Highly Diastereo- and Enantioselective Synthesis of α-Spiro-δ-lactams by an Organocascade Reaction

Article abstract of DOI:10.1002/ejoc.201700193

An asymmetric synthesis of α-spiro-δ-lactams by an organocascade reaction of easily accessible starting materials has been accomplished. The catalytic sequence begins with enantioselective Michael addition of a β-ketoamide to an α,β-unsaturated aldehyde,

Full text of DOI:10.1002/ejoc.201700193

A Journal of
Accepted Article
Title: Highly Diastereo and Enantioselective Synthesis of α-spiro-δ-
lactams via Organocascade Reaction
Authors: Kaiheng Zhang, Marta Meazza, Vojtěch Dočekal, Mark. E.
Light, jan Vesely, and Ramon Rios Torres
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700193
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700193
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10.1002/ejoc.201700193
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/chem.200((……))
Highly Diastereo and Enantioselective Synthesis of α-spiro-δ-lactams via
Organocascade Reaction
Kaiheng Zhang[a], Marta Meazza*[a], Vojtěch Dočekal [b], Mark E. Light[a], Jan Veselý *[b], Ramon
Rios*[a]
Abstract: An asymmetric synthesis of secondary amine catalyst, followed by
α-spiro-δ-lactam via organocascade hemiaminal
annulation.
Optically
Keywords: Spiro lactams ·
Organocatalysis · Asymmetric
synthesis · Michael addition ·
Enantioselective
reaction from easily accessible starting enantiopure compounds with three
materials is reported. The catalytic stereogenic centres are obtained in good
sequence undergoes enantioselective yields and excellent selectivities (up to
Michael addition of β-ketoamide to α,β- >20:1 dr and up to >99% ee).
unsaturated aldehyde catalysed by a
was reported by Rodriguez.8b Therefore, the high stereocontrol of
spirocyclic lactam compounds bearing several stereogenic centres via
new approaches remains a challenging and important objective.
Introduction
Cascade reactions are a useful methodology for the synthesis of
chemical compounds.1 Starting from easily accessible substrates,
without modifying the reaction conditions, two or more new bonds
are sequentially formed in only one-step. This avoids the process of
purification after each step and protection-deprotection of functional
groups. It increases the efficiency of the procedures, addressing the
problems of the handling of waste and the quest for environmentally
tolerable procedures. Since the renaissance of organocatalysis,
asymmetric organocascade reactions allowed for a direct access to
complex frameworks.2
The unique skeleton of bicyclic α-spiro-δ-lactam is common
among natural products, showing considerable potential in drug
discovery3 and new ligands4 (Figure 1). In previous researches, the
preparation of bicyclic spiro-lactam compounds was disclosed via
rearrangement,5 gold catalyzed reactions,6 Mn(III)-radical
cyclization7 and organocatalytic conjugate addition,8 while an
asymmetric version, catalyzed by non-covalent H-bonding activation
Figure 1. Natural and pharmaceutical products containing the spiro lactam scaffold
The diarylprolinol silyl ether chiral secondary amine catalysts
play a crucial role in one-pot asymmetric organocascade reactions.9
They were employed in previously reported double
Michael/hemiaminalization organocascade reactions for the
construction of diverse optically active molecules from simple achiral
materials. These C-C, C-N consecutive bond-forming reactions have
attracted considerable attention in the past decade.10
[a]
[b]
Kaiheng Zhang, Dr. Marta Meazza, Dr. Mark E. Light, Dr. Ramon Rios
School of Chemistry
University of Southampton
Highfield Campus, SO17 1BJ, UK
E-mail: rrt1f11@soton.ac.uk
E-mail: marta.meazza1@gmail.com
For these reasons, we planned an asymmetric synthesis of α-
spiro-δ-lactam compounds via an organocatalyzed one-pot
Michael/hemiaminalization cascade reaction, based on our
knowledge in the synthesis of hetereocycles11 and aza-spirocyclic
compounds.12 Therefore, we envisioned the enantioselective
spirocyclization between a β-ketoamide with two nucleophilic sites
and an -unsaturated aldehyde with two electrophilic sites. c.13
Vojtěch Dočekal, Dr. Jan Veselý
Department of Organic Chemistry
Charles University in Prague
128 43 Praha 2, Czech Republic
E-mail: jxvesely@natur.cuni.cz
Supporting information for this article is available on the WWW under
http://www.chemeurj.org/ or from the author.
1
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10.1002/ejoc.201700193
European Journal of Organic Chemistry
mixture. [c] Isolated yield after flash column chromatography. [d] The ee was determined
by chiral HPLC. [e] CF3CH2OH was used as solvent. [f] CH2Cl2 was used as solvent.
Scheme 1. General scheme of the reaction developed
The absence of additive (Table 1, entry 1) led to the
corresponding product 3a, in low yield but high dr. The addition of
benzoic acid (BA) or NaOAc as additives gave full conversion and
excellent dr, while higher ee and yields were obtained with BA (Table
1, entries 2 and 3). Then we tested different solvents and toluene gave
the highest enantioselectivity (Table 1, entry 3) compared with other
protic or aprotic solvents (Table 1, entries 4 and 5), therefore, toluene
was chosen as the best solvent. The screening of different benzoic
acids showed that in the presence of stronger benzoic acids
derivatives (Table 1, entries 6-8), the enantioselectivity is slightly
improved, but lower yields were obtained. To our surprise, when the
optimal reaction conditions were tested with cinnamaldehyde 2f, a
low enantioselectivity was obtained (Table 1, entry 9). We discovered
that the enantioselectivity is time dependent (as previously reported
in the synthesis of DABCO derivatives by Rodriguez and
coworkers)14, probably due to the existence of a racemic non catalytic
pathway in conjunction with a retro Michael reaction. When the
reaction was stopped after 1 h, the ee significantly increased to 82%,
maintaining high dr and the same results were obtained with catalyst
II (Table 1, entries 10 and 11). Finally, combining the
trifluoromethyl-substituted diarylprolinolsilyl ether secondary amine
catalyst II with 2,4-dinitrobenzoic acid (Table 1, entries 11-13),
rendered the final product in an almost enantiopure form (>99% ee)
while the dr were lowered to 2:1.
Results and Discussion
We first tested the conjugate addition of N-benzyl-2-
oxocyclopentane-1-carboxamide 1a to crotonaldehyde 2a, catalyzed
by the secondary amine Jørgensen-Hayashi catalyst I.
Table 1. Screening of the reaction conditions between N-benzyl-2-oxocyclopentane-1-
carboxamide and enal 2a or 2f[a]
Entry
Cat.
R
Additive
Time
(h)
Conversion[b]
dr[b]
ee %[d]
(yield %[c]
67 (47)
99 (69)
99 (79)
99
)
1
I
I
I
I
I
I
Me
Me
Me
Me
Me
Me
-
24
14
14
14
14
14
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
n.d.
82
92
77
81
97
With the optimal conditions in hand, we investigated the reaction
scope (Scheme 2), testing the reaction of N-benzyl-2-
oxocyclopentane-1-carboxamide 1a with different α,β-unsaturated
aldehydes. All the alkyl substituted enals (2a-d) performed well,
rendering the final hemiaminal products 3a-d in good yields and
excellent stereoselectivities (>99% ee, >20:1 dr). Also when an ester
substituent was present, similar results were observed in the product
3e. Next, various aromatic enals were tested. A range of different
electron withdrawing (3g,h), electron donating (3m,n) and halogens
(3i-l) substituents were well tolerated, in both ortho, meta and para
positions, rendering the final products 3f-n in good yields, excellent
enantioselectivities but low diastereoselectivities compared to the
aliphatic aldehydes. Then we turned our attention to the scope of the
β-ketoamide substrate. To our delight, when we employed alkyl
substituted β-ketoamide (1b,c), the final products 3o,p were obtained
in excellent stereoselectivities although in slightly lower yields. The
introduction of an electron donating methoxy group on the phenyl
substituted amide (1d) afforded the product 3q in higher yield but
lower dr and ee. Moreover, the reaction also worked with N-benzyl-
2-oxocyclohexane-1-carboxamide 1e, rendering the final products 3r
and 3s in lower yields, excellent dr and ee when crotonaldehyde was
used (3r) while lower ee when cinnamaldehyde was used (3s). This
can be attributed to the longer reaction time needed for 3s, due to the
steric hindrance of the aromatic ring. When a methoxy substituent
was present on the phenyl ring of the β-ketoamide 1f, the product 3t
was obtained in lower dr and good ee.
