An asymmetric synthesis of aza analogues of the tricyclic skeleton of daphnane and the ABC ring system of phorbol

Article abstract of DOI:10.1021/jo0205816

An asymmetric synthesis of aza analogues of the ABC ring system of phorbol and related compounds containing the 5-7-6-fused framework of daphnane involved construction of the central seven-membered ring by a regioselective reduction of a chiral imide and cyclization with trifluoromethane-sulfonic acid. Subsequent demethylation and oxidative dearomatization of ring C afforded an enantiopure dienone 20 with the same relative and absolute configuration at the 9- and 10-positions of the phorbol skeleton.

Full text of DOI:10.1021/jo0205816

An Asym m etr ic Syn th esis of Aza An a logu es of th e Tr icyclic
Sk eleton of Da p h n a n e a n d th e ABC Rin g System of P h or bol
Charles M. Marson,*,† J ennifer H. Pink, and David Hall
Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, U.K.
Michael B. Hursthouse
Department of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ , U.K.
Abdul Malik
Department of Chemistry, University of Wales, P.O. Box 912, Park Place, Cardiff CF1 3TB, U.K.
Christopher Smith
Rhoˆne-Poulenc Rorer Ltd., Rainham Road South, Dagenham, Essex RM10 7XS, U.K.
c.m.marson@ucl.ac.uk
Received September 3, 2002
An asymmetric synthesis of aza analogues of the ABC ring system of phorbol and related compounds
containing the 5-7-6-fused framework of daphnane involved construction of the central seven-
membered ring by a regioselective reduction of a chiral imide and cyclization with trifluoromethane-
sulfonic acid. Subsequent demethylation and oxidative dearomatization of ring C afforded an
enantiopure dienone 20 with the same relative and absolute configuration at the 9- and 10-positions
of the phorbol skeleton.
The construction of angularly fused 5-7-6-tricyclic
systems1,2 in a stereocontrolled manner is an important
challenge, in view of the variety of biologically active
compounds incorporating that skeleton. For example,
phorbol 1 (Figure 1) is extensively used in studies of
tumor promotion and for its ability to activate protein
kinase C.3 The related 5-7-6 daphnane skeleton2 is
exemplified by the antileukemic agent gnidilatin 24 and
by the irritant resiniferatoxin, which also possesses
analgesic properties.5 Aconitine 3 (X ) CH), representa-
tive of another set of complex carbocyclic systems, the
aconite alkaloids,6 notable for their cardiotonic and
† Current address: Department of Chemistry, University College
London, Christopher Ingold Laboratories, 20 Gordon Street, London
WC1H 0AJ , U.K.
(1) (a) Marson, C. M.; Benzies, D. W. M.; Hobson, A. D.; Adams, H.;
Bailey, N. A. J . Chem. Soc., Chem. Commun. 1990, 1516. (b) Marson,
C. M.; Harper, S.; Walker, A. J .; Pickering, J .; Campbell, J .; Wriggles-
worth, R.; Edge, S. J . Tetrahedron 1993, 45, 10339.
(2) Evans, F. J .; Taylor, S. E. Prog. Chem. Org. Nat. Prod. 1983,
44, 27.
(3) (a) J effrey, A. M.; Liskamp, R. M. J . Proc. Natl. Acad. Sci. U.S.A.
1986, 83, 241. (b) Wender, P. A.; Koehler, K. F.; Sharkey, N. A.; Dell′
Aquila, M. L.; Blumberg, P. M. Proc. Natl. Acad. Sci. U.S.A. 1986, 83,
F IGURE 1.
4214. (c) Wender, P. A.; Cribbs, C. M.; Koehler, K. F.; Sharkey, N. A.;
Herald, C. L.; Kamano, Y.; Pettit, G. R.; Blumberg, P. M. Proc. Natl.
Acad. Sci. U.S.A. 1988, 85, 7197. (d) For a review on protein kinase C
in tumor production, see: Nishizuka, Y. Nature 1984, 308, 693.
(4) Kupchan, S. M.; Shizuri, Y.; Sumner, W. C., J r.; Haynes, H. R.;
Leighton, A. P.; Sickles, B. R. J . Org. Chem. 1976, 41, 3850.
(5) Adolf, A.; Sorg, B.; Hergenhahn, M.; Hecker, E. J . Nat. Prod.
1982, 45, 347.
sedative properties, also contains a 5-7-6-tricyclic core.
Those examples and the antileukemic activity of the
Cephalotaxus alkaloids,7 e.g., cephalotaxine 4, suggested
that a general route to 5-7-6 fused systems that are
either carbocyclic or incorporate one nitrogen atom in the
(6) (a) Benn, M. H.; J acyno, J . M. In Alkaloids-Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1983;
Vol. 1, 153. (b) Wiesner, K. Pure Appl. Chem. 1979, 51, 689.
(7) Weinreb, S. M.; Semmelhack, M. F. Acc. Chem. Res. 1975, 8,
158.
10.1021/jo0205816 CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/12/2002
792
J . Org. Chem. 2003, 68, 792-798

Aza Analogues
SCHEME 1
alcohol 11 with aqueous 48% HBr (16 h, 20 °C) furnished
the allylic bromide 12 (80%) as an oil.13 As a model study,
N-alkylation of succinimide14 with bromide 12 (K2CO3,
DMF) proceeded smoothly to give the imide 13 in 80%
yield. Attempted reduction of 13 with sodium borohy-
1
dride15 gave a complex mixture, H NMR spectra indi-
cated that over-reduction had taken place, probably
involving the allylic ester moiety. Reduction at lower
temperature (-15 °C) proceeded slowly and was incom-
plete.
(3S)-3-Acetoxysuccinimide (15) was next selected as a
more functionalized precursor of the γ-lactam ring;
following N-alkylation16 and subsequent regioselective
reduction,16-18 a stereoselective cyclization controlled by
the absolute configuration of the acyloxy carbon atom was
envisaged. The succinimide 15 was prepared17 by suc-
cessive treatment of (S)-malic acid with acetyl chloride,
ammonia, and acetyl chloride (overall yield 50%). The
succinimide 15 was alkylated with the bromide 12 (1.0
equiv) using K2CO3 (1.0 equiv) in DMF at 20 °C over 2.5
h, furnishing the imide 16 in 62% yield.
Reduction17 of imide 16 with sodium borohydride in
methanol at -8 °C over 20 min gave a 2.5:1 ratio of
epimers 17 (87%). The major diastereoisomer was as-
signed as the (4S,5S)-cis-isomer, consistent with litera-
ture precedent.16a The amide 17 (without recrystalliza-
tion) was treated with 5% CF3SO3H18 in dichloromethane
(75 min, 20 °C), quenched with saturated aqueous sodium
hydrogen carbonate, and subjected to column chroma-
tography which gave a 3:1 mixture (70%) of 18 and its
10-methoxy regioisomer 21.19 Recrystallization (twice
from ethyl acetate) of the 3:1 mixture afforded the pure
isomer 18, of the absolute configuration depicted. Other
isomeric lactams such as 22 and 23 may have been
present in trace amounts, but they were not isolated.
