β-lactams as building blocks in the synthesis of macrocyclic spermine and spermidine alkaloids

Article abstract of DOI:10.1016/S0040-4020(02)00731-7

Syntheses of the macrocyclic spermidine alkaloids (±)-celacinnine (1) and (±)-dihydroperiphylline (2) as well as the related spermine alkaloid (±)-verbascenine (3) were accomplished by means of sequential ring expansions of smaller lactam rings. Three ring expansion methods were employed: (1) transamidation of N-(aminoalkyl)lactams, (2) β-lactam-lactim ether condensation followed by reductive cleavage of the bicyclic 4-oxotetrahydropyrimidine product with NaBH₃CN/AcOH and (3) bicyclic acyl hydrazine formation followed by N-N bond cleavage with Na/NH₃. Each synthesis features ring expansion of a 4-phenylazetidin-2-one intermediate that undergoes transamidative ring expansion or lactim ether condensation.

Full text of DOI:10.1016/S0040-4020(02)00731-7

Tetrahedron 58 (2002) 7177–7190
b-Lactams as building blocks in the synthesis of macrocyclic
spermine and spermidine alkaloids
*
Harry H. Wasserman, Haruo Matsuyama and Ralph P. Robinson
Department of Chemistry, Yale University, P.O. Box 208107, New Haven, CT 06520-8107, USA
Received 11 April 2002; accepted 13 May 2002
Abstract—Syntheses of the macrocyclic spermidine alkaloids (^)-celacinnine (1) and (^)-dihydroperiphylline (2) as well as the related
spermine alkaloid (^)-verbascenine (3) were accomplished by means of sequential ring expansions of smaller lactam rings. Three ring
expansion methods were employed: (1) transamidation of N-(aminoalkyl)lactams, (2) b-lactam-lactim ether condensation followed by
reductive cleavage of the bicyclic 4-oxotetrahydropyrimidine product with NaBH3CN/AcOH and (3) bicyclic acyl hydrazine formation
followed by N–N bond cleavage with Na/NH3. Each synthesis features ring expansion of a 4-phenylazetidin-2-one intermediate that
undergoes transamidative ring expansion or lactim ether condensation. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Alkaloids derived from the polyamines spermine and
spermidine comprise a large family of natural products in
which there has been sustained interest due to their spectrum
of biological activity.1,2 Representatives of this group,
especially those products containing the polyamine unit
within the core of a macrocylic ring, present challenging
targets for total synthesis.2,3
Early work on the synthesis of macrocyclic polyamine
alkaloids involved preparation of the large ring by direct
cyclization, usually via amide bond formation.2,3 An
alternative strategy for forming the macrocyclic system in
these alkaloids was developed in our laboratory as an
outgrowth of our interest in the use of b-lactams as reactive
sources of b-amino acyl units.4 We found that ring-opening
of these strained entities by intramolecular nucleophilic
attack could serve as a general method for incorporation of
the four atom fragment. The syntheses of the spermidine
alkaloids celacinnine (1)5 and dihydroperiphylline (2),6 and
the spermine alkaloids verbascenine (3)7 and homaline (4)8
established the viability of the ring expansion approach.
Subsequently, we applied the strategy to the synthesis of
more complex targets: the 13-membered spermidine
alkaloids cannabisativine (5),9 anhydrocannabisativine
(6)10 and dihydropalustrine (7),11 as well as the
17-membered spermine alkaloids chaenorhine (8)12 and
O-methylorantine (9).13
Keywords: celacinnine; dihydroperiphylline; verbascenine; macrocyclic
spermine and spermidine alkaloids; b-lactam; transamidation; lactim ether;
ring expansion.
*
Corresponding author. Tel.: þ1-203-432-3973; fax: þ1-203-432-9990;
e-mail: harry.wasserman@yale.edu
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00731-7

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H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
Scheme 1.
More recently, other groups, most notably that of Hesse,
have extended the above approach to efficient syntheses of
other spermidine alkaloids.14–16 Asymmetric syntheses of 1
and other spermidine alkaloids have also been reported,
employing ring expansion methodology.15–18 In related
work by Crombie, transamidative ring expansion was
studied in detail and applied to syntheses of 2, celabenzine
(a close analog of 1) and alkaloids of the homaline
group.19,20
reactive because of ring strain to overcome the relatively
unfavorable 7-membered transition states.
Particularly relevant information regarding the feasibility of
steps A1 and B1 arose from ongoing studies of Berger in the
synthesis of homaline (4).8,21 In this case, the key step
involved intramolecular attack of a secondary amine on the
4-phenylazetidin-2-one ring through a 6-membered tran-
sition state. The strong conditions required to carry out this
reaction (quinoline, 2378) suggested that the b-lactam was
kinetically more stable than anticipated, and that step A1 in
Scheme 1, requiring a 7-membered transition state, was
unlikely to be successful. Later work by Crombie,
confirmed our ideas since he found compound 10 to be
resistant to reaction under zip conditions (potassium
3-aminopropylamide, 558C).19
In this paper, we report full details of our early work on the
synthesis of macrocyclic spermine and spermidine alka-
loids, in particular, celacinnine (1), dihydroperiphylline (2),
and verbascenine (3). In each case, b-lactam ring expansion
was used in one or more key steps. Full details of the
syntheses of homaline (4) and anhydrocannabisativine (6)
have previously been disclosed.21,22
Although we did not prepare 10, we did prepare its isomer
13. The synthesis was accomplished in three steps starting
from the corresponding di-Boc spermidine derivative
(Scheme 2).24,25 However, all efforts to convert 13 to the
13-membered lactam 15 or even to the 8-membered lactam
14 proved unsuccessful. Crombie has since prepared 14 by a
different route and has established that step B2 can be
accomplished under relatively mild conditions (potassium
hexamethyldisilazide/258), albeit in low yield (21%).19
2. Early approaches to celacinnine(1) and
dihydroperiphylline (2) via transamidation
For alkaloids 1 and 2, we first considered formation of the
13-membered lactam systems by sequential transamidation
reactions analogous to the ‘zip’ reaction of Hesse (Scheme
1).23 Release of ring strain in the starting b-lactam and
medium-ring lactam intermediates would be expected to
favor ring expansion. Furthermore, as in the zip reaction,
use of a sufficiently strong base would drive formation of
the 13-membered lactams by irreversible deprotonation of
the secondary amide. Steps A2 and Bl are entirely analogous
to the individual steps in the zip reaction for which
6-membered transition states are involved. Steps Al and
B2, however, would proceed through 7-membered tran-
sition states. Although transamidations of this type were
unprecedented, we believed that the b-lactam 10 and
perhaps the 8-membered lactam 14 would be sufficiently
Considering the relative stability of the 4-phenylazetidin-2-
one ring toward intramolecular ring opening by secondary
amino groups, we then investigated ring expansion of the
simple primary amino b-lactams 16 and 18 (Scheme 3).
These were prepared from mono-Boc-1,3-diamino-
propane26 and mono-Boc-1,4-diaminobutane,26 respec-
tively, by the same sequence used in the preparation of 13
(Scheme 2). Both compounds were of potential interest as
precursors to 11 and 14 via an aminoalkylation sequence.
As anticipated, the amino b-lactam 16 underwent facile ring
Scheme 2.

H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
7179
3. Synthesis of (6)-celacinnine (1)
To prepare celacinnine (1), our plan involved conversion of
19 to its N-aminopropyl derivative 11 and subsequent ring
expansion (step A2 in Scheme 1). Alkylation of the sodium
salt of 19, formed in DMF at 508C by NaH deprotonation,
with N-(3-iodopropyl)phthalimide gave 20 (23%) (Scheme
3). Several attempts to improve this yield were made
without success and, although the hindered secondary amine
of 19 could be protected with a Boc group, the product
(described in Section 8 as 21) did not undergo the desired
alkylation under the above conditions. Conditions for
obtaining 11 and related intermediates in higher overall
yield from the corresponding 9-membered azalactams have
since appeared in the literature.14–16
Treatment of 20 with hydrazine hydrate in refluxing
EtOH furnished 11 in high yield. Transamidation to the
13-membered lactam 12 took place slowly under conditions
similar to those used for ring expansion of the amino
b-lactam 16 (2:1 1N NaOH/MeOH). Complete dis-
appearance of 11 was observed after 50 h at 50–608C and
the yield of 12 was 42% after chromatography. We later
noted that the ring expansion also occurs during the
phthalimide cleavage step. Thus, when 20 was heated
with hydrazine hydrate in refluxing EtOH for an extended
period (19 h), a 4:6 mixture of the amino lactams 11 and 12
was obtained. Further conversion to 12 (isolated in 50%
yield) was carried out by warming the mixture in 2:1 1N
NaOH/dioxane at 508C for 7 h.
Scheme 3.
expansion under mild conditions (1N NaOH/558C/12 h)27 to
give the 8-membered azalactam 17 (50% after chroma-
tography). Not surprisingly, more forcing conditions were
required to expand the homologous compound 18 via a
7-membered transition state. The compound was inert in
warm 1N NaOH, but slowly underwent conversion to the
9-membered azalactam 19 in refluxing 2,4-lutidine. Despite
long reaction times of up to 64 h, significant amounts of
starting material were invariably recovered; the yield of 19
after 64 h was 57%. This result suggested that equilibrium
between 18 and 19 was being approached. To test this
possibility, a sample of 19 was subjected to the reaction
conditions. After heating to reflux in 2,4-lutidine for 64 h,
an IR of the crude product showed the emergence of
absorption at 1740 cm21 characteristic of a b-lactam. The
TLC showed the appearance of a spot having the same Rf as
authentic 18. The product was isolated by flash chroma-
tography and although the yield was low (3% with 57% of
19 recovered), NMR confirmed the identity of the product as
18. From this result, it was concluded that 19 is only slightly
more stable than 18 (,3 kcal/mol) allowing easily detect-
able quantities of 18 to be observed at equilibrium. Thus, the
strain associated with the 9-membered azalactam ring is
comparable in magnitude to that of the b-lactam.28
The synthesis of (^)-celacinnine (1) was completed by
treatment of a solution of 12 and 4-N,N0-dimethylamino-
pyridine (DMAP) in CH2Cl2 with trans-cinnamoyl chloride.
At rt, the yield of 1 was 40% (as reported by Ganem29) with
some diacylated material also being isolated. At 278 to
2208C (conditions described by Yamamoto30), the yield of
1 was improved markedly to 85%.
4. Alternative routes to medium ring azalactams
During our investigation of transamidation routes to 1 and 2
we became interested in finding alternative, more efficient
methods of accessing the medium-ring azalactams 17 and
19. As described below, two new routes to 19 were found.31
These introduced new methodologies that were later
Scheme 4.

