Diastereoselective Synthesis of 2,6-Disubstituted-1,2,3,6-Tetrahydropyridines through a Palladium-Catalyzed Intramolecular Allylic Amination

DOI: 10.1002/ejoc.201901520

Full Paper

Tetrahydropyridine Synthesis

Diastereoselective Synthesis of 2,6-Disubstituted-1,2,3,6-

Tetrahydropyridines through a Palladium-Catalyzed

Intramolecular Allylic Amination

Alexia Visseq,^[a]Thibaut Boibessot,^[a]Lionel Nauton,^[a]Vincent Théry,^[a]Fabrice Anizon,*^[a]

and Isabelle Abrunhosa-Thomas*^[a]

Abstract: An efficient synthesis of 2,6-disubstituted-1,2,3,6- from non-activated alcohols. This method allowed a straightfor-

tetrahydropyridines is reported, featuring a highly diastereo- ward access to 2,6-trans-1,2,3,6-tetrahydropyridines with de up

selective palladium-catalyzed intramolecular allylic amination to 100 % under mild conditions, in moderate to good yields.

Introduction

Mitsunobu^[1c]reactions, allyl nitrone cyclization,^[7]aza-[2,3]-

Wittig rearragements of vinylaziridines^[8]or diastereoselective

1,2,3,6-Tetrahydropyridines (TP) are important heterocycles C–H functionalization.^[9]However, methods leading to trans-2,6-

found in numerous alkaloids and pharmaceutical compounds^[1]disubstituted-TP/piperidines are less reported, because the

that also could be used as intermediates in polysubstituted trans relative configuration is thermodynamically disfavored.^[10]

piperidines or imino sugars synthesis, with possible double For example, trans-2,6-disubstituted-TP/piperidines can be ob-

bond reduction or functionalization.^[2]Consequently, many tained by C–N bond formation and ring closure, the TP substitu-

strategies for TP synthesis have been proposed.^[1b,1c,3]Among ents at 2- and 6-positions being already present in the structure.

these approaches, the synthesis of 2,6-disubstituted-TP/piper- These methods employed allylic alcohols or their activated

idines have attracted much attention because these hetero- counterparts as precursors, and used Brønsted acid conditions,

cycles are found in many interesting products with a wide S_N2 or Mitsunobu reactions affording nitrogen attack, to form

range of pharmacological activities.^[1a,1b,3a]Various methods the unsaturated 6-membered ring.

have been described for the preparation of cis- or trans-2,6-

Knowing the importance of stereocenter configuration for

disubstituted-TP^[4]including cationic cyclization,^[3a]nucleophilic biological activities, the development of new stereoselective

substitution,^[5]ring-closing metathesis,^[6]aza-Diels–Alder^[1b]and syntheses of trans-2,6-disubstituted-TP/piperidines remains an

Scheme 1. Previous work toward the synthesis of 2,6-disubstituted-piperidines. Current methodology toward the preparation of 2,6-disubstituted-TP.

important challenge. During our previous studies, we devel-

oped a methodology to prepare stereoselectively either 2,6-cis

or 2,6-trans-disubstituted-piperidines via a Michael-type cycliza-

tion.^[11]This methodology used ꢀ′-carbamate-α,ꢀ-unsaturated

ketone^[3a]as a key precursor. We further envisioned that 2,6-

disubstituted-TP could be formed via a palladium-catalyzed

[a] Université Clermont Auvergne,CNRS, SIGMA Clermont, Institut de Chimie

de Clermont-Ferrand, 63000 Clermont-Ferrand, France

E-mail: fabrice.anizon@uca.fr (FA)

isabelle.thomas@sigma-clermont.fr (IAT)

https://iccf.uca.fr/

Supporting information and ORCID(s) from the author(s) for this article are

available on the WWW under https://doi.org/10.1002/ejoc .201901520.

Eur. J. Org. Chem. 0000, 0–0

1

Full Paper

intramolecular allylic amination. Key precursor allylic alcohols

According to the literature reporting catalyzed allylic amin-

would be prepared by reduction of the corresponding ketones, ation to form the six-membered ring of piperidines,^[3c,14]di-

as already described in previous work (Scheme 1).

hydroquinolines^[15]or substituted amines,^[16]the alcohol func-

tion can be free or activated as a carbonate or an acetate. In

order to optimize the reaction conditions for our TP synthesis,

we decided to start from either alcohol 3a or methyl carbonate

4a (Table 2). Carbonates 4a-syn and 4a-anti were prepared in

the presence of methyl chloroformate and pyridine in dichloro-

methane in 80 % and 67 % yields, respectively.

Results and Discussion

We have previously shown that ꢀ′-carbamate-α,ꢀ-unsaturated

ketone 2, starting material for this study, could be easily ob-

tained from the corresponding methyl ester in 5 steps with an

overall yield of about 30 % (Scheme 1).^[11,12]This methodology

allows the preparation of various precursors needed for the cur-

rent work. Ketones 2a–x were prepared in good to excellent

yields via Horner–Wadsworth-Emmons reaction between phos-

phonates 1a–g and various aldehydes (Table 1). The double

bond configuration was (E) in all cases, except for 2x (entry 24)

obtained in a 1:1 ratio of both stereoisomers. Starting material

3a–x for our current study were obtained in excellent yields

from 2a–x via a reduction step according to Luche proce-

dure,^[13]in MeOH at –78 °C by using 1 equivalent of both NaBH₄

and CeCl₃. The major diastereoisomer obtained was syn with a

With precursor 4a-syn in hand, the cyclization reaction was

investigated. First, and based on Unenishi transformation,^[3c]

30 mol-% of PdCl₂(CH₃CN)₂was used to validate the feasibility

of the cyclization to 5a and determine the best solvent (Table 2,

entries 1–4). At room temperature, DCE gave faster total conver-

sion in favor of a diastereoisomer with a 82:18 ratio. More polar

solvent such as THF or CH₃CN were also efficient with better

diastereoisomeric ratio but with much slower reaction. Other

palladium sources were tested in DCE, but did not yield the

desired product (entries 5–8).

Then, we have pursued our investigation using PdCl₂-

ratio up to 8:2, both anti and syn diastereoisomers being sepa- (CH₃CN)₂to see how the diastereoisomeric ratio could be im-

rable by column chromatography.

proved in DCE. First, three tests using 30 mol-% of

Table 1. Preparation of allylic alcohols.

Entry

1 (R or S)

R₃

Yield 2 [%]^[a]

Yield 3 [%]^[a](syn/anti)^[b]

1

2

3

4

5

6

7

8

1a (R)

1d (R)

1g (R)

1b (R)

1e (R)

1f (S)

1a (S)

1c (S)

1a (R)

1a (S)

1a (R)

1a (S)

1a (R)

1a (S)

1a (R)

1a (S)

1a (R)

1f (S)

1d (R)

Ph

2a (95)

2b (96)

2c (90)

2d (91)

2e (91)

2f (81)

2g (71)

2h (97)

2i (91)

2j (71)

2k (89)

2l (76)

2m (87)

2n (89)

2o (73)

2p (91)

2q (70)

2r (65)

2s (79)

2t (81)

2u (60)

2v (90)

2w (96)

2x (28)^[c]

3a (85) (90:10)

3b (94) (83:17)

3c (68) (75:25)

3d (79) (88:12)

3e (87) (87:13)

3f (93) (81:19)

3g (99) (89:11)

3h (94) (85:15)

3i (72) (80:20)

3j (90) (85:15)

3k (93) (85:15)

3l (92) (87:13)

3m (78) (80:20)

3n (99) (80:20)

3o (quant) (90:10)

3p (93) (82:18)

3q (98) (90:10)

3r (98) (85:15)

3s (90) (87:13)

3t (83) (84:16)

3u (89) (88:12)

3v (93) (84:16)

3w (80) (69:31)

3x (69) (100:0)

2-naphthalenyl

4-bromophenyl

2-bromophenyl

3-bromophenyl

4-bromophenyl

4-fluorophenyl

3-pyridinyl

2-nitrophenyl

3-nitrophenyl

4-nitrophenyl

4-methoxy-3-nitrophenyl

2-fluoro-5-nitrophenyl

4-methoxyphenyl

3-phenoxyphenyl

4-acetamidophenyl

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

C

₁₁H₂₃

Me

COOEt

[a] Isolated yield. [b] Calculated from ¹H NMR. [c] Yield of the (E) isomer.

Eur. J. Org. Chem. 0000, 0–0 www.eurjoc.org

2

Full Paper

Table 2. Reaction condition optimization.

Entry

solvent

compd

cat [mol-%]

Time [h]

t [°C]

Conv. 5a [%]^[a](trans/cis)

1

2

3

4

5

6

7

8

DCE

THF

4a-syn

4a-anti

3a-syn

3a-anti

PdCl₂(CH₃CN)₂(30)

Pd(OAc)₂(30)

Pd₂(dba)₃·CHCl₃(30)

[PdCl(allyl)]₂(30)

Pd(OAc)₂(30)

PdCl₂(CH₃CN)₂(30)

PdCl₂(CH₃CN)₂(20)

PdCl₂(CH₃CN)₂(10)

PdCl₂(CH₃CN)₂(5)

PdCl₂(CH₃CN)₂(2)

PdCl₂(CH₃CN)₂(5)

0.3

48

96

1.25

48

1.5

48

16

0.02

0.58

1.25

6

r.t.

0

80

r.t.

40

r.t.

40

100 (82:18)

100 (94:6)

90 (95:5)

100 (47:53)

SM

100 (46:54)

100 (29:71)

100 (94:6)

100 (28:72)

100 (77:23)

100 (90:10)

100 (93:7)

54 (98:2)

100 (97:3)

100 (95:5)

97 (95:5)

CH₃CN

DCM

DCE

9

10

11

12

13

14

15

16

17

18

19

20

21

72

7

4.5

3.3

6

3

[a] Conversion and ratio were calculated from ¹H NMR.

PdCl₂(CH₃CN)₂were carried out at room temperature to estab- also investigated to carry out the cyclization directly on the

lish if the ratio varied over the time or if it remained stable alcohol derivatives 3a-anti and 3a-syn, using 5 mol-% of palla-

(Table 2, entries 1, 9–12). We observed an epimerization of 5a dium (entries 18–21). The transformation was even more effi-

for a prolonged reaction time. Actually, reaction mixture tended cient with total conversion after 4.5 h at room temperature.

to an equilibrium between kinetic and thermodynamic 2,6-di- Interestingly, starting alcohols 3a-syn and 3a-anti led to the

substituted-TP diastereoisomers. We can suppose that thermo- same major diastereoisomer, with a 97:3 trans/cis ratio. More-

dynamically favored stereoisomer would be 5a-cis. Therefore, over, increasing the temperature to 40 °C allowed to reduce the

after 20 min at room temperature or 16 h at 0 °C (Table 2, reaction time without affecting diastereoisomeric ratio. To study

entries 1 and 11) the major product was certainly 5a-trans and, the scope of this methodology, the preferred conditions were

conversely, after 48 h at room temperature or less than 5 min fixed at 5 mol-% of palladium, in DCE.

at 80 °C (entries 10 and 12), the major product was 5a-cis. After

separation by chromatography of the two diastereoisomers, a

NOESY analysis was performed on 5a-trans and 5a-cis, and vali-

dated our hypothesis on the relative configuration of both 2,6-

TP stereoisomers. In order to reduce epimerization and access

to higher proportion of the trans-TP in a minimum of time with

a total conversion, we tested different amounts of palladium

catalyst (Table 2, entries 14–16). For a total conversion, the best

conditions were the use of 5 mol-% of PdCl₂(CH₃CN)₂, for 6 h

at room temperature, leading to 5a with a 93:7 trans/cis ratio.

The next step was to determine if this ratio could be influenced

by the stereochemistry of carbonate 4a. Surprisingly, cyclization

of 4a-anti resulted in the same major diastereoisomer 5a-trans

(entry 17) in the same proportion after 7 h, with a total conver-

sion.

According to Table 3, for the defined conditions, the selecti-

vity observed for the cyclization reaction was in favor of the

trans-isomer of 5. However, the rate of the reaction was mark-

edly dependent on some factors, mainly, steric hindrance

(R₁, R₂, R₃), electronic effects and nature of R₃. On the one hand,

when R₂and R₃were fixed (R₂= Me, R₃= Ph), a strong steric

hindrance of the carbamate imposed a longer time to complete

the reaction, even with a larger catalytic load, and reflux tem-

perature to obtain the desired product (see 5a–c-trans). Simi-

larly, when R₂was a propyl group (5d-trans, 5e-trans), the

smaller ethyl substituent on the carbamate was preferable to

afford the best conversion. No significant difference was ob-

served when the phenyl was replaced by a naphthalene moiety

(5g-trans). On the other hand, when R₃was an aromatic ring,

electronic effects also played on the cyclization rate. When the

Because the derivatization step of 3 into the corresponding phenyl was substituted by deactivating substituents such as

carbonate 4 generated waste and lowered atom economy, we halogens at para-position (Br, F), a positive effect on the reac-

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

3

Full Paper

tion rate was observed (5h-trans, 5k-trans, 5l-trans). Con- palladium at reflux, or even prevented the reaction. For exam-

versely, a bromine atom at ortho- or meta-position (5i-trans, ple, when a nitro was substituted at ortho- or para-position on

5j-trans), disfavored the conversion, even at reflux with, how- the phenyl ring, only the starting material was recovered after

ever, a diasteroisomeric ratio up to 95:5. Electron-withdrawing 24 h at reflux (5n, 5p). When the nitro was at the meta-position

group with strong –M effect such as nitro group slowed down (5o-trans), the TP was obtained in 27 % yield after 24 h at reflux

the transformation and requested a more important load of and 30 mol-% of catalyst. Adding a methoxy group at para-

Table 3. Scope of allyl alcohols.

Diastereoisomeric ratios are given for the crude products. [a] Not purified. [b] No conversion was observed, even with 30 mol-% of palladium, only the starting

material was recovered without any decomposition.

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

4

Full Paper

position (5q-trans) allowed to offset the deactivating nature of

the nitro group at the meta-position, with a total conversion

after 22 h at room temperature and 89 % yield. Electron-donat-

ing groups at the para-position (5s-cis, 5u-trans) greatly accel-

erated the conversion, but also the epimerization rate, even

with 5 mol-% of palladium. At the meta-position (5t-trans), phe-

noxy electron-donating group, only slowed down the reaction

and led to a 98:2 trans/cis ratio. When R₃was an alkyl group (5v,

5w), or ethoxycarbonyl and pyridin-3-yl electron-withdrawing

groups (5m, 5x), no conversion was observed, only starting ma-

terial alcohols were recovered. All these results suggested that

in order to access the desired TP, the allylic alcohol system had

to be connected to an aromatic ring and that electronic effects

played an important role in the cyclization. This led us to sup-

pose that the C–OH bond cleavage, initiated the transformation

to the η³-π-allyl palladium complex was influenced by the na-

ture on the resonance on R₃.

According to the literature,^[16b,17]the first step in nucleophilic

allylic substitution using an unactivated allylic substrate, such

as allylic alcohol, is an activation of the alcohol function. This

activation can be performed by addition of Lewis or Brønsted

acid or using a protic solvent, with or without catalyst. In our

case, there was no activation by the solvent or acidic additives.

However, the carbamate NH hydrogen could play this activation

role by promoting the departure of a water molecule, leading

to the formation of an η³-π-allylic palladium complex and sub-

sequent nitrogen nucleophilic attack and TP cycle formation

(Scheme 2).

Figure 1. Theoretical calculation for water elimination.

According these theoretical calculations and experimental

results, intermediate C, precursor of the cyclization, must be

formed to initiate the C–N bond formation. Then, after depar-

ture of water, the nitrogen atom of intermediate D, a conforma-

tional isomer of C, goes positioned close to the η³-π-allyl com-

plex to allow the cyclization via transition state E in the course

of an exergonic reaction (Figure 2). The calculated activation

energy was about 10 kcal/mol, followed by a loss of 30 kcal/

mol to complex F, in a favorable cyclization process. When no

reaction occurred, the starting material was recovered without

loss of the stereochemistry of the alcohol center, showing that

water release and formation of the η³-π-allyl complex D was a

key step for this cyclization.

Scheme 2. Proposed mechanisms for the C-O bond cleavage.

To validate our proposal, we conducted theoretical calcula-

tions. The intramolecular allylic amination of compound 3a cat-

alyzed by Pd(CH₃CN)₂, was studied with Gaussian software^[18]

using Density Functional Theory (DFT) using B3LYP hybrid func-

tional and LANL2DZ basis set for Pd and 6-31g+(d,p) basis set

for all other atoms. During the optimization, dichloroethane

Figure 2. Theoretical calculation for cyclization via C-N bond formation.

A proposed mechanism for this amination reaction is de-

was taken into account as solvent, by using the polarizable con- picted Scheme 3, starting from allylic alcohol 3a-syn. After com-

tinuum model (PCM). All energies are given in kcal/mol, after plexation of the palladium, presumably anti to the hydroxy

thermodynamic corrections, corresponding to Gibbs free ener- group, leading to A, and departure of the water molecule with

gies. This study is based on the work of Oshima^[17b]who assistance of the carbamate NH, η³-π-allyl complex intermedi-

showed that the activation energy for the water molecule re- ate D was obtained. As shown in Scheme 3, D has a sickle-

moval on the allylic alcohol system, and the subsequent forma- shaped geometry appropriate for cyclization to 5a-trans, with

tion of the η³-π-allyl complex, is favored by a coordination of nitrogen attack that occurs anti to the palladium. Alternatively,

the hydroxy group with the proton of a protic solvent. In our W-shaped complex can also be formed but would need to iso-

case, the hydroxy group was coordinated with the proton of merize to D before cyclization via an η³→η¹→η³isomerization

the carbamate nitrogen. The energies were calculated for π process. To explain the formation of 5a-cis, we could suppose

complex A, the palladium being anti to the hydroxy group, tran- an isomerization of D, with a switch of the face coordinated to

sition state B and η³-π-allyl complex C (Figure 1). Calculations the metal, via a nucleophilic displacement by palladium(0), to

showed an activation energy of 27 kcal/mol, then a loss of give D′.^[17d,19]However, due to steric hindrance, D′ would be

7 kcal/mol between B and C.

disfavored, which could explain the kinetic preference for 5a-

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

5

Full Paper

Scheme 3. Proposed mechanism for the formation of 2,6-trans-TP from 3a-syn.

Scheme 4. Formation of complexes D and D′ from 3a-anti.

trans via intermediate D, in the reaction conditions that minor from the corresponding phosphonate in two steps in good to

epimerization.

excellent yields. The configuration of the alcohol stereocenter,

generated after reduction of the corresponding ketone, did not

influence the stereochemical outcome of the cyclization reac-

tion into 2,6-trans-TP. According to calculations, the η³-π-allyl

complex could be formed with the assistance of the carbamate

NH, and the stereoselectivity could be explained by steric con-

straints in the η³-π-allyl complex.

A similar mechanistic pathway could explain why the

syn/anti relative configuration of the starting alcohol did not

affect the stereochemical outcome of the reaction. We can rea-

sonably suggest that D and D′ are common intermediates, and

that they are also formed from 3a-anti. Thus, 3a-anti would

first lead to π-allyl complex D′, and then a fast isomerization

via a nucleophilic displacement by palladium(0) would give D,

leading preferentially to the kinetic 5a-trans diastereoisomer

(Scheme 4).

