Synthesis of the atropurpuran A-ring via an organocatalytic asymmetric intramolecular Michael addition

Article abstract of DOI:10.1016/j.tet.2013.02.078

The asymmetric synthesis of the A-ring fragment 2a-b of atropurpuran 1 has been achieved in 15 steps with up to 70% ee via an organocatalytic intramolecular Michael addition of nitroalkene 10. The absolute configuration of the two contiguous carbon center

Full text of DOI:10.1016/j.tet.2013.02.078

Tetrahedron 69 (2013) 3141e3148
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Synthesis of the atropurpuran A-ring via an organocatalytic
asymmetric intramolecular Michael addition
,
b
a,b
Huan Chen a, Dan Zhang b , Fei Xue , Yong Qin
*
a Key Laboratory of Drug Targeting and Novel Delivery System of the Ministry of Education, West China School of Pharmacy, Sichuan University,
Chengdu 610041, Sichuan Province, PR China
b The Innovative Drug Research Centre and School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric synthesis of the A-ring fragment 2aeb of atropurpuran 1 has been achieved in 15 steps
with up to 70% ee via an organocatalytic intramolecular Michael addition of nitroalkene 10. The absolute
configuration of the two contiguous carbon centers in 2a and 2b was assigned to be (4S, 5R) and (4R, 5R),
respectively, using the modified Mosher’s method.
Received 19 November 2012
Received in revised form 11 February 2013
Accepted 22 February 2013
Available online 26 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Atropurpuran
Intramolecular Michael addition
Absolute configuration
Organocatalysis
1. Introduction
world. Kobayashi’s group2 and Hsung’s group3 have developed
synthetic approaches to fragment 3, but neither the total syn-
Atropurpuran (1), a novel non-alkaloidal C19-diterpenoid with
an unprecedented pentacyclic skeleton, was first isolated from
the roots of Aconitum hemsleyanum var. atropurpureum by F.P.
Wang in 2008 (Fig. 1).1 Atropurpuran possesses a topological
structure unique to C19-diterpenoids, featuring a cage framework
consisting of two fragments: (1) a highly functionalized cyclo-
hexane A-ring fragment 2 with two contiguous chiral centers, and
(2) the tetracyclo[5.3.3.04,9.04,12]tridecane 3 comprising two fused
bicyclo[2.2.2]octane units (rings BeE). The unique framework of 1
has attracted interest among synthetic chemists around the
thesis of 1 nor the synthesis of the A-ring fragment 2 has been
reported.
The biosynthetic pathway of atropurpuran 1 proposed by
Prof. Wang1 (Scheme 1) suggests that ring D should be con-
structed via an intramolecular aldol addition of aldehyde 4,
whereas rings B and E of 4 could be formed through DielseAlder
reaction of 5, which could be synthesized through a pinacol
coupling reaction of diketone 7 and several functional trans-
formations of diol 6. Synthesis of diketone 7 could be realized via
Fig. 1. Structure of atropurpuran 1 and its fragments 2 and 3.
* Corresponding author. Tel./fax: þ86 23 65678457; e-mail address: danzhang@
Scheme 1. Retrosynthetic analysis of atropurpuran 1.
cqu.edu.cn (D. Zhang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.078

3142
H. Chen et al. / Tetrahedron 69 (2013) 3141e3148
an intermolecular Michael addition of enone 8 and A-ring frag-
ment 2. Based on this biosynthetic pathway, preparation of A-
ring fragment 2 emerges as a necessary prior step in the total
synthesis of 1, which involves the installation of a highly func-
tionalized chiral cyclohexane unit.
Organocatalytic asymmetric synthesis has proven to be a reli-
able approach for stereo-controlled synthesis of complex molecules
with multiple stereocenters.4,5 Organocatalytic Michael addition
has played a particularly important role in this approach.6 Although
the intermolecular nitro-Michael addition of aldehydes and nitro-
olefins has been well studied,7 the intramolecular version of such
reaction is rare. Herein we report here an intramolecular Michael
addition of nitroalkene 10 to generate the A-ring fragment 2 with
two chiral centers, which may serve as a key intermediate in the
total synthesis of atropurpuran 1.
2.2. Organocatalytic Michael addition of nitroalkene 10
With compound 10 in hand, we investigated the designed
organocatalytic Michael addition by screening proline-type cata-
lysts (cat. IeV) and thiourea-type catalysts (cat. VIeVIII) (Fig. 2).
The catalyst screen for the organocatalytic intramolecular Michael
addition of 10 was carried out in CH2Cl2 at 25 ꢀC with 20 mol % catalyst
(Table 1). Although the reaction was slow, as expected, most catalysts
tested led to formation of the desired multi-substituted cyclohexane 9
as a mixture of four separable diastereomers (9a, 9b, 9c, and 9d) with
two newly generated stereocenters in moderate to excellent yield. Cat.
IV gave the highest combined yield (92%) and better diaster-
eoselectivity, with 9d dominating (9a:9b:9c:9d¼24:22:12:42) (Table
1, entry 4). Therefore this catalyst was used in further optimization
of the reaction conditions.
2. Results and discussion
2.1. Synthesis of nitroalkene 10
The Michael addition precursor nitroalkene 10 was assembled
in 11 steps from commercially available 1,4-butanediol 11
(Scheme 2). Selective mono-protection of 11 with TBSCl, followed
by Finkelstein reaction with NaI in reflux acetone furnished io-
dide 12 in 86% yield in three steps.8 Subsequent Stork enamine
alkylation of imine 13 with 12 using LDA as a base in HMPA at
Fig. 2. Structures of catalysts IeVIII.
0
ꢀC provided aldehyde 14 in 88% yield.9 One-pot carbonyl pro-
Table 1
tection and desilylation of 14, followed by Swern oxidation
afforded aldehyde 16 in 77% yield in two steps. Treatment of 16
with vinylmagnesium bromide in THF provided allyl alcohol 17 in
77% yield as a mixture of inseparable diastereomers. Since the
NMR spectra of 17 suggested only one set of data, and because the
newly generated stereocenter would be eliminated in later stages,
we did not determine the diastereomeric ratio of 17. The free
hydroxyl group in 17 was protected with PMB, and the resulting
olefin 18 was subjected to osmium dihydroxylation and oxidative
cleavage to afford aldehyde 19. This intermediate was easily
transformed into 20 by Henry reaction in 74% yield in three steps.
TFA-promoted cleavage of the ketal-protecting group provided
the desired nitroalkene 10 in 86% yield.
Screen of catalysts for the intramolecular Michael addition of 10a
Entry
Cat.
Solv.
T
drb
Yieldc
(%)
(d)
(9a:9b:9c:9d)
1
2
3
4
5
6
7
8
Cat. I
Cat. II
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
4
7
4
7
6
5.5
6
16:27:13:44
20:26:21:33
ND
24:22:12:42
ND
19:28:18:34
25:25:22:28
25:15:15:44
67%
88%
Trace
92%
Trace
86%
Cat. III
Cat. IV
Cat. V
Cat. VI
Cat. VII
Cat. VIII
82%
33%
a
Experimental conditions: catalyst (20 mol %) was added to a stirred solution of
10 (0.10 mmol) in CH2Cl2 (1 mL), and the reaction was vigorously stirred at 25 ꢀC.
The crude product was purified by silica gel column chromatography (17%
EtOAc/petroleum ether) to afford 9a, 9b, 9c, and 9d.
b
The diastereomeric ratio of the crude product was determined by HPLC analysis
(Gemini C6-Phenyl, water-acetonitrile 65:35, 1.0 mL/min).
c
Isolated combined yield of 9aed.
The Michael addition of 10 was investigated in various solvents
under the same conditions as the catalyst screening (25 ꢀC,
20 mol % of IV). The addition reaction of 10 gave the desired product
9 in moderate to excellent yields in all solvents tested except THF
(Table 2, entries 1e8). Although the solvents CH2Cl2, CHCl3, and
MeOH gave 9 in similarly high yield (Table 2, entries 1, 4, and 8),
MeOH was the most efficient solvent, requiring the shortest re-
action time (3.5 days). Screening the reaction in MeOH at temper-
atures between ꢁ40 ꢀC and 0 ꢀC failed to give any product (Table 2,
entry 9). Addition of acids, such as TFA and PTSA significantly re-
duced yield (Table 2, entry 10). Using the optimized conditions of
20 mol % cat. IV, 25 ꢀC, and MeOH solvent, we scaled up the Michael
addition reaction to 10 mmol to provide large quantities of in-
dividual stereomers 9aed for the synthesis of fragment 2, de-
termination of the enantiomeric excess values, and assignment of
absolute configuration.
Scheme 2. Reagents and conditions: (a) TBSCl, Et3N, DMAP, 0 ꢀC to rt; (b) TsCl, Et3N,
DMAP, CH2Cl2, rt; (c) NaI, acetone, reflux, 86% in three steps; (d) LDA, HMPA, THF, 0 ꢀC,
88%; (e) 1,3-propanediol, BF3$Et2O, 0 ꢀC, 85%; (f) DMSO, (ClCO)2, CH2Cl2, ꢁ78 ꢀC, 91%;
(g) vinylmagnesium bromide, THF, ꢁ78 ꢀC to ꢁ30 ꢀC, 77%; (h) PMBCl, NaH, DMF, 0 ꢀC
to rt, 94%; (i) OsO4, NaIO4, NMNO, Et2O/H2O 1:1, rt, 83%; (j) CH3NO2, Et3N, rt, and then
MsCl, DIPEA, CH2Cl2, ꢁ78 ꢀC, 95%; (k) TFAeH2O (v/v¼50/50), CH2Cl2
0
ꢀC to rt, 86%.