2
NaOAc
BA
BA
BA
3
4[e]
5[f]
6
99 (80)
86 (52)
3,5-CF3-
BA
7
8
I
I
Me
Me
4-CN-
BA
14
14
99 (66)
99 (66)
>20:1
>20:1
94
95
2,4-
NO2-BA
9
I
Ph
Ph
Ph
Ph
BA
BA
BA
14
1
(70)
(59)
(60)
(66)
>20:1
>20:1
>20:1
2:1
6
10
11
12
I
82
82
99
II
II
1
2,4-
1
NO2-BA
The absolute configuration of 3a catalyzed by (S)-II catalyst was
determined by X-ray analysis and the other products were assigned
by analogy (Figure 2).
13
I
Ph
2,4-
1
(65)
2:1
87
NO2-BA
[a] The reactions were performed, unless otherwise noted, between 1a (0.2 mmol, 1
equiv), 2a or 2f (1.5 equiv), catalyst I or II (20 mol%), additive (20 mol%) and 1 ml of
toluene at room temperature. [b] Determined by 1H NMR analysis of the crude reaction
2
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10.1002/ejoc.201700193
European Journal of Organic Chemistry
Scheme 2. Scope of the reaction between -ketoamides 1a,f (1 equiv) and -unsaturated aldehydes 2a,n (1.5 equiv).
The reactions were performed on 0.2 mmol scale. [a] The reaction was performed for 14 h.
corresponding spiro compound 3. In the Michael addition step the
catalyst efficiently controls the enantioselectivity of the reaction as
the bulky group blocks the bottom face of the iminium ion
intermediate 4. For this reason the nucleophile 1 attacks from the Si
face forming a new C-C bond in a highly enantioselective fashion.
The pronucleophile 1’ can attack the iminium ion 4 following two
different trajectories (Scheme 3, bottom). Trajectory A where the
bulky ketoamide is far away of the catalyst will render the major
diastereomer. In the case of aliphatic enals, the steric hindrance
between the enal and the ketoamide is small, thus affording excellent
diastereoselectivities. When bigger aromatic enals are used, the steric
hindrance of both trajectories A and B have similar energies,
explaining the lower diastereoselectivity. The last step of the cascade
reaction is the hemiaminal cyclization. We suppose that this step
occurs after the hydrolysis of the catalyst. Considering that this
Figure 2. X-ray crystal structure of 3a obtained with the (S)-II catalyst.15
The mechanism of the reaction (Scheme 3, top) starts with a
Michael addition of the ketoamide, in its enol form 1’, to the enal 2,
catalyzed by the secondary amine II, followed by the intramolecular
hemiacetalization between the amide and the aldehyde to generate the
3
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10.1002/ejoc.201700193
European Journal of Organic Chemistry
reaction is under thermodynamic control, this will generate the most
stable six membered ring 3, where both substituents R and OH are in
equatorial positions.
Scheme 5. Derivatizations of 3a
Conclusion
In summary, we developed an organocascade reaction between
ketoamides and enals, leading to diastereoselective and
a
enantioselective synthesis of α-spiro-δ-lactam compounds bearing
three stereogenic centres. The reaction goes through a [3+3]
cyclization. The combination of trifluoromethyl-substituted
Jørgensen-Hayashi catalyst and 2,3-dinitrobenzoic acid enabled
excellent enantioselectivities with both aromatic and aliphatic -
unsaturated aldehydes, while lower diastereoselectivities were
obtained with aromatic enals. Remarkably, in all the examples the
final hemiaminals were stables at r.t., and were analysed without
problems in contrast with previously reported methodologies.8,13
Probably, the use of non electron-withdrawing protecting groups on
the nitrogen, increase the stability of the compounds. When
employing TMS-substituted Jørgensen-Hayashi catalyst with benzoic
acid, only one diastereomer was obtained with both aryl and alkyl
enals but only aliphatic products maintained excellent
enantioselectivities.
Experimental Section
Scheme 3. Proposed mechanism of the 3+3 cycloaddition and rationalization of the
diastereoselectivity.
General procedure: in a small vial, β-ketoamide 1 (0.2 mmol, 1.0 equiv), -
unsaturated aldehyde 2 (0.3 mmol, 1.5 equiv), additive (0.04 mol, 0.2 equiv) and
organocatalyst (0.04 mol, 0.2 equiv) were added in 1 ml of solvent, stirred at room
temperature. The crude mixture was purified by flash column chromatography (EtOAc:
hexane = 4:1 gradient to 1:1) to obtain the hemiaminal products 3.
This is suggested also by the treatment of the crude mixture of 3f,
consisting of 2 diastereomers in a ratio of 1.4:1, with HCl to obtain
the dehydrated compound 8a (Scheme 4). The isolated product 8a
consisted of a mixture of diastereomers in the same ratio as for 3f,
suggesting that the diastereoselectivity of this reaction is due to the
different face from which the pronucleophile attacks the enal.
Compound 3a: IR (CH2Cl2 liquid film): 3400, 2962, 1739, 1640, 1496, 1453, 1385, 1262,
1152, 733 cm-1. mp: 152-163 oC. 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.20 (m, 5H), 4.97
(d, J = 14.9 Hz, 1H), 4.77 (d, J = 6.7 Hz, 1H), 4.34 (d, J = 14.8 Hz, 1H), 2.66 – 2.54 (m,
1H), 2.33 – 2.08 (m, 7H), 1.84 (dd, J = 12.6, 7.0 Hz, 1H), 1.50 – 1.42 (m, 1H), 0.81 (d, J
= 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 217.8, 172.4, 137.1, 128.7, 128.0, 127.3,
78.9, 59.7, 45.0, 39.8, 36.7, 29.4, 29.3, 19.9, 16.0. HRMS m/z (ESI) calculated for
C17H21NO3Na [M+Na]+ 310.1417, found 310.1414. The enantiomeric excess was
determined by HPLC using Chiralpak IB column (hexane/iPrOH = 95:5, flow rate = 0.7
ml/min, 230 nm); tmajor = 42.3 min, tminor = 47 min. [α]D22 = +61.4o (c = 0.6 in CHCl3).
Compound 3b: IR (CH2Cl2 liquid film): 3385, 2957, 2871, 1741, 1608, 1496, 1451, 1318,
1162, 732, 699 cm-1. mp: 135-141 oC. 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.14 (m, 5H),
4.92 (d, J = 14.8 Hz, 1H), 4.70 (dd, J = 14.8, 7.4 Hz, 1H), 4.32 – 4.26 (m, 1H), 2.77 –
2.50 (m, 2H), 2.28 – 2.05 (m, 5H), 2.00 – 1.91 (m, 1H), 1.85 – 1.76 (m, 1H), 1.31 (td, J
= 13.3, 8.8 Hz, 1H), 1.13 – 1.01 (m, 2H), 0.80 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 218.3, 172.5, 137.1, 128.7, 128.0, 127.8, 79.1, 60.0, 44.8, 40.0, 36.5, 33.3, 30.0,
23.2, 19.9, 11.9. HRMS m/z (ESI) calculated for C18H23NO3Na [M+Na]+ 324.1570, found
324.1570. The enantiomeric excess was determined by HPLC using Chiralpak IB column
(hexane/iPrOH = 95:5, flow rate = 0.7 ml/min, 230 nm); tmajor = 35.0 min, tminor = 39.7 min.
