me), 22.7, 24.7, 32.1, 33.7 (C(6), C(7), C(8), C(9)), 29.2 (C(2′)),
37.1 (C(4)), 37.5 (C(2)), 43.0 (C(1′)), 49.4 (C(3′)), 51.4 (OMe),
52.2 (C(3)), 58.3 (C(α)), 71.0 (OCH2Ph), 76.7 (C(5)), 126.8, 127.5,
127.8, 127.9, 128.1, 128.3 (o,m,p-Ph), 138.9, 144.8 (i-Ph), 172.9
(C(1)); m/z (ESI+) 517 ([M + Na]+, 100%), 495 ([M + H]+, 97%);
tert-Butyl (S,S,S)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)-
amino]-5-(benzyloxy)decanoate ent-33 and tert-Butyl
(3S,5R,αS)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)amino]-
5-(benzyloxy)decanoate ent-34. Following general procedure 1,
(S)-N-(3′-chloropropyl)-N-(α-methylbenzyl)amine15 (5.44 g, 27.6
mmol), BuLi (2.1 M, 12.6 mL, 26.5 mmol), and (RS,E)-30 (6.91 g,
20.8 mmol, >99:1 dr) were reacted in THF (190 mL) to give a 50:50
mixture of ent-33 and ent-34. Purification via flash column
chromatography (gradient elution, 5% → 6.25% Et2O in 30−40 °C
petrol) gave ent-34 as a yellow oil (4.36 g, 40%, >99:1 dr); [α]24
D
+13.3 (c 1.0 in CHCl3). Further elution gave ent-33 as a yellow oil
(3.94 g, 36%, >99:1 dr); [α]24 +16.7 (c 1.0 in CHCl3).
D
Methyl (R,R,R)-3-[N-(3′-Chloropropyl)-N-(α-methylbenzyl)-
amino]-5-(benzyloxy)decanoate 35. Following general procedure
4, 33 (3.45 g, 10.8 mmol, >99:1 dr) and SOCl2 (0.79 mL, 10.8 mmol)
in MeOH (50 mL) were reacted. Purification via flash column
chromatography (gradient elution, 0% → 6% Et2O in 30−40 °C
petrol) gave 35 as a yellow oil (2.25 g, 71%, >99:1 dr); C29H42ClNO3
requires C, 71.4%; H, 8.7%; N, 2.9%; found C, 71.3%; H, 8.6%; N,
+
HRMS (ESI+) C29H43N4O3 ([M + H]+) requires 495.3330; found
495.3326.
Methyl (3R,5S,αR)-3-[N-(3′-Azidopropyl)-N-(α-
methylbenzyl)amino]-5-(benzyloxy)decanoate 38. Following
general procedure 2, NaN3 (783 mg, 12.0 mmol), NaI (1.80 g, 12.0
mmol), and 36 (2.94 g, 6.02 mmol, >99:1 dr) in DMSO (10 mL) were
reacted. Purification via flash column chromatography (gradient
elution, 0% → 6% Et2O in 30−40 °C petrol) gave 38 as a yellow
2.7%; [α]24 −30.6 (c 1.0 in CHCl3); vmax (ATR) 1735 (CO); δH
D
(400 MHz, CDCl3) 0.94 (3H, t, J 7.3, C(10)H3), 1.26−1.59 (9H, m,
C(4)HA, C(6)H2, C(7)H2, C(8)H2, C(9)H2), 1.41 (3H, d, J 6.8, C(α)
Me), 1.75−1.83 (1H, m, C(2′)HA), 1.85−1.96 (2H, m, C(4)HB, C(2′)
9732
dx.doi.org/10.1021/jo301830j | J. Org. Chem. 2012, 77, 9724−9737

The Journal of Organic Chemistry
Article
oil (2.36 g, 79%, >99:1 dr); [α]24D −9.4 (c 1.0 in CHCl3); vmax (ATR)
2095 (NN), 1736 (CO); δH (400 MHz, CDCl3) 0.93 (3H, t, J
6.8, C(10)H3), 1.27−1.43 (6H, m, C(7)H2, C(8)H2, C(9)H2), 1.39
(3H, d, J 6.8, C(α)Me), 1.50−1.75 (6H, m, C(4)H2, C(6)H2, C(2′)
H2), 2.19 (1H, dd, J 14.5, 6.3, C(2)HA), 2.25 (1H, dd, J 14.5, 7.3, C(2)
HB), 2.58 (2H, t, J 7.6, C(1′)H2), 3.23 (2H, t, J 6.6, C(3′)H2), 3.50−
3.59 (2H, m, C(3)H, C(5)H), 3.56 (3H, s, OMe), 3.90 (1H, q, J 6.8,
C(α)H), 4.34 (1H, d, J 11.4, OCHAHBPh), 4.53 (1H, d, J 11.4,
OCHAHBPh), 7.19−7.25 (1H, m, Ph), 7.25−7.31 (5H, m, Ph), 7.32−
7.38 (4H, m, Ph); δC (100 MHz, CDCl3) 14.1 (C(10)), 19.7 (C(α)
Me), 22.7, 24.7, 29.2, 32.1, 33.7, 37.6 (C(4), C(6), C(7), C(8), C(9),
C(2′)), 37.7 (C(2)), 42.9 (C(1′)), 49.4 (C(3′)), 51.4 (OMe), 53.0
(C(3)), 58.3 (C(α)), 69.9 (OCH2Ph), 77.0 (C(5)), 127.0, 127.3,
127.5, 127.8, 128.2, 128.3 (o,m,p-Ph), 139.0, 144.1 (i-Ph), 173.0
(C(1)); m/z (ESI+) 517 ([M + Na]+, 100%), 495 ([M + H]+, 95%);
Step 2. Following general procedure 2, NaN3 (1.16 g, 17.9 mmol),
NaI (2.68 g, 17.9 mmol), and ent-35 (3.61 g, >99:1 dr) in DMSO (10
mL) were reacted to give ent-37 as a yellow oil (3.18 g, >99:1 dr).
Step 3. Following general procedure 3, ent-37 (3.18 g, >99:1 dr)
and PBu3 (1.77 mL, 7.09 mmol) in THF (30 mL) and H2O (8.0 mL)
were reacted to give ent-39 as a yellow oil (3.05 g, >99:1 dr).
Step 4. Following general procedure 5, ent-39 (3.05 g, >99:1 dr)
and Sb(OEt)3 (1.31 mL, 7.71 mmol) in PhMe (550 mL) were reacted.
Purification via flash column chromatography (eluent EtOAc) gave
ent-41 as a yellow oil (1.81 g, 60% over four steps, >99:1 dr); [α]24
D
−2.7 (c 1.0 in CHCl3).
(4R,2′S,αR)-4-[2′-(Benzyloxy)heptyl]-N(5)-(α-methylbenzyl)-
1,5-diazocan-2-one 42. Step 1. Following general procedure 3, 38
(2.55 g, 5.16 mmol, >99:1 dr) and PBu3 (1.32 mL, 5.28 mmol) in
THF (15 mL) and H2O (1.7 mL) were reacted to give 40 as a yellow
oil (3.54 g, >99:1 dr); δH (400 MHz, CDCl3) [selected peaks] 2.13−
2.24 (2H, m, C(2)H2), 2.52 (2H, td, J 7.3, 2.4, C(3′)H2), 2.59−2.67
(2H, m, C(1′)H2), 3.47−3.58 (2H, m, C(3)H, C(5)H), 3.54 (3H, s,
OMe), 3.92 (1H, q, J 6.8, C(α)H), 4.32 (1H, d, J 11.4, OCHAHBPh),
4.51 (1H, d, J 11.4, OCHAHBPh), 7.16−7.36 (10H, m, Ph).
Step 2. Following general procedure 5, 40 (3.54 g, >99:1 dr) and
Sb(OEt)3 (0.87 mL, 5.12 mmol) in PhMe (450 mL) were reacted.
Purification via flash column chromatography (eluent EtOAc) gave 42
as a yellow oil (1.86 g, 83% over two steps, >99:1 dr); C28H40N2O2
requires C, 77.0%; H, 9.2%; N, 6.4%; found C, 76.9%; H, 9.2%; N,
+
HRMS (ESI+) C29H43N4O3 ([M + H]+) requires 495.3330; found
495.3331.
