Synthesis of poison-frog alkaloids 237D, 207A, and two congeners of 235B′ for evaluation to inhibitory effect of nicotinic acetylcholine receptors

Article abstract of DOI:10.1248/cpb.53.555

Enantioselective synthesis of the poison-frog alkaloids 237D, 207A, and two congeners of 235B′ has been achieved. The absolute stereochemistry of 237D was determined to be 5S, 8S, 9R by the present synthesis

Full text of DOI:10.1248/cpb.53.555

May 2005
Chem. Pharm. Bull. 53(5) 555—560 (2005)
555
Synthesis of Poison-Frog Alkaloids 237D, 207A, and Two Congeners of
235Bꢀ for Evaluation to Inhibitory Effect of Nicotinic Acetylcholine
Receptors
,a
b
,a
*
*
Naoki TOYOOKA, Masashi KAWASAKI, and Hideo NEMOTO
a Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University; 2630 Sugitani, Toyama 930–0194,
Japan: b Department of Liberal Arts and Sciences, Faculty of Engineering, Toyama Prefectural University; 5180
Kurokawa, Kosugi-machi, Toyama 939–0398, Japan.
Received January 26, 2005; accepted March 7, 2005; published online March 10, 2005
Enantioselective synthesis of the poison-frog alkaloids 237D, 207A, and two congeners of 235Bꢀ has been
achieved. The absolute stereochemistry of 237D was determined to be 5S, 8S, 9R by the present synthesis.
Key words poison-frog alkaloid; 237D; 207A; 235Bꢀ; 5,8-disubstituted indolizidine
A large number of biologically active alkaloids have been in 2-step sequence. Hydrogenation of 7 over Pd–C under
found in amphibian skin, and the 5,8-disubstituted in- medium pressure followed by reduction of the ester moiety
dolizidines, one of the largest subclass of these alkaloids, with Super-Hydride gave rise to the alcohol 8. Treatment of 8
were detected from skin extracts of the poison-frog.1—3) with MOMCl in the presence of Hünig base provided the
Quite recently, we have found the synthetic 5,8-disubstituted MOM ether 9, which was treated with TBAF to afford the al-
indolizidine 235Bꢀ (1), isolated from Dendrobates pumilio, cohol 10. Swern oxidation of 10 followed by Wittig olefina-
acted as a potent noncompetitive and selective blocker of tion of the resulting aldehyde provided the olefin, which was
a4b2 nicotinic receptor (IC50ꢁ74 nM).4) The sensitivity of hydrogenated over Pd–C to give rise to the alkaloid 237D (2).
235Bꢀ for a4b2 receptors was comparable with that of the The absolute stereochemistry of natural 237D was deter-
best characterized antagonist of a4b2 nicotinic acetylcholine mined to be 5S, 8S, 9R by the present synthesis (see Experi-
reseptors (nAChRs), dihydro-b-erythroidine (DHbE) (IC50ꢁ mental and reference 9).
0.11 mM).5) This result shows that poison-frog alkaloids such
Swern oxidation of 10 followed by the Wittig reaction of
as indolizidine 235Bꢀ alter the function of nicotinic receptors the resulting aldehyde provided the olefin 12, which was con-
in a subtype-selective manner, suggesting that an analysis of verted to the alcohol 13. Swern oxidation of 13 and Wittig
these alkaloids may aid in the development of selective drugs reaction of the resulting aldehyde afforded the terminal olefin
to alter nicotinic cholinergic functions. As part of our ongo- 14. Deprotection of the urethane moiety in 14 using Corey’s
ing program at directing the synthesis of biologically active procedure,12) and cleavage of the MOM ether with acid fol-
alkaloids,6—8) we planned the synthesis of 237D (2, saturated lowed by indolizidine formation under the bromination reac-
congener of 1), 207A (3, bis-nor congener of 1), nor con- tion condition13) provided the alkaloid 207A (3), whose spec-
gener of 235Bꢀ (4), and homo congener of 1 (5) as potent tral data were identical with those of reported values.13,14) On
blockers for nAChRs. This paper describes a full account of the other hand, the alcohol 13 was converted to the iodide 15,
the experiments, some of which were reported in a prelimi- and the cross coupling reaction of 15 using the dibutenyl
nary communication.9)
cuprate gave rise to the homologated olefin 16. Indolizidine
The synthesis of 2 began with trisubstituted piperidine formation reaction of 16 furnished 5.
6,10,11) which was converted to the a,b-unsaturated ester 7
Finally, the nor-congener of 1 (4) was synthesized from the
Reagents and conditions: a: Swern ox.; b: (EtO)2P(O)CH2CO2Et, NaH, THF, 0 °C—rt (95%); c: 10% Pd–C, H2, EtOAc, 4 atm; d: Super-Hydride, THF, 0 °C (93%); e: MOMCl,
Hünig base CH2Cl2, 0 °C—rt (85%); f: TBAF, THF, 0 °C—rt (95%); g: Swern ox.; h: Me(CH2)5PꢂPh3Brꢃ, n-BuLi, THF, 0 °C—rt (66%); i: 10% Pd–C, H2, EtOAc, 1 atm; j: n-
PrSLi, HMPA, THF, 0 °C—rt; k: conc. HCl, MeOH, reflux; l: CBr4, Ph3P, Et3N, CH2Cl2, 0 °C—rt (42%).
Chart 1
∗ To whom correspondence should be addressed. e-mail: toyooka@ms.toyama-mpu.ac.jp
© 2005 Pharmaceutical Society of Japan

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Vol. 53, No. 5
Reagents and conditions: a: Swern ox.; b: TBDPSO(CH2)3PꢂPh3Brꢃ, n-BuLi, THF, 0 °C—rt (87%); c: 10% Pd–C, H2, EtOAc, 1 atm; d: TBAF, THF, 0 °C—rt (87%); e: Swern
ox.; f: CH3PꢂPh3Iꢃ, n-BuLi, THF, 0 °C—rt (89%); g: n-PrSLi, HMPA, THF, 0 °C—rt; h: conc. HCl, MeOH, reflux; i: CBr4, Ph3P, E t 3N, CH2Cl2, 0 °C—rt (63%); j: MsCl, Et3N,
CH2Cl2, 0 °C; k: NaI, acetone, 50 °C (96%); l: butenylmagnesium bromide, CuI, THF, ꢃ40—ꢃ30 °C (91%).
Chart 2
Reagents and conditions: a: Swern ox.; b: TBDPSO(CH2)4PꢂPh3Brꢃ, n-BuLi, THF, 0 °C—rt (97%); c: 10% Pd–C, H2, EtOAc, 1 atm; d: TBAF, THF, 0 °C—rt (74%); e: Swern
ox.; f: CH3PꢂPh3Iꢃ, n-BuLi, THF, 0 °C—rt (88%); g: n-PrSLi, HMPA, THF, 0 °C—rt; h: conc. HCl, MeOH, reflux; i: CBr4, Ph3P, Et3N, CH2Cl2, 0 °C—rt (51%).
