Design and Synthesis of Chiral oxa-Spirocyclic Ligands for Ir-Catalyzed Direct Asymmetric Reduction of Bringmann's Lactones with Molecular H2

Article abstract of DOI:10.1021/jacs.8b03642

We herein present a facile and column-free synthetic route toward a structurally unique oxa-spirocyclic diphenol, termed as O-SPINOL. Features of the synthesis include the construction of the all-carbon quaternary center at an early stage, a key double intramolecular S_NAr step to introduce the spirocycles and the feasibility of operating on >100 g scale. Both enantiomers of O-SPINOL can be easily accessed through optical resolution with l-proline by control of the solvent. The chiral tridentate ligand O-SpiroPAP derived from O-SPINOL has been successfully synthesized and applied in the iridium-catalyzed asymmetric hydrogenation of bridged biaryl lactones under mild reaction conditions, providing valuable and enantioenriched axially chiral molecules in excellent yields and enantioselectivities (up to 99% yield and >99% ee). This method represents a rare example of constructing axially chiral molecules by direct reduction of esters with H₂.

Full text of DOI:10.1021/jacs.8b03642

Subscriber access provided by - Access paid by the | UCSB Libraries
Communication
Design and synthesis of chiral oxa-spirocyclic ligands for Ir-catalyzed
direct asymmetric reduction of Bringmann’s lactones with molecular H2
Gen-Qiang Chen, Bijin Lin, Jia-Ming Huang, Ling-yu Zhao,
Qi-Shu Chen, Shi-Peng Jia, Qin Yin, and Xumu Zhang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03642 • Publication Date (Web): 19 Jun 2018
Downloaded from http://pubs.acs.org on June 19, 2018
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 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 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.
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
1
2
3
4
5
6
7
Design and synthesis of chiral oxa-spirocyclic ligands for Ir-catalyzed di-
8
9
rect asymmetric reduction of Bringmann’s lactones with molecular H2
Gen-Qiang Chen,† Bi-Jin Lin,† Jia-Ming Huang,† Ling-Yu Zhao,† Qi-Shu Chen,† Shi-Peng Jia,† Qin
Yin*, †, ‡ and Xumu Zhang*, †
†Department of Chemistry, Southern University of Science and Technology, Shenzhen 518000, People’s Republic of China
‡Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518000, People’s Republic
of China
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
Supporting Information Placeholder
synthesis of structually unique oxa-spirocyclic ligand O-SPINOL9
and the development of chiral O-SpiroPAP ligand for direct
asymmetric reduction of Bringmann’s lactones with molecular H2.
diphenol, termed as O-SPINOL. Features of the synthesis include
ABSTRACT: We herein present a facile and column-free
synthetic route towards a structurally unique oxa-spirocyclic
the construction of the all-carbon quaternary center at an early
stage, a key double intramolecular SNAr step to introduce the
spirocycles and the feasibility of operating on >100 g scale. Both
enantiomers of O-SPINOL can be easily accessed through optical
resolution with L-proline by control of the solvent. The chiral
tridentate ligand O-SpiroPAP derived from O-SPINOL has been
successfully synthesized and applied in the iridium-catalyzed
asymmetric hydrogenation of bridged biaryl lactones under mild
reaction conditions, providing valuable and enantioenriched axi-
ally chiral molecules in excellent yields and enantioselectivities
(up to 99% yield and >99% ee). This method represents a rare
example of constructing axially chiral molecules by direct reduc-
tion of esters with H2.
The development of efficient chiral ligands for transition-metal
(TM) catalyzed asymmetric synthesis continues to stimulate in-
tense research effort.1 Due to their configurational rigidity and
stability, chiral spiro ligands, complementary to axially chiral
biaryl ligands, have exhibited tremendous potential and efficacy
in asymmetric transformations.2 Since the pioneering work
reported by Chan, Jiang and Sasai et al,3 chiral spiro ligands have
become an appealing and powerful tool in TM catalysis. Notably,
Figure 1. A. Our rational design of oxa-spirocyclic diphenol O-
SPINOL. B. Birman and Zhou’s synthetic route to SPINOL. C.