(R,R,R)-4-[2′-(Benzyloxy)heptyl]-N(5)-(α-methylbenzyl)-1,5-
diazocan-2-one 41. Step 1. Following general procedure 3, 37 (2.45
g, 4.95 mmol, >99:1 dr) and PBu3 (1.32 mL, 5.28 mmol) in THF (15
mL) and H2O (1.7 mL) were reacted to give 39 as a yellow oil (3.48 g,
>99:1 dr); δH (400 MHz, CDCl3) [selected peaks] 2.17 (1H, dd, J
14.3, 6.7, C(2)HA), 2.25 (1H, dd, J 14.3, 7.2, C(2)HB), 2.48−2.65
(4H, m, C(1′)H2, C(3′)H2), 3.35−3.50 (2H, m, C(3)H, C(5)H), 3.52
(3H, s, OMe), 3.91 (1H, q, J 6.8, C(α)H), 4.45 (1H, d, J 11.4,
OCHAHBPh), 4.55 (1H, d, J 11.4, OCHAHBPh), 7.17−7.37 (10H, m,
Ph).
6.4%; [α]24 +2.5 (c 1.0 in CHCl3); vmax (ATR) 1658 (CO); δH
D
(400 MHz, CDCl3) 0.90 (3H, t, J 6.8, C(7′)H3), 1.02−1.12 (1H, m,
C(7)HA), 1.19−1.63 (12H, m, C(7)HB, C(3′)H2, C(4′)H2, C(5′)H2,
C(6′)H2, C(α)Me), 1.63−1.72 (1H, m, C(1′)HA), 1.85 (1H, br s,
C(1′)HB), 2.50−2.61 (3H, m, C(3)H2, C(6)HA), 2.81−2.90 (1H, m,
C(6)HB), 3.17−3.32 (2H, m, C(8)H2), 3.46 (1H, app quintet, J 5.8,
C(2′)H), 3.54−3.64 (1H, m, C(4)H), 3.74 (1H, q, J 6.5, C(α)H), 4.50
(1H, d, J 11.4, OCHAHBPh), 4.55 (1H, d, J 11.4, OCHAHBPh), 5.55−
5.66 (1H, m, NH), 7.19−7.24 (1H, m, Ph), 7.25−7.30 (4H, m, Ph),
7.31−7.39 (5H, m, Ph); δC (100 MHz, CDCl3) 14.2 (C(7′)), 21.9
(C(α)Me), 22.7, 24.8, 32.0, 34.0 (C(3′), C(4′), C(5′), C(6′)), 32.4
(C(7)), 33.2 (C(1′)), 38.8 (C(3)), 42.5 (C(8)), 45.6 (C(6)), 54.2
(C(4)), 62.5 (C(α)), 70.5 (OCH2Ph), 77.5 (C(2′)), 126.9, 127.4,
127.9, 128.0, 128.1, 128.3 (o,m,p-Ph), 138.9, 146.2 (i-Ph), 176.9
(C(2)); m/z (ESI+) 896 ([2M + Na]+, 100%), 874 ([2M + H]+, 18%),
459 ([M + Na]+, 96%), 437 ([M + H]+, 94%); HRMS (ESI+)
Step 2. Following general procedure 5, 39 (3.48 g, >99:1 dr) and
Sb(OEt)3 (0.87 mL, 5.12 mmol) in PhMe (450 mL) were reacted.
Purification via flash column chromatography (eluent EtOAc) gave 41
as a yellow oil (1.80 g, 83% over two steps, >99:1 dr); [α]24D −16.9 (c
1.0 in CHCl3); vmax (ATR) 1661 (CO); δH (400 MHz, CDCl3) 0.91
(3H, t, J 7.0, C(7′)H3), 1.06−1.16 (1H, br m, C(7)HA), 1.24−1.45
(7H, m, C(7)HB, C(4′)H2, C(5′)H2, C(6′)H2), 1.37 (3H, d, J 6.6,
C(α)Me), 1.49−1.59 (1H, m, C(1′)HA), 1.62−1.76 (3H, m, C(1′)HB,
C(3′)H2), 2.33 (1H, br s, C(3)HA), 2.49 (1H, dd, J 12.4, 4.3, C(3)
HB), 2.52−2.60 (1H, m, C(6)HA), 2.77 (1H, br t, J 13.1, C(6)HB),
3.12−3.23 (1H, br m, C(8)HA), 3.39 (1H, br s, C(8)HB), 3.49−3.58
(1H, m, C(2′)H), 3.69−3.83 (2H, m, C(4)H, C(α)H), 4.44 (1H, d, J
11.4, OCHAHBPh), 4.62 (1H, d, J 11.4, OCHAHBPh), 5.51 (1H, br s,
NH), 7.19−7.24 (1H, m, Ph), 7.25−7.30 (4H, m, Ph), 7.31−7.35 (5H,
m, Ph); δC (100 MHz, CDCl3) 14.2 (C(7′)), 22.7 (C(α)Me), 24.7,
32.4 (C(4′), C(5′), C(6′)), 32.2 (C(7)), 33.5 (C(3′)), 34.4 (C(1′)),
38.3 (C(3)), 41.7 (C(8)), 45.0 (C(6)), 52.4 (C(4)), 62.6 (C(α)), 71.1
(OCH2Ph), 76.7 (C(2′)), 126.8, 127.4, 127.8, 128.0, 128.1, 128.3
(o,m,p-Ph), 138.9, 146.2 (i-Ph), 176.7 (C(2));41 δH (500 MHz, PhMe-
d8, 363 K) 0.78−0.85 (1H, m, C(7)HA), 0.94 (3H, t, J 6.6, C(7′)H3),
1.10−1.19 (1H, m, C(7)HB), 1.30−1.84 (10H, m, C(1′)H2, C(3′)H2,
C(4′)H2, C(5′)H2, C(6′)H2), 1.34 (3H, d, J 6.6, C(α)Me), 2.25 (1H,
dd, J 12.5, 7.6, C(3)HA), 2.41 (1H, dd, J 12.5, 4.1, C(3)HB), 2.46 (1H,
app dt, J 15.5, 3.2, C(6)HA), 2.65 (1H, app dt, J 12.6, 2.8, C(6)HB),
2.69−2.76 (1H, m, C(8)HA), 3.07−3.16 (1H, m, C(8)HB), 3.55−3.62
(1H, m, C(2′)H), 3.70−3.79 (2H, m, C(4)H, C(α)H), 4.36 (1H, d, J
11.7, OCHAHBPh), 4.53 (1H, d, J 11.7, OCHAHBPh), 5.72 (1H, br s,
NH), 7.05−7.13 (2H, m, Ph), 7.16 (2H, app t, J 7.6, Ph), 7.20 (2H, t, J
7.3, Ph), 7.29 (4H, app dd, J 14.5, 7.3, Ph); δC (125 MHz, PhMe-d8,
363 K) 14.0 (C(7′)), 20.6 (C(α)Me), 22.9, 25.0, 33.2, 34.6, 34.9
(C(1′), C(3′), C(4′), C(5′), C(6′)), 32.5 (C(7)), 38.5 (C(3)), 41.2
(C(8)), 44.3 (C(6)), 53.1 (C(4)), 63.1 (C(α)), 71.4 (OCH2Ph), 77.4
(C(2′)), 126.9, 127.4, 128.0, 128.2, 128.4, 128.4 (o,m,p-Ph), 139.9,
146.6 (i-Ph), 174.9 (C(2)); m/z (ESI+) 896 ([2M + Na]+, 97%), 459
([M + Na]+, 100%), 437 ([M + H]+, 91%); HRMS (ESI+)
+
C28H41N2O2 ([M + H]+) requires 437.3163; found 437.3175.
(4S,2′R,αS)-4-[2′-(Benzyloxy)heptyl]-N(5)-(α-methylbenzyl)-
1,5-diazocan-2-one ent-42. Step 1. Following general procedure 4,
ent-34 (4.36 g, 8.22 mmol, >99:1 dr) and SOCl2 (1.05 mL, 14.5
mmol) in MeOH (70 mL) were reacted to give ent-36 sas a yellow oil
(4.20 g, >99:1 dr).
