Reaction discovery employing macrocycles: Transannular cyclizations of macrocyclic bis-lactams

Article abstract of DOI:10.1021/ol802729f

(Chemical Equation Presented) Macrocyclic bis-lactams have been synthesized by cyclodimerization of homoallylic amino esters employing a Zr(IV)-catalyzed ester-amide exchange protocol. Base-mediated transannular cyclizations have been identified to access

Full text of DOI:10.1021/ol802729f

ORGANIC
LETTERS
2009
Vol. 11, No. 2
413-416
Reaction Discovery Employing
Macrocycles: Transannular Cyclizations
of Macrocyclic Bis-lactams
Chong Han,† Sathish Rangarajan,† Alicia C Voukides,‡ Aaron B. Beeler,†
Richard Johnson,‡ and John A. Porco, Jr.*,†
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215, and Department of Chemistry, UniVersity of New
Hampshire, Durham, New Hampshire 03824
porco@bu.edu
Received November 25, 2008
ABSTRACT
Macrocyclic bis-lactams have been synthesized by cyclodimerization of homoallylic amino esters employing a Zr(IV)-catalyzed ester-amide
exchange protocol. Base-mediated transannular cyclizations have been identified to access both bicyclic [5-11] and tricyclic [5-8-5] frameworks
in good yield and diastereoselectivity. Preliminary mechanistic studies support an olefin isomerization-intramolecular conjugate addition
pathway.
Macrocyclic natural products often exhibit important biologi-
cal activities and have thus inspired a number of studies
involving diversity-oriented synthesis of macrocyclic frame-
works.1 Recent studies have also highlighted elegant ex-
amples of transannular cyclizations en route to complex
natural products.2 As part of our studies, we considered
preparation of macrocycles as substrates for reaction dis-
covery3 and potential complexity-generating transannular
cyclizations.4,5 In this communication, we report the prepara-
tion of 14-membered ring bis-lactams6 and their conversion
to polycyclic frameworks by divergent, transannular reaction
processes, as well as preliminary computational studies to
probe the reaction mechanism.
To access macrocyclic bis-lactam substrates, we utilized
cyclodimerization of stereochemically well-defined homoal-
lylic amino esters7 using Zr(IV)-catalyzed ester-amide ex-
change.8 Alloc-protected amino esters 1a-d were prepared
(3) (a) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am.
Chem. Soc. 2007, 129, 1413. (b) Rozenman, M. M.; Kanan, M. W.; Liu,
D. R. J. Am. Chem. Soc. 2007, 129, 14933.
† Boston University.
(4) (a) Sudau, A.; Nubbemeyer, U. Angew. Chem., Int. Ed. 1998, 37,
1140. (b) Rodríguez, G.; Castedo, L.; Domínguez, D.; Saa´, C. J. Org. Chem.
1999, 64, 4830, and references therein. (c) Surprenant, S.; Lubell, W. D.
Org. Lett. 2006, 8, 2851.
‡ University of New Hampshire.
(1) (a) Chantigny, Y. A.; Dory, Y. L.; Toro, A.; Deslongchamps, P.
Can. J. Chem. 2002, 80, 875. (b) Su, Q.; Beeler, A. B.; Lobkovsky, E.;
Porco, J. A., Jr.; Panek, J. S. Org. Lett. 2003, 5, 2149. (c) Schmidt, D. R.;
Kwon, O.; Schreiber, S. L. J. Comb. Chem. 2004, 6, 286. (d) Wessjohann,
L. A.; Ruijter, E. Mol. DiVersity 2005, 9, 159. (e) Beeler, A. B.; Acquilano,
D. E.; Su, Q.; Yan, F.; Roth, B. L.; Panek, J. S.; Porco, J. A., Jr. J. Comb.
Chem. 2005, 7, 673. (f) Shang, S.; Tan, D. S. Curr. Opin. Chem. Biol.
2005, 9, 248.
(5) For transannular cyclizations involving lactams, see: (a) Matsuura,
T.; Yamamura, S. Tetrahedron Lett. 2000, 41, 4805. (b) Appendino, G.;
Tron, G. C.; Jareva˚ng, T.; Sterner, O. Org. Lett. 2001, 3, 1609. (c) Rosales,
A.; Este´vez, R. E.; Cuerva, J. M.; Oltra, J. E. Angew. Chem., Int. Ed. 2005,
44, 319.
(6) (a) Dugat, D.; Chiaroni, A.; Riche, C.; Royer, J.; Husson, H.-P.
Tetrahedron Lett. 1997, 38, 5801. (b) Karle, M.; Bockelmann, D.;
Schumann, D.; Gridsinger, C.; Koert, U. Angew. Chem., Int. Ed. 2003, 42,
4546. (c) Dugat, D.; Valade, A.-G.; Combourieu, B.; Guyot, J. Tetrahedron
2005, 61, 5641.
(2) Select examples: (a) Ji, N.; O’Dowd, H.; Rosen, B. M.; Myers, A. G.
J. Am. Chem. Soc. 2006, 128, 14825. (b) Snider, B. B.; Zhou, J. Org. Lett.
2006, 8, 1283. (c) Scheerer, J. R.; Lawrence, J. F.; Wang, G. C.; Evans,
D. A. J. Am. Chem. Soc. 2007, 129, 8968.
10.1021/ol802729f CCC: $40.75
Published on Web 12/22/2008
2009 American Chemical Society

