Scalable C-H Oxidation with Copper: Synthesis of Polyoxypregnanes

Article abstract of DOI:10.1021/jacs.5b09463

Steroids bearing C12 oxidations are widespread in nature, yet only one preparative chemical method addresses this challenge in a low-yielding and not fully understood fashion: Sch?necker's Cu-mediated oxidation. This work shines new light onto this powerf

Full text of DOI:10.1021/jacs.5b09463

Subscriber access provided by CMU Libraries - http://library.cmich.edu
Communication
Scalable C-H Oxidation with Copper: Synthesis of Polyoxypregnanes
Yi Yang See, Aaron T Herrmann, Yoshinori Aihara, and Phil S. Baran
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b09463 • Publication Date (Web): 14 Oct 2015
Downloaded from http://pubs.acs.org on October 14, 2015
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 5
Journal of the American Chemical Society
1
2
3
4
Scalable C-H Oxidation with Copper: Synthesis of Polyoxypregnanes
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Yi Yang See, Aaron T. Herrmann, Yoshinori Aihara, Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Supporting Information Placeholder
ABSTRACT: Steroids bearing C12 oxidations are
widespread in nature yet only one preparative chemical
method addresses this challenge in a lowꢀyielding and
not fully understood fashion: Schönecker's Cuꢀmediated
oxidation. This work shines new light onto this powerful
C–H oxidation method through mechanistic investigaꢀ
tion, optimization, and wider application. Culminating in
a scalable, rapid, highꢀyielding, and operationally simple
protocol, this procedure is applied to the first synthesis
of several parent polyoxypregnane natural products, repꢀ
resenting a gateway to over 100 family members.
Given the sheer number of FDAꢀapproved medicines
and natural products containing their molecular skeleton,
steroids are perhaps the most privileged complex strucꢀ
1
ture in drug discovery. A key differentiating feature
among steroids is the myriad of different oxidation patꢀ
terns expressed in their backbone. This "oxidation barꢀ
code" serves to modulate both their physical and biologꢀ
2
ical properties. As part of a continuing collaboration
3
with LEO Pharma to use twoꢀphase terpene synthesis to
solve complex chemical problems of medicinal releꢀ
vance, natural products belonging to the utendin family
4
(
1–3, Figure 1A) were targeted. Featured in a large
number of polyoxypregnanes from Asclepiadaceae
plants (>100 isolated), a clear opportunity for innovation
resides in their unusual oxidation pattern, particularly at
5
Figure 1. (A) Steroidal natural products containing oxidation
at C12. (B) Attempted strategies towards directed C12 functionalꢀ
ization using reported chemistries.
C12. The C12 oxidation, found in numerous natural
steroids of both terrestrial and marine origin, is a classic
bottleneck for synthesis with a singular preparative
6g
Close proximity of the requisite C20 oxidation and its
1,5ꢀrelationship to the C12ꢀβꢀC–H bond inspired all of
the approaches. Given the success of a Norrish reaction
in the context of a redoxꢀrelay approach to steroid oxidaꢀ
tion, the C20 ketone was evaluated under a variety of
chemical solution. The venerable Schönecker oxidaꢀ
tion is still employed despite difficult experimental setꢀ
6
up, poor yields, and long reaction times. In this Comꢀ
munication, a renovation of this C–H oxidation protocol
and a reinvestigation of its scope and mechanism are
applied to the first synthesis of several members of the
utendin steroid family.
3
b,3c
photochemical conditions.
Unfortunately, despite
screening numerous solvents and photosensitizers, only
undesired photocleavage products resulting from scisꢀ
sion of the C17–C20 bond were obtained. Next, Barꢀ
ton’s classic photolysis was evaluated in a variety of
different solvents but only the hydrolyzed nitrite ester
6
For strategic reasons discussed below, a steroidal ∆ ꢀiꢀ
diene (4, Figure 1B) was targeted as a surrogate for the
homoallylic alcohol found in utendinꢀbased systems.
