Synthesis of (-)-haliclonadiamine

Article abstract of DOI:10.1021/ja962162u

Diastereoselective and enantioselective hydrogenation of the racemic β-keto ester 5 to give the enantiomerically pure (96% ee) ester 8 is reported. The conversion of the derived vinylstannane 11 to the antibiotic marine alkaloid (-)-haliclonadiamine (1) i

Full text of DOI:10.1021/ja962162u

22
J. Am. Chem. Soc. 1997, 119, 22-26
Synthesis of (-)-Haliclonadiamine
Douglass F. Taber* and Yanong Wang
Contribution from the Department of Chemistry and Biochemistry, UniVersity of Delaware,
Newark, Delaware 19176
ReceiVed June 26, 1996X
Abstract: Diastereoselective and enantioselective hydrogenation of the racemic â-keto ester 5 to give the
enantiomerically pure (96% ee) ester 8 is reported. The conversion of the derived vinylstannane 11 to the antibiotic
marine alkaloid (-)-haliclonadiamine (1) is described.
Introduction
Scheme 1
(-)-Haliclonadiamine (1), a pentacyclic alkaloid isolated from
the extract of a bright red encrusting marine sponge Haliclona
sp.,1 collected near Palau, shows antifungal and antibiotic
activity. Its structure and relative configuration were established
by 1- and 2-D NMR techniques and confirmed by X-ray
analysis. The extract also contained papuamine (2), the epimer
of 1, which had previously been isolated from an extract of
Haliclona sp.,2 collected near Papua. We report the first
stereocontrolled synthesis of (-)-haliclonadiamine (1).
Scheme 2
At the inception of our work, no synthesis of papuamine or
haliclonadiamine had been reported.3 Our retrosynthetic analysis
(Scheme 1) focused on vinyl stannane 3, which would have to
be prepared in high enantiomeric and diastereomeric purity. We
envisioned that 3 might be prepared from 4, which in turn could
be available by Ru-BINAP hydrogenation of the racemic â-keto
ester 5. We report here an expeditious synthesis of 5 and thus
of 4 and a straightforward strategy for the diastereoselective
coupling of 4 to make 1.
Results and Discussion
Construction of the Bicyclic â-Keto Ester 5. The key to
the synthesis of 5 was the development of a facile entry to the
trans-fused 6/5 ring system. We had earlier established, guided
by computational analysis,4 that under equilibrating conditions,
cyclozirconation (Scheme 2) of the inexpensive 1,7-octadiene
(6) proceeded to give cleanly the trans-fused diastereomer. By
combining this procedure with those developed for carbonylation
of such zirconacycles,5 we were able to prepare the desired trans-
fused ketone 7 in a single step from commercial starting
X Abstract published in AdVance ACS Abstracts, November 1, 1996.
(1) Fahy, E.; Molinski, T. F.; Harper, M. K.; Sullivan, B. W.; Faulkner,
D. J.; Parkanyl, L.; Clardy, J. Tetrahedron Lett. 1988, 29, 3427.
(2) Baker, B. J.; Scheuer, P. J.; Shoolery, J. N. J. Am. Chem. Soc. 1988,
110, 965.
(3) Three enantioselective syntheses of papuamine (2) have been reported;
see: (a) Barrett, A. G. M.; Boys, M. L.; Boehm, T. L. J. Chem. Soc., Chem.
Commun. 1994, 1881. (b) Weinreb, S. M.; Borzilleri, R. M.; Parvez, M. J.
Am. Chem. Soc. 1994, 116, 9789. (c) McDermott, T. S.; Mortlock, A.;
Heathcock, C. H. J. Org. Chem. 1996, 61, 700. (-)-Haliclonadiamine was
prepared as a byproduct in this synthesis of (-)-papuamine.
(4) Taber, D. F.; Louey, J. P.; Wang, Y.; Nugent, W. A.; Dixon, D. A.;
Harlow, R. L. J. Am. Chem. Soc. 1994, 116, 9457.
materials. Carbomethoxylation of the symmetrical 7 then gave
the racemic â-keto ester 5.
S0002-7863(96)02162-2 CCC: $14.00 © 1997 American Chemical Society

Synthesis of (-)-Haliclonadiamine
J. Am. Chem. Soc., Vol. 119, No. 1, 1997 23
Table 1. Hydrogenation of â-Keto Ester 5a
BINAP-RuCl2 will reduce the mismatched enantiomer also,
to a mixture of diastereomers.
The catalyst turnover reported in these studies is lower by
an order of magnitude than that previously observed.6-8 We do
not believe that this limitation is inherent. The reactions were
optimized originally at the half millimole scale, and the amount
of catalyst used was convenient at that scale.
The diastereoselectivity of the hydrogenation depends on the
particular acid promoter8 employed. With HCl, the trans
diastereomer was dominant. With acetic acid as the promoter,
the reaction was still fast, but the major product from the
reduction was the cis diastereomer.
