Key factors for high diastereo- And enantioselectivity of umpolung cyclizations of aldehyde-containing allylpalladium intermediates

Article abstract of DOI:10.1246/bcsj.20190167

Two palladium/chiral diphosphine-catalyzed umpolung cyc-lizations of aldehyde-containing allylic acetates and allenes with arylboronic acid are fully investigated to establish key factors in their high stereoselectivities. Both cyclization reactions afford cis-disubstituted pyrrolidine and tetrahydrofuran. These occur in high diastereo- and enantioselectivities through a common cationic (Z)-η¹-allylpalladium, toward which a ring strain generated in the cyclization step leading to trans-isomers biases the equilibrium through η³-η¹-η³-complex in the former cyclization. Varied diastereoselectivities were observed in the formation of five-membered carbocycles and six-membered heterocycles. These reflect release of a ring strain generated in the cyclization step leading to trans-isomers and a different distribution of the (Z)- and the (E)-η¹-allylpalladium intermediates generated by the oxidative addition of allylic acetates to Pd(0) or carbopalladation of allenes, respectively. A steri-cally demanding substituent at the center of the allyl moiety is necessary for high diastereo- and enantioselectivity. The enantioselectivity of the former cyclization was lowered by the presence of organometallic reductants or reagents, possibly causing the formation of neutral η¹-allylpalladium species. We used a chiral allylic acetate containing (E)-deuterium-labeled alkene to demonstrate that the electrophilic attack of the aldehyde to the allyl ligand occurred on the side where the palladium existed, consistent with the Zimmerman-Traxler transition state.

Full text of DOI:10.1246/bcsj.20190167

Advance Publication Cover Page
Key Factors for High Diastereo- and Enantioselectivity of Umpolung Cyclizations of
Aldehyde-Containing Allylpalladium Intermediates
Hirokazu Tsukamoto,* Ayumu Kawase, Hirotaka Omura, and Takayuki Doi
Advance Publication on the web July 24, 2019
doi:10.1246/bcsj.20190167
© 2019 The Chemical Society of Japan
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Publication manuscripts.

Key Factors for High Diastereo- and Enantioselectivity of Umpolung Cyclizations of
Aldehyde-Containing Allylpalladium Intermediates
Hirokazu Tsukamoto,*1, 2 Ayumu Kawase,1 Hirotaka Omura,1 and Takayuki Doi1
1 Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-aoba, Aramaki, Aoba-ku, Sendai 980-8578
2
Department of Pharmaceutical Sciences, Yokohama University of Pharmacy, 601 Matano-cho, Totsuka-ku, Yokohama 245-0066
E-mail: < hirokazu.tsukamoto@hamayaku.ac.jp >
Hirokazu Tsukamoto
Hirokazu Tsukamoto received Ph.D. degree from Tokyo Institute of Technology under the direction of Prof. Takashi
Takahashi in 1999. He worked as a researcher for Sankyo Co., LTD (1999–2000). He joined Prof. Yoshinori Kondo’s
group at Tohoku University as an assistant professor (2000–2008). He worked as a research associate for Prof. Daniel
Kahne at Harvard University (2008–2011). He joined Prof. Takayuki Doi’s group at Tohoku University as an assistant
professor (2011–2015), lecturer (2015–2018), and associate professor (2018–2019). He moved to Yokohama University of Pharmacy as a
full professor (2019–present). His research field is development of novel catalytic reactions and total synthesis of biologically active
compounds.
Abstract
Two palladium/chiral diphosphine-catalyzed umpolung
cyclizations of aldehyde-containing allylic acetates and allenes
with arylboronic acid are fully investigated to establish key
factors in their high stereoselectivities. Both cyclization
addition of allylic acetate 1 to Pd(0), and undergoes nucleophilic
substitution to afford Tsuji-Trost reaction product and Pd(0),
which enables the catalytic process.1 The isomerization of h3- to
h1-complex 6 and the subsequent electrophilic substitution can
lead to the umpolung allylation. Its catalytic reaction, however,
needs stoichiometric metallic reductants to convert the resulting
Pd(II) into Pd(0).2 The Et2Zn- or Et3B-mediated catalytic and
asymmetric nucleophilic allylation of aldehyde 4 was pioneered
by Zanoni,4a while Minnaard4b and Zhou4c,d built upon the
method and proposed that the organometallics function as
reducing alkylating agents, forming h1-allylpalladium 6 bearing
an Et group and a chiral monophosphorus ligand. Previously, the
asymmetric nucleophilic allylation was considered unfeasible
because Tamaru assumed allyl-zinc and–borane 3a, generated by
transmetalation of h3-allylpalladium 2 with Et2Zn or Et3B, were
intermediates for the non-asymmetric variant.2a The
transmetalation of Pd(II) with either allylmetal 3b5–10 or a
combination of organoboron reagent 7 and allene 811, 12 is more
suitable for the formation of h1-allyl complex 6, because a
reducing agent is unnecessary for its catalytic nucleophilic
allylation. However, a special ligand like bis(π-allyl),5, 6 PCP
pincer,7, 8 or N-heterocyclic carbene9, 10 is necessary to generate
h1-allyl complex 6, which is in equilibrium with 2, but rarely
detected. Nakamura and Yamamoto proposed h1-allylpalladium
6 with a chiral π-allyl ligand as the intermediate in
enantioselective imine allylations.5 Consequently, any Pd-
catalyzed umpolung allylations involves stoichiometric metallic
reagents. Umpolung allylations not requiring metallic reagents
are advantageous: neither the stoichiometric metallic byproducts
nor multiple allylmetal species (leading to difficult chiral
control) are generated.13, 14
reactions
tetrahydrofuran. These occur in high diastereo- and
enantioselectivities through
common cationic (Z)-h1-
afford
cis-disubstituted
pyrrolidine
and
a
allylpalladium, toward which a ring strain generated in the
cyclization step leading to trans-isomers biases the equilibrium
through h3-h1-h3-complex in the former cyclization. Varied
diastereoselectivities were observed in the formation of five-
membered carbocycles and six-membered heterocycles. These
reflect release of a ring strain generated in the cyclization step
leading to trans-isomers and a different distribution of the (Z)-
and the (E)-h1-allylpalladium intermediates generated by the
oxidative addition of allylic acetates to Pd(0) or carbopalladation
of allenes, respectively. Asterically demanding substituent at the
center of the allyl moiety is necessary for high diastereo- and
enantioselectivity. The enantioselectivity of the former
cyclization was lowered by the presence of organometallic
reductants or reagents, possibly causing the formation of neutral
h1-allylpalladium species. We used a chiral allylic acetate
containing (E)-deuterium-labeled alkene to demonstrate that the
electrophilic attack of the aldehyde to the allyl ligand occurred
on the side where the palladium existed, consistent with the
Zimmerman-Traxler transition state.
Keywords: Oxidative addition of allylic acetates,
Carbopalladation of allenes, Umpolung cyclization
1. Introduction
The allylpalladium species is one of the most versatile
intermediates in organic synthesis and it exists in equilibrium
between h3- and h1-complexes 2 and 6 with electrophilic and
2
nucleophilic properties, respectively (Scheme 1).1,
In
combination with chiral ligands, both asymmetric allylation of
nucleophiles3 (Tsuji-Trost reaction) and electrophiles4 are
possible. h3-Allylpalladium 2 is readily formed by oxidative

R2
Pd0 , L*n
M, - Pd0
b or c
R2
R2
R
O
AcO
OAc
M
a
b
1Pd+
a
P
Pd
O
P
R
R1
R1
X
X
H
R
+
L*n
R+
Pd
P
P
H
X
1st report
2nd report
η3-allylpalladium(II) 2
O
O
allyl acetate 1
allylmetal 3a
M=Zn, B, et al.
