Rhodium/Yanphos-Catalyzed Asymmetric Interrupted Intramolecular Hydroaminomethylation of trans-1,2-Disubstituted Alkenes

Article abstract of DOI:10.1021/jacs.6b03596

The first interrupted asymmetric hydroaminomethylation reaction was developed. The challenging trans-1,2-disubstituted olefins were employed as substrates, and a series of valuable chiral pyrrolidinones and pyrrolidines were obtained in high yields with high regioselectivities and excellent enantioselectivities. Several synthetic transformations were conducted, demonstrating the high synthetic utility of our method. A creative route for the synthesis of vernakalant and Enablex was also developed.

Full text of DOI:10.1021/jacs.6b03596

Subscriber access provided by University of Sussex Library
Communication
Rhodium/Yanphos-catalyzed Asymmetric Interrupted Intramolecular
Hydroaminomethylation of Trans-1, 2-disubstituted Alkenes
Caiyou Chen, Shicheng Jin, Zhefan Zhang, Biao Wei, Heng
Wang, Kai Zhang, Hui Lv, Xiu-Qin Dong, and Xumu Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Jul 2016
Downloaded from http://pubs.acs.org on July 7, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 6
Journal of the American Chemical Society
Rhodium/Yanphos-Catalyzed Asymmetric Interrupted Intramolecular
Hydroaminomethylation of Trans-1, 2-disubstituted Alkenes
1
2
3
4
5
6
7
Caiyou Chen, Shicheng Jin, Zhefan Zhang, Biao Wei, Heng Wang, Kai Zhang, Hui Lv,* Xiu-Qin Dong,*
and Xumu Zhang*
College of Chemistry and Molecular Sciences, Wuhan University, 430072, Wuhan, (P. R. China).
8
9
by interrupting the reaction through stabilization of the chi-
ral hemiacetal intermediate leaving the chiral carbon un-
touched. And importantly, the one-pot work-up using oxi-
dant or reductant will generate the valuable chiral amides or
amines (Scheme 1b).
ABSTRACT: The first interrupted asymmetric HAM reaction
was developed. The challenging trans-1, 2-disubstituted ole-
fins were employed as substrates and a series of valuable
chiral pyrrolidinones and pyrrolidines were obtained in high
yields, high regioslectivities and excellent ee. Several synthet-
ic transformations were conducted, demonstrating the high
synthetic utility of our method. A creative route for the syn-
thesis of Vernakalant and Enablex was also developed.
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
Since the first discovery by Reppe et al. at BASF in the
early 1950s,1 hydroaminomethylation (HAM) has been one of
the most efficient reactions to synthesize the valuable amines
with important biological and medicinal properties for the
construction of drugs and fine chemicals from readily
available alkenes and amines in the presence of syngas with
high atom economy.2 A typical HAM reaction includes the
hydroformylation of an alkene, the subsequent condensation
of the aldehyde with the amine, and the final hydrogenation
of the resulting imine or enamine to give the desired amine
with one carbon elongation (Scheme 1a). In that respect,
linear HAM is widely explored and recent progress has been
summarized in several reviews.3
Scheme 2. Interrupted HAM of 3-substituted allylamines with the
potential chiral ligands and the hydroformylation of 1, 2-
disubstituted olefins.
With regard to the stabilization of the intermediate, we
perceived that the cyclic five member ring hemiacetal is very
stable6 which makes the interrupted asymmetric HAM to be
possible in an intramolecular version by using the protected
3-substituted allylamine as substrate utilizing our previously
7
developed Yanphos or the steric bulky ligand L18 (Scheme
2a). As mentioned above, the five member ring hemiacetal
intermediate can be easily converted to the valuable pyrroli-
dinones and pyrrolidines which are common motifs in many
top 200 brand name drugs and natural products, such as top
drugs Vernakalant,9 Enablex,10 Merrem,11 Relpax12 and natural
Scheme 1. The widely explored HAM reaction and the new inter-
rupted asymmetric HAM reaction.
