Titanium-Mediated Cyclopropanation of Nitriles with Unsaturated Grignard Reagents: Application to the Synthesis of Constrained Lysine Derivatives

SYNTHESIS

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

©

Georg Thieme Verlag Stuttgart · New York

2015, 47, 992–1006

992

paper

Synthesis

G. Forcher et al.

Paper

Titanium-Mediated Cyclopropanation of Nitriles with Unsaturated

Grignard Reagents: Application to the Synthesis of Constrained

Lysine Derivatives

Gwénaël Forcher^a

Nathalie Clousier^a

Alice Beauseigneur^a

Paul Setzer^a

O

NH2

NHBoc

1

) MeMgBr, Ti(Oi-Pr)4

BnO

HO

BnO

CN

2

)

MgBr

⁽⁾n

NHFmoc

Fabien Boeda^a

n = 1, 2, 3

Morwenna S. M. Pearson-Long*^a

Philippe Karoyan^b^,^c^,^d^,^e

Jan Szymoniak^f

Philippe Bertus*^a

a

Université du Maine, CNRS UMR 6283, Institut des Molécules et Matériaux du Mans (IMMM), Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France

morwenna.pearson@univ-lemans.fr

philippe.bertus@univ-lemans.fr

b

c

d

e

f

Sorbonne Universités, UPMC Univ Paris 06, LBM, 4 place Jussieu, 75005 Paris, France

École Normale Supérieure-PSL Research University, Département de Chimie, 24, rue Lhomond, 75005 Paris, France

CNRS, UMR 7203 LBM, 75005 Paris, France

Glaxo-Smith-Kline, LBM, 25 avenue du Québec, 91140 Villebon-sur-Yvette, France

CNRS UMR 6229, Université de Reims-Champagne Ardenne, BP 1039, 51687 Reims Cedex 2, France

Received: 18.11.2014

Accepted after revision: 15.12.2014

Published online: 28.01.2015

tive configurations allow exploration of the side-chain ori-

1a,4

entations.

2,3-Methanoamino acid derivatives are used

5

DOI: 10.1055/s-0034-1379978; Art ID: ss-2014-t0705-op

in drug design and, for example, an important cyclopro-

pane-containing amino acid, (1R,2S)-dehydrocoronamic

acid, is the common component of a family of hepatitis C

NS3 NS4 protease inhibitors.⁶

Abstract A comparative study of the titanium-mediated cyclopro-

panation of (benzyloxy)acetonitrile and Boc-protected cyanohydrin us-

ing unsaturated Grignard reagents (but-3-enyl- and pent-4-enylmagne-

sium bromides) is described. The best conditions to provide the cis and

trans isomers of cyclopropylamines bearing unsaturation were identi-

fied and the alkene moiety was subjected to chemical modifications, as

shown by the synthesis of orthogonally protected cis- and trans-2,3-

methanolysine, cis-2,3-methanoornithine, and cis-2,3-methanohomo-

lysine.

From a synthetic point of view, 2,3-methanoamino ac-

ids are prepared by a variety of methods; these were exten-

3e

sively reviewed in 2007. Among them, low-valent-titani-

7

um-mediated cyclopropanation reactions have been found

to be a valuable entry to 2,3-methanoamino acid deriva-

tives. The Kulinkovich reaction,⁸i.e. the diastereoselective

synthesis of cyclopropanols from carboxylic esters, was ini-

tially explored. However, several steps were generally re-

quired to convert the resulting cyclopropanols into amino

acids.¹⁰The variant using tertiary amides was more

straightforward and gives a variety of amino acids accessi-

ble in a few steps;¹²the main drawback was the difficulty in

separating the diastereomers obtained in the cyclopropana-

tion step. The most recent variant using nitriles gives pri-

mary cyclopropylamines directly¹³that can be converted

into amino acids in few steps. This method was successfully

applied to a short synthesis of Boc-protected aminocyclo-

propanecarboxylic acid (ACC) 3a and coronamic acid 3b

[Scheme 1 (1)].¹⁴Subsequent enhancement of the reaction

using the cyano carbonate 4 and a catalytic amount of tita-

nium(IV) isopropoxide provided 3a in only two steps

[Scheme 1 (2)].¹⁵

,9

Key words amino acids, cyclopropane, Grignard reaction, nitriles, tita-

nium

11

If the conformational freedom of peptides is associated

with high binding affinities, it is also considered as a major

drawback in their use as suitable therapeutic agents, re-

1

sponsible for poor selectivity and metabolic stability. The

restriction of the biopolymer flexibility with tools able to

control secondary structures, while retaining crucial infor-

mation brought by amino acids side chains, allows its bio-

logical properties to be enhanced. With this aim, many

amino acids surrogates are designed to control peptide con-

formational space and among them both diastereomers of

2

2-substituted 1-aminocyclopropanecarboxylic acids (or

3

2,3-methanoamino acids) are of great interest. Indeed, the

cyclopropyl system allows simultaneous control of the con-

formation of the peptide backbone while the cis/trans rela-

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Synthesis

G. Forcher et al.

Paper

(

1)

NH2

R

HOOC

NHBoc

R

MgBr

Ti(Oi-Pr)4

BnO

R

3 steps

BnO

CN

1

4

2a (R = H, 74%)

cis-2b (R = Et, 43%)

3a (R = H, 80%)

cis-3b (R = Et, 74%)

(2)

NHBoc

EtMgBr

HO

KMnO4, NaOH

92%

3a

BocO

Ti(Oi-Pr)4 (20 mol%)

5 (65%)

(3)

C H₁₁MgCl

MeOOC

NHBoc

6

NH2 OH

BnO

OTi(Oi-Pr)3

1

FG

6

(51%)

trans-7

Scheme 1 Titanium-mediated synthesis of 2,3-methanoamino acid derivatives from nitriles

Within a project devoted to the synthesis and the bio-

logical application of functionalized constrained α-amino

acids that includes their insertion in pseudotetrapeptides,¹⁶

we have reported a new diastereoselective access to func-

tionalized trans-2,3-methanoamino acids¹⁷based on the

intramolecular ligand exchange of homoallylic alcohol to ti-

In contrast, subjecting cyano carbonate 4 to the cyclo-

propanation reaction conditions using pent-4-enylmagne-

sium bromide in diethyl ether gave selectively 8b as an in-

separable mixture of diastereomers (entry 3). When tetra-

hydrofuran was used, the obtained mixture of 8b/9b was

directly transformed into N-Boc oxazolidinone 10b (entry

4) which was isolated in low yield and diastereoselectivity.

Similar results were observed with butylmagnesium bro-

mide,¹indicating no influence of the double bond on the

outcome of the reaction.

18

tanacyclopropane. The hydroxyl side chain of the so-pre-

pared trans-disubstituted cyclopropylamine 6 was further

modified to afford various constrained functionalized ami-

5b

19

no acid analogues 7 [Scheme 1 (3)]. In order to fully un-

derstand the influence of the side chain position of amino

acids derivatives incorporated in peptidomimetics, the dia-

stereomers bearing the cis relative configuration are also re-

Table 1 Cyclopropanation of Nitrile 4 with Unsaturated Grignard Re-

agents

17

quired. However they are not accessible using the previ-

ously reported method. A general access to the two isomers

was thus envisioned from titanium complexes and unsatu-

rated Grignard reagents, and the results of the study are

presented here. The usefulness of this method is illustrated

by the synthesis of orthogonally protected cis- and trans-

O

NHBoc

MgBr HO

)n

O

NH

(

+

4

( )n

(

)n

Ti(Oi-Pr)4 (20 mol%)

solvent, r.t., 30 min

8a (n = 0)

8b (n = 1)

9a (n = 0)

9b (n = 1)

2,3-methanoamino acids bearing amino groups.

The titanium-mediated cyclopropanation of tert-butyl

cyanomethyl carbonate (4) and (benzyloxy)acetonitrile (1)

was checked with two unsaturated Grignard reagents (but-

Boc2O, Et3N

DMAP, THF

O

3

-enyl- and pent-4-enylmagnesium bromide). The results

1

0a (n = 0)

0b (n = 1)

O

NBoc

( )_n

are presented in Table 1 and Table 2, respectively.

15b

As previously reported,

the cyclopropanation reac-

tion of tert-butyl cyanomethyl carbonate (4) works well

with but-3-enylmagnesium bromide (Table 1, entries 1 and

a

Yield^b

Entry

n

Solvent

Ratio 8/9 Product

Ratio

cis/trans

2), affording a mixture of vinyl-substituted cyclopropyl-

(

%)

amine derivatives 8a and 9a in good yield. This mixture was

directly converted into a unique N-Boc-protected oxazolidi-

none 10a, which can easily be transformed into 8a using

1

2

3

0

1

Et

2

O

2.3:1

1:5.7

1:0

10a¹⁵^b

8b

74

69

60

21

1.5:1

<1:19

1:2.3

1:2.2

THF

15b

lithium hydroxide. Whereas a mixture of diastereomers

was formed in diethyl ether, excellent diastereoselectivity

was observed in tetrahydrofuran in favor of the trans iso-

mer exclusively, which was isolated in 69% yield (entry 2).

The same trend was observed with related cyano ester sub-

Et O

2

4

THF

1:1.5

10b

a

Ratio calculated by integration of characteristic signals of 8 and 9 in the

1

crude H NMR.

b

Isolated yields, diastereomeric ratio calculated from integration of crude

1

H NMR.

20

strates.

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Synthesis

G. Forcher et al.

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Table 2 Cyclopropanation of Nitrile 1 with Unsaturated Grignard Reagents

MgBr

1

)

(

)n

NH2

( )_n

BnO

(

x equiv)

BnO

CN

(

)n

1

Ti source, solvent

r.t., 30 min

) additive, r.t., 30 min

cis-11a (n = 0)

cis-11b (n = 1)

trans-11a (n = 0)

trans-11b (n = 1)

2

Titanium source^a

n

x

Solvent

Additive

dr cis/trans

b

Yield (%)

c

Entry

cis-11

trans-11

1

2

3

4

5

6

7

8

Ti(Oi-Pr)

4

0

1

2

Et

2

O

–

0

2

THF

–

2

Et

2

O

2.0:1

2.2:1

1.9:1

1.3:1

1.6:1

1:1

45

42

45

19^d

36

26^d

41

22

19

22

16^d

25

26^d

24

MeTi(Oi-Pr)

3

1.1

2

Ti(Oi-Pr)

4

+ MeMgBr

THF

2

BF

3

·OEt

2

(2 equiv)

MeTi(Oi-Pr)

3

1.1

–

9

BF

·OEt

1.3:1

a

4 3 4

Reaction conditions: 1 (1 mmol), solvent (5 mL), Ti(Oi-Pr) (1.1 equiv), MeTi(Oi-Pr) (1.1 equiv), or Ti(Oi-Pr) (1.1 equiv) then MeMgBr (1 equiv), followed by

alkenylmagnesium bromide.

b

1

Diastereomeric ratio calculated from integration of crude H NMR.

Isolated yields.

c

d

Ketones were also obtained as byproducts.

The behavior of the unsaturated Grignard reagents to-

dure was facilitated by the successive addition of methyl-

magnesium bromide (1 equiv) and the unsaturated

Grignard reagent (1.1 equiv) to the mixture of titanium(IV)

isopropoxide and the nitrile (entry 5), thus avoiding the

preparation of methyltitanium(IV) isopropoxide. This

method was reproducible on a multigram scale, and the cy-

clopropylamines cis-11b and trans-11b were isolated in

good yields (46% and 21%, respectively). The yield of cyclo-

propylamines 11b was significantly lower (35%) when the

reaction was conducted in tetrahydrofuran, and two iso-

meric ketones, namely 1-(benzyloxy)hept-6-en-2-one and

1-(benzyloxy)-3-methylhex-5-en-2-one, were also ob-

served, in 24% and 6% yields, respectively (entry 6). These

ketones are the result of an inefficient ring contraction of

the five-membered metallacycle. It was shown that Lewis

acids assist the ring contraction of azatitanacyclopentene

intermediates.¹³Indeed, the use of boron trifluoride–dieth-

yl ether provided a higher yield (61%) of 11b, but the diaste-

reoselectivity was lower than in diethyl ether (entry 7). The

same trend was observed with methyltitanium(IV) iso-

propoxide (entries 8 and 9).

ward nitrile 1 in the presence of titanium(IV) isopropoxide

was also investigated (Table 2). Surprisingly, when but-3-

enylmagnesium bromide was used with nitrile 1, no trace

of the expected 2-vinylcyclopropylamine 11a was observed

(

entries 1 and 2), whatever the conditions used. Aminocy-

clopentenes could also be formed from nitriles, titani-

um(IV) isopropoxide, and homoallylic Grignard reagents,²⁰

but the expected 1-[(benzyloxy)methyl]cyclopent-3-enyl-

amine was not detected either. Despite the complete disap-

pearance of the starting material, this organomagnesium

reagent was not suitable for the cyclopropanation of (ben-

zyloxy)acetonitrile (1), showing the marked difference of

reactivity between nitriles 1 and 4.

On the other hand, the reaction of two equivalents of

pent-4-enylmagnesium bromide with nitrile 1 in the pres-

ence of stoichiometric amount of titanium(IV) isopropoxide

in diethyl ether afforded the expected allyl-substituted cy-

clopropylamine 11b in 67% yield as a 2:1 mixture of cis and

trans diastereomers (Table 2, entry 3). Fortunately, these

isomers are easily separable by column chromatography

[

ΔR ~0.4 (EtOAc)], and the cis isomer was the major prod-

As a result of this study, only the combination of (ben-

zyloxy)acetonitrile (1) and pent-4-enylmagnesium bro-

mide was able to furnish both the cis and trans isomers in a

pure form after chromatography. The cyclopropylamines

cis-11b and trans-11b, bearing an allyl substituent, are use-

ful intermediates to access functionalized substituted 2,3-

f

uct, making this method complementary to the one using

homoallylic alcohols [Scheme 1 (3)]. In order to reduce the

amount of Grignard reagent, methyltitanium(IV) iso-

propoxide was also used in the presence of only 1.1 equiv-

alents of organomagnesium bromide (entry 4). This proce-

21

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Synthesis

G. Forcher et al.

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NHBoc

d

BnO

b, c BnO

a

cis-11b

trans-11b)

R

OMs

(

cis-13 (87%)

trans-13, 88%)

cis-12 (92%)

trans-12, 90%)

cis-14 (93%)

(trans-14, 94%)

R = N3

(

e

cis-15 (quant.)

trans-15, quant.)

i

R = NH2

(

f

NHBoc

HO

NHBoc

OMs

BnO

NHFmoc

cis-18 (98%)

(trans-18, 96%)

cis-16 (81%)

(

trans-16, 95%)

d

g

NHBoc

HO

f

HO

h

HOOC

NHBoc

R

NHFmoc

cis-17 (30% from cis-16)

77% from cis-20)

R = N3

cis-19 (85%)

trans-19, 87%)

cis-21 (75%)

(trans-21, 71%)

(

j

(

trans-17, 28% from trans-16)

cis-20 (quant.)

trans-20, 91%)

R = NH2

75% from trans-20)

(

Scheme 2 Synthesis of protected 2,3-methanolysine cis-21 and trans-21. Reagents and conditions: (a) Boc O, NaOH, t-BuOH–H O; (b) BH ·Me S, THF

2

3

2

then NaOH, H O ; (c) MsCl, Et N, CH Cl ; (d) NaN , MeCN; (e) HCO NH , Pd/C, MeOH; (f) FmocCl, Na CO , dioxane–H O; (g) DDQ, CH Cl ; (h) RuO ,

2

3

2

3

2

4

2

3

2

NaIO , CCl –MeCN–H O; (i) H (3 bar), Pd/C, MeOH; (j) H (3 bar), Pd(OH) /C, MeOH.