Since poor yields were obtained under Schönecker’s
original conditions, a conceptually new method for oxiꢀ
dizing the C12 position was initially sought. Thus, exꢀ
tensive efforts took place across various mechanistically
distinct methods ranging from radical to transitionꢀmetal
mediated C–H activation.
7
was detected. Similarly, other methods to generate the
Oꢀradical (hypoiodite photolysis, Pb(OAc) /I , AgOI)
4
2
only resulted in decomposition or αꢀcleavage of the
8
C17–C20 bond. Attempts to generate a tethered radical
were thwarted by the low reactivity of the C20 hydroxyl
group, as we were unable to prepare the required carbaꢀ
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
mate for a HofmannꢀLöfflerꢀFreytag (HLF) type reacꢀ
tion. Baldwin’s Pdꢀmediated oxime directed acetoxylaꢀ
It was next reasoned that an effective reducing agent
9
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
might achieve recycling of the postulated Cu(II) end
species in this oxidative reaction. Cu(I) was used for this
screen for operational simplicity. Numerous reducing
agents were evaluated (Entries 4–8) and it was rapidly
apparent that this variable was key to improving the reꢀ
tion gave no reaction under both stoichiometric and cataꢀ
10
lytic conditions. Finally, extensive decomposition of
the substrate was observed using Breslow’s remote funcꢀ
11
tionalization protocol.
action. Indeed, the use of either FeBr or Zn furnished a
With this string of setbacks, our attention returned to
Schönecker’s oxidation protocol. Initially developed in
2
greater than 50% yield of 7, a milestone in that it surꢀ
passed the proposed 50% "limit". Sodium ascorbate, a
reducing agent routinely employed in the CuAAC reacꢀ
tion developed by Sharpless and coꢀworkers, emerged as
the best candidate (Entries 8–12) with both Cu(I) and
6
a
2
003, this promising Cuꢀmediated C–H oxidation has
been featured in a couple of stunning steroid syntheses,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6d
namely Shair's synthesis of cephalostatin and Giannis’
6e
synthesis of cyclopamine. Testament to its powerful
ability to access to the elusive C12 oxidation, it has been
rapidly adopted in spite of its numerous shortcomings:
long reaction times, poor mass recovery, limited subꢀ
strate scope, a proposed 50% yield maximum detailed
1
3
Cu(II)ꢀbased systems. Furthermore, the addition of
MeOH provided improved conversions (Entry 10). An
array of different imines was prepared (A–E) with imine
B emerging as the best. Taken together, these improveꢀ
ments enabled a near quantitative yield of 7 in only 90
min. Notably the revised procedure is truly "dumpꢀandꢀ
stir" circumventing the laborious premixing, incubation,
and complex workup required previously.
6b,c
through studies by Schönecker, and a lack of detailed
mechanistic understanding. It is therefore somewhat
puzzling that no attention has been paid to understand-
ing and improving this incredibly useful and potentially
1
2
a
practical Cu-based C–H oxidation system.
Table 2. Scope of Directed Hydroxylation.
a
Table 1. Reaction Development and Optimization.
In the absence of a clear mechanistic picture, optimizaꢀ
tion efforts centered around modifications that would
achieve conversion above the proposed maximum 50%
threshold using dehydroꢀepiꢀandrosterone (DHEA) as a
To date, only four types of ketoneꢀderived substrates
have been enlisted in Schönecker’s C–H oxidation. The
optimized procedure derived herein proved superior
across all of these substrates in both isolated yields and
reaction time (Table 2). The conditions are compatible
with silyl ethers (13), esters (14), and tertiary amines
6b,c
model substrate (Table 1). Under Schönecker’s origiꢀ
nal conditions (Entries 1–2), low conversion of 6 to 7
was accompanied with poor mass recovery (ca. 55ꢀ
60%). Despite much effort, the structure of the remainꢀ
ing material was not identifiable; however, by simply
heating the same reaction to 50 °C (Entry 3) the overall
mass recovery could be improved to ca. 80% (7 +
DHEA) in only 1.5 hours.
