Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality

Article abstract of DOI:10.1021/ja0365781

Glycine-derived 1,4-benzodiazepine-2-ones such as diazepam are chiral by virtue of the boat-shaped conformation of the diazepine ring and exist as a racemic mixture of conformational enantiomers. However, the presence of a chiral center at C-3 of the benz

Full text of DOI:10.1021/ja0365781

Published on Web 08/28/2003
Enantioselective Synthesis of “Quaternary” 1,4-Benzodiazepin-2-one
Scaffolds via Memory of Chirality
Paul R. Carlier,* Hongwu Zhao, Joe DeGuzman, and Polo C.-H. Lam
Department of Chemistry, Virginia Tech, Blacksburg, Virginia 24061
Received June 9, 2003; E-mail: pcarlier@vt.edu
Scheme 1. Dynamic Chirality of 1a-c and Stereochemical
Cooperativity in 2b (∆Gq Values Were Determined by 1H NMR
Spectroscopy (Coalescense))
1,4-Benzodiazepines are among the most important scaffolds in
medicinal chemistry, representing the prototypical “privileged
structure”.1 Tens of thousands of these compounds have been
prepared on solid phase and in solution, and the development of
new 1,4-benzodiazepine drug candidates shows no sign of abating.2
Yet amidst this impressive diversity, the reliance of most of these
syntheses upon proteinogenic amino acid starting materials has
systematically excluded one class of targets: enantiopure benzo-
diazepines possessing a quaternary stereogenic center.3 In this
Communication, we report an enantioselective R-alkylation route
to “quaternary” 1,4-benzodiazepin-2-ones that relies upon the
intrinsic chirality of the benzodiazepine ring.
Despite the absence of a stereogenic center, glycine-derived 1,4-
benzodiazepin-2-ones 1 such as diazepam (1b) are chiral,4,5 existing
as (M)- and (P)-conformational enantiomers6 (Scheme 1). When
the N1 substituent is relatively small (H, Me, i-Pr, i.e., 1a-c),
racemization is facile at room temperature, preventing resolution
of these compounds.4,7 Only when the N1 substituent is very large
(e.g., 1d, R1 ) t-Bu) is the racemization barrier high enough to
allow preparative resolution of the (M)- and (P)-enantiomers.4,8
It is well known5,8-10 that placement of a single substituent at
C3 perturbs the conformational equilibrium of N-Me 1,4-benzodi-
azepin-2-ones (e.g., 2b), stabilizing the pseudoequatorial conformer;
thus, (3S)-stereochemistry will induce the diazepine ring to adopt
the (M)-conformation (Scheme 1). We envisioned that the effective
stereochemical cooperativity demonstrated by 3-alkyl-1,4-benzo-
diazepin-2-ones such as 2b might allow the development of an
enantioselective R-alkylation protocol. Although deprotonation of
(3S)-2b would destroy the stereogenic center at C3, the resulting
enolate would remain chiral by virtue of the nonplanar diazepine
ring. Deprotonation/alkylation sequences of glycine-derived 1,4-
benzodiazepin-2-ones have been previously reported11 as a means
to prepare novel benzodiazepines and the corresponding amino
acids, including an auxiliary-based asymmetric method.11b However,
the only reported R-alkyation route to 3,3-dialkyl-1,4-benzodiaz-
epin-2-ones affords low (0-20%) yields.11a
Enantiomerically pure 1,4-benzodiazepin-2-ones (3S)-2a and
(3S)-3a (R1 ) H) were prepared in 91% and 67% yield from (S)-
Boc-Ala and (S)-Boc-Phe, using a modification of Shea’s protocol.12
Conversion to the N-Me (2b 94%) and the N-i-Pr derivatives (2c
82%; 3c, 58%) in 100% ee was achieved upon treatment of the
sodium salts with the corresponding alkyl triflates.13 After consider-
able optimization, we determined that acceptable yields of desired
R-alkylation products could be attained by deprotonating 2b-c and
3c with LDA in the presence of HMPA, and treatment with n-BuLi
before addition of the electrophile (Table 1).14 However, application
of this protocol to the enolate of N-Me benzodiazepine (3S)-2b
and BnBr gave 4 in a disappointing 0% ee. Fortunately, identical
treatment of the N-i-Pr analogue (3S)-2c gave the desired product
5 in 97% ee (Table 1, cf. entries 1, 2). Knowing that the inversion
barrier of benzodiazepines is a function of the size of the N1
Table 1. Racemizing (2b) and Enantioselective (2c, 3c)
Deprotonation/Trapping Reactions of 1,4-Benzodiazepin-2-ones
a
entry
R
1
R
2
E
product
% yield
% eeb
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
(()-4
(+)-5
(+)-6
(+)-7
(+)-8
(+)-9
(-)-5
(+)-10
72
74
68
70
76
85d
64
57
0c
97 (3R)
95 (3R)
99
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
4-MeC6H4CH2
2-PhC6H4CH2
allyl
D
Me
allyl
94
99 (3S)
95 (3S)
86
Bn
a Electrophiles used: BnBr, 4-MeC6H4CH2Br, 2-PhC6H4CH2Br, allyl
bromide, D-OTFA, MeI. b % ee measured by chiral stationary phase HPLC
(Chiralcel OD, AD). c Racemic 4 is also obtained if BnBr is added only 10
s after deprotonation by LDA. d The extent of deuteration is 96%.
substituent (Scheme 1), we reason that an N-Me group is not large
enough to impart sufficient conformational stability to the enolate
ring at -78 °C on the deprotonation/alkylation time scale. Even
with short deprotonation times (LDA only, 10 s), N-Me benzodi-
azepine (3S)-2b produces racemic 4. In contrast, deprotonation/
trapping reactions of the N-i-Pr analogues examined thus far are
highly enantioselective. In addition to benzylation, reaction of the
enolate derived from (3S)-2c with other active electrophiles proceeds
9
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J. AM. CHEM. SOC. 2003, 125, 11482-11483
10.1021/ja0365781 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
(Table 1, entries 1, 2) may be rationalized. Finally, consistent with
this high racemization t1/2 estimate for 13c, we find that, after a
deprotonation time of 8 h at -78 °C, benzylation of the enolate of
(3S)-2c occurs in 92% ee (cf. Table 1, entry 2).
Acknowledgment. We thank the National Science Foundation
(CHE-0213525), the Jeffress Memorial Trust, and the Virginia Tech
Department of Chemistry for financial support.
Supporting Information Available: Experimental procedures,
spectroscopic data and HPLC chromatograms, and computational details
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
Figure 1. B3LYP/6-31G* equilibrium geometry and ring inversion
transition structure of N-i-Pr enolate anion 13c (relative free energies at
B3LYP/6-31+G*//B3LYP/6-31G*).
Scheme 2. Correlation of Benzodiazepines 5 and 6 by
Conversion to the Corresponding Quaternary Amino Acids 11 and
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12
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