Synthesis of unsaturated polyazamacrolides from the ladybird beetle Subcoccinella vigintiquatuorpunctata

Article abstract of DOI:10.1021/jo001200w

The pupal defensive secretion of the ladybird beetle Subcoccinella vigintiquatuorpunctata consists of a mixture of macrocyclic polyamines (polyazamacrolides, PAMLs) dominated by three dimeric, 30-membered bislactones (1, 2, and 3), which represent the three possible head-to-tail combinations of the two building blocks (S)-(Z)-11-(2-hydroxyethylamino)-5-tetradecenoic acid (4) and (S)-(5Z,8Z)-11-(2-hydroxyethylamino)-5,8-tetradecadienoic acid (5). We now report the synthesis of these three alkaloids via a route involving the nucleophilic opening of a chiral aziridine as a common step.

Full text of DOI:10.1021/jo001200w

J . Org. Chem. 2001, 66, 1075-1081
1075
Syn th esis of Un sa tu r a ted P olya za m a cr olid es fr om th e La d ybir d
Beetle Su bcoccin ella vigin tiqu a tu or pu n cta ta
Matthew R. Gronquist and J errold Meinwald*
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853
circe@cornell.edu
Received August 7, 2000
The pupal defensive secretion of the ladybird beetle Subcoccinella vigintiquatuorpunctata consists
of a mixture of macrocyclic polyamines (polyazamacrolides, PAMLs) dominated by three dimeric,
30-membered bislactones (1, 2, and 3), which represent the three possible head-to-tail combinations
of the two building blocks (S)-(Z)-11-(2-hydroxyethylamino)-5-tetradecenoic acid (4) and (S)-(5Z,8Z)-
11-(2-hydroxyethylamino)-5,8-tetradecadienoic acid (5). We now report the synthesis of these three
alkaloids via a route involving the nucleophilic opening of a chiral aziridine as a common step.
In tr od u ction
Following our initial characterization of the novel
azamacrolide alkaloids epilachnene (6) and epilachna-
diene (7) as the major components of the pupal defensive
secretion of the Mexican bean beetle Epilachna varives-
tis,1 we have gone on to examine the pupal defensive
chemistry of other coccinellid beetle species. In the case
of the squash beetle Epilachna borealis, the pupal
defensive secretion was shown to consist of a combina-
torial library comprising hundreds of macrocyclic poly-
amines, the polyazamacrolides (PAMLs), along with a
group of acetylated tocopherols.2 These two sets of insect-
derived alkaloids have proven to be of considerable
interest as synthetic targets, and their synthesis has
served to highlight some interesting methodology. Re-
ports of the syntheses of the azamacrolides have ap-
peared from several laboratories,3 and in order to estab-
lish structures and stereochemistry firmly, as well as to
provide sufficient material for further biological and
chemical characterization, we have also completed a
synthesis of epilachnene (6) as well as of five representa-
tive PAMLs ranging from 42- to 98-membered ring
examples.4
Most recently, we have shown the pupal defensive
secretion of the ladybird beetle Subcoccinella viginti-
quatuorpunctata to consist of an alkaloid mixture of
intermediate complexity.5 The mixture is dominated by
three dimeric, 30-membered bislactones (1, 2, and 3),
which represent the three possible head-to-tail combina-
tions of (S)-(Z)-11-(2-hydroxyethylamino)-5-tetradecenoic
acid (4) and (S)-(5Z,8Z)-11-(2-hydroxyethylamino)-5,8-
tetradecadienoic acid (5), the acids whose monomeric
lactones are epilachnene (6) and epilachnadiene (7),
respectively. These three new alkaloids, characterized by
a combination of HPLC-MS, NMR spectroscopy, and
chemical derivatization, had not until now been fully
characterized as individual compounds. We now report
the synthesis and complete characterization of these
unsaturated, 30-membered ring alkaloids.
(1) Attygalle, A. B.; McCormick, K. D.; Blankenspoor, C. L.; Eisner,
T.; Meinwald, J . Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5204.
(2) (a) Schroeder, F. C.; Farmer, J . J .; Smedley, S. R.; Attygalle, A.
B.; Eisner, T.; Meinwald, J . J . Am. Chem. Soc. 2000, 122, 3628. (b)
Schroeder, F. C.; Farmer, J . J .; Attygalle, A. B.; Smedley, S. R.; Eisner,
T.; Meinwald, J . Science 1998, 281, 428.
(3) (a) Furstner, A.; Langemann, K. Synthesis 1997, 7, 792. (b) King,
A. G.; Meinwald, J .; Eisner, T.; Blankenspoor, C. L. Tetrahedron Lett.
1996, 37, 2141. (c) Gribble, G. W.; Silva, R. A. Tetrahedron Lett. 1996,
37, 2145. (d) Rao, B. V.; Kumar, V. S.; Nagarajan, M.; Sitaramaiah,
D.; Rao, A. V. R. Tetrahedron Lett. 1996, 37, 8613. (e) Rao, B. V.;
Kumar, V. S. Tetrahedron Lett. 1995, 36, 147. (f) Rao, A. V. R.; Rao,
B. V.; Bhanu, M. N.; Kumar, V. S. Tetrahedron Lett. 1994, 35, 3201.
(4) (a) Farmer, J . J .; Schroeder, F. C.; Meinwald, J . Helv. Chim. Acta
2000, 83, 2594. (b) Farmer, J . J .; Attygalle, A. B.; Smedley, S. R.;
Eisner, T.; Meinwald, J . Tetrahedron Lett. 1997, 38, 2787.
(5) Schroeder, F. C.; Smedley, S. R.; Gibbons, L. K.; Farmer, J . J .;
Attygalle, A. B.; Eisner, T.; Meinwald, J . Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 13387.
Resu lts a n d Discu ssion
Starting with the enantiomerically pure tosyl aziridine
8 previously used in our synthesis of epilachnene,4 the
two complementarily protected epilachnadienoic acid
subunits (17 and 19) were produced via a synthetic
pathway that preserves the chirality of the starting
10.1021/jo001200w CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/09/2001

1076 J . Org. Chem., Vol. 66, No. 4, 2001
Gronquist and Meinwald
Sch em e 1
material. Using n-BuLi to generate the anion of THP-
protected propargyl alcohol, the aziridine 8 was opened,
through nucleophilic attack at the less hindered ring
carbon, to give the alkyne 9 (Scheme 1). The ethanola-
mine moiety was next introduced by deprotonation of the
sulfonamide nitrogen of 9 with sodium hydride, followed
by alkylation with the TBDPS derivative of bromoetha-
nol.6 Deprotection and bromination of the THP-protected
hydroxyl to give the propargylic bromide 11 was effected
in a single step using 1,2- bis(diphenylphosphino)ethane
and bromine.7
Sch em e 2
Initial attempts to couple 11 with the 4-methyl-2,6,7-
trioxabicyclo[2.2.2]octane ortho ester-protected8 deriva-
tive of 5-hexynoic acid 12 using ethylmagnesium bromide
and a catalytic amount of a cuprous halide were ineffec-
tive, with the reaction going only partially to completion.
However, the reaction was subsequently found to proceed
smoothly with n-BuLi and a stoichiometric amount of
cuprous iodide, giving the 1,4-diyne 13 in good yield
(Scheme 2).
Partial reduction of 13 with Lindlar catalyst to give
the desired (Z,Z)-1,4-diene 14 proved problematic. Elec-
trospray ionization mass spectrometric (ESI/MS) analysis
of the product, along with careful inspection of its proton
NMR spectrum, revealed the presence of 10-15% of a
byproduct with a molecular weight greater than that of
14 by 2 amu. This byproduct, which was clearly the result
of overhydrogenation, comigrated on TLC and was in-
separable by normal flash chromatography. Having failed
to find a more selective method of partial reduction, we
decided to carry the mixture forward with the hope of
being able to separate the overhydrogenated material at
a later stage.
