Lipase-catalyzed asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one derivatives by a one-pot dynamic kinetic resolution/intramolecular Diels–Alder reaction: Total synthesis of (?)-himbacine

Article abstract of DOI:10.1016/j.bmc.2017.08.019

One-pot sequential reactions using the acyl moieties installed by enzymatic dynamic kinetic resolution of alcohols have been little investigated. In this work, the acryloyl moiety installed via the lipase/oxovanadium combo-catalyzed dynamic kinetic resolution of a racemic dienol [4-(cyclohex-1-en-1-yl)but-3-en-2-ol or 1-(cyclohex-1-en-1-yl)but-2-en-1-ol] with a (Z)-3-(phenylsulfonyl)acrylate underwent an intramolecular Diels–Alder reaction in a one-pot procedure to produce an optically active naphtho[2,3-c]furan-1(3H)-one derivative (98% ee). This method was successfully applied to the asymmetric total synthesis of (?)-himbacine.

Full text of DOI:10.1016/j.bmc.2017.08.019

Accepted Manuscript
Lipase-catalyzed asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one de-
rivatives by a one-pot dynamic kinetic resolution/intramolecular Diels–Alder
reaction: Total synthesis of (–)-himbacine
Koji Sugiyama, Shinji Kawanishi, Yasuhiro Oki, Marin Kamiya, Ryosuke
Hanada, Masahiro Egi, Shuji Akai
PII:
S0968-0896(17)31252-X
http://dx.doi.org/10.1016/j.bmc.2017.08.019
BMC 13922
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 June 2017
9 August 2017
10 August 2017
Please cite this article as: Sugiyama, K., Kawanishi, S., Oki, Y., Kamiya, M., Hanada, R., Egi, M., Akai, S., Lipase-
catalyzed asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one derivatives by a one-pot dynamic kinetic
resolution/intramolecular Diels–Alder reaction: Total synthesis of (–)-himbacine, Bioorganic & Medicinal
Chemistry (2017), doi: http://dx.doi.org/10.1016/j.bmc.2017.08.019
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Bioorganic & Medicinal Chemistry
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Lipase-catalyzed asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one derivatives
by a one-pot dynamic kinetic resolution/intramolecular Diels–Alder reaction: Total
synthesis of (–)-himbacine
Koji Sugiyamaa, Shinji Kawanishia, Yasuhiro Okia, Marin Kamiyab, Ryosuke Hanadab, Masahiro Egib,c and
Shuji Akaia,∗
a Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 567-0871, Japan
b School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan
c School of Food and Nutritional Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
One-pot sequential reactions using the acyl moieties installed by enzymatic dynamic kinetic
resolution of alcohols have been little investigated. In this work, the acryloyl moiety installed
via the lipase/oxovanadium combo-catalyzed dynamic kinetic resolution of a racemic dienol
[4-(cyclohex-1-en-1-yl)but-3-en-2-ol or 1-(cyclohex-1-en-1-yl)but-2-en-1-ol] with a (Z)-3-
(phenylsulfonyl)acrylate underwent an intramolecular Diels–Alder reaction in a one-pot
procedure to produce an optically active naphtho[2,3-c]furan-1(3H)-one derivative (98% ee).
This method was successfully applied to the asymmetric total synthesis of (–)-himbacine.
Available online
Keywords:
Allylic alcohol
Asymmetric total synthesis
Dynamic kinetic resolution
Himbacine
2009 Elsevier Ltd. All rights reserved
.
Intramolecular Diels–Alder reaction
Lipase
Naphthofuranone
One-pot reaction
———
∗ Corresponding author. Tel.: +81-6-6879-8210; fax: +81-6-6879-8210; e-mail: akai@phs.osaka-u.ac.jp

1. Introduction
Hydrolase-catalyzed kinetic resolution (KR) of racemic
secondary alcohols via enantioselective esterification in organic
media has been extensively used for the preparation of optically
active compounds because of its advantages over the hydrolytic
KR in aqueous media, such as high solubility and stability of
substrates in organic solvents, easy operation, and easy product
purification.1 However, KR has the inherent limitation of
maximum 50% yield of the desired product. On the other hand,
dynamic kinetic resolution (DKR), in which enzymatic KR is
combined with rapid in situ racemization of slowly reacting
enantiomers, provides the additional benefit of quantitative
conversion of racemic substrates into optically pure compounds.
A variety of DKRs of secondary alcohols have been developed
based on the combination of hydrolases and racemization
catalysts, mainly ruthenium complexes.2 We recently reported a
novel DKR process using a combination of lipases and
racemization catalysts V-MPSs3,4 in which oxovanadium
moieties are covalently bound to the inner surface of mesoporous
silica (MPS) with a pore diameter of 2–4 nm (Fig. 1a). The
racemization proceeds via the 1,3-transposition of the hydroxyl
group of allylic alcohols in the V-MPS pores generating a
dynamic equilibrium between the two regioisomers [( )-I and
( )-II], while lipase catalyzes the enantio- and chemoselective
transesterification of alcohols with acyl donors outside the pores,
producing quantitative yields of optically pure allyl esters (R)-III
(Fig. 1b, the absolute stereochemistry of I–III is shown as
representative examples). In this DKR, the two regioisomers (I
and II) serve as equivalent substrates to afford the same product
(R)-III, unlike the above-mentioned DKR based on the use of
ruthenium complexes as racemization catalysts.

(a)
(b)
Fig. 2. A synthetic plan for optically active naphtho[2,3-c]furan-
1(3H)-one derivatives 5 via a one-pot DKR/IMDA process and its
application to the total synthesis of (–)-himbacine.
2. Results and Discussion
2.1. Asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one
derivatives by one-pot DKR/IMDA reactions
First, we examined the feasibility of the lipase-catalyzed KR
of dienol ( )-1 using different propiolates 3A as acyl donors
(Table 1). Screening of commercially available immobilized
lipases at 35 °C in MeCN revealed that Burkholderia cepacia
Fig. 1. (a) V-MPS structure; (b) Lipase/oxovanadium combo-
catalyzed DKR of racemic allylic alcohols (I or II).
lipase (Amano PS-IM) and Candida antarctica lipase
B
(Novozym 435) were most effective in forming ester 4A;
however, 4A was very unstable during chromatographic
purification on silica gel, which caused decomposition and partial
hydrolysis with regeneration of 1. To overcome this problem, the
crude mixture was filtered through a Celite pad and concentrated.
Then, a solution of the residue and 5.0 mol% 3,5-di-tert-butyl-4-
hydroxytoluene (BHT) in toluene was gradually heated to reflux
and kept at that temperature for 10 h to produce an IMDA
product 5A as a single diastereomer. The effect of various
parameters on this two-step synthesis was investigated, and some
representative results are summarized in Table 1.
The combination of multiple reactions in a single operation is
of particular interest because it minimizes the use of chemicals,
waste production, number of steps, energy, and time.5 The acyl
groups introduced into alcohol substrates via KR or DKR are
generally removed or replaced by other groups in subsequent
transformations,6 and only a few examples have been reported on
the direct use of the installed acyl moieties in subsequent
reactions.7 Domino or one-pot sequential reactions using the
installed acyl moiety, especially proceeding through
intermediates that are too unstable to be isolated, provide a
powerful synthetic tool. In this context, we reported the
preparation of fused cyclic compounds by lipase-catalyzed
domino KR (or DKR)/ intramolecular cyclization reactions.8
Firstly, the leaving group of propiolate 3A was found to
significantly affect both yield and enantiomeric excess of the
product. p-Chlorophenyl propiolate (3Aa) was reactive in the PS-
IM-catalyzed KR of ( )-1, but the enantiomeric excess of 5A was
very low (Table 1, entry 1). This result was probably due to to
acid-catalyzed racemization of 4A by the p-chlorophenol
generated from 3Aa. Although 1-ethyxvinyl esters have been
found to be effective for lipase-catalyzed KR of racemic
alcohols,10 the use of 1-ethoxyvinyl propiolate (3Ab) for the KR
of ( )-1 resulted in the formation of racemic 5A (entry 2). In this
case, highly reactive 3Ab caused non-enzymatic esterification of
( )-1 (Some experimental evidences are given in the
Supplementary Information). Whereas methyl propiolate (3Ac)
was less reactive (entry 3), the reaction using 2,2,2-trifluoroethyl
propiolate (3Ad) proceeded smoothly to give 5A (63% ee) in
37% NMR yield (entry 4).11
This paper presents advanced examples of such domino or
one-pot sequential reactions in the synthesis of naphtho[2,3-
c]furan-1(3H)-one derivatives 5 with several stereogenic carbon
centers by lipase/oxovanadium combo-catalyzed DKR of a
racemic dienol (1 or 2) with functionalized acyl donors 3
followed by intramolecular Diels–Alder (IMDA) reaction of thus
generated optically active esters 4 (Fig. 2). This method was
applied to the asymmetric synthesis of (–)-himbacine (98% ee),
the opposite enantiomer of the natural product.9
In the screening of lipases, Novozym 435 exhibited higher
reactivity than PS-IM, and similar enantioselectivity was
observed (entry 5). Moreover, lowering the reaction temperature
(25 °C) improved the enantioselectivity (entry 6).

