Synthesis of Highly Oxygenated Carbocycles by Stereoselective Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems

Article abstract of DOI:10.1021/jacs.7b06286

Densely substituted and highly oxygenated carbocycles are challenging targets for synthesis. In particular, those possessing numerous contiguous, fully substituted carbon atoms (i.e., tertiary alcohols and quaternary centers) are often not accessible in a direct fashion, necessitating the strategic decoupling of ring-formation from the establishment of functionality about the system. Here, we describe an approach to the construction of highly oxygenated mono-, di-, and polycyclic carbocycles from the reaction of disubstituted alkynes with β- or γ-dicarbonyl systems. These processes embrace a variant of metallacycle-mediated annulation chemistry where initial alkyne-carbonyl coupling is followed by a second, now intramolecular, stereoselective C-C bond-forming event. In addition to revealing the basic reactivity pattern in intermolecular settings, we demonstrate that this class of reactivity is quite powerful in a fully intramolecular context and, when terminated by a stereoselective oxidation process, can be used to generate polycyclic systems containing a fully substituted and highly oxygenated five-membered ring.

Full text of DOI:10.1021/jacs.7b06286

Subscriber access provided by UNIVERSITY OF ADELAIDE LIBRARIES
Communication
Synthesis of Highly Oxygenated Carbocycles by Stereoselective
Coupling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems
Matthew J Kier, Robert M Leon, Natasha F O'Rourke, Arnold L. Rheingold, and Glenn C. Micalizio
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 Aug 2017
Downloaded from http://pubs.acs.org on August 27, 2017
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
5
Synthesis of Highly Oxygenated Carbocycles by Stereoselective Cou-
pling of Alkynes to 1,3- and 1,4-Dicarbonyl Systems
6
7
8
9
Matthew J. Kier,1 Robert M. Leon,1 Natasha F. O’Rourke,1 Arnold L. Rheingold,2 and Glenn C. Micalizio*,1
1 Department of Chemistry, Burke Laboratory, Dartmouth College, Hanover, NH 03755.
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
2 Department of Chemistry, University of California, San Diego, La Jolla, CA 92093.
A.
ABSTRACT: Densely substituted and highly oxygenated carbo-
H
OH
H
Me
HO
H
O
cycles are challenging targets for synthesis. In particular, those
possessing numerous contiguous, fully-substituted carbon atoms
(i.e., tertiary alcohols and quaternary centers) are often not acces-
sible in a direct fashion, necessitating the strategic decoupling of
ring-formation from the establishment of functionality about the
system. Here, we describe an approach to the construction of
highly oxygenated mono-, di-, and polycyclic carbocycles from
the reaction of disubstituted alkynes with β- or γ- dicarbonyl sys-
tems. These processes embrace a variant of metallacycle-
mediated annulation chemistry where initial alkyne–carbonyl
coupling is followed by a second, now intramolecular, stereose-
lective C–C bond forming event. In addition to revealing the
basic reactivity pattern in intermolecular settings, we demonstrate
that this class of reactivity is quite powerful in a fully intramolec-
ular context and, when terminated by a stereoselective oxidation
process, can be used to generate polycyclic systems containing a
fully substituted and highly oxygenated five-membered ring.
H
OH M
Me
HO
Me
OH
Me
Me
OH
OH
O
Me
HO
Me
H
Me
HO
O
Me
O
O
i-Pr
H
i-Pr
HO
HO
O
HO
OH
ryanodol
fascicularone I
1
itol A
2
3
= quaternary center
= tertiary alcohol/ether
B.
HO
HO
(
)
n
O
O
(
)
n
(
)
n
or
R2
R2
R2
O
R1
R1
R1
R3
R3
R3
R4
R4
III
R4
HO
HO
I
II
n = 0 or 1
C.
