Synthesis of bicyclic γ-butyrolactone derivatives by rhodium catalyzed intramolecular C-H insertion of α-dizao α-phosphoryl cycloalkyl esters

Article abstract of DOI:10.1016/j.tet.2016.02.008

Under the catalysis of Rh₂(OAc)₄, several readily prepared cycloalkyl α-diazo α-phosphoryl esters undergo a intramolecular C-H insertion reaction to afford the fused bicyclic α-phosphoryl-γ-butyrolactones in varying yields (10%-80%) and dr ratios (69:14:17 to >99:1). The experimental results reveal that the reactivity of the precursors and the diastereoselectivity of the cyclization are both influenced by the ring sizes of the cycloalkyl moieties. Moreover, most of the resulting products can be further elaborated into α,α-dialkyl γ-butyrolactones via a two-step alkylation/reductive alkylation sequence with the controlled installation of two alkyl groups to the lactones. In addition, application of Horner-Wadsworth-Emmons (HWE) olefination reaction to the insertion products allows an access to bicyclic α-alkylidene-γ-butyrolactone ring systems that occur ubiquitously in biologically active natural products and synthetic molecules.

Full text of DOI:10.1016/j.tet.2016.02.008

Tetrahedron 72 (2016) 1590e1601
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of bicyclic
g
-butyrolactone derivatives by rhodium
catalyzed intramolecular CeH insertion of a-dizao a-phosphoryl
cycloalkyl esters
*
Jr-Yun Shie, Jia-Liang Zhu
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Under the catalysis of Rh2(OAc)4, several readily prepared cycloalkyl
dergo a intramolecular CeH insertion reaction to afford the fused bicyclic
olactones in varying yields (10%e80%) and dr ratios (69:14:17 to >99:1). The experimental results reveal
that the reactivity of the precursors and the diastereoselectivity of the cyclization are both influenced by
the ring sizes of the cycloalkyl moieties. Moreover, most of the resulting products can be further elab-
a
-diazo
a
-phosphoryl esters un-
-phosphoryl- -butyr-
Received 22 December 2015
Received in revised form 29 January 2016
Accepted 3 February 2016
a
g
Available online 6 February 2016
orated into a,a-dialkyl g-butyrolactones via a two-step alkylation/reductive alkylation sequence with the
controlled installation of two alkyl groups to the lactones. In addition, application of Hor-
nereWadswortheEmmons (HWE) olefination reaction to the insertion products allows an access to
Keywords:
Intramolecular CeH insertion
Rhodium catalyst
bicyclic
a-alkylidene-g-butyrolactone ring systems that occur ubiquitously in biologically active natural
a
-Diazo-
a
-phosphoryl cycloalkyl esters
products and synthetic molecules.
Bicyclic
g-butyrolactones
Ó 2016 Elsevier Ltd. All rights reserved.
Diastereoselectivity
1. Introduction
carbenoids. On the other hand, the very electron-withdrawing
group can enhance the electrophilicity of the resulting carbenoids
and consequently make them more reactive towards the CeH ac-
Transition metal-catalyzed intramolecular CeH insertion of a-
diazocarbonyls is an exceptionally powerful approach for preparing
cyclic and heterocyclic compounds.1 The reactions involve the ac-
tivation of a CeH bond by metal carbenes (carbenoids) and often
offer the products with high degree of functionality. According to
tivation. In this context, a variety of acceptor/acceptor
substrates such as -keto or
-amidoesters,4 malonates,5 acet-
amides,6 -sulfonylacetamides,7 -sulfonylesters8 and acetani-
a-diazo
b
b
b
b
lides,9 have been employed for the intramolecular CeH insertion
reactions, mostly affording five-membered rings and occasionally
giving rings of other sizes.1b,3b,4c,8 In some cases, the resulting
products could be transformed into other interesting molecules
through the modification on electron-withdrawing moieties, to
thus add additional value to the insertion protocols.11
their a-substitution, the carbonyl precursors used for the reactions
can be divided into three categories, including i) the acceptor-
substituted,2 ii) the acceptor/donor-substituted1g,3 and iii) the ac-
ceptor/acceptor-substituted4e9 (Fig. 1).10 For the acceptor/acceptor-
type precursors, early studies1c have revealed that the presence of
the second electron-withdrawing group can stabilize the diazo
function, and therefore very active catalysts, such as dirhodium
carboxylates, are usually required to decompose them into the
The phosphoryl group [eOP(OR)2] is one of the most versatile
and useful functionalities in organic synthesis.12 Our previous
studies have demonstrated it can serve as an activating group to
promote the [4þ2] cycloaddition of
a,b
-unsaturated esters,13a the
a
-alkylation of esters,13b as well as the oxidative addition of Pd(0) to
oxime NeO bond.13c Furthermore, although
a-phosphoryl a-diaz-
ocarbonyl compounds have been utilized for many years,14 metal-
catalyzed insertion reactions with these acceptor/acceptor-type
substrates are rare in literature.15e17 Among few examples, the
first recorded reaction15a is the Rh(II)-catalyzed transformation of
Fig. 1. Diazocarbonyl precursors used for generating carbenoids.
a
-diazo
Following this, Afnoso et al.16 reported the conversion of a series of
-diazo -phosphorylacetamides or acetates into - and -lactams
or lactones under rhodium catalysis. Note that both methods are
a-phosphoryl ketones into 2-phosphorylcyclopentanones.
a
a
b
g
* Corresponding author. Tel.: þ886 3 8633583; fax: þ886 3 8633570;
e-mail address: jlzhu@mail.ndhu.edu.tw (J.-L. Zhu).
http://dx.doi.org/10.1016/j.tet.2016.02.008
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
1591
restricted to producing monocyclic derivatives and no further
modifications on the insertion products were reported. More re-
cently, right after the beginning of our own program, Taylor and
Unsworth17 described an elegant strategy for synthesizing
a
-alky-
-phos-
one-pot CeH insertion/olefination
lidene-g-butyrolactones from the corresponding a-diazo-a
phorylacetates through
a
sequence. However, the majority of the CeH insertion in-
termediates were not isolated and sterically determined, especially
for those leading to the bicyclic products,17b to thus offer little in-
formation on the stereochemistry of the key insertion step.
To gain a deeper insight into the insertion/cyclization process of
diazo phosphonates, we initiated a program aimed at investigating
the intramolecular CeH insertion reaction of
cycloalkyl esters. It was expected that the reaction would afford the
fused bicyclic -phosphoryl -butyrolactones with the concomitant
creation of three stereogenic centers. Therefore the reactivity of the
precursor related to different cycloalkyl substituents, and the dia-
stereoselectivity in the cyclization would be the primary issues to
be addressed. To our knowledge, there were no prior examples of
forming fused polycyclic phosphonates as the isolated compounds
by CeH insertion reactions at the outset of our research. Addi-
a
-diazo
a
-phosphoryl
Scheme 2. Rhodium-catalyzed insertion reaction of 2a.
a
g
junction can be respectively assigned to 3a and 3a0 [3a: H8a
:
d
3.57 (ddd, J¼9.7, 9.7, 4.3 Hz); 3a0: H8a
:
d
4.57 (ddd, J¼10.5, 7.8,
4.2 Hz)]. Moreover, the C-3 configuration of 3a is unambiguously
confirmed by the NOESY correlations of H3a to H8ax, H8a to H8eq, and
in particular between H3a and the protons of one of the methyl
groups. These correlations are not observed for 3a0, and whose
stereochemistry at C-3 is tentatively deduced from the coupling
tionally, the elaboration of the insertion products into bicyclic
dialkyl -butyrolactones in a two-step alkylation/reductive alkyl-
ation sequence, or to -alkylidene- -butyrolactones through Hor-
a,a-
g
constant of H3a to H3 (J3e3a¼5.7 Hz)26 [3a: H3:
2.55 (dd, JHeP¼25.7,
d
a
g
J3e3a¼11.8 Hz); 3a0: H3:
d
2.65 (dd, JHeP¼24.5, J3e3a¼5.7 Hz)].
nereWadswortheEmmons (HWE) olefination reaction was also
examined by taking advantage of the amenability of the phosphoryl
group. Notably, the synthesis of the latter kind of compounds,
Regarding the mechanistic pathway, pioneering works by Taber
et al.3a,27 have established that the intramolecular CeH insertion
should proceed in a six-membered transition state for producing
a five-membered ring. During which, the reacting CeH and the
RheC bonds must be aligned to each other in order to facilitate the
orbital interaction. Moreover, the transfer of hydride, the dissoci-
ation of rhodium catalyst and the formation of CeC single bond all
take place in a concerted manner with the retention of the original
steric orientation on the newly created stereocenters.28 According
to these concepts and the established structures, three plausible
transition states have been proposed for forming 3a and 3a0 (Fig. 2,
A, B and C). In the transition states A and B, the ester group is placed
in an equatorial position of the cyclohexyl ring,29 and the carbene-
induced activation is expected to occur respectively with a stag-
gered-equatorial CeH bond (A) or an axial CeH bond (B). In the
context, delivery of the corresponding hydride to the Re-face (A) or
the Si-face (B) of the carbenoid center leads to the formation of 3a
or 3a0. In addition, there is another possible pathway for the gen-
eration of 3a0 (C), which involves the location of the ester group in
an axial direction and the transfer of an equatorial hydride to the
particularly bicyclic
a-methylene-g-butyrolactones, has attracted
considerable attentions of synthetic chemists18,19 due to the broad
distribution of such scaffolds in biologically active natural prod-
ucts20 and synthetic molecules.21 The preliminary results from
these studies are disclosed herein.
2. Results and discussion
2.1. Synthesis of 5,7-fused bicyclic g-butyrolactone de-
rivatives through rhodium-catalyzed insertion reaction of 2a
Since the construction of 5,7-fused rings via CeH insertion
strategy has received almost no attention in literature,1 a thorough
investigation was first carried out with cycloheptanyl a-diazo-a-
phosphorylacetate (2a) for accessing such systems. It could be
easily prepared from triethyl phosphonoacetate by trans-esterifi-
cation with cycloheptanol,22 and diazo transfer of the resulting
ester 1a with p-acetamidobenzenesulfonyl azide (p-ABSA)23
(Scheme 1). With the requisite precursor in hand, the metal-
catalyzed reaction was initially attempted by utilizing 2 mol % of
dirhodium tetraacetate [Rh2(OAc)4] in a 0.01 M CH2Cl2 solution of
2a (Scheme 2). After refluxing24 for 12 h, the insertion/cyclization
products were formed in 24% yield as an inseparable mixture of two
diastereomers (3a/3a0¼81/1925). The relative configurations of 3a
and 3a0 were elucidated by NMR analysis. Based on the coupling
constants of H8a protons,26 the fused-trans and fused-cis ring-
Scheme 1. Preparation of CeH insertion precursor 2a.
Fig. 2. Proposed transition states for formation of 3a and 3a0.

1592
J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
top-Re-face of the carbenoid to afford a conformer of 3a0. After
undergoing a conformational change to relieve the axial in-
teraction, it can convert to another form consistent with the cou-
pling constants of H8a proton. On this basis, it is further speculated
that the smaller amount of energy associated with the chair-like
geometry of A27 may account for the preferential generation of 3a.
For optimization, we continued to screen several reaction con-
ditions compiled in Table 1. By using Rh2(OAc)4 in CH2Cl2 (entries
1e5), the best result in term of the yield and diastereoselectivity
Table 1
Optimization of CeH insertion reaction of 2a
Entrya
Catalyst
Catalytic
loading
(mol %)
Solvent (Mb)
Yield (%)c
dr (3a/3a0)
Scheme 3. Alkylation of 3a/3a0 with iodomethane and iodopropane.
1d
2
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(oct)4
Rh2(oct)4
Rh2(OAc)4
Rh2(OAc)4
2
2
5
5
5
2
5
5
5
CH2Cl2 (0.02)
CH2Cl2 (0.05)
CH2Cl2 (0.01)
CH2Cl2 (0.02)
CH2Cl2 (0.05)
CH2Cl2 (0.05)
CH2Cl2 (0.05)
1,2-DCE (0.05)
CH2Cl2 (0.05)
30
28
5
37
40
29
27
7
81/19
85/15
73/27
82/18
91/9
79/21
77/23
86/14
82/18
3d
4
to the lactones with completely avoiding the over-alkylation
problem.
5d
6d
7d
8
More interestingly, all of the reactions in Schemes 3 and 4 were
found to proceed in a diastereoselective manner. For the major
trans ring-junction products 5a, 5b, 6a and 6b derived from 3a, the
2D-NOSEY experiments revealed that the alkyl groups (Me, Pr, Bn
and allyl) were uniformly introduced in a trans orientation to the H-
3a protons (Fig. 3). This stereoselective bias can be explained by the
steric effect in enolate as depicted in Fig. 4. In our cases, the eno-
lates were generated either by deprotonation or reductive de-
phosphorylation. Once formed, the C-3 substituents (Y) are
supposed to be distorted somewhat from coplanarity in order to
minimize the steric interactions with the solvated oxygen atom32
and/or the C4eC5 ethylene unit. Under this premise, the sub-
sequently introduced alkylating agents (R-X) should approach the
enolates preferentially from the lower face to avoid forcing the C-3
substituents to become eclipsed with the oxygen, to thus account
for the observed stereoselectivity. Furthermore, it is noteworthy
that the minor cis products resulted from 3a0 (5a0, 5b0, 6a00 and 6b0)
were all produced as the single diastereomer in each case. However,
determination of their C-3 configuration(s) by NMR methods
appeared to be difficult due to the overlap of key proton signals. To
resolve the stereochemistry, separation and/or crystallization of the
cis-products from the isomeric mixtures are being attempted.