The viability of functionalizing ring C of the ether 18
was tested by demethylation at position-8 using boron
tribromide; that gave, in 70% yield, the corresponding
phenol 19, which was oxidatively hydroxylated using [bis-
(trifluoroacetoxy)iodo]benzene20 to give the dienone 20 as
the only isolable compound. Under the reaction condi-
tions, extensive polar material was obtained that did not
elute and could not be identified. Side products generated
by elimination of oxygenated functionality from 20 may
have been significant. An X-ray crystallographic deter-
mination on a single crystal of dienone 20 (recrystallized
from propan-2-ol and 40-60 °C petroleum ether) con-
firmed the relative configuration as 10aR, 10bR, corre-
ring system would be useful, especially since it could also
provide access to the hitherto unknown aza analogues;8
the antimicrobial and antiparasitic bengamides incorpo-
rate a perhydroazepine ring.9To that end, we describe
here enantioselective syntheses of the first aza ana-
logues10 containing the 5-7-6-fused ring system of the
daphnane diterpenoids and the aconite alkaloids, to-
gether substantial functionality that is central to biologi-
cal activity.
A convergent strategy was envisaged (Scheme 1) in
which an intramolecular cyclization would form the
central seven-membered ring. Additionally, the location
of the nitrogen atom should facilitate the synthesis,
stereocontrol, and potential pharmacological activity of
the resulting 5-7-6 prototypes. Selection of X ) N in 5
permits consideration of an acyliminium cationic cycliza-
tion11 of 6, which, if containing a moderately activated
benzene ring, would act as an effective π-nucleophile.
Construction of 6 would proceed by N-alkylation of a
lactam 7 using an allylic electrophile such as 8, which
must be constructed with the required alkene configu-
ration. It was sought to achieve control of configuration
by rendering R2 in 8 electron deficient, so that stereo-
electronic factors would favor R2 being trans to the
conjugated aromatic ring.
In a Baylis-Hillman reaction,12 3-methoxybenzalde-
hyde (10) was reacted with methyl acrylate using 3-hy-
droxyquinuclidine as the catalyst to give alcohol 11 (91%,
Scheme 2).13 It was anticipated that SN2′ attack upon the
allylic alcohol 11 would lead to an unsaturated ester of
the desired configuration. Indeed, treatment of the
(14) Neuberger, A.; Scott, J . J . J . Chem. Soc. 1954, 1820.
(15) (a) Hubert, J . C.; Steege, W.; Speckamp, W. N.; Huisman, H.
O. Synth. Commun. 1971, 1, 103. (b) Hubert, J . C.; Wijnberg, J . B. P.
A.; Speckamp, W. N. Tetrahedron 1975, 31, 1437.
(16) (a) Wijnberg, J . B. P. A.; Shoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1978, 34, 179. (b) Hart, D. J .; Yang, T.-K. J . Chem. Soc.,
Chem. Commun. 1983, 135 (c) Choi, J .-K.; Hart, D. J . Tetrahedron
1985, 41, 3959.
(17) (a) Chamberlain, A. R.; Chung, J . Y. L. J . Am. Chem. Soc. 1983,
105, 3653. (b) Almeida, J . F.; Anaya, J .; Martin, N.; Grande, M.; Moran,
J . R.; Caballero, C. Tetrahedron: Asymmetry 1992, 3, 1431.
(18) For a review on trifluoromethanesulfonic acid see: Stang, P.
J .; White, M. R. Aldrichimica Acta 1983, 16, 15.
(8) For a total synthesis of racemic phorbol skillfully executed in
some 50 steps, see: (a) Wender, P. A.; Kogan, H.; Lee, H. Y.; Munger,
D.; Wilhelm, R. S.; Williams, P. D. J . Am. Chem. Soc. 1989, 111, 8957.
For formal asymmetric syntheses of phorbol see: (b) Wemder, P. A.;
Rice, K. D.; Schnute, M. E. J . Am. Chem. Soc. 1997, 119, 7897. (c)
Lee, K.; Cha, J . K. J . Am. Chem. Soc. 2001, 123, 5590.
(9) Quin˜oa, E.; Adamczeski, M.; Crews, P.; Bakus, G. J . J . Org.
Chem. 1986, 51, 4494.
(10) A preliminary communication of part of this work is described
in: Marson, C. M.; Pink, J . H.; Smith, C. Tetrahedron Lett. 1995, 36,
8107.
(11) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
(12) (a) Baylis, A. B.; Hillman, M. E. D. Chem. Abstr. 1972, 77,
34174q. (b) Drewes S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653.
(13) For related SN2′ displacements see: Ameer, F.; Drewes, S. E.;
Neville, D.; Kaye, P. T.; Mann, R. L. J . Chem. Soc., Perkin Trans. 1
1983, 2293.
(19) A 3:1 para/ortho-isomeric ratio has been demonstrated for
cyclizations that afford aromatic steroid precursors: J ohnson, W. S.
Bioorg. Chem. 1976, 5, 51.
(20) (a) Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura, T. J .
Org. Chem. 1991, 56, 435. (b) Tamura, Y.; Yakura, T.; Haruta, J .; Kita,
Y. J . Org. Chem. 1987, 52, 3927.
J . Org. Chem, Vol. 68, No. 3, 2003 793

Marson et al.
SCHEME 2. Syn th esis of a n En a n tiop u r e Aza d iter p en oid An a logu ea
a
(a) Methyl acrylate, 3-hydroxyquinuclidine (91%); (b) 48% HBr (aq), 16 h, 20 °C (80%); (d) AcCl; (e) ammonia; (f) AcCl; 50% overall
for (d)-(f); (g) K2CO3, DMF (62%); (h) NaBH4, MeOH, HCl (87%); (i) 5% CF3SO3H in dichloromethane, 75 min, 20 °C (65%); (j) BBr3
(70%); (k) PIFA (12%).
sponding to the 9a-hydroxy group and the 10a-hydrogen
atom in phorbol, gnidicin, gnidimacrin, and resinifera-
toxin, among other related diterpenoids. Additionally, the
absolute configurations of 18 and 20 are analogous to
those in phorbol and related diterpenoids, and follow from
the (3S)-configuration of imide 15.
In dienone 20,21 the O(1)-H(1) and H(1)-O(4) dis-
tances of 0.82 and 1.895 Å are consistent with inter-
molecular hydrogen bonding to solvent incorporated into
the crystal structure (refining as C17H17NO7‚0.5(iPrOH))
This is a significant finding, since the corresponding
O-atoms at C-4 and C-9 in phorbol interact with receptor
sites, and hydrogen bonding in phorbol2,22 and its sol-
vates23 usually involves both of those oxygen atoms,
though independently of each other. Additionally, the
methoxycarbonyl group in 20 lies out of the plane defined
by C(5)-C(6)-C(7); in the same way, the degree of
noncoplanarity of the C-20 side chain with the CdC
unsaturation in the seven-membered ring of phorbol
derivatives can moderate the pharmacological properties.
