A versatile approach to functionalized cyclic ketones bearing quaternary carbon stereocenters via organocatalytic asymmetric conjugate addition of nitroalkanes to cyclic β-substituted α,β-Enones

Article abstract of DOI:10.1016/j.tet.2021.132005

A versatile organocatalytic asymmetric conjugate addition of nitroalkanes to β-substituted cyclic α,β-enones to yield cyclic ketones bearing all-carbon quaternary stereogenic centers at β-C has been developed. This is an extension of the method that we de

Full text of DOI:10.1016/j.tet.2021.132005

Tetrahedron 84 (2021) 132005
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A versatile approach to functionalized cyclic ketones bearing
quaternary carbon stereocenters via organocatalytic asymmetric
conjugate addition of nitroalkanes to cyclic b-substituted a,b-Enones
,
,
,
b
,
, **
Si-Jia Yu a 1, Ya-Nan Zhu a 1, Jian-Liang Ye a *, Pei-Qiang Huang a
a Department of Chemical Biology and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen, 361005, PR China
b The State Key Laboratory of Bio-organic and Natural Products Chemistry, Chinese Academy of Sciences, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A versatile organocatalytic asymmetric conjugate addition of nitroalkanes to
enones to yield cyclic ketones bearing all-carbon quaternary stereogenic centers at
b
-substituted cyclic
a,b-
Received 4 January 2021
Received in revised form
1 February 2021
Accepted 3 February 2021
Available online 12 February 2021
b
-C has been
developed. This is an extension of the method that we developed during the total synthesis of
(ꢀ)-haliclonin A, which features the employment of structurally relatively simple, cheap and easily
available primary amine-thiourea derived from (R,R)-1,2-diaminocyclohexane as the chiral catalyst. The
method shows wide substrate scope, good functional group tolerance, which allows a quick access to
multi-functionalized chiral compounds. The synthetic potential of the method was demonstrated by one-
step transformations of the nitro-ketone adducts to four other classes of compounds. The absolute
configurations of adducts were determined by comparison of both the retention time of chiral HPLC
analysis and sense of specific optical rotation with those of a known compound. The enantioselective
control mechanism was rationalized based on the DFT computational studies.
Dedicated to Professor Guo-Qiang Lin in
recognition of his significant contributions
to organic chemistry.
Keywords:
All-carbon quaternary stereogenic centers
Organocatalysis
© 2021 Elsevier Ltd. All rights reserved.
Asymmetric conjugate addition
Nitroalkanes
Primary amine-thiourea
Cyclic enones
1. Introduction
synthesis of (ꢀ)-haliclonin A (1), a macrocyclic marine natural
product isolated in 2009 from a marine sponge Haliclona sp. [9].
All-carbon quaternary stereocenters are found in many struc-
turally complex natural products and biologically active molecules
[1,2], such as antibacterial and cytotoxic marine alkaloid haliclonin
A (1) [3], diterpenoid alkaloid (ꢀ)-arcutinine (2) [4], dysentery drug
conessine (3) [5], and widely employed antitumoral drug Taxol® (4)
[6] (Fig. 1). During last two decades, many asymmetric strategies
have been developed to access to such motifs [2,7,8], however the
chemoselective, catalytic enantioselective construction of func-
tionalized molecules bearing all-carbon quaternary stereocenters
remains a daunting synthetic challenge.
The cornerstone of the total synthesis was the enantioselective
construction of the all-carbon quaternary stereogenic center by
chiral bifunctional thiourea-primary amine catalyst (R,R)-cat-1-
catalyzed enantioselective conjugate addition of nitromethane to
3-substituted cyclohex-2-enone 5 (Scheme 1). The reaction was
achieved in good yield (80%) and in excellent enantioselectivity
(97% ee). Moreover, the reaction could be run at a 10 mmol scale
without decreasing enantiopurity of 6. Besides these inherent ad-
vantages, in this strategy nitromethane served as a surrogate of
umpolung methylamine carbanion synthon, and the amine group,
in turn was used to construct both the bridged ring system and the
Recently, we have accomplished the catalytic asymmetric total
* Corresponding author. Department of Chemical Biology and Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, 361005, PR China.
** Corresponding author.
E-mail addresses: yejl@xmu.edu.cn (J.-L. Ye), pqhuang@xmu.edu.cn (P.-Q. Huang).
S.-J. Yu and Y.-N. Zhu contributed equally to this work.
1
https://doi.org/10.1016/j.tet.2021.132005
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
17-membered macrocycle. Lastly, the first chiral center established
by nitromethane addition was used to induce the formation of two
other chiral centers. In addition, it has been well documented that
nitroalkanes could be converted to many other classes of com-
pounds (Scheme 2) [10].
On the other hand, cyclic ketones bearing an all-carbon ster-
eogenic center at
b-C are found or can be converted into many
natural products such as those shown in Fig. 1. Although many
methods for the organocatalytic asymmetric conjugate addition of
nitromethane to cyclic
our own work [9], very few examples of catalytic asymmetric
addition of nitromethane to -substituted cyclic -enones leading
to functionalized cyclic ketones bearing a quaternary stereogenic
center at -C have been reported [8a-c]. In this context, Ley re-
a,b-enones have been reported [11], prior to
b
a,b
b
ported one example of tetrazole derivative of proline cat-2 cata-
lyzed conjugate addition (Fig. 2) [8a]. Through five examples, Ye
and coworkers demonstrated that cinchona-thiourea primary
amine cat-3 [8b] could be used to build the nitromethylated qua-
ternary carbon stereocenters in excellent enantioselectivities. In
2011, Kwiatkowski and coworkers achieved the high-pressure
(10 Kbar)-promoted enantioselective addition of nitroalkanes to
Fig. 1. Selected bioactive natural products containing all-carbon quaternary
stereocenters.
b
-substituted enones by using cinchona-based primary amine
catalyst cat-4-PhCO2H [8c]. After we had established the method
for the catalytic asymmetric addition of nitromethane to cyclo-
hexenone 5, and turned to the total synthesis of haliclonin A (cf.
Scheme 1) [9a], Ye and coworkers reported the vicinal diamine cat-
5-PhCO2H combination catalyzed asymmetric conjugate addition,
which was shown to be versatile and highly enentioselective [8d].
In 2016, Li and coworkers also obtained good to excellent enan-
tioselectivities employing another cinchona-based primary amine
catalyst cat-6-PhCO2H in combination with proton-sponge additive
[8e]. The use of cheap and easily available catalysts is highly
desirable in the synthetic organic and medicinal chemistry com-
munities [12]. In 2008 and 2009, Wang/Duan and Chan introduced
independently the relatively simple aryl thiourea-primary amine
catalysts [2g,13] (S,S)-cat-1 [14], and (R,R)-cat-1 [15], respectively,
which are easily available from isothiocyanate and enantiomeric
pure 1,2-trans-diaminocyclohexane in one step [14e16], and are
now commercially available. Wang/Duan also reported the first
(S,S)-cat-1-catalyzed highly enantioselective conjugate addition of
nitroalkanes to acyclic enones to form chiral tertiary carbons, and
only a cyclic enone, cyclohex-2-enone was examined [17]. On the
Scheme 1. The multiple roles played by the (R,R)-cat-1 catalyzed enantioselective
conjugate addition of nitromethane in the total synthesis of (ꢀ)-haliclonin A (1).
Scheme 2. Some other known transformations of nitroalkanes.
Fig. 2. Reported organocatalysts used for the asymmetric conjugate addition of
nitroalkanes to b-substituted cyclic enones.
2

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
basis of these considerations, we decided to extend our above-
mentioned asymmetric conjugate addition reaction [9] to diverse
cyclic enones and nitroalkanes, and tried to get an insight into the
catalysis mechanism by computation, and the results are reported
herein.
and 10t’ (more polar) (17: 83 dr) in excellent combined yield (93%)
and enantioselectivities (99% and 97% ee) (entry 3). To our surprise,
the reaction of more hindrance 2-nitropropane also afforded 10u in
a good yield of 87% and in excellent enantioselectivity (98% ee).
