Quaternized α,α′-Amino Acids via Curtius Rearrangement of Substituted Malonate-Imidazolidinones

Article abstract of DOI:10.1021/acs.joc.7b01684

An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate-imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89-99% for eight cases) for quaternizing a range of proteinogenic α-amino acids. The stereogenicity in targets 5a-i supports previous conclusions that the diastereoselective alkylation step proceeds via an α-substituted malonate-imidazolidinone enolate in its Z-configuration, with the auxiliary in an s-transC-N conformation.

Full text of DOI:10.1021/acs.joc.7b01684

Subscriber access provided by UNIVERSITY OF ADELAIDE LIBRARIES
Note
Quaternized #,#'-Amino Acids via Curtius Rearrangement
of Substituted Malonate-Imidazolidinones
Maheswara Rao Gokada, Roger Hunter, Ana Andrijevic, Wade
Petersen, Sauvik Samanta, Gerhard A Venter, and Sophie Rees-Jones
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01684 • Publication Date (Web): 13 Sep 2017
Downloaded from http://pubs.acs.org on September 14, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 34
The Journal of Organic Chemistry
1
2
3
4
Quaternized α,αꢀAmino Acids via Curtius Rearrangement of Substituted
5
MalonateꢀImidazolidinones
6
7
8
9
Maheswara Rao Gokada, Roger Hunter,* Ana Andrijevic, Wade F. Petersen, Sauvik
Samanta, Gerhard Venter, and Sophie ReesꢀJones
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
Corresponding Author: *Fax: +27 21 650 5195. Eꢀmail: Roger.Hunter@uct.ac.za
ABSTRACT: An efficient synthesis protocol is presented for accessing quaternized αꢀamino
acids in chiral, nonꢀracemic form via diastereoselective malonate alkylation followed by Cꢀ
to Nꢀtransposition. The key stereodifferentiating step involves a diastereoselective alkylation
of an αꢀmonosubstituted malonateꢀimidazolidinone, which is followed first by a
chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the
transposition. The method demonstrates a high product ee (89ꢀ99% for eight cases) for
quaternizing a range of proteinogenic αꢀamino acids. The stereogenicity in the targets 5aꢀi
supports earlier conclusions that the diastereoselective alkylation step proceeds via an
αꢀ
substituted malonateꢀimidazolidinone enolate in its Zꢀconfiguration, with the auxiliary in an
sꢀtransCꢀN conformation
Intense synthetic effort has been directed recently1 towards developing methodology for
accessing acyclic2 α,α'ꢀdisubstituted amino acids in a highly enantioenriched form, in view of
their unique stability and ability to impart desirable conformational properties to peptides,
particularly in peptidomimetics.3 Methodologies reported cover the full gamut of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 34
1
2
3
4
5
6
7
8
9
disconnections for the allꢀimportant quaternization step, in which carbonꢀcarbon bondꢀ
forming quaternization methodologies via either nucleophilic4, 5 or electrophilic amino acid
substrates6, 7 are most prevalent, and carbonꢀnitrogen quaternizations via electrophilic8 and
nucleophilic9 nitrogen sources are also prominent. By comparison, effective radical,10
pericyclicꢀtype,11 and enantioselective insertion12 methodologies are far less common.
However, in spite of all these advances, many of the methods do not demonstrate direct
application to quaternizing a range of proteinogenic amino acids. We herein report on a
strategy involving Curtius rearrangement of suitably functionalized α,α’ꢀdisubstituted
malonate imidazolidinones that provides access to a range of proteinogenic amino acids in
high ee and good overall yield.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Successful strategies for using malonate as a template for elaboration into quaternized amino
acids in high ee via Cꢀ to Nꢀ transposition have involved diastereoselective alkylation13a
incorporating menthol as a chiral auxiliary into one of the carboxyl groups (albeit with
modest diastereoselectivity and limited scope in the products obtained), phaseꢀtransfer
catalysed enantioselective alkylation14 and enzymeꢀpromoted desymmetrization15 strategies.
We have recently described13b a highly diastereoselective alkylation of malonateꢀ
imidazolidinones to afford allꢀC quaternized products 2aꢀi (Scheme 1), and from the outset a
key issue regarding extending the work to a Curtius strategy for accessing quaternized α, α'ꢀ
amino acids centred on differentiation14,16 of the two carboxyl group functionalities post
alkylation. Eventually, this was satisfactorily achieved by using a PMB ester on the nonꢀ
auxiliary group, in which chemoselective deprotection (of 2aꢀi) to the half acid 3aꢀi could be
achieved using TFA in DCM at 0 °C without decarboxylation. Thereafter, the half acid was
committed to a standard Curtius sequence using diphenylphosphoryl azide (DPPA) for acyl
azide generation to afford auxiliaryꢀamines 4aꢀi following thermal rearrangement and acid
ACS Paragon Plus Environment

