Synthesis of rumphellaone A via epoxy nitrile cyclization

Article abstract of DOI:10.1016/j.tet.2012.04.035

The first enantioselective total synthesis of rumphellaone A, a cytotoxic 4,5-seco-caryophyllane isolated from the gorgonian coral Rumphella antipathies, has been achieved from a known olefinic alcohol by a 16-step sequence involving Stork's epoxy nitrile

Full text of DOI:10.1016/j.tet.2012.04.035

Tetrahedron 68 (2012) 4581e4587
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Synthesis of rumphellaone A via epoxy nitrile cyclization
Takafumi Hirokawa, Shigefumi Kuwahara *
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 April 2012
Received in revised form 7 April 2012
Accepted 9 April 2012
Available online 14 April 2012
The first enantioselective total synthesis of rumphellaone A, a cytotoxic 4,5-seco-caryophyllane isolated
from the gorgonian coral Rumphella antipathies, has been achieved from a known olefinic alcohol by a 16-
step sequence involving Stork’s epoxy nitrile cyclization as the key step to concomitantly install a cy-
clobutane ring and three contiguous stereogenic centers contained in the molecule.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Rumphellaone
Cytotoxic
Total synthesis
Epoxy nitrile
Cyclobutane
1. Introduction
double bond, the newly discovered 4,5-seco-caryophyllane 1 is dis-
tinct in the presence of a
g-lactone unit, which might possibly be
In a series of researches on the chemical constituents of the
gorgonian coral Rumphella antipathies collected off the southern
coast of Taiwan, Sung and co-workers identified a variety of novel
caryophyllane- and clovane-related sesquiterpenoids, most of which
exhibited interesting pharmacological properties, such as antibac-
terial activity against Gram-positive as well as Gram-negative bac-
teria.1 Among the compounds isolated from the coral was
formed biosynthetically via acid-catalyzed lactonization of the g,d-
unsaturated carboxylic acid portion of 2b. In contrast to a consider-
able number of synthetic studies on caryophyllane-type natural
5
products, no report on the synthesis of 4,5-seco-caryophyllanes has,
to the best of our knowledge, appeared in the literature. The lack of
synthetic studies as well as the unique structural features and in-
teresting biological activity of 1 prompted our synthetic efforts to-
6
rumphellaone A (1) (Fig. 1), which showed moderate cytotoxicity
ward 1, which recently culminated in the first total synthesis of 1. In
2
against CCRF-CEM tumor cells with an IC50 value of 12.6
mg/mL.
this article, we describe a full account of our synthesis of 1 including
From a structural viewpoint, rumphellaone A (1) belongs to a very
small family of natural products known as 4,5-seco-caryophyllanes
comprising only four compounds, 1 and 2aec. Whereas 2aec are
merely oxidative cleavage products of caryophyllene 3 at its C4eC5
some optimization processes and additional data.
3
,4
2
2
. Results and discussion
.1. Retrosynthetic analysis of 1
H
H
H
H
H
Our retrosynthetic analysis of rumphellaone A (1) is shown in
Scheme 1. The most challenging task for the synthesis of 1 would be
O
O
X
1
4
O
Y
5
the construction of the cyclobutane ring bearing two of the three
H
7
contiguous stereogenic centers (C1eC9eC8). For this end, we
1
2a: X = O, Y = CH OH
3
2
2
planned to apply Stork’s epoxy nitrile cyclization protocol to 5. If
successful, this process would lead to simultaneous installation of
the cyclobutane ring and the three contiguous asymmetric centers,
giving key intermediate 4, which would be convertible to the target
molecule 1 through chain elongation at its C2 and the C7 positions.
The epoxy nitrile intermediate 5 would be obtainable by the
Sharpless asymmetric epoxidation of allylic alcohol 6, which in turn
should readily be accessible from known olefinic alcohol 7.
(
rumphellaone A)
2b: X = O, Y = CO H
(caryophyllene)
2
c: X = OH; Y = CO H
2
Fig. 1. Rumphellaone A (1) and related natural products.
*
Corresponding author. Tel./fax: þ81 22 717 8783; e-mail address: skuwahar@
biochem.tohoku.ac.jp (S. Kuwahara).
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.035

4582
T. Hirokawa, S. Kuwahara / Tetrahedron 68 (2012) 4581e4587
application of this methodology to the synthesis of cyclobutane-
O
2
12,14
H
H
CN
containing natural products has scarcely been documented.
Furthermore, ,ε-epoxy nitriles bearing substituents at the -posi-
CN
1
d
b
9
O
O
tion of the nitrile function or oxygen-containing substituents at the
ε-position have never been subjected to the cyclization reaction.
OH
OR
8
H
H
7
O
5
OR
Thus, the success or failure of the conversion of the
b,b-dimethyl-
1
4
ε-(silyloxy)methyl- ,ε-epoxy nitrile 14 into the corresponding
d
OH
CN
cyclobutane derivative 15 (see Table 1) was considered to be not only
critical for attaining our total synthesis of 1 but also to be important
in probing the scope and limitations of this methodology.
OH
Scheme 1. Retrosynthetic analysis of 1.
7
6
Table 1
Cyclization of epoxy nitrile 14 into 15
H
H
CN
CN
CN
2
.2. Preparation of epoxy nitrile 14 as the substrate for
+
cyclobutanation
OH
OTBS
OH
OTBS
H
H
O
14
OTBS
The preparation of epoxy nitrile 14 (a protected form of 5 in
Scheme 1) to be subjected to ring closure into the corresponding
cyclobutane derivative 4 (R¼TBS) was depicted in Scheme 2. The
starting material 7, which was readily obtained in two steps by
allylation of methyl isobutylate and subsequent reduction with
LiAlH
15
16
Entry
1
Reagents and conditions
Yield (%)
NDa
Ratio (15/16/14)c
LDA (1.3 equiv), HMPA (3.0 equiv)
3:2:2
ꢀ
THF, 0 C to rt, 1.5 h
8
NDa
2
3
4
5
LDA (3.0 equiv), HMPA (5.0 equiv)
THF, rt, 1 h
5:4:0
4
based on literature protocols, was tosylated by Tanabe’s
9
procedure into 8, the exposure of which to NaCN in DMSO gave
NaHMDS (1.05 equiv)
PhMe, 0 C, 40 min
NaHMDS (2.5 equiv)
PhMe, reflux, 2.5 h
KHMDS (1.8 equiv)
PhMe, reflux, 1.5 h
NDa
90b
82b
1:1:7
nitrile 9.10 Ozonolytic cleavage of its double bond afforded aldehyde
ꢀ
10, which was then subjected to the Wittig reaction with Ph
3
P]
>20:1:0
>20:1:0
C(Me)CO Et to furnish 11 in 51% overall yield from 7 after chro-
2
matographic purification of the resulting 8.3:1 mixture of 11 and its
Z isomer. Chemoselective reduction of the ester group of 11 with
DIBAL gave allylic alcohol 12, the Sharpless asymmetric epoxida-
a
ND stands for not determined. The reaction proceeded cleanly, giving no no-
ticeable amount of byproduct other than 16.
tion of which in the presence of
L-(þ)-DIPT afforded epoxy alcohol
b
Isolated yield of 15 containing a trace amount of 16, which was difficult to
13a in 64% yield from 11. The enantiomeric excess of 13a was
remove completely.