(TBSCl, tert-chlorodimethylsilane; TsCl, 4-toluenesulfonyl chloride; DMAP, 4-
dimethylaminopyridine;
LDA,
lithium
diisopropylamide;
PMBCl,
4-
methoxybenzylchloride; NMMO, 4-N-methylmorpholine-N-oxide; DIPEA, N,N-diiso-
propylethylamine; TFA, trifluoroacetic acid).

H. Chen et al. / Tetrahedron 69 (2013) 3141e3148
3143
Table 2
Optimization of the intramolecular Michael additiona
Entry Solv.
Additive
Temp (ꢀC) T (d) drb (9a:9b:9c:9d) Yieldc (%)
1
2
3
4
5
6
7
8
CH2Cl2
THF
d
d
d
d
d
d
d
d
d
25
25
25
25
25
25
25
25
4
7
5
5
4.5
5
4.5
3.5
4
24:22:12:42
NAd
92%
Trace
75%
91%
61%
88%
87%
92%
Trace
52%
CH3CN
CHCl3
DMF
Dioxane
DMSO
MeOH
MeOH
MeOH
25:22:10:43
24:27:7:42
22:27:11:40
20:35:8:37
23:30:12:35
24:24:11:41
NAd
9
ꢁ40 to 0
10e
PTSA or TFA 25
4
NA
a
Experimental conditions: catalyst IV (20 mol %) and additives were added to
a stirred solution of 10 (0.1 mmol) in solvent (1 mL), and the reaction was vigorously
stirred at the indicated temperature until compound 10 was completely consumed.
The crude product was purified by silica gel column chromatography (17% EtOAc/
petroleum ether) to afford 9a, 9b, 9c, and 9d.
b
The diastereomeric ratio of crude product was determined by HPLC analysis
(Gemini C6-Phenyl, water/acetonitrile 65:35, 1.0 mL/min).
c
Scheme 3. Reagents and conditions: (a) 1,3-propanediol, PPTs, toluene, reflux, 89%e
92%; (b) DDQ, CH2Cl2/H2O 18:1, 91%e93%; (c) DesseMartin periodinane, CH2Cl2, 0 ꢀC to
rt, 83%e86% (PPTs, pyridinium p-toluenesulfonate; DDQ, 2,3-dichloro-5,6-
dicyanobenzoquinone).
Isolated combined yield of 9aed.
NA¼not available.
d
e
Additive, 20 mol %.
2.3. Synthesis of the A-ring fragments 2aeb of atropurpuran
and determination of their absolute configuration
positive Dd values (Dd
the MTPA plane, and protons with negative Dd values should ap-
¼
d
Sꢁ
dR) should appear on the right side of
pear on the left side.
The relative stereochemistry of 9aed was established by NOE
experiments (Fig. 3). Investigation of correlations of C5eH with
neighboring substituents revealed a cis, cis-relationship between
C5eH and neighboring C4eMe and C10eH in 9a; a cis, cis-re-
lationship between C5eH and neighboring C4eformyleH and
C10eH in 9b; a cis, trans-relationship between C5eH and neigh-
boring C4eMe and C10eH in 9c; and a cis, trans-relationship be-
tween C5eH and neighboring C4eformyleH and C10eH in 9d.
Fig. 3. Relative configurations of 9aed determined by NOE experiments.
The NOE-based assignments of relative stereochemistry for 9aed
were confirmed by converting 9aed to the corresponding A-ring
fragments 2a and 2b (Scheme 3). In these conversions, the formyl
group was protected (21), then the PMB group was removed (22) and
the resulting hydroxyl group was oxidized. In this way, compounds
9a and 9c were transformed into the same A-ring fragment 2a, and
compounds 9b and9d were converted intothe same A-ring fragment
2b. The values of enantiomeric excess (ee) for 2a and 2b were de-
termined by chiral HPLC to be as follows: 2a from 9a, 28% ee; 2a from
9c, 67% ee; 2b from 9b, 70%; and 2b from 9d, 36% ee.
Since several attempts to obtain single crystals of 2a and 2b
were unsuccessful and we had already determined the relative
stereochemistry of both compounds, we decided to elucidate the
absolute configuration of C4 and C5 using the modified Mosher’s
method.10 According to the modified Mosher’s model proposed by
Prof. H. Kakisawa10b (Scheme 4, Eq. 1), when the (S)-alcohol is
linked with Mosher’s acid, the diamagnetic effects of the benzene
ring in the MTPA group should cause the HA,B,C. and Hx,Y,Z. NMR
signals of the (R)-MTPA ester to appear, respectively, up-field and
down-field of those of the (S)-MTPA ester. Therefore, protons with
Scheme 4. Reagents and conditions: (a) Mosher’s acid, DIC, DMAP, CH2Cl2, rt, 62e71%.
The Mosher’s model illustrated in Eq. 1 was proposed by Prof. H. Kakisawa.9b (Mosher’s
acid, (R)-(þ)-
a
-methoxy-
a
-trifluoromethylphenylacetic acid, (S)-(ꢁ)-
a-methoxy-a-tri-
fluoromethylphenylacetic acid; DIC, N,N0-diisopropylcarbodiimide; DMAP, 4-
dimethylaminopyridine).
In order to calculate the Dd values, the (R)- and (S)-MTPA esters
of both 22c and 22d were prepared via condensation reactions with
Mosher’s acid in the presence of DIC and DMAP in CH2Cl2 (Scheme
4, Eqs. 2 and 3). After careful assignment and calculation of the
Dd
¼
d
Sꢁ
d
R values of the protons in the 1H NMR spectra of 23c and
23d, the Dd values of all protons on the right side in the Mosher’s

3144
H. Chen et al. / Tetrahedron 69 (2013) 3141e3148
model of 23c-MTPA and 23d-MTPA were found to be positive, while
the Dd values of all protons on the left side were negative. These
results indicate that the absolute configuration of C10 in both 23c
and 23d is (S). Based on the relative stereochemistry of 9aed de-
scribed above, we deduced the absolute configurations of C4 and C5
to be (4S, 5R) in 2a and (4R, 5R) in 2b.
1 h, the solution of compound 12 (20.0 g, 0.064 mol) in anhydrous THF
(300 mL) was slowly added via an addition funnel. After complete
consumption of 12, the reaction was quenched by dropwise addition
of saturated NH4Cl solution at 0 ꢀC, the mixture was then extracted
with EtOAc (3ꢂ300 mL), the organic phases were dried over anhy-
drous Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (5% EtOAc/
petroleum ether) to afford 14 (13.7 g, 88%) as colorless oil. 1H NMR
3. Conclusion
(400 MHz, CDCl3):
d
ppm 9.61 (s,1H, CHO), 3.60(t, J¼6.4Hz, 2H, CH2O),
In conclusion, the asymmetric synthesis of the A-ring fragment 2
of atropurpuran 1 has been achieved in 15 steps with up to 70% ee. A
key reaction is organocatalytic Michael addition of nitroalkene 10, in
which two chiral centers are assembled at the same time. The ab-
solute configurations of 2a and 2b have been determined to be (4S,
5R) and (4R, 5R), respectively, using a modified Mosher’s method.
Further synthetic efforts toward the total synthesis of atropurpuran
will focus on improving both the diastereoselectivity and enantio-
selectivity of the organocatalytic Michael addition of nitroalkene 10.
2.36e2.31 (m, 1H, CHCH3), 1.75e1.64 (m, 2H, CH2), 1.56e1.49 (m, 2H,
CH2), 1.39 (m, 2H, CH2), 1.08 (d, J¼6.8 Hz, 3H, CH3), 0.84 (9H, s, CH3),
0.04 (s, 6H, SiCH3); 13C NMR (100 MHz, CDCl3):
d ppm 105.2, 66.9, 63.1,
37.9, 33.0, 31.1, 25.9, 23.2, 18.3, 13.9, ꢁ5.3; HRMS [MþH]þ calcd for
C13H29O2Si245.1937, found245.1939;IR(KBr):2955,2931, 2856,1466,
1382, 1253, 1147, 1106, 1007, 837, 776 cmꢁ1
.