using asymmetric crotylation7of the iminium species derived
from condensation of allyl carbamate with aromatic alde-
hydes (Scheme 1). Subsequent alloc removal9 using a
transition-metal catalysts including Pd(II), Ag(I), Pt(II),
Au(I), and Au(III)12 failed to afford any cyclized products.
After reaction screening, use of NaH as base13 in DMF at
60 °C was found to provide tricyclic [5-8-5] product 5 (dr
) 5:1:1) (Scheme 3, entry 1). Reaction at room temperature
Scheme 1. Preparation of Homoallylic Amino Ester Monomers
Scheme 3. Base Evaluation for Transannular Cyclization
polymer-bound Pd(0) reagent (PS-PPh3-Pd)10 simplified
product purification and afforded amino ester monomers
2a-d.
As cyclodimerization of 2 involves consecutive intermo-
lecular and intramolecular amidations, we anticipated that
concentration may play an important role in reaction ef-
ficiency. Therefore, a range of concentrations (0.10-0.80
M) were examined for cyclodimerization of 2a using Zr(Ot-
Bu)4-2-hydroxypyridine (HYP)8 as catalyst (Scheme 2).
a Combined yields of all the diasteromers. Diastereomer ratio determined
by H NMR integration. b 0.20 equiv of base employed.
1
using NaH gave no conversion, indicating a high activation
energy for transannular cyclization (Scheme 3, entry 2).
Further optimization was conducted by evaluating different
bases and solvents. When DMF was used as the solvent,
use of Cs2CO3 as base showed no conversion, whereas NaOt-
Bu afforded full conversion (entries 3 and 4). It is noteworthy
that a 64% conversion to a mixture of 4 and 5 could be
obtained using a catalytic amount of NaOt-Bu (20 mol %)
(entry 5). Bases were also evaluated using THF as solvent;
NaOt-Bu yielded bicyclic product 4 (dr >20:1) exclusively
in 70% yield (entry 6).
Scheme 2. Synthesis of Bis-lactams via Cyclodimerization
The relative stereochemistries of 4 and 5 were determined
using NOE studies (Figure 1).10 Furthermore, a single X-ray
crystal structure for major diastereomer 5 was obtained to
fully support the structure and stereochemical assignment.10
In order to understand the potential for epimerization, either
compound 5 or an inseparable mixture of diastereomers 6
and 7 was treated with NaOt-Bu in DMF at 60 °C, which
resulted in an approximate 5:1:1 diastereomeric ratio of 5:6:
7, indicating a reversible, thermodynamically controlled
cyclization process.
We also probed the effect of aryl substitution in the
transannular cyclization process (Scheme 4). Reaction of bis-
lactam 3c with NaOt-Bu in DMA (condition a) afforded
approximately a 1:1 mixture of monocyclized product 8c and
bis-cyclized product 9c. The corresponding reaction of 3c
in THF (condition b) afforded exclusively 8c, albeit in low
yield. Reaction of 3d using DMA as solvent afforded a 1:4
mixture of 8d and tricyclic product 9d, and reaction in THF
afforded 8d exclusively in moderate yield. Transannular
Based on these studies, an optimal concentration for produc-
tion of 14-membered bis-macrolactam 3a was found to be
0.60 M. Macrocyclic bis-lactams 3b-d were also prepared
in moderate to good yield using the optimized conditions.
The structure and stereochemistry of bis-lactam 3b was
confirmed by single X-ray crystal structure analysis (one
conformer shown).10
With the target macrolactams in hand, we focused on
reaction discovery to identify complexity-generating tran-
sannular cyclizations. Initial attempted intramolecular hy-
droamidation11 of bis-lactam 3b utilizing carbophilic late-
(7) (a) Schaus, J. V.; Jain, N.; Panek, J. S. Tetrahedron 2000, 56, 10263.
(b) Lipomi, D. J.; Panek, J. S. Org. Lett. 2005, 7, 4701.
(8) Han, C.; Lee, J. P.; Lobkovsky, E.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2005, 127, 10039.
(9) Kunz, H.; Unverzagt, C. Angew. Chem., Int. Ed. 1984, 23, 436.
(10) See Supporting Information for complete experimental details.
(11) (a) Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2006, 4143,
and references therein. (b) Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett.
2006, 8, 2707.
(12) For a recent review, see: Fu¨rstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3410.
(13) For base-assisted hydroamidation, see: Yu, Y.; Stephenson, G. A.;
Mitchell, D. Tetrahedron Lett. 2006, 47, 3811.
414
Org. Lett., Vol. 11, No. 2, 2009

