Use of the oxazole-olefin Diels-Alder reaction in the total synthesis of the monoterpene alkaloids (-)-plectrodorine and (+)-oxerine

Article abstract of DOI:10.1248/cpb.54.63

A full account of the total synthesis of two monoterpene alkaloids, (-)-plectrodorine [(-)-1] and (+)-oxerine [(+)-3], is presented. The key steps involved are the formation of the oxazole alcohol 10 from the γ-butyrolactone 9 and the intramolecular Diels

Full text of DOI:10.1248/cpb.54.63

January 2006
Chem. Pharm. Bull. 54(1) 63—67 (2006)
63
Use of the Oxazole–Olefin Diels–Alder Reaction in the Total Synthesis of
the Monoterpene Alkaloids (ꢀ)-Plectrodorine and (ꢁ)-Oxerine
b
Masashi OHBA,*,a Rie IZUTA,b and Emi SHIMIZU
a Advanced Science Research Center, Kanazawa University; and b Faculty of Pharmaceutical Sciences, Kanazawa
University; Kakuma-machi, Kanazawa 920–1192, Japan. Received July 21, 2005; accepted September 20, 2005
A full account of the total synthesis of two monoterpene alkaloids, (ꢀ)-plectrodorine [(ꢀ)-1] and (ꢁ)-
oxerine [(ꢁ)-3], is presented. The key steps involved are the formation of the oxazole alcohol 10 from the g-buty-
rolactone 9 and the intramolecular Diels–Alder reaction of the oxazole–olefins 13a, b. Since the sign of specific
rotation for the synthetic (ꢁ)-3 was different from that reported for natural oxerine, the absolute configuration
of this alkaloid is not yet fully understood.
Key words oxazole–olefin; Diels–Alder reaction; cyclopenta[c]pyridine; monoterpene alkaloid; plectrodorine; oxerine
Oxazoles have been shown to behave as dependable azadi- the g-butyrolactone 6 according to the procedure of Ja-
ene components in Diels–Alder reactions.1) Since Kon- cobi.32,33)
drat’eva reported the first example of a Diels–Alder reaction
The requisite g-butyrolactone 6 was readily obtained from
of an oxazole with an olefin to produce a pyridine in 1957,2,3) Seebach’s dioxolanone 7.34,35) Thus, reduction of 7 with
this methodology has become a valuable tool for the prepara- BH3·Me2S followed by alkaline hydrolysis and acid-pro-
tion of highly substituted pyridines, such as pyridoxine and moted lactone formation afforded 6 in 73% yield. The ab-
its analogues. Despite an early recognition of the practical solute configuration of 6 was further substantiated by the
value of the oxazole–olefin Diels–Alder reaction, there are identity of specific rotation of the benzoate 8, derived from 6,
few reports applying this cycloaddition intramolecularly to with the data reported in the literature.36) After protection of
the synthesis of pyridine-containing natural products.4—19) In the tertiary hydroxy group in 6 with tert-butyldimethylsilyl
the present study, we sought to explore the feasibility of in- triflate (TBDMSOTf) to afford the lactone 9, the formation
tramolecular oxazole–olefin Diels–Alder reaction for an effi- of an oxazole ring was carried out by treatment of 9 with
cient construction of two monoterpene alkaloids possessing 2.5 eq of a-lithiated methyl isocyanide in THF at ꢀ78 °C for
the cyclopenta[c]pyridine ring system.20—23)
3 h followed by addition of AcOH, a slight modification of
Plectrodorine (1), selected as the first target for the the Jacobi method,32,33) giving the alcohol 10 in 66% yield.