Our proposed synthetic route to O-SPINOL.
great advances in this field have been witnessed since Zhou and
co-workers’ seminal contribution2a-2c on chiral spiro ligands based
on 1,1’-spirobiindane-7,7’-diol (SPINOL) (I, Figure 1) which was
The key step for the synthesis of SPINOL relies on the acid
promoted double intramolecular Friedel-Crafts reaction (Eq B,
first reported by Birman and coworkers.4 A large number of
ligands such as SDP,5a-5b SIDIM,5c SpiroAP,5d SpiroPAP,5e
Figure 1).4 This method has also been applied in the synthesis of
SpiroBox5f and SIPhox5g derived from SPINOL have been
other types of spiro diphenols,8,10 including an elegant catalytic
synthesized and applied, rendering SPINOL as a privileged ligand
asymmetric synthesis developed by Tan and coworkers.11
scaffold in asymmetric TM catalysis.6
However, this method failed to assemble the pivotal spirocyclic
skeleton of O-SPINOL, and resulted in a complex mixture. Since
The modulation of the SPINOL skeleton is extremely
the formation of spirocyclic quaternary carbon center is the key
challenging due to the lack of efficient synthetic route towards the
step, we proposed that the quaternary carbon center could
spirocyclic scaffold. We expected that the replacement of one
alternatively be introduced at an early stage and a subsequent
carbon atom with a more electronegative oxygen atom would lead
double C-O couling step would produce the spirocycle (Eq C,
to interesting and unique properties because of the shorter nature
Figure 1).
of C-O bond, especially the C(sp2)-O bond (Eq A, Figure 1). In
addition to the effort devoted to SpinPHOX with Ding and
Starting from commercially available 1,3-diflurobenzene,12 di-
coworkers,7 we also developed a six-membered O-containing
aryl-substituted acetaldehyde 3 could be accessed through a two-
spirocyclic diphenol and spiro phosphoramidite ligands.8 Herein,
we disclose our preliminary results on the design and concise
step sequence in decent yield after recrystallization, without the
isolation of intermediate 2. Key compound diol 4 was obtained in
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 6
high yield via a modified aldol/Cannizzaro cascade reaction be-
tween 3 and paraformaldehyde.13 To our delight, the subsequent
intra- and intermolecular double SNAr reactions worked well and
quantitatively furnished spiro compound 6, which was hydrogen-
ated under Pd/C to give racemic diphenol 7. Unfortunately, the
resolving reagent N-benzylcinchonidinium chloride which is very
effective for the resolution of SPINOL did not work for O-
SPINOL. Instead, Both enantiomers of O-SPINOL was efficient-
ly resolved with L-Proline. A crystal structure of (S)-SPINOL14
was obtained to further confirm its structure and absolute configu-
ration (for details see the Supporting Information).
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
Scheme 1. Column-free synthesis and optical resolution of race-
mic O-SPINOL.
