Proline Ester Enolate Claisen Rearrangement and Formal Total Synthesis of (-)-Cephalotaxine

Article abstract of DOI:10.1021/acs.joc.9b00933

A concise formal total synthesis of (-)-cephalotaxine was achieved via an ester enolate Claisen rearrangement (EECR). A series of EECRs of proline allyl esters were examined to obtain the desired relative stereochemistry of an azaspiranic tetracyclic backbone. An unexpected reversal or low diastereoselectivity of (Z)-cinnamyl ester was observed. The diastereoselectivity was controlled by substitution patterns of a styrene region. This result represents a useful guide in aiding the prediction of stereochemical outcome of EECR of α-amino allylic esters.

Full text of DOI:10.1021/acs.joc.9b00933

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Article
Proline Ester Enolate Claisen Rearrangement
and Formal Total Synthesis of (–)-Cephalotaxine
Hongjun Jeon, Yundong Chung, and Sanghee Kim
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00933 • Publication Date (Web): 04 Jun 2019
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Proline Ester Enolate Claisen Rearrangement and Formal To-
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tal Synthesis of (–)-Cephalotaxine
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Hongjun Jeon, Yundong Chung, and Sanghee Kim*
College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 08826 (Republic of Korea)
ABSTRACT: A concise formal total synthesis of (–)-cephalotaxine was achieved via an ester enolate Claisen rearrangement (EECR).
A series of EECRs of proline allyl esters were examined to obtain the desired relative stereochemistry of an azaspiranic tetracyclic
backbone. An unexpected reversal or low diastereoselectivity of (Z)-cinnamyl ester was observed. The diastereoselectivity was
controlled by substitution patterns of a styrene region. This result represents a useful guide in aiding the prediction of stereochemical
outcome of EECR of -amino allylic esters.
We herein report the study aimed to understand the factors de-
termining the stereochemistry of the EECR of proline cinnamyl
INTRODUCTION
The ester enolate Claisen rearrangement (EECR) of -amino
acids has been utilized as a powerful strategy for the synthesis
of complex nitrogen-containing molecules because this
transformation can deliver densely functionalized amino acids
ester and its utilization in the asymmetric total synthesis of
Cephalotaxus alkaloids.
1
with a defined stereochemistry. Two types of EECRs have
been widely used (eq 1, Figure 1): a silyl ketene acetal
2
intermediate-involved Ireland–Claisen rearrangement and a
3
chelate-enolate-mediated Kazmaier’s Claisen rearrangement.
These EECRs have been applied to many acyclic amino acids.
However, relatively less attention has been paid to the cyclic
amino acids such as proline and pipecolic acids, which have a
secondary -amino group (eq 2).
Figure 2. C-substituted proline-containing natural alkaloids in-
cluding Cephalotaxus alkaloids (1–3).
RESULTS AND DISCUSSION
Over the past decades, Cephalotaxus alkaloids have proven to
display useful medicinal properties, especially in cancer. More
than 70 compounds have been identified from natural sources
7
7
d
so far. (–)-Cephalotaxine (1, Figure 2) is the first member of
8
this family and homoharringtonine (2) is a representative
member of this family. Homoharringtonine, also known as
omacetaxine mepesuccinate, was approved in 2012 as a drug
Figure 1. Ester enolate Claisen rearrangement of acyclic and cyclic
-amino acids. PG = protecting group; Si-X = silyl halide; MX
n
=
metal salts.
9
for the treatment of chronic myelogenous leukemia. Due to
their biological activities and intriguing structural features,
Cephalotaxus alkaloids have been attractive synthetic target for
the last three decades.
C-substituted proline analogues are of special interest given4
the vital role of proline in the secondary structures of peptides.
5d,10
In addition, their full or modified structural motifs are found
within a number of complex natural products as depicted in Fig-
An interesting structural feature of the family of
Cephalotaxus alkaloids is an azaspiranic tetracyclic backbone.
We envisioned that the backbone structure of this family, such
as compound I in Scheme 1, could be derived from the product
of EECR of proline esters. Disconnection of the B ring of inter-
mediate I via intramolecular N-alkylation and retrosynthesis of
5
ure 2. In this regard, we and other groups have previously pre-
pared C-substituted proline derivatives by employing EECR
6
of proline allyl esters. However, some ambiguity remains in
the prediction of stereochemical outcomes of this EECR be-
cause proline is a cyclic amino acid with a secondary amine.
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a cyclopentene D ring by using a ring-closing metathesis
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(RCM) reaction provided compound II. Further analysis sug-
gested that intermediate II could be readily obtained from the
,-unsaturated carbonyl compound III, which has an erythro
relative stereochemical relationship between two stereocenters.
To obtain the erythro relative stereochemical relationship of
III, Ireland–Claisen rearrangement of either olefin-geometry
combination of (Z)-allylic ester/(Z)-silyl ketene acetal (path a)
or (E)-allylic ester/(E)-silyl ketene acetal (path b) are possible
if the rearrangement proceeds through classic chair-like
transition structures. In general, the EECR of (E)-allylic ester
affords the product with better diastereoselectivity than that of
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(Z)- allylic ester. However, we anticipated that path a, which
aReagents and conditions: (a) TrtCl, Et
h, 96%; (b) 4, Pd(PPh Cl , CuI, Et N, THF, rt, 12 h, 95%; (c) P2-
Ni, H (g), ethylenediamine, EtOH, rt, 16 h, 78%; (d) Boc-L-pro-
line, DCC, DMAP, CH Cl , rt, 1 h, 99%. DMAP = 4-(dimethyla-
3
2 2
N, DMAP, CH Cl , rt, 4
utilized (Z)-allylic ester substrate, would be a more viable route
to access the key intermediate III because our previous study
showed that proline ester compounds possessing an exocyclic
N-Boc group led to the selective formation of the (Z)-silyl
3
)
2
2
3
2
2
2
mino)pyridine; DCC = N,N′-dicyclohexylcarbodiimide.
6
e
ketene acetal.
With (Z)-allylic ester 9 in hand, we investigated EECR with
the aim to obtain the erythro rearranged product 10 (Table 1).
We first examined Kazmaier–Claisen rearrangement conditions
Scheme 1. Initial Retrosynthetic Analysis of Cephalotaxus
Family and Convergent Stereochemical Outcome of EECR
a
Products from (Z)- and (E)-Allylic Ester Substrates
(entries 1 and 2). Under standard conditions, the reactions failed
to provide the rearrangement products. The starting material
was recovered or decomposed. On the other hand, the reactions
of 9 under Ireland–Claisen rearrangement conditions afforded
the rearrangement product. When compound 9 was exposed to
LiHMDS in THF in the presence of TMSCl, the rearrangement
product was formed albeit in low yield (entry 3). Unfortunately,
no diastereoselectivity was obtained under this condition.
Changing the solvent from THF to toluene significantly in-
creased the yield, but did not affect the diastereoselectivity (en-
try 4). Use of NaHMDS as a base led to a similar yield and se-
lectivity (entry 5). When TBSCl was used instead of TMSCl,
the undesired threo product 11 was obtained as the only isomer,
albeit in very low yield (entry 6). This result indicated that the
larger TBS group forced the reaction to proceed via a boat-like
transition state (TS) by increasing the steric stress between silyl
(Si) and aryl group (Ar) in the chair-like TS (path a, Scheme 1).
In addition, it suggested that the low diastereoselectivity arose
from the steric crowding in the chair-like TS.
aPG = protecting group. Si = silyl group.
Table 1. Ester Enolate Claisen Rearrangement of (Z)-Allylic
a
ester 9
The EECR substrate, (Z)-allylic ester 9, was readily prepared
by a sequence of reactions shown in Scheme 2. The commer-
cially available, enantiomerically pure (R)-3-butyn-2-ol (4,
>
98% ee) was employed as the chiral source. The synthesis
commenced with hydroxyl group protection of known aryl io-
1
1
dide 5. Subsequent Sonogashira coupling with 4 gave propar-
gyl alcohol 7. The cis-reduction of 7 was performed with P2-Ni
to yield (Z)-allylic alcohol 8, which underwent coupling reac-
tion with Boc-L-proline to produce allylic ester 9 in high overall
yield.
b
c
entry
base
additive
solvent
THF
yield (%)
dr
-
d
1
2
3
4
5
6
LiHMDS
LDA
Al(Oi-Pr)
3
0
d
ZnCl
2
THF
0
-
Scheme 2. Synthesis of EECR Substrate (Z)-Allylic Ester 9a
LiHMDS
LiHMDS
NaHMDS
LiHMDS
TMSCl
TMSCl
TMSCl
TBSCl
THF
32
88
87
15
1:1
1:1
1:1
Toluene
Toluene
THF
e
0:1
aReagents and conditions: substrate (0.1 mmol), base (0.3
mmol), additive (0.3 mmol) and solvent (0.1 M); –78 °C to rt; 3 h.
b
c
Isolated combined yield of the two diastereomers. The diastereo-
1
d
meric ratio was determined by H NMR analysis. Additive (0.2
mmol) was used. []
e
20
D
3
= +8.1 (c 1.0, CHCl ).