[α]D22 = +100.0o (c = 0.6 in CHCl3).
Scheme 4. One-pot synthesis of 3f and subsequent dehydration
We also investigated some derivatizations of the product 3a
(Scheme 5): oxidation of hydroxyl group (9) and dehydration (8b).
Excellent yields (92 and 80% respectively) and stereoselectivities
(>20:1 dr, 91% ee) were obtained.
Compound 3c: IR (CH2Cl2 liquid film): 3386, 2925, 2854, 1741, 1606, 1496, 1451, 1285,
1120, 730, 699 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.30 (dd, J = 12.0, 8.8 Hz, 5H), 5.03
(d, J = 14.8 Hz, 1H), 4.80 (s, 1H), 4.40 (d, J = 14.8 Hz, 1H), 2.74 – 2.61 (m, 1H), 2.42 –
2.12 (m, 6H), 2.05 (ddd, J = 13.0, 7.5, 3.9 Hz, 1H), 1.97 – 1.83 (m, 1H), 1.58 (s, 1H),
1.39 (td, J = 13.3, 8.7 Hz, 1H), 1.28 – 1.12 (m, 3H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 218.3, 172.7, 137.1, 128.6, 127.9, 127.2, 79.0, 59.9, 44.8, 40.0, 34.5,
33.9, 32.6, 30.0, 20.5, 19.9, 14.1. HRMS m/z (ESI) calculated for C19H25NO3Na [M+Na]+
4
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10.1002/ejoc.201700193
European Journal of Organic Chemistry
338.1726, found 338.1727. The enantiomeric excess was determined by HPLC using
CDCl3) δ 218.1, 167.6, 146.5, 145.9, 136.3, 128.3, 127.7, 127.2, 126.4, 123.1, 77.3, 59.4,
45.7, 44.9, 39.7, 33.8, 31.7, 19.1. HRMS m/z (ESI) calculated for C22H22N2O5Na
[M+Na]+ 417.1428, found 417.1421. The enantiomeric excess was determined by HPLC
using Chiralpak OD-H column (hexane/iPrOH = 85:15, flow rate = 1.0 ml/min, 230 nm);
tmajor = 19.4 min, tminor = 40.1 min. [α]D22 = -8.7o (c = 0.6 in CHCl3).
Chiralpak OD-H column (hexane/iPrOH = 97:3, flow rate = 1.0 ml/min, 230 nm); tmajor
41.3 min, tminor = 44.9 min. [α]D22 = +56.6o (c = 0.4 in CHCl3).
=
Compound 3d: IR (CH2Cl2 liquid film): 3378, 2957, 1738, 1641, 1436, 1386, 1247, 1120,
732, 700 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.20 (ddd, J = 14.2, 7.3, 3.5 Hz, 5H), 4.91
(d, J = 14.9 Hz, 1H), 4.69 (dd, J = 14.1, 7.6 Hz, 1H), 4.30 (d, J = 14.9 Hz, 1H), 2.66 –
2.51 (m, 2H), 2.27 – 1.99 (m, 7H), 1.86 – 1.77 (m, 1H), 1.33 (td, J = 13.3, 8.8 Hz, 1H),
1.25 – 1.10 (m, 10H), 0.98 – 0.89 (m, 1H), 0.80 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 218.2, 172.7, 137.1, 128.7, 128.0, 127.3, 79.1, 60.0, 44.9, 40.0, 34.7, 34.0, 31.7,
30.4, 30.0, 29.6, 29.1, 27.4, 22.6, 19.9, 14.1. HRMS m/z (ESI) calculated for
C23H33NO3Na [M+Na]+ 394.2351, found 394.2351. The enantiomeric excess was
determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 97:3, flow rate =
1.0 ml/min, 230 nm); tmajor = 30.9 min, tminor = 33.7 min. [α]D22 = +51.4o (c = 1.3 in CHCl3).
Compound 3h, major diastereomer: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 8.7 Hz,
2H), 7.26 – 7.17 (m, 7H), 5.01 (d, J = 14.9 Hz, 1H), 4.86 (s, 1H), 4.34 (d, J = 14.9 Hz,
1H), 3.59 (dd, J = 13.6, 2.1 Hz, 1H), 3.28 (s, 1H), 2.41 (dt, J = 17.9, 8.1 Hz, 1H), 2.27
(ddd, J = 12.3, 7.9, 3.0 Hz, 2H), 2.12 (td, J = 13.4, 9.0 Hz, 1H), 1.98 – 1.82 (m, 2H), 1.81
– 1.67 (m, 1H), 0.92 (dt, J = 15.7, 7.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 217.4,
171.8, 147.2, 146.0, 136.5, 129.5, 128.8, 127.9, 127.6, 123.7, 78.6, 60.9, 44.8, 39.8, 39.3,
33.9, 30.3, 19.8. HRMS m/z (ESI) calculated for C22H22N2O5Na [M+Na]+ 417.1434,
found 417.1421. The enantiomeric excess was determined by HPLC using Chiralpak OD-
H column (hexane/iPrOH = 82:18, flow rate = 1.0 ml/min, 230nm); tmajor = 16.8 min, tminor
= 32.2 min. [α]D22 = +94.1o (c = 1.3 in CHCl3).
Compound 3e: IR (CH2Cl2 liquid film): 3372, 2982, 1735, 1498, 1451, 1368, 1239, 1096,
732, 700 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.23 (m, 5H), 5.18 (d, J = 15.0 Hz,
1H), 4.87 – 4.79 (m, 1H), 4.34 (d, J = 15.0 Hz, 1H), 4.22 – 4.14 (m, 2H), 3.75 (d, J = 9.9
Hz, 1H), 3.07 (dd, J = 8.2, 4.3 Hz, 1H), 2.70 (ddd, J = 14.5, 5.5, 4.4 Hz, 1H), 2.59 (dddd,
J = 18.8, 11.4, 6.0, 2.9 Hz, 2H), 2.49 – 2.36 (m, 1H), 2.32 – 2.21 (m, 1H), 1.95 (qdd, J =
13.7, 7.9, 4.3 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 215.4,
172.9, 169.2, 136.8, 128.7, 127.8, 127.3, 78.1, 61.8, 56.6, 45.7, 41.6, 38.0, 32.3, 29.4,
19.7, 14.0. HRMS m/z (ESI) calculated for C19H23NO5Na [M+Na]+ 368.1469, found
368.1468. The enantiomeric excess was determined by HPLC using Chiralpak OD-H
Compound 3i, minor diastereomer: IR (CH2Cl2 liquid film): 3387, 2923, 1730, 1607,
1509, 1449, 1227, 1162, 1117, 1053, 839, 732 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.33
– 7.19 (m, 5H), 7.08 – 6.99 (m, 2H), 6.98 – 6.90 (m, 2H), 5.09 (d, J = 14.7 Hz, 1H), 4.92
– 4.81 (m, 1H), 4.35 (d, J = 14.7 Hz, 1H), 3.47 (d, J = 12.3 Hz, 1H), 2.97 – 2.84 (m, 2H),
2.66 (td, J = 14.2, 5.9 Hz, 1H), 2.37 (ddd, J = 14.4, 8.0, 5.0 Hz, 1H), 2.30 – 2.17 (m, 1H),
1.95 – 1.75 (m, 3H), 0.97 (ddd, J = 12.0, 8.5, 4.7 Hz, 1H). 13C NMR (101 MHz, CDCl3)
δ 219.9, 169.1, 137.5, 129.7, 129.7, 128.7, 128.3, 127.4, 116.0, 115.8, 78.5, 61.0, 46.9,
45.7, 40.8, 35.4, 32.5, 20.0. 19F NMR (376 MHz, CDCl3) δ -114.09. HRMS m/z (ESI)
calculated for C22H22FNO3Na [M+Na]+ 390.1485, found 390.1476. The enantiomeric
excess was determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 90:10,
flow rate = 1.0 ml/min, 230 nm); tmajor = 13.0 min, tminor = 22.4 min. [α]D22 = -5.3o (c = 0.6
in CHCl3).
column (hexane/iPrOH = 95:5, flow rate = 1.0 ml/min, 230 nm); tmajor = 56.1 min, tminor
61.6 min. [α]D22 = +66.3o (c = 0.8 in CHCl3).