The modification on the insertion products by HWE reaction
was also examined. It was observed that 3a/3a0 could react with
paraformaldehyde smoothly by using t-BuOꢀKþ as a base in tetra-
9d,e
5
The bold style means the best result as depicted in the main test (40% and 91/9).
a
All reactions were performed at reflux for 12 h.
Concentration of 2a.
Isolated yield.
Cycloheptanyl 2-(diethoxyphosphoryl)-2-hydroxyl acetate (4) was formed.
3 A molecular sieve was employed (50 mg/1 mmol of 2a).
b
c
d
e
ꢀ
was received from 5 mol % catalyst loading with a 0.05 M concen-
tration of 2a, affording 40% of 3a/3a0 in a 91:9 dr (entry 5). It was
further noted that replacement of Rh2(OAc)4 with dirhodium(II)
octanoate [Rh2(oct)4], or CH2Cl2 with 1,2-dichloroethane (1,2-DCE)
led to inferior results (entries 6e8). In most cases, the generation of
by-product 4 from water insertion was observed. In circumventing
ꢀ
this problem, we introduced molecular sieve (3 A) to the reaction
conditions but such effort merely resulted in a poor formation of
the desired products (entry 9). From these results it can be seen that
2a is less reactive than the formerly employed17a alkyl-substituted
a
-diazo a-phosphoryl esters for the intramolecular insertion re-
action, and this should be attributed to the more strained and
congested character of the transition state(s) in association with the
cycloheptanyl ring.
In the previous studies, we demonstrated that the cyclic
phosphoryl esters prepared from the DielseAlder reaction of
a
a
-
-
hydrofuran (THF), to furnish the known
a
-methylene lactones25
7a33 and 7a026 in 76% yield with the NMR spectral data agreeing
well to the literature33,26 (Scheme 5). When less reactive propio-
naldehyde was employed, the reaction afforded the mixture of 7b
and 7b0 in relatively low yield (48%) with the Z-geometry being
tentatively assigned to their C]C double bonds.33 In this case, an
abnormally large inconsistency between the ratio of the products
(7b/7b0¼95/525) and the dr value of the starting materials (3a/
3a0¼81/19) was found, which is possibly ascribed to the base-
sensitive nature of 7b0.19f
phosphoryl a,b-unsaturated esters could be converted into a-alkyl
esters via a reductive alkylation operation,13a,22 which involved
treating the esters with lithium naphthalenide (LN) to induce a re-
ductive dephosphorylation followed by trapping the in situ formed
enolates with an alkylating reagent. The reaction allowed the
phosphoryl group to be replaced by an alkyl substituent with the
efficient creation of an all-carbon quaternary stereocenter. In light
of this result, we envisaged that the same operation might also be
applicable to
a-phosphoryl lactones, and the insertion products
could be used as the starting substrates to examine the possibility.
To meet the end, the alkylation reactions of 3a/3a0 with iodo-
methane or iodopropane were first carried out in the presence of t-
BuOꢀKþ,13b to provide the products25 5a/5a0 (dr: 81/19) or 5b/5b030
(dr: 97/3) (Scheme 3). The resulting mono-alkylated compounds
were then subjected to the reductive alkylation by allowing them to
react with LN at ꢀ78 ꢁC for 30 min, followed by introducing allyl
bromide or benzyl bromide and hexamethylphosphoramide
(HMPA) to the reaction mixtures (Scheme 4). From which, the de-
2.2. Synthesis of 5,5-, 5,6- and 5,8-fused bicyclic g-butyr-
olactones via CeH insertion reactions of 2bed
To explore the ring-size effect of cycloalkyl groups on the
aforementioned reactions, we further synthesized precursors 2b-
d following the same sequence in Scheme 1 (Scheme 6). The results
of their CeH insertion reactions are outlined in Scheme 7. Under the
same catalytic conditions (Table 1, entry 5), both 2b and 2c were
shown to be less reactive than 2a to afford the products 3b and 3c/
3c0/3c0025,34 in lower yields (10% and 31%). Meanwhile, we observed
that 2d exhibited much higher reactivity than other examined
sired a,a-dialkyl g
-butyrolactones25 6a/6a031/6a00 (dr: 80/14/6) and
6b/6b0 (dr: 96/4) were isolated in synthetically useful yields, to
consequently realize the introduction of two selected alkyl groups

J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
1593
Scheme 4. Reductive alkylation of 5a/5a0 and 5b/5b0.
Scheme 6. Preparation of precursors 2bed.
Fig. 3. NOSEY correlations of trans-ring junction products.
Fig. 4. Rationalization for diastereoselectivity of trans precursors.
Scheme 7. Rhodium-catalyzed insertion reactions of 2bed.
Scheme 5. HWE reactions of 3a/3a0.
precursors, in giving a good formation of the products 3d/3d0/3d00
(80%).25 Among these compounds, the stereochemistry of 3c, 3c00
and 3d were undoubtedly identified by NOSEY experiments as
depicted in Fig. 5. The coupling constants of the H7a proton of 3c0
1
Fig. 5. H-1H NOSEY experiments of 3c, 3c00 and 3d.

1594
J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
suggested a trans ring-junction configuration [
d
4.42 (ddd, J¼10.9,
substituted>cyclohexyl-substituted>cyclopentyl-substituted. From
10.9, 3.6 Hz) ppm], and its C-3 configuration could be readily de-
duced from which and the structure of 3c. For 3b, 3d0 and 3d00, their
stereochemistry were elucidated by comparing the coupling con-
stants of the ring-junction and H3 protons with those reported for
2b to 2d (2b/2c/2a/2d), the increasing ring sizes are supposed
to offer the transition states with more and more flexibility in fa-
voring of the cyclization process. Once reaching at the eight-
membered ring, its strain imposed to the transition state(s)
should become very small or ignorable, as evidenced by the com-
parable activity of 2d to those of alkyl-substituted counterparts.17a
The insertion products were then allowed to react with 1-
iodohexane, iodoethane and 1-iodopentane, respectively,36 to
give the intermediates 5c, 5d/5d025 and 5e/5e0,25 which were sub-
sequently used for the reductive alkylation (Scheme 8).
The reaction of 5c with LN and BnBr was first carried out. However,
it did not yield any dialkylated lactone(s) but rather gave a complex
polar mixture. The NMR spectrum of the crude products indicated
the disappearance of H6a proton signal, implying that the lactone
should undergo a ring opening presumably due to the high rigidity
of the 5,5-fused cyclic enolate intermediate. While the desired
product was not obtained from 5c, the reductive methylation and
benzylation of 5d/5d0 or 5e/5e0 could occur smoothly under the
C3-substituted bicyclic g
-butyrolactone analogues35 (Table 2). Ac-
cordingly, a transition state(s) has been assigned to each of these
products (see the Supplemental data). It is assumed that the tran-
sition states similar to A or B (C) in Fig. 2 lead to the formation of 3c/
3d or 3c00/3d00, while the generations of 3b, 3c0 and 3d0 are resulted
from the highly twisted boat-like models. Regarding the diaster-
eoselectivity, the inherent rigidity of the cyclopentyl ring combined
with the bond overlapping requirement for the CeH activation27
only permitted a single transition state for the reaction of 2b, in
yielding 3b, albeit in low yield, as the solo isolated isomer. Although
the remaining precursors gave the isomeric mixtures, they dis-
played the similar diastereoselectivity in resulting in the identical
relative configurations for the major trans products 3a/3c/3d and
the minor cis-isomers 3a0/3c00/3d00.
developed conditions, to afford the mixtures25 of 6c/6c0 and 6d37
/
6d0 in 43% and 65% yield, respectively. Once again, the 1H-1H NOESY
experiments were sought to establish the stereochemistry of 5d
and 5e (Fig. 6), which suggested the same stereoselective bias as
observed for the alkylation of 3a (Scheme 2). According to this and
the explanation shown in Fig. 4, the methyl and benzyl groups in 6c
and 6d were proposed in a trans steric relationship to the H3a
protons. For the compounds 5c, 5d0, 5e0, 6c0 and 6d0, the C-3 con-
figurations have so far remained to be determined.
Table 2
Key proton signals for determining the stereochemistry of insertion products in
Scheme 7
Product Chemical shifts and coupling constants
3ba
H
6a d 5.05 (tm, J¼5.5 Hz) ppm; H3 d 2.84 (dd, JHeP¼24.7,
J3e3a¼3.0 Hz) ppm35
3ca
H
7a d 3.75 (ddd, J¼10.8, 10.8, 3.7 Hz) ppm; H3 d 2.75 (dd, JHeP¼20.8,
J3e3a¼12.9 Hz) ppm
7a d 4.42 (ddd, J¼10.9, 10.9, 3.6 Hz) ppm; H3 d 2.76 (dd, JHeP¼24.9,
J3e3a¼2.3 Hz) ppm
7a d 4.83 (ddd, J¼4.3, 4.2, 4.2 Hz) ppm; H3 d 3.04 (dd, JHeP¼23.7,
J3e3a¼8.5 Hz) ppm
9a d 3.85 (ddd, J¼10.2, 8.3, 4.6 Hz) ppm; H3 d 2.50 (dd, JHeP¼23.4,
J3e3a¼10.5 Hz) ppm
a
3c0
H
a
3c00
H
3db
H
b
3d0
H
9a d 5.13 (ddd, J¼12.3, 8.3, 4.2 Hz) ppm; H3 d 2.72 (dd, JHeP¼23.3,
J3e3a¼3.6 Hz) ppm35
b
3d00
H
9a d 4.56 (ddd, J¼11.3, 7.3, 1.8 Hz) ppm; H3 d 2.60 (dd, JHeP¼24.1,
J3e3a¼7.0 Hz) ppm35
Fig. 6. 1H-1H NOSEY experiments of 5d and 5e.
a
The NMR analysis was performed in CDCl3.
The NMR analysis was conducted in C6D6.
b
Finally, the HWE olefination reactions of the insertion prod-
More importantly, based on the yields given in Table 1 and
ucts36 were conducted by employing paraformaldehyde or pro-
Scheme 7 (10%, 31%, 40% and 80%), a correlation between the
reactivity of the precursors and the ring sizes of the cycloalkyl
moieties can be established as cyclooctyl-substituted>cycloheptyl-
pionaldehyde as the reagents, to allow the generation of the
a,b-
unsaturated lactones25 in acceptable yields (Scheme 9). Among
Scheme 8. Alkylation and reductive alkylation for 5,5-, 5,6- and 5,8-fused ring systems.

J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
1595
Scheme 9. HWE reactions of 3b, 3c/3c0/3c00 and 3d/3d0/3d00.
which, the NMR spectral data of 7c,38 7d/7d019c and 7f/7f039 were all
in good agreement with those reported in literature, and the (Z)-
and (E)-configurations were respectively given to the trans prod-
ucts 7e and 7e0 based on the chemical shifts of the olefinic pro-
254) and visualized with UV light, ethanolic solution of vanillin (5%)
or aqueous KMnO4 solution (10%). The NMR spectra (1H, 31P, 13C and
2D-NOESY) were recorded on 400 or 600 MHz spectrometers using
deuteriochloroform (CDCl3) or deuterobenzene (C6D6) as the sol-
vents. The 1H NMR data are reported as the chemical shift in parts
per million, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet;
m. multiplet), coupling constants (J) in Hertz, and number of pro-
tons. The resonances of infrared (IR) spectra are reported in wave
numbers (cmꢀ1). High resolution mass spectra (HRMS) were per-
formed with electron impact (EI) ionization and a magnetic sector
analyzer.
tons33 [7e:
d d 6.61 ppm]. In addition, only a trace
5.85 ppm; 7e0:
amount19f of the cis-isomer 7e00 was detected in the reaction mix-
ture and its stereogeometry of the C]C double bond was tenta-
tively assigned in the Z-form.33
3. Conclusion
In conclusion, we have completed the investigation on the
Rh(II)-catalyzed intramolecular CeH insertion reaction of a series
4.2. Preparation of 1aed
of a-diazo a-phosphoryl cycloalkyl esters. These precursors can be
4.2.1. Cycloheptyl 2-(diethoxyphosphoryl)acetate (1a). To a 25 mL
round-bottom flask charged with toluene (12 mL), cycloheptanol
(99%, 1.6 mL, 13.14 mmol), triethyl phosphonoacetate (98%, 7.98 mL,
39.41 mmol) and DMAP (99%, 0.486 g, 3.94 mmol) were succes-
sively added under N2 protection. The reaction mixture was stirred
in an oil bath at 120 ꢁC for 2 days, then cooled to rt and concen-
trated under vacuo. The crude products were subjected to chro-
matographic purification (hexaneeEtOAc 5:1, 3:1, 2:1, 1:1, 1:3) to
afford 1a17b as a colorless oil (2.94 g, 77%). IR (neat) 1730, 1272,
readily prepared in large quantities though a common synthetic
sequence. In our studies, the stereochemistry of the resulting in-
sertion products have all been established by NMR analysis, to thus
allow for a close insight into the diastereoselectivity of the in-
sertion/cyclization process as well as the transition models leading
to them. Furthermore, the ring-size effect of the cycloalkyl moieties
on the reaction has been clarified, which, as we predict, can serve as
a valuable guide for future works on constructing fused bicyclic
scaffolds by insertion strategies. Additionally, modification of the
1053, 1025 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 4.99e1.91 (m, 1H),
products into
with considerable success in most cases. These operations, in par-
ticular the selective introduction of two alkyl groups to the
a,a-dialkyl or a-alkylidene g-butyrolactones has met
4.20e4.06 (m, 4H), 2.91 (dd, J1HeP¼21.6, J2¼1.1 Hz, 2H), 1.95e1.85
(m, 2H), 1.72e1.60 (m, 4H), 1.58e1.51 (m, 4H), 1.47e1.37 (m, 2H),
1.33 (t, J¼7.2 Hz, 3H), 1.32 (t, J¼7.0 Hz, 3H) ppm; 13C NMR (100 MHz,
g-
butyrolactones, should expand the synthetic utility of the protocol.