9
X
13
X = NTs (9a),
NBoc, O, CR2
R
10 (favored)
10' (disfavored)
O
R
X
X
X
R
H
Pd2+ , L*n
R2
R2
Y
OH R2
O
4
14
O
X
15
M
Pd
O
*
R1
L*n
R
*
OH
X
R
R
H
R
c
- Pd2+
O
O
R1
R1
PAr2
PAr2
allylmetal 3b
M=Sn, Si, B
η1-allylpalladium(II) 6
Y=Et, allyl, R2, OAc
homoallyl alcohol 5
X
O
R
OH
16
16'
O
O
12a: Ar = phenyl
ent-11
12b: Ar = 3,5-xylyl
11 (up to 97%ee)
expected byproducts
M = metal, L* = chiral ligand
n = coordination number
d
R1
a) R-B(OH)2 7, cat. Pd(OAc)2-(S)-SEGPHOS (12a), CH3CN, rt;
b) HCO2H-Bu3N, cat. Pd[P(o-tolyl)3]2-12a or (S)-DM-SEGPHOS (12b) , CH3CN, 50 °C.
8
Pd2+ , L*n
R2 B(OH)2
R2 Pd+
a oxidative addition. b reduction.
c transmetalation.d carbopalladation.
c
organoboron 7
Scheme 2. SEGPHOS-ligated Pd-catalyzed cyclizations of
allene 9 and allylic acetate 13 leading to 11
Scheme 1. Pd-catalyzed umpolung allylation of aldehydes
leading to homoallyl alcohol 5 through allylmetal 3a and h1-
allylpalladium 6
NBS, CHCl3
Me
Ph2P
Ar
PPh2
Pd
Br
18 (90%)
Me
In contrast to the intermolecular asymmetric umpolung
allylation of aldehyde and imine functionalities under palladium
catalysis, the intramolecular variant remains undeveloped15 until
we reported.12a, 16 We expected that the umpolung cyclization
would occur more readily because thermodynamically unstable
h1-allylpalladium is effectively captured by the adjacent
electrophile and that the above special ligands are unnecessary.
Firstly, we developed the arylative cyclization of allene-
aldehyde 9 with arylboronic acid 7 under Pd(II) catalysis to
afford the homoallylic alcohol 11 in high diastereo- and
enantioselectivity (Scheme 2).12a We proposed the highly
stereoselective reaction originates from the Zimmerman-Traxler
transition state 1017–19 consisting of the aldehyde and cationic h1-
allylpalladium ligated with 5,5´-bis(diphenylphosphino)-4,4´-
17 (Ar = C6F5)
Scheme 3. Kurosawa’s report on electrophilic addition of
neutral (h1-allyl)arylpalladium 17
The two cyclization reactions proceed through a common
intermediate but yield different stereoselectivities, in some cases.
Although some related cis-selective cyclizations under transition
metal catalysis exist, the reason for the diastereoselectivity
remains unclear.18, 19, 25 Herein, the two asymmetric umpolung
cyclization reactions are investigated to establish the key factors
responsible for the excellent stereoselectivity. In addition to
preliminarily reported data,12a, 16 further experimental results are
shown here to compare the effects of factors on the
stereoselectivity.
bi-1,3-benzodioxole (SEGPHOS, 12a),
a
commercially
available chiral diphosphine.20 However, the h1-allylpalladium
derived from 9 can further react with 7, to produce neutral (h1-
allyl)arylpalladium, reported by Kurosawa,21 Szabo,7
Minnaard,4b and Zhou4d as nucleophilic (Scheme 3). Secondly,
to explore the participation of the aryl ligand in the cyclization,
we developed the Pd(0)/SEGPHOS or the DM-SEGPHOS-
catalyzed enantioselective cyclization of allylic acetate-
aldehyde 13 with the aid of a formate reductant.16 The successful
cyclization proved that the two cyclization reactions proceed
through the common cationic h1-allylpalladium and that
enantiodifferentiation happens in the aldehyde allylation instead
of in the allylpalladium formation. Interestingly, neither Tsuji-
Trost-type products 1422 and 1523 nor reduced products 16 and
16' formed, although formate can reduce h3-allylpalladium.24
The latter cyclization is advantageous in: 1) no need for metallic
reagents to generate the stoichiometric metallic byproducts and
multiple allylmetal species; 2) ability to introduce a wide variety
of substituent R (other than aryl group) into the vinyl group of
the products.
2. Experimental
General procedure for umpolung cyclization of
aldehyde-containing allylic acetates (±)-13a·d–g·j and
carbonates (±)-13b·h·i (Table 1, Entry 1, Table 2, Entry 2 and
Scheme 5): To a test tube containing a solution of (±)-13a·b·d–
j (1.0 equiv) in anhydrous MeCN (0.05 M) were added Pd[P(o-
tolyl)3]2 (10 mol%), (S)-SEGPHOS or (S)-DM-SEGPHOS (15
mol%), and reductant (HCO2H-Bu3N (3.0 equiv) for 13a·d–g·j
and HCO2H (1.0 equiv) for 13b·h·i) under argon. The resulting
mixture was sealed with a screw cap and stirred at 50 °C. After
starting material 13 was consumed, the mixture was
concentrated in vacuo. The residue was purified by preparative
TLC to afford 11a·d–j and 11(f–j)'. Enantiomeric excess of the
products was determined by chiral HPLC. The relative
configuration was determined by NOESY correlation. The
absolute configurations were determined by modified Mosher’s
method26 using its (R)- and (S)-MTPA esters, which were
obtained by condensation of the products (DCC, DMAP and
DCM) with (R)- and (S)-Mosher’s acids, respectively.
General procedure for phenylative cyclization of allene-
aldehydes 9a·e–j with phenylboronic acid (Table 4, Entry 1
and Scheme 6): To a test tube containing a solution of 9a·e–j
(1.0 equiv) in anhydrous MeCN (0.1 M) were added Pd(OAc)2
(10 mol%), (S)-SEGPHOS (10 mol%), and PhB(OH)2 (1.5
equiv) under argon. The resulting mixture was sealed with a
screw cap and stirred at 50 °C. After starting material 9 was

consumed, the mixture was cooled down to room temperature
and then treated with PS-DEAM MP resinTM (polymer-bound
diethanolamine, 1.8 mmol/g, 3.0 equiv) and CHCl3 to remove an
excess of PhB(OH)2. The mixture was agitated at room
temperature for 2 h, then filtered, and washed with CHCl3
thoroughly. The filtrate was concentrated in vacuo. The residue
was purified by preparative TLC to afford 11a·e–j and 11(f–j)'.
Enantiomeric excess of the products was determined by chiral
HPLC.
1-en-2-yl)-1-tosylpyrrolidin-3-ol (5.8 mg, 0.021 mmol, 82%) [1)
TFA, CH2Cl2, 2) TsCl, Et3N, CH2Cl2], enantiomeric excess of
11m (94% ee) was determined by chiral HPLC.
