Synthesis of (±)-Cylindricines A, D, and E

Full text of DOI:10.1021/jo970536b

5630
J . Org. Chem. 1997, 62, 5630-5633
dehydration gave 60% of cyclohexenecarboxaldehyde 7.
Syn th esis of (()-Cylin d r icin es A, D, a n d E
Other procedures based on Grignard addition to an
alkoxymethylenecyclohexanone or an (alkylthio)methyl-
enecyclohexanone were much less successful.9 Addition
of 1-octynyllithium to 7 provided 64% of propargyl alcohol
8. Reduction with LAH/NaOMe10 gave the unstable
alcohol 9, which underwent allylic rearrangement on
chromatography. Similar rearrangement occurred on
reduction with LAH without NaOMe. Oxidation of crude
9 with MnO2 in CH2Cl2 afforded 71% of the requisite
dienone 5.
Barry B. Snider* and Tao Liu
Department of Chemistry, Brandeis University, Waltham,
Massachusetts 02254-9110
Received March 24, 1997
Cylindricines A-K were isolated by Blackman and co-
workers from the ascidian Clavelina cylindrica collected
in Tasmania.1-3 The two main alkaloids, cylindricines
A (1a ) and B (2b), are readily interconvertible via an
aziridinium ion intermediate.1 A 30 µM solution of the
3:2 equilibrium mixture causes significant mortality in
the brine shrimp bioassay.1 Cylindricines C (1c), D (1d ),
E (1e), and F (1f) were isolated as minor products from
these ascidians and can be prepared from the equilibrium
mixture of cylindricines A and B by reaction with the
appropriate nucleophile.2 Cylindricine H (1h ) is the
acetate of the reduction product of cylindricine F (1f),
cylindricine I (1i) is the analogous isothiocyanate, and
cylindricine J (2j) is a reduced isothiocyanate analogue
of cylindricine B.3 Patil and co-workers recently isolated
the more highly reduced thiocyanate fasicularin (3),
which shows selective activity against a DNA repair-
deficient organism, from the ascidian Nephteis fasicularis
collected in Micronesia.4
Heating 5 in 3:1 MeOH/concentrated NH4OH in a
sealed tube at 73 °C for 16 h gave 56% of 4, 19% of 10,
and 6% of 12. The pH has been shown to affect the
stereochemical ratio in the formation of 4-piperidinones
by double Michael addition of ammonia to dienones.11 As
expected,11 lowering the pH favored the undesired trans
isomer 10 at the expense of the desired cis isomer 4.
Reaction of 5 in MeOH containing 60 mg of NH4Cl per
mL of concentrated NH4OH (1:13 NH4+/NH3) provided
47% of 4, 34% of 10, and 5% of 12 while a similar reaction
containing 1 g of NH4Cl per mL of concentrated NH4OH
(1.3:1 NH4+/NH3) afforded 20% of 4, 26% of 10, and 9%
of 12.
We envisioned that cylindricines A (1a ) and B (2b)
could be prepared from butenylquinolinone 4 by either a
radical cyclization of the N-chloroamine5 or by addition
of N-chlorosuccinimide to the alkene.6 Addition of NH3
to dienone 5 should provide a simple route to 4 since
addition of NH3 to propenyl 2-methyl-1-cyclohexenyl
ketone afforded the comparable stereoisomer as one of
two major products.7
Resu lts a n d Discu ssion
Addition of 3-butenylmagnesium bromide to acetal
The structures of 4, 10, and 12 were established by 1H
NMR spectroscopic analysis and chemical equilibration.