Experimental Section

General Information: Commercially available reagents were pur-

chased from Sigma-Aldrich, Fisher, TCI, Alfa Aesar or Fluorochem

and were used without purification unless stated otherwise. Sol-

vents were purchased from VWR Chemicals or Sigma-Aldrich and

used without purification, unless stated otherwise. All ¹H and ¹³C

NMR spectra were measured at 295 K in CDCl₃or CD₃OD on a

Bruker AVANCE III HD 400 (101 MHz for ¹³C) spectrometer. NOESY

Conclusions

In conclusion, we described an efficient palladium-catalyzed

intramolecular cyclization of N-protected ꢀ-amino-allylic alco-

hols 3 as well as the stereoselectivity of the transformation into

2,6-trans-TP 5. The allylic alcohol precursors could be prepared were performed on a Bruker AVANCE III HD 500. Chemical shifts (δ)

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

6

Full Paper

are given in ppm and are calibrated to the residual proton and

carbon resonance of the solvent: CDCl₃(¹H δ = 7.26; ¹³C δ = 77.16);

CD₃OD (¹H δ = 3.31; ¹³C δ = 49.00). Coupling constant (J) are

quoted in Hertz (Hz). The following abbreviations are used: singlet

(s), broad singlet (brs), doublet (d), doublet of triplet (dt), triplet of

doublet (td), doublet of triplet of doublet (dtd), doubled doublet

7:3 cyclohexane/EtOAc) providing 2g as a white solid in 71 % yield

(356 mg, 1.14 mmol). TLC R_f= 0.17 (cyclohexane/EtOAc, 8:2); Mp

109 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.97 (s, 1H), 7.85 (m, 3H), 7.75

(d, J = 16.2 Hz, 1H), 7.68 (dd, J₁= 8.7 Hz, J₂= 1.7 Hz, 1H), 7.58–7.43

(m, 2H), 6.84 (d, J = 16.2 Hz, 1H), 5.23 (s, 1H), 4.18 (dquintd, J₁

=

8.4 Hz, J₂= 6.7 Hz, J₃= 4.8 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.07

(dd), triplet (t), quadruplet (q), quadruplet of doublet (qd), quintu- (dd, J₁= 16.0 Hz, J₂= 4.4 Hz, 1H), 2.83 (dd, J₁= 16.0 Hz, J₂= 6.5 Hz,

plet (quint), doublet of quintuplet (dquint), doublet of quintuplet of

doublet (dquintd), multiplet (m). High resolution mass spectroscopy

(HRMS) were carried out in electrospray mode. Monitoring of the

reactions was performed using silica gel TLC plates. Spots were visu-

alized by UV light at 254 nm and by dipping the plate into a solu-

tion of p-anisaldehyde/H₂SO₄/AcOH in EtOH, followed by heating.

Flash chromatography columns were performed using silica gel 60

(70–230 mesh). Melting points were obtained with the Mettler

Toledo apparatus MP50 Melting Point System.

1H), 1.31 (t, J = 6.8 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ = 198.9, 156.1, 143.6, 134.6, 133.5, 132.0, 130.8,

129.0, 128.8, 128.0, 127.6, 127.0, 126.6, 123.7, 60.8, 46.5, 44.4, 20.7,

14.8; HRMS (ESI⁺) calcd. for C₁₉H₂₂NO₃[M + H]⁺312.1594, found

312.1599.

Ethyl (S,E)-(5-(4-Bromophenyl)-3-oxo-1-phenylpent-4-en-1-yl)-

carbamate (2h): was prepared from ethyl (S)-(4-(diethoxyphos-

phoryl)-3-oxo-1-phenylbutyl)carbamate 1c (370 mg, 1.00 mmol).

The crude product was purified by silica gel column chromatogra-

phy (SiO₂, 9:1 cyclohexane/EtOAc to 7:3 cyclohexane/EtOAc) provid-

ing 2h as a white solid in 97 % yield (390 mg, 0.969 mmol). TLC

R_f= 0.38 (cyclohexane/EtOAc, 7:3); Mp 118 °C; ¹H NMR (400 MHz,

CDCl₃) δ = 7.51 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 16.1 Hz, 1H), 7.39–

Procedure A: Synthesis of Ketones 2 from Phosphonates 1: All

phosphonates 1 and ketones 2 were prepared according to the

method we reported in our previous work.^[12]To a solution of phos-

phonate 1a–g (1 equiv.) in THF (0.23 M) was added Ba(OH)₂·H₂O

(1.25 equiv.) at room temperature. After 30 min of stirring, a solu- 7.22 (m, 8H), 5.67 (brs, 1H), 5.22 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H),

tion of corresponding aldehyde (1.05 equiv.) in THF/H₂O (40:1) (0.24

M) was added at room temperature. The end of reaction was moni-

tored by TLC, and then the reaction mixture was quenched with a

saturated aqueous NH₄Cl solution and extracted 3 times with

EtOAc. Then the organic layer was dried with MgSO₄, filtered, and

concentrated under vacuum. The crude was purified by silica gel

column chromatography as described in the corresponding syn-

thetic procedure to give the ketone 2a–x.

3.34 (dd, J₁= 16.2, J₂= 5.3 Hz, 1H), 3.13 (dd, J₁= 16.2 Hz, J₂=

6.0 Hz, 1H), 1.22 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

197.8, 155.7, 143.3, 142.3, 133.3, 132.4, 129.9, 128.8, 127.7, 126.5,

126.4, 125.2, 61.2, 51.9, 46.5, 14.7; HRMS (ESI⁺) calcd. for

C₂₀H₂₁BrNO₃[M + H]⁺402.0699, found 402.0699.

Ethyl (R,E)-(6-(3-Bromophenyl)-4-oxohex-5-en-2-yl)carbamate

(2j): was prepared from ethyl (R)-(5-(diethoxyphosphoryl)-4-oxo-

pentan-2-yl) 1a (464 mg, 1.5 mmol). The crude product was purified

by silica gel column chromatography (SiO₂, 9:1 to 7:3 cyclohexane/

EtOAc) providing 2j as a white solid in 71 % yield (362 mg,

1.06 mmol). TLC R_f= 0.33 (cyclohexane/EtOAc, 7:3); Mp 67 °C; ¹H

Benzyl (R,E)-(6-Oxo-8-phenyloct-7-en-4-yl)carbamate (2e): was

prepared from benzyl (R)-(1-(diethoxyphosphoryl)-2-oxoheptan-4-

yl)carbamate 1e (1 g, 2.50 mmol). The crude product was purified

by silica gel column chromatography (SiO₂, 100 % cyclohexane to

8:2 cyclohexane/EtOAc) providing 2e as a white solid in 91 % yield

(800 mg, 2.28 mmol). TLC R_f= 0.49 (cyclohexane/EtOAc, 7:3); Mp

NMR (400 MHz, CDCl₃) δ = 7.69 (t, J = 1.8 Hz, 1H), 7.52 (dd, J₁

=

7.9 Hz, J₂= 1.8 Hz, 1H), 7.49 (d, J = 16.1 Hz, 1H), 7.46 (dt, J₁= 7.9 Hz,

J₂= 1.8 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.70 (d, J = 16.1 Hz, 1H),

93 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.62–7.48 (m, 3H), 7.42–7.37 5.09 (brs, 1H), 4.25–3.99 (m, 3H), 3.00 (dd, J₁= 16.1 Hz, J₂= 3.9 Hz,

(m, 3H), 7.36–7.27 (m, 5H), 6.72 (d, J = 16.1 Hz, 1H), 5.27 (d, J = 1H), 2.78 (dd, J₁= 16.1 Hz, J₂= 6.5 Hz, 1H), 1.27 (d, J = 6.7 Hz, 3H),

8.7 Hz, 1H), 5.08 (s, 2H), 4.11–3.99 (m, 1H), 3.02 (dd, J₁= 16.2 Hz,

4.6 Hz, 1H), 2.85 (dd, J₁= 16.2 Hz, J₂= 5.6 Hz, 1H), 1.57–1.49 (m,

2H), 1.47–1.19 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ = 199.1, 156.1, 143.4, 136.7, 134.4, 130.8, 129.1, 128.6,

128.5, 128.2, 128.1, 126.4, 66.7, 48.5, 44.8, 36.6, 19.7, 14.0; HRMS

(ESI⁺) calcd. for C₂₂H₂₆NO₃[M + H]⁺352.1907, found 352.1911.

1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 198.6, 156.0,

141.6, 136.6, 133.5, 131.1, 130.6, 127.5, 127.1, 123.2, 60.9, 46.8, 44.2,

20.6, 14.8; HRMS (ESI⁺) calcd. for C₁₅H₁₉BrNO₃[M + H]⁺340.0543,

found 340.0547.

Ethyl (S,E)-(6-(4-Fluorophenyl)-4-oxohex-5-en-2-yl)carbamate

(2l): was prepared from ethyl (S)-(5-(diethoxyphosphoryl)-4-oxo-

pentan-2-yl)carbamate 1a (500 mg, 1.62 mmol) and the correspond-

ing aldehyde (160 μL, 1.49 mmol). The crude product was purified

by silica gel column chromatography (SiO₂, 100 % cyclohexane to

7:3 cyclohexane/EtOAc) providing 2l as a white solid in 76 % yield

(317 mg, 1.13 mmol). Mp 71 °C; TLC R_f= 0.29 (cyclohexane/EtOAc,

8:2); ¹H NMR (400 MHz, CDCl₃) δ = 7.55 (d, J = 16.1 Hz, 1H), 7.54

(dd, J = 8.7 Hz, J_HF= 5.5 Hz, 2H), 7.08 (t, J_HH,HF= 8.7 Hz, 2H), 6.65

Benzyl (S,E)-(3-Oxo-1,5-diphenylpent-4-en-1-yl)carbamate 2f:

was prepared from benzyl (S)-(4-(diethoxyphosphoryl)-3-oxo-1-

phenylbutyl)carbamate 1f (100 mg, 0.231 mmol). The crude product

was purified by silica gel column chromatography (SiO₂, 100 % cy-

clohexane to 8:2 cyclohexane/EtOAc) providing 2f as a beige solid

in 81 % yield (71.6 mg, 0.186 mmol). TLC R_f= 0.47 (cyclohexane/

1

EtOAc, 7:3); Mp 114 °C; H NMR (400 MHz, CDCl₃) δ = 7.57–7.44 (m,

3H), 7.43–7.19 (m, 13H), 6.66 (d, J = 16.2 Hz, 1H), 5.86 (brs, 1H), 5.25 (d, J = 16.1 Hz, 1H), 5.11 (brs, 1H), 4.26–4.01 (m, 3H), 3.01 (dd, J₁=

(m, 1H), 5.12 (d, J = 12.0 Hz, 1H), 5.07 (d, J = 12.0 Hz, 1H), 3.35 (d,

J = 17.0 Hz, 1H), 3.16 (dd, J₁= 17.0 Hz, J₂= 6.0 Hz, 1H); ¹³C NMR

(101 MHz, CDCl₃) δ = 198.0, 155.8, 143.8, 141.4, 136.5, 134.3, 130.9,

129.1, 128.8, 128.6, 128.5, 128.2, 128.2, 127.6, 126.4, 126.1, 66.9, 52.0,

46.1; HRMS (ESI⁺) calcd. for C₂₅H₂₄NO₃[M + H]⁺386.1751, found

386.1747.

16.1 Hz, J₂= 4.3 Hz, 1H), 2.77 (dd, J₁= 16.1 Hz, J₂= 6.6 Hz, 1H),

1.29 (d, J = 6.6 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ = 198.6, 164.1 (d, J_CF= 252 Hz), 155.9, 142.1, 130.6 (d, J_CF

3 Hz), 130.3 (d, J_CF= 9 Hz), 126.0 (d, J_CF= 2 Hz), 116.2 (d, J_CF

=

22 Hz), 60.7, 46.5, 44.2, 20.5, 14.6; HRMS (ESI⁺) calcd. for C₁₅H₁₉FNO₃

[M + H]⁺280.1344, found 280.1344.

Ethyl (S,E)-(6-(Naphthalen-2-yl)-4-oxohex-5-en-2-yl)carbamate Ethyl

(S,E)-(6-(3-Nitrophenyl)-4-oxohex-5-en-2-yl)carbamate

(2g): was prepared from ethyl (S)-(5-(diethoxyphosphoryl)-4-oxo-

pentan-2-yl)carbamate 1a (500 mg, 1.62 mmol) and the correspond-

ing aldehyde (234 mg, 1.50 mmol). The crude product was purified

by silica gel column chromatography (SiO₂, 100 % cyclohexane to

(2o): was prepared from ethyl (S)-(5-(diethoxyphosphoryl)-4-oxo-

pentan-2-yl)carbamate 1a (500 mg, 1.62 mmol) and the correspond-

ing aldehyde (227 m mg, 1.50 mmol). The crude product was puri-

fied by silica gel column chromatography (SiO₂, 100 % cyclohexane

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

7

Full Paper

to 7:3 cyclohexane/EtOAc) providing 2o as a white solid in 73 % purified by silica gel column chromatography (SiO₂, 5:5 cyclohex-

yield (335 mg, 1.09 mmol). TLC R_f= 0.15 (cyclohexane/EtOAc, 8:2);

Mp > 135 °C (decomposition); ¹H NMR (400 MHz, CDCl₃) δ = 8.40

(t, J = 1.9 Hz, 1H), 8.25 (ddd, J₁= 8.2 Hz, J₂= 1.9 Hz, J₃= 0.8 Hz,

1H), 7.83 (dt, J₁= 7.8 Hz, J₂= 1.4 Hz, 1H), 7.62 (d, J = 16.1 Hz, 1H),

7.60 (t, J = 8 Hz, 1H), 6.83 (d, J = 16.1 Hz, 1H), 5.05 (brs, 1H), 4.17

(dquintd, J₁= 8.4 Hz, J₂= 6.7 Hz, J₃= 4.7 Hz, 1H), 4.10 (q, J = 7.1 Hz,

2H), 3.04 (dd,, J₁= 16.1 Hz, J₂= 4.7 Hz, 1H), 2.81 (dd, J₁= 16.1 Hz,

J₂= 6.7 Hz, 1H), 1.31 (d, J = 6.7 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C

ane/EtOAc to 2:8 cyclohexane/EtOAc) providing 2u as a white solid

in 60 % yield (286 mg, 0.898 mmol). TLC R_f= 0.2 (cyclohexane/

EtOAc, 5:5); Mp 199 °C; H NMR (400 MHz, MeOD) δ = 7.62 (d, J =

1

8.6 Hz, 2H) 7.60(d, J = 15.8 Hz, 1H), 7.58 (d, J = 8.6 Hz, 2H), 6.74 (d,

J = 15.8 Hz, 1H), 4.08 (m, 4H), 2.98 (dd, J = 15.2, 6.0 Hz, 1H), 2.73

(dd, J₁= 15.2 Hz, J₂= 6.9 Hz, 1H), 2.14 (s, 3H), 1.20 (d, J = 6.7 Hz,

3H), 1.19 (m, 3H); ¹³C NMR (101 MHz, MeOD) δ = 200.8, 171.6, 158.1,

144.5, 142.2, 131.2, 130.3, 126.0, 120.8, 61.5, 47.8, 45.2, 24.0, 21.0,

NMR (101 MHz, CDCl₃) δ = 198.2, 156.0, 148.9, 140.3, 136.3, 134.1, 14.9; HRMS (ESI⁺) calcd. for C₁₇H₂₃N₂O₄[M + H]⁺319.1652, found

130.2, 128.7, 124.9, 122.8, 60.9, 47.2, 44.2, 20.7, 14.73; HRMS (ESI⁺) 319.1644.

calcd. for C₁₅H₁₉N₂O₅[M + H]⁺307.1289, found 307.1280.

Ethyl (R,E)-(4-Oxoheptadec-5-en-2-yl)carbamate (2v): was pre-

pared from ethyl (R)-(5-(diethoxyphosphoryl)-4-oxopentan-2-yl)-

carbamate 1a (1.647 g, 5.33 mmol). The reaction was quenched

after 3h and the crude product was purified by silica gel column

chromatography (SiO₂, 9:1 to 8:2 cyclohexane/EtOAc) providing 2v

as a white solid in 90 % yield (1.63 g, 4.80 mmol). TLC R_f= 0.50

Ethyl (S,E)-(6-(4-Methoxy-3-nitrophenyl)-4-oxohex-5-en-2-yl)-

carbamate (2q): was prepared from ethyl (S)-(5-(diethoxyphos-

phoryl)-4-oxopentan-2-yl)carbamate 1a (500 mg, 1.62 mmol). The

crude product was purified by silica gel column chromatography

(SiO₂, 100 % cyclohexane to 8:2 cyclohexane/EtOAc) providing 2q

as a yellow solid in 70 % yield (380 mg, 1.13 mmol). TLC R_f= 0.61

(cyclohexane/EtOAc, 5:5); Mp 123 °C; ¹H NMR (400 MHz, CDCl₃) δ =

8.04 (d, J = 2.1 Hz, 1H), 7.72 (dd, J₁= 8.7 Hz, J₂= 2.1 Hz, 1H), 7.52

(d, J = 16.3 Hz, 1H), 7.12 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 16.3 Hz, 1H),

5.07 (s, 1H), 4.24–4.03 (m, 3H), 4.00 (s, 3H), 3.00 (dd, J₁= 16.0 Hz,

J₂= 3.8 Hz, 1H), 2.77 (dd, J₁= 16.0 Hz, J₂= 6.6 Hz, 1H), 1.27 (d, J =

6.8 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

198.2, 156.0, 154.4, 140.3, 140.0, 134.0, 127.2, 126.6, 125.3, 114.1,

60.8, 56.9, 46.9, 44.2, 20.6, 14.7; HRMS (ESI⁺) calcd. for C₁₆H₂₁N₂O₆

[M + H]⁺337.1394, found 337.1383.

1

(cyclohexane/EtOAc, 7:3); Mp 35 °C; H NMR (400 MHz, CDCl₃) δ =

6.86 (dt, J₁= 15.9 Hz, J₂= 6.9 Hz, 1H), 6.08 (dt, J₁= 15.9 Hz, J₂

=

1.5 Hz, 1H), 5.13 (brs, 1H), 4.22–3.93 (m, 3H), 2.88 (dd, J₁= 16.1 Hz,

J₂= 4.7 Hz, 1H), 2.63 (dd, J₁= 16.1 Hz, J₂= 6.5 Hz, 1H), 2.21 (qd,

J₁= 6.9 Hz, J₂= 1.5 Hz, 2H), 1.51–1.38 (m, 2H), 1.38–0.96 (m, 22H),

0.88 (t, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 199.2, 156.0,

148.9, 130.7, 60.8, 45.5, 44.2, 32.7, 32.0, 29.7, 29.7, 29.6, 29.5, 29.4,

29.3, 28.2, 22.8, 20.6, 14.7, 14.2; HRMS (ESI⁺) calcd. for C₂₀H₃₈NO₃

[M + H]⁺340.2846, found 340.2838.

Ethyl (R,E)-6-(((Benzyloxy)carbonyl)amino)-4-oxohept-2-enoate

(2x) and Ethyl (R,Z)-6-(((Benzyloxy)carbonyl)amino)-4-oxohept-

2-enoate (2x′): These compounds were prepared from benzyl (R)-

(5-(diethoxyphosphoryl)-4-oxopentan-2-yl)carbamate 1d (600 mg,

1.62 mmol). The crude product was purified by flash chromatogra-

phy (SiO₂, 8:2 pentane/EtO₂to 3:7 pentane) providing 2x as a white

solid in 28 % yield (145.7 mg, 0.456 mmol) and its isomer Z 2x′ as

a white solid in 37 % yield (188.4 mg, 0.590 mmol). 2x: TLC R_f=

0.46 (cyclohexane/EtOAc, 7:3); Mp 81 °C; ¹H NMR (400 MHz, CDCl₃)

δ = 7.40–7.28 (m, 5H), 7.02 (d, J = 16.1 Hz, 1H), 6.67 (d, J = 16.1 Hz,

1H), 5.15–4.93 (m, 3H), 4.25 (q, J = 7.1 Hz, 2H), 4.14 (dquintd, J₁=

7.6 Hz, J₂= 6.2 Hz, J₃= 4.2 Hz, 1H), 2.98 (dd, J = 16.9 Hz, J₂= 4.2 Hz,

1H), 2.79 (dd, J = 16.9 Hz, J₂= 6.2 Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H),

1.25 (d, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 198.3, 165.5,

155.7, 139.4, 136.5, 131.6, 128.7, 128.3, 128.2, 66.8, 61.6, 47.0, 43.9,

20.5, 14.2; HRMS (ESI⁺) calcd. for C₁₇H₂₂NO₅[M + H]⁺320.1493,

found 320.1483. 2x′: TLC R_f= 0.35 (cyclohexane/EtOAc, 7:3); Mp

Ethyl (S,E)-(6-(2-Fluoro-5-nitrophenyl)-4-oxohex-5-en-2-yl)carb-

amate (2r): was prepared from ethyl (S)-(5-(diethoxyphosphoryl)-4-

oxopentan-2-yl)carbamate 1a (500 mg, 1.62 mmol). The crude prod-

uct was purified by silica gel column chromatography (SiO₂, 100 %

cyclohexane to 8:2 cyclohexane/EtOAc) providing 2r as a white

solid in 65 % yield (340 mg, 1.05 mmol). TLC R_f= 0.16 (cyclohexane/

1

EtOAc, 8:2); Mp 107 °C; H NMR (400 MHz, CDCl₃) δ = 8.50 (dd, J₁=

6.2 Hz, J₂= 2.8 Hz, 1H), 8.27 (ddd, J₁= 9.1 Hz, J₂= 4.4 Hz, J₃

=

2.8 Hz, 1H), 7.69 (d, J = 16.3 Hz, 1H), 7.29 (t, J = 9.1 Hz, 1H), 6.94 (t,

J = 16.3 Hz, 1H), 5.04 (brs, 1H), 4.17 (dquintd, J₁= 8.4 Hz, J₂= 6.7 Hz,

J₃= 4.8 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.04 (dd, J₁= 16.3 Hz, J₂=

4.8 Hz, 1H), 2.84 (dd, J₁= 16.3 Hz, J₂= 6.4 Hz, 1H), 1.29 (d, J =

6.7 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

198.0, 165.5 (d, J_CF= 264 Hz), 156.0, 144.7, 132.8, 130.6 (d, J_CF

5.25 Hz), 127.0 (d, J_CF= 11 Hz), 124.6 (d, J_CF= 5 Hz), 124.0 (d, J_CF

=

14 Hz), 117.5 (d, J_CF= 25 Hz), 60.9, 47.3, 44.1, 20.7, 14.72; HRMS

1

30 °C; H NMR (400 MHz, CDCl₃) δ = 7.41–7.27 (m, 5H), 6.44 (d, J =

(ESI⁺) calcd. for C₁₅H₁₈FN₂O₅[M + H]⁺325.1194, found 325.1183.