HCl
(mol %)
conversion (%)
(of racemate)
e of desired
diastereomer (%)
13.0
9.5
8.1
98.4
43.5
33.0
29.9
44.7
96
100
100
6.2
Establishment of the Enantiomeric Purity of 9a. Silylation
of the hydroxy ester 4 followed by reduction gave the primary
alcohols 9a,b. The minor amount of 9b, from the cis alcohol
produced in the reduction, was removed at this stage. To
establish the enantiomeric purity of 9a, we prepared the
camphorsulfonate 15. The camphorsulfonate prepared from the
racemic trans alcohol (from sodium borohydride reduction of
the starting â-keto ester) showed nice resolution of the oxygen-
ated carbons in the 13C NMR (δ 74.0/73.8 and 70.0/69.9). By
this measurement, 9a was a 98:2 ratio of enantiomers.
a Hydrogenation pressure, 52 psi; temperature, 80-85 °C; time, 14
h; HCl, methanolic HCl; RuCl2-BINAP, 1.2 mol %.
Kinetic Resolution by Catalytic Hydrogenation. With the
racemic â-keto ester 5 in hand, we were then faced with the
problem of carrying it on to the enantiomerically pure and
diastereomerically defined â-hydroxy ester 4. We thought that
this might be accomplished by kinetic resolution under the
conditions of Ru-BINAP hydrogenation.6,7
The reduction was known6,7 to give predominantly the trans-
â-hydroxy ester when applied to a cyclic â-keto ester. This
reduction is thought to proceed by complexation of the
intermediate Ru-H species with the ester carbonyl with subse-
quent delivery of the nucleophilic H to the ketone. As one
enantiomer of the â-keto ester would fit the twist of the BINAP
ligand and the other would not, we thought that one enantiomer
of the ketone might reduce much more rapidly than the other.
Kinetic resolution in this manner had been reported8 but not
with good diastereocontrol.
Construction of the Iodo Stannane 18. Following this
procedure, we were able to prepare alcohol 9a in high
enantiomeric and diastereomeric purity in just five steps from
1,7-octadiene (6). To move on to the haliclonadiamine precursor
18, we had to homologate the primary alcohol of 9a to the (E)-
vinylstannane. We also had to construct the N,N′-diaminopro-
pane from two equivalents of the secondary diol, with inversion
of absolute configuration in one case and with retention
(probably double inversion) in the other.
To effect homologation, alcohol 9a was oxidized to the
aldehyde, which was subjected without purification to the Ohira
procedure9 to give the alkyne 10. Our experience has been that
this simple procedure, which can be effected at ambient
temperature, uses easily available reagents, and is not sensitive
to stoichiometry, is in general the method of choice for this
common transformation. Deprotection of 10 followed by radical
addition of tributyltin hydride10 then provided an 87% yield of
the (E)-vinylstannane 11.
We next faced the difficulty of inverting the hindered
secondary alcohol of 11. To this end, we converted a portion
of the stannane 11 that we had prepared to the iodide 12. As
expected, Mitsunobu coupling12 with 4-nitrobenzoic acid initially
was sluggish. We were pleased to observe that substitution of
benzene for THF as the reaction medium solved this problem.
Mild transesterification then liberated the desired cis alcohol
13, in 75% overall yield from the iodide 12.
In the event (Table 1), we found that the racemic â-keto ester
5 only hydrogenated smoothly in the presence of added HCl.8
By optimizing the amount of HCl added, we could control the
proportion of total ketone reduced. We were pleased to observe
that we could convert nearly 90% of the “matched” ketone
without significant reduction of the other enantiomer. It is
interesting that if too much HCl is added initially, the (S)-
(5) (a) Rousset, C. J.; Swanson, D. R.; Lamaty, F.; Negichi, E.-i.
Tetrahedron Lett. 1989, 30, 5105. (b) Akita, M.; Yasuda, H.; Yamamoto,
H.; Nakamura, A. Polyhedron 1991, 10, 1.
(6) For the first report of the reduction of Ru-BINAP-mediated
hydrogenation of â-keto esters to provide the â-hydroxy esters with excellent
yield and enantioselectivity, see: Noyori, R.; Ohkuma, T.; Kitamura, M.
J. Am. Chem. Soc. 1987, 109, 5856.
(7) For further studies of Ru-BINAP-mediated hydrogenation of â-keto
esters, see: (a) Cesarotti, E.; Mauri, A.; Pallavicini, M.; Villa, L.
Tetrahedron Lett. 1991, 32, 4381. (b) Kitamura, M.; Tokunaga, M.; Ohkuma,
T.; Noyori, R. Tetrahedron Lett. 1991, 32, 4163. (c) Kitamura, M.;
Tokunaga, M.; Noyori, R. J. Org. Chem. 1992, 57, 4053. (d) Taber, D. F.;
Silverberg, L. J. Tetrahedron Lett. 1991, 32, 4227. (e) King, S. A.;
Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57,
6689. (f) Kitamura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993,
115, 144. (g) Genet, J. P.; Pinel, C.; Ratovelomanana-Vidal, V.; Mallart,
S.; Pfister, X.; Cano De Andrade, M. C.; Laffitte, J. A. Tetrahedron 1994,
5, 665. (h) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki,
K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.;
Takaya, H. J. Org. Chem. 1994, 59, 3064. (i) Burk, M. J.; Harper, T. G. P.;
Kalberg, C. S. J. Am. Chem. Soc. 1995, 117, 4423.
