Total syntheses of (-)-papuamine and (-)-haliclonadiamine

Article abstract of DOI:10.1021/jo951647i

The pentacyclic marine alkaloids (-)-papuamine (1) and (-)-haliclonadiamine (2) have been prepared by total synthesis. The synthesis began with (-)-8, which was converted into diester 20 by way of bis-mesylate 17, dinitrile 18, and diacid 19. Dieckmann cyclization of 20 provided keto ester 21, which was transformed into acetal 22. After hydrolysis of the acetal, ketone 25 was subjected to reductive amination with 1,3-propanediamine and sodium triacetoxyborohydride to obtain diamines 26 and 27 as a 71:29 mixture of diastereomers, favoring the symmetrical isomer having the papuamine relative configuration. After transformation of the diamines to their t-Boc derivatives, the benzyl ethers were cleaved and the resulting diol was oxidized to dialdehyde 30. Application of the Seyferth procedure for conversion of aldehydes to alkynes gave a mixture of diynes 31 and 32. After removal of the t-Boc protecting groups from 31, diamino diyne 15 was treated with tributylstannane and azoisobutyronitrile te obtain the bis-vinylstannane 34. Treatment of this compound with Pd(II) and Cu(I) in the presence of air produced (-)-papuamine (1). (-)Haliclonadiamine (2) was obtained from the unsymmetrical isomer, 32. The NMR spectra of the synthetic alkaloids were identical to those of authentic samples of the natural alkaloids.

Full text of DOI:10.1021/jo951647i

700
J . Org. Chem. 1996, 61, 700-709
Tota l Syn th eses of (-)-P a p u a m in e a n d (-)-Ha liclon a d ia m in e
Todd S. McDermott, Andrew A. Mortlock, and Clayton H. Heathcock*
Department of Chemistry, University of California, Berkeley, California 94720
Received September 7, 1995X
The pentacyclic marine alkaloids (-)-papuamine (1) and (-)-haliclonadiamine (2) have been
prepared by total synthesis. The synthesis began with (-)-8, which was converted into diester 20
by way of bis-mesylate 17, dinitrile 18, and diacid 19. Dieckmann cyclization of 20 provided keto
ester 21, which was transformed into acetal 22. After hydrolysis of the acetal, ketone 25 was
subjected to reductive amination with 1,3-propanediamine and sodium triacetoxyborohydride to
obtain diamines 26 and 27 as a 71:29 mixture of diastereomers, favoring the symmetrical isomer
having the papuamine relative configuration. After transformation of the diamines to their t-Boc
derivatives, the benzyl ethers were cleaved and the resulting diol was oxidized to dialdehyde 30.
Application of the Seyferth procedure for conversion of aldehydes to alkynes gave a mixture of
diynes 31 and 32. After removal of the t-Boc protecting groups from 31, diamino diyne 15 was
treated with tributylstannane and azoisobutyronitrile to obtain the bis-vinylstannane 34. Treatment
of this compound with Pd(II) and Cu(I) in the presence of air produced (-)-papuamine (1). (-)-
Haliclonadiamine (2) was obtained from the unsymmetrical isomer, 32. The NMR spectra of the
synthetic alkaloids were identical to those of authentic samples of the natural alkaloids.
The C2-symmetric, pentacyclic alkaloid papuamine (1)
synthesis of the unnatural enantiomer of papuamine,
thereby establishing the absolute stereochemistry of the
naturally occurring material. A full account of Barrett’s
synthesis, which is conceptually very similar to our own,
appears in an accompanying Article. Shortly after Bar-
rett’s original communication, Weinreb and co-workers4
reported the total synthesis of the natural antipode of
papuamine exploiting a novel imino ene reaction.
Our original retrosynthetic analysis of 1 and 2 (Scheme
1) took advantage of the fact that these compounds are
nearly identical, being epimeric at a single stereocenter.
We thought that by establishing the stereochemistry of
this center as one of the last steps of the synthesis, both
natural products would be available from a common
advanced intermediate such as bis-imine 3 or the corre-
sponding immonium ion. Reduction of 3 where hydride
addition occurs exclusively in a Cram sense5,6 would lead
to 1, while reduction where one hydride addition occurs
in an anti-Cram sense would lead to 2. The other
expected product would be that resulting from anti-Cram/
anti-Cram hydride addition to 3; however, that would be
a minor product if the reduction were even mildly
stereospecific.
was isolated from Haliclona sp., a thin red sponge that
overgrows and kills coral reef, collected by Scheuer and
co-workers off the coast of Papua, New Guinea.1 Scheuer
reported the major metabolite (1.3% of dry weight) to be
1 on the basis of NMR and mass spectrometry data.
Shortly after the communication by Scheuer, Faulkner
and co-workers2 reported the isolation of haliclonadi-
amine (2) as the major metabolite, along with a minor
amount of 1, from Haliclona sp. that was obtained from
Palau. The structure of 2 was determined by X-ray
analysis of the N,N-diacetyl derivative. At the time they
were reported, the absolute configurations of papuamine
and haliclonadiamine were not known. Alkaloids 1 and
2 inhibit the growth of Candida albicans, Bacillus
subtilis, Staphylococcus aureus, and Trichopyton menta-
grophytes.1,2
At the inception of our efforts toward the syntheses of
1 and 2, the absolute stereochemistry of these natural
products had not been established.1,2 We arbitrarily
chose as our target the enantiomer that was later shown
by Barrett and Weinreb to be the unnatural enantiomer
of papuamine and presumably the unnatural enantiomer
of haliclonadiamine, although the latter point had not
been definitively established. Our original synthetic goal,
then, was diketone 4, the retrosynthetic analysis of which
is shown in Scheme 2. The requisite E,E-diene would
come from metal-mediated coupling of a vinyl derivative
of alkyne 5. The alkyne would be formed by reduction
of nitrile 6 followed by homologation of the resulting
Papuamine and haliclonadiamine are unique among
the known Haliclona metabolites. Papuamine contains
a central 13-membered ring and has a C2-symmetry axis
through the central methylene of the diaminopropane
bridge and dissecting the E,E-diene. Haliclonadiamine
is identical to papuamine but is epimeric at the point
where the diaminopropane portion is attached to one
hydrindan unit. These compounds presumably arise
from the same source, but nothing is known about the
biosyntheses of these unusual alkaloids.
Two syntheses of papuamine appeared in the literature
(3) Barrett, A. G. M.; Boys, M. L.; Boehm, T. L. J . Chem. Soc., Chem.
Commun. 1994, 1881-1882.
in 1994. Barrett and co-workers3 reported the total
(4) Weinreb, S. M.; Borzilleri, R. M.; Parvez, M. J . Am. Chem. Soc.
1994, 116, 9789-9790.
X Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
(1) Scheuer, P. J .; Baker, B. J .; Shoolery, J . N. J . Am. Chem. Soc.
1988, 110, 965.
(5) Cram, D. J .; Elhafez, F. A. A. J . Am. Chem. Soc. 1952, 74, 5828-
5835.
(2) Faulkner, D. J .; Fahy, E.; Molinski, T. F.; Harper, M. K.;
Sullivan, B. W. Tetrahedron Lett. 1988, 29, 3427.
(6) Felkin, H.; Cherest, M.; Prudent, N. Tetrahedron Lett. 1968,
2199-2204.
0022-3263/96/1961-0700$12.00/0 © 1996 American Chemical Society

(-)-Papuamine and (-)-Haliclonadiamine
J . Org. Chem., Vol. 61, No. 2, 1996 701
potassium salt of dimethyl (diazomethyl)phosphonate.8-10
Hydrozirconation of 5 with Cp2ZrCl(H) (Schwartz’s re-
agent)11,12 and treatment of the resulting vinylzirconium
species with CuCl13 gave diene 13 in a 57% yield. The
remainder of the material was the terminal alkene
resulting from proto-demetalation of the vinylzirconium
species. Deprotection of the bis-acetal 13 gave diketone
4 in quantitative yield. Although the deprotection reac-
tion was efficient, diketone 4 was found to be unstable,
decomposing upon standing at room temperature.
With diketone 4 in hand, a variety of conditions for
installing the amine functionality were investigated.
Reductive amination14,15 of 4 with diaminopropane, the
original synthetic plan, resulted in recovery or decom-
position of starting material, depending on conditions (eq
1). Attempts to convert 4 to the corresponding primary
Sch em e 1
amine14 (14, R ) H), with the hope of incorporating the
propane bridge by a bis-alkylation reaction, also resulted
in recovery of starting material or decomposition. At-
tempts to form the bis-imine 3 under dehydrating condi-
tions16 were also unsuccessful. The lack of reactivity of
diketone 4 to typical reductive amination conditions may
be due to tautomerization to the corresponding tetraene-
diol. Indeed, addition of methanol to 4 resulted in a
bright yellow solution that was inert to reductive ami-
nation.
Sch em e 2
Prompted by the difficulty in functionalization of 4 and
by establishment of the absolute stereochemistry of
papuamine (1) by Barrett,3 a new synthetic plan was
devised. The new plan was focused on the synthesis of
the natural enantiomer of papuamine (1) along with
haliclonadiamine (2) as depicted in Scheme 4. The 13-
membered ring would be formed by a vinyl coupling
reaction on a derivative of dialkynes 15/16. The alkyne
functionality would be installed in a manner similar to
that presented in the previous synthetic approach. The
diaminopropane portion of the molecule would be intro-
duced by reductive amination of a suitably functionalized
hydrindanone with 1,3-diaminopropane. The synthetic
plan was, again, to take advantage of the lack of complete
stereocontrol of the reductive amination reaction in order
to access both natural products in a convergent manner.
The starting point of the synthesis (Scheme 5) was (-)-
8, which was prepared by a series of steps analogous to
those reported7 for the synthesis of (+)-8, but employing
the other enantiomer of menthol. Mesylation followed
aldehyde. Nitrile 6 would arise from acetal protection
of the keto nitrile from a Thorpe-Ziegler cyclization of
dinitrile 7, which would come from known diol 8.
