An unprecedented asymmetric Nazarov cyclization for the synthesis of nonracemic indanes as endothelin receptor antagonists

Article abstract of DOI:10.1055/s-1999-2912

An asymmetric synthesis of the novel nonracemic endothelin receptor antagonists, SB 209670 (1a) and SB 217242 (1b) is described which utilizes an unprecedented asymmetric Nazarovtype ring closure of the alkylidene-1,3- carbonyl compounds. Excellent 1,5-induction is observed which establishes the required S configuration at the C-3 carbon of an indane skeleton.

Full text of DOI:10.1055/s-1999-2912

1612
LETTER
An Unprecedented Asymmetric Nazarov Cyclization for the Synthesis of
Nonracemic Indanes as Endothelin Receptor Antagonists
Lendon N. Pridgen,a* Kris Huang,a Susan Shilcrat,a Ann Tickner-Eldridge,a Charles DeBrosse,b R. Curtis Haltiwangerc
aSmithKline Beecham Pharmaceuticals, Synthetic Chemistry Department, 709 Swedeland Rd, King of Prussia, Pennsylvania, 19406, USA
bSmithKline Beecham Pharmaceuticals, Analytical Sciences Department, 709 Swedeland Rd, King of Prussia, Pennsylvania, 19406, USA
cSmithKline Beecham Pharmaceuticals, Physical and Structural Chemistry Department, 709 Swedeland Rd, King of Prussia, Pennsylvania,
19406, USA
Received 3 August 1999
the duality of allowed electrocyclization pathways. This
Abstract: An asymmetric synthesis of the novel nonracemic endo-
feature is called torquoselectivity8-10 and manifests itself
when a remote chiral substituent is present, thus, leading
to possibilities of diastereoisomers (eq 2 ).
thelin receptor antagonists, SB 209670 (1a) and SB 217242 (1b) is
described which utilizes an unprecedented asymmetric Nazarov-
type ring closure of the alkylidene-1,3-carbonyl compounds. Excel-
lent 1,5-induction is observed which establishes the required S con-
figuration at the C–3 carbon of an indane skeleton.
O
O
O
Key words: asymmetric Nazarov cyclization, 1,5-asymmetric in-
duction, endothelin receptor antagonists, indanes
COXc
Ar
COXc
H+
COXc
PrO
PrO
PrO
+
Ar
Ar
3a-c (Ar = Piperonyl)
4a-c
5a-c
Successful development of a multikilogram scale synthe-
sis of the novel endothelin receptor antagonists, SB
209670 (1a) and SB 217242 (1b) containing three contig-
uous stereogenic centers, demanded parallel exploratory
development of several potentially scaleable routes.1 De-
scriptions of several of those routes have already been,
and/or, shortly will be disclosed elsewhere.2-6 In this com-
munication, we summarize the description of an unprece-
dented asymmetric Nazarov-type ring closure of the
alkylidene-1,3-carbonyl compound 3 where excellent 1,5-
induction establishes the required S configuration at the
C–3' carbon (eq 1). In our most efficient example, an
Evan's oxazolidinone chiral auxiliary of S configuration
was employed.7
Equation 2
Shortly after this work was begun, a report by Tietze11 ap-
peared describing a cyclization to form enantiomerically
pure trans-1,2-disubstituted cyclopentanes with three ste-
reogenic centers using chiral malonic acid derivatives. In
that report, asymmetric induction was transferred across
five carbons, i.e. 1,5-induction. In our results, reported
herein, we employ similar conditions on the chiral deriv-
atives 3a-c to form selectively the indanone 4a-c with
similar 1,5-asymmetric induction.