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H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
Scheme 5.
employed in syntheses of dihydroperiphylline (2), the
related spermidine alkaloids 5–7 and the 17-membered
spermine alkaloids 3, 8 and 9.
the transamidation route and a potentially troublesome
7-membered transition state in step B2 (Scheme 1). This
would make further use of the N–N cleavage reaction and
explore the Bormann condensation for the expansion of
medium-ring lactim ethers.
In the first approach to 19, hexahydropyridazine32 was
condensed with ethyl cinnamate to provide 22 (80%)
presumably via initial 1,4-addition to the unsaturated ester
followed by amide bond formation (Scheme 4).33 Subse-
quent reduction of 22 with Na/NH3 at 2338C took place
smoothly, cleaving the N–N bond to furnish 19 in 80%
yield.34 Although the corresponding 8-membered azalactam
17 could be accessed in a similar way starting from
pyrazolidine, the N–N cleavage using Na/NH3 under
similar conditions was accompanied by significant
competing hydrogenolysis of the benzylic C–N bond.
Matsuyama has since improved the yield of this reduction
significantly.17
Azalactam 27 was obtained in a manner analogous to the
preparation of 22 (Scheme 5). Slow addition of ethyl
acrylate to hexahydropyridazine at 08C led to formation of
the Michael adduct which, on heating to 1908C underwent
cyclization with loss of EtOH to give 26 (85%). The
9-membered azalactam 27 was then obtained by Na/NH3
reduction (87%).
Compound 27 was treated with trans-cinnamoyl chloride
and DMAP to provide the acyl derivative 28 (95%). To
prepare for the subsequent incorporation of the 3-amino
propionyl unit, 28 was treated with trimethyloxonium
tetrafluoroborate to give the crude lactim ether 29 after
basic aqueous workup (78%).37 The compound was
normally used without purification in the next reaction
because of its instability on silica gel. It is noteworthy that
methylation occurred predominantly on the secondary
amide oxygen. A small amount of tertiary amide O-alkyl-
ation was evident from traces of methyl cinnamate, 27, and
28 in the crude product resulting from hydrolysis of the
imidate 31 during workup.
The second alternative route to 19 made use of the
b-lactam-lactim ether condensation reaction first reported
by Bormann35 in which 4-phenylazetidin-2-one21,36 is
heated with 2-methoxypyrroline at 1308C to form the
4-oxo-tetrahydropyrimidine 23 (80%, Scheme 4). Reaction
of 23 with 4 equiv. of NaBH3CN in glacial AcOH (258C/
1 h, 508C/1 h, 258C/22.5 h) then gave rise to 19 (31%).
The first step in the reductive opening of 23 is undoubtedly
CvN bond reduction to form the 4-oxo-hexahydropyrimi-
dine 24. A reasonable mechanism for the subsequent step
involves equilibrium between 24 and its ring-opened form
25 which, upon imine bond reduction, yields 19. As also
noted by Hesse,15 a major competing side reaction was
N-ethylation of 24.
Based upon previous studies of imino ethers, and supporting
NMR data, we assigned the E configuration to 29. Using 1H
NMR, Moriarty38 has studied the geometry of simple cyclic
(lactim) and acyclic imino ethers. Under neutral conditions,
a high-energy barrier (.23 kcal/mol) exists for intercon-
version of the geometrical isomers. Lactim ethers derived
from simple 4–11-membered lactams exist as the stable E
isomers. In these cases, the N–CH2 hydrogens absorb at d
3.40–3.41 (CDCl3). In comparison, acyclic imino ethers
and simple 12–16 membered lactim ethers were found to
exist as the stable Z isomers, with the N–CH2 group at d
3.20–3.28. Compound 29 showed absorption above base-
line between d 3.8 and 3.25 (6H), only barely into the range
5. Synthesis of (6)-dihydroperiphylline (2)
The development of the two alternative ring expansion
methods for accessing the intermediate azalactam 19 in our
synthesis of celacinnine (1), led us to consider a new
approach to dihydroperiphylline (2) that would circumvent

H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
7181
Scheme 6.
for the Z-isomer. Although there is the complication of
overlapping signals from two other N–CH2 groups, we
believe the data is more consistent with the E isomer, the
geometry expected based on ring size.
to undergo ring contraction to the aminopropyl b-lactam 18
(Scheme 3), as well as the ease of related ring contractions
reported by Hassal27 and Hesse,42 we suggest that attempts
to prepare the free 9-membered azalactam 36 by reduction
ring opening of 32 or 33 would suffer from facile conversion
to N-(aminopropyl)-pyrrolidinone (38).
The reaction of 29 with 4-phenylazetidin-2-one provided
the first example of the Bormann condensation involving a
medium ring lactim ether. After heating the reactants in
refluxing chlorobenzene (bp 1328C) for 21 h, the 4-oxo-
tetrahydropyrimidine 30 was isolated in 67% yield. The use
of chlorobenzene as solvent in the condensation is preferred
when performing the reaction on a small scale.39 Compound
30 could also be obtained by the reaction of 29 with methyl
3-amino-3-phenyl propionate under the same conditions,
albeit in lower yield (48%).40
7. Synthesis of (6)-verbascenine (3)
The synthesis of the spermine-based alkaloid verbascenine
(3), which was our first attempt to explore 17-membered
azalactams, served as a model system for the synthesis of
the more complex macrobicyclic alkaloids 8 and 9. The
synthesis required preparation of a suitably protected 13-
membered azalactam derivative having the same core
structure as 1. The 17-membered azalactam system of 3
would be accessed via subsequent amide O-alkylation,
condensation with 4-phenylazetidin-2-one and reductive
ring expansion.
The final step in the dihydroperiphylline synthesis was
carried out by treatment of 30 with 3 equiv. of NaBH3CN in
AcOH. The yield of (^)-dihydroperiphylline (2) in this step
(93%) was a significant improvement over that for the
analogous conversion of 23 to 19 (31%). It seems
reasonable to assume that the increased efficiency of the
reductive ring expansion of 30 versus 23 is related to the
relative strain energy in the rings broken and formed: in
the reduction of 23, a medium (strained) ring is formed
whereas in the reduction of 30, a medium ring is broken to
form a less strained 13-membered ring.
Attachment of a 3-aminopropyl side chain to 39 (the Boc
derivative of 27) was carried out as in the celacinnine
synthesis (Scheme 7). Thus, alkylation of 39 using
N-(3-bromopropyl)phthalimide in NaH/DMF gave 41
(75%) and subsequent phthalimide cleavage under standard
conditions took place uneventfully to afford 43 in high yield.
The relatively efficient formation of 41 was a welcome
result considering the low yields or failures encountered in
alkylating other 9-membered azalactam derivatives, e.g. 19,
21 and the acetyl derivative 40.
6. Attempted synthesis of (6)-celacinnine (1) via
9-membered lactim ether condensation
The efficiency of the dihydroperiphylline synthesis, accom-
plished without need for protecting groups, prompted us to
explore an analogous route to celacinnine (1). This required
the preparation of the 9-membered azalactam 35 (Scheme
6). Condensation of mono-Boc-1,3-diaminopropane with
succinic anhydride (catalytic p-TsOH/xylenes/reflux) pro-
vided 32 (77%).41 Reduction of 32 with NaBH4 in MeOH
yielded 33, which underwent reaction with cinnamoyl
chloride to give 34. Although NaBH3CN reduction of 34
(AcOH/508C) took place smoothly in good yield, the
product was not 35 as anticipated but instead the
N-aminopropylpyrrolidinone derivative 37. We believe
that the outcome of the reaction is related to the relative
ring strain energies of 35 and 37 and the likelihood that 37 is
far more stable (5-membered versus 9-membered ring).
Considering the readiness of the 9-membered azalactam 19
Unlike 11, the amino azalactam 43 proved to be quite
resistant toward transamidative ring expansion. The
material was recovered unchanged after prolonged reaction
with hydrazine hydrate in refluxing EtOH, or after warming
at 558C in 1:1 NaOH/dioxane for 12 h, and even after
exposure to zip reaction conditions (potassium 3-aminopro-
pylamide in 1,3-diaminopropane). Acrylamide signals were
evident in the crude product obtained after exposure of 43 to
KOtBu in toluene at reflux, indicating that b-elimination
had occurred. Fortunately, the desired reaction took place
when 43 was heated to reflux in 2,4-lutidine (19 h), the
conditions used previously for expansion of the amino
b-lactam 18. The crude product mixture was chromato-
graphed on silica gel to provide a mixture of the desired
product 45 and a trace of starting material. This mixture was
treated with 2,2,2-trichloroethyl chloroformate to obtain the

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H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
Scheme 7.
differentially protected azalactam 47 (40% from 43), which
was separable from the Troc derivative of 43. It was
important that the crude product mixture from the ring
expansion reaction be chromatographed prior to the Troc
protection. When chromatography was not performed, a
small amount of di-Troc compound 48 was obtained which
was not easily separable from 47. The formation of 48
indicates that thermolysis of the Boc group occurs to some
extent under the transamidation conditions giving rise to the
free azalactam 46. This result parallels our findings in the
synthesis of homaline (4).8,21
CH2Cl2 at rt. The reaction time was an important factor
since after prolonged exposure to the conditions, cleavage of
the Boc group occurred. This may have been due to the
presence of acid (HBF4) generated by reaction of the
trialkyloxonium ion with traces of water in the reaction
mixture. The optimized procedure for the alkylation involved
˚
carrying out the reaction in the presence of 4 A molecular
sieves for a period of 4–5 h. Excellent yields of the crude
lactim ethers 51 or 52 were obtained after basic workup. The
compounds appeared to be very pure by NMR analysis and,
because they were unstable to silica gel, were normally used
in the next step without chromatographic purification.
To help establish the structure of 47, an authentic sample of
the di-Boc derivative 49 was prepared. Deprotection of 41
(HCl/CH2Cl2) gave the amine hydrochloride 42, which was
then subjected to the phthalimide cleavage conditions
(H2NNH2/EtOH/reflux). In this instance, transamidation of
the initially formed product (44) took place very readily
under the deprotection conditions to give 46. Consumption
of 44 was complete after continued heating for 12 h (46
isolated in 58% yield). Ring expansion of 44, isolated from
early workup of the deprotection, was also complete on
warming at 508C in aqueous 1N NaOH solution for 8 h.
Spectroscopic characterization of 46 and comparison to an
authentic sample30 confirmed the assigned 13-membered
macrocyclic structure. Treatment of 46 with Boc2O then
furnished 49. The 1H NMR spectra of the azalactams 47 and
49 were almost identical, except for the singlets assigned to
the protecting groups. In addition, the NMR spectrum of 49
was identical to that of a sample prepared via 2,4-lutidine
expansion of the amino azalactam 43 to 45.
The lactim ethers 51 and 52 are believed to have the Z
configuration as predicted by Moriarty.38 Direct evidence
for the assignment was obtained from the 500 MHz 1H
NMR spectra in which both compounds exhibited a 2H
multiplet between d 3.28 and 3.20.
Condensation of 51 or 52 with 4-phenylazetidin-2-one
occurred in refluxing chlorobenzene to give 53. Remark-
ably, the yield of 53 using the ethyl lactim ether 52 (59%)
was nearly four times higher than in the case of the methyl
ether 51 (16%). Although regeneration of 47 was noted in
both instances, it was a more serious side reaction in the
case of the methyl lactim ether (51). We attribute the
formation of 47 to competing SN2 attack by the azetidin-2-
one nitrogen on the ether alkyl group, a process that is
more facile when the alkyl group is methyl. The fact
that very little dealkylation of the methyl lactim ether
29 occurred during its condensation with 4-phenylazetidin-
2-one (Scheme 5) may reflect differences in reactivity
arising from a change in lactim ether geometry (E versus
Z ).
Lactim ether formation was carried out by treatment of 47
with trimethyl or triethyloxonium tetrafluoroborate in

