Sequential ruthenium catalysis for olefin isomerization and oxidation: Application to the synthesis of unusual amino acids

Article abstract of DOI:10.1021/jacs.7b08496

How can you use a ruthenium isomerization catalyst twice? A ruthenium-catalyzed sequence for the formal two-carbon scission of allyl groups to carboxylic acids has been developed. The reaction includes an initial isomerization step using commercially available ruthenium catalysts followed by in situ transformation of the complex to a metal-oxo species, which is capable of catalyzing subsequent oxidation reactions. The method enables enantioselective syntheses of challenging α-tri- and tetrasubstituted α-amino acids including an expedient total synthesis of the antiepileptic drug levetiracetam.

Full text of DOI:10.1021/jacs.7b08496

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Article
Sequential Ruthenium Catalysis for Olefin Isomerization and
Oxidation: Application to the Synthesis of Unusual Amino Acids
Marc Liniger, Yiyang Liu, and Brian M. Stoltz
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08496 • Publication Date (Web): 16 Sep 2017
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Journal of the American Chemical Society
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Sequential Ruthenium Catalysis for Olefin Isomerization and
Oxidation: Application to the Synthesis of Unusual Amino Ac-
ids
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Marc Liniger,† Yiyang Liu, and Brian M. Stoltz*
Warren and Katherine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California 91125, United States
ABSTRACT: How can you use a ruthenium isomerization catalyst twice? A ruthenium-catalyzed sequence for the formal two-
carbon scission of allyl groups to carboxylic acids has been developed. The reaction includes an initial isomerization step using
commercially available ruthenium catalysts followed by in situ transformation of the complex to a metal-oxo species, which is ca-
pable of catalyzing subsequent oxidation reactions. The method enables enantioselective syntheses of challenging α-tri- and
tetrasubstituted α-amino acids including an expedient total synthesis of the antiepileptic drug levetiracetam.
INTRODUCTION
The use of a single metal catalyst for several chemical trans-
formations in a one-pot and/or a sequential manner1 is highly
desirable due to high material cost and limited resources of
transition metals.2 Moreover, new tools for modifying preva-
lent functional groups, which are easily installed in a chemo-
and stereoselective fashion, are needed to expand the applica-
tion of novel methodology in both academic and industrial
settings.3 In this context, allyl groups are ubiquitous and their
introduction is very well established including asymmetric
additions.4 In general, three modes for their installation can be
Scheme 1: Sequences and methods for the introduction of chiral
carboxylic acid groups.
distinguished (Figure 1): As a nucleophile5,6 (e.g. Grignard
addition7), as an electrophile8 (e.g. Tsuji-Trost allylation9) or
Although a sequence involving vinylation followed by oxi-
dative cleavage of the double bond would in theory lead to the
as a formally neutral species10 (e.g. Keck radical allylation11).
same carboxylic acid product, asymmetric vinylation reactions
are far less established than allylations (Scheme 1B).4 In par-
ticular, catalytic enantioselective vinylation of carbonyl eno-
lates is still highly challenging and limited in substrate scope
and, moreover, methods for the construction of quaternary
stereocenters are very rare.12,14 Even more scarce and far less
established are catalytic enantioselective carboxylations
Figure 1. General modes for the introduction of allyl groups.
(Scheme 1C).15
Most of these methods not only find widespread use in or-
As a result, we focused our attention on the catalytic oxida-
ganic synthesis, but also allow for the installation of allyl
tive scission of two carbons from the tail of an allyl unit in
groups in a highly stereoselective fashion, even to build chal-
order to render such groups as carboxylic acid synthesis
lenging chiral quaternary stereocenters.12 However, tools for
equivalents (Scheme 2). Herein, we present the results of that
the formal scission of two carbons of an allyl group leading to
study and provide illustrative examples of this new method in
a truncated carboxylic acid using a single transition metal cata-
the context of high value and unusual amino acid synthesis.
lyst have, to our knowledge, not been described (Scheme 1A,
M1=M2). The use of only one catalyst is in strong contrast to
RESULTS AND DISCUSSION
the field of one-pot catalysis, where for instance two transition
After exploring a variety of transition metal catalysts known
metal catalysts are used for isomerization/metathesis reac-
tions.13
for alkene isomerization (iridium, rhodium, palladium, ruthe-
nium; for details see the Supporting Information), we found
that ruthenium catalysts performed best and were amenable to
further oxidative catalysis (Scheme 2).
