From glyceraldehyde to functionalized enantiopure tetrahydronaphthalenes and indanes

Article abstract of DOI:10.1016/S0040-4039(01)01914-1

Tricyclic tetrahydronaphthalenes comprising cis- and trans-fused lactones, and aryl substituted functionalized indanes were synthesized in enantiopure form.

Full text of DOI:10.1016/S0040-4039(01)01914-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8785–8788
From glyceraldehyde to functionalized enantiopure
tetrahydronaphthalenes and indanes
Stephen Hanessian* and Jianguo Ma
Department of Chemistry, Universite´ de Montre´al, CP 6128, Succ. Centre-Ville, Montreal, PQ, Canada, H3C 3J7
Received 28 August 2001; accepted 28 September 2001
Abstract—Tricyclic tetrahydronaphthalenes comprising cis- and trans-fused lactones, and aryl substituted functionalized indanes
were synthesized in enantiopure form. © 2001 Elsevier Science Ltd. All rights reserved.
Fused carbocyclic compounds containing an aromatic
moiety such as hydronaphthalenes and indanes are
important constituents of biologically active natural
products and compounds exhibiting pharmacological
properties.1 More than often they contain one or more
carbon or heteroatom substituents on the non-aromatic
portion, thereby introducing elements of stereochem-
istry and functional diversity. Fig. 1 shows the struc-
tures of a select group of biologically and medically
relevant molecules that harbor tetrahydronaphthalene
and indane motifs.1
In spite of their merits, current methods for the synthe-
sis of functionalized tetrahydronaphthalenes and
indanes do not address the combined advantages of
introducing diversity in the aromatic portion, while also
considering functional and stereochemical issues rela-
tive to the carbocyclic core.2 Lautens and co-workers3
OR
O
O
Me
N
O
O
O
R
O
O
Me
O
N
F
N
H
NH2
MeO
OMe
HN
OMe
Thrombin Inhibitor
Etoposide
(antitumor)
Mebefradil.HCl
(antialzheimer)
MeO
MeO
OH
Ph
NH
N
OH
N
N
O
N
CONHt-Bu
O
Donepezil.HCl
Crixivan
(antihypertensive)
(anti-HIV)
Figure 1.
Keywords: 1,2-induction; cuprate addition; Friedel–Crafts; lactone.
* Corresponding author. Tel.: (514) 343-6738; fax: (514) 343-5728; e-mail: stephen.hanessian@umontreal.ca
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01914-1

8786
S. Hanessian, J. Ma / Tetrahedron Letters 42 (2001) 8785–8788
have reported on versatile rhodium- and palladium-cat-
alyzed asymmetric methods for the introduction of
hydroxy and amino groups in dihydronaphthalenes
with considerable enantioenrichment.
we reduced the mixture of 8 and 9 to afford the
tetrahydronaphthalene lactones 10 and 13 in 14 and
65% yields, respectively, demonstrating that the trans-
lactone 8 was indeed the major product arising from
the cyclization of the original anti/anti carboxylic acid
motif via its acid chloride (Scheme 1). Further manipu-
lation of 13 afforded the trisubstituted tricyclic com-
pound 14 as the trans-lactone diastereomer of 11.
Lactones comprising tricyclic systems can be found in
etoposides7 and in a thrombin inhibitor consisting of a
trans-fused lactone appended to an indane unit8 (Fig.
1). Reduction of the ketone 9 with sodium borohydride
in tetrahydrofuran afforded a 1:1 mixture of the corre-
sponding benzylic alcohols, which are formally related
to the etoposide skeleton.
We report herein a versatile and highly stereocontrolled
method for the synthesis of trisubstituted tetra-
hydronaphthalenes possessing usable functionality for
diversification. The core structure can be considered as
a semi-rigid scaffold for the deployment of biologically
relevant appendages in the context of a library design.4
Scheme 1 illustrates the methodology which capitalizes
on a series of 1,2-asymmetric inductions using an
acyclic motif 1.5 The addition of diphenylmagnesio
cuprate (as well as other substituted analogs)6 to 1 and
subsequent modification of the ester group affords the
conjugate addition product 2 in high yield. Protection
and extension generates another g-alkoxy-a,b-unsatu-
rated ester which is subjected to a 2-directional6 mixed
cuprate addition affording the anti/anti vinylic product
5. Transformation to the lactone, oxidative cleavage
and ring closure of the corresponding acid chloride
under the venerable Friedel–Crafts reaction conditions
led to a 3:1 mixture of the trans-8 and cis-9 tricyclic
lactones in good yield. Chromatography of the crude
mixture over silica gel afforded the cis-lactone 9 in 82%
yield, demonstrating the extreme tendency for the
trans-lactone 8 to isomerize (Scheme 2). Catalytic
reduction of 9 followed by removal of the pivalate ester
led to the tricyclic lactone 11, whose structure was
definitively established by single-crystal X-ray analysis.
Conversion of the primary alcohol to the corresponding
azide as in 12 afforded an amine precursor for further
diversification. Since the carbonyl group in 8 was
undoubtedly responsible for the ready isomerization,
Our approach to the indanol system also included
functional diversity in the aromatic moiety (Scheme 3).
Thus, conjugate addition of mixed diarylmagnesium
cuprates to the enolate 1 in the presence of TMSCl
afforded the corresponding adducts 16–19. We then
proceeded with the phenyl and m-methoxyphenyl
analogs as representative examples for the construction
of the indanols. A series of standard reactions gener-
ated intermediates such as 20–25 representing the two
series. Conversion to the acid chloride and Friedel–
Crafts cyclization led in each case to the indanone
dipivaloates (26, 27) in excellent yields. Finally, hydro-
genation and deesterification afforded indane diols 28
and 29, respectively. The structure and absolute
configuration of the m-methoxyphenyl analog was
ascertained by single-crystal X-ray analysis.
The prototypical enantiopure tetrahydronaphthalene
and indane analogs prepared by the presently reported
OBOM
OBOM
TBDPSO
OBOM
OH
HO
OPiv
[ref. 6 ]
1. Swern
1. PivCI, Py, 92%
2. TBAF, 86%
TBDPSO
CO2Me
2. Wittig
84%
1
2
3
O
OBOM
O
OBOM
(CH2=CH)2CuMgCI
TMSBr
CH2Cl2, 79%
OPiv
OPiv
OPiv
MeO2C
MeO2C
TMSCI, THF
85%
5
6
Syn/Anti > 8 : 1
4
O
O
O
O
O
O
RuCI3 . n H2O
NaIO4, 86%
I. (COCI)2
OPiv
OPiv
OPiv
+
2. AlCI3, CH2CI2
HO2C
O
O
9 (20%)
7
8 (60%)
Scheme 1.

