Synthesis and structure of preorganized, C(3)-symmetric trilactam scaffolds with convergently oriented (S)-acetylthiomethyl appendages.

Article abstract of DOI:10.1021/ol0261480

[reaction: see text] Efficient modular synthesis of conformationally preorganized, C(3)-symmetric trilactams is reported. The allyl acetate cyclization substrate was synthesized in five steps from Garner's L-serine-derived aldehyde. After chiral ligand-me

Full text of DOI:10.1021/ol0261480

ORGANIC
LETTERS
2002
Vol. 4, No. 13
2273-2275
Synthesis and Structure of
Preorganized, C -Symmetric Trilactam
3
Scaffolds with Convergently Oriented
(S)-Acetylthiomethyl Appendages
John E. Campbell, Erikah E. Englund, and Steven D. Burke*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue,
Madison, Wisconsin 53706-1396
burke@chem.wisc.edu
Received May 7, 2002
ABSTRACT
Efficient modular synthesis of conformationally preorganized, C -symmetric trilactams is reported. The allyl acetate cyclization substrate was
3
synthesized in five steps from Garner’s L-serine-derived aldehyde. After chiral ligand-mediated palladium cyclization, the resulting vinyl hydropyran
was transformed into the orthogonally protected amino acids for iterative coupling. The final macrolactamization was accomplished using
EDCI/HOBt or HATU/HOAt under high dilution conditions.
We have previously reported the synthesis, structural analy-
sis, and cation binding efficacy of 18-membered, cyclic
hydropyran oligolides with alternating ester and ether link-
ages.1 The rigid, conformationally preorganized nature of
these macrocycles allows for pendant functionality to be
specifically spaced2 and oriented for the attachment of
biological recognition elements such as carbohydrates3 or
peptide chains. The potential for use of these macrocycles
as templates has precipitated the need for a more robust
framework utilizing amide bonds in place of the more labile
ester bonds. Herein we discuss efforts toward the synthesis
and characterization of this new class of macrocycles as a
prelude to future template studies.
based, protected amino acid module for trimerization and
cyclization. As shown in Figure 1, it was envisioned that
Figure 1. Hydropyran module synthetic strategy.
The C3-symmetry of the targeted macrocyclic trilactams
suggested a synthetic approach employing a hydropyran-
the individual hydropyran subunits could be derived from a
stereoselective, palladium-mediated cyclization.4,5
(1) (a) Burke, S. D.; O’Donnell, C. J.; Porter, W. J.; Song, Y. J. Am.
Chem. Soc. 1995, 117, 12649-12650. (b) Burke, S. D.; McDermott, T. S.;
O’Donnell, C. J. J. Org. Chem. 1998, 63, 2715-2718.
(2) Burke, S. D.; Zhao, Q. J. Org. Chem. 2000, 65, 1489-1500.
(3) Burke, S. D.; Zhao, Q.; Schuster, M. C.; Kiessling, L. L. J. Am. Chem.
Soc. 2000, 122, 4518-4519.
(4) Trost, B. M.; Tenaglia, A. Tetrahedron Lett. 1988, 29, 2927-2930.
(5) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545-
4554.
10.1021/ol0261480 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/04/2002

alcohol in excellent yield. Deprotection of the silyl ether with
TBAF followed by selective monoacylation of the primary
alcohol yielded the allylic acetate cyclization substrate 5.
Cyclization utilized Pd2(dba)3 (1.3 mol %) with Trost’s chiral
(S,S)-N-[2,(2′-diphenylphosphino)benzamido cyclohexyl] (2′-
diphenyl-phosphino) benzamide ligand [(S,S)-DPPBA (5.3
mol %)] to produce 6 (96%) as a single diastereomer.5 With
the third stereocenter in place, oxidative cleavage of the vinyl
group produced the corresponding aldehyde, which was
oxidized under mild conditions with sodium hypochlorite to
afford the N-Cbz-protected amino acid 7.
Scheme 1. Monomer Synthesis
The monomer unit synthesis was completed by protection
of the acid as the ethyl ester followed by deprotection of
the dimethyl N,O-acetal with catalytic CSA in methanol. The
resulting hydroxymethyl side chain was protected as the TBS
ether to provide 9.
With the protected monomer in hand, saponification of
the ethyl ester or hydrogenolysis of the benzyl carbamate
gave the primary coupling partners, acid 10 and amine 11,
respectively. In early experiments, the methyl ester was
employed as the carboxyl protecting group, but the free
amine undergoes competing cyclization to the bicyclic [3.3.1]
lactam under the peptide coupling conditions. The ethyl ester
proved hindered enough to effectively prevent this deleterious
side reaction.
Standard peptide bond formation using diisopropylcarbo-
diimide (DIC) with stoichiometric 1-hydroxybenzotriazole
(HOBt) effected coupling, affording 12 in good yield
(Scheme 2). Hydrogenolysis followed by coupling to another
Scheme 2. Iterative Coupling Sequence
As detailed in Scheme 1, the cyclization substrate would
arise from Grignard addition of the TBS derivative of
6-chlorohex-2-en-1-ol (2)6 to N-Cbz-protected Garner’s al-
dehyde (1), which is readily available from L-serine in four
steps.7 There is precedence for stereoselective addition to
Garner’s aldehyde with reactive nucleophiles, such as
vinylmagnesium bromide or vinyllithium, via Felkin-Ahn
preferred attack to produce the desired erythro alcohol.8
Unfortunately, less reactive nucleophiles, such as the Grig-
nard reagent prepared from 2, react with little stereoselec-
tivity, giving the resulting alcohol as an inseparable mixture
of diastereomers (1:1, determined by HPLC). The desired
alcohol diastereomer 4 was stereoselectively produced via
Swern oxidation followed by chelation-controlled (anti-
Felkin-Ahn) reduction under modified Luche conditions.9
Using a procedure developed and optimized specifically for
this reaction, Zn(BH4)210 with CeCl3 gave the desired erythro
(6) Brennan, J. P.; Saxton, J. E. Tetrahedron 1986, 42, 6719-6734.
(7) (a) Garner, P. Tetrahedron Lett. 1984, 25, 5855-5858. (b) Garner,
P.; Park, J. M. J. Org. Chem. 1987, 52, 2361-2364.
(8) (a) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999-8003. (b)
Ageno, G.; Banfi, L.; Cascio, G.; Guanti, G.; Manghisi, E.; Riva, R.; Rocca,
V. Tetrahedron 1995, 51, 8121-8134. (c) For alternate chelation theory
see: Coleman, R. S.; Carpenter, A. J. Tetrahedron Lett. 1992, 33, 1697-
1700.
(9) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454-
5459.
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Org. Lett., Vol. 4, No. 13, 2002