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coupling as reported by Hanessian,24 or the Bus group is readi-
ly cleaved under acidic conditions to afford D-tert-leucine (5)
in 96% yield (98% ee) after ion exchange chromatography.
Stage 1
Stage 2
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On
Ru
NaIO4
[Ru]
R’
R’
R’
R
[
]
R
X
R
X
X
COOH
Alternatively, by leaving out the olefin isomerization, sul-
R and R’ = alkyl or H
X = C or N
R and R’ = alkyl or H
X = C or N
R and R’ = alkyl or H
X = C or N
finamide
3
was subjected to a similar alkene cleav-
age/sulfinamide oxidation sequence with a catalytic amount of
RuCl3 hydrate giving Bus-protected β-amino acid 6 in 93%
yield (Scheme 3B). After deprotection and ion exchange
chromatography, (S)-β-neopentylglycine (7) was obtained in
91% yield and 98% ee. Benzoyl protected amine 8, which is
accessible in enantiopure form using Schaus’ allylboration,25
performed equally well in our sequential ruthenium catalysis,
affording carboxylic acid 9 in 88% yield over 2 steps (Scheme
3C). Benzoyl deprotection with aqueous HCl in methanol pro-
vided racemic tert-leucine (5) in 57% yield.
Scheme 2. Ruthenium-catalyzed two-carbon truncation of allyl
groups to carboxylic acids.
In particular, the commercially available Grubbs second
generation catalyst 1a (Figure 2) under Nishida’s conditions16
was highly chemoselective for alkene isomerization and dis-
played good conversion (>90%) without noticeable side reac-
tions. Moreover, we discovered that the in situ formed Ru–H
complex17 1b, after solvent exchange, can be oxidized with
NaIO4 to an oxidized ruthenium species,18 which is capable of
catalyzing subsequent oxidation reactions (e.g. oxidative
cleavage of alkenes, Scheme 2).19 It has to be reinforced at this
point that we do not add a new external ruthenium source for
the second step. Instead, the crude transition metal catalyst
from the previous isomerization step is modified in situ and
reused for the catalytic oxidation reactions. Moreover, the only
operation between the two steps is evaporation of the solvent
from the isomerization reaction (toluene for 1a, acetone for 2)
followed by dissolution of the crude reaction mixture in the
solvent mixture used for oxidation (CCl4, MeCN, H2O).
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Scheme 3. a) 1. Grubbs 1a (5 mol%), VTMS, toluene, reflux, 21
h, 98% conv., E/Z 4.4:1; 2. NaIO4, CCl4, MeCN, H2O, 23°C, 2.5
d, 72% yield over 2 steps, 99% ee; b) 1. TfOH, CH2Cl2, 0°C, 2.5
h; 2. IEC, 96% yield, 98% ee; c) RuCl3ꢀH2O (5 mol%), NaIO4,
Figure 2. Identified ruthenium catalysts for olefin isomeriza-
tion/oxidation sequences – An in situ formed ruthenium-hydride
complex 1b derived from Grubbs second generation catalyst (1a)
and Grotjahn’s catalyst (2).
CCl4, MeCN, H2O, 23°C, 16 h, 93% yield; d) 1. TfOH, CH2Cl2,
0°C→23°C, 2 d; 2) IEC, 91% yield, 98% ee; e) 1. Grubbs 1a (5
mol%), VTMS, toluene, 128°C, 16 h, 97% conv., E/Z 4:1; 2.
NaIO4, CCl4, MeCN, H2O, 23°C, 22 h, 88% yield over 2 steps; f)
1. 4 M aq. HCl, MeOH, reflux, 24 h; 2. IEC, 57% yield; g) 1.
Grubbs 1a (5 mol%), VTMS, toluene, 128°C, 18 h, 92% conv.,
E/Z 4.5:1; 2. NaIO4, CCl4, MeCN, H2O, 23°C, 24 h, 62% yield
over 2 steps; h) ClCO2Et, NEt3, THF, then NH4OH, 0°C→23°C,
19 h, 67% yield, >98% ee. IEC=ion exchange chromatography,
VTMS=vinyloxy trimethylsilane.