In all three isomers, Hc absorbs as a doublet of doublets
with a large 10-12 Hz vicinal coupling constant, estab-
lishing that the hexyl side chain is equatorial. In 11,
the hexyl side chain is axial so that Hb and Hc would both
have small vicinal coupling constants. In the desired
isomer 4, Ha absorbs as dd, J ) 4, 4 Hz, establishing that
Ha is equatorial on the cyclohexane ring. In the trans-
fused isomer 10, Ha absorbs as ddd, J ) 11.7, 2.9, 0.9
Hz. The 11.7 Hz coupling constant establishes that Ha
ketone 68 followed by hydrolysis of the acetal and
(1) Blackman, A. J .; Li, C.; Hockless, D. C. R.; Skelton, B. W.; White,
A. H. Tetrahedron 1993, 49, 8645-8656.
(2) Li, C.; Blackman, A. J . Aust. J . Chem. 1994, 47, 1355-1361.
(3) Li, C.; Blackman, A. J . Aust. J . Chem. 1995, 48, 955-965.
(4) Patil, A. D.; Freyer, A. J .; Reichwein, R.; Carte, B.; Killmer, L.
B.; Faucette, L.; J ohnson, R. K.; Faulkner, D. J . Tetrahedron Lett. 1997,
38, 363-364.
(5) (a) Stella, L. Angew. Chem., Int. Ed. Engl. 1983, 22, 337-350.
(b) Broka, C. A.; Eng, K. K. J . Org. Chem. 1986, 51, 5043-5045.
(6) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321-3408. (b)
Blough, B. E.; Mascarella, S. W.; Rothman, R. B.; Carroll, F. I. J . Chem.
Soc., Chem. Commun. 1993, 758-760.
(7) Akhrem, A. A.; Ukhova, L. I.; Uskova, N. F.; Prokof’ev, T. E.
Chem. Heterocycl. Compd. (Engl. Transl.) 1977, 647-655; Khim.
Geterotsikl. Soedin. 1977, 796-804.
(8) Courtin, J . M. L.; Verhagen, L.; Biesheuvel, P. L.; Lugtenburg,
J .; van der Bend, R. L.; van Dam, K. Recl. Trav. Chim. Pays-Bas 1987,
106, 112-119.
(9) Harding, K. E.; Ligon, R. C. Synth. Commun. 1974, 4, 297-301.
(10) Molloy, B. B.; Hauser, K. L. Chem. Commun. 1968, 1017-1019.
(11) Korshevets, I. K.; Mistryukov, EÄ . A. Bull. Acad. Sci. USSR
1987, 1420-1425; Izv. Akad. Nauk SSSR, Ser. Khim. 1987, 1540-
1545.
S0022-3263(97)00536-7 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 16, 1997 5631
is axial on the cyclohexane ring, and the 0.9 Hz long-
range coupling constant to Hc indicates that both Ha and
Hc are axial on the piperidinone ring.12 In the cis-fused
isomer 12, Ha absorbs as ddd, J ) 12.0, 3.9, 0.8 Hz. The
12.0 Hz coupling constant establishes that Ha is axial on
the cyclohexane ring, and the 0.8 Hz long-range coupling
constant to Hb indicates that both Ha and Hb are
equatorial on the piperidinone ring.12
Resubjection of either pure 10 or 12 to the reaction
conditions for longer times afforded a 3:1 equilibrium
mixture of 10 and 12 containing a trace of 4, indicating
that partial equilibration of 10 and 12 by enolization is
facile. The 3:1 mixture of isomers of 10 and 12 is close
to that expected from the MM2 strain energies, which
are shown under the structures.13 Attempted equilibra-
tion of 4 gave >90% recovered 4, 6% of 10, and no 11.
The trans isomer 11 is 5 kcal/mol less stable than 4 due
to 1,3-diaxial interactions and is therefore not observed
in the original reaction or equilibration. Although 2,6-
dialkyl-4-piperidinones are reported to undergo equili-
bration by retro-Michael and Michael reactions in aque-
ous tert-butylamine at reflux,14 we were unable to effect
efficient equilibration of 10 or 12 with 4 under these or
more forcing conditions. These more highly substituted
quinolinones equilibrate slowly by retro-Michael and
Michael reactions. Therefore, the ratio of 4 to 10 and
12 is determined in the second, kinetically-controlled,
intramolecular Michael reaction.
