Asymmetric radical and anionic cyclizations of axially chiral carbamates

Article abstract of DOI:10.1021/ol802616u

Standard Boc, Alloc, and Cbz derivatives of N-2,4-dimethyl-6-iodophenyl-N- allyl anilines are axially chiral and can be readily resolved into atropisomers whose racemization barriers exceed 30 kcal/mol. The resolved axially chiral carbamates undergo radic

Full text of DOI:10.1021/ol802616u

ORGANIC
LETTERS
2009
Vol. 11, No. 1
249-251
Asymmetric Radical and Anionic
Cyclizations of Axially Chiral
Carbamates†
David B. Guthrie and Dennis P. Curran*
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
curran@pitt.edu
Received November 12, 2008
ABSTRACT
Standard Boc, Alloc, and Cbz derivatives of N-2,4-dimethyl-6-iodophenyl-N-allyl anilines are axially chiral and can be readily resolved into
atropisomers whose racemization barriers exceed 30 kcal/mol. The resolved axially chiral carbamates undergo radical and anionic cyclizations
with high levels of chirality transfer from the N-Ar axis to the new stereocenter in the substituted dihydroindole products. The carbamate
groups of the products are readily removed.
Axially chiral amides have emerged as valuable substrates for
diverse classes of stereocontrolled reactions.1 In particular,
axially chiral anilides like 1 and 3 are accessible in highly
enantioenriched form and often show very high levels of
chirality transfer in radical cyclizations to provide products 2
and 4 (Figure 1).2 In each of these cyclizations, the chiral axis
in the precursor is erased, yet its configuration is preserved in
the new stereocenter of the product. High chirality transfer has
also been recorded in Heck reactions of axially chiral anilides
related to 1.3 Recently, axially chiral diarylureas and diarylethers
have also been synthesized and studied.4
† We dedicate this paper to Professor Larry Overman on the occasion of
his 65th birthday.
(1) (a) Curran, D. P.; Qi, H.; Geib, S. J.; DeMello, N. C. J. Am. Chem.
Soc. 1994, 116, 3131–3132. (b) Clayden, J. Tetrahedron 2004, 60, 4335.
and subsequent articles in this Symposium-in-Print. (c) Zhao, H. W.; Hsu,
D. C.; Carlier, P. R. Synthesis 2005, 1–16.
(2) (a) Curran, D. P.; Liu, W. D.; Chen, C. H.-T. J. Am. Chem. Soc.
1999, 121, 11012–11013. (b) Ates, A.; Curran, D. P. J. Am. Chem. Soc.
2001, 123, 5130–5131. (c) Curran, D. P.; Chen, C. H. T.; Geib, S. J.;
Lapierre, A. J. B. Tetrahedron 2004, 60, 4413–4424. (d) Lapierre, A. J. B.,
PhD Thesis, University of Pittsburgh, 2005: http://etd.library.pitt.edu/ETD/
available/etd-11292005-113044/.
Figure 1
. Radical cyclizations of axially chiral amides occur more
rapidly than racemization by N-Ar bond rotation.
10.1021/ol802616u CCC: $40.75
Published on Web 12/04/2008
2009 American Chemical Society

