Synthesis and exploration of electronically modified (R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX in palladium-catalyzed enantio- and diastereoselective allylic alkylation: a practical alternative to (R)-(p-CF3)3-t-BuPHOX

Article abstract of DOI:10.1016/j.tetlet.2015.06.039

Abstract The synthesis of the novel electronically modified phosphinooxazoline (PHOX) ligand, (R)-5,5-dimethyl-(p-CF₃)₃-i-PrPHOX, is described. The utility of this PHOX ligand is explored in both enantio- and diastereoselective palla

Full text of DOI:10.1016/j.tetlet.2015.06.039

Tetrahedron Letters 56 (2015) 4670–4673
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and exploration of electronically modified
(R)-5,5-dimethyl-(p-CF3)3-i-PrPHOX in palladium-catalyzed
enantio- and diastereoselective allylic alkylation: a practical
alternative to (R)-(p-CF3)3-t-BuPHOX
⇑
Robert A. Craig II, Brian M. Stoltz
Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,
CA 91125, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of the novel electronically modified phosphinooxazoline (PHOX) ligand, (R)-5,5-dimethyl-
(p-CF3)3-i-PrPHOX, is described. The utility of this PHOX ligand is explored in both enantio- and
diastereoselective palladium-catalyzed allylic alkylations. These investigations prove (R)-5,5-dimethyl-
(p-CF3)3-i-PrPHOX to be an effective and cost-efficient alternative to electronically modified PHOX
ligands derived from the prohibitively expensive (R)-t-leucine.
Received 27 May 2015
Accepted 10 June 2015
Available online 17 June 2015
Keywords:
Ó 2015 Elsevier Ltd. All rights reserved.
Allylic alkylation
Diastereoselective
Enantioselective
Palladium-catalyzed
Phosphinooxazoline
Introduction
enable the formation of the corresponding products with the best
enantiomeric and diastereomeric ratios. Although (R)-t-BuPHOX
Phosphinooxazoline (PHOX) ligands, developed by Helmchen,1
Williams,2 and Pfaltz,3 have proven to be a privileged ligand scaf-
fold in transition metal catalysis.4 PHOX ligands have found appli-
cation in a variety of asymmetric transition metal-catalyzed
transformations including asymmetric hydrogenation,5 azome-
thine ylide cycloadditions,6 intermolecular Heck couplings,7 and
hydrosilylation8 as well as transition metal-catalyzed allylic sub-
stitution4,9 and protonation10 reactions. Our lab has extensively
explored the utility of the PHOX ligand scaffold in the palladium-
catalyzed enantioselective allylic alkylation of carbocyclic11 and
heterocyclic12 substrates. These investigations have revealed
electronically modified PHOX ligands (i.e. (S)-(p-CF3)3-t-BuPHOX
((S)-L1), Fig. 1)13 can profoundly enhance the rate of reaction as
well as yield, enantiomeric excess (ee) and/or diastereomeric ratio
of a product containing an all-carbon quaternary center (e.g. use of
(S)-L1 vs (S)-L2 to construct lactam 2,12e cyclohexanone 4,13c
has been employed in natural product synthesis15 and explored
in transition-metal catalyzed allylic alkylations,10a,16 these
examples are quite rare considering the nearly prohibitive cost of
the
requisite starting material for
ligand synthesis,
(R)-t-leucine.17 Previously, 5,5-geminally disubstituted (R)-valine-
derived PHOX ligands (e.g. (R)-L3 and (R)-L4, Fig. 2) have been
constructed as cost-effective alternatives to (R)-t-BuPHOX
((R)-L2).18 We sought to extend this precedent to the synthesis
of electronically modified congener (R)-5,5-dimethyl-(p-CF3)3-i-
PrPHOX ((R)-(p-CF3)3-i-PrPHOXMe2, (R)-L5, Fig. 2) and explore its
efficacy as a ligand in palladium-catalyzed enantio- and diastere-
oselective allylic alkylation reactions.
Results and discussion
Synthesis of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5)
cyclohexenone 6,13b and cyclohexanone diastereomers
10,14 Schemes 1A–C and 2, respectively).
9 and
Synthesis of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) was initiated
with acid chloride 1119 and the hydrogen chloride salt of (R)-valine
derivative 1218 (Scheme 3). Intermolecular coupling of acid chlo-
ride 11 and amino alcohol 12 in the presence of excess Et3N pro-
vides amide 13 in 79% yield. Intramolecular cyclization of amide
13 under acidic conditions furnishes oxazoline 14 in 87% yield.
Most commonly, transition metal complexes employing
tert-leucinol-derived PHOX ligands (e.g. (S)-L1 and (S)-L2., Fig. 1)
⇑
Corresponding author. Tel.: +1 626 395 6064; fax: +1 626 395 8436.
E-mail address: stoltz@caltech.edu (B.M. Stoltz).
http://dx.doi.org/10.1016/j.tetlet.2015.06.039
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

