Cyclopropanes in Nicholas reaction: Formation of spiroketals with a five-membered and a seven- or an eight-membered ring This paper is dedicated to Professor Paul A. Wender, one of the most creative contributors to the broad discipline of organic chemistry, on the occasion of the Tetrahedron Prize

Article abstract of DOI:10.1016/j.tet.2013.05.056

The consecutive treatment of 5-hydroxy-1-pentynyl 2,2-disubstituted- cyclopropyl ketones with Co₂(CO)₈ and BF ₃·OEt₂ produced the corresponding Co ₂(CO)₆-complexed dioxaspiro[4.6] derivatives. The one-carbon homologated substrates also afforded dioxaspiro[4.7]. It was found that this procedure can be applied to the substrates with gem-disubstituents as well as a mono-aryl substituent on the cyclopropane, but the mono-alkyl substituted cyclopropanes are insufficient.

Full text of DOI:10.1016/j.tet.2013.05.056

Tetrahedron 69 (2013) 7659e7669
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cyclopropanes in Nicholas reaction: formation of spiroketals with
a five-membered and a seven- or an eight-membered ring
*
Chisato Mukai , Takahiro Kojima, Takamasa Kawamura, Fuyuhiko Inagaki
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The consecutive treatment of 5-hydroxy-1-pentynyl 2,2-disubstituted-cyclopropyl ketones with
Co2(CO)8 and BF3$OEt2 produced the corresponding Co2(CO)6-complexed dioxaspiro[4.6] derivatives. The
one-carbon homologated substrates also afforded dioxaspiro[4.7]. It was found that this procedure can
be applied to the substrates with gem-disubstituents as well as a mono-aryl substituent on the cyclo-
propane, but the mono-alkyl substituted cyclopropanes are insufficient.
Received 1 March 2013
Received in revised form 13 May 2013
Accepted 15 May 2013
Available online 21 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor Paul A.
Wender, one of the most creative contribu-
tors to the broad discipline of organic
chemistry, on the occasion of the Tetrahe-
dron Prize
1. Introduction
also the simultaneous carboneoxygen bond formation by the attack
of the terminal hydroxyl functionality.
Alkynes can easily form the alkyneeCo2(CO)6 complex when
treated with a stoichiometric amount of dicobatoctacarbonyl
(Co2(CO)8). Upon exposure to a Brønsted or Lewis acid, the alky-
neeCo2(CO)6 complexes, derived from the reaction of propynol or
its ether (or ester) derivatives with Co2(CO)8, produced the corre-
sponding propynyl cation species, which were subsequently cap-
tured by various types of nucleophiles (Nicholas reaction).1 The
intramolecular Nicholas reaction of the alkynediol derivatives 1,2 for
example, provided an efficient method for the formation of the
Co2(CO)6-complexed oxacycloalkynes 3 (Fig. 1). On the other hand,
cyclopropane is well known as a useful acyclic C3-building block3
due to the easy cleavage of the three-membered ring assisted by
the relief of its high strain energy of 27.5 kcal/mol.4 As a part of our
contiguous studies on the development of a novel method for the
preparation of oxacycles5 based on the intramolecular Nicholas re-
action,6 we now describe our new tactics in the chemistry of pro-
pynyl cation species, which involves utilization of cyclopropane as
an acyclic C3-building block. We envisioned that when the Co2(CO)6-
complexed propynol derivatives 4 having a cyclopropyl moiety at
the propynyl position is exposed to the Nicholas conditions, the C3-
unit of cyclopropane might be incorporated into the resulting oxa-
cyclic framework via the initially generated propynyl cation species
I. The cationic intermediate I would accelerate not only the cyclo-
propylcarbinyl cation/homoallyl cation rearrangement (II),7 but
2. Results and discussion
At the beginning of this investigation, 1-acetoxy-1-cyclopropyl-
2-hexyn-6-ol (4) was treated with Co2(CO)8 in CH2Cl2 at room
temperature to afford the corresponding alkyneeCo2(CO)6 complex,
which was subsequently exposed to BF3$OEt2 at ꢀ78 ꢁC for 5 min to
produce the Co2(CO)6-complexed 2-cyclopropyloxacycloheptyne 5
in 82% yield (Fig. 1). The cyclopropyl-propynyl cation species I in
Fig. 1 must have been generated as expected, but it would not ring-
open the cyclopropane. Cyclization to the seven-membered ether 5
was faster (82% yield over the two steps). In order to promote cy-
clopropane opening both thermodynamically and kinetically, we
gem-disubstituted the cyclopropane ring. This would significantly
stabilize the resulting tertiary carbocation II (R4sH). Thus, both the
acetoxy and methoxy substrates 6a and 6b having a gem-diphenyl
group on the cyclopropane ring were subjected to the Nicholas
conditions to provide the (E)-olefin 7 in 60 and 78% yields, re-
spectively. The formation of the (E)-diene 7 showed that the cyclo-
propane ring of the propargyl cation opened such that the resulting
tertiary carbocation II (R4¼Ph) possessed the more stable (E)-con-
figuration. For obvious reasons it is unfavorable for the further re-
action by participation of the terminal hydroxyl group.
The selective conversion of the initially formed cationic in-
termediate I (with gem-diphenyl group) into the thermodynamically
less stable (Z)-II (R4¼Ph) seemed to be difficult. We postulated that
use of the carbonyl instead of hydroxyl functionalities might
* Corresponding author. Fax: þ81 76 234 4410; e-mail address: mukai@p.kana-
zawa-u.ac.jp (C. Mukai).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.056

7660
C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
OR1
R2
(OC)6Co2
+
Co2(CO)6
R2
1) Co2(CO)8
R2
2) acid
OH
O
3
n
OH
2
n
n
1
OR3
R4
(OC)6Co2
Co2(CO)6
1) Co2(CO)8
CH2Cl2, rt
+
-78 C
R4 = H
R4
R4
2) BF3 OEt2
CH2Cl2
O
OH
OH
n
R4
n
5
4 (R3 = Ac, R4 = H)
I
82% from 4
6a (R3 = Ac, R4 = Ph)
6b (R3 = Me, R4 = Ph)
(OC)6Co2
(OC)6Co2
(OC)6Co2
Ph
0 C
Ph
O
H
+
OH
R4
R4 = Ph
n
7
R4
n
O
II
4 R4
R
60% from 6a
78% from 6b
(OC)6Co2
(OC)6Co2
O
O L.A.
R5
Co2(CO)6
Lewis acid.
+
R5
R6
L.A.
R5
O
OH
OH
n
O
n
n
III
R6
R6
8
R5
R6
(OC)6Co2
R5
(OC)6Co2
(OC)6Co2
O
O L.A.
R6
O
+
R6
OH
R5
O
OH
n
n
n
V
IV
9
Fig. 1. Intramolecular Nicholas type reaction.
overcome this geometrical issue. Thus, our tactics were modified as
follows (Fig. 1). The Co2(CO)6-complexed 8 would react with a Lewis
acid to form III, the structure of III would accelerate the ring opening
of the cyclopropane to produce the thermodynamically more stable
(Z)-olefin species IV. The intermediate IV might be in equilibrium
with the less stable (E)-IV via the corresponding ketone form. The
terminal hydroxyl group would then be able to react with the tertiary
carbocation. Alternatively, the cation species of IV might be imme-
diately captured by the oxygen atom of the enolate moiety producing
V.8 The Lewis acid-catalyzed additional reaction between the dihy-
drofuran moiety and the terminal hydroxyl group of V might lead to
the final products 9.
Cobalt complexation of the gem-diphenyl derivative 10a with
Co2(CO)8 in CH2Cl2 at room temperature was followed by treatment
with BF3$OEt2 in toluene at ꢀ78 ꢁC to ꢀ20 ꢁC for 2 h to produce the
Co2(CO)6-complexed dioxaspiro[4.6]undecyne derivative 11a in
76% yield (Table 1, entry 1). An X-ray analysis of 11a (CCDC 926213)
established its structure as depicted in Fig. 2, thereby the dioxaspiro
[4.6]undecyne skeleton of 11a was unambiguously confirmed.
Other Lewis acids, such as TiCl4, SnCl4, In(OTf)3, InCl3, and BiCl3,
were examined, but none of them9 afforded a better result than
that of BF3$OEt2.10 The dibenzyl derivative 10b afforded the corre-
sponding dioxaspiro compound 11b in 43% yield (entry 2). Upon
exposure to BF3$OEt2 at ꢀ78 ꢁC to 0 ꢁC for 27 h, the bis(phenylethyl)
congener 10c produced 11c in 73% yield (entry 3) similar to that of
the diphenyl derivative 11a. Compound 10d without a substituent
on the cyclopropane ring did not produce the oxaspiro compound
at all. The Co2(CO)6-complexed starting material 10d became the
only isolated product in 38% yield (entry 4). In the case of com-
pound 10e with the gem-disubstituent effect on the carbon tether,
the dioxaspiro derivative 11e was isolated in 73% yield (entry 5).
The formation of the dioxaspiro[4.6]undecyne skeleton 11 can be
rationalized in terms of the acid-catalyzed acetal formation of the
plausible intermediate V in Fig. 1. The diphenyl substrates 10a,e
produced 11a,e in satisfactory yields presumably via the stable
tertiary carbocation species IV having a diphenyl group. The ter-
tiary carbocation species derived from 10c would be stabilized by
two alkyl substituents and afforded a satisfactory yield. However, it
is uncertain why 10b, which has a structure similar to that of 10c,
produced 11b in only 43% yield (entry 4). We speculate that one of

C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
7661
Table 1
Ring-closing reaction of alkyne cyclopropyl ketones 10
Entry
Substrate
R
R0
Temp
Time (h)
Product and yielda
1
2
3
4
5
10a
10b
10c
10d
10e
Ph
H
H
H
H
ꢀ78 ꢁC to ꢀ20 ꢁC
ꢀ78 ꢁC to rt
ꢀ78 ꢁC to 0 ꢁC
ꢀ78 ꢁC to 0 ꢁC
ꢀ20 ꢁC
2
10
27
24
4.5
11a (76%)
11b (43%)
11c (73%)
db
CH2Ph
(CH2)2Ph
H
Ph
Me
11e (73%)
a
Isolated yield.
b
Co2(CO)6-complexed 10d was obtained in 38% yield.
the benzyl protons of the cation species IV (R5¼CH2Ph) may be lost
in what would resemble an E1-type elimination.
The one-carbon homologated substrate 12a was next reacted
under the standard conditions to determine if this reaction could be
used for constructing the eight-membered analog (Fig. 3). The
treatment of the simple carbon tether substrate 12a with Co2(CO)8
furnished the Co2(CO)6-complexed 12a, which was subsequently
exposed to BF3$OEt2 to produce the dioxaspiro[4.7] derivative 13a
indeed. Yield (45%) of 13a would reflect the relative difficulty of for-
mation of the medium-sized rings (seven- vs eight-membered ring).
The nitrogen analog 12b provided the azadioxaspiro[4.7] compound
13b in a good yield (59%). Compound 12c having the ThorpeeIngold
effect produced the spiro product 13c in a better yield (66%). Simi-
larly, the bis(phenylsulfonyl) derivative 12d afforded the dioxaspiro
compound 13d in 60% yield. Conversion of the siloxy derivative 14a
into the hydroxyl compound 14b, a substrate for the ring-closing
reaction, was not attained, but the g-lactone derivative 16 was in-
stead isolated in 78% yield. Without removing a silyl group, 14a was
converted into the Co2(CO)6-complexed one and subsequently ex-
posed to BF3$OEt2 to afford the desired dioxaspiro[4.7] compound 15
in 38% yield. Thus, it was shown that the dioxaspiro[4.7]dodecyne
framework could be prepared like their lower homolog, i.e., the one-
carbon shortened dioxaspiro[4.6]undecyne skeleton.
Fig. 2. ORTEP drawing of 11a.
(OC)6Co2
Ph
O
1) Co2(CO)8, CH2Cl2, r.t.