O
O
CO2CH3
1. NaH, DMC (>95%)
PrO
OCH3
PrO
2. Piperonal; Piperidine
HOAc; Toluene (~70%)
O
O
H
COXc
OR
CO2H
COXc
PrO
PrO
6
7
O
PrO
O
O
O
O
O
O
O
O
COXc
1. NaOH (80%)
2. COCl2 (>95%)
3. Base / H-Xc
THF / Toluene
– 40 °C (75%)
PrO
2
SB 209670 (1a), R = -CH2CO2H
SB 217242 (1b), R = -OCH2CH2OH
3
7
Equation 1
O
O
The Nazarov cyclization is an example of a 4p-electrocy-
clic closure of a pentadienyl cation. As with all pericyclic
reactions, the mechanism and stereochemistry on cycliza-
tion are inherently related. For 4p-electrolytic cyclization,
in addition to the prerequisite stereochemical imperative
of conrotatory or disrotatory ring closure, there exists a
secondary stereochemical feature that arises because of
3a,b
3c
O
Xc =
Xc = 8–Phenylmenthol
—N
O
R
a; R = Ph
b; R = iPr
Scheme 1
Synlett 1999, No. 10, 1612–1614 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Nonracemic Indanes as Endothelin Receptor Antagonists
1613
As depicted in Scheme 1, the chiral b-keto acid deriva- an effective catalysis as any other Lewis acid explored,
tives 3 were synthesized in 5 steps starting with the acyla- suggests that metal-carbonyl complexation is not a pre-
tion of 3-propyloxyacetophenone (6) with dimethyl requisite for establishing stereoselective cyclization in
carbonate (>95%). The resulting methyl ester was trans- this particular instance.
formed by Knoevenagel condensation with piperonal to 7
(70%). The ester 7 was saponified in 80% yield and con-
verted to the acid chloride in 95% yield. Reaction of the
L
L
L
L
acid chloride with the appropriate 2-oxazolidinone and 8-
phenylmenthol chiral auxiliaries was accomplished in
64% and 75% yields, respectively. The alkylidene 1,3-di-
carbonyl compounds 3 were isolated from toluene as ex-
clusively the (E)-configuration as determined by nOe
determinations as well as full characterization by X-ray
crystallographic analysis.13
M
N
M
N
O
O
O
O
O
O
PrO
O
O
PrO
R
R
Ar
Ar
9
8
Stuctures 8 and 9
Some comments are warranted to try and explain why any
selectivity is observed in such a system where the source
of chirality is so remote. A Drieding model of 3, prepared
based on X-ray data, suggests that the highly transoid or-
dered structure as depicted by 10, positions the exocyclic
b-carbon for facile 4p-electrocyclic cylization to yield 4.
Conformations available to 3 were examined by computa-
tional methods. These conformations were generated
starting from distance and dihedral angle geometry ob-
tained from X-ray data and were energy minimized using
the MM2 procedures available in the CaChe software
suite (v 3.9, Oxford Molecular Group).13 The imide carbo-
nyls were held in a trans-coplanar geometry throughout
the conformer generation. The distance from the a,b-un-
saturated to the b-carbon to the aromatic C-6 is 2.83 Å,
well within bond forming range. Apparently, the steric de-
mands alone of the alkylidene-1,3-carbonyl are sufficient
to allow for enough p-p interaction to effect reaction to the
aromatic ring. The lack of a carbonyl in the chiral auxilia-
ry 3c and the lack of an aromatic substituent in 3b pre-
clude electronic participation by the chiral auxiliary in the
form of p-stacking involvement.
a The isomer ratio is determined by 1H NMR (300 MHz) integration
signal of the C–3´ methine proton. Minor isomers were not isolated
b
nor characterized. The major isomer in all cases is Structure 4. 1.1
equivalents of the Lewis acid was used in CH2Cl2 or toluene initially
at 0 °C. c 2 equivalents of the acid was used in CH2Cl2 or toluene at 0
°C for 3 hr. d Isolated yield of the combined isomers.
The results of the cyclization studies to form 4 are shown
in Table 1.12 The cyclization was best conducted in meth-
ylene chloride or toluene at 0 °C. Of the eight possible iso-
mers that may be formed, only three isomers were ever
observed. The results were found to be similar, regardless
of the choice of auxiliary. Best results were eventually re-
alized utilizing methanesulfonic acid as catalyst. Typical-
ly for 3a under these conditions, an isomeric ratio of 70%
d.e. was obtained and in 88% isolated yield. After much
experimentation, it was eventually discovered that the
product 4a could be isolated as a recrystallizable solid
from a warm methanol solution. The major isomer was
determined to be the trans isomer containing an S config-
uration at C–3'. Compound 4a was ultimately converted to
the final target molecule SB 217242 (1b).1 The largest mi-
nor isomer 5a was subsequently shown to have the R con-
figuration at C–3' by its conversion to ent–1b.
