C-alkylation of chiral tropane- and homotropane-derived enamines

Article abstract of DOI:10.1021/jo3025972

The synthesis and alkylation of chiral, nonracemic tropane- and homotropane-derived enamines is examined as an approach to enantioenriched α-alkylated aldehydes. The two bicyclic N auxiliaries, which differ by a single methylene group, give opposite senses of asymmetric induction on alkylation with EtI and provide modestly enantioenriched 2-ethylhexanal (following hydrolysis of the alkylated iminium). The observed stereoselectivity is supported by density functional studies of ethylation for both enamines.

Full text of DOI:10.1021/jo3025972

Article
pubs.acs.org/joc
C‑Alkylation of Chiral Tropane- and Homotropane-Derived Enamines
David M. Hodgson,* Andrew Charlton, Robert S. Paton,* and Amber L. Thompson
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: The synthesis and alkylation of chiral, non-
racemic tropane- and homotropane-derived enamines is
examined as an approach to enantioenriched α-alkylated
aldehydes. The two bicyclic N auxiliaries, which differ by a
single methylene group, give opposite senses of asymmetric
induction on alkylation with EtI and provide modestly enantioenriched 2-ethylhexanal (following hydrolysis of the alkylated
iminium). The observed stereoselectivity is supported by density functional studies of ethylation for both enamines.
Scheme 1. Synthesis and Asymmetric Alkylation of Trialkyl-
Substituted Piperidine Enamines 3a,b
INTRODUCTION
■
Chiral α-alkyl-substituted aldehydes are widely recognized as
valuable materials for synthesis. The aldehyde functional group
provides a variety of attractive possibilities for introduction of
asymmetry into more complex molecular scaffolds. Chiral α-
alkyl-substituted aldehydes have also found direct application in
the fragrance industry.1 Despite longstanding interest by the
synthetic community in the development of methodology to
access such species directly,2 success has so far been limited.3
Currently, one of the most commonly used strategies to
generate enantioenriched α-alkyl-substituted aldehydes em-
ploys Enders’ lithiated SAMP/RAMP hydrazone chemistry.4
Also effective are alkylations carried out at a higher oxidation
level, typically involving Evans’ oxazolidinone5 or Myers’
pseudoephedrine auxiliaries.6 While these methods are robust
and normally provide high levels of asymmetric induction, they
are not without limitations: Enders’ chemistry usually involves
very low temperatures (−80 to −120 °C), and all three
methods require further manipulation, e.g., ozonolysis (Enders)
or reduction (Evans/Myers), to cleave the auxiliary and obtain
the aldehyde. Recent years have seen the development of a
variety of organocatalytic approaches to achieve direct,
asymmetric α-alkylation of aldehydes.7 Despite this, alkylation
involving simple alkyl halides via intermolecular nucleophilic
substitution has yet to be achieved organocatalytically.
Difficulties with the organocatalytic approach include direct
reaction of the amine catalyst with the alkyl halide and/or
irreversible N-alkylation of the enamine intermediate.8,9 In the
case of MacMillan’s elegant combination of photoredox and
organocatalysis, a radical stabilizing group is required on the
electrophile.10
hindered lithium amides 2a,b with terminal epoxides 1.13 The
preparation of such enamines by classical condensation
techniques is not possible.
In our earlier work, 2,2,6-trimethylpiperidine-derived enam-
ine 3a gave high yields and significant levels of enantioenrich-
ment on alkylation.12 Diastereocontrol of enamine alkylation
was enhanced by moving to a sterically more demanding
substituent on the piperidine (Me → i-Pr, Scheme 1, 3b → 4b),
albeit at the expense of lower alkylation yields. These
experimental observations were rationalized through a
computational study,14 which indicates that in enamine 3a
the C-6 Me substituent resides axial in the ground-state
conformation (Figure 1; 3(ax), R = Me) so as to minimize A1,3
strain (Figure 1, 3(eq)). In contrast, the C-6 i-Pr substituent in
enamine 3b is equatorial in the ground state (Figure 1; 3(eq),
R = i-Pr), with the reactive axial conformation (where N lone
Curphey et al. originally showed that aldenamines which are
sterically crowded about N undergo preferential C-alkylation
with simple alkyl halides.11 This led us to investigate the
possibility of chiral, nonracemic, hindered enamines for
asymmetric intermolecular SN2 alkylation. We previously
reported a direct synthesis of enantioenriched mono-α-alkyl-
substituted aldehydes 4a,b by way of C-alkylation of chiral
piperidine-derived enamines 3a,b (Scheme 1).12 These
hindered about N enamines were prepared by reaction of the
Received: November 28, 2012
Published: January 29, 2013
© 2013 American Chemical Society
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pair−π* overlap becomes possible) only being attainable at
elevated temperatures; in this case 1,3-diaxial interactions,
exacerbated by the larger isopropyl substituent, outweigh allylic
strain present in the conformer with the C-6 i-Pr group
equatorial. When the C-6 substituent is equatorial, the olefinic
component of the enamine twists orthogonal to the nitrogen
lone pair, rendering the enamine inactive to C-alkylation.15 The
reactive conformation (C-6 substituent axial) which is achieved
in the transition state for enamine 3b alkylation, despite the
ground-state preference, is expected to be less accessible for
enamines derived from piperidines with larger C-6 substituents.
to the potential greater synthetic complexity associated with
inclusion of an additional stereocenter.
We first examined the synthesis and alkylating ability of an
enamine derived from racemic tropane ( )-6. While there are
several methods for the synthesis of tropanes and their typically
parent tropinones,16 there are limited examples17 of tropanes/
tropinones containing the desired substitution pattern (bridge-
head alkyl and gem-dialkyl α to a CH bridgehead). We
envisaged a synthetic sequence using a classical Robinson−
Schopf reaction to construct the azabicyclic core (Scheme 2).
̈
Sterner et al. have demonstrated that impressive yields can be
obtained by performing Robinson−Schopf reactions of
̈
dialdehydes in THF.18 Following Sterner’s protocol, but using
benzylamine (chosen for its greater nucleophilicity compared
with ammonia19 and projected reduction to access the free
amine), gave tropinone ( )-9 in satisfactory yield from readily
available (one to two steps) ketoaldehyde 7.20 A subsequent
Wolff−Kishner reaction to N-benzyltropane ( )-1021 and then
hydrogenolysis22 gave the desired tropane ( )-6 in excellent
yield (85% from ( )-9).
Figure 1. Enamine 3 conformers.
The above findings led to the present study concerning the
development of a new class of chiral amine auxiliaries, hopefully
capable of attaining elevated er levels while also retaining a high
degree of reactivity.
With tropane ( )-6 in hand, we examined the feasibility of
synthesizing enamine ( )-12 using the lithium amide−epoxide
methodology (cf., 1 → 3, Scheme 1).13a Previous studies in our
laboratory indicated that enamine formation from lithium
2,2,5,5-tetramethylpyrrolidide and 1,2-epoxyoctadecane was
slow at room temperature and generated unsatisfactory yields
at higher temperatures, the latter being due to instability of the
intermediate lithiated epoxide in refluxing THF.23 In the event,
attempted formation of enamine ( )-12 from N-lithiotropane
6 and epoxide 1 led to a complex mixture of products from
which the enamine could not be isolated by distillation or, due
to its hydrolytic sensitivity, by chromatography. Attention
turned to alternative methods of hindered aldenamine
preparation. We have previously prepared trialkylpiperidine
enamines using the unusual reaction of Grignard addition−
elimination with formamides reported by Hansson and
Wickberg,24 albeit in low yield and with prolonged reaction
time (e.g., reaction between N-formyl-2,2,6,6-tetramethylpiper-
idine and n-BuMgCl proceeded in only 32% yield after 7
days).13b To examine this strategy in the current work,
formamide ( )-11 was synthesized from tropane ( )-6
using the method of Blum and Nyberg (Scheme 2).25 The
original Hansson and Wickberg enamine work prescribes excess
formamide relative to Grignard reagent; however, we found this
inevitably resulted in some inseparable formamide contaminat-
ing the product enamine. Modification, using a slight excess
RESULTS AND DISCUSSION
■
As a starting point in the exploration of more reactive
enamines, the design of a new auxiliary centered around
modification to the scaffold of the precursor to lithium amide
2b, piperidine 5 (Figure 2). Tropane 6, which is conforma-
Figure 2. Piperidine 5 and tropane 6.
tionally locked, thus alleviating the problems associated with
unfavorable conformers, could generate enamines with
enhanced reactivity. At the outset, it was considered that the
gem-dimethyl substitution in tropane 6 (Figure 2) would mimic
the isopropyl steric encumberment of enamine 3b (albeit
without the ability to splay outward14), thereby providing
effective facial discrimination. While a single exo-methyl
substituent would also potentially suffice (i.e., tropane 6
(Meendo = H); Figure 2), this was not considered further due
Scheme 2. Synthesis of Tropane-Derived Enamine ( )-12
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(1.25 equiv) of pentylmagnesium chloride, generated the
desired enamine ( )-12 in excellent yield (Scheme 2). The
1H NMR spectrum of enamine ( )-12 showed separation
between the olefinic signals of 1.67 ppm, indicative of
alignment of the N lone pair and alkene π orbital, and
suggesting a strong C-alkylation profile.15 Indeed, C-ethylation
of enamine ( )-12 with EtI gave, after hydrolysis of the
resulting iminium, 2-ethylhexanal ( )-13 in excellent yield
(Scheme 3). By comparison, enamine 3b generated the same
aldehyde in only 58% yield under similar conditions.
Figure 3. Computed ground-state conformation for enamine 12*.
