Regioselective Iridium-Catalyzed Asymmetric Monohydrogenation of 1,4-Dienes

Article abstract of DOI:10.1021/jacs.7b06829

A highly efficient regio- and enantioselective monohydrogenation of 1,4-dienes has been realized using an iridium catalyst with a chiral N,P-ligand under mild conditions. The substrate scope was studied and included both unfunctionalized as well as functionalized substituents on the meta- or para-position. Substrates having substituents with functionalities such as silyl protected alcohols or ketals were monohydrogenated in high regioselectivity and high enantiomeric excess (up to 98% ee).

Full text of DOI:10.1021/jacs.7b06829

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Article
Regioselective iridium-catalyzed asymmetric
monohydrogenation of 1,4-dienes
Jianguo Liu, Suppachai Krajangsri, Thishana Singh, Giulia De
Seriis, Napasawan Chumnanvej, Haibo Wu, and Pher G. Andersson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06829 • Publication Date (Web): 20 Sep 2017
Downloaded from http://pubs.acs.org on September 20, 2017
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R2
R2
O
O
*
O
R1
R1
Ir-N,P
H2
R1
O
R1
R3
*
R3
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R1 = Si(Me)2tBu, Si(Et)3
R2 = alkyl, CH2CH2OSi(Me)2tBu
CH2CH2(acetal)
21 examples,
up to 99% ee
Regioselective and high yielding
R3 = alkyl, CH2CH2OSi(Me)2tBu
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a) Rhodium chiral monophosphine complex (1980)
Rh, P*, H2
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COOH
COOH
79% ee
PPh2
P*=
b) BINAP-based Ru dicarboxylate complex (1987)
Ru(S)-BINAP, H2
OH
c) Monodentate phosphoramidites Rh complex (2005)
OH
98% ee
O
P N
O
PipPhos
N
N
O
O
O
O
[Rh(COD)2]BF4, PipPhos
H2
97% ee
d) Ir-N,P complex (this work)
R2
R2
*
O
O
O
R1
R1
Ir-N,P, H2
or
or
O
R1
R1
*
R2
R2
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Regioselective Iridium-catalyzed Asymmetric Monohydro-
genation of 1,4-Dienes
Jianguo Liu,§ Suppachai Krajangsri,§ Thishana Singh, Giulia De Seriis, Napasawan Chumnanvej,
Haibo Wu and Pher G. Andersson*
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Department of Organic Chemistry, Stockholm University, 106 91, Stockholm, Sweden. (Pher.Andersson@su.se)
KEYWORDS Regioselective • asymmetric hydrogenation• iridium catalysis• 1,4 dienes.
ABSTRACT: A highly efficient regioꢀ and enantioselective monohydrogenation of 1,4ꢀdienes has been realized using an iridiꢀ
um catalyst with a chiral N,Pꢀligand under mild conditions. The substrate scope was studied and included both unfunctionalꢀ
ized as well as functionalized substituents on the metaꢀ or paraꢀposition. Substrates having substituents with functionalities
such as silyl protected alcohols or ketals were monohydrogenated in high regioselectivity and high enantiomeric excess (up to
98% ee).
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INTRODUCTION
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Synthesis of enantiopure products by asymmetric catalyꢀ
sis of organic reactions represents an important area in modꢀ
ern synthetic chemistry. Among many successful examples,
asymmetric hydrogenation has been most extensively studꢀ
ied in academia and widely applied in industry,1,2 as afꢀ
firmed by the award of the 2001 Nobel Prize in chemistry to
Knowles and Noyori.3 Today, asymmetric hydrogenation is
still one of the most widely used, reliable catalytic method
for the preparation of optically active compounds.4 In the
last few decades, significant progress has been made toꢀ
wards the asymmetric hydrogenation of C=C,5 C= N,6 and
C=O4d,7 utilizing transitionꢀmetal chiralꢀligand complexes.4,8
The reduction of olefins containing an adjacent polar group
(i.e., dehydroꢀamino acids) by Rhꢀ and Ruꢀcatalyst precurꢀ
sors modified with phosphorus ligands has a long history.
Rhodium and ruthenium catalysts have a strong preference
to hydrogenate olefins having a polar functional group next
to the C=C bond which can coordinate to the metal center
and help in achieving high levels of activity and stereo conꢀ
trol.9
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Asymmetric hydrogenation of unfunctionalized olefins
have attracted considerable interest recently10 and chiral Irꢀ
P,N complexes have been found to be extremely useful cataꢀ
lytic precursors for the asymmetric hydrogenation of miniꢀ
mally functionalized diꢀ and triꢀsubstituted olefins.11,12 Howꢀ
ever, despite the development of highly enantioselective
protocols, regioselectivity, or the ability to hydrogenate only
one out of several olefins in a certain substrate is still a genꢀ
erally unsolved task.2a,4c,5e,10e
Scheme 1. Regioselective asymmetric hydrogenation
using transition metals.
