Lewis acid mediated asymmetric Diels-Alder reactions of chiral 2-phosphonoacrylates

Article abstract of DOI:10.1016/j.tetasy.2012.11.021

2-Phosphonoacrylates containing four chiral alcohol auxiliaries were efficiently prepared and evaluated in Lewis acid mediated Diels-Alder reactions. Under the activation of SnCl₄, all reactions performed in CH ₂Cl₂ at -65 °C exclusively afforded the endo (endo-to-carboxylate) cycloadducts with dr's ranging from 50:50 to >99:1. The best facial selectivity was obtained from the substrate bearing a (-)-phenylmenthyl group, to give adducts as (dr >99:1) or almost as (dr = 99:1) single diastereomers. Detailed strategies for the structural elucidation of the cycloadducts as well as a rationalization of the observed stereoselectivity are described.

Full text of DOI:10.1016/j.tetasy.2012.11.021

Tetrahedron: Asymmetry 24 (2013) 23–36
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Lewis acid mediated asymmetric Diels–Alder reactions of chiral
2-phosphonoacrylates
⇑
Jia-Liang Zhu , Po-Erh Chen, Hue-Wen Huang
Department of Chemistry, National Dong Hwa University, Hualien 974, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 October 2012
Accepted 27 November 2012
2-Phosphonoacrylates containing four chiral alcohol auxiliaries were efficiently prepared and evaluated
in Lewis acid mediated Diels–Alder reactions. Under the activation of SnCl4, all reactions performed in
CH2Cl2 at ꢀ65 °C exclusively afforded the endo (endo-to-carboxylate) cycloadducts with dr’s ranging from
50:50 to >99:1. The best facial selectivity was obtained from the substrate bearing a (ꢀ)-phenylmenthyl
group, to give adducts as (dr >99:1) or almost as (dr = 99:1) single diastereomers. Detailed strategies for
the structural elucidation of the cycloadducts as well as a rationalization of the observed stereoselectivity
are described.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
b-methyl substituted analogues were far less reactive than phos-
phonoacrylate most likely due to steric effects.6
2-Phosphono 2-alkenoates are valuable building blocks in or-
ganic synthesis where they are commonly employed as acceptors
in Michael addition reactions for preparing many important acy-
clic, carbocyclic and in particular heterocyclic compounds.1,2 In
accordance with their activated C–C double bond, another interest-
ing application is the use of 2-phosphono 2-alkenoates as dieno-
philes in Diels–Alder reactions. However, little attention has been
paid to the Diels–Alder chemistry of 2-phosphono 2-alkenoates
compared to their numerous applications in Michael additions.
Among the few examples documented,3–5 Marchand-Brynaert
et al.3 reported several reactions between 2-phosphonoacrylates
and N-protected 1-aminobutadienes under thermal conditions. In
addition, McIntosh4 and Siegel et al.,5 respectively, demonstrated
two examples of the cycloaddition of phosphonoacrylates with iso-
prene and 6,6-diphenylfulvene. As described in these reports, the
adducts were all formed as mixtures of regio- and/or stereoiso-
mers. To address the limitations in stereo- and regiocontrol, we re-
cently reported the application of a Lewis acid strategy to the
Diels–Alder reaction of 2-phosphono 2-alkenoates.6 Of the few Le-
wis acids examined, tin (IV) chloride (SnCl4) was shown to be opti-
mal in enhancing both the regio- and stereoselectivities of the
reaction. For example, in the presence of SnCl4 in CH2Cl2 at
ꢀ30 °C, the cycloaddition between triethyl 2-phosphonoacrylate
and trans-piperylene strictly followed the endo-to-carboxylate
pathway and the ortho-rule to afford the adduct as the single
isomer (Scheme 1). Our prior work also demonstrated that the
The asymmetric Diels–Alder reactions of chiral dienophiles7,8 or
dienes9 have received a great deal of attention over the past few dec-
ades. The diastereo- or enantioselectivity of these reactions is gen-
erally achieved by the p-facial differentiation created by the chiral
elements within dienophiles or dienes. Although the same goal
can nowadays be attended by chiral ligand-based catalysts,10 the ra-
tional design of easily accessible and recoverable chiral auxiliaries
for the reagents is still an attractive research subject8m,9b for
Diels–Alder chemistry. Our previous study established that the
endo-to-carboxylate (endo) transition state is predominant for the
Diels–Alder reaction of the 2-phosphonoacrylate under the activa-
tion of SnCl4.6 Based on this premise, we envisioned that the intro-
duction of a chiral alcohol auxiliary to the carboxylate motif could
offer the possibility of controlling the facial selectivity of the cyclo-
addition. So far, these types of chiral precursors have only been used
in the 1,4-addition reactions with dimethyloxosulfonium methylide
for preparing cyclopropane derivatives,11 and not reported for the
Diels–Alder reaction. As a result, we decided to extend our protocol
to chiral 2-phosphonoacrylates and to explore the asymmetric syn-
thesis of the cyclic adducts containing the phosphono and carboxyl-
ate functionalities suited for further elaborations.
2. Results and discussion
Four enantiomerically pure alcohols, (1S)-endo-(ꢀ)-borneol,
(1R,2S)-trans-2-phenyl-1-cyclohexanol, (ꢀ)-phenylmenthol, and
(ꢀ)-menthol were chosen as the chiral auxiliaries for our investiga-
tion. Previously these alcohols or analogues were all incorporated
into other types of dienophiles as individual auxiliaries,8c,g,f,h but
they have not been systematically investigated together for a
⇑
Corresponding author. Tel.: +886 3 86335 83; fax: +886 3 86335 70.
E-mail address: jlzhu@mail.ndhu.edu.tw (J.-L. Zhu).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.021

24
J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
PO(OEt)2
EtO2C
O
O
PO(OEt)2
CO2Et
EtOC
P(OEt)2
SnCl4, CH2Cl2, -30 o
74%
C
racemate
Scheme 1.
1) t-BuO-K+, PhSeBr
O
O
O
O
DMSO, 60 oC, 5 h
P(OEt)2
P(OEt)2
R*OH, DMAP
EtO
R*O
2) t-BuO-K+, CH3I, DMSO
toluene, reflux
2 d
60 oC, 3.5 h
1a (93%)
1b (97%)
1c (98%)
1d
(94%)
O
O
P(OEt)2
O
O
R*O
P(OEt)2
SePh
H2O2, CH2Cl2
R*O
2a (63%, dr = 51:49)
2b (68%, dr = 52:48)
2c (67%, dr = 56:44)
2d (60%, dr = 55:45)
0
oC to rt, 1h
3a-d
Ph
3c (94%),
3a (98%), R* =
R* =
3b (93%), R* =
3d (99%), R* =
Ph
Scheme 2. Preparation of chiral 2-phosphonoacrylates.
Table 1
Cycloaddition between 3a and trans-piperylene under various reaction conditions
O
O
O
H
O
O
H
O
H
O
H
O
(10 equiv)
3a
+
PO(OEt)2
PO(OEt)2
PO(OEt)2
PO(OEt)2
4a'
4a
(exo)
(endo)
Entry
Reaction conditions
Toluene/80 °C
ZnCl2 (1.5 equiv)/toluene/80 °C
ZnCl2 (1.5 equiv)/ether/rt
TiCl4 (1.2 equiv)/CH2Cl2/ꢀ30 °C
BFꢁ3OEt2 (1.2 equiv)/ether/0 °C
SnCl4 (1.2 equiv)/CH2Cl2/ꢀ30 °C
SnCl4 (1.2 equiv)/CH2Cl2/ꢀ65 °C
Time (h)
Yielda (%)
endo/exob
drb
1
2
3
4
5
6
7
8
5
5
6
7
77
87
87
52
79
90
84
82:18
82:18
82:18
54:46
84:16
96:4
41:41:9:9
41:41:9:9
41:41:9:9
27:27:23:23
42:42:8:8
48:48:2:2
50:50
5
12
100:0
a
Isolated yield of mixture.
Ratio was determined by integration of the 400 MHz proton NMR spectrum.
b
certain type of Diels–Alder reaction. The preparation of the chiral
phosphonoacrylates began with the transesterification of triethyl
phosphonoacetate with the corresponding chiral alcohols (R⁄OH)
in the presence of 4-dimethyl aminopyridine (DMAP) to give the
chiral phosphonoacetates 1a–d in good yields (Scheme 2).12 This
was followed by sequential phenylselenylation13 and methylation
with phenylselenyl bromide and iodomethane to yield intermedi-
ates 2a–d, which were then subjected to oxidative elimination
with hydroperoxide in CH2Cl2 to yield the requisite substrates
3a–d in almost quantitative yields.

J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
25
NHTs
H
N
1) Dibal-H (4.2eq), toluene, -78 oC to 0 oC, 88%
2) TsNHNH2 (1 eq), EtOH, rt, 5 h, 83%
4a
PO(OEt)2
(dr = 50:50)
5
Scheme 3.
H
(EtO)2OP
(10 equiv)
O
H
O
H
H
SnCl4 (1.2 eq), CH2Cl2
-65 oC, 12 h
O
O
3a
PO(OEt)2
(dr = 53:47)
Scheme 4.
88%
4b
Compared with triethyl 2-phosphonoacrylate, substrates 3a–d
all carried bulkier ester groups that might cause a larger steric hin-
drance during the endo-like transition state. Therefore it was nec-
essary to first clarify whether the previously observed endo
pathway6 was still applicable to these precursors. To this end, we
initially examined the cycloaddition between 3a with the largest
auxiliary and trans-piperylene. As outlined in Table 1, the cycload-
dition performed in toluene under thermal reaction conditions
PO(OEt)2
O
(10 equiv)
Ph
Ph
SnCl4 (1.2 eq), CH2Cl2, -65 o
12 h, 84%
C
3b
3c
O
4c
(dr = 52:48)
14
(80 °C) produced endo adduct 4a and exo adduct 4a0 as four
(10 equiv)
PO(OEt)2
mixed diastereomers (41:41:9:9) in an endo/exo ratio of 82:18 (en-
try 1). We also observed that the use of ZnCl2 in toluene or in
diethyl ether resulted in the same endo/exo ratio (entries 2 and
SnCl4(1.2 eq), CH2Cl2, -65 o
C
O
O
3). Subsequent attempts with TiCl4 in CH2Cl2 or BFꢁ OEt2 in ether
12 h, 89%
3
to the reaction were also unsuccessful in improving the percentage
of 4a (entries 4 and 5), and with TiCl4, the endo/exo ratio was even
worse (54:46) than the uncatalyzed case (entry 1). As observed for
triethyl 2-phosphonoacrylate,6 SnCl4 again demonstrated remark-
able efficiency in improving the endo selectivity. When the reaction
was carried out with SnCl4 (1.2 equiv) in CH2Cl2 at ꢀ30 °C, the
endo/exo ratio could be dramatically increased to 96:4 (entry 6).
In an effort to further improve the ratio, we decreased the reaction
temperature to ꢀ65 °C15 and found that 4a, albeit as a 50:50
diastereomeric mixture, could be formed exclusively (entry 7). To
elucidate the structure of 4a, we transformed it into the tosylhyd-
razone 5 in two steps (Scheme 3), and whose structure was previ-
ously conformed by X-ray analysis.6 Under the same reaction
conditions, the complete endo as well as the poor facial selectivity
was similarly observed for the reaction of 3a with cyclopentadiene
to afford the endo adduct 4b in 53:47 dr.16 The endo structure of 4b
was assigned on the basis of 2D NOESY experiments as shown in
Scheme 4. From these results it was apparent that the bornyl group
was not an ideal choice for controlling the face selectivity of the
cycloaddition, whereas the combination of SnCl4 with CH2Cl2 could
ensure an endo-like transition state.
Under the developed reaction conditions [SnCl4 (1.2 equiv)/
CH2Cl2/ꢀ65 °C], we continued to screen 3b–d with cyclopentadi-
ene (Scheme 5). The cycloaddition of 3b produced the endo adduct
4c in 84% yield and 52:48 dr,16 indicating that the (1R)-trans-phe-
nyl cyclohexyl group also exerted little effect on the facial control.
The reaction of 3c proceeded with a high diastereoselectivity to
provide adduct 4d as a single diastereomer (dr >30:1).16 In com-
parison with this, a slightly low selectivity was obtained from
the reaction of 3d affording adduct 4e in 92:8 dr.16 These results
suggest that both (1R)-phenylmenthyl and (1R)-menthyl auxilia-
4d
(dr > 30:1)
PO(OEt)2
(10 equiv)
O
O
SnCl4 (1.2 eq), CH2Cl2, -65 o
C
3d
12 h, 87%
4e (dr = 92:8)
Scheme 5.
ries should have the capability to control the diastereoselectivity
of the cycloaddition with the former being more effective than
the latter. To verify this, we carried out the reactions of 3c and
3d with trans-piperylene (Scheme 6), and found that adducts 4f
(dr >30:1)16 and 4g (dr = 91:9)16,17 were formed in almost the
same distereomeric ratios as 4d and 4e.
The overlapped proton signals of compounds 4c–e made the di-
rect elucidation of their endo/exo stereochemistry by NMR meth-
ods difficult. Moreover, our attempts at crystallizations of them
and their derivatives were unsuccessful. We therefore turned to
an indirect strategy by converting them into the known aldehyde
7. Treatment of 4c–e with diisobutylaluminum hydride in CH2Cl2
at ꢀ78 °C provided alcohol 6 and aldehyde 7, in addition to a quan-
titative amount of the chiral alcohol (Scheme 7). After separation,
the compound 6 was further oxidized into 7 with the structure
being previously proven by NOESY experiment.6 As for 4f and 4g,

26
J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
Ph
assign the stereochemistry (endo/exo) of the minor isomers of the
(10 equiv)
PO(OEt)2
corresponding adducts except for 4c (dr = 52:48). Nevertheless
the endo structures of the minor isomers could be proven by the
HPLC experiments as depicted below.
SnCl4 (1.2 eq), CH2Cl2, -65 o
12 h, 88%
C
C
O
O
3c
With regard to the possible inaccuracy of using NMR inspection
to identify the dr ratios, we also performed a chiral HPLC analysis18
on the benzonate derivatives of 4d–g. Accordingly, adducts 4d and
4e were converted into 3,5-dinitrobenzoate derivative 9 as for pre-
paring 8 (Scheme 9). The HPLC analysis on 8 and 919 allowed the
precise determination of the diastereomeric ratios of 4d–g (4d:
dr >99:1; 4e: dr = 92:8; 4f: dr = 99:1; 4g: dr = 91:9). In addition,
the endo structure of the minor isomers of 4e–g could be deduced
by the same retention times of the minor components of 8 and 9
with those of one from the racemic mixtures.20
Finally we attempted to resolve the absolute stereochemistry of
4d–g by converting them into the known alcohols. With 4d, we
first conducted the reductive methylation using lithium naphthale-
nide (LN) and iodomethane.6 The reaction yielded two diastereo-
meric methylated esters 10a and 10a0, which were, respectively,
subjected to the reduction with LiAlH4 to yield the known chiral
alcohols 11a and 11a0,21 plus the recovered (ꢀ)-phenylmenthol
(Scheme 10). In the same sequence, adducts 4e–g were trans-
formed into 11a and 11b. The comparison of the specific rotations
4f
(dr > 30:1)
(10 equiv)
PO(OEt)2
SnCl4 (1.2 eq), CH2Cl2, -65 o
12 h, 81%
O
O
3d
4g
(dr = 91:9)
Scheme 6.
we, respectively, transformed them into 3,5-dinitrobenzoate deriv-
ative 8 via reduction followed by the esterification of the resulting
alcohol (Scheme 8). The X-ray crystallography of 8 confirmed the
endo stereochemistry of the major 4f and 4g. At this stage, it should
be noted that the yields of 7 and 8 were not high enough to directly
PO(OEt)2
CH2OH
6
DIBAL-H (2 eq)
toluene, -78 o
C
PDC (3 eq), CH2Cl2
rt, 12 h
4c, 4d or 4e
4 h
PO(OEt)2
CHO
7
71% from 4c
99% from 4d
86% from 4e
Scheme 7.
NO2
PO(OEt)2
O
1) DIBAL-H (6 eq), toluene
-78 oC to rt, 4 h
4f or 4g
NO2
2) 3, 5-dinitrobenzoyl chloride (20 eq)
DMAP (1.5 eq), py, rt, 12 h
O
8
55% from 4f
44% from 4g
Scheme 8.
NO2
PO(OEt)2
O
1) DIBAL-H (6 eq), toluene
-78 oC to rt, 4 h
4d or 4e
NO2
2) 3, 5-dinitrobenzoyl chloride (20 eq)
DMAP (1.5 eq), py, rt, 12 h
O
9
52% from 4d
67% from 4e
Scheme 9.

