Formal syntheses of (?)-isoretronecanol, (+)-laburnine, and a concise enantioselective synthesis of (+)-turneforcidine

Article abstract of DOI:10.1038/s41429-019-0169-9

The synthesis of functionalized pyroglutamates 15 and 16 could be achieved by the application of recently developed diastereodivergent asymmetric Michael addition reaction of iminoglycinate 7 to ethyl γ-silyloxycrotonate with >98:<2 diastereoselectivity followed by hydrolysis and lactamization. Formal syntheses of (?)-isoretronecanol and (+)-laburnine as well as a concise enantioselective synthesis of (+)-turneforcidine could be achieved from functionalized pyroglutamates 15 or 16.

Full text of DOI:10.1038/s41429-019-0169-9

The Journal of Antibiotics
https://doi.org/10.1038/s41429-019-0169-9
SPECIAL FEATURE: ARTICLE
Formal syntheses of (−)-isoretronecanol, (+)-laburnine, and a
concise enantioselective synthesis of (+)-turneforcidine
1 ●
Chuang-Chung Chung Meng-Wen Huang Biing-Jiun Uang1
1 ●
1 ●
Yu-Fu Liang
Received: 15 August 2018 / Revised: 23 January 2019 / Accepted: 31 January 2019
The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2019
©
Abstract
The synthesis of functionalized pyroglutamates 15 and 16 could be achieved by the application of recently developed
diastereodivergent asymmetric Michael addition reaction of iminoglycinate 7 to ethyl γ-silyloxycrotonate with >98:<2
diastereoselectivity followed by hydrolysis and lactamization. Formal syntheses of (−)-isoretronecanol and (+)-laburnine as well
as a concise enantioselective synthesis of (+)-turneforcidine could be achieved from functionalized pyroglutamates 15 or 16.
Introduction
diastereoselective synthesis using accessible chiral building
block that derived from L-proline [17], (R)- or (S)-malic
acid [18, 19], and carbohydrates [8, 20].
Pyrrolizidine alkaloids are azabicyclo [3.3.0]octane 1 based
natural products [1, 2], which exist widely in various plant
families and insects [3]. They have been shown to
possess biological activities such as tumor inhibitory
activities [3–6]. Some of them could be considered as
antifeedants, which can be used as insecticides and anthel-
mintics [7]. 1-Hydroxymethyl substituted pyrrolizidines
such as (−)-isoretronecanol 2 and ( + )-laburnine 3 belong
Recently, we reported the syntheses of (+)-α-allokainic
acid
and
(−)-2-epi-α-allokainic
acid
employing
ketopinic amide as chiral auxiliary (Scheme 1) [21].
Asymmetric Michael reaction of iminoglycinate 7 to
α,β-unsaturated esters has been developed with excellent
diastereoselectivity. Moreover, a reversal of diastereos-
electivity for Michael reaction at C2 of Michael adducts 8
could be controlled by the replacement of metal ions. The
synthesis of functionalized pyroglutamates could be
attained via the hydrolysis of Michael adducts followed by
lactam formation with the recovery of chiral auxiliary.
Functionalized pyroglutamates 9 are good precursors for the
syntheses of alkaloid, such as pyrrolizidine 1 and indolizi-
dine 10 natural products, which contain pyrrolidine ring
(Fig. 2). Here, we report concise enantioselective synthesis
of (+)-turneforcidine 4 as well as formal synthesis of
to
a
subclass of pyrrolizidine alkaloids [8]. 1-
Hydroxymethyl-7-hydroxy substituted pyrrolizidines, such
as (+)-turneforcidine 4, (−)-hastanecine 5, and (−)-platy-
necine 6 belong to another subclass, which are even more
often seen in nature as synthetic targets [8] (Fig. 1).
Asymmetric syntheses of these pyrrolizidines have attracted
attention for several decades, and most reported synthetic
strategies are either employing chiral auxiliary approaches
[
8–14], enantioselective catalysis [15, 16], or
(
−)-isoretronecanol 2 and (+)-laburnine 3.
This manuscript is dedicated to Professor Samuel J. Danishefsky for
his outstanding achievements in the area of total synthesis of complex
natural products and his dedication to chemical education
Results and discussion
Our retrosynthetic analysis for (−)-isoretronecanol 2,
Supplementary information The online version of this article (https://
doi.org/10.1038/s41429-019-0169-9) contains supplementary
material, which is available to authorized users.
(
+)-laburnine 3, and (+)-turneforcidine 4 are outlined in
Scheme 2. (−)-Isoretronecanol 2 and (+)-laburnine 3, in
principle, could be prepared from pyrrolizidines 11 and 12,
respectively, via reductions of double bond and amido
group, and TBS group deprotection. Bsaed on a previous
literature [22], epoxidation was favored to occur on less
hinder beta face, and established C7 hydroxyl group with
*
Biing-Jiun Uang
bjuang@mx.nthu.edu.tw
1
Department of Chemistry, National Tsing Hua University, 101
Kuang Fu Road, Section 2, 30013 Hsinchu, Taiwan

Y.-F. Liang et al.
R'
3
4
5
stereochemistry at C4 of dienes 13 and 14 will be confirmed
at a later stage. The diene mixture 13 and 14 was heated
with a catalytic amount of the second-generation Grubbs
catalyst [26] in dichloromethane to afford pyrrolizidines 11
and 12 in 83 and 8% yields, respectively (Scheme 4).
Pyrrolizidines 11 and 12 could be separated easily by silica
gel column chromatography.
Catalytic hydrogenation (Pd/C) of pyrrolizidine 11 in
EtOAc generated compound 21 in 95% yield and depro-
tection of the TBS group with HF gave compound 22.
Reduction of 22 to (−)-isoretronecanol 2 has been reported
in previous literatures [14, 27] (Scheme 5). The spectral
data of compound 22 were in agreement with the reported
values [27]. The stereochemical assignments for C4 of
compounds 11–14 are confirmed at this stage. Thus, a
formal synthesis of (−)-isoretronecanol 2 was achieved in
10 synthetic steps from iminoglycinate 7.
To establish correct stereochemistry at C7a for the
syntheses of (+)-laburnine 3 and (+)-turneforcidine 4,
diastereoselective Michael addition of iminoglycinate 7 to
α,β-unsaturated ester 17a with MDA (magnesium diiso-
propylamide) [21] was conducted and Michael adduct 23
was obtained as sole product. The stereochemistry at C2 in
23 was assigned as S-configuration based on our previous
study [21] and is in agreement with the required stereo-
chemistry at C7a for (+)-laburnine 3 and (+)-turneforcidine
4. With Michael adduct 23 in hand, one could follow the
same synthetic protocol as for the synthesis of pyrrolizidine
11 (Scheme 4) to attain pyrrolizidine 12 as the major pro-
duct (Scheme 6). Thus, treatment of Michael adduct 23 with
15% citric acid followed by heating in methanol gave lac-
tam 16 in 66% yield with a recovery of 19 in 95% yield.
N-Allylation of lactam 16 with NaH and allyl iodide gave
lactam 24 in 82% yield. Reduction of tert-butyl ester group
on lactam 24 with DIBAL-H to aldehyde followed by
Wittig olefination with methylenetriphenylphosphorane
gave a 15:1 inseparable diene mixture 14 and 13 in 45%
yield. With this observation and the previous one (lactam 20
to diene 13) that a minor epimerzation at C4, it would be
reasonable to assign the stereochemistry at C4 of dienes 13
and 14 are S and R, respectively.
