Additive Tuned Selective Synthesis of Bicyclo[3.3.0]octan-1-ols and Bicyclo[3.1.0]hexan-1-ols Mediated by AllylSmBr

Article abstract of DOI:10.1021/acs.joc.8b01170

The selective construction of bicyclo[3.3.0]octan-1-ols and bicyclo[3.1.0]hexan-1-ols was achieved by using an allylSmBr/additive(s) system. By employing HMPA as the only additive, the momoallylation/ketone-alkene coupling occurred preferably and afforded bicyclo[3.3.0]octan-1-ols in good yields with high diastereoselectivities. While the ester-alkene coupling predominated to generate bicyclo[3.1.0]hexan-1-ols in moderate yields with excellent diastereoselectivities in the presence of a proton source, such as pyrrole as the coadditive with HMPA. The tunable reactivity of allylSmBr by additive(s) would make it a versatile reagent in organic synthesis.

Full text of DOI:10.1021/acs.joc.8b01170

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Article
Additive tuned Selective Synthesis of Bicyclo[3.3.0]octan-1-
ols and Bicyclo[3.1.0]hexan-1-ols Mediated by AllylSmBr
Xiaoxia Wang, Jianyong Li, Ting Yuan, Bingxin You, Guanqun Xie, and Xin Lv
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01170 • Publication Date (Web): 26 Jun 2018
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Additive Tuned Selective Synthesis of Bicyclo[3.3.0]octan-1-ols and
Bicyclo[3.1.0]hexan-1-ols Mediated by AllylSmBr
Xiaoxia Wang,*a,b Jianyong Li,b Ting Yuan,b Bingxin You,b Guanqun Xie,a,b Xin
Lv*b
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aSchool of Environment and Civil Engineering, Dongguan University of Technology,
Dongguan, 523808, People’s Republic of China
bCollege of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004,
People’s Republic of China
E-mail: wangxx@dgut.edu.cn (X. X. Wang); lvxin@zjnu.cn (X. Lv)
R2
R1
H
H
R1
R2
allylSmBr/HMPA
THF, r.t.
allylSmBr/HMPA/pyrrole
THF, 5 o
C
OH
O
HO
= H, R2 = aryl; or
= H, R2 = aryl
R2
R1
R1
R1
O
= aryl, R2 = H
Abstract: The selective construction of bicyclo[3.3.0]octan-1-ols and
bicyclo[3.1.0]hexan-1-ols was achieved by using allylSmBr/additive(s) system. By
employing HMPA as the only additive, the momoallylation/ketone-alkene coupling
occurred preferably and afforded bicyclo[3.3.0]octan-1-ols in good yields with high
diastereoselectivities. While the ester-alkene coupling predominated to generate
bicyclo[3.1.0]hexan-1-ols in moderate yields with excellent diastereoselectivities in
the presence of a proton source, such as pyrrole as the co-additive with HMPA. The
tunable reactivity of allylSmBr by additive(s) would make it a versatile reagent in
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organic synthesis.
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Introduction
Divalent samarium reagents1 especailly SmI2 have played important roles in organic
and natural products synthesis due to the unique single-electron transfer (SET)
property for C-C bond formation reactions. New Applications2 of the reductive
coupling reactions as well as new types of coupling reactions1c,3 promoted by the
divalent samarium reagents continue to emerge.
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On the other hand, allylsamarium bromide (allylSmBr) represents a typical
divalent organosamarium reagent, which has been well known as an efficient
C-nucleophilic reagent for the allylation of a variety of compounds.4 However, the
potential of allylSmBr to act as a SET reagent has long been neglected despite the
reagent’s inclination to revert to the more stable Sm(III) oxidation state. Although a
number of additives1j have been found to enhance or tune the reactivity of SmI2 to
various extent or even switch the reaction pathways,5 only in recent years, certain
additives were found to be able to switch allylSmBr from a nucleophilic species into a
SET reagent. For example, allylSmBr combined with MeOH could achieve the
reductive dehalogenation of α-haloketones and α-haloesters.6 With MeOH or H2O as
additive, a variety of carbonyl compounds could undergo the pinacol coupling
promoted by allylSmBr, instead of being transformed into homoallylic alcohols.7
Furthermore, the unique reductive coupling ability of allylSmBr has been
demonstrated by using HMPA/H2O8 or HMPA/CuCl2.2H2O9 as co-additives, thus the
homoallylic esters were transformed into 2-(2-hydroxyalkyl)cyclopropanols and
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2‑(2-hydroxyethyl)bicycle [2.1.1]hexan-1-ols in moderate to good yields with good to
excellent diastereoselectivities. In addition, allylSmBr/HMPA/CH3SO3H system has
recently been applied in the preparation of oxobicyclo[3.1.0]hexane-1-ols via the
“ester-alkene” coupling/cyclization cascade of α-allyloxy esters.10
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The distinctive utility of allylsamarium bromide both as a nucleophilic reagent
and a single-electron transfer reagent in one pot has been reported by Zhang’s group.
Treatment of α-halo, γ-halo-α,β-unsaturated ketones or esters with allylSmBr
afforded 1,4-dienes and trienes in good to excellent yields2 via the Grignard reaction
followed by reductive removal of the halogen and oxygen at the same time.
Alternatively, the nucleophilic addition to the carbonyl compounds followed by
deoxygenation by allylSmBr/diethyl phosphate system provided a facile synthesis of
terminal olefins.11
Despite the above reports, the factors that may influence the reactivity of
allylSmBr as for its nuclophilicity or reductivity are not well known and further study
concerning the applications of the reagent in organic synthesis are still worth
exploring.
Results and Discussion
The survey began with 2-phenyl-hex-5-enoate 1a as the model substrate where an
ester group was included for either nucleophilic addition or reductive coupling. Firstly,
HMPA was used as the only additive (Table 1, entries 1-4). To the allylSmBr/THF
solution prepared in situ was added HMPA and 1a sequentially. The reaction mixture
was allowed to stir at rt until the disappearance of 1a. Unexpectedly 2a was obtained
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as the major product together with the isolation of the diallylation products 3a in 18 %
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yield (Scheme 1).
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Scheme 1. Formation of 2a as the major product with HMPA as the only additive
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OH
allylSmBr/HMPA
+
O
THF, rt
HO
O
2a
3a
1a
18%
66%
The structure of 2a has been characterized by NMR and HRMS determination
and also unambiguously ascertained by deriving into its ester of 3,5-dinitrobenzoic
acid (2a′, 79% yield) followed by single crystal diffraction analysis (Figure 1).12
Figure 1. The X-ray crystal structure of 2′a
The mechanism for the formation of 2a was then probed. By comparison with
the 13C-NMR data of 1a, three additional carbons were found to have been included in
2a. It is reasonable to deduce that the three carbons came from allylSmBr.
Accordingly, a possible mechanism was proposed in Scheme 2. The allylation of 1a
with the allylSmBr in the presence of HMPA would first generate intermediate III.
Under the circumstances, a second allylation of III by the allylSmBr/HMPA complex
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would afford 4a, or alternatively the allylSmBr/HMPA complex may function as an
electron donor to trigger the ketyl-alkene coupling of III thus converting the carbonyl
into a ketyl (IV and V). The isolation of 2a as the major product indicated the
ketyl-alkene coupling of intermediate III was preferred rather than being further
allylated. V underwent subsequent cascade radical cyclization via the chair-like
transition state would afford the predominant diastereomer 2a with the phenyl, the
hydroxyl and the methyl pointing at the same direction. The minor diastereomer of 2a
could be formed form the less preferential transition state with the methyl being anti-
to the phenyl and hydroxyl.
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Scheme 2. Proposed mechanism for the formation of 2a
Ph
HO
SmBr
3a
L
L
MeOSmBr
II
SmBr
L
LSm(II)
OMe
Ph
MeO
Ph
Ph
Ph
SmBr
L
O
O
O
OSm(III)
III
I
1a
V
Ph
Ph
OSm(III)
(III)SmO
Sm(III)
TS1
Sm(II)
TS2
Ph
Ph
Ph
OSm(III)
VIII
OSm(III)
OSm(III)
OSm(III)
VI
VII
workup
Ph
Ph
Ph
OSm(III)
2a
(Minor diastereomer)
OH
VII'
2a
(Major diastereomer)
To further rationalize the mechanism, authentic sample III was synthesized13 and
subjected to the allylSmBr/HMPA (2.2 equiv/8.8 equiv) system to examine the
ketone-alkene coupling reaction.14 The isolation of 2a in 60% yield (Scheme 3)
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provided a reasonable support to the proposed mechanism.
