Total synthesis of (5R,6R,8R,9S)-(-)-5,9Z-indolizidine 221T using sulfinimine-derived N-sulfinyl β-amino ketones

Article abstract of DOI:10.1039/b915796d

The first total asymmetric synthesis of the poison frog alkaloid (-)-221T, a 5,6,8-trisubstituted indolizidine is described. The key core piperidine ring was constructed via an acid catalyzed intramolecular cascade Mannich cyclization reaction of a N-sulf

Full text of DOI:10.1039/b915796d

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Total synthesis of (5R,6R,8R,9S)-(-)-5,9Z-indolizidine 221T using
sulfinimine-derived N-sulfinyl b-amino ketones†
Franklin A. Davis,* Minsoo Song, Hui Qiu and Jing Chai
Received 3rd August 2009, Accepted 23rd September 2009
First published as an Advance Article on the web 26th October 2009
DOI: 10.1039/b915796d
The first total asymmetric synthesis of the poison frog alkaloid (-)-221T, a 5,6,8-trisubstituted
indolizidine is described. The key core piperidine ring was constructed via an acid catalyzed
intramolecular cascade Mannich cyclization reaction of a N-sulfinyl syn-a-methyl b-amino ketone and
crotonaldehyde. The b-amino ketone was prepared via the reaction of prochiral lithium Weinreb amide
enolate with an enantiopure N-2,4,6-triisopropylphenylsulfinyl imine.
Introduction
The alkaloid 5,9-Z-indolizidine 221T (1) is one of more than 800
different alkaloids isolated from the skins of poison frogs by Daly
and co-workers.1,2 This is an example of a 5,6,8-trisubstituted
indolizidine of which about 70 alkaloids have been assigned to
this class.3 Of these alkaloids, only indolizidine 223A (2) has
been prepared (Fig. 1).4–6 Since these alkaloids were isolated in
trace amounts, their structures are tentative, being based on mass
spectral and FTIR data.1 Although little is known about their bi-
ological activity, related indolizidine alkaloids are noncompetitive
blockers of nicotinic acetylcholine receptor channels,1,2,7a and have
demonstrated binding affinity for the human d-opioid receptor.7b
Fig. 2 Intramolecular Mannich cyclization of N-sulfinyl b-amino ketones
and aldehydes.
utility of this protocol for the synthesis of 5,6,8-trisubstituted
indolizidine alkaloids.
Results and discussion
Our synthesis began with preparation of sulfinimine (R)-(-)-4
by condensing (R)-(+)-2,4,6-triisopropylphenylsulfinamide (3)16
with 3-benzyloxypropanal and Ti(OEt)4 to give the sulfinimine in
quantitative yield (Scheme 1). Sulfinimine (R)-(-)-4, 0.4 equiv, was
added to the preformed prochiral lithium Weinreb amide enolate
of N-methoxy-N-methylpropylamide (5), prepared at -78 ◦C using
LiHMDS. The syn- and anti-b-amino Weinreb amides (-)-6 and
(-)-7 were obtained in approximately a 1 : 5.1 ratio, affording the
major syn isomer (-)-7 in 77% isolated yield. Attempts to improve
the syn : anti selectivity by varying the solvent and changing
the base to LDA resulted in poorer ratios. The stereochemical
assignment of (-)-7 to the syn isomer was based on earlier studies
where it was also demonstrated that the 2,4,6-triisopropyl (TIPP)
sulfinyl auxiliary afforded the best syn : anti selectivities.14b,15 Next,
treatment of (-)-7 with 10 equiv. of n-butylmagnesium chloride
in THF gave N-sulfinyl b-amino ketone (RS,3R,3S)-(-)-8 in 91%
yield (Scheme 1).
The conversion of (-)-8 to piperidone (-)-11 involved removal of
the sulfinyl auxiliary (HCl–Et2O) to give an amine hydrochloride
salt, which was neutralized with aqueous NaOH to give amino
ketone (3R,4S)-(+)-9 in 95% yield. However, upon purification,
the amine rapidly decomposed and was used in crude form. Next,
the amine was treated with crotonaldehyde and Ti(OEt)4 to give
imine 10. The imine decomposed on attempted purification and
was simply passed through a pad of Celite prior to subjecting it
to the intramolecular Mannich cyclization (IMC) reaction. Under
optimized conditions, the crude imine was heated in toluene with
Fig. 1 Indolizidine alkaloids.
Key to the synthesis of the 5,6,8-trisubstituted indolizidines,
such as (-)-221T (1), are efficient processes for the stereo-
controlled construction of the core piperidine ring.8 In this regard,
the acid-catalyzed intramolecular Mannich cyclization reaction,
a cascade reaction, between an N-sulfinyl b-amino ketone and
an aldehyde, is a powerful method for the asymmetric synthesis
of multi-substituted stereodefined piperidones (Fig. 2).9,10 In
addition to (-)-223A (2),4 we have employed this methodology
in highly efficient asymmetric syntheses of trisubstituted piperi-
dine (-)-nupharamine,11 indolizidine (-)-209B12 and substituted
tropinones.13 The reaction of Grignard reagents with sulfinimine-
derived enantiopure N-sulfinyl b-amino Weinreb amides readily
affords the requisite N-sulfinyl b-amino ketones.14 Using this
protocol the first total synthesis of (5R,6R,8R,9S)-(-)-5,9Z-
indolizidine 221T (1) has been achieved, demonstrating the general
Department of Chemistry, Temple University, Philadelphia, PA, 19122, USA.