Umpolung cyclization of (+)-13u under Pd(0)-dppe
catalysis (Scheme 14): To a solution of (S, E)-13u (20.8 mg,
0.084 mmol) in anhydrous MeCN (0.05 M) were added Pd[P(o-
tolyl)3]2 (6.0 mg, 8.4 µmol), dppe (5.0 mg, 13 µmol), and
HCO2H-Bu3N (9.5 µL-59 µL, 0.25 mmol) under argon. The
resulting mixture was sealed with a screw cap and stirred at
50 °C for 1 d. Then the mixture was concentrated in vacuo. The
residue was purified by preparative TLC (10% EtOAc/toluene)
to afford (1R*, 2R*)-11u and (1S*, 2R*)-11u' (dr = 2:1, 24.9 mg,
0.072 mmol, 86%) as a faster- and slower-moving component,
respectively. (1R*, 2R*)-11u was further purified by chiral
HPLC (Daicel Chiralpak OD-H, i-propanol/hexane = 1:10, 0.5
mL/min, λ = 254 nm, recycled 3 times) to afford (1S, 2S)-11u
(pseudo enantiomer) (tR = 26.2 min) and (1R, 2R)-11u (tR = 29.5
Phenylative cyclization of allene-aldehyde 9a in THF by
gradual addition of PhB(OH)2 (Scheme 4): To a solution of 9a
(12.0 mg, 0.045 mmol) in anhydrous THF (0.1 M) were added
Pd(OAc)2 (1.0 mg, 4.5 µmol) and (S)-SEGPHOS (2.8 mg, 4.6
µmol) under argon. To the stirring solution was added 0.1 M
PhB(OH)2 (8.3 mg, 0.068 mmol) solution in anhydrous THF
with a syringe pump over 2 h at 50 °C. The resulting mixture
was stirred at the same temperature for another 5 h. The mixture
was cooled down to room temperature and then treated with PS-
DEAM MP resinTM (1.8 mmol/g, 3.0 equiv) and CHCl3 to
remove an excess of PhB(OH)2. The mixture was agitated at
room temperature for 2 h, then filtered, and washed with CHCl3
thoroughly. The filtrate was concentrated in vacuo and the
residue was purified by preparative TLC (50% EtOAc/hexane)
to afford (3S, 4S)-11a (8.0 mg, 0.023 mmol, 52%, 95% ee).
1
min). H-NMR analysis showed the respective inversion and
retention of the alkene geometries in (1S, 2S)- and (1R, 2R)-11u.
(1S*, 2R*)-11u' was further purified by chiral HPLC (Daicel
Chiralpak AS-H, i-propanol/hexane = 1:10, 0.5 mL/min, λ = 254
nm, recycled 2 times) to afford (1R 2S)-11u' (tR = 10.1 min) and
1
(1S, 2R)-11u' (pseudo enantiomer) (tR = 11.5 min). H-NMR
analysis showed the respective retention and inversion of the
alkene geometries in (1R, 2S)- and (1S, 2R)-11u'.
Two-step conversion of 13l' into 11k via 11l (Scheme 8)
Reductive Cyclization of 13l': To a test tube containing a
solution of 13l' (E:Z = 1:2.5, 8.4 mg, 0.023 mmol) in anhydrous
MeCN (0.05 M) were added Pd[P(o-tolyl)3]2 (1.7 mg, 2.4 µmol),
(S)-DM-SEGPHOS (2.5 mg, 3.5 µmol), and HCO2H-Bu3N (2.6
µL-16.0 µL, 0.069 mmol) under argon. The resulting mixture
was sealed with a screw cap and stirred at 50 °C for 1.5 h. Then
the mixture was concentrated in vacuo. The residue was purified
by preparative TLC (20% EtOAc/toluene) to afford 11l (4.4 mg,
0.015 mmol, 64%). Enantiomeric excess of 11l (87% ee) was
determined by chiral HPLC (Daicel Chiralpak AD-H, i-
propanol/hexane = 10:90, 0.5 mL/min, l = 254 nm): tR(3R 4R)
= 33.0 min (minor enantiomer), tR(3S, 4S) = 35.8 min (major
enantiomer).
Reduction of Cl group in 11l: To a test tube containing a
solution of 11l (15.9 mg, 0.053 mmol, 87% ee) in anhydrous
DMA (0.2 mL) were added PdCl2(PhCN)2 (2.0 mg, 5.2 µmol),
dppf (3.2 mg, 5.8 µmol), and HCO2Na (5.4 mg, 0.079 mmol)27
under argon. The resulting mixture was sealed with a screw cap
and stirred at 80 °C for 10 h. The mixture was treated with water
and the aqueous layer was extracted with EtOAc twice. The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
preparative TLC (20% EtOAc/toluene) to afford the reduced
product identical to (3S, 4S)-11k (13.1 mg, 0.049 mmol, 93%).
Chiral HPLC of the product (87% ee) showed that optical purity
of 11l was retained during the reduction.
3. Results and Discussion
Effect of reductant on the allylic acetate-aldehyde
cyclization. The effects of the reaction conditions on the
stereoselectivity of the reductive cyclization of allylic acetate-
aldehyde 13a were investigated and data are presented in Table
1. As expected, the choice of the reductant crucially influenced
the enantioselective cyclization. Hydride sources like formic
acid in combination with tributylamine28 (Entry 1) and
triethylsilane (Entry 2) gave (3S, 4S)-11a in high yield with
excellent diastereo- and enantioselectivity.29 Interestingly, the
reduction of acetate24 to 16 or 16' (Scheme 2) was absent under
the reaction conditions. Meanwhile, organometallic reagents
including Et3B and Et2Zn employed in the intermolecular
variant4 lowered the yield and the optical purity of 11a (Entries
3 and 4). The use of THF as a solvent instead of acetonitrile
allowed partial enantioselectivity recovery by the borane reagent,
whereas that with zinc generated only a trace amount of the
product (Entries 5 and 6). Additionally, the Et2Zn failed to
promote the cyclization reaction even under Minnaard’s reaction
conditions.4b
Similar to acetate 13a, carbonate 13b underwent
cyclization even without an amine, because of in situ basic
alkoxide generation from the leaving group through
decarboxylation30 (Table 2, Entries 1 and 2). The slightly lower
reaction rate and the product yield are attributed to the lower
concentration of the reductant. Similarly, an in situ generated
hydride from the leaving group of formate 13c enabled omission
of the external reductant, but seemed insufficient for the reaction
rate (Entry 3).24 The sluggish reaction was therefore accelerated
using an external formate salt (Entry 4). These results highlight
the necessity of a high concentration of the reductant for a rapid
catalytic cycle. Although formic acid also promoted the
reductive cyclization of carbonate 13b and formate 13c, the
trans-diastereomer18a–b, 19c was also obtained as a minor product
of the 13c (Entries 2 vs. 5). Since acetic acid also lowered the
diastereoselectivity (Entry 6), protic media hinders the cyclic
transition state for high stereoselectivity.18d Variants of the
reaction conditions enabled reductive cyclization of other
substrates (vide infra).
One-pot, two-step conversion of 13n' into 11m via 11n
(Scheme 9): To a test tube containing a solution of 13n' (14.2
mg, 0.038 mmol) in anhydrous MeCN (0.05 M) were added
Pd[P(o-tolyl)3]2 (2.7 mg, 3.8 µmol), (S)-SEGPHOS (3.5 mg, 5.7
µmol), and HCO2H-Bu3N (4.3 µL-25.9 µL, 0.114 mmol) under
argon. The resulting mixture was sealed with a screw cap and
stirred at 50 °C for 24 h. The mixture was treated with PBu3 (2.0
µL, 8.1 µmol) and HCO2H-Bu3N (2.9 µL-17.3 µL, 0.077 mmol).