Scheme 3. Ethylation of Enamine ( )-12
To examine asymmetric alkylation, tropane ( )-6 was
resolved by coupling with N-Boc-L-phenylalanine to give Boc-
protected α-amino amides 14, followed by deprotection and
chromatographic separation of the diastereomeric α-amino
amides 15 and then Edman degradation (Scheme 4).26 The
absolute configuration of tropane (+)-6 was determined to be
1R,5S by X-ray crystallographic analysis of the precursor α-
amino amide (S,1R,5S)-15. Surprisingly, the enamine derived
from tropane (−)-(1S,5R)-6 underwent alkylation with EtI to
give aldehyde (R)-13 in low er (55:45; Scheme 4) with a
preference for the opposite sense of asymmetric induction (i.e.
the opposite enantiomer) to that seen with piperidine-derived
enamines 3a,b (Scheme 1); similarly, enantiopure enamine
(1R,5S)-12 gave aldehyde (S)-13 in 58:42 er).
The origin of the low er and unanticipated reversal of
asymmetric induction was examined using quantum mechanical
calculations. Density functional studies of enamine 12* (Figure
3) at the B3LYP/6-31G(d) level determined that in the ground
state the lowest energy conformation GS1 (Figure 3) has the
exocyclic C−N bond pseudoaxial with respect to the six-
membered ring.
Computed transition states TS1−TS4 originating from GS1,
for the reaction of enamine 12* with EtI in MeCN at 65 °C
(Figure 4), suggest a preference for Re-face attack (with
(1S,5R)-12). The methylene group α to the CH bridgehead
influences the facial selectivity of the approaching electrophile
Figure 4. Computed TS geometries for reaction of enamine 12* with
EtI. B3LYP/6-31G(d) free energies in kJ/mol; selected distances
shown in Å.
slightly more than that of the exo-methyl substituent (x < y,
Figure 3; and similarly in the transition states TS1−TS435).
Transition states TS1 and TS2, which differ only in the
approach orientation of EtI to the Si face, lie 1.2 and 2.7 kJ
mol−1 higher in energy than TS3, respectively. The computa-
Scheme 4. Synthesis and Ethylation of Enamine (1S,5R)-12
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tionally determined face selectivity and calculated 62:38 er are
in good agreement with the experimental findings.
intramolecular aldol condensation of the required ketoaldehyde
8 led to poor yields in the early stages of the synthetic sequence
and consequently generated insufficient quantities of homo-
tropane 17 for subsequent enamine studies. Therefore, it was
decided to examine an asymmetric synthesis of homotropane
17. We were attracted to the elegant chemistry of Davis et al.,27
which involves enolate addition to chiral ketal sulfinimines
followed by Mannich cyclization to construct chiral homo-
tropinones in excellent yields and ers. However, and despite
significant experimentation, the envisaged Davis approach
(Scheme 5) was hampered by an inability to form the requisite
novel Weinreb enolate 21 (M = Li). We therefore investigated
constructing a Mannich cyclization substrate by addition of an
organometallic rather than an enolate to a sulfinimine (Scheme
5). As sulfinimines prepared from Davis’ auxiliary are known to
undergo competing S- and 1,2-addition using Grignard
reagents,28 we switched to Ellman’s tert-butyl sulfur analogue.29
Although the revised strategy relied heavily on addition of an
organometallic 23 to a severely hindered sulfinimine 24,
literature precedent suggested that promising yields and
diastereoselectivity could be achieved.30
From Figures 3 and 4 it is clear that the presence of the
embedded pyrrolidine places an undesired bias on the
orientation of the exocyclic double bond. In response to this,
we considered that formal expansion of the two-carbon bridge
of the tropane scaffold by a methylene group to generate two
rings of equal size (homotropane {6,6}, cf. tropane {6,5}),
could give an improved er, since facial discrimination should
now be solely dependent on the presence of the gem-dimethyl
group on one ring. Comparison of the computed ground-state
conformations for tropane-derived (GS1) and homotropane-
derived (GS2) enamines shows similar orientations of the
common N-propenyl group (similar values of x and y, Figures 3
and 5). However, in contrast to TS3 and TS4 (Figure 4), the
Aldehyde 25 (Scheme 6), prepared in four steps from ethyl
α-methylacetoacetate (78% overall yield),31 underwent NaOH-
mediated32 condensation with sulfinamide (R)-26 to give
sulfinimine (R)-24 in excellent yield. Addition of Grignard
reagent 23 to racemic sulfinimine 24 generated the crude bis-
ketal sulfinamide 20 in moderate dr (73:27).33 Due to the low
yield and dr from Grignard approach, we examined addition of
organolithium 27 to sulfinimine (R)-24, which gave the bis-
ketal sulfinamide (RS,R)-20 in excellent yield (91%) and dr
(98:2), with the configuration later being determined by
correlation with homotropinone (1S,5R)-18. The diastereose-
lectivity observed using organolithium 27 (opposite to that
seen with Grignard reagent 23) is consistent with that found for
reactions of other organolithiums and tert-butanesulfinyl
aldimines, which are suggested as proceeding through an
open transition state.34 Treatment of bis-ketal sulfinamide
(RS,R)-20 under the same conditions used by Davis27 to
promote cascade through to the homotropinone (NH4OAc (25
equiv), AcOH:EtOH (1:1), 36 h, 75 °C) led to deprotection of
both ketals but left the sulfinamide group intact. It was
considered that stronger acidic conditions would be required
for removal of the tert-butyl sulfinyl group. Indeed, heating
(RS,R)-20 in a methanolic−ethereal solution of HCl gave the
desired homotropinone (RS,R)-18 as a single enantiomer (by
chiral HPLC analysis), whose absolute configuration was
established by X-ray crystallographic analysis.35 Wolff−Kishner
reaction (and other common deoxygenation strategies) proved
unsuccessful for reduction of homotropinone (1S,5R)-18, but
conversion to homotropane (1S,5R)-17 was eventually
achieved by reduction to the homotropinol (1S,3R,5R)-28
and deoxygenation of the derived xanthate (1S,3R,5R)-29
under Barton−McCombie conditions.36 NOE studies35 on
xanthate (1S,3R,5R)-29 indicated that reduction of homo-
tropinol (1S,3R,5R)-28 had proceeded with exo-face hydride
delivery.
Figure 5. Computed ground-state conformation for enamine 16*.
Figure 6. Computed TS geometries for reaction of enamine 16* with
EtI. B3LYP/6-31G(d) free energies in kJ/mol; selected distances
shown in Å.
computed transition structures TS5 and TS6 for alkylation of
homotropane-derived enamine 16* with EtI (Figure 6) show
that the exocyclic C−N bond moves to being essentially
equidistant from each piperidine ring of the homotropane (x ≈
y).35 Furthermore, the calculated energies of transition states
TS5−TS8 predicted significant improvement in er (85:15),
with Si-face selectivity (with enamine (1S,5R)-16).
Ethylation of enamine (1S,5R)-16, prepared similarly to
tropane enamine 12, proceeded in reasonable yield (Scheme
7), showed a significant improvement in er compared with
tropane enamine (1R,5S)-12, and gave the same sense of
asymmetric induction seen with piperidine derived enamines
3a,b (Scheme 1).
For preparation of the required homotropane 17, we initially
investigated a Robinson−Schopf strategy similar to that used
̈
for preparing tropane 6. However, the propensity for
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Scheme 5. Retrosynthetic Analyses for Homotropane (1S,5R)-17
Scheme 6. Synthesis of Homotropane (1S,5R)-17
Scheme 7. Synthesis and Ethylation of Enamine (1S,5R)-16
In contrast with tropane enamine (1R,5S)-12, the sense of
asymmetric induction seen with homotropane enamine
(1S,5R)-16 is as originally envisaged, with the gem-dimethyl
group providing effective steric encumbrance to electrophile
approach of the enamine. This is illustrated in Figure 7, where
the most important competing diastereomeric TS geometries
have been superimposed. Approach of the electrophile toward
the Re face of enamine 16* is hindered by the gem-dimethyl
group, and as a result, the enamine is appreciably nonplanar in
the TS and thus less nucleophilic. Later TS geometries with
greater C−I distances are found for this minor pathway, lending
further support to this interpretation. In contrast, approach
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evaporated under reduced pressure. Purification of the residue by
column chromatography (deactivated SiO2, gradient elution 0−4%
EtOAc in petroleum ether, with 2% Et3N also in the eluent) gave
tropinone ( )-9 as a yellow oil (16.3 g, 42%): Rf = 0.37 (4% EtOAc in
petroleum ether); IR (film) (cm−1) 2958 m, 1708 s (CO), 1495 w,
1
1455 m, 1267 m, 1225 m, 1177 m; H NMR (400 MHz) δ 7.44 (d,
2H, J = 7 Hz, Ar (ortho)), 7.34 (t, 2H, J = 7 Hz, Ar (meta)), 7.30−7.23
(m, 1H, Ar (para)), 4.04 and 3.66 (AB, 2H, JAB = 14 Hz, PhCH2N),
2.85 (d, 1H, J = 4 Hz, COCH2CH), 2.54 and 2.27 (AB, 2H, JAB = 16
Hz, J = 4 Hz, COCH2CH), 2.50 and 2.16 (AB, 2H, JAB = 16 Hz,
COCH2CCH3), 1.61 and 1.49 (AB, 2H, JAB = 13 Hz, J = 2 Hz,
C(CH3)2CH2) 1.28 (s, 3H, CH3), 1.16 (s, 3H, CH3), 0.93 (s, 3H,
CH3); 13C NMR (101 MHz) δ 210.4 (CO), 139.8 (Ar (ipso)),
128.3 (Ar), 128.2 (Ar), 126.9 (Ar (para)), 66.1 (C(CH3)3CH), 62.6
(NCCH3), 52.9 (CH2C(CH3)2), 49.6 (NC(Me)CH2CO), 47.3
(PhCH2N), 39.0 (C(CH3)2), 37.4 (CHCH2CO), 32.4 (CH3), 25.5
(CH3), 24.9 (CH3); MS m/z (ESI+) 258.2 (M + H+, 100); HRMS m/
z (M + H+) found 258.1851, calcd for C17H24NO 258.1852.