1
c
Determined by 1H NMR analysis of the crude reaction mixture.
evaluated to be 92% by analyzing the H NMR spectra of the cor-
11
responding (R)- and (S)-MTPA esters 13b. Finally, protection of
3a as its TBS ether provided, in 96% yield, the substrate (14) for
Stork’s epoxy nitrile cyclization.
1
As shown in Table 1, treatment of 14 with LDA in THF in the
presence of HMPA at 0 C for 1.5 h did not lead to the completion of
ꢀ
the reaction, providing a mixture of the desired product 15, its C1-
epimer 16, and the starting epoxy nitrile 14 (15/16/14¼3:2:2, as
OH TsCl, Et N
OTs
CN
O3
NaHCO3
3
1
judged by the H NMR spectrum of the crude reaction mixture)
Me N·HCl
NaCN
3
(entry 1); generation of any detectable amounts of other products
CH Cl
DMSO
MeOH
2
2
including the corresponding five-membered carbocycle possibly
formed via a 5-endo epoxide opening process was not observed.
Although sufficient spectroscopic evidences to specify the relative
stereochemistry of 15 and 16 were not obtained at this stage, some
diagnostic NOEs observed in a derivative of an advanced synthetic
intermediate (see section 2.5) enabled us to confirm the stereo-
chemistry as depicted in Table 1. By raising the reaction tempera-
CH Cl
7
8
9
2
2
CN
CN
CN
Ph3P
CO
2
Et
DIBAL
CH Cl
THF
1% (4 steps)
2
2
CHO
5
CO Et
OH
2
10
11
12
ꢀ
ture from 0 C to room temperature and increasing the amounts of
LDA and HMPA, the cyclobutanation reaction proceeded to com-
pletion to give an inseparable mixture of 15 and 16, but the dia-
stereoselectivity did not improve (15/16¼5:4) (entry 2). Upon
L
-(+)-DIPT
CN
TBSCl
CN
Ti(O-iPr)4
imidazole
ꢀ
TBHP
DMF
96%
exposure of 14 to NaHMDS in toluene at 0 C for 40 min, a sub-
CH Cl
2 2
O
OR
O
14
OTBS
stantial amount of 14 remained and the ratio of 15 and 16 were 1:1
(entry 3). To our delight, the increase in the amount of the base as
well as, probably more importantly, in the reaction temperature
(from room temperature to refluxing temperature) led to remark-
able improvement in both yield and selectivity, affording 15 in
a high yield of 90% and an excellent diastereoselectivity of >20:1
(entry 4). The use of KHMDS instead of NaHMDS gave an analogous
outcome, albeit in a slightly lower yield of 82% (entry 5). Addi-
tionally, the 5:4 mixture of the 1,9-trans isomer 15 and the 1,9-cis
isomer 16 obtained in entry 2 cleanly converged into 15 when
subjected to the same reaction conditions as employed in entry 4.
These results would clearly show that the highly diastereoselective
formation of the 1,9-trans isomer 15 in entries 4 and 5 is ascribable
6
4% (2 steps)
1
3a: R = H
3b: R = MTPA
1
Scheme 2. Preparation of epoxy nitrile 14.
2
.3. Epoxy nitrile cyclization of 14
Since the first report on the base-induced cyclization of
nitriles into cyclobutane derivatives by Stork and co-workers,
a considerable number of basic studies on the epoxy nitrile cycli-
zation focusing mainly on its regio- and cis/trans-selectivity have
d,ε-epoxy
1
2
13
been described by several research groups. On the other hand,

T. Hirokawa, S. Kuwahara / Tetrahedron 68 (2012) 4581e4587
4583
to its thermodynamic stability. The highly diastereoselective and
high-yielding formation of 15 via simultaneous installation of the
cyclobutane ring and the three contiguous stereogenic centers set
the stage for chain elongation at its C2 and C7 positions toward the
completion of our synthesis of 1.
incompatible with reagents (such as DIBAL) needed to reduce the
nitrile group at the C2 position into an aldehyde function which
would probably be required for chain elongation at the C2 position.
Based on these considerations, we decided to conduct chain elon-
gation at the C2 position of 15 prior to that at the C7 position. Thus,
we first attempted the reduction of the nitrile 15 with DIBAL to
obtain aldehyde 23 (Scheme 4). Unexpectedly, this reaction turned
out to be very sluggish, giving 23 in only up to 46% yield along with
a small amount of the starting material 15 even when 15 was treated
overnight with 3 equiv of DIBAL at room temperature. The aldehyde
2
.4. Attempted chain elongation at the C7 position of 15 by
nucleophilic ring opening of an epoxide intermediate
To construct the lactone moiety of 1, we needed to add a two-
carbon unit at the C7 position of 15 (Scheme 3). For this end, com-
pound 15 was desilylated to diol 17, which was then transformed into
epoxide 19 in two steps via mesylate 18. We first attempted nucleo-
philic ring opening of 19 with allylmagnesium chloride or bromide in
the presence or absence of a copper catalyst to obtain 20; the oxi-
dative cleavage of its double bond would lead to the formation of
a carboxylic acid, which would then cyclize into a lactone in-
3
23 was subjected to Wittig reaction conditions [Ph P]CHC(O)Me
(2.5 equiv), toluene, reflux, 5 h] to give enone 24, the exposure of
which to TBAF (2 equiv) in THF for 15 min at room temperature
furnished three-carbon elongated intermediate 25. Although the
three-step sequence from 15 could afford 24, the unsatisfactory
overall yield obtained (35%) demanded some improvement.
termediate. However, all of our attempts using various reaction
2
H
H
O
ꢀ
CN
CHO
OH
conditions [(a) CH
CHCH MgBr, CuI, Et
2
]CHCH
2
MgBr, Et
2
O, 0 C to rt; (b) CH
2
]
3
Ph P
ꢀ
DIBAL
2
ꢀ
2
O, ꢁ40 C to rt; (c) CH
2 2
]CHCH MgCl, CuI, THF,
ꢀ
OH
CH Cl2
ꢁ
78 C to rt; (d) CH
CHCH MgCl, Li CuCl
CuBr$SMe
2
]CHCH
2
MgCl, CuI, THF, 0e40 C; (e) CH
2
]
2
PhMe
88%
H
H
ꢀ
46%
2
2
4
, THF, ꢁ60 C to rt; and (f) CH
2 2
]CHCH MgCl,
OTBS
OTBS
ꢀ
15
23
2
, THF, ꢁ78 to 0 C] were unsuccessful, resulting in the
formation of a complex mixture (a, b, and e), no reaction (c), or gen-
eration of a single, but undesired, byproduct (d and f). With the in-
O
O
H
H
tention of reducing the steric bulkiness of the nucleophile, we also
TBAF
ꢀ
treated 19 with vinyl anions [CH
CH
2
]CHMgBr, CuI, THF, ꢁ78 C to rt; or
OH
THF
87%
OH
OH
ꢀ
H
H
2
]CH(2-Th)Cu(CN)LiMgBr, THF, ꢁ78 C to rt] and with an acety-
ꢀ
OTBS
lide anion [TMSC^CLi, THF/HMPA. ꢁ78 C to rt], hoping to obtain 21
and 22, respectively. In these cases also, however, the desired prod-
ucts were not obtained at all. These unsuccessful results obliged us to
change methods for introducing a two-carbon unit at the C7 position.