4.3. 5-(1,3-Dioxan-2-yl)hexan-1-ol (15)
To a solution of compound 14 (10.0 g, 40.91 mmol) and 1,3-
propanediol (5.90 mL, 81.82 mol) in dry CH2Cl2 (200 mL) at 0 ꢀC,
was added dropwise boron trifluoride diethyl etherate (5.40 mL,
53.18 mmol) via syringe. After stirring at 0 ꢀC for 1 h, the reaction
was quenched with saturated NaHCO3 solution and extracted with
CH2Cl2 (3ꢂ100 mL). The organic layers were dried over anhydrous
Na2SO4 and concentrated. The resulting crude material was purified
by silica gel column chromatography (20% EtOAc/petroleum ether)
to afford colorless oil (6.56 g, 85%). 1H NMR (400 MHz, CDCl3):
4. Experimental section
4.1. General
All commercially available reagents were used without further
purification. All solvents were dried and distilled before use: tetra-
hydrofuran was dried over sodium-benzophenone; dichloro-
methane and chloroform were distilled from calcium hydride; N,N-
dimethylformamide and dimethyl sulfoxide were distilled under
reduced pressure after drying over calcium hydride; acetonitrile,
1,4-dioxane and methanol were dried over activated 4-A molecular
sieves. Chromatography was conducted by using 200e300 mesh
silica gel. All new compounds gave satisfactory spectroscopic ana-
lyzes (IR,1H NMR,13C NMR, HRMS). IR spectra were recorded on a FT
IR spectrometer. NMR spectra were recorded on a 400 MHz NMR
spectrometer. HRMS spectra were obtained by the FAB method.
d
ppm 4.31 (d, J¼4.4 Hz, 1H, CHOCH2), 4.10 (dd, J¼11.2, 4.8 Hz, 2H,
CH2O), 3.73 (t, J¼11.2 Hz, 2H, CH2O), 3.63 (m, 2H, CH2OH), 2.05 (m,
1H, CHCH3), 1.77 (s, 1H, CH2), 1.67e1.51 (m,4H, CH2), 1.49e1.30 (m,
2H, CH2), 1.26e1.24 (m, 2H, CH2), 0.91 (d, J¼6.8 Hz, 3H, CH3); 13C
NMR (100 MHz, CDCl3):
d ppm 128.0, 105.0, 66.9, 62.3, 37.6, 32.7,
30.8, 25.7, 23.0, 13.8; HRMS [MþNa]þ calcd for C10H20NaO3
211.1310, found 211.1306; IR (KBr): 3411, 2934, 2856, 1465, 1429,
1378, 1280, 1240, 1147, 1105, 1008, 916, 856 cmꢁ1
.
4.2. 6-((tert-Butyldimethylsilyl)oxy)-2-methylhexanal (14)
4.4. 5-(1,3-Dioxan-2-yl)hexanal (16)
To a solution of 1,4-butanediol (20.0 g, 0.22 mol) in CH2Cl2
(500 mL) was added triethylamine (60.6 mL, 0.44 mol), DMAP (1.3 g,
0.01 mol), and TBSCl (33.5 g, 0.22 mol) at 0 ꢀC. After stirring for 20 h at
room temperature, the reaction mixture was quenched with icewater
at 0 ꢀC and extracted with CH2Cl2 (3ꢂ500 mL). The combined organic
layers were washed with saturated NH4Cl (500 mL), brine (500 mL),
dried over Na2SO4, and concentrated. The crude material was then
dissolved in CH2Cl2 (500 mL), cooled to 0 ꢀC. To the solution, Et3N
(61.8 mL, 0.44 mol), DMAP (0.54 g, 4.40 mmol), TsCl (50.2 g, 0.26 mol)
were added successively. After being stirred at room temperature for
12 h, the solvent was removed under reduced pressure. The residue
was dissolved in acetone (500 mL), added with NaI (65.6 g, 0.44 mol)
and heated to reflux for 2 h. The reaction mixture was quenched with
saturated Na2S2O3 solution, excess acetone was removed under re-
duced pressure and the residue was extracted with petroleum ether
(3ꢂ200 mL). The combined organic layers were dried over anhydrous
Na2SO4 and concentrated. The crude material waspurified by silica gel
column chromatography (5% EtOAc/petroleum ether) to afford 12
(59.7 g, 86%, for three steps) as colorless oil.
To a stirred solution of propanal (25.0 mL, 0.34 mol) and cyclo-
hexylamine (43.6 mL, 0.38 mol) in benzene (60 mL) was added po-
tassium carbonate (23.8 g, 0.17 mol). The mixture was stirred until
a white suspension was formed. Then Na2SO4 (20.0 g) was added.
After stirring for 30 h, the reaction mixture was filtered. The filtrate
was concentrated under reduced pressure. The resulting oil 13 was
dissolved in anhydrous THF (300 mL) under N2 and was cooled to 0 ꢀC
in an ice bath. Then the freshly prepared LDA (1 M, 0.15 mol) and
HMPA (25.0 mL, 0.13 mol) were slowly added. After stirring at 0 ꢀC for
A solution of oxalyl chloride (13.7 mL, 0.16 mol) in 150 mL dry
CH2Cl2 was cooled to ꢁ78 ꢀC under N2. To above solution, a solution
of DMSO (30.8 mL, 0.40 mol) in CH2Cl2 (50 mL) was added slowly via
an addition funnel. After stirring for 30 min, a solution of compound
15 (15.0 g, 0.08 mol) in dry CH2Cl2 (100 mL) was added slowly via an
additionfunnel. The resulting white suspensionwas stirred at ꢁ78 ꢀC
for 2 h and then Et3N (112.0 mL, 0.80 mol) was added. After being
stirred at ꢁ78 ꢀC for another 2 h, the reaction mixture was warmed to
room temperature and quenched with water. The organic layer was
concentrated, and the resulting residue was dissolved in EtOAc
(100 mL), thewater phasewas extracted with EtOAc(3ꢂ200 mL). The
combined organic layers were washed with brine (200 mL), dried
over anhydrous Na2SO4, and concentrated. The crude material was
purified by silica gel column chromatography (5% EtOAc/petroleum
ether) to afford 16 (13.5 g, 91%) as colorless oil. 1H NMR (400 MHz,
CDCl3):
d
ppm 9.76 (s, 1H, CHO), 4.32 (d, J¼4.4 Hz, 1H, CHOCH2), 4.10
(dd, J¼11.2, 4.8 Hz, 2H, CH2O), 3.74 (t, J¼11.2 Hz, 2H, CH2O), 2.45e2.41
(m, 2H, CH2), 2.10e2.00 (m, 1H, CHCH3), 1.76e1.52 (m, 4H, CH2),
1.35e1.31 (m, 1H, CH2), 1.23e1.14 (m, 1H, CH2), 0.94 (d, J¼6.8 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3)
d ppm 202.7, 104.9, 66.5, 44.0, 37.6,
30.7, 25.8, 19.6, 14.0; HRMS [MþH]þ calcd for C10H19O3 187.1334,
found 187.1336; IR (KBr): 2961, 2852, 2727, 1724, 1465, 1379, 1280,
1241, 1149, 1105, 1007, 917, 896, 857 cmꢁ1
.
4.5. 7-(1,3-Dioxan-2-yl)oct-1-en-3-ol (17)
To a solution of compound 16 (7.00 g, 37.60 mmol) in anhydrous
THF (250 mL) at ꢁ78 ꢀC, vinylmagnesium bromide (1 M in THF,

H. Chen et al. / Tetrahedron 69 (2013) 3141e3148
3145
67.60 mmol) was added slowly via an addition funnel under N2. The
reaction mixture was warmed to ꢁ30 ꢀC, stirred until 16 was
completely consumed. The reaction mixture was quenched with
saturated NH4Cl solution, extracted with EtOAc (3ꢂ100 mL). The
combined organic layers were dried over anhydrous Na2SO4, and
concentrated. The crude material was purified by silica gel column
chromatography (12.5% EtOAc/petroleum ether) to afford a mixture
of two diastereomers 17 (6.17 g, 77%) as pale yellow oil. 1H NMR
J¼6.8, 2.0 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d
ppm 203.9,
159.4, 129.7, 129.4, 113.8, 105.0, 83.1, 83.0, 72.1, 66.9, 55.2, 37.7, 31.0,
30.9, 30.2, 30.1, 25.9, 22.3, 22.2, 14.0; HRMS [MþH]þ calcd for
C19H29O5 337.2015, found 337.2019; IR (KBr): 3443, 2957, 2854,
2729, 1732, 1612, 1586, 1514, 1464, 1377, 1302, 1247, 1144, 1034,
1009, 918, 822, 757, 642, 519 cmꢁ1
.