The dienone 20 incorporates oxygenated functionality
corresponding to the C-9 and C-20 positions in phorbol,
which together with C-4 is crucial to biological activity.3
The ability of both O(1) and O(4) to engage in hydrogen
bonding supports the possibility of 20 and related systems
being pharmacologically significant through binding to
receptor sites. As expected, during cyclization of the
precursor 17, the R-face attachment of the 1-acetoxy
group induced approach of the aromatic ring to the
opposite, less hindered, â-face, resulting in a 10bR-
configuration of the tricyclic systems.17
(21) Crystal data for 20: (C17H17NO7)‚0.5(C3H8O), Mr ) 377.36,
orthorhombic, C2221 (No. 20), a ) 20.254(5) Å, b ) 23.722(8) Å, c )
7.913(3) Å, U ) 3802(2) Å3, Z ) 8, Dc ) 1.319 g cm-3, µ(Mo KR) ) 1.03
cm-1, F(000) ) 1592, T ) 293(2) K. Cystallographic measurements
were made using a FAST area detector diffractometer and Mo KR
radiation (λ ) 0.71069 Å). The structure was solved by direct methods
(SHELX-S) and refined on F2 by full-matrix least-squares (SHELXL-
93) using all 2890 unique data to final Rw (on F2) ) 0.1166 and R (on
F) ) 0.0565 (for data with Fo > 4σFo)), non-H atoms anisotropic; H
atoms on the solvent ignored, others in riding model with Uiso tied to
the Ueq of the parent. Cambridge Crystallographic Data Base Deposi-
tion Number CCDC 191807.
Other cyclizations were also successful (Scheme 3).
Structural modifications were sought which would im-
prove the selectivity of the cyclization step. It was
anticipated that the introduction of a second methoxy
group to the aromatic ring would increase steric inter-
(22) Pettersen, R. C.; Birnbaum, G. I.; Ferguson, G.; Islam, K. M.
S.; Sime, J . G. J . Chem. Soc. B 1968, 980.
(23) Hoppe, W.; Zechmeister, K.; Ro¨hrl, M.; Brandl, F.; Hecker, E.;
Kreibich, G.; Bartsch, H. Tetrahedron Lett. 1969, 667.
794 J . Org. Chem., Vol. 68, No. 3, 2003

Aza Analogues
SCHEME 3 a
SCHEME 4 a
a
(a) Methyl acrylate, 3-hydroxyquinuclidine (0.2 equiv), CH2Cl2
(80%); (b) 48% HBr (aq) (87%); (c) 15, K2CO3, DMF (70%); (d)
NaBH4, MeOH, -8 °C, 20 min, quantitative; (e) 5% CF3SO3H in
CH2Cl2 (80%).
a
(a) Methyl acrylate, 3-hydroxyquinuclidine (0.2 equiv), CH2Cl2
(51%); (b) 48% HBr (aq), quantitative; (c) 15, K2CO3, DMF (73%);
(d) NaBH4, MeOH, -8 °C, 20 min (87%); (e) 5% CF3SO3H in
CH2Cl2.
actions arising from R-face attack on cyclization in
addition to avoiding regioisomeric products, since the
hydroxylactam 28 is symmetrical to ortho- and para-
attack. The strategy of Scheme 3 employed 3,5-dimethoxy-
benzaldehyde (24) in a Baylis-Hillman reaction with
methyl acrylate (3-hydroxyquinuclidine, CH2Cl2, 80%). In
this case, it was found necessary to increase the propor-
tion of catalyst used to 0.2 equiv for an efficient reaction
to occur. Bromide 26 was then formed by treatment of
the alcohol 25 with aqueous 48% hydrobromic acid (87%).
N-Alkylation of (3S)-acetoxysuccinimide 15 (K2CO3, DMF,
70%) afforded the dimethoxy derivative 27, which was
reduced (NaBH4, MeOH, - 8 °C, quantitative), and the
epimeric mixture of 28 (6:1 cis:trans) was cyclized with
5% CF3SO3H in dichloromethane to give the tricyclic
lactam 29, in 80% yield, as the only isomer isolated and
of potential use in the synthesis of aza-aconite alkaloids.
Following the synthesis of 29, the introduction of
further functionality was attempted that more closely
resembled the tumor-promoting diterpenes (Scheme 4).
5-Methylvanillin24 was selected as a suitable precursor,
since it possesses both a methyl group, which would
provide a 10-substituent in the cyclized product analo-
gous to the 11-methyl group of the natural systems, and
a 4-hydroxyl function that would enable the introduction
of long chain esters analogous to the esters at position-
12 of the gnididin types. Such aliphatic esters are crucial
to the biological activity of the natural systems and
improve penetration of lipids. To facilitate the Baylis-
Hillman reaction with methyl acrylate (Scheme 4), 5-me-
thylvanillin was converted into the acetate 30. In a
sequence analogous to Scheme 3, alcohol 31 was con-
verted into the tetrasubstituted benzenoid precursor 33,
which was reduced (NaBH4, MeOH, -8 °C, 87%), and the
4:1 epimeric mixture of the hydroxy lactam was cyclized
with 5% CF3SO3H in dichloromethane to give lactam 35
in 60% yield. The regiochemistry of the lactam 35 was
established by rotating-frame Overhauser enhancement
NMR spectroscopy. The observed interaction between the
methoxy hydrogen atoms at position-8 and the hydrogen
atom at position-7 indicated their proximity; no such
interaction was observed for the 10-methyl group and
hydrogen atom at position-7. Accordingly, ring closure
is inferred to have taken place para to the methoxy group,
as desired. The dense C-ring substitution of 35 is suitable
for development into analogues of gnididin and phorbol.
Although cyclizations involving acyliminium species
that afford six-membered rings11 are abundant, the
present examples supplement the few acyliminium cy-
clizations that result in a seven-membered ring.25 The
succinct enantioselective syntheses of the tricyclic lac-
tams 18, 29, and 35, and of the tricyclic carbinol 20
establish a convergent strategy for the synthesis of highly
functionalized aza analogues of natural products that
incorporate an angularly fused 5-7-6 tricyclic system.
Suitable modifications of such lactams can be envisaged,
including (a) elimination of acetic acid across the 1,2-
positions, (b) electrophilic substitution and/or oxidation
(25) (a) Moeller, K. D.; Rothfus, S. L.; Wong, P. L. Tetrahedron 1991,
47, 583. (b) Liao, Z.-K.; Kohn, H. J . Org. Chem. 1984, 49, 4745. (c)
Massa, S.; Mai, A.; Artico, M.; Corelli, F.; Botta, M. Tetrahedron 1989,
45, 2763. (d) Kraus, G. A., Yue, S. J . Org. Chem. 1983, 48, 2936.
(24) Sinhababu, A. K.; Borcharst, R. T. Synth. Commun. 1983, 13,
677.