Even though NaIO4 mediated oxidations of ruthenium al-
kylidene complexes and their use in sequential and tandem
catalysis19b,20 have been described previously (e.g.
RCM/dihydroxylation),21 the modification and multiple use13
of a ruthenium-hydride complex17 1b (derived from precata-
lyst 1a) or a ruthenium phosphine-imidazole complex22 2 in an
isomerization/oxidation sequence was not known, until now
(Figure 2).
The sequential ruthenium catalysis was then used for an en-
antioselective total synthesis of levetiracetam (12), the active
pharmaceutical ingredient of the antiepileptic medicine Kep-
pra® (Scheme 3D).26 The synthesis commenced from homoal-
lylic amide 10, which was prepared in four steps from com-
mercially available propionaldehyde and Ellman’s auxiliary5e
(see the Supporting Information for details). Sequential ruthe-
nium catalysis of alkene 10 with Grubbs catalyst 1a provided
access to carboxylic acid 11 in 62% yield over two steps.
Amidation of 11 was achieved via the corresponding mixed
anhydride and reaction with ammonium hydroxide as de-
Hence, chiral homoallylic amine 3, which was readily syn-
thesized via diastereoselective allylation of Ellman’s sulfin-
imine,5e was subjected to the optimized conditions using
Grubbs catalyst 1a giving the isomerized alkene in 98% con-
version (Scheme 3A). After oxidation of the crude catalyst, an
alkene cleavage/sulfinamide oxidation duet23 took place fur-
nishing Bus-protected24 D-tert-leucine (4) in 72% yield over 2
steps, notably without racemization (99% ee). The Bus pro-
tected amino acid 4 can be employed directly for a peptide
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Treatment of caprolactam 19 and glutarimide 22 with cata-
scribed previously by Sánchez.27 Levetiracetam (12) was iso-
lated in 67% yield (>98% ee) and, after one recrystallization,
was enriched to excellent enantiopurity (>99.9% ee).
1
2
lyst 1a under our optimized conditions gave, after Curtius
rearrangement, hydantoin 20 and isocyanate 23 in 65% and
34% yield over 3 steps, respectively. Anti-Bredt bicycle35-37
20 results from an intramolecular cyclization of the lactam NH
to the isocyanate. Its structure was unambiguously confirmed
by X-ray crystallography (see the Supporting Information).
Subsequent hydrolysis of 20 and 23 with aqueous HCl fur-
nished (R)-α-methyllysine33d (21) and (R)-α-methylglutamic
acid33c,38 (24), respectively, in excellent yields (92% and
99%). Given the recent availability of α-quaternary lactams
and imides,28 it is possible to envision the synthesis of a wide
range of α-substituted amino acid derivatives for a multitude
of applications.
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Scheme 4. a) 15: 1. Grubbs 1a (5 mol%), VTMS, toluene,
130°C, 18 h, 88% conv.; 2. NaIO4, CCl4, MeCN, H2O, 23°C;
3. DPPA, NEt3, MeCN, 0°C→65°C, 3 h, 27% yield over 3
steps; 16: 1. Grubbs 1a (5 mol%), VTMS, toluene, 125°C, 16
h, 96% conv. or Grotjahn 2 (2 mol%), acetone-d6, 70°C, 63 h,
95% conv.; 2. NaIO4, CCl4, MeCN, H2O, 23°C, 3. DPPA,
NEt3, MeCN, 0°C→65°C, 47% yield over 3 steps (with 1a)
and 52% yield over 3 steps (with 2); b) 17: 1. 4 M aq. HCl,
1,4-dioxane, 120°C, 12 h; 2. IEC, 61% yield; 18: 1. 2 M aq.
HCl, THF, reflux, 24 h; 2. IEC, 95% yield; c) 1. Grubbs 1a (5
mol%), VTMS, toluene, 129°C, 21 h, 96% conv., 2. NaIO4,
CCl4, MeCN, H2O, 23°C, 24 h; 3. DPPA, NEt3, MeCN,
0°C→65°C, 3 h, 65% yield over 3 steps; d) 1. 4 M aq. HCl,
dioxane, reflux, 18 h; 2. IEC, 92% yield; e) 1. Grubbs 1a (5
mol%), VTMS, toluene, 129°C, 21 h, 93% conv.; 2. NaIO4,
CCl4, MeCN, H2O, 23°C, 25 h; 3. DPPA, NEt3, MeCN,
0°C→65°C, 3 h, 34% yield over 3 steps; f) 1. 4 M aq. HCl,
dioxane, reflux, 18 h; 2. IEC, 99% yield. DPPA=diphenyl
phosphoryl azide, IEC=ion exchange chromatography,
VTMS=vinyloxy trimethylsilane.