N
H
N
H
R
6
N
2
1
7a
7
OH
OH
pyrrolizidine 1
(−)-isoretronecanol 2 (+)- laburnine 3
N
N
H
N
H
H
OH
OH
OH
OH
OH
(−)-hastanecine 5
OH
(−)-platynecine 6
(
+)-turneforcidine 4
Fig. 1 1-Hydroxymethyl substituted pyrrolizidines 2-3 and
-hydroxymethyl-7-hydroxy substituted pyrrolizidines 4-6
1
correct configuration after lithium aluminum hydride (LAH)
reduction. Therefore, (+)-turneforcidine 4 could be syn-
thesized from pyrrolizidine 12 by epoxidation and followed
by simultaneous epoxide opening and amide reduction with
LAH. In principle, pyrrolizidines 11 and 12 could be
derived from dienes 13 and 14 respectively by ruthenium-
catalyzed ring-closing metathesis (RCM) [23]. The olefinic
groups in dienes 13 and 14 could be obtained from lactams
1
5 and 16, respectively, through allylation on amide nitro-
gen atom, reduction of ester group to aldehyde, and fol-
lowed by a Wittig olefination. Lactams 15 and 16 could be
prepared from the hydrolysis of Michael adduct that derived
from a stereoselective Michael reaction of iminoglycinate 7
with γ-silyloxycrotonate 17 (Scheme 2).
The synthesis of (−)-isoretronecanol 2, (+)-laburnine 3,
and (+)-turneforcidine 4 commenced with the preparation
of pyroglutamate 15 (Scheme 3). Treatment of iminogly-
cinate 7 with LDA at −78 °C followed by the addition of α,
β-unsaturated ester 17a [24] gave Michael adduct 18 as
single product in 91% yield. The stereochemistry of
Michael adduct 18 was assigned as (2R,3S) according our
previous findings [21]. Hydrolysis of Michael adduct 18
was performed with 15% citric acid to avoid the hydrolysis
of ester groups and desilylation of Michael adduct [25].
Lactam 15 was obtained in 65% yield (2 steps) with a
recovery of 95% ketopinic amide 19 after heating of the
above hydrolysis product in methanol.
With lactam 15 in hand, we turned to synthesize the
pyrrolizidine core structure. N-Allylation of lactam 15 with
NaH and allyl iodide gave lactam 20 in 85% yield.
Reduction of tert-butyl ester group on lactam 20 with
DIBAL-H to aldehyde followed by Wittig olefination with
methylenetriphenylphosphorane, prepared from methyl-
triphenylphosphonium bromide with fresh LHMDS, gave a
Pyrrolizidine 25 was generated by the catalytic hydro-
genation of 12 with Pd/C as catalyst. Deprotection of the
TBS group in 25 with HF gave compound 26. The con-
version of compound 26 to (+)-laburnine 3 has already
been reported in the literature [14, 28] (Scheme 7). The
spectroscopic data of compound 26 were in agreement with
the reported values [28]. A formal synthesis of (+)-labur-
nine 3 could be achieved in 10 synthetic steps from imi-
noglycinate 7.
1
0:1 inseparable diene mixture 13 and 14 in 54% yield. The
stereochemistry at C4 of dienes 13 and 14 are temporarily
assigned as S and R, respectively. The formation of minor
diene 14 is presumably due to an epimerization at C4 during
DIBAL-H reduction and/or Wittig olefination. The
After completed formal syntheses of two 1-
hydroxymethyl substituted pyrrolizidines, we tried to syn-
thesize (+)-turneforcidine 4. For the synthesis of

Formal syntheses of (−)-isoretronecanol, (+)-laburnine, and a concise enantioselective synthesis of. . .
PO
Scheme 1 Enantioselective
synthesis of ( + )-α-allokainic
acid and Its C2-epimer [21]
asymmetric
Michael Reaction
CO2Et
NH
2
steps
N
CO2t-Bu
O
N
CO2t-Bu
CO2H
CO2H
+)-α-allokainic acid
O
N
N
controlled by Li
or Mg enolate
(
and C2-epimer
7
8
P= Protecting Group
pyroglutamates 15 or 16. Thus, a facile entry for the
synthesis of pyrrolizidine alkaloids had been demonstrated.
O
R
R'
N
NH
CO t-Bu
n
R
n = 1 pyrrolizidine 1
n = 2 indolizidine 10
2
9
Experimental section
Fig. 2 Core structures of pyroglutamates, pyrrolizidines and
indolizidines
General information
(
+)-turneforcidine 4, it required the introduction of a
Reagents were obtained from commercial sources and used
without further purification. Most reactions were performed
under an argon atmosphere in anhydrous solvents, which
were dried prior to use following standard procedures.
Merck Art. No. 7734 and 9385 silica gels were employed
for flash chromatography. Analytical TLC was conducted
hydroxyl group at C7 and reduction of lactam in pyrroli-
zidine 12. In order to incorporate a hydroxyl group at C7 in
(
was conducted first. However, it gave trace 27 with poor
reactivity, and most of 12 was recovered. To solve this
problem, more powerful epoxidation reagents with high
reactivity toward olefins were required and dioxiranes [29]
were selected for this purpose. Epoxidation of 12 using
in situ prepared 3-methyl-3-trifluoromethyldioxirane [29,
+)-turneforcidine 4, epoxidation of 12 with mCPBA [22]
on DC Aluminiumoxid 150 F254, neutral, and chromato-
1
grams were visualised with aq. KMnO . H NMR spectra
4
were obtained and noted at 400 MHz (Bruker DPX-400 or
1
3
Varian-Unity-400). C NMR spectra were obtained at
100 MHz. Chemical shifts are reported in values, in parts
per million (ppm) relative to residual chloroform (7.26 ppm
3
0] was conducted and a single epoxide was obtained.
Based on a previous report [22], epoxidation of C5, C6
double bond occurred from the concave face of of the
pyrrolidine and the stereochemistry was temporarily
assigned as depicted in 27. Finally, treatment of epoxide 27
with lithium aluminium hydride (LAH) resulted in con-
comitant ring opening of epoxide, desilylation [31], and
amide reduction afforded (+)-turneforcidine 4 in 75% yield
1
13
for H NMR, 77.00 ppm for C NMR) or H O (4.80 ppm
2
1
for H NMR) as an internal standard. The multiplicities of
the signals are described using the following abbreviations:
s = singlet, d = doublet, t = triplet, q = quartet, dd = doub-
let of doublets, m = multiplet, br = broad band. The melting
point was recorded on a melting point apparatus (Buchi
512– melting point system) and is uncorrected. IR spectra
were performed in a spectrophotometer Bomen MB 100
(
Scheme 7). The spectral and physical data were in accord
with the reported data [32]. (+)-Turneforcidine 4 was
achieved in nine synthetic steps with 12% overall yield
from iminoglycinate 7.
−
1
FT-IR and only noteworthy IR absorptions (cm ) are lis-
ted. Optical rotations were measured on Perkin-Elmer 241
polarimeter. Mass spectrometric analyses were performed
by the Center for Advanced Instrumentation and Depart-
ment of Applied Chemistry at National Chiao Tung Uni-
versity, Hsinchu, Taiwan.
