C19 quassinoid model studies: Preparation of trans-perhydroindans via a vinylogous Mukaiyama aldol - Free-radical cyclization route

Article abstract of DOI:10.1139/v03-197

Aldehyde 9 was prepared in 5 steps from 3,5-dimethylbenzoic acid. Treatment of 9 with ketene acetals 10 and 19 and titanium tetrachloride gave free-radical cyclization substrates 11 and 20 in 67% and 51% yields, respectively. Tri-n-butylstannane-mediated

Full text of DOI:10.1139/v03-197

314
C19 quassinoid model studies: Preparation of
trans-perhydroindans via a vinylogous Mukaiyama
aldol – free-radical cyclization route1
Matthew G. Donahue and David J. Hart
Abstract: Aldehyde 9 was prepared in 5 steps from 3,5-dimethylbenzoic acid. Treatment of 9 with ketene acetals 10
and 19 and titanium tetrachloride gave free-radical cyclization substrates 11 and 20 in 67% and 51% yields, respec-
tively. Tri-n-butylstannane-mediated cyclization of 11 and 20 gave trans-perhydroindans 14 and 21 in 60% and 63%
yields, respectively. The relationship of these studies to an approach to C19 quassinoids is discussed.
Key words: vinylogous Mukaiyama aldol reaction, free-radical cyclization, trans-perhydroindans, C19 quassinoids, 1,2-
asymmetric induction.
Résumé : L’aldéhyde 9 est préparé en 5 étapes à partir de l’acide 3,5-diméthylbenzoique. Le traitement de 9 avec les
acetals de kétène 10 et 19 et le tetrachlorure de titane donne les substrats de cyclisation par radicaux libres 11 et 20
avec des rendements respectifs de 67% et 51%. La cyclisation de 11 et 20 par le tri-n-butylstanne donne les trans-per-
hydroindanes 14 et 21 avec des rendements respectifs de 60% et 63%. On discute la relation de ces études avec une
approche vers les quassinoides en C19.
Mots clés : réaction d’aldol vinylogue de Mukaiyama, cyclisation par radicaux libres, trans-perhydroindanes, quassinoi-
des en C19, induction asymétrique-1,2.
Donahue and Hart 317
Introduction
is replaced with a methyl group and R1 and R2 are electron-
withdrawing and methyl groups, respectively. The specific
substrate selected for synthesis (11) was prepared as de-
scribed in Schemes 1 and 2. 3,5-Dimethylbenzoic acid (4)
was subjected to Birch reduction, according to an estab-
lished procedure, to provide 5 (mp 113–115 °C) in 95%
yield (4). Aldol condensation of the dianion derived from 5
with formaldehyde provided hydroxy acid 6 in 93% yield
(5). Reduction of 6 using lithium aluminum hydride pro-
vided diol 7 (mp 99 to 100 °C) in 57% yield. Treatment of 7
with NBS in tetrahydrofuran gave cycloetherification prod-
uct 8 (99%), and oxidation of the primary alcohol using
Swern’s conditions provided aldehyde 9 in 96% yield (6).
Reaction of 9 with dienol ether 10 (7) in the presence of
titanium tetrachloride gave a 6:1 mixture of vinylogous
Mukaiyama aldol products 11 (67%) and 12 (11%) (8).3 We
note that promotion of the vinylogous Mukaiyama aldol with
boron trifluoride etherate provided 11 (mp 134 to 135 °C)
and 12 (mp 83–85 °C) in 11% and 42% yields, respectively.
The C19 quassinoids are a small family of terpenoids that
have received less attention from the synthetic community
than the corresponding C20 quassinoids (1). Indeed only the
second synthesis of a C19 quassinoid was reported in 1999,
when Grieco described a synthesis of (5R)-polyandrane (1)
(2). We have been investigating a unified approach to se-
lected C19 and C20 quassinoids that involves an extension of
free-radical cyclization chemistry previously developed in
our laboratories (3). The plan for the polyandranes (Fig. 1)
involves preparation of trans-perhydroindans of type 2 via
free-radical cyclization of substrates of type 3. This commu-
nication reports preliminary results of this study.
Results and discussion
Our first objective was to prepare a substrate of type 3
where the incipient C11 hydroxyl group of the polyandranes
Received 16 September 2003. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 13 February 2004.
Dedicated to Professor Edward Piers whose commitment to science and education is admirable.
M.G. Donahue and D.J. Hart.2 Department of Chemistry, The Ohio State University, 100 W. 18th Avenue, Columbus, OH 43210,
U.S.A.
