Formal enantioselective total synthesis of schulzeines A-C via Pd-catalyzed intramolecular asymmetric allylic amination

Article abstract of DOI:10.1021/jo2009615

Formal enantioselective total synthesis of schulzeines A-C was accomplished, featuring highly efficient Pd-catalyzed asymmetric allylic amination using novel diphosphonite ligands (BOPs) to provide 1-vinyltetrahydroisoquinoline key intermediates, as well

Full text of DOI:10.1021/jo2009615

ARTICLE
pubs.acs.org/joc
Formal Enantioselective Total Synthesis of Schulzeines AꢀC via
PdꢀCatalyzed Intramolecular Asymmetric Allylic Amination
Chi-Feng Lin and Iwao Ojima*
Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, United States
S Supporting Information
b
ABSTRACT: Formal enantioselective total synthesis of schul-
zeines AꢀC was accomplished, featuring highly efficient Pd-
catalyzed asymmetric allylic amination using novel diphospho-
nite ligands (BOPs) to provide 1-vinyltetrahydroisoquinoline
key intermediates, as well as Ru-catalyzed ring-closing metath-
esis reaction to construct the key tricyclic cores in enantiopure
form with correct absolute configurations.
Scheme 1. Retrosynthetic Analysis of the Tricyclic Core of
’ INTRODUCTION
Schulzeines AꢀC
Schulzeines AꢀC, isolated from the marine sponge, Penares
schulzei, have been identified as a new class of marine natural pro-
ducts (Figure 1).1 These new alkaloids were found to exhibit
potent R-glucosidase inhibitory activity, which made them pro-
mising leads in drug development for the treatment of cancer,
diabetes, and viral infections.2ꢀ4 Therefore, it is important to
develop efficient syntheses for these natural products to provide
sufficient amounts for biological studies as well as structureꢀactivity
relationship studies for discovery of more potent analogues.
Figure 1. Schulzeines AꢀC.
moiety of 1-vinyltetrahydroisoquinoline 3 (for representative ap-
proaches to the construction of 1-vinyltetrahydroisoquinolines, see
refs 10ꢀ15), followed by ring-closing metathesis (RCM) of 516 and
hydrogenation of the resulting didehydropiperidinone ring of 6.
Then, 3 can be derived from 2 by N-deprotection, and 2 with
excellent enantiopurity can be obtained through the intramolecular
AAA of 1, which should introduce the chiral center at C11b of 7.
Five research groups have reported the synthesis of schulzeines
AꢀC tricyclic core to date.5ꢀ9 All but one of these syntheses
employed PictetꢀSpengler-type cyclization to form the central ring
of the tricyclic core, and the introduction of the critical stereocenter
at C-11b was either totally nonselective or gave only low to
moderate diastereoselectivity, wherein the separation of two dia-
stereomers was difficult in some cases. Thus, it is apparent that a
more efficient construction of the tricyclic core needs to be
developed. We envisioned that an intramolecular asymmetric allylic
amination (AAA) could serve as the key reaction in the construction
of required stereochemistry at C11b. We describe here a new and
efficient synthesis of the tricyclic core of schulzeines AꢀC based on
the AAA approach.
’ RESULTS AND DISCUSSION
The AAA substrate 1A (P = 4-methoxybenzyl (PMB), R0 = CF3)
was prepared from the N-trifluoroacetyl-O,O0-bis-PMB-resorc-
inolamine (8A) as shown in Scheme 2. The iodination of 8A
(TFA = trifluoroacetyl) with N-iodosuccinimide (NIS)17 proceeded
Our retrosynthetic analysis is illustrated in Scheme 1. The S
configuration to the C3 position of the tricyclic core 7 can be
introduced by coupling (S)-vinylglycine derivative 4 to the amine
Received: May 16, 2011
Published: June 14, 2011
r
2011 American Chemical Society
6240
dx.doi.org/10.1021/jo2009615 J. Org. Chem. 2011, 76, 6240–6249
|

The Journal of Organic Chemistry
ARTICLE
Scheme 2. Preparation of AAA Substrate 1A-aꢀc
smoothly to give 9A. No bis-iodinated product was detected by
TLC. The Sonogashira coupling of 9A with propargyl alcohol
gave 10A in fairly good yield (60ꢀ65%), wherein conversion
was 80ꢀ85% after 48 h (15ꢀ20% 9A was recovered). Selective
hydrogenation of 10A over P2ꢀNi catalyst under ambient
conditions gave cis-allylic alcohol 11A cleanly. The subsequent
acylation of the alcohol moiety with chloroformates gave the
corresponding allylic carbonates, i.e., AAA substrates 1A-aꢀc in
excellent yields. In the same manner, AAA substrates 1B-a,b were
prepared from N-trifluoroacetyl-O,O0-dibenzylresorcinolamine
(8B) in similar yields. [Note: Compound 8 (A or B) can be pre-
pared in two steps from commercially available resorcinolamine.
Alternatively, 8 (A or B) can also be prepared from commercially
available 3,5-dihydroxybenzaldehyde through PMB or benzyl
protection and nitroaldol reaction, followed by reduction and
trifluoroacetylation. See Experimental Section.]
Because our chiral monodentate phosphoramidite ligands
gave excellent results for the intramolecular AAA reaction of a
closely related catechol-based substrate,18 several phosphorami-
dite ligands were examined for the reaction of 1 (P = Me, R0 = CF3,
R00 =CHdCH2). However, to our surprise, those chiral ligands gave
2 (P = Me, R0 = CF3) with only low to moderate enantios-
electivity (Scheme 1).19 As we reported previously,18 chiral PꢀN
ligands exhibited low catalytic activity, requiring 12ꢀ23 days to
achieve good yield and high enantioselectivity in the presence of a
strong base.13 Also, a typical “DPPBA ligand”, (1R,2R)-N,N0-bis(20-
diphenylphosphinobenzoyl)-1,2-diaminocyclohexane,20 did not
achieve appreciable yield even after 2 days at room temperature.
Therefore, we examined the novel chiral biphenol-based dipho-
sphonite ligands (BOP ligands), which we had successfully devel-
oped for an intermolecular AAA reaction.21 In addition to the
previously reported BOP ligands (L1aꢀd), a library of new 3,30-
dibenzylbiphenol-based BOP ligands (L1eꢀL2c) were designed
and synthesized (Figure 2) and their efficacy was examined in the
AAA reaction of 1. For the synthesis of BOP ligands, see the
Experimental Section and ref 21.
Figure 2. BOP ligand library (only R configuration is depicted for
simplicity).
nitrogen (Scheme3). As shown inTable 1, all reactionsgave >95%
conversion in less than 6 h. There was a dramatic increase in
enantioselectivity when the 3,30-substituents were changed from
hydrogen (entry 1) to methyl and other groups (entries 2ꢀ4).
Among the four BOP ligands examined, (S)-L1b (R = Me), gave
(ꢀ)-2A with 80% ee (entry 2). Accordingly, we also carried out
the reaction of 1B-a and 1B-b to see if there was a difference in
enantioselectivity, depending on the protecting group of the
phenolic hydroxyl groups (Scheme 3). The reactions of 1B-a
and 1B-b under the same conditions as those for 1A-a were
completed in 2 and 6 h, respectively, to afford (ꢀ)-2B (P =
PhCH2) in high yield (>95%conversion) with75% ee and 76% ee,
respectively. Thus, 1A-a appeared to be a better substrate than 1B-
a and 1B-b. Also, it was found that there was a difficulty in
separating (ꢀ)-2B from a small amount of dba by flash chroma-
tography on silica gel, because of their very small difference in
polarity. In contrast, there was no problem in the separation of
(ꢀ)-2Afrom dba. Therefore, 1A seriessubstrates (P= PMB) were
selected for optimization.
New BOP ligands bearing benzyl or substituted benzyl group at
the 3,30-positions were examined, as well. Results are shown in
Table 2. Among the new BOP ligands screened, L1g (R = 3,5-
dimethylbenzyl) gave the best result so far (entry 3). Thus, this BOP
ligand was selected as the ligand of choice for further optimization.
Next, the effects of the concentration of the reaction mixture
as well as the chiral ligand/Pd ratio on enantioselectivity were
First, BOP ligands L1aꢀd were screened for the AAA reaction
of 1A-a to give 2A using Pd2(dba)3 (dba = dibenzylideneacetone)
as the catalyst precursor in DMF at room temperature under
6241
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249

The Journal of Organic Chemistry
ARTICLE
Scheme 3. Pd-Catalyzed AAA Reaction of 1
Table 3. Effect of Concentration and L*/Pd Ratio on the AAA
Reaction of 1A-aa
entry
concn (M)
L*/Pd
time (h)
conv (%)b
2A % eeb
1
2
3
4
5
0.05
0.10
0.25
0.50
0.50
1.5
1.5
1.5
1.5
1.0
6.0
5.5
5.0
5.0
4.5
>95
>95
>95
>95
>95
84.0 (+)
87.5 (+)
90.3 (+)
90.1 (+)
91.1 (+)
Table 1. Screening of BOP Ligands L1aꢀd for the AAA
Reaction of 1A-aa
a Reactions were run using Pd2(dba)3 (2.5 mol %) with (R)-L1g ligand
(L*) in DMF at room temperature under N2. b See the footnote of
Table 1.
Table 4. Electronic Effect on the Efficacy of New BOP
Ligandsa
entry
ligand (L*)
time (h)
conv (%)b
2A % eec
entry
ligand (L*)
time (h)
conv (%)b
2A % eeb
1
2
3
4
(R)-L1a
(S)-L1b
(R)-L1c
(R)-L1d
1.5
2
>95
>95
>95
>95
4 (+)
80 (ꢀ)
79 (+)
74 (+)
1
2
3
4
5
(R)-L1g
(R)-L2a
(S)-L2a
(R)-L2b
(R)-L2c
4.5
7
>95
>95
>95
>95
>95
91.1 (+)
94.0 (+)
96.1 (ꢀ)
93.3 (+)
81.5 (+)
5
5
7
a All reactions were run using Pd2(dba)3 (2.5 mol %) with a BOP ligand
7
(7.5 mol %) in DMF at room temperature under N2. b Determined by
7
1H NMR. Determined by HPLC using Chralpak AD-RH, CH3CN/
c
a Reactions were run using Pd2(dba)3 (2.5 mol %) with a BOP ligand
H2O = 50/50.
(5.0 mol %) in DMF at room temperature. b See the footnote of Table 1.