4.8. (E)-2-(6-((4-Methoxybenzyl)oxy)-8-nitrooct-7-en-2-yl)-
(400 MHz, CDCl3):
d
ppm 5.87e5.83 (m, 1H, CH), 5.22 (d, J¼17.2 Hz,
1,3-dioxane (20)
1H, CH), 5.10 (d, J¼10.4 Hz, 1H, CH), 4.32 (d, J¼4.4 Hz, 1H, CHOCH2),
4.11 (dd, J¼10.4, 4.8 Hz, 3H, CH2O, CHOH), 3.74 (t, J¼12.0 Hz, 2H,
CH2O), 2.09e2.01 (m,1H, CHCH3),1.66e1.46 (m, 5H, CH2), 1.43e1.34
To a solution of compound 19 (5.73 g, 17.03 mmol) in CH3NO2
(10.0 mL), was added Et3N (0.36 mL, 2.55 mmol). After stirring at
room temperature for 15 h, the reaction mixture was concentrated
under reduced pressure. The residue was then dissolved in anhy-
drous CH2Cl2 (100 mL), cooled to ꢁ78 ꢀC under N2. Then DIPEA
(7.43 mL, 42.57 mmol) and MsCl (1.58 mL, 20.44 mmol) were added
successively by syringe. After being stirred at ꢁ78 ꢀC for another 2 h,
the reactionwas quenched bysaturated NH4Cl solution. The mixture
was warmed to room temperature, extracted with CH2Cl2
(3ꢂ100 mL). The combined organic layers were dried over anhy-
drous Na2SO4, and concentrated. The crude material was purified by
silica gel column chromatography (12.5% EtOAc/petroleum ether) to
afford a mixture of two diastereomers 20 (6.14 g, 95%) as pale yellow
(m, 2H, CH2), 1.19e1.12 (m, 1H, CH2), 0.92 (d, J¼6.8 Hz, 3H, CH3); 13
C
NMR (100 MHz, CDCl3):
d ppm 141.2, 114.2, 114.1, 105.0, 72.7, 66.8,
37.6, 37.0, 31.0, 30.9, 29.5, 25.7, 22.7, 22.6,13.9,13.8; HRMS [MþNa]þ
calcd for C12H22NaO3 237.1467, found 237.1467; IR (KBr): 3428,
2962, 2932, 2854, 2731, 2656, 1643, 1465, 1428, 1379, 1280, 1241,
1145, 1106, 996, 919, 996, 856, 673, 646, 473 cmꢁ1
4.6. 2-(6-((4-Methoxybenzyl)oxy)oct-7-en-2-yl)-1,3-dioxane
(18)
To a solution of compound 17 (5.80 g, 27.06 mmol) in anhydrous
DMF (20 mL) at 0 ꢀC was slowly added NaH (3.25 g, 81.19 mmol, 60%
dispersion in mineral oil). After being stirred for 10 min, PMBCl
(4.80 mL, 35.18 mmol) was added slowly. The reaction mixture was
warmed to room temperature. After stirring for 12 h, the reaction
mixture was quenched by dropwise addition of saturated NH4Cl
solution at 0 ꢀC, extracted with EtOAc (3ꢂ100 mL). The combined
organic layers were washed with water (200 mL), brine (200 mL),
dried over anhydrous Na2SO4, and then concentrated. The crude
material was purified by silica gel column chromatography (7%
EtOAc/petroleum ether) to afford a mixture of two diastereomers
oil. 1H NMR (400 MHz, CDCl3):
d
ppm 7.24 (d, J¼8.4 Hz, 2H, ArH),
7.20e7.10 (m, 2H, CHCHN, CHCHN), 6.89 (d, J¼8.4 Hz, 2H, ArH), 4.50
(d, J¼11.2 Hz,1H, PhCHxCHy), 4.39 (d, J¼11.2 Hz,1H, PhCHxCHy), 4.29
(d, J¼4.4 Hz, 1H, CHOCH2), 4.12e4.08 (m, 3H, OCH2CH2, CHOPMB),
3.81 (s, 3H, CH3O), 3.73 (t, J¼11.2 Hz, 2H, OCH2CH2), 2.09e2.00 (m,
1H, CHCH3), 1.69e1.64 (m, 2H, CH2), 1.61e1.41 (m, 2H, CH2),
1.40e1.25 (m, 3H, CH2),1.16e1.05 (m,1H, CH2), 0.90 (d, J¼6.4 Hz, 3H,
CH3); 13C NMR (100 MHz, CDCl3):
d ppm 159.4, 142.4, 139.7, 129.4,
113.9, 105.0, 74.6, 71.2, 66.9, 55.2, 37.7, 34.5, 30.9, 30.8, 25.9, 22.4,
22.0, 14.1; HRMS [MþNa]þ calcd for C20H29NNaO6 402.1893, found
402.1888; IR (KBr): 2957, 2857, 1650, 1612, 1586, 1520, 1464, 1351,
18 (8.51 g, 94%) as pale yellow oil. 1H NMR (400 MHz, CDCl3):
d ppm
7.26 (d, J¼15.6 Hz, 2H, ArH), 6.88 (d, J¼15.6 Hz, 2H, ArH), 5.76e5.66
(m, 1H, CH), 5.22 (d, J¼3.6 Hz, 1H, CH), 5.18 (d, J¼11.6 Hz, 1H, CH),
4.53e4.42 (m, 1H, PhCHxCHy), 4.31e4.26 (m, 2H, PhCHxCHy,
CHOCH2), 4.10 (dd, J¼10.8, 4.8 Hz, 2H, OCH2CH2), 3.80 (s, 3H, CH3O),
3.76e3.67 (m, 3H, OCH2CH2, CHOPMB), 2.10e2.00 (m, 1H, CHCH3),
1.63e1.36 (m, 4H, CH2), 1.33e1.07 (m, 4H, CH2), 0.92e0.90 (d,
1303, 1247, 1143, 1107, 1034, 1009, 823, 761, 730, 612, 531 cmꢁ1
.
4.9. (E)-6-((4-Methoxybenzyl)oxy)-2-methyl-8-nitrooct-7-
enal (10)
To a solution of compound 20 (1.00 g, 2.63 mmol) in CH2Cl2
(40 mL) at 0 ꢀC, was slowly added 50% aq TFA (20 mL). After stirring
at room temperature for 18 h, the reaction mixture was carefully
neutralized by dropwise addition of saturated NaHCO3 solution.
The mixture was extracted with CH2Cl2 (3ꢂ20 mL), the combined
organic layers were dried over anhydrous Na2SO4 and concen-
trated. The resulting residue was purified by silica gel column
chromatography (7% acetone/petroleum ether) to afford a mixture
of two diastereomers 10 (0.73 g, 86%) as colorless oil. 1H NMR
J¼8.0 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d ppm 158.9, 139.2,
130.8, 129.3, 129.2, 116.9, 116.8, 113.7, 113.6, 116.8, 113.7, 113.6, 105.2,
80.1, 80.0, 71.4, 69.6, 66.9, 55.2, 37.9, 35.6, 31.1, 25.9, 22.8, 14.0, 13.9;
HRMS [MþNa]þ calcd for C20H30NaO4 357.2042, found 357.2036; IR
(KBr): 2933, 2852, 1612, 1584, 1513, 1464, 1440, 1379, 1303, 1246,
1174, 1145, 1108, 1036, 996, 924, 822, 754, 705,515 cmꢁ1
.
4.7. 6-(1,3-Dioxan-2-yl)-2-((4-methoxybenzyl)oxy)heptanal
(19)
(400 MHz, CDCl3):
d
ppm 9.56 (s, 1H, CHO), 7.24 (d, J¼8.8 Hz, 2H,
ArH), 7.19e7.10 (m, 2H, CHCHN, CHCHN), 6.90 (d, J¼8.8 Hz, 2H,
ArH), 4.52 (d, J¼11.6 Hz, 1H, PhCHxCHy), 4.37 (d, J¼11.6 Hz, 1H,
PhCHxCHy), 4.09 (dd, J¼10.6, 5.6 Hz, 1H, CHOPMB), 3.82 (s, 3H,
CH3O), 2.23e2.31 (m, 1H, CHCH3), 1.71e1.64 (m, 2H, CH2), 1.46e1.25
(m, 4H, CH2), 1.09 (d, J¼6.8 Hz, 3H, CH3); 13C NMR (100 MHz,
To a mixture of compound 18 (1.00 g, 2.99 mmol) in Et2O/H2O
(15 mL:15 mL), NaIO4 (1.91 g, 8.97 mmol), NMNO (1.05 g,
8.97 mmol), OsO4 (38.0 mg, 0.15 mmol) were added successively.
After stirring for 24 h, the resulting white suspension was
quenched with saturated Na2S2O3 solution, and filtered. The filtrate
was extracted with EtOAc (3ꢂ20 mL), dried over anhydrous Na2SO4,
and concentrated. The crude material was purified by silica gel
column chromatography (10% EtOAc/petroleum ether) to afford
a mixture of two diastereomers 19 (0.83 g, 83%) as pale yellow oil.
CDCl3):
d ppm 204.7, 159.9, 142.0, 139.9, 129.5, 129.2, 113.9, 74.2,
71.3, 55.2, 46.1, 46.0, 34.4, 30.0, 29.9, 22.3, 13.3; HRMS [MþNa]þ
calcd for C17H23NNaO5 344.1474, found 344.1476; IR (KBr): 2938,
2866, 2716,1723,1650,1612,1585,1517,1461,1352,1303,1249,1177,
1088, 1034, 961, 823, 761, 731, 614, 573, 521 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d ppm 9.60 (s, 1H, CHO), 7.28 (d,
J¼8.8 Hz, 2H, ArH), 6.89 (d, J¼8.4 Hz, 2H, ArH), 4.59 (dd, J¼11.4,
2.8 Hz, 1H, PhCHxCHy), 4.48 (dd, J¼11.2, 2.0 Hz, 1H, PhCHxCHy), 4.29
(d, J¼4.8 Hz, 1H, CHOCH2), 4.10 (dd, J¼11.2, 4.8 Hz, 2H, OCH2CH2),
3.81 (s, 3H, CH3O), 3.76e3.70 (m, 3H, OCH2CH2, CHOPMB),
2.08e2.02 (m, 1H, CHCH3), 1.67e1.57 (m, 3H, CH2), 1.55e1.48 (m,
2H, CH2), 1.37e1.34 (m, 2H, CH2), 1.15e1.10 (m, 1H, CH2), 0.90 (dd,
4.10. Typical procedure for the Michael addition: preparation
of aldehydes 9aed
To a solution of 10 (10 mmol) in MeOH (5 mL), was added catalyst
IV(2 mmol). The reaction mixture was vigorously stirred at room
temperature for 3.5 days. Then the solvent was removed under reduced

3146
H. Chen et al. / Tetrahedron 69 (2013) 3141e3148
pressure and the residue was purified by silica gel column chroma-
tography (17% EtOAc/petroleum ether) to afford the products 9aed.
mixture was heated to reflux. After complete consumption of 9, the
reaction was cooled to room temperature and quenched with wa-
ter, the mixture was extracted with EtOAc (3ꢂ5 mL), dried over
anhydrous Na2SO4, and concentrated. The crude material was pu-
rified by silica gel column chromatography (20% EtOAc/petroleum
ether) to afford the corresponding product 21.
