Asymmetric Synthesis of 1,2-Dihydronaphthalene-1-ols via Copper-Catalyzed Intramolecular Reductive Cyclization

Article abstract of DOI:10.1021/acs.orglett.0c02829

We describe a copper-catalyzed intramolecular reductive cyclization of easily accessible benz-tethered 1,3-dienes containing a ketone moiety. This process provided biologically active 1,2-dihydronaphthalene-1-ol derivatives in good yields with excellent enantio- and diastereoselectivity. Mechanistic investigations using density functional theory revealed that (Z)- and (E)-allylcopper intermediates formed in situ from the diene and copper catalyst undergo isomerization and selective intramolecular allylation of the (E)-allylcopper form of the major product through a six-membered boatlike transition state. The resulting products were further transformed to fully saturated naphthalene-1-ols by reactions of the olefin moiety.

Full text of DOI:10.1021/acs.orglett.0c02829

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Letter
Asymmetric Synthesis of 1,2-Dihydronaphthalene-1-ols via Copper-
Catalyzed Intramolecular Reductive Cyclization
Ranjan Kumar Acharyya, Soyoung Kim, Yeji Park, Jung Tae Han, and Jaesook Yun*
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ABSTRACT: We describe a copper-catalyzed intramolecular reductive
cyclization of easily accessible benz-tethered 1,3-dienes containing a ketone
moiety. This process provided biologically active 1,2-dihydronaphthalene-1-
ol derivatives in good yields with excellent enantio- and diastereoselectivity.
Mechanistic investigations using density functional theory revealed that (Z)-
and (E)-allylcopper intermediates formed in situ from the diene and copper
catalyst undergo isomerization and selective intramolecular allylation of the
(E)-allylcopper form of the major product through a six-membered boatlike transition state. The resulting products were further
transformed to fully saturated naphthalene-1-ols by reactions of the olefin moiety.
Scheme 1. Previous Approaches and the Present Work
ptically active homoallylic tertiary alcohols and their
Oderivatives are widely found in many natural products
and pharmaceuticals.1 In particular, 1,2-dihydronaphthalene
alcohol derivatives are a very important class of framework
present in a wide range of biologically active molecules2
including oxytetracycline (antibiotic agent),3 lacinilene C
(antibacterial),4 and active metabolite compound C5 (Figure
1).
Figure 1. Representative examples of 1,2-dihydronaphthalene-
containing natural products.
The enantioselective synthesis of cyclic homoallylic alcohols
continues to attract attention, as these are highly useful
intermediates in complex molecule synthesis and medicinal
chemistry.6 Established methods have been reported in the
literature for the synthesis of 1,2-dihydronaphthalene-1-ols. All
of these methods are based on the transition-metal-catalyzed
asymmetric ring opening (ARO) reaction of oxa- and
azabicyclic alkenes with carbon or heteroatom-containing
nucleophiles (Scheme 1a).7,8 ARO reactions have been widely
modified using various transition metals including Ir,9 Ni,10
Pd,11 Cu,12 Rh,13 and others.14
through the ARO reaction, the synthesis of such compounds
containing a tertiary alcohol is not well-defined yet. Indeed, a
few research groups have reported the syntheses of such cyclic
Received: August 23, 2020
While the synthesis of dihydronaphthalenes having secon-
dary homoallylic alcohols has been extensively explored
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tertiary alcohols using ARO,15 but the yields and enantiose-
lectivities of those reactions were not satisfactory.16 Therefore,
the development of a versatile methodology to synthesize
cyclic homoallylic tertiary alcohols from easily accessible
starting materials with higher efficiency is much sought.
In recent years, a number of research groups, including this
one, have reported approaches for copper-catalyzed reductive
functionalization of unsaturated substrates through in situ-
generated alkylcopper nucleophiles.17 Various activated
pronucleophiles such as alkenes,18 enynes,19 allenes,20 and
enones21 were successfully used in nucleophilic addition
reactions to ketones. Recently, the Buchwald,22a Xiong,22b
and Oestreich22d groups independently reported copper-
catalyzed intermolecular reductive couplings of 1,3-dienes
with ketones as well as aldehydes22c (Scheme 1b). In their
proposed mechanism, the intermolecular allylation reaction
proceeded via a stable well-organized six-membered chairlike
transition state to yield the major product.