4

2

methanoamino acids. The synthesis of several orthogonally

protected constrained lysine derivatives from 11b is de-

scribed.

After Boc-protection of the primary amine function, the

allyl-substituted cis-12 was subjected to a hydroboration–

oxidation sequence followed by a treatment with mesyl

chloride to afford pure mesylate cis-13 in 87% yield

cis-17 but in low yield (30%). A similar pattern of reactivity

was observed with the trans isomer and trans-17 was pre-

pared in 28% yield from trans-19. These low yields were

overcome by performing the hydrogenolysis on the

mesylate cis-13; the alcohol cis-18 was cleanly obtained in

98% yield and the mesylate function was next displaced by

the azide anion to give cis-19. Quantitative reduction and

subsequent amine protection as the Fmoc carbamate fur-

nished the alcohol cis-17 which was finally transformed

into the protected 2,3-aminolysine cis-21 by ruthenium(IV)

oxide/sodium periodate oxidation (39% overall yield from

cis-11). The strategy was also validated in the trans series

and the known carboxylic acid trans-21 was similarly ob-

tained in 32% yield from cyclopropylamine trans-11.

(Scheme 2). Substitution with sodium azide in refluxing

acetonitrile provided azide cis-14 which was submitted to

palladium-catalyzed hydrogenolysis conditions with the

aim of reducing the azido function and removing the ben-

zyl-protecting group in one step. Unfortunately, attempts

using hydrogen (3 or 30 bar) or ammonium formate as a

hydrogen source in the presence of palladium on charcoal

(

10% wt) in methanol, at room temperature or reflux failed

The relative configurations of cis- and trans-11, initially

attributed by NOESY spectroscopic experiments, were fur-

ther confirmed by treating the two mesylates cis- and

trans-13 with sodium hydride. Under these conditions,

trans-13 underwent intramolecular cyclization to the bicy-

clic compound 22 whereas only starting material was re-

covered from the cis isomer (Scheme 3).

Submission of the N-Boc cyclopropylamine cis-12 to

ozonolysis and subsequent reductive treatment afforded

the hydroxyethyl-substituted cyclopropylamine intermedi-

ate which was subjected to mesylation to give cis-23 in 60%

yield (Scheme 4). The azidation–hydrogenolysis sequence

developed for cis-13 was applied to cis-23 and an identical

to furnish the expected product. Only the reduction of the

azide moiety occurred to lead to the amine cis-15 in quanti-

tative yields in all cases. The reluctance of the O-benzyl

group to undergo hydrogenolysis was also reported by

de Meijere et al. on similar structures, and was mainly at-

tributed to the deactivation of the palladium surface

through complexation with the free amine released in the

media.

The primary amine was then protected giving cis-16.

Attempts to remove selectively the benzyl group by hydrog-

enolysis failed, and radical debenzylation using Birch condi-

tions led to degradation of the substrate. Only 2,3-dichloro-

11a

5,6-dicyano-1,4-benzoquinone (DDQ) afforded the alcohol

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Synthesis

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chloromethane, the metathesis led to the expected alkene

cis-27 in 79% yield. The mixture was directly subjected to

various reduction conditions inspired from recent Jubault’s

work on similar structures,²³but it was not possible to re-

Boc

N

BnO

NHBoc

NaH, THF

BnO

OMs

24

trans-13

cis-13: no cyclization)

22 (69%)

move the benzyl protecting group or to reduce the nitrile.

(

In the unique case of nitrile reduction [Pd(OH) /C, 30 bar

2

Scheme 3 Cyclization of trans-13

H ], ammonia as well as a condensation product were

2

formed, as already observed by Maschmeyer.²⁵Similar ob-

servations were made in the trans series, and trans-28 was

quantitatively obtained by hydrogenation of trans-27. Con-

sequently, the cross-metathesis was performed with meth-

yl acrylate to prepare unsaturated ester cis-29, which was

isolated in 87% yield as the unique E diastereomer. Reduc-

tion using lithium aluminum hydride afforded the saturat-

ed alcohol intermediate that was directly subjected to

mesylation to give cis-30 in 65% yield. As described for the

other analogues, palladium-catalyzed O-debenzylation fol-

lowed by treatment with sodium azide provided the alco-

hol cis-31. Hydrogenolysis then Fmoc protection led to cis-

32. Finally, the protected 2,3-methanohomolysine cis-33

was isolated in 74% yield after oxidation.

The titanium-mediated cyclopropanation reaction of ni-

triles using unsaturated Grignard reagents was found to be

strongly dependent on the nature of the substrate and the

solvent in terms of reactivity, yield, and diastereoselectivity.

The most useful result was obtained from (benzyl-

oxy)acetonitrile (1) and pent-4-enylmagnesium bromide,

affording both the cis and the trans isomers in pure form.

Although it is not diastereoselective, the simplicity of the

method, using easily available substrates and reagents, and

the easy separation of stereoisomers makes this method at-

tractive for the preparation of constrained amino acids. The

synthetic utility of the obtained cyclopropylamines was

thus illustrated by the synthesis of orthogonally protected

2,3-methanoamino acids bearing an amino side chain with

variable length, suitable for peptidic synthesis. Their incor-

poration in pseudopeptides and their behavior in biological

media are currently under investigation.

observation was made concerning the absence of O-deben-

zylation during the palladium-catalyzed hydrogenolysis of

this analogue of 14. Therefore, the removal of the benzyl

protecting group of cis-23 was carried out prior to the sub-

stitution of the mesylate by the azide moiety to give cis-24

in 82% yield. Finally, a three-step sequence consisting of

azide hydrogenolysis/Fmoc protection/oxidation provided

the protected 2,3-methanoornithine cis-26 in 47% overall

yield.

NHBoc

HO

BnO

c, d

a, b

cis-12

N3

OMs

g

cis-23 (60%)

NHBoc

cis-24 (82%)

HOOC

NHBoc

HO

e, f

NHFmoc

cis-25 (70%)

cis-26 (67%)

Scheme 4 Synthesis of protected 2,3-methanoornithine cis-26. Re-

agents and conditions: (a) O , CH Cl –MeOH then NaBH ; (b) MsCl, Et N,

3

2

4

3

CH Cl ; (c) H (3 bar), Pd/C, MeOH; (d) NaN , MeCN; (e) HCO NH ,

2

3

2

4

Pd/C, MeOH; (f) FmocCl, Na CO , dioxane–H O; (g) RuO , NaIO , CCl –

2

3

2

4

MeCN–H O.

2

The access to the 2,3-methanohomolysine series in-

volved homologation of the allylic side chain of cis-12

(

Scheme 5). Thus, cross metathesis with acrylonitrile was

22

envisaged to simultaneously introduce the nitrogen atom.

Using the 2nd generation Hoveyda–Grubbs catalyst in di-

NHBoc

BnO

a

BnO

b

cis-12

trans-12)

CN

(

cis-27 (R = CN, 79%, Z/E = 3:1)

trans-27 (R = CN, 72%, Z/E = 3:1)

cis-28 (quant.)

trans-28 (quant.)

c

NHBoc

HOOC

NHBoc

BnO

d, e BnO

f, g HO

OMs

j

CO2Me

R

NHFmoc

cis-29 (87%)

cis-30 (65%)

cis-31 (R = N , 82%)

cis-33 (74%)

3

h, i

cis-32 (R = NHFmoc, 68%)

Scheme 5 Synthesis of protected 2,3-methanohomolysine derivative cis-33. Reagents and conditions: (a) acrylonitrile, 2nd generation Hoveyda–Grubbs

catalyst, CH Cl ; (b) H (30 bar), Pd/C, MeOH; (c) methyl acrylate, 2nd generation Hoveyda–Grubbs catalyst, CH Cl ; (d) LiAlH , THF; (e) MsCl, Et N,

2

4

3

CH Cl ; (f) H (3 bar), Pd/C, MeOH; (g) NaN , MeCN; (h) HCO NH , Pd/C, MeOH; (i) FmocCl, Na CO , dioxane–H O; (j) RuO , NaIO , CCl –MeCN–H O.

2

3

2

4

2

3

2

4

2

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Synthesis

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Paper

All experiments were carried out under a N₂atmosphere. Et O, THF,

cis-2-Allyl-1-[(benzyloxy)methyl]cyclopropylamine (cis-11b) and

trans-2-Allyl-1-[(benzyloxy)methyl]cyclopropylamine (trans-11b)

2

and CH Cl were purified by passing through neutral alumina col-

2

umns under N . The Grignard reagents were prepared in anhyd Et O

or THF using the conventional method from the appropriate bromide

precursors and Mg turnings, with the exception of MeMgBr and

2

To a solution of (benzyloxy)acetonitrile 1 (4.0 g, 27.2 mmol) and

Ti(Oi-Pr)₄(8.95 mL, 29.9 mmol) in Et O (140 mL) at r.t. under argon

2

were successively added dropwise a solution of 2.95 M MeMgBr in

PhMgBr which were purchased in solution in Et O from Sigma-

2

Et O (9.22 mL, 27.2 mmol) then a solution of 0.99 M pent-4-enylmag-

2

^A^l^d^rⁱ^c^h^.^Tⁱ⁽^Oⁱ^-^P^r⁾4 was purchased from Sigma-Aldrich. Nitriles 1 and

nesium bromide in Et O (30.2 mL, 29.9 mmol). The solution went

2

4

, as well as MeTi(Oi-Pr) , were prepared according to known proce-

3

gradually from clear yellow to brown. At the end of the addition (ca.

15,23,26

dures.

Analytical TLC were performed on Alugram SIL G/UV254

30 min), the mixture was stirred for 45 min. Water (100 mL) was

silica gel sheets (Macherey-Nagel) by using 5% ethanolic vanillin solu-

tion as stated. Column chromatography was carried out using silica

gel 60 (0.040–0.063 mm) from Merck. Melting points were deter-

mined with a Büchi B-540 melting point apparatus and are uncor-

rected. H and C NMR spectra were recorded on a Bruker DPX-200

or Bruker AC-400 spectrometer relative to the residual solvent peak.

IR spectra were obtained on a Perkin Elmer Spectrum One spectro-

photometer on a single-reflection diamond ATR unit. HRMS were re-

corded on a Waters Micromass GCT Premier spectrometer.

slowly added, followed by EtOAc (30 mL) and 1 M aq HCl until the two

layers became clear (acidic pH). The aqueous phase was extracted

with EtOAc (3 × 30 mL) and the combined organic phases were

washed with brine (30 mL), dried (MgSO ), and filtered. Concentra-

4

1

13

tion under reduced pressure gave a crude mixture of diastereomers

(

1:1.9) that were separated by chromatography (silica gel, cyclohex-

ane–EtOAc, 80:20 then EtOAc). Cyclopropylamines trans-11b (1.30 g,

2%) and cis-11b (2.66 g, 45%) were isolated as yellow oils.

2

trans-11b

tert-Butyl 5-Oxo-1-allyl-6-oxa-4-azaspiro[2.4]heptane-4-carbox-

ylate (10b)

R_f= 0.50 (EtOAc).

IR (neat): 3374, 3065, 3031, 2999, 2853, 1639, 1496, 1454, 1361,

To a solution of tert-butyl cyanomethyl carbonate 4 (548 mg, 3.5

–1

1253, 1075 cm .

mmol) and Ti(Oi-Pr) (210 μL, 0.7 mmol) in THF (9 mL) under argon at

4

1

H NMR (400 MHz, CDCl ): δ = 7.33–7.24 (m, 5 H), 5.93 (ddt, J = 17.2,

0

°C was added dropwise a solution of pent-4-enylmagnesium bro-

3

10.3, 6.0 Hz, 1 H), 5.14 (dq, J = 17.2, 1.9 Hz, 1 H), 4.98 (ddt, J = 10.3, 1.9,

mide (4.3 mL, 1.70 M in Et O, 7.3 mmol). The solution gradually

2

1.5 Hz, 1 H), 4.56 (d, J = 10.4 Hz, 1 H), 4.53 (d, J = 10.4 Hz, 1 H), 3.36 (d,

turned from clear yellow to brown. At the end of the addition (30

J = 9.9 Hz, 1 H), 3.26 (d, J = 9.9 Hz, 1 H), 2.27–2.22 (m, 2 H), 1.55 (br s,

min), the mixture was stirred for 60 min. H O (13 mL) was slowly

2

H), 0.81–0.73 (m, 1 H), 0.63 (dd, J = 9.0, 4.8 Hz, 1 H), 0.29 (m, 1 H).

added, followed by EtOAc (5 mL) and 1 M HCl until the two layers be-

came clear (acidic pH). The aqueous phase was extracted with EtOAc

13

C NMR (100 MHz, CDCl ): δ = 138.6, 138.5, 128.4, 127.6, 114.1, 79.4,

3

(3 × 5 mL) and the combined organic phases were washed with brine

72.7, 37.3, 32.0, 21.9, 17.4.

(

5 mL) and dried (MgSO ). Concentration under reduced pressure

+

4

HRMS (CI-NH ): m/z [M + H] calcd for C₁₄H₂₀NO: 218.1545; found:

3

gave a crude 1:1.5 mixture of amino alcohol 8b and oxazolidinone 9b.

218.1540.

To the solution of the crude mixture of 8b and 9b in THF (3.5 mL) was

added successively Boc O (940 mg, 4.2 mmol), Et N (638 μL, 4.5

mmol), and DMAP (86 mg, 0.7 mmol). The solution was stirred at r.t.

2

3

cis-11b

R_f= 0.10 (EtOAc).

for 1 h then sat. aq NH Cl solution (8 mL) was added. The aqueous

4

IR (neat): 3373, 3065, 3031, 3000, 2851, 1639, 1497, 1453, 1361,

phase was extracted with Et O (3 × 7 mL) and the combined organic

2

–1

1274, 1075 cm .

fractions were washed with brine, dried (MgSO ), and filtered. After

4

1

concentration under reduced pressure, the crude residue was purified

by column chromatography (silica gel, cyclohexane–EtOAc, 90:10) to

afford the Boc-oxazolidinone 10b as a pure 1:2.2 mixture of cis- and

transdiastereoisomers (185 mg, 21% yield over two steps) as a yellow

H NMR (400 MHz, CDCl ): δ = 7.36–7.25 (m, 5 H), 5.89 (ddt, J = 17.1,

3

10.2, 6.2 Hz, 1 H), 5.05 (dq, J = 17.1, 1.7 Hz, 1 H), 4.98 (ddt, J = 10.2, 1.7,

1.4 Hz, 1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H), 3.51 (d,

J = 10.0 Hz, 1 H), 3.44 (d, J = 10.0 Hz, 1 H), 2.17 (m, 1 H), 1.92 (m, 1 H),

1.80 (s, 2 H), 1.04 (m, 1 H), 0.79 (dd, J = 9.1, 5.0 Hz, 1 H), 0.24 (dd, J =

oil; R = 0.37 (cyclohexane–EtOAc, 80:20).

f

6

13

.0, 5.0 Hz, 1 H).

IR (neat): 2979, 2931, 1791, 1723, 1641, 1456, 1394, 1368, 1348,

–1

1253, 1155, 1073, 1030 cm

.

C NMR (100 MHz, CDCl ): δ = 138.5, 138.0, 128.5, 127.8, 127.7,

3

1

114.6, 75.3, 73.2, 37.5, 33.7, 25.0, 18.8.

