Cation-n control of regiochemistry of intramolecular schmidt reactions en route to bridged bicyclic lactams

Article abstract of DOI:10.1021/ol901771b

The regiochemistry of the intramolecular Schmidt reaction of 2-azidoalkylketones is controlled by placing a thioether substituent at the position adjacent to the ketone to provide access to a family of unsubstituted medium bridged twisted amides. This out

Full text of DOI:10.1021/ol901771b

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4386-4389
Cation-n Control of Regiochemistry of
Intramolecular Schmidt Reactions en
Route to Bridged Bicyclic Lactams
Michal Szostak, Lei Yao, 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 July 31, 2009
ABSTRACT
The regiochemistry of the intramolecular Schmidt reaction of 2-azidoalkylketones is controlled by placing a thioether substituent at the position
adjacent to the ketone to provide access to a family of unsubstituted medium bridged twisted amides. This outcome is ascribed to the
presence of stabilizing through-space interactions between the diazonium cation and the n electrons on heteroatom and does not require a
locked conformation of the ketone.
Bridged lactams, in which the amide bond deviates consider-
ably from planarity, display properties divergent from
traditional amides and are of interest from structural and
reactivity perspectives.1,2 The importance of distorted amides
in cis/trans isomerization of peptide bonds has also been
established.3 However, the synthesis of bridged amides is
complicated by hyperreactivity of such amide bonds and their
tendency to undergo rapid hydrolysis.4
Recently, we have reported the utility of an intramolecular
Schmidt reaction to the problem of one-carbon bridged
lactam synthesis.5 Although intramolecular Schmidt reactions
of R-substituted ketones almost always afford fused lactams
by migration of the bond proximal to the azide (Figure 1a,
path a),6,7 it proved possible to reverse the regiochemistry
of the reaction to afford bridged isomers (Figure 1a, path b)
by a combination of two effects: (1) axial orientation of the
azide-containing tether and (2) favoring a specific orientation
+
(1) For twisted amide reviews, see: (a) Hall, H. K.; Elshekeil, A. Chem.
ReV. 1983, 83, 549. (b) Lease, T. G.; Shea, K. J. AdVances in Theoretically
Interesting Molecules; JAI Press Inc., 1992; Vol. 2, p 79. (c) Greenberg,
A. The Amide Linkage: Structural Significance in Chemistry, Biochemistry,
and Materials Science; Greenberg, A., Breneman, C. M., Liebman, J. F.,
Eds.; Wiley-Interscience, 2000; p 47. (d) Clayden, J.; Moran, W. J. Angew.
of the N2 leaving group by engineering a stabilizing
(3) (a) Shao, H.; Jiang, X.; Gantzel, P.; Goodman, M. Chem. Biol. 1994,
1, 231. (b) Fischer, G.; Schmid, F. X. Molecular Chaperones and Folding
Catalysts: Regulation, Cellular Functions and Mechanisms; Bakau, B., Ed.;
CRC, 1999; p 461. (c) Schmid, F. X. Protein Folding in the Cell; 2002;
Vol. 59, p 243. (d) Fischer, G. Chem. Soc. ReV. 2000, 29, 119.
Chem., Int. Ed. 2006, 45, 7118
.
(2) For selected examples see: (a) Kirby, A. J.; Komarov, I. V.; Feeder,
N. J. Chem. Soc., Perkin Trans. 2 2001, 522. (b) Bashore, C. G.; Samardjiev,
I. J.; Bordner, J.; Coe, J. W. J. Am. Chem. Soc. 2003, 125, 3268. (c) Lei,
Y.; Wrobleski, A. D.; Golden, J. E.; Powell, D. R.; Aube´, J. J. Am. Chem.
Soc. 2005, 127, 4552. (d) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731.
(e) Ribelin, T. P.; Judd, A. S.; Akritopoulou-Zanze, I.; Henry, R. F.; Cross,
J. L.; Whittern, D. N.; Djuric, S. W. Org. Lett. 2007, 9, 5119. (f) Williams,
R. M.; Lee, B. H.; Miller, M. M.; Anderson, O. P. J. Am. Chem. Soc. 1989,
111, 1073. (g) Lease, T. G.; Shea, K. J. J. Am. Chem. Soc. 1993, 115,
2248. For ab initio studies, see: (h) Greenberg, A.; Venanzi, C. A. J. Am.
Chem. Soc. 1993, 115, 6951. (i) Greenberg, A.; Moore, D. T.; DuBois,
(4) (a) Somayaji, V.; Brown, R. S. J. Org. Chem. 1986, 51, 2676. (b)
Brown, R. The Amide Linkage: Structural Significance in Chemistry,
Biochemistry, and Materials Science; Greenberg, A., Breneman, C. M.,
Liebman, J. F., Ed.; Wiley-Interscience, 2000; p 85. (c) Mujika, J. I.;
Mercero, J. M.; Lopez, X. J. Am. Chem. Soc. 2005, 127, 4445. (d) Szostak,
M.; Yao, L.; Aube´, J. J. Org. Chem. 2009, 74, 1869.
(5) Yao, L.; Aube´, J. J. Am. Chem. Soc. 2007, 129, 2766.
(6) For reviews, see: (a) Nyfeler, E.; Renaud, P. Chimia 2006, 60, 276.
(b) Lang, S.; Murphy, J. A. Chem. Soc. ReV. 2006, 35, 146. (c) Grecian,
S.; Aube´, J. Organic Azides: Syntheses and Applications; Bra¨se, S., Banert,
T. D. J. Am. Chem. Soc. 1996, 118, 8658
.
K., Eds.; John Wiley and Sons: New York, 2009.
10.1021/ol901771b CCC: $40.75
Published on Web 09/01/2009
 2009 American Chemical Society

