Enantioselective total synthesis of (+)-bucidarasins A and C

Article abstract of DOI:10.3987/COM-14-13161

In this paper, the first total synthesis of (+)-bucidarasins A and C is described. The chiral starting material was successfully obtained via reduction using a CBS catalyst and selective mono-TBS ether formation of trans -2-benzyloxymethyl-2-methylcyclohe

Full text of DOI:10.3987/COM-14-13161

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HETEROCYCLES, Vol. 91, No. 2, 2015
HETEROCYCLES, Vol. 91, No. 2, 2015, pp. 332 - 350. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 22nd December, 2014, Accepted, 9th January, 2015, Published online, 19th January, 2015
DOI: 10.3987/COM-14-13161
ENANTIOSELECTIVE TOTAL SYNTHESIS OF (+)-BUCIDARASINS A
AND C
Kenji Usui and Masahisa Nakada*
Department of Chemistry and Biochemistry, Faculty of Science and Engineering,
Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan; E-mail:
mnakada@waseda.jp
Abstract – In this paper, the first total synthesis of (+)-bucidarasins A and C is
described. The chiral starting material was successfully obtained via reduction
using a CBS catalyst and selective mono-TBS ether formation of
trans-2-benzyloxymethyl-2-methylcyclohexane-1,3-diol, which was crucial to the
successful enantioselective total synthesis of (+)-bucidarasins A and C. A
synthetic approach towards (+)-bucidarasin C, based on the Barton-McCombie
protocol, using V-70 as a radical promoter at low temperature to remove the
C6-hydroxy moiety is also described.
INTRODUCTION
In 2002, Lee’s group isolated bucidarasins A-D (Figure 1) from a crude extract of Bucida buceras.1
Bucidarasins A-D belong to clerodane diterpene, a large family of molecules comprised of cis- and
trans-fused members as well as ent-members.2 Clerodane diterpenes feature the characteristic scaffold
Figure 1. Structures of tricyclic clerodane scaffold, clerodane scaffold, and (+)-bucidarasin A-D

HETEROCYCLES, Vol. 91, No. 2, 2015
333
shown in Figure 1, while bucidarasins A-C possess a tricyclic scaffold composed of cis-dehydrodecalin
fused to a tetrahydrofuran (THF) ring with two acetyloxy groups at the C18 and C19 positions. The
tricyclic scaffold includes up to eight stereogenic centers, of which six are contiguous and two all-carbon
quaternary stereogenic centers are involved. A number of similar tricyclic cis-clerodane diterpenes have
been reported and were primarily isolated from the tropical genus Casearia;3,4 many of these compounds
have been shown to exhibit a wide range of bioactivities,1,3a,f,h,l-u,w-y,4a,b,e,h,i,k-p including
cytotoxicity.1,3a,f,h,n-r,t,u,w-y,4a,b,e,h,i,k-p Specifically, recent biological studies revealed that some members of
this family exhibit apoptotic activities5 and synergistic effects with TRAIL (tumor necrosis
factor--related apoptosis-inducing ligand), which lead to cell death.4m
Bucidarasins A-C have been reported to be inhibitors of human tumor cell replication, and have also been
reported to show various potent and wide spectrum activities. The IC50 values of bucidarasins A-C range
from 0.5 to 1.9 M against nine human tumor cell lines, and the potency is retained against drug resistant
cell lines. On the other hand, bucidarasin D exhibits no bioactivity, suggesting that the acetal moiety is
required for cytotoxicity.1 The potent bioactivity and complex structure of bucidarasins A-C and related
compounds make them attractive synthetic targets. Notably, our group succeeded in the first total
synthesis of ()-bucidarasin A.6 To the best of our knowledge, the total syntheses of the THF ring-fused
tricyclic cis-clerodane diterpenes have never been reported prior to our synthesis, though a number of
clerodane diterpenes have been synthesized.7
Unfortunately, ()-bucidarasin A synthesized by our group was the enantiomer of naturally occurring
(+)-bucidarasin A, because it was difficult to identify the absolute configuration of (+)-bucidarasin A
before beginning the total synthesis of naturally occurring bucidarasins, even though the absolute
configurations of many congeners have been reported. Hence, in pursuit of carrying out structure-activity
relationship (SAR) studies in addition to elucidating their modes of action, we began synthetic studies of
natural bucidarasins. Herein, we report the enantioselective total synthesis of (+)-bucidarasins A and C.
RESULTS AND DISCUSSION
Scheme 1 shows the preparation of previously reported chiral dienophile 7, which was used in the
enantioselective total synthesis of ()-bucidarasin A. The baker’s yeast reduction of 1 afforded 2 as the
sole product in excellent yield (94%, 94% conv) in a highly enantioselective manner (>99% ee).8
Moreover, 2 contained an all-carbon quaternary stereogenic center, which was the same configuration as
that of C9 in ()-bucidarasin A. Consequently, 2 was used as the chiral starting material for the total
synthesis of ()-bucidarasin A. Accordingly, 2 was converted to 4 via 3 by Wittig methylenation,
followed by the stereoselective hydroxy-directed hydrogenation of C10 using Crabtree’s catalyst and

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HETEROCYCLES, Vol. 91, No. 2, 2015
dehydration using POCl3 to afford 4. Compound 4 was successfully transformed to the requisite
dienophile 7 through allylic oxidation, PDC oxidation, iodination, and Pd-catalyzed carbonylation.
sucroce, baker's yeast
PPh3CH3Br
10
yeast extract, Triton X-100
nBuLi
OH
O
O
O
OH
H2O/EtOH, 30 °C, 2 d
94% (94% conv), >99% ee
91% (90% conv)
BnO
BnO
BnO
3
1
2
OH
1) H2, Ir(cod)(PCy3)(Py)PF6
(CH2Cl)2, 80 °C, 92%
SeO2, HCO2H
1,4-dioxane, 80 °C
2) POCl3, pyridine
80 °C, 98%
then, NH4OH
rt, 65%
BnO
BnO
4
5
O
O
1) PDC, MS 4 Å
CH2Cl2, rt, 86%
CO2Me
I
CO, Pd(PPh3)4 (3 mol %)
2) I2, DMAP, pyridine
CCl4, 50 °C, 98%
Et3N, MeOH, THF, 55 °C, 98%
BnO
BnO
7
6
Scheme 1. Enantioselective preparation of 76
If baker’s yeast could be modified for use in the reduction of 1 to afford ent-2, ent-7 could be easily
prepared to achieve the total synthesis of (+)-bucidarasin A. Unfortunately, to the best of our knowledge,
a baker’s yeast reduction that can convert 1 to ent-2 has not been reported to date. However, we reported
the highly enantio- and stereoselective CBS (Corey-Bakshi-Shibata) reduction of 1, which afforded the
corresponding trans-1,3-diol with excellent ee (>99% ee) and yield (94%).8 This catalytic asymmetric
reduction was expected to be a suitable alternative in the preparation of ent-7, which could not be
prepared via baker’s yeast reduction.
One potential issue in the preparation of ent-7 is the generation of the C8 stereogenic center. Since
compound 3 was successfully converted to 4 via the stereoselective hydroxy-directed hydrogenation of
C10 with Crabtree’s catalyst,9 the preparation of ent-3 was proposed from 8 (Scheme 2), which possesses
the R configuration at C10. However, the two hydroxy groups in 8, which were generated using
BH3·SMe2 and a catalytic amount of (S)-CBS catalyst, had to be chemically differentiated in order to
prepare ent-3. Nevertheless, it was expected that one of the two hydroxy groups would selectively react
with TBSOTf, because cyclohexane derivative 8 should assume the most stable chair conformation,
which would contain one hydroxy group in the equatorial position.