Chart 3
common alcohol 10 as shown in Chart 3. The alcohol 10 was the reaction mixture was stirred for 30 min at ꢃ78 °C, triethylamine
(5.47 ml, 39.56 mmol) was added to the reaction mixture. The reaction mix-
ture was warmed to 0 °C for 1 h, and quenched with H2O. The aqueous mix-
ture was extracted with Et2O (20 mlꢄ3). The organic extracts were com-
bined, dried, and evaporated to give pale yellow oil, which was used directly
converted to the olefin 17, which was hydrogenated over 10%
Pd–C in EtOAc followed by cleavage of silyl ether with
TBAF to afford the alcohol 18. Swern oxidation of 18 and
Wittig olefination reaction of the resulting aldehyde provided
the terminal olefin 19. Indolizidine formation reaction of 19
in 3-step sequence furnished 4.
Pharmacological studies on the nicotinic acetylcholine re-
ceptors of these synthesized indolizidines are now being con-
ducted, and the results will be described in due course.
in the next step.
To a stirred suspension of NaH (60%, 386 mg, 9.67 mmol) in THF (20 ml)
was added (EtO)2P(O)CH2CO2Et (1.94 ml, 9.67 mmol) at 0 °C, and the reac-
tion mixture was stirred for 30 min at 0 °C. To the mixture was added drop-
wise a solution of the above aldehyde in THF (6 ml) via a double-tipped
stainless needle. The reaction mixture was stirred at room temperature for
20 h, and quenched with H2O. The aqueous mixture was extracted with
CH2Cl2 (20 mlꢄ3). The organic extracts were combined, dried, and evapo-
rated to give pale yellow oil, which was chromatographed on SiO2 (80 g,
Experimental
General 1H- and 13C-NMR spectra were taken on a Varian Gemini 300 hexane : acetoneꢁ100 : 1—10 : 1) to afford 7 (4.29 g, 95%) as a 2 : 1 mixture
1
or Unity Plus 500 spectrometer. H-NMR spectra were recorded at the indi- of E- and Z-isomers.
1
cated field strength as solutions in CDCl3 unless otherwise indicated. Chem-
IR (neat) 2955, 1759, 1698 cmꢃ1; H-NMR (500 MHz) d 0.90, 1.11 (3H,
ical shifts are given in parts per million (ppm, d) downfield from TMS and each d, Jꢁ6.9 Hz), 1.05 (9H, s), 1.23, 1.31 (3H, each t, Jꢁ7.2 Hz), 1.44—
are referenced to CHCl3 (7.26 ppm) as internal standard. Splitting patterns
are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br,
2.08 (5H, br m), 3.11—3.21 (1H, br m), 3.48—3.58 (1H, br m), 3.61, 3.71
(3H, each s), 4.14—4.22 (2H m), 4.33—4.53 (2H br), 5.65, 5.93 (1H, each
broad. 13C-NMR spectra were recorded at the indicated field strength as so- d, each Jꢁ10.3, 14.1 Hz), 6.19, 6.89 (1H, each dd, Jꢁ10.3, 8.5, 14.1,
lutions in CDCl3 unless otherwise indicated. Chemical shifts are given in 5.5 Hz), 7.39—7.48 (6H, m), 7.66—7.74 (4H, m); MS m/z: 523 (Mꢂ).
parts per million (ppm, d) downfield from TMS and are referenced to the
center line of CDCl3 (77.0 ppm) as internal standard. Carbon signals were
Methyl 6-(tert-Butyldiphenylsilyloxymethyl)-2-(3-hydroxypropyl)-3-
methylpiperidine-1-carboxylate (8) To a stirred solution of 7 (1.2 g,
assigned by a DEPT pulse sequence, qꢁmethyl, tꢁmethylene, dꢁmethyne, 2.29 mmol) in EtOAc (20 ml) was added 10% Pd–C (50 mg), and the result-
and sꢁquaternary carbons. Infrared spectra (IR) were measured with a
ing suspension was hydrogenated under hydrogen atmosphere at 4 atm for
Perkin-Elmer 1600 series FT-IR spectrophotometer. Mass spectra (MS) and 40 h. The catalyst was removed by filtration and the filtrate was evaporated
high-resolution mass spectra (HR-MS) were measured on a JEOL JMS- to give colorless oil, which was used directly in the next step.
AX505HAD mass spectrometer. Optical rotations were measured on a
JASCO DIP-1000 digital polarimeter. Column chromatography was per-
formed on Merck silica gel 60 (No. 7734-5B) or (No. 9385).
To a stirred solution of the above oil in THF (10 ml) was added a solution
of Super-Hydride (1 M in THF, 5 ml, 5 mmol) at 0 °C, and the resulting solu-
tion was stirred at 0 °C for 1.5 h. The reaction was quenched with ice-water,
and the aqueous mixture was extracted with CH2Cl2 (10 mlꢄ5). The organic
extracts were combined, dried, and evaporated to give colorless oil, which
was chromatographed on SiO2 (20 g, hexane : acetoneꢁ30 : 1—10 : 1) to af-
ford 8 (1.02 g, 93%) as colorless oil.
Methyl 6-(tert-Butyldiphenylsilyloxymethyl)-2-(2-ethoxycarbonyl-
vinyl)-3-methylpiperidine-1-carboxylate (7) To
a stirred solution of
(COCl)2 (1.15 ml, 13.19 mmol) in CH2Cl2 (30 ml) was added DMSO
(1.87 ml, 26.37 mmol) at ꢃ78 °C, and the resulting solution was stirred at
ꢃ78 °C for 5 min. To the mixture was added dropwise a solution of 6 (4 g,
IR (neat) 3471, 1688 cmꢃ1 1H-NMR (500 MHz) d 0.90 (3H, br), 1.06
;
8.79 mmol) in CH2Cl2 (6 ml) via a double-tipped stainless steel needle. After (12H, br s), 1.14—1.79 (6H, br m), 3.38—4.66 (9H, br m), 7.43 (6H, br),

May 2005
557
7.72—7.87 (4H, br m); 13C-NMR (75 MHz) d 18.87, 19.03 (each t), 19.22,
19.37 (each t), 20.89, 21.46 (each q), 22.33, 22.57 (each t), 26.65 (q), 31.49
(t), 50.26 (d), 51.13 (d), 52.65, 52.81 (each q), 63.04, 63.56 (each d), 64.90,
65.37 (each t), 68.18, 69.40 (each d), 127.50 (d), 127.55 (d), 129.57 (d),
132.71 (s), 135.23 (d), 158.43, 158.79 (each s); MS m/z: 483 (Mꢂ); HR-MS
Calcd for C28H41NO4Si 483.2802, Found 483.2822; [a]D26 ꢂ9.7° (cꢁ1.75,
CHCl3).
ble-tipped stainless needle. The reaction was stirred at room temperature for
54 h, and quenched with 28% NH3 (aq.). The aqueous mixture was extracted
with Et2O (10 mlꢄ10), and the organic extracts were combined, dried over
K2CO3, and evaporated to give pale yellow oil, which was used directly in
the next step.
