Synthesis and ring contraction reactions of polyazamacrolides

Article abstract of DOI:10.1021/jo001247h

The synthesis of three analogues of the single most abundant component of a ladybird beetle (Epilachna borealis) defensive secretion, the trimeric 42-membered polyazamacrolide PAML 681, is described. Construction of the nonnatural macrocyclic trimers began with the preparation of the corresponding monomeric segments, followed by their oligomerization and a final macrolactonization step of the activated linear trimeric hydroxy acid. The relative rates of the O-to-N acyl migrations that are characteristic of PAML 681 itself, as well as of the synthetic analogues, were investigated. These studies showed that changes in the substitution pattern adjacent to the nucleophilic nitrogen atom, along with changes in the size of the oxaazacyclic intermediates, have substantial effects on the polyazamacrolide rearrangement rates.

Full text of DOI:10.1021/jo001247h

1082
J . Org. Chem. 2001, 66, 1082-1096
Syn th esis a n d Rin g Con tr a ction Rea ction s of P olya za m a cr olid es
Silvina Garc´ıa-Rubio and J errold Meinwald*
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University,
Ithaca, New York 14853-1301
circe@cornell.edu
Received August 16, 2000
The synthesis of three analogues of the single most abundant component of a ladybird beetle
(Epilachna borealis) defensive secretion, the trimeric 42-membered polyazamacrolide PAML 681,
is described. Construction of the nonnatural macrocyclic trimers began with the preparation of the
corresponding monomeric segments, followed by their oligomerization and a final macrolactonization
step of the activated linear trimeric hydroxy acid. The relative rates of the O-to-N acyl migrations
that are characteristic of PAML 681 itself, as well as of the synthetic analogues, were investigated.
These studies showed that changes in the substitution pattern adjacent to the nucleophilic nitrogen
atom, along with changes in the size of the oxaazacyclic intermediates, have substantial effects on
the polyazamacrolide rearrangement rates.
In tr od u ction
Studies of the chemical ecology of insects and related
arthropods reveal that these enormously diverse and
successful animals exploit a wide range of molecular
structures for defensive and communicative purposes.1
It can be anticipated that chemical defenses should be
particularly important in preadult life stages, and this
expectation has recently been confirmed in the case of
the pupae of several species of coccinellid (ladybird)
beetles. These pupae are defended by a new class of
alkaloids, the azamacrolides and their oligomeric cousins,
the polyazamacrolides, which constitute a structurally
unprecedented addition to the already rich array of insect
defensive chemicals. Among the first of these macrocycles
to be characterized were epilachnene (1) and epilachna-
diene (2) (Figure 1), from the pupal defensive secretion
of the Mexican bean beetle (Epilachna varivestis).2
Epilachnenic and epilachnadienic acids (3 and 4)
(Figure 2), the hydroxyethylamino acids from which these
15-membered lactones are derived, were subsequently
found to form three dimeric, 30-membered lactonic
alkaloids (5, 6, and 7), which are the major components
of the exudate of another coccinellid pupa, that of
Subcoccinella 24-punctata.3
F igu r e 1.
Three closely related, saturated (ω-1)-hydroxyethyl-
amino acids (8, 9 and 10) (Figure 3) provide the building
blocks for a combinatorial library of over a thousand
polyazamacrolides (PAMLs) deployed by pupae of still
another ladybird, the squash beetle Epilachna borealis.
The random incorporation of these three acids into a
series of oligomeric lactones, consisting chiefly of trimers,
tetramers, and pentamers but including everything from
* Ph: (607) 255-3301. Fax: (607) 255-3407.
(1) Meinwald, J .; Eisner, T. Proc. Natl. Acad. Sci. U.S.A. 1995, 92,
12.
F igu r e 2.
(2) King, A. G.; Meinwald, J . Chem. Rev. 1996, 96, 1105. Attygalle,
A. B.; McCormick, K. D.; Blankespoor, C. L.; Eisner, T.; Meinwald, J .
Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 5204. Attygalle, A. B.; Smedley,
S.; Eisner, T.; Meinwald, J . Experientia 1996, 52, 616.
(3) (a) Schro¨der, F.; Smedley, S.; Gibbons, L. K.; Farmer, J .;
Attygalle, A.; Eisner, T.; Meinwald, J . Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 13387. (b) Gronquist, M. R.; Meinwald, J . J . Org. Chem. 2000,
2, 1075.
dimers to at least heptamers, gives rise to the most
complex arthropod defensive secretion ever character-
ized.4a,b
A striking feature of the chemistry of PAMLs is their
tendency to undergo multiple intramolecular acyl group
10.1021/jo001247h CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/09/2001

Synthesis and Reactions of Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1083
F igu r e 4.
F igu r e 3.
migrations. This phenomena is, of course, not unique to
these alkaloids; it has been observed in a variety of
natural products, including the Solanum alkaloids,5
adenosine peptidyl derivatives,6 the immunosuppressant
drug cyclosporin A, and other peptides containing â-hy-
droxyl residues.7 This type of rearrangement also pro-
vides a useful strategy for the convergent synthesis of
peptides,8a,b peptidomimetic structures,8c proteins,8d and
macrocyclic lactones.9 In the case of the PAMLs, each of
these O-to-N acyl migration steps results in the reduction
of the ring size of the macrocycle by three members; a
basic nitrogen atom is converted into a neutral amide
nitrogen atom, and a primary hydroxyl group is exposed
(Figure 4).
F igu r e 5.
The large number of additional structures that this
pathway generates contributes greatly to the structural
diversity of this ladybird’s pupal exudate. In each of these
natural products, the nitrogen atom is able to initiate
an O-to-N acyl group transfer via a five-membered ring
intermediate. In addition, there is always a single alkyl
group on the carbon atom adjacent to the nitrogen atom.
There is no information on whether these particular
structural features are important for the biological
functioning of these compounds as insect repellents. We
have consequently become interested in exploring the
chemistry of some nonnatural polyazamacrolides, which
differ from the natural products (a) in the degree of alkyl
group substitution at the carbon adjacent to the basic
nitrogen and (b) in the distance between the nucleophilic
nitrogen atom and the nearest lactonic carbonyl group.
With these objectives in mind, we have undertaken
syntheses of three analogues of the single most abundant
component of the E. borealis secretion, the trimeric, 42-
membered PAML 681. We here report the synthesis of a
small set of nonnatural polyazamacrolides, as well as
studies of their O-to-N acyl group migration. The specific
target compounds we selected were a trisnor lactone (11),
a trismethyl lactone (12), and a trishomo lactone (13)
(Figure 5). These compounds allow us to study the
influence of the methyl substitution adjacent to the
nucleophilic nitrogen, along with the importance of the
size of the intermediate ring (five- or six-membered) in
the PAMLs’ contraction process.
(4) (a) Schro¨der, F.; Farmer, J .; Attygalle, A.; Smedley, S.; Eisner,
T.; Meinwald, J . Science 1998, 281, 428. (b) Schro¨der, F.; Farmer, J .;
Smedley, S.; Attygalle, A.; Eisner, T.; Meinwald, J . J . Am. Chem. Soc.
2000, 122, 3628. (c) Farmer, J .; Attygalle, A.; Smedley, S.; Eisner, T.;
Meinwald, J . Tetrahedron Lett. 1997, 38, 2787. (d) Farmer, J .;
Schro¨der, F.; Meinwald, J . Helv. Chim. Acta 2000, 83, 2594.
(5) Adam, G.; Schreiber, K. Chem. Ber. 1966, 99, 3173.
(6) Neumann, H.; Shashoua, V. E.; Sheehan, J . C.; Rich, A. Proc.
Natl. Acad. Sci. U.S.A. 1968, 61, 1207.
(7) (a) Pohl, E.; Sheldrick, G. M.; Bo¨lsterli, J . J .; Kallen, J .; Traber,
R.; Walkinshaw, M. D. Helv. Chim. Acta 1996, 79, 1635. Oliyai, R.;
Safadi, M.; Meier, P. G.; Hu, M. K.; Rich, D. H.; Stella, V. J . Int. J .
Peptide Protein Res. 1994, 43, 239. Ru¨egger, A.; Kuhn, M.; Lichti, H.;
Loosli, H. R.; Hugenin, R.; Quiquerez, C.; von Wartburg, A. Helv. Chim.
Acta 1976, 59, 1075. (b) Oliyai, R.; Stella, V. J . Bioorg. Med. Chem.
Lett. 1995, 5, 2735.
(8) (a) For a recent review, see: Coltart, D. M. Tetrahedron 2000,
56, 3449. See also: Offer, J .; Dawson, P. E. Org. Lett. 2000, 2, 23. Tam,
J . P.; Lu, Y.-A.; Yu, Q. J . Am. Chem. Soc. 1999, 121, 4316 and
references therein. (b) Kemp, D. S. Biopolymers 1981, 20, 1793. Kemp,
D. S.; Kerkman, D. J .; Leung, S. L.; Hanson, G. J . Org. Chem. 1981,
46, 490. Kemp, D. S.; Vellaccio, F. J . Org. Chem. 1975, 40, 3464.
Sakakibara, S.; Shin, K. H.; Hess, G. P. J . Am. Chem. Soc. 1962, 84,
4921. (c) Derrer, S.; Feeder, N.; Teat, S. J .; Davies, J . E.; Holmes, A.
B. Tetrahedron Lett. 1998, 39, 9309. (d) Camarero, J . A.; Muir, T. W.
J . Am. Chem. Soc. 1999, 121, 5597 and references therein.
(9) Gribble, G. W.; Silva, R. A. Tetrahedron Lett. 1996, 37, 2145.

1084 J . Org. Chem., Vol. 66, No. 4, 2001
Garc´ıa-Rubio and Meinwald
Sch em e 1
another equivalent of alcohol 16 using an 1-[3-(dimethyl-
amino)propyl]-3-ethylcarbodiimide (EDCI)-mediated pro-
cedure.13 After considerable experimentation, optimal
results were obtained when monomers 16 and 18 were
combined at room temperature by treatment with the
water-soluble carbodiimide and DMAP as catalyst. Al-
ternative coupling reagents (bis(2-oxo-3-oxazolidinyl)-
phosphinic chloride (BOP-Cl)14 or 2,4,6-trichlorobenzoyl
chloride15) gave far lower yields, while DCC16 complicated
the product purification. It is interesting to note that
performing the chemoselective acid-catalyzed TBDMS
ether desilylation (camphorsulfonic acid (CSA), CH2Cl2/
MeOH, 0 °C)17a was found to be capricious depending
upon reaction conditions: longer times and/or higher
temperatures afforded mixtures resulting from partial
amine deprotection.17b Reiteration of the desilylation/
coupling protocol starting with dimer 19 led to open chain
trimer 21, which was converted to hydroxy acid 23 after
removal of the benzyl and TBDMS protecting groups.
Overall, activated trimer 23 was prepared from mono-
meric precursor 16 in seven steps and 56% yield. Finally,
subjection of hydroxy acid 23 to Mukaiyama’s reagent
promoted lactonization18 under high dilution conditions
(∼3 × 10-4 M) in refluxing acetonitrile resulted in
cyclization, providing the N-Boc-protected macrocycle 24,
which was treated with neat TFA to afford the desired
42-membered polyazamacrolide 11 in 60% yield for the
two steps. Examination of the 1H, 13C, and 2D NMR
(COSY and HMQC) spectra of cyclic trimer 24 showed
1
that upon macrocyclization, only a single set of H and
13C resonances, corresponding to a mixture of rotamers
of the monomeric subunits,19 was observable. In addition,
the unequivocal identification of polyazamacrolide 11 was
supported on the basis of its LC-electrospray ionization
mass spectrometric (ESIMS) analysis, which indicated
its chromatographic homogeneity in different eluent
solvent mixtures and showed the expected MS pattern:
operating in positive ion electrospray mode, trisnor
lactone 11 produced multiple charged ions with up to
three charges corresponding to the number of basic
nitrogen atoms present in the molecule [m/z 641 (M+H)+,
321 (M+2H)2+, 214 (M+3H)3+)].
Syn th esis of Tr is(10-m eth yl)P AML 681 (12). The
PAML 681 analogue bearing gem-dimethyl substituents
vicinal to each of the nitrogen atoms was prepared to
evaluate the influence of the additional methyl group on
the chemical and functional behavior of PAML 681. The
approach implemented for the construction of 12 (Scheme
2) relies on the strategy described in the previously
reported synthesis of natural PAML 681.4a Thus, opening
of the activated 2,2-dimethyltosylaziridine 2520 with
Resu lts a n d Discu ssion
Syn th esis of Tr is(10-n or )P AML 681 (11). Construc-
tion of the first nonnatural macrocyclic trimer 11 re-
quired the preparation of the corresponding monomeric
segment (C1-C12, 16), differing from the natural build-
ing block 8 by the absence of a methyl substituent at C10,
followed by subsequent assembly and cyclization of the
activated open chain trimer 23 (Scheme 1). Benzyl 10-
hydroxydecanoate 1410 was smoothly oxidized with TPAP/
NMO11 to the aldehyde 15 in 81% yield. Formation of the
monomeric protected amino alcohol 16 was achieved by
reductive amination of 15 with ethanolamine hydrochlo-
ride in the presence of NaBH3CN, followed by acylation
of the amine with Boc2O12 (48% yield, two steps). To
obtain the dimeric unit 19, alcohol 16 was conveniently
transformed into acid 18, which was then coupled with
(13) Dhaon, M. K.; Olsen, R. K.; Ramasamy, K. J . Org. Chem. 1982,
47, 1962.
(14) Balleste-Rodes, M.; Palomo-Coll, A. L. Synth. Commun. 1984,
14, 515.
(15) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
(16) Ramage, R.; MacLeod, A. M.; Rose, G. W. Tetrahedron 1991,
47, 5625. Hassner, A.; Alexanian, V. Tetrahedron Lett. 1978, 46, 4475.
(17) (a) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031. (b)
Deprotection of N-Boc protected amines is usually achieved by using
strong acids (TFA, HCl, H2SO4, p-toluenesulfonic acid, methanesulfonic
acid) at room temperature: Greene, T. W.; Wuts, P. G.-M. In Protective
Groups in Organic Synthesis, 3rd ed.; Wiley & Sons: New York, 1999;
Chapter 7, p 518.
(18) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
(19) Askin, D.; Wallace, M. A.; Vacca, J . P.; Reamer, R. A.; Volante,
R. P.; Shinkai, I. J . Org. Chem. 1992, 57, 2771.
(20) Alul, R.; Cleaver, M. B.; Taylor, J .-S. Inorg. Chem. 1992, 31,
3636.
(10) Flippin, L. A.; Gallagher, D. W.; J alali-Araghi, K. J . Org. Chem.
1989, 54, 1430. Holt, A. D.; Luengo, J . I.; Yamashita, D. S.; Oh, H.-J .;
Konialian, A. L.; Yen, H.-K.; Rozamus, L. W.; Brandt, M.; Bossard, M.
J .; Levy, M. A.; Eggleston, D. S.; Liang, J .; Schultz, L. W.; Stout, T. J .;
Clardy, J . J . Am. Chem. Soc. 1993, 115, 9925.
(11) Ley, S. V.; Norman, J .; Griffith, W. P.; Mardsen, S. P. Synthesis
1994, 639.
(12) For the recent application and discussion of protecting group
tuning techniques to chemoenzymatic synthesis of polyazamacrolides,
see: Lu, W.; Sih, C. J . Tetrahedron Lett. 1999, 40, 4965. See also:
Woodward, R. B. et al. J . Am. Chem. Soc. 1981, 103, 3213.