J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
27
CH3
CH3
LiAlH4 (5 eq)
LN (7 eq), THF, -60 o
C
30min, then CH3I (10 eq)
-60 oC to rt, 5 h
rt, 5 h
CH2OH
CO2R*
10a (47%)
11a (79%)
[ ]D20 = +30.6 (c 0.42, CHCl3)
α
4d
(dr > 99:1)
CO2R*
CH2OH
LiAlH4 (5 eq)
CH3
CH3
10a' (41%)
rt, 5 h
11a' (74%)
[α]D20 = +60.7 (c 0.65, 95% EtOH)
61% over two steps
4e
11a
(dr = 92:8)
[α]D20 = +26.4 (c 0.66, CHCl3)
CH3
44% over two steps
CH2OH
4f
(dr = 99:1)
11b
[α]D20 = +130.4 (c 0.13, CHCl3)
52% over two steps
4g
11b
[α]D20 = +73.4 (c 0.5, CHCl3)
(dr = 91:9)
Scheme 10.
L.A.
O
O
R
PO(OEt)2
CO2R*
P(OEt)2
O
(S)
major
A
Favored
front approach of diene, R = Ph, H
L.A.
O
O
O
R
(EtO)2P
O
O
or
R
(
)
R
PO(OEt)2
CO2R*
P
(EtO)2
O
minor
B
C
Disfavored
Figure 1. Proposed stereomodels for the cycloaddition of 3c and 3d.
of synthesized 11a/11a0 and 11b with the reported ones22,23 estab-
lished the (S)-configuration of the newly created quaternary car-
bon centers of 4d as well as the major isomers of 4e–g.
As illustrated by the cycloaddition with cyclopentadiene, the
preferential generation of the (S)-isomers from 3c and 3d should
be attributed to the transition state A in Figure 1. In Figure 1, the
diene approaches the dienophiles from the front side (Si-face) in
an endo-to-carboxylate orientation. As such, the steric hindrance
LiAlH4 (6 eq), THF/CH2Cl2 (1:1), rt, 3 h
86%
4d
OH
(+)-12
Scheme 11.

28
J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
Ph
Ph
PO(OEt)2
3 steps
O
OH
O
HO
(-)-12
(+)-8-phenylmenthol
Scheme 12.
imposed by the isopropyl and 1-methyl-1-phenyl-ethyl groups on
the back side can be avoided. As for the formation of the minor (R)-
isomers, one possible pathway involves the endo addition of the
diene from the more hindered face (Re-face) of the dienophiles B.
With respect to models A and B, it is reasonable to propose that
the larger steric bias between the Re- and Si-faces of 3c should
be responsible for the better stereoselectivity of 3c versus 3d. The-
oretically, the minor isomers can also be formed through the endo
addition of the diene from the less hindered face, arranged in an
Re-trigonal geometry11 C. However, this model is considered to
be less possible than B due to the impossibility of achieving double
activation of the P@O and C@O bonds24 by a Lewis acid and/or the
unfavorable steric interaction between the phosphono and cyclo-
hexyl moieties.
drofuran and diethyl ether were freshly distilled from sodium–
benzophenone, and dichloromethane, pyridine, dimethyl sulfoxide,
and toluene were freshly distilled from calcium hydride before use.
TLC analysis was carried out on glass-backed silica gel plates, and
visualized by UV light, ethanolic solution of vanillin (5%), iodine,
or aqueous KMnO4 solution (10%). The products were purified by
flash chromatography using silica gel (70–230 mesh). NMR spectra
(1H, 13C NMR, DEPT, 2D-NOESY) were recorded on 400 or 600 MHz
spectrometers using deuteriochloroform (CDCl3) or deuterioben-
zene (C6D6) as solvents. Chemical shift measurements are reported
in delta (d) units. Splitting patterns are described as singlet (s),
doublet (d), triplet (t), quartet (q), or multiplet (m). Coupling con-
stants (J) are reported in Hertz (Hz). The resonances of infrared (IR)
spectra are reported in wave numbers (cmꢀ1). High resolution
mass spectra (HRMS) were determined in the electron impact
(EI) mode and by a magnetic sector analyzer. Specific optical rota-
The high-yielding and enantio-controlled generation of the ad-
ducts allowed us to prepare some useful chiral norbornyl deriva-
tives on large scales. In addition to replacing the phosphonyl
group with an alkyl group as shown in Scheme 10, we also applied
our recently developed LiAlH4-mediated reductive dephosphonyla-
tion operation25 to 4d to produce 2-endo-hydroxymethyl-5-nor-
bornene 12, an useful synthetic intermediate,26,27 in enantiopure
form. Upon treatment with LiAlH4 in CH2Cl2/THF, 4d could be read-
ily converted into (2R)-12 in 86% yield with the quantitative recov-
tions were measured in
a polarimeter with sodium light
(589.6 nm). The enantiomeric purity of the Diels–Alder adducts
was determined by HPLC analysis on their 3,5-dinitrobenzoate
derivative using a Chiralcel OD-H column (diameter: 4.6 mm,
length: 250 mm, particle size: 5 lm) and a UV detector (254 nm).
Melting points were determined with a capillary melting point
apparatus and are uncorrected.
ery of the chiral alcohol (Scheme 11) {½a D20
¼ þ70:6 (c 0.6, 95%
ꢂ
EtOH), lit.28
½
a 2D0
ꢂ
¼ þ79:3 (c 0.86, 95% EtOH)}. Moreover, (2S)-
4.2. Preparation of 1a–d
(ꢀ)-12 was synthesized from (+)-phenylmenthol in the same
sequence (Scheme 12). Thus, we were able to obtain both enantio-
mers of 12 in a common Diels–Alder strategy.
4.2.1. (1S,2R,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl 2-
(diethoxyphosphoryl)-acetate 1a. Typical procedure for the
transesterification
3. Conclusion
To a solution of (ꢀ)-borneol (2.5 g, 16.2 mmol) in dry toluene
(40 mL), triethyl phosphonoacetate (9.84 mL, 48.6 mmol) and 4-di-
methyl aminopyridine (600 mg, 4.86 mmol) were added succes-
sively. The mixture was stirred in an oil bath at 115 °C for 2 days,
then cooled to rt and concentrated under reduced pressure. The
residue was subjected to chromatographic purification on silica
gel (hexane–EtOAc: 10:1, 6:1, 3:1) to afford 1a as a pale yellow
oil (4.85 g, 93%) plus 91 mg of recovered phosphonoacetate. IR
In conclusion, we have applied chiral 2-phosphonoacrylates to
Diels–Alder reactions for the first time. Under the activation of
SnCl4, all precursors underwent facile cycloaddition to afford
exclusively endo products. On this basis, the phenylmenthyl group
was shown to be the most efficient auxiliary in controlling the fa-
cial selectivity of the reaction, in giving single diastereomers.
Although the same chiral template has already been used for the
asymmetric Diels–Alder reactions of several other 2-substituted
acrylates (X = PhCO–, F–, Cl–, Me–, H–, etc.),8f,29 none of these
methods gave complete endo/exo and/or diastereofacial selectivity
as observed in our case. The excellent stereoselectivity is presum-
ably due to the activating capability of the phosphono group to-
ward the C@C double bond. The recovery of the employed
auxiliaries by simple reduction should also indicate the value of
this protocol.
(neat) 2955, 1735, 1279, 1115, 1023 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 4.96–4.89 (m, 1H), 4.24–4.10 (m, 4H), 2.97 (d, JP–H
=
21.5 Hz, 2H), 2.34 (ddd, J = 18.7, 9.8, 3.9 Hz, 1H), 1.98 (ddd,
J = 12.6, 9.0, 3.9 Hz, 1H), 1.80–1.70 (m, 2H), 1.67 (t, J = 4.5 Hz,
1H), 1.34 (t, J = 7.2 Hz, 6H), 1.26–1.21 (m, 1H), 1.01 (ddd, J = 23.5,
11.2, 4.0 Hz, 1H), 0.89 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 165.9 (d, Jc–p = 6.5 Hz), 81.2, 62.4 (d, Jc–p
=
6.1 Hz), 48.8, 47.8, 44.7, 36.4, 34.5 (d, Jc–p = 133.5 Hz), 27.9, 26.9,
19.6, 18.7 16.5 (d, Jc–p = 6.2 Hz), 13.3; HRMS-EI m/z [M]+ Calcd for
C
16H29O5P 332.1753. Found: 332.1760. ½a D20
¼ ꢀ18:1 (c 0.62, 95%
ꢂ
EtOH).
4. Experimental
4.1. General
4.2.2. (1R,2S)-2-Phenylcyclohexyl 2-(diethoxyphosphoryl)-
acetate 1b
All reagents were purchased from commercial suppliers and
used without further purification. All reactions were performed
under an atmosphere of nitrogen unless otherwise noted. Tetrahy-
The typical procedure for preparing 1a was followed by using
triethyl phosphonoacetate (3.27 mL, 16.17 mmol), (1R,2S)-trans-
2-phenyl-1-cyclohexanol (950 mg, 5.39 mmol), and DMAP

J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
29
(199.54 mg, 1.62 mmol) as the reagents. The chromatographic
purification (silica gel, hexane–EtOAc, 8:1, 5:1, 3:1) yielded
1.76 g of 1b (96.8%) and 47.3 mg of recovered phosphonoacetate.
and concentrated in vacuo. The residue was purified by flash chro-
matography (silica gel, hexane–EtOAc, 8:1, 5:1, 3:1) to give 1.74 g
of methyl phosphonate intermediate plus 507 mg of recovered 1a.
Potassium tert-butoxide (762.8 mg, 6.59 mmol) was added to a
stirred solution of the freshly prepared methyl phosphonate
(1.52 g, 4.40 mmol) in dry DMSO (14.3 mL) pre-cooled at 0 °C in
an ice bath. The ice bath was then removed and stirring was con-
tinued for 15 min followed by the addition of phenylselenyl bro-
mide (3.18 g, 13.18 mmol). The reaction mixture was heated at
60 °C for 5 h, then cooled to rt and diluted with ethyl acetate
(220 mL). The solution was successively washed with aqueous ace-
tic acid solution (10%, 45 mL), saturated aqueous NaHCO3 solution
(45 mL), water (45 mL ꢃ 2), and brine (45 mL). After concentration,
the residue was purified by flash chromatography (silica gel, hex-
ane–EtOAc, 8:1, 5:1, 4:1) to furnish 812.3 mg of 2a as a mixture
of two diastereomers (51/49) (63.4%, over two steps) followed by
recovered methyl phosphonate (650 mg). IR (neat) 3057, 1718,
IR (neat) 3100, 1732, 1647, 1550, 1269, 1028, 968, 758 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d 7.26–7.21 (m, 2H), 7.21–7.10 (m, 3H),
5.02 (ddd, J = 10.1, 10.0, 5.1 Hz, 1H), 4.10–3.88 (m, 4H), 2.79–2.57
(m, 3H), 2.23–2.09 (m, 1H), 1.95–1.80 (m, 2H), 1.76 (m, 1H),
1.58–1.49 (m, 1H), 1.49–1.40 (m, 2H), 1.36–1.30 (m, 1H), 1.26 (t,
J = 7.0 Hz, 3H), 1.22 (t, J = 7.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 165.1 (d, Jc–p = 6.1 Hz), 142.9, 128.3, 127.4, 126.4, 77.1, 62.5 (d,
Jc–p = 6.3 Hz), 62.4 (d, Jc–p = 6.2 Hz), 49.4, 34.2 (d, Jc–p = 134.1 Hz),
34.2, 32.0, 25.7, 24.7, 16.3 (d, Jc–p = 6.0 Hz); HRMS-EI m/z [M]+
Calcd for C18H27O5P 354.1596. Found: 354.1587. ½a D20
¼ ꢀ17:0 (c
ꢂ
1.05, CHCl3).
4.2.3. (1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl
2-(diethoxyphosphoryl)-acetate 1c
The typical procedure for preparing 1a was followed by using
triethyl phosphonoacetate (2.48 mL, 12.3 mmol), (ꢀ)-phenylmen-
thol (950 mg, 4.09 mmol), and DMAP (151.4 mg, 1.23 mmol) as
the reagents. The chromatographic purification (silica gel, hex-
ane–EtOAc, 8:1, 5:1, 3:1) afforded 1.64 g of 1c (98%) as a colorless
oil. IR (neat) 3087, 3056, 2956, 1730, 1600, 1271, 1025, 972,
1577, 1253, 1049, 980, 830, 643, 545 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) major isomer: d 7.66–7.70 (m, 2H), 7.41–7.34 (m, 1H),
7.33–7.26 (m, 2H), 4.95–4.83 (m, 1H), 4.39–4.26 (m, 2H), 4.25–
4.14 (m, 2H), 2.39–2.27 (m, 1H), 2.16–2.05 (m, 1H), 1.80–1.64
(m, 2H), 1.47 (d, J = 15.7 Hz, 3H), 1.41–1.29 (m, 7H), 1.27–1.15
(m, 1H), 1.07–0.98 (m, 1H), 0.89 (s, 3 H), 0.87 (s, 6 H); minor iso-
mer: d 7.66–7.70 (m, 2H), 7.41–7.34 (m, 1H), 7.33–7.26 (m, 2H),
4.95–4.83 (m, 1H), 4.39–4.26 (m, 2H), 4.25–4.14 (m, 2H), 2.39–
2.27 (m, 1H), 2.16–2.05 (m, 1H), 1.80–1.64 (m, 2H), 1.46 (d,
J = 15.7 Hz, 3H), 1.41–1.29 (m, 7H), 1.27–1.15 (m, 1H), 1.07–0.98
(m, 1H), 0.88 (s, 3 H), 0.87 (s, 3H), 0.84 (s, 3H); 13C NMR
(100 MHz, CDCl3) major: d 170.3, 138.4, 129.7, 128.8, 126.0, 81.9,
63.3 (d, Jc–p = 7.3 Hz), 49.0, 47.9, 44.9, 44.8 (d, Jc–p = 145.2 Hz),
36.2, 28.0, 27.1, 19.8, 19.7, 18.9, 16.5 (d, Jc–p = 5.2 Hz), 13.4; minor:
d 170.5, 138.4, 129.7, 128.8, 126.0, 82.0, 64.3 (d, Jc–p = 4.5 Hz), 64.2
(d, Jc–p = 4.3 Hz), 48.9, 47.8, 44.8, 44.7 (d, Jc–p = 145.5 Hz), 36.2,
27.9, 27.0, 19.8, 19.7, 18.9, 16.6 (d, Jc–p = 6.1 Hz), 13.5; HRMS-EI
m/z [M]+ Calcd for C23H35O5PSe 502.1387. Found: 502.1394.
840 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.30–7.24 (m, 4H), 7.18–
;
7.07 (m, 1H), 4.83 (ddd, J = 10.7, 10.6, 4.4 Hz, 1H), 4.15–3.96 (m,
4H), 2.37 (dd, J = 21.2, 14.4 Hz, 1H), 2.08 (dd, J = 21.2, 14.4 Hz,
1H), 2.06–2.00 (m, 1H), 1.84 (tm, J = 15.2 Hz, 2H), 1.66–1.68 (m,
1H), 1.52–1.39 (m, 1H), 1.34–1.24 (m, 9H), 1.20 (s, 3H), 1.18–
1.11 (m, 1H), 1.02–0.89 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 165.0 (d, Jc–p = 5.9 Hz), 151.7, 127.9, 125.3,
125.1, 75.0, 62.3 (d, Jc–p = 5.9 Hz), 50.2, 41.3, 39.4, 34.4, 33.7 (d,
Jc–p = 132.9 Hz), 31.2, 29.2, 26.2, 23.1, 21.7, 16.2 (d, Jc–p = 6.3 Hz);
HRMS-EI m/z [M]+ Calcd for C22H35O5P 410.2222. Found:
410.2230. ½a 2D0
¼ þ14:0 (c 1.1, CHCl3).
ꢂ
4.2.4. (1R,2S,5R)-(Diethoxy-phosphoryl)-acetic acid 2-isopropyl-
5-methyl-cyclohexyl ester 1d
4.3.2. (1R,2S)-2-(Diethoxy-phosphoryl)-2-phenylselanyl-
The typical procedure for preparing 1a was followed by using
triethyl phosphonoacetate (2.91 mL, 14.4 mmol), (1R,2S,5R)-(ꢀ)-
menthol (750 mg, 4.8 mmol), and DMAP (177.7 mg, 1.44 mmol)
as the reagents. The chromatographic purification (silica gel, hex-
ane–EtOAc, 8:1, 5:1, 3:1) afforded 1.50 g of 1d (94%) as a colorless
oil, plus 28 mg of recovered phosphonoacetate. IR (neat) 2956,
propionic acid 2-phenyl-cyclohexyl ester 2b
Potassium tert-butoxide (638.4 mg, 5.58 mmol) was added to a
stirred solution of 1b (1.66 g, 4.68 mmol) in dry DMSO (24 mL) pre-
cooled at 0 °C in an ice bath. The ice bath was then removed and
stirring was continued for 15 min followed by the addition of phe-
nylselenyl bromide (1.0 g, 4.22 mmol). The mixture was heated at
60 °C for 4 h, cooled to rt and diluted with ethyl acetate (230 mL).
The solution was successively washed with aqueous acetic acid
solution (10%, 50 mL), saturated aqueous NaHCO3 solution
(50 mL), water (50 mL ꢃ 2), and brine (50 mL). After concentration,
the residue was purified by flash chromatography (silica gel, hex-
ane–EtOAc, 8:1, 4:1, 2:1) to provide 1.87 g of the phenylselenyl
phosphonate intermediate plus recovered 1b (351.3 mg). Potas-
sium tert-butoxide (1.1 g, 9.49 mmol) was added to a stirred solu-
tion of the freshly prepared phenylselenyl phosphonate (1.2 g,
2.37 mmol) in dry DMSO (4.5 mL) pre-cooled at 0 °C in an ice bath.
The ice bath was then removed and stirring was continued for
25 min followed by the addition of iodomethane (0.6 mL,
9.49 mmol). The reaction mixture was heated at 60 °C for 5 h, then
cooled to rt and diluted with ethyl acetate (210 mL). The solution
was successively washed with a saturated aqueous NH4Cl solution
(40 mL), water (40 mL ꢃ 2), and brine (40 mL) and concentrated
under reduced pressure. The residue was purified by flash chroma-
tography (silica gel, hexane–EtOAc, 10:1, 5:1, 3:1) to give 844.1 mg
of 2b (52/48) (67.8% over two steps). IR (neat) 3059, 1770, 1247,
1730, 1272, 1027 cmꢀ1 1H NMR (400 MHz, CDCl3) d 4.73 (ddd,
;
J = 10.9, 10.9, 4.4 Hz, 1H), 4.24–4.10 (m, 4H), 2.94 (d, J = 21.7 Hz,
2H), 2.06–1.92 (m, 2H), 1.68 (br d, J = 12.8 Hz, 2H), 1.54–1.35
(m 2H), 1.35 (t, J = 7.08 Hz, 6H), 1.12–0.94 (m, 3H), 0.90
(d, J = 6.6 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H), 0.76 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 165.1 (d, Jc–p = 6.1 Hz), 75.3, 62.3
(d, Jc–p = 4.7 Hz), 62.3 (d, Jc–p = 4.9 Hz), 46.7, 40.5, 34.4 (d, Jc–p
=
133.4 Hz), 34.0, 31.2, 25.6, 23.0, 21.8, 20.6, 16.2 (d, Jc–p = 6.2 Hz),
15.8; HRMS-EI m/z [M]+ Calcd for C16H31O5P 334.1909. Found:
334.1913. ½a 2D0
¼ ꢀ47:3 (c 1.1, CHCl3).
ꢂ
4.3. Preparation of 2a–d
4.3.1. (1S,2R,4S)-2-(Diethoxy-phosphoryl)-2-phenylselanyl-
propionic acid 1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl ester 2a
Potassium tert-butoxide (910.5 mg, 7.87 mmol) was added to a
stirred solution of 1a (2.2 g, 6.61 mmol) in dry DMSO (8.8 mL) pre-
cooled at 0 °C in an ice bath. The ice bath was then removed and
stirring was continued for 20 min followed by the addition of iodo-
methane (0.45 mL, 7.21 mmol). The mixture was heated at 60 °C
for 3.5 h, cooled to rt and diluted with ethyl acetate (200 mL).
The solution was successively washed with saturated aqueous
NH4Cl solution (45 mL), water (45 mL ꢃ 2), and brine (45 mL)
1066, 694 cmꢀ1 1H NMR (400 MHz, CDCl3) major: d 7.44 (br d,
;
J = 6.9 Hz, 1H), 7.32–7.07 (m, 9H), 5.08 (ddd, J = 10.4, 10.4, 4.3 Hz,
1H), 4.25–3.85 (m, 4H), 2.81–2.63 (m, 1H), 2.23–2.07 (m, 1H),
1.90 (br d, J = 13.4 Hz, 1H), 1.86–1.77 (m, 1H), 1.77–1.67 (m, 1H),

