Controlling factors for C-H functionalization versus cyclopropanation of dihydronaphthalenes

Article abstract of DOI:10.1021/jo902644f

"Chemical Equation Presented" Rhodium(lI)-catalyzed reactions of vinyldiazoacetates with dihydronaphthalenes were systematically studied. These substrates underwent cyclopropanantion and/or the combined C-H activation/ Cope rearrangement in good overall y

Full text of DOI:10.1021/jo902644f

pubs.acs.org/joc
Controlling Factors for C-H Functionalization versus Cyclopropanation
of Dihydronaphthalenes
Etienne Nadeau,† Dominic L. Ventura,‡ Jonathan A. Brekan,‡ and Huw M. L. Davies*,†
†Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, and ‡Department
of Chemistry, University at Buffalo, State University of New York, Buffalo, New York 14260-3000
hmdavie@emory.edu
Received December 14, 2009
Rhodium(II)-catalyzed reactions of vinyldiazoacetates with dihydronaphthalenes were systemati-
cally studied. These substrates underwent cyclopropanantion and/or the combined C-H activation/
Cope rearrangement in good overall yield and with good diastereo- and enantiocontrol. The
selectivity of these reactions was profoundly influenced by the nature of the chiral catalyst, the
vinyldiazoacetate, and the dihydronaphthalene. The best combinations for achieving the highest
selectivity in the cyclopropanation and the combined C-H activation/Cope rearrangement of
1,2-dihydronaphthalenes are methyl 2-diazopent-3-enoate (2a)/Rh2(S-DOSP)4 and methyl 3-(tert-
butyldimethylsilyloxy)-2-diazopent-3-enoate (2b)/Rh2(S-PTAD)4. These combinations are very
effective at enantiodivergent reactions of 1-methyl-1,2-dihydronaphthalenes.
Introduction
bonds.2b,g The presence of the donor group (typically vinyl
or aryl) is crucial for these intermolecular reactions to occur
in a selective fashion. A further advancement of this C-H
The development of new synthetic methods that rely on
C-H functionalization is an area of intense current research.1-5
Two major strategies using organometallic complexes have
been developed to achieve such transformations. The first
relies on the classic “C-H activation” approach where a
metal inserts into the C-H bond,3 while the second is based
upon the insertion of a transition metal-bound fragment,
such as a carbene, nitrene, or oxo species, into the C-H
bond.4 Other elegant approaches have also been reported for
C-H bond functionalization.5 We have shown that metal-
locarbene intermediates, generated from the reaction be-
tween chiral rhodium(II) carboxylates and donor/acceptor-
substituted diazo compounds, undergo highly diastereo-
and enantioselective intermolecular insertions into C-H
(2) For reviews see: (a) Godula, K.; Sames, D. Science 2006, 312, 67–72.
(b) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424. (c) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624-655. (d) Doyle,
M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704-724.
(e) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439–2463. (f) Collet, F.;
Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061–5074. (g) Davies, H. M. L.;
Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2903. (h) Giri, R.; Shi, B.-F.;
Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242–3272.
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Angew. Chem., Int. Ed. 2008, 47, 1115–1118. (b) Jordan-Hore, J. A.;
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for Organic Synthesis with Diazo Compounds: From Cyclopropanes to Ylides;
Wiley-Interscience: New York, 1998; pp 112-162. (b) Davies, H. M. L.; Walji,
A. M. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.;
Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005; pp
301-340. (c) Doyle, M. P. In Modern Rhodium-Catalyzed Organic Reactions;
Evans, P. A., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2005; pp 341-356. (d) Taber, D. F.; Joshi, P. V. In Modern Rhodium-Catalyzed
Organic Reactions; Evans, P. A., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA:
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DOI: 10.1021/jo902644f
r
Published on Web 02/19/2010
J. Org. Chem. 2010, 75, 1927–1939 1927
2010 American Chemical Society

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SCHEME 1. Combined C-H Activation/Cope Rearrangement
SCHEME 2. Synthesis of (þ)-Erogorgiaene and (-)-Colombiasin A via an Enantiodivergent Process
functionalization chemistry is the discovery that when an
allylic C-H bond is reacted with a vinylcarbenoid, the C-H
insertion event is interrupted by a Cope rearrangement,
generating products with two new stereocenters with excep-
tional stereocontrol (Scheme 1).6
The synthetic potential of the combined C-H activation/
Cope rearrangement has been demonstrated by its use in the
rapid assembly of natural products such as (þ)-erogorgiaene
(5)7a and (-)-colombiasin A (9).7b The challenging stereochem-
istry associated with these compounds is rapidly introduced by
enantiodivergent reactions on racemic dihydronaphthalenes 1
and 6. In the Rh2(R-DOSP)4-catalyzed reaction with vinyldia-
zoacetate 2a, one enantiomer of the dihydronaphthalene un-
dergoes the combined C-H activation/Cope rearrangement
(to form either 3 or 7), while the other undergoes cyclopropa-
nation (to form either 4 or 8) (Scheme 2). Both 3 and 7 have the
(4) For recent examples see: (a) Gauthier, D.; Dodd, R. H.; Dauban, P.
Tetrahedron 2009, 65, 8542–8555. (b) Gomes, L. F. R.; Trindade, A. F.;
Candeias, N. R.; Veiros, L. F.; Gois, P. M. P.; Afonso, C. A. M. Synthesis
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1733–1735. (b) Davies, H. M. L.; Dai, X.; Long, M. S. J. Am. Chem. Soc.
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Gan, L.-B.; Shi, Z.-J. Chem. Commun. 2009, 6002–6004. (d) Zhang, S.-Y.;
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1928 J. Org. Chem. Vol. 75, No. 6, 2010

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TABLE 1. Reaction of Dihydronaphthalene 10 with 2
FIGURE 1. Dihydronaphthalenes and diazo compounds being
studied.
ee (%)c
combined
15 yield (%)
entrya
R
2
catalyst
2a Rh2(S-DOSP)4 1.5:1
2a Rh2(S-PTAD)4
14:15b 14
1
2
3
4
H
H
>99
52
49
67
73
78
1:19 -84 -74
OTBS 2b Rh2(S-DOSP)4
OTBS 2b Rh2(S-PTAD)4
3:1
1:1
88
45
40
93
FIGURE 2. Chiral dirhodium catalysts.
aReaction conditions: (for entries 1 and 2) 10 (1 equiv), 2a (2-3
equiv), Rh(II) catalyst (0.02 equiv), room temperature, 1.5-4 h; (for
entries 3 and 4) 10 (3 equiv), 2b (1 equiv), Rh(II) catalyst (0.01 equiv),
room temperature, 18 h. 2,2-DMB = 2,2-dimethylbutane. bRatio
determined from the crude H NMR. Determined by chiral HPLC; a
negative value represents the formation of the opposite enantiomer.
three critical stereocenters of the natural products installed with
the correct configuration and are readily converted to the
natural products 5 and 9 in a concise fashion.7 In spite of this
success, as we began to extend this chemistry to more elaborate
systems, we became aware that the factors controlling the
selectivity were more subtle than we had observed in the natural
product syntheses. Therefore, we decided to conduct a systema-
tic study to better understand the controlling influences behind
the selectivity of this chemistry, which would be needed to guide
broader application of this methodology in total synthesis. The
results of this study are presented in this paper.
One parameter to be evaluated was the substituent effect in
the dihydronaphthalene substrate at positions C1 and C6 in
order to determine to what extent the steric and electronic
properties of the system influence the reaction (Figure 1). In
parallel, the influence of the diazo compound structure
was investigated. The vinyldiazoacetate used in the total
syntheses of (þ)-erogorgiaene and (-)-colombiasin A is the
pentenoate 2a.7a,b In recent years, however, β-silyloxyvinyl-
diazoacetates have been shown to be very versatile precur-
sors to vinylcarbenoids.8 Consequently, the studies were
extended to include the silyloxy counterpart 2b.
The chiral dirhodium tetracarboxylate Rh2(S-DOSP)4 is a
well-established catalyst for asymmetric intermolecular
C-H insertion reactions, generally resulting in high levels
of asymmetric induction (Figure 2).2g,9 Recently, the dirho-
dium tetracarboxylate catalyst, Rh2(S-PTAD)4, which is
related to Hashimoto’s catalysts, Rh2(S-PTPA)4 and Rh2-
(S-PTTL)4, has been developed for the reaction of donor/
acceptor carbenoids. Rh2(S-PTAD)4 gives different product
distributions and sometimes better enantioselectivity than
Rh2(S-DOSP)4.8c,10 Consequently both Rh2(S-DOSP)4 and
Rh2(S-PTAD)4 were screened in this study.
1
c
Results and Discussion
To determine a baseline for the influence of the catalyst
and vinyldiazoacetate structure on the relative reactivity for
C-H functionalization versus cyclopropanation, the first
system to be studied was the unsubstituted dihydronaphtha-
lene 10 (Table 1). The reaction could be carried out with
either the vinyldiazoacetate or the dihydronaphthalene as
the limiting reagent. 2,2-Dimethylbutane was used as an
inert solvent, although test reactions indicated that pentane
was similarly effective. When Rh2(S-DOSP)4 was used as
catalyst, the reaction of 10 with vinyldiazoacetate 2a af-
forded a 1.5:1 mixture of the C-H functionalization product
14a and the cyclopropane 15a (Table 1, entry 1). The C-H
functionalization occurred with exceptionally high enantio-
selectivity (>99% ee), while the cyclopropane 15a was
obtained with moderate enantioselectivity (52% ee). The
Rh2(S-PTAD)4-catalyzed reaction gave only a trace amount
of the C-H functionalization product 14a in -84% ee. The
major product was the cyclopropane 15a, which was formed
with improved enantioselectivity (-74% ee) compared to the
Rh2(S-DOSP)4-catalyzed reaction (Table 1, entry 2). The
Rh2(S-DOSP)4- and Rh2(S-PTAD)4-catalyzed reactions
gave rise to products of opposite asymmetric induction,
consistent with previous observations.10b,d
The use of silyloxyvinyldiazoacetate 2bwithRh2(S-DOSP)4
led to a similar result to that of 2a, except that the C-H
functionalization product 14b was favored over the cyclopro-
pane 15b by a ratio of 3:1. Once again the C-H functionaliza-
tion occurred with high enantioselectivity (88% ee), while the
cyclopropane 15b was formed with low enantioselectivity
(40% ee) (Table 1, entry 3). Interestingly the use of Rh2(S-
PTAD)4 gave a reversal in product enantioenrichement com-
pared to the reaction with Rh2(S-DOSP)4. The reaction of 2b,
catalyzed by Rh2(S-PTAD)4, produced a 1:1 mixture of
products consisting of a highly enantioenriched cyclopropane
15b (93% ee) and a poorly enriched C-H activation/Cope
rearrangement product 14b (45% ee). It is noteworthy that in
€
(8) (a) Muller, P.; Bernardinelli, G.; Allenbach, Y. F.; Ferri, M.; Flack,
H. D. Org. Lett. 2004, 6, 1725–1728. (b) Muller, P.; Bernardinelli, G.;
Allenbach, Y. F.; Ferri, M.; Grass, S. Synlett 2005, 1397–1400. (c) Reddy,
R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129, 10312–10313. (d)
Schwartz, B. D.; Denton, J. R.; Lian, Y.; Davies, H. M. L.; Williams, C. M.
