Enantioselective Synthesis of cis-Decalin Derivatives by the Inverse-Electron-Demand Diels–Alder Reaction of 2-Pyrones

Article abstract of DOI:10.1002/anie.202006841

A novel strategy for the synthesis of cis-decalins by an ytterbium-catalyzed asymmetric inverse-electron-demand Diels–Alder reaction of 2-pyrones and silyl cyclohexadienol ethers is reported here. A broad range of synthetically important cis-decalin derivatives with multiple contiguous stereogenic centers and functionalities are obtained in good yields and stereoselectivities. A full set of diastereomeric substituted cis-decalin motifs are readily accessible by tuning the absolute configurations of substituted silyl cyclohexadienol ethers (R or S) as well as the ligands (R or S). The synthetic potential is showcased by the enantioselective total synthesis of 4-amorphen-11-ol, and further demonstrated by the first total synthesis of cis-crotonin.

Full text of DOI:10.1002/anie.202006841

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Angewandte
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Accepted Article
Title: Enantioselective Synthesis of cis-Decalin Derivatives by the
Inverse-Electron-Demand Diels–Alder Reaction of 2-Pyrones
Authors: Quan Cai, Xu-Ge Si, Zhi-Mao Zhang, Cheng-Gong Zheng,
and Zhan-Ting Li
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10.1002/anie.202006841
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Synthesis of cis-Decalin Derivatives by the
Inverse-Electron-Demand Diels–Alder Reaction of 2-Pyrones
Xu-Ge Si§, Zhi-Mao Zhang§, Cheng-Gong Zheng, Zhan-Ting Li, and Quan Cai*
[
*]
X.-G. Si§, Z.-M. Zhang§, C.-G. Zheng, Prof. Dr. Z.-T. Li, Prof. Dr. Q. Cai
Department of Chemistry, Fudan University
220 Handan Rd., Shanghai 200433, China
E-mail: quan_cai@fudan.edu.cn
X.-G. Si and Z.-M. Zhang contributed equally to this work
[§]
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: A novel strategy for the synthesis of cis-decalins by an
ytterbium-catalyzed asymmetric inverse-electron-demand Diels–
Alder reaction of 2-pyrones and silyl cyclohexadienol ethers is
reported here. A broad range of synthetically important cis-decalin
derivatives with multiple contiguous stereogenic centers and
functionalities are obtained in good yields and stereoselectivities. A
full set of diastereomeric substituted cis-decalin motifs are readily
accessible by tuning the absolute configurations of substituted silyl
cyclohexadienol ethers (R or S) as well as the ligands (R or S). The
synthetic potential is showcased by the enantioselective total
synthesis of 4-amorphen-11-ol, and further demonstrated by the first
total synthesis of cis-crotonin.
ytterbium complex using 3-carboalkoxyl-2-pyrone 1 and silyl
cyclohexadienol ether 2 as the reaction partners (Scheme 1c).
The reaction proceeded efficiently with excellent chemo- and ster-
a) cis-Decalin skeleton in natural products
OH
O
O
O
H
Me
Me
H
H
H
O
OMe
Me
H
H
OH
O
O
OMe
H
H
H
H
NHCHO
Me
HO
H
solanapyrone A
isoneoamphilectane
nodusmicin
b) Retrosynthetic analysis of
-decalin skeleton
cis
Inverse-Electron-Demand Diels–Alder Reaction
EWG
Chiral cis-decalin structural motifs widely exist in bioactive
natural products and pharmaceutics (Scheme 1a).[1] Although
various methods have been developed for the synthesis of cis-
decalin ring system,[2] new strategies are still highly desirable
owing to the structural diversity of natural products with cis-
decalin motifs. Retrosynthetically, the cis-decalin motifs could be
assembled directly from electron-deficient diene II and electron-
rich cyclic diene III via an enantioselective inverse-electron-
demand Diels–Alder reaction (Scheme 1b). Such a strategy is
fascinating as the resulting cis-decalin scaffold I possesses
various chiral centers and functionalities; thus it could be an
excellent chiral synthon for further functional group
interconversion. However, the electron-rich cyclohexadiene III
has been reported as a good diene partner to react with electron-
deficient dienophile IV in a normal-electron-demand Diels–Alder
reaction (Scheme 1b),[3] and has yet to be employed as a
dienophile in an asymmetric all-carbon-based inverse-electron-
demand Diels–Alder reaction.[4] Therefore, the key to the success
of this strategy is to develop an appropriate approach to realize
the desired chemo- and stereoselectivity.
