Efficient total synthesis of enantiopure (-)-porantheridine

Full text of DOI:10.1021/jo9906476

8402
J . Org. Chem. 1999, 64, 8402-8405
Sch em e 1
Efficien t Tota l Syn th esis of En a n tiop u r e
(-)-P or a n th er id in e
Marc David, Hamid Dhimane,
Corinne Vanucci-Bacque´, and Ge´rard Lhommet*
Universite´ P. et M. Curie,
Laboratoire de Chimie des He´te´rocycles, UMR 7611,
4 Place J ussieu, 75252 Paris Cedex 05, France
Received April 19, 1999
The tricyclic alkaloid (-)-porantheridine (1) was first
isolated by J . A. Lamberton and co-workers in 1972 from
the Australian bush Poranthera corymbosa.1 Its absolute
configuration was determined by X-ray analysis1 and
ascertained by the asymmetric synthesis completed by
D. Comins and H. Huong in 1993.2 We disclose herein a
new approach to this alkaloid. Based on the retrosyn-
thetic analysis shown in Scheme 1, compound 1 was
viewed as resulting from an intramolecular cyclization
of piperidine hydroxyketone 2 via a transient bicyclic
iminium ion, as previously described.2,3 The stereoselec-
tive elaboration of the 2-hydroxypent-1-yl lateral chain
of compound 2 was expected to proceed with some level
of 1,3-asymmetric induction, through chemical manipula-
tion of the double bond of the allylic group of intermediate
3, via either a diastereoselective epoxidation or an
intramolecular halocyclocarbamation. Alternatively, di-
astereoselective reduction of ketone 4 was considered as
a backup route to access intermediate 2. In this strategy,
the stereochemical issues were totally solved provided
that 3 or 4 could be obtained in an enantiopure form. To
fulfill this requirement, we envisioned that our recently
introduced stereoselective preparation of trans 2,6-di-
substituted piperidines4 was particularly well suited.
This approach indeed features a totally stereoselective
nucleophilic substitution of the methoxy group of bicyclic
amino ether 5, via the corresponding N-acyl iminium
ion.4
Sch em e 2
These poor results prompted us to examine the elabo-
ration of the (2R)-hydroxypent-1-yl group via a two-step
sequence. The first step required the installation of the
2-oxopent-1-yl chain from 5, by direct nucleophilic dis-
placement of the methoxy group using 2-(trimethylsily-
loxy)pent-1-ene6 as the nucleophile. As previously re-
ported for other silyl enol ethers,4 this reaction was
expected to proceed with high diastereoselectivity to
deliver trans 2,6-disubstituted piperidine 4. In the second
step, the carbonyl function in 4 was expected to be
reduced diastereoselectively. However, this first approach
was rapidly abandoned insofar as the 92:8 mixture of the
regioisomeric silyl enol ethers generated from pentan-2-
one7 afforded, in turn, upon reaction with 5, a mixture
of regioisomers, which could not be separated. We then
decided to prepare ketone 4 according to a two-step
procedure (Scheme 3). Treatment of substrate 5 with silyl
enol ethers 8, readily available from ethyl butyryl
acetate,8 in the presence of TMSOTf, afforded piperidine
derivatives 9 in 90% yield. As anticipated, this reaction
occurred with total stereochemical control of the center
R to the nitrogen atom, to deliver exclusively the trans
2,6-disubstituted piperidine moiety, and with no control
at the R position of the â-ketoester substituent. Subse-
quent decarbethoxylation of this epimeric mixture af-
forded the desired bicyclic ketone 4 in 91% yield. Various
reductive conditions9 were then screened from 4 in order
Substrate 5, which was obtained from L-lysine through
an electromethoxylation key step, smoothly reacted with
allyltrimethylsilane in the presence of TiCl4, to afford the
corresponding derivative 3 in multigram scale.4 Unfor-
tunately, treatment of 3 with m-CPBA yielded a 1:1
diastereomeric mixture of the corresponding epoxides. On
the other hand, to overcome this lack of facial selectivity
and based on previous reports on the high level of 1,3-
asymmetric induction in intramolecular iodocyclocar-
bamation,5 we attempted such a reaction on intermediate
6, derived from compound 3 in two steps (Scheme 2).
However, in our case, treatment of 6 with iodine gave a
disappointing 1:1 diastereomeric mixture of iodooxazi-
nones 7 in modest yield.