4.10.1. (1S,2R,3R)-3-(4-Methoxybenzyloxy)-1-methyl-2-(nitro-
20
methyl)cyclohexanecarbaldehyde (9a). Colorless oil. [
a]
ꢁ20.2 (c
D
1.25, CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 9.63 (s, 1H, CHO),
7.23 (d, J¼8.4 Hz, 2H, ArH), 6.87 (d, J¼8.0 Hz, 2H, ArH), 4.72e4.62
(m, 2H, CH2N), 4.52 (d, J¼11.6 Hz, 1H, PhCHxCHy), 4.26 (d, J¼11.6 Hz,
1H, PhCHxCHy), 3.80 (s, 3H, CH3O), 3.66 (s, 1H, CHOPMB), 2.41e2.39
(m, 1H, CHCH2N), 2.09e2.05 (m, 2H, CH2), 1.90e1.82 (m, 1H, CH2),
4.11.1. 2-((1S,2R,3R)-3-((4-Methoxybenzyl)oxy)-1-methyl-2-(nitro-
20
methyl)cyclohexyl)-1,3-dioxane (21a). Colorless oil (89% yield). [a]
D
ꢁ3.0 (c 0.3, CHCl3); 1H NMR (400 MHz, CDCl3):
d ppm 7.28 (d,
1.56e1.51 (m, 1H, CH2), 1.40e1.32 (m, 2H, CH2), 1.07 (s, 3H, CH3); 13
C
J¼8.4 Hz, 2H, ArH), 6.88 (dd, J¼8.8, 2.0 Hz, 2H, ArH), 4.74 (dd,
J¼13.6, 6.6 Hz, 1H, CH2N), 4.64e4.59 (m, 2H, CH2N, PhCHxCHy), 4.49
(s, 2H, CHOCH2, PhCHxCHy), 4.03 (dd, J¼11.0, 4.8 Hz, 1H, OCH2CH2),
3.94 (dd, J¼11.0, 4.8 Hz,1H, OCH2CH2), 3.81 (s, 3H, CH3O), 3.70e3.60
(m, 2H, OCH2CH2, CHOPMB), 3.50e3.43 (m, 1H, OCH2CH2), 2.58 (s,
1H, CHCH2N), 1.99e1.89 (m, 1H, CH2), 1.68e1.57 (m, 4H, CH2),
NMR (100 MHz, CDCl3):
d ppm 203.2, 129.0, 113.8, 72.9, 72.5, 70.4,
55.2, 49.0, 46.1, 34.4, 31.9, 29.7, 27.2, 23.0, 16.6, 14.1, 0.98; HRMS
[MþNa]þ calcd for C17H23NNaO5 344.1474, found 344.1475; IR
(KBr): 3147, 2939, 1719, 1614, 1554, 1513, 1462, 1437, 1388, 1350,
1305, 1245, 1173, 1140, 1077, 1042, 901, 832, 751, 693, 559 cmꢁ1
.
1.44e1.40 (m, 1H, CH2), 1.25e1.18 (m, 2H, CH2), 1.03 (s, 3H, CH3); 13
C
4.10.2. (1R,2R,3R)-3-(4-Methoxybenzyloxy)-1-methyl-2-(nitro-
NMR (100 MHz, CDCl3): d ppm 159.1, 130.6, 129.2, 113.7, 104.1, 73.9,
methyl)cyclohexanecarbaldehyde (9b). White solid. Mp 73e77 ꢀC;
70.5, 67.0, 66.3, 55.2, 40.7, 28.6, 25.7, 19.8, 17.8; HRMS [MþNa]þ
calcd for C20H29NNaO6 402.1893, found 402.1899; IR (KBr): 3448,
2935, 2860, 1614, 1585, 1549, 1514, 1467, 1428, 1380, 1347, 1301,
[
a
]
20 ꢁ34.2 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d ppm 9.32 (s,
D
1H, CHO), 7.25 (d, J¼8.4 Hz, 2H, ArH), 6.88 (d, J¼8.4 Hz, 2H, ArH), 4.71
(dd, J¼13.0 Hz, 1H, CH2N), 4.49 (d, J¼11.2 Hz, 1H, PhCHxCHy), 4.37 (d,
J¼11.2 Hz,1H, PhCHxCHy), 4.26 (dd, J¼13.2, 4.8 Hz, 1H, CH2N), 3.81 (s,
3H, CH3O), 3.67e3.65 (m,1H, CHOPMB), 3.01e2.99 (m,1H, CHCH2N),
1.77e1.73 (m, 2H, CH2),1.61e1.57 (m, 2H, CH2),1.51e1.44 (m, 2H, CH2),
1249, 1176, 1143, 1032, 1005, 947, 860, 824, 685, 647, 564 cmꢁ1
.
4.11.2. 2-((1R,2R,3R)-3-((4-Methoxybenzyl)oxy)-1,3-dimethyl-2-(ni-
tromethyl)cyclohexyl)-1,3-dioxane (21b). White solid (90% yield).
1.11 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d
ppm 203.9,159.2,129.2,
Mp 38e40 ꢀC; [
a]
D
20 ꢁ41.0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
113.8, 73.2, 73.1, 70.8, 55.3, 48.5, 40.3, 31.9, 31.4, 29.7, 27.4, 23.0, 17.0,
14.1, 1.00; HRMS [MþNa]þ calcd for C17H23NNaO5 344.1474, found
344.1475; IR (KBr):3168, 2947,1733,1642,1567,1539,1488,1457,1301,
d
ppm 7.25 (d, J¼8.8 Hz, 2H, ArH), 6.87 (d, J¼8.4 Hz, 2H, ArH), 4.94 (dd,
J¼12.8, 4.8 Hz,1H, CH2N), 4.57 (dd, J¼13.0, 8.4 Hz,1H, CH2N), 4.47 (d,
J¼11.2 Hz, 1H, PhCHxCHy), 4.21 (d, J¼11.2 Hz, 1H, PhCHxCHy),
4.12e4.06 (m, 3H, CHOCH2, OCH2CH2), 3.80 (s, 3H, CH3O),
3.70e3.61(m, 3H, OCH2CH2, CHOPMB), 2.77e2.73 (m, 1H, CHCH2N),
2.04e1.95 (m, 2H, CH2), 1.74e1.64 (m, 1H, CH2), 1.52 (td, J¼12.8,
3.2 Hz, 1H, CH2), 1.41e1.24 (m, 4H, CH2), 0.99 (s, 3H, CH3); 13C NMR
1371, 1322, 1263, 1198, 1161, 1099, 1064, 911, 845, 762, 701, 572 cmꢁ1
.
4.10.3. (1S,2R,3S)-3-(4-Methoxybenzyloxy)-1-methyl-2-(nitro-
20
methyl)cyclohexanecarbaldehyde (9c). Colorless oil. [
a
]
þ22.0 (c
D
0.55, CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 9.25 (d, J¼2.0 Hz,
(100 MHz, CDCl3): d ppm 158.9, 130.8, 129.1, 128.8, 113.6, 107.2, 75.2,
1H, CHO), 7.20 (d, J¼8.4 Hz, 2H, ArH), 6.87 (d, J¼8.8 Hz, 2H, ArH),
4.78 (dd, J¼14.6, 6.4 Hz, 1H, CH2N), 4.53 (d, J¼10.8 Hz, 1H,
PhCHxCHy), 4.43e4.37 (m, 2H, PhCHxCHy, CH2N), 3.80 (s, 3H, CH3O),
3.58 (td, J¼10.8, 4.4 Hz, 1H, CHOPMB), 2.47e2.43 (m, 1H, CHCH2N),
2.23e2.19 (m, 1H, CH2), 2.02 (d, J¼7.2 Hz, 1H, CH2), 1.78e1.73 (m,
1H, CH2), 1.41 (td, J¼14.0, 3.6 Hz, 1H, CH2), 1.30e1.22 (m, 1H, CH2),
1.24 (s, 3H, CH3),1.19e1.07 (m,1H, CH2); 13C NMR (100 MHz, CDCl3):
74.6, 70.7, 67.2, 67.0, 55.1, 41.4, 40.3, 33.7, 27.5, 25.7, 16.9, 16.0; HRMS
[MþNa]þ calcd for C20H29NNaO6 402.1893, found 402.1898; IR (KBr):
3453, 2941, 2869,1628,1592,1557,1522,1477,1433,1392,1358,1309,
1255, 1187, 1152, 1040, 1011, 953, 869, 832, 694, 655, 571 cmꢁ1
.