In our previous work, after derivatization, and by single crystal
X-ray diffraction analysis, the absolute configuration of the major
product 6 obtained from the (R,R)-cat-1 catalyzed asymmetric
conjugate addition of nitromethane to 5-hexenyl cyclohexenone (5)
was determined to be (R)-6 [9a]. This result indicates that with the
structure displayed in Scheme 1, the conjugate addition takes place
2. Results and discussion
We first surveyed the scope of b-substituted cyclic a,b-enones in
the (R,R)-cat-1-catalyzed asymmetric conjugate addition with
nitromethane. The protocol established during our total synthesis
of haliclonin A (1) was employed [9], which consists of exposing a
from re-face of enone 5. A similar
was expected for enones shown in Tables 1 and 2 Notably, for
different -substituted cyclohexenones the same eface approach
aeface enantioselective addition
b
-substituted cyclohexenone 9 (0.5 mmol, 1.0 equiv) to thiourea
b
a
catalyst (R,R)-cat-1 (0.1 mmol, 0.2 equiv) in redistilled nitro-
methane (2.5 mL), and running the reaction at 45 ꢁC under an argon
atmosphere for 5e7 days [9].
could be named re-face or si-face assigned according to the Cahn-
Ingold-Prelog sequence rule. The chiral HPLC analysis (Chiralcel
AD-H) indicated that the major enantiomer (R)-6 has a shorter
In view of the widespread use of
hexanones as key intermediates for the synthesis of natural prod-
ucts [1a,4,7a], and active pharmaceutical ingredients (APIs) [18],
b
-substituted
b
-methyl cyclo-
retention time (tR
¼
8.7 min) than the minor enantiomer
(tR ¼ 10.1 min) (Table 3, entry 1). In agreement with this result, as
can be seen from entries 2e21 of Table 3, all the major enantiomers
(10a-10t) have shorter a retention time. This allows deducing that
all the products 10a-10t were formed by additions of nitroalkanes
to the specific cyclic enones from same side, namely, the major
the conjugate addition of b-methyl-cyclohexenone (9a) was first
examined (Table 1, entry 1). Subjecting to the above-mentioned
conditions, the adduct 10a was obtained in good yield (78%) and
in excellent enantioselectivity (98% ee). The asymmetric conjugate
enantiomers of 10a-10t have the absolute configurations at
b-C
addition to
b
-alkyl (ethyl, n-amyl, 4-pentenyl) substituted cyclo-
shown in Tables 1 and 2 This is confirmed by a comparison of the
sense of specific optical rotation of (R)-6 with those of the major
enantiomers of 10a-10s (Table 3, column 4, entries 1 versus 2e20).
The exceptional negative specific optical rotation of the mixture of
adducts 10t and 10t0 can be rationalized via comparisons of the
sense of specific optical rotations of (R,S)-10t and (R,R)-10t’. (R,S)-
10t is less polar and has a positive specific optical rotation
hexenones 9b-d (entries 2e4) also proceeded efficiently to give
adducts 10b-d in 80e85% yields and 94e98% ees. As can be seen
from entries 5e7, the reaction of cyclohexenones with
bearing a functional group such as OTBS, acetal, and ester, pro-
ceeded without incidence to give the expected functionalized ad-
ducts 10e-g in good yields (78%, 78%, 88%) and in excellent
enantioselectivities (91%, 95%, 98% ee). Such good functional group
is noteworthy because it affords a simple method to access chiral
cyclohexanone derivatives bearing three functional groups in a
molecule which are convertible into many compounds. However,
b-alkyl
{[a
]
¼ þ29.3 (c ¼ 1.2, CHCl3, 91% ee)}, on the contrary, more polar
D
(R,R)-10t0 has negative value {[
a
]
¼ ꢀ13.2 (c ¼ 1.1, CHCl3, 74% ee)}
D
[11b]. It is suggested that major diastereomer (R,R)-10t’ (17:83 dr,
entry 3, Table 2) has a greater contribution to the observed rotation
resulting in a negative rotation. The HPLC retention times of en-
antiomers of 10u behave differently, which didn’t allow deter-
mining the absolute configurations, but could be assigned via
comparison of sense of specific rotation data as (R)-10u for the
major enantiomer. It is worth noting that although the conclusion is
that all the major enantiomers of 10a-10u have the structures
displayed in Tables 1 and 2, the absolute configurations should be
assigned as R or S according to the Cahn-Ingold-Prelog sequence
rule.
the reactions of b-branched substrate 9h and a-branched b-cyclo-
propylcyclohexenone 9i yielded 10h and 10i in moderate 79% ee
and 75% ee, respectively (entries 8 and 9). 3,5,5-Trimethylcyclohex-
2-enone (9j) reacted to give 10j in 75% yield and 85% ee (entry 10).
These results implicates that steric hindrance is detrimental for the
enantioselectivity of the reaction.
To our delight,
suitable substrates to afford 10k and 10l in excellent ee (97% and
95%) (entries 11 and 12), whereas the reaction of -(p-methox-
ybenzyl)cyclohexenone (9m) afforded a lower ee of 87% (entry 13).
Compared with the result obtained from the -isobutyl derivative
9h, these results might reflect a beneficial effect of the aryl groups
on the asymmetric induction. The reaction of -phenyl-
cyclohexenone 9n afforded a moderate yield (58%) and an appre-
ciable ee of 89% (entry 14). For -(p-chlorophenyl)cyclohexenone
9o, both yield and ee were moderate (50% yield and 66% ee) (entry
15). Interestingly, the reaction can be extended to more rigid
methylcyclopent-2-enone (9p), which yielded compound 10p in
high ee (91%) albeit in a moderate yield of 52% (entry 16), whereas
for the relative flexible cyclohept-2-enone (9q) a good yield (84%)
and an excellent enantioselectivity (98% ee) were obtained (entry
17).
Next, the asymmetric conjugate addition reaction of 1-
nitropropane was examined (Table 2, entry 1). The reaction pro-
ceeded smoothly, and two diastereomeric adducts 10r and 10r’
(more polar) were obtained (55:45 dr) in a good combined yield
(86%) and enantioselectivities (91% and 94% ee). Finally, the
unsubstituted cyclohex-2-enone (9r) was evaluated. As expected,
the reaction worked well with the less hindered 9r, which gave
adduct 10s in 79% yield and 98% ee (entry 2). The conjugate addition
of 1-nitropropane with 9r yielded two diastereomeric adducts 10t
b-benzylcyclohexenone 9k and 9l turned out to
b
When an aldehyde is used as a pro-nucleophile in the thiourea-
primary amine catalyzed reaction, it was proposed that an enamine
was formed as a nucleophilic intermediate [19]. In the case of a
ketone, acid additive is needed to promote the formation of a
nucleophilic enamine intermediate [20]. On the other hand, for the
primary amine-catalyzed conjugate addition of an active methy-
lene compound [21] or a nitroalkane [8d] to an enone under acidic
conditions, an electrophilic eniminium intermediate was proposed.
As regarding the acid-free thiourea-primary amine catalyzed
nitromethane addition to enone at rt, Wang/Duan suggested
nitromethane carbanion and H-bonding activated enone as nucle-
ophilic and electrophilic species, respectively [17], although the
mechanism was questioned by Kwiatkowski based on the results
from the primary amine/acid dual-catalyzed reaction of enone [21].
More recently, Miura et al. postulated an transition state involving
both nitroalkane carbanion and (Z)-eniminium species in the
thiourea primary amine-sulfonamide-catalyzed addition reactions
of nitroalkanes to acyclic enones [12c]. Moreover, it has been
b
b
b
b
-
demonstrated that even the
a
-proton [pKa (DMSO) ¼ 26.4] [22] of
cyclohexanone can be deprotonated by pyrrolidine [ammonium
pKa (DMSO) ¼ 11.1] [23] to form enolate serving as reactive inter-
mediate (eq. 1) [24]. In view of the much higher acidity of the
3

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
Table 1
(R,R)-Cat-1-catalyzed asymmetric conjugate additions of nitromethane to b-substituted cyclic a,b-enones.
4

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
Table 2
(R,R)-Cat-1-catalyzed conjugate additions of nitroalkanes to cyclohexenones.
nitromethane [pKa (DMSO) ¼ 17.2] [25] as compared with cyclo-
hexanone, the generation of nitromethane carbanion as a reactive
specie in the equilibrium is reasonable (eq. 2) [26]. Under such
circumstance, the generation of a substantial amount of an enimi-
nium species as reactive intermediate is less plausible.
organized the nitromethane carbanion and 3-ethylcyclohex-2-
enone 9b to form the transition state structures. For this assem-
bling process two possible hydrogen-bond binding patterns among
the three species were investigated. Pattern 1 (R-TS1, S-TS1):
Hydrogen bonds were formed between two oxygen atoms of
nitromethane carbanion and HeN of thiourea and ammonium, and
between carbonyl oxygen of 9b and ammonium hydrogen, which
led to the transition states R-TS1 (nitromethane carbanion attacked
from re-face of 9b to afford R-configuration product), S-TS1
(attacked from si face of 9b to afford S-configuration product).