In 2005 Minnaard and coꢀworkers reported the asymmetꢀ
ric hydrogenation of enol carbamate using a Rh precursor
with chiral monodentate phosphoramidites. It was found that
the double bond adjacent to the carbamate functional group
was hydrogenated but the double bond that is further away
from the functional moiety, was not reduced.15 These examꢀ
ples illustrate that the regioselective hydrogenation using Rh
and Ru catalysts might be explained by a mechanism that
requires a chelating group adjacent to the C=C bond. Ir on
the other hand, is believed to operate via a mechanism inꢀ
volving an etaꢀ2 (η2) bonded olefin and an extra molecule of
dihydrogen coordinated to the metal that is necessary for the
first migratory insertion step.16 Overall, the regioselective
asymmetric hydrogenation using transition metals remains
unexplored and the reported examples of substrates is still
rare and limited.
A few examples have been reported and consist almost
exclusively of Rhꢀ and Ruꢀcatalyzed hydrogenations of an
olefin having a polar substituent in preference over an unꢀ
functionalized olefin in the same substrate. An early examꢀ
ple of regioselective hydrogenation of (E)ꢀ3,7ꢀdimethyloctaꢀ
2,6ꢀdienoic acid was reported in 1980 by Toth using chiral
Rh monophosphine complex (Scheme 1).13 The hydrogenaꢀ
tion was highly selective for the olefin close to the carboxyl
group and proceeded without isomerization within the limits
of detection. The pioneering work of regioselective asymꢀ
metric hydrogenation of allylic alcohols by Noyori in 1987
using Ru dicarboxylate complexes containing BINAP ligꢀ
ands follows a similar trend. Although the allylic and nonalꢀ
lylic double bonds in geraniol are both trisubstituted, the
monohydrogenated product was accompanied by less than
0.5% of dihydrocitronellol.14
Herein, we report on the Irꢀcatalyzed highly regioselective
asymmetric hydrogenation of two triꢀsubstituted olefins on
cyclic diene structures.
RESULTS AND DISCUSSION
Our initial investigation began with the hydrogenation of
1a. It was found that the regioselectivity between the two
olefins was modest when using the standard hydrogenation
conditions (entry 1ꢀ3). However, the regioselectivity was
found to depend on the catalyst and especially on the addiꢀ
tion of base. Thus, when using catalyst B (Figure 1) and
Poly(4ꢀvinylpyridine) (PVP) as the base, it was possible to
run the reaction to completion with a regioselectivity of
97:3. Interestingly, the selectivity observed was opposite to
what is normally reported for Rhꢀ and Ruꢀcatalyzed hydroꢀ
genations (Scheme 1a,b), with the Irꢀcatalyst the unfuncꢀ
tionalized olefin was hydrogenated in preference over the
enol ether. One possible explanation for the observed selecꢀ
tivity for Ir to preferentially hydrogenate the olefin and not
the enol ether could originate from the possibility of the enol
ether to form an etaꢀ3 (η3) coordination, which would comꢀ
pete with the coordination of the dihydrogen molecule to the
iridium catalyst.
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In order to improve the usefulness of the method, the silyl
enol ether 2a was chosen as the model substrate for this
study since it is easily deprotected.
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Figure 1. Catalysts used in this study.
Table 1. Optimization of asymmetric hydrogenation
conditions[a] using 1a
[a] Reaction conditions: 0.125 mmol of substrate, 0.5 mol %
catalyst, 10 mol% base, H2, 16 h, and r.t. unless otherwise statꢀ
ed. [b] Determined by H NMR spectroscopy. [c] Determined
1
by chiral GC analysis, see Supporting Information for details.
With the optimized reaction conditions established, the efꢀ
fect of the different protecting groups was evaluated (Table
3). Interestingly, the type of protecting group used had relaꢀ
tively little influence on the regioselectivities and enantioseꢀ
lectivities observed. The EOM (methoxy methyl acetal), EE
(ethoxy ethyl acetal) and the silyl protecting groups (entries
1, 2 and 4ꢀ6) all resulted in high enantioselectivities. Of all
the protecting groups, TES (triꢀethyl silyl ether) and
TBDMS (tertꢀbutyl dimethyl silyl ether) showed optimal
results and was used to investigate the scope of the reaction.