To test our idea, chiral tridentate ligands, such as f-amphox
(L1),22c f-amphol (L2)22b and f-ampha (L3)22a which are highly
efficient for Ir-catalyzed asymmetric hydrogenation of ketones,22
were first investigated in Ir-catalyzed asymmetric hydrogenation
of model substrate 8a under 80 atm of H2. Disappointedly, alco-
holysis product 10a was quantitatively formed when using L1 as
ligand, K2CO3 as base and MeOH as solvent, without detection of
the desired product 9a (entry 1, Table 1), indicating that alcohol
solvent was not suitable for the current transformation. Iridium
complexes of L1, L2 and L3 could not catalyze the current reac-
tion in THF either (Table 1, entries 2-4). In addition, the Noyori
catalyst L6 was also evaluated,22d but the desired product was still
not detected (entry 5, Table 1). We then turn our attention to seek-
ing more reactive catalysts. Inspired by Zhou and Xie’s work,5e
we synthesized an O-SPINOL based tridentate PNN ligand L4
according to a modified procedure (for details see the Supporting
Information) and tested its catalytic activity towards hydrogena-
tion of 8a. To our great delight, product 9a was obtained in 50%
yield and 98% ee under the conditions of L4 as ligand and tBuOK
as base, combined with alcoholysis products. Encouraged by this
result, weak base such as K2CO3 and Cs2CO3 were then screened
(entries 7-8, Table 1). Gratifyingly, in both cases, product 9a was
On the other hand, because of their ubiquitous existence in natu-
rally occurring compounds and extensive utilities as key elements
in catalyst designs, atropisomeric biaryls have attracted increasing
attention.15 Among the synthetic methods toward them, dynamic
kinetic resolution (DKR)16 of configurationally unstable “bridged
biaryl lactone”, originally developed by Bringmann,17 represents a
unique and efficient strategy. Due to a rapid equilibrium between
two atropoisomers ( 8A and 8B, Eq A, Scheme 2), Bringmann’s
lactones could be stereoselectively reduced in the presence of a
chiral catalyst, affording chiral biaryl diols with good conversion
and high enantioselectivity. However, stoichiometric amount of
CBS reagent is generally required to accomplish full conversion17e
and only one catalytic example has been reported.17a A catalytic
asymmetric reduction was later realized with NaBH4 as reducing
reagent by Yamada et al, wherein a chiral cobalt catalyst was
introduced yet requiring large excess amount of additives (Eq B,
scheme 2).18 Very recent contributions from Akiyama19 and
Wang20 et al disclosed the feasibility of applying organocatalysis
in the DKR of Bringmann’s lactones. Despite these advances, a
direct and efficient TM-catalyzed asymmetric reduction of
Bringmann’s lactones with more atom-economic H2 remains un-
known. A formidable challenge is, however, anticipated since the
reduction of esters with a chiral metal catalyst is rarely studied.21
o
obtained quantitatively with excellent enantioselectivity at 45 C.
The influence of temperature was also evaluated, and the reactivi-
o
ty and enantiocontrol remained excellent at 60 C (96% ee of 9a,
o
entry 11, Table 1) while decreased yield was observed at 10 C
(entry 10, Table 1). The pressure of hydrogen was subsequently
examined at rt, revealing that pressure is essential to the reactivity
as no reaction happened under 20 atm pressure (entry 12 vs entry
13, Table 1). SpiroPAP L5 developed by Zhou was also tested
under the optimal conditions, giving comparable results (entry 14,
Table 1). Besides, the reaction worked well at lower catalyst load-
ing albeit requiring more time for full conversion (entry 15, Table
1). Given both the yield and enantioselectivity of 9a, the combina-
tion of [Ir(COD)Cl]2/L4 (1 mol%) as catalyst, K2CO3 (5 mol%) as
base, THF as solvent, 50 atm of H2 at rt is the optimal condition.
Scheme 2. DKR of Bringmann’s lactones via asymmetric reduc-
tion.
With the optimal conditions in hand, we next examined the sub-
strate generality, and the results were summarized in Scheme 3.
Substrates with various substituents (Me, Cl as in 8b-8e) on the
phenolic part did not show much difference, affording desired
products 9b-9e in excellent yields and ee (95-98% yields, 97->99%
ee). Nonetheless, removal of the substituent on the C3 position of
the phenolic benzene ring, as exemplified in the cases of 8f and 8g,
resulted in obvious decrease in the enantiocontrol (79% ee for 9f
and 85% ee for 9g). Notably, binaphthyl substrates 8h and 8i are
also well tolerated, affording 9h with 96% ee and 9i with >99% ee.
Evaluation of the substituent effect on the carbonyl-containing
ACS Paragon Plus Environment

Page 3 of 6
Journal of the American Chemical Society
phenyl ring was also conducted (9j-9l, 90-96% yields, 91-98% ee).
Besides, all reactions worked well for biphenyl substrates 8m-8q
in terms of enantiocontrol, but prolonged reaction time was re-
quired for substrates 8o and 8p to fulfill good conversions.
1
2
3
4
5
Table 1. Optimization of the reaction conditions.
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
Scheme 4. DKR of hydroxyl ester 10a, lactol 11j and hydroxyl
aldehyde 12a.