HETEROCYCLES, Vol. 91, No. 2, 2015
335
Scheme 2. Reduction of 1 with (S)-CBS and BH3·SMe2, and selective formation of mono-TBS ether 9
Indeed, although the selective oxidation of one hydroxy group of 8 was unsuccessful, the reaction of 8
with TBSOTf afforded 9 in 61% yield with the concomitant formation of the bis-TBS ether of 8 (20%)
(Scheme 2). Although the formation of diastereomeric mono-TBS ether was observed via TLC during the
reaction, it readily converted to the bis-TBS ether.
In this reaction, the slow addition of TBSOTf to a solution of 8 and 2,6-lutidine in CH2Cl2 at –60 °C
using a syringe pump over 5 h, was crucial to afford 9 as the major product. The byproduct, the bis-TBS
ether of 8, was successfully separated via flash silica gel column chromatography and could be recycled
upon treatment with TBAF.
8
8
OH
OH
Me
H
Me
H
H
H
HO
Me
TBSO
Me
H
H
H
H
H
H
8
10
8
10
BnO
BnO
H
H
HO
HO
H
H
H
H
10
10
BnO
OH
OTBS
BnO
H
H
H
H
8A
8B
9A
9B
Figure 2. Structures of 8A and 9A elucidated by NMR studies
NMR studies of 8 and 9 indicated that their structures in CDCl3 solution were exclusively those of 8A and
9A, respectively (Figure 2). The observed NOE correlations indicated that both compounds existed in the
chair conformation, and the C8 and C10 substituents in 8A and 9A were axial and equatorial positions,
respectively.
Before performing the reaction of 8, it was expected that the C10 TBS ether would be preferentially
formed because the equatorial hydroxy group is generally more reactive than the sterically hindered axial
hydroxy group. However, interestingly, mono TBS ether 9 bearing an axial TBSO group at C8 was
isolated.

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HETEROCYCLES, Vol. 91, No. 2, 2015
The TBS ether formation of the equatorial C10 hydroxy group may be slow because the bulky TBS group
could suffer from steric strain owing to the presence of the vicinal equatorial BnOCH2 group. However,
the possibility that the equatorial C8 hydroxy group in the minor conformer 8B preferentially reacted with
TBSOTf, followed by a conformational change from 9B to 9A, which possessed the axial C8 TBSO
group, could not be ruled out.
Scheme 3. Enantioselective preparation of ent-3 from 9
Compound 9 was successfully converted to ent-3 (Scheme 3). Specifically, the reaction of 9 with
MOMCl (99%) and the removal of the TBS ether afforded 11 (93%). Swern oxidation of 11 (quant),
Wittig methylenation (97%), and removal of the MOM ether under acidic conditions (94%) afforded
13
ent-3, which proved to be the enantiomer of previously reported 3 by our group (1H- and C-NMR, IR,
and HRMS).6
Scheme 4. Enantioselective preparation of ent-4 via the reduction using (R)-CBS and BH3·SMe2
Compound ent-3 was prepared from 1 in an overall yield of 48% via 7 steps, but the selective protection
of 8 with TBSOTf affording 9 prompted us to develop a shorter route to the enantiomer of the reported
intermediate. Thus, an alternative synthesis of ent-4 commenced with the reduction of 1 using BH3·SMe2

HETEROCYCLES, Vol. 91, No. 2, 2015
337
in the presence of a catalytic amount of (R)-CBS catalyst to afford ent-8 (91%, >99% ee), which was
followed by the mono-TBS ether formation (72%), Dess-Martin oxidation (94%), and Wittig
methylenation (97%) to afford 12 (Scheme 4).
To generate the C8 stereogenic center with the desired configuration, suitable catalysts for the
stereoselective hydrogenation of 12 that do not catalyze the cleavage of the benzyl ether were surveyed.
After several attempts, hydrogenation with the Wilkinson catalyst was found to afford the desired isomer
as the major product in a ratio of 5.4/1. The isomers were inseparable at this stage, but could be purified
after treatment of the mixture with TBAF (74%, 2 steps). Subsequent dehydration with POCl3 in pyridine
at 80 °C afforded ent-4 in 93% yield, which proved to be the enantiomer of previously reported 4 by our
group (1H- and 13C-NMR, IR, and HRMS).6
In the latter approach (Scheme 4), ent-4 was prepared from 1 in an overall yield of 41% via 7 steps, and
ent-4 could be prepared from 1 via ent-3 in an overall yield of 43% via 9 steps using the former approach
(Schemes 2 and 3). Although the total number of steps in the former approach is greater, the undesired
isomer was not formed in the hydrogenation of ent-3, which was advantageous for the scale-up synthesis.
CO2Me
R3
AcO
HO
O
OAc
O
O
O
OTBS
SnCl4 (0.1 equiv)
Et2O, –60 °C
R4
CO2Me
+
O
ref. 6
4
OTBS
(recycling)
95%, dr = 1/9
H
H
OTBS
BnO
BnO
(+)-bucidarasin A
ent-7
14
3
4
15
15
(endo) (R = H, R = CH2OTBS)
3
4
(exo) (R = CH2OTBS, R = H)
Scheme 5. First enantioselective total synthesis of (+)-bucidarasin A
Since two enantioselective approaches toward (+)-bucidarasins A and C have been developed, ent-4 was
converted to (+)-bucidarasin A via the highly stereoselective Diels-Alder reaction of ent-7 with 1410
affording 15 (Scheme 5), which was in line with the synthetic methods reported by our group. The final
product proved to be (+)-bucidarasin A, which was the enantiomer of (–)-bucidarasin A, previously
reported by our group (1H- and 13C-NMR, IR, HRMS, and []D).6
The conversion of (+)-bucidarasin A to (+)-bucidarasin C was also investigated (Scheme 6). The
structural difference between (+)-bucidarasins A and C is only at the C6 position; i.e., (+)-bucidarasin C
does not possess a hydroxy group at the C6 position, suggesting that the selective removal of the C6
hydroxy moiety in (+)-bucidarasin A can yield (+)-bucidarasin C.

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HETEROCYCLES, Vol. 91, No. 2, 2015
Scheme 6. First enantioselective total synthesis of (+)-bucidarasin C
The C6 hydroxy group was found to be reactive though it was seemingly hindered by the C5 all-carbon
quaternary center. Indeed, methyl xantate 16 was prepared in 80 % yield from (+)-bucidarasin A. The
reaction of 16 with nBu3SnH was expected to afford (+)-bucidarasin C, but the generated radical at the C6
position could undergo cyclization with the C9 diene. Indeed, the reaction of 16 with nBu3SnH using
V-7011 proceeded at 40 °C to afford (+)-bucidarasin C in 49% yield, and the cyclized product was also
formed in 38% yield. The synthesized (+)-bucidarasin C proved to be identical to naturally occurring
(+)-bucidarasin C in all respects (1H- and 13C-NMR, IR, HRMS, []D).1
CONCLUSION
In summary, the first total synthesis of (+)-bucidarasins A and C was achieved. The chiral starting
material was successfully obtained via the reduction using CBS catalyst, and the selective mono-TBS
ether formation of trans-2-benzyloxymethyl-2-methylcyclohexane-1,3-diol was key to the successful
enantioselective total synthesis of (+)-bucidarasins A and C. We also established a synthetic approach
towards (+)-bucidarasin C, which utilizes the Barton-McCombie protocol, using V-70 as a radical
promoter at low temperature. The synthetic approach towards (+)-bucidarasins established in this study
has the potential to be useful in the synthesis of a vast number of congeners, and may lead to novel
artificial analogs that could exhibit significant biological activities.