Pattern 2 (R-TS2, S-TS2): Alternatively, hydrogen bonds between
carbonyl oxygen of 9b and HeN of thiourea, and between two
oxygen atoms of nitromethane carbanion and ammonium
hydrogen were formed to generate R-TS2 (attacked from re face to
afford R-configuration product), S-TS2 (attacked from si-face to
afford S-configuration product). And transition state R-TS1 was
more favored than S-TS1, R-TS2, S-TS2 by 3.55, 4.93, 2.48 kcal/mol,
respectively. According to these differences of free energies the
calculated ee value was determined to 96%, which was in good
agreement with the experimental value (98% ee). The results can be
rationalized by the hydrogen bond interaction and the repulsive
interaction between cyclohexanone ring and nitromethane carb-
anion in the transition states. As the H-bond binding ternary
complex of S-TS1 shown, the attacking nitromethane carbanion
To gain an insight into the mechanism of enantioselection, we
conducted DFT calculations on the key chirality-generating CeC
bond formation step at M062X-D3/def2-TZVPP-PCM//B3LYP-D3/
6-31G*-PCM level (Fig. 3, 9b employing as model substrate).
Through hydrogen bonding the pre-formed thiourea-ammonium
5

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
Table 3
Retention time (tR) and optical rotation of the enantiomeric adducts.
Entry
Adduct
tRa/min of major enantiomer
tRa/min of minor enantiomer
Optical rotation
{[
a
]
D
(c ¼ 1.0, CHCl3)}
1
2
3
4
5
6
7
8
(R)-6 [9a]
(R)-10a
(R)-10b
(R)-10c
(R)-10d
(R)-10e
(S)-10f
(R)-10g
(S)-10h
(S)-10i
(R)-10j
(S)-10k
(S)-10l
(S)-10m
(R)-10n
(R)-10o
(R)-10p
(R)-10q
(R)-10r þ (R)-10r0
8.7
10.1
18.2
14.3
4.9
11.8
7.2
53.4
44.1
5.9
16.8
17.1
18.2
21.8
25.8
16.0
23.3
64.4
30.4
26.1
12.9
16.2
11.1
11.8
11.8
þ33 (97% ee)
17.1
13.5
4.3
10.0
6.7
46.6
29.1
5.4
15.0
15.1
11.6
20.7
24.7
11.8
15.9
62.2
29.1
7.7
11.4
14.0
10.0
10.4
12.6
þ7.9 (98% ee)
þ3.0 (98%, ee)
þ2.6 (98% ee)
þ4.3 (94% ee)
þ1.7 (91% ee)
þ1.0(95% ee)
þ5.9 (98% ee)
þ4.3 (79% ee)
þ2.7 (75% ee)
þ3.3 (85% ee)
þ9.5 (97% ee)
þ10.4 (95% ee)
þ9.1 (87% ee)
þ11.3 (89% ee)
þ11.5 (66% ee)
þ8.0 (91% ee)
þ5.9 (98% ee)
þ2.4 (97, 99% ee, 55: 45 dr)
9
10
11
12
13
14
15
16
17
18
19
20
21
(R)-10s
(R,S)-10t þ (R,R)-10t’ [11b]
þ7.9 (98% ee)
ꢀ2.4 (99, 97% ee, 17: 83 dr)
22
(R)-10u
þ20.5 (98% ee)
a
HPLC analysis using AD-H or OD-H column, column temperature: 30 ꢁC, flow phase n-hexane/i-PrOH, flow rate 1.0 mL/min.
was arranged on the upside of cyclohexenone ring. Correspond-
ingly, in R-TS1 the nitromethane carbanion was approaching the
electrophilic site from one side of cyclohex-2-enone ring, thus
resulting in a less repulsive interaction between molecular planes
of nitromethane carbanion and cyclohexanone than those occur-
ring in S-TS1 (cf. the Newman projections through the forming
C1eC2 bond). Similar behavior was observed in R-TS2 and S-TS2.
Hence, R-TS1 and S-TS2 were more favored than S-TS1 and R-TS1 by
3.55 and 2.45 kcal/mol, respectively. In addition, R-TS1 preferred
over S-TS2 by 2.48 kcal/mol may be ascribe to the relatively strong
hydrogen-bonding interaction featured by the exhibited shorter
O/HN distances (R-TS1: 1.822, 2.161, 1.867, 1.574 Å vs S-TS2: 1.837,
1.843, 2.381, 1.700 Å) and more linear O/H/N angles (R-TS1: 169ꢁ,
146ꢁ, 161ꢁ, 170ꢁ vs S-TS2: 157ꢁ, 156ꢁ, 114ꢁ, 167ꢁ) [27]. These results
are in support of our suggestion that nitroalkane carbanion and H-
bond activated cyclic enone are reactive intermediates in the
asymmetric conjugate addition, which is in agreement with the
model proposed by Wang [17].
To demonstrate the utility of this methodology, one-step con-
versions of 10a into carboxylic acid 11, oxime 12, and an active
pharmaceutical ingredient (API) 13 [18] were performed. The
nitromethane oxidation using sodium nitrite in the presence of
acetic acid provided 11 in a yield of 72% (Scheme 3e1) [28].
Treatment of 10a with tributyltin hydride in the presence of 1,10-
azobis(cyclohexanecarbonitrile) (ACCN) in toluene at 90 ꢁC pro-
duced oxime 12 in good yield (75%) (Scheme 3e2) [29]. Ketal 13
was obtained in 94% yield by the BF3∙Et2O-promoted reaction with
glycol and trimethyl orthoformate (Scheme 3e3). In addition, the
tandem deprotection of acetal in 10f and intramolecular aldol
condensation of the keto-aldehyde intermediate were achieved by
treating with a 3 M HCl to give 14 in 71% yield (Scheme 4). It is
worth mentioning that the bicyclo[4.3.0]nonane core skeleton 14 is
possessed by many bioactive nature products such as acutifolone A
[30] and (þ)-axamide-4 [31].
3. Conclusions
In summary, on the basis of our previous work in the total
synthesis of (ꢀ)-haliclonin A (1), we have developed a versatile
enantioselective approach to cyclic ketones bearing all-carbon
quaternary stereogenic centers at
b-C based on a structurally
relatively simple, cheap and easily available chiral primary amine-
thiourea catalyst. Excellent enantioselectivities were obtained from
b
esubstituted cyclohex-2-enones with a0 and 0-unbranched alkyl
b
groups, and from 3-benzylcyclohex-2-enone. The reaction is
amenable to cyclohex-2-enone, esubstituted cyclopent-2-enones
b
and cyclohept-2-enones, and to other nitroalkanes. We have shown
that absolute configurations of adducts could be determined ac-
cording to the retention times of two enantiomers of each adduct
by chiral HPLC analysis. Additionally, DFT computational results of
transition states at the chirality generation step suggested that the
enantioselection control mechanism of the catalytic conjugate
addition involved the hydrogen-bonding modes between sub-
strates (nitromethane, cyclic enone) and catalyst, and the intra-
complex repulsive interaction.
4. Experimental section
4.1. General
Melting points were determined on a Büchi M560 Automatic
Melting Point apparatus and are uncorrected. Infrared spectra were
measured with a Nicolet Avatar 360 FT-IR spectrometer using film
pellet techniques. Optical rotation data were measured on an Anton
Paar MCP 500 polarimeter at 589 nm and at 20 or 25 ꢁC, using a
50 mm path-length cell in the solvent and at the concentration
indicated. HPLC analyses were carried out on an Agilent 1260 series
system with Daicel CHIRALPAK® or Daicel CHIRALCEL® columns
(4.6 ꢂ 250 mm, particle size 3
m
m). 1H and 13C NMR spectra were
6

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
Fig. 3. The DFT-calculated geometries, the corresponding Newman projections of through the forming C1eC2 bond, and relative free energies (DDG, 318 K) of transition states for
the CeC bond forming step in (R,R)-cat-1 catalyzed conjugate addition of nitromethane to the model b-ethylcyclohexenone under acid-free conditions. The energies are given in
kcal/mol. Selected distances and angles are denoted in angstroms (Å) and degrees, respectively.
recorded at 500 and 125 MHz, respectively. Chemical shifts (
d
) are
HRMS spectra were recorded on a 7.0T FT-MS apparatus. Silica gel
(300e400 mesh) was used for flash column chromatography,
eluting with EtOAc/n-hexane mixture. Reactions were performed in
oven-dried glassware under an argon atmosphere.
reported in ppm and respectively referenced to internal standard
Me4Si and solvent signals (Me4Si, 0.0 ppm for 1H NMR and CDCl3,
77.0 ppm for 13C NMR). Mass spectra were recorded on a Bruker
Dalton ESquire 3000 plus LC-MS apparatus (ESI direct injection).