To a solution of the above oil in MeOH (5 ml) was added conc. HCl (8
drops), and the reaction mixture was heated at reflux for 1 h. After cooling,
the solvent was evaporated, and the residue was washed with Et2O. To the
residue was added 28% NH3 (aq.), and the aqueous mixture was extracted
with CHCl3 (10 mlꢄ10). The organic extracts were combined, dried over
K2CO3, and evaporated to give pale yellow oil, which was used directly in
the next step.
To a stirred solution of the above oil in CH2Cl2 (5 ml) were added CBr4
(262 mg, 0.79 mmol) and Ph3P (221 mg, 0.85 mmol) at 0 °C, and the result-
ing mixture was stirred at 0 °C for 1 h. To the reaction mixture was added
triethylamine (1.25 ml, 9.01 mmol), and the stirring was continued for
30 min at room temperature. The volatiles were removed, and the residue
was extracted with pentane (5 mlꢄ4). The solvent was evaporated to give
pale orange solid, which was chromatographed on SiO2 (20 g, hexane : ace-
toneꢁ20 : 1) to afford 2 (56 mg, 42%) as pale yellow oil.
Methyl 6-(tert-Butyldiphenylsilyloxymethyl)-2-(3-methoxymethoxy-
propyl)-3-methylpiperidine-1-carboxylate (9) To a stirred solution of 8
(785 mg, 1.63 mmol) in CH2Cl2 (8 ml) were added MOMCl (0.49 ml,
6.50 mmol) and Hünig base (1.42 ml, 8.13 mmol) at 0 °C, and the resulting
mixture was stirred at room temperature for 45 h. The solvent was evapo-
rated and the residue was chromatographed on SiO2 (20 g, hexane :
acetoneꢁ30 : 1—15 : 1) to afford 9 (730 mg, 85%) as colorless oil.
IR (neat) 2953, 1695 cmꢃ1; 1H-NMR (500 MHz) d 1.05—1.18 (15H, br),
1.40—1.95 (6H, br m), 3.29 (3H, br), 3.44—4.58 (8H, br), 3.66 (3H, s),
7.39—7.42 (6H, br), 7.70—7.72 (4H, m); 13C-NMR (75 MHz) d 19.24 (q),
20.73, 21.08 (each t), 24.04 (t), 26.59 (t), 26.83 (q), 29.69, 30.32 (each t),
52.46 (q), 55.38 (q), 60.79 (d), 63.72, 64.96 (each t), 67.37 (t), 77.21 (d),
95.32 (t), 127.38 (d), 129.34 (d), 133.53, 133.69 (each s), 135.34 (d), 158.06
(s); MS m/z: 527 (Mꢂ); HR-MS Calcd for C30H45NO5Si 527.3064, Found
527.3059; [a]D26 ꢃ20.1° (cꢁ3.36, CHCl3).
Determination of absolute stereochemistry of natural 237D was as fol-
lows: Both (ꢂ)- and (ꢃ)-237D were prepared by the catalytic hydrogenation
of natural (ꢂ)-235B, isolated from D. pumilio or (ꢃ)-235B, present in an
extract of D. speciosus. Gas chromatography using flame-ionization detec-
tion and a chiral column, permethylated b-cycldextrin (SGE, 30 mꢄ
0.25 mm; 130 °C at 0.5 °C/min), resulted in a baseline separation of (ꢂ)- and
(ꢃ)-237D as previously reported. The retention times were 31.9 and
32.4 min respectively. Natural 237D present in D. pumilio or D. speciosus
was co-chromatographed with (ꢃ)-7 on the chiral column using the above
conditions. The synthetic (ꢃ)-7 and (ꢃ)-7, prepared from the hydrogenation
of 235B, were co-chromatographed on GC-MS with a non-chiral column
(Zebron-5 (Phenomenex) 100—280 °C at 5 °C/min) and had identical GC-
EI-MS and GC-FT-IR spectra providing that they had the same relative and
absolute stereochemistry.
Methyl 6-Hydroxymethyl-2-(3-methoxymethoxypropyl)-3-methyl-
piperidine-1-carboxylate (10) To
a stirred solution of 9 (730 mg,
1.39 mmol) in THF (6 ml) was added a solution of TBAF (1 M in THF,
1.56 ml, 1.56 mmol) at 0 °C, and the resulting solution was stirred at room
temperature for 2 h. The reaction was quenched with satd. NH4Cl (aq.), and
the aqueous mixture was extracted with CHCl3 (10 mlꢄ6). The organic ex-
tracts were combined, dried, and evaporated to give colorless oil, which was
chromatographed on SiO2 (20 g, hexane : acetoneꢁ10 : 1—2 : 1) to afford 10
(380 mg, 95%) as colorless oil.
IR (neat) 3475, 2951, 1692 cmꢃ1 1H-NMR (500 MHz) d 1.03 (3H, d,
;
Jꢁ6 Hz), 1.07—1.86 (9H, br m), 3.35 (3H, s), 3.54—3.91 (4H, br m),
4.04—4.23 (2H, br), 4.59, 4.72 (2H, each br); 13C-NMR (75 MHz) d 18.03
(q), 21.25 (t), 21.36 (t), 25.06 (t), 29.82 (d), 32.07 (t), 52.78 (q), 55.87 (q),
61.74 (d), 65.55 (t), 69.19 (t), 76.09 (d), 76.24 (d), 95.32 (t), 159.71 (s); MS
m/z: 289 (Mꢂ); HR-MS Calcd for C14H27NO5 289.1888, Found 289.1869;
[a]D26 ꢃ39.0° (cꢁ3.04, CHCl3).
IR (neat) 2926, 2855, 2777, 1457, 1376, 1164, 1131, 908, 733, 640 cmꢃ1
;
1H-NMR (500 MHz) d 0.88 (3H, d, Jꢁ6.8 Hz), 0.89 (3H, t, Jꢁ6.8 Hz), 0.97
(1H, q-like, Jꢁ11.5 Hz), 1.27—1.38 (13H, br m), 1.51—2.18 (10H, br m),
3.31 (1H, br); 13C-NMR (75 MHz) d 14.16 (q), 18.93 (q), 20.36 (t), 22.72
(t), 25.89 (t), 29.03 (t), 29.32 (t), 30.05 (t), 31.15 (t), 31.88 (t), 33.67 (t),
34.53 (t), 36.44 (d), 51.78 (t), 63.60 (d), 71.37 (d); MS m/z: 237 (Mꢂ); HR-
MS Calcd for C16H31N 237.2455, Found 237.2452; [a]D26 ꢃ98.9° (cꢁ1.59,
CHCl3).