H
EWG
H
Diels-Alder
reaction
EDG
EDG
+
H
not reported
(dienophile )
H
I
cis-decalin
II
III
[Ref.3]
III
Typical Diels-Alder reaction of cyclohexadiene in literatures
EDG
EDG
EWG
Diels-Alder
reaction
EWG
+
in literatures
(diene)
III
IV
V
Normal-Electron-Demand Diels–Alder Reaction
c) This work
R1O
O
CO2R1
O
OTBS
O
H
cat. [Yb]/L*
O
R2
+
R2
H
Diels-Alder
O
OTBS
reaction
1
2
3
stereodivergent synthesis
(by tuning the ligands and substrates)
O
O
O
O
CO2R1
R1O2C
H
CO2R1
H
R1O2C
H
O
O
O
O
H
R2
R2
R2
R2
H
H
H
H
TBSO
OTBS
OTBS TBSO
R3
H
H
R3
R3
H
R3
H
6 steps
The 2-pyrone is a privileged diene component in the Diels–
Alder reaction with a wide range of applications in complex natural
product synthesis.[5] Recently, the catalytic asymmetric Diels–
Alder reaction by utilizing 2-pyrone as the diene has attracted
increasing interests[6] since the pioneering work by Posner[7] and
Markó.[8] Inspired by these elegant advances, we envisaged an
electron-deficient 2-pyrone could be employed as the diene
component in our designed reaction. Herein, we reported an
enantioselective Diels–Alder reaction catalyzed by the chiral
O
synthetic applications
.
.
.
.
Chemoselective
High ee, high dr
OH
H
H
Highly functionalized decalins
With up to five continuous chiral
centers
H
Me
O
O
O
Me
cis-crotonin
.
Valuable in natural product
synthesis
H
H
4-amorphen-11-ol
Scheme 1. Enantioselective synthesis of cis-decalin motifs by inverse-electron-
demand Diels-Alder reaction of 2-pyrones.
1
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10.1002/anie.202006841
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COMMUNICATION
Table 2. Substrate scope with respect to substituted 2-pyrones and silyl dienol
eoselectivity, to give a series of highly functionalized cis-decalin
derivatives. Stereodivergent synthesis of substituted cis-decalin
motifs with up to five continuous chiral centers could be readily
achieved in one step via this method by tuning the configurations
of the ligands and substrates. Based on this strategy,
enantioselective and concise total synthesis of 4-amorphen-11-ol
was realized. In addition, the first total synthesis of cis-crotonin
was also achieved enantioselectively by the stereodivergent
strategy (Scheme 1c).
We firstly selected 2-pyrone 1a and silyl cyclohexadienol ether
2a as diene components to evaluate the reaction. To our delight,
in the presence of Yb(OTf)3/BINOL L1 (20 mol%),[6j,8] the reaction
proceeded through the desired inverse-electron-demand fashion
smoothly, affording bicyclic lactone 3a with 80% yield and 34% ee
(Table 1, entry 1). Further systematic investigation of 3,3’-
disubstituted BINOL ligands L1–L8 (entries 2–8) revealed the
utilization of L8 bearing pentafluorophenyl moieties led to 3a in
82% yield and 91% ee (entry 8). The examination of other rare
earth Lewis acids did not improve the results, and Yb(OTf)3 was
optimal (entries 9–12). By lowering the reaction temperature to 0
C, the reaction completed within 10 min in 89% yield and 97%
ee (entry 13). Of note, lower catalyst loading (5 mol%) was
tolerated and still gave the desired product 3a in 89% yield and
98% ee (entry 14).
