Intramolecular nicholas reaction enables the stereoselective synthesis of strained cyclooctynes

Article abstract of DOI:10.3390/molecules26061629

Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of 1-oxa-3-cyclooctynes starting from commercially available (1R,3S)-camphoric acid. The strategy is based on the initial preparation of propargylic alcohols, complexation of the triple bond with Co₂ (CO)₈, and treatment with BF₃·Et₂ O to induce an intramolecular Nicholas reaction with the free hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom were oriented in such a way that steric interactions were minimized in the cyclization, allowing the formation of cyclooctynes exclusively with (R) configuration, in good agreement with theoretical predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the presence of azides yielding substituted triazoles.

Full text of DOI:10.3390/molecules26061629

molecules
Article
Intramolecular Nicholas Reaction Enables the Stereoselective
Synthesis of Strained Cyclooctynes
Diego M. Monzón 1,2, Juan Manuel Betancort 2,†, Tomás Martín 2,3, Miguel Ángel Ramírez 1,2, Víctor S. Martín 1,2,
*
and David Díaz Díaz 1,2,4,
*
1
2
Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3,
38206 La Laguna, Tenerife, Spain; dmonzon@ull.edu.es (D.M.M.); mramirez@ull.edu.es (M.Á.R.)
Instituto de Bio-Orgánica Antonio González, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez
3, 38206 La Laguna, Tenerife, Spain; jmapt.8537@gmail.com (J.M.B.); tmartin@ipna.csic.es (T.M.)
Instituto de Productos Naturales y Agrobiología, CSIC, Francisco Sánchez 3, 38206 La Laguna, Tenerife, Spain
Institut für Organische Chemie, Universität Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
Correspondence: vmartin@ull.edu.es (V.S.M.); ddiazdiaz@ull.edu.es (D.D.D.)
3
4
*
†
Current address: Rakuten Medical, Inc., 11080 Roselle St., San Diego, CA 92121, USA.
Abstract: Cyclic products can be obtained through the intramolecular version of the Nicholas reaction,
which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis
of 1-oxa-3-cyclooctynes starting from commercially available (1R,3S)-camphoric acid. The strategy
is based on the initial preparation of propargylic alcohols, complexation of the triple bond with
Co2(CO)8, and treatment with BF3 Et2O to induce an intramolecular Nicholas reaction with the free
·
hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes
in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom
were oriented in such a way that steric interactions were minimized in the cyclization, allowing the
formation of cyclooctynes exclusively with (R) configuration, in good agreement with theoretical
predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the
presence of azides yielding substituted triazoles.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Monzón, D.M.; Betancort,
J.M.; Martín, T.; Ramírez, M.Á.;
Martín, V.S.; Díaz Díaz, D.
Intramolecular Nicholas Reaction
Enables the Stereoselective Synthesis
of Strained Cyclooctynes. Molecules
2021, 26, 1629. https://doi.org/
10.3390/molecules26061629
Keywords: Nicholas reaction; cyclooctyne; propargylic carbocation; cyclization; oxacycle; ring strain
1. Introduction
Academic Editor: Narciso M. Garrido
Organometallic complexes have found extensive use in organic chemistry due to the
unique properties they impart on the coordinated organic ligands. A notable transforma-
tion that showcases this altered reactivity is the Nicholas reaction [1–6]. It involves the
reaction of dicobalt hexacarbonyl-stabilized propargylic carbocations with nucleophiles.
The remarkable stability of these carbocations arises from delocalization of the cationic
charge onto the metallic complex. The mild conditions used to form the acetylenic cobalt
complexes, coupled with the versatility of the highly functionalized reaction products
obtained upon demetallation, has rendered this reaction a useful tool for the synthesis of
diverse and complex molecules [7–11].
Received: 1 March 2021
Accepted: 13 March 2021
Published: 15 March 2021
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
An extensive list of nucleophiles has been employed in this transformation, from
carbon-based entities such as ketones and enol silanes, to nitrogen nucleophiles such as
amines and sulfonamides, or oxygen centered species such as alcohols [12
ides [14 15]. In the case where the nucleophile is connected to the alkyne via a suitable chain,
the Nicholas reaction will result in intramolecular attack and formation of a ring [12 13].
This process is favored by the altered geometry of the complexed triple bond that reduces
ring strain. Of particular interest are cyclooctynes, the smallest stable cyclic alkynes. Their
inherent strain has been exploited in organic synthesis and bioorthogonal chemistry for the
,13] or epox-
Copyright:
© 2021 by the authors.
,
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
,
development of novel cycloaddition reactions and labeling agents [16
–18]. Introduction
of heteroatoms in their structure has subtle effects on the reactivity and stability of the
Molecules 2021, 26, 1629. https://doi.org/10.3390/molecules26061629
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 1629
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resulting rings [19]. Herein, we describe the synthesis of 1-oxa-3-cyclooctyne derivatives
by making use of an intramolecular Nicholas reaction. The use of this reaction has been
also reported to obtain other strained cycloalkynes such as cyclononynes [20].
2. Results and Discussion
Our synthetic design towards the preparation of strained 1-oxa-3-cyclooctynes via
the Nicholas reaction was based on the use of (1R,3S)-camphoric acid as starting material
(Scheme 1), a low-cost natural product that is commercially available in both enantiomeric
forms. Apart from the cyclopentane ring, the structure of the desired cyclooctynes is
characterized by the presence of two quaternary centers at
α- and β-positions of the triple
bond, thus providing a sterically demanding environment around it.
H
H
H
H
OH
OH
O
H
COOH
COOH
R
R
R
(CO)6Co2
OH
OH
propargylic
alcohol
(+)-(1R,3S)-camphoric
1-oxa-3-cyclooctyne
acid
Scheme 1. Retrosynthetic analysis of the cyclooctynes envisioned in this work.
In this way, we first envisioned the preparation of the corresponding propargylic alco-
hols as intermediate products, which could be obtained from (+)-(1R,3S)-camphoric acid.
The camphoric acid not only provides a cyclic structure to contribute to the preorganization
of the system prior to cyclization, but it also enables the presence of the oxygen heteroatom,
which would act as the nucleophile during formation of the oxacycle.