(14d ). The 1H and 13C NMR spectral data of 1d are
identical to those of an authentic sample.16 Treatment
of 1a with NaOAc in MeOH at 25 °C for 4 h yielded 91%
of cylindricine E (1e) whose 13C NMR spectrum corre-
sponds closely to that reported.
In conclusion, the first synthesis of cylindricine A (1a )
has been accomplished by an efficient seven-step route
using a double Michael reaction to construct the quino-
linone and a radical cyclization to prepare the (chloro-
methyl)pyrrolidine.
Exp er im en ta l Section
Gen er a l. NMR spectra were recorded at 300 MHz in CDCl3
unless otherwise indicated. Chemical shifts are reported in δ
and coupling constants in hertz. The solvent peak of C6D6
absorbs at δ 7.16 (H) and δ 128.4 (C). IR spectra are reported
in cm-1
.
2-(3-Bu ten yl)-1-cycloh exen eca r boxa ld eh yd e (7). A solu-
tion of 3-butenylmagnesium bromide was prepared under N2 by
dropwise addition of 3.5 g (25.9 mmol) of 4-bromo-1-butene at 0
°C over 40 min to 4.1 g (169 mmol) of Mg turnings in 40 mL of
dry ether. The solution was stirred for 1 h at 0 °C and then at
rt for 3.5 h. The liquid layer was transferred by cannula to
another flask under N2, which was then cooled to 0 °C.
2-(Dimethoxymethyl)cyclohexanone (6)8 (1.93 g, 11.2 mmol) in
25 mL of dry ether was then added over a period of 40 min. The
solution was warmed to rt, stirred for 1.5 h, cooled to 0 °C,
treated slowly with 200 mL of 0.1 N HCl, and extracted with
ether (3 × 80 mL). The ether layers were washed with water,
dried (Na2CO3), and concentrated to give 3.1 g of crude
2-(dimethoxymethyl)-1-(3-butenyl)cyclohexanol.
A solution of crude acetal alcohol in 30 mL of acetone was
heated at reflux. To the refluxing mixture was added 0.2 mL of
concentrated HCl slowly. Heating was continued for a further
2 h. After cooling, the acetone was evaporated under reduced
pressure. Water (40 mL) was added to the residue, which was
extracted with hexane (3 × 60 mL). The combined organic layers
were dried (Na2SO4) and concentrated giving 1.87 g of crude 7.
Purification by flash chromatography on silica gel (94:6 hexane/
EtOAc) gave 1.104 g (60%) of pure 7: 1H NMR 10.10 (1, s), 5.80
(1, ddt, J ) 16.8, 10.2, 6.8), 5.05 (1, ddt, J ) 16.8, 1.8, 1.6), 5.01
(1, ddt, J ) 10.2, 1.8, 1.1), 2.62 (2, t, J ) 7.8), 2.17-2.32 (6, m),
1.56-1.68 (4, m); 13C NMR 190.8, 159.1, 136.9, 134.0, 115.8, 33.8,
32.0, 31.5, 22.2, 22.0, 21.6; IR (neat) 1665, 1629; UV (CH3CH2OH)
λmax (ꢀmax) ) 251 (6400) nm.
2-(3-Bu ten yl)-r-(1-octyn yl)-1-cycloh exen em eth a n ol (8).
n-BuLi (2.5 M, 5 mL, 12.5 mmol) was added slowly to a solution
of 1-octyne (1.4 g, 12.7 mmol) in 20 mL of THF at -78 °C. The
mixture was warmed to rt for 20 min, and DMPU (2 mL) was
added to the mixture, which was then cooled to -78 °C.
Aldehyde 7 (1.057 g, 6.4 mmol) in 10 mL of THF was added
slowly to the mixture, which then was stirred at rt for 14 h.