Scheme 5. a) DPPA, NEt3, DCE, 23°C→reflux, 5 h, then
BnOH, reflux, 38 h, 29% yield, 98% ee; b) H2, Pd/C, MeOH,
23°C, 4 h, >99% yield; c) LiAlH4, THF, 0°C→reflux, 24 h,
then HCl/dioxane, 89% yield. DCE=1,2-dichloroethane,
DPPA= diphenyl phosphoryl azide.
The enantioenriched carboxylic acid 25, obtained by our
Ru-catalyzed isomerization oxidation method on lactam 14
(Scheme 4), is not only an intermediate in Padwa’s racemic
synthesis of desacetoxy-4-oxo-6,7-dihydrovindoro-sine39 (29),
but can also be used for the synthesis of Cbz-protected α-
amino lactam 26 (98% ee) by trapping the intermediate isocy-
anate 16 with benzyl alcohol following the Curtius rearrange-
ment (Scheme 5). Hydrogenolysis of the Cbz group gave ami-
no lactam 27 in quantitative yield, which renders Knabe’s
racemic synthesis of 3-ethyl thalidomide40 (30) enantioselec-
tive. Reduction of lactam 27 with LiAlH4, followed by pre-
cipitation as the bishydrochloride salt furnished chiral diamine
28 in 89% yield. The racemic, mono-Boc protected version of
28 was used recently by Nishio et al.41 for the synthesis of
dipeptidyl peptidase IV (DPP-4) inhibitors.
We next applied our sequential ruthenium catalysis condi-
tions to α-quaternary lactams (Scheme 4), which were readily
available in enantiopure form using palladium-catalyzed de-
carboxylative allylic alkylation.8a,28 The unprotected methyl-
and ethyl-substituted lactams 13 and 14 were treated with a
catalytic amount of Grubbs catalyst 1a and the internal alkene
was subsequently cleaved to give the crude carboxylic acids.
A Curtius rearrangement29 then furnished isocyanates 15 and
16 in 27% and 47% yield over 3 steps, respectively.30 Like-
wise, we found that 2 mol% of Grotjahn’s catalyst22 (2, Figure
2) worked equally well31 for the ruthenium-catalyzed isomeri-
zation/oxidation sequence of lactam 14 to give, after Curtius
rearrangement, isocyanate 16 in a comparable 52% yield over
3 steps.32 Hydrolysis of the isocyanate and the amide bond of
15 and 16 were achieved under acidic conditions to give ac-
cess to enantiopure (R)-α-methylornithine33 (17) and (R)-α-
ethylornithine34 (18) in 61% and 95% yield, respectively. The
latter has been synthesized for the first time as a single enanti-
omer.34 Biologically, both α -alkyl ornithine analogs are
known to be ornithine decarboxylase inhibitors.33a,34
CONCLUSIONS
In summary, we have developed a highly efficient rutheni-
um catalyzed isomerization/oxidation sequence, which ena-
bled the syntheses of challenging unnatural amino acids such
as D-tert-leucine (5), (S)-β-neopentylglycine (7), (R)-α -
methyl- and ethylornithine (17 and 18), (R)-α-methyllysine
(21) and (R)-α-methylglutamic acid (24). The reaction se-
quence performs well with not only ruthenium-hydride com-
plex 1b (derived from Grubbs catalyst 1a), but also with the
less common Grotjahn catalyst 2. We found that both isomeri-
zation catalysts 1b and 2 can be used to perform one or several
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Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
subsequent oxidation steps after NaIO4 treatment of the crude
reaction mixtures. To demonstrate the utility of our method,
we have completed an enantioselective total synthesis of the
antiepileptic drug levetiracetam (12) and enantioselective for-
mal syntheses of a vindorosine derivative 29 and of (R)-3-
ethyl thalidomide (30). Given the importance and ubiquity of
the amino acid subunit in organic chemistry, we believe that
our method will inspire many creative permutations and appli-
cations. Further usages of the method are currently under in-
vestigation.