The starting point for our synthesis is diol (+)-8, which
was prepared in optically pure form by an asymmetric
Diels-Alder reaction and a series of straightforward
steps.7 As shown in Scheme 3, diol (+)-8 was hydroge-
nated to 9 followed by mesylation and displacement with
cyanide to give dinitrile 7. Thorpe-Ziegler cyclization
of 7 using sodium N-methylanilide as a base, followed
by acid hydrolysis of the intermediate imine, gave keto
nitrile 11, as a 13:1 mixture of epimers at the newly-
formed stereocenter. Protection of the ketone as its
acetal was followed by diisobutylaluminum hydride
(DIBAL-H) reduction of the nitrile to give aldehyde 12.
Homologation to alkyne 5 was accomplished using the
(8) Seyferth, D.; Marmor, R. S.; Hilbert, P. J . Org. Chem. 1971, 36,
1379.
(9) Colvin, E. W.; Hamill, B. J . J . Chem. Soc., Perkin Trans. I 1977,
869.
(10) Gilbert, J . C.; Weerasooriya, U. J . Org. Chem. 1979, 44, 4997.
(11) Schwartz, J .; Hart, D. W. J . Am. Chem. Soc. 1974, 96, 8115.
(12) Buchwald, S. J .; LaMaire, S. J .; Neilsen, R. B.; Watson, B. T.;
King, S. M. Org. Synth. 1992, 71, 77.
(13) Negishi, E.; Takahashi, T. Aldrichimica Acta 1985, 18, 31.
(14) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897.
(15) Abdel-Magid, A.; Maryanoff, C. A.; Carson, K. G. Tetrahedron
Lett. 1990, 31, 5595.
(16) Layer, R. W. Chem. Rev. 1963, 63, 489-510.
(7) Heathcock, C. H.; Davis, B. R.; Hadley, C. R. J . Med. Chem. 1989,
32, 197-202.

702 J . Org. Chem., Vol. 61, No. 2, 1996
McDermott et al.
Sch em e 3
Sch em e 5
Sch em e 4
to primary alcohol 23 was followed by conversion to its
benzyl ether and removal of the acetal group to give
ketone 25. Reductive amination of 25 with 1,3-diami-
nopropane using sodium triacetoxyborohydride in dichlo-
roethane/acetic acid15,18 gave diamines 26/27 as a 3.4:1
mixture of diastereomers favoring the symmetrical di-
amine. Along with starting material, the mixture of
diamines was the only product isolated from the reaction.
The yield for the reductive amination based on recovered
starting material was 92%. Careful chromatography
allowed a minor amount of the symmetrical diamine (26,
corresponding to the papuamine stereochemistry) to be
isolated, but typically, this mixture was carried on and
separated at a later stage. The amines were protected
as their tert-butyl carbamates (t-Boc)19 to give 28 as an
inseparable mixture of diastereomers. The use of a t-Boc
protecting group was ideal because of its easy installa-
tion and removal; however, NMR spectra of the t-Boc-
protected diamines were very broad and of little or no
use. Catalytic hydrogenation resulted in the removal of
by cyanide displacement gave dinitrile 18. The moderate
yield obtained for the Thorpe-Ziegler cyclization in the
earlier synthetic route, along with difficulty during the
reduction of a nitrile to an aldehyde on a closely-related
model system, prompted us to investigate the use of a
Dieckmann cyclization to construct the five-membered
ring. To this end, dinitrile 18 was transformed to the
corresponding diester 20. Treatment of 20 with potas-
sium hydride at 0 °C in THF17 followed by quenching of
the resulting enolate at 0 °C resulted in the formation of
keto ester 21 in near quantitative yield as a single
diastereomer. The complete stereospecificity of the Dieck-
mann cyclization was eroded to a 20:1 mixture of ester
22 during the subsequent acetal formation. Reduction
(18) Gribble, G. W.; Nutaitis, C. F. Org. Prep. Proc. Int. 1985, 17,
317.
(19) Tarbell, D. S.; Yamamoto, Y.; Pope, B. M. Proc. Nat. Acad. Sci.
U.S.A. 1972, 69, 730-732.
(17) Brown, C. A. Synthesis 1975, 326-327.

(-)-Papuamine and (-)-Haliclonadiamine
J . Org. Chem., Vol. 61, No. 2, 1996 703
Sch em e 6
the benzyl ethers and reduction of the olefins to give diol
29. Oxidation using TPAP20 in CH2Cl2 gave dialdehyde
30 in good yield. This material decomposed upon stand-
ing and was immediately transformed to the correspond-
ing dialkyne (31) using dimethyl (diazomethyl)phos-
phonate.8-10 The symmetric (31) and unsymmetric (32)
diastereomers were separated at this point.
With 31 and 32 in hand, the cyclization to the requisite
diene was investigated. The coupling reaction that had
proved the most successful for the formation of a diene
from an alkyne in the previous approach was hydrozir-
conation of the alkyne followed by treatment with CuCl.13
High-dilution variations of the vinylzirconium coupling
conditions were attempted using dialkyne 31. The only
product obtained from these reactions, after removal of
the t-Boc protecting groups,19 was terminal alkene 33,
arising from hydrozirconation followed by proto-demeta-
lation (eq 2). The fact that this reaction returned no
toluene gave bis-vinylstannane 34 in good yield.4 Treat-
ment of 34 with Cu(NO3)2‚3H2O in THF in the presence
of an oxidant21 resulted in the formation of the alkene
33, by proto-destannylation, along with a compound
tentatively identified as the uncyclized dimer. Cycliza-
tion attempts using PdCl2(PPh3)2 in DMF open to the air4
gave predominately starting material. It was curious
that the palladium reaction gave back starting material
and none of the alkene (33) observed from the copper-
mediated reaction. It was clear that the initial step of
the palladium reaction, which is presumably transmeta-
lation to the vinylpalladium species,22 was not occurring.
Liebeskind reported that the use of copper(I) iodide as
a cocatalyst with palladium greatly increased the rate
of Stille couplings23 and of arylstannane couplings.24
Indeed, treatment of bis-vinylstannane 34 with 10%
PdCl2(PPh3)2 and 20% CuI in DMF open to air for 30 h
gave papuamine (1) in 34% yield. No other amine
products were isolated from the reaction (Scheme 6).
The cyclization protocol was repeated with dialkyne 32
(Scheme 7). Removal of the t-Boc protecting groups with
TFA/CH2Cl2 at 0 °C proceeded smoothly to give the free
amine (16) in 92% yield. Hydrostannylation using the
previously established conditions gave bis-vinylstannane
35 in 43% yield after purification. NMR analysis of the
crude reaction mixture looked promising, but much of the
material was lost during chromatography; however, this
was not a problem for the symmetrical bis-vinylstannane
34. Cyclization of 35 with PdCl2(PPh3)2 and CuI in N,N-
dimethylacetamide open to the air gave haliclonadiamine
2 as the free amine in 12% yield. This material is
considerably more polar than papuamine, and purifica-
tion by chromatography resulted in a low mass recovery.
The yields in this sequence could probably be improved
by optimization. However, because 32 is the minor
isomer of the reductive amination reaction, we were
hampered by a shortage of material for this purpose.
Samples of natural papuamine (1) and haliclonadi-
amine (2) were secured for comparison to our synthetic
starting material and that high concentrations resulted
in low mass balance, presumably due to polymerization,
indicated that the hydrozirconation step was successful
and that the resulting vinylzirconium species could not
attain a conformation suitable for cyclization.
Weinreb’s report of the successful synthesis of papua-
mine4 prompted us to investigate the metal-promoted
oxidative coupling of vinylstannanes. Weinreb reported
that hydrostannylation of an alkyne and subsequent
palladium-catalyzed coupling of the resulting vinylstan-
nane could be accomplished in the presence of the free
amines. It seemed likely that the problems with our
earlier cyclization attempts were related to the t-Boc
protecting groups. Cyclization of the free amine was an
attractive option.
(21) Kyler, K. S.; Ghosal, S.; Luke, G. P. J . Org. Chem. 1987, 52,
As shown in Scheme 6, removal of the t-Boc protecting
group of 31 gave diamine 15. Hydrostannylation of 15
with tributyltin hydride (Bu3SnH) and AIBN in refluxing
4296-4298.
(22) Oshima, K.; Kanemoto, S.; Matsubara, S.; Utimoto, K.; Nozaki,
H. Chem. Lett. 1987, 5.
(23) Liebeskind, L. S.; Feng, R. W. J . Org. Chem. 1990, 55, 5359-
5364.
(20) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625-1627.
(24) Liebeskind, L. S.; Riesinger, S. W. Tetrahedron Lett. 1991, 32,
5681-5682.

704 J . Org. Chem., Vol. 61, No. 2, 1996
McDermott et al.
filtered through a plug of Celite and thoroughly washed with
ethanol. The filtrate was concentrated to give a thick oil that
was purified by silica gel chromatography using ether as an
eluent to give 1.08 g (99%) of a white solid: mp 57-58 °C; Rf
0.3 (Et2O); 1H NMR (500 MHz, CDCl3) δ 0.99-1.04 (m, 2),
1.19-1.31 (m, 4), 1.60 (m, 2), 1.72 (m, 2), 3.38 (br s, 2), 3.50
(dd, 2, J ) 4.9, 11.0), 3.59 (dd, 2, J ) 2.1, 11.0); 13C NMR (125
MHz, CDCl3) δ 26.1, 29.8, 44.7, 67.8; IR (KBr pellet) 3610,
3400, 1445, 1050 cm-1; [R]D -23.0 (c ) 1.63, CHCl3). Anal.
Calcd for C8H16O2: C, 66.63; H, 11.18. Found: C, 66.89; H,
10.91.
