Direct synthesis of medium-bridged twisted amides via a transannular cyclization strategy

Article abstract of DOI:10.1021/ol901449y

Figur Presented The sequential RCM to construct a challenging medium-sizwd ring followed by a transannual cyclization across a medium-sized ring delivers previously unttainable twisted amides from simple acyclic precursos.

Full text of DOI:10.1021/ol901449y

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3878-3881
Direct Synthesis of Medium-Bridged
Twisted Amides via a Transannular
Cyclization Strategy
Michal Szostak and Jeffrey Aube´*
Department of Medicinal Chemistry, UniVersity of Kansas, 1251 Wescoe Hall DriVe,
Malott Hall, Room 4070, Lawrence, Kansas 66045-7852
jaube@ku.edu
Received June 25, 2009
ABSTRACT
The sequential RCM to construct a challenging medium-sized ring followed by a transannular cyclization across a medium-sized ring delivers
previously unattainable twisted amides from simple acyclic precursors.
Many lactams incorporating nitrogen at a bridgehead position
contain nonplanar or “twisted” amides.1 Due to limited
overlap of the nitrogen lone pair of electrons with the
π-system of the carbonyl group, such compounds are
extremely sensitive to hydrolysis and display other kinds of
reactivity that are sharply divergent from that of standard
lactams.2 Moreover, since a fully twisted amide represents
the transition state of the cis-trans amide bond isomerization
essential in protein folding,3 it has been suggested that
compounds that contain nonplanar amides could be useful
as inhibitors of proline isomerases.4 However, due to inherent
strain and the enhanced lability to water, twisted amides have
not fulfilled their promise as biological tools.
The vast majority of bridged amides place the carbonyl
group on a bridge containing two or more carbons (Figure
1a). Although less common, we have recently shown that
(1) For reviews, see: (a) Hall, H. K.; Elshekeil, A. Chem. ReV. 1983,
83, 549. (b) Greenberg, A., In The Amide Linkage: Structural Significance
in Chemistry, Biochemistry, and Materials Science; Greenberg, A., Bren-
eman, C. M., Liebman, J. F., Ed.; Wiley-Interscience: New York, 2000; p
47. (c) Clayden, J.; Moran, W. J. Angew. Chem., Int. Ed. 2006, 45, 7118.
(2) For leading references, see: (a) Greenberg, A.; Moore, D. T.; DuBois,
T. D. J. Am. Chem. Soc. 1996, 118, 8658. (b) Kirby, A. J.; Komarov, I. V.;
Feeder, N. J. Chem. Soc., Perkin Trans. 2 2001, 4, 522. (c) Brown, R., In
The Amide Linkage: Structural Significance in Chemistry, Biochemistry,
and Materials Science; Greenberg, A., Breneman, C. M., Liebman, J. F.,
Ed.; Wiley-Interscience: New York, 2000; p 85. (d) Mujika, J. I.; Mercero,
J. M.; Lopez, X. J. Am. Chem. Soc. 2005, 127, 4445.
Figure 1. Some twisted amides (a) with the CdO bond placed on
a 2- or 3-carbon7 or (b) on a 1-carbon bridge.8
(3) (a) Shao, H.; Jiang, X.; Gantzel, P.; Goodman, M. Chem. Biol. 1994,
1, 231. (b) Fischer, G.; Schmid, F. X. In Molecular Chaperones and Folding
Catalysts: Regulation, Cellular Functions and Mechanisms, Bakau, B., Ed.;
CRC: Boca Raton, 1999; p 461. (c) Schmid, F. X. AdV. Protein Chem.
2002, 59, p 243.
one-carbon bridged twisted amides 1 (Figure 1b) are
substantially more persistent in aqueous solutions.5 This
10.1021/ol901449y CCC: $40.75
Published on Web 08/05/2009
 2009 American Chemical Society

arises from the relatively relaxed ring sizes present in 1 and
the fact that the ring-opened amino acid corresponding to
this structure is destabilized by transannular interactions.
However, the amide bond in 1 is substantially distorted from
planarity and the lactam displays reactivity that belies this
nature.6
solution to the problem of one-carbon bridged twisted amide
synthesis (Scheme 1).