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After failure to selectively obtain the desired erythro product
10 from (Z)-allylic ester 9 (path a, Scheme 1), the EECR of (E)-
allylic ester was examined as an alternative route (path b). As
mentioned above, this route required the formation of (E)-silyl
ketene acetal intermediate. Substrate (E)-allylic ester 13 was
readily prepared from propargyl alcohol 7 (Scheme 3). Reduc-
tion of the triple bond in 7 with LiAlH stereoselectively pro-
4
vided the (E)-allylic alcohol 12. Subsequent coupling with Boc-
L-proline provided allylic ester 13.
Table 2. Ester Enolate Claisen Rearrangement of (E)-Allylic
Ester 13
a
1
2
3
4
5
6
7
8
9
1
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5
5
5
5
6
b
c
entry
base
LiHMDS
LDA
additive
TMSCl
TMSCl
TBSCl
yield (%)
dr
Scheme 3. Synthesis of EECR Substrates (E)-Allylic Ester
a
d
1
3 and 15
1
2
3
4
84
43
0
0:1
0
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0
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9
0
1:5
LDA
-
-
Et
3
N
TMSOTf
0
aReagents and conditions: substrate (0.1 mmol), base (0.3
mmol), additive (0.3 mmol) and THF (0.1 M); –78 °C to rt; 3 h.
b
c
aReagents and conditions: (a) LiAlH
Isolated combined yield of the two diastereomers. The diastereo-
4
, THF, 0 °C, 1 h, 93%; (b)
, rt, 1 h, 95% for 13; (c) PMB-
L-proline (14), EDC∙HCl, DMAP, CH Cl , rt, 20 h, 41% for 15.
1
d
20
Boc-L-proline, DCC, DMAP, CH
2
Cl
2
meric ratio was determined by H NMR analysis. []
1.0, CHCl ).
D
= –7.6 (c
2
2
3
EDC∙HCl = N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hy-
drochloride; DMAP = 4-(dimethylamino)pyridine.
We also examined the EECR of (E)-allylic ester 15 having an
N-benzyl type protecting group. There was no precedent for the
EECR of the cyclic amino acid having a tertiary -amino group.
Substrate 15 was prepared with the (E)-allylic alcohol 12 and
N-PMB-protected proline 14 (Scheme 3). Unfortunately, the
EECR product was not produced under several reaction condi-
tions including varying reaction temperature, base and solvent.
As predicted, the typical reaction conditions for the (Z)-silyl
ketene acetal formation from the exocyclic N-Boc proline ester
compounds, LiHMDS and TMSCl in THF, produced the un-
wanted threo product 11 as an only observable product in good
yield (entry 1, Table 2). The spectrum data of both threo prod-
ucts from (Z)-allylic ester 9 and (E)-allylic ester 13 are in good
agreement, but they showed different signs of optical rotation.
As the geometry of the ketene acetals would be the same for
both rearrangement intermediates, the respective formation of
enantiomeric isomers implies that the reactions with (E)-allylic
ester 13 proceed via a chair-like TS to afford the threo product
ent-11, while the reactions with (Z)-allylic ester 9 proceed via a
boat-like TS to afford 11 as shown in Scheme 4.
Since attempts to selectively generate (E)-silyl ketene acetal
intermediate have failed, the remaining choice was to relieve
the steric stress in the chair-like TS of (Z)-allylic ester substrate
9
proceeding through (Z)-silyl ketene acetal. The side-chain-
truncated substrate 19 was designed for this purpose (Scheme
). Compound 19 was readily prepared from the known iodo-
5
12
benzene 16 in a similar way to compound 9. To our delight,
the EECR of 19 with LiHMDS and TMSCl gave erythro prod-
uct 20 as a major product in a diastereomeric ratio of 6:1 in 97%
Scheme 4. Transition States and Rearrangement Products
from (Z)-Silyl Ketene Acetal Intermediates of 9 and 13
combined yield. In the presence of Ti(Oi-Pr) as a Lewis acid,
4
the diastereomeric ratio was improved to 8:1 (92% combined
1
3
yield). The enantiomeric purity of 20 was determined to be
8% ee by chiral HPLC and the absolute stereochemistry was
9
later confirmed by the total synthesis of the natural product
from 20 (vide infra).
Scheme 5. Synthesis of Side-Chain-Truncated Substrate 19
a
and its EECR
We examined several other reaction conditions to switch the
geometry of the proline ester enolate. The EECR of (E)-allylic
ester 13 was attempted using LDA, the well-known strong
amine base generally used for the formation of (E)-enolates.
The reaction with LDA provided the desired erythro product 10,
but still produced threo product 11 as a major product in a ratio
of 1:5 (entry 2, Table 2). Substitution of TMSCl with TBSCl
was detrimental to the reaction with LDA (entry 3). When a ter-
tiary amine/silyl triflate system was used for the formation of
silyl ketene acetal, no rearranged products were formed, and
several unidentified side-products were observed (entry 4).
aReagents and conditions: (a) 4 (>98% ee), Pd(PPh
N, THF, rt, 1 h, 96%; (b) P2-Ni, H (g), ethylenediamine, EtOH,
rt, 2 h, 90%; (c) Boc-L-proline, EDC∙HCl, DMAP, CH Cl , rt, 2 h,
3 2 2
) Cl , CuI,
Et
3
2
2
2
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N-(3-dimethylaminopropyl)-N′-ethylcar-
four steps via the proposed structure of cephalezomine G (26)
Page 4 of 11
1
7
9
7%. EDC∙HCl
=
1
8
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
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bodiimide hydrochloride; DMAP = 4-(dimethylamino)pyridine.
by Mori and coworkers. The NMR spectra of obtained I were
identical to those reported, and the optical rotation sign and
The above stereochemical outcome results suggest that the
ortho-substituent of the aromatic ring plays a key stereocontrol-
ling role in ECRR. In general, ortho-substituted styrene exists
2
0
value obtained were also in good agreement {[]
D
= –206.7 (c
) for 97 ee%}.
In addition, the spectral data of 26, obtained by dihydroxylation
1
9
22
1.2, CHCl
3
), lit. []
D
= –196.7 (c 1.0, CHCl
3
1
4
in a nonplanar conformation to relieve the allylic strain. The
aromatic ring of the nonplanar cis-styrene system of 9 could
cause the severe unfavorable steric interactions with the si-
lyloxy group in the chair-like TS, while no such interaction is
expected in the energetically less-favored boat-like TS, which
produces threo isomer (Scheme 6). This assumption is strength-
ened when considering the shifted diastereoselectivity toward
the threo product by increasing the bulkiness of the silyl moiety
2
0
4
of I with OsO , closely matched those reported by Mori. Thus,
we have achieved the formal asymmetric synthesis of (–)-ceph-
alotaxine (1).
Scheme 7. Completion of the Formal Total Synthesis of (–)-
a
Cephalotaxine
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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0
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0
1
2
3
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
entry 3 or 4 vs. 6, Table 1). When compared to substrate 9,
ortho-substituent free substrate 19 would have a more planar
styrene moiety, and the unfavorable steric interactions in the
chair-like TS would be alleviated to give erythro isomer 20 as
a major product.
Scheme 6. Stereocontrolling Role of the ortho Ring Substit-
uent (R) in EECR of Styrenyl Substrates
a
aR = -CH
CH OTrt; Si = silyl group.
2 2
Efforts were next directed toward the construction of a tetra-
cycle system of Cephalotaxus alkaloids by the appropriate com-
bination of functional groups of the desired rearrangement
product 20. The initial retrosynthetic strategy was revised. In-
stead of the initial plan for constructing a 7-membered benzaze-
pine ring via intramolecular N-alkylation, intermolecular N-al-
kylation followed by an intramolecular Friedel-Crafts reaction
was devised. The successful route to intermediate I from
Claisen rearrangement product 20 began with methylation of
the carboxylic acid moiety (Scheme 7). The following sequence
involving Boc-removal with TFA and reductive amination with
aReagents and conditions: (a) i) MeI, K
2
3
CO , acetone, reflux, 1
h; ii) TFA, CH
NaBH(OAc) , CH
acid, CH Cl , rt, 18 h then, t-BuNH
LiAlH , THF, 0 °C, 1 h, 97%; (d) methanesulfonyl chloride, Et
CH Cl , 0 °C, 5 min; (e) vinylmagnesium bromide, CuCN, THF, 0
C, 1 h, 72% for 2 steps; (f) Grubbs catalyst 2nd generation, CSA,
CH Cl , reflux, 3 h, 72%. (g) OsO , 4-methylmorpholine N-oxide,
TFA, acetone/H O, rt, 16 h, 75%. TFA = trifluoroacetic acid.
2
Cl
2
, rt, 2 h; iii) 2,2-dimethoxyacetaldehyde,
, rt, 2 h, 92% for 3 steps; (b) methanesulfonic
BH , 0 °C, 10 min, 51%; (c)
N,
3
2
Cl
2
2
2
2
3
4
3
2
2
°
2
2
4
2
CONCLUSION
We have examined proline ester enolate Claisen rearrangement
and achieved the formal total synthesis of (–)-cephalotaxine in
6 linear steps from commercially available starting material.