R. A. Craig II, B. M. Stoltz / Tetrahedron Letters 56 (2015) 4670–4673
4671
Completion of desired ligand (R)-L5 was accomplished over two
steps, beginning with the copper-mediated coupling of phosphine
oxide 15 with bromide 14 at elevated temperature.20 This proce-
dure produces phosphine oxide 16 in 63% yield. Reduction of phos-
phine oxide 16 was subsequently accomplished in neat Ph 2SiH2 at
140 °C over 48 hours, providing the desired ligand (R)-(p-CF3)3-i-
PrPHOXMe2 ((R)-L5) in 81% yield in the final step of the synthetic
sequence.
Figure 1. Electronically modified and unmodified (S)-t-BuPHOX ligands.
A
Pd2(dba)3 (5 mol %)
O
O
O
LIGAND (12.5 mol %)
Bz
Bz
N
O
N
toluene, 40 °C
1
2
(S)-L1: 99% ee
(S)-L2: 86% ee
Stoltz, et al. REFERENCE 12(e)
B
C
O
O
Pd2(dba)3 (5 mol %)
LIGAND (12.5 mol %)
O
O
THF, 25 °C
(S)-L1: 87% ee, 99% yield, 10 min
(S)-L2: 88% ee, 96% yield, 120 min
Stoltz, et al. REFERENCE 13(c)
3
4
Cl
O
Pd(dmdba)2 (10 mol %)
LIGAND (12.5 mol %)
O
O
O
benzene
Cl
i—BuO
(S)-L1: 99% ee, 82% yield, 11 °C
(S)-L2: 81% ee, 23% yield, 24 °C
Stoltz, et al. REFERENCE 13(b)
i—BuO
5
6
Scheme 1. Comparison of electronically modified (S)-(p-CF3)3-t-BuPHOX ((S)-L1) and unmodified (S)-t-BuPHOX ((S)-L2) in intramolecular palladium-catalyzed enantios-
elective allylic alkylation.
Figure 2. 5,5-Geminally disubstituted (R)-valine-derived PHOX ligands.
CN
8
Ph
(1.0 equiv)
CN
O
O
O
Ph
O
Ph
Pd2(dba)3 (5 mol %)
LIGAND (12.5 mol %)
+
O
NC CN
NC CN
p-dioxane, 40 °C, 48 h
7
9
10
87% ee
63% ee
77% ee
42% ee
(S)-L1: 6.1:1 d.r., 91% yield
(S)-L2: 3.1:1 d.r., 82% yield
Stoltz, et al. REFERENCE 14
Scheme 2. Comparison of electronically modified (S)-(p-CF3)3-t-BuPHOX ((S)-L1) and unmodified (S)-t-BuPHOX ((S)-L2) in diastereoselective decarboxylative alkylation
cascade.