Table 2. Screening of New BOP Ligands the AAA Reaction of
1A-aa
Table 5. Effects of the Substrate Structure and Reaction
Temperature on the AAA Reactiona
entry
ligand (L*)
time (h)
conv. (%)a
2A % eea
entry substrate (1A) temp (°C) time (h) conv (%)b 2A % eeb
1
2
3
4
5
(R)-L1e
(R)-L1f
(R)-L1g
(R)-L1h
(R)-L1i
4
4
6
4
4
>95
>95
>95
>95
>95
83 (+)
83 (+)
84 (+)
80 (+)
80 (+)
1
2
3
4
5
1A-a
1A-b
1A-c
1A-a
1A-a
25
25
25
10
0
7
>95
>95
>95
>95
76
94.0 (+)
93.6 (+)
92.0 (+)
95.0 (+)
95.6 (+)
7
7
48
96
a See the footnote of Table 1.
a Reactions were run using Pd2(dba)3 (2.5 mol %) with (R)-L2a ligand
(5.0 mol %) in DMF at room temperature. b See the footnote of Table 1.
examined using (R)-L1g. As shown in Table 3, higher concen-
trations gave better results (entries 3 and 4) than the lower
concentration (entry 1) that was employed in the screening
described above. At concentrations higher than 0.5 M, Pd species
precipitated out, resulting in low reactivity. Thus, we chose 0.5 M
concentration for further optimization, although 0.25 M con-
centration afforded a slightly higher enantioselectivity, by taking
into account the economical and environmental merit of using
less solvent.
For the optimal ligand/Pd ratio, just the use of 1 equiv of L1g to Pd
metal gave a bit better enantioselectivity than that achieved by using
1.5 equiv of the ligand to the metal (entry 5). Thus, the stoichiometric
use of the ligand was employed for further optimization.
enantioselectivity (entry 5). Accordingly, (R)-L2a, which gave
94.0% ee (entry 2), was selected as the best BOP ligand for this
reaction.
We also examined the effect of the allylic carbonate substitu-
ents on this AAA reaction. As shown in Table 5, the vinyl
carbonate (1A-a) gave a slightly better result (94.0% ee) (entry 1)
than the other two carbonates (1A-b and 1A-c; entries 2 and 3).
Effect of the reaction temperature on enantioselectivity and
reaction rate was also examined. The reaction at 10 °C and 0 °C
gave higher enantioselectivity (95.0 and 95.6% ee, respectively),
but at 0 °C, the reaction rate was substantially decreased as
compared to that at 10 °C or 25 °C (entries 4 and 5).
With the optimized conditions for the AAA reaction of 1A-a,
we prepared (+)-(S)-2A with excellent enantiopurity (94ꢀ95%
ee) in a larger quantity and set out to complete the synthesis of
the schulzeine B tricyclic core in accordance with the planned
synthetic route (Scheme 4) based on the retrosynthetic analysis
(Scheme 1) described above. [Note: The absolute configuration
of (+)-2 was tentatively assigned to S based on the sign of the
specific rotation of close related (+)-(S)-1-vinyltetrahydroiso-
quinoline that we reported previously18 and confirmed by the
known value of (S,S)-13. See Experimental Section.] (+)-(S)-2
At this point, we examined the possible electronic effect of the
diphenylphophinyl moiety of L1g on enantioselectivity as a
further optimization process. Thus, (R)-L2a-c ligands were pre-
pared (see Experimental Section) and their efficacy evaluated
in the AAA of 1A-a under the optimized conditions described
above. As shown in Table 4, the introduction of electron-
releasing substituents, i.e., Me (L2a) and MeO (L2b) groups,
at the para-position of the diphenylphosphinyl moiety of
L1g improved the efficacy (entries 2ꢀ4), while that of the
electron-withdrawing CF3 group (L2c) considerably descreased
6242
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249

The Journal of Organic Chemistry
ARTICLE
Scheme 4. Formal Total Synthesis of Schulzeine B
Scheme 5. Formal Total Synthesis of Schulzeines A and C
(94.0% ee), thus prepared, was deprotected by 2 M NaOH to
give free amine 3 in 98% yield, which was reacted with N-Fmoc-
(S)-vinylglycinyl chloride (4)22,23 in the presence of triethylamine
(1 equiv) to give (S,S)-5 (P = PMB, R = Fmoc) with 97:3 dr.
Diene 5 was subjected to RCM using the second-generation
Grubbs catalyst24 in refluxing dichloromethane to give tricyclic
RCM product (S,S)-6 as the single diastereomer in 80% yield. The
hydrogenation and hydrogenolysis of (S,S)-6 over 10% Pd/C
(20 mol %) underambient conditionsfor 48 h afforded thedesired
(S,S)-7 in 91% yield, which was then converted to the common
advanced key intermediate (S,S)-13 through Boc and benzyl
protections of the amine and resorcinol moieties. [Note: The
absolute configuration at C11b of the tricylic core was assigned
Romo paper,7 [R]D ꢀ138.7 (c 0.73, MeOH). Because the free
23
20
amine, (S,S)-7, in ourhands showed the specific rotation of [R]D
ꢀ252.3 (c 0.35, MeOH), it appears that the reported value of
(S,S)-7 is an error.7] From (S,S)-13, three groups already reported
the total synthesis of schulzeine B.6ꢀ8 Thus, a formal total
synthesis of this compound has been completed. Although O,O0-
dibenzyl protection was used in the known total syntheses, O,O0-
bis-PMB protection should work equally well. Thus, (S,S)-12 was
also prepared as an alternative key advanced intermediate through
Fmoc deprotection of (S,S)-6 with diethylamine in DCM at room
temperature for 10 h.
In the same manner, we carried out the asymmetric synthesis
of (S,R)-6, (S,R)-7-Boc, and 13, starting from (ꢀ)-(R)-2A,
which was obtained in 96.1% ee through the AAA reaction of
1A-a using (S)-L2a (Scheme 5). Diene (S,R)-5 was prepared and
subjected to the RCM reaction in the same manner as that for
(S,S)-5 to give the corresponding RCM product (S,R)-6. How-
ever, unexpectedly, substantial epimerization occurred during
the RCM reaction to give almost an equal amount of (R,R)-6.
19
based on the specific rotation of (S,S)-13, [R]D ꢀ109.2 (c 0.76,
CHCl3), with that of the literature value from the Bowen and
24
Wardrop paper,8 [R]D ꢀ108.1 (c 1.96, CHCl3). We also
20
prepared (S,S)-7 HBr salt with [R]D ꢀ138.9 (c 0.72, MeOH).
3
This value was found to be virtually identical to that of the
literature value for (S,S)-7 (free amine form) from the Liu and
6243
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249

The Journal of Organic Chemistry
ARTICLE
[Note: The PM3 energy calculation performed with the Spartan
2008 program indicates that cis-6 and trans-6 have almost same
energy, and an attempted epimerization of trans-6 to cis-6 under
the RCM conditions did not cause any epimerization. Thus, this
epimerization should have taken place during the RCM reaction.]
After screening of RCM catalysts and reaction variables, we found
that the second-generation HoveydaꢀGrubbs catalyst25 gave the
best result, so far, favoring the formation of (S,R)-6 in 3:1 ratio.
Thus, enantio- and diastereopure (S,R)-6 was isolated in 51%
yield. From(S,R)-6, (S,R)-7-Boc and (S,R)-13 weresynthesized in
a similar manner to that illustrated in Scheme 4, and thus the
formal total synthesis of schulzeines A and C have also been com-
pleted.
in DMF (150 mL) was added 4-methoxybenzyl chloride (9.60 mL, 71.7
mmol) at room temperature. Then, the mixture was stirred at 70 °C for
4 h. The reaction mixture was cooled to room temperature and diluted
with EtOAc (75 mL) and water (75 mL). The organic layer was
separated and washed with water (100 mL ꢁ 3). The organic layer
was then washed with brine and dried over anhydrous MgSO4. The dry-
ing agent was removed by filtration and the solvent evaporated in vacuo
to afford crude yellow solid. Purification of the crude product by flash
column chromatography on silica gel (hexanes/EtOAc = 10:1f4:1)
afforded 3,5-bis(4-methoxybenzyloxy)benzaldehyde as a white solid
1
(9.48 g, 77% yield): mp 70ꢀ71 °C; H NMR (400 MHz, CDCl3) δ
3.82 (s, 6H), 5.01 (s, 4H), 6.84 (t, J = 2.1 Hz, 1H), 6.92 (d, J = 8.4 Hz,
4H), 7.09 (d, J = 2.1 Hz, 2H), 7.35 (d, J = 8.4 Hz, 4H), 9.89 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 55.5, 70.4, 106.1, 108.5, 108.9, 114.3, 128.5,
129.5, 138.6, 159.9, 160.6, 192.0; HRMS (ESI+) calcd For C23H22O5Na
[M + Na]+ 401.1365, found 401.1366 (Δ = 0.2 ppm).
’ CONCLUSIONS
1,3-Bis(4-methoxybenzyloxy)-5-[(E)-2-nitroethenyl]benzene. A mix-
ture of 3,5-bis(4-methoxybenzyloxy)benzaldehyde (7.62 g, 20.2 mmol),
CH3CO2NH4 (1.56 g, 20.2 mmol), andCH3NO2 (106 mL) was placedin
a 250 mL round-bottomed flask. Then, the mixture was heated to reflux
(about 110 °C) for 1.5 h. The reaction mixture was cooled to room
temperature and diluted with Et2O (100 mL) and water (100 mL). The
aqueous layer was separated and extracted with Et2O (100 mL ꢁ 2). The
combined organic layer was washed with brine and dried over anhydrous
MgSO4. The drying agent was removed by filtration and the solvent
evaporated in vacuo to afford crude yellow solid, which was washed with
EtOH to afford 1,3-bis(4-methoxybenzyloxy)-5-[(E)-2-nitroethenyl]
A new approach toward the total synthesis of schulzeines
AꢀC, featuring efficient asymmetric allylic amination and ring-
closing metathesis as key steps has been successfully developed.
Every step in the synthesis gave good to excellent yield except for
the formation of (S,R)-6. Further optimizations of the whole
process, especially the RCM step for (S,R)-5 and mechanistic
studies are actively underway in our laboratory.
’ EXPERIMENTAL SECTION
General Methods. 1H, 13C, and 31P NMR were measured on a 500
MHz (500 MHz for 1H, and 125 MHz for 13C), a 400 MHz (400 MHz
for 1H; 100 MHz for 13C; 162 MHz for 31P), or a 300 MHz (300 MHz
for 1H; 75 MHz for 13C; 121.5 MHz for 31P) NMR spectrometer in a
deuterated solvent using residual protons (CHCl3: 1H, 7.26 ppm; 13C,
77.0 ppm, C6H6: 1H, 7.15 ppm) as the internal standard or phosphoric
acid as the external reference (31P 0.00 ppm). Analytical HPLC in
reverse phase was carried out using a Chiralpak AD-RH analytical
column. Melting points were measured on a capillary melting point
apparatus and are uncorrected. Optical rotations were measured on a
polarimeter. TLC analyses were performed using aluminum pre-
coated silica gel plates. Flash column chromatography was carried
out using silica gel (particle size 40ꢀ63 μm). High-resolution mass
spectrometric analyses were carried out at the Mass Spectrometry
Laboratory, University of Illinois UrbanaꢀChampaign, Urbana,
IL. Unless otherwise noted all reactions were carried out under
argon or nitrogen atmosphere in oven-dried glassware using stan-
dard Schlenck techniques.