Sch em e 7
(1S,2S)-Cycloh exa n e-1,2-d im eth a n ol Bis(m eth a n esu l-
fon a te) (10). A dry flask was charged with diol 9 (4.90 g,
33.98 mmol) and ether (250 mL). The flask was flushed with
argon and cooled to 0 °C. Triethylamine (14.2 mL, 101.94
mmol) was added, and then methansulfonyl chloride (6.31 mL,
81.55 mmol) was added dropwise over a period of 10 min. The
reaction mixture was stirred at 0 °C for 20 min and at rt for
2 h. The solvent was removed in vacuo, and the residue was
partitioned between water (100 mL) and CH2Cl2 (100 mL). The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 100 mL). The combined organic layers were
washed with brine (100 mL) and dried over MgSO4. Filtration
and evaporation gave a brown solid that was recrystallized
from MeOH (two crops) to give 9.158 g (90%) of a white solid:
mp 83-84 °C; Rf 0.06 (1:20 MeOH/CHCl3); 1H NMR (500 MHz,
CDCl3) δ 1.25 (m, 4), 1.68-1.80 (m, 6), 3.00 (s, 6), 4.15 (dd, 2,
J ) 3.2, 10.1), 4.25 (dd, 2, J ) 4.3, 10.1); 13C NMR (125 MHz,
CDCl3) δ 25.2, 29.1, 37.1, 38.4, 71.9; IR (KBr pellet) 3030, 1360,
1180, 945 cm-1; [R]D +16.6 (c ) 1.94, CHCl3). Anal. Calcd
for C10H20O6S2: C, 39.98; H, 6.71. Found: C, 39.99; H, 6.69.
(1R,2R)-Cycloh exa n e-1,2-d ia ceton itr ile (7). A dry flask
was charged with dimesylate 10 (2.15 g, 7.16 mmol), potassium
cyanide (1.77 g, 27.20 mmol), and freshly-distilled DMSO (35
mL). The flask was equipped with a reflux condensor, flushed
with argon, and heated to 95 °C with an oil bath for 3.5 h.
Water (40 mL) was added with vigorous stirring. The mixture
was poured into a separatory funnel and extracted with CH2-
Cl2 (3 × 30 mL). The combined organic layers were washed
with brine (50 mL) and dried over MgSO4. Filtration and
concentration gave a thick yellow oil that was contaminated
with DMSO. The residue was adsorbed onto silica gel using
ether, and the soild was loaded directly onto a silica gel column
and eluted with ether to give 1.15 g (99%) of a fluffy white
solid: mp 52-53 °C; Rf 0.3 (ether); 1H NMR (500 MHz, CDCl3)
δ 1.32 (m, 4), 1.63 (m, 2), 1.79 (m, 2), 1.87 (m, 2), 2.42 (d, 4, J
) 4.5); 13C NMR (125 MHz, CDCl3) δ 21.9, 25.2, 31.7, 37.3,
117.5; IR (neat) 2260, 1440 cm-1; [R]D +54.5 (c ) 1.67, CHCl3).
Anal. Calcd for C10H14N2: C, 74.03; H, 8.70; N, 17.27.
Found: C, 73.91; H, 8.64; N, 16.93.
material. In order to obtain the free amines, CH2Cl2
solutions of the natural materials were treated with
saturated aqueous Na2CO3. 1H NMR and 13C NMR
spectra of the synthetic and natural materials were
identical. There is evidence4 that these compounds easily
form salts, and we found that careful formation of the
free amines was necessary to obtain consistent NMR
spectra.
There was a discrepancy between the optical rotation
value reported for natural papuamine, [R]D -150 (c ) 1.5,
MeOH),1 and our synthetic material, [R]D -346 (c ) 0.46,
MeOH). We suspected that partial protonation of the
natural material might be responsible for this anomalous
result. This situation would not be surprising as chang-
ing the stereochemistry at a single center (from papua-
mine to haliclonadiamine) causes the rotation to decrease
from -150 to -18. In order to test our hypothesis, a
sample of papuamine was contaminated with 10 mol %
p-TsOH. The rotation of this material was found to be
[R]D -278 (c ) 0.46, MeOH). Addition of 1 equiv of
p-TsOH resulted in a rotation of [R]D -183 (c ) 0.52,
MeOH).
(1R,6S,7S)-7-Cya n o-8-oxobicyclo[4.3.0]n on a n e (11). A
dry flask was charged with sodium hydride (2.41 g, 60.16
mmol) that was rinsed (2 × 10 mL) with dry hexanes. The
last of the hexanes was removed under a stream of argon. THF
(130 mL) was added followed by the addition of N-methyla-
niline (6.85 mL, 63.17 mmol) with a syringe. The flask was
equipped with a reflux condensor and heated to reflux with
an oil bath for 1.5 h. The reaction mixture was allowed to
cool to rt. Dinitrile 7 (2.44 g, 15.04 mmol) was added with a
cannula as a solution in 15 mL of THF, and the reaction
mixture was heated to reflux for 12 h. After cooling to rt, the
mixture was poured into 200 mL of 2 N HCl and stirred for
30 min. The mixture was extracted with ether (3 × 100 mL).
The combined organic layers were washed with water (75 mL)
and brine (75 mL) and dried over MgSO4. Filtration and
concentration gave a thick brown oil that was purified by
chromatography using 1:3 EtOAc/hexanes as an eluent to give
2.39 g (98%) of a yellow oil that crystallized upon standing at
0 °C overnight. The crystals were collected and washed with
cold hexanes. A second recrystallization of the mother liquor
gave a total of 2.021 g (82%) of white solid: mp 51-53 °C; Rf
0.3 (1:3 EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 1.19-
1.41 (m, 4), 1.62 (m, 1), 1.82-1.91 (m, 3), 1.97-2.03 (m, 2),
2.19 (dd, 1, J ) 3.3, 13.0), 2.52 (dd, 1, J ) 7.0, 18.6), 2.85 (d,
1, J ) 13.0); 13C NMR (125 MHz, CDCl3) δ 25.5, 25.7, 29.8,
30.8, 41.6, 43.6, 46.2, 48.4, 116.2, 204.9; IR (KBr) 2260, 1745,
Exp er im en ta l Section
Gen er a l. All starting materials were obtained from com-
mercial suppliers and used without purification. THF and
ether were distilled from sodium/benzophenone immediately
prior to use. Benzene, toluene, and triethylamine (Et3N) were
distilled from CaH2 immediately prior to use. Unless other-
wise noted, all reactions were performed under an argon
atmosphere. Silica gel chromatography was performed ac-
cording to the method of Still.25 Schwartz’s reagent (Cp2Zr-
(H)Cl) was prepared according to the literature12 and stored
at -40 °C in a glovebox under an atmosphere of dry argon.
Tributyltin hydride was Kugelrohr distilled (120 °C, 0.3
mmHg) immediately prior to use. J values are given in hertz.
IR spectra were measured as thin films on NaCl plates unless
otherwise noted. Elemental analyses were performed at the
Berkeley Microanalytical Lab, University of California.
(1S,2S)-Cycloh exa n e-1,2-d im eth a n ol (9). A Parr hydro-
genation flask was charged with (+)-8 (1.07 g, 7.52 mmol) and
10 mL of absolute ethanol. Then 5% Pd/C (0.095 g, 10% by
wt) was added and the flask was evacuated and back-filled
with hydrogen three times. The system was filled with
hydrogen to a pressure of 32 psi and was vigorously shaken
for 1.5 h, at which time Celite was added and the mixture was
(25) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

(-)-Papuamine and (-)-Haliclonadiamine
J . Org. Chem., Vol. 61, No. 2, 1996 705
1422 cm-1; [R]D -139 (c ) 1.33, CHCl3). Anal. Calcd for
C10H13NO: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.44; H,
8.09; N, 8.55.
exposure to light. Alkyne 5 (0.110 g, 0.533 mmol) was added
with a cannula as a solution in THF (1 mL), and the reaction
solution was stirred for 20 min, at which time the resulting
vinylzirconium species was added with a cannula to a suspen-
sion of CuI (0.063 g, 0.640 mmol) in THF (1 mL). The original
flask and cannula were rinsed with 1 mL of THF that was
also added to the reaction mixture. The resulting mixture was
stirred at room tremperature for 2 h during which time
metallic copper could be seen plated to the sides of the reaction
flask. Water (5 mL) and ether (10 mL) were added, and the
resulting mixture was filtered through a plug of Celite and
thoroughly rinsed with ether. The filtrate was concentrated,
and the residue was partitioned between water and CH2Cl2
(7 mL). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 7 mL). The combined organic
layers were washed with brine and dried over MgSO4. Filtra-
tion and concentration gave 0.095 g (86%) of a white solid that
was purified by recrystallization from EtOAc/hexanes to give
0.063 g (57%) of a white solid: mp 188-189 °C; Rf .0.3 (1:4
EtOAc/hexanes); 1H NMR (500 MHz, CDCl3) δ 0.89-1.35 (m,
14), 1.49 (t, 2, J ) 12.8), 1.70-1.82 (m, 6), 1.99 (dd, 2, J ) 7.0,
13.3), 2.11 (dd, 2, J ) 9.4, 11.6), 3.69-3.90 (m, 8), 5.51 (m, 2),
6.02 (dd, 2, J ) 2.8, 11.7); 13C NMR (125 MHz, CDCl3) δ 26.1,
26.3, 29.9, 31.5, 42.9, 44.4, 50.5, 58.8, 64.3, 64.7, 117.5, 130.1,
132.3; IR (CHCl3) 3031, 1580, 1415, 925 cm-1; HRMS calcd
for C26H38O4 m/e 414.2770, found 414.2774.
(1R ,6S ,7S )-7-Cya n o-8-e t h yle n e d ioxyb icyclo[4.3.0]-
n on a n e (6). A flask was charged with keto nitrile 11 (0.593
g, 3.63 mmol) and benzene (30 mL). Ehtylene glycol (0.53 mL,
9.45 mmol) was added followed by p-toluenesulfonic acid
monohydrate (0.48 g, 2.50 mmol). The flask was equipped with
a Dean-Stark trap and heated to reflux with an oil bath. After
20 h the reaction mixture was allowed to cool to rt and was
diluted by the addition of ether (30 mL). The solution was
poured into 75 mL of saturated NaHCO3, and the layers were
separated. The organic layer was washed with water (50 mL)
and dried over MgSO4. Filtration and concentration gave a
thick oil that was purified by chromatography using 3:7 EtOAc/
hexanes as an eluent to give 0.65 g (87%) of a white solid: mp
1
39-40 °C; Rf 0.25 (1:15 EtOAc/hexanes); H NMR (500 MHz,
CDCl3) δ 1.02-1.08 (m, 2), 1.20-1.33 (m, 3), 1.55-1.58 (m,
1), 1.63 (dd, 1, J ) 12.6, 13.6), 1.73-1.85 (m, 3), 2.03 (m, 1),
2.06 (dd, 1, J ) 7.0, 13.6), 2.47 (d, 1, J ) 12.4), 3.88 (m, 1),
4.02 (m, 2), 4.10 (m, 1); 13C NMR (125 MHz, CDCl3) δ 25.6,
25.7, 29.6, 30.8, 42.9, 43.9, 46.3, 49.1, 65.0, 65.3, 115.2, 118.5;
IR (neat) 2260, 1290, 1175 cm-1; [R]D -19.4 (c ) 1.56, CHCl3).
Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76.
Found: C, 69.38; H, 8.19; N, 6.71.
(1R,6S,7S)-8,8-(Eth ylen ed ioxy)-7-for m ylbicyclo[4.3.0]-
n on a n e (12). A dry flask was charged with nitrile 6 (0.469
g, 2.26 mmol) and toluene (12 mL), and the solution was cooled
to -78 °C under argon. A 1.5 M solution of diisobutylalumi-
num hydride in toluene (1.81 mL, 2.72 mmol) was added
dropwise over a 15 min period, and the reaction solution was
stirred at -78 °C for 2 h. The bath was removed, and the
solution was allowed to warm to rt over 30 min. The flask
was cooled to 0 °C, MeOH (0.25 mL) was added slowly followed
by water (0.5 mL), and the mixture was vigorously stirred for
30 min. MgSO4 was added, and the mixture was stirred for
an additional 15 min and was then filtered and concentrated
to give a yellow oil. The material was purified by chromatog-
raphy using 1:1 ether/hexanes as eluent to give 0.425 g (89%)
of a white semisolid. This material was air-sensitive and was
used immediately: Rf 0.3 (1:1 Et2O/hexanes); 1H NMR (500
MHz, CDCl3) δ 1.00-1.08 (m, 2), 1.20-1.27 (m, 2), 1.38 (m,
1), 1.55 (t, 1, J ) 12.8), 1.68-1.87 (m, 5), 1.97 (dd, 1, J ) 6.3,
12.9), 2.43 (dd, 1, J ) 3.5, 11.5), 3.71 (m, 1), 3.85 (m, 2), 3.95
(m, 1), 9.58 (d, 1, J ) 3.5); 13C NMR (125 MHz, CDCl3) δ 25.9,
25.9, 30.1, 31.0, 42.9, 44.8, 45.7, 64.2, 64.7, 65.8, 117.2, 201.9;
(1R,1′R,6S,6′S,7S,7′S)-1,4-Bis(8-oxobicyclo[4.3.0]n on a n -
7-yl)bu ta -1,3-d ien e (4). A flask was charged with diene 13
(0.039 g, 0.094 mmol) and 25 mL of 10:1 acetone/water and
p-TsOH (2 mg, 0.009 mmol). The flask was equipped with a
reflux condensor and was heated at reflux for 16 h. The
solvent was removed in vacuo, and the residue was partitioned
between water and CH2Cl2 (10 mL). The layers were sepa-
rated, and the aqueous layer was extracted with CH2Cl2 (2 ×
10 mL). The combined organic layers were washed with brine
and dried over MgSO4. Filtration and concentration gave a
yellow solid that was purified by silica gel chromatography
using 1:4 EtOAc/hexanes to give 0.031 g (100%) of a white
1
solid: mp 125-126 °C; Rf 0.3 (1:4 EtOAc/hexanes); H NMR
(400 MHz, CDCl3) δ 0.84-1.45 (m, 8), 1.51-1.62 (m, 2), 1.68-
1.92 (m, 8), 1.95 (br d, 4, J ) 13.6), 2.39 (dd, 2, J ) 6.7, 18.0),
2.45 (dd, 2, J ) 7.4, 12.1), 5.47-5.56 (m, 2), 6.04-6.11 (m, 2);
13C NMR (100 MHz, CDCl3) δ 26.1, 26.3, 30.4, 31.4, 41.5, 44.6,
49.5, 59.2, 128.2, 133.1, 216.9; IR (CHCl3) 3009, 1736, 1580,
1309 cm-1; [R]D -91.7 (c ) 0.7, CHCl3).
(1R,2R)-Cycloh ex-4-en e-1,2-dim eth an ol Bis(m eth an su l-
fon a te) (17). A flask was charged with diol (-)-8 (0.949g, 6.67
mmol) and 50 mL of ether, and the solution was cooled to 0
°C. Triethylamine (2.8 mL, 20.02 mmol) was added all at once.
Freshly distilled methansulfonyl chloride (1.24 mL, 16.02
mmol) was added dropwise with a syringe over 5 min. A white
solid began to form immediately. After 30 min the bath was
removed and the mixture was allowed to warm to rt. The
mixture was allowed to stir for 24 h at which time the solvent
was removed and the residue was partitioned between water
IR (neat) 1720, 1450, 1290, 1030 cm-1
.
(1R,6S,7S)-8,8-(Eth ylen ed ioxy)-7-eth yn ylbicyclo[4.3.0]-
n on a n e (5). A flask was charged with potassium tert-butoxide
(0.87 g, 8.40 mmol) and THF (40 mL), and the mixture was
cooled to -78 °C under argon. Dimethyl (diazomethyl)-
phosphonate (1.26 g, 8.40 mmol) was added with a cannula
as a solution in 1 mL of THF, and the resulting yellow solution
was stirred for 10 min. Aldehyde 12 was added with a cannula
as a solution in 6 mL of THF. Some gas evolution could be
seen near the end of the addtion. The bath was packed with
dry ice, and the solution was stirred for 12 h, by which time
the solution had reached rt. Water (40 mL) was added
followed by CH2Cl2 (70 mL), and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (2 × 30 mL).
The combined organic layers were washed with water (50 mL)
and brine (70 mL) and were dried over MgSO4. Filtration and
concentration gave a yellow solid that was purified by chro-
matography using 1:4 EtOAc/hexanes as eluent to give 1.43 g
(95%) of a white solid: mp 54-55 °C; Rf 0.3 (1:5 Et2O/hexanes);
1H NMR (500 MHz, CDCl3) δ 0.97-1.04 (m, 2), 1.20-1.35 (m,
4), 1.57 (dd, 1, J ) 13.4, 14.5), 1.65-1.80 (m, 3), 2.00 (m, 2),
2.17 (d, 1, J ) 2.3), 2.34 (dd, 1, J ) 2.1, 11.7), 3.83 (m, 1), 3.96
(m, 1), 4.04 (m, 1), 4.11 (m, 1); 13C NMR (125 MHz, CDCl3) δ
25.9, 26.1, 29.8, 31.2, 42.6, 44.0, 47.5, 51.1, 64.6, 65.2, 71.8,
82.3, 116.1; IR (KBr) 3320, 2120, 1450, 1175 cm-1; [R]D + 34.4
(c ) 1.51, CHCl3). Anal. Calcd for C13H18O2: C, 75.69; H, 8.80.
Found: C, 75.71; H, 8.94.
and CH2
Cl2 (50 mL). The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (50 mL).The com-
bined organic layers were washed with brine and dried over
MgSO4. Filtration and concentration resulted in a thick yellow
oil that was purified by silica gel chromatography using 1:1
ethyl acetate/hexanes as eluent to give 1.918 g (96%) of a white
solid: mp 58-59 °C; Rf
MHz, CDCl3) δ 2.00 (br d, 2, J ) 13.8), 2.15 (m, 4), 3.02 (s, 6),
13C NMR (100 MHz,
0.3 (1:1 EtOAc/hexanes); 1H NMR (400
4.23 (dq, 4, J ) 4.8, 10.3), 5.63 (s, 2);
CDCl3) δ 25.8, 33.6, 37.3, 70.7, 124.7; IR (CHCl3) 3020, 1360,
1175 cm-1; [R]D -52.0 (c ) 0.825, CHCl3). Anal. Calcd for
C10H18O6S2: C, 40.25; H, 6.08. Found: C, 40.21; H, 5.93.
(1S,2S)-Cycloh ex-4-en e-1,2-d ia ceton itr ile (18). A flask
was charged with dimesylate 17 (2.15 g, 7.16 mol) and
potassium cyanide (1.77 g, 27.20 mmol). Dry DMSO (35 mL)
was added, and the flask was equipped with a reflux condensor
and was flushed with argon. The flask was heated to 95 °C
with an oil bath, and the reaction solution was allowed to stir
for 4 h. Water (40 mL) was added, and the mixture was stirred
for 10 min and then poured into a seperatory funnel and
extracted with CH2Cl2 (3 × 30 mL). The combined organic
(1R,1′R,6S,6′S,7S,7′S)-1,4-Bis(8,8-(eth ylen edioxy)bicyclo-
[4.3.0]n on a n -7-yl)bu ta -1,3-d ien e (13). A flask was charged
with Cp2Zr(H)Cl and THF (2.5 mL) and was protected from

706 J . Org. Chem., Vol. 61, No. 2, 1996
McDermott et al.
layers were washed with brine (30 mL) and dried over MgSO4.
Filtration and concentration gave a thick oil that was purified
by silica gel chromatography using ether as eluent to give 1.15
g (99%) of a fluffy white solid: mp 93-94 °C; Rf 0.3 (1:4 EtOAc/
hexanes); 1H NMR (400 MHz, CDCl3) δ 2.00-2.15 (m, 4), 2.26
(br d, 2, J ) 13.4), 2.45 (m, 4), 5.65 (d, 2, J ) 1.3); 13C NMR
(100 MHz, CDCl3) δ 21.1, 28.4, 32.7, 117.6, 124.5; IR (CHCl3)
3020, 2840, 2250, 1420 cm-1; [R]D -101 (c ) 1.10, CHCl3). Anal.
Calcd for C10H12N2: C, 74.97; H, 7.55; N, 17.48. Found: C,
74.78; H, 7.56; N, 17.48.
material showed a 20:1 mixture of diastereomers: Rf 0.35 (1:4
EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 1.27 (t, 3, J )
1
7.1), 1.87-2.06 (m, 4), 2.25-2.42 (m, 3), 2.57 (dd, 1, J ) 6.7,
6.6), 2.86 (d, 1, J ) 12.1), 4.20 (dq, 2, J ) 1.4, 7.1), 5.72 (br d,
2, J ) 1.8); 13C NMR (100 MHz, CDCl3) δ 14.2, 30.3, 31.2, 36.1,
42.6, 44.8, 61.2, 61.8, 126.2, 126.2, 126.5, 168.9, 209.8; IR (neat)
2981, 1758, 1725, 1325 cm-1; [R]D +26.5 (c ) 0.215, CHCl3).