(1) Denne, W. A.; J ohns, S. R.; Lamberton, J . A.; Mathieson, A. McL.;
Suares, H. Tetrahedron Lett. 1972, 18, 1767-1770.
(2) Comins, D. L.; Hong, H. J . Am. Chem. Soc. 1993, 115, 8851-
8852.
(3) Go¨ssinger, E. Tetrahedon Lett. 1980, 21, 2229-2232.
(4) David, M.; Dhimane, H.; Vanucci-Bacque´, C.; Lhommet, G.
Synlett 1998, 206-208.
(5) Wang, Y.; Izawa, T.; Kobayashi, S.; Ohno, M. J . Am. Chem. Soc.
1982, 104, 6465-6466.
(6) Shono, T.; Matsumura, Y.; Uchida, K.; Tsubata, K.; Makino, A.
J . Org. Chem. 1984, 49, 300-304.
(7) Xie, L.; Saunders: W. H. J . Am. Chem. Soc. 1991, 113, 3123-
3130.
(8) (a) Molander, G. A.; Cameron, K. O. J . Am. Chem. Soc. 1993,
115, 830-846. (b) Kusnezowa, I. K.; Michael, G.; Ru¨hlmann, K. J .
Prakt. Chem. 1976, 318, 413-419.
10.1021/jo9906476 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/01/1999

Notes
J . Org. Chem., Vol. 64, No. 22, 1999 8403
Sch em e 3
Sch em e 4
to obtain selectively alcohol 10a with an (R) configuration
at the resulting new chiral center. The best results were
obtained with trialkylborohydride, i.e., potassium tri-sec-
butylborohydride (K-Selectride) or lithium triethylboro-
hydride (Super-H) which gave a 4:1 mixture of alcohols
10a and 10b, in quantitative yield. Fortunately, the two
epimers were easily separated by column chromatogra-
phy. Their stereochemistries were established based on
the X-ray analysis of the minor isomer 10b, which was
isolated as a crystalline solid. Noteworthy was the
obtention of a reverse diastereoselectivity10 upon treat-
ment of ketone 4 with DIBAL-H.
with the corresponding bromide. We then envisioned the
formation of the desired carbon-carbon bond through a
Wittig reaction. To this end, we first protected the amino
function of compound 12 as a benzyl carbamate in 94%
yield. Alcohol 14 was then oxidized under Swern condi-
tions, and the resulting crude aldehyde thus obtained was
subsequently involved in a Wittig reaction with the ylide,
generated in situ from triphenylphosphonium bromide
15.13 The resulting olefin 1614 was isolated in 85% overall
yield starting from alcohol 14. Hydrogenation of the
carbon-carbon double bond and reductive cleavage of
both benzyloxy groups of compound 16 proceeded under
an atmospheric pressure of hydrogen in the presence of
Pd/C. The resulting ketal was then reacted under acid
conditions to afford, via a tandem ketal cleavage/cycliza-
tion, the expected (-)-porantheridine (1), as the free base
in 47% overall yield, after neutralization with Na2CO3.
An analytical sample of this material displayed 13C and
1H NMR spectra identical to those of synthetic racemic
porantheridine.3 The optical rotation was determined to
be [R]19D ) -25° (c 0.50, CHCl3), in good agreement with
those obtained previously for natural1 and synthetic2 (-)-
porantheridine, namely [R]D ) -26° (c 0.57, CHCl3) and
Installation of the required 4-oxopent-1-yl moiety (see
2) was envisioned by chain elongation of the hydroxym-
ethyl group resulting from the opening of the oxazolidi-
none moiety of 10a , following the benzylation of the free
hydroxy group (Scheme 4). The required benzyl ether 11
was prepared in 86% yield from alcohol 10a and then
refluxed in a methanolic aqueous NaOH solution to
deliver the corresponding amino alcohol 12 in 91% yield.
At that point, we decided to introduce the 4-oxopent-1-
yl appendage via a nucleophilic substitution of the
corresponding tosylate by an appropriate organocuprate
reagent. Bis-sulfonylation of amino alcohol 12 in the
presence of tosyl chloride and Et3N afforded in 60% yield
derivative 13, where the nitrogen atom has been pro-
tected11 and the alcohol has been activated for nucleo-
philic substitution. Compound 13 was subsequently
treated with a large excess of the cuprate species gener-
ated from the Grignard reagent of 4-bromo-2-butanone
neopentyl glycol ketal and cuprous bromide.12 Unfortu-
nately, only the starting material was recovered along
[R]23 ) -26.1° (c 0.38, CHCl3), respectively.