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Scheme 3. Generation of 2a from III
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H
OH
allylSmBr/HMPA
+
THF, r.t.
HO
Ph
dr = 92:8
O
3a
2a,
III
26%
60%
It is interesting to observe the coordination of HMPA has enhanced the SET
property of allylSmBr to such an extent that the ketyl-alkene coupling predominated
over the second alllylation of intermediate III. On the other hand, the reducing power
of allylSmBr/HMPA was not strong enough to trigger the “ester-alkene” coupling
since the momoallylation occurred prior to the reduction of ester. Based on the
elucidation on the formation of 2a, a variety of conditions were further examined for
preparative purposes and also to demonstrate the influences of other additives on the
nucleophilicity/reducibility of the reagent (Table 1).
Table 1. Reaction of 1a with AllylSmBr Under Various Conditionsa
allylSmBr/HMPA
OH
+
+
O
Ph
Ph
Ph
Ph
HO
HO
co-additive, THF, temp.
O
1a
3a
2a
4a
Entry
allylSmBr (equiv)/
HMPA(equiv)
3.3/16
Co-additive
(equiv)
Temp
(oC)
r.t.
0 oC
Yield
Yield
of 3ab
18
Yield
of 4ab
-
of 2ab
none
66
1
3.3/16
none
70
14
-
2
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3.3/16
4.4/20
2.2/8
none
-20
r.t.
55
26
-
3
none
78
Trace
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4
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none
r.t.
35
48
94%
0
trace
trace
52
5
3.3/0
none
r.t.
0
6
3.3/16
3.3/16
3.3/16
3.3/16
3.3/16
3.3/16
3.3/16
3.3/16
3.3/16
H2O (1.6)
H2O (1.6)c
H2O (3.0)
MeOH (1.6)
CuCl2∙2H2O (1.6)
r.t.
r.t
trace
40
7
0
51
8
r.t.
r.t.
r.t.
r.t.
r.t.
5 oC
-5 oC
trace
trace
trace
trace
trace
trace
trace
0
trace
37d
43 d
41d
55d
65d
53e
9
0
10
11
12
13
14
15
0
NH
HCl
NH2
0
H2N
(1.6)
H
N
0
(1.6)
(1.6)
H
N
0
H
N
0
(1.6)
aReaction conditions: 1a (1 mmol) was added to the mixture of allylSmBr (3.3 eq), HMPA (16 eq)
and co-additive (1.6 eq) in dry THF (30 mL). The reaction mixture was stirred at rt for 12 h under
b
c
N2 unless otherwise specified. Isolated yield. A mixture of 1a and H2O (1.6 eq) was added
dropwise to the allylSmBr (3.3 eq)/HMPA (16 eq) mixture. d2-Methyl-5-phenylcyclopentanol and
e
1
other unidentified by-products mixture were observed by crude H NMR. Reaction time: 24 h;
Starting 1a recovered in 21% yield and unidentified by-products were also detected.
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The investigation showed lowering the temperature to 0 C afforded a slightly
better yield of 2a. However, decrease of the temperature to -20 oC would otherwise be
beneficial for the formation of 3a (Table 1, entries 2 and 3). The employment of
excess allylSmBr/HMPA (4.4 equiv/20 equiv) led to improved yield of 2a (78%, entry
4). On the contrary, decrease in the loading of allylSmBr/HMPA (2.2 equiv/8 equiv)
would sharply lower the yield of 2a while the yield of 3a was increased (entry 5). The
results indicate the divalent samarium species II should not be the reductive coupling
reagent, and allylSmBr/HMPA was indispensable for the efficient ketone-alkene
coupling. Control experiment showed in the absence of HMPA, allylSmBr was
strongly nucleophilic and its reaction with 1a would give the diallylated 3a almost
quantitatively (Table 1, entry 6). Besides, it is interesting to find the coexistence of
H2O (1.6 equiv) would afford 4a as the major product, following an “ester-alkene”
coupling cascade cyclization.8,9 At the same time, 2a was only formed in a trace
amount (Table 1, entry 7) and 3a was not observed, indicating the reducing potential
of allylSmBr may be further facilitated by the co-existence of the proton source and at
the same time its nucleophilicity was further diminished. When a mixture of 1a and
H2O was added dropwise to the allylSmBr/HMPA, a mixture of 2a (40%) and 4a
(51%) was obtained and again the formation of 3a was not observed (entry 8).
However, increase the loading of H2O to 3.0 equiv was destructive and almost no
reaction occurred under the conditions (Table 1, entry 9). Other proton sources such
as MeOH, CuCl2·2H2O and guanidine hydrochloride were less effective than H2O,
except pyrrole, which afforded slightly better yield (entry 13). Lowering the
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temperature to 5 oC afforded a synthetically useful 65% yield of 4a (entry 14). Further
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decrease of the temperature to -5 C led to sluggish reaction and prolonging the
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9
reaction time to 24 h resulted in 53 % yield of the desired 2a, 21% recovery of the
starting materials and other unidentified by-products (entry 15).
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According to the above observations, a variety of substrates 1 were tested under
the optimized conditions (Talbe 1, entry 14) to explore the synthetic utility of the
allylSmBr/HMPA mediated monoallylation/reductive cyclization cascade. As shown
in Scheme 4, substrates 1a-1p underwent the reaction smoothly and the desired
bicyclo[3.3.0]octan-1-ols 2 were prepared in good to moderate yields. Good to
excellent diastereoselectivities were also observed. The halogen such as chloro and
bromo is well tolerated despite the strong reducing conditions. Ortho-substituion of
the aryl ring also showed good reactivity (2d, 2f and 2h). Generally, when R1 is an
electron-rich aryl, the reaction afforded better yields than their counterparts with
withdrawing aryl group. Notably the hydroxyl group could be tolerated (2o and 2p).
Thus the allylSmBr/HMPA mediated addition/coupling cascade of hex-5-enoates
afforded a facile synthesis of bicyclo[3.3.0]octan-1-ols. However, the attempt to
involve an heteroatom such as O- or N-in the bicyclo[3.3.0]octan-1-ol failed (2q, 0%;
2r, 0%). When substrate 1s, a more-substituted alkene structure was included, the
desired 2s was not obtained either. On the other hand, an unexpected product 2s′ was
isolated in 28% yield. The formation of 2s′ is not clear at the stage, nevertheless the
monoallylation and ketone-alkene coupling in a different way undoubtedly occurred.
The result indicates a more difficult ketone-alkene coupling when the alkene is more
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substituted.
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Scheme 4. Preparation of Bicyclo[3.3.0]octan-1-olsa
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R3
R2
R2
R1
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H
allylSmBr/HMPA
THF, r.t.
R1
O
= H HO
= H
, R3
R' = aryl, R2
(major diastereomer)
O
1
2
, R3
or R2 = aryl, R1
H
H
H
H
HO
HO
HO
HO
, 78%, dr = 92:8
, 84%, dr =88:12
, 85%, dr = 97:3
H
, 74%, dr = 89:11
H
2a
2b
2c
2d
H
H
HO
HO
Br
HO
Cl
HO
Br
Cl
, 64%, dr = 92:8
, 55%, dr = 94:6
, 63%, dr = 96:4
, 61%, dr = 96:4
2h
2f
2g
2e
H
H
H
H
HO
OH
HO
OH
O
MeO
, 62%, dr = 95:5
H
, 69%, dr = 87:13
, 73%, dr = 89:11
, 71%, dr = 89:11
2j
2k
2l
2i
H
H
H
OH
OH
OH
, 51%, dr = 81:19
HO
HO
OH
F
Cl
, 48%, dr = 79:21
, 54%, dr = 81:19
2p
2o
2n
, 58%, dr > 99:1
2m
O
N
HO
_
HO
HO
_
b
, 28%
,
,
b
2s'
2q
2r
3 = Me
, , R
= H
R' = Ph, R2
aReaction conditions: a mixture of substrate 1 (1 mmol), allylSmBr (4.0 eq) and HMPA (20
eq) in dry THF (30 mL) was stirred at rt for 12 h under N2. Isolated yields were reported.
bComplicated mixture.