The final challenge that we faced was construction of the
N,N′-dialkyl 1,3-diaminopropane of 18 (Scheme 3). It seemed
plausible that Mitsunobu coupling could again be efficacious.
The key to this approach was the selection of an activating group
that would make the N-H sufficiently acidic to participate in
the Mistsunobu reaction while leaving the anion sufficiently
(9) Ohira, S. Synth. Commun. 1989, 19, 561.
(8) (a) For the role of added acid in Ru-BINAP hydrogenation, see ref
7d,e. (b) The procedure described here represents a significant improvement
over that previously described for kinetic resolution of a bicyclic â-keto
ester: Kitamura, M.; Ohkuma, T.; Tokunaga, M.; Noyori, R. Tetrahedron:
Asymmetry 1990, 1, 1.
(10) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. (b)
Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem. 1990, 55, 1857.
(11) Hanson, R. N.; El-Wakil, H. J. Org. Chem. 1987, 52, 3687.
(12) (a) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(b) Caine, D.; Kotian, P. L. J. Org. Chem. 1992, 57, 6587.

24 J. Am. Chem. Soc., Vol. 119, No. 1, 1997
Taber and Wang
with liquid N2 and evacuated to about 0.001 mmHg. The solidified
reaction mixture was maintained at -78 °C, and CO was charged into
the reaction container so that the pressure of CO was kept at 1.1-1.2
atm for 1 h, until no obvious CO absorbance was observed. The
reaction mixture was warmed to room temperature and stirred 12 h.
HOAc (25.1 mL) was added to the dark reaction mixture. The resulting
yellow solution was stirred at room temperature for 30 min; then the
reaction was quenched with 10% aqueous H2SO4. The mixture was
extracted with 20% EtOAc/petroleum ether. The combined organic
extract was dried (Na2SO4) and concentrated. The residue was distilled
to give 11.5 g (79% yield) of the ketone 7: bp0.05mmHg ) 80-90 °C
(pot); 1H NMR δ 2.44-2.28 (m, 2 H), 2.05-1.02 (m, 12 H); 13C NMR
δ 218.3 (C), 45.6 (CH2), 43.9 (CH), 31.3 (CH2), 26.1 (CH2).
Scheme 3
To a suspension of NaH (60% in mineral oil, 579 mg, 14.5 mmol)
in DME (8 mL) containing a trace of methanol was added dimethyl
carbonate (978 mg, 10.9 mmol). The mixture was heated to reflux for
10 min, then the bicyclic cyclopentanone 7 (500 mg, 3.62 mmol) was
added over two h. The reaction mixture at maintained at reflux
overnight, then was quenched with HOAc (1.0 mL) and partitioned
between H2O and CH2Cl2. The combined organic extract was dried
(Na2SO4), concentrated and chromatographed to give 489 mg (55%
yield from 1,7-octadiene) of the â-keto ester 5: TLC Rf ) 0.34 (10%
1
nucleophilic. The activating group should also be easily
removed. We found that the N,N′-bistriflamide nicely met these
criteria.13 While the Mitsunobu coupling again worked poorly
in THF, reaction of 11 in benzene with two equivalents of N,N′-
bistriflyl-1,3-diaminopropane (16) gave clean conversion to the
monoalkylated diamide 17. The final Mitsunobu coupling of
17 with 13 also proceeded smoothly in benzene, to give the
desired N,N′-dialkylated diamide 18.
EtOAc/petroleum ether); H NMR δ 3.72 (s, 3 H), 2.84 (d, J ) 12.4
Hz, 1 H), 2.42 (dd, J ) 17.9, 6.7 Hz, 1 H), 2.03-1.16 (m, 11 H); 13
C
NMR δ u 210.1, 169.5, 44.9, 31.1, 30.2, 26.0, 25.8; d 61.7, 52.2, 47.3,
41.0; IR (neat) (cm-1) 1759, 1728, 1436; MS (CI) m/z 196 (M+, 11),
168 (58), 94 (100). HRMS: m/e calcd for C11H17O3(MH+), 197.1178;
found, 197.1177.
BINAP-RuCl2. A 5 mL reactivial equipped with a stir vane was
charged with (RuCl2-cyclooctadiene)n (39 mg), (S)-(-)-2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl (100 mg), triethylamine (200 mg),
and toluene (4 mL) in the dry box. The vial was capped securely and
then heated in a 140-145 °C oil bath for 3 h, until a clear red solution
was achieved. The contents of the vial were transferred with toluene
to a 100 mL round-bottom flask under nitrogen. The reaction mixture
was concentrated in Vacuo under the Schlenk line, and the residue was
taken up in THF (10 mL) in the dry box. The brown THF solution
was divided into 10 × 1 mL portions, which were stored in stoppered
vials under N2.