O
Ph
X
Ph
Ph
2) BF3 OEt2, toluene
-78 C to -20 C
2 ~ 7 h
X
O
OH
12a: X=CH2
12b: X=NTs
13a (45%)
13b (59%)
13c (66%)
13d (60%)
12c: X=C(MOM)2
12d: X=C(SO2Ph)2
(OC)6Co2
Ph
O
MeO2C
MeO2C
1) Co2(CO)8, CH2Cl2, r.t.
O
Ph
Ph
2) BF3 OEt2, toluene
-20 C, 3.5 h
MeO2C
MeO2C
O
OR
Ph
38% from 14a
15
14a: R=TBS
14b: R=H
O
MeO2C
O
Ph
Ph
O
16
Fig. 3. Ring-closing reaction of alkyne cyclopropyl ketones 10.

7662
C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
Mono-substituted alkynyl cyclopropyl ketones 17 (R¼substituent,
4. Experimental
4.1. General
R¼H) might still have a chance to be transformed into the corre-
sponding dioxaspiro[4.6] derivatives via secondary carbocations.
Thus, the cis-phenyl derivative, cis-17a (R¼Ph, R0¼H), was exposed to
the standard etherification conditions for 5 h (Table 2, entry 1). This
provided a mixture of two diastereomeric dioxaspiro[4.6] com-
pounds, 18a and epi-18a (R¼Ph), in 44% yield along with 19a (R¼Ph)
having a trans-stereochemistry in 12% yield (Table 2, entry 1). A
similar treatment of trans-17a (R¼H, R0¼Ph) for 5 h did not produce
18a. The cobalt complex 19a (R¼Ph) was obtained in 57% yield as the
only isolated product (entry 2). These two experiments indicated that
the exclusive isomerization of cis-17a into trans-17a occurred. In the
case of the bulkier mesityl derivatives 17b, the cis-congener afforded
a mixture of two dioxaspiro[4.6]derivatives(18b/epi-18b¼5:1)in20%
yield as a minor product and the isomerized trans-product 19b be-
came the major product (74%) when exposed to the reaction condi-
tions for a short time (entry 3). A prolonged reaction time (7.5 h)
produced complete conversion of cis-17b into 18b (5:1 ratio) in 72%
yield presumably via the isomerization to 19b (entry 4). On the other
hand, a mixture of 18b11 and its epimer (5:1) was obtained in 63%
yield as the only isolated product upon treating trans-17b with
BF3$OEt2 for 8 h (entry 5).12 Both mono-alkyl substituted cyclopro-
panes 17c (R, R0¼CH2Ph, H) and 17d (R, R0¼CH2CH2Ph, H) behaved
similarly toward acid. Indeed, cis-17c and cis-17d afforded a complex
mixture (entries 6 and 8), whereas the corresponding trans-17c and
trans-17d produced the corresponding Co2(CO)6 complex 19c and 19d
in 34 and 27% yields, respectively (entries 7 and 9).13 Thus, it was
found that cyclopropanes possessing mono-alkyl substituent are
barely amendable to this transformation.
Melting points are uncorrected. IR spectra were measured in
CHCl3. 1H NMR spectra were taken in CDCl3. CHCl3 (7.26 ppm) for
silyl compounds and tetramethylsilane (0.00 ppm) for compounds
without a silyl group were used as internal standards. 13C NMR
spectra were recorded in CDCl3 with CDCl3 (77.00 ppm) as an in-
ternal standard. Silica gel (Silica gel 60 N, 40e50
Chemical) was used for chromatography. All reactions were carried
out under N2 atmosphere. Organic extracts were dried over Na2SO4.
mm, Kanto
4.2. 1-Acetoxy-1-cyclopropylhex-2-yn-6-ol (4)
To
a
solution of 5-(tert-butyldimethylsilyloxy)pent-4-yne14
(465 mg, 2.40 mmol) in THF (24 mL) was added dropwise nBuLi
(1.8 mL, 2.8 mmol, 1.6 M in hexane) at ꢀ78 ꢁC. After stirring for
30 min at the same temperature, cyclopropanecarboxyaldehyde
(0.25 mL, 3.3 mmol) was added and the mixture was further stirred
for 30 min. Then the reaction was quenched by addition of satu-
rated aqueous NH4Cl, and the mixture was extracted with AcOEt.
The extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad of
silica gel with hexane/AcOEt (7:1) to afford a crude alcohol. To
a solution of the crude alcohol in CH2Cl2 (24 mL) was added DMAP
(120 mg, 1.0 mmol), Et3N (1.0 mL, 7.5 mmol), and AcCl (0.50 mL,
7.5 mmol) at 0 ꢁC. After stirring for 2.5 h at the same temperature,
the reaction was quenched by addition of water, and the mixture
Table 2
Ring-closing reaction of alkyne mono-substituted-cyclopropyl ketones 17
Entry
Substrate
Time (h)
Product and yielda
1
2
3
4
5
6
7
8
9
cis-17a (R¼Ph, R0¼H)
5
5
18a (R¼Ph)(44%)b
19a (R¼Ph)(12%)
trans-17a (R¼H, R0¼Ph)
cis-17b (R¼Mes, R0¼H)
cis-17b (R¼Mes, R0¼H)
trans-17b (R¼H, R0¼Mes)
cis-17c (R¼CH2Ph, R0¼H)
trans-17c (R¼H, R0¼CH2Ph)
cis-17d (R¼(CH2)2Ph, R0¼H)
trans-17d (R¼H, R0¼(CH2)2Ph)
d
18b (R¼Mes)(20%)d
19a (R¼Ph)(57%)
0.5c
7.5c
8c
19b (R¼Mes)(74%)
18b (R¼Mes)(72%)d
d
18b (R¼Mes)(63%)d
d
20e
25g
24g
24g
df
d
d
19c (R¼CH2Ph)(34%)
d
df
d
19d (R¼(CH2)2Ph)(27%)
a
Isolated yield.
b
c
d
e
f
A mixture of 18a and epi-18a was obtained in a ratio of 1:1.
Reaction was carried out at ꢀ20 ꢁC.
A mixture of 18b and epi-18b was obtained in a ratio of 5:1.
Reaction was carried out at 0 ꢁC to rt.
A complex mixture was obtained.
Reaction was carried out at 0 ꢁC.
g
3. Conclusions
was extracted with CH2Cl2. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was passed
through a short pad of silica gel with hexane/AcOEt (20:1) to afford
a crude alkyne as a colorless oil. To a solution of the crude alkyne in
THF (24 mL) was added dropwise TBAF (2.7 mL, 2.7 mmol, 1 M in
THF) at 0 ꢁC. After stirring for 6.5 h at room temperature, the re-
action was quenched by addition of water, and the mixture was
extracted with Et2O. The extract was washed with water and brine,
dried, and concentrated to dryness. The residue was chromato-
graphed with hexane/AcOEt (2:1) to afford 4 (439 mg, 91% from 5-
(tert-butyldimethylsilyloxy)pent-4-yne) as a colorless oil; IR 3620,
In summary, we developed a novel method for the construction
of the dioxaspiro[4.m] frameworks (m¼6,7) by combination of the
Co2(CO)6-complexed propynyl cation species with cleavage of the
cyclopropane. It became apparent that cyclopropanes possessing
gem-disubstituents as well as a mono-aryl substituent can be used,
but mono-alkyl substituted cyclopropanes are inefficient in this
transformation. More extensive studies of the scope and limita-
tions of this method as well as of mechanistic details are in
progress.

C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
7663
3448, 2235, 1732 cmꢀ1; 1H NMR (600 MHz)
d
5.18 (dt, J¼6.9, 2.0 Hz,
residue was passed through a short pad of silica gel with hexane/
AcOEt (15:1) to afford a crude methoxy derivative. To a solution of
the crude methoxy derivative in THF (6 mL) was added dropwise
TBAF (0.72 mL, 0.72 mmol, 1 M in THF) at 0 ꢁC. After stirring for 6 h
at room temperature, the reaction was quenched by addition of
water, and the mixture was extracted with Et2O. The extract was
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed with hexane/AcOEt (2:1) to af-
ford 6b (115 mg, 0.359 mmol, 58% from 5-(tert-butyldimethylsily-
1H), 3.70 (t, J¼6.5 Hz, 2H), 2.31 (td, J¼6.5, 2.0 Hz, 2H), 2.07 (s, 3H),
1.89 (br s, 1H), 1.73 (quin, J¼6.5 Hz, 2H), 1.24e1.19 (m, 1H),
0.57e0.47 (m, 3H), 0.44e0.41 (m, 1H); 13C NMR (151 MHz)
d 170.3,
85.5, 76.0, 67.9, 61.5, 31.0, 21.2, 15.2, 14.4, 3.4, 2.0; FAB MS m/z 219
(Mþþ23, 26); FAB HRMS calcd for C11H16NaO3 219.0997, found
219.1003.
4.3. Hexacarbonyl-m-{h
4-2-cyclopropyl-3,4-didehydro-
2,5,6,7-tetrahydrooxepin}dicobalt (CoeCo) (5)
loxy)pent-4-yne) as a colorless oil; IR 3624, 3435, 2220 cmꢀ1
;
1H
NMR (400 MHz) 7.46e7.44 (m, 2H), 7.30e7.18 (m, 7H), 7.13e7.09
d
To a solution of 4 (34.7 mg, 0.177 mmol) in CH2Cl2 (1.8 mL) was
added Co2(CO)8 (75 mg, 0.22 mmol) at room temperature. After
stirring for 2.5 h at the same temperature, CH2Cl2 was evaporated
off. The residue was passed through a short pad of Florisil with
hexane/AcOEt (5:1) to afford a crude alkyneecobalt complex. To
a solution of the alkyneecobalt complex in CH2Cl2 (1.8 mL) was
added dropwise BF3$OEt2 (0.25 mL, 0.19 mmol, 0.77 M in CH2Cl2
solution) at 0 ꢁC. After stirring for 5 min at the same temperature,
the reaction was quenched by addition of saturated aqueous
NaHCO3, and the mixture was extracted with AcOEt. The extract
was washed with water and brine, dried, and concentrated to
dryness. The residue was chromatographed on Florisil with hexane/
AcOEt (10:1) to afford 5 (61.2 mg, 82% from 4) as a brown oil; IR
(m,1H), 3.71 (t, J¼6.4 Hz, 2H), 3.18 (s, 3H), 3.01 (td, J¼7.7,1.8 Hz,1H),
2.31 (td, J¼6.4, 1.8 Hz, 2H), 2.06e2.00 (m, 1H), 1.78 (br s, 1H), 1.73
(quin, J¼6.4 Hz, 2H), 1.35e1.32 (m, 2H); 13C NMR (100 MHz)
d 145.8,
140.8, 130.6, 128.2, 128.1, 127.9, 126.7, 126.0, 84.7, 79.0, 72.0, 61.6,
56.2, 37.1, 31.2, 30.9, 17.2, 15.3; FAB MS m/z 343 (Mþþ23, 46); FAB
HRMS calcd for C22H24NaO2 343.1674, found 343.1676.
4.6. Hexacarbonyl-m-{h
4-(E)-1,1-diphenylnona-1,3-dien-5-yn-
9-ol}dicobalt (CoeCo) (7)
To a solution of 6a (or 6b) (0.1 mmol) in CH2Cl2 (0.1 M) was
added Co2(CO)8 (1.2 equiv) at room temperature. After stirring for
1.5 h at the same temperature, BF3$OEt2 (1.1 equiv 0.1 M in CH2Cl2
solution) was added to the mixture at 0 ꢁC and further stirred for
10e30 min. Then the reaction was quenched by addition of satu-
rated aqueous NaHCO3, and the mixture was extracted with CH2Cl2.
The extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was chromatographed on silica gel
neutralized by Et3N or Al2O3 with hexane/AcOEt (5:1) to afford 7 as
2091, 2052, 2029 cmꢀ1 1H NMR (600 MHz)
; d 4.38e4.34 (m, 1H),
3.73 (d, J¼8.2 Hz, 1H), 3.46e3.42 (m, 1H), 3.27e3.23 (m, 1H),
2.84e2.78 (m, 1H), 1.91e1.87 (m, 2H), 1.25e1.10 (m, 1H), 0.71e0.69
(m, 2H), 0.59e0.54 (m, 1H), 0.44e0.41 (m, 1H); 13C NMR (151 MHz)
d
199.9 (br), 101.2, 99.1, 86.7, 73.6, 33.5, 30.3, 17.6, 3.6, 2.7; DART MS
m/z 422 (Mþþ1, 76); DART HRMS calcd for C15H13Co2O7 422.9325,
found 422.9330.
a brown oil; IR 3628, 3447, 2087, 2048, 2021, 2017, 1601, 1495 cmꢀ1
1H NMR (400 MHz)
7.38e7.35 (m, 3H), 7.31e7.29 (m, 4H),
;
d
4.4. 1-Acetoxy-1-(2,2-diphenylcyclopropyl)hex-2-yn-6-ol (6a)
7.26e7.23 (m, 3H), 6.87e6.83 (m, 2H), 6.71 (dd, J¼15.0, 10.5 Hz, 1H),
3.76e3.72 (m, 2H), 2.96 (t, J¼7.8 Hz, 2H), 1.88 (quin, J¼7.8 Hz, 2H);
According to the procedure described for 4, 6a (220 mg) was
obtained from 5-(tert-butyldimethylsilyloxy)pent-4-yne (241 mg,
1.22 mmol) in 52% overall yield. Colorless oil; IR 3622, 3448, 2233,
13C NMR (151 MHz)
d 199.7 (br), 144.2, 141.9, 139.4, 134.4, 130.5,
129.8, 128.3, 128.1, 127.74, 127.66, 127.6, 127.2, 100.3, 90.7, 62.2, 34.6,
31.0; FAB MS m/z 575 (Mþþ1, 3.5); FAB HRMS calcd for C27H21Co2O7
574.9951, found 574.9945.
1736 cmꢀ1 1H NMR (600 MHz)
; d 7.29e7.23 (m, 8H), 7.19e7.15 (m,
2H), 4.30 (dt, J¼7.8, 2.0 Hz,1H), 3.70 (t, J¼6.5 Hz, 2H), 2.30 (td, J¼6.5,
2.0 Hz, 2H), 2.25e2.21 (m, 1H), 2.03 (s, 3H), 1.72 (quin, J¼6.5 Hz,
2H), 1.67 (br s, 1H), 1.55 (dd, J¼11.2, 5.5 Hz, 1H), 1.36 (dd, J¼8.8,
4.7. 2,2-Dibenzylcyclopropylmethanol
5.5 Hz, 1H); 13C NMR (151 MHz)
d
169.4, 145.3, 139.5, 129.9, 128.3,
To a solution of (PPh3Me)Br (290 mg, 0.80 mmol) in THF (2 mL)
t
128.2, 128.0, 127.0, 126.2, 84.8, 77.9, 65.5, 61.5, 36.7, 30.9, 29.2, 20.8,
17.4, 15.3; FAB MS m/z 371 (Mþþ23, 13); FAB HRMS calcd for
C23H24NaO3 371.1623, found 371.1631.
was added BuOK (90 mg, 0.80 mmol) at 0 ꢁC. After stirring for
30 min at room temperature, a solution of 1,3-diphenylpropan-2-
one (84.2 mg, 0.401 mmol) in THF (2 mL) was added and the
mixture was further stirred for 1 h. Then the reaction was quenched
by addition of water, and the mixture was extracted with Et2O. The
extract was washed with water and brine, dried, and concentrated
to dryness. The residue was passed through a short pad of silica gel
with hexane/AcOEt (50:1) to afford a crude alkene. To a solution of
the crude alkene in DCE (3 mL) was added copper(II) acetate
(11 mg, 0.060 mmol) at room temperature. To a solution of ethyl
diazoacetate (0.13 mL,1.2 mmol) in DCE (1 mL) was added dropwise
at the same temperature within 15 h by means of a syringe pump.
After completing the addition, DCE was evaporated off. The residue
was passed through a short pad of silica gel with hexane/AcOEt
(20:1) to afford a crude cyclopropane. To a solution of the crude
cyclopropane in THF (4 mL) was added LiAlH4 (46 mg, 1.2 mmol) at
4.5. 1-Methoxy-1-(2,2-diphenylcyclopropyl)hex-2-yn-6-ol
(6b)
To
a
solution of 5-(tert-butyldimethylsilyloxy)pent-4-yne
(123 mg, 0.618 mmol) in THF (6 mL) was added dropwise nBuLi
(0.46 mL, 0.74 mmol, 1.6 M in hexane) at ꢀ78 ꢁC. After stirring for
30 min at ꢀ78 ꢁC, 2,2-diphenylcyclopropanecarboxyaldehyde15
(160 mg, 0.74 mmol) was added and further stirred for 30 min.
Then the reaction was quenched by addition of saturated aqueous
NH4Cl, and the mixture was extracted with AcOEt. The extract was
washed with water and brine, dried, and concentrated to dryness.
The residue was passed through a short pad of silica gel with
hexane/AcOEt (7:1) to afford a crude propargyl alcohol. To a solu-
tion of the crude alcohol in THF (6 mL) was added NaH (60% in
mineral oil, 72 mg, 1.8 mmol) at 0 ꢁC. After stirring for 1 h at the
same temperature, MeI (0.19 mL, 3.0 mmol) was added to the
mixture. The reaction mixture was warmed to room temperature
and further stirred for 8 h. Then the reaction was quenched by
addition of water, extracted with AcOEt. The extract was washed
with water and brine, dried, and concentrated to dryness. The
0
ꢁC. After stirring for 1 h at room temperature, the reaction was
quenched by addition of THF and iced water (1:1), and stirred until
a white precipitate formed. The solvent was removed under re-
duced pressure and the residue was dissolved in MeOH. The sus-
pension was filtered through the pad of Celite and MeOH was
evaporated off. The residue was chromatographed with hexane/
AcOEt to afford 2,2-dibenzylcyclopropylmethanol (57.6 mg,
0.228 mmol, 57% from 1,3-diphenylpropan-2-one) as a colorless oil.

7664
C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
IR 3610, 3447 cmꢀ1
;
1H NMR (400 MHz)
d
7.31e7.25 (m, 4H),
43.8, 39.4, 30.2, 22.2, 15.4; DART MS m/z 305 (Mþþ1, 29); DART
7.23e7.18 (m, 4H), 7.15e7.14 (m, 2H), 3.79 (dd, J¼11.3, 6.5 Hz, 1H),
3.73 (dd, J¼11.3, 7.9 Hz, 1H), 2.73 (d, J¼15.1 Hz, 1H), 2.69 (d,
J¼14.4 Hz, 1H), 2.57 (d, J¼15.1 Hz, 1H), 2.37 (d, J¼14.4 Hz, 1H), 1.53
(br s, 1H), 1.31e1.27 (m, 1H), 0.79 (dd, J¼8.5, 4.8 Hz, 1H), 0.55 (dd,
HRMS calcd for C21H21O2 305.1542, found 305.1523.
4.11. 1-(2,2-Dibenzylcyclopropyl)-6-hydroxyhex-2-yn-1-one
(10b)
J¼10.2, 4.8 Hz, 1H); 13C NMR (100 MHz)
d 139.9, 139.5, 129.4, 129.1,
128.2, 128.1, 126.1, 126.0, 63.4, 42.2, 36.2, 25.4, 25.3, 16.0; FAB MS m/
z 275 (Mþþ23, 31); FAB HRMS calcd for C18H20NaO 275.1412, found
275.1410.
Colorless oil; IR 3626, 3445, 2216, 1647 cmꢀ1
;
1H NMR
(600 MHz) 7.29e7.25 (m, 4H), 7.23e7.18 (m, 2H), 7.15e7.12 (m,
d
4H), 3.71 (t, J¼6.8 Hz, 2H), 2.80, 2.74 (ABq, JAB¼15.1 Hz, 2H), 2.70,
2.58 (ABq, JAB¼14.2 Hz, 2H), 2.51 (t, J¼6.8 Hz, 2H), 2.35 (dd, J¼7.3,
5.4 Hz, 1H), 1.82 (quin, J¼6.8 Hz, 2H), 1.71 (t, J¼5.4 Hz, 1H), 1.13 (dd,
4.8. (2,2-Diphenethylcyclopropyl)methanol
J¼7.3, 5.4 Hz, 1H); 13C NMR (151 MHz)
d 185.7, 139.1, 137.9, 129.3,
129.0, 128.12, 128.09, 126.4, 126.0, 93.9, 82.5, 60.7, 41.5, 36.7, 36.4,
34.0, 30.3, 21.1, 15.4: DART MS m/z 333 (Mþþ1, 43); DART HRMS
calcd for C23H25O2 333.1855, found 333.1853.
According to the procedure described for 2,2-dibenzylcyclo
propylmethanol, (2,2-diphenethylcyclopropyl)methanol (1.08 g,
3.86 mmol) was obtained from 1,5-diphenylpentan-3-one (4.00 g,
16.8 mmol) in 23% overall yield. Colorless oil; IR 3614, 3447 cmꢀ1
;
1H NMR (400 MHz)
d
7.27 (t, J¼7.6 Hz, 4H), 7.18e7.17 (m, 6H), 3.62
4.12. 6-Hydroxy-1-(2,2-diphenethylcyclopropyl)hex-2-yn-1-
one (10c)
(dd, J¼11.3, 6.5 Hz, 1H), 3.47 (dd, J¼11.3, 8.5 Hz, 1H), 2.80e2.66 (m,
4H), 1.82e1.75 (m, 2H), 1.63e1.57 (m, 1H), 1.50e1.44 (m, 1H), 1.36
(br s, 1H), 0.92e0.87 (m, 1H), 0.51 (dd, J¼8.5, 4.5 Hz, 1H), 0.15 (t,
Colorless oil; IR 3628, 3447, 2214, 1647 cmꢀ1
(600 MHz)
;
1H NMR
J¼4.5 Hz, 1H); 13C NMR (100 MHz)
d
142.5, 142.2, 128.3, 128.2, 125.7,
d
7.30e7.24 (m, 4H), 7.22e7.14 (m, 6H), 3.69 (t, J¼6.4 Hz,
62.9, 39.1, 33.2, 32.9, 32.6, 26.7, 24.3, 16.7; FAB MS m/z 303 (Mþþ1,
2H), 2.77e2.67 (m, 3H), 2.56e2.51 (m, 1H), 2.48 (t, J¼6.4 Hz, 2H),
2.10e2.08 (m, 1H), 1.96e1.82 (m, 3H), 1.79 (quin, J¼6.4 Hz, 2H),
1.67e1.61 (m, 1H), 1.43 (t, J¼4.7 Hz, 1H), 0.95 (dd, J¼7.4, 4.7 Hz, 1H);
15); FAB HRMS calcd for C20H24NaO 303.1725, found 303.1726.
13C NMR (100 MHz)
d 185.4, 141.8, 141.5, 128.4, 128.25, 128.18, 125.9,
4.9. General procedure for preparation of alkynyl cyclopropyl
ketones (condition A)
125.7, 92.8, 82.5, 60.9, 39.1, 37.8, 36.8, 33.5, 32.8, 30.3, 23.3, 15.4;
DART MS m/z 361 (Mþþ1, 57); DART HRMS calcd for C25H29O2
361.2168, found 361.2148.