Therefore, the first objective was to form a suitable precursor of the propargylic
alcohol, from which we could introduce different R substituents. For this purpose, we
began with the reduction of (+)-(1R,3S)-camphoric acid using borane complexes to obtain
the corresponding diol
BH3 SMe2 complex in THF, affording the desired diol
different steric demand of both alcohols in , dictated by the presence of the chiral methyl
2
(Scheme 2). In this step, the best result was obtained with the
·
2
in 96% yield. Subsequently, the
2
group, made it possible to perform the selective protection of the most accessible hydroxyl
◦
group as its t-butyldiphenylsilyl ether at 0 C in 1 h, affording product
3 in excellent
yield (95%).
1. SO3·Py, DCM
Et3N, DMSO
TBDPSCl
imidazole
H
H
H
H
BH3·Me2S
THF
OH
i) n-BuLi, THF
OTBDPS
OTBDPS
Br
COOH
COOH
DCM, 0 ºC
2. CBr4, PPh3
DCM
ii)
RCHO
Br
OH
2 (96%)
OH
(+)-(1R,3S)-camphoric
4 (91%)
3 (95%)
acid
H
H
H
O
R
H
1. Co2(CO)8, DCM
TBAF
THF
OTBDPS
OH
R
NMO
DCM
O
H
R
R
2. BF3·Et2O
DCM, −20 ºC
Co2(CO)6
OH
OH
5, R = n-hexyl, 78%
6, R = H, 81%
7, R = Me, 84%
8, R = Ph, 70%
9, R = 3-butenyl, 66%
10, R = n-hexyl, 90%
11, R = H, 99%
12, R = Me, 92%
13, R = Ph, 86%
15, R = n-hexyl
16, R = H
17, R = Me
18, R = Ph
19, R = 3-butenyl
1, R = n-hexyl, 64% (from 10)
20, R = H, n.d.
21, R = Me, 58% (from 12)
22, R = Ph, 31% (from 13)
23, R = 3-butenyl, 57% (from 14)
14, R = 3-butenyl, 76%
Scheme 2. Synthetic route for the preparation of strained cyclooctynes (
(+)-(1R,3S)-camphoric acid. Abbreviation: n.d. = not detected.
1,
20−23) starting from commercially available

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The next step required the transformation of the free hydroxyl group into a termi-
nal alkyne, for which the introduction of an additional carbon atom was necessary. This
was satisfactorily achieved using the well-known Corey–Fuchs reaction [21]. Firstly, the
oxidation of the primary hydroxyl group of compound
3 was carried out using the Parikh–
Doering reaction [22], affording the corresponding aldehyde. Then, the so-formed aldehyde
was reacted with a mixture of PPh3 and CBr4 to give in good yield (91%)◦the expected
78 C was added
1,1-dibromoalkene derivative
4
[
23]. At this point, an excess of n-BuLi at
−
to compound
4 to form the corresponding alkanide anions, which were subsequently
reacted with different aldehydes (i.e., heptanal, para-formaldehyde, acetaldehyde, ben-
zaldehyde, 4-pentenal). This resulted in the formation of a series of propargylic alcohols
5
–
9
in good yields (66–84%) with different R substituents (i.e., R = hexyl, R = H, R = Me
R = Ph R = butenyl, respectively). Removal of the t-butyldiphenylsilyl ether group (TB-
DPS) using tetra-n-butylammonium fluoride in THF yielded the desired diols 10 14 in
,
,
–
good yields (76–99%), which represent the starting materials for testing the intramolecular
Nicholas reaction.
Provided an optimal interatomic distance, the nucleophilic free hydroxyl group should
attack at the propargylic position, necessary in order to obtain the desired cyclooctynes [3].
Cyclization was induced by forming a stabilized carbocation upon complexation of the
triple bond with dicobalt octacarbonyl [Co2(CO)8] and subsequent treatment with a Lewis
acid. Thus, bright red-colored cobalt complexes were easily obtained at room temperature
in DCM in almost quantitative yields upon a quick purification by column chromatography.
It is worth mentioning that the cobalt complexes were always prepared immediately
prior to◦their use, even though they were stable for several days under inert atmosphere
at
−
20 C. Long periods of time, even under these conditions, caused their slow but
gradual decomposition. Finally, the obtained cobalt complexes we◦re re-dissolved in DCM
and treated with a slight excess of BF3
·
Et2O (1.2 equiv) at
−
20 C. This prompted the
intramolecular Nicholas reaction to afford the corresponding cyclic ethers 15
were immediately treated with 4-methylmorpholine N-oxide (NMO) as a mild oxidizer to
remove the cobalt complexation of the triple bonds. The strained cycloalkynes and 21 23
–19, which
1
–
were isolated in good overall yields after three steps (31–64%). However, the expected
product 20 (R = H) could not be detected from the reaction mixture obtained from precursor
11. Further investigation will be carried out in our group to clarify this unexpected result.
Mono- and bidimensional NMR spectroscopy confirmed unequivocally the structures
of all synthesized compounds
1 and 21–23 (Figures S1–S46). Very interestingly, a series
of ROESY experiments showed that the stereochemical configuration of the chiral center
generated during cyclization was exclusively (R) for compounds 1, 22, and 23 (Figure 1).
Figure 1. 3D structural model of cyclooctyne (R)-1. Black arrows indicate nuclear Overhauser effects
(NOEs), and the alkyl group is represented in green color.
The observed stereoselectivity can be explained on the basis of the reaction mechanism
because the orientation of the substituents is fixed during the generation of the intermediate
carbocation and it is defined by steric factors (Scheme 3). In particular, large-sized R
substituents (e.g., R = n-hexyl, Ph, 3-butenyl) are oriented in such a way that they can
minimize steric interactions, as observed in the case of compounds
1, 22, and 23. In contrast,
when R substituents are of small size (e.g., R = Me) the steric interactions are smaller, and

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the free rotation of the bond between the cobalt-bonded carbon and the carbon at the
propargylic position allows for the substituent to be oriented in any direction and, hence,
the intramolecular attack occurs on both sides of the carbocation. This justifies the formation
of the two possible stereoisomers (R) and (S) in the case of compound 21. Therefore, the
side preference during the intermolecular nucleophilic attack on the carbocation depends
on both the nature of the propargylic alcohol and the size of the R substituent.
H
H
OH
OH
H
R
(CO)
3
Co
Co(CO)3
R
H
(CO)
Co
3
(CO)
Co
3
Scheme 3. The generation of (S) configuration at the stabilized carbocation in the cyclization is
hindered by steric factors in the case of large-sized R groups.