Figure 7. Superimposed TS geometries for homotropane-derived
(16*) and tropane-derived (12*) enamine alkylation.
toward the Si face of enamine 16* is unhindered and the TS
displays a planar enamine geometry and is thus energetically
preferred. However, there is a significant reduction in the er for
alkylation with enamine (1S,5R)-16 in comparison with
superficially analogous enamine 3b. The lower er may be a
consequence of the rigidity the cyclohexyl ring imposes on the
carbon bearing gem-dimethyl substitution. For enamine 3b, the
corresponding axial isopropyl group is able to slightly splay
away from the idealized chair, thus relieving 1,3-diaxial
interactions and providing increased steric shielding of the
enamine Re face.14 Comparison of TS geometries for attack of
enamine 12* (Figures 4 and 7) highlights the fact that the gem-
dimethyl substituent is now more remote from the Re face; the
combination of these effects leads to a modest inversion in the
sense of facial selectivity.
( )-8-Benzyl-1,6,6-trimethyl-8-azabicyclo[3.2.1]octane (( )-10).
A mixture of tropinone ( )-9 (4.54 g, 17.6 mmol), hydrazine
monohydrate (4.60 g, 0.09 mol), and KOH (14.99 g, 0.27 mol) in
diethylene glycol (36 mL) was heated to 190 °C (oil bath) for 24 h.
The volatile components were then removed by distillation for 2 h at
200 °C. The reaction mixture was cooled to room temperature and
combined with the distillate. The mixture was diluted with water (300
mL) and the aqueous layer extracted with Et2O (3 × 200 mL). The
combined organic layers were dried (Na2SO4) and evaporated under
reduced pressure. Purification of the residue by column chromatog-
raphy (SiO2, gradient elution 0−2% EtOAc in petroleum ether) gave
N-benzyltropane ( )-10 as a clear oil (3.66 g, 85%): Rf = 0.50 (2%
EtOAc in petroleum ether); IR (film) (cm−1) 3064 w, 3027 m, 2933 s,
1
2867 s, 1494 m, 1451 s, 1360 m, 1279 m, 1131 m; H NMR (400
MHz) δ 7.54 (d, 2H, J = 7 Hz, Ar (ortho)), 7.40 (t, 2H, J = 7 Hz, Ar
(meta)), 7.35−7.28 (m, 1H, J = 7 Hz, Ar), 3.91 and 3.86 (AB, 2H, JAB
= 14 Hz, PhCH2N), 2.49 (br s, 1H, NCH), 1.96−1.69 (m, 6H, 3 ×
CH2), 1.72 and 1.60 (AB, 2H, JAB = 13 Hz, CH2C(CH3)2), 1.29 (s,
3H, CH3), 1.24 (s, 3H, CH3), 1.17 (s, 3H, CH3); 13C NMR (101
MHz) δ 141.6 (Ar (ipso)), 128.4 (Ar (ortho)), 127.9 (Ar (meta)),
126.3 (Ar (para)), 64.6 (CHN), 60.0 (NC(CH3)), 51.9 (CH2C-
(CH3)2), 46.7 (PhCH2N), 37.8 (C(CH3)2), 33.2 (CH3), 28.9 (CH2),
26.8 (CH3), 23.7 (CH3), 18.6 (CH2), 16.6 (CH2); MS m/z (ESI+)
244.2 (M + H+, 71); HRMS m/z (M + H+) found 244.2067, calcd for
C17H26N 244.2060.
( )-1,6,6-Trimethyl-8-azabicyclo[3.2.1]octane (( )-6). A vigo-
rously stirred solution of N-benzyltropane ( )-10 (2.44 g, 10.0
mmol) in MeOH was hydrogenated at 1 atm in the presence of 10%
palladium on activated carbon (1.06 g, 10 mol %) for 17 h. After this
time, the catalyst was removed by filtration through Celite. To the
filtrate was added 1 M HCl in Et2O (ca. 25 mL). The mixture was
evaporated under reduced pressure to give the crude hydrochloride
salt, which was recrystallized from EtOAc to give the tropane
hydrochloride as a white crystalline solid (1.9 g, quant) (mp 201−203
°C). This salt (1.90 g, 10.0 mmol) was suspended in Et2O (20 mL)
and washed with 3 M aqueous NaOH (20 mL). The ethereal layer was
separated and the aqueous phase back-extracted with Et2O (3 × 20
mL). The combined organic layers were dried (Na2SO4) and
concentrated by careful evaporation (228 mm, 35 °C). Purification
of the residue by bulb-to-bulb distillation gave tropane ( )-6 as a clear
oil (1.54 g, quant): bp 50−60 °C (14 mm); IR (neat) (cm−1) 3267 w
(N−H stretch), 2929 s, 2868 s, 1730 m, 1641 w, 1599 w, 1453 s, 1374
s, 1277 s, 1183 m, 822 s, 739 s; 1H NMR (400 MHz) δ 2.71−2.63 (m,
1H, NCH), 1.83 (br s, 1H, NH), 1.77−1.35 (m, 7H, 3 × CH2 and 1 ×
CHAHB), 1.23 (d, 1H, JAB = 13 Hz, CHAHB), 1.15 (s, 3H, NC(CH3)),
1.12 (s, 3H, C(CH3)2), 1.07 (s, 3H, C(CH3)2); 13C NMR (101 MHz)
δ 65.6 (NCH), 60.3 (NC(CH3)), 50.6 (CH2), 42.9 (C(CH3)2), 39.1
(CH2), 33.0 (CH3), 28.7 (CH3), 27.4 (CH2), 23.0 (CH3), 19.0
(CH2); MS m/z (ESI+) 154.1 (M + H+, 100); HRMS m/z (M + H+)
found 154.1590, calcd for C10H20N 154.1590.
CONCLUSION
■
The synthesis and asymmetric alkylation profile of enamines
derived from chiral tropane 6 and homotropane 17 have been
examined. Tropane-derived enamines (1S,5R)- and (1R,5S)-12
showed low but reverse diastereofacial selectivity to that initially
envisaged. In contrast, homotropane-derived enamine (1S,5R)-
16 alkylated with the anticipated sense of (and with
significantly improved) diastereoselectivity. The experimental
findings are in good agreement with DFT studies for both
enamines, where the latter provide insight into the origins of
asymmetric induction. While tropane-derived enamine 12 gave
a significantly improved yield of ethylation in comparison with
enamine 3b, both auxiliaries failed to provide high levels of
asymmetric induction. However, despite the modest ers, the
congruence between theory and practical experiment coupled
with an ability to modify and, importantly, improve the er
through computational studies should assist the future design of
chiral auxiliaries and other asymmetric targets. Additionally, the
described synthesis of α,α-disubstituted homotropinone
(1S,5R)-18 demonstrates an efficient strategy to this bio-
logically significant class of chiral compounds that are otherwise
difficult to access. Investigations are ongoing to improve on the
ers obtained.
EXPERIMENTAL SECTION35
■
Tropane ( )-6 Synthesis. ( )-8-Benzyl-1,6,6-trimethyl-8-
azabicyclo[3.2.1]octan-3-one (( )-9). Benzylamine (18.0 g, 0.17
mol) was added to a solution of ketoaldehyde 720 (19.4 g, 0.15
mol) in THF (500 mL) at room temperature, followed by portionwise
addition of acetone-1,3-dicarboxylic acid (24.4 g, 0.17 mol), which
resulted in immediate gas evolution (CO2). (Caution! Ensure suitable
exhaust!) After stirring for 60 h at room temperature, the mixture was
General Procedure for Formamide Synthesis. ( )-1,6,6-
Trimethyl-8-azabicyclo[3.2.1]octane-8-carbaldehyde (( )-11). A
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mixture of tropane ( )-6 (1.54 g, 10.0 mmol), BnEt3NCl (1.03 g, 4.5
mmol), CHCl3 (7 mL, 0.09 mol), CH2Cl2 (32 mL), and 12.5 M
aqueous NaOH (25 mL) was stirred under reflux for 16 h, then diluted
with water (300 mL) and extracted with CH2Cl2 (3 × 100 mL). The
combined organic layers were washed with brine (150 mL), then 10%
aqueous HCl (100 mL), dried (MgSO4), and evaporated under
reduced pressure. Purification of the residue by bulb-to-bulb
distillation gave formamide ( )-11 as a clear oil (1.78 g, 98%): bp
140−150 °C (7.6 mm); IR (film) (cm−1) 3054 m, 2962 m, 2875 w,
carbamate ((S,1R,5S)-14) and tert-Butyl((S)-1-oxo-3-phenyl-1-
((1S,5R)-1,6,6-trimethyl-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)-
carbamate ((S,1S,5R)-14). To a stirred solution of tropane ( )-6
(1.50 g, 9.8 mmol) in CH2Cl2 (100 mL) at 0 °C was added DIPEA
(2.78 g, 21.5 mmol), N-Boc-L-PheOH (2.86 g, 10.8 mmol), and bis(2-
oxo-3-oxazolidinyl)phosphinic chloride (2.74 g, 10.8 mmol). The
reaction mixture was kept in a refrigerator at 0−4 °C for 3 days (TLC
monitoring (50% EtOAc in petroleum ether)). After this time, the
reaction mixture was diluted with ice-cold EtOAc (750 mL), washed
with ice-cold 5% aqueous HCl (500 mL) and 5% aqueous NaHCO3
(500 mL), dried (Na2SO4), and concentrated under reduced pressure.