12.0 Hz, 1H), 6.01 (d, J = 12.0 Hz, 1H), 5.21 (brs, 1H), 5.14–4.98 (m,

2H), 4.20 (q, J = 7.1 Hz, 2H), 4.20–4.09 (m, 1H), 2.89 (dd, J₁= 17.2 Hz,

J₂= 5.8 Hz, 1H), 2.81 (dd, J₁= 17.2 Hz, J₂= 5.5 Hz, 1H), 1.30 (d, J =

6.8 Hz, 3H), 1.28 (t, J = 7.1Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

202.2, 165.3, 155.8, 141.7, 136.7, 128.6, 128.1, 128.1, 125.1, 66.6, 61.4,

48.3, 43.7, 20.6, 14.1; HRMS (ESI⁺) calcd. for C₁₇H₂₂NO₅[M + H]⁺

320.1493, found 320.1483.

Ethyl (S,E)-(4-Oxo-6-(3-phenoxyphenyl)hex-5-en-2-yl)carbamate

(2t): was prepared from ethyl (S)-(5-(diethoxyphosphoryl)-4-oxo-

pentan-2-yl)carbamate 1a (500 mg, 1.62 mmol). The crude product

was purified by silica gel column chromatography (SiO₂, 100 % cy-

clohexane to 7:3 cyclohexane/EtOAc) providing 2t as a yellow oil in

81 % yield (460 mg, 1.30 mmol). TLC R_f= 0.24 (cyclohexane/EtOAc,

8:2); ¹H NMR (400 MHz, CDCl₃) δ = 7.51 (d, J = 16.2, 1H), 7.36 (m,

3H), 7.25 (s, 1H), 7.19–7.08 (m, 2H), 7.07–6.96 (m, 3H), 6.65 (d, J =

16.2 Hz, 1H), 5.12 (brs, 1H), 4.26–3.95 (m, 3H), 2.99 (dd, J₁= 16.1 Hz,

J₂= 4.5 Hz, 1H), 2.77 (dd, J₁= 16.1 Hz, J₂= 6.3 Hz, 1H), 1.26 (d, J =

6.7 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

198.8, 158.1, 156.7, 156.0, 142.8, 136.3, 130.4, 130.1, 127.1, 123.9,

123.4, 121.0, 119.3, 118.0, 60.8, 46.4, 44.2, 20.6, 14.7; HRMS (ESI⁺)

calcd. for C₂₁H₂₄NO₄[M + H]⁺354.1700, found 354.1689.

Procedure B: Synthesis of Alcohols 3 from Ketones 2: To a solu-

tion of the corresponding ketone 2a–x (1.0 equiv.) in MeOH (0.08

M) was added CeCl₃(1.0 equiv.). Then the reaction mixture was

cooled to –78 °C and then NaBH₄(1.0 equiv.) was added slowly

portionwise. The reaction mixture was stirred for 1 h, at –78 °C

and overnight at room temperature. After concentration, the crude

mixture was diluted in EtOAc and washed with a saturated aqueous

NH₄Cl solution and H₂O. The organic layer was dried with anhy-

drous MgSO₄, filtered and concentrated under reduced pressure.

The crude product was purified by silica gel column chromatogra-

phy as described in the corresponding synthetic procedure to give

the alcohols 3a–x.

Ethyl (S,E)-(6-(4-Acetamidophenyl)-4-oxohex-5-en-2-yl)carbam-

ate (2u): was prepared from ethyl (S)-(5-(diethoxyphosphoryl)-4-

oxopentan-2-yl)carbamate 1a (500 mg, 1.62 mmol) and the corre-

sponding aldehyde (245 mg, 1.50 mmol. The crude product was

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

8

Full Paper

Ethyl

((2R,4S,E)-4-Hydroxy-6-phenylhex-5-en-2-yl)carbamate

1H), 3.98 (m, 1H), 1.71 (ddd, J₁= 14.0 Hz, J₂= 10.5 Hz, J₃= 3.1 Hz,

1H), 1.49 (m, 1H), 1.46 (s, 9H), 1.21 (d, J = 6.7 Hz, 3H); ¹³C NMR

(101 MHz, CDCl3) δ = 157.1, 137.2, 131.8, 129.3, 128.6, 127.5, 126.5,

80.2, 68.6, 46.5, 43.5, 28.5, 21.7; HRMS (ESI⁺) calcd. for C₁₇H₂₅NaNO₃

[M + Na]⁺314.1727, found 314.1727. 3c-syn: TLC R_f= 0.14 (cyclo-

(3a-anti) and Ethyl ((2R,4R,E)-4-Hydroxy-6-phenylhex-5-en-2-

yl)carbamate (3a-syn): Ketone 2a (600 mg, 2.30 mmol) was used

in general procedure B. The crude product was purified by flash

chromatography (SiO₂, 9:1 cyclohexane/EtOAc to 6:4 cyclohexane/

EtOAc) providing 3a-anti as a white oil (50 mg, 0.190 mmol) and

3a-syn as a white oil (463 mg, 1.758 mmol). The alcohols 3a were

globally obtained in 85 % yield in a ratio of 90:10 in favor of the

syn product. 3a-anti: TLC R_f= 0.33 (cyclohexane/EtOAc, 7:3); ¹H

NMR (400 MHz, CDCl₃) 7.38 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz,

2H), 7.22 (t, J = 7.2 Hz, 1H), 6.63 (d, J = 15.9 Hz, 1H), 6.23 (dd, J₁=

15.9 Hz, J₂= 5.9 Hz, 1H), 4.68 (d, J = 8.3 Hz, 1H), 4.42–4.32 (m, 1H),

4.14 (q, J = 7.2 Hz, 2H), 4.09–3.95 (m, 1H), 3.86 (s, 1H), 1.74 (ddd,

J₁= 13.9 Hz, J₂= 10.6 Hz, J₃= 3.2 Hz, 1H), 1.54 (ddd, J₁= 13.9 Hz,

J₂= 10.6 Hz, J₃= 3Hz, 1H), 1.25 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.7 Hz,

3H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.5, 137.0, 131.7, 129.5, 128.6,

127.5, 126.5, 68.8, 61.3, 45.8, 44.0, 21.5, 14.7; HRMS (ESI⁺) calcd. for

1

hexane/EtOAc, 8:2); Mp 103 °C; H NMR (400 MHz, CDCl3) δ = 7.36

(d, J = 7.4 Hz, 2H), 7.29 (t, J = 7.4 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H),

6.59 (d, J = 16.0 Hz, 1H), 6.23 (dd, J₁= 16.0 Hz, J₂= 6.2 Hz, 1H),

4.57 (brs, 1H), 4.40 (td, J₁= 6.2 Hz, J₂= 6.6 Hz, 1H), 3.88 (m, 1H),

2.80 (brs, 1H), 1.76 (ddd, J₁= 14.0 Hz, J₂= 7.3 Hz, J₃= 6.6 Hz, 1H),

1.72 (m, 1H), 1.41 (s, 9H), 1.19 (d, J = 6.6 Hz, 3H); ¹³C NMR (101 MHz,

CDCl3) δ = 155.8, 136.9, 132.5, 129.9, 128.6, 127.6, 126.6, 79.6, 70.8,

45.0, 44.6, 28.5, 21.9; HRMS (ESI⁺) calcd. for C₁₇H₂₅NaNO₃[M + Na]⁺

314.1727, found 314.1727.

Ethyl

((4R,6S,E)-6-Hydroxy-8-phenyloct-7-en-4-yl)carbamate

(3d-anti) and Ethyl ((4R,6R,E)-6-Hydroxy-8-phenyloct-7-en-4-yl)-

carbamate (3d-syn). Ketone 2d (189.6 mg, 0.655 mmol) was used

in general procedure B. The crude product was purified by silica

gel column chromatography (SiO₂, cyclohexane to 8:2 cyclohexane/

EtOAc) providing 3d-anti as a colorless oil (17.6 mg, 0.0604 mmol)

and 3d-syn as a colorless oil (133.4 mg, 0.458 mmol). The alcohols

3d were globally obtained in 79 % yield in a ratio of 88:12 in favor

of the syn product. 3d-anti: TLC R_f= 0.20 (cyclohexane/EtOAc, 8:2);

¹H NMR (400 MHz, CDCl₃) δ = 7.37 (d, J = 7.5 Hz, 2H), 7.30 (t, J =

7.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 6.63 (d, J = 16.0 Hz, 1H), 6.22

(dd, J₁= 16.0 Hz, J₂= 5.6 Hz, 1H), 4.59 (d, J = 9.0 Hz, 1H), 4.37 (m,

1H), 4.08 (q, J = 7.1 Hz, 2H), 3.90 (m, 1H), 1.74 (ddd, J₁= 13.9 Hz,

J₂= 10.8 Hz, J₃= 3.0 Hz, 1H), 1.57–1.29 (m, 5H), 1.23 (t, J = 7.1 Hz,

3H), 0.93 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 158.0,

137.1, 131.8, 129.4, 128.6, 127.5, 126.5, 68.6, 61.4, 48.0, 44.5, 37.9,

19.5, 14.7, 14.0; HRMS (ESI⁺) calcd. for C₁₇H₂₅NaNO₃[M + Na]⁺

314.1727, found 314.1720. 3d-syn: TLC R_f= 0.09 (cyclohexane/

C

₁₅H₂₁NO₃Na [M + Na]⁺286.1414, found 286.1413. 3a-syn: TLC R_f=

0.19 (cyclohexane/EtOAc, 7:3); ¹H NMR (400 MHz, CDCl₃) 7.38 (d, J =

7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, 2H), 7.23 (t, J = 7.2 Hz, 1H), 6.60 (d,

J = 16.0 Hz, 1H), 6.24 (dd, J₁= 16.0 Hz, J₂= 6.1 Hz, 1H), 4.71 (s, 1H),

4.43 (q, J = 6.8 Hz, 1H), 4.16–3.97 (m, 2H), 3.91 (m, 1H), 2.46 (s, 1H),

1.78 (t, J = 6.5 Hz, 2H), 1.22 (d, J = 6.6 Hz, 3H), 1.17 (t, J = 6.8 Hz,

3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.5, 136.8, 132.3, 128.6, 128.5,

127.7, 126.5, 70.7, 60.9, 44.9, 44.6, 21.8, 14.6; HRMS (ESI⁺) calcd. for

C

₁₅H₂₁NO₃Na [M + Na]⁺286.1414, found 286.1413.

Benzyl ((2R,4S,E)-4-Hydroxy-6-phenylhex-5-en-2-yl)carbamate

(3b-anti) and Benzyl ((2R,4R,E)-4-Hydroxy-6-phenylhex-5-en-2-

yl)carbamate (3b-syn): Ketone 2b (685 mg, 2.12 mmol) was used

in general procedure B. The crude product was purified by silica

gel column chromatography (SiO₂, cyclohexane to 7:3 cyclohexane/

EtOAc) providing 3b-anti as a colorless oil (110 mg, 0.338 mmol)

and 3b-syn as a white solid (539.9 mg, 1.659 mmol). The alcohols

3b were globally obtained in 94 % yield in a ratio of 83:17 in favor

of the syn product. 3b-anti: TLC R_f= 0.39 (cyclohexane/EtOAc, 7:3);

1

EtOAc, 8:2); H NMR (400 MHz, CDCl₃) δ = 7.38 (d, J = 7.4 Hz, 2H),

7.30 (t, J = 7.4 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 6.61 (d, J = 15.5 Hz,

1H), 6.24 (dd, J₁= 15.5 Hz, J₂= 5.8 Hz, 1H), 4.58 (d, J = 8.6 Hz, 1H),

¹H NMR (400 MHz, CDCl₃) δ = 7.40–7.27 (m, 9H), 7.22 (t, J = 7.1 Hz, 4.45 (m, 1H), 4.19–3.92 (m, 2H), 3.79 (m, 1H), 2.66 (brs, 1H), 1.93–

1H), 6.61 (d, J = 15.9 Hz, 1H), 6.22 (dd, J₁= 15.9 Hz, J₂= 5.9 Hz, 1H),

5.12 (s, 2H), 4.80 (d, J = 8.7 Hz, 1H), 4.35 (m, 1H), 4.04 (m, 1H), 1.74

(ddd, J₁= 14.0 Hz, J₂= 10.6 Hz, J₃= 3.2 Hz, 1H), 1.64–1.49 (m, H₂O

+1H), 1.24 (d, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.2,

137.0, 136.4, 131.7, 129.7, 128.7, 128.7, 128.4, 128.3, 127.6, 126.6,

68.9, 67.2, 45.8, 44.3, 21.6; HRMS (ESI+) calcd. for C₂₀H₂₃NaNO₃[M +

Na]⁺348.1570, found 348.1574. 3b-syn: TLC R_f= 0.30 (cyclohexane/

1.29 (m, 6H), 1.15 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.2, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ = 156.9, 136.9, 132.4, 129.6, 128.7, 127.7, 126.6,

70.7, 61.0, 48.7, 43.5, 38.3, 19.2, 14.6, 14.1; HRMS (ESI⁺) calcd. for

C₁₇H₂₅NaNO₃[M + Na]⁺314.1727, found 314.1720.

Benzyl ((4R,6S,E)-6-Hydroxy-8-phenyloct-7-en-4-yl)carbamate

(3e-anti) and Benzyl ((4R,6R,E)-6-Hydroxy-8-phenyloct-7-en-4-

yl)carbamate (3e-syn). Ketone 2e (200.8 mg, 0.571 mmol) was

used in general procedure B. The crude product was purified by

silica gel column chromatography (SiO₂, cyclohexane to 7:3 cyclo-

hexane/EtOAc) providing 3e-anti as a white solid (23.2 mg,

0.0656 mmol) and 3e-syn as a white solid (152.2 mg, 0.430 mmol).

The alcohols 3e were globally obtained in 87 % yield in a ratio of

87:13 in favor of the syn product. 3e-anti: TLC R_f= 0.42 (cyclohex-

ane/EtOAc, 7:3); Mp 109 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.42–7.33

(m, 7H), 7.29 (t, J = 7.3 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 6.61 (d, J =

15.8 Hz, 1H), 6.22 (dd, J₁= 15.8 Hz, J₂= 5.8 Hz, 1H), 5.14 (d, J =

12.2 Hz, 1H), 5.10 (d, J = 12.2 Hz, 1H), 4.70 (d, J = 9.1 Hz, 1H), 4.35

(m, 1H), 3.94 (m, 1H), 3.79 (d, J = 2.8 Hz, 1H), 1.75 (ddd, J₁= 13.9,

J₂= 10.8, J₃= 3.0 Hz, 1H), 1.54–1.30 (m, 5H), 0.93 (t, J = 7.2 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ = 157.6, 137.1, 136.4, 131.7, 129.5,

128.7, 128.6, 128.4, 128.3, 127.6, 126.5, 68.6, 67.2, 48.2, 44.2, 37.8,

19.4, 14.0; HRMS (ESI⁺) calcd. for C₂₂H₂₇NaNO₃[M + Na]⁺376.1883,

found 376.1901. 3e-syn: TLC R_f= 0.26 (cyclohexane/EtOAc, 7:3); Mp

69 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.46–7.13 (m, 10H), 6.61 (d, J =

15.9Hz, 1H), 6.24 (dd, J₁= 15.9 Hz, J₂= 5.8 Hz, 1H), 5.08 (d, J =

11.9 Hz, 1H), 4.95 (d, J = 11.9 Hz, 1H), 4.71 (d, J = 8.6 Hz, 1H), 4.45

(td, J₁= 6.3 Hz, J₂= 5.8 Hz, 1H), 3.82 (m, 1H), 1.86 (dt, J₁= 14.4 Hz,

1

EtOAc, 7:3); H NMR (400 MHz, CDCl₃) δ = 7.41–7.19 (m, 10H), 6.60

(d, J = 15.9 Hz, 1H), 6.23 (dd, J₁= 15.9 Hz, J₂= 5.9 Hz, 1H), 5.08 (d,

J = 12.1 Hz, 1H), 4.97 (d, J = 12.1 Hz, 1H), 4.83 (brs, 1H), 4.43 (m,

1H), 3.93 (m, 1H), 1.79 (t, J = 6.5 Hz, 2H), 1.24 (d, J = 6.5 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ = 156.2, 136.8, 136.5, 132.2, 130.0,

128.7, 128.6, 128.3, 128.2, 127.8, 126.6, 70.8, 66.9, 45.1, 44.6, 21.9;

HRMS (ESI⁺) calcd. for C₂₀H₂₃NaNO₃[M + Na]⁺348.1570, found

348.1574.

tert-Butyl ((2R,4S,E)-4-Hydroxy-6-phenylhex-5-en-2-yl)carbam-

ate (3c-anti) and tert-Butyl ((2R,4R,E)-4-Hydroxy-6-phenylhex-5-

en-2-yl)carbamate (3c-syn). Ketone 2c (770 mg, 2.66 mmol) was

used in general procedure B. The crude product was purified by

silica gel column chromatography (SiO₂, 100 % cyclohexane to 8:2

cyclohexane/EtOAc) providing 3c-anti as a yellow oil (133 mg,

0.456 mmol) and 3c-syn as a white solid (396 mg, 1.36 mmol). The

alcohols 3c were globally obtained in 68 % yield in a ratio of 75:25

in favor of the syn product. 3c-anti: TLC R_f= 0.29 (cyclohexane/

1

EtOAc, 8:2); H NMR (400 MHz, CDCl3) δ = 7.37 (d, J = 7.7 Hz, 2H),

7.30 (t, J = 7.7 Hz, 2H), 7.21 (t, J = 7.7 Hz, 1H), 6.63 (d, J = 16.0 Hz,

1H), 6.24 (dd, J₁= 16.0 Hz, J₂= 5.6 Hz, 1H), 4.52 (brs, 1H), 4.34 (m,

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

9

Full Paper

1

J₂= 6.3 Hz, 1H), 1.72 (ddd, J₁= 14.4 Hz, J₂= 8.9 Hz, J₃= 6.3 Hz,

1H), 1.60–1.17 (m, 4H), 0.91 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ = 156.6, 136.9, 136.5, 132.3, 129.8, 128.7, 128.6, 128.3,

128.3, 127.7, 126.6, 70.7, 67.0, 48.8, 43.3, 38.2, 19.1, 14.0; HRMS (ESI⁺)

calcd. for C₂₂H₂₇NaNO₃[M + Na]⁺376.1883, found 376.1901.