III
[M]
O
R1
[M]
O
R1
O
Highly oxygenated carbocycles remain challenging targets for
efficient chemical synthesis.1 While a great variety of ring-
forming reactions are available to assemble diverse polycyclic
systems, even the most powerful of modern methods are not well
equipped to simultaneously establish numerous and/or contiguous
fully substituted sp3 centers (quaternary centers and tertiary alco-
hols) within the newly formed ring. This deficiency in reaction
methodology has resulted in strategies to oxygenated carbocycles
that typically proceed in two distinct phases, where ring formation
is strategically decoupled from establishing the dense functionali-
ty of the system.1d Despite impressive recent momentum in the
development of reactions capable of complementing modern ring-
forming processes with sequential functionalization chemistry,2
carbocyclic systems that contain numerous/contiguous fully sub-
stituted sp3 carbons (i.e., 1–3; Figure 1A)3 remain quite difficult to
prepare. Here, we describe a mode of reactivity that can be em-
ployed for the formation of five and six-membered rings, either in
isolation or as part of a polycyclic system, that merges the process
of ring formation with the establishment of densely oxygenated
molecular architecture (I and II, n = 0 or 1; Figure 1B).
O
(
)
O
O
n
(
)
n
[M]
R2
(
)
n
R2
R2
R4
R4
R1
R3
R3
R4
R3
(i)
(iii)
(ii)
Figure 1. Introduction.
other Group IV metal-mediated annulation reactions.6, 7 Overall, it
was reasoned that the chemical transformations targeted here
would accomplish what other annulation reactions in organic
chemistry do not, accomplishing five- or six-membered ring for-
mation while simultaneously establishing at least two tertiary
alcohols, with the most complex examples furnishing products
that house up to five contiguous fully substituted sp3 carbons.
Our first set of experiments aimed at investigating the feasibil-
ity of this reaction design is illustrated in Figure 2. These pro-
cesses proceeded with modest efficiencies (≤53% yield), yet pro-
vided the first glimpse of success associated with the basic reac-
tion design. While initial attempts to realize carbocycle formation
from the union of TMS-phenylacetylene (4) with methyl 4-
oxobutanoate (5) were met with failure (eq 1), it was soon found
that replacing the ester of 5 with a ketone led to success. As de-
picted in eq 2, Ti-mediated coupling of alkyne 4 with the γ-keto-
aldehyde 7 led to formation of the isomerically pure cyclohexene
diol 8 in a 45% isolated yield – notably, no evidence was found
for the presence of regio- or stereoisomeric products in this cou-
pling reaction. It is suspected that cyclohexene product 8 is
formed by initial regioselective alkyne–aldehyde coupling8 fol-
lowed by stereoselective intramolecular reaction of the resulting
σC–Ti bond of the oxametallacyclopentene with the pendant ke-
tone. As illustrated in eqs 3 and 4, this annulation process proved
to be effective with TMS-alkynes bearing heteroaryl- and
branched aliphatic substitution (9 and 11). In both cases cyclo-
Study began with the goal of achieving the sequence of bond
forming processes summarized in Figure 1C. Chemoselective
activation of III through formation of a metallacyclopropene (i),
was expected to be followed by carbonyl addition and result in a
functionalized oxametallacyclopentene (ii).4 This intermediate
was thought to be of potential value in a subsequent C–C bond-
forming process, where complexation of the distal carbonyl oxy-
gen to the metal center would facilitate a stereocontrolled nucleo-
philic addition en route to the bridged metal alkoxide-containing
system (iii). While such a sequence of bond forming events has,
to our knowledge, never been described for the synthesis of ste-
reodefined diols,5 reaction cascades of metallacyclopropane/ene
intermediates have been proposed as central characteristics of
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
could facilitate stereoselective oxidation. Pursuit of this concept
TMS
1
resulted in the establishment of an annulation procedure that de-
livers cyclopentene products that possess five consecutive fully
substituted sp3 carbons, doing so in a highly stereoselective man-
ner. As illustrated in eq 8, simply terminating the annulation reac-
tion by quenching with t-BuOOH14 results in the stereoselective
formation of the epoxydiol containing bicyclo[3.3.0]octane prod-
uct 20 in 79% isolated yield (no evidence was found for the pro-
duction of stereoisomeric products).15
O
TMS
Ti(Oi-Pr)4, n-BuLi
PhMe, then
TMS
Ph
2
3
(1)
O
O
O
5
H
4
5
6
7
OMe
OH
O
43%
not observed
Ph
6
4
8
9
Ti(Oi-Pr)4, n-BuLi
PhMe, then
OH
The intramolecular version of this diketone-based annulation
reaction was next explored with γ-diketone substrates to explore
the feasibility of accessing stereodefined and oxygenated hydrin-
danes. As illustrated in eq 9, Ti-mediated annulation, followed by
an oxidative quench with t-BuOOH, delivered the highly oxygen-
ated hydrindane 22 in 49% isolated yield (the structure of 22 was
confirmed by X-ray diffraction).