7

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
(c ¼ 1.0, CH2Cl2, 99% ee)]; IR (film) nmax: 2921, 2852, 1738, 1503,
1379, 1296, 1080, 437 cmꢀ1 1H NMR (500 MHz, CDCl3):
; d 0.94 (s,
3H), 1.52e1.60 (m, 1H), 1.62e1.69 (m, 1H), 1.71e1.79 (m, 1H),
1.80e1.90 (m, 1H), 2.08 (d, J ¼ 13.9 Hz, 1H), 2.14e2.23 (m, 2H), 2.27
(d, J ¼ 13.9 Hz, 1H), 4.16 (d, J ¼ 10.8 Hz, 1H), 4.20 (d, J ¼ 10.8 Hz, 1H)
ppm; 13C NMR (125 MHz, CDCl3):
d 21.3, 23.1, 33.5, 39.8, 40.5, 50.7,
84.9, 208.8 ppm; MS (ESI) m/z 194 (M þ Naþ, 100%).
4.3.2. (þ)-(R)-3-Ethyl-3-(nitromethyl)cyclohexan-1-one (10b)
Following the general procedure, the reaction of cyclohexenone
9b (62 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:8), the known compound (R)-10b [8d] (75 mg, yield:
82%) as a yellow oil. 98% ee was determined by chiral HPLC (Chir-
alcel AD-H, column temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 95: 5,
1.0 mL/min,
l
¼
220 nm), tR (major)
¼
13.5 min, tR
20
(minor) ¼ 14.3 min, [
a
]
D
¼ þ3.0 (c ¼ 1.0, CHCl3, 98% ee) [(S)-10b: lit
30
[8d]. [
2883, 1712, 1545, 1381, 1315, 1230, 1044, 756, 530 cmꢀ1
(500 MHz, CDCl3):
a
]
¼ ꢀ5.7 (c ¼ 1.0, CH2Cl2, 99% ee)]; IR (film) nmax: 2966,
D
;
1H NMR
d
0.90 (t, J ¼ 7.5 Hz, 3H), 1.41e1.51 (m, 2H),
1.67e1.80 (m, 2H), 1.82e1.92 (m, 1H), 1.93e2.00 (m, 1H), 2.26e2.36
(m, 3H), 2.38 (d, J ¼ 14.2 Hz, 1H), 4.31 (s, 2H) ppm; 13C NMR
Scheme 3. One-step conversions of nitro ketone 10a into keto carboxylic acid 11, keto
oxime 12, and nitro ketal 13.
(125 MHz, CDCl3):
d 7.1, 20.8, 28.0, 30.9, 40.5, 42.5, 49.0, 81.3,
209.1 ppm; MS (ESI) m/z 208 (M þ Naþ, 100%).
4.3.3. (þ)-(R)-3-Hexyl-3-(nitromethyl)cyclohexan-1-one (10c)
Following the general procedure, the reaction of cyclohexenone
9c (90 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:10), the known compound (R)-10c [8d] (102 mg, yield:
85%) as a yellow oil. 98% ee was determined by chiral HPLC (Chir-
alcel AD-H, column temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 90: 10,
2.0 mL/min,
l
¼ 220 nm), tR (major) ¼ 4.3 min, tR (minor) ¼ 4.9 min,
20
30
[
a
]
¼ þ2.6 (c ¼ 1.0, CHCl3, 98% ee) [(S)-10c: lit [8d]. [
a
]
¼ ꢀ1.5
Scheme 4. One-step construction of bicyclo[4.3.0]nonane skeleton 14 from 10f.
D
D
(c ¼ 1.0, CH2Cl2, 99% ee)]; IR (film) nmax: 2932, 2858, 1713, 1549,
1431, 1314, 1229, 1081, 724 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
0.86
4.2. Synthesis of starting materials 9a-9q
(t, J ¼ 6.8 Hz, 3H), 1.22e1.29 (m, 8H), 1.33e1.43 (m, 2H), 1.68e1.81
(m, 2H), 1.82e1.92 (m, 1H), 1.94e2.03 (m, 1H), 2.27e2.42 (m, 4H),
4.32 (s, 2H) ppm; 13C NMR (125 MHz, CDCl3):
d 14.0, 20.9, 22.5, 22.6,
3-Substituted cyclic enones were prepared by addition of a
Grignard reagent to a 3-ethoxy cyclic enone according to the
literature procedure [11a].
29.4, 31.3, 31.5, 35.4, 40.5, 42.4, 49.5, 81.9, 209.1 ppm; HRMS (ESI)
m/z calcd for [C13H23NNaO3]þ (M þ Naþ): 264.1570; found:
264.1569.
4.3. General synthetic method of 10a-10u
4.3.4. (þ)-(R)-3-(Nitromethyl)-3-(pent-4-en-1-yl)cyclohexan-1-
one (10d)
Into a dry 10-mL Schlenk tube equipped with a magnetic stirring
bar were added successively a 3-substituled cyclic enone 9
(0.5 mmol, 1.0 equiv), thiourea catalyst (R,R)-cat-1 (0.1 mmol, 0.2
equiv) in 2.5 mL of redistilled nitromethane at room temperature
under an argon atmosphere. And then the reaction was heated to
45 ꢁC and stirred for 5e7 days. The reaction mixture was cooled to
room temperature and quenched with 1 M HCl (5 mL). The aqueous
phase was extracted with CH2Cl2 (3 ꢂ 5 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel (EtOAc/n-Hexane) to afford product
10. The enantiomeric excess was determined by HPLC analysis on a
chiral column.
Following the general procedure, the reaction of cyclohexenone
9d (82 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:10), compound (R)-10d (90 mg, yield: 80%) as a yellow
oil. 94% ee was determined by chiral (Chiralcel AD-H, column
temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 95: 5, 1.0 mL/min,
l
¼ 220 nm), tR (major) ¼ 10.0 min, tR (minor) ¼ 11.8 min,
20
[
a
]
¼ þ4.3 (c ¼ 1.0, CHCl3, 94% ee); IR (film) nmax: 3077, 2941, 1707,
D
1640, 1542, 1459, 1316, 1230, 993, 915, 724, 667, 509 cmꢀ1; 1H NMR
(500 MHz, CDCl3): 1.30e1.43 (m, 4H),1.67e1.79 (m, 2H),1.80e1.92
d
(m, 1H), 1.92e2.06 (m, 3H), 2.24e2.41 (m, 4H), 4.30 (s, 2H),
4.88e5.03 (m, 2H), 5.62e5.83 (m, 1H) pm; 13C NMR (125 MHz,
CDCl3): d 20.8, 21.9, 31.2, 33.6, 34.7, 40.4, 42.2, 49.3, 81.7,115.3,137.6,
208.9 ppm; HRMS (ESI) m/z calcd for [C11H19NNaO3]þ (M þ Naþ):
4.3.1. (þ)-(R)-3-Methyl-3-(nitromethyl)cyclohexan-1-one (10a)
Following the general procedure, the reaction of cyclohexenone
9a (55 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:8), the known compound (R)-10a [8c] (65 mg, yield:
76%) as a yellow oil. 98% ee was determined by chiral HPLC (Chir-
alcel AD-H, column temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 95: 5,
248.1257; found: 248.1259.
4.3.5. (þ)-(R)-3-(4-((tert-Butyldimethylsilyl)oxy)butyl)-3-
(nitromethyl)cyclohexan-1-one (10e)
Following the general procedure, the reaction of cyclohexenone
9e (141 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:11), compound (R)-10e (151 mg, yield: 78%) as a yellow
oil. 91% ee was determined by chiral HPLC (Chiralcel AD-H, column
temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 97: 3, 1.0 mL/min,
1.0 mL/min,
l
¼
220 nm), tR (major)
¼
17.1 min, tR
20
(minor) ¼ 18.2 min, [
a
]
¼ þ7.9 (c ¼ 1.0, CHCl3, 98% ee) [lit [8c].
D
25
30
[
a
]
¼ þ1.7 (c ¼ 2.0, CHCl3, 98% ee); (S)-10a: lit [8d]. [
a]
¼ ꢀ6.6
D
D
8

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
20
l
¼ 220 nm), tR (major) ¼ 6.7 min, tR (minor) ¼ 7.2 min, [
(c ¼ 1.0, CHCl3, 91% ee); IR (film) nmax: 2952, 2857, 1715, 1551, 1471,
1432, 1255, 1101, 836, 776 cmꢀ1; 1H NMR (500 MHz, CDCl3):
0.00
a
]
¼ þ1.7
temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 95: 5, 1.0 mL/min,
D
l
¼ 220 nm), tR (major) ¼ 15.0 min, tR (minor) ¼ 16.8 min,
20
d
[
a
]
D
¼ þ2.7 (c ¼ 1.0, CHCl3, 75% ee); IR (film) nmax: 2924, 2854,1710,
(s, 6H), 0.87 (s, 9H),1.28e1.49 (m, 6H),1.73e1.99 (m, 4H), 2.24e2.40
1632, 1548, 1277, 1080, 965, 749 cmꢀ1; 1H NMR (500 MHz, CDCl3):
0.18e0.25 (m, 1H), 0.29e0.36 (m, 1H), 0.37e0.44 (m, 1H),
(m, 4H), 3.57 (t, J ¼ 6.2 Hz, 2H), 4.32 (s, 2H) ppm; 13C NMR
d
(125 MHz, CDCl3):
d
ꢀ5.4 (2C), 18.2, 19.1, 20.8, 25.9 (3C), 31.2, 32.8,
0.46e0.53 (m, 1H), 0.76e0.85 (m, 1H), 1.71e1.84 (m, 2H), 1.87e1.97
(m, 1H), 2.02 (d, J ¼ 15.0 Hz, 1H), 2.05e2.12 (m, 2H), 2.18 (d,
J ¼ 15.0 Hz, 1H), 2.22e2.40 (m, 2H), 4.29 (s, 2H) ppm; 13C NMR
35.2, 40.5, 42.4, 49.5, 62.4, 81.8, 209.0 ppm; HRMS (ESI) m/z calcd
for [C17H33NNaO4Si]þ (M þ Naþ): 366.2071; found: 366.2072.