Purification of the residue by column chromatography (SiO2, gradient
elution 0−10% EtOAc in petroleum ether) gave an inseparable
mixture of Boc-protected α-amino amides (S,1R,5S)-14 and
(S,1S,5R)-14 as a white foam (∼1:1 dr, 2.50 g, 64%): Rf = 0.29
(10% EtOAc in petroleum ether); IR (neat) (cm−1) 3429 w, 3294 w,
3055 m, 3030 w, 2962 s, 2873 m, 1707 s (CO), 1635 s (CO),
1
1649 s (CO), 1426 m, 1393 m, 1375 m, 1266 s, 740 s; H NMR
(400 MHz, 293 K) two rotamers (∼13:1) δ 8.15 (s, 1H, NCHO
(min)), 8.14 (s, 1H, NCHO (maj)), 3.96 (br s, 1H, NCH (maj)), 3.24
(br s, 1H, NCH (min)), 1.85−1.40 (m, 8H, 4 × CH2), 1.38 (s, 3H,
CH3 (maj)), 1.12 (s, 3H, CH3 (maj)), 1.10 (s, 3H, CH3 (min)), 1.05
(s, 3H, CH3 (min)), 0.96 (s, 3H, CH3 (maj)); 13C NMR (101 MHz,
293K) two rotamers {∼ 13:1} δ 159.2 (CO (min)), 156.7 (CO
(maj)), 67.5 (NCH (min)), 62.6 (NC(CH3) (min)), 61.3 (NCH
(maj)), 61.1 (NC(CH3) (maj)), 52.1 (CH2 (min)), 50.6 (CH2 (maj)),
40.8 (CH2 (maj)), 38.7 (NCHC(CH3)2 (maj)), 38.3 (NCHC(CH3)2
(min)), 36.6 (CH2 (min)), 32.1 (CH3 (maj)), 31.8 (CH3 (min)), 29.2
(CH2 (min)), 25.8 (CH3 (min)), 25.5 (CH2 (maj)), 24.4 (CH3
(maj)), 22.4 (CH3 (min)), 22.1 (CH3 (maj)), 18.5 (CH2 (min)),
18.4 (CH2 (maj)); MS m/z (ESI+) 204.1 (M + Na+, 31); HRMS m/z
(M + H+) found 182.1537, calcd for C11H20NO 182.1539.
1
1495 s, 1444 s, 1266 s, 1170 s, 1044 m, 739 s; H NMR (400 MHz)
two diastereomers (∼1:1) δ 7.32−7.14 (m, 10H, 2 × Ph), 5.28 (5.22)
(d, 2H, J = 9 (10) Hz, 2 × NH), 4.72−4.59 (m, 2H, 2 × NHCH), 3.67
(3.62) (br s, 2H, 2 × NCH), 3.24−3.06 (m, 2H, 2 × PhCHAHB),
2.93−2.75 (m, 2H, 2 × PhCHAHB), 2.14−2.02 (m, 1H, CHAHB),
1.95−1.19 (m, 14H, 6 × CH2 and 2 × CHAHB), 1.63 (s, 3H, CH3),
1.55 (s, 3H, CH3), 1.40 (s, 9H, t-Bu), 1.38 (s, 9H, t-Bu), 1.07 (s, 3H,
CH3), 1.012 (s, 3H, CH3), 1.006 (s, 3H, CH3), 0.79 (s, 3H, CH3),
0.49−0.30 (m, 1H, CHAHB); 13C NMR (101 MHz) two diastereomers
(∼1:1) δ 170.9 (169.8) (NHCHCO), 155.0 (154.8) (NHCO),
137.4 (136.8) (Ar (ipso)), 129.9 (129.5) (Ar (ortho)), 128.3 (128.2)
(Ar (meta)), 126.6 (126.5) (Ar (para)), 79.5 (79.4) (C(CH3)3), 68.7
(67.6) (NCHC(CH3)2), 64.6 (64.3) (NC(CH3)), 53.5 (53.4)
(NHCH), 51.6 (2 × CH2C(CH3)2), 39.8 (39.3) (PhCH2), 38.0
(37.9) (C(CH3)2), 36.7 (CH2), 35.0 (CH2), 32.0 (CH3), 31.8 (CH3),
28.29 (CH2), 28.27 (C(CH3)3), 28.23 (C(CH3)3), 27.4 (CH3), 27.1
(CH2), 27.0 (CH3), 22.6 (CH3), 22.4 (CH3), 18.4 (2 × CH2); MS m/
z (ESI+) 401.3 (M + H+, 79); HRMS m/z (M + H+) found 401.2799,
calcd for C24H37N2O3 401.2799.
(+)-(S)-2-Amino-3-phenyl-1-((1R,5S)-1,6,6-trimethyl-8-
azabicyclo[3.2.1]octan-8-yl)propan-1-one ((+)-(S,1R,5S)-15) and
(+)-(S)-2-Amino-3-phenyl-1-((1S,5R)-1,6,6-trimethyl-8-azabicyclo-
[3.2.1]octan-8-yl)propan-1-one ((+)-(S,1S,5R)-15). Anhydrous TFA
(62 mL) was added to a stirred solution of Boc-protected α-amino
amides (S,1R,5S)-14 and (S,1S,5R)-14 (9.35 g, 23.3 mmol) in
CH2Cl2 (280 mL) at room temperature. After 1 h, the mixture was
evaporated under reduced pressure and the residue dissolved in CHCl3
(300 mL). The resulting solution was washed with 10% aqueous
Na2CO3 (500 mL). The aqueous layer was separated and back-
extracted with CHCl3 (2 × 300 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure, and
the residue was purified by column chromatography (SiO2, gradient
elution 5−10% MeOH in EtOAc). The α-amino amide (S,1R,5S)-15
eluted first (minor diastereomer, 2.96 g), followed by a mixed fraction
(747 mg); the α-amino amide (S,1S,5R)-15 eluted last (major
diastereomer, 2.94 g), all white solids (55:45 dr, 6.65 g total product,
95%);
General Procedure for Enamine Synthesis. ( )-8-((E)-Hex-1-
en-1-yl)-1,6,6-trimethyl-8-azabicyclo[3.2.1]octane (( )-12). Pentyl-
magnesium chloride (2.0 M in THF, 690 μL, 1.38 mmol) was added
dropwise to a stirred solution of tropamide ( )-11 (200 mg, 1.10
mmol) in Et2O (1 mL) while the temperature was maintained between
−15 and −20 °C. The mixture was kept within this temperature range
for 15 min and then warmed to room temperature. After 16 h, the
mixture was evaporated under reduced pressure and the crude product
purified by bulb-to-bulb distillation to give enamine ( )-12 as a clear
oil (214 mg, 83%): bp 125−135 °C (0.1 mm); IR (neat) (cm−1) 2932
1
s, 2870 s, 1649 s (CCNR1R2), 1332 s, 1247 s, 1139 m, 936 s; H
NMR (400 MHz, C6D6) δ 6.06 (d, 1H, J = 14 Hz, NCH=CH), 4.38
(dt, 1H, J1 = 14 Hz, J2 = 7 Hz, NCHCH), 3.09 (br s, 1H,
NCHC(CH3)2), 2.29−2.10 (m, 3H, NCHCHCH2 and CHAHB),
1.69−1.36 (m, 8H, 3 × CH2 and 2 × CHAHB), 1.31 (d, 1H, JAB = 13
Hz, CHAHB), 1.14 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.04−0.92 (m,
2H, 2 × CHAHB), 1.01 (s, 3H, CH3), 0.95 (t, 3H, J = 7 Hz, CH2CH3);
13C NMR (101 MHz, C6D6) δ 131.1 (NCHCH), 102.3
(NCH=CH), 65.2 (NCHC(CH3)2), 61.3 (NC(CH3)), 51.7 (CH2),
38.6 (C(CH3)2), 35.5 (CH2), 34.9 (CH2), 33.6 (CH3), 32.0 (NCH
CHCH2), 26.1 (CH3), 23.5 (CH3), 23.0 (CH2), 20.1 (CH2), 18.1
(CH2), 14.7 (CH2CH3); MS m/z (ESI+) 236.2 (M + H+, 100); HRMS
m/z (M + H+) found 236.2374, calcd for C16H30N 236.2373.
General Procedure for Enamine Alkylation. ( )-2-Ethyl-
hexanal (( )-13). Enamine ( )-12 (211 mg, 0.90 mmol), d3-MeCN
(1 mL), and EtI (281 mg, 1.80 mmol) were placed in an NMR tube
fitted with a PTFE valve. This mixture was heated at 60 °C for 3 days
with occasional shaking until consumption of the enamine was
1
complete by H NMR spectroscopy. Buffer solution (AcOH (0.5 g),
AcONa (0.5 g), and H2O (1 mL); 0.5 mL) was then added and the
mixture heated at 50 °C. After 1.5 h, the mixture was partitioned
between Et2O (20 mL) and H2O (10 mL). The organic layer was
separated and the aqueous layer back-extracted with Et2O (2 × 20
mL). The combined organic layers were washed with brine (20 mL),
dried (MgSO4), and carefully reduced under vacuum (152 mm, 0 °C).