TMS
(2)
4
O
Ph
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
7
H
OH
O
45%
8
Ph
TMS
Ti(Oi-Pr)4, n-BuLi
PhMe, then
OH
TMS
(3)
A. Annulation reactions with diketones.
O
Ph
7
S
H
Me
TMS
TMS
Me
Ti(Oi-Pr)4, i-PrMgCl
THF, then
OH
Me
Me
S
Ph
OH
O
53%
(5)
9
10
O
O
14
Me
Me
Me
Me
OH
Me Me
TMS
13
15
37%
Ti(Oi-Pr)4, n-BuLi
PhMe, then
OH
TMS
Me
Me
(4)
O
Ph
a
7
Me
O
O
H
(6)
Me
Me
Me
Me
63%
HO OH
Me Me
Me OH
O
47%
Me Me
11
12
16
17
Figure 2. Intermolecular alkyne–dicarbonyl coupling reactions.
Me
Me
OH
hexene products were formed that possess a secondary and ter-
tiary allylic alcohol set in a 1,4-syn relationship (10 and 12).9
These types of functionalized cyclohexene products are not readi-
ly available from other convergent methods for carbocycle for-
mation.10
a
O
O
(7)
65%
HO
Me Me
Me Me
18
19
Me
O
Me
As illustrated in equation 5 of Figure 3, this basic reaction pro-
cess was effective for coupling an internal alkyne to a 1,3-
diketone, although success was only modest (15 was isolated as a
single isomer in 37% yield). In this initial reaction with a 1,3-
diketone, it was found that changing the nature of the reductant
from n-BuLi to i-PrMgCl was critical to achieving even this mod-
est level of success.11 While it remains unclear why this reaction
process was not effective with n-BuLi as reductant, questions
remain regarding the elementary steps of the initial reaction pro-
cess en route to the relevant Ti–alkyne complex.12
b
O
O
(8)
Me
Me
79%
HO OH
Me Me
Me Me
20
16
Me
Me
O
i-Pr
OH
O
b
(9)
i-Pr
=
49%
OH
O
from X-ray
21
22
Moving forward with the goal of exploring the potential value
of this reaction process for delivering densely functionalized pol-
ycyclic carbocycles, we shifted to investigating intramolecular
variants. Here, chemoselective Ti-mediated alkyne activation in
the presence of the dicarbonyl system was reasoned to be an im-
portant first step to achieving success.13 As illustrated in eqs 6 and
7 (Figure 3), it was found that stereoselective cyclization of al-
kyne-containing 1,3-diketones is not only possible, but more effi-
B. Challenging substrates.
Me
Pr
Me
O
O
O
Me Me
Me
Me
O
Me
Me Me
O
TBSO
O
O
23
unhindered
methyl ketone
24
conjugated alkyne
25
propargylic ether
cient than the intermolecular variant.
Here, the bicy-
clo[3.3.0]octane products 17 and 19 were isolated as single iso-
mers in 63% and 65% isolated yields, respectively. Next, we
considered the penultimate titanium-complexed intermediate in
these reactions as a potential valuable species for subsequent ste-
reoselective functionalization (i.e. compound iii of Figure 1C). In
particular, we recognized that its proximity to the product alkene
Reaction conditions: (a) Ti(Oi-Pr)4, i-PrMgCl, THF, –78 to –20 °C, then aq
NaHCO3. (b) Ti(Oi-Pr)4, i-PrMgCl, THF, –78 to –20 °C (or rt), then t-BuOOH,
then aq NaHCO3.
Figure 3. Annulation reactions involving diketones.
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
A.
R1
1
2
3
4
5
6
7
8
R1
O
H
O
H
OH Me
Me
OH
R1
HO
HO
R1
O
O
OH
HO
O
3
O
1
R2
Me
Me
R2
OH
Me
Ti-mediated
H
Me
3
1
HO
HO
4
R2
R2
OH
Me
4
O
O
annulation reaction
i-Pr
O
HO
ring
closure
O
HO
HO
O
hydrolysis
O
O
O
O
OH
ryanodol
Me
H
II
I
III
IV
B.
a
Me
OH
3
1
4
9
40%
Me
Me
O
HO
10
11
12
13
14
15
16
17
18
19
Me
O
1) H2NNMe2, TFA, PhH
1) LDA, AcCl, THF
O
O
1
29
O
3
H
Me
2) KHMDS, MeI, THF
(33% over 2 steps)
2) n-BuLi, THF, 1-iodo-3-pentyne
then, 2N HCl
Me
3
4
Me
(72% over 2 steps)
b
Me
OH
1
4
26
27
28
HO
62%
Me
30
Reaction conditions: (a) Ti(Oi-Pr)4, i-PrMgCl, THF, –78 to –20 °C, then aq NaHCO3. (b) Ti(Oi-Pr)4, i-PrMgCl, THF, –78 to –20 °C, then t-BuOOH, then aq NaHCO3.