Step 2. Following general procedure 2, NaN3 (1.16 g, 17.9 mmol),
NaI (2.68 g, 17.9 mmol), and ent-36 (4.20 g, >99:1 dr) in DMSO (10
mL) were reacted to give ent-38 as a yellow oil (3.66 g, >99:1 dr).
Step 3. Following general procedure 3, ent-38 (3.66 g, >99:1 dr)
and PBu3 (2.03 mL, 8.13 mmol) in THF (30 mL) and H2O (8.0 mL)
were reacted to give ent-40 as a yellow oil (3.46 g, >99:1 dr).
Step 4. Following general procedure 5, ent-40 (3.46 g, >99:1 dr)
and Sb(OEt)3 (1.50 mL, 8.77 mmol) in PhMe (650 mL) were reacted.
Purification via flash column chromatography (eluent EtOAc) gave
ent-42 as a yellow oil (2.48 g, 69% over four steps, >99:1 dr); [α]24
D
+16.0 (c 1.0 in CHCl3).
(R,R)-4-(2′-Hydroxyheptyl)-1,5-diazocan-2-one 43. Following
general procedure 7, 41 (140 mg, 321 μmol, >99:1 dr) and Pd(OH)2/
C (70 mg) in MeOH (2.1 mL) were reacted for 24 h to give 43 as a
white solid (49 mg, 63%, >99:1 dr); mp 84−86 °C; [α]24D +7.9 (c 1.0
in CHCl3); vmax (ATR) 3289 (N−H, O−H), 1651 (CO); δH (400
MHz, CDCl3) 0.84 (3H, t, J 7.3, C(7′)H3), 1.18−1.55 (12H, m, C(1′)
H2, C(3′)H2, C(4′)H2, C(5′)H2, C(6′)H2), 1.61−1.74 (2H, m, C(7)
H2), 2.36 (1H, dd, J 12.5, 2.7, C(3)HA), 2.53 (1H, dd, J 12.5, 9.7, C(3)
HB), 2.63−2.71 (1H, m, C(6)HA), 3.06 (1H, dt, J 10.4, 4.4, C(6)HB),
3.21−3.31 (2H, m, C(4)H, C(8)HA), 3.40−3.50 (1H, m, C(8)HB),
3.59−3.99 (3H, br m, C(2′)H, N(5)H, OH), 6.88 (1H, br s, N(1)H);
δC (100 MHz, CDCl3) 14.0 (C(7′)), 22.6, 25.0, 31.8, 38.0 (C(3′),
+
C28H41N2O2 ([M + H]+) requires 437.3163; found 437.3159.
(S,S,S)-4-[2′-(Benzyloxy)heptyl]-N(5)-(α-methylbenzyl)-1,5-
diazocan-2-one ent-41. Step 1. Following general procedure 4, ent-
33 (3.69 g, 6.96 mmol, >99:1 dr) and SOCl2 (0.91 mL, 12.5 mmol) in
MeOH (60 mL) were reacted to give ent-35 as a yellow oil (3.61 g,
>99:1 dr).
9733
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The Journal of Organic Chemistry
Article
C(4′), C(5′), C(6′)), 33.9 (C(7)), 40.9 (C(3)), 41.0 (C(8)), 41.4
(C(1′)), 42.8 (C(6)), 58.9 (C(4)), 72.4 (C(2′)), 175.9 (C(2)); m/z
(ESI+) 507 ([2M + Na]+, 100%), 485 ([2M + H]+, 93%), 265 ([M +
Na]+, 51%), 243 ([M + H]+, 97%); HRMS (ESI+) C13H27N2O2+ ([M
+ H]+) requires 243.2067; found 243.2071.
layer was extracted with CHCl3 (2 × 30 mL), and the combined
organic extracts were then dried (Na2SO4) and concentrated in vacuo
to give ent-45 as a colorless oil (1.03 g, quant, >99:1 dr); [α]24 +1.1
D
(c 1.0 in CHCl3).
(4R,2′S)-4-(2′-Hydroxyheptyl)-N(5)-methyl-1,5-diazocan-2-
one 46. Method A. Following general procedure 8, 44 (70 mg, 289
μmol, >99:1 dr), (CH2O)n (17 mg, 578 μmol), and NaBH3CN (73
mg, 1.16 mmol) in MeOH (3 mL) were reacted. Purification via flash
column chromatography (eluent CH2Cl2/MeOH, 19:1) gave 46 as a
(4R,2′S)-4-(2′-Hydroxyheptyl)-1,5-diazocan-2-one 44. Fol-
lowing general procedure 7, 42 (160 mg, 366 μmol, >99:1 dr) and
Pd(OH)2/C (80 mg) in MeOH (2 mL) were reacted for 24 h to give
44 as a colorless oil (72 mg, 81%, >99:1 dr); [α]24 +13.4 (c 1.0 in
D
colorless oil (30 mg, 40%, >99:1 dr); [α]24 −1.2 (c 1.0 in CHCl3);
CHCl3); vmax (ATR) 3298 (N−H, O−H), 1649 (CO); δH (400
MHz, CDCl3) 0.83 (3H, t, J 6.8, C(7′)H3), 1.16−1.77 (12H, m, C(7)
H2, C(1′)H2, C(3′)H2, C(4′)H2, C(5′)H2, C(6′)H2), 2.37 (1H, app d,
J 12.1, C(3)HA), 2.51−2.63 (2H, m, C(3)HB, C(6)HA), 3.03−3.12
(1H, m, C(6)HB), 3.20−3.30 (1H, m, C(8)HA), 3.30−3.39 (1H, m,
C(4)H), 3.41−3.54 (1H, m, C(8)HB), 3.69−3.77 (1H, m, C(2′)H),
4.06 (2H, br s, N(5)H, OH), 6.86 (1H, br s, N(1)H); δC (100 MHz,
CDCl3) 14.0 (C(7′)), 22.6, 25.5, 31.8, 33.2, 37.5 (C(7), C(3′), C(4′),
C(5′), C(6′)), 39.6 (C(3)), 40.4 (C(8)), 41.8 (C(1′)), 43.1 (C(6)),
55.7 (C(4)), 68.7 (C(2′)), 176.4 (C(2)); m/z (ESI+) 750 ([3M +
Na]+, 10%), 727 ([3M + H]+, 4%), 507 ([2M + Na]+, 100%), 265 ([M
D
vmax (ATR) 3293 (O−H), 1654 (CO); δH (400 MHz, CDCl3) 0.79
(3H, t, J 6.6, C(7′)H3), 1.15−1.50 (10H, m, C(7)HA, C(1′)HA, C(3′)
H2, C(4′)H2, C(5′)H2, C(6′)H2), 1.70−1.85 (2H, m, C(7)HB, C(1′)
HB), 2.40 (5H, app s, C(3)H2, NMe), 2.57 (1H, br dt, J 15.4, 3.5, C(6)
HA), 2.85 (1H, app br t, J 12.1, C(6)HB), 3.16−3.28 (3H, m, C(4)H,
C(8)H2), 3.57 (1H, br s, C(2′)H), 3.89 (1H, br s, OH), 7.05 (1H, br t,
J 6.6, NH); δC (100 MHz, CDCl3) 14.0 (C(7′)), 22.6, 25.6, 30.4, 31.9,
36.9, 37.7 (C(7), C(1′), C(3′), C(4′), C(5′), C(6′)), 37.2 (C(3)), 40.1
(NMe), 41.6 (C(8)), 45.7 (C(6)), 60.0 (C(4)), 70.0 (C(2′)), 177.1
(C(2)); m/z (ESI+) 535 ([2M + Na]+, 44%), 279 ([M + Na]+, 65%),
+
+ Na]+, 24%), 243 ([M + H]+, 22%); HRMS (ESI+) C13H27N2O2
+
257 ([M + H]+, 100%); HRMS (ESI+) C14H29N2O2 ([M + H]+)
([M + H]+) requires 243.2067; found 243.2066.
requires 257.2224; found 257.2220.