(9) As broadly estimated by 13C NMR, the use of NaBH4, H2/Raney-
Ni, and bis(2-methoxyethoxy)aluminium hydride (Red-Al) gave respec-
tively a 1:1, 2:3, and 1:3 epimeric mixture of 10a and 10b. Reactions
with H2/Pd-C and LiAlH(t-BuO)3 were ineffective.
(10) Similar behavior was observed by G. Solladie´ and co-workers
for the reduction of â-ketosulfoxides: (a) Solladie´, G.; Greck, C.;
Demailly, G.; Solladie´-Cavallo, A. Tetrahedron Lett. 1982, 23, 5047-
5050. Unlike these authors, the use of additives such as ZnCl2, CeCl3,
and MgBr2 did not affect the observed ratios in the case of the reduction
of ketone 4: (b) Solladie´, G.; Demailly, G.; Greck, C. Tetrahedron Lett.
1985, 26, 435-438.
D
In summary, the total synthesis of the naturally
occurring alkaloid (-)-porantheridine has been achieved
in nine steps and 20% overall yield from bicyclic amino
ether 5, readily available from L-lysine. This synthesis
nicely documents the scope of our recently reported
strategy for the stereocontrolled elaboration of trans 2,6-
disubstituted piperidine substructures.
(11) Protection of the nitrogen atom as carbamate was not conceiv-
able here, since we previously noticed that tosylation of compound 6
quantitatively led to the obtention of the bicyclic oxazolidinone 3
through intramolecular nucleophilic displacement of the tosylate group
by the carbamate moiety.
(12) Paquette, L. A.; Kang, H. J . Am. Chem. Soc. 1991, 113, 2610-
2621.
(13) (a) Sakata, Y.; Hirano, Y.; Tatemitsu, H.; Misumi, S.; Ochiai,
H.; Shibata, H. Tetrahedron 1989, 45, 4717-4727. (b) Krohn, K.;
Bernhard, S. J . Prakt. Chem. 1998, 340, 26-33.
(14) According to 13C NMR, this Wittig reaction seemed to afford
16 as a single stereoisomer whose stereochemistry (E or Z) could not
be assigned.

8404 J . Org. Chem., Vol. 64, No. 22, 1999
Notes
3H), 0.87 (br t, J ) 7.35 Hz, 3H); 13C NMR δ 202.0, 167.3, 156.5,
68.0, 62.0, 59.3, 50.9, 48.8, 44.2, 30.2, 26.2, 18.0, 16.9, 13.9, 13.5;
IR (HCBr3) 1735, 1705 cm-1. Anal. Calcd for C15H23NO5: C,
60.59; H, 7.79; N, 4.71. Found: C, 60.72; H, 7.83; N, 4.78.
(5S,8a S)-5-(2-Oxo-p en t-1-yl)h exa h yd r ooxa zolo-[3,4-a ]p y-
r id in -3-on e (4). A mixture of compounds 9 (2.80 g, 9.43 mmol)
and potassium carbonate (8.40 g, 60.87 mmol) in a 2:1 mixture
of water and ethyl alcohol (40.5 mL) was stirred at 90 °C for 12
h. NaCl (1 g, 17 mmol) was then added, and the aqueous phase
was extracted with Et2O. The combined extracts were dried over
Na2SO4 and concentrated in vacuo. The crude mixture was
subjected to purification by column chromatography (6:4 EtOAc/
Exp er im en ta l Section 15
(2S,6S)-6-Allyl-N-(ca r boben zyloxy)-2-(h yd r oxym eth yl)-
p ip er id in e (6). A mixture of allyl oxazinone 34 (1.62 g, 8.95
mmol) and KOH (17.5 g, 312 mmol) in water (45 mL) and
methanol (75 mL) was heated at 120 °C (bath temperature) for
63 h. After cooling to room temperature, brine (38 mL) and CH2-
Cl2 (125 mL) were added. The reaction mixture was stirred and
then decanted, and the two phases were separated. The aqueous
layer was extracted with CH2Cl2, and the combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The
obtained crude amino alcohol was dissolved in CH2Cl2 (55 mL),
and Na2CO3 (2.1 g, 19.8 mmol) was added. After cooling to 0 °C,
benzyl chloroformate (1.40 mL, 9.81 mmol) was added dropwise.