After being stirred at 50 °C for another 6 h, the mixture was
concentrated in vacuo. The residue was purified by preparative
TLC (20% EtOAc/toluene) to afford 11m (5.7 mg, 0.025 mmol,
66%). After conversion of 11m (5.7 mg, 0.025 mmol) to 4-(prop-

the enantioselectivity of the allylic acetate-aldehyde cyclization
was unaffected by the aprotic solvent, that of allene-aldehyde
cyclization was partially affected (Table 3 vs. Table 4). It is
noteworthy that the protic media (i.e., methanol), again caused
low diastereoselectivity particularly in the former cyclization
(Table 3, Entry 5).
Table 1. Effects of the reductant on the enantioselectivity of
allylic acetate-aldehyde cyclization.
Ph
AcO
Ph
10 mol% Pd[P(o-tolyl)3]2
15 mol% (S)-SEGPHOS
4
TsN
TsN
Reductant (3 equiv)
3
OH
O
CH3CN (0.05 M), 50 °C
(±)-13a
(3S, 4S)-11a
Table 3. Effects of the solvent on the enantioselectivity of
Entry
Reductant
Solvent Time Yield
Ee
(%)[a]
95
allylic acetate-aldehyde cyclization.
(h)
4
(%)
87
Ph
AcO
Ph
10 mol% Pd[P(o-tolyl)3]2
15 mol% (S)-SEGPHOS
4
1[b]
2
HCO2H-Bu3N CH3CN
TsN
TsN
HCO2H-Bu3N (3 equiv)
Solvent (0.05 M), 50 °C
3
OH
O
Et3SiH
Et3B[c]
Et2Zn[d]
Et3B[c]
Et2Zn[d]
CH3CN
CH3CN
CH3CN
THF
6
78
94
(±)-13a
(3S, 4S)-11a
3
72
36
72
36
41
49
Entry Solvent
Time
(h)
4
Yield
(%)
87
Dr
Ee
(cis:trans)[a] (%)[b]
4
11
79
1[c]
2
CH3CN
THF
>20:1
>20:1
>20:1
19:1
95
95
95
95
90
5
43
83
6
THF
trace
–
3
71
[a] Enantiomeric excess of cis-isomer 11a was determined by
chiral HPLC. [b] reported in ref. 16. [c] 5 equiv of Et3B was used.
[d] 3.5 equiv of Et2Zn was used.
3
DMF
6
69
4
DCM
1.5
83
5
MeOH
48
70
3.7:1
Table 2. Effects of the leaving group on the reductive
[a] Diastereomeric ratio was determined by 1H-NMR analysis of
a mixture of diastereomers. [b] Enantiomeric excess of cis-
isomer was determined by chiral HPLC. [c] reported in ref. 16.
cyclization.
Ph
X
Ph
10 mol% Pd[P(o-tolyl)3]2
15 mol% (S)-SEGPHOS
4
TsN
TsN
Additive
CH3CN (0.05 M), 50 °C
3
OH
O
Table 4. Effects of the solvent on the enantioselectivity of
(±)-13b, c
(3S, 4S)-11a
X = OCO2Et (b), OCHO (c)
allene-aldehyde cyclization.
Entry
X
Additive
Time Yield
Ee
Ph
10 mol% Pd(OAc)2
10 mol% (S)-SEGPHOS
4
(h)
4
(%)
84
(%)[a]
95
TsN
TsN
PhB(OH)2 (1.5 equiv)
Solvent (0.1 M), 50 °C
3
OH
O
9a
(3S, 4S)-11a
1
OCO2Et HCO2H-Bu3N
(3 equiv)
Entry Solvent
Time
Yield
(%)
93
Dr
Ee
2[b]
OCO2Et
HCO2H
(1 equiv)
None
7
70
90
(h)
2
(cis:trans)[a] (%)[b]
1[c]
2
CH3CN
THF
cis only
18:1
97
77
82
86
67
3[b]
4
OCHO
OCHO
72
17
54
66
91
93
2.5
5
81
HCO2H-Bu3N
(1 equiv)
HCO2H
3
DMF
84
>20:1
>20:1
15:1
4
DCM
3
81
5
6
OCHO
OCHO
24
60[c] 91
5
MeOH
48
39
[a] Diastereomeric ratio was determined by 1H-NMR analysis of
a mixture of diastereomers. [b] Enantiomeric excess of cis-
isomer 11a was determined by chiral HPLC. [c] reported in ref.
12a.
(1 equiv)
AcOH
108
29[d] nd[e]
(1 equiv)
[a] Enantiomeric excess of cis-isomer 11a was determined by
chiral HPLC. [b] reported in ref. 16. [c] (–)-Trans-isomer was
also obtained in 15% yield. [d] (–)-Trans-isomer was also
obtained in 3% yield. [e] nd = not determined.
Excess organometallic reagent likely decreases
enantioselectivity through the formation of neutral h1-
allylpalladium species like 17 in Scheme 3. The loss of
enantioselectivity observed in the THF (Table 4, Entry 2) was
dramatically suppressed by gradual addition of phenylboronic
acid to maintain its low concentration (Scheme 4). The use of
acetonitrile as a solvent prevents cationic h1-allylpalladium
intermediates from further transmetalation because of its high
coordination ability to the palladium center.
Comparison of solvent effect. Since the reaction
conditions for the reductive cyclization were adapted to those for
the arylative cyclization of allene-aldehydes12a, acetonitrile, the
best solvent for the latter was chosen as the solvent. Although

Ph
AcO
Ph
4
condition Aa, d
81% yield
Ph
10 mol% Pd(OAc)2
BocN
BocN
4
10 mol% (S)-SEGPHOS
3
OH
O
TsN
TsN
(±)-13d
(3S, 4S)-11d
90% ee
PhB(OH)2 (1.5 equiv)
(slow addition over 2 h)
THF (0.05 M), 50 °C, 5 h
3
OH
O
9a
(3S, 4S)-11a
Ph
AcO
Ph
52% (95% ee)
4
condition Aa, d
72% yield
O
O
3
OH
O
Scheme 4. Effects of gradual addition of PhB(OH)2 on the
enantioselectivity of the arylative cyclization of 9a
(±)-13e
(3S, 4S)-11e
97% ee
Ph
Ph
Ph
AcO
2
2
condition Aa
Comparison of diastereoselectivities. The best reaction
conditions for the reductive cyclization of sulfonamide-tethered
allylic acetate 13a (Tables 1 and 3, Entry 1), converted Boc-
protected nitrogen-tethered 13d into 11d in 53% yield and 90%
ee (data not shown). We presumed reduced electrophilicity of the
adjacent carbonyl group due to the weak electron-withdrawing
carbamate, causing lower chemical yield. Gratifyingly, slightly
modified conditions involving more s-donating DM-SEGPHOS
(12b) than SEGPHOS (12a) produced 11d in much better yield,
with retention of high enantioselectivity (Scheme 5). The s-
donating phosphines aid the allyl ligand to become nucleophilic
rather than electrophilic. The DM-SEGPHOS ligand also served
effectively for reductive cyclization of other substrates 13e–i
(Scheme 5). The oxygen-tethered substrate 13e converted to cis-
disubstituted tetrahydrofuran 11e in high diastereo- and
enantioselectivities. Unfortunately, the diastereomeric ratio of
five-membered carbocycles 11f and 11g, and six-membered
heterocycles 11h and 11i were cis/trans = 1.5:1 ~ 3.0:1, although
diastereomers 11f–i and 11(f–i)' possess high optical purities.