13
products Salinosporamide A, Lactacystin (Scheme 3). As a
result, the interrupted asymmetric HAM of protected 3-
substituted allylamine will be highly desirable. However, the
first step of the asymmetric HAM of the protected 3-
substituted allylamines, the asymmetric hydroformylation of
1, 2-disubstituted olefins, remains a very challenging prob-
lem.14 Up to now, only a few examples were reported.15
Among these examples, the asymmetric hydroformylation of
the cis-1,2-disubstituted olefins were realized with good regi-
oselectivities and enantioselectivities.15a-b, 15f, However, with
respect to the hydroformylation of the readily available
trans-1,2-disubstituted olefins, it was shown to be much
more challenging and generally lower reactivities and enan-
With respect to the asymmetric HAM, unavoidable race-
mization of the chiral iminium often occurs through the fast
isomerization to the non-chiral enamine (Scheme 1a). Con-
sequently, very rare work was reported in terms of the
asymmetric HAM.4 Recently, Kalck et al. tried the rhodium
complex with chiral diphosphine ligands catalyzed asymmet-
ric HAM.4a However, only racemic amine was obtained. The
results were explained by the detailed computational study
which revealed that the hydrogenation of the imine interme-
diate follows the similar energetic pathway regardless of the
chiral ligands used.4a Owing to our long-term interest in
HAM,5 we envision that the chiral product can be obtained
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
tioselectivities were observed (Scheme 2b).15b, 15f Herein, we
strate. These results indicated that the protecting group on
1
2
3
4
5
6
report the first rhodium (N-Bn)-Yanphos (Scheme 2a) cata-
lyzed interrupted asymmetric HAM of the very challenging
substrates, trans-1,2-disubstuted olefins, to afford the valua-
ble chiral pyrrolidinones and pyrrolidines in one-pot with
excellent regio- (>99:1) and enantioselectivities (up to 96%
ee).
the amine moiety was very critical to the reaction and only
the electron-withdrawing groups give the desired products.
Ts group was selected as the best in terms of the high enan-
tioselectivity.
Table 1. Screening of the conditions for the one-pot interrupted
asymmetric HAM to afford chiral pyrrolidinone a
7
8
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
Entry Rb
L/Rh CO/H2 Temp. Iso.
Ee%d
(bar)
Yield%c
(°C)
1
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
2.0
1.5
10:10
10:10
10:10
5:5
70
70
70
70
70
80
60
70
70
70
70
70
70
70
93 (3)
95 (3)
98 (3)
41 (3)
93
84
12
95
10
90
94
94
93
-
2
3
1.1
4
2.0
2.0
2.0
2.0
2.0
2.0
2.0
5e
20:20
10:10
10:10
10:10
10:10
10:10
10:10
10:10
10:10
10:10
66 (3)
97 (3)
57 (3)
77 (3)
81 (3)
Scheme 3. Representative top 200 brand name drugs and natural
products featuring the pyrrolidine and pyrrolidinone motifs.
6
The reaction was initiated by investigating the one-pot
method for the preparation of chiral pyrrolidinones. We were
pleased to find that the one-pot reaction proceeded smoothly
by adding PCC (pyridinium chlorochromate)/NaOAc to the
reaction system once the hydroformylation reaction stopped
with high yield and excellent regioselectivity (for the screeing
of oxidants, see supporting information). In the presence of
Rh/Yanphos, the reaction only took place in the  position
with the desired chiral pyrrolidinone 3a obtained exclusively
in 93% ee (Table 1, entry 1). The effects of reaction conditions
on the one-pot interrupted asymmetric HAM were subse-
quently investigated. As shown in table 1, lowering of the
L/Rh ratio gave higher yield, on the contrast of which, the ee
dropped significantly (Table 1, entries 1-3). The yield dropped
sharply by lowering the syngas pressure although slightly
higher ee was observed (Table 1, entry 4). Increasing of the
syngas pressure to 20:20 bar gave rise to the presence of the
dehydrated product in 30% yield and moreover, the ee
dropped sharply (Table 1, entry 5). Increasing of the tempera-
ture gave higher yield but lower ee while lowering of the
temperature, on the contrast, gave lower yield but slightly
higher ee (Table 1, entries 6-7). It was also found that shorter
reaction time and lower catalyst loading gave lower yield
while the ee almost remained the same (Table 1, entries 8-9).
