Highly enantioselective Rh-catalyzed carboacylation of olefins: Efficient syntheses of chiral poly-fused rings

Article abstract of DOI:10.1021/ja309978c

Here we report the first highly enantioselective Rh-catalyzed carboacylation of olefins via C-C bond activation of benzocyclobutenones. Good yields and excellent enantioselectivities (92-99% ee, 14 examples) were obtained for substrates with various steric and electronic properties. In addition, fully saturated poly-fused rings were prepared from the carboacylation products through a challenging catalytic reductive dearomatization approach. These investigations provide a distinct way to prepare chiral carbon frameworks that are nontrivial to access with conventional methods.

Full text of DOI:10.1021/ja309978c

Subscriber access provided by Univ. of Tennessee Libraries
Communication
Highly Enantioselective Rh-Catalyzed Carboacylation of
Olefins: Efficient Syntheses of Chiral Poly-Fused Rings
Tao Xu, Haye Min Ko, Nikolas Alexander Savage, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja309978c • Publication Date (Web): 21 Nov 2012
Downloaded from http://pubs.acs.org on November 23, 2012
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Highly Enantioselective Rh-Catalyzed Carboacylation of Ole-
fins: Efficient Syntheses of Chiral Poly-Fused Rings
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Tao Xu‡, Haye Min Ko‡, Nikolas A. Savage and Guangbin Dong*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
Supporting Information Placeholder
To the best of our knowledge, the work reported earli-
er this year by Murakami and coworkers is the only ex-
ABSTRACT: Here, we report the first highly enantiose-
lective Rh-catalyzed carboacylation of olefins via C–C
bond activation of benzocyclobutenones. Good yields
and excellent enantioselectivity (92-99% ee, 14 exam-
ples) have been obtained for substrates with various ste-
ric and electronic properties. In addition, fully saturated
poly-fused rings were prepared from the carboacylation
ample of catalytic enantioselective carboacylation of ole-
fins (Scheme 1A).4a In this seminal work, the cyclobuta-
none C–C bond is cleaved via Ni-mediated cyclometalla-
tion/β-carbon elimination to afford bridged-ring prod-
ucts. In search of effective ways to access fused rings, we
recently reported a “Cut & Sew” strategy using a Rh-
products through
a challenging catalytic reductive
catalyzed intramolecular olefin carboacylation with ben-
zocyclobutanones, where racemic products were ob-
tained using dppb as the ligand.10 To develop a highly
enantioselective reaction for this transformation, two
challenges must be addressed. The first is general; a
larger energy difference is needed between the diastere-
omeric transition states at high temperatures to achieve
the same level of enantioselectivity (i.e. to obtain 95% ee,
∆G =12.3 kJ/mol is needed at 130 C vs ∆G =9.1 kJ/mol
at rt). The second derives from the sensitivity of this Rh-
catalyzed reaction to the ligand employed,10 where find-
ing conditions that give both high enantioselectivity and
high reactivity is nontrivial.
dearomatization approach. These investigations provide
a distinct way to prepare chiral carbo-frameworks that
are nontrivial to access with conventional methods.
Transition metal-catalyzed carbon–carbon (C–C) bond
activation/subsequent functionalization provides
a
‡
‡
o
unique strategy to access novel carbo-frameworks
and/or chiral all-carbon quaternary centers.1 These
structural motifs are of significant synthetic value and
could be challenging to prepare using conventional
methods.
Scheme 1. Catalytic asymmetric carboacylation of ole-
fins.