=
Compound 3f, minor diastereomer: IR (CH2Cl2 liquid film): 3386, 2928, 2853, 1740
(C=O), 1627, 1529, 1450, 1278, 1156, 1078, 730, 700 cm-1. 1H NMR (400 MHz, CDCl3)
δ 7.32 – 7.20 (m, 8H), 7.09 – 7.03 (m, 2H), 5.09 (d, J = 14.7 Hz, 1H), 4.87 (t, J = 6.7 Hz,
1H), 4.36 (d, J = 14.7 Hz, 1H), 3.63 (s, 1H), 2.96 – 2.83 (m, 2H), 2.70 (td, J = 14.2, 6.0
Hz, 1H), 2.43 – 2.33 (m, 1H), 2.21 (dt, J = 15.3, 8.0 Hz, 1H), 1.82 (dddd, J = 18.7, 14.5,
10.2, 6.5 Hz, 3H), 0.96 – 0.84 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 207.0, 169.3,
139.4, 137.6, 128.9, 128.6, 128.2, 128.2, 127.9, 127.3, 78.6, 61.0, 46.8, 46.6, 40.8, 35.2,
32.5, 19.9. The enantiomeric excess was determined by HPLC using Chiralpak IB column
(hexane/iPrOH = 90:10, flow rate = 1.0 ml/min, 230 nm); tmajor = 12.0 min, tminor = 13.4
min. HRMS m/z (ESI) calculated for C22H23NO3Na [M+Na]+ 372.1575, found 372.1570.
[α]D22 = -10.6o (c = 0.6 in CHCl3).
Compound 3i, major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.19 (m, 5H),
7.01 (dd, J = 8.4, 5.4 Hz, 2H), 6.91 (t, J = 8.6 Hz, 2H), 5.05 (d, J = 14.8 Hz, 1H), 4.87 (d,
J = 5.9 Hz, 1H), 4.36 (d, J = 14.8 Hz, 1H), 3.48 (d, J = 13.1 Hz, 1H), 2.59 (s, 1H), 2.38
(s, 1H), 2.34 – 2.20 (m, 2H), 2.03 (ddd, J = 13.3, 10.1, 6.8 Hz, 2H), 1.88 (dt, J = 19.8, 6.4
Hz, 1H), 1.82 – 1.71 (m, 1H), 0.98 – 0.85 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 218.0,
172.4, 136.8, 129.9, 129.8, 128.8, 128.0, 127.5, 115.6, 115.4, 78.9, 61.0, 44.9, 40.0, 38.7,
34.5, 30.5, 19.8. 19F NMR (376 MHz, CDCl3) δ -114.88. HRMS m/z (ESI) calculated for
C22H22FNO3Na [M+Na]+ 390.1487, found 390.1476. The enantiomeric excess was
determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 90:10, flow rate =
1.0 ml/min, 230 nm); tmajor = 14.2 min, tminor = 17.8 min. [α]D22 = +42.3o (c = 0.9 in CHCl3).
Compound 3f, major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.44 (m, 8H),
7.35 – 7.29 (m, 2H), 5.33 (d, J = 14.8 Hz, 1H), 5.13 (d, J = 5.2 Hz, 1H), 4.63 (d, J = 14.8
Hz, 1H), 3.75 (dd, J = 13.4, 2.4 Hz, 1H), 2.94 (dd, J = 10.4, 6.6 Hz, 1H), 2.58 (dddd, J =
28.3, 20.8, 14.5, 8.1 Hz, 3H), 2.43 – 2.29 (m, 2H), 2.16 – 1.98 (m, 2H), 1.16 – 1.03 (m,
1H). 13C NMR (101 MHz, CDCl3) δ 218.2, 172.5, 138.5, 136.9, 128.8, 128.6, 128.3, 128.0,
127.5, 127.4, 79.0, 61.0, 44.8, 40.0, 39.4, 34.3, 30.7, 19.8. HRMS m/z (ESI) calculated
for C22H23NO3Na [M+Na]+ 372.1575, found 372.1570. The enantiomeric excess was
determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 95:5, flow rate =
1.0 ml/min, 230 nm); tmajor = 33.0 min, tminor = 35.3 min. [α]D22 = +59.0o (c = 1.0 in CHCl3).
Compound 3j, minor diastereomer: IR (CH2Cl2 liquid film): 3371, 2958, 1738, 1608,
1492, 1450, 1293, 1160, 1031, 833, 734, 699, 616, 587 cm-1. 1H NMR (400 MHz, CDCl3)
δ 7.45 – 7.35 (m, 7H), 7.15 (d, J = 8.5 Hz, 2H), 5.23 (d, J = 14.7 Hz, 1H), 5.01 (t, J = 6.5
Hz, 1H), 4.51 (d, J = 14.7 Hz, 1H), 3.71 (s, 1H), 3.10 – 2.96 (m, 2H), 2.82 (td, J = 14.2,
6.1 Hz, 1H), 2.50 (ddd, J = 14.3, 7.8, 4.8 Hz, 1H), 2.44 – 2.34 (m, 1H), 2.10 – 1.91 (m,
3H), 1.23 – 1.12 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 219.7, 169.0, 137.9, 137.5,
133.8, 129.5, 129.1, 128.7, 128.3, 127.4, 78.4, 60.8, 46.8, 45.9, 40.8, 35.2, 32.5, 20.0.
HRMS m/z (ESI) calculated for C22H22ClNO3Na [M+Na]+ 406.1187, found 406.1180.
The enantiomeric excess was determined by HPLC using Chiralpak OD-H column
(hexane/iPrOH = 95:5, flow rate = 1.0 ml/min, 230 nm); tmajor = 19.9 min, tminor = 38.8 min.
[α]D22 = +16.1o (c = 0.7 in CHCl3).
Compound 3g, minor diastereomer: 1H NMR (400 MHz, CDCl3) δ 8.13 – 8.07 (m, 1H),
7.96 (d, J = 1.8 Hz, 1H), 7.51 – 7.39 (m, 2H), 7.31 – 7.21 (m, 5H), 5.11 (d, J = 14.6 Hz,
1H), 4.94 – 4.84 (m, 1H), 4.36 (d, J = 14.6 Hz, 1H), 3.45 (d, J = 11.5 Hz, 1H), 3.06 (dd,
J = 13.9, 4.9 Hz, 1H), 2.97 – 2.87 (m, 1H), 2.77 (td, J = 14.1, 6.0 Hz, 1H), 2.45 – 2.37
(m, 1H), 2.34 – 2.25 (m, 1H), 1.98 – 1.84 (m, 2H), 1.78 (dt, J = 13.3, 6.8 Hz, 1H), 1.02
(ddd, J = 14.0, 9.0, 5.0 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 219.2, 168.6, 148.5, 141.7,
137.3, 134.0, 130.1, 128.7, 128.5, 127.5, 123.5, 123.0, 78.3, 60.5, 46.8, 46.0, 40.7, 35.1,
32.6, 20.1. HRMS m/z (ESI) calculated for C22H22N2O5Na [M+Na]+ 417.1425, found
417.1421. The enantiomeric excess was determined by HPLC using Chiralpak OD-H
column (hexane/iPrOH = 90:10, flow rate = 1.0 ml/min, 230 nm); tmajor = 26.3 min, tminor
= 39.5 min. [α]D22 = -35.8o (c = 0.3 in CHCl3).
