Enantioselective total synthesis of the macrocyclic spermidine alkaloid (-)-oncinotine

Article abstract of DOI:10.1021/jo9518258

The macrocyclic spermidine alkaloid (-)-oncinotine (1), isolated from Oncinotis nitida (Apocynaceae), was synthesized enantioselectively for the first time based on intramolecular iminium ion cyclization utilizing enantiomerically pure (2S)-N-[(benzyloxy)

Full text of DOI:10.1021/jo9518258

J . Org. Chem. 1996, 61, 1023-1029
1023
En a n tioselective Tota l Syn th esis of th e Ma cr ocyclic Sp er m id in e
Alk a loid (-)-On cin otin e
Hiroji Ina, Masayuki Ito, and Chihiro Kibayashi*
School of Pharmacy, Tokyo University of Pharmacy & Life Science,
Horinouchi, Hachioji, Tokyo 192-03, J apan
Received October 10, 1995X
The macrocyclic spermidine alkaloid (-)-oncinotine (1), isolated from Oncinotis nitida (Apocynaceae),
was synthesized enantioselectively for the first time based on intramolecular iminium ion cyclization
utilizing enantiomerically pure (2S)-N-[(benzyloxy)carbonyl]-2-piperidineacetaldehyde (8) as a chiral
starting material. The required 8 was derived from the erythro adduct 16, which was obtained by
diastereoselective 1,3-dipolar cycloaddition between 2,3,4,5-tetrahydropyridine 1-oxide (4) and (3S)-
3-[(tert-butyldiphenylsilyl)oxy]-4-methyl-1-pentene (15). Wittig condensation of 8 with [8-(meth-
oxycarbonyl)octyl]triphenylphosphonium iodide (21) followed by saponification provided the chiral
piperidine moiety 23, which was coupled with the N-propyl-1,4-butanediamine segment 29 by using
diethoxyphosphoryl cyanide in the presence of triethylamine to afford the tertiary amide 30.
Conversion of 30 to the aldehyde 34 via desilylation and Swern oxidation, followed by hydrogenation
over a palladium hydroxide catalyst under high dilution led to in situ formation of the transient
iminium ion 35, which was further hydrogenated to form 33 in a single operation. Subsequent
removal of the Boc protecting group resulted in (-)-oncinotine (1).
In tr od u ction
(-)-Oncinotine (1), (-)-neooncinotine (2), and (-)-
isooncinotine (3), isolated from the stem bark of Oncinotis
nitida (Apocynaceae),1,2 are a group of isomeric polyamine
alkaloids which are characterized by macrocyclic lactams
containing the biogenetic base spermidine.3 Since onci-
notine (1) and neooncinotine (2) are not easily separated,
whereas isolation of isooncinotine (3) can be readily
achieved, pure oncinotine was obtained by treating the
natural mixture of 1 and 2 with potassium tert-butoxide;
under these conditions neooncinotine can be completely
converted into isooncinotine with oncinotine unchanged.2
Degradation and spectroscopic analysis established the
structures of these three bicyclic spermidine alkaloids.
In these structure elucidation studies the absolute con-
the cycloadducts 6 as major isomer, which can be
converted to (R)-(-)-coniine (9) via enantiomerically pure
(2S)-N-[(benzyloxy)carbonyl]-2-piperidineacetaldehyde (8)
(Scheme 1). In this paper we detail the first enantio-
selective total synthesis of (-)-oncinotine (1) utilizing 8
as a chiral starting material based on a new approach
involving macrocyclization to the 17-membered ring by
intramolecular N-alkylation via an iminium ion inter-
mediate.8 Our synthesis unambiguously confirmed the
absolute configuration of (-)-oncinotine to be 17R as
earlier proposed.
figuration of the alkaloids was deduced to be R as
depicted in structures 1-3 by means of the CD measure-
ment by relating the degradation product to (R)-(-)-N-
methylconiine.2 These three alkaloids have been syn-
thesized in racemic form by Hesse, Schmid, and co-
workers,4,5 and more recently a new synthetic route to
racemic oncinotine has been reported by Hesse et al.6
However, no report on the chiral synthesis of these
spermidine alkaloids has appeared.
We have recently demonstrated7 that 1,3-dipolar cy-
cloaddition of chiral allyl ethers 5 to a cyclic nitrone 4
proceeds with erythro (with respect to C-2-O and C-1′-
O) selectivity due to an “inside alkoxy effect” to afford
Resu lts a n d Discu ssion
The construction of macrocyclic lactam rings has been
a pivotal object in the total synthesis of macrocyclic
lactam alkaloids, which in many cases has been per-
formed by intramolecular amidation.3,9 As outlined in
Scheme 2, our synthetic strategy toward the framework
X Abstract published in Advance ACS Abstracts, J anuary 15, 1996.
(1) Badawi, M. M.; Guggisberg, A.; van den Broek, P.; Hesse, M.;
Schmid, H. Helv. Chim. Acta 1968, 51, 1813.
(2) Guggisberg, A.; Badawi, M. M.; Hesse, M.; Schmid, H. Helv.
Chim. Acta 1974, 57, 414.
(3) For reviews of macrocyclic spermidine alkaloids, see: (a) Mat-
suyama, H. Yuki Gosei Kagaku Kyokaishi 1981, 39, 1151. (b) Wasser-
man, H. H.; Wu, J . S. Heterocycles 1982, 17, 581. (c) Guggisberg, A.;
Hesse, M. In The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando,
1983; Vol. 22, Chapter 3, p 85.
(4) Schneider, F.; Bernauer, K.; Guggisberg, A.; van den Broek, P.;
Hesse, M; Schmid, H. Helv. Chim. Acta 1974, 57, 434.
(5) Guggisberg, A.; van den Broek, A.; Hesse, M.; Schmid, H.;
Schneider, F.; Bernauer, K. Helv. Chim. Acta 1976, 59, 3013.
(6) Bienz, S.; Guggisberg, A.; Walchli, R.; Hesse, M. Helv. Chim.
Acta 1988, 71, 1708.
(7) Ito, M.; Maeda, M.; Kibayashi, C. Tetrahedron Lett. 1992, 33,
3765. For inside alkoxy effect in the nitrone cycloaddition, see also:
Ito, M.; Kibayashi, C. Tetrahedron Lett. 1991, 32, 1659.
(8) For a preliminary account of this work, see: Ina, H.; Ito, M.;
Kibayashi, C. J . Chem. Soc., Chem. Commun. 1995, 1015.
(9) For a recent review of ring closure methods in the synthesis of
macrocyclic natural products, see: Meng, Q.; Hesse, M. Top. Curr.
Chem. 1992, 161, 107.
0022-3263/96/1961-1023$12.00/0 © 1996 American Chemical Society

1024 J . Org. Chem., Vol. 61, No. 3, 1996
Ina et al.