107, 8186. (d) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem.
Soc. 1993, 115, 8467. (e) Liu, G.; Cogan, D. A.; Ellman, J. A. J. Am.
Chem. Soc. 1997, 119, 9913. (f) Cogan, D. A.; Liu, G.; Ellman, J.
Tetrahedron 1999, 55, 8883. (g) Kinnaird, J. W. A.; Ng, P. Y.; Kubo-
ta, K.; Wang, X.; Leighton, J. L. J. Am. Chem. Soc. 2002, 124, 7920.
(h) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008,
130, 6340. (i) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem.
Soc. 2008, 130, 14891. (j) Beeson, T. D.; Mastracchio, A.; Hong, J.-
B.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316, 582. (k)
Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2011, 133, 3332. (l) Silverio, D. L.; Torker, S.; Pilyugina, T.; Vieira,
E. M.; Snapper, M. L.; Haeffner, F.; Hoveyda, A. H. Nature 2013,
494, 216.
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ASSOCIATED CONTENT
Experimental procedures, characterization data, and crystallo-
graphic information files. This material is available free of charge
via the Internet at http://pubs.acs.org.
(6) For recent reviews see: (a) Denmark, S. E.; Fu, J. Chem. Rev.
2003, 103, 2763. (b) Bower, J. F.; Kim, I. S.; Patman, R. L.; Krische,
M. J. Angew. Chem. Int. Ed. 2009, 48, 34. (c) Yus, M.; González-
Gómez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774.
AUTHOR INFORMATION
(7) (a) Grignard, V. C. R. Hebd. Acad. Sci. 1900, 130, 1322. (b)
Hutchison, D. A.; Beck, K. R.; Benkeser, R. A.; Grutzner, J. B. J. Am.
Chem. Soc. 1973, 95, 7075. (c) Benkeser, R. A. Synthesis 1971, 347.
(8) For selected references of electrophilic allylation see: (a) Be-
henna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044. (b)
Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira, E. M. Science
2013, 340, 1065. (c) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz,
B. M. J. Am. Chem. Soc. 2013, 135, 10626. (d) Pupo, G.; Properzi, R.;
List, B. Angew. Chem. Int. Ed. 2016, 55, 6099. For selected reviews
see: (e) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(f) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921. (g)
Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461. (h)
Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013, 2745. (i) Zhuo,
C.-X.; Zheng, C.; You, S.-L. Acc. Chem. Res. 2014, 47, 2558.
(9) (a) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett.
1965, 6, 4387. (b) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc.
1973, 95, 292.
Corresponding Author
* stoltz@caltech.edu
Present Address
† Givaudan Schweiz AG, Fragrances S&T / Ingredients Research,
Ueberlandstrasse 138, CH-8600 Dübendorf, Switzerland
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Dedicated to Professor Albert Padwa on the occasion of his 80th
birthday. The authors wish to thank NIH-NIGMS
(R01GM080269), Amgen, the Gordon and Betty Moore Founda-
tion and Caltech for financial support. M.L. thanks the Swiss Na-
tional Science Foundation (SNSF) for a postdoctoral fellowship
(P2EZP2_148751). Dr. Scott Virgil and the Caltech Center for
Catalysis and Chemical Synthesis are acknowledged for the gen-
erous donation of catalyst 2 and Materia Inc. for the donation of
catalyst 1a. The authors thank Dr. Michael Takase and Larry
Henling for X-ray structural determinations. The Hsieh-Wilson
group is acknowledged for nanopure water and the Dougherty
group for using their freeze-drying equipment. Lukas Hilpert,
Kyle Virgil and Katerina Korch are thanked for experimental
assistance. Beau P. Pritchett is gratefully acknowledged for re-
cording analytical data and for proofreading this manuscript.
(10) For examples of tin-free radical allylations see: (a) Quiclet-
Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 1996, 118, 1209. (b)
Schaffner, A.-P.; Renaud, P. Angew. Chem. Int. Ed. 2003, 42, 2658.
(c) Debien, L.; Quiclet-Sire, B.; Zard, S. Z. Acc. Chem. Res. 2015, 48,
1237.