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EXPERIMENTAL
1
1H and 13C NMR spectra were recorded on a JNM-ECS400 (400 MHz) spectrometer. H and 13C
chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane (TMS, δ scale),
1
13
using residual protonated solvent as internal standard (CDCl3 at H: 7.26 ppm, C: 77.2 ppm). The
following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad. IR spectra were recorded on a JASCO FT/IR-8300. Mass spectra and elemental
analyses were provided at the Materials Characterization Central Laboratory, Waseda University. All
reactions were carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous
conditions, unless otherwise noted. All reactions were monitored by thin-layer chromatography carried
out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and
phosphomolybdic acid and heat as developing agents. E. Merck silica gel (60, particle size 0.040-0.063
mm) was used for flash chromatography. Preparative thin-layer chromatography (PTLC) separations were
carried out on self-made 0.3 mm E. Merck silica gel plates (60F-254). THF and Et2O were distilled from
sodium/benzophenone ketyl. MeOH was distilled with a small amount of magnesium and I2. DMF was distilled prior
to use. CH2Cl2 was distilled from CaH2, and all other reagents were purchased from Aldrich, Wako Pure Chemical
Industries, Ltd., Tokyo Chemical Industry Co., Ltd., or Kanto Chemical Co. Ltd.
(1R,3R)-2-Benzyloxymethyl-2-methylcyclohexane-1,3-diol (8). To a stirred mixture of (S)-CBS (1.0 M
solution in toluene, 6.09 mL, 6.09 mmol) and 90% BH3-SMe2 (10.3 mL, 97.4 mmol) in CH2Cl2 (1850
mL) was added a solution of 2-benzyloxymethyl-2-methylcyclohexane-1,3-dione (10.0 g, 40.6 mmol) in
CH2Cl2 (750 mL) at 30 °C via a syringe pump over 6 h. The reaction was quenched with MeOH (20 mL),
and 2N HCl (120 mL) was added to the reaction mixture, and the resultant solution was stirred at room
temperature for 10 h. After dilution with CH2Cl2 (100 mL), the organic layer was separated, washed with
brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc = 5/1) to afford 8 (9.55 g, 94%, >99% ee) as a white
solid: Rf = 0.17 (hexane/EtOAc = 2/1); mp 77.2-78.3 °C; 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (5H, m),
4.60 (1H, d, J = 11.9 Hz), 4.53 (1H, d, J = 11.9 Hz), 4.15 (1H, dd, J = 11.0, 4.6 Hz), 3.80 (1H, t, J = 3.2 Hz),
3.68 (1H, d, J = 9.2 Hz), 3.56 (1H, d, J = 9.2 Hz), 3.35 (1H, br s), 1.89 (1H, br), 1.90-1.70 (3H, m),
1.69-1.41 (4H, m), 0.85 (3H, s); 13C NMR (125 MHz, CDCl3) δ137.5 (Cq), 128.5 (CH), 127.9 (CH), 127.6
(CH), 77.3 (CH2), 75.8 (CH), 73.6 (CH2), 69.0 (CH), 43.0 (Cq), 29.8 (CH2), 28.3 (CH2), 18.7 (CH2), 14.4
(CH3); IR (neat) νmax 3399, 2943, 2863, 1454, 1364, 1070, 1047, 998, 741, 694 cm-1; HRMS (ESI)
[M+Na]+ calculated for C15H22O3Na: 273.1461, found: 273.1461; [α]D23 –18 (c 1.0, CHCl3).
(1R,2S,3R)-2-Benzyloxymethyl-3-tert-butyldimethylsilyloxy-2-methylcyclohexanol
(9);
(2R,6R)-2,6-Bis(tert-butyldimethylsilyloxy)-1-methylcyclohexylmethoxymethylbenzene (9’). To a
solution of 8 (16.1 g, 64.3 mmol) and 2,6-lutidine (15.0 mL, 129 mmol) in CH2Cl2 (700 mL) was added a

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HETEROCYCLES, Vol. 91, No. 2, 2015
solution of TBSOTf (16.2 mL, 70.7 mmol) in CH2Cl2 (20 mL) at –60 °C via a syringe pump over 7 h, and
the reaction mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with
saturated aqueous NaHCO3 solution (100 mL), and the aqueous layer was extracted with CH2Cl2 (150 mL
 2). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc
= 20/1) to afford 9 (14.2 g, 61%, a colorless oil), 9’ (6.23 g, 20%, a colorless oil), and starting material
(2.54 g, 16%). 9: Rf = 0.51 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 7.37-7.27 (5H, m), 4.55
(1H, d, J = 11.8 Hz), 4.50, (1H, d, J = 11.8 Hz), 4.01 (1H, dd, J = 11.3, 4.5 Hz), 3.88 (1H, d, J = 8.6 Hz),
3.57 (1H, s), 3.36 (1H, s), 3.25 (1H, d, J = 8.6 Hz), 1.77-1.68 (1H, m), 1.68-1.56 (2H, m), 1.52-1.31 (3H,
m), 0.99 (3H, s), 0.84 (9H, s), –0.013 (3H, s), –0.048 (3H, s); 13C NMR (100 MHz, CDCl3) δ 137.8 (Cq),
128.4 (CH), 127.7 (CH), 127.6 (CH), 79.9 (CH2), 74.5 (CH), 73.8 (CH2), 72.9 (CH), 43.4 (Cq), 29.3
(CH2), 28.4 (CH2), 25.8 (CH3), 18.0 (Cq), 18.0 (CH2), 14.2 (CH3), –4.41 (CH3), –5.27 (CH3); IR (neat)
νmax 3436, 2930, 2856, 1471, 1360, 1252, 1075, 1026, 859, 773, 696 cm-1; HRMS (ESI) [M+Na]+
calculated for C21H36O3NaSi: 387.2326, found: 387.2327; [α]D23 –13 (c 0.58, CHCl3).
1
9’: Rf = 0.91 (hexane/EtOAc = 4/1); H NMR (400 MHz, CDCl3) δ 7.33-7.22 (5H, m), 4.56 (1H, d, J =
11.9 Hz), 4.34, (1H, d, J = 11.9 Hz), 3.93 (1H, dd, J = 6.0, 1.8 Hz), 3.80 (1H, dd, J = 8.7, 3.7 Hz) , 3.50
(1H, d, J = 8.2 Hz) , 3.37 (1H, d, J = 8.2 Hz), 1.66-1.37 (6H, m), 0.97 (3H, s), 0.88 (9H, s), 0.82 (9H, s),
0.018 (3H, s), 0.0079 (3H, s), –0.0013 (3H, s), –0.032 (3H, s); 13C NMR (100 MHz, CDCl3) δ 139.1 (Cq),
128.1 (CH), 127.4 (CH), 127.1 (CH), 73.7 (CH), 73.1 (CH), 72.2 (CH2), 71.2 (CH2), 44.9 (Cq), 29.9
(CH2), 28.7 (CH2), 25.9 (CH3), 25.8 (CH3), 18.6 (CH2), 18.1 (Cq), 18.0 (Cq), 16.0 (CH3), –4.02 (CH3),
–4.32 (CH3), –5.10 (CH3), –5.27 (CH3); IR (neat) νmax 2928, 2856, 1471, 1360, 1251, 1079, 831, 772, 696
cm-1; HRMS (ESI) [M+Na]+ calculated for C27H50O3NaSi2: 501.3191, found: 501.3192; [α]D –18 (c
23
0.98, CHCl3).
(1R,2S,3R)-(2-Benzyloxymethyl-3-methoxymethoxy-2-methylcyclohexyloxy)(tert-butyl)dimethyl-
silane (9a). To a stirred solution of 9 (15.4 g, 42.2 mmol) in CH2Cl2 (420 mL) was added DIPEA (29.4
mL, 169 mmol), MOMCl (6.42 mL, 84.5 mmol), and NaI (6.33 g, 42.2 mmol) successively at room
temperature. The reaction mixture was stirred at 35 °C for 2 d, quenched with H2O (100 mL), and the
aqueous layer was extracted with CH2Cl2 (100 mL  2). The combined organic layer was washed with
brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc = 40/1) to afford 9a (17.1 g, 99%) as a colorless oil: Rf
= 0.63 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 7.36-7.23 (5H, m), 4.64 (1H, d, J = 6.9 Hz),
4.55 (1H, d, J = 11.9 Hz), 4.53 (1H, d, J = 6.9 Hz), 4.38 (1H, d, J = 11.9 Hz), 3.92 (1H, dd, J = 5.5, 2.3
Hz), 3.69 (1H, dd, J = 8.7, 4.1 Hz), 3.59 (1H, d, J = 8.2 Hz), 3.44 (1H, d, J = 8.2 Hz), 3.31 (3H, s),
1.80-1.69 (1H, m), 1.69-1.39 (5H, m), 1.05 (3H, s), 0.88 (9H, s), 0.021 (3H, s), 0.0090 (3H, s); 13C NMR