E-mail: fdavis@temple.edu; Fax: +1 215-204-0478; Tel: +1 215-204-0477
† Electronic supplementary information (ESI) available: 1H and 13C NMR
data for all new compounds. See DOI: 10.1039/b915796d
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5067–5073 | 5067
©

View Article Online
Scheme 1
Scheme 2
2 equiv. of anhydrous p-toluenesulfonic acid at 75 ◦C for 8 h to give
piperidone (2R,3S,5S,6S)-(-)-11 in 51% yield for the three step
sequence (Scheme 2). Use of toluenesulfonic acid hydrate, longer
or shorter reaction times, and lower temperatures all resulted in
poor yields (30–40%) of the piperidone. The structure of (-)-11 was
based on the fact that the IMC reaction of b-amino ketones and
aldehydes gives piperidones where the C-2 and C-6 substituents
have a cis relationship and NOE studies (Scheme 2).4,11,12
To prepare the unsaturated indolizidine from (-)-11, the idea
was to allylate the piperidone nitrogen and use ring-closing
metathesis (RCM) to generate the pyrrolidine ring. Allylation
of (-)-11 with 10 equiv. of allyl bromide/Na2CO3 in ethanol
and heating gave amino diene (+)-12 in 72% yield (Scheme 3).
The amino diene (+)-12 was heated at 40 ◦C in DCM with the
Grubbs “first generation” catalyst16 for 18 h to give a blue colored
solution. However, less then 10% of the desired unsaturated
indolizidine (+)-13 was detected. Unexpectedly, the major product
was keto pyrrole (+)-14, isolated in 62% yield (Scheme 3). The
structure of the pyrrole is based on HRMS data, and the 2,5- and
3,4-pyrrole protons at d 6.5 ppm and d 6.0 ppm, respectively.
When the temperature and time were reduced to rt and to 8 h, it
was possible to isolate the unsaturated indolizidine (+)-13 in about
69% yield, but contaminated with the pyrrole.
When (+)-13 was heated at 80 ◦C in benzene for 16 h, a
4 : 1 mixture of 13 : 14 resulted, and with the Grubbs catalyst at
40 ◦C in DCM for 16 h, a 1 : 6 ratio of 13 : 14 was obtained. The
formation of the pyrrole (+)-14 is consistent with a retro-Mannich
reaction of (+)-13 affording species 15, which aromatizes to the
pyrrole. Pyrrole formation in the RCM of diallylamines has been
reported.17 Here, the Grubbs catalyst apparently isomerizes the
alkene and functions as a dehydrogenation reagent. This does not
appear to be what is happening in the formation of pyrrole (+)-14
from (+)-13 because the transformation can be thermally induced.
We suggest that the Grubbs catalyst promotes the retro-Mannich
reaction by associating with the piperidone oxygen. Because it
was difficult to isolate (+)-13 free of the pyrrole the mixture
was hydrogenated (H2/Pd–C) to give (5R,6S,8S,9S)-(-)-16 in 62%
yield (Scheme 3).
5068 | Org. Biomol. Chem., 2009, 7, 5067–5073
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
Scheme 3
With (-)-16 in hand, removal of the C-7 oxo group was
accomplished by reduction with NaBH4 to give a mixture of
isomeric alcohols 17 in quantitative yield. The crude alcohols
were subjected to the Barton–McCombie radical deoxygenation
reaction, giving indolizidine (5R,6R,8R,9S)-(-)-18 in 55% yield for
the two steps (Scheme 4). Deprotection of the benzyloxy group
(TFA, 20% Pd(OH)2, H2, 1 atm) gave alcohol (5R,6R,8R,8aS)-
(-)-19 in 79% yield. Swern oxidation gave an aldehyde, which was
not stable to purification and was carried on to the next step in
crude form. A Wittig reaction (Ph3PCH3/n-BuLi) was used to
install the methylene group, completing the first total synthesis of
(5R,6R,8R,9S)-(-)-5,9Z-Indolizidine 221T (1) (Scheme 4).
In conclusion, we have accomplished the first total synthesis
of (5R,6R,8R,9S)-(-)-5,9Z-indolizidine 221T (1) in 15 steps
with a 4.4% overall yield. Highlights of the synthesis include
a novel intramolecular Mannich cyclization cascade reaction
of a sulfinimine-derived syn-a-methyl N-sulfinyl-b-amino ketone
(-)-8, prepared form N-sulfinyl b-amino Weinreb amide (-)-7.
Scheme 4
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5067–5073 | 5069
©

View Article Online
isomer and 0.529 g (18%) of a colorless oil as a minor isomer.
Major isomer: [a]2D0 -27.6 (c 0.975, CHCl3); IR (neat) 2961, 2869,
1652, 1079 cm-1; 1H NMR (CDCl3) d 7.32 (m, 5H), 7.05 (s, 2H),
5.16 (d, J = 8.0 Hz, 1H), 4.45 (s, 2H), 3.95 (bs, 2H), 3.74 (m,
4H), 3.57 (m, 3H), 3.20 (s, 3H), 2.87 (m, 1H), 2.14 (m, 1H),
2.03 (m, 1H), 1.28 (d, J = 6.6 Hz, 3 H), 1.23 (m, 18 H); 13C
NMR (CDCl3) d 176.1, 151.6, 147.4, 138.8, 138.6, 128.4, 127.6,
127.5, 123.0, 73.0, 67.8, 61.6, 56.9, 40.5, 34.4, 32.0, 31.3, 28.5, 24.4,
24.3, 23.9, 13.6. HRMS calcd for C30H47N2O4S (M + H) 531.3257.
Found 531.3280.
Experimental
General information
All reagents were used as received unless otherwise noted.
Tetrahydrofuran (THF), diethyl ether, dichloromethane (DCM),
and toluene were purified by filtration on a Glass Contour Solvent
System. Column chromatography was performed on silica gel,
Merck grade 60 (230-400 mesh). TLC plates were visualized with
UV, in an iodine chamber, or with phosphomolybdic acid, unless
otherwise noted. H NMR and 13C NMR spectra were recorded
1
on a Bruker 400 and a Varian 300 MHz NMR spectrometer.
