Syntheses of isomerically pure reference octalins and hydrindanes

Article abstract of DOI:10.1016/j.tetlet.2009.07.068

We describe herein the development of efficient and stereoselective synthetic routes to a range of cis- and trans-octalin and hydrindane target compounds.

Full text of DOI:10.1016/j.tetlet.2009.07.068

Tetrahedron Letters 50 (2009) 5482–5484
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Tetrahedron Letters
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Syntheses of isomerically pure reference octalins and hydrindanes
Jun Hee Lee a, Woo Han Kim b, Samuel J. Danishefsky a,b,
*
a Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
b Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein the development of efficient and stereoselective synthetic routes to a range of cis- and
trans-octalin and hydrindane target compounds.
Received 22 June 2009
Revised 10 July 2009
Accepted 14 July 2009
Available online 18 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
In the context of a program underway in our laboratory,1 wherein
we are exploring fresh extensions of Diels–Alder-based strategies,
we required access to several simple homogeneous, stereochemi-
cally defined unsubstituted cis- and trans-octalins and hydrindanes
(compounds 1–5, Fig. 1). Remarkably, a comprehensive survey of the
synthetic literature revealed that only a few of the required com-
pounds had been described previously.2a–e Moreover, the routes
for the synthesis of such compounds gave mixtures of stereoisomers
which were not purified. Additional reaction steps would be
required to gain access to homogeneous material. For instance, the
synthesis of tricyclic trans-3, accomplished through acid-catalyzed
rearrangement of a precursor dodecahydroanthracene, furnished a
low yield of the desired compound (15%), along with several other
by-products. An analytical sample of trans-3 could be obtained only
by preparative gas chromatography. Among the target compounds,
only cis-4 was obtained in a stereochemically secure manner,
through Diels–Alder reaction of cyclopentadiene with 2,3-di-
methyl-1,3-butadiene followed by regioselective hydrogenation of
the cyclopentene olefin.
unsuccessful, leading to low recovery of the desired compounds,
and formation of a variety of polar by-products. Epimerization of
the cis-diketones 7b–c was preferably conducted at room tempera-
ture with 1 M NaOH (1.2 equiv) for 10 min to afford 8b and 8c in 40%
and 79% yields, respectively. However, Wolff–Kishner reduction of
CH3
CH3
CH3
1
2
3
CH3
CH3
CH3
5
4
Figure 1. cis- and trans-decalins and hydrindanes prepared in this study.
O
O
O
H
H
H
H
H
H
R
R
R
b
a
In order to obtain the required quantities of our target systems
through viable pathways, we were obliged to devise modified syn-
theses of the target compounds (1–5). In this Letter, we relate how
these goals were accomplished.
R'
R'
R'
O
O
O
6a R = R' = CH3
6b R = H, R' = CH3
6c R = R' = (CH2)4
7a R = R' = CH3
7b R = H, R' = CH3
7c R = R' = (CH2)4
8a R = R' = CH3
8b R = H, R' = CH3
8c R = R' = (CH2)4
We first describe routes to the trans-octalin derivatives, 1–3
(Scheme 1). Our key building blocks are the known cyclohexen-
1,4-diones, 6a–c, themselves prepared through Diels–Alder reaction
of 1,4-benzoquinonewiththeappropriatedienes (2,3-dimethyl-1,3-
butadiene,2a isoprene,2b and 1,2-dimethylenecyclohexane,3 respec-
tively). Chemoselective reduction of 6a–c (Zn in aqueous AcOH)
yielded the cis-diketones 7a–c.2a,2b Following literature prece-
dents,2a a solution of cis-diketone 7a in 1,4-dioxane was treated with
1 M NaOH (1.07 equiv) at 80 °C for 10 min, to yield the higher melt-
ing trans-isomer, 8a. Attempts to achieve epimerization of cis-dike-
tones 7b and 7c at comparably high temperatures were
TsHNN
H
H
H
R
R
c
d
R'
R'
H
TsHNN
9a R = R' = CH3
9b R = H, R' = CH3
9c R = R' = (CH2)4
trans-1 R = R' = CH3
trans-2 R = H, R' = CH3
trans-3 R = R' = (CH2)4
Scheme 1. Synthesis of trans-1, trans-2, and trans-3. Reagents and conditions: (a)
Zn, AcOH/H2O (2:1, v/v), 50 °C or <30 °C, 85% (7a), 93% (7b), 87% (7c); (b) 1.0 M
NaOH, 1,4-dioxane, 80 or 23 °C, 10 min, 92% (8a), 40% (8b), 79% (8c); (c) TsNHNH2,
EtOH, reflux, 20 min; 72% (9a), 85% (9b), 78% (9c); (d) catecholborane, CHCl3/
THF(2:1, v/v), À10 to 0 °C, 1 h; then NaOAcÁ3H2O, reflux, 1 h, 66% (trans-1), 82%
(trans-2), 41% (trans-3).
* Corresponding author. Tel.: +1 212 639 5501; fax: +1 212 772 8691.
E-mail address: s-danishefsky@ski.mskcc.org (S.J. Danishefsky).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.068