Table 1. Screening of propiolates and lipases for the KR of
racemic 1 followed by IMDAa
entry
1
propiolate 3A
lipase
5A
yield (%)b ee (%)
PS-IM
44
2
3Aa
3Ab
2
3
4
PS-IM
PS-IM
PS-IM
41
13
37
0
75
63
3Ac
Scheme 1. DKR/IMDA reaction of ( )-1 using different acyl
donors (3A–3E).
3Ad
5
3Ad
3Ad
3Ad
3Ad
Novozym 435
Novozym 435
Novozym 435
Novozym 435
43
36
46e
22
52
71
91
92
6c
7c,d
8c,d,f
aThe KR was conducted with 3A (2.0 equiv) and lipase (1.5 w/w) in MeCN
(80 mM) at 35 °C for 20 h. The reaction mixture was filtered through a Celite
pad, and the filtrate was concentrated in vacuo. Toluene (5 mM) and BHT
(5.0 mol%) were added to the residue, the mixture was gradually heated to
reflux, and heating was continued for 10 h. PS-IM: Burkholderia cepacia
lipase from Amano Enzyme; Novozym 435: Candida antarctica lipase B
from Novozymes .
Table 2. Optimization of the DKR/IMDA reaction of ( )-1 using
3Bd or 3Bba
entry 3B
conditions
5B
yield (%)b
ee (%)c
70
1
3Bd 35 °C, 4 days
84
78
72
84
72
2
3Bd 25 °C, 4 days then reflux, 2 h
3Bd 15 °C, 4 days then reflux, 2 h
3Bb 35 °C, 4 days
77
bDetermined by 1H NMR analysis with 1,1,2,2-tetrachloroethane as the
internal standard.
3
90
4
81
cThe KR was conducted at 25 °C for 20 h.
5d
3Bb 25 °C, 36 h then reflux, 2 h
98
dThe IMDA reaction was conducted by heating a solution of crude KR
products in toluene in an oil bath preheated at 120 °C for 3 h.
aThe DKR was conducted with acyl donor 3Bd or 3Bb (1.5 equiv; unless
otherwise noted), Novozym 435 (3.0 w/w), and V-MPS3 (1.0 mol%) in
MeCN (80 mM) at the temperature and for the time given in the table.
eIsolated yield by silica gel column chromatography.
fThe IMDA reaction was conducted without BHT.
bIsolated yield after column chromatography. A 4:1 mixture of two
diastereomers was obtained.
cOptical purity of each diastereomer determined by HPLC using a chiral
column.
In addition, rapid heating of the crude mixture containing 4A
was found to be critical to minimize hydrolysis and
decomposition of 4A. Thus, a solution of crude (R)-4A in toluene
was placed in an oil bath preheated at 120 °C and kept at the
same temperature for 3 h to give 5A in 46% isolated yield and
with 91% ee (entry 7). On the other hand, gradual heating from
room temperature to reflux followed by heating at the same
temperature for 10 h produced 5A in a lower yield (36%) and
with lower enantiomeric excess (71% ee) (entry 6). The use of
BHT was also important in suppressing the decomposition of 4A
(entry 8).
dThe DKR was conducted with acyl donor 3Bb (0.90 equiv), Novozym 435
(3.0 w/w), and V-MPS3 (1.0 mol%) in MeCN (80 mM) at 25 °C. 3Bb (0.90
equiv) was added portionwise in three equal batches at an interval of 12 h,
and the reaction mixture was stirred for another 12 h (total reaction time: 36
h) at 25 °C. The mixture was heated at reflux in an oil bath for 2 h to produce
5B, whose yield was based on ( )-1.
The applicability of other acyl donors 3B–3E bearing
different dienophile moieties to the Novozym 435-catalyzed
DKR/IMDA process was then examined,13 and the use of (Z)-3-
(phenylsulfonyl)acrylates (3Bd and 3Bb) was found to produce
the corresponding cycloadduct 5B even at 35 °C. Based on this
finding, we have devised a more reliable method for this
transformation. Thus, the treatment of ( )-1 with 3Bd (1.5
equiv), Novozym 435 (3.0 w/w), and V-MPS3 (1.0 mol%) in
MeCN at 35 °C resulted in the generation of ester (R)-4B
followed by gradual IMDA cyclization under the same reaction
conditions. After 4 days at 35 °C, a 4:1 diastereomeric mixture of
tricyclic 5B was isolated in a total yield of 84% and with 70% ee
for both diastereomers (Table 2, entry 1). Next, we attempted to
improve the enantiomeric excess of the products by performing
the DKR at a lower temperature, namely 25 °C and 15 °C;
however, the IMDA reaction was sluggish under these
conditions. Thus, after 4 days at 25 °C or 15 °C, the crude
mixture was heated at reflux for 2 h to drive the IMDA reaction
to completion, and a 4:1 diastereomeric mixture of 5B was
obtained with 77% ee (entry 2) or 90% ee (entry 3), respectively.
We next focused our attention on the DKR of ( )-1 with 3Ad
and V-MPS312 followed by IMDA. The DKR was performed in
MeCN at 25 °C for 24 h, and the reaction mixture was
concentrated in vacuo (Scheme 1). Toluene and BHT (5.0 mol%)
were added to the residue, and the flask was placed in an oil bath
preheated at 120 °C for 3 h to produce the IMDA product 5A
with higher enantioselectivity (95% ee) than that achieved with
the KR/IMDA process (Table 1, entry 7), but no improvement in
the isolated yield (45%) was observed. In order to increase the
yield of 5A, a variety of additives and solvents were screened,
and the addition of QuadraPure AMPA (1.0 w/w) significantly
improved the yield of 5A to up to 81%. However, the yield of 5A
varied in the range of 50–80% depending on the reaction scale,
probably because of partial decomposition of 4A during heating
of the toluene solution of the crude mixture.

In other attempts to increase the enantioselectivity, the more
reactive 1-ethoxyvinyl ester 3Bb was used. The DKR using 3Bb
(1.5 equiv) at 35 °C for 4 days provided 5B (81% ee) in 84%
yield (entry 4). A more dramatic improvement was achieved by
portionwise addition of 3Bb (0.90 equiv) in three equal batches
every 12 h at 25 °C followed by heating at reflux for 2 h, which
afforded 5B (a 4:1 mixture of two diastereomers, each with 98%
ee) in 72% isolated yield (entry 5). The absolute structure of its
major isomer is shown in Scheme 1 (for the determination of its
stereochemistry, see: Supplementary Information). Notably, this
method gave reproducible results regardless of the reaction scale.
Although 5B was always obtained as a 4:1 mixture of two
diastereomers, this diastereomeric mixture quantitatively
afforded 5A (98% ee) as a single stereoisomer by treatment with
1 equiv of DBU in CH2Cl2 at room temperature (Scheme 1).14
The diastereomeric mixture of 5B was treated with 1 equiv of
DBU to give 5A, which was then subjected to the olefin-selective
reduction with Mg in MeOH to afford 9 in quantitative yield.24
The lactone was protected as its acetal 10 (4:1 diastereomeric
mixture), and the olefin moiety was then converted into
secondary alcohol 11 (a mixture of four diastereomers) by the
standard hydroboration/oxidation protocol.
Dess–Martin
periodinane (DMP)-oxidation followed by DBU-mediated
epimerization quantitatively produced ketone 12. Notably, these
transformations converted the mixture of four diastereomers of
11 into 12 as a single stereoisomer. The spectroscopic data (1H
NMR, 13C NMR, and IR), melting point, and specific optical
rotation of 12 were in agreement with those of the compound
synthesized by Terashima et al.21c; thus, the absolute structure of
12 was unambiguously determined as shown in Scheme 2. Next,
homologation of the carbonyl of 12 into sulfone 15 was achieved
by Wittig olefination, hydroboration/oxidation, Mitsunobu
reaction with PhSH, and oxidation. The spectroscopic data of 15
were in agreement with those of its enantiomer, the key synthetic
intermediate of (+)-himbacine reported by Hart/Kozikowski18
and Terashima.21c Specific optical rotation of 15 was identical
with that of the same compound reported by Terashima.21c
2.2. Asymmetric total synthesis of (–)-himbacine
With these results in hand, we applied our DKR/IMDA
strategy to the asymmetric total synthesis of himbacine,9
a
tetracyclic piperidine alkaloid isolated from the bark of the
Australian pine tree of Galbulimima species. Himbacine is an
interesting natural product with strong selective affinity for M2
muscarinic receptor subtypes15 and potential medicinal
applications such as in the treatment of Alzheimer’s disease.16
The total syntheses of himbacine reported to date are based on
the construction of the optically active naphtho[2,3-c]furan-
1(3H)-one ring system by intra- or intermolecular Diels–Alder
reaction of optically active compounds with an (S)-stereogenic
center at the C3 position (the numbering refers to the
naphtho[2,3-c]furan-1(3H)-one skeleton) (Fig. 3),17-23 in which
more than five steps are required to prepare the substrates for the
IMDA reactions.