Although of significant interest, catalytic asymmetric
transformation via C–C activation2 has been much less
explored compared to the related asymmetric C–H acti-
vation.3 Generally, β-carbon elimination and metal inser-
tion into C–C bonds constitute two major reaction path-
ways for C–C activation (Figure 1).1b To date, asymmetric
metal-catalyzed C–C cleavage reactions have been mainly
(A) Previous work (the only example)
R1
R1
O
cat. Nio
L*
R2
R2
O
NiL*
achieved
via
β-carbon
elimination
of
tert-
cyclobutanolates that are generated either in situ from
cyclobutanones (by Murakami4) or through deprotona-
tion of the corresponding tert-cyclobutanols (by Uemu-
ra,5 Trost,6 and Cramer7). Despite elegant work on the
asymmetric activation of C–CN bonds,8 enantioselective
transformations mediated by metal insertion into C–C σ
bonds are much underdeveloped. In this communica-
tion, we describe the first enantioselective Rh-catalyzed
carboacylation of olefins via metal-insertion of benzo-
cyclobutenone C–C bonds,9 and also show our efforts to
access chiral saturated tricyclic-fused rings from the
carboacylation products through a catalytic reductive
dearomatization reaction (Scheme 1B).
-carbon
elimination
R1
R1
reductive
elimination
80-93% ee
R2
O
R2
O
NiL*
bridged rings
(B) This work
n
R2
O
n
O
R2
P
*
O
P
P
Rh
P
O
*
RhI
2
1
R1
oxidative
addition
R1
proposed intermediate
n=1 or 2
O
nR2
O
R2
H
catalytic
H
hydrogenation
*
*
*
*
H
R1
*
R1
O
O
H
92-99% ee
tricyclic fused rings
4 contiguous stereocenters!
Figure 1. Two major reaction pathways for C–C activation.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
We initiated the study by using benzocyclobutenone 1a tricyclic ketone 2a was determined through heavy-atom
1
2
3
4
5
6
7
8
as a model substrate (Table 1). Given the importance of
bidentate ligands with wide bite angles in this transfor-
mation,10 chiral bidentate phosphine ligands with a four-
carbon linkage were examined first. Although the com-
monly used BINAP and Tol-BINAP only provided low
yield and low enantioselectivity,10 use of DIOP as the
ligand provided good yield (73%) and ee (83%) (entry 1).
Aiming to further enhance the enantioselectivity, two
bulkier DIOP* ligands, first prepared by Zhang11a and
RajanBabu11b, were employed (entries 2 and 3); unfortu-
nately, no improvement of ee was observed.
X-ray crystallography of derivative 3 (Figure 2).
Me
(
)
X-ray structure
9
Figure 2. View of compound 3 showing the atom labeling
scheme. Displacement ellipsoids are scaled to the 50%
probability level.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Selected optimization studiesa
With the optimal conditions in hand, we sought to ex-
plore the substrate scope (Table 2).12 A number of benzo-
cyclobutenone substrates with different steric and elec-
tronic properties were examined; delightedly, high to
excellent enantioselectivities were obtained. It was found
that changing the electron density of the aromatic ring
did not affect the enantioselectivity, and 97-99% ee’s
were observed (entries 1-4). Not surprisingly, increasing
the steric bulk on the olefin substituent from methyl to
ethyl, OTBS-methyl, isopropyl or cyclopentyl slowed
down the reaction; however, products with high optical-
purity (93-98% ee) were still isolated in 40-65% yield
(entries 5-8).13 When substrates containing different ar-
yl-olefins were subjected to the reaction conditions, the
observed enantioselectivity was generally over 95% ee
(entries 9–12) except for substrate 1j (54% yield, 89% ee
with DTBM-SEGPHOS). Interestingly, DIOP was found
to be a more efficient ligand for substrates 1j and 1m, as
both the yield and ee were enhanced (entries 10 and 13).
It is noteworthy that, beyond disubstituted alkenes, ter-
minal-olefin substrate (1n) also afforded excellent enan-
tioselectivity (94% ee, entry 14), where a dihydropyran
ring was formed. Overall, many functional groups were
compatible to this reaction, such as esters, ketones,
ethers, free tertiary alcohols, silyl ethers, trifluoromethyl
groups, electron-rich and poor arenes, which shows po-
tential for application in complex molecule synthesis.14
With the enantiomerically enriched benzo-tricyclic
compounds in hand, we hypothesized that if a stereose-
lective reductive dearomatization can be performed, new
types of chiral poly-fused ring structures with four con-
tiguous stereocenters would be afforded (Scheme 2).