Synthesis and Reactions of Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1085
Sch em e 2
N-Boc derivative required long reaction times and cata-
lytic amounts of DMAP, manifesting the low reactivity
of the hindered neopentyl nitrogen atom.24 After protect-
ing group exchange, ozonolysis of carbamate 29 under
carefully controlled reaction conditions followed by im-
mediate Wittig olefination of the crude ozonide25 with
4-carboxybutyltriphenylphosphonium ylide provided un-
saturated monomer 30 in 94% overall yield from 29. In
accordance with expectations for a nonstabilized ylide, a
cis configuration of the double bond for unsaturated
carbamate 29 was observed on the basis of the absence
1
of large trans H,1H coupling constants for the olefinic
protons (2H at δ 5.29-5.45, 2m). Additional benzylation
of acid 30 (BnOH/EDCI/DMAP, CH2Cl2, rt)26 and TBDMS
ether cleavage with CSA gave monoprotected 32, which
was coupled with its monomeric partner 30 to afford
dimer 33 in 90% yield. Desilylation of dimer 33, followed
by chain elongation and deprotection, afforded alcohol 36
in up to 54% yield. Simultaneous hydrogenation-deben-
zylation of 36 gave long chain hydroxy acid 37, which
was converted to cyclic trimer 38 after macrolactonization
in the presence of Mukaiyama’s reagent. In comparing
1
the H and 13C NMR data of N-Boc-protected polyazamac-
rolide 38 with the data previously observed for the trisnor
analogue 24, disappearance of carbamate rotamers was
evident. This difference is most likely due to severe steric
interaction between the gem-dimethyl substituents and
the tert-butoxycarbonyl protecting group.27 Finally, car-
bamate deprotection allowed the isolation of tris(10-
methyl)PAML 681 (12) as its tris(trifluoroacetate) 39 (8%
overall yield, 14 steps), which displayed NMR and MS
characteristics consistent with the desired macrocyclic
structure. As a consequence of the unexpectedly high
rates for the O-to-N acyl migration of the corresponding
free amine 12, deprotonation of tris(10-methyl)PAML 681
tris(trifluoroacetate) was deferred until performance of
the rearrangement rate studies (vide infra).
Syn t h esis of Tr is(10-n or )P AML 681 Hom ologu e
(13). To provide a model for exploring the chemistry of
PAMLs analogues with an additional carbon atom be-
tween the nitrogen and the nearest carbonyl group, we
prepared the PAML homologue 13 starting from com-
mercially available 11-aminodecanoic acid as outlined in
Scheme 3. The reaction sequence was initiated by Michael
addition of sodium 11-aminodecanoate to methyl acrylate,
followed by protection of the resulting secondary amine
as its Boc derivative to furnish hemi ester 40 in a one-
pot procedure and 77% yield. Chemoselective reduction
of 40 with LiBH4-MeOH28 in refluxing Et2O resulted in
the formation of hydroxy acid 41, the monomer used to
prepare linear trimer 49. Once again, EDCI-mediated
magnesium bis(3-butenyl) copper reagent21 was accom-
plished with excellent regioselectivity to afford tosyl
amide 26; the exclusive presence of the desired single
regioisomer was shown by 1H NMR examination of
unpurified reaction products. The slightly lower yields
compared to those obtained for the R-monomethylamino
derivative4a are easily rationalized on the basis of in-
creased steric hindrance, since nucleophilic attack to
electronically deficient aziridines is known to involve an
SN2-type mechanism.22 Subsequent alkylation of 26
(NaH/tert-(butyldimethylsilyloxy)ethyl bromide, DMF, 0
°C) led to silyl ether 27 (72% yield, two steps). Following
tosyl group removal,23 conversion of amine 28 into its
(24) For extensive leading references to the reactivity of sterically
hindered amines, see: Guziek, F. S.; Torres, F. F. J . Org. Chem. 1993,
58, 1604. See also: Kim, H.-O.; Gardner, B.; Kahn, M. Tetrahedron
Lett. 1995, 36, 6013. Kim, H.-O.; Kahn, M. Synlett 1995, 549.
(25) The unusual stability of the intermediate ozonide in tert-butyl
methyl ether made possible its direct treatment with 4-carboxybutyl-
triphenylphosphonium ylide to afford unsaturated acid 30: Farmer,
J . J . Ph.D. Thesis, Cornell University, 1999.
(21) Sha, C. K.; Tsong Shin, J .; Wang, D. C. Tetrahedron Lett. 1990,
31, 3745.
(26) Attempts to benzylate acid 30 in the presence of DCC resulted
in a difficult isolation of the product and lower yields. See Protective
Groups in Organic Synthesis, 3rd ed.; Wiley & Sons: New York, 1999;
Chapter 7, p 415.
(27) Marcovici-Mizrahi, D.; Gottlieb, H. E.; Marks, V. Nudelman,
A. J . Org. Chem. 1996, 61, 8402. Moraczevski, A. L.; Banaszynski, L.
A.; From, A. M.; White, C. E.; Smith, B. D. J . Org. Chem. 1998, 63,
7258. Sugg, E. E.; Griffin, J . F.; Portoghese, P. S. J . Org. Chem. 1985,
50, 5032.
(22) The mechanism and regioselectivity of the nucleophilic attack
on 2,2-dimethylaziridines depend on the degree of leaving group
activation: Lin, P.-Y.; Bellos, K.; Stamm, H.; Onistschenko, A.
Tetrahedron 1992, 48, 2359. Onistschenko, A.; Buchholz, B.; Stamm,
H. Tetrahedron 1987, 43, 565. Stamm, H.; Assithianakis, P.; Buchholz,
B.; Weib, R. Tetrahedron Lett. 1982, 23, 5021.
(23) Heathcock, C. H.; Blumenkopf, T. A.; Smith, K. M. J . Org.
Chem. 1989, 59, 1548.
(28) Soai, K.; Ookawa, A. J . Org. Chem. 1986, 51, 4000.

1086 J . Org. Chem., Vol. 66, No. 4, 2001
Garc´ıa-Rubio and Meinwald
Sch em e 3
on O-to-N acyl migrations, which sequentially convert
polyazamacrolides into the rearranged, ring-contracted
amides. While this type of transformation is well-
documented for individual structures in the literature,7-10
polyazamacrolides 11, 12, and 13, along with PAML 681,
offered an excellent opportunity to study these rear-
rangements in a closely related group of compounds. A
combination of spectroscopic and chromatographic meth-
ods allowed us to observe mono- and bisamide intermedi-
ates, to estimate relative rearrangement rates, and to
investigate the effects of discrete structural modifications
on polyazamacrolide reactivities.
Conversion of each polyazamacrolide into its amide
counterpart was performed under identical conditions at
50 °C in sealed NMR tubes with C6D6 as solvent (0.015
M). Monitoring the disappearance of a 1H NMR signal
characteristic of the lactone moiety, as well as the
appearance of diagnostic signals for the developing
amide, provided a convenient way to follow the progress
of the O-to-N acyl migration. In addition, complementary
1
spectroscopic data (13C NMR, 2D H-13C NMR, IR, MS)
along with LC separation were fully consistent with the
1
progressive ester to amide rearrangement. The H NMR
spectral changes with time are illustrated for polyazamac-
rolide 13 in Figure 6. The O-to-N acyl migration affects
all the proton chemical shifts in the substrate, particu-
larly those corresponding to methylene groups attached
to heteroatoms. Protons R to the oxygen atoms (δ 4.15-
4.25 ppm) move upfield (δ 3.55-3.65 ppm) as a conse-
quence of liberating the primary hydroxyl group, while
the methylene protons R to the amine experience a
downfield shift (from δ 2.45-2.60 to δ 2.65-3.40 ppm)
as a consequence of amide formation. Moreover, HPLC-
MS analysis suggests that the individual O-to-N acyl
migration steps proceed at comparable rates, resulting
in the coexistence during the rearrangement process of
the starting polyamine with monoamide, bisamide, and
the fully rearranged trisamide.4a,b The progress of this
rearrangement can also be followed by monitoring the
disappearance of the ester carbonyl stretching band (1730
cm-1) and the growth of the amide band (1625 cm-1) in
the IR spectra of the reaction mixture (Figure 7). Studies
of the rearrangement of PAML 681, 11, and 12 gave
results entirely analogous to those observed for 13.
Quantification of the time-dependent disappearance of
methylene protons R to the ester carbonyl group in the
1H NMR spectra of each of the macrocyclic lactones we
studied followed first-order kinetics, affording relative
rate constants for the acyl transfer in PAML 681 and the
three synthetic polyazamacrolide analogues.29 A clear but
modest rate difference was observed to result from the
addition of a methylene group between the O and N
atoms (comparing 11 with 13); more striking differences
resulted from changing the degree of substitution adja-
cent to the nucleophilic amino group (comparing PAML
681 with 11 and 12). Thus, rearrangement via the
formation of a five-membered hydroxyoxazolidine inter-
mediate was found to proceed four times faster than the
rearrangement via a six-membered hydroxyoxazinane.30
Similar differences in relative rates have been described
by Bruice and Benkovic for the intramolecular attack by
an amino group on a neighboring ester group in linear
coupling between suitably protected monomers 42 and
44 gave dimer 45 with an overall yield of 80% from
hydroxy acid 41 after TBDMS ether cleavage. Subsequent
exposure of dimer 45 to a second sequence of desilylation,
esterification, and protecting group removal set the stage
for the crucial cyclization of linear trimer 49. As before,
macrolactonization was carried out using Mukaiyama’s
reagent under high dilution conditions to provide mac-
rocyle 50, whose amino groups were deprotected to give
the targeted polyamine 13. Including the hydrolysis step,
48-membered polyazamacrocycle 13 was obtained from
precursor hydroxy acid 49 in 40% overall yield. In
1
addition to its simplified H NMR, 14-line 13C NMR and
2D NMR spectra, the ESIMS spectrum supported the
structure 13, showing positive ions at m/z ) 725, 363,
and 242, corresponding to singly, doubly, and triply
charged molecular ions, respectively. Although there are
reports of macrolactonizations promoted by Mukaiyama’s
reagent that undergo undesired intermolecular dimer-
ization,18 no trace of hexamers could be detected by LC-
ESIMS in any of the macrocyclizations reported herein.
The observed selectivity indicates the enormous capabil-
ity of this methodology to afford intramolecular esteri-
fications starting from open chain hydroxy acids.
(29) Observed rate constants, including contributions from all
lactonic species generated during the O-to-N acyl migrations, were
determined by a nonlinear least-squares analysis showing excellent
fits in all cases.
O-to-N Acyl Migr a tion in P olya za m a cr olid es. With
PAML 681 and analogues in hand, we focused our study

Synthesis and Reactions of Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1087
1
F igu r e 6. Monitoring of the O-to-N acyl migration of polyazamacrolide 13 by H NMR (400 MHz, C6D6, 50 °C, TMS as external
standard). (a) t ) 0, (b) t ) 4 d, (c) t ) 12 d, (d) t ) 20 d, (e) t ) 27 d.
4- and 5-aminoalkanoates.31a These results suggest that
the macrocyclic structures themselves have a negligible
effect on the O-to-N acyl migrations; this conclusion is
in full agreement with the obvious conformational flex-
ibility of the original polyazamacrolides, as well as of the
monoamide and bisamide intermediates formed on the
way to the fully rearranged products. The larger influence
of methyl group substitution adjacent to the nucleophilic
nitrogen atoms of the lactone on the O-to-N acyl group
migration rates proved to be somewhat of a surprise. The
lowest rearrangement rate was observed for PAML 681
itself. Removal of the R-methyl group entirely (11)
resulted in a 30-fold faster rearrangement.24 Interest-
ingly, addition of three additional R-methyl substituents
(12) resulted in a 280-fold acceleration. This effect of the
gem-dimethyl groups is particularly striking, since the
substituents are not actually on the five-membered ring
intermediate through which the rearrangement proceeds
but lie outside the hydroxyoxazolidine ring.30a,32 It seems
conceivable that the effect of the gem-dimethyl group is
a consequence of favoring a ground state conformation
in 12, which more closely resembles the conformation of
the transition state leading to the corresponding five-
membered hydroxyoxazolidine rearrangement intermedi-
ate. These observations prompted us to search for an
understanding of the PAML rearrangements in terms of
a conformational analysis of PAML 681, its 10-nor
derivative 11 and gem-dimethyl analogue 12.
Molecular mechanics calculations were performed on
the PAMLs in an effort to assist the rationalization of
the experimental data regarding the relative rates of
rearrangement.33 Following a considerable amount of
(32) The so-called “gem-dialkyl effect” accounts for the ease of
cyclization processes upon alkyl substitution on the backbone chain:
Beesley, R. M.; Ingold, C. K.; Thorpe, J . F. J . Chem. Soc. 1915, 107,
1080. Ingold, C. K. J . Chem. Soc. 1921, 119, 305. Hammond, G. S.
Steric Effects in Organic Chemistry; Newman, M. S., Ed.; Wiley: New
York, 1956. Allinger, N. L.; Zalkow, V. J . Org. Chem. 1960, 25, 701.
Bruice, T. C.; Pandit, U. K. J . Am. Chem. Soc. 1960, 82, 5858. Schleyer,
P. v. R. J . Am. Chem. Soc. 1961, 83, 1368. Parrill, A. L.; Dolata, D. P.
Tetrahedron Lett. 1994, 35, 7319. Parrill, A. L.; Dolata, D. P.
THEOCHEM, J . Mol. Struct. 1996, 370, 182. J ung, M. E. Synlett 1999,
843. For excellent reviews, see: Eliel, E. Stereochemistry of Carbon
Compounds; McGraw-Hill: New York, 1962; p 197. Capon, B.; Mc-
Manus, S. P. Neighboring Group Participation; Plenum Press: New
York, 1976; Vol. I, p 43. See also: J ung, M. E.; Gervay, J . J . Am. Chem.
Soc. 1991, 113, 224. Keese, R.; Meyer, M. Tetrahedron 1993, 49, 2055
and references therein.
(30) (a) The kinetic premium on the formation of five-membered
rings has been measured in terms of “effective molarity” for a variety
of related lactamizations involving secondary amines: Kirby, A. J . Adv.
Phys. Org. Chem. 1980, 183 and references therein. (b) For a discussion
on the factors responsible for the efficiency of intramolecular aminolysis
reactions, see: Fife, T. H.; Chauffe, L. J . Org. Chem. 2000, 65, 3579.
Fife, T. H.; Duddy, N. W. J . Am. Chem. Soc. 1983, 105, 74.
(31) (a) Bruice, T. C.; Benkovic, S. J . J . Am. Chem. Soc. 1963, 85, 1.
(b) Bruice, T. C.; Benkovic, S. J . Bioorganic Mechanisms; W. A.
Benjamin: New York, 1966; Vol. 1.