The final part of the total synthesis was carried out according
to the method of Hart and Kozikowski.18 The anion generated
from 15 was coupled with optically pure 16,21c,25 prepared from
(S)-piperidine-2-carboxylic acid according to the method
reported for ent-16,18 and the resulting diastereomeric mixture
was treated with sodium amalgam and Na2HPO4 in MeOH to
afford olefin 17. Hydrolysis of 17 followed by oxidation and Boc
deprotection produced (–)-himbeline 18, and final N-methylation
gave (–)-himbacine (Scheme 2). The spectroscopic data (1H
NMR, 13C NMR, and IR) and melting point of the product were
identical to the reported values,18b and the specific optical
rotation was in good agreement with that of (+)-himbacine18b and
(–)-himbacine.21c Hence, the use of commercial lipases in our
DKR/IMDA strategy led to the formation of (–)-himbacine, the
opposite enantiomer of the natural product. Notably, the core
tricyclic structure with the same absolute stereochemistry is
found in the FDA-approved thrombin receptor antagonist,
vorapaxar (Scheme 2).26
3. Conclusion
In contrast to the extensively developed lipase-catalyzed DKR
of racemic secondary alcohols, effective use of the acyl group
installed during KR or DKR, as part of the constituent structure
for subsequent reactions has been little investigated so far. In this
study, highly enantioselective DKR was achieved by suitable
choice of acyl donors and lipases, which was then directly
followed by IMDA reaction of the installed acyl moiety to
produce tricyclic products with up to 98% ee in a one-pot
procedure.
Fig. 3. Reported syntheses of (+)-himbacine.
In contrast, application of our DKR/IMDA reaction to the
total synthesis of himbacine is particularly attractive because it
allows the use of racemic alcohols (1 or 2) as substrates, which
are readily prepared from commercially available compounds in
only one or two steps.
As above-mentioned, compound 5A (72% yield, 98% ee) was
prepared from ( )-1, which was synthesized from enyne 6 in two
steps and 94% overall yield (Scheme 2). A similar one-pot
DKR/IMDA reaction was performed on the regioisomer ( )-2 (a
1:1 mixture of E- and Z-isomers), obtained in quantitative yield
from commercially available aldehyde 7 and the Grignard
reagent 8 (E/Z mixture). Treatment of ( )-2 with 3Bb (0.30 equiv
× 3) in the presence of Novozym 435 (3.0 w/w) and V-MPS3
(1.0 mol%) in MeCN at 25 °C for 36 h followed by refluxing for
2 h afforded 5B in 73% isolated yield as a 4:1 mixture of
diastereomers (98% ee for both diastereomers) (Scheme 2). The
latter results have proved that V-MPS3 catalyzed the 1,3-
migration of the hydroxyl group along with Z-to-E isomerization
and racemization via the allyl cation intermediate as shown in
Fig. 1b.
The practical effectiveness of our DKR/IMDA strategy was
demonstrated in the asymmetric synthesis of himbacine, using
commercial lipases. As most lipases exhibit catalytic activity
toward the (R)-enantiomers of secondary alcohols to produce (R)-
esters, our strategy led to the synthesis of (–)-himbacine, the
opposite enantiomer of the natural product. Notably, the (–)-
himbacine scaffold is found in vorapaxar (Scheme 2), a thrombin
receptor antagonist recently approved by the FDA for reducing
the risk of cardiovascular events.26 The (S)-selective DKR
process can be performed using other hydrolases, such as
subtilisin Carlsberg,27,28 Candida antarctica lipase A,29 and a
Novozym 435 mutant.30 Hence, the synthesis of both (R)- and
(S)-esters from racemic secondary alcohols can be achieved by
the choice of suitable enzymes, and the obtained compounds can

be used in the construction of fused cyclic compounds by the
one-pot DKR/IMDA process.
The oxovanadium-catalyzed DKR offers the possibility to
use regioisomeric allylic alcohols as equivalent substrates, which
makes the overall transformation shorter and more effective, and
represents an important advantage over the well-known DKR
requiring redox catalysts for the racemization.2 Our findings will
pave the way for a broader application of enzymatic DKR in the
production of optically active fused cyclic compounds. Further
application of the oxovanadium/hydrolase combo-catalyzed
DKR/intramolecular cyclization process is currently under
investigation in our group.
OH
(a), (b)
(±)-
1
6
O
OH
BrMg
(c)
8
H
7
(±)-
(
= 1:1)
E/Z
2
4. Experimental
H
H
3Bb
(e)
CAL-B
4.1. General considerations
(±)-
1
(±)-
1
O
(
)-
4B
R
(d)
or
(±)-
H
O
Melting points were determined on BUCHI Melting Point M-565
and Yanagimoto melting point apparatuses were uncorrected.
Infrared (IR) absorption spectra were recorded on SHIMADZU
FTIR-8400S and SHIMADZU IRAffinity-1S spectrophotometers. 1H
and 13C NMR spectra were measured on JEOL JNM-ECA500 (1H:
500 MHz, 13C: 125 MHz), JEOL AL-400 (1H: 400 MHz, 13C: 100
MHz), and JEOL AL-300 (1H: 300 MHz, 13C: 75 MHz) instruments
with chemical shifts reported in ppm relative to the residual
deuterated solvent. The mass spectra (MS) were measured on JEOL
JMS-S3000 (MALDI), Bruker Daltonics micrOTOF (ESI), and
JEOL JMS-700 (FAB) instruments. Yield refers to the isolated yield
V-MPS
2
PhO2S
(dr = 4:1)
5B
(±)-
(f)
2
H
H
H
H
(g), (h)
O
O
O
H
H
H
H
O
O
OMe
9
5A
(dr = 4:1)
10
X
OH
H
H
H
H
H
(j), (k)
(m), (n)
(i)
O
O
1
of a compound greater than 95% purity as determined by H NMR
H
H
H
OMe
(l)
OMe
analysis. 1H NMR and melting points (where applicable) of all
known compounds were taken. All new products were further
characterized by 13C NMR, IR and high resolution mass spectrum
(HRMS). HPLC analyses were carried out using a JASCO LC-
2000Plus system (HPLC pump: PU-2080, UV detectors: MD-2018
and MD-4017) equipped with a Daicel CHIRALPAK AD-3 column.
All optically active compounds are detected by 254 nm wavelength
absorption unless otherwise noted. Optical rotations were measured
on a JASCO P-1020 polarimeter.
11
(X = O)
12
(X = CH )
13
2
S(O)nPh
H
NBoc
NBoc
NR
H
H
H
H
CHO
H
16
(r)–(t)
O
OMe
(o)
H
H
H
H
H
H
(p), (q)
H
O
O
(n = 0)
(n = 2)
14
15
H
H
OMe
O
Burkholderia cepacia lipases PS-IM immobilized on
diatomaceous earth, supplied by Amano Enzyme Inc., Japan, and
Candida antarctica lipase B (Novozym 435) immobilized on a
support (commercial name: Chirazyme L-2 C4), purchased from
Novozymes, were used as received without further purification. V-
MPS3 was prepared according to the report.4a Silica gel 60N
purchased from Kanto Chemical Co., Inc., Japan was used for
column chromatography. All reagents were of reagent grade unless
otherwise stated. In general, the reactions were carried out in
commercial anhydrous solvents.
(R = H)
18
17
(u)
(–)-himbacine
(R = Me)
F
N
H
H
H
H
O
O
O
4.2 Preparation of racemic alcohols (1 and 2)
EtO
N
vorapaxar
H
Racemic alcohols (1 and 2) were prepared from the
commercially available compounds (6 and 7) as shown in Scheme 2.
Scheme 2. Total synthesis of (–)-himbacine. Reagents and
conditions: (a) nBuLi then MeCHO. (b) LiAlH4, 94% yield over two
steps. (c) 8 then H3O+, 99% yield (1:1 mixture of E- and Z-isomers).
