Enantioselective deprotonative ring contraction of N1-Methyl-N4-Boc-benzo[e][1,4]diazepine-2,5-diones

Article abstract of DOI:10.1021/ol502586n

N1-Methyl-N4-Boc-benzo[e][1,4]diazepine-2,5-diones were prepared in good yield and high stereochemical purity from five amino acids. Upon deprotonation, these compounds undergo ring contraction to the corresponding quinolone-2,4-diones with high enantioselectivity, providing efficient entry to a potentially useful drug scaffold. Mechanistic commentary and comparisons to related reactions are provided.

Full text of DOI:10.1021/ol502586n

Letter
pubs.acs.org/OrgLett
Enantioselective Deprotonative Ring Contraction of
N1‑Methyl‑N4‑Boc-benzo[e][1,4]diazepine-2,5-diones
Stephanie A. Antolak, Zhong-Ke Yao, Gary M. Richoux, Carla Slebodnick, and Paul R. Carlier*
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061, United States
*
S Supporting Information
ABSTRACT: N1-Methyl-N4-Boc-benzo[e][1,4]diazepine-
,5-diones were prepared in good yield and high stereo-
2
chemical purity from five amino acids. Upon deprotonation,
these compounds undergo ring contraction to the correspond-
ing quinolone-2,4-diones with high enantioselectivity, provid-
ing efficient entry to a potentially useful drug scaffold.
Mechanistic commentary and comparisons to related reactions
are provided.
enzo[e][1,4]diazepin-2,5-diones feature prominently in
axially chiral enolate. Recently Dewynter reported that
deprotonation of a Val-derived (S)-3b in the absence of an3
electrophile resulted in enantioselective ring contraction to 4b.
Interestingly, LiHMDS and KHMDS were found to give
enantiomeric products, in 86% and 62% ee, respectively. This
ring contraction constitutes an example of the acyl-amino
1
B
medicinal chemistry, and we have previously reported
enantioselective synthetic methods to increase available
2
diversity within this scaffold. Deprotonation of Pro-derived
(
S)-1a at −100 °C in the presence of carbon electrophiles gives
quaternary benzodiazepine-2,5-diones such as (R)-2a in high
yield and enantiomeric excess (Scheme 1). If this reaction is
performed at a warmer temperature (−78 °C), racemic 2a is
obtained, suggesting the intermediacy of a quickly racemizing,
4
variant of the Chan reaction, and a related transformation of a
benzodiazepine-2,5-dione affording achiral products has been
5
recently disclosed. We were intrigued by the enantiodivergent
paths taken by the Li and K enolates derived from (S)-3b, as
2
Scheme 1. Enantioselective Deprotonation/Alkylation and
Deprotonative Ring-Contraction Reactions of
Benzo[e][1,4]diazepin-2,5-diones
well as the potential usefulness of 3,3-disubstituted quinoline-
3
6
2,4-diones such as 4b as drug scaffolds. Unfortunately, (S)-3b
was the only substrate investigated in this reaction. Whereas
Val-derived (S)-5b was easily transformed to the N1, N4-di-Boc
derivative (S)-3b, the same transformation was not possible
with substrates derived from L-Ala, Ile, Phe, and phenylglycine;
in these reactions only mono- and tri-Boc derivatives 6 and 7
3
were obtained.
To improve the scope and enantioselectivity of this
deprotonative ring contraction we explored replacing the N1-
Boc substituent of the ring-contraction substrates with an alkyl
group. Based on the proposed mechanism of the acylamino
4b
variant of the Chan reaction, only N4 would require
activation by an acyl group to facilitate the desired ring
contraction. Thus, L-Val, Ala, Met, Leu, and Phe were reacted
with N-methylisatoic anhydride 8 in acetic acid at reflux,
affording N1-Me benzo[e][1,4]diazepin-2,5-diones (S)-9b−f
(
Scheme 2). Partial racemization occurred in these reactions,
and the moderate to good yields reported for 9b−f reflect
recrystallization to improve enantiomeric enrichment. This
strategy worked well for all compounds except 9f, which was
not highly crystalline; in this case final enantiomeric enrichment
was carried out by recrystallizing the N4-Boc derivative 10f.
Received: September 3, 2014
Published: September 23, 2014
©
2014 American Chemical Society
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Organic Letters
Letter
Scheme 2. Preparation of Ring-Contraction Reaction
Substrates (S)-10b−f
Figure 2. Conformational isomerism in 10. Axial chirality descriptors
(
M)- and (P)- are determined by the sign of the C2−N1−C10−C11
7c
dihedral.
Consistent with this proposal, NMR spectroscopy of (S)-
0c−f at 0 °C accomplished decoalescence, demonstrating
1
doubling of most nuclei in each compound. In addition, X-ray
crystallographic analysis of (S)-10e remarkably shows both
conformers in the unit cell: the R-pseudoequatorial (M)-
conformer is well-resolved, but the R-pseudoaxial (P)-isomer is
partly disordered (Figure 3).