4.11.3. 2-((1S,2R,3S)-3-((4-Methoxybenzyl)oxy)-1-methyl-2-(nitro-
20
methyl)cyclohexyl)-1,3-dioxane (21c). Colorless oil (91% yield). [a]
D
d
ppm 204.3, 159.1, 130.0, 129.2, 113.7, 76.5, 75.3, 70.6, 55.2, 51.1,
þ16.0 (c 1.9, CHCl3); 1H NMR (400 MHz, CDCl3):
d ppm 7.20 (d,
47.9, 34.7, 30.7, 21.3, 20.7; HRMS [MþNa]þ calcd for C17H23NNaO5
344.1474, found 344.1472; IR (KBr): 3131, 2927, 1698, 1601, 1541,
1489, 1447, 1420, 1361, 1332, 1287, 1221, 1151, 1113, 1052, 1022, 882,
J¼8.8 Hz, 2H, ArH), 6.87 (d, J¼8.8 Hz, 2H, ArH), 4.58 (dd, J¼13.0,
2.0 Hz, 1H, CH2N), 4.50 (d, J¼11.6 Hz, 1H, PhCHxCHy), 4.39e4.30 (m,
3H, PhCHxCHy, CH2N, CHOCH2), 4.09e4.03 (m, 2H, OCH2CH2), 3.79 (s,
3H, CH3O), 3.67e3.51 (m, 3H, CHOPMB, OCH2CH2), 2.40e2.35 (m,1H,
CHCH2N), 2.23e2.19 (m, 1H, CH2), 2.02e1.88 (m, 2H, CH2), 1.60e1.57
(m, 1H, CH2), 1.53e1.42 (m, 1H, CH2), 1.31e1.20 (m, 2H, CH2), 1.14 (td,
J¼13.6, 4.4 Hz,1H, CH2),1.05 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
813, 741, 682, 546 cmꢁ1
.
4.10.4. (1R,2R,3S)-3-(4-Methoxybenzyloxy)-1-methyl-2-(nitro-
20
methyl)cyclohexanecarbaldehyde (9d). Colorless oil. [
a]
þ13.4 (c
D
0.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 9.43 (s, 1H, CHO),
d ppm 159.0,130.3,129.3,113.6,103.4, 77.3, 76.2, 70.2, 67.1, 66.8, 55.2,
7.20 (d, J¼8.4 Hz, 2H, ArH), 6.88 (d, J¼8.8 Hz, 2H, ArH), 4.52 (d,
J¼11.2 Hz, 1H, PhCHxCHy), 4.36 (d, J¼11.2 Hz, 1H, PhCHxCHy), 4.32
(dd, J¼13.2, 8.0 Hz, 1H, CH2N), 4.14 (dd, J¼13.2, 4.0 Hz, 1H, CH2N),
3.81 (s, 3H, CH3O), 3.41 (td, J¼9.2, 4.0 Hz, 1H, CHOPMB), 2.88 (td,
J¼8.0, 4.0 Hz, 1H, CHCH2N), 2.14e2.10 (m, 1H, CH2), 1.87e1.82 (m,
1H, CH2), 1.71e1.64 (m,1H, CH2),1.54e1.32 (m, 3H, CH2), 0.98 (s, 3H,
50.1, 41.7, 35.8, 31.1, 25.6, 22.1, 19.7; HRMS [MþNa]þ calcd for
C20H29NNaO6 402.1893, found 402.1894; IR (KBr): 3466, 2953, 2874,
1641, 1608, 1573, 1536, 1488, 1441, 1408, 1371, 1319, 1264, 1201, 1169,
1055, 1023, 961, 877, 841, 702, 662, 581 cmꢁ1
.
4.11.4. 2-((1R,2R,3S)-3-((4-Methoxybenzyl)oxy)-1-methyl-2-(nitro-
20
CH3); 13C NMR (100 MHz, CDCl3):
d
ppm 202.7, 159.2, 129.3, 113.8,
methyl)cyclohexyl)-1,3-dioxane (21d). Colorless oil (92% yield). [a]
D
75.6, 75.2, 70.2, 55.2, 49.1, 42.8, 37.5, 31.6, 29.5, 21.5, 18.6, 14.9;
HRMS [MþNa]þ calcd for C17H23NNaO5 344.1474, found 344.1477;
IR (KBr): 3155, 2947, 1730, 1628, 1561, 1527, 1477, 1448, 1394, 1362,
þ10.4 (c 0.95, CHCl3); 1H NMR (400 MHz, CDCl3):
d ppm 7.20 (d,
J¼8.4 Hz, 2H, ArH), 6.86 (d, J¼8.8 Hz, 2H, ArH), 4.87 (dd, J¼14.0,
4.4 Hz, 1H, CH2N), 4.54 (d, J¼11.2 Hz, 1H, PhCHxCHy), 4.34e4.29 (m,
2H, PhCHxCHy, CH2N), 4.17 (s, 1H, CHOCH2), 4.09e4.02 (m, 2H,
OCH2CH2), 3.80 (s, 3H, CH3O), 3.69e3.60 (m, 2H, OCH2CH2), 3.25
(td, J¼10.6, 4.4 Hz, 1H, CHOPMB), 2.73e2.68 (m, 1H, CHCH2N),
2.21e2.18 (m, 1H, CH2), 2.03e1.94 (m, 1H, CH2), 1.68e1.64 (m, 1H,
CH2), 1.45e1.19 (m, 5H, CH2), 0.84 (s, 3H, CH3); 13C NMR (100 MHz,
1316, 1253, 1188, 1157, 1089, 1053, 913, 846, 767, 701, 572 cmꢁ1
.
4.11. General procedure for preparation of acetal 21aed
To a mixture of 9 (0.50 mmol) and 1,3-propanediol (2.50 mmol)
in toluene (5.0 mL), was added a catalytic amount of PPTs. Then the
CDCl3): d ppm 159.1, 130.2, 129.3, 113.7, 107.0, 75.1, 70.0, 67.1, 66.7,

H. Chen et al. / Tetrahedron 69 (2013) 3141e3148
3147
55.2, 53.4, 44.7, 41.8, 33.6, 31.0, 29.7, 25.7, 19.1, 14.4; HRMS [MþNa]þ
calcd for C20H29NNaO6 402.1893, found 402.1898; IR (KBr): 3431,
2924, 2847, 1602, 1573, 1532, 1493, 1457, 1411, 1372, 1329, 187, 1235,
CDCl3): d ppm 106.9, 75.0, 67.1, 66.8, 46.6, 41.9, 36.3, 33.4, 25.6, 19.4,
14.5; HRMS [MþNa]þ calcd for C12H21NNaO5 282.1317, found
282.1316; IR (KBr): 3549, 2927, 2850, 1541, 1452, 1425, 1369, 1235,
1162, 1131, 1021, 994, 931, 847, 810, 673, 632, 551 cmꢁ1
.
1123, 1092, 1013, 998, 921, 847, 678, 549 cmꢁ1
.
4.12. General procedure for preparation of alcohol 22aed
To a mixture of 21 (0.10 mmol) in CH2Cl2/H2O (5.4 mL:0.3 mL) at
4.13. General procedure for preparation of ketone 2aed
To a solution of 22 (0.20 mmol) in anhydrous CH2Cl2 (5 mL) at
0 ꢀC, was slowly added DesseMartin periodinane (0.30 mmol), then
the mixture was warmed to room temperature. After stirring for
1 h, the reaction mixture was diluted with CH2Cl2 (5 mL), quenched
with saturated Na2SO3 solution and extracted with CH2Cl2
(3ꢂ5 mL). The combined organic layers were washed with satu-
rated NaHCO3 solution (5 mL), brine (5 mL), dried over anhydrous
Na2SO4, and concentrated. The crude material was purified by silica
gel column chromatography (20% EtOAc/petroleum ether) to afford
the corresponding product 2.
0
ꢀC, was added DDQ (0.15 mmol). After being stirred at room
temperature for 2 h, the reaction mixture was quenched with sat-
urated NaHCO3 solution and extracted with CH2Cl2 (3ꢂ5 mL). The
combined organic layers were washed with saturated NaHCO3 so-
lution (5 mL), water (5 mL), brine (5 mL), dried over anhydrous
Na2SO4 and concentrated. The resulting residue was purified by
silica gel column chromatography (33% EtOAc/petroleum ether) to
afford the corresponding product 22.
4.12.1. (1R,2R,3S)-3-(1,3-Dioxan-2-yl)-3-methyl-2-(nitromethyl)cy-
20
clohexanol (22a). White solid (91% yield). Mp 127e131 ꢀC; [
a
]
4.13.1. (2R,3S)-3-(1,3-Dioxan-2-yl)-3-methyl-2-(nitromethyl)cyclo-
D
20
þ9.8 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 4.83 (dd,
hexanone (2a from 9a). White solid (85% yield). Mp 65e70 ꢀC; [
a]
D
J¼13.4, 8.8 Hz, 1H, CH2N), 4.68 (dd, J¼13.4, 3.6 Hz, 1H, CH2N), 4.44
(s, 1H, CHOCH2), 4.11 ( td, J¼12.0, 4.8 Hz, 2H, OCH2CH2), 3.88e3.86
(m, 1H, CHOH), 3.77e3.66 (m, 2H, OCH2CH2), 3.20 (s, 1H, OH),
2.38e2.36 (m, 1H, CHCH2N), 2.10e2.00 (m, 1H, CH2), 1.81e1.67 (m,
3H, CH2), 1.58e1.50 (m, 1H, CH2), 1.43e1.32 (m, 2H, CH2), 1.26e1.19
þ12.1 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3):
d ppm 5.04 (dd,
J¼15.4, 9.6 Hz, 1H, CH2N), 4.42 (dd, J¼15.2, 2.4 Hz, 1H, CH2N), 4.21
(s, 1H, CHOCH2), 4.09e4.03 (m, 2H, OCH2CH2), 3.68e3.58 (m, 2H,
OCH2CH2), 3.09 (dd, J¼9.2, 2.4 Hz, 1H, CHCH2N), 2.50e2.45 (m, 1H,
CH2), 2.38e2.30 (m, 1H, CH2), 2.07e1.86 (m, 4H, CH2), 1.69e1.61 (m,
1H, CH2), 1.30 (d, J¼13.6 Hz, 1H, CH2), 1.12 (s, 3H, CH3); 13C NMR
(m, 1H, CH2), 1.07 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d ppm
106.0, 74.1, 67.1, 65.8, 47.6, 40.3, 32.6, 25.6, 23.9, 17.4; HRMS
[MþNa]þ calcd for C12H21NNaO5 282.1317, found 282.1319; IR (KBr):
3558, 2936, 2858, 1550, 1469, 1431, 1380, 1241, 1143, 1107, 1029,
(100 MHz, CDCl3): d ppm 104.2, 70.7, 67.1, 66.7, 54.6, 40.2, 35.8, 29.7,
25.4, 22.8, 21.7. The enantiomeric excess was determined to be 28%
ee by HPLC with an OJ-H chiral column (hexane/i-PrOH¼90:10,
1005, 935, 859, 687, 561 cmꢁ1
.