The steric bulky ligand L1 (Scheme 2) was also tested (for the
screening of other ligands, see supporting information),
however, only the dehydrated product was obtained (Table 1,
entry 10). We further investigated the effect of the substitu-
ents on the amine moiety. It was found that no desired prod-
uct was observed by changing the Ts group into the Ts(OMe)
group (Table 1, entry 11). Instead, the hemiacetal intermedi-
ate dehydrated and was further oxidized by PCC to give a
new aldehyde (See supporting information). With the elec-
tron-donating benzyl group attached to the substrate, the
7
8f
9g
10h
11i
12j
13
14
85 (10)
89 (10)
94 (10)
90 (3)
86 (3)
Ts(OMe) 2.0
-
Bn
Boc
Bz
2.0
2.0
2.0
-
41
56
a The reaction was conducted in 0.1 mmol scale in 0.5 mL of toluene,
Rhacac(CO)2 (acac = acetylacetone) was used as metal precursor, (S,
R)-(N-Bn)-Yanphos as ligand, S/C = 20, reaction time = 70 h, PCC =
0.2 mmol, NaOAc = 0.2 mmol. Ts = 4-methylbenzenesulfonyl,
Ts(OMe) = 4-methoxybenzenesulfonyl, Bn = benzyl, Boc = t-butyl
b
c
oxide carbonyl, Bz =benzoyl. Isolated yield of the chiral pyrroli-
d
dinones. Enantiomeric excess of the product, determined by chiral
HPLC. e The dehydrated product was isolated in 30% yield. f Reaction
time = 48 h; g S/C = 50. h L1 was used as ligand, only the dehydrated
product was obtained in 85% yield without using the oxidant
i
PCC/NaOAc. Only the new aldehyde product was obtained in 89%
yield. j Only the dehydrated product was obtained in 94% yield
without using the oxidant PCC/NaOAc.
With the optimized reaction conditions in hand, substrate
scope of the one-pot asymmetric HAM to afford chiral pyr-
rolindinones was simultaneously investigated. As summa-
rized in table 2, a series of chiral pyrrolidinones were ob-
tained in high yields and excellent ee (For all the products, ee
was higher than 90%). It was found that, electron-donating
groups on the benzene ring tended to deactivate the sub-
strates affording lower isolated yields, however, the ee re-
mained very high (Table 2, 3a-3c). On the contrast, with the
electron-withdrawing groups attached to the benzene ring,
the substrate was activated and shorter reaction time was
needed while the ee was not influenced (Table 2, 3d-3h). For
example, when the trifluoromethyl group or three fluorine
atoms were attached to the substrates, only 36 h was needed
for full conversion (Table 2, 3g, 3h). Interestingly, the
dehydrated product was obtained exclusively in high yield
5e
(Table 1, entry 12)
. It is only when the electron-
withdrawing Boc or Bz group attached to the substrate that
the desired chiral pyrrolidinones formed (Table 2, entries 13-
14). However, the ee dropped significantly, which is probably
due to the fast racemization of the hemiacetal product when
the strong electron-withdrawing group attached to the sub-
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
thienyl, furyl, and naphthyl substrates were also tolerated
ble 3, 4a-4e), electron-withdrawing (Table 3, 4f-4k), hetero-
1
2
3
4
5
6
7
8
and the corresponding valuable products 3i, 3j and 3k were
obtained in very high yields and excellent ee. Importantly,
the cis-configured acetoxy substrate 2l was also smoothly
converted with much lower catalyst loading and much short-
er reaction time, giving the product 3l in very high yield and
ee. Furthermore, 3-propyl allylic amine was also employed as
the substrate. To our delight, the desired chiral pyrrolidinone
product 30 was obtained in good yield albeit with the for-
mation of the aldehyde product 3p. It is notable that, in all
cases, the reaction proceeded in very high regioselectivity
with only the desired regio-isomer observed as determined
by NMR analysis, demonstrating the high efficiency of our
catalytic system.