[a] Reaction conditions: 0.125 mmol of substrate, 0.5 mol %
catalyst, 10 mol% base, H2, and r.t. unless otherwise stated. [b]
Determined by 1H NMR spectroscopy. [c] Determined by chiral
GC analysis, see Supporting Information for details. [d] N.D. =
Not Determined.
A number of 1,4ꢀdiene substrates were prepared in high
yield using the Birch reduction and were selectively hydroꢀ
genated to the corresponding protected silyl enol olefins in
high yield and good to excellent enantioselectivities. Having
the substituent at the meta position in the silyl protected enol
ethers resulted in all cases in very high enantioselectivities
(between 95% to 99%, Table 4, entries 1ꢀ7). These are surꢀ
prisingly high levels of stereoselectivities, given that the
olefin being reduced only have aliphatic substituents, someꢀ
thing that normally results in lower ee's. Having the substitꢀ
uent at the para position was also investigated for both the
TBDMS (entry 8) and the TES protected enol ethers (entries
9ꢀ10). Although the TBDMS protected 13a only resulted in
an ee of 80%, the ee TES protected enol gave good enantiꢀ
oselectivities (entry 9ꢀ10). The tetrasubstituted enol comꢀ
pounds 16a and 17a also resulted in excellent enantioselecꢀ
tivities of 95% and 98%. Also, some substrates having funcꢀ
tionalized sideꢀchains were prepared and evaluated: 18a,
19a, 20a were hydrogenated in excellent enantioselectiviꢀ
ties. Finally, having a functionalized substituent in the para
position also resulted in high enantioselectivity (entry 16).
A screening of some Ir N,Pꢀligand catalysts revealed that
silyl enol ether 2a gave full conversion and good to high
enantioselectivies (Table 2, entries 1ꢀ6). The best enantioseꢀ
lectivity was obtained for catalyst F, which gave 2a' in 95%
ee (entry 6). Next, the reaction was optimized with regards
to solvent effects, base and pressure. The combination of
PhꢀCF3 as solvent and K3PO4 as base under 10 bar of hydroꢀ
gen was the most suitable reaction condition for this reacꢀ
tion (entry 11). (See Supporting Information for results of
hydrogenations carried out at shorter time intervals.)
Table 2. Optimization of asymmetric hydrogenation
conditions[a] using 2a
In order to investigate if the observed regioselectivity for
some reason was limited to 1,4ꢀcyclohexadienes, a number
of acyclic substrates containing two olefins were also preꢀ
pared and evaluated. The acyclic substrates 22a-24a were
thus tested in this reaction, resulting in similar high regioseꢀ
lectivities for all the substrates. Excellent enantioselectivity
were obtained for prochiral substrates and products 24a’ and
25a’ was isolated in 99% and 98% ees, respectively.
Table 3. Asymmetric hydrogenation with different types
of protecting groups[a]
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[a] Reaction conditions: 0.125 mmol of substrate, 0.5 mol %
catalyst, 10 mol% base, H2, 12 h, and r.t. unless otherwise statꢀ
1
ed. [b] Determined by H NMR spectroscopy. [c] Determined
by chiral GC analysis, see Supporting Information for details.
[d] Absolute configuration of the hydrogenated product was
assigned on the basis of elution order of hydrolysis product
compared
with
commercially
available
(R)ꢀ(+)ꢀ3ꢀ
methylcyclohexanone.
Although the chiral, meta or para substituted enol ethers
constitutes a useful class of building blocks in their own
right, the usefulness of the regioselective hydrogenation
could be further demonstrated by conversion of the enol
ether into the corresponding α,βꢀunsaturated ketone. This
facilitates a straightforward, yet flexible route to chiral cyꢀ
clohexenones, which have served as starting materials in a
large number of total syntheses of biologically active comꢀ
pounds and natural products (Figure 2).17,18
Table 4. Asymmetric hydrogenation of different silyl
protected substrates[a]
[a] Reaction conditions: 0.25 mmol of substrate, 0.5 mol %
catalyst, 2 mL of PhꢀCF3, 10 bar H2. 12 h, and r.t. unless otherꢀ
wise stated. [b] NMR yield using internal standard 1,3,5ꢀ
trimethoxybenzene. [c] Isolated yield. [d] Determined by chiral
GC or SFC analysis, see Supporting Information for details. [e]
Absolute configuration of the hydrogenated product was asꢀ
signed on the basis of elution order of hydrolysis product comꢀ
pared
with
commercially
available
(R)ꢀ(+)ꢀ3ꢀ
methylcyclohexanone. [f] Observed 5ꢀ10% over reduction
product, see Supporting Information for details. [g] Conversion
1
determined by H NMR spectroscopy. [h] Reaction conditions:
0.25 mmol of substrate, 0.5 mol % catalyst, 2 mL of PhꢀCF3, 20
bar H2. 24 h, and r.t.