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 68.92;
H, 7.83.
(1S,6R,7S)-Eth yl (8,8-(Eth ylen edioxy)bicyclo[4.3.0]n on -
3-en e-7-ca r boxyla te (22). A flask was charged with keto
ester 21 (1.022 g, 4.91 mmol), benzene (20 mL), ethylene glycol
(0.82 mL, 14.7 mmol), and p-toluenesulfonic acid (0.093 g,
0.491 mmol). The flask was equipped with a Dean-Stark trap
and condensor, and the solution was heated at reflux for 16
h. The solution was allowed to cool to rt, pyridine (1.5 mL)
was added, and the solution was stirred for 30 min and poured
into saturated NaHCO3 (20 mL). The layers were separated,
and the aqueous layer was extracted with ether (2 × 20 mL).
The combined organic layers were washed water (20 mL) and
brine (20 mL) and were dried over MgSO4. Filtration and
concentration gave a yellow oil that was purified by silica gel
chromatography using 1:4 EtOAc/hexanes as eluent to give
1.002 g (81%) of a colorless oil. 1H NMR analysis of the
purified material showed a 25:1 mixture of diastereomers: Rf
0.4 (1:4 EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 1.26
(t, 3, J ) 7.2), 1.56-1.72 (m, 2), 1.75-1.89 (m, 2), 2.02-2.18
(m, 2), 2.23-2.30 (m, 2), 2.63 (d, 1, J ) 11.3), 3.78-3.90 (m,
3), 4.06-4.25 (m, 3), 5.66 (br t, 2, J ) 1.7); 13C NMR (100 MHz,
CDCl3) δ 14.2, 30.6, 31.1, 37.3, 42.3, 44.9, 60.3, 60.5, 64.4, 65.3,
116.8, 126.4, 126.6, 171.1; IR (neat) 2978, 1732, 1282, 1040
cm-1; [R]D -60.2 (c ) 1.54, CHCl3). Anal. Calcd for
C14H20O4: C, 66.65; H, 7.99. Found: C, 66.96; H, 8.01.
(1S ,6R ,7R )-8,8-(E t h yle n e d ioxy)-7-(h yd r oxym e t h yl)-
bicyclo[4.3.0]n on -3-en e (23). A dry flask was charged with
LiAlH4 (0.264 g, 6.61 mmol) and ether (40 mL), and the
mixture was cooled to 0 °C under argon. Ester 22 (1.39 g, 5.51
mmol) was added with a cannula as a solution in ether (10
mL) over a 20-25 min period. The mixture was stirred at 0
°C for 1 h at which time water (0.26 mL) was added slowly
followed by 3 N NaOH (0.26 mL) and then water (0.79 mL).
The resulting mixture was stirred for 30 min as it warmed to
rt. MgSO4 was added, and stirring was continued for an
additional 10 min period. The mixture was filtered, and the
residue was thoroughly washed with ether. Concentration
gave 1.168 g (100%) of a colorless oil. This material was
usually used crude, but an analytical sample was purified by
silica gel chromatography using 2:3 EtOAc/hexanes as an
eluent: Rf 0.4 (2:3 EtOAc/hexanes); 1H NMR (400 MHz, CDCl3)
δ 1.37 (dd, 1, J ) 12.9, 11.7), 1.58-1.73 (m, 2), 1.77-1.894
(m, 2), 2.08 (dd, 1, J ) 6.3, 12.9), 2.19-2.32 (m, 2), 2.49 (dd, 1,
J ) 3.4, 8.3), 3.59-3.66 (m, 1), 3.79-4.03 (m, 6), 5.68 (s, 2);
13C NMR (100 MHz, CDCl3) δ 30.5, 31.4, 37.7, 40.3, 44.2, 55.1,
60.0, 63.7, 64.5, 117.8, 126.6, 126.8; IR (neat) 3447, 2956, 1640,
1437, 1025 cm-1; [R]D -120 (c ) 0.985, CHCl3). Anal. Calcd
for C12H18O3: C, 68.55; H, 8.63. Found: C, 68.74; H, 8.98.
(1S,6R,7R)-7-(Ben zyloxym et h yl)-8,8-(et h ylen ed ioxy)-
bicyclo[4.3.0]n on -3-en e (24). A dry flask was charged with
60% NaH in oil (0.313 g, 7.83 mmol) that was washed with
hexanes (3 × 5 mL) to remove the oil. The last of the hexanes
was removed under a stream of argon. THF (14 mL) was
added to give a gray suspension. Alcohol 23 (1.432 g, 6.81
mmol) was added with a cannula as a solution in THF (3 mL),
and the resulting gray mixture was stirred at rt for 1.5 h.
Benzyl bromide (0.97 mL, 8.17 mmol) was added with a syringe
over a 1 min period followed by the addition of solid tetrabu-
tylammonium iodide (0.025 g, 0.068 mmol). The flask was
flushed with argon, and the reaction solution was stirred for
72 h at rt. The solution was concentrated in vacuo, and the
residue was taken up in CH2Cl2, filtered through a plug of
Celite, and thoroughly washed with CH2Cl2. Concentration
(1S,2S)-Cycloh ex-4-en e-1,2-d iet h a n oic Acid (19).
A
flask was charged with dinitrile 18 (4.648 g, 29.01 mmol), 40
mL of ethylene glycol, and solid KOH (15.3 g, 232.08 mmol).
The flask was equipped with a reflux condensor and was placed
in an oil bath at 130 °C. The bath temperature was increased
to 150 °C. The mixture became clear after 30 min and was
stirred for an additional 4.5 h. The solution was allowed to
cool to rt, and water (50 mL) was added. The solution was
washed with ether (2 × 25 mL), which was discarded. The
aqueous layer was acidified with concd HCl and was extracted
with ether (3 × 75 mL). The combined organic layers were
washed with brine and dried over MgSO4. Filtration and
concentration gave 5.30 g (92%) of a pink solid. This material
could be used crude. An analytical sample was purified by
silica gel chromatography using 30:68:2 EtOAc/hexanes/HOAc
to give a white solid: mp 148-149 °C; Rf 0.29 (3:7 EtOAc/
1
hexanes); H NMR (400 MHz, CD3OD) δ 1.83 (br dquin, 2, J
) 18.0, 2.3), 2.03-2.19 (m, 2), 2.23 (br dd, 2, J ) 6.7, 10.0),
2.43 (dd, 2, J ) 5.0, 15.0), 4.93 (br s, 2), 5.59 (d, 2, J ) 1.4);
13C NMR (100 MHz, CD3OD) δ 29.6, 34.9, 39.3, 126.0, 176.8;
IR (KBr pellet) 3038, 1693, 1437, 1168 cm-1; [R]D -52.6 (c )
0.81, EtOH). Anal. Calcd for C10H14O4: C, 60.59; H, 7.12.
Found: C, 60.90; H, 7.08.
(1S,2S)-Dieth yl Cycloh ex-4-en e-1,2-d ieth a n oa te (20). A
flask was charged with diacid 19 (3.70 g, 18.72 mmol) and 70
mL of absolute ethanol. Concd H2SO4 (1.0 mL, 18.72 mmol)
was added as a solution in 5 mL of absolute ethanol. The flask
was equipped with a reflux condensor, and the reaction
solution was heated to reflux with an oil bath. After 21 h the
solution was allowed to cool to rt and was concentrated in
vacuo. The residue was partitioned between water and CH2-
Cl2 (20 mL). The layers were separated, and the aqueous layer
was extracted with CH2Cl2 (2 × 20 mL). The combined organic
layers were washed with saturated NaHCO3 (1 × 40 mL) and
brine (40 mL) and dried over MgSO4. Filtration and concen-
tration gave 4.69 g (98%) of yellow oil. This material was
generally used crude, but an analytic sample was purified by
silica gel chromatography using 1:4 EtOAc/hexanes as an
eluent: Rf 0.4 (2:3 EtOAc/hexanes); 1H NMR (400 MHz, CDCl3)
δ 1.22 (t, 6, J ) 7.2), 1.79-1.85 (m, 2), 2.00-2.05 (m, 2), 2.10-
2.25 (m, 4), 2.40 (dd, 2, J ) 5.0, 14.9), 4.11 (q, 4, J ) 7.2), 5.56
(s, 2); 13C NMR (100 MHz, CDCl3) δ 14.2, 28.4, 33.5, 38.5, 60.3,
124.9, 172.9; IR (neat) 2970, 2900, 1735, 1370 cm-1; [R]D -46.0
(c ) 0.385, CHCl3). Anal. Calcd for C14H22O4: C, 66.12; H,
8.72. Found: C, 65.84; H, 8.75.
(1S,6R,7S)-Eth yl 8-Oxobicyclo[4.3.0]n on -3-en e-7-ca r -
boxyla te (21). A dry flask was charged with 35% KH in oil
(0.178 g, 1.55 mmol) that was washed with dry hexanes (3 ×
1.5 mL) under argon to remove the oil. The last of the hexanes
was removed under a stream of argon. THF (5.5 mL) was
added, and the suspension was cooled to 0 °C. Diester 20
(0.328 g, 1.29 mmol) was added as a solution in THF (0.8 mL)
with a syringe over a 20 min period. An additional 0.2 mL
portion of THF was used to rinse the flask and syringe and
was added to the solution mixture. At the end of the addition
the solution solution was clear and light brown. The solution
was stirred at 0 °C for 15 min at which time the it was poured
into cold 1 M HCl (20 mL) and was allowed to warm to rt.