Methyl 6-Hept-1-enyl-2-(3-methoxymethoxypropyl)-3-methylpiperi-
dine-1-carboxylate (11) To
a stirred solution of (COCl)2 (0.25 ml,
1.95 mmol) in CH2Cl2 (5 ml) was added DMSO (0.43 ml, 3.90 mmol) at
ꢃ78 °C, and the resulting solution was stirred at ꢃ78 °C for 5 min. To the
mixture was added dropwise a solution of 10 (380 mg, 1.31 mmol) in
CH2Cl2 (3 ml) via a double-tipped stainless steel needle. After the reaction
mixture was stirred for 30 min at ꢃ78 °C, triethylamine (1.3 ml, 5.85 mmol)
was added to the reaction mixture. The reaction mixture was warmed to 0 °C
for 1 h, and quenched with H2O. The aqueous mixture was extracted with
Et2O (10 mlꢄ3). The organic extracts were combined, dried, and evaporated
to give pale yellow oil, which was used directly in the next step.
Methyl 6-[4-(tert-Butyldiphenylsilyloxy)but-1-enyl]-2-(3-methoxy-
methoxypropyl)-3-methylpiperidine-1-carboxylate (12) To a stirred so-
lution of (COCl)2 (0.32 ml, 3.63 mmol) in CH2Cl2 (10 ml) was added DMSO
(0.52 ml, 7.27 mmol) at ꢃ78 °C, and the resulting solution was stirred at
ꢃ78 °C for 5 min. To the mixture was added dropwise a solution of 10
(700 mg, 2.42 mmol) in CH2Cl2 (6 ml) via a double-tipped stainless steel
needle. After the reaction mixture was stirred for 30 min at ꢃ78 °C, triethyl-
amine (1.5 ml, 10.90 mmol) was added to the reaction mixture. The reaction
mixture was warmed to 0 °C for 1 h, and quenched with H2O. The aqueous
mixture was extracted with Et2O (15 mlꢄ3). The organic extracts were com-
bined, dried, and evaporated to give pale yellow oil, which was used directly
in the next step.
To a stirred suspension of hexyltriphenylphsphoniumbromide (2.8 g,
6.56 mmol) in THF (10 ml) was added a solution of n-BuLi (1.6 M in hexane,
3.7 ml, 5.92 mmol) at 0 °C, and the resulting orange solution was stirred for
10 min at 0 °C. To the mixture was added dropwise a solution of the above
aldehyde in THF (4 ml) via a double-tipped stainless steel needle. After the
reaction mixture was stirred for 14 h at room temperature, the reaction was
quenched with H2O. The aqueous mixture was extracted with Et2O
(10 mlꢄ3), and the organic extracts were combined, dried, and evaporated to
give pale yellow oil, which was chromatographed on SiO2 (20 g,
hexane : acetoneꢁ100 : 1—15 : 1) to afford 11 (310 mg, 66%) as pale yellow
oil.
To a stirred suspension of TBDPSO(CH2)3PꢂPh3Brꢃ (6.96 g, 10.90 mmol)
in THF (18 ml) was added a solution of n-BuLi (1.6 M in hexane, 6 ml,
9.69 mmol) at 0 °C, and the resulting orange solution was stirred at 0 °C for
10 min. To the mixture was added dropwise a solution of the above aldehyde
in THF (4 ml) via a double-tipped stainless needle. The reaction was stirred
at room temperature for 21 h, and quenched with H2O. The aqueous mixture
was extracted with Et2O (15 mlꢄ3). The organic extracts were combined,
dried, and evaporated to give pale yellow oil, which was chromatographed
on SiO2 (40 g, hexane : acetoneꢁ100 : 1—40 : 1) to afford 12 (1.19 g, 87%)
as pale yellow oil.
1
IR (neat) 2953, 1694 cmꢃ1; H-NMR (500 MHz) d 0.86—0.93 (6H, m),
1.02—1.43 (10H, br m), 1.53—2.18 (7H, br m), 3.36 (3H, s), 3.67 (3H, s),
3.65—3.79 (2H, br), 3.90 (1H, br), 4.60 (2H, s), 4.83 (1H, br), 5.38 (1H, m),
5.68 (1H, m); MS m/z: 355 (Mꢂ).
; d 1.03 (3H, d,
IR (neat) 2956, 1691 cmꢃ1 1H-NMR (500 MHz)
5-Heptyl-8-methyloctahydroindolizine (Indolizidine 237D, 2) To a
stirred solution of 11 (200 mg, 0.56 mmol) in EtOAc (10 ml) was added 10%
Pd–C (30 mg), and the resulting suspension was hydrogenated under hydro-
gen atmosphere at 1 atm for 48 h. The catalyst was removed by filtration and
the filtrate was evaporated to give colorless oil, which was used directly in
the next step.
Jꢁ7.4 Hz), 1.06 (9H, s), 1.18—1.24 (1H, m), 1.28—1.30 (1H, m), 1.56—
1.93 (7H, br m), 2.38—2.42 (1H, m), 2.52—2.55 (1H, m), 3.37 (3H, s),
3.52—3.59 (2H, m), 3.63 (3H, s), 3.62—3.73 (2H, m), 3.92, 4.06 (1H, each
br), 4.61 (2H, s), 4.87—4.92 (1H, br), 5.46—5.50 (1H, m), 5.61—5.68 (1H,
m), 7.37—7.45 (6H, m), 7.67—7.74 (4H, m); MS m/z: 567 (Mꢂ).
Methyl 6-(4-Hydroxybutyl)-2-(3-methoxymethoxypropyl)-3-methyl-
To a stirred solution of n-PrSH (0.51 ml, 5.63 mmol) in HMPA (2.5 ml)
was added a solution of n-BuLi (1.6 M in hexane, 3.3 ml, 5.35 mmol) at 0 °C,
and the reaction mixture was stirred at 0 °C for 30 min. To the reaction mix-
ture was added dropwise a solution of the above oil in THF (3 ml) via a dou-
piperidine-1-carboxylate (13) To
a stirred solution of 12 (1.08 g,
1.90 mmol) in EtOAc (20 ml) was added 10% Pd–C (100 mg), and the re-
sulting suspension was hydrogenated under hydrogen atmosphere at 1 atm

558
Vol. 53, No. 5
1
1088, 909 cmꢃ1; H-NMR (500 MHz) d 0.86 (3H, d, Jꢁ6.4 Hz), 0.98 (1H,
qd-like, Jꢁ14.1, 4.7 Hz), 1.20—2.09 (17H, br m), 3.26 (1H, t-like,
Jꢁ8.7 Hz), 4.93 (1H, dd, Jꢁ10.1, 2.2 Hz), 4.99 (1H, dd, Jꢁ17.1, 2.2 Hz),
5.76—5.84 (1H, m); 13C-NMR (75 MHz) d 18.96 (q), 20.42 (t), 25.21 (t),
29.13 (t), 31.29 (t), 33.72 (t), 34.12 (t), 34.16 (t), 36.60 (d), 51.87 (t), 63.36
(d), 71.32 (d), 114.31 (t), 138.69 (d); MS m/z: 207 (Mꢂ); [a]D26 ꢃ86.7°
(cꢁ2.64, CHCl3); lit.13) [a]D28 ꢃ86.5° (cꢁ0.95, CHCl3); lit.14) [a]D22.5
ꢃ103.2° (cꢁ0.47, CHCl3).
for 48 h. The catalyst was removed by filtration and the filtrate was evapo-
rated to give colorless oil, which was used directly in the next step.