The reaction mixture was stirred for 16 h and then filtered and
concentrated in vacuo. Column chromatography of the residue
(3:7 EtOAc/cyclohexane) yielded alcohol 6 (1.45 g, 56%) as a
cyclohexane), yielding compound 4 (1.92 g, 91%) as a yellow oil:
1
[R]24 ) -10.8° (c 1.11, MeOH); H NMR δ 4.55-4.45 (m, 1H),
D
4.37 (t, J ) 8.10 Hz, 1H), 3.87 (dd, J ) 8.10, 6.05 Hz, 1H), 3.75-
3.60 (m, 1H), 2.64 (1/2 AB q, J ) 7.8 Hz, 1H), 2.63 (1/2 AB q, J )
7.8 Hz, 1H), 2.55-2.30 (m, 2H), 1.85-1.25 (m, 8H), 0.87 (t, J )
7.40 Hz, 3H); 13C NMR δ 208.2, 156.6, 68.3, 50.7, 45.9, 44.4, 43.1,
30.2, 27.2, 17.9, 17.0, 13.6; IR (neat) 1735, 1705 cm-1. Anal. Calcd
for C12H19NO3: C, 63.98; H, 8.50; N, 6.22. Found: C, 63.98; H,
8.52; N, 6.18.
yellow oil: [R]23 ) -32° (c 0.99, MeOH); 1H NMR δ 7.40-7.15
D
(m, 5H), 5.75-5.50 (m, 1H), 5.15-4.85 (m, 4H), 4.30-4.12 (m,
1H), 3.95 (br s, 1H), 3.85-3.60 (m, 2H), 3.60-3.40 (m, 1H), 2.50-
2.35 (m, 1H), 2.25-2.05 (m, 1H), 1.80-1.40 (m, 6H); 13C NMR δ
156.2, 136.5, 134.9, 128.5, 128.0, 127.8, 117.1, 67.0, 65.0, 55.1,
52.6, 36.2, 25.7 (2C), 16.9; IR (neat) 3450, 1690 cm-1. Anal. Calcd
for C17H23NO3: C, 70.56; H, 8.00; N, 4.84. Found: C, 70.43; H,
8.08; N, 4.85.
(5S,8a S)-5[(2R)-(2-H yd r oxyp en t yl)]h exa h yd r ooxa zolo-
[3,4-a ]p yr id in -3-on e (10a ) a n d (5S,8a S)-5[(2S)-(2-Hyd r oxy-
p en tyl)]-h exa h yd r ooxa zolo[3,4-a ]p yr id in -3-on e (10b). To a
cooled solution of ketone 4 (2.63 g, 11.69 mmol) in THF (40 mL)
at -78 °C was added dropwise a 1 M solution of lithium
triethylborohydride (Super-H) in THF (14.6 mL, 14.6 mmol). The
reaction mixture was stirred for 12 h at -78 °C and then
quenched at this temperature with a saturated aqueous solution
of sodium bicarbonate (20 mL). The reaction mixture was then
stirred at 0 °C (ice bath) for 30 min, and 35% aqueous hydrogen
peroxide solution (10 mL) was added. After stirring for 30 min
more, the reaction mixture was concentrated in vacuo. The
aqueous layer was extracted with CH2Cl2. The combined organic
layers were dried over Na2SO4 and concentrated in vacuo.