H NMR (400 MHz, CDCl ): δ = 5.91–5.81 (m, 1 H), 5.11 (ddd, J = 16.1,

.1, 1.6 Hz, 0.7 H), 5.08 (ddd, J = 10.3, 3.1, 1.6 Hz, 0.7 H), 5.07 (ddd, J =

3

+

3

HRMS (CI-NH ): m/z [M + H] calcd for C₁₄H₂₀NO: 218.1545; found:

3

17.2, 3.0, 1.5 Hz, 0.3 H), 5.02 (ddd, J = 10.1, 3.0, 1.5 Hz, 0.3 H), 4.39 (d,

218.1537.

J = 8.1 Hz, 0.3 H), 4.29 (d, J = 8.4 Hz, 0.7 H), 4.13 (d, J = 8.4 Hz, 0.7 H),

3

6

0

.85 (d, J = 8.1 Hz, 0.3 H), 2.31–1.93 (m, 3.7 H), 1.53 (s, 2.7 H), 1.52 (s,

.3 H), 1.04–0.96 (m, 0.3 H), 0.94–0.88 (m, 0.3 H), 0.33 (t, J = 6.1 Hz,

.7 H).

tert-Butyl cis-2-Allyl-1-[(benzyloxy)methyl]cyclopropylcarbamate

(cis-12); Typical Procedure

To a solution of the cyclopropylamine cis-11b (3.62 g, 16.7 mmol) in

13

C NMR (100 MHz, CDCl ): δ = 157.3, 152.8, 150.2, 149.1, 136.6,

3

t-BuOH–H O (3:2, 60 mL), were successively added 3 M aq NaOH (8.3

2

135.8, 116.0, 115.4, 84.2, 84.1, 71.8, 65.9, 45.3, 43.8, 32.5, 31.2, 28.2,

mL, 25 mmol) and Boc O (11.3 g, 25 mmol). The solution was stirred

2

28.1, 24.6, 17.5, 14.9, 10.8.

for 30 min at 35 °C then water (120 mL) was added. The aqueous

+

HRMS (ESI): m/z [M + Na] calcd for C₁₃H₁₉NNaO : 276.1206; found:

phase was extracted with Et

fractions were washed with brine, dried (MgSO

4

2

O (3 × 40 mL) and the combined organic

4

276.1208.

), and filtered. After

concentration under reduced pressure, the crude product was puri-

fied by flash chromatography (silica gel, cyclohexane–Et O, 90:10) to

2

afford the pure carbamate cis-12 (4.88 g, 92%) as a colorless oil; R =

f

0.25 (cyclohexane–EtOAc, 90:10).

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

9

98

Synthesis

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Paper

+

IR (neat): 3334, 3074, 3058, 2977, 2928, 1714, 1641, 1495, 1454,

HRMS (CI-NH ): m/z [M + H] calcd for C₂₀H₃₂NO S: 414.1950; found:

3 6

414.1958.

1

391, 1365, 1167, 1074 cm^–¹

.

1

H NMR (400 MHz, CDCl ): δ = 7.36–7.22 (m, 5 H), 5.92 (ddt, J = 17.2,

3

1

0.2, 6.3 Hz, 1 H), 5.12 (br s, 1 H), 5.08 (ddt, J = 17.2, 1.7, 1.5 Hz, 1 H),

trans-3-{2-[(Benzyloxy)methyl]-2-[(tert-butoxycarbonyl)ami-

no]cyclopropyl}propyl Methanesulfonate (trans-13)

5.00 (ddt, J = 10.2, 1.7, 1.4 Hz, 1 H), 4.55 (d, J = 12.3 Hz, 1 H), 4.52 (d,

J = 12.3 Hz, 1 H), 3.73–3.63 (m, 1 H), 3.50 (d, J = 10.4 Hz, 1 H), 2.34 (dt,

J = 12.6, 6.3 Hz, 1 H), 1.94–1.86 (m, 1 H), 1.44 (s, 9 H), 1.16 (m, 1 H),

Applying the previous procedure on trans-12 (2.10 g, 6.62 mmol) af-

forded trans-13 as a colorless oil (2.40 g, 88%); R = 0.23 (cyclohex-

f

1.03 (dd, J = 8.6, 5.6 Hz, 1 H), 0.53 (dd, J = 6.4, 5.8 Hz, 1 H).

ane–EtOAc, 70:30).

1

3

C NMR (100 MHz, CDCl ): δ = 156.6, 138.5, 137.5, 128.4, 127.7,

IR (neat): 3380, 2976, 2935, 1702, 1498, 1453, 1350, 1246, 1168, 1071

cm .

3

–1

1

27.6, 115.0, 79.3, 73.2, 71.5, 36.8, 33.3, 28.5, 24.8, 18.4.

+

1

HRMS (CI-NH ): m/z [M + H] calcd for C₁₉H₂₈NO : 318.2069; found:

H NMR (400 MHz, CDCl ): δ = 7.37–7.26 (m, 5 H), 4.98 (br s, 1 H),

3

18.2062.

4.53 (s, 2 H), 4.29 (t, J = 6.4 Hz, 2 H), 3.50 (d, J = 10.1 Hz, 1 H), 3.43 (d,

J = 10.1 Hz, 1 H), 2.99 (s, 3 H), 1.89 (quint, J = 6.9 Hz, 2 H), 1.72–1.63

(m, 1 H), 1.44 (s, 9 H), 1.42–1.34 (m, 1 H), 0.97–0.86 (m, 2 H), 0.54–

0.48 (m, 1 H).

tert-Butyl trans-2-Allyl-1-[(benzyloxy)methyl]cyclopropylcarba-

mate (trans-12)

13

Applying the previous procedure on trans-11b (1.0 g, 4.61 mmol) af-

C NMR (50 MHz, CDCl ): δ = 156.1, 138.4, 128.5, 127.7, 127.6, 79.6,

3

forded trans-12 as a colorless oil (1.31 g, 90%); R = 0.25 (cyclohex-

75.0, 73.1, 69.9, 37.5, 37.5, 29.1, 28.4, 24.1, 22.3, 17.2.

f

ane–EtOAc, 90:10).

IR (neat): 2975, 1707, 1487, 1166, 1069, 697 cm^–¹

+

HRMS (CI-NH ): m/z [M + H] calcd for C₂₀H₃₂NO S: 414.1950; found:

414.1947.

3

6

.

1

H NMR (400 MHz, CDCl ): δ = 7.35–7.23 (m, 5 H), 5.92 (ddt, J = 17.2,

3

1

0.3, 5.9 Hz, 1 H), 5.21 (dq, J = 17.2, 1.8 Hz, 1 H), 5.01 (ddt, J = 10.3, 1.7,

.5 Hz, 1 H), 4.97 (br s, 1 H), 4.55 (d, J = 12.3 Hz, 1 H), 4.52 (d, J = 12.3

tert-Butyl cis-2-(3-Azidopropyl)-1-[(benzyloxy)methyl]cyclopro-

pylcarbamate (cis-14); Typical Procedure

Hz, 1 H), 3.55 (d, J = 10.0 Hz, 1 H), 3.38 (d, J = 10.0 Hz, 1 H), 2.23 (m, 1

H), 2.11 (m, 1 H), 1.43 (s, 9 H), 1.04–0.92 (m, 2 H), 0.61–0.50 (m, 1 H).

To a solution of mesylate cis-13 (4.15 g, 10.0 mmol) in MeCN (100 mL)

was added NaN₃(1.63 g, 25 mmol). The solution was refluxed over-

night then water (80 mL) was added. The aqueous phase was extract-

ed with EtOAc (3 × 30 mL) and the combined organic extracts were

13

C NMR (10 MHz, CDCl ): δ = 156.1, 138.6, 137.7, 128.4, 127.6, 127.5,

3

114.8, 79.4, 75.1, 73.1, 37.1, 32.5, 28.5, 21.7, 17.2.

washed with brine, dried (MgSO ), and filtered. Concentration under

+

4

HRMS (CI-NH ): m/z [M + H] calcd for C₁₉H₂₈NO : 318.2069; found:

3

reduced pressure afforded the pure azide cis-14 (3.35 g, 93%) as a pale

318.2061.

yellow oil; R = 0.64 (cyclohexane–EtOAc, 70:30).

f

IR (neat): 3337, 2975, 2933, 2866, 2093, 1712, 1494, 1453, 1365,

cis-3-{2-[(Benzyloxy)methyl]-2-[(tert-butoxycarbonyl)amino]cy-

clopropyl}propyl Methanesulfonate (cis-13); Typical Procedure

–1

1246, 1166, 1095, 1069 cm .

1

H NMR (400 MHz, CDCl ): δ = 7.36–7.26 (m, 5 H), 5.10 (br s, 1 H),

To a solution of cis-12 (3.65 g, 11.5 mmol) in THF (80 mL) at 0 °C was

3

4.57 (d, J = 12.1 Hz, 1 H), 4.52 (d, J = 12.1 Hz, 1 H), 3.63 (d, J = 10.2 Hz,

added BH ·Me S (3.83 mL, 40.3 mmol) and the mixture was stirred for

3

2

1

H), 3.51 (d, J = 10.2 Hz, 1 H), 3.30 (t, J = 6.8 Hz, 2 H), 1.80–1.69 (m, 2

1

2

h at r.t. The solution was cooled to 0 °C and 12 M aq NaOH (24.0 mL,

88 mmol) and 30% aq H O (23.0 mL, 207 mmol) were successively

H), 1.62–1.53 (m, 1 H), 1.43 (s, 9 H), 1.35–1.25 (m, 1 H), 1.12–1.04 (m,

2

1

H), 1.00 (dd, J = 9.0, 5.4 Hz, 1 H), 0.49 (dd, J = 6.3, 5.4 Hz, 1 H).

added carefully. The mixture was stirred for 10 min at 0 °C then water

50 mL) was added. The aqueous phase was extracted with Et O (3 ×

13

(

C NMR (50 MHz, CDCl ): δ = 155.7, 138.4, 129.8, 128.5, 127.8, 79.4,

2

3

20 mL) and the combined organic extracts were washed with sat.

73.3, 71.7, 51.2, 36.8, 28.8, 28.5, 26.5, 25.2, 18.6.

Na S O solution, dried (MgSO ), filtered, and concentrated under re-

+

2

3

4

HRMS (CI-NH ): m/z [M + H] calcd for C₁₉H₂₉N O : 361.2240; found:

361.2234.

3

4

3

duced pressure. After dissolution of the residue in CH Cl (60 mL), the

2

resulting solution was cooled to –10 °C and Et N (2.87 mL, 20.7

3

mmol) then MsCl (0.98 mL, 12.7 mmol) were slowly added. The mix-

ture was allowed to warm up to r.t. and water (50 mL) was added. The

aqueous phase was extracted with CH Cl (3 × 15 mL) and the com-

tert-Butyl trans-2-(3-Azidopropyl)-1-[(benzyloxy)methyl]cyclo-

propylcarbamate (trans-14)

2

Applying the previous procedure on trans-13 (2.40 g, 5.8 mmol) af-

bined organic extracts were dried (MgSO ), filtered, and concentrated

4

forded trans-14 as a pale yellow oil (1.97 g, 94%); R = 0.50 (cyclohex-

under reduced pressure. Purification by flash chromatography (silica

gel, cyclohexane–EtOAc, 90:10 then 70:30) afforded the mesylate cis-

f

ane–EtOAc, 80:20).

1

3 (4.15 g, 87%) as a colorless oil; R = 0.23 (cyclohexane–EtOAc,

IR (neat): 3352, 3321, 2975, 2937, 2865, 2092, 1703, 1494, 1452,

1390, 1165, 1069 cm .

f

–1

70:30).

1

IR (neat): 3383, 2975, 2934, 1707, 1498, 1453, 1350, 1246, 1168, 1071

H NMR (200 MHz, CDCl ): δ = 7.38–7.27 (m, 5 H), 5.02 (br s, 1 H),

3

–1

cm

.

4.52 (s, 2 H), 3.45 (s, 2 H), 3.32 (t, J = 6.7 Hz, 2 H), 1.82–1.57 (m, 3 H),

1

1.43 (s, 9 H), 1.39–1.20 (m, 1 H), 0.97–0.80 (m, 2 H), 0.49 (m, 1 H).

H NMR (400 MHz, CDCl ): δ = 7.37–7.26 (m, 5 H), 5.11 (br s, 1 H),

3

13

4

.54 (d, J = 12.1 Hz, 1 H), 4.49 (d, J = 12.1 Hz, 1 H), 4.28–4.22 (m, 2 H),

.60 (d, J = 10.2 Hz, 1 H), 3.54 (d, J = 10.2 Hz, 1 H), 2.97 (s, 3 H), 2.00–

.85 (m, 2 H), 1.60–1.50 (m, 1 H), 1.47–1.37 (m, 10 H), 1.06 (m, 1 H),

.00 (dd, J = 9.2, 5.5 Hz, 1 H), 0.50 (dd, J = 6.4, 5.5 Hz, 1 H).

C NMR (50 MHz, CDCl ): δ = 156.1, 138.5, 128.5, 127.7, 127.6, 79.5,

3

1

75.1, 73.1, 51.1, 37.4, 28.8, 28.4, 25.3, 22.5, 17.2.

+

HRMS (CI-NH ): m/z [M + H] calcd for C₁₉H₂₉N O : 361.2240; found:

3

4

3

361.2235.

13

C NMR (50 MHz, CDCl ): δ = 155.6, 138.3, 128.4, 127.7, 126.6, 79.3,

3

73.2, 71.6, 69.9, 37.2, 36.7, 29.0, 28.4, 25.2, 24.9, 18.5.

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

9

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Synthesis

G. Forcher et al.

Paper

tert-Butyl cis-2-(3-Aminopropyl)-1-[(benzyloxy)methyl]cyclopro-

pylcarbamate (cis-15)

2 H), 4.54 (d, J = 12.1 Hz, 1 H), 4.48 (d, J = 12.1 Hz, 1 H), 4.41 (d, J = 6.9

Hz, 2 H), 4.23 (t, J = 6.9 Hz, 1 H), 3.66 (d, J = 10.2 Hz, 1 H), 3.49 (m, 1

H), 3.26–3.14 (m, 2 H), 1.72–1.63 (m, 2 H), 1.47–1.38 (m, 10 H), 1.18–

To a solution of azide cis-14 (3.33 g, 9.24 mmol) in MeOH (90 mL)

were successively added 10% Pd/C (831 mg, 20 wt%) and ammonium

formate (2.91 g, 46.2 mmol). The mixture was refluxed for 10 min

then allowed to cool to r.t. After filtration through a pad of Celite and

concentration under reduced pressure, the residue was taken up in

EtOAc (60 mL). The organic solution was washed with 3 M aq NaOH

1.06 (m, 1 H), 1.03–0.97 (m, 1 H), 0.92–0.84 (m, 1 H), 0.63 (t, J = 6.0

Hz, 0.07 H), 0.47 (t, J = 5.9 Hz, 0.93 H).

13

C NMR (100 MHz, CDCl ): δ = 156.4 (C5 or C8), 155.6 (C5 or C8),

3

144.0, 143.8, 141.2, 138.0, 128.3, 127.6, 127.5, 126.9, 124.9, 119.8,

79.3, 73.2, 71.5, 66.4, 47.3, 40.1, 36.9, 29.5, 28.5, 26.6, 25.5, 18.7.