cyclic (Table 3, 4l, 4m) or naphthyl (Table 3, 4n). However,
when the 1-substituted naphthalene was employed as the
substrate, lower yield and ee were observed (Table 3, 4o),
which is probably due to the ortho steric hindrance of the
substituted ring. Interestingly, the reaction also tolerated the
homoallylic amines giving the chiral piperidine product 4p in
good yield and ee. As aforementioned, electron-donating
groups on the substrate gave lower reaction rate and elec-
tron-withdrawing groups gave higher reaction rate requiring
much shorter reaction time. It is noteworthy that, the ee
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
Table 3. Substrate scope of the preparation of chiral pyrrolidines
through the interrupted asymmetric HAM a
Table 2. Substrate scope of the preparation of chiral pyrrolidinones
through the interrupted asymmetric HAMa
a The reaction was conducted in 0.1 mmol scale in 0.5 mL of toluene,
Rhacac(CO)2 (acac = acetylacetone) as metal precursor, (S, R)-(N-
Bn)-Yanphos as ligand, CO/H2 = 10:10 bar, S/C = 20, PCC = 0.2 mmol,
NaOAc = 0.2 mmol, the configuration of all the products was deter-
mined as (S), only the desired regio-isomer was obtained as deter-
mined by NMR analysis. b The cis configured substrate was used, S/C
= 100.
a The reaction was conducted in 0.1 mmol scale in 0.5 mL of toluene,
Rhacac(CO)2 (acac = acetylacetone) as metal precursor, (S, R)-(N-
Bn)-Yanphos as ligand, CO/H2 = 10:10 bar, S/C = 20, HSiEt3 = 0.3
mmol, BF3·Et2O = 0.3 mmol, the configuration of all the products
was determined as (S) except 4m and 4o, only the desired regio-
isomer was obtained as determined by NMR analysis.
With regard to the preparation of the chiral pyrrolidines,
the one-pot method was also developed simply by adding
HSiEt3 and BF3·Et2O to the reaction system under low tem-
perature (-10 °C) when the hydroformylation reaction
stopped without isolation of the hemiacetal intermediate.
The substrate scope for the preparation of the chiral pyrroli-
dines through the interrupted asymmetric HAM was also
investigated. Due to the common feature of chiral pyrroli-
dines in many drug structures, apart from the representative
substrates in table 2, some other substrates were also tested.
As summarized in table 3, the one-pot interrupted HAM
method to afford chiral pyrrolidines has a broad substrate
scope. A series of chiral pyrrolidines was obtained in very
high yields and excellent ee (>90%), regardless of the sub-
stituents on the pyrrolidine ring were electron-donating (Ta-
obtained in the preparation of the chiral pyrrolidines was
generally higher than that obtained in the preparation of the
chiral pyrrolidinones when strong electron-withdrawing
groups were attached to the substrates. This is probably due
to the slow racemization of the chiral pyrrolidinones. Similar
to the preparation of the chiral pyrrolidinones, for all the
substrates tested in table 3, only one regio-isomer was ob-
served as determined by NMR analysis. Moreover, in order to
determine the absolute configuration of the products, X-ray
analysis of 4g was conducted and the configuration was de-
termined as (S). 16
In order to further demonstrate the synthetic utility of the
interrupted asymmetric HAM, several transformations were
conducted as summarized in scheme 4. Interestingly, we
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
found that the ee remained the same regardless of whether
whether the substrate is cis or trans. Several synthetic
1
2
3
4
5
6
7
8
the substrate is cis or cis/trans mixture, which makes the
method to be very convenient without the tedious isolation
of the cis/trans mixture (Scheme 4a). The interrupted asym-
metric HAM reaction was also conducted on gram scale with
lower catalyst loading (Scheme 4b). Satisfyingly, we found
that the hemiacetal 5 was very stable and was isolated in high
yield and excellent regio- and enantioselectivity albeit with
low dr ratio. The hemiacetal 5 was subsequently treated with
indole or allyltrimethylsilane in the presence of BF3·Et2O. It
was found that the desired products 6 and 7 were obtained in
high yields without losing any ee (Scheme 4c). Importantly,
very high d.r. value was observed when 2a was treated with
indole. Moreover, the chiral pyrrolidine 4a was deprotected
efficiently in high yield without losing any ee (Scheme 4d).