Column chromatography (7:3 EtOAc/cyclohexane) allowed the
separation of the two diastereoisomers 10a (2.14 g, 81%) as a
colorless oil and 10b (483 mg, 18%) as a white solid. For 10a :
(5S,8S)-8-(Hyd r oxym eth yl)-3-(iod om eth yl)h exa h yd r op y-
r id o[1,2-c][1,3]oxa zin -1-on e (7). To a solution of piperidine 6
(146 mg, 0.51 mmol) in CH2Cl2 (5 mL) at 0 °C was added iodine
(519 mg, 2.05 mmol). The reaction mixture was stirred for 18 h
at this temperature. After stirring at room temperature for 4 h
more, a saturated aqueous solution of sodium thiosulfate (3 mL)
was added. The organic layer was dried over Na2SO4 and
concentrated in vacuo. Two successive column chromatography
fractionations (3:7 EtOAc/cyclohexane then 1:9 EtOAc/cyclohex-
ane) allowed the separation of the two diastereomers 7a (35 mg,
21%) and 7b (36 mg, 22%) as colorless liquids. For 7a (less
polar): 1H NMR δ 4.60-4.45 (m,1H), 4.35-4.17 (m, 1H), 3.78
(t, J ) 11.35 Hz, 1H), 3.61 (dd, J ) 11.35, 4.40 Hz, 1H), 3.55-
3.40 (m, 1H), 3.35 (dd, J ) 10.40, 5.08 Hz, 1H), 3.25 (dd, J )
10.40, 8.13 Hz, 1H), 2.67 (br s, 1H), 2.17 (dt, J ) 14.23, 6.88 Hz,
1H), 1.92 (ddd, J ) 14.23, 6.23, 4.58 Hz, 1H), 1.70-1.15 (m, 6H);
13C NMR δ 154.7, 73.1, 61.5, 53.4, 46.8, 32.8, 29.8, 24.9, 19.6,
4.6; IR (neat) 3340, 1680 cm-1; For 7b (more polar): 1H NMR δ
4.70-4.50 (m, 1H), 4.30-4.10 (m, 1H), 3.74 (t, J ) 11.30 Hz,
1H), 3.59 (dd, J ) 11.30, 6.08 Hz, 1H), 3.55-3.35 (m, 1H), 3.30
(dd, J ) 10.44, 4.43 Hz, 1H), 3.16 (dd, J ) 10.44, 7.10 Hz, 1H),
2.50 (br s, 1H), 2.29 (ddd, J ) 13.58, 4.70, 1.78 Hz, 1H), 1.75 (t,
J ) 13.58, 1H), 1.65-0.60 (m, 6H); 13C NMR δ 154.2, 73.9, 61.5,
[R]22 ) -5.7° (c 1.12, MeOH); 1H NMR δ 4.38-4.29 (m, 1H),
D
4.05 (m, 1H), 3.85-3.75 (m, 2H), 3.65-3.52 (m, 1H), 2.90 (br s,
1H), 1.85-1.10 (series of m, 12H), 0.85 (t, J ) 7.05 Hz, 3H); 13
C
NMR δ 157.2, 69.2, 66.5, 50.6, 47.5, 39.7, 37.4, 30.6, 27.9, 18.6,
17.9, 13.9. For 10b: mp 45.5-46.5 °C; [R]24 ) + 13.5° (c 1.08,
D
MeOH); 1H NMR δ 4.50 (t, J ) 8.1 Hz, 1H), 4.32-4.10 (m, 1H),
3.97-3.55 (m, 3H), 3.55-3.30 (m, 1H), 2.00-1.05 (series of m,
12H), 0.90 (t, J ) 6.53 Hz, 3H); 13C NMR δ 158.4, 69.4, 67.0,
50.5, 45.9, 39.1, 38.8, 30.6, 28.2, 19.2, 18.2, 14.1; IR (HCBr3)
3430, 1720 cm-1. Anal. Calcd for C12H21NO3: C, 63.41; H, 9.31;
N, 6.16. Found: C, 63.41; H, 9.32; N, 6.08.
52.5, 49.6, 35.7, 33.0, 24.8, 18.8, 6.1; IR (neat) 3350, 1680 cm-1
.
(5S,8a S)-Eth yl 3-Oxo-2-(3-oxoh exa h yd r ooxa zolo[3,4-a ]-
p yr id in -5-yl)h exa n oa te (9). To a cooled solution of compound
5 (1.80 g, 10.53 mmol) in CH2Cl2 (50 mL) at -78 °C was added
successively ethyl 3-(trimethylsilyloxy)-2-hexenoate8 8 (12.3 g,
53.48 mmol) and slowly trimethylsilyl triflate (4 mL, 20.70
mmol). The reaction mixture was allowed to warm to room
temperature and then quenched with saturated aqueous solution
of sodium bicarbonate. The organic layer was washed with water,
and the combined aqueous layers were extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4 and
concentrated in vacuo. Column chromatography (1:1 EtOAc/
cyclohexane) allowed the separation of the two diastereoisomers
9a (1.35 g) and 9b (1.45 g) as yellow solids (90% overall yield).