Furthermore, these results were found to be in good agreement with theoretical
calculations. Specifically, the structural analysis of the cycloalkyne
1 was performed at the
B3LYP/6-31G* level to determine the bond angle between the carbon atoms of the triple
bond and the neighboring carbons and the stability of both stereoisomers (i.e., (R) and
(S) at the chiral center connected to the◦O atom). The results showed that the deviation
from linearity at the triple bond was 53.2 , corresponding to two sp3-sp angles of 155.4 and
151.4◦ for (R)-
1
(left and right of the image, respectively, Figure 2a), and 155.8 and 155.4◦
for the isomer (S)-1.
(a)
Figure 2.
(b)
) Calculated angle-strain in cyclooctyne
(c)
(a
1; (
b
) 3D ball-and-stick molecular model of
minimized (R)-1; (c) 3D ball-and-stick molecular model of minimized (R)-15 (hydrogen atoms are
omitted for clarity).
Furthermore, the stability of compound 1, which has an (R) configuration at the chiral
center (marked with an arrow in Figure 2a) was 1.51 kcal/mol higher than its analog with
(S) configuration. In addition, calculations performed for the cobalt-complex precursor
15, with B3LYP/def2SVP optimization, revealed that such difference in stability increased
to 7.62 kcal/mol. Thus, the product with (R) configuration is favored enthalpically, as
is the formation of the cobalt complex precursor. Clearly, the angular stress release as
a consequence of complexation favors the Nicholas reaction, being that its selectivity is
controlled by the electrostatic and steric effects generated in the new scenario.
Finally, a simple preliminary test was carried out in order to evaluate the potential
use of these compounds in the strain-promoted azide-alkyne cycloaddition (SPAAC) [17].
In this experiment, a solution of benzyl azide in CD3CN was added to a solution of 1 in
CD3CN, in a 1:1 ratio (azide/cycloalkyne) ◦(Scheme 4), and the reaction was monitored
1
over time by H-NMR spectroscopy at 25 C (Figure S47). The analysis of the spectra
clearly showed the disappearance of the signals ascribed to the protons in the benzylic
position of the benzyl azide as well as the appearance of new benzylic protons associated
to the formation of the corresponding triazole rings (24 and 25). However, despite the large
size of the bicyclic structure, no regioselectivity was detected and both regioisomers were

Molecules 2021, 26, 1629
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obtained in almost the same proportion. In terms of kinetics, the second-order rate constant
was estimated in 7.6 × 10−3 M−1s−1, which is in the range of other cyclooctynes [24].
H
H
H
H
O
O
N3
H
C6H13
C6H13
H
O
+
N
N
N
N
CD3CN
N
N
C6H13
1
24
25
Scheme 4. Strain-promoted azide-alkyne cycloaddition (SPAAC) between synthesized cyclooctyne
1
and benzylazide.
It is worth noting that other strained cyclooctynes such as 23, bearing a terminal double
bond, may also expand the potential uses of these compounds since further functionaliza-
tion can be achieved through another “click” reaction such as the thiol-ene reaction [25].
3. Materials and Methods
3.1. Instrumental Techniques
•
Nuclear magnetic resonance (NMR)
1H-NMR spectra were recorded in BRUKER AVANCE spectrometers (Bruker Corpo-
ration, Billerica, MA, USA) at 500 and 600 MHz, and 13C-NMR spectra were recorded at
125 and 150 MHz. Chemical shifts were reported in units (ppm) by assigning tetramethylsi-
lane resonance in the 1H-NMR spectrum as 0.00 ppm (chloroform, 7.26 ppm). Data were
reported as follows: chemical shift, multiplicity coupling constant (J values) in Hz and
integration. Chemical shifts for 13C-NMR spectra were recorded in ppm from tetramethyl-
silane using the central peak of CDCl3 (77.0 ppm) as the internal standard. In 1H-NMR
spectra, multiplicity is indicated by the following abbreviations: singlet = s, doublet = d,
triplet = t, quartet = q, double doublet = dd, double double doublet = ddd, multiplet = m.
In 13C-NMR spectra, multiplicity is indicated as following: CH3 = q, CH2 = t, CH = d, C = s
Copies of all NMR spectra are included as Supplementary Material in Appendix A.
.
• Mass spectrometry
Accurate mass (HRMS) was determined by electrospray ionization (ESI-TOF) and
electronic impact (EI-TOF).
•
Melting point
Melting point was measured by a Büchi B-540 equipment (BUCHI corporation, New
Castle, DE, USA), using a Standard vanillin sample (Büchi N
º
37454) with a melting point
value of 81.7 ◦C ± 0.7 ◦C as a reference standard.
•
Specific rotation (polarimetry)
◦
Specific rotation measurements were carried out at 25 C in a Perkin-Elmer 241
(PerkinElmer Corporation, Waltham, MA, USA) polarimeter equipped with a Na lamp.
The concentration of the samples was indicated in each case using 1 dm long cells.
3.2. Chromatographic Techniques
Flash column chromatography was performed using silica gel, 60 Å and 0.2–0.5 mm,
with the indicated solvent system according to standard techniques. Compounds were
visualized on TLC plates by use of UV light, or vanillin with acetic and sulfuric acid in
ethanol with heating.

Molecules 2021, 26, 1629
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3.3. Solvents and Reagents
DCM, Et2O, and THF were dried and distilled under argon atmosphere immediately
prior to use. Other commercially available solvents properly stored were used without
further purification. All reagents were purchased from commercial suppliers and used
without further purification, unless otherwise stated.
3.4. Nomenclature
Chemical nomenclature was generated using ChemDraw Professional version 17.1.0.105
(19) software (PerkinElmer corporation, Massachusetts, USA), and in accordance with
IUPAC rules. The atoms of the compounds were numbered following the abovementioned
nomenclature, unless noted otherwise.
3.5. Synthesis and Characterization of Compounds
3.5.1. ((1R,3S)-1,2,2-trimethylcyclopentane-1,3-diyl)dimethanol (2)
To a solution of camphoric acid (7.1 g, 35.0 mmol) in 250 mL THF at 0 ◦C under inert
atmosphere, we added 46 mL of BH3 SMe2 (2.0 M in THF) dropwise, and the reaction
·
mixture was stirred for 23 h at RT. The reaction was quenched by adding 17 mL of MeOH
dropwise at 0 ◦C. Then, the solvent was evaporated under reduced pressure. The crude
was purified by flash chromatography (silica gel, gradient n-hexane/EtOAc 60:40 to 40:60)
to obtain 5.8 g (96% yield) of 2 as a white solid.