ethers.[a,b,c]
O
Yb(OTf)3 (5 mol%)
R1O
O
O
(R)-L8 (6 mol%)
DIPEA (18 mol%)
4 Å M.S., DCM, 0 °C
CO2R1
H
OTBS
R3
O
O
R2
+
H
R2
OTBS
R3
1
2
3
2-Pyrones
3a, R1 = CH2CH2Ph
O
O
, R2 = Me,
3d
CO2R1
89%, 98% ee
3b, R1 = Me
CO2Me
25 oC, 58%, 80% ee
O
R2
O
H
H
H
, R2 = Ph,
96%, 97% ee
H
3e
, R1 = Allyl
3c
OTBS
O
OTBS
99%, 61% ee
81%, 96% ee
, R2 = 4-Me-Ph,
83%, 96% ee
, R2 = 4-Br-Ph,
3f, R2 = Me, 81%, 94% ee
3g, R2 = Et, 89%, 98% ee
3j
CO2Et
O
H
3k
3h, R2 = iPr, 95%, 93% ee
R2
H
97%, 96% ee
, R2 = Br, 84%, 48% ee
OTBS 3i, R2 = Ph, 89%, 97% ee
3l
Silyl dienol ethers
O
O
3o
, n = 1,
, R3 = Me,
3m
CO2Me
H
88%, 96% ee
CO2Me
89%, 96% ee
O
O
H
H
3p, n = 2,
84%, 94% ee
3n, R3 = Et,
H
88%, 94% ee[d]
OTBS
OTBS
R3
O
3q
, n = 3,
R3
O
84%, 85% ee
n
3t
3s
3u
3r
O
O
O
CO2Me
H
CO2Me
O
H
CO2Me
CO2Me
H
O
O
Me
H
H
Me
OTBS
Me
90%, 94% ee
OTBS
OTBS
OTBS
oC, trace, n.d.
0
Me
Table 1. Optimization of the reaction conditions.
0%, n.d.
39%, 3% ee
25 oC, 24%, 63% ee
R
O
R'O
O
O
Lewis acid (20 mol%)
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol) were used. [b] Isolated yield
of 3. [c] The ee of 3 was determined by HPLC analysis. [d] The absolute
configuration of 3n was assigned by the X-ray crystallographic analysis.
L
(R)- (24 mol%)
CO2R'
O
O
DIPEA (48 mol%)
4 Å M.S., DCM, 25 °C
OH
OH
H
H
OTBS
OTBS
R' = CH2CH2Ph
R
The substrate scope was investigated after the optimized
reaction conditions were established (Table 2). A broad range of
2-pyrones worked efficiently. Of note, the ester group of 2-pyrone
had little effect on the enantioselectivity control. 2-Pyrones 1a–c
led to the corresponding products with good yields and
comparable enantioselectivities. For 4-methyl-substituted 2-
pyrone 1d, the product 3d was obtained in 58% yield and 80% ee.
The 2-pyrone 1e bearing a 4-phenyl group was also tolerated but
gave 3e in moderate ee (99% yield, 61% ee). Significantly,
various C5-alkyl or aryl substituted 2-pyrones were all compatible,
and gave 3f–3k in excellent yields and ee (81%–97% yields,
93%–98% ee). However, when 2-pyrone 1l bearing a Br atom at
the C5 position was used, the product 3l was delivered with
decreased ee (84% yield, 48% ee). In addition, the scope with
respect to the substituted silyl cyclohexadienol ethers was
examined. Diverse silyl cyclohexadienol ethers with dimethyl,
diethyl, cyclobutyl, cyclopentyl, or cyclohexyl group at C5 or C6
position were well accommodated, giving the corresponding
substituted cis-decalin derivatives 3m–3r in 84%–90% yields and
85%–96% ee. In contrast, the reaction of 2-methyl-subsituted silyl
cyclohexadienol ether 2h gave a complex mixture, and the
desired product 3s was not observed. 4-Methyl-subsituted silyl
cyclohexadienol ether 2i was not compatible owing to the steric
effect, giving the racemic product 3t in low yield (39% yield, 3%
ee). Furthermore, the acyclic butadienol silyl ether 2j was
examined, affording the desired product 3u with 24% yield and
63% ee at 25 oC. The low reactivity and moderate
enantioselectivity indicated the pivotal role of cyclic dienol silyl
ethers in this reaction.