The modified Mosher’s method26 revealed the same absolute
configuration for each pair of diastereomers at the a-position of
the hydroxyl group, and the opposite stereochemistry substituted
by the a-styryl group. It should be noted that the treatment of the
acetate counterparts of 13h and 13i with formic acid and
tributylamine accompanied the formation of side-products 1931
and 20, respectively, which were derived from base-promoted b-
elimination of sulfonamide followed by reduction of h3-
allylpalladium and Tsuji-Trost type reaction, respectively
(Figure 1). The base-free conditions employed for the
cyclization of the carbonate 13b (Table 2, Entry 2) completely
suppressed the side reactions and converted carbonates 13h and
13i into cis- and trans-products 11h–i and 11h–i'. Moreover, the
cyclization of tertiary allylic acetate 13j produced a 2:1
diastereomeric mixture of a quaternary carbon-containing
pyrrolidine 11j and 11j' in 90% and 70% ee, respectively. The
diastereoselectivity was significantly below that of secondary
allylic acetate 13a (Table 1, Entry 1).
+
H2C
H2C
H2C
1
1
OH
OH
O
96% yield
dr (cis:trans) 3.0:1
(±)-13f
(1R, 2R)-11f
(1R, 2S)-11f’
97% ee
90% ee
Ph
Ph
Ph
AcO
2
2
condition Aa, d
BnO
BnO
BnO
BnO
BnO
+
1
BnO
1
OH
OH
99% yield
dr (cis:trans) 2.4:1
O
(±)-13g
(1R, 2R)-11g
(1R, 2S)-11g’
93% ee
94% ee
Ph
Ph
Ph
MeO2CO
3
3
condition Ab
+
TsN
TsN
OH
TsN
OH
4
O
4
78% yield
dr (cis:trans) 1.8:1
(±)-13h
(3S, 4R)-11h
(3R, 4R)-11h'
95% ee
93% ee
Ph
MeO2CO
Ph
Ph
4
4
condition Ab
+
OH
OH
O
3
3
TsN
(±)-13i
TsN
TsN
99% yield
dr (cis:trans) 1.5:1
(3S, 4R)-11i
(3S, 4S)-11i'
97% ee
92% ee
Ph
AcO
Ph
Me
Ph
Me
condition Aa, c
4
4
Me
+
TsN
TsN
TsN
3
3
OH
OH
99% yield
dr (cis:trans) 2.0:1
O
(±)-13j
(3S, 4S)-11j
(3S, 4R)-11j'
90% ee
70% ee
condition A: 10 mol% Pd[P(o-tolyl)3]2, 15 mol% (S)-DM-SEGPHOS, reductant,
CH3CN (0.05 M), 50 °C. a reductant = 3 equiv HCO2H–Bu3N. b reductant =
1 equiv HCO2H. c (S)-SEGPHOS was used as a ligand. d reported in ref. 16.
Scheme 5. The reductive cyclizations of aldehyde-containing
allylic acetates 13d–g·j and carbonates 13h·i.
Ph
Ph
TsN
TsHN
O
19
20
Figure 1. Side-products 19 and 20 obtained from the acetate
counterparts of 13h and 13i under basic conditions
These products are also obtained by the phenylative
cyclization of allene-aldehydes 9e–i (Scheme 6). Regardless of
the tethered atom and the length in the substrates, the latter
cyclization showed superior diastereoselectivity than the former,
generating cis-disubstituted tetrahydrofuran 11e, five-membered
carbocycles 11f and 11g, and six-membered heterocycles 11h
and 11i, exclusively or preferentially (Scheme 5 vs. 6). The two
cyclizations showed comparably high enantioselectivities. In
contrast, the phenylative cyclization of methyl-substituted allene
9j was more diastereoselective, but less enantioselective than the

OAc
Ph
reductive equivalent of 13j to yield common products 11j and
11j' containing a quaternary carbon.
Ph
Ph
4
4
condition A (1.5 h)
+
TsN
TsN
TsN
75% yield
3
3
OH
OH
O
cis only
(Z)-13a'
(3S, 4S)-11a
(3S, 4R)-11a'
Ph
76% (97% ee)
0%
4
condition B
Ph
O
O
condition A (4 h)
3
OH
O
O
77% yield
69% (91 ee)
4% (nd)
TsN
(E)-13a'
OAc
73% yield
dr (cis:trans) 17:1
9e
(3S, 4S)-11e
95% ee
O
Ph
Ph
2
2
condition B
OAc
Ph
+
H2C
H2C
H2C
Ph
Ph
1
1
OH
OH
2
2
condition A (10 h)a
82% yield
dr (cis:trans) 5.8:1
BnO
BnO
BnO
BnO
BnO
BnO
+
9f
(1R, 2R)-11f
98% ee
(1R, 2S)-11f'
94% ee
1
1
OH
59% yield
dr (cis:trans) 4.3:1
OH
O
(Z)-13g'
(1R, 2R)-11g
(1R, 2S)-11g'
49% (97% ee)
11% (76% ee)
Ph
Ph
2
condition B
65% yield
BnO
BnO
BnO
BnO
condition A (10 h)a
BnO
BnO
23% (71% ee)
54% (99% ee)
OAc
1
OH
O
O
78% yield
9g
(1R, 2R)-11g
dr (cis:trans) 1:2.4
(E)-13g'
93% ee
condition A: 10 mol% Pd[P(o-tolyl)3]2, 15 mol% (S)-DM-SEGPHOS,
3 equiv HCO2H–Bu3N, CH3CN (0.05 M), 50 °C. a reported in ref. 16.
Ph
Ph
3
3
Scheme 7. Reductive cyclizations of (Z)- and (E)-primary
allylic acetates 13a' and 13g'
condition B
+
TsN
TsN
OH
TsN
OH
O
4
4
85% yield
dr (cis:trans) 19:1
9h
(3S, 4R)-11h
(3R, 4R)-11h'
98% ee
90% ee
Substituent effect on the allylic acetate-aldehyde
cyclization. Since the arylative cyclization of allene-aldehydes
accompanies the introduction of a sterically demanding aryl
group into the allene central carbon,12a the steric effect of the
substituent at the C-2 in the allylpalladium moiety on the
diastereo- and enantioselectivities was unclear. In contrast to the
phenyl-substituted substrate 13a, the reaction of 2-unsubstituted
Ph
Ph
4
4
condition B
+
OH
OH
O
3
3
TsN
TsN
TsN
81% yield
dr (cis:trans) 12:1
9i
Me
9j
(3S, 4R)-11i
98% ee
(3S, 4S)-11i'
87% ee
Ph
Me
Ph
Me
allylic acetate 13k (X
= OAc) in the presence of
condition B
tributylammonium formate produced Tsuji-Trost type O-
allylation product 14k33 along with a diastereomeric mixture of
cyclized products 11k and 11k' (Table 5, Entry 1). While the
substitution of SEGPHOS (12a) with the s-donating DM-
SEGPHOS (12b) did not prevent the formation of side-product
14k (Entry 2), the combination of the carbonate 13j (X =
OCO2Me) and the formic acid caused suppression, generating
11k and 11k' in the highest combined yield (Entry 3). These
results indicated that the presence of an amine promoted the
formation of enolate, that is susceptible to electrophilic allylation
with the less hindered h3-allylpalladium. It is noteworthy that the
enantiomeric ratio of the cis-product 11k was below that of the
phenyl-substituted 11a but was still good (er = ca. 4.7:1). The
lower enantioselectivity reflects a lower difference in the
activation energies of the Zimmerman-Traxler transition states
10 and 10' (R = H) (Scheme 2).34 Gratifyingly, the
enantiomerically enriched product 11k was obtained by the
reduction of chloro-substituted one 11l,27 which was prepared by
the diastereo- and enantioselective cyclization of isomeric allylic
acetate 13l' (Scheme 8). 16
The methyl-substituted allylic carbonate 13m also
underwent reductive cyclization to yield 4-(1-methylethenyl)-
pyrrolidin-3-ol derivative 11m, but with low enantioselectivity
(79% ee; Scheme 9, top). Instead, the use of di-carbonate 13n'
solved the problem and produced the 11m in 94% ee after one-
pot reduction of in situ generated mono-carbonate 11n (Scheme
9, bottom). A (methoxycarbonyloxy)methyl group in 13n' acted
as a surrogate for the methyl group and improved the
enantioselectivity in the cyclization step.