J . Org. Chem, Vol. 68, No. 3, 2003 795

Marson et al.
sulfate and filtered, and the solvent was evaporated to give a
solid that was purified by column chromatography (1:1 ethyl
acetate/light petroleum) to afford 16 as a viscous colorless oil
(3.16 g, 62%): νmax (film) 1749, 1720 cm-1; δH 7.88 (1H, s), 7.25
(1H, t, J ) 5.0 Hz), 6.86 (3H, m), 5.15 (1H, dd, J ) 9, 5.5 Hz),
4.56 (2H, s), 3.76 (3H, s), 3.73 (3H, s), 2.92 (1H, dd, J ) 18.0,
9.0 Hz), 2.43 (1H, dd, J ) 18.0, 5.5 Hz), 2.07 (3H, s); δC 172.9
(s), 172.5 (s), 169.7 (s), 166.6 (s), 159.6 (s), 143.2 (d), 135.8 (s),
129.7 (d), 125.3 (s), 121.0 (d), 114.8 (d), 113.9 (d), 67.1 (d), 55.3
(q), 52.2 (q), 36.8 (t), 35.6 (t), 20.5 (q); m/z (EI) 361 (100%),
329 (47), 269 (31), 241 (83), 204 (49), 172 (71), 145 (50), 69
(47), 55 (60). HRMS Calcd for C18H19NO7: 361.1162. Found:
361.1166.
of the aromatic ring, and (c) manipulation of the C-5 ester
group to give the desired pharmacological activity.3
Exp er im en ta l Section
Gen er a l. Melting points were determined on a microscope
1
hot stage and are uncorrected. H and 13C NMR spectra were
recorded at 250 and 68.8 MHz, respectively, in CDCl3 unless
otherwise stated. Thin-layer chromatography was performed
on 0.2 mm aluminum-backed silica plates and visualized using
ultra violet light or developed using an alkaline potassium
permanganate spray. Flash column chromatography was
performed using silica gel. Petroleum ether (40-60 °C fraction)
and ethyl acetate were distilled prior to use, dichloromethane
was distilled over calcium hydride, and THF was distilled from
sodium and benzophenone. Evaporation refers to the removal
of solvent under reduced pressure.
1-[2-Ca r bom eth oxy-3-(3-m eth oxyp h en yl)-2-p r op en yl]-
(4S)-a cetoxy-5-h yd r oxy-p yr r olid in -2-on e (17). The imide
16 (0.50 g, 1.38 mmol) was stirred in methanol (45 mL) at -8
°C. To this was added sodium borohydride (0.26 g, 6.92 mmol)
and stirring was continued for 20 min, before pouring into a
stirred mixture of saturated aqueous sodium hydrogen carbon-
ate solution (40 mL) and dichloromethane (40 mL). The
aqueous layer was extracted with additional dichloromethane
(3 × 30 mL). The combined organic layers were dried over
magnesium sulfate and filtered, and the solvent was evapo-
rated to give the product as a mixture of diastereoisomers
(2.5:1 cis/trans, 0.44 g, 87%) which was then recrystallized
from dichloromethane-light petroleum to afford amide 17
(0.25 g, 50%) as white prisms of a single diastereoisomer, mp
5-Methylvanillin24 and (3S)-acetoxysuccinimide17a were pre-
pared according to literature procedures.
Meth yl 3-(3-Meth oxyp h en yl)-2-(br om om eth yl)p r op e-
n oa te (12).13 A mixture of 9 (4.00 g, 29.4 mmol) and methyl
propenoate (3.16 g, 36.7 mmol) was treated with a solution of
3-hydroxyquinuclidine (0.19 g, 1.47 mmol) in dichloromethane
(1 mL). The mixture was stirred at 20 °C for 3 days before the
volatile components were evaporated. The viscous oil was
treated with aqueous hydrobromic acid (30 mL, 48%), and the
mixture was stirred at 20 °C for 16 h and then poured into
diethyl ether (75 mL). The layers were separated, and the
aqueous layer was extracted with diethyl ether (2 × 50 mL).
The combined organic extracts were washed with saturated
aqueous sodium hydrogen carbonate (2 × 100 mL), dried over
magnesium sulfate, filtered, and evaporated. The residue was
purified by column chromatography (1:10 ethyl acetate/light
petroleum) to give 12 (6.62 g, 79%) as a colorless oil: νmax (film)
2900, 2795, 1710, 1610, 1590 cm-1; δH 7.82 (1H, s), 7.37 (1H,
t, J ) 8.0 Hz), 7.13 (2H, m), 6.97 (1H, m), 4.40 (2H, s), 3.90
(3H, s), 3.85 (3H, s); δC 166.6 (s), 159.8 (s), 143.0 (d), 135.5 (s),
129.9 (d), 128.8 (s), 122.9 (d), 115.9 (d), 114.2 (d), 55.4 (q), 52.5
(q), 27.0 (t); m/z (EI) 286 (7), 284 (7), 205 (60), 145 (100), 131
(15), 115 (31), 103 (25). HRMS Calcd for C12H1379BrO3:
284.0048. Found: 284.0045.
1-[2-Ca r bom eth oxy-3-(3-m eth oxyp h en yl)-2-p r op en yl)]-
p yr r olid in e-2,5-d ion e (13). The bromide 12 (1.00 g, 3.34
mmol) was added to a solution of succinimide (0.33 g, 3.34
mmol) in DMF (1 mL), and the mixture was washed in with
more solvent (1 mL). Anhydrous potassium carbonate (0.46 g,
3.34 mmol) was added in small portions (to minimize ring
opening), and the mixture was stirred at 20 °C for 16 h.
Dichloromethane (20 mL) was then added, and the solution
was poured into water (80 mL). The layers were separated,
and the aqueous layer was extracted with dichloromethane
(3 × 25 mL). The combined organic extracts were washed with
water (2 × 25 mL), dried over magnesium sulfate, and filtered,
and the solvent was evaporated. Purification by column
chromatography (1:1 ethyl acetate/light petroleum) gave 13
(0.81 g, 80%) as a viscous, colorless oil: νmax (film) 1777, 1705
cm-1; δH 7.86 (1H, s), 7.29 (1H, t, J ) 7.0 Hz), 6.80 (3H, m),
4.57 (2H, s), 3.82 (3H, s), 3.79 (3H, s), 2.51 (4H, s); δC 176.7
(s), 176.6 (s), 166.7 (s), 159.5 (s), 142.6 (d), 135.9 (s), 129.6 (d),
125.9 (s), 121.0 (d), 114.6 (d), 113.8 (d), 52.3 (q), 52.2 (q), 36.6
(t), 28.0 (t), 28.0 (t).