30
J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
1.63–1.47 (m, 1H), 1.47–1.38 (m, 2H), 1.21 (t, J = 7.8 Hz, 6H), 1.16
(d, J = 6.6 Hz, 3H), 1.35–1.12 (m, 1H); minor: d 7.44 (br d,
J = 6.9 Hz, 1H), 7.32–7.07 (m, 9H), 4.98 (ddd, J = 10.5, 10.4, 4.4 Hz,
1H), 4.25–3.87 (m, 4H), 2.81–2.63 (m, 1H), 2.23–2.07 (m, 1H),
1.90 (br d, J = 13.4 Hz, 1H), 1.86–1.77 (m, 1H), 1.77–1.67 (m, 1H),
1.63–1.47 (m, 1H), 1.47–1.38 (m, 2H), 1.30 (t, J = 7.0 Hz, 3H), 1.26
(t, J = 7.1 Hz, 3H), 1.20 (d, J = 7.2 Hz, 3 H), 1.35–1.12 (m, 1H); 13C
NMR (100 MHz, CDCl3) major: d 169.6, 143.2, 138.4, 129.4, 128.3,
127.5, 126.3, 126.2, 125.9, 77.5, 63.9 (d, Jc–p = 6.6 Hz), 63.8
(d, Jc–p = 5.9 Hz), 49.6, 44.9 (d, Jc–p = 145.5 Hz), 34.8, 34.0, 31.8,
31.7, 25.7, 24.6, 19.5 (d, Jc–p = 2.4 Hz), 16.5 (d, Jc–p = 5.5 Hz), 16.4
(d, Jc–p = 5.9 Hz); minor: d 169.4, 143.0, 138.3, 129.4, 128.6,
127.8, 126.5, 126.2, 125.8, 78.0, 63.4 (d, Jc–p = 7.1 Hz),, 63.2
(d, Jc–p = 7.1 Hz), 49.2, 44.8 (d, Jc–p = 145.6 Hz), 34.8, 34.0, 31.8,
31.7, 25.7, 24.5, 19.8 (d, Jc–p = 2.0 Hz), 16.5 (d, Jc–p = 5.5 Hz), 16.4
(d, Jc–p = 5.9 Hz); HRMS-EI m/z [M]+ Calcd for C25H33O5PSe
524.1231. Found: 524.1221.
3H), 1.54–1.40 (m, 2H), 1.39–1.31 (m, 6H), 1.08–0.95 (m, 2H),
0.93–0.86 (m, 7H), 0.81 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) major: d 169.6, 138.4, 129.6, 128.7, 126.1 (d, Jc–p = 3.1 Hz),
76.0, 64.0 (d, Jc–p = 7.4 Hz), 63.3 (d, Jc–p = 7.2 Hz), 46.8, 44.5
(d, Jc–p = 144.8 Hz), 40.2, 34.1, 31.3, 25.0, 22.7, 22.0, 21.0, 19.9
(d, Jc–p = 2.2 Hz), 16.4 (d, Jc–p = 5.9 Hz), 15.6; minor: d 170.0,
138.3, 129.6, 128.7, 125.9 (d, Jc–p = 4.1 Hz), 76.1, 63.9 (d, Jc–p
=
7.3 Hz), 63.5 (d, Jc–p = 7.0 Hz), 47.0, 44.7 (d, Jc–p = 145.0 Hz), 40.3,
34.2, 31.3, 25.6, 23.0, 22.0, 20.9, 19.9 (d, Jc–p = 2.3 Hz), 16.4
(d, Jc–p = 3.7 Hz), 15.9; HRMS-EI m/z [M]+ Calcd for C23H37O5PSe
504.1544. Found: 504.1549.
4.4. Preparation of 3a–d
4.4.1. (1S,2R,4S)-2-(Diethoxy-phosphoryl)acrylic acid 1,7,7-
trimethyl-bicyclo[2.2.1]hept-2-yl ester 3a. Typical procedure for
the synthesis of 3
To a solution of 2a (812 mg, 1.62 mmol) in CH2Cl2 (16 mL) pre-
cooled in an ice bath was added dropwise aqueous H2O2 (35%,
0.57 mL, 6.46 mmol) over 5 min. The resulting mixture was contin-
ued to stir at rt for an additional 1 h, then diluted with CH2Cl2
(230 mL) and successively washed with saturated aqueous NaH-
CO3 solution (45 mL), water (45 mL ꢃ 2) and brine (45 mL). After
separation, the organic layer was dried with Na2SO4, filtered and
concentrated under reduced pressure to give crude 3a
(534.98 mg, 98%), which was found to decompose easily upon
exposure to air within one day. The crude product with enough
purity (>90%) was then used directly for the subsequent reaction
without chromatographic purification. IR (neat) 1721, 1607,
4.3.3. (1R,2S,5R)-2-(Diethoxy-phosphoryl)-2-phenylselanyl-
propionic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclo-
hexyl ester 2c
The typical procedure for preparing 2b was followed by using
1c (1.6 g, 3.40 mmol) as the starting material. The phenylselenyla-
tion reaction produced 1.74 g of intermediate plus 359 mg of
recovered 1c. The subsequent methylation of phenylselenyl phos-
phonate (1.73 g) gave 2c as mixture of two diastereomers (56/
44) (1.20 g, 66.5% over two steps) after chromatographic purifica-
tion (silica gel, hexane–EtOAc, 10:1, 6:1, 4:1). IR (neat) 3056,
1715, 1249, 1023, 971, 766, 546 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
major: d 7.72 (br d, J = 7.6 Hz, 2H), 7.41–7.27 (m, 7H), 7.17–7.12
(m, 1H), 4.90 (ddd, J = 10.7, 10.8, 4.2 Hz, 1H), 4.39–4.10 (m, 4H),
2.03–1.86 (m, 2H), 1.46–1.35 (m, 10H), 1.35–1.23 (m, 8H), 1.05–
0.88 (m, 2H), 0.84 (d, J = 6.4 Hz, 3H), 0.79–0.67 (m, 1H); minor: d
7.76 (d, J = 7.6 Hz, 2H), 7.41 -7.27 (m, 7H), 7.17–7.12 (m, 1H),
4.98 (ddd, J = 10.6, 10.6, 4.4 Hz, 1H), 4.39–4.10 (m, 4H), 1.99–1.88
(m, 2H), 1.44–1.35 (m, 10H), 1.33–1.23 (m, 8H), 1.04–0.88 (m,
2H), 0.85 (d, J = 6.4 Hz, 3H), 0.77–0.67 (m, 1H); 13C NMR
(100 MHz, CDCl3) major: d 169.6, 150.4, 138.6, 129.7, 128.8,
1269, 1024, 973, 816 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.03 (dd,
;
J = 42.13, 1.9 Hz, 1H), 6.77 (dd, J = 20.3, 1.9 Hz, 1H), 5.00 (ddd,
J = 9.9, 3.1, 2.4 Hz, 1H), 4.24–4.07 (m, 4H), 2.41 (dddd, J = 13.4,
9.1, 4.4, 1.8 Hz, 1H), 2.11 (ddd, J = 13.4, 9.2, 4.6 Hz, 1H), 1.82–
1.73 (m, 1H), 1.71 (br t, J = 4.5 Hz, 1H), 1.38–1.32 (m, 1H), 1.34
(td, J = 7.2, 1.3 Hz, 6H), 1.28–1.21 (m, 1H), 1.08–0.97 (m, 1H),
0.92 (s, 3H), 0.89 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 163.9 (d, Jc–p = 15.1 Hz), 143.7 (d, Jc–p = 5.5 Hz), 133.2 (d, Jc–p
=
183.8 Hz), 81.4, 62.3 (d, Jc–p = 3.1 Hz), 62.2 (d, Jc–p = 3.2 Hz), 48.8,
47.7, 44.7, 36.6, 27.9, 26.8, 19.5, 18.7, 16.2 (d, Jc–p = 6.0 Hz), 13.3.
128.0, 125.8, 125.4, 77.3, 64.1 (d, Jc–p = 7.4 Hz), 63.6 (d, Jc–p
=
7.1 Hz), 50.4, 44.8 (d, Jc–p = 147.4 Hz), 41.2, 40.5, 34.4, 31.3, 29.9,
27.5, 24.2, 23.6, 21.8, 19.7, 19.3, 16.6 (d, Jc–p = 5.1 Hz), 16.4
(d, Jc–p = 6.2 Hz); minor: d 169.3, 150.7, 138.7, 129.6, 128.7,
4.4.2. (1R,2S)-2-(Diethoxy-phosphoryl)acrylic acid 2-phenyl-
cyclohexyl ester 3b
128.1, 125.7, 125.3, 77.5, 64.6 (d, Jc–p = 7.4 Hz), 63.3 (d, Jc–p
=
The typical procedure for preparing 3a was followed. From
593.8 mg of 2b (1.13 mmol), 386.5 mg of crude 3b was obtained
7.3 Hz), 50.2, 46.1 (d, Jc–p = 143.5 Hz), 41.4, 40.4, 34.3, 31.1, 29.9,
27.3, 24.2, 23.6, 21.8, 19.6, 19.2, 16.5 (d, Jc–p = 5.0 Hz), 16.4
(d, Jc–p = 6.2 Hz); HRMS-EI m/z [M]+ Calcd for C29H41O5PSe
580.1857. Found: 580.1868.
(93%). IR (neat) 3097, 1720, 1647, 1261, 1027, 968, 802 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d 7.29–7.12 (m, 5H), 6.70 (dd, J = 41.9,
1.8 Hz, 1H), 6.62 (dd, J = 22.4, 1.8 Hz, 1H), 5.15 (ddd, J = 10.3,
10.3, 4.4 Hz, 1H), 4.11–3.85 (m, 4H), 2.79 (ddd, J = 11.4, 11.8,
3.6 Hz, 1H), 2.32–2.02 (m, 1H), 2.03–1.75 (m, 3H), 1.66–1.47 (m,
3H), 1.45–1.36 (m, 1H), 1.25 (t, J = 7.0 Hz, 3H), 1.24 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 162.8 (d, Jc–p = 16.3 Hz), 143.0
(d, Jc–p = 4.7 Hz), 142.7, 133.0 (d, Jc–p = 183.6 Hz), 128.1, 127.3,
126.3, 77.0, 62.3 (d, Jc–p = 5.6 Hz), 62.2 (d, Jc–p = 5.6 Hz), 49.5,
33.9, 32.0, 25.6, 24.5, 16.1 (d, Jc–p = 6.0 Hz).
4.3.4. (1R,2S,5R)-2-(Diethyl-phosphinoyl)-2-phenylselanyl-
propionic acid 2-isopropyl-5-methyl-cyclohexyl ester 2d
The typical procedure for preparing 2b was followed by using
1d (1.45 g, 4.34 mmol) as the starting material. The phenylseleny-
lation reaction produced 1.59 g of intermediate plus 347 mg of
recovered 1d. The subsequent methylation of phenylselenyl phos-
phonate (1.40 g) gave 2d as a mixture of two diastereomers (55/45)
(878.6 mg, 60% over two steps) after chromatographic purification
(silica gel, hexane–EtOAc, 8:1, 5:1, 3:1). IR (neat) 3057, 1716, 1253,
1050, 989, 744, 647, 547 cmꢀ1; 1H NMR (400 MHz, CDCl3) major: d
7.72 (d, J = 7.6 Hz, 2H), 7.39 (br t, J = 7.4 Hz, 1H), 7.30 (br t,
J = 7.6 Hz, 2H), 4.71 (ddd, J = 12.6, 10.8, 4.4 Hz, 1H), 4.37–4.15 (m,
4H), 2.23–1.88 (m, 2H), 1.69 (br d, J = 11.0 Hz, 2H), 1.47 (d,
J = 15.7 Hz, 3H), 1.54–1.40 (m, 2H), 1.39–1.31 (m, 6H), 1.08–0.95
(m, 2H), 0.93–0.86 (m, 7H), 0.74 (d, J = 6.9 Hz, 3H); minor: d 7.68
(d, J = 7.6 Hz, 2H), 7.39 (br t, J = 7.4 Hz, 1H), 7.30 (br t, J = 7.6 Hz,
2H), 4.74 (ddd, J = 10.8, 10.8, 4.4 Hz, 1H), 4.37–4.15 (m, 4H),
2.23–1.88 (m, 2H), 1.69 (br d, J = 11.0 Hz, 2H), 1.46 (d, J = 15.7,
4.4.3. (1R,2S,5R)-2-(Diethoxy-phosphoryl)-acrylic acid 5-methyl-
2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester 3c
The typical procedure for preparing 3a was followed. From
755.4 mg of 2c (1.30 mmol), 517.1 mg of crude 3c was obtained
(94%). IR (neat) 3088, 1714, 1632, 1297, 1094, 979, 796 cmꢀ1 1H
;
NMR (400 MHz, CDCl3) d 7.32–7.20 (m, 4H), 7.14–7.03 (m, 1H),
6.42 (br d, J = 20.9 Hz, 1H), 6.05 (br d, J = 42.7 Hz, 1H), 4.71 (ddd,
J = 10.7, 10.6, 4.3 Hz, 1H), 4.28–4.07 (m, 4H), 2.11 (ddd, J = 10.7,
10.7, 3.0 Hz, 1H), 1.90–1.94 (m, 1H), 1.76–1.60 (m, 2H), 1.56–
1.41 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.3 Hz, 3H), 1.30
(s, 3H), 1.21 (s, 3H), 1.14–1.01 (m, 2H), 0.88 (d, J = 6.4 Hz, 3H);