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(10) (a) Denton, J. R.; Cheng, K.; Davies, H. M. L. Chem. Commun. 2008,
1238–1240. (b) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8,
3437–3440. (c) Denton, J. R.; Davies, H. M. L. Org. Lett. 2009, 11, 787–790.
(d) Ventura, D. L.; Li, Z.; Coleman, M. G.; Davies, H. M. L. Tetrahedron
2009, 65, 3052–3061.
J. Org. Chem. Vol. 75, No. 6, 2010 1929

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TABLE 2. Reaction of Dihydronaphthalene 11 with 2b
ee (%)c
entrya
catalyst
17:18:19b
17
18
19
combined yield (%)
1
2
Rh2(S-DOSP)4
Rh2(S-PTAD)4
2:0:1
1:1:0.2
90
33
90
45
90
82
95
aReaction conditions: 11 (3 equiv), 2b (1 equiv), Rh(II) catalyst (0.01 equiv), room temperature, 18 h. bRatio determined from the crude 1H NMR.
cDetermined by chiral HPLC.
obtained with Rh2(S-PTAD)4. Such insertions at activated
benzylic positions are well documented in the literature.13 These
results demonstrate that in this electronically activated system,
benzylic C-H insertion is competing with the cyclopropana-
tion and the combined C-H activation/Cope rearrangement,
and with vinyldiazoacetate 2a, the reaction cannot be effectively
controlled.
SCHEME 3. Reaction of Dihydronaphthalene 11 with 2a
The reaction of 11 with silyloxyvinyldiazoacetate 2b gave a
much cleaner reaction than that with 2a, but the benzylic
C-H insertion was still a competing pathway. However, the
nature of the catalysts had a major influence on the product
distribution. The reaction of 11 with 2b catalyzed by Rh2(S-
DOSP)4 afforded the rearrangement product 17 as the major
product, but the minor product was the benzylic C-H
insertion product 19 (2:1 ratio) (Table 2, entry 1). None of
the cyclopropane 18 or double functionalized adducts were
observed. Both products were obtained with high enantio-
selectivity (90% ee for both 17 and 19). When Rh2(S-PTAD)4
was used as catalyst, only traces of the benzylic C-H insertion
product 19 were observed (Table 2, entry 2). The major
products were a 1:1 mixture of the C-H functionalization
product 17 and the cyclopropane 18. The cyclopropane
was formed with very high enantioselectivity (95% ee) but
the C-H activation/Cope rearrangement product was af-
forded with low enantioselectivity (33% ee). These results
indicate that the carbenoid derived from silyloxyvinyldiazo-
acetate 2b is more selective than the carbenoid derived
from 2a, and in the reaction of 2b, Rh2(S-PTAD)4 equally
favors the C-H functionalization product 17 and the cyclo-
propane 18.
An intriguing aspect of the reaction of dihydronaphtha-
lenes is the possibility for enantiomer differentiation when 1-
substituted dihydronaphthalenes are used as substrates.7
This was tested in the reaction with 1-methyl-1,2-dihydro-
naphthalene (12). The Rh2(S-DOSP)4-catalyzed reaction of
racemic 12 with 2a afforded a 1:1 mixture of C-H activa-
tion/Cope rearrangement product 20a and cyclopropane 21a
in which 20a was obtained with excellent enantioselectivity
(91% ee) (Table 3, entry 1). The enantioselectivity for 20a
could be further improved to 96% ee when the same reaction
was conducted at 0 °C. The cyclopropane 21a was obtained
as a 4:1 mixture of diastereomers and with moderate
enantioselectivity (74% ee for the major and 50% ee for
the minor). These conditions are similar to those used in the
total synthesis of (þ)-erogorgiaene (5) and (-)-colombiasin A
this case, Rh2(S-DOSP)4 and Rh2(S-PTAD)4 led to the
selective formation of the same enantiomers of 14b and 15b.
This behavior is characteristic for the Rh2(S-DOSP)4- and
Rh2(S-PTAD)4-catalyzed reactions of silyloxyvinyldiazoace-
tate 2b,8c,d however these two catalysts often give opposite
asymmetric induction in the reactions of other types of donor/
acceptor carbenoids. These studies show that Rh2(S-DOSP)4-
catalyzed reactions have a greater preference for C-H func-
tionalization compared to Rh2(S-PTAD)4-catalyzed reactions
and silyloxyvinyldiazoacetate 2b also has a greater preference
for C-H functionalization compared to vinyldiazoacetate 2a.
Many of the natural products accessible through this
chemistry would require the use of electron-rich dihydro-
naphthalenes.11 Therefore, as a test system, the reaction of
6-methoxydihydronaphthalene 11 was examined. In an attempt
to obtain racemic material, the reaction of 11 with an excess of
2a (3 equiv) in a Rh2(R/S-DOSP)4-catalyzed process led to a
complex mixture of C-H insertion and cyclopropanation
products, from which was isolated 16 as a single diastereomer,
resulting from the double functionalization of 11 (Scheme 3).
The relative configuration of 16 was determined by X-ray
crystallography (see the Supporting Information).12 When
the same reaction was conducted with an excess of dihydro-
naphthalene 11 (3 equiv), a complex mixture was obtained, but
still, a trace amount of 16 was observed. Similar mixtures were
(11) Heckrodt, T. J.; Mulzer, J. Top. Curr. Chem. 2005, 244, 1–41.
(12) The crystal structures of 16 and 21b have been deposited at the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2
1EZ, U.K. [fax: þ44(0) 1223 336033 or e-mail deposit@ccdc.cam.ac.uk],
under CCDC reference nos. CCDC 757794 and CCDC 757795.
(13) (a) Davies, H. M. L.; Hedley, S. J.; Bohall, B. R. J. Org. Chem. 2005,
70, 10737–10742. (b) Davies, H. M. L.; Loe, O. Synthesis 2004, 2595–2608.
(c) Davies, H. M. L.; Jin, Q. Tetrahedron: Asymmetry 2003, 14, 941–949.
(d) Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org. Chem. 2002,
67, 4165–4169.
1930 J. Org. Chem. Vol. 75, No. 6, 2010

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TABLE 3. Reaction of Dihydronaphthalene 12 with 2
insertion product 24a. The cyclopropane 23a was again a 9:1
mixture of diastereomers while the C-H functionalization pro-
ducts 22a and 24a were produced as single diastereomers. How-
ever, the diastereomer of 24a formed in the Rh2(S-PTAD)4-
catalyzed reaction was different from that obtained from the
Rh2(R-DOSP)4-catalyzed reaction. The competing C-H inser-
tion at a benzylic tertiary position is relatively unusual because
such sites are generally not particularly reactive toward donor/
acceptor carbenoids due to steric hindrance and typically more
forcing reaction conditions would be required.15
The reactions of silyloxyvinyldiazoacetate 2b with 13 were
much cleaner, as there was no competing benzylic C-H
insertion. The outcome of the reactions was very similar to
the results obtained in the reactions of dihydronaphthalene
12. The Rh2(S-DOSP)4-catalyzed reaction favored the
C-H activation/Cope rearrangement, while Rh2(S-PTAD)4
afforded a 1:1 mixture of the C-H activation/Cope rearran-
gement product 22b (88% ee) and the cyclopropane 23b
(96% ee) with excellent enantiodifferentiation (Table 4,
entries 3 and 4). These results confirm the trend that the
carbenoid derived from silyloxyvinyldiazoacetate 2b is more
selective than the carbenoid derived from 2a, and in the
reaction of 2b, Rh2(S-PTAD)4 equally favors the C-H
functionalization product 22 and the cyclopropane 23. Ad-
ditionally, direct C-H insertion at the electronically acti-
vated tertiary benzylic site in 13 is less prevalent than the
direct C-H insertion into the secondary benzylic site in 11.
This is another example of how steric hindrance can protect
an electronically activated site from C-H insertion by
donor/acceptor carbenoids.
The absolute configuration of the C-H functionalization
products 14a, 20a, and 22a derived from vinyldiazoacetate
2a was tentatively assigned on the basis of the known
absolute configuration of analogous products obtained in
model studies or natural products syntheses, which were
unambiguously determined by X-ray crystallography and/or
conversion to natural products.7 The absolute configuration
of 20b, derived from the silyloxyvinyldiazoacetate 2b, was
established via derivatization (Scheme 4). Reaction of 12
with 2b in the presence of Rh2(S-DOSP)4 afforded a mixture
of C-H activation/Cope rearrangement and cyclopropana-
tion products which was then treated with TBAF. Further
reaction with PhNTf2 afforded vinyl triflate 25, which was
then hydrogenated to give 26.16 The same product was
prepared in a similar sequence from 12 and 2a via hydro-
genation of 20a.7 It was found that the same enantiomer of 26
was obtained in both cases, showing that diazo compounds
2a and 2b led to C-H activation/Cope rearrangement
products with the same sense of enantioinduction in Rh2-
(S-DOSP)4-catalyzed reactions. The relative and absolute
configurations of the direct benzylic C-H insertion products
19 and 24 were not determined.
ee (%)c
combined
yield (%)
entrya
R
2
catalyst
20:21b
20
21
74e
1
2
3
4
H
H
2a Rh2(S-DOSP)4 1:1
2a Rh2(S-PTAD)4 1:7
91(96)d
-40
86
72
42
58
90
-34f
53
OTBS 2b Rh2(S-DOSP)4 3:1
OTBS 2b Rh2(S-PTAD)4 1:1
88
96
aReaction conditions: (for entries 1 and 2) 12 (1 equiv), 2a (2-3 equiv),
Rh(II) catalyst (0.02 equiv), room temperature, 3-16 h; (for entries 3 and
4) 12 (1 equiv), 2b (4 equiv), Rh(II) catalyst (0.01 equiv), room tempera-
ture, 18 h. bRatio determined from the crude 1H NMR. cDetermined by
chiral HPLC; a negative value represents the formation of the opposite
enantiomer. dReaction at 0 °C. edr = 4:1. The major diastereomer is 74%
f
ee. The minor diastereomer is 50% ee. dr = 2.3:1. The major diaster-
eomer is -34% ee. The minor diastereomer is -78% ee.
(9), except Rh2(R-DOSP)4 was used as the catalyst in these
cases.7a,b The same reaction catalyzed by Rh2(S-PTAD)4 af-
forded the cyclopropane 21a as the major product in a 2.3:1
mixture of diastereomers (-34% ee for the major, -78% ee for
the minor) along with recovered starting material and a minimal
amount of the C-H activation product (Table 3, entry 2).