These saturated structures are found in terpene natural
products and often nontrivial to synthesize using con-
ventional methods.15 Success of this approach would
greatly enlarge the scope of the fused-ring scaffolds that
can be obtained using the Rh-catalyzed C–C activation
method. Moreover, it may be considered as a “reaction
surrogate” for using the saturated cyclobutanones as the
asymmetric carboacylation substrate (Scheme 2), which
is known to be a more difficult reaction.16
a) 5 mol % Rh precatalyst and 12 mol % ligand were used on
a 0.1 mmol scale reaction with 20h reaction time. b) Isolat-
ed yield; numbers in parentheses are brsm yield. c) ee was
determined using chiral HPLC. d) Reaction time was 48h.
Fruitful results were obtained upon surveying other
ligands with axial chirality. SYNPHOS gave excellent
enantioselectivity (94% ee), albeit only 14% yield (entry
4, Table 1). The yield and ee were further improved by
switching to SEGPHOS (entry 5). We hypothesized that
the electron-rich ligands would help enhance the catalyst
reactivity by promoting oxidative addition of the C–C σ
bond.1b Indeed, by using the more electron-rich DTBM-
SEGPHOS (entry 6), the yield was further improved to
60% (quantitative yield brsm). Furthermore, by optimiz-
ing the solvent and reaction time (entries 7-12), the ben-
zo-tricycle (2a) was obtained in 81% yield and 97% ee
(entry 12). The structure and absolute configuration of
Scheme 2. Saturated poly-fused rings
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
extensive experimentations, we were delighted to discov-
Table 2. Substrate scopea
1
2
er that the benzene rings of tricycles 2a, 2b and 2i can
be effectively reduced to the substituted cyclohexanes via
a Rh-catalyzed hydrogenation reaction, a procedure orig-
inally reported by Alper18 (Table 3).19 These reactions
were conducted at room temperature under phase-
transfer and near neutral conditions. We found that it
was critical to use hydrogen gas with enhanced pressure
as no reaction occurred at low pressure.
Yieldb
Entry
Substrate
Me
eec
Product
O
3
4
5
6
7
8
9
O
Me
O
1
97%
81%
O
Me
O
O
Me
O
2
77%
74%
61%
65%
98%
98%
Me
O
Me
Table 3. Catalytic reductive dearomatization
Me
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
3
4
Pr
Me
O
Pr
O
O
Me
O
99%
98%
MeO2C
O
MeO2C
O
Et
O
Et
O
5
6
O
O
O
O
O
O
OTBS
OTBS
O
O
53%
97%
iPr
O
iPr
O
7
8
44%
40%
52%
97%
93%
96%
O
O
O
O
O
O
Ph
O
Ph
9
-Tol
O
O
O
O
-Tol
O
76%
55%
92%
97%
95%
92%
It is interesting to note that, although ketones are gen-
erally much easier to reduce than arenes, under these
hydrogenation conditions the aryl groups reacted faster
and the ketones were only partially reduced to alcohols.
To ensure that the ketones were the sole products isolat-
ed, Ley oxidation20 was carried out subsequently. For
substrates 2a and 2b, the hydrogenation proceeded ste-
reoselectively on the convex face of the tricycles likely
governed by the all-carbon quaternary center, providing
ketones 4a and 4b as single diastereomers. Note that
substrate 2b, with four electron-donating groups on the
benzene ring, still afforded 49% (63% brsm) yield over
two steps, and consequently, four new stereocenters are
generated. Reaction with substrate 2i is rather intri-
guing; under the hydrogenation conditions, the phenyl
group (-C6H5) is selectively reduced first to the cyclohex-
yl group,21 and due to the bulkiness of the cyclohexyl
group, the second hydrogenation occurs on both convex
and concave faces of the resultant intermediate, giving
two separable products 4i-I and 4i-II in a high overall
yield (75%).22 Structures of all the products described in
Table 3 were unambiguously determined by 1H/13C-
NMR, IR, HRMS and X-ray crystallography. Interest-
ingly, as illustrated by the X-ray crystallography, com-
pounds 4a, 4b and 4i-I with all cis-fused rings adopted
a “half-cage”-like structure.