To gain further insight into the asymmetric induction process,
compounds 10a, 11j and 12a were prepared and subjected to the
standard reaction conditions (Scheme 4). Interestingly, 10a was
quantitatively transformed to 9a in the same enantioselective
manner compared to that from 8a, suggesting in situ generation of
compound 8a from 9a under basic conditions. Similar stereo out-
put was obtained for substrates 11j and 8j, indicating that the
reaction of 8j probably goes through a lactol intermediate. Im-
portantly, for the hydroxyl aldehyde 12a, product 9a was obtained
with dramatically decreased ee compared to that from 8a.
Based on the literature precedents17b,18,19,23 and our experi-
mental observations (for more experiments see the Supporting
Information), a rationalization of the asymmetric induction was
illustrated (Scheme 5). 8A and 8B are in a rapid equilibrium with
each other, and 8 can also be produced from 10 in the presence of
a base. Overall, the asymmetric induction process is highly de-
pendent on the structure of the substrates.23 The first DKR process
(step A) can preferentially produce enantioenriched lactol 11A,
which quickly isomerize to chiral intermediate 12A for 2,6,2’,6’-
tetra-substituted substrates. Further reduction of enantioenriched
12A (step B) produced the final product 9 in high enantioselec-
tivity. Whereas, racemization would occur for 2,6,2’-tri-
substituted lactols due to unstable configuration. Both DKR pro-
cesses possibly contribute to the enantiocontrol in the reduction of
compound 8j, which is supported by the fact that racemic 11j was
transformed to 9j with 89% ee. The dramatically decreased enan-
tiocontrol of 12a versus 8a implies that the DKR of 12a is not
very effective due to low interconversion rate between the two
Scheme 3. Substrate scope.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 6
enantiomers of 12a (For the details see the Supporting Infor-
Qin Yin: 0000-0003-3534-3786
Xumu Zhang: 0000-0001-5700-0608
Notes
mation).19,24
1
2
3
Scheme 5. Proposed asymmetric induction mechanism.
The authors declare no competing financial interests.
4
5
ACKNOWLEDGMENT
6
7
8
9
G.-Q. Chen gratefully acknowledges the Presidential Excel-
lent Postdoctoral Scholarship of SUSTech (2016–2017) and
Free Exploration Fund from the Science and Technology
Innovation
Committee
of
Shenzhen
(JCYJ20170817105056467). Q. Yin is indebted to Free Explora-
tion Fund from the Science and Technology Innovation
Committee of Shenzhen (JCYJ20170817110055425). X. Zhang is
indebted to the start-up fund from SUSTech, financial sup-
port from Science and Technology Innovation Committee of
Shenzhen (No. KQTD20150717103157174) and National Natu-
ral Science Foundation of China (No. 21432007). Dedicated to
Prof. X. Lu (SIOC) on the occasion of his 90th birthday.
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
The protocol can be easily scaled up to 2 mmol scale at a higher
concentration (0.5 M), affording 9a in quantitative yield and 98%
ee (Scheme 6). It is noteworthy that 9a can be easily elaborated to
synthetically useful chiral monophosphine ligand 1317c and chiral
aminophenol ligand 14.17d,20
REFERENCES
(1) (a) Ding, K. Acta Chim. Sinica 2014, 72, 755. (b) Noyori, R.
Angew. Chem. Int., Ed, 2002, 41, 2008. (c) Zhang, W.; Chi, Y.; Zhang,
X.; Acc. Chem. Res. 2007, 40, 1278. (d) Tang, W.; Zhang, X. Chem.
Rev. 2003, 103, 3029. (e) Fundamentals of Asymmetric Catalysis,
Walsh, P. J.; Kozlowski, M. C.; University Science Books, Sausalito,
California, 2008.
(2) (a) Xie, J.; Zhou, Q. Acta Chim. Sinica 2014, 72, 778. (b) Xie, J.-
H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581. (c) Zhu, S.-F.; Zhou,
Q.-L. Acc. Chem. Res. 2012, 45, 1365. (d) Zhu, S.-F.; Zhou, Q.-L. Acc.