Figure 4. Exploring synthesis design with the alkyne–dicarbonyl annulation reaction – control of relative stereochemistry in the ring-forming process,
and application to the synthesis of fused tricyclic carbocycles containing a fully substituted cyclopentene or cyclopentane, and including up to six contig-
uous stereocenters.
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
Not unlike other newly discovered reactions in organic chemis-
try, this annulation process was found to have limitations. As
illustrated in Figure 3B, the diketone 23 delivered a product mix-
ture containing ~30% of a product derived from monocyclization
and intermolecular addition of a propyl group to the unhindered
methyl ketone. Alternatively, substrates containing a conjugated
alkyne (24) or a propargylic ether (25) were also problematic,
perhaps due to varying rates associated with reaction of the inter-
mediate Ti-based organometallic [(i-Pr)2Ti(Oi-Pr)2, or decomposi-
tion products thereof]12 with the alkyne vs. the dicarbonyl system.
ing hydrazone, alkylation with 1-iodo-3-pentyne, and hydrolysis.
Next, regioselective generation of the kinetic enolate was fol-
lowed by acylation and stereoselective methylation to deliver
substrate 28. To our delight, it was found that exposure of 28 to
the standard conditions for annulation delivered the stereodefined
tricyclic product 29 as a single isomer in 40% isolated yield.
Similarly, oxidative quenching of this annulation process with t-
BuOOH delivered the complex epoxydiol 30 in 62% yield. As we
have encountered throughout these investigations, no evidence
was found for the production of stereoisomeric products in the
intramolecular annulation reactions of 28.
Despite observing some limitations, this alkyne–dicarbonyl-
based annulation reaction could be valuable in helping to stimu-
late the invention of new synthesis strategies to complex polyoxy-
genated targets. To facilitate such adoption of this reactivity in
synthesis design, it is important to demonstrate that stereoselectiv-
ity of the annulation process can be achieved by substrate control,
where pre-existing substrate chirality can be used to control the
stereochemical course of the process. In efforts that seek to ex-
plore both of these points, focus shifted to considering how the
annulation reaction may be wielded to address a complex target-
oriented synthesis problem in a unique way.
In conclusion, we report a general annulation strategy for the
synthesis of densely functionalized and highly oxygenated carbo-
cycles that proceeds through the union of alkynes with dicarbonyl
systems. The reactions that have emerged through these studies
are complementary to classic carbocycle-forming processes in
organic chemistry, delivering products not readily available from
Pauson–Khand, Diels–Alder, or Robinson annulation chemistry.
The reactivity realized is thought to proceed through a metallacy-
cle-centered reaction cascade that engages each metal–carbon
bond of a metallacyclopropene in reactions with two different
carbonyl systems. In addition to establishing the basic coupling
process and exploring its utility in intramolecular settings, our
studies have demonstrated the ability to conduct this annulation
reaction in an oxidative manner, delivering carbocyclic products
that bear 4–5 contiguous fully substituted sp3 carbons with all C–
O bonds residing on a single face of the carbocyclic system. Fi-
nally, we have demonstrated that relative stereoselection is possi-
ble to control with a chiral cyclic substrate, and use of this annula-
tion reaction delivers complex and highly oxygenated tricyclic
carbocycles (i.e., 29 and 30) in just a handful of steps from com-
mercially available starting materials (i.e., 26). We look forward
to exploring key features of this annulation reaction in ongoing
methods development projects and target-oriented synthesis cam-
paigns.16
As illustrated in Figure 4A, a synthesis pathway that embraces
the alkyne–dicarbonyl annulation reaction was conceived to be of
potential value for accessing the densely functionalized carbocy-
clic core of ryanodol – a structure that contains a central cyclo-
pentane that is composed of five fully substituted sp3 carbons
(four tertiary ‘alcohols’ and one quaternary center). Here, a chiral
substrate akin to I was viewed as a potential precursor to the
epoxydiol-containing tricycle II – an intermediate that was postu-
lated to be of value in establishing tricyclic species IV through
lactone hydrolysis and ring closure. In the key annulation reac-
tion proposed (I → II), stereochemistry would need to be con-
trolled by the C4 stereocenter, leading to attack at C3 from the α-
face and translation of that newly formed stereochemistry to the
next C–C bond-forming event. After establishing the C1 tertiary
alcohol, the stage would be set for directed epoxidation of the
remaining alkene to deliver II.
