Copper carbenoid, reactant and catalyst for one-pot diazo ester coupling cascade rearrangement of enediynes: Formation of two contiguous tetrasubstituted stereocenters

Article abstract of DOI:10.1002/adsc.201200045

The copper-catalyzed reaction of enediynes with diazo esters leads to cyclic amino esters bearing two contiguous tetrasubstituted stereogenic centers through a one-pot, five-step cascade. Copper iodide catalyzes the formation of an intermediate 3-alkynoate and copper carbenoid promotes its reversible isomerization to the corresponding allenoate. The alkynoate-allenoate equilibrium is completely shifted to the right by the rapid consumption of the allenoate by Myers-Saito cyclization. This is followed by 1,5-H atom transfer and recombination of the resulting biradical. Memory of chirality phenomenon explains the high enantioselectivity. Copyright

Full text of DOI:10.1002/adsc.201200045

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DOI: 10.1002/adsc.201200045
Copper Carbenoid, Reactant and Catalyst for One-Pot Diazo
Ester Coupling Cascade Rearrangement of Enediynes: Formation
of Two Contiguous Tetrasubstituted Stereocenters
Shovan Mondal,a Malek Nechab,a,* Damien Campolo,a Nicolas Vanthuyne,b
and Michꢀle P. Bertranda,*
a
Aix-Marseille Universitꢁ, CNRS, Institut Chimie Radicalaire (ICR), UMR 7273, 13397 Marseille Cedex 20, France
E-mail: malek.nechab@univ-amu.fr or michele.bertrand@univ-amu.fr
Aix-Marseille Universitꢁ, CNRS, ISM2 UMR 7313, 13397 Marseille Cedex 20, France
b
Received: January 17, 2012; Published online: July 2, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200045.
Abstract: The copper-catalyzed reaction of ene- allenoate by Myers–Saito cyclization. This is fol-
diynes with diazo esters leads to cyclic amino esters lowed by 1,5-H atom transfer and recombination of
bearing two contiguous tetrasubstituted stereogenic the resulting biradical. Memory of chirality phenom-
centers through a one-pot, five-step cascade. Copper enon explains the high enantioselectivity.
iodide catalyzes the formation of an intermediate 3-
alkynoate and copper carbenoid promotes its reversi-
ble isomerization to the corresponding allenoate. Keywords: allenes; carbenoids; diazo compounds;
The alkynoate-allenoate equilibrium is completely enediyne rearrangement; memory of chirality; radi-
shifted to the right by the rapid consumption of the cal reactions
Introduction
Searching to devise a one-pot route to potentially
bioactive analogues[10] bearing two contiguous tetra-
Interest in the chemistry of enediynes and enyne-al- substituted stereocenters, we were interested in apply-
lenes has dramatically increased since the discovery ing the strategy published in 2004 by Fu for the prep-
of the antitumor activity of natural enediynes.[1] The aration of 3-alkynoates.[11a] As exemplified in
bioactivity of enediyne-connected amino esters, nota- Scheme 1, in this very simple procedure alkyne 1,
bly the evaluation of enediyne peptide conjugates as 1 equivalent of ethyl diazoacetate (Figure1), and
DNA damaging and protein cleavage agents, has been
the subject of recent interest.[2] However, their chemi-
cal reactivity has hardly been explored.[3–6]
Investigations of the enantioselective rearrange-
ment of this type of enediynes were recently started
in our group.[7,8] The Myers–Saito cycloaromatization
of substrates where the formation of the key allenic
motive is activated by a base-catalyzed 1,3-proton
shift from a propargylic sulfone was investigated
Scheme 1. Cu-catalyzed coupling of phenylacetylene with
first.[7] These reactions were shown to lead to cyclic ethyl diazo ester.
amino esters bearing a tetrasubstituted stereogenic
center adjacent to a tertiary one, in good yields and
with a high level of enantioselectivity based on
memory of chirality phenomenon.[9] The Crabbꢁ ho-
mologation of related terminal enediynes leads direct-
ly through a one-pot procedure to polycyclic amino
esters with a very high stereocontrol of the unique
tetrasubstituted center.[8]
Figure 1. Structures of diazo esters 7.
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Scheme 2. Synthesis of substrates.
5 mol% of CuI in acetonitrile, were the only reac- Results and Discussion
tants. Alkynoate 2 was isolated in 76% yield together
with atrace amount of the isomeric allene 3. While we As depicted in Scheme 2, the enantiopure substrates
were applying this protocol to amino ester-connected 4–6 (Figure1) were readily available from nucleophil-
terminal enediynes (4–6) (Scheme 2), another proce- ic substitution of 1-iodo-2-(3-iodoprop-1-ynyl)benzene
dure, designed to give directly the allenoates was re- by nitrogen-centered nucleophiles, derived from the
ported by Fox and co-workers.[12]
chiral pool, followed by a one-pot Sonogashira-TBAF
In this new protocol, the reaction was conducted in deprotection .
the presence of a ligand, and 2 equivalents of potassi-
Under Fuꢃs conditions, that is, at room temperature
um carbonate in addition to the copper catalyst. A in the presence of 1 equivalent of diazo ester 7a
mechanism involving the insertion of a copper carbe- (Figure 1) in acetonitrile, 8a was isolated in 42% yield
À
noid in the alkyne C H bond followed by reductive from (S)-4 (Scheme 3). Trace amounts of tetracyclic
elimination and base-induced proton migration was ester 9a were simultaneously detected. Much to our
proposed. In closely related studies, Wang and co- satisfaction, in the absence of any base or ligand, the
workers proposed a slightly different, alternative yield of 9a increased up to 58%, when the reaction
mechanism, in which, a copper acetylide intermediate was performed in the presence of 1.4 equivalents of
was involved in the formation of trisubstituted al- ethyl diazoacetate (7a) at 808C. Ester 9a was isolated
lenes.[13]
as 1:1 mixture of diastereoisomers with 94 and 81%
ee, for the cis and trans isomers, respectively. The rela-
Scheme 3. Rearrangement of (S)-4.
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Copper Carbenoid, Reactant and Catalyst for One-Pot Diazo Ester Coupling Cascade Rearrangement
sters) occurred which justifies the necessity of using 7
in excess.
Similar results were obtained when (S)-4 (Table 1,
entry 1) was allowed to react with diazo ester 7b
(Figure 1). At 808C, the overall yield was lowered by
the competitive formation of the tetrayne resulting
from a Glaser–Hay homocoupling reaction.[15]
Lowering the temperature to 508C (entry 2), al-
lowed the tetracyclic product 9b (Figure 3 and
Figure 4) to be isolated in 65% yield in only 0.5 h, as
a 1:1 mixture of diastereomers. At room temperature,
the cascade process not only remained efficient, but it
led to improved yields (Table 1, entry 3). Nearly total
retention of configuration[16] (95 and 94% ee for the
trans and the cis isomers, respectively) was observed.
The synthesis of such compounds bearing two contig-
Figure 2. X-ray structure of cis-9a.
tive stereochemistry was confirmed by X-ray data uous tetrasubstituted stereogenic centers is still a chal-
(Figure 2).[14] A larger excess of diazo ester (2 equiv.) lenge for organic chemists.[17]
did not improve the overall yield. Like in all the reac-
Tetracyclic compound cis-9c (Figure 3) was isolated
tions described in the following, the well-known dime- in 30% and 93% ee (Table 1, entry 4) when (S)-4 was
rization of the diazo ester (to fumaric and maleic die- reacted with 7c (Figure 1). Competitive formation of
Table 1. Tandem alkynoate formation/cascade rearrangement of compounds 4, 5 and 6.
Entry
1
Substrate (ee [%])
(S)-4 (96)
7
Time [h]
0.5
Temperature [8C]
Product (ee [%])[a]
Yield [%][b]
–
Overall yield
41[c]
7b
80
cis-9b (92)
trans-9b (94)
cis-9b (92)
trans-9b (94)
cis-9b (94)
trans-9b (95)
cis-9c (93)
trans-9c (91)
(S)-11 (93)
cis-9d (91)
trans-9d (79)
(Æ)-cis-9’d
2
3
4
(S)-4 (96)
(S)-4 (96)
(S)-4 (96)
7b
7b
7c
0.5
2
50
r.t.
80
–
65
70
73
35
35
30
13[d]
30
28
35
37
37
32
46
39
45
28
40
34[f]
9[d]
30
24
9
2
5
(S)-4 (96)
(Æ)-4’
7d
7d
7b
7b
7b
7c
2
2
2
2
2
1
2
80
80
r.t.
r.t.
r.t.
80
80
63
6
74
(Æ)-trans-9’d
cis-10b (95)
trans-10b (91)
ent-cis-10b (97)
ent-trans-10b (89)
cis-10b (95)
trans-10b (91)
ACHTUNGTREN(NUNG S,R)-10c (97)
12
cis-13a (80)
trans-13a (88)
14a
7
(S)-5 (99)
(R)-5 (>99.5)
(S)-5 (99)
(S)-5 (99)
(S)-6 (99)
78
8
83
9
68[e]
44
10
11
7a
63
12
(S)-6 (99)
7b
2
rt
cis-13b (94)
trans-13b (92)
14b
30
30
13
73
[a]
The ee was determined by chiral HPLC.
Isolated yield of the two diastereoisomers, unless otherwise stated.
At 808C, the Glaser–Hay homocoupling product was formed in 40% yield.
NMR yield (trans-9c and 12 could not be isolated as pure samples, their yield was determined from the crude mixture).
1 equiv. of 7b was used
The second diastereomer was detected in a trace amount.
[b]
[c]
[d]
[e]
[f]
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Figure 3. Structures of rearranged products 9–13.
(S)-11 (Figure 5) accounted for the 30% yield. It is in-
teresting to note that the later was isolated in 93% ee.
Attempts to enhance the diastereoselectivity of the
process by replacing the ethyl ester on the diazo ester
by a bulkier ester group 7d (Figure 1, namely, a tert-
butyl ester) did not lead to the expected result. No
significant effect was recorded either on the diaste-
reoselectivity or on the enantioselectivity (entry 5).
