A piperidine chiron for the Veratrum alkaloids

Article abstract of DOI:10.1021/jo2026228

A Veratrum piperidine chiron was prepared over 11 steps (7.9% yield) from (-)-citronellal. Three methods for the installation of the propargylic side chain onto a cyclic enamide are presented.

Full text of DOI:10.1021/jo2026228

Article
pubs.acs.org/joc
A Piperidine Chiron for the Veratrum Alkaloids
Douglass F. Taber* and Peter W. DeMatteo
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: A Veratrum piperidine chiron was prepared over 11 steps
(7.9% yield) from (−)-citronellal. Three methods for the installation of the
propargylic side chain onto a cyclic enamide are presented.
of our research toward a convergent total synthesis of
(−)-veratramine 1, we have prepared the Veratrum piperidine
chiron 7 (Scheme 1) from commercial (−)-citronellal 5.
INTRODUCTION
■
Veratramine (1) is an alkaloid isolated from plants of the genus
Veratrum.1 This class of alkaloids also includes cyclopamine (2)
and germine (3) (Figure 1). The hedgehog pathway, which is
Scheme 1
RESULTS AND DISCUSSION
The starting point for the synthesis was the protected (−)-
norcitronellamine 9 (Scheme 2). While this could be synthesized
■
Scheme 2
Figure 1. Three representative Veratrum alkaloids.
blocked by cyclopamine, has come to prominence as a potential
chemotherapeutic target over the course of the past decade for
the treatment of inoperable cancers such as basal cell
carcinoma, medulloblastoma, and rhabdomyosarcoma.2
A semisynthetic derivative of cyclopamine 2, IPI-926 4 (eq 1),
is currently3 in phase 2 clinical trials for pancreatic cancer. As
by our previously reported method,6 the one-carbon degrada-
tion of (−)-citronelllic acid was more readily scalable.
The first step was the oxidation of commercial (−)-citronellal
to (−)-citronellic acid. The gram-scale Tollens oxidation intro-
duced by Paquette7 proved particularly efficient. It was convenient
natural supplies of Veratrum alkaloids are limited, modern
Received: December 19, 2011
Published: March 8, 2012
synthetic approaches toward them are being pursued.4,5 As part
© 2012 American Chemical Society
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to recycle the stoichiometric silver residues produced in the
oxidation by digestion with concentrated nitric acid.
Carbamate inversion of the acid was accomplished via a
mixed anhydride approach.8 Ozonolysis of (-)-N-tosyl norcit-
ronellamine 9 proceeded, after filtration through silica gel,
directly to the enesulfonamide 6.
2-butadiene 16,14 a propargylic methyl chiron that hereto-
fore has only been applied to polyketide synthesis.15 Reaction
of bromohydrin 10 with the P-allene gave adduct 17 as the only
diastereomer detected, while reaction with the M-allene gave
adduct 18. The structures were unambiguously established by
X-ray crystallography. The facial selectivity of the addition was
controlled by the adjacent bromine, while the absolute
configuration at the propargylic position was defined by the
enantiomer of allene used. These readily prepared piperidines
might well be useful for the preparation of other alkaloids, such
as (−)-deoxynupharidine.16
Exposure of 6 (Scheme 3) to N-bromosuccinimide at low
temperatures delivered the crystalline bromohydrin 10 as a
Scheme 3
In an attempt to prepare 7 via the Lewis acid/allene
approach, the bromohydrin 10 (Scheme 5) and the M-allene
Scheme 5
were combined and exposed sequentially to KH(P) to convert
10 into the corresponding epoxide and then to BF3·OEt2. The
result was a complicated mixture that contained no detectable
1
traces of debenzylated 7 by H NMR. The prolinol 19, also
characterized by X-ray crystallography, was the only product
identified from the reaction. Apparently, exposure of the
intermediate epoxide to Lewis acid effected rearrangement to
the aldehyde, to which the allene was added. While there were
superficial differences between isomers 13 and 19 by 1H NMR,
the 13C NMR spectra showed the aminated methylene reso-
nance at δ > 50 for piperidine 13 and at δ < 50 for pyrrolidine 19.
Recently, Giannis described the preparation of the lactone
245b (Scheme 6). We used the approach outlined above to
prepare 24 and then investigated its methylation. While we did
not optimize this conversion, we did observe that 25, the only
diastereomer detected, had the same relative and absolute con-
figuration (X-ray) as 7.
single dominant diastereomer. Potassium hydride in paraffin
[KH(P)]9 was used to generate the epoxide in situ. Addition of
commercial 2- butenylmagnesium chloride then delivered a
separable 1:1 mixture of the two crystalline diastereomers 13
and 14, the relative configurations of which were established by
X-ray crystallography. Sequential benzylation10 and conversion to
the alkyne11 completed the preparation of the Veratrum chiron 7
(11 steps, 7.9% overall yield from commercial (−)-citronellal).
In order to access a complementary 2,5-cis-piperidine
scaffold, Lewis acid mediated homologation was attempted
on the bromohydrin 10 (Scheme 4). Such additions are known
CONCLUSION
■
Two approaches toward the preparation of the Veratrum chiron
7 have been established. The flexibility of bromohydrins 10 and
22 and their in situ derived epoxides under cationic and anionic
conditions have been demonstrated. We have also shown that
addition of (M/P)-1-tributylstannyl-1,2-butadiene to the
bromohydrin 10 delivered predictable and complementary
diastereomers. Further application of 7 in the total synthesis of
(−)-veratramine will be reported in due course.