H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
7183
After exchange of the Boc group for an acetyl group
(HCl/CH2Cl2, followed by treatment with AcCl/DMAP) to
obtain 54, the 17-membered lactam 55 was obtained (88%)
by reductive opening with NaBH3CN in AcOH. Removal of
the Troc protecting group was achieved using Zn/AcOH
affording the azalactam 56. The final step, selective
cinnamoylation of 56, was carried out under conditions
similar to those for the analogous acylation in the
celacinnine synthesis. In this way, racemic verbascenine
(3) was obtained in 58% yield overall from 55.
were distilled from calcium hydride. Tetrahydrofuran and
1,4-dioxane were freshly distilled from sodium metal.
Pyridine and triethylamine were distilled from anhydrous
barium oxide. N,N-dimethylformamide was purchased
˚
from Baker and stored over 4 A molecular sieves prior to
use. Anhydrous diethyl ether was used as supplied by
Mallinckrodt. Unless otherwise noted, all other reagents
were used as obtained from the manufacturers. Reactions
were generally run under nitrogen; those requiring anhy-
drous conditions were carried out in flame-dried or oven-
dried (1208C). Chromatography was performed on silica gel
60 (40–63 mm EM Laboratories) under flash conditions.
For thin layer chromatographic analysis throughout this
work, Merck precoated (silica gel F-254, 0.25 mm) glass
plates were used. Ethyl acetate and dichloromethane were
distilled for chromatography; otherwise, reagent grade
solvents were used as supplied.
An unsuccessful attempt was made to introduce the trans-
cinnamoyl group at an earlier stage and thereby shorten the
synthesis. Acylation of the Boc-azalactam 45 with cinna-
moyl chloride yielded the corresponding Boc/cinnamoyl
derivative 50. From our experience in the synthesis of 2,
there was good reason to believe that selective O-alkylation
of the secondary amide group could be accomplished.
However, the reaction with trimethyloxonium tetrafluoro-
borate (CH2Cl2/258C, followed by aq. NaHCO3) gave a
number of products including a poor yield of the desired
lactim ether. Substantial amounts of methyl cinnamate
appeared to form from competing O-alkylation of the
tertiary amide. Based on this result and attempts to
O-alkylate other 13-membered azalactam amide derivatives
chemoselectively, it is now clear that the secondary amino
groups must be protected in the form of carbamates
(e.g. Boc) to insure lactim ether formation with a minimum
of side reactions.
8.1.1. [3-(2-Oxo-4-phenylazetidin-1-yl)propyl]carbamic
acid, tert-butyl ester. A solution of N,N0-dicyclohexyl-
carbodiimide (DCC) (2.06 g, 10 mmol) in CH2Cl2 (10 mL)
was added to a suspension of 3-bromo-3-phenylpropionic
acid43 (2.29 g, 10 mmol) in CH2Cl2 (50 mL) at 08C. After
stirring the solution for 0.5 h at 08C, N-tert-butoxycarbonyl-
1,3-diaminopropane26 (1.74 g, 10 mmol) in CH2Cl2 (30 mL)
was added dropwise. The mixture was then stirred for 10 h
at rt, filtered through Celite and then concentrated. The
residue was diluted with Et2O (100 mL) and filtered to
remove the precipitate. Evaporation left the crude amide
(3.6 g, 94%) as a white foam. 1H NMR (90 MHz): d 7.5–7.2
(m, 5H), 6.7 (br s, 1H), 5.5 (t, J¼7 Hz, 1H), 5.0 (br t,
J¼7 Hz, 1H), 3.40–2.95 (m, 6H), 1.7–1.4 (m, 2H), 1.45 (s,
9H).
8. Experimental
8.1. General
A solution of the amide (3.6 g, 9.3 mmol) in CH2Cl2
(64 mL) and DMF (16 mL) was added slowly, over a period
of 2 h, to a suspension of hexane-washed NaH (0.5 g,
21 mmol) in CH2Cl2 (64 mL) and DMF (16 mL) at rt. When
addition was complete, the mixture was stirred for 10 h
and then poured into saturated aq. NH4Cl (150 mL). The
mixture was extracted twice with Et2O (1£150, 1£100 mL)
and the combined Et2O fractions washed with H2O
(6£100 mL) and brine (50 mL). The Et2O solution was
dried (MgSO4) and concentrated to leave a pale yellow oil.
The title compound (1.88 g, 62%) was obtained by
chromatography, eluting with 0.5% MeOH/CHCl3. An
analytical sample was prepared by running a second column
(33% EtOAc/CH2Cl2) and carefully evaporating the solvent
with a stream of dry N2. The last traces of solvent were
removed by warming the sample at 508C under high
vacuum. 1H NMR (90 MHz): d 7.35 (s, 5H), 5.0 (br s, 1H),
4.55 (dd, J¼2.5, 5 Hz, 1H), 3.6–2.7 (m, 6H), 1.8–1.5 (m,
2H), 1.45 (s, 9H). IR: 3440, 1740, 1710, 1515 cm21. MS
(20 eV): Mþ 304 (3), 248 (16), 174 (15), 131 (33), 104
(100), 56 (60). Anal. calcd for C17H24N2O3: C, 67.08; H,
7.95; N, 9.20. Found: C, 66.86; H, 7.97; N, 9.11.
Melting points were determined on a Thomas-Hoover
melting point apparatus and, except where otherwise
indicated, open capillary tubes were used. All melting and
1
boiling points are uncorrected. The H NMR spectra were
recorded on a Varian EM-390, a Bruker HX-270, or a
Bruker WM-500 spectrometer. Unless otherwise noted, all
NMR spectra were run in deuterochloroform. The chemical
shifts are expressed in parts per million downfield from
internal tetramethylsilane (d 0). Splitting patterns are
indicated as s, singlet; d, doublet; t, triplet; q, quartet;
quin, quintet; m, multiplet; br, broad peak. The infrared (IR)
spectra were recorded on a Perkin–Elmer 700A spectro-
photometer or a Nicolet 7000 spectrophotometer (FT).
Except where indicated, all IR spectra were obtained on
chloroform solutions (CHCl3 or CDCl3). Mass spectra (MS)
were obtained on a Hewlett Packard GC 5840A/MS 5985A
system. Peaks are reported as m/z (relative percent). Non-
volatile compounds were analyzed on this instrument by
direct input into the mass spectrometer. High-resolution
mass spectra were obtained at the Midwest Center for Mass
Spectrometry, the University of Nebraska-Lincoln or at the
Mass Spectrometry Facility, Pennsylvania State University.
Elemental analyses were performed by Dr Robert Rittner,
Olin Laboratories, New Haven, CT, or at Atlantic Microlab,
Inc., Atlanta, GA.
8.1.2. 1-(3-Aminopropyl)-4-phenylazetidin-2-one (16).
Gaseous HCl was bubbled through a solution of [3-(2-
oxo-4-phenylazetidin-1-yl)propyl]carbamic acid, tert-butyl
ester (0.44 g, 1.44 mmol) in CH2Cl2 (10 mL) for ,10 min
at 08C. The solution was stirred at 08C for 1 h and then
concentrated. The residue was dissolved in saturated aq.
Reaction solvents and reagents were prepared for use as
follows. Dichloromethane, chlorobenzene and 2,4-lutidine

