Total synthesis of (+)-papuamine: An antifungal pentacyclic alkaloid from a marine sponge, Haliclona sp.

Article abstract of DOI:10.1021/jo951413z

The total synthesis of (+)-papuamine, the antipode of the C₂-symmetric, optically active, pentacyclic diamine natural product, starting from a chiral diol is described. The diol is available via an asymmetric Diels-Alder reaction between 1,3-bu

Full text of DOI:10.1021/jo951413z

J . Org. Chem. 1996, 61, 685-699
685
Tota l Syn th esis of (+)-P a p u a m in e: An An tifu n ga l P en ta cyclic
Alk a loid fr om a Ma r in e Sp on ge, Ha liclon a sp .
Anthony G. M. Barrett,*,† Mark L. Boys,‡ and Terri L. Boehm†
Departments of Chemistry, Imperial College of Science, Technology and Medicine,
London SW7 2AY, England, and Colorado State University, Fort Collins Colorado 80523
Received September 7, 1995X
The total synthesis of (+)-papuamine, the antipode of the C2-symmetric, optically active, pentacyclic
diamine natural product, starting from a chiral diol is described. The diol is available via an
asymmetric Diels-Alder reaction between 1,3-butadiene and di-(-)-menthyl fumarate. The key
transformation in the synthesis is an intramolecular Pd(0)-catalyzed (Stille) coupling reaction to
form the central 13-membered diazadiene macrocyclic ring.
Sch em e 1
In tr od u ction
In 1988, Scheuer and co-workers reported the isolation
of papuamine (1) from Haliclona sp., a marine sponge,
collected at South Lion Island, Papua, New Guinea.1 The
structure was assigned as a C2-symmetric, optically
active, pentacyclic diamine from spectroscopic data al-
though the absolute configuration was not defined at that
time.1 Papuamine (1) was shown to inhibit the growth
of the dermatophyte Trichophyton mentagrophytes.1 Sub-
sequently, Faulkner and Clardy et al. reported the
isolation of both papuamine (1) and haliclonadiamine (2)
from a specimen of Haliclona collected in Palau.2 The
structure of haliclonadiamine (2), the major component,
was assigned unequivocally from a single-crystal X-ray
structure determination on the diacetamide derivative.
Again, however, the absolute stereochemistry was not
defined.2 The unique C2 symmetrical structure and
biological activity make papuamine (1) an interesting
target for total synthesis.
pane or more complex such as an electronically activated
allylic halide. Secondly, the nitrogen protecting/activat-
ing group X in dienes 4 and 5 may be extensively varied.4
Finally, the Z substituents in diene 5 can be changed to
accommodate a legion of organometallic approaches to
close the medium size ring heterocycle. All this flexibility
proved to be essential since initial approaches to close
the macrocycle were unsuccessful.
Herein we report a total synthesis of (+)-papuamine,
the antipode of the natural product.3 In planning our
approach, it is logical to disconnect the molecule at the
C2 axis to give two equivalent homochiral fragments and
thus make molecular assembly simple and convergent.
In the design, there are two distinct approaches to close
the 13-membered diamino diene unit (Scheme 1), namely,
macrocyclization, via N,N′-dialkylation, using a C3 di-
electrophile (path a) or macrocyclization via carbon-
carbon bond formation to reveal the diene entity (path
b). There is much flexibility in both of these designs. The
dielectrophile 3 may be simple such as a 1,3-dibromopro-
Resu lts a n d Discu ssion
Nitr oa lken e Ap p r oa ch . Initially, we sought to elabo-
rate papuamine using the Michael addition reaction of
substituted alkenyl organometallic reagents to the ni-
troalkene 14. Our synthesis began from the known
enantiomerically pure diol 6 which was prepared from
the Diels-Alder reaction of di-(-)-menthyl fumarate with
1,3-butadiene and subsequent lithium aluminum hydride
mediated reduction.5,6
The choice of the absolute stere-
ochemistry of the isomer 6 was completely arbitrary,
since the absolute configuration of papuamine (1) was
at that time unknown. (+)-Diol 6 was converted into the
unsaturated ketone 10 using methods largely similar to
those reported for the corresponding racemic material
† Imperial College of Science, Technology and Medicine.
‡ Colorado State University.
X Abstract published in Advance ACS Abstracts, J anuary 1, 1996.
(1) Baker, B. J .; Scheuer, P. J .; Shoolery, J . N. J . Am. Chem. Soc.
1988, 110, 965.
(4) Protecting Groups in Organic Synthesis, 2nd ed.; Greene, T. W.,
Wuts, P. G. M., Eds.; Wiley: New York, 1991.
(5) Heathcock, C. H.; Davis, B. R.; Hadley, C. R. J . Med. Chem. 1989,
32, 197.
(2) Fahy, E.; Molinski, T. F.; Harper, M. K.; Sullivan, B. W.;
Faulkner, D. J .; Parkanyi, L.; Clardy, J . Tetrahedron Lett. 1988, 29,
3427.
(3) Barrett, A. G. M.; Boys, M. L.; Boehm, T. L. J . Chem. Soc, Chem.
Commun. 1994, 1881.
(6) Furuta, K.; Iwanaga, K.; Yamamoto, H. Tetrahedron Lett. 1986,
27, 4507.
0022-3263/96/1961-0685$12.00/0 © 1996 American Chemical Society

686 J . Org. Chem., Vol. 61, No. 2, 1996
Barrett et al.
Sch em e 2
sylhydrazone 15. Following the Corey modification12 of
the Shapiro-Bond reaction,13 lithiation of the trisylhy-
drazone 15 and stannylation of the derived vinyllithium
reagent gave the vinylstannane 16. This substance, in
turn, was allowed to react with tetranitromethane12 to
give nitroalkene 14. Additionally, large quantities of the
nitroalkene 14 were prepared as the racemate starting
from racemic trans-diethyl 4-cyclohexene-1,2-dicarboxy-
late.7
Sch em e 3
With nitroalkene 14 in hand, the reaction with the
higher order vinylcuprate 1714 was investigated. When
racemic 14 was allowed to react with cuprate 17 at -78
°C in THF solution and the reaction was quenched with
acetic and hydrochloric acids,15 a mixture of diastereoi-
someric Michael adducts was formed in 62% yield (Scheme
4). Chromatography gave a single pure racemic isomer
(18) in 52% yield and a fraction containing other isomers
(10%). Attempts to determine the stereochemistry of 18
using both NOE and decoupling NMR experiments were
inconclusive, and the material was taken on further in
the synthesis. Reduction of the nitroalkane 18 under
transfer hydrogenation conditions16 gave the correspond-
ing racemic amine 19 in good yields, as long as the
reaction mixture was anhydrous. The amine 19 was
successfully converted to a number of crystalline deriva-
tives, but unfortunately none were suitable for an X-ray
structure determination, to aid in the determination of
the stereochemistry of 18.
(Scheme 2).7 Dieckmann cyclization of the diester 8 gave
the (-)-â-keto ester 9 as a mixture of epimers (R:S ) 11:
1) reflecting the thermodynamic control of the reaction.
Hydrolysis of the â-keto ester 9 and decarboxylation gave
the corresponding tetrahydroindanone 10 (92%). Sub-
sequent hydrogenation of alkene 10 to the saturated
ketone 11 was carried out using rhodium on alumina as
a catalyst to avoid any ring junction isomerization.
In principle, it should be possible to convert this ketone
11 directly into the corresponding nitroalkane 13 via
oxidation of the derived oxime using pertrifluoroacetic
acid.8 However, this method requires the use of 90%
hydrogen peroxide, which is no longer commercially
available; thus an alternative method was developed.
Ketone 11 was first converted to the oxime and then
reduced to the hydroxylamine 12 using the conditions of
Borch and co-workers.9 Subsequent condensation of
hydroxylamine 12 with 4-nitrobenzaldehyde gave an
intermediate nitrone10 which was not purified but directly
subjected to ozonolysis10b to produce the nitroalkane 13
in good yield. Phenylselenenylation of the lithium nitr-
onate derived from 13 followed by selenoxide elimination
using the conditions of Sakakibara11 gave the nitroalkene
14 (44%). In parallel, we have examined a second
synthesis of the target nitroalkene 14 (Scheme 3).
Condensation of the ketone 11 with (2,4,6-triisopropyl-
benzenesulfonyl)hydrazine gave the corresponding tri-
The enantiomerically pure amine 19 was synthesized
by the route shown in Scheme 4 starting with (-)-
nitroalkene 14. Attempts were made to convert the
amine 19 into the corresponding diene 21 using a double-
alkylation strategy. Amine 19 was first protected as its
tert-butoxycarbonyl derivative 20 and allowed to react
with 1,3-diiodopropane under basic conditions to estab-
lish the 1,3-propanediyl bridge. Unfortunately, reaction
of 20 with 1,3-diiodopropane in the presence of sodium
hydride in DMF, lithium diisopropylamide in THF, or
potassium hydride and 18-crown-6 in THF was unsuc-
cessful. Only the allylated derivative 22 could be ob-
tained in reasonable yields (Scheme 4).
Since alkylation of 20 failed, an alternative procedure
was investigated. Reaction of amine 19 with malonyl
dichloride (ca. 0.5 equiv) gave moderate yields of the
malonic amide dimer 23. Protodestannylation17 of 23
gave 24, which was a crystalline solid, and a single-
(7) (a) Krawczyk, A. R.; J ones, J . B. J . Org. Chem. 1989, 54, 1795.
(b) Mundy, B. P.; Theodore, J . J . J . Am. Chem. Soc. 1980, 102, 2005.
(c) Turecek, F.; Vystrcil, A. Collect. Czech. Chem. Commun. 1976, 41,
1571.
(8) Emmons, W. D.; Pagano, A. S. J . Am. Chem. Soc. 1955, 77, 4557.
(9) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem. Soc.
1971, 93, 2897.
(12) Corey, E. J .; Estreicher, H. Tetrahedron Lett. 1980, 21, 1113.
(13) (a) Chamberlain, A. R.; Stemke, J . E.; Bond, F. T. J . Org. Chem.
1978, 43, 147. (b) Adlington, R. M.; Barrett, A. G. M. Acc. Chem. Res.
1983, 16, 55.
(10) (a) Inouye, Y.; Watanabe, Y.; Takahashi, S.; Kakisawa, H. Bull.
Chem. Soc. J pn. 1979, 52, 3763. (b) Aebischer, B.; Vasella, A. Helv.
Chim. Acta 1983, 66, 789.
(11) Sakakibara, T.; Takai, I.; Ohara, E.; Sudoh, R. J . Chem. Soc.,
Chem. Commun. 1981, 261.
(14) Behling, J . R.; Ng, J . S.; Babiak, K. A.; Campbell, A. L.;
Elsworth, E.; Lipshutz, B. H. Tetrahedron Lett. 1989, 30, 27.
(15) Corey, E. J .; Estreicher, H. J . Am. Chem. Soc. 1978, 100, 6294.
(16) Barrett, A. G. M.; Spilling, C. D. Tetrahedron Lett. 1988, 29,
5733.

Total Synthesis of (+)-Papuamine
J . Org. Chem., Vol. 61, No. 2, 1996 687
Sch em e 4
F igu r e 1.
failure. Additionally, attempts to isomerize the nitroal-
kane 18 via double lithiation19 were also unsuccessful.
On the basis of these disappointing results, an alternative
strategy was investigated.
Th e â-Keto Ester Ap p r oa ch . The relative stereo-
chemistry at C7 in the (-)-â-keto ester 9 is predominately
(11:1) as is required for the natural product (1). It was
envisioned that the direct functionalization of the hy-
drindan ring system of ketone 9 should proceed with the
correct relative stereochemical control. Thus ketone 9
was converted into the corresponding ketal 26 by con-
densation with ethylene glycol. Fortuitously, this reac-
tion, which is subject to thermodynamic control, resulted
in an enhancement of the isomer ratio to 25:1. Sequen-
tial reduction of the ester 26, O-benzylation, and ketal
hydrolysis gave the â-benzyloxy ketone 27c. We antici-
pated that reductive amination of ketone 27c should
provide the cis amino ether.20 As anticipated, reductive
amination of 27c with benzylamine under mild condi-
tions21 gave predominately (4.5:1) the required cis-isomer
28 in 70% yield after chromatography (Scheme 5). In
order to prove the relative stereochemistry of 28, the
secondary amine was converted into the primary amine
29 by reaction with ammonium formate in the presence
of palladium on carbon.22 It is interesting to note that
this reaction proceeded with both alkene hydrogenation
and selective hydrogenolysis of the N-benzyl substituent
without loss of the benzyl ether. This chemoselectivity
is unusual and warrants further study. The amine 29
was converted to its tert-butoxycarbonyl derivative 30
under standard conditions23 (Scheme 5). The carbamate
30 was crystalline and a single-crystal X-ray study
confirmed the stereochemical assignment.18
crystal X-ray structure determination revealed the rela-
tive stereochemistry shown in Scheme 4.18 As is seen in
comparison with the natural product 1, the malonamide
24 unfortunately has the incorrect relative stereochem-
istry of the vinyl side chains (stereocenters a and a′). This
must mean that the facial selectivity in the attack of
higher order vinylcuprate 17 on nitroalkene 14 is con-
trolled by stereoelectronics rather than by steric factors
(Figure 1). Thus the vinylcuprate reagent must approach
the nitroalkene 14 along a pseudoaxial trajectory and cis
to the ring carbon rather than cis to the ring hydrogen
atom. This should produce the nitronate 25 and subse-
quently, on protonation, nitroalkane 18. Several at-
tempts were made to alter the stereochemical outcome
of the Michael addition reaction by using alternative
vinyl organometallic reagents. All met with unmitigated
With an appropriate method for obtaining the properly
substituted hydrindan ring system, a strategy was
needed for homologating the protected alcohol moiety in
carbamate 30 to intermediates suitable for an organo-
metallic coupling reaction to reveal the conjugated diene
unit of papuamine. Initially, it was decided to form the
1,3-diene unit of papuamine (1) first and to close the 13-
(19) Seebach, D.; Beck, A. K.; Mukhopadhyay, T.; Thomas, E. Helv.
Chim. Acta 1982, 65, 1101.
(20) (a) Hutchins, R. O.; Su, W.-Y. Tetrahedron Lett. 1984, 25, 695.
(b) Hutchins, R. O.; Su, W.-Y.; Sivakumar, R.; Cistone, F.; Stercho, Y.
P. J . Org. Chem. 1983, 48, 3412. (c) Wrobel, J . E.; Ganem, B.
Tetrahedron Lett. 1981, 22, 3447.
(21) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron
Lett. 1990, 31, 5595.
(22) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.
(23) Tarbell, D. S.; Yamamoto, Y.; Pope, B. M. Proc. Natl. Acad. Sci.
U.S.A. 1972, 69, 730.
(17) Davies, A. G. Tin. In Comprehensive Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Davies, A. G., Eds.;
Pergamon Press: Oxford, 1995; Vol. 2, pp 241-2.
(18) The author has deposited atomic coordinates for compounds 24
and 30 with the Cambridge Crystallographic Data Centre. The
coordinates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
U.K.

688 J . Org. Chem., Vol. 61, No. 2, 1996
Barrett et al.
Sch em e 5
to provide the corresponding pure (E)-vinyl iodide
35 (82%). Alternatively, the iodide 35 was formed
directly from the aldehyde 31b using the Takai proce-
dure.29 With the coupling partners 34 and 35 in hand,
the Stille coupling reaction was attempted. Unfortu-
nately, this reaction proved to be problematic under a
variety of conditions.24,30 The diene synthesis was at-
tempted using diverse catalysts [Pd(MeCN)2Cl2, PdCl2-
(PPh3)2, Pd(PPh3)4 or Pd2(dba)2] in THF, DMF, or NMP
in the presence or absence of additives [Ph3As, TBAF, or
(2-Fur)3P]. All of these reactions did indeed provide the
desired 1,3-diene; however, in most cases yields were low
and the required (E,E)-diene was isolated admixed with
other geometric isomers. In consequence of these unfor-
tunate facts, the approach to papuamine based upon a
late double-alkylation reaction (Scheme 1, path a) was
placed aside. Instead we then sought to close the
macrocycle using an intramolecular palladium(0)-cata-
lyzed reaction to elaborate the conjugated diene unit
(path b, Scheme 1).
Ap p r oa ch es to th e Ma cr ocycle. The carbamate 33
was converted via amine 37 into the corresponding
trifluoromethanesulfonamide 38 and doubly alkylated
using 1,3-dibromopropane31 to yield dimer 39 in moderate
yield. We sought to convert this intermediate into the
papuamine derivative 40 using an intramolecular reduc-
tive diyne coupling. We considered that hydrozirconation
and transmetalation (Zr to Cu) of the diyne 39 might
provide a means to form the macrocycle 40 via a homo-
coupling reaction.32 This reaction works effectively in an
intermolecular sense, on unfunctionalized substrates. For
example, in our hands hydrozirconation of 1-decyne with
Schwartz’s reagent32 (Cp2ZrHCl) followed by reaction
with copper(I) chloride gave (E,E)-9,11-eicosadiene (79%).
Sadly, attempts to form the macrocycle 40 utilizing this
chemistry were unsuccessful. None of the desired cy-
clization product could be detected, nor indeed could
diene of any description (Scheme 7). It was possible that
the labile trifluoromethanesulfonamido group was inter-
fering with the organometallic chemistry in this case. An
attempt was made to carry out an intramolecular acety-
lenic coupling reaction. However, reaction of diyne 39
under the Eglinton conditions33 at high dilution gave only
intractable products. A 13-membered ring containing a
conjugated diyne such as 41 would be extremely strained,
and thus very difficult to form.33
Sch em e 6
Since the direct reductive macrocyclization of diyne 39
was unsuccessful, we sought to complete the synthesis
of papuamine using a Stille reaction to construct the
diene unit. Although the preparation of the diene 36 was
complicated by poor geometric control, we considered that
the palladium-catalyzed macrocyclization reaction should
be more geometrically faithful. This optimism ultimately
proved well founded. The amine 29 was converted to the
trifluoromethanesulfonamide and toluene-4-sulfonamide
derivatives4 42a and 42b (Scheme 8). Although the
reaction between sulfonamide 42b and 1,3-dichloropro-
membered macrocycle by the addition of the three-carbon
bridge (path a, Scheme 1). This analysis led us to target
the vinylstannane 34 and vinyl iodide 35, which would
be subjected to a palladium(0)-catalyzed coupling reac-
tion24 to provide the desired 1,3-diene. Preparation of
the coupling partners 34 and 35 is shown in Scheme 6.
Deprotection of the benzyl ether 30 was effected by
hydrogenolysis over palladium on carbon. Subsequent
Swern oxidation25 of the resulting alcohol 31a to the
aldehyde 31b was followed by conversion to the terminal
alkyne 33 via the dibromide 32.26 Hydrostannylation27
gave the vinylstannane 34 as an 85:15 mixture of E and
Z isomers. Vinylstannane 34 was iododestannylated28
(28) Hanson, R. N.; El-Wakil, H. J . Org. Chem. 1987, 52, 3687.
(29) (a) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986,
108, 7408. (b) Evans, D. A.; Black, W. C. J . Am. Chem. Soc. 1992, 114,
2260.
(30) (a) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585.
(b) Hatanaka, Y. Hiyama, T. Synlett 1991, 845.
(31) Hendrickson, J . B.; Bergeron, R.; Sternbach, D. D. Tetrahedron
1975, 31, 2517.
(32) Yoshifuji, M.; Loots, M. J .; Schwartz, J . Tetrahedron Lett. 1977,
18, 1303.
(33) Advances in Organic Chemistry, Vol. 4; Eglinton, G., McCrea,
W., Eds.; Interscience: New York, 1963; pp 225-328.
(24) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813.
(25) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651. (b)
Omura, K.; Sharma, A. K.; Swern, D. J . Org. Chem. 1976, 41, 957.
(26) Corey, E. J .; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(27) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.

