Approach to the core structure of abeo-abietanes and gibberellins via Stork-Danheiser sequence followed by Friedel-Crafts alkylations

Article abstract of DOI:10.1016/j.tetlet.2013.01.002

A mild and efficient protocol for the synthesis of [6,5,6]-tricyclic framework (4) of abeo-abietanes (1) and gibberellins (2) via Stork-Danheiser sequence on a bicyclic vinylogous ester followed by Lewis acid-catalyzed Friedel-Crafts alkylations of 3-aryl-2-hydroxymethyl-2-cyclohexenones (5) is developed. A variety of 2-cyclohexenone derivatives (5) underwent smooth Friedel-Crafts alkylations to craft the [6,5,6]-tricyclic skeleton (4) in good to excellent yields. Copyright

Full text of DOI:10.1016/j.tetlet.2013.01.002

Tetrahedron Letters 54 (2013) 1436–1439
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Approach to the core structure of abeo-abietanes and gibberellins
via Stork–Danheiser sequence followed by Friedel–Crafts alkylations
⇑
Badrinath N. Kakde, Subhajit Bhunia, Alakesh Bisai
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, ITI (Gas Rahat) Building, Govindpura, Bhopal, MP 462 023, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient protocol for the synthesis of [6,5,6]-tricyclic framework (4) of abeo-abietanes (1) and
gibberellins (2) via Stork–Danheiser sequence on a bicyclic vinylogous ester followed by Lewis acid-cat-
alyzed Friedel–Crafts alkylations of 3-aryl-2-hydroxymethyl-2-cyclohexenones (5) is developed. A vari-
ety of 2-cyclohexenone derivatives (5) underwent smooth Friedel–Crafts alkylations to craft the
[6,5,6]-tricyclic skeleton (4) in good to excellent yields.
Received 8 October 2012
Revised 31 December 2012
Accepted 3 January 2013
Available online 10 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
[6,5,6]-Tricycle
abeo-Abietanes
Gibberellins
Strok–Danheiser sequence
Friedel–Crafts alkylations
abeo-Abietanes are architecturally interesting and biologically
active diterpenoids having an unusual [6,5,6]-tricyclic skeleton
with an all-carbon quaternary stereocenter1 (Fig. 1). Some of the
members of this family are shown to have aromatase inhibitory
activities,2 and therefore, they could serve as potential candidates
for the treatment of breast cancer.2 A few reports also indicate that
some diterpenoids of this family exhibit cytotoxic and antitumor
activities.3 Especially, compounds with 4a-methyltetra-(or hexa-)
hydrofluorene moiety, exhibit an array of interesting biological
activities and thus coupled with their unique structural features,
this class has gained a significant interest from the synthetic com-
munity.4 Several reports from different research groups are known
for the formal5 and total syntheses6 of the diterpenoids, taiwani-
aquinoids (1a–b).7
Further, it has been reported that conformationally rigified
phencyclidine [1-(1-phenylcyclohexyl)piperidine, PCP] namely
hexahydrofluorenamine (Fig. 1) having [6,5,6]-carbocyclic skeleton
such as cis-1,2,3,4,9,9a-hexahydro-N-methyl-4aH-fluoren-4a-
amine (1f–g, Fig. 1) acts as noncompetitive antagonist at the N-
methyl-
1f–g can block the ion channel that is coupled to NMDA (N-
D
-aspartate (NMDA) receptor.8a,b Compound of the type
methyl-D-aspartate) subtype of L-glutamate receptor in the brain.
