Highly diastereodivergent synthesis of tetrasubstituted cyclohexanes catalyzed by modularly designed organocatalysts

Article abstract of DOI:10.1002/anie.201404072

A highly diastereodivergent synthesis of tetrasubstituted cyclohexanes has been achieved using modularly designed organocatalysts (MDOs) which are self-assembled in situ from amino acids and cinchona alkaloid derivatives. Diastereodivergence is realized through controlling the stereoselectivity of the individual steps of a tandem Michael/Michael reaction. Up to 8 of the 16 possible stereoisomers have been successfully obtained in high stereoselectivities using MDOs for the tandem reaction and an ensuing epimerization. The method was used in the enantioselective synthesis of the natural products (-)-α- and β-lycoranes.

Full text of DOI:10.1002/anie.201404072

Angewandte
Chemie
DOI: 10.1002/anie.201404072
Carbocycle Synthesis
Highly Diastereodivergent Synthesis of Tetrasubstituted Cyclohexanes
Catalyzed by Modularly Designed Organocatalysts**
Nirmal K. Rana, Huicai Huang, and John C.-G. Zhao*
Abstract: A highly diastereodivergent synthesis of tetrasub-
stituted cyclohexanes has been achieved using modularly
designed organocatalysts (MDOs) which are self-assembled
in situ from amino acids and cinchona alkaloid derivatives.
Diastereodivergence is realized through controlling the stereo-
selectivity of the individual steps of a tandem Michael/Michael
reaction. Up to 8 of the 16 possible stereoisomers have been
successfully obtained in high stereoselectivities using MDOs
for the tandem reaction and an ensuing epimerization. The
method was used in the enantioselective synthesis of the natural
products (À)-a- and b-lycoranes.
obtain conventional diastereomeric catalysts separate syn-
theses are required, and therefore are tedious and time
consuming.
Recently there has been growing interest in applying self-
assembled organocatalysts[8,9] in asymmetric catalyses.[10]
Previously we demonstrated that modularly designed organo-
catalysts (MDOs),[11] self-assembled from amino acids and
cinchona alkaloid thiourea derivatives, are highly efficient
catalysts for Michael, hetero-Diels–Alder, aldol, and Man-
nich reactions. Both the amino acid and the cinchona alkaloid
thiourea modules of the MDO play an important role in the
stereocontrol in these reactions.[11] Since quinidine thiourea
(QDT) and quinine thiourea (QNT) are pseudoenantiomeric
(Figure 1), the MDOs self-assembled from QDT and QNT
With the advent of novel methods based on metal catalysis,
biocatalysis, and organocatalysis, individual enantiomers of
many organic compounds can now be routinely obtained in
high enantiopurity.[1] Nonetheless, despite the great progress
made on asymmetric catalysis in the past decades, for
compounds containing multiple stereogenic centers, it still
remains a great challenge to freely access all the possible
stereoisomers from the same starting materials with high
stereocontrol. Previously, diastereodivergence has been ach-
ieved by changing the solvent,[2] using different chiral
catalysts,[3] or adding additives.[4] MacMillan and co-workers
also developed cycle-specific organocatalysis to achieve
diastereodivergence by employing two different chiral
amine catalysts in a sequential reaction with separate iminium
and enamine activation.[5] Most recently, Carreira and co-
workers demonstrated an elegant synthesis of all four
stereoisomers of a-allyl aldehydes using dual catalysis which
involves amine and iridium activations.[6]
Figure 1. Structures of selected precatalyst modules.
The tandem reaction is a highly efficient way for assem-
bling complex molecules with multiple stereogenic centers
from relatively simple starting materials.[7] We envisioned
that, if the stereochemistry of the individual steps of a tandem
reaction could be separately controlled by different moieties
of the catalyst, diastereodivergence would be achieved with
diastereomeric catalysts. Theoretically, multiple diastereo-
mers of a compound with more than two stereogenic centers
can be accessed using this novel approach. Unfortunately, to
and a given enantiomer of proline (i.e., l-Pro or d-Pro,
Figure 1) are pseudodiastereomeric. Thus, it is very conven-
ient to obtain pseudodiastereomeric catalysts in this way.