Table 5. Asymmetric hydrogenation of different silyl
protected substrates[a, f]
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[a] Reaction conditions: 0.178 mmol of substrate, 0.5 mol %
catalyst, 2 mL of PhꢀCF3, 5 bar H2. 14 h, and r.t. unless otherꢀ
wise stated. [b] Reaction time, 3 h [c] 0.120 mmol of substrate.
[d] 0.089 mmol of substrate. [e] Determined by chiral GC or
SFC analysis, see Supporting Information for details. [f] Obꢀ
served 2ꢀ5% over reduction product, see Supporting Inforꢀ
mation for details.
[a] Reaction conditions: 0.25 mmol of substrate, 10 mol %
Pd(OAc)2, 5 mL of DMSO, balloon O2. 16 h, and r.t. [b] NMR
yield using internal standard 1,3,5ꢀtrimethoxybenzene. [c] Isoꢀ
lated yield. [d] Determined by chiral GC or SFC analysis, see
Supporting Information for details. [e] Absolute configuration
of the hydrogenated product was tentatively assigned based on
specific optical rotation compared with literature. [f] 0.25 mmol
of substrate, 20 mol % Pd(OAc)2, 5 mL of DMSO, balloon O2.
24 h, and r.t. [g] 0.25 mmol of substrate, 30 mol % Pd(OAc)2, 5
mL of DMSO, balloon O2. 48 h, and r.t.
CONCLUSION
We have described a new and efficient regioꢀ and highly
enantioselective hydrogenation of 1,3ꢀ and 1,4ꢀdisubstituted
1,4ꢀcyclohexadienes resulting in chiral, silyl protected enol
ethers. A variety of substituents were tolerated on both the
meta and para positions demonstrating the broad scope of
the reaction. Oxidation of the chiral enol ethers was perꢀ
formed using a Saegusaꢀtype reaction and led to the correꢀ
sponding chiral α,βꢀunsaturated ketones in good isolated
yields and with preserved enantiomeric purity.
Figure 2. Examples of total syntheses of biologically ac-
tive compounds originating from chiral 7a’’
The conversion of the enol ethers into α,βꢀunsaturated keꢀ
tones was realized by a Saegusaꢀtype oxidation.19 The best
method for the relatively volatile compounds in this study
was the recently reported modification by Herzon20 using
10% Pd and O2 as oxidant. A range of meta or para substiꢀ
tuted enol ethers having alkyl or functionalized sideꢀchains
was oxidized using this protocol. In all cases the correꢀ
sponding chiral α,βꢀunsaturated ketones could be isolated in
good yields and with full preservation of the chiral centres
(Table 5).
Supporting Information
Experimental procedures and spectroscopic data. This material
is available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
Table 6. Synthesis of α,β−unsaturated ketones[a]
*Pher.Andersson@su.se
Author Contributions
§J.L and S.K contributed equally to this work.
ACKNOWLEDGMENT
The Swedish Research Council (VR), Stiftelsen Olle Engkvist
Byggmästare and The Swedish Energy Agency supported this
work. Jianguo Liu thanks the Guangzhou Elite Scholarship
Council for the PhD fellowship. Thishana Singh acknowledges
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Utsumi, N.; Tsutsumi, K.; Murata, K.; Sandoval, C. A.; Noyori, R.
the NRF and the College of Agriculture, Engineering and Sciꢀ
ence, University of KwaZuluꢀNatal, South Africa for a postdocꢀ
toral research fellowship. Napasawan Chumnanvej thanks
VR/SIDA for the threeꢀmonth exchange fellowship to Stockꢀ
holm University. Giulia De Seriis thanks the University of Boꢀ
logna for an Erasmus scholarship. Many thanks to Prof. David
Tanner from the Technical University of Denmark for helpful
suggestions and discussions in the early stages of this work.
.
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(11) Paptchikhine, A.; Itto, K.; P. G. Andersson. Chem. Com-
mun. 2011, 47, 3989. (b) Zhu, Y.; Burgess, K. Acc. Chem. Res.
2012, 45, 1623; (c) Margarita, C.; Andersson, P. G. J. Am. Chem.
Soc. 2017, 139, 1346.
(12) (a) Schrems, M. G.; Neumann, E.; Pfaltz, A. Angew. Chem.
Int. Ed. 2007, 46, 8274; (b) Peters, B. K.; Liu, J.; Margarita, C.;
Rabten, W.; Kerdphon, S.; Orebom, A.; Morsch, T.; P. G. Andersꢀ
son. J. Am. Chem. Soc. 2016, 138, 11930.