Scheme 4
EXPERIMENTAL SECTION
■
General Procedures. 1H NMR and 13C NMR spectra were
recorded as solutions in deuteriochloroform (CDCl3), unless other-
wise indicated, at 400 and 100 MHz, respectively. 13C multiplicities
were determined with the aid of a JVERT pulse sequence, differen-
tiating the signals for methyl and methine carbons as “down” from
methylene and quaternary carbons as “up”. Rf values indicated refer to
thin-layer chromatography (TLC) on 2.5 × 10 cm, 250 μm analytical
plates coated with silica gel GF, and developed in the solvent system
indicated. All glassware was rinsed with dry solvent before use. THF
and diethyl ether were distilled from sodium metal/benzophenone
ketyl under dry nitrogen. Toluene and dichloromethane were distilled
for cyclic hemiacetals12 and hemiaminals,13 but none had been
reported utilizing the Marshall reagent, (M/P)-1-tributylstannyl-1,
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(S)-N-(2,6-Dimethylhept-5-enyl)-4-toluenesulfonamide (9). To
(−)-citronellic acid 8 (8.00 g, 47 mmol) in 240 mL of anhydrous
acetone was added triethylamine (8.0 mL, 57.5 mmol). The solution
was cooled to 0 °C. Ethyl chloroformate (8.00 g, 73.7 mmol) was then
added with vigorous stirring causing a white precipitate to form instan-
taneously. After 60 min, sodium azide (8.0 g, 123 mmol dissolved in
60 mL H2O) was added, and the biphasic mixture was stirred for
another 1 h. H2O (200 mL) was then added and the organic phase
partitioned. The aqueous phase was extracted with another 3 × 125
mL of EtOAc. The combined organic extracts were then partitioned
against 100 mL of brine and dried with Na2SO4. After decantation,
benzyl alcohol (16 mL, 154 mmol), 4 Å molecular sieves (10.00 g),
and toluene (50 mL) were added, and the solution was subjected to
atmospheric pressure short-path distillation which was halted when the
head temperature reached 110 °C. The bottoms were then taken up
with 3 × 50 mL of EtOAc. The solution was filtered, and the filtrate
was concentrated. The residue was subjected to bulb-to-bulb distilla-
tion (pot = 100 °C, 2 mmHg) to ensure complete removal of the
toluene and residual benzyl alcohol.
Scheme 6
Diethyl ether (300 mL) was then used to dissolve the pot residue
(under N2), and 300 mL of anhydrous NH3 was condensed into the
system. Li metal (high Na, 3.0 g) was then added until a deep blue
color persisted for 5 min, indicating complete reduction of the benzylic
position. The solution was then allowed to come to rt, and 300 mL
of H2O was added to dissolve the remaining solids. The biphasic
solution was acidified to pH = 5 with concentrated HCl and then
rendered alkaline to pH = 11 with solid sodium bicarbonate (foams!).
p-Toluenesulfonyl chloride (9.5 g, 50 mmol) was then added with an
equimolar amount of NaHCO3 (3.7 g, 50 mmol) and 100 mL of ethyl
acetate, and the solution was allowed to stir overnight. The mixture
was extracted with ethyl acetate (3 × 100 mL). The combined organic
extract was dried (Na2SO4) and concentrated, and the residue was
chromatographed to yield 9 as an oil that solidified on standing (11.12 g,
37.6 mmol, 80% yield from 5): TLC Rf = 0.20 (10% EtOAc/PE);
[α]D20 = 5.48 (c = 0.157 CHCl3); 1H NMR (400 MHz, CDCl3) δ ppm
0.86 (d, J = 6.7 Hz, 3 H), 1.04−1.16 (m, 1 H), 1.27−1.39 (m, 1 H),
1.49−1.70 (m, 7 H), 1.90 (td, J = 15.8, 7.3 Hz, 2 H), 2.42 (s, 3 H),
2.66−2.93 (m, 2 H), 4.94−5.08 (m, 2 H), 7.27−7.32 (d, J = 7.2 Hz, 2 H),
7.74−7.79 (d, J = 7.2 Hz, 2 H); 13C NMR (101 MHz, CDCl3) δ ppm
(up) 143.2, 136.8, 131.7, 48.9, 33.9, 25.0 (down) 129.6, 127.0, 123.9, 32.5,
25.6, 21.5, 17.5, 17.2; IR (film) 3283, 2963.3, 2924, 1452, 1325, 1150 cm−1;
HRMS calcd for C16H25NO2NaS 318.1504, obsd 318.1510.
(S)-3-Methyl-1-tosyl-1,2,3,4-tetrahydropyridine (6). The sulfon-
amide 9 (3.0 g, 10 mmol) was taken up in 100 mL of CH2Cl2. Sudan III
(10 mg) was added as an indicator. The solution was cooled to −78 °C,
and ozone was bubbled through until the red color faded. Methyl sulfide
(1.0 mL, 13.5 mmol) was then added to reduce the ozonide. The
solution was evaporated to silica gel and directly chromatographed to
give 6 as an off-white solid (1.6 g, 6.5 mmol, 65% yield from 9): mp =
83−85 °C; TLC Rf = 0.36 (10% EtOAc/PE); [α]D18 = −3.6 (c = 0.02
CHCl3); 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (d, J = 6.7 Hz, 3 H),
1.54 (dd, J = 17.4, 9.3 Hz, 1 H), 1.71−1.82 (m, 1 H), 1.94−2.04 (m, 1
H), 2.42 (s, 3 H), 2.64 (t, J = 10.8 Hz, 1 H), 3.59 (d, J = 11.7 Hz, 1 H),
4.89−4.96 (m, 1 H), 6.63 (d, J = 8.1 Hz, 1 H), 7.31 (d, J = 7.9 Hz, 2 H),
7.66 (d, J = 7.9 Hz, 2 H); 13C NMR (101 MHz, CDCl3) δ ppm (up)
143.5, 135.1, 49.8, 29.3; (down) 129.7, 127.0, 124.5, 107.3, 26.4, 21.5,
18.6; IR (film) 3062, 2950.0, 2922, 1649, 1598, 1458, 1347, 1257 cm−1;
HRMS calcd for C13H17NO2NaS 274.0878, obsd 274.0886.
from calcium hydride under dry nitrogen. MTBE is methyl tert-butyl
ether, and PE is petroleum ether. All reactions were conducted under
N2 and stirred magnetically unless otherwise noted.