4
4
+
TsN
TsN
TsN
3
3
OH
OH
63% yield
dr (cis:trans) 8.9:1
O
(3S, 4S)-11j
76% ee
(3S, 4R)-11j'
41% ee
condition B: 10 mol% Pd(OAc)2, 15 mol% (S)-SEGPHOS,
1.5 equiv PhB(OH)2, CH3CN (0.1 M), 50 °C.
Scheme 6. Highly diastereoselective phenylative cyclizations
of allene-aldehydes 9e–j
.
Diastereoselectivities of the reductive cyclizations of
isomeric primary allylic acetate-aldehydes. Further
experiments to understand the differences in the
diastereoselectivities of two types of the cyclizations were still
required, because the use of secondary allylic acetates 13a and
13g renders the ratio of the anti- and syn-h3-allylpalladium
intermediates kinetically generated in situ obscure. The stereo-
defined h3-allylpalladiums were prepared predominantly from
the (Z)- and the (E)-primary allylic acetates 13a' and 13g'
(Scheme 7).32 Interestingly, both of the nitrogen-tethered
isomers (Z)- and (E)-13a' converted into cis-diastereomer 11a
exclusively or preferentially, although the latter substrate caused
a slight decrease in the optical purity of 11a. In contrast, the (Z)-
and the (E)-allylic acetates 13g' containing a carbon-tether also
underwent cyclization to produce diastereomeric mixtures of 11g
and 11g', but with reverse selectivity, i.e., 4.3:1 and 1:2.4,
respectively. It is noteworthy that minor diastereomers derived
from primary allylic acetates 13g' showed enantiomers of lower
purity than those from secondary allylic acetate 13g (Scheme 5).

ascribed to steric repulsion between the methyl group and
pseudoequatorial phenyl group in the SEGPHOS ligand in
transition state 10 shown in Scheme 2. This phenomenon is
consistent with previous observations on the arylative
cyclization of allene-ketone.12a
Table 5. Effect of the reaction conditions on the cyclization of
allylic acetate- or carbonate-aldehydes.
H
H
O
H
H
10 mol% Pd[P(o-tolyl)3]2
15 mol% 12a or 12b
X
4
4
+
+
TsN
TsN
TsN
TsN
O
Reductant
3
3
OH
OH
CH3CN (0.05 M), 50 °C
Ph
AcO
Ph
(±)-13k
(3S, 4S)-11k
(3S, 4R)-11k'
14k
10 mol% Pd[P(o-tolyl)3]2
15 mol% (S)-SEGPHOS
4
TsN
TsN
3
Entry
X
12 Reductant Yield[a]
of 11k
Yield[a]
HCO2H-Bu3N (3 equiv)
CH3CN, 80 °C, 12 h
OH
O
Me
(±)-13o
Me
11o
of 11k'
53% (45% ee)
1[b]
2[b]
3
OAc
12a
HCO2H
-Bu3N
26%,
6%,
Scheme 10. Reductive cyclization of allylic acetate-methyl
ketone 13o
66% ee 55% ee
(3 equiv)
HCO2H
-Bu3N
Plausible mechanism of the allylic acetate-aldehyde
cyclization. The diastereoselectivities observed in the reductive
cyclization of allylic acetate-aldehydes (Schemes 5 and 7)
provide clues on the generation and participation of
allylpalladium intermediates in the cyclization (Scheme 11).
Oxidative addition of allylic acetate (±)-13 to Pd(0) produces
anti- and syn-h3-allylpalladiums 21 and 21', that are in
equilibrium with the (Z)- and the (E)-h1-allylpalladiums 22 and
22', respectively. A sterically demanding substituent R in the
allylic moiety favors the anti-h3-allylpalladium 21 over the syn-
complex 21' kinetically and thermodynamically through h1-
OAc
12b
39%,
7%,
66% ee 55% ee
(3 equiv)
HCO2H
OCO2Me 12b
68%
15%,
(1 equiv) 65% ee 57% ee
[a] Enantiomeric excess of 11k and 11k' was determined by
chiral HPLC. [b] 14k was obtained in 40% and 37% yields in
Entries 1 and 2, respectively.
allylpalladium 23.35 Contrarily, S
N
2- or S 2'-type oxidative
N
addition of the (Z)- and the (E)-allylic acetates 13' to Pd(0)
predominantly generates anti- and syn-h3-allylpalladium 21 and
21', respectively.32 Among the four six-membered transition
states with R groups oriented toward the upper left to avoid a
steric repulsion with the pseudoequatorial phenyl group in the
(S)-SEGPHOS ligand (see Scheme 2), chair-like transition states
24 and 25 are much more favorable than boat-like 24' and 25'.
The Zimmerman-Traxler transition states 24 and 25 generate (1R,
2R)- and (1R, 2S)-cyclopentanols 11 and 11' (X = carbon),
respectively, whereas minor transition states 25' and 24' provide
counter enantiomers to reduce the optical purity of each
diastereomer overall. Based on the experimental results on the
formation of five-membered carbocycles 11g and 11g' (Schemes
5 and 7), the ratios of (1R, 2R)-11g to (1S, 2R)-11g' and those of
(1R, 2S)-11g' to (1S, 2S)-11g are estimated at 99/1~97/3 and
94/6~92/8, respectively and reflect the degree of contribution of
the transition states 24/24' and 25/25'. The relatively lower
optical purities of the minor diastereomers trans-11g' and cis-
11g prepared from the (Z)- and the (E)-allylic acetates 13g'
(Scheme 7) are attributed to partial participation of the boat
transition states 24' and 25'. The reverse diastereoselectivity
observed in the cyclizations of the (Z)- and the (E)-13g' indicates
that the isomerization of each h3-allylpalladium to a primary h1-
allylpalladium and the subsequent cyclization, are faster than the
syn-anti isomerization through the secondary h1-allylpalladium
23. In addition to higher activation energies for transition states
Cl
Cl
10 mol% Pd[P(o-tolyl)3]2
15 mol% (S)-DM-SEGPHOS
4
TsN
TsN
OAc
3
HCO2H-Bu3N (3 equiv)
CH3CN (0.05 M)
50 °C, 1.5 h
OH
O
13l' (E:Z=1:2.5)
(3S, 4S)-11l
64% (87% ee)a
a reported in ref. 16
H
10 mol% PdCl2(PhCN)2
11 mol% dppf
4
TsN
3
OH
HCO2Na (1.5 equiv)
DMA, 80 °C, 9 h
(3S, 4S)-11k
93% (87% ee)
Scheme 8. Alternative approach leading to 11k
CH3
CH3
10 mol% Pd[P(o-tolyl)3]2
15 mol% (S)-SEGPHOS
MeO2CO
BocN
4
3
BocN
HCO2H-Bu3N (3 equiv)
CH3CN, 50 °C, 7 h
OH
O
(3S, 4S)-11m
96% (79% ee)
13m
OCO2Me
OCO2Me
10 mol% Pd[P(o-tolyl)3]2
15 mol% (S)-SEGPHOS
4
3
BocN
BocN
OCO2Me
HCO2H-Bu3N (3 equiv)
CH3CN, 50 °C, 24 h
OH
O
13n'
(3S, 4S)-11n
H3C
; 20 mol% PBu3
HCO2H-Bu3N (2 equiv)
25 and 25', S 2'-type oxidative addition of (Z)- and (E)-allylic
N
4
acetates 13g', which results in the direct formation of secondary
h1-allylpalladium 23 (an intermediate between 21 and 21'
formed via s-bond rotation), may account for the incomplete
diastereoselectivity observed with a different relative ratio (4.3:1
vs. 1:2.4, Scheme 7).