24
25
H
H
TMSOTf
,6-lutidine
CN
CHO
2
DIBAL
15
CH Cl2
quant
OTMS CH Cl2
OTMS
OTBS
2
2
H
H
H
H
H
90%
CN
CN
CN
OTBS
TBAF
THF
91%
MsCl, Et
OH DMAP
CH Cl2
3
N
26
27
OH
OTBS
OH
OMs
O
O
H
H
H
NOEs observed in 29a
(MeO) P
7
2
2
OH
15
17
18
H
OR
NaH, DME
84%
O
H
H
H
H
CN
CN
CN
OTMS
OTBS
H
H
DBU. PhMe
M
M
TBAF
THF
25
57% (2 steps)
OH
OTMS
OTBS
H
O
H
29a: R = H
9b: R = MTPA
H
84%
2
19
20
H
28
Scheme 4. Chain elongation at the C2 position.
TMS
Li
HMPA, THF
Suspecting undesirable effects of the free hydroxy group in 15,
we protected it as its TMS ether 26 and then subjected to reduction
with DIBAL (1.5 equiv). This protection brought about significant
improvement in chemical yield, giving the corresponding aldehyde
H
OH
CN
OH
H
21
H
27 in 90% yield without any recovery of the starting material 26.
The aldehyde 27 was treated with (MeO) P(O)CH C(O)Me and NaH
in DME to afford 28; unlike the conversion of 23 into 24, the use of
2
2
22
TMS
Scheme 3. Attempted chain elongation at the C7 position via epoxide intermediate 19.
3
Ph P]CHC(O)Me led to a marked decrease both in reaction rate
and in chemical yield, requiring more than three days for the
completion of the reaction in refluxing toluene and providing 28 in
ca. 50e60 % yield. Finally, removal of the two silyl protecting groups
in 28 with TBAF furnished 25 in an improved overall yield of 64%
from 15. The 1,9-trans relationship of 27 was ascertained indirectly
by observing diagnostic NOESY correlations in 29a derived by re-
2
.5. Chain elongation at the C2 position of 15
As a reliable method for two-carbon elongation at the C7 posi-
tion, we envisaged the Wittig or HornereWadswortheEmmons re-
action [using Ph P]CHCO R or (RO) P(O)CH CO R, respectively] of
an aldehyde, possibly derived by oxidation at the C7 position of 15, to
provide the corresponding -unsaturated ester. In those cases,
however, the ester group in the resulting product would be
4
duction of 27 (NaBH , MeOH, rt, 2 h). We also made sure that the
3
2
2
2
2
enantiomeric excess of 27 remained to be 92% (determined at the
stage of 13a in Scheme 2) by converting 29a into the corresponding
a,b
1
(R)- and (S)-MTPA esters 29b and analyzing their H NMR spectra.

4584
T. Hirokawa, S. Kuwahara / Tetrahedron 68 (2012) 4581e4587
2
.6. Completion of the total synthesis of rumphellaone A
of the cyclobutane derivative 15 from the
d,ε-epoxy nitrile 14
bearing -dimethyl and ε-siloxymethyl substituents extended the
b,b
Having succeeded in the three-carbon elongation at the C2 po-
scope of applicability of this base-induced cyclobutanation re-
action. Synthetic studies on other 4,5-seco-caryophyllanes as well
as caryophyllane-related natural products are now in progress and
will be reported in due course.
sition of 15, we set about the final stage of the total synthesis of
rumphellaone A (1), which began with the ParikheDoering oxida-
tion of the chain elongation product 25 (Scheme 5). The oxidation of
the diol 25 proceeded uneventfully, furnishing
0 in 83% yield. Two-carbon elongation at the C7 position of 30 was
conducted by its Wittig olefination with Ph P]CHCO Et to give
a-hydroxy aldehyde
3
4. Experimental
4.1. General
3
2
a,b-
unsaturated ester 31, the two double bonds of which were saturated
by catalytic hydrogenation to afford 32. This hydroxy ester 32 was, in
most cases, obtained as a mixture with its spontaneous lactonization
IR spectra were recorded by a Jasco FT/IR-4100 spectrometer
using an ATR (ZnSe) attachment. NMR spectra were recorded with
TMS as an internal standard in CDCl by a Varian MR-400 spec-
3
product 1.15 Finally, treatment of the mixture of 32 and 1 with
1
camphorsulfonic acid in CH
2
Cl
2
gave rumphellaone A (1), the H and
13
1
13
C NMR data of which were identical with those of the natural
trometer (400 MHz for H and 100 MHz for C). Optical rotation
values were measured with a Horiba Septa-300 polarimeter, and
the mass spectra were obtained with Jeol JMS-700 spectrometer
operated in the EI or FAB mode. Merck silica gel 60 (7e230 mesh)
was used for column chromatography. Solvents for reactions were
distilled prior to use: THF from Na and benzophenone; CH
DMSO, and DMF from CaH . All air- or moisture-sensitive reactions
were conducted under a nitrogen atmosphere.
product.2 The synthetic material shared the same sign of specific
rotation as natural rumphellaone A, but they were significantly dif-
ferent in the magnitude of specific rotation [observed data for the
30
16
synthetic sample, ½
a
ꢂ
þ83.4 (c 0.450, CHCl
3
); reported data for
D
2
5
2
natural rumphellaone A, ½
a
ꢂ
þ257 (c 0.014, CHCl
3
)]. Judging from
2 2
Cl ,
D
the facts that the enantiomeric excess of our synthetic sample (1)
was determined unambiguously to be 92% both at the stages of in-
termediates 13a and 27 by the MTPA method and that the chemical
purity of 1 seems to be pure enough for use in the measurement of
specific rotation (see NMR spectra in Supplementary data), the
genuine specific rotation value of rumphellaone A would be esti-
mated to be around þ90. At present, we are unable to account for the
difference in the magnitude of specific rotation, but the discrepancy
might be ascribable to the presence of some impurity with a very
large rotation value either in the natural or in the synthetic sample,
or possibly to the very low concentration (c 0.014) of the natural
material employed for the measurement of specific rotation.