equivalent of 10 afforded pseudotrimer 13. At this point, the
carboxyl terminus was deprotected, followed by hydro-
genolysis to yield the macrolactamization substrate, amino
acid 14.
Macrolactamization to 15 proceeded under high dilution
conditions (0.002 M) in 1:1 CH2Cl2/DMF with either 1-[3-
(dimethylamino)propyl]-3-ethyl carbodiimide (EDCI) and
HOBt or O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-
uronium hexafluorophosphate (HATU) and 1-hydroxy-7-
azabenzotriazole (HOAt)11 over a period of 16-60 h. HATU/
HOAt couplings required significantly reduced reaction times
and were generally higher yielding.
Deprotection of the siloxymethyl side chains with metha-
nolic HCl afforded triol 16 as a waxy solid. Preparation of
the triacetate derivative 17 yielded a crystalline compound
(mp 198-201 °C) for structural confirmation by X-ray
diffraction (Figure 2). The 18-membered core favors an open,
nearly planar macrocycle with the acetoxymethyl side chains
pointing nearly perpendicular to the mean core plane (Figure
2b). A best fit least-squares approximation places the cavity
defining heteroatoms (O1, O5, O9, N1, N2, N3) as coplanar
to within 0.13 Å. These attributes parallel those of the related
ester analogues,1 suggesting that the preorganized nature of
the triester and triamide families is comparable.
There was initial concern that the carbonyl oxygens in the
macrocycle would react with the activated hydroxymethyl
side chains during the Mitsunobu transformation. Such a
reaction would result in the formation of trioxazoline
derivatives. Although a successful test reaction was per-
formed on the monomer, it was feared that the macrocyclic
cabonyls could have a more reactive orientation as a result
of conformational constraints. From the crystal stucture it is
apparent that the opposite is true. The degree to which the
carbonyl oxygens are pointing downward and away from
the hydroxymethyl side chains was reassuring. The Mit-
sunobu reaction converting 16 to 18 proceeded cleanly in
THF on all three of the template side chains to yield the
trithiol triacetate as the exclusive product (80%) upon
extended reaction times.
In summary, a new class of C3-symmetric macrotrilactams
has been synthesized in high yield from readily available
precursors. The synthetic route displays the utility of
palladium-mediated cyclizations for stereoselective synthesis
of functionalized hydropyrans. Successful introduction of
ester and protected thiol functionality in the convergently
oriented appendages presages the utilization of these macro-
cycles as scaffolds and catalysts.
Acknowledgment. We thank the UW-Madison Graduate
School Research Committee for generous support of this
research. The NIH (1S10RR08389-01) and NSF (CHE-
9208463) are acknowledged for their support of the NMR
facilities of the University of Wisconsin-Madison Department
of Chemistry. Special thanks go to Dr. Ilia Guzei for solving
crystal structures required for stereochemical determination.
Supporting Information Available: Experimental pro-
cedures and spectral data for compounds 3-13, 15-18, and
crystallographic data for compound 17. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0261480
(10) Bayquen, A. V.; Read, R. W. Tetrahedron 1996, 52, 13467-13482.
(11) Stachel, S. J.; Lee, C. B.; Spassova, M.; Chappell, M. D.; Bornmann,
W. G.; Danishefsky, S. J.; Chou, T.-C.; Guan, Y. J. Org. Chem. 2001, 66,
4369-4378.
Figure 2. ORTEP 40% ellipsoid crystal structure of macrocyclic
triacetate 17: (a) top view, (b) edge view.
Org. Lett., Vol. 4, No. 13, 2002
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