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H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
NaHCO3 (30 mL) and then extracted with CHCl3
(3£20 mL). The combined CHCl3 fractions were dried
at 08C. The solution was stirred at 08C for 2.5 h and
concentrated. The residue was dissolved in 1N aq. NaOH
(30 mL) and then extracted with CH2Cl2 (4£30 mL). The
combined CH2Cl2 fractions were dried (Na2SO4) and
evaporated. The pure amino b-lactam (209 mg, 54%) was
obtained by chromatography eluting with EtOAc and then
25:1:1 CHCl3/MeOH/i PrNH2. 1H NMR (90 MHz): d 7.3 (s,
5H), 4.5 (dd, J¼2.5, 5 Hz, 1H), 3.6–3.15 (m, 2H), 3.0–2.45
(m, 4H), 1.65–1.3 (m, 4H), 1.3–1.0 (br s, 2H). IR:
1740 cm21. MS (70 eV): Mþ 218 (l), 118 (18), 104 (93),
91 (23), 78 (14), 70 (100). HRMS calcd for C13H18N20:
218.1419. Found: 218.1418.
1
(Na2SO4) and evaporated to leave 16 (116 mg, 69%). H
NMR (90 MHz): d 7.25 (s, 5H), 4.45 (dd, J¼2.5, 5 Hz 1H),
3.6–3.1 (m, 2H), 3.0–2.5 (m, 4H), 1.8–1.3 (m, 4H). IR:
1740 cm21
.
8.1.3. 4-Phenyl[1,5]diazocan-2-one (17). A solution of 16
(41 mg, 0.2 mmol) in 1N aq. NaOH (5 mL) was warmed at
558C for 12 h. After the solution was cooled, it was
extracted with CH2Cl2. The CH2Cl2 fractions were
combined, dried (Na2SO4) and concentrated. The IR
spectrum of the product indicated complete disappearance
of the starting b-lactam. Chromatography with 1%
MeOH/CHCl3 as eluant provided pure 17 (20 mg, 50%) as
a white crystalline solid that was recrystallized from
CH2Cl2/hexanes, mp 130–1318C (lit.19 mp 128–1308C).
1H NMR (270 MHz): d 7.43–7.25 (m, 5H), 5.76 (br s, 1H),
4.04 (dd, J¼2, 11 Hz, 1H), 3.98–3.82 (m, 1H), 3.31–3.16
(m, 2H), 2.92 (dd, J¼11, 12 Hz, 1H), 2.63–2.51 (m, 1H),
2.47 (dd, J¼2, 12 Hz, 1H), 1.84–1.52 (m, 3H). IR: 3650,
3380, 1655, 1470 cm21. MS (70 eV): Mþ 204 (47), 132
(77), 118 (100), 104 (42), 91 (28), 77 (24). Anal. calcd for
C12H16N2O: C, 70.56; H, 7.89; N, 13.71. Found: C, 70.50;
H, 7.93; N, 13.68.
8.1.6. 4-Phenyl[1,5]diazonan-2-one (19) by transamida-
tion of 18. A solution of 18 (35 mg, 0.16 mmol) in
2,4-lutidine (10 mL) was purged with N2 for 5 min. and
then heated to reflux for 64 h. The lutidine was removed
under vacuum to leave a brown oil. Chromatography,
eluting successively with EtOAc and 25:1:1 CHCl3/MeOH/
i PrNH2, gave pure 19 (20 mg, 57%) and unreacted 18
(14 mg, 40%).
8.2. Ring contraction of 19
A solution of the 9-membered azalactam 19 (35 mg,
0.16 mmol) in 2,4-lutidine (10 mL) was purged with N2
for 5 min and then heated to reflux for 64 h. The lutidine was
removed under vacuum to leave a brown oil showing
IR absorption at 1740 and 1670 cm21 (neat). Thin layer
chromatography (25:1:1 CHCl3/MeOH/i PrNH2) clearly
showed the presence of the b-lactam 18 and unreacted 19
in the crude product. The oil was chromatographed eluting
successively with EtOAc and 25:1:1 CHCl3/MeOH/i PrNH2
to obtain 18 (,1 mg, 3%) and recovered 19 (20 mg, 57%).
8.1.4. [4-(2-Oxo-4-phenylazetidin-1-yl)butyl]carbamic
acid, tert-butyl ester. N,N0-dicyclohexylcarbodiimide
(DCC) (1.3 g, 6.3 mmol) was added to a suspension of
3-bromo-3-phenyl propionic acid (1.37 g, 6.0 mmol) in
CH2Cl2 (20 mL) at 258C. After stirring this mixture for
0.5 h, N-tert-butoxycarbonyl-1,4-diaminobutane26 (1.13 g,
6.0 mmol) in CH2Cl2 (5 mL) was added dropwise. The
mixture was then stirred for 1.5 h at rt, filtered through
Celite and concentrated to leave the crude amide as a white
1
foam (,100%). H NMR (90 MHz): d 7.5–7.15 (m, 5H),
8.2.1. 3-Phenylhexahydropyrazolo[1,2-a]pyridazin-1-
one (22). A mixture of hexahydropyridazine32 (3 g,
34.8 mmol) and ethyl cinnamate (7.1 g, 40.3 mmol) was
heated to reflux in an oil bath at 1608C for 1 h. The
condenser was replaced with an 8 cm Vigreux column fitted
with a short-path distillation head. Heating of the reaction
mixture at 1608C was resumed for 10.5 h and was
accompanied by distillation of EtOH. On cooling, the
crude product crystallized. Chromatography with EtOAc as
eluant provided pure 22 (6.0 g, 80%) as a white crystal-
line solid. An analytical sample was prepared by two
recrystallizations from hot hexanes to give white crystals,
6.85 (br t, J¼5 Hz, 1H), 5.45 (dd, J¼7, 8 Hz, 1H), 5.0–4.7
(br m, 1H), 3.4–2.85 (m, 6H), 2.0–1.0 (br m, 4H), 1.4 (s,
9H).
A solution of the amide (6 mmol) in CH2Cl2 (50 mL) and
DMF (12 mL) was added slowly over a period of 4 h, to a
suspension of hexane-washed NaH (0.36 g, 15 mmol) in
CH2Cl2 (50 mL) and DMF (12 mL) at rt. When addition was
complete, the mixture was stirred for 2 h and quenched with
saturated aq. NH4Cl (100 mL). The mixture was extracted
with Et2O (1£200 mL, 1£100 mL) and the combined Et2O
fractions washed with H2O (6£100 mL) and brine
(100 mL). The Et2O solution was dried (MgSO4) and
evaporated to a pale yellow oil containing some solid.
The title compound (1.40 g, 73%) was then obtained by
chromatography eluting with 0.5% MeOH/CHCl3. 1H NMR
(90 MHz): d 7.3 (s, 5H), 4.9–4.6 (br m, 1H), 4.5 (dd, J¼2.5,
5 Hz, 1H), 3.5–2.65 (m, 6H), 1.7–1.3 (m, 4H), 1.4 (s, 19H).
IR: 3450, 1740, 1710, 1515 cm21. MS (20 eV): Mþ 318 (l),
262 (14), 149 (24), 114 (17), 104 (48), 70 (100), 1 57 (15).
HRMS calcd for C14N18N2O3 (parent minus C4H8):
262.1317. Found: 262.1306.
1
mp 65–668C. H NMR (270 MHz): d 7.44–7.25 (m, 5H),
4.18 (br d, J¼12.4 Hz, 1H), 3.84 (dd, J¼8.1, 11.7 Hz, 1H),
3.08–2.98 (m, 2H), 2.88 (dd, J¼8.1, 16.8 Hz, 1H), 2.56 (dd,
J¼11.7, 16.8 Hz, 1H), 2.30–2.21 (m, 1H), 1.77–1.33 (m,
4H). FT IR: 1676 cm21. MS (70 eV): 217 (14), m 216 (100),
139 (25), 104 (45), 85 (54), 56 (34), 41 (25). Anal. calcd for
C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.10;
H, 7.29; N, 13.02.
8.2.2. 4-Phenyl[1,5]diazonan-2-one (19) by Na/NH3
reduction of 22. Sodium metal (0.53 g, 23 mmol) was
carefully added in portions to a refluxing mixture of 22
(2.0 g, 9.25 mmol) and liquid NH3 (50 mL). The resulting
blue solution was allowed to reflux (2338C) for 1.25 h. The
reaction was quenched by slow addition of solid NH4Cl
(1.5 g, 28 mmol). After evaporation of NH3, the residue was
8.1.5. 1-(4-Aminobutyl)-4-phenylazetidin-2-one (18).
Gaseous HCl was bubbled through a solution of [4-(2-
oxo-4-phenylazetidin-1-yl)butyl]carbamic acid, tert-butyl
ester (0.56 g, 1.76 mmol) in CH2Cl2 (40 mL) for ,5 min