(13) Valentine, D., Jr.; Johnson, K. K.; Priester, W.; Sun, R. C.;
Toth, K.; Saucy, G. J. Org. Chem. 1980, 45, 3698.
(14) Takaya, H.; Ohta, T.; Sayo, N.; Kumobayashi, H.; Akutaꢀ
gawa, S.; Inoue, S.; Kasahara, I.; Noyori, R. J. Am. Chem. Soc.
1987, 109, 1596ꢀ1598.
ABBREVIATIONS
COD 1,5ꢀcyclooctadiene; EE, Ethoxy ethyl acetal; EOM,
Methoxy methyl acetal; GC/MS Gas Chromatography Mass
Spectroscopy; HPLC High Performance Liquid Chromatogꢀ
raphy; PVP, Poly(4ꢀvinylpyridine); TBDMS, Tertꢀbutyl dimeꢀ
thyl silyl ether; TES, Triꢀethyl silyl ether; TESCl, Chlorotriꢀ
ethylsilane; THP, Tetraꢀhydro pyranyl acetal; TIPS, Triꢀ
isopropyl silyl ether.
10
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REFERENCES
(1) (a) Asymmetric Catalysis in Organic Synthesis; R. Noyori,
Eds.; Wiley, New York, 1994; (b) Catalytic Asymmetric Synthesis;
I. Ojima, Eds.; WileyꢀVCH, Weinheim, 1999; (c) Comprehensive
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds.; Vol. 1, Springer, Berlin, 1999; (d) Principles and Applica-
tions of Asymmetric Synthesis; Lin, G.ꢀQ.; Li, Y.ꢀM.; Chan, A. S.
C., Eds.; JohnWiley & Sons, New York, 2001; (e) Modern Rhodi-
um-Catalyzed Organic Reactions; Chi, Y. X.; Tang, W. J.; Zhang,
X. M., Eds.; 2005, 1; (f) In Stereoselective Formation of Amines,
ed. W. Li, X. M. Zhang, 2014, 343, 103. (g) Comprehensive Chi-
rality; E. M. Carreira, Eds.; Elsevier Science, Amsterdam, 2012.
(h) In Science of Synthesis, Stereoselective Synthesis 1; De Vries,
J. G., Eds.; Georg Thieme Verlag: Stuttgart, Germany, 2011. (i)
Chen, Z.ꢀP.; Zhou, Y.ꢀG. Synthesis 2016, 48, 1769. (j) Zhang, Z.;
Butt, N. A.; Zhang, W. Chem. Rev. 2016, 116, 14769.
(2) (a) Cui, X.; Burgess, K. Chem. Rev. 2005, 105, 3272ꢀ3296;
(b) Jaekel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912; (c) Johnꢀ
son, N. B.; Lennon, I. C.; Moran, P. H.; Ramsden, J. A. Acc. Chem.
Res. 2007, 40, 1291; (d) Minnaard, A. J.; Feringa, B. L.; Lefort, L.;
De Vries, J. G. Acc. Chem. Res. 2007, 40, 1267; (e) Roseblade, S.
J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402; (f) Shimizu, H.;
Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T. Acc. Chem. Res.
2007, 40,1385; (g) Church, T. L.; Andersson, P. G. Coord. Chem.
Rev. 2008, 252, 513; (h) Palmer, A. M.; ZanottiꢀGerosa, A. Curr.
Opin. Drug. Discov. Devel. 2010, 13, 698.
(3) (a) Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41,1998; (b)
Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008.
(4) (a) Woodmansee, D. H.; Pfaltz, A. Iridium Catalysis; Anꢀ
dersson, P. G., Ed. 2011, 34, 31; (b) Blaser, H. U.; Pugin, B.; Spinꢀ
dler, F. Organometallics as Catalysts in the Fine Chemical Indus-
try, 2012, 42, 65; (c) Verendel, J. J.; Pàmies, O.; Diéguez, M.;
Andersson, P. G. Chem. Rev. 2014, 114, 2130; (d) Xie, J. H.; Bao,
D. H.; Zhou, Q. L. Synthesis-Stuttgart. 2015, 47, 460; (e)
Khumsubdee, S.; Burgess, K. Acs Catalysis 2013, 3, 237.