The reaction of silyloxyvinyldiazoacetate 2b with 12 was
quite different from the reaction of 2a. The Rh2(S-DOSP)4-
catalyzed reaction of 2b with 12 generated a 3:1 mixture of
20b and 21b in a 58% combined yield (Table 3, entry 3). The
C-H activation/Cope rearrangement showed a high level of
enantioinduction (86% ee) but the cyclopropane 21b was
obtained with low enantioselectivity (53% ee). In contrast,
the Rh2(S-PTAD)4-catalyzed reaction of 2b with 12 went
very smoothly, affording a 1:1 mixture of 20b and 21b, both
of which were formed with excellent enantioinduction (88%
ee and 96% ee, respectively) (Table 3, entry 4). These studies
indicate that Rh2(S-DOSP)4 is the best catalyst for enantio-
differentiation of 12 with use of 2a as the carbenoid pre-
cursor, while Rh2(S-PTAD)4 is the best catalyst when 2b is
used as the carbenoid precursor.
The final system to be examined was 13, an electron-rich
1-substituted dihydronaphthalene. The Rh2(R-DOSP)4-catalyzed
reaction yielded a nearly equimolar mixture of the C-H activa-
tion/Cope rearrangement product 22a and cyclopropane 23a
while small amounts of benzylic C-H insertion product 24a were
also observed.14 Cyclopropane 23a was obtained as a 9:1 mixture
of diastereomers; however, 22a and 24a were single diastereomers
and were obtained in -81% and 98% ee, respectively. Interest-
ingly, when the reaction was catalyzed by Rh2(S-PTAD)4, the
C-H activation/Cope rearrangement product 22a was obtained
as a minor product and with low enantioinduction, with the major
products being the cyclopropane 23a and the benzylic C-H
The relative configuration of the cyclopropanes 15, 18, 21,
and 23 was determined on the basis of the distinctive chemical
shift for the methyl ester and NOE experiments on cyclopro-
pane 21a (see the Supporting Information). The absolute
(15) Nadeau, E.; Li, Z.; Morton, D.; Davies, H. M. L. Synlett 2009, 151–
154.
(16) (a) Jigajinni, V. B.; Wightman, R. H. Tetrahedron Lett. 1982, 23,
(14) The reaction of vinyldiazoacetate 2a with 13 was conducted with the
enantiomeric catalyst Rh2(R-DOSP)4 as this simplified the chiral HPLC
analysis.
117–120. (b) Martınez, A. G.; Alvarez, R. M.; Casado, M. M.; Subramanian,
´
L. R.; Hanack, M. Tetrahedron 1987, 43, 275–279. (c) Comins, D. L.;
Benjelloun, N. R. Tetrahedron Lett. 1994, 35, 829–832.
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TABLE 4. Reaction of Dihydronaphthalene 13 with 2
ee (%)c
entrya
R
2
catalyst
22:23:24b
22
23
24
combined yield (%)
1
2
3
4
H
H
OTBS
OTBS
2a
2a
2b
2b
Rh2(R-DOSP)4
Rh2(S-PTAD)4
Rh2(S-DOSP)4
Rh2(S-PTAD)4
0.9:1:0.1
0.1:1:0.7
5:1:0
-81d
-36
85
NDe
NDe
59
98f
ND
84
75
55
90
1:1:0
88
96
aReaction conditions: (for entries 1 and 2) 13 (1 equiv), 2a (2-3 equiv), Rh(II) catalyst (0.02 equiv), room temperature, 1.5-2 h; (for entries 3 and 4) 13
(1 equiv), 2b (3 equiv.), Rh(II) catalyst (0.01 equiv), room temperature, 18 h. bRatio determined from the crude 1H NMR. cDetermined by chiral HPLC; a
negative value represents the formation of the opposite enantiomer. dDetermined after hydrogenation and reduction of the ester. edr = 9:1. fDetermined
after hydrogenation.
SCHEME 4. Confirmation of Absolute Stereochemistry
configuration was tentatively assigned based on the estab-
lished predictive model for Rh2(S-DOSP)4-catalyzed cyclo-
propanations.17 For cyclopropane 21b (Table 3, entry 4), the
absolute stereochemistry was unambiguously assigned by
X-ray crystallography (see the Supporting Information).12
Excellent predictive models have been developed for both the
Rh2(S-DOSP)4-catalyzed C-H activation/Cope rearrange-
ment6b and cyclopropanation.17 The chiral catalyst is considered
to adopt a D2 symmetric arrangement (in nonpolar solvents)
and can be viewed simply as having a blocking group in the front
and another in the back.2g,18 Applying these models to chiral
dihydronaphthalenes (12 and 13) shows that an enantiodiver-
gent process can take place in which one enantiomer is matched
for a C-H activation/Cope rearrangement while the other
enantiomer prefers a matched cyclopropanation.7 C-H activa-
tion is considered to occur by approach of the substrate from the
front face of the vinylcarbenoid and is interrupted by the
interaction of the alkene in the dihydronaphthalene, which
triggers the Cope rearrangement (Figure 3).6,7 In the case of
the (R)-enantiomer of the substrate, the C1 methyl group is
pointing forward away from the carbenoid (TS-1) and thus the
C-H functionalization is favored. The (S)-enantiomer of the
substrate is unable to approach the vinylcarbenoid due to steric
interaction by the C1 methyl group (TS-2) thereby inhibiting the
C-H transformation.
(17) Nowlan, D. T. III; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A.
J. Am. Chem. Soc. 2003, 125, 15902–15911.
(18) (a) Hansen, J.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252, 545–
555. (b) Hansen, J.; Autschbach, J.; Davies, H. M. L. J. Org. Chem. 2009, 74,
6555–6563.
In the case of the cyclopropanation reaction, the (S)-
enantiomer of the dihydronaphthalene gives the matched
1932 J. Org. Chem. Vol. 75, No. 6, 2010

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FIGURE 3. Rh2(S-DOSP)4 predictive model for the combined C-H activation/Cope rearrangement (X = H, OTBS).
FIGURE 4. Rh2(S-DOSP)4 predictive model for the cyclopropanation reaction (X = H, OTBS).
reaction (TS-3), while the (R)-enantiomer gives the mis-
matched reaction (TS-4), as illustrated in Figure 4. The
influence of the C1 methyl group in the cyclopropanation is
not as dominating as it is in the C-H functionalization, as it is
further away from the site of attack. In the case of the
unsubstituted vinyldiazoacetate (X = H), a mixture of dia-
stereomeric cyclopropanes is formed, but with the more
sterically demanding silyloxyvinyldiazoacetate (X = OTBS),
only the matched reaction is observed.
The reactions catalyzed by Rh2(S-PTAD)4 also undergo an
enantiodivergent process, which is similar to the enantiodiver-
gent step catalyzed by Rh2(S-DOSP)4. Hashimoto reported
that the crystal structure of the chiral dirhodium tetracarboxy-
FIGURE 5. C2 symmetrical Rh2(S-PTPA)4 predictive model.
late Rh2(S-PTPA)4 adopts a C2 symmetrical arrangement, in
which two adjacent phthalimido groups are positioned on the
top face of the complex, while the next two are positioned on
the bottom face. This structure was used to develop a pre-
dictive model for the stereoselection of intramolecular C-H
insertion reactions (Figure 5).19 Two possible orientations of
the carbenoid are possible and the preferred orientation would
place the smaller group pointing toward the phthalimido
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JOCArticle
FIGURE 6. Rh2(S-PTAD)4 predictive model for the combined C-H activation/Cope rearrangement with vinylcarbenoids derived from diazo
compounds 2a (TS-5) and 2b (TS-6).
FIGURE 7. Rh2(S-PTTL)4 predictive model.
group. The two adjacent phthalimido groups would then block
the attack to one of the two faces of the carbenoid.
Recently, Fox20 and Charette21 independently reported the
crystal structure of chiral dirhodium tetracarboxylate Rh2(S-
PTTL)4 and other phthalimido-derived catalysts, which are
closely related to Rh2(S-PTAD)4. Interestingly, they found that
their structure is considerably different from that of Rh2(S-
PTPA)4. Indeed, the four phthalimide groups were found to be
orientated on the same face of the catalyst, providing a “chiral
crown” environment.20 For Rh2(S-PTTL)4, Fox suggested that
two opposite groups are acting as blocking groups, while the
two others are slightly tilted, thus leading to a cavity with
narrow (∼11 A) and wide (∼15 A) dimensions.20 From this
structure, a model was proposed to explain highly enantiose-
lective cyclopropanation reactions of alkyldiazoacetates
(Figure 7).
Application of the Hashimoto model to rationalize the
Rh2(S-PTAD)4-catalyzed reactions with dihydronaphtha-
lenes is shown in Figure 6.8d In this model, the back-face of
the vinylcarbenoid is blocked by the two adjacent phthali-
mide groups. With the unsubstituted vinyldiazoacetate 2a,
it is assumed that the methylvinyl moiety is small enough to
fit in the most encumbered pocket of the catalyst. Approach
of the substrate from the front, with the C1 methyl group
pointing away from the blocking groups, would lead to the
opposite enantiomer to the one obtained from a Rh2(S-
DOSP)4-catalyzed reaction, which is in accordance with
experimental data (Figure 6, TS-5). With silyloxyvinyldia-
zoacetate 2b, the electron-donating group of the carbenoid is
significantly larger, and therefore, it prefers an orientation in
which the bulky silyl group is away from the blocking groups
(Figure 6, TS-6). Hence, unlike 2a, the silyloxyvinyldiazoa-
cetate 2b generates products of the same overall asymmetric
induction with both Rh2(S-PTAD)4 and Rh2(S-DOSP)4.
The Fox model was applied to our reactions with dihydro-
naphthalenes, but the current version of the model predicted
the opposite asymmetric induction to what was observed. As
shown in Figure 8 for the reaction with silyloxyvinyldiazo-
acetate 2b, the bulky silyloxyvinyl group should be located in
(20) DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. J. Am.
Chem. Soc. 2009, 131, 7230–7231.
(21) Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem. Soc. 2009,
131, 16383–16385.
(19) (a) Hashimoto, S.; Watanabe, N.; Sato, T.; Shiro, M.; Ikegami, S.
Tetrahedron Lett. 1993, 34, 5109–5112. (b) Watanabe, N.; Ohtake, Y.;
Hashimoto, S.; Shiro, M.; Ikegami, S. Tetrahedron Lett. 1995, 36, 1491–1494.
1934 J. Org. Chem. Vol. 75, No. 6, 2010

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FIGURE 8. Alternative Rh2(S-PTAD)4 predictive model for the combined C-H activation/Cope rearrangement with vinylcarbenoid derived
from diazo compound 2b.
the less hindered quadrant of the catalyst cavity and the
dihydronaphthalene should approach from the front, over
the tilted phthalimide group (TS-7). However, this model
predicts the wrong absolute stereochemistry of the reaction.