Compound 3j, major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.18 (m, 7H),
6.97 (d, J = 8.5 Hz, 2H), 5.02 (d, J = 14.8 Hz, 1H), 4.84 (s, 1H), 4.34 (d, J = 14.9 Hz,
1H), 3.46 (dd, J = 13.6, 2.2 Hz, 1H), 2.87 (s, 1H), 2.39 (dt, J = 16.7, 8.0 Hz, 1H), 2.31 –
2.17 (m, 2H), 2.09 – 1.94 (m, 2H), 1.93 – 1.82 (m, 1H), 1.82 – 1.71 (m, 1H), 0.93 (dt, J
= 12.0, 7.5 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 217.9, 172.3, 137.0, 136.7, 133.4,
129.7, 128.8, 128.8, 128.0, 127.5, 78.8, 60.9, 44.8, 39.9, 38.8, 34.3, 30.4, 19.8. HRMS
m/z (ESI) calculated for C22H22ClNO3Na [M+Na]+ 406.1189, found 406.1180. The
enantiomeric excess was determined by HPLC using Chiralpak OD-H column
(hexane/iPrOH = 95:5, flow rate = 1.0 ml/min, 230 nm); tmajor = 33.5 min, tminor = 47.8 min.
[α]D22 = +41.7o (c = 2.3 in CHCl3).
1
Compound 3g, major diastereomer: H NMR (400 MHz, CDCl3) δ 8.06 (dt, J = 5.1,
2.3 Hz, 1H), 7.97 (s, 1H), 7.39 (d, J = 2.7 Hz, 1H), 7.32 – 7.15 (m, 6H), 5.06 (d, J = 14.8
Hz, 1H), 4.96 – 4.83 (m, 1H), 4.36 (d, J = 14.9 Hz, 1H), 3.63 (dd, J = 13.7, 2.4 Hz, 1H),
2.77 (d, J = 7.8 Hz, 1H), 2.51 – 2.39 (m, 1H), 2.38 – 2.26 (m, 2H), 2.16 (td, J = 13.5, 8.9
Hz, 1H), 2.02 – 1.89 (m, 2H), 1.81 – 1.70 (m, 1H), 1.05 – 0.92 (m, 1H). 13C NMR (101
MHz, CDCl3) δ 217.2, 171.7, 148.4, 140.7, 136.6, 135.3, 129.9, 128.9, 128.0, 127.6,
122.8, 122.6, 78.6, 60.8, 44.9, 39.7, 39.0, 34.1, 30.2, 19.8. HRMS m/z (ESI) calculated
for C22H22N2O5Na [M+Na]+ 417.1411, found 417.1421. The enantiomeric excess was
determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 90:10, flow rate =
1.0 ml/min, 230 nm); tmajor = 36.0 min, tminor = 44.3 min. [α]D22 = +21.1o (c = 1.0 in CHCl3).
Compound 3k, minor diastereomer: IR (CH2Cl2 liquid film): 3376, 2960, 1730, 1616,
1567, 1449, 1327, 1294, 1169, 885, 788, 734, 698, 542 cm-1. 1H NMR (400 MHz, CDCl3)
δ 7.36 (ddd, J = 8.0, 1.9, 1.0 Hz, 1H), 7.25 (ddd, J = 12.8, 4.2, 2.2 Hz, 6H), 7.12 (t, J =
7.9 Hz, 1H), 6.99 (dd, J = 6.5, 1.3 Hz, 1H), 5.10 (d, J = 14.7 Hz, 1H), 4.86 (ddd, J = 12.3,
7.9, 5.9 Hz, 1H), 4.34 (d, J = 14.7 Hz, 1H), 3.49 (d, J = 12.3 Hz, 1H), 2.93 – 2.82 (m,
2H), 2.65 (td, J = 14.2, 5.9 Hz, 1H), 2.37 (ddd, J = 14.4, 8.0, 5.0 Hz, 1H), 2.30 – 2.20 (m,
1H), 1.96 – 1.77 (m, 3H), 1.07 – 0.98 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 219.7,
168.9, 141.8, 137.5, 131.5, 131.1, 130.5, 128.7, 128.2, 127.4, 126.7, 123.0, 78.4, 60.8,
46.8, 46.2, 40.8, 35.2, 32.5, 20.0. HRMS m/z (ESI) calculated for C22H22BrNO3Na
[M+Na]+ 450.0668, found 450.0675. The enantiomeric excess was determined by HPLC
using Chiralpak OD-H column (hexane/iPrOH = 93:7, flow rate = 1.0 ml/min, 230 nm);
tmajor = 22.5 min, tminor = 28.7 min. [α]D22 = +9.8o (c = 0.7 in CHCl3).
Compound 3h, minor diastereomer: IR (CH2Cl2 liquid film): 3378, 2960, 1738, 1606,
1519, 1451, 1347, 1159, 1073, 857, 733, 699 cm-1. 1H NMR (400 MHz, CDCl3) δ 8.11
(d, J = 8.8 Hz, 2H), 7.30 – 7.20 (m, 7H), 5.08 (d, J = 14.7 Hz, 1H), 4.88 (d, J = 6.1 Hz,
1H), 4.37 (d, J = 14.7 Hz, 1H), 3.53 (d, J = 10.9 Hz, 1H), 3.04 (dd, J = 13.9, 4.7 Hz, 1H),
2.94 – 2.84 (m, 1H), 2.77 (td, J = 14.1, 6.3 Hz, 1H), 2.40 – 2.24 (m, 2H), 1.94 – 1.84 (m,
2H), 1.80 – 1.72 (m, 1H), 1.02 (ddd, J = 14.2, 9.1, 5.3 Hz, 1H). 13C NMR (101 MHz,
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700193
European Journal of Organic Chemistry
o
Compound 3k, major diastereomer: mp: 133-140 C; 1H NMR (400 MHz, CDCl3) δ
7.26 (ddd, J = 33.3, 17.1, 8.7 Hz, 7H), 7.08 (t, J = 7.9 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H),
5.05 (d, J = 14.8 Hz, 1H), 4.85 (td, J = 8.7, 5.7 Hz, 1H), 4.34 (d, J = 14.8 Hz, 1H), 3.46
(dd, J = 13.6, 2.1 Hz, 1H), 2.70 (d, J = 7.9 Hz, 1H), 2.49 – 2.34 (m, 1H), 2.34 – 2.18 (m,
2H), 2.10 – 1.95 (m, 2H), 1.84 (dtd, J = 18.1, 14.2, 6.4 Hz, 2H), 0.95 (dt, J = 11.9, 7.5
Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 217.7, 172.2, 140.9, 136.7, 131.2, 130.7, 130.1,
128.8, 128.0, 127.5, 127.3, 122.8, 78.8, 60.9, 44.9, 39.9, 39.1, 34.2, 30.5, 19.8. HRMS
m/z (ESI) calculated for C22H22BrNO3Na [M+Na]+ 450.0685, found 450.0675. The
enantiomeric excess was determined by HPLC using Chiralpak IB column
(hexane/iPrOH = 97:3, flow rate = 1.0 ml/min, 230 nm); tmajor = 58.2 min, tminor = 61.5 min.
[α]D22 = +54.2o (c = 1.7 in CHCl3).