4672
R. A. Craig II, B. M. Stoltz / Tetrahedron Letters 56 (2015) 4670–4673
Scheme 3. Synthesis of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5).
Use of (R)-(p-CF3)3-i-PrPHOXMe2 in palladium-catalyzed
asymmetric transformations
Application of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) was initially
explored in the intermolecular palladium-catalyzed enantioselec-
tive allylic alkylation of silyl enol ether 17 with mesylate 18
(Scheme 4). Previously we disclosed the initial development and
optimization of this transformation using (S)-t-BuPHOX ((S)-L2),
which afforded chloroallylketone (S)-19 in 82% yield and 92% ee
(entry 1).12d Substitution of (S)-L2 with the electronically
modified (S)-(p-CF3)3-t-BuPHOX ((S)-L1) provided the product
((S)-19) in a slightly diminished 91% ee (entry 2). Switching the
ligand
to
(S)-5,5-diphenyl-i-PrPHOX
((S)-L3)
furnished
chloroallylketone (S)-19 in 90% ee (entry 3). Moving into the
opposite enantiomeric series, the use of (R)-5,5-dimethyl-i-
PrPHOX ((R)-L4) provided chloroallylketone (R)-19 in
a
somewhat diminished 89% ee (entry 4) compared to the
originally optimized reaction conditions (entry 1). Alternatively,
we were pleased to find that (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5)
afforded chloroallylketone (R)-19 in the same 91% ee (entry 5) in
the opposite enantiomeric series compared to the use of (S)-(p-
CF3)3-t-BuPHOX (entry 2). It is noteworthy that the required
reaction time (20 h) and isolated yield (80-82%) of
chloroallylketone 19 were independent of the ligand employed.
Thus, (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) can allow access to the
enantiomeric series of products to those afforded in reactions
employing (S)-L1 without any loss in product ee in a cost-
effective manner, being derived from (R)-valine, which is less
than 2% of the cost of (R)-t-leucine.
Scheme 4. Ligand comparison in enantioselective palladium-catalyzed intermolec-
ular allylic alkylation.
inherent selectivity for the formation of diastereomer 22 in a 2:1
ratio with diastereomer 23 when achiral PHOX ligand L6 was
employed (entry 1),21 the use of (S)-t-BuPHOX ((S)-L2) can override
this substrate bias, providing diastereomer 23 as the major product
(entry 2). Comparatively, the use of (R)-t-BuPHOX ((R)-L2) rein-
forces the inherent selectivity, providing diastereomer 22 in a
12:1 ratio with minor diastereomer 23 in a combined 73% yield
(entry 3). Pleasingly, the employment of (R)-(p-CF3)3-i-
PrPHOXMe2 ((R)-L5) further improved this transformation, furnish-
ing an 18:1 mixture of products in favor of diastereomer 22 in an
improved 85% combined yield (entry 4). These studies revealed
that (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) was the optimal ligand for
the highly diastereoselective formation of allylic alkylation product
The utility of (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5) was further
demonstrated in the intermolecular palladium-catalyzed diastere-
oselective decarboxylative allylic alkylation of b-ketoester 20 with
allyl electrophile 21 (Scheme 5).16a While the system displays an