Recent studies by Charette suggest that Rh2(S-PTTL)4 may
be conformationally mobile in solution and not locked in the
“chiral crown” configuration.21 Further studies will be neces-
sary to determine if there is a defined orientation for the
Hashimoto catalysts including Rh2(S-PTAD)4, which can
rationalize all the types of asymmetric transformations that
have been achieved with these catalysts.
In summary, these studies demonstrate that 2a/Rh2(S-
DOSP)4 and 2b/Rh2(S-PTAD)4 are the best combinations
for achieving high selectivity in the cyclopropanation and the
combined C-H activation/Cope rearrangement of 1,2-dihy-
dronaphthalenes, and hence are the most effective for en-
antiodivergent reactions in these systems. The 2a/Rh2(S-
PTAD)4 combination strongly favors cyclopropanation,
while the 2b/Rh2(S-DOSP)4 combination strongly favors
the combined C-H activation/Cope rearrangement. The
2a/Rh2(S-DOSP)4 combination gives high enantioselectivity
for the combined C-H activation/Cope rearrangement with
achiral substrates and substrates capable of enantiodiver-
gent reactions. In contrast, the 2b/Rh2(S-PTAD)4 combina-
tion gives high enantioselectivity only with substrates
capable of enantiodivergent reactions. With chiral dihydro-
naphthalenes, 2b/Rh2(S-PTAD)4 is generally more selective
than 2a/Rh2(S-DOSP)4, and therefore, it is a good backup
system when the 2a/Rh2(S-DOSP)4 fails to give a clean
enantiomer differentiation.
naphthalene 10 (65 mg, 0.5 mmol, 1 equiv) and Rh2(S-DOSP)4
(19 mg, 0.01 mmol, 0.02 equiv) in 5.5 mL of 2,2-DMB. After 0.5 h of
additional stirring, the solvent was removed under vacuum and the
remaining residue was purified on silica gel (hexane:ether 98:2) to
afford 14a and 15a (59 mg, 49% combined yield). Analytically pure
products were obtained by purification on silica gel impregnated
22
with 5% AgNO3 (hexane:ether). Table 1, entry 2: 2a (140 mg,
1 mmol, 2 equiv) in 4.5 mL of 2,2-DMB was added by syringe pump
over 1 h to a solution of dihydronaphthalene 10 (65 mg, 0.5 mmol,
1 equiv) and Rh2(S-PTAD)4 (16 mg, 0.01 mmol, 0.02 equiv) in
5.5 mL of 2,2-DMB. After 3 h of additional stirring, the solvent was
removed under vacuum and the remaining residue was purified on
silica gel (hexane:ether 98:2) to afford 14a and 15a (81 mg, 67%
combined yield). Analytically pure products were obtained by
purification on silica gel impregnated with 5% AgNO3 (hexane:
ether).
14a: colorless oil; Rf 0.57 (hexane:ethyl acetate 80:20); IR
(neat) ν 3028, 2966, 2872, 1720; 1H NMR (600 MHz, CDCl3) δ
7.15-7.21 (3H, m), 7.13 (1H, d, J = 7.1 Hz), 7.09 (1H, dd, J =
15.9, 6.9 Hz), 6.07-6.10 (1H, m), 5.82 (1H, d, J = 15.9 Hz),
5.74-5.78 (1H, m), 3.75 (3H, s), 3.62 (1H, ddd, J = 8.0, 3.9,
3.9 Hz), 3.27-3.40 (2H, m), 2.77-2.84 (1H, m), 0.84 (3H, d, J =
7.1 Hz); 13C NMR (100 MHz, CDCl3) δ 167.2, 152.7, 136.4,
135.4, 128.2, 128.0, 127.4, 126.1(2C), 125.4, 120.3, 51.5, 44.1,
43.8, 30.2, 13.2; HRMS (APCI) calcd for C16H19O2 (MHþ)
243.1380, found 243.1379; [R]20D -172.7 (c 0.7, CHCl3) for 99%
ee; HPLC anal. 99% ee with Rh2(S-DOSP)4 and -84% ee
with Rh2(S-PTAD)4 (Chiralcel OD-H, 0.5% i-PrOH in hexane,
1 mL/min, λ = 254 nm, tR = 8.97, 10.63 min).
15a: white solid; mp 33-34 °C; Rf 0.57 (hexane:ethyl acetate
80:20); IR (neat) ν 3021, 2926, 1713, 1232; 1H NMR (400 MHz,
CDCl3) δ 7.28-7.32 (1H, m), 7.10-7.18 (2H, m), 6.98-7.02
(1H, m), 5.21-5.33 (2H, m), 3.70 (3H, s), 2.81 (1H, d, J =
9.1 Hz), 2.62 (1H, ddd, J = 16.6, 7.0, 4.1 Hz), 2.44 (1H, ddd, J =
16.6, 9.8, 7.3 Hz), 2.23 (1H, ddd, J = 9.1, 5.7, 2.9 Hz), 1.92-2.08
(2H, m), 1.48 (3H, d, J = 4.8 Hz); 13C NMR (150 MHz, CDCl3)
δ 174.3, 135.7, 133.1, 132.2, 130.2, 128.3, 126.3, 125.9, 121.7,
52.3, 35.6, 29.9, 27.8, 26.6, 18.4, 17.9; HRMS (APCI) calcd for
C16H19O2 (MHþ) 243.1380, found 243.1380; [R]20D þ3.2 (c 2.5,
CHCl3) for -74% ee; HPLC anal. 48% ee with Rh2(S-DOSP)4
and -74% ee with Rh2(S-PTAD)4 ((S,S)-Whelk-O 1, 0.5%
i-PrOH in hexane, 1 mL/min, λ = 254 nm, tR = 13.24, 14.47 min).
(1R,1aS,3R,7bS)-Methyl 6-Methoxy-3-((R,E)-1-methoxy-1-oxo-
pent-3-en-2-yl)-1-((E)-prop-1-enyl)-1a,2,3,7b-tetrahydro-1H-cyclo-
propa[a]naphthalene-1-carboxylate (16) (Scheme 3). 2a (315 mg,
2.25 mmol, 3 equiv) in 7 mL of 2,2-DMB was added by syringe
pump over 1 h to a solution of dihydronaphthalene 11 (120 mg,
0.75 mmol, 1 equiv) and Rh2(R/S-DOSP)4 (28 mg, 0.015 mmol,
0.02 equiv) in 8 mL of 2,2-DMB. After 1 h of additional stirring,
the solvent was removed under vacuum and the remaining residue
was purified on silica gel (hexane:ether 98:2-80:20). 16 was
Experimental Section
General Considerations. All reactions were conducted in
flame-dried glassware under an inert atmosphere of dry argon.
All reagents were used as received from commercial suppliers
unless otherwise stated. 2,2-Dimethylbutane (2,2-DMB) was
distilled from sodium metal. Pentane, tetrahydrofuran, and
toluene were obtained through drying columns. All solvents
used for C-H functionalization reactions were degassed by
bubbling argon through the solvent for 15 min prior to use.
Diastereomeric ratios were determined by values derived from
1
the H NMR spectra of the crude reaction mixtures. Enantio-
meric excess was determined by high performance liquid chro-
matography (HPLC), using chiral analytical columns with
2-propanol in hexane as eluant.
(R,E)-Methyl 4-((S)-1,4-Dihydronaphthalen-1-yl)pent-2-enoate
(14a) and (1R,1aS,7bS)-Methyl 1-((E)-Prop-1-enyl)-1a,2,3,7b-tetra-
hydro-1H-cyclopropa[a]naphthalene-1-carboxylate (15a). Table 1,
entry 1: 2a (210 mg, 1.5 mmol, 3 equiv) in 4.5 mL of 2,2-DMB
was added by syringe pump over 1 h to a solution of dihydro-
(22) Li, T.-S.; Li, J.-T.; Li, H.-Z. J. Chromatogr., A 1995, 715, 372–375.
J. Org. Chem. Vol. 75, No. 6, 2010 1935

Nadeau et al.
JOCArticle
further purified by recrystallization from hexane to afford 76 mg
(26%) of 16.
(R,E)-Methyl 4-((1S,4R)-7-Methoxy-4-methyl-1,4-dihydro-
naphthalen-1-yl)pent-2-enoate (22a) and (1R,1aS,3S,7bS)-Methyl
6-Methoxy-3-methyl-1-((E)-prop-1-enyl)-1a,2,3,7b-tetrahydro-
1H-cyclopropa[a]naphthalene-1-carboxylate (23a). Table 4, entry
1: 2a (4.80 g, 34.4 mmol, 2 equiv) in20mL of2,2-DMB was added
by syringe pump over 1 h to a solution of dihydronaphthalene 13
(3.00 g, 17.2 mmol, 1 equiv) and Rh2(R-DOSP)4 (650 mg, 0.344
mmol, 0.02 equiv) in 60 mL of 2,2-DMB. After 0.5 h of additional
stirring, the solvent was removed under vacuum and the remain-
ing residue was purified on silica gel (hexane:ethyl acetate 90:10)
to afford 22a, 23a, and 24a (4.14 g, 84% combined yield). Table 4,
entry 2: 2a (168 mg, 1.2 mmol, 2 equiv) in 5 mL of 2,2-DMB
was added by syringe pump over 1 h to a solution of dihydro-
naphthalene 13 (105 mg, 0.6 mmol, 1 equiv) and Rh2(S-PTAD)4
(19 mg, 0.012 mmol, 0.02 equiv) in 7 mL of 2,2-DMB. After 1 h of
additional stirring, the solvent was removed under vacuum and
the remaining residue was purified on silica gel (hexane:ether
95:5-80:20) to afford 22a, 23a, and epi-24a (129 mg, 75% com-
bined yield). Analytically pure products were obtained by purifica-
tion on silica gel impregnated with 5% AgNO3 (hexane:ether).
22a: colorless oil; Rf 0.53 (hexane:ethyl acetate 80:20); IR
(neat) ν3024, 2963, 2871, 2836, 1720; 1HNMR(400MHz, CDCl3)
δ 7.21 (1H, d, J = 8.6 Hz), 7.13 (1H, dd, J = 15.7, 6.5 Hz), 6.80
(1H, dd, J = 8.6, 2.5 Hz), 6.72 (1H, d, J = 2.5 Hz), 5.89 (1H, ddd,
J = 10.2, 2.7, 1.1 Hz), 5.85 (1H, dd, J = 15.7, 1.7 Hz), 5.64 (1H,
ddd, J = 10.2, 4.1, 2.5 Hz), 3.81 (3H, s), 3.75 (3H, s), 3.56-3.62
(1H, m), 3.30-3.38 (1H, m), 2.80-2.88 (1H, m), 1.33 (3H, d, J =
7.3 Hz), 0.78 (3H, d, J = 6.7 Hz); 13C NMR (100 MHz, CDCl3) δ
167.4, 158.0, 153.1, 137.4, 134.7, 133.2, 128.2, 123.3, 120.5, 112.6,
112.5, 55.4, 51.7, 44.3, 43.6, 32.2, 23.2, 12.9; HRMS (APCI) calcd
for C18H23O3 (MHþ) 287.1647, found 287.1643; HPLC anal. -36%
with Rh2(S-PTAD)4 ((S,S)-Whelk-O 1, 0.5% i-PrOH in hexane,
1 mL/min, λ = 254 nm, tR = 22.52, 26.51 min).