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The substrates 1 were then treated with allylSmBr/HMPA/pyrrole at 5 oC for the
preparation of bicyclo[3.1.0]hexan-1-ols 4. Usually only one diastereomer was
observed, showing excellent diastereoselectivity. In view of the analogous mechanism
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for
the
formation
of
bicyclo[3.1.0]hexan-1-ols
4
and
oxobicyclo[3.1.0]hexane-1-ols,9the stereochemistry of 4 was tentatively designated
and the results were listed in Scheme 5.
Substrates with R1 being an aryl generally afforded the desired 4 in good yields
except 1j, which afforded a mixture of 4j and 4j′. Surprisingly, 1k with R2 being the
phenyl afforded a complicated mixture. Substrate 1q and 1r, where the β-carbon
substituted
by an
heteroatom,
afforded
moderate
yields
of
the
oxobicyclo[3.1.0]hexane-1-ol 4q and azabicyclo[3.1.0]hexane-1-ol 4r. Substrte 1s
afforded complicated mixture, from which the major product was isolated and
characterized as 4s′ (25 % yield). The desired ester-alkene coupling did proceed
although the desired 4s was not obtained with additional substitution on the C=C
bond.
It is worth mentioning that the switch of reactivity of allylSmBr to generate 4
could be well accounted for by the proton coupled electron transfer (PCET)
mechanism.15 Only in the presence of a coordinating proton source, the reduction of
the unactiviated ester is likely and the ester-alkene coupling could occur. Hoz and
Flowers recently demonstrated a range of amines have high affinity of Sm(II).16 It is
possible that pyrrole in the presence of the basic HMPA also has high affinity with
Sm(II) and therefore afforded relatively better result for the production of 4 than other
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proton sources examined.
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Scheme 5. Preparation of Bicyclo[3.1.0]hexan-1-olsa
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R3
H
R2
R1
allylSmBr/HMPA/pyrrole
OH
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+
OH
THF,5 o
C
R2
R2
O
R1
= H
, R3
R1
4'
R' = aryl, R2
= H
O
, R3
or R2 = aryl, R1
4
1
H
H
H
H
HO
HO
HO
HO
4ba
4ca
4da
, 63%
, 68%
, 70%
4aa
, 65%
H
H
H
H
HO
HO
HO
Cl
MeO
HO
16%b
Br
4ga
4ia
, 54%
, 72%
4fa
, 55%
4j,
O
H
N
H
OH
HO
OH
, 25%
HO
, -
c
, 41%, dr = 81:19
c
4k
, 46%
4q
4s'
4r
= H, R3 = Me
R' = Ph, R2
a
Reaction conditions: a mixture of substrate 5 (1 mmol), allylSmBr (3.3 eq), HMPA (16 eq) and
H2O (1.6 eq) in dry THF (30 mL) was stirred at 5 oC for 12 h under N2. Isolated yields were given.
bTogether with 0.11 g of inseparable mixture of 4j and 4j′ (4j: 4j′. = 1.5:1, determined by
1HNMR). cComplicated mixture.
Conclusions
In conclusion, HMPA was found to moderately tuning up the reducing power while
tuning down the nucleophilic ability of allylSmBr. With HMPA as the additive, the
hex-5-enoates afforded bicyclo[3.3.0]octan-1-ols in moderate to good yields via the
intermolecular monoallylation/intramolecular ketyl-alkene coupling cascade, which is
unprecedented for the Sm(II) reagent. Preparation of the bicyclo[3.3.0]octan-1-ols
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with versatile substitution patterns from the readily available hex-5-enoates make the
approach advantageous as compared with the alternative methods via the Barbier
reaction of δ-iodocyclopentanone17 or ketone/alkene coupling of olefinic
cyclopentanones promoted by SmI2/HMPA.14a, b On the other hand, the co-existence
of a proton source was found to greatly enhance the reducing power while
diminishing the nucleophilicity of allylSmBr at the same time, as was demonstrated
by the fact that the hex-5-enoates preferred to undergo the ester-alkene coupling
cascade and produced bicyclo[3.1.0]hexan-1-ols as the major products. Synthetically,
the latter reaction was less attractive since the Kulinkovich reactions18 could afford
better yields of bicyclo[3.1.0]hexan-1-ols from the same substrates. Further studies
concerning further tuning the nucleophilicity and reductivity of the divalent
organosamarium reagent is still underway in our lab.
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Experimental Section
General Information. Metallic samarium and other solvents were obtained from
commercial sources, and used without further purification, if not stated otherwise.
THF was distilled from sodium/benzophenone. Unless otherwise noted, all the
cascade reactions were carried out under a nitrogen atmosphere in oven-dried flasks.
All melting points are uncorrected. The NMR spectra were recorded in CDCl3 on a
400 M Hz or 600 M Hz instrument with TMS as internal standard. Chemical shifts (δ)
were reported in parts per million (ppm) downfield from TMS. Data are represented
as follows: chemical shift, mutiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, b = broad), coupling constant (J, Hz) and integration. Thin layer
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chromatography (TLC) was performed with 0.2 mm thick silica gel plates (GF 254).
Visualization was accomplished by UV light or by using phospho molybdate as the
chromogenic reagent. The columns were hand packed with silica gel (200–300 mesh).
Unknown products were additionally confirmed by high-resolution mass spectra
(HRMS) using a TOF-MS instrument with ESI or APCI ionization. Compound 1a19 is
known compound and was prepared using method A;20 Compounds 1k21 is known
compound and was prepared using method B.22 Compounds 1o23 is a known
compound and was prepared using method C.24 Substrate 1q is a known compound
and was prepared according to the literature.10
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General procedure for the preparation of substrates 1
Substrates 1a-1j were prepared using method A.20 To a 0 °C solution of iPr2NH (1
mL, 6.6 mmol) in THF (30 mL) was added n-BuLi (2.5 M in Et2O, 2.6 mL, 6.6 mmol)
dropwise. The reaction mixture was stirred for 10 minutes, and then cooled to -78 °C.
The respective methyl arylacetate (6.0 mmol) in THF (2 mL) was added dropwise,
and the reaction mixture was stirred for 30 min. The 4-bromobut-1-ene (0.972 g, 7.2
mmol) was added in THF (2 mL) followed by HMPA (0.6 mL, 3.7 mmol). It was then
warmed to room temperature and stirred overnight. The reaction was diluted with 1:1
Et2O :Hexanes, washed with sat. aq. NH4Cl and brine, dried (MgSO4), and
concentrated in vacuo. Purification by column chromatography (20:1 Hex: EtOAc)
afforded 1a-1j and 1s as pure compounds. 1b-1j and 1s are new compounds.
1
Methyl 2-phenylhex-5-enoate (1a).19 Oil (1.05 g, 86% yield); H NMR (400 MHz,
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CDCl3) δ 7.34–7.23 (m, 5H), 5.83–5.73 (m, 1H), 5.03–4.96 (m, 2H), 3.64 (s, 3H),
3.58 (t, J = 7.6 Hz, 1H), 2.24–2.14 (m, 1H), 2.01 (dd, J = 14.4, 6.8 Hz, 2H), 1.92–1.83
(m, 1H).
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Methyl 2-(p-tolyl)hex-5-enoate (1b). Oil (1.22 g, 93% yield); H NMR (600 MHz,
CDCl3) δ 7.18 (d, J = 7.6 Hz, 2H), 7.11 (d, J = 7.6 Hz, 2H), 5.83–5.70 (m, 1H),
5.02–4.94 (m, 2H), 3.61 (s, 3H), 3.56–3.53 (m, 1H), 2.30 (s, 3H), 2.19–2.12 (m, 1H),
13
2.01 (dd, J = 9.8, 4.2 Hz, 2H), 1.88–1.82 (m, 1H); C NMR (151 MHz, CDCl3) δ
174.3, 137.4, 136.7, 135.8, 129.2, 127.7, 115.2, 51.7, 50.1, 32.3, 31.3, 20.9; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C14H19O2 219.1380; Found: 219.1383.