Revised Tollens Procedure/Procedure for Recycling Ag0/Ag2O
Solids: Preparation of (−)-Citronellic Acid (7). The combined solids
from a previous Tollens oxidation (105 g) were washed with 3 × 100
mL of hot water and 1 × 100 mL of acetone. The solids were then
vacuum filtered to dryness. The solids were transferred to a three-neck
2 L flask fitted with a mechanical stirrer and air inlet. The filter funnel
was then rinsed with cHNO3 into the three-neck flask. Minimum
water was added to slurry the black solids, and cHNO3 was added
dropwise with evolution of reddish-brown gas. Acid addition was
continued with stirring until no more black precipitate remained and
gas evolution ceased, as evidenced by no color in the reaction
headspace (ca. 85 mL of cHNO3, 1.35 mol). The solution was then
filtered to remove solids, giving a pale yellow HNO3/AgNO3 solution,
suitable for incorporation into the next Tollens oxidation. The solution
was diluted to 250 mL and returned to the three-neck flask. At this
point, one can follow the procedure put forth by Paquette et al., which
is included here for convenience.8 Aqueous NaOH solution (250 mL,
5 M) was added dropwise to the AgNO3 solution with vigorous
stirring. The pH = 14 at about 75% addition of the NaOH solution.
The remainder of the NaOH solution was added, and the slurry was
allowed to age approximately 30 min. (−)-Citronellal (21.73 g, 140 mmol)
was added in one portion and rinsed with petroleum ether (∼25 mL). The
suspension was allowed to stir overnight under air. In the morning, a
silver mirror was observed on the glassware, and GC analysis of an
acidified aliquot indicated complete conversion of the aldehyde. The
foamy black suspension was then vacuum filtered with 3 × 100 mL
rinses of hot water to give ∼1 L aqueous carboxylate solution that was
then acidified with 25 mL of cHCl. The system was then extracted
with 3 × 250 mL of EtOAc, and the combined organic extracts were
dried (Na2SO4) and concentrated to leave citronellic acid (23.73 g,
139 mmol, 99%). The 3S-citronellic acid so prepared could be used
without further purification.
(2R,3S,5S)-3-Bromo-5-methyl-1-tosylpiperidin-2-ol (10). The ene
sulfonamide 6 (1.30 g, 5.3 mmol) was dissolved in 100 mL of 95%
acetone/water at rt. Ammonium acetate (100 mg, 1.3 mmol) was added
as a catalyst. The solution was cooled to −78 °C, and N-bromo-
succinimide (1.15 g, 6.4 mmol) was added in one portion. The yellow
mixture was allowed to warm to rt over 3 h. Sodium bisulfite (1.0 g,
10 mmol) was then added, and the acetone was removed via rotary
evaporation. Water (20 mL) was added to dissolve solids, and the
resulting biphasic solution was extracted with CH2Cl2 (3 × 50 mL).
The combined organic extract was dried (Na2SO4) and evaporated
directly to silica gel for chromatography to give the bromohydrin 10
(1.206 g, 3.6 mmol, 70% yield from 6): mp = 100−102 °C, crystals
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from EtOAc/heptanes; TLC Rf = 0.64 (25% EtOAc/PE); [α]D20 = 7.14
(c = 0.11 CHCl3); H NMR (400 MHz, CDCl3) δ ppm 0.93 (d, J =
13C NMR (101 MHz, CDCl3) δ ppm (up) 142.2, 138.3, 138.2, 114.7,
1
70.1, 46.1, 29.6; (down) 141.0, 128.8, 128.2, 127.7, 127.5, 127.4, 73.6,
61.3, 39.6, 26.0, 21.4, 20.0, 18.8; IR (film) 2927, 1716, 1599, 1456,
1330, 1152 cm−1; HRMS calcd for C24H31NO3NaS 436.1966, obsd
436.1961.
(2S,3R,5S)-3-Benzyloxy-2-((S)-but-3-yn-2-yl)-5-methyl-1-tosylpi-
peridine (7). Olefin 15 (256 mg, 0.60 mmol) and methanesulfonamide
(95 mg, 1 mmol) were combined with 5 mL of t-BuOH and 5 mL of
H2O with good stirring. After dissolution, the solution was cooled to
0 °C, and 1.4 g of AD-mix α was added. After 1 week of stirring at room
temperature, TLC indicated complete consumption of the olefin.
NaHSO3 (0.5 g, 5 mmol) was added along with 10 mL of CH2Cl2,and
the suspension was stirred for 1 h. The suspension was then extracted
with 3 × 20 mL of CH2Cl2, and the combined organic phases were
concentrated.