Herein we report an asymmetric intramolecular copper-
catalyzed reductive coupling of 1,3-dienes with benz-tethered
ketones for the easy acquisition of substituted dihydronaph-
thalene-1-ol derivatives (Scheme 1c). Attaining a favorable
transition state and controlling the diastereo- and enantiose-
lectivity in an intramolecular allylation reaction, especially in a
benz-tethered system, are envisioned to be difficult because of
a low level of flexibility and high ring strain for the cyclization
and thus are considered the primary challenges.
Figure 2. Structures of the chiral ligands.
desired product 2a in 69% yield but with a low level of
enantioselectivity (45%) (entry 1). Next, SEGphos (L2) as the
ligand furnished the product in a poor yield with similar
enantioselectivity (entry 2). Switching to (S,S)-Ph-BPE (L3)
showed better results and provided product 2a in an increased
yield of 70% with a dramatic increase in enantioselectivity
(89%) (entry 3). Other bisphosphine ligands such as QuinoxP
(L4), Josiphos (L5), and BDPP (L6) furnished the product in
low yields and low to moderate dr and ee (entries 4−6). After
evaluation of the ligand efficiency, we focused on optimizing
the silane reactivity in the reaction. The use of more stable and
less flammable dimeric 1,1,3,3-tetramethyldisiloxane
(TMDSO) resulted in a slightly increased yield of 75% with
90% ee (entry 7). Ethereal solvents such as MTBE and diethyl
ether provided results similar to those with THF (entries 8 and
9). The halogenated solvent 1,2-DCE gave the product in
lower yield (65%) but with similar ee (88%) (entry 10),
whereas toluene furnished the product in good yield (73%)
and ee (89%) (entry 11). The reaction showed better
performance at 60 °C in THF as the solvent, providing the
product in 78% yield with 93% ee and 20:1 dr (entry 12).
These were chosen as the optimal reaction conditions for the
intramolecular cyclization.
We started our investigation by taking the simple 1,3-diene-
containing acetophenone substrate 1a as our model substrate
(Table 1 and Figure 2). At first, we performed the reaction in
the presence of BenzP* (L1) as the ligand, Cu(OAc)2 as the
catalyst, and 2.0 equiv of diethoxy(methyl)silane (DEMS) as
the hydride source in THF solvent at 40 °C, which yielded the
Table 1. Optimization of the Copper-Catalyzed Reductive
a
Cyclization Reaction
With the optimized conditions established, we proceeded to
examine the substrate scope of the reductive intramolecular
ketone allylation. As summarized in Table 2, a wide range of
substituted dienes containing aryl ketones 1 were found to be
suitable substrates under mild conditions and furnished the
corresponding homoallylic cyclic tertiary alcohols 2 in good to
excellent yields and enantioselectivities as well as high
diastereoselectivities.
b
c
d
entry ligand
silane
yield (%)
dr (syn:anti)
syn-2a ee (%)
1
2
3
4
5
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
DEMS
DEMS
DEMS
DEMS
DEMS
DEMS
TMDSO
TMDSO
TMDSO
TMDSO
TMDSO
TMDSO
69
30
70
72
45
70
75
72
70
65
73
78
15:1
16:1
19:1
14:1
16:2
10:1
20:1
18:1
17:1
17:1
19:1
20:1
45
47
89
37
57
22
90
89
85
88
89
93
Variation of the substituent of the aromatic ring (R1) was
first investigated. Substrates containing an electron-donating
substituent (Me, OMe) reacted smoothly to afford the
corresponding products 2b and 2c in good yields with
excellent ee and dr. Substrates bearing electron-withdrawing
substituents such as −F, −Cl, and −CF3 were also valid
substrates for the reductive cyclization reaction, providing
products 2d, 2e, and 2f with good efficiency. Naphthalene-
tethered substrate 1g provided the corresponding cyclized 1,2-
dihydrophenanthrene product 2g in alower yield (40%), but
excellent enantioselectivity (96%) and dr (20:1) were
observed.