R. A. Craig II, B. M. Stoltz / Tetrahedron Letters 56 (2015) 4670–4673
4673
21
OCO2Me
O
Ph
O
Ph
O
Ph
(1.2 equiv)
TBAT
+
CO2CH2CH2TMS
Pd2(dba)3 (5 mol %)
LIGAND (12.5 mol %)
THF, 25 °C
>99% ee
20
22
23
a
b
Entry Ligand
% yield
dr (22 :23)
1
2
3
4
79
79
73
85
2:1
1:2
12:1
18:1
L6
O
(S)-L2
(R)-L2
(R)-L5
N
Ph2P
L6
a Isolated yield of 22 and 23 b Determined by
.
1H NMR analysis of the crude reaction mixture
and analytical GC analysis
Scheme 5. Diastereoselective decarboxylative allylic alkylation employing (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-L5).
8. (a) Frölander, A.; Moberg, C. Org. Lett. 2007, 9, 1371–1374; (b) Sudo, A.;
Yoshida, H.; Saigo, K. Tetrahedron: Asymmetry 1997, 8, 3205–3208.
9. (a) Liu, Y.; Liniger, M.; McFadden, R. M.; Roizen, J. L.; Malette, J.; Reeves, C. M.;
Behenna, D. C.; Seto, M.; Kim, J.; Mohr, J. T.; Virgil, S. C.; Stoltz, B. M. Beilstein J.
Org. Chem. 2014, 10, 2501–2512; (b) 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., Jr.; White, D. E.; Levine, S. R.;
Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. Eur. J. 2011, 17,
14199–14223; (c) García-Yebra, C.; Janssen, J. P.; Rominger, F.; Helmchen, G.
Organometallics 2004, 23, 5459–5470.
10. (a) Doran, R.; Carroll, M. P.; Akula, R.; Hogan, B. F.; Martins, M.; Fanning, S.;
Guiry, P. J. Chem. Eur. J. 2014, 20, 15354–15359; (b) Carroll, M. P.; Müller-Bunz,
H.; Guiry, P. J. Chem. Commun. 2012, 11142–11144; (c) Marinescu, S. C.;
Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039–1042; (d) Mohr,
J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128,
11348–11349.
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137, 1040–1043; (b) Reeves, C. M.; Behenna, D. C.; Stoltz, B. M. Org. Lett. 2014,
16, 2314–2317; (c) Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2013, 52, 6718–6721; (d) Enquist, J. A., Jr.; Stoltz, B. M. Nature
2008, 453, 1228–1231; (e) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B.
M. Angew. Chem., Int. Ed. 2005, 44, 6924–6927; (f) Behenna, D. C.; Stoltz, B. M. J.
Am. Chem. Soc. 2004, 126, 15044–15045.
22. Additionally, other research groups have found (R)-(p-CF3)3-i-
PrPHOXMe2 ((R)-L5) to be a uniquely effective ligand for the
palladium-catalyzed diastereoselective allylic alkylation of other
carbocyclic substrates.22
Conclusion
Herein, we have disclosed the synthesis of a new, electronically
modified phosphinooxazoline (PHOX) ligand, (R)-5,5-dimethyl-(p-
CF3)3-i-PrPHOX ((R)-(p-CF3)3-i-PrPHOXMe2, (R)-L5). Derived from
(R)-valine, this cost-effective alternative to (R)-(p-CF3)3-t-BuPHOX
((R)-L1) has proved effective in both palladium-catalyzed enantio-
and diastereoselective allylic alkylations, furnishing the alkylation
products in comparable ee and improved diastereomeric ratio.
Efforts to further explore the utility of the readily available (R)-
(p-CF3)3-i-PrPHOXMe2 ligand in palladium-catalyzed stereoselec-
tive transformations are currently underway.
12. (a) Numajiri, Y.; Jiménez-Osés, G.; Wang, B.; Houk, K. N.; Stoltz, B. M. Org. Lett.
2015, 17, 1082–1085; (b) Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.;
Horne, D.; Stoltz, B. M. Angew. Chem., Int. Ed. 2015, 54, 179–183; (c) Bennett, N.
B.; Duquette, D. C.; Kim, J.; Liu, W.-B.; Marziale, A. N.; Behenna, D. C.; Virgil, S.
C.; Stoltz, B. M. Chem. Eur. J. 2013, 19, 4414–4418; (d) Craig, R. A., II; Roizen, J.
L.; Smith, R. C.; Jones, A. C.; Stoltz, B. M. Org. Lett. 2012, 14, 5716–5719; (e)
Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M.
Nat. Chem. 2012, 4, 130–133; (f) Seto, M.; Roizen, J. L.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2008, 47, 6873–6876.
13. (a) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M.
Tetrahedron Lett. 2010, 51, 5550–5554; (b) White, D. E.; Stewart, I. C.; Grubbs,
R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 810–811; (c) Tani, K.; Behenna, D.
C.; McFadden, R. M.; Stoltz, B. M. Org. Lett. 2007, 9, 2529–2531.
Acknowledgements
The authors wish to thank the NIH-NIGMS (R01GM080269),
Amgen, the Gordon and Betty Moore Foundation, and Caltech for
financial support. R.A.C. gratefully acknowledges the support of
this work provided by a fellowship from the National Cancer
Institute of the National Institutes of Health under Award
Number F31A17435.
14. Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nat. Chem. 2010, 2, 192–196.
15. (a) Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2011, 50, 6814–6818; (b) Levine, S. R.; Krout, M. R.; Stoltz,
B. M. Org. Lett. 2009, 11, 289–292; (c) Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org.
Lett. 2009, 11, 293–295.
16. (a) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135,
10626–10629; (b) Fang, X.; Johannsen, M.; Yao, S.; Gathergood, N.; Hazell, R.
G.; Jørgensen, K. A. J. Org. Chem. 1999, 64, 4844–4849.
17. The cost of (R)-t-leucine ranges between $350 and $400 per gram, depending
on the size of the order from Sigma-Aldrich, as advertised on their
sigmaaldrich.com, accessed 30 April, 2015. The synthesis of t-BuPHOX
ligands, however, can be accomplished with ease on large scale, see: Mohr, J.
T.; Krout, M. R.; Stoltz, B. M. Org. Synth. 2009, 86, 194–211.
18. (a) Bélanger, É.; Pouliot, M.-F.; Courtemanche, M.-A.; Paquin, J.-F. J. Org. Chem.
2012, 77, 317–331; (b) Bélanger, É.; Pouliot, M.-F.; Paquin, J.-F. Org. Lett. 2009,
11, 2201–2204.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.
039.
References and notes
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19. Acid chloride 11 was synthesized in two steps from 2-bromo-5-
(trifluoromethyl)benzonitrile by a known procedure, see: Ref. 13b.
20. The procedure for the coupling of phosphine oxide 15 with oxazoline 14 and
sequential reduction was adapted from Ref. 13a.
21. Control experiments were performed using achiral PHOX ligand L6, bearing no
substituent on the oxazoline ring, see Ref. 16a for full details.
6. Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431–1436.
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