Materials. Solvents were reagents grade and freshly distilled before
use and diethyl ether (Et2O) were dried and degassed using a solvent
purification system. Toluene and methanol (MeOH) were distilled from
calcium hydride. Anhydrous N,N-dimethylformamide (DMF) was
purchased and used without further purification. Other solvents were
used without purification. Benzylidene[1,3-bis(2,4,6trimethylphenyl)-2-
imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (2nd-
generation Grubbs catalyst), [1,3-bis(2,4,6-trimethylphenyl)2-imidazo-
lidinylidene]dichloro(o-isopropoxyphenylmethylene)ruthenium (2nd-
generation HoveydaꢀGrubbs catalyst), and N-iodosuccinimide were
purchased and used as received. (S)-N-Fmoc-vinylglycinyl chloride was
synthesized in five steps from commercial available L-methionine
methyl ester hydrochloride.22 3,5-Dibenzyloxybenzaldehyde was pre-
pared from commercially available 3,5-dihydroxybenzaldehyde by the
reported procedure.26 Other chemicals and reagents were purchased
and used without further purification unless otherwise noted. Chiral
biphenols and chiral BOP ligands, L1aꢀL1i were prepared according to
the procedure previously reported by our laboratory.21
1
benzene as a yellow solid (7.21 g, 85% yield): mp 128ꢀ130 °C: H
NMR (300 MHz, CDCl3) δ 3.83 (s, 6H), 4.99 (s, 4H), 6.73 (m, 3H), 6.93
(d, J = 8.7 Hz, 4H), 7.34 (d, J = 8.7 Hz, 4H), 7.51 (d, J = 13.5 Hz, 1H), 7.90
(d, J = 13.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 55.5, 70.4, 106.1,
108.4, 114.3, 128.4, 129.5, 131.9, 137.7, 139.3, 159.9, 160.6; HRMS
(ESI+) calcd For C24H23NO6Na [M + Na]+ 444.1423, found 444.1422
(Δ = ꢀ0.2 ppm).
1,3-Bis(4-methoxybenzyloxy)-5-[2-(N-trifluoroacetamido)ethyl]b-
enzene (8A). To a suspension of LiAlH4 (2.54 g, 66.4 mmol) in THF
(50 mL) was added dropwise a solution of 1,3-bis(4-methoxyben-
zyloxy)-5-[(E)-2-nitroethenyl]benzene (6.98 g, 16.6 mmol) in THF
(120 mL) at 0 °C under nitrogen. Then, the mixture was heated to 65 °C
for 3 h. The reaction mixture was cooled to room temperature, diluted
with Et2O (30 mL), and quenched with 20% KOH (50 mL) at 0 °C. The
resulting precipitate was removed by filtration, and the aqueous layer
was separated and extracted with Et2O (50 mL ꢁ 3). The combined
organic layer was washed with brine and dried over anhydrous K2CO3.
The drying agent was removed by filtration, and the solvent was
concentrated in vacuo to afford the crude product as brown oil. The
brown oil was dissolved in DCM (120 mL), and NEt3 (5.77 mL, 41.5
mmol) was added. To this mixture was added slowly (CF3CO)2O
(3.04 mL, 21.6 mmol) at 0 °C. The reaction mixture was stirred at 0 °C
for 1 h, and water (10 mL) was added to quench the reaction. The
aqueous layer was separated and extracted with DCM (50 mL ꢁ 3). The
combined organic layer was washed with brine and dried over anhydrous
MgSO4. The drying agent was removed by filtration and the solvent
evaporated in vacuo to afford the crude product as a brown solid.
Purification of the crude product by flash column chromatography on
silica gel (hexanes/EtOAc = 20:1f5:1) afforded 8A as a white solid
(4.68 g, 58% yield for two steps): mp 116ꢀ117 °C; 1H NMR (400 MHz,
CDCl3) δ 2.81 (t, J = 6.6 Hz, 2H), 3.60 (q, J = 6.6 Hz, 2H), 3.82 (s, 6H),
4.94 (s, 4H), 6.26 (br, 1H), 6.41 (d, J = 2.4 Hz, 2H), 6.51 (t, J = 2.4 Hz,
1H), 6.93 (d, J = 8.4 Hz, 4H), 7.34 (d, J = 8.4 Hz, 4H); 13C NMR (100
MHz, CDCl3) δ 35.3, 40.9, 55.5, 70.1, 100.8, 107.9, 114.3, 116.0 (q, J =
286 Hz), 128.9, 129.5, 139.9, 157.3 (q, J = 37 Hz), 159.7, 160.6; HRMS
(ESI+) calcd For C26H27NO5F3 [M + H]+ 490.1841, found 490.1840
(Δ = ꢀ0.2 ppm).
3,5-Bis(4-methoxybenzyloxy)benzaldehyde. To a stirred solution of
3,5-dihydroxybenzaldehyde (4.50 g, 32.6 mmol) and K2CO3 (6 equiv)
6244
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249

The Journal of Organic Chemistry
ARTICLE
2,4-Bis(4-methoxybenzyloxy)-1-iodo-6-[2-(trifluoroacetamido)et-
hyl)]benzene (9A). To a solution of 8A (3.26 g, 6.65 mmol) in
anhydrous DMF (12 mL) was added N-iodosuccinimide (NIS) (1.87 g,
8.31 mmol) all at once at room temperature. The mixture was stirred
at room temperature until TLC indicated the completion of the reaction
(18 h). The reaction mixture was then diluted with EtOAc (50 mL) and
filtered through a pad of Celite. The filtrate was washed with distilled
water (50 mL), and the aqueous layer was extracted with EtOAc
(50 mL ꢁ 2). The combined organic layer was washed with saturated
Na2SO3 (50 mL ꢁ 2) and brine and dried over anhydrous MgSO4. The
drying agent was removed by filtration and the solvent evaporated in
vacuo to afford the crude product as a yellow solid. Recrystallization of
the crude product from hexanes/EtOAc (4/1) afforded 9A as a white
solid (3.71 g, 91% yield): mp 134ꢀ135 °C; 1H NMR (300 MHz,
CDCl3) δ 3.07 (t, J = 6.9 Hz, 2H), 3.64 (q, J = 6.9 Hz, 2H), 3.82 (s, 6H),
4.93 (s, 2H), 5.03 (s, 2H), 6.34 (br, 1H), 6.45 (d, J = 2.7 Hz, 1H), 6.51
(d, J = 2.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 4H), 7.32 (d, J = 8.7 Hz, 2H), 7.40
(d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 39.9, 40.0, 55.4,
55.5, 70.3, 71.2, 82.9, 100.2, 108.6, 114.2, 114.3, 116.0 (q, J = 287 Hz),
128.5, 128.6, 128.9, 129.5, 142.6, 157.5 (q, J = 37 Hz), 158.6, 159.6,
159.9, 160.5; HRMS (ESI+) calcd for C26H25NO5F3NaI [M + Na]+
638.0627, found 638.0626 (Δ = ꢀ0.2 ppm).
on silica gel (hexanes/EtOAc = 7:3f1:1) afforded 11A as a white solid
(759 mg, 96% yield): mp 74ꢀ76 °C; 1H NMR (300 MHz, CDCl3) δ
1.73 (m, 1H), 2.83 (t, J = 6.9 Hz, 2H), 3.54 (q, J = 6.9 Hz, 2H), 3.81
(s, 3H), 3.82 (s, 3H), 3.92 (dd, J = 0.9, 7.2 Hz, 2H), 4.91 (s, 2H), 4.95
(s, 2H), 6.01 (dt, J = 7.2, 10.8 Hz, 1H), 6.31 (d, J = 10.8 Hz, 1H), 6.44 (d,
J = 2.4 Hz, 1H), 6.47 (br, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 8.7
Hz, 2H), 6.93 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7
Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 33.2, 40.0, 55.5, 55.6, 60.5,
70.2, 70.9, 100.0, 107.8, 114.3, 114.4, 116.0 (q, J = 287 Hz), 118.4, 124.8,
128.6, 128.9, 129.4, 129.5, 133.5, 138.3, 157.2, 157.4 (q, J = 38 Hz),
159.4, 159.8; HRMS (ESI+) calcd For C29H30NO6F3Na [M + Na]+
568.1923, found 568.1918 (Δ = ꢀ0.9 ppm).
1,3-Bis(4-methoxybenzyloxy)-6-(3-ethenyloxycarbonyloxyprop-1-
enyl)-[2-(trifluoroacetamido)ethyl]benzene (1A-a). To a solution of
11A (221 mg, 0.404 mmol) and pyridine (0.8 mL) in DCM (8 mL) was
added slowly vinyl chloroformate (0.050 mL, 0.48 mmol) in DCM
(2.4 mL) at 0 °C. After the mixture was stirred at 0 °C for 3 h, the
reaction was quenched by saturated CuSO4 (10 mL). The aqueous
layer was separated and extracted with Et2O (15 mL ꢁ 4). Combined
organic layer was washed with water and brine and dried over
anhydroud MgSO4. The drying agent was removed by filtration and
the solvent evaporated in vacuo to afford the crude product as an off-
white solid. Purification of the crude product by flash column
chromatography on silica gel (hexanes/EtOAc = 5:1f7:3) afforded
1A-a as a white solid (231 mg, 93% yield): mp 109ꢀ110 °C; 1H NMR
(300 MHz, CDCl3) δ 2.89 (t, J = 6.6 Hz, 2H), 3.54 (q, J = 6.6 Hz, 2H),
3.82 (s, 3H), 3.83 (s, 3H), 4.51 (dd, J = 1.2, 6.3 Hz, 2H), 4.55 (dd, J =
2.1, 6.3 Hz, 1H), 4.88 (dd, J = 2.1, 13.8 Hz, 1H), 4.91 (s, 2H), 4.94
(s, 2H), 5.90 (dt, J = 6.3, 11.1 Hz, 1H), 6.42 (d, J = 2.1 Hz, 1H), 6.46
(dt, J = 2.1, 11.1 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 6.68 (br, 1H), 6.89
(d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.88ꢀ6.95 (m, 1H), 7.30
(d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 32.9, 39.5, 55.5, 55.6, 66.9, 70.2, 70.6, 98.3, 99.8, 107.9,
114.2, 114.3, 116.0 (q, J = 287 Hz), 117.0, 127.0, 127.4, 128.8, 128.9,
129.3, 129.6, 138.5, 142.6, 153.1, 157.4, 157.5 (q, J = 38 Hz), 159.7,
159.8; HRMS (ESI+) calcd For C32H32NO8F3Na [M + Na]+
638.1978, found 638.1979 (Δ = 0.2 ppm).