Sch em e 1
Sch em e 3
Sch em e 2
size of the alkyl substituent attached to the allylic chiral
center. On the basis of this protocol, we employed as a
dipolarophile the (S)-allyl ether 15 bearing the isopropyl
group which provides the increased erythro selectivity
as well as better yield for cycloaddition. The preparation
of 15 (see Scheme 3) began with ethyl (S)-2-hydroxy-3-
methylbutanoate (12), prepared in two steps (NaNO2, H2-
SO4, and then esterification) from L-valine.11 After the
hydroxy group of 12 was protected as the tert-butyldiphe-
nylsilyl ether, the resulting ester 13 was subjected to
reduction with DIBALH providing the aldehyde 14 in
89% overall yield. To avoid racemization of the chiral
center adjacent to the formyl group, methylenation of 14
was performed under mild, nonbasic conditions.12 Thus,
a dichloromethane solution of 14 was treated with a THF
solution of the Zn-CH2Br2-TiCl4 reagent13 to give the
(S)-allyl ether 15 in 75% yield. When heated with an
excess of 2,3,4,5-tetrahydropyridine 1-oxide (4)14 in tolu-
ene, 15 underwent [3 + 2] cycloaddition to afford a 93:7
mixture (determined by HPLC) of the erythro and threo
bicyclic oxazolidines 16 and 17 in favor of 16 in 85%
combined yield. This mixture was separated by column
chromatography on silica gel, and the pure erythro isomer
16 was obtained in 69% yield. The NMR analysis showed
that compound 16 exists as a 4.5:1 mixture of two
conformers at ambient temperature, probably due to
pyramidal inversion at the ring nitrogen.
of (-)-oncinotine (1) is based upon a disconnection of the
carbon-nitrogen bond between C-2 and N-1 of the 17-
membered lactam ring. This disconnective analysis
illustrates the crucial intramolecular iminium ion cy-
clization step for macrocyclic lactam formation which has
previously been developed in this laboratory for the
synthesis of the monocyclic spermidine alkaloid dihydro-
periphyline.10 Precursor 10, with two interacting sites
for facile iminium ion formation, can be obtained from
(S)-2-piperidineacetaldehyde (8) which is available ac-
cording to the nitrone cycloaddition protocol described
above in Scheme 1.
The silyl protecting group in 16 was subsequently
removed to yield 18 (86% yield) which was also found to
exist as a 2:1 conformational mixture (by NMR analysis).
Hydrogenolytic cleavage of the N-O bond in 18 with
hydrogen and a palladium(II) chloride catalyst at 6.5 atm
Prior studies7 in this laboratory on the nitrone cyclo-
addition with chiral allyl ethers demonstrated that the
erythro selectivity was remarkably dependent upon the
(11) Vigneron, J . P.; Dhaenens, M.; Horeau, A. Tetrahedron 1977,
33, 507.
(12) Cf. Ito, M.; Kibayashi, C. Synthesis 1993, 137.
(13) Takai, K.; Hotta, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1978, 2417.
(10) Kaseda, T.; Kikuchi, T.; Kibayashi, C. Tetrahedron Lett. 1989,
30, 4539.
(14) Prepared according to: Murahashi, S.; Shiota, T. Tetrahedron
Lett. 1987, 28, 5223.

Enantioselective Total Synthesis of (-)-Oncinotine
J . Org. Chem., Vol. 61, No. 3, 1996 1025
Sch em e 4
Sch em e 6
Sch em e 5
provided the amino alcohol 19, which was converted to
the benzyl carbamate 20 (77% yield from 18) by treat-
ment with 2.5 equiv of benzyl chloroformate in aqueous
Na2CO3 and subsequent ester hydrolysis by prolonged
stirring of the reaction mixture. Cleavage of the glycol
in 20 by oxidation with periodic acid resulted in the
aldehyde 8 in 84% yield (Scheme 4).
The nine-carbon homologation was performed by Wit-
tig condensation of 8 with [8-(methoxycarbonyl)octyl]-
triphenylphosphorane (from the phosphonium salt 21
and t-BuOK)15 followed by saponification with KOH in
methanol which afforded the unsaturated carboxylic acid
23 in 54% overall yield (Scheme 5). To construct the
spermidine moiety, the N-propyl-1,4-butanediamine seg-
ment was prepared via a straightforward sequence as
shown in Scheme 6. Thus, N-alkylation of 3-amino-1-
propanol (24) with N-Boc protected 4-bromobutylamine
25 produced 26 in 52% yield, which immediately under-
went N-protection with benzyl chloroformate to yield the
carbamate 27 (88% yield). Subsequent silylation of the
alcohol function followed by hydrogenolytic removal of
the Cbz group over palladium hydroxide converted 27 to
29 in 78% overall yield. This N-propyl-1,4-butanedi-
amine segment 29 was coupled with the chiral piperidine
23 by using diethoxyphosphoryl cyanide16 in the presence
of triethylamine in DMF to furnish the tertiary amide
30 in 95% yield. In an attempt to construct the 17-
membered framework of oncinotine by intramolecular
N-alkylation, 30 was desilylated to give 31, which was
converted by catalytic hydrogenation to the amino alcohol
32, a linear bifunctional precursor. This amino alcohol
was immediately treated under Mitsunobu conditions17
or an intramolecular N-alkylation procedure utilizing
PPh3-CBr4.18 However, these and other attempted C-N
coupling methods under high dilution were all sluggish
and did not result in the desired N-Boc oncinotine (33).
For an alternative solution to macrocyclic ring forma-
tion, we envisaged to utilize a bifunctional precursor with
amino and formyl groups in the molecule, which can
readily combine to generate an iminium ion. Accordingly,
the alcohol 31 was converted to the aldehyde 34 in 72%
yield by oxidation with the Swern reagent.19 Compound
34 was then treated with hydrogen over a palladium
hydroxide catalyst under high dilution (4 × 10-3 M in
MeOH) conditions. As shown in Scheme 7 during this
reaction, hydrogenation of the alkene and deprotection
of the amine took place, leading to in situ formation of
the transient iminium ion 35, which was further hydro-
genated to form 33 in a single operation in 66% yield.
The synthesis was completed by removal of the Boc
(15) Gunn, B. P. Heterocycles 1985, 23, 3061.
(16) Yamada, S.; Kasai, Y.; Shioiri, T. Tetrahedron Lett. 1973, 1595.
(17) Mitsunobu, O. Synthesis 1981, 1.
(18) Shishido, Y.; Kibayashi, C. J . Org. Chem. 1992, 57, 2876.
(19) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480.

1026 J . Org. Chem., Vol. 61, No. 3, 1996
Ina et al.
1H NMR spectra were run at 300, 400, or 500 MHz. 13C NMR
spectra were determined at 75, 100, or 125 MHz. Chemical
shifts were reported in δ scale relative to CHCl3 as an internal
reference (7.26 ppm for 1H and 77.0 ppm for 13C), unless
otherwise indicated. MeOH (3.35 ppm for 1H and 49.0 ppm
for 13C), DOH (4.75 ppm for 1H), and dioxane (67.4 ppm for
13C) were occasionally used as internal references. Peak
assignments of 13C NMR spectra were confirmed by DEPT
experiments. Mass spectra were measured at 70 eV. HPLC
analyses were performed using a Sim-pak silica gel column
(6.0 × 150 mm) with detection at 254 nm and hexane-EtOAc
(3:1) as eluent at flow rate of 1 mL/min. TLC was performed
on precoated silica gel 60 F 254 plates (Merck) and silica gel
60 (230-400 mesh) (Merck) was used for column chromatog-
raphy. Microanalyses were carried out by the Microanalytical
Laboratory at Tokyo University of Pharmacy & Life Science.
E t h yl (2S)-2-[(ter t-Bu t yld ip h en ylsilyl)oxy]-3-m et h yl-
bu ta n oa te (13). To a solution of ethyl (2S)-2-hydroxy-3-
methylbutanoate (12)11 (2.22 g, 15.2 mmol) in DMF (20 mL)
were added imidazole (1.24 g, 18.2 mmol) and tert-butyldiphe-
nylsilyl chloride (5.00 g, 18.2 mmol), and the mixture was
stirred at 80 °C. After being stirred for 7 h, the mixture was
diluted with water (60 mL) and extracted with CH2Cl2 (3 ×
60 mL). The combined extracts were washed with brine, dried
(MgSO4), and concentrated in vacuo. Column chromatography
Sch em e 7
on silica gel (hexane) gave 13 (5.40 g, 92%) as a colorless oil:
1
[R]26 -37.4° (c 1.47, CHCl3); H NMR (CDCl3) δ 0.93 (3H, d,
D
J ) 6.7 Hz), 0.95 (3H, d, J ) 6.7 Hz), 1.12 (9H, s), 1.04 (3H, t,
J ) 7.2 Hz), 2.03 (1H, d quint, J ) 6.7, 4.7 Hz), 3.83 (2H, dq,
J ) 7.2, 4.0 Hz), 4.06 (1H, d, J ) 4.7 Hz), 7.32-7.45 (6H, m),
7.63-7.70 (4H, m); 13C NMR (CDCl3) δ 14.1, 17.6, 18.7, 19.7,
27.1 (3 carbons), 33.5, 60.2, 77.8, 127.4 (2 carbons), 127.6 (2
carbons), 129.7, 129.8, 133.7, 135.8, 136.0 (2 carbons), 136.2
(2 carbons), 172.6; CIMS (isobutane) m/ z (rel intensity) 384
(M+, 0.13), 307 (100). Anal. Calcd for C23H32O3Si: C, 71.83;
H, 8.39. Found: C, 71.72; H, 8.33.