55.2, 45.0, 40.0, 39.5, 34.4, 30.9, 19.8. The enantiomeric excess was determined by
HPLC using Chiralpak OD-H column (hexane/iPrOH = 90:10, flow rate = 1.0 ml/min,
230 nm); tmajor = 17.4 min, tminor = 19.8 min. HRMS m/z (ESI) calculated for C23H25NO4Na
[M+Na]+ 402.1673, found 402.1676. [α]D22 = +35.4o (c = 0.5 in CHCl3).
Compound 3o: mp: 134-143 oC. IR (CH2Cl2 liquid film): 3386, 2929, 2853, 1739 (C=O),
1
1627, 1529, 1450, 1347, 1296, 1145, 1059 cm-1. H NMR (400 MHz, CDCl3) δ 5.24 (d,
J = 5.8 Hz, 1H), 4.14 – 4.01 (m, 1H), 2.75 (ddt, J = 11.7, 9.7, 6.4 Hz, 1H), 2.42 (ddd, J =
9.7, 8.8, 5.0 Hz, 3H), 2.33 (ddd, J = 12.3, 6.8, 3.2 Hz, 2H), 2.06 – 1.95 (m, 4H), 1.93 –
1.76 (m, 5H), 1.64 (ddd, J = 20.1, 9.5, 4.2 Hz, 1H), 1.57 – 1.39 (m, 3H), 1.36 – 1.27 (m,
1H), 1.01 (d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 218.0, 172.4, 78.2, 60.1,
55.7, 39.7, 37.2, 31.9, 29.9, 29.5, 29.3, 26.3, 26.3, 25.6, 19.8, 16.0. The enantiomeric
excess was determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 97:3,
flow rate = 0.7 ml/min, 230 nm); tmajor = 32.4 min, tminor = 34.6 min. HRMS m/z (ESI)
calculated for C16H25NO3Na [M+Na]+ 302.1732, found 302.1727. [α]D22 = +20.3o (c = 0.3
in CHCl3).
Compound 3l, minor diastereomer: IR (CH2Cl2 liquid film): 3369, 2938, 1752, 1608,
1492, 1450, 1293, 1160, 823, 733, 700, 650 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.37 (d,
J = 8.5 Hz, 2H), 7.29 – 7.20 (m, 5H), 6.94 (d, J = 8.5 Hz, 2H), 5.08 (d, J = 14.7 Hz, 1H),
4.85 (ddd, J = 12.3, 7.8, 6.1 Hz, 1H), 4.35 (d, J = 14.7 Hz, 1H), 3.52 (d, J = 12.3 Hz, 1H),
2.93 – 2.81 (m, 2H), 2.66 (td, J = 14.2, 6.0 Hz, 1H), 2.35 (ddd, J = 14.3, 7.9, 4.9 Hz, 1H),
2.29 – 2.18 (m, 1H), 1.95 – 1.83 (m, 2H), 1.83 – 1.74 (m, 1H), 1.07 – 0.97 (m, 1H). 13
C
Compound 3p: IR (CH2Cl2 liquid film): 3370, 3002, 2951, 1741 (C=O), 1617, 1510,
1461, 1292(aliphatic OCH3), 1067 cm-1. 1H NMR (400 MHz, CDCl3) δ 4.90 (td, J = 6.7,
4.1 Hz, 1H), 4.45 (dd, J = 6.4, 3.8 Hz, 1H), 4.25 (d, J = 4.0 Hz, 1H), 3.78 (dd, J = 14.2,
3.7 Hz, 1H), 3.38 (d, J = 1.5 Hz, 6H), 3.35 – 3.29 (m, 1H), 3.14 (dd, J = 14.2, 6.4 Hz,
1H), 2.51 (ddd, J = 15.3, 9.0, 5.7 Hz, 1H), 2.26 (ddd, J = 12.2, 6.8, 3.7 Hz, 1H), 2.22 –
2.11 (m, 4H), 1.85 – 1.78 (m, 1H), 1.47 (ddd, J = 13.8, 12.4, 7.1 Hz, 1H), 0.82 (d, J = 6.8
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 217.6, 172.9, 103.0, 81.2, 59.9, 55.9, 55.5, 47.9,
39.6, 35.7, 29.6, 29.4, 19.8, 16.1. The enantiomeric excess was determined by HPLC
using Chiralpak OD-H column (hexane/iPrOH = 90:10, flow rate = 1.0 ml/min, 230 nm);
tmajor = 13.1 min, tminor = 13.6 min. HRMS m/z (ESI) calculated for C14H23NO5Na [M+Na]+
308.1467, found 308.1468. [α]D22 = +1.6o (c = 0.6 in CHCl3).
NMR (101 MHz, CDCl3) δ 219.7, 169.0, 138.5, 137.5, 132.1, 129.9, 128.7, 128.2, 127.4,
121.9, 78.4, 60.7, 46.8, 45.9, 40.8, 35.2, 32.5, 20.0. HRMS m/z (ESI) calculated for
C22H22BrNO3Na [M+Na]+ 450.0686, found 450.0675. The enantiomeric excess was
determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 90:10, flow rate =
1.0 ml/min, 230 nm); tmajor = 12.1 min, tminor = 21.4 min. [α]D22 = -1.8o (c = 0.6 in CHCl3).
Compound 3l, major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.5 Hz,
2H), 7.31 – 7.19 (m, 5H), 6.92 (d, J = 8.4 Hz, 2H), 5.04 (d, J = 14.8 Hz, 1H), 4.85 (dd, J
= 8.9, 5.6 Hz, 1H), 4.35 (d, J = 14.8 Hz, 1H), 3.45 (dd, J = 13.6, 2.3 Hz, 1H), 2.40 (dt, J
= 16.4, 8.0 Hz, 1H), 2.32 – 2.20 (m, 2H), 2.11 – 1.72 (m, 5H), 1.01 – 0.89 (m, 1H). 13C
NMR (101 MHz, CDCl3) δ 217.8, 172.2, 137.5, 136.7, 131.7, 130.1, 128.8, 128.0, 127.5,
121.6, 78.8, 60.8, 44.9, 39.9, 38.9, 34.2, 30.4, 19.8. HRMS m/z (ESI) calculated for
C22H22BrNO3Na [M+Na]+ 450.0685, found 450.0675. The enantiomeric excess was
determined by HPLC using OD-H column (hexane/iPrOH = 90:10, flow rate = 1.0 ml/min,
230 nm); tmajor = 15.7 min, tminor = 21.9 min. [α]D22 = +50.0o (c = 0.8 in CHCl3).
Compound 3q: mp: 163-167 oC. IR (CH2Cl2 liquid film): 3378, 2962, 1740 (C=O), 1622,
1
1509, 1443, 1245, 1181(aromatic OCH3), 1064, 830 cm-1. H NMR (400 MHz, CDCl3)
δ 7.07 (d, J = 8.8 Hz, 2H), 6.92 – 6.88 (m, 2H), 5.15 (dt, J = 8.0, 5.7 Hz, 1H), 3.78 (s,
3H), 2.91 (d, J = 5.0 Hz, 1H), 2.50 (tdd, J = 9.7, 8.6, 4.8 Hz, 2H), 2.33 (dd, J = 11.0, 4.7
Hz, 1H), 2.28 – 2.09 (m, 4H), 1.92 – 1.80 (m, 1H), 1.68 – 1.60 (m, 1H), 0.92 (d, J = 6.8
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 217.4, 172.3, 159.0, 130.9, 129.8, 114.7, 81.7,
59.9, 55.5, 39.7, 35.4, 29.5, 29.3, 19.7, 16.1. The enantiomeric excess was determined by
HPLC using Chiralpak OD-H column (hexane/iPrOH = 88:12, flow rate = 1.0 ml/min,
230 nm); tmajor = 18.7 min, tminor = 31.1 min. HRMS m/z (ESI) calculated for C17H21NO4Na
[M+Na]+ 326.1358, found 326.1363. [α]D22 = +61.4o (c = 0.6 in CHCl3).
