Stereocontrolled synthesis of substituted bicyclic ethers through oxy-Favorskii rearrangement: Total synthesis of (±)-communiol e

Article abstract of DOI:10.1021/jo201064h

The potential of the oxy-Favorskii rearrangement to form branched cis-fused bicyclic ethers was explored. Both tertiary and quaternary centers were constructed in highly stereospecific manners. Methanol and primary amines were effective nucleophiles for the rearrangement. The total synthesis of (±)-communiol E was achieved based on this method.

Full text of DOI:10.1021/jo201064h

ARTICLE
pubs.acs.org/joc
Stereocontrolled Synthesis of Substituted Bicyclic Ethers through
Oxy-Favorskii Rearrangement: Total Synthesis of (()-Communiol E
Shoji Kobayashi,*,† Tatsuhiro Kinoshita,‡ Takuji Kawamoto,‡ Masato Wada,† Hiroyuki Kuroda,†
Araki Masuyama,† and Ilhyong Ryu‡
†Department of Applied Chemistry, Faculty of Engineering, Osaka Institute of Technology, 5-16-1 Ohmiya, Asahi-ku,
Osaka 535-8585, Japan
‡Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai 599-8531, Japan
S Supporting Information
b
ABSTRACT: The potential of the oxy-Favorskii rearrangement
to form branched cis-fused bicyclic ethers was explored. Both
tertiary and quaternary centers were constructed in highly
stereospecific manners. Methanol and primary amines were
effective nucleophiles for the rearrangement. The total synthesis
of (()-communiol E was achieved based on this method.
’ INTRODUCTION
Oxabicycles are important core structures of natural products
and bioactive molecules. Communiol E (1),1 laurenenyne A
(2),2 and dysiherbaine (3)3 are representatives of this family
(Figure 1). A key structure in these molecules is the cis-fused
bicyclic ether that has an alkyl substituent cis to the bridgehead
hydrogen at the carbon adjacent to the ring oxygen. Various
synthetic approaches to such molecules have been described,1b,4
but stereocontrolled routes to the substituted oxabicycles are still
being researched.5
Base-induced ring contraction of R-halolactones, i.e., the oxy-
Favorskii rearrangement, is a promising method for constructing
Figure 1. Structures of oxabicyclic natural products.
branched oxacyclic systems.6 Several synthetic applications have
been reported;7 however, the generality of substrates, scope of
expected to occur from the convex face to give 6. It is thought
nucleophiles, and detailed stereospecificity remain unclear. We
that oxy-Favorskii rearrangement takes place through the alko-
conducted a systematic study with sterically rigid bicyclic mol-
xide intermediate 8 and intramolecular SN2-type displacement
delivers the trans-ester 9. We envisioned that the entire synthetic
process might be stereospecific and applicable to a variety of
bicyclic lactones.
ecules not only to evaluate the potential of the oxy-Favorskii
rearrangement but also to provide a new synthetic method for
the construction of substituted oxabicyclic skeletons in the above
natural products. Herein, we wish to report a highly convenient,
Thus, three kinds of racemic carboxylic acids, (()-4aꢀc,
stereocontrolled route to branched cis-fused bicyclic ethers based
which varied in ring size and length of carbon chain, were prepared8
on halolactonization, R-bromination, and oxy-Favorskii rearran-
(Scheme 2). Iodolactonization of (()-4aꢀcunder the conventional
gement. It is important to note that both the tertiary and the
conditions,9 followed by radical reduction, afforded the cis-fused
quaternary centers were constructed in highly stereospecific
bicyclic lactones 5aꢀc exclusively.10 Subsequent R-bromination was
manners. We also succeeded in the total synthesis of (()-
communiol E (1), a bicyclic polyketide isolated from Podospora
communis, by the newly developed oxy-Favorskii methodology.
best realized by treatment with LiN(TMS)2/TMSCl followed by
NBS.11 In all cases, β-bromolactones 6aꢀc predominated. The
selectivity was clearly dependent on the ring size. For a small-ring
compound like 5c, the concave face is highly shielded such that the
electrophile must approach from the less hindered convex face,
’ RESULTS AND DISCUSSION
thereby providing 6c as a single isomer.
Scheme 1 shows the general concept. The cis ring juncture in
the oxabicycle would be established by halolactonization with
carboxylic acid 4. After reduction or functionalization of the
resulting halide, halogenation at the R-position in 5 would be
Received: May 25, 2011
Published: July 25, 2011
r
2011 American Chemical Society
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Scheme 1. Concept of this Work
Table 1. Oxy-Favorskii Rearrangementa
Scheme 2. Iodolactonization and r-Bromination
a The reactions were carried out in MeOH (0.1 M) in the presence of
1
K2CO3 (1 equiv). b Isolated yield. c Determined by crude H NMR.
d NMR yield.
Table 2. Diversity of Nucleophiles
entry nucleophile
temp
9 (Nu)
yielda (%) (9:10)b
1
MeOH
iPrOH
MeNH2
iPrNH2
Et2NH
ꢀ78 °C to rt 9b (OMe)
78 (15:1)
0c
The stage was set for the oxy-Favorskii rearrangement. The
stereochemically pure β-bromolactones 6aꢀc were treated with
K2CO3 in MeOH at room temperature (Table 1). The expected
ring-contracted esters 9aꢀc were obtained as the major products
(entries 1, 3, and 5). Remarkably, formation of the five-membered
ring was quite efficient, while the oxetane ring was inaccessible,
probably due to ring strain. Contrary to our expectations,
considerable amounts of epimeric esters 10aꢀc were detected,
which suggested that epimerization at the R-position took place.
A comparative study with R-bromolactone 6b0, the minor
component in the R-bromination step, revealed that the reaction
was stereospecific and there was no equilibrium between 9b and
10b (entry 7). In other words, partial racemization occurred
before rearrangement, not after formation of the product. This
led us to investigate the reaction under low temperature. Indeed,
racemization was minimized when the temperature was first
cooled to ꢀ78 °C and then warmed to room temperature
(entries 2 and 4).
2
rt
rt
rt
rt
9d (OiPr)
9e (NHMe)
9f (NHiPr)
9g (NEt2)
3d
4d
5d
100 (>20:1)
74 (6:1)
0e
a Isolated yield. b Determined by 1H NMR analysis of the crude mixture.
c Racemization at C3 was observed. d The reaction was carried out
in DMF. e R,β-Unsaturated lactone was exclusively obtained.
rearrangement (entry 5). The reaction was not applicable
to thiol and selenol nucleophiles, where the SN2 reaction
occurred instead.12
We next turned our attention to the formation of the
quaternary center, which is found in natural products such as
dysiherbaine (3). Owing to the highly stereospecific nature of the
oxy-Favorskii reaction, it was expected that both stereoisomers
could be accessed by conducting an alkylationꢀbromination
sequence in the appropriate order. Thus, successive methylationꢀ
bromination with the bicyclic lactone 5b furnished bromolactone
11, in which the C3-methyl and C4a-H are in a trans relationship
(Scheme 3). In contrast, a brominationꢀmethylation sequence
with 5b afforded 13, where the C3-methyl and C4a-H are cis, as
the major product. These stereochemical outcomes are rationa-
lized by the preferential addition of the electrophiles from the
less hindered convex face. Subsequent rearrangements of 11
and 13 proceeded stereoselectively, providing esters 12 and 14,
We next explored the generality of the oxy-Favorskii rearran-
gement by varying the nucleophiles (Table 2). Interestingly,
neither a secondary alcohol (iPrOH) nor a tertiary alcohol
(tBuOH) induced rearrangement (entry 2), while primary
amines such as MeNH2 and iPrNH2 resulted in good
yields and selectivities (entries 3 and 4). With a secondary
amine (e.g., Et2NH), E2-type elimination prevailed over
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Scheme 3. Stereodivergent Formation of the
Quaternary Center
ethylation and deprotection to furnish (()-communiol E (1).