The more efficient catalytic system to promote the insertion pro-
cess is currently under active investigation, as is the evaluation of
applying the developed procedures to the synthesis of other in-
teresting target molecules.
CDCl3)
d
165.2 (d, JCeP¼6.3 Hz), 76.6, 62.6 (d, JCeP¼6.2 Hz), 62.6 (d,
JCeP¼6.2 Hz), 34.7 (d, JCeP¼132.8 Hz), 33.6, 28.2, 22.8, 16.3 (d,
JCeP¼6.2 Hz), 16.3 (d, JCeP¼6.2 Hz) ppm; 31P NMR (161 MHz, CDCl3)
d
20.1 ppm; HRMS-EI: m/z [M]þ calcd for C13H25O5P: 292.1400;
found: 292.1440.
4. Experimental
4.1. General
4.2.2. Cyclopentyl 2-(diethoxyphosphoryl)acetate (1b). The titled
compound was similarly prepared as 1a by using cyclopentanol
(99%, 1.06 mL, 11.61 mmol) as the reagent. After chromatographic
purification (hexaneeEtOAc 3:1, 2:1, 1:1, 1:3), 2.51 g of 1b17b was
obtained (82%) as a pale yellow oil. IR (neat) 1732, 1274, 1052,
All of the reagents were purchased from commercial suppliers
and used without further purification. All of the solvents used for
the reactions were properly dried and freshly distilled before each
use. Flash chromatography was performed using silica gel (70e230
mesh) with the indicated solvents. All of the reactions were mon-
itored by thin-layer chromatography on 0.25 mm silica plates (60F-
1024 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 5.23e5.14 (m, 1H),
4.19e4.09 (m, 4H), 2.90 (dd, J1HeP¼21.5, J2¼6.4 Hz, 2H), 1.89e1.79
(m, 2H), 1.75e1.67 (m, 4H), 1.62e1.53 (m, 2H), 1.33 (t, J¼6.5 Hz, 3H),
1.31 (t, J¼6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 165.5 (d,
JCeP¼6.1 Hz), 78.4, 62.5 (d, JCeP¼6.2 Hz), 62.5 (d, JCeP¼6.2 Hz), 34.6

1596
J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
(d, JCeP¼132.8 Hz), 32.5, 23.7, 16.3 (d, JCeP¼6.2 Hz), 16.3 (d,
7.98 mmol) as the starting material. After chromatographic purifi-
cation (hexaneeEtOAc 3:1, 2:1, 1:1), 2.17 g of 2c17b was obtained
JCeP¼6.2 Hz) ppm; 31P NMR (161 MHz, CDCl3)
d 20.0 ppm.
(89%) as a colorless oil. IR (neat) 2129, 1698, 1284, 1023 cmꢀ1 1H
;
4.2.3. Cyclohexyl 2-(diethoxyphosphoryl)acetate (1c). The titled
compound was similarly prepared as 1a by using cyclohexanol
(99%, 1.07 mL, 9.98 mmol) as the reagent. After chromatographic
purification (hexaneeEtOAc 3:1, 2:1, 1:1, 1:3), compound 1c17b was
obtained (2.22 g, 80%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
NMR (400 MHz, CDCl3)
d
4.84 (ddd, J¼12.6, 8.5, 3.7 Hz, 1H),
4.23e4.07 (m, 4H), 1.84e1.76 (m, 2H), 1.72e1.63 (m, 2H), 1.51e1.34
(m, 4H), 1.31 (t, J¼7.0 Hz, 6H), 1.35e1.27 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3)
d
162.9 (d, JCeP¼11.8 Hz), 74.1, 63.5 (d,
JCeP¼5.7 Hz), 63.5 (d, JCeP¼5.7 Hz), 53.9 (d, JCeP¼226.5 Hz), 31.5,
d
4.80 (ddd, J¼13.0, 8.9, 3.7 Hz, 1H); 4.22e4.08 (m, 4H), 2.94 (d,
25.2, 23.3, 16.1 (d, JCeP¼6.9 Hz), 16.1 (d, JCeP¼6.9 Hz) ppm; 31P NMR
JHeP¼21.5 Hz, 2H), 1.89e1.82 (m, 2H), 1.78e1.70 (m, 2H), 1.58e1.40
(m, 3H), 1.34 (t, J¼7.1 Hz, 6H), 1.39e1.29 (m, 2H), 1.38e1.23 (m, 1H)
(161 MHz, CDCl3) d
10.2 ppm; HRMS-EI: m/z [M]þ calcd for
C12H21N2O5P: 304.1188; found: 304.1187.
ppm; 13C NMR (100 MHz, CDCl3)
d
165.3 (d, JCeP¼6.3 Hz), 74.0, 62.6
(d, JCeP¼6.2 Hz), 62.6 (d, JCeP¼6.2 Hz), 34.7 (d, JCeP¼132.8 Hz), 31.4,
4.3.4. Cyclooctyl 2-diazo-2-(diethoxyphosphoryl)acetate (2d). The
titled compound was similarly prepared as 2a by using 1d (2.09 g,
6.83 mmol) as the starting material. After chromatographic puri-
fication (hexaneeEtOAc 5:1, 3:1, 1:1, 1:2), 2.12 g of 2d was obtained
25.3, 23.6, 16.3 (d, JCeP¼6.2 Hz), 16.3 (d, JCeP¼6.2 Hz) ppm; 31P NMR
(161 MHz, CDCl3)
d 20.1 ppm.
4.2.4. Cyclooctyl 2-(diethoxyphosphoryl)acetate (1d). The titled
compound was similarly prepared as 1a by using cyclooctanol (97%,
1.06 mL, 7.80 mmol) as the reagent. After chromatographic purifica-
tion (hexaneeEtOAc 3:1, 2:1,1:1, 1:2), 2.14 g of 1d was obtained (90%)
as a pale yellow oil. IR (neat) 1730, 1275, 1048, 1026 cmꢀ1; 1H NMR
(94%) as a colorless oil. IR (neat) 2129, 1697, 1282, 1024 cmꢀ1 1H
;
NMR (400 MHz, CDCl3)
d 5.00e4.89 (m, 1H), 4.17e3.69 (m, 4H),
1.76e1.54 (m, 6H), 1.49e1.34 (m, 8H), 1.24 (t, J¼6.8 Hz, 6H) ppm; 13
C
NMR (100 MHz, CDCl3)
d
162.8 (d, JCeP¼11.8 Hz), 76.7, 63.4 (d,
JCeP¼5.6 Hz), 63.4 (d, JCeP¼5.6 Hz), 53.8 (d, JCeP¼224.7 Hz), 31.3,
(400 MHz, CDCl3)
d
4.94 (dddd, J¼8.4, 8.3, 4.1, 4.0 Hz, 1H), 4.18e4.04
26.9, 25.1, 22.6, 16.0 (d, JCeP¼6.8 Hz), 16.0 (d, JCeP¼6.8 Hz) ppm; 31
P
(m, 4H), 2.88 (d, JHeP¼21.5 Hz, 2H), 1.84e1.54 (m, 7H), 1.53e1.44 (m,
NMR (161 MHz, CDCl3) d
10.2 ppm; HRMS-EI: m/z [M]þ calcd for
7H), 1.32 (t, J¼7.1 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3)
d
165.1 (d,
C14H25N2O5P: 332.1501; found: 332.1508.
JCeP¼6.5 Hz), 76.6, 62.6 (d, JCeP¼6.1 Hz), 62.6 (d, JCeP¼6.1 Hz), 34.7 (d,
JCeP¼132.9 Hz), 31.3, 27.0, 25.3, 22.9, 16.3 (d, JCeP¼6.2 Hz), 16.3 (d,
4.4. Typical procedure for the Rh(II)-catalyzed insertion re-
actions (Table 1, entry 5)
JCeP¼6.2 Hz) ppm; 31P NMR (161 MHz, CDCl3)
d 20.1 ppm; HRMS-EI:
m/z [M]þ calcd for C14H27O5P: 306.1596; found: 306.1591.
To a 50 mL round-bottom flask containing a solution of 2a
(228.9 mg, 0.719 mmol, 0.05 M) in dry CH2Cl2 (14.4 mL), Rh2(OAc)4
(98%, 16.22 mg, 0.036 mmol) was added under an argon atmo-
sphere. The resulting green suspension was degassed with argon
for 3 min. The flask was then attached to a condenser equipped
with a joint fitted with a balloon of argon, and placed into an oil
bath at 45 ꢁC. The reaction mixture was refluxed for 12 h, cooled to
rt, and concentrated under vacuo. The crude products was purified
by flash chromatography (hexaneeEtOAc 2:1, 1:1, 1:2) to afford the
mixture of 3a/3a0 (83.5 mg, 40%; dr: 91:9)25 and a trace amount of 4
(7.77 mg, 3.5%).
4.3. Preparation of 2aed
4.3.1. Cycloheptyl 2-diazo-2-(diethoxyphosphoryl)acetate (2a). To
a solution of 1a (2.94 g, 10.07 mmol) in THF (106 mL) under N2
atmosphere, NaH (60%, 604.2 mg, 15.11 mmol) was added in one
portion. The suspension was stirred at 0 ꢁC for 50 min before the
addition of p-ABSA (98%, 2.59 g, 10.57 mmol). The reaction mixture
was continued to stir at rt for 1 h, then diluted by CH3CO2Et
(350 mL) and successively washed with aqueous HCl solution (10%,
60 mLꢂ2), water (50 mLꢂ2) and brine (50 mLꢂ1). The organic layer
was separated and concentrated under reduced pressure. The crude
mixture was purified by flash chromatography (hexaneeEtOAc 3:1,
1:1) to provide 2.7 g of 2a17b as a yellowish oil (84%). IR (neat) 2130,
4.4.1. Diethyl (3R*,3aS*,8aS*)-2-oxooctahydro-2H-cyclohepta[b]fu-
ran-3-yl phosphonate (3a) and diethyl (3S*,3aS*,8aR*)-2-
oxooctahydro-2H-cyclohepta[b]furan-3-yl phosphonate (3a0). IR
1700, 1280, 1024 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 5.09e5.00 (m,
1H), 4.26e4.11 (m, 4H), 1.94e1.84 (m, 2H), 1.75e1.60 (m, 4H),
(neat) 1768, 1251, 1020, 967 cmꢀ1 1H NMR (400 MHz, C6D6) 3a:
;
1.59e1.53 (m, 4H), 1.49e1.40 (m, 2H), 1.34 (t, J¼7.2 Hz, 6H) ppm; 13
C
d
4.35e3.90 (m, 4H), 3.57 (ddd, J¼9.7, 9.7, 4.3 Hz, 1H), 2.61e2.51 (m,
NMR (100 MHz, CDCl3)
d
163.0 (d, JCeP¼11.9 Hz), 76.8, 63.5 (d,
1H), 2.55 (dd, JHeP¼25.7, J¼11.8 Hz, 1H), 2.20e2.11 (m, 1H),
2.05e1.93 (m, 1H), 1.35e1.19 (m, 6H), 1.13 (t, J¼7.1 Hz, 3H), 1.07 (t,
JCeP¼5.6 Hz), 63.5 (d, JCeP¼5.6 Hz), 54.0 (d, JCeP¼225.6 Hz), 33.8,
28.1, 22.8, 16.1 (d, JCeP¼6.9 Hz), 16.1 (d, JCeP¼6.9 Hz) ppm; 31P NMR
J¼7.0 Hz, 3H), 0.97e0.89 (m, 2H) ppm; 3a0:
4.57 (ddd, J¼10.5, 7.8,
d
(161 MHz, CDCl3)
d
10.4 ppm; HRMS-EI: m/z [M]þ calcd for
4.2 Hz, 1H), 4.35e3.90 (m, 4H), 2.96e2.83 (m, 1H), 2.65 (dd,
JHeP¼24.5, J¼5.7 Hz, 1H), 1.76e1.67 (m, 1H), 1.53e1.44 (m, 1H),
1.35e1.19 (m, 6H), 1.13 (t, J¼7.1 Hz, 3H), 1.07 (t, J¼7.0 Hz, 3H),
C
13H23N2O5P: 318.1345; found: 318.1342.