l
¼254 nm, 1.0 mL/min); tmajor¼13.44 min, tminor¼15.73 min. HRMS
[MþNa]þ calcd for C12H19NNaO5 280.1161, found 280.1158; IR (KBr):
4.12.2. (1R,2R,3R)-3-(1,3-Dioxan-2-yl)-3-methyl-2-(nitromethyl)cy-
3439, 2974, 2877, 1712, 1476, 1428, 1381, 1275, 1228, 1197, 1148,
20
clohexanol (22b). White solid (92% yield). Mp 127e131 ꢀC; [
a
]
1104, 1002, 945, 916, 867, 703 cmꢁ1
.
D
ꢁ18.4 (c 1.15, CHCl3); 1H NMR (400 MHz, CDCl3):
d ppm 5.03 (dd,
J¼11.0, 4.4 Hz, 1H, CH2N), 4.61 (dd, J¼12.8, 9.2 Hz, 1H, CH2N),
4.14e4.09 (m, 3H, CHOCH2, OCH2CH2), 3.99 (m, 1H, CHOH),
3.74e3.63 (m, 2H, OCH2CH2), 2.66e2.62 (m, 1H, CHCH2N),
2.07e1.98 (m, 1H, CH2), 1.82e1.70 (m, 2H, CH2), 1.60e1.42 (m, 3H,
CH2), 1.38e1.25 (m, 2H, CH2), 1.03 (s, 3H, CH3); 13C NMR (100 MHz,
4.13.2. (2R,3R)-3-(1,3-Dioxan-2-yl)-3-methyl-2-(nitromethyl)cyclo-
hexanone (2b from 9b). White solid (84% yield). Mp 155e160 ꢀC;
20
[a
]
þ10.7 (c 1.45, CHCl3); 1H NMR (400 MHz, CDCl3):
d ppm
D
4.82e4.73 (m, 2H, CH2N), 4.24 (s, 1H, CHOCH2), 4.14 (td, J¼10.6,
4.8 Hz, 2H, OCH2CH2), 3.78e3.65 (m, 3H, OCH2CH2, CHCH2N),
2.43e2.39 (m, 2H, CH2), 2.11e2.20 (m, 3H, CH2), 1.82e1.79 (m, 1H,
CH2), 1.57e1.54 (m, 1H, CH2), 1.34 (d, J¼13.6 Hz, 1H, CH2), 0.81 (s,
CDCl3): d ppm 107.4, 75.5, 67.3, 67.1, 41.4, 40.3, 33.8, 32.8, 25.8, 16.9,
15.6; HRMS [MþNa]þ calcd for C12H21NNaO5 282.1317, found
282.1320; IR (KBr): 3567, 2944, 2865, 1561, 1473, 1445, 1392, 1253,
3H, CH3); 13C NMR (100 MHz, CDCl3):
d ppm 209.3, 105.7, 70.6, 67.2,
1152, 1120, 1032, 1013, 946, 867, 693, 572 cmꢁ1
.
51.3, 45.8, 40.8, 33.3, 25.6, 21.5, 15.4. The enantiomeric excess was
determined to be 70% ee by HPLC with an OJ-H chiral column
4.12.3. (1S,2R,3S)-3-(1,3-Dioxan-2-yl)-3-methyl-2-(nitromethyl)cy-
(hexane/i-PrOH¼95:5, ¼254 nm, 1.0 mL/min); tmajor¼17.99 min,
l
20
clohexanol (22c). White solid (93% yield). Mp 101e106 ꢀC; [
a
]
tminor¼20.78 min. HRMS [MþNa]þ calcd for C12H19NNaO5 280.1161,
D
þ15.4 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 4.68 (dd,
found 280.1160; IR (KBr): 3449, 2982, 2885, 1722, 1481, 1439, 1390,
J¼14.4, 2.0 Hz, 1H, CH2N), 4.54 (dd, J¼14.4, 8.4 Hz, 1H, CH2N), 4.45
(s, 1H, CHOCH2), 4.09 (dd, J¼11.4, 4.0 Hz, 2H, OCH2CH2), 3.85e3.80
(m, 1H, CHOH), 3.70e3.62 (m, 2H, OCH2CH2), 2.23e2.17 (m, 1H,
CHCH2N), 2.08e2.03 (m, 1H, CH2), 2.02e1.94 (m, 1H, CH2),
1.93e1.89 (m,1H, CH2),1.60e1.53 (m, 2H, CH2),1.40 (d, J¼6.4 Hz,1H,
CH2), 1.35e1.24 (m, 2H, CH2), 1.06 (s, 3H, CH3); 13C NMR (100 MHz,
1287, 1233, 1205, 1153, 1114, 1010, 956, 927, 873, 711 cmꢁ1
.
4.13.3. (2R,3S)-3-(1,3-Dioxan-2-yl)-3-methyl-2-(nitromethyl)cyclo-
20
hexanone (2a from 9c). White solid (83% yield). Mp 85e87 ꢀC; [
a]
D
þ23.2 (c 0.5, CHCl3). The enantiomeric excess was determined to be
67% ee by HPLC with an OJ-H chiral column (hexane/i-PrOH¼90:10,
CDCl3):
d
ppm 103.1, 71.3, 67.1, 66.9, 52.3, 41.9, 36.2, 35.9, 25.6, 21.9,
l¼254 nm, 1.0 mL/min); tmajor¼13.44 min, tminor¼15.73 min.
20.1; HRMS [MþNa]þ calcd for C12H21NNaO5 282.1317, found
282.1318; IR (KBr): 3571, 2947, 2871, 1569, 1481, 1452, 1407, 1259,
4.13.4. (2R,3R)-3-(1,3-Dioxan-2-yl)-3-methyl-2-(nitromethyl)cyclo-
20
1157, 1129, 1041, 1023, 952, 873, 701, 581 cmꢁ1
.
hexanone (2b from 9d). White solid (86% yield). Mp 58e62 ꢀC; [
a]
D
þ5.4 (c 1.55, CHCl3). The enantiomeric excess was determined to be
36% ee by HPLC with a OJ-H chiral column (hexane/i-PrOH¼95:5,
4.12.4. (1S,2R,3R)-3-(1,3-Dioxan-2-yl)-3-methyl-2-(nitromethyl)cy-
clohexanol (22d). white solid (93% yield). Mp 80e85 ꢀC; [
a
]
20 þ5.4
l
¼254 nm, 1.0 mL/min); tmajor¼17.99 min, tminor¼20.78 min.
D
(c 0.9, CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 4.95 (dd, J¼14.2,
4.8 Hz, 1H, CH2N), 4.52 (dd, J¼14.0, 5.2 Hz, 1H, CH2N), 4.16 (s, 1H,
CHOCH2), 4.08e4.06 (m, 2H, OCH2CH2), 3.68e3.62 (m, 2H,
OCH2CH2), 3.50e3.47 (m, 1H, CHOH), 2.55e2.50 (m, 1H, CHCH2N),
2.08e1.94 (m, 2H, CH2), 1.65e1.63 (m, 1H, CH2), 1.51e1.43 (m, 3H,
CH2), 1.30e1.25 (m, 2H, CH2), 0.88 (s, 3H, CH3); 13C NMR (100 MHz,
4.14. General procedure for the preparation of MTPA esters
23c and 23d
To a mixture of 22c or 22d (0.05 mmol) and Mosher’s acid
(0.075 mmol) in dry CH2Cl2 (1 mL) was added DIC (0.20 mmol) and

3148
H. Chen et al. / Tetrahedron 69 (2013) 3141e3148
DMAP (0.12 mmol). After stirring at room temperature for 24 h, the
solvent was removed under reduced pressure. The resulting residue
was purified by silica gel column chromatography (10% acetone/
petroleum ether) to afford the corresponding ester 23c or 23d.