We have explored a number of conditions in the ethylation step
and found that treatment of 19 with EtLi in THF at 0 °C gave the
best yield and selectivity.15,16 The major drawback of the reaction
was the recovery of starting material, which might be caused by
enolization of the aldehyde. This problem was not resolved by
using other organometallic reagents such as EtMgBr, EtMgBr/
CeCl3,17 and EtLi/CeCl3 or by using additives such as HMPA18
and ZnCl2. All spectral data of synthetic 1 were identical to those
of the natural product.
’ CONCLUSION
We have shown the potential of the oxy-Favorskii rearrange-
ment in the synthesis of substituted oxabicycles. All synthetic
processes were stereospecific and useful for constructing
branched cis-fused bicyclic hydrofurans. Methanol and primary
amines were effective nucleophiles for the rearrangement. The
quaternary center was also constructed stereospecifically by
conducting an alkylationꢀbromination rearrangement sequence
in the appropriate manner. Furthermore, total synthesis of (()-
communiol E was achieved. Further studies to synthesize other
natural products including laurenenynes and dysiherbaine are
currently underway in our laboratory.
Scheme 4. Total Synthesis of (()-Communiol E
’ EXPERIMENTAL SECTION
(()-3-(Cyclohex-2-enyl)propanoic Acid (4a). To a suspen-
sion of magnesium turnings (166 mg, 6.83 mmol) in THF (5 mL) was
added dropwise a solution of 2-(2-bromoethyl)-1,3-dioxolane (1.24 g,
6.83 mmol) in THF (5 mL). After dissolution of all of the magnesium, a
solution of 3-bromocyclohexene (1.00 g, 6.21 mmol) in THF (5 mL)
was slowly added to the Grignard reagent. The solution was stirred at
room temperature for 1.5 h before addition of saturated aqueous NH4Cl
solution. The resulting mixture was extracted with Et2O (2ꢁ), and the
combined organic layer was dried over anhydrous MgSO4 and concen-
trated. The residue was purified by flash column chromatography
(hexane/EtOAc = 5) to give 2-(2-cyclohex-2-enylethyl)-1,3-dioxolane19
(1.05 g, 5.76 mmol, 93%). To a solution of dioxolane (1.05 g, 5.76
mmol) in CH3CN-H2O (3:1, 57 mL) was added 1 M aqueous H2SO4
(19 mL). The mixture was stirred at room temperature for 19 h before
addition of saturated NaHCO3 solution. The resulting mixture was
extracted with Et2O (2ꢁ), and the combined organic layer was dried
over anhydrous MgSO4. Concentration of the ethereal solution gave the
corresponding aldehyde (796 mg). To a solution of aldehyde (796 mg,
5.76 mmol) in t-BuOH-H2O (4:1, 12 mL) were added 2-methyl-2-
butene (3.05 mL, 28.8 mmol), KH2PO4 (784 mg, 5.76 mmol), and
NaClO2 (1.56 g, 17.3 mmol) at 0 °C. The mixture was stirred at room
temperature for 3 h before addition of CHCl3 and 1 M aqueous HCl. The
resulting mixture was extracted with CHCl3 (2ꢁ), and the combined
organic layer was washed with 1 M aqueous NaOH. The aqueous layer
was acidified with 1 M aqueous HCl and extracted again with CHCl3.
The organic layer was dried over anhydrous MgSO4 and concentrated to
give carboxylic acid 4a (315 mg, 2.04 mmol, 35% for 2 steps). 4a:
colorless oil; 1H NMR (400 MHz, CDCl3) δ 5.71 (ddd, 1H, J = 10, 5.6,
2.8 Hz), 5.54 (br dd, 1H, J = 10, 2.0 Hz), 2.40 (t, 2H, J = 7.6 Hz),
2.15ꢀ2.06 (m, 1H), 2.02ꢀ1.94 (m, 2H), 1.83ꢀ1.46 (m, 5H),
1.26ꢀ1.17 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 180.4, 130.9,
128.0, 34.6, 31.6, 31.0, 28.7, 25.4, 21.4; FT-IR (film) 3018, 2927, 2861,
2667, 1713, 1650, 1452, 1415, 1313, 1278, 1252, 1216, 1160, 1137, 1092,
respectively, in reasonable yields. It should be noted that the
intramolecular nucleophilic substitution onto the tertiary bromide
proceeded smoothly without the influence of stereochemistry.
After identifying the generality of the oxy-Favorskii rearrange-
ment for the bicyclic system, we undertook the total synthesis of
communiol E (1) (Scheme 4). Iodolactone (()-15 was sub-
mitted to the recently developed tin-free radical/ionic hydro-
xymethylation conditions to afford hydroxylactone 16.13 It is
noted that the highly susceptible lactone moiety survived under
these reduction conditions, albeit in modest yield. After protec-
tion of the hydroxyl group as a TBS ether, bromination was
effected to provide an inseparable mixture of bromolactones 17
in favor of the desired diastereomer. The crucial rearrangement
was realized in a stereospecific manner and afforded ester 18
quantitatively.14 DIBAL reduction of 18 at ꢀ78 °C gave alde-
hyde 19 without forming the alcohol, which was followed by
1060 cmꢀ1
.
(()-(4aR,8aR)-Octahydro-2H-chromen-2-one (5a).20 To a
solution of carboxylic acid 4a (102 mg, 0.660 mmol) in 0.5 M aqueous
NaHCO3 (3.7 mL, 1.85 mmol) were added 2.8 M aqueous NaOH
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ARTICLE
(59 μL, 0.165 mmol), KI (657 mg, 3.96 mmol), and iodine (335 mg,
1.32 mmol). The mixture was stirred at room temperature for 6 h and
then diluted with CHCl3 and saturated Na2S2O3 solution. The resulting
mixture was extracted with CHCl3 (2ꢁ), and the combined organic
layer was dried over anhydrous MgSO4 and concentrated to give the
corresponding iodolactone (147 mg, 0.525 mmol, 80%), which was used
for the next reaction without further purification.
2.0 Hz), 2.06ꢀ2.02 (m, 1H), 1.89ꢀ1.80 (m, 1H), 1.78ꢀ1.64 (m, 3H),
1.55ꢀ1.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 177.9, 86.5, 38.0,
36.2, 33.7, 33.6, 23.5. 2-Oxabicyclo[3.2.1]octan-3-one: colorless solid;
1H NMR (400 MHz, CDCl3) δ 4.85ꢀ4.84 (m, 1H), 2.71 (ddd, 1H, J =
18.4, 5.2, 2.4 Hz), 2.55ꢀ2.52 (m, 1H), 2.57 (dt, 1H, J = 18.4, 2.0 Hz),
2.15 (td, 1H, J = 9.6, 2.4 Hz), 2.00ꢀ1.86 (m, 2H), 1.73ꢀ1.62 (m, 3H);
13C NMR (100 MHz, CDCl3) δ 177.9, 86.5, 38.0, 36.2, 33.7, 33.6, 23.5.