HO
Me
O
OH
Me
OH
Me
b
Me
Me
Me
Me
Me
c
a
NHR
b
Overman
Me
rearrangement
Me
Me
Me
CHO
H
a
O
a
Me
c
Me
c
Me
b
H
[6,5,6]-abeo-Abietane
(-)-dichroanal B (1b)
(-)-dichroanone (1a)
HO
skeleton (1)
H
(1h)
OHC
OR
OR
OR
OR
Me
R= H (1f); potent drug to treat stroke
R = Me, (1g);
c
a
cis-1,2,3,4,9,9a-hexahydro-
N-methyl-4aH-fluoren-4a-amine
OR
OR
b
H
HO
(1c)
(1d)
(1e)
Figure 1. The representative taiwaniaquinoids (1a–b) and hexahydrofluorenamine (1f–g) sharing a [6,5,6]-carbocyclic skeleton.
⇑
Corresponding author. Tel.: +91 755 4092318; fax: +91 755 4092392.
E-mail address: alakesh@iiserb.ac.in (A. Bisai).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.002

B. N. Kakde et al. / Tetrahedron Letters 54 (2013) 1436–1439
1437
H
8 steps12
H
O
O
OH
O
O
O
OH
OH
c
a
b
HO
Corey's
approach
O
(3a)
(3b)
Me
Me
H
H
OMe
OMe
O
O
Cl
Cl
H
6 steps13
OMe
H
gibberellic acid (GA3, 2b)
GA109 methyl ester (2a)
OMe
c
a
(potent plant
growth-regulating properties)
(an antheridigen)
b
Banwell's
approach
H
Cl
H
(3c)
(3d)
Figure 2. The gibberellins (2a–b) sharing a [6,5,6]-carbocyclic skeleton.
Table 1
O
X
Optimization of Friedel–Crafts alkylation
X
O
O
OH
O
O
Lewis acid, CH2Cl2,
O
O
O
45 °C, 8-24 h
(5)
common intermediate (4)
O
(6a)
up to 98% yields
OH
(5k)
Scheme 1. Our hypothesis to the [6,5,6]-skeleton (4).
O
(4k)
O
Entry
Lewis acid
Equiva (mol %)
Temp (°C)
Time (h)
Yieldb (%)
O
O
THF,0 °C - rt, 3 h
4(N) HCl, 2h
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
PPA
100
100
50
100
100
100
100
100
25
25
25
25
25
45
45
45
45
45
45
45
45
45
45
45
45
55
55
45
45
12
8
88
98
82
33
62
40
92
84
60
68
95
75
78c
68c
79
58d
OH
BF3ꢀOEt2
BF3ꢀOEt2
AlCl3
O
R
15
24
24
24
8
12
16
18
12
16
14
14
12
24
+
ArMgBr
R
up to 75% yields
R
O
X
R
Cu(OTf)2
Zn(OTf)2
In(OTf)3
Sn(OTf)2
Sc(OTf)3
Sn(OTf)2
Bi(OTf)3
In(OTf)3
Bi(OTf)3
In(OTf)3
Bi(OTf)3
Bi(OTf)3
(6a-b)
(5a-l)
R=H, Me
O
O
O
OH
OH
OH
R
R
R
R
OMe
OMe
R
R
R
R
25
15
5
OMe
MeO
R=H (5a); 72%
R=Me (5b); 68%
R=H (5c); 65%
R=Me (5d); 66%
R=H (5e); 75%
R=Me (5f); 72%
a
Reactions were carried out on a 0.50 mmol of 5k in the presence of Lewis acid in
4 mL of solvent at indicated temperature, unless noted otherwise.
b
Isolated yields after column chromatography.
Reactions were performed in chloroform.
34% of 5k was recovered.
O
O
O
c
d
OH
OH
OH
R
R
OMe
OMe
O
O
R
R
through cyclopropane ring-cleavage reactions.13 Abundant litera-
ture reports are available for the preparation of 4a-methylhydro-
fluorene. For instance, via an acid-catalyzed cyclization of
substituted benzyl cyclohexanols reported by Ghatak and et al.,14
inter- and intramolecular (3+2)-cycloaddition approach,15a and
the cyclization of an arylpalladium species,15b arylradical ap-
proach,15c,d or aryllithium15e tethered to methylene cyclohexane,
intramolecular Friedel–Crafts cyclization of 1,3-bis-exocyclic die-
ne,15f and many others.16
OMe
OMe
R=H (5g); 69%
R=Me (5h); 64%
R=H (5k); 67%
R=Me (5l); 62%
R=H (5i); 70%
R=Me (5j); 65%
Scheme 2. Stork–Danheiser’s sequence of bicyclic vinylogous esters 6a–b.