6
7
e
8
f
9
g
h
i
10
11
12
a
b
Reactions were conducted on a 0.2 mmol scale of 1a. Isolated yields
c
of syn-2a. Diastereomeric ratios were determined by 1H NMR
analysis of the crude reaction mixtures using dimethylformamide as an
internal standard. The ee values for syn-2a were determined by chiral
HPLC analysis. MTBE was used as the solvent. Diethyl ether was
used as the solvent. 1,2-Dichloroethane was used as the solvent.
Toluene was used as the solvent. The reaction was performed on a 2
mmol scale at 60 °C.
d
Substrates having a different R2 substitution of the keto
functionality were examined. Cyclization of primary-alkyl-
substituted keto substrates (R2 = alkyl) provided the
corresponding cyclized products (2h and 2i) in excellent
yields and ee. Aryl-substituted substrates (R2 = aryl) were also
e
f
g
h
i
B
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desired products 2t, 2u, 2v, and 2w in good yields (68−70%)
and ee (75−91%). The reaction was also applied to aldehydes
to get secondary cyclic homoallylic alcohols, but unfortunately,
the reduced primary alcohol was obtained as the major product
rather than the cyclized product. Finally, the absolute
configuration of compound (1R,2R)-2u was unambiguously
confirmed by X-ray crystal analysis, and the stereochemistries
of the other products were assigned by analogy.
Table 2. Substrate Scope for the Synthesis of 1,2-
Dihydronaphthalene-1-ols
a
To obtain a detailed understanding of the reaction
mechanism, we performed density functional theory (DFT)
calculations. Taking 1a as our model substrate, we hypothe-
sized that hydrocupration of 1,3-butadiene with an active Cu−
H catalyst might proceed either via direct 1,4-hydrocupration
or via 1,2-hydrocupration followed by 1,3-allylic migration.
Detailed analysis of the hydrocupration step revealed that the
process strongly prefers to occur through 1,2-addition to form
secondary allylcopper intermediates 3 and 3′ over 1,4-
hydrocupration.22a,23 The initial 1,2-hydrocupration proceeds
with good π-facial selectivity leading to (S)-allylcopper
intermediate 3 as the major product and (R)-allylcopper
intermediate 3′ via TS1a and TS1b, respectively. Intermediate
3 rapidly undergoes facile isomerization via either TS2-cis or
TS2-trans to form stable benzylic allylcopper intermediates 4-
cis and 4-trans (Figure 3).
Extensive DFT calculations of the intramolecular cyclization
of the allylcopper species identified TS3a and TS3b as the
most favorable pathways for each allylation. The activation
energy from (E)-allylcopper intermediate 4-trans to TS3a is
8.9 kcal/mol, whereas the activation energy for 4-cis to TS3b is
20.6 kcal/mol. In TS3a, the methyl groups on the ketone and
the allylcopper are placed in an equatorial orientation of a six-
membered boat-type transition state, whereas TS3b suffers
from steric congestion, meaning that TS3b requires a higher-
energy transition state. Because of the low activation energy of
the 4-trans intermediate, it immediately cyclizes to provide
copper−alkoxide intermediate 6, whereas (Z)-allylcopper (4-
cis) isomerizes back to 3. In previous reports, (Z)-allylcopper
intermediates were responsible for the major product
formation in intermolecular22a and intramolecular24 allylation
of ketones and imines. In contrast, the (E)-allylcopper
intermediate plays a vital role in furnishing the major six-
membered cyclized product in this intramolecular ketone
allylation.
On the basis of the DFT calculations, the preferred catalytic
cycle for the intramolecular ketone allylation is shown in
Figure 4. The cycle consists of 1,2-hydrocupration, 1,3-allylic
migration of copper, and cyclization through the six-membered
boat-type transition state TS3a leading to syn-alkoxycopper
intermediate 6. Subsequent protonation furnishes the product
syn-2a and regenerates the active Cu−H catalyst.
Biologically important tetrahydronaphthalene-1-ol deriva-
tives25 can be easily accessed by organic transformations of our
resulting 1,2-dihydronaphthalene-1-ol products (Scheme 2).