Chem. Res. 2017, 50, 988. e) Ding, K.; Han, Z.; Wang, Z. Chem. Asian.
J. 2009, 4, 32.
(3) (a) Chan, A. S. C.; Hu, W.; Pai, C.-C.; Lau, C.-P.; Jiang, Y.; Mi,
A.; Yan, M.; Sun, J.; Lou, R.; Deng, J. J. Am. Chem. Soc. 1997, 119, 9570.
(b) Arai, M. A.; Arai, T.; Sasai, H. Org. Lett. 1999, 1, 1795. (c) Arai, M.
A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907.
(d) Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. Chirality 2003, 15, 101.
(4) (a) Birman, V. B.; Rheingold, A. L.; Lam, K.-C. Tetrahedron:
Asymmetry 1999, 10, 125. For an updated synthesis of SPINOL, see:
(b) Zhang, J.-H.; Liao, J.; Cui, X.; Yu, K.-B.; Zhu, J.; Deng, J.-G.; Zhu,
S.-F.; Wang, L.-X.; Zhou, Q.-L.; Chung, L. W.; Ye, T. Tetrahedron:
Asymmetry 2002, 13, 1363.
(5) (a) Fan, B.; Li, S.; Xie, J.; Wang, L.; Tu, Y.; Zhou, Q. Sci. China,
Ser. B 2006, 49, 81. (b) Xie, J.-H.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Fan,
B.-M.; Duan, H.-F.; Zhou, Q.-L. J. Am. Chem. Soc. 2003, 125, 4404. (c)
Zhang, Y.-Z.; Zhu, S.-F.; Wang, L.-X.; Zhou, Q.-L. Angew. Chem. Int.,
Ed. 2008, 47, 8496. (d) Xie, J.-B.; Xie, J.-H.; Liu, X.-Y.; Kong, W.-L.;
Li, S.; Zhou, Q.-L. J. Am. Chem. Soc. 2010, 132, 4538. (e) Xie, J.-H.; Liu,
X.-Y.; Xie, J.-B.; Wang, L.-X.; Zhou, Q. -L. Angew. Chem. Int., Ed.
2011, 50, 7329. (f) Cheng, Q.-Q.; Zhu, S.-F.; Zhang, Y.-Z.; Xie, X.-L.;
Zhou, Q.-L. J. Am. Chem. Soc. 2013, 135, 14094. (g) Song, S.; Zhu, S.-F.;
Pu, L.-Y.; Zhou, Q.-L. Angew. Chem. Int., Ed. 2013, 52, 6072.
(6) Zhu, S.-F.; Zhou, Q.-L. In Privileged Chiral Ligands and Cata-
lysts; Zhou, Q.-L.; Ed.; Wiley-VCH: Weinheim, 2011; Chapter 4, p 137.
(7) Han, Z.; Wang, Z.; Zhang, X.; Ding, K. Angew. Chem., Int. Ed.
2009, 48, 5345.
Scheme 6. Scalable synthesis of product 9a and its synthetic elab-
orations.
In conclusion, a new oxa-spirocyclic scaffold has been designed
and synthesized featuring a novel double intramolecular SNAr
reaction from cheap and commercially available starting materi-
als. Both enantiomers of O-SPINOL can be divergently resolved
on large scale upon the choice of solvents with L-Proline. Impres-
sively, the synthesis towards enantiopure O-SPINOL relies only
on recrystallization and does not need any column chromatog-
raphy operation. The ligand O-SpiroPAP derived from O-
SPINOL has been successfully synthesized and applied in iridi-
um-catalyzed DKR of Bringmann’s lactones via asymmetric hy-
drogenation, providing an atom-economic and facile method to
valuable chiral biaryl molecules. Additionally, some control ex-
periments were also performed to gain insight into the asymmetric
induction mechanism.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
(8) Wu, S.; Zhang, W.; Zhang, Z.; Zhang, X. Org. Lett. 2004, 6,
3565.
(9) During the preparation of this paper, Nagorny group reported
an elegant synthesis of spiroketal-containing ligand, see: Argüelles, A.