Hydroxy Ester 8. Under N2, a modified Parr bottle equipped with
a stir bar was charged with racemic bicyclic â-keto ester 5 (250 mg,
1.28 mmol), methanol (1.65 mL), BINAP-RuCl2 as prepared above
(0.5 mL, from 5 mg of BINAP), and 1.35 mL (0.162 mmol) of a 0.12
N HCl-methanol solution (prepared by dissolving 1.0 mL of concen-
trated aqueous HCl in 99 mL of methanol). The bottle was flushed
with hydrogen for 5 min, and hydrogenation was then carried out at
50-52 psi of H2 for 14 h in an 80-85 °C oil bath. The reaction mixture
was concentrated in Vacuo and chromatographed to give 132 mg of
residual â-keto ester and 110 mg (87% of theory) of the product
hydroxy ester 8 as a colorless oil, which subsequent analysis showed
to be 96% ee: TLC Rf ) 0.19 (10% EtOAc/petroleum ether); 1H NMR
δ 4.48 (m, 1 H), 3.71 (s, 3 H), 2.75 (s, br, 1 H), 2.33 (dd, J ) 11.1, 5.1
Hz, 1 H), 1.95-0.98 (m, 12 H); 13C NMR δ u 175.3, 41.0, 31.4, 30.5,
25.9 (2); d 75.0, 59.9, 51.6, 49.2, 43.8; IR (neat) (cm-1) 3445, 1733;
MS (CI) m/z 199 (M+ + H, 1), 170 (80), 74 (100). HRMS: m/e calcd
for C11H19O3(MH+), 199.1334; found, 199.1328.
Synthesis of (-)-Haliclonadiamine (1). With the iodo
stannane 18 in hand, the final assembly of (-)-haliclonadiamine
(1) was straightforward (Scheme 3). Thus, following the report
by Barrett3a in the synthesis of (+)-papuamine, slow addition
of 18 to 20 mol % of Pd(PPh3)4 at 100-105 °C in toluene
followed by 36 h at reflux gave the cyclized product 19 in 43%
yield. Deprotection of the bistriflamide 19 with LiAlH4 in
ether14 (LiAlH4 in THF was not effective) then gave the free
1
base of (-)-haliclonadiamine (1). The H NMR, 13C NMR,
and MS of synthetic 1 were identical with the spectra of natural
1
(-)-haliclonadiamine.1 The H NMR was also identical with
that recorded for a synthetic sample.3c
Conclusion
During the course of this total synthesis of the unusual marine
alkaloid (-)-haliclonadiamine (1), an efficient diastereoselective
preparation of the â-keto ester 5 via intramolecular diene
cyclozirconation and carbonylation was developed. The dias-
tereoselective and enantioselective Ru-BINAP-mediated hy-
drogenation of â-keto ester 5 to the â-hydroxy ester 4 was also
achieved. Finally, the sequential Mitsunobu coupling with
bistriflamide 16 as the nucleophile proved very efficient even
with the sterically hindered secondary alcohols 11 and 13.
Protected Diol 9. A mixture of the hydroxy ester (581 mg, 2.93
mmol), imidazole (999 mg, 14.7 mmol), and tert-butyldimethylsilyl
chloride solution (2.0 M in CH2Cl2, 2.2 mL, 4.40 mmol) in dry CH2-
Cl2 (14 mL) was stirred at room temperature overnight. The reaction
mixture was partitioned between saturated aqueous NaHCO3 and CH2-
Cl2. The combined organic extract was dried (Na2SO4), concentrated,
and chromatographed to give 920 mg of the silyl ether ester (99%) as
a colorless oil: TLC Rf ) 0.80 (10% EtOAc/petroleum ether); 1H NMR
δ 4.42 (m, 1 H), 3.85 (s, 3 H), 2.30 (dd, 1 H), 2.90-1.42 (m, 6 H),
1.35 (m, 4 H), 0.90 (s, 9 H), -0.02 (s, 6 H); 13C NMR δ 175.75; IR
(neat) (cm-1) 2927, 2855, 2361, 1735; MS (EI) m/z 312 (M+, 1), 255
(69), 89 (100). HRMS: m/e calcd for C17H31O3Si (M+), 312.2042;
found, 312.2056.
Experimental Section15
â-Keto Ester 5. To 1,7-octadiene (11.52 g, 0.105 mol) and
zirconocene dichloride (36.7 g, 0.125 mol) in toluene (250 mL) was
added n-BuLi (1.99 M, 126 mL) via syringe at -78 °C over 30 min
under argon. The resulting light yellow mixture was stirred at room
temperature and then warmed to 75-80 °C for 3 h. After cooling to
room temperature, the dark brown reaction mixture was further cooled
(13) After this work was completed, an independent report of efficient
Mitsunobu coupling of an alkyl triflamide appeared; see: Bell, K. E.; Knight,
D. W.; Gravestock, M. B. Tetrahedron Lett. 1995, 36, 8681.
(14) (a) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 3839.
(b) Hendrickson, J. B.; Bergeron, R.; Sternbach, D. J. Am. Chem. Soc. 1973,
95, 3412.
Dibal-H (1.0 M solution in CH2Cl2, 1.64 mL) was added dropwise
via syringe to the solution of the silyl ether ester (170 mg, 0.545 mmol)
in CH2Cl2 (5 mL) at -78 °C over 15 min. The reaction mixture was
(15) For general experimental procedures, see: Taber, D. F.; Houze, J.