To a solution of cyclopropanemethanol derivative in CH2Cl2
(0.1 M) was added PCC (5 equiv) at 0 ꢁC. After stirring for 1.5e2.5 h at
room temperature, iPrOH (5 equiv) was added and the mixture was
further stirred for 0.5e1.5 h. Then the suspension was filtered
through the pad of Celite and CH2Cl2 was evaporated off. The residue
was passed through a short pad of silica gel with hexane/AcOEt to
afford a crude cyclopropylcarboxyaldehyde derivative. To a solution
of alkyne (1.1e1.2 equiv) in THF (0.1 M) was added dropwise nBuLi
(1.1e1.2 equiv) at ꢀ78 ꢁC. After stirring for 30e45 min at ꢀ78 ꢁC, the
crude cyclopropylcarboxyaldehyde derivative was added and the
mixture was further stirred for 15e45 min. Then the reaction was
quenched by addition of saturated aqueous NH4Cl, and the mixture
was extracted with AcOEt. The extract was washed with water and
brine, dried, and concentrated to dryness. The residue was passed
through a short pad of silica gel with hexane/AcOEt to afford a crude
propargyl alcohol. To a solution of the crude propargyl alcohol in
THF (0.1 M) was added dropwise AcOH/TBAF (17:1) (10e20 equiv) at
4.13. 1-Cyclopropyl-6-hydroxyhex-2-yn-1-one (10d)
Colorless oil; IR 3628, 3447, 2220, 1649 cmꢀ1
(600 MHz)
3.68 (t, J¼6.5 Hz, 2H), 2.59 (br s, 1H), 2.45 (t, J¼6.5 Hz,
2H), 2.00e1.96 (m, 1H), 1.77 (quin, J¼6.5 Hz, 2H), 1.19e1.16 (m, 2H),
;
1H NMR
d
1.00e0.97 (m, 2H); 13C NMR (151 MHz)
d 189.0, 93.5, 78.8, 60.8,
30.3, 24.3, 15.3, 10.9; DART MS m/z 153 (Mþþ1, 67); DART HRMS
calcd for C9H13O2 153.0916, found 153.0903.
4.14. 7-Hydroxy-1-(2,2-diphenylcyclopropyl)hept-2-yn-1-one
(12a)
Colorless oil; IR 3620, 3458, 2216, 1655 cmꢀ1
;
1H NMR
(400 MHz) 7.35e7.28 (m, 2H), 7.28e7.23 (m, 6H), 7.20e7.14 (m,
d
2H), 3.58 (t, J¼6.4 Hz, 2H), 2.90 (dd, J¼7.7, 5.9 Hz, 1H), 2.40 (dd,
J¼5.9, 5.0 Hz, 1H), 2.24 (t, J¼6.4 Hz, 2H), 2.05 (br s, 1H), 1.74 (dd,
0
ꢁC. After stirring for 12e41 h at room temperature, the reaction
J¼7.7, 5.0 Hz, 1H), 1.60e1.48 (m, 4H); 13C NMR (100 MHz)
d
184.4,
was quenched by addition of saturated aqueous NaHCO3, and the
mixture was extracted with AcOEt. The extract was washed with
water and brine, dried, and concentrated to dryness. The residue
was chromatographed with hexane/AcOEt to afford a crude diol
derivative. To a solution of the diol derivative in CH2Cl2 (0.1 M) was
added MnO2 (20e40 equiv) at room temperature. After stirring for
17e44 h at the same temperature, the suspension was filtered
through the pad of Celite and CH2Cl2 was evaporated off. The residue
was chromatographed with hexane/AcOEt to afford alkynyl cyclo-
propyl ketones.
144.5, 139.1, 130.2, 128.4, 128.3, 127.3, 127.0, 126.6, 95.1, 81.3, 61.8,
43.7, 39.4, 31.5, 23.8, 22.1, 18.6; DART MS m/z 319 (Mþþ1, 29); DART
HRMS calcd for C22H23O2 319.1698, found 319.1689.
4.15. 1-(tert-Butyldimethylsilyloxy)-3,3-bis(methoxymethyl)
hex-5-yne
To a solution of 2-[2-(tert-butyldimethylsilanyloxy)ethyl]-2-
prop-2-ynylmalonic acid dimethyl ester16 (512 mg, 1.63 mmol) in
THF (15 mL) was added LiAlH4 (170 mg, 4.5 mmol) at 0 ꢁC. After
stirring for 1 h at the same temperature, the reaction was quenched
by addition of water, and stirred until a white precipitate formed.
Then the mixture was passed through a pad of Celite, and the fil-
trate was concentrated to dryness. The residue was passed through
a short pad of silica gel with hexane/AcOEt (2:1) to afford a crude
diol. To a solution of the crude diol in THF (15 mL) was added NaH in
60% mineral oil (61 mg,1.6 mmol) at 0 ꢁC. After stirring for 1 h at the
same temperature, MeI (0.11 mL, 1.8 mmol) was added and further
stirred for 15 min. Then the reaction was quenched by addition of
saturated aqueous NH4Cl, and the mixture was extracted with
4.10. 6-Hydroxy-1-(2,2-diphenylcyclopropyl)hex-2-yn-1-one
(10a)
Colorless oil; IR 3628, 3448, 2216, 1655 cmꢀ1
;
1H NMR
(600 MHz) 7.36e7.34 (m, 2H), 7.30e7.24 (m, 6H), 7.22e7.17 (m,
d
2H), 3.65 (t, J¼6.2 Hz, 2H), 2.90 (dd, J¼7.8, 6.2 Hz, 1H), 2.41 (dd,
J¼6.2, 4.8 Hz, 1H), 2.36e2.33 (m, 2H), 2.02 (br s, 1H), 1.76 (dd, J¼7.8,
4.8 Hz, 1H), 1.69 (quin, J¼6.2 Hz, 2H); 13C NMR (151 MHz)
d 184.5,
144.5, 139.2, 130.3, 128.4, 128.3, 127.3, 127.0, 126.6, 94.7, 81.2, 60.9,

C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
7665
AcOEt. The extract was washed with water and brine, dried, and
concentrated to dryness. The residue was chromatographed with
hexane/AcOEt (50:1) to afford 1-(tert-butyldimethylsilyloxy)-3,3-
bis(methoxymethyl)hex-5-yne (172 mg, 0.601 mmol, 37% from 2-
[2-(tert-butyldimethylsilanyloxy)ethyl]-2-prop-2-ynylmalonic acid
dimethyl ester) as a colorless oil; IR 3308 cmꢀ1; 1H NMR (400 MHz)
126.8, 93.5, 81.5, 61.1, 32.2, 30.2, 29.5, 15.3, 13.4; DART MS m/z 229
(Mþþ1, 32); DART HRMS calcd for C15H17O2 229.1229, found
229.1212. The relative stereochemistry of cis-17a has been de-
termined by NOE experiments.
4.19. 6-Hydroxy-1-[(1R
1-one (trans-17a)
*
, 2R )-2-phenylcyclopropyl]hex-2-yn-
*
d
3.67 (t, J¼7.2 Hz, 2H), 3.26 (s, 6H), 3.24e3.22 (m, 4H), 2.22 (d,
J¼2.8 Hz, 2H), 1.90 (t, J¼2.8 Hz, 1H), 1.61 (t, J¼7.2 Hz, 2H), 0.84 (s,
9H), 0.00 (s, 6H); 13C NMR (100 MHz)
d
81.4, 74.9, 70.0, 59.4, 59.1,
Colorless oil; IR 3620, 3447, 2218, 1647 cmꢀ1
;
1H NMR
40.8, 35.0, 25.9, 22.6, 18.2, ꢀ5.4; DART MS m/z 301 (Mþþ1, 48);
(400 MHz) 7.31e7.27 (m, 2H), 7.23e7.20 (m, 1H), 7.11e7.09 (m,
d
DART HRMS calcd for C16H33O3Si 301.2199, found 301.2190.
2H), 3.74 (t, J¼6.4 Hz, 2H), 2.73e2.67 (m, 1H), 2.51 (t, J¼6.4 Hz, 2H),
2.35e2.31 (m, 1H), 2.12 (br s, 1H), 1.86e1.80 (m, 3H), 1.52e1.47 (m,
4.16. General procedure for preparation of alkynyl cyclo-
propyl ketones (condition B)
1H); 13C NMR (100 MHz)
d 186.4, 139.4, 128.5, 126.7, 126.1, 94.3,
80.0, 60.9, 35.6, 30.3, 29.3, 19.2, 15.4; DART MS m/z 229 (Mþþ1, 25);
DART HRMS calcd for C15H17O2 229.1229, found 229.1214. The rel-
ative stereochemistry of trans-17a has been determined by NOE
experiments.
To a solution of cyclopropanemethanol derivative in CH2Cl2
(0.1 M) was added PCC (5 equiv) at 0 ꢁC. After stirring for 1.5e2.5 h at
room temperature, iPrOH (5 equiv) was added and the mixture was
further stirred for 0.5e1.5 h. Then the suspension was filtered
through the pad of Celite and CH2Cl2 was evaporated off. The residue
was passed through a short pad of silica gel with hexane/AcOEt to
afford a crude cyclopropylcarboaldehyde derivative. To a solution of
the crude cyclopropylcarboaldehyde derivative (1.1e1.2 equiv) in
THF (0.1 M) was added dropwise nBuLi (1.1e1.2 equiv) at ꢀ78 ꢁC.
After stirring for 30e45 min at the same temperature, cyclo-
propylcarboaldehyde derivative was added and the mixture was
further stirred for 15e45 min, the reaction was quenched by addi-
tion of saturated aqueous NH4Cl, and the mixture was extracted
with AcOEt. The extract was washed with water and brine, dried,
and concentrated to dryness. The residue was passed through
a short pad of silica gel with hexane/AcOEt to afford a crude prop-
argyl alcohol derivative. To a solution of the crude propargyl alde-
hyde in CH2Cl2 (0.1 M) was added MnO2 (20e40 equiv) at room
temperature. After stirring for 17e44 h at the same temperature, the
suspension was filtered through the pad of Celite and CH2Cl2 was
evaporated off. The residue was chromatographed with hexane/
AcOEt to afford ketone derivative (diastereomer mixture of cis-17
and trans-17 was separated). To a solution of the ketone derivative in
THF (0.1 M) was added dropwise AcOH/TBAF (17:1) (10e20 equiv) at
4.20. 6-Hydroxy-1-[(1R
*
, 2S )-2-mesitylcyclopropyl]hex-2-yn-
*
1-one (cis-17b)
Colorless oil; IR 3630, 3448, 2216, 1637 cmꢀ1
(600 MHz, 55 ꢁC)
;
1H NMR
d
6.77 (s, 2H), 3.53 (t, J¼6.5 Hz, 2H), 2.50e2.46 (m,
1H), 2.44e2.40 (m, 1H), 2.33 (s, 6H), 2.21 (s, 3H), 2.20e2.16 (m, 2H),
1.88e1.85 (m, 1H), 1.74 (br s, 1H), 1.68 (td, J¼8.2, 4.8 Hz, 1H), 1.56
(quin, J¼6.5 Hz, 2H); 13C NMR (151 MHz, 55 ꢁC)
d 186.1, 138.2, 136.0,
130.0, 128.8, 94.3, 80.0, 61.0, 32.1, 30.3, 25.9, 20.7, 20.6, 18.3, 15.2;
DART MS m/z 271 (Mþþ1, 22); DART HRMS calcd for C18H23O2
271.1698, found 271.1686. The relative stereochemistry of cis-17b
has been determined by NOE experiments.
4.21. 6-Hydroxy-1-[(1R
1-one (trans-17b)
*
, 2R )-2-mesitylcyclopropyl]hex-2-yn-
*
Colorless oil; IR 3630, 3456, 2216, 1647 cmꢀ1
(600 MHz)
;
1H NMR
d
6.82 (s, 2H), 3.74 (t, J¼6.5 Hz, 2H), 2.59 (br s, 1H), 2.53
(t, J¼6.5 Hz, 2H), 2.50e2.48 (m, 1H), 2.33 (s, 6H), 2.24 (s, 3H), 2.11
(dt, J¼7.8, 4.8 Hz, 1H), 1.90e1.87 (m, 1H), 1.84 (quin, J¼6.5 Hz, 2H),
1.31 (dt, J¼7.8, 4.8 Hz, 1H); 13C NMR (151 MHz)
d 187.9, 138.0, 136.4,
0
ꢁC. After stirring for 12e41 h at room temperature, the reaction
132.4, 128.8, 94.4, 79.6, 60.8, 34.5, 30.4, 26.1, 20.7, 20.4, 20.1, 15.4;
DART MS m/z 271 (Mþþ1, 15); DART HRMS calcd for C18H23O2
271.1698, found 271.1678. The relative stereochemistry of trans-17b
has been determined by NOE experiments.
was quenched by addition of saturated aqueous NaHCO3, and the
mixture was extracted with AcOEt. The extract was washed with
water and brine, dried, and concentrated to dryness. The residue
was chromatographed with hexane/AcOEt to afford alkynyl cyclo-
propyl ketones.