1088 J . Org. Chem., Vol. 66, No. 4, 2001
Garc´ıa-Rubio and Meinwald
F igu r e 7. (1) HPLC-MS analysis of a reaction mixture for the O-to-N acyl migration of polyazamacrolide 13 (total ion current
chromatogram; for each of the displayed chromatograms, the largest peak is normalized to 100%). (a) t ) 0 d, (b) t ) 20 d, (c) t
) 80 d. (2) Monitoring the O-to-N acyl migration of 13 by IR spectroscopy. (d) t ) 0 d, (e) t ) 20 d, (f) t ) 80 d.
computational effort, apparent global minimum conforma-
tions34a were found after standard Monte Carlo Multiple
Minimum Search34b using the GLOBAL-MMX program
(MMX force field) as implemented in PC Model V7.0.35
Starting from structures with different internal coordi-
nates, a variable number of conformational families con-
taining conformations calculated within 3 kcal/mol of the
apparent global minimum were obtained. Interestingly,
despite the expected shallowness of their potential energy
surface (363, (3N-6) degrees of freedom calculated for
PAML 681), the lowest energy conformers of the polyaza-
macrolides were found to adopt a folded geometry in
which the cavity of the macrocycle collapses. Every
(34) (a) Saunders: M.; Houk, K. N.; Wu, Y.-D.; Still, C.; Lipton, M.;
Chang, G.; Guida, W. C. J . Am. Chem. Soc. 1990, 112, 1419. Saunders,
M. J . Am. Chem. Soc. 1987, 109, 3150. (b) For the application of this
MM computational protocol in the conformational analysis of simple
macrocyclic structures, see: Ram´ırez, M. C.; Toscano, R. A.; Arnason,
J .; Omar, S.; Cerda-Garc´ıa-Rojas, C. M.; Mata, R. Tetrahedron 2000,
56, 5085. Clyne, D. S.; Weiler, L. Tetrahedron 2000, 56, 1281 and
references therein. Taylor, R. E.; Zajicek, J . J . Org. Chem. 1999, 64,
7224. Keller, T. H.; Weiler, L. J . Am. Chem. Soc. 1990, 112, 450.
Kaisalo, L.; Koskimies, J .; Hase, T. J . Chem. Soc., Perkin Trans. 2 2000,
1477.
(33) 1H NMR spectral overlap observed for polyazamacrolides along
with the formation of rearranged products precluded a conformational
analysis based on vicinal coupling constants and intramolecular NOE
measurements.

Synthesis and Reactions of Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1089
attempt to locate open annular structures proved to be
unsuccessful, resulting in a significant destabilization
(approximately 30 kcal/mol) above folded conformers.36
Though the calculated structures are not fully energy
minimized, the following gross structural elements were
consistently found for different ground-state structures:
(a) a strong conformation dependence on the presence of
methyl substituents vicinal to each of the N atoms, (b)
the preferred accommodation of the methyl substituents
outside the ring system in the case of PAML 681, (c) the
location of the gem-dimethyl-substituted carbon atoms
in a corner position34,36a for analogue 12, and (d) the more
stable s-trans conformation of the ester function in all
polyazamacrolides. These features agree with those
previously found in the crystal structures of 12- and 14-
membered macrolides,36c,37 suggesting that the local
environment of the functional groups plays a significant
role in determining the conformational preferences of
large macrocycles with a low degree of functionaliza-
tion.34,38 In addition, the conformational profiles show a
remarkable tendency for favoring 1,5-intramolecular
nitrogen-carbonyl interactions, which is consistent with
the observed transannular acylation leading to cyclic
amides.39 The rate enhancing effect of the gem-dimethyl
substitution in the O-to-N acylation process may be
attributable to the increased population of distorted
conformers that show nitrogen-carbonyl separation dis-
tances just inside the sum of the van der Waals radii for
the N-C(O) atom pair.40 This conformational pre-
organization of the ground-state structures contributing
to the rates of intramolecular reactions has been defined
by Bruice and Lightstone with the term “near attack
conformation” (Figure 8).41
F igu r e 8. Calculated conformations of tris(10-methyl)PAML
681 (12) showing the features of near attack conformation,
N-C(O) distances ∼3 Å. The conformations were selected
among structures obtained within 3 kcal/mol of the apparent
global minimum.
detailed as follows: (a) the tetrahedral geometries at the
acyl carbon and the amine nitrogen in the cyclic rate-
determining transition structure,43 (b) the trans,anti
orientation of the RC-CO and N-RC bonds about the
forming C-N bond,44 and (c) the antiperiplanar arrange-
ment of the N lone pair and the C-O alkyl bond to be
broken.45 As noted by Kemp and co-workers, the achieve-
ment of these stereoelectronic requirements is highly
dependent on the conformational rigidity of the template
that links the reactive amine and ester functional
groups.46 A careful examination of the oxazolidine inter-
mediates derived from PAML 681 and its synthetic
analogues by using MMX force field calculations47 and
Dreiding models suggests that the bicyclic structures can
meet the stereoelectronic requirements. While the con-
formational flexibility of the original macrocycles allows
the necessary conditions for the migration, conforma-
tional restrictions that might be imagined to result from
amide bond formation in the partially rearranged lactone-
lactams do not appear to significantly inhibit the mono-
and bisamides from rearranging at rates comparable to
those of the original macrolides since no intermediate
lactone-lactam accumulation is observed.
The prominence of intramolecular acyl migration in
biopolymers and other natural products5-7 has led to a
large number of studies since Bergmann’s pioneering
investigations of amino alcohols.42 In particular, selective
amide formation by amine capture has been extensively
explored in accord with its great potential for solid-phase
peptide synthesis.8 In this context, the essential features
of the intramolecular O-to-N acyl migration have been
(35) MMX force field calculations were performed using PC Model
V7.0; Serena Software, Inc. Gajewski, J . J .; Gilbert, K. E.; MacKelvey,
J . Adv. Mol. Model. 1990, 2, 65.
(36) (a) The inherent skeletal strain in the open annular conforma-
tion of some cyclic polyesters has been correlated to an even number
of CH2 groups in each polymethylene chain of the corresponding
hydroxy acid: Dale, J . Angew. Chem., Int. Ed. Engl. 1966, 5, 1000. (b)
For the crystal structure and distorted molecular shape of a 10-
membered oxa-azamacrocycle, see: Kuksa, V.; Marshall, C.; Wardell,
S.; Kong Thoo Lin, P. Synthesis 1999, 1034. (c) The crystal structures
of a variety of 14-membered macrolides revealed unexpected twist
conformations: Keller, T. K.; Neeland, E. G.; Retting, S.; Trotter, J .;
Weiler, L. J . Am. Chem. Soc. 1988, 110, 7858. Hauske, J . R.;
Gaudliana, M.; Kostek, G.; Shulte, G. J . Org. Chem. 1987, 52, 4622.
(37) Fridrichson, J .; Mathieson, A. M.; Sutor, J . Acta Crystallogr.
1963, 16, 1075.
In summary, we have carried out syntheses of several
analogues of the single most important polyazamacrolide,
(38) Hoffmann proposed the expression “flexible molecules with a
defined shape” for molecules that show an unrestricted conformational
mobility but have preferentially populated conformations: Hoffmann,
R. W. Angew. Chem., Int. Ed. 2000, 39, 2054. Hoffmann, R. W. Angew.
Chem., Int. Ed. Engl. 1992, 31, 1124.
(39) Existence of 1,5-intramolecular interactions (so-called “pentane
interactions”) has been proposed in the conformational studies of
cyclodocosane and cyclohexadecane on the basis of vibrational spec-
trosopic analyses: Shannon, V. L.; Strauss, H. L.; Snyder, R. G.;
Elliger, C. A.; Mattice, W. L. J . Am. Chem. Soc. 1989, 111, 1947.
(40) Desper, J . M.; Gellman, S. H.; Wolf, R. E., J r.; Cooper, S. R. J .
Am. Chem. Soc. 1991, 113, 8663. Alder, R. W.; Maunder, C. M.; Orpen,
A. G. Tetrahedron Lett. 1990, 31, 6717. See also ref 38.
(43) Menger, F. M.; Smith, J . H. J . Am. Chem. Soc. 1972, 94, 3824.
J ohnson, S. L. Adv. Phys. Org. Chem. 1967, 5, 237.
(44) Kemp, D. S.; Choong, S.-L. H.; Pekaar, J . J . Org. Chem. 1974,
39, 3841.
(45) Deslongchamps, P.; Atlani, P.; Fre´hel, D.; Malaval, A. Can. J .
Chem. 1972, 50, 3405.
(46) Kemp, D. S.; Galakatos, N. G.; Bowen, B.; Tan, K. J . Org. Chem.
1986, 51, 1829.
(47) MM calculations (MM2 and MM3) have been used along with
semiempirical MO methods to study the tetrahedral intermediates in
the N-to-O acyl migration of polysubstituted 3-acetamidopropanols:
Ivanov, P. M.; Pojarlieff, I. G. An. Quim. Int. Ed. 1996, 92, 171.
(48) Each 13C signal corresponds to three carbons. Carbons were
numbered in accordance to the numbering used for the monomeric
units (see Figure 3).
(41) Bruice, T. C.; Lightstone, F. C. Acc. Chem. Res. 1999, 32, 127.
Lightstone, F. C.; Bruice, T. C. J . Am. Chem. Soc. 1996, 118, 2595.
(42) Bergmann, M.; Brand, E.; Dreyer, F. Ber. 1921, 54, 936.

1090 J . Org. Chem., Vol. 66, No. 4, 2001
Garc´ıa-Rubio and Meinwald
residue purified by chromatography (80:20 to 50:50 hexanes-
Et2O) to yield carbamate 16 as an oil (520 mg, 48%): 1H NMR
(400 MHz, CDCl3) δ 1.20-1.40 (m, 10H), 1.45 (s, 9H), 1.47-
1.51 (m, 2H), 1.60-1.65 (m, 2H), 2.34 (t, J ) 7.6 Hz, 2H), 3.16-
3.27 (m, 2H), 3.36-3.40 (m, 2H), 3.70-3.74 (m, 2H), 5.11 (s,
2H), 7.35-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 24.7,
26.5, 28.2, 28.9, 29.0, 29.1, 29.2, 34.1, 48.0 (mi) and 48.5 (ma),
49.4 (mi) and 49.9 (ma), 61.1 (mi) and 62.1 (ma), 65.9, 79.7,
128.0, 128.3, 135.9, 155.4 (mi) and 157.2 (ma), 173.5; IR 3446,
1738, 1694, 1168 cm-1; MS (FAB) m/z (rel int) 422 [13, (MH)+],
PAML 681, making these nonnatural macrocyclic lac-
tones available for chemical and/or biological studies. We
have also studied the influence of small structural
changes on the rates at which all of these lactones
rearrange to ring-contracted lactams via intramolecular
O-to-N acyl migration. The change from a methyl sub-
stituent to a gem-dimethyl substituent (adjacent to the
nucleophilic nitrogen atom but external to the five-
membered ring through which the rearrangement pro-
ceeds) results in a 280-fold rearrangement rate increase,
suggesting that a detailed conformational analysis of
these macrocycles should be of particular interest. The
biological activities of PAML 681 and the synthesized
analogues are currently being evaluated.
322 [100, (MH-Boc)+], 246 (10); HRMS FAB calcd for C24H40
NO5 [MH]+ 422.2906, found 422.2907.
-
Ben zyl N-(ter t-Bu toxycar bon yl)-N-[2-(ter t-bu tyldim eth -
ylsilyloxy)eth yl]-10-a m in od eca n oa te (17). A solution of
alcohol 16 (285 mg, 0.68 mmol), tert-butyldimethylsilyl chloride
(TBDMSCl, 112 mg, 0.74 mmol), and imidazole (92 mg, 1.35
mmol) in CH2Cl2 (20 mL) was stirred at room temperature for
2 h. The reaction mixture was then diluted with CH2Cl2 and
sequentially washed with 3% aqueous NH4Cl, 3% aqueous Na2-
CO3, and water. The organic extracts were dried and concen-
trated. Chromatographic purification (60:40 hexanes-Et2O)
afforded silyl ether 17 (360 mg, quantitative) as an oil: 1H
NMR (400 MHz, CDCl3) δ 0.05 (s, 6Η), 0.89 (s, 9H), 1.18-
1.26 (m, 10H), 1.45 (s, 9H), 1.43-1.50 (m, 2H), 1.58-1.70 (m,
2H), 2.35 (t, J ) 7.2 Hz, 2H), 3.20-3.30 (m, 4H), 3.66-3.72
(m, 2H), 5.11 (s, 2H), 7.30-7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ -5.6, 18.0, 24.7, 25.7, 26.6, 28.3, 28.8, 28.9, 29.1, 29.2,
34.0, 48.0 and 48.6, 49.2 and 49.3, 61.5, 65.7, 78.7 and 78.8,
127.9, 128.3, 135.9, 155.1 and 155.3, 173.2; IR 1740, 1696, 1160
cm-1; MS (ESI) m/z (rel int) 536 [100, (MH)+], 480 [22, (M-
C4H9)+], 436 [22, (MH-Boc)+]; HRMS FAB calcd for C25H46NO3-
Si [MH-Boc]+ 436.3247, found 436.3245.
N-(ter t-Bu toxyca r bon yl)-N-[2-(ter t-bu tyld im eth ylsilyl-
oxy)eth yl]-10-a m in od eca n oic Acid (18). To a solution of
ester 17 (155 mg, 0.29 mmol) in EtOH (50 mL) was added 5%
Pd-C (25 mg). The mixture was hydrogenated at room
temperature and atmospheric pressure for 4 h. After removal
of the solvent in vacuo, the residue was diluted in CH2Cl2,
filtrated through Celite, and concentrated to yield acid 18 (128
mg, quantitative), which was used as-is in the following step:
1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6Η), 0.89 (s, 9H), 1.20-
1.40 (m, 10H), 1.45 (s, 9H), 1.43-1.50 (m, 2H), 1.62 (qn, J )
7.2 Hz, 2H), 2.34 (t, J ) 7.2 Hz, 2H), 3.20-3.30 (m, 4H), 3.66-
3.76 (m, 2H); 13C NMR (100 MHz, CDCl3) δ -5.5, 18.2, 24.6,
25.8, 26.7, 28.4, 28.9, 29.1, 29.2, 29.3, 34.0, 48.2 and 48.8, 49.3
and 49.4, 61.5 and 61.6, 79.1 and 79.2, 155.4 and 155.6, 173.3;
IR 1742, 1696, 1160 cm-1; MS (FAB) m/z (rel int) 346 [100,
(MH-Boc)+]; HRMS FAB calcd for C18H40NO3Si [MH-Boc]+
346.2777, found 346.2775.
Ben zyl N,N′-Bis(ter t-b u t oxyca r b on yl)-N-{N′-[2-(ter t-
bu tyldim eth ylsilyloxy)eth yl]-10-am in odecan oyloxyeth yl}-
10-a m in od eca n oa te (19). To a stirred solution of acid 18 (105
mg, 0.23 mmol), 4-(dimethylamino)pyridine (DMAP, 15 mg,
0.12 mmol), and alcohol 16 (100 mg, 0.23 mmol) in CH2Cl2 (3
mL) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodi-
imide hydrochloride (EDCI‚HCl, 50 mg, 0.26 mmol) with ice
cooling. The resulting mixture was stirred at 0 °C for 2 h and
then stirred at room temperature for a further 12 h. The
solution was concentrated to dryness in vacuo, and the residue
was taken up in AcOEt and water. The organic extract was
separated and successively washed with saturated aqueous
NH4Cl, saturated aqueous Na2CO3, and water. The organic
layer was dried and concentrated to give an oil, which was
purified by chromatography (60:40 hexanes-Et2O) to yield
ester 19 (197 mg, 98%): 1H NMR (400 MHz, CDCl3) δ 0.05 (s,
6Η), 0.89 (s, 9H), 1.20-1.40 (m, 20H), 1.45 (s, 18H), 1.43-
1.56 (m, 4H), 1.56-1.70 (m, 4H), 2.29 (t, J ) 7.6 Hz, 2H), 2.35
(t, J ) 7.6 Hz, 2H), 3.14-3.24 (m, 6H), 3.26-3.36 (m, 2H),
3.64-3.76 (m, 2H), 4.12-4.20 (br s, 2H), 5.12 (s, 2H), 7.30-
7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ -5.5, 18.1, 24.7,
24.8, 25.8, 26.6, 26.7, 28.3, 28.4, 28.9, 29.0, 29.0, 29.1, 29.2,
29.2, 29.3, 29.3, 34.1, 34.2, 45.7 and 45.8, 47.8 and 47.9, 48.2
and 48.8, 49.3 and 49.4, 61.6, 62.1 and 62.3, 65.9, 78.9 and
79.0, 79.3 and 79.4, 128.0, 128.4, 136.0, 155.1 and 155.3, 155.4,
173.4, 173.5; IR 1740, 1698, 1160 cm-1; MS (ESI) m/z (rel int)
Exp er im en ta l Section
Gen er a l Meth od s. NMR spectra were recorded in CDCl3
or C6D6 on Varian XL-400 or Varian Unity 500 spectrometers
1
operating at 499.93 or 399.86 MHz for H and 100.58 MHz for
1
13C. H NMR chemical shifts are reported in δ (ppm) relative
to Me4Si as internal standard. 13C NMR chemical shifts are
given in δ (ppm) values relative to the solvent (CDCl3 77.00
ppm or C6D6 128.4 ppm). Multiplicities are indicated with the
following abbreviations: s ) singlet, d ) doublet, t ) triplet,
q ) quartet, qn ) quintet, m ) multiplet, and br ) broad.
Several of the NMR signals of products containing carbamate
and amide moieties were doubled in the rotamer ratio as
indicated by ma for major and mi for minor. IR spectra were
recorded with a Perkin-Elmer 1605 series FTIR infrared
spectrophotometer using NaCl pellets. Mass spectra were
obtained on a Hewlett-Packard 5970 instrument. HPLC-MS
analyses were carried out in a Micromass Quattro I mass
spectrometer operated in positive ion electrospray mode (nega-
tive ion for carboxylic acids 37 and 49) with a 250 mm × 4.6
mm Inertsil 5-µm ODS-3 (Metachem) HPLC column. High-
resolution mass spectrometry measurements were performed
in the Mass Spectrometry Laboratory at University of Illinois
(Urbana-Champaign) in the FAB mode unless otherwise
specified. Melting points are uncorrected. Drying of organic
extracts during work up of reactions was performed over
anhydrous Na2SO4. Chromatography refers to flash chroma-
tography and was carried out on SiO2 (EM Science silica gel
60, 230-400 mesh ASTM). All reactions were carried out
under argon atmosphere with dry, freshly distilled solvents.
Ben zyl 10-Oxod eca n oa te (15). To a suspension of benzyl
10-hydroxydecanoate (14, 2.8 g, 10 mmol), 4-methylmorpho-
line-4-oxide (NMO, 1.76 g, 15 mmol), and powdered 4 Å
molecular sieves (550 mg/mmol) in CH2Cl2 (40 mL) at 0 °C
was added tetrapropylammonium perruthenate (TPAP, 0.18
g, 0.5 mmol), and the resulting mixture was stirred at room
temperature for 0.5 h. The reaction mixture was filtered
through a short pad of silica eluting with CH2Cl2, and the
filtrate was concentrated to yield aldehyde 15 (4.5 g, 81%) as
a pale yellow oil, which was not further purified because of
its relative instability: 1H NMR (400 MHz, CDCl3) δ 1.20-
1.40 (m, 8H), 1.56-1.70 (m, 4H), 2.36 (t, J ) 7.2 Hz, 2H), 2.42
(td, J ) 7.2 and 2 Hz, 2H), 5.12 (s, 2H), 7.34-7.37 (m, 5H),
9.76 (t, J ) 2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.7,
24.6, 28.7, 28.8, 28.9, 33.9, 43.5, 66.0, 127.9, 128.2, 135.9, 173.3,
202.5.
Ben zyl N-(ter t-Bu toxyca r bon yl)-N-(2-h yd r oxyeth yl)-
10-a m in od eca n oa te (16). To a solution of ethanolamine
hydrochloride (995 mg, 10.4 mmol) in absolute MeOH (25 mL)
were added aldehyde 15 (730 mg, 2.6 mmol) and NaBH3CN
(330 mg, 5.2 mmol), and the resulting mixture was stirred at
room temperature for 2 days. Next, 1 N HCl was added, and
stirring was maintained for 0.5 h. MeOH was evaporated at
reduced pressure, and the aqueous solution was basified with
K2CO3 and extracted with CH2Cl2. The combined organic
extracts were dried and concentrated in vacuo, and the
intermediate amino alcohol was treated with ditert-butyl
dicarbonate (Boc2O, 480 mg, 2.2 mmol) in THF (60 mL) at room
temperature for 3 h. The mixture was concentrated and the