Purification of the residue by column chromatography (SiO2, 5% Et2O
in petroleum ether) gave 2-ethylhexanal (( )-13)13 as a clear oil (93
mg, 81%): Rf = 0.41 (5% Et2O in petroleum ether); IR (neat) (cm−1)
2961 m, 2930 m, 2861 m, 2694 w, 1725 s (CO), 1461 m, 1381 w,
1154 w, 899 w; 1H NMR (400 MHz) δ 9.56 (d, 1H, J = 3 Hz, CHO),
2.23−2.10 (m, 1H, CHCHO), 1.71−1.20 (m, 8H, 4 × CH2), 0.91 (t,
3H, J = 7 Hz, CH3), 0.88 (t, 3H, J = 7 Hz, CH3); 13C NMR (101
MHz) δ 205.7 (CO), 53.4 (CHCHO), 29.2 (CH2), 28.1 (CH2),
22.7 (CH2), 21.8 (CH2), 13.9 (CH3), 11.4 (CH3).
Data for minor diastereomer (S,1R,5S)-15: mp 69−71 °C; Rf =
25
0.52 (10% MeOH in EtOAc); [α]D = +23.4° (c = 0.5, MeOH); IR
(KBr) (cm−1) 3390 w, 2999 m, 2940 s, 1631 s (CO), 1493 m, 1442
s, 1341 m, 928 m, 750 s, 704 s; 1H NMR (400 MHz) δ 7.33−7.10 (m,
5H, Ar), 3.68 (t, 1H, J = 7 Hz, NH2CH), 3.49 (br s, 1H, CONCH),
3.09 and 2.72 (AB, 2H, JAB = 13 Hz, J = 7 Hz, PhCH2), 1.89 (td, 1H,
JAB = 13 Hz, J = 6 Hz, CHAHB), 1.77−1.21 (m, 8H, NH2, 2 × CH2, 1
× CHAHB and 1 × CHAHB), 1.64 (s, 3H, CH3), 1.07 (s, 3H, CH3),
1.06 (s, 3H, CH3), 0.77−0.58 (m, 1H, CHAHB); 13C NMR (101
MHz) δ 173.4 (CO), 138.5 (Ar (ipso)), 129.6 (Ar), 128.4 (Ar),
126.4 (Ar), 67.5 (CONCH), 64.2 (NC(CH3)), 55.2 (NH2CH), 51.3
(CH2), 41.5 (PhCH2), 38.1 (NCHC(CH3)2), 36.1 (CH2), 32.2
(CH3), 27.4 (CH3), 27.4 (CH2), 22.5 (CH3), 18.5 (CH2); MS m/z
(ESI+) 301.2 (M + H+, 72); HRMS m/z (M + H+) found 301.2277,
calcd for C19H29N2O 301.2274.
Resolution of Tropane ( )-6. tert-Butyl((S)-1-oxo-3-phenyl-1-
((1R,5S)-1,6,6-trimethyl-8-azabicyclo[3.2.1]octan-8-yl)propan-2-yl)-
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Data for major diastereomer (S,1S,5R)-15: mp 33−35 °C, Rf = 0.45
(10% MeOH in EtOAc); [α]D25 = +66.0° (c = 0.5, MeOH); IR (KBr)
(cm−1) 3347 br m (NH2), 2927 s, 1638 s (CO), 1560 m, 1443 s,
1367 m, 1288 m, 1120 m, 927 m, 744 s, 703 s; 1H NMR (400 MHz) δ
7.35−7.13 (m, 5H, Ar), 3.75 (br s, 1H, NH2CH), 3.57 (br s, 1H,
NCHC(CH3)2), 3.07 and 2.72 (AB, 2H, JAB = 13 Hz, J1 = 8 Hz, J2 = 5
Hz, PhCH2), 2.12 (td, 1H, JAB = 13 Hz, J = 6 Hz, CHAHB), 2.00 (br s,
2H, NH2), 1.90−1.55 (m, 5H, 2 × CH2 and 1 × CHAHB), 1.62 (s, 3H,
CH3), 1.46 (d, 1H, JAB = 13 Hz, CHAHB), 1.32 (dd, 1H, JAB = 13 Hz, J
= 6 Hz, CHAHB), 1.12 (s, 3H, CH3), 0.94 (s, 3H, CH3); 13C NMR
(101 MHz) δ 174.1 (CO), 137.9 (Ar (ipso)), 129.3 (Ar), 128.5
(Ar), 126.6 (Ar), 68.3 (NCHC(CH3)2), 64.4 (NC(CH3)), 54.9
(NH2CH), 51.6 (CH2), 42.9 (PhCH2), 38.0 (C(CH3)2), 35.1 (CH2),
32.3 (CH3), 28.4 (CH2), 27.4 (CH3), 22.6 (CH3), 18.5 (CH2); MS
m/z (ESI+) 301.2 (M + H+, 75); HRMS m/z (M + H+) found
301.2277, calcd for C19H29N2O 301.2274.
Asymmetric Alkylation of Enamines (1R,5S)-12 and (1S,5R)-
12 with EtI. According to the general procedure for enamine
alkylation, reaction of enamine (1R,5S)-12 (151 mg, 0.64 mmol) with
EtI (200 mg, 1.28 mmol) in d3-MeCN (690 μL) at 65 °C for 16 h
gave, following hydrolysis with acidic buffer (0.5 mL) at room
temperature for 5 min, aldehyde (S)-1312 (58:42 er,12,38 60 mg, 73%).
According to the general procedure for enamine alkylation, reaction
of enamine (1S,5R)-12 (214 mg, 0.91 mmol) with EtI (284 mg, 1.82
mmol) in d3-MeCN (1 mL) at 65 °C for 16 h gave, following
hydrolysis with acidic buffer (0.5 mL) at room temperature for 5 min,
aldehyde (R)-1312 (55:45 er,12,38 91 mg, 78%).
Homotropane (1S,5R)-17 Synthesis. 2-Methyl-2-(2-methyl-1,3-
dioxolan-2-yl)propanal (25). 2-Methyl-2-(2-methyl-1,3-dioxolan-2-
yl)propan-1-ol31 (7.2 g, 44.9 mmol) was dissolved in CH2Cl2 (40
mL) at room temperature. The resulting solution was added rapidly to
a suspension of PCC (14.5 g, 67.3 mmol) in CH2Cl2 (70 mL) at room
temperature with stirring. The mixture immediately turned black on
addition of the alcohol. After stirring overnight at room temperature,
the mixture was diluted with anhydrous Et2O (200 mL), the solvent
decanted, and the residual black solid washed with Et2O (3 × 100
mL). The combined organic layers were passed through a small pad of
Florisil, and the filtrate was concentrated under reduced pressure.
Purification of the residue by bulb-to-bulb distillation gave aldehyde
2539 as a clear oil (6.6 g, 93%): bp 75−80 °C (11 mm) (lit.39 bp 90−
95 °C (7 mm)); Rf = 0.44 (10% EtOAc in petroleum ether); IR (neat)
(cm−1) 2984 m, 2888 m, 1725 s (CO), 1471 w, 1376 m, 1215 m,
(+)-(1R,5S)-1,6,6-Trimethyl-8-azabicyclo[3.2.1]octane
((+)-(1R,5S)-6) and (−)-(1S,5R)-1,6,6-trimethyl-8-azabicyclo[3.2.1]-
octane ((−)-(1S,5R)-6). PhNCS (340 mg, 2.51 mmol) was added to a
stirred solution of α-amino amide (S,1R,5S)-15 (686 mg, 2.28 mmol)
in CH2Cl2 (40 mL) at room temperature. A distillation head,
condenser, and receiver flask were connected to the reaction vessel,
and CH2Cl2 was removed over an oil bath (100 °C). The distillate was
recombined with the contents of the reaction vessel, and the
distillation procedure was repeated until α-amino amide (S,1R,5S)-
15 had been consumed (determined by TLC (10% MeOH in
EtOAc)). Upon completion, the mixture was concentrated to dryness
and TFA (20 mL) added to the residue. The resulting solution was
heated at 50 °C for 20 min. After this time, the reaction mixture was
evaporated under reduced pressure and the residue dissolved in CHCl3
(100 mL). This solution was partitioned with H2O (100 mL), and the
aqueous layer was separated and basified with 3 M aqueous NaOH.
The resulting suspension was washed with Et2O (5 × 100 mL). The
combined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by bulb-to-bulb distillation
(bp 50−60 °C (14 mm)) to give tropane (1R,5S)-6 as a clear oil (316
1
1163 m, 1099 m, 1045 s (O−C−O), 755 s; H NMR (400 MHz) δ
9.69 (s, 1H, CHO), 4.07−3.86 (m, 4H, C2H4), 1.23 (s, 3H, CH3CO),
1.10 (s, 6H, C(CH3)2); 13C NMR (101 MHz) δ 205.3 (CO), 111.8
(O−C−O), 64.9 (C2H4), 53.7 (C(CH3)2), 20.2 (CH3C{OC2H4O}),
17.8 (C(CH3)2); MS m/z (ESI+) 181.1 (M + Na+, 6); HRMS m/z (M
+ Na+) found 181.0831, calcd for C8H14NaO3 181.0835.