(5S,8aS)-5-[(2R)-2-(Ben zyloxy)pen tyl]h exah ydr ooxazolo-
[3,4-a ]p yr id in -3-on e (11). To a mixture of NaH (0.84 g, 35
mmol) and tetrabutylammonium iodide (35 mg, 0.095 mmol) in
anhydrous DMF (31 mL) was added a solution of alcohol 10a
(1.95 g, 8.59 mmol) in DMF (30 mL) at room temperature. The
mixture was stirred for 1 h, and then benzyl bromide (1.13 mL,
9.50 mmol) was added. The reaction mixture was stirred for 16
h and then treated with 3 M HCl aqueous solution. The aqueous
layer was extracted with EtOAc. The combined organic layers
were washed with aqueous 3 M HCl solution, dried over Na2-
SO4, and concentrated in vacuo. Column chromatography (1:1
EtOAc/cyclohexane) afforded the expected compound 11 (2.35
g, 86%) as a yellow oil: [R]22D ) -13.7° (c 1.18, MeOH); 1H NMR
δ 7.31-7.19 (m, 5H), 4.48 (d, J ) 11.38 Hz, 1H), 4.32 (d, J )
11.38, 1H), 4.02-3.91 (m, 2H), 3.75-3.45 (m, 2H), 3.35 (quint,
J ) 5.5 Hz, 1H), 2.00-1.80 (m, 2H), 1.60-1.15 (m, 10 H), 0.87
(t, J ) 7.25 Hz, 3H); 13C NMR δ 156.8, 138.5, 128.0, 127.5, 126.9,
76.4, 70.3, 68.0, 50.1, 47.2, 35.4, 34.2; 30.4, 27.7, 17.8 (2C), 14.0;
IR (neat) 1750 cm-1. Anal. Calcd for C19H27NO3: C, 71.89; H,
8.57; N, 4.41. Found: C, 71.79; H, 8.56; N, 4.37.
For 9a (less polar): mp 74.5-75.5 °C; [R]23 ) + 56.5° (c 1.01,
D
MeOH); 1H NMR δ 4.79 (dd, J ) 11.68, 4.30 Hz, 1H), 4.35-4.15
(m, 3H), 3.89 (dd, J ) 8.60, 3.90 Hz, 1H), 3.82-3.65 (m, 2H),
2.69 (dt, J ) 18.33, 7.10 Hz, 1H), 2.43 (dt, J ) 18.33, 7.10 Hz,
1H), 1.85-1.37 (series of m, 8H), 1.28 (t, J ) 7.13 Hz, 3H), 0.86
(t, J ) 7.45 Hz, 3H); 13C NMR δ 203.3, 167.7, 156.8, 68.1, 61.8,
60.3, 50.5, 49.0, 40.6, 30.0, 26.2, 17.9, 16.5, 14.0, 13.3; For 9b
(more polar): mp 74.5-75.5 °C; [R]24D ) + 78.4° (c 0.98, MeOH);
1H NMR δ 4.72 (dd, J ) 11.40, 4.93 Hz, 1H), 4.30 (t, J ) 7.50
Hz, 1H), 4.15 (q, J ) 7.10 Hz, 2H), 3.95-3.75 (m, 3H), 2.47 (br
t, J ) 7.18 Hz, 2H), 1.95-1.27 (m, 8H), 1.20 (t, J ) 7.10 Hz,
(2S,6S)-2-(Hyd r oxym eth yl)-6-[(2R)-2-(ben zyloxy)p en tyl]-
p ip er id in e (12). A solution of compound 11 (2.4 g, 7.57 mmol)
and NaOH (15 g, 375 mmol) in a mixture of water (36 mL) and
MeOH (66 mL) was heated at reflux temperature for 64 h. The
reaction mixture was then cooled to room temperature and
concentrated in vacuo. The aqueous layer was extracted with
CH2Cl2, and the combined organic layers were dried over Na2-
SO4. Concentration in vacuo gave a crude product which was
(15) For general experimental information, please see Dhimane, H.;
Vanucci-Bacque´, C.; Hamon, L.; Lhommet, G. Eur. J . Org. Chem. 1998,
1955-1963.

Notes
J . Org. Chem., Vol. 64, No. 22, 1999 8405
purified by column chromatography (88.5:10:1.5 CH2Cl2/MeOH/
Et2O (50 mL) was then added, and the organic layer was washed
with water before drying over Na2SO4. Concentration in vacuo
afforded crude intermediate aldehyde.