The mixture was treated with saturated NH4Cl (20 mL). The
organic layer was separated, and the aqueous layer was ex-
tracted with ether (3 × 40 mL). The combined organic layers
were washed with brine, dried (Na2SO4), and concentrated under
reduced pressure to give 1.56 g of crude 8. Flash chromatog-
raphy on silica gel (9:1 hexane/EtOAc) gave pure 8 (1.12 g,
64%): 1H NMR 5.82 (1, ddt, J ) 17.1, 10.1, 7.2), 5.31 (1, br s),
5.02 (1, dd, J ) 17.1, 2.0), 4.97 (1, dd, J ) 10.1, 2.0), 2.32-2.08
(6, m), 2.21 (2, dt, J ) 2.1, 7.0), 2.06-1.97 (2, m), 1.76-1.28 (12,
m), 0.89 (3, t, J ) 6.6); 13C NMR 138.4, 133.9, 130.8, 114.7, 85.6,
80.1, 61.5, 32.9, 32.5, 31.3, 30.1, 28.6, 28.5, 23.5, 22.9, 22.8, 22.5,
Reaction of piperidinone 4 with N-chlorosuccinimide
in CH2Cl2 afforded 96% of N-chloropiperidinone 135
rather than the desired (chloromethyl)pyrrolidines 1a
and 14a resulting from addition of Cl to the double
bond.6b The NMR spectra of 13 showed broadening of
the protons and carbons in the piperidinone ring due to
slow pyramidal inversion of the nitrogen.15 Radical
cyclization of 13 by the Stella procedure5a using CuCl and
CuCl2 in 2:1:1 THF/AcOH/H2O provided a 55:45 mixture
of cylindricine A (1a ) and epi-cylindricine A (14a ), which
were readily separated by flash chromatography on silica
gel to provide 42% of 1a and 41% of 14a . As expected,5
the radical cyclization afforded only (chloromethyl)pyr-
rolidines 1a and 14a and none of the chloropiperidine
1
2b and its epimer. The H and 13C NMR spectral data
of 1a are identical to those of an authentic sample.16
Although the radical cyclization is nonselective, the
undesired isomer 14a can be recycled by reduction with
Zn dust in 7:1 MeOH/concentrated HCl to give 86% of 4.
Since cylindricine A (1a ) equilibrates with 2b and is
unstable toward nucleophiles, the structure was con-
firmed by preparation of the more stable cylindricines D
(1d ) and E (1e) as described by Li and Blackman.2
Cyclization of 13 and treatment of the crude mixture of
1a and 14a with sodium methoxide in MeOH at 25 °C
for 6 h provided 32% of 1d and 35% of epi-cylindricine D
(12) Long-range coupling in cyclohexanones is observed between
both diequatorial and diaxial 2- and 6-protons, but not between
equatorial and axial protons: J ackman, L. M.; Sternhell, S. Applica-
tions of Nuclear Magnetic Resonance Spectroscopy in Organic Chem-
istry, 2nd ed.; Pergamon: Oxford, 1969; p 338.
(13) Model, version KS 2.99 obtained from Kosta Steliou, Boston
University, was used for MM2 calculations.
(14) Mistryukov, E. A.; Smirnova, G. N. Tetrahedron 1971, 27, 375-
377.
(15) Chlorination of the nitrogen raises the barrier to inversion by
≈4 kcal/mol: (a) Anet, F. A. L.; Yavari, I. Tetrahedron Lett. 1977,
3207-3210. (b) Anet, F. A. L.; Yavari, I. J . Am. Chem. Soc. 1977, 99,
2794.
(16) We thank Prof. Blackman for copies of the 1H and 13C NMR
spectra of cylindricines A, B, and D.