1
Methyl 2-(m-tolyl)hex-5-enoate (1c). Oil (1.18 g, 90% yield); H NMR (600 MHz,
CDCl3) δ 7.20-7.17 (m, 1H), 7.10-7.04 (m, 3H), 5.83–5.70 (m, 1H), 5.02–4.94 (m,
2H), 3.61 (s, 3H), 3.55–3.52 (m, 1H), 2.30 (s, 3H), 2.19–2.12 (m, 1H), 2.01 (dd, J =
9.8, 4.2 Hz, 2H), 1.88–1.82 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 174.3, 138.8,
138.1, 137.5, 128.5, 128.4, 127.9, 124.9, 115.2, 51.7, 50.6, 32.4, 31.4, 21.3; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C14H19O2 219.1380; Found: 219.1381.
1
Methyl 2-(o-tolyl)hex-5-enoate (1d). Oil (1.14 g, 87% yield); H NMR (600 MHz,
CDCl3) δ 7.32-7.30 (m, 1H), 7.18–7.11 (m, 3H), 5.87–5.70 (m, 1H), 5.06–4.94 (m,
2H), 3.87 (t, J = 7.0 Hz, 1H), 3.62 (s, 3H), 2.37 (s, 3H), 2.24–2.19 (m, 1H), 2.08–2.02
(m, 2H), 1.85–1.81 (m, 1H); 13C NMR (151 MHz, CDCl3) δ 174.4, 137.6, 137.4,
135.9, 130.4, 126.8, 126.6, 126.3, 115.2, 51.7, 45.8, 32.0, 31.5, 19.6; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C14H19O2 219.1380; Found: 219.1382.
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Methyl 2-(3-chlorophenyl)hex-5-enoate (1e). Oil (1.29 g, 90% yield); H NMR (400
MHz, CDCl3) δ 7.29 (s, 1H), 7.24–7.15 (m, 3H), 5.84–5.70 (m, 1H), 5.02–4.96 (m,
2H), 3.65 (s, 3H), 3.55 (t, J = 7.6 Hz, 1H), 2.21–2.11 (m, 1H), 2.03–1.97 (m, 2H),
1.89–1.81 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 173.7, 140.8, 137.1, 134.4, 129.8,
128.1, 127.4, 126.2, 115.6, 52.0, 50.3, 32.3, 31.3; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C13H16ClO2 239.0833; Found: 239.0830.
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Methyl 2-(2-chlorophenyl)hex-5-enoate (1f). Oil (1.30 g, 91% yield); H NMR (600
MHz, CDCl3) δ 7.36-7.34 (m, 2H), 7.23–7.14 (m, 2H), 5.80–5.74 (m, 1H)), 5.02–4.94
(m, 2H), 4.17 (t, J = 7.5 Hz, 1H), 3.64 (s, 3H), 2.22–2.14 (m, 1H), 2.09–1.98 (m, 2H),
1.89–1.82 (m, 1H); 13C NMR (151 MHz, CDCl3) δ 173.6, 137.3, 136.7, 133.9, 129.6,
128.6, 128.2, 127.0, 115.3, 52.0, 46.5, 31.8, 31.3; HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C13H16ClO2 239.0833; Found: 239.0834.
1
Methyl 2-(3-bromophenyl)hex-5-enoate (1g). Oil (1.49 g, 88% yield); H NMR (400
MHz, CDCl3) δ 7.46 (s, 1H), 7.41–7.36 (m, 1H), 7.24–7.15 (m, 2H), 5.81–5.70 (m,
1H), 5.05–4.95 (m, 2H), 3.65 (s, 3H), 3.54 (t, J = 7.6 Hz, 1H), 2.22–2.11 (m, 1H),
13
2.00 (dd, J = 14.1, 7.1 Hz, 2H), 1.89–1.79 (m, 1H); C NMR (101 MHz, CDCl3) δ
173.6, 141.1, 137.1, 131.0, 130.4, 130.1, 126.6, 122.6, 115.6, 52.0, 50.3, 32.3, 31.3;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H16BrO2 283.0328; Found: 283.0330.
1
Methyl 2-(2-bromophenyl)hex-5-enoate (1h). Oil (1.39 g, 82% yield); H NMR (600
MHz, CDCl3) δ 7.56 (dd, J = 8.0, 1.2 Hz, 1H), 7.37-7.35 (m, 1H), 7.29–7.26 (m, 1H),
7.12–7.08 (m, 1H), 5.82– 4.75 (m, 1H), 5.06–4.94 (m, 2H), 4.18 (t, J = 7.4 Hz, 1H),
3.66 (s, 3H), 2.19–2.13 (m, 1H), 2.12–2.06 (m, 1H), 2.05–1.98 (m, 1H), 1.89–1.83 (m,
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1H); C NMR (151 MHz, CDCl3) δ 173.7, 138.5, 137.4, 133.0, 128.7, 128.6, 127.7,
124.7, 115.4, 52.0, 49.2, 32.2, 31.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C13H16BrO2 283.0328; Found: 283.0323.
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Methyl 2-(4-methoxyphenyl)hex-5-enoate (1i). Oil (1.22 g, 87% yield); 1H NMR (600
MHz, CDCl3) δ 7.22-7.18 (m, 2H), 6.85–6.83 (m, 2H), 5.79–5.73 (m, 1H), 5.01–4.95
(m, 2H), 3.75 (s, 3H), 3.62 (s, 3H), 3.52 (t, J = 7.0 Hz, 1H), 2.16–2.11 (m, 1H), 1.99
13
(dd, J = 14.4, 7.1 Hz, 2H), 1.87-1.85 (m, 1H); C NMR (151 MHz, CDCl3) δ 174.4,
158.6, 137.4, 130.7, 128.7, 115.1, 113.8, 54.9, 51.6, 49.6, 32.3, 31.2; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C14H19O3 235.1329; Found: 235.1326.
1
Methyl 2-(naphthalen-1-yl)hex-5-enoate (1j). Oil (1.28 g, 84% yield); H NMR (600
MHz, CDCl3) δ 8.24–8.22 (m, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.2 Hz, 1H),
7.62 (dd, J = 8.3, 7.0 Hz, 2H), 7.56–7.51 (m, 2H), 5.96–5.87 (m, 1H), 5.15–5.09 (m,
2H), 4.56–4.50 (m, 1H), 3.70 (s, 3H), 2.54–2.47 (m, 1H), 2.26–2.17 (m, 2H),
2.16–2.09 (m, 1H); 13C NMR (151 MHz, CDCl3) δ 174.4, 137.4, 135.2, 133.9, 131.4,
128.8, 127.6, 126.2, 125.5, 125.4, 124.8, 123.0, 115.4, 51.8, 45.7, 32.1, 31.7; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H19O2 255.1380; Found: 255.1381.
1
Methyl 5-methyl-2-phenylhex-5-enoate (1s). Oil (0.93 g, 71% yield); H NMR (600
MHz, CDCl3) δ 7.31–7.27 (m, 4H), 7.24–7.21 (m, 1H), 4.73 (s, 1H), 4.66 (d, J = 0.7
Hz, 1H), 3.62 (s, 3H), 3.55 (t, J = 7.5 Hz, 1H), 2.26–2.20 (m, 1H), 2.00–1.86 (m, 3H),
1.69 (s, 3H); 13C NMR (151 MHz, CDCl3) δ 174.2, 144.4, 138.9, 128.5, 127.8, 127.1,
110.6, 51.7, 50.7, 35.3, 31.2, 22.1; HRMS (APCI-TOF) m/z: [M + H]+ Calcd for
C14H19O2 219.1380; Found: 219.1381.
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Substrates 1k-1n were prepared using method B.22
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A reaction vessel containing 4Å molecular sieves (1.0 g) was flame-dried under
vacuum and placed under N2. A solution of anhydrous TBAF (0.2 g, 0.77 mmol; 1.0
M in THF) was then added. The respective methyl cinnamate (6 mmol) dissolved
DMF (10 mL) was then added. A solution of HMPA (3.31 g, 18.5 mmol) and freshly
distilled allylsilane (2.05 g, 18 mmol) in DMF (20 mL) was then added dropwise to
the reaction vessel at rt. Coloration occurred immediately. After 10 min, TLC analysis
revealed that reaction was complete. After methanolysis of the reaction mixture using
10 mL of 1M HCl in methanol, the reaction mixture was diluted with 200 mL of water.