(

30 mL), then the aqueous phase was extracted with EtOAc (3 × 15

+

HRMS (CI-NH ): m/z [M + H] calcd for C₃₄H₄₁N O : 557.3015; found:

3

2

5

mL) and the combined organic fractions were dried (MgSO ) and fil-

tered. Concentration under reduced pressure afforded the pure amine

4

557.3018.

cis-15 (3.09 g, quant.) as a pale yellow oil.

tert-Butyl trans-1-[(Benzyloxy)methyl]-2-{3-[9H-fluoren-9-yl-

methoxy)carbonylamino)]propyl}cyclopropylcarbamate (trans-16)

IR (neat): 3358, 3315, 2974, 2934, 2864, 2360, 1693, 1536, 1494,

–1

1

452, 1390, 1165, 1068 cm .

Applying the previous procedure on trans-15 (2.13 g, 6.37 mmol) af-

1

H NMR (400 MHz, CDCl ): δ = 7.35–7.26 (m, 5 H), 5.16 (br s, 1 H),

3

forded trans-16 as a pale yellow oil (3.38 g, 95%); R = 0.36 (cyclohex-

f

4.55 (d, J = 12.1 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 3.64 (m, 1 H), 3.50

ane–EtOAc, 70:30).

(d, J = 10.2 Hz, 1 H), 2.71 (m, 2 H), 2.06 (br s, 2 H), 1.65–1.52 (m, 3 H),

IR (neat): 3351, 3064, 2931, 2865, 1693, 1504, 1450, 1365, 1246,

1.42 (s, 9 H), 1.21–1.14 (m, 1 H), 1.11–1.04 (m, 1 H), 0.97 (m, 1 H),

–1

1

165, 1072 cm .

0.46 (t, J = 5.9 Hz, 1 H).

1

H NMR (400 MHz, CDCl ): δ (75:25 mixture of rotamers) = 8.07 (m,

13

3

C NMR (50 MHz, CDCl ): δ = 155.7, 138.4, 128.4, 127.8, 127.7, 79.3,

3

0

.5 H), 7.76 (d, J = 7.5 Hz, 1.5 H), 7.71–7.56 (m, 2 H), 7.55–7.26 (m, 9

H), 4.95 (br s, 2 H), 4.58–4.49 (m, 2 H), 4.40 (d, J = 6.8 Hz, 2 H), 4.23

(m, 1 H), 3.55–3.33 (m, 2 H), 3.31–3.16 (m, 2 H), 1.75–1.55 (m, 2 H),

73.2, 71.8, 41.6, 36.8, 32.8, 28.5, 26.6, 25.5, 18.7.

+

HRMS (CI-NH ): m/z [M + H] calcd for C19^H N O : 335.2335; found:

3

31

2

3

335.2345.

1.50–1.34 (m, 10 H), 1.26 (m, 1 H), 0.98–0.82 (m, 2 H), 0.58 (m, 0.25

H), 0.48 (m, 0.75 H).

tert-Butyl trans-2-(3-Aminopropyl)-1-[(benzyloxy)methyl]cyclo-

propylcarbamate (trans-15)

13

C NMR (100 MHz, CDCl ): δ = 156.6, 156.6, 144.2, 144.1, 141.5,

3

140.9, 138.5, 130.2, 129.8, 128.5, 127.8, 127.7, 127.2, 125.2, 120.1,

Applying the previous procedure on trans-14 (2.45 g, 6.8 mmol) af-

forded trans-15 as a pale yellow oil (2.27 g, quant.).

79.6, 75.1, 73.2, 66.6, 47.5, 40.9, 37.5, 29.8, 28.5, 25.5, 22.8, 17.4.

+

HRMS (CI-NH ): m/z [M + H] calcd for C₃₄H₄₁N O : 557.3015; found:

3

2

5

IR (neat): 3360, 3313, 2975, 2933, 2862, 2360, 1687, 1536, 1495,

557.3023.

–1

1452, 1390, 1166, 1071 cm .

1

H NMR (200 MHz, CDCl ): δ = 7.40–7.28 (m, 5 H), 6.04 (br s, 1 H),

.58 (d, J = 12.4 Hz, 1 H), 4.51 (d, J = 12.4 Hz, 1 H), 3.64 (m, 1 H), 3.36–

cis-3-{2-[(tert-Butoxycarbonyl)amino]-2-(hydroxymethyl)cyclo-

propyl}propyl Methanesulfonate (cis-18); Typical Procedure

3

4

3

.28 (m, 1 H), 3.87–3.76 (m, 2 H), 1.60–1.40 (m, 13 H), 0.95–0.85 (m, 2

To a solution of the mesylate cis-13 (2.05 g, 4.96 mmol) in MeOH (40

mL) was added 10% Pd/C (205 mg, 10 wt%) and the mixture was

H), 0.49 (m, 1 H).

13

C NMR (50 MHz, CDCl ): δ = 156.4, 138.7, 128.4, 127.6, 127.5, 79.0,

stirred at r.t. under H

and washing with CH

2

(3 bar) for 1 h. After filtration on a pad of Celite

Cl , the solution was concentrated under re-

3

75.3, 73.0, 40.9, 37.3, 32.8, 28.5, 25.0, 22.7, 17.2.

2

+

duced pressure to afford the pure alcohol cis-18 (1.57 g, 98%) as a col-

orless oil.

HRMS (CI-NH ): m/z [M + H] calcd for C₁₉H₃₁N O : 335.2335; found:

3

2

3

335.2339.

IR (neat): 3406, 2972, 2935, 1687, 1504, 1471, 1349, 1168, 1042 cm^–¹

.

1

tert-Butyl cis-1-[(Benzyloxy)methyl]-2-{3-[(9H-fluoren-9-yl-

methoxy)carbonylamino]propyl}cyclopropylcarbamate (cis-16);

Typical Procedure

H NMR (400 MHz, CDCl ): δ = 5.15 (br s, 1 H), 4.29 (dt, J = 9.8, 6.4 Hz,

3

1 H), 4.28 (dt, J = 9.8, 6.4 Hz, 1 H), 3.83 (d, J = 11.7 Hz, 1 H), 3.57 (d, J =

11.7 Hz, 1 H), 2.99 (s, 3 H), 2.01–1.88 (m, 2 H), 1.66 (m, 1 H), 1.55–

1

.47 (m, 1 H), 1.42 (s, 9 H), 1.12 (m, 1 H), 0.91 (dd, J = 9.3, 5.5 Hz, 1 H),

To a solution of the amine cis-15 (3.09 g, 9.24 mmol) and Na CO

2

3

0.51 (m, 1 H).

(

1.96 g, 18.5 mmol) in dioxane–H O (1:1, 90 mL) cooled to 0 °C was

2

13

added FmocCl (2.51 g, 9.70 mmol). The solution was stirred overnight

at r.t. and the solvents were evaporated under reduced pressure. The

residue was taken up in water (40 mL) and CH Cl (20 mL) and the

C NMR (100 MHz, CDCl ): δ = 158.0, 80.4, 69.9, 66.8, 38.6, 37.5, 29.2,

3

28.4, 26.3, 25.9, 18.9.

2

+

HRMS (CI-NH /CH ): m/z [M + H] calcd for C₁₃H₂₆NO S: 324.1481;

found: 324.1471.

3

4

6

aqueous phase was extracted with CH Cl (2 × 20 mL). The combined

2

organic extracts were dried (MgSO ) and filtered. After concentration

4

under reduced pressure, the crude product was purified by flash

chromatography (silica gel, cyclohexane–EtOAc, 80:20) to afford the

trans-3-{2-[(tert-Butoxycarbonyl)amino]-2-(hydroxymethyl)cy-

clopropyl}propyl Methanesulfonate (trans-18)

protected amine cis-16 (4.18 g, 81%) as a pale yellow oil; R = 0.36 (cy-

f

Applying the previous procedure on trans-13 (1.64 g, 3.97 mmol) af-

forded trans-18 as a pale yellow oil (1.23 g, 96%).

clohexane–EtOAc, 70:30).

IR (neat): 3326, 2962, 2926, 2854, 1694, 1514, 1450, 1365, 1258,

–1

IR (neat): 3259, 2974, 2936, 2858, 1677, 1527, 1458, 1349, 1290,

1

165, 1071, 1020 cm .

–1

1

171, 1022 cm .

1

H NMR (400 MHz, CDCl ): δ (93:7 mixture of rotamers) = 8.10 (d, J =

3

7.4, 2.2 Hz, 0.14 H), 7.61 (dd, J = 7.2, 3.7 Hz, 1.86 H), 7.45 (t, J = 7.8 Hz,

0.14 H), 7.40 (t, J = 7.5 Hz, 1.86 H), 7.35–7.25 (m, 7 H), 5.28–5.10 (br s,

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

1

000

Synthesis

G. Forcher et al.

Paper

1

H NMR (400 MHz, CDCl ): δ = 5.06 (br s, 1 H), 4.27 (t, J = 6.3 Hz, 1 H),

.26 (t, J = 6.3 Hz, 1 H), 3.72 (d, J = 11.1 Hz, 1 H), 3.38 (d, J = 11.1 Hz, 1

IR (neat): 3293, 2974, 2931, 2867, 1685, 1501, 1453, 1390, 1365,

1249, 1165, 1027 cm .

3

–1

4

H), 2.99 (s, 3 H), 1.95–1.85 (m, 2 H), 1.63 (m, 1 H), 1.46–1.35 (m, 2 H),

1

H NMR (400 MHz, CDCl ): δ = 6.14 (br s, 1 H), 4.27 (br s, 3 H), 3.63

3

1.42 (s, 9 H), 1.06 (m, 1 H), 0.94 (dd, J = 8.9, 5.7 Hz, 1 H), 0.42 (t, J = 5.7

(m, 1 H), 3.40 (m, 1 H), 2.85 (m, 2 H), 1.75–1.40 (m, 4 H), 1.42 (s, 9 H),

Hz, 1 H).

1

13

.10–0.90 (m, 2 H), 0.44 (m, 1 H).

13

C NMR (100 MHz, CDCl ): δ = 158.2, 80.4, 70.5, 69.8, 39.6, 37.5, 29.1,

3

C NMR (100 MHz, CDCl ): δ = 158.1, 79.8, 69.7, 40.3, 39.3, 30.7, 28.4,

3

5.1, 22.7, 17.9.

28.4, 24.4, 22.9, 18.2.

2

+

HRMS (CI-NH /CH ): m/z [M + H]^c^a^l^c^d^f^o^r^C13^H26NO S: 324.1481;

+

3

4

6

HRMS (CI-NH /CH ): m/z [M + H] calcd for C₁₂H₂₅N O : 245.1865;

found: 245.1856.

3

4

2

3

found: 324.1475.

tert-Butyl cis-2-(3-Azidopropyl)-1-(hydroxymethyl)cyclopropyl-

carbamate (cis-19); Typical Procedure

tert-Butyl trans-2-(3-Aminopropyl)-1-(hydroxymethyl)cyclopro-

pylcarbamate (trans-20)

To a solution of the mesylate cis-18 (1.57 g, 4.85 mmol) in MeCN (50

Applying the previous procedure on trans-19 (852 mg, 3.15 mmol) af-

forded trans-20 as a colorless oil (698 mg, 91%).

mL) was added NaN (789 mg, 12.1 mmol). The mixture was refluxed

3

overnight then water (40 mL) was added. The aqueous phase was ex-

tracted with EtOAc (3 × 15 mL) and the combined organic fractions

IR (neat): 3293, 2975, 2931, 2867, 1685, 1499, 1453, 1391, 1365,

–1

1249, 1165, 1027 cm

.

were washed with brine, dried (MgSO ), and filtered. After concentra-

4

¹H NMR (400 MHz, CDCl

): δ = 5.31 (br s, 1 H), 3.84 (d, J = 12.0 Hz, 1

tion under reduced pressure, the crude residue was filtered through a

3

pad of silica gel (cyclohexane–Et O, 30:70) to afford the azide cis-19

H), 3.49 (d, J = 12.0 Hz, 1 H), 2.82 (br s, 2 H), 2.76 (t, J = 6.5 Hz, 2 H),

1.64–1.53 (m, 3 H), 1.45–1.35 (m, 2 H), 1.40 (s, 9 H), 1.10 (m, 1 H),

0.91 (dd, J = 9.4, 5.1 Hz, 1 H), 0.44 (t, J = 5.1 Hz, 1 H).

2

(

1.11 g, 85%) as a pale yellow oil; R_f= 0.62 (cyclohexane–EtOAc,

0:70).

IR (neat): 3323, 2974, 2933, 2873, 2093, 1685, 1498, 1453, 1391,

3

¹³C NMR (100 MHz, CDCl

26.1, 26.0, 18.5.

): δ = 157.2, 79.9, 65.6, 40.9, 39.0, 32.6, 28.4,

3

–1

1

366, 1250, 1164, 1102, 1024 cm .

1

): m/z [M + H]⁺calcd for C12

H NMR (400 MHz, CDCl ): δ = 5.16 (br s, 1 H), 3.81 (d, J = 11.7 Hz, 1

HRMS (CI-NH

found: 245.1857.

3

/CH H N O : 245.1865;

4

2

5

2

3

H), 3.63 (br s, 1 H), 3.58 (d, J = 11.7 Hz, 1 H), 3.31 (t, J = 6.7 Hz, 2 H),

1

9

.82–1.61 (m, 3 H), 1.42–1.25 (m, 10 H), 1.10 (m, 1 H), 0.90 (dd, J =

.3, 5.7 Hz, 1 H), 0.50 (br t, J = 5.7 Hz, 1 H).

tert-Butyl cis-2-{3-[(9H-Fluoren-9-ylmethoxycarbonyl)ami-

no]propyl}-1-(hydroxymethyl)cyclopropylcarbamate (cis-17); Typ-

ical Procedures

1

3

C NMR (100 MHz, CDCl ): δ = 157.9, 82.2, 66.8, 51.1, 38.5, 28.9, 28.4,

3

2

6.7, 26.5, 19.0.

+

Procedure 1 from cis-16: To a solution of the benzylated alcohol cis-16

HRMS (CI-NH /CH ): m/z [M + H] calcd for C₁₂H₂₃N O : 271.1770;

found: 271.1775.

3

4

3

(

3.38 g, 6.1 mmol) in CH Cl (60 mL) was added DDQ (4.13 g, 18.2

2 2

mmol). The mixture was stirred at r.t. for 3 d then EtOAc (100 mL) was

added. The solution was washed with sat. aq NaHCO₃solution (30

mL) then with water (30 mL). The combined aqueous phases were ex-

tracted with EtOAc (2 × 30 mL) and the combined organic extracts

tert-Butyl trans-2-(3-Azidopropyl)-1-(hydroxymethyl)cyclopro-

pylcarbamate (trans-19)

Applying the previous procedure on trans-18 (1.23 g, 3.80 mmol) af-

forded trans-19 as a pale yellow oil (897 mg, 87%); R = 0.55 (cyclo-

were dried (MgSO ), and filtered. After concentration under reduced

4

f

pressure, the crude residue was purified by flash chromatography

hexane–EtOAc, 30:70).

(silica gel, cyclohexane–EtOAc, 80:20 then 50:50) to afford the alco-

IR (neat): 3344, 2976, 2933, 2871, 2093, 1685, 1497, 1453, 1391,

hol cis-17 (855 mg, 30%) as a white solid.

–1

1366, 1249, 1164, 1102, 1024 cm .

Procedure 2 from cis-20: To a solution of the amine cis-20 (916 mg,

1

H NMR (400 MHz, CDCl ): δ = 5.08 (br s, 1 H), 3.75 (br s, 1 H), 3.69 (d,

3.75 mmol) and Na CO (797 mg, 7.52 mmol) in dioxane–water (1:1,

3

2

3

J = 11.3 Hz, 1 H), 3.40 (m, 1 H), 3.32 (t, J = 6.6 Hz, 1 H), 3.31 (t, J = 6.6

Hz, 1 H), 1.78–1.68 (m, 2 H), 1.61 (m, 1 H), 1.42 (s, 9 H), 1.37–1.26 (m,

40 mL) cooled to 0 °C was added FmocCl (1.02 g, 3.94 mmol). The

solution was stirred overnight at r.t. and solvents were evaporated

under reduced pressure. The residue was taken up in water (20 mL)

and CH Cl (10 mL) and the aqueous phase was extracted with CH Cl

1

H), 1.02 (m, 1 H), 0.94 (dd, J = 8.9, 5.7 Hz, 1 H), 0.40 (br t, J = 5.7 Hz, 1

H).