(()-(3R,4aR,8aR)-3-Bromooctahydro-2H-chromen-2-one
(6a). To a solution of lactone 5a (49.9 mg, 0.324 mmol) in THF
(1.6 mL) was added LiN(TMS)2 (1.0 M solution in THF, 363 μL, 0.363
mmol) at ꢀ78 °C. The mixture was stirred at ꢀ78 °C for 1 h followed by
the addition of TMSCl (51.0 μL, 0.405 mmol). The reaction mixture
was allowed to warm to room temperature and stirred for 0.5 h. The
mixture was again cooled to ꢀ78 °C followed by the addition of NBS
(86.5 mg, 0.486 mmol) in THF (1.5 mL). The mixture was warmed
to room temperature and stirred for 1 h. The reaction mixture was
quenched with H2O and extracted with Et2O (2ꢁ). The combined
organic layer was dried over anhydrous MgSO4 and concentrated.
The residue was purified by flash column chromatography (hexane/
EtOAc = 5) to give bromolactones 6a (23.1 mg, 0.0991 mmol, 31%) and
6a0 (17.9 mg, 0.0768 mmol, 24%). 6a: colorless oil; 1H NMR (400 MHz,
CDCl3) δ 4.86 (quint, 1H, J = 3.2 Hz), 4.55 (dd, 1H, J = 6.4, 5.6 Hz),
2.45ꢀ2.29 (m, 2H), 2.24ꢀ2.16 (m, 1H), 1.97ꢀ1.90 (m, 1H),
1.71ꢀ1.30 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 167.8, 79.0,
38.8, 35.5, 32.0, 30.0, 27.3, 23.7, 20.6; FT-IR (film) 2935, 2860, 1736,
1448, 1352, 1309, 1263, 1228, 1207, 1184, 1144, 1113, 1061,
1022 cmꢀ1; HRMS (FAB) m/z calcd for C9H1479BrO2 [M + H]+
233.0177, found 233.0138. 6a0: colorless oil; 1H NMR (400 MHz,
CDCl3) δ 4.69 (dd, 1H, J = 11.2, 8.4 Hz), 4.59ꢀ4.54 (m, 1H),
2.78ꢀ2.70 (m, 1H), 2.18ꢀ2.09 (m, 1H), 2.03ꢀ1.95 (m, 2H),
1.71ꢀ1.24 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 168.2, 77.8,
42.0, 36.8, 34.7, 29.6, 29.1, 23.8, 20.6.
(()-(3R,4aR,7aR)-3-Bromohexahydrocyclopenta[b]pyran-
2(3H)-one (6b). To a solution of lactone 5b (557 mg, 3.97 mmol) in
THF (14 mL) was added LiN(TMS)2 (1.0 M solution in THF, 4.45 mL,
4.45 mmol) at ꢀ78 °C. The mixture was stirred at ꢀ78 °C for 1 h
followed by the addition of TMSCl (630 μL, 4.96 mmol). The reaction
mixture was allowed to warm to room temperature and stirred for 0.5 h.
The mixture was again cooled to ꢀ78 °C followed by the addition of
NBS (1.06 g, 5.96 mmol) in THF (9 mL). The mixture was warmed
to room temperature and stirred for 1 h. The reaction mixture was
quenched with H2O and extracted with Et2O (2ꢁ). The combined
organic layer was dried over anhydrous MgSO4 and concentrated.
The residue was purified by flash column chromatography (hexane/
EtOAc = 5) to give bromolactones 6b (680 mg, 3.10 mmol, 78%) and
6b0 (46.1 mg, 0.210 mmol, 5%). 6b: colorless oil; 1H NMR (400 MHz,
CDCl3) δ 5.15 (sextet, 1H, J = 3.2 Hz), 4.46 (t, 1H, J = 3.2 Hz),
2.57ꢀ2.47 (m, 2H), 2.12ꢀ1.92 (m, 3H), 1.85ꢀ1.75 (m, 1H),
1.65ꢀ1.54 (m, 1H), 1.50ꢀ1.41 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 168.0, 83.4, 39.4, 34.5, 33.9, 33.1, 32.3, 23.5; FT-IR (film) 2957, 2871,
1746, 1470, 1452, 1439, 1351, 1291, 1260, 1204, 1142, 1117, 1078, 1053,
1024 cmꢀ1; HRMS (FAB) m/z calcd for C8H1279BrO2 [M + H]+
219.0021, found 218.9990. 6b0: colorless oil; 1H NMR (400 MHz,
CDCl3) δ 4.79 (td, 1H, J = 5.6, 3.6 Hz), 4.59 (dd, 1H, J = 13.2, 5.6 Hz),
2.80ꢀ2.73 (m, 1H), 2.48ꢀ2.37 (m, 1H), 2.08ꢀ1.81 (m, 5H),
1.63ꢀ1.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.0, 82.9,
43.2, 39.5, 36.6, 33.4, 32.4, 23.1; FT-IR (film) 2957, 2872, 1752, 1658,
1639, 1457, 1439, 1316, 1261, 1171, 1132, 1076, 1045 cmꢀ1; HRMS
(FAB) m/z calcd for C8H1279BrO2 [M + H]+ 219.0021, found 219.0011.
(()-(3R,3aS,6aR)-3-Bromohexahydro-2H-cyclopenta[b]
furan-2-one (6c). To a solution of lactone 5c (72.8 mg, 0.577 mmol)
in THF (3 mL) was added LiN(TMS)2 (1.0 M solution in THF, 646 μL,
0.646 mmol) at ꢀ78 °C. The mixture was stirred at ꢀ78 °C for 5 min
followed by the addition of TMSCl (91.5 μL, 0.721 mmol). The reaction
To a solution of iodolactone (147 mg, 0.525 mmol) in benzene
(5 mL) were added Bu3SnH (212 μL, 0.787 mmol) and AIBN (8.60 mg,
52.5 μmol). The mixture was stirred at 80 °C for 2 h and concentrated.
The residue was purified by flash column chromatography (hexane/
EtOAc = 3) to give lactone 5a (70.1 mg, 0.455 mmol, 87%). 5a: colorless
oil; 1H NMR (400 MHz, CDCl3) δ 4.49ꢀ4.46 (m, 1H), 2.50 (t, 2H, J =
7.6 Hz), 2.05ꢀ1.87 (m, 3H), 1.71ꢀ1.25 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ 172.7, 78.4, 32.7, 30.4, 27.0, 26.6, 24.5, 24.4, 20.2; FT-IR
(film) 2933, 2860, 1734, 1448, 1350, 1296, 1244, 1196, 1161, 1138,
1107, 1065 cmꢀ1
.
(()-(4aR,7aR)-Hexahydrocyclopenta[b]pyran-2(3H)-one
(5b).21 To a solution of carboxylic acid 4b13 (100 mg, 0.713 mmol) in
0.5 M aqueous NaHCO3 (4.0 mL, 2.00 mmol) were added 2.8 M
aqueous NaOH (63.5 μL, 0.178 mmol), KI (711 mg, 4.28 mmol), and
iodine (507 mg, 2.00 mmol). The mixture was stirred at room
temperature for 3.5 h and then diluted with CHCl3 and saturated
Na2S2O3 solution. The resulting mixture was extracted with CHCl3
(3ꢁ), and the combined organic layer was dried over anhydrous
MgSO4 and concentrated to give a corresponding iodolactone (158
1
mg, 0.594 mmol, 83%). Pale yellow solid; H NMR (CDCl3, 400
MHz) δ 4.91 (dd, 1H, J = 6.8, 2.0 Hz), 4.36ꢀ4.33 (m, 1H), 2.86ꢀ2.77
(m, 1H), 2.52ꢀ2.45 (ddd, 1H, J = 16.8, 6.4, 4.8 Hz), 2.38ꢀ2.30 (m,
1H), 2.27ꢀ2.18 (m, 1H), 2.12ꢀ2.04 (m, 1H), 1.67ꢀ1.59 (m, 1H),
1.58ꢀ1.50 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 171.6, 90.3,
36.0, 34.0, 30.1, 28.4, 27.9, 23.7; IR (neat) 2950, 2871, 1745 cmꢀ1
;
HRMS (EI) m/z calcd for C8H11IO2 [M]+ 265.9804, found
265.9806.