(2S )-2-[(t e r t -B u t y ld i p h e n y ls i ly l)o x y ]-3-m e t h y l-
bu ta n a l (14). To a stirred, cold (-85 °C) solution of 13 (211
mg, 0.584 mmol) in Et2O (5 mL) under Ar was added via
syringe a 0.94 M solution of DIBALH (0.64 mL, 0.60 mmol) in
hexane, and stirring was continued at -85 °C. After 6 h, the
mixture was quenched by addition of water (0.5 mL) and
allowed to warm to rt. The precipitate was removed by
filtration through a Celite pad and thoroughly rinsed with
Et2O, and the filtrate was washed with brine and dried
(MgSO4). After removal of the solvent, the residue was
purified by column chromatography on silica gel (hexane) to
protecting group. Thus, treatment of 33 with methanolic
HCl resulted in (-)-oncinotine (1) in 71% yield. The
synthetic material had optical rotations, [R]26 -28.7° (c
D
2.6, CHCl3) and [R]26D -32.7° (c 2.1, MeOH), and spectral
data (IR and MS) consistent with those recorded1,2 for
the natural alkaloid ([R]D -29° (CHCl3) and [R]D -33°
give 14 (181 mg, 97%) as a colorless oil: [R]26 -35.1° (c 1.30,
D
CHCl3); 1H NMR (CDCl3) δ 0.94 (3H, d, J ) 6.9 Hz), 0.95 (3H,
d, J ) 6.9 Hz), 1.13 (9H, s), 2.01 (1H, d quint, J ) 6.9, 4.3 Hz),
3.86 (1H, dd, J ) 4.3, 2.1 Hz), 7.34-7.46 (6H, m), 7.62-7.65
(4H, m), 9.54 (1H, d, J ) 2.1 Hz); 13C NMR (CDCl3) δ 17.1,
18.4, 19.6, 27.1 (3 carbons), 32.6, 82.4, 127.8 (4 carbons), 130.0
(2 carbons), 133.8, 135.9 (5 carbons), 204.5.
1
(MeOH)). Furthermore, the H and 13C NMR spectra of
the hydrochloride salt 1‚2HCl of the synthetic sample
were identical with those of the hydrochloride salt of
racemic oncinotine.6
In summary, the first chiral total synthesis of (-)-
oncinotine utilizing enantioselectively prepared 8 has
been accomplished, confirming the previously assigned
absolute configuration of natural alkaloid. The required
chiral center in the piperidine fragment (C-17 in onci-
notine) could be set by diastereoselective nitrone 1,3-
dipolar cycloaddition with the (S)-allyl ether 15 as a
dipolarophile. The central 17-membered macrocyclic
framework was efficiently achieved based on an iminium
ion cyclization of the reactive linear precursor possessing
amino and formyl groups at both the ends, which was
generated from 34 during catalytic hydrogenation. This
iminium ion cyclization strategy should prove useful as
a means for preparing other macrocyclic spermidine
alkaloids.
(3S)-3-[(ter t-Bu t yld ip h en ylsilyl)oxy]-4-m et h yl-1-p en -
ten e (15). To a stirred, cold (-40 °C) suspension of the Zn-
CH2Br2-TiCl4 reagent in THF (16 mL), prepared from zinc
dust (1.84 g, 28.1 mmol), dibromomethane (1.59 g, 9.15 mmol),
and TiCl4 (1.28 g, 6.75 mmol), according to the literature,13
was added a solution of 14 (2.31 g, 6.78 mmol) in CH2Cl2 (25
mL) under Ar, and the mixture was stirred at rt for 2 h. After
dilution of the mixture with hexane (20 mL), a suspension of
Na2CO3 (30 g) in water (20 mL) was added to the mixture and
stirring was continued for an additional 2 h at rt. The solid
was filtered and rinsed with Et2O (100 mL). The filtrate was
washed with water, dried (MgSO4), and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (hexane-EtOAc, 100:1) to give 15 (1.73 g, 75%) as a
colorless oil: [R]28D +22.8° (c 0.18, CHCl3); 1H NMR (CDCl3) δ
0.79 (3H, d, J ) 6.9 Hz), 0.85 (3H, d, J ) 6.8 Hz), 1.07 (9H, s),
1.71 (1H, m), 3.96 (1H, t, J ) 6.9 Hz), 4.88 (1H, d, J ) 17.3
Hz), 4.96 (1H, d, J ) 10.4 Hz), 5.77 (1H, ddd, J ) 17.3, 10.4,
6.9 Hz), 7.32-7.43 (6H, m), 7.65-7.70 (4H, m); 13C NMR
(CDCl3) δ 17.0, 18.3, 19.5, 27.1 (3 carbons), 34.3, 79.7, 115.7,
127.3 (2 carbons), 127.4 (2 carbons), 129.4, 129.5, 134.6, 136.0
(2 carbons), 136.1 (3 carbons), 138.2; CIMS (isobutane) m/ z
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected.
Optical rotations were measured on a digital polarimeter in a
1-dm cell. IR spectra were recorded on an FTIR instrument.

Enantioselective Total Synthesis of (-)-Oncinotine
J . Org. Chem., Vol. 61, No. 3, 1996 1027
(rel intensity) 339 (M+ + 1, 0.4), 281 (100). Anal. Calcd for
C22H30OSi: C, 78.05; H, 8.93. Found: C, 78.05; H, 9.02.
Cycloa d d ition Rea ction of th e Nitr on e 4 w ith th e (S)-
Allyl Eth er 15. A solution containing 4 (2.51 g, 25.4 mmol)
and 15 (857 mg, 2.54 mmol) in toluene (25 mL) was refluxed
under Ar for 14 h. The mixture was diluted with benzene (30
mL), washed with brine, and dried (MgSO4). After removal
of the solvent by evaporation, the product was purified by silica
gel chromatography (hexane-AcOEt, 20:1) to yield an oily
mixture (942 mg, 85%) of [2R,2(1S),3aS]-2-[1-[(tert-butyldi-
phenylsilyl)oxy]-2-methylpropyl]-3,3a,4,5,6,7-hexahydro-2H-
isoxazolo[2,3-a]pyridine (16) and [2R,2(1S),3aR]-2-[1-[(tert-
butyldiphenylsilyl)oxy]-2-methylpropyl]-3,3a,4,5,6,7-hexahydro-
2H-isoxazolo[2,3-a]pyridine (17) in a 93:7 ratio (by HPLC
analysis), which was separated by further chromatography on
a silica gel column (hexane-EtOAc, 40:1). The first fractions
contained 17 (44 mg, 4%) as a colorless oil: 1H NMR (CDCl3)
δ 0.89 (3H, d, J ) 7.0 Hz), 0.92 (3H, d, J ) 7.0 Hz), 1.05 (9H,
s), 1.23-1.78 (8H, m), 1.94 (1H, m), 2.07 (1H, m), 2.29 and
2.56 (total 1H in 3.5:1 ratio, each m), 2.87 and 3.29 (total 1H
in 1:3.5 ratio, m and br s, respectively), 3.72 (1H, m), 4.01 (1H,
q, J ) 7.0 Hz), 7.34-7.44 (6H, m), 7.69-7.77 (4H, m); 13C NMR
(CDCl3) for the major conformer δ 16.9, 18.6, 23.7, 24.7, 27.2
(3 carbons), 29.1, 29.7, 31.7, 39.7, 55.3, 67.3, 76.2, 80.6, 127.8
(4 carbons), 129.7 (2 carbons), 134.9 (2 carbons), 136.2 (2
carbons), 136.3 (2 carbons); for the minor conformer δ 19.1,
19.9, 23.7, 24.7, 27.2 (3 carbons), 29.1, 29.7, 32.0, 39.7, 55.3,
67.3, 76.2, 80.6, 127.4 (2 carbons), 127.5 (2 carbons), 129.4,
129.5, 134.4, 135.3, 136.2 (2 carbons), 136.3 (2 carbons).