The introduction of two bulky tert-butyl esters, that is,
reaction of (Æ)-4’ with 7d, did not improve the diaste-
reomeric ratio of (Æ)-9’d either (Figure 3, Table 1,
entry 6).
Figure 4. X-ray structures of trans-9b and trans-10b.
This rearrangement was then extended to substrates
5 and 6 with diazo esters 7a–c.[18] An overall yield, as
high as 83%, in isolated 10b (Figure 3) was obtained
Very similar data were obtained from the reaction
from oxazolidinone (R)-5 and diazo ester 7b with of (S)-6 with 7b. Tetrahydrobenzoisoquinolines (R,R)-
a very high level of memory of chirality. The reaction 13b[16] (Figure 3 and Figure 6) and (S,R)-13b, bearing
performed on (S)-5 led to the enantiomeric products also two contiguous tetrasubstituted stereocenters,
(Table 1, entries 7 and 8).
were obtained in a 1:1 ratio (60% yield) with 94 and
As already observed for the reaction of (S)-4 with 92% ee for the cis and the trans isomers, respectively
7c, (S)-5 led to 12 (Figure 5) in 9% NMR yield. A (Table 1, entry 12). Alkene 14b (Figure 5) was formed
closely related behaviour was observed when alkyne in 13% yield.
(S)-6 was submitted to the above described protocol
and allowed to react with either 7a or 7b. Two diaste-
reomers of 13a were formed in 30% (80% ee) and Mechanistic Investigations
24% (88% ee) yields, respectively, (Table 1, entry 11),
together with 14a, isolated in 9% yield (Figure 3 and The involvement of a Myers–Saito cyclization in the
Figure 5).
rearrangement process made it obvious that, in the
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Copper Carbenoid, Reactant and Catalyst for One-Pot Diazo Ester Coupling Cascade Rearrangement
to 9a when it was allowed to react with mesoporous
silica grafted with a tertiary amino group (GA-
SBA15) as the base. (ii) No reaction occurred when
8a was submitted to the action of either diazo ester 7a
alone, or to the action of copper iodide alone. Both
reagents are necessary for the rearrangement to pro-
ceed. (iii) A catalytic amount of diazo ester (40%)
and copper iodide (5%) led to the complete conver-
sion of alkynoate 8a into 9a.
Therefore in this process, the copper carbenoid[21]
would play at the same time the role of reagent and
that of 1,3-proton shift catalyst.
In order to validate this hypothesis we have applied
the same procedure to compound 15. Tan has recently
reported that the isomeric allenoate 16 could be
trapped intramolecularly to afford 2-alkylidenetetra-
hydrofuran 17 through Michael addition.[22] Surpris-
ingly, when 3-butyn-1-ol was submitted to the action
of 1.4 equivalents of 7a at 808C, the cyclized product
was not observed (Scheme 4). Only alkynoate 15 was
formed.
Figure 5. Alkenes 11, 12 and 14.
From these observations, it can be postulated that
chelation of the copper carbenoid by the ortho-diyne
is required to activate the alkyne-allene isomerization
via 1,3-proton migration. The mechanism proposed
for the overall five-step rearrangement is detailed in
Scheme 5, taking the reaction of enediyne 4 as a pro-
totype. The necessity of an additional ligand is in
agreement with the observations made by Fox[12] and
Wang.[13] In our protocol, the only difference resides
in the absence of any base.
As shown in Scheme 5, once formed, the enyne-
allene C undergoes fast Myers–Saito cycloaromatiza-
tion to give biradical D. The latter rearranges accord-
ing to a 1,5-H atom transfer. Subsequent recombina-
tion of the newly formed biradical E gives the con-
Figure 6. Determination of absolute configuration of (R,R)-
trans-13b by X-ray analysis.
presence of the copper catalyst and the diazo ester, strained heterocyclic targets. This last step is crucial
and in the absence of any additional base, an equilib- for the memory of chirality. The recombination of
rium was established between the alkynoate and the radicals should be faster than the rates of rotations
isomeric allenoate. The base-catalyzed isomerization around the a and b bonds that would racemize the
of 3-alkynoates to allenoates is known to be reversi- conformationally chiral captodative radical center in
ble.[19] Furthermore, complexation could increase E.[7,8]
either the propargylic proton acidity or the stability
of the allenoate.[20] The fact that reactions involving
7b could be promoted at room temperature is consis-
tent with both proposals.
In the case of the enediyne substrates, the equilibri-
um would be completely shifted to the right by the
rapid consumption of the allenoate by Myers–Saito
cyclization.
When strictly 1 equivalent of diazo ester was used,
the overall yield was decreased by only 10% (sub-
strate (S)-5, Table 1, entry 9). This led us to propose
that the copper carbenoid intermediate would play
a double role. This was confirmed by the following
experiments: (i) 8a was shown to be an intermediate
Scheme 4. Tentative tandem Cu-catalyzed coupling of 3-bu-
in the cascade reaction. An isolated sample of 8a led tynol with 7a/Michael cyclization.
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Shovan Mondal et al.
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Scheme 5. Proposed mechanism.
were performed on silica gel 60 ꢄ (70–230 mesh). Analytical
thin layer chromatography was performed on pre-coated
silica gel plates. Visualization was accomplished by UV
(254 nm) and with phosphomolybdic acid in ethanol. Optical
rotations were measured on a polarimeter at 589 nm. 1H
and 13C NMR spectra were recorded at 400 MHz and
Competitive disproportionation occurs when
a methyl group is linked to one of the radical centers
in intermediate E. This disproportionation had previ-
ously been observed with substrates bearing a sulfone
group in the alanine series.[7,8] Alkene side products
were also isolated in the case where the methyl group
is attached to the benzylic radical center. In this case,
the formal 1,7-hydrogen atom transfer occurs with
memory of chirality (formation of 11 in 93% ee).
1
100 MHz, for H and 13C, respectively. Chemical shifts (d)
are reported in ppm and are reported relative to internal
CHCl3 (1H, d=7.26) and CDCl3 (13C, d=77.16). Multiplicity
is indicated by one or more of the following: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), br (broad).
Coupling constants (J) are listed in the order of the multi-
plicity assignment and are reported in Hertz (Hz). APT was
used for the assignment of 13C spectra. All melting points
were uncorrected.
Conclusions
The copper-catalyzed reaction of terminal enediynes
4–6 with diazo esters 7a–d leads directly through
a five-step cascade rearrangement to the formation of
heterocyclic analogues of aspartic esters bearing con-
tiguous tetrasubstituted stereogenic centers. The phe-
nomenon of memory of chirality explains the high
enantioselectivity of the process. This reaction pro-
ceeds via a copper carbenoid, which acts both as reac-
tant and as a catalyst by promoting the isomerization
the intermediate 3-alkynoates to the transient alle-
noates.
Purified compounds were analyzed by chiral HPLC with
double detection, with UV and circular dichroꢅsm (CD) de-
tectors. The solvents for chiral chromatography (n-hexane,
2-PrOH, ethanol) were HPLC grade, they were degassed
and filtered on a 0.45 mm membrane before use. The col-
umns used are Chiralpak IA, AD-H, Chiralpak IB, OD-3,
Chiralpak IC and Lux-Cellulose-4. Enantiomeric excesses
were determined by integration of the peaks on the chroma-
tograms obtained by UV detection at 230, 240 or 254 nm,
and confirmed by circular dichroꢅsm detection at 254 nm.
The sign given by the on-line circular dichroꢅsm detector for
one enantiomer is the sign in the solvent used for the chro-
matographic separation. Retention times Rt (in minutes),
retention factors ki =(RtiÀRt0)/Rt0, enantioselectivity factor
a=k2/k1, and resolution are given. Rt0 was determined by
injection of tris-tert-butylbenzene.
Experimental Section
All reactions were performed under an argon atmosphere.
CH3CN (Teflon-sealed) was HPLC grade. THF was distilled
over sodium benzophenone ketyl prior to use. Purifications
1992
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Copper Carbenoid, Reactant and Catalyst for One-Pot Diazo Ester Coupling Cascade Rearrangement
HR-MS (ESI): m/z=426.0563, calcd. for [M+H]+
C18H21NO3I: 426.0561.
(S)-Methyl 1-[3-(2-ethynylphenyl)prop-2-ynyl]-5-oxo-
pyrrolidine-2-carboxylate (4)
To (S)-methyl 1-[3-(2-iodophenyl)prop-2-ynyl]-5-oxopyrroli-
dine-2-carboxylate[7a] (3 g, 7.83 mmol) in THF (75 mL), Et3N
(15 mL) was added and the reaction mixture was degassed
with argon bubbling for 15 min. Then the catalyst,
tert-Butyl 1-[3-(2-Ethynylphenyl)prop-2-ynyl]-5-oxo-
pyrrolidine-2-carboxylate (Æ)-4’
Enediyne 4’ was prepared as described above for 4 from
(Æ)-tert-butyl 1-[3-(2-iodophenyl)prop-2-ynyl]-5-oxopyrroli-
PdACHTUNGTRENNUNG(PPh3)2Cl2 (110 mg, 2 mol%), and the co-catalyst, CuI
(60 mg, 4 mol%), were added to the reaction mixture. After
stirring for 10 min trimethylsilylacetylene (1.66 mL,
11.74 mmol) was added and the reaction mixture was stirred
for additional 2 h at room temperature. The conversion of
the starting material was monitored by TLC. A solution of
TBAF (12 mL of 1M in THF, 12 mmol) was then added and
the reaction mixture stirred further for 30 min. The reaction
mixture was then passed through a small celite bed, concen-
trated and the residue was purified by column chromatogra-
phy on silica gel, using ethyl acetate/pentane (3:7) as eluent,
to afford compound 4 as a brown liquid: yield: 1.72 g (78%
over 2 steps). 1H NMR (400 MHz, CDCl3): d=7.48–7.45
(1H, m, CHar), 7.40–7.38 (1H, m, CHar), 7.29–7.25 (2H, m,
CHar), 4.89 (1H, d, J=17.8 Hz, CH2N, A part of an AB pat-
tern), 4.65–4.62 (1H, m, CHCO2Me), 4.02 (1H, d, J=
17.8 Hz, CH2N, B part of an AB pattern), 3.75 (3H, s,
CO2CH3), 3.31 (1H, s, CꢀCH), 2.49–2.36 (3H, m, CH2),
2.13–2.10 (1H, m, CH2); 13C NMR (100 MHz, CDCl3): d=
174.5 (CO), 172.2 (CO), 132.6 (CHar), 132.1 (CHar), 128.6
(CHar), 128.3 (CHar), 125.4 (Car), 124.7 (Car), 86.7 (CCꢀC),
dine-2-carboxylate (700 mg, 1.65 mmol), PdACHTUNGTRNEG(UN PPh3)2Cl2
(23 mg, 2 mol%), CuI (12.5 mg, 4 mol%), trimethylsilylace-
tylene (0.46 mL, 3.29 mmol), Et3N (4 mL) in THF (10 mL).