CDCl3 was used as a solvent and TMS as an internal standard.
NOE studies were done after assigning the chemical shifts of
protons and carbons using COSY, HECTOR(HMQC) and DEPT
experiments. Optical rotations were measured on a PerkinElmer
341 instrument. HRMS were obtained on a G ZAB2SE high
resolution mass spectrometer.
(R)-(+)-2,4,6-Triisopropylphenylsulfinamide (3) and N-
methoxy-N-methylpropylamide (5) were prepared as previously
described.16 3-Benzyloxypropanal was purchased from Aldrich.
(RS,2R,3R)-(-)-N-Methoxy-N,2-dimethyl-3-(2,4,6-triisopropyl-
phenylsulfinamido)-5-benzyloxypentanamide (6)
Minor isomer: [a]2D0 -48.6 (c 1.05, CHCl3); IR (neat) 2961, 2869,
1653, 1457 cm-1; 1H NMR (CDCl3) d 7.29 (m, 5H), 7.05 (s, 2H),
4.90 (d, J = 8.4 Hz, 1H), 4.51 (d, J = 2.4 Hz, 2H), 4.02 (bs,
2H), 3.80 (m, 1H) 3.65 (m, 2H), 3.52 (s, 3H), 3.11 (m, 4H), 2.86
(m, 1H), 2.16 (m, 1H), 1.96 (m, 1H), 1.23 (m, 21H); 13C NMR
(CDCl3) d 166.6, 151.6, 147.4, 139.2, 138.6, 128.6, 128.0, 127.8,
123.1 73.4, 67.7, 61.5, 58.6, 40.2, 34.5, 33.8, 32.5, 28.6, 24.8, 24.4,
24.0, 15.1. HRMS calcd for C30H47N2O4S (M + Na) 531.3257.
Found 531.3280.
(R)-(-)-N-(3-(Benzyloxy)propylidene)-2,4,6-triisopropylbenzene-
sulfinamide (4)
In a 1000 mL, oven-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, rubber septum and an
argon balloon was placed (R)-(+)-3 (3.56 g, 13.3 mmol) and
3-benzyloxypropanal (2.30 g, 14.0 mmol) in DCM (200 mL). The
N-[(RS,3R,4S)-(-)-1-(Benzyloxy)-4-methyl-5-oxononan-3-yl]-
2,4,6-triisopropyl-benzenesulfinamide (8)
In a 25 mL, flame-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar and a rubber septum
was placed (-)-6 (2.07 g, 3.95 mmol) in THF (50 mL), and
the solution was cooled to 0 ◦C. To the solution was added n-
butylmagnesium chloride (19.7 mL, 39.5 mmol, 2.0 M solution in
THF) via syringe, and the reaction mixture was stirred for 2 h at rt,
quenched by addition of sat. aqueous NH4Cl (5 mL) at 0 ◦C and
extracted with Et2O (2 ¥ 50 mL). The combined organic phases
were dried (MgSO4), and concentrated. Chromatography (50%
hexanes–EtOAc) provided 1.89 g (91%) of a colorless oil; [a]D20
-42.6 (c 0.47, CHCl3); IR (neat) 2960, 2869, 1700, 1457 cm-1; 1H
NMR (CDCl3) d 7.30 (m, 5H), 7.04 (s, 2H), 5.20 (d, J = 8.8 Hz,
1H), 4.42 (s, 2H), 3.90 (bs, 2H), 3.66 (m, 1H), 3.51 (m, 2H), 3.23
(m, 1H), 2.86 (dq, J = 6.8 Hz, 1H), 2.48 (m, 2H), 1.88 (m, 2H),
1.53 (m, 2H), 1.22 (m, 23 H), 0.90 (t, J = 7.4 Hz, 3H); 13C NMR
(CDCl3) d 213.9, 151.1, 146.8, 138.2, 137.9, 127.9, 127.1, 127.0,
122.5, 72.6, 67.0, 56.9, 50.0, 41.0, 33.9, 31.7, 28.0, 25.2, 23.9, 23.8,
23.3, 21.9, 13.5, 13.3. HRMS calcd for C32H50NO3S (M + H)
528.3511. Found 528.3487.
◦
mixture was cooled to 0 C and Ti(OEt)4 (13.8 mL, 66.5 mmol)
was added. The solution was warmed to rt and stirred for
4 h. At this time, the reaction mixture was diluted with DCM
(300 mL), the solution was vigorously stirred and H2O (13.8 mL)
was added dropwise. The mixture was filtered through a Celite
pad, washed with DCM (100 mL) and the combined organic
phases concentrated. Flash chromatography (20% Et2O–hexane)
provided 5.44 g (99%) of a colorless oil; [a]2D0 -139.1 (c 0.83,
1
CHCl3); IR (neat) 1083 cm-1; H NMR (CDCl3) d 8.40 (t, J =
4.8 Hz, 1H), 7.30 (m, 5H), 7.07 (s, 2H), 4.53 (s, 2H), 3.76 (m, 4H),
2.86 (m, 3H), 1.25 (m, 21H); 13C NMR (CDCl3) d 165.9, 152.8,
149.7, 138.0, 134.5, 128.5, 127.8, 123.0, 73.3, 66.3, 36.8, 34.5, 27.9,
24.5, 24.0, 23.8 (one carbon could not be identified due to overlap).
HRMS calcd for C25H36NO2S (M + H) 414.2467. Found 414.2450.