(5) Some examples: (a) Bell, S.; Wüstenberg, B.; Kaiser, S.;
Menges, F.; Netscher, T.; Pfaltz, A. Science 2006, 311, 642; (b)
Hedberg, C.; Källström, K.; Brandt, P.; Hansen, L. K.; Andersson,
P. G. J. Am. Chem. Soc. 2006, 128, 2995; (c) Hou, G.ꢀH.; Xie, J.ꢀ
H.; Wang, L.ꢀX.; Zhou, Q.ꢀL. J. Am. Chem. Soc. 2006, 128, 11774;
(d) Liu, Y.; Sandoval, C. A.; Yamaguchi, Y.; Zhang, X.; Wang, Z.;
Kato, K.; Ding. K. J. Am. Chem. Soc. 2006, 128, 14212; (e) Zhu,
Y.; Burgess, K. Acc. Chem. Res. 2012, 45, 1623.
(6) Some examples: (a) Moessner, C.; Bolm, C. Angew. Chem.
Int. Ed. 2005, 44, 7564; (b) Yang, Q.; Shang, G.; Gao, W.; Deng,
J.; Zhang, X. Angew. Chem. Int. Ed. 2006, 45, 3832; (c) Zhu, S.ꢀF.;
Xie, J.ꢀB.; Zhang, Y.ꢀZ.; Li, S.; Zhou, Q.ꢀL. J. Am. Chem. Soc.
2006, 128, 12886; (d) FleuryꢀBregeot, N.; De La Fuente, V.; Casꢀ
tillon, S.; Claver, C. Chemcatchem 2010, 2, 1346; (e) Wang, D. S.;
Chen, Q. A.; Lu, S. M.; Zhou, Y. G. Chem. Res. 2012, 112, 2557;
(f) Chen, Z. P.; Zhou, Y. G. Synthesis-Stuttgart. 2016, 48, 1769.
(7) Some examples: (a) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97; (b) Reetz, M. T.; Li. X. J. Am. Chem. Soc. 2006,
128, 1044; (c) Huang, H.; Okuno, T.; Tsuda, K.; Yoshimura, M.;
Kitamura, M. J. Am. Chem. Soc. 2006, 128, 8716; (d) Ohkuma, T.;
(15) L. Panella, B. L. Feringa, J. G. de Vries, A. J. Minnaard,
Org. Let. 2005, 7, 4177.
(16) (a) Gruber, S.; Neuburger, M.; Pfaltz, A. Organometallics
2013, 32, 4702; (b) Gruber, S.; Pfaltz, A. Angew. Chem. Int. Ed.
2014, 53, 1896; (c) Brandt, P.; Hedberg, C.; Andersson, P. G.
Chem.-Eur. J. 2003, 9, 339; (d) Church, T. L.; Rasmussen, T.;
Andersson, P. G. Organometallics 2010, 29, 6769.
(17) For Lyconadin A see: (a) Nishimura, T.; Unni, A. K.; Yoꢀ
koshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2011, 133, 418; (b)
Cheng, X.; Waters, S. P. Org. Lett. 2013, 15, 4226; (c) Nishimura,
T.; Unni, A. K.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc.
2013, 135, 3243; (d) Nishimura, T.; Unni, A. K.; Yokoshima, S.;
Fukuyama, T. J. Am. Chem. Soc. 2014, 136, 5817; (e) Yang, Y.;
Haskins, C. W.; Zhang, W.; Low, P. L.; Dai, M. Angew. Chem., Int.
Ed. 2014, 53, 3922. For Fawcettimine see: (f) Liu, K.ꢀM.; Chau,
C.ꢀM.; Sha, C.ꢀK. Chem. Commun. 2008, 91ꢀ93; (g) Li, H.; Wang,
X.; Lei, X. Angew. Chem., Int. Ed. 2012, 51, 491. For Grandisine
see: (h) Kurasaki, H.; Okamoto, I.; Morita, N.; Tamura, O. Chem. -
Eur. J. 2009, 15, 12754. For Lycojapodine see: (i) Zhang, X.ꢀM.;
Shao, H.; Tu, Y.ꢀQ.; Zhang, F.ꢀM.; Wang, S.ꢀH. J. Org. Chem.
2012, 77, 8174. For Lycopladine see: (j) Staben, S. T.; Kennedyꢀ
Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D.
Angew. Chem., Int. Ed. 2006, 45, 5991. For Norzoanthamine see:
(k) Miyashita, M.; Sasaki, M.; Hattori, I.; Sakai, M.; Tanino, K.
Science 2004, 305, 495. Some selected examples: (l) Cheng, X.;
Waters, S. P. Org. Lett. 2013, 15, 4226; (m) Fleming, I.; Maiti, P.;
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Ramarao, C. Org. Biomol. Chem. 2003, 1, 3989; (n) Shen, S.ꢀJ.; Li,
62, 9323; (c) Fleming, I.; Maiti, P.; Ramarao, C. Org. Biomol.