Ideally, if the individual steps of a tandem reaction are
separately controlled by these two modules, then diastereo-
divergence should be achieved. Herein we report that up to 8
of the 16 possible stereoisomers of tetrasubstituted cyclo-
hexanes[12] may be synthesized from the same substrates in
high diastereo- and enantioselectivities using MDOs self-
assembled from both enantiomers of Pro and the cinchona
alkaloid thiourea derivatives QDT and QNT (Figure 1),
through a diastereodivergent tandem Michael/Michael reac-
tion coupled with an epimerization.
To test our hypothesis, we designed a tandem Michael/
Michael reaction between the nitroalkenes 1 and compounds
2 (Scheme 1). The substrates were so chosen that the first
intermolecular Michael reaction would involve amine catal-
ysis via an enamine intermediate[13] and the second intra-
molecular Michael reaction would be catalyzed by the
thiourea moiety through noncovalent catalysis.[14] Using
[*] Dr. N. K. Rana, Dr. H. Huang, Prof. Dr. J. C.-G. Zhao
Department of Chemistry, University of Texas at San Antonio
One UTSA Circle, San Antonio, TX 78249-0698 (USA)
E-mail: cong.zhao@utsa.edu
[**] This work was financially supported by the Welch Foundation (Grant
No. AX-1593) and partially by the NSF (Grant No. CHE 0909954).
We thank Dr. Hadi Arman for the assistance with the X-ray
crystallographic analysis of the reaction products.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404072.
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Table 1: Synthesis of four 1,2-syn diastereomers of cyclohexanes using
MDOs.[a]
Entry
1
2
d.r.[b]
1,2-syn/anti
3 or 4
Yield
[%][c]
ee
3/4
[%][d]
1[e]
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1d
1d
1d
1d
1e
1e
1e
1e
1c
1c
1c
1c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
80:20
82:18
82:18
80:20
84:16
90:10
87:13
85:15
86:14
88:12
88:12
91:9
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
85:15
86:14
85:15
87:13
96:4
3a
4a
ent-3a
ent-4a
3b
73
72
74
72
79
83
80
80
77
80
79
82
90
92
92
91
92
90
81
92
79
79
78
81
>99
>99
>99
99
>99
99
2[f]
6:94
92:8
5:95
3[g]
4[h]
5[e]
94:6
10:90
93:7
8:92
93:7
7:93
92:8
8:92
95:5
6:94
94:6
5:95
91:9
10:90
92:8
7:93
95:5
4:96
94:6
8:92
6[f]
4b
7[g]
ent-3b
ent-4b
3c
>99
99
8[h]
9[e]
>99
>99
>99
>99
>99
>99
>99
>99
99
10[f]
11[g]
12[h]
13[e,i]
14[f,i]
15[g,i]
16[h,i]
17[e,i]
18[f,i]
19[g,i]
20[h,i]
21[e]
22[f]
23[g]
24[h]
4c
ent-3c
ent-4c
3d
Scheme 1. MDO for the synthesis of four 1,2-syn diastereomers of
tetrasubstituted cyclohexanes from common substrates.
4d
ent-3d
ent-4d
3e
trans-b-nitrostyrene (1a, R1 = Ph) and the compound 2a
(R2 = Ph) as the model substrates, we first screened the
MDOs self-assembled from proline and cinchona alkaloid
thioureas for their ability to achieve the desired diastereodi-
vergence.[15] Indeed, the MDO of QDT/l-Pro and its pseudo-
diastereomer QNT/l-Pro led to the formation of different
diastereomers (Scheme 1).
