Asymmetric dipolar cycloadditions of Me3SiCHN2. Synthesis of a novel class of amino acids: Azaprolines

Full text of DOI:10.1021/ja971708p

J. Am. Chem. Soc. 1997, 119, 8379-8380
Asymmetric Dipolar Cycloadditions of Me SiCHN
Scheme 1
8379
3
2
.
Synthesis of a Novel Class of Amino Acids:
Azaprolines
Michael R. Mish, Francisco M. Guerra, and
Erick M. Carreira*
Arnold and Mabel Beckman Laboratory for
Chemical Synthesis, California Institute of Technology
Pasadena, California 91125
ReceiVed May 27, 1997
Dipolar cycloadditions are a powerful class of synthetic
reactions for the construction of diversely functionalized five-
membered heterocycles. In particular, cycloadditions involving
captopril and enalopril), immunomodulation, coagulation, and
6
-8
protein-ligand interactions (SH3-domains), the amino acid
analogs reported herein should find important applications as
proline surrogates.
1
nitrile oxides, azomethine ylides, carbonyl ylides, nitrones, and
nitronates as dipoles have been well studied and applied toward
several elegant complex-molecule syntheses.2 The use of
diazoalkanes, however, has not been extensively examined.
Synthetic applications of these dipoles have typically been
limited to the preparation of the derived cyclopropanes or
pyrazoles obtained by nitrogen extrusion or aromatization of
the initial [3 + 2] adduct, respectively.5 However, the pyra-
zoline cycloadducts which result from the reaction of diazoal-
kanes with chiral R,â-unsaturated carboxylic acid derivatives
can serve as useful optically active, functionalized intermediates
that in turn are amenable to further synthetic elaboration
-4
(1)
The lack of synthetic methodology involving the use of
diazoalkanes in asymmetric dipolar cycloadditions may be a
consequence of the fact that diazoalkanes (1) have not been
readily available, (2) are not typically amenable to prolonged
(
Scheme 1). Herein, we describe the novel diastereoselective
cycloaddition of Me3SiCHN2, an item of commerce, and
camphor sultam-derived dipolarophiles 1 to furnish ∆ -pyra-
2
zolines 2 following acidic work-up (eq 1). Additionally, using
this method, we delineate the asymmetric synthesis of a novel
class of R-amino acids: azaprolines. Given the prominence of
prolines in biologically important peptide sequences relevant
to metallopeptidase activity (e.g., ACE inhibitors such as
9
storage, and (3) may be thermally unstable. The recent
availability of Me3SiCHN2 as an easily handled, stable item of
commerce permits the examination of its use for asymmetric
synthesis. At the outset of our investigations, however, we were
aware of a potential problem (eq 2): prior studies on the
cycloadditions of diazoalkanes with R,â-unsaturated esters had
(1) For general references, see: (a) Carruthers, W. Cycloaddition
Reactions in Organic Sythesis; Pergammon: Oxford, 1990; p 269. (b)
Padwa, A. In ComprehensiVe Organic Synthesis; Trost, B., Ed.; Wiley: New
York, 1991; Vol. 4, p 1069. (c) Wade, P. A. In ComprehensiVe Organic
Synthesis; Trost, B., Ed.; Wiley: New York, 1991; Vol. 4, p 1111. (d)
Little, R. D. In ComprehensiVe Organic Synthesis; Trost, B., Ed.; Wiley:
New York, 1991; Vol. 5, p 239.
(
2)
(
2) For an excellent review, see: Kim, B. H.; Curran, D. P. Tetrahedron
993, 49, 293.
3) For recent references, see: (a) Curran, D. P.; Yoon, M. H.
1
1
indicated that the ∆ -pyrazolines 3 initially formed in such
cycloadditions readily isomerized to the corresponding conju-
The result of such an isomerization in
the system of interest would be the loss of the desired R-amino
(
Tetrahedron 1997, 53, 1971. (b) Fern a´ ndez-Mateos, A.; Coca, G. P.;
Gonz a´ lez, R. R.; Hern a´ ndez, C. T. J. Org. Chem. 1996, 61, 9097. (c)
Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 1996, 61,
5a,b
gated pyrazoline 4.
3
1
1
46. (d) Hudlicky, T.; Olivo, H. F.; McKibben, B. J. Am. Chem. Soc. 1994,
16, 5108. (e) Oppolzer, W.; Kingma, A. J.; Pillai, S. K. Tetrahedron Lett.
991, 32, 4893.
stereocenter.
In our initial investigations, we observed that N,N-dialkyl
(
4) (a) Cinquini, M.; Cozzi, F. In StereoselectiVe Synthesis; Helmchen,
10
acrylamides were unreactive toward Me3SiCHN2. In contrast,
N-tosyl acrylamides proved sufficiently reactive, providing
quantitative yields of cycloadducts (23 °C, 4-6 h). Our interest
in studying diastereoselective diazoalkane cycloaddition reac-
G., Hoffman, R., Mulzer, J., Schaumann, E., Eds.; Thieme: Stuttgart, 1996;
p 2953. (b) Denmark, S. E.; Parker, D. L.; Dixon, J. A. J. Org. Chem.