(d) 3Bb (0.30 equiv × 3), Novozym 435 (3.0 w/w), V-MPS3 (1.0
mol%), MeCN, 25 °C, 36 h then reflux 2 h, 72% yield, 98% ee, dr =
4:1 from 1, 73% yield 98% ee, dr = 4:1 from 2. (e) DBU. (f) Mg,
MeOH, quant. over two steps. (g) DIBAL-H. (h) BF3•Et2O, MeOH,
84% yield over two steps (dr = 4:1). (i) BH3•Me2S then H2O2,
NaOH, 89% yield (a mixture of four diastereomers). (j) DMP. (k)
DBU, quant. over two steps. (l) Ph3P=CH2, 81% yield. (m) 9-BBN,
then H2O2, NaOH. (n) PhSH, DEAD, Ph3P, 86% yield over two
steps. (o) mCPBA, 97% yield. (p) nBuLi, 16. (q) Na(Hg), 33% yield
(84% yield based on recovery of 15) over two steps. (r) 10% aq.
HCl, (s) PDC, (t) CF3CO2H, 67% yield over three steps. (u)
NaBH3CN, HCHO, 82% yield.
4.2.1. (E)-4-(1-Cyclohexenyl)-3-buten-2-ol (1)
Under an argon atmosphere, n-BuLi (2.6 M in hexanes, 57 mL,
0.148 mol) was added into a solution of 1-ethynylcyclohexene (6)
(15.0 g, 0.141 mol) in THF (0.23 L) at –78 °C. The mixture was
stirred at the same temperature for an additional 15 min before a
solution of acetaldehyde (11.9 mL, 0.21 mol) in THF (20 mL) was
added. After being stirred at the same temperature for 30 min, the
reaction mixture was warmed up to 0 °C and then quenched with sat.
aq. NH4Cl. The product was extracted with EtOAc three times. The
combined organic phases were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (hexanes/EtOAc = 2:1) to give 4-(cyclohex-
1-en-1-yl)but-3-yn-2-ol (21 g, 0.140 mol) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δ: 1.46 (t, J = 6.5 Hz, 3H), 1.53–1.67 (m, 4H),

1.76 (d, J = 3.5 Hz, 1H), 2.03–2.14 (m, 4H), 4.60–4.68 (m, 1H),
6.07–6.13 (m, 1H).
(m, 0.8H), 4.87–4.94 (m, 0.2H), 5.56 (d, J = 2.0 Hz, 0.2H), 5.60 (d, J
= 2.0 Hz, 0.8H), 7.56–7.61 (m, 2H), 7.71–7.66 (m, 1H), 7.97–7.93
(m, 2H). IR (neat) ν: 1778 cm–1. HRMS (ESI) m/z calcd for
C19H22NaO4S [M+Na]+: 369.1132. Found: 369.1131.
Under an an argon atmosphere, a solution of 4-(cyclohex-1-en-1-
yl)but-3-yn-2-ol (21 g, 0.140 mol) in THF (50 mL) was dropwise
added to an ice-cold suspension of LiAlH4 (16 g, 0.42 mol) in THF
(0.65 L). After being stirring at the same temperature for 1 h, the
reaction mixture was quenched with 15% aq. NaOH, and the whole
mixture was filtered through a Celite pad. The filtrate was
concentrated under reduced pressure, and the residue was purified by
column chromatography (hexanes/EtOAc = 1:2) to give 1 (20.2 g,
94% yield over 2 steps) as a colorless oil. 1H NMR (500 MHz,
CDCl3) δ: 1.29 (d, J = 6.0 Hz, 3H), 1.54–1.73 (m, 4H), 2.07–2.15
(m, 4H), 4.31–4.39 (m, 1H), 5.59 (dd, J = 16.0, 7.0 Hz, 1H), 5.73–
5.78 (m, 1H), 6.18 (d, J = 16.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ: 22.4, 22.5, 23.5, 24.5, 25.8, 69.2, 129.4, 130.1, 133.4,
135.0; IR (CHCl3) ν: 3607 cm–1. HRMS (ESI) m/z calcd for C10H17O
[M+H]+: 153.1274. Found; 153.1279.
A pure major isomer of 5B was obtained by recrystalization of
the abovementioned 4:1 diastereomixture of 5B and its
1
stereochemistry was determined by H HMR and NOESY analyses
(in detail, see: Supplementary Information). [α]1D9 = +31.8 (c 1.00,
1
CHCl3). Mp 144–145 °C. H NMR (400 MHz, CDCl3) δ: 1.24 (tq, J
= 4.0, 13.0 Hz, 1H), 1.34 (dq, J = 3.0, 12.5 Hz, 1H), 1.48–1.62 (m,
1H), 1.54 (d, J = 6.0 Hz, 3H), 1.63–1.70 (m, 1H), 1.80–1.90 (m, 2H),
2.10–2.22 (m, 1H), 2.27–2.35 (m, 1H), 2.63 (dd, J = 3.0, 14.0 Hz,
1H), 2.93–3.01 (m, 1H), 3.24–3.33 (m, 1H), 3.53 (d, J = 3.0 Hz, 1H),
4.11 (qd, J = 6.0, 10.5 Hz, 1H), 5.58–5.62 (m, 1H), 7.56–7.62 (m,
2H), 7.65–7.72 (m, 1H), 7.93–7.97 (m, 2H). 13C NMR (125 MHz,
CDCl3) δ: 18.5, 26.6, 28.0, 35.6, 36.1, 40.0, 43.1, 44.2, 63.4, 80.4,
116.4, 128.5, 129.5, 134.3, 139.7, 143.6, 172.3.
4.2.2. 1-(1-Cyclohexenyl)-2-buten-1-ol (2)
4.3.2. From ( )-2:
Under an argon atmosphere, 1-propenylmagnesium bromide 8 (a
mixture of E- and Z-isomers, 0.5 M in THF, 1.1 mL, 0.54 mmol) was
added to a solution of 7 (50 mg, 0.45 mmol) in THF (2 mL) at –78
°C. After being stirred at the same temperature for 5 min, the
reaction mixture was warmed up to 0 °C, quenched with sat. aq.
NH4Cl, and extracted three times with Et2O. The combined organic
phases were dried over MgSO4, filtered, and concentrated under
reduced pressure. The residue was purified by column
chromatography (hexanes/EtOAc = 3:1) to give 2 (69 mg, 99%
Similarly to the preparation of 5B from ( )-1, 5B (165 mg, 73%
yield), a 4:1 mixture of (3R,3aS,8aR,9S,9aS)-3-methyl-9-(phenyl-
sulfonyl)-3a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-
one (98% ee) and its diastereomer (98% ee), was obtained from ( )-2
(100 mg, 0.66 mmol), Novozym 435 (300 mg, 3.0 w/w), V-MPS3
(33 mg, vanadium component: 6.6 µmol) and 3Bb (56 mg x 3, 0.20
mmol x 3). The spectroscopic data of the obtained product 5B were
in good agreement with 5B obtained from ( )-1.
4.4. (3R,3aS,8aS)-3-Methyl-3a,5,6,7,8,8a-hexahydronaphtho[2,3-
c]furan-1(3H)-one (5A)
1
yield) as a 1:1 mixture of E- and Z-2. A colorless oil. H NMR (500
MHz, CDCl3) δ: 1.43-1.50 (m, 1H), 1.52-1.68 (m, 5H), 1.705 (t, J =
6.0 Hz, 1.5H), 1.707 (t, J = 6.0 Hz, 1.5H),1.90-2.08 (m, 4H),4.40 (d,
J = 7.0 Hz, 0.5H), 4.82 (d, J = 8.5 Hz, 0.5H),5.42-5.55 (m, 0.5H),
(qdd, J = 1.5, 7.0, 8.5 Hz, 0.5H), 5.57-5.64 (m, 0.5H), 5.66-5.76 (m,
1.5H);13C NMR (125 MHz, CDCl3) δ: 13.3, 17.7, 22.5, 22.6, 24.2,
24.3, 25.0, 71.5, 122.1, 122.5, 126.5, 127.2, 131.6, 132.2, 139.3,
139.4; IR (CHCl3) ν: 3350, 2930 cm-1. HRMS (ESI) m/z calcd for
C10H17O [M+H]+: 153.1274. Found; 153.1276.