3h-anti: TLC R_f= 0.27 (cyclohexane/EtOAc, 7:3); H NMR (400 MHz,

CDCl₃) δ = 7.42 (d, J = 8.4 Hz, 2H), 7.39–7.27 (m, 5H), 7.21 (d, J =

8.4 Hz, 2H), 6.55 (d, J = 15.8 Hz, 1H), 6.21 (dd, J₁= 15.8 Hz, J₂

=

6.0 Hz, 1H), 5.36 (d, J = 8.1, 1H), 5.03 (m, 1H), 4.36 (m, 1H), 4.10 (q,

J = 7.0 Hz, 2H), 3.51 (brs, 1H), 2.07–1.95 (m, 2H), 1.25 (t, J = 7.0 Hz,

3H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.3, 141.6, 135.9, 132.3, 131.8,

129.0, 128.9, 128.1, 127.8, 126.5, 121.5, 69.0, 61.5, 52.4, 44.3, 14.7;

HRMS (ESI⁺) calcd. for C₂₀H₂₂BrNaNO₃[M + Na]⁺426.0675, found

426.0671. 3h-syn: TLC R_f= 0.17 (cyclohexane/EtOAc, 7:3); ¹H NMR

(400 MHz, CDCl₃) δ = 7.42 (d, J = 8.5 Hz, 2H), 7.39–7.25 (m, 5H),

Benzyl (1S,3S,E)-(3-Hydroxy-1,5-diphenylpent-4-en-1-yl)carb-

amate (3f-anti) and Benzyl (1S,3R,E)-(3-Hydroxy-1,5-diphenyl-

pent-4-en-1-yl)carbamate (3f-syn): Ketone 2f (50.9 mg,

0.132 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 9:1 cyclo-

hexane/EtOAc to 8:2 cyclohexane/EtOAc) providing 3f-anti as a col-

orless oil (9 mg, 0.0232 mmol) and 3f-syn as a white oil (38.5 mg,

0.993 mmol). The alcohols 3f were globally obtained in 93 % yield

in a ratio of 81:19 in favor of the syn product. 3f-anti: TLC R_f= 0.42

(cyclohexane/EtOAc, 7:3); The product was not stable and deterio-

rated. 3f-syn: TLC R_f= 0.33 (cyclohexane/EtOAc, 7:3); ¹H NMR

(400 MHz, CDCl₃) δ = 7.40–7.17 (m, 15H), 6.55 (d, J = 16.0 Hz, 1H),

6.21 (dd, J₁= 16.0 Hz, J₂= 6.3 Hz, 1H), 5.44 (d, J = 7.3 Hz, 1H), 5.05

(d, J = 12.4 Hz, 1H), 5.01 (d, J = 12.4 Hz, 1H), 4.92 (m, 1H), 4.30 (m,

1H), 2.30–1.85 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.0, 142.3,

136.6, 136.5, 131.8, 130.4, 128.9, 128.7, 128.6, 128.4, 128.3, 127.9,

127.7, 126.6, 126.6, 70.8, 67.0, 53.6, 44.2; HRMS (ESI⁺) calcd. for

7.20 (d, J = 8.5 Hz, 2H), 6.50 (d, J = 15.9 Hz, 1H), 6.21 (dd, J₁

=

15.9 Hz, J₂= 6.1 Hz, 1H), 5.27 (d, J = 6.7 Hz, 1H), 4.89 (m, 1H), 4.31

(m, 1H), 4.05 (q, J = 7.0 Hz, 2H), 2.25–1.96 (m, 2H), 1.18 (t, J = 7.0 Hz,

3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.3, 142.4, 135.6, 132.8, 131.8,

129.0, 128.9, 128.1, 127.8, 126.6, 121.6, 70.7, 61.2, 53.3, 44.2, 14.7;

HRMS (ESI⁺) calcd. for C₂₀H₂₂BrNaNO₃[M + Na]⁺426.0675, found

426.0671.

Ethyl

((2R,4S,E)-6-(2-Bromophenyl)-4-hydroxyhex-5-en-2-yl)-

carbamate (3i-anti) and Ethyl ((2R,4R,E)-6-(2-Bromophenyl)-4-

hydroxyhex-5-en-2-yl)carbamate (3i-syn): Ketone 2i (77 mg,

0.226 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 85:15

cyclohexane/EtOAc to 7:3 cyclohexane/EtOAc) providing 3i-anti as

a yellow oil (10.9 mg, 0.0319 mmol) and 3i-syn as a colorless oil

(44.5 mg, 0.130 mmol). The alcohols 3i were globally obtained in

72 % yield in a ratio of 80:20 in favor of the syn product. 3i-anti:

TLC R_f= 0.16 (cyclohexane/EtOAc, 8:2); The product was not stable

C

₂₅H₂₅NaNO₃[M + Na]⁺410.1727, found 410.1715.

Ethyl ((2S,4R,E)-4-Hydroxy-6-(naphthalen-2-yl)hex-5-en-2-yl)-

carbamate (3g-anti) and Ethyl ((2S,4S,E)-4-Hydroxy-6-(naphth-

alen-2-yl)hex-5-en-2-yl)carbamate (3g-syn): Ketone 2g (297 mg,

0.954 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 9:1 cyclo-

hexane/EtOAc to 6:4 cyclohexane/EtOAc) providing 3g-anti as a

white solid (31.2 mg, 0.10 mmol) and 3g-syn as a white solid

(265 mg, 0.846 mmol). The alcohols 3g were globally obtained in

99 % yield in a ratio of 89:11 in favor of the syn product. 3g-anti:

TLC R_f= 0.33 (cyclohexane/EtOAc, 7:3); Mp 70 °C; ¹H NMR (400 MHz,

CDCl₃) δ = 7.79–7.75 (m, 3H), 7.76 (d, J = 1.2 Hz, 1H), 7.59 (dd, J₁=

8.6 Hz, J₂= 1.8 Hz, 1H), 7.48–7.39 (m, 2H), 6.81 (d, J = 15.9 Hz, 1H),

6.35 (dd, J₁= 15.9 Hz, J₂= 5.8 Hz, 1H), 4.75 (d, J = 8.5 Hz, 1H), 4.42

(m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.04 (m, 2H), 1.79 (ddd, J₁= 3.2 Hz,

J₂= 10.6 Hz, J₃= 14.0 Hz, 1H), 1.56 (ddd, J₁= 2.7 Hz, J₂= 10.5 Hz,

J₃= 14.0 Hz, 1H), 1.26 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.7 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ = 157.6, 134.5, 133.7, 133.0, 132.1,

129.6, 128.2, 128.1, 127.7, 126.4, 126.3, 125.9, 123.7, 68.8, 61.4, 45.9,

44.1, 21.6, 14.7; HRMS (ESI⁺) calcd. for C₁₉H₂₃NNaO₃[M + Na]⁺

336.1570, found 336.1573. 3g-syn: TLC R_f= 0.21 (cyclohexane/

1

and deteriorated. 3i-syn: TLC R_f= 0.09 (cyclohexane/EtOAc, 8:2); H

NMR (400 MHz, CDCl₃) δ = 7.54 (dd, J₁= 7.8 Hz, J₂= 1.2 Hz, 1H),

7.49 (dd, J₁= 7.8 Hz, J₂= 1.7 Hz, 1H), 7.28–7.22 (m, 1H), 7.10 (td,

J₁= 7.8 Hz, J₂= 1.7 Hz, 1H), 6.94 (dd, J₁= 15.9 Hz, J₂= 1.1 Hz, 1H),

6.20 (dd, J₁= 15.9 Hz, J₂= 6.0 Hz, 1H), 4.71 (brs, 1H), 4.48 (qd, J₁=

6.1 Hz, J₂= 1.4 Hz, 1H), 4.14–3.98 (m, 2H), 3.92 (m, 1H), 1.80 (t, J =

7.1 Hz, 2H), 1.25 (d, J = 6.6 Hz, 3H), 1.17 (t, J = 7.3 Hz, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ = 156.5, 136.7, 135.5, 133.0, 128.9, 128.5, 127.5,

127.2, 123.8, 70.6, 61.0, 44.9, 44.5, 21.8, 14.7; HRMS (ESI⁺) calcd. for

C

₁₅H₂₀BrNaNO₃[M + Na]⁺364.0519, found 364.0518.

Ethyl ((2R,4S,E)-6-(3-Bromophenyl)-4-hydroxyhex-5-en-2-yl)-

carbamate (3j-anti) and Ethyl ((2R,4R,E)-6-(3-Bromophenyl)-4-

hydroxyhex-5-en-2-yl)carbamate (3j-syn): Ketone 2j (230 mg,

0.676 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 8:2 cyclo-

hexane/EtOAc to 7:3 cyclohexane/EtOAc) providing 3j-anti as a col-

orless oil (31.1 mg, 0.0909 mmol) and 3j-syn as a colorless oil

(177.2 mg, 0.518 mmol). The alcohols 3j were globally obtained in

90 % yield in a ratio of 85:15 in favor of the syn product. 3j-anti:

TLC R_f= 0.27 (cyclohexane/EtOAc, 7:3); ¹H NMR (400 MHz, CDCl₃)

δ = 7.50 (t, J = 1.8 Hz, 1H), 7.33 (ddd, J₁= 7.9 Hz, J₂= 1.8 Hz, J₃=

1.1 Hz, 1H), 7.26 (ddd, J₁= 7.9 Hz, J₂= 1.8 Hz, J₃= 1.5 Hz, 1H), 7.15

(t, J = 7.9 Hz, 1H), 6.56 (dd, J₁= 16.0 Hz, J₂= 1.3 Hz, 1H), 6.21 (dd,

J₁= 16 Hz, J₂= 5.5 Hz, 1H), 4.74 (d, J = 8.6 Hz, 1H), 4.35 (m, 1H),

4.12 (q, J = 7.1 Hz, 2H), 4.09–3.90 (m, 2H), 1.72 (ddd, J₁= 14.0 Hz,

J₂= 10.8 Hz, J₃= 3.2 Hz, 1H), 1.51 (ddd, J₁= 14.0 Hz, J₂= 10.7 Hz,

J₃= 2.9 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H), 1.23 (d, J = 6.7 Hz, 3H); ¹³C

1

EtOAc, 7:3); Mp 60 °C; H NMR (400 MHz, CDCl₃) δ = 7.83–7.73 (m,

3H), 7.71 (d, J = 1.1 Hz, 1H), 7.57 (dd, J₁= 8.6 Hz, J₂= 1.7 Hz, 1H),

7.48–7.39 (m, 2H), 6.77 (d, J = 15.8 Hz, 1H), 6.35 (dd, J₁= 15.8 Hz,

J₂= 6.1 Hz, 1H), 4.73 (brs, 1H), 4.49 (brs, 1H), 4.15–4.04 (m, 1H), 3.93

(m, 1H), 2.51 (brs, 1H), 1.81 (dd, J₁= 7.0 Hz, J₂= 7.8 Hz, 1H), 1.63–

1.52 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H); ¹³C

NMR (101 MHz, CDCl₃) δ = 156.5, 134.3, 133.7, 133.1, 132.7, 129.9,

128.3, 128.1, 127.8, 126.5, 126.4, 126.0, 123.7, 70.8, 60.9, 44.9, 44.8,

28.5, 21.9, 14.7; HRMS (ESI⁺) calcd. for C₁₉H₂₃NNaO₃[M + Na]⁺

336.1570, found 336.1573.

Ethyl ((1S,3S,E)-5-(4-Bromophenyl)-3-hydroxy-1-phenylpent-4- NMR (101 MHz, CDCl₃) δ = 157.7, 139.3, 133.3, 130.3, 130.2, 129.3,

en-1-yl)carbamate (3h-anti) and Ethyl ((1S,3R,E)-5-(4-Bromo-

phenyl)-3-hydroxy-1-phenylpent-4-en-1-yl)carbamate (3h-syn):

127.9, 125.2, 122.8, 68.4, 61.4, 46.0, 44.0, 21.6, 14.7; HRMS (ESI⁺)

calcd. for C₁₅H₂₀BrNaNO₃[M + Na]⁺364.0519, found 364.0518. 3j-

Ketone 2h (90 mg, 0.224 mmol) was used in general procedure B. syn: TLC R_f= 0.16 (cyclohexane/EtOAc, 7:3); ¹H NMR (400 MHz,

The crude product was purified by silica gel column chromatogra-

CDCl₃) δ = 7.51 (t, J = 1.8 Hz, 1H), 7.35 (ddd, J₁= 7.9 Hz J₂= 1.8 Hz,

phy (SiO₂, 9:1 cyclohexane/EtOAc to 7:3 cyclohexane/EtOAc) provid- J₃= 1.5 Hz, 1H), 7.27 (ddd, J₁= 7.9 Hz, J₂= 1.8 Hz, J₃= 1.5 Hz, 1H),

ing 3h-anti as a colorless oil (12.7 mg, 0.0314 mmol) and 3h-syn as 7.17 (t, J = 7.9 Hz, 1H), 6.54 (dd, J₁= 15.9 Hz J₂= 1.6 Hz, 1H), 6.24

a colorless oil (72.5 mg, 0.179 mmol). The alcohols 3h were globally (dd, J₁= 15.9, J₂= 5.8 Hz, 1H), 4.67 (brs, 1H), 4.43 (q, J = 5.8 Hz,

obtained in 94 % yield in a ratio of 85:15 in favor of the syn product. 1H), 4.15–3.95 (m, 2H), 3.90 (m, 1H), 1.88–1.69 (m, 2H), 1.23 (d, J =

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

10

Full Paper

6.7Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

0.711 mmol) was used in general procedure B. The crude product

156.5, 139.1, 134.0, 130.4, 130.1, 129.3, 128.1, 125.3, 122.8, 70.3, 61.0, was purified by silica gel column chromatography (SiO₂, 4:6 cyclo-

44.7, 44.6, 21.8, 14.6; HRMS (ESI⁺) calcd. for C₁₅H₂₀BrNaNO₃[M +

Na]⁺364.0519, found 364.0518.

hexane/EtOAc to 2:8 cyclohexane/EtOAc) providing 3m-anti as a

white solid (29.1 mg, 0.110 mmol) and 3m-syn as a white solid

(117.1 mg, 0.443 mmol). The alcohols 3m were globally obtained in

78 % yield in a ratio of 80:20 in favor of the syn product. 3m-anti:

TLC R_f= 0.13 (cyclohexane/EtOAc, 4:6); Mp 151 °C; ¹H NMR

(400 MHz, CDCl₃) δ = 8.58 (m, 1H), 8.45 (m, 1H), 7.67 (d, J = 7.8 Hz,

1H), 7.19 (m, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.29 (dd, J₁= 16.0 Hz,

J₂= 5.4 Hz, 1H), 4.84 (m, 1H), 4.37 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H),

3.98 (m, 1H), 1.72 (ddd, J₁= 13.9, J₂= 10.9 Hz, J₃= 3.2 Hz, 1H), 1.53

(ddd, J₁= 13.9, J₂= 10.6 Hz, J₃= 2.7 Hz, 1H), 1.34–1.02 (m, 6H); ¹³C

NMR (101 MHz, CDCl₃) δ = 157.7, 148.4, 148.2, 137.1, 136.3, 134.3,

133.0, 125.7, 68.4, 61.4, 46.0, 44.0, 21.7, 14.7; HRMS (ESI⁺) calcd. for

C₁₄H₂₁N₂O₃[M + H]⁺265.1547, found 265.1545; 3m-syn: TLC R_f=

0.06 (cyclohexane/EtOAc, 4:6); Mp 115 °C; ¹H NMR (400 MHz, CDCl₃)

δ = 8.63 (m, 1H), 8.50 (m, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.27 (m, 1H),

6.62 (d, J = 15.9 Hz, 1H), 6.34 (dd, J₁= 15.9 Hz, J₂= 5.5 Hz, 1H),

4.68 (brs, 1H), 4.47 (q, J = 5.5 Hz, 1H), 4.12–3.86 (m, 3H), 2.77 (brs,

1H), 1.88–1.67 (m, 2H), 1.24 (d, J = 6.7 Hz, 3H), 1.16 (t, J = 6.9 Hz,

3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.5, 148.4, 148.2, 136.9, 135.1,

133.1, 125.9, 123.7, 70.3, 61.0, 44.8, 44.8, 22.0, 14.7; HRMS (ESI⁺)

calcd. for C₁₄H₂₁N₂O₃[M + H]⁺265.1547, found 265.1545.

Ethyl

((2R,4S,E)-6-(4-Bromophenyl)-4-hydroxyhex-5-en-2-yl)-

carbamate (3k-anti) and Ethyl ((2R,4R,E)-6-(4-Bromophenyl)-4-

hydroxyhex-5-en-2-yl)carbamate (3k-syn): Ketone 2k (224 mg,

0.658 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 8:2 cyclo-

hexane/EtOAc to 7:3 cyclohexane/EtOAc) providing 3k-anti as a

white solid (31.5 mg, 0.0920 mmol) and 3k-syn as a white solid

(177.6 mg, 0.519 mmol). The alcohols 3k were globally obtained in

93 % yield in a ratio of 85:15 in favor of the syn product. 3k-anti:

TLC R_f= 0.43 (cyclohexane/EtOAc, 6:4); Mp 65 °C; ¹H NMR (400 MHz,

CDCl₃) δ = 7.42 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 6.58 (d,

J = 15.8 Hz, 1H), 6.22 (dd, J₁= 15.8 Hz, J₂= 5.6 Hz, 1H), 4.64 (d, J =

8.7 Hz, 1H), 4.35 (m, 1H), 4.14 (q, J = 7.0 Hz, 2H), 4.01 (m, 1H), 1.72

(ddd, J₁= 13.9 Hz, J₂= 10.7 Hz, J₃= 3.2 Hz, 1H), 1.62–1.46 (m, 1H),

1.26 (t, J = 7.0 Hz, 3H), 1.24 (d, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ = 157.7, 136.1, 132.5, 131.8, 128.3, 128.1, 121.3, 68.5, 61.4,

46.0, 44.0, 21.7, 14.7; HRMS (ESI⁺) calcd. for C₁₅H₂₀BrNaNO₃[M +

Na]⁺364.0519, found 364.0518. 3k-syn: TLC R_f= 0.29 (cyclohexane/

EtOAc, 6:4); Mp 76 °C; ¹H NMR (400 MHz, CDCl₃) δ = 7.43 (d, J =

8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 6.53 (d, J = 15.9 Hz, 1H), 6.23

(dd, J₁= 15.9 Hz, J₂= 5.9 Hz, 1H), 4.67 (brs, 1H), 4.42 (m, 1H), 4.14–

3.96 (m, 2H), 3.90 (m, 1H), 2.57 (s, 1H, OH), 1.77 (m, 2H), 1.22 (d, J =

6.6 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

156.5, 135.8, 133.2, 131.8, 128.5, 128.1, 121.4, 70.6, 61.0, 44.8, 44.8,

22.0, 14.7; HRMS (ESI⁺) calcd. for C₁₅H₂₀BrNaNO₃[M + Na]⁺

364.0519, found 364.0518.