Conclusion
Enantioselective formal syntheses of pyrrolizidine alkaloids
(
−)-isoretronecanol 2, (+)- laburnine 3, and a total synth-
Ethyl (E)-4-hydroxybut-2-enoate (28)
esis of (+)-turneforcidine 4 were accomplished. The
syntheses started with Michael reaction of the enolate from
iminoglycinate 7 to α,β-unsaturated ester 17a in high dia-
stereoselectivity as key step. Subsequent hydrolysis of the
Michael adduct generated functionalized pyroglutamate,
and provided a concise pathway to the corresponding pyr-
rolizidine alkaloids (−)-isoretronecanol 2, (+)-laburnine 3,
A solution of commercial-available monoethyl fumarate
(5.00 g, 34.7 mmol) in THF (34.7 mL) was added
BH ·Me S (17.3 mL, 34.7 mmol, 2.00 M in THF) at –10 °C
for a period of 10 min [33]. The reaction mixture was
allowed to warm to room temperature and stirred for 16 h.
The reaction mixture was quenched with 5 mL of 50%
AcOH, concentrated, and the residual slurry was treated
3
2
and
(+)-turneforcidine
4
from
functionalized

Y.-F. Liang et al.
N
H
N
H
Allylation
O
O
OH
−)-isoretronecanol 2
OH
N
N
(
(+)- Laburnine 3
Wittig Olefination
H
H
RCM
N
OTBS
OTBS
α-H: 13
β-H: 14
α-H: 11
β-H: 12
H
OH
OH
(
+)-turneforcidine 4
O
NH
CO2t-Bu
1
2
) asymmetric
Michael reaction
) hydrolysis
O
N
CO2t-Bu
+
TBSO
H
O
OR
N
OTBS
7
17
α-H: 15
β-H: 16
Scheme 2 Retrosynthetic analysis for 2, 3, and 4
and DMAP (119 mg, 0.98 mmol) at 0 °C [24]. The
reaction mixture was stirred at 0 °C for 5 min, and the
solution of TBSCl (2.56 g, 19.6 mmol) in THF (5 mL)
was added slowly. The reaction mixture was allowed to
warm to room temperature and stirred for 5 h. The
O
OEt
TBSO
N
1
. LDA, THF,
0.5 h, -78 o
, then
TBSO
Ot-Bu
C
N
Ot-Bu
O
O
O
N
OEt
17a
O
N
7
reaction mixture was quenched by sat. NaHCO aq and
O
1
8
3
4
h, -78 oC, 91 %
extracted with EtOAc (3 × 10 mL). The organic layer was
washed with brine, dried over anhydrous Na SO , and
1
. 15% citric acid,
2
4
7
d
O
concentrated. The residue was purified by flash chro-
matography (eluent: EtOAc/Hexanes, 1/6) to provide
2
. MeOH, reflux
3 h
,
+
NH
O
O
(
65% for 2 steps)
17a (4.53 g, 18.6 mmol, 95%) as colorless oil. R = 0.52
f
TBSO
CO2t-Bu
N
(
EtOAc/Hexanes, 1/4); IR (neat) 2979, 2936, 2863,
15
19 (95%)
2
1
6
290, 1732, 1682, 1515, 1456, 1422, 1369, 1301, 1249,
Scheme 3 Synthesis of lactam 15 from iminoglycinate 7
−1 1
156, 1095, 1034 cm ; H NMR (400 MHz, CDCl ): δ
3
.95 (dt, J = 15.4, 3.4 Hz, 1 H), 6.05 (dt, J = 15.4, 2.3
with saturated aqueous NaHCO3 at 0 °C. The resulting
mixture was extracted with EtOAc (3 × 20 mL). The com-
bined organic layers were washed with water, brine, dried
over anhydrous Na SO , and concentrated. The residue was
Hz, 1 H), 4.29 (dd, J = 3.3, 2.3 Hz, 2 H), 4.15 (q, J = 7.1
Hz, 2 H), 1.24 (t, J = 7.1 Hz, 3 H), 0.88 (s, 9 H), 0.04 (s,
1
3
6 H); C NMR (100 MHz, CDCl ): δ 166.5, 147.2,
3
119.5, 62.0, 60.1, 25.7 (3 C), 18.2, 14.2, −5.6 (2 C);
2
4
purified by flash chromatography (eluent: EtOAc/Hexanes,
/3) to provide 28 (1.58 g, 12.1 mmol, 35%) as colorless oil.
HRMS (HRFD) m/z: [M]+ Calcd for C H O Si
1
2
24
3
1
244.1495; Found 244.1493.
1
H NMR (400 MHz, CDCl ): δ 6.92 (dt, J = 16.0, 3.6 Hz, 1
3
H), 5.98 (dt, J = 16.0, 2.0 Hz, 1 H), 4.21−4.10 (m, 2 H),
1-tert-Butyl ethyl (2R,3S)-N-2-(((1R,4R)-1-(N,N-
4
3
6
.09 (q, J = 6.8 Hz, 2 H), 3.47 (br, 1 H), 1.19 (t, J = 6.8 Hz,
diisopropylaminocarbonyl)-7,7-dimethylbicyclo
[2.2.1]heptan-2-ylidene)amino)-3-((tert-
butyldimethylsilyl)oxy)-methyl) glutamate (18)
1
3
H); C NMR (100 MHz, CDCl ): δ 166.2, 147.3, 118.9,
3
0.6, 59.8, 13.4.
Ethyl (E)-4-((tert-butyldimethylsilyl)oxy)but-2-
enoate (17a)
A solution of LDA in THF was prepared under argon
with diisopropylamine (0.55 mL, 3.96 mmol), THF (4.2
mL), and n-BuLi solution (2.30 M solution in hexane,
1.61 mL, 3.70 mmol) at 0 °C. After stirring for 30 min,
the solution was cooled to −78 °C with a dry ice-acetone
A solution of allyl alcohol 28 (2.54 g, 19.6 mmol) in
CH Cl (15 mL) was added Et N (3.25 mL, 23.5 mmol),
2
2
3

Formal syntheses of (−)-isoretronecanol, (+)-laburnine, and a concise enantioselective synthesis of. . .