3a
1a
(R)-L
2a
Entry[a]
Lewis
acid
(R)-L
t
Yield
ee
[min]
[%][b]
[%][c]
R
1
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Y(OTf)3
L1, R = H
L2, R = Br
120
30
80
79
79
50
76
63
88
82
71
73
78
34
65
47
−11
52
8
2
3
L3, R = 4-F-C6H4
120
120
30
4
L4, R = 4-CF3-C6H4
L5, R = 4-NO2-C6H4
5
6
L6, R = 3,5-(CF3)2-C6H3
L7, R = 3,5-F2-C6H3
L8, R = C6F5
30
7
120
10
84
91
87
89
78
8
9
L8, R = C6F5
10
10
11
Lu(OTf)3
Gd(OTf)3
L8, R = C6F5
10
L8, R = C6F5
30
12
Eu(OTf)3
Yb(OTf)3
Yb(OTf)3
L8, R = C6F5
L8, R = C6F5
L8, R = C6F5
30
10
10
trace
89
n.d.
97
13[d]
14[d,e]
89
98
[a] Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Yb(OTf)3 (20 mol%),
(R)-L (24 mol%), DIPEA (48 mol%), 4 Å M.S. (25 mg) in DCM (0.5 mL) at 25
C. [b] Isolated yield of 3a. [c] Determined by HPLC analysis. [d] The reaction
was conducted at 0 oC. [e] 1a (0.2 mmol), 2a (0.3 mmol), Yb(OTf)3 (5 mol%),
(R)-L (6 mol%), DIPEA (18 mol%), 4 Å M.S. (50 mg) in DCM (0.5 mL). DIPEA
= N,N-diisopropylethylamine, M.S. = molecular sieves, n.d. = not determined.
2
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10.1002/anie.202006841
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COMMUNICATION
Next, we investigated the substrate scope with respect to 6-
substituted 2-pyrones (Table 3). Interestingly, bicyclic or
polycyclic cyclohexadienes 4a–4i were obtained with 40%–78%
yields and 87%–99% ee in one step through tandem Diels–Alder
reaction and in situ retro-[4+2] extrusion of CO2. This observation
was in line with our previous finding, that the substituents on the
C6 position of 2-pyrones could facilitate the extrusion of CO2 from
[2,2,2]-bicyclic lactones.[6j,9]
cyclohexadienol ether (S)-2l (89% ee) gave the corresponding
product in enantiopure form (> 99% ee) with good yields and
diastereoselectivities (92% and 85% yield, 15:1 and 16:1 dr).
When substrates bearing bulkier substituents such as (R)-2m
(95% ee, isopropyl-) and (S)-2n (90% ee, phenyl-) were employed,
the utilization of stereo-matched ligand (S)-L8 led to (R, S, R, R,
R)-3x and (R, S, R, S, R)-3y with excellent dr. Gratifyingly, while
with stereo-mismatched ligand (R)-L8, (S, R, S, R, S)-3x and (S,
R, S, S, S)-3y bearing steric-hindered substituents (isopropyl- or
phenyl-) on the concave side of the cis-decalin motif were also
obtained with good diastereoselectivities (7:1 and 8:1).
Table 3. Substrate scope with respect to 6-substituted 2-pyrones.[a,b,c]
MeO
R3
O
O
MeO
O
H
Yb(OTf)3 (10 mol%)
(R)-L8 (12 mol%)
DIPEA (36 mol%)
OTBS
R1O
O
O
a.
