Total synthesis of LFA-1 antagonist BIRT-377 via organocatalytic asymmetric construction of a quaternary stereocenter

Article abstract of DOI:10.1021/ol047368b

(Chemical Equation Presented) A catalytic route for enantioselective total synthesis of cell adhesion inhibitor BIRT-377 is described. The quaternary stereocenter was constructed through L-proline-derived, tetrazole-catalyzed direct asymmetric α-amination

Full text of DOI:10.1021/ol047368b

ORGANIC
LETTERS
2005
Vol. 7, No. 5
867-870
Total Synthesis of LFA-1 Antagonist
BIRT-377 via Organocatalytic
Asymmetric Construction of a
Quaternary Stereocenter
Naidu S. Chowdari and Carlos F. Barbas, III*
The Skaggs Institute for Chemical Biology and the Departments of Chemistry and
Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
carlos@scripps.edu
Received December 22, 2004
ABSTRACT
A catalytic route for enantioselective total synthesis of cell adhesion inhibitor BIRT-377 is described. The quaternary stereocenter was constructed
through -proline-derived, tetrazole-catalyzed direct asymmetric -amination of 3-(4-bromophenyl)-2-methylpropanal with dibenzyl azodicarboxylate.
In the course of these studies, a one-pot trifluoro acetylation/selective benzyloxycarbonyl deprotection method was developed.
L
r
BIRT-377 (1) is a potent inhibitor of the interaction between
intercellular adhesion molecule-1 (ICAM-1) and lymphocyte
function-associated antigen-1 (LFA-1). BIRT-377 has po-
tential for treatment of a number of inflammatory and
immune disorders. Reported syntheses of BIRT-377 are
based on a chiral pool approach involving Seebach’s self-
regeneration of stereocenters strategy.1 Asymmetric synthesis
of quaternary amino acids, like BIRT-377, is a challenging
task since these types of stereocenters cannot be made by
catalytic asymmetric hydrogenation. Some of these unusual
amino acids are components of enzyme inhibitors and their
incorporation into peptides has been used to modulate
secondary and tertiary structural conformations.2 Existing
methods for the synthesis of quaternary amino acids include
auxiliary controlled Strecker syntheses3 and diastereoselective
alkylation of chiral enolates.4 Recently, asymmetric phase
transfer catalysis reactions5 and other catalytic methods6 have
been reported. However development of a highly economical
and broadly useful catalytic method for synthesis of quater-
nary amino acids is highly desirable.
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10.1021/ol047368b CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/28/2005

Recently, proline- and proline derivative-catalyzed asym-
metric aldol,7 Mannich,8 Michael,9 Diels-Alder,10 amina-
tion,11 oxidation,12 chlorination,13 Robinson annulation,14 and
multicomponent or assembly reactions15 have been devel-
oped. Our laboratory recently reported the synthesis of all
carbon quaternary stereogenic centers via organocatalytic
Aldol-,7g Mannich-,8i and Michael-type9g strategies. Here we
report a direct catalytic asymmetric amination reaction for
synthesis of an aldehyde containing an amino-substituted
quaternary carbon center and the elaboration of this aldehyde
into BIRT-377.
Scheme 2. Synthesis of 3-(4-Bromophenyl)-2-methylpropanal
A retrosynthetic analysis of BIRT-377 leads to quaternary
amino acid 2, which we envisioned could be prepared by
organocatalytic amination of aldehyde 4 (Scheme 1). We
double-bond reducing reagents are available,17 we used
LiAlH4 reduction followed by oxidation as a more practical
strategy. Accordingly, the unsaturated aldehyde was reduced
with LiAlH4 and oxidized using Swern conditions to afford
aldehyde 4.
Scheme 1. Retrosynthetic Analysis of BIRT-377
We first evaluated the amination of aldehyde 4 with
dibenzyl azodicarboxylate using a catalytic amount of
L-proline (30 mol %) in CH3CN at room temperature.18 The
reaction was complete in 5 days and provided the amino
aldehyde in 90% yield with moderate enantioselectivity (44%
ee). To improve enantioselectivity, we screened a number
of catalysts and solvents. For example R-methyl-L-proline
and (S)-4-(pyrrolidin-2-ylmethyl)morpholine with trifluoro-
acetic acid additive provided 69 and 57% ee, respectively.
Tetrazole catalyst19 (15 mol %) in CH3CN gave the amination
(9) (a) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Barbas, C,
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prepared the aldehyde 5 by condensation of propionaldehyde
with 4-bromobenzaldehyde using dimethylammonium di-
methyl carbamate16 as a recoverable and reusable reaction
medium and promoter (Scheme 2). Although selective
(7) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000,
122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am.
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(18) L-Proline was reported to be an excellent catalyst for amination of
linear aldehydes (ref 11a,c) as well as R-aryl branched aldehydes, but failed
to induce high ee’s in cases involving R,R-dialkyl aldehydes (ref 11d).
868
Org. Lett., Vol. 7, No. 5, 2005