O
Xc
O
O
O
Xc
PrO
CH3SO3H (5 eq)
CH2Cl2, 0 °C
PrO
H
O
O
O
O
4a-c
10
Structures 10 and 4 a-c
In accordance with the observation reported by Tietze,11
the protonation to form the stereogenic center C–2' is
highly stereoselective. At no point in our recrystallization
studies, employing various refluxing solvents to include
toluene and isopropanol, did we observe interconversion
of isomers. Therefore, we also conclude that the stereo-
genic center at C–2' is formed under kinetic control. This
was of no consequence in our case, since destruction of
the centers at C–1' and at C–2' was necessary for enol
The conversion of 3a-c to 4a-c may be accomplished un-
der either protic or Lewis acid catalysis. Initially, we had
assumed that only Lewis acid catalysis (i.e. SnCl4 or
TiCl4) would be effective in promoting the stereoselective
cyclization. This assumption was primarily based on the
premise that cyclization proceeded through a chelated
model similar to Structure 8. However, the success of 8-
phenylmenthol as an effective chiral transfer auxiliary
combined with the fact that methanesulfonic acid is just as
Synlett 1999, No. 10, 1612–1614 ISSN 0936-5214 © Thieme Stuttgart · New York

1614
L. N. Pridgen
LETTER
0-10 °C, methanesulfonic acid (2 equiv) was added to this
ether formation to complete the eventual synthesis of 1a
and 1b. For a discussion of our synthesis efforts towards
1a and 1b using 4a and a methyl ester derivative see ref-
erences 4 and 6.
slurry. A reddish-brown two phase suspension resulted which
was allowed to warm to ambient temperature and stir 1 hr. The
reaction mixture was transferred to a separatory funnel and a
heavy reddish-brown oil separated from the organic layer and
was removed. Enough NaHCO3 (5% aqueous solution) was
slowly added to the separatory funnel to adjust the pH of the
toluene solution to within the 7-8 range. The aqueous layer
was then discarded. The organic layer was washed with water
(2 x 50 mL) and brine (30 mL) then was concentrated under
vacuum to yield 4.4 g (88%) of 4a and 5a as a 85 / 15 mixture
of diastereoisomers. The glassy amorphous solid was
dissolved in warm methanol (~50 °C) but yielded on cooling
the solid, single diastereoisomer 4a: mp 136–138 °C; [a]+
42.3 ° (c 1.0, CHCl3); IR (KBr) n = 1785, 1722, 1697, 1485,
1335 cm–1; d 1H NMR (300 MHz, CDCl3) d = 1.03 (t, 3 H, J
= 7.5 Hz), 1.8 (m, 2 H), 3.95 (t, 2 H, J = 6.5 Hz), 4.25 (dd, 1
H, J = 8.8, 5.4 Hz), 4.71 (1 H, t, J = 9.1 Hz), 4.98 (1 H, d, J =
5.2 Hz), 5.4 (bs, 1 H), 5.45 ( dd, 1 H, J = 9.0, 5.5 Hz), 5.9 (s,
2 H), 6.6 – 6.75 (m, 3 H), 7.1 – 7.5 (m, 8 H); 13C NMR (75
MHz, CDCl3) d = 10.43, 22.4, 45.7, 56.2, 58.4, 64.2, 69.9,
70.0, 72.5, 101.1, 105.7, 108.2, 108.4, 121.5, 125.2, 125.9,
127.1, 128.6, 128.9, 135.4, 135.7, 138.3, 146.9, 148.1, 148.2,
153.4, 159.4, 167.0, 196.9; MS (m/z ) 500 (M–H)+, 378, 337,
215, 173, 164. Anal. Calcd. for C29H25NO7: C, 69.73; H, 5.04;
N 2.80. Found: C, 70.00; H, 4.75; N, 2.83.
Acknowledgement
The authors are indepted to Mr. M. Olsen and P. Cummings for
mass spectra data; Ms. P. Offen for NMR data; and Mr. G. Zuber
for FT/IR.
References and Notes
(1) Elliot, J. D; Lago, M. A.; Cousins, R. D.; Gao, A.; Leber, J. D.