2
4.1.1. Ethyl 6-cyano-2,5,5-trimethyl-2-hexenoate (11). To a stirred
mixture of 7 (2.50 g, 21.9 mmol), Et N (4.6 mL, 32.9 mmol), and
Me N$HCl (0.259 g, 2.71 mmol) in CH
3
3
2
Cl
2
(20 mL) was added
ꢀ
portionwise TsCl (5.03 g, 26.3 mmol) at 0 C, and the mixture was
warmed to room temperature. After 18 h, the mixture was
quenched with satd NaHCO
tract was successively washed with satd CuSO
dried (MgSO ), and concentrated in vacuo to give crude 8, which
was taken up in DMSO (15 mL). To the solution was added NaCN
3
aq and extracted with ether. The ex-
4
aq, water, and brine,
4
(
2.20 g, 44.8 mmol) while stirring at room temperature and the
ꢀ
resulting mixture was heated at 150 C for 19 h. The mixture was
O
O
H
H
H
diluted with water and extracted with Et
washed with brine, dried (MgSO ), and concentrated under atmo-
spheric pressure. The residue was filtered through a pad of SiO
using pentane/Et O as eluent. The filtrate was concentrated under
atmospheric pressure to give crude 9, which was dissolved in
2
O. The extract was
SO
i-Pr
3
·Py
NEt
Ph3P
CO
2
Et
4
2
2
OH
OH
DMSO
3%
OH
CHO
THF
71%
H
2
8
25
30
CH
2
Cl
2
/MeOH (5:1, 36 mL). To the solution was added NaHCO
3
ꢀ
(6.02 g, 71.7 mmol) and the resulting mixture was cooled to ꢁ78 C.
O
O
Ozone was bubbled into the mixture for 2 h. After removal of excess
ozone by a stream of O (for ca. 10 min), Me S (10 mL, 136 mmol)
H
H
H
2
2
H
2
, Pd/C
was added. The mixture was gradually warmed to room tempera-
ture and then filtered through a pad of Celite. The filtrate was
concentrated under atmospheric pressure to give crude 10, which
OH
MeOH
OH
CO
H
2
Et
31
CO Et
32 (+ 1)
CSA, CH Cl2
was taken up in THF (30 mL). To the solution was added Ph P]
2
3
C(Me)CO
2
Et (6.88 g, 19.0 mmol), and the mixture was stirred at
2
ꢀ
64% (2 steps)
room temperature for 4.5 h and then at 40 C for 14 h. To the so-
lution was added additional Ph
and the mixture was stirred at 40
concentrated in vacuo to give crude 11 as an 8.3:1 E/Z mixture,
which was purified by silica gel column chromatography (hexane/
3
P]C(Me)CO
2
Et (1.57 g, 4.33 mmol),
O
H
H
ꢀ
C for 1.5 h. The mixture was
O
O
EtOAc¼10:1) to give 2.32 g of 11 as a colorless oil (51% from 7). IR:
1
1
nmax 2242 (w), 1708 (s), 1262 (m); H NMR:
d
1.13 (6H, s), 1.31 (3H, t,
J¼7.1 Hz), 1.87 (3H, br d, J¼1.5 Hz), 2.26 (2H, dd, J¼7.9, 0.6 Hz), 2.27
Scheme 5. Completion of the total synthesis of rumphellaone A (1).
13
(
2H, s), 4.21 (2H, t, J¼7.1 Hz), 6.75 (2H, tq, J¼7.9, 1.5 Hz); C NMR:
d
12.7, 14.2, 26.8 (2C), 30.3, 34.3, 39.7, 60.7, 118.0, 131.0, 136.0, 167.7;
þ
3
. Conclusion
In conclusion, the first total synthesis of the 4,5-seco-caryo-
HRMS (EI): m/z calcd for C12
09.1420.
H19NO
2
(M ), 209.1416; found,
2
phyllane rumphellaone A (1) was accomplished in 6.8% overall
yield from the known olefinic alcohol 7 by a 16-step sequence in-
volving Stork’s epoxy nitrile cyclization as the key step to construct
the cyclobutane ring and to concomitantly install the three con-
tiguous stereogenic centers contained in 1. The efficient formation
4.1.2. 4-[(2S,3S)-3-Hydroxymethyl-3-methyl-2-oxiranyl]-3,3-
dimethylbutanenitrile (13a). To a stirred solution of 11 (5.51 g,
26.3 mmol) in CH
2
Cl
2
(100 mL) was added dropwise DIBAL (1.0 M in
ꢀ
hexane, 58.0 mL, 59.7 mmol) at ꢁ78 C, and the mixture was stirred
for 1 h at the same temperature. Then the mixture was gradually

T. Hirokawa, S. Kuwahara / Tetrahedron 68 (2012) 4581e4587
4585
ꢀ
warmed to ꢁ30 C and stirred for an additional 3 h. The mixture
and extracted with ether. The extract was successively washed
with satd NH Cl aq, water, and brine, dried (MgSO ), and con-
was quenched with satd Rochelle salt aq, warmed to room tem-
4
4
perature, and filtered through a pad of Celite. The filtrate was
centrated in vacuo. The residue was purified by silica gel column
chromatography (hexane/EtOAc¼10:1) to give 3.73 g (90%) of 15
extracted with CH
2 2
Cl , and the extract was washed with brine,
3
0
dried (MgSO ), and concentrated in vacuo. The residue was purified
4
as a colorless oil. ½
a
ꢂ
þ25.8 (c 1.01, CHCl
3
); IR
n
max 3484 (w), 2233
D
1
by silica gel column chromatography (hexane/EtOAc¼5:1e1:1) to
(w), 1254 (m), 1089 (s), 835 (s), 776 (m); H NMR: d 0.058 (3H, s),
give 3.76 g of 12, which was contaminated with a trace amount of
0.063 (3H, s), 0.90 (9H, s), 1.13 (3H, s), 1.14 (3H, s), 1.33 (3H, s), 1.63
1
an aldehydic byproduct. IR:
NMR:
n
max 3429 (s), 2243 (w), 1014 (s);
H
(1H, ddd, J¼11.1, 9.0, 0.8 Hz), 1.88 (1H, dd, J¼11.1, 10.0 Hz), 2.41
d
1.09 (6H, s), 1.47 (1H, br s, OH), 1.69 (3H, s), 2.12 (2H, d,
(1H, s, OH), 2.49 (1H, br q, J¼9.4 Hz), 2.90 (1H, dd, J¼9.5, 0.8 Hz),
13
13
J¼7.8 Hz), 2.23 (2H, s), 4.05 (2H, br s), 5.46 (1H, tm, J¼7.8 Hz);
C
3.33 (1H, d, J¼9.5 Hz), 3.36 (1H, d, J¼9.5 Hz); C NMR:
d
ꢁ5.6,
NMR:
d
13.9, 26.7 (2C), 30.0, 34.2, 39.0, 68.6, 118.5, 120.0, 138.3;
ꢁ5.5, 18.2, 21.9, 25.3, 25.8 (3C), 29.3, 32.6, 33.7, 34.6, 41.6, 68.9,
þ
þ
HRMS (EI): m/z calcd for C10
1
H
17ON ([MþH] ), 167.1311; found,
70.9, 120.5; HRMS (FAB): m/z calcd for C16
H
32NO
2
Si ([MþH] )
ꢀ
1
67.1309. To a stirred suspension of pulverized 4 A molecular sieves
298.2203, found 298.2202. From the H NMR spectrum of the
mixture obtained in entry 2 in Table 1, the signals for compound
(
10.0 g),
L
-(þ)-diisopropyl tartrate (6.75 mL, 32.1 mmol), and
i
Ti(O Pr)
4
(8.5 mL, 28.7 mmol) in CH
2
Cl
2
(80 mL) was added a solu-
16 were assigned as follows: d 0.05 (6H, s), 0.89 (9H, s), 1.278 (3H,
ꢀ
tion of TBHP (5.6 M in toluene, 12.0 mL, 67.2 mmol) at ꢁ20 C. After
s), 1.284 (3H, s), 1.29 (3H, s), 1.70 (1H, ddd, J¼11.3, 9.0, 2.4 Hz), 2.20
(1H, br t, J¼ca. 10.7 Hz), 2.37 (1H, s, OH), 2.67 (1H, br q, J¼ca.