Further pharmaceutical studies of compound 1f–g revealed the
fact that they exert pronounced depressant effects upon the central
nervous system.8c,d
The [6,5,6]-carbocyclic system, being present in many naturally
occurring bioactive terpenoids as well as drug molecules drew our
attention toward this. In this Letter, we delineate our efforts to-
Like abeo-abietanes, gibberellins (GAs) (2a–b) are another large
class of structurally complex diterpenoids having [6,5,6]-tricyclic
skeleton (Fig. 2) exhibiting potent plant growth-regulating proper-
ties.9 These diterpenoids of GA family including gibberellic acid
(GA3, 2b) are of considerable agricultural and commercial signifi-
cance.10 Therefore, a major research interest has been devoted to-
ward the synthetic approaches and total synthesis of gibberellins
(GAs).11 In 1970, Corey reported that [6,5,6]-tricycle 3a could serve
as intermediate for the bridged-ring functionality (3b) of the gib-
berellins (Fig. 1).12 Recently in 2006, Banwell utilized tricycle 3c
for the synthesis of tetracyclic frame work of gibberellins (Fig. 1)
ward the synthesis of [6,5,6]-tricyclic skeleton employing
a
Stork–Danheiser sequence17 followed by a Friedel–Crafts (F-C)
alkylation in the presence of a Lewis acid (Scheme 1).18 We envis-
aged that the functionalized skeleton of abeo-abietanes (1a–b) can
be achieved from enantio-enriched intermediate 1c (Fig. 1). The
latter can be accessed using Rh-catalyzed decarbonylation19 of
1d, which in turn can be achieved from
(Scheme 1) via a Corey–Bakshi–Shibata reduction20 (1e and 1h)
followed by a [3,3]-sigmatropic rearrangement. -Substituted en-
one 4 can be achieved from allylic alcohol 5 as shown in Scheme 1
a-substituted enone 4
a

1438
B. N. Kakde et al. / Tetrahedron Letters 54 (2013) 1436–1439
MeO
MeO
Me
Me
OMe
OMe
(4c), 93%, 8 h (A)
(4c), 88%, 9 h (B)
4b
), 69%, 14 h (A)
4a
(
(
), 80%, 12 h (A)
O
O
O
(4b), 60%, 12 h (B)
(4a), 60%, 15 h (B)
OMe
Me
Me
Me
Me
OMe
OMe
OMe
(4d), 90%, 8 h (A)
(4d), 82%, 10 h (B)
4e
(
), 86%, 8 h (A)
(4f), 80%, 12 h (A)
(4f), 75%, 15 h (B)
O
O
O
4e
(
), 80%, 9 h (B)
OMe
OMe
OMe
Me
Me
OMe
OMe
O
O
O
O
4h
(
4g
), 91%, 10 h (A)
), 88%, 12 h (B)
(
), 94%, 7 h (A)
), 92%, 8 h (B)
(4i), 93%, 7 h (A)
4h
(
4g
(
(4i), 92%, 9 h (B)
Me
Me
OMe
OMe
Me
Me
O
O
O
O
OMe
O
O
(4j), 89%, 8 h (A)
(4l), 90%, 12 h (A)
(4l), 95%, 10 h (B)
(4k), 98%, 8 h (A)
(4k), 95%, 12 h (B)
(4j), 85%, 10 h (B)
Condition A: 100 mol% BF3.OEt2; Condition B: 25 mol% Bi(OTf)3.