Chem. 2003, 1, 3989; (d) Nicolaou, K. C.; Montagnon, T.; Baran,
P. S. Angew. Chem., Int. Ed. 2002, 41, 1386. (e) Altman, R. A.;
Nilsson, B. L.; Overman, L. E.; Read de Alaniz, J.; Rohde, J. M.;
Taupin, V. J. Org. Chem. 2010, 75, 7519.
(19) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43,
1011ꢀ1013.
(20) Herzon, S. B.; Lu, L.; Woo, C. M.; Gholap, S. L. J. Am.
Chem. Soc. 2011, 133, 7260ꢀ7263.
W.ꢀD. Z. J. Org. Chem. 2013, 78, 7112; (o) Lauchli, R.; Whitney,
J. M.; Zhu, L.; Shea, K. J. Org. Lett. 2005, 7, 3913; (p) Lin, K.ꢀW.;
Ananthan, B.; Tseng, S.ꢀF.; Yan, T.ꢀH. Org. Lett. 2015, 17, 3938;
(q) Takahashi, S.; Hongo, Y.; Ye, Y. Q.; Koshino, H. Tetrahedron:
Asymmetry. 2011, 22, 703; (r) Goudedranche, S.; Raimondi, W.;
Bugaut, X.; Constantieux, T.; Bonne, D.; Rodriguez, J. Synthesis-
Stuttgart . 2013, 45, 1909.
(18) (ꢀ)ꢀ(R)ꢀ5ꢀMethylꢀ2ꢀcyclohexenꢀ1ꢀone was usually prepared
from commercially available (R)ꢀ(+)ꢀpulegone via 4 steps, in an
overall yield of 44%. See reference: (a) Caine, D.; Procter, K.;
Cassell, R. A. J. Org. Chem. 1984, 49, 2647; This method has been
modified by a number of research groups, see: (b) Chong, B.ꢀD.; Ji,
Y.ꢀI.; Oh, S.ꢀS.; Yang, J.ꢀD.; Baik,W.; Koo, S. J. Org. Chem. 1997,
1
2
3
4
5
6
7
8
(21) Matveenko, M.; Liang, G.; Lauterwasser, E. M. W.; Zubía,
E.; Trauner, D. J. Am. Chem. Soc. 2012, 134, 9291..
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Ph
Ph
Ph
Ph
P
Ph
Ph
P
P
Ir(COD)
Ir(COD)
N
Ir(COD)
BArF
N
BArF
t-Bu
N
BArF
Ph
Ph
O
S
S
A
C
B
Ph
P
Ph
Ph
Ph
P
Ph
Ph
N
P
Ir(COD)
N
BArF
O
Ir(COD)
Ir(COD)
BArF
BArF
N
N
Ph
O
N
Ph
S
D
F
E
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1
2
3
4
5
6
7
O
H
H
O
N
8
HO
9
O
O
OH
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
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48
49
50
51
52
53
54
55
56
57
58
59
60
Grandisine D
N
OMe
(-)-Cannabispirenone A
H
(-)-Lycopladine A
O
O
OH
OH
O
O
OH
7a''
N
HO
O
(-)-Fawcettimine
HN
H
H
N
(-)-2-Carbathysanone
Me
H
H
Lyconadin A
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2
3
4
5
6
O
n-Pent
O
n-Pent
O
n-Pent
*
*
0.5 mol% Ir catalyst
20 bar H2, DCM, r.t.
*
1a
1a'
1a''
7
8
(1a') ee (%)[c]
1a' / 1a''[c]
Cat.
Conv. (%)[b]
Entry
Time
Base
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
A
A
1
2
12 min
30 min
No
No
91
98
83
81
79/21
47/53
N.D.[d]
A
3
2 h
No
99
1/99
99/1
3/97
B
B
4
5
12 min
3 h
No
No
50
99
83
N.D.[d]
B
6
3 h
PVP
98
84
97/3
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2
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5
6
7
8
9
10
11
12
13
O
*
*
O
O
*
0.5 mol % Ir catalyst
H2 , r.t., 16 h
TBDMS
TBDMS
TBDMS
+
2a
2a'
2a''
2a' / 2a'' (2a') ee (%)[c]
Conv. (%)[b]
99
Entry
Pressure (bar)
Base
Cat.