To a solution of iodolactone (123 mg, 0.464 mmol) in benzene
(4 mL) were added Bu3SnH (187 μL, 0.696 mmol) and AIBN (7.6 mg,
46 μmol). The mixture was stirred at 80 °C for 2 h and concentrated.
The residue was purified by flash column chromatography (hexane/
EtOAc = 1) to give lactone 5b (48.7 mg, 0.347 mmol, 75%). 5b:
colorless oil; 1H NMR (300 MHz, CDCl3) δ 4.73 (td, 1H, J = 6.0, 3.2
Hz), 2.51ꢀ2.45 (m, 1H), 2.39ꢀ2.25 (m, 2H), 2.21ꢀ2.13 (m, 1H),
2.03ꢀ1.76 (m, 4H), 1.63ꢀ1.54 (m, 2H), 1.50ꢀ1.42 (m, 1H); 13C NMR
(CDCl3, 75 MHz) δ 173.7, 83.4, 37.0, 33.7, 31.0, 28.8, 23.7, 23.1; IR
(film) 2953, 2873, 1743, 1459, 1436, 1344, 1322, 1250, 1185, 1138,
1097, 1077, 1045, 1020 cmꢀ1; HRMS (FAB) m/z calcd for C8H13O2
[M + H]+ 141.0916, found 141.0862.
(()-(3aR,6aR)-Hexahydro-2H-cyclopenta[b]furan-2-one
(5c).22 To a solution of 2-(cyclopent-2-enyl)acetic acid (100 mg, 0.792
mmol) in 0.5 M aqueous NaHCO3 (4.44 mL, 2.22 mmol) were added
2.8 M aqueous NaOH (70.7 μL, 0.178 mmol), KI (789 mg, 4.75 mmol),
and iodine (401 mg, 1.58 mmol). The mixture was stirred at room
temperature for 1.5 h and then diluted with CHCl3 and saturated
Na2S2O3 solution. The resulting mixture was extracted with CHCl3
(3ꢁ), and the combined organic layer was dried over anhydrous MgSO4
and concentrated to give a 4:1 inseparable mixture of 5-exo-cyclized
iodolactone and 6-endo-cyclized iodolactone (196 mg, 0.778 mmol,
98%). To a solution of iodolactones (188 mg, 0.747 mmol) in benzene
(7 mL) were added Bu3SnH (301 μL, 1.12 mmol) and AIBN (12.3 mg,
74.7 μmol). The mixture was stirred at 80 °C for 2 h and concentrated.
The residue was purified by flash column chromatography (hexane/
EtOAc = 3) to give lactone 5c (69.8 mg, 0.553 mmol, 74%) and
2-oxabicyclo[3.2.1]octan-3-one (17.4 mg, 0.140 mmol, 18%). 5c: color-
1
less oil; H NMR (400 MHz, CDCl3) δ 4.98 (br t, 1H, J = 6.8 Hz),
2.91ꢀ2.83 (m, 1H), 2.82 (dd, 1H, J = 17, 1.0 Hz), 2.27 (dd, 1H, J = 17,
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mixture was warmed to 0 °C and stirred for 30 min. The mixture was
again cooled to ꢀ78 °C followed by the addition of NBS (154 mg, 0.866
mmol) in THF (2 mL). The resulting mixture was warmed to room
temperature and stirred for 1.5 h. The reaction mixture was quenched
with water and extracted with EtOAc (2ꢁ). The combined organic layer
was dried over anhydrous MgSO4 and concentrated. The residue was
purified by flash column chromatography (hexane/EtOAc = 10f3) to
give bromolactone 6c (89.3 mg, 0.436 mmol, 75%). 6c: colorless oil; 1H
NMR (400 MHz, CDCl3) δ 5.19 (br t, 1H, J = 5.2 Hz), 4.19 (br s, 1H),
3.03 (quint, 1H, J = 5.2 Hz), 2.16ꢀ2.11 (m, 1H), 2.07ꢀ1.97 (m, 1H),
1.86ꢀ1.72 (m, 3H), 1.61ꢀ1.52 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 173.4, 86.0, 50.4, 43.4, 32.3, 30.9, 23.9; FT-IR (film) 2966, 2875, 1778,
1470, 1451, 1437, 1349, 1330, 1319, 1286, 1260, 1236, 1186, 1134, 1087,
1039, 1026 cmꢀ1; HRMS (FAB) m/z calcd for C7H1079BrO2 [M + H]+
204.9864, found 204.9827.
(()-(2S,3aR,7aR)-Methyl Octahydrobenzofuran-2-car-
boxylate (9a). To a solution of bromolactone 6a (41.4 mg, 0.189
mmol) in MeOH (3.8 mL) was added K2CO3 (26.1 mg, 0.189 mmol) at
ꢀ78 °C. The reaction mixture was allowed to warm to room tempera-
ture with stirring for 1 h. After concentration, the residue was purified by
flash column chromatography (hexane/EtOAc = 3) to give a 10:1
inseparable mixture of esters 9a and 10a (27.2 mg, 0.148 mmol, 78%).
The following data were selected from the spectra obtained by a mixture
of 9a and 10a. Colorless oil: 1H NMR (300 MHz, CDCl3, for 9a) δ 4.59
(t, 1H, J = 7.2 Hz), 4.12 (dd, 1H, J = 6.3, 2.7 Hz), 3.74 (s, 3H, OMe),
2.11ꢀ1.99 (m, 5H), 1.67ꢀ1.14 (m, 6H); 13C NMR (75 MHz, CDCl3,
for 9a) δ 174.9, 78.6, 75.2, 52.1, 37.7, 37.3, 27.9, 27.4, 24.2, 20.3; FT-IR
(neat) 2930, 2857, 1758, 1738, 1458, 1436, 1368, 1270, 1230, 1155,
1110, 1082, 1050, 1023 cmꢀ1; HRMS (FAB) m/z calcd for C10H17O3
[M + H]+ 185.1178, found 185.1136.
for 9c) δ 5.31 (t, 1H, J = 4.4 Hz), 4.50 (d, 1H, J = 4.4 Hz), 3.81 (s, 3H),
3.18ꢀ3.14 (m, 1H), 2.21ꢀ1.51 (m, 6H); 13C NMR (100 MHz, CDCl3,
for 9c) δ 173.3, 87.5, 81.0, 52.3, 43.3, 34.4, 30.4, 23.7; HRMS (EI) m/z
calcd for C8H13O3 [M + H]+ 157.0865, found 157.0866.
(()-(2S,3aR,6aR)-N-Methylhexahydro-2H-cyclopenta-
[b]furan-2-carboxamide (9e). To a solution of bromolactone 6b
(27.5 mg, 0.137 mmol) in DMF (456 μL) were added methylamine
(40% in water, 30.4 μL, 0.348 μmol) and K2CO3 (18.9 mg, 0.137 mmol).
