as DOE (design of experiments) are powerful
tools for synthesis ( 30–32), yet they typically
focus on performing minimal numbers of experiments, as large numbers of experiments are
often resource- and time-intensive to conduct.
However, because large numbers of experiments
are readily feasible with this nanomole-scale chemistry platform, we were able to construct a three-factorial, four-level response surface modeling
experiment to study the loading of catalyst against
varying stoichiometries of base and nucleophile
in the reaction of chloride 6 with amine 10. In this
DOE experiment, each condition was repeated
twice, resulting in 128 total reactions with < 3 mg
of 6. Indeed, a high-quality response surface
model was generated with the nanomole-scale
chemistry approach (Fig. 2D), which helped to
define the critical charges of nucleophile and
base for optimal reaction performance. The optimized conditions used 15 mol 42 at 0.05 M
concentration; by translating to more practical
conditions of 5 mol 42 and 0.24 M concentration, we obtained full conversion and a 79%
isolated yield of 46 on a 25-mg scale, which was
reproduced to obtain a 76% isolated yield on a 1-g
scale (Fig. 2D). This result shows that advanced
statistical reaction analysis, which is typically
reserved for chemistry opportunities where material is plentiful, can be applied to reactions in the
material-limited front lines of drug discovery or
natural product synthesis.
In biomedical research, chemical synthesis
should not limit access to any molecule that is
designed to answer a biological question. This
work demonstrates an example of how conditions
for complex Pd-catalyzed C-O, C-N, and C-C cross-coupling reactions can be evolved into a powerful,
substrate-focused approach to chemistry miniaturization to overcome limited access to complex
products. With innovative research, other high-value modern chemistry reactions could be similarly designed into this paradigm to improve
synthesis in material-limited environments by
evolution of catalysts and reagents to perform
in DMSO, NMP, or other high-boiling solvents
at ambient temperature.
REFERENCES AND NOTES
1. M. R. Friedfeld et al., Science 342, 1076–1080 (2013).
2. D. A. DiRocco et al., Angew. Chem. Int. Ed. 53, 4802–4806
3. D. W. Robbins, J. F. Hartwig, Science 333, 1423–1427 (2011).
4. A. McNally, C. K. Prier, D. W. C. MacMillan, Science 334,
5. K. D. Collins, T. Gensch, F. Glorius, Nat. Chem. 6, 859–871 (2014).
6. R. Moreira, M. Havranek, D. Sames, J. Am. Chem. Soc. 123,
7. S. M. Preshlock et al., J. Am. Chem. Soc. 135, 7572–7582 (2013).
8. A. Bellomo et al., Angew. Chem. Int. Ed. 51, 6912–6915
9. J. R. Schmink, A. Bellomo, S. Berritt, Aldrichim. Acta 46, 71–80
10. M. Peplow, Nature 512, 20–22 (2014).
11. T. Rodrigues, P. Schneider, G. Schneider, Angew. Chem. Int. Ed.
53, 5750–5758 (2014).
12. S. Monfette, J. M. Blacquiere, D. E. Fogg, Organometallics 30,
13. P. M. Murray, S. N. G. Tyler, J. D. Moseley, Org. Process Res.
Dev. 17, 40–46 (2013).
14. S. D. Roughley, A. M. Jordan, J. Med. Chem. 54, 3451–3479 (2011).
15. T. W. J. Cooper, I. B. Campbell, S. J. F. Macdonald, Angew.
Chem. Int. Ed. 49, 8082–8091 (2010).
16. A. Nadin, C. Hattotuwagama, I. Churcher, Angew. Chem. Int. Ed.
51, 1114–1122 (2012).
17. Merck internal study of electronic notebooks.
18. M. M. Hann, G. M. Keserü, Nat. Rev. Drug Discov. 11, 355–365
19. F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 52,
20. H. A. Malik et al., Chem. Sci. 5, 2352–2361 (2014).
21. R. E. Tundel, K. W. Anderson, S. L. Buchwald, J. Org. Chem. 71,
22. D. S. Surry, S. L. Buchwald, Chem. Sci. 2, 27− 50 (2011).
23. N. C. Bruno, M. T. Tudge, S. L. Buchwald, Chem. Sci. 4,
24. T. Ishikawa, Y. Kondo, H. Kotsuki, T. Kumamoto, D. Margetic,
K. Nagasawa, W. Nakanishi, in Superbases for Organic
Synthesis: Guanidines, Amidines, Phosphazenes and Related
Organocatalysts, T. Ishikawa, Ed. (Wiley, West Sussex, UK, ed.