1,3-Bis(4-methoxybenzyloxy)-6-(3-phenoxycarbonyloxyprop-1-en-
yl)-[2-(trifluoroacetamido)ethyl]benzene (1A-b). The carbonate 1A-b
was synthesized in the same manner as that described for 1A-a: White
solid (88% yield); mp 109ꢀ110 °C; 1H NMR (300 MHz, CDCl3): δ
2.88 (t, J = 6.6 Hz, 2H), 3.51 (q, J = 6.6 Hz, 2H), 4.60 (d, J = 6.6 Hz, 2H),
4.90 (s, 2H), 4.92 (s, 2H), 5.92 (dt, J = 6.6, 11.1 Hz, 1H), 6.39 (d, J = 2.1
Hz, 1H), 6.48 (d, J = 11.1 Hz, 1H), 6.55 (d, J = 2.1 Hz, 1H), 6.66 (br,
1H), 6.90 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 7.04ꢀ7.37 (m,
9H); 13C NMR (100 MHz, CDCl3) δ 32.9, 39.4, 55.5, 55.6, 67.0, 70.1,
70.6, 99.8, 107.9, 114.2, 114.3, 115.9 (q, J = 286 Hz), 117.1, 121.1, 126.3,
127.1, 127.4, 128.8, 128.9, 129.3, 129.5, 129.6, 138.5, 151.2, 154.1, 157.3,
157.4 (q, J = 37 Hz), 159.6, 159.7, 159.8; HRMS (ESI+) calcd For
C36H34NO8F3Na [M + Na]+ 688.2134, found 688.2131 (Δ = ꢀ0.4
ppm).
1,3-Bis(4-methoxybenzyloxy)-6-(3-hydroxyprop-1-ynyl)-5-[2-(trifl-
uoroacetamido)ethyl]benzene (10A). A mixture of 9A (1.52 g, 2.47
mmol), Pd(PPh3)2Cl2 (86.7 mg, 0.124 mmol), and CuI (47.0 mg, 0.247
mmol) was placed in a 50 mL round-bottomed flask. After purging the
flask with nitrogen, Et2NH (30 mL) was added to the mixture, and the
solution was stirred for 20 min at 30 °C to dissolve 9A. Propargyl alcohol
(0.29 mL, 4.94 mmol) was added to this mixture via a syringe at the same
temperature. The reaction mixture was heated to reflux until TLC
indicated the completion of the reaction (48 h). Then, saturated NH4Cl
solution (25 mL) was added to quench the reaction. The aqueous layer
was extracted with EtOAc (30 mL ꢁ 3). The combined organic layer was
washed with brine and dried over anhydrous MgSO4. The drying agent
was removed by filtration and the solvent evaporated in vacuo to afford
the crude product as brown oil. Purification of the crude product by
flash column chromatography on silica gel (hexanes/EtOAc = 5:1f1:1)
afforded 10A as an off-white solid (851 mg, 63% yield): mp 123ꢀ
124 °C; 1H NMR (300 MHz, CDCl3) δ 2.44 (t, J = 6.3 Hz, 1H), 3.03 (t, J
= 7.2 Hz, 2H), 3.64 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 4.53
(d, J = 6.3 Hz, 2H), 4.93 (s, 2H), 4.93 (s, 2H), 5.05 (s, 2H), 6.42 (d, J =
2.1 Hz, 1H), 6.45 (d, J = 2.1 Hz, 1H), 6.63 (br, 1H), 6.90 (d, J = 8.7 Hz,
2H), 6.92 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz,
2H); 13C NMR (100 MHz, CDCl3) δ 34.5, 40.7, 52.0, 55.5, 55.6, 70.2,
70.7, 80.2, 95.2, 99.8, 105.6, 107.9, 114.2, 114.3, 116.0 (q, J = 286 Hz),
128.5, 128.8, 128.9, 129.5, 142.9, 157.6 (q, J = 37 Hz), 159.6, 159.9,
160.1, 161.1; HRMS (ESI+) calcd For C29H29NO6F3 [M + H]+
544.1947, found 544.1947 (Δ = 0.0 ppm).
1,3-Bis(4-methoxybenzyloxy)-6-[(Z)-3-hydroxyprop-1-enyl]5-[2-
(trifluoroacetamido)ethyl]benzene (11A). P2ꢀNi catalyst was gener-
ated in situ by adding NaBH4 (85.9 mg, 1.70 mmol) to a suspension of
Ni(OAc)2 (271.3 mg, 0.893 mmol) in EtOH (7 mL) at room tempera-
ture under nitrogen with stirring. After 30 min, neat ethylenediamine
(140 μL, 2.05 mmol) was added to the reaction mixture via a syringe.
After the catalyst solution was stirred for another 10 min, 10A (790 mg,
1.45 mmol) in EtOH (50 mL) was added. The nitrogen atmosphere was
then replaced by hydrogen (1 atm). The reaction mixture was stirred
until TLC indicated the completion of the reaction (18 h). The reaction
was quenched by addition of water (20 mL), and the aqueous layer was
extracted with EtOAc (25 mL ꢁ 3). The combined organic layer was
washed with saturated NaHCO3 solution and brine and dried over
anhydrous MgSO4. The drying agent was removed by filtration and the
solvent evaporated in vacuo to afford the crude product as an off-white
solid. Purification of the crude product by flash column chromatography
1,3-Bis(4-methoxybenzyloxy)-6-[3-(2,6-dimethylphen-1-oxy)car-
bonyloxyprop-1-enyl]-[2-(trifluoroacetamido)ethyl]benzene (1A-c).
The carbonate 1A-c was synthesized in the same manner as that
1
described for 1A-a: Colorless oil (92% yield); H NMR (400 MHz,
CDCl3) δ 2.12 (s, 6H), 2.88 (t, J = 6.8 Hz, 2H), 3.49 (q, J = 6.8 Hz, 2H),
3.82 (s, 6H), 4.57 (dd, J = 1.2 and 6.8 Hz, 2H), 4.90 (s, 2H), 4.92 (s, 2H),
5.91 (dt, J = 6.8, 10.8 Hz, 1H), 6.39 (d, J = 2.0 Hz, 1H), 6.48 (d, J = 10.8
Hz, 1H), 6.55 (d, J = 2.0 Hz, 1H), 6.67 (t, J = 6.8 Hz, 1H), 6.90 (d, J = 8.4
Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.02 (s, 3H), 7.29 (d, J = 8.4 Hz, 2H),
7.33 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 15.8, 15.9,
32.7, 39.1, 55.3, 66.8, 69.9, 70.3, 99.6, 107.7, 113.9, 114.0, 115.7 (q, J =
282 Hz), 116.8, 126.1, 126.9, 127.2, 128.5, 128.6, 129.1, 129.3, 129.9,
138.3, 148.2, 153.3, 157.0, 157.3 (q, J = 36 Hz), 159.4, 159.5, 159.6;
6245
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249

The Journal of Organic Chemistry
ARTICLE
HRMS (ESI+) calcd For C38H38NO8F3Na [M + Na]+ 716.2447, found
716.2451 (Δ = 0.6 ppm).
3.52 (q, J = 6.6 Hz, 2H), 4.60 (d, J = 6.6 Hz, 2H), 4.99 (s, 4H), 5.95 (dt,
J = 6.3, 11.1 Hz, 1H), 6.40 (d, J = 2.1 Hz, 1H), 6.50 (d, J = 11.1 Hz, 1H),
6.56 (d, J = 2.1 Hz, 1H), 6.67 (br, 1H), 7.04ꢀ7.25 (m, 5H), 7.32ꢀ7.44
(m, 10H); 13C NMR (100 MHz, CDCl3) δ 32.9, 39.4, 67.0, 70.4, 70.8,
99.8, 108.0, 116.3 (q, J = 287 Hz), 117.2, 121.1, 126.3, 127.1, 127.4,
127.5, 127.8, 128.2, 128.3, 128.8, 128.9, 129.6, 136.8, 138.6, 151.1, 154.1,
157.2, 157.5 (q, J = 37 Hz), 159.6; HRMS (ESI+) calcd For C34H30NO6F3-
Na [M + Na]+ 628.1923, found 628.1917 (Δ = ꢀ1.0 ppm).
In the same manner as that described for 8Aꢀ1Aaꢀc, 8Bꢀ1Ba,b
were prepared. Characterization data are shown below:
1,3-Dibenzyloxy-5-[(E)-2-nitroethenyl]benzene. Yellow solid; 65%
yield; mp 110ꢀ112 °C; 1H NMR (300 MHz, CDC13) δ 5.06 (s, 4H),
6.75 (br, 3H), 7.35ꢀ7.42 (m, 10H), 7.50 (d, J = 13.5 Hz, 1H), 7.90 (d,
J = 13.5 Hz, 1H). 13C NMR (100 MHz, CDC13) δ 70.5, 106.0, 108.4,
127.7, 128.4, 128.9, 132.0, 136.4, 137.7, 139.2, 160.6; HRMS (ESI+)
calcd For C22H20NO4 [M + H]+ 362.1392, found 362.1396 (Δ = 1.1
ppm).
General Procedure for Intramolecular Asymmetric Allylic
Amination. Typical procedure is described for the reaction of 1A-a to
afford (+)-(S)-6,8-bis-(4-methoxybenzyloxy)-1-ethenyl-2-trifluoroace-
tyl-3,4-dihydro-1H-isoquinoline, (+)-(S)-2A: A solution of BOP ligand
(R)-L2a (28.5mg, 0.0319 mmol) and Pd2(dba)3 (14.8mg, 0.0159 mmol)
in DMF (1.3 mL) was added to a reaction tube with a stirring bar under
nitrogen. The solution was stirred at room temperature until the color of
the solution turned to light yellow from purple. Then, 1A-a (400 mg,
0.638 mmol) was added to the catalyst solution via a syringe. The mixture
was stirred at room temperature until TLC indicated completion of the
reaction. The resulting solution was diluted with water (20 mL). The
aqueous layer was separated and extracted with Et2O (25 mL ꢁ 3). The
combined organic layer was washed with water (20 mL ꢁ 5) and brine
and dried over anhydrous MgSO4. The drying agent was removed by
filtration and the solvent evaporated in vacuo to afford the crude product
as orange oil. The conversion of the reaction was checked by 1H NMR,
which indicated over 95% conversion and 100% product selectivity.