(RS,2S,3R)-(-)-N-Methoxy-N,2-dimethyl-3-(2,4,6-triisopropyl-
phenylsulfinamido)-5-benzyloxypentanamide (7)
In a 100 mL, oven-dried, single-neck round-bottomed flask
equipped with a magnetic stirring bar and a rubber septum was
placed LiHMDS (13.85 mL, 13.85 mmol, 1.0 M solution in
THF), and a solution of N-methoxy-N-methylpropylamide (5)
(1.62 g, 13.85 mmol) in THF (40.0 mL) was added at -78 ◦C via
cannula. The solution was stirred for 2 h at -78 ◦C at which time
sulfinimine (R)-(-)-4 (2.29 g, 5.54 mmol) in THF (16.0 mL) was
added dropwise. The reaction mixture was stirred for 1 h at this
temperature and quenched by addition of sat. aqueous NH4Cl
(10 mL). The solution was extracted with EtOAc (2 ¥ 50 mL), and
the combined organic phases were washed with brine (2 ¥ 20 mL),
dried (MgSO4) and concentrated. Chromatography (50% Et2O–
hexanes) provided 2.26 g (77%) of a colorless oil as the major
(2R,3S,5S,6S,E)-(-)-2-(2-(Benzyloxy)ethyl)-3-methyl-6-(prop-1-
enyl)-5-propylpiperidin-4-one (11)
(a) In a 250 mL, flame-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, rubber septum and an
argon balloon was placed (-)-8 (1.71 g, 3.24 mmol) in anhydrous
MeOH (103 mL). The solution was cooled to 0 ◦C, HCl (6.5 mL,
12.98 mmol, 2.0 M solution in Et2O) was added via syringe, and
the reaction mixture was stirred for 20 min at 0 ◦C. At this time,
◦
enough aqueous NaOH solution was added at 0 C to bring the
pH of the solution to 9. The mixture was extracted with DCM
(2 ¥ 20 mL), the combined organic phases washed with brine
5070 | Org. Biomol. Chem., 2009, 7, 5067–5073
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
(2 ¥ 20 mL), dried (NaSO4), and concentrated. The crude amine
(+)-9 was used in the next step without further purification.
(b) In a 250 mL, oven-dried, single-necked round-bottomed
flask equipped with a magnetic stirring bar, rubber septum and
an argon balloon was placed crude (+)-9 in DCM (52 mL),
crotonaldehyde (2.76 mL, 32.5 mmol), and Ti(OEt)4 (3.31 mL,
16.25 mmol) were added at 0 ◦C via syringe. The reaction mixture
was stirred for 3 h at rt, diluted with DCM (100 mL), stirred
vigorously, and quenched by dropwise addition of sat. NaHCO3
(6.62 mL). The mixture was filtered through a Celite pad and
the Celite was washed with DCM (100 mL). The combined
organic phases were washed with brine and dried (MgSO4). The
crude imine 10 was carried on to the next step without further
purification.
3 H); 13C NMR (CDCl3) d 214.6, 138.7, 128.7, 127.98, 127.95,
73.4, 68.5, 51.8, 50.4, 42.1, 35.9, 26.1, 22.7, 14.2, 10.7. HRMS
calcd for C17H28NO2 (M + H) 278.2120. Found 278.2111.
(2R,3S,5S,6S,E)-(+)-1-Allyl-2-(2-(benzyloxy)ethyl)-3-methyl-6-
(prop-1-enyl)-5-propylpiperidin-4-one (12)
In a 50 mL, flame-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, rubber septum and an argon
balloon was placed piperidone (-)-11 (0.465 g, 1.413 mmol) in
absolute EtOH (40 mL). Anhydrous Na2CO3 (2.15 g, 20.28 mmol)
and allyl bromide (1.21 mL, 14.13 mmol) we◦re added at rt and the
reaction mixture was stirred for 15 h at 70 C. The solution was
filtered through a Celite pad, the Celite was washed with DCM
(2 ¥ 10 mL) and the combined organic phases were concentrated.
To the residue was added H2O (5 mL) and the solution was
extracted with DCM (2 ¥ 20 mL). The combined organic phases
were washed with brine (2 ¥ 10 mL), dried (MgSO4), and
concentrated. Chromatography (10% Et2O–hexanes) provided
0.376 g (72%) of a yellow oil; [a]2D0 +14.5 (c 0.75, CHCl3); IR
(c) In a 250 mL, oven-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, rubber septum and an argon
balloon was placed anhydrous TsOH (1.04 g, 6.48 mmol), and a
solution of the crude imine 10 in anhydrous toluene (103 mL)
was added via ◦a cannula. At this time the reaction mixture was