H
H
Diels-Alder
reaction
O
O
OTBS
O
R3
4 Å M.S., DCM, 25 °C
+
O
+
R2
then HCl, THF
H
R2
R2
Me
Me
(R)- or (S)-
Yb(OTf)3 (5 mol%)
1
2a
4b
Me
4
cis-decalin with
1
4a
O
H
O
O
H
2k
5k
4c
(S)- or (R)-
methyl group
OMe
O
OMe
H
OMe
O
Yb(OTf)3 (5 mol%)
b.
O
O
L8
L8
(R)- (6 mol%)
(S)- (6 mol%)
Me
CO2Me
MeO2C
H
H
DIPEA (18 mol%)
DIPEA (18 mol%)
O
H
H
O
S
R
R
H
S
4 Å M.S., DCM, 0 °C
4 Å M.S., DCM, 0 °C
O
Me
40%, 87% ee[d,e]
S
R
R
78%, 99% ee
77%, 98% ee
H
S
H
S
2k
(
)- , > 99% ee
(S)-2k, > 99% ee
TBSO
OTBS
O
S
H
O
H
O
H
4d
Me
S
4f
4e
Me
H
MeO
O
O
OMe
O
OMe
O
OMe
O
-3v
(S, R, S, S, S)
H
(R, S, R, S, R)-3v
99%, > 20:1 dr, > 99% ee
O
O
O
95%, > 20:1 dr, > 99% ee
O
H
H
H
Cl
F3C
CO2Me
O
1a
MeO2C
78%, 98% ee
91%, 99% ee
81%, 97% ee
O
S
R
H
H
R
S
4g
4h
4i
F
2k
(R)- , > 99% ee
R
2k
)- , > 99% ee
(
O
Me
O
H
O
H
S
R
H
S
R
H
OTBS Yb(OTf)3 (5 mol%)
(R)-L8 (6 mol%)
Yb(OTf)3 (5 mol%)
(S)-L8 (6 mol%)
TBSO
H
R
Me
R
OMe
O
OMe
O
OMe
O
H
Me
H
DIPEA (18 mol%)
DIPEA (18 mol%)
4 Å M.S., DCM, 0 °C
Me
H
-3v
(R, S, R, R, R)-3v
H
(S, R, S, R, S)
H
4 Å M.S., DCM, 0 °C
90%, > 20:1 dr, > 99% ee
c.
96%, > 20:1 dr, > 99% ee
50%, 97% ee[d]
40%, 97% ee[d]
46%, 89% ee[e]
O
O
O
CO2Me
CO2Me
CO2Me
O
O
S
O
S
S
H
H
H
R
R
R
S
S
S
H
H
S
H
S
S
[a] Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol) were used. [b] Isolated yield
of 4. [c] The ee of 4 was determined by HPLC analysis. [d] The reaction was
conducted at 40 C. [e] The reaction was heated at 80 C for the complete
extrusion of CO2 after the Diels−Alder reaction was finished. For details, see the
Supporting Information.