Workup afforded the residue, which was purified by column chromatography to afford
the corresponding 1k-1n. 1l-1n are new compounds.
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Methyl 3-phenylhex-5-enoate (1k).21 Oil (0.89 g, 73% yield); H NMR (400 MHz,
CDCl3) δ 7.31–7.25 (m, 2H), 7.21–7.16 (m, 3H), 5.70–5.60 (m, 1H), 5.03–4.92 (m,
2H), 3.56 (s, 3H), 3.27–3.16 (m, 1H), 2.69 (dd, J = 15.4, 6.7 Hz, 1H), 2.57 (dd, J =
15.4, 8.3 Hz, 1H), 2.42–2.34 (m, 2H).
Methyl 3-(4-methoxyphenyl)hex-5-enoate (1l). Oil (1.12 g, 80% yield); 1H NMR (600
MHz, CDCl3) δ 7.10 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 5.68–5.61 (m, 1H),
5.00–4.95 (m, 2H), 3.76 (s, 3H), 3.56 (s, 3H), 3.20–3.13 (m, 1H), 2.66 (dd, J = 15.3,
6.6 Hz, 1H), 2.53 (dd, J = 15.3, 8.5 Hz, 1H), 2.36 (t, J = 7.1 Hz, 2H); 13C NMR (151
MHz, CDCl3) δ 172.7, 158.1, 136.0, 135.5, 128.2, 116.7, 113.7, 55.0, 51.3, 40.9,
40.64, 40.55; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H19O3 235.1329; Found:
235.1325.
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Methyl 3-(4-chlorophenyl)hex-5-enoate (1m). Oil (1.06 g, 74% yield); H NMR (600
MHz, CDCl3) δ 7.25–7.22 (m, 2H), 7.11–7.08 (m, 2H), 5.65–5.55 (m, 1H), 4.99–4.94
(m, 2H), 3.55 (s, 3H), 3.21–3.15 (m, 1H), 2.66 (dd, J = 15.6, 6.4 Hz, 1H), 2.51 (dd, J
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= 15.6, 8.7 Hz, 1H), 2.34 (t, J = 7.1 Hz, 2H); C NMR (151 MHz, CDCl3) δ 172.4,
141.9, 135.4, 132.1, 128.7, 128.5, 117.1, 51.4, 41.1, 40.4, 40.1; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C13H16ClO2 239.0833; Found: 239.0838.
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Methyl 3-(4-fluorophenyl)hex-5-enoate (1n). Oil (0.95 g, 71% yield); H NMR (400
MHz, CDCl3) δ 7.20–7.11 (m, 2H), 6.99-6.95 (m, 2H), 5.68–5.58 (m, 1H), 5.01–4.96
(m, 2H), 3.57 (s, 3H), 3.28–3.14 (m, 1H), 2.68 (dd, J = 15.4, 6.4 Hz, 1H), 2.53 (dd, J
13
= 15.4, 8.6 Hz, 1H), 2.36 (t, J = 7.2 Hz, 2H); C NMR (101 MHz, CDCl3) δ 172.5,
161.5 (d, J = 245.4 Hz), 139.2 (d, J = 3.2 Hz), 135.6, 128.8 (d, J = 7.8 Hz), 117.0,
115.2 (d, J = 21.2 Hz), 51.4, 41.0, 40.6, 40.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C13H16FO2 223.1129; Found: 223.1132.
Substrates 1o and 1p were prepared using method C.24
To a mixture of ethyl 3-oxobutanoate (or methyl 3-oxo-4-phenylbutanoate) (5.7 mmol)
and allyl bromide (2.1 g, 17.2 mmol) in 30 mL of MeOH/0.1 N HCl (1:4) was added
indium powder (1.98 g, 17.2 mmol) in one portion. The reaction mixture was
stoppered and stirred vigorously at rt for 10 hr. The reaction was then quenched by the
addition of 1N HCl and extracted with ether (4 × 10 mL). Drying over Na2SO4 and
removal of the solvent afforded a residue, which was purified by column
chromatography to afford the corresponding 1o and 1p. 1p is a new compound.
Ethyl 3-hydroxy-3-methylhex-5-enoate (1o).23 Oil (0.85g, 87% yield); H NMR (600
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MHz, CDCl3) δ 5.95–5.73 (m, 1H), 5.12–5.03 (m, 2H), 4.20–4.12 (m, 2H), 3.84 (s, br,
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1H), 2.51–2.38 (m, 2H), 2.32–2.26 (m, 2H), 1.28–1.20 (m, 6H).
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Methyl 3-benzyl-3-hydroxyhex-5-enoate (1p). Oil (1.09g, 82% yield); H NMR (600
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MHz, CDCl3) δ 7.28–7.19 (m, 5H), 5.95–5.88 (m, 1H), 5.19–5.03 (m, 2H), 3.65 (s, br,
1H), 3.63 (s, 3H), 2.84 (q, J = 13.7 Hz, 2H), 2.41 (dd, J = 48.3, 15.9 Hz, 2H),
2.38–2.25 (m, 2H); 13C NMR (151 MHz, CDCl3) δ 173.1, 136.7, 133.4, 130.5, 127.9,
126.4, 118.6, 72.7, 51.4, 45.6, 44.2, 41.4; HRMS (ESI-TOF) m/z: [M + H − H2O]+
Calcd for C14H17O2 217.1223; Found: 217.1222.
Substrates 1q was prepared using method D.25
To a solution of the methyl 2-hydroxy-2-phenylacetate (9.0 mmol) in ether (50 mL)
was added allyl bromide (1.2 mL, 13.5 mmol) and silver oxide (4.2 g, 18.0 mmol)
under an atmosphere of nitrogen. The mixture was refluxed for 2 hours and then
stirring was continued for 48 hours at room temperature. The silver salts were
removed by filtration, washed with ether (50 mL) and the solvent was removed in
vacuo to give the residue. Purification by chromatography on silica gel (200–300
mesh) using petroleum ether/EtOAc (25/1, v : v) as eluent afforded the pure 1q.
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Methyl 2-(allyloxy)-2-phenylacetate (1q).10 Oil (1.39 g, 75% Yield). H NMR (600
MHz, CDCl3) δ 7.48–7.40 (m, 2H), 7.41–7.34 (m, 3H), 5.98–5.94 (m, 1H), 5.31 (dd, J
= 17.2, 1.6 Hz, 1H), 5.25 (dd, J = 10.3, 1.3 Hz, 1H), 4.97 (s, 1H), 4.08–4.07 (m, 2H),
3.74–3.71 (m, 3H).
Substrates 1r was prepared using method E.26
To a solution of benzylamine (3.4 mL, 31.2 mmol) and NaI (22.8 mg, 0.15 mmol)
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in DMSO (20 mL) was added dropwise 3-bromopropene (1.32 mL, 15.24 mmol) via a
syringe at 0 °C. After stirring for 18 h at room temperature, to the reaction mixture
was added 1M aqueous NaHCO3 (36 mL), and the aqueous layer was extracted with
Et2O (5 × 20 mL). The combined organic layer was washed with brine (20 mL), dried
over anhydrous MgSO4 and filtered. The solution was concentrated in vacuo followed
by silica gel flash column chromatography (eluent; n-hexane/ethyl acetate = 8/1) to
provide N-benzyl-2-propenylamine as yellow oil (1.1 g, 48%).
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To a suspension of N-allyl benzylamine (1.1 g, 7.48 mmol) and K2CO3 (2.06 g,
14.9 mmol) in CH3CN (20 mL) was added methyl bromoacetate (0.90 mL, 8.58 mmol)
and the resultant solution stirred for 20 h. The reaction mixture was poured into sat.