The layers were separated, and the aqueous layer was
extracted with ether (2 × 10 mL). The combined organic layers
were washed with water (10 mL) and brine (10 mL) and were
dried over MgSO4. Filtration and concentration gave 0.264 g
(98%) of colorless oil. 1H MNR analysis of the crude product
showed a single diastereomer. The material was generally
used crude but could be purified by silica gel chromatography
using 1:4 EtOAc/hexanes. 1H NMR analysis of the purified
resulted in
a yellow oil that was purified by silica gel
chromatography using 1:5 EtOAc/hexanes as eluent to give
1.815 g (89%) of a colorless oil and 0.107 g (0.509 mmol) of
recovered starting material. An analytical sample was puri-
fied by Kugelrohr distillation (150 °C at 300 mmHg): Rf 0.3

(-)-Papuamine and (-)-Haliclonadiamine
J . Org. Chem., Vol. 61, No. 2, 1996 707
1
(1:4 EtOAc/hexanes); H NMR (400 MHz, CDCl3) δ 1.36 (dq,
p a n e (27): Rf 0.35 (4% NH3-saturated MeOH/CHCl3); 1H NMR
(400 MHz, CDCl3) δ 0.97 (q, 1, J ) 7.9), 1.19-1.25 (m, 1), 1.34-
1.47 (m, 4), 1.54-1.69 (m, 4), 1.74-1.95 (m, 7), 2.16-2.23 (m,
5), 2.42-2.64 (m, 4), 2.92 (t, 1, J ) 6.8), 3.23 (q, 1, J ) 7.6),
3.44 (t, 1, J ) 7.5), 3.51-3.59 (m, 1), 3.67 (t, 1, J ) 9.0), 4.45-
4.54 (m, 4), 5.29 (br s, 4), 7.26-7.34 (m, 10); 13C NMR (100
MHz, CDCl3) δ 31.5, 31.6, 31.9, 32.1, 38.3, 39.7, 39.8, 40.6,
42.9, 44.0, 47.0, 47.3, 48.2, 53.3, 58.8, 62.5, 70.0, 73.1, 73.3,
84.1, 126.8, 126.9, 127.1, 127.3, 127.3, 127.4, 127.6, 127.7,
128.3, 128.4, 138.4, 138.7; IR (neat) 3019, 1639 (w), 1364.0,
1096.5 cm-1; [R]D -94.0 (c ) 0.615, CHCl3).
1, J ) 5.1, 11.1), 1.45 (t, 1, J ) 12.2), 1.64 (dquin, 1, J ) 5.3,
5.8), 1.72-1.80 (m, 1), 1.86-1.93 (m, 1), 2.01 (td, 1, J ) 6.6,
13.3), 2.08 (dd, 1, J ) 6.5, 13.0), 2.19-2.35 (m, 2), 3.47 (dd, 1,
6.3, 9.5), 3.61 (dd, 1, J ) 7.1, 9.5), 3.78-3.84 (m, 2), 3.87 (q, 1,
J ) 5.0), 3.95-3.97 (m, 1), 4.53 (d, 2, J ) 1.3), 5.66 (br. s, 2),
7.26-7.33 (m, 5); 13C NMR (100 MHz, CDCl3) δ 31.5, 31.5, 37.9,
44.3, 44.7, 53.8, 64.0, 65.1, 69.9, 73.1, 116.7, 126.7, 127.0, 127.3,
127.5, 128.3, 138.7; IR (neat) 3121, 1641(w), 1537, 1366, 1094
cm-1; [R]D -68.9 (c ) 2.29, CHCl3). Anal. Calcd for
C19H24O3: C, 75.97; H, 8.05. Found: C, 75.90; H, 8.14.
(1S,6R,7R)-7-(Ben zyloxym eth yl)-8-oxobicyclo[4.3.0]n on -
3-en e (25). A flask was charged with acetal 24 (1.623 g, 5.40
mmol) and 27 mL of 10:1 acetone/water. Pyridinium p-
toluenesulfonate (0.136 g, 0.54 mmol) was added, and the
solution was heated to reflux with an oil bath for 3.5 h. The
solvent was removed in vacuo, and the residue was partitioned
between water and CH2Cl2 (15 mL). The layers were sepa-
rated, and the aqueous layer was extracted with CH2Cl2 (2 ×
15 mL). The combined organic layers were washed with brine
and dried over MgSO4. Filtration and concentration gave a
thick oil that was purified by silica gel chromatography using
1:4 EtOAc/hexanes as eluent to give 1.344 g (97%) of a colorless
oil. This material solidified upon standing and was recrystal-
lized from hexanes to give a fluffy white solid: mp 52-53 °C;
Rf 0.3 (1:4 EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 1.88
(t, 2, J ) 11.8), 1.81-2.05 (m, 4), 2.36-2.55 (m, 3), 3.70 (dq, 2,
J ) 3.4, 9.6), 4.49 (dd, 2, J ) 12.2, 17.6), 5.74 (br. s, 2), 7.25-
7.35 (m, 5); 13C NMR (100 MHz, CDCl3) δ 30.9, 31.5, 36.6, 41.7,
45.2, 56.3, 67.4, 73.3, 126.7, 126.9, 127.4, 127.5, 128.3, 138.3,
216.9; IR (neat) 3023, 1744, 1436, 1092 cm-1; [R]D +51.5 (c )
0.75, CHCl3). Anal. Calcd for C17H20O2: C, 79.65; H, 7.86.
Found: C, 79.65; H, 7.88.
(1S ,1′S ,6R ,6′R ,7S ,7′S ,8R ,8′R )-N ,N ′-B i s (7-(b e n z y l-
oxym eth yl)bicyclo[4.3.0]n on -3-en -8-yl)-1,3-d ia m in op r o-
p a n e (26). A dry three-necked flask was charged with acetic
acid (8.05 mL, 140.6 mmol) and 45 mL of dichloroethane. The
flask was equipped with a stopper, a septum, and an addition
elbow containing NaBH4 (1.56 g, 41.35 mmol). The flask was
equipped with a bubbler needle, and the solution was cooled
to 0 °C. The NaBH4 was added in small portions from the
addition elbow over a period of 35 min. The mixture was
stirred at 0 °C for 15 min and rt for 15 min and was then cooled
to 0 °C. Ketone 25 (4.24 g, 16.54 mmol) was added with a
cannula as a solution in 10 mL of dichloroethane followed by
the addition of 1,3-diaminopropane (0.69 mL, 8.27 mmol) with
a syringe. The cloudy mixture was allowed to warm to rt and
was stirred for 48 h. Then 1 N HCl (50 mL) was added and
the mixture was allowed to stir for 15 min. The mixture was
treated with solid KOH until basic by pH paper, and the
mixture was extracted with CH2Cl2 (3 × 75 mL). The
combined organic layers were washed with water (75 mL) and
brine (75 mL) and were dried over K2CO3. Filtration and
evaporation gave a thick yellow oil that was purified by silica
gel chromatography using 4% NH3-saturated MeOH/CHCl3 as
eluent to give 2.68 g (58%) of a pale yellow oil. 1H NMR
analysis of this material showed a 3.4:1 mixture of diastere-
omers. The diastereomers could be partially separated by
careful chromatography but were typically carried on as a
mixture and separated at a later stage. The non-amine
products were combined and chromatographed using 1:4
EtOAc/hexanes as eluent to give 1.21 g (4.74 mmol) of ketone
25 starting material. The total yield based on recovered
starting material was 82%: Rf 0.3 (4% NH3-saturated MeOH/
CHCl3); 1H NMR (500 MHz, C6D6) δ 1.01 (dt, 2, J ) 7.6, 11.8),
134-1.51 (m, 6), 1.67 (q, 2, J ) 6.7), 1.72-1.81 (m, 4), 1.88-
1.92 (m, 2), 2.09-2.21 (m, 6), 2.53 (dq, 2, J ) 11.2, 6.5), 2.70
(dt, 2, J ) 11.1, 6, 9), 3.23 (q, 2, J ) 7.4), 3.51 (dd, 2, J ) 9.0,
4.8), 3.74 (t, 2, J ) 8.7), 4.36 (d, 2, J ) 12.0), 4.39 (d, 12.1, 2),
5.70 (br s, 4), 7.09 (t, 2, J ) 7.4), 7.19 (t, 4, J ) 7.5), 731 (d, 4,
J ) 7.5); 13C NMR (100 MHz, CDCl3) δ 30.7, 31.4, 31.9, 39.7,
40.5, 42.8, 46.9, 48.2, 58.8, 70.0, 73.2, 126.8, 127.3, 127.6, 127.7,
128.4, 138.4; IR (neat) 1639 (w), 1453, 1365, 1095 cm-1; [R]D
-138 (c ) 1.29, CH2Cl2).
(1S ,1′S ,6R ,6′R ,7S ,7′S ,8R ,8′R )-N ,N ′-B i s (7-(b e n z y l-
oxym eth yl)bicyclo[4.3.0]n on -3-en -8-yl)-N,N′-bis(ter t-bu -
t oxyca r b on yl)-1,3-d ia m in op r op a n e (28). A flask was
charged with diamine 26/27 (0.067 g, 0.121 mmol) and 1 mL
of CH2
Cl2. Di-tert-butyl dicarbonate (0.79 g, .362 mmol) was
added all at once, the flask was flushed with argon, and the
reaction solution was allowed to stir at rt overnight. Excess
ethanolamine was added, and the mixture was stirred for 30
min. The solvent was removed in vacuo, and the residue was
partitioned between water and ether (5 mL). The layers were
separated, and the aqueous layer was extracted with ether (2
× 5 mL). The combined organic layers were washed with
water (3 × 10 mL) and brine (10 mL) and dried over MgSO4.
Filtration and concentration gave a thick oil that was purified
by silica gel chromatography using 1:5 ether/hexanes as an
eluent to give 0.86 g (95%) of a colorless oil.
1H NMR and 13C
NMR analysis showed only broad signals due to the t-Boc
protecting groups: IR (neat) 2901, 1689, 1364, 1163 cm-1; [R]D
+4.1 (c ) 0.685, CHCl3). Anal. Calcd for C47H66N2O6: C,
74.77; H, 8.81; N, 3.71. Found: C, 74.67; H, 8.96; N, 3.51.
(1S ,1′S ,6R ,6′R ,7S ,7′S ,8R ,8′R )-N ,N ′-B is (7-(h y d r o x y -
m et h yl)b icyclo[4.3.0]n on a n -8-yl)-N,N′-b is(ter t-b u t oxy-
ca r bon yl)-1,3-d ia m in op r op a n e (29). A flask was charged
with benzyl ether 28 (0.547 g, 0.725 mmol), 12 mL of 95%
ethanol, and 10% palladium on carbon (0.164 g, 30% by wt).