4e
>99
99
ent-3e
ent-4e
3 f
4 f
ent-3 f
ent-4 f
>99
>99
>99
>99
>99
[a] Unless otherwise indicated, all reactions were conducted with
Through careful screening (see Tables S1 and S2 in the
Supporting Information),[15] we eventually found that l-Pro
and d-Pro are the best reaction-center modules[11] and that
QDT and QNT are the best stereocontrolling modules[11] for
this reaction. As summarized in Table 1 and Scheme 1, under
the optimized reaction conditions, the MDO of QDT/l-Pro
led to the formation the major syn,anti,anti-product 3a in
toluene at room temperature (Scheme 1, upper left), whereas
the pseudodiastereomeric MDO of QNT/l-Pro led to the
formation of the major syn,anti,syn-product 4a (Scheme 1,
upper right). The enantiomers of these two compounds (ent-
3a and ent-4a) may be obtained by using the pseudoenan-
tiomers of these two catalysts, QNT/d-Pro and QDT/d-Pro,
respectively (Scheme 1, lower left and right). While all these
MDOs lead to 1,2-syn compounds as the major products, they
differ in the stereochemical outcome at C3/C4. In contrast,
the trans-configuration of b-nitrostyrene is completely
retained in these four products. The diastereoselectivities at
C1/C2 (1,2-syn/1,2-anti) are around 80:20, where in the major
products the diastereoselectivities at C3/C4 are no less than
92:8. Most importantly, all of the major diastereomeric
products were obtained essentially as a pure enantiomer (ꢀ
99% ee) in good yields (Table 1, entries 1–4). Control experi-
ments indicate that the present catalysis is not a cycle-specific
process since both of the two MDO modules are important
for the observed reactivity and stereoselectivities in each of
the two individual Michael steps (see the control experiments
in Scheme S3).[15] Similar results were also obtained for 4-
chloro- (R1 = 4-ClC6H4; 1b) and 4-bromo-substituted (R1 = 4-
BrC6H4; 1c) trans-b-nitrostyrenes, except that slightly higher
1,2-syn/1,2-anti diastereoselectivities were obtained in these
cases (entries 5–12). When an aliphatic trans-1-nitrohex-1-ene
(R1 = n-C4H9; 1d) was used as the substrate, only the 1,2-syn-
1 (0.22 mmol), 2 (0.20 mmol), and 10 mol% (0.020 mmol) of each of the
two precatalyst modules in toluene (1.0 mL) at RT for 1 h. [b] Determined
by 1H NMR analysis of the crude reaction mixture. [c] Combined yield of
both diastereomers (3 and 4) after column chromatography. [d] Deter-
mined by HPLC analysis on the corresponding reduced alcohol using
a chiral stationary phase. [e] With the catalyst QDT/l-Pro (A). [f] With the
catalyst QNT/l-Pro (B). [g] With the catalyst QNT/d-Pro (C). [h] With the
catalyst QDT/d-Pro (D). [i] The reaction time was 2 h.
diastereomers were formed (1,2-syn/1,2-anti > 99:1 in all
cases), whereas the diastereoselectivities at C3/C4 and the
ee values of these four diastereomers remain excellent
(entries 13–16). Similar results were also obtained for the
products of 2-phenylethyl-substituted nitroalkene 1e
(entries 17–20). As expected, when 1c and 2b (R2 = 4-
MeOC6H4) were used as the substrates, similar results to
those listed in entries 1–12 were obtained (entries 21–24).
During the catalyst screening, we also noticed that the
formyl-substituted C1 stereogenic center in 3a and 4a is
prone to epimerization under the reaction conditions.
Actually this is the competing process which leads to the
lower 1,2-syn diastereoselectivities observed for the 2-aryl-
substituted products (i.e., 3a–c, f and 4a–c, f) compared to
those of the 2-alkyl-substituted ones (i.e., 3d–e and 4d–e).
Although this property is undesirable for obtaining the 1,2-
syn-diastereomers, we realized that it could be utilized to
access the 1,2-anti diastereomers, which were formed only as
minor products in the tandem reactions.[16]
After some optimization, we found that, by conducting
the reaction at room temperature first and then elevating the
reaction temperature to 408C for 9 hours, all the 1,2-syn-
diastereomers could be completely converted into the corre-
sponding 1,2-anti diastereomers. As shown in Scheme 2
2
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prone to this epimerization process and the in situ epimeriza-
tion with the MDOs is very slow even at elevated temper-
ature. Instead, these compounds may be isolated from the
tandem reactions using the MDOs (Table 1) and then
epimerized using the pyrrolidine/acetic acid combination as
the catalyst at 408C. When the reaction finally reaches
equilibrium (5 h), a 1,2-anti/syn ratio around 80:20 may be
achieved without affecting the original d.r. at C3/C4 and the
product ee values (see Table S4).[15]
The relative and absolute configurations of the cyclohex-
ane derivatives obtained in this study were determined by
NOE experiments (using compounds 3a, ent-4a, 5a) and X-
ray crystallography of the compounds 3c, the reduced ent-5a,
and a tosylate derivative of the reduced ent-6c (see Figure S2–
S4).[15]
The lycorane-type alkaloids are natural products possess-
ing many biological activities.[17] Therefore, considerable
effort has been made towards the total synthesis of these
alkaloids. However, most of the syntheses yield racemic
Scheme 2. MDO for the synthesis of four 1,2-anti diastereomers.