2

1

3

(2 × 10 mL). The combined organic extracts were dried (MgSO ) and

4

C NMR (100 MHz, CDCl ): δ = 158.2, 80.4, 70.6, 51.2, 39.5, 28.8, 28.4,

3

filtered. After concentration under reduced pressure, the crude prod-

uct was purified by flash chromatography (silica gel, cyclohexane–

EtOAc, 50:50) to afford the protected amine cis-17 (1.35 g, 77%) as a

2

5.5, 23.1, 18.2.

+

HRMS (CI-NH /CH ): m/z [M + H] calcd for C₁₂H₂₃N O : 271.1770;

found: 271.1763.

3

4

3

white solid; mp 55 °C; R = 0.21 (cyclohexane–EtOAc, 50:50).

f

IR (neat): 3333, 2929, 1691, 1518, 1449, 1365, 1248, 1164, 1025 cm^–¹

.

tert-Butyl cis-2-(3-Aminopropyl)-1-(hydroxymethyl)cyclopropyl-

carbamate (cis-20); Typical Procedure

1

H NMR (400 MHz, CDCl ): δ = 7.77 (d, J = 7.5 Hz, 2 H), 7.61 (d, J = 7.5

3

Hz, 2 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.32 (t, J = 7.5 Hz, 2 H), 5.19 (br s, 1 H),

To a solution of the azide cis-19 (1.06 g, 3.92 mmol) in MeOH (20 mL)

5

.13 (br s, 1 H), 4.39 (d, J = 6.9 Hz, 2 H), 4.23 (t, J = 6.9 Hz, 1 H), 3.89 (d,

was added Pd(OH) /C (212 mg, 10–20% Pd(OH) /C, 50% H O) and the

2

J = 11.3 Hz, 1 H), 3.69 (br s, 1 H), 3.59 (d, J = 11.3 Hz, 1 H), 3.26 (m, 2

H), 1.72 (m, 2 H), 1.59 (m, 1 H), 1.45 (s, 9 H), 1.29–1.22 (m, 1 H), 1.19–

mixture was stirred at r.t. under H (3 bar) for 1 h. After filtration on a

2

pad of Celite and washing with CH Cl , the solution was concentrated

2

1

.11 (m, 1 H), 0.90 (dd, J = 9.2, 5.6 Hz, 1 H), 0.51 (t, J = 5.6 Hz, 1 H).

¹H NMR (400 MHz, DMSO-d

, 363 K): δ = 7.85 (d, J = 7.5 Hz, 2 H), 7.67

d, J = 7.5 Hz, 2 H), 7.41 (td, J = 7.5, 1.2 Hz, 2 H), 7.33 (td, J = 7.4, 1.2 Hz,

under reduced pressure to afford the pure amino alcohol cis-20 (956

mg, quant.) as a colorless oil.

6

(

2

H), 6.81 (br s, 1 H), 6.47 (br s, 1 H), 4.32 (d, J = 6.7 Hz, 2 H), 4.22 (t, J =

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

1

001

Synthesis

G. Forcher et al.

Paper

6.7 Hz, 1 H), 3.56 (d, J = 11.5 Hz, 1 H), 3.50 (d, J = 11.5 Hz, 1 H), 3.05 (t,

Methyl cis-1-[(tert-Butoxycarbonyl)amino]-2-{3-[(9H-fluoren-9-

J = 6.6 Hz, 1 H), 3.03 (t, J = 6.6 Hz, 1 H), 1.56 (m, 2 H), 1.47 (m, 1 H),

ylmethoxycarbonyl)amino]propyl}cyclopropanecarboxylate

1

5

.40 (s, 9 H), 1.29–1.20 (m, 1 H), 1.00–0.92 (m, 1 H), 0.78 (dd, J = 9.2,

.0 Hz, 1 H), 0.38 (dd, J = 6.7, 5.0 Hz, 1 H).

To a solution of the acid cis-21 (33 mg, 0.069 mmol) in CH Cl –MeOH

2

(7:1, 0.7 mL) was slowly added a 2 M solution TMSCHN₂in hexanes

13

C NMR (100 MHz, CDCl ): δ = 158.0, 156.7, 144.2, 141.4, 127.8,

(36 μL, 0.072 mmol). The solution was stirred at r.t. for 15 min then

opened to the air. After evaporation of solvents under reduced pres-

sure, the crude product was purified by flash chromatography (silica

gel, cyclohexane–EtOAc, 70:30) to afford the methyl ester (32 mg,

3

127.1, 125.2, 120.0, 80.5, 66.8, 66.7, 47.4, 40.8, 38.7, 29.7, 28.5, 26.9,

26.8, 19.1.

+

HRMS (CI-NH ): m/z [M + H] calcd for C₂₇H₃₅N O : 467.2546; found:

3

2

5

9

4%) as a colorless oil; R = 0.20 (cyclohexane–EtOAc, 70:30).

f

467.2549.

IR (neat): 2993, 2922, 1695, 1513, 1449, 1366, 1247, 1162, 1047 cm^–¹

.

1

tert-Butyl trans-2-{3-[(9H-Fluoren-9-ylmethoxycarbonyl)ami-

no]propyl}-1-(hydroxymethyl)cyclopropylcarbamate (trans-17)

H NMR (200 MHz, CDCl ): δ = 7.77 (dd, J = 6.7, 0.8 Hz, 2 H), 7.60 (dd,

3

J = 7.2, 0.8 Hz, 2 H), 7.40 (td, J = 7.2, 1.1 Hz, 2 H), 7.33 (td, J = 7.3, 1.4

Hz, 2 H), 5.14 (br s, 1 H), 5.02 (br s, 1 H), 4.38 (d, J = 6.7 Hz, 2 H), 4.21

Applying the previous procedure 1 on trans-16 (1.0 g, 1.94 mmol) af-

forded trans-17 (253 mg, 28%)) and applying the procedure 2 on

trans-20 (638 mg, 2.61 mmol) afforded trans-17 (908 mg, 75%) as a

(t, J = 6.7 Hz, 1 H), 3.71 (s, 3 H), 3.22 (br s, 2 H), 1.70–1.00 (m, 15 H),

0

.85 (br s, 1 H).

13

pale yellow oil; R = 0.21 (cyclohexane–EtOAc, 50:50).

C NMR (50 MHz, CDCl ): δ = 172.5. 156.6. 156.1, 144.2, 141.4, 127.8,

f

3

1

27.2, 125.2, 120.1, 80.2, 66.7, 52.5. 47.4, 40.8, 38.8, 31.6, 28.4, 27.1,

IR (neat): 3341, 2970, 2931, 2861, 1738, 1692, 1537, 1510, 1463,

–1

24.5, 23.6.

1448, 1366, 1231, 1217, 1165, 1046 cm .

+

1

HRMS (CI-NH ): m/z [M + H] calcd for C₂₈H₃₅N O : 495.2495; found:

H NMR (400 MHz, CDCl ): δ = 7.77 (d, J = 7.5 Hz, 2 H), 7.60 (d, J = 7.5

3

2

6

3

495.2462.

Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.32 (t, J = 7.5 Hz, 2 H), 4.99 (br s, 1 H),

.90 (br s, 1 H), 4.41 (d, J = 6.8 Hz, 2 H), 4.22 (t, J = 6.8 Hz, 1 H), 3.73 (d,

J = 11.2 Hz, 1 H), 3.70 (br s, 1 H), 3.42 (d, J = 11.2 Hz, 1 H), 3.28–3.22

m, 2 H), 1.71–1.64 (m, 2 H), 1.61–1.55 (m, 1 H), 1.40 (s, 9 H), 1.32–

.26 (m, 1 H), 1.10–1.01 (m, 1 H), 0.96 (dd, J = 8.7, 5.6 Hz, 1 H), 0.42 (t,

4

trans-1-[(tert-Butoxycarbonyl)amino]-2-{3-[(9H-fluoren-9-yl-

methoxycarbonyl)amino]propyl}cyclopropanecarboxylic Acid

(trans-21)

(

1

18

J = 5.6 Hz, 1 H).

Using trans-17 (220 mg, 0.47 mmol), the oxidation procedure de-

scribed using the alcohol cis-17 afforded trans-21 as a beige solid

1

H NMR (400 MHz, DMSO-d , 363 K): δ = 7.85 (d, J = 7.5 Hz, 2 H), 7.66

6

18

(

d, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.32 (t, J = 7.5 Hz, 2 H), 6.78

br s, 1 H), 6.31 (br s, 1 H), 4.31 (d, J = 6.8 Hz, 2 H), 4.22 (t, J = 6.8 Hz, 1

(160 mg, 71%); mp 96–98 °C (Lit. 97–98 °C); R = 0.40 (EtOAc).

f

1

H NMR (200 MHz, CDCl ): δ = 8.91 (br s, 1 H), 7.76 (d, J = 7.3 Hz, 2 H),

3

H), 3.48 (d, J = 11.0 Hz, 1 H), 3.34 (d, J = 11.0 Hz, 1 H), 3.25 (br s, 1 H),

7

.59 (d, J = 6.7 Hz, 2 H), 7.45–7.25 (m, 4 H), 5.08 (br s, 1 H), 4.53–4.29

m, 2 H), 4.24 (m, 1 H), 3.30–3.03 (br s, 2 H), 1.80–1.22 (m, 15 H), 0.87

m, 1 H).

3.02 (m, 2 H), 1.57–1.45 (m, 3 H), 1.40 (s, 9 H), 1.16–1.07 (m, 1 H),

(

1

0.89–0.82 (m, 1 H), 0.78 (dd, J = 8.8, 5.5 Hz, 1 H), 0.33 (t, J = 5.5 Hz, 1

H).

H NMR (200 MHz, DMSO-d ): δ = 12.19 (br s, 1 H), 7.89 (d, J = 6.9 Hz,

6

13

C NMR (100 MHz, CDCl ): δ = 158.0, 156.5, 144.0, 141.3, 127.7,

3

2 H), 7.68 (d, J = 6.9 Hz, 2 H), 7.46–7.21 (m, 6 H), 4.38–4.16 (m, 3 H),

.13–2.87 (br s, 2 H), 1.66–0.95 (m, 14 H), 0.85 (m, 1 H), 0.69 (br s, 1

H).

127.1, 125.1, 120.0, 80.3, 70.8, 66.7, 47.4, 40.8, 39.6, 30.0, 28.4, 25.5,

3

23.3, 18.4.

+

HRMS (CI-NH ): m/z [M + H] calcd for C27^H N O : 467.2546; found:

13

3

35

2

5

C NMR (100 MHz, CDCl ): δ = 178.5, 156.7, 144.1, 141.4, 127.8,

3

467.2530.

127.1, 125.2, 120.0, 80.2, 66.7, 47.4, 40.8, 38.2, 29.5. 28.4. 25.4, 22.8.

cis-1-[(tert-Butoxycarbonyl)amino]-2-{3-[(9H-fluoren-9-ylmeth-

oxycarbonyl)amino]propyl}cyclopropanecarboxylic Acid (cis-

tert-Butyl 1-[(Benzyloxy)methyl]-2-azabicyclo[4.1.0]heptane-2-

carboxylate (22)

27

21); Typical Procedure

To a solution of the mesylate trans-13 (205 mg, 0.50 mmol) in THF (5

mL) cooled to 0 °C was added NaH (80 mg, 60% in oil, 2 mmol). The

solution was stirred overnight at r.t. and water (5 mL) was added. The

solution was acidified by the addition of 1 M aq HCl and the aqueous

phase was extracted with EtOAc (3 × 5 mL). The combined organic ex-

^T^o^a^s^o^l^u^tⁱ^oⁿ^o^f^t^h^e^a^l^c^o^h^o^l^cⁱ^s^-¹⁷⁽¹⁵⁰^m^g^,⁰^.³²^m^m^o^l⁾ⁱⁿ^C^C^l4^–

MeCN–H O (2:2:3, 5 mL) were successively added NaIO (413 mg,

2

4

1

.93 mmol) and RuO ·H O (5 mg, 0.03 mmol). The solution was

2 2

stirred at r.t. for 1 h and water (3 mL) was added. The aqueous phase

was extracted with CH Cl (3 × 3 mL) and the combined organic ex-

2

tracts were washed with brine, dried (MgSO ), and filtered. After con-

4

tracts were dried (MgSO ) and filtered. After concentration under re-

4

centration under reduced pressure, the crude residue was purified by

flash chromatography (silica gel, cyclohexane–EtOAc, 95:5) to afford

duced pressure, the crude product was purified by flash chromatogra-

phy (silica gel, 100% EtOAc) to afford the acid cis-21 (115 mg, 75%) as

the bicyclic product 22 (109 mg, 69%) as a colorless oil; R = 0.23 (cy-

f

a beige solid, which was recrystallized (CH Cl –petroleum ether); mp

2

clohexane–EtOAc, 70:30).

>

300 °C; R = 0.40 (EtOAc).

f

IR (neat): 3063, 3003, 2972, 2931, 2860, 1691, 1496, 1477, 1453,

IR (neat): 3371, 2970, 1698, 1514, 1449, 1392, 1367, 1249, 1162, 1048

–1

1390, 1363, 1164, 1092, 1070 cm

.

–1

cm

.

1

H NMR (400 MHz, CDCl ): δ (70:30 mixture of rotamers) = 7.36–7.23

3

1

H NMR (200 MHz, MeOH-d ): δ = 7.89 (d, J = 7.6 Hz, 2 H), 7.64 (d, J =

4

(m, 5 H), 4.58–4.48 (m, 2 H), 4.32 (d, J = 10.8 Hz, 0.3 H), 4.14 (d, J =

7.4 Hz, 2 H), 7.44–7.25 (m, 4 H), 4.33 (d, J = 7.1 Hz, 2 H), 4.19 (m, 1 H),

1

(

0.3 Hz, 0.7 H), 3.90 (dt, J = 12.7, 4.0 Hz, 0.7 H), 3.74 (m, 0.3 H), 3.26

d, J = 10.8 Hz, 0.3 H), 2.92 (d, J = 10.3 Hz, 0.7 H), 2.75 (m, 0.3 H), 2.65

(m, 0.7 H), 1.96 (m, 1 H), 1.74 (m, 1 H), 1.58 (m, 1 H), 1.47 (s, 0.9 H),

3

.13 (br s, 2 H), 1.70–1.00 (m, 15 H), 0.72 (br s, 1 H).

+

•

HRMS (EI): m/z [M ] calcd for C₂₇H₃₂N O : 480.2260; found:

2

6

480.2279.

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

1

002

Synthesis

G. Forcher et al.

Paper

1

1.45 (s, 2.1 H), 1.44 (s, 1.8 H), 1.42 (s, 4.2 H), 1.29–1.20 (m, 2 H), 0.93

H NMR (400 MHz, CDCl ): δ = 5.15 (br s, 1 H), 4.47–4.35 (m, 2 H),

3

(

0

m, 0.3 H), 0.85 (m, 0.7 H), 0.51 (t, J = 6.3 Hz, 0.3 H), 0.43 (t, J = 6.3 Hz,

.7 H).