Total Synthesis of (+)-Papuamine
J . Org. Chem., Vol. 61, No. 2, 1996 689
Sch em e 7
resulted in the formation of a statistical mixture of
starting material 47, the desired iodostannane 48, and
regenerated diiodide 46. Both dienes 46 and 47 were
recycled. The intramolecular Stille reaction37 was at-
tempted using 48 as the substrate. Recently, this
strategy has been applied to the total synthesis of
rapamycin38 and by Pattenden and Thom for the con-
struction of polyene macrolactams.39 Reaction of the
iodostannane 48 with Pd(PPh3)4 (40 mol %) in THF
solution under high-dilution conditions provided a prod-
uct in ca. 28% yield, of which the proton NMR spectrum
was consistent with formation of the macrocyclic diene
49. High-resolution mass spectrometry confirmed that
macrocyclization had indeed taken place. Efforts to
improve the yield of this reaction, by varying the solvent,
failed. Diene 49 appeared to be a propitious compound,
but this initial optimism soon turned to dust. The
material proved to be air sensitive, and we were further
aggravated to find that deprotection of this material, to
give the desired bis-amine, failed under a variety of
conditions. At this point we decided to use a more labile
amine protecting group, namely, the trifluoromethylsul-
fonyl residue, hoping that it could be removed more easily
to reveal the desired diamine, papuamine.
Hydrogenolysis of benzyl ether 43 (Scheme 9) was
carried out under standard conditions.4 The product diol
50 was Swern oxidized,25 and the resulting dialdehyde,
which proved to be delicate and particularly prone to the
â-elimination of trifluoromethanesulfonamide, was con-
verted directly into the (E,E)-diiodide 51, again using the
Takai method.29 Reaction of diiodide 51 with excess
hexamethyldistannane in the presence of Pd(PPh3)2Cl2
and Li2CO3,36 to sequester any HI generated in the
reaction, gave the (E,E)-bis-vinylstannane 52. Again this
substance was subject to desymmetrization. Treatment
of the distannane 52 with a stoichiometric quantity of
iodine in ether28 provided iodostannane 53 in 44% yield
along with recovered starting material 52 (24%) and
regenerated diiodide 51 (24%), which were again dutifully
recycled. The syringe pump addition of a solution of the
iodostannane 53 in toluene to a solution of Pd(PPh3)4 in
toluene at 100 °C did indeed provide the desired macro-
cycle 54 in 39% yield. Deprotection of 54 to the target
diamine papuamine (55) was carried out using lithium
aluminium hydride in diethyl ether at reflux. The
diamine 55 was then converted to its dihydrochloride 56
in quantitative yield by treatment with concentrated
hydrochloric acid in aqueous methanol, and the product
salt was isolated following lyophilization.
We also considered that it should be possible to prepare
the diene 54 directly from diiodide 51. However, instead
of attempting a reductive homocoupling reaction, we
reasoned that if a stoichiometric quantity of hexameth-
ylditin was reacted with 51 in the presence of a pal-
ladium(0) catalyst, then the iodostannane generated in
situ should undergo cyclization to give the desired diene
54. It was found that slow addition of a solution of 51
and hexamethylditin in toluene to a solution of Pd(PPh3)4
in toluene at 100 °C did indeed provide the macrocycle.
Unfortunately, this material could not be readily sepa-
rated by chromatography from the generated iodostan-
pane to provide 44b was inefficient (48%) and ac-
companied by extensive elimination to produce N-allyl-
toluene-4-sulfonamide derivatives, the trifluoromethane-
sulfonamide 42a was coupled with 1,3-dibromopropane31
to produce the symmetrical dimer 43 in excellent yield.
Deprotection of the trifluoromethanesulfonyl groups was
carried out using sodium bis(methoxyethoxy)aluminum
hydride (REDAL)31 and replaced by the more robust
toluene-4-sulfonyl group4 to give 44b. The benzyl ether
residues in 44b were resistant to standard hydrogenoly-
sis conditions4 but were cleaved using W-2 Raney nickel
under a hydrogen atmosphere.4 The resulting diol 45a
was Swern oxidized25 and the product dialdehyde 45b
converted into the diiodide 46 using the Takai method.29
Attempted macrocyclization via lithium-halogen ex-
change with n-butyllithium at low temperature followed
by the addition of a stoichiometric quantity of Pd(PPh3)2-
Cl2 was unsuccessful. Macrocyclization of 46 was also
attempted using nickel(0) complexes [Ni(COD)2 and Ni-
(PPh3)4],34 but these reactions also failed.
It is known from the work of Danilova et al. that 1,3-
dienes can be prepared from the palladium(0)-catalyzed
homocoupling of vinylstannanes.35 Thus we sought to
examine whether such a process would elaborate the
required macrocycle. Reaction of diiodide 46 with excess
of hexamethyldistannane in the presence of Pd(PPh3)2-
Cl2 gave the bis-stannane 47.36 Unfortunately, all at-
tempts to convert 47 into the macrocycle 49 by the
elimination of hexamethyldistannane were unsuccessful.
At this point we realized that we were obliged to run the
gauntlet of desymmetrization. Reaction of the bis-
stannane 47 with a stoichiometric quantity of iodine28
(34) (a) Takagi, K.; Hayama, N.; Sasaki, K. Bull. Chem. Soc. J pn.
1984, 57, 1887. (b) Takagi, K.; Mimura, H.; Inokawa, S. Bull. Chem.
Soc. J pn. 1984, 57, 3517. (c) Semmelhack, M. F.; Helquist, P.; J ones,
L. D.; Keller, L.; Mendelson, L.; Ryono, L. S.; Smith, J . G.; Stauffer,
R. D. J . Am. Chem. Soc. 1981, 103, 6460.
(35) Tolstikov, G. A.; Miftakhov, M. S.; Danilova, N. A.; Vel’der, Y.
L.; Spirikhin, L. V. Synthesis 1989, 633.
(37) (a) Stille, J . K.; Tanaka, M. J . Am. Chem. Soc. 1987, 109, 3785.
(b) Kalivretenos, A.; Stille, J . K.; Hegedus, L. S. J . Org. Chem. 1991,
56, 2883.
(36) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J .
Org. Chem. 1986, 51, 277.
(38) Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa,
N.; Bertinato, P. J . Am. Chem. Soc. 1993, 115, 4419.
(39) Pattenden, G.; Thom, S. M. Synlett 1993, 215.

690 J . Org. Chem., Vol. 61, No. 2, 1996
Barrett et al.
Sch em e 8
Sch em e 9
nane 53. The desired macrocycle 54 could, however, be
isolated in pure form (14% yield), if an additional portion
of catalyst was added to the mixture after the addition
of diiodide 51 and the hexamethylditin solution was
complete.
both (-)-papuamine and (-)-haliclonadiamine.41 Inter-
estingly, both these authors reported that palladium(0)-
catalyzed macrocyclization of bis-stannane 57 to provide
papuamine (1) was only successful when no secondary
amine protecting group (X ) H) was used!!! Weinreb also
commented on difficulties in handling papuamine free
base. We have observed exactly the same behavior,
which is possibly due to formation of a bicarbonate salt,
and recommend that papuamine is best handled as its
dihydrochloride.
Our synthetic (+)-papuamine 55 and its dihydro-
chloride 56 showed spectral characteristics (1H NMR,
13C NMR, HRMS, and IR) that were identical with
those reported for the natural material. Additionally,
our synthetic sample of the dihydrochloride 56 was
identical with an authentic sample. Synthetic papua-
mine dihydrochloride 56 exhibited an optical rotation
{[R]D +139° (c ) 0.34, MeOH)} which corresponds
exactly, albeit antipodally, with the natural product
{[R]D -140° (c ) 1.3, MeOH)}1 and UV λmax ) 236 nm
(MeOH) {lit.1 UV λmax ) 241 nm (MeOH)}. Shortly
after our preliminary publication,3 Weinreb and co-
workers reported the total synthesis of (-)-papuamine
dihydrochloride.40 Additionally, Heathcock and co-
workers have also described the total synthesis of
It is clear from our results and those from both the
Weinreb and Heathcock groups that palladium(0)-
catalyzed macrocyclization is a viable strategy for the
synthesis of the structurally unusual natural product
papuamine and its antipode.
(40) Borzilleri, R. M.; Weinreb, S. M. J . Am. Chem. Soc. 1994, 116,
9789. Borzilleri, R. M.; Weinreb, S. M.; Parvez, M. J . Am. Chem. Soc.
1995, 117, 10905.
(41) McDermott, T. S.; Mortlock, A.; Heathcock, C. H. J . Org. Chem.
1996, 61, 700.

Total Synthesis of (+)-Papuamine
Exp er im en ta l Section
J . Org. Chem., Vol. 61, No. 2, 1996 691
A solution of 8 (32.0 g, 126 mmol) in dry THF (50 mL) was
added dropwise to the refluxing mixture. After refluxing for
2.5 h, the reaction was complete by TLC (hexane:EtOAc 4:1).
The mixture was allowed to cool, and glacial AcOH (8.6 mL,
150 mmol) was added. To the resulting gelatinous mixture
were added H2O (200 mL) and Et2O (100 mL), the phases were
separated, and the aqueous phase was extracted with Et2O (3
× 50 mL). The combined organic phases were washed with
H2O (3 × 50 mL), aqueous NaHCO3 (50 mL), and brine (50
mL) and dried (MgSO4). Rotary evaporation gave the crude
product as a yellow oil which was chromatographed (hexane:
EtOAc 4:1) to give 9 (25.2 g, 96%) as a colorless oil: TLC Rf )
0.21 (hexane:Et2O 4:1); [R]D ) -24.1° (c ) 1.62, CHCl3); IR
(neat) 2906, 1756, 1724, 1372, 1270, 1132, 1052, 1025, 668,
Gen er a l P r oced u r es. Solvents were dried by distillation
under N2 or Ar, from sodium benzophenone ketyl (THF, Et2O,
PhH, PhMe), CaH2 (CH2Cl2, MeCN, DMF, Et3N, pyridine),
KOH (i-Pr2NH), and Mg and I2 (MeOH). Raney Ni (type W-2)
was purchased from the Aldrich Chemical Co. and was used
immediately after opening in order to be effective. All other
reagents were used as received unless otherwise stated. All
reactions were performed in oven-dried (110 °C) glassware
under N2 or Ar unless otherwise mentioned. Mass spectra and
high-resolution mass spectra were obtained from the North-
western University Analytical Services Laboratory and Impe-
rial College Analytical Services. Combustion analyses were
performed by G.D. Searle & Co., Skokie, IL, or Imperial
College, London, U.K. Unless stated to the contrary, all TLC
was carried out on E. Merck precoated silica gel 60 F254 plates.
Plates were visualized using UV radiation (254 nm) or with
KMnO4 reagent. Unless stated to the contrary, chromatog-
raphy refers to flash chromatography on E. Merck silica gel
60, 230-400 mesh ASTM. Racemic ketone 11 was prepared
from diethyl fumarate following the methods described else-
where.7 Samples of racemic intermediates including those
corresponding to 7, 8, 9, and 10 showed characteristics which
were identical with the spectroscopic data reported for the pure
enantiomers below.
456 cm-1 1H NMR (300 MHz, CDCl3) δ 5.76-5.65 (m, 2H),
;
4.20 (q, J ) 7.1 Hz, 2H), 2.86 (d, J ) 11.6 Hz, 1H), 2.57 (dd,
J ) 16.7, 6.4 Hz, 1H), 2.47-2.19 (m, 3H), 2.08-1.80 (m, 4H),
1.25 (t, J )7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 210.0,
169.0, 126.6, 126.3, 61.9, 61.3, 44.9, 42.7, 36.2, 31.3, 30.4, 14.2.
(1R,6R)-Bicyclo[4.3.0]-3-n on en -8-on e (10). A solution of
9 (25.0 g, 120 mmol) in DMSO (100 mL) and H2O (5 mL) under
Ar was heated at 155 °C for 2.5 h. The mixture was allowed
to cool, added to H2O (250 mL), and extracted with Et2O (3 ×
100 mL). The combined extracts were washed with H2O (3 ×
100 mL), dried (MgSO4), and evaporated to give a solid. This
material was purified by chromatography (hexane:Et2O 4:1)
to give 10 (15.1 g, 92%) as a white solid: TLC Rf ) 0.25
(1R,2R)-4,5-Bis(cya n om eth yl)cycloh exen e (7).7a The
bis(toluene-4-sulfonate) and dinitrile 7 were prepared as
described in the literature for racemic material.7a (1S,2S)-
Cyclohex-4-ene-1,2-dimethanol5 ((+)-6) (34.4 g, 0.242 mol) gave
the disulfonate (91.4 g, 84%) as white crystals: mp 110-111
°C (MeOH); TLC Rf ) 0.25 (hexanes:EtOAc 5:1); [R]D ) +43.4°
(c ) 1.52, CHCl3); IR (neat) 2904, 1598, 1358, 1176, 1097, 940,
814, 666, 554 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.75 (d, J )
8.5 Hz, 4H), 7.35 (d, J ) 8.5 Hz, 4H), 5.51 (s, 2H), 4.00-3.90
(m, 4H), 2.47 (s, 6H), 2.02-1.97 (m, 4H), 1.88-1.82 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 144.9, 132.7, 129.8, 127.9, 124.6,
71.2, 33.0, 25.4, 21.6. (1S,2S)-4,5-Bis[(toluene-4-sulfonyloxy)-
methyl]cyclohexene (91.0 g, 0.202 mol) gave 7 (30.7 g, 95%)
as a cream-colored solid: mp 97-99 °C (not recrystallized);
TLC Rf ) 0.23 (hexanes:EtOAc 5:1); [R]D ) +111° (c ) 1.40,
CHCl3); IR (neat) 3042, 2968, 2919, 2908, 2887, 2843, 2246,
1656, 1448, 1427, 1376, 1339, 1312, 1166, 1102, 993, 909, 872,
852, 732, 665 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.68 (s, 2H),
1
(hexane:Et2O 4:1); [R]D ) -122° (c ) 1.78, CHCl3); H NMR
(400 MHz, CDCl3) δ 5.80-5.70 (m, 2H), 2.55-2.30 (m, 4H),
2.00-1.80 (m, 6H); 13C NMR (70 MHz, CDCl3) δ 217.4, 126.5,
45.0, 38.5, 31.2.
(1R,6R)-Bicyclo[4.3.0]n on a n -8-on e (11). A solution of 10
(15.0 g, 110 mmol) in absolute EtOH (150 mL) was stirred with
rhodium on alumina (5%, 1.4 g) under a H2 atmosphere for 3
h. The mixture was filtered (Celite), washing with EtOH.
Rotary evaporation and then distillation gave 11 (13.5 g, 89%)
as a colorless oil: bp 95 °C at 20 mmHg; [R]D ) -308° (c )
1.54, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.32 (dd, J ) 17.0,
5.7 Hz, 2H), 2.00-1.91 (m, 2H), 1.90-1.75 (m, 4H), 1.62-1.50
(m, 2H), 1.42-1.30 (m, 2H), 1.28-1.11(m, 2H); 13C NMR (75
MHz, CDCl3) δ 218.3, 46.0, 44.4, 31.8, 26.7.
(1R,6R)-8-(Hyd r oxyla m in o)bicyclo[4.3.0]n on a n e (12).
To a solution of 11 (5.00 g, 36.2 mmol) in EtOH (100 mL) and
H2O (30 mL) were added NH2OH‚HCl (2.51 g, 36.2 mmol) and
KOH (2.24 g, 40.0 mmol). The mixture was stirred at room
temperature for 4 h, added to H2O (500 mL), and extracted
with Et2O (3 × 300 mL). The combined extracts were washed
with H2O (3 × 300 mL), dried (MgSO4), and rotary evaporated
to give the crude oxime (5.41 g, 98%) as a white solid which
was used directly in the next step without purification: TLC
Rf ) 0.09 (hexane:Et2O 4:1); [R]D ) -97.6° (c ) 1.20, CHCl3);
IR (neat) 3247, 2926, 2850, 933, 751 cm-1; 1H NMR (300 MHz,
CDCl3) δ 9.25 (br, s, 1H), 2.75 (dd, J ) 17.4, 6.3 Hz, 1H), 2.47
(dd, J ) 15.5, 5.3 Hz, 1H), 2.00-1.65 (m, 6H), 1.35-0.95 (m,
6H); 13C NMR (75 MHz, CDCl3) δ 165.2, 44.9, 44.3, 37.1, 33.7,
31.3, 31.2, 26.2, 26.1.
2.51-2.45 (m, 4H), 2.31-2.25 (m, 2H), 2.18-2.02 (m, 4H); 13
NMR (75 MHz, CDCl3) δ 124.4, 117.7, 32.7, 28.3, 21.0.
C
(1R,2R)-Dieth yl 4-Cycloh exen e-1,2-d ia ceta te (8).7c Di-
ester 8 was prepared using a combination of literature
procedures for racemic material.7a,c A solution of 7 (9.00 g,
56.2 mmol) and aqueous KOH (6 N, 60 mL) were heated at
reflux with stirring for 24 h. The resulting solution was cooled
to 0 °C (ice bath), and aqueous orthophosphoric acid (85%, 60
mL) was added dropwise with stirring. The resulting solid
was collected by filtration, washed with warm H2O, and dried
under vacuum to give impure diacid (10.60 g, 95%): 1H NMR
(300 MHz, DMSO-d6) δ 12.08 (br, s, 2H), 5.57 (s, 2H), 2.40-
2.23 (m, 2H), 2.20-2.00 (m, 4H), 1.98-1.83 (m, 2H), 1.82-
1.65 (m, 2H). The crude diacid was taken up as a suspension
in absolute EtOH (200 mL) and stirred with the addition of
H2SO4 (98%, 5 mL). After 48 h the EtOH was removed under
vacuum to ca. 50 mL, and the mixture was added to H2O (200
mL) and extracted with Et2O (3 × 150 mL). The extracts were
combined, washed with H2O (3 × 50 mL) and aqueous NaHCO3
(50 mL), and dried (MgSO4). Evaporation and chromatography
of the residue (hexane:Et2O 2:1) gave 8 (11.06 g, 82%) as a
colorless oil: TLC Rf ) 0.28 (hexane:Et2O 4:1); [R]D ) +49.3°
(c ) 1.52, CHCl3); IR (neat) 3026, 2981, 2906, 1734, 1446, 1373,
1346, 1264, 1155, 1096, 1029, 935, 864, 664, 457 cm-1; 1H NMR
(200 MHz, CDCl3) δ 5.57 (s, 2H), 4.10 (q, J ) 6.7 Hz, 4H), 2.39
(dd, J ) 13.9, 5.6 Hz, 2H), 2.29-1.97 (m, 6H), 1.89-1.72 (m,
2H), 1.22 (t, J ) 6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
172.9, 124.9, 60.3, 38.5, 33.6, 28.4, 14.2.
To a solution of the crude oxime (5.41 g, 35.5 mmol) in
MeOH (70 mL) was added methyl orange indicator (several
crystals). NaBH3CN (2.50 g, 39.8 mmol) was added portion-
wise, with simultaneous addition of hydrochloric acid (37%)
to maintain ca. pH 3 (indicator red). After stirring for 30 min,
MeOH was removed by rotary evaporation. The residue was
taken up in H2O (100 mL), basified to pH > 10 with aqueous
KOH (6N), and extracted with CH2Cl2 (4 × 100 mL). The
extracts were combined and dried (MgSO4), and the solution
was rotary evaporated to give 12 (5.33 g, 97%) as a white
solid: mp 109-110 °C (not recrystallized); TLC Rf ) 0.03
(hexane:Et2O 1:1); [R]D ) -43° (c ) 0.10, CHCl3); IR (neat)
1
3258, 3155, 2921, 2852, 2361, 1508, 1438, 467, 455 cm-1; H
NMR (300 MHz, CDCl3) δ 5.45 (br, s, 2H), 3.57-3.50 (m, 1H),
2.10-1.99 (m, 1H), 1.85-1.65 (m, 5H), 1.35-0.85 (m, 8H); 13C
NMR (70 MHz, CDCl3) δ 60.7, 45.7, 44.0, 36.5, 36.4, 31.6, 31.5,
26.3. Anal. Calcd for C9H17NO: C, 69.63; H, 11.04; N, 9.02.
Found: C, 69.52; H, 10.90; N, 9.00.
(1R,6S,7R)-7-(Eth oxyca r bon yl)bicyclo[4.3.0]n on -3-en -
8-on e (9). NaH (60% dispersion in mineral oil, 5.54 g, 139
mmol) was washed with dry hexane (2 × 15 mL) under Ar.
Dry THF (80 mL) was added and the mixture heated to reflux.
(1R,6R)-8-Nitr obicyclo[4.3.0]n on a n e (13). A solution of
12 (5.33 g, 34.3 mmol) and 4-nitrobenzaldehyde (5.19 g, 34.3