monoterpene alkaloids, was isolated as a racemate together With a view to introducing an olefinic dienophile, the alcohol
with isoplectrodorine (2) from the aerial parts of Plectronia 10 was converted into the aldehyde 11 in 85% yield by
odorata (Rubiaceae) by Koch and co-workers.24) The struc- means of the Swern oxidation.37)
ture and relative stereochemistry of 1 were elucidated
Coupling reaction of the aldehyde 11 and methyl trans-3-
through a combination of spectral analysis and chemical iodoacrylate38) with CrCl2 and a catalytic amount of NiCl2 in
transformation. The Koch group25) then described the isola- DMSO39—41) was first performed directed toward the synthe-
tion of oxerine from the aerial parts of Oxera morieri (Verbe- sis of plectrodorine (1), furnishing the allylic alcohol 12a as
naceae) and proposed its absolute stereochemistry to be a 2 : 1 diastereoisomeric mixture in 61% yield. The oxa-
(5R,7S)-3 by partial synthesis of oxerine from harpagide of zole–olefin 13a desired for the intramolecular Diels–Alder
known absolute configuration.26) We chose (5R,7S)-3 as the reaction was then obtained in 89% yield by oxidation of 12a
second target to demonstrate the versatility of our synthetic with the Dess–Martin periodinane.42—44) When a 0.05 M solu-
strategy, although racemic synthesis of oxerine has been ac- tion of 13a in o-dichlorobenzene (o-DCB) was heated at
complished by several research groups.27—30) A brief account 150 °C for 48 h, the bicyclic pyridine 14a was obtained in
of the results reported here has been published in a prelimi- 37% yield, together with recovered 13a (23%). On treatment
nary form.31)
For the construction of the cyclopenta[c]pyridine skeleton
via the intramolecular Diels–Alder reaction of oxazoles, we
planned to employ the oxazole–olefin 4. The introduction of
suitable olefinic dienophiles to the oxazole aldehyde 5 would
provide 4, whereas the oxazole ring of 5 was envisaged to
arise from the addition of a-lithiated methyl isocyanide to
Chart 1
∗ To whom correspondence should be addressed. e-mail: ohba@p.kanazawa-u.ac.jp
© 2006 Pharmaceutical Society of Japan

64
Vol. 54, No. 1
Chart 2
of the solution at the higher temperature (180 °C) for 24 h,
both the yield of 14a and the recovery of 13a decreased to
19% and 10%, respectively. The carbonyl group of 14a was
reduced with NaBH4 in MeOH at 0 °C to generate the alco-
hol 15a (75% yield), whose stereochemistry was determined
on the basis of 7% NOE enhancements of C(6)-Hb signal
observed on separate irradiations of C(5)-H and C(7)-Me
signals, together with its C(5)-epimer (10% yield). The high
stereoselectivity in reduction of 14a is probably due to access
of the hydride from an orientation avoiding the bulky tert-
butyldimethylsilyloxy group at the 7-position. Finally, depro-
tection of 15a with tetrabutylammonium fluoride gave the
first target (ꢀ)-1 in 73% yield. The synthetic (ꢀ)-1 proved to
be virtually identical with natural plectrodorine24) by a direct
comparison of the UV, 1H-NMR, and mass spectra.
Chart 3
We next turned our attention to the synthesis of oxerine
(3). On treatment with vinylmagnesium bromide in THF at
ꢀ10 °C, the aldehyde 11 was converted into a 1 : 1 di-
astereoisomeric mixture of the allylic alcohol 12b (82%
yield), which was then oxidized with the Dess–Martin perio-
dinane to provide the oxazole–olefin 13b in 93% yield. The
intramolecular Diels–Alder reaction of 13b was carried out
by heating its 0.05 M o-DCB solution at 150 °C, affording the
desired pyridine 14b as a sole isolable product in 23% yield
with the complete disappearance of 13b after 9 h. A parallel
result was also obtained by the reaction of 13b at 180 °C.
The observed low yield of 14b is presumably due to the de-
composition of the terminal olefin 13b at elevated tempera-
ture. Although we have recently reported that the conversion
of the oxazole–olefin 16 into the bicyclic pyridine 17 was
promoted by addition of a catalytic amount of Cu(OTf)2,45)
the catalyst was not effective for 13b. Thus, treatment of 13b
in the presence of Cu(OTf)2 (2 mol%) in o-DCB at 180 °C
for 40 min proceeded with accompanying deprotection fol-
lowed by elimination of H2O, furnishing the olefin 1846) in
38% yield. Reduction of 14b with NaBH4 in EtOH at 0 °C
provided the alcohol 15b as a sole isomer in 84% yield.
Again, the stereochemistry of 15b was ascertained by the
NOE experiments. The second target (ꢁ)-3 [[a]D23 ꢁ10.6°
(cꢂ0.21, MeOH)] was obtained in 91% yield via deprotec-
tion of 15b with tetrabutylammonium fluoride. Although the
Fig. 1. NOE Data of the Alcohols 15a, b
Chart 4
found to match those of natural oxerine [[a]D20 ꢀ11°
(cꢂ0.20, MeOH)],25) the signs of specific rotation for the two
samples were opposite. Unfortunately, we were unable to
draw a chiroptical comparison between (ꢁ)-3 and oxerine on
account of paucity of the natural sample. The circular dichro-
ism (CD) spectrum and specific rotation [[a]D24 ꢁ8.0°
(cꢂ0.15, MeOH)] of a sample newly derived from harpagide
by Koch as well as its 1H-NMR spectrum were identical with
those of (ꢁ)-3. However, because of an incomplete identifi-
1
UV, H-NMR, and mass spectra of the synthetic (ꢁ)-3 were

January 2006
65
tion (4.0 ml, 6.0 mmol) of BuLi in hexane was added dropwise over 15 min.