NH4OH (28%)) yielding amino alcohol 12 (2 g, 91%) as a yellow
oil: [R]22 ) -20.9° (c 1.03, MeOH); 1H NMR δ 7.55-7.30 (m,
D
To a cooled solution of triphenylphosphonium bromide 1513
(1.81 g, 3.63 mmol) in THF (25 mL) at -40 °C was added a 1.35
M solution of n-BuLi in hexane (2.95 mL, 3.98 mmol). The
mixture was stirred for 30 min at this temperature before the
dropwise addition of a solution of the previously obtained
aldehyde in THF (5 mL). The reaction mixture was allowed to
warm to room temperature and stirred for 2 h more. Water (30
mL) and NaCl (1 g, 17 mmol) were then added. The aqueous
layer was extracted with Et2O. The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. Column chroma-
tography (1:4 EtOAc/cyclohexane) yielded compound 16 (692 mg,
85%) as an orange oil: [R]19D ) +37.9° (c 1.05, MeOH); 1H NMR
δ 7.80-7.30 (m, 10H), 6.00-5.65 (m, 2H), 5.50-5.20 (m, 2H),
5.05-4.85 (m, 1H), 4.69 (AB q, J ) 11.5 Hz, 2H), 4.45-4.25 (m,
1H), 3.80-3.50 (m, 5H), 2.85-2.65 (m, 2H), 2.40-1.35 (series
of m including s at δ 1.55, 3H, total 15H), 1.30-0.85 (m, 9H);
13C NMR δ 155.9, 139.1, 137.0, 133.0, 128.5, 128.4, 127.8, 127.7,
127.4, 125.2, 98.9, 76.4, 70.4, 70.2, 66.8, 50.1, 49.8, 38.2, 36.0,
35.0, 30.0, 28.0, 25.6, 22.7, 22.6, 21.2, 18.6, 16.0, 14.3; IR (neat)
3050, 1705 cm-1. Anal. Calcd for C35H49NO5: C, 74.57; H, 8.76;
N, 2.48. Found: C, 74.58; H, 8.86; N, 2.42.
P or a n th er id in e (1). Compound 16 (198 mg, 0.35 mmol)
dissolved in MeOH (10 mL) was subjected to hydrogenation (1
atm) in the presence of 10% Pd/C (198 mg) at room temperature
for 5 h. The mixture was then filtered over a Celite pad, which
was rinsed with MeOH. The solvent was evaporated in vacuo
yielding an intermediate amino alcohol (110 mg, 92%). A mixture
of the latter and p-TsOH (65 mg, 0.34 mmol) in benzene (5 mL)
was stirred at reflux temperature for 3 h, at which point 4 Å
molecular sieves (3 g) were added. Stirring at reflux temperature
was continued for 3 h. The reaction mixture was then filtered
and the solid residue washed with Et2O. The organic layer was
stirred in the presence of Na2CO3 (2 g, 19 mmol) for 15 min
before filtration and evaporation of the solvent in vacuo. Column
chromatography (2:8 CH2Cl2/MeOH) of the residue yielded
expected porantheridine (1) (39 mg, 47% from 16) as a colorless
oil: [R]19D ) -25° (c 0.50, CHCl3); 1H NMR δ 4.05-3.85 (m, 1H),
3.80-3.60 (m, 1H), 3.05-2.85 (m, 1H), 2.05-1.10 (series of m,
21H), 0.92 (t, J ) 7 Hz, 3H); 13C NMR δ 86.2, 69.1, 49.5, 48.4,
40.0, 39.2, 34.1, 34.0, 30.8, 27.3, 23.7, 19.7, 19.3, 18.0, 14.3.
5H), 4.70 (d, J ) 11.55 Hz, 1H), 4.57 (d, J ) 11.55 Hz, 1H), 3.75-
3.45 (m, 3H), 3.20-3.00 (m, 2H), 2.33 (br s, 2H), 2.00-1.25 (m,
12H), 1.06 (t, J ) 7.08 Hz, 3H); 13C NMR δ 138.8, 128.4, 127.9,
127.6, 77.1, 70.7, 63.4, 52.0, 48.0, 39.0, 36.1, 31.6, 27.3, 20.0,
18.3, 14.4; IR (neat) 3400 cm-1
.