111-113 °C: νmax (Nujol mull) 3165, 1733, 1708, 1664 cm-1
;
δH 7.92 (1H, s), 7.58 (1H, t, J ) 5.0 Hz), 7.02 (2H, m), 6.94
(1H, m), 5.25 (1H, d, J ) 6.0 Hz), 5.05 (1H, m), 4.75 (1H, d, J
) 8.0 Hz), 4.19 (1H, d, J ) 8.0 Hz), 3.88 (3H, s), 3.57 (3H, s),
2.67 (2H, d, J ) 7.5 Hz), 2.15 (3H, s); δC 171.0 (s), 170.6 (s),
169.3 (s), 159.7 (s), 145.1 (d), 135.2 (s), 129.8 (d), 125.6 (s),
122.3 (d), 115.9 (d), 114.5 (d), 80.7 (d), 67.6 (d), 55.4 (q), 52.7
(q), 37.3 (t), 34.3 (t), 20.7 (q). Anal. Calcd for C18H22NO7: C,
59.33; H, 5.99; N, 3.84. Found: C, 59.48; H, 5.82; N, 3.81.
1r-Acet oxy-5-ca r b om et h oxy-1,2,4,10br-t et r a h yd r o-8-
m eth oxy-3a -a za ben z[e]a zu len -3-on e (18). The lactam 17
(0.20 g, 0.55 mmol; 2.5:1 cis/trans) was dissolved in dichloro-
methane (0.95 mL) under nitrogen. Trifluoromethanesulfonic
acid (0.05 mL) was added, and the mixture was stirred for 1.5
h. Saturated aqueous sodium hydrogen carbonate was added
cautiously to neutralize the excess acid. The mixture was
diluted with water (15 mL), and the product was extracted
with dichloromethane (3 × 20 mL). The combined extracts
were dried over magnesium sulfate, filtered, and evaporated
to give a mixture of 18 and 21 (70% yield determined by 1H
NMR spectroscopy). Two recrystallizations from ethyl acetate-
light petroleum afforded the single diastereoisomer 18 (35 mg,
20
18%) as microprisms, mp 180-182 °C: RD +144° (c ) 0.1,
CHCl3); νmax (Nujol mull) 1736, 1717, 1692 cm-1; δH 7.56 (1H,
s), 7.47 (1H, d, J ) 8.0 Hz), 6.86 (2H, m), 5.53 (1H, m), 4.79
(1H, d, J ) 2.0 Hz), 4.67 (1H, d, J ) 18.0 Hz), 4.06 (1H, d, J
) 18.0 Hz), 3.79 (3H, s), 3.77 (3H, s), 2.74 (1H, dd, J ) 18.0,
6.0 Hz), 2.39 (1H, dd, J ) 18.0, 2.0 Hz), 2.18 (3H, s); δC 171.9
(s), 170.6 (s), 166.4 (s), 159.1 (s), 140.7 (d), 134.4 (s), 130.5 (s),
129.7 (s), 128.0 (d), 119.2 (d), 115.4 (d), 111.7 (d), 72.9 (d), 66.9
(d), 55.4 (q), 52.4 (q), 40.8 (t), 36.3 (t), 21.1 (q). Anal. Calcd for
C
18H19NO6: C, 62.60; H, 5.55; N, 4.06. Found: C, 62.57; H,
5.60; N, 4.22.
1r-Acet oxy-5-ca r b om et h oxy-1,2,4,10br-t et r a h yd r o-8-
h yd r oxy-3a -a za ben z[e]a zu len -3-on e (19). The lactam 18
(100 mg, 0.29 mmol) was stirred in dichloromethane (1 mL)
under nitrogen. Boron tribromide in dichloromethane (2.0 mL,
1 M) was added, and stirring was continued for 1.5 h. The
mixture was then poured into water (10 mL) and extracted
with dichloromethane (4 × 10 mL). The combined organic
extracts were then dried over sodium sulfate and filtered, and
the solvent was evaporated. The residue was purified by
column chromatography (8:2 ethyl acetate/light petroleum) to
afford 19 (67 mg, 70%) as an oil: δH 7.54 (1H, s), 7.45 (1H, d,
J ) 8.0 Hz), 6.86 (2H, m), 5.56 (1H, m), 4.83 (1H, d, J ) 2.0
[1-[2-Car bom eth oxy-3-(3-m eth oxyph en yl)-2-pr open yl)]-
(3S)-a cetoxy-p yr r olid in e-2,5-d ion e (16). (3S)-Acetoxysuc-
cinimide (15) (2.20 g, 14.0 mmol) was dissolved in DMF (5 mL).
To this solution was added bromide 12 (3.99 g, 14.0 mmol),
and the residues were washed in with more solvent (1 mL).
Anhydrous potassium carbonate (1.94 g, 14.0 mmol) was added
in small portions, and the mixture was stirred under nitrogen
for 2.5 h. Dichloromethane (80 mL) was added, and the
solution was poured into water (300 mL). The aqueous layer
was separated and extracted with dichloromethane (3 × 150
mL). The combined organic layers were dried over sodium
796 J . Org. Chem., Vol. 68, No. 3, 2003

Aza Analogues
Hz), 4.72 (1H, d, J ) 18.0 Hz), 4.11 (1H, d, J ) 18.0 Hz), 3.78
(3H, s), 2.77 (1H, dd, J ) 18.0, 6.0 Hz), 2.45 (1H, dd, J ) 18.0,
2.0 Hz), 2.13 (3H, s); δC 171.4 (s), 170.8 (s), 166.6 (s), 156.6 (s),
141.3 (d), 134.2 (s), 129.7 (s), 128.3 (s), 128.1 (d), 121.0 (s),
117.2 (s), 72.9 (d), 67.3 (d), 52.5 (q), 40.9 (t), 36.5 (t), 21.1 (q);
m/z EI 331 (0.5%), 314 (6), 271 (39), 256 (11), 173 (17). HRMS
Calcd for C17H17NO6: 331.1056. Found: 331.1058.