1H-NMR (500 MHz, CDCl3, 298 K):
δ ppm 3.73 (dd, J = 5.3, 10.3 Hz, 1H), 3.58 (d,
J = 10.8 Hz, 1H), 3.51 (dd, J = 8.3, 10.3 Hz, 1H), 3.47 (d, J = 10.8 Hz, 1H), 2.08 (ddd, J = 5.3,
9.3, 17.8 Hz, 1H), 1.99–1.91 (m, 1H), 1.63–1.56 (m, 1H), 1.41–1.32 (m, 2H), 1.25 (br, 2H), 1.02
(s, 3H), 1.01 (s, 3H), 0.79 (s, 3H).
13C-NMR (125 MHz, CDCl3, 298 K):
δ
ppm 69.2 (t), 65.0 (t), 50.5 (d), 48.8 (s), 44.0 (s),
33.7 (t), 25.5 (t), 24.2 (q), 20.4 (q), 18.5 (q).
HRMS (ESI-negative): m/z: calculated for C10H19O [M
−
H+]: 171.1385, found:
171.1391.
Melting point: 130–132 ◦C.
[α]25D = + 54.1 (c 2.19, CHCl3).
3.5.2. ((1R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2,2-trimethylcyclopentyl)methanol (3)
The diol
2 (8.4 g, 48.8 mmol) was dissolved in 500 mL of DCM (0.1 M) under inert
atmosphere (Ar). The solution was then cooled to 0 ◦C and imidazole (10.0 g, 146.3 mmol,
3 equiv) was added. Finally, TBDPSCl (13 mL, 48.8 mmol, 1.0 equiv) was added dropwise
and the mixture was stirred for 3–4 h. The reaction was quenched with 800 mL of water and
the 2 phases were separated. The aqueous layer was extracted with DCM (2
×
400 mL). The
organic layers were collected, dried over anhydrous MgSO4, and filtered, and the solvent
was removed under reduced pressure. The crude was purified by flash chromatography
(silica gel, gradient n-hexane/EtOAc, 90:10 to 80:20) to obtain 19.1 g (95% yield) of the
compound 3 as a colorless oil.
1H-NMR (500 MHz, CDCl3, 298 K):
δ ppm 7.69–7.66 (m, 4H), 7.45–7.36 (m, 6H), 3.70
(dd, J = 6.4, 10.1 Hz, 1H), 3.57–3.52 (m, 2H), 3.45 (d, J = 10.8 Hz, 1H), 2.14 (ddd, J = 7.2, 9.6,
16.4 Hz, 1H), 1.92–1.83 (m, 1H), 1.58–1.50 (m, 1H), 1.36–1.24 (m, 2H), 1.04 (s, 9H), 0.99 (s,
3H), 0.97 (s, 3H), 0.75 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 135.6 (d), 134.1 (s), 134.0 (s), 129.5 (d), 129.5
(d), 127.6 (d), 69.3 (t), 65.5 (t), 50.1 (d), 48.9 (s), 43.9 (s), 33.7 (t), 26.9 (q), 25.2 (t), 24.4 (q), 20.4
(q), 19.2 (s), 18.4 (q).
HRMS (ESI): m/z: calculated for C26H38O2Si [M + Na+]: 433.2539, found: 433.2536
[α]25D = + 20.5 (c 2.12, CHCl3).

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3.5.3. tert-Butyl(((1S,3S)-3-(2,2-dibromovinyl)-2,2,3-trimethylcyclopentyl)methoxy)
diphenylsilane (4)
To a solution of
3
(10.1 g, 24.59 mmol) in 82 mL of DCM (0.3 M) under inert atmosphere
◦
(Ar) at 0 C, we sequentially added DMSO (16.2 mL, 0.66 mL/mmol) triethylamine (17.3 mL,
122.97 mmol, 5 equiv) and finally the SO3 Py complex (11.7 g, 3 equiv). The mixture
·
was stirred for 2 h. After that, the reaction was quenched with 100 mL of water, and
then the organic layer was separated and the aqueous phase was extracted with DCM
(2 × 100 mL). The organic extracts were collected, dried over anhydrous MgSO4, and
filtered, and the solvent was evaporated under reduced pressure. The crude was purified
by flash chromatography (silica gel, n-hexane/EtOAc, 95:5) to obtain 9.3 g (93% yield) of
the corresponding aldehyde, which was immediately used in the next step.
Intermediate aldehyde: 1H-NMR (500 MHz, CDCl3, 298 K):
δ ppm 9.63 (s, 1H)
7.68–7.65 (m, 4H), 7.45–7.37 (m, 6H), 3.6 (dd, J = 6.7, 10.2 Hz, 1H), 3.57 (dd, J = 6.9, 10.2 Hz,
1H), 2.29 (ddd, J = 5.8, 11.5, 13.2, Hz, 1H), 2.15 (ddd, J = 6.9, 9.3, 16.3 Hz, 1H), (dddd, J = 6.1,
9.5, 13.6, 13.6 Hz, 1H), 1.92–1.83 (m, 1H), 1.45–1.29 (m, 2H), 1.07 (s, 3H), 1.05 (s, 12H), 0.82
(s, 3H).
To a solution of the so-formed aldehyde (1.73 g, 4.23 mmol) in DCM (42.3 mL, 0.1 M) at
0 C under inert atmosphere (Ar), we added 7.8 g of PPh3, and when it was dissolved, 5.0 g
◦
of CBr4 was added in portions. The mixture was stirred overnight. Next, the solvent was
removed under reduced pressure until one-quarter of the volume remained. Then, 50 mL
of Et2O was added and the suspension was filtered through celite. Finally, the solvent from
the filtrate was removed in vacuo. The crude was purified by flash chromatography (silica
gel, n-hexane/DCM, 98:2) to obtain 2.17 g (91% yield) of the compound 4.
1H-NMR (500 MHz, CDCl3, 298 K):
δ ppm 7.69–7.65 (m, 4H), 7.45–7.36 (m, 6H). 6.61
(s, 1H), 3.69 (dd, J = 6.9, 10.1 Hz, 1H), 3.56 (dd, J = 7.0, 10.1 Hz, 1H), 2.09–1.81 (m, 4H),
1.31–1.23 (m, 1H), 1.06 (s, 3H), 1.05 (s, 9H), 0.94 (s, 3H), 0.70 (s, 3H).