1This article is part of a Special Issue dedicated to Professor Ed Piers.
2Corresponding author (e-mail: hart@chemistry.ohio-state.edu).
3The stereochemical assignments at C7 for 11 and 12 were based on NMR correlations with related compounds, including one for
which an X-ray crystal structure was obtained. NMR studies on the cyclization products derived from 11 and 12 also clearly
defined C7 stereochemistry.
Can. J. Chem. 82: 314–317 (2004)
doi: 10.1139/V03-197
© 2004 NRC Canada

Donahue and Hart
315
Scheme 2. Vinylogous Mukaiyama aldol – free-radical cycliza-
Fig. 1. Synthetic plan.
tion.
(9a) and Ahn and Eisenstein (9b). Thus, a complex between
the Lewis acid and 9, which involves bridging of the bro-
mine and carbonyl oxygen with titanium, is conformation-
ally constrained such that attack anti to the C8—C14 bond
should be stereoelectronically preferred, giving rise to 11 in
a conformation in which substituents are staggered along the
C7—C8 bond.
Scheme 1. Synthesis of aldehyde 9.
Treatment of 11 with tri-n-butylstannane in the presence
of 2,2′-azobisisobutyronitrile (AIBN) provided cyclization
products 14 (60%) and small amounts (less than 6%) of ma-
terial suspected to be the C10 epimer of 14. We note that a
less than 1% yield of 15, an interesting product derived from
an initial 6-endo cyclization, was also isolated. The stereo-
chemistry of 14 was established by difference NOE experi-
ments, which confirmed a cis-relationship between the C7
hydrogen and C20 methylene group, a cis-relationship be-
tween the C20 and C5 methylene groups, and a cis-relation-
ship between the C9 hydrogen and C19 methyl group. This
result established the viability of the proposed preparation of
compounds of type 2 by free-radical cyclization of com-
pounds of type 3. It also demonstrated that this approach
was unlikely to directly afford the required C9–C10 stereo-
chemical relationship.4
Two attempts to address the C9–C10 stereochemical prob-
lem are described in Fig. 2 and Scheme 3. An examination
of molecular models suggested that lactone 17 was con-
strained such that cyclization would provide the desired C9–
C10 stereochemistry. Treatment of 9 with 3-methyl-1-tri-
methylsiloxy-1,3-butadiene in the presence of potassium
tert-butoxide followed by Jones oxidation of the resulting
lactols 16 provided 17 in 33% overall yield (Fig. 2) (10). We
were disappointed to find that attempts to cyclize 17 under a
variety of conditions failed (11). For example, typical tri-n-
In addition, titanium tetrachloride mediated reaction of des-
bromo compound 13 with 10 gave a complex mixture of
products that contained very little material resulting from a
vinylogous aldol. Thus, the nature of the Lewis acid and the
presence of a bromine atom in 9 play a central role in the
observed diastereoselectivity. We speculate that the stereo-
selectivity observed with titanium tetrachloride is due to a
combination of a chelation effect and principles for 1,2-
asymmetric induction introduced by Felkin and co-workers
4 Similar cyclization of 12 provided a 76% yield of the C7 epimer. We note that derivatives of 11 and 12 lacking the impending C10 methyl
group were prepared and cyclized with comparable results. In these cases compounds of type 14 (53%–72%) and the corresponding C10
epimer (15%–18%) were isolated, and the structures of all products were rigorously established.
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Can. J. Chem. Vol. 82, 2004
Fig. 2. Lactone substrates and products.
Characterization data for compounds in
synthesis of 21
13C NMR multiplicities in parentheses determined by
DEPT spectroscopy.
Hydroxy acid 6
mp 107–110 °C. IR (thin film) (cm–1): 3334, 1707, 1694.
1H NMR (CDCl3, 400 MHz) δ: 1.73 (s, 6H), 2.47, 2.51
(AB q, J = 22.2 Hz, 2H), 3.61 (s, 2H), 5.43 (s, 2H); neither
the acidic nor the alcoholic proton were recorded. 13C NMR
(CDCl3, 100 MHz) δ: 23.4 (q), 36.5 (t), 53.2 (s), 69.1 (t),
118.3 (d), 136.5 (s), 179.8 (s). Exact mass calcd. for
C10H14O3 ([M + Na]+) m/z: 205.0835; found: 205.0841.
Anal. calcd. for C10H14O3: C 65.90, H 7.75; found: C 65.84,
H 7.73.