Figure 3. Substrates scope of Friedel–Crafts alkylations of 5a–l.
via a Lewis acid-catalyzed Friedel–Craft alkylation, which could in
turn be accessed from 6a21 following a Stork–Danheiser sequence
(Scheme 1). We envisioned that [6,5,6]-carbocyclic tertiaryamines
1f–g can be accessed from enantio-enriched allylic alcohol 1h via
Overman rearrangement22 followed by directed hydrogenation
(Fig. 1). Functionalized skeleton of gibberellins (GAs) (2a–b) could
also be accessed from the enantio-enriched allylic alcohol such as
1e following Banwell’s approach (Fig. 2).
We began our studies by carrying out a Stork–Danheiser se-
quence on the bicyclic vinylogous esters 6a–b21c by subjecting it
with a variety of aryl magnesium bromides in THF at 0 °C followed
by treatment of dilute HCl. This resulted in a smooth reaction to
provide a variety of 3-aryl-2-hydroxymethyl-2-cyclohexenenones
5a–l in the range of 62–75%, without event (Scheme 2).23 These
substituted cyclohexenones having a hydroxymethyl group at the
2-position have the potential for further functionalization in order
to access an interesting complex structure. For instance, with these
compounds in hand, we looked forward to optimize the Lewis acid
catalyzed Friedel–Crafts alkylation to access the proposed tricyclic
skeletons present in abeo-abietanes (1a–b), hexahydrofluorenam-
ines (1f–g), and gibberellins (2a–b).
Initially the Friedel–Crafts alkylation of 5k was done in dichlo-
romethane at room temperature in the presence of 1 equiv of
BF3ꢀOEt2. Due to longer reaction time (24 h, 42% isolated yields),
we decided to do further studies under reflux condition (Table 1).
In the presence of polyphosphoric acid (PPA), the product yield
was 88% (entry 1). A variety of other Lewis acids were screened
and it was found that BF3ꢀOEt2, In(OTf)3, Sn(OTf)2 afforded products
with 98% (entry 2), 92% (entry 7), 84% (entry 8), respectively, when
1 equiv of catalysts was used. However, Cu(OTf)2 and Zn(OTf)2 (en-
tries 5–6) were inferior in terms of providing chemical yields under
a similar condition. AlCl3, which is generally a good catalyst for Fri-
edel–Crafts reactions, provided products in just 33% yield (entry 4)
with the decomposition of rest of the mass balance. This was not
surprising to us, as in this case the process could be associated with
unwanted dealkylations of aromatic ether linkage.24
95% (entry 11) and 75% (entry 12) yields, respectively. However,
under a similar condition Sc(OTf)3 and Sn(OTf)2 afforded F–C prod-
ucts only in 60% (entry 9) and 68% (entry 10) yields, respectively. It
was also found that, the chemical yields also dropped down when
the reactions were performed in chloroform (entries 13 and 14).
The yields of the reaction slowly dropped down to 79% and 58%
when the reaction was carried out in the presence 15 mol % and
5 mol % of Bi(OTf)3, respectively (entries 15–16). Thus, it was
decided to carry out the substrates scope of Friedel–Crafts reaction
in the presence of 25 mol % of Bi(OTf)3 (entry 11).
Ultimately, the conversion of the enone intermediates 5a–l to
tricyclic products 4a–l, was carried out in two different conditions
viz. 1 equiv of BF3ꢀOEt2 (Condition A) and 25 mol % Bi(OTf)3 (Condi-
tion B) as Lewis acids and the results so obtained are summarized
in Figure 3. As electron-rich aromatics are known to be the best
substrates for oxidative dearomatization processes [in order to ac-
cess the skeleton of abeo-abietanes (1a–b) and gibberellins (2a–
b)], we decided to explore the Friedel–Crafts alkylations using a
variety of enones (5a–l) having electron-rich aromatics. It is note-
worthy that, in all the cases, Friedel–Crafts alkylations afforded
good-to-excellent yields (60–98%) of tricyclic enones 4a–l in 7–
12 h under refluxing dichloromethane (Fig. 3).