2
,2-dimethoxyacetaldehyde yielded 21 in 92% yield for three
steps without purification of any synthetic intermediate. Treat-
ment of 21 with MsOH affected the intramolecular Friedel-
Crafts reaction. Direct one-pot reduction of the resulting
Friedel-Crafts adduct with borane tert-butylamine complex pro-
1
The diastereoselectivity of EECR was shifted depending on the
ortho-substitution pattern of the aromatic ring of proline (Z)-
cinnamyl ester substrate. This type of stereocontrolling effect is
the first example discovered in the class of [3,3]-sigmatropic
rearrangement of (Z)-allylic ester. This phenomenon can be ex-
plained in terms of the nonplanarity of ortho-substituted sty-
rene. By employing ortho-side-chain-truncated substrate,
which has a more planar conformation of the styrenyl moiety,
we obtained the desired stereoisomer in high selectivity, from
which the asymmetric synthesis of cephalotaxine was accom-
plished in a concise manner. A computational study of the ob-
served stereocontrolling effect and synthesis of other Cephalo-
taxus alkaloids with this strategy will be reported in due course.
1
5
vided tricyclic compound 22.
The formation of the cyclopentene ring of I was achieved us-
ing an ester group and olefin moiety. To this end, methyl ester
22 was reduced to -amino alcohol 23 by LiAlH . Treatment of
4
amino alcohol 19 with methanesulfonyl chloride provided the
aziridinium 24 very quickly even at low temperatures. The
crude aziridinium 24 was treated with in situ generated vinyl
6
e,16
cuprate to provide diene 25 in 72% yield for two steps.
The
RCM reaction of 25 was performed with Grubbs-II catalyst (5
mol%) to construct the azaspirocycle system of intermediate I.
The addition of camphorsulfonic acid was crucial for the suc-
cess of this RCM reaction. The azaspiranic tetracyclic com-
pound I was previously transformed to (–)-cephalotaxine (1) in
10d
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EXPERIMENTAL SECTION
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168 L) was added to the reaction mixture, which was stirred for
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
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2
2
2
2
2
2
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an additional 10 min. Then, propargyl alcohol 7 (1.0 equiv, 5.0
mmol, 2.4 g) in EtOH (13 mL) was added. After 16 h, the reaction
mixture was concentrated in vacuo, diluted with EtOAc, and sub-
jected to a Celite filter. The filtrate was concentrated in vacuo
again. The crude product was purified by flash chromatography on
General Information. All chemicals used herein were of rea-
gent grade and were used as received. All reactions were performed
under an inert atmosphere consisting of dry nitrogen using distilled
dry solvents. The reactions were monitored by thin-layer chroma-
tography (TLC) performed on silica gel 60 F254 TLC plates. The
synthesized products were purified by flash column chromatog-
raphy on silica gel 60 (40–63 m, 230–400 mesh, Merck). Melting
points were measured on a Büchi B-545 apparatus (Büchi Labor-
technik AG, Postfach, Switzerland). Optical rotations were meas-
ured on a JASCO P-2000 polarimeter (Hachioji, Tokyo, Japan) us-
ing a 10 cm cell, and IR spectra were acquired using an Agilent
silica gel (hexane/EtOAc, 3:1) to yield (Z)-allylic alcohol 8 (1.9 g,
20
7
8%) as a yellow oil. R
f
= 0.3 (hexane/EtOAc, 4:1); []
); H NMR (500 MHz, CDCl
7.24–7.27 (m, 5H), 7.19–7.22 (m, 4H), 6.68 (s, 1H), 6.63 (s, 1H),
D
= –7.6
1
(
c 0.20, CHCl
3
3
) δ 7.35–7.36 (m, 6H),
6
1
.41 (d, J = 11.3 Hz, 1H), 5.90 (s, 2H), 5.56 (dd, J = 11.3, 9.3 Hz,
H), 4.42 (app dd, J = 9.0, 6.3 Hz, 1H), 3.11–3.15 (m, 2H), 2.82 (t,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
1
J = 7.1 Hz, 2H), 1.16 (d, J = 6.3 Hz, 3H); C{ H} NMR (125 MHz,
CDCl ) δ 146.8, 145.7, 144.1 (3C), 135.7, 130.9, 129.0, 128.6 (6C),
28.5, 127.7 (6C), 126.9 (3C), 110.4, 109.5, 100.9, 86.6, 64.2, 64.1,
3
5
500a FTIR (Agilent, USA). NMR spectra were obtained on a
JNM-ECZ400S/L1 (JEOL, Tokyo, Japan), a Bruker AVANCE 500
Bruker, Rheinstetten, Germany), a JEOL JNM-ECA600 (JEOL,
1
3
4.1, 23.4; IR (neat) ṽ = 3353, 3058, 2965, 2874, 1502, 1482, 1035,
(
-
1
+
702 cm ; HRMS (FAB): calcd. for C32
found: 478.2147.
H
30
O
4
: 478.2144 ([M] ),
Tokyo, Japan), or an 800-MHz Bruker Avance III HD spectrometer
with a 5-mm triple resonance inverse (TCI) CryoProbe (Bruker Bi-
oSpin, Germany). High resolution mass spectra were obtained with
a JEOL JMS-700 double focusing magnetic sector mass spectrom-
eter (JEOL, Tokyo, Japan) operated in the FAB mode.
1
-(tert-Butyl)
2-((R,Z)-4-(6-(2-
(
trityloxy)ethyl)benzo[d][1,3]dioxol-5-yl)but-3-en-2-yl) (S)-pyr-
rolidine-1,2-dicarboxylate (9). To a solution of (Z)-allylic alcohol
(1.0 equiv, 3.8 mmol, 1.8 g) in CH Cl (38 mL) were added N-
8
2
2
5
-Iodo-6-(2-(trityloxy)ethyl)benzo[d][1,3]dioxole (6). To a so-
Boc-L-proline (2.0 equiv, 7.5 mmol, 1.6 g), N,N'-dicyclohexylcar-
bodiimide (2.2 equiv, 8.3 mmol, 1.7 g), and 4-(dimethylamino)pyr-
idine (10 mol%, 0.38 mmol, 46 mg) at room temperature. The re-
action mixture was stirred for 1 h at room temperature, subjected to
a Celite filter, and washed with EtOAc. The filtrate was concen-
trated in vacuo and purified by flash chromatography on silica gel
lution of alcohol 5 (1.0 equiv, 17 mmol, 5.1 g) were added trityl
chloride (1.8 equiv, 31.3 mmol, 8.7 g), triethylamine (1.8 equiv, 31
mmol, 4.4 mL) and 4-(dimethylamino)pyridine (0.2 equiv, 3.5
mmol, 424 mg) at room temperature. The reaction mixture was
stirred for 4 h at room temperature and poured to water, extracted
with EtOAc, washed with brine, dried over MgSO , and concen-
4
trated in vacuo. The crude product was purified by flash chroma-
tography on silica gel (hexane/EtOAc, 15:1) to yield compound 6
f
(hexane/EtOAc, 4:1) to yield 9 (2.5 g, 99%) as a white foam. R =
20
1
0
.3 (hexane/EtOAc, 4:1); []
D
= –69.5 (c 0.55, CHCl
3
3
); H NMR
(
major rotamer, 800 MHz, CDCl
) δ 7.34–7.35 (dd, J = 8.2, 1.0 Hz,
(8.9 g, 96%) as a white solid. R
f
= 0.3 (hexane/EtOAc, 15:1); mp
29 °C; H NMR (800 MHz, CDCl ) δ 7.36–7.39 (m, 6H), 7.13–
.27 (m, 6H), 7.18–7.22 (m, 4H), 6.73 (s, 1H), 5.91 (s, 2H), 3.23 (t,
1
6H), 7.23–7.25 (m, 6H), 7.18–7.20 (m, 3H), 6.70 (s, 1H), 6.62 (s,
1H), 6.45 (d, J = 10.2 Hz, 1H), 5.89 (s, 2H), 5.52–5.58 (m, 2H),
4.18 (dd, J = 8.8, 3.6 Hz, 1H), 3.52–3.54 (m, 1H), 3.41–3.44 (m,
1
2
1
7
3
1
3
1
J = 6.9 Hz, 2H), 2.95 (t, J = 6.9 Hz, 1H); C{ H} NMR (200 MHz,
CDCl ) δ 148.2, 146.9, 144.1, 135.0, 128.7, 127.7, 126.9, 118.4,
10.4, 101.5, 88.0, 86.7, 63.3, 41.1; IR (neat) ṽ = 3056, 2926, 1468,
H), 3.11–3.17 (m, 2H), 2.77–2.84 (m, 1H), 2.71–2.75 (m, 1H),
.17–2.21 (m, 1H), 1.87–1.93 (m, 3H), 1.39 (s, 9H), 1.11 (d, J =
3
1
1
5
13
1
-
1
3
5.8 Hz, 3H); C{ H} NMR (major rotamer, 200 MHz, CDCl ) δ
220, 1043, 930 cm ; HRMS (FAB): m/z calcd. for C28
H
23
O
3
I:
+
172.1, 153.9, 147.0, 145.9, 144.1 (3C), 131.2, 130.9, 130.2, 128.6
(7C), 127.7 (6C), 126.9 (3C), 110.2, 109.0, 100.9, 86.7, 79.8, 68.4,
64.1, 59.2, 46.3, 33.9, 30.9, 28.4 (3C), 23.5, 20.7; IR (neat) ṽ =
34.0692 ([M] ), found: 534.0690.