The second fractions yielded 16 (765 mg, 69%) as a colorless
hydrogenated at 6.5 atm for 37 h. After filtration of the
catalyst, the solvent was evaporated in vacuo to give [2S,2-
(2R),2(3S)]-2-(2,3-dihydroxy-4-methylpentyl)piperidine (19) (1.25
g, 91%) as a colorless oil, which was dissolved in CH2Cl2 (15
mL), and a solution of Na2CO3 (3.30 g, 31.1 mmol) in water
(25 mL) was added. This mixture was stirred and cooled (0
°C), and a solution of benzyl chloroformate (2.67 g, 15.6 mmol)
in CH2Cl2 (15 mL) was added dropwise. After continuation of
stirring at rt for 14 h, water (15 mL) was added and the organic
layer was separated. The aqueous layer was extracted with
CHCl3 (3 × 20 mL), and the combined organic layers were
washed with water, dried (MgSO4), and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (hexane-EtOAc, 6:1) to yield 20 (1.77 g, 85%) as a colorless
oil: [R]26 -24.4° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 0.83 (3H,
D
d, J ) 6.8 Hz), 0.98 (3H, d, J ) 6.6 Hz), 1.37-1.84 (8H, m),
2.06 (1H, t, J ) 13.4 Hz), 2.20 (1H, br s), 2.76 (1H, dt, J )
13.4, 2.4 Hz), 3.36 (2H, br s), 4.08 (1H, br d, J ) 12.4 Hz,),
4.34 (1H, br s), 4.50 (1H, br d, J ) 12.4 Hz), 5.12 and 5.20
(2H, br AB q, J ) 10.4 Hz), 7.37-7.38 (5H, m); 13C NMR
(CDCl3) δ 18.6, 19.1, 19.3, 25.5, 29.7, 30.3, 39.5, 47.4, 67.6,
68.0, 79.3, 127.9, 128.2 (2 carbons), 128.6 (2 carbons), 136.7,
157.0; EIMS m/ z (rel intensity) 336 (M+ + 1, 0.1), 262 (2),
218 (20), 174 (41), 128 (10), 91 (100); CIMS m/ z (rel intensity)
336 (M+ + 1, 9), 91 (100). Anal. Calcd for C19H29NO4: C,
68.02; H, 8.72; N, 4.18. Found: C, 67.73; H, 8.76; N, 4.21.
(2S)-N-[(Ben zyloxy)ca r bon yl]-2-(for m ylm eth yl)p ip er i-
d in e (8). A mixture of 20 (576 mg, 1.72 mmol), periodic acid
(588 mg, 2.58 mmol), THF (4 mL), and H2O (4 mL) was stirred
at 0 °C for 2 h. The reaction mixture was extracted with Et2O
(4 × 10 mL), and the combined extracts were washed with
water, dried (MgSO4), and concentrated in vacuo. Purification
of the residue by column chromatography on silica gel (hex-
oil: [R]25 +11.7° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 0.74 (3H,
D
d, J ) 7.0 Hz), 0.84 (3H, d, J ) 7.0 Hz), 1.08 (9H, s), 1.10-
1.18 (7H, m), 1.87 (1H, br d, J ) 13.1 Hz), 2.08 (1H, dd, J )
17.6, 8.3 Hz), 2.33 (1H, ddd, J ) 11.3, 6.5, 4.8 Hz), 2.41 and
2.63 (total 1H in 4.5:1 ratio, ddd, J ) 12.0, 9.1, 2.8 Hz and br
t, J ) 11.4 Hz, respectively), 3.03 and 3.41 (total 1H in 1:4.5
ratio, br d, J ) 11.4 Hz and br d, J ) 9.1 Hz, respectively),
3.73 and 3.80 (total 1H in 1:4.5 ratio, br s and t, J ) 2.8 Hz,
respectively), 4.06 and 4.37 (total 1H in 4.5:1 ratio, dt, J )
8.4, 4.1 Hz and br s, respectively), 7.32-7.44 (6H, m), 7.68-
7.78 (4H, m); 13C NMR (CDCl3) for the major conformer δ 17.6,
18.4, 19.8, 24.0, 25.0, 27.3 (3 carbons), 29.6, 32.3, 36.6, 54.9,
66.7, 76.9, 77.6, 127.4 (2 carbons), 127.5 (2 carbons), 129.6,
129.7, 134.1, 134.8, 136.1 (2 carbons), 136.3 (2 carbons); for
the minor conformer δ 18.1, 18.7, 19.8, 24.3, 25.5, 27.3 (3
carbons), 32.0, 32.6, 49.8, 60.2, 66.7, 76.9, 78.6, 127.4 (2
carbons), 127.5 (2 carbons), 129.6, 129.7, 134.1, 134.8, 136.1
(2 carbons), 136.3 (2 carbons); EIMS m/ z (rel intensity) 437
(M+, 13), 380 (23), 281 (11), 253 (16), 239 (17), 199 (40), 183
(28), 100 (100). Anal. Calcd for C27H39NO2Si: C, 74.09; H,
8.98; N, 3.20. Found: C, 73.72; H, 8.92; N, 3.14.
ane-EtOAc, 8:1) gave 8 (376 mg, 84%) as a colorless oil: [R]20
D
-40.9° (c 6.5, CHCl3); IR (neat) 2940, 2862, 1724, 1695, 1498,
1471, 1423, 1354, 1319, 1262, 1213, 1176, 1143, 1076, 1055,
1030, 1015, 766, 738, 699 cm-1; 1H NMR (CDCl3) δ 1.37-1.77
(6H, m), 2.60 (1H, ddd, J ) 15.6, 6.9, 2.1 Hz), 2.75 (1H, ddd,
J ) 15.6, 8.0, 2.9 Hz), 2.85 (1H, br t, J ) 12.6 Hz), 4.07 (1H,
br d, J ) 13.2 Hz), 4.92 (1H, br s), 5.12 (2H, s), 7.29-7.40 (5H,
m), 9.70 (1H, br s); 13C NMR (CDCl3) δ 18.3 (CH2), 24.7 (CH2),
28.2 (CH2), 39.1 (CH2), 43.9 (CH2), 45.7 (CH), 66.6 (CH2), 127.3
(CH), 127.5 (2 × CH), 128.0 (2 × CH), 136.2 (C), 154.6 (C),
199.9 (CH); EIMS m/ z (rel intensity) 261 (M+, 1.6), 233 (11),
218 (11), 174 (55), 126 (20), 108 (15), 92 (30), 91 (100). Anal.
Calcd for C15H19NO3: C, 68.94; H, 7.33; N, 5.36. Found: C,
68.85; H, 7.36; N, 5.31.