(11) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829.
(12) Quasdorf, K. W.; Overman, L. E. Nature 2014, 516, 181.
(13) For selected examples of one-pot catalysis with 1a and 2 using
a second catalyst, see: (a) Baader, S.; Podsiadly, P. E.; Cole-
Hamilton, D. J.; Goossen, L. J. Green Chem. 2014, 16, 4885. (b)
Dobereiner, G. E.; Erdogan, G.; Larsen, C. R.; Grotjahn, D. B.;
Schrock, R. R. ACS Catal. 2014, 4, 3069. (c) Higman, C. S.; De
Araujo, M. P.; Fogg, D. E. Catal. Sci. Technol. 2016, 6, 2077.
(14) (a) Chieffi, A.; Kamikawa, K.; Åhman, J.; Fox, J. M.; Buch-
wald, S. L. Org. Lett. 2001, 3, 1897. (b) Taylor, A. M.; Altman, R. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900. (c) Liu, Y., Vir-
gil, S. C.; Grubbs, R. H.; Stoltz, B. M. Angew. Chem. Int. Ed. 2015,
54, 11800.
(15) The only example we could find for a homogeneous carboxy-
lation using CO2 is a nickel-catalyzed asymmetric carboxylative cy-
clization of bis-1,3-dienes: Takimoto, M.; Nakamura, Y.; Kimura, K.;
Mori, M. J. Am. Chem. Soc. 2004, 126, 5956.
(16) (a) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. An-
gew. Chem. Int. Ed. 2002, 41, 4732. (b) Arisawa, M.; Terada, Y.;
Takahashi, K.; Nakagawa, M.; Nishida, A. J. Org. Chem. 2006, 71,
4255.
(17) (a) Trnka, T. M.; Morgan, J. P.; Sanford, M. S.; Wilhelm, T.
E.; Scholl, M.; Choi, T.-L.; Ding, S.; Day, M. W.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 2546. (b) Dinger, M. B.; Mol, J. C. Eur. J.
Inorg. Chem. 2003, 2827. (c) Hong, S. H.; Day, M. W.; Grubbs, R. H.
J. Am. Chem. Soc. 2004, 126, 7414.
(18) This oxidized ruthenium species might be similar to RuO4.
However, the exact nature has not been unambiguously established.
(19) For reviews about RuO4 mediated oxidations see: (a) Gore, E.
S. Platinum Metals Rev. 1983, 27, 111. (b) Piccialli, V. Molecules
2014, 19, 6534.
REFERENCES
(1) For the definition of sequential transformations see: Tietze, L.
F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 32, 131.
(2) (a) North, M. Sustainable Catalysis: Without Metals or Other
Endangered Elements, Part 1; North, M., Ed.; The Royal Society of
Chemistry: Cambridge, 2016; pp 1-2. (b) Holzwarth, M. S.; Plietker,
B. ChemCatChem 2013, 5, 1650. (c) Roeder, M. H.; Eigenbrodt, B.
C.; Paul, J. J. Catalysis for Sustainability: Goals, Challenges, and
Impacts; Umile, T. P., Ed.; CRC Press: Boca Raton, 2016; pp 149-
176.
(3) (a) Industrial Applications of Asymmetric Synthesis, Vol. 9. In
Comprehensive Chirality; Carreira, E. M.; Yamamoto, H., Eds.; Else-
vier: Amsterdam, 2012; pp 1-506. (b) Brown, D. G.; Boström, J. J.
Med. Chem. 2016, 59, 4443.
(4) (a) Carreira, E. M.; Kvaerno; L. Classics in Stereoselective Syn-
thesis, Chapter 5; Wiley-VCH: Weinheim, 2008; pp 153-186. (b)
Carreira, E. M.; Kvaerno; L. Classics in Stereoselective Synthesis,
Chapter 14; Wiley-VCH: Weinheim, 2008; pp 457-482.