The reaction mixture was stirred for 2 h. The deprotection
was carried out with TBAF solution (1M in THF) (5 mL,
5 mmol). The product was purified by column chromatogra-
phy (20% ethyl acetate/pentane) to afford compound 4 as
a brown liquid; yield: 400 mg (75%). 1H NMR (400 MHz,
CDCl3): d=7.48–7.46 (1H, m, CHar), 7.41–7.38 (1H, m,
CHar), 7.27–7.25 (2H, m, CHar), 4.92 (1H, d, J=17.6 Hz,
CH2N, A part of an AB pattern), 4.52–4.49 (1H, m, CH),
3.98 (1H, d, J=17.8 Hz, CH2N, B part of an AB pattern),
ꢀ
3.28 (1H, s, -C CH), 2.48–2.32 (3H, m), 2.11–2.02 (1H, m),
1.45 (9H, s, t-Bu); 13C NMR (100 MHz, CDCl3): d=174.5
(CO), 170.8 (CO), 132.6 (CHar), 132.0 (CHar), 128.6 (CHar),
128.2 (CHar), 125.5 (Car), 124.7 (Car), 86.8 (C), 83.1 (CCꢀC),
82.4 (CCꢀ), 82.2 (C ), 81.0 (C H), 59.2 (CH), 32.2 (CH2N),
ꢀ
ꢀ
C
C
29.6 (CH2), 28.0 (3CH3), 22.9 (CH2); HR-MS (ESI): m/z=
324.1593, calcd. for [M+H]+ C20H22NO3: 324.1594.
83.3 (CCꢀC), 82.2 (CCꢀ ), 81.1 (C CH), 58.4 (CH), 52.6
ꢀ
C
(S)-3-[3-(2-Ethynylphenyl)prop-2-ynyl]-4-
phenyloxazolidin-2-one (5)
(OCH3), 32.3 (CH2N), 29.6 (CH2), 22.9 (CH2); HR-MS
(ESI): m/z=282.1125, calcd for [M+H]+ C17H16NO3:
282.1125. Chiral HPLC separation of enantiomers (Chiral-
pak IC, hexane/ethanol 8/2, 1 mLminÀ1, detection UV and
CD 254 nm): Rt(S)=13.41, Rt(R)=14.78, k(S)=3.47,
k(R)=3.93, a=1.13 and Rs=1.95; ee=96%; [a]2D5: +12.4 (c
0.78, CH2Cl2).
Enediyne 5 was prepared, as described above, from (S)-3-[3-
(2-iodophenyl)prop-2-ynyl]-4-phenyloxazolidin-2-one[7a]
(3.20 g, 7.94 mmol), Pd
(60.5 mg, 4 mol%),
ACHTUNGTRENNUNG
11.90 mmol), Et3N (16 mL) in THF (80 mL). The reaction
mixture was stirred for 12 h. The deprotection was carried
out with TBAF solution (1M in THF) (12 mL, 12 mmol).
The product was purified by column chromatography (20%
ethyl acetate/pentane) to yield compound 5 as a brown
tert-Butyl 1-[3-(2-Iodophenyl)prop-2-ynyl)-5-oxo-
pyrrolidine-2-carboxylate [(Æ)-1’]
1
This compound was synthesized with slight modification ac-
cording to a known methodology.[23] 1-Iodo-2-(3-iodoprop-1-
ynyl)benzene[7a] (2.3 g, 6.25 mmol) was dissolved in DMF
(15 mL) and Cs2CO3 (3.1 g, 9.38 mmol) was added followed
liquid; yield: 1.57 g (66% over 2 steps). H NMR (400 MHz,
CDCl3): d=7.38–7.36 (1H, m, CHar), 7.29–7.25 (5H, m,
CHar), 7.17–7.12 (3H, m, CHar), 5.01 (1H, t, J=8.3 Hz), 4.55
(1H, d, J=17.8 Hz, CH2N, A part of an AB pattern), 4.53
(1H, t, J=8.8 Hz), 4.05 (1H, t, J=8.0 Hz), 3.51 (1H, d, J=
by
tert-butyl
oxopyrrolidine-2-carboxylate[24]
(1.4 g,
7.5 mmol), the reaction mixture was stirred for 1 h under
argon, poured into water (30 mL), and then extracted with
EtOAc (3ꢆ30 mL). The organic layer was washed with
water (2ꢆ30 mL) and brine (30 mL) and dried over anhy-
drous sodium sulfate. After evaporation of the solvent, the
residue was purified over a short pad of silica gel (pentane/
EtOAc, 90/10) to afford (Æ)-1’ as brown oil; yield: 2.26 g
(85% over 2 steps). 1H NMR (400 MHz, CDCl3): d=7.81
(1H, dd, J=8.0 and 1.0 Hz, CHar), 7.40 (1H, dd, J=7.8 and
1.8 Hz, CHar), 7.28 (1H, td, J=7.5 and 1.0 Hz, CHar), 7.00
(1H, td, J=8.0 and 1.8 Hz, CHar), 4.93 (1H, d, J=17.8 Hz,
CH2N, A part of an AB pattern), 4.57–4.54 (1H, m, CH),
3.99 (1H, d, J=17.8 Hz, CH2N, B part of an AB pattern),
2.53–2.33 (3H, m), 2.12–2.03 (1H, m), 1.47 (9H, s, t-Bu);
13C NMR (100 MHz, CDCl3): d=174.7 (CO), 170.9 (CO),
138.8 (CHar), 132.9 (CHar), 129.8 (CHar), 129.2 (Car), 128.0
(CHar), 100.8 (Car), 86.8 (CCꢀC), 86.7 (CCꢀC), 82.5 (C), 59.5
(CH), 32.3 (CH2N), 29.7 (CH2), 28.2 (3CH3), 22.9 (CH2);
ꢀ
17.8 Hz, CH2N, B part of an AB pattern), 3.15 (1H, s, -C
CH); 13C NMR (100 MHz, CDCl3): d=157.9 (CO), 136.9
(Car), 132.7 (CHar), 132.2 (CHar), 129.4 (2CHar), 129.3
(CHar), 128.7 (CHar), 128.4 (CHar), 127.5 (2CHar), 125.4
(Car), 124.8 (Car), 86.2 (CCꢀC), 83.5 (CCꢀC), 82.4 (CCꢀC), 81.2
(C CH), 70.0 (OCH2), 59.0 (CH), 33.1 (CH2N); HR-MS
ꢀ
(ESI): m/z=302.1176, calcd. for [M+H]+ C20H16NO2:
302.1176. Chiral HPLC separation of enantiomers (Chiral-
pak IB, hexane/ethanol 9/1, 1 mLminÀ1, detection UV
230 nm and CD 254 nm): Rt(R)=9.63, Rt(S)=10.61, k(R)=
2.21, k(S)=2.54, a=1.15; ee=99%; [a]2D5: +169.7 (c 0.67,
CH2Cl2).
(S)-Methyl-2-{N-[3-(2-ethynylphenyl)prop-2-ynyl]-4-
methylphenylsulfonamido}propanoate (6)
Enediyne 6 was prepared from (S)-methyl 2-{N-[3-(2-iodo-
phenyl)prop-2-ynyl]-4-methylphenylsulfonamido}propano-
Adv. Synth. Catal. 2012, 354, 1987 – 2000
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1993

Shovan Mondal et al.
FULL PAPERS
A
E
Rt
R
k
E
kACTHNGUTERNNU(G 12R,12aS)=
CuI (61.3 mg, 4 mol%), trimethylsilylacetylene (1.7 mL,
12.06 mmol), Et3N (20 mL) in THF (100 mL). The reaction
mixture was stirred for 2 h. Deprotection was carried out
with TBAF solution (1M in THF) (12.5 mL, 12.5 mmol).
The product was purified by column chromatography (20%
ethyl acetate/pentane) to afford compound 6 as a brown
9.41, a=1.35 and Rs=4.32; ee=94%; [a]3D0: À71.4 (c 0.63,
CH2Cl2). The structure was confirmed by X-ray crystallogra-
phy.