H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
7185
extracted with several portions of CH2Cl2 which were
combined and concentrated to leave a yellow solid.
Chromatography with EtOAc as eluant afforded 19
(1.60 g, 79%) as a white crystalline solid. An analytical
sample was obtained by recrystallization from hexanes/
CH2Cl2 to give white crystals, mp 97–988C.44 1H NMR
(270 MHz): d 7.40–7.22 (m, 5H), 6.98 (br s, 1H), 3.86–
3.67 (m, 1H), 3.58 (dd, J¼2.2, 12.2 Hz, 1H), 2.90–2.70 (m,
3H), 2.52 (t, J¼12.2 Hz, 1H), 2.37 (dd, J¼2.2, 12.2 Hz, 1H),
1.98–1.32 (m, 5H). FT IR: 3341, 1670, 1549 cm21. MS
(70 eV): Mþ 218 (33), 158 (30), 146 (72), 132 (45), 119
(36), 118 (91), 106 (52), 104 (100), 91 (42), 70 (34). Anal.
calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C,
71.38; H, 8.23; N, 12.81.
crystalline solid which was recrystallized from CH2Cl2/
hexanes, mp 147–1488C. 1H NMR (90 MHz): d 7.25 (br s,
5H), 6.5, 5.6–5.0 (br s, br m, total 1H), 4.7–4.0 (m, 1H),
4.0–2.4 (series of br m, 6H), 2.2–1.55 (br s, 4H), 1.55–0.9
(3 br s, total 9H). IR: 3430, 3370, 1680, 1520 cm21. MS
(20 eV): Mþ 318 (1), 262 (100), 218 (6), 146 (27), 104 (19),
70 (16), 57 (41). Anal. calcd for C18H26N2O3: C, 67.90; H,
8.23; N, 8.80. Found: C, 68.03; H, 8.28; N, 8.78.
8.2.6. 1-(3-Aminopropyl)-4-phenyl[1,5]diazonan-2-one
(11). A solution of 20 (190 mg, 0.47 mmol) and 85%
hydrazine hydrate (0.25 mL) in absolute EtOH was heated
for 1 h. A white solid precipitated during this time. After
evaporation of EtOH, the residue was dissolved in concd aq.
NH4OH (5 mL). The solution was diluted with H2O (5 mL),
saturated with NaCl, and extracted four times with CH2Cl2.
The combined CH2Cl2 fractions were dried (Na2SO4) and
concentrated to afford the crude azalactam 11 (130 mg,
100%) as a yellow oil. Except for a trace of the ring-
expanded product (12), this material was quite pure as
determined by 1H NMR and IR. 1H NMR (90 MHz): d 7.25
(s. 5H), 4.9–4.5 (m, 1H), 4.1–3.65 (m, 2H), 3.4–2.4 (m,
8.2.3. 4-Phenyl[1,5]diazonan-2-one (19) by NaBH3CN
reduction of 23. To a solution of 2335 (428 mg, 2 mmol) in
glacial AcOH (5 mL) at rt was added NaBH3CN (504 mg,
8 mmol) in portions. The mixture was stirred at rt for 2 h,
warmed at 508C for 1 h and then stirred overnight at rt
(22.5 h). After cooling the mixture to 08C in an ice bath,
H2O (12 mL) was added and the solution made strongly
basic by addition of 50% aq. NaOH. The mixture was
extracted with CH2Cl2 (3£50 mL). The combined CH2Cl2
fractions were washed with brine, dried over K2CO3 and
concentrated to a yellow oil. Pure 19 (134 mg, 31%) was
obtained by chromatography with EtOAc as eluant.
8H), 2.2–1.2 (m, 9H). IR: 1620, 1475 cm21
.
8.2.7. 2-Phenyl-1,5,9-triazacyclotridecan-4-one (12). A
solution of 20 (259 mg, 0.64 mmol) and 85% hydrazine
hydrate (0.35 mL) in absolute EtOH (7 mL) was heated to
reflux for 19 h. After cooling, the EtOH was evaporated to
leave a white residue that was dissolved in concd aq.
NH4OH (8 mL). The solution was diluted with H2O
(10 mL), saturated with NaCl and extracted with CH2Cl2
(6£20 mL). The combined CH2Cl2 fractions were dried and
concentrated to leave a partially solid yellow residue. The
relative integral intensity of the signals at d 8.5 (amide NH,
1H) for 12 and d 4.9–4.5 (m, 1H) for 11 indicated that the
ratio of 12 to 11 in this mixture was ,6:4. The material was
dissolved in 1N aq. NaOH (4 mL) and dioxane (2 mL).
After it was warmed at 508C for 7 h, the solution was diluted
with H2O (10 mL), saturated with NaCl and extracted with
CH2Cl2 (6£25 mL). The combined organic fractions were
dried (Na2SO4) and concentrated to leave the crude product.
This was chromatographed eluting with 10:5:1 CHCl3/
MeOH/i PrNH2 and then 5:5:1 CHCl3/MeOH/i PrNH2. The
white crystalline azalactam 12 (86 mg, 50%) eluted with the
latter solvent system. A small amount of impure 11 was
eluted in advance of 12. Analytically pure white crystals of
12, mp 128–1318C (lit.30 mp 132–1338C), were obtained
8.2.4. 2-[3-(2-Oxo-4-phenyl[1,5]diazonan-1-yl)propyl]-
isoindole-1,3-dione (20). A 60% suspension of NaH in oil
(140 mg, 3.5 mmol) was rinsed with hexane. To this was
added DMF (6 mL) and 19 (500 mg, 2.3 mmol). The
mixture was mechanically stirred while it was warmed in
an oil bath at 50–558C. Evolution of H2 was observed and
when this was complete, the resulting solution was allowed
to cool to rt. Solid N-(3-iodopropyl)phthalimide45 (795 mg,
2.5 mmol) was then added in one portion. The reaction
mixture was stirred for 2 h at rt and quenched by addition of
saturated aq. NH4Cl (25 mL). The aqueous mixture was
extracted with EtOAc (2£50 mL). The combined EtOAc
extracts were washed with H2O (10£50 mL), dried
(Na2SO4) and concentrated to a yellow oil. Chromatography
with EtOAc as eluant gave pure 20 (215 mg, 23%) and
unreacted 19 (100 mg, 20%). The material was recrystal-
lized from benzene/hexanes, mp 122–1238C. 1H NMR
(270 MHz): d 7.87–7.80 (m, 2H), 7.75–7.66 (m, 2H),
7.38–7.20 (m, 5H), 4.86–4.75 (m, 1H), 4.00–3.89 (m, 1H),
3.78–3.71 (m, 3H), 3.29 (dd, J¼5, 14 Hz, 1H), 3.16 (dd,
J¼11, 12.5 Hz, 1H), 2.98–2.76 (m, 3H), 2.59 (d, J¼
12.5 Hz, 1H), 2.05–1.33 (m, 7H). FT IR: 1771, 1713,
1615 cm21. MS (70 eV): Mþ 405 (12), 259 (37), 245 (42),
244 (37), 243 (22), 188 (23), 160 (100), 159 (98), 158 (30),
146 (53), 132 (35), 118 (39), 104 (58), 91 (35), 84 (26), 77
(25), 70 (34). Anal. calcd for C24H27N3O3: C, 71.09; H,
6.71; N, 10.36. Found: C, 70.99; H, 6.90; N, 10.14.
1
by recrystallization from CH2Cl2/hexanes. H NMR (500
MHz): d 8.50 (br s, 1H), 7.40–7.10 (m, 5H), 3.93 (dd,
J¼5.0, 9.1 Hz, 1H), 3.70–3.61 (m, 1H), 3.30–3.22 (m, 1H),
2.95–2.88 (m, 1H), 2.83–2.77 (m, 1H), 2.77–2.66 (m, 2H),
2.60–2.53 (m, 1H), 2.52–2.47 (m, 2H), 2.42–2.34 (m, 1H),
2.10–1.82 (br s, 2H), 1.82–1.71 (m, 3H), 1.71–1.60 (m,
1H), 1.60–1.50 (m, 1H), 1.48–1.38 (m, 1H). IR: 3650,
3210, 1650 1530 cm21. MS (70 eV): Mþ 275 (7), 259 (16),
258 (100), 191 (9), 160 (17), 146 (31), 126 (17), 118 (19),
104 (28), 84 (17). Anal. calcd for C16H25N3O: C, 69.78; H,
9.15; N, 15.26. Found: C, 69.90; H, 9.21; N, 14.98.
8.2.5. 2-Phenyl-4-oxo-[1,5]diazonane-1-carboxylic acid,
tert-butyl ester (21). A solution of the azalactam 19
(110 mg, 0.5 mmol) and di-tert-butyldicarbonate (130 mg,
0.6 mmol) in dioxane (2 mL) was warmed at 608C for 22 h.
The solvent was evaporated to leave a clear oil that
crystallized on standing. Chromatography with EtOAc as
eluant provided pure 21 (150 mg, 94%) as a white
8.2.8. (6)-Celacinnine (1). The title compound was
prepared from the azalactam 12 according to the procedure
of Yamamoto and Maruoka.30 A solution of 12 (114 mg,
0.41 mmol) and DMAP (150 mg, 1.23 mmol) in CH2Cl2

7186
H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
(20 mL) was cooled to 2788C. A solution of cinnamoyl
chloride (103 mg, 0.62 mmol) in CH2Cl2 (2mL) was then
added dropwise. The reaction was stirred at 2788C for 2.5 h
and allowed to stand at 2208C for 8 h. The mixture was
poured into 14% aq. NH4OH (10 mL). The aqueous layer
was extracted with CH2Cl2 (3£25 mL). Evaporation of the
combined CH2Cl2 fractions (dried over Na2SO4) left a clear
oil that crystallized on standing. Pure (^)-celacinnine (1)
(142 mg, 85%) was obtained by chromatography with 6%
MeOH/CHCl3 as eluant. White crystals, mp 181–1858C
(lit.30 mp 178–1818C) were obtained by crystallization from
CH2Cl2/hexanes. 1H NMR (270 MHz): d 7.71 (d, J¼
15.4 Hz, 1H), 7.57–6.96 (11H), 6.83 (d, J¼15.4 Hz,
,0.5H), 6.81 (d, J¼15.7 Hz, ,0.5H), 4.01–3.93 (m, 1H),
3.85–3.06 (m, 6H), 2.75–2.61 (m, 1H), 2.57–2.36 (m, 3H),
2.20–1.31 (m, 7H). FT IR: 3450, 3210, 1656 (sh), 1649,
1598, 1548, 1520, 1496 cm21. MS (70 eV): Mþ 405 (9),
274 (70), 260 (13), 188 (12), 160 (21), 159 (14), 146 (35),
131 (100), 104 (23), 103 (62), 100 (25), 91 (23), 84 (27), 70
(35), 69 (21), 56 (19), 44 (34), 43 (21).
C, 59.13; H, 9.92; N, 19.70. Found: C, 59.38; H, 10.11; N,
19.94.
8.2.11. (E )-5-(3-Phenylacryloyl)[1,5]diazonan-2-one
(28). To a solution of the azalactam 27 (1.42 g, 10 mmol)
and DMAP (1.22 g, 10 mmol) in CH2Cl2 (30 mL) at rt was
added cinnamoyl chloride (1.67 g, 10 mmol). The reaction
was stirred overnight (10 h) and washed with 0.5N aq. HCl
(10 mL) and H2O (20 mL). The solution was dried
(Na2SO4) and concentrated to leave 28 (2.57 g, 95%) as a
white crystalline solid. This material was recrystallized
from CH2Cl2/hexanes, mp 147–1488C. 1H NMR (90 MHz):
d 7.9–6.7 (m, 7H), 5.8–5.4 (br s, 1H), 3.9–3.0 (m, 5H),
2.9–2.3 (m, 3H), 2.0–1.4 (m, 4H). IR: 3320, 1650,
1600 cm21. MS (70 eV): Mþ 272 (17), 131 (100), 103
(38), 77 (23). Anal. calcd for C16H20N2O2: C, 70.56; H,
7.40; N, 10.29. Found: C, 70.40; H, 7.40; N, 10.17.
8.2.12. (E )-1-(4-Methoxy-2,3,6,7,8,9-hexahydro[1,5]dia-
zonin-1-yl)-3-phenylprop-2-en-1-one (29). To a solution
of the lactam 28 (545 mg, 2.0 mmol) in CH2Cl2 (15 mL)
was added trimethyloxonium tetrafluoroborate (316 mg,
2.1 mmol). The reaction was stirred at rt for 12 h and then
quenched by addition of a solution of K2CO3 (0.33 g) in
H2O (0.35 mL). The mixture was diluted with CH2Cl2, dried
(Na2SO4) and concentrated to leave the crude lactim ether
29 (448 mg, 78%). Thin layer chromatography (10%
An excellent correlation was observed between the
270 MHz 1H NMR and FT-IR spectra of synthetic
(^)-celacinnine and the corresponding spectra obtained
from a sample of authentic (^)-1 provided by Dr Bruce
Ganem, Cornell University. The TLC properties of the
synthetic and reference material were identical (acetone:
Rf¼0.54; 10% MeOH/EtOAc: Rf¼0.30).
1
MeOH/CHCl3) and H NMR (90 MHz) indicated that only
traces of impurities, including starting material and methyl
cinnamate were present. Since 29 was found to decompose
on silica gel the crude product was normally used directly,
without purification, for the subsequent reaction. However,
a sample of pure 29 (a colorless oil) could be obtained by
chromatography on a short column eluting with EtOAc. 1H
NMR (90 MHz): d 7.7 (d, J¼15 Hz, 1H), 7.7–7.3 (m, 5H),
7.0 (d, J¼15 Hz, 1H), 3.8–3.25 (m, 6H), 3.65 (s. 3H), 2.8–
2.6 (m, 2H), 2.0–1.7 (m, 2H), 1.7–1.4 (m. 2H). IR: 1670,
1650, 1600 cm21. MS (70 eV): Mþ 286 (11), 271 (9), 155
(48), 131 (100), 113 (21), 103 (48), 82 (31), 77 (23), 70 (18).
HRMS calcd for C17H22N2O2: 286.1682. Found: 286.1685.
8.2.9. Hexahydropyrazolo[1,2-a]pyridazin-1-one (26).
Ethyl acrylate (16.9 g, 0.17 mol) was added slowly to
hexahydropyridazine (13.2 g, 0.15 mol) cooled in an ice
bath. The mixture was initially heated to reflux in an oil bath
at 1908C for 3 h. A short path distillation head was then
attached to the flask and heating was continued at 1708C for
10 h with EtOH distilling off. The reaction mixture was
then distilled to give 26 as an oil (18.1 g, 85%), bp
78–818C/0.07 mm Hg. 1H NMR (90 MHz): d 4.35–2.15 (br
m, 8H), 1.95–1.2 (br m, 4H). IR (neat): 1680 cm21. MS
(70 eV): Mþ 140 (55), 84 (38), 56 (100), 41 (72). Elemental
analysis was obtained on the HCl salt (HCl/Et2O;
recrystallized from MeOH/Et2O). Anal. calcd for
C7H13ClN2O: C, 47.59; H, 7.42; N, 15.86; Cl, 20.07.
Found: C, 47.61; H, 7.53; N, 15.99; Cl, 20.28.
8.2.13. (E)-2-Phenyl-9-(3-phenylacryloyl)-2,5,6,7,8,9,10,
11-octahydro-3H-1,4a,9-triaza-benzocyclononen-4-one
(30). A solution of crude 29 (448 mg, 1.56 mmol) and
4-phenylazetidin-2-one21,36 (240 mg, 1.60 mmol) in chloro-
benzene (2 mL) was heated to reflux for 21 h. After
evaporation, the residue was chromatographed on a short
column eluting with EtOAc. The product (30) (636 mg,
67%) was recrystallized from CH2Cl2/hexanes to obtain an
8.2.10. [1,5]Diazonan-2-one (27). Lactam 26 (2.80 g,
20 mmol) was dissolved in refluxing anhydrous liquid
NH3. Sodium metal (1.38 g, 60 mmol) was then added in
small pieces to the solution. During the addition of Na, a
permanent blue color developed. The mixture was kept at
reflux for 1.75 h and then quenched by addition of an excess
of NH4Cl (4.3 g, 80 mmol). The NH3 was evaporated under
a stream of N2 to leave a solid residue that was extracted
with CH2Cl2. The combined CH2Cl2 extracts were dried
(K2CO3) and concentrated. The crude crystalline product
was distilled under vacuum (bp 114–1168C/0.8 mm Hg) to
afford pure 27 (2.49 g, 87%) as a white crystalline solid
1
analytical sample, mp 195–1978C. H NMR (270 MHz,
508C): d 7.72 (d, J¼15.4 Hz, 1H), 7.54–7.25 (m, 10H), 6.97
(d, J¼15.4 Hz, 1H), 4.65 (dd, J¼4.81 13.4 Hz, 1H), 4.34–
2.57 (m, 10H), 2.11–1.39 (m, 4H). IR: 1690, 1640,
1600 cm21. MS (70 eV): 402 (20), Mþ 401 (31), 270 (12),
227 (14), 131 (100), 103 (64), 84 (22), 77 (25). Anal. calcd
for C25H27N3O2: C, 74.79; H, 6.78; N, 10.47. Found: C,
74.56; H, 6.62; N, 10.43.
1
which was recrystallized from hexanes, mp 82–848C. H
NMR (90 MHz): d 6.8, 5.6 (2 br s, total 1H), 3.9–3.6 (m,
1H), 3.6–2.6 (m, 4H), 2.55–2.35 (m, 1H), 2.15 (t, J¼6 Hz,
2H), 2.05 (s, 1H), 1.8–1.2 (br m, 4H). IR: 3640, 3370,
1670, 1555 cm21. MS (70 eV): Mþ 142 (39), 114 (100),
84 (57), 70 (93), 57 (97), 43 (41). Anal. calcd for C7H14N2O:
8.2.14. (6)-Dihydroperiphylline (2). A solution of 30
(400 mg, 1.0 mmol) and NaBH3CN (190 mg, 3.0 mmol) in
AcOH (3.5 mL) was stirred for 3 h at rt, 2 h at 508C and then
overnight (12 h) at rt. While it was cooled in an ice bath,
the solution was diluted with H2O (10 mL) and made