transformations were conducted, demonstrating the high
synthetic utility of the current reaction. A creative route for
the synthesis of Venakalant and Enablex was also developed.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and compound characterization
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
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
AUTHOR INFORMATION
Corresponding Author
xumu@whu.edu.cn; xiuqindong@whu.edu.cn;
huilv@whu.edu.cn
ACKNOWLEDGMENT
We thank the grant from Wuhan University (203273463,
203410100064), and “111” Project of the Ministry of Education
of China for financial support and the National Natural Sci-
ence Foundation of China (Grant No. 21372179, 21402145,
21432007, 21502145). We also thank Prof. Wenjun Tang at
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences for the kind suggestions.
REFERENCES
(1) Reppe W, Vetter H. Liebigs Ann Chem, 1953, 582, 133-161.
(2) (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2009, 26, 170−237; (b) Blunt, J. W.;
Copp, B. R.; Keyzers, R. A.; Munro, M. H. G.; Prinsep, M. R. Nat. Prod.
Rep. 2012, 29, 144−122.
(3) (a) Eilbracht, P.; Barfacker, L.; Buss, C.; Hollmann, C.; Kitsos-
Rzychon, B. E.; Kranemann, C. L.; Rische, T.; Roggenbuck, R.;
Schmidt, A. Chem. Rev. 1999, 99, 3329−3365. (b) Eilbracht, P.,
Schmidt, A. M. In Transition Metals for Organic Synthesis, 2nd ed.;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 1, pp 57−85. (c) Eilbracht, P.; Schmidt, A. M. Top. Organomet.
Chem. 2006, 18, 65−95. (d) Crozet, D.; Urrutigoïty, M.; Kalck, P.
ChemCatChem 2011, 3, 1102−1118.
(4) (a) Crozet D.; Kefalidis C E.; Urrutigoïty M.; Maron L.; Kalck P.;
ACS Catal, 2014, 4, 435; (b) Noonan G M.; Newton D.; Cobley C J.;
Suárez A.; Pizzano A.; Clarke M L. Adv Synth Catal, 2010, 352, 1047-
1054.
(5) (a) Li, S.; Huang, K.; Zhang, J.; Wu, W.; Zhang, X. Org. Lett. 2013,
15, 1036-1039; (b) Liu, G.; Huang, K.; Cai, C.; Cao, B.; Chang, M.; Wu,
W.; Zhang, X. Chem. - Eur. J. 2011, 17, 14559-14563; (c) Liu, G.; Huang,
K.; Cao, B.; Chang, M.; Li, S.; Yu, S.; Zhou, L.; Wu, W.; Zhang, X. Org.
Lett. 2012, 14, 102-105; (d) Li, S.; Huang, K.; Zhang, J.; Wu, W.; Zhang,
X. Org. Lett. 2013, 15, 3078-3081; (e) Zheng, X.; Cao, B.; Zhang, X.
Tetrahedron Lett. 2014, 55, 4489-4491.