Scheme 1. RCM/Cyclization Strategy
In general, existing synthetic approaches to one-carbon
bridged twisted amides are limited to particular structural
types9 and do not allow for synthesis of larger number of
diverse analogues.10 There is no general method of synthesis
of one-carbon bridged twisted amides. The observation that
lactams 1 can reform in water once hydrolyzed, plus the rich
history of transannular cyclizations in synthesis11 (including
limited precedent from the twisted amide chemistry),12
suggested that such ring systems might be accessible using
a direct cyclization approach. Although only limited prece-
dent supported the synthesis of medium-ring nitrogen-
containing heterocycles with appropriately placed amine and
carboxylic acid derivative functionalities,13 we believed that,
if successful, RCM would allow for rapid construction of
diverse precursors to the key cyclization.14 Herein, we report
the realization of these ideas to provide a highly general
Our initial investigations focused on the preparation of
the [4.3.1] bicyclic ring system previously studied in this
laboratory.5,6,8b Thus, malonate 2a was prepared and sub-
jected to range of RCM conditions. After extensive experi-
mentation, it was found that Hoveyda-Grubbs 2 catalyst15
Table 1. Optimization of RCM
(4) Greenberg, A., In The Amide Linkage: Structural Significance in
Chemistry, Biochemistry, and Materials Science; Greenberg, A., Breneman,
C. M., Liebman, J. F., Ed.; Wiley-Interscience: New York, 2000; p 78.
(5) Szostak, M.; Yao, L.; Aubé, J. J. Org. Chem. 2009, 74, 1869.
(6) Lei, Y.; Wrobleski, A. D.; Golden, J. E.; Powell, D. R.; Aubé, J.
J. Am. Chem. Soc. 2005, 127, 4552.
entry diene (P) catalyst mol (%) T (°C) time (h) yielda (%)
(7) (a) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731. (b) Somayaji, V.;
Brown, R. S. J. Org. Chem. 1986, 51, 2676.
1
2
3
4
5
6
7
8
9
Ts (2a)
Ts (2a)
Ts (2a)
Ts (2a)
Ts (2a)
Ts (2a)
Ts (2a)
Ts (2a)
Ts (2a)
G1
100
50
20
50
20
5
5
5
5
5
40
24
40
40
80
80
80
80
80
80
80
80
80
26
25
22
21
21
21
21
21
8
87
54
41
43
76
72
69
81
(8) (a) Williams, R. M.; Lee, B. H.; Miller, M. M.; Anderson, O. P.
J. Am. Chem. Soc. 1989, 111, 1073. (b) Yao, L.; Aubé, J. J. Am. Chem.
Soc. 2007, 129, 2766.
Fu¨rstner
Fu¨rstner
G2
(9) For previous examples of one-carbon medium-bridged amides, see:
(a) Refs 5 and 8. (b) Arata, Y.; Kobayashi, T. Chem. Pharm. Bull. 1972,
20, 325. (c) Schill, G.; Priester, C. U.; Windhovel, U. F.; Fritz, H.
Tetrahedron 1987, 43, 3747.
G2
G2
G2c
(10) Failed approaches to one-carbon bridged amides include a variety
of strategies. Amide coupling reactions: (a) Ref 9c. Intramolecular SN2
displacement: (b) Smissman, E. E.; Wirth, P. J.; Abernethy, D.; Ayres, J. W.
J. Org. Chem. 1972, 37, 3486. (c) Smissman, E. E.; Ayres, J. W. J. Org.
Chem. 1971, 36, 2407. (d) Smissman, E. E.; Robinson, R. A.; Matuszak,
A. J. J. Org. Chem. 1970, 35, 3823. (e) Brouillette, W. J.; Friedrich, J. D.;
Muccio, D. D. J. Org. Chem. 1984, 49, 3227. Selenium-mediated electro-
philic cyclization: (f) Toshimitsu, A.; Terao, K.; Uemura, S. Tetrahedron
Lett. 1984, 25, 5917. (g) Toshimitsu, A.; Terao, K.; Uemura, S. J. Org.