J.; Sun, S.; Budaitis, B. G.; Nagorny, P. Angew. Chem. Int. Ed. 2018, 57,
5325.
(10) (a) Huo, X.-H.; Xie, J.-H.; Wang, Q.-S.; Zhou, Q.-L. Adv.
Synth. Catal. 2007, 349, 2477. (b) Cheng, X.; Hou, G.-H.; Xie, J.-H.;
Zhou, Q.-L. Org. Lett. 2004, 6, 2381.
(11) Li, S.; Zhang, J. W.; Li, X. L.; Cheng, D. J.; Tan, B. J. Am. Chem.
Soc. 2016, 138, 16561.
Detailed experimental procedures, spectral data, and
analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
yinq@sustc.edu.cn; zhangxm@sustc.edu.cn
ORCID
Gen-Qiang Chen: 0000-0003-2276-6800
ACS Paragon Plus Environment

Page 5 of 6
Journal of the American Chemical Society
(12) Various 1,3-di-substituted arenes which are prone to lithia-
tion at the 2-position were evaluated. 1,3-Difluorobene was selected
because of its facile lithiation at the 2-position, the small size of
fluorine atom and the high SNAr reactivity of the C-F bond, which
are very important for the success of the subsequent steps.
(13) (a) Markees, D. G.; Burger, A. J. Am. Chem. Soc. 1949, 71, 2031.
(14) The crystal data of compound (S)-7 has been deposited in
CCDC with number 1821575.
(15) For selected reviews, see: (a) Zilate, B.; Castrogiovanni, A.;
Sparr, C. ACS Catal. 2018, 8, 2881. (b) Wang, Y.-B.; Tan, B. Acc.
Chem. Res. 2018, 51, 534. (c) Loxq, P.; Manoury, E.; Poli, R.; Deydier,
E.; Labande, A. Coord. Chem. Rev. 2016, 308, 131. (d) Wencel-Delord,
J.; Panossian, A.; Leroux, F. R.; Colobert, F. Chem. Soc. Rev. 2015, 44,
3418. (e) Ma, G.; Sibi, M. P. Chem. Eur. J. 2015, 21, 11644. (f) Bring-
mann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner, J.;
Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384. And references
therein.
(16) For selected examples of DKR of axial compounds see: (a)
Zhao, K.; Duan, L.; Xu, S.; Jiang, J.; Fu, Y.; Gu, Z. Chem, 2018, 4, 599.
(b) Zhang, J.; Wang, J. Angew. Chem., Int. Ed. 2018, 57, 465. (c) Horn-
illos, V.; Carmona, J. A.; Ros, A.; Iglesias-Sigueenza, J.; López-
Serrano, J.; Fernández, R.; Lassaletta, J. M. Angew. Chem., Int. Ed.
2018, 57, 3777. (d) Yao, Q.-J.; Zhang, S.; Zhan, B.-B.; Shi, B.-F. Angew.
Chem., Int. Ed. 2017, 56, 6617. (e) Zheng, J.; Cui, W.-J.; Zheng, C.; You,
S.-L. J. Am. Chem. Soc. 2016, 138, 5242. (f) Ramírez-López, P.; Ros, A.;
Romero-Arenas, A.; Iglesias-Sigüenza, J.; Fernández, R.; Lassaletta, J.
M. J. Am. Chem. Soc. 2016, 138, 12053. (g) Miyaji, R.; Asano, K.;
Matsubara, S. J. Am. Chem. Soc. 2015, 137, 6766. (h) Mori, K.; Ichika-
wa, Y.; Kobayashi, M.; Shibata, Y.; Yamanaka, M.; Akiyama, T. J. Am.
Chem. Soc. 2013, 135, 3964. (i) Ros, A.; Estepa, B.; Ramirez-López, P.;
Álvarez, E.; Fernández, R.; Lassaletta, J. M. J. Am. Chem. Soc. 2013,
135, 15730. (j) Bhat, V.; Wang, S.; Stoltz, B. M.; Virgil, S. C. J. Am.
Chem. Soc. 2013, 135, 16829. (k) Nushiro, K.; Kikuchi, S.; Yamada, T.