After the mixture had been stirred for 15 min, a solution of 9 (560 mg,
2.4 mmol) in THF (5 ml) was introduced dropwise over 10 min. Stirring was
then continued for a further 3 h, and the reaction was quenched by adding
AcOH (6.0 ml). The mixture was brought to room temperature and concen-
trated under reduced pressure. The residue was partitioned between H2O and
ether, and the ethereal extracts were washed with saturated aqueous NaCl,
dried, and concentrated. Purification of the residual oil by flash chromatogra-
cation of oxerine and the sample prepared from harpagide,
the absolute configuration of oxerine remains undefined until
this alkaloid is further isolated from natural sources.
In conclusion, the total synthesis of (ꢀ)-plectrodorine
[(ꢀ)-1] and (ꢁ)-oxerine [(ꢁ)-3] possessing the cyclopenta-
[c]pyridine ring system has been accomplished in eight steps,
respectively, from the g-butyrolactone 6. It also exemplifies
the usefulness of the intramolecular oxazole–olefin Diels–
Alder reaction for the synthesis of annulated pyridine-con-
taining natural products.
phy [AcOEt–hexane (1 : 1)] gave 10 (438 mg, 66%) as a colorless oil, [a]D24
film
ꢀ27.4° (cꢂ0.51, CHCl3); CI-MS m/z: 272 (MꢁHꢁ); IR n : 3370 cmꢀ1
max
1
(OH); H-NMR (CDCl3) d: ꢀ0.11 and 0.04 (3H each, s, SiMe2), 0.89 (9H,
s, tert-Bu), 1.68 (3H, s, CMe), 1.98 (1H, ddd, Jꢂ14, 6.5, 5.5 Hz) and 2.20
(1H, ddd, Jꢂ14, 7, 6 Hz) [C(b)H2], 2.37 (1H, br, OH), 3.77 [2H, m,
C(a)H2], 6.94 [1H, s, C(4)H], 7.83 [1H, s, C(2)H]; HR-FAB-MS m/z Calcd
for C13H26NO3Si: 272.1682, Found: 272.1687.
Experimental
General Notes All melting points were determined on a Yamato MP-1
capillary melting point apparatus. Flash chromatography47) was carried out
using Merck silica gel 60 (No. 9385). The organic solutions obtained after
(
bS)-b-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-b-methyl-5-oxa-
zolepropanal (11) A solution of oxalyl chloride (0.37 ml, 4.2 mmol) in
extraction were dried over anhydrous MgSO4 and concentrated under re- CH2Cl2 (12 ml) was cooled to ꢀ60 °C in an atmosphere of N2, and a solution
duced pressure. The ratios of solvents in mixtures are shown in v/v. Spectra
of DMSO (0.60 ml, 8.5 mmol) in CH2Cl2 (2 ml) was added. After the mix-
reported herein were recorded on a JEOL JMS-SX102A mass spectrometer, ture had been stirred for 5 min, a solution of 10 (562 mg, 2.1 mmol) in
a Hitachi 330 UV spectrophotometer, a Shimadzu IR-460 or a Shimadzu CH2Cl2 (4 ml) was added dropwise over 2 min. Stirring was then continued
FTIR-8100 IR spectrophotometer, a JASCO J-725 spectropolarimeter, or a at ꢀ60 °C for a further 30 min. The reaction mixture, after addition of Et3N
JEOL JNM-GSX-500 (1H 500 MHz) NMR spectrometer. Chemical shifts
(2.4 ml), was brought to room temperature and partitioned between CH2Cl2
are reported in ppm downfield from internal Me4Si. Optical rotations were and H2O. The CH2Cl2 extracts were washed with saturated aqueous NaCl,
measured with a Horiba SEPA-300 polarimeter using a 1-dm sample tube.
dried, and concentrated to leave a yellow oil. Purification by flash chro-
The following abbreviations are used: brꢂbroad, dꢂdoublet, ddꢂdoublet- matography [hexane–AcOEt (2 : 1)] furnished 11 (474 mg, 85%) as a
of-doublets, dddꢂdoublet-of-dd’s, mꢂmultiplet, sꢂsinglet, shꢂshoulder.
(3S)-Dihydro-3-hydroxy-3-methyl-2(3H)-furanone (6) A stirred solu-
tion of 7 (326 mg, 1.5 mmol) in THF (8 ml) was cooled to 0 °C, and a 2.0 M
solution (1.8 ml, 3.6 mmol) of BH3·Me2S in THF was added dropwise over
slightly yellow oil, [a]D24 ꢀ44.1° (cꢂ0.51, CHCl3); FAB-MS m/z: 270 (Mꢁ
film 1
Hꢁ); IR n : 1725 cmꢀ1 (CHO); H-NMR (CDCl3) d: ꢀ0.12 and 0.04 (3H
max
each, s, SiMe2), 0.87 (9H, s, tert-Bu), 1.73 (3H, s, CMe), 2.70 and 2.89 [1H
each, dd, Jꢂ15.5, 3 Hz, C(a)H2], 6.98 [1H, s, C(4)H], 7.85 [1H, s, C(2)H],
15 min. After stirring at room temperature for 28 h, H2O (3 ml) and K2CO3 9.86 (1H, dd, Jꢂ3, 3 Hz, CHO); HR-FAB-MS m/z Calcd for C13H24NO3Si:
(360 mg) were added successively under cooling. The mixture was then ex-
tracted with ether and the ethereal extracts were washed with saturated aque-
270.1526, Found: 270.1525.