(R,R)-4-(2′-Hydroxyheptyl)-N(5)-methyl-1,5-diazocan-2-one
45. Method A. Following general procedure 8, 43 (97 mg, 400 μmol,
>99:1 dr), (CH2O)n (24 mg, 799 μmol), and NaBH3CN (101 mg,
1.61 mmol) in MeOH (4 mL) were reacted. Purification via flash
column chromatography (eluent CH2Cl2/MeOH, 19:1) gave 45 as a
Method B. Following general procedure 7, 42 (154 mg, 353 μmol,
>99:1 dr), (CH2O)n (20 mg, 666 μmol), and Pd(OH)2/C (77 mg) in
AcOH (2.3 mL) were reacted for 24 h. The residue was partitioned
between CHCl3 (10 mL) and satd aq NaHCO3 (10 mL). The aqueous
layer was extracted with CHCl3 (2 × 10 mL), and the combined
organic extracts were then dried (Na2SO4) and concentrated in vacuo
to give 46 as a colorless oil (90 mg, quant, >99:1 dr).
colorless oil (46 mg, 45%, >99:1 dr); [α]24 −1.2 (c 1.0 in CHCl3);
D
vmax (ATR) 3291 (O−H), 1657 (CO); δH (400 MHz, CDCl3) 0.79
(3H, t, J 6.5, C(7′)H3), 1.12−1.40 (9H, m, C(1′)HA, C(3′)H2, C(4′)
H2, C(5′)H2, C(6′)H2), 1.43−2.57 (2H, m, C(7)HA, C(1′)HB), 1.88−
1.99 (1H, m, C(7)HB), 2.20−2.43 (2H, m, C(3)H2), 2.45 (3H, s,
NMe), 2.72 (1H, app br d, J 15.4, C(6)HA), 2.97 (1H, app br t, J 12.4,
C(6)HB), 3.17−3.34 (3H, m, C(4)H, C(8)H2), 3.68 (1H, br s, C(2′)
H), 7.18 (1H, br s, NH); δC (100 MHz, CDCl3) 14.0 (C(7′)), 22.6,
25.0, 29.6, 31.8, 37.9 (C(7), C(1′), C(3′), C(4′), C(5′), C(6′)), 36.7
(C(3)), 39.0 (NMe), 41.9 (C(8)), 45.4 (C(6)), 63.4 (C(4)), 72.5
(C(2′)), 176.5 (C(2));42 m/z (ESI+) 535 ([2M + Na]+, 25%), 279
([M + Na]+, 59%), 257 ([M + H]+, 100%); HRMS (ESI+)
(4S,2′R)-4-(2′-Hydroxyheptyl)-N(5)-methyl-1,5-diazocan-2-
one ent-46. Following general procedure 7, ent-42 (50 mg, 115 μmol,
>99:1 dr), (CH2O)n (7 mg, 233 μmol), and Pd(OH)2/C (25 mg) in
AcOH (0.75 mL) were reacted for 24 h. The residue was partitioned
between CHCl3 (4 mL) and satd aq NaHCO3 (4 mL). The aqueous
layer was extracted with CHCl3 (2 × 44 mL), and the combined
organic extracts were then dried (Na2SO4) and concentrated in vacuo.
Purification via flash column chromatography (gradient elution, 1% →
5% MeOH in CHCl3) gave ent-46 as a colorless oil (25 mg, 85%,
>99:1 dr); [α]24 +1.3 (c 1.0 in CHCl3).
+
C14H29N2O2 ([M + H]+) requires 257.2224; found 257.2219.
D
(4′R,4″R,2‴S,αR)-1-[2′-Oxo-4′-pentyl-N(5′)-methyl-1′,5′-di-
azocan-N(1′)-yl]-4-{2″-oxo-4″-[2‴-(benzyloxy)heptyl]-N(5″)-(α-
methylbenzyl)-1″,5″-diazocan-N(1′)-yl}butane 48. Following
general procedure 6B, 42 (104 mg, 238 μmol, >99:1 dr), 1815 (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% → 3% MeOH in CHCl3) gave 48 as a colorless
Method B. Following general procedure 7, 41 (150 mg, 344 μmol,
>99:1 dr), (CH2O)n (21 mg, 699 μmol), and Pd(OH)2/C (75 mg) in
MeOH (2.0 mL) were reacted for 72 h. Purification via flash column
chromatography (gradient elution, 1% → 8% MeOH in CH2Cl2) gave
47 as a colorless oil (12 mg, 14%, >99:1 dr); [α]24 −26.7 (c 0.6 in
D
CHCl3); vmax (ATR) 1663 (CO); δH (500 MHz, CDCl3) 0.88 (3H,
t, J 7.3, CH3), 1.23−1.55 (10H, m, C(4)H2, C(3)CH2CH2CH2CH2),
1.59−1.66 (1H, m, C(9)HA), 1.69−1.78 (1H, m, C(9)HB), 2.27 (1H,
br s, C(5)HA), 2.59 (1H, br t, J 10.7, C(5)HB), 2.85 (2H, br s, C(10)
H2), 3.21−3.47 (4H, m, C(3)H, C(4a)H, C(8)H2), 4.23 (1H, br d, J
9.2, C(1)HA), 4.46 (1H, d, J 9.2, C(1)HB), 5.98 (1H, br s, NH); δC
(125 MHz, CDCl3) 14.0 (CH3), 22.6, 24.7, 31.8, 33.2 (C(3)
CH2CH2CH2CH2), 33.7 (C(9)), 36.2 (C(4)), 38.7 (C(5)), 42.8
(C(8)), 47.4 (C(10)), 58.6 (C(4a)), 77.0 (C(3)), 87.7 (C(1)), 175.3
(C(6)); m/z (ESI+) 531 ([2M + Na]+, 88%), 509 ([2M + H]+, 54%),
277 ([M + Na]+, 100%), 255 ([M + H]+, 86%); HRMS (ESI+)
C14H27N2O2+ ([M + H]+) requires 255.2067; found 255.2068. Further
elution gave 45 as a colorless oil (26 mg, 29%, >99:1 dr).
oil (32 mg, 21%, >99:1 dr); [α]24 −16.9 (c 1.0 in CHCl3); vmax
D
(ATR) 1632 (CO); δH (500 MHz, PhMe-d8, 363 K) 0.85−1.01
(7H, m, C(4′)(CH2)4CH3, C(7″)HA, C(7‴)H3), 1.18−1.69 (27H, m,
C(2)H2, C(3)H2, C(7′)HA, C(4′)(CH2)4, C(7″)HB, C(1‴)H2, C(3‴)
H2, C(4‴)H2, C(5‴)H2, C(6‴)H2, C(α)Me), 1.98 (1H, br s, C(7′)
HB), 2.33 (3H, s, NMe), 2.34−2.48 (4H, m, C(3′)H2, C(6′)HA, C(3″)
HA), 2.53 (1H, br dt, J 15.1, 2.5, C(6″)HA), 2.58−2.77 (3H, m, C(6′)
HB, C(3″)HB, C(6″)HB), 2.86−2.93 (1H, m, C(4′)H), 3.02−3.21
(3H, m, NCHA HB (CH2 )2 CH2 ), 3.22−3.33 (3H, m,
NCHAHB(CH2)2CH2, C(8′)HA, C(8″)HA), 3.35−3.45 (1H, m,
C(8″)HB), 3.45−3.60 (3H, m, C(8′)HB, C(4″)H, C(2‴)H), 3.75
(1H, q, J 6.3, C(α)H), 4.56 (2H, s, OCH2Ph), 6.98−7.03 (1H, m, Ph),
7.06−7.13 (2H, m, Ph), 7.15−7.23 (4H, m, Ph), 7.25−7.30 (2H, m,
Ph), 7.39−7.45 (1H, m, Ph); δC (125 MHz, PhMe-d8, 363 K) 14.0
(C(4′)(CH2)4CH3, C(7‴)), 21.3 (C(α)Me), 22.9, 25.2, 26.1, 27.0,
29.1, 31.5, 32.3, 32.4, 34.4 (C(2), C(3), C(4′)(CH2)4, C(1‴), C(3‴),
C(4‴), C(5‴), C(6‴)), 30.5 (C(7″)), 34.6 (C(7′)), 39.0 (C(3″)), 39.9
(NMe), 40.4 (C(3′)), 44.7 (C(6″)), 45.8, 47.4, 47.7 (C(1), C(4),
C(8′)), 45.8 (C(8″)), 47.2 (C(6′)), 54.9 (C(4″)), 62.6 (C(α)), 63.6
(C(4′)), 70.8 (OCH2Ph), 77.9 (C(2‴)), 127.1, 127.3, 128.1, 128.3,
129.0 (o,m,p-Ph), 140.2, 146.6 (i-Ph), 172.3 (C(2′), C(2″)); m/z
(ESI+) 726 ([M + Na]+, 100%), 704 ([M + H]+, 56%); HRMS (ESI+)
Method C. Following general procedure 7, 41 (750 mg, 1.72 mmol,
>99:1 dr), (CH2O)n (98 mg, 3.26 mmol), and Pd(OH)2/C (375 mg)
in AcOH (11.3 mL) were reacted for 24 h. The residue was
partitioned between CHCl3 (10 mL) and satd aq NaHCO3 (10 mL).