OTBS
OTBS
OTBS
Ph
Et
iPr
R
S
S
H
H
H
3w[a]
3x[a]
3y[a]
(S, R, S, S, S)-
(S, R, S, S, S)-
(S, R, S, R, S)-
(R)-L8, 87%, 7:1 dr
(R)-L8, 92%, 15:1 dr
major, > 99% ee
minor, 15% ee
O
(R)-L8, 96%, 8:1 dr
major, > 99% ee
major, > 99% ee
minor, 59% ee
O
minor, 21% ee
O
The cis-decalin scaffold with a methyl group exemplified in
Scheme 2a is commonly distributed in natural products such as
amorphane sesquiterpenes, cadinene sesquiterpenes, and
clerodane diterpenoids.[10] Retrosynthetically, this motif could be
MeO2C
O
MeO2C
H
MeO2C
O
O
R
R
R
H
H
S
S
S
R
R
R
R
R
R
H
H
H
TBSO
TBSO
TBSO
H
R
H
S
S
H
Ph
iPr
(R, S, R, R, R)-3x[a]
Et
obtained from 2-pyrone
1
and 5-methyl-substituted silyl
(R, S, R, S, R)-3w[a]
3y[b]
(R, S, R, S, R)-
cyclohexadienol ether 2k via the current reaction. Compound 2k
would be obtained in one-step from 5-methylcyclohex-2-en-1-one
5k, whose two enantiomers could be readily prepared from chiral
isopulegol[11] or from easily available starting materials by
asymmetric catalysis.[12] We supposed if the current ytterbium
catalysis exerted good stereocontrol on this reaction, then the
stereodivergent synthesis[13] of methyl-substituted cis-decalin
scaffolds could be achieved. To our delight, by tuning of the
configurations of the ligand [(R)-L8 or (S)-L8] and dienol ether
[(S)-2k (> 99% ee) or (R)-2k (> 99% ee)], a full array of
stereoisomers of methyl-substituted decalins 3v were obtained in
excellent yields, with good enantioselectivities and excellent
diastereoselectivities (90%–99% yields, > 99% ee, > 20:1 dr;
Scheme 2b).
L8
(S)- , 85%, 16:1 dr
L8
L8
(S)- , 86%, > 20:1 dr
(S)- , 83%, 20:1 dr
major, > 99% ee
minor, 84% ee
> 99% ee
> 99% ee
Scheme 2. Stereodivergent synthesis of substituted cis-decalin scaffolds. [a] 1a
(0.2 mmol), 2 (0.3 mmol), Yb(OTf)3 (5 mol%), (R) or (S)-L8 (6 mol%), DIPEA
(18 mol%), 4 Å M.S. (50 mg) in DCM (0.5 mL) at 0 C. [b] 1a (0.2 mmol), (S)-2n
(0.3 mmol), Yb(OTf)3 (10 mol%), (S)-L8 (12 mol%), DIPEA (36 mol%) 4 Å M.S.
(50 mg) in DCM (0.5 mL) at 0 C.
To demonstrate the practicability of this method, we conducted
the reaction in gram-scale. Scheme 3a showed that the reaction
of 1b and 2a proceeded smoothly in gram-scale, providing the
product 3b with comparable yield and ee (6.62 g, 91% yield, 96%
ee). Moreover, the enantioselective total synthesis of 4-
amorphen-11-ol (10) [14] began with the gram-scale reaction of 1b
and 2a catalyzed by Yb(OTf)3/(S)-L8 (Scheme 3b, 2.23 g, 94%
yield, 98% ee). The resulting ent-3b was then refluxed in
chlorobenzene to afford the bicyclic hexadiene 6 in 95% yield and
Encouraged by the above success, we further examined this
strategy in the stereodivergent synthesis of other substituted cis-
decalin scaffolds. By using (R)-L8 or (S)-L8 as the ligand
(Scheme 2c), the reaction of ethyl-substituted silyl
3
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10.1002/anie.202006841
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COMMUNICATION
98% ee via retro-Diels–Alder extrusion of CO2 (chlorobenzene,
reflux). The highly regioselective and stereoselective 1,6-Michael
addition of 6 (Me2CuLi, TMSI, 91% yield) furnished β,γ-
unsaturated ester 7. With 7 in hand, the key intermediate 8 was
obtained in 56% yield by a three-step reaction sequence,
including selective hydrogenation of the olefin (PtO2, H2),
methylation of the ester/in situ hydrolysis of the silyl enol ether
(MeLi, then aq. HCl), and subsequent Wittig reaction (Ph3PMeBr,
tBuOK). Treatment of 8 with base (tBuOK, DMSO, 140 C)
induced the double bond migration, giving 3-amorphen-11-ol (9)
2k (> 99% ee). To our delight, in the presence of Yb(OTf)3 (10
mol%) and (S)-L8 (12 mol%, stereo-mismatched), the Diels–Alder
reaction proceeded smoothly with good diastereoselectivity,
providing a pair of diastereoisomers 3z in 12% yield and 3z’ in
47% yield after in situ removal of the silyl group (Et3N•3HF).