warmed to 75 C, stirred for 8 h, cooled to rt, and diluted with
Et2O (20 mL). Enough sat. aq. NaHCO3 solution was added until
the aqueous phase reached pH 8, at which time the aqueous phase
was extracted with DCM (2 ¥ 10 mL). The combined organic
phases were washed with brine (2 ¥ 20 mL), dried (MgSO4)
and concentrated. Chromatography (10% EtOAc–hexanes) gave
0.545 g (51%) of a yellow oil; [a]2D0 -5.7 (c 0.667, CHCl3); IR (KBr)
3343, 1707, 1455 cm-1; 1H NMR (CDCl3) d 7.24 (m, 5H), 5.57 (dq,
J = 6.4, 15.2 Hz, 1H), 5.41 (ddq, J = 1.6, 8.4, 15.2 Hz, 1H), 4.48
(m, 2H), 3.65 (m, 1H), 3.59 (m, 1H), 2.97 (dd, J = 8.4, 10.2 Hz,
1H), 2.61 (ddd, J = 2.4, 8.6, 10.8 Hz, 1H), 2.27 (ddq, J = 1.1, 6.4,
10.8, 1H), 2.16 (ddd, J = 1.1, 6.5, 10.2, 1H), 1.95 (m, 1H), 1.74 (m,
1H), 1.69 (dd, J = 1.6, 6.4 Hz, 3H), 1.61 (m, 1H), 1.36 (m, 1H),
1.16 (m, 2H), 0.98 (d, J = 6.4 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H),
1
(KBr) 1716, 1455 cm-1; H NMR (CDCl3) d 7.31 (m, 5H), 5.77
(m, 1H), 5.50 (dq, J = 6.4, 15.0 Hz, 1H), 5.27 (ddq, J = 1.6, 9.4,
15.0 Hz, 1H), 5.11 (m, 1H), 5.08 (s, 1H), 4.51 (s, 2H), 3.64 (dd, J =
7.2, 7.2 Hz, 2H), 3.47 (dd, J = 6.0, 16.0 Hz, 1H), 3.29 (dd, J = 7.0,
16.0 Hz, 1H), 2.96 (dd, J = 9.4, 9.4 Hz, 1H), 2.59 (m, 1H), 2.47
(dq, J = 6.4, 7.2, 1H), 2.25 (m, 1H), 2.05 (m, 1H), 1.91 (m, 1H),
1.71 (dd, J = 1.6, 6.4 Hz, 3H), 1.60 (m, 1H), 1.31 (m, 1H), 1.14
(m, 2H), 1.05 (d, J = 6.4 Hz, 3H), 0.84 (t, J = 6.8 Hz, 3H); 13C
NMR (CDCl3) d 211.9, 138.7, 133.7, 132.8, 128.9, 128.5, 127.7,
117.7, 73.3, 69.6, 66.6, 64.1, 53.4, 51.6, 48.0, 30.9, 28.6, 21.1, 17.8,
14.5, 12.5 (one unsaturated carbon could not be assigned). HRMS
calcd for C24H36NO2 (M + H) 370.2746. Found 370.2747.
(3R,4S)-(+)-1-(Benzyloxy)-4-methyl-3-(1H-pyrrol-1-yl)nonan-5-
one (14)
the NH proton was partially overlapped with peak at d 2.27; 13
C
NMR (CDCl3) d 211.3, 138.4, 132.7, 128.6, 128.5, 127.8, 127.5,
73.2, 68.7, 65.3, 62.6, 55.9, 50.9, 34.0, 27.6, 21.2, 17.9, 14.6, 10.3.
HRMS calcd for C21H32NO2 (M + H) 330.2433. Found 330.2428.
Upon irradiation of the C-2 proton at d 2.55 ppm, a positive
NOE was observed on the C-6 proton at d 2.91 (4.8%), indicating
a cis-relationship between the C-2 and the C-6 protons. Upon
irradiation of the C-3 methyl at d 0.92 ppm, a positive NOE was
observed on the C-5 proton at d 2.11 (2.0%), indicating the trans
relationship between the C-3 methyl group and the C-5 proton.
Upon irradiation of the C-5 methyl group at d 0.79 ppm, a positive
NOE was observed on the C-6 proton at d 2.91 (1.5%), indicating a
cis-relationship between the C-5 methyl group and the C-6 proton.
Upon irradiation of the C-5 proton at d 2.11, a positive NOE was
observed on the C-6 vinyl proton at d 5.35 (3.8%), indicating a
cis-relationship between the C-5 and the C-6 vinyl protons.
In a 100 mL, oven-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, condenser, rubber septum
and an argon balloon was placed piperidone (+)-12 (0.340 g,
0.92 mmol) in anhydrous DCM (49 mL), and 5 mol%, Grubs “first
generation” catalyst (0.038 g 0.46 mmol). The reaction mixture
was heated at 40 ◦C for 48 h at which time the blue solution
was concentrated. Chromatography (33.3% Et2O–hexanes) to give
0.208 (69%) of a blue oil; [a]2D0 +1.5 (c 0.733, CHCl3); IR (neat)
3446, 3031, 2958, 2870, 1716 cm-1; 1H NMR (CDCl3) d 7.23 (m,
5H), 6.5 (t, J = 2.2 Hz, 2H), 6.0 (t, J = 2.0 Hz, 2H), 4.29 (s, 2H),
4.24 (ddd, J = 3.6, 10.1, 12.1 Hz, 1H), 3.25 (m, 1H), 2.94 (m, 2H),
2.12 (m, 2H), 1.81 (m, 2H), 1.23 (m, 2H), 1.05 (d, J = 7.6 Hz,
3H), 1.02 (m, 2H), 0.72 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3)
d 213.1, 138.2, 128.4, 127.7, 127.6, 119.4, 108.0, 73.2, 66.3, 58.8,
51.8, 42.4, 32.8, 25.2, 22.0, 14.5, 13.8. HRMS calcd for C21H29NO2
(M) 327.2198. Found 327.2207.