(2S,6S)-Tolu en e-4-su lfon ic Acid 6-(2-(ben zyloxy)p en tyl)-
1-(tolu en e-4-su lfon yl)p ip er id in -2-yl Meth yl Ester (13). To
an ice-cooled mixture of amino alcohol 12 (458 mg, 1.57 mmol)
and tosyl chloride (1.20 g, 6.32 mmol) in CH2Cl2 (3 mL) was
added dropwise Et3N (3 mL, 21.5 mmol). The reaction mixture
was then stirred at room temperature for 5 h. Water (10 mL)
was added, and stirring was continued for 1 h. The separated
organic layer was washed with 3 M aqueous HCl solution. The
combined aqueous layers were extracted with CH2Cl2. The
combined organic layers were dried over Na2SO4, concentrated
in vacuo, and column chromatographed (1:4 EtOAc/cyclohexane)
to afford compound 13 (567 mg, 60%) as an oil: [R]25 ) -17.8°
D
(c 1.03, MeOH); 1H NMR δ 7.57 (d, J ) 8.33 Hz, 2H), 7.47 (d, J
) 8.33 Hz, 2H), 7.20-6.90 (m, 9H), 4.35-3.90 (m, 4H), 3.80-
3.55 (m, 2H), 3.10-2.95 (m, 1H), 2.26 (s, 3H), 2.20 (s, 3H), 1.70-
0.90 (series of m, 12 H), 0.68 (t, J ) 7.08 Hz, 3H); 13C NMR δ
145.0, 143.1, 139.3, 138.7, 132.8, 130.0, 129.6, 128.4, 128.0, 127.9,
127.6, 127.2, 75.4, 70.4, 54.4, 52.8, 36.1, 35.9, 27.0, 26.4, 21.7,
21.5, 19.0, 18.4, 14.2; IR (neat) 3050, 815 cm-1
.
(2S,6S)-N-(Ben zyloxyca r b on yl)-2-(h yd r oxym et h yl)-6-
[(2R)-2-(ben zyloxy)p en tyl]p ip er id in e (14). To a mixture of
compound 12 (0.8 g, 2.75 mmol) and sodium carbonate (290 mg,
20.74 mmol) in CH2Cl2 (15 mL) was added dropwise benzyl
chloroformate (390 µL, 2.73 mmol). The reaction mixture was
stirred for 19 h and then filtered and concentrated in vacuo.
Column chromatography (1:1 EtOAc/cyclohexane) afforded the
expected compound 14 (1.1 g, 94%) as a colorless oil: [R]20
)
D
1
-11.9° (c 0.97, MeOH); H NMR δ 7.40-7.05 (m, 10H), 5.10 (s,
2H), 4.50-4.25 (m, 3H), 4.00 (br s, 1H), 3.80-3.55 (m, 2H), 3.50-
3.15 (m, 2H), 2.00-1.10 (series of m, 12H), 0.79 (t, J ) 7.08 Hz,
3H); 13C NMR δ 156.2, 138.8, 136.6, 128.6, 128.4, 128.1, 128.0,
127.9, 127.6, 76.0, 70.6, 67.3, 65.0, 55.7, 50.6, 35.9, 35.3, 27.2,
26.9, 18.4, 18.3, 14.3; IR (neat) 3450, 1685 cm-1. Anal. Calcd for
C
26H35NO4: C, 73.38; H, 8.29; N, 3.29. Found: C, 73.39; H, 8.38;
N, 3.25.
(2S,6S)-N-(Ben zyloxyca r bon yl)-2-[3-(2,5,5-tr im eth yl[1,3]-
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
data for 1, 7, 12, and 13 and X-ray structural analyses of
alcohol 10b containing ORTEP diagram, crystal data, tables
of atomic coordinates, thermal parameters, bond lengths and
angles. This material is available free of charge via the
Internet at http://pubs.acs.org.
d ioxa n -2-yl)p r op en -1-yl]-6-[(2R)-2-(ben zyloxy)p en tyl]p ip -
er id in e (16). To a cooled solution of oxalyl chloride (190 µL,
2.18 mmol) in CH2Cl2 (25 mL) at -78 °C was added dropwise
DMSO (310 µL, 4.37 mmol). After stirring for 15 min, a solution
of alcohol 14 (616 mg, 1.45 mmol) in CH2Cl2 (5 mL) was added
dropwise. The reaction mixture was stirred for 1 h at -78 °C,
and then triethylamine (930 µL, 6.68 mmol) was added. The
reaction mixture was allowed to warm to room temperature.
J O9906476