13C-NMR (125 MHz, CDCl3, 298 K):
δ ppm 144.1 (d), 135.6 (d), 133.9 (s), 133.9 (s), 129.6
(d), 129.5 (d), 127.6 (d), 85.3 (s), 65.6, (t), 53.4 (s), 47.4 (d), 45.8 (s), 33.8 (t), 26.9 (q), 24.9 (t),
22.2 (q), 20.9 (q), 19.4 (q), 19.2 (s).
HRMS (ESI): m/z: calculated for C27H3679Br81BrOSi [M + Na+]: 587.0779, found:
587.0780.
[α]25D = + 12.8 (c 2.95, CHCl3).
3.5.4. Compounds 5–9
General procedure: Compound
inert atmosphere (Ar), we added 3 equiv of n-BuLi solution (2.3 M in hexane) at 0 C.
4
was dissolved in dry THF (6 mL, 0.15M), and under
◦
The reaction mixture was stirred for 15 min and then the corresponding aldehyde (i.e.,
heptanal
→
compound
5
; para-formaldehyde
→
compound
6
; acetaldehyde
→
compound
◦
7; benzaldehyde
→
compound
8
; 4-pentanal
→
compound
9) was added at
−
78 C.
The mixture was allowed to reach RT while it was stirred overnight. The reaction was
quenched by adding 20 mL of saturated NH4Cl solution, and then it was extracted with
Et2O (3 × 20 mL). The organic layer was collected, dried over anhydrous MgSO4, filtered,
and concentrated under reduced pressure. The crude was purified by flash chromatography
(silica gel) yielding the corresponding propargyl alcohol.
1-((1R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2,2-trimethylcyclopentyl)non-1-yn-3-ol
1
(
5
). H-NMR (600 MHz, CDCl3, 298 K):
δ
ppm 7.68–7.65 (m, 4H), 7.44–7.36 (m, 6H), 4.35
(ddd, J = 2.2, 6.5, 6.5 Hz, 1H), 3.71 (dd, J = 6.7, 10.0 Hz, 1H), 3.57 (dd, J = 7.5, 10.0 Hz, 1H),
2.08–2.02 (m, 1H), 1.97–1.91 (m, 1H), 1.88–1.81 (m, 1H), 1.70–1.59 (m, 2H), 1.34–1.26 (m, 8H),
1.13 (s, 3H), 1.05 (s, 9H), 0.96 (s, 3H), 0.90 (s, 3H), 0.89 (t, J = 6.7 Hz, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 135.6 (d), 134.0 (s), 133.9 (s), 129.5 (d), 129.5
(d), 127.6 (d), 90.9 (s), 83.0 (s), 66.0 (t), 62.8 (d), 48.1 (d), 45.7 (s), 45.3 (s), 45.3 (s), 38.3 (t),
37.5 (t), 37.5 (t), 31.7 (t), 28.9 (t), 26.9 (q), 25.3 (t), 25.2 (t), 24.1 (q), 23.4 (q), 22.5 (t), 20.6 (q),
19.2 (s), 14.0 (q).
Column chromatography: n-hexane/EtOAc (95:5).

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3-((1R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2,2-trimethylcyclopentyl)prop-2-yn-1-
1
ol (6
). H-NMR (500 MHz, CDCl3, 298 K):
δ
ppm 7.69–7.66 (m, 4H), 7.45–7.36 (m, 6H), 4.25
(s, 2H), 3.71 (dd, J = 6.7, 10.0 Hz, 1H), 3.57 (dd, J = 7.4, 10.0 Hz, 1H), 2.10–2.02 (m, 1H),
1.99–1.91 (m, 1H), 1.90–1.81 (m, 1H), 1.64–1.57 (m, 1H), 1.42 (br, 1H), 1.39–1.30 (m, 1H), 1.14
(s, 3H), 1.05 (s, 9H), 0.97 (s, 3H), 0.91 (s, 3H).
13C-NMR (125 MHz, CDCl3, 298 K):
δ ppm 135.6 (d), 134.0 (s), 133.9 (s), 129.5 (d), 129.5
(d), 127.6 (d), 91.9 (s), 79.9 (s), 66.0 (t), 51.5 (t), 48.1 (d), 45.7 (s), 45.3 (s), 37.4 (t), 26.9 (q), 25.3
(t), 24.0 (q), 23.4 (q), 22.5 (t), 20.6 (q), 19.2 (s).
HRMS (ESI): m/z: calculated for C28H38O2Si [M + Na+]: 457.2539, found: 457.2535.
Column chromatography: n-hexane:EtOAc (80:20).
4-((1R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2,2-trimethylcyclopentyl)but-3-yn-2-ol
1
(7
). H-NMR (600 MHz, CDCl3, 298 K):
δ
ppm 7.67 (d, J = 7.8 Hz, 4H), 7.44–7.40 (m, 6H),
4.51 (dd, J = 6.0, 12.4 Hz, 1H), 3.71 (dd, J = 6.7, 10.1 Hz, 1H), 3.56 (dd, J = 7.7, 9.6 Hz, 1H),
2.08–2.02 (m, 1H), 1.96–1.90 (m, 1H), 1.89–1.81 (m, 1H), 1.63 (br, 1H), 1.59 (ddd, J = 4.7, 10.1,
13.7 Hz, 1H), 1.40 (d, J = 6.5 Hz, 3H), 1.37–1.30 (m, 1H), 1.13 (s, 3H), 1.05 (s, 9H), 0.96 (s,
3H), 0.90 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 135.6 (d), 134.0 (s), 133.9 (s), 129.5 (d), 129.5
(d), 127.6 (d), 90.1 (s), 83.9 (s), 66.0 (t), 58.6 (d), 48.1 (t), 45.5 (s), 45.3 (s), 45.3 (s), 37.5 (t), 37.4
(t), 26.9 (q), 25.3 (t), 24.9 (q), 24.0 (q), 23.4 (q), 20.6(q), 19.2 (s).
HRMS (ESI): m/z: calculated for C29H40O2Si [M + Na+]: 471.2695, found: 471.2696.
Column chromatography: n-hexane/EtOAc (gradient 95:5–80:20).