Sch em e 3
The relative stability of 14 made this a logical inter-
mediate in the synthesis from which to remove the tosyl
group, as the conditions used in its removal would be
incompatible with retaining the lactone functionality once
it is introduced. While our initial attempts to carry out
tosylate cleavage using sodium naphthalenide tended to
cause the 1,4-diene system to rearrange into conjugation,
as evidenced by 1H NMR spectroscopic analysis, this
problem could be eliminated by carefully stopping addi-
tion of the sodium naphthalenide solution to the sulfona-
mide precisely at the visible endpoint of the deprotection
reaction. The resulting secondary amine 15 was im-
mediately reprotected as its BOC derivative 16. Hydroly-
sis of ortho ester 16 under standard conditions (Scheme
3) gave the hydroxy-protected, BOC-derivative of (S)-
(5Z,8Z)-11-(2-hydroxyethylamino)-5,8-tetradecadienoic acid
17. The analogous hydroxy-protected, BOC-derivative of
(S)-(Z)-11-(2-hydroxyethylamino)-5-tetradecenoic acid 20
was prepared by the synthetic pathway previously used
in our synthesis of epilachnene.4
(6) Paquette, L. A.; Doherty, A. M.; Rayner, C. M. J . Am. Chem.
Soc. 1992, 114, 3910.
(7) Schmidt, S. P.; Brooks, D. W. Tetrahedron Lett. 1987, 28, 767.
(8) Prepared as described by: Corey, E. J .; Shimoji, K. J . J . Am.
Chem. Soc. 1983, 105, 1662. For an alternate route to this ortho ester,
see: Corey, E. J .; Raju, N. Tetrahedron Lett. 1983, 24, 5571.
The selection of a suitable carboxylic acid protecting

Synthesis of Unsaturated Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1077
Sch em e 4
Sch em e 6
Sch em e 5
group for the controlled coupling of the subunits took
some consideration. We needed an ester that could later
be selectively removed in the presence of the second
internal ester function linking the two subunits. The fact
that our target structures were unsaturated precluded
the use of a benzyl ester, with subsequent removal of the
benzyl group by hydrogenolysis, as had been successfully
used in the synthesis of the PAMLs from E. borealis.4
Protection as a methyl ester for subsequent SN2 removal
by LiI in refluxing pyridine was partially satisfactory,
but the deprotection proceeded in poor yield. We eventu-
ally decided on using an allyl ester as the protecting
group of choice. This functionality could be introduced
under mild conditions using standard DCC coupling
methodology, and the allyl group could be selectively
removed with a palladium catalyst. We were concerned
that the palladium catalyst might also facilitate the
conversion of the skipped diene system into a conjugated
system, but this was not the case. Protection of the
carboxylic acid functions of 17 and 20 as their allyl esters
and subsequent removal of the TBDPS and TBDMS
protecting groups with TBAF gave the two carboxy- and
BOC-protected derivatives of (S)-(5Z,8Z)-11-(2-hydroxy-
ethylamino)-5,8-tetradecadienoic acid 19 and (S)-(Z)-11-
(2-hydroxyethylamino)-5-tetradecenoic acid 22, respec-
tively (Schemes 3 and 4).
nated silica. By this means, the small amounts of over-
reduced byproducts from the earlier Lindlar hydrogenation
step were readily separated, as evidenced by ESI/MS
analysis.
The final removal of the BOC groups from each of the
cyclization products was effected with TFA, either neat
in the case of 32 or added to dichloromethane solutions
of 33 and 34, giving the three natural products 1, 2, and
1
3. The H NMR spectra of the three synthetic alkaloids,
obtained now for the first time, are consistent with those
of the three-component, semipurified mixture that was
used in the initial characterization of this pupal defensive
secretion.5
Exp er im en ta l Section
With the four protected subunits (17, 19, 20, and 22)
in hand, assembly of the three desired protected, open-
chain dimers (23, 24, and 25) was effected by carbodi-
imide-promoted coupling of each of the carboxy-protected
subunits with the appropriate hydroxy-protected subunit,
giving the three possible linear head-to-tail combinations
(Scheme 5). Removal of the allyl protecting group from
each “dimer” using palladium acetate, triphenylphos-
phine, and morpholine in THF, followed by removal of
the silyl group with TBAF, set the stage for cyclization,
which was effected using Mukaiyama’s methodology in
yields of ca. 60% (Scheme 6).9 At this point, the tri- and
tetraenic BOC-protected alkaloids 33 and 34 were sub-
jected to flash chromatography with 10% AgNO3-impreg-
Gen er a l Meth od s. All reagents were purchased from
Aldrich or Fluka and were used without further purification.
Solvents were either used as purchased or distilled using
common practices where appropriate. For flash chromatogra-
phy, ICN Silitech silica (32-63D, 60 Å) was used with elution
solvent compositions given as volume percent per total volume.
Reactions were monitored by TLC using Baker-flex (J . T.
Baker) 2.5 cm × 7.5 cm plates precoated with silica gel IB-F
(200 µm), and spots were visualized by UV and by anisalde-
hyde stain.
(9) Mukaiyama, T.; Narasaka, K.; Kikuchi, K. Chem. Lett. 1977, 441.
A lower yield of 46% for the triene 33 reflects the combination of the
cyclization step with removal of the over-reduced byproducts by silica/
silver nitrate chromatography.

1078 J . Org. Chem., Vol. 66, No. 4, 2001
Gronquist and Meinwald
4-Meth yl-N-[(S)-1-p r op yl-5-(tetr a h yd r op yr a n -2-yloxy)-
p en t-3-yn yl]ben zen esu lfon a m id e (9). To a stirred solution
of tetrahydro-2-(2-propynyloxy)-2H-pyran (12.87 g, 91.8 mmol)
in dry THF (50 mL) under Ar was added n-BuLi (1.6 M in
hexane; 57 mL, 91.2 mmol). After 15 min, 8 (5.46 g, 22.8 mmol)
in THF (25 mL) was added dropwise, and stirring was
continued at room temperature for 24 h. The mixture was
quenched with saturated aqueous NaHCO3 and extracted with
Et2O. The organic extract was dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash
chromatography (silica gel, elution with 14% EtOAc in hex-
anes) to give 7.6 g (20 mmol, 88%) of 9 (diastereomeric mixture)
N-[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-4-m eth yl-N-
[(S)-10-(4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]oct-1-yl)-1-p r o-
p yld eca -3,6-d iyn yl]ben zen esu lfon a m id e (13). To a stirred
slurry of 12 (0.331 g, 1.69 mmol) and CuI (0.316 g, 1.66 mmol)
in dry THF (2 mL) under Ar at -170 °C was added n-BuLi
(1.60 M in hexane, 1.20 mL, 1.92 mmol). After 15 min, 11
(0.857 g, 1.34 mmol) in THF (4.5 mL) was added, the mixture
was slowly brought to 35 °C, and stirring was continued for
27 h. The reaction was quenched with saturated aqueous
NaHCO3 and extracted with Et2O. The organic extract was
dried (K2CO3), filtered through Celite, and concentrated in
vacuo. The residue was purified by flash chromatography
(silica gel, elution with 33% ether in hexanes containing 2%
Et3N) to give 0.837 g (1.11 mmol, 83%) of 13 as a pale yellow
as a pale yellow oil: [R]20 -77.6 (c 1.65, CH2Cl2); IR (film)
D
3274 (br) cm-1; H NMR (CDCl3, 500 MHz) δ 7.75-7.78 (m,
1
2H), 7.28-7.31 (m, 2H), 4.80 (d, 1/2H, J ) 9.7 Hz), 4.82 (d,
1/2H, J ) 9.7 Hz), 4.77 (t, 1/2H, J ) 3.4 Hz), 4.76 (t, 1/2H, J
) 3.4 Hz), 4.244 (dt, 1/2H, J ) 15.4, 2.2 Hz), 4.240 (dt, 1/2H,
J ) 15.4, 2.2 Hz), 4.175 (dt, 1/2H, J ) 15.4, 2.2 Hz), 4.170 (dt,
1/2H, J ) 15.4, 2.1 Hz), 3.82-3.89 (m, 1H), 3.51-3.57 (m, 1H),
3.30-3.39 (m, 1H), 2.43 (s, 3H), 2.27-2.30 (m, 2H), 1.71-1.88
(m, 2H), 1.43-1.66 (m, 6H), 1.12-1.35 (m, 2H), 0.813 (t, 1.5H,
J ) 7.3 Hz), 0.810 (t, 1.5H, J ) 7.3 Hz); 13C NMR (CDCl3, 100
MHz) δ 143.33, 143.32, 138.19, 138.17, 129.66, 129.65, 127.0,
97.2, 97.0, 81.4, 79.33, 79.26, 62.3, 62.1, 54.7, 54.6, 51.7, 36.42,
36.39, 30.4, 30.3, 25.4, 25.3, 25.25, 25.20, 21.5, 19.2, 19.1, 18.82,
18.81, 13.6; HRMS (FAB, m/z) calcd for C20H30NO4S (M + H)+
380.1896, found 380.1900.