In summary, an efficient strategy for the construction of [6,5,6]-
carbocyclic framework has been developed. The strategy involves a
Stork–Danheiser sequence on a bicyclic vinylogous ester 6, fol-
lowed by Lewis acid-catalyzed Friedel–Crafts alkylations of 3-
aryl-2-hydroxymethyl-2-hexenones (5a–l) in refluxing dichloro-
methane. Further synthetic elaboration of these [6,5,6]-carbocyclic
enone intermediates (4a–l) through enantio-selective Corey–Bak-
shi–Shibata reduction and its application toward the synthesis of
naturally occurring biologically active diterpenoids and other re-
lated drug molecules are currently ongoing and will be reported
in due course.
Acknowledgments
On decreasing the catalysts loading, it was interestingly found
that, 25 mol % of Bi(OTf)3 and In(OTf)3 were afforded products in
We sincerely thank Professor Vinod K. Singh, the Director, In-
dian Institute of Science Education and Research (IISER) Bhopal

B. N. Kakde et al. / Tetrahedron Letters 54 (2013) 1436–1439
1439
Tetrahedron Lett. 1986, 27, 1731; (h) Nagaoka, H.; Shimano, M.; Yamada, Y.
Tetrahedron Lett. 1989, 30, 971; (i) Toyota, M.; Odashima, T.; Wada, T.; Ihara, M.
J. Am. Chem. Soc. 2000, 122, 9036.
for research facilities. A.B. thanks the Board of Research in Nuclear
Sciences (BRNS), Department of Atomic Energy (DAE), India, for a
research grant through Young Scientist Award. B.N.K. and S.B.
thank the Council of Scientific and Industrial Research (CSIR),
New Delhi, for doctoral fellowships. Facilities from the Department
of Chemistry, IISER Bhopal is gratefully acknowledged.
12. (a) Corey, E. J.; Narisada, M.; Hiraoka, T.; Ellison, R. A. J. Am. Chem. Soc. 1970, 92,
396; (b) Ziegler, F. E.; Condon, M. E. J. Org. Chem. 1971, 36, 3707.
13. For synthetic approach starting from 3c, see: Banwell, M. G.; Phillis, A. T.;
Willis, A. C. Org. Lett. 2006, 8, 5341.
14. (a) Ghatak, U. R.; Chakravarty, J.; Dasgupta, R.; Chakraborti, P. C. J. Chem. Soc.,
Perkin Trans. 1 1975, 2438; (b) Chakarborti, P. C.; Ghosh, S.; Kanjilal, P. R.;
Satyanarayana, G. O. S. V.; Ghatak, U. R. J. Indian Chem. 1979, 18B, 183.
15. (a) Angle, S. R.; Arnaiz, D. O. J. Org. Chem. 1992, 57, 5937; (b) Mukhopadhyaya, J.
K.; Pal, S.; Ghatak, U. R. Synth. Commun. 1995, 25, 1641; (c) Ishibashi, H.;
Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org. Chem. 2000, 65, 9022; (d)
Ishibashi, H.; Kobayashi, T.; Takamasu, D. Synlett 1999, 1286; (e) Bailey, W. F.;
Daskapan, T.; Rampalli, S. J. Org. Chem. 2003, 68, 1334; (f) Lomberget, T.; Bentz,
E.; Bouyssi, D.; Blame, G. Org. Lett. 2003, 5, 2055.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.002.
16. For synthetic approaches to the hexahydrofluorenone, see: (a) Cook, J. W.;
Hewett, C. L. J. Chem. Soc. 1936, 62; (b) Dev, S. J. Indian Chem. Soc. 1957, 34, 169;
(c) Conia, J. M.; Leriverend, M. L. Tetrahedron Lett. 1968, 2101; (d) Middlemiss,
D. Synthesis 1979, 987; (e) Denmark, S. E.; Wallace, M. E.; Walker, C. B., Jr. J. Org.
Chem. 1990, 55, 5543; (f) Handy, S. T.; Omune, D. Org. Lett. 2005, 7, 1553. and
references cited.