692 J . Org. Chem., Vol. 61, No. 2, 1996
Barrett et al.
mmol) in CHCl3 (75 mL) with CaCl2 (1.2 g) and 3 Å molecular
sieves (40 g) were heated at reflux under N2 for 18 h. EtOH
(30 mL) was added and the mixture filtered (Celite). Evapora-
tion of solvent gave impure nitrone: TLC Rf ) 0.35 (hexane:
Et2O 1:1); 1H NMR (270 MHz, CDCl3:CD3OD 3:1, TMS) δ 8.40,
8.25 (AB, J AB ) 9 Hz, 4H), 7.68 (s, 1H), 4.65-4.52 (m, 1H),
THF (THF) (100 mL) at -78 °C under N2 was added sec-BuLi
(39.6 mmol, 1.3 M solution in cyclohexane) dropwise, main-
taining an internal temperature of e -70 °C. The exact
volume of sec-BuLi added was judged from the end point color
change, colorless to yellow, for monoanion formation.13b The
resulting orange solution was stirred at -78 °C for 1 h, allowed
to warm to -5 °C until evolution of N2 had ceased (ca. 10 min),
and recooled to -78 °C. A solution of Me3SnCl (9.86 g, 49.5
mmol) in dry THF (30 mL) was added slowly via cannula
(maintaining an internal temperature of e -65 °C). The
mixture was allowed up to warm to room temperature and
solvent removed under vacuum. The residue was partitioned
between H2O (50 mL) and hexanes (50 mL). The organic layer
was separated, dried (MgSO4), and filtered through a plug of
silica, washing with hexanes. Removal of solvent gave (()-
16 (3.99 g, 71%) as a colorless oil: TLC Rf ) 0.62 (hexane); IR
(neat) 2978, 2922, 2852, 2826, 1445, 816, 766, 710, 527, 511
cm-1; 1H NMR (400 MHz, CDCl3) δ 5.98 (d, J ) 1.1 Hz, 3J Sn-H
) 41.9 Hz, 1H), 2.39 (dd, J ) 13.6, 5.7 Hz, 1H), 2.10-1.70 (m,
2.35-2.20 (m, 2H), 2.00-1.50 (m, 7H), 1.40-0.85 (m, 5H); 13
C
NMR (70 MHz, CDCl3:CD3OD 3:1) δ 147.5, 136.1, 131.5, 128.8,
123.5, 75.0, 45.9, 45.1, 37.8, 37.7, 31.0, 30.8, 26.0, 25.9.
The crude nitrone was taken up in MeOH (250 mL) and
CH2Cl2 (250 mL) and cooled to -78 °C. Ozone was passed
into the solution with stirring, until the color had changed from
yellow through green to blue (no nitrone remaining by TLC).
Me2S (3.8 mL) was added, and the solution was allowed to
warm to room temperature. The solution was rotary evapo-
rated, and the residue was dissolved in Et2O (150 mL). The
solution was washed with H2O (3 × 50 mL) and dried (MgSO4)
and the solvent evaporated. Chromatography of the residue
(hexane:Et2O 4:1) gave 13 (4.74 g, 82%) as a colorless oil: TLC
Rf ) 0.60 (hexane:Et2O 4:1); [R]D ) +22.9° (c ) 1.40, CHCl3);
IR (neat) 2926, 2853, 1548, 1445, 1376, 1362, 1349, 1312, 848
cm-1; 1H NMR (300 MHz, CDCl3) δ 4.95-4.82 (m, 1H), 2.51-
2.32 (m, 2H), 1.97-1.68 (m, 5H), 1.63-1.40 (m, 2H), 1.30-
0.90 (m, 5H); 13C NMR (70 MHz, CDCl3) δ 84.4, 45.8, 44.3,
2
5H), 1.42-1.05 (m, 6H), 0.11 (s, J Sn-H ) 53.6 Hz, 9H); 13C
NMR (75 MHz, CDCl3) δ 146.7, 144.5, 53.0, 50.6, 43.2, 30.7,
30.5, 27.1, 26.8, -10.2 (3C). Owing to stability problems it
was not possible to obtain a microanalytically pure sample of
16, and material was carried on to the next step without
further attempts at purification.
38.8, 38.2, 31.0, 30.9, 26.00, 25.95. Anal. Calcd for C9H15
-
NO2: C, 63.88; H, 8.93; N, 8.28. Found: C, 63.94; H, 9.02; N,
8.18.
(()-tr a n s-8-Nitr obicyclo[4.3.0]n on -7-en e (14). To a so-
lution of (()-16 (2.00 g, 7.02 mmol) in dry DMSO (7.5 mL)
and HMPA (7.5 mL) at 0 °C were added C(NO2)4 (0.92 mL,
7.7 mmol) and AcOH (0.44 mL, 7.7 mmol). The mixture was
stirred under Ar in the dark at 0 °C for 6 h, poured into H2O
(100 mL), and extracted with hexane:Et2O (1:1, 3 × 50 mL).
The combined extracts were washed with H2O (6 × 30 mL),
dried (MgSO4), and filtered through a pad of silica, washing
with hexane:Et2O (20:1). After removing solvent, the residue
was chromatographed (hexane:Et2O 20:1) to give (()-14 (442
mg, 38%) as a pale yellow solid spectroscopically and chro-
matographically identical with the previously prepared mate-
rial. On a scale of 100 mg, a 44% yield of (()-14 was obtained.
(1R,6S,7R,8S)-7-((E)-1-(Tr i-n -bu tylsta n n yl)eth en -2-yl)-
8-n itr obicyclo[4.3.0]n on a n e (18). To dry thiophene (144 µL,
1.79 mmol) in dry THF (4 mL) at 0 °C under N2 was added
n-BuLi (1.88 mmol, 2.5 M in hexanes). The mixture was
stirred at 0 °C for 30 min, cooled to -78 °C, and added via
cannula to a suspension of copper(I) cyanide (161 mg, 1.79
mmol) at -78 °C in THF (1 mL). The suspension was allowed
to warm to near 0 °C until a beige solution formed and then
recooled to -78 °C. To a solution of (E)-bis(tri-n-butylstannyl)-
ethylene43 (1.09 g, 1.79 mmol) in dry THF (6 mL) at -78 °C
under N2 was added n-BuLi (1.88 mmol, 2.5 M in hexanes)
dropwise over 10 min. The mixture was stirred at -78 °C for
1 h and transferred, via cannula, into the lithium (2-thienyl)-
cyanocopper solution. After 30 min at -78 °C, a solution of
14 (200 mg, 1.20 mmol) in THF (2 mL) was added via cannula,
and the mixture was stirred for 1.5 h. A mixture of AcOH
and hydrochloric acid (0.1 N) (1:2, 6 mL) was added, and the
mixture was allowed to warm up to room temperature and
stirred for 1 h. H2O (40 mL) was added and the mixture
extracted with Et2O (3 × 30 mL). The combined extracts were
washed with H2O (3 × 30 mL) and aqueous NaHCO3 (30 mL),
dried (MgSO4), and concentrated under vacuum. Chromatog-
raphy (hexane:Et2O 40:1) gave the major product 18 (302 mg,
52%) as a colorless oil containing a single diastereoisomer:
TLC Rf ) 0.57 (hexane:Et2O 20:1); [R]D ) +70.7° (c ) 1.05,
CHCl3); IR (neat) 2956, 2926, 1549, 1374, 1362 cm-1; 1H NMR
(300 MHz, CDCl3) δ 5.95 (d, J ) 19.0 Hz, 1H), 5.75 (dd, J )
19.0, 7.8 Hz, 1H), 4.79 (ddd, J ) 8.1, 7.5, 2.1 Hz, 1H), 3.16
(ddd, J ) 7.6, 7.5, 2.1 Hz, 1H), 2.47 (ddd, J ) 13.2, 8.1, 6.5
Hz, 1H), 1.90-0.75 (m, 38H); 13C NMR (70 MHz, CDCl3) δ
145.2, 131.1, 90.0, 55.8, 48.2, 42.5, 38.5, 31.6, 29.2, 28.0, 27.0,
26.0, 25.9, 13.9, 9.9. Anal. Calcd for C23H43NO2Sn: C, 57.04;
H, 8.95; N, 2.89. Found: C, 57.14; H, 9.09; N, 2.85. Also
isolated was a second fraction (58 mg, 10%) as a colorless oil
(1R,6S)-8-Nitr obicyclo[4.3.0]n on -7-en e (14). To a solu-
tion of 13 (2.00g, 11.8 mmol) in dry THF (40 mL) under N2 at
-78 °C was added n-BuLi (23.6 mmol, 2.5 M in hexanes), and
the mixture was stirred at -78 °C for 45 min. A solution of
PhSeBr (5.85 g, 24.5 mmol) in dry THF (30 mL) was added
via cannula and the mixture allowed to reach 0 °C (ice bath).
After 30 min, hydrogen peroxide (30%, 6.5 mL) was added
slowly. After 20 min, the mixture was added to H2O (200 mL)
and extracted with pentane (3 × 50 mL). The combined
extracts were washed with H2O (3 × 50 mL) and brine (50
mL), dried (MgSO4), and rotary evaporated. The residue was
chromatographed (hexane:Et2O 40:1) to give 14 (864 mg, 44%)
as a pale green solid: TLC Rf ) 0.25 (hexane:Et2O 20:1); [R]D
) -159° (c ) 1.30, CHCl3); IR (neat) 2934, 2857, 1608, 1506,
1448, 1374, 1356, 1316, 1289, 1230, 1224, 1078, 1022, 911, 893,
876, 780, 758, 726, 560 cm-1; 1H NMR (270 MHz, CDCl3, TMS)
δ 6.99 (s, 1H), 2.81 (dd, J ) 15.1, 6.9 Hz, 1H), 2.48 (m, 1H),
2.33-2.17 (br, m, 1H), 2.13-1.98 (m, 1H), 1.90-1.77(m, 4H),
1.42-1.27 (m, 4H); 13C NMR (70 MHz, CDCl3) δ 153.6, 141.8,
50.4, 48.7, 35.1, 29.6, 29.4, 26.3, 26.1. Due to stability
problems it was not possible to obtain a microanalytically pure
sample of 14, and the material was carried on to the next step
without further attempts at purification.
(()-tr a n s-Bicyclo[4.3.0]n on a n -8-on e (2,4,6-Tr iisop r o-
p ylben zen esu lfon yl)h yd r a zon e (15). (2,4,6-Triisopropyl-
benzenesulfonyl)hydrazine42 (7.93 g, 26.2 mmol) was dissolved
in MeOH (50 mL) and THF (10 mL) under N2. A solution of
11 (3.50 g, 25.3 mmol) in MeOH (20 mL) was added and the
mixture stirred for 4 h. To the resulting white suspension was
added H2O (20 mL) dropwise, with cooling to 0 °C. The solid
was collected by filtration and recrystallized from MeOH:THF:
H2O to give 15 (8.55 g, 81%) as white crystals: mp 210 °C
dec; IR (CHCl3) 3400, 3000, 1700, 1650, 1600, 1500, 1400, 1350,
1
1180, 1150, 1050, 950, 600 cm-1; H NMR (400 MHz, CDCl3)
δ 7.17 (s, 2H), 6.99 (s, 1H), 4.23 (septet, J ) 6.8 Hz, 2H), 2.90
(septet, J ) 6.8 Hz, 1H), 2.45 (dd, J ) 17.0, 5.7 Hz, 1H), 2.39
(dd, J ) 17.0, 5.7 Hz, 1H), 2.20-1.85 (m, 3H), 1.80-1.55 (m,
3H), 1.26 (2d, J ) 6.8 Hz, 18H), 1.40-1.00 (m, 6H); 13C NMR
(100 MHz, CDCl3) δ 164.0, 153.1, 151.2 (2C), 131.8, 123.7 (2C),
44.5, 44.4, 39.8, 34.1, 31.2, 31.1, 29.9 (2C), 26.0, 25.9, 24.77
(2C), 24.75 (2C), 23.5 (2C); MS(EI) m/e 419 (M + H+), 355,
340, 283, 282, 267, 252, 203, 152, 138, 93, 80. Anal. Calcd
for C24H38N2O2S: C, 68.86; H, 9.15; N, 6.69. Found: C,
68.50: H, 9.08; N, 6.67.
(()-t r a n s-8-(Tr im e t h ylst a n n yl)b icyclo[4.3.0]n on -7-
en e (16). To a solution of (()-15 (8.30 g, 19.8 mmol) in dry
(43) (a) Corey, E. J .; Wollenberg, R. H. J . Am. Chem. Soc. 1974, 96,
5581. (b) Bottaro, J . C.; Hanson, R. N.; Seitz, D. E. J . Org. Chem. 1981,
46, 5221.
(42) Cusack, N. J .; Reese, C. B.; Risius, A. C.; Roozpeikar, B.
Tetrahedron 1976, 32, 2157.