(
R)-4-(6-(2-(Trityloxy)ethyl)benzo[d][1,3]dioxol-5-yl)but-3-
yn-2-ol (7). To a solution of compound 6 (1.0 equiv, 15 mmol, 8.0
g) in THF/Et N (1:1, 75 mL) were added (R)-(+)-3-butyn-2-ol (4,
-
1
2
976, 2876, 1740, 1691, 1483, 1396, 1159, 1033, 907 cm ; HRMS
3
+
(FAB): calcd. for C42
7
H45NO : 675.3196 ([M] ), found: 675.3203.
1.2 equiv, 18 mmol, 1.4 mL) and copper iodide (10 mol%, 1.5
mmol, 286 mg), followed by bubbling nitrogen gas at room tem-
perature for 20 min. Bis(triphenylphosphine)palladium(II) dichlo-
ride (5 mol%, 0.75 mmol, 526 mg) was subsequently added to the
reaction pot, and the reaction mixture was stirred at room tempera-
ture for 12 h, followed by filtration through a pad of Celite and
concentration of the filtrate in vacuo. The dark brown crude product
was purified by flash chromatography on silica gel (hexane/EtOAc,
Representative procedure for ester enolate Claisen rear-
rangement. To a solution of a substrate (1.0 equiv) in anhydrous
solvent was added silyl halide (3.0 equiv) and the mixture was
cooled to –78 °C followed by the addition of a base (3.0 equiv).
The reaction was allowed to slowly warm to room temperature for
a period of 3 h, recooled to 0 °C, and quenched by aqueous satu-
rated NH
4
Cl. The resulting solution was poured to water, extracted
, and con-
twice with EtOAc, washed with brine, dried over MgSO
4
4
R
:1) to yield propargyl alcohol 7 (6.8 g, 95%) as a light yellow oil.
2
0
1
centrated in vacuo. The crude product was purified by flash chro-
matography on silica gel (hexane/EtOAc, 3:1 to hex-
ane/EtOAc/AcOH, 3:1:0.04) to yield the erythro and threo prod-
ucts as an inseparable mixture.
f
= 0.2 (hexane/EtOAc, 3:1); []
) δ 7.35–7.38 (m, 6H), 7.23–7.26 (m, 6H),
.18–7.21 (m, 3H), 6.82 (s, 1H), 6.67 (s, 1H), 5.91 (s, 2H), 4.62–
.66 (m, 1H), 3.26 (t, J = 7.0 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 1.72
D
3
= +38.4 (c 0.85, CHCl ); H
NMR (800 MHz, CDCl
3
7
4
(
d, J = 5.4 Hz, 1H), 1.44 (d, J = 6.6 Hz, 3H); 13C{ H} NMR (200
) δ 147.9, 145.7, 144.2 (3C), 136.4, 128.7 (6C), 127.7
(6C), 126.9 (3C), 115.1, 111.5, 110.0, 101.2, 93.1, 86.5, 82.7, 63.8,
1
1-(tert-Butoxycarbonyl)-2-((S,E)-1-(6-(2-
(
trityloxy)ethyl)benzo[d][1,3]dioxol-5-yl)but-2-en-1-yl)pyrroli-
dine-2-carboxylic acid (11). A white foam; R = 0.3 (hex-
ane/EtOAc/AcOH, 3:1:0.04); H NMR (800 MHz, CDCl ) δ 7.34–
7.35 (dd, J = 8.2, 1.0 Hz, 6H), 7.23–7.25 (m, 6H), 7.18–7.20 (m,
H), 6.70 (s, 1H), 6.62 (s, 1H), 6.45 (d, J = 10.2 Hz, 1H), 5.89 (s,
MHz, CDCl
3
f
1
3
5
9
8.8, 35.1, 24.4; IR (neat) ṽ = 3559, 2875, 1481, 1467, 1211, 1055,
-
1
+
28 4
22 cm ; HRMS (FAB): m/z calcd. for C32H O : 476.1988 ([M] ),
3
found: 476.1987.
R,Z)-4-(6-(2-(Trityloxy)ethyl)benzo[d][1,3]dioxol-5-yl)but-3-
2H), 5.52–5.58 (m, 2H), 4.18 (dd, J = 8.8, 3.6 Hz, 1H), 3.52–3.54
(m, 1H), 3.41–3.44 (m, 1H), 3.11–3.17 (m, 2H), 2.71–2.82 (m, 2H),
(
en-2-ol (8). Sodium borohydride (0.8 equiv, 4.0 mmol, 153 mg)
was added portionwise to a solution of nickel(II) acetate tetrahy-
drate (0.4 equiv, 2.0 mmol, 501 mg) in EtOH (12 mL) to give a
colloidal black precipitate, simultaneously. After stirring for 30
min at room temperature, ethylenediamine (0.5 equiv, 2.5 mmol,
2
5
1
1
5
.17–2.21 (m, 1H), 1.87–1.93 (m, 3H), 1.39 (s, 9H), 1.11 (d, J =
1
3
1
3
.8 Hz, 3H); C{ H} NMR (100 MHz, CDCl ) δ 173.3, 158.2,
46.1, 145.9, 144.4 (3C), 132.3, 130.8, 129.3, 129.1, 128.8 (6C),
28.0 (6C), 127.1 (3C), 111.4, 108.0, 101.1, 86.9, 82.9, 75.4, 64.9,
0.2, 45.8, 34.2, 32.8, 28.4 (3C), 22.5, 18.1; IR (neat) ṽ = 2976,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 11
-
1
2
876, 1740, 1691, 1483, 1396, 1159, 1033, 907 cm ; HRMS
MHz, CD
3
OD) δ 173.5, 163.2, 134.0 (2C), 124.4, 116.3 (2C), 69.6,
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(FAB): calcd. for C42
7
H45NO : 675.3196 ([M] ), found: 675.3203.
R,E)-4-(6-(2-(Trityloxy)ethyl)benzo[d][1,3]dioxol-5-yl)but-3-
en-2-ol (12). To a solution of propargyl alcohol 7 (1.0 equiv, 2.1
mmol, 1.0 g) in THF was added 1 M solution of lithium aluminum
hydride in THF (1.2 equiv, 2.5 mmol, 2.5 mL) at 0 °C and the re-
action mixture was stirred for 2 h at the same temperature. After
59.8, 56.6, 55.9, 30.5, 24.5; IR (neat) ṽ = 1684, 1614, 1517, 1255,
1200, 1180, 1130 cm ; HRMS (FAB): calcd. for C13
236.1287 ([M+H] ), found: 236.1292.
(R,E)-4-(6-(2-(Trityloxy)ethyl)benzo[d][1,3]dioxol-5-yl)but-
3-en-2-yl (4-methoxybenzyl)-L-prolinate (15). To a solution of N-
PMB proline (14, 2 equiv, 393 mg, 1.7 mmol) in CH Cl (8 mL)
-
1
(
H18NO
3
:
+
2
2
reaction completion, H
2
O (0.2 mL), 1 N NaOH (0.2 mL), and H
2
O
were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hy-
drochloride (2 equiv, 321 mg, 1.7 mmol) and 4-(dimethyla-
mino)pyridine (0.3 equiv, 31 mg, 0.25 mmol) at room temperature.
After 10 min, (E)-allyl alcohol 12 (1 equiv, 400 mg, 0.84 mmol)
was added to the reaction mixture. The reaction was allowed to stir
at the same temperature for 20 h, poured into water and extracted
(0.6 mL) was slowly added to the reaction pot at 0 °C in sequence,
and then the reaction mixture was vigorously stirred at room tem-
perature for 30 min. The suspension was filtered through a pad of
Celite and the filtrate was concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (hexane/EtOAc,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
:1) to yield (E)-allylic alcohol 12 (904 mg, 93%) as a colorless oil.
with CH
2 2
Cl . The organic layer was washed with brine, dried over
20
1
R
f
= 0.2 (hexane/EtOAc, 4:1); []
) δ 7.36–7.39 (m, 6H), 7.23–7.28 (m, 6H),
7.19–7.23 (m, 3H), 6.93 (s, 1H), 6.71 (d, J = 15.7 Hz, 1H), 6.61 (s,
D
= +8.0 (c 0.26, CHCl
3
); H
MgSO , filtered and concentrated in vacuo. The residue was puri-
4
NMR (800 MHz, CDCl
3
fied by column chromatography on silica gel (hexane/acetone, 6:1)
to give compound 15 (240 mg, 0.34 mmol, 41%) as a colorless oil.