(Nujol mull) 1750, 1720, 1715 cm-1; δH 7.83 (1H, s), 6.50 (2H,
d, J ) 2.0 Hz), 6.40 (1H, t, J ) 2.0 Hz), 5.20 (1H, dd, J ) 9.5,
5.5 Hz), 4.60 (2H, s), 3.75 (9H, s), 2.95 (1H, dd, J ) 18.0, 9.5
Hz), 2.50 (1H, dd, J ) 18.0, 5.5 Hz), 2.10 (3H, s); δC 172.9 (s),
172.6 (s), 169.7 (s), 166.5 (s), 160.8 (s), 143.1 (d), 136.3 (s), 125.6
(s), 106.4 (d), 101.0 (d), 67.1 (d), 55.4 (q), 52.2 (q), 36.7 (t), 35.5
(t), 20.4 (q). Anal. Calcd for C19H2lNO8: C, 58.31; H, 5.41; N,
3.57. Found: C, 59.68; H, 5.49; N, 3.33.
1r-Acetoxy-5-ca r bom eth oxy-10a r-h yd r oxy-8-oxo-1,2,-
10a r,10b r-t et r a h yd r o-4H -3a -a za b en z[e]a zu len e-3,8-d i-
on e (20). The phenol 19 (293 mg, 0.88 mmol) was stirred at 0
°C in acetonitrile/water (12 mL, 4:1). Bis(trifluoroacetoxy)-
iodobenzene (PIFA, 456 mg, 1.06 mmol) was added, and
stirring was continued for 50 min. Solid sodium hydrogen
carbonate was added to neutralize the mixture, which was
then evaporated. The residue was diluted with water (10 mL)
and extracted with dichloromethane (4 × 15 mL). The com-
bined organic extracts were dried over sodium sulfate and
filtered, and the solvent was evaporated. The residue was
purified by column chromatography (8:2 ethyl acetate/light
petroleum) to afford 20 (38 mg, 12%) as white microprisms,
1-[2-Ca r bom eth oxy-3-(3,5-d im eth oxyp h en yl)-2-p r op e-
n yl]-(4S)-a cet oxy-5-h yd r oxyp yr r olid in -2-on e (28). The
imide 27 (2.64 g, 6.74 mmol) was stirred in methanol (250 mL)
at -8 °C. Sodium borohydride (1.30 g, 34.5 mmol) was added,
and after being stirred for 20 min the mixture was poured into
a stirred mixture of saturated aqueous sodium hydrogen
carbonate (150 mL) and dichloromethane (150 mL). The
organic layer was separated, and the aqueous layer was
further extracted with dichloromethane (2 × 50 mL). The
combined organic layers were dried over magnesium sulfate
and filtered, and the solvent was evaporated to give the
product as a mixture of diastereoisomers (6:1 cis/trans, quan-
titative) which was recrystallized from ethyl acetate-light
petroleum to give the pure cis amide 28 (1.83 g, 69%) as white
prisms, mp 100-103 °C: νmax (Nujol mull) 3225, 1734, 1709,
1694 cm-1; δH 7.80 (1H, s), 6.55 (2H, d, J ) 2.0 Hz), 6.42 (1H,
t, J ) 2.0 Hz), 5.19 (1H, d, J ) 5.5 Hz), 5.00 (1H, m), 4.67
(1H, d, J ) 15.5 Hz), 4.08 (1H, d, J ) 15.5 Hz), 3.79 (3H, s),
3.73 (6H, s), 2.60 (2H, d, J ) 9.5 Hz), 2.07 (3H, s); δC 171.0 (s),
170.6 (s), 169.2 (s), 160.9 (s), 145.2 (d), 135.7 (s), 125.8 (s), 107.5
(d), 102.3 (d), 80.7 (d), 67.6 (d), 55.5 (q), 52.7 (q), 37.3 (t), 34.3
(t), 20.7 (q). Anal. Calcd for C19H23NO8: C, 58.02; H, 5.89; N,
3.56. Found: C, 58.04; H, 5.57; N, 3.60.
20
mp 128-130 °C: RD +307° (c ) 0.043, CHCl3); δH 7.43 (1H,
bd s), 7.04 (1H, d, J ) 8.5 Hz), 6.78 (1H, dd, J ) 8.5, 3.0 Hz),
6.64 (1H, d, J ) 3.0 Hz), 5.38 (1H, dd, J ) 6.5, 1.5 Hz), 5.37
(1H, s), 4.97 (1H, dd, J ) 18.5, 1.5 Hz), 4.00 (1H, dd, J ) 18.5,
2.0 Hz), 3.84 (3H, s), 2.12 (3H, s), 2.09 (1H, d, J ) 8.5 Hz),
2.13-2.05 (2H, m); m/z (EI) 347 (91%), 305 (38), 279 (29), 255
(58), 205 (60), 191 (77), 147 (100). HRMS Calcd for C17H17
NO7: 347.1005. Found: 347.1002.
-
Met h yl
2-[(3,5-Dim et h oxyp h en yl)h yd r oxym et h yl]-
p r op en oa te (25). 3,5-Dimethoxybenzaldehyde (3.32 g, 20.0
mmol) and methyl acrylate (8.61 g, 100 mmol) were stirred
together under nitrogen until the mixture was homogeneous.
3-Hydroxyquinuclidine (0.51 g, 4.00 mmol) in dichloromethane
(2 mL) was added, and the mixture was stirred 20 °C for 4
days. The excess methyl acrylate was then removed in vacuo,
and the residue was purified by column chromatography (3:7
ethyl acetate/light petroleum) to give 25 (4.33 g, 86%) as a
colorless oil: νmax (film) 3484, 1715 cm-1; δH 6.5 (2H, d, J )
3.0 Hz), 6.35 (1H, t, J ) 2.0 Hz), 6.3 (1H, s), 5.8 (2H, t, J ) 2.0
Hz), 3.75 (6H, s), 3.7 (3H, s); δC 166.8 (s), 160.8 (s), 143.9 (s),
141.7 (s), 126.2 (t), 104.6 (d), 99.7 (d), 73.0 (d), 55.3 (q), 51.9
(q). Anal. Calcd for C13Hl6O5: C, 61.89; H, 6.39. Found: C,
61.55; H, 6.06.
Meth yl 2-(Br om om eth yl)-3-(3,5-d im eth oxyp h en yl)p r o-
p en oa te (26). The alcohol 25 (3.70 g, 14.6 mmol) was stirred
overnight with aqueous hydrobromic acid (40 mL, 48%).
Following neutralization (1 M sodium hydroxide) the aqueous
layer was extracted with dichloromethane (3 × 50 mL). The
combined organic extracts were washed with water (2 × 40
mL), dried over magnesium sulfate, and filtered, and the
solvent was evaporated. The crude residue was purified by
column chromatography (3:7 ethyl acetate/light petroleum) to
give 26 as white microprisms (4.02 g, 87%), mp 50-55 °C: νmax
(Nujol mull) 1712 cm-1; δH 7.75 (2H, s), 6.75 (2H, d, J ) 2.0
Hz), 6.50 (1H, t, J ) 2.0 Hz), 4.40 (2H, s), 3.90 (3H, s), 3.80
(6H, s); δC 166.5 (s), 161.0 (s), 161.0 (s), 143.2 (d), 136.0 (s),
129.0 (s), 107.2 (d), 107.2 (d), 102.2 (d), 55.5 (q), 55.5 (q), 52.5
(q), 21.0 (t). Anal. Calcd for C13H15BrO4: C, 49.54; H, 4.79;
Br, 25.35. Found: C, 49.76; H, 4.83; Br, 25.31.
1-[2-Ca r bom eth oxy-3-(3,5-d im eth oxyp h en yl)-2-p r op e-
n yl]-(3S)-a cetoxy-p yr r olid in e-2,5-d ion e (27). (3S)-Acetox-
ysuccinimide (15)17a (1.89 g, 12.0 mmol) was dissolved in DMF
(5 mL) and stirred with the bromide 26 (3.80 g, 12.1 mmol).