of intramolecular Schmidt reactions involves formation of
chairlike azidohydrins followed by the selective migration
of the C-C bond antiperiplanar to the leaving diazonium
group.9b In this scenario, a bridged lactam can be obtained
only when the azide-containing chain occupies a pseudoaxial
orientation (see Supporting Information for details of this
published argument). Accordingly, we hypothesize that
lactam 2a is formed from the azidohydrin 4a (Scheme 1,
box) in which a stabilizing electrostatic 1,3-diaxial interaction
between the cation and thiomethyl groups becomes possible.
Figure 1. (a) Regiochemical options for the intramolecular Schmidt
Table 1. Synthesis of Bridged and Fused Lactams
reaction of R-substituted ketones. (b) Formation of bridged amides
and proposed intermediate leading to the major isomer.5
cation-π interaction8 into the key azidohydrin intermediate
(Figure 1b).
Herein, we report that the presence of an R-heteroatomic
group can also direct the regiochemistry of the intramolecular
Schmidt reaction toward path b (Figure 1). This stabilization
obviates the necessity for the locked conformation of the
reactive azidohydrin intermediate, significantly expanding the
utility of Schmidt reaction in the synthesis of one-carbon
bridged lactams. In addition, we provide explicit experimen-
tal confirmation that the regiochemistry of these reactions
depends on whether the azide-containing tether occupies an
axial or equatorial position.
entry azide
R1
R2 2:3 ratioa yield (%)b
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
SMe
H
80:20
86:14
>5:95
>5:95
>5:95
87:13
80
74
75
85
96
75
SMe, trans
SMe, cis
Hc
t-Bu
t-Bu
H
Phd
H
4-(MeO)C6H4, transd t-Bu
a
Determined by H NMR of the crude reaction mixture. b Combined
1
yield, see Supporting Information for full experimantal details. c Ref 9, TFA
instead of TfOH. d Ref 5, MeAlCl2 instead of TfOH.
Control experiments demonstrated that the axial orientation
of the azide-containing side-chain is required for the forma-
tion of bridged lactams (Table 1, entries 2 and 3) and that
the use of thiomethyl is crucial to the outcome of the reaction
(entries 1, 4, and 5). The selectivity observed with the
conformationally locked azide 1b equals the highest selectiv-
ity for a bridged isomer obtained in the previous study (cf.
entries 2 and 6). Thus, it appears that the R-thiomethyl effect
is comparable to those arising from cation-π interactions
as previously reported.5 However, a significant remarkable
advantage is that the thiomethyl-containing substrate does
not require an additional conformational constraint (entries