J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
31
13C NMR (100 MHz, CDCl3) d 162.6 (d, Jc–p = 17.9 Hz), 151.6, 142.9
(d, Jc–p = 4.4 Hz), 132.7 (d, Jc–p = 187.9 Hz), 128.1, 125.3, 125.0,
75.6, 62.7 (d, Jc–p = 5.9 Hz), 62.6 (d, Jc–p = 5.8 Hz), 50.3, 41.6, 39.6,
34.5, 31.3, 27.8, 26.6, 25.2, 21.7, 16.4 (d, Jc–p = 5.9 Hz).
36.3, 33.1, 28.0, 27.1, 25.2 (d, Jc–p = 3.9 Hz), 22.5 (d, Jc–p = 4.6 Hz),
19.6, 18.9, 18.0 (d, Jc–p = 5.0 Hz), 16.5 (d, Jc–p = 6.2 Hz), 16.4
(d, Jc–p = 6.7 Hz), 13.5; 4a0 isomer one: d 171.1 (d, Jc–p = 3.3 Hz),
131.5 (d, Jc–p = 13.6 Hz), 125.2, 81.1, 62.7 (d, J = 6.3 Hz), 51.9
(d, J = 132.3 Hz), 48.8, 47.8, 44.8, 36.1, 33.0, 27.9, 27.3, 26.0
(d, J = 4.0 Hz), 22.4 (d, J = 5.0 Hz), 20.6, 20.5, 18.5 (d, J = 3.1 Hz),
16.4 (d, J = 5.7 Hz), 13.5; 4a0 isomer two: d 171.0 (d, Jc–p = 4.4 Hz),
131.5 (d, Jc–p = 13.6 Hz), 125.2, 81.0, 62.7 (d, J = 6.3 Hz), 51.9
(d, J = 132.3 Hz), 48.8, 47.8, 44.8, 36.0, 33.0, 27.9, 27.3, 25.2
(d, J = 3.9 Hz), 22.3 (d, J = 6.1 Hz), 20.5, 20.4, 18.5 (d, J = 3.0 Hz),
16.4 (d, J = 5.7 Hz), 13.4; HRMS-EI m/z [M]+ Calcd for C22H37O5P
412.2379. Found: 412.2387.
4.4.4. (1R,2S,5R)-2-(Diethoxy-phosphoryl)-acrylic acid 2-iso-
propyl-5-methyl-cyclohexyl ester 3d
The typical procedure for preparing 3a was followed. From
717 mg of 2d (1.42 mmol), 489 mg of crude 3d was obtained
(99%). IR (neat) 1718, 1607, 1265, 1027, 927, 846 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 6.92 (dd, J = 42.2, 1.6 Hz, 1H), 6.69 (dd,
J = 20.4, 1.6 Hz, 1H), 4.75 (ddd, J = 10.9, 10.8, 4.4 Hz, 1H), 4.19–
4.00 (m, 4H), 2.09 (br d, J = 12.0 Hz, 1H), 1.95–1.84 (m, 1H), 1.64
(br d, J = 11.4 Hz, 1H), 1.49–1.36 (m, 2H), 1.28 (t, J = 7.0 Hz, 6H),
1.06–0.94 (m, 2H), 0.86 (d, J = 6.1 Hz, 3H), 0.84 (d, J = 6.3 Hz, 3H),
0.87–0.82 (m, 1H), 0.70 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 163.4 (d, Jc–p = 15.7 Hz), 134.4 (d, Jc–p = 5.1 Hz), 133.5 (d,
Jc–p = 184.7 Hz), 75.7, 62.6 (d, Jc–p = 5.7 Hz), 62.5 (d, Jc–p = 5.7 Hz),
47.0, 40.6, 34.1, 31.4, 25.8, 23.1, 21.9, 20.8, 16.3 (d, Jc–p = 6.3 Hz),
16.0.
4.5.2. Formation of 4a. Typical procedure for the SnCl4-
mediated Diels–Alder reaction
To a solution of 3a (151 mg, 0.44 mmol) in CH2Cl2 (2.3 mL) pre-
cooled at ꢀ65 °C was added SnCl4 (1 M in CH2Cl2, 0.53 mL,
0.53 mmol, 1.2 equiv). After stirring for 45 min, trans-piperylene
(0.46 mL, 4.39 mmol) was introduced and the reaction mixture
was continued to stir at ꢀ65 °C for 12 h, and diluted with ethyl ace-
tate (190 mL). The solution was washed with water (30 mL ꢃ 2)
and brine (30 mL), and concentrated in vacuo. The crude residue
was subjected to chromatographic purification (silica gel, hex-
ane–EtOAc, 10:1, 5:1, 2:1) to give 156.6 mg (84.1%) of 4a as a mix-
ture of two endo diastereomers (dr = 50:50). IR (neat) 3054, 1727,
4.5. Diels–Alder reactions of 3
4.5.1. Formation of the mixture of (1S,2R,4S)-1,7,7-trimethyl
bicyclo[2.2.1]heptan-2-yl (1R⁄,2R⁄)-1-(diethoxyphosphoryl)-2-
methylcyclohex-3-ene carboxylate 4a and (1S,2R,4S)-1,7,7-
trimethylbicyclo[2.2.1]heptan-2-yl (1R⁄,2S⁄)-1-(diethoxy phosph-
oryl)-2-methylcyclohex-3-ene carboxylate 4a0
1242, 1028, 964, 738 cmꢀ1 1H NMR (400 MHz, CDCl3) isomer
;
one: d 5.77–5.46 (m, 2H), 4.99–4.77 (m, 1H), 4.28–4.05 (m, 4H),
3.04–2.85 (m, 1H), 2.46–2.18 (m, 3H), 2.17–1.95 (m, 3H), 1.82–
1.63 (m, 3H), 1.32 (t, J = 6.9 Hz, 6H), 1.29–1.19 (m, 1H), 1.27 (d,
J = 7.3 Hz, 3H), 1.05–1.00 (m, 1H), 0.89 (s, 3H), 0.86(s, 3H), 0.87(s,
3H); isomer two: d 5.77–5.46 (m, 2H), 4.99–4.77 (m, 1H), 4.28–
4.05 (m, 4H), 3.04–2.85 (m, 1H), 2.46–2.18 (m, 3H), 2.17–1.95
(m, 3H), 1.82–1.63 (m, 3H), 1.32 (t, J = 6.9 Hz, 6H), 1.29–1.19 (m,
1H), 1.23 (d, J = 7.2 Hz, 3H), 1.05–1.00 (m, 1H), 0.89 (s, 3H),
0.86(s, 3H), 0.87(s, 3H); 13C NMR (100 MHz, CDCl3) isomer one: d
170.7 (d, Jc–p = 7.7 Hz), 131.3 (d, JC–P = 9.6 Hz), 125.2, 81.3, 62.8
(d, Jc–p = 6.9 Hz), 62.1 (d, Jc–p = 6.3 Hz), 51.5 (d, Jc–p = 135.7 Hz),
48.8, 47.7, 44.8, 36.4, 33.2, 28.0, 27.2, 26.0 (d, Jc–p = 4.0 Hz), 22.6
Dry toluene (4 mL) was added to ZnCl2 (flame-dried, 213.8 mg,
1.57 mmol, 1.5 equiv) in a round-bottom flask under N2. The
resulting suspension was stirred for 30 min and then added to a
solution of 3a (360 mg, 1.05 mmol) in dry toluene (2 mL). After
stirring for 20 min, trans-piperylene (1.1 mL, 10.46 mmol) was
introduced and the reaction mixture was continued to stir at
80 °C for 5 h, cooled to rt and diluted with ethyl acetate
(200 mL). The solution was washed with water (35 mL ꢃ 2) and
brine (35 mL), and concentrated in vacuo. The residue was sub-
jected to chromatographic purification (silica gel, hexane–EtOAc,
10:1, 5:1, 2:1) to give 376 mg (87.3%) of product as a mixture of
four isomers (4a (endo)/4a0 (exo) = 82:18; dr = 41:41:9:9). IR (neat)
3054, 1727, 1242, 1028, 964, 738 cmꢀ1; 1H NMR (400 MHz, CDCl3)
4a isomer one: d 5.77–5.46 (m, 2H), 4.99–4.77 (m, 1H), 4.28–4.05
(m, 4H), 3.04–2.85 (m, 1H), 2.46–2.18 (m, 3H), 2.17–1.95 (m,
3H), 1.82–1.63 (m, 3H), 1.32 (t, J = 6.9 Hz, 6H), 1.29–1.19 (m, 1H),
1.27 (d, J = 7.3 Hz, 3H), 1.05–1.00 (m, 1H), 0.89 (s, 3H), 0.86(s,
3H), 0.87(s, 3H); 4a isomer two: d 5.77–5.46 (m, 2H), 4.99–4.77
(m, 1H), 4.28–4.05 (m, 4H), 3.04–2.85 (m, 1H), 2.46–2.18 (m,
3H), 2.17–1.95 (m, 3H), 1.82–1.63 (m, 3H), 1.32 (t, J = 6.9 Hz, 6H),
1.29–1.19 (m, 1H), 1.23 (d, J = 7.2 Hz, 3H), 1.05–1.00 (m, 1H),
0.89 (s, 3H), 0.86(s, 3H), 0.87(s, 3H); 4a0 isomer one: d 5.77–5.46
(m, 2H), 4.99–4.77 (m, 1H), 4.28–4.05 (m, 4H), 3.17–3.05 (m,
1H), 2.46–2.18 (m, 3H), 2.17–1.95 (m, 3H), 1.82–1.63 (m, 3H),
1.34 (t, J = 6.4 Hz, 6H), 1.29–1.19 (m, 1H), 1.22 (d, J = 6.8 Hz, 3H),
1.07–1.01 (m, 1H), 0.89 (s, 3H), 0.86(s, 3H), 0.83(s, 3H); 4a0 isomer
two: d 5.77–5.46 (m, 2H), 4.99–4.77 (m, 1H), 4.28–4.05 (m, 4H),
3.17–3.05 (m, 1H), 2.46–2.18 (m, 3H), 2.17–1.95 (m, 3H), 1.82–
1.63 (m, 3H), 1.34 (t, J = 6.4 Hz, 6H), 1.29–1.19 (m, 1H), 1.22
(d, J = 7.0 Hz, 3H), 1.07–1.01 (m, 1H), 0.89 (s, 3H), 0.86(s, 3H),
0.83(s, 3H); 13C NMR (100 MHz, CDCl3) 4a isomer one: d 170.7
(d, Jc–p = 5.5 Hz), 19.6, 18.9, 18.1 (d, Jc–p = 5.6 Hz), 16.5 (d, Jc–p
6.2 Hz), 16.4 (d, Jc–p = 6.7 Hz), 13.6; isomer two: d 170.6 (d, Jc–p
=
=
7.8 Hz), 131.9 (d, Jc–p = 8.7 Hz), 124.9, 81.2, 62.8 (d, Jc–p = 6.9 Hz),
62.1 (d, Jc–p = 6.3 Hz), 51.3 (d, Jc–p = 135.7 Hz), 48.7, 47.7, 44.8,
36.3, 33.1, 28.0, 27.1, 25.2 (d, Jc–p = 3.9 Hz), 22.5 (d, Jc–p = 4.6 Hz),
19.6, 18.9, 18.0 (d, Jc–p = 5.0 Hz), 16.5 (d, Jc–p = 6.2 Hz), 16.4
(d, Jc–p = 6.7 Hz), 13.5; HRMS-EI m/z [M]+ Calcd for C22H37O5P
412.2379. Found: 412.2381.
4.5.3. (1R⁄,2S⁄,4R⁄)-2-(Diethoxy-phosphoryl)-bicyclo[2.2.1]hept-
5-ene-2-carboxylic acid (1S,2R,4S)-1,7,7-trimethylbicyclo-
[2.2.1]hept-2-yl ester 4b
The typical procedure for preparing 4a was followed by using
3b (189 mg, 0.55 mmol), cyclopentadiene (363 mg, 5.49 mmol)
(pre-generated by the thermolysis of dicyclopentadiene), and SnCl4
(1 M in CH2Cl2, 0.66 mL, 0.66 mmol). The chromatographic purifi-
cation of the crude products (silica gel, hexane–EtOAc, 15:1, 8:1,
4:1) produced 4b (198.6 mg, 88%) as a mixture of two endo diaste-
reomers (dr = 53:47). IR (neat) 3107, 1728, 1245, 1025, 963,
884 cmꢀ1 1H NMR (400 MHz, CDCl3) major: d 6.29–6.17 (m, 1H),
;
6.02 (m, 1H), 4.79 (ddd, J = 9.9, 2.8, 2.6 Hz, 1H), 4.26–4.03 (m,
4H), 3.52 (br s, 1H), 2.96 (br s, 1H), 2.42 (ddd, J = 12.1, 3.8,
3.7 Hz, 1H), 2.34–2.23 (m, 1H), 2.13–2.00 (m, 2H), 1.97–1.89 (m,
1H), 1.81–1.62 (m, 2H), 1.41–1.30 (m, 2H), 1.34 (t, J = 7.3 Hz, 3H),
1.27 (t, J = 7.0 Hz, 3H), 1.24–1.16 (m, 1H), 1.02–0.92 (m, 1H),
0.89–0.81 (m, 9H); minor: d 6.29–6.17 (m, 1H), 5.97 (m, 1H),
4.69 (ddd, J = 9.7, 2.6, 2.6 Hz, 1H), 4.26–4.03 (m, 4H), 3.51 (br s,
1H), 2.96 (br s, 1H), 2.37 (ddd, J = 12.1, 3.7, 3.6 Hz, 1H), 2.34–2.23
(d, Jc–p = 7.7 Hz), 131.3 (d, JC–P = 9.6 Hz), 125.2, 81.3, 62.8 (d, Jc–p
6.9 Hz), 62.1 (d, Jc–p = 6.3 Hz), 51.5 (d, Jc–p = 135.7 Hz), 48.8, 47.7,
44.8, 36.4, 33.2, 28.0, 27.2, 26.0 (d, Jc–p = 4.0 Hz), 22.6 (d, Jc–p
5.5 Hz), 19.6, 18.9, 18.1 (d, Jc–p = 5.6 Hz), 16.5 (d, Jc–p = 6.2 Hz),
16.4 (d, Jc–p = 6.7 Hz), 13.6; 4a isomer two: d 170.6 (d, Jc–p
=
=
=
7.8 Hz), 131.9 (d, Jc–p = 8.7 Hz), 124.9, 81.2, 62.8 (d, Jc–p = 6.9 Hz),
62.1 (d, Jc–p = 6.3 Hz), 51.3 (d, Jc–p = 135.7 Hz), 48.7, 47.7, 44.8,

