A 6-exo-trig radical cyclization approach to the hydrochrysene skeleton

Article abstract of DOI:10.1016/S0040-4039(02)01728-8

The synthetic approach to a functionalized hydrochrysene skeleton is described. The route is highlighted by a Birch reduction-alkylation sequence and a 6-exo-trig radical cyclization.

Full text of DOI:10.1016/S0040-4039(02)01728-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7605–7608
A 6-exo-trig radical cyclization approach to the hydrochrysene
skeleton
Xuqing Zhang,* Timothy Guzi, Liping Pettus and Arthur G. Schultz†
Chemistry Department, Rensselaer Polytechnic Institute, Troy, NY 12180, USA
Received 22 July 2002; revised 15 August 2002; accepted 16 August 2002
Abstract—The synthetic approach to a functionalized hydrochrysene skeleton is described. The route is highlighted by a Birch
reduction–alkylation sequence and a 6-exo-trig radical cyclization. © 2002 Elsevier Science Ltd. All rights reserved.
The hydrochrysene skeleton is found in many steroidal
natural product, as well as a number of alkaloids and
terpenoids.1 Because of the wide occurrence and phar-
macological importance of these compounds, the devel-
opment of a new stereospecific route to access this ring
system remains an attractive objective in organic syn-
thesis. Most of the previous syntheses have relied on a
cationic cyclization cascade initiated from a polyene
precursor for the efficient construction of polycyclic
carbocyclic and heterocyclic systems.2 While this strat-
egy remains extremely powerful for constructing
hydrochrysene skeletons, the efficiency of this process
depends largely on the suitable choice of an initiator.3
To complement these traditional methods, a new syn-
thetic alternative which can better accommodate labile
functional groups in the substrate during ring forma-
tion is desirable.4 In an ongoing effort directed towards
the development of a strategy for the synthesis of
natural products containing a hydrochrysene core, we
report here a fast and convenient approach to the
construction of a functionalized hydrochysene 1 utiliz-
ing a low temperature radical cyclization.
Retrosynthetically, we envisaged hydrochrysene 1 (Fig.
1) arising via a 6-exo-trig radical cyclization of the
dienone 2, which could be prepared from the naph-
thoate 35 and the allyl bromide 46 via Birch reduction–
alkylation.
In practice, the Birch reduction of the naphthoates 3a–c
followed by alkylation with the corresponding allyl
bromides 4a–b provided the dienes 5a–d in 65–79%
overall yield.7 Oxidation of the dienes 5a–d at the
bis-allylic positions gave the benzo-annulated 2,5-cyclo-
hexadienones 6a–d in 80–92% yield (Scheme 1).8
Our initial investigations on the radical cyclization of
the dienones 6 were carried out under standard condi-
Figure 1.
* Corresponding author. Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Fax: (908)526-6469; e-mail: xzhang5@
prdus.jnj.com
† Deceased on January 20, 2000.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01728-8