9.5 Hz), 2.85 (1H, ddd, J¼9.6, 2.4, 1.0 Hz), 3.29 (1H, d, J¼9.5 Hz),
3.33 (1H, d, J¼9.5 Hz).
3
0 min, a solution of 12 (3.76 g) in CH
2 2
Cl (30 mL) was added, and
the resulting mixture was stirred for 17 h at the same temperature
before being quenched with FeSO
4
$7H
2
O (18.9 g, 68.0 mmol) and
. The extract was washed
10% aq tartaric acid (112 mL). The mixture was warmed to room
temperature and extracted with CHCl
with brine, dried (MgSO
3
4.1.6. (1R,4S)-4-[(R)-2-(tert-Butyldimethylsilyloxy)-1-methyl-1-(tri-
methylsilyloxy)ethyl]-2,2-dimethylcyclobutanecarbonitrile (26). To
a stirred solution of 15 (438 mg, 1.47 mmol) and 2,6-lutidine
4
), and concentrated in vacuo. The residue
was purified by silica gel column chromatography (hexane/
EtOAc¼4:1e1:1) to give 3.09 g (64% from 11) of 13a as a colorless
(430
(450
m
L, 3.72 mmol) in CH
2
Cl
2
(10 mL) was added TMSOTf
3
1
ꢀ
oil. ½
a
ꢂ
ꢁ31.7 (c 1.04, CHCl
3
); IR:
n
max 3451 (s), 2243 (w), 1471 (m),
mL, 2.49 mmol) at 0 C. After 30 min, the mixture was
D
1
1
038 (s), 772 (s); H NMR:
1H, dd, J¼14.6, 8.2 Hz), 1.74 (1H, dd, J¼14.6, 3.9 Hz), 1.76 (1H, dd,
J¼8.6, 4.5 Hz), 2.35 (1H, d, J¼16.6 Hz), 2.39 (1H, d, J¼16.6 Hz), 3.13
d
1.19 (3H, s),1.20 (3H, s),1.30 (3H, s),1.55
quenched with satd NH
was washed with brine, dried (MgSO
4
Cl aq and extracted with ether. The extract
), and concentrated in vacuo.
(
4
The residue was purified by silica gel column chromatography
(
1H, dd, J¼8.2, 3.9 Hz), 3.61 (1H, dd, J¼12.3, 8.6 Hz), 3.70 (1H, dd,
(hexane/EtOAc¼100:1) to give 544 mg (quant) of 26 as a colorless
13
24
J¼12.3, 4.5 Hz); C NMR:
d
14.4, 26.8, 27.4, 30.6, 33.3, 39.1, 56.0,
oil. ½
a
ꢂ
þ22.4 (c 0.980, CHCl
3
); IR: nmax 2231 (w), 1252 (m), 1106
d 0.03 (3H, s), 0.04 (3H, s), 0.14 (9H, s), 0.89
D
þ
1
5
1
9.9, 65.0, 118.2; HRMS (FAB): m/z calcd for C10
H18NO
2
([MþH] ),
(m), 834 (s); H NMR:
(9H, s), 1.10 (3H, s),1.19 (3H, s), 1.31 (3H, s),1.54 (1H, ddd, J¼10.7, 9.0,
.8 Hz), 1.82 (1H, dd, J¼10.7, 9.4 Hz), 2.60 (1H, ddd, J¼9.4, 9.4,
9.0 Hz), 2.79 (1H, d, J¼9.4 Hz), 3.24 (1H, d, J¼9.5 Hz), 3.29 (1H, d,
84.1338; found, 184.1339.
0
4.1.3. Determination of the enantiomeric excess of 13a. Compound
13
1
3a was converted into the corresponding (R)- and (S)-MTPA esters
J¼9.5 Hz); C NMR: ꢁ5.6, ꢁ5.5, 2.5 (3C), 18.3, 22.4, 25.7, 25.8 (3C),
d
11
(
13b) according to the literature. The MTPAO-bearing methylene
protons of the (S)-MTPA ester were observed at 4.27 (1H, d,
4.44 (1H, d, J¼11.7 Hz) in H NMR (400 MHz,
), while those of the (R)-MTPA esters were detected at 4.17
1H, d, J¼11.7 Hz) and 4.44 (1H, d, J¼11.7 Hz). Comparison of the
two spectra indicated the enantiomeric excess of 13a to be 92%.
29.3, 32.0, 32.9, 33.7, 41.6, 67.9, 75.6, 121.0; HRMS (FAB): m/z calcd
ꢁ
d
for C19
H
38NO
2
Si
2
([MꢁH] ), 368.2441; found, 368.2438.
1
J¼11.7 Hz) and
CDCl
d
3
d
4.1.7. (1R,4S)-4-[(R)-2-(tert-Butyldimethylsilyloxy)-1-methyl-1-(tri-
methylsilyloxy)ethyl]-2,2-dimethylcyclobutanecarbaldehyde (27). To
(
d
a stirred solution of 26 (115 mg, 0.311 mmol) in CH
2
2
Cl (3 mL) was
added dropwise DIBAL (1.0 M in hexane, 467
mL, 0.467 mmol) at
ꢀ
4.1.4. 4-{(2S,3S)-3-[(tert-Butyldimethylsilyloxy)methyl]-3-methyl-2-
ꢁ20 C. After 20 min, the mixture was gradually warm to room
temperature and stirred for 26 h. The mixture was quenched with
satd Rochelle salt aq and filtered through a pad of Celite. The filtrate
was extracted with ether, and the extract was washed with brine,
oxiranyl}-3,3-dimethylbutanenitrile (14). To a stirred solution of 13a
(
(
3.02 g, 16.5 mmol) and imidazole (2.29 g, 33.6 mmol) in DMF
40 mL) was added portionwise TBSCl (2.71 g, 18.0 mmol) at 0 C.