B. J. Org. Chem. 1994, 59, 4004.

Synthesis of (-)-Haliclonadiamine
J. Am. Chem. Soc., Vol. 119, No. 1, 1997 25
stirred at -78 °C for 1 h and then partitioned between saturated aqueous
NaHCO3 and CH2Cl2. The combined organic extract was dried (Na2-
SO4), concentrated, and chromatographed to give 117 mg of trans-
monoprotected diol 9a (76% yield) and 6 mg (3.9%) of cismonopro-
tected diol 9b.
9a: TLC Rf ) 0.53 (10% EtOAc/petroleum ether); 1H NMR δ 4.08
(m, 1 H), 3.75 (dd, J ) 10.5, 4.6 Hz, 1 H), 3.65 (m, 1 H), 1.86-0.91
(m, 13 H), 0.88 (s, 9 H), 0.059 (s, 3 H), 0.055 (s, 3 H); 13C NMR δ u
63.7, 41.4, 31.7, 30.4, 26.3, 26.2, 18.0; d 75.8, 56.9, 46.5, 43.9, 25.8,
-4.4, -4.8; IR (neat) (cm-1) 3359, 1471, 1446; MS (EI) m/z 269 (M+
- Me, 1), 135 (90), 75 (100); HRMS: m/e calcd for C16H33O2Si (MH+),
285.2250; found, 285.2255.
9b: TLC Rf ) 0.65 (10% EtOAc/petroleum ether); 1H NMR δ 4.38
(dd, J ) 13.4, 7.1 Hz, 1 H), 3.85 (ddd, J ) 3.0, 2.9, 11.5 Hz, 1 H),
3.61 (m, 1 H), 2.90 (dd, J ) 9.6, 3.3 Hz, 1 H), 2.20-2.10 (m, 1 H),
1.92-0.98 (m, 11 H), 0.88 (s, 9 H), 0.059 (s, 3 H), 0.055 (s, 3 H).
Camphorsulfonate Derivative 15. To the trans monoprotected diol
9a (5 mg, 0.0176 mmol) and triethylamine (5.3 mg, 0.0528 mmol) in
CH2Cl2 (1 mL) was added (1S)-camphorsulfonyl chloride (6.6 mg,
0.0264 mmol). The mixture was stirred at room temperature for 24 h
and then concentrated. The residue was chromatographed to give 8.5
mg (99%) of product 15: TLC Rf ) 0.72 (5% petroleum ether/tert-
butyl methyl ether/CH2Cl2 ) 8/2/1).
was concentrated and chromatographed to give 425 mg (87% yield) of
the vinylstannane product 11 as a mixture of isomers (E:Z ) 16:1):
TLC Rf ) 0.57 (10% EtOAc/petroleum ether); [R]D ) 5.4° (c ) 0.0075,
1
CH2Cl2); H NMR δ 5.92 (d, J ) 18.8 Hz, 1 H), 5.79 (dd, J ) 18.8,
7.1 Hz, 1 H), 4.05 (m, 1 H), 2.02-0.77 (m, 40 H); 13C NMR δ u 40.8,
31.8, 30.0, 29.1, 27.2, 26.4, 26.3, 9.5; d 150.3, 128.8, 77.7, 64.4, 50.8,
43.8, 13.6; IR (neat) (cm-1) 3332, 2595; MS (EI) m/z 455 (1), 399
(100), 177 (25). HRMS: m/e calcd for C19H35OSn (M+
399.1709. found, 399.1717.
- Bu),
Vinyl Iodide 12. To a solution of the vinylstannane 11 (135 mg,
0.30 mmol) in Et2O (2 mL) was added iodine (83 mg, 0.33 mmol).
After 30 min, the reaction mixture was partitioned between Et2O (20
mL) and 10% aqueous Na2S2O3. The combined organic extract was
dried (Na2SO4), concentrated and chromatographed to give 83 mg (96%
yield) of the vinyl iodide 12 as a colorless oil. TLC Rf ) 0.29 (5%
EtOAc/petroleum ether); [R]D) -36.4° (c ) 0.006, CH2Cl2); 1H NMR
δ 6.41 (dd, J ) 13.9, 9.0 Hz, 1 H), 6.06 (d, J ) 13.9 Hz, 1 H), 4.06
(m, 1 H), 2.02-1.94 (m, 1 H), 1.91-0.88 (m, 12 H); 13C NMR δ u
40.8, 31.6, 29.7, 26.1, 26.0; d 147.6, 143.1, 76.8, 62.5, 50.3, 43.4; IR
(neat) (cm-1) 3332, 1602, 1446; MS (EI) m/z 292 (3), 165 (15), 147
(42), 76 (100). HRMS: m/e calcd for C11H17O1I (M+), 292.0324. found,
292.0358.