To an ice-cold solution of 5B (a 4:1 mixture of two diastereomer,
0.20 g, 0.58 mmol) in CHCl3 (2 mL) was added DBU (86 µl, 0.58
mmol). The reaction mixture was stirred at room temperature for 1.5
h and was concentrated under reduced pressure. The residue was
purified by flash column chromatography (hexanes/EtOAc = 5:1) to
afford 5A (198 mg, quant., 98% ee) as a white solid. The
enantiomeric excess was determined by HPLC analysis at 20 °C,
using
a
CHIRALCPAK AD-3 column (hexanes/2-propanol
=
=
4.3. (3R,3aS,8aR,9S,9aS)-3-Methyl-9-(phenylsulfonyl)-
97.5:2.5, 1.0 mL/min; retention times 10.7 (R), 13.9 min (S)). [α]2D0
3a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one and its
diastereomer (5B)
7.90 (c 0.95, CHCl3). Mp 84–85 °C. 1H NMR (500 MHz, CDCl3) δ:
1.12 (qd, J = 13.0, 3.5 Hz, 1H), 1.23 (qt, J = 13.0, 4.0 Hz, 1H) ,
1.55–1.44 (m, 1H), 1.53 (d, J = 6.5 Hz, 3H) , 1.77–1.87 (m, 2H) ,
2.02–2.10 (m, 2H) , 2.34–2.40 (m, 1H), 2.85–2.77 (m, 1H), 3.07–
3.00 (m, 1H), 4.11 (dq, J = 10.0, 6.5 Hz, 1H), 5.41 (dd, J = 2.5, 4.5
Hz, 1H), 6.50 (t, J = 2.5 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ:
19.2, 26.0, 26.9, 34.3, 34.9, 38.7, 45.8, 80.6, 113.5, 128.4, 136.2,
141.3, 169.8; IR (neat) ν: 1744 cm–1. HRMS (ESI) m/z calcd for
C13H17O2 [M+H]+: 205.1222. Found: 205.1223.
4.3.1. From ( )-1:
Under an argon atmosphere immobilized Candida antarctica
lipase B (Novozym 435) (300 mg, 3.0 w/w), V-MPS3 (33 mg,
vanadium component: 6.6 µmol) and 3Bb (56 mg, 0.197 mmol) were
added to a solution of ( )-1 (100 mg, 0.66 mmol) in MeCN (8 mL,
0.08 M). The reaction mixture was stirred at 25 °C for 12 h, and
another 3Bb (56 mg, 0.197 mmol) was added, and the reaction
mixture was stirred at 25 °C for 12 h. This procedure was repeated
one more time (the reaction mixure was stirred for totally 36 h), and
then the mixture was heated at reflux temperature for 2 h. After
cooling, the reaction mixture was filtered through a Celite pad, and
the filtrate was concentrated under reduced pressure. The residue
was purified by column chromatography (hexanes/EtOAc = 10:1) to
4.5. (3R,3aS,8aS,9aR)-3-Methyl-3a,5,6,7,8,8a,9,9a-
octahydronaphtho[2,3-c]furan-1(3H)-one (9)
Under an argon atmosphere, magnesium (0.20 g, 8.3 mmol) was
added to an ice-cold solution of 5A (0.85 g, 4.2 mmol) in MeOH (21
mL). The reaction mixture was stirred at room temperature for 1 h
and then filtered through a short pad of silica gel. The filtrate was
concentrated under reduced pressure. To the residue was added
CH2Cl2, and the mixture was filtered through a Celite pad. The
filtrate was concentrated under reduced pressure, and the residue was
purified by column chromatography (hexanes/EtOAc = 10:1) to give
9 (0.86 g, quant.) as a white solid. [α]1D8 = 15.3 (c 1.01, CHCl3). Mp
75–76 °C. 1H NMR (500 MHz, CDCl3) δ: 0.97 (qd, J = 12.0, 3.5 Hz,
1H), 1.22 (qt, J = 13.0, 3.5 Hz, 1H), 1.31–1.45 (m, 2H) , 1.45 (d, J =
6.5 Hz, 3H), 1.73–1.80 (m, 2H), 1.89–2.08 (m, 4H), 2.27 (ddq, J =
14.5, 4.0, 2.0 Hz, 1H), 2.47–2.53 (m, 1H), 2.59–2.67 (m, 1H), 4.27
(dq, J = 9.0, 5.5 Hz, 1H), 5.29 (qd, J = 2.5, 4.5 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ: 19.2, 25.8, 27.0, 29.0, 34.7, 34.9, 35.8, 39.3,
give 5B (164 mg, 72% yield) as
(3R,3aS,8aR,9S,9aS)-3-methyl-9-(phenylsulfonyl)-
a
4:1 mixture of
3a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one (98%
ee) and its diastereomer (98% ee). A white solid. The enantiomeric
excess of each diastereomer was determined by HPLC analysis at 20
°C using a Daicel CHIRALCPAK AD-3 column (hexanes/2-
propanol = 95:5, 1.0 mL/min. Retention times; major isomer: 16.5
(R), 18.3 min (S), minor isomer: 20.5 (R), 22.4 min (S)). [α]2D8 = –
1
36.2 (c 0.82, CHCl3). H NMR (500 MHz, CDCl3) δ: 1.18–1.39 (m,
2H) , 1.49–1.61 (m, 4H) , 1.63–1.70 (m, 1H) , 1.80–1.89 (m, 2H),
2.19–2.21 (m, 1H) , 2.28–2.37 (m, 1H), 2.62 (dd, J = 14.0, 3.0 Hz,
0.8H), 2.69 (dd, J = 14.0, 3.5 Hz, 0.2H) , 2.92–3.00 (m, 1H), 3.24–
3.32 (m, 0.8H), 3.51–3.56 (m, 1H), 3.84–3.92 (m, 0.2H) , 4.07–4.15

43.7, 81.4, 114.8, 144.0, 178.9; IR (neat) ν: 1770 cm–1. HRMS (ESI)
m/z calcd for C13H19O2 [M+H]+: 207.1382. Found: 207.1380.
product 12 were in good agreement with those of ent-12 reported in
the literature.21c
4.6. (1R,3S,3aR,4aS,9aS)-3-Methoxy-1-methyl-
4.9. (1S,3R,3aR,4aR,8aS,9aR)-1-Methoxy-3-methyl-4-methylene-
dodecahydronaphtho[2,3-c]furan (13)
1,3,3a,4,4a,5,6,7,8,9a-decahydronaphtho[2,3-c]furan (10)
Under an argon atmosphere, DIBAL-H (1.0 M in hexane, 0.72
mL, 0.72 mmol) was dropwise added to a solution of 9 (99 mg, 0.49
mmol) in Et2O (5.0 mL) at –78 °C. After being stirred at the same
temperature for 10 min, the reaction mixture was quenched with
MeOH (0.1 mL) and filtered through a silica gel pad. The pad was
washed with EtOAc, and the combined filtrates were concentrated
under reduced pressure. To the residue was added EtOAc, and the
mixture was filtered through a Celite pad. The filtrate was
concentrated under reduced pressure. The residue was dissolved in
MeOH (5.0 mL), and BF3•Et2O (3 µL, 14 µmol) was added at 0 °C.
The mixture was warmed to room temperature over a period of 3 h
and filtered through a silica gel pad. The pad was washed with
EtOAc, and the combined filtrates were concentrated under reduced
pressure. The residue was purified by flash chromatography
(hexanes/EtOAc = 20:1) to give 10 (89 mg, 84% yield) as a 4:1
mixture of two diastereomers. A colorless oil. [α]1D9 = 33.4 (c 1.01,
Under an argon atmosphere, n-butyl lithium (1.6 M in hexane,
2.4 mL, 4.0 mmol) was dropwise added to a suspension of methyl-
triphenylphosphonium iodide (1.7 g, 4.2 mmol) in THF (10 mL) at –
78 °C. The reaction mixture was stirred at 0 °C for 30 min and cooled
down to –78 °C, to which a solution of 12 (0.40 g, 2.1 mmol) in THF
(5 mL) was added. The reaction mixture was warmed up to room
temperature, stirred at the same temperature for 1.5 h, quenched with
saturated aq. NH4Cl, and extracted with Et2O three times. The
combined organic phases were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexanes/EtOAc =
20:1) to give 13 (0.16 g, 81% yield) as a colorless oil. [α]2D0 = –65.5
23
D
(c 0.49, CHCl3) (lit.21c [α]
= –58 (c 0.29, CHCl3)). The
spectroscopic data of the obtained product 13 (1H NMR, 13C NMR
and IR) were in good agreement with those of ent-13 reported in the
literature.21c
1
CHCl3). H NMR (500 MHz, CDCl3) δ: 0.90 (qd, J = 12.5, 3.5 Hz,
4.10. (1S,3R,3aR,4S,4aR,8aS,9aR)-1-Methoxy-3-methyl-4-
1H) , 1.08–1.36 (m, 3H) , 1.27 (d, J = 5.5 Hz, 0.6H), 1.33 (d, J = 5.5
Hz, 2.4H) , 1.70–1.77 (m, 3H), 1.83–2.04 (m, 3H) , 2.12–2.27 (m,
2H) , 2.33–2.40 (m, 1H), 3.33 (s, 2.4H), 3.44 (s, 0.6H), 3.78 (dq, J =
10.0, 6.0 Hz, 0.2H), 3.89 (dq, J = 9.0, 6.0 Hz, 0.8H), 4.61 (s, J =
0.8H), 5.10 (d, J = 5.5 Hz, 0.2H), 5.20–5.23 (m, 0.2H), 5.31–5.34
(m, 0.8H). 13C NMR (125 MHz, CDCl3) δ: 18.8, 21.2, 26.0, 27.0,
27.2, 28.0, 31.1, 34.7, 34.8, 35.1, 35.2, 36.1, 36.6, 40.8, 44.2, 44.4,
47.4, 54.2, 56.5, 77.7, 82.1, 06.4, 109.5, 116.1, 117.2, 141.7, 143.3;
IR (neat) ν: 1069 cm–1. HRMS (ESI) m/z calcd for C14H22NaO2
[M+Na]+: 245.1503. Found: 245.1512.