10d
O
-OMePh
-OMePh
O
11
12
O
-CF3Ph
O
O
-CF3Ph
O
47%
(64%)
O
Me
O
O
O
Me
HO
HO
nBu
nBu
97%
13d
14
nBu
nBu
O
O
O
H
O
94%
44%
(85%)
O
a) Reaction conditions: [Rh(COD)Cl]2 (5 mol %), (R)-
DTBM-SEGPHOS (12 mol %), dioxane, 133 C, 48h. b) Iso-
lated yield; numbers in parentheses are brsm yield. c) ee
was determined by chiral HPLC. d) (R,R)-DIOP was used as
the chiral ligand and THF was used as the solvent instead.
o
Despite being an attractive transformation, reduction
of poly-substituted (≥ 3) electron-rich benzene rings is
very challenging, as in general less hindered and elec-
tron-deficient arenes is easier to reduce.17 However, after
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(2) For recent highlights on asymmetric transformation via C–C actiꢀ
In summary, we have developed the first enantioselec-
tive Rh-catalyzed carboacylation of olefins via C–C bond
activation of benzocyclobutenones. Further, preliminary
success to synthesize fully saturated poly-fused rings was
demonstrated using a catalytic reductive dearomatiza-
vation, see: (a) Winter, C.; Krause, N. Angew. Chem., Int. Ed.
2009, 48, 2460. (b) Najera, C.; Sansano, J. M. Angew. Chem., Int.
Ed. 2009, 48, 2452. (c) Seiser, T.; Cramer, N. Org. Biomol.
Chem. 2009, 7, 2835.
1
2
3
4
5
6
7
8
(3) For recent reviews on: asymmetric C–H activation, see: (a) Morꢀ
ton, D.; Davis, H. M. L. Chem. Soc. Rev. 2011, 40, 1857. (b) Giri,
R.; Shi, B.ꢀF., Engle, K. M.; Maugel, N.; Yu, J.ꢀQ. Chem. Soc.
Rev. 2009, 38, 3242. (b) Davis, H. M. L.; Beckwith, R. E. J.
Chem. Rev. 2003, 103, 2861.
(4) (a) Liu, L.; Ishida, N.; Murakami, M. Angew. Chem., Int. Ed.
2012, 51, 2485. (b) Matsuda, T.; Shigeno, M.; Makino, M.; Muꢀ
rakami, M. Org. Lett. 2006, 8, 3379. (c) Matsuda, T.; Shigeno,
M.; Murakami, M. J. Am. Chem. Soc. 2007, 129, 12086. (d) Shiꢀ
geno, M.; Yamamoto, T.; Murakami, M. Chem. Eur. J. 2009, 15,
12929.
(5) (a) Nishimura, T.; Matsumura, Y.; Maeda, Y.; Uemura, S. Chem.
Commun. 2002, 50. (b) Matsumura, Y.; Maeda, Y.; Nishimura,
T.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 8862. (c) Nishiꢀ
mura, T.; Matsumura, S.; Maeda, Y.; Uemura, S. Tetrahedron
Lett. 2002, 43, 3037.
tion approach, which offers
a distinct and atom-
economical strategy to prepare chiral “half-cage”-like
structures with multiple stereocenters. The highly enan-
tioselective carboacylation reaction, as well as the chal-
lenging catalytic hydrogenation of poly-substituted elec-
tron-rich arenes described here, should have broad im-
plications beyond this work, such as new strategy design
for terpenoid synthesis. Efforts to discover more efficient
chiral catalysts (i.e. those compatible with Lewis acids)
and to further extend the scope of catalytic reductive
dearomatization23 are currently ongoing.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ASSOCIATED CONTENT
(6) (a) Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162.