17. (a) Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775. For recent
applications in total syntheses, see:; (b) West, S. P.; Bisai, A.; Lim, A. D.;
Narayan, R. R.; Sarpong, R. J. Am. Chem. Soc. 2009, 131, 11187.
18. (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3,
pp 293–339. Chapter 1.8; (b) Meima, G. R.; Lee, G. S.; Garces, J. M. In Friedel–
Crafts Alkylation; Sheldon, R. A., Bekkum, H., Eds.; Wiley-VCH: New York, 2001;
pp 151–160; (c) Rappoport, Z. The Chemistry of Phenols; John Wiley and Sons:
New York, 2003; (d) Heaney, H. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 2, pp 733–752; (e)
Sethna, S. Friedel–Crafts and Related Reactions In Olah, G. A., Ed.; Interscience:
New York, 1964; p 911. Vol. 3; (f) Gore, P. H. Chem. Rev. 1955, 55, 229.
19. For decarbonylation reaction using (PPh3)3RhCl, see: (a) Ashimori, A.; Bachand,
B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6477; (b) Takahata, H.;
Ouchi, H.; Ichinose, M.; Nemoto, H. Org. Lett. 2002, 4, 3459. and references cited
therein.
References and notes
1. (a)Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis;
Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim Germany, 2005; (b) Trost,
B. M.; Jiang, C. H. Synthesis 2006, 369; (c) Christoffers, J.; Baro, A. Adv. Synth.
Catal. 2005, 347, 1473; (d) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5363.
2. (a) Iwamoto, M.; Ohtsu, H.; Tokuda, H.; Nishino, H.; Matsunaga, S.; Tanaka, R.
Bioorg. Med. Chem. 2001, 9, 1911; (b) Minami, T.; Iwamoto, M.; Ohtsu, H.;
Ohishi, H.; Tanaka, R.; Yoshitake, A. Planta Med. 2002, 68, 742; (c) Ohtsu, H.;
Iwamoto, M.; Ohishi, H.; Matsunaga, S.; Tanaka, R. Tetrahedron Lett. 1999, 40,
6419.
3. (a) Lin, W. H.; Fang, J. M.; Cheng, Y. S. Phytochemistry 1996, 42, 1657; (b)
Kawazoe, K.; Yamamoto, M.; Takaishi, Y.; Honda, G.; Fujita, T.; Sezik, E.;
Yesilada, E. Phytochemistry 1999, 50, 493; (c) Chang, C. I.; Chang, J. Y.; Kuo, C. C.;
Pan, W. Y.; Kuo, Y. H. Planta Med. 2005, 71, 72.
4. For a review on taiwanaquinoids, see: (a) Majetich, G.; Shimkus, J. M. J. Nat.
Prod. 2010, 73, 284; For a review on icetaxane diterpenoids, see: (b) Simmons,
E. M.; Sarpong, R. Nat. Prod. Rep. 2009, 26, 1195.
5. For semisynthesis and synthetic approaches, see: (a) Majetich, G.; Shimkus, J.
M. Tetrahedron Lett. 2009, 50, 3311; (b) Jana, C. K.; Scopelliti, R.; Gademann, K.
Chem. Eur. J. 2010, 16, 7692.
20. For leading references on CBS reduction, see: (a) Corey, E. J.; Bakshi, R.; Shibata,
S. J. Am. Chem. Soc. 1987, 109, 7925; (b) Corey, E. J.; Link, J. O. J. Am. Chem. Soc.
1992, 114, 1906.
6. For total synthesis, see: (a) Banerjee, M.; Mukhopadhyay, R.; Achari, B.;
Banerjee, A. K. Org. Lett. 2003, 5, 3931; (b) Fillion, E.; Fishlock, D. J. Am. Chem.