Chem. Lett. 2013, 42, 165. (l) Gustafson, J. L.; Lim, D.; Miller, S. J.
Science 2010, 328, 1251. And references therein.
(17) For selected examples of asymmetric ring-opening methodology,
see: (a) Bringmann, G.; Breuning, M.; Henschel, P.; Hinrichs, J. Org.
Synth. 2002, 79, 72. (b) Bringmann, G.; Breuning, M.; Tasler, S. Synthe-
sis 1999, 525. (c) Bringmann, G.; Wuzik, A.; Breuning, M.; Henschel,
P.; Peters, K.; Peters, E.-M. Tetrahedron: Asymmetry 1999, 10, 3025.
(d) Bringmann, G.; Breuning, M. Tetrahedron: Asymmetry 1998, 9,
667. (e) Bringmann, G.; Hartung, T. Angew. Chem., Int. Ed. 1992, 31,
761.
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
(18) Ashizawa, T.; Tanaka, S.; Yamada, T. Org. Lett. 2008, 10, 2521.
(19) Mori, K.; Itakura, T.; Akiyama, T. Angew. Chem., Int. Ed. 2016,
55, 11642.
(20) Yu, C.; Huang, H.; Li, X.; Zhang, Y.; Wang, W. J. Am. Chem.
Soc. 2016, 138, 6956.
(21) (a) Yang, X.-H.; Yue, H.-T.; Yu, N.; Li, Y.-P.; Xie, J.-H.; Zhou,
Q.-L. Chem. Sci. 2017, 8, 1811. (b) Yang, X.-H.; Wang, K.; Zhu, S.-F.;
Xie, J.-H.; Zhou, Q.-L. J. Am. Chem. Soc. 2014, 136, 17426; (c) Yang, X.-
H.; Xie, J.-H.; Liu, W.-P.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2013, 52,
7833; During the preparation of this paper, a Ru(II)-catalyzed
example was reported, see: (d) Arai, N.; Namba, T.; Kawaguchi, K.;
Matsumoto, Y.; Ohkuma, T. Angew. Chem., Int. Ed. 2018, 57, 1386. (e)
Ito, M.; Ootsuka, T.; Watari, R.; Shiibashi, A.; Himizu, A.; Ikariya, T. J.
Am. Chem. Soc., 2011, 133, 4240.(22) (a) Yu, J.; Jiao, L.; Yang, Y.; Wu,
W.; Xue, P.; Chung, L. W.; Dong, X.-Q.; Zhang, X. Org. Lett. 2017, 19,
690. (b) Yu, J.; Duan, M.; Wu, W.; Qi, X.; Xue, P.; Lan, Y.; Dong, X.-
Q.; Zhang, X. Chem. Eur. J. 2017, 23, 970; (c) Wu, W.; Liu, S.; Duan,
M.; Tan, X.; Chen, C.; Xie, Y.; Lan, Y.; Dong, X.-Q.; Zhang, X. Org.
Lett. 2016, 18, 2938. (d) Ohkuma, T.; Ooka, H.; Hashiguchi, S.; Ikari-
ya, T.; Noyori, R. J. Am. Chem. Soc., 1995, 117, 2675.
(23) The equilibrium between the lactol and aldehyde
intermediate is highly dependent on the structure of the substrates.
The lactol from dominates for tri-substituted substrates, and the
aldehyde form dominates for tetra-substituted substrates. See
Bringmann, G.; Breuning, M.; Endress, H.; Vitt, D. Peters, K.; Peters,
E.-M. Tetrahedron, 1998, 54, 10677.
(24) Bringmann, G.; Hartung, T. Liebigs Ann. Chem. 1994, 313.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 6
1
2
3
4
5
OH
OH
Column-free
>100 g scale
O
O
O
O
F
KOtBu
F
F
OH
OH
F
F
F
6
7
8
9
R1
R2
R1
R2
OH
O
O
O
N
[Ir(COD)Cl]2/L
H2, rt
H
N
OH
O
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
P(DTB)2
H2 as reductant
wide substrate scope
L
up to 99% yield, >99% ee
ACS Paragon Plus Environment