Chem. 1987, 52, 2018. Claisen condensation: (h) Smissman, E. E.; Wirth,
P. J.; Glynn, D. R. J. Org. Chem. 1975, 40, 281. Direct RCM: (i) Doodeman,
R. University of Amsterdam, 2002. (j) Preston, A. J.; Gallucci, J. C.;
Paquette, L. A. J. Org. Chem. 2006, 71, 6573. (k) Lei, Y. University of
Kansas, 2006 (bond isomerization was observed rather than formation of
strained twisted amides). [2 + 2] cycloaddition: (l) Booker-Milburn, K. I.;
Anson, C. E.; Clissold, C.; Costin, N. J.; Dainty, R. F.; Murray, M.; Patel,
D.; Sharpe, A. Eur. J. Org. Chem. 2001, 8, 1473. Oxidative coupling: (m)
Szostak, M.; Aube´, J. Unpublished results.
HG2
HG2d
HG2e
87b
95b
93b
85b
89b
10 Ts (2a)
8
11 Ns (2b) HG2d
12 Boc (2c) HG2d
13 Cbz (2d) HG2e
5
5
5
16
17
8
a Determined by 1H NMR. b Isolated yields. c With Ti(O-i-Pr)4. d Argon
bubbled through the reaction. e Open to air. G1 ) Grubbs catalyst 1, G2 )
Grubbs catalyst 2, Fu¨rstner ) Fu¨rstner catalyst, HG2 ) Hoveyda-Grubbs
catalyst 2. RCM ) ring-closing metathesis. Ns ) 2-nitrobenzenesulfonyl.
Cbz ) carbobenzyloxy.
most effectively led to the 9-membered heterocycle 3a (Table
1). Use of these conditions allowed synthesis of a series of
analogues containing various amine substitutions, including
(11) For pioneering work, see: (a) Leonard, N. J.; Fox, R. C.; Oki, M.;
Chiavarelli, S. J. Am. Chem. Soc. 1954, 76, 630. For selected examples
from the recent literature, see: (b) Balskus, E. P.; Jacobsen, E. N. Science
2007, 317, 1736. (c) Chandler, C. L.; List, B. J. Am. Chem. Soc. 2008,
130, 6737. (d) Vital, P.; Hosseini, M.; Shanmugham, M. S.; Gotfredsen,
C. H.; Harris, P.; Tanner, D. Chem. Commun. 2009, 14, 1888.
(12) (a) Reference 9c. (b) Bashore, C. G.; Samardjiev, I. J.; Bordner,
J.; Coe, J. W. J. Am. Chem. Soc. 2003, 125, 3268.
(14) For selected reviews, see: (a) Phillips, A. J.; Abell, A. D. Aldrichim.
Acta 1999, 32, 75. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013.
(c) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199. (d) Chatto-
padhyay, S. K.; Karmakar, S.; Biswas, T.; Majumdar, K. C.; Rahaman, H.;
Roy, B. Tetrahedron 2007, 63, 3919. (e) Compain, P. AdV. Synth. Catal.
2007, 349, 1829.
(13) For reviews, see: (a) Maier, M. E. Angew. Chem., Int. Ed. 2000,
39, 2073. (b) Nubbemeyer, U. Top. Curr. Chem. 2001, 216, 125. (c)
Michaut, A.; Rodriguez, J. Angew. Chem., Int. Ed. 2006, 45, 5740. For
selected approaches from the recent literature, see: (d) Kan, T.; Fujiwara,
A.; Kobayashi, H.; Fukuyama, T. Tetrahedron 2002, 58, 6267. (e) David,
O.; Meester, W. J. N.; Bieraugel, H.; Schoemaker, H. E.; Hiemstra, H.;
van Maarseveen, J. H. Angew. Chem., Int. Ed. 2003, 42, 4373. (f) Klapars,
A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004,
126, 3529.
(15) For a review, see: (a) Hoveyda, A. H.; Gillingham, D. G.; Van
Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.; Harrity,
J. P. A. Org. Biomol. Chem. 2004, 2, 8. For recent examples of the use of
Hoveyda-Grubbs catalysts in demanding RCM reactions, see: (b) Brown,
M. K.; Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 12904. (c) Farina,
V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. H.
Org. Process Res. DeV. 2009, 13, 250.