3.93 (d, J = 12.0 Hz, 1 H), 3.72 (br s, 1 H), 3.52 (d, J = 12.0 Hz, 1 H), 3.04

(s, 3 H), 2.04–1.83 (m, 2 H), 1.43 (s, 9 H), 1.25 (m, 1 H), 0.99 (dd, J = 9.5

Hz, 5.6 Hz, 1 H), 0.60 (t, J = 5.6 Hz, 1 H).

1

H NMR (400 MHz, DMSO-d , 363 K): δ = 7.36–7.24 (m, 5 H), 4.52 (d,

6

13

J = 12.1 Hz, 1 H), 4.48 (d, J = 12.1 Hz, 1 H), 4.12 (d, J = 10.3 Hz, 1 H),

C NMR (100 MHz, CDCl ): δ = 157.5, 80.0, 70.2, 66.0, 38.1, 37.1, 29.0,

3

3.71 (m, 1 H), 2.99 (d, J = 10.3 Hz, 1 H), 2.61 (m, 1 H), 1.93 (m, 1 H),

28.3, 22.7, 18.1.

1

.63 (m, 1 H), 1.53 (m, 1 H), 1.41 (s, 3 H), 1.40 (s, 6 H), 1.25–1.16 (m, 2

+

HRMS (ESI): m/z [M + Na] calcd for C₁₂H₂₃NNaO S: 332.1138; found:

6

H), 0.88 (m, 1 H), 0.41 (t, J = 6.3 Hz, 1 H).

332.1127.

13

C NMR (100 MHz, CDCl ): δ (70:30 mixture of rotamers) = 156.5

3

To a solution of the previous mesylate intermediate (506 mg, 1.63

mmol) in MeCN (16 mL) was added NaN₃(266 mg, 4.1 mmol). The

mixture was refluxed overnight then water (10 mL) was added. The

aqueous phase was extracted with EtOAc (3 × 5 mL) and the com-

bined organic fractions were washed with brine, dried (MgSO ), and

filtered. After concentration under reduced pressure, the crude resi-

due was purified by column chromatography (silica gel, cyclohexane–

(

0.7 C), 155.5 (0.3 C), 139.0 (0.3 C), 138.8 (0.7 C), 128.4 (1.4 C), 128.4

0.6 C), 127.5 (0.9 C), 127.4 (2.1 C), 79.3 (0.7 C), 79.3 (0.3 C), 75.3 (0.7

C), 74.9 (0.3 C), 73.1 (0.3 C), 72.9 (0.7 C), 43.4 (0.3 C), 41.9 (0.7 C), 38.4

0.3 C), 38.0 (0.7 C), 28.6 (0.7 C), 22.3 (0.3 C), 22.1 (0.3 C), 21.8 (0.7 C),

1.3 (0.7 C), 18.5 (0.7 C), 18.1 (0.3 C), 17.4 (0.7 C), 16.8 (0.3 C).

(

2

4

+

•

HRMS (EI): m/z [M ] calcd for C₁₉H₂₇NO : 317.1991; found: 317.1971.

3

EtOAc, 60:40) to afford cis-24 (346 mg, 82%) as a colorless oil; R =

f

0

.18 (cyclohexane–EtOAc, 70:30).

cis-2-{2-[(Benzyloxy)methyl]-2-[(tert-butoxycarbonyl)amino]cy-

clopropyl}ethyl Methanesulfonate (cis-23)

IR (neat): 3500–3300, 2101, 1685, 1503, 1453, 1391, 1365, 1247,

1163, 1100, 1025 cm .

–1

To a solution of cis-12 (1.05 g, 3.30 mmol) in CH Cl –MeOH (1:1, 33

2

mL) cooled to –60 °C was bubbled O until blue coloration appeared;

1

3

H NMR (400 MHz, CDCl ): δ = 5.12 (br s, 1 H), 3.91 (d, J = 11.9 Hz, 1

3

excess O was removed from the flask by an argon flow. NaBH (373

3

4

H), 3.69 (m, 1 H), 3.57–3.42 (m, 3 H), 1.90–1.55 (m, 2 H), 1.43 (s, 9 H),

mg, 10 mmol) was added at –60 °C and the mixture was stirred over-

night at r.t. Water (50 mL) was then slowly added and the aqueous

phase was extracted with CH Cl (3 × 20 mL). The combined organic

1

5

.25–1.10 (m, 1 H), 0.97 (dd, J = 9.4 Hz, 5.7 Hz, 1 H), 0.57 (dd, J = 6.2,

.7 Hz, 1 H).

2

13

C NMR (100 MHz, CDCl ): δ = 157.7, 80.5, 66.6, 51.5, 38.6, 29.1, 28.4,

3

extracts were washed with brine, dried (MgSO ), filtered, and con-

4

24.4, 18.6.

centrated under reduced pressure. The crude alcohol intermediate

was dissolved in CH Cl (15 mL) and the resulting solution was cooled

+

HRMS (ESI): m/z [M + Na] calcd for C11^H N NaO : 279.1428; found:

20

4

3

2

279.1435.

to –10 °C. Et N (0.81 mL, 5.94 mmol) then MsCl (0.28 mL, 3.63 mmol)

3

were slowly added and the mixture was allowed to warm up to r.t.

Water (20 mL) was added and the aqueous phase was extracted with

CH Cl (3 × 5 mL) and the combined organic extracts were dried

tert-Butyl cis-2-{2-[(9H-Fluoren-9-ylmethoxycarbonyl)ami-

no]ethyl}-1-(hydroxymethyl)cyclopropylcarbamate (cis-25)

2

(

MgSO ), filtered, and concentrated under reduced pressure. Purifica-

4

To a solution of cis-24 (294 mg, 1.15 mmol) in MeOH (11 mL) were

successively added 10% Pd/C (74 mg, 25 wt%) and ammonium for-

mate (360 mg, 5.75 mmol). The mixture was refluxed for 30 min then

allowed to cool to r.t. After filtration through a pad of Celite and con-

centration under reduced pressure, the crude amine was dissolved in

tion by flash chromatography (silica gel, cyclohexane–EtOAc, 80:20)

afforded cis-23 (790 mg, 60%) as a white solid; mp 81–86 °C; R = 0.18

f

(cyclohexane–EtOAc, 70:30).

IR (neat): 3410, 2978, 2941, 2902, 1691, 1497, 1395, 1350, 1248,

1

–1

169, 1076 cm

.

dioxane–H O (1:1, 12 mL) and Na CO (1.96 g, 18.5 mmol) was added.

2

3

1

The solution was cooled to 0 °C and FmocCl (327 mg, 1.26 mmol) was

added. The mixture was stirred overnight at r.t. and solvents were

evaporated under reduced pressure. The residue was taken up in wa-

ter (10 mL) and CH Cl (10 mL) and the aqueous phase was extracted

H NMR (400 MHz, CDCl ): δ = 7.39–7.27 (m, 5 H), 5.15 (br s, 1 H),

.56 (d, J = 12.0 Hz, 1 H), 4.49 (d, J = 12.0 Hz, 1 H), 4.41–4.27 (m, 2 H),

.69 (d, J = 10.4 Hz, 1 H), 3.43 (d, J = 10.4 Hz, 1 H), 2.97 (s, 3 H), 1.79

3

4

3

2

(br s, 2 H), 1.41 (s, 9 H), 1.24–1.11 (m, 1 H), 1.11–1.00 (m, 1 H), 0.58 (t,

with CH Cl (2 × 10 mL). The combined organic extracts were dried

2

J = 6.1 Hz, 1 H).

(

MgSO ) and filtered. After concentration under reduced pressure, the

4

13

C NMR (100 MHz, CDCl ): δ = 155.6, 138.3, 128.6, 127.9, 127.8, 79.6,

3

crude product was purified by flash chromatography (silica gel, cyclo-

hexane–EtOAc, 50:50) to afford cis-25 (360 mg, 70%) as a white solid;

7

3.4, 71.7, 70.0, 37.4, 36.7, 29.1, 28.5, 21.9, 18.2.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₉H₃₀NO S: 400.1788; found:

mp 124–126 °C; R = 0.24 (cyclohexane–EtOAc, 50:50).

6

f

400.1789.

IR (neat): 3300, 2900, 1678, 1518, 1478, 1448, 1391, 1365, 1249,

–1

1163, 1104, 1059, 1019 cm .

tert-Butyl cis-2-(2-Azidoethyl)-1-(hydroxymethyl)cyclopropylcar-

bamate (cis-24)

1

H NMR (400 MHz, CDCl ): δ = 7.75 (d, J = 7.5 Hz, 2 H), 7.67–7.62 (m, 2

3

H), 7.39 (t, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 6.63 (br s, 1 H), 5.28

To a solution of cis-23 (500 mg, 1.25 mmol) in MeOH (12 mL) was

added 10% Pd/C (50 mg, 10 wt%) and the mixture was stirred at r.t.

(br s, 1 H), 4.40–4.30 (m, 2 H), 4.20 (t, J = 7.1 Hz, 1 H), 3.73 (m, 1 H),

3

.59 (m, 1 H), 3.49 (m, 1 H), 3.29 (m, 1 H), 2.78 (br s, 1 H), 1.95–1.75

under H (3 bar) for 1.5 h. After filtration on a pad of Celite and wash-

2

(m, 2 H), 1.46 (s, 9 H), 1.16 (m, 1 H), 0.90 (m, 1 H), 0.48 (t, J = 6.0 Hz, 1

H).

ing with CH Cl , the solution was concentrated under reduced pres-

2

sure to afford the debenzylated mesylate intermediate as a white sol-

13

C NMR (100 MHz, CDCl ): δ = 157.6, 157.0, 144.3, 144.2, 141.4,

3

id (386 mg, quant.); mp 81–83 °C; R = 0.18 (cyclohexane–EtOAc,

f

1

3

27.7, 127.1, 127.1, 125.4, 125.3, 120.0, 80.4, 66.7, 65.5, 47.4, 40.8,

8.5, 29.6, 28.5, 25.2, 17.6.

70:30).

IR (neat): 3272, 1672, 1528, 1474, 1347, 1170, 1028 cm^–¹

.

+

HRMS (ESI): m/z [M + Na] calcd for C₂₆H₃₂N NaO : 475.2203; found:

2

5

475.2190.

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

1

003

Synthesis

G. Forcher et al.

Paper

cis-1-[(tert-Butoxycarbonyl)amino)]-2-{2-[(9H-fluoren-9-ylmeth-

oxycarbonyl)amino]ethyl}cyclopropanecarboxylic Acid (cis-26)

tert-Butyl trans-1-[(Benzyloxy)methyl]-2-(3-cyanoallyl)cyclopro-

pylcarbamate (trans-27)

To a solution of cis-25 (73 mg, 0.16 mmol) in CCl –MeCN–H O (2:2:3,

The previous procedure was applied using trans-12 (96 mg, 0.30

mmol) and afforded trans-27 as a white solid (74 mg, 72%, ratio Z/E

4

2

2.6 mL) were successively added NaIO₄(198 mg, 0.93 mmol) and

RuO ·H O (2.4 mg, 0.02 mmol). The solution was stirred at r.t. for 1 h

3:1); mp 65–68 °C; R = 0.31 (cyclohexane–EtOAc, 80:20).

2

f

and water (1.6 mL) was added. The aqueous phase was extracted with

CH Cl (3 × 3 mL) and the combined organic extracts were dried

IR (neat): 2157, 1971, 1940, 1701, 1493, 1453, 1389, 1365, 1245,

2

1166, 1071 cm

–1

.

(

MgSO ) and filtered. After concentration under reduced pressure, the

4

1

H NMR (400 MHz, CDCl ): δ = 7.40–7.24 (m, 5 H), 6.82 (dt, J = 16.4,

3

crude product was purified by flash chromatography (silica gel,

EtOAc) to afford cis-26 (51 mg, 67%) as a white solid; mp 65–69 °C;

R_f= 0.11 (cyclohexane–EtOAc, 50:50).

5.7 Hz, 0.25 H), 6.69–6.54 (m, 0.75 H), 5.66 (dt, J = 16.4, 1.8 Hz, 0.25

H), 5.32 (m, 0.75 H), 5.04 (br s, 0.75 H), 4.95 (br s, 0.25 H), 4.54 (d, J =

12.2 Hz, 1 H), 4.51 (d, J = 12.2 Hz, 1 H), 3.69 (d, J = 9.9 Hz, 0.75 H), 3.50

IR (neat): 1692, 1507, 1449, 1392, 1336, 1249, 1160, 1103, 1048 cm^–¹

.

(d, J = 9.9 Hz, 0.25 H), 3.42 (d, J = 10.0 Hz, 0.25 H), 3.27 (d, J = 10.0 Hz,

1

H NMR (400 MHz, CDCl ): δ = 7.72 (d, J = 7.5 Hz, 2 H), 7.61–7.59 (m, 2

0.75 H), 2.66–2.26 (m, 2 H), 1.44 (s, 6.75 H), 1.43 (s, 2.25 H), 1.07–0.96

3

H), 7.35 (t, J = 7.5 Hz, 2 H), 7.26 (dt, J = 7.5, 1.1 Hz, 2 H), 5.98 (br s, 1 H),

(m, 1.5 H), 0.95–0.84 (m, 0.5 H), 0.64–0.52 (m, 1 H).

5

.20 (br s, 1 H), 4.39–4.31 (m, 1 H), 4.17 (t, J = 6.9 Hz, 2 H), 3.38–3.17

13

C NMR (100 MHz, CDCl ): δ (Z-isomer) = 156.0, 154.3, 138.3, 128.5,

3

(m, 2 H), 1.93–1.82 (m, 1 H), 1.77–1.67 (m, 1 H), 1.60–1.52 (m, 1 H),

127.8, 127.7, 116.0, 99.6, 79.8, 74.3, 73.2, 37.7, 30.7, 28.4, 21.4, 16.7; δ

1.45 (s, 9 H), 1.36–1.33 (m, 1 H), 1.16 (ddt, J = 9.6, 4.8 Hz, 1 H), 0.96–

(

E-isomer) = 156.0, 154.9, 138.2, 128.6, 127.9, 127.6, 117.7, 100.2,

0.81 (m, 1 H).

79.9, 74.8, 73.3, 37.3, 31.9, 28.4, 20.0, 17.0.

13

C NMR (100 MHz, CDCl ): δ = 177.0, 157.1, 157.0, 144.5, 144.4,

+

3

HRMS (ESI): m/z [M + Na] calcd for C₂₀H₂₆N NaO : 365.1836; found:

2

3

141.4, 141.3, 127.7, 127.7, 127.3, 127.2, 125.7, 125.5, 119.9, 119.9,

365.1829.

80.6, 66.7, 47.5, 40.4, 31.6, 29.8, 28.4, 27.2, 22.8.

+

HRMS (ESI): m/z [M + Na] calcd for C 6^H N NaO : 489.1996; found:

2

30

2

6

tert-Butyl cis-1-[(Benzyloxy)methyl]-2-(3-cyanopropyl)cyclopro-

pylcarbamate (cis-28)

489.1985.

To a solution of cis-27 (100 mg, 0.29 mmol) in MeOH (5 mL) was add-

ed 10% Pd/C (10 mg, 10 wt%) and the mixture was stirred at r.t. under

H₂(30 bar) for 72 h. After filtration on a pad of Celite and washing

with EtOAc, the solution was concentrated under reduced pressure to

tert-Butyl cis-1-[(Benzyloxy)methyl]-2-(3-cyanoallyl)cyclopropyl-

carbamate (cis-27); Typical Procedure

To a Schlenk tube filled with argon was introduced cis-12 (464 mg,

1.46 mmol). After several vacuum–refill cycles, anhydrous and de-

afford pure cis-28 (102 mg, quant.) as a colorless oil; R = 0.27 (cyclo-

f

gassed CH Cl (14 mL, 0.1 M/substrate) then acrylonitrile (180 μL,

hexane–EtOAc, 80:20).