Soc. 2005, 127, 13144; (c) Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee,
A. K. J. Org. Chem. 2006, 71, 2787; (d) Planas, L.; Mogi, M.; Takita, H.; Kajimoto,
T.; Node, M. J. Org. Chem. 2006, 71, 2896; (e) Liang, G. X.; Xu, Y.; Seiple, I. B.;
Trauner, D. J. Am. Chem. Soc. 2006, 128, 11022; (f) Li, S. L.; Chiu, P. Tetrahedron
Lett. 2008, 49, 1741; (g) Tang, S. C.; Xu, Y. F.; He, J. M.; He, Y. P.; Zheng, J. Y.; Pan,
X. F.; She, X. G. Org. Lett. 2008, 10, 1855; (h) Tapia, R.; Guardia, J. J.; Alvarez, E.;
Haidöur, A.; Ramos, J. M.; Alvarez-Manzaneda, R.; Chahboun, R.; Alvarez-
Manzaneda, E. J. Org. Chem. 2012, 77, 573. and references cited therein.
7. For enantioselective syntheses, see: (a) McFadden, R. M.; Stoltz, B. M. J. Am.
Chem. Soc. 2006, 128, 7738; (b) Node, M.; Ozeki, M.; Planas, L.; Nakano, M.;
Takita, H.; Mori, D.; Tamatani, S.; Kajimoto, T. J. Org. Chem. 2010, 75, 190; Liao,
X.; Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2088. and references
cited therein.
21. For use of bicyclic vinylogous ester, see: Guanacastepene A: (a) Brummond, K.
M.; Gao, D. Org. Lett. 2003, 5, 3491; Neovibsanins: (b) Imagawa, H.; Saijo, H.;
Yamaguchi, H.; Maekawa, K.; Kurisaki, T.; Yamamoto, H.; Nishizawa, M.; Oda,
M.; Kabura, M.; Nagahama, M.; Sakurai, J.; Kubo, M.; Nakai, M.; Makino, K.;
Ogata, M.; Takahashi, H.; Fukuyama, Y. Biorg. Med Chem. Lett. 2012, 22, 2089;
For synthesis of bicyclic vinylogous ester, see: (c) Smith, A. B., III; Dorsey, B. D.;
Ohba, M.; Lupo, A. T., Jr.; Malamas, M. S. J. Org. Chem. 1988, 53, 4314.
22. For recent examples on Overman rearrangement, see: (a) Fernandez de la
Pradilla, R.; Colomer, I.; Viso, A. Org. Lett. 2012, 14, 3068; (b) Hama, N.; Aoki, T.;
Miwa, S.; Yamazaki, M.; Sato, T.; Chida, N. Org. Lett. 2011, 13, 616; (c) Watson,
M. P.; Overman, L. E.; Bergman, R. G. J. Am. Chem. Soc. 2007, 129, 5031. and
references cited therein.
23. General procedure for Stork–Danheiser sequence of bicyclic vinylogous esters (6a
and 6b):
A flame-dried round-bottom flask was charged with bicyclic
8. (a) Chen, G. Arch. Int. Pharmacodyn. Ther. 1966, 157, 193; (b) Kozikowski, A. P.;
Pang, Y.-P. Synlett 1990, 58; (c) Godefroi, E. F.; Simanyi, A. H. J. Org. Chem. 1963,
1112; (d) Bigge, C. F.; Hays, S. J.; Johnson, G.; Novak, P. M.; Ortwine, D. F. U.S.
Patent 5,071,853, 1991.; (e) Hays, S. J.; Novak, P. M.; Ortwine, D. F.; Bigge, C. F.;
Colbry, N. L.; Jhonson, G.; Lescosky, L. J.; Malone, T. C.; Michael, A.; Reily, M. D.;
Coughenour, L. L.; Brahce, L. J.; Shillis, J. L.; Probert, A., Jr. J. Med. Chem. 1993, 36,
654.