(b) Trost, B. M.; Xie, J. J. Am. Chem. Soc. 2006, 128, 6044.
(7) (a) Waibel, M.; Cramer, N. Chem. Commun. 2011, 345. (b) Seisꢀ
er, T.; Cramer, N. J. Am. Chem. Soc. 2010, 132, 5340. (c) Seiser,
T.; Cramer, N. Chem. Eur. J. 2010, 16, 3383. (d) Seiser, T.;
Cramer, N. Angew. Chem., Int. Ed. 2010, 49, 10163. (e) Seiser,
T.; Roth, O. A.; Cramer, N. Angew. Chem., Int. Ed. 2009, 48,
6320. (f) Seiser, T.; Cramer, N. Angew. Chem., Int. Ed. 2008, 47,
9294.
(8) For Niꢀcatalyzed asymmetric carbocyanation of olefins, see: (a)
Watson, M. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
12594. (b) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa,
M.; Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874. (c) Yasui,
Y.; Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303.
(9) For seminal work of studying the mechanism of Rh insertion into
benzocyclobutanones, see: (a) Huffman, M. A.; Liebeskind, L. S.;
Pennington, W. T. Organometallics 1990, 9, 2194. (b) Huffman,
M. A.; Liebeskind, L. S.; Pennington, W. T. Organometallics
1992, 11, 255. For recent synthesis and utilization of benzocycloꢀ
butenones, see: (c) AlvarezꢀBercedo, P.; FloresꢀGaspar, A.; Marꢀ
tin, R. J. Am. Chem. Soc. 2010, 132, 466. (d) FloresꢀGaspar, A.;
GutierrezꢀBonet, A.; Martin, R. Org. Lett. 2012, 14, 5234. (e) Hoꢀ
soya, T.; Hasegawa, T.; Kuriyama, Y.; Matsumoto, T.; Suzuki, K.
Synlett 1995, 177. (f) Stevens, R. V.; Bisacchi, G. S. J. Org.
Chem. 1982, 47, 2393. (g) Aidhen, I. S.; Ahuja, J. R. Tetrahedron
Lett. 1992, 33, 5431.
Supporting Information. Experimental procedures;
spectral data; and crystallographic data (CIF). This material
is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* gbdong@cm.utexas.edu
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
We thank UT Austin and CPRIT for a start-up fund, and
thank the Welch Foundation for research grants. GD thanks
ORAU for a new faculty enhancement award. We also thank
faculty members from the organic division at UT Austin for
their generous support, and particularly thank Prof. Anslyn
for a helpful discussion. Dr. Lynch is acknowledged for X-
ray crystallography. We thank Ms. Spangenberg and Mr.
Sorey for their NMR assistance. Johnson Matthew is
thanked for a loan of Rh salts. Chiral Technologies is
acknowledged for their generous donation of chiral HPLC
columns.
(10) Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2012, 51, 7567.
(11) (a) Li, W.; Zhang, X. J. Org. Chem. 2000, 65, 5871. (b) Yan, Y.ꢀ
Y.; RajanBabu, T. V. J. Org. Chem. 2000, 65, 900.
(12) Unfortunately, ZnCl2 is not compatible with these enantioselective
conditions, because both SEGPHOS and DIOP ligands were
found decomposed by heating together with ZnCl2, which is likeꢀ
ly due to the acidꢀlabile ketal groups of both ligands. Thus, when
more challenging substrates (i.e. trisubstituted olefins, see ref 10)
were used, low reactivity was observed under current asymmetric
conditions. For example, the following two substrates have been
attempted under the optimized conditions with DTBMꢀ
SEGPHOS; however, almost no reaction was observed.
ABBREVIATIONS
BRSM, based on recovered starting material; TBS, tert-butyl
dimethyl silyl; rt, room temperature; dppb, 1,1-
bis(diphenylphosphino)butane; THS, tetrabutylammonium
hydrogen sulfate; DIOP, [(2,2-dimethyl-1,3-dioxolane-4,5-
diyl)bis(methylene)]bis(diphenylphosphine); DCE, 1,2-
dichloroethane; TPAP, tetrapropylammonium perruthe-
nate; NMO, N-methylmorpholine-N-oxide.