16: white solid; mp 108-109 °C; Rf 0.36 (hexane:ethyl acetate
80:20); IR (neat) ν 2949, 1716, 1193, 1158; 1H NMR (400 MHz,
CDCl3) δ 6.87 (1H, d, J = 8.5 Hz), 6.78 (1H, d, J = 2.6 Hz), 6.61
(1H, dd, J = 8.5, 2.6 Hz), 5.69 (1H, dq, J = 15.2, 6.4 Hz), 5.51
(1H, ddq, J = 15.2, 9.5, 1.6 Hz), 5.44 (1H, dq, J = 15.9, 6.6 Hz),
4.86 (1H, dq, J = 15.9, 1.7 Hz), 3.76 (3H, s), 3.72 (3H, s), 3.43
(3H s), 3.24 (1H, dd, J = 10.0, 10.0 Hz), 2.77-2.82 (1H, m), 2.77
(1H, d, J = 8.9 Hz), 2.22 (1H, ddd, J = 14.5, 9.1, 2.2 Hz), 2.08
(1H, ddd, J = 9.1, 9.1, 6.4 Hz), 1.73 (3H, dd, J = 6.4, 1.6 Hz),
1.56-1.62 (1H, m), 1.55 (3H, dd, J = 6.6, 1.7 Hz); 13C NMR
(100 MHz, CDCl3) δ 174.5, 174.1, 158.4, 133.7, 132.8, 131.8,
129.7, 129.2, 127.8, 121.9, 115.5, 112.6, 55.8, 55.1, 52.3, 51.3,
40.6, 35.8, 28.6, 23.2, 21.6, 18.8, 17.9; HRMS (APCI) calcd for
C23H29O5 (MHþ) 385.2010, found 385.2012.
(R,E)-Methyl 4-((1S,4R)-4-Methyl-1,4-dihydronaphthalen-1-yl)-
pent-2-enoate (20a) and (1R,1aS,3S,7bS)-Methyl 3-Methyl-1-((E)-
prop-1-enyl)-1a,2,3,7b-tetrahydro-1H-cyclopropa[a]naphtha-
lene-1-carboxylate (21a). Table 3, entry 1: 2a (210 mg, 1.5 mmol,
3 equiv) in 4.5 mL of 2,2-DMB was added by syringe pump over
1 h to a solution of dihydronaphthalene 12 (72 mg, 0.5 mmol,
1 equiv) and Rh2(S-DOSP)4 (19 mg, 0.01 mmol, 0.02 equiv) in
5.5 mL of 2,2-DMB. After 2 h of additional stirring, the solvent
was removed under vacuum and the remaining residue was
purified on silica gel (hexane:ether 98:2) to afford 20a and 21a
(92 mg, 72% combined yield). Analytically pure products were
obtained by purification on silica gel impregnated with 5% AgNO3
(hexane:ether). Table 3, entry 2: 2a (140 mg, 1 mmol, 2 equiv) in
4.5 mL of 2,2-DMB was added by syringe pump over 1 h to a
solution of dihydronaphthalene 12 (72 mg, 0.5 mmol, 1 equiv) and
Rh2(S-PTAD)4 (16 mg, 0.01 mmol, 0.02 equiv) in 5.5 mL of 2,2-
DMB. After 15 h of additional stirring, the solvent was removed
under vacuum and the remaining residue was purified on silica gel
(hexane:ether 98:2) to afford 20a and 21a (54 mg, 42% combined
yield). Analytically pure products were obtained by purification on
silica gel impregnated with 5% AgNO3 (hexane:ether).
23a: major/minor = 90:10; colorless oil; Rf 0.53 (hexane:ethyl
1
acetate 80:20); IR (neat) ν 3021, 2952, 1713, 1230; major: H
NMR (400 MHz, CDCl3) δ 7.03 (1H, d, J = 8.3 Hz), 6.83 (1H, d,
J = 2.9 Hz), 6.71 (1H, dd, J = 8.3, 2.9 Hz), 5.35 (1H, dq, J =
15.7, 6.5 Hz), 5.11 (1H, dq, 15.7, 1.6 Hz), 3.79 (3H, s), 3.71 (3H,
s), 2.79 (1H, d, J = 9.2 Hz), 2.52-2.61 (1H, m), 2.19 (1H, ddd,
J = 9.2, 7.0, 4.3 Hz), 1.94 (1H, ddd, J = 14.4, 6.0, 4.3 Hz), 1.78
(1H, ddd, J = 14.4, 7.0, 7.0 Hz), 1.51 (3H, dd, J = 6.7, 1.6 Hz),
1.24 (3H, d, J = 6.7 Hz); 13C NMR (100 MHz, CDCl3) δ 174.5,
157.7, 134.4, 133.3, 132.7, 127.5, 122.0, 115.1, 112.8, 55.2, 52.3,
35.6, 30.7, 29.8, 26.9, 25.6, 22.3, 18.6; HRMS (APCI) calcd for
C18H23O3 (MHþ) 287.1642, found 287.1643.
(S)-4-((1R,4S)-7-Methoxy-4-methyl-1,2,3,4-tetrahydronaphtha-
len-1-yl)pentan-1-ol.7a The purified mixture of 22a, 23a, and 24a
(4.14 g, from the Rh2(R-DOSP)4-catalyzed reaction, Table 4,
entry 1) was taken up in100mL ofethyl acetateand transferred to
a Parrhydrogenationbottlecontaining 5%Pd/C(1.80 g, 90 mgof
Pd, 0.85 mmol). The vessel was purged with H2. The reaction was
shaken under H2 atmosphere (35 psi) for 12 h at rt, then filtrated
on a short plug of silica gel. The plug was washed with ethyl
acetate and the solvent was removed under reduced pressure. The
crude product was purified by flash chromatography (hexane:
ethyl acetate 95:5) to yield 1.38 g (28% over 2 steps from 13) of
the C-H activation/Cope rearrangement product. The latter
(200 mg, 0.7 mmol) was dissolved in 5 mL of THF and cooled
to 0 °C. The reaction vessel was purged with argon and LiAlH4
(50 mg, 1.4 mmol) was added portionwise to the stirring solution
against positive argon pressure. The reaction was stirred for
0.5 h, quenched slowly with H2O (10 mL), followed by 10%
HCl (5 mL). The aqueous layer was extracted with ether (3 ꢀ
10 mL). The organic extracts were combined and dried with
MgSO4, filtered, and evaporated under reduced pressure. The
crude product was purified on silica gel (hexane:ethyl acetate
60:40) to give 160 mg (87%) of the titled compound. Colorless
oil; IR (neat) ν 2927, 1607, 1491, 1279, 1237, 1051, 804; 1H NMR
20a: colorless oil; Rf 0.63 (hexane:ethyl acetate 80:20); IR
(neat) ν 3024, 2966, 2872, 1721, 1271, 1173; 1H NMR (400 MHz,
CDCl3) δ 7.28-7.31 (1H, m), 7.19-7.24 (3H, m), 7.13 (1H, dd,
J = 15.8, 6.5 Hz), 5.91 (1H, ddd, J = 10.2, 2.6, 1.3 Hz), 5.84
(1H, dd, J = 15.8, 1.6 Hz), 5.67 (1H, ddd, 10.2, 4.4, 2.5 Hz), 3.75
(3H, s), 3.61-3.65 (1H, m), 3.36-3.44 (1H, m), 2.81-2.89 (1H,
m), 1.36 (3H, d, J = 7.3 Hz), 0.78 (3H, d, J = 7.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 167.4, 153.2, 140.8, 136.1, 134.4, 127.7,
127.2, 126.5, 126.3, 123.7, 120.5, 51.7, 43.9, 43.5, 32.8, 23.1, 13.0;
HRMS (APCI) calcd for C17H21O2 (MHþ) 257.1536, found
257.1540; [R]20D -189.2 (c 0.3, CHCl3) for 91% ee; HPLC anal.
91% ee with Rh2(S-DOSP)4 and -40% ee with Rh2(S-PTAD)4
(ChiralcelOD-H, 0.5%i-PrOH in hexane, 1 mL/min, λ= 254nm,
tR = 7.57, 8.37 min).
21a: major/minor = 80:20; colorless oil; Rf 0.63 (hexane:ethyl
acetate 80:20); IR (neat) ν 3021, 2954, 1715, 1233; major: 1HNMR
(400 MHz, CDCl3) δ 7.23-7.29 (1H, m), 7.09-7.19 (3H, m), 5.33
(1H, dq, J = 15.9, 6.5 Hz), 5.10 (1H, dq, J = 15.9, 1.7 Hz), 3.71
(3H, s), 2.82 (1H, d, J = 9.5 Hz), 2.58-2.67 (1H, m), 2.21 (1H,
ddd, J = 9.5, 7.3, 4.4 Hz), 1.95 (1H, ddd, J = 14.4, 5.8, 4.4 Hz),
1.81 (1H, ddd, J = 14.4, 7.3, 6.4 Hz), 1.50 (3H, dd, J = 6.5,
1.7 Hz), 1.27 (3H, d, J = 7 Hz); 13C NMR (150 MHz, CDCl3) δ
174.6, 142.3, 132.8, 132.1, 130.6, 126.6, 126.0, 122.1, 52.3, 35.6,
31.6, 29.4, 26.6, 25.3, 22.2, 18.6; HRMS (APCI) calcd for
C17H21O2 (MHþ) 257.1536, found 257.1539; HPLC anal. major
diastereomer 74% ee with Rh2(S-DOSP)4 and -34% ee with
Rh2(S-PTAD)4 ((S,S)-Whelk-O 1, 100% hexane, 0.5 mL/min,
λ = 254 nm, tR = 13.55, 14.93 min), minor diastereomer 50% ee
with Rh2(S-DOSP)4 and -78% ee with Rh2(S-PTAD)4 (Chiralcel
OD-H, 0.5% i-PrOH in hexane, 1 mL/min, λ = 254 nm, tR
=
5.84, 6.58 min).
1936 J. Org. Chem. Vol. 75, No. 6, 2010

Nadeau et al.