oil: [R]25 +5.3 (c 0.89, CH2Cl2); 1H NMR (CDCl3, 500 MHz) δ
D
7.63-7.67 (m, 6H), 7.37-7.48 (m, 6H), 7.23-7.26 (m, 2H), 3.89
(s, 6H), 3.87 (dt, 1H, J ) 9.1, 5.9 Hz), 3.74-3.8 (m, 1H), 3.70
(dt, 1H, J ) 9.1, 5.9 Hz), 3.21 (ddd, 1H, J ) 14.8, 9.0, 5.9 Hz),
3.15 (ddd, 1H, J ) 14.8, 9.0, 5.9 Hz), 2.92 (quin, 2H, J ) 2.4
Hz), 2.41 (s, 3H), 2.18 (tt, 2H, J ) 7.1, 2.4 Hz), 2.09 (ddt, 1H,
J ) 16.7, 7.6, 2.4 Hz), 2.02 (ddt, 1H, J ) 16.7, 6.3, 2.4 Hz),
1.46-1.79 (m, 5H), 1.10-1.25 (m, 3H), 1.06 (s, 9H), 0.80 (s,
3H), 0.77 (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ
143.2, 137.9, 135.7,133.65, 133.61, 129.97, 129.95, 129.7, 128.0,
127.4, 109.1, 80.3, 77.4, 77.1, 74.4, 72.8, 63.7, 57.6, 45.1, 35.9,
35.2, 30.4, 27.1, 23.8, 22.8, 21.7, 19.7, 19.3, 18.7, 14.8, 13.9,
9.9; HRMS (FAB, m/z) calcd for C44H58NO6SSi (M + H)+
756.3754, found 756.3740.
N-[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-4-m eth yl-N-
[(S)-1-p r op yl-5-(t et r a h yd r op yr a n -2-yloxy)p en t -3-yn yl]-
ben zen esu lfon a m id e (10). To a stirred slurry of NaH (0.253
g, 10.5 mmol) in dry DMF (25 mL) under Ar at 0 °C was added
9 (2.82 g, 7.4 mmol) in DMF (10 mL) over 1 h via syringe pump.
The mixture was stirred for an additional 30 min at 0 °C, and
then (2-bromoethoxy)-tert-butyldiphenylsilane (3.83 g, 10.5
mmol) in DMF (10 mL) was added dropwise. The mixture was
brought to 40 °C, and stirring was continued for 48 h. The
reaction was quenched with H2O, extracted with Et2O, dried
(MgSO4), filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (silica gel, elution with 17%
EtOAc in hexanes) to give 3.94 g (5.95 mmol, 80%) of 10
N-[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-4-m eth yl-N-
[(S)-(3Z,6Z)-10-(4-m eth yl-2,6,7-tr ioxa bicyclo[2.2.2]oct-1-
yl)-1-p r op yld eca -3,6-d ien yl]ben zen esu lfon a m id e (14). To
a solution of 13 (8.5 mg, 11 µmol) in 2:1 EtOAc/EtOH (300
µL) was added Lindlar catalyst (1 mg). The reaction was
stirred under a positive pressure of hydrogen and followed by
TLC. After 1.5 h, the mixture was filtered and concentrated
in vacuo to give 8.5 mg (11 µmol) of 14 as a mixture containing
approximately 15% of a second compound that gives (M + H)+
of 2 amu greater than that of 14 by ESI/MS: [R]25 -6.27 (c
D
1
6.05, CH2Cl2); H NMR (CDCl3, 500 MHz): δ 7.60-7.69 (m,
6H), 7.37-7.47 (m, 6H), 7.22-7.25 (m, 2H), 5.37 (dtt, 1H, J )
10.7, 7.3, 1.6 Hz), 5.18-5.26 (m, 2H), 5.04-5.11 (m, 1H), 3.903
(dt, 1H, J ) 9.9, 5.6 Hz), 3.895 (s, 6H), 3.73 (dt, 1H, J ) 9.9,
5.5 Hz), 3.55-3.63 (m, 1H), 3.21 (ddd, 1H, J ) 14.8, 10.0, 5.7
Hz), 3.06 (ddd, 1H, J ) 14.8, 10.0, 5.6 Hz), 2.49-2.66 (m, 2H),
2.40 (s, 3H), 1.96-2.05 (m, 3H), 1.64-1.76 (m, 3H), 1.48-1.56
(m, 2H), 1.07 (s, 9H), 0.84-1.29 (m, 4H), 0.80 (s, 3H), 0.73 (t,
3H, J ) 7.2 Hz);13C NMR (CDCl3, 100 MHz) δ 143.1, 138.1,
135.8, 133.75, 133.70, 130.3, 130.2, 129.95, 129.94, 129.7,
127.9, 127.8, 127.4, 126.0, 109.2, 72.8, 63.8, 58.6, 44.8, 36.4,
35.3, 31.3, 30.4, 27.14, 27.10, 25.9, 23.3, 21.7, 19.9, 19.4, 14.7,
13.9; HRMS (FAB, m/z) calcd for C44H62NO6SSi (M + H)+
760.4067, found 760.4065.
(diastereomeric mixture) as a pale yellow oil: [R]20 +6.23 (c
D
2.66, CH2Cl2); 1H NMR (CDCl3, 400 MHz) δ 7.61-7.62 (m, 6H),
7.38-7.47 (m, 6H), 7.22-7.26 (m, 2H), 4.74-4.77 (m, 1H),
4.07-4.19 (m, 2H), 3.68-3.91 (m, 4H), 3.49-3.55 (m, 1H),
3.12-3.24 (m, 2H), 2.41 (s, 3H), 2.19 (ddt, 1H, J ) 16.7, 7.6,
2.1 Hz), 2.119 (ddt, 1/2H, J ) 16.7, 6.1, 2.1 Hz), 2.114 (ddt,
1/2H, J ) 16.7, 6.1, 2.1 Hz), 1.02-1.88 (m, 10H), 1.06 (s, 9H),
0.76 (t, 3H, J ) 7.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 143.3,
137.9, 135.8, 133.65, 133.61, 130.0, 129.7, 128.0, 127.4, 96.93,
96.91, 83.0, 78.4, 63.7, 62.3, 57.5, 54.6, 45.2, 34.9, 30.5, 27.1,
25.6, 24.2, 21.7, 19.7, 19.40, 19.35, 13.85; HRMS (FAB, m/z)
calcd for C38H52NO5SSi (M + H)+ 662.3335, found 662.3333.
N-[(S)-5-Br om o-1-p r op ylp en t-3-yn yl)-N-[2-(ter t-bu tyl-
d ip h e n ylsila n yloxy)e t h yl]-4-m e t h ylb e n ze n e su lfon a -
m id e (11). To a stirred solution of 1,2-bis(diphenylphosphino)-
ethane (1.50 g, 3.77 mmol) in CH2Cl2 (20 mL) at 0 °C was
added bromine (1.22 g, 7.55 mmol). After 10 min, 10 (1.98 g,
2.99 mmol) in CH2Cl2 (7 mL) was added dropwise, and the
mixture brought to room temperature. At 3.5 h, a 1:2 mixture
of ether and pentane (180 mL) was added, resulting in an
increased white precipitate in the already cloudy mixture. The
mixture was filtered and concentrated in vacuo, and the
residue was purified by flash chromatography (silica gel,
elution with 13% EtOAc in hexanes) to give 1.48 g (2.31 mmol,
77%) of 11 as a clear oil: [R]20D +7.58 (c 4.13, CH2Cl2); 1H NMR
(CDCl3, 500 MHz) δ 7.63-7.68 (m, 6H), 7.39-7.47 (m, 6H),
7.24-7.27 (m, 2H), 3.72-3.89 (m, 3H), 3.74 (t, 2H, J ) 2.3
Hz), 3.19 (t, 2H, J ) 7.8 Hz), 2.42 (s, 3H), 2.23 (ddt, 1H, J )
2.4, 7.2, 16.8 Hz), 2.17 (ddt, 1H, J ) 2.4, 6.4, 16.8 Hz), 1.43-
1.52 (m, 1H), 1.06-1.28 (m, 3H), 1.07 (s, 9H), 0.78 (t, 3H, J )
7.19 Hz); 13C NMR (CDCl3, 100 MHz) δ 143.3, 137.9, 135.8,
133.59, 133.57, 130.0, 129.8, 128.0, 127.4, 84.6, 77.7, 63.6, 57.3,
45.3, 35.0, 27.1, 24.3, 21.7, 19.8, 19.3, 15.3, 13.9; HRMS (FAB,
m/z) calcd for C33H43BrNO3SSi (M + H)+ 640.1916, found
640.1918.