(5) For selected seminal publications of nucleophilic allylation see:
(a) Hosomi, A.; Sakurai, H. Tetrahedron Lett. 1976, 17, 1295. (b)
Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092. (c)
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(20) For reviews about sequential and tandem Ru catalysis see: (a)
Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9, 1258. (b) Alcaide,
B.; Almendros, P.; Luna, A. Chem. Rev. 2009, 109, 3817.
in agreement with a lower catalyst loading used for 2 (2 mol%) com-
pared to 1b (5 mol%). Since we had large quantities of 1a available in
our lab and catalyst 2 was rather expensive at the time (commercially
available from Strem Chemicals and abcr GmbH, CAS 930601-66-4),
we preferred to use 1a for Scheme 4. However, similar yields are
expected for both catalysts 1a and 2 as we have shown for substrate
14.
(32) When we used forcing conditions for the second step with cat-
alyst 2 (5 and 10 mol%), we observed a “lactam oxidation/alkene
cleavage/decarboxylation/hydroxylation” reaction quartet for 32. The
tertiary alcohol 33 was isolated in 16% and 32% yield over 2 steps,
respectively. Unfortunately, the reaction led to a racemic product.
1
2
3
4
5
6
7
8
(21) For the use of Ru complexes in sequential and tandem cataly-
sis coupled to an oxidation step see: (a) Louie, J.; Bielawski, C. W.;
Grubbs, R. H. J. Am. Chem. Soc. 2001, 123, 11312. (b) Beligny, S.;
Eibauer, S.; Maechling, S.; Blechert, S. Angew. Chem. Int. Ed. 2006,
45, 1900. (c) Scholte, A. A.; An, M. H.; Snapper, M. L. Org. Lett.
2006, 8, 4759. (d) Neisius, N. M.; Plietker, B. J. Org. Chem. 2008,
73, 3218. (e) Schmidt, B.; Krehl, S. Chem. Commun. 2011, 47, 5879.
(f) Kato, H.; Ishigame, T.; Oshima, N.; Hoshiya, N.; Shimawaki, K.;
Arisawa, M.; Shuto, S. Adv. Synth. Catal. 2011, 353, 2676. (g)
Schmidt, B.; Krehl, S.; Hauke, S. J. Org. Chem. 2013, 78, 5427. (h)
Dornan, P. K.; Wickens, Z. K.; Grubbs, R. H. Angew. Chem. Int. Ed.
2015, 54, 7134. (i) Malik, M.; Ceborska, M.; Witkowski, G.; Jarosz,
S. Tetrahedron: Asymmetry 2015, 26, 29. (j) Dornan, P. K.; Lee, D.;
Grubbs, R. H. J. Am. Chem. Soc. 2016, 138, 6372.
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
(22) (a) Grotjahn, D. B.; Larsen, C. R.; Gustafson, J. L.; Nair, R.;
Sharma, A. J. Am. Chem. Soc. 2007, 129, 9592. (b) Erdogan, G.;
Grotjahn, D. B. J. Am. Chem. Soc. 2009, 131, 10354. (c) Larsen, C.
R.; Grotjahn, D. B. J. Am. Chem. Soc. 2012, 134, 10357. (d) Erdogan,
G.; Grotjahn, D. B. Org. Lett. 2014, 16, 2818.
(23) For this classification of tandem reactions see: Jones, A. C.;
May, J. A.; Sarpong, R.; Stoltz, B. M. Angew. Chem. Int. Ed. 2014,
53, 2556.
(33) (a) Bey, P.; Danzin, C.; Van Dorsselaer, V.; Mamont, P.; Jung,
M.; Tardif, C. J. Med. Chem. 1978, 21, 50. (b) Kirihata, M.; Mihara,
S.; Ichimoto, I.; Ueda, H. Agric. Biol. Chem. 1978, 42, 185. (c)
Yamamoto, Y.; Kirihata, M.; Ichimoto, I.; Ueda, H. Agric. Biol.
Chem. 1985, 49, 1761. (d) Gander-Coquoz, M.; Seebach, D. Helv.
Chim. Acta 1988, 71, 224.
(34) For the only racemic synthesis see: Abdel-Monem, M. M.;
Newton, N. E.; Ho, B. C.; Weeks, C. E. J. Med. Chem. 1975, 18, 600.
(35) For a recent review on the synthesis and reactivity of bridged
lactams, see: Szostak, M.; Aubé, J. Chem. Rev. 2013, 113, 5701.
(36) For previous studies from our group in the topic of twisted lac-
tams, see: (a) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731. (b) Ly,
T.; Krout, M.; Pham, D. K.; Tani, K.; Stoltz, B. M.; Julian, R. R. J.