JOCArticle
(500 MHz, CDCl3) δ 7.17 (1H, d, J = 8.5 Hz), 6.77 (1H, d, J =
2.5 Hz), 6.71 (1H, dd, J = 8.5, 2.5 Hz), 3.79 (3H, s), 3.69 (2H, t,
J = 6.5 Hz), 2.86-2.92 (1H, m), 2.65-2.74 (1H, m), 2.08-2.16
(1H, m), 1.89-1.95 (1H, m), 1.78-1.84 (1H, m), 1.60-1.73 (2H,
m), 1.44-1.58 (3H, m), 1.28-1.41 (2H, m), 1.26 (3H, d, J =
6.5 Hz), 0.66 (3H, d, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ
157.5, 141.2, 135.9, 127.5, 112.9, 110.8, 63.3, 55.2, 42.1, 37.3, 32.5,
31.8, 31.2(2C), 21.9, 21.6, 14.5; HRMS (EI) calcd for C17H26O2
14b: colorless oil; Rf 0.56 (pentane:ether 80:20); IR (neat) ν1723,
1626, 1201, 1161, 1080, 839, 825, 782, 747; 1H NMR (500 MHz,
C6D6) δ 7.31 (1H, d, J = 7.5 Hz), 7.10 (1H, t, J = 7.5 Hz), 7.04
(1H, t, J = 7.0 Hz), 6.91 (1H, d, J = 7.5 Hz), 5.80 (2H, s), 5.33
(1H, s), 4.12-4.18 (1H, m), 3.44 (3H, s), 2.98-3.13 (2H, m),
2.71-2.73 (1H, m), 1.08 (9H, s), 0.64 (3H, d, J= 7.0 Hz), 0.45 (3H,
s), 0.30 (3H, s); 13C NMR (75 MHz, C6D6) δ 169.1, 164.9, 136.8,
135.0, 128.0, 126.8, 126.7, 125.9, 125.6, 124.1, 98.3, 49.4, 48.4,
40.6, 29.5, 25.5, 18.3, 10.8, -4.2, -4.4; HRMS (ESI) calcd for
C22H33O3Si(MHþ) 373.2193, found 373.2196; [R]20D -92.1 (c1.12,
CHCl3) for 88% ee; HPLC anal. 88% ee with Rh2(S-DOSP)4 and
45% ee with Rh2(S-PTAD)4 (Chiralcel OD-H, 0.2% i-PrOH in
hexane, 0.5 mL/min, λ = 254 nm, tR = 10.3 (major), 12.2 min
(minor)).
(Mþ) 262.1927, found 262.1937; [R]20 þ76.7 (c 1.1, CHCl3);
D
HPLC anal. 81% ee (Chiralcel OJ, 0.5% i-PrOH in hexane, 0.8
mL/min, λ = 254 nm, tR = 29.9, 47.9 min).
Methyl 2-(6-Methoxy-1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-
pentanoate(27). Typical experimental procedure for hydrogenation
of 24a epimers: In a Parr hydrogenation bottle was added epi-24a
(Table 4, entry 2) (29 mg, 0.1 mmol), 30 mL of ethyl acetate, and
5% Pd/C (32 mg, 1.6 mg of Pd, 0.015 mmol). The vessel was
purged with H2. The reaction mixture was shaken under H2
atmosphere (40 psi) for 18 h, then filtrated on a short plug of silica
gel. The plug was washed with ethyl acetate and the solvent was
removed under reduced pressure. The crude product was purified
byflash chromatography (hexane:ether 98:2-96:4) toyield 18 mg
(62%) of the titled compound.
epi-27 (Table 4, entry 2): 62% yield (18 mg); colorless oil; Rf
0.58 (hexane:ethyl acetate 80:20); IR (neat) ν 2956, 2933, 2871,
1730; 1H NMR (400 MHz, CDCl3) δ 7.24 (1H, d, J = 8.7 Hz),
6.69 (1H, dd, J = 8.7, 2.9 Hz), 6.54 (1H, d, J = 2.9 Hz), 3.76
(3H, s), 3.37 (3H, s), 2.77 (1H, dd, J = 12.1, 2.9 Hz), 2.62-2.74
(2H, m), 2.19 (1H, ddd, J = 13.5, 10.8, 3.0 Hz), 1.88-1.96 (1H,
m), 1.62-1.77 (2H, m), 1.54-1.61 (1H, m), 1.43-1.52 (1H, m),
1.31 (3H, s), 1.14-1.30 (2H, m), 0.90 (3H, t, J = 7.3 Hz); 13C
NMR (100 MHz, CDCl3) δ 175.9, 157.3, 138.8, 135.2, 129.1,
113.3, 111.7, 55.6, 55.3, 50.9, 39.1, 33.2, 30.8, 30.1, 28.4, 22.0,
19.6, 14.3; HRMS (APCI) calcd for C18H27O3 (MHþ) 291.1955,
found 291.1956.
27 (Table 4, entry 1): 5% yield (250 mg) (yield over 2 steps
from 13); colorless oil; Rf 0.57 (hexane:ethyl acetate 80:20); IR
(neat) ν 2957, 2871, 2837, 1732, 1501; 1H NMR (500 MHz,
CDCl3) δ 7.13 (1H, d, J = 8.9 Hz), 6.71 (1H, dd, J = 8.9,
2.4 Hz), 6.58 (1H, d, J = 2.4 Hz), 3.77 (3H, s), 3.65 (3H, s), 2.85
(1H, dd, J = 11.8, 2.3 Hz), 2.65-2.76 (2H, m), 2.00 (1H, ddd,
J = 13.6, 10.9, 2.9 Hz), 1.80-1.87 (1H, m), 1.64-1.74 (2H, m),
1.58 (1H, ddd, J = 13.6, 6.6, 2.6 Hz), 1.28 (3H, s), 1.15-1.24
(1H, m), 1.04-1.14 (1H, m), 0.93-1.02 (1H, m), 0.79 (3H, t, J =
7.3 Hz); 13C NMR (125 MHz, CDCl3) δ 175.7, 157.1, 138.9,
135.1, 127.3, 113.3, 112.3, 55.7, 55.0, 51.0, 39.2, 32.3, 30.9, 30.1,
29.3, 21.6, 19.5, 13.8; HRMS (EI) calcd for C18H26O3 (Mþ)
290.1876, found 290.1880; [R]20D -14.8 (c 3.09, CHCl3); HPLC
anal. 98% ee (Chiralcel OJ, 0.4% i-PrOH in hexane, 0.4 mL/
min, λ = 254 nm, tR = 15.10, 17.12 min).
(S,Z)-Methyl 3-(tert-Butyldimethylsilyloxy)-4-((S)-1,4-dihy-
dronaphthalen-1-yl)pent-2-enoate(14b) and (1R,1aS,7bS)-Methyl
1-((Z)-1-(tert-Butyldimethylsilyloxy)prop-1-enyl)-1a,2,3,7b-tetra-
hydro-1H-cyclopropa[a]naphthalene-1-carboxylate (15b). Table 1,
entry 3: 2b (270 mg, 1 mmol, 1 equiv) in 5 mL of 2,2-DMB was
added by syringe pump over 2 h to a solution of dihydronaphtha-
lene 10 (390 mg, 3 mmol, 3 equiv) and Rh2(S-DOSP)4 (19 mg, 0.01
mmol, 0.01 equiv) in 5 mL of 2,2-DMB. After 16 h of additional
stirring, the solvent was removed under vacuum and the remaining
residue was purified on silica gel (pentane:ether 99.5:0.5) to afford
14b and 15b (272 mg, 73% combined yield). Table 1, entry 4: 2b
(270 mg, 1 mmol, 1 equiv) in 5 mL of 2,2-DMB:toluene (5:1) was
added by syringe pump over 2 h to a solution of dihydronaphtha-
lene 10 (390 mg, 3 mmol, 3 equiv) and Rh2(S-PTAD)4 (16 mg,
0.01 mmol, 0.01 equiv) in 5 mL of 2,2-DMB:toluene (5:1). After
16 h of additional stirring, the solvent was removed under
vacuum and the remaining residue was purified on silica gel
(pentane:ether 99.5:0.5) to afford 14b and 15b (291 mg, 78%
combined yield).
15b: colorless oil; Rf 0.52 (pentane:ether 80:20); IR (neat) ν
1721, 1675, 1494, 1472, 1462, 1435, 1334, 1305, 1239, 1203,
1160, 1076, 874, 837, 799, 779, 753; 1H NMR (500 MHz, CDCl3)
δ 7.21-7.23 (1H, m), 7.07-7.12 (2H, m), 6.95-6.97 (1H, m),
3.98 (1H, br s), 3.70 (3H, s), 2.78 (1H, d, J = 9.0 Hz), 2.57-2.64
(1H, m), 2.50 (1H, dd, J = 16.5, 7.0 Hz), 2.25-2.31 (2H, m),
1.88-1.95 (1H, m), 1.25 (3H, d, J = 6.0 Hz), 0.91 (9H, br s), 0.14
(3H, s), 0.08 (3H, s); 13C NMR (75 MHz, CDCl3) δ 173.9, 143.1,
136.4, 133.1, 129.9, 128.0, 126.2, 125.6, 110.7, 52.0, 38.9, 33.4,
28.3, 25.8, 25.6, 18.5, 18.4, 11.1, -4.3, -4.8; HRMS (EI) calcd
for C22H32O3Si (Mþ) 372.2115, found 372.2113; [R]20 -22.6
D
(c 0.72, CHCl3) for 93% ee; HPLC anal. 40% ee with Rh2(S-
DOSP)4 and 93% ee with Rh2(S-PTAD)4 (Chiralcel OD-H,
100% hexane, 0.8 mL/min, λ=230nm,tR = 11.8 (major), 14.3 min
(minor)).
(S,Z)-Methyl 3-(tert-Butyldimethylsilyloxy)-4-((S)-7-methoxy-
1,4-dihydronaphthalen-1-yl)pent-2-enoate (17), (1R,1aS,7bS)-
Methyl 1-((Z)-1-(tert-Butyldimethylsilyloxy)prop-1-enyl)-6-methoxy-
1a,2,3,7b-tetrahydro-1H cyclopropa[a]naphthalene-1-carboxylate
(18), and (Z)-Methyl 3-(tert-Butyldimethylsilyloxy)-2-(6-methoxy-
1,2-dihydronaphthalen-1-yl)pent-3-enoate (19). Table 2, entry 1:
2b (270 mg, 1 mmol, 1 equiv) in 5 mL of 2,2-DMB was added by
syringe pump over 2 h to a solution of dihydronaphthalene 11
(480 mg, 3 mmol, 3 equiv) and Rh2(S-DOSP)4 (19 mg, 0.01
mmol, 0.01 equiv) in 5 mL of 2,2-DMB. After 16 h of additional
stirring, the solvent was removed under vacuum and the remain-
ing residue was purified on silica gel (pentane:ether 98:2) to
afford 17, 18, and 19 (362 mg, 90% combined yield). Table 2, entry
2: 2b (270 mg, 1 mmol, 1 equiv) in 5 mL of 2,2-DMB:toluene (5:1)
was added by syringe pump over 2 h to a solution of dihydro-
naphthalene 11 (480 mg, 3 mmol, 3 equiv) and Rh2(S-PTAD)4 (16
mg, 0.01 mmol, 0.01 equiv) in 5 mL of 2,2-DMB:toluene (5:1).
After 16 h of additional stirring, the solvent was removed under
vacuum and the remaining residue was purified on silica gel (pentane:
ether 98:2) to afford 17, 18, and 19 (330 mg, 82% combined yield).