To a stirred solution of the above oil in THF (8 ml) was added a solution
of TBAF (1 M in THF, 2.1 ml, 2.1 mmol) at 0 °C, and the mixture was stirred
at room temperature for 2 h. The reaction was quenched with satd. NH4Cl
(aq.), and the aqueous mixture was extracted with CHCl3 (10 mlꢄ7). The or-
ganic extracts were combined, dried, and evaporated to give colorless oil,
which was chromatographed on SiO2 (20 g, hexane : acetoneꢁ15 : 1—2 : 1)
to afford 13 (548 mg, 87%) as colorless oil.
Methyl 6-(4-Iodobutyl)-2-(3-methoxymethoxypropyl)-3-methylpiperi-
dine-1-carboxylate (15) To a stirred solution of 13 (257 mg, 0.78 mmol)
in CH2Cl2 (3 ml) were added triethylamine (0.41 ml, 2.95 mmol) and MsCl
(0.17 ml, 2.18 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for
30 min. The reaction was quenched with satd. NaHCO3 (aq.), and the aque-
ous mixture was extracted with CH2Cl2 (10 mlꢄ3). The organic extracts
were combined, dried, and evaporated to give pale yellow oil, which was
used directly in the next step.
IR (neat) 3442, 2941, 1672 cmꢃ1; 1H-NMR (500 MHz) d 0.91—0.93 (3H,
br), 1.09—1.87 (15H, br m), 2.86 (1H, br), 3.27 (3H, s), 3.43 (2H, br s), 3.50
(2H, br s), 3.58 (3H, s), 3.72—4.02 (2H, br), 4.52 (2H, s); 13C-NMR
(75 MHz) d 18.88 (q), 19.21 (t), 21.55 (t), 22.02 (t), 23.20 (t), 27.33 (t),
30.63 (d), 32.30 (t), 32.83 (t), 34.87 (t), 50.63 (d), 52.25 (q), 54.87 (d), 56.52
(d), 62.10 (t), 67.36 (t), 96.03 (t), 157.27 (s); MS m/z: 331 (Mꢂ); HR-MS
Calcd for C17H33NO5 331.2357, Found 331.2370; [a]D26 ꢃ11.2° (cꢁ0.82,
CHCl3).
To a stirred solution of the above oil in acetone (10 ml) was added NaI
(582 mg, 3.88 mmol), and the resulting mixture was heated at 50 °C for 2 h.
After cooling, the reaction was quenched with 10% Na2S2O3 in satd.
NaHCO3 (aq.), and the aqueous mixture was extracted with CH2Cl2
(15 mlꢄ3). The organic extracts were combined, dried, and evaporated to
give pale yellow oil, which was chromatographed on SiO2 (20 g,
hexane : acetoneꢁ30 : 1) to afford 15 (330 mg, 96%) as colorless oil.
Methyl 2-(3-Methoxymethoxypropyl)-3-methyl-6-pent-4-enylpiperi-
dine-1-carboxylate (14) To
a stirred solution of (COCl)2 (0.1 ml,
1.15 mmol) in CH2Cl2 (2 ml) was added DMSO (0.17 ml, 2.30 mmol) at
ꢃ78 °C, and the resulting solution was stirred at ꢃ78 °C for 5 min. To the
mixture was added dropwise a solution of 13 (150 mg, 0.45 mmol) in
CH2Cl2 (2 ml) via a double-tipped stainless steel needle. After the reaction
mixture was stirred for 30 min at ꢃ78 °C, triethylamine (0.5 ml, 3.45 mmol)
was added to the reaction mixture. The reaction mixture was warmed to 0 °C
for 1 h, and quenched with H2O. The aqueous mixture was extracted with
Et2O (10 mlꢄ3). The organic extracts were combined, dried, and evaporated
to give pale yellow oil, which was used directly in the next step.
IR (neat) 2944, 1701 cmꢃ1
; d 0.99 (3H, d,
1H-NMR (500 MHz)
Jꢁ7.2 Hz), 1.15—1.17 (1H, m), 1.32—1.89 (14H, br m), 3.17 (2H, t-like,
Jꢁ6.9 Hz), 3.34 (3H, s), 3.49—3.52 (2H, m), 3.66 (3H, s), 3.80 (1H, br),
4.08 (1H, br), 4.60 (2H, s); 13C-NMR (75 MHz) d 6.94 (t), 19.42 (q), 21.76
(t), 22.20 (t), 27.52 (t), 28.01 (t), 30.78 (d), 33.09 (t), 33.19 (t), 34.14 (t),
50.53 (d), 52.42 (q), 55.09 (q), 56.65 (d), 67.52 (t), 96.27 (t), 157.28 (s); MS
m/z: 441 (Mꢂ); HR-MS Calcd for C17H32INO4 441.1375, Found 441.1387;
[a]D26 ꢃ8.60° (cꢁ5.31, CHCl3).
To a stirred suspension of MePꢂPh3Iꢃ (915 mg, 2.27 mmol) in THF (8 ml)
was added a solution of n-BuLi (1.6 M in hexane, 1.27 ml, 2.04 mmol) at
0 °C, and the resulting orange solution was stirred at 0 °C for 10 min. To the
mixture was added dropwise a solution of the above aldehyde in THF (4 ml)
via a double-tipped stainless needle. The reaction was stirred at room tem-
perature for 17 h, and quenched with H2O. The aqueous mixture was ex-
tracted with Et2O (15 mlꢄ3). The organic extracts were combined, dried,
and evaporated to give pale yellow oil, which was chromatographed on SiO2
(20 g, hexane : acetoneꢁ100 : 1—20 : 1) to afford 14 (132 mg, 89%) as pale
yellow oil.
Methyl 2-(3-Methoxymethoxypropyl)-3-methyl-6-oct-7-enylpiperi-
dine-1-carboxylate (16) To
a stirred suspension of CuI (501 mg,
2.63 mmol) in THF (5 ml) was added a solution 1-butenylmagnesium bro-
mide in THF (prepared from 4-bromo-1-butene (0.53 ml, 5.26 mmol) and
magnesium (126 mg, 5.26 mmol) in THF (3 ml), reflux) at ꢃ40 °C, and the
reaction was stirred at ꢃ40—35 °C for 15 min. To the reaction mixture was
added 15 (290 mg, 0.66 mmol) in THF (4 ml) at the same temperature, and
the stirring was continued for 5 h. The reaction was quenched with satd.