1997, 62, 435. (c) Denmark, S. E.; Thorarensen, A. J. Am. Chem. Soc.
1997, 119, 125. (d) Padwa, A.; Brodney, M. A.; Marino, J. P.; Osterhout,
M. H.; Price, A. T. J. Org. Chem. 1997, 62, 67. (e) Padwa, A.; Brodney,
M. A.; Marino, J. P.; Sheehan, S. M. J. Org. Chem. 1997, 62, 78. (f) Padwa,
A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223. (g) Denmark, S. E.;
Thorarensen, A. Chem. ReV. 1996, 96, 137. (h) Kozikowski, A. P. Acc.
Chem. Res. 1984, 17, 410. (i) DeShong, P.; Dicken, C. M.; Leginus, J. M.;
Whittle, R. R. J. Am. Chem. Soc. 1984, 106, 5598. (j) Roush, W. R.; Walts,
A. E. J. Am. Chem. Soc. 1984, 106, 721.
tions led us to examine the reaction of dipolarophiles derived
2,11
from the camphor sultam auxiliary.
The dipolarophile
substrates 5-8 were readily synthesized from the commercially
available (R)-camphor sultam chiral auxiliary and the corre-
sponding acid chlorides. When solutions of substrates 5-8 in
hexane/toluene were treated at 23 °C with a solution of Me3-
SiCHN2 (2 M in hexane, 1-3 equiv), 3-trimethylsilyl-substituted-
∆ -pyrazolines could be isolated in quantitative yields following
evaporation of the volatiles; exposure of these adducts to acid
(CF3CO2H/CH2Cl2) furnished ∆ -pyrazolines 9-12 (Table 1).
Analysis of the unpurified reaction mixtures by HPLC revealed
(
5) (a) Galley, G.; P a¨ tzel, M.; Jones, P. G. Tetrahedron 1995, 51, 1631.
b) Bartels, A.; Liebscher, J. Tetrahedron: Asymm. 1994, 5, 1451. (c)
Aoyama, T.; Nakano, T.; Nishigaki, S.; Shioiri, T. Heterocycles 1990, 30,
75. (d) Lappert, M. F.; Poland, J. S. J. Chem. Soc. (C) 1971, 3910. (e)
Seyferth, D.; Menzel, H.; Dow, A. W.; Flood, T. C. J. Chem. Soc. 1968,
0, 1081. (f) The cycloaddition of vinyl boronates and ethyl diazoacetate
(
1
3
9
2
2
has been shown to give the corresponding non-conjugated ∆ -pyrazoline
following hydrolysis of the boronate adduct, see: Matteson, D. S. J. Org.
Chem. 1962, 27, 4293.
(
6) Attwood, M. R.; Hassall, C. H.; Kr o¨ hn, A.; Lawton, G.; Redshaw,
(9) Prudent Practices for Handling Hazardous Chemicals in Laborato-
ries; National Academy Press: Washington, D.C., 1981; p 65.
(10) We have observed that unreactive dipolarophiles may be activated
toward cycloaddition upon treatment with Lewis acids.
(11) For a review, see: (a) Oppolzer, W. Tetrahedron 1987, 43, 1969.
(b) Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241.
S. J. Chem. Soc., Perkin Trans. 1 1986, 1011.
(
7) (a) Vanhoof, G.; Goossens, F.; De Meester, I.; Hendriks, D.; Scharpe,
S. The FASEB Journal 1995, 9, 736. (b) Kini, R. M.; Evans, H. J. Biochem.
Biophys. Res. Commun. 1995, 212, 1115.
(
8) Simon, J. A.; Schreiber, S. L. Chem. Biol. 1995, 2, 53.
S0002-7863(97)01708-3 CCC: $14.00 © 1997 American Chemical Society

8380 J. Am. Chem. Soc., Vol. 119, No. 35, 1997
Communications to the Editor
2
a
Table 1. Asymmetric Synthesis of ∆ -Pyrazolines
(3)
carbamates 17-20 isolated in 50-70% yield two steps.1
3,14
Protection proved to be highly chemoselective, providing only
the carbamates 17-20 for all of the pyrazolidines examined.1
Cleavage of the chiral auxiliary was readily carried out upon
treatment of 17-20 with Mg(OCH3)2 in methanol (0-23 °C)
5
1
4,16
2
and afforded 21-24 (51-67%).