Meth yl [11(2S)]-11-[2-[N-[(Ben zyloxy)ca r bon yl]p ip e-
r id in yl]]-9-u n d ecen oa te (22). To a cooled (0 °C), stirred
mixture of 8 (830 mg, 3.18 mmol), [8-(methoxycarbonyl)octyl]-
triphenylphosphonium iodide (21)15 (3.20 g, 5.72 mmol), and
THF (35 mL) was added under Ar potassium tert-butoxide (535
mg, 4.77 mmol). After stirring for 20 min at 0 °C, an aqueous
[2R,2(1S),3aS]-2-(1-Hydr oxy-2-m eth ylpr opyl)-3,3a,4,5,6,7-
h exa h yd r o-2H-isoxa zolo[2,3-a ]p yr id in e (18). To a stirred
solution of 16 (1.70 g, 3.89 mmol) in THF (30 mL) was added
a 1.0 M solution of tetrabutylammonium fluoride (15.5 mL,
15.5 mmol) in THF, and the mixture was stirred under Ar at
45 °C for 1.5 h. After evaporation of the solvent in vacuo, the
residue was dissolved in Et2O (100 mL) and the solution was
washed with brine and dried (MgSO4). Removal of the solvent
and purification by silica gel chromatography (hexane-EtOAc,
saturated solution of NH4
Cl (20 mL) was added and stirring
was continued for an additional 30 min at the same temper-
ature. To this mixture was added Et2O (150 mL), and the
separated organic phase was washed with brine and dried
(MgSO4). Concentration followed by column chromatography
on silica gel (hexane-EtOAc, 20:1) gave 22 (739 mg, 56%) as
a colorless oil: [R]26 -40.6° (c 2.0, CHCl3); IR (neat) 2931,
D
3:1) gave 18 (665 mg, 86%) as a colorless oil: [R]25 +38.9° (c
2855, 1739, 1698, 1498, 1422, 1343, 1319, 1259, 1205, 1171,
1089, 1045, 733, 698 cm-1; 1H NMR (CDCl3) δ 1.28 (9H, br s),
1.56-1.63 (7H, m), 2.00 (2H, br q, J ) 6.6 Hz), 2.23-2.39 (2H,
m), 2.29 (2H, t, J ) 7.6 Hz), 2.86 (1H, td, J ) 13.2, 2.3 Hz),
3.66 (3H, s), 4.06 (1H, br d, J ) 11.6 Hz), 4.31 (1H, br s), 5.11
and 5.13 (2H, AB q, J ) 12.5 Hz), 5.23-5.34 (1H, m), 5.35-
D
1.1, CHCl3); 1H NMR (CDCl3) δ 0.89 (3H, d, J ) 6.8 Hz), 1.02
(3H, d, J ) 6.6 Hz), 1.15-1.50 (3H, m), 1.57-2.15 (6H, m),
2.24 (1H, unresolved), 2.45 and 2.85 (total 1H in 2:1 ratio, br
t, J ) 9.3 Hz and br s, respectively), 3.04 and 3.44 (total 2H
in 1:5 ratio, each br s), 4.14 and 4.42 (total 1H in 2:1 ratio, br
dd, J ) 5.1, 4.1 Hz and br s, respectively); 13C NMR (CDCl3)
for the major conformer δ 18.8 (2 carbons), 23.9, 24.9, 29.6,
30.8, 34.3, 55.2, 67.7, 75.9, 77.6; for the minor conformer δ
19.2, 19.7, 23.0, 25.9, 29.6, 30.8, 31.1, 50.1, 60.6, 77.7, 78.0;
EIMS m/ z (rel intensity) 199 (M+, 11), 156 (3), 100 (100). Anal.
Calcd for C11H21NO2: C, 66.29; H, 10.62; N, 7.03. Found: C,
66.03; H, 10.55; N, 6.83.
5.44 (1H, m), 7.29-7.36 (5H, m);
13C NMR (CDCl3) δ 18.9
(CH2), 24.9 (CH2), 25.5 (CH2), 27.4 (CH2), 27.5 (CH2), 27.6
(CH2
), 29.07 (2 × CH2), 29.14 (CH2), 29.5 (CH2), 34.1 (CH2),
39.4 (CH2), 50.9 (CH), 51.4 (CH3), 66.8 (CH2), 125.7 (CH), 127.7
(CH), 127.8 (2 × CH), 128.4 (2 × CH), 132.0 (CH), 137.0 (C),
155.5 (C), 174.3 (C); EIMS m/ z (rel intensity) 384 (M+
- OMe,
0.9), 280 (1.3), 277 (1.2), 218 (44), 174 (100). Anal. Calcd for
C25H37NO4: C, 72.26; H, 8.79; N, 3.37. Found: C, 72.25; H,
8.98; N, 3.36.
[2S,2(2R),2(3S)]-N-[(Ben zyloxy)ca r b on yl]-2-(2,3-d ih y-
d r oxy-4-m eth ylp en tyl)p ip er id in e (20). A mixture of 18
(1.36 g, 6.83 mmol), PdCl2 (140 mg), and MeOH (40 mL) was
[11(2S)]-11-[2-[N-(Ben zyloxy)ca r b on yl]p ip er id yl]]-9-

1028 J . Org. Chem., Vol. 61, No. 3, 1996
Ina et al.
u n d ecen oic Acid (23). A mixture of 22 (880 mg, 2.12 mmol),
3 N KOH (2 mL), and MeOH (10 mL) was stirred at rt for 5 h.
After neutralization with 1 N HCl, the mixture was extracted
with EtOAc (4 × 20 mL). The extracts were washed with
water, dried (MgSO4), and concentrated in vacuo. Purification
of the residue by column chromatography on silica gel (hex-
ane-EtOAc, 2:1) gave 23 (816 mg, 96%) as a colorless oil:
the major rotamer δ -5.6 (2 × CH3), 17.9 (C), 25.6 (CH2), 25.6
(3 × CH3), 27.1 (CH2), 28.2 (3 × CH3), 31.7 (CH2), 39.9 (CH2),
43.8 (CH2), 47.1 (CH2), 60.1 (CH2), 66.5 (CH2), 78.6 (C), 127.5
(CH), 127.6 (2 × CH), 128.2 (2 × CH), 136.7 (C), 155.7 (2 ×
C); for the minor rotamer δ -5.6 (2 × CH3), 17.9 (C), 25.1
(CH2), 25.6 (3 × CH2), 27.1 (CH2), 28.2 (3 × CH2), 31.0 (CH2),
39.9 (CH2), 44.4 (CH2), 46.6 (CH2), 60.1 (CH2), 66.5 (CH2), 78.6
(C), 127.5 (CH), 127.6 (2 × CH), 128.2 (2 × CH), 136.7 (C),
155.7 (2 × C); CIMS (isobutane) m/ z (rel intensity) 495 (M+
+ 1, 8), 439 (62), 420 (14), 395 (100), 380 (24), 337 (22), 273
(21), 161 (12), 144 (13), 114 (13). Anal. Calcd for C26H46N2O5-
Si: C, 63.12; H, 9.37; N, 5.66. Found: C, 63.14; H, 9.47; N,
5.60.