Interestingly, in the case of Met-derived 9d, the racemate
crystallized out of solution, and the enantiomerically pure
material remained in solution. Installation of a single Boc group
on (S)-9b−f was not problematic, and derivatives (S)-10b−f
were prepared in moderate to excellent yields and in 94 to
>
99% ee.
The NMR spectra of (S)-9b−f are easily interpreted and are
consistent with one predominant conformation. Based on our
previous studies of 3-substituted benzodiazepine-2-ones, we
7
expected the C3-substituent to adopt a pseudoequatorial
orientation, and X-ray crystallography demonstrates this
conformation for (±)-9d (Figure 1). In contrast, with the
Figure 3. Anisotropic ellipsoid drawing (50%) of (S)-10e. Both (M)-
and (P)-conformations are present in the unit cell, with the i-Bu
substituents in the pseudoequatorial and pseudoaxial positions,
respectively. Except at C3, hydrogens are omitted for clarity. The
(
P)-conformer (right) is partly disordered: the major (66%)
orientation is shown here, and the minor orientation (34%) is
shown in the Supporting Information.
With the desired substrates (S)-10b−f in hand we carried out
deprotonations with LiHMDS and KHMDS in THF (Table 1).
As can be seen, reaction of (S)-10b with both bases gave the
desired ring-contracted product (−)-11b in good yield and
excellent enantioselectivity (98% ee). Furthermore, chiral
stationary phase HPLC indicated that both bases gave the
same major enantiomer, contrary to the published observations
3
of (S)-3b (Scheme 1). This levorotatory product was
crystallized, and anomalous dispersion indicated (R)-config-
uration (Supporting Information). Reactions of (S)-10c−f
proceeded similarly in moderate to good yields and good to
excellent enantioselectivities. Again, in each case, reactions with
LiHMDS and KHMDS gave the same major enantiomer. In the
case of 10c and 10e, KHMDS gave superior enantioselectivity;
for 10f, LiHMDS proved optimum. Only in the case of (S)-10e
(KHMDS, 92% ee) was greater than 95% ee not attained. The
absolute configurations of the products 11c−f derived from
(S)-10c−f are all deduced to be (R)- by analogy, supported by
two additional observations. First, the major enantiomers of
11b−f derived from (S)-10b−f are uniformly first-eluting on
Chiralcel OD HPLC. Second, in each case the sign of optical
rotation of the products conforms to that of the starting
materials.
Figure 1. Anisotropic ellipsoid drawing (50%) of (±)-9d. The left and
right molecules are (R)- and (S)-configured, respectively. Figure
generated using OLEX2.
8
exception of (S)-10b, the room temperature NMR spectra of
the N4-Boc derivatives (S)-10 are broad and often difficult to
interpret. We speculated that these compounds exist as slowly
interconverting mixtures of pseudoaxial and -equatorial con-
formers (Figure 2). We have previously demonstrated such
conformational isomerism in 3,3-disubstituted (“quaternary”)
2b,7
benzodiazepin-2-ones,
and this conformation mobility was
invoked to explain the stereochemical course of ring
3
contractions of related substrate (S)-3b.
5
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Organic Letters
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Table 1. Deprotonative Ring-Contraction Reactions
Scheme 4. Possible Stereochemical Pathways for
Deprotonation of (S)-3b and 10b (Adapted from
3
Dewynter )
entry
substrate
M
product
yield
% ee (config)
a
1
2
3
4
5
6
7
8
9
(S)-(−)-10b
Li
K
(−)-11b
(−)-11b
(+)-11c
(+)-11c
(−)-11d
(−)-11d
(−)-11e
(−)-11e
(−)-11f
(−)-11f
84
84
69
57
91
63
56
58
85
82
98 (R)
a
98 (R)
b
(S)-(+)-10c
(S)-(−)-10d
(S)-(−)-10e
(S)-(−)-10f
Li
K
92 (R)
b
97 (R)
b
Li
K
>99 (R)
b
>99 (R)
b
Li
K
84 (R)
b
92 (R)
b
Li
K
98 (R)
b
1
0
92 (R)
a
The absolute configuration of (−)-11b was established as (R)- by X-
b
ray crystallography (Supporting Information). The products of
rearrangement of (S)-10c−f (11c−f) are assigned an (R)-config-
uration based on HPLC elution order and conformity of optical
rotation (in every case the sign of rotation is preserved from (S)-10b−
f to products 11b−f).
Since the N1-Me, N4-Boc substrates (S)-10b−f gave (R)-
configured ring-contraction products 11b−f regardless of
whether LiHMDS or KHMDS was used, we thought it prudent
to independently confirm the literature reactions of (S)-3b.