((phenylthio)methyl)dodecahydronaphtho[2,3-c]furan (14)
Under an argon atmosphere, 9-BBN (0.5 M in THF, 10.4 mL,
5.2 mmol) was dropwise added to an ice-cold solution of 13 (0.41 g,
1.73 mmol) in THF (30 mL). The reaction mixture was stirred at
room temperature for 15 h and cooled to 0 °C. Then, 1 N aq. NaOH
(8.7 mL) and 35% aq. H2O2 (0.84 mL) were added. The reaction
mixture was stirred at 0 °C for 15 min and extracted with Et2O three
times. The combined organic phases were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexanes/EtOAc = 5:1) to afford
the primary alcohol (0.40 g, 91% yield) as single isomer. The
obtained alcohol (0.35 g) was dissolved in CH2Cl2 (0.3 mL), and
diethyl azodicarboxylate (40%, 1.2 g, 2.8 mmol), Ph3P (0.72 g, 2.8
mmol) and thiophenol (0.28 mL, 2.8 mmol) were added at 0 °C. The
reaction mixture was stirred at room temperature for 12 h, quenched
with saturated aq. NH4Cl, and extracted with Et2O three times. The
combined organic phases were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (hexanes/EtOAc = 40:1 to 4:1) to give 14
(0.45 g, 86% yield over 2 steps) as a white solid. [α]2D0 = –165 (c 0.50,
CHCl3) (lit.21c [α]2D5 = –140 (c 0.15, CHCl3) for 14, lit.18b [α]2D0 +138.5
(c 0.73, CHCl3) for ent-14). Mp 51 °C (lit.21c 42–43°C for ent-14).
The spectroscopic data (1H NMR, 13C NMR and IR) of the obtained
product 14 were in good agreement with those of ent-14 reported in
the literature.18b,21c
4.7. (1S,3R,3aR,8aS,9aR)-1-Methoxy-3-methyldodecahydro-
naphtho[2,3-c]furan-4-ol and its diastereomers (11)
Under an argon atmosphere, BH3•Me2S (1.0 g, 12.0 mmol) was
added to an ice-cold solution of 10 (0.90 g, 4.0 mmol) in THF (20
mL). After being stirred at 30 °C for 1 h, the reaction mixture was
cooled to 0 °C, and then 1 N aq. NaOH (20 mL) and 30% aq. H2O2
(2.3 mL) were added. After being stirred at 0 °C for 30 min, the
reaction mixture was poured into saturated aq. NH4Cl and extracted
with Et2O three times. The combined organic phases were washed
with brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatography
(hexanes/EtOAc = 5:1) to give 11 (0.87 g, 89% yield) as a mixture of
four diastereomers. A colorless oil. The spectroscopic data (1H NMR
and IR) of one component of this mixture was in good agreement
with
those
of
(1S,3R,3aR,8aS,9aR)-1-methoxy-3-
methyldodecahydronaphtho[2,3-c]furan-4-ol reported in the
4.11. (1S,3R,3aR,4S,4aR,8aS,9aR)-1-Methoxy-3-methyl-4-
((phenylsulfonyl)methyl)dodecahydronaphtho[2,3-c]furan (15)
To an ice-cold suspension of 14 (0.45 g, 1.30 mmol) and
NaHCO3 (0.55 g, 6.5 mmol) in CH2Cl2 (50 mL) was portionwise
added mCPBA (77% pure, 0.78 g, 3.2 mmol). The reaction mixture
was stirred at 0 °C for 1 h, diluted with Et2O, and washed with aq.
NaHCO3. The organic phase was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (hexanes/EtOAc = 6:1 to 2:1) to give 15 (0.48
g, 97% yield) as a white solid. [α]2D0 = –103 (c 0.98, CHCl3) (lit.21c
[α]2D2 = –104 (c 0.35, CHCl3)). Mp 132 °C (lit.21c 129–130 °C). The
spectroscopic data (1H NMR and 13C NMR) of the obtained product
15 were in good agreement with those of ent-15 reported in the
literature.18b,21c
literature.21c
4.8. (1S,3R,3aS,4aR,8aS,9aR)-1-methoxy-3-methyldecahydro-
naphtho[2,3-c]furan-4(1H)-one (12)
Dess–Martin periodinane (1.6 g, 3.8 mmol) was added to a
solution of 11 (0.62 g, 2.6 mmol) in CH2Cl2 (60 mL). After being
stirred at room temperature for 0.5 h, the mixture was concentrated
under reduced pressure. The residue was purified by flash
chromatography (hexanes/Et2O = 5:1) to give a ketone (0.61 g,
quant.) as a colorless oil. The ketone (0.60 g, 2.5 mmol) was
dissolved in CHCl3 (20 mL), and DBU (0.38 mL, 2.5 mmol) was
added at room temperature. After being stirred at reflux temperature
for 3 h, the reaction mixture was concentrated under reduced
pressure. The residue was purified by flash chromatography
(hexanes/EtOAc = 10:1) to give 12 (0.60 g, quant.) as a single
compound. A white solid. [α]2D0 = –167 (c 0.53, CHCl3) (lit.21c [α]2D1
=
4.12. tert-Butyl (2S,6R)-2-((E)-2-((1R,3R,3aS,4S,4aR,8aS,9aR)-1-
methoxy-3-methyldodecahydronaphtha[2,3-c]furan-4-yl)vinyl)-6-
methylpiperidine-1-carboxylate (17)
–165 (c 0.41, CHCl3)). Mp 87–88 °C (lit.21c Mp 86–87 °C). The
spectroscopic data (1H NMR, 13C NMR and IR) of the obtained

Under an argon atmosphere, n-butyl lithium (2.6 M in hexane,
100 µL, 0.26 mmol) was dropwise added to a solution of 15 (100
mg, 0.26 mmol) in THF (2.0 mL) at –78 °C. The reaction mixture
was stirred at –50 °C for 30 min, and a solution of 16 (90 mg, 0.40
mmol) in THF (1.0 mL) was added. The reaction mixture was stirred
at –60 °C for 2 h, quenched with H2O, and extracted with Et2O three
times. The combined organic phases were dried over Na2SO4,
filtered, and concentrated under reduced pressure to give a residue.