6.8 Hz, 3 H), 1.84−2.02 (m, 2 H), 2.17 (dt, J = 6.8, 4.5 Hz, 1 H), 2.44
(s, 3 H), 2.80−2.92 (m, 2 H), 3.46 (dd, J = 11.6, 4.3 Hz, 1 H), 4.29 (q,
J = 2.8 Hz, 1 H), 5.56 (t, J = 2.8 Hz, 1 H), 7.29−7.36 (m, 2 H), 7.78−
7.85 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ ppm (up) 143.9,
136.1, 45.7, 34.0; (down) 129.6, 127.6, 78.9, 48.9, 25.2, 21.5, 18.1; IR
(film) 3473, 2958, 2876, 1598, 1458, 1334, 1162 cm−1; HRMS calcd
for C13H18NO3NaSBr 370.0088, obsd 370.0078.
(2S,3R,5S)-2-((R/S)-But-3-en-2-yl)-5-methyl-1-tosylpiperidin-3-ol
(13/14). KH(P) (480 mg, 6.0 mmol) was suspended in 10 mL of
toluene and brought to 60 °C with stirring. Stirring was stopped and
the KH precipitated. Approximately 9 mL of toluene was then
removed from the reactor as it cooled to rt. CH2Cl2 (3.0 mL) was
added and stirring was resumed. The bromohydrin 9 (694 mg,
2 mmol) was added dropwise as a solution in 5.0 mL of CH2Cl2 over
5 min. The opaque yellow solution was stirred for an additional 30 min.
Commercial 2-butenylmagnesium chloride (6.0 mL, 0.5 M in THF)
was diluted with an equal portion of THF and cooled to −78 °C. The
cyclized bromohydrin mixture was added dropwise to the Grignard
solution with stirring. Upon completion of addition, the cooling bath
was removed, and the reaction was allowed to come to rt over 45 min.
The reaction was quenched with 10 mL of saturated aqueous NH4Cl.
The aqueous layer was separated and extracted with 3 × 10 mL
methylene chloride. The combined organic extracts were dried
(Na2SO4) and chromatographed to give 210 mg of diastereomer 13
and 210 mg of diastereomer 14 in 65% total yield from the starting
bromohydrin.
The residue was taken up in 10 mL of Et2O, 10 mL of H2O, and
3 mL of saturated aqueous NaHCO3. The biphasic mixture was cooled
to 0 °C, and NaIO4 (426 mg, 2.0 mmol) was added in one portion.
After 6 h, the reaction was extracted with 3 × 20 mL of Et2O. The
combined organic extracts were dried (Na2SO4) and chromatographed
to give the intermediate aldehyde which was not characterized, as well
as 116 mg of recovered diols, that was recycled into recycled into
1
subsequent cleavage reactions. For the 15-diols mixture: H NMR
(400 MHz, CDCl3) δ 0.66−0.75 (m, 3 H), 0.95 (d, J = 7.1 Hz, 3 H),
1.74−1.88 (m, 2 H), 2.08−2.17 (m, 1 H), 2.27−2.38 (m, 3 H), 3.08−
3.18 (m, 1 H), 3.47 (dd, J = 13.5, 4.9 Hz, 1 H), 3.56 (dd, J = 12.0,
8.5 Hz, 1 H), 3.63−3.70 (m, 1 H), 3.90−3.98 (m, 1 H), 4.07−4.13 (m,
1 H), 4.41 (d, J = 1.5 Hz, 2 H), 6.93−7.05 (d, J = 8.1 Hz, 2 H), 7.19−
7.28 (m, 2 H), 7.31−7.42 (m, 3 H), 7.65−7.74 (m, 2 H).
Front diastereomer: (2S,3R,5S)-2-((R)-but-3-en-2-yl)-5-methyl-1-
tosylpiperidin-3-ol (13): TLC Rf = 0.40 (30% EtOAc/PE); [α]D19
=
The crude aldehyde was dissolved in 5 mL of THF and added
immediately to an aged solution (15 min) of TMS diazomethane
(1.0 mL of 2.0 M) and nBuLi (0.75 mL of 2.5 M) in 3 mL of THF
at −78 °C. The cooling bath was removed. After 30 min, the mixture
was quenched with 10 mL of saturated aqueous NH4Cl. The mixture
was extracted with 3 × 20 mL CH2Cl2. The combined organic extracts
were dried (Na2SO4) and chromatographed to give the alkyne (100
mg, 0.24 mmol, 40% yield from 15 (70% based on recovered diols)):
TLC Rf = 0.50 (15% EtOAc/PE); [α]D19 = 53.5 (c = 0.01 CHCl3); 1H
NMR (400 MHz, CDCl3) δ ppm 0.72 (d, J = 6.9 Hz, 3 H), 1.22−1.29
(m, 1 H), 1.32 (d, J = 7.0 Hz, 3 H), 1.77−1.90 (m, 2 H), 2.12 (d, J =
2.6 Hz, 1 H), 2.34 (s, 3 H), 2.84 (m, 1 H), 3.15 (dd, J = 13.4, 5.2 Hz,
1 H), 3.54 (dd, J = 13.4, 5.2 Hz, 1 H), 3.61 (td, J = 4.7, 2.3 Hz, 1 H),
4.17 (dd, J = 7.5, 2.3 Hz, 1 H), 4.39−4.52 (m, 2 H), 7.24−7.38 (m, 5
H), 7.65−7.77 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ ppm (up)
142.6, 138.2, 137.7, 85.4, 71.5, 70.2, 46.7, 30.4; (down) 129.0, 128.3,
127.8, 127.5, 127.5, 74.6, 60.7, 29.0, 26.0, 21.5, 20.2, 18.8; IR (film)
3302, 3032, 2931, 2254, 1810, 1731, 1599, 1496, 1456, 1331 cm−1;
HRMS calcd for C24H29NO3NaS 434.1760, obsd 434.1759.