2
0
1
1
1
6
1
H), 5.95 (dd, J = 15.6, 6.6 Hz, 1H), 5.89 (s, 2H), 4.37–4.42 (m,
H), 3.21 (t, J = 7.2 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H), 1.29 (d, J =
.5 Hz, 3H); C{ H} NMR (200 MHz, CDCl
[]
D
3 3
= +4.1 (c 1.0, CHCl ); H NMR (500 MHz, CDCl ) δ 7.33–
7.39 (m, 6H), 7.17–7.28 (m, 12H), 6.94 (s, 1H), 6.76–6.82 (m, 3H),
6.61 (s, 1H), 5.91 (m, 1H), 5.90 (s, 2H), 5.51 (m, 1H), 3.89 (d, J =
12.7, 1H), 3.74 (s, 3H), 3.45 (d, J = 12.7 Hz, 1H), 3.20 (m, 3H),
3.01 (app t, J = 8.2 Hz, 1H), 2.81–2.95 (m, 2H), 2.36 (td, J = 8.1,
8.0 Hz, 1H), 2.11 (m, 1H), 1.83–1.97 (m, 2H), 1.72–1.79 (m, 1H),
1
3
1
3
) δ 147.0, 146.5,
44.1 (3C), 133.6, 130.5, 129.3, 128.6 (6C), 127.7 (6C), 126.9
(3C), 126.7, 110.3, 105.6, 100.9, 86.6, 69.1, 64.3, 33.7, 23.4; IR
-1
(neat) ṽ = 3530, 2660, 2875, 1482, 1251, 1043, 934 cm ; HRMS
+
13
1
(FAB): calcd. for C32
-(tert-Butyl)
H
30
O
4
: 478.2144 ([M] ), found: 478.2147.
3
1.33 (d, J = 6.4 Hz, 3H); C{ H} NMR (125 MHz, CDCl ) δ 173.2,
1
2-((R,E)-4-(6-(2-
158.6, 147.3, 146.5, 144.1 (3C), 130.9, 130.6, 130.3 (2C), 129.0,
128.9, 128.7, 128.6 (6C), 127.7 (6C), 126.8 (3C), 113.5 (2C),
110.3, 105.5, 100.9, 86.6, 71.3, 65.2, 64.3, 57.7, 55.1, 52.9, 33.6,
(
trityloxy)ethyl)benzo[d][1,3]dioxol-5-yl)but-3-en-2-yl) (S)-pyr-
rolidine-1,2-dicarboxylate (13). To a solution of (E)-allylic alcohol
2 (1.0 equiv, 1.7 mmol, 800 mg) in CH Cl (17 mL) were added
1
2
2
29.2, 22.9, 20.5; IR (neat) ṽ = 1734, 1721, 1510, 1483, 1248, 1168,
-1
N-Boc-L-proline (2.0 equiv, 3.3 mmol, 720 mg), N,N′-dicyclohex-
ylcarbodiimide (2.2 equiv, 3.7 mmol, 759 mg), and 4-(dimethyla-
mino)pyridine (10 mol%, 0.17 mmol, 21 mg) at room temperature.
The reaction mixture was stirred for 1 h at room temperature, sub-
jected to a Celite filter, and washed with EtOAc. The filtrate was
concentrated in vacuo and purified by flash chromatography on sil-
ica gel (hexane/EtOAc, 4:1) to yield compound 13 (1.37 g, 95%)
1038, 707 cm ; HRMS (FAB): calcd. for C45
H46NO
6
: 696.3325
+
([M+H] ), found: 696.3329.
5-Iodo-1,3-benzodioxole (16). To a solution of commercially
available 1,3-benzodioxole (1 equiv, 227 mmol, 28 g) in acetoni-
trile (453 mL) were added N-iodosuccinimide (1 equiv, 227 mmol,
51 g) and TFA (0.3 equiv, 67 mmol, 5.1 mL). The reaction mixture
was allowed to stir at room temperature for 16 h, then it was
quenched with saturated aqueous sodium thiosulfate solution,
poured to water, extracted twice with EtOAc, washed with brine,
2
0
as a white foam. R
f
= 0.3 (hexane/EtOAc, 3:1); []
); H NMR (major rotamer, 500 MHz, CDCl
.36 (m, 6H), 7.24–7.27 (m, 6H), 7.19–7.22 (m, 3H), 6.90 (s, 1H),
D
= +8.1 (c
1
0
7
.72, CHCl
3
3
) δ 7.35–
4
dried over MgSO , and concentrated in vacuo. The residue was pu-
rified by flash chromatography on silica gel (hexane/EtOAc, 9:1)
6.78 (d, J = 15.7 Hz, 1H), 6.61 (s, 1H), 5.91 (s, 3H), 5.86–5.92 (m,
H), 5.46–5.49 (m, 1H), 4.20 (dd, J = 8.6, 3.5 Hz, 1H), 3.54–3.57
m, 1H), 3.42–3.45 (m, 1H), 3.16–3.23 (m, 2H), 2.78–2.95 (m, 2H),
1
(
to yield iodobenzene 16 (30 g, 50%) as a pale yellow oil, and the
1
H NMR spectrum was in good agreement with that of a previous
1
2 1
2
6
1
.14–2.23 (m, 1H), 1.76–1.95 (m, 2H), 1.37 (s, 9H), 1.33 (d, J =
.4 Hz, 3H); C{ H} NMR (major rotamer, 200 MHz, CDCl
72.4, 153.8, 147.3, 146.5, 144.1 (3C), 131.0, 129.4, 128.8, 128.6
3
report. H NMR (400 MHz, CDCl ) δ 7.11–7.16 (m, 2H), 6.59 (d,
1
3
1
3
) δ
J = 8.0 Hz, 1H), 5.96 (s, 2H).
(R)-4-(Benzo[d][1,3]dioxol-5-yl)but-3-yn-2-ol (17). (R)-(+)-3-
butyn-2-ol (4, 1.2 equiv, 48 mmol, 3.8 mL) and copper iodide (10
mol%, 4.0 mmol, 762 mg) were added to a solution of 5-iodo-1,3-
(6C), 128.4, 127.7 (6C), 126.9 (3C), 110.4, 105.5, 100.9, 86.7, 79.8,
71.9, 64.3, 59.3, 46.5, 33.6, 30.9, 28.3 (3C), 23.6, 20.5; IR (neat) ṽ
= 2975, 2875, 1737, 1695, 1482, 1393, 1247, 1159, 1034, 760, 704
3
benzodioxole 16 (1.0 equiv, 40 mmol, 10 g) in THF/Et N (1:1, 200
-
1
+
cm ; HRMS (FAB): calcd. for C42
found: 675.3203.
H
45NO
7
: 675.3196 ([M] ),
mL), followed by bubbling nitrogen gas at room temperature for 15
min. Bis(triphenylphosphine)palladium(II) dichloride (5 mol%, 2.0
mmol, 1.4 g) was subsequently added to the reaction pot, and the
reaction mixture was stirred at room temperature for 1 h. The mix-
ture was poured to water and extracted twice with EtOAc, washed
with water and brine, dried over MgSO , and concentrated in
4
vacuo. The dark brown crude product was purified by flash chro-
matography on silica gel (hexane/EtOAc, 4:1) to yield propargyl
alcohol 17 (7.3 g, 96%) as a light yellow oil. R = 0.3 (hex-
f
(4-Methoxybenzyl)-L-proline (14). Sodium triacetoxyborohy-
dride (1.5 equiv, 1.5 g, 7.2 mmol) was added to a solution of L-
proline t-butyl ester hydrochloride (1 equiv, 1.0 g, 4.8 mmol) and
4-methoxybenzaldehyde (1 equiv, 585 μL, 4.8 mmol) in CH
(48 mL) at 0 °C. The reaction was allowed to stir at room tempera-
ture for 4 h and was quenched with NaHCO . The organic layer
was washed with brine, dried over MgSO , filtered and concen-
trated in vacuo. Trifluoroacetic acid (8 mL) was slowly added to a
solution of the crude N-PMB t-butyl proline ester in CH Cl (32
mL). The reaction was stirred at room temperature for 15 h. The
mixture was concentrated in vacuo, and the residue was purified by
column chromatography on silica gel (CH
2
Cl
2
3
4
2
0
1
ane/EtOAc, 3:1); []
MHz, CDCl ) δ 6.92 (dd, J = 8.0, 1.6 Hz, 1H), 6.84 (d, J = 1.6 Hz,
1H), 6.71 (d, J = 8.1 Hz, 1H), 5.94 (s, 2H), 4.67–4.72 (m, 1H), 2.05
D
3
= +25.7 (c 0.67, CHCl ); H NMR (800
2
2
3
13
1
(d, J = 4.4 Hz, 1H, OH), 1.51 (d, J = 6.6 Hz, 3H); C{ H} NMR
(200 MHz, CDCl ) δ 147.9, 147.3, 126.3, 115.8, 111.6, 108.4,
2
Cl
2
/MeOH/AcOH,
3
9
0:10:2) to give compound 14 (904 mg, 3.6 mmol, 74% for 2 steps)
101.3, 89.3, 83.8, 58.8, 24.4; IR (neat) ṽ = 3378, 2976, 2901, 1497,
2
0
1
-1
as a white solid. mp 92 °C; []
D
= +183.8 (c 1.0, MeOH); H
1436, 1319, 1245, 1206, 1036, 929, 854, 811 cm ; HRMS (FAB):
+
NMR (500 MHz, CD
3
OD) δ 7.44 (d, J = 8.5 Hz, 2H), 6.97 (d, J =
calcd. for C11
H
10
O
3
: 190.0630 ([M] ), found: 190.0631.