BocN
3
OH
50 °C, 6 h
(3S, 4S)-11m
66% (94% ee)
Scheme 9. Reductive cyclizations of 13m and 13n' producing
11m
The substitution of an aldehyde with a methyl ketone also
caused great loss in enantioselectivity (Scheme 10). This loss is

R
R
enantioselectivity (Table 5, Entry 3).
Pd+
O
H
X
2
1
X
OAc
R
OH
R
Pd+
X
R
Plausible mechanism of the allene-aldehyde cyclization.
The arylative cyclization of allene-aldehyde 9 proceeds through
(Z)-h1-allylpalladium 22 (R = H, Me), that is kinetically formed
by carbopalladation of the terminal double bond in 9 from the
less hindered face (Scheme 13).36, 37 This retains the high cis-
selectivity even during the formation of cyclopentanols 11f and
11g, six-membered heterocycles 11h and 11i, and pyrrolidine 11j
containing a tertiary carbon (Scheme 6).
Pd+
O
chair TS-24
(1R, 2R)-11
a
b
H
O
X
O
R
X
R
O
2
(Z)-22
(Z)-13'
anti-21
Pd+
X
X
X
1
ring strain
for X = N, O
H
OH
R
AcO
R
boat TS-24’
(1S, 2R)-11'
Pd+
X
a
a
b
O
X
O
R
R
O
23
2
(±)-13
Pd+
X
1
H
OH
R
Pd+
boat TS-25’
(1S, 2S)-11
R
R
b
Pd+
O
X
OAc
O
R
Ph
O
X
X
Ph
H
R
Pd+
H
O
R
2
Pd+
O
(E)-13'
syn-21’
(E)-22’
H
R
2
X
ring strain
for X = N, O
X
Pd+
Ph
1 OH
X
1
X
OH
Ph
R
chair TS-25
(1R, 2S)-11'
a oxidative addition. b 3-η1-η3 isomerization.
η
Pd+
O
chair TS-24
(1R, 2R)-11
R
O
Scheme 11. Plausible mechanism for the reductive cyclizations
of 13 and (Z)- and (E)-13'
X
X
Ph
R
R = small
group
Ph
O
(Z)-22
2
Pd+
R
X
X
1
ring strain
H
OH
R
Ph
Ph
for X = N, O
Pd+
boat TS-24’
(1S, 2R)-11'
To support the interpretation above, cyclic allylic acetates
13p and 13q were employed as the substrates because of the
provision of the geometrically fixed allyl complexes 21p·q and
22p·q (Scheme 12). Expectedly, the diastereoselective
transformation of 13p and 13q into spiro compounds 11p and
11q was observed. The result demonstrates that the geometry of
the h3-allylpalladium intermediate considerably affects the
diastereoselectivity of the reductive cyclization reaction.
X
a
O
X
R
23’
O
Ph
R
Ph
O
9
2
Pd+
X
X
1
H
OH
R
R = large
group
boat TS-25’
(1S, 2S)-11
Pd+
O
Pd+
Ph
Ph
R
X
R
Ph
Pd+
O
O
(E)-22’
H
2
X
R
X
ring strain
for X = N, O
1 OH
X
R
a carbopalladation from the less hindered side.
(1R, 2S)-11'
chair TS-25
Pd+
AcO
condition A
Pd+
O
5
Scheme 13. Plausible mechanism for the phenylative
cyclizations of 9
O
1
OH
O
(±)-13p
anti-21p
(Z)-22p
(1R, 5R)-11p
57% (86% ee)a
Pd+
The above reaction mechanism suggests that substitution
by R larger than a methyl group in Scheme 13 renders the
arylative cyclization of 1,1-disubstituted allenes less
stereoselective. The isobutyl group in 9r in fact caused a
significant reduction in diastereo- and enantioselectivity (Table
6, Entries 1,2 vs. 3). The low diastereoselectivity stems from the
competitive carbopalladation producing (E)-h1-allylpalladium
22' (Scheme 13). In the case of the 1,1-disubstituted allene, the
(E)-h1-allylpalladium 22' failed to undergo the isomerization
into (Z)-h1-allylpalladium 22, because it proceeds through an
unlikely tertiary h1-allylpalladium 23'.32 Instead, the ring strain
in the chair-TS 25 (X = NTs) relatively lowers the activation
eneregies of boat TS-25' to generate (1S, 2S)-11, which accounts
for the low enantioselectivity of cis-11. Although the reason for
the trans-isomers 11j' and 11r' being much less enantiomerically
enriched than cis-isomers 11j and 11r (Table 6, Entries 2 and 3)
remains unclear, a disturbance in the chair TS-25 caused by an
alkyl group at the axial position rather than the boat TS-24'
contributed. In contrast, the phenylative cyclization of the 9s and
9t homologues dramatically restored enantioselectivity and
retained diastereoselectivity due to release of the ring strain in
TS-25 (Table 6, Entries 2 vs. 5, 3 vs. 6 and Scheme 13).
Pd+
O
AcO
condition A
5
O
1
OH
O
anti-21q
(Z)-22q
(±)-13q
(1R, 5R)-11q
77% (91% ee)a
condition A: 10 mol% Pd[P(o-tolyl)3]2, 15 mol% (S)-DM-SEGPHOS,
3 equiv HCO2H–Bu3N, CH3CN (0.05 M), 80 °C. a reported in ref. 16
Scheme 12. Diastereoselective cyclizations of 13p and 13q
leading to spiro compounds 11p and 11q
Meanwhile, the formation of five-membered heterocycles
accompanies a ring strain in the trans-fused 25 and 24'. This is
explained by the shorter carbon-nitrogen and carbon-oxygen
relative to carbon-carbon bonds, that raises the acitavation
energy of 25 and 24' and dramatically increases the ratio of the
cis-11 to trans-11' (Scheme 11). Again, the slight reduced optical
purity of the cis-11a is attributed to participation of the boat
transition state 25' through the syn-h3-allylpalladium 21',
generated in higher quantities from (E)-allylic acetate 13a' than
the (Z)-isomer 13a' (Scheme 7). As illustrated in Scheme 5, an
elongation of the tether by a carbon releases the strain and
increases the amount of the trans-adduct 11h' and 11i'. Low
diastereoselectivity observed in the cyclization of tertiary allylic
acetate 13j (Scheme 5) indicates that the methyl substituent
would block the isomerization between anti- and syn-h3-
allylpalladiums with a little difference in thermodynamic
stabilities, which must be intermediated by tertiary h1-
allylpalladium 23' (Scheme 13) formed unlikely.32 In addition, a
small R group (R = H, Me; Scheme 11) reduces thermodynamic
stability of the anti-h3-allylpalladium 21 and the difference in
activation energies of the Zimmerman-Traxler transition states
10 and 10' (Scheme 2) yielding lower diastereo- and

1
2
OH
D
Table 6. Substituent effect on the stereoselectivity of allene-
H
H
Ph
Ph
Pd+
Pd+
O
O
H
H
H
aldehyde cyclization.