3-((1R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2,2-trimethylcyclopentyl)-1-phenylprop-
1
2-yn-1-ol (
8
). H-NMR (600 MHz, CDCl3, 298 K):
δ
ppm 7.66 (d, J = 7.5 Hz, 8H), 7.54 (d,
J = 7.5 Hz, 4H), 7.44–7.40 (m, 4H), 7.40–7.34 (m, 12H), 7.33–7.29 (m, 2H), 5.45 (s, 2H), 3.71
(dd, J = 6.9, 10.0 Hz, 2H), 3.57 (dd, J = 7.6, 9.6 Hz, 2H), 2.10–2.04 (m, 2H), 2.03–1.97 (m, 4H),
1.90–1.83 (m, 2H), 1.67–1.61 (br, 2H), 1.38–1.31 (m, 2H), 1.19 (s, 3H), 1.18 (s, 3H), 1.04, (s,
18H), 0.97 (s, 3H), 0.98 (s, 3H), 0.93 (s, 3H), 0.92 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 141.4 (s), 141.4 (s), 135.6 (d), 134.0 (s), 133.9
(s), 129.5 (d), 129.5 (d), 128.5 (d), 128.1 (d), 127.6 (d), 126.7 (d), 93.1 (s), 81.5 (s), 65.9 (t), 64.9
(d), 48.1 (d), 45.8 (s), 45.5 (s), 37.5 (t), 37.4 (t), 26.9 (q), 25.3 (t), 24.1 (q), 24.0 (q), 23.4 (q), 20.7
(q), 20.7 (q), 19.2 (s).
HRMS (ESI): m/z: calculated for C34H42O2Si [M + Na+]: 533.2852, found: 533.2857.
Column chromatography: n-hexane/EtOAc (gradient 95:5–90:10).
1-((1R,3S)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-1,2,2-trimethylcyclopentyl)hept-6-en-1-
1
yn-3-ol (
9
). H-NMR (600 MHz, CDCl3, 298 K):
δ
ppm 7.68–7.65 (m, 8H), 7.44–7.36 (m, 12H),
5.87–5.80, (m, 2H), 5.05, (dd, J = 1.6, 17.1 Hz, 2H), 4.98 (ddd, J = 0.9, 0.9, 10.2 Hz, 2H), 4.38
(ddd, J = 2.2, 6.5, 6.5 Hz, 2H), 3.71 (dd, J = 6.8, 10.0 Hz, 2H), 3.56 (dd, J = 7.4, 10.0 Hz, 2H),
2.24–2.19 (m, 4H), 2.08–2.02 (m, 2H), 1.97–1.91 (m, 2H), 1.89–1.81 (m, 2H), 1.80–1.70 (m, 4H),
1.62–1.57 (m, 4H), 1.36–1.3 (m, 2H), 1.14 (s, 6H), 1.05 (s, 18H), 0.96 (s, 6H), 0.91 (s, 3H), 0.90
(s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 137.9 (d), 135.6 (d), 134.0 (s), 133.9 (s), 129.5
(d), 129.5 (d), 127.6 (d), 115.1 (t), 91.3 (s), 82.6 (s), 66.0 (t), 62.3 (d), 48.1 (d), 45.7 (s), 45.3 (s),
37.5 (t), 37.4 (t), 29.6 (t), 26.9 (q), 25.3 (t), 24.1 (q), 23.9 (q), 20.6 (q), 19.2 (s).
HRMS (ESI): m/z: calculated for C32H44O2Si [M + Na+]: 511.3008, found: 511.3015.
Column chromatography: n-hexane/EtOAc (gradient 95:5–90:10).
3.5.5. Compounds 10–14
Compounds 5–9 were each dissolved in THF (0.1 M concentration), and 1.5 equiv
of TBAF solution (1.0 M in THF) was added to the mixture, which was stirred until
monitorization by TLC showed that reaction was finished. Next, 15 mL of water was
added to the reaction mixture, and after that it was extracted with Et2O (3
×
20 mL). The
organic layer was collected, dried over anhydrous MgSO4, then filtered and concentrated
by rotavap. The crude was purified by flash chromatography (silica gel) to furnish products
10–14.

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1-((1R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl)non-1-yn-3-ol (10). H-NMR (500 MHz,
CDCl3, 298 K):
δ ppm 4.37 (t, J = 6.6 Hz, 1H), 3.74 (dd, J = 5.6, 10.2 Hz, 1H), 3.55 (dd, J = 8.0,
10.2 Hz, 1H), 2.04–1.96 (m, 2H), 1.95–1.88 (m, 1H), 1.73–1.60 (m, 4H), 1.47–1.38 (m, 3H),
1.36–1.24 (m, 7H), 1.15 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H), 0.88 (t, J = 6.9 Hz, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 90.6 (s), 83.2 (s), 65.4 (t), 62.8 (d), 48.6 (d),
45.6 (s), 45.3 (s), 45.3 (s), 38.3 (t), 37.5 (t), 37.5 (t), 31.7 (t), 28.9 (t), 25.6 (t), 25.2 (t), 23.9 (q),
23.9 (q), 23.4 (q), 22.5 (t), 20.7 (q), 14.0 (q).
HRMS (ESI): m/z: calculated for C18H32O2 [M + Na+]: 303.2300, found: 303.2303.
Column chromatography: n-hexane:EtOAc (50:50).
3-((1R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl)prop-2-yn-1-ol (11). 1H-NMR
(500 MHz, CDCl3, 298 K):
δ ppm 4.28 (d, J = 4.5 Hz, 2H), 3.74 (dd, J = 5.5, 10.2 Hz, 1H), 3.57
(dd, J = 8.2, 10.0 Hz, 1H), 2.04–1.89 (m, 3H), 1.69–1.63 (m, 1H), 1.54 (br, 1H), 1.47–1.39 (m,
1H), 1.27 (br, 1H), 1.16 (s, 3H), 0.99 (s, 3H), 0.95 (s, 3H).
13C-NMR (125 MHz, CDCl3, 298 K):
δ ppm 91.6 (s), 80.2 (s), 65.3 (t), 51.5 (t), 48.5 (d),
45.6 (s), 45.3 (s), 37.5 (t), 25.5 (t), 23.9 (q), 23.3 (q), 20.7 (q).
HRMS (ESI): m/z: calculated for C12H20O2 [M + Na+]: 219.1361, found: 219.1369.
Column chromatography: n-hexane/EtOAc (40:60).