17: colorless oil; Rf 0.57 (pentane:ether 80:20); IR (neat) ν
1722, 1624, 1503, 1464, 1434, 1370, 1277, 1254, 1239, 1201, 1160,
1081, 1042, 968, 895, 837, 810, 782; 1H NMR (500 MHz, CDCl3)
δ 7.03 (1H, d, J = 8.0 Hz), 6.74-6.76 (2H, m), 6.07-6.09 (1H,
m), 5.70-5.72 (1H, m), 5.11 (1H, s), 3.92-3.96 (1H, m), 3.78
(3H, s), 3.67 (3H, s), 3.23-3.34 (2H, m), 2.64-2.70 (1H, m), 1.05
(9H, s), 0.72 (3H, d, J = 7.0 Hz), 0.32 (3H, s), 0.28 (3H, s); 13C
NMR (75 MHz, CDCl3) δ 169.6, 166.0, 158.0, 138.1, 129.2,
127.6, 127.5, 124.0, 112.6, 111.6, 98.7, 55.1, 50.5, 48.8, 41.1, 29.3,
26.0, 18.7, 11.4, -3.8, -4.0; HRMS (EI) calcd for C23H34O4Si
(Mþ) 402.2221, found 402.2219; [R]20 -53.2 (c 0.54, CHCl3)
D
for 33% ee; HPLC anal. 90% ee with Rh2(S-DOSP)4 and 33%
ee with Rh2(S-PTAD)4 (Chiralcel OD-H, 0.4% i-PrOH in
hexane, 0.5 mL/min, λ = 254 nm, tR = 10.6 (major), 12.1 min
(minor)).
18: colorless oil; Rf 0.51 (pentane:ether 80:20); IR (neat) ν
1720, 1676, 1610, 1505, 1463, 1435, 1334, 1304, 1238, 1193, 1167,
1113, 1076, 1040, 866, 837, 779; 1H NMR (500 MHz, CDCl3) δ
6.87 (1H, d, J = 8.0 Hz), 6.79 (1H, d, J = 2.5 Hz), 6.65 (1H, dd,
J. Org. Chem. Vol. 75, No. 6, 2010 1937

Nadeau et al.
JOCArticle
J = 8.0, 2.5 Hz), 4.02 (1H, br s), 3.79 (3H, s), 3.70 (3H, s), 2.72
(1H, d, J = 9.0 Hz), 2.40-2.55 (2H, m), 2.24-2.30 (2H, m),
1.85-1.92 (1H, m), 1.26 (3H, br s), 0.91 (9H, br), 0.14 (3H, s),
0.08 (3H, s); 13C NMR (75 MHz, CDCl3) δ 173.9, 157.5, 143.1,
134.1, 128.8, 128.6, 115.0, 112.2, 110.4, 55.2, 52.0, 38.9, 33.6,
28.3, 25.7, 24.7, 18.8, 18.5, 11.1, -4.3, -4.7; HRMS (EI) calcd
O3Si (Mþ) 386.2272, found 386.2266; [R]20 -12.1 (c 0.32,
D
CHCl3) for 96% ee; HPLC anal. 53% ee with Rh2(S-DOSP)4
and 96% ee with Rh2(S-PTAD)4 (Chiralcel OD-H, 100%
hexane, 0.25 mL/min, λ = 254 nm, tR = 39.5 (major), 44.0 min
(minor)).
(S,Z)-Methyl 3-(tert-Butyldimethylsilyloxy)-4-((1S,4R)-7-meth-
oxy-4-methyl-1,4-dihydronaphthalen-1-yl)pent-2-enoate (22b) and
(1R,1aS,6S,7aS,Z)-Methyl 1-(1-(tert-Butyldimethylsilyloxy)prop-
1-enyl)-3-methoxy-6-methyl-1a,6,7,7a-tetrahydro-1H cyclopropa-
[a]naphthalene-1-carboxylate (23b). Table 4, entry 3: 2b (811 mg,
3 mmol, 3 equiv) in 5 mL of 2,2-DMB was added by syringe pump
over 2 h to a solution of dihydronaphthalene 13 (174 mg, 1 mmol,
1 equiv) and Rh2(S-DOSP)4 (19 mg, 0.01 mmol, 0.01 equiv) in
5 mL of 2,2-DMB. After 16 h of additional stirring, the solvent was
removed under vacuum and the remaining residue was purified on
silica gel (pentane:ether 98:2) to afford 22b and 23b (229 mg, 55%
combined yield). Table 4, entry 4: 2b (811 mg, 3 mmol, 3 equiv) in
5 mL of 2,2-DMB:toluene (5:1) was added by syringe pump over
2 h to a solution of dihydronaphthalene 13 (174 mg, 1 mmol,
1 equiv) and Rh2(S-PTAD)4 (16 mg, 0.01 mmol, 0.01 equiv) in
5 mL of 2,2-DMB:toluene (5:1). After 16 h of additional stirring,
the solvent was removed under vacuum and the remaining residue
was purified on silica gel (pentane:ether 98:2) to afford 22b and 23b
(375 mg, 90% combined yield).
for C23H34O4Si (Mþ) 402.2221, found 402.2228; [R]20 þ26.0
D
(c 0.64, CHCl3) for 95% ee; HPLC anal. 95% ee with Rh2(S-
PTAD)4 (Chiralcel OD-H, 0.2% i-PrOH in hexane, 0.5 mL/min,
λ = 230 nm, tR = 18.6 (major), 21.2 min (minor)).
19: colorless oil; Rf 0.56 (pentane:ether 80:20); IR (neat) ν
1738, 1668, 1603, 1572, 1496, 1432, 1344, 1261, 1204, 1186, 1146,
1091, 1048, 880, 837, 778, 704; 1H NMR (600 MHz, CDCl3) δ
7.05 (1H, d, J = 8.6 Hz), 6.59-6.64 (2H, m), 6.44 (1H, dd, J =
9.3, 2.9 Hz), 5.93 (1H, ddd, J = 9.3, 6.4, 2.5 Hz), 4.93 (1H, q, J =
6.7 Hz), 3.77 (3H, s), 3.43 (3H, s), 3.14-3.19 (2H, m), 2.52 (1H,
dd, J = 16.9, 6.4Hz), 2.35-2.41(1H, m), 1.59(3H, d, J=6.7Hz),
0.96 (9H, s), 0.13 (3H, s), 0.12 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 173.0, 158.7, 147.4, 134.4, 129.6, 128.3, 127.6, 127.3,
111.74, 111.71, 104.6, 55.2, 54.6, 51.4, 38.8, 26.2, 25.9, 18.3, 11.1,
-3.9, -4.2; HRMS (ESI) calcd for C23H34O4SiNa (MNaþ)
425.2119, found 425.2122; [R]20 þ16.9 (c 0.10, CHCl3) for
D
90% ee; HPLC anal. 90% ee with Rh2(S-DOSP)4 and 45% ee
with Rh2(S-PTAD)4 (Chiralcel OD-H, 0.1% i-PrOH in hexane,
0.5 mL/min, λ = 254 nm, tR = 48.4 (major), 65.6 min (minor)).
(S,Z)-Methyl 3-(tert-Butyldimethylsilyloxy)-4-((1S,4R)-4-methyl-
1,4-dihydronaphthalen-1-yl)pent-2-enoate (20b) and (1R,1aS,3S,
7bS)-Methyl 1-((Z)-1-(tert-Butyldimethylsilyloxy)prop-1-enyl)-
3-methyl-1a,2,3,7b-tetrahydro-1H cyclopropa[a]naphthalene-1-
carboxylate (21b). Table 3, entry 3: 2b (540 mg, 2 mmol, 4 equiv)
in 5 mL of 2,2-DMB was added by syringe pump over 2 h to a
solution of dihydronaphthalene 12 (73 mg, 0.5 mmol, 1 equiv)
and Rh2(S-DOSP)4 (9 mg, 0.005 mmol, 0.01equiv) in5 mLof2,2-
DMB. After 16 h of additional stirring, the solvent was removed
under vacuum and the remaining residue was purified on silica gel
(pentane:ether 99.5:0.5) to afford 20b and 21b (112 mg, 58%
combined yield). Table 3, entry 4: 2b (540 mg, 2 mmol, 4 equiv) in
5 mL of 2,2-DMB:toluene (5:1) was added by syringe pump over
2 h to a solution of dihydronaphthalene 12 (73 mg, 0.5 mmol,
1 equiv) and Rh2(S-PTAD)4 (8 mg, 0.005 mmol, 0.01 equiv) in
5 mL of 2,2-DMB:toluene (5:1). After 16 h of additional stirring,
the solvent was removed under vacuum andthe remaining residue
was purified on silica gel (pentane:ether 99.5:0.5) to afford 20b
and 21b (174 mg, 90% combined yield).
22b: colorless oil; Rf 0.61 (pentane:ether 80:20); IR (neat) ν
1723, 1625, 1253, 1202, 1163, 826, 781; H NMR (500 MHz,
1
CDCl3) δ 7.20 (1H, d, J = 8.5 Hz), 6.79 (1H, dd, J = 8.5, 2.5 Hz),
6.74 (1H, d, J = 2.5 Hz), 5.90 (1H, d, J = 10.0 Hz), 5.65-5.63
(1H, m), 5.11 (1H, s), 3.92-3.94 (1H, m), 3.79 (3H, s), 3.68 (3H, s),
3.30-3.40 (1H, m), 2.68-2.72 (1H, m), 1.32 (3H, d, J = 7.0 Hz),
1.05 (9H, s), 0.67 (3H, d, J = 6.5 Hz), 0.32 (3H, s), 0.28 (3H, s);
13C NMR (75 MHz, C6D6) δ 169.8, 165.6, 158.6, 137.9, 134.5,
133.2, 128.6, 122.7, 113.1, 111.7, 99.0, 54.7, 50.2, 48.9, 41.2, 32.5,
26.3, 23.5, 19.0, 11.4, -3.4, -3.9; HRMS (EI) calcd for C24H36-
O4Si (Mþ) 416.2377, found 416.2379; [R]20D -18.0 (c 1.2, CHCl3)
for 88% ee; HPLC anal. 85% ee with Rh2(S-DOSP)4 and 88% ee
with Rh2(S-PTAD)4 (Chiralcel OD-H, 0.2% i-PrOH in hexane,
0.5 mL/min, λ = 254 nm, tR = 11.7 (major), 16.5 min (minor)).