Purification of the crude product by flash column chromatography on
silicagel(hexanes/EtOAc= 10:1f5:1) afforded(+)-(S)-2Aasacolorless
oil (285 mg, 85% yield). The pure product was then subjected to chiral
HPLC analysis, using a Chiralcel AD-RH column (CH3CN/H2O = 50/
50, 0.7 mL/min), which indicated that the enantiopurity of the product
(+)-(S)-2A was 94.0% ee. The S configuration was tentatively assigned by
comparison of the sign of the optical rotation of (+)-(S)-2 with that of
structurally close (+)-(S)-1-ethenyl-2-trifluoroacetyl-6,7-dimethoxy-1,2,3,-
4-tetrahydroisoquinoline and further confirmed by converting (+)-(S)-2A
to literature known (ꢀ)-(S,S)-128 (see below).
1,3-Dibenzyloxy-5-[2-(N-trifluoroacetamido)ethyl]benzene (8B).
White crystals; 55% yield for two steps from 1,3-dibenzyloxy-5-[(E)-
nitroethenyl]benzene: mp 85ꢀ87 °C; 1H NMR (400 MHz, CDCl3) δ
2.82 (t, J = 6.8 Hz, 2H), 3.61 (q, J = 6.8 Hz, 2H), 5.03 (s, 4H), 6.26 (br,
1H), 6.43 (d, J = 2.4 Hz, 2H), 6.54 (t, J = 2.4 Hz, 1H), 7.32ꢀ7.43 (m,
10H); 13C NMR (100 MHz, CDCl3) δ 35.4, 40.9, 70.3, 100.8, 108.1,
116.0 (q, J = 286 Hz), 127.7, 128.3, 128.8, 136.9, 140.1, 157.3 (q, J = 36
Hz), 160.6; HRMS (ESI+) calcd For C24H23NO3F3 [M + H]+
430.1630, found 430.1629 (Δ = ꢀ0.2 ppm).
2,4-Dibenzyloxy-1-iodo-6-[2-(trifluoroacetamido)ethyl)]benzene
1
(9B). White solid; 92% yield; mp 139ꢀ141 °C; H NMR (300 MHz,
CDCl3) δ 3.08 (t, J = 6.9 Hz, 2H), 3.61 (q, J = 6.9 Hz, 2H), 5.00 (s, 2H),
5.10 (s, 2H), 6.37 (br, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.52 (d, J = 2.4 Hz,
1H), 7.31ꢀ7.50 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 39.9, 40.0,
70.6, 71.3, 82.9, 100.1, 108.6, 116.0 (q, J = 286 Hz), 127.3, 127.7, 128.2,
128.5, 128.8, 128.9, 136.4, 136.5, 142.7, 157.5 (q, J = 36 Hz), 158.5,
160.5. HRMS (ESI+) calcd For C24H21NO3F3NaI [M + Na]+ 578.0416,
found 578.0415 (Δ = ꢀ0.2 ppm).
1,3-Dibenzyloxy-6-(3-hydroxyprop-1-ynyl)-5-[2-(trifluoroacetam-
ido)ethyl]benzene (10B). Off-white solid; 55% yield; mp 121ꢀ123 °C;
1H NMR (300 MHz, CDCl3) δ 2.50 (t, J = 6.0 Hz, 1H), 3.03 (t, J = 7.2
Hz, 2H), 3.64 (q, J = 7.2 Hz, 2H), 5.00 (s, 2H), 5.12 (s, 2H), 6.43 (d, J =
2.4 Hz, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.68 (br, 1H), 7.31ꢀ7.45 (m,
10H); 13C NMR (100 MHz, CDCl3) δ 34.5, 40.7, 51.9, 70.4, 70.8, 80.1,
95.3, 99.8, 105.7, 107.9, 116.0 (q, J = 287 Hz), 127.1, 127.8, 128.1, 128.4,
128.8, 128.9, 136.5, 136.8, 142.9, 157.7 (q, J = 37 Hz), 160.0, 161.0.
HRMS (ESI+) calcd For C27H24NO4F3Na [M + Na]+ 506.1555, found
506.1551 (Δ = ꢀ0.8 ppm).
21
1
(+)-(S)-2A: [R]D +66.0 (c 1.5, CH2Cl2); H NMR (300 MHz,
CDCl3) (a mixture of two rotamers) δ 2.76ꢀ2.82 (m, 1H), 2.88ꢀ3.05
(m, 1H), [3.30ꢀ3.40 (m, 0.67H), 3.58ꢀ3.66 (m, 0.33H)], 3.81 (s, 3H),
3.82 (s, 3H), [3.92ꢀ4.00 (m, 0.33H), 4.35ꢀ4.42 (m, 0.33H)], 4.93ꢀ
4.99 (m, 5H), 5.19ꢀ5.24 (m, 1H), 5.87ꢀ6.00 (m, 1H), [5.80ꢀ5.84 (m,
0.67H), 6.20ꢀ6.24 (m, 0.67H)], [6.35 (d, J = 2.1 Hz, 0.67H), 6.38 (d, J =
2.1 Hz, 0.33H)], 6.48 (d, J = 2.1 Hz, 1H), 6.89 (d, J = 7.5 Hz, 2H), 6.92
(d, J = 7.5 Hz, 2H), 7.31 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 7.5 Hz, 2H); 13C
NMR (100 MHz, CDCl3) (a mixture of two rotamers) (major) δ 29.5,
39.9, 51.6, 55.5, 70.0 70.1, 99.1, 105.6, 114.2, 114.3, 115.4, 116.7, 116.8
(q, J = 287 Hz), 128.8, 128.9, 129.0, 129.4, 135.1, 135.4, 155.9 (q, J = 36
Hz), 156.0, 159.1, 159.6, 159.8; (minor) δ 28.0, 38.0, 53.4, 55.5, 70.0,
70.1, 99.0, 105.9, 114.2, 114.3, 115.4, 116.8 (q, J = 287 Hz), 117.1, 128.8,
128.9, 129.0, 129.5, 135.8, 136.2, 155.8 (q, J = 36 Hz), 156.6, 159.4,
159.6, 159.8; HRMS (ESI+) calcd For C29H28NO5F3Na [M + Na]+
550.1817, found 550.1818 (Δ = 0.2 ppm).
1,3-Dibenzyloxy-6-[(Z)-3-hydroxyprop-1-enyl]-5-[2-(trifluoroac-
etamido)ethyl]benzene (11B). White solid; 98% yield; mp 138ꢀ
140 °C; 1H NMR (300 MHz, CDCl3) δ 2.84 (t, J = 6.9 Hz, 2H), 3.55
(q, J = 6.9 Hz, 2H), 3.94 (d, J = 7.2 Hz, 2H), 5.00 (s, 2H), 5.02 (s, 2H),
6.03 (dt, J = 7.2, 11.1 Hz, 1H), 6.34 (d, J = 11.1 Hz, 1H), 6.44 (d, J = 2.4
Hz, 1H), 6.50 (br, 1H), 6.56 (d, J = 2.4 Hz, 1H), 7.32ꢀ7.42 (m, 10H);
13C NMR (100 MHz, CDCl3) δ 33.1, 39.9, 60.4, 70.4, 71.0, 99.9, 107.8,
116.0 (q, J = 286 Hz), 118.4, 124.8, 127.6, 127.8, 128.3, 128.4, 128.8,
128.9, 133.5, 136.7, 136.8, 138.3, 157.2, 157.5 (q, J = 36 Hz), 159.3;
HRMS (ESI+) calcd For C27H26NO4F3Na [M + Na]+ 508.1712, found
508.1714 (Δ = 0.4 ppm).
1,3-Dibenzyloxy-6-(3-ethenyloxycarbonyloxyprop-1-enyl)-[2-(tri-
fluoroacetamido)ethyl]benzene (1B-a). White sticky solid; 89% yield;
1H NMR (300 MHz, CDCl3) δ 2.89 (t, J = 6.9 Hz, 2H), 3.55 (q, J = 6.9
Hz, 2H), 4.55 (m, 3H), 4.88 (dd, J = 2.1, 13.8 Hz, 2H), 4.98 (s, 2H), 5.01
(s, 2H), 5.90 (dt, J = 7.2, 11.1 Hz, 1H), 6.44 (d, J = 2.1 Hz, 1H), 6.48 (d,
J = 11.1 Hz, 1H), 6.56 (d, J = 2.1 Hz, 1H), 6.73 (br, 1H), 6.95 (dd, J = 7.2,
13.8 Hz, 1H), 7.32ꢀ7.44 (m, 10H); 13C NMR (125 MHz, CDCl3) δ
32.7, 39.3, 66.6, 70.2, 70.6, 98.1, 99.6, 107.8, 115.8 (q, J = 286 Hz), 117.0,
126.9, 127.3, 127.6, 128.0, 128.1, 128.6, 136.5, 136.6, 138.4, 142.4, 152.9,
157.1, 157.5 (q, J = 37 Hz), 159.4; HRMS (ESI+) calcd For C30H28-
NO6F3Na [M + Na]+ 578.1766, found 578.1762 (Δ = ꢀ0.7 ppm).
1,3-Dibenzyloxy-6-(3-phenoxycarbonyloxyprop-1-enyl)-[2-(tri-
fluoroacetamido)ethyl]benzene (1B-b). White solid; 91% yield; mp
112ꢀ114 °C. 1H NMR (300 MHz, CDCl3) δ 2.89 (t, J = 6.6 Hz, 2H),
(ꢀ)-(R)-6,8-Bis(4-methoxybenzyloxy)-1-ethenyl-2-trifluoroacetyl-
3,4-dihydro-1H-isoquinoline,(ꢀ)-(R)-2A. The compound (ꢀ)-(R)-2A
was obtained in the same manner as that described for the synthesis of
(+)-(S)-2A except for using (S)-L2a as the chiral ligand: 85% yield;
96.1% ee. All characterization data were identical to those of (+)-(S)-2A
21
except for [R]D ꢀ67.1 (c 1.5, CH2Cl2). HRMS (ESI+) calcd For
C29H29NO5F3 [M + H]+ 528.1998, found 528.1996 (Δ = ꢀ0.4 ppm).