[R]28 -41.3° (c 1.1, CHCl3); IR (neat) 3173, 3011, 2932, 2856,
D
1733, 1699, 1668, 1426, 1345, 1320, 1261, 1240, 1212, 1173,
1148, 1091, 1074, 1046, 733, 698 cm-1; 1H NMR (CDCl3) δ 1.31
(9H, br s), 1.59-1.66 (7H, m), 1.99-2.03 (2H, m), 2.24-2.42
(2H, m), 2.35 (2H, t, J ) 7.5 Hz), 2.86 (1H, td, J ) 13.3, 2.6
Hz), 4.06 (1 H, br d, J ) 2.0 Hz), 4.31 (1H, br s), 5.11 and 5.14
(2H, AB q, J ) 12.5 Hz), 5.26-5.34 (1H, m), 5.38-5.47 (1H,
m), 7.33-7.38 (5H, m); 13C NMR (CDCl3) δ 18.9 (CH2), 24.6
(CH2), 25.4 (CH2), 27.3 (CH2), 27.4 (CH2), 27.6 (CH2), 28.9
(CH2), 29.0 (CH2), 29.1 (CH), 29.5 (CH2), 34.0 (CH2), 39.4 (CH2),
50.9 (CH), 66.9 (CH2), 125.7 (CH), 127.7 (CH), 127.8 (2 × CH),
128.3 (2 × CH), 131.9 (CH), 136.9 (C), 155.5 (C), 179.5 (C);
EIMS m/ z (rel intensity) 402 (M+ + 1, 0.2), 356 (3), 218 (46),
174 (100). Anal. Calcd for C24H35NO4: C, 71.79; H, 8.79; N,
3.49. Found: C, 71.79; H, 8.80; N, 3.46.
N-[4-[(ter t-Bu t oxyca r b on yl)a m in o]b u t yl]-N-[3-[(ter t-
bu tyld im eth ylsilyl)oxy]p r op yl]a m in e (29). A mixture of
28 (5.16 g, 10.4 mmol), Pd(OH)2 (780 mg), and MeOH (40 mL)
was hydrogenated at atmospheric pressure for 30 min. After
removal of the catalyst by filtration, the filtrate was concen-
trated in vacuo to give 29 (3.57 g, 95%) as a colorless oil: IR
(neat) 3343, 2932, 2858, 1698, 1525, 1473, 1463, 1391, 1365,
1253, 1176, 1099, 1006, 837, 815, 777, 662 cm-1 1H NMR
;
(CDCl3) δ -0.03 (3H, s), -0.02 (3H, s), 0.81 (3H, s), 0.82 (6H,
s), 1.37 (11H, s), 1.43-1.46 (2H, m), 1.63 (2H, br t, J ) 6.3
Hz), 2.52-2.56 (2H, m), 2.61 (2H, td, J ) 6.9, 1.4 Hz), 3.05-
N-[(Ben zyloxy)ca r bon yl]-N-[4-[(ter t-bu toxyca r bon yl)-
a m in o]bu tyl]-N-(3-h yd r oxyp r op yl)a m in e (27). A mixture
of 1-bromo-4-[(tert-butoxycarbonyl)amino]butane (25) (1.95 g,
77.3 mmol), K2CO3 (2.14 g, 154.6 mmol), 3-amino-1-propanol
(24) (581 mg, 77.3 mmol), and DMF (10 mL) was stirred under
Ar at 90 °C for 3 h. The mixture was poured into ice-water
(70 mL) and extracted with EtOAc (4 × 40 mL). The combined
organic layers were washed with water, dried (MgSO4), and
concentrated in vacuo. Rapid chromatography on a short
column of silica gel (CHCl3-MeOH-NH4OH, 40:9:1) gave
N-[4-[(tert-butoxycarbonyl)amino]butyl]-N-(3-hydroxypropyl)-
amine (26) (991 mg, 52%) as a colorless oil. A solution of Na2-
CO3 (657 mg, 6.20 mmol) in water (8 mL) was added to a
solution of 26 (763 mg, 3.10 mmol) in CH2Cl2 (12 mL), and
the mixture was cooled (0 °C) and stirred. To this was added
dropwise a solution of benzyl chloroformate (634 mg, 3.72
mmol) in CH2Cl2 (4 mL) and stirring was continued at 0 °C.
After 30 min, water (10 mL) was added and the organic layer
was was separated. The aqueous phase was extracted with
CH2Cl2 (3 × 15 mL). The combined organic phases were
washed with brine, dried (MgSO4), and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (EtOAc-hexane, 1:1) to yield 27 (1.04 g, 88%) as a colorless
oil: IR (neat) 3354, 3033, 2936, 1685, 1526, 1480, 1426, 1391,
3.34 (2H, m), 3.61 (2H, td, J ) 6.1, 1.5 Hz), 5.06 (1H, br s); 13
C
NMR (CDCl3) δ -5.5 (2 × CH3), 18.1 (C), 25.8 (3 × CH3), 27.4
(CH2), 27.8 (CH2), 28.3 (3 × CH3), 32.7 (CH2), 40.4 (CH2), 47.2
(CH2), 49.6 (CH2), 61.7 (CH2), 78.6 (C), 155.9 (C); EIMS m/ z
(rel intensity) 369 (M+, 44), 315 (17), 304 (37), 300 (18), 247
(82), 215 (20), 202 (42), 187 (43), 145 (21), 132 (36), 101 (33),
75 (27), 57 (100). This material was used immediately without
purification for the next reaction.
[11(2S)]-N-[4-[(ter t-Bu toxyca r bon yl)a m in o]bu tyl]-N-[3-
[(ter t-bu tyldim eth ylsilyl)oxy]pr opyl]-11-[2-[N-(ben zyloxy)-
ca r bon yl]p ip er id yl]-9-u n d ecen a m id e (30). A mixture of
23 (2.01 g, 5.00 mmol), 29 (2.70 g, 7.50 mmol), triethylamine
(1.52 g, 15.0 mmol), diethoxyphosphoryl cyanide16 (1.05 g, 6.00
mmol), and DMF (18 mL) was stirred under Ar at rt for 14 h.
After addition of H2O (200 mL), the mixture was extracted
with Et2O (4 × 100 mL). The combined organic layers were
washed with water, dried (MgSO4), and concentrated in vacuo.
Chromatography of the residue on silica gel (hexane-EtOAc,
2:1) gave 30 (3.53 g, 95%) as a colorless oil: [R]26 -20.8° (c
D
4.5, CHCl3); IR (neat) 3346, 3005, 2930, 2856, 1700, 1642, 1520,
1455, 1423, 1390, 1364, 1343, 1319, 1257, 1173, 1143, 1096,
1044, 1007, 969, 837 cm-1 1H NMR (CDCl3) δ 0.03 (3H, s),
;
1367, 1253, 1210, 1171, 1062, 913, 866, 770, 753, 699 cm-1
;
0.04 (3H, s), 0.87 (3H, s), 0.88 (6H, s), 1.28 (9H, br s), 1.42
(6H, s), 1.43 (3H, s), 1.47-1.76 (14H, m), 1.91-2.01 (3H, m),
2.23-2.34 (4H, m), 2.84 (1H, td, J ) 13.3, 2.0 Hz), 3.11 (2H,
br d, J ) 5.8 Hz), 3.22-3.38 (3H, m), 3.60 (2H, t, J ) 5.8 Hz),
4.05 (1H, br d, J ) 11.9 Hz), 4.30 (1H, br s), 5.05 and 5.13
(2H, AB q, J ) 12.5 Hz), 5.23-5.31 (1H, m), 5.35-5.43 (1H,
m), 7.30-7.34 (5H, m); 13C NMR (CDCl3) δ (rotamers) 5.64,
5.56, 17.9, 18.0, 18.7, 24.8, 25.2, 25.6, 25.7, 26.1, 27.1, 27.2,
27.4, 28.2, 28.9, 29.0, 29.2, 29.4, 30.7, 31.8, 32.8, 39.1, 39.8,
39.9, 42.8, 44.3, 44.9, 47.7, 50.6, 59.4, 60.5, 66.48, 66.54, 78.5,
125.4, 127.4, 127.5, 128.1, 131.8, 136.8, 155.2, 155.8, 172.4,
172.7; EIMS m/ z (rel intensity) 743 (M+, 8), 668 (5), 608 (7),
525 (18), 500 (10), 467 (16), 342 (12), 218 (48), 174 (100). Anal.
Calcd for C42H73N3O6Si: C, 67.79; H, 9.89; N, 5.65. Found:
C, 67.76; H, 10.10; N, 5.62.