ꢀ
The mixture was stirred at room temperature for 1.5 h, quenched
with satd NH Cl aq, and extracted with EtOAc. The extract was
washed with brine, dried (MgSO ), and concentrated in vacuo. The
residue was purified by silica gel column chromatography (hexane/
dried (MgSO
4
), and concentrated in vacuo. The residue was purified
4
by silica gel column chromatography (hexane/EtOAc¼100:1) to
1
9
4
give 104 mg (90%) of 27 as a colorless oil. ½
a
ꢂ
D
þ6.8 (c 1.04, CHCl
3
);
1
IR: nmax 1715 (m), 1251 (m), 1104 (m), 833 (s); H NMR: d 0.04 (6H,
3
0
EtOAc¼15:1e5:1) to give 4.69 g (96%) of 14 as a colorless oil. ½
a
ꢂ
s), 0.13 (9H, s), 0.90 (9H, s), 1.02 (3H, s), 1.12 (3H, s), 1.21 (3H, s), 1.44
(1H, br t, J¼9.8 Hz), 1.82 (1H, br t, J¼9.8 Hz), 2.72 (1H, br q,
J¼9.2 Hz), 2.86 (1H, dm, J¼9.2 Hz), 3.29 (2H, br s), 9.77 (1H, d,
D
ꢁ
13.8 (c 1.01, CHCl
3
); IR: nmax 2241 (w), 1471 (m), 1253 (m), 1123
1
(
m), 1094 (m), 836 (s), 771 (s); H NMR:
d
0.05 (3H, s), 0.06 (3H, s),
13
0
8
4
d
.90 (9H, s), 1.18 (3H, s), 1.19 (3H, s), 1.28 (3H, s), 1.53 (1H, dd, J¼14.4,
J¼2.0 Hz); C NMR: ꢁ5.5, ꢁ5.4, 2.5 (3C), 18.3, 22.6, 24.5, 25.9 (3C),
d
.0 Hz),1.70 (1H, dd, J¼14.4, 4.3 Hz), 2.36 (2H, s), 2.95 (1H, dd, J¼8.0,
30.7, 32.9, 36.0, 36.2, 55.1, 68.5, 76.0, 204.4; HRMS (FAB): m/z calcd
13
þ
.3 Hz), 3.57 (1H, d, J¼11.2 Hz), 3.62 (1H. dd, J¼11.2 Hz); C NMR:
for C19
40
H O
3
Si
2
Na ([MþNa] ), 395.2414; found, 395.2417.
ꢁ5.4, ꢁ5.3, 14.4, 18.3, 25.8 (3C), 26.7, 27.4, 30.6, 33.3, 39.1, 56.9,
þ
6
0.0, 67.4, 118.2; HRMS (FAB): m/z calcd for C16
H32NO
2
Si ([MþH] ),
4.1.8. 4-{(1R,4S)-4-[(R)-2-(tert-Butyldimethylsilyloxy)-1-methyl-1-
(trimethylsilyloxy)ethyl]-2,2-dimethylcyclobutyl}-3-buten-2-one
2
98.2202; found, 298.2206.
(28). To a stirred suspension of NaH (60% in mineral oil, 10 mg,
4
.1.5. (1R,4S)-4-[(R)-2-(tert-Butyldimethylsilyloxy)-1-hydroxy-1-
0.25 mmol) in DME (1 mL) was added MeCOCH P(O)(OMe) (32 L,
2
2
m
methylethyl]-2,2-dimethylcyclobutanecarbonitrile (15). NaHMDS
1.0 M in THF, 35.0 mL, 35.0 mmol) was added dropwise to a so-
0.23 mmol) at room temperature. After 1 h, a solution of 27 (55 mg,
0.15 mmol) in DME (0.6 mL) was added, and the resulting mixture
(
lution of 14 (4.15 g, 13.9 mmol) in toluene (80 mL) while refluxing
the reaction mixture. After being stirred at the refluxing tem-
was stirred for four days. The mixture was quenched with satd NH
aq and extracted with ether. The extract was washed with brine,
dried (MgSO ), and concentrated in vacuo. The residue was purified
4
Cl
perature for 2.5 h, the mixture was quenched with satd NH
4
Cl aq
4

4586
T. Hirokawa, S. Kuwahara / Tetrahedron 68 (2012) 4581e4587
by silica gel column chromatography (hexane/EtOAc¼100:1) to give
(268 mg, 0.769 mmol) at room temperature. After being stirred at
50 C for 3 h, the mixture was cooled to room temperature and
1
7
ꢀ
5
1 mg (84%) of 28 as a colorless oil. ½
a
ꢂ
þ56.6 (c 1.10, CHCl
3
); IR:
0.03 (s, 6H),
.13 (9H, s), 0.90 (9H, s),1.01 (3H, s),1.03 (3H, s),1.04 (3H, s),1.44 (1H,
D
1
n
max 1676 (m), 1250 (m), 1100 (m), 834 (s); H NMR:
d
concentrated in vacuo. The residue was purified by silica gel column
chromatography (hexane/EtOAc¼5:1) to give 135 mg (71%) of 31 as
0
1
9
dd, J¼10.0, 9.1 Hz), 1.75 (1H, br t, J¼10.0 Hz), 2.26 (3H, s), 2.33 (1H, q,
a colorless oil. ½
a
ꢂ
þ79.6 (c 1.00, CHCl
3
); IR:
n
max 3478 (m), 1714 (s),
D
1
J¼9.1 Hz), 2.71 (1H, dd, J¼9.1, 8.7 Hz), 3.24 (2H, s), 6.03 (1H, dd,
1668 (s), 1617 (m), 1366 (m), 1280 (s), 1178 (s); H NMR:
d
1.03 (3H,
1
3
J¼15.9, 0.9 Hz), 6.82 (1H, dd, J¼15.9, 8.7 Hz); C NMR:
d
ꢁ5.5, ꢁ5.4,
s), 1.08 (3H, s), 1.21 (3H, s), 1.29 (3H, t, J¼7.1 Hz), 1.54 (1H, dd, J¼10.7,
9.2 Hz), 1.66 (1H, dd, J¼10.7, 10.2 Hz), 1.82 (1H, s), 2.26 (3H, s), 2.37
(1H, br q, J¼9.2 Hz), 2.76 (1H, dd, J¼9.2, 8.4 Hz), 4.20 (2H, q,
J¼7.1 Hz), 6.01 (1H, d, J¼15.6 Hz), 6.09 (1H, dd, J¼16.1, 0.8 Hz), 6.80
2
6
.6 (3C), 18.3, 22.9, 24.4, 25.9 (3C), 26.9, 29.9, 32.6, 35.9, 41.0, 46.9,
8.5, 76.4,130.9, 149.9, 198.7; HRMS (FAB): m/z calcd for C22
H O Si
45 3 2
þ
(
[MþH] ), 413.2907; found, 413.2906.