(125 MHz, CDCl3):
d 1.2, 1.7, 18.4, 20.6, 32.1, 40.5, 41.3, 45.3, 83.4,
4.3.6. (þ)-(S)-3-(2-(1, 3-Dioxolan-2-yl)ethyl)-3-(nitromethyl)
cyclohexan-1-one (10f)
209.5 ppm; HRMS (ESI) m/z calcd for [C11H19NNaO3]þ (M þ Naþ):
220.0944; found: 220.0943.
Following the general procedure, the reaction of cyclohexenone
9f (98 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:2), compound (S)-10f (100 mg, yield: 78%) as a yellow
oil. 95% ee was determined by chiral HPLC (Chiralcel OD-H, column
temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 90: 10, 1.5 mL/min,
4.3.10. (þ)-(R)-3, 3, 5-Trimethyl-5-(nitromethyl)cyclohexan-1-one
(10j)
Following the general procedure, the reaction of cyclohexenone
9j (70 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:15), the known compound (R)-10j [8c] (75 mg, yield:
75%) as a yellow oil. 85% ee was determined by chiral HPLC (Chir-
alcel AD-H, column temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 96.2:
l
¼ 220 nm), tR (minor) ¼ 46.6 min, tR (major) ¼ 53.4 min,
20
[
a
]
¼ þ1.0 (c ¼ 1.0, CHCl3, 95% ee); IR (film) nmax: 2955, 2885,1712,
D
1549, 1457, 1382, 1279, 1142, 1079, 1033, 894, 640 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): 1.47e1.57 (m, 2H),1.62e1.68 (m, 2H),1.73e1.80
d
3.8, 1.0 mL/min,
l
¼
220 nm), tR (major)
¼ þ 3.3 (c ¼ 1.0, CHCl3, 85% ee) [lit [8c].
¼
15.1 min, tR
20
(m, 2H), 1.83e1.98 (m, 2H), 2.24e2.42 (m, 4H), 3.77e3.83 (m, 2H),
3.87e3.92 (m, 2H), 4.29 (s, 2H) 4.80 (t, J ¼ 4.4 Hz,1H) ppm; 13C NMR
(minor) ¼ 17.1 min, [
a]
D
25
30
[
a
]
D
¼ þ7.6 (c ¼ 2.0, CHCl3, 99% ee); (S)-10j: lit [8d]. [
a]
¼ ꢀ8.6
D
(125 MHz, CDCl3):
d
20.7, 27.2, 29.2, 31.1, 40.4, 41.8, 49.4, 64.9 (2C),
(c ¼ 1.0, CH2Cl2, 96% ee)]; IR (film) nmax: 2959, 2925, 1715, 1551,
81.5, 103.6, 208.7 ppm; HRMS (ESI) m/z calcd for [C12H19NNaO5]þ
1461, 1429, 1283, 1248, 1081, 660 cmꢀ1; 1H NMR (500 MHz, CDCl3):
(M þ Naþ): 280.1155; found: 280.1156.
d
1.05e1.09 (m, 6H), 1.20 (s, 3H), 1.65 (d, J ¼ 14.4 Hz, 1H), 1.79 (d,
J ¼ 14.4 Hz, 1H), 2.18e2.25 (m, 3H), 2.44e2.50 (m, 1H), 4.26 (d,
4.3.7. (þ)-Ethyl (R)-2-(1-(nitromethyl)-3-oxocyclohexyl) acetate
(10g)
J ¼ 10.9 Hz, 1H), 4.29 (d, J ¼ 10.9 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3):
d 25.8, 30.0, 32.4, 35.5, 39.6, 46.7, 49.5, 53.6, 86.3,
Following the general procedure, the reaction of cyclohexenone
9g (91 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:10), compound (R)-10g (107 mg, yield: 88%) as a yellow
oil. 98% ee was determined by chiral HPLC (Chiralcel AD-H, column
temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 96.2: 3.8, 1.0 mL/min,
209.2 ppm; MS (ESI) m/z 222 (M þ Naþ, 100%).
4.3.11. (þ)-(S)-3-Benzyl-3-(nitromethyl)cyclohexan-1-one (10k)
Following the general procedure, the reaction of cyclohexenone
9k (93 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:5), the known compound (S)-10k [8c] (96 mg, yield:
78%) as a yellow oil. 97% ee was determined by chiral HPLC (Chir-
alcel AD-H, column temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 90: 10,
l
¼ 220 nm), tR (major) ¼ 29.1 min, tR (minor) ¼ 44.1 min,
20
[
a
]
¼ þ5.6 (c ¼ 1.0, CHCl3, 98% ee); IR (film) nmax: 2957, 2924,
D
2855, 1722, 1631, 1550, 1462, 1188, 1081, 964, 814, 770 cmꢀ1
NMR (500 MHz, CDCl3):
;
1H
d
1.25 (t, J ¼ 7.1 Hz, 3H), 1.76e1.83 (m, 1H),
1.0 mL/min,
l
¼
220 nm), tR (major)
¼
11.6 min, tR
20
1.87e1.96 (m, 2H), 1.96e2.04 (m, 1H), 2.31e2.41 (m, 2H), 2.44e2.54
(m, 4H), 4.14 (q, J ¼ 7.1 Hz, 2H), 4.61 (d, J ¼ 11.4 Hz, 1H), 4.70 (d,
(minor) ¼ 18.2 min, [
a]
D
¼ þ9.5 (c ¼ 1.0, CHCl3, 97% ee) [lit [8c].
25
30
[
a
]
D
¼ þ20.0 (c ¼ 2.0, CHCl3, 97% ee); (S)-10k: lit [8d]. [
a]
¼ ꢀ18
D
J ¼ 11.4 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3):
d
14.1, 20.8, 31.5,
(c ¼ 1.0, CH2Cl2, 99% ee)]; IR (film) nmax: 3029, 2926, 2855, 1712,
1650, 1548, 1378, 1228, 1079, 962, 704 cmꢀ1 1H NMR (500 MHz,
CDCl3): 1.75e1.89 (m, 2H), 2.02e2.11 (m, 2H), 2.25e2.30 (m, 1H),
38.9, 40.4, 41.2, 48.9, 60.8, 80.8, 169.9, 208.0 ppm; HRMS (ESI) m/z
;
calcd for [C11H17NNaO5]þ (M þ Naþ): 266.0999; found: 266.0999.
d
2.34e2.43 (m, 3H), 2.77e2.84 (m, 2H), 4.21 (d, J ¼ 11.5 Hz, 1H), 4.28
4.3.8. (þ)-(S)-3-Isobutyl-3-(nitromethyl)cyclohexan-1-one (10h)
Following the general procedure, the reaction of cyclohexenone
9h (83 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:10), the known compound (S)-10h [8c] (83 mg, yield:
78%) as a yellow oil. 79% ee was determined by chiral HPLC (Chir-
alcel AD-H, column temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 95: 5,
(d, J ¼ 11.5 Hz, 1H), 7.19e7.23 (m, 2H), 7.26e7.36 (m, 3H) ppm; 13
C
NMR (125 MHz, CDCl3): d 21.1, 31.4, 40.5, 41.9, 43.4, 48.2, 80.9,127.2,
128.5 (2C),130.7 (2C),134.9, 209.3 ppm; MS (ESI) m/z 270 (M þ Naþ,
100%).