The flask was equipped with a H2 balloon and allowed to stir
for 8 h. Celite and ether were added, and the mixture was
filtered through a plug of Celite that was thoroughly washed
with ether. The solvent was removed in vacuo, and the residue
was partitioned between water and CH2Cl2 (10 mL). The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (2 × 10 mL). The combined organic layers were
washed with brine and dried over MgSO4. Filtration and
concentration gave a white foam that was purified by silica
gel chromatography using 3:7 EtOAc/hexanes + 2% MeOH as
eluent to give 0.424 g (100%) of a white solid. 1H NMR and
13C NMR analysis showed only broad signals due to the t-Boc
protecting groups: mp 205-206.5 °C; Rf 0.3 (3:7 EtOAc/
hexanes + 2% MeOH); IR (CHCl3) 3436, 1657, 1478, 1368,
1147 cm-1; [R]D +54.4 (c ) 0.55, CHCl3). Anal. Calcd for
C33H58N2O6: C, 68.48; H, 10.10; N, 4.84. Found: C, 68.28; H,
10.12; N, 4.48.
(1S,1′S,6R,6′R,7S,7′S,8R,8′R)-N,N′-Bis(7-for m ylbicyclo-
[4.3.0]n on a n -8-yl)-N,N′-b is(ter t-b u t oxyca r b on yl)-1,3-d i-
a m in op r op a n e (30). A dry flask was charged with diol 29
(79 mg, 0.137 mmol), CH2
Cl2 (2.7 mL), 4 Å molecular sieves
(80 mg), and N-methylmorpholine N-oxide (48 mg, 0.409
mmol). Tetrapropylammonium perruthenate (TPAP) (4.8 mg,
0.014 mmol) was added all at once, the flask was flushed with
argon, and the mixture was stirred at rt for 20 min. The crude
reaction mixture was loaded directly onto a silica gel column
and was eluted with 1:4 EtOAc/hexanes to give 72 mg (92%)
of a white foam as a mixture of diastereomers. 1H NMR and
13C NMR analysis showed only broad signals due to the t-Boc
protecting groups. Because of the unstable nature of this
compound, it was used directly in the next reaction: Rf 0.4
(1:4 EtOAc/hexanes); IR (neat) 2973, 1712, 1690, 1680, 1366,
1143 cm-1; [R]D -0.93 (c ) 2.05, CHCl3).
(1S,1′S,6R,6′R,7R,7′R,8R,8′R)-N,N′-Bis(7-eth yn ylbicyclo-
[4.3.0]n on a n -8-yl)-N,N′-b is(ter t-b u t oxyca r b on yl)-1,3-d i-
a m in op r op a n e (31). A dry flask was charged with potassium
tert-butoxide (32 mg, 0.314 mmol) and THF (1 mL). The
mixture was cooled to -78 °C under argon. Dimethyl (diazo-
methyl)phosphonate (35 mg, 0.329 mmol) was added with a
cannula as a solution in 1 mL of THF. The yellow solution
(1S ,1′S ,6R ,6′R ,7S ,7′S ,8R ,8′S )-N ,N ′-B i s (7-(B e n z y l-
oxym eth yl)bicyclo[4.3.0]n on -3-en -8-yl)-1,3-d ia m in op r o-

708 J . Org. Chem., Vol. 61, No. 2, 1996
McDermott et al.
was allowed to stir for 15 min at which time a diastereomeric
mixture of dialdehyde 30 (86 mg, 0.150 mmol) was added with
a cannula as a solution in 1 mL of THF. The bath was packed
with dry ice, and the reaction solution was allowed to stir for
12 h and to slowly warm to room temperature. Water (5 mL)
was added, and the mixture was extracted with ether (3 × 7
mL). The combined organic layers were washed with brine
(7 mL) and dried over MgSO4. Filtration and concentrantion
gave a yellow oil that was purified by silica gel chromatography
using 1:3 ether/hexanes as an eluent to give 16 mg (44%) of
the unsymmetrical dialkyne 32, 11 mg (13%) of a mixture of
dialkynes, and 54 mg (64%) of the C2-symmetric dialkyne 31.
The total yield of dialkyne was 81 mg (95%). 1H NMR and
13C NMR analysis showed only broad signals due to the t-Boc
protecting groups: Rf 0.3 (1:3 Et2O/hexanes); IR (neat) 3308,
2114, 1690, 1365, 1170 cm-1; [R]D +61.2 (c ) 1.75, CHCl3).
Anal. Calcd for C35H54N2O4: C, 74.16; H, 9.60; N, 4.94.
Found: C, 74.27; H, 995; N, 4.53.
(1S,1′S,6R,6′R,7R,7′R,8R,8′S)-N,N′-Bis(7-eth yn ylbicyclo-
[4.3.0]n on a n -8-yl)-N,N′-b is(ter t-b u t oxyca r b on yl)-1,3-d i-
a m in op r op a n e (32). 1H NMR and 13C NMR analysis showed
only broad signals due to the t-Boc protecting groups: Rf 0.35
(1:3 Et2O/hexanes); IR (neat) 2973, 2112, 1690, 1365, 1170
cm-1; [R]D +39.03 (c ) 1.03, CHCl3). Anal. Calcd for
C35H54N2O4: C, 74.16; H, 9.60; N, 4.94. Found: C, 74.07; H,
9.73; N, 5.01.
(100 MHz, C6D6) δ 26.3, 26.4, 26.4, 26.6, 30.4, 30.6, 31.1, 31.9,
32.0, 39.2, 40.5, 41.9, 43.9, 44.6, 44.8, 47.2, 47.4, 50.9, 52.6,
58.3, 65.3, 69.6, 72.2, 84.3, 87.4; IR (neat) 3306, 2111, 1340,
1125 cm-1; [R]D -20.5 (c ) 1.9, CHCl3).
(1S,1′S,6R,6′R,7R,7′R,8R,8′R)-N,N′-Bis(7-((E)-2-(t r ib u -
tylsta n n yl)-vin yl)bicyclo[4.3.0]n on a n -8-yl)-1,3-d ia m in o-
p r op a n e (34). A flask was charged with dialkyne 15 (31.7
mg, 0.87 mmol) and 0.9 mL of dry toluene. The flask was
equipped with a reflux condensor and was flushed with argon.
AIBN (4.4 mg, 0.027 mmol) was added followed by freshly
distilled tributyltin hydride (0.14 mL, 0.519 mmol), and the
solution was heated from room temperature to reflux with an
oil bath over a 30 min period. After an additional 3 h period,
the reaction solution was allowed to cool to room temperature
and the toluene was removed in vacuo. The residue was
loaded onto a silica gel column, and 1:1 EtOAc/hexanes (100
mL) was flushed through to remove nonpolar materials and
then the column was eluted with 2% Et3N/EtOAc to give 74.6
mg (91%) of colorless oil: Rf 0.4 (1:4 EtOAc/hexanes on Et3N-
1
treated silica gel plates); H NMR (500 MHz, C6D6) δ 0.86-
1.30 (m, 40), 1.38-1.45 (m, 14), 1.58-1.74 (m, 22), 1.83-1.85
(m, 2), 1.96-1.98 (m, 2), 2.13-2.20 (m, 4), 2.63-2.74 (m, 4),
3.23 (q, 2, J ) 8.2), 6.10 (d, 2, J ) 19.0), 6.30 (dd, 2, J ) 8.4,
19.0);
13C NMR (125 MHz, C6D6) δ 9.9, 14.0, 26.7, 27.0, 27.7,
29.7, 30.7, 31.8, 32.4, 41.5, 44.9, 47.7, 50.0, 59.0, 60.8, 129.2,
150.8; IR (neat) 2954, 1592, 1376, 1341 cm-1; [R]D -61.8 (c )
1.86, C6H6).
(1S,1′S,6R,6′R,7R,7′R,8R,8′R)-N,N′-Bis(7-vin ylb icyclo-
[4.3.0]n on a n -8-yl)-1,3-d ia m in op r op a n e (33): Rf 0.35 (5%
(1S ,1S ,6R ,6′R ,7R ,7′R ,8R ,8′S )-N ,N ′-B is(7-((E )-2-(t r i-
bu tylsta n n yl)vin yl)bicyclo[4.3.0]n on a n -8-yl)-1,3 d ia m i-
n op r op a n e (35). A dry flask was charged with dialkyne 16
(100 mg, 0.273 mmol), toluene (2.7 mL), and AIBN (7.5 mg).
The flask was equipped with a reflux condensor and was
1
NH3-saturated MeOH/CHCl3); H NMR (400 MHz, CDCl3) δ
0.80-0.90 (m, 2), 0.95-1.35 (m, 11), 1.60-1.85 (m, 11), 2.07-
2.15 (m, 4), 2.43-2.60 (m, 4), 3.14 (dd, 2, J ) 7.2, 15.8), 4.98-
5.10 (m, 4), 5.81 (td, 2, J ) 9.8, 17.1).
(1S,1′S,6R,6′R,7R,7′R,8R,8′R)-N,N′-Bis(7-eth yn ylbicyclo-
[4.3.0]n on a n -8-yl)-1,3-d ia m in op r op a n e (15). A flask was
charged with dialkyne 31 (0.157 g, 0.277 mmol) and CH2Cl2
(1 mL). The flask was equipped with a septum, flushed with
argon, and cooled to 0 °C. Trifluoroacetic acid (1 mL) was
added dropwise with a syringe over a period of 5 min. The
solution was stirred for 2 h at 0 °C. The solvent was removed
in vacuo, and the residue was stirred with a 1:1 mixture of
CH2Cl2 and 1 M NaOH for 15 min. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL).