O
O
O
N
N
NaH, Allyl iodide
THF, 8 h
1. DIBAL-H, DCM
,
o
-78 C
NH
CO2t-Bu
N
TBSO
TBSO
8
5 %
2. PPh3MeBr
LHMDS, THF,
1
3
TBSO
TBSO
CO2t-Bu
20
o
O
1
5
-78 C , 54%
13:14=10:1
O
O
N
14
Grubbs 2nd
5 mol%)
N
(
TBSO
TBSO
H
H
DCM, reflux, 4 h
12 (8%)
1
1 (83%)
Scheme 4 Synthesis of pyrrolizidine 11 and 12
O
O
O
N
references
14 and 27
Pd/C, H2 (1 atm)
HF, MeCN
N
N
N
o
8
h, 40 C
94%
EtOAc, 3 h
95%
HO
TBSO
TBSO
H
HO
H
H
H
1
1
21
22
(−)-isoretronecanol 2
Scheme 5 Synthesis of (−)-isoretronecanol 2
O
OEt
1
2
. 15% citric acid,
TBSO
N
O
7
d
. MeOH, reflux
, 3 h
1. MDA, -78 oC, 1 h
Ot-Bu
NH + 19 (95%)
N
Ot-Bu
O
O
then, 17a, 16 h, - 78
o
C
(66% for 2 steps)
TBSO
O
2
CO t-Bu
N
O
O
85 %
N
7
16
2
3
O
O
NaH, Allyl iodide,
THF, 8 h
1. DIBAL-H, DCM
Grubbs 2nd
(5 mol%)
N
N
N
78 o
-
C
N
TBSO
TBSO
TBSO
H
DCM, reflux, 4 h
82 %
3
2. PPh MeBr
1
2 (85%)
TBSO
CO
t-Bu
14
2
LHMDS, THF,
-78 oC , 45 %
O
2
4
O
14:13=15:1
N
TBSO
H
1
1 (6%)
1
3
Scheme 6 Synthesis of pyrrolizidine 12 as major product
O
O
N
O
N
references
14 and 28
Pd/C, H2 (1 atm)
N
HF, MeCN
8 h, 40 oC
N
EtOAc, 3 h
TBSO
94%
TBSO
H
HO
HO
(+)-laburnine 3
H
H
H
9
0%
2
5
12
26
CF3COCH3, Oxone
O
N
,
EDTA, Na2CO3,
CH3CN, 0 oC, 0.5 h
LAH, THF, rt, 1h
then, reflux 3 h
N
80 %
TBSO
HO
H
O
H
7
5%
OH
2
7
(
+)-turneforcidine 4
Scheme 7 Syntheses of ( + )-laburnine 3 and ( + )-turneforcidine 4

Y.-F. Liang et al.
bath and a solution of iminoglycinate 7 (1.00 g, 2.64
mmol) in THF (1.8 mL) was added over 20 min. The
mixture was stirred for 30 min, then a solution of 17a
(3 × 20 mL). The combined organic phases were washed
with brine (20 mL), dried over anhydrous Na SO , and
concentrated in vacuo. The residue was purified by flash
2
4
(
0.77 g, 3.17 mmol) in THF (0.8 mL) was added slowly.
chromatography (eluent: EtOAc/Hexanes, 1/8 + 1% Et N)
3
The mixture was stirred for 4 h at −78 °C, then a solution
to provide 23 (1.40 g, 1.85 mmol, 85%) as pale yellow oil.
2
2
of 2% H C O (aq) (10 mL) was added. The reaction
R = 0.52 (EtOAc/Hexanes, 1/6); ½αŠ + 5.6 (c 1.0,
2
2
4
f
D
mixture was warmed to 0 °C then was neutralized with
CH Cl ); IR (neat) 2959, 2931, 2886, 1735, 1678, 1630,
2 2
−
1 1
additional 2% H C O (aq) to pH = 6~7. The aqueous
1367, 1335, 1254, 1157, 1100, 836, 777 cm ; H NMR
2
2
4
layer was extracted with EtOAc (3 × 20 mL). The com-
bined organic phases were washed with brine (20 mL),
dried over anhydrous Na SO , and evaporated in vacuo.
(400 MHz, CDCl ): δ 4.26 (septet, J = 6.6 Hz, 1 H), 4.17
3
(d, J = 5.0 Hz, 1 H), 4.07 (q, J = 7.1 Hz, 2 H), 3.60 (dd,
J = 10.1, 5.1 Hz, 1 H), 3.38−3.22 (m, 2 H), 2.74−2.63
(m, 1 H), 2.52 (dd, J = 16.2, 3.3 Hz, 1 H), 2.24 (dd, J =
16.2, 9.8 Hz, 1 H), 2.14−2.05 (m, 1 H), 2.03−1.88 (m, 2
H), 1.82 (d, J = 3.7 Hz, 1 H), 1.73 (t, J = 4.4 Hz, 1 H),
1.42 (s, 9 H), 1.40 (d, J = 6.8 Hz, 3 H), 1.34 (d, J = 6.8
Hz, 3 H), 1.30−1.22 (m, 1 H), 1.20 (t, J = 7.1 Hz, 3 H),
1.15 (d, J = 6.3 Hz, 3 H), 1.13 (s, 6 H), 1.04 (d, J = 6.9
Hz, 3 H), 0.86 (d, J = 1.3 Hz, 1 H), 0.84 (s, 9 H), 0.00
2
4
The residue was purified by flash chromatography (elu-
ent: EtOAc/Hexanes, 1/8 + 1% Et N) to provide 18
3
(
(
(
1
1.50 g, 2.40 mmol, 91%) as colorless liquid. R = 0.50
f
2
2
EtOAc/Hexanes, 1/6); ½αŠ –2.4 (c 1.0, CH Cl ); IR
D
2
2
neat) 2959, 2931, 2859, 1730, 1675, 1631, 1367, 1335,
−
1 1
253, 1162, 836, 777 cm ; H
NMR (400 MHz, CDCl ): δ 4.25−4.16 (m, 1 H), 4.07 (q,
3
1
3
J = 7.2 Hz, 2 H), 3.97 (d, J = 8.9 Hz, 1 H), 3.70−3.56 (m,
H), 3.45 (dd, J = 9.9, 3.6 Hz, 1 H), 3.28 (septet, J = 6.8
(s, 3 H), −0.01(s, 3 H); C NMR (100 MHz, CDCl3):
δ 181.4, 173.0, 170.3, 170.0, 80.7, 65.3, 63.4, 62.5, 60.1,
50.5, 48.1, 46.0, 43.9, 40.1, 35.5, 32.3, 28.6, 28.0 (3 C),
1
Hz, 1 H), 2.72-2.52 (m, 2 H), 2.51−2.41 (m, 1 H), 2.35 (dd,
J = 16.0, 3.7 Hz, 1 H), 2.22−2.07 (m, 1 H), 2.01−1.83 (m,
27.4, 25.8 (3 C), 21.8, 21.6, 20.9 (2 C), 20.3 (2 C), 18.1,
+
3
H), 1.77−1.68 (m, 1 H), 1.45−1.35 (m, 2 H), 1.37 (s, 9
H), 1.33 (d, J = 6.6 Hz, 3 H), 1.22 (t, J = 7.1 Hz, 3 H), 1.19
1.14 (m, 1 H), 1.17 (d, J = 6.6 Hz, 3 H), 1.09 (s, 3 H),
14.2, −5.5 (2 C); HRMS (ESI) m/z: [M H] Calcd for
+
C H N O Si 623.4450; Found 623.4452.
3
4
63
2
6
−
1
0
.04 (d, J = 6.6 Hz, 3 H), 0.95 (dd, J = 10.3, 6.6 Hz, 2 H),
.89−0.81 (m, 2 H), 0.86 (s, 9 H), 0.00 (s, 3 H), −0.01(s, 3
tert-Butyl (2 R,3 S)-3-(((tert-butyldimethylsilyl)oxy)
methyl)-5-oxopyrrolidine-2-carboxylate (15)
1
3
H); C NMR (100 MHz, CDCl ): δ 181.3, 172.6, 170.0,
3
1
3
2
69.7, 81.1, 66.1, 65.4, 60.8, 60.2, 51.8, 48.1, 46.0, 43.9,
9.8, 36.2, 32.0, 29.2, 27.8 (3C), 27.2, 25.9 (3C), 23.1,
1.8, 20.8, 20.6, 20.5, 20.3, 18.2, 14.2, −5.6 (2C); HRMS
A solution of 18 (1.37 g, 2.20 mmol) in THF (7.4 mL) was
added a solution of 15 % aqueous citric acid (4.8 mL, 2.3
mmol). The mixture was stirred at room temperature for 7
day. After evaporation of THF, the residue was dissolved
(
HRFD) m/z: [M]+ Calcd for C H N O Si 622.4372;
34 62 2 6
Found 622.4366.