Diol 7
1
mp 99 to 100 °C. IR (thin film) (cm–1): 3301 (br). H
NMR (CDCl3, 400 MHz) δ: 1.40 (t, J = 6.0 Hz, 2H), 1.69 (s,
6H), 2.43 (s, 2H), 3.37 (d, J = 6.1 Hz, 4H), 5.16 (s, 2H). 13
C
Scheme 3. Synthesis and cyclization of 20.
NMR (CDCl3, 100 MHz) δ: 23.5 (q), 37.0 (t), 47.8 (s), 68.8
(t), 121.5 (d), 137.0 (s). Exact mass calcd. for C10H16O2
([M + Na]+) m/z: 191.1043; found: 191.1045. Anal. calcd.
for C10H16O2: C 71.38, H 9.59; found: C 70.88, H 9.47.
Bromo ether 8
mp 49–51 °C. IR (neat) (cm–1): 3419 (br). 1H NMR
(CDCl3, 400 MHz) δ: 1.30 (s, 3H), 1.53 (s, 1H), 1.63 (s,
3H), 2.02 (d, J = 18.1 Hz, 1H), 2.34 (d, J = 18.1 Hz, 1H),
3.65, 3.67 (AB q, J = 11.2 Hz, 2H), 3.81, 3.90 (AB q, J =
6.8 Hz, 2H), 3.96 (s, 1H), 5.19 (s, 1H). 13C NMR (CDCl3,
100 MHz) δ: 22.3 (q), 23.6 (q), 44.3 (t), 50.1 (s), 55.8 (d),
63.0 (t), 76.4 (t), 81.5 (s), 122.8 (d), 135.9 (s). Exact mass
calcd. for C10H15BrO2 m/z: 246.0255; found: 246.0285.
Anal. calcd. for C10H15BrO2: C 48.74, H 6.14; found: C
48.45, H 6.19.
Aldehyde 9
1
mp 45–48 °C. IR (neat) (cm–1): 2729, 1729. H NMR
(CDCl3, 400 MHz) δ: 1.43 (s, 3H), 1.79 (s, 3H), 2.17 (d, J =
18.2 Hz, 1H), 2.45 (d, J = 18.3 Hz, 1H), 4.01, 4.10 (AB q,
J = 7.1 Hz, 2H), 4.29 (s, 1H), 5.91 (s, 1H), 9.67 (s, 1H). 13C
NMR (CDCl3, 100 MHz) δ: 20.9 (q), 21.6 (q), 42.7 (t), 52.0
(d), 58.8 (s), 74.3 (t), 81.2 (s), 117.4 (d), 135.7 (s), 197.4
(d). Exact mass calcd. for C10H13BrO2 ([M + Na]+) m/z:
266.9991; found: 267.0009. Anal. calcd. for C10H13BrO2: C
49.18, H 5.37; found: C 49.02, H 5.42.
butylstannane conditions gave only reduction product 18
(mp 135 to 136 °C). Apparently, conformational constraints
present in 17 severely retard radical cyclization rates relative
to 11. A potentially useful modification of the chemistry in-
volved cyclization of 20. This substrate was prepared in
51% yield by reaction of ketene acetal 19 with aldehyde 9
(12).5,6 Free-radical cyclization of 20 provided 21 in 63%
yield. We imagine the reductive decarboxylation of 21 will
afford the required C10 methyl group.
Ketene acetal 19
IR (neat) (cm–1): 3078, 1650, 1605. 1H NMR (C6D6,
500 MHz) δ: 0.17 (s, 9H), 3.04 (s, 3H), 3.14 (dd, J = 6.5,
1.2 Hz, 2H), 4.21 (s, 1H), 4.95 (d, J = 2.4 Hz, 1H), 5.05 (dd,
J = 10.1, 2.1 Hz, 1H), 5.16 (dd, J = 17.1, 2.0 Hz, 1H), 5.31
(d, J = 2.5 Hz, 1H), 6.05 (dddd, J = 17.1, 10.2, 6.8, 6.6 Hz,
1H). 13C NMR (C6D6, 125 MHz) δ: 0.47 (q), 42.4 (t), 54.6
5 Ketene acetal 19 was prepared by deprotonation and silylation of methyl (E)-3-methylhexa-2,5-dienoate (12). The reaction of 9 with 19 also
provided 6% of the C7 diastereomer of 20 and several minor products (perhaps lactones) whose structures have yet to be determined.