AHCTUNGTRENNUNG
carboxylate (trans-9a): Colorless oil. 1H NMR (400 MHz,
CDCl3): d=7.78 (2H, m, CHar), 7.74 (1H, s, CHar), 7.70
(1H, s, CHar), 7.49–7.43 (2H, m, CHar), 5.15 (1H, d, J=
17.3 Hz, CH2N, A part of an AB pattern), 4.68 (1H, d, J=
17.1 Hz, CH2N, B part of an AB pattern), 4.63 (1H, s, CH),
4.16–4.00 (2H, AB part of an ABX3 pattern, OCH2), 3.54
(3H, s, OCH3), 2.64–2.54 (1H, m), 2.52–2.36 (3H, m), 1.17
(3H, t, J=7.0 Hz, CH3); 13C NMR (100 MHz, CDCl3): d=
liquid; yield: 2.45 g (77% over 2 steps). H NMR (400 MHz,
CDCl3): d=7.83 (2H, d, J=8.3 Hz, CHar), 7.48 (1H, m,
CHar), 7.29–7.23 (5H, m, CHar), 4.71 (1H, q, J=7.3 Hz,
CHCH3), 4.64 (1H, d, J=18.8 Hz, CH2N, A part of an AB
pattern), 4.41 (1H, d, J=18.8 Hz, CH2N, B part of an AB
pattern), 3.65 (3H, s, CO2CH3), 3.24 (1H, s, -C CH), 2.36
(3H, s, CH3), 1.57 (3H, d, J=7.3 Hz, CH3); 13C NMR
(100 MHz, CDCl3): d=172.0 (CO), 143.6 (Car), 137.3 (Car),
132.7 (CHar), 132.2 (CHar), 129.6 (2CHar), 128.5 (CHar),
128.3 (CHar), 127.7 (2CHar), 125.5 (Car), 124.6 (Car), 88.6
174.7 (CO), 172.6 (CO), 170.0 (CO), 133.2ACTHNUTRGNEG(UN Car), 132.2 (Car),
129.4 (Car), 128.5 (CHar), 128.0 (Car), 127.7 (CHar), 127.5
(CHar), 126.8 (CHar), 126.3 (CHar), 126.2 (CHar), 67.2 (C-
12a), 61.8 (OCH2), 53.3 (CH), 52.1 (OCH3), 43.0 (CH2N),
29.5 (CH2), 27.8 (CH2), 14.1 (CH3); HR-MS (ESI): m/z=
368.1494, calcd. for [M+H]+ C21H22NO5: 368.1492. Chiral
HPLC separation of enantiomers (Chiralpak IC, hexane/eth-
anol 7/3, 1 mLminÀ1, detection UV 230 nm and CD
(CCꢀC), 83.0 (CCꢀC), 82.0 (CCꢀ ), 81.1 (C CH), 55.1 (CHCH3),
52.4 (OCH3), 35.2 (CH2N), 21.6 (CH3 of Ts), 16.5 (CHCH3);
HR-MS (ESI): m/z=396.1264, calcd. for [M+H]+
C22H22NO4S: 396.1264. Chiral HPLC separation of enantio-
mers (Chiralcel OD-3, hexane/2-propanol 8/2, 1 mLminÀ1,
detection UV and CD 254 nm): Rt(S)=12.04, Rt(R)=13.00,
k(S)=3.01, k(R)=3.33, a=1.11 and Rs=1.22; ee=99%.
[a]2D5: À35.8 (c 0.5, CH2Cl2).
254 nm):
kACTHNUTRGNENG(U 12S,12aS)=3.74, kACHTUGNTREN(NUNG 12R,12aR)=4.33, a=1.16 and Rs=
2.20; ee=81%; [a]3D0: À34.9 (c 0.91, CH2Cl2).
Coupling of (S)-4 with 7b: Enediyne (S)-4 (200 mg,
0.71 mmol), diazo ester 7b[25] (190 mg, 1.00 mmol) and CuI
(7 mg, 5 mol%) in dry acetonitrile (500 mL) were allowed to
react for 2 h at room temperature. The products were puri-
fied by column chromatography (30% ethyl acetate/pen-
tane) to afford (12R,12aR)-9b (yield: 109 mg, 35%, ee=
94%) and (12S,12aR)-9b (yield: 109 mg, 35%, ee=95%).
General Protocol for the One-Pot Copper-Catalyzed
Reaction of Diazoesters 7 with Terminal Alkynes and
Cascade Rearrangement
Coupling of (S)-4 with 7a: Argon gas was bubbled through
a solution of enediyne (S)-4 (200 mg, 0.71 mmol) and diazo
ester 7a (113 mg, 1 mmol) in dry acetonitrile (500 mL) for
10 min. Then CuI (7 mg, 5 mol%) was added, and the reac-
tion mixture was heated for 2 h at 808C. Then the reaction
mixture was evaporated under vacuum and the residue re-
dissolved in DCM. After filtration through a celite bed, the
filtrate was concentrated under vacuum and the crude prod-
uct was purified by column chromatography on silica gel
using 3:7 ethyl acetate:pentane as eluent. This led to the iso-
lation of (12S,12aR)-9a (yield: 75 mg, 29%, ee=94%) and
(12R,12aR)-9a (yield: 75 mg, 29%, ee=81%).
N
1
line-12,12a-dicarboxylate (cis-9b): Yellowish oil. H NMR
(400 MHz, CDCl3): d=8.50 (1H, s, CHar), 7.76 (1H, d, J=
8.0 Hz, CHar), 7.71 (1H, d, J=8.0 Hz, CHar), 7.68 (1H, s,
CHar), 7.43 (1H, td, J=6.8 and 1.2 Hz, CHar), 7.37 (1H, td,
J=6.8 and 1.2 Hz, CHar), 7.30 (3H, m, CHar), 6.91–6.89 (2H,
m, CHar), 5.41 (1H, d, J=17.8 Hz, CH2N, A part of an AB
pattern), 4.44 (2H, q, J=7.0 Hz, OCH2), 4.30 (1H, d, J=
17.6 Hz, CH2N, B part of an AB pattern), 3.65 (3H, s,
OCH3), 2.87–2.79 (1H, m), 2.33–2.20 (2H, m), 1.4 (3H, t,
J=7.0, CH3), 1.37–1.30 (1H, superimposed m); 13C NMR
(100 MHz, CDCl3): d=175.3 (CO), 172.2 (CO), 172.1 (CO),
carboxylate (cis-9a): White solid; mp 160.48C (CH3CN).
1H NMR (400 MHz, CDCl3): d=7.81 (1H, s, CHar), 7.80–
7.77 (2H, m, CHar), 7.67 (1H, s, CHar), 7.49–7.45 (2H, m,
CHar), 5.16 (1H, d, J=16.1 Hz, CH2N, A part of an AB pat-
tern), 4.60 (1H, d, J=15.8 Hz, CH2N, B part of an AB pat-
tern), 4.23 (1H, s, CH), 4.26–4.12 (2H, AB part of an ABX3
pattern, OCH2), 3.70 (3H, s, OCH3), 2.75 (1H, ddd, J=1.5,
8.3 and 12.8 Hz), 2.57–2.51 (1H, m), 2.32 (1H, ddd, J=1.5,
9.0 and 16.6 Hz), 2.11 (1H, m), 1.27 (3H, t, J=7.0 Hz,
CH3); 13C NMR (100 MHz, CDCl3): d=174.6 (CO), 172.2
(CO), 170.8 (CO), 132.7 (Car), 132.6 (Car), 132.0 (Car), 128.4
(CHar), 128.1 (Car), 127.8 (CHar), 127.6 (CHar), 126.9 (CHar),
126.2 (CHar), 125.3 (CHar), 67.2 (C-12a), 61.9 (OCH2), 54.9
(CH), 52.9 (OCH3), 41.9 (CH2N), 32.9 (CH2), 30.0 (CH2),
14.2 (CH3); HR-MS (ESI): m/z=368.1499, calcd. for [M+
H]+ C21H22NO5: 368.1492. Chiral HPLC separation of enan-
tiomers (Chiralpak IC, hexane/ethanol 7/3, 1 mLminÀ1, de-
141.3 (Car), 134.8ACTHNURTGNE(NUG Car), 132.5 (Car), 132.0 (Car), 130.7 (CHar),
129.0 (2CHar), 128.7 (CHar), 128.6 (Car), 128.4 (2CHar), 127.7
(CHar), 126.8 (CHar), 126.6 (CHar), 125.7 (CHar), 124.3
(CHar), 71.4 (C-12a), 62.0 (OCH2), 60.9 (C12), 53.0 (OCH3),
41.7 (CH2N), 29.1 (CH2), 26.9 (CH2), 14.2 (CH3); HR-MS
(ESI): m/z=444.1803, calcd. for [M+H]+ C27H26NO5:
444.1805. Chiral HPLC separation of enantiomers (Chiral-
pak IC, hexane/ethanol 8/2, 1 mLminÀ1, detection UV
230 nm
and
CD
254 nm):
RtACHTUNTGRENNUNG
Rt(12S,12aS)=20.22, k
G
R
ACHTUNGTRENNUNG
a=1.12 and Rs=1.74; ee=94%; [a]30: +2 (c 4.47, CH2Cl2).