NaHCO3 (30 mL) and extracted with CH2Cl2. The combined organic phases were
dried (MgSO4) and concentrated. Purification by chromatography (pentane:EtOAc 6:1)
provided 1r (1.29 g, 78%) as a colorless oil
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Methyl 2-(allyl(benzyl)amino)acetate (1r). H NMR (600 MHz, CDCl3) δ 7.35–7.29
(m, 4H), 7.26–7.22 (m, 1H), 5.91–5.84 (m, 1H), 5.24–5.13 (m, 2H), 3.77 (s, 2H), 3.67
(s, 3H), 3.32 (s, 2H), 3.27 (d, J = 6.5 Hz, 2H); 13C NMR (151 MHz, CDCl3) δ 171.7,
138.5, 135.4, 128.9, 128.2, 127.0, 117.9, 57.7, 56.8, 53.4, 51.2; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C13H18NO2 220.1332; Found: 220.1336.
General procedures for the preparation of bicyclo[3.3.0]octan-1-ols 2
An oven-dried two-necked flask (50 mL) containing finely powdered samarium
(0.75 g, 5 mmol) was evacuated and backfilled with N2 for three times. Under a
positive pressure of nitrogen, a solution of allylBr (0.38 mL, 4.4 mmol) in dry THF
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(30 mL) was added via a syringe, and a grain of iodine was then added. The mixture
was allowed to stir at rt for 1 h (the mixture color was deep purple). HMPA (3.4 mL,
16 mmol) was then added followed by addition of a solution of substrate 1 (1 mmol)
in dry THF (3 mL) via a syringe. The reaction mixture was stirred at rt until the
completion of the reaction (monitored by TLC). The reaction was quenched by a sat.
potassium sodium tartrate solution (5 mL). The mixture was extracted by ethyl acetate
(3 × 15 mL). The combined extracts were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by chromatography on
silica gel (200–300 mesh) using petroleum/EtOAc (10/1, v : v) as eluent to afford the
corresponding product 2a-2p and 2s′. Compound 3 was obtained with the procedure
described above except that HMPA was not added.
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2-Methyl-4-phenyloctahydropentalen-3a-ol (2a). Oil (0.168 g, 78% yield); H NMR
(600 MHz, CDCl3) δ 7.26–7.34 (m, 5H), 2.73 (dd, J = 13.2, 5.4 Hz, 1H), 2.40 (q, J =
9.0 Hz, 1H), 2.12–2.17 (m, 2H), 2.03 – 2.08 (m, 1H), 1.97 (dd, J = 12.6, 5.4 Hz, 1H),
1.84–1.88 (m, 1H), 1.55–1.60 (m, 1H), 1.49–1.52 (m, 1H), 1.10–1.21 (m, 3H), 1.04 (d,
J = 6.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 139.4, 129.2, 128.4, 126.9, 90.4, 56.5,
51.5, 48.6, 40.7, 33.6, 32.7, 31.1, 19.4; HRMS (ESI-TOF) m/z: [M + H − H2O]+ Calcd
for C15H19 199.1481; Found: 199.1480.
2-Methyl-4-(p-tolyl)octahydropentalen-3a-ol (2b). Oil (0.193 g, 84% yield); major: 1H
NMR (600 MHz, CDCl3) δ 7.25–7.19 (m, 4H), 2.76 (dd, J = 13.3, 5.4 Hz, 1H),
2.43–2.36 (m, 1H), 2.32 (s, 3H), 2.17–2.09 (m, 2H), 2.08–1.99 (m, 1H), 1.98–1.94 (m,
1H), 1.85–1.81 (m, 1H), 1.60–1.53 (m, 2H), 1.23 (s, br, 1H), 1.21–1.08 (m, 2H), 1.04
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(d, J = 6.5 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 136.4, 136.1, 129.00, 128.97, 90.1,
56.0, 51.3, 48.5, 40.6, 33.4, 32.6, 31.1, 21.0, 19.3; HRMS (ESI-TOF) m/z: [M + H −
H2O]+ Calcd for C16H21 213.1638; Found: 213.1636.
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Minor: H NMR (600 MHz, CDCl3) δ 7.25–7.19 (m, 4H), 2.88–2.85 (m, 1H),
2.43–2.36 (m, 1H), 2.32 (s, 3H), 2.26–2.22 (m, 1H), 2.17–2.09 (m, 2H), 2.08–1.99 (m,
1H), 1.78–1.68 (m, 2H), 1.43–1.38 (m, 1H), 1.21–1.08 (m, 2H), 1.01 (d, J = 6.5 Hz,
3H); 13C NMR (151 MHz, CDCl3) δ 136.3, 136.2, 129.1, 128.3, 91.4, 56.6, 54.0, 50.5,
43.9, 37.6, 33.2, 31.3, 19.5, 19.3.
2-Methyl-4-(m-tolyl)octahydropentalen-3a-ol (2c). Oil (0.196 g, 85% yield); 1H NMR
(600 MHz, CDCl3) δ 7.25 – 7.29 (m, 1H), 7.11 – 7.16 (m, 3H), 2.76 (dd, J = 13.2, 5.4
Hz, 1H), 2.45 (q, J = 9.0, 1H), 2.41 (s, 3H), 2.17 – 2.22 (m, 2H), 2.10 – 2.15 (m, 1H),
2.03 (dd, J = 12.0, 5.4 Hz, 1H), 1.88 – 1.92 (m, 1H), 1.60 – 1.66 (m, 1H), 1.54 – 1.57
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(m, 1H), 1.32 (s, br, 1H), 1.16 – 1.24 (m, 2H), 1.10 (d, J = 6.0 Hz, 3H); C NMR
(150 MHz, CDCl3) δ 139.3, 137.9, 123.0, 128.3, 127.7, 126.3, 90.3, 56.4, 51.5, 48.6,
40.7, 33.6, 32.8, 31.1, 21.5, 19.4; HRMS (ESI-TOF) m/z: [M + H − H2O]+ Calcd for
C16H21 213.1638; Found: 213.1639.
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2-Methyl-4-(o-tolyl)octahydropentalen-3a-ol (2d). Oil (0.17 g, 74% yield); major: H
NMR (600 MHz, CDCl3) δ 7.38-7.36 (m, 1H), 7.22–7.10 (m, 3H), 3.12 (dd, J = 12.8,
5.4 Hz, 1H), 2.45–2.36 (m, 4H), 2.22–2.12 (m, 2H), 2.06–1.99 (m, 1H), 1.88–1.79 (m,
2H), 1.59 (dd, J = 21.6, 11.3 Hz, 1H), 1.52 (dd, J = 12.0, 6.0 Hz, 1H), 1.39 (s, 1H),
1.27–1.19 (m, 1H), 1.15 (t, J = 12.1 Hz, 1H), 1.04 (d, J = 6.4 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 137.9, 136.8, 130.8, 129.2, 126.4, 125.8, 90.9, 51.4, 50.5, 48.8, 40.8,
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33.7, 33.1, 32.8, 20.7, 19.5; HRMS (ESI-TOF) m/z: [M + H − H2O]+ Calcd for C16H21
213.1638; Found: 213.1636.
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Minor: 1H NMR (600 MHz, CDCl3) δ 7.38-7.36 (m, 1H), 7.22–7.10 (m, 3H), 3.21 (dd,
J = 11.7, 5.8 Hz, 1H), 2.45–2.36 (m, 4H), 2.22–2.12 (m, 2H), 2.06–1.99 (m, 1H),
1.74–1.71 (m, 2H), 1.59 (dd, J = 21.6, 11.3 Hz, 1H), 1.52 (dd, J = 12.0, 6.0 Hz, 1H),
1.36 (s, 1H), 1.27–1.19 (m, 1H), 1.15 (t, J = 12.1 Hz, 1H), 1.00 (d, J = 6.4 Hz, 3H).
4-(3-Chlorophenyl)-2-methyloctahydropentalen-3a-ol (2e). Oil (0.153 g, 61% yield);
1H NMR (600 MHz, CDCl3) δ 7.25 – 7.34 (m, 4H), 2.74 (dd, J = 13.2, 5.4 Hz, 1H),
2.42-2.38 (m, 1H), 2.12 – 2.17 (m, 2H), 2.05 – 2.08 (m, 1H), 1.97 – 2.00 (m, 1H),
1.84 – 1.88 (m, 1H), 1.55 – 1.61 (m, 1H), 1.49 – 1.52 (m, 1H), 1.21 – 1.10 (m, 3H),
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1.05 (d, J = 6.0 Hz, 3H); C NMR (150 MHz, CDCl3) δ 139.4, 129.2, 128.6, 128.4,
127.9, 126.93, 90.4, 56.5, 51.5, 48.6, 40.7, 33.6, 32.7, 31.1, 19.3; HRMS (ESI-TOF)
m/z: [M + H − H2O]+ Calcd for C15H18Cl 233.1092; Found: 233.1096.