Following a slight modification of the original procedure, we
prepared (S)-3b and subjected it to both bases (Scheme 3).
Scheme 3. Confirmation of Enantiodivergent Outcomes in
Reactions of (S)-3b (97% ee) with LiHMDS and KHMDS
Thus, for any given base we would normally expect that
pseudoaxial deprotonation (Path A) to dominate, leading to the
observed invertive course of reaction seen for (S)-3b with
LiHMDS and that for (S)-10b−f with both bases.
3
As reported by Dewynter and co-workers, we found that
deprotonation of (S)-3b with LiHMDS gave (R)-(−)-4b, and
deprotonation with KHMDS gave (S)-(+)-4b. Comparing the
different outcomes of related substrates (S)-3b and (S)-10b
with KHMDS, it is clear the identity of the N1 substituent plays
a major role in the stereochemical course of these reactions.
How can the enantiodivergent outcomes of (S)-3b with
LiHMDS and KHMDS be reconciled with the uniform (R)-
selectivity seen in reactions of (S)-10b−f? In the case of (S)-3b,
Dewynter and co-workers proposed that deprotonation of both
To account for pseudoequatorial deprotonation of (S)-3b by
KHMDS (Path B) would require detailed computational
studies of possible transition structures. Nevertheless, compar-
ison of the solid-state structures of the substrates involved
might provide a clue as to how a Path B deprotonation of
(S)‑3b might be more favorable than that of (S)-10b−f. To that
end an X-ray quality crystal of (S)-3b was obtained, which
demonstrated that the C3-substituent adopts a pseudoaxial
conformation (Figure 4). So the (P)-conformation of (S)-3b
required for Path B deprotonation is readily accessible or even
(
M)- and (P)-conformers could occur, with LiHMDS favoring
3
the former, and KHMDS the latter (Scheme 4). As can be
seen, the C3 protons of (M)-(S)-3b and (M)-(S)-10b are
pseudoaxial and appear stereoelectronically well-disposed for
deprotonation, as we have established in studies of related
In contrast the C3 protons of (P)-
S)-3b and (P)-(S)-10b are pseudoequatorial and deprotona-
3
preferred, as suggested by previous calculations. The structures
of (M)-(S)-10e, (P)-(S)-10e, and (P)-(S)-3b were then
2
compared. In all three structures sp -hydridization at N was
2b,7a,c,9
benzodiazepin-2-ones.
indicated by the sum of angles at N1 and N4 (θ ≥ 357.9°,
Supporting Information). However, these structures differ in
the extent of amide resonance within, and external to, the
benzodiazepine ring. We assessed the extent of resonance by
(
tion appears difficult because of poor overlap between the
C3−H σ and the C2−O π*.
5
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Organic Letters
Letter
enantioenriched 3-amino-3-alkylquinolone-2,4-diones 11. Work
is in progress to further expand the scope of this reaction as
well as to better understand the enantiodivergent outcomes of
(
S)-3b.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Synthetic procedures, analytical data, chromatograms, NMR
spectra, X-ray structure of (R)-11b, and .cif files for (S)-3b,
(
±)-9d, (S)-10e, and (R)-11b. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
Figure 4. Anisotropic ellipsoid drawing (50%) of (S)-3b.
*E-mail: pcarlier@vt.edu.
Notes
1
0
examining amide twist torsion angles τ along the N1−C2,
N4−C5, N4−C15, and N1−C12 bonds (where applicable, see
The authors declare no competing financial interest.
Table 2). For (S)-10e (both conformers), values of τ1 and
−2
ACKNOWLEDGMENTS
We gratefully acknowledge financial support from the NSF
CHE-0750006) and the Department of Chemistry, Virginia
■
(
a
Table 2. Select Torsion Angles for (S)-10e and (S)-3b
Tech.
REFERENCES
■
(
1) (a) Loudni, L.; Roche, J.; Potiron, V.; Clarhaut, J.; Bachmann, C.;
Gesson, J.-P.; Tranoy-Opalinski, I. Bioorg. Med. Chem. Lett. 2007, 17,
4
819. (b) Joseph, C. G.; Wilson, K. R.; Wood, M. S.; Sorenson, N. B.;
Phan, D. V.; Xiang, Z.; Witek, R. M.; Haskell-Luevano, C. J. Med.
Chem. 2008, 51, 1423. (c) Cheng, M.-F.; Yu, H.-M.; Ko, B.-W.; Chang,
Y.; Chen, M.-Y.; Ho, T.-I.; Tsai, Y.-M.; Fang, J.-M. Org. Biomol. Chem.
b
(
M)-(S)-10e
(P)-(S)-10e
(P)-(S)-3b
Boc
R′
R
Me
Me
2
006, 4, 510.