(12S,12aR)-12-Ethyl
12a-methDyl
3-oxo-12-phenyl-
1,2,3,5,12,12a-hexahydrobenzo[g]pyrroloAHCTUNGTERGUN[NN 1,2-b]isoquino-
line-12,12a-dicarboxylate (trans-9b): Yellowish solid; mp
181.28C (CH3CN). 1H NMR (400 MHz, CDCl3): d=7.76
(1H, s, CHar), 7.71 (1H, d, J=8.3 Hz, CHar), 7.66 (1H, s,
CHar), 7.57 (1H, d, J=8.3 Hz, CHar), 7.38 (1H, pseudo t, J=
tection UV 230 nm and CD 254 nm): RtACTHNUTRGNEUNG(12S,12aR)=23.95,
1994
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1987 – 2000

Copper Carbenoid, Reactant and Catalyst for One-Pot Diazo Ester Coupling Cascade Rearrangement
7.3 Hz, CHar), 7.30 (1H, pseudo t, J=7.3 Hz, CHar), 7.31–
7.26 (5H, m, CHar), 5.18 (1H, d, J=17.6 Hz, CH2N, A part
of an AB pattern), 4.73 (1H, d, J=17.6 Hz, CH2N, B part of
an AB pattern), 3.98–3.86 (2H, AB part of an ABX3 pat-
tern, OCH2), 3.14 (3H, s, OCH3), 2.79–2.76 (1H, m), 2.46–
2.37 (3H, m), 0.89 (3H, t, J=7.0 Hz, CH3); 13C NMR
(100 MHz, CDCl3): d=174.6 (CO), 171.4 (CO), 169.7 (CO),
136.9 (Car), 132.7 (Car), 131.7 (Car), 131.6 (Car), 131.2 (Car),
130.6 (CHar), 130.0 (CHar), 128.3 (CHar), 128.0 (2CHar),
127.9 (2CHar), 127.1 (CHar), 126.8 (CHar), 125.7 (CHar),
124.7 (CHar), 70.9 (C-12a), 62.7 (C-12), 61.9 (OCH2), 52.3
(OCH3), 42.9 (CH2N), 29.5 (CH2), 26.4 (CH2), 13.7 (CH3);
HR-MS (ESI): m/z=444.1803, calcd. for [M+H]+
C27H26NO5: 444.1805. Chiral HPLC separation of enantio-
mers (Chiralpak IC, hexane/ethanol 5/5, 1 mLminÀ1, detec-
1.5 Hz, Hb of =CHaHb), 5.24 (1H, d, J=15.3 Hz, CH2N, A
part of an AB pattern), 4.28–4.20 (2H, AB part of an ABX3
pattern, OCH2CH3), 4.03 (1H, d, J=15.3 Hz, CH2N, B part
of an AB pattern), 3.90 (1H, dd, J=9.3 and 2.8 Hz, CH),
3.65 (3H, s, OCH3), 2.52 (1H, pseudo dt, J=16.8 and
9.5 Hz), 2.38 (1H, ddd, J=3.5, 9.5, and 16.8 Hz), 2.22 (1H,
dtt, J=13.0, 9.5, and 9.3 Hz), 2.02 (1H, ddt, J=12.8, 9.5,
and 3.3 Hz), 1.30 (3H, t, J=7.0 Hz, CH2CH3); 13C NMR
(100 MHz, CDCl3): d=175.0 (CO), 172.4 (CO), 166.3 (CO),
140.9 (Car), 135.4 (Car), 133.1 (Car), 132.8 (Car), 132.1 (C),
129.7 (CHar), 129.3 (=CH2), 128.2 (CHar), 127.8 (CHar),
127.6 (CHar), 126.7 (CHar), 126.6 (CHar), 61.5 (OCH2), 58.5
(CH), 52.4 (OCH3), 43.9 (CH2N), 29.6 (CH2), 22.9 (CH2),
14.3 (CH3); HR-MS (ESI): m/z=382.1649, calcd for [M+
H]+ C22H24NO5: 382.1649. Chiral HPLC separation of enan-
tiomers (Chiralpak IC, hexane/ethanol 7/3, 1 mLminÀ1, de-
tection UV 230 nm and CD 254 nm): Rt(R)=15.98, Rt(S)=
17.78, k(R)=4.33, k(S)=4.93, a=1.14 and Rs=1.98; ee=
93%; [a]3D0: +3.8 (c 0.42, CH2Cl2).
tion UV 230 nm and CD 254 nm): RtACHTNUGTRENNUNG
Rt
N
kA
kACHTUNGTRENNUNG
7.68, a=2.12 and Rs=9.40; ee=95%; [a]3D0: À13.4 (c 3.57,
CH2Cl2). The structure was confirmed by X-ray crystallogra-
phy.
Coupling of (S)-4 with 7d: Enediyne (S)-4 (200 mg,
0.71 mmol), was allowed to react with diazo ester 7d
(142 mg, 0.99 mmol) and CuI (7 mg, 5 mol%) in dry acetoni-
trile (500 mL) for 2 h at 808C. The products was purified by
column chromatography (30% ethyl acetate/pentane) to
yield (12S,12aR)-9d (yield: 80 mg, 28%, ee=91%) and
(12R,12aR)-9d (yield: 97 mg, 35%, ee=79%).
Coupling of (S)-4 with 7c: Enediyne (S)-4 (100 mg,
0.35 mmol) was allowed to react with diazo ester 7c[26]
(64 mg, 0.49 mmol) and CuI (3.5 mg, 5 mol%) in dry aceto-
nitrile (250 mL) for 1 h at 808C. The products were purified
by column chromatography (DCM) to yield (12R,12aR)-9c
(yield: 40 mg, 30%, ee=91%) and olefin (S)-11 (yield:
40 mg, 30%, ee=93%). The cis diastereomer, detected in
the crude mixture (13% NMR yield, 93% ee) could not be
isolated as a pure sample.
A
12a-methyl
3-oxo-
AHCTUNGTRENNUNG
1
line-12,12a-dicarboxylate (cis-9d): Yellowish oil. H NMR
(400 MHz, CDCl3): d=7.80 (1H, s, CHar), 7.80–7.78 (2H, m,
CHar), 7.66 (1H, s, CHar), 7.50–7.43 (2H, m, CHar), 5.14
(1H, d, J=16.0 Hz, CH2N, A part of an AB pattern), 4.58
(1H, d, J=15.8 Hz, CH2N, B part of an AB pattern), 4.17
(1H, s, CH), 3.69 (3H, s, OCH3), 2.76 (1H, ddd, J=1.5, 8.5
and 12.8 Hz), 2.59–2.51 (1H, dddd, J=1.0, 8.5, 11.3, and
16.6 Hz), 2.31 (1H, ddd, J=1.2, 9.0 and 16.6 Hz), 2.07 (1H,
ddd, J=9.0, 11.5 and 12.6 Hz), 1.42 (9H, s, CH3 t-Bu). The
stereochemical assignment was supported by a 2D NOESY
spectrum, which showed correlations cross-peaks between
the protons of the OMe and the tert-butyl groups. No detect-
able significant cross-peak was detected from the NOESY
spectrum of the second diastereoisomer. 13C NMR
(100 MHz, CDCl3): d=174.6 (CO), 172.1 (CO), 169.8 (CO),
132.6 (Car), 132.5 (Car), 132.0 (Car), 128.6 (Car), 128.1 (CHar),
127.8 (CHar), 127.5 (CHar), 126.7 (CHar), 126.1 (CHar), 125.2
(12R, 12aR)-12-Ethyl 12a-methyl 12-methyl-3-oxo-
1,2,3,5,12,12a-hexahydrobenzo[g]pyrrolo
line-12,12a-dicarboxylate (trans-9c):
ACHTUNGTRENNUNG
1H NMR (400 MHz, CDCl3): d=7.94 (1H, s, CHar), 7.77
(2H, t, J=8.5 Hz, CHar), 7.63 (1H, s, CHar), 7.48–7.41 (2H,
m, CHar), 5.12 (1H, d, J=17.3 Hz, CH2N, A part of an AB
pattern), 4.66 (1H, d, J=17.0 Hz, CH2N, B part of an AB
pattern), 4.39–4.20 (2H, AB part of an ABX3 pattern,
OCH2), 3.55 (3H, s, OCH3), 2.77–2.70 (1H, m), 2.63–2.54
(1H, m), 2.49–2.39 (2H, m), 1.62 (3H, s, CH3), 1.31 (3H, t,
J=7.0 Hz, CH3). The stereochemical assignment was sup-
ported by a 2D NOESY spectrum, which showed correla-
tion cross-peaks between the protons of the singlet Me
group at 1.62 ppm and those of the OMe group at 3.55 ppm.
1
The characteristic H NMR signals of the minor cis diaste-
reomer are: d=5.06 (1H, d, J=16.8 Hz), 4.74 (1H, d, J=
16.8 Hz), 3.44 (3H, s), 2.81–2.73 (1H, m), 1.88 (3H, s);
13C NMR (100 MHz, CDCl3): d=174.9 (CO), 172.3 (CO),
171.9 (CO), 135.4 (Car), 132.4 (Car), 132.3 (Car), 129.1 (Car),
128.1 (CHar), 127.1 (CHar), 126.6 (CHar), 126.3 (CHar), 125.9
(CHar), 125.0 (CHar), 70.3 (C-12a), 61.9 (OCH2), 53.8 (C12),
52.7 (OCH3), 42.7 (CH2N), 29.9 (CH2), 26.6 (CH2), 24.3
(CH3), 14.2 (CH3); HR-MS (ESI): m/z=382.1649, calcd. for
[M+H]+ C22H24NO5: 382.1649. Chiral HPLC separation of
(CHar), 82.7 [OCACHTUNTRGNEG(UN CH3)3], 67.1 (C-12a), 55.9 (CH), 52.7
(OCH3), 41.9 (CH2N), 32.8 (CH2), 30.1 (CH2), 28 (3CH3);
HR-MS (ESI): m/z=396.1805, calcd. for [M+H]+
C23H26NO5: 396.1805. Chiral HPLC separation of enantio-
mers (Chiralpak IA, hexane/ethanol/chloroform 8/1/1,
1 mLminÀ1, detection UV 230 nm and CD 254 nm):
Rt
G
G
kACTHNGUTERNNU(G 12S,12aR)=
1.07, kACTHNUGNRTE(NUG 12R,12aS)=2.12, a=1.98 and Rs=5.10; ee=91%;
enantiomers
(Chiralpak
IC,
hexane/ethanol
(12R,12aR)=20.05,
(12S,12aS)=7.02,
7/3,
[a]30: À58.6 (c 1.41, CH2Cl2).
1 mLminÀ1, detection UV 230 nm): Rt
G
(D12R,12aR)-12-tert-Butyl
12a-methyl
3-oxo-
Rt
G
(12R,12aR)=5.68, k
G
1,2,3,5,12,12a-hexahydrobenzo[g]pyrrolo
line-12,12a-dicarboxylate (trans-9d):
ACHTUNGTREN[NUGN 1,2-b]isoquino-
a=1.24; ee=91%; [a]30: À33.9 (c 0.28, CH2Cl2).
Yellowish
oil.
(S)-Methyl
1-{[3-D(3-ethoxy-3-oxoprop-1-en-2-yl)naph-
1H NMR (400 MHz, CDCl3): d=7.80 (2H, m, CHar), 7.72
(1H, s, CHar), 7.69 (1H, s, CHar), 7.49–7.42 (2H, m, CHar),
5.12 (1H, d, J=17.3 Hz, CH2N, A part of an AB pattern),
4.66 (1H, d, J=17.3 Hz, CH2N, B part of an AB pattern),
4.49 (1H, s, CH), 3.52 (3H, s, OCH3), 2.64–2.53 (1H, m),
thalen-2-yl]methyl}-5-oxopyrrolidine-2-carboxylate (S-11):
Yellowish oil. 1H NMR (400 MHz, CDCl3): d=7.81–7.78
(2H, m, CHar), 7.64 (2H, s, CHar), 7.50–7.47 (2H, m, CHar),
6.58 (1H, d, J=1.5 Hz, Ha of =CHaHb), 5.82 (1H, d, J=
Adv. Synth. Catal. 2012, 354, 1987 – 2000
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1995

Shovan Mondal et al.