8
4
2
.5 Hz, 2H), 4.41 (d, J = 12.9 Hz, 1H), 4.22 (d, J = 12.9 Hz, 1H),
.00 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 3.52 (m, 1H), 3.23 (m, 1H),
.47 (m, 1H), 2.11 (m, 2H), 1.95 (m, 1H); C{ H} NMR (125
(R,Z)-4-(Benzo[d][1,3]dioxol-5-yl)but-3-en-2-ol (18). Sodium
borohydride (0.8 equiv, 29 mmol, 1.1 g) was added portionwise to
a solution of nickel(II) acetate tetrahydrate (0.4 equiv, 15 mmol,
13
1
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The Journal of Organic Chemistry
-
1
3
.6 g) in EtOH (185 mL) to give colloidal black precipitate, simul-
1403, 1246, 1158, 1038, 909, 728 cm ; HRMS (FAB): calcd. for
+
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
taneously. After stirring for 30 min at room temperature, ethylene-
diamine (0.5 equiv, 19 mmol, 1.2 mL) was added to the reaction
mixture, stirred for additional 20 min, and followed by the addition
of propargyl alcohol 17 (1.0 equiv, 37 mmol, 7.0 g). After 2 h, the
reaction mixture was concentrated in vacuo, diluted with ethyl ac-
etate, subjected to a Celite filter, and concentrated in vacuo again.
The crude product was purified by flash chromatography on silica
gel (hexane/EtOAc, 4:1) to yield (Z)-allylic alcohol 18 (5.5 g, 78%)
as an ivory solid. mp 70 °C; R
=
1
6
1
6
C
21
H28NO
6
: 390.1917 ([M+H] ), found: 390.1911.
Methyl (R)-2-((S,E)-1-(benzo[d][1,3]dioxol-5-yl)but-2-en-1-
yl)-1-(2,2-dimethoxyethyl)pyrrolidine-2-carboxylate (21). Potas-
sium carbonate (3.0 equiv, 38 mmol, 5.2 g) and iodomethane (5.0
equiv, 63 mmol, 3.9 mL) were added to a solution of 20 (1.0 equiv,
13 mmol, 4.9 g) in acetone (63 mL), and the reaction mixture was
refluxed for 1 h under vigorous stirring. The reaction mixture was
poured to water and extracted with EtOAc, washed with brine,
2
0
f
= 0.3 (hexane/EtOAc, 3:1); []
); H NMR (800 MHz, CDCl ) δ 6.76 (d, J =
D
dried over MgSO
crude mixture in CH
the reaction mixture was stirred for 2 h at room temperature. The
mixture was slowly quenched with saturated aqueous NaHCO so-
lution at 0 °C and poured to water, extracted with CH Cl , washed
with brine, dried over Na SO , and concentrated in vacuo. To a so-
lution of this crude mixture in CH Cl (60 mL) was added 2,2-di-
methoxyacetaldehyde solution (60 wt% in H O, 1.5 equiv, 20
mmol, 2.9 mL) and NaBH(OAc) (1.5 equiv, 20 mmol, 4.3 g). The
reaction mixture was stirred at room temperature. After 2 h, it was
poured to water, extracted twice with CH Cl , washed with brine,
dried over MgSO , and concentrated in vacuo. The crude product
was purified by flash chromatography on silica gel (hexane/EtOAc,
3:1) to yield acetal 21 (4.7 g, 92% for 3 steps) as a colorless oil. R
4
, and concentrated in vacuo. To a solution of the
1
–11.1 (c 1.1, CHCl
3
3
2
Cl (60 mL) was then added TFA (8 mL) and
2
.8 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 6.71 (dd, J = 8.1, 1.5 Hz, 1H),
.34 (d, J = 11.7 Hz, 1H), 5.91 (s, 2H), 5.56 (dd, J = 11.6, 9.0 Hz,
H), 4.69–4.75 (m, 1H), 2.04 (d, J = 3.0 Hz, 1H, OH), 1.31 (d, J =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
2
13
1
.4 Hz, 3H); C{ H} NMR (200 MHz, CDCl
3
) δ 147.5, 146.6,
2
4
134.6, 130.6, 129.5, 122.5, 108.9, 108.0, 100.9, 63.9, 23.5; IR
(neat) ṽ = 3308, 2971, 2897, 1498, 1485, 1438, 1255, 1230, 1036,
9
2
2
2
-
1
16, 886, 621 cm ; HRMS (FAB): calcd. for C11
H
12
O
3
: 192.0786
3
+
(
[M] ), found: 192.0788.
-((R,Z)-4-(Benzo[d][1,3]dioxol-5-yl)but-3-en-2-yl) 1-(tert-
butyl) (S)-pyrrolidine-1,2-dicarboxylate (19). To a solution of (Z)-
allylic alcohol 18 (1.0 equiv, 28 mmol, 5.4 g) in CH Cl (140 mL)
2
2
2
4
2
2
were added N-Boc-L-proline (1.5 equiv, 42 mmol, 9.1 g), N-(3-di-
methylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5
equiv, 42 mmol, 8.1 g), and 4-(dimethylamino)pyridine (10 mol%,
f
2
0
1
= 0.4 (hexane/EtOAc, 3:1); []
D
= +13.4 (c 0.1, MeOH); H NMR
(500 MHz, CD OD) δ 6.79 (s, 1H), 6.64–6.67 (m, 2H), 5.86–5.92
3
2
.8 mmol, 342 mg) at room temperature. The reaction mixture was
stirred for 2 h, poured to water, extracted with EtOAc, washed with
brine, dried over MgSO , and concentrated in vacuo. The crude
(m, 3H), 5.34–5.40 (m, 1H), 4.38 (t, J = 5.2 Hz, 1H), 3.87 (d, J =
7.7 Hz, 1H), 3.55 (s, 3H), 3.37 (s, 3H), 3.36 (s, 3H), 3.25–3.33 (m,
2H), 3.10 (dd, J = 13.7, 4.9 Hz, 1H), 2.38–2.46 (m, 2H), 1.90–2.10
4
13
1
product was purified by flash chromatography on silica gel (hex-
ane/EtOAc, 3:1) to yield (Z)-allylic ester 19 (11 g, 97%) as a white
solid. mp 131 °C; R
0.85, CHCl
6
5
(m, 2H), 1.66 (d, J = 6.5 Hz, 3H), 1.57–1.72 (m, 3H); C{ H}
NMR (125 MHz, CD OD) δ 175.5, 149.4, 148.3, 137.0, 132.7,
3
2
0
f
= 0.3 (hexane/EtOAc, 3:1); []
); H NMR (major rotamer, 800 MHz, CDCl
.75 (m, 3H), 6.37 (d, J = 11.8 Hz, 1H), 5.88–5.92 (m, 2H), 5.78–
.84 (m, 1H), 5.50 (dd, J = 11.7, 9.4 Hz, 1H), 4.16 (dd, J = 8.7, 3.8
D
= +38.4 (c
129.2, 124.8, 111.7, 109.3, 107.5, 102.9, 76.9, 55.4, 55.2, 54.6,
1
3
3
) δ 6.71–
53.9, 52.9, 52.2, 32.8, 23.4, 19.2; IR (neat) ṽ = 2975, 1743, 1692,
-
1
1487, 1389, 1364, 1241, 1147, 1037 cm ; HRMS (FAB): calcd. for
+
C
21
H30NO
6
: 392.2073 ([M+H] ), found: 392.2073.
Hz, 1H), 3.48–3.52 (m, 1H), 3.39 (td, J = 10.4, 7.3 Hz, 1H), 2.13–
Methyl (10aR,11S)-11-((E)-prop-1-en-1-yl)-5,9,10,11-tetrahy-
2
3
1
.19 (m, 1H), 1.76–1.92 (m, 3H), 1.35 (s, 9H), 1.33 (d, J = 6.4 Hz,
dro-6H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]pyrrolo[1,2-a]aze-
pine-10a(8H)-carboxylate (22). Methanesulfonic acid (10.0 equiv,
112 mmol, 7.3 mL) was slowly added to a solution of acetal 21 (1.0
13
1
H); C{ H} NMR (major rotamer, 200 MHz, CDCl
3
) δ 172.1,
53.8, 147.6, 146.9, 130.8, 130.0, 129.8, 122.4, 108.7, 108.2,
101.0, 79.7, 68.1, 59.1, 46.2, 30.8, 28.2 (3C), 23.4, 20.7; IR (neat)
ṽ = 2969, 2875, 1744, 1691, 1484, 1394, 1189, 1159, 1121, 1036,
2 2
equiv, 11 mmol, 4.4 g) in CH Cl (110 mL) at room temperature.