Cyclizations of substrates like 3 might have value in synthesis
of chiral dihydroindoles (indolines) and related molecules, but
the flexibility of the downstream chemistry is limited because
the amide substituent of products like 4 can be difficult to
remove. Herein we report that attractive intermediates bearing
standard carbamate protecting groups on nitrogen can be
accessed with high stereoselectivity through radical and anionic
reactions of axially chiral carbamates.
Although rotation barriers for several o-substituted N-aryl
carbamates have been measured5a,b and a stable carbamate
atropisomer has recently been reported,5c to the best of our
knowledge, these are the first asymmetric reactions of axially
chiral carbamates. They are also the first examples of chirality
transfer from an N-Ar axis to a stereocenter in an anionic
cyclization.
Racemic substrates 5a-c bearing N-allyloxycarbonyl (Alloc),
N-tert-butyloxycarbonyl (Boc), and N-benzyloxy-carbonyl
(Cbz) groups were readily prepared and resolved into their
enantiomeric components by preparative chiral HPLC (see
Supporting Information).6 We expected that the carbamates
might have lower rotation barriers than analogous amides
because alkoxy groups are smaller than alkyl groups by most
measures of size, including a measure based on biaryl rotation.7
However, the resolved enantiomers of 5 were quite stable at
room temperature during extended storage. Convenient race-
mization rates were accessed by heating samples in 90/10
hexane/isopropanol in sealed tubes at 115 °C. Rotation barriers
were measured in the usual way and are shown in Figure 2.
The yields and levels of chirality transfer in the radical and
anionic cyclizations of substrates 5a-c are summarized in Table
1. The radical cyclizations were conducted in benzene at
ambient temperature by a standard procedure with tributyltin
hydride (0.01 M) as the reductant and triethylborane as the
initiator (conditions “R”). The yields of isolated, purified
products 6a-c were generally excellent (86-97%). The enan-
tiomeric ratios of both the precursors and the products were
assessed by chiral HPLC analysis to provide the level of chirality
transfer of about 90%. This is comparable to the levels of
chirality transfer typically observed in radical cyclizations of
axially chiral amides like 3.2c,d
Anionic cyclizations of 5 were conducted at -98 °C with
n-BuLi and TMSCl in THF/ether/hexane (conditions “A”)8
without compromising either the carbamate or the ester func-
tionalities. After standard workup and purification, the isolated
yields of the products 6 were somewhat lower than in the radical
reactions (68-74%); however, the levels of chirality transfer
were even higher (>90%). In each case, a given enantiomer of
the precursor 5 produced the same major enantiomer of the
product 6 in both the radical and organolithium cyclizations.
The anionic cyclization conditions proved quite general, and
seven other cyclizations of racemic or achiral carbamates are
described in the Supporting Information.
Removal of the carbamate groups from S-6a-c under
standard conditions (see Supporting Information) yielded
the same enantiomer S-7 as assessed by chiral HPLC
(Scheme 1). These experiments demonstrate the facile
Scheme 1
.
Assignments of Product Configurations By
Correlation
Figure 2. Structures and rotation barriers of axially chiral carbam-
ates 5.
These barriers (∼32 kcal/mol) are comparable to axially chiral
amides bearing alkyl groups on the carbonyl carbon atom and
larger than amides bearing aryl groups.2 The surprisingly high
barriers are convenient for handling (t1/2 for racemization at 25
°C is several centuries) and for onward axial chirality transfer
applications. For comparison, carbamates related to 5 but lacking
the ortho-methyl group have a rotation barrier of about 19 kcal/
mol (t1/2 for racemization at 25 °C is a few seconds).4a,b
removal of the nitrogen substituent and show that the sense
of chirality transfer is the same for all three different
(5) (a) Juliá, S.; Ginebreda, A.; Sala, P.; Sancho, M.; Annunziata, R.;
Cozzi, F. Org. Magn. Res. 1983, 21, 573–575. (b) See compound 4b in ref
4a. The stable atropisomeric carbamate is compound 3df in: (c) Tanaka,
K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006, 128, 4586–4587.
(6) In addition to N-Ar rotation, precursors 5 existed as rotamers about
the carbamate N-CO bond in ratios 2.5-5.0/1 according to NMR
spectroscopic analysis. The NMR spectra of the products did not show
evidence for carbamate rotamers.
(3) Lapierre, A. J. B.; Geib, S. J.; Curran, D. P. J. Am. Chem. Soc. 2007,
129, 494–495.
(4) (a) Adler, T.; Bonjoch, J.; Clayden, J.; Font-Bard´ıa, M.; Pickworth,
M.; Solans, X.; Sole´, D.; Vallverdu´, L. Org. Biomol. Chem. 2005, 3, 3173–
3183. (b) Betson, M. S.; Bracegirdle, A.; Clayden, J.; Helliwell, M.; Lund,
A.; Pickworth, M.; Snape, T. J.; Worrall, C. P. Chem. Commun. 2007, 754–
756. (c) Clayden, J.; Turner, H.; Helliwell, M.; Moir, E. J. Org. Chem.
2008, 73, 4415–4423.
(7) Bott, G.; Field, L. D.; Sternhell, S. J. J. Am. Chem. Soc. 1980, 102,
5618–5626.
250
Org. Lett., Vol. 11, No. 1, 2009