1
−19.6 (c = 0.01 CHCl3); mp = 103−104 °C; H NMR (400 MHz,
CDCl3) δ ppm 0.81 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 7.1 Hz, 3 H),
1.31−1.43 (m, 1 H), 1.75−1.91 (m, 2 H), 1.99 (d, J = 6.1 Hz, 1 H),
2.31−2.46 (m, 4 H) 3.21 (dd, J = 13.6, 4.3 Hz, 1 H), 3.40−3.52 (m, 1
H), 3.66 (d, J = 10.9 Hz, 1 H), 3.92 (m, 1 H), 4.95−5.08 (m, 2 H),
5.64 (ddd, J = 17.0, 10.0, 9.1 Hz, 1 H), 7.26−7.30 (d, J = 8.3 Hz, 2 H),
7.76 (d, J = 8.3 Hz, 2 H); 13C NMR (101 MHz, CDCl3) δ ppm (up)
143.1, 137.9, 115.8, 45.5, 32.0; (down) 140.9, 129.4, 127.5, 66.7, 63.5,
39.1, 26.0, 21.5, 20.7, 18.1; IR (film) 3524, 2928, 1598, 1456, 1324,
1152 cm−1; HRMS calcd for C17H25NO3NaS 346.1447, obsd
346.1448.
Back diastereomer: (2S,3R,5S)-2-((S)-but-3-en-2-yl)-5-methyl-1-
tosylpiperidin-3-ol (14): TLC Rf = 0.27 (30% EtOAc/PE); [α]D19
=
1
34.6 (c = 0.01 CHCl3); mp = 107−108 °C; H NMR (400 MHz,
CDCl3) δ ppm 1.04 (m, 7 H) 1.41−1.51 (m, 1 H), 1.78−1.95 (m, 2
H), 2.25 (d, J = 6.6 Hz, 1 H), 2.35−2.47 (m, 4 H) 3.23 (m, 1 H), 3.51
(m, 1 H), 3.64 (d, J = 10.4 Hz, 1 H), 3.92 (m, 1 H), 4.71 (dd, J = 10.1,
1.5 Hz, 1 H), 4.92 (dd, J = 17.2, 1.5 Hz, 1 H), 5.23 (m, 1 H), 7.26−
7.33 (d, J = 8.3 Hz, 2 H), 7.73 (d, J = 8.3 Hz, 2 H); 13C NMR (101
MHz, CDCl3) δ ppm (up) 143.0, 138.0, 114.5, 45.9, 32.7; (down)
140.5, 129.3, 127.6, 66.5, 64.1, 39.1, 26.0, 21.5, 20.8, 18.6; IR (film)
3520, 2929, 1598, 1458, 1325, 1150 cm−1; HRMS calcd for
C17H25NO3NaS 346.1447, obsd 346.1445.
(2R, 3S, 5S)-3-Bromo-2-((R)-but-3-yn-2-yl)-5-methyl-1-tosylpipe-
ridine (17). Bromohydrin 10 (0.549 g, 1.64 mmol) and P-Marshall
reagent 16 (600 mg, 1.74 mmol) were dissolved in 16 mL of CH2Cl2
at rt. The solution was cooled to −78 °C, and BF3·OEt2 (250 μL,
1.92 mmol) was added in one portion. TLC indicated reaction com-
pletion in 30 min. Saturated aqueous NaHCO3 (1 mL) along with
1 mL of saturated aqueous KF were added, and the reaction was allowed
to come to rt. Precipitates were filtered, and the resulting biphasic
solution was extracted with methylene chloride (3 × 25 mL). The
combined organic fractions were dried (Na2SO4) and evaporated to
silica gel for chromatography to give 17 as a white crystalline solid
(2S,3R,5S)-3-Benzyloxy-2-((S)-but-3-en-2-yl)-5-methyl-1-tosylpi-
peridine (15). KH(P) (160 mg, 2 mmol) was suspended in 10 mL of
toluene and brought to 60 °C with stirring. Stirring was ceased and the
KH precipitated. Approximately 9 mL of toluene was then removed
from the reactor as it cooled to rt. Benzyl bromide (1 mL) was then
added, and the suspension was reheated to 60 °C. The alcohol 13
(210 mg, 0.65 mmol) in 5.0 mL of THF was added dropwise to the
KH suspension over 5 min. After 3 h, the mixture was quenched with
10 mL of H2O and then extracted with 3 × 10 mL CH2Cl2. The
combined organic extracts were dried (Na2SO4) and chromatographed
to give 15 (256 mg, 0.60 mmol, 95%) as a colorless oil: TLC Rf = 0.52
(338 mg, 0.88 mmol, 54%): TLC Rf = 0.34 (15% EtOAc/PE); [α]D18
=
1
−13.6 (c = 0.07 CHCl3); mp = 153−155 °C; H NMR (400 MHz,
CDCl3) δ ppm 0.84 (d, J = 6.1 Hz, 3 H), 1.37 (d, J = 6.9 Hz, 3 H),
1.82−2.03 (m, 3 H), 2.12 (d, J = 2.5 Hz, 1 H), 2.42 (s, 3 H), 2.82−
3.02 (m, 2 H), 3.59 (dd, J = 14.3, 4.1 Hz, 1 H), 4.37 (d, J = 7.8 Hz,
1 H), 4.49 (d, J = 1.8 Hz, 1 H), 7.20−7.39 (m, 3 H), 7.87 (d, J = 8.3
Hz, 2 H); 13C NMR (101 MHz, CDCl3) δ ppm (up) 142.9, 137.9,
84.97, 72.6, 47.6, 36.8; (down) 129.1, 128.0, 62.9, 48.9, 39.2, 24.4,
21.5, 19.6, 18.1.; IR (film) 2954, 2871, 1737, 1453, 1336, 1169 cm−1;
HRMS calcd for C17H23NO2SBr 384.0633, obsd 384.0630.