1H NMR (CDCl3) δ 1.38-1.58 (4H, m), 1.43 (9H, s), 1.66-1.76
(2H, m), 3.06-3.10 (2H, m), 3.22 (2H, br t, J ) 7.1 Hz), 3.41
(2H, br t, J ) 5.9 Hz), 3.53-3.63 (2H, m), 4.61 (1H, br s), 5.13
(2H, s), 7.34 (5H, s); 13C NMR (CDCl3) for the major rotamer
δ 25.6 (CH2), 27.3 (CH2), 28.3 (3 × CH3), 30.5 (CH2), 39.9 (CH2),
43.3 (CH2), 46.5 (CH2), 58.4 (CH2), 67.2 (CH2), 79.1 (C), 127.8
(2 × CH2), 128.0 (CH), 128.4 (2 × CH2), 136.5 (C), 155.9 (C),
157.2 (C); for the minor rotamer δ 25.1 (CH2), 27.3 (CH2), 28.3
(CH3, 3 carbons), 31.5 (CH2), 39.9 (CH2), 43.3 (CH2), 47.1 (CH2),
59.5 (CH2), 67.0 (CH2), 79.1 (C), 127.8 (CH, 2 carbons), 128.0
(CH), 128.4 (CH, 2 carbons), 136.5 (C), 155.9 (C), 157.2 (C);
EIMS m/ z (rel intensity) 380 (M+, 0.5), 279 (30), 263 (20), 235
(15), 188 (58), 114 (100). Anal. Calcd for C20H32N2O5: C,
63.14; H, 8.48; N, 7.36. Found: C, 63.02; H, 8.56; N, 7.30.
N-[(Ben zyloxy)ca r bon yl]-N-[4-[(ter t-bu toxyca r bon yl)-
a m in o]bu tyl]-N-[3-[(ter t-bu tyld im eth ylsilyl)oxy]p r op yl]-
a m in e (28). To a solution of 27 (870 mg, 2.29 mmol) in DMF
(10 mL) were added imidazole (390 mg, 5.73 mmol) and tert-
butyldimethylsilyl chloride (415 mg, 2.75 mmol). The mixture
was stirred at rt for 14 h, diluted with water (70 mL), and
extracted with EtOAc (4 × 40 mL). The extracts were washed
with brine, dried (MgSO4), and concentrated in vacuo. Column
chromatography on silica gel (hexane-EtOAc, 10:1) gave 28
(928 mg, 82%) as a colorless oil: IR (neat) 3358, 2931, 2858,
1701, 1520, 1474, 1423, 1390, 1366, 1253, 1214, 1175, 1100,
[11(2S)]-N-[4-[(ter t-Bu toxyca r bon yl)a m in o]bu tyl]-N-(3-
h ydr oxypr opyl)-11-[2-[N-(ben zyloxy)car bon yl]piper idyl]-
9-u n d ecen a m id e (31). To a stirred solution of 30 (2.86 g,
3.84 mmol) in THF (30 mL) was added a 1.0 M solution of
tetrabutylammonium fluoride (9.2 mL, 9.2 mmol) in THF.
After being stirred at rt for 2 h, the mixture was diluted with
EtOAc (100 mL), washed with water, dried (MgSO4), and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane-EtOAc, 1:1) to yield 31
(2.42 g, 100%) as a colorless oil: [R]26 -20.5° (c 4.7, CHCl3);
D
IR (neat) 3356, 2931, 2856, 1696, 1625, 1526, 1425, 1390, 1365,
1319, 1258, 1172, 1074, 1047, 734, 699 cm-1; 1H NMR (CDCl3)
δ 1.28 (9H, br s), 1.42 (9H, s), 1.45-1.70 (11H, m), 1.96-2.00
(3H, m), 2.22-2.38 (2H, m), 2.30 (2H, t, J ) 7.6 Hz), 2.84 (1H,
td, J ) 13.8, 2.3 Hz), 3.12 (2H, t, J ) 6.3 Hz), 3.14 (2H, t, J )
1
1007, 837, 776, 736, 698 cm-1; H NMR (CDCl3) δ 0.02 (6H,
s), 0.87 (9H, s), 1.33-1.60 (4H, m), 1.43 (9 H, s), 1.65-1.78
(2H, m), 3.04-3.12 (2H, m), 3.29 (4H, br q, J ) 7.5 Hz), 3.56-
3.63 (2H, m), 5.11 (2H, s), 7.33 (5H, s); 13C NMR (CDCl3) for

Enantioselective Total Synthesis of (-)-Oncinotine
J . Org. Chem., Vol. 61, No. 3, 1996 1029
6.6 Hz), 3.28-3.38 (1H, m), 3.42-3.50 (3H, m), 4.02-4.10 (2H,
m), 4.29 (1H, br s), 5.08 and 5.12 (2H, AB q, J ) 12.5 Hz),
23.55, 23.60, 23.8, 24.2, 24.4, 24.6, 24.8, 24.9, 25.3, 25.7, 26.0,
26.3, 26.4, 26.6, 26.7, 26.9, 26.97, 27.04, 27.3, 27.4, 27.7, 27.8,
27.85, 28.3, 29.0, 30.1, 30.5, 32.2, 32.4, 39.9, 40.0, 42.9, 45.2,
46.4, 47.2, 50.6, 51.0, 51.3, 52.3, 59.9, 60.4, 78.8, 79.0, 155.9,
172.7, 173.0; EIMS m/ z (rel intensity), 479 (M+, 10), 406 (5),
123 (100), 112 (78); HRMS calcd for C28H53N3O3 (M+) 479.4087,
found 479.4106.
5.22-5.31 (1H, m), 5.35-5.43 (1H, m), 7.30-7.34 (5H, m); 13
C
NMR (CDCl3) δ (rotamers) 18.8, 24.7, 25.3, 25.5, 25.9, 27.2,
27.4, 27.5, 28.3, 29.0, 29.2, 29.3, 29.5, 30.2, 31.7, 32.8, 32.9,
39.3, 39.7, 41.4, 44.6, 45.1, 47.4, 50.7, 57.9, 59.1, 66.7, 79.1,
125.6, 127.6, 127.7, 128.2, 131.8, 136.8, 155.4, 155.9, 173.0,
174.3; EIMS m/ z (rel intensity) 529 (M+ + 1 - (CH3)3COCO,
33), 512 (26), 479 (12), 440 (12), 426 (27), 422 (16), 412 (100).
Anal. Calcd for C36H59N3O6: C, 68.65; H, 9.44; N, 6.67.
Found: C, 68.68; H, 9.62; N, 6.59.