The reaction mixture was stirred for 18 h and cooled to 0 °C. Bo-
rane tert-butylamine complex (1.5 equiv, 17 mmol, 1.5 g) was
added to the reaction pot portionwise (Caution: Hydrogen gas is
evolved during the addition of borane tert-butylamine complex.).
After 10 min, the mixture was quenched with saturated aqueous
-
1
+
9
34 cm ; HRMS (FAB): calcd. for C21
found: 389.1838.
R)-2-((S,E)-1-(Benzo[d][1,3]dioxol-5-yl)but-2-en-1-yl)-1-
tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (20). To a so-
6
H27NO : 389.1838 ([M] ),
(
(
lution of compound 19 (1.0 equiv, 21 mmol, 8.0 g) in anhydrous
THF were added chlorotrimethylsilane (3.0 equiv, 62 mmol, 7.8
mL) and titanium(IV) isopropoxide (10 mol%, 2.1 mmol, 622 L)
at room temperature. The mixture was cooled to –78 °C, followed
by the addition of 1 M solution of LiHMDS in THF (3.0 equiv, 62
mmol, 62 mL). The reaction was allowed to slowly warm to room
temperature for a period of 3 h, recooled to 0 °C, and quenched by
aqueous saturated NH
ter, extracted twice with EtOAc, washed with brine, dried over
MgSO , and concentrated in vacuo. The crude product was purified
NaHCO
min. It was poured to water and extracted twice with CH
washed with water and brine, dried over MgSO , and concentrated
3
at 0 °C, warmed to room temperature, and stirred for 10
2
Cl
2
,
4
in vacuo. The crude product was purified by flash chromatography
on silica gel (hexane/EtOAc, 2:1) to yield compound 22 (1.9 g,
51%) as a white solid. mp 105 °C; R
f
= 0.3 (hexane/EtOAc, 3:1);
20
1
[]
D
= –28.1 (c 0.12, CHCl
3
); H NMR (800 MHz, CDCl ) δ 6.66
3
4
Cl. The resulting solution was poured to wa-
(s, 1H), 6.56 (s, 1H), 6.22 (ddd, J = 15.2, 10.1, 1.6 Hz, 1H), 5.85
(d, J = 1.5 Hz, 1H), 5.83 (d, J = 1.5 Hz, 1H), 5.54 (qd, J = 15.0, 6.5
Hz, 1H), 3.63 (d, J = 10.1 Hz, 1H), 3.38 (s, 3H), 3.20–3.26 (m, 1H),
3.08–3.16 (m, 2H), 2.97 (ddd, J = 12.3, 5.3, 2.4 Hz, 1H), 2.92 (ddd,
J = 10.1, 9.1, 5.5 Hz, 1H), 2.58 (dd, J = 14.5, 4.7 Hz, 1H), 2.05
(ddd, J = 12.6, 8.9, 2.1 Hz, 1H), 1.84–1.89 (m, 1H), 1.76–1.81 (m,
4
by flash chromatography on silica gel (hexane/EtOAc, 3:1 to hex-
ane/EtOAc/AcOH, 3:1:0.04) to yield compound 20 with an insep-
arable threo product (7.4 g, 92% combined yield) as a colorless oil.
2
0
13
1
[
3
]
D
= +14.5 (c 1.0, CHCl
3
); R
f
= 0.3 (hexane/EtOAc/AcOH,
) δ 6.70
1H), 1.75 (dd, J = 6.4, 1.6 Hz, 3H), 1.49–1.55 (m, 1H); C{ H}
NMR (200 MHz, CDCl ) δ 174.0, 145.6, 145.3, 134.7, 134.3,
1
:1:0.04); H NMR (major diastereomer, 800 MHz, CDCl
3
3
(d, J = 1.3 Hz, 1H), 6.65–6.68 (m, 2H), 5.86–5.88 (m, 2H), 5.63–
130.5, 128.2, 109.5, 107.8, 100.6, 71.2, 54.0, 52.9, 50.6, 47.7, 37.3,
5.67 (m, 2H), 4.54 (d, J = 8.3 Hz, 1H), 3.46–3.51 (m, 1H), 3.17
(ddd, J = 11.9, 10.6, 5.9 Hz, 1H), 2.44 (dd, J = 12.8, 6.4 Hz, 1H),
1
35.7, 19.1, 17.9; IR (neat) ṽ = 2883, 1730, 1483, 1254, 1166, 1040,
-
1
985, 935 cm ; HRMS (FAB): calcd. for C19
H24NO
4
: 330.1705
+
.99 (dt, J = 12.6, 6.4 Hz, 1H), 1.71–1.76 (m, 1H), 1.68 (d, J = 5.0
([M+H] ), found: 330.1700.
1
3
1
Hz, 3H), 1.58–1.64 (m, 1H), 1.48 (s, 9H); C{ H} NMR (major
diastereomer, 200 MHz, CDCl ) δ 171.8, 158.0, 147.5, 146.7,
32.0, 130.9, 126.2, 122.0, 108.6, 108.2, 100.9, 82.5, 75.1, 50.2,
8.8, 30.8, 28.3 (3C), 22.4, 18.3; IR (neat) ṽ = 2979, 1745, 1605,
((10aR,11S)-11-((E)-Prop-1-en-1-yl)-5,9,10,11-tetrahydro-
6H-[1,3]dioxolo[4',5':4,5]benzo[1,2-d]pyrrolo [1,2-a]azepin-
10a(8H)-yl)methanol (23). To a solution of compound 22 (1.0
3
1
4
equiv, 4.6 mmol, 1.5 g) in anhydrous THF (23 mL) was added 1 M
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 11
solution of lithium aluminum hydride in THF (1.5 equiv, 6.8 mmol,
6.8 mL) at –78 °C. The reaction mixture was warmed to 0 °C and
stirred for 1 h. In sequence, H O (0.5 mL), 1 N NaOH (0.5 mL) and
O (1.5 mL) were added to the reaction mixture, which was al-
lowed to stir at room temperature for an additional 30 min. The
white precipitate produced was filtered off through a Celite filter,
washed with EtOAc, and the filtrate was concentrated in vacuo.
The crude product was purified by flash chromatography on silica
EtOAc. The organic layer was washed with brine, dried over
MgSO , and concentrated in vacuo. DMSO (500 L) was added to
a solution of the crude mixture in CH Cl (2 mL), and the mixture
was stirred for 12 h at room temperature for the efficient removal
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
2
2
2
H
2
2
1
of catalyst. The reaction mixture was poured to water and ex-
tracted with CH Cl , dried over MgSO , and concentrated in vacuo.
2
2
4
The crude product was purified by flash chromatography on silica
gel (hexane/EtOAc, 1:1) to yield intermediate I (310 mg, 72%) as
20
gel (CH
2
Cl
2
/MeOH, 15:1) to yield alcohol 23 (1.3 g, 97%) as a
a light yellow oil. R = 0.2 (hexane/EtOAc, 1:1); [] = –206.7 (c
f
D
2
0
1
white solid. mp 140 °C; R
f
= 0.2 (CH
); H NMR (800 MHz, CDCl
.54 (s, 1H), 5.88 (d, J = 1.5 Hz, 1H), 5.86 (d, J = 1.6 Hz, 1H), 5.71
ddd, J = 15.1, 10.2, 1.6 Hz, 1H), 5.45–5.51 (m, 1H), 3.83 (d, J =
.8 Hz, 1H), 3.34 (t, J = 13.1 Hz, 1H), 3.25–3.30 (m, 1H), 3.26 (d,
2
Cl
2
/MeOH, 15:1); []
D
=
1.2, CHCl
3
); H NMR (800 MHz, CDCl
3
) δ 6.64 (s, 1H), 6.58 (s,
1
+
6
(
9
102.7 (c 1.33, CHCl
3
3
) δ 6.64 (s, 1H),
1H), 5.88 (d, J = 1.7 Hz, 1H), 5.86 (d, J = 1.7 Hz, 1H), 5.76–5.79
(m, 1H), 5.49–5.53 (m, 1H), 3.85–3.87 (m, 1H), 3.18 (ddd, J = 14.0,
12.5, 7.4 Hz, 1H), 3.06 (dt, J = 9.2, 4.3 Hz, 1H), 2.90 (dt, J = 12.0,
6.9 Hz, 1H), 2.71–2.75 (m, 1H), 2.53 (dd, J = 11.4, 7.4 Hz, 1H),
2.38 (dt, J = 9.9, 6.1 Hz, 1H), 2.31 (dd, J = 14.2, 6.6 Hz, 1H), 1.95–
1.99 (m, 1H), 1.92–1.95 (m, 2H), 1.73–1.79 (m, 1H), 1.67–1.73 (m,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 10.8 Hz, 1H), 3.22 (d, J = 10.8 Hz, 1H), 3.02 (dd, J = 14.2, 4.5
Hz, 1H), 2.93–2.98 (m, 1H), 2.84–2.89 (m, 1H), 2.27 (dd, J = 14.7,
4.6 Hz, 1H), 1.82–1.91 (m, 2H), 1.74 (dd, J = 6.4, 1.6 Hz, 3H),
1
3
1
3
1H); C{ H} NMR (200 MHz, CDCl ) δ 146.2, 145.8, 132.24
1
3
1
1
1
5
1
.65–1.75 (m, 2H); C{ H} NMR (200 MHz, CDCl
3
) δ 145.7,
132.18, 131.7, 128.6, 110.8, 109.7, 100.6, 67.9, 62.3, 53.4, 48.9,
45.2, 135.1, 134.6, 130.7, 127.7, 109.4, 108.5, 100.8, 65.2, 59.6,
0.8, 49.5, 45.7, 32.8, 31.7, 20.1, 18.0; IR (neat) ṽ = 3166, 2909,
501, 1481, 1250, 1036, 933, 870 cm ; HRMS (FAB): calcd. for
43.2, 34.6, 30.5, 19.8; IR (neat) ṽ = 2875, 1502, 1484, 1223, 1039,
-
1
936 cm ; HRMS (FAB): calcd. for C17
H20NO
2
: 270.1494
-
1
+
([M+H] ), found: 270.1496.