32
J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
(m, 1H), 2.13–2.00 (m, 2H), 1.97–1.89 (m, 1H), 1.81–1.62 (m, 2H),
1.41–1.30 (m, 2H), 1.34 (t, J = 7.3 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H),
1.24–1.16 (m, 1H), 1.02–0.92 (m, 1H), 0.89–0.81 (m, 9H); 13C
4.5.6. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl (1R,2S,4R)-2-
(diethoxyphosphoryl)bicyclo[2.2.1]hept-5-ene-2-carboxylate 4e
The typical procedure for preparing 4a was followed by using
NMR (100 MHz, CDCl3) major:
d
171.2, 139.3, 134.9 (d, Jc–
3d
(402.2 mg,
1.16 mmol),
cyclopentadiene
(767.5 mg,
p = 13.0 Hz), 80.8, 62.6 (d, Jc–p = 7.1 Hz), 55.0 (d, Jc–p = 130.8 Hz),
49.0, 48.9, 47.7, 47.5, 44.8, 42.6, 36.1, 32.8, 28.0, 27.1, 19.6, 18.8,
16.3 (d, Jc–p = 5.9 Hz), 13.6; minor: d 171.1, 139.4, 134.6 (d, Jc–
p = 13.1 Hz), 81.3, 62.4 (d, Jc–p = 6.5 Hz), 62.4 (d, Jc–p = 6.2 Hz),
54.9 (d, Jc–p = 130.8 Hz), 48.9, 48.5, 47.6, 47.4, 44.8, 42.6, 36.0,
32.3, 27.9, 27.1, 19.6, 18.8, 16.5 (d, Jc–p = 5.7 Hz), 16.4 (d, Jc–
p = 5.7 Hz), 13.2; HRMS-EI m/z [M]+ Calcd for C22H35O5P
410.2222. Found: 410.2223.
11.61 mmol) (pre-generated by the thermolysis of dicyclopentadi-
ene), and SnCl4 (1 M in CH2Cl2, 1.39 mL, 1.39 mmol). The chro-
matographic purification of the crude products (silica gel,
hexane–EtOAc, 10:1, 4:1, 2:1) produced 4e (415 mg, 87%) as a mix-
ture of two diastereomers (dr = 92:8) as indicated by NMR analysis.
IR (neat) 3098, 1725, 1243, 1029, 963, 714 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) major: d 6.22 (dd, J = 5.3, 3.0 Hz, 1H), 5.94 (dd,
J = 5.3, 2.4 Hz, 1H), 4.52 (ddd, J = 10.9, 10.9, 4.2 Hz, 1H), 4.26–4.01
(m, 4H), 3.46 (br d, J = 4.8 Hz, 1H), 2.93 (br s, 1H), 2.33 (ddd,
J = 19.5, 12.2, 3.6 Hz, 1H), 2.07–1.96 (m, 3H), 1.92 (ddd, J = 11.9,
9.0, 2.5 Hz, 1H), 1.65 (d, J = 11.3 Hz, 1H), 1.46–1.31 (m, 3H), 1.34
(t, J = 7.0 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H), 1.07–0.93 (m, 2H), 0.89
(d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.85–0.79 (m, 1H), 0.72
(d, J = 7.0 Hz, 3H); minor: d 6.20 (m, 1H), 6.04–5.97 (m, 1H), 4.61
(ddd, J = 10.9, 10.8, 4.2 Hz, 1H), 4.26–4.01 (m, 4H), 3.46 (br d,
J = 4.8 Hz, 1H), 2.93 (br s, 1H), 2.39 (ddd, J = 15.9, 12.1, 3.7 Hz,
1H), 2.07–1.96 (m, 3H), 1.92 (ddd, J = 11.9, 9.0, 2.5 Hz, 1H), 1.65
(d, J = 11.3 Hz, 1H), 1.46–1.31 (m, 3H), 1.34 (t, J = 7.0 Hz, 3H),
1.27 (t, J = 7.0 Hz, 3H), 1.07–0.93 (m, 2H), 0.89 (d, J = 7.0 Hz, 3H),
0.86 (d, J = 6.7 Hz, 3H), 0.85–0.79 (m, 1H), 0.64 (d, J = 6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3) major: d 170.5, 139.4, 134.6 (d, Jc–
p = 13.1 Hz), 75.7, 62.6 (d, Jc–p = 7.3 Hz), 62.5 (d, Jc–p = 6.8 Hz),
55.1 (d, Jc–p = 131.2 Hz), 49.1, 47.7, 46.9, 42.5, 40.2, 34.2, 32.3,
31.3, 25.6, 22.8, 22.0, 20.9, 16.5 (d, Jc–p = 6.2 Hz), 16.3 (d, Jc–
p = 6.0 Hz), 15.7; minor: d 170.5, 139.4, 134.8 (d, Jc–p = 13.1 Hz),
75.3, 62.6 (d, Jc–p = 7.3 Hz), 62.5 (d, Jc–p = 6.8 Hz), 55.2 (d, Jc–
p = 131.2 Hz), 48.9, 47.7, 46.9, 42.5, 40.5, 34.2, 32.2, 31.4, 25.6,
22.6, 22.0, 20.9, 16.5 (d, Jc–p = 6.2 Hz), 16.3 (d, Jc–p = 6.0 Hz), 15.7;
HRMS-EI m/z [M]+ Calcd for C22H37O5P 412.2379. Found:
4.5.4. (1R⁄,2S⁄,4R⁄)-2-(Diethoxy-phosphoryl)-bicyclo[2.2.1]hept-
5-ene-2-carboxylic acid (1R,2S)-2-phenyl-cyclohexyl ester 4c
The typical procedure for preparing 4a was followed by using 3b
(322 mg, 0.76 mmol), cyclopentadiene (504 mg, 7.62 mmol) (pre-
generated by the thermolysis of dicyclopentadiene), and SnCl4
(1 M in CH2Cl2, 0.91 mL, 0.91 mmol). The chromatographic purifica-
tion of the crude products (silica gel, hexane–EtOAc, 10:1, 6:1, 3:1)
produced 4c (277 mg, 84%) as a mixture of two diastereomers
(dr = 52:48). IR (neat) 3193, 1725, 1647, 1550, 1242, 1028, 962,
706 cmꢀ1 1H NMR (400 MHz, CDCl3) major: d 7.29–7.06 (m, 5H),
;
5.84–5.72 (m, 1H), 5.61–5.53 (m, 1H), 4.78 (ddd, J = 10.6, 10.5,
4.4 Hz, 1H), 4.23–3.84 (m, 4H), 3.01–3.09 (m, 1H), 2.78–2.58 (m,
2H), 2.34–1.61 (m, 5H), 1.61–1.16 (m, 11H), 1.06–1.10 (m, 2H);
minor: d 7.29–7.06 (m, 5H), 5.84–5.72 (m, 1H), 5.53–5.43 (m, 1H),
4.98 (ddd, J = 10.6, 10.5, 4.4 Hz, 1H), 4.23–3.84 (m, 4H), 3.33–3.24
(m, 1H), 2.78–2.58 (m, 2H), 2.34–1.61 (m, 5H), 1.61–1.16 (m,
11H), 1.12–1.15 (m, 2H); 13C NMR (100 MHz, CDCl3) major: d
170.1, 143.6, 138.5, 134.2 (d, Jc–p = 12.9 Hz), 128.5, 127.6, 126.6,
77.6, 62.4 (d, Jc–p = 7.1 Hz), 62.3 (d, Jc–p = 7.0 Hz), 54.7 (d, Jc–
p = 130.4 Hz), 49.7, 48.9, 47.3, 42.4, 34.2, 32.2, 31.6, 25.8, 24.5,
16.4 (d, Jc–p = 5.9 Hz), 16.3 (d, Jc–p = 5.9 Hz); minor: d 170.1, 143.4,
138.7, 135.0 (d, Jc–p = 12.9 Hz), 128.2, 127.5, 126.2, 76.4, 62.6 (d,
Jc–p = 7.4 Hz), 62.5 (d, Jc–p = 7.3 Hz), 55.3 (d, Jc–p = 130.4 Hz), 49.5,
48.8, 46.9, 42.3, 35.0, 32.3, 31.8, 25.7, 24.6, 16.6 (d, Jc–p = 6.2 Hz),
16.4 (d, Jc–p = 5.9 Hz); HRMS-EI m/z [M]+ Calcd for C24H33O5P
432.2066. Found: 432.2061.
412.2375. ½a 2D0
¼ þ17:2 (c 0.81, CHCl3).
ꢂ
4.5.7. (1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl
(1S,2S)-1-(diethoxyphosphoryl)-2-methylcyclohex-3-ene
carboxylate 4f
The typical procedure for preparing 4a was followed by using 3c
(517.1 mg, 1.22 mmol), trans-piperylene (1.28 mL, 12.24 mmol),
and SnCl4 (1 M in CH2Cl2, 1.47 mL, 1.47 mmol). The chromato-
graphic purification of the crude products (silica gel, hexane–
EtOAc, 15:1, 5:1, 2:1) produced 4f in 88% yield (530.2 mg)
4.5.5. (1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl
(1R,2S,4R)-2-(diethoxyphosphoryl)bicyclo[2.2.1]hept-5-ene-2-
carboxylate 4d
(dr >30:1). IR (neat) 3021, 1717, 1244, 1026, 962, 699 cmꢀ1 1H
;
The typical procedure for preparing 4a was followed by using 3c
(360.7 mg, 0.85 mmol), cyclopentadiene (564.3 mg, 8.53 mmol)
(pre-generated by the thermolysis of dicyclopentadiene), and SnCl4
(1 M in CH2Cl2, 1.02 mL, 1.02 mmol). The chromatographic purifi-
cation of the crude products (silica gel, hexane–EtOAc, 8:1, 4:1,
NMR (400 MHz, CDCl3) d 7.29–7.23 (m, 4H), 7.19–7.05 (m, 1H),
5.61 (br d, J = 10.2 Hz, 1H), 5.55 (br d, J = 10.8 Hz, 1H), 4.91 (ddd,
10.5, 10.4, 3.9 Hz, 1H), 4.20–4.05 (m, 4H), 3.02–2.84 (m, 1H),
2.36–2.11 (m, 3H), 2.04–1.95 (m, 2H), 1.89 (ddd, J = 11.7 10.8,
3.1 Hz, 1H), 1.45–1.34 (m, 5H), 1.31 (t, J = 6.9 Hz, 6H), 1.26 (s,
3H), 1.20 (d, J = 7.1 Hz, 3H), 1.18–1.10 (m, 1H), 0.99–0.85 (m,
2H), 0.80 (d, J = 6.3 Hz, 3H), 0.76–0.60 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 170.3 (d, Jc–p = 2.1 Hz), 150.6, 130.6 (d, Jc–
p = 7.6 Hz), 128.0, 125.8, 125.7, 125.3, 77.0, 62.8 (d, Jc–p = 7.1 Hz),
62.2 (d, Jc–p = 7.4 Hz), 51.4 (d, Jc–p = 136.0 Hz), 50.5, 41.6, 40.5,
34.4, 33.2 (d, Jc–p = 2.1 Hz), 31.4, 27.7, 23.8 (d, Jc–p = 2.9 Hz), 22.7
(d, Jc–p = 6.9 Hz), 22.6, 21.8, 18.6 (d, Jc–p = 6.7 Hz), 16.5 (d, Jc–
p = 6.3 Hz), 16.4 (d, Jc–p = 6.8 Hz); HRMS-EI m/z [M]+ Calcd for
2:1) produced 4d (370 mg, 89%) as
(dr >30:1) as revealed by NMR analysis. IR (neat) 3113, 1718,
1243, 1028, 963, 767 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.32–
a single diastereomer
;
7.29 (m, 4H), 7.20–7.13 (m, 1H), 6.26 (dd, J = 5.3, 3.0 Hz, 1H),
5.97 (dd, J = 5.3, 2.4 Hz, 1H), 4.68 (ddd, J = 10.5, 10.5, 3.8 Hz, 1H),
4.28–4.08 (m, 4H), 3.47 (br d, J = 5.72 Hz, 1H), 2.95 (br s, 1H),
2.28 (ddd, J = 19.0, 12.4, 3.5 Hz, 1H), 2.04 (m, 2H), 1.97–1.83 (m,
2H), 1.45 (s, 3H), 1.44–1.34 (m, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.32–
1.28 (m, 1H), 1.30 (t, J = 7.0 Hz, 3H), 1.24 (s, 3H), 1.17–1.10 (m,
1H), 0.90–0.82 (m, 2H), 0.81 (d, J = 6.3 Hz, 3H), 0.74–0.64 (m,
1H); 13C NMR (100 MHz, CDCl3) d 170.2, 150.8, 139.7, 134.0 (d,
JC–P = 13.1 Hz), 128.0, 125.7, 125.3, 77.9, 62.9 (d, JC–P = 7.2 Hz),
62.4 (d, JC–P = 6.8 Hz), 55.2 (d, JC–P = 134.6 Hz), 50.7, 50.0, 47.7,
42.9, 41.0, 40.4, 34.6, 31.4, 31.3, 30.9, 27.7, 22.6, 21.8, 16.6 (d, JC–
P = 5.8 Hz), 16.4 (d, JC–P = 5.6 Hz); HRMS-EI m/z [M]+ Calcd for
C
28H43O5P 490.2848. Found: 490.2857. ½a D20
¼ þ3:8 (c 1.5, CHCl3).
ꢂ
4.5.8. (1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl) (1S,2S)-1-
(diethoxyphosphoryl)-2-methylcyclohex-3-ene carboxylate 4g
The typical procedure for preparing 4a was followed by using
3d (355.6 mg, 1.03 mmol), trans-piperylene (1.08 mL, 10.27 mmol),
and SnCl4 (1 M in CH2Cl2, 1.23 mL, 1.23 mmol). The chromato-
graphic purification of the crude products (silica gel, hexane–
EtOAc, 10:1, 5:1, 2:1) produced 4 g (344.5 mg, 81%) as a mixture
C
28H41O5P 488.2692. Found: 488.2696.
½
a 2D0
ꢂ
¼ þ48:5 (c 0.63,
CHCl3).