Inverted Hydroxy Vinyl Iodide 13: To the vinyl iodide 12 (45
mg, 0.15 mmol), triphenylphosphine (201 mg, 0.77 mmol), and
4-nitrobenzoic acid (113 mg, 0.68 mmol) in benzene (3 mL) was added
DEAD (134 mg, 0.77 mmol) dropwise via syringe. The reaction
mixture was stirred at room temperature for 14 h and then concentrated
and chromatographed to give 55 mg (82%) of the 4-nitrobenzoate
product as a white foam: TLC Rf ) 0.75 (5% EtOAc/petroleum ether);
1H NMR δ 8.28 (d, J ) 9.0 Hz, 2 H), 8.14 (d, J ) 9.0 Hz, 2 H), 6.52
(dd, J ) 14.5, 8.9 Hz, 1 H), 6.11 (d, J ) 14.5, 1 H), 5.45 (dt, J ) 7.4,
4.5 Hz, 1 H), 2.56-2.45 (m, 1 H), 2.36-2.35 (m, 1 H), 1.92-1.77
(m, 4H), 1.54-0.86 (m, 7H); 13C NMR δ u 165.1, 135.9, 129.0, 39.2,
31.6, 29.8, 26.2, 26.0; d 143.5, 130.6, 130.5, 129.0, 123.6, 76.9, 54.5,
48.6, 44.0.
A mixture of 4-nitrobenzoate (40 mg, 0.091 mmol) and anhydrous
K2CO3 (0.182 mmol) in methanol (4 mL) was stirred for 24 h. The
reaction mixture was concentrated, then partitioned between 50%
EtOAc/petroleum ether and water. The combined organic extract was
dried (Na2SO4) and concentrated. The residue was chromatographed
to give 25 mg (96%) of the desired vinyl iodide 13 as a white foam:
TLC Rf ) 0.43 (10% EtOAc/petroleum ether). [R]D ) -72.0° (c )
0.0058, CH2Cl2); 1H NMR δ 6.58 (dd, J ) 14.5, 9.2 Hz, 1 H), 6.05 (d,
J ) 14.5 Hz, 1 H), 4.26 (m, 1 H), 2.30 (m, 1 H), 2.04-1.97 (m, 1 H),
1.85-1.71 (m, 4H), 1.58-0.80 (m, 7H); 13C NMR δ u 41.5, 32.7, 29.9,
26.4, 26.1; d 145.1, 128.3, 73.1, 57.9, 47.6, 44.3; MS (EI) m/z 292
(M+, 1), 147 (40), 76 (100). HRMS: m/e calcd for C11H17O1I (M+),
292.0324; found, 292.0348.
N,N′-Bistriflyl-1,3-diaminopropane (16). To the mixture of 1,3-
diaminopropane (200 mg, 2.70 mmol) and Et3N (1.09 g, 10.8 mmol)
in CH2Cl2 (5 mL) was added triflic anhydride (1.60 g, 5.68 mmol) at
-78 °C over 5 min. The mixture was stirred at -78 °C for 1 h; then
the reaction was quenched with saturated aqueous NaHCO3 and the
mixture partitioned between CH2Cl2 and water. The combined organic
extract was dried (Na2SO4), concentrated, and chromatographed to give
674 mg of 16: TLC Rf ) 0.12 (10% EtOAc/petroleum ether); 1H NMR
δ 5.45 (bs, 2 H), 3.45 (t, J ) 6.8 Hz, 4 H), 1.90 (m, 2 H); 13C NMR
δ 119.6 (CF3, J ) 318 Hz), u 40.5, 31.1; MS (EI) m/z 338 (1), 162
(55), 69 (100).
Racemic derivative: 1H NMR δ 4.31 (m, 2 H), 4.06 (m, 1 H),
3.07 (d, J ) 15.0 Hz, 1 H), 2.95 (d, J ) 15.0 Hz, 1 H), 2.54-2.8 (m,
1 H), 2.12-0.90 (m, 19 H), 1.14 (s, 3 H), 0.88 (s, 9 H), 0.059 (s, 3 H),
0.055 (s, 3 H); 13C NMR δ u 214.4, 70.0 + 69.9 (1:1), 57.9, 47.9,
46.6, 42.6, 41.6, 31.5, 30.2, 26.9, 26.2, 26.1, 24.9 (CH2), 19.9, 17.9; d
74.0 + 73.8 (1:1), 54.5, 46.8, 43.6, 42.8, 25.8, 19.9, 19.7, -4.8, -4.8.
1
Enantiomerically enriched derivative: H NMR δ 4.34 (dd, J )
9.7, 4.6 Hz, 1 H), 4.25 (dd, J ) 9.7, 5.1 Hz, 1 H), 3.07 (d, J ) 15.0
Hz, 1 H), 2.95 (d, J ) 15.0 Hz, 1 H), 2.54-2.8 (m, 1 H), 2.12-0.90
(m, 19H), 1.14 (s, 3H), 0.88 (s, 9H), 0.059 (s, 3H), 0.055 (s, 3H); 13
C
NMR δ u 214.4, 70.0 + 69.9 (98:2), 57.9, 47.9, 46.6, 42.6, 41.6, 31.5,
30.2, 26.9, 26.2, 26.1, 24.9 (CH2), 19.9, 17.9; d 74.0 + 73.8 (98:2),
54.5, 46.8, 43.6, 42.8, 25.8, 19.9, 19.7, -4.8, -4.8; IR (neat) (cm-1
1750, 1700, 1653, 1558.