6 We note that reaction of 9 with a 1:1 mixture of 19 and its geometrical isomer provided lactones (stereochemistry at C7 unknown) as the
major products (Fig. 1). Thus, ketene acetal geometry influences the stereochemistry of this vinylogous Mukaiyama aldol.
© 2004 NRC Canada

Donahue and Hart
317
(q), 80.1 (d), 108.6 (t), 115.2 (t), 138.3 (d), 142.0 (s), 157.8
(s). Exact mass calcd. for C11H20O2Si ([M]+) m/z: 212.1227;
found: 212.1222.
tions of this chemistry, incorporating more appropriate func-
tionality at C11, are being developed.
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Dienone 20
1
mp 98 to 99 °C. H NMR (CDCl3, 500 MHz) δ: 1.37 (s,
3H), 1.73 (s, 3H), 1.95 (dd, J = 13.7, 11.1 Hz, 1H), 2.10 (d,
J = 18.1 Hz, 1H), 2.25 (br s, 1H), 2.40 (d, J = 18.1 Hz, 1H),
2.66 (d, J = 13.9 Hz, 1H), 3.23 (dd, J = 13.7, 7.2 Hz, 1H),
3.72 (s, 3H), 3.74 (dd, J = 13.8, 6.0 Hz, 1H), 3.80 (d, J =
6.6 Hz, 1H), 3.88 (d, J = 10.8 Hz, 1H), 4.01 (d, J = 6.6 Hz,
1H), 4.24 (s, 1H), 5.13 (d, J = 10.0 Hz, 1H), 5.18 (dd, J =
17.2, 1.5 Hz, 1H), 5.30 (s, 1H), 5.8–5.9 (m, 1H), 5.86 (s,
1H). 13C NMR (CDCl3, 100 MHz) δ: 22.5 (q), 23.5 (q), 36.8
(t), 41.1 (t), 44.3 (t), 51.5 (q), 52.3 (s), 56.1 (d), 68.6 (d),
72.4 (t), 81.3 (s), 117.6 (t), 119.4 (d), 122.4 (d), 135.2 (d),
136.7 (s), 157.2 (s), 166.5 (s). Exact mass calcd. for
C18H25BrO4 ([M + Na]+) m/z: 407.0828; found: 407.0802.
Anal. calcd. for C18H25BrO4: C 56.11, H 6.54; found: C
56.20, H 6.58.
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Perhydroindan 21
1
IR (neat) (cm–1): 3441, 3075, 3013, 1732, 1639. H NMR
(CDCl3, 500 MHz) δ: 1.46 (s, 3H), 1.68 (s, 3H), 1.76 (s,
1H), 1.87 (d, J = 15.4 Hz, 1H), 2.13 (d, J = 17.8 Hz, 1H),
2.36 (d, J = 17.8 Hz, 1H), 2.35 (s, 1H), 2.42 (dd, J = 13.3,
7.5 Hz, 1H), 2.55 (dd, J = 15.4, 5.0 Hz, 1H), 2.66 (d, J =
14.5 Hz, 1H), 2.71 (dd, J = 13.6, 7.6 Hz, 1H), 2.88 (d, J =
14.5 Hz, 1H), 3.62 (d, J = 7.6 Hz, 1H), 3.69 (s, 3H), 3.92 (d,
J = 7.7 Hz, 1H), 4.13 (d, J = 4.9 Hz, 1H), 5.17 (d, J =
4.2 Hz, 1H), 5.20 (s, 1H), 5.89–5.96 (m, 1H), 5.96 (s, 1H).
13C NMR (CDCl3, 125 MHz) δ: 22.2 (q), 23.4 (q), 40.4 (t),
45.3 (s), 47.8 (t), 48.4 (t), 51.7 (q), 52.6 (t), 61.7 (d), 62.3
(s), 73.2 (d), 79.2 (t), 85.4 (s), 119.1 (t), 128.2 (d), 135.6 (s),
135.8 (d), 173.3 (s). Exact mass calcd. for C18H26O4 ([M +
Na]+) m/z: 329.1723; found: 329.1728.
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Conclusions
In summary, a seven-step synthesis of 21 from 3,5-
dimethylbenzoic acid has been developed. The chemistry ex-
tends the scope of a free-radical cyclization route to perhy-
droindans and reveals some interesting stereochemical
features of the vinylogous Mukaiyama aldol condensation.
Compound 21 is functionalized appropriately for the pursuit
of the polyandranes at all positions except C11. Modifica-
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