(15% EtOAc/PE); [α]D19 = 73.8 (c = 0.01 CHCl3); H NMR (400
1
MHz, CDCl3) δ ppm 0.67 (d, J = 7.0 Hz, 3 H), 1.08 (d, J = 6.6 Hz,
3 H), 1.34−1.45 (m, 1 H), 1.69−1.86 (m, 2 H), 2.31 (s, 3 H), 2.36−2.49
(m, 1 H), 3.08−3.28 (m, 2 H), 3.53−3.62 (m, 1 H), 4.08 (d, J = 10.1
Hz, 1 H), 4.36−4.54 (m, 2 H), 4.98−5.07 (m, 2 H), 5.93 (m, 1 H),
6.97 (d, J = 8.2 Hz, 2 H), 7.22−7.42 (m, 5 H) 7.66 (d, J = 8.2 Hz, 2 H);
4238
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(2R,3S,5S)-3-Bromo-2-((S)-but-3-yn-2-yl)-5-methyl-1-tosylpipe-
ridine (18). Bromohydrin 10 (0.247 g, 0.74 mmol) and M-Marshall
reagent 16 (330 mg, 1.0 mmol) were dissolved in 10 mL of CH2Cl2
at rt. The solution was cooled to −78 °C, and BF3·OEt2 (125 μL,
1.0 mmol) was added in one portion. TLC indicated that the reaction
was complete in 30 min. Saturated aqueous NaHCO3 (1 mL) along
with 1 mL of saturated aqueous KF were added, and the reaction was
allowed to come to rt. Precipitates were filtered, and the resulting
biphasic solution was extracted with methylene chloride (3 × 25 mL).
The combined organic fractions were dried (Na2SO4) and evaporated
to silica gel for chromatography to give 18 as a white crystalline solid
(159 mg, 0.42 mmol, 76%). Crystals precipitated spontaneously during
column chromatography. X-ray quality crystals could be grown in a
diffusion chamber from hexanes and CHCl3: mp = 104−106 °C; TLC
Rf = 0.36 (15% EtOAc/PE); [α]D18 = +8.7 (c = 0.03 CHCl3); 1H NMR
(400 MHz, CDCl3) δ ppm 0.82 (d, J = 6.5 Hz, 3 H), 1.34 (d, J =
6.9 Hz, 3 H), 1.69−1.78 (m, 1 H), 1.79−1.89 (m, 1 H), 1.90−1.98
(m, 1 H), 2.22 (d, J = 2.4 Hz, 1 H), 2.42 (s, 3 H), 2.53 (dd, J = 14.0,
11.4 Hz, 1 H), 2.73−2.87 (m, 1 H), 3.55 (dd, J = 14.0, 4.00 Hz, 1 H),
4.33 (d, J = 10.4 Hz, 1 H), 4.93−5.01 (m, 1 H), 7.23−7.34 (m, 2 H),
7.79−7.90 (m, 2 H); 13C NMR (101 MHz, CDCl3) δ ppm (up)
143.14, 137.53, 84.87, 71.74, 46.77, 36.18; (down) 129.05, 127.87,
63.33, 49.12, 26.80, 24.31, 21.50, 18.42, 18.06; IR (film) 2954, 2871,
1737, 1453, 1336, 1169 cm−1; HRMS calcd for C17H23NO2SBr 384.0633,
obsd 384.0631.
(1R,2R)-2-Methyl-1-((2R,4S)-4-methyl-1-tosylpyrrolidin-2-yl)but-
3-yn-1-ol (19). KH(P) (240 mg, 3.0 mmol) was suspended in 10 mL
of toluene and brought to 60 °C with stirring. Stirring was ceased and
the KH precipitated. Approximately 9 mL of toluene was then
removed from the reactor as it cooled to rt. Then 3.0 mL of CH2Cl2
was added, and stirring was resumed. To this was added dropwise a
solution composed of bromohydrin 10 (296 mg, 1.0 mmol) and
M-Marshall reagent 16 (332 mg, 1.0 mmol) dissolved in 5 mL of
CH2Cl2. After 30 min of stirring at rt, the solution was cooled to
−78 °C, and BF3·OEt2 (125 μL, 1.0 mmol) was added in one portion.
After 1 h, 1 mL of saturated aqueous NaHCO3 was added along with
1 mL of saturated aqueous KF. The reaction was allowed to come to rt.