(15). Returning to the original objective of this work,
implementation of the new oxidation conditions with
Cu(I) enabled C12 oxidation of the highly functionalized
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
6
steroidal ∆ ꢀiꢀdiene (12), a critical starting material for
the synthesis of utendin (vide infra).
Cu(I) and released, allowing for further substrate enꢀ
1
7
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
gagement. Besides acting as a reductant, ascorbate
18
could also participate as a weak ligand to copper. The
A series of NMR studies was conducted to gain mechꢀ
anistic insight into the reaction (Figure 2). Initial studies
with subꢀstoichiometric amounts of Cu(OTf)2 (0.5
equiv) and sodium ascorbate (1.5 equiv) led to no obꢀ
servable C12 oxidation over 60 min suggesting that the
remaining Cu(II)/pregnane tridentate complex 20 is preꢀ
sumably stable and inert to further oxidations. Despite
repeated attempts by Schönecker and us, we were not
successful in obtaining Xꢀray quality crystals of any of
the proposed intermediates.
previously proposed [Cu O ]ꢀsubstrate dimer complex is
2
2
unlikely to be responsible for the reactivity seen in this
Armed with a scalable and robust C12 oxidation, the
first synthesis of complex polyoxypregnanes was acꢀ
complished (Scheme 1). The use of a ∆ ꢀiꢀdiene to mask
6b,c
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
system.
Oxidation was only detected (~12% at 120
6
min) after further Cu(OTf) (0.25 equiv) was titrated
2
into the reaction. Additional Cu(OTf) (0.5 equiv) and
the Aꢀring functionality of a steroid as part of a synthesis
is a strategic decision without precedent. Such a conꢀ
struct was chosen to minimize protecting group fluctuaꢀ
tions and chemoselectivity concerns during the ensuing
redoxꢀrelay. The synthesis commenced with inexpensive
2
sodium ascorbate (1.0 equiv) added over 2.5 h led to a
minor increase in conversion. In stark contrast, titration
of sodium ascorbate into a solution of substrate and a
slight excess of Cu(OTf) (1.05 equiv) gave 50% conꢀ
2
6
version to product in only 30 minutes. Additional sodiꢀ
um ascorbate (0.75 equiv) over 3.5 h allowed for near
complete conversion.
DHEA (ca. $3/gram), which is transformed to ∆ ꢀiꢀdiene
1
9
via triflation and elimination (35%). The remaining
mass balance was accounted for by an ammonium adꢀ
duct by the attack of triethylamine into the allylic triflate
(see SI for structure). Next, the Cuꢀmediated C–H oxiꢀ
dation was employed on gramꢀscale as discussed above
to deliver 12 in 40% yield. Saegusa oxidation (59%)
followed by a recently developed olefin isomerization
A. NMR experiments: Titration of Cu(OTf) (Cu)
2
C6
C12
C3
C16
Cu SA
(eq.) (eq.)
Product
2
2
70 min
10 min
1.25 2.25
1.00 2.00
0.75 1.75
0.50 1.50
0.50 1.50
1
20 min
0 min
30 min
min
insert NMR
6
0
0
0
3a
protocol (57%) delivered the diene 21. Stereoꢀ and
B. NMR experiments: Titration of sodium ascorbate (SA)
Cu SA
chemoselective Mukaiyama hydration took place
C6
C12
C3
C16
Product
70 min
210 min
(eq.) (eq.)