HETEROCYCLES, Vol. 91, No. 2, 2015
341
(100 MHz, CDCl3) δ 139.1 (Cq), 128.1 (CH), 127.3 (CH), 127.2 (CH), 96.0 (CH2), 77.5 (CH2), 73.7 (CH),
73.1 (CH2), 72.4 (CH), 55.4 (CH3), 44.3 (Cq), 28.6 (CH2), 26.6 (CH2), 25.9 (CH3), 18.5 (CH2), 18.1 (Cq),
16.3 (CH3), –4.41 (CH3), –5.16 (CH3); IR (neat) νmax 2929, 2856, 1471, 1360, 1250, 1080, 1030, 833, 774,
696 cm-1; HRMS (ESI) [M+Na]+ calculated for C23H40O4NaSi: 431.2588, found: 431.2586; [α]D22 –17 (c
0.96, CHCl3).
(1R,2R,3R)-2-Benzyloxymethyl-3-methoxymethoxy-2-methylcyclohexanol (11). To a stirred solution
of 9a (17.1 g, 41.8 mmol) in THF (250 mL) was added TBAF (1.0 M solution in THF, 62.8 mL, 62.8
mmol), and the reaction mixture was stirred at 60 °C for 24 h. The reaction mixture was quenched with
saturated aqueous NH4Cl solution (50 mL), and the aqueous layer was extracted with Et2O (100 mL  2).
The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc
= 20/1) to afford 11 (11.4 g, 93%) as a colorless oil: Rf = 0.29 (hexane/EtOAc = 4/1); 1H NMR (400 MHz,
CDCl3) δ 7.38-7.27 (5H, m), 4.63 (1H, d, J = 11.9 Hz), 4.61 (1H, d, J = 11.9 Hz), 4.53 (2H, s), 4.11 (1H,
br s), 4.03 (1H, dd, J = 10.5, 4.6 Hz), 3.84 (1H, t, J = 2.7 Hz) , 3.75 (1H, d, J = 9.2 Hz), 3.36 (1H, d, J =
9.2 Hz), 3.34 (3H, s), 1.92-1.68 (2H, m), 1.66-1.43 (4H, m), 0.84 (3H, s); 13C NMR (100 MHz, CDCl3) δ
137.3 (Cq), 128.5 (CH), 127.9 (CH), 127.7 (CH), 96.1 (CH2), 76.6 (CH2), 76.5 (CH), 74.5 (CH), 73.6
(CH2), 55.3 (CH), 42.8 (Cq), 28.2 (CH2), 27.3 (CH2), 18.8 (CH2), 15.3 (CH3); IR (neat) νmax 3472, 2939,
1453, 1362, 1213, 1143, 1032, 915, 735, 697 cm-1; HRMS (ESI) [M+Na]+ calculated for C17H26O4Na:
317.1723, found: 317.1729; [α]D22 +0.38 (c 1.6, CHCl3).
(2S,3R)-2-Benzyloxymethyl-3-methoxymethoxy-2-methylcyclohexanone (11a). To a stirred solution of
oxalyl chloride (5.07 mL, 58.15 mmol) and DMSO (5.50 mL, 77.4 mmol) in CH2Cl2 (192 mL) was added
a solution of 11 (11.4 g, 38.7 mmol) in CH2Cl2 (30 mL) via a cannula at –78 °C. After 15 min, to the
reaction mixture was added Et3N (18.9 mL, 136 mmol), and the reaction mixture was stirred at the same
temperature for 1 h, and at room temperature for 1 h. The mixture was quenched with saturated aqueous
NH4Cl solution (50 mL). The aqueous layer was extracted with CH2Cl2 (100 mL  2). The combined
organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography (hexane/EtOAc = 6/1) to afford 11a
1
(11.3 g, 100%) as a colorless oil: Rf = 0.36 (hexane/EtOAc = 4/1); H NMR (400 MHz, CDCl3) δ
7.36-7.24 (5H, m), 4.63 (1H, d, J = 13.3 Hz), 4.61 (1H, d, J = 13.3 Hz), 4.55 (1H, d, J = 11.9 Hz), 4.47
(1H, d, J = 11.9 Hz), 4.05 (1H, dd, J = 9.2, 3.7 Hz), 3.71 (1H, d, J = 8.7 Hz), 3.37 (1H, d, J = 8.7 Hz),
3.35 (3H, s), 2.45-2.27 (2H, m), 2.11-2.01 (1H, m), 1.98-1.78 (2H, m), 1.70-1.60 (1H, m), 1.06 (3H, s);
13C NMR (100 MHz, CDCl3) δ 211.8 (Cq), 138.3 (Cq), 128.2 (CH), 127.6 (CH), 127.5 (CH), 96.2 (CH2),
77.5 (CH), 73.3 (CH2), 71.4 (CH2), 55.6 (CH), 55.5 (Cq), 37.9 (CH2), 26.4 (CH2), 19.7 (CH2), 15.8