4-(2-Chlorophenyl)-2-methyloctahydropentalen-3a-ol (2f). Oil (0.138 g, 55% yield);
1H NMR (600 MHz, CDCl3) δ 7.24 – 7.34 (m, 4H), 2.73 (dd, J = 13.2, 5.4 Hz, 1H),
2.40 (q, J = 9.0 Hz, 1H), 2.12 – 2.17 (m, 2H), 2.03 – 2.09 (m, 1H), 1.98 (dd, J = 12.0,
5.4 Hz, 1H), 1.84 – 1.88 (m, 1H), 1.55 – 1.61 (m, 1H), 1.49 – 1.52 (m, 1H), 1.10 –
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1.22 (m, 3H), 1.05 (d, J = 6.6 Hz, 3H); C NMR (151 MHz, CDCl3) δ 139.4, 129.2,
128.4, 126.9, 90.4, 56.5, 51.5, 48.6, 40.7, 33.6, 32.7, 31.1, 19.4; HRMS (ESI-TOF)
m/z: [M + H − H2O]+ Calcd for C15H18Cl 233.1092; Found: 233.1090.
4-(3-Bromophenyl)-2-methyloctahydropentalen-3a-ol (2g). White solid (0.186 g, 63%
yield), mp 48–49oC; 1H NMR (400 MHz, CDCl3) δ 7.24 – 7.35 (m, 4H), 2.74 (dd, J =
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31.1, 19.3; HRMS (ESI-TOF) m/z: [M + H − H2O]+ Calcd for C15H18Br 277.0586;
Found: 277.0588.
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4-(2-Bromophenyl)-2-methyloctahydropentalen-3a-ol (2h). Oil (0.189 g, 64% yield);
1H NMR (400 MHz, CDCl3) δ 7.27 – 7.39 (m, 4H), 2.78 (dd, J = 13.2, 5.4 Hz, 1H),
2.44 (q, J = 8.8 Hz, 1H), 2.00 – 2.22 (m, 4H), 1.87 – 1.93 (m, 1H), 1.52 – 1.68 (m,
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2H), 1.14 – 1.24 (m, 3H), 1.08 (d, J = 6.4 Hz, 3H); C NMR (100 MHz, CDCl3) δ
139.4, 129.2, 128.5, 128.44, 128.35, 126.9, 90.4, 56.4, 51.5, 48.6, 40.7, 33.6, 32.7,
31.1, 19.3; HRMS (ESI-TOF) m/z: [M + H − H2O]+ Calcd for C15H18Br 277.0586;
Found: 277.0589.
4-(4-Methoxyphenyl)-2-methyloctahydropentalen-3a-ol (2i). Oil (0.175 g, 71% yield);
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major: H NMR (600 MHz, CDCl3) δ 7.26 (d, J = 8.2 Hz, 3H), 6.92 (d, J = 8.2 Hz,
2H), 3.83 (s, 3H), 2.73 (dd, J = 13.3, 5.4 Hz, 1H), 2.41 (q, J = 9.3 Hz, 1H), 2.18–2.15
(m, 2H), 2.05–1.98 (m, 1H), 1.98–1.92 (m, 1H), 1.85–1.81 (m, 1H), 164–1.52 (m, 2H),
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1.22 (s, br, 1H), 1.20–1.08 (m, 2H), 1.04 (d, J = 6.5 Hz, 3H); C NMR (151 MHz,
CDCl3) δ 158.6, 131.3, 130.0, 113.8, 90.0, 55.6, 55.2, 51.2, 48.5, 40.6, 33.4, 32.6,
31.2, 19.3; HRMS (ESI-TOF) m/z: [M + H − H2O]+ Calcd for C16H21O 229.1587;
Found: 229.1588.
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Minor: H NMR (600 MHz, CDCl3) δ 7.26 (d, J = 8.2 Hz, 3H), 6.92 (d, J = 8.2 Hz,
2H), 3.83 (s, 3H), 2.86 (dd, J = 12.9, 5.5 Hz, 1H), 2.41 (q, J = 9.3 Hz, 1H), 2.18–2.15
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(m, 2H), 2.05–1.98 (m, 1H), 1.98–1.92 (m, 1H), 1.75–1.73 (m, 2H), 1.42–1.38 (m,
1H), 1.20–1.08 (m, 2H), 1.01 (d, J = 6.5 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ
158.4, 131.3, 129.4, 113.8, 91.3, 56.2, 54.0, 50.5, 43.9, 37.6, 33.42, 33.37, 31.3, 19.5.
2-Methyl-4-(naphthalen-1-yl)octahydropentalen-3a-ol (2j). White solid (0.165 g, 62%
yield), mp 97–98oC; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 1H), 7.85 (d,
J = 8.5 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.45 – 7.55 (m, 4H), 3.75 (dd, J = 12.5, 5.5
Hz, 1H), 2.48 – 2.53 (m, 1H), 2.32 – 2.38 (m, 1H), 2.19 – 2.27 (m, 2H), 1.99 (dd, J =
12.5, 5.5 Hz, 1H), 1.89 – 1.93 (m, 1H), 1.60 – 1.66 (m, 2H), 1.31 – 1.37 (m, 2H), 1.04
– 1.09 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 135.6, 134.2, 132.9, 129.0, 127.2,
126.7, 126.0, 125.4, 125.2, 123.5, 90.4, 51.4, 49.1, 47.9, 40.8, 33.8, 33.1, 32.7, 19.5;
HRMS (ESI-TOF) m/z: [M + H − H2O]+ Calcd for C19H21 249. 1638; Found: 249.
1641.
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2-Methyl-5-phenyloctahydropentalen-3a-ol (2k). Oil (0.149 g, 69% yield); H NMR
(400 MHz, CDCl3) δ 7.23 – 7.35 (m, 5H), 3.26 – 3.33 (m, 1H), 2.37 –2.44 (m, 2H),
2.04 – 2.26 (m, 3H), 1.74 – 1.80 (m, 2H), 1.55 – 1.59 (m, 1H), 1.30 – 1.41 (m, 2H),
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1.08 (d, J = 6.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 143.9, 128.3, 127.0, 126.1,
90.5, 52.4, 50.13, 50.08, 44.4, 42.8, 40.2, 33.3, 19.2; HRMS (APCI-TOF) m/z: [M +
H − H2O]+ Calcd for C15H19 199.1481; Found: 199.1482.
2-(4-Methoxyphenyl)-5-methyloctahydropentalen-3a-ol (2l). White solid (0.18 g, 73%
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yield), mp 63–64oC; major: H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.6 Hz, 2H),
6.83 (d, J = 8.6 Hz, 2H), 3.78 (s, 3H), 3.27–3.14 (m, 1H), 2.39–2.29 (m, 2H), 2.17 (dd,
J = 13.0, 5.8 Hz, 1H), 2.11–1.92 (m, 2H), 1.76–1.65 (m, 2H), 1.53–1.50 (m, 1H),
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1.32–1.26 (m, 2H), 1.04 (d, J = 6.3 Hz, 3H); C NMR (101 MHz, CDCl3) δ 157.9,
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136.0, 127.7, 113.7, 90.4, 55.2, 52.4, 50.2, 50.1, 43.5, 43.0, 40.1, 37.0, 19.1; HRMS
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(ESI-TOF) m/z: [M + H − H2O]+ Calcd for C16H21O 229.1587; Found: 229.1583.
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Minor: H NMR (400 MHz, CDCl3) δ 7.16 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz,
2H), 3.78 (s, 3H), 3.46–3.38 (m, 1H), 2.39–2.29 (m, 2H), 2.17 (dd, J = 13.0, 5.8 Hz,
1H), 2.11–1.92 (m, 2H), 1.76–1.65 (m, 2H), 1.53–1.50 (m, 1H), 1.32–1.26 (m, 2H),
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1.02 (d, J = 6.3 Hz, 3H); C NMR (101 MHz, CDCl3) δ 157.9, 136.0, 127.7, 113.7,
91.4, 55.3, 52.4, 50.7, 49.8, 47.0, 43.0, 42.2, 33.2, 19.2.