The aqueous layer was extracted with CHCl3 (2 × 10 mL), and the
combined organic extracts were then dried (Na2SO4) and concen-
trated in vacuo to give 45 as a colorless oil (395 mg, 90%, >99:1 dr).
(S,S)-4-(2′-Hydroxyheptyl)-N(5)-methyl-1,5-diazocan-2-one
ent-45. Following general procedure 7, ent-41 (1.75 g, 4.01 mmol,
>99:1 dr), (CH2O)n (229 mg, 7.63 mmol), and Pd(OH)2/C (875 mg)
in AcOH (25 mL) were reacted for 24 h. The residue was partitioned
between CHCl3 (30 mL) and satd aq NaHCO3 (30 mL). The aqueous
+
C44H71N4O3 ([M + H]+) requires 703.5521; found 703.5537.
9734
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The Journal of Organic Chemistry
Article
(4′R,4″R,2‴S)-1-[2′-Oxo-4′-pentyl-N(5′)-methyl-1′,5′-diazo-
can-N(1′)-yl]-4-[2″-oxo-4″-(2‴-hydroxyheptyl)-N(5″)-methyl-
1″,5″-diazocan-N(1″)-yl]butane 49. Method A. Following general
procedure 6A, 46 (39 mg, 152 μmol, >99:1 dr), 1815 (48 mg, 138
μmol), KOH (34 mg, 609 μmol), K2CO3 (26 mg, 185 μmol), and
TEBAC (4 mg, 19.0 μmol) in DMSO (0.75 mL) were reacted for 48
h. Purification via column chromatography (gradient elution, 1% →
4% MeOH in CHCl3) gave 49 as a colorless oil (19 mg, 26%, >99:1
C(7″)H2, C(1‴)H2, C(3‴)H2, C(4‴)H2, C(5‴)H2, C(6‴)H2, C(4′)-
(CH2)4), 2.30 (3H, s, NMe), 2.32−2.46 (4H, m, C(3′)H2, C(6′)HA,
C(6″)HA), 2.33 (3H, s, NMe), 2.52−2.57 (2H, m, C(3″)H2), 2.63
(1H, ddd, J 14.8, 11.0, 3.2, C(6″)HB), 2.72 (1H, ddd, ′J 13.9, 10.1, 2.8,
C(6′)HB), 2.88−2.93 (1H, m, C(4′)H), 3.00 (1H, app dt, J 15.1, 4.7,
C(8″)HA), 3.05−3.42 (8H, m, C(1)H2, C(4)H2, C(8′)H2, C(4″)H,
C(8″)HB), 3.61−3.67 (1H, m, C(2‴)H); δC (125 MHz, PhMe-d8, 363
K) 14.2, 14.2 (C(7‴), C(4′)(CH2)4CH3), 23.1, 23.2, 26.1, 26.1, 26.2,
27.2, 29.1, 29.4, 31.7, 32.5, 32.7, 38.3, 38.7 (C(2), C(3), C(7′), C(7″),
C(1‴), C(3‴), C(4‴), C(5‴), C(6‴), C(4′)(CH2)4), 39.2, 39.5
(C(3′), C(3″)), 40.2 (NMe), 40.8 (NMe), 45.9, 46.0, 46.2, 47.1, 47.5,
47.7 (C(1), C(4), C(6′), C(6″), C(8′), C(8″)), 61.9 (C(4″)), 63.9
(C(4′)), 70.3 (C(2‴)), 172.7, 173.2 (C(2′), C(2″)); m/z (ESI+) 545
([M + Na]+, 58%), 523 ([M + H]+, 100%); HRMS (ESI+)
dr); [α]24 −18.4 (c 1.0 in CHCl3); vmax (ATR) 3399 (O−H), 1626
D
(CO); δH (500 MHz, PhMe-d8, 363 K) 0.88−0.97 (6H, m, C(7‴)
H3, C(4′)(CH2)4CH3), 1.21−1.63 (26H, m, C(2)H2, C(3)H2, C(7′)
H2, C(7″)H2, C(1‴)H2, C(3‴)H2, C(4‴)H2, C(5‴)H2, C(6‴)H2,
C(4′)(CH2)4), 2.31 (3H, s, NMe), 2.32−2.47 (4H, m, C(3′)H2, C(6′)
HA, C(6″)HA), 2.33 (3H, s, NMe), 2.51−2.58 (2H, m, C(3″)H2), 2.64
(1H, app ddd, J 15.5, 11.0, 2.8, C(6″)HB), 2.72 (1H, app ddd, J 14.8,
10.1, 3.5, C(6′)HB), 2.87−2.96 (1H, m, C(4′)H), 3.01 (1H, dt, J 15.5,
4.7, C(8″)HA), 3.07−3.43 (8H, m, C(1)H2, C(4)H2, C(8′)H2, C(4″)
H, C(8″)HB), 3.61−3.69 (1H, m, C(2‴)H); δC (125 MHz, PhMe-d8,
363 K) 14.2, 14.2 (C(7‴), C(4′)(CH2)4CH3), 23.1, 23.2, 26.1, 26.1,
26.2, 27.2, 29.1, 29.4, 30.3, 32.5, 32.7, 38.3, 38.7 (C(2), C(3), C(7′),
C(7″), C(1‴), C(3‴), C(4‴), C(5‴), C(6‴), C(4′)(CH2)4), 39.2, 39.5
(C(3′), C(3″)), 40.2 (NMe), 40.8 (NMe), 46.0, 46.0, 46.3, 47.2, 47.5,
47.7 (C(1), C(4), C(6′), C(6″), C(8′), C(8″)), 61.9 (C(4″)), 63.9
(C(4′)), 70.2 (C(2‴)), 172.7, 173.2 (C(2′), C(2″)); m/z (ESI+) 545
([M + Na]+, 100%), 523 ([M + H]+, 95%); HRMS (ESI+)
+
C30H59N4O3 ([M + H]+) requires 523.4582; found 523.4574.
(4′R,4″S,2‴S)-1-[2′-Oxo-4′-pentyl-N(5′)-methyl-1′,5′-diazo-
can-N(1′)-yl]-4-[2″-oxo-4″-(2‴-hydroxyheptyl)-N(5″)-methyl-
1″,5″-diazocan-N(1″)-yl}butane 52. Following general procedure
6A, ent-45 (142 mg, 554 μmol, >99:1 dr), 18 (175 mg, 504 μmol),
KOH (125 mg, 2.23 mmol), K2CO3 (92 mg, 664 μmol), and TEBAC
(15 mg, 66 μmol) were reacted in DMSO (2.9 mL) for 60 h.