Remarkably, the main isomer 3z’ had five contiguous chiral
centers, three of which shared the same stereochemistry as cis-
crotonin (15). The retro-Diels–Alder extrusion of CO2 from 3z’
(chlorobenzene, reflux) followed by the subsequently protection
with ethylene glycol led to dienyl ester 11 in 95% yield.
in 26% yield and 4-amorphen-11-ol (10) in 69% yield. Interestingly, Stereoselective hydrogenation of 11 from the convex face by
3-amorphen-11-ol (9) could be recycled to 10 by re-subjection to
the basic reaction conditions (tBuOK, DMSO, 120 C, 28% with
70% recovered 9), affording 4-amorphen-11-ol (10) in 76%
combined yield.
Raney nickel produced ester 12 that was then subjected to
allylation to afford the γ,δ-unsaturated ester 13 (allylic iodide, LDA,
90% yield). At this stage, five contiguous stereocenters in cis-
crotonin were concisely constructed. The ester 13 was treated
with OsO4/NaIO4, leading to aldehyde 14 in 65% yield. In the
presence of chiral amino alcohol ligand (S)-La (20 mol%), the 1,2-
addition of aldehyde 14 with 3-furylzinc reagent generated from
furylboronic acid and diethylzinc,[17] followed by the spontaneous
lactonization and then hydrolysis of the ketal group, gave cis-
crotonin 15 in 62% yield.
O
a.
MeO
O
O
a) Yb(OTf)3 (5 mol%)
(R)-L8 (6 mol%)
DIPEA (18 mol%)
CO2Me
H
O
O
OTBS
+
H
4 Å M.S., DCM, 0 °C, 0.5 h
OTBS
H
1b
1b
2a
6.62 g,
91%, 96% ee
3b
O
b.
MeO
O
O
b) Yb(OTf)3 (5 mol%)
L8
S
(
)- (6 mol%)
OTBS
O
a) Yb(OTf)3 (10 mol%)
O
O
DIPEA (18 mol%)
H
+
L8
(S)- (12 mol%)
O
MeO2C
CO2Me
H
DIPEA (30 mol%)
4 Å M.S., DCM, 0 °C, 24 h
then Et3N•3HF, rt, 4 h
MeO2C
H
4 Å M.S., DCM, 0 °C, 0.5 h
Me OMe
O
O
O
Me
Me
OTBS
2a
2.23 g
, 94%, 98% ee
3b
ent-
+
H
H
c) C6H5Cl,
95%
98% ee
O
O
OTBS
Me
H
reflux, 5 h
O
O
H
Me
3z
CO2Me
H
CO2Me
d) Me2CuLi, TMSI
> 99% ee
1d
, 12%
b) C6H5Cl, reflux, 3 h
3z'
, 47%
OTBS
H
H
R
2k
)-
(
Et2O, 78 °C, 0.5 h
OTBS
Me
then PTSA (0.1 mol%), (CH2OH)2
benzene, reflux, 12 h
91%
95%
COOMe
H
7
6
COOMe
c) H2 (50 bar), Raney Ni (20 mol%)
EtOAc, rt, 24 h
e) H2, PtO2, EtOAc, rt, 0.5 h
f) MeLi, THF, 78 °C, 30 min
then HCl, rt, 1 h
H
H
O
O
H
Me
Me
56%
i) tBuOK, DMSO
120 oC, 23 h
O
O
3 steps
61%
g) Ph3PMeBr, tBuOK, DMSO
60 °C, 1 h
9
10
H
(70%),
(28%)
Me
Me
OH
OH
OH
12
11
H
h) tBuOK, DMSO
140 oC, 3 h
H
H

d) LDA, DMPU, THF, 78 °C, 3 h
90%
+
then allyl iodide, 0 °C, 2 h
O
O
O
9
10
(69%)
(26%),
OMe
Me
e) OsO4 (5 mol%), NaIO4
iPrOH/H2O (2:1), rt, 16 h
O
H
H
OMe
Me
H
H
O
H
3-amorphen-11-ol (9)
10
)
4-amorphen-11-ol(
8
O
O
65%
H
B(OH)2
Me
H
Scheme 3. Gram-scale experiment and enantioselective total synthesis of 4-
14
Me
13
f)
O
Et2Zn, toluene/hexane, 60 oC, 18 h
,
amorphen-11-ol.