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(CH3); IR (neat) νmax 2942, 2874, 1709, 1453, 1369, 1093, 1028, 916, 736, 698 cm-1; HRMS (ESI)
[M+Na]+ calculated for C17H24O4Na: 315.1567, found: 313.51569; [α]D23 –15 (c 2.0, CHCl3).
(1S,2R)-2-Methoxymethoxy-1-methyl-6-methylenecyclohexylmethoxymethylbenzene (11b). To a
stirred suspension of PPh3CH3Br (38.7 g, 108 mmol) in THF (127 mL) was added KHMDS (0.5 M
solution in toluene, 193 mL, 96.6 mmol) dropwise at 0 °C, and the reaction mixture was stirred at room
temperature for 30 min. Then, to the reaction mixture was added a solution of 11a (11.3 g, 38.6 mmol) in
THF (30 mL) via a cannula at 0 °C. After the addition, the mixture was stirred at room temperature for 1
h, and then was quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous layer was
extracted with Et2O (100 mL  2). The combined organic layer was washed with brine (50 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash
chromatography (hexane/EtOAc = 20/1) to afford 11b (10.9 g, 97%) as a colorless oil: Rf = 0.64
1
(hexane/EtOAc = 4/1); H NMR (400 MHz, CDCl3) δ 7.38-7.24 (5H, m), 4.86 (1H, d, J = 1.4 Hz), 4.82
(1H, d, J = 1.4 Hz), 4.64 (1H, d, J = 10.4 Hz), 4.62 (1H, d, J = 10.4 Hz), 4.54 (1H, d, J = 11.8 Hz), 4.48
(1H, d, J = 11.8 Hz), 3.72 (1H, dd, J = 8.2, 4.1 Hz), 3.52 (1H, d, J = 9.1 Hz), 3.39 (1H, d, J = 9.1 Hz),
3.35 (3H, s), 2.27-2.09 (2H, m), 1.88-1.78 (1H, m), 1.77-1.65 (2H, m), 1.48-1.35 (1H, m), 1.09 (3H, s);
13C NMR (100 MHz, CDCl3) δ 150.4 (Cq), 138.4 (Cq), 128.3 (CH), 127.7 (CH), 127.5 (CH), 109.5 (CH2),
96.3 (CH2), 78.5 (CH), 73.8 (CH2), 73.3 (CH2), 55.5 (CH), 46.2 (Cq), 32.4 (CH2), 27.3 (CH3), 23.2 (CH2),
18.2 (CH3); IR (neat) νmax 2935, 2860, 1640, 1454, 1144, 1099, 1035, 892, 734, 697 cm-1; HRMS (ESI)
[M+Na]+ calculated for C18H26O3Na: 313.1774, found: 313.1774; [α]D22 +2.2 (c 1.2, CHCl3).
(1R,2S)-2-Benzyloxymethyl-2-methyl-3-methylenecyclohexanol (ent-3). To a stirred solution of 11b
(10.8 g, 37.2 mmol) in MeOH (186 mL) was added 5N HCl (18.6 mL), and the reaction mixture was
stirred at 50 °C for 12 h. To the reaction mixture was added H2O (200 mL), and the aqueous layer was
extracted with Et2O (100 mL  3). The combined organic layer was washed with brine (50 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash
chromatography (hexane/EtOAc = 15/1) to afford ent-3 (8.58 g, 94%) as a colorless oil.
Rf = 0.39 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (5H, m), 4.74 (1H, s), 4.60 (1H,
d, J = 12.4 Hz), 4.56 (1H, d, J = 12.4 Hz), 4.49 (1H, s), 3.73 (1H, d, J = 8.7 Hz), 3.68 (1H, ddd, J = 10.5,
4.1, 1.4 Hz), 3.65 (1H, d, J = 8.7 Hz), 3.61 (1H, d, J = 1.4 Hz), 2.22 (1H, ddd, J = 13.7, 13.7, 4.6 Hz),
2.06 (1H, ddd, J = 13.7, 3.2, 3.2 Hz), 1.85-1.70 (2H, m), 1.63-1.49 (1H, m), 1.37-1.22 (1H, m), 1.18 (3H,
13
s); C NMR (100 MHz, CDCl3) δ 151.7 (Cq), 137.7 (Cq), 128.5 (CH), 127.8 (CH), 127.5 (CH), 107.7
(CH2), 79.2 (CH2), 76.3 (CH), 73.8 (CH2), 44.6 (Cq), 32.5 (CH2), 29.7 (CH2), 24.2 (CH2), 16.1 (CH3); IR
(neat) νmax 3438, 2935, 2859, 1637, 1453, 1358, 1071, 895, 734, 696 cm-1; HRMS (ESI) [M+Na]+
calculated for C16H22O2Na: 269.1512, found: 269.1512; [α]D27 –13 (c 1.1, CHCl3).

HETEROCYCLES, Vol. 91, No. 2, 2015
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(1S,2R,3S)-2-Benzyloxymethyl-3-tert-butyldimethylsilyloxy-2-methylcyclohexan-1-ol (ent-9). To a
solution of (1S,3S)-2-benzyloxymethyl-2-methylcyclohexane-1,3-diol (93.7 mg, 0.374 mmol) and
2,6-lutidine (87.2 μL, 0.749 mmol) in CH2Cl2 (15 mL) was added a solution of TBSOTf (0.129 mL,
0.561 mmol) in CH2Cl2 (15 mL) at –60 °C via a syringe pump over 5 h, and the reaction mixture was
stirred at the same temperature for 2 h. The reaction mixture was quenched with H2O (20 mL), and the
aqueous layer was extracted with CH2Cl2 (20 mL  2). The combined organic layer was washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc = 20/1) to afford ent-9 (98.4 mg, 72%) and its di-TBS
ether ent-9’ (24.7 mg, 13%) as a colorless oil. Starting material (14.0 mg, 15%) was recovered: Rf = 0.51
(hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 7.38-7.24 (5H, m), 4.55 (1H, d, J = 11.9 Hz), 4.50,
(1H, d, J = 11.9 Hz), 4.01 (1H, dd, J = 11.0, 4.1 Hz), 3.88 (1H, d, J = 8.7 Hz), 3.57 (1H, s), 3.36 (1H, s),
3.25 (1H, d, J = 8.7 Hz), 1.78-1.56 (3H, m), 1.52-1.32 (3H, m), 0.99 (3H, s), 0.83 (9H, s), -0.014 (3H, s),
13
-0.049 (3H, s); C NMR (100 MHz, CDCl3) δ 137.8 (Cq), 128.4 (CH), 127.6 (CH), 127.6 (CH), 79.7
(CH2), 74.4 (CH), 73.7 (CH2), 72.8 (CH), 43.4 (Cq), 29.3 (CH2), 28.3 (CH2), 25.7 (CH3), 18.0 (Cq), 18.0
(CH2), 14.1 (CH3), -4.46 (CH3), -5.31 (CH3); IR (neat) νmax 3448, 2928, 2856, 1471, 1360, 1252, 1074,
1026, 859, 773, 696 cm-1; HRMS (ESI) [M+Na]+ calculated for C21H36O3NaSi: 387.2326, found:
387.2325; [α]D25 +14 (c 0.6, CHCl3).
[(1S,3S)-2-Benzyloxymethyl-3-tert-butyldimethylsilyloxy-2-methylcyclohexyloxy](tert-butyl)-
dimethyl-silane (ent-9’). Rf = 0.91 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (5H,
m), 4.57 (1H, d, J = 11.9 Hz), 4.35, (1H, d, J = 11.9 Hz), 3.94 (1H, dd, J = 5.5, 1.8 Hz), 3.82 (1H, dd, J =
8.7, 4.1 Hz) , 3.51 (1H, d, J = 8.2 Hz) , 3.38 (1H, d, J = 8.2 Hz), 1.73-1.34 (6H, m), 0.99 (3H, s), 0.89 (9H,
s), 0.83 (9H, s), 0.027 (3H, s), 0.017 (3H, s), 0.0079 (3H, s), -0.022 (3H, s); 13C NMR (100 MHz, CDCl3)
δ 139.2 (Cq), 128.1 (CH), 127.4 (CH), 127.1 (CH), 73.8 (CH), 73.2 (CH), 72.2 (CH2), 71.2 (CH2), 44.9
(Cq), 29.9 (CH2), 28.7 (CH2), 26.0 (CH3), 25.9 (CH3), 18.6 (CH2), 18.1 (Cq), 18.0 (Cq), 16.1 (CH3), -4.02
(CH3), -4.31 (CH3), -5.08 (CH3), -5.25 (CH3); IR (neat) νmax 2928, 2856, 1471, 1360, 1251, 1078, 1070,
831, 772, 696 cm-1; HRMS (ESI) [M+Na]+ calculated for C27H50O3NaSi2: 501.3191, found: 501.3192;
[α]D26 +18 (c 1.0, CHCl3).
(2S,3S)-2-Benzyloxymethyl-3-tert-butyldimethylsilyloxy-2-methylcyclohexan-1-one (ent-9a). To a
solution of ent-9 (189 mg, 0.518 mmol) in CH2Cl2 (13 mL) was added Dess-Martin periodinane (331 mg,
0.778 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, and then, quenched
with saturated aqueous NaHCO3 solution (10 mL) and saturated aqueous Na2S2O3 solution (10 mL). The
aqueous layer was extracted with CH2Cl2 (10 mL  2). The combined organic layer was washed with
brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc = 20/1) to afford ent-9a (177 mg, 94%) as a colorless