4.22. 1-[(1R
*
, 2R )-2-Benzylcyclopropyl]-6-hydroxyhex-2-yn-
*
1-one (cis-17c)
4.17. 6-Hydroxy-5,5-dimethyl-1-(2,2-diphenylcyclopropyl)
hex-2-yn-1-one (10e)
Colorless oil; IR 3628, 3447, 2212, 1649 cmꢀ1
(600 MHz)
;
1H NMR
d
7.30e7.26 (m, 2H), 7.21e7.18 (m, 3H), 3.73 (t, J¼6.5 Hz,
Colorless oil; IR 3628, 3447, 2214, 1647 cmꢀ1
;
1H NMR
2H), 2.88 (dd, J¼14.8, 6.9 Hz, 1H), 2.78 (dd, J¼14.8, 7.6 Hz, 1H), 2.50
(t, J¼6.5 Hz, 2H), 2.36e2.32 (m, 1H), 1.82 (quin, J¼6.5 Hz, 2H),
1.77e1.71 (m, 1H), 1.68 (br s, 1H), 1.43e1.41 (m, 1H), 1.18 (td, J¼7.6,
(400 MHz) 7.36e7.33 (m, 2H), 7.28e7.24 (m, 6H), 7.20e7.16 (m,
d
2H), 3.28 (s, 2H), 2.91 (dd, J¼7.7, 6.1 Hz, 1H), 2.41 (dd, J¼6.1, 5.0 Hz,
1H), 2.21 (s, 2H), 2.04 (br s, 1H), 1.74 (dd, J¼7.7, 5.0 Hz, 1H), 0.92 (s,
4.5 Hz, 1H); 13C NMR (151 MHz)
d 186.2, 141.1, 128.4, 128.3, 126.0,
6H); 13C NMR (151 MHz)
d
184.2, 144.7, 139.2, 130.2, 128.5, 128.4,
93.1, 82.6, 61.0, 32.2, 30.3, 29.7, 27.7, 15.9, 15.4; DART MS m/z 243
(Mþþ1, 19); DART HRMS calcd for C16H19O2 243.1385, found
243.1373. The relative stereochemistry of cis-17c has been de-
termined by NOE experiments.
127.4, 127.1, 126.6, 93.3, 82.9, 70.3, 43.7, 39.4, 35.9, 28.6, 23.7, 21.9;
DART MS m/z 333 (Mþþ1, 36); DART HRMS calcd for C23H25O2
333.1855, found 333.1839.
4.18. 6-Hydroxy-1-[(1R
1-one (cis-17a)
*
, 2S
*
)-2-phenylcyclopropyl]hex-2-yn-
4.23. 1-[(1R
*
, 2S )-2-Benzylcyclopropyl]-6-hydroxyhex-2-yn-
*
1-one (trans-17c)
Colorless oil; IR 3614, 3447, 2218, 1647 cmꢀ1
(600 MHz)
;
1H NMR
Colorless oil; IR 3628, 3447, 2218, 1647 cmꢀ1
(600 MHz)
2H), 2.76 (dd, J¼14.7, 6.5 Hz, 1H), 2.63 (dd, J¼14.7, 7.2 Hz, 1H), 2.46
(t, J¼6.5 Hz, 2H), 2.02 (br s,1H),1.95 (dt, J¼8.2, 4.2 Hz,1H),1.91e1.85
(m, 1H), 1.79 (quin, J¼6.5 Hz, 2H), 1.48 (dt, J¼8.2, 4.2 Hz, 1H),
;
1H NMR
d
7.28e7.25 (m, 4H), 7.21e7.18 (m, 1H), 3.63 (t, J¼6.2 Hz,
d
7.31e7.29 (m, 2H), 7.24e7.20 (m, 3H), 3.71 (t, J¼6.5 Hz,
2H), 2.80 (q, J¼8.6 Hz, 1H), 2.55e2.51 (m, 1H), 2.37e2.28 (m, 2H),
1.96 (dt, J¼7.5, 5.5 Hz, 1H), 1.68 (quin, J¼6.2 Hz, 2H), 1.60 (br s, 1H),
1.47e1.44 (m, 1H); 13C NMR (151 MHz)
d 184.6, 135.7, 129.7, 128.0,

7666
C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
1.04e1.01 (m, 1H); 13C NMR (151 MHz)
d
187.7, 139.6, 128.4, 128.2,
49.1, 44.3, 39.0, 38.1, 22.1, 21.5; DART MS m/z 474 (Mþþ1, 45); DART
126.3, 93.7, 79.4, 60.8, 38.3, 31.9, 30.3, 26.0, 17.7, 15.3; DART MS m/z
243 (Mþþ1, 28); DART HRMS calcd for C16H19O2 243.1385, found
243.1380. The relative stereochemistry of trans-17c has been de-
termined by NOE experiments.
HRMS calcd for C28H28NO4S 474.1739, found 474.1720.
4.27. 7-Hydroxy-5,5-bis(methoxymethyl)-1-(2,2-
diphenylcyclopropyl)hept-2-yn-1-one (12c)
To a solution of 6-(tert-butyldimethylsilyloxy)-3,3-bis(metho
xymethyl)hex-5-yne (216 mg, 0.717 mmol) in THF/HMPA (4:1,
7 mL) was added nBuLi (0.68 mL, 1.0 mmol, 1.49 M in hexane) at
ꢀ78 ꢁC. After stirring for 30 min at the same temperature, 2,2-
diphenylcyclopropanecarboxyaldehyde14 (94.0 mg, 0.42 mmol)
was added and the mixture was further stirred for 30 min. Then the
reaction was quenched by addition of saturated aqueous NH4Cl, and
the mixture was extracted with AcOEt. The extract was washed
with water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with hexane/
AcOEt (10:1) to afford a crude propargyl alcohol. To a solution of the
crude propargyl alcohol in CH2Cl2 (7 mL) was added MnO2 (0.73 g,
8.4 mmol) at room temperature. After stirring for 48 h at the same
temperature, the suspension was filtered through the pad of Celite
and CH2Cl2 was evaporated off. The residue was passed through
a short pad of silica gel with hexane/AcOEt (7:1) to afford a crude
ketone. To a solution of the crude ketone in THF (7 mL) was added
dropwise AcOH/TBAF (17:1) (7 mL) at 0 ꢁC. After stirring for 13 h at
room temperature, the reaction was quenched by addition of sat-
urated aqueous NaHCO3, and the mixture was extracted with
AcOEt. The extract was washed with water and brine, dried, and
concentrated to dryness. The residue was chromatographed with
hexane/AcOEt (2:1) to afford 12c (93.2 mg, 0.230 mmol, 32% from
2,2-diphenylcyclopropanecarboxyaldehyde) as a colorless oil; IR
4.24. 6-Hydroxy-1-[(1R
yn-1-one (cis-17d)
*
, 2S )-2-phenethylcyclopropyl]hex-2-
*
Colorless oil; IR 3628, 3447, 2214, 1651 cmꢀ1
;
1H NMR
(600 MHz)
d
7.28e7.25 (m, 2H), 7.18e7.16 (m, 3H), 3.72 (t, J¼6.4 Hz,
2H), 2.62 (t, J¼7.3 Hz, 2H), 2.50 (t, J¼6.4 Hz, 2H), 2.25e2.22 (m, 1H),
2.10 (br s, 1H), 1.90e1.74 (m, 4H), 1.50e1.43 (m, 1H), 1.27e1.24 (m,
1H), 1.10e1.07 (m, 1H); 13C NMR (151 MHz)
d 186.2, 141.7, 128.4,
128.2, 125.7, 92.8, 82.4, 61.0, 35.9, 30.3, 29.5, 28.3, 26.5, 15.8, 15.4:
DART MS m/z 257 (Mþþ1, 44); DART HRMS calcd for C17H21O2
257.1542, found 257.1537. The relative stereochemistry of cis-17d
has been determined by NOE experiments.
4.25. 6-Hydroxy-1-[(1R
2-yn-1-one (trans-17d)
*
, 2R )-2-phenethylcyclopropyl]hexa-
*
Colorless oil; IR 3628, 3447, 2218, 1645 cmꢀ1
;
1H NMR
(600 MHz)
d
7.28e7.26 (m, 2H), 7.19e7.15 (m, 3H), 3.69 (t, J¼6.4 Hz,
2H), 2.71 (t, J¼7.5 Hz, 2H), 2.54 (br s, 1H), 2.46 (t, J¼6.4 Hz, 2H),
1.80e1.76 (m, 3H), 1.68e1.58 (m, 3H), 1.41e1.39 (m, 1H), 0.90e0.87
(m, 1H); 13C NMR (151 MHz)
d 188.0, 141.3, 128.3, 128.2, 125.8, 93.5,
79.4, 60.7, 35.2, 34.7, 32.0, 30.3, 25.6, 18.1, 15.3; DART MS m/z 257
(Mþþ1, 42); DART HRMS calcd for C17H21O2 257.1542, found
257.1543. The relative stereochemistry of trans-17d has been de-
termined by NOE experiments.
3414, 2214, 1655 cmꢀ1 1H NMR (600 MHz)
; d 7.34e7.33 (m, 2H),
7.28e7.23 (m, 6H), 7.20e7.15 (m, 2H), 3.62 (t, J¼5.8 Hz, 2H), 3.32 (s,
6H), 3.27e3.22 (m, 4H), 2.91 (dd, J¼7.8, 6.2 Hz, 1H), 2.42e2.38 (m,
3H), 1.73 (dd, J¼7.8, 4.8 Hz, 1H), 1.63 (t, J¼5.8 Hz, 2H); 13C NMR
4.26. N-[4-(2,2-Diphenylcyclopropyl)-4-oxobut-2-ynyl]-N-(2-
hydroxyethyl)-4-methylbenzenesulfonamide (12b)
(151 MHz) d 183.7, 144.6, 139.1, 130.1, 128.4, 128.3, 127.3, 127.1, 126.6,
91.8, 83.2, 75.3, 59.2, 58.1, 43.6, 41.5, 39.4, 37.0, 23.3, 21.7; DART MS
m/z 407 (Mþþ1, 69); DART HRMS calcd for C26H31O4 407.2222,
found 407.2240.
To a solution of N-[2-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-
N-(prop-2-ynyl)benzenesulfonamide17 (260 mg, 0.72 mmol) in THF
(7 mL) was added dropwise nBuLi (0.14 mL, 0.72 mmol, 1.5 M in
hexane) at ꢀ78 ꢁC. After stirring for 30 min at the same temperature,
2,2-dipenylcyclopropanecarboxyaldehyde15 (134 mg, 0.602 mmol)
was added and the mixture was further stirred for 30 min. Then the
reaction was quenched by addition of saturated aqueous NH4Cl, and
the mixture was extracted with AcOEt. The extract was washed with
water and brine, dried, and concentrated to dryness. The residue was
passed through a short pad of silica gel with hexane/AcOEt (4:1) to
afford a crude propargyl alcohol. To a solution of the crude propargyl
alcohol in DMSO/AcOEt (1:1) (7 mL) was added IBX (500 mg,
1.8 mmol) at room temperature. After stirring for 1.5 h at the same
temperature, the reaction was quenched by addition of saturated
aqueous Na2S2O3, and the mixture was extracted with Et2O. The
residue was chromatographed with hexane/AcOEt (5:1) to afford
a crude ketone. To a solution of the crude ketone in THF (7 mL) was
added dropwise AcOH/TBAF (17:1) (7 mL) at 0 ꢁC. After stirring for
2.5 h at room temperature, the reaction was quenched by addition of
saturated aqueous NaHCO3, and the mixture was extracted with
AcOEt. The extract was washed with water and brine, dried, and
concentrated to dryness. The residue was chromatographed with
hexane/AcOEt (1:1) to afford 12b (117 mg, 0.247 mmol, 41% from 2,2-
dipenylcyclopropanecarboxyaldehyde) as a colorless oil. IR 3690,
4.28. 7-Hydroxy-1-(2,2-diphenylcyclopropyl)-5,5-
bis(phenylsulfonyl)hept-2-yn-1-one (12d)
To a solution of 3-(tert-butyldimethylsilyl)-1,1-bis(pheny-lsul-
fonyl)propane18 (99.1 mg, 0.218 mmol) in DMF (2.2 mL) was added
NaH in 60% mineral oil (18 mg, 0.44 mmol) at room temperature.