62%
then , (S)- , 0 oC, 1 h, then H2O, rt, 5 h
14
La
2 steps
g) HCl, MeOH, reflux, 1 h
O
O
O
convex
Ph
Crotonins are a class of 19-nor-clerodane diterpenoids with
interesting structural features and a broad range of biological
activities.[15,16] However, there are inherent challenges in
preparing these compact and densely functionalized decalin core
structures. It is difficult to accurately control the exact
configurations of multiple contiguous stereocenters in the
molecule. In addition, in the structures of some members of
crotonin, such as cis-crotonin (15), the C4-methyl group locates
on the concave side of the molecule, which is challenging to
synthesize. Thus, the total synthesis of any member of crotonin
family has yet to be realized.[16] We envisaged our stereodivergent
strategy which could overcome the steric effect of bulky
substituents on the concave side of the product would provide an
efficient solution to these synthetic challenges of crotonins. As
shown in Scheme 4, our enantioselective total synthesis of cis-
crotonin (15) commenced with the stereodivergent Diels–Alder
reaction of 4-methyl-substituted 2-pyrone 1d and enantiopure (R)-
Ph
H
12
12
H
Me
H
8
OH
4
N
O
O
Me
CPh3
H
8
4
O
O
O
Me
Me
15
concave
(S)-La
H
15
)
cis-crotonin (
)
cis-crotonin (
Scheme 4. Enantioselective total synthesis of cis-crotonin. PTSA
toluenesulfonic acid, LDA = lithium diisopropylamide. DMPU = 1,3-dimethyl-
tetrahydropyrimidin-2(1H)-one.
= p-
In conclusion, we have developed an asymmetric inverse-
electron-demand Diels–Alder reaction of 2-pyrones and silyl
cyclohexadienol ethers catalyzed by ytterbium/BINOL complex.
This method enables the synthesis of a series of cis-decalin
derivatives with excellent yields and stereoselectivities. The
stereodivergent synthesis of various substituted cis-decalin motifs
has been realized by simple variations of the absolute
4
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10.1002/anie.202006841
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configurations of the ligands and substrates. The practicality and
robustness of this method offered the gram-scale synthesis. In
addition, the straightforward enantioselective total synthesis of 4-
amorphen-11-ol and the first total synthesis of cis-crotonin by the
stereodivergent strategy illustrates the synthetic potential of this
reaction. Further investigations of the mechanism regarding the
chemo- and stereoselectivity as well as applications of this
reaction in total synthesis of other bioactive natural products are
ongoing in our laboratory.
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Acknowledgements
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6
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Entry for the Table of Contents
O
OH
O
O
R1O
O
OTBS
H
CO2R1
Asymmetric
Diels-Alder Reaction
H
O
O
H
+
R2
O
O
R2
O
H
H
H
OTBS
dienophile
4-amorphen-11-ol
cis-crotonin
. . .
.
.
Chemoselective
High ee, high dr
Highly functionalized
decalins
With multiplechiral
centers
Valuable in natural
product synthesis
A new strategy for the synthesis of cis-decalin derivatives is realized by an asymmetric inverse-electron-demand Diels–Alder
reaction between two different conjugate dienes. Within this method, the enantioselective total synthesis of 4-amorphen-11-ol and the
first total synthesis of cis-crotonin have been achieved.
7
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