1, 2009), pp. 1–326.
25. Compounds were generally purified by MS-directed
purification. Isolated yields ranged from 1 to 100%, but we
made no attempt to maximize the isolated yields in these
reactions and instead focused on obtaining high-purity
compounds as quickly as possible, which is typical in most
medicinal chemistry campaigns. Some reactions showed
product formation by UPLC-MS analysis but were either
insufficiently pure or too low in yield for purification.
26. M. Liu et al., ACS Comb. Sci. 14, 51–59 (2012).
27. Some electrophiles were not fully soluble in DMSO, so NMP
was used instead. Even though three stock solutions in NMP
still displayed mild insolubility, the TTP Mosquito operates on
positive-displacement pipetting, so viscous solutions or
suspensions of small particulates are easily transferred.
28. W. Schafer, X. Bu, X. Gong, L. A. Joyce, C. J. Welch, in
Comprehensive Organic Synthesis, C. J. Welch, Ed. (Elsevier,
Oxford, ed. 2, 2014), vol. 9, pp. 28−53.
29. C. J. Welch et al., Tetrahedron Asymmetry 21, 1674–1681 (2010).
30. J. C. Ianni, V. Annamalai, P.-W. Phuan, M. Panda, M. C. Kozlowski,
Angew. Chem. Int. Ed. 45, 5502–5505 (2006).
31. S. E. Denmark, C. R. Butler, J. Am. Chem. Soc. 130, 3690–3704
32. K. C. Harper, M. S. Sigman, Science 333, 1875–1878 (2011).
We thank S. Krska, M. Tudge, G. Hughes, and E. Parmee for helpful
discussions; M. Liu, E. Streckfuss, T. Meng, N. Pissarniski, and
W. Li for assistance in purification of compounds; M. Christensen
and J. Voigt for experimental assistance; and S. M. O’Brien and
M. McColgan for graphic design. S.B. was supported by an NSF
GOALI Grant associated with the University of Pennsylvania.
Supported by the MRL Postdoctoral Research Fellows Program
(A.B.S. and E.L.R.).
Materials and Methods
Figs. S1 to S32
Tables S1 to S11
References ( 33–40)
Data Files S1 to S5
25 July 2014; accepted 11 November 2014
Published online 20 November 2014;
Quantum harmonic oscillator state
synthesis by reservoir engineering
D. Kienzler,* H.-Y. Lo, B. Keitch, L. de Clercq, F. Leupold, F. Lindenfelser,
M. Marinelli, V. Negnevitsky, J. P. Home*
The robust generation of quantum states in the presence of decoherence is a primary
challenge for explorations of quantum mechanics at larger scales. Using the mechanical motion
of a single trapped ion, we utilize reservoir engineering to generate squeezed, coherent, and
displaced-squeezed states as steady states in the presence of noise. We verify the created state
by generating two-state correlated spin-motion Rabi oscillations, resulting in high-contrast
measurements. For both cooling and measurement, we use spin-oscillator couplings that
provide transitions between oscillator states in an engineered Fock state basis. Our approach
should facilitate studies of entanglement, quantum computation, and open-system quantum
simulations in a wide range of physical systems.
Reservoir engineering is a method in which specially designed couplings between a sys- tem of interest and a zero-temperature nvironment can be used to generate quan- tum superposition states of the system as
the steady state of the dissipative process, independent of the initial state of the system (1– 3).
Theoretical work has shown the potential for
using such engineered dissipation for univer-
sal quantum computation ( 4) and in providing
new routes to many-body states ( 5–7). Experi-
mentally, these techniques have been used to
generate entangled superposition states of qubits
in atomic ensembles ( 8), trapped ions ( 9, 10), and
superconducting circuits ( 11). Theoretical proposals
for quantum harmonic oscillator state synthesis
by reservoir engineering extend from trapped
ions (2, 3) to superconducting cavities ( 12, 13)
and nanomechanics ( 14).
Here, we experimentally demonstrate the generation and stabilization of quantum harmonic
oscillator states by reservoir engineering based
on the original proposal of Cirac et al. (1), which
we use to generate and stabilize squeezed,
SCIENCE sciencemag.org 2 JANUARY 2015 • VOL 347 ISSUE 6217 53
Institute for Quantum Electronics, ETH Zürich, Otto-Stern-Weg 1,
8093 Zürich, Switzerland.
*Corresponding author. E-mail: firstname.lastname@example.org
(D.K.); email@example.com (J.P.H.)