J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
33
of two diastereomers (dr = 91:9) as indicated by NMR spectra. IR
(neat) 3085, 1730, 1247, 1027, 961, 789 cmꢀ1 1H NMR
1.92–1.96 (m, 1H), 1.42–1.44 (m, 1H), 1.36 (t, J = 6.9 Hz, 3H), 1.35
(t, J = 6.9 Hz, 3H), 0.78 (ddd, J = 12.4, 9.9, 2.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 137.5, 135.6 (d, Jc–p = 13.2 Hz), 66.4 (d, Jc–
p = 2.3 Hz), 62.3 (d, Jc–p = 7.2 Hz), 62.2 (d, Jc–p = 7.4 Hz), 47.7, 47.6
(d, Jc–p = 138.5 Hz), 45.9 (d, Jc–p = 2.5 Hz), 42.1, 31.1, 16.5 (d, Jc–
p = 5.6 Hz); HRMS-EI m/z [M]+ Calcd for C12H21O4P 260.1177.
Found: 260.1183. To a solution of 6 (48.4 mg) in dry CH2Cl2
(4.6 mL) was added pyridium dichromate (214.2 mg, 0.56 mmol).
The reaction mixture was continued to stir for 10 h, filtered
through a Celite pad and concentrated. Chromatographic purifica-
tion of the crude residue on silica gel (hexane–EtOAc, 6:1, 3:1, 1:1)
afforded the known aldehyde 7 (45.1 mg, 71% over two steps based
on recovered 4c) as a single endo isomer. The spectroscopic data
agree well with the previously reported ones.6 Compound 7: 1H
NMR (400 MHz, C6D6) d 9.51 (br s, 1H), 5.89 (dd, J = 5.4, 3.2 Hz,
1H), 5.78 (dd, J = 5.4, 2.6 Hz, 1H), 3.98–3.83 (m, 4H), 3.44 (br d,
J = 5.4 Hz, 1H), 2.63 (br s, 1H), 2.35 (d, J = 8.4 Hz, 1H), 2.24 (ddd,
J = 19.0, 12.1, 3.4 Hz, 1H), 2.08 (ddd, J = 11.7, 8.9, 2.6 Hz, 1H), 1.29
(br d, J =8.4 Hz, 1H), 1.01 (t, J = 7.0 Hz, 3H), 0.96 (t, J = 7.0 Hz,
3H); 13C NMR (100 MHz, C6D6) d 196.0, 139.8, 133.3 (d, Jc–
p = 13.6 Hz), 62.4 (d, Jc–p = 6.7 Hz), 62.2 (d, Jc–p = 7.0 Hz), 61.4 (d,
Jc–p = 129.7 Hz), 47.3, 47.0, 43.4 (d, Jc–p = 2.8 Hz), 30.9, 16.2 (d, Jc–
p = 6.1 Hz), 16.1 (d, Jc–p = 6.3).
;
(400 MHz, CDCl3) major: d 5.56 (br d, J = 10.5 Hz, 1H), 5.50 (br d,
J = 10.1 Hz, 1H), 4.64 (ddd, J = 10.9, 10.8, 4.3 Hz, 1H), 4.27–3.87
(m, 4H), 3.10–2.80 (m, 1H), 2.41–2.26 (m, 1H), 2.20–2.11 (m,
1H), 2.09–1.86 (m, 4H), 1.64 (br d, J = 11.6 Hz, 2H), 1.49–1.35 (m,
2H), 1.28 (t, J = 7.0, 6H), 1.23 (d, J = 7.3 Hz, 3H), 1.09–0.87 (m,
3H), 0.85 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 7.1 Hz, 3H), 0.68 (d,
J = 7.0 Hz, 3H); minor: d 5.48–5.16 (m, 2H), 4.64 (ddd, J = 10.9,
10.8, 4.3 Hz, 1H), 4.27–3.87 (m, 4H), 3.10–2.80 (m, 1H), 2.41–
2.26 (m, 1H), 2.20–2.11 (m, 1H), 2.09–1.86 (m, 4H), 1.64 (br d,
J = 11.6 Hz, 2H), 1.49–1.35 (m, 2H), 1.35–1.25 (m, 6H), 1.19 (d,
J = 7.2 Hz, 3H), 1.09–0.87 (m, 3H), 0.85 (d, J = 6.5 Hz, 3H), 0.84 (d,
J = 7.1 Hz, 3H), 0.68 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
major: d 169.7 (d, Jc–p = 2.4 Hz), 131.4 (d, Jc–p = 10.3 Hz), 124.7,
75.1, 62.6 (d, Jc–p = 7.1 Hz), 62.0 (d, Jc–p = 7.3 Hz), 51.4 (d, Jc–
p = 135.5 Hz), 46.9, 40.4, 34.1, 33.5, 31.3, 26.2 (d, Jc–p = 4.2 Hz),
25.1, 22.6, 22.5 (d, Jc–p = 9.1 Hz), 21.9, 20.9, 18.1 (d, Jc–p = 4.2 Hz),
16.4 (d, Jc–p = 6.0 Hz), 16.3 (d, Jc–p = 6.3 Hz), 15.5; minor: d 169.7
(d, Jc–p = 2.4 Hz), 131.4 (d, Jc–p = 10.3 Hz), 124.8, 75.2, 62.6 (d, Jc–
p = 7.1 Hz), 62.0 (d, Jc–p = 7.3 Hz), 51.4 (d, Jc–p = 135.5 Hz), 46.9,
40.5, 34.1, 33.5, 31.3, 26.2 (d, Jc–p = 4.2 Hz), 25.2, 22.6, 22.5 (d, Jc–
p = 9.1 Hz), 21.9, 20.9, 18.1 (d, Jc–p = 4.2 Hz), 16.4 (d, Jc–p = 6.0 Hz),
16.3 (d, Jc–p = 6.3 Hz), 15.6; HRMS-EI m/z [M]+ Calcd for
C
22H39O5P 414.2535. Found: 414.2549. ½a D20
ꢂ
¼ þ9:3 (c 1.0, CHCl3).
4.7.2. Conversion of 4d into 7
Treatment of 4d (dr >30:1,16 105 mg) with DIBAL-H (1 M in tol-
uene, 0.43 mL) under the same reaction conditions as Section 4.7.1
produced 6 (11.4 mg), 7 (17 mg), (ꢀ)-phenylmenthol (30 mg), and
recovered 4d (50.4 mg, dr >30:116). Subsequent oxidation of 6
(11.4 mg) by PDC furnished 10.9 mg of 7 (99.5%, over two steps
based on recovered 4d).
4.6. Conversion of 4a into tosylhydrazone 5
AT first, DIBAL-H (1 M in toluene, 1.0 mL, 1 mmol) was added to
a solution of 4a (98.9 mg, 0.24 mmol) in toluene (5 mL) pre-cooled
to ꢀ78 °C in 2 min. The mixture was then stirred at 0 °C for 80 min,
diluted with ethyl acetate (80 mL), and successively washed with
aqueous HCl solution (10%, 10 mL ꢃ 2), water (10 mL ꢃ 2), and
brine (15 mL). After concentration, the residue was subjected to
chromatographic purification (silica gel, hexane–EtOAc, 8:1, 5:1,
2:1) to afford the aldehyde intermediate (55 mg, 88%) plus recov-
ered (ꢀ)-borneol (40 mg). p-Toluenesulfonhydrazide (40.6 mg,
0.218 mmol) was then added to a solution of freshly prepared alde-
hyde (55 mg, 0.212 mmol) in absolute ethanol (5 mL). The mixture
was continued to stir for 5 h and concentrated under reduced pres-
sure. The crude product was purified by flash chromatography (sil-
ica gel, hexane–EtOAc, 5:1, 2:1) to give tosylhydrazone 5 (75 mg,
82%) with spectroscopic data (1H and 13C NMR) identical to previ-
ously reported ones.6
4.7.3. Conversion of 4e into 7
Treatment of 4e (dr = 91:9,16 119.5 mg) with DIBAL-H (1 M in
toluene, 0.58 mL) under the same reaction conditions as Sec-
tion 4.7.1 produced 6 (36 mg), 7 (15 mg), (1R,2S,5R)-(ꢀ)-menthol
(26.3 mg), and recovered 4e (24.5 mg, dr = 91:916). Subsequent
oxidation of 6 (36 mg) by PDC furnished 31 mg of 7 (86%, over
two steps based on recovered 4e).
4.8. Conversion of 4f/4g into 8 and 4d/4e into 9
4.8.1. Conversion of 4f and 4g into 8
Under an N2 atmosphere, diisobutylaluminum hydride (1 M in
toluene, 1.31 mL, 1.31 mmol) was dropwise added to a solution
of 4f (dr >30:1,16 107 mg, 0.22 mmol) in dry toluene (4.4 mL)
pre-cooled at ꢀ78 °C. After being stirred at ꢀ78 °C for 5 min and
at rt for an additional 4 h, the reaction mixture was slowly
quenched with 10% HCl aqueous solution (2 mL) and diluted with
ethyl acetate (200 mL). The solution was washed with water
(30 mL ꢃ 2) and brine (30 mL) and concentrated in vacuo. The res-
idue was subjected to chromatographic purification on silica gel
(hexane–EtOAc, 6:1, 3:1, 1:1) to give 40 mg of alcoholic intermedi-
ate together with 30 mg of recovered (ꢀ)-phenylmenthol. To a stir-
red solution of the freshly prepared alcohol (16.5 mg, 0.06 mmol)
in dry pyridine (2.7 mL) was successively added 3,5-dinitrobenzoyl
chloride (293 mg, 1.27 mmol) and 4-dimethyl aminopyridine
(11.65 mg, 0.10 mmol). The reaction mixture was stirred for 12 h
and diluted with ethyl acetate (95 mL). The solution was washed
with 10% aqueous HCl solution (20 mL ꢃ 3), water (20 mL ꢃ 2),
and brine (30 mL). After concentration, the crude residue was sub-
jected to chromatographic purification on silica gel (hexane–EtOAc
3:1, 1:1) to produce 23 mg of 3,5-dinitro-benzoic acid 1-(diethoxy-
phosphoryl)-2-methyl-cyclohex-3-enylmethyl ester 8 (78%, 55%
over two steps). Crystallization in hexane/ethyl acetate/dichloro-
methane (3:1:1, v/v/v) furnished yellow crystals. Compound 8: IR
4.7. Conversion of 4c–e into the known aldehyde 7 via alcoholic
intermediate 6
4.7.1. Conversion of 4c into 7
Under an N2 atmosphere, diisobutylaluminum hydride (1 M in
toluene, 1 mL, 1 mmol) was dropwise added to a solution of 4c
(dr = 52:48,16 215.8 mg, 0.50 mmol) in dry toluene (10 mL) pre-
cooled at ꢀ78 °C. After stirring at ꢀ78 °C for 5 min, ꢀ25 °C for
1 h and 0 °C for an additional 2 h, the reaction mixture was slowly
quenched with a 10% HCl aqueous solution (2.5 mL) and diluted
with ethyl acetate (190 mL). The solution was washed with water
(30 mL ꢃ 2) and brine (30 mL) and concentrated in vacuo. The res-
idue was subjected to chromatographic purification on silica gel
(hexane–EtOAc, 5:1, 3:1, 1:1) to give the known 2-formyl-bicy-
clo[2.2.1]hept-5-en-2-yl)-phosphonic acid diethyl ester
7
(19.8 mg, 20.6), (2-hydroxymethyl-bicyclo[2.2.1]hept-5-en-2-yl)-
phosphonic acid diethyl ester 6 (48.4 mg, 93%), (1R,2S)-trans-2-
phenyl-1-cyclohexanol (57 mg), and recovered 4c (54.8 mg,
dr = 52:48). Compound 6: 1H NMR (400 MHz, CDCl3) d 6.25–6.14
(m, 2H), 4.26–4.13 (m, 4H), 3.68 (dd, J = 15.8, 10.5 Hz, 3H), 3.36–
3.27 (m, 3H), 2.89 (br s, 1H), 2.02 (ddd, J = 20.3, 12.4, 3.7 Hz, 1H),