Compound 3m, minor diastereomer: IR (CH2Cl2 liquid film): 3361, 2956, 1738, 1607,
1492, 1450, 1137, 1091, 1031, 823, 734, 699 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.30 –
7.19 (m, 5H), 7.04 (d, J = 7.9 Hz, 2H), 6.94 (d, J = 8.1 Hz, 2H), 5.09 (d, J = 14.7 Hz, 1H),
4.85 (s, 1H), 4.35 (d, J = 14.7 Hz, 1H), 3.62 (d, J = 11.0 Hz, 1H), 2.92 – 2.80 (m, 2H),
2.66 (td, J = 14.2, 5.9 Hz, 1H), 2.36 (ddd, J = 14.3, 8.0, 5.0 Hz, 1H), 2.26 (d, J = 3.8 Hz,
3H), 2.19 (dd, J = 12.9, 5.2 Hz, 1H), 1.85 (dddd, J = 18.4, 15.4, 12.5, 7.5 Hz, 3H), 0.99 –
0.90 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 220.1, 169.4, 137.7, 136.3, 129.6, 128.6,
128.2, 128.0, 127.3, 126.2, 78.6, 61.1, 46.8, 46.3, 40.8, 35.4, 32.5, 21.0, 20.0. HRMS m/z
(ESI) calculated for C23H25NO5Na [M+Na]+ 386.1733, found 386.1727. The
enantiomeric excess was determined by HPLC using Chiralpak OD-H column
(hexane/iPrOH = 90:10, flow rate = 1.0 ml/min, 230 nm); tmajor = 9.3 min, tminor = 16.2 min.
[α]D22 = +10.5o (c = 0.9 in CHCl3).
Compound 3r: mp: 123-134 oC. IR (CH2Cl2 liquid film): 3369, 2940, 1661, 1525, 1453,
1371, 1278, 700, 682 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.27 (dd, J = 6.8, 4.2 Hz, 5H),
5.05 (d, J = 15.0 Hz, 1H), 4.81 – 4.75 (m, 1H), 4.34 (d, J = 15.0 Hz, 1H), 2.78 – 2.68 (m,
1H), 2.63 (ddd, J = 10.3, 6.8, 3.6 Hz, 1H), 2.47 (dt, J = 15.9, 5.9 Hz, 2H), 2.39 – 2.24 (m,
2H), 1.93 (ddd, J = 21.4, 9.9, 5.8 Hz, 3H), 1.67 (ddd, J = 19.9, 10.4, 5.5 Hz, 3H), 0.98 (d,
J = 6.9 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 210.6, 170.8, 137.2, 128.7, 127.9, 127.6,
78.5, 59.8, 46.0, 40.5, 34.3, 29.3, 29.0, 25.3, 20.4, 16.3. HRMS m/z (ESI) calculated for
C18H23NO3Na [M+Na]+ 324.1564, found 324.1570. The enantiomeric excess was
determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 97:3, flow rate =
1.0 ml/min, 230 nm); tmajor = 49.8 min, tminor = 54.1 min. [α]D22 = +40.2o (c = 0.9 in CHCl3).
Compound 3m, major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.30 – 7.18 (m,
5H), 7.01 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 5.04 (d, J = 14.9 Hz, 1H), 4.84 (d,
J = 5.8 Hz, 1H), 4.35 (d, J = 14.8 Hz, 1H), 3.43 (d, J = 12.1 Hz, 1H), 2.42 – 2.18 (m, 6H),
2.10 – 2.01 (m, 2H), 1.87 – 1.70 (m, 2H), 1.63 (s, 1H), 0.88 (dd, J = 12.6, 7.1 Hz, 1H).
13C NMR (101 MHz, CDCl3) δ 218.3, 172.6, 137.1, 136.9, 135.4, 129.3, 128.7, 128.2,
128.0, 127.4, 126.2, 79.0, 61.0, 44.8, 39.0, 39.1, 34.4, 30.7, 21.0, 19.8. HRMS m/z (ESI)
calculated for C23H25NO5Na [M+Na]+ 386.1729, found 386.1727. The enantiomeric
excess was determined by HPLC using Chiralpak OD-H column (hexane/iPrOH = 90:10,
flow rate = 1.0 ml/min, 230 nm); tmajor = 12.5 min, tminor = 15.2 min. [α]D22 = +42.9o (c =
1.8 in CHCl3).
Compound 3s: IR (CH2Cl2 liquid film): 3377, 2933, 2865, 1656, 1451, 1309, 1233, 1180,
730, 700 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.44 (m, 8H), 7.39 – 7.35 (m, 2H),
5.39 (d, J = 14.9 Hz, 1H), 5.07 (dd, J = 13.9, 6.8 Hz, 1H), 4.65 – 4.59 (d, J = 14.9 Hz,
1H), 4.12 (dd, J = 10.5, 4.2 Hz, 1H), 2.93 – 2.77 (m, 2H), 2.56 – 2.38 (m, 4H), 2.14 (ddd,
J = 16.3, 9.7, 5.3 Hz, 1H), 2.07 – 1.97 (m, 2H), 1.74 – 1.58 (m, 2H). 13C NMR (101 MHz,
CDCl3) δ 210.9, 171.6, 139.3, 137.1, 129.1, 128.8, 128.7, 128.6, 128.1, 127.3, 78.8, 59.9,
45.3, 40.4, 40.0, 33.5, 29.5, 23.6, 20.4. HRMS m/z (ESI) calculated for C23H25NO3Na
[M+Na]+ 386.1730, found 372.1727. The enantiomeric excess was determined by HPLC
using Chiralpak IB column (hexane/iPrOH = 95:5, flow rate = 0.5 ml/min, 230 nm); tmajor
= 48.1 min, tminor = 53.2 min. [α]D22 = +29.4o (c = 0.8 in CHCl3).
Compound 3n, minor diastereomer: IR (CH2Cl2 liquid film): 3376, 2959, 1738, 1605,
1520, 1493, 1452, 1268 (aromatic OCH3), 1154, 858, 789, 734, 699 cm-1. 1H NMR (400
MHz, CDCl3) δ 7.34 – 7.20 (m, 5H), 7.18 – 7.12 (m, 1H), 6.75 (ddd, J = 8.3, 2.5, 0.8 Hz,
1H), 6.64 (d, J = 7.7 Hz, 1H), 6.62 – 6.57 (m, 1H), 5.10 (d, J = 14.7 Hz, 1H), 4.86 (ddd,
J = 12.4, 8.0, 5.8 Hz, 1H), 4.35 (d, J = 14.7 Hz, 1H), 3.71 (s, 3H), 3.57 (d, J = 12.3 Hz,
1H), 2.88 (ddd, J = 14.0, 7.9, 4.8 Hz, 2H), 2.66 (td, J = 14.2, 5.8 Hz, 1H), 2.39 (ddd, J =
14.4, 8.1, 5.0 Hz, 1H), 2.29 – 2.18 (m, 1H), 2.02 – 1.91 (m, 1H), 1.89 – 1.76 (m, 2H),
1.05 – 0.93 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 220.0, 169.2, 159.9, 141.0, 137.6,
130.0, 128.6, 128.3, 127.3, 120.4, 114.2, 113.0, 78.5, 61.0, 55.2, 46.9, 46.7, 40.9, 35.3,
32.5, 20.0. The enantiomeric excess was determined by HPLC using Chiralpak OD-H
column (hexane/iPrOH = 90:10, flow rate = 1.0 ml/min, 230 nm); tmajor = 17.9 min, tminor
= 28.3 min. HRMS m/z (ESI) calculated for C23H25NO4Na [M+Na]+ 402.1676, found
402.1676. [α]D22 = +83.3o (c = 0.6 in CHCl3).