17(R )-5-(4-Am i n o b u t y l)-1,5-d i a z a b i c y c lo [15.4.0]-
h en icosa n -6-on e ((-)-On cin otin e) (1). To a cooled (0 °C),
stirred MeOH (3 mL) solution of 33 (248 mg, 0.653 mmol) was
added 3 N HCl (3 mL) and stirring was continued at rt for 3
h. After concentration of the mixture in vacuo, the residue
was dissolved in H2O (16 mL), made basic (pH 10) with K2-
CO3, and extracted with CHCl3 (5 × 16 mL). The combined
organic phases were washed with water, dried (MgSO4), and
concentrated in vacuo. Purification of the residue by column
chromatography on silica gel (CHCl3-MeOH-NH4OH, 200:
[11(2S)]-N-[4-[(ter t-Bu toxyca r bon yl)a m in o]bu tyl]-N-(2-
for m yleth yl)-11-[2-[N-[(ben zyloxy)ca r bon yl]p ip er id yl]]-
9-u n d ecen a m id e (34). To a stirred, cold (-78 °C) solution
of oxalyl chloride (142 mg, 1.12 mmol) in CH2Cl2 (2 mL) was
added via syringe a solution of dimethyl sulfoxide (175 mg,
2.24 mmol) in CH2Cl2 (2 mL), and the mixture was stirred at
-78 °C for 1 h. To this mixture was added dropwise a solution
of 31 (353 mg, 0.560 mmol) in CH2Cl2 (2 mL) over a period of
5 min, and stirring was continued at -78 °C. After 2 h,
triethylamine (340 mg, 3.36 mmol) was added to the reaction
mixture, and the mixture was allowed to warm to rt. Addition
of water (30 mL) and extraction with CH2Cl2 (4 × 30 mL)
afforded a CH2Cl2 solution, which was washed with water,
dried (MgSO4), and concentrated in vacuo. The residue was
subjected to silica gel column chromatography (EtOAc-
9:1) gave 1 (140 mg, 71%) as a colorless oil: [R]26 -28.7° (c
D
2.6, CHCl3), [R]26D -32.7° (c 2.1, MeOH); IR (CCl4) 3584, 3369,
2929, 2856, 1636, 1461, 1378, 1320, 1231, 1126, 1045, 823
cm-1; 1H NMR (CDCl3) δ 1.21-1.72 (32H, m), 2.12-2.39 (5H,
m), 2.49-2.61 (1H, m), 2.67 (2H, dt, J ) 4.1, 6.8 Hz), 2.72-
2.84 (1H, m), 3.08-3.26 (3H, m), 3.35 (1H, dt, J ) 13.4, 6.7
Hz); 13C NMR (CDCl3) δ (rotamers) 23.1, 23.6, 23.6, 23.8, 24.3,
24.8, 24.9, 25.0, 25.4, 25.6, 25.8, 26.4, 26.6, 26.7, 26.8, 27.0,
27.1, 27.3, 27.7, 27.9, 28.1, 30.0, 30.2, 30.5, 30.8, 30.9, 32.4,
32.5, 41.8, 43.1, 45.5, 46.5, 47.5, 50.7, 51.3, 51.8, 52.4, 60.0,
172.7, 172.9; EIMS m/ z (rel intensity) 379 (M+, 20), 350 (10),
150 (34), 137 (14), 123 (100), 112 (57), 98 (50), 84 (47) 70 (52);
HRMS calcd for C23H45N3O (M+) 379.3563, found 379.3574.
A part of the synthetic sample was converted to the
hydrochloride salt (1‚2HCl) by treatment with concentrated
HCl-MeOH followed by evaporation in vacuo as a colorless
oil: 1H NMR (CD3OD) δ 1.20-2.35 (30H, m), 2.40-2.51 (2H,
m), 3.01 (2H, br s), 3.12-3.35 (5H, m), 3.40-3.64 (4H, m); 1H
NMR (D2O) δ 1.26-2.00 (30H, m), 2.32-2.46 (2H, m), 2.95 (2H,
br s), 3.02-3.18 (5H, m), 3.30-3.51 (4H, m); 13C NMR (CD3-
OD) δ (rotamers) 19.6, 22.2, 22.4, 23.1, 23.6, 23.7, 24.0, 24.26,
24.32, 24.6, 25.0, 25.1, 25.3, 25.37, 25.42 25.7, 25.9, 26.0, 26.7,
26.8, 27.1, 27.2, 27.5, 27.6, 27.7, 27.8, 27.85, 27.93, 28.0, 28.1,
28.2, 28.3, 28.4, 28.5, 28.7, 28.8, 28.9, 29.6, 30.1, 30.8, 33.0,
40.3, 40.4, 40.5, 43.6, 43.9, 46.6, 48.3, 51.1, 51.2, 51.36, 51.45,
52.7, 54.9, 61.9, 62.3, 64.7, 64.9, 176.2, 176.5, 176.7; 13C NMR
(D2O) δ dioxane (rotamers) 19.2, 22.4, 22.5, 23.0, 23.2, 23.7,
24.0, 24.2, 24.4, 24.9, 25.1, 25.2, 25.3, 25.4, 25.5, 26.0, 26.2,
26.3, 26.4, 27.0, 27.1, 27.3, 27.5, 27.7, 27.9, 28.0, 28.2, 28.3,
28.4, 28.7, 29.1, 29.7, 30.2, 30.6, 33.3, 33.4, 40.5, 43.6, 43.7,
46.4, 46.45, 46.5, 48.8, 49.3, 50.3, 50.4, 51.3, 51.5, 53.6, 55.2,
61.5, 62.0, 64.6, 64.7, 177.1, 177.2, 178.0, 178.2.
hexane, 1:1) to give 34 (253 mg, 72%) as a colorless oil: [R]27
D
-28.9° (c 2.6, CHCl3); IR (neat) 3346, 2931, 2856, 1695, 1635,
1525, 1424, 1390, 1365, 1319, 1259, 1172, 1090, 1046, 1005,
1
764, 735, 699 cm-1; H NMR (CDCl3) δ 1.28 (9H, br s), 1.43
(9H, s), 1.46-1.63 (10H, m), 1.96-2.01 (3H, m), 2.22-2.34 (4H,
m), 2.70-2.89 (3H, m), 3.11-3.85 (2H, m), 3.29 (2H, br t, J )
7.4 Hz), 3.6 (2H, t, J ) 6.5 Hz), 4.03-4.07 (1H, m), 4.30 (1H,
br s), 5.09 and 5.13 (2H, AB q, J ) 12.4 Hz), 5.23-5.31 (1H,
m), 5.35-5.44 (1H, m), 7.30-7.35 (5H, m), 9.77 (1H, t, J ) 1.5
Hz); 13C NMR (CDCl3) δ (rotamers) 18.6, 24.5, 24.9, 25.1, 26.0,
27.0, 27.2, 27.3, 28.1, 28.8, 28.9, 29.0, 29.2, 32.6, 32.8, 39.0,
39.5, 39.9, 40.3, 42.6, 42.9, 44.8, 48.0, 50.5, 66.4, 78.7, 125.4,
127.3, 127.4, 128.0, 131.6, 136.7, 155.1, 155.7, 172.3, 172.8,
199.2, 200.5; EIMS m/ z (rel intensity) 554 (M+ - (CH3)3CO,
42), 549 (14), 526 (20), 510 (42), 498 (100), 592 (24). Anal.
Calcd for C36H57N3O6: C, 68.87; H, 9.15; N, 6.69. Found: C,
68.70; H, 9.35; N, 6.65.
17(R )-5-[4-[(t er t -Bu t oxyca r b on yl)a m in o]b u t yl]-1,5-
d ia za bicyclo[15.4.0]h en icosa n -6-on e (33). A mixture of 34
(146 mg, 0.233 mmol), Pd(OH)2 (40 mg), and MeOH (58 mL)
was stirred in an atmosphere of hydrogen at atmospheric
pressure for 4 days. After filtration of the catalyst, the solvent
was evaporated in vacuo and purification of the residue by
column chromatography on silica gel (CHCl3-MeOH-NH4OH,
500:9:1) gave 33 (74 mg, 66%) as a colorless oil: [R]27 -18.9°
Ack n ow led gm en t. We are grateful to Professor M.
D
(c 4.8, CHCl3); IR (neat) 3331, 2930, 2857, 2106, 1709, 1636,
Hesse (Institute of Organic Chemistry, University of
1
Zurich) for providing H and 13C NMR spectra of the
1525, 1458, 1390, 1365, 1270, 1252, 1174, 1043, 1005, 870, 754
cm-1 1H NMR (CDCl3) δ 1.17-1.80 (31H, m), 1.37 (9H, s),
;
racemate of oncinotine hydrochloride.
2.12-2.88 (6H, m), 3.04-3.26 (4H, m), 3.28-3.37 (2H, unre-
solved), 4.75 (1H, br s); 13C NMR (CDCl3) δ (rotamers) 22.3,
J O9518258