34
J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
(neat) 3101, 1736, 1548, 1027, 1274, 958, 735 cmꢀ1
;
1H NMR
0.99 (m, 2H), 0.98 (s, 3H), 0.86 (d, J = 6.5 Hz, 3H), 0.84–0.71 (m,
2H); 13C NMR (100 MHz, CDCl3) d 178.3, 151.2, 138.6, 133.7,
128.1, 125.6, 125.2, 75.0, 50.0, 49.8, 49.6, 49.2, 42.8, 41.6, 40.2,
37.8, 34.6, 31.3, 28.4, 27.2, 25.7, 24.0, 21.8.; HRMS-EI m/z [M]+
Calcd for C25H34O2 366.2559. Found: 366.2571.
(400 MHz, CDCl3) d 9.21 (s, 3H), 5.72 (br d, J = 9.7 Hz, 1H), 5.50–
5.33 (m, 1H), 4.64 (dd, J = 55.3, 11.8 Hz, 1H), 4.59 (dd, J = 72.2,
12.1 Hz, 1H), 4.28–4.09 (m, 4H), 2.95 (br s, 1H), 2.28–1.87 (m,
4H), 1.33 (t, J = 7.0 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H), 1.17 (d,
J = 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 162.4, 148.7, 134.0,
130.9 (d, Jc–p = 12.7 Hz), 129.6, 125.3, 122.4, 64.4 (d, Jc–p = 5.3 Hz),
63.0 (d, Jc–p = 7.3 Hz), 61.8 (d, Jc–p = 7.6 Hz), 40.8 (d, Jc–
p = 143.0 Hz), 32.8 (d, Jc–p = 1.9 Hz), 24.8 (d, Jc–p = 2.5 Hz), 20.9 (d,
Jc–p = 11.0 Hz), 17.0, 16.7 (d, Jc–p = 5.2 Hz), 16.5 (d, Jc–p = 5.6 Hz);
HRMS-EI m/z [M]+ Calcd for C19H25N2O9P 456.1298. Found:
456.1301.
To a stirred suspension of LiAlH4 (95%, 21.8 mg, 0.55 mmol) in
dry THF (0.6 mL) pre-cooled to 0 °C in an ice bath, a solution of
10a (40 mg, 0.11 mmol) in 0.6 mL of THF was added dropwise via
syringe under a nitrogen atmosphere. The ice bath was then re-
moved and stirring was continued for 4 h at room temperature.
The reaction mixture was re-cooled in an ice bath and 5% NaOH
aqueous solution (1 mL) was added cautiously. The resulting pale
gray suspension was diluted with ethyl acetate (60 mL) and suc-
cessively washed with water (10 ml ꢃ 2) and brine (10 mL). After
concentration, the crude residue was subjected to the chromato-
graphic purification on silica gel (hexane–EtOAc: 15:1, 10:1, 5:1)
to afford (1R,2R,4R)-2-methylbicyclo[2.2.1]hept-5-en-2-yl)metha-
nol 11a (11.9 mg, 79%). The NMR spectroscopic data were in agree-
ment with those reported in the literature.21 1H NMR (400 MHz,
CDCl3) d 6.11 (dd, J = 5.8, 2.9 Hz, 1H), 6.09 (dd, J = 5.9, 2.8 Hz, 1H),
3.31 (d, J = 10.4 Hz, 1H), 3.24 (d, J = 10.4 Hz, 1H), 2.79 (br s, 1H),
2.54–2.46 (m, 1H), 1.60–1.62 (m, 1H), 1.46–1.41 (m, 1H), 1.38 (d,
J = 3.7 Hz, 1H), 1.35 (d, J = 3.7 Hz, 1H), 1.25 (s, 3H), 0.86 (dd,
J = 11.7, 2.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 136.4, 135.2,
Compound 8 was similarly prepared from 4g (dr = 91:916) in
44% yield over two steps.
4.8.2. Conversion of 4d and 4e into 9
The typical procedure for preparing 8 was followed. 3,5-Dinitro-
benzoic acid 2-(diethoxy-phosphoryl)-bicyclo[2.2.1]hept-5-en-2-
ylmethyl ester (9) was obtained from 4d and 4e in 52% and 67%
yields, respectively, over two steps. Compound 9: IR (neat) 3101,
1734, 1546, 1275, 1023, 957, 726 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 9.21 (s, 3H), 6.32 (dd, J = 4.9, 4.8 Hz, 1H), 6.14–5.98 (m, 1H), 4.33
(dd, J = 166.7, 11.7 Hz, 1H), 4.30–4.10 (m, 4H), 4.28 (dd, J = 184.0,
11.9 Hz, 1H), 3.34 (br s, 1H), 3.01 (br s, 1H), 2.36 (ddd, J = 20.2,
12.4, 3.5 Hz, 1H), 2.19 (br d, J = 8.6 Hz, 1H), 1.47–1.50 (m, 1H),
1.32 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H), 0.93–0.86 (m, 1H);
13C NMR (100 MHz, CDCl3) d 161.9, 148.7, 139.2, 134.2 (d, Jc–
p = 12.5 Hz), 134.1, 129.6, 122.4, 70.0 (d, Jc–p = 4.4 Hz), 62.7 (d, Jc–
p = 7.2 Hz), 62.2 (d, Jc–p = 7.2 Hz), 48.0, 46.9, 45.5 (d, Jc–
p = 144.2 Hz), 42.6, 31.6, 16.7 (d, Jc–p = 5.1 Hz), 16.6 (d, Jc–
p = 5.4 Hz); HRMS-EI m/z [M]+ Calcd for C19H23N2O9P 454.1141.
Found: 454.1139.
71.1, 49.6, 47.6, 43.7, 42.6, 37.0, 24.9; ½a D20
¼ þ30:6 (c 0.42, CHCl3).
ꢂ
{Lit. ½a 2D0
ꢂ
¼ þ33:9 (CHCl3)}.22
The same treatment of 10a0 (53.7 mg, 0.15 mmol) with LiAlH4
(95%, 29.3 mg, 0.73 mmol) afforded (1R,2S,4R)-2-methylbicy-
clo[2.2.1]hept-5-en-2-yl)methanol 11a0 (14.9 mg, 74%). The NMR
spectroscopic data were in agreement with those reported in the
literature.21 1H NMR (400 MHz, CDCl3) d 6.14 (dd, J = 5.6, 2.9 Hz,
1H), 6.10 (dd, J = 5.4, 3.0 Hz, 1H), 2.78 (br s, 1H), 2.56 (br s, 1H),
1.55–1.57 (m, 1H), 1.45 (dd, J = 11.7, 3.7 Hz, 1H), 1.39–1.35 (m,
1H), 1.25 (br s, 1H), 0.93 (s, 3H), 0.79 (dd, J = 11.7, 2.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 136.8, 135.4, 72.3, 47.8, 47.6, 43.7,
4.9. Conversion of 4d–g into compounds 11
4.9.1. Conversion of 4d into 11a/11a0 via 10a/10a0
Under a nitrogen atmosphere, a 0.34 M solution of lithium
naphthalenide (LN) (7 mL, 2.38 mmol) in THF pre-cooled to
43.1, 37.3, 22.8;
½
a 2D0
ꢂ
¼ þ60:7 (c 0.65, 95% EtOH). {Lit.
½
a 2D0
ꢂ
¼ þ68:1 (95% EtOH)}.22
ꢀ60 °C was quickly added by syringe to
a
solution of 4d
4.9.2. Conversion of 4e into 11a
(166.1 mg, 0.34 mmol) in anhydrous THF (3 mL) at ꢀ60 °C. The
resulting dark-green mixture was stirred at ꢀ60 °C for 30 min, then
iodomethane (0.21 mL, 3.40 mmol) was added, and stirring was
continued at ꢀ20 °C for 3 h and rt for 2 h. The mixture was then
quenched with water (10 mL) and extracted with EtOAc
(100 mL ꢃ 2). The combined organic extracts were washed with
water (20 mL) and brine (20 mL), dried over Na2SO4, filtered and
concentrated. Flash chromatography (silica gel, hexane–EtOAc,
100:0, 250:1, 100:1) afforded methylated esters 10a (43 mg, 47%)
and 10a0 (37 mg, 41%). 10a: IR (neat) 3058, 1714, 1646,
An analogous procedure for the preparation of 11a/11a0 from 4d
was used. The reductive methylation of 4e (226.4 mg, 0.55 mmol)
afforded a methylated ester (127.2 mg, 80%) as a 91:9 mixture of
two diastereomers after chromatographic purification. 1H NMR
(400 MHz, CDCl3) major: d 6.13 (dd, J = 5.6, 3.0 Hz, 1H), 6.00 (dd,
J = 5.7, 2.8 Hz, 1H), 4.52 (ddd, J = 10.8, 10.8, 4.3 Hz, 1H), 2.81 (br
s, 1H), 2.77 (br s, 1H), 2.01–1.83 (m, 3H), 1.72–1.60 (m, 2H),
1.54–1.56 (m, 1H), 1.48–1.32 (m, 4H), 1.40 (s, 3H), 1.09–0.96 (m,
1H), 0.93–0.82 (m, 2H), 0.91 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.6 Hz,
3H), 0.74 (d, J = 7.0 Hz, 3H); minor: d 6.21–5.86 (m, 1H), 4.62–
4.53 (m, 1H), 2.77 (br s, 1H), 2.75 (br s, 1H), 2.01–1.83 (m, 3H),
1.72–1.60 (m, 2H), 1.54–1.56 (m, 1H), 1.48–1.32 (m, 4H), 1.40 (s,
3H), 1.09–0.96 (m, 1H), 0.93–0.82 (m, 2H), 0.91 (d, J = 7.1 Hz,
3H), 0.88 (d, J = 6.6 Hz, 3H), 0.71 (d, J = 7.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) major: d 177.0, 137.8, 135.1, 74.1, 51.0, 49.9,
47.0, 42.5, 40.6, 37.5, 34.3, 31.3, 26.5, 25.9, 23.0, 22.0, 20.9, 15.8;
minor: d 177.0, 137.6, 135.5, 73.8, 50.9, 50.3, 47.1, 46.7, 42.6,
40.7, 38.0, 34.3, 31.4, 26.4, 26.0, 23.1, 22.0, 20.9, 15.8.
1101 cmꢀ1 1H NMR (400 MHz, CDCl3) d 7.26–7.22 (m, 4H), 7.16–
;
7.09 (m, 1H), 6.08 (dd, J = 5.6, 3.0 Hz, 1H), 5.98 (dd, J = 5.6, 2.8 Hz,
1H), 4.70 (ddd, J = 10.6, 10.6, 4.2 Hz, 1H), 2.75 (br s, 1H), 2.70 (br
s, 1H), 1.93 (ddd, J = 12.0, 10.6, 3.4 Hz, 1H), 1.87–1.80 (m, 1H),
1.69 (dd, J = 12.1, 2.6 Hz, 1H), 1.52–1.46 (m, 2H), 1.43–1.34 (m,
3H), 1.34 (s, 3H), 1.31 (s, 3H), 1.26–1.20 (m, 1H), 1.19 (s, 3H),
0.98–0.85 (m, 2H), 0.81 (d, J = 6.5 Hz, 3H), 0.77–0.65 (m, 1H); 13C
NMR (100 MHz, CDCl3) d 176.8, 151.2, 137.6, 135.0, 128.0, 125.6,
125.2, 75.5, 51.7, 50.2, 49.7, 47.0, 42.7, 41.7, 40.2, 36.8, 34.7,
31.3, 28.9, 27.3, 26.2, 24.9, 21.8; HRMS-EI m/z [M]+ Calcd for
C25H34O2 366.2559. Found: 366.2564. 10a0: IR (neat) 3073, 1707,
The reduction of the methylated ester (44 mg, 0.15 mmol) with
LiAlH4 produced 16 mg of 11a (61% over two steps) plus 17.5 mg of
recovered (ꢀ)-menthol. The specific rotation of 11a obtained was
1648, 1081 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 7.34–7.27 (m, 4H),
measured as
(CHCl3)}.22
½
a 2D0
ꢂ
¼ þ26:4 (c 0.66, CHCl3).{Lit.
½
a 2D0
ꢂ
¼ þ33:9
7.20–7.11 (m, 1H), 6.18 (dd, J = 5.6, 3.0 Hz, 1H), 6.01 (dd, J = 5.5,
3.1 Hz, 1H), 4.89 (ddd, J = 10.6, 10.6, 4.3 Hz, 1H), 2.83 (br s, 1H),
2.74 (br s, 1H), 2.12 (dd, J = 14.0, 3.9 Hz, 1H), 2.04 (ddd, J = 12.1,
10.7, 3.4 Hz, 1H), 1.94–1.83 (m, 1H), 1.60–1.54 (m, 1H), 1.50–
1.41 (m, 3H), 1.37 (s, 3H), 1.31–1.28 (m, 1H), 1.25 (s, 3H), 1.09–
4.9.3. Conversion of 4f into 11b
An analogous procedure for the preparation of 11a/11a0 from 4d
was used. The reductive methylation of 4f (159 mg, 0.32 mmol)