Total Synthesis of (+)-Papuamine
J . Org. Chem., Vol. 61, No. 2, 1996 693
containing a minor diastereoisomer of 18 and the product of
protodestannylation of 18: TLC Rf ) 0.29 (hexanes:Et2O 20:
NMR (300 MHz, CDCl3) δ 6.80 (d, J ) 8.9 Hz, 2H), 5.85 (d, J
) 18.6 Hz, 2H), 5.75 (dd, J ) 18.6, 8.3 Hz, 2H), 4.12 (dddd, J
) 8.9, 8.9, 8.9, 2.0 Hz, 2H), 3.05 (s, 2H), 2.45-2.30 (m, 4H),
1.80-0.75 (m, 74H); 13C NMR (70 MHz, CDCl3) δ 166.5, 148.1,
128.7, 57.2, 54.8, 48.5, 43.5, 42.7, 40.4, 32.2, 29.2, 28.2, 27.2,
26.5, 26.2, 13.6, 9.7; MS(FAB) isotope cluster (abundance) (M+
- 57) 911 (1.4), 912 (2.5), 913 (2.5), 914 (11.8), 915 (14.8), 916
(38.1), 917 (43.8), 918 (86.4), 919 (76.3), 920 (100.0), 921 (67.5),
922 (81.6), 923 (39.3), 924 (33.8), 925 (15.6), 926 (18.9), 927
(7.7), 928 (3.7), 929 (1.3), 930(1.4). Calcd for M+: 968 (1.3),
969 (3.2), 970 (3.2), 971 (13.7), 972 (17.2), 973 (39.8), 974 (45.0),
975 (84.7), 976 (76.9), 977 (100.0), 978 (70.6), 979 (81.2), 980
(43.3), 981 (35.3), 982 (18.8), 983 (20.8), 984 (9.5), 985 (4.5),
986 (1.6), 987 (1.6). HRMS (FAB) calcd for C49H89N2O2120Sn2:
(M - H+), 977.4965. Found: 977.4791.
1
1); H NMR (270 MHz, CDCl3) δ 6.01 (d, J ) 18.6 Hz, 0.5H),
5.75-5.57 (m, 1H), 5.18-5.03 (m, 1.5H), 4.78-4.69 (m, 0.5H),
3.27-3.10 (m, 1H), 2.66-2.35 (m, 1H), 2.05-0.70 (m, 38H);
13C NMR (70 MHz, CDCl3) δ 141.8, 135.8, 135.2, 117.1, 90.1,
88.8, 56.4, 52.4, 49.1, 48.0, 42.4, 41.9, 38.3, 35.4, 31.9, 31.6,
29.0, 28.2, 27.6, 27.2, 26.0, 25.9, 25.8, 13.7, 9.7.
(1R,6S,7R,8S)-7-((E)-1-(Tr i-n -bu tylsta n n yl)eth en -2-yl)-
bicyclo[4.3.0]n on a n -8-a m in e (19). To a solution of 18 (300
mg, 0.619 mmol) in dry THF:MeOH (1:1, 3 mL) were added
dry (sublimed) ammonium formate (390 mg, 6.19 mmol) and
Pd/C (10%, 60 mg). The mixture was stirred under N2 at room
temperature for 7 h, diluted with Et2O (50 mL), and filtered
(Celite), washing with Et2O. Rotary evaporation gave a
residue which was purified by chromatography (Et2O followed
by Et2O:MeOH:NH4OH 100:5:1) to give 19 (186 mg, 66%) as a
colorless oil: TLC Rf ) 0.10 (Et2O:hexanes:NH4OH 200:100:
3); IR (neat) 2955, 2922, 2852, 1592, 1446, 1376, 1292, 1184,
Bis[(1R,6S,7R,8S)-7-eth en ylbicyclo[4.3.0]n on -8-yl]m a -
lon a m id e (24). To a solution of 23 (15 mg, 0.015 mmol) in
dry Et2O (1 mL) under N2 was added TsOH‚H2O (6.5 mg, 0.040
mmol). The solution was stirred for 30 min and rotary
evaporated, and the residue was chromatographed (EtOAc) to
give 24 (6 mg, 98%) as a white solid: TLC Rf ) 0.50 (EtOAc);
IR (neat) 3278, 2923, 2853, 1637, 1544, 910 cm-1; [R]D ) -20.8°
1071, 992, 960, 866, 812, 690, 604, 505 cm-1 1H NMR (270
;
MHz, CDCl3, TMS) δ 5.96-5.65 (m, 2H), 3.20 (ddd, J ) 7.8,
7.8, 2.6 Hz, 1H), 2.28-2.10 (m, 2H), 1.92-1.80 (br m, 1H),
1.80-0.75 (m, 39H); 13C DEPT NMR (75 MHz, CDCl3) δ 150.3
(CH), 127.0 (CH), 61.4 (CH), 57.7 (CH), 47.9 (CH), 43.4(CH),
42.8 (CH2), 32.2 (CH2), 29.1 (3CH2), 28.3 (CH2), 27.2 (3CH2),
26.5 (CH2), 26.2 (CH2), 13.7 (3CH3), 9.5 (3CH2).
1
(c ) 0.25, CHCl3); H NMR (270 MHz, CDCl3) δ 6.95 (br d, J
) 8.0 Hz, 2H), 5.70 (ddd, J ) 18, 13, 9.0 Hz, 2H), 4.98 (2d,
overlapping, J ) 13.0 Hz, 4H), 4.08 (dddd, J ) 8.0, 8.0, 8.0,
2.0 Hz, 2H), 3.08 (s, 2H), 2.40-2.20 (m, 4H), 1.95-0.80 (m,
22H); 13C NMR (75 MHz, CDCl3) δ 166.7, 138.2, 115.1, 55.0,
53.8, 48.1, 43.3, 42.6, 40.0, 32.0, 27.9, 26.3, 26.0. The sample
was crystallized by vapor diffusion of hexanes into an EtOAc
solution to obtain crystals suitable for a single-crystal X-ray
diffraction study.
(1R,6S,7R,8S)-N-(ter t-Bu toxyca r bon yl)-7-((E)-1-(tr i-n -
bu tylstan n yl)eth en -2-yl)bicyclo[4.3.0]n on an -8-am ide (20).
To a solution of 19 (125 mg, 0.275 mmol) in 1,4-dioxane (2
mL) and H2O (0.25 mL) were added Et3N (57 µL, 0.41 mmol)
and tert-butyl S-(4,6-dimethylpyrimidin-2-yl) thiocarbonate (73
mg, 0.30 mmol). The mixture was stirred at 25 °C under N2
for 10 h, added to H2O (15 mL), and extracted into Et2O (3 ×
10 mL). The combined extracts were dried (MgSO4) and rotary
evaporated. The residue was purified by chromatography
(hexanes:Et2O 10:1) to give 20 (134 mg, 87%) as a colorless
(1R,6S,7R)-Eth yl 8,8-(Eth ylen ed ioxy)bicyclo[4.3.0]n on -
3-en e-7-ca r box-yla te (26). A solution of 9 (8.60 g, 41.3 mmol)
in PhH (200 mL) and ethylene glycol (70 mL) with TsOH‚H2O
(20 mg) was heated at reflux, with a Sohxlet thimble of
molecular sieves (3 Å, 50 g) between the reaction flask and
condenser. After 12 h, the mixture was allowed to cool and
added to H2O (100 mL) and Et2O (200 mL). The organic phase
was separated, washed with H2O (3 × 50 mL) and brine (50
mL), dried (MgSO4), and rotary evaporated to give 26 (10.3 g,
99%) as a colorless oil: TLC Rf ) 0.21 (hexanes:Et2O 4:1); [R]D
) +72.7° (c ) 1.64, CHCl3); IR (neat) 3022, 2978, 2896, 2834,
2360, 1734, 1642, 1438, 1380, 1332, 1282, 1227, 1202, 1159,
1
oil: TLC Rf ) 0.19 (hexanes:Et2O 10:1); H NMR (300 MHz,
CDCl3) δ 5.95-5.65 (m, 2H), 4.57 (br s, 1H), 3.80 (br s, 1H),
2.40-2.20 (m, 2H), 1.90-1.80 (m, 1H), 1.77-0.70 (m, 46H); 13
C
NMR (75 MHz, CDCl3) δ 155.5, 148.5, 128.0, 79.0, 57.3, 55.8,
48.2, 42.6, 40.9, 32.1, 29.1, 28.5, 28.0, 27.4, 26.7, 26.1, 13.9,
9.5. The material was used directly without any further
purification.
1090, 1039, 982, 948, 904, 870 cm-1 1H NMR (300 MHz,
;
Attem p ted P r ep a r a tion of Dim er 21. A solution of 20
(20 mg, 0.036 mmol) in dry THF (0.25 mL) was added via
cannula to KH (3 mg, 0.07 mmol) and 18-crown-6 (5 mg, 0.02
mmol). The mixture was stirred at 25 °C for 1 h and cooled
to 0 °C. A solution of 1,3-diiodopropane (5.3 mg, 0.020 mmol)
in THF (0.25 mL) was added via cannula, and stirring was
continued for 1 h. The mixture was added to H2O (10 mL)
and extracted into EtOAc (2 × 10 mL). The combined extracts
were dried (MgSO4) and rotary evaporated. The residue was
purified by chromatography (hexanes:Et2O 20:1) to give as the
major isolated product 22 (11 mg, 51%) as a colorless oil: 1H
NMR (300 MHz, CDCl3) δ 5.90-5.62 (m, 3H), 5.12-5.01 (m,
2H), 4.01-3.91 (m, 1H), 3.85-3.65 (m, 2H), 2.68-2.58 (m, 1H),
1.90-1.80 (m, 2H), 1.78-0.70 (m, 46H); 13C NMR (75 MHz,
CDCl3) δ 155.2, 150.5, 136.0, 127.2, 115.1, 79.5, 77.2, 63.2, 53.5,
49.0, 48.7, 42.8, 37.4, 31.8, 29.2, 28.5, 27.3, 26.6, 26.1, 13.7,
9.5.
CDCl3) δ 5.67-5.55 (m, 2H), 4.20-4.00 (m, 3H), 3.90-3.70 (m,
3H), 2.59 (d, J ) 11.2 Hz, 1H), 2.30-2.00 (m, 4H), 1.90-1.50
(m, 4H), 1.25 (t, J ) 7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 171.1, 126.5, 126.4, 116.7, 65.3, 64.4, 60.5, 60.3, 44.8, 42.2,
37.2, 31.0, 30.6, 14.2; MS(EI) m/e 252 (M+•), 207, 198, 169, 125,
112, 99, 91, 86. Anal. Calcd for C14H20O4: C, 66.65; H, 7.99.
Found: C, 66.42; H, 8.01.
(1R,6S,7S)-[8,8-(Eth ylen ed ioxy)bicyclo[4.3.0]n on -3-en -
7-yl]m eth a n ol (27a ). A solution of 26 (10.08 g, 39.90 mmol)
in dry Et2O (100 mL) was added dropwise to LiAlH4 (2.08 g,
58.1 mmol) in Et2O (100 mL) at 0 °C under N2 with stirring.
The mixture was stirred at room temperature for 5 h and
cooled to 0 °C. Saturated aqueous sodium potassium tartrate
(11 mL) was added cautiously with stirring. The resulting
mixture was heated at reflux for 1 h, allowed to cool, and
stirred at room temperature for 18 h. The white solids were
removed by filtration and the filtrate rotary evaporated to
leave 27a (8.31 g, 99%) as a colorless oil: TLC Rf ) 0.16
(hexanes:EtOAc 2:1); [R]D ) +128.8° (c ) 1.40, CHCl3); IR
(neat) 3449, 3019, 2956, 2887, 2832, 1641, 1473, 1437, 1401,
1359, 1314, 1276, 1231, 1202, 1151, 1085, 1024, 948, 913, 853,
Bis[(1R,6S,7R,8S)-7-((E)-1-(tr i-n -bu tylsta n n yl)eth en -2-
yl)bicyclo[4.3.0]n on -8-yl]m a lon a m id e (23). To a solution
of 19 (100 mg, 0.220 mmol) in dry CH2Cl2 (3 mL) under N2 at
-78 °C were added simultaneously via cannula malonyl
dichloride (17 mg, 0.12 mmol) in CH2Cl2 (0.5 mL) and Et3N
(46 µL, 0.33 mmol) in CH2Cl2 (0.5 mL) over ca. 5 min. Further
malonyl dichloride (7 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) were
added, and TLC indicated complete consumption of starting
material (Et2O:NH4OH 100:1). The reaction mixture was
allowed to warm to room temperature, added to H2O (10 mL),
and extracted into Et2O (2 × 10 mL). The combined extracts
were dried (MgSO4) and rotary evaporated. The residue was
purified by chromatography on Et3N-doped silica (hexanes:
Et2O 5:1) to give 23 (48 mg, 45%) as a colorless oil: TLC Rf )
0.36 (Et2O); [R]D ) +34.9° (c ) 1.60, CHCl3); IR (neat) 3265,
662, 595, 560, 521, 487, 461, 454 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 5.70-5.55 (m, 2H), 4.00-3.50 (m, 6H), 2.50 (dd, J )
8.9, 4.2 Hz, 1H), 2.35-2.10 (m, 2 H), 2.06 (dd, J ) 12.8, 6.1
Hz, 1H), 1.85-1.50 (m, 5H), 1.35 (dd, J ) 12.8, 11.7 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 126.8, 126.6, 117.8, 64.5, 63.7,
60.0, 55.0, 44.2, 40.2, 37.7, 31.4, 30.4; MS(EI) m/e 210 (M+•),
156, 125, 91, 79, 77, 55. Anal. Calcd for C12H18O3: C, 68.55;
H, 8.63. Found: C, 68.43, H, 8.54.
(1R,6S,7S)-7-[(Ben zyloxy)m eth yl]-8,8-(eth ylen ed ioxy)-
bicyclo[4.3.0]n on -3-en e (27b). To a solution of 27a (8.12 g,
38.6 mmol) in dry DMF (100 mL) under Ar was added NaH
1
2956, 2922, 2850, 1633, 1552, 1445, 1321, 988, 452 cm -1; H