FULL PAPERS
2.52–2.36 (3H, m), 1.32 (9H, s, t-Bu); 13C NMR (100 MHz,
CDCl3): d=174.6 (CO), 172.7 (CO), 169.2 (CO), 133.2 (Car),
132.2 (Car), 129.4 (Car), 128.5 (Car), 128.1 (CHar), 127.7
(CHar), 127.5 (CHar), 126.7 (CHar), 126.2 (CHar), 126.0
boxylate (cis-10b): Yellowish oil. 1H NMR (400 MHz,
CDCl3): d=7.87 (1H, s, CHar), 7.84 (1H, s, CHar), 7.83 (1H,
superimposed d, J=7.5 Hz, CHar), 7.64 (1H, d, J=8.0 Hz,
CHar), 7.49 (1H, td, J=6.8 and 1.3 Hz, CHar), 7.41 (2H, 2
superimposed td, J=7.0 and 1.0 Hz, CHar), 7.27 (2H, t, J=
8.0 Hz, CHar), 7.01 (1H, tt, J=7.3 and 1.0 Hz, CHar), 6.95–
6.93 (2H, m, CHar), 6.88 (2H, t, J=8.3 Hz, CHar), 6.44 (2H,
br d, J=7.5 Hz, CHar), 5.31 (1H, d, J=8.8 Hz, CH2O, A
part of an AB pattern), 5.18 (1H, d, J=17.3 Hz, CH2N, A
part of an AB pattern), 5.06 (1H, d, J=16.8 Hz, CH2N, B
part of an AB pattern), 4.62 (1H, d, J=8.8 Hz, CH2O, B
part of an AB pattern), 4.18–4.07 (2H, A part of an ABX3
pattern, OCH2), 1.04 (3H, t, J=7.0 Hz, CH2); 13C NMR
(100 MHz, CDCl3): d=171.7 (CO), 158.9 (CO), 142.9 (Car),
135.6 (Car), 132.6 (Car), 132.2 (Car), 131.7 (Car), 131.5
(2CHar), 130.7 (CHar), 130.2 (Car), 128.6 (2CHar), 128.4
(CHar), 128.2 (CHar), 127.6 (2CHar), 127.5 (CHar), 127.1
(CHar), 127.0 (2CHar), 126.1 (CHar), 125.2 (CHar), 74.6
(OCH2), 67.2 (C-12a), 64.8 (C-12), 62.3 (OCH2), 46.1
(CH2N), 13.8 (CH3); HR-MS (ESI): m/z=464.1855, calcd.
for [M+H]+ C30H26NO4: 464.1856. Chiral HPLC separation
of enantiomers (Chiralpak IB, hexane/ethanol 7/3,
1 mLminÀ1, detection UV 230 nm and CD 254 nm):
(CHar), 82.6 [OCACHTUNGTRENNUNG(CH3)3], 67.2 (C-12a), 53.4 (CH), 53.2
(OCH3), 43.1 (CH2N), 29.5 (CH2), 27.9 (3CH3), 27.6 (CH2);
HR-MS (ESI): m/z=396.1804, calcd. for [M+H]+
C23H26NO5: 396.1805. Chiral HPLC separation of enantio-
mers (Chiralpak IC, hexane/ethanol 7/3, 1 mLminÀ1, detec-
tion UV 240 nm and CD 254 nm): RtACHTNUGTRENNUNG
Rt
(12R,12aR)=11.58,
k
(12S,12aS)=2.05,
kACHTUNGTRENNUNG
2.86, a=1.39 and Rs=2.95; ee=79%; [a]3D0: À30.1 (c 2.58,
CH2Cl2).
Coupling of (Æ)-4’ with 7d: Enediyne (Æ)-4’ (100 mg,
0.31 mmol), diazo ester 7d (61.5 mg, 0.43 mmol) and CuI
(3 mg, 5 mol%) in dry acetonitrile (250 mL) for 2 h at 808C.
The mixture was purified by column chromatography (30%
ethyl acetate/pentane) to afford (Æ)-cis-9’d (yield: 50 mg,
37%) and (Æ)-trans-9’d (yield: 50 mg, 37%).
(Æ)-Di-tert-butyl
3-oxo-1,2,3,5,12,12a-hexahydro-
benzo[g]pyrroloACHTUNGTRENNUNG[1,2-b]isoquinoline-12,12a-dicarboxylate
(cis-9’d): Yellowish oil. 1H NMR (400 MHz, CDCl3): d=
7.86 (1H, s, CHar), 7.80–7.75 (2H, m, CHar), 7.64 (1H, s,
CHar), 7.49–7.42 (2H, m, CHar), 5.11 (1H, d, J=16.3 Hz,
CH2N, A part of an AB pattern), 4.58 (1H, d, J=16.3 Hz,
CH2N, B part of an AB pattern), 4.10 (1H, s, CH), 2.78
(1H, ddd, J=1.2, 8.5 and 12.6 Hz), 2.62–2.53 (1H, m), 2.32
(1H, ddd, J=1.3, 9.3 and 16.6 Hz), 2.09–2.01 (1H, m), 1.47
(9H, s, t-Bu), 1.30 (9H, s, t-Bu). The assignment follows
from the analogy with the spectrum of cis-9d. 13C NMR
(100 MHz, CDCl3): d=174.7 (CO), 170.2 (CO), 169.5 (CO),
132.5 (Car), 132.4 (Car), 131.8 (Car), 129.2 (Car), 127.9 (CHar),
127.6 (CHar), 127.4 (CHar), 126.5 (CHar), 126.0 (CHar), 124.9
(CHar), 82.9 (C), 82.5 (C), 67.4 (C), 55.6 (CH), 42.3 (CH2N),
32.5 (CH2), 30.2 (CH2), 28.2 (3 CH3), 27.9 (3CH3); HR-MS
(ESI): m/z=438.2272, calcd. for [M+H]+ C26H32NO5:
438.2275.
Rt
G
E
kACTHNGUTERNNU(G 12S,12aR)=
1.24, kAHCNUTGTRENNUNG
0.41, CH2Cl2).
(12R, 12aR)-Ethyl 3-oxo-12,12a-diphenyl-3,5,12,12a-
tetrahydro-1H-benzo[g]oxazolo [3,4-b]isoquinoline-12-car-
boxylate (trans-10b): White solid; mp 90.38C. 1H NMR
(400 MHz, CDCl3): d=8.80 (1H, s, CHar), 7.80 (1H, d, J=
8.8 Hz, CHar), 7.73 (1H, d, J=7.8 Hz, CHar), 7.59 (1H, s,
CHar), 7.46–7.42 (2H, m, CHar), 7.29–7.24 (5H, m, CHar),
7.19–7.16 (3H, m, CHar), 7.03 (2H, 2 superimposed dt, J=
6.7 and 1.8 Hz, CHar), 5.05 (1H, d, J=17.3 Hz, CH2N, B of
an AB pattern), 4.87 (1H, d, J=10.3 Hz, CH2O, A part of
an AB pattern), 4.68 (1H, d, J=10.6 Hz, CH2O, B part of
an AB pattern), 4.29–4.20 (2H, AB part of an ABX3 pat-
tern, OCH2), 4.02 (1H, d, J=17.1 Hz, CH2N, B part of an
AB pattern), 1.02 (3H, t, J=7.0 Hz, CH3); 13C NMR
(100 MHz, CDCl3): d=172.2 (CO), 156.2 (CO), 141.6 (Car),
141.5 (Car), 134.8 (Car), 132.6 (Car), 131.9 (Car), 130.7 (CHar),
128.8 (2CHar), 128.7 (CHar), 128.66 (2CHar), 128.60 (2CHar),
128.5 (Car), 128.0 (CHar), 127.9 (CHar), 126.9 (CHar), 126.8
(CHar), 126.7 (2CHar), 126.0 (CHar), 124.8 (CHar), 75.0
(OCH2), 66.9 (C12a), 61.9 (OCH2), 60.5 (C-12), 41.6 (CH2N),
13.6 (CH3); HR-MS (ESI): m/z=464.1848, calcd. for [M+
H]+ C30H26NO4: 464.1856. Chiral HPLC separation of enan-
tiomers (Chiralpak IC, hexane/ethanol 9/1, 1 mLminÀ1, de-
(Æ)-Di-tert-butyl
3-oxo-1,2,3,5,12,12a-hexahydro-
benzo[g]pyrrolo[1,2-b]isoquinoline-12,12a-dicarboxylate
ACHTUNGTRENNUNG
(trans-9’d): White solid; mp 142.08C (CH3CN). 1H NMR
(400 MHz, CDCl3): d=7.79–7.77 (2H, m, CHar), 7.69 (2H, s,
CHar), 7.49–7.42 (2H, m, CHar), 5.07 (1H, d, J=17.1 Hz,
CH2N, A part of an AB pattern), 4.66 (1H, d, J=17.0 Hz,
CH2N, B part of an AB pattern), 4.40 (1H, s, CH), 2.61–2.53
(1H, m), 2.49–2.37 (3H, m), 1.32 (9H, s, t-Bu), 1.11 (9H, s,
t-Bu); 13C NMR (100 MHz, CDCl3): d=174.6 (CO), 171.2
(CO), 169.3 (CO), 133.1 (Car), 132.1 (Car), 130.0 (Car), 129.0
(Car), 128.0 (CHar), 127.7 (CHar), 127.5 (CHar), 126.6 (CHar),
126.1 (CHar), 125.8 (CHar), 83.0 (C), 82.5 (C), 67.8 (C), 54.1
(CH), 43.6 (CH2N), 29.7 (CH2), 27.9 (3CH3), 27.6 (3CH3),
27.2 (CH2); HR-MS (ESI): m/z=438.2276, calcd. for [M+
H]+ C26H32NO5: 438.2275.
tection UV 230 nm and CD 254 nm): RtACHTNUGTRENNUNG
Rt
N
k
A
kACHTUNGTRENNUNG
5.47, a=1.14; ee=91%. [a]3D0: +123.7 (c 1.46, CH2Cl2). The
structure was confirmed by X-ray crystallography.