Ethyl ((2R,4S,E)-4-Hydroxy-6-(2-nitrophenyl)hex-5-en-2-yl)carb-

amate 3n-anti and Ethyl ((2R,4R,E)-4-Hydroxy-6-(2-nitro-

phenyl)hex-5-en-2-yl)carbamate (3n-syn): Ketone 2n (167 mg,

0.545 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 7:3 cyclo-

hexane to 6:4 cyclohexane/EtOAc) providing 3n-anti as a yellow

oil (33.5 mg, 0.109 mmol) and 3n-syn as a yellow oil (132.4 mg,

0.429 mmol). The alcohols 3n were globally obtained in 99 % yield

in a ratio of 80:20 in favor of the syn product. 3n-anti: TLC R_f= 0.36

(cyclohexane/EtOAc, 6:4); ¹H NMR (400 MHz, CDCl₃) δ = 7.85 (dd,

J₁= 8.2 Hz, J₂= 1.1 Hz, 1H), 7.52 (dd, J₁= 7.9 Hz, J₂= 1.7 Hz, 1H),

7.47 (ddd, J₁= 7.9 Hz, J₂= 7.4 Hz, J₃= 1.7 Hz, 1H), 7.31 (ddd, J₁=

Ethyl

((2S,4R,E)-6-(4-Fluorophenyl)-4-hydroxyhex-5-en-2-yl)-

carbamate 3l-anti and Ethyl ((2S,4S,E)-6-(4-Fluorophenyl)-4-

hydroxyhex-5-en-2-yl)carbamate (3l-syn): Ketone 2l (260 mg,

0.931 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 9:1 cyclo-

hexane/EtOAc to 6:4 cyclohexane/EtOAc) providing 3l-anti as a

white solid (30.7 mg, 0.109 mmol) and 3l-syn as a colorless oil

(209.5 mg, 0.745 mmol). The alcohols 3l were globally obtained in

92 % yield in a ratio of 87:13 in favor of the syn product. 3l-anti:

TLC R_f= 0.33 (cyclohexane/EtOAc, 7:3); Mp 64 °C; ¹H NMR (400 MHz,

CDCl₃) δ = 7.32 (dd, J_HH= 8.7 Hz, J_HF= 5.4 Hz, 2H), 6.98 (t, J =

8.1 Hz, J₂= 7.4 Hz, J₃= 1.1 Hz, 1H), 6.99 (dd, J₁= 15.8 Hz, J₂

=

1.5 Hz, 1H), 6.16 (dd, J₁= 15.8 Hz, J₂= 5.8 Hz, 1H), 4.70 (d, J =

8.5 Hz, 1H), 4.33 (m, 1H), 4.07 (q, J = 7.1 Hz, 2H), 3.94 (m, 1H), 1.67

(ddd, J₁= 13.8 Hz, J₂= 10.8 Hz, J₃= 3.2 Hz, 1H), 1.49 (ddd, J₁

=

13.8 Hz, J₂= 10.6 Hz, J₃= 2.8 Hz, 1H), 1.19 (t, J = 7.1 Hz, 3H), 1.17

(d, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.7, 148.0,

137.4, 133.1, 132.8, 128.8, 128.1, 124.9, 124.6, 68.6, 61.4, 45.7, 43.9,

21.6, 14.7; HRMS (ESI⁺) calcd. for C₁₅H₂₁N₂O₅[M + H]⁺309.1445,

8.7 Hz, 2H), 6.61 (d, J = 15.7 Hz, 1H), 6.13 (dd, J₁= 15.7 Hz, J₂

=

1

5.8 Hz, 1H), 4.72 (d, J = 8.6 Hz, 1H), 4.40–4.34 (m, 1H), 4.11 (q, J =

7.1 Hz, 2H), 3.98 (m, 1H), 1.74 (ddd, J₁= 14.0 Hz, J₂= 10.6 Hz, J₃=

3.2 Hz, 1H), 1.52 (ddd, J₁= 14.0 Hz, J₂= 10.5 Hz, J₃= 2.9 Hz, 1H),

1.24 (t, J = 7.1 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ = 162.3 (d, J_CF= 246 Hz), 157.6, 133.2, 131.4 (d, J_CF= 2 Hz),

128.4, 127.9 (d, J_CF= 8 Hz), 115.5 (d, J_CF= 22 Hz), 68.6, 61.4, 46.0,

44.0, 21.6, 14.7; HRMS (ESI⁺) calcd. for C₁₅H₂₀FNNaO₃[M + Na]⁺

304.1319, found 304.1313. 3l-syn: TLC R_f= 0.23 (cyclohexane/EtOAc,

found 309.1454. 3n-syn: TLC R_f= 0.26 (cyclohexane/EtOAc, 6:4); H

NMR (400 MHz, CDCl₃) δ = 7.93 (d, J = 7.9 Hz, 1H), 7.52–7.59 (m,

2H), 7.42 (ddd, J₁= 8.4 Hz, J₂= 6.6 Hz, J₃= 2.1 Hz, 1H), 7.07 (dd,

J₁= 15.8 Hz, J₂= 1.2 Hz, 1H), 6.24 (dd, J₁= 15.8 Hz, J₂= 5.8 Hz,

1H), 4.71 (brs, 1H), 4.49 (q, J = 7.1 Hz, 1H), 4.00–4.12 (m, 2H), 3.92

(m, 1H), 2.60 (s, 1H), 1.75–1.87 (m, 2H), 1.26 (d, J = 6.7 Hz, 3H), 1.16

(t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.5, 148.0, 137.9,

133.2, 132.7, 128.9, 128.2, 125.2, 124.7, 70.5, 61.0, 45.0, 44.5, 21.9,

14.7; HRMS (ESI⁺) calcd. for C₁₅H₂₁N₂O₅[M + H]⁺309.1445, found

309.1450.

7:3); ¹H NMR (400 MHz, CDCl₃) δ = 7.33 (dd, J_HH= 8.7 Hz, J_HF

=

5.5 Hz, 2H), 6.99 (t, J_HH,HF= 8.7 Hz, 2H), 6.57 (d, J = 16.0 Hz, 1H),

6.15 (dd, J₁= 16.0 Hz, J₂= 6.1 Hz, 1H), 4.69 (brs, 1H), 4.41 (m, 1H),

4.16–3.96 (m, 2H), 3.90 (m, 1H), 2.51 (brs, 1H), 1.77 (t, J = 6.3 Hz,

2H), 1.22 (d, J = 6.6 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H); ¹³C NMR

Ethyl ((2S,4R,E)-4-Hydroxy-6-(3-nitrophenyl)hex-5-en-2-yl)carb-

amate 3o-anti and Ethyl ((2S,4S,E)-4-Hydroxy-6-(3-nitro-

phenyl)hex-5-en-2-yl)carbamate (3o-syn): Ketone 2o (296 mg,

0.966 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 85:15 cy-

clohexane/EtOAc to 6:4 cyclohexane/EtOAc) providing 3o-anti as a

yellow oil (30.0 mg, 0.0973 mmol) and 3o-syn as a yellow oil

(101 MHz, CDCl₃) δ = 162.4 (d, J_CF= 247 Hz), 156.6, 133.0 (d, J_CF

=

2 Hz), 132.0, 128.7, 128.1 (d, J_CF= 8 Hz), 115.6 (d, J_CF= 21 Hz), 70.7,

61.0, 44.8, 44.8, 21.9, 14.7; HRMS (ESI⁺) calcd. for C₁₅H₂₀FNNaO₃

[M + Na]⁺304.1319, found 304.1313.

Ethyl ((2R,4S,E)-4-Hydroxy-6-(pyridin-3-yl)hex-5-en-2-yl)carb- (267.9 mg, 0.869 mmol). The alcohols 3o were globally obtained in

amate 3m-anti and Ethyl ((2R,4R,E)-4-Hydroxy-6-(pyridin-3- 100 % yield in a ratio of 90:10 in favor of the syn product. 3o-anti:

yl)hex-5-en-2-yl)carbamate (3m-syn): Ketone 2m (186.5 mg,

TLC R_f= 0.23 (cyclohexane/EtOAc, 7:3); The product was not stable

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

11

Full Paper

and deteriorated. 3o-syn: TLC R_f= 0.14 (cyclohexane/EtOAc, 7:3); ¹H

NMR (400 MHz, CDCl₃) δ = 8.20 (d, J = 1.7 Hz, 1H), 8.07 (d, J =

8.2 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.47 (dd, J₁= 8.2 Hz, J₂= 7.8 Hz,

1H), 6.69 (dd, J₁= 15.9 Hz, J₂= 1.5 Hz, 1H), 6.39 (dd, J₁= 15.9, J₂=

5.4 Hz, 1H), 4.64 (m, 1H), 4.48 (m, 1H), 4.19–3.77 (m, 3H), 2.86 (brs,

1H), 1.92–1.69 (m, 2H), 1.24 (d, J = 6.6 Hz, 3H), 1.15 (t, J = 6.9 Hz,

3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.6, 148.7, 138.8, 135.8, 132.5,

129.6, 127.2, 122.2, 121.0, 70.2, 61.1, 44.9, 44.7, 22.0, 14.6; HRMS

(ESI⁺) calcd. for C₁₅H₂₁N₂O₅[M + H]⁺309.1445, found 309.1444.

(234.3 mg, 0.718 mmol). The alcohols 3r were globally obtained in

98 % yield in a ratio of 85:15 in favor of the syn product. 3r-anti:

TLC R_f= 0.42 (cyclohexane/EtOAc, 6:4); ¹H NMR (400 MHz, CDCl₃)

δ = 8.34 (dd, J_HF= 6.4 Hz, J_HH= 2.8 Hz, 1H), 8.07 (ddd, J_HH= 9.2 Hz,

J_HF= 4.2 Hz, J_HH= 2.8 Hz, 1H), 7.17 (t, J_HF,HH= 9.2 Hz, 1H), 6.81 (d,

J₁= 16.2 Hz, 1H), 6.46 (dd, J₁= 16.2 Hz, J₂= 5.0 Hz, 1H), 4.76 (d,

J = 8.2 Hz, 1H), 4.40 (m,1H), 4.13 (q, J = 7.1 Hz, 2H), 4.01 (m, 1H),

1.71 (ddd, J₁= 13.8 Hz, J₂= 10.9 Hz, J₃= 2.7 Hz, 1H), 1.54 (ddd,

J₁= 13.8 Hz, J₂= 10.9 Hz, J₃= 2.7 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H),

1.24 (d, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 163.4 (d,

Ethyl ((2R,4S,E)-4-Hydroxy-6-(4-nitrophenyl)hex-5-en-2-yl)carb-

amate 3p-anti and Ethyl ((2R,4R,E)-4-Hydroxy-6-(4-nitro-

phenyl)hex-5-en-2-yl)carbamate (3p-syn): Ketone 2p (169.0 mg,

0.552 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 7:3 cyclo-

hexane/EtOAc to 6:4 cylohexane/EtOAc) providing 3p-anti as a yel-

low solid (29.2 mg, 0.0947 mmol) and 3p-syn as a yellow oil

(129.2 mg, 0.419 mmol). The alcohols 3p were globally obtained in

93 % yield in a ratio of 82:18 in favor of the syn product. 3p-anti:

TLC R_f= 0.36 (cyclohexane/EtOAc, 6:4); Mp 115 °C; ¹H NMR

(400 MHz, CDCl₃) δ = 8.15 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz,

2H), 6.73 (d, J = 15.9 Hz, 1H), 6.40 (dd, J₁= 15.9 Hz, J₂= 5.0 Hz, 1H),

4.67 (d, J = 8.3 Hz, 1H), 4.32 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 4.01

(m, 1H), 1.74 (ddd, J₁= 14.0 Hz, J₂= 11.0 Hz, J₃= 3.3 Hz, 1H), 1.54

(ddd, J₁= 14.1 Hz, J₂= 10.9 Hz, J₃= 2.8 Hz, 1H), 1.25 (t, J = 7.1 Hz,

3H), 1.24 (d, J = 6.6 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.8,

146.9, 143.8, 136.7, 127.2, 127.0, 124.1, 68.1, 61.5, 46.0, 44.0, 21.7,

14.7; HRMS (ESI⁺) calcd. for C₁₅H₂₀NaN₂O₅[M + Na]⁺331.1264,

J

_CF= 260.2 Hz), 157.8, 144.5 (d, J_CF= 2.9 Hz), 137.7 (d, J_CF= 4.5 Hz),

126.5 (d, J_CF= 14.4 Hz), 124.0 (d, J_CF= 10.2 Hz), 123.3 (d, J_CF

=

6.0 Hz), 119.6 (d, J_CF= 3.0 Hz), 116.8 (d, J_CF= 16.8 Hz), 68.2, 61.5,

45.9, 43.9, 21.6, 14.7; HRMS (ESI⁺) calcd. for C₁₅H₂₀FN₂O₅[M + H]⁺

327.1351, found 327.1352. 3r-syn: TLC R_f= 0.28 (cyclohexane/

EtOAc, 6:4); ¹H NMR (400 MHz, CDCl₃) δ = 8.31 (dd, J_HF= 6.4 Hz,

J_HH= 2.8 Hz, 1H), 8.06 (ddd, J_HH= 9.1 Hz, J_HF= 4.4 Hz, J_HH= 2.8 Hz,

1H), 7.14 (t, J_HF,HH= 9.2 Hz, 1H), 6.72 (d, J₁= 16.0 Hz, 1H), 6.46 (dd,

J₁= 16.0 Hz, J₂= 5.3 Hz, 1H), 4.84 (d, J = 8.0 Hz, 1H), 4.45 (m, 1H),

4.12–3.82 (m, 3H), 3.14 (brs, 1H), 1.82–1.75 (m, 2H), 1.22 (d, J =

6.7 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

163.4 (d, J_CF= 260.4 Hz), 156.6, 144.5 (d, J_CF= 2.6 Hz), 138.5, 126.3

(d, J_CF= 14.7 Hz), 124.1 (d, J_CF= 10.3 Hz), 123.3 (d, J_CF= 6.1 Hz),

119.7, 116.8 (d, J_CF= 24.9 Hz), 70.2, 61.0, 44.7, 44.6, 21.7, 14.6; HRMS

(ESI⁺) calcd. for C₁₅H₂₀FN₂O₅[M + H]⁺327.1351, found 327.1352.

Ethyl ((2R,4S,E)-4-Hydroxy-6-(4-methoxyphenyl)hex-5-en-2-yl)-

carbamate (3s-anti) and Ethyl ((2R,4R,E)-4-Hydroxy-6-(4-

methoxyphenyl)hex-5-en-2-yl)carbamate (3s-syn). Ketone 2s

(159.0 mg, 0.546 mmol) was used in general procedure B. The crude

product was purified by silica gel column chromatography (SiO₂,

8:2 cyclohexane/EtOAc to 6:4cyclohexane/EtOAc) providing 3s-anti

as a colorless oil (19.1 mg, 0.0651 mmol) and 3s-syn as a colorlessoil

(124.2 mg, 0.423 mmol). The alcohols 3s were globally obtained in

90 % yield in a ratio of 87:13 in favor of the syn product. 3s-anti:

TLC R_f= 0.39 (cyclohexane/EtOAc, 6:4); ¹H NMR (400 MHz, CDCl₃)

δ = 7.30 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 6.56 (d, J =

15.8 Hz, 1H), 6.08 (dd, J₁= 15.8 Hz, J₂= 6.1 Hz, 1H), 4.75 (d, J =

8.5 Hz, 1H), 4.35 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.07–3.93 (m, 1H),

3.79 (s, 3H), 1.73 (ddd, J₁= 13.9 Hz, J₂= 10.6 Hz, J₃= 3.3 Hz, 1H),

1.59–1.47 (ddd, J₁= 13.9 Hz, J₂= 10.5 Hz, J₃= 3.0 Hz, 1H), 1.31–

1.14 (m, 6H); ¹³C NMR (101 MHz, CDCl₃) δ = 159.3, 157.5, 129.8,

129.6, 129.2, 127.7, 114.1, 69.0, 61.3, 55.4, 45.9, 44.1, 21.6, 14.7;

HRMS (ESI⁺) calcd. for C₁₆H₂₃NaNO₄[M + Na]⁺316.1519, found

316.1516. 3s-syn: TLC R_f= 0.27 (cyclohexane/EtOAc, 6:4); ¹H NMR

(400 MHz, CDCl₃) δ = 7.30 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz,

2H), 6.54 (d, J = 15.8 Hz, 1H), 6.09 (dd, J₁= 15.8 Hz, J₂= 6.3 Hz, 1H),

4.72 (brs, 1H), 4.40 (q, J = 6.3 Hz, 1H), 4.17–3.96 (m, 2H), 3.86 (m,

1H), 3.79 (s, 3H), 1.82–1.69 (m, 2H), 1.22 (d, J = 6.6 Hz, 3H), 1.19 (t,

J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) 159.4, 156.5, 130.1, 129.6,

129.4, 127.8, 114.1, 71.0, 61.1, 55.4, 45.0, 44.8, 21.9, 14.7; HRMS (ESI⁺)

calcd. for C₁₆H₂₃NaNO₄[M + Na]⁺316.1519, found 316.1516.

1

found 331.1262. 3p-syn: TLC R_f= 0.23 (cyclohexane/EtOAc, 6:4); H

NMR (400 MHz, CDCl₃) 8.19 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz,

2H), 6.71 (dd, J₁= 15.9 Hz, J₂= 1.0 Hz, 1H), 6.44 (dd, J₁= 15.9 Hz,

J₂= 5.2 Hz, 1H), 4.64 (brs, 1H), 4.49 (m, 1H), 3.86–4.14 (m, 3H), 2.86

(s, 1H), 1.88–1.73 (m, 2H), 1.26 (d, J = 6.7 Hz, 3H), 1.16 (t, J = 7.1 Hz,

3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.6, 147.0, 143.5, 137.4, 127.4,

127.1, 124.1, 70.3, 61.2, 45.0, 44.7, 22.1, 14.7; HRMS (ESI⁺) calcd. for

C₁₅H₂₀NaN₂O₅[M + Na]⁺331.1264, found 331.1262.

Ethyl ((2S,4R,E)-4-Hydroxy-6-(4-methoxy-3-nitrophenyl)hex-5-

en-2-yl)carbamate 3q-anti and Ethyl ((2S,4S,E)-4-Hydroxy-6-(4-

methoxy-3-nitrophenyl)hex-5-en-2-yl)carbamate (3q-syn): Ket-

one 2q (320 mg, 0.951 mmol) was used in general procedure B. The

crude product was purified by silica gel column chromatography

(SiO₂, 8:2 cyclohexane/EtOAc to 55:45 cyclohexane/EtOAc) provid-

ing 3q-anti as a yellow oil (33.3 mg, 0.0984 mmol) and 3q-syn as a

yellow oil (280.6 mmol 0.829 mmol). The alcohols 3q were globally

obtained in 98 % yield in a ratio of 90:10 in favor of the syn product.

3q-anti: TLC R_f= 0.15 (cyclohexane/EtOAc, 6:4). The product was

not stable and deteriorated. 3q-syn: TLC R_f= 0.08 (cyclohexane/

1

EtOAc, 6:4); H NMR (400 MHz, CDCl₃) δ = 7.86 (d, J = 2.3 Hz, 1H),

7.51 (dd, J₁= 8.6 Hz, J₂= 2.3Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.57

(dd, J₁= 16.0 Hz, J₂= 1.4 Hz, 1H), 6.20 (dd, J₁= 16.0 Hz, J₂= 5.7 Hz,

1H), 4.67 (brs, 1H), 4.43 (quint, J = 5.7 Hz, 1H), 4.22–3.98 (m, 2H),

3.96 (s, 3H), 3.89 (m, 1H), 2.70 (brs, 1H), 1.81–1.73 (m, 2H), 1.23 (d,

J = 6.9 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃)

δ = 156.6, 152.3, 139.8, 133.4, 132.1, 129.9, 126.9, 123.3, 113.7, 70.4,

61.0, 56.8, 44.9, 44.8, 22.0, 14.7; HRMS (ESI⁺) calcd. for C₁₆H₂₂N₂NaO₆

[M + Na]⁺361.1370, found 361.1364.

Ethyl ((2S,4R,E)-4-Hydroxy-6-(3-phenoxyphenyl)hex-5-en-2-yl)-

carbamate (3t-anti) and Ethyl ((2S,4S,E)-4-Hydroxy-6-(3-phen-

oxyphenyl)hex-5-en-2-yl)carbamate (3t-syn): Ketone 2t (400 mg,

1.13 mmol) was used in general procedure B. The crude product

was purified by silica gel column chromatography (SiO₂, 9:1 cyclo-

hexane/EtOAc to 5:5 cyclohexane/EtOAc) providing 3t-anti as a col-

orless oil (54.1 mg, 0.152 mmol) and 3t-syn as a colorless oil

(280 mg,0.788 mmol). The alcohols 3t were globally obtained in

83 % yield in a ratio of 84:16 in favor of the syn product. 3t-anti:

TLC R_f= 0.40 (cyclohexane/EtOAc, 7:3); The product was not stable

and deteriorated. 3t-syn: TLC R_f= 0.28 (cyclohexane/EtOAc, 7:3); ¹H

Ethyl ((2S,4R,E)-6-(2-Fluoro-5-nitrophenyl)-4-hydroxyhex-5-en-

2-yl)carbamate 3r-anti and Ethyl ((2S,4S,E)-6-(2-Fluoro-5-nitro-

phenyl)-4-hydroxyhex-5-en-2-yl)carbamate (3r-syn): Ketone 2r

(280 mg, 0.863 mmol) was used in general procedure B. The crude

product was purified by silica gel column chromatography (SiO₂,

9:1 cyclohexane/EtOAc, 6:4 cyclohexane/EtOAc) providing 3r-anti

as a colorless oil (42.3 mg, 0.130 mmol) and 3r-syn as a yellow oil NMR (400 MHz, CDCl₃) δ = 7.34 (dd, J₁= 8.5 Hz, J₂= 7.4 Hz, 2H),

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

12 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper

7.26 (t, J = 7.9 Hz, 1H), 7.13–7.07 (m, 2H), 7.02–6.99 (m, 3H), 6.88

(ddd, J₁= 7.9 Hz, J₂= 2.5 Hz, J₃= 0.8 Hz, 1H), 6.55 (dd, J₁= 15.9 Hz,

J₂= 1.1 Hz, 1H), 6.20 (dd, J₁= 15.9 Hz, J₂= 6.0 Hz, 1H), 4.69 (brs,

1H), 4.41 (q, J = 6.2 Hz, 1H), 4.19–3.97 (m, 2H), 3.89 (m, 1H), 2.57

(brs, 1H), 1.75 (t, J = 6.2 Hz, 2H), 1.21 (d, J = 6.7 Hz, 3H), 1.17 (t, J =

7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.5, 157.2, 156.4, 138.7,

133.0, 129.8, 129.7, 129.0, 123.3, 121.6, 118.8, 118.1, 116.7, 70.5, 60.9,

44.8, 44.6, 21.8, 14.6; HRMS (ESI⁺) calcd. for C₂₁H₂₅NNaO₄[M + Na]⁺

378.1676, found 378.1673.