694 J . Org. Chem., Vol. 61, No. 2, 1996
Barrett et al.
(2.16 g, 53.9 mmol, 60% dispersion in mineral oil), and the
mixture was stirred at room temperature for 1 h under Ar.
PhCH2Br (4.18 mL, 38.6 mmol) was added, and the mixture
was stirred for 20 h. A small portion was worked up (H2O/
Et2O), and TLC (Et2O) indicated some starting material.
Further NaH (0.20 g, 5.0 mmol, 60% dispersion in mineral oil)
and PhCH2Br (0.80 mL, 7.4 mmol) were added. After a further
2 h, the reaction was complete (TLC) and the mixture was
added to H2O (300 mL) and extracted into Et2O (3 × 100 mL).
The combined extracts were washed with H2O (3 × 50 mL)
and brine (50 mL) and dried (MgSO4). The solution was rotary
evaporated and the residue chromatographed (hexanes, then
hexanes:EtOAc gradient 1:0 to 4:1) to give 27b (11.7 g, 100%)
as a colorless oil: TLC Rf ) 0.60 (Et2O); [R]D ) +69.9° (c )
1.58, CHCl3); IR (neat) 3021, 2957, 2883, 1641, 1496, 1453,
1436, 1366, 1306, 1286, 1202, 1153, 1094, 1028, 948, 922, 853,
J ) 13.0 Hz, 1H), 3.68 (d, J ) 13.0 Hz, 1H), 3.60 (dd, J ) 9.0,
5.0 Hz, 1H), 3.41 (dd, J ) 9.0, 8.5 Hz, 1H), 3.04 (ddd, J ) 8.6,
6.5, 2.0 Hz, 1H), 2.30-2.15 (m, 2H), 1.95-1.65 (m, 6H), 1.50-
1.15 (m, 2H).
(1R ,6S ,7R ,8S )-7-[(Be n zyloxy)m e t h yl]b icyclo[4.3.0]-
n on a n -8-a m in e (29). To a solution of 28 (4.55 g, 13.1 mmol)
in dry MeOH (90 mL) under Ar were added anhydrous
(sublimed) ammonium formate (4.09 g, 65.4 mmol) and Pd/C
(10%, 1.37 g). The mixture was heated at reflux for 3 h,
allowed to cool, and filtered (Celite), washing with EtOAc. The
combined filtrate and washings were rotary evaporated and
the residue chromatographed (EtOAc:EtOH:NH4OH gradient
100:10:1 to 100:20:1) to give 29 (2.60 g, 77%) as a cream-colored
solid: mp 38-40 °C (not recrystallized); TLC Rf ) 0.36 (EtOAc:
EtOH:NH4OH 100:20:1); [R]D ) +58.6° (c ) 1.23, CHCl3); IR
1
(neat) 2919, 2851, 1451, 1368, 1098, 734, 697 cm-1; H NMR
1
735, 698, 663 cm-1; H NMR (300 MHz, CDCl3) δ 7.40-7.20
(300 MHz, CDCl3, TMS) δ 7.40-7.21 (m, 5H), 4.52 (2d, J )
22.1 Hz, 2H), 3.63-3.54 (m, 3H), 2.30-2.23 (m, 1H), 1.90-
1.71 (m, 7H), 1.26-0.90 (m, 7H); 13C NMR (75 MHz, CDCl3) δ
138.4,128.4, 127.7, 127.6, 73.2, 69.2, 51.4, 48.4, 46.0, 44.7, 41.9,
31.7, 30.7, 26.4, 26.1; MS(EI) m/e 259 (M+), 169, 168, 153, 152,
136, 91; HRMS(EI) calcd for C17H25NO (M+) 259.1936, found
(M+) 259.1925.
(m, 5H), 5.72-5.60 (m, 2H), 4.50 (s, 2H), 4.00-3.75 (m, 4H),
3.61 (dd, J ) 9.5, 7.1 Hz, 1H), 3.48 (dd, J ) 9.5, 6.2 Hz, 1H),
2.40-2.15 (m, 2H), 2.15-1.55 (m, 5H), 1.50-1.30 (m, 2H); 13
C
NMR (75 MHz, CDCl3) δ 138.6, 128.2, 127.4, 127.3, 126.9,
126.6, 116.6, 73.0, 69.8, 65.0, 63.9, 53.7, 44.6, 44.2, 37.8, 31.4;
MS(EI) m/e 300 (M+•), 238, 209, 194, 151, 140, 125, 112, 99,
91, 79, 77. Anal. Calcd for C19H24O3: C, 75.97; H, 8.05.
Found: C, 76.32; H, 8.01.
(1R,6S,7R,8S)-N-(ter t-Bu toxyca r bon yl)-7-[(ben zyloxy)-
m eth yl]bicyclo[4.3.0]n on a n -8-a m id e (30). A solution of 29
(2.49 g, 9.58 mmol) and NaOH (588 mg, 14.7 mmol) in 1,4-
dioxane (80 mL) and H2O (20 mL) was cooled to 0 °C under
Ar. Di-tert-butyl dicarbonate (2.64 mL, 11.5 mmol) was added
and the mixture stirred at room temperature for 6 h. The
reaction mixture was added to H2O (200 mL) and extracted
into Et2O (3 × 100 mL). The combined extracts were dried
(MgSO4) and rotary evaporated. The residue was chromato-
graphed (hexanes:Et2O 10:1) to give 30 (3.19 g, 93%) as a white
solid: mp 77-78 °C (not recrystallized); TLC Rf ) 0.16
(hexanes:Et2O 10:1); [R]D ) -7.6° (c ) 1.48, CHCl3); IR (neat)
2921, 2852, 2360, 1716, 1506, 1456, 1364, 1244, 1173, 736, 698,
(1R,6S,7S)-7-[(Ben zyloxy)m et h yl]b icyclo[4.3.0]n on -3-
en -8-on e (27c). A solution of 27b (11.5 g, 38.3 mmol) in THF
(220 mL) and hydrochloric acid (0.2 N, 22 mL) under Ar was
stirred at 60 °C for 3 h. The mixture was allowed to cool,
added to H2O (500 mL), and extracted into Et2O (3 × 150 mL).
The combined extracts were washed with H2O (3 × 100 mL)
and brine (10 mL) and dried (MgSO4). The solution was rotary
evaporated to give a pale yellow oil which solidified on standing
to leave 27c (9.72 g, 99%) as a cream-colored solid: mp 43-
45 °C (not recrystallized); TLC Rf ) 0.20 (hexanes:Et2O 4:1);
[R]D ) -44.2° (c ) 1.64, CHCl3); IR (neat) 3023, 2893, 1743,
1641, 1496, 1453, 1436, 1408, 1363, 1315, 1230, 1203, 1152,
1
668 cm-1; H NMR (300 MHz, CDCl3, TMS) δ 7.40-7.25 (m,
1093, 1027, 923, 789, 737, 698, 665, 604, 572, 535, 468 cm-1
;
5H), 5.40 (br, d, J ) 7.5 Hz, 1H), 4.49 (s, 2H), 4.25-4.00 (br,
m, 1H), 3.53 (d, J ) 3.5 Hz, 2H), 2.30-2.18 (m, 1H), 1.90-
1.65 (m, 5H), 1.45 (s, 9H), 1.40-0.85 (m, 7H); 13C NMR (75
MHz, CDCl3) δ 156.1, 138.3, 128.3, 127.8, 127.6, 78.6, 73.5,
68.3, 51.4, 46.4, 45.8, 43.6, 41.1, 31.4, 30.4, 28.5, 26.4, 26.2.
Anal. Calcd for C22H33NO3: C, 73.50; H, 9.25; N, 3.90.
Found: C, 73.59; H, 9.29; N, 3.87. A racemic sample of 30
was prepared in an identical fashion starting from racemic
amine 29. Suitable crystals were obtained for a single-crystal
X-ray structure determination which proved the stereochem-
ical assignment.
1H NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 5H), 5.79-5.68
(m, 2H), 4.50 (d, J ) 3.2 Hz, 2H), 3.80-3.60 (m, 2H), 2.60-
2.30 (m, 3H), 2.10-1.75 (m, 6H); 13C NMR (75 MHz, CDCl3) δ
216.7, 138.2, 128.2, 127.4, 127.3, 126.7, 126.6, 73.1, 67.2, 56.2,
45.0, 41.5, 36.5, 31.4, 30.8. Anal. Calcd for C17H20O2: C, 79.65;
H, 7.86. Found: C, 79.62; H, 8.04.
(1R,6S,7R,8S)-N-Ben zyl-7-[(ben zyloxy)m eth yl]bicyclo-
[4.3.0]n on -3-en -8-a m in e (28). To a solution of 27c (5.00 g,
19.5 mmol) in dry THF under Ar were added PhCH2NH2 (2.34
mL, 21.5 mmol), NaBH(OAc)3 (6.20 g, 29.3 mmol), and AcOH
(2.23 mL, 39.0 mmol). The mixture was stirred with ice cooling
for 1 h and at room temperature for 24 h. TLC (hexanes:Et2O
1:1) revealed some starting material. Further PhCH2NH2
(0.25 mL, 2.3 mmol), NaBH(OAc)3 (2.0 g, 9.5 mmol), and AcOH
(0.75 mL, 13 mmol) were added, and mixture was stirred at
room temperature for a further 24 h. The mixture was added
to aqueous NaOH (1 N, 300 mL) and extracted into Et2O (3 ×
150 mL). The combined extracts were dried (MgSO4) and
rotary evaporated. Chromatography on silica, pretreated with
1% Et3N in hexanes (hexanes, then hexanes:Et2O gradient 8:1
to 5:1) gave 28 (4.72 g, 70%) as a pale yellow oil which solidified
on standing to leave a cream-colored solid: mp 35-37 °C (not
recrystallized); TLC Rf ) 0.22 (hexanes:Et2O:Et3N 75:25:1);
[R]D ) +116.3° (c ) 1.16, CHCl3); IR (neat) 3022, 2899, 1744,
(1R ,6S ,7R ,8S )-N -(t er t -Bu t oxyca r b on yl)-7-(h yd r oxy-
m eth yl)bicyclo[4.3.0]n on a n -8-a m id e (31a ). A solution of
30 (1.50 g, 4.16 mmol) in absolute EtOH (30 mL) was stirred
under a H2 atmosphere with Pd/C (10%, 100 mg) for 6 h.
Further Pd/C (100 mg) was added and stirring continued for
18 h. The mixture was filtered (Celite), washing with EtOH,
and the solvent was removed by rotary evaporation. Chro-
matography (hexanes:EtOAc 4:1) gave 31a (1.11 g, 99%) as a
white solid: mp 88-89 °C (not recrystallized); TLC Rf ) 0.33
(hexanes:EtOAc 2:1); [R]D ) -46.7° (c ) 1.20, CHCl3); IR (neat)
3327, 2923, 2853, 1677, 1534, 1449, 1391, 1366, 1315, 1286,
1249, 1173, 1090, 1027, 924, 881, 863, 734, 472, 456 cm-1; 1H
NMR (300 MHz, CDCl3) δ 4.58 (br d, J ) 6.2 Hz, 1H), 4.14-
4.09 (m, 1H), 3.60-3.46 (m, 2H), 3.25 (br, OH), 2.43-2.33 (m,
1H), 1.86-1.65 (m, 5H), 1.42 (s, 9H), 1.22-0.73 (m, 7H); 13C
NMR (70 MHz, CDCl3) δ 156.9, 79.9, 60.5, 51.9, 51.1, 45.7,
44.3, 39.9, 31.90, 31.87, 30.4, 28.4, 26.4, 26.1. Anal. Calcd
for C15H27NO3: C, 66.88; H, 10.10; N, 5.20. Found: C, 66.92;
H, 10.03; N, 5.13.
(1R,6S,7S,8S)-N-(ter t-Bu toxycar bon yl)-7-for m ylbicyclo-
[4.3.0]n on a n -8-a m id e (31b). Oxalyl chloride (5.93 mmol, 2
M solution in CH2Cl2) was added to dry CH2Cl2 (16 mL) at
-78 °C under Ar. DMSO (0.84 mL, 12 mmol) was added
slowly as a solution in CH2Cl2 (2 mL) via cannula, and the
mixture was stirred until effervescence had ceased (15-30
min). A solution of 31a (1.07 g, 3.95 mmol) in CH2Cl2 (30 mL)
was added, and the mixture was stirred at -78 °C for 30 min.
Et3N (2.8 mL, 20 mmol) was added, and the solution was
1640, 1495, 1453, 1366, 1200, 1093, 1028, 734, 698, 664 cm-1
;
1H NMR (300 MHz, CDCl3, TMS) δ 7.34-7.23 (m, 10H), 5.67
(dd, J ) 1.7, 1.7 Hz, 2H), 4.48 (2d, J ) 18.7 Hz, 2H), 3.84-
3.72 (m, 2H), 3.63-3.56 (m, 2H), 3.32 (ddd, J ) 8.9, 8.9, 7.4
Hz, 1H), 2.35-2.15 (m, 3H), 2.10-1.67 (m, 4H), 1.55-1.35 (m,
2H), 1.18-1.02 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 140.8,
138.3, 128.3, 128.34, 128.27, 128.0, 127.6, 127.3, 126.7, 126.6,
73.3, 70.0, 57.7, 52.2, 48.3, 42.7, 40.3, 39.8, 31.9, 31.4; MS (CI)
m/e 375 (M + NH4+), 348 (M + H+), 256, 242, 198, 106, 91.
Anal. Calcd for C24H29NO: C, 82.95; H, 8.41; N, 4.03.
Found: C, 82.69; H, 8.51; N, 3.65. Also isolated was the minor
stereoisomer (1.10 g, 15%) as a colorless oil: TLC Rf ) 0.10
(hexanes:Et2O:Et3N 75:25:1); 1H NMR (300 MHz, CDCl3) δ
7.38-7.15 (m, 10H), 5.72-5.61 (m, 2H), 4.50 (2d, 2H), 3.81 (d,

Total Synthesis of (+)-Papuamine
J . Org. Chem., Vol. 61, No. 2, 1996 695
warmed to 0 °C. The mixture was added to H2O (50 mL) and
extracted into CH2Cl2 (3 × 50 mL). The combined extracts
were washed with brine (50 mL), dried (Na2SO4), and rotary
evaporated. The residue was chromatographed (hexanes:
EtOAc 4:1) to give 31b (1.02 g, 96%) as a white solid: mp 115-
116 °C (not recrystallized); TLC Rf ) 0.50 (hexanes:EtOAc 2:1);
[R]D ) -92.4° (c ) 1.08, CHCl3); IR (neat) 3306, 2927, 1714,
44.2 (E), 1C], 40.6, 31.7, 30.3, 29.1 (3C), 28.4 (3C), [27.3 (Z),
27.2 (E), 3C], 26.4, 26.2, 13.6 (3C), [10.3 (Z), 9.4 (E), 3C]; MS-
t
(EI) m/e 498 (M - Bu+), 442, 424, 381, 310, 177, 147, 57;
HRMS(EI) calcd for C24H44NO2120Sn (M - Bu+), 498.2394,
t
t
found: (M - Bu+), 498.2419.
(1R,6S,7S,8S)-N-(ter t-Bu toxyca r bon yl)-7-((E)-1-iod oet-
h en -2-yl)bicyclo[4.3.0]n on a n -8-a m id e (35). To a suspen-
sion of CrCl2 (800 mg, 6.46 mmol) in dry 1,4-dioxane (6 mL)
and THF (1 mL) under Ar at 25 °C were added a mixture of
31b (288 mg, 1.08 mmol) and CHI3 (850 mg, 2.15 mmol) in
1,4-dioxane (6 mL) and THF (1 mL) via cannula. The mixture
was stirred at room temperature for 4 h, added to hydrochloric
acid (1 N, 100 mL), and extracted into EtOAc (3 × 100 mL).
The combined extracts were dried (MgSO4) and rotary evapo-
rated. The crude material was preabsorbed onto silica and
dry loaded onto a column of silica. Elution with hexanes and
EtOAc (20:1 to 10:1) gave 35 (275 mg, 65%) as a white solid:
mp 129-131 °C (not recrystallized); TLC Rf ) 0.49 (hexanes:
EtOAc 4:1); [R]D ) -33.0° (c ) 1.15, CHCl3); IR (neat) 3368,
2918, 2852, 1678, 1519, 1389, 1366, 1316, 1278, 1245, 1171,
1018, 760 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.40 (dd, J )
13.0 Hz, 10.0 Hz, 1H), 5.98 (d, J ) 13.0 Hz, 1H), 4.45-4.26
(br m, 1H), 4.25-3.90 (br m, 1H), 2.35-2.10 (m, 1H), 1.90-
1.55 (m, 4H), 1.42 (s, 9H), 1.30-0.75 (m, 7H); 13C NMR (75
MHz, CDCl3) δ 155.8, 145.5, 79.8, 76.6, 55.5, 52.0, 49.8, 44.5,
40.0, 32.0, 30.5, 29.0, 26.5; MS(FAB) m/e 392 (M + H+), 369,
336, 307, 275, 208; HRMS(EI) calcd for C12H16INO2 (M + H -
tBu+), 335.0382, found (M‚H+ - tBu), 335.0406. Anal. Calcd
for C16H26INO2: C, 49.11; H,6.70; N, 3.58. Found: C, 49.50;
H, 6.80; N, 3.53.
Alter n a tive P r oced u r e for th e P r ep a r a tion of Vin yl
Iod id e 35. To a solution of 33 (95 mg, 0.17 mmol) in dry Et2O
(1 mL) under N2 was added I2 (48 mg, 0.19 mmol), and the
mixture was stirred for 30 min. Aqueous Na2S2O3 (1 mL) was
added, and the mixture was added to H2O (5 mL). The mixture
was extracted into EtOAc (2 × 10 mL), and the combined
extracts were dried (MgSO4) and rotary evaporated. The
residue was purified by chromatography (hexanes:EtOAc 10:
1) to give the (E)-vinyl iodide 34 (55 mg, 82%) as a white solid.
This material was identical to a sample prepared via the
previous method.
1674, 1531, 1286, 1170 cm-1 1H NMR (300 MHz, CDCl3) δ
;
9.75 (d, J ) 1.6 Hz, 1H), 4.56 (br, d, J ) 7.9 Hz, 1H), 4.39
(dddd, J ) 8.3, 8.3, 7.9, 7.9 Hz, 1H), 2.65 (dd, J ) 9.9, 9.9 Hz,
1H), 2.30-2.20 (m, 1H), 1.90-1.80 (m, 2H), 1.75-1.65 (m, 2H),
1.62-1.50 (m, 2H), 1.38 (s, 9H), 1.30-0.90 (m, 7H); 13C NMR
(75 MHz, CDCl3) δ 203.1, 155.2, 79.7, 60.1, 50.9, 45.6, 43.4,
40.0, 31.3, 30.5, 28.2, 26.0, 25.9. Anal. Calcd for C15H25NO3:
C, 67.38; H, 9.42; N, 5.24. Found: C, 67.45; H, 9.29; N, 5.24.
(1R,6S,7S,8S)-N-(ter t-Bu toxyca r bon yl)-7-(1,1-d ibr om o-
eth en -2-yl)-bicyclo[4.3.0]n on a n -8-a m id e (32). CBr4 (7.19
g, 21.7 mmol) in dry CH2Cl2 (50 mL) under Ar at 0 °C was
stirred with the addition of Ph3P (11.4 g, 43.4 mmol). After
30 min, the mixture was cooled to -78 °C. A solution of 31b
(0.966 g, 3.61 mmol) in dry CH2Cl2 (20 mL) was added, and
the mixture was stirred for 20 min at -78 °C and warmed to
0 °C. Et3N (25 mL) was added, followed by EtOAc (50 mL).
The mixture was filtered through a plug of silica, washing with
EtOAc. The solution was rotary evaporated and the filtration
process repeated, washing with hexanes and EtOAc (1:1).
Following rotary evaporation, the residue was chromato-
graphed (hexanes:EtOAc 10:1) to give 32 (1.45 g, 95%) as a
white solid: mp 176-178 °C (not recrystallized); TLC Rf )
0.30 (hexanes:EtOAc 10:1); [R]D ) +3.1° (c ) 1.22, CHCl3); IR
(neat) 3384, 2918, 2848, 1681, 1513, 1366, 1272, 1246, 1171,
1016, 870, 773 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.24 (br d,
J ) 9.1 Hz, 1H), 4.34 (br s, 1H), 4.15 (br s, 1H), 2.48-2.34 (br
m, 1H), 2.33-2.26 (m, 1H), 1.87-1.65 (m, 4H), 1.42 (s, 9H),
1.21-0.80 (m, 7H); 13C NMR (70 MHz, CDCl3) δ 155.2, 138.2,
89.4, 79.5, 53.0, 51.6, 51.5, 50.8, 44.1, 39.9, 31.7, 30.1, 28.4,
26.2. Anal. Calcd for C16H25Br2NO2: C, 45.41; H, 5.95; N,
3.31. Found: C, 45.44; H, 5.99; N, 3.39.
(1R,6S,7S,8S)-N-(ter t-Bu toxyca r bon yl)-7-eth yn ylbicy-
clo[4.3.0]-n on a n -8-a m id e (33). To a solution of dry i-Pr2-
NH (3.22 mL, 23.0 mmol) in dry THF (34 mL) under Ar at 0
°C was added n-BuLi (23.0 mmol, 2.5 M solution in hexanes).
The solution was stirred for 10 min and cooled to -78 °C, and
a solution of 32 (1.39 g, 3.28 mmol) in dry THF (20 mL) was
added via cannula over 10 min. The mixture was stirred for
1 h at -78 °C, warmed to 0 °C, and stirred for a further 1 h
and 15 min. The reaction was quenched with saturated
aqueous NH4Cl (50 mL), and the solution was extracted into
EtOAc (3 × 50 mL) and CHCl3 (50 mL). The combined extracts
were dried (Na2SO4) and rotary evaporated. The residue was
chromatographed twice (hexanes:EtOAc 10:1) to give 33 (649
mg, 75%) as a pale yellow solid: mp 74-76 °C (not recrystal-
lized); TLC Rf ) 0.30 (hexanes:EtOAc 10:1); [R]D ) -20.5° (c
) 1.30, CHCl3); IR (neat) 3311, 2975, 2926, 2853, 2360, 1703,
(1R,6S,7S,8S)-N-(Tr iflu or om eth a n esu lfon yl)-7-eth yn -
ylbicyclo[4.3.0]n on a n -8-a m id e (38). The carbamate 33 (400
mg, 1.52 mmol) and HCl in MeOH (10.6 mmol, 1.6 M) were
stirred at room temperature for 8 h. A further aliquot of HCl
in MeOH (10.6 mmol) was added and stirring continued for
15 h. The mixture was rotary evaporated, and the residue
was dissolved in a minimum volume of EtOH and basified with
NH4OH. The solution was applied to a column of silica and
eluted with EtOAc:EtOH:NH4OH (100:10:1) to give the free
amine 37 (244 mg): TLC Rf ) 0.43 (EtOAc:EtOH:NH4OH 100:
20:1); IR (neat) 2922, 2851, 626 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 3.37 (ddd, J ) 7.2, 7.2, 7.2 Hz, 1H), 2.35-2.19 (m,
2H), 2.16 (d, J ) 2.4 Hz, 1H), 2.07-1.95 (m, 1H), 1.87-1.63
(m, 3H), 1.43 (br s, NH2), 1.30-0.80 (m, 7H); 13C NMR (75
MHz, CDCl3) δ 84.1, 72.1, 51.4, 49.9, 44.4, 43.5, 41.4, 31.7,
30.2, 26.2, 26.1. The amine was not completely characterized
but was taken up in dry CH2Cl2 (5 mL) and Et3N (1.25 mL)
and cooled to -78 °C under Ar. (CF3SO2)2O (0.28 mL, 1.65
mmol) was added, and the mixture was stirred for 1 h at -78
°C. The reaction was quenched with H2O (20 mL), and the
mixture was allowed to warm to room temperature and
extracted into CH2Cl2 (2 × 30 mL). The combined extracts
were washed with H2O (30 mL) and brine (30 mL) and dried
(MgSO4). The solution was rotary evaporated and the residue
chromatographed (hexanes:EtOAc 10:1) to give 38 (341 mg,
76%) as a cream-colored solid: mp 53-54 °C (not recrystal-
lized); TLC Rf ) 0.29 (hexanes:EtOAc 10:1); [R]D ) +15.1° (c
) 1.20, CHCl3); IR (neat) 3308, 2929, 2856, 2360, 1451, 1379,
1499, 1451, 1390, 1365, 1244, 1173, 1014, 862, 778, 624 cm-1
;
1H NMR (300 MHz, CDCl3) δ 4.82 (br s, 1H), 4.20-3.90 (br m,
1H), 2.43 (ddd, J ) 9.2, 9.2, 2.5 Hz, 1H), 2.34-2.25 (m, 1H),
2.14 (d, J ) 2.5 Hz, 1H), 2.10-2.00 (m, 1H), 1.90-1.60 (m,
3H), 1.40 (s, 9H), 1.30-0.80 (m, 7H); 13C NMR (75 MHz,
CDCl3) δ 155.6, 83.1, 79.0, 72.2, 51.7, 50.4, 43.9, 40.6, 40.1,
31.3, 30.1, 28.4, 26.0. Anal. Calcd for C16H25NO2: C, 72.97;
H, 9.57; N, 5.32. Found: C, 72.87; H, 9.39; N, 5.39.
(1R,6S,7S,8S)-N-(ter t-Bu t oxyca r b on yl)-7-((E)-1-(t r i-n -
bu tylstan n yl)eth en -2-yl)bicyclo[4.3.0]n on an -8-am ide (34).
A solution of 33 (50 mg, 0.19 mmol) and Bu3SnH (250 µL, 0.950
mmol) in dry PhMe (0.5 mL) under Ar was heated with AIBN
(5 mg) at 105 °C for 2 h. The mixture was allowed to cool and
directly chromatographed (hexanes, then hexanes:EtOAc 20:
1) to give 34 (102 mg, 97%) as a mixture of isomers, E:Z 85:
15: TLC Rf ) 0.55 (hexanes:EtOAc 10:1); [R]D ) +9.0° (c )
0.50, CHCl3); IR (neat) 2924, 2852, 1702, 1499, 1364, 1173,
1336, 1232, 1194, 1147, 1084, 963, 936, 606, 571, 504 cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.26 (br s, 1H), 4.02 (ddd, J )
8.4, 8.4, 8.4 Hz, 1H), 2.60 (ddd, J ) 10.4, 8.4, 2.5 Hz, 1H),
2.43-2.35 (m, 1H), 2.36 (d, J ) 2.5 Hz, 1H), 2.09-2.00 (m,
1H), 1.90-1.69 (m, 3H), 1.32-0.95 (m, 7H); 13C NMR (75 MHz,
CDCl3) δ 119.6 (q, 1J C-F ) 321 Hz, CF3), 81.4, 74.7, 54.3, 52.1,
43.7, 41.2, 40.1, 30.9, 30.0, 25.9, 25.8; MS(EI) m/e 295 (M+•),
1
459 cm-1; H NMR (300 MHz, CDCl3) δ 5.90 (d, J ) 19.3 Hz,
1H), 5.77 (dd, J ) 19.3, 6.7 MHz, 1H), 4.60-4.30 (br m, 1H),
4.15-3.90 (br m, 1H), 2.35-2.10 (br m, 2H), 1.90-0.65 (m,
47H); 13C NMR (75 MHz, CDCl3) δ 155.3, [147.1 (Z), 146.9 (E),
1C], [132.8 (Z), 130.2 (E), 1C], 78.6, 55.2, 51.5, 49.2, [44.5 (Z),