Page 3 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
hydrolysis, with the auxiliary still attached. Auxiliary deprotection in the final step via
methanolysis (NaOMe) then afforded quaternized amino acid esters 5aꢀi as shown in Scheme
1.
9
Scheme 1. Malonateꢀimidazolidinone alkylation / Curtius sequence for quaternized
α,α−amino acid esters 5aꢀi
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Specifically, the sequence begins with sequential double alkylation of malonateꢀ
imidazolidinone 1 according to our earlier communication,13b in which 1 was readily
prepared by a sequential double DCC coupling of malonic acid with first PMBOH followed
by the auxiliary in around 85% yield for each step (see the Experimental Section). Following
the double alkylation with KHMDS (1.2 eq), the pivotal allꢀcarbon quaternized malonates 2aꢀ
i were obtained in high diastereoselectivity (de = 86 ꢀ > 99%) after column chromatography
1
as evidenced by HPLC analysis on a C18 column. Their H NMR spectra according to
reliable markers that consistently allowed facile identification of the diastereomeric ratio (the
auxiliary benzylic H and Me doublets together with the NꢀMe singlet) indicated a virtually
pure diastereomer in each case. The diastereomers eluted together and while very small
amounts of the minor diastereomer may have been lost during fraction collection, the high
des observed from the HPLC data we consider to closely reflect the de in the reaction itself.
An overall yield for the two alkylation steps was in excess of 80 % overall, while the R2
(second) group could only be introduced as Me, allyl, propargyl or benzyl in keeping with the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 34
1
2
3
4
5
6
7
8
9
need to use a reactive SN2 electrophile. The sense of diastereoselectivity was based on our
earlier findings13b that reaction proceeds via a (Z)ꢀ, sꢀtransCꢀN malonateꢀimidazolidinone
enolate intermediate in which R2 is introduced anti to the face bearing the bulky groups on
the auxiliary. This mechanistic view, in conjunction with the known retention of
configuration in the Curtius step, was corroborated by optical rotation data for 5a, 5b, 5e, and
5g in which the signs of rotation were all in agreement with those in the literature (see the
Experimental), while the other products were obtained as new compounds. Figure 1 presents
a transition state model that accommodates these ideas.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Proposed transitionꢀstate model for quaternization.
Thereafter, compounds 2aꢀi were deprotected with TFA in DCM at rt to afford acid products
3aꢀi, which could be cleanly isolated via an acid/base extraction without recourse to
chromatography. Conversion of the half acid to its acyl azide using diphenylphosphoryl azide
(DPPA) with triethylamine in THF followed by a Curtius rearrangement in refluxing
acetonitrile achieved a clean conversion to the isocyanate, which was hydrolysed to auxiliaryꢀ
amines 4aꢀi with aqueous mineral acid. The amine product could also be isolated in high
purity using an acid/base extraction, also without the need for chromatography and in an
overall yield for the four steps from 2aꢀi of around 70%. Finally, auxiliary deprotection with
sodium methoxide in methanol furnished the quaternized targets 5aꢀi in around 75% yield
after column chromatography, with virtually quantitative recovery of the auxiliary (on a small
scale). Amino acid esters 5aꢀi were quite stable, were relatively nonꢀpolar on chromatography
and generally didn’t require Nꢀprotection for characterisation unless to introduce a UVꢀactive
chromophore for HPLC ee evaluation (via Nꢀbenzamide formation). Table 1 reveals the range
ACS Paragon Plus Environment

Page 5 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
of amino acids synthesized. The high enantioselectivities of quaternization were extremely
pleasing, and according to chiral HPLC data closely correlated with the de of the
corresponding dialkylated malonateꢀimidazolidinones 2aꢀi. Furthermore, the range of ees
shown in Table 1 agreed with earlier work in that ees generally increased with the steric bulk
of the R1 group ꢀ lowest ee with allyl (5b; 89%); highest with tryptophan (5i; 99%). By way
of HPLC standards, racemates for 2a, 2b and 2e were prepared via alkylation of the
respective amino acid pꢀbromophenyl imine according to a literature procedure,17 modifying
the base (from KOH to NaH for 2a and 2b, and KHMDS for 2e). For 5a, owing to
asymmetry in the HPLC trace, the ee (reported as 99%) is probably closer to its de value
(96%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Ees of Quaternized αꢀAmino Acids 5aꢀi
Entry
Product 2
Product 5
de of 2a
ee of 5b
96
99
1
2
86
67
89
70
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 34
1
2
3
4
5
92
92
4
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
97
99
99
99
98
98
5
6
7
PMBO
N
N
2ee
Ph
O
O
O
PMBO
N
N
2g
Ph
Br
O
O
O
> 99
> 99
8
9
PMBO
N
N
2h
Ph
N
Ts
93
90
aMeasured by HPLC on a C18 column. Measured using chiral HPLC on a Chiralcel OD or AD column. Nꢀ
b
c
benzamide used for the HPLC determination. dUsing 3ꢀbromoꢀ1ꢀtrimethylsilylpropyne to introduce the R2 group
(The TMS group removed subsequently by TBAF). Isobutyl group introduced as the R1 group at the malonate
e
level. f ee evaluated via its NꢀBoc derivative.
The R groups were chosen to cover a range of commonly employed amino acids in synthesis,
including Ala and Phe (5aꢀd, g, i), Leu (5e), Lys (5f), Trp (5h) and Pro (5i), the latter derived
ACS Paragon Plus Environment