J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
35
afforded 105 mg of methylated ester (80%) as a single diastereomer
after chromatography (silica gel, hexane–EtOAc, 100:0, 300:1,
100:1). 1H NMR (400 MHz, CDCl3) d 7.32–7.27 (m, 4H), 7.19–7.12
(m, 1H), 5.60–5.47 (m, 2H), 4.89 (ddd, J = 10.6, 10.6, 4.3 Hz, 1H),
2.09–1.99 (m, 2H), 1.98–1.83 (m, 3H), 1.71 (ddd, J = 13.6, 10.4,
6.5 Hz, 1H), 1.55–1.51 (m, 1H), 1.50–1.40 (m, 3H), 1.35 (s, 3H),
1.23 (s, 3H), 1.10 (s, 3H), 1.03–0.95 (m, 2H), 0.91 (d, J = 7.0 Hz,
3H), 0.85 (d, J = 6.6 Hz, 3H), 0.83–0.75 (m, 1H); 13C NMR
(100 MHz, CDCl3) d 176.8, 151.4, 130.9, 128.1, 125.5, 125.1,
124.3, 75.0, 50.0, 44.0, 41.9, 40.1, 37.9, 34.6, 31.3, 28.4, 27.2, 25.6,
24.5, 22.5, 22.0, 21.8, 18.2.
(400 MHz, CDCl3) d 6.14 (dd, J = 5.7, 3.0 Hz, 1H), 5.96 (dd, J = 5.7,
2.9 Hz, 1H), 3.40 (dd, J = 10.5, 6.4 Hz, 1H), 3.25 (dd, J = 10.5,
8.9 Hz, 1H), 2.93 (br s, 1H), 2.81(br s, 1H), 2.34–2.25 (m, 1H),
1.82 (ddd, J = 11.6, 9.2, 3.9 Hz, 1H), 1.45 (br d, J = 8.2 Hz, 1H),
1.26 (br d, J = 8.6 Hz, 2 H), 0.52 (ddd, J = 11.6, 4.4, 2.6 Hz, 1H);
HRMS-EI m/z [M]+ Calcd for C8H12O 124.0888. Found: 124.0883.
4.11. Preparation of (ꢀ)-12
4.11.1. (1S,2R,5S)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl-
2-(diethoxyphosphoryl)-acetate
The reduction of the methylated intermediate (23 mg,
0.06 mmol) with LiAlH4 produced 5.9 mg (44% over two steps) of
(1R,2S)-1,2-dimethylcyclohex-3-enyl)methanol 11b and 10.7 mg
of (ꢀ)-phenylmenthol after chromatography (silica gel, hexane–
EtOAc, 10:0, 3:1). 11b: 1H NMR (400 MHz, CDCl3) d 5.66–5.57 (m,
1H), 5.54–5.44 (m, 1H), 3.46 (d, J = 10.6 Hz, 1H), 3.41 (d,
J = 10.7 Hz, 1H), 2.06–1.97 (m, 3H), 1.54 (ddd, J = 13.1, 6.6, 6.6 Hz,
2H), 1.23–1.18 (m, 1H), 0.99 (s, 3H), 0.93 (d, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 132.1, 125.3, 68.3, 37.5, 35.9, 27.9, 22.5,
This compound was similarly prepared as for 1c. From 250 mg of
(+)-8-phenylmenthol, 411 mg of product was obtained (93%) after
purification. 1H NMR (400 MHz, CDCl3) d 7.27–7.26 (m, 4H), 7.16–
7.10 (m, 1H), 4.83 (ddd, J = 10.7, 10.7, 4.4 Hz, 1H), 4.11–3.98 (m,
4H), 2.37 (dd, J = 21.2, 14.4 Hz, 1H), 2.07 (dd, J = 21.2, 14.4 Hz, 1H),
2.06–2.00 (m, 1H), 1.85 (brt, J = 15.4 Hz, 2H), 1.67 (br d,
J = 13.0 Hz, 1H), 1.48–1.42 (m, 1H), 1.32–1.27 (m, 9H), 1.2 (s, 3H),
1.16–1.09 (m, 1H), 1.00–0.90 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 165.1 (d, Jc–p = 6.1 Hz), 151.8, 127.9,
125.4, 125.1, 75.1, 62.4 (d, Jc–p = 5.7 Hz), 50.3, 41.3, 39.5, 34.5, 33.9
(d, Jc–p = 132.1 Hz), 31.3, 29.2, 26.3, 23.2, 21.8, 16.3 (d, Jc–p = 6.3 Hz).
22.3, 16.1; ½a 2D0
ꢂ
¼ þ130:4 (c 0.13, CHCl3).{Lit. ent-11b, ½a D20
¼ ꢀ147
ꢂ
(CHCl3}}.22
4.9.4. Conversion of 4g into 11b
4.11.2. (1S,2R,5S)-2-(Diethoxy-phosphoryl)-2-phenylselanyl-
propionic acid 5-methyl-2-(1-methyl-1-phenyl-ethyl)-cyclo-
hexyl ester
An analogous procedure for the preparation of 11a/11a0 from 4d
was used. The reductive methylation of 4g (195 mg, 0.47 mmol)
afforded 92 mg of a methylated ester (73%) as a 90:10 mixture of
two diastereomers. 1H NMR (400 MHz, CDCl3) major: d 5.62–5.48
(m, 2H), 4.62 (ddd, J = 10.8, 10.8, 4.2 Hz, 1H), 2.22–2.13 (m, 1H),
2.06–1.84 (m, 5H), 1.71–1.62 (m, 2H), 1.57–1.36 (m, 3H), 1.19 (s,
3H), 1.07–1.00 (m, 1H), 0.92 (d, J = 7.0 Hz, 3H), 0.91–0.85 (m, 2H),
0.89 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H), 0.73 (d, J = 7.0 Hz,
3H); minor: d 5.62–5.48 (m, 2H), 4.69–4.62 (m, 1H), 2.22–2.13
(m, 1H), 2.06–1.84 (m, 5H), 1.71–1.62 (m, 2H), 1.57–1.36 (m,
3H), 1.19 (s, 3H), 1.07–1.00 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H), 0.91–
0.85 (m, 2H), 0.89 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H), 0.72
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) major: d 176.9,
130.9, 124.4, 74.0, 47.0, 44.2, 40.8, 37.7, 34.3, 31.4, 25.9, 25.2,
23.0, 22.5, 22.4, 22.1, 20.9, 18.1, 15.9; minor: d 176.8, 130.7,
124.7, 74.0, 47.1, 44.0, 40.8, 37.7, 34.3, 31.4, 26.1, 25.6, 22.9,
22.5, 22.3, 22.2, 20.8, 18.0, 15.8.
This compound was similarly prepared as for 2c. From 411 mg
of starting material, 174 mg of product (dr = 62:38)16 was obtained
in 30% yield over two steps. 1H NMR (400 MHz, CDCl3) major: d
7.72 (br d, J = 7.0 Hz, 2H), 7.42–7.28 (m, 7H), 7.17–7.13 (m, 1H),
5.00–4.88 (m, 1H), 4.37–4.13 (m, 4H), 2.00–1.89 (m, 2H), 1.47–
1.35 (m, 11H), 1.34–1.25 (m, 7H), 1.02–0.90 (m, 2H), 0.85 (d,
J = 2.8 Hz, 3H), 0.81–0.66 (m, 1H); minor: d 7.76 (br d, J = 7.0 Hz,
2H), 7.42–7.28 (m, 7H), 7.17–7.13 (m, 1H), 5.00–4.88 (m, 1H),
4.37–4.13 (m, 4H), 2.00–1.89 (m, 2H), 1.47–1.35 (m, 11H), 1.34–
1.25 (m, 7H), 1.02–0.90 (m, 2H), 0.84 (d, J = 2.8 Hz, 3H), 0.81–
0.66 (m, 1H); 13C NMR (100 MHz, CDCl3) major: d 169.6, 150.4,
138.5, 129.7, 128.8, 128.0, 125.8, 125.7, 125.3, 64.1 (d, Jc–
p = 7.3 Hz), 63.6 (d, Jc–p = 7.3 Hz), 50.4, 44.9 (d, Jc–p = 146.6 Hz),
41.2, 40.5, 34.4, 31.3, 31.0, 27.5, 23.6, 21.6, 19.7 (d, Jc–p = 2.0 Hz),
16.6 (d, Jc–p = 5.1 Hz), 16.5 (d, Jc–p = 5.1 Hz); minor: 169.3, 150.6,
138.7, 129.6, 128.7, 128.1, 125.8, 125.7, 125.3, 64.6 (d, Jc–
p = 7.3 Hz), 63.3 (d, Jc–p = 7.3 Hz), 50.2, 46.1 (d, Jc–p = 142.5 Hz),
41.3, 40.4, 34.4, 31.3, 29.9, 27.3, 24.2, 21.6, 19.3 (d, Jc–p = 2.0 Hz),
16.5 (d, Jc–p = 5.1 Hz), 16.4 (d, Jc–p = 5.1 Hz).
The reduction of methylated ester (34 mg, 0.12 mmol) with
LiAlH4 produced 11.5 mg of 11b (52% over two steps) and
13.4 mg of (ꢀ)-menthol. The specific rotation of 11b obtained
was determined as ½a D20
¼ þ73:4 (c 0.5, CHCl3). {Lit. ent-11b,
ꢂ
½
a 2D0
ꢂ
¼ ꢀ147 (CHCl3)}.22
4.11.3. (1S,2R,5S)-2-(Diethoxy-phosphoryl)-acrylic acid 5-
methyl-2-(1-methyl-1-phenyl-ethyl)-cyclohexyl ester
4.10. Conversion of 4d into (2R)-2-endo-hydroxymethyl-5-
norbornene (+)-12
This compound was similarly prepared as for 3c. From 141 mg
of starting material, 95.2 mg of crude product was obtained
(88%). 1H NMR (400 MHz, CDCl3) d 7.27–7.22 (m, 4H), 7.11–7.06
(m, 1H), 6.42 (br d, J = 21.0 Hz, 1H), 6.05 (br d, J = 42.8 Hz, 1H),
4.94 (ddd, J = 10.7, 10.7, 4.3 Hz, 1H), 4.21–4.09 (m, 4H), 2.10
(ddd, J = 10.6, 10.8, 3.5 Hz, 1H), 1.93 (d, J = 12.0 Hz, 1H), 1.72–
1.64 (m, 2H), 1.51–1.46 (m, 1H), 1.38–1.26 (m, 10H), 1.21 (s, 3H),
1.17–0.98 (m, 2H), 0.87 (d, J = 6.5 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 162.6 (d, Jc–p = 18.1 Hz), 151.6, 142.9 (d, Jc–p = 4.4 Hz),
132.7 (d, Jc–p = 186.7 Hz), 128.1, 125.4, 125.1, 75.7, 62.7 (d, Jc–
p = 5.9 Hz), 62.6 (d Jc–p = 5.8 Hz), 50.3, 41.6, 39.7, 34.5, 31.3, 27.8,
26.7, 25.3, 21.7, 16.4 (d, Jc–p = 5.9 Hz).
To a stirred suspension of LiAlH4 (95%, 435 mg, 10.9 mmol) in
dry CH2Cl2 (9 mL) and THF (9 mL) pre-cooled at 0 °C in an ice bath,
a solution of 4d (666 mg, 1.364 mmol) in 18 mL of mixed CH2Cl2
and THF (v/v: 1/1) was added dropwise over 2 min via syringe un-
der a nitrogen atmosphere. The ice bath was then removed and
stirring was continued for an additional 3 h at room temperature.
The reaction mixture was re-cooled in an ice bath and cautiously
quenched with a 5% NaOH aqueous solution (20 mL). The resulting
pale gray suspension was diluted with CH2Cl2 (150 mL) and suc-
cessively washed with water (30 ml ꢃ 2) and brine (30 mL), dried
over Na2SO4, filtered and concentrated under reduced pressure.
The crude residue was purified by flash chromatography on silica
gel (hexane–EtOAc: 15:1, 8:1) to afford 146 mg (86%) of (+)-12
4.11.4. (1S,2R,5S)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl-
(1S,2R,4S)-2(diethoxyphosphoryl)bicycle-[2.2.1]-hept-5-ene-2-
carboxylate
This compound was similarly prepared as for 4d. From 93 mg of
starting dienophile, 98 mg of adduct was obtained in 91% yield as a
{½a 2D0
ꢂ
¼ þ70:6 (c 0.6, 95% EtOH), lit.28
½
a 2D0
ꢂ
¼ þ79:3 (c 0.86, 95%
EtOH)} plus recovered (ꢀ)-phenylmenthol (285 mg). The 1H NMR
data were in agreement previously reported ones.27 1H NMR

36
J.-L. Zhu et al. / Tetrahedron: Asymmetry 24 (2013) 23–36
single diastereomer (dr >30:1).16 1H NMR (400 MHz, CDCl3) d 7.29–
7.27 (m, 4H), 7.18–7.14 (m, 1H), 6.28 (dd, J = 5.4, 3.0 Hz, 1H), 5.99
(dd, J = 5.3, 2.6 Hz, 1H), 4.70 (ddd, J = 10.5, 10.5, 3.9 Hz, 1H), 4.28–
4.12 (m, 4H), 3.49 (br d, J = 5.8 Hz, 1H), 2.97 (br s, 1H), 2.30 (ddd,
J = 19.1, 12.3, 3.6 Hz, 1H), 2.07–2.03 (m, 2H), 1.97–1.86 (m, 2H),
1.47 (s, 3H), 1.45–1.36 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.36–1.30
(m, 1H), 1.32 (t, J = 7.0 Hz, 3H), 1.26 (s, 3H), 1.16–1.12 (m, 1H),
0.90–0.84 (m, 2H), 0.82 (d, J = 6.4 Hz, 3H), 0.75–0.68 (m, 1H); 13C
Asymmetry 1991, 2, 1247–1262; (d) Boeckman, R. K., Jr.; Nelson, S. G.; Gaul, M.
D. J. Am. Chem. Soc. 1992, 114, 2258–2260; (e) Oppolzer, W.; Seletsky, B. M.;
Bernardinelli, G. Tetrahedron Lett. 1994, 35, 3509–3512; (f) Yamauchi, M.;
Honda, Y.; Matsuki, N.; Watanabe, T.; Data, K.; Hiramatsu, H. J. Org. Chem. 1996,
61, 2719–2725; (g) Brimble, M. A.; McEwan, J. F.; Turner, P. Tetrahedron:
Asymmetry 1998, 9, 1239–1255; (h) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Giannetto, P.; Nicolò, F.; Rizzo, S. Tetrahedron: Asymmetry 1999, 10, 3907–3917;
(i) Henderson, J. R.; Chesterman, J. P.; Parvez, M.; Keay, B. A. J. Org. Chem. 2010,
75, 988–991; (j) Bañuelos, P.; García, J. M.; Gómez-Bengoa, E.; Herrero, A.;
Odriozola, J. M.; Oiarbide, M.; Palomo, C.; Razkin, J. J. Org. Chem. 2010, 75, 1458–
1473; (k) Timoshenko, V. M.; Siry, S. A.; Rozhenko, A. B.; Shermolovich, Y. G. J.
Fluorine Chem. 2010, 131, 172–183; (l) Calmes, M.; Escale, F.; Didierjean, C.;
Martinez, J. Chirality 2011, 23, 245–249; (m) Benjamin, N. M.; Martin, S. F. Org.
Lett. 2011, 13, 450–453.
NMR (100 MHz, CDCl3)
d 170.3, 150.8, 139.8, 134.0 (d, Jc–
p = 13.0 Hz), 128.0, 125.8, 125.3, 77.9, 62.9 (d, Jc–p = 7.2 Hz), 62.4
(d, Jc–p = 7.0 Hz), 54.8 (d, Jc–p = 133.6 Hz), 50.7, 50.0, 47.7, 42.9,
41.0, 40.4, 34.6, 31.4, 31.3, 31.0, 27.7, 22.6, 21.8, 16.6 (d, Jc–
p = 6.0 Hz), 16.4 (d, Jc–p = 5.6 Hz).
9. For recent examples on asymmetric intermolecular Diels–Alder reactions of
chiral dienes, see: (a) Morris, E. N.; Nenninger, E. K.; Pike, R. D.; Scheerer, J. R. .
Org. Lett. 2011, 13, 4430–4433; (b) Duarte, F. J. S.; Santos, A. G. . J. Org. Chem.
2012, 77, 3252–3261.
10. For examples, see: (a) Kagan, H. B.; Riant, O. Chem. Rev. 1992, 92, 1007–1019;
(b) Jørgensen, K. A. Angew. Chem., Int. Ed. 2000, 39, 3558–3588; (c) Schotes, C.;
Althaus, M.; Aardoom, R.; Mezzetti, A. J. Am. Chem. Soc. 2012, 134, 1331–1343;
(d) Didier, D.; Schulz, E. Synlett 2012, 1309–1314.
11. Takagi, R.; Hashizume, M.; Nakamura, M.; Begum, S.; Hiraga, Y.; Kojima, S.;
Ohkata, K. . J. Chem. Soc., Perkin Trans. 1 2002, 179–190.
4.11.5. (2S)-2-endo-Hydroxymethyl-5-norbornene (ꢀ)-12
This compound was similarly prepared as for (+)-12. From 91 mg
of the adduct, 19 mg (80%) of (ꢀ)-12 was obtained after purifica-
tion. The proton NMR data agreed with reported ones.27 1H NMR
(400 MHz, CDCl3) d 6.14 (dd, J = 5.7, 3.0 Hz, 1H), 5.96 (dd, J = 5.7,
2.9 Hz, 1H), 3.39 (dd, J = 10.4, 6.5 Hz, 1H), 3.25 (dd, J = 10.4,
8.9 Hz, 1H), 2.93 (br s, 1H), 2.81 (br s, 1H), 2.33–2.25 (m,1H), 1.82
(ddd, J = 11.6, 9.2, 3.8 Hz, 1H), 1.45 (br d, J = 8.2 Hz, 1H), 1.25 (br
d, J = 8.5 Hz, 2H), 0.52 (ddd, J = 11.6, 4.5, 2.6 Hz, 1H);
12. Hatakeyama, S.; Satoh, K.; Sakurai, K.; Takano, S. Tetrahedron Lett. 1987, 28,
2713–2716.
13. Except for 2a, the phenylselenylation was conducted before the methylation in
order to avoid dimethylation.
14. The ortho regiochemistry of 4a0 was confirmed by the 13C–C–C–31P coupling of
C-2 methyl signals on the 13C NMR spectrum [d 18.5 ppm (d, Jc–p = 3.1 Hz) and
18.0 ppm (d, Jc–p = 5.0 Hz)].
{½a 2D5
ꢂ
¼ ꢀ74:6 (c 0.5, 95% EtOH), lit.27
½
a 2D5
ꢂ
¼ ꢀ93 (c 0.5, 95% EtOH).
15. A further decrease in temperatures, for example, ꢀ78 °C, did not change the
diastereomeric ratio but rather led to poorer conversion of 4a.
16. The diastereomeric ratio was determined by integration of the 400 MHZ proton
NMR spectrum.
Acknowledgments
17. The ortho stereochemistry of the minor isomer of 4g was confirmed by the 13C–
C–C–31P coupling of the C-2 methyl signal on the 13C NMR spectrum [d
18.1 ppm (d, JC–P = 4.2 Hz)].
We are grateful to the National Science Council of Republic of
China (Taiwan) for financial support, the Department of Chemistry
of National Chung Hsing University, and Professor Chin-Piao Chen’s
group for the help in HRMS and HPLC analyses.
18. Hall, A.; Harris, L. D.; Jones, C. L.; Jenkins, R. L.; Tomkinson, N. C. O. Tetrahedron
Lett. 2003, 44, 111–114.
19. The chiral HPLC analysis was carried out on a Chiralcel OD-H column, eluting
with 10% IPA/hexane at 0.1, 0.3, or 0.5 mL minꢀ1 rate. [8: Rt = 233 min (major
enantiomer; 0.1 mL minꢀ1), Rt = 296 min (minor enantiomer; 0.1 mL minꢀ1);
Rt = 76 min (major enantiomer; 0.3 mL minꢀ1), Rt = 95 min (minor enantiomer;
0.3 mL minꢀ1); 9: Rt = 69 min (major enantiomer; 0.5 mL minꢀ1), Rt = 61 min
(minor enantiomer; 0.5 mL minꢀ1)].
References
1. For reviews, see: (a) Dembitsky, V. M.; Quntar, A. A. A.; Haj-Yehia, A.; Srebnik,
M. Mini-Rev. Org. Chem. 2005, 2, 91–109; (b) Janecki, T.; Kedzia, J.; Wasek, T.
Synthesis 2009, 1227–1254.
20. Racemic 8 and 9 were synthesized from our previously reported endo adducts6
as the references for HPLC analysis.
2. For selected examples, see: (a) Kleschick, W. A.; Heathcock, C. H. . J. Org. Chem.
1978, 43, 1256–1259; (b) Corbet, J. P.; Benezra, C. J. Org. Chem. 1981, 46, 1141–
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21. For the determination of the endo/exo stereochemistry of 11a and 11a0, see: Hu,
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22. For the reported rotations, see: Ref. 8e {11a: lit. ½a D20
¼ þ33:9 (c 2.08, CHCl3);
ꢂ
11a0: lit. ½a 2D0
ꢂ
¼ þ68:1 (c 0.16, 95% EtOH); ent-11b: lit. ½a D20
¼ ꢀ147, (c 0.63,
ꢂ
CHCl3)}.
23. Since the NMR data of 11b had not been reported, it was further oxidized into
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M.; Fowler, F. W. J. Org. Chem. 1988, 53, 963–972
PDC (3 eq)
CHO
11b
CH Cl , rt, 12 h
2
2
61%
.
24. The double activation of the P@O and C@O by SnCl4 is evidenced by the
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IR stretching frequencies of complexed 3c relative to 3c.
)
Marchand-Brynaert, J. J. Chem. Soc., Perkin Trans.
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