The residue was purified by flash chromatography (hexanes/EtOAc
= 5:1) to give the coupling product (59 mg, 40% yield) as a white
solid along with the recovery of 15 (60 mg, 60% yield). To a solution
of thus obtained coupling product (59 mg) in MeOH (5 mL) were
added 6% sodium amalgam (2.1 g) and disodium hydrogen
phosphate (0.44 g) at room temperature. After being stirred at the
same temperature for 2 h, the reaction mixture was quenched with
H2O, and filtered through a Celite pad. The filtrate was extracted
with Et2O three times. The combined organic phases were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexanes/EtOAc =
9:1) to give 17 [39 mg, 33% yield (84% yield based on recovery of
15) over 2 steps] as a white solid. [α]1D9 = –96.3 (c 0.39, CHCl3)
(lit.21c [α]2D3 = –88 (c 0.35, CHCl3), lit.18b [α]2D0 = +90.5 (c 0.38,
CHCl3) for ent-17). Mp 92 °C (lit.21c 90–92 °C, lit.18b 92–93 °C for
ent-17). The spectroscopic data (1H NMR, 13C NMR and IR) of the
obtained product 17 were in good agreement with those for ent-17
reported in the literature.18b,21c
Sodium cyanoborohydride (7.5 mg, 0.119 mmol) was added to a
mixture of 18 (18 mg, 54 µmol) and 37 wt% aq. formaldehyde (40
µL, 0.54 mmol) in MeCN (1.0 mL). The reaction mixture was stirred
at room temperature for 30 min, and acetic acid was added dropwise
to make the reaction mixture neutral (pH 7). The resulting mixture
was stirred at same temperature for an additional 1.5 h and cooled to
0 °C. 15% aq. NaOH (2 mL) was added, and the mixture was
extracted with Et2O three times. The combined organic phases were
dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash chromatography
(EtOAc/MeOH = 1:3) to give (–)-himbacine (15.3 mg, 82%) as a
white solid. [α]1D9 = –59.8 (c 0.70, CHCl3) (lit.21c [α]2D3 = –59 (c 0.29,
CHCl3) for (–)-himbacine), lit.18b [α]2D0 = +51.4 (c 1.01, CHCl3) for
(+)-himbacine). Mp 130-131 °C (lit.21c 128–130 °C for (–)-
himbacine, lit.18b 129–130 °C for (+)-himbacine). 1H NMR (500
MHz, CDCl3) δ: 0.65-0.83 (m, 1H), 0.89-1.06 (m, 3H), 0.99 (d, J =
6.5 Hz, 3H), 1.08–1.32 (m, 3H), 1.35-1.48 (m, 2H), 1.39 (d, J = 6.0
Hz, 3H), 1.48–1.60 (m, 2H), 1.60–1.81 (m, 6H), 1.86 (dd, J = 6.5,
12.5 Hz, 1H), 2.04-2.16 (m, 1H), 2.18–2.29 (m, 1H), 2.21 (s, 3H),
2.61 (td, J = 6.5, 13.5 Hz, 1H), 2.78–2.90 (m, 1H), 2.97–3.09 (m,
1H), 4.62 (qd, J = 6.0, 11.0 Hz, 1H), 5.25 (dd, J = 10.0, 15.0 Hz,
1H), 5.57 (dd, J = 9.5, 15.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ:
13.9, 18.9, 22.2, 26.1, 26.4, 31.4, 32.0, 32.5, 33.2, 33.6, 39.9, 41.1,
41.5, 42.2, 45.7, 49.1, 53.4, 61.3, 76.8, 133.4, 133.5, 178.3; IR (neat)
ν: 1778, 1454 cm–1. HRMS (ESI) m/z calcd for C22H36NO2 [M+H]+:
346.2741. Found: 346.2746. The abovementioned spectroscopic data
were in good agreement with those for natural (+)-himbacine
reported in the literature.18b,21c
4.13. (3R,3aS,4S,4aR,8aS,9aR)-4-((E)-2-((2S,6R)-1,6-
dimethylpiperidin-2-yl)vinyl)-3-methyldecahydronaphtho[2,3-
c]furan-1(3H)-one (18, ent-himbeline)
Acknowledgments
To an ice-cold solution of 17 (55 mg, 0.123 mmol) in acetone
(4.0 mL) was added 10% aq. HCl (2.0 mL). The reaction mixture
was stirred at room temperature for 30 min, quenched with aq.
NaHCO3, and extracted with EtOAc three times. The combined
organic phases were dried over Na2SO4, filtered and concentrated
under reduced pressure to give a hemiacetal (51 mg). To a solution
of thus obtained hemiacetal (51 mg) in CH2Cl2 (2.0 mL) were added
pyridinium dichromate (90 mg, 0.24 mmol) and molecular sieves 4A
(0.55 g). The reaction mixture was stirred at 30 °C for 1 h, diluted
with a 3:1 mixture of hexanes and EtOAc, and filtered through a
silica gel pad. The pad was washed with a 3:1 mixture of hexanes
and EtOAc, and the combined filtrates were concentrated under
reduced pressure. The residue was purified by flash chromatography
(hexanes/EtOAc = 4:1) to give tert-butyl (2R,6S)-2-methyl-6-((E)-
2-((3R,3aS,4S,4aR,8aS,9aR)-3-methyl-1-oxododecahydro-
naphtho[2,3-c]furan-4-yl)vinyl)piperidine-1-carboxylate (43 mg,
81% yield over 2 steps) as a colorless oil. [α]2D8 = –50.2 (c 0.14,
CHCl3) (lit.21c [α]2D5 = –63 (c 0.50, CHCl3), lit.18b [α]2D0 = +60.6 (c
This study was supported by JSPS KAKENHI [Grant
Numbers: JP16H01151 (Middle Molecular
Strategy),
JP15H04631, and JP26670002] and the Platform Project for
Supporting Drug Discovery and Life Science Research funded by
Japan Agency for Medical Research and Development (AMED).
We acknowledge the Japan Society for the Promotion of Science
for the pre-doctoral fellowship to KS, Amano Enzyme, Inc. for
supplying the lipase.
References and notes
1.
(a) Faber K. Biotransformations in Organic Chemistry; A Textbook.
6th Ed. Heidelberg: Springer; 2011;
(b) Busto E, Gotor-Fernández V, Gotor V. Chem Rev. 2011;111:3998–
4035;
(c) de Melo Carvalho ACL, de Sousa Fonseca T, de Mattos MC, de
Oliveira MCF, de Lemos TLG, Molinari F, Romano D, Serra I. Int J
Mol Sci. 2015;16:29682–29716.
1
0.55, CHCl3) for ent-isomer). H NMR data of the obtained product
2.
(a) Akai S. Chem Lett. 2014;43:746–754;
were in good agreement with those for its enantiomer reported in the
(b) Verho O, Bäckvall J-E. J Am Chem Soc. 2015;137:3996–4009;
(c) Långvik O, Saloranta T, Murzin DY, Leino R. ChemCatChem.
2015;7:4004–4015;
(d) de Miranda AS, Miranda LSM, de Souza ROMA. Biotechnol Adv.
2015;33:372–393.
V-MPSs were prepared from MPSs with a pore diameter of 2–4 nm
and are named as V-MPS2 to V-MPS4 based on the pore size of
MPS.4b
(a) Egi M, Sugiyama K, Saneto M, Hanada R, Kato K, Akai S. Angew
Chem Int Ed. 2013;52:3654–3658;
(b) Sugiyama K, Oki Y, Kawanishi S, Kato K, Ikawa T, Egi M, Akai
S. Catal Sci Technol. 2016;6:5023–5030;
See also: (c) Akai S, Tanimoto K, Kanao Y, Egi M, Yamamoto T, Kita
Y. Angew Chem Int Ed. 2006;45:2592–2595;
(d) Akai S, Hanada R, Fujiwara N, Kita Y, Egi M. Org Lett.
2010;12:4900–4903.
(a) Suga S, Yamada D, Yoshida J-i. Chem Lett. 2010;39:404–406;
(b) Yoshida J-i, Saito K, Nokami T, Nagaki A. Synlett. 2011;1189–
1194.
For an example, see: Warner MC, Shevchenko GA, Jouda S, Bogár K,
Bäckvall J-E. Chem Eur J. 2013;19:13859–13864.
literature.18b,21c
Trifluoroacetic acid (0.5 mL) was added to a solution of thus
obtained compound (30 mg, 38 µmol) in CH2Cl2 (1.0 mL). The
reaction mixture was stirred at room temperature for 30 min,
quenched with 6N aq. NaOH, and extracted with CH2Cl2 three times.
The combined organic phases were dried over K2CO3, filtered, and
concentrated under reduced pressure. The residue was purified by
flash chromatography (EtOAc/MeOH = 3:1) to give 18 (ent-
himbeline) (9.2 mg, 83% yield) as a colorless oil. [α]1D9 = –20 (c 0.17,
CHCl3) (lit.21c [α]2D2 = –15 (c 0.44, CHCl3) for ent-himbeline), lit.18b
[α]2D0 = +17.1 (c 0.56, CHCl3) for himbeline). The spectroscopic data
(1H NMR, 13C NMR and IR) of the obtained product were in good
agreement with those for its enantiomer reported in the
literature.18b,21c
3.
4.
5.
6.
4.14. (–)-Himbacine

7.
For examples on the use of the installed acyl donors, see:
(a) Ghogare A, Kumar GS. J Chem Soc Chem Commun. 1990;134–
135;
(c) Hofman S, Gao L-J, Van Dingenen H, Hosten NGC, Van Haver D,
De Clercq PJ, Milanesio M, Viterbo D. Eur J Org Chem. 2001;2851–
2860;
(b) Brenna E, Fuganti C, Grasselli P, Serra S. Eur J Org Chem.
2001;1349–1357;
(c) Gruttadauria M, Meo PL, Noto R. Tetrahedron Lett. 2004;45:83–
85;
(d) Gao L-J, Waelbroeck M, Hofman S, Van Haver D, Milanesio M,
Viterbo D, De Clercq PJ. Bioorg Med Chem Lett. 2002;12:1909–1912.
20. (a) Chackalamannil S, Davies RJ, Asberom T, Doller D, Leone D. J
Am Chem Soc. 1996;118:9812–9813;
(d) Sundby E, Perk L, Anthonsen T, Aasen AJ, Hansen TV.