effect (k1/k2) 2.3) was observed when methylene-deuterated
substrate 10 was utilized in comparison to 3b to afford
monocyclized product 4.14 These results suggest that the rate-
determining step for production of 4 likely involves meth-
ylene deprotonation.15
On the basis of our experimental results, we propose an
olefin isomerization-conjugate addition mechanism for the
base-mediated transannular cyclization (Scheme 6).2b,c,16 1H
Scheme 6. Proposed Reaction Pathway
Figure 1. Determination of relative stereochemistry.
cyclization of both 3c and 3d also afforded slightly reduced
diastereomeric ratios of the bis-cyclized products with
Scheme 4. Preparation of Bicyclic and Tricyclic Products
NMR studies indicate that the initial step is likely deproto-
nation of bis-lactam 3b, generating anionic species 12.10
Proton transfer may occur at the R position (red) or
transannularly (blue) to afford olefin-isomerized intermediate
13. Subsequent conjugate addition affords the bicyclic
product 4. The bicyclic product may undergo further
deprotonation-isomerization to afford intermediate 14,
which may be followed by conjugate addition to provide 5.
In contrast to use of DMF as solvent, we speculate that the
absence of a second cyclization in the less polar solvent
THF17 may be due to diminished acidity of the methylene
hydrogens of 4, which bears a neighboring tertiary amide
relative to those in macrolactam 3b.
a Conditions: (a) NaOt-Bu (2.0 equiv), DMA, 60 °C, 12 h; (b) NaOt-
Bu (2.0 equiv), THF, 60 °C, 24 h. b Diastereomeric ratios determined by
1H NMR integration.
To understand the stereochemical outcome of the reaction,
we carried out computational studies based on our proposed
mechanism. The studies included conformational searches
and M052X density functional calculations10 on bis-lactam
3b, key proposed intermediates (15, 17, and 18), cyclized
products (4-7, 16), and transition states. Scheme 7 sum-
marizes relative energies for neutral species. Enone conjuga-
tion is endothermic, consistent with our failure to isolate
conjugated intermediates. The two cyclization steps define
an energy cascade with the experimentally observed products
of lowest energy as might be expected for an equilibrium
process.
diastereoselectivity of monocyclized products remaining
high.
To probe the reaction mechanism, we performed kinetic
isotope effect experiments employing 3b and deuterated
substrates 10 and 11 (Scheme 5). A significant kinetic isotope
Scheme 5. Kinetic Isotope Effect Experiments
Transition state searching for the conjugate addition steps
posed a greater challenge. In macrocyclic rings, there are
few systematic methods to simultaneously search both
(14) Approximately 20% deuteration remained at R′′ when the reactions
were quenched by addition of H2O.
(15) For related examples of kinetic isotope effects in enolate chemistry,
see: (a) Held, G.; Xie, L. Microchem. J. 1997, 55, 261. (b) Dudley, G. B.;
Danishefsky, S. J.; Sukenick, G. Tetrahedron Lett. 2002, 43, 5605.
(16) Johnson, S. J. J. Org. Chem. 1995, 60, 8089
.
a Determined by HPLC analysis. See Supporting Information for details.
(17) For solvent effects on acidities of the R-hydrogens of amides, see:
Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1981, 46, 4327.
Org. Lett., Vol. 11, No. 2, 2009
415