Author Information:
As illustrated in Figure 4B, the key steps of this annulation
were tested with a model system. Cyclohexanone (26) was ad-
vanced to the alkynyl ketone 27 by conversion to its correspond-
Corresponding Author
*glenn.c.micalizio@dartmouth.edu
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(11) All attempts to use more highly substituted alkynes or diketones
Notes
in this reaction were unsuccessful, and extension of the basic re-
action design for the establishment of cycloheptenes was not suc-
cessful.
1
2
3
The authors declare no competing financial interest.
ACKNOWLEDGMENT:
(12) See: Eisch, J. J.; Adeosun, A. A.; Gitua, J. N. Eur. J. Org. Chem.
2003, 4721-4727.
4
5
6
7
8
9
We gratefully acknowledge financial support of this work by the
National Institutes of Health – NIGMS (GM080266 and
GM124004). The authors also thank Skyler Svendsen for per-
forming an early example of the alkyne coupling reaction to a γ-
keto aldehyde.
(13)An intramolecular Ti-mediated alkyne–ketone cyclization has
been reported: Morlender-Vais, N.; Solodovnikova, N.; Marek, I.
Chem. Commun. 2000, 1849-1850.
(14) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974-5976. For a recent examples of employing a metal alkoxide
intermediate in directed epoxidation by the addition of Ti(Oi-Pr)4
and t-BuOOH, see: (b) Kelly, A. R.; Lurain, A. E.; Walsh, P. J. J.
Am. Chem. Soc. 2005, 127, 14668-14674. (c) Kim, J. G.; Waltz,
K. M.; Garcia, I. F.; Kwiatkowski, D.; Walsh, P. J. J. Am. Chem.
Soc. 2004, 126, 12580-12585.
(15) The increase in isolated yield observed for product 20, in com-
parison to 17, likely reflects the increased stability of the epoxide
product (in comparison to the ene-diol) to the chromatographic
conditions employed for purification of the crude reaction mix-
ture.
(16) For a recent review on the use of metallacycle-mediated cross-
coupling chemistry in natural product total synthesis, see:
O’Rourke, N. F.; Kier, M. J.; Micalizio, G. C. Tetrahedron 2016,
72, 7093-7123.
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 PARAGRAPH:
Experimental procedures and tabulated spectroscopic data for new
compounds and crystollagrophic data for compound 22 (PDF and
CIF) are available free of charge via the Internet at
http://pubs.acs.org/page/jacsat/submission/authors.html.
REFERENCES:
(1) (a) Wender, P. A. Nat. Prod. Rep. 2014, 31, 433-440. (b) Ihihara,
Y.; Baran, P. S. Synlett 2010, 1733-1745. (c) Burns, N. Z.; Baran,
P. S.; Hoffmann, R. W. Angew. Chem. Int. Ed. 2009, 48, 2854-
2867. (d) Chen, K.; Baran, P. S. Nature 2009, 459, 824-828.
(2) For recent reviews, see: (a) Hartwig, J. F. J. Am. Chem. Soc. 2016,
138, 2-24. (b) Qiu, Y.; Gao, S. Nat. Prod. Rep. 2016, 33, 562-581.
(c) Nakamura, A.; Nakada, M. Synthesis 2013, 45, 1421-1451. (d)
Chen, D. Y.-K.; Youn, S. W. Chem. Eur. J. 2012, 18, 9452-9474.
(e) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40,
1976-1991.
(3) (a) Akasaka, H.; Shione, Y.; Murayama, T.; Ikeda, M. Helv. Chim.