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X. Zhang et al. / Tetrahedron Letters 43 (2002) 7605–7608
Scheme 1.
tions with Bu3SnH, Ph3SnH or (TMS)3SiH and AIBN
as an initiator at 80°C in benzene over 2 h. Unfortu-
nately, the only products obtained under these condi-
tions were the doubly-cyclized adducts 7b–c resulting
from a 6-exo-trig followed by 5-exo-trig cyclization9
(Scheme 2). We reasoned that since the first 6-exo-trig
cyclization should occur much more rapidly than the
second 5-exo-trig cyclization, lower temperatures would
allow for the reduction of the intermediate radical
species immediately following the first 6-exo-trig radical
cyclization thereby eliminating the by-product arising
from tandem cyclization.
double bond of 8b to the thermodynamically more
stable endo double bond was accomplished by treat-
ment with RhCl3·H2O in EtOH in 92% yield (Scheme
3). Decarboxylation of 9 under thermodynamical con-
trol with LiI in collidine afforded the adduct 10 as a
single diastereomer in 64% yield, along with its
regioisomers 11 as minor by-products (ꢀ17%).12 The
cis ring junction of the hydrochrysene derivative 10 was
assigned based on molecular modeling studies and
confirmed by NOE studies. Molecular mechanics, semi-
empirical and ab-initio calculations using Spartan soft-
ware calculated the cis isomer 10 to be
thermodynamically more stable [DE (Ecis−Etrans)=−5.01
kcal/mol, MMFF; DE=−2.30 AM1; DE=−3.03,
31G**) than its corresponding trans isomer. An NOE
between the angular H at l 3.99 and the angular CH3
at l 0.96 confirmed the cis ring junction of 10.
There is much precedence for the use of stoichiometric
Ph3SnH with Et3B as the initiator for low temperature
radical cyclizations.10 Applying these conditions to our
system, we were pleased to find that the cyclo-
hexadieones 6a–d smoothly cyclized to give 8a–d as the
major products.11 The results of the temperature effect
on this cyclization are summarized in Table 1. At
−78°C, the radical cyclization cleanly gave the desired
hydrochrysene derivative 8b with some starting material
remaining. At higher temperatures, as expected, the
ratio of the by-product 7b to the desired product 8b
increased. Ultimately, we found that the optimal tem-
perature for the formation of the desired 8b was 0°C.
Table 1. Temperature effect on transformation of 6b to 7b
and 8ba
Reaction temp. (°C)
6b (%)
7b (%)
8b (%)
−78
−10
0
33
10
0
0
5
10
20
67
85
90
80
25
0
Compound 8b could be further transformed into the
key intermediate 10, which constitutes a hydrochrysene
skeleton such as 1. Thus, isomerization of the exo
a The percentage of 6b, 7b and 8b was calculated from integration of
CO2-Me groups on 1H NMR.
Scheme 2.

X. Zhang et al. / Tetrahedron Letters 43 (2002) 7605–7608
7607
Scheme 3.
In conclusion, a sequential Birch reduction–alkylation
and 6-exo-trig radical cyclization approach to the
hydrochrysene skeleton has been developed resulting in
the efficient synthesis of several versatile intermediates.
Further exploration of this methodology will be
reported in due course.
6. Compound 3a and 3b were prepared from 1-bromonaph-
thalene and 1-bromo-2-methylnaphthalene by carboxyla-
tion and esterification. For the preparation of 3c, see:
Bright, J. H. US Patent 4,590,290, 1986.
7. For the Birch reduction–alkylation of naphthoates, see:
(a) Beckwith, A. L. J.; Roberts, D. H. J. Am. Chem. Soc.
1986, 108, 5893; (b) Bhattacharyya, S.; Basu, B.; Mukher-
jee, D. Tetrahedron 1983, 39, 4221.
Acknowledgements
8. Schultz, A. G.; Taveras, A. G.; Harrington, R. E. Tetra-
hedron Lett. 1988, 29, 3907.
9. Preparation of 7c. A solution of (TMS)3SiH (0.02 mL,
0.065 mmol) and AIBN (2 mg) in deoxygenated PhH (0.5
mL) was added dropwise via syringe pump over 30 min
to the dienone 6a (25 mg, 0.056 mmol) and AIBN (2 mg)
in PhH (5 mL) at reflux. The solution was refluxed for an
additional 2 h. The solvent was removed in vacuo and the
residue was purified by flash chromatography using 4:1
hexanes: EtOAc as eluent to give 7c as a white solid (8.0
We thank Dr. Xin Chen for molecular modeling study.
This work was supported by a grant from the National
Institute of Health (Grant Number GM 26568).
References
1
1. (a) Johnson, W. S.; Marshall, J. A.; Keana, J. F. W.;
Frank, R. W.; Martin, D. G.; Bauer, V. J. Tetrahedron
(Suppl.) 1966, 8, Part II, 541–601; (b) Kutney, J. P.; By,
A. Can. J. Chem. 1964, 42, 591; (c) Nagata, W.; Hirai, S.;
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Tetrahedron 1979, 35, 911 and references cited therein.
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mg, 44% yield). H NMR (500 MHz, CDCl3): l 8.11 (d,
J=7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.40 (t, J=7.6
Hz, 1H), 7.28–7.25 (m, 1H), 7.20–7.19 (m, 3H), 7.08 (d,
J=7.6 Hz, 1H), 3.67 (s, 3H), 2.78 (s, 1H), 2.62 (d,
J=13.0 Hz, 1H), 1.95 (d, J=13.0 Hz, 1H), 1.51 (s, 3H),
1.47 (s, 3H); 13C NMR (125 MHz, CDCl3) 196.8, 172.6,
151.0, 148.3, 144.4, 133.7, 131.4, 127.6, 127.5, 127.0,
126.1, 124.9, 121.1, 118.0, 77.7, 62.1, 60.3, 53.1, 51.8,
47.6, 14.1, 13.0.
10. For a low temperature radical cyclization initiated by
Et3B, see: (a) Nozaki, K.; Oshima, K.; Utimoto, K. J.
Am. Chem. Soc. 1987, 109, 2547; (b) Satoh, S.; Sodeoka,
M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1991, 56,
2278; (c) Brown, H. C.; Midland, M. M. Angew. Chem.,
Int. Ed. Engl. 1972, 11, 692.
3. (a) Johnson, W. S. Acc. Chem. Res. 1968, 1, 1; (b)
Johnson, W. S. Bioorg. Chem. 1976, 5, 51; (c) Bartlett, P.
A. In Asymmetric Synthesis; Morrison, J. D., Ed.; Aca-
demic Press: Orlando, FL, 1984; Vol. 3, pp. 341–409; (d)
Vandewalle, M.; Clercq, P. D. Tetrahedron 1985, 41,
1767; (e) Sutherland, J. K. In Comprehensive Organic
Synthesis: Selectivity, Strategy and Efficiency; Fleming,
I.; Trost, B. M., Eds.; Pergamon Press: Oxford, 1991;
Vol. 3, pp. 341–377.
11. Preparation of 8b. To a solution of 6b (59 mg, 0.122
mmol) and Ph3SnH (64 mg, 0.182 mmol) in distilled
toluene (15 mL) at 0°C was added dropwise Et3B (134 mL
of 1.0 M solution in hexane, 0.134 mmol). The resulting
solution was stirred for 2 h at 0°C, warmed to room
temperature and quenched with saturated NH4Cl. The
reaction mixture was diluted with EtOAc, partitioned
between water and EtOAc, and aqueous layer was
extracted with EtOAc(2×). The combined organic layer
was dried over anhydrous Na2SO4 and concentrated to
give the crude product. Flash chromatography purifica-
tion using 4:1 hexanes: EtOAc as eluent afforded 8b as a
4. Hirai, G.; Oguri, H.; Moharram, S. M.; Koyama, K.;
Hirama, M. Tetrahedron Lett. 2001, 42, 5783.
5. Synthesis of the alkylating agents:

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X. Zhang et al. / Tetrahedron Letters 43 (2002) 7605–7608
1
white solid (31 mg, 59%). H NMR (500 MHz, CDCl3):
l 7.83 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.41
(m, 1H), 7.35 (m, 2H), 6.85 (s, 1H), 6.61 (d, J=8.3 Hz,
1H), 5.24 (s, 1H), 4.83 (s, 1H), 3.75 (s, 3H), 3.69 (s, 3H),
3.57 (d, J=18.6 Hz, 1H), 3.47 (d, J=15.5 Hz, 1H), 3.31
(d, J=15.7 Hz, 1H), 3.21 (d, J=18.6 Hz, 1H), 1.46 (s,
3H); 13C NMR (125 MHz, CDCl3) 196.0, 173.3, 159.7,
141.3, 138.1, 133.3, 128.1, 127.4, 127.0, 126.6, 12.8, 125.3,
112.5, 111.7, 108.8, 55.0, 53.9, 52.3, 47.6, 43.5, 40.6, 28.6.
IR (film, cm−1) 1726, 1691. CIMS 363 (M++1, 100).
12. Selected data for 10. H NMR (500 MHz, CDCl3): l 8.15
1
(d, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.65 (t,
J=7.4 Hz, 1H), 7.41 (t, J=6.9 Hz, 1H), 7.33 (d, J=8.3
Hz, 1H), 6.85 (s, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.22 (s,
1H), 3.99 (s, 1H), 3.85 (s, 3H), 3.31 (d, J=16.4 Hz, 1H),
2.98 (d, J=16.4 Hz, 1H), 2.21 (s, 3H), 0.96 (s, 3H). CIMS
305 (M++1, 100). Anal. calcd for C21H20O2: C, 82.86; H,
6.62. Found: C, 82.75; H, 6.68%.