Table 1. Radical and Anionic Cyclizations of Axially Chiral Carbamates
entry
sm
er 5
conda
prod
yieldb
er 6
ctc
1
2
3
4
5
6
7
8
P-5a
P-5a
M-5a
M-5a
P-5b
P-5b
M-5b
M-5b
P-5c
P-5c
M-5c
M-5c
99/1
99/1
87/13
87/13
99/1
R
A
R
A
R
A
R
A
R
A
R
A
S-6a
S-6a
R-6a
R-6a
S-6b
S-6b
R-6b
R-6b
S-6c
S-6c
R-6c
R-6c
97%
67%
100%
70%
87%
72%
91%
72%
93%
74%
97%
71%
92/8
98/2
93
99
86
94
87
91
91
93
92
98
87
92
75/25
82/18
86/14
90/10
82/18
81/19
91/9
97/3
77/23
82/18
99/1
90/10
87/13
99/1
99/1
89/11
89/11
9
10
11
12
a R ) radical: Bu3SnH, Et3B, C6H6, rt; A ) anionic: n-BuLi, TMSCl, THF/ether/hexane, -98 °C. b Isolated yield after flash chromatography. c ct )
chirality transfer, the percentage of major enantiomer of the product expected from an enantiopure sample of the precursor.
carbamate precursors. To assign the absolute configura-
tion of the products, the ester of S-6a was hydrolyzed,
and the resulting acid was subjected to Barton decarboxy-
lation.9 Palladium-catalyzed removal of the Alloc group
followed by benzoylation provided a sample of S-8
whose configuration was assigned by comparison
(rotation, chiral HPLC retention time) with an authentic
sample.2c,2d
To assign the configuration ofl the precursors 5, we rely on
the similarities between the new carbamate and prior anilide
radical cyclizations. The radical cyclization of M-3 is known
to give R-4 (Figure 1).2c,2d Assuming the same sense of radical
cyclization with 5, it follows that the precursor to R-6 must be
M-5 while S-6 comes from P-5.
The high levels of transfer of axial chirality of 5 to the
new stereocenter of 6 show that the cyclizations are faster
than rotation of an intermediate radical or anion around
the N-Ar bond axis. This lack of rotation is necessary
but not sufficient for chirality transfer because the alkene
has two diastereotopic faces in the transition state that
lead to enantiomeric products after the chiral axis is erased.
Thus, the results also require a face-selective cyclization.
Figure 3 shows the proposed favored and disfavored
transition states for the radical and anionic cycliza-
tions.2c
Figure 3. Transition state models for chirality transfer in radical
and anionic cyclizations. The anionic TS is simplified by omitting
lithium.
The synthetic value of the products 6 in Table 1 is somewhat
limited since they all bear an ortho-Me group that is used to
lock out rotation in the atropisomers 5. However, by analogy
to anilide radical cyclizations, it should be possible to conduct
cyclizations with substrates bearing other ortho substituents,
including removable ones,10 or even with no ortho substitu-
ents.11 Thus, the method has good potential for extension to
make diverse chiral dihydroindoles. The features of high rotation
barrier, high chirality transfer, and ease of removal of the
N-substituent unite to make axially chira carbamates valuable
precursors for radical, anionic, and presumably other types of
transformations.
Acknowledgment. We thank the National Science Founda-
tion for funding this work.
(8) (a) Ko¨brich, G.; Trapp, H. Chem. Ber. 1966, 99, 670–679. (b) Horne,
S.; Taylor, N.; Collins, S.; Rodrigo, R. J. Chem. Soc., Perkin Trans. 1 1991,
3047–3051.
Supporting Information Available: Contains experimental
procedures, complete compound characterization, and additional
examples of anionic cyclizations. This material is available free
of charge via the Internet at http://pubs.acs.org.
(9) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985,
41, 3901–3924.
(10) Petit, M.; Geib, S. J.; Curran, D. P. Tetrahedron 2004, 60, 7543–
7552.
(11) Petit, M.; Lapierre, A. J. B.; Curran, D. P. J. Am. Chem. Soc. 2005,
127, 14994–14995.
OL802616U
Org. Lett., Vol. 11, No. 1, 2009
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