44.7, 32.3, 32.1, 29.8, 29.6, 29.5, 29.4, 29.3, 22.8, 22.0, 14.8, 14.3;

HRMS (ESI⁺) calcd. for C₂₀H₃₉NaNO₃[M + Na]⁺364.2822, found

364.2823.

Benzyl (1S,3S,E)-(3-Hydroxy-1-phenylhex-4-en-1-yl)carbamate

(3w-anti) and Benzyl (1S,3R,E)-(3-Hydroxy-1-phenylhex-4-en-1-

yl)carbamate (3w-syn): Ketone 2w (250 mg, 0.773 mmol) was used

in general procedure B. The crude product was purified by silica

gel column chromatography (SiO₂, 8:2 cyclohexane/EtOAc to 7:3

cylohexane/EtOAc) providing 3w-anti as a colorless oil (62.9 mg,

0.193 mmol) and 3w-syn as a brown solid (138.2 mg, 0.425 mg).

The alcohols 3w were globally obtained in 80 % yield in a ratio of

69:31 in favor of the syn product. 3w-anti: TLC R_f= 0.25 (cyclohex-

Ethyl ((2S,4R,E)-6-(4-Acetamidophenyl)-4-hydroxyhex-5-en-2-

yl)carbamate (3u-anti) and Ethyl ((2S,4S,E)-6-(4-Acetamido-

phenyl)-4-hydroxyhex-5-en-2-yl)carbamate (3u-syn): Ketone 2u

(232 mg, 0.729 mmol) was used in general procedure B. The crude

product was purified by silica gel column chromatography (SiO₂, 4:6

cyclohexane/EtOAc to 2:8 cyclohexane/EtOAc) providing 3u-anti as

a white solid (24.8 mg, 0.0774 mmol) and 3u-syn as a white solid

(182 mg, 0.568 mmol). The alcohols 3u were globally obtained in

89 % yield in a ratio of 88:12 in favor of the syn product. 3u-anti:

TLC R_f= 0.21 (cyclohexane/EtOAc, 7:3); Mp 122 °C; ¹H NMR

(400 MHz, CDCl₃) δ = 7.78 (brs, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.23 (d,

J = 8.4 Hz, 2H), 6.52 (d, J = 16.0 Hz, 1H), 6.13 (dd, J₁= 16.0 Hz, J₂=

6.0 Hz, 1H), 4.91 (d, J = 8.5 Hz, 1H), 4.34 (m, 1H), 4.11 (q, J = 7.0 Hz,

2H), 4.01 (m, 1H), 2.14 (s, 3H), 1.71 (ddd, J₁= 13.8 Hz, J₂= 10.6 Hz,

J₃= 3.2 Hz, 1H), 1.53 (ddd, J₁= 13.8 Hz, J₂= 10.6 Hz, J₃= 3.2 Hz,

1H), 1.24 (t, J = 7.0 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ = 168.7, 157.6, 137.4, 133.0, 130.8, 129.1, 127.0,

120.1, 68.9, 61.3, 45.7, 44.1, 24.6, 21.6, 14.7; HRMS (ESI⁺) calcd. for

C₁₇H₂₄N₂NaO₄[M + Na]⁺343.1628, found 343.1626. 3u-syn: TLC R_f=

0.14 (cyclohexane/EtOAc); Mp 128 °C; ¹H NMR (400 MHz, MeOD)

δ = 7.50 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 6.48 (d,

J = 15.7 Hz, 1H), 6.17 (dd, J₁= 15.7 Hz, J₂= 6.6 Hz, 1H), 4.25 (q,

J = 6.6 Hz, 1 H), 4.03 (q, J = 7.0 Hz, 2H), 3.78 (dquint, J₁= 8.3 Hz,

J₂= 6.6 Hz, 1H), 2.14 (s, 3H), 1.82 (ddd, J₁= 13.7 Hz, J₂= 8.3 Hz,

J₃= 6.6 Hz, 1H), 1.62 (ddd, J₁= 13.7 Hz, J₂= 8.3 Hz, J₃= 6.7 Hz,

1H), 1.22 (t, J = 7.0 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H); ¹³C NMR

(101 MHz, MeOD) δ = 171.5, 158.4, 139.2, 134.3, 132.4, 130.7, 127.9,

121.1, 71.2, 61.5, 45.2, 45.2, 23.8, 21.6, 15.0; HRMS (ESI⁺) calcd. for

C₁₇H₂₄N₂NaO₄[M + Na]⁺343.1628, found 343.1626.

1

ane/EtOAc, 7:3); H NMR (400 MHz, CDCl₃) δ = 7.45–7.18 (m, 10H),

5.63 (m, 1H), 5.51 (dd, J = 14.4 Hz, J₂= 6.6 Hz, 1H), 5.13 (d, J =

12.2 Hz, 1H), 5.07 (d, J = 12.2 Hz, 1H), 4.96 (m, 1H), 4.08 (m, 1H),

2.79 (brs, 1H), 1.97 (ddd, J₁= 14.0 Hz, J₂= 4.3 Hz, J₃= 9.0 Hz, 1H),

1.89 (ddd, J₁= 14.0 Hz, J₂= 3.7 Hz, J₃= 8.7 Hz, 1H), 1.67 (d, J =

6.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.6, 141.8, 136.5, 133.3,

132.6, 128.8, 128.7, 128.3, 127.6, 127.0, 126.5, 69.4, 67.1, 52.7, 43.9,

17.8; HRMS (ESI⁺) calcd. for C₂₀H₂₃NaNO₃[M + Na]⁺348.1570, found

348.1565. 3w-syn: TLC R_f= 0.18 (cyclohexane/EtOAc, 7:3); Mp 57 °C;

¹H NMR (400 MHz, CDCl₃) δ = 7.41–7.23 (m, 10H), 5.62 (m, 1H),

5.55–5.34 (m, 2H), 5.09 (d, J = 12.3 Hz, 1H), 5.03 (d, J = 12.3 Hz, 1H),

4.82 (m, 1H), 4.05 (m, 1H), 2.06–1.83 (m, 2H), 1.66 (d, J = 6.4 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ = 155.9, 142.6, 136.6, 133.7, 128.8,

128.6, 128.3, 128.2, 127.5, 127.5, 126.5, 71.0, 66.9, 53.7, 44.1, 17.8;

HRMS (ESI⁺) calcd. for C₂₀H₂₃NaNO₃[M + Na]⁺348.1570, found

348.1565.

Ethyl (4R,6R,E)-6-(((Benzyloxy)carbonyl)amino)-4-hydroxyhept-

2-enoate (3x-syn): Ketone 2x (124 mg, 0.388 mmol) was used in

general procedure B. The crude product was purified by silica gel

column chromatography (SiO₂, cyclohexane to 6:4 cyclohexane/

EtOAc) providing 3x-syn as a colorless oil (86 mg, 0.268 mmol) in

69 % yield. TLC R_f= 0.23 (cyclohexane/EtOAc, 7:3); ¹H NMR

(400 MHz, CDCl₃) δ = 7.40–7.28 (m, 5H), 6.96 (dd, J₁= 15.7 Hz, J₂=

4.2 Hz, 1H), 6.07 (dd, J₁= 15.5 Hz, J₂= 1.3 Hz, 1H), 5.12 (d, J =

12.2 Hz, 1H), 5.00 (d, J = 12.2 Hz, 1H), 4.76 (brs, 1H), 4.44 (m, 1H),

4.17 (d, J = 7.2 Hz, 2H), 3.92 (m, 1H), 2.98 (s, 1H), 1.89–1.66 (m, 2H),

1.26 (t, J = 7.2 Hz, 3H), 1.22 (d, J = 6.7 Hz, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ = 166.7, 156.3, 150.4, 136.4, 128.6, 128.2, 128.1, 119.8, 69.0,

66.9, 60.6, 44.7, 43.8, 21.5, 14.3; HRMS (ESI⁺) calcd. for C₁₇H₂₄NO₅

[M + H]⁺322.1649, found 322.1639.

Ethyl ((2R,4S,E)-4-Hydroxyheptadec-5-en-2-yl)carbamate (3v-

anti) and Ethyl ((2R,4R,E)-4-Hydroxyheptadec-5-en-2-yl)carb-

amate (3v-syn): Ketone 2v (1.00 g, 2.95 mmol) was used in general

procedure B. The crude product was purified by silica gel column

chromatography (SiO₂, 9:1 cyclohexane/EtOAc to 6:4 cyclohexane/

EtOAc) providing 3v-anti as a colorless oil (150 mg, 0.439 mmol)

Synthesis of Carbonates 4 from Alcohols 3

and 3v-syn as a colorless oil (785 mg, 2.30 mmol). The alcohols 3v Ethyl ((2R,4R,E)-4-((Methoxycarbonyl)oxy)-6-phenylhex-5-en-2-

were globally obtained in 93 % yield in a ratio of 84:16 in favor of yl)carbamate (4a-syn): To a solution of alcohol 3a-syn (110 mg,

the syn product. 3v-anti: TLC R_f= 0.34 (cyclohexane/EtOAc, 8:2); ¹H 0.418 mmol, 1 equiv.) in dry DCM (5 mL) at 0 °C was added anhy-

NMR (400 MHz, CDCl₃) δ = 5.66 (dtd, J₁= 15.3 Hz, J₂= 6.8 Hz, J₃=

1.1 Hz, 1H), 5.44 (dd, J₁= 15.4 Hz, J₂= 6.3 Hz, 1H), 4.76 (d, J =

8.6 Hz, 1H), 4.17 (m, 1H), 4.13 (q, J = 7.2 Hz, 2H), 3.95 (m, 1H), 2.32

drous pyridine (135 μL, 1.67 mmol, 4.8 equiv.). The solution was

stirred for 10 min then methyl chloroformate (195 μL, 2.52 mmol,

6 equiv.) was added dropwise at 0 °C. The reaction mixture was

(t, J = 7.5 Hz, 1H), 2.00 (q, J = 6.8 Hz, 2H), 1.62 (ddd, J₁= 14.0 Hz, stirred for 30 min at 0 °C and overnight at room temperature. A 0.1

J₂= 10.4 Hz, J₃= 3.5 Hz, 1H), 1.42 (ddd, J₁= 14.0 Hz, J₂= 10.1 Hz,

J₃= 3.0 Hz, 1H), 1.47–1.11 (m, 21H), 1.19 (d, J = 6.7 Hz, 3H), 0.87 (t,

J = 7.2 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 157.3, 131.8, 131.5,

68.8, 61.1, 45.6, 44.0, 32.3, 31.9, 29.7, 29.6, 29.6, 29.5, 29.4, 29.2, 29.2,

22.7, 21.4, 14.6, 14.1; HRMS (ESI⁺) calcd. for C₂₀H₃₉NaNO₃[M + Na]⁺

364.2822, found 364.2821. 3v-syn: TLC R_f= 0.24 (cyclohexane/

M HCl aqueous solution was added until pH 2. The aqueous layer

was then extracted with DCM. The organic layer was washed with

a saturated aqueous NaHCO₃, dried with anhydrous MgSO₄, filtered

and concentrated under reduced pressure. The crude product was

purified by silica gel column chromatography (SiO₂, 100 % cyclo-

hexane to 8:2 cyclohexane/EtOAc) providing the carbonate 4a-syn

EtOAc, 8:2); ¹H NMR (400 MHz, CDCl₃) δ = 5.66 (dt, J₁= 15.4 Hz, as a yellow solid in 80 % yield (107 mg, 0.333 mmol). TLC R_f= 0.43

1

J₂= 6.7 Hz, 1H), 5.46 (ddt, J₁= 15.4 Hz, J₂= 6.8 Hz, J₃= 1.4 Hz, 1H),

4.72 (brs, 1H), 4.17 (q, J = 6.8 Hz, 1H), 4.09 (q, J = 7.0 Hz, 2H), 3.80

(m, 1H), 2.01 (q, J = 6.7 Hz, 2H), 1.93 (brs, 1H), 1.71–1.56 (m, 3H),

1.40–1.15 (m, 20H), 1.19 (d, J = 6.6 Hz, 3H), 0.88 (t, J = 6.7 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ = 156.8, 132.6, 132.4, 71.2, 60.8, 45.3,

(cyclohexane/EtOAc, 7:3); Mp 106 °C; H NMR (400 MHz, CDCl₃) δ =

7.38 (d, J = 7.2 Hz, 2H), 7.30 (t, J = 7.2 Hz, 2H), 7.24 (t, J = 7.2 Hz,

1H), 6.70 (t, J = 15.9 Hz, 1H), 6.15 (dd, J₁= 15.9 Hz, J₂= 7.1 Hz, 1H),

5.31 (td, J₁= 7.1 Hz, J₂= 6.7 Hz, 1H), 4.64 (brs, 1H), 4.09 (q, J =

7.0 Hz, 2H), 3.83 (m, 1H), 3.77 (s, 3H), 2.00 (ddd, J₁= 14.8 Hz, J₂=

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

13

Full Paper

7.1 Hz, J₃= 6.7 Hz, 1H), 1.79 (m, 1H), 1.26–1.15 (m, 6H); ¹³C NMR solide was washed with DCM and the filtrate was concentrated.

1

(101 MHz, CDCl₃) δ = 156.0, 155.2, 136.1, 133.6, 128.7, 128.3, 126.8,

Conversions and trans/cis ratios were determined by H-NMR inte-

126.3, 76.9, 60.8, 54.8, 44.2, 41.9, 21.8, 14.7; HRMS (ESI⁺) calcd. for gration analysis on crude mixtures. The crude was then purified by

C₁₇H₂₃NaNO₅[M + Na]⁺344.1468, found 344.1465.

silica gel column chromatography as described in the correspond-

ing synthetic procedure to give the tetrahydropyridines 5a–x. When

separable, the two trans and cis stereoisomers were purified by col-

umn chromatography. Characterization were performed for the ma-

jor and/or stable diastereoisomer.

Ethyl ((2R,4S,E)-4-((Methoxycarbonyl)oxy)-6-phenylhex-5-en-2-

yl)carbamate (4a-anti): To a solution of alcohol 3a-anti (44 mg,

0.167 mmol, 1 equiv.) in dry DCM (2 mL) at 0 °C was added anhy-

drous pyridine (40 μL, 0.495 mmol, 3 equiv.). The solution was

stirred for 10 min then methyl chloroformate (80 μL, 1.04 mmol,

Ethyl (2R,6S)-2-Methyl-6-phenyl-3,6-dihydropyridine-1(2H)-

6.2 equiv.) was added dropwise at 0 °C. These additions were re- carboxylate (5a-trans): Alcohol 3a-syn (100 mg, 0.380 mmol) was

peated 2 times (cooling to 0 °C, addition of 3 equiv. of anhydrous used in general procedure C. The reaction mixture was stirred at

pyridine, stirring for 10 min at 0 °C, slowly addition of 6 equiv. of

methyl chloroformate, stirring at 0 °C for 30 min and overnight at

room temperature) in order to complete reaction. A 0.1 M HCl aque-

ous solution was added until pH 2. The aqueous layer was then

40 °C for 3 h 20 min. The conversion, compared to the starting

material, was 100 % and the ratio between the products 5a-cis and

5a-trans was 5:95 in favor of the trans product. The crude mixture

was purified by silica gel column chromatography (SiO₂, cyclohex-

extracted with DCM. The organic layer was washed with a saturated ane to 95:5 cyclohexane/EtOAc) providing a mixture of 5a-cis and

aqueous NaHCO₃, dried with anhydrous MgSO4, filtered and con-

centrated under reduced pressure. The crude product was purified

by silica gel column chromatography (SiO₂, 100 % cyclohexane to

8:2 cyclohexane/EtOAc) providing the carbonate 4a-anti as a yellow

5a-trans (4:96) as a colorless oil in 61 % yield (56.7 mg,

0.231 mmol). 5a-trans: TLC R_f= 0.75 (cyclohexane/EtOAc, 7:3); ¹H

NMR (400 MHz, CDCl₃) δ = 7.31–7.22 (m, 4H), 7.20 (m, 1H), 5.76 (d,

J = 10.4, 1H), 5.72 (d, J = 10.4 Hz, 1H), 5.07 (m, 1H), 4.55 (m, 1H),

oil in 67 % yield (35.8 mg, 0.111 mmol). TLC R_f= 0.40 (cyclohexane/ 4.21–3.77 (m, 2H), 2.62 (dd, J₁= 14.8 Hz, J₂= 5.8 Hz, 1H), 2.08 (dd,

1

EtOAc, 7:3); H NMR (400 MHz, CDCl₃) δ = 7.37 (d, J = 7.1 Hz, 2H),

7.31 (t, J = 7.1 Hz, 2H), 7.24 (t, J = 7.1 Hz, 1H), 6.66 (d, J = 15.9 Hz,

1H), 6.13 (dd, J₁= 15.9 Hz, J₂= 7.6 Hz, 1H), 5.30 (dt, J₁= 7.6 Hz,

J₂= 4.7 Hz, 1H), 4.59 (d, J = 6.5 Hz, 1H), 4.06 (q, J = 7.0 Hz, 2H), 3.88

(m, 1H), 3.76 (s, 3H), 1.94 (ddd, J₁= 14.2 Hz, J₂= 8.4 Hz, J₃= 4.7 Hz,

1H), 1.80 (m, 1H), 1.24–1.16 (m, 6H); ¹³C NMR (101 MHz, CDCl₃) δ =

156.0, 155.1, 136.1, 133.7, 128.7, 128.3, 126.8, 126.5, 76.4, 60.8, 54.8,

43.9, 41.8, 21.6, 14.7; HRMS (ESI⁺) calcd. for C₁₇H₂₃NaNO₅[M + Na]⁺

344.1468, found 344.1465.

J₁= 14.8 Hz, J₂= 2.0 Hz, 1H), 1.25 (d, J = 6.5 Hz, 3H), 1.13–0.64 (m,

3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.6, 144.6, 129.1, 128.4, 126.7,

126.2, 121.2, 61.1, 56.9, 47.0, 30.6, 19.4, 14.4; HRMS (ESI⁺) calcd. for

C₁₅H₂₀NO₂[M + H]⁺246.14886, found 246.1491.

Benzyl (2R,6S)-2-Methyl-6-phenyl-3,6-dihydropyridine-1(2H)-

carboxylate (5b-trans): Alcohol 3b-syn (102.0 mg, 0.313 mmol)

was used in general procedure C. The reaction mixture was stirred

at 40 °C for 6 h. The conversion, compared to the starting material,

was 100 % and the ratio between the products 5b-cis and 5b-trans

was 4:96 in favor of the trans product. The crude mixture was puri-

fied by silica gel column chromatography (SiO₂, 100 % cyclohexane

tert-Butyl ((2R,4R,E)-4-((Methoxycarbonyl)oxy)-6-phenylhex-5-

en-2-yl)carbamate (4c-syn): To a solution of alcohol 3c-syn

(201 mg, 0.690 mmol, 1 equiv.) in dry DCM (5 mL) at 0 °C was added + 0.5 % NEt₃to 95:5 cyclohexane/EtOAc + 0.5 % NEt₃) providing a

anhydrous pyridine (223 μL, 2.76 mmol, 4 equiv.). The solution was

stirred for 10 min then methyl chloroformate (267 μL, 3.46 mmol,

5 equiv.) was added dropwise at 0 °C. The reaction mixture was

stirred for 30 min at 0 °C and overnight at room temperature.

mixture of 5b-cis and 5b-trans (5:95) as a yellow oil in 56 % yield

(53.7 mg, 0.175 mmol). 5b-trans: TLC R_f= 0.62 (cyclohexane/EtOAc,

8:2); ¹H NMR (400 MHz, CDCl₃) δ = 7.43–7.10 (m, 10H), 5.85–5.66

(m, 2H), 5.19 (m, 1H), 5.05 (d, J = 11.4 Hz, 1H), 4.94 (d, J = 11.4 Hz,

Methyl chloroformate (54 μL, 0.690 mmol, 1 equiv.) was again 1H), 4.60 (m, 1H), 2.64 (dd, J₁= 15.9 Hz, J₂= 5.4 Hz 1H), 2.08 (m,

added dropwise at room temperature and the reaction mixture was

stirred for 2 h. A 0.1 M HCl aqueous solution was added until pH 2.