Synthesis and Reactions of Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1091
871 [40, (MNa)+], 849 [100, (MH)+]; HRMS FAB calcd for
C
Ben zyl N,N′-Bis(ter t-bu toxycar bon yl)-N-[N′-(2-h ydr oxy-
30.0, 30.1, 30.2, 34.5, 34.7, 46.7, 48.6 (ma) and 49.1 (mi), 48.6,
50.3 (mi) and 50.8 (ma), 61.9 (mi) and 62.7 (ma), 62.8, 79.6
and 79.7, 79.8, 155.6 and 156.0, 157.7, 173.4, 177.8 and 177.9.
42H77N2O7Si [MH-Boc]+ 749.5500, found 749.5501.
et h yl)-10-a m in od eca n oyloxyet h yl]-10-a m in od eca n oa t e
(20). To a solution of the silyl ether 19 (120 mg, 0.14 mmol)
in a mixture of CH2Cl2-MeOH (9:1, 15 mL) at 0 °C was added
camphor-10-sulfonic acid (CSA, 16 mg, 0.07 mmol), and the
resulting mixture was allowed to warm at room temperature.
The solvent was removed at reduced pressure, and the residue
was partitioned between CH2Cl2 and saturated aqueous
NaHCO3. The organic layer was dried and concentrated.
Chromatography of the residue (20:80 hexanes-Et2O) yielded
alcohol 20 (80 mg, 80%): 1H NMR (400 MHz, CDCl3) δ 1.24-
1.40 (m, 20H), 1.45 (s, 9H), 1.46 (s, 9H) 1.46-1.52 (m, 4H),
1.58-1.66 (m, 4H), 2.29 (t, J ) 7.6 Hz, 2H), 2.35 (t, J ) 7.6
Hz, 2H), 3.12-3.28 (m, 4H), 3.32-3.46 (m, 4H), 3.73 (br t, J
) 4.4 Hz, 2H), 4.10-4.20 (m, 2H), 5.11 (s, 2H), 7.30-7.40 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 24.7, 24.8, 26.7, 26.7, 28.3,
29.0, 29.0, 29.1, 29.2, 29.2, 29.3, 29.3, 34.2, 34.2, 45.7 and 45.8,
47.9 and 48.0, 48.7 50.1, 62.1 and 62.4, 62.6, 66.0, 79.4 and
79.5, 79.9, 128.1, 128.5, 136.0, 155.2 and 155.5, 157.6, 173.6;
MS (FAB) m/z (rel int) 735 [4, (MH)+], 635 [58, (MH-Boc)+],
579 [100, (M-Boc-C4H9)+], 503 (54), 246 (40); HRMS FAB calcd
for C36H63N2O7Si [MH-Boc]+ 635.4635, found 635.4638.
Ben zyl N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-N-{N′-[N′′-
(2-{ter t-bu tyld im eth ylsilyloxy}eth yl)-10-a m in od eca n oyl-
o x y e t h y l]-10-a m in o d e c a n o y lo x y e t h y l}-10-a m in o d e -
ca n oa te (21). Trimeric ester 21 was obtained from alcohol
20 (90 mg, 0.12 mmol), acid 18 (75 mg, 0.17 mmol), DMAP (8
mg, 0.06 mmol), and EDCI‚HCl (25 mg, 0.13 mmol) following
the procedure for the preparation of ester 19. Final purification
was accomplished by column chromatography (50:50 hexanes-
Et2O) to afford the title compound (120 mg, 86%) as a colorless
oil: 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6Η), 0.90 (s, 9H),
1.20-1.40 (m, 30H), 1.46 (s, 27H), 1.46-1.56 (m, 6H), 1.58-
1.70 (m, 6H), 2.30 (t, J ) 7.6 Hz, 4H), 2.36 (t, J ) 7.6 Hz, 2H),
3.14-3.32 (m, 8H), 3.38-3.44 (m, 4H), 3.64-3.76 (m, 2H),
4.12-4.20 (m, 4H), 5.12 (s, 2H), 7.30-7.40 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ -5.5, 18.2, 24.8, 24.8, 25.8, 26.7, 26.7, 28.3,
28.4, 29.0, 29.0, 29.1, 29.1, 29.2, 29.3, 29.3, 29.3, 34.1, 34.2,
45.7 and 45.8, 47.9 and 48.0, 48.2 and 48.8, 49.3 and 49.4, 61.6,
62.1 and 62.4, 65.9, 78.9 and 79.0, 79.4 and 79.5, 128.1, 128.4,
N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-1,15,29-tr ioxa -4,18,-
32-tr ia za cyclod otetr a con ta n e-14,28,42-tr ion e (24). To a
refluxing solution of 2-chloro-1-methylpyridinium iodide (37
mg, 0.15 mmol) in CH3CN (100 mL) was added via syringe
pump a mixture of the hydroxy acid 23 (35 mg, 0.04 mmol)
and Et3N (40 µL, 0.29 mmol) in CH3CN (5 mL) over 2 h. The
resulting solution was refluxed for an additional 0.5 h, cooled
to room temperature, and concentrated at reduced pressure.
The residue was taken up in water and extracted with Et2O.
The organic extracts were dried and concentrated, and the
resulting residue was purified by flash chromatography (40:
60 hexanes-Et2O) to yield the macrocycle 24 (20 mg, 60%):
1H NMR (400 MHz, C6D6) δ 1.10-1.30 (m, 30H, CH2), 1.40-
1.50 (m, 6H, CH2CH2N), 1.46 (s, 27H, CH3), 1.50-1.65 (m, 6H,
CH2CH2CO), 2.15-2.22 (m, 6H, CH2CO), 3.10-3.45 (m, 12H,
CH2N), 4.15-4.30 (m, 6H, CH2O); 13C NMR (100 MHz, C6D6)48
δ 25.6 (C3), 27.5 (C9), 28.8 (CH3), 29.7, 29.8, 30.0, 30.0, (C4-
C8), 34.7 (C2), 47.0 (CH2N), 48.9 (C10), 63.0 and 63.2 (CH2O),
79.5 (CMe3), 155.4 and 155.8 (NCO2), 173.2 (CO); IR 1740,
1696, 1156 cm-1; MS (ESI) m/z (rel int) 984 [22, (MK)+], 963
[32, (MNa)+], 941 [100, (MH)+], 885 [18, (M-C4H9)+], 841 [25,
(MH-Boc)+], 343 (54); HRMS FAB calcd for C46H86N3O10 [MH-
Boc]+ 840.6313, found 840.6315.
1,15,29-Tr ioxa -4,18,32-tr ia za cyclod otetr a con ta n e-14,-
28,42-tr ion e [Tr is(10-n or )P AML 681, (11)]. The lactame 24
(18 mg, 19 µmol) was dissolved in trifluoroacetic acid (TFA,
190 µL) and strirred at room temperature for 15 min. The
excess of acid was removed at reduced pressure, and the
residue was partitioned between 20% aqueous K2CO3 and
Et2O. After vigorous stirring, the aqueous phase was separated
and extracted with Et2O. The combined organic extracts were
filtered through anhydrous K2CO3 and concentrated to give
the triamine 11 (12 mg, quantitative): 1H NMR (400 MHz,
C6D6) δ 1.16-1.30 (m, 30H, CH2), 1.34-1.44 (m, 6H, CH2-
CH2N), 1.55-1.65 (m, 6H, CH2CH2CO), 2.19 (t, J ) 7.2 Hz,
6H, CH2CO), 2.47 (t, J ) 7.2 Hz, 6H, CH2N), 2.64 (t, J ) 5.2
Hz, 6H, NCH2CH2O), 4.16 (t, J ) 5.2 Hz, 6H, CH2O); 13C NMR
(100 MHz, C6D6) δ 25.7 (C3), 27.9 (C9), 29.7, 29.8, 30.1, 30.1,
30.9 (C4-C8), 34.8 (C2), 49.1 (CH2N), 50.3 (C10), 64.5 (CH2O),
173.4 (CO); IR 1736, 1176 cm-1; MS (ESI) m/z (rel int) 641
[37, (MH)+], 428 (18), 321 [100, (M+2H)2+], 312 [55, (M-
H2O+2H)2+], 309 (20), 227(38), 214 [100, (M+3H)3+], 196 (65)
120 (69); HRMS FAB calcd for C36H70N3O6 [MH]+ 640.5265,
found 640.5267.
136.0, 155.1 and 155.3, 155.5, 173.5; IR 1740, 1698, 1158 cm-1
;
MS (ESI) m/z (rel int) 1185 [80, (MNa)+], 1163 [33, (MH)+],
1107 [18, (M-C4H9)+], 1063 [18, (MH-Boc)+], 454 (100); HRMS
FAB calcd for C59H108N3O11Si [MH-Boc]+ 1062.7753, found
1062.7756.
Ben zyl N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-N-{N′-[N′′-
(2-h yd r oxyeth yl)-10-a m in od eca n oyloxyeth yl]-10-a m in o-
d eca n oyloxyeth yl}-10-a m in od eca n oa te (22). Operating in
a manner analogous to that employed for the preparation of
alcohol 20, from 21 (110 mg, 0.09 mmol) alcohol 22 (83 mg,
84%) was obtained after chromatographic purification (Et2O):
1H NMR (400 MHz, CDCl3) δ 1.20-1.35 (m, 30H), 1.44-1.54
(m, 6H), 1.45 (s, 18H), 1.47 (s, 9H), 1.58-1.68 (m, 6H), 2.30 (t,
J ) 7.6 Hz, 4H), 2.35 (t, J ) 7.6 Hz, 2H), 3.14-3.24 (m, 6H),
3.34-3.44 (m, 6H), 3.70-3.78 (m, 2H), 4.10-4.20 (m, 4H), 5.12
(s, 2H), 7.30-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 24.8,
24.8, 26.6, 26.7, 26.7, 28.3, 29.0, 29.0, 29.0, 29.1, 29.1, 29.2,
29.2, 29.3, 29.3, 29.3, 34.1, 34.2, 45.8, 47.9, 48.6, 50.1, 62.1
and 62.4, 62.6, 65.9, 79.4 and 79.5, 79.8, 128.0, 128.4, 136.0,
Rea r r a n gem en t of Tr is(10-n or )P AML 681. (A) 1H NMR
Sp ectr oscop ic An a lysis. An NMR tube was charged with a
solution of polyazamacrolide 11 (0.015 M, 0.7 mL) in C6D6,
sealed, and placed in a thermostated bath at 50 ( 1 °C. 1H
NMR spectra were periodically recorded in a Varian XL-400
spectrometer (50 ( 1 °C) at intervals chosen to ensure an
adequate sampling. The rearrangement was monitored by
1
following the disappearance of the H NMR signal character-
istic of the methylene protons adjacent to the oxigen atom of
the lactone moiety (δ 4.14-4.18 ppm) relative to the internal
tetramethylsilane (TMS) standard. An observed rate constant
(kobsd ) 0.084 ( 0.002) including contributions from all lactonic
species generated during the O-to-N acyl migration of
polyazamacrolide 11 was determined by a nonlinear least-
squares analysis showing an excellent fit. Following the
formation of the corresponding rearranged lactames by mea-
suring the integration of the protons R to the hydroxyl group
(δ 3.60-3.70 ppm) afforded an equivalent rate constant.
Representative data are included in Supporting Information.
155.1 and 155.5, 157.4, 173.5; IR 3466, 1740, 1696, 1160 cm-1
;
MS (FAB) m/z (rel int) 949 [62, (MH-Boc)+], 893 [100, (M-
C4H9)+], 749 (75), 579 (97), 503 (62); HRMS FAB calcd for
C
53H94N3O11 [MH-Boc]+ 948.6888, found 948.6888.
N,N′,N′′-Tr is(ter t-bu toxycar bon yl)-N-{N′-[N′′-(2-h ydr oxy-
eth yl)-10-am in odecan oyloxyeth yl]-10-am in odecan oyloxy-
eth yl}-10-a m in od eca n oic a cid (23). Hydrogenolysis of ben-
zyl ester 22 (83 mg, 0.08 mmol) using the conditions employed
for the preparation of 18 furnished hydroxy acid 23 (73 mg,
97%): 1H NMR (400 MHz, C6D6) δ 1.10-1.30 (m, 30H), 1.40-
1.50 (m, 6H), 1.46 (s, 27H), 1.50-1.70 (m, 6H), 2.20 (br t, J )
7.6 Hz, 6H), 2.96-3.16 (m, 4H), 3.20-3.30 (m, 6H), 3.40-3.50
(m, 2H), 3.60-3.75 (m, 2H), 4.10-4.30 (m, 4H); 13C NMR (100
MHz, C6D6) δ 25.5, 25.6, 27.4, 27.5, 28.8, 29.7, 29.8, 29.9, 30.0,
(B) HP LC-MS An a lysis. The rearrangement was followed
by analyzing aliquots of a solution of 11 (0.015 M in C6H6)
placed in a thermostated bath at 50 ( 1 °C in a Hewlett-
Packard 1090 II system equipped with a 250 mm × 4.6 mm
Inertsil 5-µm ODS-3 reversed-phase column (Metachem) linked
to a Micromass Quattro I mass spectrometer. The HPLC was
operated with a flow rate of 1 mL/min with the folllowing