Tetrahedron 2004;60:521–524;
(b) Doller D, Chackalamannil S, Czarniecki M, McQuade R, Ruperto
V. Bioorg Med Chem Lett. 1999;9:901–906;
(e) Langille NF, Panek JS. Org Lett. 2004;6:3203–3206;
(f) Kawanishi S, Sugiyama K, Oki Y, Ikawa T, Akai S. Green Chem.
2017;19:411–417;
See also: (g) Coelho P, Blanco L. Eur J Org Chem. 2000;3039–3046.
We have developed some strategies for the effective use of the
installed acyl moieties for constructing multi-ring fused optically
active molecules by domino processes.
(a) Akai S, Naka T, Omura S, Tanimoto K, Imanishi M, Takebe Y,
Matsugi M, Kita Y. Chem Eur J. 2002;8:4255–4264;
(b) Akai S, Tanimoto K, Kanao Y, Omura S, Kita Y. Chem Commun.
2005;2369–2371;
(c) Chackalamannil S, Davies RJ, Wang Y, Asberom T, Doller D,
Wong J, Leone D, McPhail AT. J Org Chem. 1999;64:1932–1940;
(d) Chackalamannil S, Davies R, McPhail AT. Org Lett. 2001;3:1427–
1429.
8.
21. (a) Takadoi M, Katoh T, Ishiwata A, Terashima S. Tetrahedron Lett.
1999;40:3399–3402;
(b) Takadoi M, Terashima S. Bioorg Med Chem Lett. 2002;12:2871–
2873;
(c) Takadoi M, Katoh T, Ishiwata A, Terashima S. Tetrahedron.
2002;58:9903–9923;
(d) Takadoi M, Yamaguchi K, Terashima S. Bioorg Med Chem.
2003;11:1169–1186.
(c) Akai S, Tanimoto K, Kita Y. Angew Chem Int Ed. 2004;43:1407–
1410;
22. (a) Wong LS-M, Sharp LA, Xavier NMC, Turner P, Sherburn MS. Org
Lett. 2002;4:1955–1957;
(b) Wong LS-M, Sherburn MS. Org Lett. 2003;5:3603–3606.
23. For some other recent studies of himbacine analogs:
(a) Howell JM, Liu W, Young AJ, White MC. J Am Chem Soc.
2014;136:5750–5754;
(d) Nemoto H, Tanimoto K, Kanao Y, Omura S, Kita Y, Akai S.
Tetrahedron 2012;68:7295–7301.
(a) Pinhey JT, Ritchie E, Taylor WC. Aust J Chem. 1961;14:106–134;
(b) Brown FFC, Drummond R, Fogerty AC, Hughes GK, Pinhey JT,
Ritchie E, Taylor WC. Aust J Chem. 1956;9:283–287.
9.
10. Kita Y, Akai S. Chem Rec. 2004;4:363–372 and references cited
therein.
11. The absolute stereochemistries of 4A and 5A were tentatively assigned
(b) Zaks A, Tamarez M, Li T. Adv Synth Catal. 2009;351:2351–2357;
(c) Casey M, McCarthy R. Synlett. 2011;801–804;
(d) Larson RT, Pemberton RP, Franke JM, Tantillo DJ, Thomson RJ. J
as shown in Table
1 according to general tendency of the
Am Chem Soc. 2015;137:11197–11204;
enantioselectivity of PS-IM and Novozym 435, which preferentially
catalyze esterification of (R)-alcohols. Later, the absolute
stereochemistry of 12, derived from 5A, was confirmed by the
comparison with the known compound (vide infra).
(e) Knight E, Robinson E, Smoktunowicz N, Chambers RC, Aliev AE,
Inglis GG, Chudasama V, Caddick S. Org Biomol Chem.
2016;14:3264–3274.
24. The reductive removal of the sulfonyl group from 5B was intensively
examined to directly produce 9. Some examples include the treatment
of 5B with Mg (5 equiv) in MeOH to produce 10 (28% yield) along
with the recovery of 5B (66% yield). The use of Me3SiOK in MeCN
followed by quenching with 20% aq HCl solution produced 9 (30%
yield) along with the aromatized compound, 3-methyl-5,6,7,8-
tetrahydronaphtho[2,3-c]furan-1(3H)-one (70% yield).
25. Beak P, Lee WK. J Org Chem. 1993;58:1109–1117.
26. (a) Chackalamannil S, Wang YG, Greenlee WJ, Hu ZY, Xia Y, Ahn
H-S, Boykow G, Hsieh YS, Palamanda J, Agans-Fantuzzi J, Kurowski
S, Graziano M, Chintala M. J Med Chem. 2008;51:3061–3064;
(b) Fala L. Am Health Drug Benefits. 2015;8:148–151;
(c) Krantz MJ, Kaul S. JAMA Intern Med. 2015;175:9–10.
12. V-MPS3, prepared from MPS with a pore diameter of 3 nm, was
mainly used in this work. We also have found that V-MPS4,4b which is
now commercially available from Wako Pure Chemical Industries,
Ltd. produces similar results.
13. The use of acrylate 3Cd and (Z)-3-chloroacrylate 3Dd afforded the
corresponding esters (R)-4C (89% isolated yield, 95% ee) and (R)-4D
(92% isolated yield, 97% ee), respectively, under the DKR conditions
at 35 °C for 24 h. However, the subsequent IMDA reaction did not
proceed in refluxing toluene. Other trials on the IMDA of 4C in
refluxing toluene in the presence of acid catalysts, such as BF3•Et2O,
InCl3 and montmorillonite K-10, resulted in no reaction or formation of
a complex mixture. The use of (E)-3-(phenylsulfonyl)acrylate 3Ed
caused the formation of a complex mixture.
27.
(a) Kim M-J, Chung YI, Choi YK, Lee HK, Kim D, Park J. J Am
14. The use of 1 equiv of DBU was found to be crucial for the quantitavive
formation of 5A with high reproducibility. When more than one
equivalent of DBU was used, the yield of 5A dramatically decreased
due to the formation of side products, among which an olefin-
migration product was observed as a major component.
Chem Soc. 2003;125:11494–11495;
(b) Choi JH, Choi YK, Kim YH, Park ES, Kim EJ, Kim M-J, Park J. J
Org Chem. 2004;69:1972–1977.
28. (a) Borén L, Martín-Matute B, Xu Y, Córdova A, Bäckvall J-E. Chem
Eur J. 2006;12:225–232;
15. Wang J-X, Roeske WR, Wang W, Yamamura HI. Brain Res.
(b) Norinder J, Bogár K, Kanupp L, Bäckvall J-E. Org Lett.
1988;446:155–158.
2007;9:5095–5098;
16. (a) Sheardown MJ. Expert Opin Ther Pat. 2002;12:863–870;
(b) Stoll C, Eltze M, Lambrecht G, Zentner J, Feuerstein TJ, Jackisch
R. J Neurochem. 2009;110:837–847.
17. For reviews on asymmetric total synthesis of (+)-himbacine, see:
(a) Rinner U, Lentsch C, Aichinger C. Synthesis. 2010;3763–3784;
(b) Bhattacharyya D. Tetrahedron. 2011;67:5525–5542.
(c) Thalén LK, Sumic A, Bogár K, Norinder J, Persson AKÅ, Bäckvall
J-E. J Org Chem. 2010;75:6842–6847.
29. Kim S, Choi YK, Hong J, Park J, Kim M-J. Tetrahedron Lett.
2013;54:1185–1188.
30. Engström K, Vallin M, Syrén P-O, Hult K, Bäckvall J-E. Org Biomol
Chem. 2011;9:81–82.
18. (a) Hart DJ, Wu W-L, Kozikowski AP.
1995;117:9369–9370;
J
Am Chem Soc.
(b) Hart DJ, Li J, Wu W-L, Kozikowski AP.
1997;62:5023–5033.
J
Org Chem.
Supplementary Material
19. (a) De Baecke G, De Clercq PJ. Tetrahedron Lett. 1995;36:7515–7518;
(b) Hofman S, De Baecke G, Kenda B, De Clercq PJ. Synthesis
1998;479–489;
Supplementary data associated with this article can be found, in
the online version, at xxxxxxxxxxxxxx.

Graphical
Abstract
Lipase-catalyzed asymmetric synthesis of naphtho-
[2,3-c]furan-1(3H)-one derivatives by a one-pot
dynamic kinetic resolution/intramolecular Diels–
Alder reaction: Total synthesis of (–)-himbacine
Leave this area blank for abstract info.
Koji Sugiyama, Shinji Kawanishi, Yasuhiro Oki, Marin Kamiya, Ryosuke Hanada, Masahiro Egi, Shuji Akai