696 J . Org. Chem., Vol. 61, No. 2, 1996
Barrett et al.
294 (M - H+), 213, 162, 145, 105, 91; HRMS(EI) calcd for
C12H15F3NO2S (M - H+) 294.0776, found (M - H+), 294.0801.
Anal. Calcd for C12H16F3NO2S: C, 48.80; H, 5.46; N, 4.74.
Found: C, 48.99; H, 5.59; N, 4.60.
for 18 h, added to H2O (30 mL), and extracted into EtOAc (3
× 30 mL). The combined extracts were dried (MgSO4) and
rotary evaporated. The residue was chromatographed (hex-
anes:EtOAc gradient 10:1 to 5:1) to give 42b (400 mg, 100%)
as a pale yellow gum: TLC Rf ) 0.32 (hexanes:EtOAc 10:1);
[R]D ) +12.8° (c ) 1.70, CHCl3); IR (neat) 3284, 2921, 2852,
2360, 1452, 1337, 1161, 1093, 815, 736, 698, 662, 548, 464 cm-1;
1H NMR (300 MHz, CDCl3) δ 7.62 (d, J ) 9.7 Hz, 2H), 7.42-
7.28 (m, 5H), 7.21 (d, J ) 9.7 Hz, 2H), 4.96 (2d, J ) 11.6 Hz,
2H), 3.75-3.61 (m, 1H), 3.48-3.38 (m, 2H), 2.40 (s, 3H), 2.01-
1.90 (m, 1H), 1.80-1.60 (m, 5H), 1.30-0.75 (m, 7H); 13C NMR
(75 MHz, CDCl3) δ 142.8, 138.3, 137.7, 129.5 (2C), 128.5 (2C),
128.0 (2C), 127.9, 126.9 (2C), 73.5, 67.9, 54.3, 46.2, 45.5, 43.5,
41.3, 31.1, 30.2, 26.2, 26.1, 21.5.
N,N′-Bis[(1R,6S,7S,8S)-7-et h yn ylb icyclo[4.3.0]n on -8-
yl]-N,N′-bis(t r iflu or om et h a n esu lfon yl)-1,3-p r op a n ed ia -
m id e (39). A solution of the sulfonamide 38 (340 mg, 1.15
mmol), 1,3-dibromopropane (116 mg, 0.576 mmol) in dry MeCN
(4 mL) with anhydrous K2CO3 (318 mg, 2.30 mmol), and KI (5
mg, 0.03 mmol) was heated at reflux under Ar for 22 h. The
solvent was removed by rotary evaporation, and the residue
was dissolved in CHCl3 and filtered (Celite), washing with
CHCl3. The solvent was again removed by rotary evaporation,
and the residue was chromatographed on silica (hexanes:
EtOAc gradient 60:1 to 40:1) to give 39 (194 mg, 53%) (on a
scale of 40 mg a yield of 63% was obtained) as a colorless
gum: TLC Rf ) 0.16 (hexanes:EtOAc 40:1); [R]D ) -15.6° (c
) 1.18, CHCl3); IR (neat) 3296, 2929, 2855, 1449, 1384, 1224,
1190, 1141, 1112, 1003, 962, 608, 508, 468, 462 cm-1; 1H NMR
(300 MHz, CD5CD3 at 343 K) δ 4.27 (ddd, J ) 9.3, 9.3, 9.3 Hz,
2H), 3.70-3.55 (m, 2H), 3.40-3.23 (m, 2H), 2.33-2.19 (m, 4H),
1.97-1.87 (m, 2H), 1.90 (d, J ) 2.6 Hz, 2H), 1.81 (ddd, J )
12.9, 7.5, 5.3 Hz, 2H), 1.63-1.50 (m, 6H), 1.45-0.80 (m, 10H),
0.72-0.40 (m, 4H); 13C NMR (75 MHz, CD5CD3 at 343 K) δ
120.8 (q, 1J C-F ) 324 Hz, 2CF3), 82.8 (2C), 73.6 (2C), 61.7 (2C),
53.5 (2C), 46.6 (2C), 43.3 (2C), 40.3 (2C), 37.4 (2C), 33.7, 31.2
(2C), 30.7 (2C), 26.3 (4C); MS(FAB) m/e 631 (M + H+), 497,
363, 212, 147. Anal. Calcd for C27H36N2O4S2: C, 51.42; H,
5.75; N, 4.44. Found: C, 51.65; H, 5.80; N, 4.28.
(E,E)-9,11-Eicosa d ien e. To a suspension of Cp2ZrHCl (98
mg, 0.38 mmol) in dry THF (1 mL) under Ar in the dark was
added 1-decyne (50 mg, 0.36 mmol) in THF (1 mL) via cannula.
The mixture was stirred for 30 min, and the resulting pale
yellow solution was added via cannula to a suspension of
copper(I) chloride (39 mg, 0.40 mmol) in dry THF (1 mL) under
Ar. After stirring in the dark for 3 h, H2O (0.5 mL) was added
and stirring continued for 30 min. The mixture was filtered
(Celite), and the filter pad was washed with hexanes. The
solution was dried (MgSO4) and rotary evaporated. The
residue was purified by chromatography (hexanes) to give
(E,E)-9,11-eicosadiene (40 mg, 79%) as a white solid: TLC Rf
) 0.56 (hexanes); 1H NMR (300 MHz, CDCl3) δ 6.05-5.92 (m,
2H), 5.60-5.50 (m, 2H), 2.10-2.00 (m, 4H), 1.45-1.15 (m,
24H), 0.88 (t, J ) 6.4 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
132.4 (2C), 130.3 (2C), 32.6 (2C), 31.9 (2C), 29.51 (2C), 29.47
(2C), 29.30 (2C), 29.26 (2C), 22.7 (2C), 14.1 (2C).
N,N′-Bis[(1R,6S,7R,8S)-7-[(ben zyloxy)m eth yl]bicyclo-
[4.3.0]n on -8-yl]-N,N′-b is(t r iflu or om et h a n esu lfon yl)-1,3-
p r op a n ed ia m id e (43). The trifluoromethanesulfonamide
42a (3.53 g, 9.03 mmol) and 1,3-dibromopropane (504 µL, 4.96
mmol) with anhydrous K2
CO3 (2.50 g, 18.0 mmol) and KI (15
mg, 0.09 mmol) in dry MeCN (30 mL) under Ar were heated
at reflux for 3 days. The reaction mixture was allowed to cool,
diluted with CHCl3 (100 mL), and filtered (Celite). The solvent
was removed under vacuum and the residue chromatographed
(hexanes:Et2O 20:1) to give 43 (3.09 g, 83%) as a colorless
gum: TLC Rf ) 0.38 (hexanes:Et2O 10:1); [R]D ) -11.8° (c )
1.25, CHCl3); IR (neat) 2923, 2360, 1382, 1222, 1189, 1144,
1
736, 698, 608, 454 cm-1; H NMR (300 MHz, CDCl3) δ 7.32-
7.25 (m, 10H), 4.43 (s, 4H), 4.25 (br s, 2H), 3.53 (2d, J ) 4.6
Hz, 4H), 3.30-3.10 (br m, 2H), 2.95 (br s, 2H), 2.00-1.70 (m,
14H), 1.30-0.90 (m, 14H); 13C NMR (75 MHz, C6D6 at 335 K)
1
δ 138.8, 128.6, 127.9, 127.8, 120.7 (q, J C-F ) 324 Hz, 2CF3),
73.6, 68.7, 61.9, 48.0, 47.8, 45.9, 43.3, 36.7, 31.3, 31.2, 26.5.
Anal. Calcd for C39H52F6N2O6S2: C, 56.92; H, 6.37; N, 3.40.
Found: C, 56.57; H, 6.59; N, 3.38.
N,N′-Bis[(1R,6S,7R,8S)-7-[(ben zyloxy)m eth yl]bicyclo-
[4.3.0]n on -8-yl]-1,3-p r op a n ed ia m in e (44a ). To a solution
of 43 (3.07 g, 3.73 mmol) in dry PhMe (30 mL) under Ar was
added sodium bis(methoxyethoxy)aluminum hydride (REDAL)
(29.8 mmol, 3.4 M solution in PhMe). The mixture was heated
at 100 °C for 18 h and allowed to cool. The solution was added
to aqueous NaOH (6N, 150 mL) and extracted into Et2O (3 ×
100 mL). The combined extracts were washed with brine (100
mL), dried (Na2SO4), and rotary evaporated. The residue was
chromatographed (EtOAc:EtOH:NH4OH 200:5:2) to give 44a
(1.75 g, 84%) as a white, waxy solid: TLC Rf ) 0.58 (EtOAc:
EtOH:NH4OH 100:10:1); [R]D ) +84.0° (c ) 1.00, CHCl3); IR
1
(neat) 2918, 2894, 1451, 1098, 734, 697, 456 cm-1
; H NMR
(1R ,6S ,7R ,8S )-N -(T r i flu o r o m e t h a n e s u lfo n y l)-7-
[(b en zyloxy)m et h yl]b icyclo[4.3.0]n on a n -8-a m id e (42a ).
To a solution of 29 (2.39 g, 9.21 mmol) in dry CH2Cl2 (50 mL)
and Et3N (10 mL) at -78 °C under Ar was added (CF3SO2)2O
(1.71 mL, 10.14 mmol) over 10 min. The mixture was stirred
at -78 °C for 1 h, the reaction was quenched by the addition
of H2O (10 mL), and the solution was allowed to reach room
temperature. The mixture was extracted into CHCl3 (3 × 50
mL), and the combined extracts were washed with brine (50
mL) and dried (MgSO4). The solution was rotary evaporated
and the residue chromatographed (hexanes:EtOAc 10:1) to give
42a (3.54 g, 98%) as a pale yellow oil: TLC Rf ) 0.30 (hexanes:
Et2O 10:1); [R]D ) +9.8˚ (c ) 1.20, CHCl3); IR (neat) 2924, 2854,
(300 MHz, CDCl3) δ 7.34-7.20 (m, 10H), 4.47 (2d, J ) 16.1
Hz, 4H), 3.64 (dd, J ) 9.2, 9.2 Hz, 2H), 3.52 (dd, J ) 9.1, 4.1
Hz, 2H), 3.17 (ddd, J ) 7.9, 7.9, 7.9 Hz, 2H), 2.60-2.50 (m,
2H), 2.45-2.35 (m, 2H), 2.08-1.95 (m, 2H), 1.90-1.50 (m,
14H), 1.20-0.80 (m, 14H); 13
C NMR (75 MHz, CDCl3) δ 138.2,
128.3, 127.6, 127.4, 73.1, 69.6, 58.2, 47.5, 46.7, 46.5, 44.3, 40.0,
31.6, 30.8, 30.3, 26.3, 26.1; MS(EI) m/e 559 (M + H
+), 558 (M+•),
468, 286, 272, 259, 258, 210, 208, 164, 91. HRMS(EI) calcd.
for C37
H54N2O2 (M+•) 558.4185, found (M+•) 558.4188.
N,N′-Bis[(1R,6S,7R,8S)-7-[(ben zyloxy)m eth yl]bicyclo-
[4.3.0]n on -8-yl]-N,N′-bis(tolu en e-4-su lfon yl)-1,3-pr opan edi-
a m id e (44b). To a solution of 44a (1.00 g, 1.79 mmol) in dry
CH2Cl2 (3 mL) and Et3N (6 mL) at 0 °C under Ar was added
TsCl (6.80 g, 35.8 mmol). The mixture was stirred at room
temperature for 3 days, added to aqueous NaOH (2 N, 100
mL), and extracted into EtOAc (3 × 50 mL). The combined
extracts were washed with brine (50 mL), dried (MgSO4), and
rotary evaporated. The residue was chromatographed (hex-
anes:EtOAc gradient 20:1 to 10:1 to 7:1) to give 44b (1.50 g,
97%) as a pale yellow gum: TLC Rf ) 0.13 (hexanes:EtOAc
10:1); [R]D ) -20.9° (c ) 1.10, CHCl3); IR (neat) 2921, 2852,
1452, 1335, 1152, 1090, 814, 735, 698, 658, 547, 467 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.61 (d, J ) 8.3 Hz, 4H), 7.35-7.18
(m, 14H), 4.36 (s, 4H), 4.32-4.15 (br, m, 2H), 3.50-3.32 (m,
4H), 3.20-3.05 (m, 2H), 2.98-2.80 (m, 2H), 2.38 (s, 6H), 2.00-
1.55 (m, 14H), 1.32-0.85 (m, 14H); 13C NMR (75 MHz, CDCl3)
δ 142.8, 138.8, 138.7, 129.6, 128.3, 127.4, 127.3, 126.9, 73.0,
70.0, 59.3, 49.1, 47.0, 44.1, 43.4, 36.4, 31.3, 26.2, 21.5; MS(EI)
m/e 776 (M - C7H7+), 714, 713, 712, 606, 286, 91; HRMS(EI)
1
1437, 1379, 1231, 1190, 1149, 1095, 700, 605 cm-1; H NMR
(300 MHz, CDCl3) δ 7.42-7.26 (m, 5H), 6.40 (d, J ) 9.0 Hz,
NH), 4.55 (d, J ) 11.6 Hz, 1H), 4.46 (d, J ) 11.6 Hz, 1H), 4.05
(dddd, J ) 9.0, 9.0, 9.0, 9.0 Hz, 1H), 3.68 (dd, J ) 10.3, 2.6
Hz, 1H), 3.60 (dd, J ) 10.3, 2.6 Hz, 1H), 2.32-2.21 (m, 1H),
1.90-1.67 (m, 5H), 1.49-1.34 (m, 1H), 1.30-0.80 (m, 6H); 13
C
NMR (75 MHz, CDCl3) δ 137.2, 128.6, 128.1, 128.0, 119.7 (q,
1J C-F ) 321 Hz, CF3), 73.6, 67.1, 56.3, 46.2, 45.0, 43.3, 42.0,
31.0, 30.0, 26.1, 26.0; MS (CI) m/e 409 (M + NH4+), 392 (M +
H+), 258, 176, 152, 135, 121, 108, 91. Anal. Calcd for
C18H24F3NO3S: C, 55.23; H, 6.18; N, 3.58. Found: C, 55.24;
H, 6.37; N, 3.55.
(1R,6S,7R,8S)-N-(Tolu en e-4-su lfon yl)-7-[(b en zyloxy)-
m eth yl]bicyclo[4.3.0]n on a n -8-a m id e (42b). To a solution
of the amine 29 (250 mg, 0.964 mmol) in dry CH2Cl2 (5 mL)
and Et3N (1 mL) at 0 °C under Ar was added TsCl (202 mg,
1.06 mmol). The mixture was stirred at room temperature