5632 J . Org. Chem., Vol. 62, No. 16, 1997
Notes
18.8, 14.0; IR (neat) 3458. Anal. Calcd for C19H30O: C, 83.21;
H, 10.94. Found: C, 83.09; H, 10.84.
lin d r icin e A (1a ) a n d epi-Cylin d r icin e A (14a )). A solution
of 13 (18.0 mg, 0.056 mmol) in 1.0 mL of THF was cooled to 0
°C (under N2) and treated over 10 min with a solution of CuCl
(5 mg, 0.05 mmol) and CuCl2 (27 mg, 0.19 mmol) in 1.6 mL of
THF/AcOH/H2O (2:1:1) (solvents were purged with N2 to remove
dissolved oxygen). The solution was stirred at 0 °C for 40 min
and concentrated under reduced pressure. Flash chromatogra-
phy of the residue on silica gel containing 0.8 g of Na2SO4 on
top (97:3 hexane/EtOAc) provided 7.4 mg (41%) of 14a followed
by 7.6 mg (42%) of 1a .
1-(2-(3-Bu ten yl)-1-cycloh exen yl)-2(E)-n on en -1-on e (5). A
solution of 8 (1.09 g, 3.98 mmol), 6.3 mL of a 1 M solution of
LiAlH4 in THF (6.3 mmol), and suspended NaOMe (680 mg, 12.6
mmol) in 40 mL of THF was refluxed for 45 min and then
quenched with water (60 mL). The solution was extracted with
ether (3 × 60 mL), and the combined organic layers were dried
(Na2CO3) and concentrated under reduced pressure to give 1.67
g of crude 9.
Da ta for 1a : 1H NMR (C6D6) 3.37 (1, dd, J ) 10.5, 2.6), 3.20
(1, dddd, J ) 9.5, 9.5, 2.6, 2.6), 2.98 (1, dd, J ) 10.5, 9.5), 3.03-
2.94 (1, m), 2.35 (1, br d, J ) 12.6), 2.09 (1, dd, J ) 12.9, 2.1),
1.77-1.01 (23, m), 0.89 (3, t, J ) 7.1); 13C NMR (C6D6) 208.5,
70.5, 58.6, 55.3, 51.1, 49.8, 43.4, 36.5, 35.6, 35.1, 32.5, 29.9, 27.5,
27.5, 25.0, 23.6, 23.3, 22.6, 14.6; IR (neat) 1707. The 1H and
13C NMR spectral data are identical to those reported,1 except
that the literature data were referenced to C6D6 at δ 7.40 and δ
128.7.
Crude 9 was dissolved in 50 mL of CH2Cl2, and 3.5 g of MnO2
(85% activated, 34.2 mmol) was added. The solution was stirred
for 12 h, and an additional 6.6 g of MnO2 (85% activated, 64.5
mmol) was added. After being stirred for 36 h, the mixture was
filtered through a bed of Celite 521. The residue was washed
with CH2Cl2 (3 × 20 mL). The combined filtrates were concen-
trated under reduced pressure. Flash chromatography of the
residue on silica gel (9:1 hexane/EtOAc) provided 772 mg (71%)
of 5: 1H NMR 6.79 (1, dt, J ) 15.8, 6.9), 6.13 (1, dt, J ) 15.8,
1.4), 5.74 (1, ddt, J ) 10.2, 17.0, 6.3), 4.97 (1, ddt, J ) 17.0, 1.7,
0.9), 4.92 (1, ddt, J ) 10.2, 1.7, 0.9), 2.24 (2, ddt, J ) 1.4, 6.9,
6.9), 2.18-2.03 (8, m), 1.62-1.68 (4, m), 1.46 (2, tt, J ) 7.1, 7.1),
1.35-1.25 (6, m), 0.89 (3, t, J ) 6.8); 13C NMR 200.8, 150.3,
138.2, 137.5, 133.6, 130.5, 114.5, 34.2, 32.5, 32.3, 31.5, 28.8, 28.6,
28.0, 27.3, 22.5, 22.5, 22.2, 14.0; IR (neat) 1651, 1618; UV
Da ta for 14a : 1H NMR (C6D6) 3.37 (1, dd, J ) 10.0, 2.2),
3.08-3.01 (1, m), 2.94 (1, dd, J ) 10.0, 10.0), 2.87-2.78 (1, m),
2.40 (1, br d, J ) 12.0), 2.37 (1, dd, J ) 15.2, 3.4), 1.90 (1, br s),
1.60 (1, dd, J ) 15.2, 9.6), 1.78-0.94 (21, m), 0.91 (3, t, J ) 6.6);
13C NMR (C6D6) 208.5, 67.1, 60.0, 57.9, 52.8, 49.7, 47.9, 37.2,
32.7, 32.6, 30.2, 28.4, 27.1, 26.8, 24.4, 24.0, 23.4, 22.0, 14.7; IR
(neat) 1707.