4.3.2. Cyclopentyl 2-diazo-2-(diethoxyphosphoryl)acetate (2b). The
titled compound was similarly prepared as 2a by using 1b (2.51 g,
9.50 mmol) as the starting material. After chromatographic puri-
fication (hexaneeEtOAc 3:1, 1:1), 2.12 g of 2b17b was obtained (77%)
0.84e0.74 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) 3a:
d 171.2, 84.7
(d, JCeP¼14.0 Hz), 63.6 (d, JCeP¼6.5 Hz), 62.5 (d, JCeP¼6.6 Hz), 47.1
(d, JCeP¼151.3 Hz), 44.2 (d, JCeP¼1.5 Hz), 32.6, 30.1, 27.4, 25.0, 24.8,
16.4 (d, JCeP¼6.4 Hz), 16.3 (d, JCeP¼6.6 Hz) ppm; 3a0:
d 171.3 (d,
as a yellow oil. IR (neat) 2128, 1697, 1278, 1022 cmꢀ1
;
1H NMR
JCeP¼3.4 Hz), 83.2 (d, JCeP¼5.6 Hz), 63.5 (d, JCeP¼6.7 Hz), 62.4 (d,
JCeP¼6.7 Hz), 47.7 (d, JCeP¼138.8 Hz), 41.9 (d, JCeP¼2.3 Hz), 31.1,
30.5, 28.0, 24.8, 23.5, 16.4 (d, JCeP¼6.4 Hz), 16.3 (d, JCeP¼6.6 Hz)
(400 MHz, CDCl3)
d
5.28 (dddd, J¼5.8, 4.8, 3.0, 2.6 Hz, 1H),
4.26e4.09 (m, 4H), 1.92e1.80 (m, 2H), 1.78e1.67 (m, 4H), 1.67e1.58
(m, 2H), 1.35 (t, J¼7.1 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3)
ppm; 31P NMR (161 MHz, CDCl3) 3a:
d d 20.7 ppm;
20.6 ppm; 3a0:
d
163.0 (d, JCeP¼12.4 Hz), 78.6, 63.3 (d, JCeP¼5.7 Hz), 63.3 (d,
HRMS-EI: m/z [M]þ calcd for C13H23O5P: 290.1283; found:
JCeP¼5.7 Hz), 53.7 (d, JCeP¼224.6 Hz), 32.6, 23.4, 15.9 (d,
290.1278.
JCeP¼6.8 Hz), 15.9 (d, JCeP¼6.8 Hz) ppm; 31P NMR (161 MHz, CDCl3)
d
10.3 ppm.
4.4.1.1. Cycloheptyl 2-(diethoxyphosphoryl)-2-hydroxyacetate
(4). IR (neat) 3281, 1739, 1245, 1024, 968 cmꢀ1
;
1H NMR
4.3.3. Cyclohexyl 2-diazo-2-(diethoxyphosphoryl)acetate (2c). The
titled compound was similarly prepared as 2a by using 1c (2.22 g,
(400 MHz, CDCl3)
4.28e4.16 (m, 4H), 3.40 (br s, 1H), 2.00e1.86 (m, 2H), 1.79e1.63 (m,
d
5.14e5.05 (m, 1H), 4.48 (d, JHeP¼15.2 Hz, 1H),

J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
1597
4H), 1.59e1.53 (m, 4H), 1.50e1.38 (m, 2H), 1.34 (t, J¼7.0 Hz, 6H)
ppm; 13C NMR (100 MHz, CDCl3)
168.8, 78.0, 68.9 (d,
1.94e1.86 (m, 1H), 1.49e1.23 (m, 6H), 1.12 (t, J¼7.0 Hz, 3H), 1.07 (t,
d
J¼7.2 Hz, 3H), 1.16e1.05 (m, 2H), 0.98e0.83 (m, 2H) ppm; 3d0:
d 5.13
JCeP¼154.1 Hz), 63.7 (d, JCeP¼6.8 Hz), 63.4 (d, JCeP¼6.9 Hz), 33.5 (d,
(ddd, J¼12.3, 8.3, 4.2 Hz, 1H), 4.32e3.93 (m, 4H), 2.87e2.79 (m, 1H),
2.72 (dd, JHeP¼23.3, J¼3.6 Hz, 1H), 1.82e1.74 (m, 1H), 1.62e1.53 (m,
1H), 1.49e1.23 (m, 6H), 1.12 (t, J¼7.0 Hz, 3H), 1.07 (t, J¼7.2 Hz, 3H),
JCeP¼18.0 Hz), 28.2, 22.6, 16.4 (d, JCeP¼5.8 Hz), 16.4 (d, JCeP¼5.8 Hz)
ppm; 31P NMR (161 MHz, CDCl3)
d
16.1 ppm; HRMS-EI: m/z [M]þ
calcd for C13H25O6P: 308.1389; found: 308.1382.
1.16e1.05 (m, 2H), 0.98e0.83 (m, 2H) ppm; 3d00:
d
4.56 (ddd, J¼11.3,
7.3, 1.8 Hz, 1H), 4.32e3.93 (m, 4H), 2.76e2.56 (m, 1H), 2.60 (dd,
JHeP¼24.1, J¼7.0 Hz, 1H), 1.94e1.86 (m, 1H), 1.71e1.64 (m, 1H),
1.49e1.23 (m, 6H), 1.12 (t, J¼7.0 Hz, 3H), 1.07 (t, J¼7.2 Hz, 3H),
1.16e1.05 (m, 2H), 0.98e0.83 (m, 2H) ppm; 13C NMR (100 MHz,
4.4.2. Diethyl (3R*,3aS*,6aR*)-2-oxohexahydro-2H-cyclopenta[b]fu-
ran-3-yl phosphonate (3b). The titled compound was similarly
prepared as 3a/3a0 by using 2b (360.8 mg, 1.243 mmol) as the
starting material. After chromatographic purification (hex-
aneeEtOAc 3:1, 1:1, 1:2), 31.3 mg of 3b was obtained (10%) as
C6D6) 3d:
d
170.1, 84.2 (d, JCeP¼11.3 Hz), 63.4 (d, JCeP¼6.3 Hz), 61.8
(d, JCeP¼6.4 Hz), 47.9 (d, JCeP¼147.0 Hz), 42.4, 34.8, 34.4, 26.8, 26.5,
a colorless oil. 1H NMR (400 MHz, CDCl3)
d
5.05 (tm, J¼5.5 Hz, 1H),
23.9, 21.5, 16.3 (d, JCeP¼5.6 Hz), 16.2 (d, JCeP¼5.9 Hz) ppm; 3d0:
4.29e4.15 (m, 4H), 3.24e3.12 (m, 1H); 2.84 (dd, JHeP¼24.7, J¼3.0 Hz,
1H), 2.10e1.01 (m, 2H), 1.80e1.64 (m, 3H), 1.60e1.54 (m, 1H), 1.36 (t,
J¼7.2 Hz, 3H), 1.34 (t, J¼7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
170.3, 84.2 (d, JCeP¼11.3 Hz), 63.4 (d, JCeP¼6.3 Hz), 62.7 (d,
JCeP¼6.5 Hz), 45.2 (d, JCeP¼177.9 Hz), 41.8, 31.4, 31.2, 28.0, 27.9, 25.3,
22.8, 16.3 (d, JCeP¼5.6 Hz), 16.2 (d, JCeP¼5.9 Hz) ppm; 3d00:
d 169.2,
d
172.0 (d, JCeP¼4.4 Hz), 85.7 (d, JCeP¼2.3 Hz), 63.5 (d, JCeP¼6.7 Hz),
83.4 (d, JCeP¼7.6 Hz), 63.5 (d, JCeP¼5.4 Hz), 62.0 (d, JCeP¼6.3 Hz),
48.1 (d, JCeP¼140.9 Hz), 42.0, 28.9, 28.1, 27.0, 26.3, 25.1, 25.0, 16.3 (d,
JCeP¼5.6 Hz), 16.2 (d, JCeP¼5.9 Hz) ppm; 31P NMR (161 MHz, CDCl3)
63.1 (d, JCeP¼6.6 Hz), 47.7 (d, JCeP¼135.8 Hz), 41.3 (d, JCeP¼3.1 Hz),
33.7 (d, JCeP¼11.9 Hz), 33.3, 23.4, 16.4 (d, JCeP¼3.0 Hz), 16.3 (d,
JCeP¼2.9 Hz) ppm; 31P NMR (161 MHz, CDCl3)
d
19.6 ppm; HRMS-
3d: d d d 21.3 ppm; HRMS-EI: m/z
21.8 ppm; 3d0: 19.1 ppm; 3d00:
EI: m/z [M]þ calcd for C11H19O5P: 262.0970; found: 262.0960.
[M]þ calcd for C14H25O5P: 304.1440; found: 304.1443.
4.4.3. Diethyl (3R*,3aS*,7aS*)-2-oxooctahydrobenzofuran-3-yl phos-
phonate (3c) diethyl (3S*,3aS*,7aS*)-2-oxooctahydrobenzofuran-3-yl
p h o s p h o n a t e ( 3 c 0) a n d d i e t h y l ( 3 S * , 3 a S * , 7 a R * ) - 2 -
oxooctahydrobenzofuran-3-yl phosphonate (3c00). The titled com-
pounds were similarly prepared as 3a/3a0 by using 2c (125.7 mg,
0.4131 mmol) as the starting material. After chromatography
(hexaneeEtOAc 3:1, 2:1, 1:1, 1:2), a mixture 3c/3c0/3c00 (dr: 69/14/
17)25 was obtained as a colorless oil (35.7 mg, 31%). IR (neat) 1778,
4.5. Typical procedure for alkylation of insertion products
Under N2 protection, t-BuOꢀKþ (97%, 283 mg, 2.446 mmol) was
added to a stirred solution of 3a/3a0 (177.5 mg, 0.6115 mmol, dr: 82/
18) in DMSO (7 mL) pre-cooled at 0 ꢁC in an ice bath. The ice bath
was then removed and stirring was continued for 30 min to dis-
solve t-BuOꢀKþ followed by the addition of CH3I (99%, 0.15 mL,
2.385 mmol). The reaction mixture was stirred at rt for 14 h in dark,
diluted with water (20 mL) and extracted by ethyl acetate
(50 mLꢂ2). The organic layers were combined and successively
washed with saturated aqueous NH4Cl solution (20 mLꢂ2), water
(20 mL) and brine (20 mL). After concentration, the crude mixture
was subjected to chromatographic purification (hexaneeEtOAc 3:1,
2:1, 1:1, 0:100) to afford a mixture of 5a/5a0 (dr: 81/19)25 as a pale
yellow oil (148.3 mg, 80%).