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1
oil: Rf = 0.56 (hexane/EtOAc = 4/1); H NMR (400 MHz, CDCl3) δ 7.36-7.23 (5H, m), 4.55 (1H, d, J =
12.4 Hz), 4.41 (1H, d, J = 12.4 Hz), 4.00 (1H, dd, J = 6.0, 2.7 Hz), 3.68 (1H, d, J = 9.2 Hz), 3.63 (1H, d, J
= 9.2 Hz), 2.47 (1H, ddd, J = 14.7, 9.6, 6.0 Hz), 2.36-2.24 (1H, m), 2.13-1.89 (2H, m), 1.86-1.75 (1H, m) ,
1.74-1.62 (1H, m), 1.24 (3H, s), 0.86 (9H, s), 0.033 (3H, s), 0.024 (3H, s); 13C NMR (100 MHz, CDCl3) δ
213.5 (Cq), 138.6 (Cq), 128.2 (CH), 127.4 (CH), 127.3 (CH), 75.5 (CH), 73.2 (CH2) , 71.7 (CH2), 55.1
(Cq), 37.8 (CH2), 28.7 (CH2), 25.8 (CH3), 20.4 (CH2), 19.4 (CH3), 18.0 (Cq), -4.43 (CH3), -5.27 (CH3);
IR (neat) νmax 2928, 2855, 1707, 1462, 1360, 1249, 1078, 830, 774, 696 cm-1; HRMS (ESI) [M+Na]+
calculated for C21H34O3NaSi: 385.2169, found: 385.2170; [α]D25 +0.56 (c 0.71, CHCl3).
[(1S,2S)-2-Benzyloxymethyl-2-methyl-3-methylidenecyclohexyloxy](tert-butyl)dimethylsilane (12).
To a stirred suspension of PPh3CH3Br (482 mg, 1.35 mmol) in THF (6.0 mL) was added KHMDS (0.50
M solution in toluene, 2.25 mL, 1.12 mmol) dropwise at 0 °C, and the reaction mixture was stirred for 30
min. Then, to the reaction mixture was added a solution of 2 (163 mg, 0.450 mmol) in THF (6.0 mL) via
a cannula at 0 °C. After the addition, the reaction mixture was stirred at 60 °C for 1.5 h, and then was
quenched with saturated aqueous NH4Cl solution (10 mL). The aqueous layer was extracted with Et2O
(10 mL  2). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by flash chromatography
(hexane/EtOAc = 100/1) to afford 12 (157 mg, 97%) as a colorless oil: Rf = 0.77 (hexane/EtOAc = 10/1);
1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (5H, m), 4.85 (1H, d, J = 1.8 Hz), 4.71 (1H, d, J = 1.8 Hz), 4.53
(1H, d, J = 12.4 Hz), 4.48 (1H, d, J = 12.4 Hz), 3.68 (1H, d, J = 9.2 Hz), 3.49 (1H, d, J = 9.2 Hz), 3.47
(1H, dd, J = 8.7, 3.7 Hz), 2.24-2.09 (2H, m), 1.81-1.648 (2H, m), 1.63-1.49 (1H, m), 1.40-1.24 (1H, m),
13
1.19 (3H, s), 0.85 (9H, s) 0.00 (6H, s); C NMR (100 MHz, CDCl3) δ 151.6 (Cq), 139.0 (Cq), 128.2
(CH), 127.4 (CH), 127.2 (CH), 109.3 (CH2), 76.7 (CH), 73.2 (CH2), 72.5 (CH2), 46.7 (Cq), 32.5 (CH2),
30.6 (CH2), 25.8 (CH3), 24.0 (CH2), 20.8 (CH3), 18.0 (Cq), -4.14 (CH3), -5.08 (CH3); IR (neat) νmax 2930,
2855, 1638, 1461, 1360, 1250, 1080, 830, 772, 696 cm-1; HRMS (ESI) [M+Na]+ calculated for
C22H36O2NaSi: 383.2377, found: 383.2376; [α]D25 +31 (c 0.69, CHCl3).
[(1S,2S)-2-Benzyloxymethyl-2,3-dimethylcyclohexyloxy](tert-butyl)dimethylsilane (12a). To a stirred
solution of 12 (151 mg, 0.418 mmol) in benzene (8.4 mL) was added Wilkinson catalyst (19.4 mg, 5
mol %). The reaction mixture was stirred at 60 °C for 2 h under an atmosphere of hydrogen, and then, the
reaction mixture was diluted with hexane/EtOAc (5/1, 10 mL), filtered through a Celite pad, and the
filtrate was concentrated. The residue was purified by flash chromatography (hexane/EtOAc = 100/1) to
afford a mixture of 12a and its isomer (150 mg, 99%) as a colorless oil. Major product: Rf = 0.76
(hexane/EtOAc = 10/1); 1H NMR (400 MHz, CDCl3) δ 7.36-7.22 (5H, m), 4.46 (2H, s), 3.63 (1H, d, J =
9.2 Hz), 3.39 (1H, d, J = 9.2 Hz), 3.35 (1H, dd, J = 9.6, 5.0 Hz), 1.75-1.17 (7H, m), 1.03 (3H, d, J = 6.9
1
Hz), 0.97 (3H, s), 0.88 (9H, s), 0.024 (6H, s). Minor product: Rf = 0.76 (hexane/EtOAc = 10/1); H

HETEROCYCLES, Vol. 91, No. 2, 2015
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NMR (400 MHz, CDCl3) δ 7.36-7.22 (5H, m), 4.54 (1H, d, J = 12.4 Hz), 4.36 (1H, d, J = 12.4 Hz), 3.84
(1H, br s), 3.48 (1H, d, J = 8.2 Hz), 3.25 (1H, d, J = 8.2 Hz), 1.87-1.76 (1H, m), 1.75-1.17 (6H, m), 0.90
(9H, s), 0.88 (3H, s), 0.74 (3H, d, J = 6.9 Hz), 0.0045 (6H, s); HRMS (ESI) [M+Na]+ calculated for
C22H38O2NaSi: 385.2533, found: 385.2533.
[(1S,2S,3R)-2-Benzyloxymethyl-2,3-dimethylcyclohexyloxy](tert-butyl)dimethylsilane (12b). To a
solution of 12a (135 mg, 0.372 mmol) in THF (3.7 mL) was added TBAF (1.0 M solution in THF, 745
μL, 0.745 mmol), and the reaction mixture was stirred at 75 °C for 24 h. The reaction mixture was
quenched with saturated aqueous NH4Cl solution (10 mL), and the aqueous layer was extracted with Et2O
(10 mL  2). The combined organic layer was washed with brine (5.0 mL), dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by flash chromatography
(hexane/EtOAc = 50/1) to afford 12b (69.4 mg, 75%) and 12b’ (12.8 mg, 14%) as a colorless oil: Rf =
0.41 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 7.38-7.27 (5H, m), 4.49 (2H, s), 3.95 (1H, d, J
= 9.2 Hz), 3.99-3.70 (1H, br), 3.55 (1H, d, J = 9.2 Hz), 3.24 (1H, dd, J = 11.9, 4.1 Hz), 1.90-1.80 (1H, m),
1.76-1.66 (1H, m), 1.65-1.43 (1H, m), 1.42-1.27 (3H, m), 1.26 (3H, s), 1.23-1.05 (1H, m), 0.83 (3H, d, J
= 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 137.7 (Cq), 128.4 (CH), 127.8 (CH), 127.5 (CH), 127.3 (CH),
79.7 (CH), 74.0 (CH2), 72.6 (CH2), 41.3 (Cq), 40.7 (CH), 31.8 (CH2), 30.3 (CH2), 24.4 (CH2), 21.7 (CH3),
15.8 (CH3); IR (neat) νmax 3450, 2927, 2858, 1453, 1074, 1015, 733, 696 cm-1; HRMS (ESI) [M+Na]+
calculated for C16H24O2Na: 271.1669, found: 271.1667; [α]D25 +3.7 (c 0.60, CHCl3).
[(1S,2S,3S)-2-Benzyloxymethyl-2,3-dimethylcyclohexyloxy](tert-butyl)dimethylsilane (12b’). Rf =
0.46 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (5H, m), 4.57 (1H, d, J = 11.9 Hz),
4.47 (1H, d, J = 11.9 Hz), 3.72 (1H, t, J = 2.7 Hz), 3.57 (1H, d, J = 11.9 Hz), 3.32 (1H, d, J = 11.9 Hz),
2.21-2.08 (1H, m), 1.83-1.68 (1H, m), 1.67-1.52 (2H, m), 1.48-1.36 (2H, m), 1.29-1.14 (1H, m), 0.76 (3H,
13
d, J = 6.9 Hz), 0.70 (3H, s); C NMR (100 MHz, CDCl3) δ 137.6 (Cq), 128.5 (CH), 127.8 (CH), 127.7
(CH), 78.1 (CH2), 76.1 (CH), 73.6 (CH2), 40.7 (Cq), 29.8 (CH2), 28.9 (CH), 28.8 (CH2), 20.0 (CH2), 15.4
(CH3), 15.2 (CH3); IR (neat) νmax 3483, 2932, 2856, 1454, 1071, 1014, 734, 696 cm-1; HRMS (ESI)
[M+Na]+ calculated for C16H24O2Na: 271.1669, found: 271.1667; [α]D25 +1.0 (c 0.53, CHCl3).
[(1R,6R)-1,6-Dimethylcyclohex-2-en-1-yl]methoxymethylbenzene (ent-4). To a stirred solution of 12b
(65.0 mg, 0.262 mmol) in pyridine (2.5 mL) was added POCl3 (71.2 μL, 0.785 mmol) at 0 °C, and the
mixture was stirred at 80 °C for 2 h. The reaction mixture was quenched with H2O (5.0 mL), and the
aqueous layer was extracted with Et2O (10 mL  2). The combined organic layer was washed with brine
(5.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified
by flash chromatography (hexane/EtOAc = 100/1) to afford ent-4 (56.1 mg, 93%) as a colorless oil: Rf =
1
0.77 (hexane/EtOAc = 8/1); H NMR (400 MHz, CDCl3) δ 7.40-7.24 (5H, m), 5.70 (1H, ddd, J = 10.1,
3.7, 3.7 Hz), 5.44 (1H, ddd, J = 10.1, 2.3, 2.3 Hz), 4.50 (2H, s), 3.28 (2H, s), 2.09-1.94 (2H, m), 1.65-1.53