1
3
(
1H, dd, J¼16.1, 8.4 Hz), 6.87 (1H, d, J¼15.6 Hz); C NMR:
d 14.2,
4
.1.9. 4-{(1R,4S)-4-[(R)-1,2-Dihydroxy-1-methylethyl]-2,2-
23.9, 25.8, 27.1, 29.8, 32.9, 36.1, 42.8, 47.3, 60.5, 72.9, 119.2, 131.3,
dimethylcyclobutyl}-3-buten-2-one (25). To a stirred solution of 28
46 mg, 0.11 mmol) in THF (1.5 mL) was added TBAF (1.0 M in THF,
30 L, 0.330 mmol) at room temperature. After 1 h, the mixture
was quenched with satd NH Cl aq and extracted with CH Cl . The
extract was washed with brine, dried (MgSO ), and concentrated in
148.2, 152.2, 166.6, 198.4; HRMS (FAB): m/z calcd for C17
([MþH] ), 295.1910; found, 295.1906.
H
27
O
4
þ
(
3
m
4
2
2
4.1.13. (S)-5-[(1S,2R)-3,3-Dimethyl-2-(3-oxobutyl)cyclobutyl]dihy-
dro-5-methyl-2(3H)-furanone (1). A mixture of 31 (112 mg,
0.380 mmol) and 10% Pd/C (138 mg) in MeOH (4 mL) was stirred at
room temperature for 30 min under a hydrogen atmosphere. The
mixture was filtered through a pad of Celite, and the filtrate was
concentrated in vacuo to give a mixture of 32 and 1 (32/1¼ca. 2:1),
4
vacuo. The residue was purified by silica gel column chromatog-
raphy (hexane/EtOAc¼2:1e1:2) to give 21 mg (84%) of 25 as a col-
2
4
orless oil. ½
a
ꢂ
þ88.5 (c 0.97, CHCl
3
); IR: nmax 3414 (s), 1666 (s), 1615
D
1
(
m), 1365 (m), 1262 (m), 1047 (m); H NMR:
s), 1.09 (3H, s), 1.61 (1H, dd, J¼10.7, 8.8 Hz), 1.79 (1H, dd, J¼10.7,
0.2 Hz), 2.08(2H, br s), 2.26 (3H, s), 2.34 (1H, br q, J¼9.4 Hz), 2.74
1H, dd, J¼9.4, 8.6 Hz), 3.33 (1H, d, J¼10.9 Hz), 3.39 (1H, d,
d 1.04 (3H, s), 1.06 (3H,
which was then taken up in CH
added CSA (46 mg, 0.20 mmol) while stirring at room temperature.
After 15 min, the mixture was quenched with satd NaHCO aq and
extracted with EtOAc. The extract was washed with brine, dried
(MgSO ), and concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane/EtOAc¼10:1e5:1) to
2 2
Cl (4 mL). To the solution was
1
(
3
J¼10.9 Hz), 6.08 (1H, dd, J¼16.0, 0.9 Hz), 6.79 (1H, dd, J¼16.0,
8
7
(
.6 Hz); 13C NMR:
d
22.1, 23.9, 27.1, 29.8, 33.1, 36.7, 40.8, 47.6, 68.7,
4
2.5, 131.2, 148.4, 198.5; HRMS (FAB): m/z calcd for C13
[MþH] ), 227.1647; found, 227.1645.
H
23
O
3
þ
19
give 61 mg (64% from 31) of 1 as a colorless oil. ½
a
ꢂ
þ83.4 (c 0.450,
D
2
25
D
CHCl
3
) (lit. ½
a
ꢂ
þ257 (c 0.014, CHCl
3
)); IR:
nmax 1765 (vs), 1713 (s),
1.04 (3H, s),1.07 (3H, s),1.32
1
4
2
d
.1.10. Determination of the enantiomeric excess of 29a. Compound
1248 (m),1161 (m), 936 (m); H NMR:
d
1
7 was reduced [NaBH
0.055 (3H, s), 0.064 (3H, s), 0.14 (9H, s), 0.90 (9H, s), 1.03 (3H, s),
.05 (3H, s), 1.15 (3H, s), 1.49 (1H, dd, J¼10.5, 8.5 Hz), 1.70 (1H, dd,
J¼10.5, 9.5 Hz), 2.06 (1H, dt, J¼8.5, 9.5 Hz), 2.14 (1H, ddd, J¼9.5, 7.8,
4
(3.2 equiv), MeOH, rt, 2 h] to 29a [ H NMR:
(3H, s), 1.43 (1H, br t, J¼10.3 Hz), 1.57 (1H, dd, J¼10.7, 8.7 Hz),
1.64e1.70 (2H, m), 1.82e1.93 (2H, m), 1.99e2.09 (2H, m), 2.13 (3H,
s), 2.37 (2H, br t, J¼7.7 Hz), 2.54 (1H, ddd, J¼18.2, 10.0, 5.1 Hz), 2.64
1
1
3
(1H, ddd, J¼18.2, 9.7, 8.9 Hz); C NMR:
d 22.5, 24.9, 25.1, 29.1, 29.9,
6
.3 Hz), 2.40 (1H, dd, J¼8.4, 2.9 Hz. OH), 3.40 (1H, d, J¼9.9 Hz), 3.51
30.6, 30.9, 33.0, 33.5, 42.0, 44.2, 44.5, 87.2, 177.0, 208.6; HRMS (FAB)
13
þ
(
1H, d, J¼9.9 Hz), 3.51e3.63 (2H, m); C NMR:
3C), 18.3, 22.5, 22.7, 25.9 (3C), 30.7, 32.1. 34.3, 44.0, 46.6, 63.7, 68.8,
6.5]. The alcohol 29a was converted into the corresponding (R)-
d
ꢁ5.5, ꢁ5.4, 2.5
m/z calcd for C15
H
25
O
3
([MþH] ) 253.1804, found 253.1805.
(
7
Acknowledgements
11
and (S)-MTPA esters (29b) according to the literature. The
MTPAO-bearing methylene protons of the (S)-MTPA ester were
This work was financially supported, in part, by a Grant-in-Aid
for Scientific Research (B) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan (No. 22380064).
observed at
1
d
4.18 (1H, br t, J¼11.2 Hz) and
1.2 Hz) in H NMR (400 MHz, CDCl ), while those of the (R)-MTPA
esters were detected at 4.34 (1H,
d
4.42 (1H, dd, J¼4.3,
1
3
d
4.24 (1H, br t, J¼11.2 Hz) and
d
dd, J¼4.3, 11.2 Hz). Comparison of the two spectra indicated the
enantiomeric excess of 29a to be 92%.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.035. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
4
.1.11. (R)-2-[(1S,2R)-3,3-Dimethyl-2-(3-oxo-1-butenyl)cyclobutyl]-2-
hydroxypropanal (30). To stirred solution of 25 (104 mg,
NEt (1.60 mL, 9.19 mmol) in DMSO (4 mL) was
added a solution of SO $Py (780 mg, 4.90 mmol) in DMSO (4 mL) at
a
i
0
.460 mmol) and Pr
2
3
room temperature. After 1 h, the mixture was quenched with water
and extracted with EtOAc. The extract was washed with brine, dried
References and notes
(
MgSO
4
), and concentrated in vacuo. The residue was purified by
1. (a) Chuang, L.-F.; Fan, T.-Y.; Li, J.-J.; Sung, P.-J. Biochem. Syst. Ecol. 2007, 35,
470e471; (b) Chung, H.-M.; Hwang, T.-L.; Chen, Y.-H.; Su, J.-H.; Lu, M.-C.; Chen,
silica gel column chromatography (hexane/EtOAc¼2:1) to give
1
8
J.-J.; Li, J.-J.; Fang, L.-S.; Wang, W.-H.; Sung, P.-J. Bull. Chem. Soc. Jpn. 2011, 84,
119e121 and references cited therein.