Acta 2005, 88, 2944-2950. (b) Chai, X.-Y.; Bai, C.-C.; Shi, H.-
M.; Xu, Z.-R.; Ren, H.-Y.; Li, F.-F.; Lu, Y.-N.; Song, Y.-L., Tu,
P.-F. Tetrahedron 2008, 64, 5743-5747. (c) Kelly, R. B.; Whit-
tingham, D. J.; Wiesner, K. Can. J. Chem. 1951, 29, 905-910. (d)
Srivastava, S. N.; Przybylska, M. Can. J. Chem. 1967, 46, 795-
797. For an impressive synthetic route to ryanodol and ryanodine,
see: (e) Chuang, K. V.; Xu, C.; Reisman, S. E. Science, 2016,
353, 912-915, and (f) Xu, C.; Han, A.; Virgil, S. C.; Reisman, S.
E. ACS Central Science, 2017, 3, 278-282.
(4) For an example of a Ti–ethylene complex reacting with an alde-
hyde, see: (a) Cohen, S. A.; Bercaw, J. E. Organometallics 1985,
4, 1006-1014. For an example of regioselective coupling of a Ti–
alkyne complex to an aldehyde, see: (b) Harada, K.; Urabe, H.;
Sato, F. Tetrahedron Lett. 1995, 36, 3203-3206.
(5) For a related reaction design that does not deliver stereodefined
products, see the following that describe Nb- and Ta-mediated en-
tries to substituted naphthols: (a) Hartung, J. B.; Pedersen, S. F. J.
Am. Chem. Soc. 1989, 111, 5468-5469. (b) Kataoka, Y.; Miyai, J.;
Tezuka, M.; Takai, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett.
1990, 369-372.
(6) For a recent review of the Kulinkovich reaction, see: (a) Wolan,
A.; Six, Y. Tetrahedron 2010, 66, 15-61. For the titanacycle-to-
carbocycle relay reaction, see: (b) Urabe, H.; Narita, M.; Sato, F.
Angew. Chem. Int. Ed. 1999, 38, 3516-3518.
(7) For previous uses of Ti(Oi-Pr)4 and n-BuLi in metallacycle-
mediated coupling chemistry, see: (a) Tarselli, M. A.; Micalizio,
G. C. Org. Lett. 2009, 11, 4596-4599. (b) Yang, D.; Micalizio, G.
C. J. Am. Chem. Soc. 2011, 133, 9216-9219. (c) Chen, M. Z.; Mi-
calizio, G. C. J. Am. Chem. Soc. 2012, 134, 1352-1356. (d) Jeso,
V.; Aquino, C.; Cheng, X.; Mizoguchi, H. Nakashige, M.; Mical-
izio, G. C. J. Am. Chem. Soc. 2014, 136, 8209-8212. (e) Rassidin,
V. A.; Six, Y. Tetrahedron 2014, 70, 787-794. (f) Mizoguchi, H.;
Micalizio, G. C. J. Am. Chem. Soc. 2015, 137, 6624-6628. (g)
Chen, X.; Micalizio, G. C. J. Am. Chem. Soc. 2016, 138, 1150-
1153. (h) Mizoguchi, H.; Micalizio, G. C. Angew. Chem. Int. Ed.
2016, 55, 13099-13103.
(8) It is known that such Ti–alkyne complexes react in a regioselec-
tive manner with aldehydes, where C–C bond formation occurs
distal to the TMS group. For additional information, see ref. 4(b).
(9) While the isolated yields of products for this cyclohexene-forming
annulation hovered around 50%, the dicarbonyl 7 was completely
consumed, and an additional product was routinely identified
where two equivalents of the intermediate Ti–alkyne intermediate
reacted at both carbonyl systems (~20%).
(10) Syn-1,4-diols like those present in these products of annulation
(eqs 2-4) may be accessible from cycloaddition of the parent cy-
clohexadiene with 1O2, followed by reduction; see: Clennan, E. L.;
Pace, A. Tetrahedron 2005, 61, 6665-6691.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
TOC Figure:
6
7
8
9
• four σ-bonds
Ti(Oi-Pr)4
n-BuLi or RMgX
HO
( )n
R2
• four stereocenters
• 5- or 6-membered
ring formation
• up to 5-contiguous
fully substituted carbons
• single isomer
( )n
O
O
O
R2
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
R1
then
t-BuOOH
R1
R3
R3
R4
HO
X
n = 0 or 1, X = OR4 or R4
= quaternary center
= tertiary alcohol/ether
ACS Paragon Plus Environment