(CH3CH2OH) λ
(ꢀmax) ) 228 (11 900) nm.
max
(2r,4a r,8a r)-, (2r,4a r,8a â)-, a n d (2r,4a â,8a â)-8a -(3-Bu ten -
yl)-2-h exylocta h yd r o-4(1H)-qu in olin on e (4, 10, a n d 12).
NH4Cl (440 mg, 8.2 mmol) and 7.2 mL of concentrated am-
monium hydroxide were added to a solution of 5 (500 mg, 1.82
mmol) in 42 mL of MeOH at rt in a resealable tube. The tube
was sealed, and the reaction mixture was heated to 76 °C. After
16 h of stirring, the solution was cooled to rt, removed from the
reaction tube, and concentrated under reduced pressure. The
resulting oily solid was diluted with 1:1 (v/v) EtOAc and
saturated aqueous Na2CO3 (40 mL). The layers were separated,
and the organic layer was washed with saturated aqueous
Na2CO3 (1 × 10 mL). The combined aqueous layers were
extracted with EtOAc (2 × 20 mL). The combined organic layers
were dried (Na2SO4) and concentrated under reduced pressure
to give a quantitative yield of crude quinolinones. Flash
chromatography on silica gel (9:1 hexane/EtOAc) provided 12
(26 mg, 5%), followed by 4 (247 mg, 47%) and 10 (180 mg, 34%).
Da ta for 4: 1H NMR 5.87 (1, ddt, J ) 16.9, 10.2, 6.6), 5.07
(1, br d, J ) 16.9), 4.99 (1, br d, J ) 10.2), 3.12 (1, dddd, J )
11.5, 2.7, 6.0, 6.0), 2.37 (1, dd, J ) 13.5, 2.7), 2.25 (1, dd, J )
4.0, 4.0), 2.05-2.21 (2, m), 1.96 (1, dd, J ) 13.5, 11.5), 1.87-
1.20 (20, m), 0.88 (3, t, J ) 6.5); 13C NMR 210.9, 138.8, 114.6,
58.1, 53.8, 49.9, 48.8, 37.8, 37.6, 31.7, 31.6, 29.2, 27.2, 25.6, 22.6,
22.5, 21.4, 21.1, 14.0; IR (neat) 3318, 1709.
Recyclin g 14a . A solution of 14a (7.0 mg, 0.022 mmol) in
0.7 mL of MeOH was added to a mixture of concentrated HCl
(12.1 M, 0.7 mL) and 4.5 mL of MeOH. Zinc dust (740 mg, 11.4
mmol) was added to the solution, and H2 liberation started. The
mixture was stirred for 4 h, more zinc dust (690 mg, 10.6 mmol)
was added, and the mixture was stirred for another 12 h.
Workup was accomplished by adding saturated Na2CO3 solution
(5 mL) and CH2Cl2 (10 mL) to the solution, which was then
filtered through a Celite 521 bed. The residue was washed with
CH2Cl2 (3 × 10 mL), the organic layer was separated from the
combined filtrates, and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give 10.2
mg of crude 4. Flash chromatography on silica gel (96:4 hexane/
EtOAc) gave 5.4 mg (86%) of pure 4.