Scheme 7
.
DFT Relative Energies (kcal/mol) for Neutral
Species
Scheme 8. Diastereoselective Alkylation
conformations and transition states.18 Transition state con-
formational searches were carried out by Monte Carlo
methods, with a constrained length (1.9 Å) for the nascent
transannular bond. The 50-100 candidate structures of
lowest energy were further optimized with the AM1 method,
followed by single point HF/3-21G calculation. Finally, the
lowest energy collection of structures was subjected to
M052X/6-31G(d) optimization and frequency analysis.10 The
predicted transition state energy barriers of 6-15 kcal/mol
are consistent with the facile nature of these reactions. Each
anionic cyclization step is endothermic10 and as a conse-
quence, the product distribution is thermodynamically con-
trolled consistent with the relative energies shown in Scheme
7.
Further functionalization of the tricyclic core structure of
5 was conducted in an effort to generate further complexity.
Stereoselective bis-alkylations were achieved in good yield
by treatment of 5 with LiHMDS at -78 °C and subsequent
quenching with alkyl halides (Scheme 8) to afford alkylated
products (20-22) as single diastereomers. Stereoselectivity
may be derived by approach of the electrophile from the
convex face of the dienolate intermediate 19. The structure
and stereochemistry of bis-alkylated product 20 was con-
firmed by single crystal X-ray analysis.10
amino ester monomers employing Zr(IV)-catalyzed ester-
amide exchange. Reaction discovery has led to the identifica-
tion of transannular cyclizations to provide bicyclic [5-11]
or tricyclic [5-8-5] frameworks in good yield and diastereo-
selectivity. Diastereoselective C-alkylation was developed
to further elaborate structures. Preliminary mechanistic
studies including computational analyses support an olefin
isomerization-intramolecular conjugate addition pathway.
Further studies involving reaction discovery of macrocyclic
frameworks are in progress and will be reported in due
course.
Acknowledgment. Financial support from the NIGMS
(P50 GM067041), the Northrup Grumman Corporation
(R.J.), and the Defense Microelectronics Activity (DMEA)
for purchase of a multiprocessor computer (R.J.) are grate-
fully acknowledged. We thank Professors Scott Schaus,
James Panek, and Corey Stephenson (Boston University) for
helpful discussions.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds and
summary energetics for stationary points from density
functional calculations. X-ray crystal structure coordinates
and files in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, macrocyclic bis-lactams have been ef-
ficiently synthesized by cyclodimerization of homoallylic
(18) For discussions of transition state conformational searches, see: (a)
Wolfe, S.; Buckley, A. V.; Weinberg, N. Can. J. Chem. 2001, 79, 1284.
(b) Baldwin, J. E.; Raghavan, A. S.; Hess, B. A., Jr.; Smentek, L. J. Am.
Chem. Soc. 2006, 128, 14854. (c) Koslover, E. F.; Wales, D. J. J. Chem.
Phys. 2007, 127, 1341.
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