The aqueous layer was then extracted with DCM. The organic layer

was washed with a saturated aqueous NaHCO₃, dried with anhy-

drous MgSO4, filtered and concentrated under reduced pressure.

The crude product was purified by silica gel column chromatogra-

phy (SiO₂, 100 % cyclohexane to 8:2 cyclohexane/EtOAc) providing

the carbonate 4c-syn as a white solid in 91 % yield (219 mg,

1H), 1.28 (d, J = 6.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.3,

144.5, 136.6, 129.1, 128.6, 128.4, 127.9, 127.8, 126.7, 126.1, 121.2,

67.1, 57.0, 47.3, 30.5, 19.5; HRMS (ESI ⁺) calcd. for C₂₀H₂₂NO₂(M +

H)⁺308.1645, found 308.1649.

tert-Butyl (2R,6S)-2-Methyl-6-phenyl-3,6-dihydropyridine-

1(2H)-carboxylate (5c-trans): To a solution of carbonate 4c-syn

(100 mg, 0.286 mmol) under argon in dry DCE (0.03 M) was added

the catalyst PdCl₂(MeCN)₂(22.3 mg, 0.0860 mmol, 0.3 equiv.). After

56 h at room temperature, the reaction mixture was refluxed be-

cause no significant conversion was observed by TLC. After 46 h of

reflux, catalyst was added (15 mg, 0.0578 mmol, 0.2 equiv.). The

reaction mixture was refluxed another 44 h. The reaction mixture

was filtered through a pad of Celite which was then washed with

DCM. The filtrate was concentrated. The conversion, compared to

the starting material, was 46 % and the ratio between the products

5c-cis and 5c-trans was 2:98 in favor of the trans product. The

crude mixture was purified by silica gel column chromatography

1

0.627 mmol). TLC R_f= 0.70 (cyclohexane/EtOAc, 7:3); Mp 104 °C; H

NMR (400 MHz, CDCl₃) δ = 7.39 (d, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz,

2H), 7.25 (m, 1H), 6.68 (d, J = 15.9 Hz, 1H), 6.15 (dd, J₁= 15.9 Hz,

J₂= 7.4 Hz, 1H), 5.31 (q, J = 7.4 Hz, 1H), 4.45 (brs, 1H), 3.80 (m, 1H),

3.78 (s, 3H), 1.99 (dd, J₁= 14 Hz, J₂= 7.4 Hz, J₃= 6.8 Hz 1H), 1.77

(m, 1H), 1.44 (s, 9H), 1.18 (d, J = 6.7 Hz, 3H). ¹³C NMR (101 MHz,

CDCl₃) δ = 155.3, 155.2, 136.2, 133.7, 128.7, 128.3, 126.9, 126.4, 79.3,

77.0, 54.8, 43.8, 41.9, 28.5, 21.8; HRMS (ESI⁺) calcd. for C₁₉H₂₇NaNO₅

[M + Na]⁺372.1781, found 372.1788.

Procedure C: Synthesis of 1,2,3,6-Tetrahydropyridines 5 from (SiO₂, 100 % cyclohexane + 0.5 % NEt₃to 95:5 cyclohexane/EtOAc

Alcohols 3 or Carbonates 4: To a solution of alcohol 3a–x or carb-

onate 4a/4c-syn (1 equiv.) in DCE (0.03 M) was added the catalyst

PdCl₂(MeCN)₂(5 to 30 mol-%). The reaction mixture was then stirred

at the temperature specified in the corresponding synthetic proce-

dure (room temperature, 40 °C or reflux). The reaction was moni-

tored by TLC and stopped by filtration through a pad of Celite. The

+ 0.5 % NEt₃) providing 5c-trans (3:97) as a colorless oil in 20 %

yield (16 mg, 58.5 μmol). TLC R_f= 0.70 (cyclohexane/EtOAc, 8:2); ¹H

NMR (400 MHz, CDCl₃) δ = 7.37–7.00 (m, 5H), 5.73–5.55 (m, 2H),

4.93 (m, 1H), 4.59 (m, 1H), 2.57 (dd, J₁= 15.5 Hz, J₂= 4.5 Hz, 1H),

2.06 (dd, J₁= 15.5 Hz, J₂= 5.0 Hz, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.22–

1.08 (brs, 9H); ¹³C NMR (101 MHz, CDCl₃) δ = 155.7, 138.9, 129.2,

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

14

Full Paper

128.4, 126.5, 125.8, 120.8, 79.8, 56.9, 46.5, 30.6, 29.8, 28.2; HRMS

(ESI⁺) calcd. for C₁₇H₂₃NO₂[M + Na]⁺296.1621, found 296.1624.

providing a mixture of 5g-cis and 5g-trans (3:97) as a yellow oil in

58 % yield (26.9 mg, 0.0910 mmol). 5g-trans: TLC R_f= 0.20 (cyclo-

hexane/EtOAc, 95:5); ¹H NMR (400 MHz, CDCl₃) δ = 7.82–7.74 (m,

3H), 7.68 (s, 1H), 7.48–7.36 (m, 3H), 5.84–5.74 (m, 2H), 5.25 (m, 1H),

4.60 (m, 1H), 4.06–3.84 (m, 2H), 2.72 (dd, J = 16.4 Hz, J = 5.4 Hz,

1H), 2.13 (dd, J = 16.4 Hz, J = 5.3 Hz, 1H), 1.27 (d, J = 6.5 Hz, 3H),

1.07–0.78 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.6, 141.8, 133.5,

132.6, 128.9, 128.1, 127.7, 127.6, 125.9, 125.4, 124.6 (2C), 121.5, 61.1,

57.0, 47.0, 30.6, 19.3, 14.3; HRMS (ESI⁺) calcd. for C₁₉H₂₂NO₂[M +

H]⁺296.1645, found 296.1648.

Ethyl (2R,6S)-6-Phenyl-2-propyl-3,6-dihydropyridine-1(2H)-

carboxylate (5d-trans): Alcohol 3d-syn (24.8 mg, 0.0851 mmol)

was used in general procedure C. The reaction mixture was stirred

at 40 °C for 21 h. Because of the low conversion, the reaction mix-

ture was then refluxed 2 h 30 min in order to complete reaction.

The conversion, compared to the starting material, was 100 % and

the ratio between the products 5d-cis and 5d-trans was 4:96 in

favor of the trans product. The crude mixture was purified by silica

gel column chromatography (SiO₂, 100 % cyclohexane to 85:15 cy-

clohexane/EtOAc) providing a mixture of 5d-cis and 5d-trans (3:97)

as a colorless oil in 81 % yield (18.9 mg, 0.0691 mmol). 5d-trans:

TLC R_f= 0.70 (cyclohexane/EtOAc, 8:2); ¹H NMR (400 MHz, CDCl₃)

δ = 7.40–7.22 (m, 4H), 7.22–7.11 (m, 1H), 5.73 (d, J = 10.5 Hz, 1H),

5.72 (d, J = 10.5 Hz, 1H), 5.05 (m,1H), 4.29 (m, 1H), 4.12–3.74 (m,

2H), 2.52 (ddd, J₁= 17.0 Hz, J₂= 5.3 Hz, J₃= 2.7 Hz, 1H), 2.21 (d,

J₁= 17.0 Hz, J₂= 3.9 Hz, 1H), 1.71–1.52 (m, 2H), 1.42–1.17 (m, 2H),

1.17–0.62 (m, 3H), 0.90 (t, J = 7.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃)

δ = 156.8, 144.5, 129.4, 128.4, 126.7, 126.3, 121.6, 61.0, 57.4, 51.2,

35.6, 28.0, 20.2, 14.3, 14.1; HRMS (ESI⁺) calcd. for C₁₇H₂₄NO₂[M +

H]⁺274.1802, found 274.1809.

Ethyl (2S,6S)-6-(4-Bromophenyl)-2-phenyl-3,6-dihydropyridine-

1(2H)-carboxylate (5h-trans): Alcohol 3h-syn (46.7 mg,

0.116 mmol) was used in general procedure C. The reaction mixture

was stirred at 40 °C for 24 h. The conversion, compared to the

starting material, was 100 % and the ratio between the products

5h-cis and 5h-trans was 5:95 in favor of the trans product. The

crude mixture was purified by silica gel column chromatography

(SiO₂, 100 % cyclohexane +0.5 % NEt₃to 95:5 cyclohexane/EtOAc

+0.5 %NEt₃) providing a mixture of 5h-cis and 5h-trans (4:96) as

a yellow oil in 71 % yield (31.7 mg, 0.0821 mmol). TLC R_f= 0.68

(cyclohexane/EtOAc, 7:3); ¹H NMR (400 MHz, CDCl₃) δ = 7.44 (d, J =

8.4 Hz, 2H), 7.36–7.13 (m, 7H), 5.88 (m, 1H), 5.70 (m, 1H), 5.52 (m,

1H), 5.40 (m, 1H), 4.00–3.83 (m, 2H), 2.94 (ddt, J₁= 16.8 Hz, J₂

=

Benzyl (2R,6S)-6-Phenyl-2-propyl-3,6-dihydropyridine-1(2H)-

carboxylate (5e-trans): Alcohol 3e-syn (24.6 mg, 69.6 μmol) was

used in general procedure C. The reaction mixture was stirred at

40 °C for 24 h. Because of the low conversion, the reaction mixture

was then refluxed 8 h. The conversion, compared to the starting

material, by proton NMR, was 15 % and the ratio between the prod-

ucts 5e-cis and 5e-trans was up to 4:96 in favor of the trans prod-

uct. Due to the low conversion and quantity of engaged product,

5e-trans was not isolated as pur product. TLC R_f= 0.82 (cyclohex-

ane/EtOAc, 7:3).

6.0 Hz, J₃= 2.6 Hz, 1H), 2.55 (dd, J₁= 16.8 Hz, J₂= 6.0 Hz, 1H), 0.90

(t, J = 7.1 Hz, 3H); ¹³C NMR (400 MHz, CDCl₃) δ = 156.6, 139.3, 136.9,

131.7, 129.6, 128.4, 128.1, 126.9, 126.1, 121.8, 61.5, 57.6, 54.5, 30.8,

14.3; HRMS (ESI⁺) calcd. for C₂₀H₂₁BrNO₂[M + H]⁺386.0750, found

386.0752.

Ethyl (2R,6S)-6-(2-Bromophenyl)-2-methyl-3,6-dihydropyridine-

1(2H)-carboxylate (5i-trans): Alcohol 3i-syn (31.2 mg, 91.2 μmol)

was used in general procedure C. After 24 h at 40 °C, the conversion,

compared to the starting material, was 25 %. Because of the low

conversion, the reaction mixture was then refluxed 30 h in order to

complete reaction. The conversion, compared to the starting mate-

rial, was then 66 % and the ratio between the products 5i-cis and

5i-trans was 2:98 in favor of the trans product. The crude mixture

was purified by silica gel column chromatography (SiO₂, 100 % cy-

clohexane + 0.5 % NEt₃to 95:5 cyclohexane/EtOAc + 0.5 % NEt₃)

providing 5i-trans as a colorless oil in 38 % yield (11.1 mg,

34.2 μmol). TLC R_f= 0.35 (cyclohexane/EtOAc, 9:1); ¹H NMR

(400 MHz, CDCl₃) δ = 7.49 (d, J₁= 8.6 Hz, 1H), 7.28 (dd, J₁= 7.3 Hz,

J₂= 1.8 Hz, 1H), 7.21 (td, J₁= 7.3 Hz, J₂= 1.4 Hz, 1H), 7.03 (ddd,

J₁= 8.0 Hz, J₂= 7.3 Hz, J₃= 1.8 Hz, 1H), 5.93–5.70 (m, 2H), 5.50 (m,

Benzyl (2S,6R)-2,6-Diphenyl-3,6-dihydropyridine-1(2H)-carb-

oxylate 5f-cis and Benzyl (2S,6S)-2,6-Diphenyl-3,6-dihydro-

pyridine-1(2H)-carboxylate (5f-trans): Alcohol 3f-syn (23.4 mg,

0.0604 mmol) was used in general procedure C. The reaction mix-

ture was stirred at 40 °C for 21 h. To complete the reaction, the

reaction mixture was then refluxed for 2 h 30 min. The conversion,

compared to the starting material, was 100 % and the ratio be-

tween the products 5f-cis and 5f-trans was 10:90 in favor of the

trans product. The crude mixture was purified by silica gel column

chromatography (SiO₂, 100 % cyclohexane + 0.5 % NEt₃to 95:5 cy-

clohexane/EtOAc + 0.5 % NEt₃) providing 5f–cis (2 mg, 5.41 μmol)

as a colorless oil and 5f–trans (11.8 mg, 0.0319 mmol) as a white

solid. The tetrahydropyridines 5f–cis and 5f–trans were obtained

with a global yield of 62 %. 5f–trans: TLC R_f= 0.66 (cyclohexane/

1H), 4.69 (m, 1H), 4.18–3.80 (m, 2H), 2.68 (dd, J₁= 16.6 Hz, J₂

=

3.1 Hz, 1H), 2.07 (dd, J₁= 16.6 Hz, J₂= 6.2 Hz, 1H), 1.36–1.13 (m,

3H), 1.25 (d, J = 6.3 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.4,

144.2, 132.7, 128.0 (2CH), 126.6, 126.5, 126.4, 122.1, 121.5, 61.2, 55.7,

47.0, 30.3, 19.4, 14.3; HRMS (ESI⁺) calcd. for C₁₅H₁₈BrNaNO₂[M +

Na]⁺346.0413, found 346.0409.

1

EtOAc, 8:2); Mp 132 °C; H NMR (400 MHz, CDCl₃) δ = 7.48–7.10 (m,

13H), 6.80 (m, 2H), 5.97 (m, 1H), 5.68 (m, 1H), 5.74–5.41 (m, 2H), 4.99

(d, J = 12.5 Hz, 1H), 4.86 (d, J = 12.5 Hz, 1H), 2.98 (ddt, J₁= 16.7 Hz,

J₂= 3.0 Hz, J₃= 6.0 Hz, 1H), 2.52 (dd, J₁= 16.7 Hz, J₂= 6.4 Hz, 1H);

¹³C NMR (101 MHz, CDCl₃) δ = 156.3, 140.0 136.4, 130.1, 128.7,

128.4, 128.3, 127.7, 127.6, 127.0, 126.8, 126.2 (2C), 121.3, 120.8, 67.2,

58.2, 54.9, 31.0; HRMS (ESI⁺) calcd. for C₂₅H₂₄NO₂[M + H]⁺370.1802,

found 370.1796.

Ethyl (2R,6S)-6-(3-Bromophenyl)-2-methyl-3,6-dihydropyridine-

1(2H)-carboxylate (5j-trans): Alcohol 3j-syn (50.7 mg, 0.148 mmol)

was used in general procedure C. After 27 h at 40 °C, the conversion,

compared to the starting material, was 40 %. Because of the low

conversion, the reaction mixture was then refluxed 6 h in order to

complete reaction. The conversion, compared to the starting mate-

rial, was then 86 % and the ratio between the products 5j-cis and

5j-trans was 5:95 in favor of the trans product. The crude mixture

was purified by silica gel column chromatography (SiO₂, 100 % cy-

Ethyl (2S,6R)-2-Methyl-6-(naphthalen-2-yl)-3,6-dihydropyr-

idine-1(2H)-carboxylate (5g-trans): Alcohol 3g-syn (49.5 mg,

0.158 mmol) was used in general procedure C. The reaction mixture

was stirred at room temperature for 3 h. The conversion, compared

to the starting material, was 100 % and the ratio between the prod- clohexane + 0.5 % NEt₃to 95:5 cyclohexane/EtOAc + 0.5 % NEt₃)

ucts 5g-cis and 5g-trans was 6:94 in favor of the trans product. The providing a mixture of 5j-cis and 5j-trans (3:97) as a colorless oil in

crude mixture was purified by silica gel column chromatography 36 % yield (17.4 mg, 0.0537 mmol). TLC R_f= 0.68 (cyclohexane/

(neutralized SiO₂, 100 % cyclohexane to 95:5 cyclohexane/EtOAc)

EtOAc, 7:3); ¹H NMR (400 MHz, CDCl₃) δ = 7.38 (t, J = 1.6 Hz, 1H),

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

15

Full Paper

7.31 (dt, J₁= 7.6 Hz, J₂= 1.6 Hz, 1H), 7.19 (dt, J₁= 7.6 Hz, J₂

1.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 5.76 (m, 1H), 5.69 (ddd, J₁

=

1H), 2.12 (ddt, J₁= 17.1 Hz, J₂= 6.4 Hz, J₃= 1.8 Hz, 1H), 1.36–0.76

(m, 3H), 1.26 (d, J = 6.5 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ =

156.5, 148.6, 147.0, 132.6, 129.4, 127.9, 122.4, 121.9, 121.3, 61.5, 56.4,

47.0, 30.5, 19.2, 14.5; HRMS (ESI⁺) calcd. for C₁₅H₁₉N₂O₄[M + H]⁺

291.1339, found 291.1339.

10.0 Hz, J₂= 4.0 Hz, J₃= 2.9 Hz, 1H), 5.05 (m, 1H), 4.54 (m, 1H),

4.16–3.78 (m, 2H), 2.63 (m, 1H), 2.07 (ddt, J₁= 16.8 Hz, J₂= 6.5 Hz,

J₃= 1.8 Hz, 1H), 1.27 (d, J = 6.5 Hz, 3H), 1.18–0.80 (m, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ = 156.5, 147.1, 130.0, 129.8, 129.2, 128.4, 125.0,

122.5, 121.8, 61.3, 56.5, 47.0, 30.5, 19.3, 14.4; HRMS (ESI⁺) calcd. for

Ethyl (2S,6R)-6-(4-Methoxy-3-nitrophenyl)-2-methyl-3,6-dihy-

dropyridine-1(2H)-carboxylate (5q-trans): Alcohol 3q-syn (51 mg,

0.151 mmol) was used in general procedure C. The reaction mixture

was stirred at room temperature for 22 h. The conversion, compared

to the starting material, was 100 % and the ratio between the prod-

ucts 5q-cis and 5q-trans was 4:96 in favor of the trans product. The

crude mixture was purified by silica gel column chromatography

(neutralized SiO₂, 9:1 cyclohexane/EtOAc to 8:2 cyclohexane/EtOAc)

providing 5q-cis (2 mg, 6.24 μmol), 5q-trans (36.1 mg, 0.113 mmol)

and a mixture of 5q-cis and 5q-trans (15:85) (5 mg, 0.0156 mmol)

as colorless oils. The tetrahydropyridines were obtained with a

global yield of 89 %. Due to low quantity obtained for 5q-cis, only

5q-trans the major product was described. TLC R_f= 0.85 (cyclohex-

ane/EtOAc, 9:1); ¹H NMR (400 MHz, CDCl₃) δ = 7.73 (d, J = 2.2 Hz,

1H), 7.46 (dd, J₁= 8.6 Hz, J₂= 2.2 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H),

5.80 (m, 1H), 5.67 (dt, J₁= 9.9 Hz, J₂= 3.7 Hz, 1H), 5.56 (m, 1H), 4.52

(m, 1H), 4.12–3.93 (m, 2H), 3.91 (s, 3H), 2.64 (m, 1H), 2.09 (ddt, J₁=

16.9 Hz, J₂= 6.5 Hz, J₃= 1.7 Hz, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.20–

0.96 (m, 3H); ¹³C NMR (101 MHz, CDCl₃) δ = 156.6, 151.9, 139.5,

137.0, 132.6, 128.2, 123.8, 122.2, 113.5, 61.4, 56.7, 55.7, 47.0, 30.5,

19.2, 14.5; HRMS (ESI⁺) calcd. for C₁₆H₂₁N₂O₅[M + H]⁺321.1445,

found 321.1447.