Anhydrous potassium carbonate (1.66 g, 12.0 mmol) was then
added in small portions, and the mixture was stirred under
nitrogen for 2.5 h. Dichloromethane (80 mL) was added, and
the solution was poured into water (200 mL). The aqueous
layer was separated and extracted with dichloromethane (2
× 50 mL). The combined organic extracts were dried over
magnesium sulfate and filtered, and the solvent was evapo-
rated. Column chromatography (2:3 ethyl acetate/light petro-
leum) afforded 27 (3.30 g, 70%) as a viscous, colorless oil: νmax
1r-Acetoxy-5-ca r bom eth oxy-1,2,4,10b r-tetr a h yd r o-8,-
10-d im et h oxy-3a -a za b en z[e]a zu len -3-on e (29). Trifluo-
romethanesulfonic acid (0.05 mL) was added to a stirred
solution of 28 (0.20 g, 0.51 mmol) in dichloromethane (1 mL)
under nitrogen, and stirring was continued for 2 h. Saturated
aqueous sodium hydrogen carbonate was then added cau-
tiously until the solution was neutral. The mixture was diluted
with water (15 mL) and extracted with dichloromethane (3 ×
20 mL). The combined extracts were washed with water (20
mL) and then with brine (20 mL), dried over magnesium
sulfate, and filtered, and the solvent was evaporated. Purifica-
tion by column chromatography (1:1 ethyl acetate/light petro-
leum) gave 29 (0.13 g, 80%) as white microprisms, mp 185-
20
187 °C: RD -269° (c ) 0.1, CHCl3); νmax (Nujol mull) 1727,
1709, 1694 cm-1; δH 7.35 (1H, d, J ) 2.0 Hz), 6.45 (1H, d, J )
2.0 Hz), 6.40 (1H, d, J ) 2.0 Hz), 5.25 (1H, d, J ) 6.3 Hz),
5.10 (1H, m), 4.90 (1H, d, J ) 18.0 Hz), 3.75 (9H, s), 3.55 (1H,
dd, J ) 18.0, 2.0 Hz), 2.60 (1H, dd, J ) 18.0, 9.0 Hz), 2.20
(1H, d, J ) 18.0 Hz), 2.10 (3H, s); δC 171.9 (s), 169.8 (s), 166.4
(s), 159.9 (s), 158.7 (s), 140.6 (d), 134.2 (s), 133.1 (s), 120.7 (s),
110.6 (d), 100.0 (d), 73.0 (d), 67.4 (d), 55.8 (q), 55.0 (q), 52.3
(q), 39.8 (t), 37.3 (t), 21.1 (q). Anal. Calcd for C19H2lNO7: C,
60.85; H, 5.64; N, 3.76. Found: C, 60.64; H, 5.45; N, 3.65.
4-Acetoxy-3-m eth oxy-5-m eth ylben za ld eh yd e (30). A
solution of acetyl chloride (30.6 mL, 0.34 mol) in dichloro-
methane (420 mL) was added dropwise to a well-stirred
mixture of 5-methylvanillin24 (60.0 g, 0.36 mol), dichloro-
methane (1.5 L), tetrabutylammonium hydrogen sulfate (480
mg), and powdered sodium hydroxide (36.1 g, 0.90 mol) over
90 min. The mixture was stirred at 20 °C for 3 h and then
diluted with water (1.0 L), and the product was extracted with
dichloromethane (3 × 800 mL). The combined organic layers
were washed with brine, dried over magnesium sulfate,
filtered, and evaporated. Column chromatography (4:1 ethyl
acetate/light petroleum) afforded 30 (48.8 g, 65%) as white
prisms, mp 58 °C: νmax (Nujol mull) 1764, 1691 cm-1; δH 9.40
(1H, s), 7.35 (1H, s), 7.32 (1H, s), 3.86 (3H, s), 2.36 (3H, s),
2.24 (3H, s); m/z (EI) 208 (12%), 166 (100%), 165 (49%). Anal.
Calcd for C11H12O4: C, 63.45; H, 5.81. Found: C, 63.45; H,
5.84.
J . Org. Chem, Vol. 68, No. 3, 2003 797

Marson et al.
Meth yl 2-[(4-Acetoxy-3-m eth oxy-5-m eth ylp h en yl)h y-
d r oxym eth yl]p r op en oa te (31). The aldehyde 30 (14.0 g, 67.2
mmol) was stirred under nitrogen with methyl acrylate (7.24
g, 84.0 mol) in dichloromethane (5 mL). 3-Hydroxyquinuclidine
(1.71 g, 13.4 mmol) in dichloromethane (5 mL) was added, and
the solution was stirred at 20 °C for 4 days. The mixture was
concentrated in vacuo to remove the solvent and excess methyl
acrylate. The oily residue was subjected to column chroma-
tography (light petroleum/ethyl acetate (4:1 increased to 7:3))
to give alcohol 31 (10.1 g, 51%) as a viscous oil: νmax (film)
3493 (br), 1761, 1722 cm-1; δH 6.84 (1H, s), 6.77 (1H, s), 6.32
(1H, s), 5.85 (1H, s), 5.48 (1H, d, J ) 6.0 Hz), 3.77 (3H, s),
3.72 (3H, s), 3.13 (1H, d, J ) 6.0 Hz), 2.30 (3H, s), 2.13 (3H,
s); δC 168.9 (s), 166.7 (s), 151 (s), 141.8 (s), 139.5 (s), 137.8 (s),
131.2 (s), 126.0 (t), 120.6 (d), 108.2 (d), 72.6 (d), 55.9 (q), 52.0
(q), 20.4 (q), 16.0 (q); m/z (EI) 294 (54%), 252 (100%), 220 (45%),
192 (32%), 167 (36%), 165 (72%), 138 (43%), 84 (29%). HRMS
Calcd for C15H18O4: 294.1103. Found: 294.1097.
Met h yl 3-(4-Acet oxy-3-m et h oxy-5-m et h ylp h en yl)-2-
(br om om eth yl)p r op en oa te (32). The alcohol 31 (7.00 g, 23.8
mmol) was stirred in aqueous hydrobromic acid (100 mL, 48%)
for 16 h and then poured into diethyl ether (150 mL). The
layers were separated, and the aqueous layer was extracted
with diethyl ether (2 × 200 mL). The combined organic extracts
were washed with saturated aqueous sodium hydrogen car-
bonate (2 × 150 mL), dried over magnesium sulfate, filtered,
and evaporated. The residue was purified by column chroma-
tography (5:95 ethyl acetate/light petroleum) to give 32 (8.35
g, 98%) as white prisms, mp 82-83 °C: νmax (Nujol mull) 1748,
1723 cm-1; δH 7.76 (1H, s), 7.15 (1H, d, J ) 1.0 Hz), 7.01 (1H,
d, J ) 1.0 Hz), 4.42 (2H, s), 3.87 (3H, s), 3.86 (3H, s), 2.36
(3H, s), 2.21 (3H, s); δC 168.4 (s), 166.4 (s), 151.2 (s), 142.7 (d),
139.3 (s), 132.2 (s), 132.0 (s), 128.3 (s), 124.5 (d), 110.6 (d),
56.0 (q), 52.4 (q), 27.1 (t), 20.3 (q), 16.0 (q). Anal. Calcd for
1-[2-Ca r bom eth oxy-3-(4-a cetoxy-3-m eth oxy-5-m eth yl-
p h en yl)-2-p r op en yl)]-(4S)-a cetoxy-5-h yd r oxyp yr r olid in -
2-on e (34). Imide 33 (0.50 g, 1.38 mmol) was stirred in
methanol (45 mL) at -8 °C. Sodium borohydride (0.26 g, 6.92
mmol) was then added, and stirring was continued for 20 min.