(−)-(R,E)-2-Methyl-N-(2-methyl-2-(2-methyl-1,3-dioxolan-2-yl)-
propylidene)propane-2-sulfinamide ((−)-(R)-24). Finely ground
NaOH (28 mg, 0.70 mmol) was added to a stirred solution of
sulfinamide (R)-26 (86 mg, 0.71 mmol) in MeOH (3.5 mL) at room
temperature. After 15 min, aldehyde 25 (112 mg, 0.71 mmol) was
added. After 16 h, the reaction mixture was evaporated under reduced
pressure and the residue dissolved in Et2O (2 mL) and washed with
saturated aqueous NH4Cl (2 mL). The aqueous layer was separated
and back-extracted with Et2O (4 × 2 mL), and the organic layers were
combined, dried (Na2SO4), and concentrated under reduced pressure,
to give chiral sulfinimine (R)-24 as a clear oil (175 mg, 94%): Rf = 0.10
(10% EtOAc in petroleum ether); [α]D25 = −246.5° (c = 0.3, CHCl3);
IR (neat) (cm−1) 2981 m, 2885 m, 1620 m (CN), 1474 m, 1459 m,
1363 m, 1163 m, 1143 m, 1084 s and 1042 s (SO and O−C−O),
25
mg, 90%): [α]D = +85.7° (c = 1.4, CHCl3); other data as above.
Following the same procedure, reaction of the α-amino amide
(S,1S,5R)-15 (3.27 g, 10.9 mmol) with PhNCS (1.62 g, 12.0 mmol) in
CH2Cl2 (170 mL) gave, after treatment with TFA (85 mL), tropane
(1S,5R)-6 (1.34 g, 80%): [α]D25 = −89.6° (c = 1.4, CHCl3); other data
as above.
Synthesis of Chiral Formamides (1R,5S)-11 and (1S,5R)-11.
(+)-(1R,5S)-1,6,6-Trimethyl-8-azabicyclo[3.2.1]octane-8-carbalde-
hyde ((+)-(1R,5S)-11). According to the general procedure for
formamide synthesis, reaction of tropane (1R,5S)-6 (597 mg, 3.90
mmol), BnEt3NCl (399 mg, 1.75 mmol), CHCl3 (2.9 mL, 0.04 mol),
and 12.5 M aqueous NaOH (9.7 mL) in CH2Cl2 (12.7 mL) at reflux
for 17 h gave formamide (1R,5S)-11 as a clear oil (656 mg, 93%):
1
949 m, 886 m; H NMR (400 MHz) δ 8.14 (s, 1H, HCN), 4.05−
3.85 (m, 4H, C2H4), 1.27 (s, 3H, CH3), 1.21 (s, 3H, CH3), 1.20 (s,
3H, CH3), 1.19 (s, 9H, C(CH3)3); 13C NMR (101 MHz) δ 173.4
(CN), 112.2 (O−C−O), 65.1 (OCH2CH2O), 65.0 (OCH2CH2O),
56.8 (C(CH3)3), 49.5 (C(CH3)2), 22.3 (C(CH3)3), 20.7 (CH3), 20.6
(CH3), 20.1 (CH3); MS m/z (ESI+) 284.1 (M + Na+, 100); HRMS
m/z (M + Na+) found 284.1288, calcd for C12H23NNaO3S 284.1291.
Grignard Addition to Sulfinimine ( )-24. ( )-2-Methyl-N-(2-
methyl-2,6-bis(2-methyl-1,3-dioxolan-2-yl)hexan-3-yl)propane-2-
sulfinamides (( )-(SS,R)-20 and ( )-(RS,S)-20). Magnesium turnings
were stirred vigorously under argon overnight,40 resulting in a color
change from gray to black. THF (1.3 mL) was added, followed by 1,2-
dibromoethane (2−3 drops), at which point the mixture started to
bubble. With close monitoring of the reaction mixture, 2-(3-
chloropropyl)-2-methyl-1,3-dioxolane41 (1.05 g, 6.4 mmol) was
added dropwise, ensuring the temperature did not exceed 50 °C
(ice bath). After addition, the mixture was stirred for 2 h at room
temperature and then diluted with THF (1.9 mL). A portion of the
freshly prepared solution of Grignard reagent 23 (190 μL) was added
to a stirred solution of sulfinimine ( )-24 (50 mg, 0.19 mmol) in
THF (1.7 mL) at −78 °C and the resultant mixture warmed to room
temperature after 30 min. After 16 h the reaction mixture was
quenched with saturated aqueous NH4Cl (2 mL), diluted with H2O (2
mL), and extracted with Et2O (3 × 5 mL). The combined organic
25
[α]D = +88.0° (c = 1.0, MeOH); other data as above.
(−)-(1S,5R)-1,6,6-Trimethyl-8-azabicyclo[3.2.1]octane-8-carbal-
dehyde ((−)-(1S,5R)-11). According to the general procedure for
formamide synthesis, reaction of tropane (1S,5R)-6 (1.28 g, 8.4
mmol), BnEt3NCl (856 mg, 3.8 mmol), CHCl3 (6.2 mL, 0.08 mol),
and 12.5 M aqueous NaOH (20.7 mL) in CH2Cl2 (27 mL) at reflux
for 17 h gave formamide (1S,5R)-11 as a clear oil (1.25 g, 82%):
25
[α]D = −69.0° (c = 0.9, MeOH); other data as above.
Synthesis of Chiral Enamines (1R,5S)-12 and (1S,5R)-12.
(1R,5S)-8-((E)-Hex-1-en-1-yl)-1,6,6-trimethyl-8-azabicyclo[3.2.1]-
octane ((1R,5S)-12). According to the general procedure for enamine
synthesis, reaction of formamide (1R,5S)-11 (621 mg, 3.43 mmol)
with pentylmagnesium chloride (2.0 M in THF, 2.14 mL, 4.28 mmol)
in Et2O (2.5 mL) at room temperature for 17 h gave, after distillation,
enamine (1R,5S)-12 (676 mg, 84%):37 other data as above.
(1S,5R)-8-((E)-Hex-1-en-1-yl)-1,6,6-trimethyl-8-azabicyclo[3.2.1]-
octane ((1S,5R)-12). According to the general procedure for enamine
synthesis, reaction of formamide (1S,5R)-11 (684 mg, 3.77 mmol)
with pentylmagnesium chloride (2.0 M in THF, 2.42 mL, 4.84 mmol)
in Et2O (5 mL) at room temperature for 17 h gave, after distillation,
enamine (1S,5R)-12 (504 mg, 57%):37 other data as above.
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layers were dried (Na2SO4) and evaporated under reduced pressure.
Purification of the residue by column chromatography (SiO2, gradient
elution 10−100% Et2O in petroleum ether) gave inseparable
diastereomers of bis-ketal sulfinamide ( )-20 (73:27 dr) and an
unknown, inseparable impurity. From this mixture it was possible, by
precipitation with petroleum ether, to partially extract the racemic
major diastereomers ( )-(SS,R)-20 and ( )-(RS,S)-20 as a white
solid (34 mg, 45%); the rest of the material was obtained as a crude
mixture (39 mg): mp 75−79 °C; Rf = 0.12 (50% EtOAc in petroleum
ether); IR (neat) (cm−1) 3444 w, 3297 w (N−H stretch), 2981 m,
2880 m, 1707 w, 1650 w, 1474 m, 1373 m, 1128 m, 1045 s (SO and
a clear crystalline solid (1.04 g, 83%); mp 40−42 °C; Rf = 0.36 (10%
25
MeOH in EtOAc); [α]D = −94.4° (c = 0.3, CHCl3); IR (neat)
(cm−1) 3310 w (N−H stretch), 2953 m, 2930 m, 1699 s (CO),
1655 w, 1457 m, 1380 m, 1201 m, 909 m, 730 s; 1H NMR (400 MHz)
δ 2.93 (br s, 1H NCH), 2.35 and 2.17 (AB, 2H, JAB = 16 Hz, CH2C
O), 1.88 (br s, 1H, NH), 1.82 (d, 1H, JAB = 13 Hz, NCHCHAHB),
1.57−1.32 (m, 4H, CH2, CHAHB and CHAHB), 1.31−1.15 (m, 1H,
CHAHB), 1.22 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.02 (s, 3H, CH3);
13C NMR (101 MHz) δ 216.2 (CO), 60.8 (NCH), 53.7 (NCCH3),
50.0 (CH2CO), 46.8 (C(CH3)2), 38.6 (CH(CH2)2CH2), 31.5
(CH3), 27.7 (CH3), 27.2 (NCHCH2), 21.3 (CH3), 17.9
(CH2CH2CH2); MS m/z (ESI+) 182.1 (M + H+, 52); HRMS m/z
(M + H+) found 182.1534, calcd for C11H20NO 182.1539.
1
O−C−O), 876 m; H NMR (400 MHz) δ 4.05−3.82 (m, 8H, 2 ×
OC2H4O), 3.61 (d, 1H, J = 6 Hz, NH), 3.15−3.00 (m, 1H, J = 6 Hz,
NHCH), 2.10−1.98 (m, 1H, NHCHCHAHB), 1.88−1.78 (m, 1H,
CHCH2CHAHB), 1.77−1.66 (m, 1H, JAB = 14 Hz, CH-
(CH2)2CHAHB), 1.65−1.54 (m, 1H, JAB = 14 Hz, CH(CH2)2CHAHB),
1.50−1.36 (m, 2H, NHCHCHAHB and CHCH2CHAHB), 1.34 (s, 3H,
CH3), 1.243 (s, 9H, C(CH3)3), 1.235 (s, 3H, CH3), 1.01 (s, 3H, CH3),
0.92 (s, 3H, CH3); 13C NMR (101 MHz) δ 113.8 (O−C−O), 110.2
(O−C−O), 64.7 (OCH2), 64.6 (OCH2), 64.5 (OCH2), 64.2 (OCH2),
63.6 (NHCH), 56.5 (C(CH3)3), 46.6 (C(CH3)2), 39.1 (CHCH2CH2),
32.3 (NHCHCH2), 23.9 (CH3), 23.1 (C(CH3)3), 22.0 (CH-
(CH2)2CH2), 21.7 (CH3), 19.9 (CH3), 19.6 (CH3); MS m/z (ESI+)
414.2 (M + Na+, 100); HRMS m/z (M + H+) found 392.2470, calcd
for C19H38NO5S 392.2465.