D
D
Ph
pseudo-ent-
anti-21u
pseudo-ent-
(Z)-22u
(1S, 2S, E)-11u
(pseudo-ent-11u)
Ph
Ph
10 mol% Pd(OAc)2
10 mol% (S)-SEGPHOS
R
R
R
4
3
4
3
+
TsN
TsN
TsN
Pd+
Ph
Ph
n
PhB(OH)2 (1.5 equiv)
CH3CN (0.1 M), 50 °C
n
n
Ph
Ph
D
OH
OH
O
D
D
Pd+
O
H
H
H
D
a
2
9a·j·r: n =1
9h·s·t: n =2
(3S, 4S)-11
(3S, 4R)-11'
O
H
H
H
AcO
O
H
1
OH
(S, E)-13u
(97% ee)
anti-21u
(Z)-22u
(1R, 2R, Z)-11u
9
R
Dr
Ee
Ee
Entry
Yield
(%)
93
(cis:trans) (cis) (trans)
1
OH
[a]
[b]
[b]
H
H
H
H
Ph
Ph
Ph
Pd+
Pd+
O
O
O
D
D
D
2
D
1[c]
2
H
H
H
Ph
9a
9j
H
cis only
8.9:1
97%
76%
37%
-
AcO
syn-21u'
(E)-22u'
(1S, 2R, Z)-11u'
Me
63
41%
22%
Pd+
Ph
Ph
Ph
H
H
D
H
+
H
Pd
O
H
2
9r iso-
80
2.4:1
3
O
D
Bu
D
1
OH
pseudo-ent-
syn-21u'
pseudo-ent-
(E)-22u'
(1R, 2S, E)-11u'
(pseudo-ent-11u')
9h
H
85
78
59
19:1
9.0:1
2.9:1
98%
80%
71%
90%
70%
62%
4
5
6
a 10 mol% Pd[P(o-tolyl)3]2, 15 mol% dppe, CH3CN, 50 °C.
(1R*, 2R*)-11u: 57%, (1R, 2R):(1S, 2S)=51:49
(1S*, 2R*)-11u': 29%, (1R, 2S):(1S, 2R)=50:50
9s Me
9t iso-
Scheme 14. Reductive cyclization of deuterium-labeled chiral
allylic acetate (S, E)-13u under Pd0-dppe catalysis
Bu
[a] Diastereomeric ratio was determined by 1H-NMR analysis of
a mixture of diastereomers. [b] Enantiomeric excess of 11 and
11' was determined by chiral HPLC. [c] reported in ref. 12a.
4. Conclusion
This study has uncovered the differences between two
asymmetric umpolung cyclizations of aldehyde-containing
allylpalladium intermediates generated in situ by the oxidative
addition of allylic acetate and carbopalladation of allene. In the
former cyclization, the use of organometallic reductants like the
Et2Zn and the Et3B instead of formate and silane lowered the
yield and the optical purity of products. The effects of solvent on
the enantioselectivity were not observed in the former
cyclization, but in the latter. The enantioselectivity lowered by
THF for the latter cyclization was completely restored by
gradual addition of phenylboronic acid. This again indicates that
the presence of an excess organometallic reagent in the
formation of a neutral (h1-allyl)palladium complex causes loss
of enantioselectivity. Although the cyclization reactions
Facial selectivity of the reductive allylation of aldehyde.
The Zimmerman-Traxler transition states involved in these
cyclization reactions necessitate nucleophilc attacks of the
allylpalladium intermediates to the intramolecular aldehyde
from the side occupied by the palladium. To trace the facial
selectivity, the chiral allylic acetate (S, E)-13u hosting (E)-
deuterium-labeled alkene was utilized for cyclization under
achiral diphosphine (dppe)-ligated palladium catalysis (Scheme
14). The oxidative addition of allylic acetate (S, E)-13u to Pd(0)
provided a mixture of the anti-21u and the syn-21u' via a well-
known inversion of the configuration.38 The h3-h1 isomerization
of the anti-21u and the syn-21u' produced (Z)- and (E)-h1-
allylpalladium 22u and 22u', respectively, generating (1R, 2R)-
11u and (1S, 2R)-11u' retaining the alkene geometry. In addition,
the s-bond rotations shown in Scheme 14 are faster than the
cyclizations and cause the formation of pseudo-enantiomers of
(1S, 2S)-11u and (1R, 2S)-11u' with inversion of the alkene
geometry (fast epimerization is requisite for the asymmetric
variant). In fact, each pseudo-diastereomer from the crude
pseudo-racemic mixture was isolated by preparative TLC and
separated by chiral HPLC to eventually produce four
stereoisomers. The absolute configurations were determined by
a modified Mosher’s method26 using MTPA esters of (1R, 2R)-
11f and (1R, 2S)-11f' (Scheme 5), which were parent non-labeled
produced
common
cis-disubstituted
five-membered
heterocycles including pyrrolidine and tetrahydrofuran, in
excellent yields with high diastereo- and enantioselectivity,
different stereoselectivities were observed in the formation of
five-membered carbocycles, six-membered heterocycles, and
pyrrolidine containing a tertiary carbon. Comparison between
nitrogen- or carbon-tethered primary (Z)- or (E)-allylic acetates
13a' and 13g', which leads to geometrically defined h3-
allylpalladium, disclosed that the highly stereoselective
formation of five-membered heterocycles in the former
cyclization can be ascribed to a ring strain in the transition state
to give trans-disubstituted one, and isomerization of (E)- to (Z)-
h1-allylpalladium through h3-h1-h3-complex. The other
different behaviors are attributed to the geometry of
allylpalladium species; these behaviors depend on how the
allylpalladium species is generated. The former cyclization
commences with the oxidative addition of secondary allylic
acetate to create geometrically obscure h3-allylpalladium. The
latter cyclization begins with carbopalladation of allene from the
less hindered side, directly forming primary (Z)-h1-
allylpalladium. The stereochemistry of products provided useful
information about allylpalladium intermediates which are
difficult to isolate and characterize. The Zimmerman-Traxler
transition state was supported by the chirality transfer reaction
of the optically active allylic acetate with deuterium-labeled
1
counterparts of 11u and 11u'. H-NMR analysis of the isomers
revealed that each pair of pseudo-enantiomers (1R*, 2R*)-11u
and (1R*, 2S*)-11u' has the reverse alkene geometry. The
distribution of these products was consistent with our prediction.

alkene. Further studies on another method that generates
allylpalladium intermediates via allylic C-H activation are
underway.
50, 2232.
8.
9.
a) O. A. Wallner, V. J. Olsson, L. Eriksson, K. J. Szabó,
Inorg. Chim. Acta 2006, 359, 1767; b) J. Aydin, K. S.
Kumar, M. J. Sayah, O. A. Wallner, K. J. Szabó, J. Org.
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Acknowledgement
This work was partly supported by The Research
Foundation for
Pharmaceutical
Sciences,
SUNTRY
FOUNDATION for LIFE SCIENCES, Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research (BINDS)) from AMED under Grant Number
JP18am0101095 and JP18am0101100, and JSPS KAKENHI
Grant Numbers JP24590004 and JP15H05837 in Middle
Molecular Strategy. The authors would like to thank Enago
(www.enago.jp) for the English language review.
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