After stirring for 30 min at 80 ꢁC, the reaction was added propargyl
bromide (72 mL, 0.66 mmol, 9.2 M in toluene solution) and further
stirred for 1.5 h. Then the reaction was quenched by addition of
water, and the mixture was extracted with AcOEt. The extract was
washed with water and brine, dried, and concentrated to dryness.
The residue was passed through a short pad of silica gel with
hexane/AcOEt (10:1) to afford a crude alkyne. To a solution of
HMDS (0.10 mL, 0.48 mmol) in THF (0.5 mL) was added dropwise
nBuLi (0.29 mL, 0.44 mmol, 1.52 M in hexane) at ꢀ78 ꢁC. After
stirring for 30 min at the same temperature, a solution of alkyne
in THF (2 mL) was added dropwise and the mixture was
further stirred for 30 min. Then
a
solution of 2,2-
diphenylcyclopropanecarboxyaldehyde (107 mg, 0.48 mmol) in
THF (2 mL) was added to the mixture at the same temperature and
stirred for 30 min. The reaction was quenched by addition of sat-
urated aqueous NH4Cl, and the mixture was extracted with AcOEt.
The extract was washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad of
silica gel with hexane/AcOEt (3:1) to afford a crude propargyl al-
cohol. To a solution of the crude propargyl alcohol in DMSO/AcOEt
(1:1) (2 mL) was added IBX (120 mg, 0.44 mmol) at room
3545, 2218, 1663 cmꢀ1 1H NMR (600 MHz)
; d 7.71e7.69 (m, 2H),
7.29e7.25 (m, 8H), 7.21e7.19 (m, 4H), 4.29, 4.22 (ABq, JAB¼18.9 Hz,
2H), 3.75 (t, J¼5.2 Hz, 2H), 3.25e3.18 (m, 2H), 2.72 (dd, J¼7.8, 6.2 Hz,
1H), 2.34 (s, 3H), 2.27 (dd, J¼6.2, 4.8 Hz, 1H), 2.04 (br s, 1H), 1.70 (dd,
J¼7.8, 4.8 Hz, 1H); 13C NMR (151 MHz)
d 182.8, 144.2, 138.9, 135.1,
130.2, 129.8, 128.6, 128.5, 127.6, 127.34, 127.27, 126.9, 85.5, 84.6, 60.7,

C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
7667
temperature. After stirring for 4 h at the same temperature, the
reaction was quenched by addition of saturated aqueous Na2S2O3,
and the mixture was extracted with Et2O. The residue was passed
through a short pad of silica gel with hexane/AcOEt (5:1) to afford
a crude ketone. To a solution of the crude ketone in THF (2 mL) was
added HFePyridine (0.05 mL) at 0 ꢁC. After stirring for 1 h at the
same temperature, the reaction was quenched by addition of sat-
urated aqueous NaHCO3, and the mixture was extracted with
AcOEt. The extract was washed with water and brine, dried, and
concentrated to dryness. The residue was chromatographed with
hexane/AcOEt (2:1) to afford 12d (23.5 mg, 0.0392 mmol, 18% from
extract was washed with water and brine, dried, and concentrated
to dryness. The residue was chromatographed on Florisil with
hexane/AcOEt to afford 1,6-dioxaspiro[4.6] or [4.7] derivatives.
4.31. Hexacarbonyl-m-{h
4-2,2-diphenyl-1,6-dioxaspiro[4.6]
undec-10-yne}dicobalt (CoeCo) (11a)
Brown plates: mp 94e95 ꢁC (hexane); IR 2093, 2054,
2029 cmꢀ1; 1H NMR (400 MHz)
d 7.44e7.38 (m, 4H), 7.31e7.27 (m,
4H), 7.22e7.18 (m, 2H), 4.27e4.21 (m, 1H), 3.68e3.62 (m, 1H),
3.24e3.18 (m, 1H), 2.99e2.89 (m, 2H), 2.78 (ddd, J¼12.4, 7.0, 1.4 Hz,
1H), 2.43 (dt, J¼12.4, 7.0 Hz, 1H), 2.30 (ddd, J¼12.4, 7.0, 1.4 Hz, 1H),
3-(tert-butyldimethylsilyl)-1,1-bis(phenylsulfonyl)propane)
a colorless oil; IR 3448, 2224, 1663, 1649, 1335, 1313, 1150 cmꢀ1; 1H
NMR (400 MHz) 8.06e8.03 (m, 4H), 7.72e7.68 (m, 2H), 7.60e7.54
as
1.87e1.80 (m, 2H); 13C NMR (151 MHz)
d 199.8 (br), 147.6, 146.1,
d
127.9, 126.8, 126.6, 126.1, 125.9, 109.1, 98.7, 97.2, 91.7, 64.7, 40.6, 37.1,
33.7, 29.5; DART MS m/z 591 (Mþþ1, 37); DART HRMS calcd for
C27H21Co2O8 590.9900, found 590.9909. The structure of 11a was
unambiguously determined by an X-ray crystallography (CCDC
926213).
(m, 4H), 7.32e7.18 (m, 10H), 4.02 (t, J¼6.8 Hz, 2H), 3.32, 3.26 (ABq,
JAB¼18.3 Hz, 2H), 2.85 (dd, J¼7.9, 5.9 Hz, 1H), 2.58e2.51 (m, 2H),
2.40 (dd, J¼5.9, 5.0 Hz, 1H), 1.71 (dd, J¼7.9, 5.0 Hz, 1H); 13C NMR
(100 MHz)
d 182.8, 144.3, 138.9, 135.9, 135.8, 135.2, 131.40, 131.38,
130.3, 128.99, 128.95, 128.6, 128.5, 127.5, 127.2, 126.9, 87.8, 85.3,
85.0, 57.9, 44.8, 39.3, 33.2, 22.0, 21.8; DART MS m/z 599 (Mþþ1, 7);
DART HRMS calcd for C34H31O6S2 599.1562, found 599.1551.
4.32. Hexacarbonyl-m-{h
4-2,2-dibenzyl-1,6-dioxaspiro[4.6]
undec-10-yne}dicobalt (CoeCo) (11b)
4.29. Dimethyl 2-[2-(tert-butyldimethylsilyloxy)ethyl]-2-[4-
Brown oil; IR 2093, 2054, 2027 cmꢀ1 1H NMR (600 MHz)
;
(2,2-diphenylcyclopropyl)-4-oxobut-2-ynyl]malonate (14a)
d 7.34e7.33 (m, 2H), 7.29e7.25 (m, 5H), 7.23e7.20 (m, 2H), 7.15e7.14
(m, 1H), 4.27e4.19 (m, 1H), 3.67e3.64 (m, 1H), 3.22e3.20 (m, 1H),
3.07 (d, J¼14.9 Hz, 1H), 2.97e2.93 (m, 2H), 2.91 (d, J¼14.9 Hz, 1H),
2.85 (d, J¼14.9 Hz, 1H), 2.35e2.30 (m, 1H), 2.20e2.16 (m, 1H),
To a solution of 2-[2-(tert-butyldimethylsilyloxy)ethyl]-2-prop-
2-ynylmalonic acid dimethyl ester16 (188 mg, 0.573 mmol) in THF
(6 mL) was added dropwise nBuLi (0.45 mL, 0.69 mmol, 1.52 M in
hexane) at ꢀ78 ꢁC. After stirring for 30 min at the same tempera-
2.14e2.10 (m, 2H), 1.84e1.78 (m, 2H); 13C NMR (100 MHz)
d 199.9
(br), 138.1, 137.8, 130.6, 130.5, 128.1, 128.0, 126.4, 126.2, 108.9, 98.6,
98.1, 90.6, 64.6, 45.9, 44.2, 40.0, 33.7, 32.6, 29.6; DART MS m/z 619
(Mþþ1, 60); DART HRMS calcd for C29H25Co2O8 619.0213, found
619.0218.
ture,
2,2-diphenylcyclopropanecarboxyaldehyde
(130
mg,
0.69 mmol) was added and the mixture was further stirred for
30 min. Then the reaction was quenched by addition of saturated
aqueous NH4Cl, and the mixture was extracted with AcOEt. The
extract was washed with water and brine, dried, and concentrated
to dryness. The residue was passed through a short pad of silica gel
with hexane/AcOEt (4:1) to afford a crude propargyl alcohol. To
a solution of the crude propargyl alcohol in CH2Cl2 (6 mL) was
added MnO2 (1.5 g,17 mmol) at room temperature. After stirring for
24 h at the same temperature, the suspension was filtered through
the pad of Celite and CH2Cl2 was evaporated off. The residue was
chromatographed with hexane/AcOEt to afford 14a (217 mg,
0.396 mmol, 69% from 2-[2-(tert-butyldimethylsilyloxy)ethyl]-2-
prop-2-ynylmalonic acid dimethyl ester) as a colorless oil; IR
4.33. Hexacarbonyl-
[4.6]undec-10-yne}dicobalt (CoeCo) (11c)
m-{h
4-2,2-diphenethyl-1,6-dioxaspiro
Brown oil; IR 2092, 2054, 2027 cmꢀ1
;
1H NMR (400 MHz)
d
7.33e7.25 (m, 4H), 7.21e7.18 (m, 6H), 4.28e4.22 (m, 1H),
3.85e3.82 (m, 1H), 3.21e3.17 (m, 1H), 2.95e2.86 (m, 1H), 2.78e2.60
(m, 4H), 2.42 (td, J¼12.3, 9.2 Hz, 1H), 2.26 (dd, J¼12.3, 7.3 Hz, 1H),
2.20e2.07 (m, 2H), 2.03e1.92 (m, 4H), 1.87e1.86 (m, 2H); 13C NMR
(100 MHz)
d 199.9 (br), 142.4, 142.2, 128.5, 128.4, 128.3, 128.2,
125.83, 125.80, 108.6, 98.4, 98.1, 89.4, 64.2, 42.8, 40.5, 40.3, 34.4,
33.6, 31.2, 30.7, 29.7; DART MS m/z 647 (Mþþ1, 47); DART HRMS
calcd for C31H29Co2O8 647.0526, found 647.0520.
2220, 1736, 1661 cmꢀ1 1H NMR (600 MHz)
; d 7.39e7.38 (m, 2H),
7.35e7.31 (m, 6H), 7.26e7.23 (m, 2H), 3.79 (s, 3H), 3.78 (s, 3H), 3.71
(t, J¼6.2 Hz, 2H), 3.09 (s, 2H), 2.98 (dd, J¼7.8, 5.8 Hz, 1H), 2.45 (t,
J¼5.8 Hz, 1H), 2.41e2.33 (m, 2H), 1.76 (dd, J¼7.8, 5.8 Hz, 1H), 0.95 (s,
4.34. Hexacarbonyl-
dioxaspiro[4.7]dodec-11-yne}dicobalt (CoeCo) (11e)
m-{h
4-9,9-dimethyl-2,2-diphenyl-1,6-
9H), 0.10 (s, 6H); 13C NMR (151 MHz)
d 183.1, 170.0, 144.6, 139.0,
130.1, 128.4, 128.3, 127.5, 127.0, 126.6, 88.9, 83.5, 58.9, 55.1, 52.8,
44.1, 39.4, 34.6, 25.8, 23.3, 21.4, 18.2, ꢀ5.6; DART MS m/z 549
(Mþþ1, 100); DART HRMS calcd for C32H41O6Si 549.2672, found
549.2678.