Total Synthesis of (+)-Papuamine
J . Org. Chem., Vol. 61, No. 2, 1996 697
calcd for C44H59N2O6S2 (M - C7H7+) 775.3815, found (M -
C7H7+) 775.3815.
-64.9° (c ) 0.205, CHCl3); IR (neat) 2922, 1335, 1156, 757,
661, 546, 456 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J )
8.2 Hz, 4H), 7.28 (d, J ) 8.2 Hz, 4H), 6.12 (dd, J ) 14.4, 8.5
Hz, 2H), 5.67 (dd, J ) 14.4, 0.9 Hz, 2H), 4.35 (ddd, J ) 10.2,
10.2, 7.8 Hz, 2H), 3.32-3.18 (m, 2H), 2.97-2.82 (m, 2H), 2.41
(s, 6H), 2.16 (ddd, J ) 10.2, 10.2, 10.2 Hz, 2H), 2.05-1.63 (m,
12H), 1.45-1.30 (m, 2H), 1.30-0.95 (m, 10H), 0.90-0.71 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 144.7, 143.1, 138.3, 129.9,
127.0, 76.6, 59.6, 53.7, 50.4, 45.1, 43.2, 36.9, 33.4, 31.2, 30.5,
26.1, 26.0, 21.6; MS(FAB) m/e 953 (M + Na+), 931 (M + H+),
804, 803, 776, 775, 657, 649, 648; HRMS(FAB) calcd for
C39H52I2N2O4S2H (M + H+) 931.1540, found (M + H+) 931.1475.
N,N′-Bis[(1R,6S,7S,8S)-7-((E)-1-(tr im eth ylstan n yl)eth en -
2-yl)bicyclo[4.3.0]n on -8-yl]-N,N′-bis(tolu en e-4-su lfon yl)-
1,3-p r op a n ed ia m id e (47). A mixture of 46 (29 mg, 31 µmol)
and (Ph3P)2PdCl2 (2 mg, 2.85 µmol) was taken up in dry,
oxygen free THF (2 mL) under Ar. (Me3Sn)2 (44 µL, 0.19
mmol) was added and the mixture stirred in the dark at 50
°C for 18 h. The reaction mixture was added to H2O (20 mL)
and extracted into EtOAc (3 × 20 mL). The combined extracts
were washed with brine (20 mL), dried (MgSO4), and rotary
evaporated. The residue was chromatographed (hexanes:
EtOAc gradient 15:1 to 10:1 to 2:1) to give 47 (18 mg, 57%) as
a colorless gum/foam: TLC Rf ) 0.42 (hexanes:EtOAc); 1H
NMR (300 MHz, CDCl3) δ 7.63 (d, J ) 8.2 Hz, 4H), 7.22 (d, J
) 8.2 Hz, 4H), 5.81 (d, J ) 19.2 Hz, 2H), 5.65 (dd, J ) 19.2,
6.0 Hz, 2H), 4.36 (ddd, J ) 9.4, 9.4, 9.4 Hz, 2H), 3.25-3.08
(m, 2H), 2.85-2.68 (m, 2H), 2.39 (s, 6H), 2.23 (ddd, J ) 10.9,
10.9, 5.5 Hz, 2H), 1.90-1.60 (m, 12H), 1.35-0.75 (m, 14H),
Alter n a tive P r oced u r e for th e P r ep a r a tion of Bis-
Su lfon a m id e (44b). The toluene-4-sulfonamide 42b (70 mg,
0.169 mmol) and 1,3-dichloropropane (9 µL, 0.093 mmol) with
anhydrous Cs2CO3 (110 mg, 0.339 mmol) in dry DMF (1 mL)
under Ar where heated at 90 °C for 1 day. Further 1,3-
dichloropropane (1 µL, 0.011 mmol) was added, and the
mixture was heated at 90 °C for a further 24 h. The reaction
mixture was added to H2O (30 mL) and extracted into EtOAc
(3 × 30 mL). The combined extracts were washed with H2O
(30 mL) and brine (30 mL), dried (MgSO4), and rotary
evaporated. The residue was chromatographed (hexanes:
EtOAc gradient 10:1 to 7:1) to give bis-sulfonamide 44b (35
mg, 48%) as a colorless oil. This material was identical to a
sample prepared via the previous method.
N,N′-Bis[(1R,6S,7R,8S)-7-(h ydr oxym eth yl)bicyclo[4.3.0]-
n on -8-yl]-N,N′-b is(t olu en e-4-su lfon yl)-1,3-p r op a n ed ia -
m id e (45a ). A solution of 44b (663 mg, 0.765 mmol) in EtOH
(25 mL) was stirred with the addition of Raney Ni (Type W-2,
5 mL, 50% slurry in H2O, pH > 9) under an atmosphere of
H2. After 18 h, the reaction was complete by TLC (hexanes:
EtOAc 1:1). The mixture was filtered (Celite) under a flow of
Ar, and the filter pad was washed with EtOAc. The solution
was rotary evaporated and the residue chromatographed
(hexanes:EtOAc 2:1) to give 45a (511 mg, 97%) as a colorless
oil: TLC Rf ) 0.20 (hexanes:EtOAc 1:1); [R]D ) +47.6° (c )
1.05, CHCl3); IR (neat) 3504, 2923, 2852, 2360, 2342, 1598,
1447, 1400, 1328, 1152, 1088, 1030, 912, 813, 732, 659, 588,
2
0.06 (s, J Sn-H ) 53 Hz, 18H); 13C NMR (75 MHz, CDCl3)
1
548 cm-1; H NMR (300 MHz, CDCl3) δ 7.67 (d, J ) 8.2 Hz,
δ 146.9, 142.6, 139.1, 130.2, 129.5 126.8, 60.3, 53.2, 49.6,
45.1, 43.1, 37.1, 33.0, 31.3, 30.9, 26.2, 26.2, 21.5, -9.6 (1J Sn-C
) 338 Hz, 6C); HRMS(EI) calcd for C44H67N2O4S2118Sn2
(M - Me+), 987.2574, found (M-Me+) 987.2595; calcd for
C44H67N2O4S2118Sn120Sn: (M-Me+), 989.2580; Found (M-Me+),
989.2596.
4H), 7.27 (d, J ) 8.2 Hz, 4H), 4.21 (ddd, J ) 8.8, 8.8, 8.8 Hz,
2H), 3.67-3.56 (m, 4H), 3.37-3.27 (m, 2H), 3.08-2.98 (m, 2H),
2.75-2.10 (br, 2OH), 2.42 (s, 6H), 2.06-1.96 (m, 2H), 1.92-
1.60 (m, 12H), 1.28-0.83 (m, 14H); 13C NMR (75 MHz, CDCl3)
δ 143.5, 137.0, 129.8, 127.1, 61.1, 59.0, 51.3, 48.0, 44.7, 43.8,
34.8, 31.8, 31.3, 30.9, 26.2, 26.0, 21.6; HRMS(FAB) calcd for
C37H54N2O6S2H (M + H+) 687.3502, found (M + H+) 687.3488.
N,N′-Bis[(1R,6S,7R,8S)-7-for m ylbicyclo[4.3.0]n on -8-yl]-
N,N′-bis(tolu en e-4-su lfon yl)-1,3-p r op a n ed ia m id e (45b).
Oxalyl chloride (4.39 mmol, 2.2 M solution in CH2Cl2) was
added to a solution of dry DMSO (0.62 mL, 8.8 mmol) in dry
CH2Cl2 (5 mL) at -78 °C under Ar. The mixture was stirred
until effervescence had ceased (30 min), and a solution of 45a
(503 mg, 0.732 mmol) in CH2Cl2 (3 mL) was added. The
mixture was stirred for 30 min, Et3N (2 mL) was added, and
the mixture was allowed to reach 0 °C and added to H2O (50
mL). The organic material was extracted into EtOAc (3 × 50
mL), and the combined extracts were washed with brine (50
mL), dried (MgSO4), and rotary evaporated. The residue was
chromatographed (hexanes:EtOAc gradient 10:1 to 5:1 to 2:1)
to give 45b (480 mg, 96%) as a white foam: TLC Rf ) 0.40
(hexanes:EtOAc 2:1); [R]D ) -32.4° (c ) 0.38, CHCl3); IR (neat)
2926, 2853, 1716, 1447, 1336, 1160, 1089, 914, 815, 732, 660
N-[(1R,6S,7S,8S)-7-((E)-1-Iod o-2-eth en yl)bicyclo[4.3.0]-
8-n on yl]-N′-[(1R,6S,7S,8S)-7-((E)-1-(tr im eth ylsta n n yl)-2-
eth en yl)bicyclo[4.3.0]-8-n on yl]-N,N′-bis(4-tolu en esu lfon yl)-
1,3-p r op a n ed ia m id e (48). To a solution of 47 (130 mg, 0.129
mmol) in dry Et2O (3 mL) under Ar was added a solution of I2
(32.8 mg, 0.129 mmol) in Et2O (2 mL) via cannula, and the
mixture was stirred for 30 min. The mixture was added to
H2
O (10 mL) and extracted into Et2O (3 × 10 mL). The
combined extracts were dried (MgSO4) and rotary evaporated.
The residue was chromatographed (hexanes:EtOAc 15:1) to
give the starting distannane 47 (32 mg, 25%), the desired
product 48 (43 mg, 34%) as a white foam [TLC Rf
) 0.38
1
(hexanes:EtOAc 4:1); H NMR (300 MHz, CDCl3) δ 7.65 (2d,
overlapping, 4H), 7.23 (2d, overlapping, 4H), 6.09 (dd, J ) 14.4,
8.3 Hz, 1H), 5.82 (d, J ) 19.2 Hz, 1H), 5.66 (d, J ) 14.4 Hz,
1H), 5.65 (dd, J ) 19.2, 6.2 Hz, 1H), 4.45-4.25 (m, 2H), 3.30-
3.10 (m, 2H), 2.90-2.70 (m, 2H), 2.40 (s, 3H), 2.39 (s, 3H),
2.30-2.10 (m, 2H), 1.95-1.60 (m, 12H), 1.40-0.70 (m, 14H),
1
cm-1; H NMR (300 MHz, CDCl3) δ 9.52 (d, J ) 1.6 Hz, 2H),
7.69 (d, J ) 8.2 Hz, 4H), 7.30 (d, J ) 8.2 Hz, 4H), 4.55 (ddd,
J ) 10.6, 10.6, 7.6, 2H), 3.10-2.90 (m, 2H), 2.85-2.70 (m, 2H),
2.56 (ddd, J ) 11.1, 10.6, 1.6, 2H), 2.41 (s, 6H), 1.95-1.60 (m,
14H), 1.40-0.77 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 203.1,
143.6, 137.0, 129.9, 127.1, 58.6, 58.3, 45.8, 44.1, 42.7, 36.3,
32.2, 30.9, 30.8, 25.9, 25.8, 21.6; HRMS (FAB) calcd for
C37H50N2O6S2H (M + H+) 683.3189, found (M + H+), 683.3182.
N,N′-Bis[(1R,6S,7S,8S)-7-((E)-1-iod o-2-eth en yl)bicyclo-
[4.3.0]-8-n on yl]-N,N′-bis(4-tolu en esu lfon yl)-1,3-pr opan edi-
a m id e (46). A mixture of 45b (300 mg, 0.438 mmol) and CHI3
(1.38 g, 3.51 mmol) in dry 1,4-dioxane (6 mL) and THF (1 mL)
was added to a suspension of CrCl2 (1.29 g, 10.5 mmol) in 1,4-
dioxane (6 mL) and THF (1 mL), under Ar at room tempera-
ture. The mixture was stirred for 5 h, added to hydrochloric
acid (1 N, 150 mL), and extracted into EtOAc (3 × 50 mL).
The combined extracts were washed with H2O (50 mL) and
brine (50 mL) and dried (MgSO4). The solvent was removed
by rotary evaporation, the residue was taken up in CHCl3 (10
mL) and mixed with silica (ca. 5 g), and the solvent was
removed and then dry loaded onto a silica column. Elution
(hexanes:EtOAc gradient 20:1 to 10:1) gave 46 (266 mg, 65%)
0.07 (s, 2J Sn-H ) 54 Hz, 9H); 13C NMR (75 MHz, CDCl3) δ 146.9,
144.7, 143.0, 142.7, 139.0, 138.4, 130.4, 129.8, 129.6, 126.9,
76.5, 60.4, 59.6, 53.5, 53.3, 50.3, 49.7, 45.1, 43.1, 37.2, 36.8,
33.0, 31.3, 31.1, 30.9, 30.5, 29.7, 26.24, 26.17, 26.0, 21.54, 21.50,
-9.5], and finally the diiodide 46 (37 mg, 31%) identical with
the previously prepared material.
N,N′-Bis(tolu en e-4-su lfon yl)p a p u a m in e (49). A solution
of 48 (20 mg, 0.021 mmol) and (Ph3P)4Pd (10 mg, 8.3 µmol) in
dry, O2 free THF (200 mL) was stirred under Ar at 55 °C in
the dark for 24 h and rotary evaporated and the residue
partitioned between H2O (5 mL) and EtOAc (5 mL). The
aqueous layer was extracted with EtOAc (2 × 5 mL). The
combined organic phases were washed with brine (5 mL), dried
(MgSO4), and rotary evaporated. Chromatography (hexanes:
EtOAc gradient 8:1 to 4:1) gave 49 (4 mg, 28%) as a pale yellow
gum (slightly impure): TLC Rf ) 0.36 (hexanes:EtOAc 4:1);
1H NMR (300 MHz, CDCl3) δ 7.65 (d, J ) 8.5 Hz, 4H), 7.25 (d,
J ) 8.5 Hz, 4H), 6.15 (d, J ) 14.0 Hz, 2H), 5.95 (dd, J ) 14.0,
6.4 Hz, 2H), 4.35-4.25 (m, 2H), 3.00 (t, J ) 6.4 Hz, 4H), 2.55
(ddd, J ) 9.6, 9.6, 6.4 Hz, 2H), 2.40 (s, 6H), 2.15-1.60 (m, 12H),
1.45-0.70 (m, 14H); HRMS(EI) calcd for C39H52N2O4S2 (M+•),
676.3369, found (M+•) 676.3364.
as a white foam: TLC Rf ) 0.42 (hexanes:EtOAc 4:1); [R]D
)