4-((1R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl)but-3-yn-2-ol (12). 1H-NMR (600 MHz,
CDCl3, 298 K):
δ ppm 4.54 (dd, J = 6.5, 13.1 Hz, 1H), 3.74 (dd, J = 5.7, 10.4 Hz, 1H), 3.56 (dd,
J = 8.3, 10.1 Hz, 1H), 2.03–1.89 (m, 3H), 1.68–1.62 (m, 1H), 1.43 (d, J = 6.5 Hz, 4H), 1.15 (s,
3H), 0.98 (s, 3H), 0.94 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 89.9 (s), 84.1 (s), 65.4 (t), 58.6 (d), 48.6 (d),
45.5 (s), 45.4 (s), 45.3 (s), 37.5 (t), 37.5 (t), 25.6 (t), 24.9 (q), 23.9 (q), 23.4 (q), 20.6 (q).
HRMS (ESI): m/z: calculated for C13H22O2 [M + Na+]: 233.1517, found: 233.1513.
Column chromatography: n-hexane/EtOAc (50:50).
1
3-((1R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl)-1-phenylprop-2-yn-1-ol (13). H-
NMR (600 MHz, CDCl3, 298 K): ppm 7.55 (d, J = 7.4 Hz, 4H), 7.38 (t, J = 7.5 Hz, 4H), 7.32
δ
(t, J = 7.3 Hz, 2H), 5.48 (s, 2H), 3.73 (dd, J = 5.6, 10.3 Hz, 2H), 3.54 (dd, J = 8.1, 10.1 Hz, 1H),
2.12 (br, 2H), 2.09–1.91 (m, 6H), 1.73–1.67 (m, 2H), 1.58 (br, 2H), 1.48–1.41 (m, 2H), 1.21 (s,
3H), 1.21 (s, 3H), 1.01 (s, 3H), 1.01 (s, 3H), 0.97 (s, 3H), 0.96 (s, 3H).
13C-NMR R (150 MHz, CDCl3, 298 K):
δ ppm 141.4 (s), 128.5 (d), 128.2 (d), 126.7 (d),
92.8 (s), 81.8 (s), 65.3 (t), 64.9 (d), 48.6 (d), 45.8 (s), 45.5 (s), 37.5 (t), 37.5 (t), 25.6 (t), 23.9 (q),
23.9 (q), 23.4 (q), 20.8 (q).
HRMS (ESI): m/z: calculated for C18H24O2 [M + Na+]: 295.1674, found: 295.1675.
Column chromatography: DCM/EtOAc (gradient 90:10–50:50).
1-((1R,3S)-3-(hydroxymethyl)-1,2,2-trimethylcyclopentyl)hept-6-en-1-yn-3-ol (14). 1H-NMR
(500 MHz, CDCl3, 298 K): δ ppm 5.89–5.79, (m, 1H), 5.07, (dd, J = 1.7, 17.1 Hz, 1H), 5.00–4.96
(m, 1H), 4.40 (t, J = 6.5 Hz, 1H), 3.73 (dd, J = 5.6, 10.2 Hz, 1H), 3.56 (dd, J = 8.0, 10.2 Hz, 1H),
2.28–2.16 (m, 2H), 2.05–1.88 (m, 3H), 1.84–1.71 (m, 3H), 1.69–1.62 (m, 1H), 1.46–1.38 (m, 1H),
1.16 (s, 3H), 0.99 (s, 3H), 0.94 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 137.9 (d), 115.1 (t), 91.0 (s), 82.9 (s), 65.3 (t),
62.2 (d), 48.5 (d), 45.6 (s), 45.3 (s), 45.3 (s), 37.5 (t), 37.5 (t), 37.3 (t), 29.6 (t), 25.6 (t), 23.9 (q),
23.4 (q), 20.7 (q).
HRMS (ESI): m/z: calculated for C16H26O2 [M + Na+]: 273.1831, found: 273.1834.
Column chromatography: n-hexane/EtOAc (70:30).
3.5.6. Compounds 1, 20–23
General procedure: To a solution of the corresponding diol (10–14) in DCM (0.1 M)
under inert atmosphere (Ar), we added dicobalt octacarbonyl complex (1.2 equiv), and
the mixture was stirred until the reaction was finished, which was monitored by TLC.
Afterwards, the solvent was evaporated in vacuo, and the crude solid was adsorbed in
silica gel and then separated by flash chromatography. The resulting compounds were
again dissolved in DCM (0.05 M) under inert atmosphere (Ar), and the solution was cooled
to
−
20 ◦C before dropwise addition of 1.3 equiv of BF3
Et2O. The resulting mixture was
·

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placed in a fridge to maintain the temperature at
−
20 ◦C during 36 h. Next, the reaction
mixture was poured in a vigorously stirred solution of saturated NaHCO3 (30 mL). Then,
the organic layer was collected, and the aqueous layer was extracted with DCM (3 × 20 mL).
The organic extracts were dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The alkyne–Co2(CO)6 complexes from the crude were isolated by flash
chromatography (silica gel). Finally, 6 equiv of 4-methylmorpholine N-oxide (NMO) were
added to a DCM solution containing the resulting complexes under inert atmosphere (Ar),
and the mixture was stirred for 36 h. After filtration of the NMO residues, the solvent
was removed by rotavap and the crude was purified by flash chromatography (silica gel)
obtaining compounds 1 and 21–23.
1
(1S,4R,7R)-4-hexyl-7,10,10-trimethyl-3-oxabicyclo[5.2.1]dec-5-yne (
1
). H-NMR (500 MHz,
CDCl3, 298 K):
δ
ppm 4.24 (dd, J = 5.9, 6.9 Hz, 1H), 3.85 (dd, J = 8.7, 14.0 Hz, 1H), 3.54 (d,
J = 14.0 Hz, 1H), 2.26–2.16 (m, 1H), 1.88–1.71 (m, 4H), 1.65–1.52 (m, 2H), 1.41–1.22 (m, 8H),
1.15 (s, 3H), 0.97 (s, 3H), 0.87 (t, 6.9 Hz, 3H), 0.86 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 110.5 (s), 93.1 (s), 73.6 (d), 67.7 (t), 54.3 (s),
50.1 (d), 47.4 (s), 38.4 (t), 34.2 (t), 31.7 (t), 29.1 (t), 26.0 (q), 25.3 (t), 22.5 (t), 20.6 (q), 18.8 (t),
15.4 (q), 14.1 (q).
HRMS (ESI): m/z: calculated for C18H30O [M + H+]: 263.2375, found: 263.2377.
Column chromatography: n-hexane/EtOAc (gradient 85:15–70:30).