product (3) in 95% yield with 80% ee (Scheme 3). Upon
recrystallization from ethyl acetate/hexane (3:7), the amino-
aldehyde was obtained in >99% ee (71% yield).
tion we found that treatment of ester 8 with pyridine at 40
°C for 16 h followed by addition of trifluoroacetic anhydride
(TFAA) gave the product 9 through selective removal of one
of the carbamate groups. Although trifluoro acetic acid did
not cleave any of the carbamate groups present in 8,
presumably the product formed after the trifluoroacetylation
of product 8 underwent simultaneous carbamate cleavage.
Selective N-N bond cleavage of 9 was readily achieved
using SmI2 and afforded the Cbz-protected quaternary amino
acid methyl ester 2. This one-pot trifluoroacetylation/selective
benzyloxycarbonyl deprotection protocol should prove useful
for the synthesis of a variety of Cbz-protected amino acids
from precursors obtained through organocatalytic amination
reactions.
Scheme 3. Organocatalytic Amination for the Synthesis of
Quaternary Stereocenter
When compound 2 was treated with 3,5-dichloroaniline
in the presence of nBuLi, hydantoin 11 was obtained in 33%
yield. Use of different bases such as NaOMe, NaH, or LDA
did not provide any product. Better results were obtained
when the Cbz group of 2 was removed with HBr/AcOH to
give free amine 10. The amine was treated with 3,5-
dichlorophenyl isocyanate in the presence of Na2CO3 in
dimethyl sulfoxide to obtain the hydantoin 11 in quantitative
yield. N-methylation of hydantoin 11 was achieved using
lithium bis(trimethylsilyl)amide to afford 1 in excellent yield
(94%). The overall yield for the synthesis of BIRT-377 from
aldehyde 4 in eight steps was 51%. The absolute stereo-
chemistry of amino aldehyde was determined by comparison
of optical rotation of 1 with the literature value.21
The amino aldehyde (3) was selectively oxidized with
NaClO2 at 4 °C to obtain the corresponding carboxylic acid
(7) in 86% yield (Scheme 4). The carboxylic acid was treated
Scheme 4. Synthesis of BIRT-377
The synthesis of quaternary amino acids through organo-
catalytic amination reactions is challenging since the cis and
trans enamines derived from R-branched aldehydes are
energetically less distinct as compared to the cis and trans
enamine intermediates in reactions involving linear alde-
hydes, and this leads to the low enantioselectivity observed
for this class of amination reactions.22 The higher reactivity
and ee obtained with tetrazole catalyst relative to L-proline
is ascribed to the lower pKa and increased steric bulk of
tetrazole relative to L-proline. Tetrazole and L- proline have
pKa’s of ∼8 and ∼12, respectively, in DMSO. The hydrogen
bonding interactions in the transition state of the reaction
with the two catalysts are likely different and provide
different levels of enantioselection. Based on the absolute
configuration of the amino aldehyde and previous proline-
catalyzed reactions,7 we propose the transition state shown
in Scheme 5. The approach of azodicarboxylate might be
directed by interaction of the incoming nitrogen atom with
the proton of the tetrazole of enamine intermediate.11a,c
with (trimethylsilyl)diazomethane to afford the corresponding
ester 8. Next we attempted selective cleavage of the N-N
bond in hydrazino ester 8 using SmI2, which effectively
cleaves trifluoroacetylated hydrazines,20 but no product was
obtained. We next tried trifluoroacetylation. Upon optimiza-
Scheme 5. Transition State for Organocatalytic Amination of
3-(4-Bromophenyl)-2-methylpropanal
(19) Prepared according to literature procedure. See: Almquist, R. G.;
Chao, W.-R.; White, C. J. J. Med. Chem. 1985, 28, 1067.
(20) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637.
Org. Lett., Vol. 7, No. 5, 2005
869

In conclusion, we have developed the first catalytic
asymmetric route to the total synthesis of BIRT-377.
Quaternary amino aldehyde was constructed from readily
available precursors using a small organic molecule catalyst.
This method allows the synthesis of both enantiomers of
BIRT-377. Analogues can be readily obtained by changing
the R,R-disubstituted aldehyde and catalyst. Many of the
steps reported here gave quantitative yields and did not
require purification. Most of these reactions can be performed
under operationally simple and safe conditions without the
requirement for an inert atmosphere, dry solvents, or cooling
equipment. This synthetic route should prove useful for high-
throughput synthesis of BIRT-377 analogues. Full studies
regarding scope of quaternary aminoaldehydes synthesis will
be reported in due course.
Acknowledgment. This study was supported in part by
the NIH (CA27489) and the Skaggs Institute for Chemical
Biology.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) R]25 ) 131.6 (c ) 1.0, EtOH) [lit.1e [R]25 ) 127.3 (c ) 0.78,
D
D
EtOH)]; HPLC (Daicel Chirapak AD, hexane/EtOH/Et2NH ) 300:10:1,
flow rate 1.0 mL/min, λ ) 254 nm): tR ) 15.62 min, (+) 1 (BIRT-377);
tR ) 17.23 min (-) 1.
(22) The energy difference between cis and trans enamines of 3-(4-
bromophenyl)-2-methyl propanal with L-proline is 0.266 kcal/mol, whereas
propanal has a difference of 2.934 kcal/mol (based on MOPAC, PM3
calculations).
OL047368B
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Org. Lett., Vol. 7, No. 5, 2005