Precipitates were filtered, and the resulting biphasic solution was
extracted with CH2Cl2 (4 × 10 mL). The combined organic fractions
were dried (Na2SO4) and evaporated directly to silica gel for chro-
matography to give 19 initially as an oil (97 mg, 0.30 mmol, 30% yield
from 10). X-ray quality crystals were grown in a diffusion chamber
from hexanes and CHCl3: TLC Rf = 0.32 (15% EtOAc/PE); 1H NMR
(400 MHz, CDCl3) δ ppm 0.70 (d, J = 6.7 Hz, 3 H), 1.20 (dt, J = 12.6,
8.8 Hz, 1 H), 1.35 (d, J = 6.8 Hz, 3 H), 2.04−2.11 (m, 1 H), 2.13 (d,
J = 2.4 Hz, 1 H), 2.25−2.43 (m, 3 H), 2.45 (s, 3 H), 2.59−2.70 (m,
1 H), 3.62 (dd, J = 9.6, 6.5 Hz, 1 H), 3.92 (ddd, J = 8.9, 4.2, 2.5 Hz,
1 H), 4.12 (dt, J = 9.6, 2.8 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.74 (d,
J = 8.1 Hz, 2 H); 13C NMR (101 MHz, CDCl3, rotamers) δ ppm (up)
143.8, 132.8, 85.4, 70.1, 57.0, 33.3; (down) 129.6, 128.0, 75.7, 62.6,
31.9, 29.3, 21.6, 18.1, 17.6.
18.6; IR (film): 2956, 1711, 1655, 1411, 1344 cm−1; HRMS calcd for
C14H18NO2 232.1338, obsd 232.1344.
(2S,3R,5S)-Benzyl 2-Allyl-3-hydroxy-5-methylpiperidine-1-carbox-
ylate (23). Enecarbamate 21 (911 mg, 3.9 mmol) was dissolved in 100
mL of 95% acetone/H2O at rt. Ammonium acetate (20 mg) was added
as a catalyst. The solution was cooled to −78 °C, and N-bromo-
succinimide (842 mg, 4.7 mmol) was added in one portion. The
yellow solution was allowed to warm to rt over 3 h. Sodium bisulfite
(1 g) was then added, and the acetone was removed via rotary
evaporation. Water (20 mL) was added to dissolve solids, and the
resulting biphasic solution was extracted with CH2Cl2 (3 × 50 mL).
The organic extract was dried (Na2SO4) and evaporated directly to
silica gel for chromatography to give 22 as an oil (846 mg, 2.4 mmol,
62%): TLC Rf = 0.38 (25% EtOAc/PE); [α]D18 = +26.0 (c = 0.075
1
CHCl3); H NMR (400 MHz, CDCl3, rotamers) δ ppm 0.93 (d, J =
6.47 Hz, 3 H), 1.87−2.05 (m, 2 H), 2.19 (td, J = 11.32, 6.63 Hz, 1 H),
4.36 (br s, 1 H), 5.14 (s, 2 H), 5.90 (br s, 1 H), 7.28−7.41 (m, 5 H);
13C NMR (101 MHz, CDCl3) δ ppm (up) 136.2, 67.6, 34.6; (down)
128.6, 128.2, 128.0, 49.9, 25.0, 18.3; IR (film): 3394, 2956, 1681, 1431,
1343, 1253 cm−1.
KH(P) (1.0 g, 13.6 mmol) was suspended in 20 mL of toluene and
brought to 60 °C with stirring. Stirring was ceased and the KH
precipitated. Approximately 19 mL of toluene was removed from the
reactor as it cooled to rt. Methylene chloride (10 mL) was added, and
stirring was resumed. Bromohydrin 22 (1.11 g, 3.4 mmol) was added
dropwise as a solution in 10 mL of CH2Cl2. The opaque yellow
solution was allowed stirred for an additional 30 min. The solution was
then cooled to −78 °C. Stirring was increased, and allylmagnesium
chloride (4.0 mL, 1.7 M in THF) was added dropwise over 5 min.
Upon completion of addition, the cooling bath was removed. The
reaction was allowed to come to rt over 45 min and then quenched
with 25 mL of saturated aqueous NH4Cl. The aqueous layer was
separated and extracted with 3 × 10 mL CH2Cl2. The combined
organic extracts were dried (Na2SO4) and chromatographed to give 23
(840 mg, 53% yield from 21): TLC Rf = 0.2 (30% EtOAc/PE); [α]D19
=
1
+37.17 (c = 0.035 CHCl3); H NMR (400 MHz, CDCl3) δ ppm 0.90
(t, J = 6.95 Hz, 1 H), 1.17 (d, J = 6.82 Hz, 2 H), 1.21−1.39 (m,
1 H), 1.52 (d, J = 13.89 Hz, 1 H), 1.73 (d, J = 18.95 Hz, 2 H), 1.86−
2.03 (m, 2 H), 2.22−2.47 (m, 2 H), 3.15 (dd, J = 13.52, 3.92 Hz, 1 H),
3.77 (d, J = 13.39 Hz, 1 H), 3.85 (br s, 1 H), 4.27 (t, J = 6.57 Hz, 1 H),
4.99−5.26 (m, 4 H), 5.69−5.85 (m, 1 H), 7.30−7.44 (m, 5 H); 13C
NMR (101 MHz, CDCl3) δ ppm (up) 156.9, 136.9, 117.5, 67.1, 44.3,
34.7, 33.1 (down) 134.4, 128.4, 127.9, 127.8, 68.7, 57.9, 27.0, 20.4; IR
(film): 3426, 2928, 1677, 1430, 1320, 1250 cm−1; HRMS calcd for
C17H24NO3 290.1756, obsd 290.1742.