The reaction mixture was stirred at room temperature for 2 h before
addition of water. The resulting mixture was extracted with Et2O (4ꢁ)
and EtOAc (3ꢁ), and the combined organic layer was dried over
anhydrous MgSO4 and concentrated to give amide 9e (23.2 mg, 0.137
1
mmol, 100%). 9e: colorless oil; H NMR (400 MHz, CDCl3) δ 6.64
(br s, 1H), 4.57 (br t, 1H, J = 4.4 Hz), 4.37 (t, 1H, J = 7.2 Hz), 2.79 (d,
3H, J = 5.2 Hz), 2.68ꢀ2.60 (m, 1H), 2.22ꢀ2.15 (m, 1H), 2.05ꢀ1.99 (m,
1H), 1.81ꢀ1.40 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 173.7, 86.6,
79.4, 42.7, 37.8, 34.7, 32.4, 25.7, 24.6; FT-IR (film) 3431, 3332, 2951,
2869, 2804, 1659, 1537, 1468, 1452, 1437, 1408, 1348, 1330, 1306, 1280,
1238, 1212, 1188, 1155, 1134, 1110, 1069, 1053, 1027 cmꢀ1; HRMS
(FAB) m/z calcd for C9H16NO2 [M + H]+ 170.1181, found 170.1132.
(()-(2S,3aR,6aR)-N-Isopropylhexahydro-2H-cyclopenta-
[b]furan-2-carboxamide (9f). To a solution of bromolactone 6b
(35.5 mg, 162 μmol) in DMF (456 μL) were added isopropylamine
(58.8 μL, 685 μmol) and K2CO3 (22.4 mg, 162 μmol). The reaction
mixture was stirred at room temperature for 15 h before addition of
water. The resulting mixture was extracted with Et2O (2ꢁ), and the
combined organic layer was dried over anhydrous MgSO4 and concen-
trated to give a 6:1 inseparable mixture of amide 9f and 10f (23.6 mg,
120 μmol, 74%). The following data were selected from the spectra
1
obtained by a mixture of 9f and 10f. Colorless solid: H NMR (400
MHz, CDCl3, for 9f) δ 6.43 (br s, 1H), 4.57 (br t, 1H, J = 5.2 Hz), 4.33
(t, 1H, J = 7.2 Hz), 4.14ꢀ3.98 (m, 1H), 2.67ꢀ2.61 (m, 1H), 2.17 (dt,
1H, J = 12.8, 7.6 Hz), 2.01 (ddd, 1H, J = 12.4, 6.8, 3.6 Hz), 1.82ꢀ1.40
(m, 6H), 1.14 (d, 3H, J = 6.4 Hz), 1.13 (d, 3H, J = 6.4 Hz); 13C NMR
(100 MHz, CDCl3, for 9f) δ 172.0, 86.6, 79.3, 42.7, 40.7, 37.8, 34.7, 32.4,
24.7, 23.0, 22.8; FT-IR (film) 3279, 2971, 2954, 2934, 2894, 2863, 1646,
1541, 1467, 1456, 1447, 1380, 1362, 1339, 1327, 1307, 1290, 1251, 1207,
1168, 1157, 1128, 1109, 1070, 1052, 1019 cmꢀ1; HRMS (FAB) m/z
calcd for C11H20NO2 [M + H]+ 198.1494, found 198.1498.
(()-(2S,3aR,6aR)-Methyl Hexahydro-2H-cyclopenta[b]
furan-2-carboxylate (9b). To a solution of bromolactone 6b (17.7mg,
80.8 μmol) in MeOH (2 mL) was added K2CO3 (11.2 mg, 80.8 μmol).
The reaction mixture was stirred for 2 h before addition of saturated
NH4Cl solution. The resulting mixture was extracted with EtOAc, and
the organic layer was washed with brine, dried over anhydrous MgSO4,
and concentrated. The residue was purified by flash column chroma-
tography (hexane/EtOAc = 5) to give a 7:1 inseparable mixture of esters
9b and 10b (10.7 mg, 62.9 μmol, 78%). The analytical samples were
obtained by repeated flash column chromatography. 9b: colorless oil; 1H
NMR (400 MHz, CDCl3) δ 4.73 (br t, 1H, J = 5.2 Hz), 4.54 (dd, 1H, J =
7.6, 4.8 Hz), 3.73 (s, 3H), 2.74ꢀ2.66 (m, 1H), 2.31ꢀ2.24 (m, 1H),
1.94ꢀ1.82 (m, 2H), 1.73ꢀ1.39 (m, 5H); 13C NMR (100 MHz, CDCl3)
δ 173.9, 86.7, 77.8, 52.1, 42.3, 37.9, 34.3, 32.8, 24.1; FT-IR (film) 2952,
2868, 1752, 1737, 1452, 1436, 1364, 1309, 1273, 1206, 1133, 1108, 1090,
1047, 1028 cmꢀ1; HRMS (FAB) m/z calcd for C9H15O3 [M + H]+
171.1021, found 171.0977. 10b: 1H NMR (300 MHz, CDCl3) δ 4.47 (t,
1H, J = 5.4 Hz), 4.23 (dd, 1H, J = 9.6, 6.6 Hz), 3.74 (s, 3H), 2.73ꢀ2.64
(m, 1H), 2.46 (ddd, 1H, J = 12, 9.0, 6.3 Hz), 2.01ꢀ1.96 (m, 1H),
1.74ꢀ1.43 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 172.4, 86.6, 77.9,
52.2, 42.6, 38.1, 33.7, 32.9, 23.5. HRMS (FAB) m/z calcd for C9H15O3
[M + H]+ 171.1021, found 171.0993.
(()-(1S,5R,7S)-Methyl 6-Oxabicyclo[3.2.0]heptane-7-car-
boxylate (9c). To a solution of bromolactone 6c (27.7 mg, 0.135
mmol) in MeOH (2.7 mL) was added K2CO3 (18.7 mg, 0.135 mmol).
The reaction mixture was stirred at room temperature for 8 h before
addition of saturated NH4Cl solution. The resulting mixture was
extracted with EtOAc (2ꢁ), and the combined organic layer was washed
with brine, dried over anhydrous MgSO4, and concentrated. The residue
was purified by flash column chromatography (hexane/EtOAc = 3) to
give a 2.5:1 inseparable mixture of 9c and 3-epi-6c (4.9 mg). Yields were
calculated from the 1H NMR spectrum and determined to be 15% for 9c
and 6% for 3-epi-6c. The following data were selected from the spectra
obtained by a mixture of 9c and 3-epi-6c. 1H NMR (400 MHz, CDCl3,
(()-(3R,4aR,7aR)-3-Bromo-3-methylhexahydrocyclope-
nta[b]pyran-2(3H)-one (11). To a solution of lactone 5b (50.2 mg,
0.358 mmol) in THF (4.3 mL) was added LiN(TMS)2 (1.0 M solution
in THF, 428 μL, 0.428 mmol) at ꢀ78 °C. The mixture was stirred
at ꢀ78 °C for 1.5 h, followed by the addition of HMPA (186 μL,
1.07 mmol), and the stirring was continued for 30 min at ꢀ78 °C. After
addition of CH3I (133 μL, 2.14 mmol), the reaction mixture was allowed
to warm to room temperature and stirred for 1.5 h. The reaction
mixture was quenched with water and extracted with Et2O (2ꢁ). The
combined organic layer was washed with brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by flash column
chromatography (hexane/EtOAc = 5) to give the methylated lactone
(36.9 mg, 0.239 mmol, 67%) and its C3-epimer (0.4 mg, 2.6 μmol,
0.7%). Colorless oil; 1H NMR (300 MHz, CDCl3) δ 4.83 (dt, 1H, J =
6.6, 3.3 Hz), 2.62ꢀ2.50 (m, 1H), 2.39ꢀ2.29 (m, 1H), 2.03ꢀ1.75 (m,
6H), 1.63ꢀ1.53 (m, 2H), 1.27 (d, 3H, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl3) δ 175.3, 84.6, 35.3, 35.1, 31.7, 31.4, 29.8, 23.3, 16.5; FT-IR
(film) 2961, 2938, 2873, 1732, 1558, 1458, 1379, 1338, 1319, 1338,
1319, 1294, 1257, 1195, 1166, 1135, 1102, 1074, 1055 cmꢀ1; HRMS
(FAB) m/z calcd for C9H15O2 [M + H]+ 155.1072, found 155.1048.