Org. Lett., Vol. 11, No. 17, 2009
3879

readily removable carbamate groups (Table 1, entries 12 and
13).16
Table 2. Synthesis of Bridged Lactams
We now wished to determine whether the desired lactams
could be obtained via direct cyclization of the substrates.
Previously, we had determined that some bicyclic amino
acids analogous to 3 were in equilibrium with their closed
forms (even in water) but that the hydrolysis reactions were
irreversible if the medium-sized ring adopted a conformation
with the carboxylic acid in an exo position. In the present
cases, we controlled this through the use of gem-diester
substitution. In the event, deprotection and cyclization of the
Ns precursor could be carried out in a single operation to
deliver 4b under very mild conditions (Scheme 2). Although
yields,
ring system steps 1/2 (%) notes
entry series (n, m)
R
1
2
3
4
5
6
7
e (1, 1)
f (1, 2)
g (2, 2)
h (1, 3)
i (3, 1)
j (3, 1)
j (3, 1)
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
[4.2.1]
[5.2.1]
[5.3.1]
[6.2.1]
[4.4.1]
[4.4.1]
[4.4.1]
90/75
94/85
90/64
92/41
79/0
a
b, c
d
76/33
60/86
e
g
Scheme 2. Synthesis of [4.3.1] Lactam
Phf
a Step 2 run for 13 h. b Compound 3g obtained as 5:1 mixture of Z/E
isomers. c Step 2: (i) PhSH, Cs2CO3; (ii) DBU, PhMe, 200 °C, 3 h. d Step
2: (i) PhSH, Cs2CO3; (ii) DBU, PhMe, 180 °C, 12 h. e Step 2: (i) PhSH,
Cs2CO3; (ii) DBU, PhMe, 220 °C, 10 h. f PhO2C instead of MeO2C. g Step
2 run at 110 °C for 16 h.
the medium-sized rings save one (entry 3) were obtained as
exclusive cis double bond isomers. This study provides very
rare examples of the successful use of catalytic RCM in the
formation of 9- and 10-membered nitrogen-containing ring
systems with minimal conformational constraints.17 Further-
more, the cyclization of the medium ring amino diesters to
bridged lactams proved gratifyingly general. Although the
cyclization of compound 3g proved sluggish under our
initially identified conditions, the [5.3.1] twisted amide could
be generated by treatment with DBU after deprotection (entry
3). While malonate could not be applied for preparation of
the [4.4.1] system (entry 5) due to competing decarboxyla-
tion, use of the phenyl acetate (entry 6) allowed for
preparation of the desired compound, albeit in a conservative
yield. The experiment in entry 7 was performed to explore
the effect of leaving group on cyclization reaction. Replacing
methoxide with phenoxide dramatically improved the yield
of the transannular cyclization, delivering lactam 4j in 86%
yield.
this material showed modest sensitivity to flash chromatog-
raphy, it could be isolated in ca. 50% yield after PTLC.
We have also determined that the Boc precursor 3c could
be utilized for preparation of twisted amides (Scheme 3, top).
Scheme 3. Synthesis from Orthogonally Protected Systems
Several methods to prepare saturated lactams were also
investigated (Table 3). This normally straightforward process
was complicated by the tendency of some twisted amides to
undergo unusual C-N cleavage reaction under mild hydro-
genolysis conditions.6 Thus, when twisted amides prepared
in the current study were treated with standard hydrogenoly-
sis conditions, [4.3.1] and [4.4.1] scaffolds showed the
highest reactivity, participating in C-N cleavage to the
corresponding monocyclic amides (Table 3; entries 1 and
2), while [4.2.1], [5.2.1], [5.3.1], and [6.2.1] twisted amides
were less reactive, undergoing only traditional reduction to
In contrast, the use of Cbz derivatives could be problematic.
Deprotection and cyclization of 3d (Scheme 3, bottom)
proceeded smoothly, but the twisted amide proved to be
unstable to the hydrogenation conditions, giving piperidone
4d by C-N ring cleavage.6
The sequential RCM/transannular cyclization strategy was
extended to a series of dienes, thus providing a systematic
series of twisted lactam ring systems (Table 2). In general,
the RCM reactions proceeded in very good yields. All of
(17) For selected examples of RCM reactions in the formation of 9-
and 10-membered nitrogen-containing ring systems, see: (a) Bamford, S. J.;
Goubitz, K.; van Lingen, H. L.; Luker, T.; Schenk, H.; Hiemstra, H. J. Chem.