REFERENCES
(1) For recent reviews of C–C bond activation, see: (a) Rybtchinski,
B.; Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 870. (b) Muraꢀ
kami, M.; Ito, Y. Top. Organomet. Chem. 1999, 3, 97. (c) van der
Boom, M. E.; Milstein, D. Chem. Rev. 2003, 103, 1759. (d) Jun,
C.ꢀH. Chem. Soc. Rev. 2004, 33, 610. (e) Satoh, T.; Miura, M.
Top. Organomet. Chem. 2005, 14, 1. (f) Jun, C.ꢀH.; Park, J.ꢀW.
Top. Organomet. Chem. 2007, 24, 117. (g) Necas, D.; Kotora, M.
Curr. Org. Chem. 2007, 11, 1566. (h) Korotvicka, A.; Necas, D.;
Kotora, M. Curr. Org. Chem. 2012, 16, 1170. (i) Crabtree, R. H.
Chem. Rev. 1985, 85, 245. (j) Jones, W. D. Nature 1993, 364,
676. (k) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew.
Chem., Int. Ed. 2011, 50, 7740.
(13) The yields with substrates 2d-2f were higher (92ꢀ94%) when
dppb ligand was used (see ref 10), which is likely attributed to the
structural difference between SEGPHOS ligands and dppb ligꢀ
ands. We further found that shorter reaction time and higher
yields were generally observed with DIOP, a dppbꢀlike ligand.
For a detailed report and comparison of the results between
DTBMꢀSEGPHOS and DIOP ligands, see SI (Table S1).
(14) A carbonꢀtethered substrate has also been attempted (eq 1): excelꢀ
lent diastereoselectivity was observed albeit in an almost racemic
form (the dr with dppb ligand is only 1.3:1, see ref 10). The cause
for such selectivity with this substrate is unclear.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
(21) By controlling the reaction time and H2 pressure, partially reduced
product 4i’ can be selectively obtained (eq 2).
1
2
3
4
5
6
7
8
9
(15) For a recent book on terpene natural products, see: Breitmaier, E.
Terpenes: flavors, fragrances, pharmaca, pheromones, WILEYꢀ
VCH, Weinheim, Germany: 2006.
(16) (a) Murakami, M.; Amii, H.; Ito, Y. Nature 1994, 370, 540. (b)
Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124,
13976.
(17) (a) For a review of Birch reduction, see: Rabideau, P. W.; Marciꢀ
now, Z. Org. React. 1992, 42, 1. (b) For transition metalꢀ
catalyzed hydrogenative dearomatization, see: Rylander, P. N. in
Catalytic Hydrogenation in Organic Synthesis, Academic Press,
New York, 1979, p.175.
(18) Januszklewicz, K. R.; Alper, H. Organometallics, 1983, 2, 1055.
For a review of biphasic homogeneous catalysis, see: Kalck, P.;
Monteil, F. Adv. Organomet. Chem. 1992, 34, 219.
(22) Reductive dearomatization of ethyl and iꢀpropyl substituted subꢀ
strates (2e and 2g) has been attempted (eq 3). The selectivity for
the “concaveꢀface addition” products increases with raising the
steric hindrance from the methyl to ethyl to iꢀpropyl.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(23) Reductive dearomatization of substrates (2d and 2l) has also been
attempted; unfortunately, only deposition and starting material reꢀ
covery (ca. 40%) were observed for 2d; a complex mixture of
partially hydrogenated products was obtained for 2l.
(19) Attempts to combine the Rhꢀcatalyzed carboacylation and hydroꢀ
genation into a oneꢀpot reaction were unsuccessful so far.
(20) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J.
Soc. Chem., Chem. Commun. 1987, 1625.
ACS Paragon Plus Environment