+
C
18
H24NO
3
: 302.1756 ([M+H] ), found: 302.1760.
(13R,14aS)-2,3,5,6,11b,12,13,14-Octahydro-1H-[1,3]diox-
olo[4',5':4,5]benzo[1,2-d]cyclopenta[b]pyrrolo[1,2-a]azepine-
12,13-diol (26). To a solution of intermediate I (1.0 equiv, 1.1
(10aS,11S)-10a-Allyl-11-((E)-prop-1-en-1-yl)-
5,8,9,10,10a,11-hexahydro-6H-[1,3]dioxolo[4',5':4,5]benzo[1,2-
d]pyrrolo[1,2-a]azepine (25). To a solution of alcohol 23 (1.0
2
mmol, 300 mg) in acetone/H O (3:1, 11 mL) were added trifluoro-
equiv, 2.8 mmol, 850 mg) in CH
amine (3.0 equiv, 8.5 mmol, 1.2 mL) and methanesulfonyl chloride
3.0 equiv, 8.5 mmol, 655 L) at 0 °C. After 5 min, the reaction
2
Cl
2
(14 mL) were added triethyl-
acetic acid (5.0 equiv, 5.6 mmol, 426 L), 4-methylmorpholine N-
oxide (2.0 equiv, 2.2 mmol, 257 mg) and osmium tetroxide solution
(2.5 wt.% in t-BuOH, 10 mol%, 0.11 mmol, 1.4 mL). The reaction
was allowed to stir at room temperature. After 16 h, the reaction
(
mixture was concentrated in vacuo. The crude mixture was dis-
solved in THF (10 mL), stirred vigorously for 5 min at room tem-
perature, and filtered off to remove the insoluble solid. The filtrate
was concentrated in vacuo to give crude aziridinium salt 24. Sim-
ultaneously, cuprate solution was generated in situ using the fol-
lowing procedure: A suspension of copper(I) cyanide (5.0 equiv,
was quenched with aqueous saturated Na
2 3 3
SO and NaHCO . The
mixture was poured to water and extracted twice with EtOAc, dried
over MgSO
purified
4
, and concentrated in vacuo. The crude product was
by flash chromatography on silica gel
, 100:10:1) to yield diol 26 (253 mg,
3
= 0.1 (CH Cl /MeOH/28% aq. NH ,
2 2 3
(CH Cl /MeOH/28% aq. NH
1
5 mmol, 1.3 g) in THF (10 mL) was cooled to 0 °C under a nitro-
75%) as a white solid. R
f
2
2
2
0
1
gen atmosphere. To this reaction pot, 1 M solution of vinylmagne-
sium bromide in THF (10.0 equiv, 29 mmol, 29 mL) was slowly
added. The suspension was allowed to stir for 0.5–1 h at the same
temperature and it became a dark colored solution. The solution of
crude aziridinium salt 24 in THF (20 mL) was slowly added to the
cuprate at 0 °C and the reaction was stirred for 2 h and quenched
100:10:1); []D = –10.5 (c 1.0, MeOH); H NMR (CDCl , 500
3
MHz) δ 6.65 (s, 1H), 6.61 (s, 1H), 5.87 (s, 2H), 4.30 (dd, J = 9.5,
3.9 Hz, 1H), 4.20 (app t, J = 4.0 Hz, 1H), 3.03 (d, J = 9.6 Hz, 1H),
2.85–3.05 (m, 3H), 2.34–2.71 (m, 3H), 2.52 (dd, J = 14.3, 6.1 Hz,
1H), 2.28–2.33 (m, 1H), 1.97 (app d, J = 13.5 Hz, 1H), 1.74–1.82
(m, 1H), 1.64–1.71 (m, 3H).
by aqueous saturated NH
extracted twice with EtOAc, washed with water and brine, dried
over MgSO , and concentrated in vacuo. The crude product was
purified by flash chromatography on silica gel (CH Cl /MeOH,
20:1) to yield diene 25 (632 mg, 72%) as a brown oil. R = 0.2
= +39.4 (c 1.2, MeOH); H NMR
OD) δ 6.67 (s, 1H), 6.63 (s, 1H), 5.86–5.88 (m, 2H),
.85–5.89 (m, 1H), 5.79 (tdd, J = 17.2, 9.9, 7.5 Hz, 1H), 5.48–5.54
4
Cl. The mixture was poured to water and
ASSOCIATED CONTENT
Supporting Information
4
2
2
f
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
2
0
1
(CH
2
Cl
2
/MeOH, 20:1); []
D
(600 MHz, CD
3
1
5
Chiral HPLC data for compound 20 and copies of the H and
C NMR spectra for all new products (PDF)
1
3
(
1
(
2
m, 1H), 5.00 (app d, J = 12.4 Hz, 1H), 4.87 (app d, J = 17.0 Hz,
H), 3.67 (d, J = 10.1 Hz, 1H), 3.21 (td, J = 9.8, 3.7 Hz, 1H), 3.16
ddd, J = 14.5, 12.4, 2.1 Hz, 1H), 2.92 (dd, J = 13.3, 3.7 Hz, 1H),
.72–2.76 (m, 2H), 2.54 (dd, J = 14.6, 5.5 Hz, 1H), 1.77–1.87 (m,
AUTHOR INFORMATION
1
3
1
4H), 1.75 (dd, J = 6.4, 1.9 Hz, 3H), 1.69–1.73 (m, 2H); C{ H}
NMR (150 MHz, CD OD) δ 148.1, 147.7, 137.7, 137.0, 135.6,
33.4, 129.6, 118.8, 111.5, 110.3, 102.9, 67.3, 56.2, 53.3, 48.0,
6.3, 35.9, 34.4, 20.4, 18.9; IR (neat) ṽ = 2916, 1482, 1252, 1038,
Corresponding Author
3
1
3
9
*E-mail: pennkim@snu.ac.kr.
-
1
ORCID
2
35, 862 cm ; HRMS (FAB): calcd. for C20H26NO : 312.1964
+
([M+H] ), found: 312.1963.
Sanghee Kim: 0000-0001-9125-9541
Notes
The authors declare no competing financial interest.
(11bS,14aS)-2,3,5,6,11b,14-Hexahydro-1H-[1,3]diox-
olo[4',5':4,5]benzo[1,2-d]cyclopenta[b]pyrrolo[1,2-a]azepine
(intermediate I). To a solution of diene 25 (1.0 equiv, 1.6 mmol,
5
(
0
00 mg) in CH
1.1 equiv, 1.8 mmol, 409 mg) and Grubbs 2 catalyst (5 mol%,
.08 mmol, 68 mg). The reaction mixture was refluxed for 3 h and
then cooled to room temperature. It was quenched with aqueous
saturated NaHCO , poured to water, and extracted twice with
2
Cl
2
(32 mL) were added 10-camphorsulfonic acid
ACKNOWLEDGMENT
This work was supported by the Mid-Career Researcher Program
nd
(Grant NRF-2016R1A2A1A05005375) of the National Research
3
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The Journal of Organic Chemistry
Foundation of Korea (NRF) funded by the Government of Korea
(MSIP).
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(
19) Goncalves-Martin, M. G.; Zigmantas, S.; Renaud, P. Formal
Structural Elucidation of (–)-Cephalezomine G. Org. Lett. 2019, 21,
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the Efficient Removal of Ruthenium Byproducts Generated during
Olefin Metathesis Reactions. Org. Lett. 2001, 3, 1411–1413.
uct cephalezomine G, which led us to elucidate the structure of this
natural product, see; Jeon, H.; Cho, H.; Kim, S. Total Synthesis and
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