1255, 1051, 1026, 970 cmꢀ1 1H NMR (400 MHz, CDCl3) 3c:
;
d
4.35e4.11 (m, 4H), 3.75 (ddd, J¼10.8, 10.8, 3.7 Hz, 1H), 2.75 (dd,
JHeP¼20.8, J¼12.9 Hz, 1H), 2.27e2.15 (m, 2H), 2.00e1.86 (m, 1H),
1.83e1.76 (m, 1H), 1.72e1.41 (m, 2H), 1.34 (t, J¼7.0 Hz, 3H), 1.33 (t,
J¼7.3 Hz, 3H), 1.40e1.22 (m, 3H) ppm; 3c0:
4.42 (ddd, J¼10.9, 10.9,
d
3.6 Hz, 1H), 4.35e4.11 (m, 4H), 2.76 (dd, JHeP¼24.9, J¼2.3 Hz, 1H),
2.27e2.15 (m, 2H), 2.00e1.86 (m, 1H), 1.83e1.76 (m, 1H), 1.72e1.41
(m, 2H), 1.34 (t, J¼7.0 Hz, 3H), 1.33 (t, J¼7.3 Hz, 3H), 1.40e1.22 (m,
3H) ppm; 3c00:
d
4.83 (ddd, J¼4.3, 4.2, 4.2 Hz,1H), 4.35e4.11 (m, 4H),
4.5.1. Diethyl (3R*,3aS*,8aS*)-3-methyl-2-oxooctahydro-2H-cyclo-
hepta[b]furan-3-yl phosphonate (5a) and diethyl (3aS*,8aR*)-3-
3.04 (dd, JHeP¼23.7, J¼8.5 Hz, 1H), 2.27e2.15 (m, 2H), 2.00e1.86 (m,
1H), 1.83e1.76 (m, 1H), 1.72e1.41 (m, 2H), 1.35 (t, J¼7.5 Hz, 3H), 1.33
(t, J¼7.3 Hz, 3H), 1.40e1.22 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3)
methyl-2-oxooctahydro-2H-cyclohepta[b]furan-3-yl
(5a0). IR (neat) 1765, 1241, 1047, 1022, 967 cmꢀ1
(400 MHz, C6D6) 5a:
phosphonate
;
4.35e3.91 (m, 4H), 3.67 (ddd, J¼10.3, 10.3,
1H NMR
3c:
d
171.2, 84.5 (d, JCeP¼17.3 Hz), 63.5 (d, JCeP¼6.4 Hz), 62.4 (d,
d
JCeP¼6.6 Hz), 46.6 (d, JCeP¼1.8 Hz), 45.6 (d, JCeP¼155.8 Hz), 30.0,
4.7 Hz, 1H), 2.84e2.72 (m, 1H), 2.09e2.00 (m, 1H), 1.94e1.85 (m,
1H), 1.44e1.34 (m, 2H), 1.27 (d, JHeP¼17.3 Hz, 3H), 1.32e1.25 (m,
3H), 1.21e1.15 (m, 1H), 1.11 (t, J¼7.0 Hz, 3H), 1.03 (t, J¼7.0 Hz, 3H),
28.2, 25.1, 23.9, 16.5 (d, JCeP¼5.7 Hz), 16.4 (d, JCeP¼5.8 Hz) ppm; 3c0:
d
171.6 (d, JCeP¼4.5 Hz), 83.3, 63.6 (d, JCeP¼6.9 Hz), 62.2 (d,
JCeP¼6.9 Hz), 44.4 (d, JCeP¼132.5 Hz), 37.6 (d, JCeP¼2.1 Hz), 30.7,
1.07e1.01 (m, 1H), 0.97e0.89 (m, 1H) ppm; 5a0:
d 4.35e3.91 (m,
28.3, 25.6, 23.7,16.5 (d, JCeP¼5.7 Hz),16.4 (d, JCeP¼5.8 Hz) ppm; 3c00:
4H), 3.93 (ddd, J¼7.6, 7.5, 3.2 Hz, 1H), 3.53e3.39 (m, 1H), 2.20e2.11
(m, 1H), 2.09e2.00 (m, 1H), 1.44e1.34 (m, 2H), 1.26 (d, JHeP¼17.3 Hz,
3H), 1.32e1.25 (m, 3H), 1.21e1.15 (m, 1H), 1.11 (t, J¼7.0 Hz, 3H), 1.03
(t, J¼7.0 Hz, 3H), 1.07e1.01 (m, 1H), 0.97e0.89 (m, 1H) ppm; 13C
d
172.1 (d, JCeP¼3.9 Hz), 78.4 (d, JCeP¼2.2 Hz), 63.5 (d, JCeP¼6.4 Hz),
62.9 (d, JCeP¼6.7 Hz), 48.6 (d, JCeP¼134.5 Hz), 46.6 (d, JCeP¼1.8 Hz),
28.2, 27.4, 22.8, 19.6, 16.5 (d, JCeP¼5.7 Hz), 16.4 (d, JCeP¼5.8 Hz)
ppm; 31P NMR (161 MHz, CDCl3) 3c:
d
20.4 ppm; 3c0:
d
17.7 ppm;
NMR (100 MHz, C6D6) 5a:
d
175.1, 82.3 (d, JCeP¼12.6 Hz), 63.7 (d,
3c00:
found: 276.1130.
d
19.4 ppm; HRMS-EI: m/z [M]þ calcd for C12H21O5P: 276.1127;
JCeP¼5.8 Hz), 61.7 (d, JCeP¼6.0 Hz), 48.5 (d, JCeP¼151.3 Hz), 46.1,
32.7, 26.9, 25.3, 24.9, 23.8, 16.3 (d, JCeP¼5.4 Hz), 16.2 (d,
JCeP¼5.6 Hz), 13.5 (d, JCeP¼4.6 Hz) ppm; 5a0:
d 170.1, 82.2 (d,
4.4.4. Diethyl (3R*,3aS*,9aS*)-2-oxodecahydrocycloocta[b]furan-3-yl
phosphonate (3d) diethyl (3S*,3aS*,9aS*)-2-oxodecahydrocycloocta
[b]furan-3-yl phosphonate (3d0) and diethyl (3S*,3aS*,9aR*)-2-
oxodecahydrocycloocta[b]furan-3-yl phosphonate (3d00). The titled
compounds were similarly prepared as 3a/3a0 by using 2d
(374.4 mg, 1.126 mmol) as the starting material. After chromatog-
raphy (hexaneeEtOAc 3:1, 2:1, 1:1, 1:2), a mixture 3d/3d0/3d00 (dr:
75/7/18)25 was obtained as a colorless oil (274.3 mg, 80%). IR (neat)
JCeP¼16.0 Hz), 63.9 (d, JCeP¼6.2 Hz), 63.0 (d, JCeP¼6.2 Hz), 49.2 (d,
JCeP¼113.3 Hz), 44.8, 31.4, 26.4, 25.1, 25.0, 23.9, 16.5 (d,
JCeP¼4.9 Hz), 15.6 (d, JCeP¼5.4 Hz), 13.5 (d, JCeP¼4.6 Hz) ppm; 31P
NMR (161 MHz, C6D6) 5a: d d 39.2 ppm; HRMS-EI: m/
24.7 ppm; 5a0:
z [M]þ calcd for C14H25O5P: 304.1440; found: 304.1445.
4.5.2. Diethyl
(3R*,3aS*,8aS*)-2-oxo-3-propyloctahydro-2H-cyclo-
hepta[b]furan-3-yl phosphonate (5b) and diethyl (3aS*,8aR*)-2-oxo-
1771, 1252, 1052, 1022, 971 cmꢀ1
4.32e3.93 (m, 4H), 3.85 (ddd, J¼10.2, 8.3, 4.6 Hz, 1H), 2.76e2.56
(m, 1H), 2.50 (dd, JHeP¼23.4, J¼10.5 Hz, 1H), 2.11e2.04 (m, 1H),
;
1H NMR (400 MHz, C6D6) 3d:
3-propyloctahydro-2H-cyclohepta[b]furan-3-yl
phosphonate
d
(5b0). The titled compounds were similarly prepared as 5a/5a0 by
using 3a/3a0 (124.8 mg, 0.494 mmol, dr: 82/18) as the starting

1598
J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
materials and 1-iodopropane as the alkylating reagent. After
chromatography (hexaneeEtOAc 6:1, 3:1, 2:1, 1:1), a mixture 5b/
5b0 (dr: 97/3)25 was obtained as a colorless oil (112.4 mg, 78%). IR
(neat) 1766, 1246, 1052, 1020, 968 cmꢀ1; 1H NMR (400 MHz, C6D6)
CDCl3) 5d: d d
24.9 ppm; 5d0: 22.9 ppm; HRMS-EI: m/z [M]þ
calcd for C14H25O5P: 304.1440; found: 304.1429.
4.5.5. Diethyl (3R*,3aS*,9aS*)-2-oxo-3-pentyldecahydrocycloocta[b]
furan-3-yl phosphonate (5e) and diethyl (3aS*,9aR*)-2-oxo-3-
pentyldecahydrocycloocta[b]furan-3-yl phosphonate(5e0). The titled
compounds were similarly prepared as 5a/5a0 by using 3d/3d0/3d00
(115.2 mg, 0.3786 mmol, dr: 75/7/18) as the starting materials and
1-iodopentane as the alkylating reagent. After chromatography
(hexaneeEtOAc 5:1, 3:1, 1:1, 1:2), a mixture of 5e/5e0 (dr: 90/10)25
was obtained as a colorless oil (66.8 mg, 63%). IR (neat) 1766,
5b:
d
4.33e3.92 (m, 4H), 3.84 (ddd, J¼10.3, 10.3, 4.1 Hz, 1H),
3.04e2.91 (m, 1H), 2.24e2.13 (m, 1H), 2.13e2.04 (m, 1H), 1.96e1.87
(m, 1H), 1.77e1.66 (m, 1H), 1.58e1.49 (m, 1H), 1.46e1.20 (m, 6H),
1.20e1.14 (m, 2H), 1.10 (t, J¼7.0 Hz, 3H), 1.04 (t, J¼7.0 Hz, 3H),
1.13e1.08 (m, 1H), 0.76 (t, J¼7.3 Hz, 3H) ppm; 5b0:
d 4.33e3.92 (m,
4H), 4.12 (ddd, J¼7.2, 7.1, 3.2 Hz, 1H), 3.04e2.91 (m, 1H), 2.24e2.13
(m, 1H), 2.13e2.04 (m, 1H), 1.96e1.87 (m, 1H), 1.77e1.66 (m, 1H),
1.58e1.49 (m, 1H), 1.46e1.20 (m, 6H), 1.20e1.14 (m, 2H), 1.10 (t,
J¼7.0 Hz, 3H), 1.04 (t, J¼7.0 Hz, 3H), 1.13e1.08 (m, 1H), 0.82 (t,
1248, 1052, 1024, 968 cmꢀ1 1H NMR (400 MHz, CDCl3) 5e:
; d 4.27
(ddd, J¼9.4, 9.4, 4.1 Hz, 1H), 4.23e4.07 (m, 4H), 2.89e2.76 (m, 1H),
2.34e2.07 (m, 2H), 2.03e1.89 (m, 2H), 1.87e1.58 (m, 7H), 1.46e1.37
(m, 5H), 1.29 (t, J¼7.0 Hz, 3H), 1.28 (t, J¼7.0 Hz, 3H), 1.32e1.25 (m,
J¼7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) 5b:
d 174.7, 83.6 (d,
JCeP¼12.8 Hz), 63.6 (d, JCeP¼6.8 Hz), 62.6 (d, JCeP¼7.2 Hz), 52.9 (d,
JCeP¼147.2 Hz), 46.5, 33.8, 31.0 (d, JCeP¼3.3 Hz), 27.0, 25.3, 24.6,
24.2, 19.5 (d, JCeP¼13.2 Hz), 16.4 (d, JCeP¼5.7 Hz), 16.3 (d,
4H), 0.82 (t, J¼6.9 Hz, 3H) ppm; 5e0:
4.66 (ddd, J¼10.1, 7.4, 3.8 Hz,
d
1H), 4.23e4.07 (m, 4H), 2.89e2.76 (m, 1H), 2.34e2.07 (m, 2H),
2.03e1.89 (m, 2H), 1.87e1.58 (m, 7H), 1.46e1.37 (m, 5H), 1.29 (t,
J¼7.0 Hz, 3H), 1.28 (t, J¼7.0 Hz, 3H), 1.32e1.25 (m, 4H), 0.82 (t,
JCeP¼5.8 Hz), 14.4 ppm; 5b0:
179.8, 83.4 (d, JCeP¼8.2 Hz), 63.7 (d,
d
JCeP¼5.4 Hz), 62.5 (d, JCeP¼7.9 Hz), 52.9 (d, JCeP¼147.2 Hz), 44.7,
33.6, 31.0 (d, JCeP¼3.3 Hz), 26.9, 25.1, 24.5, 24.2, 19.5 (d,
JCeP¼13.2 Hz), 16.4 (d, JCeP¼5.7 Hz), 16.3 (d, JCeP¼7.8 Hz),
J¼6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) 5e:
d 174.4, 85.5 (d,
JCeP¼11.7 Hz), 63.5 (d, JCeP¼6.8 Hz), 62.8 (d, JCeP¼7.2 Hz), 53.3 (d,
JCeP¼145.8 Hz), 45.4, 35.3, 32.1, 28.9 (d, JCeP¼3.3 Hz), 27.5, 27.3, 27.1,
25.9 (d, JCeP¼13.7 Hz), 25.3, 22.6, 22.3, 16.5 (d, JCeP¼3.3 Hz), 16.4 (d,
14.6 ppm; 31P NMR (161 MHz, CDCl3) 5b:
d
24.9 ppm; 5b0:
d
24.6 ppm; HRMS-EI: m/z [M]þ calcd for C16H29O5P: 332.1753;
found: 332.1756.
JCeP¼3.4 Hz), 13.9 ppm; 5e0:
d
173.7, 83.9 (d, JCeP¼8.4 Hz), 63.7 (d,
JCeP¼7.1 Hz), 62.5 (d, JCeP¼7.4 Hz), 52.9 (d, JCeP¼138.6 Hz), 43.3,
33.2, 32.3, 30.1, 29.6 (d, JCeP¼3.9 Hz), 29.2, 27.7, 25.6 (d,
JCeP¼8.9 Hz), 25.4, 22.9, 22.4, 16.4 (d, JCeP¼3.4 Hz), 16.1 (d,
4.5.3. Diethyl (3aS*,6aR*)-3-hexyl-2-oxohexahydro-2H-cyclopenta
[b]furan-3-yl phosphonate (5c). The titled compound was similarly
prepared as 5a/5a0 by using 3b (9.2 mg, 0.0351 mmol) as the
starting material and 1-iodohexane as the alkylating reagent. After
chromatography (hexaneeEtOAc 5:1, 3:1, 1:1, 0:100), 5c was ob-
tained as a single diastereomer (8.0 mg, 66%). IR (neat) 1762, 1247,
JCeP¼6.6 Hz), 14.2 ppm; 31P NMR (161 MHz, CDCl3) 5e:
d 24.9 ppm;
5e0: 21.6 ppm; HRMS-EI: m/z [M]þ calcd for C19H35O5P: 374.2222;
d
found: 374.2214.