Am. Chem. Soc. 2007, 129, 1864. (c) Liniger, M.; VanderVelde, D.
G.; Takase, M. K.; Shahgholi, M.; Stoltz, B. M. J. Am. Chem. Soc.
2016, 138, 969.
(37) A few 1,7-diazabicyclo[4.2.1]nonane-8,9-dione derivatives are
known: (a) Akhtar, M. S.; Brouillette, W. J.; Waterhous, D. V. J. Org.
Chem. 1990, 55, 5222. (b) Brouillette, W. J.; Jestkov, V. P.; Brown,
M. L.; Akhtar, M. S.; DeLorey, T. M.; Brown, G. B. J. Med. Chem.
1994, 37, 3289. (c) Knaup, G. Ger. Offen. 2001, DE10020818.
(38) (a) Aebi, J. D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1507.
(b) Acher, F.; Azerad, R. Tetrahedron: Asymmetry 1994, 5, 731. (c)
Obrecht, D.; Bohdal, U.; Daly, J.; Lehmann, J.; Schönholzer, P.; Mül-
ler, K. Tetrahedron 1995, 51, 10883. (d) Sawamura, M.; Nakayama,
Y.; Tang, W.-M.; Ito, Y. J. Org. Chem. 1996, 61, 9090. (e) Chinchil-
la, R.; Galindo, N.; Nájera, C. Synthesis 1999, 704. (f) Abellán, T.;
Chinchilla, R.; Galindo, N.; Nájera, C.; Sansano, J. M. J. Heterocyclic
Chem. 2000, 37, 467.
(24) Hanessian, S.; Wang, X. Synlett 2009, 2803.
(25) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem. Soc. 2007,
129, 15398.
(26) Lyseng-Williamson, K. A. Drugs 2011, 71, 489.
(27) Boschi, F.; Camps, P.; Comes-Franchini, M.; Muñoz-Torrero,
D.; Ricci, A.; Sánchez, L. Tetrahedron: Asymmetry 2005, 16, 3739.
(28) (a) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S.
C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novák, Z.; Krout, M.
R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A.; White, D. E.;
Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M.
Chem. Eur. J. 2011, 17, 14199. (b) Behenna, D. C.; Liu, Y.; Yurino,
T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2012,
4, 130.
(29) Similar stereoselective Curtius rearrangements have been used
previously to prepare α-tertiary amines, isocyanates and α-quaternary
amino acids: (a) Leuser, H.; Perrone, S.; Liron, F.; Kneisel, F. F.;
Knochel, P. Angew. Chem. Int. Ed. 2005, 44, 4627. (b) Iosub, V.;
Haberl, A. R.; Leung, J.; Tang, M.; Vembaiyan, K.; Parvez, M.; Back,
T. G. J. Org. Chem. 2010, 75, 1612. (c) Banerjee, S.; Wiggins, W. J.;
Geoghegan, J. L.; Anthony, C. T.; Woltering, E. A.; Masterson, D. S.
Org. Biomol. Chem. 2013, 11, 6307.
(30) It should be noted that the isocyanates were stable to purifica-
tion by column chromatography and could be stored as solids under
high vacuum. However, upon exposure to air moisture, they decom-
posed and polymerized quickly (within hours).
(31) The major difference between the reactivity of catalyst 1b and
2 is that ruthenium hydride complex 1b is highly selective for the
isomerization of just one position to give the 2-ene product. In con-
trast, catalyst 2 is more reactive and less selective, which may lead to
over isomerization for substrates containing a proton in position 4 of
the allyl group such as for 3, 8 and 10. This difference in reactivity is
(39) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556.
(40) Knabe, J.; Omlor, G. Arch. Pharm. 1989, 322, 499.
(41) Nishio, Y.; Kimura, H.; Sawada, N.; Sugaru, E.; Horiguchi,
M.; Ono, M.; Furuta, Y.; Sakai, M.; Masui, Y.; Otani, M.; Hashizuka,
T.; Honda, Y.; Deguchi, J.; Nakagawa, T.; Nakahira, H. Bioorg. Med.
Chem. 2011, 19, 5490.
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Ru
NaIO4
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R and R’ = alkyl or H
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