2

.70 mmol) were added. A solution of 2nd generation Hoveyda–

_I_R₍_n_e_a_t₎_:₃₃₃₄_,₂₉₃₀_,₁₇₀₈_,₁₄₉₄_,₁₃₆₄_,₁₂₄₅_,₁₁₆₅_,₁₀₇₁_c_m–1

.

Grubbs catalyst (42 mg, 0.05 mmol) in CH Cl (1 mL) was prepared

2

1

H NMR (400 MHz, CDCl ): δ = 7.37–7.26 (m, 5 H), 5.14 (br s, 1 H),

3

under an argon atmosphere and was transferred into the Schlenk

tube. The mixture was heated at 45 °C overnight under an argon at-

mosphere and the green solution turned to dark red. After cooling

down to r.t., ethyl vinyl ether (1 mL) was added to the mixture and the

solution was concentrated under reduced pressure. The black oil was

purified by column chromatography (silica gel, cyclohexane–EtOAc,

4.55 (d, J = 12.1 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 3.60 (d, J = 10.1 Hz,

1

H), 3.52 (d, J = 10.1 Hz, 1 H), 2.39 (t, J = 6.9 Hz, 2 H), 1.84–1.78 (m, 2

H), 1.60–1.50 (m, 1 H), 1.49–1.42 (m, 1 H), 1.42 (s, 9 H), 1.11–1.04 (m,

H), 1.03–0.97 (m, 1 H), 0.51 (br t, J = 5.8 Hz, 1 H).

¹³C NMR (100 MHz, CDCl

): δ = 155.7, 138.4, 128.6, 127.8, 119.9, 79.5,

1

3

80:20) to afford cis-27 as a colorless oil (394 mg, 79%, ratio Z/E 3:1);

73.3, 71.6, 36.8, 28.5, 28.3, 25.3, 24.8, 18.5, 16.9.

^Rf ⁼⁰^.³⁴⁽^c^y^c^l^o^h^e^x^aⁿ^e^–^E^t^O^A^c^,⁸⁰^:²⁰⁾^.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₀H₂₉N O : 345.2173; found:

2

3

IR (neat): 2157, 1971, 1940, 1701, 1493, 1453, 1389, 1365, 1245,

345.2170.

–1

1166, 1071 cm .

1

tert-Butyl trans-1-[(Benzyloxy)methyl]-2-(3-cyanopropyl)cyclo-

propylcarbamate (trans-28)

H NMR (400 MHz, CDCl ): δ = 7.37–7.27 (m, 5 H), 6.81 (dt, J = 16.4,

.2 Hz, 0.3 H), 6.76–6.61 (m, 0.7 H), 5.63–5.53 (m, 0.3 H), 5.33 (dt, J =

3

6

10.9, 1.5 Hz, 0.7 H), 5.15 (br s, 1 H), 4.58 (d, J = 12.2 Hz, 0.3 H), 4.55 (d,

To a solution of trans-27 (100 mg, 0.29 mmol) in MeOH (5 mL) was

J = 12.2 Hz, 0.7 H), 4.51 (d, J = 12.2 Hz, 0.7 H), 4.49 (d, J = 12.2 Hz, 0.3

H), 3.68 (d, J = 10.5 Hz, 0.7 H), 3.63 (d, J = 10.5 Hz, 0.3 H), 3.49 (d, J =

added 10% Pd/C (10 mg, 10 wt%) and the mixture was stirred at r.t.

under H (30 bar) for 72 h. After filtration on a pad of Celite and wash-

2

10.5 Hz, 0.7 H), 3.44 (d, J = 10.5 Hz, 0.3 H), 2.60–2.47 (m, 0.7 H), 2.46–

2.30 (m, 1 H), 2.20–2.13 (m, 0.3 H), 1.43 (s, 2.7 H), 1.42 (s, 6.3 H),

1.25–1.18 (m, 0.7 H), 1.17–1.12 (m, 0.3 H), 1.11–1.02 (m, 1 H), 0.63 (t,

ing with EtOAc, the solution was concentrated under reduced pres-

sure to afford pure trans-28 (102 mg, quant.) as a colorless oil; R =

f

0.26 (cyclohexane–EtOAc, 80:20).

J = 6.2 Hz, 0.7 H), 0.57 (t, J = 6.0 Hz, 0.3 H).

_I_R₍_n_e_a_t₎_:₃₃₄₀_,₂₉₃₀_,₁₇₀₄_,₁₄₉₅_,₁₃₆₅_,₁₂₄₃_,₁₁₆₅_,₁₀₇₂_c_m–1

.

13

C NMR (100 MHz, CDCl ): δ (Z-isomer) = 157.6, 154.3, 138.2, 128.6,

1

3

H NMR (400 MHz, CDCl ): δ = 7.36–7.25 (m, 5 H), 4.95 (br s, 1 H),

3

127.9, 127.8, 116.1, 99.7, 79.6, 73.4, 71.5, 36.9, 31.6, 28.5, 23.8, 18.3; δ

4.52 (s, 2 H), 3.55 (d, J = 9.5 Hz, 1 H), 3.37 (d, J = 9.5 Hz, 1 H), 2.40–2.36

(

E-isomer) = 157.6, 153.9, 138.1, 128.6, 127.9, 127.8, 116.1, 100.5,

(m, 2 H), 1.82–1.75 (m, 3 H), 1.43 (s, 9 H), 1.42–1.36 (m, 1 H), 0.95 (dd,

79.6, 73.4, 71.4, 36.9, 32.8, 28.5, 22.9, 18.3.

J = 8.9, 5.3 Hz, 1 H), 0.91–0.87 (m, 1 H), 0.51 (br s, 1 H).

+

HRMS (ESI): m/z [M + Na] calcd for C 0^H N NaO : 365.1836; found:

13

2

26

2

3

C NMR (100 MHz, CDCl ): δ = 156.1, 138.4, 128.5, 127.8, 127.7,

3

365.1835.

119.8, 79.7, 74.8, 73.2, 37.4, 28.4, 27.2, 25.4, 22.1, 17.1, 17.0.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₀H₂₉N O : 345.2173; found:

2

3

345.2172.

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

1

004

Synthesis

G. Forcher et al.

Paper

Methyl (E)-4-{cis-2-[(Benzyloxy)methyl]-2-[(tert-butoxycarbon-

yl)amino]cyclopropyl}but-2-enoate (cis-29)

IR (neat): 3392, 2973, 2932, 2863, 1708, 1495, 1351, 1245, 1168, 1073

–1

cm

.

1

To a Schlenk tube filled with argon was introduced cis-12 (969 mg,

.05 mmol). After several vacuum–refill cycles, anhydrous and de-

gassed CH Cl (27.5 mL) then methyl acrylate (2.76 mL, 30.5 mmol)

H NMR (400 MHz, CDCl ): δ = 7.37–7.25 (m, 5 H), 5.13 (br s, 1 H),

3

4.55 (d, J = 12.2 Hz, 1 H), 4.50 (d, J = 12.2 Hz, 1 H), 4.20 (t, J = 6.6 Hz, 2

H), 3.62 (d, J = 9.9 Hz, 1 H), 3.49 (d, J = 9.9 Hz, 1 H), 2.97 (s, 3 H), 1.78–

1.73 (m, 2 H), 1.59–1.54 (m, 3 H), 1.42 (s, 9 H), 1.20–1.13 (m, 1 H),

1.10–1.02 (m, 1 H), 0.99–0.96 (m, 1 H), 0.46 (t, J = 5.7 Hz, 1 H).

13

2

were added. A solution of 2nd generation Hoveyda–Grubbs catalyst

96 mg, 0.15 mmol) in CH Cl (2.5 mL) was prepared under an argon

(

2

atmosphere and was transferred into the Schlenk tube. The mixture

was heated at 45 °C overnight under an argon atmosphere; the green

solution became dark red. After cooling to r.t., ethyl vinyl ether (1 mL)

was added to the mixture and the solution was concentrated under

reduced pressure. The black solid was purified by column chromatog-

raphy (silica gel, cyclohexane–EtOAc, 90:10) to afford cis-29 as a

C NMR (100 MHz, CDCl ): δ = 155.6, 138.5, 128.5, 127.7, 79.3, 73.2,

3

7

1.8, 70.1, 37.5, 36.8, 29.0, 28.7, 28.5, 25.5, 18.6.

HRMS (ESI): m/z [M + H]⁺^c^a^l^c^d^f^o^r^C21^H34NO S: 428.2101; found:

4

6

28.2103.

white solid (1.0 g, 87%); mp 51–54 °C; R = 0.37 (cyclohexane–EtOAc,

tert-Butyl cis-2-(4-Azidobutyl)-1-(hydroxymethyl)cyclopropylcar-

bamate (cis-31)

f

80:20).

To a solution of the mesylate cis-30 (462 mg, 1.08 mmol) in MeOH (10

mL) was added 10% Pd/C (46 mg, 10 wt%) and the mixture was stirred

IR (neat): 1720, 1684, 1649, 1499, 1365, 1247, 1164, 1090, 1070, 1028

–1

cm

.

at r.t. under H (3 bar) for 1.5 h. After filtration on a pad of Celite and

1

2

H NMR (400 MHz, CDCl ): δ = 7.37–7.27 (m, 5 H), 7.03 (dt, J = 15.7,

3

washing with CH Cl , the solution was concentrated under reduced

2

6

.4 Hz, 1 H), 5.91 (d, J = 15.7 Hz, 1 H), 5.14 (br s, 1 H), 4.55 (d, J = 12.1

Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 3.72 (s, 3 H), 3.71 (d, J = 10.4 Hz, 1

H), 3.41 (d, J = 10.4 Hz, 1 H), 2.54–2.41 (m, 1 H), 2.07–1.96 (m, 1 H),

pressure to afford the debenzylated mesylate intermediate as a color-

less oil (367 mg, quant.); R = 0.13 (cyclohexane–EtOAc, 70:30).

f

IR (neat): 3389, 2933, 1683, 1503, 1348, 1248, 1166, 1024 cm^–¹

.

1.42 (s, 9 H), 1.20–1.13 (m, 1 H), 1.12–1.04 (m, 1 H), 0.56 (t, J = 5.9 Hz,

1

H).

H NMR (400 MHz, CDCl ): δ = 5.22 (br s, 1 H), 4.20 (t, J = 6.5 Hz, 2 H),

3

1

3

3.77 (d, J = 11.5 Hz, 1 H), 3.77–3.60 (br s, 1 H), 3.50 (d, J = 11.5 Hz, 1

H), 2.97 (s, 3 H), 1.80–1.72 (m, 2 H), 1.71–1.61 (m, 1 H), 1.58–1.51 (m,

C NMR (100 MHz, CDCl ): δ = 167.1, 155.6, 147.9, 138.2, 128.5,

3

1

27.8, 121.4, 79.5, 73.3, 71.6, 51.5, 36.8, 31.6, 28.5, 23.5, 18.4.

2

9

H), 1.39 (s, 9 H), 1.32–1.22 (m, 2 H), 1.10–1.02 (m, 1 H), 0.87 (dd, J =

.2, 5.5 Hz, 1 H), 0.47 (t, J = 5.5 Hz, 1 H).

+

HRMS (ESI): m/z [M + Na] calcd for C₂₁H₂₉NNaO : 398.1938; found:

3

5

98.1954.

13

C NMR (100 MHz, CDCl ): δ = 157.9, 80.2, 70.1, 66.8, 38.5, 37.4, 28.9,

3

2

8.8, 28.4, 26.8, 25.5, 18.9.

4

-{cis-2-[(Benzyloxy)methyl]-2-[(tert-butoxycarbonyl)amino]cy-

+

clopropyl]butyl Methanesulfonate (cis-30)

HRMS (ESI): m/z [M + Na] calcd for C14

H

27NNaO

S: 360.1451; found:

6

360.1451.

To a solution of cis-29 (665 mg, 1.77 mmol) in THF (30 mL) cooled at 0

°

C was added LiAlH₄(107 mg, 2.83 mmol). After 15 min at 0 °C the

To a solution of the previous mesylate intermediate (367 mg, 1.08

mixture was stirred at r.t. for 2 h. The excess of LiAlH was destroyed

mmol) in MeCN (10.5 mL) was added NaN (176 mg, 2.7 mmol). The

4

3

by addition of EtOAc (6 mL) then water (0.6 mL). The resulting sus-

pension was stirred for 15 min and Na SO was added. After filtration

mixture was refluxed overnight then water (6 mL) was added. The

aqueous phase was extracted with EtOAc (3 × 5 mL) and the com-

2

4

on a pad of Celite and washing with EtOAc, the solution was concen-

trated under reduced pressure to afford the pure saturated alcohol

bined organic fractions were washed with brine, dried (MgSO ), and

filtered. After concentration under reduced pressure, the crude resi-

due was purified by column chromatography (silica gel, cyclohexane–

4

(

616 mg, quant.) as a colorless oil; R = 0.11 (cyclohexane–EtOAc,

f

80:20).

EtOAc, 70:30) to afford cis-31 (252 mg, 82%) as a colorless oil; R =

f

0

.31 (cyclohexane–EtOAc, 60:40).

IR (neat): 3397, 2929, 2862, 1694, 1495, 1453, 1389, 1247, 1166,

–1

1070, 1028 cm .

IR (neat): 3329, 2975, 2932, 2862, 2092, 1682, 1495, 1454, 1391,

1365, 1247, 1164, 1101, 1024 cm .

–

1

H NMR (400 MHz, CDCl ): δ = 7.37–7.27 (m, 5 H), 5.15 (br s, 1 H),

3

1

4.56 (d, J = 12.1 Hz, 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 3.67–3.50 (m, 3 H),

H NMR (400 MHz, CDCl ): δ = 5.11 (br s, 1 H), 3.80 (d, J = 10.2 Hz, 1

3

.53 (d, J = 10.1 Hz, 1 H), 1.82 (br s, 1 H), 1.65–1.54 (m, 2 H), 1.54–1.45

H), 3.61 (br s, 1 H), 3.60 (d, J = 10.2 Hz, 1 H), 3.27 (t, J = 6.8 Hz, 2 H),

1.73–1.59 (m, 3 H), 1.58–1.48 (m, 2 H), 1.42 (s, 9 H), 1.27 (dt, J = 14.7,

7.1 Hz, 1 H), 1.09 (ddd, J = 14.7, 9.0, 6.0 Hz, 1 H), 0.89 (dd, J = 9.0, 6.0

Hz, 1 H), 0.50 (t, J = 6.0 Hz, 1 H).

(m, 2 H), 1.45–1.37 (m, 10 H), 1.24–1.16 (m, 1 H), 1.13–1.03 (m, 1 H),

0.97–0.91 (m, 1 H), 0.45 (t, J = 5.9 Hz, 1 H).

13

C NMR (100 MHz, CDCl ): δ = 155.7, 138.5, 128.5, 127.8, 127.7, 79.4,

3

13

73.3, 71.9, 62.9, 36.8, 32.5, 29.1, 28.5, 27.0, 25.7, 18.7.

C NMR (100 MHz, CDCl ): δ = 158.0, 80.4, 67.0, 51.5, 38.6, 29.1, 28.7,

3

+

28.5, 27.0, 26.8, 19.1.

HRMS (ESI): m/z [M + Na] calcd for C₂₀H₃₁NNaO : 372.2145; found:

4

+

372.2141.