1 and 6), allowing for the synthesis of otherwise unsubstituted
bridged lactams.
Scheme 1
The first example of an intramolecular Schmidt reaction
to afford a bridged bicyclic lactam without relying on the
locked conformation of cyclohexanone was encountered
when a thiomethyl was placed in the R position to the ketone
(Scheme 1).4d We orginally proposed that the mechanism
The proposed reactive intermediates are shown in Scheme
2. The fact that the trans isomer 1b leads primarily to the
bridged product while the cis isomer 1c affords only fused
product provides the first experimental support for the
original hypothesis of the intramolecular Schmidt reaction
requiring the azidoalkyl chain in the axial orientation to give
(7) For selected examples from the recent literature, see: (a) Frankowski,
K. J.; Golden, J. E.; Zeng, Y. B.; Lei, Y.; Aube´, J. J. Am. Chem. Soc.
2008, 130, 6018. (b) Iyengar, R.; Schildknegt, K.; Morton, M.; Aube´, J. J.
Org. Chem. 2005, 70, 10645. (c) Wrobleski, A.; Sahasrabudhe, K.; Aube´,
J. J. Am. Chem. Soc. 2004, 126, 5475. (d) Lertpibulpanyaa, D.; Marsden,
S. P. Org. Biomol. Chem. 2006, 4, 3498. (e) Zhao, Y. M.; Gu, P.; Zhang,
H. J.; Zhang, Q. W.; Fan, C. A.; Tu, Y. Q.; Zhang, F. M. J. Org. Chem.
2009, 74, 3211.
(8) For reviews, see: (a) Dougherty, D. A. Science 1996, 271, 163. (b)
Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97, 1303. (c) Yamada, S.
Org. Biomol. Chem. 2007, 5, 2903. For selected examples, see: (d) Katz,
C. E.; Aube´, J. J. Am. Chem. Soc. 2003, 125, 13948. (e) Katz, C. E.; Ribelin,
T.; Withrow, D.; Basseri, Y.; Manukyan, A. K.; Bermudez, A.; Nuera, C. G.;
Day, V. W.; Powell, D. R.; Poutsma, J. L.; Aube´, J. J. Org. Chem. 2008,
73, 3318. (f) Monje, P.; Paleo, M. R.; Garcia-Rio, L.; Sardina, F. J. J. Org.
Chem. 2008, 73, 7394. (g) Ishihara, K.; Fushimi, N.; Akakura, M. Acc.
Chem. Res. 2007, 40, 1049.
(9) (a) Aube´, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965.
(b) Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem. Soc. 1995,
117, 10449. (c) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang,
W. K.; Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183. (d) Smith,
B. T.; Gracias, V.; Aube´, J. J. Org. Chem. 2000, 65, 3771. For examples
of Schmidt reaction involving 4-C tether, see: (e) Gracias, V.; Zeng, Y.;
Desai, P.; Aube´, J. Org. Lett. 2003, 5, 4999. (f) Smith, B. T.; Wendt, J. A.;
Aube´, J. Org. Lett. 2002, 4, 2577. (g) Ref 7c. For examples of Schmidt
reaction involving 8- and larger rings, see: ref 9b.
Org. Lett., Vol. 11, No. 19, 2009
4387