(−)-(1S,3R,5R)-1,4,4-Trimethyl-9-azabicyclo[3.3.1]nonan-3-ol
((−)-(1S,3S,5R)-28). LAH (361 mg, 9.5 mmol) was dissolved in THF
(10 mL) with stirring and external cooling (ice bath). Homotropinone
(1S,5R)-18 (1.50 g, 8.3 mmol) in THF (10 mL) was added, dropwise,
with stirring at 0 °C. The reaction temperature was maintained at 0 °C
for 30 min and then warmed to room temperature and stirred
overnight. After this time, the mixture was recooled to 0 °C and
quenched: H2O (360 μL), then 15% aqueous NaOH (360 μL), and
then H2O (1.1 mL). (Caution!) The resulting suspension was filtered
and the filter cake washed with CH2Cl2 (100 mL). The filtrate was
concentrated under reduced pressure, to give homotropinol
(1S,3R,5R)-28 as a white solid (1.38 g, 91%): mp 105−110 °C; Rf
= 0.10 (20% MeOH in EtOAc); [α]D25 = −22.4° (c = 1.9, CHCl3); IR
(neat) (cm−1) 3130 br m (O−H and N−H), 2898 m, 1459 m, 1418
m, 1287 m, 1106 m, 1047 s, 968 s, 821 s; 1H NMR (500 MHz) δ 3.62
(dd, 1H, J1 = 6 Hz, J2 = 3 Hz, CHOH), 2.70 (d, 1H, J = 4 Hz, NCH),
2.59−2.41 (m, 1H, CH2CHAHBCH2), 2.12 (br s, 2H, NH and OH),
1.84 (dd, 1H, JAB = 14 Hz, J = 6 Hz, CHAHBCHOH), 1.77 (dd, 1H,
JAB = 14 Hz, J = 6 Hz, NCHCHAHB), 1.59−1.45 (m, 3H,
CHAHBCHOH, NCHCHAHB and CH(CH2)2CHAHB), 1.43−1.32
(m, 2H, CHCH2CHAHBCHAHB), 1.09 (s, 3H, CH3), 1.05 (s, 3H,
CH3), 0.97 (s, 3H, CH3); 13C NMR (125 MHz) δ 71.7 (CHOH), 58.2
(NCH), 47.9 (NC(CH3)), 41.0 (CH2CHOH), 36.8 (CH(CH2)2CH2),
36.0 (C(CH3)2), 33.3 (CH3), 30.4 (CH3), 25.9 (NCHCH2), 21.8
(CH3), 17.2 (CH2CH2CH2); MS m/z (ESI+) 184.2 (M + H+, 32);
HRMS m/z (M + H+) found 184.1695, calcd for C11H22NO 184.1696.
(−)-S-Methyl O-((1S,3R,5R)-1,4,4-Trimethyl-9-azabicyclo[3.3.1]-
nonan-3-yl)carbonodithioate ((−)-(1S,3R,5R)-29). Homotropinol
(1S,3R,5R)-28 (299 mg, 1.63 mmol) was dissolved in THF (5 mL)
with stirring at room temperature. Imidazole (25 mg, 0.36 mmol) and
NaH (203 mg, 8.46 mmol) were added, and the resulting mixture was
stirred at room temperature for 30 min. CS2 (647 μL, 10.76 mmol)
was added, dropwise, resulting in an orange coloration. The mixture
was heated at 70 °C for 16 h, then cooled to room temperature and
MeI (203 μL, 3.26 mmol) added, dropwise. The resulting mixture was
stirred at room temperature for 16 h, then evaporated under reduced
pressure. Purification of the residue by column chromatography (SiO2,
gradient elution 0−20% MeOH in EtOAc) gave xanthate (1S,3R,5R)-
29 as an orange solid (336 mg, 75%): mp 40−44 °C; [α]D25 = −17.3°
(c = 0.8, CHCl3); Rf = 0.21 (20% MeOH in EtOAc); IR (neat) (cm−1)
2920 m, 1704 w, 1592 w, 1424 m, 1374 m, 1226 s (CS), 1049 s
Organolithium 27 Addition to Sulfinimine (R)-24. (−)-(R)-2-
Methyl-N-((R)-2-methyl-2,6-bis(2-methyl-1,3-dioxolan-2-yl)hexan-
3-yl)propane-2-sulfinamide ((−)-(RS,R)-20). 2-(3-Iodopropyl)-2-
methyl-1,3-dioxolane42 (5.88 g, 23.0 mmol) was dissolved in
pentane/Et2O (3:2, 225 mL) at room temperature with stirring. The
resulting solution was cooled to −78 °C, and t-BuLi (1.7 M in
pentane, 28.4 mL, 48.3 mmol) was added dropwise. The mixture was
stirred at −78 °C for 5 min and then warmed to room temperature,
which resulted in formation of a white slurry. The mixture was stirred
at room temperature for 1 h and then recooled to −78 °C. The freshly
prepared organolithium 27 was transferred, dropwise via cannula, to a
solution of sulfinimine (R)-24 (3.00 g, 11.5 mmol) in THF (57 mL) at
−78 °C. After 16 h at −78 °C the mixture was quenched with MeOH
(100 mL), warmed to room temperature, and then diluted with H2O
(400 mL). The organic layer was separated and the aqueous layer
extracted with Et2O (4 × 250 mL). The combined organic layers were
dried (Na2SO4) and evaporated under reduced pressure. Purification
of the residue by column chromatography (SiO2, gradient elution 50−
80% EtOAc in petroleum ether) gave bis-ketal sulfinamide (RS,R)-20
(98:2 dr, 4.09 g, 91%): Rf = 0.12 (50% EtOAc in petroleum ether);
25
[α]D = −78.8° (c = 2.2, CHCl3); IR (neat) (cm−1) 3275 w (N−H
stretch), 2979 m, 2881 m, 1474 m, 1377 m, 1217 m, 1157 m, 1062 s
1
and 1041 s (SO and O−C−O), 949 m, 874 m; H NMR (400
MHz) δ 5.25 (br s, 1H, NH), 4.07−3.84 (m, 8H, 2 × OC2H4O), 3.24
(br s, 1H, NHCH), 1.77−1.55 (m, 4H, 1 × CH2 and 2 × CHAHB),
1.50−1.36 (m, 2H, 2 × CHAHB), 1.32 (s, 3H, CH3), 1.30 (s, 3H,
CH3), 1.21 (s, 9H, C(CH3)3), 1.05 (s, 3H, CH3), 0.92 (s, 3H, CH3);
13C NMR (101 MHz) δ 114.6 (O−C−O), 109.9 (O−C−O), 65.2
(OCH2), 64.6 (2 × OCH2), 63.6 (OCH2), 58.7 (NHCH), 55.4
(C(CH3)3), 45.3 (C(CH3)2), 39.4 (CH2), 33.1 (NHCHCH2), 23.8
(CH3), 23.2 (CH3), 22.9 (C(CH3)3), 22.8 (CH2), 19.3 (CH3), 16.8
(CH3); MS m/z (ESI+) 392.2 (M + H+, 100); HRMS m/z (M + Na+)
found 414.2275, calcd for C19H37NNaO5S 414.2285.
(−)-(1S,5R)-1,4,4-Trimethyl-9-azabicyclo[3.3.1]nonan-3-one
((−)-(1S,5R)-18). HCl (2 M in Et2O, 86 mL) was added to a stirred
solution of bis-ketal sulfinamide (RS,R)-20 (2.69 g, 6.9 mmol) in
MeOH (250 mL) at room temperature. The resulting mixture was
heated at 75 °C for 2 days. After this time, the mixture was cooled to
room temperature, and the volatiles were removed by evaporation
under reduced pressure. Aqueous NaOH (3 M, 100 mL) was added to
the residue and the resulting suspension stirred for 15 min and then
washed with CH2Cl2 (5 × 100 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure.
Purification of the residue by column chromatography (SiO2, gradient
elution 0−10% MeOH in EtOAc) gave homotropinone (1S,5R)-18 as
1
(MeS−CS−O−R), 965 m, 753 m; H NMR (500 MHz) δ 5.60 (dd,
1H, J1 = 6 Hz, J2 = 2 Hz, CH−O−CS2Me), 2.75 (d, 1H, J = 5 Hz,
NCH), 2.60 (s, 3H, SCH3), 2.39−2.25 (m, 1H, CH2CHAHBCH2),
2.00−1.86 (m, 2H, O−CHCHAHB and NCHCHAHB), 1.77 (dd, 1H,
JAB = 16 Hz, J = 2 Hz, O−CHCHAHB), 1.71−1.57 (m, 1H,
NCHCHAHB), 1.55−1.39 (m, 3H, CHCH2CHAHBCH2), 1.23 (s, 3H,
CH3), 1.08 (s, 3H, CH3), 0.99 (s, 3H, CH3); 13C NMR (125 MHz) δ
215.7 (CS), 83.9 (CH−OCS2Me), 57.7 (NCH), 47.4 (NC(CH3)),
37.8 (O−CHCH2), 36.4 (C(CH3)2), 35.9 (CH(CH2)2CH2), 33.3
(CH3), 29.9 (CH3), 25.5 (NCHCH2), 22.5 (CH3), 18.9 (SMe), 16.9
(CH2CH2CH2); MS m/z (ESI+) 274.2 (M + H+, 100); HRMS m/z
(M + H+) found 274.1286, calcd for C13H24NOS2 274.1294.