HRMS (ESI): m/z [M + Na] calcd for C₁₃H₂₄N NaO : 307.1753; found:

4

3

307.1741.

The crude alcohol intermediate was dissolved in CH Cl (12 mL) and

2

the resulting solution was cooled to –10 °C. Et N (434 μL, 3.19 mmol)

3

then MsCl (151 μL, 1.95 mmol) were slowly added and the mixture

was allowed to warm up to r.t. Water (16 mL) was added and the

aqueous phase was extracted with CH Cl (3 × 5 mL) and the com-

tert-Butyl cis-2-{4-[(9H-Fluoren-9-ylmethoxycarbonyl)amino]bu-

tyl}-1-(hydroxymethyl)cyclopropylcarbamate (cis-32)

2

To a solution of cis-31 (252 mg, 0.89 mmol) in MeOH (8.5 mL) were

successively added 10% Pd/C (25 mg, 10 wt %) and ammonium for-

mate (279 mg, 4.43 mmol). The mixture was refluxed for 30 min then

allowed to cool to r.t. After filtration through a pad of Celite and con-

centration under reduced pressure, the crude amine was dissolved in

bined organic extracts were dried (MgSO ), filtered, and concentrated

4

under reduced pressure. Purification by flash chromatography (silica

gel, cyclohexane–EtOAc, 80:20) afforded cis-30 (491 mg, 65%) as a

colorless oil; R = 0.21 (cyclohexane–EtOAc, 70:30).

f

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

1

005

Synthesis

G. Forcher et al.

Paper

dioxane–H O (1:1, 9.2 mL) and Na CO (1.51 g, 14.3 mmol) was add-

Supporting Information

2

3

ed. The solution was cooled to 0 °C and FmocCl (252 mg, 0.975 mmol)

was added. The mixture was stirred overnight at r.t. and the solvents

were evaporated under reduced pressure. The residue was taken up in

water (7.5 mL) and CH Cl (10 mL) and the aqueous phase was ex-

Supporting information for this article is available online at

http://dx.doi.org/10.1055/s-0034-1379978.

S

u

p

ortioIgnfmr oaitn

S

u

p

o

nrtogI

i

f

rm oaitn

2

tracted with CH Cl (2 × 10 mL). The combined organic extracts were

2

References

dried (MgSO ) and filtered. After concentration under reduced pres-

4

sure, the crude product was purified by flash chromatography (silica

gel, cyclohexane–EtOAc, 70:30) to afford cis-32 (360 mg, 68%) as a

(

1) (a) Jiménez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M. J. Am.

Chem. Soc. 1998, 120, 9452. (b) Huang, F.; Nau, W. N. Angew.

Chem. Int. Ed. 2003, 42, 2269; and references therein.

colorless oil that crystallizes upon standing; mp 52–54 °C; R = 0.26

f

(cyclohexane–EtOAc, 50:50).

(

2) (a) Cowell, S. M.; Lee, Y. S.; Cain, J. P.; Hruby, V. J. Curr. Med.

Chem. 2004, 11, 2785. (b) Hanessian, S.; Auzzas, L. Acc. Chem.

Res. 2008, 41, 1241. (c) Chatterjee, J.; Gilon, C.; Hoffman, A.;

Kessler, H. Acc. Chem. Res. 2008, 41, 1331. (d) Avan, I.; Hall, C. D.;

Katritsky, A. R. Chem. Soc. Rev. 2014, 43, 3575.

IR (neat): 3326, 2973, 2930, 2859, 1693, 1515, 1478, 1449, 1391,

–1

1

366, 1245, 1164, 1101, 1023 cm .

1

H NMR (400 MHz, CDCl ): δ = 7.74 (d, J = 7.5 Hz, 2 H), 7.58 (d, J = 7.5

3

Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.29 (dt, J = 7.5 Hz, 1.0 Hz, 2 H), 4.97

(

br s, 1 H), 4.82 (br s, 1 H), 4.41 (d, J = 6.8 Hz, 2 H), 4.24 (t, J = 6.8 Hz, 1

H), 3.79 (d, J = 11.7 Hz, 1 H), 3.61 (d, J = 11.7 Hz, 1 H), 3.31 (s, 1 H),

.23–3.13 (m, 2 H), 1.62–1.55 (m, 2 H), 1.54–1.48 (m, 3 H), 1.44 (s, 9

(3) (a) Alami, A.; Calmes, M.; Daunis, J.; Jacquier, R. Bull. Soc. Chim.

Fr. 1993, 130, 5. (b) Burgess, K.; Ho, K. K.; Moye-Sherman, D.

Synlett 1994, 575. (c) Cativiela, C.; Diaz-de-Villegas, M. D. Tetra-

hedron: Asymmetry 2000, 11, 645. (d) Salaün, J. Top. Curr. Chem.

2000, 207, 1. (e) Brackmann, F.; de Meijere, A. Chem. Rev. 2007,

107, 4493.

3

H), 1.37–1.30 (m, 1 H), 1.13–1.06 (m, 1 H), 0.88 (dd, J = 9.5, 5.5 Hz, 1

H), 0.48 (dd, J = 6.5, 5.5 Hz, 1 H).

1

3

C NMR (50 MHz, CDCl ): δ = 156.8, 156.7, 144.2, 141.4, 127.8, 127.2,

3

(

4) For some representative examples, see: (a) Campbell, M. M.;

Horwell, D. C.; Mahon, M. F.; Pritchard, M. C.; Walford, S. P.

Bioorg. Med. Chem. Lett. 1993, 3, 667. (b) Lim, D.; Moye-Sher-

man, D.; Ham, I.; Jin, S.; Scholtz, J. M.; Burgess, K. Chem.

Commun. 1998, 2375. (c) Reichelt, A.; Martin, S. F. Acc. Chem.

Res. 2006, 39, 433.

1

2

25.2, 120.1, 80.4, 67.0, 66.7, 47.4, 40.9, 38.6, 29.6, 29.1, 28.5, 27.1,

6.7, 19.1.

+

HRMS (ESI): m/z [M + Na] calcd for C₂₈H₃₆N NaO : 503.2514; found:

5

2

5

03.2516.

cis-1-[(tert-Butoxycarbonyl)amino]-2-{4-[(9H-fluoren-9-ylmeth-

oxycarbonyl)amino]butyl}cyclopropanecarboxylic Acid (cis-33)

(5) (a) See, for instance: Pages, R. A.; Burger, A. J. Med. Chem. 1966,

9

, 766. (b) Ahmad, S.; Philips, R. S.; Stammer, C. H. J. Med. Chem.

To a solution of cis-32 (100 mg, 0.21 mmol) in CCl –MeCN–water

1992, 35, 1410. (c) Balsamini, C.; Bedini, A.; Spadoni, G.; Tarzia,

G.; Tontini, A.; Balduini, W.; Cimino, M. Farmaco 1998, 53, 181.

(d) Sibille, P.; Lopez, S.; Brabet, I.; Valenti, O.; Oueslati, N.;

Gaven, F.; Goudet, C.; Bertrand, H.-O.; Neyton, J.; Marino, M. J.;

Amalric, M.; Pin, J.-P.; Acher, F. C. J. Med. Chem. 2007, 50, 3585.

4

(2:2:3, 3.5 mL) were successively added NaIO₄(267 mg, 1.24 mmol)

and RuO ·H O (3.3 mg, 0.02 mmol). The solution was stirred at r.t. for

2

1

h and water (2 mL) was added. The aqueous phase was extracted

with CH Cl (3 × 3 mL) and the combined organic extracts were dried

2

(

MgSO ) and filtered. After concentration under reduced pressure, the

(6) (a) Chatel-Chaix, L.; Baril, M.; Lamarre, D. Viruses 2010, 2, 1752.

(b) Harper, S.; McCauley, J. A.; Rudd, M. T.; Ferrara, M.;

DiFilippo, M.; Crescenzi, B.; Koch, U.; Petrocchi, A.; Holloway, M.

K.; Butcher, J. W.; Romano, J. J.; Bush, K. J.; Gilbert, K. F.;

McIntyre, C. J.; Nguyen, K. T.; Nizi, E.; Carroll, S. S.; Ludmerer, S.

W.; Burlein, C.; DiMuzio, J.; Graham, D. J.; McHale, C. M.;

Stahlhut, M. W.; Olsen, D. B.; Monteagudo, E.; Cianetti, S.;

Giuliano, C.; Pucci, V.; Trainor, N.; Fandozzi, C. M.; Rowley, M.;

Coleman, P. J.; Vacca, J. P.; Summa, V.; Liverton, N. J. ACS Med.

Chem. Lett. 2012, 3, 332.

4

crude product was purified by flash chromatography (silica gel, EtOAc

1

0

00%) to afford cis-33 (76 mg, 74%) as a white solid; mp >300 °C; R =

f

.32 (EtOAc).

IR (neat): 3326, 2930, 2868, 1694, 1514, 1450, 1392, 1366, 1246,

1

–1

160, 1102, 1049, 1024 cm .

1

H NMR (400 MHz, CDCl ): δ = 7.73 (d, J = 7.5 Hz, 2 H), 7.57 (dd, J = 7.5,

3

0

.9 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.28 (dt, J = 7.5, 1.2 Hz, 2 H), 5.26

(br s, 1 H), 4.89 (br s, 1 H), 4.40 (d, J = 6.8 Hz, 2 H), 4.20 (t, J = 6.8 Hz, 2

H), 3.19–3.10 (m, 2 H), 1.65–1.57 (m, 2 H), 1.56–1.57 (m, 4 H), 1.44 (s,

9

(

7) For recent reviews on titanium-mediated cyclopropanation of

carboxylic acid derivatives, see: (a) Wolan, A.; Six, Y. Tetrahe-

dron 2010, 66, 15. (b) Bertus, P.; Boeda, F.; Pearson-Long, M. S.

M. Science of Synthesis Knowledge Updates 2012/1; Georg Thieme

Verlag: Stuttgart, 2012, 1. (c) Cha, J. K.; Kulinkovich, O. G. Org.

React. 2012, 77, 1.

H), 1.32–1.24 (m, 2 H), 0.94–0.82 (m, 1 H).

1

3

C NMR (100 MHz, CDCl ): δ = 177.2, 156.8, 156.7, 144.1, 141.4,

3

1

2

27.8, 127.2, 125.2, 120.1, 80.4, 66.8, 47.4, 41.0, 38.8, 32.0, 29.4, 28.4,

6.6, 26.3, 23.4.

+

HRMS (ESI): m/z [M + Na] calcd for C₂₈H₃₄N NaO : 517.2312; found:

5

2

6

(8) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.;

Pritytskaya, T. S. J. Org. Chem. USSR 1989, 25, 2027.

17.2309.

(b) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevski, D. A.;

Pritytskaya, T. S. Synthesis 1991, 234. (c) Kulinkovich, O. G. Eur. J.

Org. Chem. 2004, 4517.

Acknowledgment

(

9) For a recent review on the use of Kulinkovich reaction in natural

product synthesis, see: Haym, I.; Brimble, M. A. Org. Biomol.

Chem. 2012, 10, 7649.

We gratefully acknowledge the ‘Agence Nationale de la Recherche’

ANR BLAN07-2_194466), the ‘Centre National de la Recherche Scien-

tifique’, the ‘Région Pays-de-la-Loire’ and the ‘Ministère de l’Ensei-

gnement Supérieur et de la Recherche’ for Ph.D. and postdoc

fellowships. We also thank A. Durand, P. Gangnery, F. Legros, and E.

Mebold for technical assistance and analyses.

(

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

1

006

Synthesis

G. Forcher et al.

Paper

(

10) (a) Kozyrkov, Y. Y.; Pukin, A.; Kulinkovich, O. G.; Ollivier, J.;

(18) Pradhan, T. K.; Joosten, A.; Vasse, J.-L.; Bertus, P.; Karoyan, P.;

Szymoniak, J. Eur. J. Org. Chem. 2009, 5072.

(19) Joosten, A.; Vasse, J.-L.; Bertus, P.; Szymoniak, J. Synlett 2008,

2455.

(20) Bertus, P.; Menant, C.; Tanguy, C.; Szymoniak, J. Org. Lett. 2008,

10, 777.

Salaün, J. Tetrahedron Lett. 2000, 41, 6399. (b) Racouchot, S.;

Sylvestre, I.; Ollivier, J.; Kozyrkov, Y. Y.; Pukin, A.; Kulinkovich,

O. G.; Salaün, J. Eur. J. Org. Chem. 2002, 2160. (c) Lecornué, F.;

Ollivier, J. Chem. Commun. 2003, 584.

(11) (a) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl.

1

996, 35, 413. (b) de Meijere, A.; Kozhushkov, S. I.; Savchenko, A.

(21) Reetz, M. T.; Westermann, J.; Steinbach, R. R.; Wenderoth, B.;

Peter, R.; Ostarek, R.; Maus, S. Chem. Ber. 1985, 118, 1421.

(22) Miao, X.; Dixneuf, P. H.; Fischmeister, C.; Bruneau, C. Green

Chem. 2011, 13, 2258.

I. J. Organomet. Chem. 2004, 689, 2033.

(

12) (a) Kordes, M.; Winsel, H.; de Meijere, A. Eur. J. Org. Chem. 2000,

3235. (b) Brackmann, F.; de Meijere, A. Synthesis 2005, 2008.

(

13) (a) Bertus, P.; Szymoniak, J. Chem. Commun. 2001, 1792.

(23) Milanole, G.; Couve-Bonnaire, S.; Bonfanti, J.-F.; Jubault, P.;

Pannecoucke, X. J. Org. Chem. 2013, 78, 212.

(b) Bertus, P.; Szymoniak, J. J. Org. Chem. 2003, 68, 7133.

c) Bertus, P.; Szymoniak, J. Synlett 2007, 1346.

(

(24) Conditions tried for cis-27 reduction: Pd/C, Pd(OH) /C, PtO cat-

2

(14) Bertus, P.; Szymoniak, J. J. Org. Chem. 2002, 67, 3965.

alysts, H₂pressures from 1 up to 30 bar, EtOAc, MeOH, EtOH

(

15) (a) Laroche, C.; Harakat, D.; Bertus, P.; Szymoniak, J. Org. Biomol.

Chem. 2005, 3, 3482. (b) Pearson-Long, M. S. M.; Beauseigneur,

A.; Karoyan, P.; Szymoniak, J.; Bertus, P. Synthesis 2010, 3410.

16) Guitot, K.; Larregola, M.; Pradhan, T. K.; Vasse, J.-L.; Lavielle, S.;

Bertus, P.; Szymoniak, J.; Lequin, O.; Karoyan, P. ChemBioChem

with 1 equiv of CHCl (HCl source) solvents.

(25) Yap, A. J.; Chan, B.; Yuen, A. K. L.; Ward, A. J.; Masters, A. F.;

Maschmeyer, T. ChemCatChem 2011, 9, 1496.

3

(

(26) Kachinsky, J. L. C.; Salomon, R. G. J. Org. Chem. 1986, 51, 1393.

1

13

(27) Since the H NMR signals were broad and that some C NMR

signals were not observed in several solvents, the acid cis-21

was converted into the corresponding methyl ester to confirm

its structure.

2011, 12, 1039.

(

17) The cis or trans configuration refers here to the relationship

between the two carbon-containing substituents of the cyclo-

propane ring.

©

Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 992–1006

Article Doi

Titanium-Mediated Cyclopropanation of Nitriles with Unsaturated Grignard Reagents: Application to the Synthesis of Constrained Lysine Derivatives

DOI: 10.1055/s-0034-1379978

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Article abstract of DOI:10.1055/s-0034-1379978

Full text of DOI:10.1055/s-0034-1379978

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