2) (a) MacQuarrie-Hunter, S.; Carlier, P. R. Org. Lett. 2005, 7, 5305.
b) Carlier, P. R.; Zhao, H.; MacQuarrie-Hunter, S. L.; DeGuzman, J.
C.; Hsu, D. C. J. Am. Chem. Soc. 2006, 128, 15215.
3) Farran, D.; Archirel, P.; Toupet, L.; Martinez, J.; Dewynter, G.
Eur. J. Org. Chem. 2011, 2043.
4) (a) Lee, S. D.; Chan, T. H.; Kwon, K. S. Tetrahedron Lett. 1984,
i-Bu
i-Bu
i-Pr
(
τ1−2
τ4−5
τ4−15
4.7 ± 0.4°
3.4 ± 0.4°
−45.6 ± 0.4°
na
−13.5 ± 1.8°
−16.7 ± 0.9°
−39.6 ± 0.7°
na
−36.4 ± 0.3°
−31.9 ± 0.4°
−19.4 ± 0.3°
3.3 ± 0.3°
21.6 ± 0.2°
(
(
τ1
−12
HC3C2O13
132.8 ± 0.2°
15.2 ± 1.3°
(
a
Error in torsion angles calculated from ESDs (Supporting
25, 3399. (b) Hara, O.; Ito, M.; Hamada, Y. Tetrahedron Lett. 1998, 39,
5537. (c) Wipf, P.; Methot, J.-L. Org. Lett. 2001, 3, 1261.
(5) Vrijdag, J. L.; Van den Bogaert, A. M.; De Borggraeve, W. M. Org.
Lett. 2013, 15, 1052.
b
Information). The (P)-conformer of (S)-10e is disordered; torsion
angles are listed for the major orientation (see Figure 3).
(
6) (a) McCormick, J. L.; McKee, T. C.; Cardellina, J. H.; Boyd, M.
τ4−5 are much closer to zero than are the values of τ4−15
,
R. J. Nat. Prod. 1996, 59, 469. (b) Ahmed, N.; Brahmbhatt, K. G.;
Sabde, S.; Mitra, D.; Singh, I. P.; Bhutani, K. K. Bioorg. Med. Chem.
indicating endocyclic amide resonance (N1−C2, N4−C5) is
more important than exocyclic (N4−C15) amide resonance
2
010, 18, 2872. (c) Seong, C. M.; Park, W. K.; Park, C. M.; Kong, J.
(
Table 2). However, in (P)-(S)-3b the situation is reversed: the
Y.; Park, N. S. Bioorg. Med. Chem. Lett. 2008, 18, 738.
exocyclic amide resonance of N1 and N4 with their attached
Boc groups is stronger than that within the ring (cf. τ1−12 and
τ1−2, τ4−15 and τ4−5, Table 2).
(7) (a) Carlier, P. R.; Zhao, H.; DeGuzman, J.; Lam, P. C.-H. J. Am.
Chem. Soc. 2003, 125, 11482. (b) Lam, P. C.-H.; Carlier, P. R. J. Org.
Chem. 2005, 70, 1530. (c) Hsu, D. C.; Lam, P. C.-H.; Slebodnick, C.;
Carlier, P. R. J. Am. Chem. Soc. 2009, 131, 18168.
Reduced endocyclic amide resonance for 3b compared to
0b−f suggests greater flexibility of 3b along the N1−C2 and
(
8) Dolomanov, O. V.; Bouris, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, 42, 339.
9) Carlier, P. R.; Sun, Y.-S.; Hsu, D. C.; Chen, Q.-h. J. Org. Chem.
010, 75, 6588.
10) (a) Otani, Y.; Nagae, O.; Naruse, Y.; Inagaki, S.; Ohno, M.;
1
N4−C5 axes. Thus, stereoelectronically acceptable HC3C2O13
torsion angles might be more easily obtained in the KHMDS
deprotonation of (P)-(S)-3b than that of (P)-(S)-10b−f. In the
solid state the HC3C2O13 torsion angle for (P)-(S)-3b is
indeed larger than that of (P)-(S)-10e (21.6° vs 15.2°).
In conclusion we have repeated the findings of Dewynter and
(
2
(
Yamaguchi, K.; Yamamoto, G.; Uchiyama, M.; Ohwada, T. J. Am.
Chem. Soc. 2003, 125, 15191. (b) Dunitz, J. D.; Winkler, F. K. Acta
Crystallogr. 1975, B31, 251.
3
co-workers on deprotonation of (S)-3b and found that, by
replacing the N1-Boc group by an alkyl group (Me), a wider
variety of ring-contraction substrates may be prepared. Unlike
(
S)-3b, deprotonations of (S)-10b−f are (R)-selective with
both LiHMDS and KHMDS. Enantioselective ring contractions
of (S)-10b−f occur in higher enantiomeric excess than that of
(S)-3b, potentially opening a route to diversely functionalized
5
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