(ꢀ)-(R)-6,8-Dibenzyloxy-1-ethenyl-2-trifluoroacetyl-3,4-dihydro-1H-
isoquinoline [(ꢀ)-(R)-2B]. Colorless oil; 83% yield; 75% ee; 1H NMR
(400 MHz, CDCl3) (a mixture of two rotamers) δ 2.73ꢀ2.85
(m, 1H), 2.90ꢀ3.06 (m, 1H), [3.32ꢀ3.42 (m, 0.36H), 3.58ꢀ3.69
(m, 0.64H)], [3.90ꢀ4.00 (m, 0.64H), 4.35ꢀ4.44 (m, 0.36H)], 4.93ꢀ
5.10 (m, 5H), 5.19ꢀ5.27 (m, 1H), 5.99 (ddd, J = 4.4, 10.4, 17.2 Hz, 1H),
6246
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249

The Journal of Organic Chemistry
ARTICLE
[5.85ꢀ5.90 (m, 0.36H), 6.25ꢀ6.30 (m, 0.64H)], [6.37 (d, J = 2.0 Hz,
0.64H), 6.39 (d, J = 2.0 Hz, 0.36H)], 6.48 (d, J = 2.0 Hz, 1H), 7.35ꢀ7.42
(m, 10H); 13C NMR (100 MHz, CDCl3) (a mixture of two rotamers)
(major) δ 29.5, 39.8, 51.6, 70.3 70.5, 99.1, 105.8, 115.6, 116.8 (q, J = 287
Hz), 116.9, 117.0, 117.2, 127.3, 128.3, 128.8, 135.1, 135.9, 136.8, 137.0,
155.8 (q, J = 36 Hz), 156.6, 159.1; (minor) δ 28.0, 38.0, 53.4, 70.2, 70.4,
99.0, 106.1, 115.5, 116.7, 116.8 (q, J = 287 Hz), 117.1, 117.3, 127.1,
127.7, 128.1, 135.0, 135.8, 136.3, 136.9, 155.9, 156.2 (q, J = 36 Hz),
159.1; HRMS (ESI+) calcd For C27H25NO3F3 [M + H]+ 468.1787,
found 468.1786 (Δ = ꢀ0.2 ppm).
4.65ꢀ4.70 (m, 1H), 4.89ꢀ5.08 (m, 5H), 5.39 (d, J = 5.7 Hz, 1H),
5.95ꢀ6.08 (m, 2H), 6.39 (d, J = 2.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H),
6.90ꢀ6.95 (m, 4H), 7.26ꢀ7.40 (m, 8H), 7.62 (d, J = 6.6 Hz, 2H), 7.76
(d, J = 6.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 30.1, 40.4, 47.4,
51.5, 52.8, 55.5, 55.6, 67.4, 70.1, 70.2, 99.3, 106.1, 114.3, 114.4, 114.5,
115.8, 120.2, 125.4, 127.3, 127.9, 128.4, 128.5, 128.9, 129.0, 129.1, 129.5,
129.9, 137.9, 141.5, 144.1, 144.2, 156.4, 158.9, 159.7, 159.8, 167.5;
HRMS (ESI+) calcd For C44H41N2O7 [M + H]+ 709.2914, found
709.2906 (Δ = ꢀ1.1 ppm).
(ꢀ)-(3S,11bS)-3-Amino-9,11-bis(4-methoxybenzyloxy)-2,3,6,7-tet-
rahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one, (ꢀ)-(S,S)-12. To a
stirred solution of (ꢀ)-(S,S)-6 (25 mg, 0.036 mmol) in DCM (4.0 mL)
was added Et2NH (37 μL, 0.36 mmol) at room temperature, and the
mixture was stirred at room temperature for 10 h. Solvents were
evaporated under reduced pressure to give the crude product as brown
(+)-(S)-6,8-Bis(4-methoxybenzyloxy)-3,4-dihydro-1-ethenyl-1H-
isoquinoline, (+)-(S)-3. To a stirred solution of (+)-(S)-2A (280 mg,
0.531 mmol, 94.0% ee) in EtOH (5 mL) was added slowly 2 M NaOH
solution (1 mL) at room temperature, and the mixture was stirred at
room temperature for 16 h. Then, EtOH was evaporated under reduced
pressure, and the resulting oil was diluted with Et2O (20 mL) and water
(20 mL). The aqueous layer was separated and extracted with Et2O
(20 mL ꢁ 3). The combined organic layer was washed with water and
brine and dried over anhydrous Na2SO4. The drying agent was removed
by filtration and the solvent evaporated in vacuo to afford (+)-(S)-3 (225
1
oil. H NMR analysis of the crude product indicated a quantitative
formation of the desired product, (ꢀ)-(S,S)-12. Purification of the crude
product by flash column chromatography on silica gel (CH2Cl2/(2 M
NH3 in MeOH) = 99:1f98:2) afforded (ꢀ)-(S,S)-12 as a light yellow
21
oil (13 mg, 72% yield): [R]D ꢀ197.8 (c 0.45, CHCl3); 1H NMR (400
21
MHz, CD3OD) δ 2.60ꢀ2.80 (m, 3H), 3.78 (s, 6H), 3.84ꢀ3.87 (m, 1H),
4.77ꢀ4.80 (m, 1H), 4.91ꢀ5.04 (m, 4H), 5.35ꢀ5.37 (m, 1H), 5.81 (ddd,
J = 2.0, 3.2, 9.6 Hz, 1H), 6.18 (ddd, J = 2.0, 3.2, 9.6 Hz, 1H), 6.41 (d, J =
2.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.90 (d, J = 8.4 Hz, 4H), 7.31 (d, J =
8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CD3OD) δ
29.6, 40.0, 53.8, 54.5, 69.7, 69.9, 99.1, 106.5, 113.7, 113.8, 115.9, 127.6,
128.9, 129.1, 129.3, 137.6, 156.4, 158.9, 159.8, 159.9, 171.3; HRMS
(ESI+) calcd For C29H31N2O5 [M + H]+ 487.2233, found 487.2220
(Δ = ꢀ2.7 ppm).
mg, 98% yield) as a light yellow solid: mp 83ꢀ85 °C; [R]D +25.8
(c 0.62, CHCl3); 1H NMR (400 MHz, CDCl3) δ 2.61ꢀ2.66 (m, 1H),
2.78ꢀ2.90 (m, 1H), 2.97ꢀ3.04 (m, 1H), 3.09ꢀ3.20 (m, 1H), 3.80
(s, 3H), 3.81 (s, 3H), 4.70 (d, J = 5.2 Hz, 1H), 4.86ꢀ4.95 (m, 5H), 5.11
(dt, J = 10.0, 1.2 Hz, 1H), 6.01ꢀ6.12 (m, 1H), 6.35 (d, J = 2.0 Hz, 1H),
6.42 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H),
7.28 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 29.4, 38.1, 52.6, 55.5, 69.8, 70.0, 98.5, 106.1, 114.1, 114.2,
116.2, 118.1, 128.9, 129.2, 129.3, 129.5, 136.9, 139.0, 156.8, 158.5, 159.5,
159.7; HRMS (ESI+) calcd For C27H30NO4 [M + H]+ 432.2175, found
432.2163 (Δ = ꢀ2.8 ppm).
(ꢀ)-(3S,11bS)-3-Amino-9,11-dihydroxy-2,3,6,7-tetrahydro-1H-
pyrido[2,1-a]isoquinolin-4(11bH)-one, (ꢀ)-(S,S)-7. To (ꢀ)-(S,S)-6
(40 mg, 0.055 mmol) and 10% Pd/C (12 mg, 0.011 mmol) placed in
a 10 mL round-bottomed flask were added MeOH (1.5 mL) and THF
(1.5 mL) at room temperature. The nitrogen atmosphere was then
replaced with hydrogen (1 atm), and the reaction mixture was stirred for
48 h. The reaction mixture was filtered through Celite and washed with
MeOH (30 mL), and the filtrate was concentrated under reduced
pressure. Purification of the residue by flash column chromatography
on silica gel [CH2Cl2/(2 M NH3 in MeOH) = 30:1f10:1) afforded
(ꢀ)-(R)-6,8-Bis(4-methoxybenzyloxy)-3,4-dihydro-1-ethenyl-1H-
isoquinoline, (ꢀ)-(R)-3. The compound (ꢀ)-(R)-3 was obtained in
98% yield in the same manner as that described for the synthesis of
(+)-(S)-3. All characterization data were identical to those of (+)-(S)-3
21
except for [R]D ꢀ27.0 (c 0.62, CHCl3). HRMS (ESI+) calcd For
C27H30NO4 [M + H]+ 432.2175, found 432.2172 (Δ = ꢀ0.7 ppm).
(ꢀ)-(3S,11bS)-9,11-Bis(4-methoxybenzyloxy)-3-(9H-fluoren-9-yl)
methoxycarbonylamino-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquin-
olin-4(11bH)-one, (ꢀ)-(S,S)- 6. To a stirred solution of (+)-(S)-3 (94%
ee) (58.3 mg, 0.135 mmol) and Et3N (18.8 μL, 0.135 mmol) in distilled
DCM (0.8 mL) was added (S)-N-Fmoc-vinylglycinyl chloride (4) (50.8
mg, 0.149 mmol) in DCM (2 mL) at 0 °C under nitrogen. The mixture
was then stirred at room temperature for 16 h, and the reaction was
quenched by adding Et2O (10 mL) and water (10 mL). The aqueous
layer was separated and extracted with Et2O (15 mL ꢁ 2). The
combined organic layer was washed with 1 M hydrochloric acid, water,
and brine and dried over anhydrous MgSO4. The drying agent was
removed by filtration and the solvent evaporated in vacuo to afford the
crude product as yellow oil. Purification of the crude product by flash
column chromatography on silica gel (hexanes/EtOAc = 5:1f2:1)
afforded (+)-(S,S)-5 as a colorless oil (83 mg, 84% yield): cis/trans >
20/1 by 1H NMR); [R]D21 +61.0 (c 1.0, CH2Cl2); HRMS (ESI+) calcd
For C46H45N2O7 [M + H]+ 737.3227, found 737.3232 (Δ = 0.7 ppm).
To a stirred solution of (+)-(S,S)-5 (63 mg, 0.086 mmol) in DCM
(3.5 mL) was added the second-generation Grubbs catalyst (7.4 mg, 10
mol %) under nitrogen, and the mixture was heated to reflux for 16 h.
The reaction mixture was cooled to room temperature, and DCM was
evaporated under reduced pressure to give the crude product as a brown
solid. Purification of the crude product by flash column chromatography
on silica gel (hexanes/EtOAc = 4:1f1:1) afforded (ꢀ)-(S,S)-6 as a
20
(ꢀ)-(S,S)-7 as a white paste (13 mg, 91% yield): [R]D ꢀ252.3 (c 0.35,
MeOH); 1H NMR (300 MHz, CD3OD) δ 1.28ꢀ1.52 (m, 3H),
2.22ꢀ2.31 (m, 1H), 2.47ꢀ2.74 (m, 4H), 3.58 (t, J = 8.1 Hz, 1H),
4.62ꢀ4.66 (m, 1H), 4.79 (dd, J = 3.6 and 14.4 Hz, 2H), 6.11 (d, J = 2.4
Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ
28.1, 29.1, 30.6, 40.5, 50.8, 52.1, 102.1, 107.5, 115.5, 138.6, 156.4, 158.1,
175.2; HRMS (ESI+) calcd For C13H17N2O3 [M + H]+ 249.1239,
found 249.1232 (Δ = ꢀ2.8 ppm).