C

₁₅H₁₉BrNO₂[M + H]⁺324.0594, found 324.0600.

Ethyl (2R,6S)-6-(4-Bromophenyl)-2-methyl-3,6-dihydropyridine-

1(2H)-carboxylate (5k-trans): Alcohol 3k-syn (74.6 mg,

0.218 mmol) was used in general procedure C. The reaction mixture

was stirred at 40 °C for 1 h 45 min. The conversion, compared to

the starting material, was 100 % and the ratio between the prod-

ucts 5k-cis and 5k-trans was 3:97 in favor of the trans product. The

crude mixture was purified by silica gel column chromatography

(SiO₂, 100 % cyclohexane + 0.5 % NEt₃to 95:5 cyclohexane/EtOAc

0.5 % NEt₃) providing a mixture of 5k-cis and 5k-trans (3:97) as a

colorless oil in 84 % yield (59.2 mg, 0.183 mmol). TLC R_f= 0.61

(cyclohexane/EtOAc, 7:3); ¹H NMR (400 MHz, CDCl₃) δ = 7.39 (d, J =

8.5 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 5.74 (m, 1H), 5.68 (ddd, J₁

=

10.0 Hz, J₂= 5.0 Hz, J₃= 6.5 Hz, 1H), 5.06 (m, 1H), 4.53 (m, 1H),

4.10–3.88 (m, 2H), 2.62 (ddt, J₁= 16.9 Hz, J₂= 5.0 Hz, J₃= 2.5 Hz,

1H), 2.08 (dddd, J₁= 16.9 Hz, J₂= 6.3 Hz, J₃= 2.1 Hz, J₄= 1.6 Hz,

1H), 1.24 (d, J = 6.5 Hz, 3H), 1.17–0.79 (m, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ = 156.6, 143.8, 131.6, 128.6, 128.0, 121.6, 120.3, 61.3, 56.4,

47.0, 30.5, 19.3, 14.5; HRMS (ESI⁺) calcd. for C₁₅H₁₉BrNO₂[M + H]⁺

324.0594, found 324.0580.

Ethyl (2S,6R)-6-(4-Fluorophenyl)-2-methyl-3,6-dihydropyridine-

1(2H)-carboxylate (5l-trans): Alcohol 3l-syn (49.4 mg, 0.176 mmol)

was used in general procedure C. The reaction mixture was stirred

at room temperature for 1 h 30 min. The conversion, compared to

the starting material, was 100 % and the ratio between the prod-

ucts 5l-cis and 5l-trans was 3:97 in favor of the trans product. The

crude mixture was purified by silica gel column chromatography

(neutralized SiO₂, cyclohexane to 95:5 cyclohexane/EtOAc) provid-

ing a mixture of 5l-cis and 5l-trans (2:98) as a colorless oil in 67 %

yield (31 mg, 0.118 mmol). TLC R_f= 0.37 (cis), 0.33 (trans) (cyclohex-

ane/EtOAc, 9:1); ¹H NMR (400 MHz, CDCl₃) δ = 7.22 (dd, J₁= 8.4 Hz,

J₂= 5.6 Hz, 2H), 6.96 (t, J_HH,HF= 8.4 Hz, 2H), 5.74 (m, 1H), 5.69 (ddd,

J₁= 10.0 Hz, J₂= 4.4 Hz, J₃= 6.4 Hz, 1H), 5.06 (s, 1H), 4.52 (m, 1H),

4.13–3.86 (m, 2H), 2.62 (ddd, J₁= 16.7 Hz, J₂= 4.4 Hz, J₃= 2.4 Hz,

1H), 2.07 (dddd, J₁= 16.8 Hz, J₂= 6.4 Hz, J₃= 1.8 Hz, J₄= 1.4 Hz,

1H), 1.25 (d, J = 6.5 Hz, 3H), 1.16–0.92 (m, 3H); ¹³C NMR (101 MHz,

Ethyl (2R,6R)-6-(4-Methoxyphenyl)-2-methyl-3,6-dihydropyr-

idine-1(2H)-carboxylate 5s-cis and Ethyl (2R,6S)-6-(4-Methoxy-

phenyl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (5s-

trans): Alcohol 3s-syn (48.0 mg, 0.164 mmol) was used in general

procedure C. The reaction mixture was stirred at 40 °C for 1 min.

The conversion, compared to the starting material, was 100 % and

the ratio between the products 5s-cis and 5s-trans was 79:21 in

favor of the cis product. The crude mixture was purified by silica

gel column chromatography (SiO₂, 100 % cyclohexane + 0.5 % NEt₃

to 95:5 cyclohexane/EtOAc + 0.5 NEt₃) providing 5s–cis (19 mg.

69.0 μmol) and two mixtures of 5s–cis and 5s–trans (44:56 and

10:90) (10.7 mg, 38.9 μmol and 4.3 mg, 15.6 μmol) as a colorless

oils. The tetrahydropyridines 5s–cis and 5s–trans were obtained

with a global yield of 75 %.

Alcohol 3s-syn (26.0 mg, 88.6 μmol mmol) was used in general pro-

cedure C. The reaction mixture was stirred at room temperature for

25 min. The conversion, compared to the starting material, was

100 % and the ratio between the products 5s-cis and 5s-trans was

79:21 in favor of the cis product. The crude mixture was purified by

CDCl₃) δ = 161.8 (d, J_CF= 244 Hz), 156.7, 140.4, 129.1, 127.9 (d, J_CF

=

8 Hz), 121.4, 115.3 (d, J_CF= 21 Hz), 61.3, 56.3, 47.1, 30.6, 19.4, 14.6;

HRMS (ESI⁺) calcd. for C₁₅H₁₉NO₂[M + H]⁺264.1394, found

264.1394.

Ethyl (2S,6R)-2-Methyl-6-(3-nitrophenyl)-3,6-dihydropyridine- silica gel column chromatography (SiO₂, 100 % cyclohexane + 0.5 %

1(2H)-carboxylate (5o-trans): Alcohol 3o-syn (43.2 mg,

0.140 mmol) was used in general procedure C with 30 mol-% of

PdCl₂(MeCN)₂. The reaction mixture was stirred at room tempera-

ture for 24 h. The conversion, compared to the starting material,

was 100 % and no cis product was observed. The crude mixture

was purified by silica gel column chromatography (neutralized SiO₂,

100 % cyclohexane to 9:1 cyclohexane/EtOAc) providing 5o-trans

as a yellow oil in 27 % yield (10.9 mg, 0.0375 mmol). No cyclization

was observed when the reaction was performed at 40 °C or reflux

with 5 mol-% of catalyst. TLC R_f= 0.23 (cyclohexane/EtOAc, 9:1); ¹H

NMR (400 MHz, CDCl₃) δ = 8.10 (t, J = 2.0 Hz, 1H), 8.06 (ddd, J₁=

7.8 Hz, J₂= 2.0 Hz, J₃= 1.1 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.45 (t,

NEt₃to 95:5 cyclohexane/EtOAc + 0.5 NEt₃) providing two mixtures

of 5s-cis and 5s-trans (96:4 and 53:47) (4.3 mg, 15.6 μmol and

7.4 mg, 26.9 μmol) as a colorless oils. The tetrahydropyridines 5s-

cis and 5s-trans were obtained with a global yield of 48 %. 5s-cis:

TLC R_f= 0.55 (cyclohexane/EtOAc, 7:3); The product was not stable

and quickly deteriorated. 5s-trans: TLC R_f= 0.50 (cyclohexane/

EtOAc, 7:3); H NMR (400 MHz, CDCl₃) δ = 7.18 (d, J = 8.6 Hz, 2H),

6.82 (d, J = 8.6 Hz, 2H), 5.80–5.65 (m, 2H), 5.04 (m, 1H), 4.54–4.42

(m, 1H), 4.11–3.90 (m, 2H), 3.78 (s, 3H), 2.61 (ddd, J₁= 16.7 Hz, J₂=

1

5.7 Hz, J₃= 2.6 Hz, 1H), 2.07 (ddd, J₁= 16.7 Hz, J₂= 6.2 Hz, J₃

=

2.4 Hz, 1H), 1.6 (d, J = 6.5 Hz, 3H), 1.17–0.92 (m, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ = 158.4, 156.6, 136.5, 129.4, 127.5, 121.0, 113.8,

J = 7.8 Hz, 1H), 5.82 (m, 1H), 5.70 (ddd, J₁= 10.0 Hz, J₂= 4 Hz, J₃= 61.0, 56.3, 55.3, 47.1, 30.6, 19.4, 14.5; HRMS (ESI⁺) calcd. for

3.0 Hz, 1H), 5.12 (m, 1H), 4.59 (m, 1H), 4.15–3.88 (m, 2H), 2.70 (m,

C₁₆H₂₂NO₃[M + H]⁺276.1594, found 276.1599.

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

16

Full Paper

[1] a) N. N. Mateeva, L. L. Winfield, K. K. Redda, Curr. Med. Chem. 2005, 12,

551–571; b) F.-X. Felpin, J. Lebreton, Eur. J. Org. Chem. 2003, 2003, 3693–

3712; c) C. Allais, W. R. Roush, Org. Lett. 2017, 19, 2646–2649.

[2] a) S. Chen, B. Q. Mercado, R. G. Bergman, J. A. Ellman, J. Org. Chem. 2015,

80, 6660–6668; b) M. G. P. Buffat, E. J. Thomas, Tetrahedron 2016, 72,

451–463; c) X. E. Hu, N. K. Kim, B. Ledoussal, A.-O. Colson, Tetrahedron

Lett. 2002, 43, 4289–4293; d) R. Kumar, R. Chandra, Adv. Heterocycl. Chem.

2001, 78, 269–313.

[3] a) Y. Dudognon, J. Rodriguez, T. Constantieux, X. Bugaut, Eur. J. Org.

Chem. 2018, 2018, 2432–2442; b) F. A. Davis, H. Xu, J. Zhang, J. Org.

Chem. 2007, 72, 2046–2052; c) S. M. Hande, N. Kawai, J. Uenishi, J. Org.

Chem. 2009, 74, 244–253; d) S. Mix, S. Blechert, Adv. Synth. Catal. 2007,

349, 157–160; e) P. Das, J. T. Njardarson, Org. Lett. 2015, 17, 4030–4033;

f) M. Ferles, J. Pliml, Adv. Heterocycl. Chem. 1970, 12, 43–101.

[4] F.-X. Felpin, J. Lebreton, Curr. Org. Synth. 2004, 1, 83–109.

[5] a) T. Xin, S. Okamoto, F. Sato, Tetrahedron Lett. 1998, 39, 6927–6930; b)

X. Dong, Y. Han, F. Yan, Q. Liu, P. Wang, K. Chen, Y. Li, Z. Zhao, Y. Dong,

H. Liu, Org. Lett. 2016, 18, 3774–3777.

Ethyl (2S,6R)-2-Methyl-6-(3-phenoxyphenyl)-3,6-dihydropyr-

idine-1(2H)-carboxylate (5t-trans): Alcohol 3t-syn (49.4 mg,

0.139 mmol) was used in general procedure C. The reaction mixture

was stirred at room temperature for 23 h. The conversion, compared

to the starting material, was 100 % and the ratio between the prod-

ucts 5t-cis and 5t-trans was 2:98 in favor of the trans product. The

crude mixture was purified by silica gel column chromatography

(neutralized SiO₂, 100 % cyclohexane to 95:5 cyclohexane/EtOAc)

providing a mixture of 5t-cis and 5t-trans (3:97) as a yellow oil in

78 % yield (36.5 mg, 0.108 mmol). TLC R_f= 0.40 (cyclohexane/EtOAc,

9:1); ¹H NMR (400 MHz, CDCl₃) δ = 7.32 (dd, J₁= 7.7 Hz, J₂= 7.4 Hz,

2H), 7.23 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 7.01 (d, J =

7.9 Hz, 1H), 6.98 (d, J = 7.7 Hz, 2H), 6.94 (t, J = 1.8 Hz, 1H), 6.80 (dd,

J₁= 7.9 Hz, J₂= 1.8 Hz, 1H), 5.75 (d, J = 10.0 Hz, 1H), 5.72 (d, J =

10.0 Hz, 1H), 5.03 (m, 1H), 4.52 (m, 1H), 4.15–3.86 (m, 2H), 2.58 (dd,

J₁= 15.0 Hz, J₂= 5.8 Hz, 1H), 2.05 (dd, J₁= 15.0 Hz, J₂= 2.5 Hz,

1H), 1.24 (d, J = 6.5 Hz, 3H), 1.16–0.94 (m, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ = 157.4, 157.2, 156.5, 146.9, 129.8, 129.7, 128.7, 123.2,

121.5, 121.0, 118.8, 116.9, 116.7, 61.1, 56.6, 46.9, 30.5, 19.4, 14.5;

HRMS (ESI⁺) calcd. for C₂₁H₂₄NO₃[M + H]⁺338.1751, found

338.1737.

[6] F.-X. Felpin, K. Boubekeur, J. Lebreton, Eur. J. Org. Chem. 2003, 2003,

4518–4527.

[7] P. G. M. Wuts, Y. W. Jung, J. Org. Chem. 1988, 53, 1957–1965.

[8] J. Åhman, T. Jarevång, P. Somfai, J. Org. Chem. 1996, 61, 8148–8159.

[9] a) G. Wang, Y. Mao, L. Liu, Org. Lett. 2016, 18, 6476; b) M. B. Tait, S.

Butterworth, J. Clayden, Org. Lett. 2015, 17, 1236–1239.

[10] Y. N. Bubnov, E. V. Klimkina, A. V. Ignatenko, I. D. Gridnev, Tetrahedron

Lett. 1997, 38, 4631–4634.

[11] I. Abrunhosa-Thomas, A. Plas, A. Vogrig, N. Kandepedu, P. Chalard, Y.

Troin, J. Org. Chem. 2013, 78, 2511–2526.

[12] I. Abrunhosa-Thomas, A. Plas, N. Kandepedu, P. Chalard, Y. Troin, Beilstein

J. Org. Chem. 2013, 9, 486–495.

[13] a) E. Schweizer, T. Gaich, L. Brecker, J. Mulzer, Synthesis 2007, 3807–3814;

b) J. W. Bae, S. H. Lee, Y. J. Jung, C.-O. M. Yoon, C. M. Yoon, Tetrahedron

Lett. 2001, 42, 2137–2139; c) A. C. Rodriguez, A. P. Ramos, G. E. Hawkes,

F. Berti, M. Resmini, Tetrahedron: Asymmetry 2004, 15, 1847–1855.

[14] a) H. Yokoyama, Y. Hayashi, Y. Nagasawa, H. Ejiri, M. Miyazawa, Y. Hirai,

Tetrahedron 2010, 66, 8458–8463; b) H. Makabe, L. K. Kong, M. Hirota,

Org. Lett. 2003, 5, 27–29; c) C. Welter, A. Dahnz, B. Brunner, S. Streiff, P.

Dübon, G. Helmchen, Org. Lett. 2005, 7, 1239–1242; d) C. Gnamm, C. M.

Krauter, K. Brödner, G. Helmchen, Chem. Eur. J. 2009, 15, 2050–2054.

[15] Z. Wang, S. Li, B. Yu, H. Wu, Y. Wang, X. Sun, J. Org. Chem. 2012, 77,

8615–8620.

Ethyl (2S,6R)-6-(4-Acetamidophenyl)-2-methyl-3,6-dihydropyr-

idine-1(2H)-carboxylate (5u-trans): Alcohol 3u-syn (50.7 mg,

0.158 mmol) was used in general procedure C. Due to a poor solu-

bility of the product in DCE, the solution of 3u-syn in DCE was

0.015 M instead of 0.03 M. The reaction mixture was stirred at room

temperature for 1 h. The conversion, compared to the starting ma-

terial, was 100 % and the ratio between the products 5u-cis and

5u-trans was 26:74 in favor of the trans product. The crude mixture

was purified by silica gel column chromatography (neutralized SiO₂,

8:2 cyclohexane/EtOAc to 5:5 cyclohexane/EtOAc) providing a mix-

ture of 5u-cis (4.8 mg, 0.0159 mmol), 5u-trans (28.1 mg,

0.0929 mmol) and a mixture of 5u-cis and 5u-trans (38:62) (1.3 mg,

4.3 μmol) as a colorless oils. The tetrahydropyridines 5u-cis and 5u-

trans were obtained with a global yield of 71 %. 5u-cis: TLC

R_f= 0.20 (cyclohexane/EtOAc, 6:4); The product was not stable and

deteriorated. 5u-trans: TLC R_f= 0.15 (cyclohexane/EtOAc, 6:4); ¹H

NMR (400 MHz, CDCl₃) δ = 7.76 (brs, 1H), 7.37 (d, J = 8.1 Hz, 2H),

7.16 (d, J = 8.1 Hz, 2H), 5.76–5.63 (m, 2H), 5.02 (m, 1H), 4.50 (m, 1H),

4.23–3.83 (m, 2H), 2.60 (dd, J₁= 16.4 Hz, J₂= 5.4 Hz, 1H), 2.16–1.97

(m, 1H), 2.11 (s, 3H), 1.27 (d, J = 6.7 Hz, 3H), 1.26–0.94 (m, 3H); ¹³C

NMR (101 MHz, CDCl₃) δ = 168.6, 156.6, 140.2, 136.7, 129.0, 126.7,

121.1, 120.1, 61.2, 56.4, 47.0, 30.5, 24.5, 19.4, 14.5; HRMS (ESI⁺) calcd.

for C₁₇H₂₃N₂O₃[M + H]⁺303.1703, found 303.1701.

[16] a) P. Kothandaraman, S. J. Foo, P. W. H. Chan, J. Org. Chem. 2009, 74,

5947–5952; b) J. Jing, X. Huo, J. Shen, J. Fu, Q. Meng, W. Zhang, Chem.

Commun. 2017, 53, 5151–5154.

[17] a) S. Sawadjoon, P. J. R. Sjöberg, A. Orthaber, O. Matsson, J. S. M. Samec,

Chem. Eur. J. 2014, 20, 1520–1524; b) H. Kinoshita, H. Shinokubo, K.

Oshima, Org. Lett. 2004, 6, 4085–4088; c) N. A. Butt, W. Zhang, Chem.

Soc. Rev. 2015, 44, 7929–7967; d) S. Akkarasamiyo, S. Sawadjoon, A.

Orthaber, J. S. M. Samec, Chem. Eur. J. 2018, 24, 3488–3498.

[18] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.

Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Na-

katsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G.

Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hase-

gawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.

Montgomery Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Broth-

ers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghava-

chari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega,

J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J.

Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi,

C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski,

G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö.

Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian 09,

Revision ABCD.0123, Gaussian, Inc., Wallingford CT, 2016.

Acknowledgments

Computations have been performed on the supercomputer fa-

cilities of the Mésocentre Clermont Auvergne. We acknowledge

the CNRS and the Ministère de l'Enseignement Supérieur et de

la Recherche for providing research facilities and financial sup-

port.

Keywords: Tetrahydropyridines · Intramolecular allylic

amination · Diastereoselective cyclization · Palladium

catalysis

[19] K. L. Granberg, J.-E. Bäckvall, J. Am. Chem. Soc. 1992, 114, 6858–6863.

Received: October 16, 2019

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

17

Full Paper

Tetrahydropyridine Synthesis

A. Visseq, T. Boibessot,

L. Nauton, V. Théry, F. Anizon,*

I. Abrunhosa-Thomas* ................... 1–18

Diastereoselective Synthesis of 2,6-

Disubstituted-1,2,3,6-Tetrahydropyr-

idines through a Palladium-Cata-

lyzed Intramolecular Allylic Amin-

ation

A highly diastereoselective palladium- stituted-1,2,3,6-tetrahydropyridines

catalyzed intramolecular allylic amin- under mild conditions in moderate to

ation from non-activated allylic alco- good yields.

hols is reported, leading to 2,6-disub-

DOI: 10.1002/ejoc.201901520

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

18

Article Doi

Diastereoselective Synthesis of 2,6-Disubstituted-1,2,3,6-Tetrahydropyridines through a Palladium-Catalyzed Intramolecular Allylic Amination

DOI: 10.1002/ejoc.201901520

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201901520

Full text of DOI:10.1002/ejoc.201901520

Products guided by the article

R&D Labs maybe for 1425667-11-3

Relevant to this article

Hot Product