Scheme 2
Table 2. Effect of Substituents and Ring Sizes on Synthesis of
Bridged and Fused Lactams
yield (%)
entry
azide
XR
n
m
2
3
4
1
2
3
4
5
6
7
8
1a
1g
1h
1i
1j
1k
1l
SMe
SPh
1
1
1
1
0
2
3
1
1
1
1
1
1
1
1
2
65
35
23
48
-
62
-
-
15
32
52a
13a
43
11a
-
-
-
-
-
-
20
30
53
OMe
SO2Me
SMe
SMe
SMe
SMe
1m
-
a Combined yield of elimination products;11 see Supporting Information
for full details.
a cation-π component cannot be excluded. It is not possible
to completely discard a role for migratory aptitude based on
our results. However, the enhanced bridged/fused ratio where
XR ) SMe over analogues containing better electron-
withdrawing groups seems to be more consistent with the
proposed attractive nonbonding effect being responsible.
the bridged lactam.9b Moreover, since azides 1b and 1c are
isomeric, the results cannot be solely explained by electronic
migratory aptitude considerations. We propose that the
bridged isomer 2b is formed due to stabilizing cation-n
interaction favoring the orientation of diazonium cation in
pseudoaxial position in the azidohydrin intermediate. The
effect of the R substituent is shown in the bottom part of
Scheme 2. All of the cyclohexyl-containing substrates lacking
a tert-butyl group are expected to exist in a ground-state
equilibrium between eq-tether and ax-tether, presumably
favoring the former; however, the 2-SMe substrate 1a stands
apart from the others in that the predominant product from
the ring expansion reaction arises from the ax-tether
intermediate.
We also probed the effect of varying heteroatom substit-
uents and ring sizes on the outcome of the reaction (Table
2). Thiophenyl and methoxy groups allowed for the synthesis
of bridged lactams, albeit in lower yield. Sulfur substitution
with either an electron-withdrawing group (entry 2) or a less
polarizable methoxy group (entry 3) led to diminished
amounts of bridged lactams. The low amounts of bridged
lactam with azide 1h were surprising since a methoxy group
proved to be a very effective cation-n stabilizing group in
another type of ring expansion reaction.10 Interestingly, these
reactions were very dependent on the acid used for rear-
rangement suggesting that cation coordination likely has a
profound effect on the product distribution (see Supporting
Information for details). Sulfonyl was also found to be an
efficient directing group (entry 4). However, since in this
case the interaction takes place between cation and oxygen,
Examination of different ring sizes revealed that bridged
lactams are formed efficiently for six- and seven-membered
rings in which the azide is separated from the ring by a three-
carbon tether. Extending the ring size or the tether length
decelerated the reaction, and decomposition of azide to
aldehyde was the only reaction pathway observed (entries 7
and 8). As determined earlier for intramolecular Schmidt
reactions,9 substitution with an electron-withdrawing sub-
stitutent slows down the rate of migration. This is likely why
the Schmidt reaction of the eight-membered ketone (entry
7) or the 4-carbon tether (entry 8) is not observed in the
current case.9d-g
Thiomethyl is a valuable synthetic handle,12 and we used
it to obtain a family of structurally related bridged amides
(Scheme 3). Noteworthy is the chemoselective oxidation of
thiomethyl in the presence of sensitive twisted amide
functionalities (5, 6, 8), reductive thiomethyl removal
proceeding with generation of a bridgehead radical (7), and
isolation of the bridged amide 9 containing also a bridgehead
olefin in the same functionality.
(11) From 3b, N-acyl iminium ion is formed, followed by deprotonation
or hydrolysis in ca. 1:1 ratio. Similar reactions are observed with 3i and
3k. An analogous ring opening has been observed earlier: Forsee, J. E.;
Aube´, J. J. Org. Chem. 1999, 64, 4381
(10) Ribelin, T.; Katz, C. E.; English, D. G.; Smith, S.; Manukyan, A. K.;
Day, V. W.; Neuenswander, B.; Poutsma, J. L.; Aube´, J. Angew. Chem.,
Int. Ed. 2008, 47, 6233.
(12) Block, E. The Chemistry of Ethers, Crown Ethers, Hydroxyl Groups
and Their Sulphur Analogues; Patai, S., Ed.; Wiley: New York, 1980; p
539.
4388
Org. Lett., Vol. 11, No. 19, 2009

(1) participation of intermediates subjected to nonbonding
through-space interactions and (2) efficient synthesis of
previously unattainable bridged amides lacking a conforma-
tional control feature like a tert-butyl group. This laboratory
is currently enagaged in extending the concept of cation-n
stabilization in synthesis and the study of the unusual
properties of medium-bridged twisted amides.
Scheme 3a
a Conditions: 5 (n ) 2), mCPBA (1.0 equiv), 72%. 6 (n ) 1), mCPBA
(2.0 equiv), 67%. 7 (n ) 2), Raney Ni, 86%. 8 (n ) 2), NCS, 58%. 9 (n
) 2), i. mCPBA (1.0 equiv), ii. 110 °C, 72 h, 36%.
Acknowledgment. This work was supported by the
National Institute of General Medical Sciences (GM-49093).
The authors thank Dr. Kevin Frankowski (University of
Kansas) for reading the manuscript.
Overall, we have demonstrated that the regiochemistry of
the intramolecular Schmidt reaction is amenable to control
by the addition of certain heteroatom-containing groups and
propose that this phenomenon is due to electrostatic cation-n
interactions. The significant features of this chemistry include
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.
OL901771B
Org. Lett., Vol. 11, No. 19, 2009
4389