1052, 1023, 965 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
4.88 (ddd, J¼6.1,
4.6. Typical procedure for the reductive alkylation of lactones
solution of 5a/5a0 (71.1 mg,
5.6, 2.0 Hz, 1H), 4.30e4.14 (m, 4H), 2.75e2.67 (m, 1H), 2.37e2.26
(m, 1H), 1.99e1.79 (m, 6H), 1.60e1.50 (m, 2H), 1.34 (t, J¼6.3 Hz, 6H),
1.39e1.26 (m, 7H), 0.87 (t, J¼6.6 Hz, 3H) ppm; 13C NMR (100 MHz,
Under N2 protection,
a
0.2336 mmol, dr: 81/19) in dry THF (4 mL) was stirred at ꢀ78 ꢁC
for 40 min followed by the addition of the LN solution in THF22
(0.186 M, 8 mL, 1.49 mmol) pre-cooled at ꢀ78 ꢁC via a syringe.
The resulting dark-green solution was stirred at ꢀ78 ꢁC for
30 min, then was successively added with CH2]CHCH2Br (99%,
0.12 mL, 1.365 mmol) and HMPA (99%, 0.12 mL, 0.6825 mmol).
The reaction mixture was continued to stir at ꢀ78 ꢁC for 30 min
and rt for 1 h, then quenched by water (2 mL) and extracted with
ethyl acetate (150 mL). The organic layer was separated and
washed with water (30 mLꢂ2) and brine (20 mL). After con-
centration, the crude mixture was purified by flash chromatog-
raphy (hexaneeEtOAc 100:0, 60:1, 40:1, 20:1, 10:1) to afford
a mixture of 6a/6a0/6a00(21 mg, 43%, dr: 80/14/1625) as a colorless
oil.
CDCl3)
d
175.9, 84.7 (d, JCeP¼9.4 Hz), 63.0 (d, JCeP¼6.6 Hz), 62.6 (d,
JCeP¼7.1 Hz), 53.8 (d, JCeP¼150.8 Hz), 47.9, 35.9 (d, JCeP¼3.3 Hz),
32.7, 31.5, 29.6, 29.5, 25.0 (d, JCeP¼8.4 Hz), 24.7, 22.5, 16.5 (d,
JCeP¼4.7 Hz), 16.4 (d, JCeP¼5.1 Hz), 14.0 ppm; 31P NMR (161 MHz,
CDCl3)
d
23.0 ppm; HRMS-EI: m/z [M]þ calcd for C17H31O5P:
346.1909; found: 346.1903.
4.5.4. Diethyl (3R*,3aS*,7aS*)-3-ethyl-2-oxooctahydrobenzofuran-3-
yl phosphonate (5d) and diethyl (3aS*,7aR*)-3-ethyl-2-
oxooctahydrobenzofuran-3-yl phosphonate (5d0). The titled com-
pounds were similarly prepared as 5a/5a0 by using 3c/3c0/3c00
(95.4 mg, 0.3454 mmol, dr: 69/14/17) as the starting materials
and iodoethane as the alkylating reagent. After chromatography
(hexaneeEtOAc 3:1, 1:1, 0:100), a mixture of 5d/5d0 was obtained
as a colorless oil (132.8 mg, 94%). IR (neat) 1770, 1246, 1035,
4.6.1. (3S*,3aR*,8aS*)-3-Allyl-3-methyloctahydro-2H-cyclohepta[b]
furan-2-one (6a), (3R*,3aR*,8aS*)-3-allyl-3-methyloctahydro-2H-cy-
clohepta[b]furan-2-one (6a0) and (3aR*,8aR*)-3-allyl-3-
966 cmꢀ1 1H NMR (400 MHz, CDCl3) 5d:
; d 4.34e4.06 (m, 4H),
3.97 (ddd, J¼11.0, 11.0, 3.8 Hz, 1H), 2.49e2.38 (m, 1H), 2.29e2.19
(m, 1H), 2.09e1.64 (m, 6H), 1.62e1.49 (m, 1H), 1.35 (t, J¼6.7 Hz,
3H), 1.32 (t, J¼6.5 Hz, 3H), 1.37e1.30 (m, 2H), 1.14 (t, J¼7.6 Hz,
methyloctahydro-2H-cyclohepta[b]furan-2-one
3042, 1769, 1655, 1151, 1004, 916 cmꢀ1; 1H NMR (400 MHz, CDCl3)
6a:
(6a00). IR (neat)
3H) ppm; 5d0:
d
4.64e4.59 (m, 1H), 4.34e4.06 (m, 4H),
d
5.83e5.70 (m, 1H), 5.11 (br d, J¼11.3 Hz, 1H), 5.10 (br d,
2.38e2.33 (m, 1H), 2.29e2.19 (m, 1H), 2.09e1.64 (m, 6H),
1.62e1.49 (m, 1H), 1.35 (t, J¼6.7 Hz, 3H), 1.32 (t, J¼6.5 Hz, 3H),
1.37e1.30 (m, 2H), 1.11 (t, J¼7.8 Hz, 3H) ppm; 13C NMR (100 MHz,
J¼15.4 Hz, 1H), 4.23 (ddd, J¼10.2, 10.2, 4.7 Hz, 1H), 2.40e2.25 (m,
1H), 2.30 (dd, J¼14.5, 7.9 Hz, 1H), 2.13 (dd, J¼14.5, 7.6 Hz, 1H), 1.97
(ddd, J¼11.0, 10.7, 3.6 Hz, 1H), 1.78e1.66 (m, 3H), 1.64e1.44 (m,
CDCl3) 5d:
d
174.5 (d, JCeP¼1.4 Hz), 81.7 (d, JCeP¼13.8 Hz), 63.4
6 Hz), 1.18 (s, 3H) ppm; 6a0:
d 5.82e5.68 (m, 1H), 5.10e5.06 (m, 2H),
(d, JCeP¼6.7 Hz), 62.5 (d, JCeP¼7.0 Hz), 51.9 (d, JCeP¼151.7 Hz),
49.8, 30.8, 25.3, 24.7, 23.9, 20.5 (d, JCeP¼3.4 Hz), 16.4 (d,
JCeP¼5.1 Hz), 16.3 (d, JCeP¼4.8 Hz), 10.8 (d, JCeP¼6.2 Hz) ppm;
4.16 (ddd, J¼10.2, 10.1, 4.2 Hz, 1H), 2.40e2.25 (m, 2H), 2.17 (dd,
J¼17.6, 8.8 Hz, 1H), 2.09e2.05 (m, 1H), 1.78e1.66 (m, 3H), 1.64e1.44
(m, 6 Hz), 1.09 (s, 3H) ppm; 6a00:
d 6.18e6.01 (m, 1H), 5.10e5.06 (m,
5d0:
d
175.6 (d, JCeP¼2.4 Hz), 81.7 (d, JCeP¼13.8 Hz), 63.6
2H), 4.58 (ddd, J¼11.4, 8.3, 3.6 Hz, 1H), 2.40e2.09 (m, 3H),
(d, JCeP¼6.1 Hz), 62.7 (d, JCeP¼6.7 Hz), 56.5 (d, JCeP¼152.3 Hz),
42.3, 27.5, 24.9, 24.8, 23.4, 19.6, 16.4 (d, JCeP¼5.1 Hz), 16.3
(d, JCeP¼4.8 Hz), 10.4 (d, JCeP¼0.6 Hz) ppm; 31P NMR (161 MHz,
2.09e1.89 (m, 1H), 1.78e1.66 (m, 3H), 1.64e1.44 (m, 6 Hz), 1.15 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3) 6a:
d
180.4, 133.2, 118.8, 81.9,
52.9, 47.3, 37.7, 33.4, 27.2, 25.8, 24.0, 23.8, 22.1 ppm; 6a0:
d
180.4,

J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
1599
133.4, 118.8, 82.1, 52.9, 47.6, 37.7, 33.4, 27.2, 25.7, 24.0, 23.8,
22.5, 14.1 ppm; HRMS-EI: m/z [M]þ calcd for C22H32O2: 328.2402;
found: 328.2408.
22.1 ppm; 6a00:
d
181.1, 133.0, 118.9, 82.2, 52.9, 46.8, 37.7, 33.1, 27.1,
25.6, 24.3, 24.1, 22.1 ppm; HRMS-EI: m/z [M]þ calcd for C13H20O2:
208.1463; found: 208.1461.
4.7. Typical procedure for the HWE reactions
4.6.2. (3S*,3aR*,8aS*)-3-Benzyl-3-propyloctahydro-2H-cyclohepta[b]
furan-2-one (6b) and (3aR*,8aR*)-3-benzyl-3-propyloctahydro-2H-
cyclohepta[b]furan-2-one (6b0). The titled compounds were simi-
larly prepared as 6a/6a0/6a00 by using 5b/5b0 (103.9 mg,
0.3126 mmol, dr: 97/3) as the starting materials and BnBr as the
alkylating reagent. After chromatography (hexaneeEtOAc 100:0,
80:1, 40:1, 30:1, 10:1), a mixture of 6b/6b0 (dr: 96/4)25 was ob-
tained as a yellow oil (54 mg, 60%). IR (neat) 3062, 3029, 1767,
Under N2 protection, t-BuOꢀKþ (98%, 24.5 mg, 0.214 mmol) was
added to a solution of 3a/3a0 (51.8 mg, 0.1784 mmol, dr: 82/18) in
THF (3.6 mL) pre-cooled at 0 ꢁC. After stirring at 0 ꢁC for 1 h then
ꢀ80 ꢁC for 10 min, paraformaldehyde (90%, 11.9 mg, 0.357 mmol)
was introduced in one portion. The reaction mixture was continued
to stir at 0 ꢁC for 1 h, then diluted by ethyl acetate (100 mL), washed
with saturated aqueous NH4Cl solution (20 mLꢂ2), water (20 mL)
and brine (20 mL). After concentration, the crude mixture was
subjected to flash chromatography [silica gel: pre-washed with
200 mL of Et3N/hexane (v/v 1/100); hexaneeEtOAc 5:1] to give
a mixture of 7a33/7a026 (22.5 mg, 76%, dr: 82/18).25
1603, 1165, 1007, 728, 700 cmꢀ1 1H NMR (400 MHz, CDCl3) 6b:
;
d
7.30e7.21 (m, 3H), 7.20e7.15 (m, 2H), 3.77 (ddd, J¼10.2, 10.2,
4.6 Hz, 1H), 2.85 (d, J¼13.8 Hz, 1H), 2.77 (d, J¼13.8 Hz, 1H),
2.30e2.18 (m, 2H), 1.88e1.78 (m, 1H), 1.74e1.58 (m, 5H), 1.57e1.37
(m, 6H), 1.30e1.20 (m, 1H), 0.93 (t, J¼7.2 Hz, 3H) ppm; 6b0:
4.7.1. (3aR*,8aS*)-3-Methyleneoctahydro-2H-cyclohepta[b]furan-2-
d
7.30e7.21 (m, 3H), 7.20e7.15 (m, 2H), 4.14e4.06 (m, 1H), 3.13 (d,
one (7a) and (3aR*,8aR*)-3-methyleneoctahydro-2H-cyclohepta[b]
J¼13.6 Hz, 1H), 2.70 (d, J¼13.6 Hz, 1H), 2.05e1.96 (m, 2H),
1.88e1.78 (m, 1H), 1.74e1.58 (m, 5H), 1.57e1.37 (m, 6H), 1.30e1.20
(m, 1H), 0.90 (t, J¼7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) 6b:
furan-2-one (7a0). 1H NMR (400 MHz, CDCl3) 7a:
d
6.16 (d, J¼3.5 Hz,
1H), 5.45 (d, J¼3.5 Hz, 1H), 4.13 (ddd, J¼10.3, 10.1, 4.2 Hz, 1H),
2.82e2.72 (m, 1H), 2.42e2.33 (m, 1H), 2.21e2.10 (m, 1H), 1.82e1.68
d
179.6, 136.5, 130.4, 128.2, 126.9, 81.4, 52.5, 48.6, 38.7, 37.4, 33.8,
(m, 3H), 1.68e1.53 (m, 4H), 1.50e1.40 (m, 1H) ppm; 7a0:
d 6.25 (d,
27.0, 26.0, 23.9, 23.9, 17.7, 14.5 ppm; 6b0:
d
180.0, 137.7, 130.1,
J¼3.0 Hz, 1H), 5.53 (d, J¼3.0 Hz, 1H), 4.69 (ddd, J¼10.5, 7.8, 3.7 Hz,
1H), 3.26e3.19 (m, 1H), 2.38e2.31 (m, 1H), 2.08e2.01 (m, 1H),
1.96e1.68 (m, 3H), 1.68e1.53 (m, 4H), 1.39e1.23 (m, 1H) ppm; 13C
128.5, 126.6, 80.7, 51.4, 47.5, 38.5, 35.7, 31.6, 27.6, 25.7, 23.8, 23.8,
18.0, 14.7 ppm; HRMS-EI: m/z [M]þ calcd for C19H26O2: 286.1933;
found: 286.1931.