The mixture was poured into a stirred mixture of saturated
aqueous sodium hydrogen carbonate (40 mL) and dichlo-
romethane (40 mL). The aqueous layer was extracted with
additional dichloromethane (3 × 30 mL). The combined organic
layers were dried over magnesium sulfate and filtered, and
the solvent was evaporated to give amide 34 (0.52 g, 87%) as
a
4:1 ratio of cis/trans diastereoisomers. A sample was
recrystallized from dichloromethane/light petroleum to give the
pure cis-diastereoisomer (0.33 g, 55%) as colorless prisms, mp
120-121 °C: νmax (Nujol mull) 3205 (br), 1764, 1737, 1711,
1672 cm-1; δH 7.83 (1H, s), 6.95 (2H, m), 5.19 (1H, d, J ) 5.0
Hz), 5.00 (1H, m), 4.79 (1H, d, J ) 15.0 Hz), 4.11 (1H, d, J )
15.0 Hz), 3.84 (3H, s), 3.81 (3H, s), 2.63 (2H, d, J ) 8.0 Hz),
2.32 (3H, s), 2.16 (3H, s), 2.11 (3H, s); δC 171.1 (s), 170.6 (s),
169.4 (s), 168.6 (s), 151.3 (s), 144.6 (d), 132.0 (s), 131.9 (s), 125.0
(s), 125.0 (s), 124.9 (d), 110.9 (d), 80.5 (d), 67.5 (d), 56.2 (q),
52.8 (q), 37.1 (t), 34.3 (t), 20.7 (q), 20.4 (q), 15.9 (q). Anal. Calcd
for C21H25NO9: C, 57.93; H, 5.79; N, 3.22. Found: C, 57.73;
H, 6.08; N, 3.11.
1r-Acet oxy-5-ca r b om et h oxy-1,2,4,10br-t et r a h yd r o-9-
a ce t oxy-8-m e t h oxy-10-m e t h yl-3a -a za b e n z[e]a zu le n -3-
on e (35). The amide 34 (3.70 g, 8.50 mmol) was dissolved in
dichloromethane (14.0 mL). Trifluoromethanesulfonic acid
(0.75 mL, 8.50 mmol) was then added, and the mixture was
stirred at 20 °C under nitrogen for 1.25 h. The mixture was
then neutralized with saturated aqueous sodium hydrogen
carbonate and extracted with dichloromethane, dried over
sodium sulfate, and filtered, and the solvent was evaporated.
Purification by column chromatography (4:1 ethyl acetate/light
petroleum) afforded the single diastereoisomer 35 (2.10 g, 60%)
C
15H17BrO5: C, 50.44; H, 4.80; Br, 22.37. Found: C, 50.53; H,
20
as prisms, mp 216 °C (dec.): RD -215° (c ) 0.1, CHCl3); νmax
4.94; Br, 22.34.
1750, 1704 cm-1; δH 7.40 (1H, d, J ) 2.5 Hz), 6.78 (1H, s), 5.28
(1H, s), 5.03 (1H, dt, J ) 6.5, 1.5 Hz), 5.01 (1H, d, J ) 16.5
Hz), 3.83 (3H, s), 3.82 (3H, s), 3.56 (1H, dd, J ) 16.5, 2.5 Hz),
2.67 (1H, dd, J ) 18.0, 6.5 Hz), 2.35 (3H, s), 2.28 (1H, dd, J )
18.0, 1.5 Hz), 2.15 (3H, s), 2.12 (3H, s); δC 171.6 (s), 169.8 (s),
168.3 (s), 166.3 (s), 150.2 (s), 140.5 (d), 140.0 (s), 133.1 (s), 131.8
(s), 131.4 (s), 131.1 (s), 116.5 (d), 74.3 (d), 68.7 (d), 56.0 (q),
52.4 (q), 39.8 (t), 37.2 (t), 21.0 (q), 20.4 (q), 13.2 (q). Anal. Calcd
for C21H23NO8: C, 60.43; H, 5.55; N, 3.36. Found: C, 60.29;
H, 5.69; N, 3.26.
1-[2-Ca r bom eth oxy-3-(4-a cetoxy-3-m eth oxy-5-m eth yl-
p h en yl)-2-p r op en yl]-(3S)-a cet oxyp yr r olid in e-2,5-d ion e
(33). (3S)-Acetoxysuccinimide (15)17a (6.12 g, 39.0 mmol) was
stirred in DMF (5 mL) at 20 °C, and to the mixture was added
32 (13.91 g, 39.0 mmol). Anhydrous potassium carbonate (5.38
g, 39.0 mmol) was then added in small portions, and the
mixture was stirred under nitrogen for 3.5 h before pouring
into water (800 mL). The aqueous layer was extracted with
dichloromethane (4 × 300 mL), the combined organic layers
were dried over sodium sulfate and filtered, and the solvent
was evaporated. The oil was purified by column chromatog-
raphy (3:2 light petroleum/ethyl acetate) to give the imide 33
(12.4 g, 73%) as a colorless viscous oil: δH 7.82 (1H, s), 6.81
(1H, d, J ) 1.0 Hz), 6.74 (1H, d, J ) 1.0 Hz), 5.09 (1H, dd, J
) 8.0, 5.0 Hz), 4.64 (2H, s), 3.79 (6H, s), 2.92 (1H, dd, J )
18.5, 8.0 Hz), 2.44 (1H, dd, J ) 18.5, 5.0 Hz), 2.33 (3H, s),
2.16 (3H, s), 2.10 (3H, s); δC 173.0 (s), 172.8 (s), 169.7 (s), 168.7
(s), 166.6 (s), 151.0 (s), 141.9 (d), 138.6 (s), 132.4 (s), 131.8 (s),
125.2 (s), 122.5 (d), 109.7 (d), 67.2 (d), 55.9 (q), 52.3 (q), 36.8
(t), 35.3 (t), 20.4 (q), 20.4 (q), 15.8 (q); m/z (EI) 433 (12%), 391
(100%), 331 (15%), 271 (31%), 234 (19%), 203 (15%), 121 (28%).
HRMS Calcd for C21H23NO9: 433.1373. Found: 433.1367.
Ack n ow led gm en t. This work was supported by the
Engineering and Physical Sciences Research Council
and Rhoˆne-Poulenc Rorer Ltd., Dagenham as a CASE
studentship (to J .H.P.). We are also grateful for use of
the EPSRC National Crystallography Service.
Su p p or tin g In for m a tion Ava ila ble: Atomic coordinates,
bond lengths, bond angles, and an ORTEP representation of
20. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0205816
798 J . Org. Chem., Vol. 68, No. 3, 2003