C3-epimer: colorless oil; 1H NMR (300 MHz, CDCl3) δ 4.84 (td, 1H,
J = 7.2, 4.2 Hz), 2.47ꢀ2.34 (m, 1H), 2.04ꢀ1.66 (m, 6H), 1.56ꢀ1.36
(m, 3H), 1.23 (d, 3H, J = 9.6 Hz); FT-IR (film) 2965, 2871, 1729, 1471,
1456, 1389, 1367, 1352, 1295, 1274, 1230, 1200, 1142, 1069, 1052,
1028, 1016, 1000 cmꢀ1
.
7100
dx.doi.org/10.1021/jo201064h |J. Org. Chem. 2011, 76, 7096–7103

The Journal of Organic Chemistry
ARTICLE
To a solution of the methylated lactone (74.5 mg, 0.483 mmol) in
THF (2 mL) was added LiN(TMS)2 (1.0 M solution in THF, 1.74 mL,
1.74 mmol) at ꢀ78 °C. The mixture was stirred at ꢀ78 °C for 15 min
followed by the addition of TMSCl (221 μL, 1.74 mmol). The reaction
mixture was allowed to warm to 0 °C and stirred for 30 min. The mixture
was again cooled to ꢀ78 °C followed by the addition of NBS (386 mg,
2.17 mmol) in THF (5 mL). The resulting mixture was warmed to room
temperature and stirred for 1 h. The reaction mixture was quenched
with water and extracted with Et2O (2ꢁ). The combined organic layer
was washed with brine, dried over anhydrous MgSO4 and concentrated.
The residue was purified by flash column chromatography (hexane/
EtOAc = 10) to give bromolactone 11 (87.2 mg, 0.374 mmol, 77%). 11:
colorless needles; 1H NMR (300 MHz, CDCl3) δ 5.16 (td, 1H, J = 6.6,
3.3 Hz), 2.61ꢀ2.47 (m, 2H), 2.07ꢀ1.86 (m, 3H), 1.96 (s, 3H),
1.81ꢀ1.63 (m, 2H), 1.61ꢀ1.52 (m, 1H), 1.49ꢀ1.38 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 170.1, 83.4, 53.4, 41.7, 35.8, 34.8, 32.8, 29.7,
23.6; FT-IR (film) 2956, 2873, 1738, 1445, 1380, 1361, 1291, 1281,
to give ester 14 (50.7 mg, 0.274 mmol, 72%). 14: colorless oil; 1H NMR
(300 MHz, CDCl3) δ 4.60 (t, 1H, J = 5.4 Hz), 3.73 (s, 3H), 2.80ꢀ2.70
(m, 1H), 2.13 (dd, 1H, J = 12.6, 9.0 Hz), 1.94 (dd, 1H, J = 12.6, 6.0 Hz),
1.95ꢀ1.85 (m, 1H), 1.67ꢀ1.40 (m, 5H), 1.38 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 175.1, 85.5, 84.5, 52.4, 43.6, 42.6, 34.0, 32.6, 24.1, 23.8;
FT-IR (film) 2952, 2869, 1752, 1436, 1371, 1275, 1242, 1131, 1105,
1031 cmꢀ1; HRMS (FAB) m/z calcd for C10H17O3 [M + H]+ 185.1178,
found 185.1169.
(()-(4aS,7S,7aR)-7-(Hydroxymethyl)hexahydrocyclopen-
ta[b]pyran-2(3H)-one (16)13. Iodolactone 15 (133 mg, 0.500
mmol), n-Bu4NBH4 (158 mg, 0.62 mmol), AIBN (24 mg, 0.15 mmol),
and CH3CN (1 mL) were placed in a 30 mL stainless steel autoclave.
The autoclave was closed, purged three times with CO, pressurized with
75 atm of CO, and then heated at 80 °C for 5 h. Exess CO was discharged
at room temperature. The reaction mixture was concentrated, and the
residue was purified by flash column chromatography (hexane/EtOAc =
2 f 1) to give alcohol 16 (28.1 mg, 0.165 mmol, 33%). 16: colorless oil;
1H NMR (400 MHz, CDCl3) δ 4.61 (dd, 1H, J = 7.3, 5.0 Hz), 3.74 (dd,
1H, J = 10.4, 5.6 Hz), 3.65 (dd, 1H, J = 10.4, 6.4 Hz), 2.50 (dt, 1H, J =
16.5, 4.4 Hz), 2.39ꢀ2.28 (m, 3H), 2.18ꢀ2.11 (m, 1H), 2.01ꢀ1.90 (m,
2H), 1.64ꢀ1.44 (m, 2H), 1.42ꢀ1.32 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 173.4, 84.6, 63.7, 49.1, 36.4, 30.7, 29.1, 26.2, 23.5; FT-IR
(film) δ 3414, 2945, 2872, 1727 cmꢀ1; MS (EI) m/z (rel intensity) 170
(M+, 13), 114 (100), 96 (24), 80 (20), 67 (34), 55 (29); HRMS (EI) m/
z calcd for C9H14O3 [M]+ 170.0943, found 170.0944.
1266, 1252, 1224, 1206, 1195, 1129, 1058, 1047, 1012, 1004 cmꢀ1
;
HRMS (EI) m/z calcd for C9H1479BrO2 [M + H]+ 233.0177, found
233.0155.
(()-(2S,3aR,6aR)-Methyl 2-Methylhexahydro-2H-cyclo-
penta[b]furan-2-carboxylate (12). To a solution of bromolactone
11 (42.3 mg, 0.181 mmol) in MeOH (3.6 mL) was added K2CO3 (25.0
mg, 0.181 mmol) at ꢀ78 °C. The reaction mixture was allowed to warm
to room temperature with stirring for 1 h. The reaction was quenched
with water and extracted with Et2O (2ꢁ). The combined organic layer
was washed with brine, dried over anhydrous MgSO4, and concentrated.
The residue was purified by flash column chromatography (hexane/
EtOAc = 10) to give ester 12 (22.7 mg, 0.123 mmol, 68%). 12: colorless
oil; 1H NMR (300 MHz, CDCl3) δ 4.60 (t, 1H, J = 6.0 Hz), 3.72 (s, 3H),
2.73ꢀ2.63 (m, 3H), 1.90ꢀ1.84 (m, 1H), 1.70ꢀ1.38 (m, 5H), 1.47
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.0, 85.8, 84.8, 52.3, 44.7,
42.7, 34.0, 33.2, 24.1, 23.2; FT-IR (film) 2952, 2867, 1747, 1734, 1650,
1448, 1436, 1372, 1315, 1303, 1290, 1277, 1253, 1213, 1200, 1154, 1141,
1108, 1071, 1049, 1035, 1000 cmꢀ1; HRMS (FAB) m/z calcd for
C10H17O3 [M + H]+ 185.1178, found 185.1123.