2
1.05 2.25
1.05 2.00
1.05 1.75
1.05 1.50
1.05 1.50
smoothly to furnish diol 22 in 67% yield as verified by
3
a
1
20 min
60 min
insert NMR
Xꢀray crystallography. The D ring methyl ketone subuꢀ
nit was then installed using an organolanthanum reagent
derived from lithiated ethyl vinyl ether in 51% yield
3
0 min
0 min
0
0
2
0
(
along with 20% recovered 22). At this juncture, the
C. Proposed mechanistic pathway
L
Me
O
CuL
n 2
, O
N
allylic cyclopropane, which remained chemically silent
until this point, was cleanly dismantled using HBr to
Me
CuII
N
sodium ascorbate
O
CuI
O
12
Me
N
H
sodium
ascorbate
21
Me N
12
afford the homoallylic bromide. Silverꢀassisted solvolꢀ
1
6
20
16
ysis followed by acid treatment produced the natural
product pergularin 2 (60% over 3 operations). From this
point, two additional natural polyoxypregnanes were
accessed by sequential stereoselective reductions.
16
H
CuILn
H
dehydro-ascorbate
L
CuII
H
O
L
L
Me
L
N
O
CuIII
O
CuII
O
CuII
O
Me
L
N
N
L
O
H
CuII
N
CuIII
N
Me
N
NaBH treatment of 2 delivered utendin, 1 (75%), which
Me
H
4
12
12
Me
H
19
Me
could then be hydrogenated over Pd/C to tomentogenin,
3 (80%). The structure of tomentogenin was unambiguꢀ
ously confirmed by Xꢀray crystallography. Over 100
natural products with promising bioactivity can, in prinꢀ
ciple, be accessed from these three parent natural prodꢀ
ucts, differing only in the location and identity of variꢀ
ous ester and sugar side chains. Such studies are ongoing
and now enabling biological inquiries at LEO Pharma.
1
2
16
1
7
18
6
16
1
H
H
Current mechanistic proposal: L = sodium ascorbate, MeCN, OTf, acetone
Schönecker's mechanistic proposal: L = DHEA imine, MeCN, OTf, acetone
Figure 2. (A) NMR studies of Cu titration. (B) NMR studies
of sodium ascorbate titration (C) Revised mechanistic proposal.
A new mechanistic picture that is consistent with the
observed data is shown in Figure 2C. Following initial
Cu binding to give 16, additional uncoordinated Cu(I)
The fascinating Cuꢀmediated Schönecker oxidation,
the only practical solution to the challenge of siteꢀ
specific steroidal C12 functionalization, has been reinꢀ
vestigated and dramatically improved. The new imine
directing group and alternative reducing agent render
this an operationally simple reaction that is no longer
limited to a 50% maximum yield with long reaction
times. The newly developed C–H oxidation protocol was
studied mechanistically and applied to a range of addiꢀ
tional substrates, including a key intermediate for the
and O could complex to form the imine complex 17, a
2
6
c,14
[
Cu O ] species.
The active Cuꢀspecies is likely the
2
2
14
bis(µꢀoxo)dicopper(III) complex 18 but it could also
be a mixed bis(µꢀoxo)Cu(II)/Cu(III) complex. Oxidaꢀ
tion of the proximal C–H bond then presumably occurs
1
5
6c,16
through an oxygenꢀrebound mechanism.
The resultꢀ
ing Cu(II) that is not directly ligated to the substrate in
the [Cu O ] complex 19 is then reduced by ascorbate to
2
2
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
6
first synthesis of polyhydroxylated pregnanes belonging
to the utendin class (1–3). Salient features of this syntheꢀ
Scheme 1. Synthesis of utendin (1), pergularin (2), and tomentogenin (3).
sis involve the inaugural use of a ∆ ꢀiꢀdiene in complex
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
stae,broid synthesis and stereoselective redoxꢀrelay events.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
Reagents and conditions: (a) TMSOTf, Et
, PhSiH , PPh , O
O; (g) TFA, THF/H
mation for Xꢀray structures.