in H O (5 mL). The aqueous phase was adjusted to pH 7
2
using Na CO and extracted with dichloromethane (3 ×
2
3
1
-tert-Butyl ethyl (2 S,3 S)-N-2-(((1 R,4 R)-1-(N,N-
diisopropylaminocarbonyl)-7,7-dimethylbicyclo
2.2.1]heptan-2-ylidene)amino)-3-((tert-
30 mL). The combined organic phases were dried over
anhydrous Na SO and concentrated in vacuo. The crude
2
4
[
amino ester was used without purification. The crude
amino ester was dissolved in MeOH (7.4 mL). The mix-
ture was refluxed for 3 h, then MeOH was evaporated
in vacuo. The residue was purified by flash chromato-
graphy (eluent: EtOAc/Hexanes, 1/2 to DCM/MeOH, 10/
1) to provide 15 (470 mg, 1.43 mmol, 65%) as colorless
liquid and recover auxiliary 19 (555 mg, 2.09 mmol,
butyldimethylsilyl)oxy)-methyl) glutamate (23)
A solution of MDA in THF was prepared under argon
with diisopropylamine (0.56 mL, 3.96 mmol), THF (6.7
mL), and methylmagnesium bromide solution (1.00 M
solution in THF, 3.70 mL, 3.70 mmol) at 0 °C. After
stirring for 30 min, the solution was cooled to –78 °C with
a dry ice-acetone bath and a solution of iminoglycinate 7
2
D
3
95%). R = 0.52 (DCM/ MeOH, 20/1); ½αŠ −3.4 (c 1.0,
f
CH Cl ); IR (neat) 3232, 2956, 2930, 2886, 1712, 1632,
2
2
(
1.00 g, 2.64 mmol) in THF (1.80 mL) was added over 20
min. The mixture was stirred for 1 h, then a solution of
7a (0.64 g, 2.64 mmol) in THF (2.6 mL) was added
1473, 1392, 1368, 1253, 1229, 1157, 1104, 1006, 939,
−
1 1
838 cm ; H NMR (400 MHz, CDCl ): δ 6.92 (br, 1 H),
3
1
4.12 (d, J = 7.7 Hz, 1 H), 3.71−3.62 (m, 1 H), 3.48
(t, J = 9.0 Hz, 1 H), 2.84−2.67 (m, 1 H), 2.36 (dd, J =
16.8, 8.4 Hz, 1 H), 2.27 (dd, J = 16.8, 6.7 Hz, 1 H), 1.41
slowly. The mixture was warmed to −60 °C, and stirred
for an additional 18 h, then a solution of 2% H C O (aq)
(
0
2
2
4
1
3
10 mL) was added. The reaction mixture was warmed to
°C then neutralized with additional 2% H C O (aq) to
(s, 9 H), 0.81 (s, 9 H), 0.00 (s, 6 H); C NMR (100 MHz,
CDCl ): δ 177.6, 169.4, 82.2, 62.1, 58.6, 39.8, 33.6, 27.9
2
2
4
3
pH = 7~8. The aqueous layer was extracted with EtOAc
(3 C), 25.6 (3 C), 18.0, −5.6 (2 C); HRMS (ESI) (m/z):

Formal syntheses of (−)-isoretronecanol, (+)-laburnine, and a concise enantioselective synthesis of. . .
[
M + H]+ Calcd for C H NO Si 330.2101; Found
tert-Butyl (2 S,3 S)-1-allyl-3-(((tert-butyldimethylsilyl)
1
6
32
4
3
30.2102.
oxy)methyl)-5-oxopyrrolidine-2-carboxylate (24)
tert-Butyl (2 S,3 S)-3-(((tert-butyldimethylsilyl)oxy)
methyl)-5-oxopyrrolidine-2-carboxylate (16)
Starting with 16 (400 mg, 1.21 mmol), and followed the
same procedure as in the synthesis of 20 provided 24 (367
mg, 0.99 mmol, 82%). Rf = 0.36 (EtOAc/Hexanes, 1/2);
2
5
Starting with 23 (1.00 g, 1.60 mmol), and followed the same
procedure as in the synthesis of 15 provided 16 (348 mg,
½αŠ + 29.8 (c 1.0, CH Cl ); IR (neat) 2955, 2931, 2858,
D
2
2
1737, 1704, 1410, 1369, 1253, 1228, 1156, 1109, 990, 837
−
1 1
1
.06 mmol, 66%) and recovered auxiliary 19 (404 mg, 1.52
cm ; H NMR (400 MHz, CDCl ): δ 5.70−5.56 (m, 1 H),
3
2
5
mmol, 95%). R = 0.31 (EtOAc/Hexanes, 1/1); ½αŠ −6.4
5.13−5.05 (m, 2 H), 4.28 (dd, J = 15.2, 5.1 Hz, 1 H), 3.89
(d, J = 3.2 Hz, 1 H), 3.56 (dd, J = 10.0, 5.2 Hz, 1 H), 3.53
−3.41 (m, 2 H), 2.53 (dd, J = 16.9, 9.3 Hz, 1 H), 2.42−2.32
(m, 1 H), 2.15 (dd, J = 16.9, 3.6 Hz, 1 H), 1.41 (s, 9 H),
f
D
(
c 1.0, CH Cl ); IR (neat) 3233, 2955, 2930, 2886, 2858,
2 2
−
1
1
1
738, 1708, 1369, 1252, 1158, 1110, 837, 777 cm ; H
NMR (400 MHz, CDCl ): δ 7.03 (br, 1 H), 3.94 (d, J = 5.5
3
1
3
Hz, 1 H), 3.64 (dd, J = 10.1, 5.1 Hz, 1 H), 3.58 (dd, J =
0.83 (s, 9 H), −0.01 (s, 6 H); C NMR (100 MHz, CDCl3):
δ 174.1, 170.9, 132.0, 118.6, 82.0, 63.9, 61.8, 44.3, 38.3,
32.5, 27.9 (3 C), 25.7 (3 C), 18.1, −5.5, −5.6; HRMS (ESI)
m/z: [M + H]+ Calcd for C H NO Si 370.2414; Found
10.1, 5.2 Hz, 1 H), 2.59−2.47 (m, 1 H), 2.35 (dd, J = 17.0,
9.1 Hz, 1 H), 2.21 (dd, J = 16.8, 6.6 Hz, 1 H), 1.39 (s, 9 H),
0
.81 (s, 9 H), −0.01 (s, 6 H); 13C NMR (100 MHz, CDCl3):
19
36
4
δ 177.3, 171.0, 82.0, 63.0, 57.5, 40.8, 32.3, 27.8 (3 C), 25.6
370.2415.
+
(
3 C), 18.0, −5.6 (2 C); HRMS (ESI) m/z: [M + H] Calcd
for C H NO Si 330.2101; Found 330.2095.