H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
7187
alkaline by addition of 50% aq. NaOH (5 mL). The mixture
was extracted with CH2Cl2 (2£100 mL) and the combined
extracts dried (Na2SO4) and concentrated to yield
(^)-dihydroperiphylline (2) (375 mg, 93%) as a white
solid. The recrystallized material (CH2Cl2/hexanes) dis-
played anomalous melting behavior, slowly turning from a
white solid to a white foam on heating above 358C. 1H NMR
(270 MHz, 508C): d 7.67 (d, J¼15.4 Hz, 1H), 7.47–7.16 (m,
11H), 6.79 (d, J¼15.4 Hz, 1H), 3.91 (m, 1H), 3.89–3.06 (m,
6H), 2.68–2.55 (m, 1H), 2.50–2.32 (m, 3H), 2.01–1.49 (m,
7H). FT IR: 3300, 1648, 1601, 1546, 1523 cm21. MS
(70 eV): Mþ 405 (3), 350 (7), 314 (18), 288 (2), 274 (20),
260 (7), 201 (9), 163 (9), 146 (31), 131 (100), 118 (18), 103
(50), 98 (13), 91 (17), 84 (10), 77 (18), 70 (22), 44 (15). TLC
(Rf¼0.50, 10% MeOH/CHCl3).
H2O, saturated aq. NaHCO3 and brine (50 mL each). The
solution was dried (MgSO4) and concentrated to red
oil. Chromatography eluting with EtOAc and then 10%
MeOH/EtOAc afforded 34 as a white foam (1.9 g, 85%). IR:
1695, 1650, 1605 cm21. MS (70 eV): 271 (8), Mþ 270 (44),
139 (100), 131 (97), 103 (36), 77 (20).
8.2.18. 4-Oxo-[1,5]diazonane-1-carboxylic acid, tert-
butyl ester (39). To a solution of the azalactam 27
(2.69 g, 18.9 mmol) in CH2Cl2 (30 mL) at rt was added a
solution of di-tert-butyldicarbonate (4.3 g, 19.7 mmol) in
CH2Cl2 (20 mL). The reaction mixture was stirred until
evolution of CO2 was complete (,20 min). The solvent was
evaporated to leave a clear oil that was chromatographed on
a short column eluting with EtOAc. Pure 39 (4.55 g, 99%)
was obtained as a colorless oil. Crystallization from
CH2Cl2/hexanes provided analytically pure white crystals,
The structure of 2 was confirmed by using natural
periphylline46 (kindly provided by Dr H. P. Husson, Institut
de Chemie des Substances Naturelles, C.N.R.S., Gif-sur-
Yvette, France) as a reference material. Hydrogenation of 2
with PtO2 in EtOH yielded tetrahydroperiphylline, identical
(NMR, IR, TLC) with the product obtained from periphyl-
line by the uptake of 2 mol of hydrogen. Selective reduction
of periphylline by using NaBH3CN in formic acid yielded a
dihydro product identical (NMR, MS, TLC) with synthetic
(^)-dihydroperiphylline (2).
1
mp 91–928C. H NMR (90 MHz): d 6.0, 5.2 (2 br s, total
1H), 3.6–3.0 (m, 6H), 2.8–2.3 (m, 2H), 1.8–1.6 (m, 4H),
1.5 (s, 9H). IR: 1680, 1660, 1520 cm21. MS (20 eV): Mþ
242 (1), 186 (23), 142 (22), 125 (28), 114 (46), 70 (33), 57
(100). Anal. calcd for C12H22N2O3: C, 59.48; H, 9.15; N,
11.56. Found: C, 59.20; H, 8.93; N, 11.44.
8.2.19. 5-[3-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)propyl]-
4-oxo[1,5]diazonane-1-carboxylic acid, tert-butyl ester
(41). A 60% suspension of NaH in oil (1 g, 25 mmol) was
rinsed with hexane. To this was added DMF (55 mL) and
the azalactam 39 (4.0 g, 16.5 mmol). The mixture was
mechanically stirred while it was warmed in an oil bath at
50–558C. Evolution of H2 was observed and when this was
complete, the resulting solution was allowed to cool to rt.
Solid N-(3-bromopropyl))phthalimide (6.7 g, 25 mmol) was
then added. The reaction was stirred for 3 h at rt and
quenched by addition of saturated aq. NH4Cl (100 mL). The
mixture was diluted with H2O (100 mL) and extracted with
Et2O (2£150 mL). The Et2O extracts were combined,
washed with H2O (5£120 mL) and brine (100 mL), dried
(MgSO4), and concentrated to a yellow oil. Chroma-
tography with EtOAc as eluant provided pure 41 (5.3 g,
75%) as a colorless oil which could be crystallized from
hexanes/benzene to give analytically pure white crystals,
8.2.15. 3,4,7,8-Tetrahydro-2H-pyrrolo[1,2-a]pyrimidin-
6-one (32). A mixture of N-tert-butoxycarbonyl-1,3-dia-
minopropane (8.05 g, 46 mmol), succinic anhydride (4.6 g,
46 mmol) and xylenes (20 mL) was heated to reflux for
30 min. After cooling the solution, additional xylenes
(50 mL) and p-TsOH·H2O (0.2 g) were added. The mixture
was then heated to reflux for 17.5 h, collecting water in a
Dean–Stark trap. The apparatus was fitted with a short path
distillation head and the solvent was distilled off at 1 atm.
The dark residue was transferred to a smaller flask and
distilled under vacuum collecting material boiling between
,160 and 1808C at ,4 mm Hg. The crude distillate was
again distilled under vacuum to afford 32 as an oil that
solidified on cooling (4.6 g, 72%), bp 113–1228C/
0.15 mm Hg, mp 44–468C (lit.41 mp 23–258C). IR: 1740,
1675 cm21. Anal. calcd for C7H10N2O: C, 60.85; H, 7.29;
N, 20.27. Found: C, 60.72; H, 7.20; N, 20.34.
1
mp 105–1068C. H NMR (500 MHz, 508C): d 7.83–7.81
(m, 2H), 7.70–7.68 (m, 2H), 3.70 (t, J¼7.1 Hz, 2H), 3.62–
2.95 (br m, 8H), 2.85–2.60 (br m, 2H), 1.97 (quin, J¼
7.1 Hz, 2H), 1.87–1.64 (br m, 2H), 1.48 (s, 3H), 1.64–1.00
(br m, 2H). IR: 1775, 1715, 1690, 1625 cm21. MS (20 eV):
Mþ 429 (20), 329 (77), 285 (51), 243 (98), 217 (63), 70 (50),
57 (100). Anal. calcd for C23H31N3O5: C, 64.32; H, 7.27; N,
9.78. Found: C, 64.10; H, 7.12; N, 9.66.
8.2.16. Hexahydropyrrolo[1,2-a]pyrimidin-6-one (33).
To a solution of 32 (3.0 g, 21.7 mmol) in MeOH (50 mL)
was added solid NaBH4 (1.6 g, 42 mmol) in portions. After
it was stirred at rt for 15 h, the solvent was evaporated. The
remaining solid was extracted repeatedly with Et2O and
CH2Cl2. The combined organic extracts were dried over
K2CO3 and concentrated to a white gelatinous solid. This
was chromatographed, eluting with 1:2:25 i PrNH2/MeOH/
CHCl3 to afford 33 as a clear oil (1.30 g, 43%). IR:
1680 cm21. MS (70 eV): Mþ 140 (81), 139 (100). HRMS
calcd for C7H12N2O: 140.0942. Found: 140.0949.
8.2.20. 5-(3-Aminopropyl)-4-oxo[1,5]diazonane-1-car-
boxylic acid, tert-butyl ester (43). A solution of 41
(4.3 g, 10 mmol) and 85% hydrazine hydrate (5.7 mL) in
absolute EtOH (110 mL) was heated to reflux for 1 h. A
white solid precipitated shortly after the reaction began. The
EtOH was evaporated and the residue dissolved in concd aq.
NH4OH (120 mL). The resulting solution was saturated
with NaCl and extracted with CH2Cl2 (4£100 mL). The
combined CH2Cl2 fractions were dried (Na2SO4) and
concentrated to a yellow oil. Chromatography eluting with
5:2:1 CHCl3/MeOH/i PrNH2 gave pure 43 (2.8 g, 93%) as a
pale yellow oil. 1H NMR (500 MHz, 508C): d 3.85–2.95 (br
8.2.17. 1-(3-Phenylacryloyl)-hexahydropyrrolo[1,2-a ]-
pyrimidin-6-one (34). To a solution of 33 (1.16 g,
8.3 mmol), Et3N (1.4 mL, 10.0 mmol) and DMAP (50 mg,
0.41 mmol) in CH2Cl2 (50 mL) at rt was added cinnamoyl
chloride (1.4 g, 8.4 mmol). The reaction mixture was stirred
for 30 min and then washed successively with 1N aq. HCl,