(3R,4S)-(+)-3-Amino-1-(benzyloxy)-4-methylnonan-5-one (9)
An analytical sample was purified by chromatography (5%
MeOH–CH2Cl2, 0.5% Et3N) to give a colorless oil that slowly
decomposed on standing: [a]2D0 +32.6 (c 0.35, CHCl3); IR (neat)
3386, 2933, 2870, 1705 cm-1; 1H NMR (CDCl3) d 7.31 (m, 5 H),
4.50 (s, 2 H), 3.59 (m, 2 H), 3.26 (dt, J = 4.8, 8.4 Hz, 1 H), 2.56
(dq, J = 4.8,6.8 Hz, 1 H), 2.45 (m, 2 H), 1.63 (m, 2 H), 1.52 (m, 2
H), 1.28 (m, 4 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.90 (t, J = 7.4 Hz,
(5R,6S,8S,9S)-(+)-5-(2-(Benzyloxy)ethyl)-6-methyl-8-propyl-
5,6,8,8a-tetrahydroindolizin-7(3H)-one (13)
In a 250 mL, oven-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, condenser, rubber septum
and an argon balloon was placed piperidone (+)-12 (0.373 g,
1.011 mmol) in anhydrous DCM (50 mL), and 5 mol% Grubs “first
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5067–5073 | 5071
©

View Article Online
generation” catalyst (0.083 g, 0.46 mmol). The reaction mixture
was stirred at rt for 8 h, concentrated, and applied directly to a
silica gel column. Chromatography (10% Et2O–hexanes) to give
0.227 g (69%) of a yellow oil that slowly turned blue on standing;
[a]2D0 +44.7 (c 0.094, CHCl3); IR (KBr) 3010, 2958, 2872, 2767,
(b) In a 50 mL, oven-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, rubber septum and an argon
balloon was placed NaH (0.160 g, 2.007 mmol) in anhydrous
petroleum ether (2 mL). The mixture was gently stirred for 30 s and
the petroleum ether was removed by syringe. The sticky mixture
was evacuated for 2 min, filled with argon, and this sequence was
repeated twice. To the NaH was added THF (5.6 mL) and the
crude alcohols in THF (5.6 mL). The solution was stirred for 1 h
at rt, CS2 (0.120 mL, 2.007 mmol) was added, and the solution was
stirred for 2 h. At this time MeI (0.208 mL, 3.35 mmol) was added,
the reaction mixture was stirred for 16 h at rt, and quenched by
cautious addition of H2O (2 mL). The solution was diluted with
Et2O (20 mL), washed with H2O (3 ¥ 3 mL), the organic phases
were combined, washed with brine (2 ¥ 20 mL), dried (MgSO4),
and concentrated. The residue was used in the next step without
further purification.
1
1702 cm-1; H NMR (CDCl3) d 7.23 (m, 5H), 6.0 (m, 1H), 5.91
(m, 1H), 4.44 (s, 2H), 3.59 (m, 3H), 3.30 (m, 2H), 2.63 (m, 1H),
2.39 (m, 1H), 2.15 (m, 1H), 1.94 (m, 1H), 1.82 (m, 1H), 1.73 (m,
1H), 1.36 (m, 1H), 1.13 (m, 2H), 0.95 (d, J = 6.8 Hz, 3H), 0.82 (t,
J = 7.2 Hz, 3H); 13C NMR (CDCl3) d 211.7, 138.6, 132.3, 129.0,
128.5, 127.7 (2C), 73.2, 72.6, 67.4, 63.3, 54.9, 52.5, 47.0, 31.9, 28.1,
21.3, 14.5, 10.8. HRMS calcd for C21H30NO2 (M + H) 370.2746.
Found 370.2747.
(5R,6S,8S,9S)-(-)-5-[2-(Benzyloxy)ethyl]-6-methyl-8-propyl-
hexahydroindolizin-7(1H)-one (16)
(c) In a 25 mL, oven-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, rubber septum and an
argon balloon was placed AIBN (0.0275 g, 0.167 mmol), and
the residue from the previous step in benzene (1.4 mL) was added
via syringe. The mixture was warmed to 85 ◦C and a solution
of n-Bu3SnH (0.33 mL, 1.23 mmol) in benzene (1.4 mL) was
added using syringe drive over 3.5 h. At this time the reaction
mixture was stirred for 30 min at this temperature, cooled to rt,
and concentrated. Chromatography (10% Et2O–hexanes to 50%
Et2O–hexanes) provided 0.058 g (55% for the 3 steps) of a colorless
oil; [a]2D0 -61.7 (c 0.12, CHCl3); IR (neat) 3020, 2956, 2869 cm-1;
1H NMR (CDCl3) d 7.22 (m, 5H), 4.51 (s, 2H), 3.59 (dd, J = 7.8,
7.8 Hz, 2H), 3.18 (ddd, J = 1.2, 8.4, 8.8 Hz, 1H), 1.05–1.95 (m,
15H), 0.98 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H), 0.87 (t, J = 7.0 Hz,
3H), 0.65 (m, 1H); 13C NMR (CDCl3) d 138.9, 128.4, 127.6, 127.5,
73.0, 70.5, 67.5, 67.4, 52.2, 40.8, 40.5, 35.7, 34.8, 31.0, 29.2, 21.0,
19.8, 18.7, 14.5. HRMS calcd for C21H34NO (M+H) 316.2640.
Found 316.2650.
(a) In a 250 mL, oven-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, rubber septum and an argon
balloon was placed piperidone (+)-12 (0.340 g, 0.92 mmol) in
anhydrous DCM (49 mL), and 5 mol% of Grubs “first generation”
catalyst (0.083 g, 0.46 mmol) was added. The solution was stirred
for 3 h at rt, concentrated, and applied directly to a short-pad silica
gel column eluting with 33.3% Et2O–hexanes. The blue colored
solution was concentrated in a 50 mL single-necked round bottom
flask and the unstable blue residue was carried on to the next step
without further purification.
(b) To the round bottomed flask was added a magnetic stirring
bar, rubber septum, and anhydrous MeOH (15 mL). To the
solution was added 10 wt% Pd/C (0.184 g, 0.092 mmol) at rt.