2. Chung, H.-M.; Chen, Y.-H.; Lin, M.-R.; Su, J.-H.; Wang, W.-H.; Sung, P.-J. Tetra-
hedron Lett. 2010, 51, 6025e6027.
8
3
d
6 mg (83%) of 30 as a colorless oil. ½
a
ꢂ
ꢁ8.9 (c 0.76, CHCl
3 max
); IR: n
D
1
472 (m), 1729 (s), 1669 (s), 1618 (m), 1365 (m), 1262 (m); H NMR:
1.04 (3H, s), 1.09 (3H, s), 1.20 (3H, s), 1.41 (1H, dd, J¼10.9, 8.6 Hz),
3
4
5
. (a) Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H. Liebigs Ann. Chem. 1984,
03e511; (b) Jakupovic, J.; Pathak, V. P.; Bohlmann, F.; King, R. M.; Robinson, H.
Phytochemistry 1987, 26, 803e807; (c) Zdero, C.; Bohlmann, F.; Anderberg, A.;
King, R. M. Phytochemistry 1991, 30, 2643e2650; (d) Quijano, L.; Vasquez-C, A.;
Ríos, T. Phytochemistry 1995, 38, 1251e1255.
1
2
.60 (1H, dd, J¼10.9, 10.0 Hz), 2.27 (3H, s), 2.57 (1H, br q, J¼9.2 Hz),
5
.92 (1H, dd, J¼9.0, 8.4 Hz), 3.30 (1H, s), 6.12 (1H, d, J¼16.1 Hz), 6.83
13
(
3
1H, dd, J¼16.1, 8.4 Hz), 9.43 (1H, s); C NMR:
d 20.5, 24.0, 27.3, 29.6,
1.7, 37.0, 38.5, 46.9, 78.0, 131.3, 147.4, 198.2, 202.3; HRMS (FAB): m/z
. Additionally, an atmospheric oxidation product of
b
-caryophyllene was tenta-
-car-
þ
calcd for C13
H O
21 3
([MþH] ), 225.1491; found, 225.1490.
tively identified as 4,5-seco-12-nor-caryophyllane and named
a
b
yophyllinic acid Jaoui, M.; Lewandowski, M.; Kleindienst, T. E.; Offenberg, J. H.;
Edney, E. O. Geophys. Res. Lett. 2007, 34, 1e4 For the numbering of carbon
atoms, see Ref. 2.
. (a) Takao, K.; Hayakawa, N.; Yamada, R.; Yamaguchi, T.; Saegusa, H.; Uchida, M.;
Samejima, S.; Tadano, K. J. Org. Chem. 2009, 74, 6452e6461 and references cited
4
.1.12. Ethyl (R)-4-[(1S,2R)-3,3-dimethyl-2-(3-oxo-1-butenyl)cyclo-
butyl]-4-hydroxy-2-pentenoate (31). To a stirred solution of 30
144 mg, 0.642 mmol) in THF (3 mL) was added Ph P]CHCO Et
(
3
2

T. Hirokawa, S. Kuwahara / Tetrahedron 68 (2012) 4581e4587
4587
therein; (b) Pirrung, M. C.; Morehead, A. T., Jr.; Young, B. G. In; Goldsmith, D.,
Ed. The Total Synthesis of Natural Products; John Wiley: New York, NY, 2000;
Vol. 11, pp 174e177; (c) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. In; ApSimon, J., Ed. The Total Synthesis of Natural Products; John
Wiley: New York, NY, 1983; Vol. 5, pp 391e393; (d) Heathcock, C. H. In; Ap-
Simon, J., Ed. The Total Synthesis of Natural Products; John Wiley: New York, NY,
12. Stork, G.; Cohen, J. F. J. Am. Chem. Soc. 1974, 96, 5270e5272.
13. (a) Lallemand, J. Y.; Onanga, M. Tetrahedron Lett. 1975, 16, 585e588; (b) Pet-
schen, I.; Parrilla, A.; Bosch, M. P.; Amela, C.; Botar, A. A.; Camps, F.; Guerrero, A.
Chem.dEur. J. 1999, 5, 3299e3309; (c) Avila-Z ꢁa rraga, J. G.; Maldonado, L. M.
Chem. Lett. 2000, 512e513; (d) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58,
1e23; (e) Luj ꢁa n-Montelongo, J. A.; V aꢁ zquez-S ꢁa nchez, A.; Avila-Zarraga, J. G.
ꢁ
ꢁ
Heterocycles 2009, 78, 1955e1976; (f) Luj aꢁ n-Montelongo, J. A.; Avila-Zarraga, J.
ꢁ
ꢁ
1
973; Vol. 2, pp 474e481.
. Hirokawa, T.; Nagasawa, T.; Kuwahara, S. Tetrahedron Lett. 2012, 53, 705e706.
. The numbering of carbon atoms follows that adopted in Ref. 2.
. (a) Crimmins, M. T.; Carroll, C. A.; Wells, A. J. Tetrahedron Lett. 1998, 39,
6
7
8
G. Tetrahedron Lett. 2010, 51, 2232e2236.
14. (a) Petschen, I.; Bosch, M. P.; Guerrero, A. Tetrahedron: Asymmetry 2000, 11,
1691e1695; (b) Tanino, K.; Takahashi, M.; Tomata, Y.; Tokura, H.; Uehara, T.;
Narabu, T.; Miyashita, M. Nat. Chem. 2011, 3, 484e488.
7005e7008; (b) Jeong, Y.; Kim, D.-Y.; Choi, Y.; Ryu, J.-S. Org. Biomol. Chem. 2011,
9
, 374e378.
15. For some unknown reason, compound 32 was, in some cases, isolated in an
9
. Yoshida, Y.; Sakakura, Y.; Aso, N.; Okada, S.; Tanabe, Y. Tetrahedron 1999, 55,
183e2192.
0. Russell, G. A.; Chen, P. J. Phys. Org. Chem. 1998, 11, 715e721.
1. Kageyama, M.; Nagasawa, T.; Yoshida, M.; Ohrui, H.; Kuwahara, S. Org. Lett. 2011,
3, 5264e5266.
almost pure state, as reported in Ref. 6.
2
16. We previously reported the specific rotation of 1 to be þ75.8 (c 1.11, CHCl3), see
Ref. 6. Several remeasurements, however, made us correct the specific rotation
of 1 to þ83.4 as a reproducible value.
1
1
1