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13
(3H, m), 1.07 (3H, s), 0.94 (3H, d, J = 6.9 Hz); C NMR (100 MHz, CDCl3) δ 139.0 (Cq), 134.2 (CH),
128.2 (CH), 127.3 (CH), 127.2 (CH), 126.4 (CH), 76.0 (CH2), 73.3 (CH2), 38.5 (Cq), 36.8 (CH), 27.2
(CH2), 25.0 (CH3), 24.3 (CH2), 15.8 (CH3); IR (neat) νmax 2957, 2921, 2859, 1453, 1365, 1095, 732, 695
cm-1; HRMS (ESI) [M+Na]+ calculated for C16H22ONa: 253.1563, found: 253.1563; [α]D +33 (c 2.0,
26
CHCl3).
(1S,3R,5R,6aS,7R,8R,10S,10aS)-1,3-Bis(acetyloxy)-10-hydroxy-7,8-dimethyl-7-[(2E)-3-methylpenta-
2,4-dien-1-yl]-1H,3H,5H,6H,6aH,7H,8H,9H,10H-naphtho[4,4a-c]furan-5-yl
2-methylpropanoate
((+)-bucidarasin A). To a solution of the C2-hydroxy derivative of (+)-bucidarasin A (15.0 mg, 0.0345
mmol), which was synthesized from ent-4 according to the procedure reported by our group,1 in CH2Cl2
(1.5 mL) were added triethylamine (48.1 μL, 0.345 mmol) and isobutyryl chloride (10.9 μL, 0.104 mmol)
successively at 0 °C, and the reaction mixture was stirred at 35 °C for 30 min. The reaction mixture was
quenched with saturated aqueous NH4Cl solution (5.0 mL) and ca.25% NH4OH solution (5.0 mL)
successively, and the aqueous layer was extracted with CH2Cl2 (10 mL  2). The combined organic layer
was washed with brine (5.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash chromatography (hexane/EtOAc = 3/1) to afford (+)-bucidarasin A
1
(17.0 mg, 98%) as a white amorphous: Rf = 0.43 (hexane/EtOAc = 1/1); H NMR (400 MHz, CDCl3) δ
6.73 (1H, dd, J = 1.4, 1.4 Hz), 6.51 (1H, s), 6.27 (1H, dd, J = 17.4, 10.5 Hz), 5.99 (1H, dd, J = 4.1, 1.4
Hz), 5.47-5.41 (1H, m), 5.41-5.32 (1H, m), 5.09 (1H, d, J = 17.4 Hz), 4.93 (1H, d, J = 10.5 Hz), 3.80 (1H,
ddd, J = 12.4, 9.6, 3.7 Hz), 2.64 (1H, qq, J = 6.9, 6.9 Hz), 2.36 (1H, dd, J = 11.4, 5.5 Hz), 2.24 (1H, dd, J
= 16.5, 7.8 Hz), 2.10 (3H, s), 1.94 (3H, s), 1.92-1.83 (2H, m), 1.82-1.54 (4H, m), 1.66 (3H, s), 1.22 (3H, d,
J = 6.9 Hz), 1.20 (3H, d, J = 6.9 Hz), 0.93 (3H, d, J = 6.9 Hz), 0.81 (3H, s); 13C NMR (100 MHz, CDCl3)
δ 176.4 (Cq), 170.1 (Cq), 169.4 (Cq), 145.3 (Cq), 141.2 (CH), 135.7 (Cq), 129.0 (CH), 121.8 (CH), 111.0
(CH2), 97.0 (CH), 95.6 (CH), 72.8 (CH), 66.1 (CH), 53.5 (Cq), 37.6 (CH2), 37.3 (Cq), 36.8 (CH), 36.7
(CH), 34.0 (CH), 30.3 (CH2), 26.7 (CH2), 25.0 (CH3), 21.6 (CH3), 21.2 (CH3), 19.1 (CH3), 18.7 (CH3),
15.6 (CH3), 11.9 (CH3); IR (neat) νmax 3469, 2969, 2933, 2878, 1749, 1728, 1605, 1371, 1225, 889, 735
cm-1; HRMS (ESI) [M+Na]+ calculated for C28H40O8Na: 527.2615, found: 527.2616; [α]D +34 (c 0.85,
25
MeOH).
(1S,3R,5R,6aS,7R,8R,10S,10aS)-1,3-Bis(acetyloxy)-7,8-dimethyl-7-[(2E)-3-methylpenta-2,4-dien-1-
yl]-10-methylsulfanylmethanethioyloxy-1H,3H,5H,6H,6aH,7H,8H,9H,10H-naphtho[4,4a-c]furan-5-
yl 2-methylpropanoate (16). To a stirred solution of (+)-bucidarasin A (14.0 mg, 0.0277 mmol) in THF
(2.0 mL) was added CS2 (10.1 μL, 0.166 mmol) and NaH (60%, 3.3 mg, 0.0832 mmol) successively at
0 °C. After the addition, the reaction mixture was stirred at room temperature for 15 min, and then to the
reaction mixture was added MeI (13.8 μL, 0.222 mmol). The reaction mixture was stirred at room
temperature for 14 h, quenched with saturated aqueous NH4Cl solution (5.0 mL), and the aqueous layer