[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-[(S)-(3Z,6Z)-10-
(4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]oct-1-yl)-1-pr opyldeca-
3,6-d ien yl]a m in e (15). A mixture of sodium metal (65 mg,
2.8 mmol) and naphthalene (200 mg, 1.6 mmol) in dry DME
was stirred under Ar at room temperature for 3 h to give a
solution of sodium naphthalenide. This solution was added
dropwise to a stirred solution of 14 (58 mg, 76 mmol) in dry
DME at -75 °C until a dark green color persisted. The mixture
was slowly brought to room temperature, quenched with
EtOH, and concentrated in vacuo to give a solid white residue,
which was taken up in H2O and extracted with Et2O. The
organic extract was dried (K2CO3), filtered, and concentrated
in vacuo. The residue was purified by flash chromatography
(silica gel, elution with 33% EtOAc in hexanes containing 2%
Et3N) to give 45 mg (110 µmol, 97%) of 15 as a pale yellow oil:
1
[R]20 -4.97 (c 4.68, CH2Cl2); IR (film) 3324 (w, br) cm-1; H
D
NMR (CDCl3, 500 MHz) δ 7.66-7.69 (m, 4H), 7.36-7.45 (m,
6H), 5.30-5.49 (m, 4H), 3.89 (s, 6H), 3.78 (t, 2H, J ) 5.4 Hz),
2.69-2.86 (m, 4H), 2.52-2.60 (m, 1H), 2.19 (t, 2H, J ) 6.3
Hz), 2.06 (q, 2H, J ) 7.3 Hz), 1.64-1.72 (m, 2H), 1.30-1.56
(m, 6H), 1.05 (s, 9H), 0.92 (t, 3H, J ) 6.9), 0.79 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 135.8, 133.90, 133.87, 130.5, 130.0,
129.8, 128.3, 127.8, 127.0, 109.2, 72.8, 63.6, 57.7, 49.4, 36.6,

Synthesis of Unsaturated Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1079
36.4, 32.2, 30.4, 27.2, 27.0, 26.1, 23.4, 19.4, 19.3, 14.8, 14.6;
HRMS (FAB, m/z) calcd for C37H56NO4Si (M + H)+ 606.3979,
found 606.3978.
purified by flash chromatography (silica gel, elution with 29%
EtOAc in hexanes) to give 5.1 mg (12 µmol, 80%) of 19 as a
clear oil: [R]20D -17.4 (c 0.90, CH2Cl2); IR (film) 3448 (br), 1738,
1
1690 cm-1; H NMR (conformeric mixture, CDCl3, 500 MHz)
[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-[(S)-(3Z,6Z)-10-
(4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]oct-1-yl)-1-pr opyldeca-
3,6-d ien yl]ca r ba m ic Acid Dim eth yleth yl Ester (16). To
a stirred solution of 15 in THF (0.5 mL) was added di-tert-
butyl dicarbonate (25 mg, 0.11 mmol). The mixture was stirred
at room temperature for 17 h and then concentrated under a
stream of Ar. The residue was purified by flash chromatog-
raphy (silica gel, elution with 9% EtOAc in hexanes containing
2% Et3N) to give 43 mg (61 µmol, 96%) of 16 as a clear oil:
δ 5.93 (ddt, 1H, J ) 17.1, 10.4, 5.8 Hz), 5.34-5.44 (m, 4H),
5.32 (dq, 1H, J ) 17.1, 1.4 Hz), 5.24 (dq, 1H, J ) 10.4, 1.4
Hz), 4.59 (dt, 2H, J ) 5.8, 1.4 Hz), 3.63-4.11 and 3.17-3.35
(2m, 5H total), 2.72-2.82 (m, 2H), 2.36 (t, 2H, 7.5 Hz), 2.09-
2.33 (m, 4H), 1.72 (quin, 2H, J ) 7.5 Hz), 1.47 (s, 9H), 1.25-
1.51 (m, 4H), 0.92 (t, 3H, 7.2 Hz); HRMS (ESI, m/z) calcd for
C
24H42N1O5 (M + H)+ 424.3063, found 424.3084.
(S)-(5Z,8Z)-11-[ter t-Bu toxyca r bon yl-(2-{(S)-(5Z-8Z)-11-
[R]20 -9.75 (c 4.22, CH2Cl2); IR (film) 1688 cm-1 1H NMR
;
[[2-(t er t -b u t y ld ip h e n y ls ila n y lo x y )e t h y l](d im e t h y l-
eth oxyca r bon yl)a m in o]tetr a d eca -5,8-d ien lyloxy}eth yl)-
a m in o]tetr a d eca -5,8-d ien oic Acid Allyl Ester (25). To a
stirred solution of 19 (11.9 mg, 28.1 µmol), DMAP (3.6 mg, 29
µmol), and DCC (1 M in CH2Cl2,, 30 µl, 30 µmol) in CH2Cl2
(0.25 mL) was added 17 (17.7 mg, 28.5 µmol) in CH2Cl2 (0.5
mL). The mixture was stirred at room temperature for 4.5 h
and then concentrated under a stream of N2. The residue was
purified by flash chromatography (silica gel, elution with 11%
EtOAc in hexanes) to give 23.6 mg (23.0 µmol, 82%) of 25 as
a pale yellow oil: [R]20D -14.4 (c 1.61, CH2Cl2); IR (film) 1738,
D
(conformeric mixture, CDCl3, 500 MHz) δ 7.66-7.69 (m, 4H),
7.37-7.45 (m, 6H), 5.20-5.40 (m, 4H), 3.90 (s, 6H), 3.61-3.94
and 3.09-3.29 (2m, 5H total), 2.61-2.77 (m, 2H), 2.13 (t, 2H,
J ) 7.0 Hz), 1.92-2.15 (m, 2H), 1.65-1.73 (m, 2H), 1.48-1.57
(m, 2H), 1.36 and 1.43 (2s, 9H total), 1.15-1.39 (m, 4H), 1.05
and 1.06 (2s, 9H), 0.81-0.84 (m, 3H), 0.80 (s, 3H); 13C NMR
(this compound did not give a suitable 13C NMR spectrum);10
HRMS (FAB, m/z) calcd for C35H52NO3Si [(M-Boc) + H]+
562.3716, found 562.3716.
(S)-(5Z,8Z)-11-[[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-
(d im et h ylet h oxyca r b on yl)a m in o]t et r a d eca -5,8-d ien oic
Acid (17). A stirred solution of 16 (105 mg, 148 µmol) in 5:1
DME/H2O (7 mL) at 0 °C was brought to pH 3 by the addition
of aqueous sodium bisulfate (3 drops of a 0.173 g/L solution).
At 1 h, the mixture was brought to pH 12 with aqueous lithium
hydroxide (11 drops of a 10.25 g/L solution) and then brought
to room temperature. This pH was maintained, and stirring
was continued for 8 h. The mixture was brought to pH 4 with
aqueous sodium bisulfate and extracted with ether. The
organic extract was dried (MgSO4), filtered, and concentrated
in vacuo. The residue was purified by flash chromatography
(silica gel, elution with 17% EtOAc in hexanes containing 1%
HOAc) to give 75.7 mg (122 µmol, 82%) of 17 as a clear oil:
1
1694 cm-1; H NMR (conformeric mixture, CDCl3, 500 MHz)
δ 7.65-7.69 (m, 4H), 7.36-7.45 (m, 6H), 5.92 (ddt, 1H, J )
17.2, 10.4, 5.7 Hz), 5.22-5.40 (m, 8H), 5.32 (dq, 1H, J ) 17.1,
1.5 Hz), 5.24 (dq, 1H, J ) 10.4, 1.4 Hz), 4.58 (dt, 2H, J ) 5.8,
1.4 Hz), 4.13 and 4.17 (2t, 2H total, J ) 6.6 Hz for both), 3.61-
4.06 (m, 4H), 3.09-3.36 (m, 4H), 2.63-2.83 (m, 4H), 2.36 (t,
2H, J ) 7.7 Hz), 1.93-2.36 (m, 10H), 1.72 (quin, 2H, J ) 7.3
Hz), 1.66-1.74 (m, 2H), 1.458 and 1.462 (2s, 9H total), 1.36
and 1.43 (2s, 9H total), 1.14-1.39 (m, 8H), 1.046 and 1.053
(2s, 9H total), 0.91 (t, 3H, J ) 7.0 Hz), 0.80-0.84 (m, 3H);
HRMS (ESI, m/z) calcd for C61H95N2O9Si (M + H)+ 1027.6807,
found 1027.6723.