4.3.12. (þ)-(S)-3-(4-Fluorobenzyl)-3-(nitromethyl)cyclohexan-1-
one (10l)
2.0 mL/min,
l
¼ 220 nm), tR (major) ¼ 5.4 min, tR (minor) ¼ 5.9 min,
20
25
[
a
]
¼ þ4.3 (c ¼ 1.0, CHCl3, 79% ee) [lit [8c]. [
a
]
¼ ꢀ1.8 (c ¼ 2.0,
Following the general procedure, the reaction of cyclohexenone
9l (102 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:5), compound (S)-10l (107 mg, yield: 81%) as a yellow
oil. in 95% ee was determined by chiral HPLC (Chiralcel AD-H, col-
umn temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 93: 7, 1.0 mL/min,
D
D
CH2Cl2, 97% ee)]; IR (film) nmax: 2958, 2872, 1713, 1549, 1378, 1228,
1080, 963, 760 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
d
0.96 (d,
J ¼ 6.6 Hz, 6H), 1.30e1.42 (m, 2H), 1.69e1.85 (m, 3H), 1.87e2.03 (m,
2H), 2.27e2.42 (m, 4H), 4.35 (d, J ¼ 11.0 Hz, 1H), 4.38 (d, J ¼ 11.0 Hz,
1H) ppm; 13C NMR (125 MHz, CDCl3):
d
21.0, 23.6, 24.9, 25.0, 31,7,
l
¼ 220 nm), tR (major) ¼ 20.7 min, tR (minor) ¼ 21.8 min,
20
40.5, 43.2, 44.4, 49.7, 82.2, 209.2 ppm; HRMS (ESI) m/z calcd for
[
a
]
¼ þ10.4 (c ¼ 1.0, CHCl3, 95% ee); IR (film) nmax: 2925, 1712,
D
[C11H19NNaO3]þ (M þ Naþ): 236.1257; found: 236.1259.
1604, 1550, 1509, 1248, 1226, 1161, 842, 660 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): 1.72e1.79 (m, 1H), 1.79e1.86 (m, 1H),
d
4.3.9. (þ)-(S)-3-Cyclopropyl-3-(nitromethyl)cyclohexan-1-one
(10i)
Following the general procedure, the reaction of cyclohexenone
9i (78 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:10), compound (S)-10i (89 mg, yield: 76%) as a yellow
oil. 75% ee was determined by chiral HPLC (Chiralcel AD-H, column
2.00e2.07 (m, 2H), 2.20e2.26 (m, 1H), 2.31e2.38 (m, 3H),
2.73e2.80 (m, 2H), 4.18 (d, J ¼ 11.7 Hz, 1H), 4.24 (d, J ¼ 11.7 Hz, 1H),
6.97e7.02 (m, 2H), 7.15e7.21 (m, 2H) ppm; 13C NMR (125 MHz,
CDCl3):
2C), 130.6 (d, JC-F ¼ 3.5 Hz), 132.3 (d, JC-F ¼ 7.9 Hz, 2C), 162.0 (d, JC-
246.2 Hz), 209.0 ppm; HRMS (ESI) m/z calcd for
d
21.1, 31.6, 40.5, 40.9, 43.5, 48.1, 80.6,115.4 (d, JC-F ¼ 21.0 Hz,
¼
F
9

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
[C14H16FNNaO3]þ (M þ Naþ): 288.1006; found: 288.1007.
(c ¼ 1.0, CH2Cl2, 96% ee)]; IR (film) nmax: 2964, 2924, 1743, 1550,
1381, 1255, 1168, 1034, 639, 518 cmꢀ1 1H NMR (500 MHz, CDCl3):
;
4.3.13. (þ)-(S)-3-(4-Methoxybenzyl)-3-(nitromethyl)cyclohexan-1-
one (10m)
d
1.24 (s, 3H), 1.91e1.98 (m, 1H), 1.99e2.07 (m, 1H), 2.18e2.25 (m,
1H), 2.35e2.41 (m, 3H), 4.38e4.45 (m, 2H) ppm; 13C NMR
Following the general procedure, the reaction of cyclohexenone
9m (108 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:4), compound (S)-10m (117 mg, yield: 85%) as a yellow
oil. 87% ee was determined by chiral HPLC (Chiralcel AD-H, column
temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 92: 8, 1.0 mL/min,
(125 MHz, CDCl3): d 23.5, 33.0, 36.0, 40.2, 49.7, 84.3, 215.7 ppm; MS
(ESI) m/z 180 (M þ Naþ, 100%).
4.3.17. (þ)-(R)-3-Methyl-3-(nitromethyl)cycloheptan-1-one (10q)
Following the general procedure, the reaction of cyclo-
heptenone 9q (62 mg, 0.5 mmol) gave, after FC on silica gel (eluent:
EtOAc/n-hexane ¼ 1:6), the known compound (R)-10q [8c] (78 mg,
yield: 84%) as a yellow oil. 98% ee was determined by chiral HPLC
(Chiralcel OD-H, column temperature: 30 ꢁC, n-hexane: i-
l
¼ 220 nm), tR (major) ¼ 24.7 min, tR (minor) ¼ 25.8 min,
20
[
a
]
¼ þ9.1 (c ¼ 1.0, CHCl3, 87% ee); IR (film) nmax: 2925, 2853,1711,
D
1611, 1549, 1512, 1381, 1249, 1033, 840, 644 cmꢀ1
;
1H NMR
(500 MHz, CDCl3): 1.70e1.85 (m, 2H), 1.96e2.08 (m, 2H),
d
2.20e2.27 (m, 1H), 2.30e2.38 (m, 3H), 2.71 (s, 2H), 3.77 (s, 3H), 4.17
(d, J ¼ 11.5 Hz, 1H), 4.24 (d, J ¼ 11.5 Hz, 1H), 6.83 (d, J ¼ 8.5 Hz, 2H),
PrOH ¼ 95: 5, 1.0 mL/min,
l
¼ 220 nm), tR (minor) ¼ 29.1 min, tR
20
(major) ¼ 30.4 min, [
a]
D
¼ þ5.9 (c ¼ 1.0, CHCl3, 98% ee) [lit [8c].
25
30
7.10 (d, J ¼ 8.5 Hz, 2H) ppm; 13C NMR (125 MHz, CDCl3):
d
21.0, 31.3,
[
a
]
D
¼ þ28.8 (c ¼ 2.2, CHCl3, 99% ee); (S)-10q: lit [8d]. [
a
]
¼ ꢀ31
D
40.4, 40.9, 43.5, 48.1, 55.1, 80.9, 113.8 (2C), 126.7, 131.7 (2C), 158.6,
209.3 ppm; HRMS (ESI) m/z calcd for [C15H19NNaO4]þ (M þ Naþ):
300.1206; found: 300.1207.
(c ¼ 1.0, CH2Cl2, 98% ee)]; IR (film) nmax: 2924, 2853, 1693, 1549,
1462, 1377, 1186, 964, 818, 654 cmꢀ1 1H NMR (500 MHz, CDCl3):
1.05 (s, 3H), 1.55e1.65 (m, 2H), 1.67e1.88 (m, 4H), 2.33e2.44 (m,
2H), 2.47 (d, J ¼ 12.3 Hz, 1H), 2.67 (d, J ¼ 12.3 Hz, 1H), 4.22 (s, 2H)
;
d
4.3.14. (þ)-(R)-3-(Nitromethyl)-3-phenylcyclohexan-1-one (10n)
Following the general procedure, the reaction of cyclohexenone
9n (86 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:5), the known compound (R)-10n [8c] (68 mg, yield:
58%) as a yellow solid. 89% ee was determined by chiral HPLC
(Chiralcel AD-H, column temperature: 30 ꢁC, n-hexane: i-
ppm; 13C NMR (125 MHz, CDCl3):
d 23.6 (2C), 23.7, 36.5, 39.4, 43.7,
51.5, 85.2, 211.1 ppm; MS (ESI) m/z 208 (M þ Naþ, 100%).
4.3.18. (þ)-(R)-3-Methyl-3-((S/R)-1-nitropropyl)cyclohexan-1-one
(10r þ 10r0)
Following the general procedure, the reaction of cyclohexenone
9a (55 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:4), a mixture of inseparable diastereomers (R)-10r and
(R)-10r’ [11c] (86 mg, yield: 86%, dr ¼ 55: 45, determined by 1H
NMR) as a yellow oil. 91, 94% ee were determined by chiral HPLC
(Chiralcel AD-H, column temperature: 30 ꢁC, hexane: i-PrOH ¼ 90:
PrOH ¼ 90: 10, 1.0 mL/min,
l
¼ 220 nm), tR (major) ¼ 11.8 min, tR
20
(minor) ¼ 16.0 min, [
a]
D
¼ þ11.3 (c ¼ 1.0, CHCl3, 89% ee) [lit [8c].