NH4Cl (aq.), and the insoluble materials were filtered off. The filtrate was
extracted with CH2Cl2 (15 mlꢄ4). The organic extracts were combined,
dried, and evaporated to give pale yellow oil, which was chromatographed
on SiO2 (20 g, hexane : acetoneꢁ50 : 1—20 : 1) to afford 16 (220 mg, 91%)
as colorless oil.
IR (neat) 3071, 2940, 1694 cmꢃ1 1H-NMR (500 MHz) d 1.00 (3, d,
;
Jꢁ7 Hz), 1.12—1.19 (1H, m), 1.30—1.44 (3H, m), 1.45—1.63 (5H, br m),
1.71—1.89 (4H, m), 1.98—2.09 (2H, m), 3.34 (3H, s), 3.47—3.55 (2H, m),
3.66 (3H, s), 3.72—3.92 (1H, br), 4.03—4.13 (1H, br), 4.60 (2H, s), 4.93
(1H, dq-like, Jꢁ9.9, 1 Hz), 4.98 (1H, dq-like, Jꢁ16.1, 1.7 Hz), 5.78 (1H,
ddt, Jꢁ16.1, 9.9, 6.5 Hz); 13C-NMR (75 MHz) d 19.32 (q), 21.67 (t), 22.18
(t), 26.46 (t), 27.48 (t), 30.72 (d), 32.94 (t), 33.61 (t), 34.83 (t), 50.76 (d),
52.38 (q), 55.07 (q), 56.66 (d), 67.57 (t), 96.32 (t), 114.48 (t), 138.68 (d),
157.57 (s); MS m/z: 327 (Mꢂ); HR-MS Calcd for C18H33NO4 327.2408,
Found 327.2441; [a]D26 ꢃ10.9° (cꢁ0.95, CHCl3).
IR (neat) 3073, 2941, 1696 cmꢃ1 1H-NMR (500 MHz) d 0.97 (3H, d,
;
Jꢁ6.8 Hz), 1.11—1.58 (16H, br m), 1.72—1.84 (3H, m), 1.97—2.00 (2H,
m), 3.31 (3H, s), 3.45—3.51 (2H, m), 3.63 (3H, s), 3.80 (1H, br), 4.04 (1H,
br), 4.56 (2H, s), 4.88 (1H, dm, Jꢁ9.8 Hz), 4.94 (1H, dm, Jꢁ17 Hz), 5.71—
5.80 (1H, m); 13C-NMR (75 MHz) d 19.35 (q), 21.73 (t), 22.12 (t), 27.15 (t),
27.47 (t), 28.83 (t), 29.03 (t), 29.37 (t), 30.78 (d), 32.96 (t), 33.70 (t), 35.34
(t), 50.84 (d), 52.25 (q), 54.96 (q), 56.58 (d), 67.47 (t), 96.16 (t), 113.95 (t),
138.82 (d), 157.27 (s); MS m/z: 369 (Mꢂ); HR-MS Calcd for C21H39NO4
369.2877, Found 369.2871; [a]D26 ꢃ5.20° (cꢁ11.0, CHCl3).
8-Methyl-5-pent-4-enyloctahydro-indolizine (Indolizidine 207A, 3)
To a stirred solution of n-PrSH (0.38 ml, 4.20 mmol) in HMPA (2.5 ml) was
added a solution of n-BuLi (1.6 M in hexane, 2.5 ml, 4.02 mmol) at 0 °C, and
the reaction mixture was stirred at 0 °C for 30 min. To the reaction mixture
was added dropwise a solution of 14 (138 mg, 0.42 mmol) in THF (3 ml) via
a double-tipped stainless needle. The reaction was stirred at room tempera-
ture for 49 h, and quenched with 28% NH3 (aq.). The aqueous mixture was
extracted with Et2O (10 mlꢄ10), and the organic extracts were combined,
dried over K2CO3, and evaporated to give pale yellow oil, which was used
directly in the next step.
To a solution of the above oil in MeOH (5 ml) was added conc. HCl (5
drops), and the reaction mixture was heated at reflux for 1 h. After cooling,
the solvent was evaporated, and the residue was washed with Et2O. To the
residue was added 28% NH3 (aq.), and the aqueous mixture was extracted
with CHCl3 (10 mlꢄ10). The organic extracts were combined, dried over
K2CO3, and evaporated to give pale yellow oil, which was used directly in
the next step.
To a stirred solution of the above oil in CH2Cl2 (7 ml) were added CBr4
(195 mg, 0.59 mmol) and Ph3P (166 mg, 0.63 mmol) at 0 °C, and the result-
ing mixture was stirred at 0 °C for 1 h. To the reaction mixture was added
triethylamine (0.9 ml, 6.47 mmol), and the stirring was continued for 30 min
at room temperature. The volatiles were removed, and the residue was ex-
tracted with pentane (5 mlꢄ4). The solvent was evaporated to give pale or-
ange solid, which was chromatographed on SiO2 (20 g, hexane : acetoneꢁ
20 : 1) to afford 3 (55 mg, 63%) as pale yellow oil.
8-Methyl-5-oct-7-enyloctahydroindolizine (5) To a stirred solution of
n-PrSH (0.55 ml, 5.99 mmol) in HMPA (4 ml) was added a solution of n-
BuLi (1.6 M in hexane, 3.6 ml, 5.77 mmol) at 0 °C, and the reaction mixture
was stirred at 0 °C for 30 min. To the reaction mixture was added dropwise a
solution of 16 (220 mg, 0.60 mmol) in THF (6 ml) via a double-tipped stain-
less needle. The reaction was stirred at room temperature for 49 h, and
quenched with 28% NH3 (aq.). The aqueous mixture was extracted with
Et2O (10 mlꢄ10), and the organic extracts were combined, dried over
K2CO3, and evaporated to give pale yellow oil, which was used directly in
the next step.
To a solution of the above oil in MeOH (15 ml) was added conc. HCl (10
drops), and the reaction mixture was heated at reflux for 1 h. After cooling,
the solvent was evaporated, and the residue was washed with Et2O. To the
residue was added 28% NH3 (aq.), and the aqueous mixture was extracted
with CHCl3 (10 mlꢄ10). The organic extracts were combined, dried over
K2CO3, and evaporated to give pale yellow oil, which was used directly in
the next step.
To a stirred solution of the above oil in CH2Cl2 (10 ml) were added CBr4
(280 mg, 0.84 mmol) and Ph3P (237 mg, 0.90 mmol) at 0 °C, and the result-
ing mixture was stirred at 0 °C for 1 h. To the reaction mixture was added
triethylamine (1.33 ml, 9.66 mmol), and the stirring was continued for
IR (neat) 3074, 2933, 2872, 2775, 2701, 1642, 1455, 1336, 1242, 1165,

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559
To a stirred suspension of MePꢂPh3Iꢃ (700 mg, 1.74 mmol) in THF (8 ml)
was added a solution of n-BuLi (1.6 M in hexane, 1.04 ml, 1.67 mmol) at
0 °C, and the resulting orange solution was stirred at 0 °C for 10 min. To the
mixture was added dropwise a solution of the above aldehyde in THF (4 ml)
via a double-tipped stainless needle. The reaction was stirred at room tem-
perature for 22 h, and quenched with H2O. The aqueous mixture was ex-
tracted with Et2O (15 mlꢄ3). The organic extracts were combined, dried,
and evaporated to give pale yellow oil, which was chromatographed on SiO2
(20 g, hexane : acetoneꢁ60 : 1—20 : 1) to afford 19 (104 mg, 88%) as pale
yellow oil.