7.41e7.38 (m, 3H, ArH), 4.92 (td, J¼11.2, 4.4 Hz, 1H, CHOCO), 4.74
(dd, J¼14.8, 5.6 Hz, 1H, CH2N), 4.15 (s, 1H CHOCH2), 4.06e3.95 (m,
3H, CH2N, OCH2CH2), 3.65e3.55 (m, 2H, OCH2CH2), 3.45 (s, 3H,
CH3O), 2.86e2.81 (m, 1H, CHCH2N), 2.19e2.16 (m, 1H, CH2),
1.99e1.89 (m, 1H, CH2), 1.68e1.65 (m, 1H, CH2), 1.59e1.45 (m, 2H,
CH2), 1.36e1.24 (m, 3H, CH2), 0.94 (s, 3H, CH3); 13C NMR (100 MHz,
20
4.14.1. 23c-(R)-MTPA. Colorless oil (62% yield). [
a]
þ136.0 (c 0.5,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 7.54e7.53 (m, 2H, ArH),
CDCl3): d ppm 166.5, 131.5, 129.7, 128.8, 128.5, 127.3, 126.9, 121.8,
7.42e7.41 (m, 3H, ArH), 5.32 (td, J¼10.8, 4.8 Hz,1H, CHOCO), 4.67 (dd,
J¼15.2, 3.6 Hz, 1H, CH2N), 4.47 (s, 1H, CHOCH2), 4.13e4.07 (m, 3H,
CH2N, OCH2CH2), 3.73e3.64 (m, 2H, OCH2CH2), 3.52 (s, 3H, CH3O),
2.51e2.46 (m, 1H, CHCH2N), 2.33e2.29 (m, 1H, CH2), 2.04e1.93 (m,
2H, CH2), 1.73e1.53 (m, 2H, CH2), 1.48e1.41 (m, 1H, CH2), 1.33 (d,
J¼13.6 Hz,1H, CH2),1.16 (td, J¼13.6, 4.4 Hz,1H, CH2),1.02 (s, 3H, CH3);
106.3, 75.2, 73.3, 67.0, 66.0, 55.2, 42.7, 42.3, 33.0, 31.3, 29.7, 25.4,
18.8, 14.4; HRMS [MþNa]þ calcd for C22H28F3NNaO7 498.1716,
found 498.1714; IR (KBr): 3466, 2985, 2944, 2873, 1763, 1577, 1468,
1401, 1283, 1198, 1131, 1040, 966, 945, 914, 822, 791, 737, 674 cmꢁ1
.
13C NMR (100 MHz, CDCl3):
d ppm 132.0, 129.6, 128.4, 127.1, 103.7,
Acknowledgements
76.1, 73.6, 67.1, 66.8, 55.4, 47.8, 42.4, 35.6, 31.7, 29.7, 25.6, 22.5, 19.7;
HRMS [MþNa]þ calcd for C22H28F3NNaO7 498.1716, found 498.1711;
IR (KBr): 3449, 2962, 2926, 2854, 1746, 1554, 1446, 1382, 1263, 1175,
This work was supported by grants from the NSFC (21202209,
21021001, and 21132006), and the National Basic Research Program
of China (973 program, 2010CB833200).
1110, 1020, 942, 924, 897, 802, 773, 719, 652 cmꢁ1
.
20
4.14.2. 23c-(S)-MTPA. Colorless oil (65% yield). [
a
]
ꢁ12.0 (c 0.35,
D
Supplementary data
CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 7.48e7.46 (m, 2H, ArH),
7.41e7.40 (m, 3H, ArH), 5.27 (td, J¼10.8, 4.8 Hz, 1H, CHOCO), 4.79
(dd, J¼15.4, 7.2 Hz, 1H, CH2N), 4.47 (s, 1H, CHOCH2), 4.25 (dd,
J¼15.4, 6.4 Hz, 1H, CH2N), 4.12 (dd, J¼11.2, 4.8 Hz, 2H, OCH2CH2),
3.69 (q, J¼12.0 Hz, 2H, OCH2CH2), 3.44 (s, 3H, CH3O), 2.53e2.48 (m,
1H, CHCH2N), 2.24e2.20 (m, 1H, CH2), 2.05e1.97 (m, 1H, CH2),
1.94e1.90 (m, 1H, CH2), 1.70e1.54 (m, 2H, CH2), 1.36e1.24 (m, 2H,
CH2), 1.15 (td, J¼13.6, 4.4 Hz, 1H, CH2), 1.04 (s, 3H, CH3); 13C NMR
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.02.078.
References and notes
1. Tang, P.; Chen, Q. H.; Wang, F. P. Tetrahedron Lett. 2009, 50, 460.
2. Takahiro, S.; Aya, S.; Naoki, E.; Susumu, K. Angew. Chem., Int. Ed. 2011, 50, 9177.
3. Ryuji, H.; Ma, Z. X.; Richard, P. H. Org. Lett. 2012, 14, 252.
(100 MHz, CDCl3):
d ppm 166.5, 129.7, 129.6, 128.8, 128.4, 127.4,
126.8, 121.8. 103.8. 76.5, 74.2, 67.2, 66.9, 55.3, 47.6, 43.0, 42.3, 35.5,
31.1, 25.6, 22.5, 19.5; HRMS [MþNa]þ calcd for C22H28F3NNaO7
498.1716, found 498.1718; IR (KBr): 3450, 2964, 2928, 2854, 1750,
1556, 1448, 1389, 1260, 1170, 1112, 1025, 940, 928, 890, 800, 770,
720, 654 cmꢁ1. HRMS [MþNa]þ calcd for C22H28F3NNaO7 498.1716,
found 498.1711; IR (KBr): 3432, 2951, 2911, 2843, 1732, 1543, 1435,
4. For selected reviews of asymmetric organocatalysis, see: (a) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138; (b)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (c) List, B.; Yang, J.
W. Science 2006, 313, 1584; (d) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem.
Res. 2004, 37, 580; (e) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719; (f)
Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167; (g) Ramachary, D. B.;
Jain, S. Org. Biomol. Chem. 2011, 9, 1277; (h) MacMillan, D. W. C. Nature 2008,
455, 304.
5. For selected examples of the stereocontrolled formation of multiple stereo-
centers, see: (a) Hong, B. C.; Nimije, R. Y.; Lin, C. W.; Liao, J. H. Org. Lett. 2011, 13,
1278; (b) Imashiro, R.; Uehara, H.; Barbas, C. F. Org. Lett. 2010, 12, 5250; (c) Tan,
B.; Chua, P. J.; Zeng, X.; Lu, M.; Zhong, G. Org. Lett. 2008, 10, 3489; (d) Reyes, E.;
Jiang, H.; Milelli, A.; Elsner, P.; Hazell, R. G.; Jorgensen, K. A. Angew. Chem., Int.
Ed. 2007, 46, 9202; (e) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew.
Chem., Int. Ed. 2007, 46, 4922; (f) Tan, B.; Chua, P. J.; Li, Y. X.; Zhong, G. F. Org.
Lett. 2008, 10, 2437; (g) Wang, Y.; Han, R. G.; Zhao, Y. L.; Yang, S.; Xu, P. F.; Dixon,
D. J. Angew. Chem., Int. Ed. 2009, 48, 9834.
6. For selected examples of organocatalytic Michael additions, see: (a) Ma, A. Q.;
Ma, D. W. Org. Lett. 2010, 12, 3634; (b) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.;
Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 3732; (c) Nodes, W. J.; Nutt,
D. R.; Chippindale, A. M.; Cobb, A. J. A. J. Am. Chem. Soc. 2009, 131, 16016; (d)
Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2004, 43, 1272;
(e) Li, H.; Zu, L. S.; Xie, H. X.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9,
1833.
1371, 1252, 1166, 1101, 1013, 931, 913, 886, 793, 762, 703, 640 cmꢁ1
.
20
4.14.3. 23d-(R)-MTPA. Colorless oil (68% yield). [
a]
þ44.4 (c 0.5,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d
ppm 7.56e7.49 (m, 2H, ArH),
7.44e7.35 (m, 3H, ArH), 4.92 (td, J¼11.2, 4.8 Hz, 1H, CHOCO), 4.57
(dd, J¼15.0, 6.0 Hz, 1H, CH2N), 4.12 (s, 1H, CHOCH2), 4.04e3.96 (m,
2H, OCH2CH2), 3.82 (dd, J¼14.8, 2.8 Hz, 1H, CH2N), 3.65e3.57 (m,
2H, OCH2CH2), 3.54 (s, 3H, CH3O), 2.81e2.76 (m, 1H, CHCH2N),
2.29e2.25 (m, 1H, CH2), 1.97e1.88 (m, 1H, CH2), 1.72e1.68 (m, 1H,
CH2), 1.56e1.52 (m, 1H, CH2), 1.48e1.36 (m, 3H, CH2), 1.24e1.22 (m,
1H, CH2), 0.93 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3):
d ppm 166.2,
132.1, 129.7, 128.8, 126.9, 124.7, 121.8, 106.2, 74.8, 72.7, 66.9, 66.6,
55.5, 42.8, 42.3, 33.0, 31.8, 25.4, 18.8, 14.4; HRMS [MþNa]þ calcd for
C22H28F3NNaO7 498.1716, found 498.1715; IR (KBr): 3457, 2973,
2935, 2862, 1750, 1563, 1455, 1391, 1274, 1180, 1120, 1032, 955, 933,
7. (a) Lalonde, M. P.; Chen, Y. G.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
6366; (b) McCooey, S. H.; Connon, S. J. Org. Lett. 2007, 9, 599.
8. Milton, L. B. Bioorg. Med. Chem. 2009, 17, 7056.
903, 810, 780, 728, 663 cmꢁ1
.
9. Stork, G.; Dowd, S. R. J. Am. Chem. Soc. 1963, 85, 2178.
10. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 38, 2143; (b) Ohitani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092; (c)
Kusumi, T.; Fukushima, T.; Ohtami, I.; Kakisawa, H. Tetrahedron Lett. 1991, 32,
2939.
4.14.4. 23d-(S)-MTPA. Colorless oil (71% yield). [
CHCl3); 1H NMR (400 MHz, CDCl3):
a
]
20 ꢁ10.4 (c 0.45,
D
d
ppm 7.49e7.47 (m, 2H, ArH),