(upper left and right), in this way, the diastereomers 5 and 6
were readily obtained from the MDOs which lead to the
formation of 3 and 4, respectively. Similarly, their enantio-
mers could be obtained from the reactions that form ent-3 and
ent-4, respectively (Scheme 2, lower left and right). As the
data in Table 2 show, pure 1,2-anti diastereomers (1,2-anti/1,2-
syn > 99:1) were obtained in excellent yields, while the
original diastereoselectivities at C3/C4 and the product
ee values were not affected (entries 1–4). Similarly, the 2-
aryl-substituted 3b, 3c, 4b, 4c, 3 f, and 4 f were by completely
converted in situ into their corresponding 1,2-anti diastereo-
mers (1,2-anti/syn > 99:1) using the respective MDOs under
similar reaction conditions, without affecting the d.r. at C3/C4
and the product ee values (entries 5–16). In contrast, the 2-
alkyl-substituted 3d, 4d, 3e, and 4e (Scheme 1) are much less
Table 2: Synthesis of the 1,2-anti diastereomers using MDOs.[a]
Entry
1
2
Cat.[b]
d.r.[c]
3,4-anti/syn
5 or 6
Yield
[%][d]
ee
[%][e]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1c
1c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
A
B
C
D
A
B
C
D
A
B
C
D
A
B
C
D
96:4
6:94
92:8
5:95
94:6
10:90
93:7
8:92
93:7
7:93
92:8
8:92
95:5
96:4
6:94
8:92
5a
94
93
93
93
93
91
94
92
92
94
93
94
90
91
92
92
99
99
99
6a
ent-5a
ent-6a
5b
99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
6b
ent-5b
ent-6b
5c
9
10
11
12
13
14
15
16
6c
ent-5c
ent-6c
5 f
6 f
ent-5 f
ent-6 f
Scheme 3. Enantioselective total synthesis of (À)-b-lycorane and
formal total synthesis of (À)-a-lycorane. Reaction conditions: a) QDT/
l-Pro (10 mol%), toluene, RT, 4 h, then 408C, 10 h; b) 1. NaBH4,
CH2Cl2/EtOH (5:1, v/v), À788C, 2.5 h; 2. TBDMSCl, DMAP, imidazole,
DMF, RT, 18 h; c) mCPBA, NaHCO3, CH2Cl2, RT, 48 h; d) NaBH4,
NiCl2·6H2O, MeOH, 08C to RT, 18 h; e) (CH2O)x, TFA, CH2Cl2, RT,
18 h; f) PCC, CH2Cl2, RT, 3 h; g) [Rh(PPh3)3Cl], benzonitrile, reflux,
18 h; h) LiAlH4, THF, reflux, 18 h; i) QNT/l-Pro (10 mol%), toluene,
RT, 4 h, then 408C, 10 h. DMAP=4-(N,N-dimethylamino)pyridine,
DMF=N,N-dimethylformamide, mCPBA=meta-chloroperbenzoic
acid, PMP=para-methoxyphenyl, TBDMS=tert-butyldimethylsilyl,
TFA=trifluoroacetic acid.
[a] The reactions were first conducted at RT as described in Table 1 and
then continued at 408C for 9 h. [b] Catalysts: A: QDT/l-Pro; B: QNT/l-
Pro; C: QNT/d-Pro; D: QDT/d-Pro. [c] Determined by 1H NMR analysis
of the crude products; 1,2-anti/1,2-syn >99:1 in all cases. [d] Combined
yield of both diastereomers (5 and 6) after column chromatography.