Purification via column chromatography (gradient elution, 1% → 4%
MeOH in CHCl3) and further purification via supercritical fluid chiral
HPLC (eluent MeOH/CO2/diethanolamine, 49.9:50:0.1) gave 52 as a
colorless oil (11 mg, 4%, >99:1 dr); [α]24D +5.8 (c 1.0 in CHCl3); vmax
(ATR) 3405 (O−H), 1622 (CO); δH (500 MHz, PhMe-d8, 363 K)
0.88−1.01 (6H, m, C(7‴)H3, C(4′)(CH2)4CH3), 1.14−1.68 (26H, m,
C(2)H2, C(3)H2, C(7′)H2, C(7″)H2, C(1‴)H2, C(3‴)H2, C(4‴)H2,
C(5‴)H2, C(6‴)H2, C(4′)(CH2)4), 2.26 (3H, s, NMe), 2.28−2.50
(6H, m, C(3′)H2, C(6′)HA, C(3″)H2, C(6″)HA), 2.34 (3H, s, NMe),
2.72 (2H, app t, J 12.5, C(6′)HB, C(6″)HB), 2.91 (1H, br s, C(4′)H),
2.99−3.44 (9H, m, C(1)H2, C(4)H2, C(8′)H2, C(4″)H, C(8″)H2),
3.76 (1H, br s, C(2‴)H), 3.95 (1H, br s, OH); δC (125 MHz, PhMe-
d8, 363 K) 14.2, 14.2 (C(7′), C(7″)), 23.1, 23.2, 25.8, 26.1, 26.3, 27.3,
28.3, 29.4, 31.7, 32.5, 32.7, 38.6, 38.7 (C(2), C(3), C(7′), C(7″),
C(1‴), C(3‴), C(4‴), C(5‴), C(6‴), C(4′)(CH2)4), 38.8, 39.3
(C(3′), C(3″)), 39.3 (NMe), 40.2 (NMe), 46.0, 46.1, 46.2, 47.4, 47.5,
47.7 (C(1), C(4), C(6′), C(6″), C(8′), C(8″)), 63.1 (C(4″)), 63.9
(C(4′)), 71.9 (C(2‴)), 172.3, 172.7 (C(2′), C(2″)); m/z (ESI+) 545
([M + Na]+, 62%), 523 ([M + H]+, 100%); HRMS (ESI+)
+
C30H59N4O3 ([M + H]+) requires 523.4582; found 523.4577.
Method B. Following general procedure 7, 48 (25 mg, 35.6 μmol,
>99:1 dr), (CH2O)n (2 mg, 66.6 μmol), and Pd(OH)2/C (13 mg) in
AcOH (1.0 mL) were reacted for 24 h. The residue was partitioned
between CHCl3 (5 mL) and satd aq NaHCO3 (5 mL). The aqueous
layer was extracted with CHCl3 (2 × 5 mL), and the combined organic
extracts were then dried (Na2SO4) and concentrated in vacuo.
Purification via column chromatography (gradient elution, 0% → 3%
MeOH in CHCl3) gave 49 as a colorless oil (7 mg, 38%, >99:1 dr).
(R,R,R)-1-[2′-Oxo-4′-pentyl-N(5′)-methyl-1′,5′-diazocan-
N(1′)-yl]-4-[2″-oxo-4″-(2‴-hydroxyheptyl)-N(5″)-methyl-1″,5″-
diazocan-N(1″)-yl]butane [(−)-hoprominol] 50. Following gen-
eral procedure 6A, 45 (39 mg, 152 μmol, >99:1 dr), 1815 (48 mg, 138
μmol), KOH (34 mg, 609 μmol), K2CO3 (26 mg, 185 μmol), and
TEBAC (4 mg, 19.0 μmol) in DMSO (0.75 mL) were reacted for 48
h. Purification via column chromatography (gradient elution, 1% →
4% MeOH in CHCl3) gave 50 as a colorless oil (17 mg, 24%, >99:1
+
C30H59N4O3 ([M + H]+) requires 523.4582; found 523.4588.
(S)-N(1)-(4′-Bromobutyl)-4-phenyl-N(5)-methyl-1,5-diazo-
can-2-one 54. Following general procedure 6B, 5315 (150 mg, 687
μmol, >99:1 er), 1,4-dibromobutane (0.24 mL, 2.01 mmol), and KOH
(155 mg, 2.76 mmol) in DMSO (1.4 mL) were reacted for 18 h.
Purification via column chromatography (gradient elution, 50% →
100% Et2O in 30−40 °C petrol) gave 54 as a yellow oil (143 mg,
dr); [α]24 −17.5 (c 1.0 in CHCl3); vmax (ATR) 3390 (O−H), 1626
D
(CO); δH (500 MHz, PhMe-d8, 363 K) 0.88−0.99 (6H, m, C(7‴)
H3, C(4′)(CH2)4CH3), 1.15−1.63 (26H, m, C(2)H2, C(3)H2, C(7′)
H2, C(7″)H2, C(1‴)H2, C(3‴)H2, C(4‴)H2, C(5‴)H2, C(6‴)H2,
C(4′)(CH2)4), 2.26 (3H, s, NMe), 2.31−2.46 (6H, m, C(3′)H2, C(6′)
HA, C(3″)H2, C(6″)HA), 2.33 (3H, s, NMe), 2.72 (2H, app ddd, J
15.1, 10.4, 3.2, C(6′)HB, C(6″)HB), 2.87−2.95 (1H, m, C(4′)H),
2.98−3.42 (9H, m, C(1)H2, C(4)H2, C(8′)H2, C(4″)H, C(8″)H2),
3.72−3.79 (1H, m, C(2‴)H); δC (125 MHz, PhMe-d8, 363 K) 14.2,
14.2 (C(7‴), C(4′)(CH2)4CH3), 23.1, 23.2, 25.8, 26.1, 26.3, 27.2, 28.3,
29.4, 30.3, 31.7, 32.5, 32.7, 38.6 (C(2), C(3), C(7′), C(7″), C(1‴),
C(3‴), C(4‴), C(5‴), C(6‴), C(4′)(CH2)4), 38.8, 39.2 (C(3′),
C(3″)), 39.4 (NMe), 40.2 (NMe), 46.0, 46.1, 46.2, 47.5, 47.5, 47.7
(C(1), C(4), C(6′), C(6″), C(8′), C(8″)), 63.1 (C(4″)), 63.9 (C(4′)),
71.9 (C(2‴)), 172.3, 172.7 (C(2′), C(2″)); m/z (ESI+) 545 ([M +
Na]+, 100%), 523 ([M + H]+, 98%); HRMS (ESI+) C30H59N4O3+ ([M
+ H]+) requires 523.4582; found 523.4577.
59%); [α]24 −15.0 (c 1.0 in CHCl3); vmax (ATR) 1635 (CO); δH
D
(400 MHz, CDCl3) 1.57−1.95 (6H, m, C(7)H2, C(2′)H2, C(3′)H2),
2.27 (3H, s, NMe), 2.45−2.56 (2H, m, C(3)HA, C(6)HA), 2.99 (1H,
ddd, J 15.4, 7.8, 3.0, C(6)HB), 3.11−3.20 (2H, m, C(3)HB, C(1′)HA),
3.30 (1H, app dt, J 15.4, 3.5, C(8′)HA), 3.41−3.51 (2H, m, C(4′)H2),
3.68−3.75 (1H, m, C(1′)HB), 3.85 (1H, app br t, J 13.5, C(8)HB),
4.00 (1H, dd, J 11.6, 3.3, C(4)H), 7.22−7.35 (5H, m, Ph); δC (100
MHz, CDCl3) 26.7 (C(7)), 29.9 (C(3′)), 30.0 (C(2′)), 33.7 (C(4′)),
41.1 (C(3)), 43.8 (NMe), 45.3 (C(1′)), 48.1 (C(8)), 50.9 (C(6)), 67.9
(C(4)), 127.2, 127.5, 128.3 (o,m,p-Ph), 141.7 (i-Ph), 173.5 (C(2)); m/
z (ESI+) 377 ([M(81Br) + Na]+, 96%), 375 ([M(79Br) + Na]+, 95%),
355 ([M(81Br) + H]+, 100%), 353 ([M(79Br) + H]+, 94%); HRMS
(ESI+) C17H2681BrN2O+ ([M(81Br) + H]+) requires 355.1203; found
355.1202; C17H2679BrN2O+ ([M(79Br) + H]+) requires 353.1223;
found 353.1219.
(4′R,4″S,2‴R)-1-[2′-Oxo-4′-pentyl-N(5′)-methyl-1′,5′-diazo-
can-N(1′)-yl]-4-[2″-oxo-4″-(2‴′-hydroxyheptyl)-N(5″)-methyl-
1″,5″-diazocan-N(1″)-yl]butane 51. Following general procedure
6A, ent-46 (74 mg, 289 μmol, >99:1 dr), 1815 (91 mg, 262 μmol),
KOH (65 mg, 1.15 mmol), K2CO3 (48 mg, 349 μmol), and TEBAC
(8 mg, 35.9 μmol) in DMSO (1.4 mL) were reacted for 60 h.