(2E,6S)-6-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-4-hydroxy-6-(5-oxa-
ous NaCl, dried, and concentrated. The resulting yellow oil was dissolved in zolyl)-2-heptenoic Acid Methyl Ester (12a) A solution of 11 (472 mg,
EtOH (6 ml) and cooled to 0 °C. After addition of 2 N aqueous NaOH (3 ml),
the solution was stirred at room temperature for 30 min, concentrated in
vacuo by half, acidified with 10% aqueous HCl, and continuously extracted
1.75 mmol) and methyl trans-3-iodoacrylate38) (1.12 g, 5.3 mmol) in DMSO
(25 ml) was stirred in an atmosphere of Ar, and CrCl2 (1.29 g, 10.5 mmol)
containing NiCl2 (2.3 mg, 0.018 mmol) was added in portions. The resulting
with ether for 10 h. The ethereal extracts were dried and concentrated to dark green mixture was then stirred at room temperature for 72 h. The reac-
leave a pale yellow oil, which was purified by flash chromatography tion mixture was quenched by addition of saturated aqueous NH4Cl (10 ml)
[hexane–AcOEt (1 : 1)] to yield 6 (128 mg, 73%) as a colorless oil, [a]D23
under cooling and extracted with ether. The combined ethereal extracts were
ꢀ36.3° (cꢂ0.51, CHCl3); IR n mfilamx cmꢀ1: 3410 (OH), 1768 (lactone CO); 1H- washed with saturated aqueous NaCl, dried, and concentrated. Purification
NMR (CDCl3) d: 1.51 (3H, s, Me), 2.26 (1H, ddd, Jꢂ13, 7, 4.5 Hz) and 2.44
(1H, ddd, Jꢂ13, 8, 8 Hz) [C(4)H2], 2.66 (1H, s, OH), 4.23 (1H, ddd, Jꢂ9.5,
of the residual oil by flash chromatography [hexane–AcOEt (1 : 1)] provided
12a (381 mg, 61%) as a slightly yellow oil, [a]D24 ꢀ22.6° (cꢂ0.57, CHCl3);
film
8, 7 Hz) and 4.42 (1H, ddd, Jꢂ9.5, 8, 4.5 Hz) [C(5)H2]; HR-EI-MS m/z FAB-MS m/z: 356 (MꢁHꢁ); IR n
cmꢀ1: 3410 (OH), 1725 (ester CO);
max
Calcd for C5H8O3: 116.0473, Found: 116.0470.
1H-NMR (CDCl3) d: ꢀ0.18 (1H), ꢀ0.03 (2H), 0.04 (1H), and 0.12 (2H) (s
(3S)-3-(Benzoyloxy)dihydro-3-methyl-2(3H)-furanone (8) A mixture each, SiMe2), 0.89 (3H) and 0.93 (6H) (s each, tert-Bu), 1.72 (2H) and 1.78
of 6 (70 mg, 0.6 mmol), Et3N (121 mg, 1.2 mmol), and 4-(dimethyl- (1H) (s each, CMe), 1.80 (1/3H, dd, Jꢂ14.5, 2 Hz), 1.95 (2/3H, dd, Jꢂ14.5,
amino)pyridine (10 mg, 0.08 mmol) in CH2Cl2 (3 ml) was stirred at 0 °C, and
a solution of benzoyl chloride (127 mg, 0.9 mmol) in CH2Cl2 (1 ml) was
added. After having been stirred at room temperature for 16 h, the reaction
mixture was washed successively with saturated aqueous NaHCO3 and satu-
9.5 Hz), 2.01 (2/3H, dd, Jꢂ14.5, 2.5 Hz), and 2.25 (1/3H, dd, Jꢂ14.5,
10.5 Hz) [C(5)H2], 3.72 (2H) and 3.73 (1H) (s each, CO2Me), 3.85 (2/3H)
and 3.88 (1/3H) (br each, OH), 4.48 (2/3H) and 4.71 (1/3H) (m each,
CHOH), 6.09 (2/3H) and 6.14 (1/3H) [dd each, Jꢂ15.5, 2 Hz, C(2)H], 6.81
rated aqueous NaCl, dried, and concentrated. Purification of the residual (2/3H, dd, Jꢂ15.5, 4.5 Hz) and 6.87 (1/3H, dd, Jꢂ15.5, 4 Hz) [C(3)H], 6.97
solid by flash chromatography [hexane–AcOEt (2 : 1)] provided 8 (127 mg,
(1/3H) and 6.99 (2/3H) [s each, C(4ꢃ)H], 7.85 [1H, s, C(2ꢃ)H]; 48) HR-FAB-
96%) as a colorless solid, which was recrystallized from AcOEt–hexane MS m/z Calcd for C17H30NO5Si: 356.1893, Found: 356.1902.