(−)-(1S,5R)-1,4,4-Trimethyl-9-azabicyclo[3.3.1]nonane
((−)-(1S,5R)-17). Xanthate (1S,3R,5R)-29 (750 mg, 2.74 mmol) and
AIBN (135 mg, 0.82 mmol) were dried under vacuum (0.1 mm) for 1
h. Benzene (degassed under Ar for 1 h, 24 mL) was added, followed by
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Bu3SnH (740 μL, 2.75 mmol), dropwise with stirring at room
temperature. The mixture was heated at 85 °C for 16 h, then cooled to
room temperature and diluted with 5% aqueous HCl (20 mL). The
aqueous layer was washed with CH2Cl2 (20 mL) and the organic layer
separated. The aqueous layer was basified with 3 M aqueous NaOH
and the resulting suspension extracted with Et2O (3 × 50 mL). The
combined organic layers were dried (Na2SO4), and the mixture
concentrated by careful evaporation (228 mm, 35 °C). Purification of
the residue by bulb-to-bulb distillation gave homotropane (1S,5R)-17
as a clear oil (316 mg, 69%): bp 75−85 °C (10 mm); Rf = 0.59 (20%
MeOH in EtOAc); [α]D25 = −2.2° (c = 1.0, CHCl3); IR (neat) (cm−1)
2949 s, 1486 m, 1450 m, 1361 m, 1196 m, 1061 m, 945 m, 865 m, 753
s; 1H NMR (500 MHz) δ 2.55 (d, 1H, J = 5 Hz, NCH), 2.02−1.87 (m,
3H, 3 × CHAHB), 1.74−1.29 (m, 8H, 3 × CHAHB, 2 × CH2 and NH),
1.08 (s, 3H, CH3), 1.01 (s, 3H, CH3), 0.93 (s, 3H, CH3); 13C NMR
(125 MHz) δ 58.2 (NCH), 47.7 (NCCH3), 37.6 (CH2), 35.2 (CH2),
34.9 (CH2), 33.3 (CH3), 32.1 (C(CH3)2), 28.9 (CH3), 28.3 (CH3),
26.6 (NCHCH2), 20.4 (CH2CH2CH2); MS m/z (ESI+) 168.6 (M +
H+, 42); HRMS m/z (M + H+) found 168.1744, calcd for C11H21N
168.1747.
minima or transition states, possessing zero imaginary frequencies and
one imaginary frequency, respectively. This level of DFT calculation
has been shown in previous studies to compute relative TS energies in
quantitative accord with experimental selectivities.14 The Pople 6-
31G(d) basis set was used for all elements except I, which was
described with the LANL2DZ effective core potential and associated
valence basis of Hay and Wadt.45 Effects of solvation due to
acetonitrile were implicitly included in all geometry optimizations and
in the evaluation of energies using a conductor-like polarizable
continuum model (CPCM).46 Free energies were evaluated at the
reaction temperature of 65 °C employing the so-called quasi-harmonic
approximation, where all vibrational frequencies lower than 100 cm−1
were raised to 100 cm−1 as a way to correct for the well-known
breakdown of the harmonic oscillator model for the free energies of
low-frequency vibrational modes.47 All possible conformational
isomers of the diastereomeric transition structures arising from
rotation about the incipient C−C bond were considered and
optimized for each enamine: in each case there are two TS geometries
for attack from either enamine diastereoface lying within 10 kJ/mol of
the global minimum energy structure and thus are the major
contributors to the selectivity.
(−)-(1S,5R)-1,4,4-Trimethyl-9-azabicyclo[3.3.1]nonane-9-carbal-
dehyde ((−)-(1S,5R)-30). According to the general procedure for
formamide synthesis, reaction of homotropane (1S,5R)-17 (156 mg,
0.93 mmol), BnEt3NCl (104 mg, 0.46 mmol), CHCl3 (749 μL, 9.36
mmol), and 12.5 M aqueous NaOH (2.5 mL) in CH2Cl2 (3.3 mL) at
reflux for 16 h gave formamide (1S,5R)-30 as a clear oil (178 mg,
98%): bp 130−140 °C (1.5 mm); Rf = 0.33 (Et2O); [α]D25 = −0.6° (c
= 1.0, CDCl3); IR (film) (cm−1) 2935 m, 1644 s (CO), 1450 m,
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, tables, and CIF files giving H and 13C NMR
1
spectra for all new compounds, 77Se NMR for determination of
er, NOEs of xanthate (1S,3R,5R)-29 for assignment of
stereochemistry, HPLC traces showing enantiopurity, X-ray
diffraction data for determination of absolute configuration,
Cartesian coordinates, imaginary frequencies, computed
energies, and x,y distances for TS1−TS8. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
1391 s, 1358 m, 1280 m, 1139 m, 1110 m, 910 w, 752 w; H NMR
(400 MHz) δ 8.34 (s, 1H, J = 5 Hz, CHO), 4.26 (d, 1H, J = 5 Hz,
NCH), 2.12−1.86 (m, 3H, 3 × CHAHB), 1.83−1.71 (m, 2H, 2 ×
CHAHB), 1.67−1.48 (m, 4H, 4 × CHAHB), 1.36 (s, 3H, CH3), 1.31
(dd, 1H, JAB = 14 Hz, J = 6 Hz, CHAHB), 0.98 (s, 3H, CH3), 0.94 (s,
3H, CH3); 13C NMR (101 MHz) δ 158.8 (CO), 53.3 (NC(CH3)),
52.4 (NCH), 39.3 (CH2), 36.2 (CH2), 34.5 (CH2), 33.8 (C(CH3)2),
28.7 (CH3), 27.7 (CH3), 27.1 (CH3), 25.2 (CH2), 19.9 (CH2); MS
m/z (ESI+) 196.2 (M + H+, 7); HRMS m/z (M + H+) found
196.1697, calcd for C12H22NO 196.1696.
AUTHOR INFORMATION
Corresponding Author
*E-mail: david.hodgson@chem.ox.ac.uk (D.M.H.); robert.
paton@chem.ox.ac.uk (R.S.P.; computational studies).
■
(1S,5R)-9-((E)-Hex-1-en-1-yl)-1,4,4-trimethyl-9-azabicyclo[3.3.1]-
nonane ((1S,5R)-16). According to the general procedure for enamine
synthesis, reaction of formamide (1S,5R)-30 (174 mg, 0.89 mmol)
with pentylmagnesium chloride (2.0 M in THF, 557 μL, 1.11 mmol)
in Et2O (810 μL) at room temperature for 16 h gave, after distillation,
enamine (1S,5R)-16 (170 mg, 77%): bp 125−130 °C (0.1 mm); IR
(neat) (cm−1) 3059 w, 2952 s, 2918 s, 2871 m, 1640 s (CCNR1R2),
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC and GlaxoSmithKline for an Organic
Synthesis Studentship (A.C.), Oxford University Press John
Fell Fund (R.S.P.), and the Royal Society (RG 110617; R.S.P.).
Additionally, we wish to thank Dr. Arne Dieckmann (UCLA)
for helpful discussions and for sharing computer code, Dr.
Barbara Odell for NOE 1D NMR analysis, and Dr. Andrew J.
Whitehead for helpful discussions.
1
1451 m, 1258 s, 1108 s, 936 s, 903 s, 768 m; H NMR (400 MHz,
C6D6) δ 6.36 (d, J = 14 Hz, NCHCH), 4.40 (dt, 1H, J1 = 14 Hz, J2
= 7 Hz, NCHCH), 3.13 (d, 1H, J = 5 Hz, NCHCH2), 2.21 (dt, 2H,
J1 = J2 = 7 Hz, CHCHCH2), 2.05−1.64 (m, 4H, 4 × CHAHB),
1.53−1.16 (m, 10H, 4 × CHAHB and 3 × CH2), 1.15 (s, 3H, CH3),
1.04 (s, 3H, CH3), 0.96 (t, 3H, CH2CH3), 0.87 (s, 3H, CH3); 13C
NMR (101 MHz, C6D6) δ 133.9 (NCHCH), 98.5 (NCHCH),
58.0 (NCH), 53.3 (NC(CH3)), 37.1 (CH2), 36.4 (CH2), 35.8 (CH2),
35.0 (CH2), 34.7 (C(CH3)2), 32.0 (CHCHCH2), 30.4 (CH3), 29.2
(CH3), 28.8 (CH3), 23.0 (CH2), 21.7 (CH2), 19.5 (CH2), 14.7
(CH2CH3); MS m/z (ESI+) 250.3 (M + H+, 100); HRMS m/z (M +
H+) found 250.2528, calcd for C17H32N 250.2529.37
Asymmetric Alkylation of Enamine (1S,5R)-16 with EtI.
According to the general procedure for enamine alkylation, reaction
of enamine (1S,5R)-16 (125 mg, 0.50 mmol) with EtI (156 mg, 1.00
mmol) in d3-MeCN (536 μL) at 65 °C for 16 h gave, following
hydrolysis with acidic buffer (0.5 mL) at room temperature for 5 min,
aldehyde (S)-1312 (72:28 er,12,38 41 mg, 64%).
Computational Methodology. Density functional theory (DFT)
calculations were performed using the Gaussian 09 package.43
Optimizations of the enamine ground-state structures and of
transition-state structures for alkylation were performed with the
B3LYP density functional44 using the default (fine) grid density for
numerical integration. Harmonic vibrational frequencies were
computed for all optimized structures to verify that they were either
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