Purification via column chromatography (gradient elution, 1% → 4%
MeOH in CHCl3) gave 51 as a colorless oil (36 mg, 26%, >99:1 dr);
(4′S,4″R,2‴S)-1-[2′-Oxo-4′-phenyl-N(5′)-methyl-1′,5′-diazo-
can-N(1′)-yl]-4-[2″-oxo-4″-(2‴-hydroxyheptyl)-N(5″)-methyl-
1″,5″-diazocan-N(1″)-yl]butane 55. Following general procedure
6A, 46 (39 mg, 152 μmol), 54 (49 mg, 138 μmol, >99:1 dr), KOH (34
mg, 609 μmol), K2CO3 (26 mg, 185 μmol), and TEBAC (4 mg, 19.0
μmol) in DMSO (0.75 mL) were reacted for 48 h. Purification via
column chromatography (gradient elution, 1% → 4% MeOH in
CHCl3) gave 55 as a colorless oil (26 mg, 36%, >99:1 dr); [α]24D −9.3
[α]24 −2.4 (c 1.0 in CHCl3); vmax (ATR) 3391 (O−H), 1625 (C
D
O); δH (500 MHz, PhMe-d8, 363 K) 0.89−0.95 (6H, m, C(7‴)H3,
C(4′)(CH2)4CH3), 1.23−1.73 (26H, m, C(2)H2, C(3)H2, C(7′)H2,
9735
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Article
(c 1.0 in CHCl3); vmax (ATR) 3401 (O−H), 1625 (CO); δH (500
MHz, PhMe-d8, 363 K) 0.89−0.97 (3H, m, C(7‴)H3), 1.26−1.73
(18H, m, C(2)H2, C(3)H2, C(7′)H2, C(7″)H2, C(1‴)H2, C(3‴)H2,
C(4‴)H2, C(5‴)H2, C(6‴)H2), 2.18 (3H, s, N(5′)Me), 2.30 (3H, s,
N(5″)Me), 2.31−2.44 (2H, m, C(3″)HA, C(6″)HA), 2.51−2.67 (4H,
m, C(3′)HA, C(6′)H2, C(3″)HB), 2.72 (1H, ddd, J 15.5, 7.6, 2.8,
C(6″)HB), 2.91 (1H, app t, J 11.4, C(3′)HB), 2.96−3.12 (4H, m, C(1)
HA, C(8′)HA, C(4″)H, C(8″)HA), 3.19−3.33 (2H, m, C(4)HA, C(8′)
HB), 3.34−3.41 (1H, m, C(4)HB), 3.50 (1H, br t, J 12.9, C(8″)HB),
3.62−3.70 (2H, m, C(1)HB, C(2‴)H), 3.99 (1H, dd, J 11.4, 3.2, C(4′)
H), 7.05−7.09 (1H, m, Ph), 7.14−7.20 (4H, m, Ph); δC (125 MHz,
PhMe-d8, 363 K) 14.2 (C(7‴)), 23.2, 26.0, 26.1, 26.4, 29.0, 30.3, 30.6,
32.6, 38.3 (C(2), C(3), C(7′), C(7″), C(1‴), C(3‴), C(4‴), C(5‴),
C(6‴)), 38.7 (C(3″)), 39.5 (N(5″)Me), 42.0 (C(3′)), 43.4 (N(5′)
Me), 46.0 (C(4)), 46.4 (C(1), C(6″)), 47.1 (C(8′)), 48.1 (C(8″)),
51.5 (C(6′)), 62.0 (C(4″)), 68.8 (C(4′)), 70.2 (C(2‴)), 128.0, 128.4,
128.6 (o,m,p-Ph), 143.5 (i-Ph), 172.7 (C(2″)), 173.2 (C(2′)); m/z
(ESI+) 551 ([M + Na]+, 100%), 529 ([M + H]+, 92%); HRMS (ESI+)
(C(4″)), 68.8 (C(4′)), 70.2 (C(2‴)), 127.3, 128.0, 128.6 (o,m,p-Ph),
143.5 (i-Ph), 172.7 (C(2″)), 173.2 (C(2′)); m/z (ESI+) 551 ([M +
Na]+, 100%), 529 ([M + H]+, 88%); m/z (ESI+) 551 ([M + Na]+,
+
100%), 529 ([M + H]+, 96%); HRMS (ESI+) C31H53N4O3 ([M +
H]+) requires 529.4112; found 529.4099.
(S,S,S)-1-[2′-Oxo-4′-phenyl-N(5′)-methyl-1′,5′-diazocan-
N(1′)-yl]-4-[2″-oxo-4″-(2‴-hydroxyheptyl)-N(5″)-methyl-1″,5″-
diazocan-N(1″)-yl}butane 58. Following general procedure 6A, ent-
45 (74 mg, 289 μmol, >99:1 dr), 54 (93 mg, 262 μmol), KOH (65
mg, 1.15 mmol), K2CO3 (48 mg, 349 μmol), and TEBAC (8 mg, 35.9
μmol) in DMSO (1.4 mL) were reacted for 60 h. Purification via
column chromatography (gradient elution, 1% → 4% MeOH in
CHCl3) gave 58 as a white solid (82 mg, 59%, >99:1 dr); mp 110−115
°C; [α]24 +2.1 (c 1.0 in CHCl3); vmax (ATR) 3409 (O−H), 1625
D
(CO); δH (500 MHz, PhMe-d8, 363 K) 0.93 (3H, br t, J 6.9, C(7‴)
H3), 1.19−1.25 (1H, m, C(7′)HA), 1.26−1.66 (17H, m, C(2)H2, C(3)
H2, C(7′)HB, C(7″)H2, C(1‴)H2, C(3‴)H2, C(4‴)H2, C(5‴)H2,
C(6‴)H2), 2.19 (3H, s, N(5′)Me), 2.29 (3H, s, N(5″)Me), 2.33−2.50
(4H, m, C(6′)HA, C(6″)HA, C(3″)H2), 2.54 (1H, dd, J 12.6, 3.2,
C(3′)HA), 2.70−2.77 (2H, m, C(6′)HB, C(6″)HB), 2.92 (1H, br t, J
12.3, C(3′)HB), 2.97−3.10 (3H, m, C(1)HA, C(8′)HA, C(8″)HA),
3.12−3.38 (4H, m, C(4)H2, C(8′)HB, C(4″)H), 3.51 (1H, app br t, J
12.9, C(8″)HB), 3.64−3.71 (1H, m, C(1)HB), 3.77 (1H, br s, C(2‴)
H), 3.99 (1H, dd, J 11.0, 3.2, C(4′)H), 7.06−7.12 (1H, m, Ph), 7.14−
7.21 (4H, m, Ph); δC (125 MHz, PhMe-d8, 363 K) 14.2 (C(7‴)), 23.2,
25.8, 26.0, 26.3, 28.3, 30.3, 30.6, 32.7, 38.8 (C(2), C(3), C(7′), C(7″),
C(1‴), C(3‴), C(4‴), C(5‴), C(6‴)), 38.5 (C(3″)), 39.6 (N(5″)Me),
42.0 (C(3′)), 43.4 (N(5′)Me), 46.1 (C(4)), 46.3 (C(1)), 46.4
(C(6″)), 47.5 (C(8′)), 48.0 (C(8″)), 51.5 (C(6′)), 62.9 (C(4″)),
68.8 (C(4′)), 71.6 (C(2‴)), 127.3, 128.0, 128.6 (o,m,p-Ph), 143.5 (i-
Ph), 172.4 (C(2″)), 172.7 (C(2′)); m/z (ESI+) 551 ([M + Na]+,
100%), 529 ([M + H]+, 88%); HRMS (ESI+) C31H52N4NaO3+ ([M +
Na]+) requires 551.3932; found 551.3918.
+
C31H52N4NaO3 ([M + Na]+) requires 551.3932; found 551.3918.