The mixture was evacuated and filled with H2, and this sequence
was repeated 5 times and the solution was stirred for 2 h at rt
under an H2 atmosphere (1 atm, H2-filled balloon). The mixture
was filtered through a Celite pad and the Celite was washed with
Et2O (20 mL). Chromatography (25% EtOAc–hexanes) provided
0.181 g (60%) of a colorless oil; [a]2D0 -12.0 (c 0.28, CHCl3); IR
(neat) 3031, 2957, 2870, 2786 cm-1; 1H NMR (CDCl3) d 7.27 (m,
5H) 4.48 (s, 2H), 3.63 (ddd, J = 1.6, 7.2, 7.4 Hz, 2H), 3.20 (ddd, J =
2.4, 8.4, 8.8 Hz, 1H), 2.43 (ddq, J = 1.2, 6.4, 8.4, 1H), 2.24 (m, 1H),
2.0 (m, 6H), 1.80 (m, 1H), 1.68 (m, 2H), 1.54 (m, 1H), 1.37 (m, 1H),
1.15 (m, 2H), 0.99 (d, J = 6.4 Hz, 3H), 0.80 (t, J = 7.2 Hz, 3H);
13C NMR (CDCl3) d 211.7, 138.6, 128.5, 127.6, 127.56, 73.1, 69.6,
66.3, 66.1, 55.3, 50.7, 47.2, 31.4, 30.2, 28.2, 21.4, 21.2, 14.6, 10.7.
HRMS calcd for C21H32NO2 (M+H) 330.2433. Found 330.2418.
2-(5R,6R,8R,9S)-(-)-6-Methyl-8-propyl-octahydroindolizin-
5-yl)ethanol (19)
In a 10 mL, flame-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar was placed indolizidine
(-)-18 (0.055 g, 0.174 mmol) in anhydrous THF (6.8 mL) and
MeOH (2.4 mL). To the solution was added 20% Pd(OH)2/C
(0.551 g, 1000 wt%) and TFA (0.215 mL, 2.79 mmol). The mixture
was evacuated for 30 s and filled with H2, and this sequence
was repeated 5 times. The mixture was stirred for 28 h at rt
under 1 atm H2 (hydrogen balloon). The reaction mixture was
filtered through a Celite pad, and the Celite was washed with Et2O
(20 mL). The combined solutions were concentrated and washed
with 5 mL of sat. NaHCO3 solution until the pH of the aqueous
phase was greater than 7. At this time, the solution was extracted
with DCM (3 ¥ 10 mL), and the combined organic phases were
dried (MgSO4) and concentrated. Preparative TLC (6% MeOH–
CH2Cl2) provided 0.0308 g (79%) of a yellow oil; [a]2D0 -56.2 (c 1.04,
CHCl3); IR (neat) 3394, 2956, 2870, 2781 cm-1; 1H NMR (CDCl3)
d 3.98 (dt, J = 2.8, 11.6 Hz, 1H), 3.66 (m, 1H), 3.61 (broad t, J =
8.0 Hz, 1H), 2.14 (m, 1H), 2.00 (m, 2H), 1.87 (m, 3H), 1.68 (m,
4H), 1.24 (m, 5H), 1.00 (m, 1H), 0.90 (d, J = 6.4 Hz, 3H), 0.86 (t,
J = 7.0 Hz, 3H), 0.72 (q, J = 11.9 Hz, 1H); 13C NMR (CDCl3) d
71.0, 68.3, 59.9, 52.7, 40.3, 39.8, 35.5, 31.9, 29.1 (2C), 20.6, 19.7,
(5R,6R,8R,9S)-(-)-5-(2-(Benzyloxy)ethyl)-6-methyl-8-propyl-
octahydroindolizine (18)
(a) In a 50 mL, oven-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar, rubber septum and an argon
balloon was placed (-)-16 (0.110 g, 0335 mmol) in anhydrous
MeOH (11.5 mL). To the solution was added NaBH4 (0.101 g,
◦
1.338 mmol) at 0 C and the solution was stirred for 2 h at this
temperature. The reaction mixture was concentrated, diluted with
H2O (3 mL), and extracted with Et2O (2 ¥ 10 mL). The combined
organic phases were dried (MgSO4) and concentrated. The crude
alcohol isomers were carried on to the next step without further
purification.
5072 | Org. Biomol. Chem., 2009, 7, 5067–5073
This journal is
The Royal Society of Chemistry 2009
©

View Article Online
18.7, 14.5. HRMS calcd for C14H28NO (M + H) 226.2171. Found
226.2173.
References
1 J. W. Daly, T. F. Spande and H. M. Garraffo, J. Nat. Prod., 2005, 68,
1556–1575.
2 (a) H. M. Garraffo, P. Jain, J. T. F Spande and J. W. Daly, J. Nat.
Prod., 1997, 60, 2–5; (b) J. W. Daly, H. M. Garraffo and T. F. Spande,
in Alkaloids: Chemical and Biological Perspectives, ed. S. W. Pelletier,
Pergamon Press, New York, 1999, vol. 13, pp 1–161.
3 For leading references to this class of alkaloids see: J. P. Michael, C. B.
de Koning and C. W. van der Westhyzen, Org. Biomol. Chem., 2005, 3,
836–847.
4 F. A. Davis and B. Yang, J. Am. Chem. Soc., 2005, 127, 8398–8407.
5 For asymmetric syntheses of 223A, see: (a) P. Ghosh, W. R. Judd, T.
Ribelin and J. Aube, Org. Lett., 2009, 11, 4140–4141; (b) N. Toyooka,
A. Fukutome, H. Nemoto, J. W. Daly, T. F. Spande, H. M. Garraffo
and T. Kaneto, Org. Lett., 2002, 4, 1715–1717; (c) X. Pu and D. Ma,
J. Org. Chem., 2003, 68, 4400–4405; (d) N. Toyooka, A. Fukutome,
H. Shinoda and H. Nemoto, Tetrahedron, 2004, 60, 6197–6216; (e) W.
Zhu, D. Dong, X. Pu and D. Ma, Org. Lett., 2005, 7, 705–708.