1092 J . Org. Chem., Vol. 66, No. 4, 2001
Garc´ıa-Rubio and Meinwald
eluents: 0.05% HCO2H/70% H2O/30% CH3CN for 4 min,
gradient to 0.05% HCO2H/42% H2O/58% CH3CN in 16 min,
hold for 10 min. Operating in positive ion electrospray mode,
monoamide and bisamide intermediates formed in the way to
the fully rearranged product generated multiple charged ions
with charge numbers corresponding to the number of basic
nitrogen atoms present in the molecule. Rearranged monoa-
N-[2-(ter t-Bu t yld im et h ylsilyloxy)et h yl]-N-(2-m et h yl-
h ep t-6-en -2-yl)a m in e (28). A solution of sodium naphtha-
lenide in DME (7 mL, 0.3 M) was added dropwise to a solution
of sulfonamide 27 (900 mg, 2.0 mmol) in DME (30 mL) at -78
°C until a green color persisted. The reaction mixture was
warmed to room temperature and quenched with EtOH. After
concentration at reduced pressure, the residue was taken up
in water and extracted with Et2O. The organic extracts were
washed with saturated aqueous NaCl, dried, and concentrated
to give a brown solid, which was purified by chromatography
(from 95:5:0 to 78:20:2 hexanes-Et2O-diethylamine) to yield
amine 28 (340 mg, 58%): 1H NMR (400 MHz, CDCl3) δ 0.06
(s, 6Η), 0.90 (s, 9H), 1.05 (s, 6H), 1.35-1.40 (m, 4H), 2.02-
2.06 (m, 2H), 2.61 (t, J ) 5.2 Hz, 2H), 3.71 (t, J ) 5.2 Hz, 2H),
4.95 (dm, J ) 10 Hz, 1H), 5.01 (dm, J ) 17.2 Hz, 1H), 5.81
(ddt, J ) 17.2, 10 and 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ -5.5, 18.1, 23.0, 25.8, 27.1, 34.2, 40.0, 44.0, 51.6, 62.9, 114.3,
138.7; IR 1256, 1090 cm-1; MS (FAB) m/z (rel int) 286 [60,
(MH)+], 216 [100, (M-C5H9)+] 176 [24, (M-C8H13)+]; HRMS FAB
calcd for C16H36NOSi [MH]+ 286.2566, found 286.2566.
N-[2-(ter t-Bu t yld im et h ylsilyloxy)et h yl]-N-(2-m et h yl-
h ep t-6-en -2-yl)-ter t-bu toxyca r ba m a te (29). A solution of
amine 28 (330 mg, 1.16 mmol), Boc2O (510 mg, 2.32 mmol),
DMAP (140 mg, 1.16 mmol), and Et3N (160 µL, 1.16 mmol) in
THF (30 mL) was stirred at room temperature for 3 days. After
evaporation of the solvent at reduced pressure, chromatogra-
phy of the residue (from 100:0 to 96:4 hexane-AcOEt) yielded
carbamate 29 (340 mg, 75%): 1H NMR (400 MHz, CDCl3) δ
0.05 (s, 6Η), 0.89 (s, 9H), 1.20-1.30 (m, 2H), 1.34 (s, 6H), 1.45
(s, 9H), 1.77-1.83 (m, 2H), 2.02 (br q, J ) 7.2 Hz, 2H), 3.34 (t,
J ) 6.6 Hz, 2H), 3.62 (t, J ) 6.6 Hz, 2H), 4.93 (dm, J ) 10.4
Hz, 1H), 4.99 (dm, J ) 17.2 Hz, 1H), 5.79 (ddt, J ) 17.2, 10.4
and 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ -5.3, 18.3, 23.9,
26.0, 28.2, 28.6, 34.1, 40.0, 47.1, 57.9, 62.6, 79.1, 114.3, 139.0,
155.3; IR 1700, 1682 cm-1; MS (FAB) m/z (rel int) 286 [5, (MH-
Boc)+], 216 [100, (M-Boc-C5H9)+], 176 [24, (M-C8H13)+], 162
(54); HRMS FAB calcd for C16H36NOSi [MH-Boc]+ 286.2566,
found 286.2566.
mide: tR ) 2.2 min, 100%; m/z 640 (MH)+, 321 (M+2H)2+
.
Rearranged bisamide: tR ) 11.7 min, 100%; m/z 640 (MH)+.
Rearranged trisamide: tR ) 18.3 min, 100%; m/z 640 (MH)+.
These analytical data are included in the Supporting Informa-
tion.
After 40 days, the totally rearranged trisamide was obtained
as the only product: 1H NMR (400 MHz, C6D6) δ 1.00-1.60
(m, 36H), 1.73 (br t, J ) 7.2 Hz, 6H), 2.10-2.20 (m, 4H), 2.20-
2.30 (m, 2H), 2.80-3.00 (m, 4H), 3.00-3.20 (m, 2H), 3.20-
3.40 (m, 6H), 3.60-3.70 (m, 6H); 13C NMR (100 MHz, C6D6) δ
25.9, 27.2, 29.6, 29.9, 29.9, 29.9, 29.9, 33.4, 46.5 (ma) and 46.7
(mi), 49.8 (mi) and 50.7 (ma), 61.0 (mi) and 63.2 (ma), 174.6
(mi) and 174.8 (ma); IR 3394, 1620 cm-1; MS (FAB) m/z (rel
int) 641 [100, (MH)+], 623 [61, (MH-H2O)+], 578 (9), 214 (11);
HRMS FAB calcd for C36H70N3O6 [MH]+ 640.5265, found
640.5267.
N-(2-Meth ylh ep t-6-en -2-yl)tolu en e-4-su lfon a m id e (26).
A solution of 3-butenylmagnesium bromide in Et2O (50 mL)
was prepared from magnesium metal (0.66 g, 27.1 mmol) and
4-bromo-1-butene (2.0 mL, 20.2 mmol) and slowly added to a
slurry of CuI (0.77 g, 4.0 mmol) in Et2O (50 mL) at -78 °C.
After the solution was allowed to warm to room temperature
and cooled at -78 °C, a suspension of 2,2-dimethyl-1-(toluene-
4-sulfonyl)aziridine (25, 1.3 g, 5.8 mmol) in Et2O was added
in one portion. The reaction was warmed to room temperature,
stirred overnight, and quenched with a mixture of NH4Cl-
NH4OH (4:1). The resulting mixture was stirred for 2 h, the
organic layers were separated, and the aqueous phase was
extracted with Et2O. The combined organic phases were dried
and concentrated to afford a colorless oil, which was purified
by chromatography (80:20 hexane-AcOEt) to yield 26 as a
white solid (1.3 g, 78%), mp 62-64 °C: 1H NMR (400 MHz,
CDCl3) δ 1.17 (s, 6H), 1.30-1.38 (m, 2H), 1.45-1.50 (m, 2H),
1.94 (qt, J ) 7.2 and 1.2 Hz, 2H), 2.42 (s, 3H), 4.65 (s, 1H),
4.93 (ddt, J ) 10, 2 and 1.6 Hz, 1H), 4.96 (ddd, J ) 17.2, 2
and 1.6 Hz, 1H), 5.72 (ddt, J ) 17.2, 10.4 and 6.8 Hz, 1H),
7.28 (d, J ) 8 Hz, 2H), 7.78 (dt, J ) 8 and 2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.4, 23.1, 27.6, 33.7, 42.2, 56.9, 114.5,
126.8, 129.3, 138.4, 140.6, 142.6; IR 1324, 1306, 1150, 1092
cm-1; MS (EI) m/z (rel int) 281 (5, M+), 266 [49, (M-CH3)+],
212 [100, (M-C5H9)+], 172 [6, (M-C8H14)+], 155 [30, (M-
C8H15N)+], 91 (17); HRMS EI calcd for C15H23NO2S [M]+
281.1450, found 281.1456.
(5Z)-N-(ter t-Bu t oxyca r b on yl)-N-[2-(ter t-b u t yld im et h -
ylsilyloxy)eth yl]-10-a m in o-10-m eth ylu n d ec-5-en oic Acid
(30). (i) To a slurry of 4-carboxytriphenylphosphonium bro-
mide (850 mg, 1.1 mmol) in THF (10 mL) was added potassium
bis(trimethylsilyl)amide (5 mL, 1 M solution in THF). After
stirring for 0.5 h, the resulting slurry was decanted, and a
clear ylide solution was obtained. (ii) Separately, a stirred
solution of carbamate 27 (140 mg, 0.36 mmol) in tert-butyl
methyl ether (10 mL) at -78 °C was charged with a constant
stream of ozone. After the solution turned pale blue (∼3 min)
it was purged with argon during 15 min. 4-Carboxybutyl-
triphenylphosphonium ylide (2.2 mL, ∼1 M solution in THF)
was added via cannula dropwise, and the reaction mixture was
warmed to room temperature, stirred for 2 h, and quenched
with water. The crude was washed with 1:1 mixture of
saturated aqueous NaCl and 1 N HCl, and the aqueous layers
were extracted with CH2Cl2. The combined organic extracts
were dried and concentrated to yield a residue that after
chromatographic purification (79:20:1 hexanes-Et2O-AcOH)
afforded acid 30 (160 mg, 94%): 1H NMR (400 MHz, CDCl3) δ
0.06 (s, 6Η), 0.90 (s, 9H), 1.20-1.30 (m, 2H), 1.35 (s, 6H), 1.47
(s, 9H), 1.70 (qn, J ) 7.2 Hz, 2H), 1.77-1.83 (m, 2H), 1.99 (q,
J ) 7.6 Hz, 2H), 2.09 (q, J ) 7.6 Hz, 2H), 2.35 (t, J ) 7.6 Hz,
2H), 3.35 (t, J ) 6.6 Hz, 2H), 3.63 (t, J ) 6.6 Hz, 2H), 5.29-
5.35 (m, 1H), 5.39-5.45 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ -5.4, 18.3, 24.5, 26.0, 26.4, 27.4, 28.2, 28.6, 33.4, 40.1, 47.1,
N-[2-(ter t-Bu t yld im et h ylsilyloxy)et h yl]-N-(2-m et h yl-
h ep t-6-en -2-yl)-p-tolu en esu lfon yla m id e (27). Sulfonamide
26 (1.2 g, 4.2 mmol)] was slowly added via syringe pump to a
slurry of NaH (0.12 g, 5.2 mmol) in DMF (40 mL) at 0 °C. The
resulting mixture was stirred at 0 °C for 0.5 h, and tert-
(butyldimethylsilyloxy)ethyl bromide (1.1 mL, 5.1 mmol) was
added dropwise. The mixture was allowed to warm to room
temperature, and stirring was continued for 4 days. The
reaction was quenched with water, and the resulting mixture
was extracted with 90:10 pentane-Et2O. The combined ex-
tracts were dried and concentrated to give a yellow oil.
Chromatography of the residue (from 90:10 to 80:20 hexanes-
Et2O) yielded silyl ether 27 (0.95 g, 92% based on the
consumption of 26) and recovered 26 (0.54 g, 45%): 1H NMR
(400 MHz, CDCl3) δ 0.09 (s, 6Η), 0.90 (s, 9H), 1.28 (s, 6H),
1.32-1.36 (m, 2H), 1.63-1.68 (m, 2H), 1.99 (q, J ) 7.2 Hz,
2H), 2.41 (s, 3H), 3.45 (t, J ) 7.2 Hz, 2H), 3.84 (t, J ) 7.2 Hz,
2H), 4.94 (dm, J ) 16.8 Hz, 1H), 4.97 (dm, J ) 10.4 Hz, 1H),
5.75 (ddt, J ) 16.8, 10.4 and 6.8 Hz, 1H), 7.26 (d, J ) 7.6 Hz,
2H), 7.72 (d, J ) 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
-5.4, 18.2, 21.4, 23.8, 25.9, 27.3, 33.9, 41.1, 47.8, 61.9, 63.6,
57.9, 62.6, 79.2, 128.4, 131.1, 155.4, 179.2; IR 1708, 1680 cm-1
MS (FAB) m/z (rel int) 372 [40, (MH-Boc)+], 216 (100); HRMS
;
FAB calcd for
372.2934.
C
20H42NO3Si [MH-Boc]+ 372.2934, found
Ben zyl (5Z)-N-(ter t-Bu toxyca r bon yl)-N-[2-(ter t-bu tyl-
dimethylsilyloxy)ethyl]-10-amino-10-methylundec-5-enoate
(31). Coupling of acid 30 (100 mg, 0.21 mmol) and benzyl
alcohol (23 mg, 0.21 mmol) was performed by using the same
conditions described for the preparation of ester 19. Column
chromatography (80:20 hexanes-Et2O) yielded benzyl ester
31 (114 mg, 96%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
114.6, 126.9, 129.3, 138.3, 141.0, 142.5; IR 1156, 1090 cm-1
;
MS (FAB) m/z (rel int) 440 [7, (MH)+], 330 [100, (M-C8H15)+],
272 (41); HRMS FAB calcd for C23H42NO3SiS [MH]+ 440.2655,
found 440.2661.