(4S,5 S)-1-Allyl-4-(((tert-butyldimethylsilyl)oxy)
methyl)-5-vinylpyrrolidin-2-one (13) and (4 S,5 R)-1-
allyl-4-(((tert-butyldimethylsilyl)oxy)methyl)-5-
vinylpyrrolidin-2-one (14)
1
6
32
4
tert-Butyl (2 R,3 S)-1-allyl-3-(((tert-
butyldimethylsilyl)oxy)methyl)-5-oxopyrrolidine-2-
carboxylate (20)
To a solution of 20 (0.50 g, 1.35 mmol) in DCM (4.5 mL) was
added DIBAL-H (3.38 mL, 3.38 mmol, 1.00 M solution in
toluene) at −78 °C under an argon atmosphere. After 90 min,
the reaction mixture was quenched with sat. potassium sodium
tartrate (aq) and warmed to room temperature. The reaction
mixture was stirred vigorously for 1 h, and two phases were
separated. The aqueous layer was extracted with EtOAc (3 ×
15 mL). The combined organic phases were dried over
anhydrous Na SO , and concentrated in vacuo. The crude
A suspension of sodium hydride (295 mg, 7.37 mmol,
6
0% in mineral oil) in dry THF (60 mL) was stirred for 10
min at 0 °C, then a solution of 15 (2.21 g, 6.70 mmol) in
THF (7 mL) was added and the mixture was warmed to
room temperature for 30 min. After 30 min, the reaction
mixture was again cooled to 0 °C, and allyl iodide (0.92
mL, 10.1 mmol) was added slowly with stirring for 8 h.
Finally, the reaction mixture was quenched with sat.
2
4
NaHCO (aq) solution. The organic phase was separated
and the aqueous phase was extracted with EtOAc (3 ×
aldehyde was used without purification. To a 25 mL round-
bottom flask charged with methyltriphenylphosphonium bro-
mide (675 mg, 1.89 mmol) and THF (3.4 mL) at room tem-
perature was slowly added lithium bis(trimethylsilyl)amide
(1.66 mL, 1.76 mmol, 1.06 N in toluene). The mixture was
stirred for 0.5 h at room temperature, then was added to a
solution of crude aldehyde in THF (3.4 mL) at −78 °C in a 25
mL round-bottom flask. The reaction mixture was stirred for
1 h at –78 °C, and was quenched by the addition of saturated
aqueous sodium bicarbonate solution (15.0 mL) followed by
the extraction with ethyl acetate (3 × 15 mL). The combined
organic layers were dried over anhydrous Na SO , filtered,
3
3
0 mL). The combined organic layers were washed with
water, brine, dried over anhydrous Na SO , and con-
2
4
centrated. The residue was purified by flash chromato-
graphy (eluent: EtOAc/Hexanes, 1/1) to provide 20 (2.10
g, 5.70 mmol, 85%) as yellow liquid. R = 0.39 (EtOAc/
f
2
D
5
Hexanes, 1/2); ½αŠ –11.3 (c 1.0, CH Cl ); IR (neat) 2955,
2
2
2
1
930, 2858, 1735, 1707, 1472, 1409, 1368, 1252, 1156,
−
1 1
110, 1006, 837, 777 cm ; H NMR (400 MHz, CDCl ):
3
δ 5.68−5.51 (m, 1 H), 5.14−4.97 (m, 2 H), 4.13 (dd, J =
1
1
1
5.2, 5.5 Hz, 1 H), 3.92 (d, J = 8.3 Hz, 1 H), 3.62 (dd, J =
0.1, 6.8 Hz, 1 H), 3.47−3.40 (m, 1 H), 3.36 (dd, J =
5.1, 7.4 Hz, 1 H), 2.68−2.55 (m, 1 H), 2.31 (dd,
2
4
and concentrated in vacuo. The residue was purified by col-
umn chromatography (eluent: EtOAc/Hexanes, 1/1) to give an
inseparable mixture of 13 and 14 (215 mg, 0.73 mmol, 54%;
J = 16.5, 8.4 Hz, 1 H), 2.20 (dd, J = 16.5, 10.6 Hz, 1 H),
.34 (s, 9 H), 0.76 (s, 9 H), −0.08 (s, 6 H); 13C NMR
100 MHz, CDCl ): δ 174.2, 169.0, 131.9, 118.4, 82.0,
1
ratio 10:1). (The ratio was determined by chemical shifts at
1
(
3.32 and 3.26 ppm in H NMR spectrum) Diene 13: R = 0.27
3
f
6
1
2.5, 61.8, 44.3, 38.1, 33.5, 27.7 (3 C), 25.5 (3 C),
7.9, −5.6, −5.7; HRMS (ESI) m/z: [M + H] Calcd for
(EtOAc/Hexanes, 1/2); IR (neat) 2954, 2928, 2857,
+
1699, 1643, 1471, 1410, 1251, 1116, 1085, 991, 923, 838,
−1
1
C H NO Si 370.2414; Found 370.2417.
776 cm ; H NMR (400 MHz, CDCl ): δ 5.73−5.56
1
9
36
4
3

Y.-F. Liang et al.
(
m, 2 H), 5.28−5.03 (m, 4 H), 4.31 (dd, J = 15.4, 4.5 Hz, 1
(m, 1 H), 5.85−5.76 (m, 1 H), 4.47−4.29 (m, 2 H), 3.76 (dd,
J = 10.2, 4.4 Hz, 1 H), 3.66−3.55 (m, 2 H), 2.49 (dd, J =
17.8, 11.6 Hz, 1 H), 2.43−2.30 (m, 1 H), 2.30−2.20 (dd, J =
H), 4.07 (t, J = 8.0 Hz, 1 H), 3.58−3.51 (m, 2 H), 3.26 (ddd,
J = 15.5, 7.4, 1.0 Hz, 1 H), 2.64−2.53 (m, 1 H), 2.35 (dd, J =
1
1
3
6.5, 8.5 Hz, 1 H), 2.19 (ddd, J = 16.6, 10.5, 0.5 Hz, 1 H),
14.8, 7.6 Hz, 1 H), 0.85 (s, 9 H), 0.02 (s, 6 H); C NMR (100
0
.83 (s, 9 H), 0.00 (s, 3 H), −0.01 (s, 3 H); 13C NMR (100
MHz, CDCl ): δ 177.0, 130.6, 127.8, 71.0, 64.0, 49.7, 46.6,
3
+
MHz, CDCl ): δ 173.7, 133.1, 132.4, 119.0, 117.5, 62.2, 62.2,
36.2, 25.7 (3 C), 18.1, −5.6 (2 C); HRMS (HRFD) m/z: [M]
3
42.9, 39.0, 32.8, 25.7 (3 C), 18.0, −5.6 (2 C);
Calcd for C H NO Si 267.1655; Found 267.1649.