25
30
[
a
]
¼ þ63.6 (c ¼ 2.0, CHCl3, 98% ee); (S)-10n: lit [8d]. [
a]
¼ ꢀ23
D
D
(c ¼ 0.55, CH2Cl2, 98% ee)]; mp: 91e93 ꢁC; IR (film) nmax: 2955,
2924, 2854, 1711, 1650, 1548, 1462, 1375, 1185, 1080, 948, 697 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
1.45e1.57 (m, 1H), 1.88e1.97 (m, 1H),
10, 1.0 mL/min,
l
¼
230 nm), tR (major)
¼
7.7 min, tR
2.07e2.17 (m, 1H), 2.28e2.36 (m, 2H), 2.40e2.48 (m, 1H), 2.75 (d,
J ¼ 14.8 Hz, 1H), 3.21 (d, J ¼ 14.8 Hz, 1H), 4.53 (d, J ¼ 11.1 Hz, 1H),
4.59 (d, J ¼ 11.1 Hz, 1H) 7.27e7.41 (m, 5H) ppm; 13C NMR (125 MHz,
(minor) ¼ 26.1 min, tR (major) ¼ 11.4 min, tR (minor) ¼ 12.9 min,
25
[
a
]
D
¼ þ2.4 (c ¼ 1.0, CHCl3, 91, 94% ee). IR (film) vmax: 2948, 1712,
1546, 1364, 1232, 810, 510 cmꢀ1
mixture:
;
1H NMR (500 MHz, CDCl3)
CDCl3):
d
20.6, 33.4, 40.4, 46.6, 48.4, 85.8, 126.5, 127.9, 129.2, 139.1,
d
0.83 (td, J ¼ 7.2, 2.8 Hz, 3.15H), 0.90 (d, J ¼ 10.4 Hz,
208.3 ppm; MS (ESI) m/z 256 (M þ Naþ, 100%).
3.12H), 1.38e1.55 (m, 1.11H), 1.63e1.77 (m, 3.18H), 1.82e2.01 (m,
2.67H), 2.10e2.29 (m, 3.20H), 2.43 (d, J ¼ 13.7 Hz, 0.55H), 4.18 (ddd,
J ¼ 11.8, 6.7, 2.0 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3) mixture:
4.3.15. (þ)-(R)-3-(4-Chlorophenyl)-3-(nitromethyl)cyclohexan-1-
one (10o)
d
10.6, 20.0, 20.1, 20.8, 20.9, 21.0, 32.4, 32.6, 40.2, 40.3, 40.9, 41.4,
Following the general procedure, the reaction of cyclohexenone
9o (103 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:5), compound (R)-10o (66 mg, yield: 50%) as a yellow
solid. 66% ee was determined by chiral HPLC (Chiralcel AD-H, col-
umn temperature: 30 ꢁC, n-hexane: i-PrOH ¼ 90: 10, 1.0 mL/min,
48.6, 49.8, 98.1, 99.2, 209.0 ppm; HRMS (ESI) m/z calcd for
[C10H17NO3Na]þ (M þ Naþ): 222.1101; found: 222.1098.
4.3.19. (þ)-(R)-3-(Nitromethyl)cyclohexan-1-one (10s)
Following the general procedure, the reaction of cyclohexenone
9r (48 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:10), the known compound (R)-10s [12c] (62 mg, yield:
79%) as a yellow oil. 98% ee was determined by chiral HPLC (Chir-
alcel AD-H, column temperature: 30 ꢁC, hexane: i-PrOH ¼ 90: 10,
l
¼ 220 nm), tR (major) ¼ 15.9 min, tR (minor) ¼ 23.3 min,
20
[
a
]
¼ þ11.5 (c ¼ 1.0, CHCl3, 66% ee); mp: 117e119 ꢁC; IR (film)
D
nmax: 2956, 2925, 2854, 1711, 1681, 1453, 1361, 1190, 1082, 847,
771 cmꢀ1 1H NMR (500 MHz, CDCl3):
; d 1.46e1.57 (m, 1H),
1.88e1.98 (m, 1H), 2.06e2.16 (m, 1H), 2.26e2.42 (m, 3H), 2.74 (d,
J ¼ 14.6 Hz, 1H), 3.16 (d, J ¼ 14.6 Hz, 1H), 4.53 (d, J ¼ 11.2 Hz, 1H),
4.56 (d, J ¼ 11.2 Hz, 1H), 7.26 (d, J ¼ 8.0 Hz, 2H), 7.35 (d, J ¼ 8.0 Hz,
1.0 mL/min,
l
¼
210 nm), tR (major)
¼
14.0 min, tR
25
(minor) ¼ 16.2 min, [
a]
¼ þ7.9 (c ¼ 1.0, CHCl3, 98% ee) [lit [12c].
D
25
[
a
]
D
¼ þ10.6 (c ¼ 0.5, CHCl3, 96% ee)]; IR (film) vmax: 2962, 2924,
2H) ppm; 13C NMR (125 MHz, CDCl3):
d
20.6, 33.5, 40.3, 46.4, 48.5,
2853, 1261, 1019, 799 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d 1.42e1.60
85.6, 128.1 (2C), 129.4 (2C), 134.0, 137.6, 207.9 ppm; HRMS (ESI) m/z
(m, 1H), 1.67e1.82 (m, 1H), 1.95e2.04 (m, 1H), 2.08e2.21 (m, 2H),
2.25e2.36 (m,1H), 2.41e2.54 (m, 2H), 2.59e2.72 (m,1H), 4.28e4.51
calcd for [C13H14ClNNaO3]þ (M þ Naþ): 290.0554; found: 290.0559.
(m, 2H) ppm; 13C NMR (125 MHz, CDCl3):
d 24.1, 28.2, 37.1, 40.8,
4.3.16. (þ)-(R)-3-Methyl-3-(nitromethyl)cyclopentan-1-one (10p)
Following the general procedure, the reaction of cyclo-
pentenone 9p (55 mg, 0.5 mmol) gave, after FC on silica gel (eluent:
EtOAc/n-hexane ¼ 1:4), the known compound (R)-10p [8c] (41 mg,
yield: 52%) as a yellow oil. 91% ee was determined by chiral HPLC
(Chiralcel OD-H, column temperature: 30 ꢁC, n-hexane: i-
44.4, 80.0, 208.1 ppm; HRMS (ESI) m/z calcd for [C7H11O3Na]þ
(M þ Naþ): 180.0631; found: 180.0630.
4.3.20. (þ)-(R)-3-((S)-1-Nitropropyl)cyclohexan-1-one (10t) þ
(ꢀ)-(R)-3-((R)-1-Nitropropyl)cyclohexan-1-one (10t0)
Following the general procedure, the reaction of cyclohexenone
9r (48 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:8), a mixture of inseparable diastereomers (R,S)-10t and
(R,R)-10t’ [11b] (86 mg, yield: 93%, dr ¼ 17: 83, determined by 1H
PrOH ¼ 95: 5, 1.0 mL/min,
l
¼ 220 nm), tR (minor) ¼ 62.2 min, tR
20
(major) ¼ 64.4 min, [
a]
D
¼ þ 8.0 (c ¼ 1.0, CHCl3, 91% ee) [lit [8c].
25
30
[
a
]
¼ þ77.5 (c ¼ 2.1, CHCl3, 88% ee); (S)-10p: lit [8d]. [
a
]
¼ ꢀ28
D
D
10

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
NMR) as a yellow oil. 99, 97% ee were determined by chiral HPLC
(Chiralcel OD-H, column temperature: 30 ꢁC, hexane: i-PrOH ¼ 90:
2H), 2.30e2.38 (m, 1H), 2.59 (d, J ¼ 13.9 Hz, 1H), 7.30 (s, 1H), 8.60 (s,
1H) ppm; 13C NMR (125 MHz, CDCl3):
d 21.2, 25.6, 34.5, 40.4, 41.0,
10, 1.0 mL/min,
l
¼
210 nm), tR (major)
¼
10.0 min, tR
49.9, 156.1, 210.3 ppm; HRMS (ESI) m/z calcd for [C8H13NO2Na]þ
(M þ Naþ): 178.0838; found: 178.0842.