S. Hanessian, J. Ma / Tetrahedron Letters 42 (2001) 8785–8788
8787
O
O
O
O
1.MeONa, MeOH
+
8
9
H2, Pd/C
Chromatography
OPiv
OPiv
The crude mixture
2. TsOH, THF, 80%
AcOH, 82%
on silica gel
O
82% from 7
10
9
O
H
H
H
DEAD, PPh3
DPPA, THF
O
OH
O
O
O
O
81%
H
N3
HO
12
11
11
O
O
O
O
+
H2, Pd/C
AcOH
OPiv
8
9
OPiv
The crude mixture
+
(14%)
(65%)
10
13
O
O
H
OH
1. MeONa, MeOH
2. TsOH, THF, 74%
O
13
O
H
HO
14
Scheme 2.
OBOM
OH
TBDPSO
[ ref. 6 ]
TBDPSO
OH
1. Dibal-H,
2. H2, Pd/C, MeOH
PivCl, DMAP
CH2Cl2
1
CO2Me
80-86%
15 R=H
16 R=p-Me
17 R=p-OMe
18 R=p-F
R
R
19 R=m-OMe
20 R=H, 84%
21 R=OMe, 80%
OPiv
OPiv
OPiv
1. TBAF, AcOH
.
2. SO3 Py, DMSO
Et3N
OPiv
I. (COCI)2
OPiv
TBDPSO
OPiv
O
HO2C
2. AlCI3, CH2CI2
3. NaClO2, NaH2PO4
t-BuOH, H2O
2-Methyl-2-butene
R
R
R
22 R=H, 94%
23 R=OMe, 95%
OH
26 R= H, 82%
27 R= OMe, 84%
24 R= H, 71%
25 R= OMe, 73%
OH
1. H2, Pd/C, AcOH
2. Dibal-H, Toluene
OH
OH
R
R= OMe
R
28 R= H, 79%
29 R= OMe, 76%
Scheme 3.

8788
S. Hanessian, J. Ma / Tetrahedron Letters 42 (2001) 8785–8788
methodology will be useful scaffolds in the context of
drug design and natural product synthesis.9
Int. Ed. 2000, 39, 1045.
4. See for example: Perrone, R.; Berardi, F.; Colabufo, N.
A.; Leopoldo, M.; Tortorella, V.; Fiorentini, F.; Olgiati,
V.; Ghiglieri, A.; Govoni, S. J. Med. Chem. 1995, 38, 942.
5. (a) Hanessian, S.; Sumi, K. Synthesis 1991, 1083; (b)
Hanessian, S.; Wang, W.; Gai, Y.; Olivier, E. J. Am.
Chem. Soc. 1997, 119, 10034; (c) Hanessian, S.; Gai, Y.;
Wang, W. Tetrahedron Lett. 1996, 37, 7473.
6. Hanessian, S.; Ma, J.; Wang, W. Tetrahedron Lett. 1999,
40, 4627; for other examples of two-directional synthesis,
see: Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27,
9; Still, W. C.; Barrish, J. C. J. Am. Chem. Soc. 1983, 105,
2487; for a review, see: Magnuson, S. R. Tetrahedron 1995,
51, 2167.
Acknowledgements
We thank NSERC for financial assistance through the
Medicinal Chemistry Chair and Dr. Michel Simard for
X-ray analysis.
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