Both the ∆ -pyrazolines
and pyrazolidines participate in peptide coupling reactions. For
example, treatment of 9 (entry 1, Table 1) with Mg(OMe)2
2
furnished the corresponding ∆ -pyrazoline-5-carboxylic acid
methyl ester 25, which was coupled with N-Boc-(L)-Phe (DCC,
DMAP, THF) giving dipeptide 26 in 82% yield (eq 4).
Condensation of pyrazolidine 13 with N-Boc-(L)-Phe (DCC,
a
3 2
Conducted at 23 °C in 1:1 hexane/toluene, 1-3 equiv of Me SiCHN .
Upon completion, volatiles were removed and the residue treated with
CF CO H/CH Cl . Xc ) (1R)-(+)-2,10-camphorsultam. Diastereo-
3 2 2 2
selectivity was assayed by HPLC, see Supporting Information. All
diastereomeric products were fully characterized. The absolute con-
figuration was established by X-ray crystallography. Configuration
b
c
(4)
d
e
assigned by analogy.
DMAP, THF) furnished dipeptide 27, which was subsequently
converted to 28 upon treatment with Mg(OMe)2 (eq 5).17
Chart 1
(5)
The dipolar cycloaddition reaction of Me3SiCHN2 with chiral
2
acrylates provides access to optically active ∆ -pyrazolines. This
asymmetric process has several salient features: (1) the starting
materials (camphor sultam auxiliary and Me3SiCHN2) are
commercially available; (2) the products are furnished in good
yields with useful levels of regioselectivity and diastereoselec-
tivity; and (3) these heterocyclic products are amenable to
synthetic transformations including reduction, chemoselective
peptide coupling reactions, and auxiliary removal. The meth-
odology described not only documents the asymmetric dipolar
cycloadditions of Me SiCHN but also, importantly, provides
that 9-12 had been formed in 90-94% diastereoselectivity as
single regioisomers. In all cases the diastereomeric products
were readily separated by chromatography on silica gel. The
configuration of the diastereomers was confirmed by single
crystal X-ray crystallographic analysis of 9-11, consistent with
the typical facial selectivity observed for such camphor sultam-
derived systems.12 Surprisingly, the conjugated pyrazolines such
as 4 (eq 2) were not observed as products of the reaction.
3
2
access to analogs of proline, an amino acid for which there are
few readily synthesized congeners. Recent studies have dem-
onstrated dramatic conformational changes in peptides incor-
porating proline analogs, with a concomitant alteration of
biological response. Azaprolines may prove to be important
surrogates due to the variability of ring substitution afforded
by both the choice of the acryloyl moiety used in the dipolar
cycloaddition as well as the capacity to diversely functionalize
2
The optically active ∆ -pyrazolines isolated provide novel
substituted proline analogs, which have not previously been
prepared. In order to demonstrate the utility of the methodology
described herein as a means of providing access to synthetically
useful azaproline analogs, we have studied reactions that result
in CdN reduction, auxiliary removal, chemoselective protection,
and peptide bond formation.
δ
the Cγ-N of the pyrazolidine.
Acknowledgment. F.M.G. is grateful for an FPI Program fellowship
from the Ministerio de Educaci o´ n y Ciencia, Spain. This research has
been supported by the Sloan Foundation, Packard Foundation, NSF,
NIH, and generous gifts from Lilly, Merck, Pfizer, Pharmacia-UpJohn,
and Zeneca.
2
Reduction of the ∆ -pyrazolines was readily effected upon
treatment with NaCNBH3 in acetic acid to give the pyrazolidines
1
3-16 (eq 3, and Chart 1) which were most effectively handled
following protection as the corresponding N-Cbz or N-Boc
Supporting Information Available: Experimental procedures and
spectral data for all compounds (8 pages). See any current masthead
page for ordering and Internet access instructions.
(12) To the best of our knowledge, the absolute configuration of dipolar
cycloadducts derived from the R-methacryloyl sultam 7 has not been
unambiguously established previously. We have obtained an X-ray crystal
structure that indicates the cycloadduct formed from the same diastereoface
as acryloyl sultams 5, 6, and 8.
JA971708P
1
(15) H NMR data for 17-20 are consistent with peptide bond formation
δ
(
13) The unprotected pyrazolidines proved to be unstable, necessitating
their derivatization as N-Boc and N-Cbz protected derivatives.
14) To determine if steroisomerization had occurred in the formation
at Cγ-N .
(16) Esters 22-24 were observed as the only diastereomers of the
1
13
(
reaction as determined by H and C NMR spectroscopy.
(17) Experiments similar to those in ref 14 using ent-13 and ent-25
established the absence of stereoisomerization in carbamate formation,
auxiliary removal, and peptide coupling reactions. See Supporting Informa-
tion.
1
of 17 and 21, both 21 and ent-21 were coupled to N-Boc-(L)-Phe. H NMR
analysis of the unpurified reaction products established that racemization
does not occur upon auxiliary removal, as dipeptide diasteromer mixtures
were not observed. See Supporting Information.