(ꢀ)-(3S,11bS)-3-Amino-9,11-dihydroxy-2,3,6,7-tetrahydro-1H-py-
rido[2,1-a]isoquinolin-4(11bH)-one Hydrobromide, (ꢀ)-(S,S)-7 HBr.
3
To (ꢀ)-(S,S)-7 (5.5 mg, 0.022 mmol) in a 5 mL round-bottomed flask
were added 16% hydrobromic acid (0.6 mL) and MeOH (2.4 mL) at
room temperature, and the mixture was stirred for 4 h. All volatiles were
removed under high vacuum to give (ꢀ)-(S,S)-7 HBr as a light yellow
3
20
paste (7.3 mg, 100% yield): [R]D ꢀ138.9 (c 0.73, MeOH); 1H NMR
(300 MHz, D2O) δ 1.41ꢀ1.56 (m, 1H), 1.67ꢀ1.83 (m, 1H), 2.35ꢀ2.53
(m, 2H), 2.66ꢀ2.86 (m, 3H), 4.21 (dt, J = 7.8, 11.7 Hz, 1H), 4.44ꢀ4.51
(m, 1H), 4.82ꢀ4.84 (m, 1H), 6.25ꢀ6.41 (m, 2H); 13C NMR (125
MHz, D2O): δ 22.3, 27.0, 28.4, 39.5, 48.8, 49.8, 101.3, 107.1, 114.4,
138.3, 153.9, 155.4, 168.3; LRMS (ESI-) calcd For C13H17N2O3Br [M ꢀ
H]ꢀ 327.0, found 327; HRMS (ESI+) calcd For C13H17N2O3 [M ꢀ Br]+
249.1239, found 249.1237 (Δ = ꢀ0.8 ppm).
21
white solid (48 mg, 80% yield): mp 125ꢀ127 °C (decomp); [R]D
(ꢀ)-(3S,11bS)-3-(tert-Butoxycarbonylamino)-9,11-dihydroxy-2,3,-
6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one, (ꢀ)-(S,S)-7-
Boc.6 To a stirred solution of (ꢀ)-(S,S)-7 (5.8 mg, 0.023 mmol) in
ꢀ132 (c 0.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 2.63ꢀ2.85 (m,
3H), 3.83 (s, 6H), 4.26 (t, J = 7.2 Hz, 1H), 4.41 (d, J = 7.2 Hz, 2H),
6247
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249

The Journal of Organic Chemistry
ARTICLE
MeOH (0.5 mL) was added Boc2O (7.4 mg, 0.030 mmol) under
nitrogen, and the mixture was stirred at room temperature for 20 h.
The solvent was evaporated under reduced pressure to give the crude
product as a light yellow oil. Purification of the crude product by flash
column chromatography on silica gel (hexanes/EtOAc = 4:1f1:1)
40 h. The reaction mixture was cooled to room temperature, and toluene
was evaporated under reduced pressure to give the crude product as a
brown solid. The 1H NMR analysis of the crude product indicated that
(S,R)-6 and (R,R)-6 were formed in 3:1 ratio. Purification of the crude
product by flash column chromatography on silica gel (hexanes/EtOAc =
2:1f1:1) afforded (S,R)-6 as an off-white solid (20 mg, 51% yield).
Because (+)-(S,R)-6 was found to be rather unstable and prone to
decompose, the purified compound was immediately used for the next
step without further characterization.
(+)-(3S,11bR)-3-(tert-Butoxycarbonylamino)-9,11-dihydroxy-2,3,-
6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one, (+)-(S,R)-7-
Boc. To (+)-(S,R)-6 (20 mg, 0.028 mmol), thus obtained, and 10% Pd/
C (6.0 mg, 0.0056 mmol) placed in a 5 mL round-bottomed flask were
added MeOH (0.8 mL) and THF (0.8 mL) at room temperature. The
nitrogen atmosphere was then replaced with hydrogen (1 atm). The
mixture was stirred at room temperature for 48 h, and Boc2O (9.0 mg,
0.036 mmol) in MeOH (0.2 mL) was added without removing Pd/C.
The reaction mixture was stirred at room temperature for 20 h. The solid
was then filtered, and the filtrate was evaporated under reduced pressure
to give the crude product as a light yellow oil. Purification of the crude
product by flash column chromatography on silica gel (hexanes/
EtOAc = 2:1f1:1) afforded (+)-(S,R)-7-Boc as colorless oil (6.1 mg,
63% yield for two steps): [R]D20 +184.3 (c 0.51, MeOH); 1H NMR (300
MHz, CD3OD) δ 1.34ꢀ1.51 (m, 1H), 1.45 (s, 9H), 1.91ꢀ2.12 (m, 2H),
2.49ꢀ2.70 (m, 3H), 3.05ꢀ3.09 (m, 1H), 3.92ꢀ4.05 (m, 1H),
4.73ꢀ4.79 (m, 2H), 6.08 (d, J = 2.1 Hz, 1H), 6.16 (d, J = 2.1 Hz,
1H). 1H NMR data are in agreement with the literature values. Gurjar
et al.6 reported the specific rotation of this compound to be [R]D +122
(c 1.4, MeOH). However, the value was [R]D20 +184.3 (c 0.51, MeOH)
inour hands, as shownabove. Itappears thatthe reported valueiseither an
error or their compound is enantiomerically not pure.
22
afforded (ꢀ)-(S,S)-7-Boc as colorless oil (6.4 mg, 79% yield): [R]D
ꢀ176.6 (c 0.64, MeOH); 1H NMR (400 MHz, CD3OD) δ 1.28ꢀ1.40
(m, 1H), 1.42 (s, 9H), 1.46ꢀ1.55 (m, 1H), 2.22ꢀ2.37 (m, 1H),
2.48ꢀ2.52 (m, 1H), 2.59ꢀ2.75 (m, 3H), 4.32 (t, J = 8.4 Hz, 1H),
4.59ꢀ4.62 (m, 1H), 4.80ꢀ4.81 (m, 1H), 6.11 (d, J = 2.4 Hz, 1H), 6.18
(d, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 26.3, 28.7, 29.2,
30.3, 40.4, 50.8, 51.2, 80.5, 102.0, 107.3, 115.1, 138.4, 156.3, 158.0, 158.2,
172.4. All data are in agreement with the literature values except for the
specific rotation. Gurjar et al.6 reported the specific rotation of this
compound to be [R]D ꢀ49.1 (c 0.90, MeOH). However, the value was
22
[R]D ꢀ176.6 (c 0.64, MeOH) in our hands, as shown above. It appears
that the reported value is either an error or their compound is enan-
tiomerically not pure.
(ꢀ)-(3S,11bS)-3-(tert-Butoxycarbonylamino)-9,11-bis(benzyloxy)-
2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one, (ꢀ)-
(S,S)-13. To a stirred solution of (S,S)-7-Boc (6.4 mg, 0.019 mmol),
tetrabutylammonium iodide (TBAI) (0.2 mg, 0.0005 mmol), and
Cs2CO3 (18 mg, 0.057 mmol) in DMF (0.5 mL) was added benzyl
bromide (0.026 mL, 0.042 mmol) at 0 °C under nitrogen, and the
mixture was stirred under the same temperature for 3 h. The reaction
was quenched with water (5 mL) and diluted with EtOAc (5 mL). The
aqueous layer was separated and extracted with EtOAc (5 mL ꢁ 2). The
combined organic layer was washed with water and brine and dried over
anhydrous Na2SO4. The drying agent was removed by filtration and the
solvent evaporated in vacuo to afford the crude product as a light yellow
oil. Purification of the crude product by flash column chromatography
on silica gel (hexanes/EtOAc = 10:1f4:1) afforded (ꢀ)-(S,S)-13 as a
(+)-(3S,11bR)-3-(tert-Butoxycarbonylamino)-9,11-bis(benzyloxy)-
2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-4(11bH)-one, (+)-(S,R)-
13. Compound (+)-(S,R)-13 was obtained in 78% yield as colorless oil
in the same manner as that described for the synthesis of (ꢀ)-(S,S)-13:
[R]D19 +177.2 (c 0.57, CHCl3) [lit.8 [R]D24 +182.2 (c 1.33, CHCl3)];
1H NMR (400 MHz, CDCl3): δ 1.40ꢀ1.53 (m, 1H), 1.45 (s, 9H),
1.69ꢀ1.75 (m, 1H), 2.41ꢀ2.49 (m, 1H), 2.57ꢀ2.66 (m, 2H),
2.83ꢀ2.90 (m, 1H), 3.04ꢀ3.08 (m, 1H), 3.99ꢀ4.06 (m, 1H), 4.78
(dd, J = 3.6, 11.2 Hz, 1H), 4.89ꢀ4.94 (m, 1H), 4.98ꢀ5.08 (m, 4H), 5.32
(br s, 1H), 6.36 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 7.32ꢀ7.42
(m, 10H). 1H NMR data are in agreement with the literature values.8
Gurjar et al.6 reported the specific rotation of this compounds to be
colorless oil (7.6 mg, 78% yield): [R]D ꢀ109.2 (c 0.76, CHCl3) [lit.8
19
24
1
[R]D ꢀ108.1 (c 1.97, CHCl3)]; H NMR (400 MHz, CDCl3) δ
1.35ꢀ1.42 (m, 2H), 1.46 (s, 9H), 2.41ꢀ2.60 (m, 2H), 2.71ꢀ2.82 (m,
3H), 4.30ꢀ4.36 (m, 1H), 4.72ꢀ4.76 (m, 1H), 4.89ꢀ4.92 (m, 1H), 5.00
(s, 2H), 5.07 (s, 2H), 5.75 (d, J = 5.2 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H),
6.48 (d, J = 2.1 Hz, 1H), 7.30ꢀ7.42 (m, 10H); 13C NMR (100 MHz,
CDCl3) δ 26.0, 28.6, 28.7, 29.9, 39.0, 49.0, 50.0, 70.4, 79.7, 99.2, 106.0,
117.6, 127.4, 127.7, 128.3, 128.4, 128.8, 129.0, 136.7, 136.9, 137.5, 155.9,
156.2, 158.7, 170.8. All data are in good agreement with those reported
by Bowen and Wardrop.8 However, the specific rotation reported by
Gurjar et al.6 was [R]D ꢀ102 (c 1.1, CHCl3), which is considerably lower
than our value as well as that of Bowen and Wardrop.