2-(4-Chlorophenyl)-5-methyloctahydropentalen-3a-ol (2m). Oil (0.146 g, 58% yield);
1H NMR (600 MHz, CDCl3) δ 7.27 (d, J = 7.2 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 3.23
– 3.27 (m, 1H), 2.35 – 2.42 (m, 2H), 2.21 (dd, J = 12.6, 4.8 Hz, 1H), 2.03 – 2.10 (m,
2H), 1.78 (s, br, 1H), 1.72–1.70 (m, 1H), 1.54 – 1.59 (m, 2H), 1.28 – 1.34 (m, 2H),
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1.07 (d, J = 5.4 Hz, 3H); C NMR (150 MHz, CDCl3) δ 142.4, 131.6, 128.4, 128.3,
90.4, 52.4, 50.1, 50.0, 43.75, 42.8, 40.1, 33.3, 19.1; HRMS (ESI-TOF) m/z: [M + H −
H2O]+ Calcd for C15H18Cl 233.1092; Found: 233.1093.
2-(4-Fluorophenyl)-5-methyloctahydropentalen-3a-ol (2n). Oil (0.126 g, 54% yield);
1H NMR (400 MHz, CDCl3) δ 7.18 – 7.23 (m, 2H), 6.97 – 7.01 (m, 2H), 3.21 – 3.29
(m, 1H), 2.33 – 2.43 (m, 2H), 2.18 – 2.23 (m, 1H), 2.02 – 2.11 (m, 2H), 1.66 – 1.77
(m, 2H), 1.53 – 1.57 (m, 2H), 1.27 – 1.36 (m, 2H), 1.07 (d, J = 6.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 161.2 (d, J = 245.1 Hz), 139.4 (d, J = 3.5 Hz), 128 (d, J =7.9
Hz), 115.0 (d, J = 20.9 Hz), 90.4, 52.4, 50.2, 50.1, 43.6, 42.9, 40.1, 33.3, 19.1; HRMS
(APCI-TOF) m/z: [M + H − H2O]+ Calcd for C15H18F 217.1387; Found: 217.1384.
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2,5-Dimethyloctahydropentalene-2,3a-diol (2o). Oil (0.082 g, 48% yield); major: H
NMR (600 MHz, CDCl3) δ 3.31 (s, br, 1H), 2.74 (s, br, 1H), 2.53 (q, J = 9.0 Hz, 1H),
2.14–2.10 (m, 1H), 1.92–1.84 (m, 3H), 1.64–1.62 (m, 1H), 1.57–1.52 (m, 1H), 1.40
(dd, J = 12.6, 5.7 Hz, 1H), 1.35 (s, 3H), 1.31–1.20 (m, 2H), 1.01 (d, J = 6.1 Hz, 3H);
13C NMR (151 MHz, CDCl3) δ 91.3, 81.3, 54.0, 51.3, 49.2, 48.0, 40.0, 32.8, 26.1,
19.0; HRMS (ESI-TOF) m/z: [M + H − H2O]+ Calcd for C10H17O 153.1274; Found:
153.1275.
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Minor: H NMR (600 MHz, CDCl3) δ 3.26 (s, br, 1H), 2.95 (s, br, 1H), 2.53 (q, J =
9.0 Hz, 1H), 2.37–2.29 (m, 2H), 2.14–2.10 (m, 1H), 2.02–1.93 (m, 3H), 1.64–1.62 (m,
1H), 1.35 (s, 3H), 1.31–1.20 (m, 2H), 0.98 (d, J = 6.5 Hz, 3H); 13C NMR (151 MHz,
CDCl3) δ 92.3, 84.3, 54.8, 54.1, 48.0, 44.0, 37.2, 32.8, 26.7, 19.3.
2-Benzyl-5-methyloctahydropentalene-2,3a-diol (2p). Oil (0.125 g, 51% yield); major:
1H NMR (600 MHz, CDCl3) δ 7.32–7.18 (m, 5H), 3.06 (s, 1H), 2.89–2.83 (m, 2H),
2.46 (q, J = 9.2 Hz, 1H), 2.05 (s, br, 1H), 2.03–1.98 (m, 1H), 1.97–1.82 (m, 3H),
1.74-1.72 (m, 1H), 1.67–1.47 (m, 1H), 1.41–1.38 (m, 1H), 1.32–1.25 (m, 2H), 1.01 (d,
J = 6.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 137.5, 130.0, 128.3, 126.6, 90.4, 83.3,
52.4, 50.9, 47.8, 47.2, 45.9, 40.0, 32.7, 18.9; HRMS (ESI-TOF) m/z: [M + H − H2O]+
Calcd for C16H21O 229.1587; Found: 229.1585.
Minor: 1H NMR (600 MHz, CDCl3) δ 7.32–7.18 (m, 5H), 3.06 (s, 1H), 2.89–2.83 (m,
2H), 2.34–2.29 (m, 2H), 2.03–1.98 (m, 1H), 1.97–1.82 (m, 3H), 1.72 (t, J = 13.8 Hz,
1H), 1.67–1.47 (m, 1H), 1.41–1.38 (m, 1H), 1.32–1.25 (m, 1H), 1.20–1.16 (m, 1H),
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0.97 (d, J = 6.5 Hz, 1H); C NMR (151 MHz, CDCl3) δ 137.4, 130.0, 128.3, 126.6,
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3,4-Dimethyl-2-(4-methyl-1-phenylpent-4-en-1-yl)cyclopentanol (2s′). Oil (0.075 g,
28% yield); 1H NMR (600 MHz, CDCl3) δ 7.34–7.27 (m, 5H), 4.70 (s, 1H), 4.61 (d, J
= 0.7 Hz, 1H), 2.53 (dd, J = 11.0, 3.4 Hz, 1H), 2.15 (dd, J = 13.5, 7.6 Hz, 1H),
2.07–1.91 (m, 6H), 1.80 (d, J = 8.2 Hz, 1H), 1.69 (s, 3H), 1.53 (dd, J = 13.4, 5.6 Hz,
1H), 1.45 (s, br, 1H), 1.17 (dd, J = 13.7, 6.5 Hz, 1H), 0.99 (d, J = 6.9 Hz, 3H), 0.94 (d,
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J = 6.8 Hz, 3H); C NMR (151 MHz, CDCl3) δ 145.9, 141.9, 129.5, 128.3, 126.7,
110.1, 84.3, 56.1, 47.8, 47.2, 37.4, 37.2, 36.1, 28.0, 22.6, 15.62, 15.59; HRMS
(APCI-TOF) m/z: [M + H − H2O]+ Calcd for C19H27 255.2107; Found: 255.2112.
4-Allyl-5-phenylnona-1,8-dien-4-ol (3a). Oil (0.241g, 94% yield); 1H NMR (400 MHz,
CDCl3) δ 7.32–7.22 (m, 5H), 5.86–5.73 (m, 3H), 5.16–5.10 (m, 3H), 5.04–5.01 (m,
1H), 4.91–4.87 (m, 2H), 2.72–2.70 (m, 1H), 2.34–2.31 (m, 2H), 2.18–2.15 (m, 1H),
2.09–2.06 (m, 1H), 1.97–1.84 (m, 3H), 1.72–1.69 (m, 1H), 1.52 (br, s, 1H); 13C NMR
(151 MHz, CDCl3) δ 140.6, 138.5, 133.9, 133.8, 129.9, 128.1, 126.6, 118.61, 118.55,
114.6, 75.2, 52.3, 42.1, 41.5, 32.0, 28.1; HRMS (ESI-TOF) m/z: [M + H − H2O]+
Calcd for C18H23 239.1794; Found: 239.1797.
Typical procedures for the preparation of the ester 2a′27
2-Methyl-4-phenyloctahydropentalen-3a-ol (2a) (0.216 g, 1 mmol) is mixed with
3,5-dinitrobenzoyl chloride (0.461g, 2 mmol) in chilled pyridine (0.8 mL, 10 equiv)
and allowed to react for 6 h at rt. The reaction mixture was poured into cold water and
extracted with Et2O (3 × 20 mL). The organic phase was dried over anhydrous sodium,
and concentrated under reduced pressure. The residue was purified by
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