Coupling of (S)-5 with 7b: Enediyne (S)-5 (50 mg,
0.166 mmol) was allowed to react with diazo ester 7b
(44.2 mg, 0.23 mmol) and CuI (1.6 mg, 5 mol%) in dry ace-
tonitrile (125 mL) for 2 h at room temperature. The products
was purified by column chromatography (30% ethyl acetate/
pentane) to afford compounds 12S,12aR)-10b (yield: 25 mg,
32%, ee=95%) and (12R,12aR)-10b (35 mg, 46%, ee=
91%).
Coupling of (R)-5 with 7b: Enediyne (R)-5 (200 mg,
0.66 mmol, >99.5% ee) was allowed to react with diazo
ester 7b (177 mg, 0.93 mmol) and CuI (6 mg, 5 mol%) in dry
acetonitrile (500 mL) for 2 h at room temperature. The prod-
ucts was purified by column chromatography (30% ethyl
acetate/pentane) to afford compounds (12R,12aS)-10b
(yield: 118.5 mg, 39%, ee=97%) and (12S,12aS)-10b (yield:
138 mg, 45%, ee=89%).
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
1996
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1987 – 2000

Copper Carbenoid, Reactant and Catalyst for One-Pot Diazo Ester Coupling Cascade Rearrangement
A
(CH), 44.5 (CH2N), 14.3 (CH3); HR-MS (ESI): m/z=
402.1699, calcd. for [M+H]+ C25H24NO4: 402.1700.
Coupling of (S)-6 with 7a: Enediyne (S)-6 (100 mg,
0.25 mmol) was allowed to react with diazo ester 7a
(40.4 mg, 0.35 mmol) and CuI (2.5 mg, 5 mol%) in dry ace-
tonitrile (250 mL) for 2 h at 808C. The products were puri-
fied by column chromatography (DCM) to afford (3R,4S)-
13a (yield: 36 mg, 30%, ee=80%), (3R,4R)-13a (yield:
28.5 mg, 24%, ee=88%). The presence of alkene 14 was in-
ferred from the analysis of the 1H NMR spectrum of the
crude reaction mixture. No pure sample could be isolated.
An approximate 10% yield was calculated from this spec-
trum. The characteristic signals were obtained from an en-
riched intermediate chromatographic fraction.
ACHTUNGTRENNUNG
Coupling of (S)-5 with 7c: Enediyne (S)-5 (100 mg,
0.33 mmol) was allowed to react with diazo ester 7c
(59.5 mg, 0.46 mmol) and CuI (3.2 mg, 5 mol%) in dry ace-
tonitrile (250 mL) for 1 h at 808C. The products were puri-
fied by column chromatography (DCM) to afford com-
pounds (12S, 12aR)-10c (yield: 45 mg, 34%, ee=97.5%) and
olefin S-12 (yield: 15 mg, 9% (corrected yield. Compound
12 could not be isolated as a pure sample as it was contami-
nated by 10% of 10c).
G
12-methyl-3-oxo-12a-phenyl-
[3,4-b]isoquino-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
line-12-carboxylate (10c): Yellowish oil. 1H NMR
(400 MHz, CDCl3): d=8.90 (1H, s, CHar), 8.00 (1H, m,
CHar), 7.81 (1H, m, CHar), 7.60 (1H, s, CHar), 7.58 (2H, m,
CHar), 7.31–7.29 (2H, m, CHar), 7.26–7.24 (3H, m, CHar),
5.28 (1H, d, J=10.3 Hz, CH2O, A part of an AB pattern),
5.09 (1H, d, J=17.6 Hz, CH2N, A part of an AB pattern),
4.92 (1H, d, J=10.3 Hz, CH2O, B part of an AB pattern),
4.35 (1H, d, J=17.1 Hz, CH2N, B part of an AB pattern),
4.35–4.27 (2H, superimposed AB part of an ABX3 pattern,
OCH2), 1.93 (3H, s, CH3), 1.25 (3H, t, J=7.0, CH2CH3).
The stereochemical assignment follows from the observation
of a cross-peak between the signal of protons of the methyl
group at 1.93 ppm and that of one the protons in position
a relative to nitrogen atom (5.28 ppm). This correlation is in
agreement with the Chem-3D model. Such a spatial proxim-
ity does not exist in the other diastereomer. 13C NMR
(100 MHz, CDCl3): d=173.2 (CO), 157.1 (CO), 141.0 (Car),
135.7 (Car), 132.5 (Car), 131.9 (Car), 128.5 (CHar), 128.4
(2CHar), 128.0 (CHar), 127.8 (Car), 127.4 (CHar), 127.1
(2CHar), 126.9 (CHar), 126.7 (CHar), 126.1 (CHar), 125.4
(CHar), 74.6 (OCH2), 66.3 (C-12a), 61.7 (OCH2), 52.2 (C-
12), 42.4 (CH2N), 27.6 (CH3), 13.9 (CH3); HR-MS (ESI):
m/z=402.1699, calcd. for [M+H]+ C25H24NO4: 402.1700.
Chiral HPLC separation of enantiomers (Chiralpak IA,
hexane/ethanol 1/1, 1 mLminÀ1, detection UV and CD
1
Colorless oil. H NMR (400 MHz, CDCl3): d=7.81 (2H, d,
J=8.3, CHar), 7.78–7.65 (2H, m, CHar), 7.75 (1H, s, CHar),
7.61 (1H, s, CHar), 7.50–7.45 (2H, m, CHar), 7.28 (2H, d, J=
8.3 Hz, CHar), 4.90 (1H, d, J=15.0 Hz, CH2N, A part of an
AB pattern), 4.79 (1H, d, J=14.8 Hz, CH2N, B part of an
AB pattern), 4.38 (1H, s, CH), 4.19 (2H, q, J=7.3 Hz,
OCH2), 3.63 (3H, s, OCH3), 2.41 (3H, s, CH3), 1.74 (3H, s,
CH3), 1.26 (3H, t, J=7.3 Hz, CH3). The stereochemical as-
signment follows from the presence of a cross-peak between
the signals of the protons of the methoxy group at 3.63 ppm
and those of the methyl group of CO2Et (t at 1.26 ppm) and
another cross-peak between the signal of the proton at
4.38 ppm and the protons of methyl (s at 1.74 ppm).
13C NMR (100 MHz, CDCl3): d=173.1 (CO), 169.3 (CO),
143.4 (Car), 138.8 (Car), 132.8 (Car), 132.7 (Car), 131.3 (Car),
129.7 (2CHar), 129.1 (Car), 127.9 (CHar), 127.6 (CHar), 127.3
(2CHar), 126.7 (CHar), 126.7 (CHar), 126.3 (CHar), 124.8
(CHar), 65.3 (C), 61.6 (OCH2), 54.7 (CH), 53.0 (OCH3), 47.8
(CH2N), 21.6 (2CH3), 14.2 (CH3); HR-MS (ESI): m/z=
482.1630, calcd. for [M+H]+ C26H28NO6S: 482.1632. Chiral
HPLC separation of enantiomers (Chiralpak IB, hexane/2-
propanol 95/5, 1 mLminÀ1, detection UV 230 nm and CD
254 nm): Rt
6.87, k
(3R,4S)=8.60, a=1.25 and Rs=2.83; ee=80%; [a]3D0:
+7.4 (c 0.60, CH2Cl2).
(3R,4R)-4-Ethyl 3-methyl 3-methyl-2-tosyl-1,2,3,4-tet-
rahydrobenzo[g]isoquinoline-3,4-dicarboxylate (trans-
ACHTUNGTNER(UNGN 3S,4R)=23.61, RtACHTUNRTGENG(NUN 3R,4S)=28.81, kACTHNUGTRENUN(GN 3S,4R)=
AHCTUNGTRENNUNG
254 nm):
Rt
G
RtACTHUNGTERNNU(G 12S,12aR)=6.50,
AHCTUNGTRENNUNG
kACHTUNGTRENNUNG(12R,12aS)=0.86, kACHUTNGTREN(NGUN 12S,12aR)=1.17, a=1.36 and Rs=
2.97; ee=97%; [a]3D0: +145.4 (c 1.46, CH2Cl2).
13a): Colorless oil. 1H NMR (400 MHz, CDCl3): d=7.89
(2H, d, J=8.3 Hz, CHar), 7.80–7.76 (2H, m, CHar), 7.67
(1H, s, CHar), 7.58 (1H, s, CHar), 7.49–7.47 (2H, m, CHar),
7.28 (2H, d, J=8.0 Hz, CHar), 4.76 (1H, d, J=14.3 Hz,
CH2N, A part of an AB pattern), 4.60 (1H, d, J=14.6 Hz,
CH2N, B part of an AB pattern), 4.18–4.09 (2H, AB part of
an ABX3 pattern, OCH2), 4.05 (1H, s, CH), 3.81 (3H, s,
OCH3), 2.41 (3H, s, CH3), 1.70 (3H, s, CH3), 1.22 (3H, t, J=
7.3 Hz, CH3); 13C NMR (100 MHz, CDCl3): d=172.2 (CO),
169.8 (CO), 143.6 (Car), 137.6 (Car), 133.1 (Car), 132.8 (Car),
131.5 (Car), 129.7 (2CHar), 129.0 (Car), 128.0 (2CHar), 127.8
(CHar), 127.7 (CHar), 127.5 (CHar), 126.8 (CHar), 126.5
(CHar), 125.4 (CHar), 65.7 (C), 61.8 (OCH2), 57.7 (CH), 52.9
(OCH3), 47.1 (CH2N), 26.3 (CH3), 21.7 (CH3), 14.1 (CH3).