3
N, CH
2 2 2 3 2 3 2 2 7 8
Cl , 0 °C; (b) Pd(OAc) , MeCN, 23 °C, 24 h; FeCl ; K CO (59%, rsm 21%); (c) SiO , iPr NEt, C F , 24h, (57%,
rsm 17%); (d) Mn(acac)
TFA, H
2
3
3
2
, EtOH, 3h, (67%); (e) (1ꢀethoxylvinyl)lithium, THF, ꢀ78 °C, 5 h (51%, 20% rsm); (f) HBr, AcOH, EtOAc, 15 min; Agꢀ
b
2
2
O, 24 h (60% over 3 steps); (h) NaBH
4
, MeOH, 0 °C (75%, 5:1 dr); (i) Pd/C, MeOH, 23 °C, 24 h, (80%, 5:1 dr). See supporting inforꢀ
Beilstein J. Org. Chem. 2014, 10, 1564. (g) Pellissier, H.;
Santelli, M. Organic Preparations and Procedures Interna-
tional 2001, 33, 1
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
analytical data ( H and C NMR, MS) for all new comꢀ
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
13
(7) Allen, J.; Boar, R. B.; McGhie, J. F.; Barton, D. H. R. J.
Chem. Soc., Perkin Trans. 1 1973, 2402.
(8) (a) Heusler, K.; Kalvoda, J. Angew. Chem., Int. Ed. 1964, 3,
5
25. (b) Shi, J.; Manolikakes, G.; Yeh, CꢀH.; Guerrero, C. A.;
Shenvi, R. A.; Shigehisa, H.; Baran, P. S. J. Am. Chem. Soc.,
011, 133, 8014ꢀ8027.
9) Chen, K.; Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008,
30, 7247.
AUTHOR INFORMATION
Corresponding Authors
2
(
Eꢀmail: pbaran@scripps.edu (P.S.B.).
Notes
The authors declare no competing financial interest.
1
(10) (a) Baldwin, J. E.; Nájera, C.; Yust, M. J. Chem. Soc., Chem.
Commun. 1985, 126. (b) Desai, L. V.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 9542. (c) Neufeldt, S. R.;
Sanford, M. S. Org. Lett. 2010, 12, 532.
(11) Breslow, R.; Corcoran, R. J.; Snider, B. B.; Doll, R. J.; Khanꢀ
na, P. L.; Kaleya, R. J. Am. Chem. Soc. 1977, 99, 905.
ACKNOWLEDGMENT
Financial support for this work was provided by NIH (GMꢀ
0
fellowship to Y.Y.S.) and the Hewitt Foundation (postꢀ
doctoral fellowship to A.T.H.). We thank Prof. A. L.
Rheingold and Dr. C. E. Moore for Xꢀray crystallographic
analysis.
97444), LEO Pharma, NSS (PhD) A*STAR (predoctoral
(12) See supporting information for a summary of the current
mechanistic understanding of the Schönecker oxidation.
(
13) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.,
Int. Ed. 2001, 40, 2004. (b) Wu, P.; Feldman, A. K.; Nugent,
A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, J.; Frechet, J.
M. J.; Sharpless, ́ K. B.; Fokin, V. V. Angew. Chem., Int. Ed.
REFERENCES
2004, 43, 3928. (c) Knöpfel, T. F.; Carreira, E. M. J. Am.
Chem. Soc. 2003, 125, 6054. (d) Padh, H. Biochem. Cell Biol.
1990, 68, 1166. (e) Englard, S.; Seifter, S. Ann. Rev. Nutr.
1986, 6, 365.
(
1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem.
014, 57, 10257 and references therein.
2
(
(
2) Biellmann, JꢀF. Chem. Rev. 2003, 103, 2019.
3) (a) Michaudel, Q.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res.
2015, 48, 712. (b) Renata, H.; Zhou, Q.; Dünstl, G.; Felding,
J.; Merchant, R. R.; Yeh, C.ꢀH.; Baran, P. S. J. Am. Chem.
Soc. 2015, 137,1330. (c) Renata, H.; Zhou, Q.; Baran, P.S.
Science 2013, 339, 59.