Synthesis and Reactions of Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1093
δ 0.06 (s, 6Η), 0.90 (s, 9H), 1.17-1.25 (m, 2H), 1.34 (s, 6H),
1.45 (s, 9H), 1.70 (qn, J ) 7.6 Hz, 2H), 1.75-1.82 (m, 2H),
1.97 (q, J ) 7.2 Hz, 2H), 2.06 (q, J ) 7.2 Hz, 2H), 2.36 (t, J )
7.2 Hz, 2H), 3.34 (t, J ) 6.8 Hz, 2H), 3.62 (t, J ) 6.8 Hz, 2H),
5.12 (s, 2H), 5.29-5.36 (m, 1H), 5.35-5.42 (m, 1H), 7.30-7.40
(m, 5H); 13C NMR (100 MHz, CDCl3) δ -5.3, 18.3, 24.6, 24.9,
26.0, 26.5, 27.4, 28.2, 28.6, 33.7, 40.1, 47.1, 57.9, 62.6, 66.1,
79.0, 128.2, 128.5, 131.0, 136.1, 155.3, 173.5; IR 1740, 1698,
1680 cm-1; MS (FAB) m/z (rel int) 462 [20, (MH-Boc)+], 220
(37), 216 (100), 176 (29); HRMS FAB calcd for C27H48NO3Si
[MH-Boc]+ 462.3403, found 462.3402.
6H), 1.90-2.00 (m, 6H), 2.00-2.10 (m, 6H), 2.30 (t, J ) 7.6
Hz, 4H), 2.36 (t, J ) 7.6 Hz, 2H), 3.33 (t, J ) 6.6 Hz, 2H), 3.46
(t, J ) 6.6 Hz, 4H), 3.62 (t, J ) 6.6 Hz, 2H), 4.09 (t, J ) 6.6
Hz, 4H), 5.11 (s, 2H), 5.28-5.42 (m, 6H), 7.32-7.38 (m, 5H);
13C NMR (100 MHz, CDCl3) δ -5.3, 18.3, 24.5, 24.8, 26.0, 26.6,
27.4, 27.4, 27.4, 28.2, 28.5, 28.6, 33.6, 33.7, 40.1, 43.5, 47.1,
57.8, 58.0, 62.6, 63.4, 66.1, 79.0, 79.5, 128.2, 128.5, 128.5, 128.6,
130.8, 131.0, 136.0, 155.1, 155.3, 173.4; IR 1740, 1700, 1682
cm-1; MS (FAB) m/z (rel int) 1141 [3, (MH-Boc)+], 1085 [5, (M-
Boc-C4H9)+], 613 (10), 216 (100); HRMS FAB calcd for
C
65H114N3O11Si [MH-Boc]+ 1140.8223, found 1140.8225.
Ben zyl (5Z)-N-(ter t-Bu toxyca r bon yl)-N-(2-h yd r oxyeth -
yl)-10-a m in o-10-m eth ylu n d ec-5-en oa te (32). Operating in
a manner analogous to that employed for the preparation of
20, starting from 31 (114 mg, 0.20 mmol) alcohol 32 was
obtained (90 mg, quantitative) after chromatographic purifica-
tion (50:50 hexanes-Et2O): 1H NMR (400 MHz, CDCl3) δ
1.20-1.30 (m, 2H), 1.32 (s, 6H), 1.47 (s, 9H), 1.71 (qn, J ) 7.6
Hz, 2H), 1.74-1.80 (m, 2H), 1.99 (q, J ) 7.2 Hz, 2H), 2.06 (q,
J ) 7.2 Hz, 2H), 2.36 (t, J ) 6.8 Hz, 2H), 3.47 (t, J ) 5.6 Hz,
2H), 3.68 (t, J ) 5.6 Hz, 2H), 5.12 (s, 2H), 5.33 (td, J ) 10.8
and 6.8 Hz, 1H), 5.39 (td, J ) 10.8 and 6.8 Hz, 1H), 7.30-7.40
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 24.4, 24.8, 26.5, 27.3,
28.5, 33.7, 40.4, 47.4, 58.1, 64.3, 66.1, 80.3, 128.2, 128.5, 128.7,
130.7, 136.0, 157.5, 173.4.
Ben zyl (5Z,5′Z,5′′Z)-N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-
N-{N′-[N′′-(2-h yd r oxyeth yl)-10-a m in o-10-m eth ylu n d ec-5-
en oyloxyet h yl]-10-a m in o-10-m et h ylu n d ec-5-en oyloxy-
eth yl}-10-am in o-10-m eth ylu n dec-5-en oate (36). Proceeding
from ester 35 (50 mg, 0.05 mmol) in the manner described for
for the preparation of 19, alcohol 36 (38 mg, 84%) was isolated
after chromatographic purification (Et2O): 1H NMR (400 MHz,
CDCl3) δ 1.16-1.30 (m, 6H), 1.33 (s, 12H), 1.34 (s, 6H), 1.45
(s, 9H), 1.46 (s, 9H), 1.48 (s, 9H), 1.64-1.72 (m, 6H), 1.75-
1.83 (m, 6H), 1.99 (q, J ) 6.8 Hz, 6H), 2.00-2.08 (m, 6H), 2.30
(t, J ) 7.6 Hz, 2H), 2.31 (t, J ) 7.6 Hz, 2H), 2.32 (t, J ) 7.6
Hz, 2H), 3.09 (br s, 1H), 3.47 (t, J ) 6.4 Hz, 4H), 3.48 (t, J )
5.6 Hz, 2H), 3.69 (q, J ) 5.6 Hz, 2H), 4.10 (t, J ) 6.4 Hz, 4H),
5.12 (s, 2H), 5.28-5.43 (m, 6H), 7.35-7.40 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 24.4, 24.5, 24.8, 24.8, 24.8, 26.5, 26.5, 27.3,
28.2, 28.4, 28.5, 33.6, 33.7, 40.1, 40.4, 43.5, 47.4, 58.0, 58.1,
63.4, 64.2, 66.1, 79.6, 80.2, 128.1, 128.5, 128.6, 128.7, 130.7,
130.8, 130.8, 136.0, 155.1, 157.4, 173.4.
(5Z,5′Z,5′′Z)-N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-N-{N′-
[N′′-(2-h yd r oxyeth yl)-10-a m in o-10-m eth ylu n d ec-5-en oyl-
oxyet h yl]-10-a m in o-10-m et h ylu n d ec-5-en oyloxyet h yl}-
10-am in o-10-m eth ylu n dec-5-en oic Acid (37). Hydrogenolysis
of benzyl ester 36 (38 mg, 0.03 mmol) using the conditions
employed for the preparation of 18 furnished hydroxy acid 37
(30 mg, 79%): 1H NMR (400 MHz, CDCl3) δ 1.10-1.20 (m,
6H), 1.24-1.30 (m, 24H), 1.33 (s, 12H), 1.34 (s, 6H), 1.46 (s,
18H), 1.48 (s, 9H), 1.58-1.63 (m, 6H), 1.72-1.80 (m, 6H), 2.30
(t, J ) 7.6 Hz, 6H), 2.36 (br s, 1H), 3.47 (t, J ) 6.6 Hz, 4H),
3.48 (t, J ) 5.2 Hz, 2H), 3.70 (q, J ) 5.2 Hz, 2H), 4.10 (t, J )
6.6 Hz, 4H); 13C NMR (100 MHz, C6D6) δ 25.1, 25.2, 25.2, 25.6,
25.6, 28.6, 28.8, 28.9, 29.8, 29.9, 30.0, 30.0, 30.1, 30.2, 30.3,
30.7, 30.8, 34.7, 34.8, 41.1, 41.5, 44.3, 48.0, 58.5, 58.7, 64.1,
64.2, 79.7, 80.1, 155.5, 157.4, 173.4; MS (ESI) m/z (rel int) 1041
[45, (M-H)-], 941 [5, (M-H-Boc)-], 358 (44), 258 (100).
N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-5,5,19,19,33,33-h ex-
am eth yl-1,15,29-tr ioxa-4,18,32-tr iazacyclodotetr acon tan e-
14,28,42-tr ion e (38). Following the macrolactonization pro-
cedure described for the preparation of 24, starting from
hydroxy acid 37 (30 mg, 0.03 mmol), macrocycle 38 (20 mg,
69%) was obtained after chromatography (60:40 hexanes-
Et2O): 1H NMR (400 MHz, C6D6) δ 1.15-1.25 (m, 30H), 1.30
(s, 18H), 1.41 (s, 27H), 1.52-1.62 (m, 6H), 1.84-1.92 (m, 6H),
2.16 (t, J ) 7.6 Hz, 6H), 3.46 (t, J ) 6.4 Hz, 6H), 4.25 (t, J )
6.4 Hz, 6H); 13C NMR (100 MHz, C6D6) δ 25.2, 25.6, 28.6, 28.9,
29.8, 29.8, 30.2, 30.7, 34.8, 41.2, 44.3, 58.7, 64.1, 79.5, 155.4,
173.3; IR 1740, 1696 cm-1; MS (FAB) m/z (rel int) 925 [14,
(MH-Boc)+], 869 [35, (M-Boc-C4H9)+], 528 (54), 282 (100), 242
(60); HRMS FAB calcd for C52H99N3O10 [MH-Boc]+ 925.7330,
found 925.7332.
Ben zyl (5Z,5′Z)-N,N′-Bis(ter t-bu toxyca r bon yl)-N-{N′-
[2-(ter t-bu tyld im eth ylsilyloxy)eth yl]-10-a m in o-10-m eth -
ylu n d ec-5-en oyloxyet h yl}-10-a m in o-10-m et h ylu n d ec-5-
en oa te (33). The dimeric ester 33 was obtained from acid 30
(32 mg, 0.07 mmol), alcohol 32 (30 mg, 0.07 mmol), DMAP (4
mg, 0.03 mmol), and EDCI‚HCl (13 mg, 0.07 mmol) following
the procedure for the preparation of 19. Final chromatographic
purification (60:40 hexanes-Et2O) afforded the title ester (50
mg, 90%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.06
(s, 6Η), 0.90 (s, 9H), 1.15-1.30 (m, 4H), 1.33 (s, 12H), 1.46 (s,
18H), 1.60-1.75 (m, 4H), 1.75-1.85 (m, 4H), 1.94-2.00 (m,
4H), 2.00-2.10 (m, 4H), 2.30 (t, J ) 7.6 Hz, 2H), 2.36 (t, J )
7.6 Hz, 2H), 3.34 (t, J ) 6.6 Hz, 2H), 3.46 (t, J ) 6.6 Hz, 2H),
3.62 (t, J ) 6.6 Hz, 2H), 4.10 (t, J ) 6.6 Hz, 2H), 5.12 (s, 2H),
5.30-5.40 (m, 4H), 7.27-7.40 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ -5.3, 18.3, 24.6, 24.8, 26.0, 26.6, 26.6, 27.4, 27.5, 28.2,
28.5, 28.6, 33.7, 33.7, 40.1, 43.5, 47.2, 57.9, 58.0, 62.6, 63.4,
66.1, 79.0, 79.5, 128.2, 128.2, 128.5, 128.5, 128.6, 130.8, 131.0,
136.1, 155.1, 155.3, 173.5; IR 1740, 1700, 1682 cm-1; MS (FAB)
m/z (rel int) 801 [10, (MH-Boc)+], 745 [21, (M-Boc-C4H9)+], 515
(22), 459 (27), 216 (100), 162 (43); HRMS FAB calcd for
C
46H81N2O7Si [MH-Boc]+ 801.5813 found 801.5813.
Ben zyl (5Z,5′Z)-N,N′-Bis(ter t-bu toxyca r bon yl)-N-[N′-(2-
h yd r oxyeth yl)-10-a m in o-10-m eth ylu n d ec-5-en oyloxyeth -
yl]-10-a m in o-10-m eth ylu n d ec-5-en oa te (34). Proceeding
from 33 (76 mg, 0.08 mmol) in the manner described for for
the preparation of 20, alcohol 34 (50 mg, 76%) was obtained
after chromatographic purification (50:50 hexanes-Et2O): 1H
NMR (400 MHz, CDCl3) δ 1.17-1.30 (m, 4H), 1.33 (s, 12H),
1.46 (s, 9H), 1.48 (s, 9H), 1.65-1.72 (m, 4H), 1.74-1.81 (m,
4H), 1.95-2.02 (m, 4H), 2.00-2.10 (m, 4H), 2.31 (t, J ) 7.6
Hz, 2H), 2.36 (t, J ) 7.6 Hz, 2H), 3.09 (br s, 1H), 3.46 (t, J )
6.8 Hz, 2H), 3.48 (t, J ) 5.2 Hz, 2H), 3.69 (q, J ) 5.2 Hz, 2H),
4.10 (t, J ) 6.8 Hz, 2H), 5.12 (s, 2H), 5.28-5.42 (m, 4H), 7.30-
7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 24.4, 24.5, 24.8,
24.8, 26.5, 26.5, 27.3, 28.2, 28.4, 28.5, 33.6, 33.7, 40.1, 40.4,
43.5, 47.4, 58.0, 58.1, 63.4, 64.1, 66.0, 79.5, 80.2, 128.1, 128.5,
128.6, 128.7, 130.7, 130.8, 136.0, 155.1, 157.4, 173.4.
Ben zyl (5Z,5′Z,5′′Z)-N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-
N-(N′-{N′′-[2-(ter t-bu tyld im eth ylsilyloxy)eth yl]-10-a m in o-
10-m eth ylu n dec-5-en oyloxyeth yl}-10-am in o-10-m eth ylu n -
d e c -5-e n o y lo x y e t h y l)-10-a m in o -10-m e t h y lu n d e c -5-
en oa te (35). Following the procedure for the preparation of
ester 19, starting from acid 30 (30 mg, 0.06 mmol), alcohol 34
(50 mg, 0.06 mmol), DMAP (4 mg, 0.03 mmol), and EDCI‚HCl
(12 mg, 0.06 mmol), trimeric ester 35 (66 mg, 85%) was
obtained as a colorless oil after chromatographic purification
(60:40 hexanes-Et2O): 1H NMR (400 MHz, CDCl3) δ 0.06 (s,
6Η), 0.90 (s, 9H), 1.18-1.26 (m, 6H), 1.33 (s, 6H), 1.34 (s, 12H),
1.45 (s, 18H), 1.46 (s, 9H), 1.63-1.72 (m, 6H), 1.77-1.82 (m,
5,5,19,19,33,33-H exa m et h yl-1,15,29-t r ioxa -4,18,32-t r i-
a za cyclod otetr a con ta n e-14,28,42-tr ion e Tr is(d 3-tr iflu o-
r oa cetic) Sa lt (39). Lactame 38 (8 mg, 8 µmol) was dissolved
in trifluoroacetic acid-d4 (100 µL) and stirred at room temper-
ature for 15 min. Evaporation of excess acid in vacuo yielded
trifluoroacetic salt 39 (8 mg, quantitative): 1H NMR (400 MHz,
CDCl3) δ 1.20-1.40 (m, 30H), 1.54 (s, 18H), 1.50-1.70 (m,
12H), 2.35 (t, J ) 7.6 Hz, 6H), 3.25-3.35 (m, 6H), 4.30-4.40
(m, 6H); 13C NMR (100 MHz, CDCl3) δ 23.3, 23.4, 24.5, 25.5,
28.9, 29.0, 29.1, 29.5, 33.7, 39.6, 60.2, 89.3, 114.4 (q, J ) 285
Hz), 156.2 (q, J ) 41 Hz), 174.3; IR 1778, 1744, 1676, 1174
cm-1
.
Rea r r a n gem en t of Tr is(10-m eth yl)P AML 681. The O-
to-N acyl migration of polyazamacrolide 12 was monitored
using 1H NMR and HPLC-MS techniques in the same manner