(6) Boal, B. W.; Schammel, A. W.; Garg, N. K. Org Lett 2009, 11, 3458-
3461.
(7) Yan, Y.; Zhang, X. J. Am. Chem. Soc., 2006, 128, 7198–7202.
(8) Xu, K.; Zheng, X.; Wang, Z.; Zhang, X. Chem. - Eur. J. 2014, 20,
4357-4352.
(9) Boyd, D. R.; Sharma, N. D.; Dalton, H.; Clarke, D. A. Chem.
Commun. 1996, 45-46.
(10) Peter, E.; Alexander, R. M. U.S. Patent 005096890A, 1992.
(11) Baldwin, C. M.; Lyseng-Williamson, K. A.; Keam, S. J. Drugs,
2008, 68, 803-838.
Scheme 4. Synthetic transformation.
Furthermore, a creative synthetic route for Vernakalant
and Enablex was developed. Starting from 2l, the one-pot
interrupted HAM reaction proceeded smoothly to give 4q in
very high yield and excellent ee (Scheme 5). Deprotection of
the acetoxy group gave 9 in high yield without losing any ee.
Starting from 9, Vernakalant17 and Enablex10 can be
synthesized readily following literature procedures.
(12) Kumar, U. S.; Sankar, V. R.; Rao, M. M.; Jaganathan, T. S.; Buchi
Reddy, R. Org. Process. Res. Dev. 2012, 16, 1917-1920.
(13) Stadler, M., Bitzer, J., Mayer-Bartschmid, A., Mu ¨ller, H., Benet-
Buchholz, J. Gantner, F., Tichy, H., Reinemer, P., BaconO, K. J. Nat.
Prod. 2007, 70, 246-252.
(14) Franke, R.; Selent, D.; Borner, A. Chem. Rev. 2012, 112, 5675-5732.
(15) For representative examples: (a) Sakai, N.; Nozaki, K.; Takaya, H.
J. Chem. Soc., Chem. Commun. 1994, 4, 395−396. (b) McDonald, R. I.;
Wong, G. W.; Neupane, R. P.; Stahl, S. S.; Landis, C. R. J. Am. Chem.
Scheme 5. Creative synthesis of Vernakalant and Enablex.
In summary, the first interrupted asymmetric HAM
reaction was developed. The challenging trans-1,2-
disubstituted olefins were employed as substrates and a
series of valuable chiral pyrrolidinones and pyrrolidines were
obtained in high yields, high regioslectivities and excellent ee.
It was found that the ee remained the same regardless of
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
Soc. 2010, 132, 14027−14029; (c) Nozaki, K.; Sakai, N.; Nanno, T.; Hi-
no. CCDC 1468105. Copies of the data can be obtained, free of charge,
on application to the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[Fax: +44 (1223)336033 or E-mail: deposit@ccdc.cam.ac.uk].
(17) Limanto, J.; Ashley, E. R.; Yin, J.; Beutner, G. L.; Grau, B. T.; Kas-
sim, A. M.; Kim, M. M.; Klapars, A.; Liu, Z.; Strotman, H. R.; Truppo,
M. D. Org. Lett 2014, 16, 2716-2719.
gashijima, T.; Mano, S.; Horiuchi, T.; Takaya, H. J. Am. Chem. Soc.
1997, 119, 4413-4423; (d) Watkins, A. L.; Hashiguchi, B. G.; Landis, C.
R. Org Lett 2008, 10, 4553-4556; (e) Watkins, A. L.; Landis, C. R. Org
Lett 2011, 13, 164-167. (f) Abrams, M. L.; Foarta, F.; Landis, C. R. J. Am.
Chem. Soc. 2014, 136, 14583-14588.
1
2
3
4
5
6
(16) The X-ray crystal data of 4g has been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
7
8
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
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
TOC Graphic:
1
2
3
4
5
6
7
8
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
ACS Paragon Plus Environment
6