A
Solvent
DCM
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
PVP
20
65/35
90
1
PVP
PVP
B
C
2
3
4
20
20
99
99
93/7
78
82
DCM
DCM
67/33
PVP
PVP
PVP
D
E
F
20
20
20
99
99
99
81/19
27/73
78/22
90
94
95
DCM
DCM
DCM
5
6
K3PO4
K3PO4
K3PO4
F
F
F
7
20
20
20
99
99
99
72/28
40/60
41/59
91
91
94
DCM
Benzene
Toluene
8
9
Ph-CF3
Ph-CF3
K3PO4
K3PO4
F
F
10
11
20
10
99
99
85/15
93/7
96
96
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*
O
*
O
O
*
0.5 mol% [Ir(COD)F ] BArF
Ph-CF3, K3PO4, H2 , rt.12 h
R
R
R
+
6
7
8
9
P1
P2
Conv.[b]
65
P1 ee(%)[c][d]
P1/P2[b]
Entry
1
Substrate
O
Product
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
O
EOM
EE
EOM
96(R)
99/1
O
O
97(R)
94/6
93
70
73
99
99
2
EE
O
O
O
O
THP
TIPS
TES
83(R)
97(R)
96(R)
96(R)
99/1
99/1
THP
TIPS
3
4
O
O
86/14
93/7
5
6
TES
O
O
TBDMS
TBDMS
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R2
R4
R2
R4
O
O
*
0.5 mol % Ir catalyst
R1
R1
1
2
3
4
5
*
R3
R3
Ph-CF3 , K3PO4 , H2 , r.t., 12 h
6
7
8
9
10
ee (%)d
96(R)e
Entry
Catalyst
F
Substrate
O
Product
O
Yield (%)
58b
TBDMS
TBDMS
1
11
12
13
14
2a'
2a
O
O
TES
TES
TES
TES
2
F
E
79c,f
96(R)e
99(S)
15
16
17
18
7a
8a
7a'
8a'
O
O
Et
O
O
Et
56c,f
19
3
20
21
22
23
n-Bu
n-Bu
TBDMS
TBDMS
F
F
54b
55c
92(R)
95(R)
4
24
25
26
27
28
9a
9a'
O
n-Bu
O
n-Bu
TES
TES
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
5
10a
10a'
11a'
O
n-Pent
O
n-Pent
TBDMS
TBDMS
F
F
78b
70b
96(R)
95(R)
6
7
11a
O
n-Pent
O
n-Pent
TES
TES
12a
12a'
O
O
TBDMS
TBDMS
8
9
F
F
45b
80(R)
95(R)
13a
14a
13a'
14a'
O
O
TES
TES
75c,f
O
O
TES
TES
F
E
56c,f
92(R)
95(S)
10
11
n-Pr
n-Pr
15a
15a'
O
O
TBDMS
TBDMS
81c
16a
16a'
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O
O
1
2
TES
TES
79c
12
E
98(S)
3
4
17a
17a'
5
6
7
TBDMSO
OTBDMS
F
TBDMSO
OTBDMS
13h
89g
97(R)
95(R)
8
9
18a
18a'
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
O
O
O
O
TBDMSO
TBDMSO
TBDMSO
TBDMSO
F
F
89c
14
15
O
O
19a
19a'
20a'
O
O
82c
98(R)
94(R)
20a
21a
TBDMSO
TBDMSO
16h
94g
F
OTBDMS
OTBDMS
21a'
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2
3
4
5
6
7
8
9
ee (%)e
Entry
Catalyst
Substrate
Product
Isolated Yield (%)
81
10
11
12
13
- -
17
B
14
15
16
17
18
19
20
OTBDMS
OTBDMS
22a'
22a
OTBDMS
OTBDMS
78b
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
18
19
- -
B
F
23a
23a'
82c
99 (R)
OTIPS
OTIPS
24a'
24a
OTBDMS
OTBDMS
93d
20
98 (R)
Ph
Ent-A
Ph
25a
25a'
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O
R2
*
O
R1
*
R2
6
7
8
9
10 mol % Pd(OAc)2 , O2
DMSO, r.t., 16 h
or
or
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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30
31
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39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1
*
*
R2
R2
ee (%)d
95(R)
Product
O
Entry
1
Yield (%)
Substrate
O
TES
86b
7a'
7a''
O
O
TES
68b
2
95(R)
92(R)
14a''
14a'
O
O
TES
78b
3
n-Pr
15a''
15a'
n-Pr
O
TBDMSO
OTBDMS
4f
97(R)e,21
59c
56c
51c
OTBDMS
18a'
18a''
19a''
O
O
O
O
O
TBDMSO
5g
O
O
O
O
95(R)
19a'
O
O
TBDMSO
6g
98(R)
20a'
20a''
21a''
TBDMSO
62c
7f
94(S)
OTBDMS
OTBDMS
21a'
ACS Paragon Plus Environment