[e] Determined by HPLC analysis on the corresponding reduced alcohol
using a chiral stationary phase.
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lycoranes.[18] The asymmetric syntheses of b-lycorane[19] and
a-lycorane[19b,20] are limited. To show the synthetic utility of
this novel diastereodivergent catalysis, we applied our
method to the facile enantioselective synthesis of (À)-b-
lycorane (12) and a formal synthesis of (À)-a-lycorane (14)
from the same substrates, 1d and 2b, and using QDT/l-Pro
and QNT/l-Pro as the catalyst, respectively (Scheme 3). As
shown in Scheme 3, both (À)-b-lycorane and the key pre-
cursor[20a] to (À)-a-lycorane were obtained in good overall
yields.
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In summary, we have developed a conceptually different
approach to achieve diastereodivergence through controlling
stereochemistry of the individual steps of a tandem reaction
using pseudodiastereomeric MDOs self-assembled from pro-
line and cinchona alkaloid thioureas. Up to eight stereoiso-
mers of tetrasubstituted cyclohexane derivatives may be
readily obtained in high diastereoselectivities and excellent
enantioselectivities using a MDOs for a tandem Michael/
Michael addition and an ensuing epimerization. The method
may be used in the enantioselective synthesis of natural
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diastereodivergent synthesis of other functional molecules is
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General procedure for the synthesis of 1,2-syn products 3 and 4: The
precatalyst module QDT (11.9 mg, 0.020 mmol, 10.0 mol%), l-Pro
(2.3 mg, 0.020 mmol, 10.0 mol%), and dry toluene (1.0 mL) were
added to a vial sequentially. The resulting mixture was stirred at room
temperature for 15 min. (E)-7-Oxo-7-phenylhept-5-enal (2a, 40.5 mg,
0.20 mmol) was then added and the mixture was stirred for 5 min
before the addition of the trans-nitroalkene 1 (0.22 mmol). The
reaction mixture was stirred at RT for the time as specified in Table 1
(monitored by TLC). Upon the completion of the reaction, diaste-
reomeric ratio was determined by 1H NMR analysis of the crude
reaction mixture. Then the mixture was purified by flash column
chromatography (EtOAc/hexanes 1:1, v/v as the eluent) to obtain 3.
The enantiomeric excess was determined after converting the
aldehyde into the corresponding alcohol.
General procedure for the synthesis of 1,2-anti products 5 and 6:
The reaction was set up exactly as described above for the 1,2-syn
products, except that the reaction mixture was first stirred at RT for
1 h and then at 408C for 9 h. Diastereomeric ratio at this stage was
1
determined by the H NMR analysis of the crude reaction mixture.
Then the mixture was purified by flash column chromatography
(EtOAc/hexanes 1:1, v/v as the eluent) to obtain 5. Enantiomeric
excess was determined after converting the aldehyde into the
corresponding alcohol.
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[10] For general reviews on organocatalysis, see: a) Asymmetric
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D. Sinha, N. K. Rana, V. Trieu-Do, J. C.-G. Zhao, J. Org. Chem.
2013, 78, 10947 – 10953.
Received: April 7, 2014
Published online: && &&, &&&&
Keywords: carbocycles · cyclization · diastereoselectivity ·
.
organocatalysis · synthetic methods
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Angewandte
Chemie
[12] Polyfunctional cyclohexanes are very useful building blocks in
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[15] For details, please see the Supporting Information.
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Angewandte
Communications
Communications
Carbocycle Synthesis
N. K. Rana, H. Huang,
J. C.-G. Zhao*
&&&& — &&&&
Highly Diastereodivergent Synthesis of
Tetrasubstituted Cyclohexanes Catalyzed
by Modularly Designed Organocatalysts
Stereoisomer made to order: Diastereo-
divergence is realized through controlling
the stereoselectivity of the individual
steps of a tandem Michael/Michael
reaction. Up to 8 of the 16 possible
stereoisomers have been successfully
obtained in high enantio- and diastereo-
selectivities using modularly designed
organocatalysts for the tandem reaction
and an ensuing epimerization. QDT=
quinidine thiourea, QNT=quinine thio-
urea.
6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!