14
25
2
Diene 14
(1 S,7aS)-1-(((tert-Butyldimethylsilyl)oxy)methyl)
hexahydro-3H-pyrrolizin-3-one (21)
Rf = 0.27 (EtOAc/Hexanes, 1/2); 1H NMR (400 MHz,
CDCl ): δ 5.73−5.56 (m, 2 H), 5.28−5.03 (m, 4 H), 4.23
To a two-necked round-bottom flask containing a suspen-
sion of 5% Pd/C (12.0 mg) in EtOAc (1.3 mL) was added
11 (62.0 mg, 0.23 mmol in EtOAc (1.0 mL). The mixture
3
(dd, J = 15.4, 4.5 Hz, 1 H), 4.07 (t, J = 8.0 Hz, 1 H), 3.84
(dd, J = 8.6, 5.0 Hz, 1 H), 3.84−3.80 (m, 1 H), 3.32
(dd, J = 15.5, 7.4, 1 H), 2.64−2.53 (m, 1 H), 2.44 (dd, J =
was stirred vigorously for 3 h under H atmosphere (1 atm),
2
1
0
6.5, 8.5 Hz, 1 H), 2.19 (ddd, J = 16.6, 10.5, 0.5 Hz, 1 H),
then was filtered through a short pad of Celite. The filtrate
was concentrated in vacuo to afford 21 (59.0 mg, 0.22
.83 (s, 9 H), 0.00 (s, 3 H), −0.01 (s, 3 H); 1 C NMR
3
(
6
100 MHz, CDCl ): δ 176.8, 137.2, 132.2, 118.4, 117.7,
mmol, 95%) as colorless oil. R = 0.18 (EtOAc/Hexanes,
3
f
2
3
2.8, 62.2, 40.5, 39.0, 32.6, 25.7 (3 C), 18.0, −5.6 (2 C);
1/1); ½αŠ –26.1 (c 1.0, CH Cl ); IR (neat) 2953, 2929,
D
2
2
+
HRMS (ESI) for a mixture of 13 and 14, m/z: [M + H]
Calcd for C H NO Si 296.2046; Found 296.2039.
2884, 2863, 2857, 1700, 1472, 1419, 1254, 1106, 837,
−
1 1
776 cm ; H NMR (400 MHz, CDCl ): δ 3.98−3.87 (m, 1
1
6
30
2
3
H), 3.60−3.48 (m, 2 H), 3.47−3.35 (m, 1 H), 3.06−2.96
(m, 1 H), 2.74 (dd, J = 16.8, 8.9 Hz, 1 H), 2.58−2.45 (m, 1
H), 2.13 (dd, J = 16.8, 3.2 Hz, 1 H), 2.10−2.01 (m, 1 H),
1.99−1.87 (m, 1 H), 1.78−1.68 (m, 1 H), 1.64−1.51 (m, 1
(
1
(
1
1 S,7aS)-1-(((tert-Butyldimethylsilyl)oxy)methyl)-
,2,5,7a-tetrahydro-3H-pyrroli- zin-3-one (11) and
1 S,7aR)-1-(((tert-butyldimethylsilyl)oxy)methyl)-
,2,5,7a-tetrahydro-3H-pyrrolizin-3-one (12)
1
3
H), 0.81 (s, 9 H), −0.02 (s, 6 H); C NMR (100 MHz,
CDCl ): δ 173.9, 63.8, 62.8, 40.7, 37.6, 36.2, 26.6, 25.6 (3
C), 25.3, 17.9, −5.7 (2 C); HRMS (ESI) m/z: [M + H]
3
+
To a 100 mL round-bottom flask containing a mixture of
dienes 13 and 14 (200 mg, 0.68 mmol) in DCM (68 mL)
was added Grubbs 2nd generation catalyst (29.0 mg, 0.03
mmol). The reaction mixture was refluxed for 4 h, then was
cooled to room temperature and concentrated in vacuo. The
residue was purified by column chromatography (eluent:
EtOAc/Hexanes, 1/1) to give 11 (150 mg, 0.56 mmol, 83%,
as brown liquid) and 12 (13.0 mg, 0.05 mmol, 8%, as brown
Calcd for C H NO Si 270.1889; Found 270.1895.
1
4
28
2
(1 S,7aR)-1-(((tert-Butyldimethylsilyl)oxy)methyl)
hexahydro-3H-pyrrolizin-3-one (25)
Starting with 12 (50.0 mg, 0.19 mmol), and followed the same
procedure as in the synthesis of 21 provided 25 (47.0 mg,
liquid). Lactam 11: R = 0.24 (EtOAc/Hexanes, 1/1);
0.18 mmol, 94%) as colorless oil. R 0.23 (EtOAc/Hexanes,
f
f =
25
23
½
አ−24.4 (c 1.0, CH Cl ); IR (neat) 2953, 2929, 2857,
1/1); ½αŠ + 12.1 (c 1.0, CH Cl ); IR (neat) 2954, 2929,
D
2
2
D
2
2
−1 1
1
8
703, 1471, 1381, 1254, 1197, 1102, 1077, 1004, 938, 837,
2884, 2856, 1698, 1412, 1253, 1113, 837 cm ; H NMR
−
1 1
13 cm ; H NMR (400 MHz, CDCl ): δ 5.96−5.87 (m, 1
(400 MHz, CDCl ): δ 3.65 (dd, J = 10.0, 5.0 Hz, 1 H),
3
3
H), 5.85−5.78 (m, 1 H), 4.80−4.72 (m, 1 H), 4.39−4.26
3.64−3.59 (m, 1 H), 3.55 (dd, J = 10.1, 7.3 Hz, 1 H),
3.51−3.44 (m, 1 H), 2.99 (td, J = 9.1, 2.9 Hz, 1 H), 2.49 (dd,
J = 16.1, 10.8 Hz, 1 H), 2.37 (dd, J = 16.2, 8.4 Hz, 1 H),
2.31−2.19 (m, 1 H), 2.10−1.90 (m, 3 H), 1.44−1.29 (m, 1
(
m, 1 H), 3.68−3.56 (m, 1 H), 3.43 (dd, J = 10.2, 7.7 Hz, 1
H), 3.30 (dd, J = 10.2, 6.0 Hz, 1 H), 2.78 (dd, J = 16.4, 7.8
Hz, 1 H), 2.67 (quintet, J = 7.1, 1 H), 2.11 (d, J = 16.4 Hz,
H), 0.81 (s, 9 H), −0.04 (s, 6 H); 13C NMR (100 MHz,
H), 0.84 (s, 9 H), 0.00 (s, 6 H); C NMR (100 MHz, CDCl3):
13
1
CDCl ): δ 176.7, 128.2, 128.0, 69.5, 62.4, 49.3, 41.2, 37.3,
δ 173.8, 65.2, 64.3, 44.5, 41.0, 37.8, 31.6, 26.8, 25.7 (3 C),
18.1, −5.6 (2 C); HRMS (ESI) m/z: [M + H]+ Calcd for
C H NO Si 270.1889; Found 270.1886.
3
+
2
5.7 (3 C), 18.1, −5.6 (2 C); HRMS (ESI) m/z: [M + H]
Calcd for C H NO Si 268.1733; Found 268.1726.
1
4
26
2
14 28
2
Lactam 12
R = 0.29 (EtOAc/Hexanes, 1/1); ½αŠ + 1.2 (c 1.0, CH Cl );
(1 S,7aS)-1-(Hydroxymethyl)hexahydro-3H-
pyrrolizin-3-one (22)
2
D
2
f
2
2
IR (neat) 2954, 2929, 2857, 1706, 1417, 1387, 1351, 1253,
To 21 (32 mg, 0.12 mmol) and MeCN (0.6 mL) in 5 mL
plastic round-bottom flask at room temperature was added
−1 1
1
113, 1078 cm . H NMR (400 MHz, CDCl ): δ 5.98−5.86
3

Formal syntheses of (−)-isoretronecanol, (+)-laburnine, and a concise enantioselective synthesis of. . .