(S)-(5Z,8Z)-11-[ter t-Bu toxyca r bon yl-(2-{(S)-(5Z-8Z)-11-
[[2-(t er t -b u t y ld ip h e n y ls ila n y lo x y )e t h y l](d im e t h y l-
eth oxyca r bon yl)a m in o]tetr a d eca -5,8-d ien lyloxy}eth yl)-
a m in o]tetr a d eca -5,8-d ien oic Acid (28). To solution of 25
(20.4 mg, 19.9 µmol) in THF (0.5 mL, purged with Ar) was
added palladium(II) acetate (approximately 0.3 mg, 1 µmol),
morpholine (2.2 mg, 25 µmol), and triphenylphosphine (8.2 mg,
31 µmol). The mixture was stirred under Ar for 7 h. Aqueous
hydrochloric acid (1.0 N) was added, and the mixture was
extracted with ether. The organic extract was concentrated
under a stream of N2, and the residue was purified by flash
chromatography (silica gel, 9% EtOAc in hexanes containing
1% HOAc) to give 17.8 mg (18.0 µmol, 90%) of 28 as a pale
[R]20 -11.2 (c 1.79, CH2Cl2); IR (film) 3100 (br), 1738, 1694
D
cm-1; 1H NMR (conformeric mixture, CDCl3, 500 MHz) δ 7.66-
7.69 (m, 4H), 7.36-7.45 (m, 6H), 5.23-5.45 (m, 4H), 3.64-
3.91 (m, 3H), 3.13-3.31 (m, 2H), 2.65-2.82 (m, 2H), 2.34 (t,
2H, J ) 6.8), 2.09-2.16 (m, 4H), 1.61-1.75 (m, 2H), 1.43 and
1.36 (2s, 9H total), 1.14-1.39 (m, 4H), 1.05 and 1.06 (2s, 9H
total), 0.80-0.84 (m, 3H); HRMS (FAB, m/z) calcd for C32H48
-
NO3Si [(M-Boc) + H]+ 522.3403, found 522.3401.
(S)-(5Z,8Z)-11-[[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-
(d im et h ylet h oxyca r b on yl)a m in o]t et r a d eca -5,8-d ien oic
Acid Allyl Ester (18). To a stirred solution of 17 (33 mg, 53
µmol), allyl alcohol (7 mg, 120 µmol), and DMAP (7 mg, 57
µmol) in CH2Cl2 (0.75 mL) was added DCC (1 M in CH2Cl2;
60 µL, 60 µmol). The mixture was stirred under Ar at room
temperature for 18 h and then concentrated under a stream
of N2. The residue was purified by flash chromatography (silica
gel, elution with 5% EtOAc in hexanes) to give 27 mg (40 µmol,
yellow oil: [R]20 -13.1 (c 1.49, CH2Cl2); IR (film) 3200 (br),
D
1
1738, 1692 cm-1; H NMR (conformeric mixture, CDCl3, 500
MHz) δ 7.66-7.69 (m, 4H), 7.37-7.45 (m, 6H), 5.27-5.46 (m,
8H), 3.62-4.21 (m, 6H), 3.11-3.34 (m, 4H), 2.64-2.86 (m, 4H),
1.92-2.38 (m, 12H), 1.68-1.74 (m, 4H), 1.15-1.51 (m, 26H),
1.05 (s, 9H), 0.91 (t, 3H, J ) 7.3 Hz), 0.80-0.84 (m, 3H) HRMS
(ESI, m/z) calcd for C58H91N2O9Si (M + H)+ 987.6470, found
987.6494.
76%) of 18 as a pale yellow oil: [R]20 -10.8 (c 1.69, CH2Cl2);
D
IR (film) 1738, 1692 cm-1
;
1H NMR (conformeric mixture,
CDCl3, 500 MHz) δ 7.66-7.69 (m, 4H), 7.36-7.46 (m, 6H), 5.93
(ddt, 1H, J ) 17.1, 10.3, 5.7 Hz), 5.26-5.40 (m, 4H), 5.24 (dq,
1H, 10.4, 1.4 Hz), 5.32 (dq, 1H, 17.1, 1.5 Hz), 4.58 (dt, 2H, J )
5.8, 1.5 Hz), 3.62-3.80 and 3.90-3.97 (2m, 3H total), 3.09-
3.31 (m, 2H), 2.63-2.78 (m, 2H), 2.35 (t, 2H, J ) 7.6 Hz), 1.92-
2.17 (m, 4H), 1.72 (quin, 2H, J ) 7.4 Hz), 1.36 and 1.44 (2s,
9H total), 1.15-1.38 (m, 4H), 1.05 and 1.06 (2m, 9H total),
0.83 and 0.82 (2t, 3H total, J ) 7.4 Hz for both); HRMS (FAB,
m/z) calcd for C35H52NO3Si [(M-Boc) + H]+ 562.3716, found
562.3716.
(S)-(5Z,8Z)-11-[ter t-Bu toxyca r bon yl-(2-h yd r oxyeth yl)-
a m in o]tetr a d eca -5,8-d ien oic Acid Allyl Ester (19). To a
stirred solution of 18 (9.6 mg, 15 µmol) in THF (0.4 mL) was
added TBAF (1 M in THF; 19 µL, 19 µmol). At 2 h, the mixture
was concentrated under a stream of N2, and the residue was
(S)-(5Z,8Z)-11-[ter t-Bu toxyca r bon yl-(2-{(S)-(5Z-8Z)-11-
[(ter t-bu toxyca r bon yl-(2-h yd r oxyeth yl)a m in o]tetr a d eca -
5,8-d ien lyloxy}eth yl)a m in o]tetr a d eca -5,8-d ien oic Acid
(31). To a stirred solution of 28 (17.0 mg, 17.2 µmol) in THF
(0.3 mL) was added TBAF (1 M in THF; 20 µl, 20 µmol). At 4
h, the mixture was concentrated under a stream of N2. The
residue was purified by flash chromatography (silica gel,
elution with 29% EtOAc in hexanes containing 1% HOAc) to
give 12.1 mg (16.2 µmol, 94%) of 31 as a clear oil: [R]20D -21.9
(c 0.77, CH2Cl2); IR (film) 3400 (br), 3100 (br), 1738, 1694 cm-1
;
1H NMR (conformeric mixture, CDCl3, 500 MHz) δ 5.28-5.47
(m, 8H), 4.13-4.21 (m, 2H), 3.81-4.10 (m, 2H), 3.71-3.75 (m,
2H), 3.20-3.33 (m, 4H), 2.72-2.85 (m, 4H), 2.00-2.38 (m,
12H), 1.61-1.75 (m, 4H), 1.25-1.52 (m, 26 H), 0.94 (t, 6H, J
) 7.0 Hz); HRMS (ESI, m/z) calcd for C42H73N2O9 (M + H)+
749.5316, found 749.5302.
(10) The existence of stable conformers resulted in unsuitable 13C
NMR spectra for all Boc-protected intermediates. Attempts to obtain
NMR spectra of these compounds in DMSO at elevated temperature
led to product decomposition.
(7Z,10Z,22Z,25Z)-(5S,20S)-15,30-Dioxo-5,20-d ip r op yl-1,-
16-d ioxa -4,19-d ia za cyclotr ia con ta -7,10,22,25-tetr a en e-4,-
19-d ica r boxylic Acid Di-ter t-bu tyl Ester (34). A mixture

1080 J . Org. Chem., Vol. 66, No. 4, 2001
Gronquist and Meinwald
of 31 (8.1 mg, 10.8 µmol) and Et3N (13 µL, 93 µmol) in
acetonitrile (2.3 mL) was added to a refluxing solution of
2-chloro-1-methylpyridinium iodide (11.4 mg, 44.6 µmol) in
acetonitrile (12 mL) over a period of 2 h via syringe pump.
The mixture was refluxed for an additional 0.5 h, then cooled,
and concentrated in vacuo. The solid yellow residue was taken
up in H2O and extracted with ether. The organic extract was
dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash chromatography (silica gel, 13% EtOAc
in hexanes) to give 5.0 mg of 34 (6.8 µmol, 63% yield for
cyclization) as a mixture containing approximately 15% of the
over-reduced byproduct, which was carried through from the
Lindlar reduction, as evidenced by ESI/MS.