1
(1S,7R)-4,7,10,10-tetramethyl-3-oxabicyclo[5.2.1]dec-5-yne (21). H-NMR (500 MHz, CDCl3,
298 K):
δ ppm 4.33 (dd, J = 6.6, 13.2 Hz, 2H), 3.83 (dd, J = 8.6, 14.0 Hz, 1H), 3.55 (d,
J = 14.0 Hz, 1H), 2.26–2.18 (m, 1H), 1.88–1.71 (m, 4H), 1.30 (d, J = 6.6 Hz, 1H), 1.14 (s, 3H),
0.97 (s, 3H), 0.86 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 109.6 (s), 93.9 (s), 68.9 (d), 67.8 (t), 54.4 (s),
50.3 (d), 47.4 (s), 38.5 (t), 26.1 (q), 20.6 (q), 20.6 (q), 18.9 (t), 15.4 (q).
HRMS (ESI): m/z: calculated for C13H20O [M + Na+]: 215.1412, found: 215.1414.
Column chromatography: n-hexane/DCM (gradient 90:10–80:20).
(1S,4R,7R)-7,10,10-trimethyl-4-phenyl-3-oxabicyclo[5.2.1]dec-5-yne (22). 1H-NMR (500 MHz,
CDCl3, 298 K):
δ ppm 7.46–7.46 (m, 2H), 7.37–7.28 (m, 3H), 5.30 (s, 1H), 3.99 (dd, J = 8.7,
13.9 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 2.35–2.28 (m, 1H), 1.98–1.91 (m, 1H), 1.88–1.78 (m,
1H), 1.24 (s, 3H), 1.03 (s, 3H), 0.90 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 138.1 (s), 128.4 (d), 128.4 (d), 127.5 (d),
112.4 (s), 91.3 (s), 75.5 (d), 68.2 (t), 54.5 (s), 50.2 (d), 47.5 (s), 38.5 (t), 26.0 (q), 20.7 (q), 19.0 (t),
15.3 (q).
HRMS (ESI): m/z: calculated for C18H22O [M + Na+]: 277.1568, found: 277.1570.
Column chromatography: n-hexane/DCM (gradient 85:15–70:30).
(1S,4R,7R)-4-(but-3-en-1-yl)-7,10,10-trimethyl-3-oxabicyclo[5.2.1]dec-5-yne (23).1H-NMR
(500 MHz, CDCl3 298 K): δ ppm 5.82–5.74 (m, 1H), 5.01 (dd, J = 1.7, 17.2 Hz, 1H), 4.93 (d,
J = 10.2 Hz, 1H), 4.25 (t, J = 6.2 Hz, 1H), 3.81 (dd, J = 8.7, 14.0 Hz, 1H), 3.51 (d, J = 14.0 Hz,
1H), 2.20–2.07 (m, 2H), 1.86–1.59 (m, 3H), 1.12 (s, 3H), 0.95 (s, 3H), 0.83 (s, 3H).
13C-NMR (150 MHz, CDCl3, 298 K):
δ ppm 137.8 (d), 114.8 (t), 111.0 (s), 92.6 (s), 72.9
(d), 67.6 (t), 54.3 (s), 50.1 (d), 47.3 (s), 38.4 (t), 33.2 (t), 29.4 (t), 26.0 (q), 20.6 (q), 18.8 (t), 15.3
(q).
HRMS (ESI): m/z: calculated for C16H24O [M + Na+]: 255.1725, found: 255.1720.
Column chromatography: n-hexane/EtOAc (gradient 95:5–70:30).
4. Conclusions
In conclusion, a series of strained 1-oxa-3-cyclooctynes were synthesized from com-
mercially available (1R,3S)-camphoric acid. The key cyclization step is an intramolecular
Nicholas reaction. The synthetic route involves the preparation of propargylic alcohols
as key precursors. Firstly, a terminal alkyne was installed in the core structure through a
Corey–Fuchs reaction. Subsequent generation of the corresponding alkanide anion and
reaction with different aldehydes provided in good yield the desired propargylic alco-
hols. Complexation of the triple bond with Co2(CO)8 and treatment with a Lewis acid

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(BF3
·
Et2O) induced the intramolecular Nicholas reaction in which a free hydroxyl group
acts as nucleophile. Finally, oxidative deprotection of the triple bonds with NMO afforded
the desired cyclooctynes in good yields (31–64% overall yield from the propargylic alco-
hols). Importantly, large-sized R substituents (e.g., R = n-hexyl, Ph, 3-butenyl) at the chiral
center connected to the O atom were oriented during the cyclization step in such a way that
steric interactions were minimized, affording the corresponding cyclooctynes exclusively
with (R) configuration. The results indicate that the preorganization of the system and
steric factors are key aspects in the outcome of the cyclization. Preliminary experiments
also showed that these cyclooctynes are reactive in the presence of azides, affording the
corresponding substituted triazoles.
Current efforts in our laboratories are focused on the development of an analogue
route for the synthesis of aza-cyclooctynes and a detailed evaluation of these compounds
as building blocks for sequential catalyst-free click reactions.
Supplementary Materials: NMR spectra (Figures S1–S47) are available online.
Author Contributions: Conceptualization, J.M.B., V.S.M., and D.D.D.; methodology, J.M.B., D.M.M.,
and M.Á.R.; experimental work, J.M.B. and D.M.M.; writing—original draft preparation, D.M.M.,
J.M.B., and D.D.D.; writing—review and editing, J.M.B., D.M.M., T.M., V.S.M., and D.D.D.; super-
vision, T.M. and V.S.M.; funding acquisition, T.M., V.S.M., and D.D.D. All authors have read and
agreed to the published version of the manuscript.
Funding: This research was supported by the Spanish MINECO and MCIU/AEI (CTQ2014-56362-
C2-1-P, CTQ2014-59649-P, PGC2018-094503-B-C22, and PGC2018-094503-B-C21), co-financed by the
European Regional Development Fund (ERDF), and the Spanish Ministry of Science and Innovation
(PID2019–105391GB–C21).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data is contained within the article and supplementary material.
Acknowledgments: D.M.M. thanks MINECO for an FPI fellowship. D.D.D. thanks the Spanish
Ministry of Science and Innovation for the Senior Beatriz Galindo Award (BEAGAL18/00166) and
NANOtec, INTech, Cabildo de Tenerife, and ULL for laboratory facilities.
Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or
in the decision to publish the results.
Sample Availability: Samples of the compounds are available from the authors.
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