NMR (100 MHz, CDCl3) 7a:
d
170.5, 141.0, 119.6, 83.3, 45.6, 33.0,
d 170.3, 140.4, 122.0, 82.3, 43.1, 31.8,
28.0, 27.3, 25.3, 25.1 ppm; 7a0:
4.6.3. (3R*,3aR*,7aS*)-3-Ethyl-3-methylhexahydrobenzofuran-
2 ( 3 H ) - o n e ( 6 c ) a n d ( 3 a R * , 7 a R * ) - 3 - e t h y l - 3 -
methylhexahydrobenzofuran-2(3H)-one (6c0). The titled com-
pounds were similarly prepared as 6a/6a0/6a00 by using 5d/5d0
(40.4 mg, 0.1327 mmol, dr: 82/18) as the starting materials and
CH3I as the alkylating reagent. After chromatography (hex-
aneeEtOAc 100:0, 70:1, 40:1, 30:1, 10:1), a mixture of 6c/6c0 (dr:
44/56)25 was obtained as a colorless oil (10 mg, 43%). IR (neat)
31.2, 30.7, 27.4, 24.2 ppm.
4.7.2. (3aR*,8aS*,Z)-3-Propylideneoctahydro-2H-cyclohepta[b]furan-
2-one (7b) and (3aR*,8aR*,Z)-3-propylideneoctahydro-2H-cyclohepta
[b]furan-2-one (7b0). The titled compounds were similarly pre-
pared as 7a/7a0 by using 3a/3a0 (87.2 mg, 0.3003 mmol, dr: 81/19)
as the starting materials and propionaldehyde as the aldehyde
component. After chromatography (hexaneeEtOAc 30:1, 10:1, 5:1,
3:1, 1:1), a mixture of 7b/7b0 (dr: 95/5)25 was obtained as a pale
yellow oil (28.3 mg, 48%). IR (neat) 3055, 1753, 1669, 1128, 1008,
1770, 1115, 1029 cmꢀ1 1H NMR (400 MHz, CDCl3) 6c:
; d 3.86 (ddd,
J¼10.9, 10.8, 3.6 Hz, 1H), 2.29e2.25 (m, 1H), 1.97e1.87 (m, 1H),
1.83e1.51 (m, 6H), 1.50e1.30 (m, 2H), 1.17e1.11 (m, 1H), 1.07 (s,
887 cmꢀ1
;
1H NMR (400 MHz, CDCl3) 7b:
d
5.95 (td, J¼7.5, 2.6 Hz,
3H), 0.92 (t, J¼7.5 Hz, 3H) ppm; 6c0:
d
4.64 (m, 1H), 2.25e2.21 (m,
1H), 4.10 (ddd, J¼10.1, 9.9, 4.0 Hz,1H), 2.80e2.64 (m, 3H), 2.39e2.28
1H), 1.97e1.87 (m, 1H), 1.83e1.51 (m, 6H), 1.50e1.30 (m, 2H),
(m, 1H), 2.14e2.03 (m, 1H), 1.81e1.49 (m, 7H), 1.43e1.33 (m, 1H),
1.17e1.11 (m, 1H), 1.23 (s, 3H), 0.92 (t, J¼7.5 Hz, 3H) ppm; 13C NMR
1.04 (t, J¼7.4 Hz, 3H) ppm; 7b0:
d
6.08 (td, J¼7.5, 2.6 Hz, 1H), 4.62
(100 MHz, CDCl3) 6c:
d
181.6, 80.1, 49.0, 45.9, 30.7, 29.4, 25.4, 24.4,
d 182.1, 75.4, 50.3, 43.8, 27.8, 24.3, 23.8,
(ddd, J¼10.5, 9.8, 4.5 Hz, 1H), 2.80e2.64 (m, 3H), 2.28e2.19 (m, 1H),
2.00e1.93 (m, 1H), 1.81e1.49 (m, 7H), 1.29e1.17 (m, 1H), 1.04 (t,
24.1, 16.0, 8.7 ppm; 6c0:
23.6, 19.8, 18.9, 8.2 ppm; HRMS-EI: m/z [M]þ calcd for C11H18O2:
J¼7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) 7b:
d 170.1, 143.0,
182.1307; found: 182.1314.
130.1, 82.7, 46.3, 33.2, 28.3, 27.3, 25.4, 25.3, 20.8, 13.7 ppm; 7b0:
d
167.4, 145.9, 131.1, 81.4, 44.4, 34.0, 32.0, 31.7, 25.5, 25.3, 21.0,
4.6.4. (3S*,3aR*,9aS*)-3-Benzyl-3-pentyloctahydrocycloocta[b]furan-
2 ( 3 H ) - o n e ( 6 d ) a n d ( 3 a R * , 9 a R * ) - 3 - b e n z y l - 3 -
pentyloctahydrocycloocta[b]furan-2(3H)-one (6d0). The titled com-
pounds were similarly prepared as 6a/6a0/6a00 by using 5e/5e0
(39 mg, 0.1082 mmol, dr: 90/10) as the starting materials and
BnBr as the alkylating reagent. After chromatography (hex-
aneeEtOAc 100:0, 60:1, 30:1, 10:1), a mixture of 6d/6d0 (dr: 83/
17)25 was obtained as a pale yellow oil (23 mg, 65%). IR (neat)
13.7 ppm; HRMS-EI: m/z [M]þ calcd for C12H18O2: 194.1307; found:
194.1301.
4.7.3. (3aR*,6aR*)-3-Methylenehexahydro-2H-cyclopenta[b]furan-2-
one (7c). The titled compound were similarly prepared as 7a/7a0 by
using 3b (30.6 mg, 0.1167 mmol) as the starting material and
paraformaldehyde as the aldehyde component. After chromatog-
raphy (silica gel: pre-washed with 100 mL of Et3N/hexane (v/v 1/
100); hexaneeEtOAc 15:1, 5:1, 1:1), 7c38 was obtained as a pale
3060, 3028, 1764, 1602, 1179, 747, 700 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) 6d:
d
7.24e7.12 (m, 5H), 3.80 (ddd, J¼9.6, 9.5, 3.6 Hz, 1H),
yellow oil (5.3 mg, 67%). 1H NMR (400 MHz, CDCl3)
d 6.25 (d,
J¼2.6 Hz,1H), 5.64 (d, J¼2.6 Hz,1H), 4.99 (t, J¼6.3 Hz,1H), 3.41 (ddd,
J¼8.7, 6.3, 2.1 Hz, 1H), 2.10e2.03 (m, 1H), 2.00e1.89 (m, 1H),
1.77e1.65 (m, 3H), 1.62e1.53 (m, 1H) ppm; 13C NMR (100 MHz,
2.83 (d, J¼13.8 Hz, 1H), 2.74 (d, J¼13.8 Hz, 1H), 2.28e2.21 (m, 1H),
2.17e2.07 (m, 1H), 1.95e1.70 (m, 3H), 1.70e1.53 (m, 5H), 1.41e1.24
(m, 10H), 0.88 (t, J¼6.8 Hz, 3H), 0.93e0.86 (m, 1H) ppm; 6d0:
d
7.24e7.12 (m, 5H), 4.40 (ddd, J¼8.9, 8.9, 3.6 Hz, 1H), 3.22 (d,
CDCl3) d 171.1, 140.4, 122.7, 83.2, 43.0, 35.6, 33.8, 23.0 ppm.
J¼13.7 Hz, 1H), 2.61 (d, J¼13.7 Hz, 1H), 2.35e2.28 (m, 1H),
1.96e1.89 (m, 1H), 1.89e1.70 (m, 3H), 1.70e1.53 (m, 5H), 1.41e1.24
(m, 10H), 0.91 (t, J¼7.0 Hz, 3H), 0.93e0.86 (m, 1H) ppm; 13C NMR
4.7.4. (3aR*,7aS*)-3-Methylenehexahydrobenzofuran-2(3H)-one
(7d) and (3aR*,7aR*)-3-methylenehexahydrobenzofuran-2(3H)-one
(7d0). The titled compounds were similarly prepared as 7a/7a0 by
using 3c/3c0/3c00 (34.23 mg, 0.1239 mmol, dr: 69/14/17) as the
(100 MHz, CDCl3)37 6d0:
d 179.6, 137.5, 130.2, 128.4, 126.8, 83.6,
52.8, 45.1, 40.8, 34.5, 33.8, 32.5, 29.7, 28.0, 26.8, 25.7, 24.2, 22.6,

1600
J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
starting materials and paraformaldehyde as the aldehyde compo-
nent. After chromatography (hexaneeEtOAc 10:1, 5:1, 3:1, 1:1),
a mixture19c of 7d/7d0 (dr: 88/12)25 was obtained as a yellow oil
and Miss Ly-Mei Syu and Miss Mei-Yue Jian from the Department of
Chemistry of National Chung Hsing University for the helps in
HRMS and NMR analyses.
(12.7 mg, 67%). 1H NMR (400 MHz, CDCl3) 7d:
d
6.06 (d, J¼3.2 Hz,
1H), 5.37 (d, J¼3.2 Hz, 1H), 3.70 (ddd, J¼11.1, 11.0, 3.6 Hz, 1H),
2.44e2.35 (m, 1H), 2.29e2.22 (m, 1H), 2.16e2.10 (m, 1H), 1.99e1.93
(m, 1H), 1.88e1.82 (m, 1H), 1.67e1.57 (m, 1H), 1.48e1.30 (m, 3H)
Supplementary data
Supplementary data (The 1H, 13C NMR spectra of all compounds
in this article, the 31P NMR spectra of the phosphoryl compounds,
the NOSEY spectra of the mixtures of 3a/3a0, 3c/3c0/3c00, 3d/3d0/3d00,
5a/5a0, 5b/5b0, 5d/5d0, 5e/5e0, 6a/6a0/6a00 and 6b/6b0, and the pro-
posed transition states for forming 3b, 3c/3c0/3c00 and 3d/3d0/3d00)
associated with this article can be found in the online version, at
http://dx.doi.org/10.1016/j.tet.2016.02.008.
ppm; 7d0:
d
6.19 (d, J¼2.4 Hz, 1H), 5.51 (d, J¼2.4 Hz, 1H), 4.53 (ddd,
J¼6.3, 6.3, 6.3 Hz, 1H), 3.06e2.98 (m, 1H), 2.29e2.22 (m, 1H),
2.16e2.10 (m, 1H), 2.02e1.81 (m 2H), 1.70e1.54 (m, 1H), 1.48e1.23
(m, 3H) ppm; 13C NMR (100 MHz, CDCl3) 7d:
d
170.7, 139.6, 117.1,
83.1, 48.9, 30.5, 25.8, 24.9, 24.0 ppm; 7d0:
d 171.0, 139.9, 119.7, 83.1,
39.6, 28.9, 26.3, 21.1, 20.5 ppm.
4.7.5. (3aR*,7aS*,Z)-3-Propylidenehexahydrobenzofuran-2(3H)-one
(7e), (3aR*,7aS*,E)-3-propylidenehexahydrobenzofuran-2(3H)-one
References and notes
(7e0) and (3aR*,7aR*,Z)-3-propylidenehexahydrobenzofuran-2(3H)-
one (7e00). The titled compounds were similarly prepared as 7a/7a0
by using 3c/3c0/3c00 (68.5 mg, 0.248 mmol, dr: 69/14/17) as the
starting materials and propionaldehyde as the aldehyde compo-
nent. Chromatographic purification (hexaneeEtOAc 40:1, 30:1,
10:1, 5:1) afforded 7e (11.7 mg, 46%) followed by a mixture of 7e0/
7e00 (4.6 mg, 20%, dr: 93/7).25 7e: IR (neat) 1760, 1682, 1287, 1004,
1. For reviews, see: (a) Doyle, M. P. Chem. Rev. 1986, 86, 919e939; (b) Ye, T.;
McKervey, M. A. Chem. Rev. 1994, 94, 1091e1160; (c) Davies, H. M. L.; Beckwith,
R. E. J. Chem. Rev. 2003, 103, 2861e2903; (d) Gois, P. M. P.; Afonso, C. A. M. Eur. J.
Org. Chem. 2004, 3773e3788; (e) Wee, A. G. H. Curr. Org. Synth. 2006, 3,
499e555; (f) Zhang, Z.; Wang, J. Tetrahedron 2008, 64, 6577e6605; (g) Davies,
H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061e3071.
2. For examples, see: (a) Wenkert, E.; Davis, L. L.; Mylari, B. L.; Solomon, M. F.; da
Silva, R. R.; Shulman, S.; Warnet, R. J. J. Org. Chem. 1982, 47, 3242e3247; (b)
Estevan, F.; Herbst, K.; Lahuerta, P. Organometallics 2001, 20, 950e957; (c)
Harada, S.; Kono, M.; Nozaki, T.; Menjo, Y.; Nemoto, T.; Hamada, Y. J. Org. Chem.
2015, 80, 10317e10333.
792 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
5.85 (td, J¼7.7, 2.8 Hz, 1H),
3.64 (ddd, J¼11.1, 11.1, 3.7 Hz, 1H), 2.73e2.56 (m, 2H), 2.39e2.30 (m,
1H), 2.24e2.17 (m, 1H), 2.07e2.01 (m, 1H), 1.97e1.90 (m, 1H),
1.86e1.79 (m, 1H), 1.65e1.52 (m, 1H), 1.44e1.20 (m, 3H), 1.03 (t,
3. Forexamples, see: (a) Taber, D. F.; Paquette, C. M.; Gu, P.; Tian, W. J. Org. Chem. 2013,
78, 9772e9780; (b) Fu, L.; Wang, H.; Davies, H. M. L. Org. Lett. 2014,16, 3036e3039;
(c) Ma, X.; Wu, F.; Yi, X.; Wang, H.; Chen, W. Chem. Commun. 2015, 6862e6865.