30 min at room temperature. The volatiles were removed, and the residue
was extracted with pentane (10 mlꢄ4). The solvent was evaporated to give
pale orange solid, which was chromatographed on SiO2 (20 g, hexane : ace-
toneꢁ20 : 1) to afford 5 (83 mg, 56%) as pale yellow oil.
IR (neat) 3077, 2936, 2870, 2779, 2702, 1640, 1455, 1332, 1243, 1166,
1133, 1109, 992, 907 cmꢃ1; 1H-NMR (500 MHz) d 0.85 (3H, d, Jꢁ6.4 Hz),
0.87—0.98 (1H, m), 1.17—1.54 (13H, br m), 1.58—1.66 (2H, m), 1.70—
1.85 (3H, br m), 1.84 (1H, m), 1.90—1.98 (2H, m), 2.01—2.05 (2H, m),
3.25 (1H, t-like, Jꢁ8.0 Hz), 4.91 (1H, dd, Jꢁ10.2, 2.2 Hz), 5.00 (1H, dd,
Jꢁ16.8, 2.2 Hz), 5.80 (1H, m); 13C-NMR (75 MHz) d 18.96 (q), 20.42 (t),
25.82 (t), 28.93 (t), 29.13 (two t), 29.95 (t), 31.29 (t), 33.74 (t), 33.83 (t),
34.66 (t), 36.62 (d), 51.86 (t), 63.51 (d), 71.31 (d), 114.00 (t), 138.98 (d);
MS m/z: 249 (Mꢂ); HR-MS Calcd for C17H31N 249.2455; Found 249.2450;
[a]D26 ꢃ73.1° (cꢁ3.44, CHCl3).
Methyl 6-[5-(tert-Butyldiphenylsilyloxy)pent-1-enyl]-2-(3-methoxy-
methoxypropyl)-3-methylpiperidine-1-carboxylate (17) To a stirred so-
lution of (COCl)2 (0.14 ml, 1.59 mmol) in CH2Cl2 (2 ml) was added DMSO
(0.22 ml, 3.18 mmol) at ꢃ78 °C, and the resulting solution was stirred at
ꢃ78 °C for 5 min. To the mixture was added dropwise a solution of 10
(300 mg, 1.04 mmol) in CH2Cl2 (2 ml) via a double-tipped stainless steel
needle. After the reaction mixture was stirred for 30 min at ꢃ78 °C, triethyl-
amine (0.64 ml, 4.77 mmol) was added to the reaction mixture. The reaction
mixture was warmed to 0 °C for 1 h, and quenched with H2O. The aqueous
mixture was extracted with Et2O (10 mlꢄ3). The organic extracts were com-
bined, dried, and evaporated to give pale yellow oil, which was used directly
in the next step.
IR (neat) 3071, 2942, 1692 cmꢃ1 1H-NMR (500 MHz) d 1.00 (3H, d,
;
Jꢁ6.8 Hz), 1.13—1.85 (15H, br m), 2.03 (2H, q-like, Jꢁ7.3 Hz), 3.34 (3H,
s), 3.48—3.54 (2H, m), 3.66 (3H, s), 3.80 (1H, br), 4.07 (1H, br), 4.60 (2H,
s), 4.91 (1H, d-like, Jꢁ10.3 Hz), 4.99 (1H, d-like, Jꢁ15 Hz), 5.74—5.82
(1H, m); 13C-NMR (75 MHz) d 19.42 (q), 21.78 (t), 22.17 (t), 26.71 (t),
27.54 (t), 28.80 (t), 30.81 (d), 33.04 (t), 33.70 (t), 35.19 (t), 50.87 (d), 52.34
(q), 55.06 (q), 56.66 (t), 96.24 (t), 114.18 (t), 138.71 (d), 157.35 (s); MS
m/z: 341 (Mꢂ); HR-MS Calcd for C19H35NO4 341.2564, Found 341.2573;
[a]D26 ꢃ5.2° (cꢁ3.93, CHCl3).
5-Hex-5-enyl-8-methyloctahydroindolizine (4) To a stirred solution of
n-PrSH (0.35 ml, 3.81 mmol) in HMPA (2.5 ml) was added a solution of n-
BuLi (1.6 M in hexane, 2.3 ml, 3.63 mmol) at 0 °C, and the reaction mixture
was stirred at 0 °C for 30 min. To the reaction mixture was added dropwise a
solution of 19 (130 mg, 0.38 mmol) in THF (3 ml) via a double-tipped stain-
less needle. The reaction was stirred at room temperature for 49 h, and
quenched with 28% NH3 (aq.). The aqueous mixture was extracted with
Et2O (10 mlꢄ10), and the organic extracts were combined, dried over
K2CO3, and evaporated to give pale yellow oil, which was used directly in
the next step.
To a solution of the above oil in MeOH (6 ml) was added conc. HCl (8
drops), and the reaction mixture was heated at reflux for 1 h. After cooling,
the solvent was evaporated, and the residue was washed with Et2O. To the
residue was added 28% NH3 (aq.), and the aqueous mixture was extracted
with CHCl3 (10 mlꢄ10). The organic extracts were combined, dried over
K2CO3, and evaporated to give pale yellow oil, which was used directly in
the next step.
To a stirred solution of the above oil in CH2Cl2 (6 ml) were added CBr4
(177 mg, 0.53 mmol) and Ph3P (150 mg, 0.57 mmol) at 0 °C, and the result-
ing mixture was stirred at 0 °C for 1 h. To the reaction mixture was added
triethylamine (0.84 ml, 6.10 mmol), and the stirring was continued for
30 min at room temperature. The volatiles were removed, and the residue
was extracted with pentane (5 mlꢄ4). The solvent was evaporated to give
pale orange solid, which was chromatographed on SiO2 (20 g, hexane : ace-
toneꢁ20 : 1) to afford 4 (43 mg, 51%) as pale yellow oil.
To a stirred suspension of TBDPSO(CH2)4PꢂPh3Brꢃ (2.72 g, 4.16 mmol)
in THF (18 ml) was added a solution of n-BuLi (1.6 M in hexane, 2.5 ml,
3.95 mmol) at 0 °C, and the resulting orange solution was stirred at 0 °C for
10 min. To the mixture was added dropwise a solution of the above aldehyde
in THF (4 ml) via a double-tipped stainless needle. The reaction was stirred
at room temperature for 21 h, and quenched with H2O. The aqueous mixture
was extracted with Et2O (15 mlꢄ3). The organic extracts were combined,
dried, and evaporated to give pale yellow oil, which was chromatographed
on SiO2 (20 g, hexane : acetoneꢁ60 : 1—20 : 1) to afford 17 (584 mg, 97%)
as pale yellow oil.