(3r,5â,7a â,11a R*)- a n d (3â,5â,7a â,11a R*)-5-Hexylocta h y-
d r o-3-(m eth oxym eth yl)-1H-p yr r olo[2,1-j]qu in olin -7(7a H)-
on e (Cylin d r icin e D (1d ) a n d epi-Cylin d r icin e D (14d )). 13
(18 mg, 0.056 mmol) was treated by the same procedure as above
to provide 19 mg of crude 1a and 14a . The crude mixture was
dissolved in 4 mL of dry methanol, and NaOMe (10 mg, 0.19
mmol) was added to the solution at rt. The mixture was stirred
at rt for 6 h. After removal of the solvent under reduced
pressure, water (5 mL) was added and the solution was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure to give 16
mg of crude 1d and 14d . Purification by flash chromatography
on silica gel (97:3 hexane/EtOAc) gave 6.3 mg (35%) of 14d
followed by 5.7 mg (32%) of 1d .
Da ta for 10: 1H NMR 5.79 (1, ddt, J ) 17.1, 10.2, 6.6), 5.01
(1, dd, J ) 17.1, 1.2), 4.94 (1, dd, J ) 10.2, 1.2), 3.02 (1, dddd, J
) 12.0, 3.6, 5.7, 5.7), 2.35 (1, dd, J ) 13.4, 3.6), 2.30 (1, ddd, J
) 11.7, 2.9, 0.9), 2.08 (1, ddd, J ) 13.4, 12.0, 0.9), 1.12-1.93
(22, m), 0.89 (3, t, J ) 6.5); 13C NMR 210.4, 138.3, 114.4, 60.3,
58.5, 51.3, 48.8, 37.5, 35.8, 31.6, 29.2, 26.0, 26.0, 25.7, 24.9, 22.5,
21.5, 20.1, 13.9; IR (neat) 3307, 1709.
Da ta for 1d : 1H NMR (C6D6) 3.34 (1, dd, J ) 9.1, 3.0), 3.33-
3.28 (1, m), 3.18 (3, s), 3.18-3.10 (1, m), 3.00 (1, dd, J ) 9.1,
9.2), 2.40 (1, br d, J ) 13.5), 2.15 (1, dd, J ) 12.6, 2.2), 1.96-
0.93 (23, m), 0.89 (3, t, J ) 6.9); 13C NMR (C6D6) 209.1, 79.0,
70.1, 59.1, 56.2, 55.8, 51.3, 43.5, 36.7, 35.8, 35.5, 32.5, 30.1, 27.7,
27.3, 25.2, 23.7, 23.4, 22.8, 14.7; IR (neat) 1707, 1113. The 1H
and 13C NMR spectral data are identical to those reported,2
except that the literature data were referenced to C6D6 at δ 7.40
and δ 128.7 and the H6 absorption at δ 2.40 was not reported.
Da ta for 14d : 1H NMR (C6D6) 3.37 (1, dd, J ) 8.7, 3.2), 3.16
(3, s), 3.24-3.08 (1, m), 3.00 (1, dd, J ) 8.7, 8.7), 3.00-2.92 (1,
m), 2.47 (1, dd, J ) 15.0, 3.3), 2.52-2.42 (1, m), 2.11 (1, br s),
1.90-1.75 (4, m), 1.71-1.00 (18, m), 0.91 (3, t, J ) 6.8); 13C NMR
(C6D6) 209.2, 79.2, 66.6, 59.2, 58.0, 57.8, 53.3, 48.2, 37.3, 33.5,
32.6, 30.3, 28.3, 27.5, 26.9, 24.5, 24.1, 23.4, 22.2, 14.7; IR 1706,
1110.
(3r,5â,7a â,11a R*)-3-(Acetoxym eth yl)-5-h exylocta h yd r o-
1H-p yr r olo[2,1-j]qu in olin -7(7aH)-on e (Cylin d r icin e E (1e)).