The combined organic layers were washed with brine (10 mL)
and were dried over K2CO3. Filtration and concentration gave
a yellow oil that was purified by silica gel chromatography
using 4% NH3-saturated MeOH/CHCl3 as eluent to give 0.096
g (94%) of a yellow oil: Rf 0.3 (4% NH3-saturated MeOH/
CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.92-1.07 (m, 8), 1.13-
1.23 (m, 6), 1.35 (qd, 2, J ) 10.7, 2.9), 1.67-1.83 (m, 8), 2.03
(dd, 2, J ) 12.4, 2.8), 2.10 (t, 2, J ) 6.7), 2.16 (d, 2, J ) 2.5),
2.35 (ddd, 2, J ) 11.7, 8.5, 2.5), 2.58-2.72 (m, 4), 3.14 (q, 2, J
) 6.7); 13C NMR (100 MHz, C6D6) δ 26.4, 26.6, 30.7, 31.4, 32.0,
40.5, 41.9, 44.6, 47.2, 50.8, 58.4, 72.2, 84.4; IR (neat) 3307,
2111, 1343, 1150 cm- 1; [R]D -71.1 (c ) 1.26, CHCl3).
flushed with argon. Freshly distilled Bu3SnH (0.44 mL, 1.64
mmol) was added, and the solution was heated from room
temperature to reflux over a period of 30 min and was heated
at reflux for 2.5 h. The reaction solution was allowed to cool
to room temperature and was loaded directly onto a silica gel
column (2.2 × 10 cm), and 200 mL of 1:1 EtOAc/hexanes was
run through to remove nonpolar materials. The column was
eluted with 1:1 EtOAc/hexanes + 2% Et3
N to give 0.192 g
(74%) of a colorless oil: Rf 0.3 (84:15:1 hexanes/EtOAc/Et3N);
1H NMR (400 MHz, C6D6) δ 0.96 (t, 9, J ) 7.3), 0.97 (t, 9, J )
7.3), 0.99-1.12 (m, 24), 1.41 (sept, 12, J ) 7.4), 1.56-1.74 (m,
21), 1.83-1.85 (m, 2), 1.97 (2.00, m, 3), 2.11 (2.12, m, 1), 2.16-
2.25 (m, 1), 2.62-2.75 (m, 4), 3.00-3.03 (m, 1), 3.18-3.22 (m,
1), 6.10-6.13 (m, 2), 6.12 (d, 1, J ) 19.0), 6.30 (dd, 1, J ) 8.4,
19.0); 13C NMR (100 MHz, C6D6) δ 9.8, 9.9, 14.0, 14.0, 26.6,
26.7, 26.8, 26.9, 27.7, 27.7, 29.6, 29.7, 30.5, 30.7, 31.7, 32.3,
32.4, 39.2, 41.4, 44.4, 44.8, 47.9, 48.0, 50.0, 51.4, 58.9, 60.8,
36.3, 64.2, 127.6, 129.2, 150.8, 153.2; IR (neat) 3302, 1594,
1376, 1072 cm-1
; [R]D -7.8 (c ) 1.6, CHCl3).
P a p u a m in e (1). A flask was charged with bis-vinylstan-
nane 34 (45.2 mg, 0.0476 mmol), DMF (4.8 mL), and PdCl2-
(PPh3)2 (3.3 mg, 0.0048 mmol) to give a clear, light yellow
solution. CuI (1.8 mg, 0.095 mmol) was added, and the
solution was stirred open to the air. The reaction solution was
dark orange within 5 min and faded to light green over a period
of 1 h. After a total of 22 h, an additional portion of PdCl2-
(PPh3)2 (3.3 mg, 0.0048 mmol) was added, causing the reaction
solution to turn from green to yellow and gradually back to
green. The solution was stirred for an additional 7 h at which
time it was loaded directly onto a silica gel column (2.2 × 8
cm) and was eluted with 200 mL of 5% NH3-saturated MeOH/
CHCl3. Concentration in vacuo gave an oily residue that was
partitioned between 1 M HCl and ether (20 mL). The layers
were separated, and the aqueous layer was extracted with
ether (20 mL). The organic layers were dried over K2CO3.
Filtration and concentration gave a yellow semisolid that was
subjected to silica gel chromatography using 1:5:94 Et3N/
EtOAc/hexanes to give 2.9 mg (0.0031 mmol) of bis-vinylstan-
nane 34. The acidic aquious layer was neutralized with solid
Na2CO3 and extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine and dried over K2CO3.
Filtration and concentration gave 6 mg (34%) of papuamine
(1) as a white solid: mp 165-167 °C; Rf 0.35 (5% NH3-
saturated MeOH/CHCl3); 1H NMR (400 MHz, CDCl3) δ 0.79-
(1S,1′S,6R,6′R,7R,7′R,8R,8′S)-N,N′-Bis(7-eth yn ylbicyclo-
[4.3.0]n on a n -8-yl)-1,3-d ia m in op r op a n e (16). A dry flask
was charged with dialkyne 32 (0.168 g, 0.296 mmol) and 1
mL of CH2Cl2, and the flask was equipped with a septum,
flushed with argon, and cooled to 0 °C. Trifluoroacetic acid (1
mL) was added dropwise with a syringe over a period of 10
min. The solution was allowed to stir at 0 °C for 2 h at which
time the solvent was removed, and the resulting oil was stirred
with a 1:1 mixture of CH2Cl2 and 1 M NaOH (10 mL) for 10
min. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL). The combined organic
layers were washed with water and brine and dried over
K2CO3. Filtration and removal of the solvent gave 107 mg of
yellow oil that was purified by silica gel chromatography using
5% NH3-saturated MeOH/CHCl3 as eluent to give 100 mg
(92%) of a colorless oil: Rf 0.3 (5% NH3-saturated MeOH/
1
CHCl3); H NMR (400 MHz, C6D6) δ 0.70-0.94 (m, 5), 0.95-
1.10 (m, 4), 1.10-1.25 (m, 2), 1.28-1.50 (m, 5), 1.52-1.70 (m,
7), 1.92 (dt, 1, J ) 12.2, 6.8), 1.99 (d, 1, J ) 2.4), 2.02 (d, 1, J
) 2.5), 2.07 (ddd, 1, J ) 10.9, 6.5, 2.4), 2.12-2.15 (m, 2), 2.20
(ddd, 1, J ) 11.2, 8.1, 2.5), 2.59-2.76 (m, 3), 2.78-2.84 (m, 1),
2.97 (q, 1, J ) 7.1), 3.28 (ddd, 1, J ) 8.8, 6.5, 2.3); 13C NMR

(-)-Papuamine and (-)-Haliclonadiamine
J . Org. Chem., Vol. 61, No. 2, 1996 709
0.92 (m, 4), 0.95-1.08 (m, 4), 1.09-1.24 (m, 6), 1.49-1.54 (m,
2), 1.67-1.73 (m, 4), 1.77-1.84 (m, 4), 2.17-2.28 (m, 6), 2.40-
2.46 (m, 2), 2.96 (br q, 2, J ) 8.0), 5.69-5.77 (m, 2), 6.06-6.13
(m, 2); 13C NMR (100 MHz, CDCl3) δ 26.4, 26.4, 30.5,
31.3, 31.7, 42.1, 43.8, 45.9, 48.8, 51.2, 61.0, 129.5, 130.8; IR
(CHCl3) 3686, 1602, 1518, 1197.4 cm-1; [R]D -346 (c ) 0.46,
MeOH).
chromatography using 10% NH3-saturated MeOH/CHCl3 as
eluent to give 2.5 mg (12%) of haliclonadiamine (2) as a light
yellow solid: mp 97-102 °C dec; Rf 0.35 (10% NH3-saturated
MeOH/CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.85-1.40 (m,
12), 1.50-1.90 (m, 14), 1.99 (td, 1, J ) 7.1, 12.1), 2.08 (ddd, 1,
J ) 4.9, 7.3, 12.1), 2.13-2.20 (m, 1), 2.39 (dt, 1, J ) 4.2, 11.0),
2.49 (dt, 1, J ) 6.1, 10.7), 2.56 (dt, 1, J ) 6.0, 9.8), 2.95 (td, 1,
J ) 6.7, 12.5), 3.15 (br q, 1, J ) 8.5), 5.30 (dd, 1, J ) 9.7, 15.2),
5.55 (dd, 1, J ) 10.2, 15.3), 6.11 (dd, 1, J ) 10.4, 15.3), 6.23
(dd, 1, J ) 10.4, 15.2); 13C NMR (100 MHz, CDCl3) δ 26.3, 26.3,
26.5, 26.7, 30.1, 30.5, 31.6, 32.2, 32.2, 37.0, 41.0, 44.0, 44.8,
47.1, 48.7, 49.6, 51.2, 51.4, 60.1, 62.6, 68.2, 132.0, 132.5, 133.9,
134.0; IR (CH2Cl2) 3685, 1606, 1247 cm-1; [R]D -5.0 (c ) 0.12,
CHCl3).
Ha liclon a d ia m in e (2). A flask was charged with bis-
vinylstannane 35 (55.2 mg, 0.058 mmol), N,N-dimethylaceta-
mide (5.8 mL), and PdCl2(PPh3)2 (4.1 mg, 0.0058 mmol) to give
a clear, yellow solution. CuI (1.3 mg, 0.012 mmol) was added,
causing the solution to turn orange. The reaction solution was
stirred for 23 h at which time an additional portion of PdCl2-
(PPh3)2 (4.1 mg, 0.0058 mmol) was added and the resulting
solution was stirred for 18 h. The reaction solution was loaded
directly onto a silica gel column (2.2 × 8 cm) and was eluted
with 200 mL of 10% NH3-saturated MeOH/CHCl3. Concentra-
tion in vacuo gave a yellow oil that was partitioned between 1
M HCl and ether (15 mL). The layers were separated, and
the aqueous layer was extracted with ether (15 mL). The
organic extracts were discarded. The aqueous layer was
neutrlized with solid Na2CO3 and was extracted with CH2Cl2
(3 × 10 mL). The combined orgainc layers were washed with
brine and dried over K2CO3. Filtration and concentration gave
Ack n ow led gm en t. We thank Professors Anthony
Barrett and Steven Weinreb for discussions regarding
the synthesis of papuamine. We are grateful to Profes-
sor J ohn Faulkner for providing samples of natural
papuamine and natural haliclonadiamine and for help-
ful discussions concerning their comparison to our
synthetic material. This research was supported by a
research grant from the National Science Foundation.
1
10 mg of a yellow solid that was shown by H NMR analysis
to be mostly product. This material was purified by silica gel
J O951647I