Erhard, K. F.; Nambi, P.; Elshoursbagy, N. A.; Kumar, C.;
Lee, J. A.; Bean, J. W.; DeBrosse, C. W.; Eggleston, D.S.;
Brooks, D. P.; Feurerstein, G.; Ruffolo, R. R. Jr.; Weinstock,
J.; Gleason, J.G.; Peishoff, C. E.; Ohlstein, E.H.; J. Med.
Chem. 1994, 37, 1553.
(2) Mills, R. J.; Ping, L.-J.; Kowalski, C. J. manuscript to be
submitted.
(3) Wood, J. L.; Mellinger, M.; Su, Q. manuscript to be submitted.
(4) Clark, W. C.; Tickner–Eldridge, A. M.; Huang, G. K.;
Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N.
H. J. Am. Chem. Soc. 1998, 120, 4550. See also reference 6.
(5) McGuire, M. A.; Shilcrat, S. C.; Sorenson, E. Tetrahedron
Lett. 1999, 40, 3293.
(6) Pridgen, L. N.; Huang, G. K. Tetrahedron Lett. 1998, 39,
8421.
(7) A chiral auxiliary of opposite configuration may be
substituted to obtain the enantiomer of 4a.
(8) Habermas, K. L; Denmark, S. E. Jones, S. E. in Organic
Reactions Vol. 45 Paquette, L. A. Ed.; John Wiley & Sons:
New York, 1994, Vol. 45, p 1.
(9) (a) Denmark, S. E. in Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I. Eds.; Pergamon Press: Oxford, 1991,
Vol. 5, p 751. (b) Ramaiah, M. Synthesis 1983, 429. (c)
Bender, J. A; Blize, A. E.; Browder, C. C.; Giese, S.; West, F.
G J. Org. Chem. 1998, 63, 2430.
(10) For relevant achiral examples of Nazarov cyclizations see:
(a) Bergmann, J.; Venemalm, L. Tetrahedron Lett. 1987, 28,
3741. (b) Sartori, G.; Bigi, F.; Maggi, R.; Luca, G.; Bernardi,
G. L. Tetrahedron Lett. 1993, 34, 7339. (c) Ichikawa, J.;
Fujiwara, T.; Okauchi, T.; Minami, T. Synlett 1998, 927.
(d) Kajioka, T.; Oda, M.; Yamada, S.; Kawamori, Y.;
Miyatake, R.; Kuroda, S. Synthesis 1999, 184.
(11) (a) Tietze, L. F.; Schünke, C. Angew. Chem. Int. Ed., Engl.
1995, 34 , 1731. (b) Tietze, L. F.; Schünke, C. Eur. J. Org.
Chem. 1998, 10, 2089.
(13) Crystal data for 3a: [X1] C29H25NO7, M=499.50, monoclinic,
space group P21, a=13.992(3), b=6.0210(10), c=15.310(3) Å,
β =108.38(3), V=1224.0(4) Å3, Z=2, ρcalcd=1.355Mg/m3,
F(000) = 524, T=223(2)K, µ(MoKα)=0.805cm-1,crystal
dimensions 0.50 x 0.18 x 0.04mm3. Enraf-Nonius CAD4
diffractometer, graphite monochromator, λ=1.54178Å, scan
range 6° < 2θ < 125°. Of 2296 measured reflections, 2157 were
independent (Rint = 0.04) and 2059 had I > 2σ (I). The
structure was solved by direct methods using SHELXS-90 and
refined with all data (336 parameters) by full-matrix least
squares of F2 using SHELXL-93 (G. M. Sheldrick, Gottingen,
1993). All non-hydrogen atoms were refined anisotropically
and hydrogen atoms were included in idealized positions with
a riding model. Final R values are R1 = 0.046 (I > 2σ (I)) and
wR2 = 0.134 (all data). Crystallographic data (excluding
structure factors) for the structures reported in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication nos. CCDC-102250.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB21EZ,
UK (fax: int. code + (44)1223 336-033; e-mail:
deposit@ccdc.cam.ac.uk).
Article Identifier:
1437-2096,E;1999,0,10,1612,1614,ftx,en;S03699ST.pdf
(12) General procedure for compound 4a. With stirring and
cooling to 0–10 °C, solid 3a (5 g, 0.01 mol) was added to a
flask containing 50 mL of toluene. Over a 10 minute period, at
Synlett 1999, No. 10, 1612–1614 ISSN 0936-5214 © Thieme Stuttgart · New York