1H, J ) 17.1, 10.4, 5.7 Hz), 5.29-5.42 (m, 2H), 5.32 (dq, 1H,
J ) 17.1, 1.5 Hz), 5.23 (dq, 1H, J ) 10.4, 1.3 Hz), 4.58 (dt, 2H,
J ) 5.7, 1.4 Hz), 3.85-4.10 (m, 1H), 3.71 (t, 2H, J ) 4.7 Hz),
3.16-3.29 (m, 3H), 2.34 (t, 2H, J ) 7.5 Hz), 2.07 (q, 2H, J )
7.3 Hz), 1.99-2.03 (m, 2H), 1.70 (quin, 2H, J ) 7.4 Hz), 1.46
(s, 9H), 1.24-1.45 (m, 10H), 0.91 (t, 3H, J ) 7.0 Hz); HRMS
(FAB, m/z) calcd for C19H36NO3 (M + H)+ 326.2695, found
326.2695.
(S)-(Z)-11-[ter t-Bu toxyca r bon yl-(2-{(S)-(Z)-11-[[2-(ter t-
bu tyldim eth ylsilan yloxy)eth yl](dim eth yleth oxycar bon yl)-
a m in o]tetr a d ec-5-en lyloxy}eth yl)a m in o]tetr a d ec-5-en o-
ic Acid Allyl Ester (23). To a stirred solution of 20 (23.6 mg,
47.2 µmol), 22 (17.1 mg, 40.2 µmol), and DMAP (2.5 mg, 20
µmol) in CH2Cl2 (0.5 mL) at 0 °C was added EDCI (8 mg, 40
µmol). The mixture was slowly brought to room temperature,
stirred for 3 h, and then concentrated under a stream of N2.
The residue was purified by flash chromatography (silica gel,
6% EtOAc in hexanes) to give 21.9 mg (24.1 µmol, 60%) of 23
as a pale yellow oil: [R]25D +3.0 (c 1.68, CH2Cl2); IR (film) 1736,
Flash chromatography of 2.0 mg of this mixture (silica gel
containing 10% silver nitrate, elution with a step gradient from
9% to 50% EtOAc in hexanes, then flushing column with 5%
MeOH in CH2Cl2) gave 1.4 mg (1.9 µmol) of pure 34 as a clear
oil: [R]20 -30.0 (c 0.27, CH2Cl2); IR (film) 1738, 1694 cm-1
;
D
1H NMR (conformeric mixture, CDCl3, 500 MHz) δ 5.30-5.45
(m, 8H), 4.12-4.20 and 3.83-3.94 (2m, 6H total), 3.18-3.30
(m, 4H), 2.72-2.84 (m, 4H), 2.08-2.35 (m, 12H), 1.67-1.75
(m, 4H), 1.44 and 1.47 (2s, 18H total), 1.26-1.49 (m, 8H), 0.92
(t, 6H, J ) 7.2 Hz); HRMS (ESI, m/z) calcd for C42H70N2O8Na
(M + Na)+ 753.5030, found 753.5004.
1
1692 cm-1; H NMR (conformeric mixture, CDCl3, 500 MHz)
δ 5.92 (ddt, 1H, J ) 17.2, 10.4, 5.7 Hz), 5.29-5.42 (m, 4H),
5.32 (dq, 1H, J ) 17.1, 1.5 Hz), 5.24 (dq, 1H, J ) 10.4, 1.3
Hz), 4.58 (dt, 2H, J ) 5.8, 1.4 Hz), 4.17 and 4.14 (2t, 2H total,
J ) 6.9 Hz for both), 3.75-4.09 (m, 2H), 3.70 and 3.62-3.66
(t and m respectively, 2H total, J ) 7.0 Hz), 3.03-3.31 (m,
4H), 2.27-2.36 (m, 4H), 1.95-2.10 (m, 8H), 1.66-1.73 (m, 4H),
1.446, 1.452, 1.462 and 1.470 (4s, 18H total), 1.20-1.43 (m,
20H), 0.90 and 0.91 (2s, 9H total), 0.88-0.92 (m, 6H), 0.068
and 0.073 (2s, 6H total); HRMS (FAB, m/z) calcd for C42H79N2O7-
Si [(M-Boc, isobutene) + H]+ 751.5657, found 751.5658.
(S)-(Z)-11-[ter t-Bu toxyca r bon yl-(2-{(S)-(Z)-11-[[2-(ter t-
bu tyldim eth ylsilan yloxy)eth yl](dim eth yleth oxycar bon yl)-
a m in o]tetr a d ec-5-en lyloxy}eth yl)a m in o]tetr a d ec-5-en o-
ic Acid (26). Starting with 23 (16.5 mg, 18.2 µmol), the
procedure for 28 was followed to give 11.7 mg (13.5 µmol, 74%)
of 26 as a pale yellow oil: [R]25D +2.9 (c 1.09, CH2Cl2); IR (film)
(7Z,10Z,22Z,25Z)-(5S,20S)-5,20-Dip r op yl-1,16-d ioxa -4,-
19-diazacyclotr iacon ta-7,10,22,25-tetr aen e-15,30-dion e (3).
To a stirred solution of 34 (1.4 mg, 1.9 µmol) in CH2Cl2 (0.4
mL) at 0 °C was added TFA (80 µl, 1.0 mmol). The mixture
was brought to room temperature, and stirring was continued.
After 45 min the mixture was concentrated under a stream of
N2 to give the TFA salt of 3. The salt was taken up in H2O
and washed with hexane. The aqueous mixture was basified
with 20% aqueous potassium carbonate and extracted with
ether. The organic extract was dried (K2CO3), filtered, and
concentrated in vacuo to give 1.0 mg of 3 (1.9 µmol, 100%) as
a clear oil: [R]20 -6.2 (c 0.15, CH2Cl2); IR (film) 3008, 1736
D
cm-1; 1H NMR (C6D6, 500 MHz) δ 5.47-5.53 (m, 2H, 2NCHCH2-
CHdCH), 5.41-5.47 (m, 2H, 2CHdCHCH2CH2CH2CO2R),
5.35-5.40 (m, 2H, 2NCHCH2CHdCH), 5.26-5.33 (m, 2H,
2CHdCHCH2CH2CH2CO2R), 4.19 (ddd, 2H, J ) 11.0, 6.1, 4.4
Hz, 2OCHaHbCH2N), 4.12 (ddd, 2H, J ) 11.0, 7.2, 4.4 Hz,
2OCHaHbCH2N), 2.80-2.91 (m, 4H, 2CHdCHCH2CHdCH),
2.69 (ddd, 2H, J ) 12.4, 7.2, 4.4 Hz, 2OCH2CHaHbN), 2.63
(ddd, 2H, J ) 12.4, 6.1, 4.4 Hz, 2OCH2CHaHbN), 2.46 (quin,
2H, J ) 5.8 Hz, 2NCH), 2.20 (t, 4H, J ) 7.3 Hz, 2CH2CO2R),
2.17-2.33 (m, 2H, 2NCHCHaHbCHdCH), 2.13-2.07 (m, 2H,
2NCHCHaHbCHdCH), 2.06 (q, 4H, J ) 7.3 Hz, 2CH2CH2CH2-
CO2R), 1.66 (quin, 4H, J ) 7.3 Hz, 2CH2CH2CO2R), 1.19-1.40
3192 (br), 1738, 1694 cm-1 1H NMR (conformeric mixture,
;
CDCl3, 500 MHz) δ 5.27-5.43 (m, 4H), 4.14 and 4.18 (2t, 2H
total, J ) 6.7 Hz), 3.78-4.08 (m, 2H), 3.64 and 3.70 (2t, 2H
total, J ) 6.8 and 7.5 Hz respectively), 3.05-3.28 (m, 4H),
2.28-2.37 (m, 4H), 1.96-2.19 (m, 8H), 1.65-1.76 (m, 4H),
1.448, 1.454, 1.464, and 1.482 (4s, 18H total), 1.21-1.43 (m,
20H), 0.90 and 0.91 (2s, 9H total), 0.88-0.93 (m, 6H), 0.070
and 0.074 (2s, 6H total); HRMS (FAB, m/z) calcd for C43H83N2O7-
Si [(M-Boc) + H]+ 767.5970, found 767.5964.