(4′S,4″R,2‴R)-1-[2′-Oxo-4′-phenyl-N(5′)-methyl-1′,5′-diazo-
can-N(1′)-yl]-4-[2″-oxo-4″-(2‴-hydroxyheptyl)-N(5″)-methyl-
1″,5″-diazocan-N(1″)-yl]butane [(−)-Hopromalinol] 56. Follow-
ing general procedure 6A, 45 (39 mg, 152 μmol, >99:1 dr), 54 (49 mg,
138 μmol), KOH (34 mg, 609 μmol), K2CO3 (26 mg, 185 μmol), and
TEBAC (4 mg, 19.0 μmol) in DMSO (0.75 mL) were reacted for 48
h. Purification via column chromatography (gradient elution, 1% →
4% MeOH in CHCl3) gave 56 as a colorless oil (41 mg, 56%, >99:1
dr); [α]24 −16.8 (c 1.0 in CHCl3); vmax (ATR) 3385 (O−H), 1623
D
(CO); δH (500 MHz, PhMe-d8, 363 K) 0.90 (3H, br s, C(7‴)H3),
1.11−1.19 (1H, m, C(7′)HA), 1.20−1.61 (16H, m, C(2)H2, C(3)H2,
C(7′)HB, C(7″)H2, C(1‴)H2, C(3‴)H2, C(4‴)H2, C(5‴)H2, C(6‴)
H2), 2.15 (3H, s, N(5′)Me), 2.24 (3H, s, N(5″)Me), 2.28−2.41 (4H,
m, C(6′)HA, C(3″)H2, C(6″)HA), 2.51 (1H, dd, J 12.6, 2.6, C(3′)HA),
2.64−2.75 (3H, m, C(6′)HB, C(6″)HB, OH), 2.87 (1H, app t, J 12.0,
C(3′)HB), 2.93−3.04 (3H, m, C(1)HA, C(8′)HA, C(8″)HA), 3.05−
3.20 (3H, m, C(4)HA, C(4″)H, C(8′)HB), 3.34−3.43 (1H, m, C(4)
HB), 3.46 (1H, app t, J 13.4, C(8″)HB), 3.62−3.76 (2H, m, C(1)HB,
C(2‴)H), 3.96 (1H, dd, J 11.4, 2.5, C(4′)H), 7.02−7.08 (1H, m, Ph),
7.10−7.17 (4H, m, Ph); δC (125 MHz, PhMe-d8, 363 K) 14.2
(C(7‴)), 23.2, 25.8, 26.0, 26.3, 28.3, 30.3, 30.6, 32.7, 38.8 (C(2), C(3),
C(7′), C(7″), C(1‴), C(3‴), C(4‴), C(5‴), C(6‴)), 38.6 (C(3″)),
39.4 (N(5″)Me), 42.0 (C(3′)), 43.4 (N(5′)Me), 46.1 (C(4)), 46.3,
46.3 (C(1), C(6″)), 47.6 (C(8′)), 48.0 (C(8″)), 51.5 (C(6′)), 63.0
(C(4″)), 68.8 (C(4′)), 71.9 (C(2‴)), 127.3, 128.0, 128.6 (o,m,p-Ph),
143.6 (i-Ph), 172.4 (C(2″)), 172.7 (C(2′)); m/z (ESI+) 551 ([M +
Na]+, 89%), 529 ([M + H]+, 100%); HRMS (ESI+) C31H53N4O3+ ([M
+ H]+) requires 529.4112; found 529.4120.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H, 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: steve.davies@chem.ox.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We would like to thank the EPSRC−Pharma Synthesis
Network for a CASE award (J.A.L.).
(4′S,4″S,2‴R)-1-[2′-Oxo-4′-phenyl-N(5′)-methyl-1′,5′-diazo-
can-N(1′)-yl]-4-[2″-oxo-4″-(2‴-hydroxyheptyl)-N(5″)-methyl-
1″,5″-diazocan-N(1″)-yl}butane 57. Following general procedure
6A, ent-46 (74 mg, 289 μmol, >99:1 dr), 54 (93 mg, 262 μmol), KOH
(65 mg, 1.15 mmol), K2CO3 (48 mg, 349 μmol), and TEBAC (8 mg,
35.9 μmol) in DMSO (1.4 mL) were reacted for 60 h. Purification via
column chromatography (gradient elution, 1% → 4% MeOH in
CHCl3) gave 57 as a white solid (31 mg, 22%, >99:1 dr); mp 120−122
■
REFERENCES
■
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D
(CO); δH (500 MHz, PhMe-d8, 363 K) 0.89 (3H, br s, C(7‴)H3),
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HA), 3.04−3.17 (2H, m, C(4)HA, C(4″)H), 3.21−3.30 (1H, m, C(8′)
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The Journal of Organic Chemistry
Article
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(16) Crombie, L.; Jones, R. C. F.; Haigh, D. Tetrahedron Lett. 1986,
27, 5147.
(35) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(17) Crombie, L.; Haigh, D.; Jones, R. C. F.; Mat-Zin, A. R. J. Chem.
Soc., Perkin Trans. 1 1993, 2055.
(36) Love, B. E.; Jones, E. G. J. Org. Chem. 1999, 64, 3755.
(37) Denmark, S. E.; Nguyen, S. T. Org. Lett. 2009, 11, 781.
(38) Yang, Y.; Wang, D. Phosphorus, Sulfur Silicon Relat. Elem. 1998,
139, 193.
(39) Because of substantial peak overlap, it was not possible to
unambiguously assign the 1H and 13C NMR spectra for the
diastereoisomers of 31.
(40) Because of substantial peak overlap, it was not possible to
unambiguously assign the 1H and 13C NMR spectra for the
diastereoisomers of 32.
(41) A resonance corresponding to one of either C(4′), C(5′), or
C(6′) was not observed in the 100 MHz 13C NMR spectrum of 41 at
room temperature.
(18) Itoh, N.; Matsuyama, H.; Yoshida, M.; Kamigata, N.; Iyoda, M.
Bull. Chem. Soc. Jpn. 1995, 68, 3121.
(19) (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.
(20) For selected examples of the application of this methodology in
the synthesis of natural products, see: (a) Abraham, E.; Candela-Lena,
J. I.; Davies, S. G.; Georgiou, M.; Nicholson, R. L.; Roberts, P. M.;
́ ́
Russell, A. J.; Sanchez-Fernandez, E. M.; Smith, A. D.; Thomson, J. E.
Tetrahedron: 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.
(42) A resonance corresponding to one of either C(7), C(1′), C(3′),
C(4′), C(5′), or C(6′) was not observed in the 100 MHz 13C NMR
spectrum of 45 at room temperature.
(21) For a review, see: Davies, S. G.; Smith, A. D.; Price, P. D.
Tetrahedron: Asymmetry 2005, 16, 2833.
(22) 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)-7.
(23) α,β-Unsaturated esters 5 and 6 were prepared from the
corresponding (commercially available) aldehydes in >99:1 dr using
our highly (E)-selective MeMgBr-mediated Wadsworth−Emmons
procedure, see: 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.
(24) Finkelstein, H. Ber. Dtsch. Chem. Ges. 1910, 43, 1528.
(25) For example, see: (a) Davies, S. G.; Ichihara, O. Tetrahedron:
Asymmetry 1996, 7, 1919. (b) Ma, D.; Zhu, W. Tetrahedron Lett. 2003,
44, 8609. (c) Davies, S. G.; Ichihara, O.; Roberts, P. M.; Thomson, J.
E. Tetrahedron 2011, 67, 216.
(26) Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(27) (a) Davies, S. G.; Foster, E. M.; Frost, A. B.; Lee, J. A.; Roberts,
P. M.; Thomson, J. E. Org. Biomol. Chem. 2012, 10, 6186. (b) Davies,
S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E.; Yin, J. Org. Lett. 2012,
14, 218.
(28) It was not possible to accurately determine the diastereose-
lectivity of these reactions as considerable peak overlap was observed
in the 1H NMR spectra of the crude reaction mixtures; this was
particularly significant for conjugate addition to α,β-unsaturated
methyl ester (RS)-29 due to the presence of substantial quantities of
other products.
(29) Marco, J. A.; García-Pla, J.; Carda, M.; Murga, J.; Falomir, E.;
Trigili, C.; Notararigo, S.; Díaz, J. F.; Barasoain, I. Eur. J. Med. Chem.
2011, 46, 1630.
(30) The ee of homoallylic alcohol was determined via 31P NMR
analysis of a derivative, see: Feringa, B. L.; Smaardijk, S.; Wynberg, H.
J. Am. Chem. Soc. 1985, 107, 4798.
(31) Das, B.; Laxminarayana, K.; Krishnaiah, M.; Kumar, D. N. Helv.
Chim. Acta 2009, 92, 1840.
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