698 J . Org. Chem., Vol. 61, No. 2, 1996
Barrett et al.
N,N′-Bis[(1R,6S,7R,8S)-7-(h ydr oxym eth yl)bicyclo[4.3.0]-
n on -8-yl]-N,N ′-b is(t r iflu or om e t h a n e su lfon yl)-1,3-p r o-
p a n ed ia m id e (50). A solution of 43 (2.67 g, 3.24 mmol) in
absolute EtOH (150 mL) was stirred under a H2 atmosphere
with Pd/C (10%, 1.30 g) for 14 h. The reaction mixture was
filtered (Celite), washing with EtOH, and the filtrate rotary
evaporated. The residue was chromatographed (hexanes:
EtOAc 2:1) to give 50 (1.98 g, 95%) as a white foam: TLC Rf
) 0.23 (hexanes:EtOAc 2:1); [R]D ) -20.1° (c ) 1.25, CHCl3);
IR (neat) 3569, 3408, 3400, 3394, 2929, 2855, 1447, 1381, 1220,
1191, 1142, 1032, 759, 609 cm-1; 1H NMR (270 MHz, CDCl3) δ
4.32 (m, 2H), 3.74 (d, J ) 5.0 Hz, 4H), 3.58-3.40 (m, 2H),
3.21-3.11 (br m, 2H), 2.13-1.74 (m, 16H), 1.43-0.98 (m, 14H);
45.8, 43.1, 36.7, 31.1, 30.7, 26.1, -9.8; HRMS(EI) calcd for
C32H53N2O4S2F6120Sn2 (M - Me+), 947.1395, found (M - Me+),
947.1396; calcd for C32H53N2O4S2F6118Sn120Sn (M - Me+)
945.1389, found (M - Me+) 945.1392. Anal. Calcd for
C33H56F6N2O4S2Sn2 C, 41.27; H, 5.88; N, 2.92. Found: C,
41.49; H, 5.86; N, 2.96.
N-[(1R,6S,7S,8S)-7-((E)-1-Iod o-2-eth en yl)bicyclo[4.3.0]-
8-n on yl]-N′-[(1R,6S,7S,8S)-7-((E)-1-(t r im et h ylst a n n yl)-
e t h e n -2-yl)b icyclo[4.3.0]-8-n on -yl]-N ,N ′-b is(t r iflu or o-
m eth a n esu lfon yl)-1,3-p r op a n ed ia m id e (53). To a solution
of 52 (0.265 g, 0.276 mmol) in dry Et2O (5.0 mL) under N2
was added a solution of I2 (0.070 g, 0.276 mmol) in Et2O (5.0
mL) via cannula, and the mixture was stirred in the dark at
room temperature for 30 min. The reaction mixture was
poured into H2O (25 mL) and extracted with Et2O (3 × 25 mL).
The combined organic layers were washed with brine (25 mL),
dried (MgSO4), and rotary evaporated. The residue was
chromatographed (hexanes:Et2O 60:1) to give the starting
distannane 52 (61 mg, 24%), the desired product 53 (0.111 g,
44%) as a white foam: [TLC Rf ) 0.39 (hexanes:Et2O 40:1);
[R]D ) +5.0° (c ) 1.10, CHCl3); IR (neat) 2927, 2855, 1383,
13C NMR (67.5 MHz, CDCl3) δ 119.6 (q, 1J
) 324 Hz, 2CF3),
C-F
61.1, 60.6, 49.5, 47.5, 45.0, 43.2, 35.9, 31.0, 30.8, 26.0; HRMS-
(EI) calcd for C25H40N2O6S2F6‚NH4 (M + NH4+) 660.2576, found
(M + NH4+) 660.2576. Anal. Calcd for C25H40F6N2O6S2: C,
46.72; H, 6.27, N, 4.36. Found: C, 47.01; H, 6.33; N, 4.19.
N,N′-Bis[(1R,6S,7S,8S)-7-((E)-1-iod o-2-eth en yl)bicyclo-
[4.3.0]n on -8-yl]-N,N′-b is(t r iflu or om et h a n esu lfon yl)-1,3-
p r op a n ed ia m id e (51). Oxalyl chloride (9.36 mmol, 2.0 M
solution in CH2Cl2) was added to a solution of dry DMSO (1.33
mL, 18.72 mmol) in dry CH2Cl2 (12 mL) at -78 °C under N2.
The mixture was stirred until effervescence had ceased (30
min), and a solution of 50 (1.00 g, 1.56 mmol) in CH2Cl2 (12
mL) was added. The mixture was stirred at -78 °C for 30
min, Et3N (5 mL) was added, and the mixture was slowly
allowed to warm up to 0 °C. The mixture was added to ice-
cold H2O (125 mL) and extracted into EtOAc (3 × 125 mL).
The combined extracts were washed with brine (125 mL), dried
(Na2SO4), filtered, and rotary evaporated.
1223, 1192, 1146, 1111, 762, 608 cm-1 1H NMR (270 MHz,
;
CDCl3) δ 6.42 (dd, J ) 14.4, 8.2 Hz, 1H), 6.22 (d, J ) 14.4 Hz,
1H), 6.12 (d, J ) 19.8 Hz, 1H), 5.91 (dd, J ) 19.1, 6.93 Hz,
1H), 4.39-4.30 (m, 2H), 3.45-3.25 (br m, 2H), 3.00-2.60 (br
m, 2H), 2.45-2.35 (m, 2H), 2.13-1.76 (m, 12H), 1.43-0.87 (m,
14H), 0.15 (s, 2J Sn-H ) 54 Hz, 9H); 13C NMR (67.5 MHz, CDCl3)
1
δ 145.4, 143.7, 133.7, 119.5 (q, J C-F ) 323 Hz, 2CF3), 78.9,
62.7, 61.9, 54.3, 53.8, 50.7, 50.0, 45.6, 43.0, 36.7, 31.0, 30.7,
120
30.4, 26.0, 25.9, -9.7; HRMS(FAB) calcd for C29H44F6IN2O4S2
-
Sn (M - Me+) 909.0713, found (M - Me+) 909.0727. Anal.
Calcd for C30H47F6IN2O4S2Sn: C, 39.02; H, 5.13; N, 3.03.
Found: C, 39.24; H, 4.87; N, 2.94], and finally the diiodide 51
(60 mg, 24%) identical with the previously prepared material.
N,N′-Bis(tr iflu or om eth an esu lfon yl)papu am in e (54). To
a solution of (Ph3P)4Pd (8.7 mg, 8 µmol) in PhMe (25 mL) under
N2 was added as a solution (0.2 mL) of 53 (35 mg, 36 µmol) in
PhMe (5 mL), and the mixture was heated to 100 ( 5 °C in
the dark. The remainder of the solution of 53 was added over
a 6.5 h period with a syringe pump. The resulting mixture
was maintained at 100 ( 5 °C for 2 h, at which time an
additional portion of (Ph3P)4Pd (4.1 mg, 4 µmol) was added.
The resulting mixture was heated to 100 ( 5 °C, with stirring
in the dark, under an atmosphere of N2 for 13.5 h and allowed
to cool to room temperature. The mixture was filtered (Celite),
washing with EtOAc, and the combined filtrates were rotary
evaporated. The residue was dissolved in Et2O, preabsorbed
onto silica gel, and chromatographed (hexanes:Et2O 30:1) to
give 54 (9 mg, 39%) as a cream-colored foam: TLC Rf ) 0.17
(hexanes:Et2O 60:1); [R]D ) +55.9o (c ) 1.05, CHCl3); IR (neat)
A mixture of the crude dialdehyde and CHI3 (7.37 g, 18.72
mmol) in dry 1,4-dioxane (24 mL) and dry THF (4 mL) was
added to a suspension of CrCl2 (6.90 g, 56.16 mmol) in 1,4-
dioxane (24 mL) and THF (4 mL), under N2 at room temper-
ature. The mixture was stirred in the dark for 2 h, then added
to hydrochloric acid (1 N, 800 mL), and extracted into EtOAc
(3 × 250 mL). The combined organic extracts were washed
with brine (250 mL), dried (MgSO4), and rotary evaporated.
The residue was dissolved in CHCl3, absorbed onto silica gel,
and chromatographed (hexanes:Et2O 40:1) to give 51 (0.984
g, 71%) as a white foam: TLC Rf ) 0.28 (hexanes:Et2O 30:1);
[R]D ) +6.4° (c ) 1.05, CHCl3); IR (neat) 2926, 2854, 1383,
1222, 1192, 1145, 1112, 758, 607, 582, 574 cm-1; 1H NMR (270
MHz, CDCl3) δ 6.44 (dd, J ) 14.4, 8.4 Hz, 2H), 6.22 (d, J )
14.4 Hz, 2H), 4.40-4.29 (m, 2H), 3.47-3.35 (m, 2H), 2.94-
2.86 (br, m, 2H), 2.47-2.36 (ddd, J ) 10.1, 10.1, 10.1 Hz, 2H),
2.15-1.77 (m, 12H), 1.48-0.85 (m, 14H); 13C NMR (67.5 MHz,
1
CDCl3) δ 143.7, 119.5 (q, J C-F ) 324 Hz, 2CF3), 79.0, 61.9,
53.9, 50.6, 45.6, 43.0, 36.4, 31.0, 30.4, 25.9; HRMS (FAB) calcd
for C27H37F6I2N2O4S2 (M - H+) 885.0189, found (M - H+)
885.0156. Anal. Calcd for C27H38F6I2N2O4S2: C, 36.58; H,
4.32; N, 3.16. Found: C, 36.87; H, 3.98; N, 3.20.
1
2927, 2854, 1382, 1223, 1186, 1144, 602, 578, 449 cm -1; H
NMR (CDCl3) δ 6.17 (d, J ) 15.1 Hz, 2H), 5.87-5.75 (br m,
2H), 4.48-3.95 (br m, 2H), 3.22 (br t, 4H), 2.59-2.45 (br m,
2H), 2.01-1.58 (m, 12H), 1.46-0.82 (m, 14H); 13C NMR
(CDCl3) δ 147.2, 130.3, 120.1 (q, J ) 324 Hz, 2CF3), 64.2, 47.8,
46.9, 42.5, 35.4, 30.9, 30.7, 29.7, 26.1, 26.0; MS(CI) m/e 650
(M + NH4+), 633 (M + H+), 632, 499, 367, 121; HRMS(CI) calcd
for C27H38F6N2S2O4‚NH4 (M + NH4+), 650.2521, found (M +
NH4+) 650.2547.
Alt er n a t ive P r oced u r e for t h e P r ep a r a t ion of N,N′-
Bis(tr iflu or om eth a n esu lfon yl)p a p u a m in e (54). To a solu-
tion of (Ph3P)4Pd (4.8 mg, 4.0 µmol) and Li2CO3 (1.5 mg, 20
µmol) in PhMe (25 mL) under N2, heated to 100 ( 5 °C, was
added a solution of 51 (30 mg, 34 µmol) and (Me3Sn)2 (18 µL,
85 µmol) in PhMe (5.0 mL) over a 4 h period with a syringe
pump. The resulting mixture was maintained at 100 ( 5 °C,
for 6 h, at which time an additional portion of (Ph3P)4Pd (5.8
mg, 5.0 µmol) was added. The resulting mixture was heated
to 100 ( 5 °C, with stirring in the dark, under an atmosphere
of N2 for 13 h and allowed to cool to room temperature. The
mixture was filtered (Celite), washing with EtOAc, and the
combined filtrates were rotary evaporated. The residue was
dissolved in Et2O, preabsorbed onto silica gel, and chromato-
graphed (hexanes:Et2O 30:1) to give 54 (3 mg, 14%) as an oily
residue. This material was identical to a sample prepared via
the previous method.
N,N′-Bis[(1R,6S,7S,8S)-7-((E)-1-(tr im eth ylstan n yl)eth en -
2-yl)b icyclo[4.3.0]n on -8-yl]-N,N′-b is(t r iflu or om et h a n e-
su lfon yl)-1,3-p r op a n ed ia m id e (52). A mixture of 51 (0.400
g, 0.451 mmol) and (Ph3P)2PdCl2 (32 mg, 45 µmol) and Li2-
CO3 (0.100 g, 1.35 mmol) was taken up in dry, O2 free THF
(40 mL) under N2. (Me3Sn)2 (0.40 mL, 1.93 mmol) was added,
and the mixture was stirred in the dark at 60 °C for 12.5 h.
The reaction mixture was cooled and partitioned between H2O
(200 mL) and EtOAc (200 mL). The aqueous layer was further
extracted with EtOAc (2 × 200 mL). The combined organic
layers were washed with brine (200 mL), dried (MgSO4), and
rotary evaporated. The residue was dissolved in CHCl3,
absorbed onto silica gel, and chromatographed (silica pre-
treated with 1% Et3N in hexanes, hexanes:Et2O 60:1) to give
52 (0.223 g, 51%) as a white foam/gum: TLC Rf ) 0.23
(hexanes:Et2O 60:1); [R]D ) +5.1° (c ) 1.30, CHCl3); IR (neat)
2977, 2925, 2854, 1384, 1233, 1192, 1146, 1138, 1110, 1004,
765, 607, 582 cm-1; 1H NMR (270 MHz, CDCl3) δ 6.17 (d, J )
19.1 Hz, 2H), 5.90 (dd, J ) 19.1, 6.7 Hz, 2H), 4.46-4.35 (br
m, 2H), 3.41-3.25 (br m, 2H), 3.05-2.78 (br m, 2H), 2.51-
2.40 (m, 2H), 2.12-1.76 (m, 12H), 1.43-0.87 (m, 14H), 0.14
2
(s, J Sn-H ) 55 Hz, 18H); 13C NMR (67.5 MHz, CDCl3) δ
1
145.5, 133.5, 119.5 (q, J C-F ) 324 Hz, 2CF3), 62.7, 54.2, 50.1,

Total Synthesis of (+)-Papuamine
J . Org. Chem., Vol. 61, No. 2, 1996 699
(+)-P a p u a m in e Dih yd r och lor id e (56). To a solution of
54 (33 mg, 0.052 mmol) in Et2O (3.0 mL), under N2, was added
a solution of LiAlH4 (0.90 mmol, 1.0 M in Et2O), and the
resulting mixture was heated to reflux for 87 h. The reaction
mixture was cooled to 0 °C, and then a saturated solution of
potassium sodium tartrate (10 drops) was slowly added
dropwise with stirring. The resulting mixture was heated at
reflux for 1 h, allowed to cool to room temperature, and filtered,
and the filtrate was rotary evaporated. The residue was
chromatographed and subsequently further purified by pre-
parative TLC (CH2Cl2:MeOH: NH4OH (35%) 87:12:1) to give
49 (8 mg, 42%) as an off-white solid: TLC Rf ) 0.44 (CH2Cl2:
MeOH: NH4OH (35%) 87:12:1); [R]D ) +179.7° (c ) 0.39,
Ack n ow led gm en t. We thank Professor Oren P.
Andeson and Dr. Mary M. Miller (Colorado State
University) for the X-ray crystallographic studies on 24
and 30 which are included as supporting information,
Glaxo Group Research Ltd., for the most generous Glaxo
endowment (to A.G.M.B), the Wolfson Foundation for
establishing the Wolfson Centre for Organic Chemistry
in Medical Science, the National Institutes of Health
(Grant AI-22252), the J ames Black Foundation, Merck
Sharp & Dohme Research Laboratories, Myco Pharma-
ceuticals Inc., Parke Davis, Pfizer Central Research, The
Proctor and Gamble Company, Quest International,
Rhoˆne-Poulenc Rorer Ltd., Roche Products Ltd., Rohm
and Haas Company, G.D. Searle & Company, Smith-
Kline Beecham, and ZENECA Corporate Research and
Technology for generous support of our program. We
additionally thank Professor Paul J . Scheuer (Univer-
sity of Hawaii at Manoa) for the authentic sample of
papuamine dihydrochloride and Professor Clayton H.
Heathcock (University of California at Berkeley) for
details of their work prior to publication.
MeOH); IR (CHCl3) 3443, 2923, 2852, 1564, 1461, 1186 cm-1
;
1H NMR (500 MHz, MeOH-d4) δ 6.18 (ddd, J ) 15.0, 12.4, 7.0,
2H), 5.75-5.68 (complex m, 2H), 2.98 (br ddd, J ) 8.4, 8.3,
8.2 Hz, 2H), 2.60-2.55 (m, 2H), 2.31-2.20 (m, 6H), 2.19-2.16
(m, 2H), 1.89-1.75 (m, 8H), 1.57-1.54 (m, 2H), 1.37-0.89 (m,
14H); 13C NMR (125 MHz, MeOH-d4) δ 130.8, 129.5, 61.00,
51.22, 48.9, 45.9, 43.8, 42.0, 31.7, 31.2, 30.5, 26.43, 26.41.
Diamine 55 (6 mg, 15.5 µmol) was dissolved in MeOH (10
mL) and H2O (30 mL), and concentrated HCl (1 mL) was slowly
added. The MeOH was removed under reduced pressure, and
the H2O was removed by lyophilization to give 56 (6.8 mg,
100%) as an off-white solid: TLC Rf ) 0.35 (CH2Cl2:MeOH:
NH4OH (35%) 87:12:1); [R]D ) +138.6° (c ) 0.34, MeOH); IR
-1
(CHCl3) 3401, 2927, 2854, 1571, 1448, 1215, 1014, 758 cm
;
Su p p or tin g In for m a tion Ava ila ble: X-ray data for com-
pounds 24 and 30 (9 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
1
UV λmax ) 236, MeOH; H NMR (500 MHz, MeOH-d4) δ 6.52
(complex m, 2H), 5.90-5.86 (complex m, 2H), 3.60 (m, 2H),
3.23-3.16 (m, 2H), 3.08-3.04 (m, 2H), 2.66 (ddd, J ) 10.9,
9.2, 9.1 Hz, 2H), 2.44 (m, 2H), 2.02-1.80 (m 10H), 1.4-0.89
(m 14H); 13C NMR (125 MHz, MeOH-d4) δ 136.1, 130.4, 62.1,
50.5, 46.8, 44.6, 39.1, 32.1, 30.7, 27.0, 24.0; HRMS(FAB) calcd
for C25H41N2: (M+•), 369.3270, found (M+•), 369.3285.
J O951413Z