Compound 3t: IR (CH2Cl2 liquid film): 3405, 2931, 1669, 1607, 1510, 1441, 1381, 1297,
1254, 1178, 729 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.16 – 7.12 (m, 2H), 6.84 – 6.81 (m,
2H), 5.21 (t, J = 2.4 Hz, 1H), 3.72 (s, 3H), 2.53 (ddd, J = 13.1, 9.6, 2.0 Hz, 1H), 2.40 (tdd,
J = 13.1, 8.5, 4.6 Hz, 2H), 2.32 – 2.25 (m, 1H), 1.78 – 1.70 (m, 2H), 1.58 – 1.52 (m, 2H),
1.45 (ddd, J = 6.8, 5.0, 2.6 Hz, 3H), 1.27 (td, J = 13.4, 4.3 Hz, 1H), 0.92 (d, J = 7.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 170.8, 157.9, 132.0, 125.7, 114.3, 98.4, 84.6, 55.5,
52.2, 39.1, 36.8, 27.0, 26.2, 22.6, 22.0, 18.1. The enantiomeric excess was determined by
HPLC using Chiralpak OD-H column (hexane/iPrOH = 95:5, flow rate = 1.0 ml/min, 230
nm); tminor = 28.3 min, tmajor = 37.0 min. HRMS m/z (ESI) calculated for C18H24NO4
[M+H]+ 318.1695, found 318.1700. [α]D22 = +12.8o (c = 0.5 in CHCl3).
Compound 3n, major diastereomer: 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.20 (m, 5H),
7.13 (t, J = 7.9 Hz, 1H), 6.72 (dd, J = 8.2, 1.9 Hz, 1H), 6.67 – 6.56 (m, 2H), 5.08 (d, J =
14.8 Hz, 1H), 4.87 (dd, J = 14.0, 8.5 Hz, 1H), 4.36 (d, J = 14.8 Hz, 1H), 3.70 (s, 3H),
3.47 (dd, J = 13.3, 2.4 Hz, 1H), 2.47 – 2.31 (m, 3H), 2.31 – 2.22 (m, 1H), 2.12 – 2.00 (m,
2H), 1.93 – 1.77 (m, 2H), 0.99 – 0.87 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 218.0,
172.4, 159.7, 140.2, 136.9, 129.7, 128.8, 128.1, 127.5, 120.6, 114.3, 112.6, 79.0, 60.9,
c: To a stirring mixture of 3a (0.2 mmol, 1 equiv) in 1 ml of toluene, 0.2 equiv of
concentrated HCl were added. The reaction was allowed to stir for 30 minutes, monitored
by TLC. The crude mixture was purified by flash column chromatography (EtOAc:
hexane = 1:1) to render the product 8b.
6
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10.1002/ejoc.201700193
European Journal of Organic Chemistry
Compound 8b: IR (CH2Cl2 liquid film): 2964, 1764, 1663, 1496, 1381, 1252, 731, 699
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.21 (ddd, J = 15.3, 10.5, 1.5 Hz, 5H), 5.88 (dd, J =
7.7, 2.5 Hz, 1H), 4.87 (dd, J = 7.7, 3.2 Hz, 1H), 4.66 (d, J = 15.0 Hz, 1H), 4.52 (d, J =
15.0 Hz, 1H), 3.04 – 2.94 (m, 1H), 2.56 – 2.45 (m, 1H), 2.21 – 2.12 (m, 1H), 2.08 – 1.96
(m, 3H), 1.87 – 1.77 (m, 1H), 0.87 (d, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
216.4, 170.2, 136.9, 128.7, 127.6, 127.6, 127.3, 112.0, 59.1, 48.9, 39.3, 31.7, 28.0, 19.1,
14.7. HRMS m/z (ESI) calculated for C17H19NO2Na [M+Na]+ 292.1300, found 292.1308.
The enantiomeric excess was determined by HPLC using Chiralpak OD-H column
(hexane/iPrOH = 95:5, flow rate = 1.0 ml/min, 230 nm); tmajor = 17.4 min, tminor = 21.5min.
[α]D22 = +111.3o (c = 0.6 in CHCl3).
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J. Cossy, A. Bouzide, C. Leblanc, J. Org. Chem. 2000, 65, 7257-7265.
For selected examples see: (a) S. Goudedranche, X. Bugaut, T. Constantieux, D.
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Procedure for the synthesis of 9: To a stirring mixture of hemiaminal product 3a (0.2
mmol, 1.0 equiv) in 2 ml of CH2Cl2, DCC (0.3 mmol, 1.5 equiv) was added. The reaction
was allowed to stir for 3 h, monitored by TLC. The crude mixture was purified by flash
column chromatography (EtOAc: hexane = 1:1) to render the oxidation product 9.
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8942–8950. (e) X. Wu, X. Dai, H. Fang, L. Nie, J. Chen, W. Cao, G. Zhao, Chem.
Eur. J. 2011, 17, 10510-10514. (f) A. Noole, M. Borissova, M. Lopp, T. Kanger,
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Compound 9: IR (CH2Cl2 liquid film): 2939, 1726, 1666, 1496, 1269, 1023, 733, 699
cm-1. 1H NMR (400 MHz, CDCl3) δ 7.20 (dd, J = 5.4, 4.4 Hz, 5H), 4.86 (d, J = 6.1 Hz,
2H), 2.99 – 2.92 (m, 1H), 2.50 – 2.18 (m, 5H), 2.05 (dddd, J = 20.4, 17.0, 9.2, 5.3 Hz,
2H), 1.94 – 1.85 (m, 1H), 0.87 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 214.4,
172.5, 171.1, 137.0, 128.5, 128.3, 127.4, 60.4, 43.2, 38.8, 37.0, 29.6, 29.1, 19.4, 16.2.
HRMS m/z (ESI) calculated for C17H20NO3 [M+Na]+ 286.1430, found 286.1438. The
enantiomeric excess was determined by HPLC using Chiralpak OD-H column
(hexane/iPrOH = 95:5, flow rate = 1.0 ml/min, 230 nm); tmajor = 15.6 min, tminor = 17.9 min.
[α]D22 = +43.7o (c = 0.7 in CHCl3).
For 1H-NMR, 13C-NMR, 19F-NMR spectra and HPLC traces see Supporting Information.
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Acknowledgements
K.Z., M.M. and R.R are grateful for EPSRC Core Capability Funding (EP/K039466/1).
V.D. and J.V. gratefully acknowledge financial support from the Grant Agency of Charles
University Grant Agency (393615). We thank Diamond Light Source for the allocation
of beam time MT8521 on beamline I19.
[13] During the submission of the present paper Han and coworkers published a similar
methodology: X. Li, W. Huang, Y.-Q. Li, J.-W. Kang, D. Xia, G. He, C. Peng, B.
Han, J. Org. Chem. 2017, 82, 397-406.
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on application to Cambridge Crystallographic Data Centre, 12 Union Road,
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7
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10.1002/ejoc.201700193
European Journal of Organic Chemistry
An asymmetric synthesis of α-spiro-δ-
lactam via organocascade reaction
from easily accessible starting
materials is reported. The catalytic
sequence undergoes enantioselective
Michael addition of β-ketoamide to
α,β-unsaturated aldehyde catalysed by
a secondary amine catalyst, followed
by hemiaminal annulation. Optically
enantiopure compounds with three
stereogenic centres are obtained in
good yields and excellent selectivities
(up to >20:1 dr and up to >99% ee).
Organocascade Reaction
Kaiheng Zhang, Marta Meazza*,
Vojtech Docekal, Mark E. Light, Jan
Vesely*, Ramon Rios*
Highly Diastereo and
Enantioselective Synthesis of α-
spiro-δ-lactams Bearing Three
Contiguous Stereogenic Centers via
Organocascade Reaction
8
This article is protected by copyright. All rights reserved.