(2 : 1) to afford colorless plates, mp 144—146 °C; [a]D23 ꢀ16.3° (cꢂ0.91,
(
gS)-g-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-a-ethenyl-g-methyl-5-
1
CHCl3). The melting point, specific rotation, and H-NMR spectral data for oxazolepropanol (12b) A mixture of THF (5 ml) and a 0.95 M solution
this sample were in agreement with those reported in the literature.36)
(3S)-3-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]dihydro-3-methyl- ꢀ10 °C in an atmosphere of N2, and a solution of 11 (308 mg, 1.1 mmol) in
(1.7 ml, 1.6 mmol) of vinylmagnesium bromide in THF was cooled to
2(3H)-furanone (9) A solution of 6 (741 mg, 6.4 mmol) in CH2Cl2 (20 ml)
was stirred at 0 °C, and TBDMSOTf (3.7 ml, 16.1 mmol) and 2,6-lutidine
(2.6 ml, 22.3 mmol) were added in that order. After having been stirred at
THF (2 ml) was added dropwise over 5 min. After the mixture had been
stirred at ꢀ10 °C for 30 min, the reaction was quenched by adding saturated
aqueous NH4Cl (3 ml). The whole was extracted with ether, and the ethereal
room temperature for 2 h, the reaction mixture was washed with saturated extracts were washed with saturated aqueous NaCl, dried, and concentrated
aqueous NaCl, dried, and concentrated to leave a pale orange oil. Purifica-
tion by flash chromatography [hexane–AcOEt (10 : 1)] gave 9 (1.46 g, 99%)
to leave a pale yellow oil. Purification by flash chromatography [hexane–
AcOEt (5 : 2)] gave 12b (280 mg, 82%) as a colorless oil, [a]D23 ꢀ26.7°
film
as a colorless solid, mp 29.5—31 °C; [a]D24 ꢁ12.9° (cꢂ0.51, CHCl3); CI-MS (cꢂ0.49, CHCl3); FAB-MS m/z: 298 (MꢁHꢁ); IR n : 3380 cmꢀ1 (OH);
max
m/z: 231 (MꢁHꢁ); IR nmNauxjol: 1771 cmꢀ1 (lactone CO); 1H-NMR (CDCl3) d: 1H-NMR (CDCl3) d: ꢀ0.19, ꢀ0.04, 0.03, and 0.11 (3/2H each, s, SiMe2),
0.12 and 0.18 (3H each, s, SiMe2), 0.87 (9H, s, tert-Bu), 1.48 (3H, s, CMe),
0.88 and 0.93 (9/2H each, s, tert-Bu), 1.71 and 1.77 (3/2H each, s, CMe),
2.16 (1H, ddd, Jꢂ13, 7, 7 Hz) and 2.32 (1H, ddd, Jꢂ13, 7, 5 Hz) [C(4)H2], 1.74 (1/2H, dd, Jꢂ14.5, 2 Hz), 1.94 (1/2H, dd, Jꢂ14.5, 3 Hz), 1.99 (1/2H,
4.21 (1H, ddd, Jꢂ9, 7, 5 Hz) and 4.35 (1H, ddd, Jꢂ9, 7, 7 Hz) [C(5)H2];
HR-FAB-MS m/z Calcd for C11H23O3Si: 231.1416, Found: 231.1418.
dd, Jꢂ14.5, 9 Hz), and 2.27 (1/2H, dd, Jꢂ14.5, 10.5 Hz) [C(b)H2], 3.48 and
3.62 (1/2H each, br s, OH), 4.30 and 4.51 (1/2H each, br m, CHOH), 5.04
(gS)-g-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-g-methyl-5-oxa- and 5.08 (1/2H each, ddd, Jꢂ10.5, 1.5, 1.5 Hz, CHꢂCH2), 5.20 and 5.28
zolepropanol (10) A solution of methyl isocyanide (246 mg, 6.0 mmol) in
THF (12 ml) was stirred at ꢀ78 °C in an atmosphere of N2, and a 1.5 M solu-
(1/2H each, ddd, Jꢂ17.5, 1.5, 1.5 Hz, CHꢂCH2), 5.77 and 5.83 (1/2H each,
ddd, Jꢂ17.5, 10.5, 6 Hz, CHꢂCH2), 6.96 and 6.97 [1/2H each, s, C(4)H],

66
Vol. 54, No. 1
7.84 and 7.85 [1/2H each, s, C(2)H]; HR-FAB-MS m/z Calcd for was partitioned between CHCl3 and H2O. The CHCl3 extracts were washed
C15H28NO3Si: 298.1838, Found: 298.1842. with saturated aqueous NaCl, dried, and concentrated to leave a colorless oil,
(2E,6S)-6-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6-(5-oxazolyl)-4- which was then subjected to flash chromatography [hexane–AcOEt (3 : 1)].