19
[R]D +116 (c 1.35, MeOH). However, the value was [R]D +177.2
24
(+)-(3S,11R)-9,11-Bis(4-methoxybenzyloxy)-3-(9H-fluoren-9-yl)me-
thoxycarbonylamino-2,3,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-
4(11bH)-one, (+)-(S,R)-6. To a stirred solution of (ꢀ)-(R)-3 (96.1% ee)
(76.5 mg, 0.177 mmol) and Et3N (24.6 μL, 0.177 mmol) in DCM
(1 mL) was added 4 (72.7 mg, 0.212 mmol) in DCM (3 mL) at 0 °C
under nitrogen, and the mixture was stirred at room temperature for
18 h. The reaction mixture was diluted with Et2O (10 mL) and water
(10 mL). The aqueous layer was separated and extracted with Et2O
(15 mL ꢁ 2). The combined organic layer was washed with 1 M
hydrochloric acid, water, and brine and dried over anhydrous MgSO4.
The drying agent was removed by filtration and the solvent evaporated
in vacuo to afford the crude product as yellow oil. Purification of the
crude product by flash column chromatography on silica gel (hexanes/
EtOAc = 5:1f2:1) afforded (ꢀ)-(S,R)-5 as colorless oil (105 mg, 81%
(c 0.57, CHCl3) in our hands and [R]D +182.2 (c 1.33, CHCl3) by
Bowen and Wardrop,8 as shown above. It appears that the reported value
by Gurjar et al.6 is either an error or their compound is enantiomerically
not pure. We believe that a small difference in our specific rotation and
that by Bowen and Wardrop8 is due to the difference in concentration
and temperature for the measurement.
General Procedure for the Synthesis of Chiral Dipho-
sphonite Ligands. To a solution of a chiral biphenol12 (1 mmol),
DMAP (10 mol %) and Et3N (0.8 mL, 6 mmol) in DCM (10 mL) at
0 °C was added a solution of a chlorodiarylphosphine (2.5 mmol) in
DCM (5 mL) over the period of 20 min via a syringe. The mixture was
stirred at the same temperature for additional 3 h and concentrated in
vacuo. The residue was dissolved in dry Et2O (20 mL) and filtered
through a pad of Celite. The filtrate was concentrated in vacuo, and the
crude product was purified on a silica gel column pretreated with Et3N
using (hexanes: NEt3 = 99:1) as the eluent.
yield): trans/cis > 20/1 by 1H NMR; [R]D ꢀ36.8 (c 1.25, CH2Cl2);
20
HRMS (ESI+) calcd For C46H45N2O7 [M + H]+ 737.3227, found
737.3218 (Δ = ꢀ1.2 ppm).
(R)-2,20-Bis[bis(4-methylphenyl)phosphinoxy]-3,30-bis(3,5-dimeth-
ylbenzyl)-5,50,6,60-tetramethyl-1,10-biphenyl, (R)-L2a. Colorless oil;
To a stirred solution of (ꢀ)-(S,R)-5 (41 mg, 0.055 mmol) in toluene
(5.5 mL) was added second generation HoveydaꢀGrubbs catalyst (7.0
mg, 20 mol %) under nitrogen, and the mixture was heated to 90 °C for
50% yield; [R]D ꢀ72.5 (c 0.69, CH2Cl2); 1H NMR (300 MHz,
21
CDCl3) δ 1.68 (s, 6H), 1.81 (s, 6H), 2.22 (s, 18H), 2.27 (s, 6H), 3.45
6248
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249

The Journal of Organic Chemistry
ARTICLE
(d, J = 15.6 Hz, 2H), 3.57 (d, J = 15.6 Hz, 2H), 6.34 (s, 2H), 6.63 (s, 4H),
6.81 (t, J = 8.1 Hz, 6H), 7.01 (d, J = 7.8 Hz, 4H), 7.15 (t, J = 7.8 Hz, 4H),
7.31 (t, J = 7.8 Hz, 4H); 31P NMR (121.5 Hz, CDCl3) δ 111.0; HRMS
(EI) calcd C62H64O4P2 [M + O2]+ 934.4280, found 934.4267 (Δ =
ꢀ1.3 ppm).
(9) Miyazaki, M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka, H.;
Kanemitsu, T.; Nagata, K.; Odanaka, Y.; Nakamura, K. T.; Itoh, T.
J. Org. Chem. 2011, 76, 534.
(10) Vicario, J. L.; Badía, D.; Carrillo, L.; Etxebarria, J. Curr. Org.
Chem. 2003, 7, 1775.
(11) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004,
104, 3341.
(12) Kaufman, T. S. Synthesis 2005, 339.
(13) Ito, K.; Akashi, S.; Saito, B.; Katsuki, T. Synlett 2003, 1809.
(14) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143.
(15) Teichert, J. F.; Fa~nanꢀas-Mastral, M.; Feringa, B. L. Angew.
Chem., Int. Ed. 2011, 50, 688.
(16) For the use of RCM for the third ring from 1-vinyltetrahydroi-
soquinoline using achiral ω-alkenylamide tethers, see Kinderman, S. S.;
Wekking, M. M. T.; van Maarseveen, J. H.; Schoemaker, H. E.; Hiemstra,
H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 5519.
(17) Denmark, S. E.; Regens, C. S.; Kobayashi, T. J. Am. Chem. Soc.
2007, 129, 2774.
(18) Shi, C.; Ojima, I. Tetrahedron 2007, 63, 8563.
(19) Shi, C. Ph.D. Thesis, Development and Applications of Chiral
Phosphorus Ligands Transition-Metal Catalyzed Asymmetric Reactions.
Stony Brook University, Stony Brook, NY, 2008.
(20) Trost, B. M.; Breit, B.; Peukert, S.; Zambrano, J.; Ziller, J. W.
Angew. Chem., Int. Ed. 1995, 34, 2386.
(21) Shi, C.; Chien, C.-W.; Ojima, I. Chem. Asian J. 2011, 6, 674.
(22) Organ, M. G.; Xu, J.; N’Zemba, B. Tetrahedron Lett. 2002,
43, 8177.
(S)-2,20-Bis[bis(4-methylphenyl)phosphinyloxy]-3,30-bis(3,5-dimet-
hylbenzyl)-5,50,6,60-tetramethyl-1,10-biphenyl, (S)-L2a. Colorless oil;
45% yield; [R]D +74.4 (c 0.73, CH2Cl2); 1H NMR (300 MHz,
21
CDCl3) δ 1.68 (s, 6H), 1.81 (s, 6H), 2.22 (s, 18H), 2.27 (s, 6H), 3.45
(d, J = 15.6 Hz, 2H), 3.57 (d, J = 15.6 Hz, 2H), 6.34 (s, 2H), 6.63 (s, 4H),
6.81 (t, J = 8.1 Hz, 6H), 7.01 (d, J = 7.8 Hz, 4H), 7.15 (t, J = 7.8 Hz, 4H),
7.31 (t, J = 7.8 Hz, 4H); 31P NMR (121.5 Hz, CDCl3) δ 110.9; HRMS
(EI) calcd C62H64O2P2 [M]+ 902.4382, found 902.4399 (Δ = 1.7 ppm).
(R)-2,20-Bis[bis(4-methoxyphenyl)phosphinyloxy]-3,30-bis(3,5-dim-
ethylbenzyl)-5,50,6,60-tetramethyl-1,10-biphenyl, (R)-L2b. Colorless
21
oil; 62% yield; [R]D ꢀ31.4 (c 0.51, CH2Cl2); 1H NMR (300 MHz,
CD2Cl2) δ 1.67 (s, 6H), 1.84 (s, 6H), 2.22 (s, 12H), 3.44 (d, J = 15.3 Hz,
2H), 3.60 (d, J = 15.3 Hz, 2H), 3.69 (s, 6H), 3.75 (s, 6H), 6.39 (s, 2H),
6.64 (s, 4H), 6.53 (d, J = 8.4 Hz, 4H), 6.66 (s, 4H), 6.76ꢀ6.79 (m, 4H),
7.16ꢀ7.21 (m, 4H), 7.33ꢀ7.38 (m, 4H); 31P NMR (121.5 Hz, CD2Cl2)
δ 112.7; HRMS (EI) calcd C62H64O8P2 [M + O2]+ 998.4076, found
998.4059 (Δ = ꢀ1.4 ppm).
(R)-2,20-Bis[bis(4-trifluoromethylphenyl)phosphinyloxy]-3,30-bis(3,5-
dimethylbenzyl)-5,50,6,60-tetramethyl-1,10-biphenyl, (R)-L2c. Color-
23
1
less oil; 35% yield; [R]D ꢀ115.8 (c 1.2, CH2Cl2); H NMR (300
MHz, CDCl3) δ 1.77 (s, 6H), 1.86 (s, 6H), 2.19 (s, 12H), 3.40 (d, J =
15.6 Hz, 2H), 3.62 (d, J = 15.6 Hz, 2H), 6.42 (s, 2H), 6.49 (s, 4H), 6.77
(s, 2H), 7.30ꢀ7.44 (m, 14H) 31P NMR (121.5 Hz, CDCl3) δ 103.5;
HRMS (EI) calcd C62H52O2F12P2 [M]+ 1118.3251, found 1118.3233
(Δ = ꢀ1.8 ppm).
(23) Rajendra, G.; Miller, M. J. J. Org. Chem. 1987, 52, 4471.
(24) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953.
(25) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(26) Thakkar, K.; Geahlen, R. L.; Cushman, M. J. Med. Chem. 1993,
36, 2950.
’ ASSOCIATED CONTENT
Supporting Information. Copies of 1H, 13C, and 31P NMR
S
b
spectra of new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: iojima@notes.cc.sunysb.edu.
’ ACKNOWLEDGMENT
This work was supported by a grant from the National Science
Foundation (CHE-0809315).
’ REFERENCES
(1) Takada, K.; Uehara, T.; Nakao, Y.; Matsunaga, S.; van Soest,
R. W. M.; Fusetani, N. J. Am. Chem. Soc. 2004, 126, 187.
(2) Braun, C.; Brayer, G. D.; Withers, S. G. J. Biol. Chem. 1995,
270, 26778.
(3) Dwek, R. A.; Butters, T. D.; Platt, F. M.; Zitzmann, N. Nat. Rev.
Drug Discovery 2002, 1, 65.
(4) Mehta, A.; Zitzmann, N.; Rudd, P. M.; Block, T. M.; Dwek, R. A.
FEBS Lett. 1998, 430, 17.
(5) Kuntiyong, P.; Akkarasamiyo, S.; Eksintkun, G. Chem. Lett. 2006,
35, 1008.
(6) Gurjar, M. K.; Pramanik, C.; Bhattasali, D.; Ramana, C. V.;
Mohapatra, D. K. J. Org. Chem. 2007, 72, 6591.
(7) Liu, G.; Romo, D. Org. Lett. 2009, 11, 1143.
(8) Bowen, E. G.; Wardrop, D. J. J. Am. Chem. Soc. 2009, 131, 6062.
6249
dx.doi.org/10.1021/jo2009615 |J. Org. Chem. 2011, 76, 6240–6249