6 For a racemic synthesis of 223A, see: (a) J. M. Harris and A. Padwa,
J. Org. Chem., 2003, 68, 4371–4381See also; R. Kumareswaran, J.
Gallucci and T. V. RajanBabu, J. Org. Chem., 2004, 69, 9151–9158.
7 (a) J. W. Daly, J. Med. Chem., 2003, 46, 445–452; (b) P. L. Katavic, D. A.
Venables, T. Rali and A. R. Carroll, J. Nat. Prod., 2007, 70, 872–875.
8 For reviews on the asymmetric synthesis of piperidines, see: (a) S.
Laschat and T. Dickner, Synthesis, 2000, 1781–1813; (b) F-X. Felpin
and J. Lebreton, Eur. J. Org. Chem., 2003, 3693–3712; (c) P. M.
Weintraub, J. S. Sabol, J. M. Kane and D. R. Borcherding, Tetrahedron,
2003, 59, 2953–2989; (d) M. G. P. Buffat, Tetrahedron, 2004, 60, 1701–
1729.
(5R,6R,8R,9S)-(-)-5, 9Z-Indolizidine 221T (1)
(a) In a 5 mL, flame-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar was placed DMSO
(0.02 mL, 0.282 mmol) in DCM (0.5 mL) and (COCl)2 (0.012 mL,
0.137 mmol) was added at -78 ◦C. After stirring for 45 min, alcohol
(-)-19 (0.026 g, 0.114 mmol) in DCM (1.9 mL) was added dropwise
over◦10 min using a syringe pump. After stirring for 30 min at
-78 C, the reaction mixture was quenched by addition of Et3N
(0.095 mL, 0.683 mmol), slowly warmed to rt, diluted with DCM
(10 mL), washed with sat. aqueous NaHCO3 (2 ¥ 5 mL), washed
with brine (2 ¥ 20 mL), dried (MgSO4), and concentrated. The
crude aldehyde was unstable and taken on to the next step without
further purification.
(b) In a 5 mL, flame-dried, single-necked round-bottomed flask
equipped with a magnetic stirring bar was placed Ph3P+CH3I-
(0.144 g, 0.356 mmol) in THF (1.8 mL). To the solution was added
n-BuLi (0.142 mL, 0.356 mmol, 2.5 M in hexanes) at 0 ◦C. After
stirring for 30 min, a solution of the aldehyde in THF (1 mL)
was added, and the reaction mixture was stirred for 4 h at rt.
At this time the reaction was quenched with saturated aqueous
NH4Cl (1 mL) and extracted with EtOAc (2 ¥ 10 mL). The organic
phases were washed with brine (2 ¥ 20 mL), dried (MgSO4), and
concentrated. Chromatography (3% MeOH–CH2Cl2, 1% Et3N)
provided 0.012 g (76% for the 2 steps) of a yellow oil; [a]2D0 -36.3
(c 0.08, CHCl3); IR (KBr) 3394, 2956, 2870, 2781 cm-1; 1H NMR
(CDCl3) d 5.97 (m, 1H), 5.17 (d, J = 6.8 Hz, 1H), 5.14 (s, 1H), 3.91
(m, 1H), 2.82 (m, 2H), 2.6 (m, 3H), 2.46 (m, 1H), 2.25 (m, 4H),
1.98 (m, 3H), 1.29 (m, 3H), 1.02 (m, 1H), 0.96 (d, J = 6.4 Hz, 3H),
0.85 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3) d 135.8, 116.5, 70.9,
69.4, 52.3, 51.4, 40.6, 53.9, 53.2, 34.1, 29.3, 21.2, 19.9, 18.8, 14.7.
HRMS calcd for C15H28N (M + H) 222.2222. Found 222.2221.
9 F. A. Davis, J. Org. Chem., 2006, 71, 8993–9003.
10 For reviews on the Mannich reaction see: (a) W. N. Speckamp and
H. Hiemstra, Tetrahedron, 1985, 41, 4367–4416; (b) M. Arend, B.
Westermann and N. Risch, Angew. Chem., Int. Ed., 1998, 37, 1044–
1070.
11 F. A. Davis and M. Santhanaraman, J. Org. Chem., 2006, 71, 4222–
4226.
12 F. A. Davis and B. Yang, Org. Lett., 2003, 5, 5011–5014.
13 F. A. Davis, N. Theddu and P. M. Gaspari, Org. Lett., 2009, 11, 1647–
1650.
14 (a) F. A. Davis, M. B. Nolt, Y. Wu, K. R. Prasad, D. Li, B. Yang, K.
Bowen, S. H. Lee and J. H. Eardley, J. Org. Chem., 2005, 70, 2184–2190;
(b) F. A. Davis and M. Song, Org. Lett., 2007, 9, 2413–2416.
15 Prochiral enolates to sulfinimnes afford the syn product as the major
isomer. See ref. 4 and F. A. Davis, Y. Zhang and H. Qiu, Org. Lett.,
2007, 9, 833–836.
16 (a) R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413–4450;
(b) A. K. Chatterjee and R. H. Grubbs, Org. Lett., 1999, 1, 1751–1753.
17 (a) C. Yang, W. V. Murry and L. J. Wilson, Tetrahedron Lett., 2003,
44, 1783–1786; (b) N. Dieltiens, C. V. Stevens, D. De Vos, B. Allaert,
R. Drozdzak and F. Verpoort, Tetrahedron Lett., 2004, 45, 8995–8998;
(c) Q. Yang, X-Y. Li, H. Wu and W-J. Xiao, Tetrahedron Lett., 2006,
47, 3893–3896.
Acknowledgements
We thank Dr. Charles DeBrosse, Director of Temple NMR
facilities, for aid with the NOE experiments. This work was
supported by a grant from the National Institutes of General
Medical Sciences (GM 57870).
This journal is
The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 5067–5073 | 5073
©