7188
H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
m, 8H), 2.85–2.50 (br m, 2H), 2.68 (t, J¼6.8 Hz, 2H),
1.85–1.55 (m, 4H), 1.67 (quin, J¼6.8 Hz, 2H), 1.55–1.05
(m, 2H), 1.47 (s, 9H). IR: 1685, 1620 cm21. MS (20 eV):
Mþ 299 (24), 281 (9), 226 (24), 213 (41), 199 (36), 182 (34),
156 (43), 141 (28), 125 (40), 113 (45), 84 (60), 70 (38), 57
(100). HRMS calcd for C15H29N3O3: 299.2209. Found:
299.2214.
concentrated. The white residue was dissolved in concd
aq. NH4OH (15 mL), diluted with H2O (10 mL) and
saturated with NaCl. This solution was extracted with
CH2Cl2 (4£50 mL). The combined organic fractions were
dried (Na2SO4) and evaporated to leave 46 (124 mg, 58%)
as a white crystalline solid which was recrystallized from
EtOAc/hexanes, mp 115–1178C (lit.30 mp 113.5–1158C).
1H NMR (90 MHz): d 8.5 (br s, 1H), 3.5–3.25 (m, 2H), 3.15
(br s, 2H), 3.0–2.55 (m, 8H), 2.5–2.25 (m, 2H), 1.8–1.5 (br
m, 6H). IR: 3650, 3250, 1650, 1540 cm21. MS (70 eV): Mþ
199 (27), 182 (33), 156 (31), 141 (30), 128 (27), 112 (26),
8.2.21. 4-Oxo-1,5,9-triazacyclotridecane-1-carboxylic
acid, tert-butyl ester (45). A solution of the azalactam 43
(1.0 g, 3.3 mmol) in 2,4-lutidine (300 mL) was heated to
reflux for 19 h. After cooling the solution, the 2,4-lutidine
was removed by distillation under vacuum to leave an
orange oil. The crude material was chromatographed with
25:2:1 CHCl3/MeOH/i PrNH2 as eluant to yield partially
purified 45 (0.48 g) containing a small amount of the
starting material. The oily mixture crystallized on standing.
An analytical sample was prepared by two recrystallizations
from CH2Cl2/hexanes to provide white crystals, mp 112–
1138C. The partially purified material was normally used in
the subsequent step. 1H NMR (500 MHz, 508C): d 7.5 (br s,
1H), 3.64–3.62 (m, 2H), 3.47–3.44 (m, 2H), 3.30 (t,
J¼6.5 Hz, 2H), 2.78–2.76 (m, 2H), 2.67–2.65 (m, 2H),
2.47–2.45 (m, 2H), 1.73–1.62 (m, 4H), 1.62–1.35 (m, 3H),
1.47 (s, 9H). IR: 1680, 1660 (sh), 1525 cm21. MS (20 eV):
Mþ 299 (27), 198 (100), 156 (22), 141 (28), 129 (42), 112
(21), 100 (23), 84 (34), 70 (24), 57 (40). Anal. calcd for
C15H29N3O3: C, 60.17; H, 9.76; N, 14.03. Found: C, 59.94;
H, 9.79; N, 13.97.
1
100 (65), 84 (100), 70 (91), 56 (31). The H NMR, IR and
MS spectra of this material compared well with the
corresponding spectra of authentic 46 provided by Dr
K. Maruoka, Nagoya University, Japan.30
8.2.24. 4-Oxo-1,5,9-triazacyclotridecane-1,9-dicarboxylic
acid, di-tert-butyl ester (49). To a solution of 46 (50 mg,
0.25 mmol) in CH2Cl2 (1 mL) was added a solution of
di-tert-butyldicarbonate (120 mg, 0.55 mmol) in CH2Cl2
(2 mL). After stirring the solution at 258C for 1 h, the
solvent was evaporated to a clear oil. Chromatography with
EtOAc as eluant provided pure 49 (90 mg, 90%). 1H NMR
(90 MHz): d 6.25 (br t, J¼6 Hz, 1H), 3.8–3.6 (m, 2H),
3.5–3.05 (m, 8H), 2.4–2.2 (m, 2H), 2.0–1.7 (m, 2H),
1.7–1.4 (m, 4H), 1.48 (s, 9H), 1.43 (s, 9H).
8.2.25. 4-Methoxy-1,5,9-triazacyclotridec-4-ene-1,9-di-
carboxylic acid, 1-tert-butyl ester, 9-(2,2,2-trichloro-
ethyl) ester (51). To a solution of the azalactam 47
˚
8.2.22. 4-Oxo-1,5,9-triazacyclotridecane-1,9-dicarboxylic
acid, 1-tert-butyl ester, 9-(2,2,2-trichloroethyl) ester (47).
To a solution of the partially purified azalactam 45 (0.41 g,
1.37 mmol) and DMAP (250 mg, 2.05 mmol) in CH2Cl2
(11 mL) at rt was added 2,2,2-trichloroethylchloroformate
(0.23 mL, 1.67 mmol). The reaction was stirred at rt for
45 min and then concentrated. The residue (containing
insoluble DMAP hydrochloride) was chromatographed
eluting with EtOAc to yield pure 47 (0.56 g, 40% from
43) as a colorless oil. The less polar 2,2,2-trichloroethyl-
carbonyl derivative of 43 eluted separately in advance of 47.
An analytical sample of 47 was prepared by running a
second column as above and carefully evaporating the
solvent with a stream of dry N2. The last traces of solvent
were removed by warming the sample at 508C under high
vacuum. 1H NMR (500 MHz, 508C): d 5.87 (br t, 1H), 4.77
(s, 2H), 3.72–3.60 (br m, 2H), 3.53–3.36 (m, 6H), 3.20 (t,
J¼6.5 Hz, 2H), 2.45–2.32 (br m, 2H), 2.03–1.93 (m, 2H),
1.68–1.45 (m, 4H), 1.48 (s, 9H). IR: 1710 (sh), 1700 (sh),
1680, 1520 cm21. MS (20 eV): 477 (3), 475 (8), 473 (10),
376 (32), 375 (46), 374 (77), 373 (54), 372 (77), 338 (36),
334 (43), 332 (44), 270 (40), 208 (46), 141 (44), 127 (32),
115 (35), 114 (44), 84 (41), 69 (50), 57 (100). Anal. calcd
for C18H30Cl3N3O5: C, 45.53; H, 6.37; Cl, 22.40; N, 8.85.
Found: C, 45.62; H, 6.39; Cl, 22.42; N, 8.78.
(582 mg, 1.23 mmol) in CH2Cl2 (6.5 mL) over 4 A
molecular sieves (1.5 g) was added trimethyloxonium
tetrafluoroborate (273 mg, 1.84 mmol) under N2 in a glove
bag. The mixture was stirred for 4.5 h at rt. After it was
cooled to 08C, the reaction mixture was quenched by
addition of saturated aq. NaHCO3 (4 mL) and stirred for an
additional 5 min. The aqueous and organic layers were
separated and the aqueous layer washed several times with
CH2Cl2. The combined CH2Cl2 fractions were dried
(K2CO3) and concentrated to a colorless oil (0.55 g, 91%).
Thin layer chromatography (EtOAc) and 1H NMR
(90 MHz) indicated that only traces of impurities, including
starting material, were present. Since lactim ether 51 was
found to decompose on silica gel, the crude material was
normally used directly, without purification, in the subse-
quent coupling step. However, a sample of pure 51 (a
colorless oil) was obtained by chromatography on a short
1
column eluting with EtOAc. H NMR (500 MHz, 508C): d
4.75 (s, 2H), 3.64 (s, 3H), 3.57–3.45 (m, 4H), 3.42–3.31
(m, 4H), 3.28–3.20 (m, 2H), 2.58–2.49 (m, 2H), 1.98–1.89
(m, 2H), 1.72–1.63 (m, 2H), 1.61–1.45 (m, 2H), 1.46 (s,
9H). IR: 1710, 1680, 1480 cm21. MS (20 eV): 491 (26), 489
(79), Mþ 35Cl3 487 (80), 432 (42), 430 (43), 388 (100), 386
(98), 374 (46), 372 (49), 347 (20), 345 (25), 340 (80), 252
(32), 174 (49), 155 (31), 141 (23), 114 (37), 112 (80), 111
(47), 100 (53), 91 (47), 84 (30), 57 (20). HRMS calcd for
C19H32Cl3N3O5: 487.1407. Found: 487.1394.
8.2.23. 1,5,9-Triazacyclotridecan-4-one (46). Gaseous
HCl was bubbled for 10 min through a solution of 41
(458 mg, 1.07 mmol) at 08C. The solution was stirred at 08C
for another 10 min and then concentrated. The HCl salt (42)
was dissolved in absolute EtOH (10 mL) and to the solution
was added 85% hydrazine hydrate (0.8 mL). The mixture
was then heated to reflux for 12 h, cooled and then
8.2.26. 4-Ethoxy-1,5,9-triazacyclotridec-4-ene-1,9-dicar-
boxylic acid, 1-tert-butyl ester, 9-(2,2,2-trichloroethyl)
ester (52). Prepared in the same manner as 51 from 47
(595 mg, 1.25 mmol) and triethyloxonium tetrafluoroborate
(400 mg, 2.1 mmol) in CH2Cl2 (6.7 mL). After a reaction