IR (neat) 2952, 1692 cmꢃ1
; d 1.03 (3H, d,
1H-NMR (500 MHz)
Jꢁ7.3 Hz), 1.07 (9H, s), 1.17—1.22 (1H, m), 1.27—1.33 (1H, m), 1.55—
1.93 (9H, br m), 2.17—2.23 (1H, m), 2.29—2.35 (1H, m), 3.37 (3H, s),
3.49—3.57 (2h, m), 3.63 (3H, s), 3.69 (2H, t-like, Jꢁ6.4 Hz), 3.92 (1H, br),
4.62 (2H, s), 4.96 (1h, br), 5.35—5.40 (1H, m), 5.56—5.60 (1H, m), 7.38—
7.45 (6H, m), 7.68—7.74 (4H, m); MS m/z: 581 (Mꢂ).
Methyl 6-(5-Hydroxypentyl)-2-(3-methoxymethoxypropyl)-3-methyl-
piperidine-1-carboxylate (18) To
a stirred solution of 17 (581 mg,
1 mmol) in EtOAc (20 ml) was added 10% Pd–C (100 mg), and the resulting
suspension was hydrogenated under hydrogen atmosphere at 1 atm for 48 h.
The catalyst was removed by filtration and the filtrate was evaporated to give
colorless oil, which was used directly in the next step.
IR (neat) 3076, 2935, 2871, 2776, 2702, 1642, 1458, 1334, 1243, 1165,
1132, 1108, 1088, 992, 909 cmꢃ1 1H-NMR (500 MHz) d 0.86 (3H, d,
;
Jꢁ6.3 Hz), 0.93—0.98 (1H, m), 1.20—2.08 (19H, br m), 3.30 (1H, t-like,
Jꢁ8.8 Hz), 4.91 (1H, dm, Jꢁ10.1 Hz), 4.99 (1H, dm, Jꢁ17.1 Hz), 5.73—
5.86 (1H, m); 13C-NMR (75 MHz) d 18.95 (q), 20.36 (t), 25.39 (t), 28.98 (t),
29.32 (t), 31.05 (t), 33.62 (t), 33.78 (t), 34.27 (d), 51.78 (t), 63.67 (d), 71.48
(d), 114.25 (t), 138.84 (d); MS m/z: 221 (Mꢂ); HR-MS Calcd for C15H27N
221.2142; Found 221.2157; [a]D26 ꢃ103.9° (cꢁ0.60, CHCl3).
To a stirred solution of the above oil in THF (8 ml) was added a solution
of TBAF (1 M in THF, 1.1 ml, 1.1 mmol) at 0 °C, and the mixture was stirred
at room temperature for 2 h. The reaction was quenched with satd. NH4Cl
(aq.), and the aqueous mixture was extracted with CHCl3 (10 mlꢄ7). The or-
ganic extracts were combined, dried, and evaporated to give colorless oil,
which was chromatographed on SiO2 (20 g, hexane : acetoneꢁ15 : 1—2 : 1)
to afford 18 (246 mg, 74%) as colorless oil.
Acknowledgments We are grateful to Drs. Jhon W. Daly, Thomas F.
Spande, and H. Martin Garraffo, NIH, for comparison of synthetic 237D
with natural product. This work was supported in part by The Research
Foundation for Pharmaceutical Sciences.
IR (neat) 3444, 2945, 1678 cmꢃ1 1H-NMR (500 MHz) d 0.96 (3H, d,
;
Jꢁ6.9 Hz), 1.12—1.83 (16H, br m), 2.43 (1H, br), 3.31 (3H, s), 3.47 (2H,
m), 3.56 (2H, t-like, Jꢁ6.6 Hz), 3.62 (3H, s), 3.80 (1H, br), 4.06 (1H, br),
4.56 (2H, s); 13C-NMR (75 MHz) d 19.35 (q), 21.70 (t), 22.22 (t), 25.47 (t),
26.75 (t), 27.47 (t), 30.78 (d), 32.54 (t), 32.96 (t), 35.26 (t), 50.64 (d), 52.38
(q), 55.03 (q), 56.65 (d), 62.46 (t), 67.52 (t), 96.19 (t), 157.40 (s); MS m/z:
345 (Mꢂ); HR-MS Calcd for C18H35NO5 345.2513; Found 345.2533; [a]D26
ꢃ9.0° (cꢁ4.71, CHCl3).
References and Notes
1) Daly J. W., J. Med. Chem., 46, 445—452 (2003).
2) Daly J. W., Garraffo H. M., Spande T. F., “Alkaloids: Chemical and Bi-
ological Perspective,” Vol. 13, ed. by Pelletier S. W., Pergamon Press,
New York, 1999, pp. 1—161.
Methyl 6-Hex-5-enyl-2-(3-methoxymethoxypropyl)-3-methylpiperi-
3) Daly J. W., “The Alkaloids,” Vol. 50, ed. by Cordell G. A., Academic
Press, New York, 1998, pp. 141—169.
dine-1-carboxylate (19) To
a stirred solution of (COCl)2 (0.1 ml,
1.15 mmol) in CH2Cl2 (2 ml) was added DMSO (0.17 ml, 2.30 mmol) at
ꢃ78 °C, and the resulting solution was stirred at ꢃ78 °C for 5 min. To the
mixture was added dropwise a solution of 18 (120 mg, 0.35 mmol) in
CH2Cl2 (2 ml) via a double-tipped stainless steel needle. After the reaction
mixture was stirred for 30 min at ꢃ78 °C, triethylamine (0.5 ml, 3.45 mmol)
was added to the reaction mixture. The reaction mixture was warmed to 0 °C
for 1 h, and quenched with H2O. The aqueous mixture was extracted with
Et2O (10 mlꢄ3). The organic extracts were combined, dried, and evaporated
to give pale yellow oil, which was used directly in the next step.
4) Tsuneki H., You Y., Toyooka N., Kagawa S., Kobayashi S., Sasaoka T.,
Nemoto H., Kimura I., Dani J. A., Mol. Pharmacol., 66, 1061—1069
(2004).
5) Chavez-Noriega L. E., Crona J. H., Washburn M. S., Urrutia A., Elliott
K. L., Johnson E. C., J. Pharmacol. Exp. Ther., 280, 346—356 (1997).
6) Toyooka N., Nemoto H., “Studies in Natural Products Chemistry,” Vol.
29, ed. by Atta-ur-Rahman, Elsevier, Amsterdam, 2003, pp. 419—448.
7) Toyooka N., Nemoto H., Recent Res. Devel. Organic Chem., 6, 611—
624 (2002).

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