(()-(3S,4aS,7S,7aR)-3-Bromo-7-((tert-butyldimethyl-
silyloxy)methyl)hexahydrocyclopenta[b]pyran-2(3H)-one
(17). To a solution of alcohol 16 (410 mg, 2.41 mmol) and imidazole
(820 mg, 12.0 mmol) in DMF (12 mL) was added TBSCl (904 mg, 6.00
mmol). The mixture was stirred at room temperature for 2 h before
addition of hexane and saturated NH4Cl solution. The resulting mixture
was extracted with hexane (3ꢁ), and the combined organic layer was
dried over anhydrous MgSO4 and concentrated. The residue was
purified by flash column chromatography (hexane/EtOAc = 10) to give
a corresponding TBS ether (618 mg, 2.17 mmol, 90%). Colorless oil; 1H
NMR (400 MHz, CDCl3) δ 4.57 (dd, 1H, J = 7.0, 4.4 Hz), 3.69 (dd, 1H,
J = 10, 4.8 Hz), 3.60 (dd, 1H, J = 10, 4.8 Hz), 2.48 (dt, 1H, J = 16, 5.2 Hz),
2.39ꢀ2.21 (m, 3H), 2.17ꢀ2.08 (m, 1H), 1.98ꢀ1.82 (m, 2H),
1.63ꢀ1.38 (m, 3H), 0.88 (s, 9H, TBS), 0.04 (s, 6H, TBS); 13C NMR
(100 MHz, CDCl3) δ 173.3, 84.3, 63.2, 49.0, 36.6, 30.8, 29.0, 26.0, 25.8,
23.4, 18.2, ꢀ5.5, ꢀ5.4; FT-IR (film) 2952, 2930, 2858, 2710, 1746,
(()-(3S,4aR,7aR)-3-Bromo-3-methylhexahydrocyclopen-
ta[b]pyran-2(3H)-one (13). To a solution of lactone 6b (50.0 mg,
0.227 mmol) in THF (2.3 mL) was added LiN(TMS)2 (1.0 M solution
in THF, 272 μL, 0.272 mmol) at ꢀ78 °C. The mixture was stirred at
ꢀ78 °C for 1.5 h, followed by the addition of HMPA (118 μL, 0.681
mmol), and the stirring was continued for 30 min at ꢀ78 °C. After
addition of CH3I (846 μL, 1.36 mmol), the reaction mixture was allowed
to warm to room temperature and stirred for 1.3 h. The reaction mixture
was quenched with water and extracted with Et2O (2ꢁ). The combined
organic layer was washed with brine, dried over anhydrous MgSO4, and
concentrated. The residue was purified by flash column chromatography
(hexane/EtOAc = 10 f 1) to give lactone 13 (28.5 mg, 0.122 mmol,
54%) and its diastereomer 11 (6.6 mg, 0.028 mmol, 12%). 13: colorless
1471, 1463, 1434, 1388, 1361, 1321, 1251, 1177, 1067, 1017 cmꢀ1
;
HRMS (EI) m/z calcd for C15H28O3Si [M ꢀ tBu]+ 227.1103, found
227.1123.
To a solution of TBS ether (204 mg, 0.717 mmol) in THF (3 mL)
was added LiN(TMS)2 (1.0 M solution in THF, 803 μL, 0.803 mmol) at
ꢀ78 °C. The mixture was stirred at ꢀ78 °C for 5 min followed by the
addition of TMSCl (114 μL, 0.896 mmol). The reaction mixture was
warmed to 0 °C and stirred for 30 min. The mixture was again cooled to
ꢀ78 °C followed by the addition of NBS (1.06 g, 5.96 mmol) in THF
(9 mL). The resulting mixture was warmed to room temperature and
stirred for 2 h. The reaction was quenched with water and extracted with
Et2O (2ꢁ). The combined organic layer was dried over anhydrous
MgSO4 and concentrated. The residue was purified by flash column
chromatography (hexane/EtOAc = 10) to give a 5:1 inseparable
diastereomeric mixture of bromolactone 17 (246 mg, 0.652 mmol,
1
solid; H NMR (300 MHz, CDCl3) δ 4.86 (dt, 1H, J = 6.3, 4.2 Hz),
2.64ꢀ2.40 (m, 2H), 2.05ꢀ1.97 (m, 2H), 2.03 (s, 3H), 1.93ꢀ1.71 (m,
3H), 1.63ꢀ1.55 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 170.8, 84.0,
56.0, 43.3, 35.8, 34.5, 31.3, 28.9, 22.9; FT-IR (film) 2959, 2871, 1745,
1381, 1332, 1283, 1274, 1225, 1195, 1178, 1157, 1132, 1118, 1094, 1039,
1020 cmꢀ1; HRMS (FAB) m/z calcd for C9H1479BrO2 [M + H]+
233.0177, found 233.0138.
(()-(2R,3aR,6aR)-Methyl 2-Methylhexahydro-2H-cyclo-
penta[b]furan-2-carboxylate (14). To a solution of bromolactone
13 (88.8 mg, 0.381 mmol) in MeOH (7.6 mL) was added K2CO3 (52.7
mg, 0.381 mmol) at ꢀ78 °C. The mixture was allowed to warm to room
temperature with stirring for 1 h. The reaction was quenched with water
and extracted with Et2O (2ꢁ). The combined organic layer was washed
with brine, dried over anhydrous MgSO4, and concentrated. The residue
was purified by flash column chromatography (hexane/EtOAc = 5 f 2)
1
91%). 17 (dr = 5:1): colorless oil; H NMR (400 MHz, CDCl3, for
major isomer) δ 4.97 (dd, 1H, J = 7.2, 4.8 Hz), 4.46 (t, 1H, J = 3.2 Hz),
3.74 (dd, 1H, J = 10, 5.2 Hz), 3.66 (dd, 1H, J = 10, 4.4 Hz), 2.54ꢀ2.43
(m, 2H), 2.36ꢀ2.26 (m, 1H), 2.08ꢀ1.99 (m, 2H), 1.94ꢀ1.82 (m, 1H),
1.56ꢀ1.40 (m, 2H), 0.89 (s, 9H, TBS), 0.06 (s, 3H, TBS), 0.05 (s, 3H,
TBS); 13C NMR (100 MHz, CDCl3, for major isomer) δ 167.9, 84.4,
63.0, 49.8, 39.3, 33.9, 33.0, 32.1, 26.6, 26.0, 18.4, ꢀ5.32, ꢀ5.30; FT-IR
(film) 2952, 2928, 2857, 2738, 2710, 1743, 1471, 1463, 1440, 1388,
7101
dx.doi.org/10.1021/jo201064h |J. Org. Chem. 2011, 76, 7096–7103

The Journal of Organic Chemistry
ARTICLE
1361, 1299, 1254, 1201, 1146, 1103, 1078 cmꢀ1; HRMS (EI) m/z calcd
for C15H27BrO3Si [M ꢀ tBu]+ 307.0189, found 307.0157.