(S)-(Z)-11-[ter t-Bu toxyca r bon yl(2-{(S)-(Z)-11-[(ter t-bu -
toxycar bon yl(2-h ydr oxyeth yl)am in o]tetr adec-5-en lyloxy}-
eth yl)a m in o]tetr a d ec-5-en oic Acid (29). Starting with 26
(10.2 mg, 11.8 µmol), the procedure for 31 was followed to give
8.0 mg (10 µmol, 90%) of 29 as a pale yellow oil: [R]25D +1.7 (c
0.80, CH2Cl2); IR (film) 3446 (br), 3200 (br), 1738, 1686, 1652
cm-1; 1H NMR (conformeric mixture, CDCl3, 500 MHz) δ 5.27-
5.43 (m, 4H), 4.15 and 4.18 (2t, 2H total, J ) 6.7 Hz for both),
3.81-4.09 (m, 2H), 3.72 (t, 2H, J ) 5.1 Hz), 3.13-3.29 (m, 4H),
2.35 (t, 2H, J ) 7.0 Hz), 2.28-2.34 (m, 2H), 1.95-2.19 (m, 8H),
1.63-1.76 (m, 4H), 1.46, 1.47, and 1.48 (3s, 18H total), 1.20-
1.43 (m, 20H), 0.90 and 0.91 (2t, 6H total, J for both ) 7.2
Hz); HRMS (FAB, m/z) calcd for C37H69N2O7 [(M-Boc) + H]+
653.5105, found 653.5104.
(m, 8H, 2CH2CH2CH3), 0.91 (t, 6H, J ) 6.6 Hz, 2CH2CH3); 13
C
NMR (C6D6, 100 MHz) δ 173.2, 130.8, 129.7, 129.6, 127.7, 64.9,
57.7, 46.4, 37.3, 34.0, 32.9, 27.2, 26.6, 25.5, 19.6, 15.0; HRMS
(ESI, m/z) calcd for C32H55N2O4 (M + H)+ 531.4162, found
531.4181.
(S )-(Z)-11-[[2-(t er t -Bu t yld im e t h ylsila n yloxy)e t h yl]-
(d im eth yleth oxyca r bon yl)a m in o]tetr a d ec-5-en oic Acid
Allyl Ester (21). Starting with 20 (33.3 mg, 66.6 µmol) the
procedure for 18 was followed to give 30.6 mg (56.7 µmol, 85%)
of 21 as a pale yellow oil: [R]20D +2.1 (c 1.11, CH2Cl2); IR (film)
1
1738, 1692 cm-1; H NMR (conformeric mixture, CDCl3, 500
MHz) δ 5.92 (ddt, 1H, J ) 17.0, 10.4, 5.8 Hz), 5.28-5.42 (m,
2H), 5.31 (dq, 1H, J ) 17.1, 1.5 Hz), 5.23 (dq, 1H, J ) 10.4,
1.3 Hz), 4.58 (dt, 2H, J ) 5.7, 1.4 Hz), 3.74-4.07 (m, 1H), 3.69
and 3.62-3.65 (t and m respectively, 2H total, J ) 6.8 Hz),
3.13 and 3.04-3.08 (t and m respectively, 2H total, J ) 6.8
Hz), 2.336 and 2.340 (2t, 2H total, J ) 7.6 Hz), 1.93-2.09 (m,
4H), 1.66-1.73 (m, 2H), 1.44 and 1.46 (2s, 9H total), 1.19-
1.42 (m, 10H total), 0.80-0.91 (m, 3H), 0.89 and 0.90 (2s, 9H
total), 0.063 and 0.068 (2s, 6H total); HRMS (FAB, m/z) calcd
for C25H50NO3Si [(M-Boc) + H]+ 440.3560, found 440.3560.
(S)-(Z)-11-[ter t-Bu toxycar bon yl(2-h ydr oxyeth yl)am in o]-
tetr a d ec-5-en oic Acid Allyl Ester (22). Starting with 21
(30.6 mg, 56.7 µmol) the procedure for 19 was followed to give
23.0 mg (54.0 µmol, 95%) of 22 as a pale yellow oil: [R]20D +0.50
(10Z,25Z)-(5S,20S)-15,30-Dioxo-5,20-dipr opyl-1,16-dioxa-
4,19-d ia za cyclot r ia con t a -10,25-d ien e-4,19-d ica r b oxylic
Acid Di-ter t-bu tyl Ester (32). Starting with 29 (7.1 mg, 9.4
µmol), the procedure for 34 was followed, with the omission
of the (silica/silver nitrate) chromatography step, to give 4.1
mg (5.6 µmol, 59%) of 32 as a clear oil: [R]25 +2.0 (c 0.41,
D
CH2Cl2); IR (film) 1738, 1694 cm-1
;
1H NMR (conformeric
mixture, CDCl3, 500 MHz) δ 5.29-5.43 (m, 4H), 4.12-4.24 (m,
4H), 3.72-4.08 (m, 2H), 3.13-3.34 (m, 4H), 2.29-2.33 (m, 4H),
1.96-2.09 (m, 8H), 1.65-1.73 (m, 4H), 1.46 and 1.47 (2s, 18H
total), 1.20-1.43 (m, 20H), 0.91 (t, 6H, J ) 7.5 Hz); HRMS
(FAB, m/z) calcd for C33H59N2O6 [(M-Boc; isobutene) + H]+
579.4373, found 579.4372.
(10Z,25Z)-(5S,20S)-5,20-Dip r op yl-1,16-d ioxa -4,19-d ia za -
cyclotr ia con ta -10,25-d ien e-15,30-d ion e (1). The Boc-pro-
tected diene 32 (3.7 mg, 5.0 µmol) was taken up in TFA (100
(c 2.09, CH2Cl2); IR (film) 3454 (br), 1740, 1690, 1664 cm-1
1H NMR (conformeric mixture, CDCl3, 500 MHz) δ 5.92 (ddt,
;

Synthesis of Unsaturated Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1081
µl) and allowed to sit for 15 min. The TFA was removed under
a stream of N2, and the residue was taken up in 20% aqueous
potassium carbonate and extracted with ether. The organic
extract was dried (K2CO3), filtered, and concentrated in vacuo
mixture, CDCl3, 500 MHz) δ 5.26-5.45 (m, 6H), 4.13-4.20 (m,
2H), 3.71-4.10 (m, 4H), 3.15-3.32 (m, 4H), 2.77 (t, 2H, J )
5.7 Hz), 1.96-2.37 (m, 12H), 1.66-1.76 (m, 4H), 1.46, 1.47 and
1.48 (3s, 18H total), 1.23-1.51 (m, 14H), 0.89-0.94 (m, 6H);
HRMS (ESI, m/z) calcd for C42H74N2O9 (M + H)+ 751.5473,
found 751.5463.
to give 2.7 mg (5.0 µmol, 100%) of 1 as a clear oil: [R]25 +8.5
D
1
(c 0.25, CH2Cl2); IR (film) 3350 (w, br), 1735 cm-1; H NMR
(C6D6, 500 MHz) δ 5.47 (dtt, 2H, J ) 10.8, 7.3, 1.5 Hz, 2CHd
CHCH2CH2CH2CO2R), 5.34 (dtt, 2H, J ) 10.8, 7.4, 1.5 Hz,
2CHdCHCH2CH2CH2CO2R), 4.19 (ddd, 2H, J ) 11.0, 5.9, 5.0
Hz, 2OCHaHbCH2N), 4.14 (ddd, 2H, 11.0, 6.4, 5.0 Hz, 2OCHaHb-
CH2N), 2.63-2.70 (m, 4H, 2OCH2CH2N), 2.40-2.44 (m, 2H,
2NCH), 2.20 (t, 4H, J ) 7.3 Hz, 2CH2CO2R), 2.05 (q, 8H, J )
7.2 Hz, 2CH2CHdCHCH2), 1.67 (quin, 4H, J ) 7.3 Hz, 2CH2-
CH2CO2R), 1.23-1.38 (m, 20 H, 2CH2CH2CH2CHNCH2CH2-
CH3, 0.92 (t, 6H, J ) 7.1 Hz, 2CH2CH3); 13C NMR (C6D6, 100
MHz) δ 172.9, 131.1, 129.1, 64.6, 57.0, 45.6, 37.1, 34.4, 33.6,
30.3, 27.6, 26.9, 25.6, 25.2, 19.2, 14.6; HRMS (FAB, m/z) calcd
for C32H59N2O4 [(M-Boc) + H)]+ 535.4475, found 535.4477.