23b: colorless oil; Rf 0.47 (pentane:ether 80:20); IR (neat) ν
1720, 1500, 1464, 1434, 1332, 1306, 1237, 1218, 1168, 1070, 1048,
860, 837, 800; 1H NMR (500 MHz, CDCl3) δ 7.10 (1H, d, J =
8.5 Hz), 6.82 (1H, d, J = 2.5 Hz), 6.72 (1H, dd, J = 8.5, 2.5 Hz),
4.12 (1H, br s), 3.79 (3H, s), 3.72 (3H, s), 2.77 (1H, d, J = 9.0 Hz),
2.60-2.67 (1H, m), 2.24-2.30 (2H, m), 1.63 (1H, ddd, J = 14.2,
10.7, 5.2 Hz), 1.27 (3H, d, J = 6.5 Hz), 1.24 (3H, d, J = 7.0 Hz),
0.93 (9H, s), 0.17 (3H, s), 0.10 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 173.9, 157.2, 143.0, 134.0, 133.4, 126.1, 115.1, 112.1,
110.5, 55.0, 51.9, 39.1, 34.0, 28.5, 27.8, 27.5, 25.6, 20.1, 18.3, 11.0,
-4.3, -4.8; HRMS (EI) calcd for C24H36O4Si (Mþ) 416.2377,
found 416.2382; [R]20D þ22.8 (c 1.3, CHCl3) for 96% ee; HPLC
anal. 59% ee with Rh2(S-DOSP)4 and 96% ee with Rh2(S-
PTAD)4 (Chiralcel OD-H, 0.1% i-PrOH in hexane, 0.8 mL/
min, λ = 235 nm, tR = 24.1 (minor), 34.8 min (major)).
(S,Z)-Methyl 4-((1S,4R)-4-Methyl-1,4-dihydronaphthalen-1-
yl)-3-(trifluoromethylsulfonyloxy)pent-2-enoate (25).16 Diazo
compound 2b (1.08 g, 4 mmol, 4 equiv) in 10 mL of 2,2-DMB
was added dropwise by syringe pump over 2 h to a solution of
1-methyl-1,2-dihydronaphthalene 12 (0.144 g, 1 mmol, 1 equiv)
and Rh2(S-DOSP)4 (0.038 g, 0.02 mmol, 0.02 equiv) in 10 mL of
2,2-DMB. The reaction mixture was stirred for an additional
14 h, then concentrated in vacuo. The crude was quickly purified
by flash chromatography (hexane:ether 99:1 to 98:2) to yield
217 mg of a mixture of 20b and 21b. This mixture was dissolved
in 10 mL of THF and cooled to 0 °C. TBAF (211 mg, 0.67 mmol,
1.2 equiv) was added to the solution in one portion. After 0.7 h,
the reaction was diluted with 30 mL of ether and 10 mL of
distilled water. The aqueous layer was extracted with ether (3 ꢀ
30 mL). The organic extracts were combined and washed with
20b: colorless oil; Rf 0.67 (pentane:ether 80:20); IR (neat) ν
1721, 1624, 1250, 1202, 838, 778; 1H NMR (400 MHz, CDCl3) δ
7.27-7.31 (1H, m), 7.18-7.24 (3H, m), 5.91 (1H, ddd, J = 10.2,
2.9, 1.6 Hz), 5.67 (1H, ddd, J = 10.2, 4.0, 2.4 Hz), 5.12 (1H, s),
3.95-3.99 (1H, m), 3.68 (3H, s), 3.37-3.45 (1H, m), 2.72 (1H,
dq, J = 7.0, 4.1 Hz), 1.35 (3H, d, J = 7.3 Hz), 1.04 (9H, s), 0.66
(3H, d, J = 7.0 Hz), 0.31 (3H, s), 0.29 (3H, s); 13C NMR
(100 MHz, CDCl3) δ 169.7, 166.0, 140.8, 136.4, 133.8, 127.3,
126.7, 126.3, 126.2, 122.7, 98.9, 50.6, 48.2, 40.2, 32.7, 26.0, 23.2,
18.7, 11.4, -3.7, -3.8; HRMS (EI) calcd for C23H34O3Si (Mþ)
386.2272, found 386.2283; [R]20D þ70.8 (c 0.68, CHCl3) for 88%
ee; HPLC anal. 86% ee with Rh2(S-DOSP)4 and 88% ee with
Rh2(S-PTAD)4 (Chiralcel OD-H, 100% hexane, 0.25 mL/min,
λ = 254 nm, tR = 27.7 (major), 33.0 min (minor)).
21b: white solid; mp 100-102 °C; Rf 0.63 (pentane:ether
80:20); IR (neat) ν 1721, 1675, 1462, 1434, 1332, 1305, 1239,
1165, 1124, 1076, 837, 777, 755; 1H NMR (600 MHz, CDCl3) δ
7.23 (1H, d, J = 7.1 Hz), 7.10-7.19 (3H, m), 4.06 (1H, br s), 3.71
(3H, s), 2.79 (1H, d, J = 9.1 Hz), 2.64-2.72 (1H, m), 2.24-2.28
(2H, m), 1.66 (1H, ddd, J = 14.6, 10.4, 4.6 Hz), 1.26 (3H, d, J =
6.7 Hz), 1.24 (3H, d, J = 6.7 Hz), 0.91 (9H, s), 0.14 (3H, s), 0.08
(3H, s); 13C NMR (75 MHz, CDCl3) δ 174.0, 143.1, 141.3, 132.8,
130.2, 126.5, 125.5, 125.3, 110.8, 52.0, 39.2, 33.8, 28.7, 28.2, 27.3,
25.7, 20.1, 18.4, 11.0, -4.3, -4.7; HRMS (EI) calcd for C23H34-
1938 J. Org. Chem. Vol. 75, No. 6, 2010

Nadeau et al.
JOCArticle
10 mL of distilled water and 10 mL of saturted aqueous NaCl,
dried over MgSO4, filtered, and concentrated under vacuum.
The crude was quickly purified by flash chromatography
(hexane:ether 95:5 to 93:7) to yield 88 mg of a mixture of
C-H activation/Cope rearrangement product and cyclopro-
pane. The mixture was dissolved in 3 mL of dry THF and cooled
to 0 °C. NaH (23 mg, 0.96 mmol) was added to the solution,
followed 5 min later by PhNTf2 (229 mg, 0.64 mmol). After 1 h,
the cold bath was removed and the reaction allowed to reach rt.
After 6 h, the reaction was diluted with 30 mL of ether and
10 mL of distilled water. The aqueous layer was extracted with
ether (2 ꢀ 30 mL). The organic extracts were combined and
washed with 5 mL of distilled water and 5 mL of saturted
aqueous NaCl, dried over MgSO4, filtered, and concentrated
under vacuum. The crude was purified by flash chromatography
(hexane:ether 95:5 to 90:10) to yield 25 mg (12%, theorical yield
from R-12) of vinyl triflate 25.
water and 10 mL of saturated aqueous NaCl, dried over MgSO4,
filtered, and concentrated under reduced pressure. The crude
product was purified by flash chromatography (hexane:ether
99:1) to yield 4 mg (90%) of 26.
From 20a:16 In a Parr hydrogenation bottle was added 20a
(14mg, 0.055mmol), 30 mLofethylacetate, and5%Pd/C(24mg,
1.2 mg of Pd, 0.011 mmol). The vessel was purged with H2. The
mixture was shaken under H2 atmosphere (30 psi) for 13 h at rt,
then filtrated on a short plug of silica gel. The plug was washed
with ethyl acetate and the solvent was removed under reduced
pressure. The crude product was purified by flash chromatography
(hexane:ether 99:1) to yield 12.5 mg (89%) of 26.
26: colorless oil; Rf 0.62 (hexane:ethyl acetate 80:20); IR (neat)
ν 3022, 2954, 2930, 2869, 1738, 1168; 1H NMR (600 MHz,
CDCl3) δ 7.23-7.26 (1H, m), 7.17-7.21 (1H, m), 7.11-7.15
(2H, m), 3.70 (3H, s), 2.90-2.94 (1H, m), 2.74-2.81 (1H, m),
2.34-2.46 (2H, m), 2.10-2.18 (1H, m), 1.92-1.98 (1H, m),
1.75-1.87 (2H, m), 1.62-1.69 (1H, m), 1.52-1.59 (1H, m),
1.32-1.39 (1H, m), 1.29 (3H, d, J = 6.7 Hz), 0.66 (3H, d, J =
6.7 Hz); 13C NMR (100 MHz, CDCl3) δ 174.4, 143.3, 139.4,
127.4, 126.7, 125.5, 125.3, 51.6, 41.6, 36.9, 33.1, 32.6, 31.4, 30.2,
21.8, 21.5, 14.2; HRMS (APCI) calcd for C17H25O2 (MHþ)
261.1849, found 261.1849; [R]20D -36.5 (c 0.97, CHCl3); HPLC
anal. 93% ee ((S,S)-Whelk-O 1, 0.5% i-PrOH in hexane, 1 mL/
min, λ = 254 nm, tR = 11.04, 12.56 min).
25: white solid; mp 83-85 °C; Rf 0.60 (hexane:ethyl acetate
80:20); IR (neat) ν 3027, 2977, 2959, 2932, 1739, 1430, 1207; 1H
NMR (400 MHz, CDCl3) δ 7.29-7.32 (1H, m), 7.20-7.25 (2H,
m), 7.14-7.17 (1H, m), 6.00 (1H, ddd, J = 10.3, 2.9, 1.4 Hz),
5.75 (1H, d, J = 1.3 Hz), 5.57 (1H, ddd, J = 10.3, 4.1, 2.4 Hz),
3.94-3.98 (1H, m), 3.82 (3H, s), 3.38-3.46 (1H, m), 3.02-3.08
(1H, m), 1.37 (3H, d, J = 7.3 Hz), 0.75 (3H, d, J = 7.0 Hz); 13
C
NMR (100 MHz, CDCl3) δ 163.0, 161.3, 140.5, 135.5, 134.5,
127.4, 126.8, 126.7 (2C), 120.8, 118.5 (q, J = 320 Hz), 111.6,
52.1, 45.7, 39.6, 32.6, 23.1, 11.2; 19F NMR (375 MHz, CDCl3) δ
-74.6; HRMS (APCI) calcd for C18H20O5F3S (MHþ) 405.0978,
found 405.0979.
Acknowledgment. This research was supported by the
National Institutes of Health (GM080337). E.N. thanks
ꢀ ꢀ
the Fonds Quebecois de la Recherche sur la Nature et les
(R)-Methyl 4-((1S,4R)-4-Methyl-1,2,3,4-tetrahydronaphtha-
len-1-yl)pentanoate (26).16 From vinyl triflate 25: In a Parr
hydrogenation bottle was added vinyl triflate 25 (7 mg, 0.017
mmol), 20 mL of MeOH, PtO2 (1.2 mg, 0.0051 mmol), and
Li2CO3 (2.5 mg, 0.034 mmol). The vessel was purged with H2.
The mixture was shaken under H2 atmosphere (30 psi) for 14 h at
rt, then diluted with 40 mL of ether and 20 mL of distilled water.
The aqueous layer was extracted with ether (3 ꢀ 40 mL). The
combined organic extracts were washed with 10 mL of distilled
ꢀ
Technologies (FQRNT, Quebec, Canada) for a postdoctoral
research fellowship.
Supporting Information Available: Detailed experimental
procedures, full characterization, and spectra for all new com-
pounds, and crystallographic data for compounds 16 and 21b
(CIFs). This material is available free of charge via the Internet
at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 6, 2010 1939