4
9.4% HF aqueous solution (0.02 mL, 0.36 mmol) then
chromatography (eluent: EtOAc) to afford 27 (61.0 mg,
2
1 +
stirred for 8 h at 40 °C [27]. The reaction was quenched by
the addition of saturated sodium bicarbonate aqueous
solution (10 mL) then extracted with dichloromethane (3 ×
0.22 mmol, 80%). R = 0.54 (EtOAc); ½αŠ
3.2 (c 1.0,
f
D
CH Cl ); IR (neat) 3417, 2953, 2929, 2884, 2857, 1704,
2
2
−
1 1
1419, 1407, 1360, 1253, 1225, 1112, 1079 cm ; H NMR
1
0 mL). The combined organic layers were dried over
(400 MHz, CDCl ): δ 3.93 (d, J = 13.3 Hz, 1 H), 3.82−3.70
3
anhydrous sodium sulfate then filtered and concentrated
in vacuo to afford the crude material. The crude material
was purified by flash chromatography (MeOH/DCM, 1/10)
to provide 22 (17.0 mg, 0.11 mmol, 94%) as colorless oil.
(m, 2 H), 3.64−3.46 (m, 3 H), 2.94 (dd, J = 13.2, 0.6 Hz, 1
H), 2.70−2.57 (m, 1 H), 2.39 (dd, J = 16.4, 10.2 Hz, 1 H),
2.31 (dd, J = 16.2, 9.4 Hz, 1 H), 0.85 (s, 9 H), 0.02 (s, 6 H);
1
3
C NMR (100 MHz, CDCl ): δ 177.1, 64.0, 64.0, 56.1,
3
25
R = 0.30 (DCM/MeOH, 10/1); ½αŠ −63.3 (c 1.0, EtOH);
55.6, 44.4, 38.5, 36.3, 25.7 (3 C), 18.0, −5.5, −5.6; HRMS
f
D
IR (neat) 3395, 2957, 2924, 2886, 2858, 1664, 1455,
(ESI) m/z: [M + H]+ Calcd for C H NO Si 284.1682;
1
4
26
3
−
1 1
1
1
6
422 cm ; H NMR (400 MHz, CDCl ): δ 4.01−3.95 (m,
Found 284.1675.
3
H), 3.68 (dd, J = 10.4, 7.6 Hz, 1 H), 3.59 (dd, J = 10.4,
.4 Hz, 1 H), 3.48−3.38 (m, 1 H), 3.08−2.98 (m, 1 H), 2.79
(+)-Turneforcidine (4)
(
dd, J = 16.8, 8.8 Hz, 1 H), 2.63−2.55 (m, 1 H), 2.23 (dd,
J = 16.8, 3.6 Hz, 1 H), 2.13−2.02 (m, 1 H), 2.02−1.92 (m,
1
To a solution containing 27 (24.0 mg, 0.08 mmol) in THF
(1.5 mL) was slowly added lithium aluminum hydride (15.0
mg, 0.40 mmol) at 0 °C. The reaction mixture was warmed
to room temperature and stirred for 1 h, then was refluxed
for 3 h. The reaction was quenched by the addition of three
drops of 1 N NaOH and two drops of de-ionized water at
0 °C with vigorous stirring for 1 h. The reaction mixture
was filtered through a short pad of celite to remove solid,
and the solid was washed with methanol (3 × 0.5 mL). The
filtrate was dried over anhydrous Na SO and concentrated
H), 1.84−1.75 (m, 2 H), 1.62−1.54 (m, 1 H); 1 C NMR
3
(
2
1
100 MHz, CDCl ): 174.3, 63.8, 61.8, 44.6, 37.7, 36.1,
3
+
5.5, 25.0; HRMS (HRFD) m/z: [M] Calcd for C H NO
8
13
2
55.0946; Found 155.0940.
(1 S,7aR)-1-(Hydroxymethyl) hexahydro-3H-
pyrrolizin-3-one (26)
Starting with 25 (50.0 mg, 0.19 mmol), and followed the
same procedure as in the synthesis of 22 provided 26 (26.0
2
4
in vacuo. The residue was purified by column chromato-
mg, 0.18 mmol, 90%) as colorless oil [28]. R = 0.23
graphy (eluent: DCM/MeOH/NH OH, 5/4/1) to give 4
f
4
25
(
3
DCM/MeOH = 10/1); ½αŠ −15.0 (c 0.5, EtOH); IR (neat)
(9.0 mg, 0.06 mmol, 75%) as pale yellow liquid. R = 0.13
D
f
−
1
1
23
365, 2917, 2923, 2856, 2758, 1624, 1413 cm ; H NMR
(DCM/ MeOH/ NH OH, 5/4/1); ½αŠ + 11.1 (c 1.0, MeOH)
4
D
2
0
(
400 MHz, CDCl ) δ 3.78 (dd, J = 10.5, 5.4 Hz, 1 H), 3.74
{Enantiomer Lit [34]. ½αŠ –10.0 (c, 0.8, MeOH)}; IR
3
D
−
1 1
−
3.63 (m, 2 H), 3.54 (dt, J = 11.6, 7.9 Hz, 1 H),
.11−3.00 (m, 1 H), 2.61−2.45 (m, 2 H), 2.40−2.30 (m, 1
H), 2.16−1.95 (m, 3 H), 1.81−1.71 (br, 1 H), 1.48−1.35
(neat) 3330, 2940, 2930, 1460, 1156, 1110 cm ; H NMR
3
(400 MHz, CDCl ) δ 4.34 (q, J = 4.8 Hz, 1 H), 3.80 (dd,
3
J = 9.8, 4.6 Hz, 1 H), 3.46-3.38 (m, 2 H), 3.30 (dd, J = 8.3,
5.6 Hz, 1 H), 3.17 (t, J = 7.4 Hz, 1 H), 3.05−2.95 (m,1 H),
2.70−2.41 (m, 3 H), 2.10−1.83 (m, 4 H), 1.68−1.53 (m, 1
1
3
(
4
m, 1 H); C NMR (100 MHz, CDCl ) δ 173.8, 65.1, 64.3,
3
+
4.0, 41.1, 38.1, 31.7, 26.9; HRMS (HRFD) m/z: [M]
1
3
Calcd for C H NO 155.0946; Found 155.0940.
H); C NMR (100 MHz, CDCl ) δ 74.2, 71.5, 65.3, 55.0,
5
8
13
2
3
+
2.1, 40.2, 35.4, 30.9; HRMS (HRFI) m/z: [M] Calcd for
(1aS,6S,6aS,6bR)-6-(((tert-Butyldimethylsilyl)oxy)
C H NO 157.1103; Found 157.1097.
8 15 2
methyl)hexahydro-4H-oxireno[2,3-a]-pyrrolizin-4-
one (27)
Acknowledgements We thank the Ministry of Science and Technol-
ogy, Taiwan for financial support (MOST 106-2113-M-007-003).
To a stirred solution of olefin 12 (72.0 mg, 0.27 mmol) was
added 1,1,1-trifluoroacetone (0.24 mL, 2.69 mmol) in a
mixture of acetonitrile (2.70 mL) and EDTA (1.80 mL,
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
−
4
1
0
M in water) at 0 °C. A premixed mixture of oxone
(
0.83 g, 1.35 mmol) and Na CO (0.17 g, 2.02 mmol) was
2
3
added to the above mixture in three portions over 30 min.
After being stirred for an additional 0.5 h at 0 °C, the
reaction mixture was diluted with water, and the aqueous
phase was extracted with dichloromethane (3 × 10 mL). The
combined organic layers were dried over anhydrous
Na SO , filtered, and concentrated in vacuo to afford the
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jurisdictional claims in published maps and institutional affiliations.
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