Soc., Perkin Trans. 1 2000, 3, 345. (b) Fu¨rstner, A.; Guth, O.; Duffels, A.;
Seidel, G.; Liebl, M.; Gabor, B.; Mynott, R. Chem.sEur. J. 2001, 7, 4811.
(c) Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin, K.; Lannou,
M. I.; Runsink, J.; Raabe, G. J. Org. Chem. 2005, 70, 10538.
(16) For selected examples of RCM reactions influenced by the presence
of carbamate or ester functionalities, see: (a) Campagne, J. M.; Ghosez, L.
Tetrahedron Lett. 1998, 39, 6175. (b) Brouwer, A. J.; Liskamp, R. M. J. J.
Org. Chem. 2004, 69, 3662. (c) Fu¨rstner, A.; Langemann, K. J. Am. Chem.
Soc. 1997, 119, 9130.
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Org. Lett., Vol. 11, No. 17, 2009

Table 3. Hydrogenation/Hydrogenolysis of Bicyclic Lactams
Table 4. Spectroscopic Properties of Saturated Lactams
lactam
lactam
entry lactam ring system CdO 13C (ppm) IR νCdO (cm-1
)
1
2
3
4
5
6
5e
5f
5h
4c
5g
5j
[4.2.1]
[5.2.1]
[6.2.1]
[4.3.1]
[5.3.1]
[4.4.1]
183.4
180.1
173.4
181.0
176.6
186.3
1716
1693
1685
1679
1647
1643
of twist (Table 4). As expected, several of the ring systems
containing larger rings are able to relax into values closer to
those of analogous fused lactams (entries 3 and 5). We note
that the infrared stretching frequencies cover a range that
begins at that for a “normal” amide (entry 6) and go all the
way to a value that would be expected for a saturated,
“normal” ketone (entry 1). This bodes well for the use of
this suite of compounds for the systematic evaluation of the
effect of amide bond geometry on reactivity. Interestingly,
there is not a perfect correlation between IR stretching
frequencies and 13C NMR carbonyl chemical shifts (also
noted by Yamada18), suggesting that subtle electronic effects
beyond bond angle likely effect these parameters.
In summary, a sequential RCM/transannular cyclization
strategy has been developed that provides access to an
expanded family of one-carbon bridged lactams. This route
highlights the rapid assembly of previously inaccessible,
functionalized ring systems from readily available starting
materials. The mild conditions for the transannular cycliza-
tion allow for isolation of strained amides by a route similar
to classical amide bond formation but facilitated by close
proximity of the reactive functionalities. Work is currently
underway on further development of this methodology and
its application to the synthesis of a whole gamut of twisted
amides. As already exemplified by hydrogenolysis reactions,
this in turn will allow for the systematic study of strain
influence on chemical and biological properties of amide
bonds.
a Only products of hydrogenation of corresponding unsaturated lactams
4e-h shown.
the saturated analogues (entry 3; only products shown). As
expected, allylic olefins are more susceptible to hydrogenoly-
sis than isolated bonds. Interestingly, when hydrogenation
of [4.4.1] scaffold was carried out in the presence of
Willkinson’s catalyst, the amide bond remained intact and
the saturated amide was obtained in high yield (entry 4).
One goal of the present project is to obtain a series of
varied ring systems to allow systematic exploration of the
effect of amide twist on chemical and spectroscopic proper-
ties. For example, nonplanar amides often display spectral
features consistent with less “amide-like” and greater “ketone-
like” nature of the carbonyl group.18 Although the medium-
bridged lactams prepared herein do not contain perfectly
orthogonal Nlone pair-carbonyl groupings, most of the ring
systems prepared here show substantially higher 13C chemical
shifts for the carbonyl carbon and higher carbonyl stretches
in the infrared spectra, consistent with a substantial degree
Acknowledgment. This work was supported by the
National Institute of General Medical Sciences (GM-49093).
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) Yamada, S. ReV. Heteroatom. Chem. 1999, 19, 203.
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