4. (a) Taber, D. F.; Schuchardt, J. L. J. Am. Chem. Soc. 1985, 107, 5289e5290; (b)
Taber, D. F.; Malcolm, S. C. J. Org. Chem. 2001, 66, 944e953; (c) Rodriguez-
J¼7.6 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d 170.2, 140.1, 129.3,
82.9, 49.3, 30.4, 25.9, 24.8, 23.9, 20.9, 13.7 ppm; HRMS-EI: m/z [M]þ
calcd for C11H16O2: 180.1150; found: 180.1158. 7e0/7e00: IR (neat)
ꢁ
Cardenas, E.; Sabala, R.; Romero-Ortega, M.; Ortiz, A.; Olivo, H. F. Org. Lett. 2012,
14, 238e240; (d) Padwa, A.; Zou, Y. J. Org. Chem. 2015, 80, 1802e1808.
5. Lee, E.; Jung, K. W.; Kim, Y. S. Tetrahedron Lett. 1990, 31, 1023e1026.
6. Doyle, M. P.; Tauton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397e5400.
7. (a) Yoon, C. H.; Zaworotko, M. J.; Moulton, B.; Jung, K. W. Org. Lett. 2001, 3,
3539e3542; (b) Yoon, C. H.; Flanigan, D. L.; Chong, B. D.; Jung, K. W. J. Org. Chem.
2002, 67, 6582e6584.
8. Wolckenhauer, S. A.; Devlin, A. S.; Bois, J. D. Org. Lett. 2007, 9, 4363e4366.
9. (a) Wee, A. G. H.; Liu, B.; Zhang, L. J. Org. Chem. 1992, 57, 4404e4414; (b) Padwa,
A. P.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.; Protopopova, M. N.;
Winchester, W. R.; Tran, A. J. Am. Chem. Soc. 1993, 115, 8669e8680.
10. For the acceptor/acceptor precursors shown in Fig. 1, independent assortment
of COX and/or Y substitutions is considered.
11. For examples, see: (a) Taber, D. F.; Petty, E. H.; Raman, K. J. Am. Chem. Soc. 1985,
107, 196e199; (b) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79e82;
(c) Anada, M.; Mita, O.; Watanabe, H.; Kitagaki, S.; Hashimoto, S. Synlett 1999,
1775e1777.
12. Savignac, P.; Iorga, B. Modern Phosphonate Chemistry; CPR Press: Boca Raton,
2003.
1764, 1682, 1208, 1006, 730 cmꢀ1 1H NMR (400 MHz, CDCl3) 7e0:
;
d
6.61 (td, J¼7.8, 3.0 Hz, 1H), 3.69 (ddd, J¼11.0, 11.0, 3.6 Hz, 1H),
2.52e2.36 (m, 2H), 2.36e2.20 (m, 2H), 1.98e1.90 (m, 1H), 1.87e1.81
(m, 1H), 1.65e1.57 (m, 1H), 1.57e1.45 (m, 1H), 1.44e1.34 (m, 2H),
1.27e1.23 (m, 1H), 1.06 (t, J¼7.5 Hz, 3H) ppm; 7e00:
d 5.25 (br t,
J¼4.9 Hz, 1H), 4.43e4.39 (m, 1H), 2.52e2.36 (m, 2H), 2.36e2.20 (m,
2H), 1.90e1.84 (m, 1H), 1.76e1.72 (m, 1H), 1.65e1.57 (m, 1H),
1.57e1.45 (m, 1H), 1.44e1.34 (m, 2H), 1.23e1.20 (m, 1H), 1.08 (t,
13
J¼7.5 Hz, 3H) ppm; C NMR (100 MHz, CDCl3) 7e0:
d
171.8, 140.3,
177.5,
129.1, 82.7, 48.1, 30.4, 27.4, 25.5, 23.8, 21.3, 13.6 ppm; 7e00:
d
140.1, 124.8, 81.7, 50.2, 29.7, 29.7, 26.5, 25.5, 19.3, 13.4 ppm; HRMS-
EI: m/z [M]þ calcd for C11H16O2: 180.1150; found: 180.1148.
13. (a) Liao, C. C.; Zhu, J. L. J. Org. Chem. 2009, 74, 7873e7884; (b) Zhu, J. L.; Bau, J. S.;
Shih, Y. C. Synlett 2012, 863e866; (c) Zhu, J. L.; Wu, S. T.; Shie, J. Y. J. Org. Chem.
2014, 79, 3623e3633.
4.7.6. (3aR*,9aS*)-3-Methyleneoctahydrocycloocta[b]furan-2(3H)-
one (7f) and (3aR*,9aR*)-3-methyleneoctahydrocycloocta[b]furan-
2(3H)-one (7f0). The titled compounds were similarly prepared as
7a/7a0 by using 3d/3d0/3d00 (110.1 mg, 0.3618 mmol, dr: 75/7/18) as
the starting materials and paraformaldehyde as the aldehyde
component. After chromatography (silica gel: pre-washed with
200 mL of Et3N/hexane (v/v 1/100); hexaneeEtOAc 20:1, 10:1, 5:1),
a mixture39 of 7f/7f0 (dr: 83/17)25 was obtained as a yellow oil
€
14. Muller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521e522.
15. (a) Corbel, B.; Hernot, D.; Haelters, J.-P.; Sturtz, G. Tetrahedron Lett. 1987, 28,
6605e6608 For the similar reaction catalyzed by Cu(II), see: (b) Slattery, C. N.;
Maguire, A. R. Tetrahedron Lett. 2013, 54, 2799e2801.
16. (a) Gois, P. M. P.; Afonso, C. A. M. Eur. J. Org. Chem. 2003, 3798e3810; (b) Gois, P.
M. P.; Candeias, N. R.; Afonso, C. A. M. J. Mol. Catal. A: Chem. 2005, 227, 17e24;
(c) Candeias, N. R.; Gois, P. M. P.; Afonso, C. A. M. J. Org. Chem. 2006, 71,
5489e5497.
17. (a) Lloyd, M. G.; Taylor, R. J. K.; Unsworth, W. P. Org. Lett. 2014, 16, 2772e2775;
(b) Lloyd, M. G.; D’Acunto, M.; Taylor, R. J. K.; Unsworth, W. P. Tetrahedron 2015,
71, 7107e7123.
18. For a review, see: Kiston, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew. Chem.,
Int. Ed. 2009, 48, 9426e9451.
(51.5 mg, 79%). 1H NMR (400 MHz, CDCl3) 7f:
d
6.19 (d, J¼3.5 Hz,
1H), 5.48 (d, J¼3.5 Hz, 1H), 4.40 (ddd, J¼10.2, 7.6, 4.5 Hz, 1H), 2.85
(dddd, J¼14.3, 7.6, 3.6, 3.4 Hz, 1H), 2.28e2.17 (m, 1H), 2.12e2.04 (m,
1H), 1.84e1.70 (m, 4H), 1.58e1.40 (m, 5H), 1.38e1.28 (m, 1H) ppm;
7f0:
d
6.21 (d, J¼3.1 Hz, 1H), 5.52 (d, J¼3.1 Hz, 1H), 4.68 (ddd, J¼10.7,
19. For examples on constructing bicyclic a-alkylidene-g-butyrolactone scaffolds,
see: (a) Marcos, I.; Redero, E.; Bermejo, F. Tetrahedron Lett. 2000, 41,
8451e8455; (b) Kang, S. K.; Kim, K. J.; Hong, Y. T. Angew. Chem., Int. Ed. 2002, 41,
1584e1586; (c) Hon, Y. S.; Liu, Y. W.; Hsieh, C. H. Tetrahedron 2004, 60,
4837e4860; (d) Yu, C. M.; Hong, Y. T.; Lee, J. H. J. Org. Chem. 2004, 69,
8506e8509; (e) Fuchs, S.; Berl, V.; Lepoittevin, J.-P. Eur. J. Org. Chem. 2007,
1145e1152; (f) Kiston, R. R. A.; Taylor, R. J. K.; Wood, J. L. Org. Lett. 2009, 11,
5338e5341; (g) Takizawa, S.; Nguyen, T. M.-N.; Grossmann, A.; Enders, D.;
Sasai, H. Angew. Chem. 2012, 124, 5519e5522 and references cited therein.
20. (a) Hoffmann, N. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl. 1985, 24, 94e110; (b)
Picman, A. K. Biochem. Syst. Ecol. 1986, 14, 255e281; (c) Connolly, J. D.; Hill, R. A.
Dictionary of Terpenoids; Chapman and Hall: London, 1991, Vol. 1, pp 476e541;
(d) Koch, S. S. C.; Chamberlin, A. R. In Studies in Natural Products Chemistry; Att-
ur-Rahman, Ed.; Elsevier Science: New York, 1995; Vol. 16, pp 687e725.
8.3, 1.5 Hz, 1H), 2.98 (dddd, J¼14.3, 7.9, 2.9, 2.9 Hz, 1H), 2.28e2.17
(m, 1H), 2.12e2.04 (m, 1H), 1.84e1.70 (m, 4H), 1.58e1.40 (m, 5H),
1.27e1.13 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) 7f:
d
170.1, 141.2,
120.9, 83.9, 43.6, 35.2, 33.5, 26.8, 26.7, 23.5, 21.6 ppm; 7f0:
d
170.0,
140.4, 121.6, 83.4, 43.3, 29.7, 28.6, 27.5, 27.1, 25.6, 25.1 ppm.
Acknowledgements
We are grateful to the Ministry of Science and Technology of
Taiwan, ROC for financial support (MOST-103-2113-M-259-011),

J.-Y. Shie, J.-L. Zhu / Tetrahedron 72 (2016) 1590e1601
1601
21. Shaikenov, T. E.; Adekenov, S. M.; Williams, R. M.; Baker, F. L.; Prashad, N.;
Madden, T. L.; Newman, R. Oncol. Rep. 2001, 173e179.
22. Zhu, J. L.; Chen, P. E.; Huang, H. W. Tetrahedron: Asymmetry 2013, 24, 23e36.
23. Hirayama, T.; Okaniwa, M.; Imada, T.; Ohashi, A.; Ohori, M.; Iwai, K.; Mori, K.;
Kawamoto, T.; Yokota, A.; Tanaka, T.; Ishikawa, T. Bioorg. Med. Chem. 2013, 21,
5488e5502.
24. The products could not be formed at ambient temperature even after pro-
longed reaction time (>2 days).
25. The ratio was determined by the integrations on proton NMR spectrum.
26. Ando, M.; Kataoka, N.; Yasunami, M.; Takase, K.; Hirata, N.; Yanagi, Y. J. Org.
Chem. 1987, 52, 1429e1437.
32. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry Part B: Reactions and
Synthesis, 4th ed.; Plenum Press: New York, 2000; pp 17e19.
33. Bachi, M.; Bosch, E. J. Org. Chem. 1992, 57, 4696e4705.
34. For the synthesis of a stereoisomer of 3c/3c0/3c00 in another method, see: Jackson,
A. A.; Hammond, G. B.; Wiemer, D. F. J. Org. Chem. 1989, 54, 4750e4754.
35. (a) For the resolution of the stereochemistry of 3b, see: Smith, D. B.; Waltos, A.
M.; Loughhead, D. G.; Weikert, R. J.; Morgans, D. J.; Rohloff, J. C., Jr.; Link, J. O.;
Zhu, R. J. Org. Chem. 1996, 61, 2236e2241; (b) For the elucidation of the con-
figurations of 3d0 and 3d00, see: Fristad, W. E.; Peterson, J. R.; Ernst, A. B. J. Org.
Chem. 1985, 50, 3143e3148.
36. The ratios of 3c/3c0/3c00 and 3d/3d0/3d00 used for reactions were as the same as
those indicated in Scheme 7.
27. Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 547e556.
28. Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Ba-
gheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958e964.
29. Bocian, D. F.; Pickett, H. M.; Rounds, T. C.; Strauss, H. L. J. Am. Chem. Soc. 1975, 97,
687e995.
37. 6d was found to be not stable upon a long exposure to silica gel or deuterium
solvents presumably due to the congested nature of the C-3 carbon center, and
its C NMR data were not obtained due to the decomposition.
38. Murray, T. F.; Samsel, E. G.; Varma, V.; Norton, J. R. J. Am. Chem. Soc. 1981, 103,
7520e7528.
30. Formation of the O-alkylation product from 3a0 was observed.
31. The stereochemistry at the ring junction of 6a0 was deduced from the coupling
39. Kuroda, C.; Kobayashi, K.; Koito, A.; Anzai, S. Bull. Chem. Soc. Jpn. 2001, 74,
1947e1961.
constants of H8a proton [H8a
:
d
4.16 ppm (ddd, J¼10.2, 10.1, 4.2 Hz)].