1094 J . Org. Chem., Vol. 66, No. 4, 2001
Garc´ıa-Rubio and Meinwald
as described for 11. 1H NMR sp ectr oscop ic a n a lysis:
following the disappearance of the 1H NMR signals charac-
teristic of the methylene protons adjacent to the oxigen atom
of the lactone moiety (δ 4.30-4.40 ppm) afforded an observed
rate constant (kobsd ) 0.82 ( 0.03). Following the formation of
the corresponding rearranged lactames by measuring the
integration of the protons R to the hydroxyl group (δ 3.60-
3.70 ppm) afforded an equivalent rate constant. Representative
data are included in Supporting Information. H P LC-MS
a n a lysis: rearranged monoamide: tR ) 8.9 min, 100%; m/z
725 (MH)+, 363 (M+2H)2+. Rearranged bisamide: tR ) 14.1
min, 100%; m/z 725 (MH)+. Rearranged trisamide: tR ) 23.1
min, 100%; m/z 725 (MH)+. These analytical data are included
in the Supporting Information. After 4 d the final product was
the totally rearranged trisamide: 1H NMR (500 MHz, CDCl3/
pyridine-d5) δ 1.24-1.36 (m, 30H), 1.52 (s, 18H), 1.50-1.54
(m, 6H), 1.60-1.64 (m, 6H), 2.18 (t, J ) 7.5 Hz, 6H), 3.41 (q,
J ) 5 Hz, 6H), 3.71 (q, J ) 5 Hz, 6H), 6.10 (br s, 3H); 13C
NMR (100 MHz, CDCl3/pyridine-d5) δ 23.3, 23.4, 25.4, 25.6,
29.1, 29.1, 29.5, 36.6, 42.2, 62.2, 174.3.
N-(ter t-Bu t oxyca r b on yl)-N-(m et h oxyca r b on ylet h yl)-
11-a m in ou n d eca n oic Acid (40). To a vigorously stirred
suspension of 11-aminoundecanoic acid (10.0 g, 49.7 mmol) in
MeOH (400 mL) were added NaOH pellets (2.0 g, 50 mmol).
By the time the salt solubilized, a solution of methyl acrylate
(2.2 mL, 25 mmol) in MeOH (20 mL) was added dropwise.
After stirring at room temperature for 4 h, half of the solvent
was evaporated at reduced pressure, and Boc2O (10.9 g, 49.7
mmol) was added in one portion. The mixture was stirred at
room temperature for 36 h, and the solvent was removed in
vacuo. The residue was dissolved in 1 N HCl with ice cooling
and immediately extracted with AcOEt. The organic extracts
were dried and concentrated to give a colorless oil. Chromato-
graphic purification (from CH2Cl2 to 98:2 CH2Cl2-MeOH)
yielded acid 40 (14.9 g, 77%): 1H NMR (400 MHz, CDCl3) δ
1.20-1.40 (m, 12H), 1.46 (br s, 9H), 1.45-1.55 (m, 2H), 1.64
(q, J ) 7.4 Hz, 2H), 2.35 (t, J ) 7.4 Hz, 2H), 2.54-2.62 (m,
2H), 3.10-3.22 (m, 2H), 3.40-3.52 (m, 2H), 3.69 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 24.6, 26.6, 28.3, 28.9, 29.1, 29.2,
29.4, 33.2 and 33.7, 34.0, 43.1, 47.4 and 47.8, 51.6, 79.5, 155.2
and 155.4, 172.3 and 172.5, 179.2.
N-(ter t-Bu toxyca r bon yl)-N-(3-h yd r oxyp r op yl)-11-a m i-
n ou n d eca n oic Acid (41). To a solution of the acid 40 (5.5 g,
14.2 mmol) and MeOH (1.15 mL, 28.4 mmol) in Et2O (250 mL)
at 0 °C was added LiBH4 (0.62 g, 28.4 mmol), and the resulting
suspension was refluxed for 6 h. The reaction was quenched
by addition of water and 1 N HCl in an ice bath, and the
mixture was extracted with CH2Cl2. The combined organic
extracts were dried and concentrated to give the hydroxy acid
41 (4.75 g, 93%), which was used in the following step without
further purification: 1H NMR (400 MHz, CDCl3) δ 1.20-1.40
(m, 12H), 1.44 (s, 9H), 1.42-1.56 (m, 2H), 1.60-1.70 (m, 4H),
2.33 (t, J ) 7.4 Hz, 2H), 3.09 (br t, J ) 6.8 Hz, 2H), 3.32-3.40
(m, 2H), 3.53-3.60 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 24.6,
26.7, 28.3, 28.9, 29.1, 29.2, 29.2, 29.3, 30.4, 34.0, 42.5, 47.1,
58.1, 79.9, 157.1, 178.6.
N-(ter t-Bu toxyca r bon yl)-N-[3-(ter t-bu tyld im eth ylsilyl-
oxy)p r op yl]-11-a m in ou n d eca n oic Acid (42). Hydroxy acid
41 (2.7 g, 7.6 mmol) was treated with TBDMSCl (2.5 g, 16.8
mmol) and imidazole (1.6 g, 22.9 mmol) in CH2Cl2 (300 mL)
in the conditions described above for the preparation of 17 to
give ter t-bu tyld im eth ylsilyl N-(ter t-bu toxyca r bon yl)-N-
[3-(ter t-b u t yld im et h ylsilyloxy)p r op yl]-11-a m in ou n d e-
ca n oa te as an oil (4.5 g, quantitative): 1H NMR (400 MHz,
CDCl3) δ 0.05 (s, 6H), 0.27 (s, 6H), 0.90 (s, 9H), 0.94 (s, 9H),
1.20-1.40 (m, 12H), 1.45 (s, 9H), 1.45-1.55 (m, 2H), 1.56-
1.64 (m, 2H), 1.68-1.78 (m, 2H), 2.31 (t, J ) 7.4 Hz, 2H), 3.10-
3.20 (m, 2H), 3.20-3.30 (m, 2H), 3.62 (t, J ) 6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ -5.5, -5.0, 17.4, 18.1, 24.9, 25.4,
25.8, 26.7, 28.4, 29.0, 29.2, 29.2, 29.3, 29.4, 31.3 and 31.9, 35.9,
44.0, 47.2, 60.6, 78.8, 155.5, 174.2. To a solution of the above
silylester (4.5 g, 7.6 mmol) in a 4:1 mixture of MeOH and water
(200 mL) was added K2CO3 (4.5 g, 32.6 mmol), and the
resulting solution was stirred at room temperature for 2 h.
The MeOH was removed in vacuo, and the residue was diluted
with aqueous NH4Cl (pH 5-6) and extracted with Et2O. The
combined organic extracts were dried and concentrated to yield
a residue that was dissolved in CH2Cl2 and filtered through
Celite. Concentration of the filtrate yielded acid 42 (3.6 g,
quantitative) which was used as-is in the following step: 1H
NMR (400 MHz, CDCl3) δ 0.04 (s, 6H), 0.89 (s, 9H), 1.20-
1.40 (m, 12H), 1.44 (s, 9H), 1.45-1.55 (m, 2H), 1.58-1.66 (m,
2H), 1.68-1.78 (m, 2H), 2.33 (t, J ) 7.4 Hz, 2H), 3.10-3.20
(m, 2H), 3.20-3.30 (m, 2H), 3.62 (t, J ) 6.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ -5.4, 18.2, 24.7, 25.9, 26.8, 28.5, 29.0,
29.2, 29.3, 29.5, 31.4 and 32.0, 34.0, 44.2, 47.3, 60.7, 79.0,
155.6, 179.5; IR 1742, 1698, 1174 cm-1. MS (FAB) m/z (rel int)
374 [100, (MH-Boc)+]; HRMS FAB calcd for C20H44NO3Si [MH-
Boc]+ 374.3090, found 374.3091.
Ben zyl N-(ter t-Bu toxycar bon yl)-N-[3-(ter t-bu tyldim eth -
ylsilyloxy)p r op yl]-11-a m in ou n d eca n oa te (43). Following
the procedure for the preparation of 19, acid 42 (2.0 g, 4.2
mmol) and benzyl alcohol (0.44 mL, 4.2 mmol) were coupled
using DMAP (0.26 g, 2.1 mmol) and EDCI‚HCl (0.82 g, 4.2
mmol). Chromatography of the resulting crude (99:1 CH2Cl2-
MeOH) gave ester 43 (2.0 g, 86%): 1H NMR (400 MHz, CDCl3)
δ 0.05 (s, 6H), 0.90 (s, 9H), 1.20-1.40 (m, 12H), 1.45 (s, 9H),
1.45-1.55 (m, 2H), 1.64 (qn, J ) 7.4 Hz, 2H), 1.68-1.78 (m,
2H), 2.36 (t, J ) 7.4 Hz, 2H), 3.10-3.20 (m, 2H), 3.20-3.30
(m, 2H), 3.62 (t, J ) 6 Hz, 2H), 5.12 (s, 2H), 7.27-7.40 (m,
5H); 13C NMR (100 MHz, CDCl3) δ -5.5, 18.1, 24.8, 25.8, 26.7,
28.3, 29.0, 29.1, 29.2, 29.4, 31.4 and 31.9, 34.1, 44.0, 47.2, 60.6,
65.8, 78.7, 128.0, 128.4, 136.0, 155.4, 173.4; MS (ESI) m/z (rel
int) 586 [28, (MNa)+], 564 [100, (MH)+], 508 [84, (M-C4H9)+],
464 [72, (MH-Boc)+], 292 (14), 214 (16); HRMS FAB calcd for
C
27H50NO3Si [MH-Boc]+ 464.3560, found 464.3558.
Ben zyl N-(ter t-Bu toxyca r bon yl)-N-(3-h yd r oxyp r op yl)-
11-a m in ou n d eca n oa te (44). Proceeding from ester 43 (0.42
g, 0.74 mmol) in the manner described for for the preparation
of 20, alcohol 44 (0.33 g, 98%) was obtained after chromato-
graphic purification (97:3 CH2Cl2-MeOH): 1H NMR (400
MHz, CDCl3) δ 1.20-1.40 (m, 12H), 1.46 (s, 9H), 1.48-1.53
(m, 2H), 1.60-1.66 (m, 4H), 2.35 (t, J ) 7.6 Hz, 2H), 3.06-
3.16 (m, 2H), 3.32-3.40, (m, 2H), 3.50-3.60 (m, 2H), 5.12 (s,
2H), 7.27-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 24.8,
26.7, 28.2 (ma) and 28.4 (mi), 28.9, 29.0, 29.1, 29.2, 29.3, 30.5
(ma) and 31.4 (mi), 34.1, 42.5 (ma) and 43.4 (mi), 47.0, 58.2
(ma) and 59.6 (mi), 65.9, 79.6, 128.0, 128.4, 136.0, 156.9, 173.5;
IR 3448, 1738, 1694, 1670, 1168 cm-1; MS (FAB) m/z (rel int)
450 [4, (MH)+], 350 [100, (MH-Boc)+]; HRMS FAB calcd for
C
26H44NO5 [MH]+ 450.3219, found 450.3219.
Ben zyl-N,N′-b is(ter t-b u t oxyca r b on yl)-N-{N′-[3-(ter t-
bu tyld im eth ylsilyloxy)p r op yl]-11-a m in ou n d eca n oyloxy-
p r op yl}-11-a m in ou n d eca n oa te (45). Ester 45 was obtained
starting from acid 42 (1.0 g, 2.14 mmol), alcohol 44 (0.96 g,
2.14 mmol), DMAP (0.13 g, 1.07 mmol), and EDCI‚HCl (0.41
g, 2.35 mmol) following the procedure for the preparation of
ester 19. Final chromatographic purification (98:2 CH2Cl2-
MeOH) yielded 45 (1.7 g, 88%) as a colorless oil: 1H NMR (400
MHz, CDCl3) δ 0.05 (s, 6H), 0.89 (s, 9H), 1.20-1.40 (m, 24H),
1.45 (s, 18H), 1.48-1.53 (m, 4H), 1.60-1.66 (m, 4H), 1.66-
1.80 (m, 2H), 1.80-1.90 (m, 2H), 2.29 (t, J ) 7.6 Hz, 2H), 2.35
(t, J ) 7.6 Hz, 2H), 3.06-3.20 (m, 4H), 3.20-3.30 (m, 4H),
3.62 (t, J ) 6.4 Hz, 2H), 4.08 (t, J ) 6.4 Hz, 2H), 5.11 (s, 2H),
7.27-7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ -5.4, 18.2,
24.9, 24.9, 25.9, 26.8, 28.4, 28.4, 29.1, 29.1, 29.2, 29.3, 29.4,
29.5, 29.5, 31.4, 32.0, 34.3, 44.1, 47.3, 60.7, 62.1, 66.0, 78.9,
79.2, 128.1, 128.5, 136.1, 155.6, 173.6, 173.8; IR 1738, 1694,
1174 cm-1; MS (ESI) m/z (rel int) 928 [8, (MNa)+], 906 [100,
(MH)+], 850 [8, (M-C4H9)+], 806 [30, (MH-Boc)+], 375 (33), 353
(45); HRMS FAB calcd for C46H85N2O7Si [MH-Boc]+ 805.6126,
found 805.6130.
Ben zyl N,N′-Bis(ter t-bu toxycar bon yl)-N-[N′-(3-h ydr oxy-
p r op yl)-11-a m in ou n d eca n oyloxyp r op yl}-11-a m in ou n d e-
ca n oa te (46). Proceeding from ester 45 (0.63 g, 0.70 mmol)
in a manner analogous to that employed for the preparation
of 20, alcohol 46 (0.52 g, 95%) was obtained after chromato-
graphic purification (97:3 CH2Cl2-MeOH): 1H NMR (400
MHz, CDCl3) δ 1.20-1.40 (m, 24H), 1.45 (s, 9H), 1.46 (s, 9H),
1.48-1.54 (m, 4H), 1.56-1.70 (m, 6H), 1.82-1.90 (m, 2H), 2.29