9. For comprehensive review, see: (a) Fujita, E.; Node, M. Heterocycles 1977, 7,
709; (b) Mander, L. N. Acc. Chem. Res. 1983, 16, 48; (c) Mander, L. N. Chem. Rev.
1992, 92, 573; (d) MacMillan, J. Nat. Prod. Rep. 1997, 14, 221; (e) Mander, L. N.
Nat. Prod. Rep. 2003, 20, 49.
10. (a) Sasaki, A.; Ashikari, M.; Ueguchi-Tanaka, M.; Itoh, H.; Nishimura, A.;
Swapan, D.; Ishiyama, K.; Saito, T.; Kobayashi, M.; Khush, G. S.; Kitano, H.;
Matsuoka, M. Nature 2002, 416, 701; (b) Spielmeyer, W.; Ellis, M. H.; Chandler,
P. M. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 9043.
11. (a) Mori, K.; Takemoto, I.; Matsui, M. Tetrahedron 1976, 32, 1497; (b) Nagata,
W.; Wakabayashi, T.; Narisada, M.; Hayase, Y.; Kamata, S. J. Am. Chem. Soc.
1971, 93, 5740; (c) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Siret, P.;
Keck, G. E.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8031; (d) Corey, E. J.;
Danheiser, R. L.; Chandrasekaran, S.; Keck, G. E.; Gopalan, B.; Larsen, S. D.; Siret,
P.; Gras, J.-L. J. Am. Chem. Soc. 1978, 100, 8034; (e) Corey, E. J.; Munroe, J. E. J.
Am. Chem. Soc. 1982, 104, 6129; (f) Corey, E. J.; Guzman-Perez, A.; Loh, T.-P. J.
Am. Chem. Soc. 1994, 116, 3611; (g) Grootaert, W. M.; De Clercq, P. J.
vinylogous ester 6a or 6b (5 mmol), THF (30 mL) and cooled to 0 °C. To this
solution, 1 (M) solution of aryl magnesium bromide (7.5 mmol) in THF was
added dropwise via syringe over 10 min. After stirring for 3.0–3.5 h at 0 °C, the
reaction mixture was quenched by the addition of 1 N HCl (20 mL) at 0 °C. The
reaction mixture was stirred for 3 h while it was allowed to warm to room
temperature and then neutralized by the addition of saturated NaHCO3
(25 mL). The resulting mixture was extracted with EtOAc (4 ꢁ 20 mL). The
combined organic layers were dried over MgSO4 and concentrated under
vacuum. The crude product was purified by flash chromatography (petroleum
ether and EtOAc as eluents) to give 3-aryl-2-hydroxymethyl-2-hexenone.
2-(Hydroxymethyl)-20-methoxy-5,6-dihydro-[1,10-biphenyl]-3(4H)-one (5a): 72%
yield as colorless gel, Rf = 0.45 (50% EtOAc in hexane). 1H NMR (400 MHz,
CDCl3) d 7.29–7.34 (m, 1H), 7.09 (dd, J = 7.48, 1.72 Hz, 1H), 7.09 (dt, J = 7.40,
0.92 Hz, 1H), 6.93 (d, J = 8.36 Hz, 1H),4.20 (m, 1H), 3.98 (m, 1H), 3.80 (s, 3H),
2.97 (br, 1H), 2.80 (m, 1H), 2.53 (m, 3H), 2.10 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 201.4, 158.3, 155.5, 135.2, 129.8, 128.52, 128.46, 120.6, 111.1, 59.0,
55.5, 38.1, 32.0, 22.5; IR (film) mmax 3527, 2960, 2874, 2361, 1726, 1654, 1490,
1458, 1361, 1287, 1121, 1074, 1024, 754 cmꢂ1; HRMS (ESI) m/z 255.0997
[(M+Na)+; calculated for [C14H16O3+Na]+: 255.0992].
24. For cleavage of the methyl ether under Friedel–Crafts acylations, see: Wood, J.
L.; Pujanauski, B. G.; Sarpong, R. Org. Lett. 2009, 11, 3128.