J. H. Lee et al. / Tetrahedron Letters 50 (2009) 5482–5484
5483
H3C
R
CO2CH3
CO2CH3
H3C
R
H3C
R
thetrans-diketones8a–caffordedunsatisfactorymixturesofcis-and
trans-olefins 1–3. Fortunately, reduction4 of trans-bitosylhydraz-
ones 9a–c (which were readily prepared from 8a–c) afforded pure
octalin derivatives trans-1–3.
Having synthesized compounds 1–3 in the trans series, we next
sought to prepare the corresponding cis-octalin derivatives,
namely cis-1–3 (Scheme 2). The known cis-bicyclic ketones, 10a–
b,5 were prepared by Diels–Alder reaction of cyclohex-2-en-1-
one with 2,3-dimethyl-1,3-butadiene and isoprene, respectively,
in the presence of catalytic CH3AlCl2. The formation of the trans-
isomeric cycloadducts could be suppressed by conducting the reac-
tion at 0 °C.
Similarly, CH3AlCl2-catalyzed Diels–Alder reaction between
cyclohex-2-en-1-one and 1,2-dimethylenecyclohexane afforded
the tricyclic ketone 10c in 55% yield. Again, reduction of com-
pounds 10a–c (NaBH4, CH3OH, À30 °C) furnished the correspond-
ing carbinols 11a–c as diastereomeric mixtures of alcohols. All
major diastereomers of 11a–c were separated from their minor
isomers by simple column chromatography on silica gel.6 Actually
we could not, at this stage, confidently assign the stereochemistry
of the hydroxy-bearing center. In any case, derived Barton–
McCombie reduction7 of xanthate esters 12a–c gave the target
compounds, cis-1–3.
c
OX
OX
X
X
a
14a R = CH3, X = H
14b R = X = H
16a R = CH3, X = CN
16b R = H, X = CN
13a R = CH3
13b R = H
b
d
15a R = CH3, X = Ts
15b R = H, X = Ts
17a R = CH3, X = CO2H
17b R = H, X = CO2H
H
H
H3C
R
H3C
f, g
H3C
i
CO2Et
CO2Et
e
X
R
R
H
H
18a R = CH3
18b R = H
19a R = CH3, X = O
19b R = H, X = O
trans-4 R = CH3
trans-5 R = H
h
20a R = CH3, X = NNHTs
20b R = H, X = NNHTs
Scheme 3. Synthesis of trans-4 and trans-5. Reagents and conditions: (a) LiAlH4,
THF, 0–23 °C, 60 min, 93% (14a), 99% (14b); (b) p-TsCl, pyridine, 0 °C, 3 h; (c) NaCN,
EtOH, reflux, 60 h, 83% over two steps (16a), 79% over two steps (16b); (d) 6 M KOH,
reflux, 24 h; (e) EtOH, H2SO4, 48 h, 83% over two steps (18a), 81% over two steps
(18b); (f) NaH, THF, reflux, 2.5 h; (g) DMSO, H2O, 155 °C, 2.5 h, 81% over two steps
(19a), 76% over two steps (19b); (h) H2NNHTs, EtOH, reflux, 40 min, 91% (20a), 90%
(20b); (i) catecholborane, CHCl3/THF(2:1, v/v), À10 to 0 °C, 1 h; then NaOAcÁ3H2O,
reflux, 1 h, 63% (trans-4), 59% (trans-5).
hydroindanones 19a–b. With the hydrocarbon skeletons of the two
trans-hydrindane derivatives fully assembled, the remaining task
was the deoxygenation of 19a–b. Treatment of refluxing ethanolic
solutions of 19a–b with p-toluenesulfonyl-hydrazide furnished the
corresponding tosylhydrazones 20a–b as white crystalline solids.
Reduction of 20a–b with catecholborane4 provided the target
trans-hydrindanes, trans-4 and trans-5, in 63% and 59% yields,
respectively (Scheme 3).
The availability for the first time of these reference compounds
enables confident structure assignments in our ongoing Diels–Al-
der program, the results of which will be described in due course.
Finally, we report the syntheses of the cis-fused hydrindanes,
cis-4 and cis-5. As shown in Scheme 4, the known bicyclic ketones
21a–b were reduced (NaBH4, CH3OH, À30 °C) to afford alcohols
22a–b as diastereomeric mixtures, which were then converted to
23a–b as shown. Treatment of these xanthate esters with nBu3SnH
and catalytic amounts of AIBN afforded cis-4 and cis-5. The 13C
NMR spectrum of the former was identical to that reported in
the literature.2e As observed in the octalin series (vide supra), the
ring junction carbons of cis-4–5 are more shielded than those of