(S)-(5Z,8Z)-11-[[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-
(d im et h ylet h oxyca r b on yl)a m in o]t et r a d eca -5,8-d ien oic
Acid 2-[((S)-(Z)-10-Allyloxyca r bon yl-1-p r op yld ec-6-en yl)-
ter t-bu toxyca r bon yla m in o]eth yl Ester (24). Starting with
17 (20.9 mg, 33.6 µmol) and 22 (15.3 mg, 35.9 µmol), the
procedure for 25 was followed to give 24.6 mg (23.9 µmol, 71%)
(10Z,22Z25Z)-(5S,20S)-15,30-Dioxo-5,20-d ip r op yl-1,16-
d ioxa -4,19-d ia za cyclot r ia con t a -10,22,25-t r ien e-4,19-d i-
ca r boxylic Acid Di-ter t-bu tyl Ester (33). Starting with 30
(14.3 mg, 19.0 µmol), the procedure for 34 was followed until
the crude residue from the ether extraction was obtained. The
residue was purified by flash chromatography (silica gel
containing 10% silver nitrate by mass, elution with a step
gradient from 33% to 50% EtOAc in hexanes) to give 6.4 mg
(8.7 µmol, 46%) of 33 as a clear oil: [R]20 -1.1 (c 0.49, CH2-
D
Cl2); IR (film) 1736, 1690 cm-1; 1H NMR (conformeric mixture,
CDCl3, 500 MHz) δ 5.28-5.43 (m, 6H), 4.09-4.25 (m, 4H),
3.71-4.09 (m, 2H), 3.12-3.37 (m, 4H), 2.78 (t, 2H, J ) 5.9
Hz), 2.22-2.36 (m, 6H), 1.99-2.14 (m, 6H), 1.64-1.75 (m, 4H),
1.22-1.52 (m, 32H), 0.091 and 0.092 (2t, 6H, J ) 7.4 Hz for
both); HRMS (ESI, m/z) calcd for C42H73N2O8 (M + H)+
733.5367, found 733.5381.
(10Z,22Z,25Z)-(5S,20S)-5,20-Dip r op yl-1,16-d ioxa -4,19-
d ia za cyclotr ia con ta -10,22,25-tr ien e-15,30-d ion e (2). Start-
ing with 33 (5.4 mg, 7.4 µmol), the procedure for 3 was followed
of 24 as a pale yellow oil: [R]20 -5.13 (c 2.24, CH2Cl2); IR
D
(film) 1738, 1690 cm-1; 1H NMR (conformeric mixture, CDCl3,
500 MHz) δ 7.66-7.68 (m, 4H), 7.36-7.45 (m, 6H), 5.92 (ddt,
1H, J ) 17.2, 10.4, 5.8 Hz), 5.23-5.42 (m, 7H), 5.24 (dq, 1H,
J ) 10.4, 1.3 Hz), 4.58 (dt, 2H, J ) 5.7, 1.4 Hz), 4.14 and 4.18
(2t, 2H total, J ) 6.8 Hz for both), 3.83-4.09 (m, 2H), 3.62-
3.80 (m, 2H), 3.13-3.31 (m, 4H), 2.64-2.77 (m, 2H), 2.34 (t,
2H, J ) 7.6 Hz), 2.28-2.35 (m, 2H), 1.94-2.17 (m, 8H), 1.66-
1.74 (m, 4H), 1.36, 1.43, 1.46 and 1.47 (4s, 18H total), 1.17-
1.45 (m, 14H), 1.05 (s, 9H), 0.91 (t, 3H, J ) 7.2 Hz), 0.80-
0.85 (m, 3H); HRMS (ESI, m/z) calcd for C61H97N2O9Si (M +
H)+ 1029.6963, found 1029.6894.
to give 3.5 mg (6.6 µmol, 89%) of 2 as a clear oil: [R]20 -0.09
D
1
(c 0.32, CH2Cl2); IR (film) 3324 (w, br), 1736 cm-1; H NMR
(C6D6, 500 MHz) δ 5.29-5.57 (m, 6H, 3CHdCH), 4.09-4.21
(m, 4H, 2OCH2CH2N), 2.79-2.91 (m, 2H, CHdCHCH2CHd
CH), 2.61-2.73 (m, 4H, 2OCH2CH2N), 2.40-2.49 (m, 2H,
2NCH), 2.21 (t, 2H, J ) 7.2 Hz, CH2CO2R), 2.20 (t, 2H, J )
7.2 Hz, CH2CO2R), 2.17-2.23 (m, 1H, NCHCHaHbCHdCH),
2.08-2.14 (m, 1H, NCHCHaHbCHdCH), 2.06 (q, 6H, J ) 7.3
Hz, CH2CH2CHdCHCH2CH2 and CH2CHdCHCH2CHdCHCH2-
CHN), 1.63-1.70 (m, 4H, 2CH2CH2CO2R), 1.20-1.40 (m, 14H,
CH2CH2CH2CHN and 2CH2CH2CH3), 0.92 (t, 3H, J ) 7.0 Hz,
CH2CH3), 0.91 (t, 3H, J ) 6.8 Hz, CH2CH3); 13C NMR (C6D6,
100 MHz) δ 173.29, 173.27, 131.5, 130.7, 129.7, 129.6, 129.5,
127.7, 65.03, 64.93, 57.7, 57.4, 46.4, 46.0, 37.5, 37.3, 34.7, 34.02,
34.01, 32.9, 30.7, 28.0, 27.28, 27.26, 26.6, 25.9, 25.6, 25.5, 19.7,
19.6, 15.04, 15.00; HRMS (ESI, m/z) calcd for C32H57N2O4 (M
+ H)+ 533.4318, found 533.4286.
(S)-(5Z,8Z)-11-[[2-(ter t-Bu tyld ip h en ylsila n yloxy)eth yl]-
(d im et h ylet h oxyca r b on yl)a m in o]t et r a d eca -5,8-d ien oic
Acid 2-[ter t-Bu toxyca r bon yl-((S)-(Z)-10-ca r boxy-1-p r o-
p yld ec-6-en yl)a m in o]eth yl Ester (27). Starting with 24
(24.6 mg, 23.9 µmol), the procedure for 28 was followed to give
22.0 mg (22.2 µmol, 93%) of 27 as a pale yellow oil: [R]20D -5.2
(c 1.81, CH2Cl2); IR (film) 3200 (br), 1738, 1694 cm-1; 1H NMR
(conformeric mixture, CDCl3, 400 MHz) δ 7.65-7.69 (m, 4H),
7.36-7.46 (m, 6H), 5.23-5.43 (m, 6H), 4.15 and 4.19 (2t, 2H
total, J ) 6.7 Hz for both), 3.62-4.09 (m, 4H), 3.09-3.31 (m,
4H), 2.64-2.78 (m, 2H), 2.35 (t, 2H, J ) 7.3 Hz), 2.27-2.34
(m, 2H), 1.92-2.20 (m, 8H), 1.66-1.76 (m, 4H), 1.36, 1.43, 1.46
and 1.48 (4s, 18H total), 1.16-1.48 (m, 14H), 1.05 (s, 9H),
0.88-0.93 (m, 3H), 0.80-0.85 (m, 3H); HRMS (ESI, m/z) calcd
for C58H92N2O9Si (M + H)+ 989.6650, found 989.6640.
Ackn owledgm en t. Frank Schroeder and Jay Farmer
provided invaluable guidance. Electrospray ionization
mass spectrometry was carried out by Athula Attygalle,
Cornell Mass Spectrometry Facility. The photograph
used for the cover art was provided by Professor Tom
Eisner. The partial support of this research by the NIH
(grant GM 53830 and training grant GM 08500) is
acknowledged with pleasure.
(S)-(5Z,8Z)-11-[ter t-Bu toxyca r bon yl-(2-h yd r oxyeth yl)-
a m in o]tetr a d eca -5,8-d ien oic Acid 2-[ter t-Bu toxyca r bo-
n yl-((S)-(Z)-10-ca r boxy-1-p r op yld ec-6-en yl)a m in o]eth yl
Ester (30). Starting with 27 (21.1 mg, 21.3 µmol), the
procedure for 31 was followed to give 14.2 mg (18.9 µmol, 89%)
of 30 as a pale yellow oil: [R]20D -8.1 (c 1.23, CH2Cl2); IR (film)
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
all synthesized compounds and 13C NMR spectra of compounds
1-3, 9-11, and 13-15. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
3432 (br), 3200 (br), 1738, 1690 cm-1; H NMR (conformeric
J O001200W