(14) (a) Itoh, S.; Kondo, T.; Komatsu, M.; Ohsiro, Y.; Li, C.;
Kanehisa, N.; Kai, Y.; Fukuzumi, S. J. Am. Chem. Soc. 1995,
117, 4714. (b) Itoh, S.; Nakao, H.; Berreau, L. M.; Kondo, T.;
Komatsu, M.; Fukuzumi, S. J. Am. Chem. Soc. 1998, 120,
2890. (c) Gamez, P.; Aubel, P. G.; Driessen, W. L.; Reedijk,
J. Chem. Soc. Rev. 2001, 30, 376.
(
(
4) (a) Abisch. E., Tamm. Ch., Reichstein. T., Helv. Chim. Acta.
1
959, 42, 1014. (b) Mitsuhashi, H., Nomura, T., Shimizu, Y.
(15) Blain, I.; Giorgi, M.; DeRiggi, I.; Reglier, M. Eur. J. Inorg.
Chem. 2000, 393.
Takemori, I., Yamada, E Chem. Pharm. Bull. 1962, 10, 811.
(c) Mitsuhashi, H., Takemori, I., Shimizu, Y., Nomura, T.,
Yamada, E. Chem. Pharm. Bull. 1964, 10, 804.
(
16) (a) Citek, C.; Lin, B.ꢀL.; Phelps, T. E.; Wasinger, E. C.;
Stack, T. D. P. J. Am. Chem. Soc. 2014, 136, 14405. (b)
Citek, C.; Gary, J. B.; Wasinger, E. C.; Stack, T. D. P. J. Am.
Chem Soc. 2015, 137, 6991. (c) Chen, P.; Solomon, E. I.
Proc. Natl. Acad. Sci. 2004, 101, 13105. (d) Decker, A.; Solꢀ
omon, E. I. Curr. Opin. Chem. Biol. 2005, 9, 152.
5) For examples, see: (a) Gupta, V.; Kumar, A.; Khare, A.;
Khare, N. K. Nat. Prod. Res. 2011, 25, 959. (b) Leo, M. D.;
Tommasi, N. D.; Sanogo, R.; Autore, G.; Marzocco, S.; Pizza,
C.; Morelli, I.; Braca, A. Steroids 2005, 70, 573.
(6) (a) Schönecker, B.; Zheldakova, T.; Liu, Y.; Kötteritzsch, M.;
(17) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2004, 6, 2853.
(18) Grzybowski, J. J.; Merrell, P. H.; Urbach, F. L. Inorg. Chem.
1978, 17, 3078.
(19) Nagasawa, T.; Handa, Y.; Onoguchi, Y.; Suzuki, K. Bull.
Chem. Soc. Jpn. 1996, 69, 31.
(20) Stereochemical rational of organolithium addition: Beloeil, J.
C.; Bertranne, M.; Fetizon, M.; Tetrahedron, 1983, 39, 3937.
(21) Riegel, B.; Hager, G. P.; Zenitz, B. L. J. Am. Chem. Soc.
1946, 68, 2562.
Günther, W.; Görls, H. Angew. Chem., Int. Ed. 2003, 42,
3
240. (b) Schönecker, B.; Zheldakova, T.; Lange, C.; Günꢀ
ther, W.; Görls, H.; Bohl, M. Chem. Eur. J. 2004, 10, 6029.
c) Schönecker, B.; Lange, C.; Zheldakova, T.; Günther, W.;
(
Görls, H.; Vaughan, G. Tetrahedron 2005, 61, 103. (d) Fortꢀ
ner, K. C.; Kato, D.; Tanaka, Y.; Shair, M. D. J. Am. Chem.
Soc. 2010, 132, 275. (e) Giannis, A.; Heretsch, P.; Sarli, V.;
Stößel, A. Angew. Chem., Int. Ed. 2009, 48, 7911. (f) Rabe,
S.; Moschner, J.; Bantzi, M.; Heretsch, P.; Giannis, A.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Graphical abstract
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
5
ACS Paragon Plus Environment