The deshielding of the carbon of the methyl group at
26.3 ppm in trans isomer/21.6 ppm in the cis isomer (where
there is an additional gauche interaction) confirms the ste-
reochemical assignment. HR-MS (ESI): m/z=482.1627,
calcd. for [M+H]+ C26H28NO6S: 482.1632. Chiral HPLC
(S)-Ethyl 2-{3-[(2-oxo-4-phenyloxazolidin-3-yl)methyl]-
napthalen-2-yl}acrylate (S-12): sample contaminated with
10c; 1H NMR (400 MHz, CDCl3): d=7.82–7.79 (1H, m,
CHar), 7.74–7.71 (1H, m, CHar), 7.64 (1H, s, CHar), 7.50–7.48
(1H, m, CHar), 7.49 (1H, superimposed d, J=9.5 Hz, CHar),
7.42 (1H, s, CHar), 7.37–7.35 (2H, m, CHar), 7.11–7.09 (3H,
m, CHar), 6.52 (1H, d, J=1.5 Hz, =CHaHb), 5.68 (1H, d, J=
1.5 Hz, =CHaHb), 5.02 (1H, d, J=15.0 Hz, CH2N, A part of
an AB pattern), 4.54 (1H, pseudo t, J=8.8 Hz, CH), 4.44
(1H, dd, J=9.0 and 5.2 Hz, CH2O), 4.21–4.18 (2H, AB part
of an ABX3 pattern, OCH2), 4.10 (1H, dd, J=8.3 and
5.2 Hz, CH2O), 3.78 (1H, d, J=15.0 Hz, CH2N, B part of an
AB pattern), 1.27 (3H, t, J=7.3 Hz, CH2CH3); 13C NMR
(100 MHz, CDCl3): d=166.4 (CO), 158.0 (CO), 140.5 (Car),
138.2 (Car), 135.5 (Car), 132.9 (Car), 132.8 (Car), 131.4 (Car),
129.7 (CHar), 129.3 (2CHar), 129.3 (=CH2), 129.1 (CHar),
128.6 (CHar), 127.8 (CHar), 127.7 (CHar), 127.2 (2CHar),
126.7 (CHar), 126.6 (CHar), 70.1 (OCH2), 61.5 (OCH2), 58.6
Adv. Synth. Catal. 2012, 354, 1987 – 2000
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1997

Shovan Mondal et al.
FULL PAPERS
separation of enantiomers (Chiralpak IC, hexane/ethanol
1/1, 1 mLminÀ1, detection UV 230 nm and CD 254 nm):
48.2 (CH2N), 21.7 (CH3), 19.9 (CH3), 13.7 (CH3); HR-MS
(ESI): m/z=558.1942, calcd. for [M+H]+ C32H32NO6S:
558.1945. Chiral HPLC separation of enantiomers (Lux-Cel-
lulose-4, hexane/ethanol 1/1, 1 mLminÀ1, detection UV and
Rt
N
Rt
A
kACHTNGUTERN(UNG 3R,4R)=2.05,
kACHTUNGTRENNUNG
CD
kG
254 nm):
Rt
N
RtACHTNGUTERNNU(G 3S,4R)=25.37,
+49.5 (c=0.22, CH2Cl2).
Characteristic signals of 14a: 1H NMR (400 MHz,
CDCl3): d=6.17 (1H, s, =CHaHb), 5.61 (1H, s, =CHaHb),
4.83 (2H, s, CH2N), 4.10 (2H, s, CH2O), 3.58 (3H, s, CH3O),
1.27 (3H, t, J=7.3, CH3).
ee=92%; [a]3D0: À8.3 (c=0.30, CH2Cl2). The absolute config-
uration could be determined from X-ray cyrstallographic
(Cu-irradiation) data.
Methyl 2-{N-[(3-(2-ethoxy-2-oxo-1-phenylethyl)naphtha-
len-2-yl]methyl}-4-methylphenylsulfonamido)acrylate (14b):
Colourless oil; H NMR (400 MHz, CDCl3): d=7.88 (1H, s,
Coupling of (S)-6 with 7b: Enediyne (S)-6 (100 mg,
0.25 mmol) was allowed to react with diazo ester 7b
(67.3 mg, 0.35 mmol) and CuI (2.4 mg, 5 mol%) in dry ace-
tonitrile (250 mL) for 2 h at room temperature. The products
were purified by preparative HPLC [the product was dis-
solved in a mixture of ethanol and chloroform and separated
under the following conditions: Chiralpak IA (250ꢆ10 mm),
eluent hexane/2-propanol (80/20), 5 mLminÀ1, UV detector
at 254 nm] to afford (3R,4S)-13b (yield: 42 mg, 30%, ee=
94%), (3R,4R)-13b (yield: 42 mg, 30%, ee=92%) and
alkene 14b (yield: 18 mg, 13%). The chiral column was used
to separate the diastereomers, which did not affect the ees.
1
CHar), 7.80 (1H, d, J=8.0 Hz, CHar), 7.69 (2H, d, J=8.0 Hz,
CHar), 7.66 (1H, d, J=7.8 Hz, CHar), 7.55 (1H, s, CHar),
7.49–7.41 (3H, m, CHar), 7.32–7.30 (6H, m, CHar), 6.10 (1H,
s, CH), 5.70 (1H, s, =CHaHb), 5.57 (1H, s, =CHaHb), 4.83
(1H, d, J=13.6, CH2N, A part of an AB pattern), 4.59 (1H,
d, J=13.6, CH2N, B part of an AB pattern), 4.25 (2H, q, J=
7.0 Hz, OCH2CH3), 3.54 (3H, s, OCH3), 2.45 (3H, s, CH3),
1.27 (3H, t, J=7.0 Hz, CH2CH3); 13C NMR (100 MHz,
CDCl3): d=172.8 (CO), 164.0 (CO), 144.0 (Car), 137.8 (Car),
135.5 (Car), 134.7 (Car), 133.2 (Car), 132.4 (Car), 131.0 (CHar),
130.9 (Car), 130.3 (C), 129.6 (3CHar), 129.4 (2CHar), 128.6
(2CHar), 128.1 (2CHar), 128.0 (CHar), 127.9 (CHar), 127.5
(CHar), 127.4 (CHar), 126.8 (CHar), 126.5 (=CH2), 61.5
(OCH2), 52.5 (CH), 52.3 (OCH3), 50.7 (CH2N), 21.8 (CH3),
14.1 (CH3); HR-MS (ESI): m/z=482.1627, calcd. for [M+
H]+ C26H28NO6S: 482.1632.
ACHTUNGTRENNUNG(3R,4S)-4-Ethyl 3-methyl 3-methyl-4-phenyl-2-tosyl-
1,2,3,4-tetrahydrobenzo[g]isoquinoline-3,4-dicarboxylate
1
(cis-13b): Colourless oil; H NMR (400 MHz, CDCl3): d=
7.82 (2H, d, J=8.3 Hz, CHar), 7.80 (1H, s, CHar), 7.77 (1H,
d, J=8.0 Hz, CHar), 7.68 (1H, s, CHar), 7.64 (1H, d, J=
8.3 Hz, CHar), 7.45 (1H, td, J=7.8 and 1.0 Hz, CHar), 7.38
(1H, td, J=8.0 and 1.0 Hz, CHar), 7.30–7.26 (7H, m, CHar),
5.08 (1H, d, J=16.0 Hz, CH2N, A part of an AB pattern),
4.68 (1H, d, J=16.0 Hz, CH2N, B part of an AB pattern),
4.17–4.10 (1H, m, OCH2), 3.96–3.88 (1H, m, OCH2), 3.62
(3H, s, OCH3), 2.42 (3H, s, CH3), 1.43 (3H, s, CH3), 0.87
(3H, t, J=7.3 Hz, CH3); 13C NMR (100 MHz, CDCl3): d=
171.7 (CO), 170.8 (CO), 143.6 (Car), 138.5 (Car), 137.7 (Car),
133.1 (Car), 132.3 (Car), 132.1 (Car), 132.0 (CHar), 130.8 (Car),
129.8 (CHar), 129.5 (2CHar), 128.2 (CHar), 127.9 (2CHar),
127.8 (CHar), 127.1 (2CHar), 127.0 (CHar), 126.8 (CHar),
125.9 (CHar), 124.3 (CHar), 68.8 (C), 64.4 (C), 61.7 (OCH2),
52.6 (OCH3), 46.9 (CH2N), 22.0 (CH3), 21.7 (CH3), 13.6
(CH3); HR-MS (ESI): m/z=558.1947, calcd. for [M+H]+
C32H32NO6S: 558.1945. Chiral HPLC separation of enantio-
mers (Chiralpak AD-H, hexane/2-propanol 8/2, 1 mLminÀ1,
Acknowledgements
The work is funded by ANR-10-JCJC-0710-MOCER2 and
the University de Provence via the post-doctoral grant of S.
Mondal. We also acknowledge Arie Vander-Lee and Michel
Giorgi for X-ray analyses, Christophe Chendo for HR-MS
and Marion Jean for chiral HPLC.
References
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Rt(3R,4R)=28.43, k(3S,4S)=7.48, k(3R,4R)=8.48, a=1.13
and Rs=1.62; ee=94%; [a]3D0: +41.5 (c 0.55, CH2Cl2).
(3R,4R)-4-Ethyl 3-methyl 3-methyl-4-phenyl-2-tosyl-
ACHTUNGTREN(NGNU 3S,4S)=25.45,
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G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
1,2,3,4-tetrahydrobenzo[g]isoquinoline-3,4-dicarboxylate
(trans-13b): White solid; mp 167.08C (CH3CN). 1H NMR
(400 MHz, CDCl3): d=7.85 (2H, d, J=8.3 Hz, CHar), 7.81
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tern), 4.86 (1H, d, J=14.8 Hz, CH2N, B part of an AB pat-
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(3H, s, CH3), 1.88 (3H, s, CH3), 0.93 (3H, t, J=7.3 Hz,
CH3); 13C NMR (100 MHz, CDCl3): d)=172.0 (CO), 170.5
(CO), 143.2 (Car), 140.0 (Car), 136.5 (Car), 133.2 (Car), 133.0
(Car), 132.7 (Car), 132.4 (Car), 131.9 (2CHar), 129.6 (2CHar),
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127.3 (CHar), 127.1 (2CHar), 126.7 (CHar), 125.8 (CHar),
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