ꢀ5.2; FT-IR (film) 3451, 2955, 2930, 2859, 2738, 1471, 1463, 1388,
1361, 1254, 1101, 1070, 1032, 1005 cmꢀ1; HRMS (FAB) m/z calcd for
C17H35O3Si [M + H]+ 315.2355, found 315.2310.
(()-(2R,3aS,6S,6aR)-Methyl 6-((tert-Butyldimethylsilylox-
y)methyl)hexahydro-2H-cyclopenta[b]furan-2-carboxylate
(18). To a solution of bromolactone 17 (227 mg, 0.601 mmol) in
MeOH (12 mL) was added K2CO3 (83.1 mg, 0.601 mmol) at ꢀ78 °C.
The mixture was allowed to warm to room temperature with stirring for
5 h. The reaction mixture was quenched with saturated NH4Cl solution
and extracted with EtOAc (2ꢁ). The combined organic layer was dried
over anhydrous MgSO4 and concentrated. The residue was purified by
flash column chromatography (hexane/EtOAc = 10) to give a 5:1
inseparable diastereomeric mixture of ester 18 (189 mg, 0.601 mmol,
To a solution of alcohol (5.1 mg, 16 μmol) in THF (162 μL) was
added TBAF (1.0 M solution in THF, 24 μL, 24 μmol). The mixture was
stirred at room temperature for 17 h and quenched with saturated
NaHCO3 solution. The resulting mixture was extracted with Et2O (2ꢁ)
and EtOAc (3ꢁ), and the combined organic layer was dried over
MgSO4 and concentrated. The residue was purified by flash column
chromatography (EtOAc only) to give communiol E (1) (2.7 mg,
14 μmol, 83%). 1: colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.34 (dd,
1H, J = 7.6, 4.4 Hz), 3.93 (ddd, 1H, J = 10.4, 5.6, 3.6 Hz), 3.76 (td, 1H, J =
6.4, 3.2 Hz), 3.65 (dd, 1H, J = 10.8, 6.8 Hz), 3.60 (dd, 1H, J = 10.4, 7.6
Hz), 2.68 (quint, 1H, J = 8.0 Hz), 2.11ꢀ2.02 (m, 1H), 2.00ꢀ1.91 (m,
2H), 1.86ꢀ1.79 (m, 1H), 1.52 (br dd, 1H, J = 12.4, 5.6 Hz), 1.42 (quint,
2H, J = 7.6 Hz), 1.39ꢀ1.29 (m, 2H), 0.99 (t, 3H, J = 7.6 Hz); 13C NMR
(100 MHz, CDCl3) δ 88.1, 80.9, 72.8, 65.2, 50.0, 43.1, 31.8, 31.3, 28.6,
25.9, 10.6; FT-IR (film) 3367, 2957, 2939, 2872, 1465, 1448, 1374, 1304,
1234, 1146, 1074, 1044, 1019 cmꢀ1; HRMS (FAB) m/z calcd for
C11H21O3 [M + H]+ 201.1491, found 201.1523.
1
100%). 18 (dr = 5:1): colorless oil; H NMR (400 MHz, CDCl3, for
major isomer) δ 4.53 (t, 1H, J = 7.2 Hz), 4.49 (dd, 1H, J = 7.2, 2.8 Hz),
3.74 (s, 3H, OMe), 3.60 (dd, 1H, J = 10, 5.2 Hz), 3.52 (dd, 1H, J = 10, 6.4
Hz), 2.74ꢀ2.62 (m, 1H), 2.20ꢀ2.13 (m, 2H), 2.02ꢀ1.74 (m, 3H),
1.55ꢀ1.34 (m, 2H), 0.88 (s, 9H, TBS), 0.03 (s, 6H, TBS); 13C NMR
(100 MHz, CDCl3, for major isomer) δ 173.7, 88.9, 77.3, 64.2, 52.2,
49.0, 42.7, 37.5, 31.5, 28.0, 26.1, 18.5, ꢀ5.3; FT-IR (film) δ 2952, 2931,
2882, 2858, 2361, 1757, 1740, 1471, 1463, 1437, 1388, 1362, 1255, 1205,
1154, 1094, 1006 cmꢀ1; HRMS (EI) m/z calcd for C16H30O4Si [M ꢀ
tBu]+ 257.1209, found 257.1194.
’ ASSOCIATED CONTENT
(()-(2R,3aS,6S,6aR)-6-((tert-Butyldimethylsilyloxy)me-
thyl)hexahydro-2H-cyclopenta[b]furan-2-carbaldehyde
(19). To a solution of ester 18 (81.9 mg, 0.260 mmol) in CH2Cl2
(2.6 mL) was added DIBAL (1.04 M solution in hexane, 275 μL, 0.286
mmol) at ꢀ78 °C. After stirring for 40 min at ꢀ78 °C, the reaction
mixture was treated with hexane and saturated Rochelle salt solution.
The resulting mixture was stirred at room temperature for 3 h and
extracted with Et2O (2ꢁ). The combined organic layer was dried over
anhydrous MgSO4 and concentrated. The residue was purified by flash
column chromatography (hexane/EtOAc = 10 f 3) to give a 5:1
inseparable diastereomeric mixture of aldehyde 19 (70.7 mg, 0.249
mmol, 96%). 19: colorless oil; 1H NMR (300 MHz, CDCl3, for major
isomer) δ 9.64 (d, 1H, J = 1.8 Hz), 4.43 (dd, 1H, J = 6.6, 2.7 Hz), 4.33
(td, 1H, J = 7.5, 1.8 Hz), 3.56 (d, 2H, J = 6.3 Hz), 2.72ꢀ2.61 (m, 1H),
2.21ꢀ2.16 (m, 1H), 2.08 (dt, 1H, J = 12.6, 8.1 Hz), 1.99ꢀ1.77 (m, 3H),
1.52ꢀ1.35 (m, 2H), 0.88 (s, 9H, TBS), 0.04 (s, 6H, TBS); 13C NMR
(100 MHz, CDCl3, for major isomer) δ 203.0, 89.6, 83.4, 64.6, 49.6,
43.2, 34.7, 31.9, 28.6, 26.4, 18.8, ꢀ4.95, ꢀ4.97; FT-IR (film) 3410, 2952,
2930, 2885, 2858, 2802, 2738, 2711, 1736, 1558, 1541, 1471, 1463, 1388,
1361, 1255, 1101, 1074, 1007 cmꢀ1; HRMS (EI) m/z calcd for
C15H28O3Si [M ꢀ tBu]+ 227.1103, found 227.1132.
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra for all new synthetic compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: koba@chem.oit.ac.jp.
’ ACKNOWLEDGMENT
This work was supported in part by a Grant-in-Aid for
Scientific Research on Innovative Areas (No. 2105) from MEXT
and KAKENHI (22550115) from the JSPS.
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alcohol (11.3 mg, 0.0363 mmol, 47%) and a mixture of other stereoisomers
(5.3 mg, 0.017 mmol, 22%). Colorless oil; 1H NMR (400 MHz, CDCl3)
δ 4.31 (dd, 1H, J = 6.8, 3.6 Hz), 3.90 (ddd, 1H, J = 10.4, 5.2, 3.2 Hz),
3.78ꢀ3.72 (m, 1H), 3.61 (dd, 1H, J = 10, 5.6 Hz), 3.54 (dd, 1H, J = 10,
6.4 Hz), 2.64 (quint, 1H, J = 7.6 Hz), 2.10ꢀ2.01 (m, 2H), 1.98ꢀ1.89
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7102
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The Journal of Organic Chemistry
ARTICLE
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7103
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