oxo-2-heptenoic Acid Methyl Ester (13a) A solution of 12a (341 mg,
Earlier fractions provided 15a (38.0 mg, 75%) as a colorless oil, [a]D24 ꢀ4.0°
film
0.96 mmol) in CH2Cl2 (3 ml) was added to a stirred solution of the Dess–
(cꢂ0.94, CHCl3); FAB-MS m/z: 338 (MꢁHꢁ); IR n
cmꢀ1: 3480 (OH),
max
Martin periodinane42—44) (610 mg, 1.4 mmol) in CH2Cl2 (10 ml). After hav- 1708 (ester CO); H-NMR (CDCl3) d: 0.04 and 0.14 (3H each, s, SiMe2),
1
ing been stirred at room temperature for 45 min, the reaction mixture was
poured into saturated aqueous NaHCO3 (10 ml) containing Na2S2O3 (1.8 g).
The biphasic mixture was stirred for 5 min and extracted with ether. The or-
0.89 (9H, s, tert-Bu), 1.48 (3H, s, CMe), 2.33 (1H, dd, Jꢂ12.5, 8 Hz) and
2.76 (1H, dd, Jꢂ12.5, 7.5 Hz) [C(6)H2], 4.01 (3H, s, CO2Me), 5.0 (1H, br,
OH), 5.39 [1H, dd, Jꢂ8, 7.5 Hz, C(5)H], 8.79 [1H, s, C(1)H], 9.15 [1H, s,
ganic phases were combined, washed successively with saturated aqueous C(3)H]; HR-FAB-MS m/z Calcd for C17H28NO4Si: 338.1788, Found:
NaHCO3 and saturated aqueous NaCl, dried, and concentrated to leave a yel- 338.1791.
low oil, which was purified by flash chromatography [hexane–AcOEt (2 : 1)]
Later fractions in the above chromatography afforded C(5)-epimer
to afford 13a (301 mg, 89%) as a pale yellow oil, [a]D23 ꢀ90.7° (cꢂ0.50, (5.2 mg, 10%) of 15a as a colorless solid, mp 69—72 °C; [a]D24 ꢁ8.8° (cꢂ
CHCl3); FAB-MS m/z: 354 (MꢁHꢁ); IR n
cmꢀ1: 1731 (ester CO), 1690
0.26, CHCl31); FAB-MS m/z: 338 (MꢁHꢁ); IR nmNauxjol cmꢀ1: 3140 (OH), 1722
film
max
(CO); 1H-NMR (CDCl3) d: ꢀ0.16 and ꢀ0.03 (3H each, s, SiMe2), 0.84 (9H, (ester CO); H-NMR (CDCl3) d: ꢀ0.03 and 0.01 (3H each, s, SiMe2), 0.81
s, tert-Bu), 1.73 (3H, s, CMe), 2.95 and 3.26 [1H each, d, Jꢂ14 Hz, C(5)H2],
3.80 (3H, s, CO2Me), 6.62 and 7.11 [1H each, d, Jꢂ16 Hz, C(2)H, C(3)H],
(9H, s, tert-Bu), 1.73 (3H, s, CMe), 2.22 (1H, dd, Jꢂ13.5, 4.5 Hz) and 2.64
(1H, dd, Jꢂ13.5, 7.5 Hz) [C(6)H2], 4.01 (3H, s, CO2Me), 4.37 (1H, br, OH),
6.94 [1H, s, C(4ꢃ)H], 7.83 [1H, s, C(2ꢃ)H];48) HR-FAB-MS m/z Calcd for 5.61 [1H, m, C(5)H], 8.76 [1H, s, C(1)H], 9.13 [1H, s, C(3)H]; HR-FAB-MS
C17H28NO5Si: 354.1737, Found: 354.1743.
m/z Calcd for C17H28NO4Si: 338.1788, Found: 338.1789.