(minor) ¼ 11.1 min; tR (major) ¼ 10.4 min, tR (minor) ¼ 11.8 min);
25
[
a
]
¼ ꢀ2.4 (c ¼ 1.0, CHCl3, 97, 99% ee) [lit [11b]. less polar (R,S)-
D
10t: [
[a]
D
a
]
D
¼ þ29.3 (c ¼ 1.2, CHCl3, 91% ee), more polar (R,R)-10t’:
4.6. (R)-7-Methyl-7-(nitromethyl)-1,4-dioxaspiro[4.5]decane (13)
¼ ꢀ13.2 (c ¼ 1.1, CHCl3, 74% ee)]; IR (film) vmax: 2924, 2854,
1713, 1546, 1462, 1260, 1098, 804 cmꢀ1; 1H NMR (500 MHz, CDCl3)
mixture:
0.77 (td, J ¼ 7.3, 3.1 Hz, 3H), 1.27e1.35 (m, 1H), 1.41e1.57
(m, 1H), 1.61e2.06 (m, 5H), 2.06e2.31 (m, 4H), 4.14e4.26 (m, 1H)
ppm; Major disastereomer: 13C NMR (125 MHz, CDCl3)
9.7, 23.6,
23.9, 26.9, 40.3, 40.8, 43.0, 93.9, 208.2 ppm; Minor disastereomer:
To a solution of compound 10a (86 mg, 0.5 mmol) in CH2Cl2
(5 mL) was added ethylene glycol (621 mg, 10 mmol), trimethyl
orthoformate (1061 mg, 10.0 mmol) and BF3$OEt2 (28 mg,
0.2 mmol) at room temperature under an argon atmosphere for
12 h. The reaction was quenched with NaHCO3 (5 mL). The aqueous
phase was extracted with CH2Cl2 (3 ꢂ 5 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent: EtOAc/n-Hexane ¼ 1:8) to
afford the desired product 13 (101 mg, yield: 94%) as a yellow oil; IR
(film) vmax: 2942, 2882, 1547, 1462, 1376, 1177, 1140, 1098, 1054,
d
d
13C NMR (125 MHz, CDCl3):
d 9.8, 23.4, 23.7, 26.9, 40.3, 41.0, 43.1,
93.7, 208.3 ppm HRMS (ESI) m/z calcd for [C9H15NO3Na]þ
(M þ Naþ): 208.0944; found: 208.0942.
4.3.21. (þ)-(R)-3-(2-Nitropropan-2-yl)cyclohexan-1-one (10u)
Following the general procedure, the reaction of cyclohexenone
9r (48 mg, 0.5 mmol) gave, after FC on silica gel (eluent: EtOAc/n-
hexane ¼ 1:10), the known compound (R)-10u [11d] (81 mg, yield:
87%) as a white solid. 98% ee was determined by chiral HPLC
(Chiralcel AD-H, column temperature: 30 ꢁC, hexane: i-PrOH ¼ 90:
1043, 943, 832, 732 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d 1.04 (s, 3H),
1.19e1.26 (m, 1H), 1.46e1.54 (m, 2H), 1.58e1.67 (m, 4H), 1.71 (d,
J ¼ 14.1 Hz, 1H), 3.79e3.96 (m, 4H), 4.38 (d, J ¼ 10.8 Hz, 1H), 4.51 (d,
J ¼ 10.8 Hz, 1H) ppm; 13C NMR (125 MHz, CDCl3):
d 19.4, 26.2, 34.6,
34.7, 36.6, 43.4, 64.0, 64.4, 83.5, 108.2 ppm; HRMS (ESI) m/z calcd
10, 1.0 mL/min,
l
¼
210 nm), tR (major)
¼ þ20.5 (c ¼ 1.0, CHCl3, 98% ee) [lit [11d].
¼
12.6 min, tR
25
(minor) ¼ 11.8 min, [
a
]
for [C10H17NO4Na]þ (M þ Naþ): 238.1050; found: 238.1051.
D
26
[
a
]
¼ ꢀ13.7 (c ¼ 1.0, CHCl3)]; mp: 64e65 ꢁC; IR (film) vmax: 2923,
D
2854, 1714, 1533, 1457, 1261, 1092, 1022, 800 cmꢀ1
;
1H NMR
4.7. (S)-7a-(Nitromethyl)-1, 2, 5, 6, 7, 7a-hexahydro-4H-inden-4-
one (14)
(500 MHz, CDCl3):
1.57e1.63 (m, 1H), 1.71e1.82 (m, 1H), 2.02e2.13 (m, 2H), 2.15e2.42
(m, 4H) ppm; 13C NMR (125 MHz, CDCl3):
22.5, 23.1, 24.2, 25.8,
d
1.33e1.45 (m, 1H), 1.52 (d, J ¼ 7.8 Hz, 6H),
d
To a solution of compound 10f (64 mg, 0.5 mmol) in MeOH
(5 mL) was added 3 M HCl (5 mL) at 0 ꢁC. The reaction was heated to
45 ꢁC for 24 h. The resulting mixture was quenched with saturated
aqueous solution of NaHCO3 (5 mL). The organic phase was sepa-
rated and aqueous phase was extracted with CH2Cl2 (3 ꢂ 5 mL). The
combined organic phases dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (EtOAc/n-Hexane) to afford
40.6, 42.4, 46.4, 90.5, 208.8 ppm; HRMS (ESI) m/z calcd for
[C9H15NO3Na]þ (M þ Naþ): 208.0944; found: 208.0946.
4.4. (R)-1-Methyl-3-oxocyclohexane-1-carboxylic acid (11)
A mixture of compound 10a (86 mg, 0.5 mmol), sodium nitrite
(104 mg, 1.5 mmol), and acetic acid (300 mg, 5.0 mmol) in dime-
thylsulfoxide (2.0 mL) was stirred at 40 ꢁC for 6 h [28]. The reaction
mixture was cooled to room temperature, diluted with water
(3 mL) and acidified with hydrochloric acid (3 M) to pH 2. The
aqueous phase was extracted with CH2Cl2 (3 ꢂ 5 mL). The com-
bined organic layers were dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified
by flash chromatography on silica gel (eluent: EtOAc/n-
Hexane ¼ 1:1) to afford the desired product 11 (56 mg, yield: 72%)
as a pale yellow oil; IR (film) vmax: 3321, 2965, 2925, 1730, 1463,
the desired product 14 (70 mg, yield: 71%) as a yellow oil,
20
[
a
]
D
¼ ꢀ1.1 (c ¼ 1.0, CHCl3); IR (film) nmax: 2923, 2851, 1705, 1614,
1455, 1378, 1318, 1169, 1082 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
d
1.59e1.70 (m, 1H), 1.79e1.89 (m, 1H), 1.97e2.10 (m, 2H), 2.16e2.24
(m, 1H), 2.25e2.37 (m, 1H), 2.49e2.59 (m, 3H), 2.60e2.68 (m, 1H),
4.19 (d, J ¼ 11.1 Hz, 1H), 4.45 (d, J ¼ 11.1 Hz, 1H), 6.71 (t, J ¼ 2.4 Hz,
1H) ppm; 13C NMR (125 MHz, CDCl3):
d 20.3, 29.6, 33.0, 36.9, 39.8,
52.1, 77.6, 141.6, 143.8, 198.0 ppm; HRMS (ESI) m/z calcd for
[C10H13NNaO3]þ (M þ Naþ): 218.0788; found: 218.0785.
1413, 1260, 1102, 1113, 803 cmꢀ1; 1H NMR (500 MHz, CDCl3):
(s, 3H), 1.65e1.98 (m, 3H), 2.10e2.46 (m, 4H), 2.75 (d, J ¼ 14.5 Hz,
1H), 8.69 (s, 1H) ppm; 13C NMR (125 MHz, CDCl3):
22.0, 24.5, 34.2,
d 1.30
Declaration of competing interest
d
40.2, 46.3, 49.5, 181.7, 209.2 ppm; HRMS (ESI) m/z calcd for
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
[C8H12O3Na]þ (M þ Naþ): 179.0679; found: 179.0670.
4.5. (R,E)-1-Methyl-3-oxocyclohexane-1-carbaldehyde oxime (12)
Acknowledgement
A solution of compound 10a (86 mg, 0.5 mmol), 1,10-azo-
bis(cyanocyclohexane) (122 mg, 0.5 mmol), and n-Bu3SnH (728 mg,
2.5 mmol) in toluene (5 mL) was stirred at 90 ꢁC for 6 h. The re-
action mixture was cooled to room temperature and quenched
with H2O (5 mL). The aqueous phase was extracted with EtOAc
(3 ꢂ 5 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
EtOAc/n-Hexane ¼ 1:4) to afford the desired product 12 (58 mg,
yield: 75%) as a yellow oil; IR (film) vmax: 3277, 2964, 2923, 2853,
S.-Y. Yu and Y.-N. Zhu contributed equally to this work. The
authors are thankful for the financial support from the National Key
R&D Program of China (2017YFA0207302), the National Natural
Science Foundation of China (22071204 and 21931010), and the
Program for Changjiang Scholars and Innovative Research Team in
University of the Ministry of Education, China.
Appendix A. Supplementary data
1709, 1462, 1260, 1187, 963, 801 cmꢀ1
;
1H NMR (500 MHz, CDCl3):
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132005.
d
1.15 (s, 3H), 1.63e1.71 (m, 1H), 1.78e1.91 (m, 3H), 2.14e2.25 (m,
11

S.-J. Yu, Y.-N. Zhu, J.-L. Ye et al.
Tetrahedron 84 (2021) 132005
245e249;
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