Synthesis and Reactions of Polyazamacrolides
J . Org. Chem., Vol. 66, No. 4, 2001 1095
(t, J ) 7.6 Hz, 2H), 2.35 (t, J ) 7.6 Hz, 2H), 3.06-3.16 (m,
4H), 3.18-3.30 (m, 2H), 3.30-3.40 (m, 2H), 3.50-3.60 (m, 2H),
4.08 (t, J ) 6.4 Hz, 2H), 5.11 (s, 2H), 7.27-7.40 (m, 5H); 13C
NMR (100 MHz, CDCl3) δ 24.7, 26.7, 28.2, 28.3, 28.9, 29.0,
29.0, 29.0, 29.1, 29.2, 29.3, 30.5, 34.1, 42.4, 43.9, 47.0, 47.1,
58.1 (ma) and 59.6 (mi), 61.9, 65.8, 79.0, 79.6, 127.9, 128.3,
1174 cm-1; MS (ESI) m/z (rel int) 1048 [10, (MNa)+], 1042 [15,
(MNH4)+], 1025 [100, (MH)+], 684 (12) 513 [28, (M+2H)2+], 485
(22); HRMS FAB calcd for C52H98N3O10 [MH-Boc]+ 924.7252,
found 924.7264.
1,17,33-Tr ioxa -5,21,37-t r ia za cyclooct a t et r a con t a n e-
16,32,48-tr ion e [tr is(10-n or )P AML 681 Hom ologu e (13)].
Deprotection of lactame 50 (12 mg, 12 µmol) as in the case of
11 yielded triamine 13 (9 mg, quantitative): 1H NMR (500
MHz, C6D6) δ 1.24-1.35 (m, 36H, CH2), 1.43 (qn, J ) 7.5 Hz,
6H, CH2CH2N), 1.62 (qn, J ) 7.5 Hz, 6H, CH2CH2CO), 1.64
(qn, J ) 7.5 Hz, 6H, CH2CH2OCO), 2.20 (t, J ) 7.5 Hz, 6H,
CH2CO2), 2.49 (t, J ) 7 Hz, 6H, CH2N), 2.53 (t, J ) 7 Hz, 6H,
NCH2(CH2)2O), 4.20 (t, J ) 6.5 Hz, 6H, CH2O); 13C NMR (100
MHz, C6D6) δ 25.4 (C3), 27.6 (C10), 29.3, 29.5, 29.7, 29.8 (C4-
C9), 30.6 (CH2CH2OCO), 34.8 (C2), 46.8 (NCH2), 50.2 (C11),
62.6 (CH2O), 173.0 (CO); IR 1736, 1176 cm-1; MS (ESI) m/z
(rel int) 725 [4, (MH)+], 363 [63, (M+2H)2+], 242 [100,
(M+3H)3+]; HRMS CI calcd for C42H82N3O6 [MH]+ 724.6204,
found 724.6197.
135.9, 155.3, 156.9, 173.4, 173.6; IR 1736, 1694, 1166 cm-1
;
MS (FAB) m/z (rel int) 791 [5, (MH)+], 691 [95, (MH-Boc)+],
635 [100, (M-Boc-C4H9)+]; HRMS FAB calcd for C45H78N2O9
[MH]+ 791.5786, found 791.5789.
Ben zyl N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-N-({N′-[N′′-
[3-(ter t-b u t yld im et h ylsilyloxy)p r op yl]-11-a m in ou n d e-
ca n oyloxyp r op yl}-11- a m in ou n d eca n oyloxyp r op yl)-11-
a m in ou n d eca n oa te (47). Following the procedure for the
preparation of 19, starting from 42 (0.30 g, 0.64 mmol), 46
(0.51 g, 0.64 mmol), DMAP (0.04 g, 0.32 mmol), and EDCI‚
HCl (0.12 g, 0.64 mmol), ester 47 (0.80 g, quantitative) was
obtained after chromatographic purification (60:40 hexane-
AcOEt): 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6H), 0.90 (s,
9H), 1.20-1.40 (m, 36H), 1.45 (s, 27H), 1.45-1.55 (m, 6H),
1.58-1.64 (m, 6H), 1.70-1.78 (m, 2H), 1.80-1.90 (m, 4H), 2.30
(t, J ) 7.6 Hz, 4H), 2.35 (t, J ) 7.6 Hz, 2H), 3.10-3.20 (m,
6H), 3.20-3.30 (m, 6H), 3.62 (t, J ) 6.4 Hz, 2H), 4.08 (t, J )
6.4 Hz, 4H), 5.12 (s, 2H), 7.28-7.40 (m, 5H); 13C NMR (100
MHz, CDCl3) δ -5.5, 18.1, 24.8, 24.8, 25.8, 26.8, 28.3, 28.4,
29.0, 29.1, 29.1, 29.2, 29.2, 29.3, 29.4, 29.5, 31.4, 32.0, 34.2,
44.0, 47.2, 60.6, 62.0, 65.9, 78.8, 79.1, 128.0, 128.4, 136.0, 155.3,
155.5, 173.5, 173.7; IR 1738, 1694, 1174 cm-1; MS (ESI) m/z
(rel int) 1247 [36, (MH)+], 734 (46), 624 [65, (M+2H)2+], 506
(100), 488 (47), 392 (92), 225 (78); HRMS FAB calcd for
Rea r r a n gem en t of Tr is(10-n or )P AML 681 Hom ologu e.
The O-to-N acyl migration of polyazamacrolide 13 was moni-
tored using 1H NMR and HPLC-MS techniques in the same
1
manner as described for 11. H NMR sp ectr oscop ic a n a ly-
sis: following the disappearance of the 1H NMR signals
characteristic of the methylene protons adjacent to the oxigen
atom of the lactone moiety (δ 4.25-4.35 ppm) afforded an
observed rate constant (kobsd ) 0.020 ( 0.001). Following the
formation of the corresponding rearranged lactames by mea-
suring the integration of the protons R to the hydroxyl group
(δ 3.30-3.40 ppm) afforded an equivalent rate constant.
Representative data are depicted in Figure 7. Additional data
are included in Supporting Information. HP LC-MS a n a ly-
sis: rearranged monoamide: tR ) 9.4 min, 100%; m/z 725
(MH)+, 363 (M+2H)2+. Rearranged bisamide: tR ) 14.6 min,
100%; m/z 725 (MH)+. Rearranged trisamide: tR ) 25.6 min,
100%; m/z 725 (MH)+. Representative data are depicted in
Figure 7. After 180 days the final product was the rearranged
trisamide: 1H NMR (400 MHz, toluene-d8) δ 1.00-1.08 (m,
6H, CH2), 1.10-1.40 (m, 36H, CH2), 1.42-1.50 (m, 6H, CH2),
1.68-1.76 (m, 6H,CH 2), 2.06-2.11 (m, 6H, CH2CO), 2.72 (br
t, J ) 7.6 Hz, 6H, CH2N), 3.34 (br t, J ) 5.2 Hz, 6H, NCH2-
EtOH), 3.51 (br t, J ) 5.2 Hz, 6H, CH2OH); 13C NMR (100
MHz, toluene-d8) δ 26.1 (C3), 27.4 (C10), 29.6, 29.9, 30.0, 30.1,
30.1, 31.6 (C4-C9 and CH2CH2OCO), 33.2 (C2), 42.1 (CH2N),
C
65H120N3O11Si [MH-Boc]+ 1146.8692, found 1146.8677.
Ben zyl N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-N-(N′-{N′′-
[3-(h yd r oxyp r op yl)]-11-a m in ou n d eca n oyloxyp r op yl}-11-
am in ou n decan oyloxypr opyl)-11-am in ou n decan oate (48).
Ester 48 (0.50 g, 96%) was obtained from 47 (0.57 g, 0.46
mmol) in a manner analogous to that employed for the
preparation of alcohol 20, after chromatographic purification
(97:3 CH2Cl2-MeOH): 1H NMR (400 MHz, CDCl3) δ 1.20-
1.40 (m, 36H), 1.44 (s, 18H), 1.45 (s, 9H), 1.45-1.55 (m, 6H),
1.58-1.64 (m, 8H), 1.80-1.90 (m, 4H), 2.28 (t, J ) 7.6 Hz, 4H),
2.34 (t, J ) 7.6 Hz, 2H), 3.10-3.20 (m, 6H), 3.20-3.30 (m, 4H),
3.34-3.40 (m, 2H), 3.50-3.58 (m, 2H), 4.07 (t, J ) 6.4 Hz, 4H),
5.11 (s, 2H), 7.35 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 24.8,
26.7, 28.3, 28.4, 29.0, 29.1, 29.1, 29.2, 29.2, 29.3, 29.4, 29.5,
30.6, 34.2, 34.2, 42.4, 44.0, 47.1, 58.1, 62.0, 65.9, 79.1, 79.6,
128.0, 128.4, 136.0, 155.4, 157.0, 173.5, 173.7.
N,N′,N′′-Tr is(ter t-b u t oxyca r b on yl)-N-(N′-{N′′-[3-(h y-
d r oxyp r op yl)]-11-a m in ou n d eca n oyloxyp r op yl}-11-a m i-
n ou n decan oyloxypr opyl)-11-am in ou n decan oic Acid (49).
Hydrogenolysis of benzyl ester 48 (113 mg, 0.10 mmol) using
the conditions employed for the preparation of 18 furnished
hydroxy acid 49 (85 mg, 80%): 1H NMR (400 MHz, CDCl3) δ
1.20-1.40 (m, 36H), 1.44 (s, 18H), 1.45 (s, 9H), 1.45-1.55 (m,
6H), 1.58-1.64 (m, 8H), 1.80-1.90 (m, 4H), 2.29 (t, J ) 7.6
Hz, 4H), 2.32 (t, J ) 7.6 Hz, 2H), 3.04-3.20 (m, 8H), 3.20-
3.30 (m, 4H), 3.34-3.40 (m, 2H), 3.50-3.58 (m, 2H), 4.07 (t, J
) 6.4 Hz, 4H); 13C NMR (100 MHz, CDCl3) δ 24.9, 26.8, 28.4,
29.0, 29.1, 29.1, 29.2, 29.3, 29.3, 29.3, 29.4, 29.4, 29.5, 29.5,
30.5, 34.2, 42.5, 44.1, 47.1, 58.2, 62.0, 79.3, 79.9, 155.5, 157.2,
173.8, 177.7; MS (ESI) m/z (rel int) 1041 [100, (M-H)-], 700
(37), 600 (15), 358 (68), 258 (93), 226 (47).
N,N′,N′′-Tr is(ter t-bu toxyca r bon yl)-1,17,33-tr ioxa -5,21,-
37-tr ia za cycloocta tetr a con ta n e-16,32,48-tr ion e (50). Fol-
lowing the macrolactonization procedure described for the
preparation of 24, starting from hydroxy acid 49 (30 mg, 0.03
mmol), macrocycle 50 (12 mg, 40%) was obtained after
chromatographic purification (80:20 hexane-AcOEt): 1H NMR
(500 MHz, C6D6) δ 1.20-1.40 (m, 36H, CH2), 1.48 (s, 27H
(CH3)3O), 1.45-1.55 (m, 6H, CH2CH2N), 1.58-1.66 (m, 6H,
CH2CH2CO), 1.74-1.79 (m, 6H, CH2CH2O), 2.21 (t, J ) 7.5
Hz, 6H, CH2CO2), 3.06-3.13 (2m, 6H, CH2N), 3.23-3.29 (2m,
6H, NCH2(CH2)2O), 4.08 (t, J ) 6 Hz, 6H, CH2O); 13C NMR
(100 MHz, C6D6) δ 25.7 (C3), 27.5 (C10), 28.9 (CH3), 29.8, 29.9,
30.1, 30.2 (C4-C9), 34.8 (C2), 44.9 (NCH2), 48.0 (C11), 62.5
(CH2O), 79.2 (CMe3), 155.7 (NCO), 173.2 (CO2); IR 1738, 1694,
48.0 (C11), 58.5 (CH2OH), 173.9 (CON); IR 3400, 1621 cm-1
;
MS (ESI) m/z (rel int) 725 [100, (MH)+], 363 [70, (M+2H)2+],
242 [17, (M+3H)3+]; HRMS ESI calcd for C42H82N3O6 [MH]+
724.6203, found 724.6192.
Ca lcu la tion s. A molecular mechanics search for the lowest
energy conformations of PAML 681, 11, and 12 was conducted
using the Global MMX (GMMX) program, a part of the PC
Model V 7.0 molecular modeling program developed by Serena
Software.35 Conformational space was searched using the
MMX force fields, with the Mixed search method and the
H-bonds option ON. The Mixed search method alternates
between the Bonds method (that selects randomly a subset of
the bonds designated for rotation, causing large changes in
the shape of a molecule) and the Cartesian method (in which
all atoms are moved in the 3D space causing small changes
in the shape of the molecule). We selected for rotation all the
carbon-carbon bonds Cx-Cy and carbon-heteroatom bonds
Cx-Ny and Cx-Oy, with exception of the π systems. The
original structure was minimized to generate the initial
minimum energy conformation; the resulting structure was
then modified by the Mixed search method, and the new
conformation was minimized until the gradient fell below
0.0001. After minimization, only an energy acceptable con-
former that did not duplicate a previously stored one was
saved, and its geometry was used to spawn a new conformer;
otherwise it was rejected. Processing by GMMX was done in
two stages; the first cycle randomly searched over the rotable
bonds and kept all the conformers minimized within 3.5 kcal
of the lowest energy conformer found during the minimization.
The second cycle reminimized the structures found in the first
cycle and kept only those that are within 3 kcal of the lowest

1096 J . Org. Chem., Vol. 66, No. 4, 2001
Garc´ıa-Rubio and Meinwald
energy conformers. To ensure an exhaustive search of the
potential surface, 20,000 conformations were generated and
minimized from different starting structures.
William Smith Colleges) for her valuable comments on
this manuscript. The picture on the cover was provided
by Professor Tom Eisner, to whom the authors are
deeply thankful.
Ack n ow led gm en t. S.G.R. thanks the Pew Founda-
tion (Latin American Fellows Program) for a postdoc-
toral fellowship (P0236SC). Partial support of this
research by the National Institutes of Health (GM53830)
also is gratefully acknowledged. The authors are in-
debted to Dr. Athula Attygalle, Cornell University, for
the determination of the mass spectral data and for
valuable comments on this work. Thanks are also due
to Prof. Charles Wilcox for a copy of the PC Model 7.0
conformational search program and for helpful discus-
sions, as well as to Prof. Carol Parish (Hobart and
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 15-24, 11, 26-39, 40-50, and
13 and the totally rearranged products of 11, 12, and 13.1H
NMR and HPLC-MS monitoring for the rearrangement of
compounds 11, 12, and PAML 681. A listing of selected
conformations found within 3 kcal/mol of the apparent global
minimum for 11, 12, and PAML 681. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O001247H