)
Protected Alkyne 10. DMSO (441 mg, 5.65 mmol) in dry CH2Cl2
(2 mL) was added dropwise to a solution of oxalyl chloride (388 mg,
3.06 mmol) in CH2Cl2 (3 mL) at -78 °C. After 10 min, the alcohol
9a (668 mg, 2.35 mmol) in CH2Cl2 (2 mL) was added. The reaction
mixture was stirred at -78 °C for 1 h and then warmed to -50 °C.
Triethylamine (1.19 g, 11.76 mmol) was added, the ice bath was
removed, and the mixture was allowed to warm to room temperature
for 5 h. The reaction mixture was partitioned between saturated
aqueous NaHCO3 and CH2Cl2. The combined organic extract was dried
(Na2SO4) and concentrated in Vacuo to provide a light yellow syrup.
To the crude aldehyde in anhydrous methanol (10 mL) were added
dimethyl (1-diazo-2-oxopropyl)phosphonate (903 mg, 4.70 mmol) and
K2CO3 (811 mg, 5.88 mmol) successively at 0 °C. The reaction mixture
was gradually warmed to room temperature overnight and then
partitioned between saturated aqueous NaHCO3 solution and CH2Cl2.
The combined organic extract was dried (Na2SO4), concentrated, and
chromatographed to give 553 mg (85% from alcohol 9a) of the alkyne
1
product 10. TLC Rf ) 0.52 (10% EtOAc/petroleum ether); H NMR
δ 4.23 (m, 1 H), 2.09 (d, J ) 1.8 Hz, 1 H), 2.18-0.98 (m, 13 H), 1.04
(s, 9 H), 0.06 (s, 3 H), 0.05 (s, 3 H); 13C NMR δ u 86.6, 69.4, 41.8,
31.5, 30.0, 26.0, 25.9, 18.1; d 78.9, 72.3, 51.9, 46.8, 43.4, 25.9, -4.5,
-4.8; MS (EI) m/z 278 (1), 221 (100), 145 (27). HRMSm/z calcd for
C17H30OSi, 278.2066; found, 278.2059.
Vinylstannane Bistriflamide 17. To the vinylstannane 11 (133 mg,
0.29 mmol), N,N′-bistriflyl-1,3-diaminopropane (16) (194 mg, 0.58
mmol), and triphenylphosphine (191 mg, 0.73 mmol) in benzene (3
mL) was added DEAD (127 mg, 0.73 mmol) via syringe dropwise at
room temperature. The reaction mixture was stirred at room temper-
ature for 20 h and then concentrated. The residual syrup was taken up
in ether (5 mL), and the suspension was filtered to remove the white
precipitate. The filtrate was concentrated and chromatographed to give
74 mg (66%) of the desired product 17 as a colorless oil: TLC Rf )
0.69 (10% EtOAc/petroleum ether); [R]D ) 15.2° (c ) 0.0025, CH2-
Vinylstannane 11. The mixture of starting material 10 (180 mg,
0.79 mmol) and Dowex-50 sulfonic acid resin (1.0 g) in methanol (5
mL) was stirred at room temperature overnight. The reaction mixture
was filtered, and the solid was washed thoroughly with methanol. The
filtrate was concentrated in Vacuo, and the residue was chromatographed
to give 122 mg (95% yield) of the deprotected hydroxy alkyne: TLC
1
Rf ) 0.52 (10% EtOAc/petroleum ether); H NMR δ 4.30 (m, 1 H),
2.12-0.91 (m, 16 H).
To a solution of the hydroxy alkyne (188 mg, 1.15 mmol) and AIBN
(10 mg) in toluene (3 mL) was added Bu3SnH at room temperature
under argon. The reaction mixture was heated at 100-105 °C for 3 h
and then stirred at room temperature overnight. The reaction mixture
1
Cl2); H NMR δ 6.07 (d, J ) 19.0 Hz, 1 H), 5.86 (dd, J ) 7.0, 19.0
Hz, 1 H), 5.03 (m, 1 H), 4.31 (m, 1 H), 3.54-3.13 (m, 6H), 2.38 (m,
1 H), 2.20-0.80 (m, 39H); 13C NMR δ 119.5 (CF3, J ) 325 Hz); u

26 J. Am. Chem. Soc., Vol. 119, No. 1, 1997
Taber and Wang
a white foam: TLC Rf ) 0.57 (4% EtOAc/petroleum ether); [R]D
41.7, 31.2, 30.8, 30.6, 29.3, 29.1, 29.0, 28.9, 27.3, 26.1, 26.0, 9.4; d
145, 133.6, 50.4, 43.2, 13.6; MS (EI) m/z 455 (1), 399 (100), 285 (17).
HRMS: m/e calcd for C19H35OSn (M+ - Bu); 397.1704; found,
397.1704.