(5S)-5-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-(5-oxazolyl)-1-hexen-
3-one (13b) A mixture of 12b (563 mg, 1.9 mmol) and the Dess–Martin
periodinane42—44) (1.23 g, 2.9 mmol) in CH2Cl2 (23 ml) was stirred at room
(5R,7S)-7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6,7-dihydro-7-
methyl-5H-cyclopenta[c]pyridin-5-ol (15b) A solution of 14b (62.1 mg,
0.22 mmol) in EtOH (1.5 ml) was treated with NaBH4 (12.5 mg, 0.33 mmol)
temperature for 80 min. The reaction mixture was worked up as described at 0 °C for 30 min. The reaction mixture was worked up as described above
above for 13a. Purification of a crude oil by flash chromatography
for 15a, and purification of a crude oil by flash chromatography [AcOEt–
hexane (2 : 1)] provided 15b (52.8 mg, 84%) as a pale yellow solid, mp
104—107 °C; [a]D24 ꢁ31.0° (cꢂ1.03, CHCl3); FAB-MS m/z: 280 (MꢁHꢁ);
IR nmNauxjol: 3140 cmꢀ1 (OH); 1H-NMR (CDCl3) d: 0.05 and 0.08 (3H each, s,
[hexane–AcOEt (5 : 2)] furnished 13b (521 mg, 93%) as a colorless oil,
film
[a]D23 ꢀ70.8° (cꢂ0.49, CHCl3); FAB-MS m/z: 296 (MꢁHꢁ); IR n
:
max
1694 cmꢀ1 (CO); 1H-NMR (CDCl3) d: ꢀ0.16 and ꢀ0.02 (3H each, s,
SiMe2), 0.84 (9H, s, tert-Bu), 1.74 (3H, s, CMe), 2.98 and 3.19 [1H each, d, SiMe2), 0.86 (9H, s, tert-Bu), 1.54 (3H, s, CMe), 2.20 and 2.62 [1H each,
Jꢂ14 Hz, C(4)H2], 5.75 (1H, dd, Jꢂ10.5, 1 Hz) and 6.18 (1H, dd, Jꢂ17.5, dd, Jꢂ12.5, 6.5 Hz, C(6)H2], 2.6 (1H, br, OH), 5.05 [1H, dd, Jꢂ6.5, 6.5 Hz,
1 Hz) [C(1)H2], 6.34 [1H, dd, Jꢂ17.5, 10.5 Hz, C(2)H], 6.93 [1H, s, C(4ꢃ)- C(5)H], 7.37 [1H, d, Jꢂ5 Hz, C(4)H], 8.55 [1H, d, Jꢂ5 Hz, C(3)H], 8.61
H], 7.82 [1H, s, C(2ꢃ)H];48) HR-FAB-MS m/z Calcd for C15H26NO3Si:
296.1682, Found: 296.1682.
[1H, s, C(1)H]; HR-FAB-MS m/z Calcd for C15H26NO2Si: 280.1733, Found:
280.1732.
(7S)-7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6,7-dihydro-7-methyl-
(5R,7S)-6,7-Dihydro-5,7-dihydroxy-7-methyl-5H-cyclopenta[c]pyri-
5-oxo-5H-cyclopenta[c]pyridine-4-carboxylic Acid Methyl Ester (14a) dine-4-carboxylic Acid Methyl Ester [(ꢀ)-Plectrodorine] [(ꢀ)-1]
A
A solution of 13a (177 mg, 0.50 mmol) in o-DCB (10 ml) was heated at
150 °C in an atmosphere of Ar for 48 h. The reaction mixture was then con-
1.0 M solution (0.26 ml, 0.26 mmol) of tetrabutylammonium fluoride in THF
was added to a stirred solution of 15a (29.4 mg, 0.087 mmol) in THF
centrated in vacuo to leave a dark brown oil, which was subjected to flash (1.0 ml). After having been stirred at room temperature for 2 h, the reaction
chromatography [hexane–AcOEt (3 : 1)]. Earlier fractions furnished 14a
mixture was concentrated in vacuo to leave a yellow oil. Purification by flash
chromatography [CHCl3–MeOH (15 : 1)] furnished (ꢀ)-1 (14.2 mg, 73%) as
a colorless oil, [a]D24 ꢀ78.4° (cꢂ0.40, MeOH); HR-EI-MS m/z Calcd for
(61.8 mg, 37%) as a slightly yellow oil, [a]D22 ꢁ105.7° (cꢂ0.50, CHCl3);
film
FAB-MS m/z: 336 (MꢁHꢁ); IR n : 1730 cmꢀ1 (br, ester CO and CO); 1H-
max
NMR (CDCl3) d: 0.00 and 0.11 (3H each, s, SiMe2), 0.86 (9H, s, tert-Bu), C11H13NO4: 223.0844, Found: 223.0847. The UV (MeOH), 1H-NMR
1.71 (3H, s, CMe), 2.91 and 2.99 [1H each, d, Jꢂ18 Hz, C(6)H2], 3.99 (3H, (CDCl3), and mass spectral data of this sample were in agreement with those
s, CO2Me), 8.98 [1H, s, C(1)H], 9.17 [1H, s, C(3)H]; HR-FAB-MS m/z
reported for natural plectrodorine.24)
Calcd for C17H26NO4Si: 336.1631, Found: 336.1614.