Brown oil; IR 2093, 2052, 2027 cmꢀ1 1H NMR (600 MHz)
7.44e7.43 (m, 2H), 7.41e7.40 (m, 2H), 7.30e7.27 (m, 4H), 7.20e7.18
;
d
(m, 2H), 4.19 (d, J¼13.4 Hz, 1H), 3.05e3.03 (m, 2H), 2.98e2.93 (m,
2H), 2.82e2.78 (m, 1H), 2.41e2.38 (m, 2H), 1.07 (s, 3H), 0.90 (s, 3H);
4.30. General procedure for preparation of 1,6-dioxaspiro[4.6]
or [4.7] derivatives
13C NMR (100 MHz)
d 200.1 (br), 147.8, 146.3, 128.0, 127.9, 126.7,
126.5, 125.9, 125.8, 109.2, 94.9, 94.7, 91.4, 72.5, 46.7, 40.8, 37.5, 35.8,
28.6, 24.2; DART MS m/z 619 (Mþþ1, 53); DART HRMS calcd for
C29H25Co2O8 619.0213, found 619.0202.
To a solution of hydroxyalkynyl cyclopropyl ketones in CH2Cl2
(0.1 M) was added Co2(CO)8 (1.2e2.0 equiv) at room temperature.
After stirring for 1e3.5 h at the same temperature, CH2Cl2 was
evaporated off. The residue was passed through a short pad of
Florisil with hexane/AcOEt to afford alkyneeCo complex as a brown
oil. To a solution of alkyneecobalt complex in toluene (0.1 M) was
added BF3$OEt2 (3.3e10.0 equiv, 0.77 M in toluene solution) at the
optimum temperature. After stirring for 2e27 h at the optimum
temperature, the reaction was quenched by addition of saturated
aqueous NaHCO3, and the mixture was extracted with AcOEt. The
4.35. Hexacarbonyl-m-{h
4-2,2-diphenyl-1,6-dioxaspiro[4.7]
dodec-11-yne}dicobalt (CoeCo) (13a)
Brown oil; IR 2090, 2052, 2027 cmꢀ1 1H NMR (600 MHz)
;
7.46e7.43 (m, 4H), 7.30e7.25 (m, 4H), 7.20e7.15 (m, 2H), 3.96 (td,
J¼13.0, 2.4 Hz,1H), 3.24e3.22 (m,1H), 3.20e3.19 (m,1H), 3.07e3.02
(m, 1H), 2.90e2.86 (m, 1H), 2.76 (ddd, J¼11.7, 6.5, 2.4 Hz, 1H),
2.39e2.32 (m, 2H), 1.85e1.82 (m, 2H), 1.79e1.73 (m, 1H), 1.51e1.46
d

7668
C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
(m, 1H); 13C NMR (151 MHz)
d
199.8 (br), 147.7, 146.9, 128.0, 126.6,
4.40. Hexacarbonyl-m-{h
4-2-phenyl-1,6-dioxaspiro[4.6]un-
126.5, 125.8, 125.4, 110.3, 100.1, 96.8, 90.9, 61.8, 42.0, 37.7, 34.2, 29.0,
25.3; DART MS m/z 605 (Mþþ1, 57); DART HRMS calcd for
C28H23Co2O8 605.0057, found 605.0063.
dec-10-yne}dicobalt (CoeCo) (18a)
A mixture of 18a and epi-18a in the ratio of 1:1 was obtained as
a brown oil. IR 2093, 2056, 2027 cmꢀ1 1H NMR (600 MHz)
;
4.36. Hexacarbonyl-m-{h
4-2,2-diphenyl-9-tosyl-9-aza-1,6-
dioxaspiro[4,7]dodec-11-yne}dicobalt (CoeCo) (13b)
d
7.39e7.27 (m, 5H), 5.24e5.20 (m, 1H), 4.36e4.32 (m, 1Hꢂ50/100),
4.27e4.24 (m, 1Hꢂ50/100), 3.95e3.93 (m, 1Hꢂ50/100), 3.90e3.87
(m, 1Hꢂ50/100), 3.20e3.17 (m, 1H), 2.93e2.85 (m, 1H), 2.63e2.57
(m, 1Hꢂ50/100), 2.47e2.44 (m, 1H), 2.40e2.35 (m, 1H), 2.34e2.30
(m, 1Hꢂ50/100), 2.22e2.18 (m, 1Hꢂ50/100), 1.96e1.91 (m, 1Hꢂ50/
Brown oil; IR 2096, 2062, 2033 cmꢀ1; 1H NMR (400 MHz)
d 7.69
(d, J¼7.8 Hz, 2H), 7.41e7.39 (m, 4H), 7.32 (d, J¼7.8 Hz, 2H), 7.28e7.24
(m, 4H), 7.19e7.15 (m, 2H), 4.84 (d, J¼16.0 Hz, 1H), 4.04 (d,
J¼16.0 Hz, 1H), 4.04e4.00 (m, 1H), 3.65 (td, J¼12.3, 2.7 Hz, 1H), 3.22
(dt, J¼14.2, 2.7 Hz, 1H), 3.09e3.01 (m, 1H), 2.83e2.76 (m, 2H), 2.43
100), 1.88e1.87 (m, 2H); 13C NMR (100 MHz)
d 199.9 (br), 142.7,
142.5, 128.33, 128.28, 127.5, 127.3, 126.4, 125.6, 109.1, 108.7, 98.8,
98.4, 98.0, 97.2, 84.6, 81.7, 64.7, 64.2, 41.3, 39.7, 33.7, 33.5, 33.4, 33.2,
29.8, 29.7; DART MS m/z 515 (Mþþ1, 43); DART HRMS calcd for
C21H17Co2O8 514.9587, found 514.9582.
(s, 3H), 2.41e2.39 (m, 2H); 13C NMR (100 MHz)
d 198.82 (br), 147.3,
146.4, 143.5, 135.3, 129.8, 128.02, 127.99, 127.1, 126.7, 126.6, 125.7,
125.4, 110.4, 95.1, 92.4, 91.5, 61.4, 50.1, 49.4, 41.7, 37.1, 21.5; FAB MS
4.41. Hexacarbonyl-m{h
4-2-mesityl-1,6-dioxaspiro[4.6]undec-
10-yne}dicobalt (CoeCo) (18b)
m/z 760 (Mþþ1, 75); FAB HRMS calcd for C34H28Co2NO10
S
760.0098, found 760.0104.
A mixture of 18b and epi-18b in the ratio of 5:1 was obtained as
4.37. Hexacarbonyl-m-{h
4-9,9-bis(methoxymethyl)-2,2-
diphenyl-1,6-dioxaspiro[4.7]dodeca-11-yne}dicobalt (CoeCo)
(13c)
a brown oil. IR 2093, 2056, 2027 cmꢀ1; 1H NMR (600 MHz)
d 6.83 (s,
2H), 5.57e5.54 (m, 1Hꢂ83/100), 5.51e5.48 (m, 1Hꢂ17/100),
4.33e4.29 (m, 1Hꢂ17/100), 4.23e4.19 (m, 1Hꢂ83/100), 3.95e3.92
(m, 1Hꢂ17/100), 3.89e3.86 (m, 1Hꢂ83/100), 3.19e3.17 (m, 1H),
2.88e2.83 (m, 1H), 2.57e2.51 (m, 1H), 2.43 (s, 3Hꢂ17/100), 2.40 (s,
6H), 2.383e2.52 (m, 1H), 2.55 (s, 3Hꢂ83/100), 2.09e2.02 (m, 1H),
Brown oil; IR 2091, 2050, 2025 cmꢀ1
;
1H NMR (600 MHz)
d
7.44e7.42 (m, 4H), 7.30e7.25 (m, 4H), 7.20e7.16 (m, 2H), 4.03
(ddd, J¼13.7, 8.5, 2.4 Hz, 1H), 3.39 (ddd, J¼13.7, 6.8, 2.7 Hz, 1H), 3.35
(s, 3H), 3.34e3.31 (m, 2H), 3.30 (s, 3H), 3.27e3.16 (m, 4H), 2.97 (dt,
J¼12.2, 6.8 Hz, 1H), 2.78 (dd, J¼11.5, 6.8 Hz, 1H), 2.37 (dt, J¼12.2,
6.8 Hz, 1H), 2.31 (dd, J¼11.5, 6.8 Hz, 1H), 1.69 (ddd, J¼15.8, 6.8,
2.4 Hz, 1H), 1.55 (ddd, J¼15.8, 8.5, 2.7 Hz, 1H); 13C NMR (151 MHz)
1.89e1.84 (m, 3H); 13C NMR (100 MHz)
d 199.5 (br), 136.9, 136.7,
132.8, 129.9, 108.6, 99.1, 96.5, 77.6, 63.3, 40.1, 33.5, 29.5, 29.0, 20.8,
20.6; DART MS m/z 557 (Mþþ1, 28); DART HRMS calcd for
C24H23Co2O8 557.0057, found 557.0067.
d
199.9 (br), 147.5, 146.5, 128.0, 126.7, 126.6, 125.9, 125.7, 109.4, 96.7,
4.42. Hexacarbonyl-
m-{
h
4-6-hydroxy-1-[(1R
*
,2R )-2-
*
94.7, 91.4, 76.5, 60.4, 59.2, 59.0, 44.3, 42.0, 38.8, 37.4, 33.3; FAB MS
m/z 693 (Mþþ1, 82); FAB HRMS calcd for C32H31Co2O10 693.0581,
found 693.0589.
phenylcyclopropyl]hex-2-yn-1-one}dicobalt (CoeCo) (19a)
Brown oil; IR 2098, 2062, 2037, 1647 cmꢀ1; 1H NMR (400 MHz)
d
7.31e7.20 (m, 3H), 7.13e7.11 (m, 2H), 3.70 (t, J¼6.4 Hz, 2H),
3.06e3.02 (m, 2H), 2.72e2.67 (m, 1H), 2.43e2.39 (m, 1H), 1.95e1.85
(m, 3H), 1.58e1.53 (m, 1H); 13C NMR (100 MHz)
200.8, 198.6 (br),
139.4, 128.6, 126.7, 126.0, 99.9, 99.4, 61.5, 34.4, 34.2, 30.7, 30.6, 19.7;
DART MS m/z 515 (Mþþ1, 60); DART HRMS calcd for C21H17Co2O8
514.9587, found 514.9597. The relative stereochemistry of 19a has
been determined by NOE experiments.
4.38. Hexacarbonyl-m-{h
4-2,2-diphenyl-9,9-
bis(phenylsulfonyl)-1,6-dioxaspiro[4.7]dodec-11-yne}dico-
balt(CoeCo) (13d)
d
Brown oil; IR 2096, 2058, 2035, 2023, 1331, 1312, 1148 cmꢀ1; 1H
NMR (400 MHz)
d 8.07e8.05 (m, 4H), 7.81e7.77 (m, 1H), 7.73e7.64
(m, 3H), 7.68e7.64 (m, 2H), 7.39e7.36 (m, 2H), 7.30e7.16 (m, 8H),
4.21 (dt, J¼14.5, 3.7 Hz, 1H), 4.17, 4.15 (ABq, JAB¼16.9 Hz, 2H), 3.41
(ddd, J¼14.5, 9.6, 1.8 Hz, 1H), 2.90 (ddd, J¼12.4, 7.3, 1.8 Hz, 1H), 2.80
(td, J¼12.4, 7.3 Hz,1H), 2.64 (ddd, J¼16.5, 9.6, 3.7 Hz,1H), 2.46e2.42
4.43. Hexacarbonyl-
m
-{
h
4-6-hydroxy-1-[(1R
*
,2R )-2-
*
mesitylcyclopropyl]hex-2-yn-1-one}dicobalt (CoeCo) (19b)
(m, 1H), 2.40e2.29 (m, 2H); 13C NMR (100 MHz)
d 199.2 (br), 147.7,
Brown oil; IR 3626, 3452, 2098, 2062, 2037, 1645 cmꢀ1; 1H NMR
145.5, 135.9, 135.9, 135.1, 134.7, 131.8, 131.5, 129.1, 128.6, 128.1, 128.0,
127.0, 126.6, 125.9, 125.5, 109.8, 95.7, 92.2, 92.1, 87.7, 58.2, 41.4, 36.3,
34.0, 32.4; FAB MS m/z 885 (Mþþ1, 29); FAB HRMS calcd for
C40H31Co2O12S2 884.9921, found 884.9906.