Catalytic hydrogenation of compound 2a yielded tetrahydro-
naphthalene compound 7 in 80% yield with retention of the ee.
The absolute configuration of compound 2a was confirmed by
comparing its optical rotation data with the literature value.26
Hydroxyl-group-directed epoxidation of 2a furnished epoxide
8 in 90% yield without a change in enantiomeric excess and
with a 5:1 diasteromeric ratio. Epoxide ring opening of 8 in the
presence of NaN3 provided fully saturated naphthalene
product 9 containing four consecutive stereogenic centers in
80% yield.
a
The reactions were carried out on a 0.2 mmol scale. The dr is the
ratio of syn-2 to anti-2. Isolated yields and ee values for syn-2 as a
single isomer are shown; the ee values for syn-2 were determined by
chiral HPLC analysis. The reaction was performed at 0 °C and was
complete within 30 min. 0.1 mmol scale.
b
c
suitable for the cyclization reaction. Substrates containing
electron-donating substituents (−Me, −OMe, dioxolane)
furnished the corresponding cyclized products (2k, 2l, and
2m) with excellent performance, but substrates 1n and 1o
containing electron-deficient substituents (−F, −CF3) pro-
vided the desired products with moderate ee. Naphthalene-
substituted substrate 1p also provided the desired cyclized
product in good yield with moderate ee. Heteroaromatic-
substituted substrates furnished the desired cyclized products
2q, 2r, and 2s with excellent performance. Furthermore,
variation of substituents on the diene part (R3) was also
examined. Notably, challenging the internal 1,3-diene sub-
strates with a methyl or n-pentyl substituent provided the
C
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Figure 3. Computed energy profiles of the CuH-catalyzed reductive cyclization of 1a. All energies are reported with respect to diene 1a (the
Gaussian 09 program was used for calculations in the gas phase at the M06-2X/6-13G* level).
Scheme 2. Application of Enantioenriched 1,2-
Dihydronaphthalene Derivatives
observed products. Additionally, our products can also be
transformed to fully functionalized tetrahydronaphthalene
moieties.
Figure 4. Proposed catalytic cycle and transition state.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02829.
In summary, we have developed an efficient and
straightforward approach for the synthesis of enantioenriched
substituted 1,2-dihydronaphthalene-1-ols through copper-
catalyzed asymmetric intramolecular reductive coupling of
(E)-dienylarenes with a benz-tethered ketone moiety. The
(S,S)-Ph-BPE* (L3)−copper catalyst was suitable for this
intramolecular process, furnishing cyclic tertiary alcohols
containing two adjacent stereocenters in good to high yields
with excellent enantioselectivity of up to 98%. DFT
calculations explained the selectivity-determining factor for
this strained intramolecular cyclization. From an isomerizable
mixture of (E)- and (Z)-allylcopper intermediates, selective
cyclization of the (E)-allylcopper complex generates the
Experimental procedures, characterization data, copies of
1H and 13C spectra for all new compounds, and X-ray
data for compound 2u (PDF)
Accession Codes
CCDC 2017520 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
D
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AUTHOR INFORMATION
Corresponding Author
■
Jaesook Yun − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea; orcid.org/0000-0003-
4380-7878; Email: jaesook@skku.edu
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Cheng, C.-H. Adv. Synth. Catal. 2014, 356, 2239−2246. (d) Shukla,
P.; Sharma, A.; Pallavi, B.; Cheng, C.-H. Tetrahedron 2015, 71, 2260−
2266. (e) Deng, Y.; Yang, W.; Yao, Y.; Yang, X.; Zuo, X.; Yang, D.
Org. Biomol. Chem. 2019, 17, 703−711.
Authors
Ranjan Kumar Acharyya − Department of Chemistry,
Sungkyunkwan University, Suwon 16419, Korea
Soyoung Kim − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea
Yeji Park − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea
́
́
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Chem., Int. Ed. 2004, 43, 3944−3947. (b) Zhang, T.-K.; Mo, D.-L.;
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Jung Tae Han − Department of Chemistry, Sungkyunkwan
University, Suwon 16419, Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02829
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (Grants 2019R1A2C2005706 and
2019R1A4A2001440).
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