(5R,7S)-6,7-Dihydro-7-methyl-5H-cyclopenta[c]pyridine-5,7-diol [(ꢁ)-
Later fractions in the above chromatography gave the starting oxazole– Oxerine] [(ꢁ)-3] Deprotection of 15b (52.8 mg, 0.19 mmol) with tetra-
olefin 13a (41.4 mg, 23% recovery). butylammonium fluoride and work-up of the reaction mixture were carried
(7S)-7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6,7-dihydro-7-methyl- out as described above for (ꢀ)-1. Purification of a crude oil by flash chro-
5H-cyclopenta[c]pyridin-5-one (14b) solution of 13b (292 mg, matography [CHCl3–MeOH (10 : 1)] gave (ꢁ)-3 (28.4 mg, 91%) as a color-
A
MeOH
0.99 mmol) in o-DCB (20 ml) was heated at 150 °C in an atmosphere of Ar
for 9 h. The reaction mixture was then concentrated in vacuo to leave a dark
brown oil, which was purified by flash chromatography [hexane–AcOEt 214 (ꢀ2.17); HR-EI-MS m/z Calcd for C9H11NO2: 165.0790, Found:
less solid, mp 120—122 °C; [a]D23 ꢁ10.6° (cꢂ0.21, MeOH); CD l
nm
ext
(De): 267 (ꢁ2.54), 264 (ꢁ2.00), 261 (ꢁ2.15), 244 (ꢀ1.04), 231 (ꢀ0.39),
1
(4 : 1)] to afford 14b (62.8 mg, 23%) as a slightly yellow solid, mp 58— 165.0788. The UV (MeOH), H-NMR (CD3OD), and mass spectral data of
59 °C; [a]D28 ꢁ84.8° (cꢂ0.50, CHCl3); FAB-MS m/z: 278 (MꢁHꢁ); IR this sample were virtually identical with those of natural oxerine.25)
nmNauxjol: 1728 cmꢀ1 (CO); H-NMR (CDCl3) d: ꢀ0.05 and 0.04 (3H each, s,
1
SiMe2), 0.86 (9H, s, tert-Bu), 1.73 (3H, s, CMe), 2.86 and 2.94 [1H each, d,
Jꢂ18.5 Hz, C(6)H2], 7.52 [1H, dd, Jꢂ5, 1.5 Hz, C(4)H], 8.78 [1H, d,
Jꢂ5 Hz, C(3)H], 9.08 [1H, d, Jꢂ1.5 Hz, C(1)H]; HR-FAB-MS m/z Calcd for
C15H24NO2Si: 278.1576, Found: 278.1573.
Acknowledgement We are grateful to Professor M. Koch (Université
René Descartes-Paris V) for his invaluable help in making a comparison be-
tween the natural and synthetic alkaloids.
5-(5-Oxazolyl)-1,4-hexadien-3-one (18)
A stirred mixture of 13b References and Notes
(70.4 mg, 0.24 mmol) and Cu(OTf)2 (1.7 mg, 2 mol%) in o-DCB (4.8 ml)
was heated at 180 °C in an atmosphere of Ar for 40 min. The reaction mix-
ture was concentrated in vacuo, and the residual brown oil was purified by
1) For a recent review on the oxazole Diels–Alder reactions, see Levin J.
I., Laakso L. M., “The Chemistry of Heterocyclic Compounds,” Vol.
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5) Levin J. I., Weinreb S. M., J. Org. Chem., 49, 4325—4332 (1984).
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flash chromatography [hexane–AcOEt (5 : 2)] to give 18 (14.8 mg, 38%) as a
Nujol
max
pale yellow solid, mp 35—36 °C; EI-MS m/z: 163 (Mꢁ); IR n
:
1665 cmꢀ1 (CO); 1H-NMR (CDCl3) d: 2.47 (3H, s, Me), 5.85 (1H, d,
Jꢂ10.5 Hz) and 6.31 (1H, d, Jꢂ17 Hz) [C(1)H2], 6.52 [1H, dd, Jꢂ17, 10.5
Hz, C(2)H], 6.96 [1H, s, C(4)H], 7.37 [1H, s, C(4ꢃ)H], 7.93 [1H, s, C(2ꢃ)-
H];48) HR-EI-MS m/z Calcd for C9H9NO2: 163.0633, Found: 163.0633.
(5R,7S)-7-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-6,7-dihydro-5-hy-
droxy-7-methyl-5H-cyclopenta[c]pyridine-4-carboxylic Acid Methyl
Ester (15a) A stirred solution of 14a (50.3 mg, 0.15 mmol) in MeOH
(1.5 ml) was cooled to 0 °C, and NaBH4 (5.7 mg, 0.15 mmol) was added.
After the mixture had been stirred at 0 °C for 30 min, acetone (0.1 ml) was
added. The resulting mixture was concentrated in vacuo, and the residual oil

January 2006
67
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