the corresponding trans-isomers. For example, the 13C NMR chem-
ical shifts of the two ring junction carbons of cis-3-methylbicy-
clo[4.3.0]non-3-ene (cis-5) appear at 36.82 and 35.77 ppm as
singlets, whereas two singlets are observed at 42.90 and
42.18 ppm in the 13C NMR spectrum of trans-5.6
In accord with Casadevall’s observation,8 the ring junction car-
bons of cis-1–3 are more shielded than those of trans-1–3. For
example, the 13C NMR chemical shifts of the two ring junction car-
bons of cis-3-methylbicyclo[4.4.0]dec-3-ene (cis-2) appear at 33.65
and 33.50 ppm as singlets, whereas two singlets are observed at
38.61 and 38.15 ppm in the 13C NMR spectrum of trans-2.6
With the target compounds in the cis- and trans-octalin series in
hand, we next turned our attention to the preparation of the cis-
and trans-hydrindane target compounds, 4 and 5. Our route to
trans-4 and trans-5 began from the known chiral racemic diols,
14a–b,9 themselves prepared through Diels–Alder reaction of di-
methyl fumarate with the appropriate dienes, followed by LiAlH4
reduction (13 ? 14). As shown in Scheme 3, diols 14a–b were
converted to ketones 19a–b using methods analogous to those
employed in the preparation of trans-bicyclo[4.3.0]non-3-en-8-
one.10 Thus, treatment of 14a–b with p-TsCl in pyridine at 0 °C
afforded ditosylates 15a–b, which were then subjected, without
further purification, to the action of ethanolic solutions of sodium
cyanide, under reflux. Thus 16a–b were obtained, which were
immediately converted to the corresponding diesters 18a–b by
Fisher esterification. Sequential Dieckmann cyclization, hydrolysis
of the resultant b-keto esters, and decarboxylation provided tetra-
O
HO
O
H
H
H
H
R
In summary, we have described herein the development of
workable protocols for the preparation of the cis- and trans-junc-
tion isomers of a range of octalin and hydrindane structures.
R
R
a
b
+
R'
R'
R'
10a R = R' = CH3
10b R = H, R' = CH3
10c R = R' = (CH2)4
11a R = R' = CH3
11b R = H, R' = CH3
11c R = R' = (CH2)4
S
S
H3C
H
R
O
X
H
H
S
O
H
H
H
H
CH3
S
R
c
H
H
d
R
R
b
R
c
R'
H
H3C
H3C
H3C
R'
cis-1 R = R' = CH3
cis-2 R = H, R' = CH3
cis-3 R = R' = (CH2)4
cis-4 R = CH3
cis-5 R = H
21a R = CH3, X = O
21b R = H, X = O
23a R = CH3
23b R = H
12a R = R' = CH3
12b R = H, R' = CH3
12c R = R' = (CH2)4
a
22a R = CH3, X = H, OH
22b R = H, X = H, OH
Scheme 2. Synthesis of cis-1, cis-2, and cis-3. Reagents and conditions: (a) CH3AlCl2
(20 or 50 mol %), CH2Cl2, 0 °C, 20–22 h; 70% (10a), 53% (10b), 55% (10c); (b) NaBH4,
CH3OH, À30 to 0 °C, 82% (11a), 72% (11b), 78% (11c); (c) NaH, THF, 23 °C, 30 min;
CS2, 23 °C, 40 min; then CH3I, 50 °C, 2 h, 98% (12a), 99% (12b), 93% (12c); (d)
nBu3SnH, AIBN, benzene, 85 °C, 23% (cis-1), 17% (cis-2), 39% (cis-3).
Scheme 4. Synthesis of cis-4 and cis-5. Reagents and conditions: (a) NaBH4, CH3OH,
À30 to 0 °C, 96% (22a), 95% (22b); (b) NaH, THF, 23 °C, 30 min; CS2, 23 °C, 40 min;
then CH3I, 50 °C, 2 h, 90% (23a), 88% (23b); (c) nBu3SnH, AIBN, benzene, 85 °C,
40 min, 31% (cis-4), 15% (cis-5).

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J. H. Lee et al. / Tetrahedron Letters 50 (2009) 5482–5484
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Acknowledgments
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This work was supported by the NIH (HL25848 to S.J.D.). W.H.K.
is grateful for a Korean Research Foundation Grant funded by Kor-
ean Government (KRF-2007-357-c00060). We thank Ms. Rebecca
Wilson for valuable help in editing of this Letter.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.07.068.
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