A solution of 1a (7.8 mg, 0.024 mmol) in 1.5 mL of MeOH was
treated with sodium acetate (8 mg, 0.098 mmol) at rt, and the
mixture was stirred at rt for 4 h. After removal of the solvent
under reduced pressure, water (5 mL) was added and the
solution was extracted with CH2Cl2 (3 × 5 mL). The combined
Da ta for 12: 1H NMR 5.79 (1, ddt, J ) 17.1, 10.2, 6.7), 4.99
(1, ddt, J ) 17.1, 1.8, 1.6), 4.93 (1, ddt, J ) 10.2, 1.8, 1.2), 2.95
(1, dddd, J ) 10.5, 4.2, 7.4, 7.4), 2.21 (1, dd, J ) 10.5, 14.7), 2.13
(1, ddd, J ) 4.2, 14.7, 0.8), 2.07 (1, ddd, J ) 3.9, 12.0, 0.8), 1.13-
2.04 (22, m), 0.89 (3, t, J ) 6.9); 13C NMR 214.5, 138.6, 114.4,
58.2, 54.9, 50.5, 44.0, 38.0, 37.6, 35.7, 31.8, 29.4, 27.0, 26.4, 25.7,
25.4, 22.6, 20.9, 14.1; IR (neat) 3332, 1704.
(2r,4a r,8a r)-8a -(3-Bu ten yl)-1-ch lor o-2-h exylocta h yd r o-
4(1H)-qu in olin on e (13). Amine 4 (120 mg, 0.41 mmol) and
N-chlorosuccinimide (150 mg, 1.10 mmol) were dissolved in 12
mL of CH2Cl2 at rt, and the solution was stirred for 18 h. The
solution was concentrated under reduced pressure. Flash chro-
matography of the residue on silica gel (94:6 hexane/EtOAc) gave
130 mg (96%) of 13: 1H NMR 5.88 (1, ddt, J ) 17.3, 10.2, 6.9),
5.07 (1, br d, J ) 17.3), 4.97 (1, br d, J ) 10.2), 3.54 (1, br),
2.64-2.55 (3, br), 2.27-2.19 (3, br), 2.06-1.59 (3, m), 1.47-1.24
(16, m), 0.88 (3, t, J ) 6.3); 13C NMR 208.7, 138.9, 114.4, 69.6,
59.7 (br), 50.3, 43.1 (br), 35.1, 34.1, 31.7, 30.2 (br), 29.7, 29.0,
26.3, 25.1 (br), 23.1, 22.8, 21.1, 14.1; IR (neat) 1711.
(3r,5â,7aâ,11aR*)- an d (3â,5â,7aâ,11aR*)-3-(Ch lor om eth yl)-
5-h exyloctah ydr o-1H-pyr r olo[2,1-j]qu in olin -7(7aH)-on e (Cy-

Notes
J . Org. Chem., Vol. 62, No. 16, 1997 5633
organic layers were dried (Na2SO4) and concentrated under
reduced pressure to give 10.8 mg of crude 1e. Purification by
flash chromatography on silica gel (97:3 hexane/EtOAc) gave 7.6
mg (91%) of pure 1e: 1H NMR (CDCl3) 4.12 (1, dd, J ) 10.5,
3.4), 3.68 (1, dd, J ) 10.5, 8.7), 3.55-3.45 (1, m), 3.28-3.16 (1,
m), 2.28-2.14 (3, m), 2.07 (3, s), 1.84-1.04 (22, m), 0.88 (3, t, J
) 6.0); 13C NMR (CDCl3) 211.0, 171.0, 70.0, 68.6, 55.2, 54.5, 51.1,
42.9, 36.0, 34.9 (2 C), 31.8, 29.3, 27.1, 26.4, 24.4, 22.9, 22.6, 21.9,
21.0, 14.0; IR (neat) 1747, 1707, 1227. The 13C NMR spectral
data are identical to those reported,2 except that (1) the
literature data are at ≈0.8 δ larger chemical shift than our data
and (2) Li and Blackman reported two absorptions at δ 21.8 and
we observed one at δ 21.0 and another at δ 29.3.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health for financial support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for most compounds (22 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O970536B