(3αS,6S,7αR)-Benzyl 6-Methyl-2-oxohexahydrofuro[3,2-β]-
pyridine-4(2H)-carboxylate (24). The alcohol 23 (720 mg, 2.5 mmol)
was dissolved in 50 mL of 95% acetone/H2O solution.17 The solution
was cooled to −78 °C, and ozone was bubbled through until the
solution turned blue. The solution was sparged with air until colorless,
and then 1 mL of methyl sulfide was added. The bulk of the acetone
was removed by rotary evaporation, and the residue was partitioned
between 20 mL of brine and 100 mL of CH2Cl2. The combined
organic extracts were dried (Na2SO4) and concentrated to an oil,
which was then dissolved in 5 mL of t-BuOH. K2CO3 (552 mg,
4.0 mmol) and I2 (756 mg, 3.0 mmol) were added sequentially, and
the solution was heated at 60 °C overnight under N2. Water (10 mL)
was then added along with 0.50 g of sodium bisulfite, and the solution
was stirred until the iodine color faded. The mixture was extracted
with CH2Cl2 (3 × 25 mL). The combined organic extracts were dried
(Na2SO4) and evaporated directly to silica gel for to give the bicyclic
lactone 24 as an oil (380 mg, 1.31 mmol, 53% yield from 23. The
spectroscopic data (1H, 13C NMR) matched that which was previously
published.5b
(S)-Benzyl 3-Methyl-3,4-dihydropyridine-1(2H)-carboxylate (18).
(2S)-N-Cbz norcitronellamine 20 (1.36 g, 4.6 mmol) prepared as for 9
was taken up in 100 mL of CH2Cl2. Sudan III (10 mg) was then added
as an indicator. The solution was cooled to −78 °C, and ozone was
bubbled through until the red color faded. Methyl sulfide (1 mL) was
then added to reduce the ozonides, and the mixture was concentrated
to an oil. Toluene (100 mL) and 10 mg of pyridinium p-toluene-
sulfonate were added, and the mixture was subjected to Dean−Stark
distillation until 20 mL of distillate was collected. The solution was
then cooled and evaporated directly to silica gel for chromatography to
give 21 as an oil (465 mg, 2.0 mmol, 44%): TLC Rf = 0.70 (15%
EtOAc/PE); [α]D18 = +41.7 (c = 0.09 CHCl3); H NMR (400 MHz,
1
CDCl3, rotamers) δ ppm 0.94−1.02 (m, 3 H), 1.61−1.72 (m, 1 H),
1.90 (d, J = 3.2 Hz, 1 H), 2.09 (dt, J = 17.2, 5.0 Hz, 1 H), 2.84−3.02
(m, 1 H), 3.77−3.99 (m, 1 H), 4.75−5.01 (m, 1 H), 5.17 (s, 2 H),
6.73−6.93 (m, 6 H), 7.26−7.48 (m, 5 H); 13C NMR (101 MHz,
CDCl3, rotamers) δ ppm (up) 153.4, 153.0, 136.2, 67.3, 67.2, 48.4,
48.0, 29.7, 29.5; (down) 128.3, 128.0, 127.8, 124.8, 124.3, 26.8, 26.7,
(3R,3αS,6S,7αR)-Benzyl 3,6-Dimethyl-2-oxohexahydrofuro[3,2-
β]pyridine-4(2H)-carboxylate (25). Bicyclic lactone 24 (80 mg,
0.28 mmol) was dissolved in 3.0 mL of THF at rt. Triphenylmethane
(10 mg) was added as an indicator. In a separate vessel at 0 °C, 9.0 mL
of THF, diisopropylamine (303 mg, 3.0 mmol), and n-BuLi (1.0 mL,
2.49 M) were combined. The LDA solution was aged for 15 min.
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Article
Meanwhile, the lactone solution was cooled to −78 °C, at which point
the LDA solution was added dropwise until an olive green color
persisted (∼1 mL). After 30 min, iodomethane (200 μL, 3.2 mmol)
was added in one portion and the solution turned yellow. The solution
was diluted with water and extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were dried (Na2SO4) and evaporated
directly to silica gel for chromatography gave 25 as an oil (30 mg, 0.10
mmol, 30% yield from 24). Crystallization was effected in a CH2Cl2/
PE diffusion chamber: mp = 105−106 °C; TLC Rf = 0.57 (30%
EtOAc/PE); 1H NMR (400 MHz, CDCl3) δ ppm 1.06 (d, J = 6.7 Hz,
3 H), 1.22−1.31 (m, 4 H), 1.81−1.96 (m, 1 H), 2.33 (dt, J = 11.1, 3.9
Hz, 1 H), 2.58 (dd, J = 13.0, 11.1 Hz, 1 H), 3.19 (dd, J = 10.1, 6.7 Hz,
1 H), 3.30 (quin, J = 7.2 Hz, 1 H), 4.02 (dd, J = 13.0, 4.0 Hz, 1 H),
4.14 (ddd, J = 11.9, 10.0, 4.0 Hz, 1 H), 5.15 (s, 2 H), 7.31−7.47 (m,
5 H); 13C NMR (101 MHz, CDCl3) δ ppm (up) 177.8, 157.0, 135.7,
67.8, 53.1, 35.6; (down) 128.7, 128.6, 128.5, 128.4, 77.2, 62.1, 41.4,
28.7, 19.1, 9.5.
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S
* Supporting Information
1H NMR and 13C NMR spectra for all new compounds as well
as 50% probability figures and CIF for compounds 13, 14, 17−
19, and 25. This material is available free of charge via the
Internet at http://pubs.acs.org.
Tzagkaroulaki, L.; Zahn, S.; Kirchner, B.; Giannis, A. Chem. Commun.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: taberdf@udel.edu.
■
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Notes
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The authors declare no competing financial interest.
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■
We thank John Dykins for high-resolution mass spectrometry
under the financial support of NSF 054117, Dr. Shi Bai for
NMR spectra financially supported by NSF CRIF:MU, CHE
080401, Glenn Yap for X-ray crystallography help, and the
National Institutes of Health (GM060287) for financial support
of this work.
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