H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
7189
time of 1.5 h and workup, crude 52 was isolated (615 mg,
1
98%). Thin layer chromatography (EtOAc) and H NMR
EtOAc and then 5% MeOH/EtOAc to provide pure 54
1
(140 mg, 80%). H NMR (500 MHz, 508C): d 7.46–7.17
(90 MHz) indicated that only traces of impurities including
starting material were present. Since 52 was found to
decompose on silica gel, the crude material was normally
used directly in the next step. A sample of pure 52 (a
colorless oil) was obtained via chromatography on a short
(m, 5H), 4.79 (s, 2H), 4.65 (dd, J¼3.9, 12.7 Hz, 1H), 4.03–
3.78 (m, 3H), 3.78–3.65 (m, 1H), 3.65–3.32 (m, 6H), 2.95–
2.68 (m, 3H), 2.55–2.43 (m, 1H), 2.11 and 2.09 (2s, total
3H), 2.02–1.87 (br m, 2H), 1.87–1.60 (br m, 4H). IR: 1710,
1640 cm21. MS (20 eV): 546 (22), Mþ 35Cl3 544 (27), 503
(14), 501 (17), 397 (17), 314 (20), 287 (35), 244 (24), 227
(53), 216 (45), 215 (100), 202 (42), 201 (65), 131 (11).
HRMS calcd for C24H31Cl3N4O4: 544.1411. Found:
544.1437.
1
column eluting with EtOAc. H NMR (500 MHz, 508C): d
4.74 (s, 2H), 4.06 (q, J¼7.1 Hz, 2H), 3.56–3.44 (m, 4H),
3.39–3.29 (m, 4H), 3.27–3.20 (m, 2H), 2.56–2.48 (m, 2H),
1.95–1.88 (m, 2H), 1.71–1.63 (m, 2H), 1.61–1.40 (m, 2H),
1.45 (s, 9H), 1.25 (t, J¼7.1 Hz, 3H). IR: 1715, 1680,
1480 cm21. MS (20 eV): 505 (12), 503 (31), Mþ 35Cl3 501
(37), 446 (27), 444 (33), 402 (84), 400 (100), 374 (77), 372
(93), 361 (21), 359 (24), 354 (31), 252 (21), 188 (21), 155
(25), 141 (40), 128 (71), 126 (87), 125 (63), 114 (80), 101
(53), 84 (61), 57 (70). HRMS calcd for C20H34Cl3N3O5:
501.1565. Found: 501.1586.
8.2.29. 13-Acetyl-6-oxo-8-phenyl-1,5,9,13-tetraazacyclo-
heptadecane-1-carboxylic acid, 2,2,2-trichloroethyl ester
(55). To a solution of 54 (104 mg, 0.19 mmol) in glacial
AcOH (2 mL) at rt was added NaBH3CN (40 mg,
0.64 mmol). The mixture was stirred for 3 h at rt, warmed
at 508C for 1 h and then stirred at rt overnight (12 h). The
solution was diluted with CH2Cl2 (70 mL) and washed with
H2O (30 mL) and saturated aq. NaHCO3 (30 mL). After it
was dried (Na2SO4), the solution was concentrated to leave
a clear oil. The pure azalactam 55 (92 mg, 88%) was
obtained by chromatography with 8% MeOH/EtOAc as
8.2.27. 4-Oxo-2-phenyl-3,4,6,7,9,10,11,12,14,15-decahy-
dro-2H,5H-1,4a,8,13-tetraazabenzocyclotridecene-8,13-
dicarboxylic acid, 13-tert-butyl ester, 8-(2,2,2-trichloro-
ethyl) ester (53). A solution of 52 (285 mg, 0.57 mmol) and
4-phenylazetidin-2-one (84 mg, 0.57 mmol) in chloro-
benzene (0.5 mL) was heated to reflux in an oil bath for
15 h. The reaction was cooled and concentrated to leave a
red oil that was chromatographed eluting with CH2Cl2, 20%
EtOAc/CH2Cl2 and then 33% EtOAc/CH2Cl2. A 1.6:1
mixture (235 mg) of 53 and 4-phenylazetidin-2-one was
1
eluant. H NMR (500 MHz, 508C): d 7.8–6.88 (m, 6H),
4.75 (s, 2H), 4.08–3.93 (m, 1H), 3.8–3.22 (m, 9H), 3.22–
3.08 (m, 1H), 2.68–2.33 (m, 4H), 2.26–1.56 (series of br m,
9H), 2.04 and 2.02 (2s, total 3H). IR: 1710, 1660, 1635,
1520 cm21. MS (20 eV): 550 (2), Mþ 35013 548 (3), 507
(2), 505 (3), 401 (9), 374 (8), 333 (8), 331 (9), 291 (7), 289
(9), 245 (10), 214 (34), 189 (31), 176 (31), 163 (11), 155
(15), 146 (100), 145 (33), 132 (21), 112 (15), 100 (13), 98
(10), 84 (17), 56 (16). HRMS calcd for C22H33N4O3 (parent
minus Cl3CCH2O): 401.2553. Found: 401.2583.
1
obtained as determined by H NMR integration. From this
ratio, the mass of 53 was calculated to be 205 mg (59%).
The mixture was chromatographed again with 20%
EtOAc/CH2Cl2 as eluant to achieve partial separation of
53 and the b-lactam. An analytical sample of 53 was
prepared by running a third column (20% EtOAc/CH2Cl2)
on a clean fraction of 53 and carefully evaporating the
solvent with a stream of dry N2. The last traces of solvent
were removed by warming the oily sample at 508C under
high vacuum. The less pure fractions of 53 obtained above
were combined and used directly in the next step. 1H NMR
(500 MHz, 508C): d 7.6–7.24 (m, 5H), 4.78 (d, J¼12.0 Hz,
1H), 4.75 (d, J¼12.0 Hz, 1H), 4.63 (dd, J¼4.6, 13.0 Hz,
1H), 4.0–3.88 (m, 1H), 3.88–3.2 (series of br m, 9H), 2.90–
2.70 (m, 3H), 2.48 (t, J¼13 Hz, 1H), 2.07–1.95 (m, 1H),
1.95–1.84 (m, 1H), 1.84–1.65 (br m, 4H), 1.45 (s, 9H).
IR: 1705 (sh), 1690, 1650 (sh) cm21. Anal. calcd for
C27H37Cl3N4O5: C, 53.69; H, 6.17; N, 9.28. Found: C,
53.71; H, 6.21; N, 9.18.
8.2.30. (6)-Verbascenine (3). A mixture of 55 (64 mg,
0.12 mmol) and powdered Zn (500 mg) in AcOH (2 mL)
was stirred at rt for 18.5 h. The reaction mixture was diluted
with CH2Cl2 (70 mL) and filtered through Celite. The
filtrate was washed with H2O (30 mL) and saturated aq.
NaHCO3 (30 mL). The combined aqueous fractions were
then made basic with 1N aq. NaOH, saturated with NaCl
and extracted with CH2Cl2 (8£50 mL). The combined
CH2Cl2 fractions were dried and concentrated to leave the
crude azalactam 56 as an oil (37 mg). The 90 MHz 1H NMR
spectrum of this material confirmed the absence of the 2,2,2-
trichloroethyloxycarbonyl protecting group (no s at d 4.8).
The azalactam 56 (37 mg, 0.1 mmol), Et3N (50 mL,
0.36 mmol) and DMAP (6 mg, 0.05 mmol) were dissolved
in CH2Cl2 (1 mL) and the solution cooled to 2788C. A
solution of cinnamoyl chloride (17 mg, 0.1 mmol) in
CH2Cl2 (0.25 mL) was added dropwise. The reaction was
stirred at 2788C for 4 h and then allowed to stand at 2208C
overnight (14 h). The reaction was quenched by addition of
14% aq. NH4OH (10 mL) and the mixture extracted several
times with CH2Cl2. The combined CH2Cl2 fractions were
dried (Na2SO4) and evaporated to leave the crude oily
product. Chromatography with 15% MeOH/EtOAc as
eluant provided (^)-verbascenine (3) (35 mg, 58% from
8.2.28. 13-Acetyl-4-oxo-2-phenyl-2,3,4,6,7,9,10,11,12,13,
14,15-dodecahydro-5H-1,4a,8,13-tetraazabenzocyclo-
tridecene-8-carboxylic acid, 2,2,2-trichloroethyl ester
(54). A mixture of 53 (,190 mg, 0.32 mmol) and
4-phenylazetidin-2-one (,50 mg, 0.32 mmol) in CH2Cl2
(10 mL) was cooled to 08C in an ice bath. The solution was
saturated with HCl gas, stirred at 08C for 1 h, and
concentrated to leave a pale yellow solid. The solid was
dissolved in CH2Cl2 (3 mL). To the solution at rt was added
DMAP (190 mg, 1.56 mmol) and then acetyl chloride
(45 mL, 0.63 mmol). The reaction mixture was stirred at rt
for 1 h. After quenching with a few drops of i PrNH2, the
solvent was evaporated. The residue (containing insoluble
DMAP hydrochloride) was chromatographed eluting with
1
55) as a clear oil. The H NMR, IR and mass spectra of
the synthetic (^)-verbascenine compared very favorably
with the corresponding spectra obtained from natural
(2)-verbascenine, a sample of which was kindly supplied
by Dr K. Seifert, Institut fur Biochemie de Pflanzen Halle,

7190
H. H. Wasserman et al. / Tetrahedron 58 (2002) 7177–7190
DDR.47 1H NMR (500 MHz, 508C): d 7.9, 6.92 (2 br s,
,0.5H), 7.72 (d, J¼15.3 Hz, ,0.6H), 7.71 (d, J¼15.3 Hz,
,0.4H), 7.51 (br s, 2H), 7.46–7.17 (m, ,8.5H), 6.84 (d,
J¼15.3 Hz, ,0.4H), 6.83 (d, J¼15.3 Hz, ,0.6H), 4.12–
3.93 (br m, 1H), 3.70–3.10 (series of br m, 10H), 2.65–2.30
(m, 4H), 2.15–1.50 (series of br m, 9H), 2.06, 2.01 (2s, total
3H). IR: 1650, 1635 (sh), 1605 (sh), 1430, 1240–1210 (br).
MS (20 eV): Mþ 504 (5), 449 (65), 373 (56), 359 (21), 245
(31), 228 (20), 188 (20), 169 (37), 157 (21), 146 (100), 131
(93), 112 (46), 100 (25), 98 (25), 84 (59), 70 (24). The
synthetic and natural verbascenine also displayed identical
behavior on TLC (Rf¼0.45, 20% MeOH/EtOAc).
20. (a) Crombie, L.; Haigh, D.; Jones, R. C. F.; Mat-Zin, A. R.
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and has reported similar results.
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