(600 MHz)
d 6.85 (s, 2H), 3.79e3.77 (m, 2H), 3.08e3.05 (m, 2H),
2.78e2.75 (m, 2H), 2.35 (s, 6H), 2.34e2.31 (m, 1H), 2.26 (s, 3H), 1.95
(quin, J¼6.5 Hz, 2H), 1.78e1.74 (m, 1H), 1.46e1.41 (m, 1H); 13C NMR
(100 MHz)
d 202.7, 198.6 (br), 198.4, 138.1, 136.6, 133.0, 129.0, 99.9,
87.1, 61.5, 34.4, 32.3, 30.5, 25.3, 23.3, 20.8, 20.6; DART MS m/z 557
(Mþþ1, 55); DART HRMS calcd for C24H23Co2O8 557.0057, found
557.0076. The relative stereochemistry of 19b has been determined
by NOE experiments.
4.39. Hexacarbonyl-m{h
4-9.9-dimethoxycarbonyl-2,2-
diphenyl-1,6-dioxaspiro[4.7]dodec-11-yne}dicobalt (CoeCo)
(15)
Brown oil; IR 2093, 2056, 2031, 1732 cmꢀ1; 1H NMR (400 MHz)
7.44e7.42 (m, 4H), 7.33e7.26 (m, 4H), 7.24e7.15 (m, 2H), 4.00
4.44. 10-Triethlsilyl-2-mesityl-1,6-dioxaspiro[4.6]undec-10-
ene (20)
d
(ddd, J¼14.2, 7.7, 1.8 Hz, 1H), 3.84 (d, J¼15.5 Hz, 1H), 3.80 (s, 3H),
3.74 (s, 3H), 3.61 (d, J¼15.5 Hz, 1H), 3.49e3.43 (m, 1H), 2.97 (dt,
J¼12.3, 6.8 Hz, 1H), 2.73 (ddd, J¼12.3, 6.8, 1.5 Hz, 1H), 2.48 (ddd,
J¼15.6, 6.8, 1.5 Hz, 1H), 2.39e2.26 (m, 2H), 2.00 (ddd, J¼16.0, 7.7,
To a solution of 18b and epi-18b (55.6 mg, 0.100 mmol, dr¼5:1)
in benzene (3 mL) was added Et3SiH (75 mL, 0.50 mmol) at room
temperature. After stirring for 2 h at 65 ꢁC, benzene was evaporated
off. The residue was chromatographed with hexane/AcOEt (50:1) to
afford 20 (32.1 mg, 0.0832 mmol, 84% for three steps). A mixture of
cis-20 and trans-20 in the ratio of 5:1 was obtained as a colorless oil.
1.3 Hz, 1H); 13C NMR (100 MHz)
d 199.3 (br), 171.3, 170.9, 147.0,
146.5, 128.0, 127.9, 126.62,126.60,125.7, 125.4, 108.9, 99.8, 97.1, 91.2,
60.0, 57.6, 53.0, 52.8, 42.3, 37.9, 37.8, 34.6; FAB MS m/z 721 (Mþþ1,
96); FAB HRMS calcd for C32H27Co2O12 721.0167, found 712.0157.
IR 3009, 1612 cmꢀ1; 1H NMR (600 MHz)
d
6.82 (s, 1Hꢂ83/100), 6.80

C. Mukai et al. / Tetrahedron 69 (2013) 7659e7669
7669
naoka, N. Tetrahedron 1998, 54, 823e850; (d) Mukai, C.; Yamashita, H.; Ichiryu,
T.; Hanaoka, M. Tetrahedron 2000, 56, 2203e2209; (e) Mukai, C.; Yamaguchi, S.;
Sugimoto, Y.; Miyakoshi, N.; Kasamatsu, E.; Hanaoka, M. J. Org. Chem. 2000, 65,
6761e6765; (f) Mukai, C.; Yamaguchi, S.; Kim, I. J.; Hanaoka, M. Chem. Pharm.
Bull. 2001, 49, 613e618; (g) Mukai, C.; Yamashita, H.; Sassa, M.; Hanaoka, M.
Tetrahedron 2002, 58, 2755e2762.
7. (a) Xiao, H.-Q.; Shu, X.-z.; Ji, K.-g.; Qi, C.-z.; Liang, Y.-m. New J. Chem. 2007,
31, 2041e2043; (b) Mothe, S. R.; Chan, P. W. H. J. Org. Chem. 2009, 74,
5887e5893.
(s, 1Hꢂ17/100), 5.80 (d, J¼2.4 Hz, 1Hꢂ83/100), 5.67 (d, J¼2.4 Hz,
1Hꢂ17/100), 5.47e5.45 (m, 1Hꢂ83/100), 5.37e5.35 (m, 1Hꢂ17/
100), 4.06e4.00 (m, 1Hꢂ17/100), 3.98e3.95 (m, 1Hꢂ83/100),
3.74e3.71 (m, 1Hꢂ17/100), 3.68e3.66 (m, 1Hꢂ83/100), 2.62e2.55
(m,1H), 2.42 (s, 3Hꢂ17/100), 2.36 (s, 6H), 2.32e2.27 (m,1H), 2.24 (s,
3Hꢂ83/100), 2.21e2.05 (m, 2H), 2.02e1.94 (m, 3H), 1.70e1.63 (m,
1Hꢂ83/100), 1.62e1.58 (m, 1Hꢂ17/100), 0.93 (t, J¼7.9 Hz, 9H), 0.61
(q, J¼7.9 Hz, 6Hꢂ17/100), 0.60 (q, J¼7.9 Hz, 6Hꢂ83/100); 13C NMR
8. The AgOTf-assisted ring-expansion of an alk-1-ynylcyclopropyl ketone to form
a 2-(alk-1-ynyl)-4,5-dihydrofurane is reported. Wang, H.; Denton, J. R.; Davies,
H. M. L. Org. Lett. 2011, 13, 4316e4319.
(151 MHz)
d 142.2, 140.22, 140.16, 137.6, 136.72, 136.68, 136.52,
136.46, 130.07, 130.04, 112.5, 111.6, 80.2, 75.6, 60.8, 60.7, 39.2, 38.7,
29.9, 29.6, 28.6, 28.1, 24.7, 23.8, 21.0, 20.73, 20.66, 20.4, 7.5, 7.4, 2.41,
2.38; DART MS m/z 387 (Mþþ1, 100); DART HRMS calcd for
C24H39O2Si 387.2719, found 387.2703. The relative stereochemistry
of cis-20 and trans-20 has been determined by NOE experiments.
9. Among them, InCl3 (73%) and BiCl3 (62%) afforded relatively better yields.
10. Several other solvents (MeCM, DMF, Et2O) were also screened and toluene was
found to be the better one for the formation of 11a.
11. The stereochemistry of 18b and its epimer was confirmed by the spectral
analysis of the vinylsilane 20, which were derived from Et3SiH and 18b and epi-
18b, respectively, by the known procedure.
Acknowledgements
This work was supported in part by a Grant-in Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, for, which we are thankful.
References and notes
1. (a) Nicholas, K. M.; Pettit, R. J. Organomet. Chem. 1972, 44, C21eC24; (b) Lock-
wood, R. F.; Nicholas, K. M. Tetrahedron Lett. 1977, 4163e4165; (c) Nicholas, K. M.
Acc. Chem. Res. 1987, 20, 207e214; (d) Teobald, B. J. Tetrahedron 2002, 58,
4133e4170.
2. (a) Isobe, M.; Yenjai, C.; Tanaka, S. Synlett 1994, 916e918; (b) Yenjai, C.; Isobe,
M. Tetrahedron 1998, 54, 2509e2520; (c) Liu, T.-Z.; Isobe, M. Synlett 2000,
266e268; (d) Kira, K.; Isobe, M. Tetrahedron Lett. 2000, 41, 5951e5955; (e)
Quintal, M. M.; Closser, K. D.; Shea, K. M. Org. Lett. 2004, 6, 4949e4952; (f)
Hamajima, A.; Isobe, M. Org. Lett. 2006, 8, 1205e1208; (g) Closser, K. D.; Quintal,
M. M.; Shea, K. M. J. Org. Chem. 2009, 74, 3680e3688.
3. (a) Wender, P. A.; Takahashi, H.; Witulski, B. J. Am. Chem. Soc. 1995, 117,
4720e4721; (b) Wender, P. A.; Sperandio, D. J. Org. Chem. 1998, 63, 4164e4165;
(c) Wender, P. A.; Dyckman, A. J.; Husfeld, C. O.; Kadereit, D.; Love, J. A.; Rieck, H.
J. Am. Chem. Soc. 1999, 121, 10442e10443; (d) Wender, P. A.; Dyckman, A. J. Org.
Lett. 1999, 1, 2089e2092; (e) Wender, P. A.; Bi, F. C.; Brodney, M. A.; Gosselin, F.
Org. Lett. 2001, 3, 2105e2108; (f) Wender, P. A.; Williams, T. J. Angew. Chem., Int.
Ed. 2002, 41, 4550e4553; (g) Inagaki, F.; Sugikubo, K.; Miyashita, Y.; Mukai, C.
Angew. Chem., Int. Ed. 2010, 49, 2206e2210.
12. The predominant formation of 18b over its epimer might be rationalized by
the preferential attack of the terminal hydroxyl group from the opposite face
of the mesityl functionality of the dihydrofuran derivative V (see Fig. 1). The
epimerization of cis-III (R5¼aryl, R6¼H) to a more stable trans-III (R5¼H,
R6¼aryl) via IV would be accelerated to avoid the nonbonding interaction
between the activated carbonyl tether and a phenyl group (or mesityl group)
in a cis-relationship. In particular, cis-mesityl derivative 17b would suffer
a serious nonbonding interaction ending up with easy epimerization to the
trans-one.
13. A treatment of 19c (or 19d) with CAN in methanol afforded trans-17c (or trans-
17d).
14. Cleary, L.; Yoo, H.; Shea, K. J. Org. Lett. 2011, 13, 1781e1783.
15. Alberti, M. N.; Orfanopoulos, M. Org. Lett. 2009, 11, 1659e1662.
4. Knowlton, J. W.; Rossini, F. D. J. Res. Natl. Bur. Stand. (U.S.) 1949, 43, 113e115.
5. Kleinke, A. S.; Webb, D.; Jamison, T. F. Tetrahedron 2012, 68, 6999e7018.
6. (a) Mukai, C.; Ikeda, Y.; Sugimoto, Y.; Hanaoka, M. Tetrahedron Lett. 1994, 35,
2179e2182; (b) Mukai, C.; Sugimoto, Y.; Ikeda, Y.; Hanaoka, M. J. Chem. Soc.,
Chem. Commun. 1994, 1161e1162; (c) Mukai, C.; Sugimoto, Y.; Ikeda, Y.; Ha-
ꢀ
ꢁ
16. Beaufils, F.; Denes, F.; Renaud, P. Org. Lett. 2004, 6, 2563e2566.
17. Tsukamoto, H.; Matsumoto, T.; Kondo, Y. Org. Lett. 2008, 10, 1047e1050.
18. Thompson, W. J.; Tucker, T. J.; Schwering, J. E.; Barnes, J. L. Tetrahedron Lett.
1990, 31, 6819e6822.