)
1
-7.8° (c ) 0.005, CH2Cl2); H NMR δ 6.19 (d, J ) 14.7 Hz, 2 H),
5.51-5.45 (m, 2 H), 5.22 (m, 1 H), 4.36 (m, 1 H), 3.37-3.11 (m, 4
H), 2.59-2.52 (m, 2 H), 2.15-0.80 (m, 26 H); 13C NMR δ 120.2 (CF3,
J ) 320 Hz); u 65.3, 64.0, 39.7, 34.4, 31.9, 31.5, 31.0, 30.5, 29.7,
29.5, 29.4, 28.4, 26.4; d 1345, 127.5, 125.2, 124.2, 65.2, 52.2, 49.5,
47.6, 43.8, 43.0, 42.9, 30.0; MS (EI) m/z 632 (20), 499 (95), 191 (100).
(-)-Haliclonadiamine (1). In a 1 mL reactivial, LiAlH4 (1.0 M in
Et2O, 0.5 mL, 0.5 mmol) was added to a solution of 19 (3.0 mg, 3.1
µmol) in Et2O (0.2 mL), and the mixture was heated (sealed tube, 70
°C) for 4 days. The reaction mixture was cooled to 0 °C, and then
saturated aqueous sodium potassium tartrate solution (2 drops) was
added. The reaction mixture was heated to reflux for 1 h and then
was cooled to room temperature and filtered with EtOAc. The
combined organic was concentrated in Vacuo. The residue was purified
by reverse phase HPLC to give 0.6 mg (34% yield) of 1: TLC Rf )
0.30 (CH2Cl2/MeOH/35% NH4OH ) 87/12/1); 1H NMR δ 6.25-6.18
(m, 1 H), 6.14-6.06 (m, 1 H), 5.58-5.50 (m, 1 H), 5.35-5.28 (m, 1
H), 3.20-2.90 (m, 2 H), 2.65-1.90 (m, 6 H), 1.90-0.98 (m, 26 H);
13C NMR δ 134.0, 133.9, 132.5, 132.0, 68.2, 62.6, 60.1, 51.5, 51.2,
49.6, 48.7, 47.1, 44.8, 44.0, 41.0, 37.0, 32.25, 32.19, 31.6, 30.5, 30.1,
26.8, 26.5, 26.34, 26.31; MS (CI) m/z 369 (12), 279 (4), 185 (100).
HRMS (CI): m/e calcd for C25H40N2 (M+): 368.3191; found, 368.3177.
Iodo Stannane 18. To the mixture of vinylstannane 17 (20 mg,
0.026 mmol), inverted iodo alcohol 13 (7.5 mg, 0.026 mmol), and
triphenylphosphine (8.5 mg, 0.032 mmol) in benzene (0.75 mL) was
added DEAD (5.6 mg, 0.032 mmol) dropwise via syringe at room
temperature. The reaction mixture was stirred for 28 h and then
concentrated and chromatographed to give 2.5 mg (13%) of the
recovered vinyl stannane starting material and 15 mg (56% yield based
on starting material not recovered) of product 18 as a white foam: TLC
Rf ) 0.82 (10% EtOAc/petroleum ether); [R]D ) 9.2° (c ) 0.004, CH2-
1
Cl2); H NMR δ 6.31 (dd, J ) 14.6, 8.63 Hz, 1 H), 6.15 (d, J ) 14.6
Hz, 1 H), 6.08 (d, J ) 19.0 Hz, 1 H), 5.85 (dd, J ) 19.0, 6.82 Hz, 1
H), 4.36 (m, 1 H), 3.42-2.82 (m, 6 H), 2.40-0.92 (m, 44 H), 0.87 (t,
J ) 7.20 Hz, 9 H); 13C NMR δ 119.5 (CF3, J ) 320 Hz); u 60.4, 43.4,
31.5, 31.2, 30.7, 29.4, 29.1, 29.0, 27.3, 26.9, 26.2, 26.0, 25.9, 25.6,
21.0, 9.5; d 145.5, 133.2, 115.8, 64.0, 62.6, 60.4, 56.4, 54.9, 50.3, 49.1,
44.8, 43.4, 43.2, 13.7; IR (neat) (cm-1) 1653, 1457, 1383; MS (EI)
m/z 1049 (M+, 1), 993 (100), 179 (64).
Bistriflylhaliclonadiamine 19. To a solution of (PPh3)4Pd (8.4 mg,
0.0082 mmol) in toluene (20 mL) under argon was added one-twentieth
of iodo stannane 18 (36 mg, 0.036 mmol) in toluene (5.0 mL), and the
mixture was heated to 100-105 °C in the dark. The remaining solution
of 18 was added over 6 h via syringe pump. The reaction mixture
was maintained at 100-105 °C for 2 h, and additional (PPh3)4Pd (4.2
mg, 0.0041 mmol) was added. The resulting mixture was maintained
at 100-105 °C for 14 h in the dark and then cooled to room
temperature. The mixture was filtered through Celite, washing
thoroughly with EtOAc. The combined filtrate was concentrated and
chromatographed to give 9.5 mg (43%) of the cyclized product 19 as
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical Society,
for support of this work. We also thank Professor Clayton
Heathcock for providing spectra of both natural and synthetic
(-)-haliclonadiamine. This article is dedicated to John Alex-
ander Oates, mentor and friend.
JA962162U