HETEROCYCLES, Vol. 91, No. 2, 2015
347
was extracted with Et2O (10 mL  2). The combined organic layer was washed with brine (10 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash
chromatography (hexane/EtOAc = 20/1) to afford 16 (13.2 mg, 80%) as a colorless oil: Rf = 0.63
1
(hexane/EtOAc = 2/1); H NMR (400 MHz, CDCl3) δ 6.69 (1H, s), 6.53 (1H, dd, J = 1.7, 1.7 Hz), 6.29
(1H, dd, J = 17.0, 10.8 Hz), 6.00 (1H, br d), 5.96 (1H, dd, J = 11.9, 4.0 Hz), 5.49-5.43 (1H, m), 5.41-5.36
(1H, m), 5.11 (1H, d, J = 17.0 Hz), 4.95 (1H, d, J = 10.8 Hz), 2.64 (1H, qq, J = 6.8, 6.8 Hz), 2.58 (3H, s),
2.47 (1H, dd, J = 13.0, 3.4 Hz), 2.28 (1H, dd, J = 17.0, 8.5 Hz), 2.08 (3H, s), 2.11-1.99 (1H, m), 1.96 (3H,
s), 1.98-1.87 (3H, m), 1.81-1.64 (2H, m), 1.68 (3H, s), 1.23 (3H, d, J = 6.8 Hz), 1.21 (3H, d, J = 6.8 Hz),
0.95 (3H, d, J = 6.8 Hz), 0.85 (3H, s); 13C NMR (100 MHz, CDCl3) δ 215.1 (Cq), 176.3 (Cq), 170.0 (Cq),
169.4 (Cq), 143.6 (Cq), 141.1 (CH), 135.9 (Cq), 128.7 (CH), 123.4 (CH), 111.2 (CH2), 97.1 (CH), 95.1
(CH), 82.2 (CH), 65.8 (CH), 52.2 (Cq), 37.7 (CH), 37.6 (Cq), 36.2 (CH), 34.0 (CH), 32.3 (CH2), 30.3
(CH2), 26.7 (CH2), 25.0 (CH3), 21.7 (CH3), 21.2 (CH3), 19.1 (CH3), 18.7 (CH3), 18.5 (CH3), 15.4 (CH3),
12.0 (CH3); IR (neat) νmax 2970, 2934, 1755, 1732, 1601, 1471, 1323, 1222, 1055, 836, 737 cm-1;
HRMS (ESI) [M+Na]+ calculated for C30H42O8NaS2: 617.2213, found: 617.2212; [α]D +54 (c 0.53,
24
CHCl3).
(1S,3R,5R,6aS,7R,8R,10aS)-1,3-Bis(acetyloxy)-7,8-dimethyl-7-[(2E)-3-methylpenta-2,4-dien-1-yl]-
1H,3H,5H,6H,6aH,7H,8H,9H,10H-naphtho[4,4a-c]furan-5-yl 2-methylpropanoate ((+)-bucidarasin
C). To a solution of 16 (10.0 mg, 0.0168 mmol) in degassed toluene (1.0 mL) were added a catalytic
amount of V-70 and n-Bu3SnH (44.1 μL, 0.168 mmol) successively at 0 °C. The reaction mixture was
stirred at 40 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was
purified by flash chromatography (hexane/EtOAc = 30/1) to afford (+)-bucidarasin C (4.0 mg, 49%) and
17 (3.1 mg, 38%, mixture of diastereomers (dr = 10/7)) as a colorless oil: Rf = 0.31 (hexane/EtOAc =
1
4/1); H NMR (400 MHz, CDCl3) δ 6.67 (1H, dd, J = 1.5, 1.5 Hz), 6.36 (1H, s), 6.28 (1H, dd, J = 17.2,
10.8 Hz), 5.89 (1H, dd, J = 4.6, 1.5 Hz), 5.42 (1H, br s), 5.38 (1H, br d), 5.08 (1H, d, J = 17.2 Hz), 4.92
(1H, d, J = 10.8 Hz), 2.63 (1H, qq, J = 6.9, 6.9 Hz), 2.23 (1H, dd, J = 16.1, 8.2 Hz), 2.22 (1H, br t), 2.10
(3H, s), 1.94 (3H, s), 1.92-1.87 (2H, m), 1.79-1.69 (2H, m), 1.67 (3H, s), 1.64-1.58 (1H, m), 1.53-1.41
13
(2H, m), 1.22 (3H, d, J = 6.9 Hz), 1.20 (3H, d, J = 6.9 Hz), 0.89 (3H, d, J = 6.9 Hz), 0.83 (3H, s); C
NMR (100 MHz, CDCl3) δ 176.4 (Cq), 170.3 (Cq), 169.7 (Cq), 147.0 (Cq), 141.3 (CH), 135.6 (Cq),
129.3 (CH), 120.3 (CH), 110.8 (CH2), 98.8 (CH), 94.5 (CH), 66.3 (CH), 49.1 (Cq), 37.4 (Cq), 36.5 (CH),
34.7 (CH), 34.1 (CH), 30.4 (CH2), 29.1 (CH2), 27.4 (CH2), 26.1 (CH2), 25.7 (CH3), 21.4 (CH3), 21.2
(CH3), 19.2 (CH3), 18.7 (CH3), 15.6 (CH3), 12.0 (CH3); IR (neat) νmax 2940, 1750, 1731, 1458, 1374,
1230, 1152, 1066, 935, 669 cm-1; HRMS (ESI) [M+Na]+ calculated for C28H40O7Na: 511.2666, found:
511.2679; [α]D25 +17 (c 0.20, MeOH).

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HETEROCYCLES, Vol. 91, No. 2, 2015
(1R,2S,3S,5R,8R,10S,11R,12R)-3,5-Bis(acetyloxy)-14-(but-2-en-2-yl)-11,12-dimethyl-4-oxatetra-
cyclo[9.2.2.0²,⁶.0²,¹⁰]pentadec-6-en-8-yl 2-methylpropanoate (17). Major product: Rf = 0.40
(hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 6.58 (1H, dd, J = 1.8, 1.8 Hz), 6.33 (1H, br s), 6.02
(1H, br s), 5.65-5.56 (1H, m), 5.32-5.24 (1H, m), 2.66-2.57 (1H, m), 2.51-2.40 (1H, m), 2.28-2.20 (1H,
m), 2.19 (3H, s), 2.20-2.16 (1H, m), 2.10 (3H, s), 1.81-1.58 (7H, m), 1.61 (3H, s), 1.58-1.49 (1H, m),
1.38-1.24 (1H, m), 1.21 (3H, d, J = 6.9 Hz), 1.21 (3H, d, J = 6.9 Hz), 0.86 (3H, s), 0.78 (3H, d, J = 6.0
Hz). Minor product: Rf = 0.40 (hexane/EtOAc = 4/1); 1H NMR (400 MHz, CDCl3) δ 6.70 (1H, s), 6.66
(1H, dd, J = 1.8, 1.8 Hz), 6.01 (1H, br s), 5.47-5.34 (2H, m), 2.63-2.54 (1H, m), 2.39-2.29 (1H, m),
2.21-2.15 (1H, m), 2.14 (3H, s), 2.05 (3H, s), 1.88-1.81 (1H, m), 1.81-1.58 (2H, m), 1.70 (3H, s), 1.65
(3H, br d) 1.50-1.41 (1H, m), 1.38-1.24 (1H, m), 1.20 (6H, d, J = 6.9 Hz), 0.97 (3H, d, J = 6.9 Hz), 0.97
(3H, s); HRMS (ESI) [M+Na]+ calculated for C28H40O7Na: 511.2666, found: 511.2679.
ACKNOWLEDGEMENTS
This work was financially supported in part by the Grant-in-Aid for Scientific Research (B) (25293003)
by MEXT, and a Waseda University Grant for Special Research Projects.
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