Page 7 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
from 5i via a short sequence as shown in Scheme 2. Using the (4R, 5S) auxiliary (numbering
based on the free auxiliary) as shown in Scheme 1 meant that the quaternizing group R2
always replaced the H of an (S)ꢀαꢀamino acid. The outcome of 5c is interesting in that using
R1 as propargyl delivered a lowerꢀthanꢀnormal ee of 70% (67% de for 2c). This was in
agreement with our earlier findings13b that the steric size of the R1 group controls sꢀtrans to sꢀ
cis auxiliary interconversion. Propargyl is presumably on the cusp between ethyl and methyl,
the latter being too small to inhibit auxiliary conformation interconversion (the de was close
to zero for R1 = Me, while about 90% with Et13b). Reversal of the order of introduction of the
two groups (benzyl and propargyl) led to complications with R2 as propargyl, probably due to
the acidity of the terminal alkyne hydrogen. This could be resolved by using 3ꢀbromoꢀ1ꢀ
trimethylsilylpropyne as the second electrophile, which following desilylation with TBAF
(quantitative yield) and committing to the Curtius sequence afforded 5d in high ee (92%).
Similarly, the quaternized leucine derivative 5e (99% ee) could be accessed from 2e, in which
the isobutyl group was installed into diethyl malonate first. Hydrolysing the latter to the
diacid, carrying out the double DCC coupling to afford the malonateꢀimidazolidinone with R1
as an isobutyl group already installed, and carrying out the second alkylation then gave
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
18
access to 2e. Azide 5f was obtained from 2f using Br(CH2)4N3 as the electrophile for
introducing the R1 group in the first alkylation. The ee of 5f was determined via its Nꢀ
benzamide, which could be converted into N2ꢀBz, N6ꢀBoc αꢀallyllysine methyl ester via a
Staudinger / NꢀBoc protection sequence on the terminal azide (see the Supplementary
Information). Both 5f and the protected lysine derivative were obtained in an excellent ee of
98%. Product 5g containing a pꢀbromobenzyl / methyl combination is the enantiomer of a
key intermediate in the synthesis of the LFAꢀ1 antagonist BIRTꢀ377,15c,19 and was obtained in
an ee of 98% ee, which compares extremely favourably to other reported stereoselectivities,
The actual enantiomer in question could in principle be easily accessed by simply using the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 34
1
2
3
4
5
6
7
8
9
(4S, 5R) auxiliary antipode. Similarly, the tryptophan derivative 5h, using Nꢀtosylꢀ3ꢀ
chloromethylindole20 in the first alkylation en route to 2h, was produced essentially
enantiopure (ee > 99%) as its Nindꢀtosyl derivative ꢀ the use of sulfonamide as protecting
group avoided complications using NindꢀBoc in the TFA deprotection step. Finally, product 5i
(90% ee), containing a terminal benzyloxy group, could be converted into quaternized
α−benzylproline methyl ester 6 as its (R)ꢀenantiomer in 91% ee via a straightforward
sequence as shown in Scheme 2 below. One quaternized amino acid that couldn’t be
accessed, however, was that of serine. Several attempts to install a C1 moiety, either as a first
or second R group and involving a range of hydroxymethylene C1 surrogates such as
CH2SPh, CH2TMS, CH2OBn or CH2O(CH2)2TMS, introduced via either direct alkylation
with the halide or via thiophenol Michael addition21 to the malonate exoꢀmethylene
derivative, all failed. An alternative viable methodology developed in the group (using
malonateꢀimidazolidinones) for accessing quaternized serines5b will be reported elsewhere.
Scheme 2. Synthesis of (R)ꢀαꢀbenzylproline Me ester 6 from 5i
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSION
In summary, this study has significantly improved the scope13a of accessing quaternised αꢀ
amino acids in high ee via a diastereoselective auxiliaryꢀcontrolled malonate alkylation /
Curtius rearrangement sequence. Based on the results, the method would appear to offer
access to most of the proteinogenic amino acids (serine excluded) in high ee, whose
stereogenicity can be predicted by a transitionꢀstate model.
ACS Paragon Plus Environment

Page 9 of 34
The Journal of Organic Chemistry
1
2
3
4
EXPERIMENTAL SECTION
5
6
7
8
9
Unless otherwise specified, all reagents were purchased from commercial sources and used
without further purification. THF was freshly distilled over sodium wire and benzophenone.
1H NMR and 13C NMR spectra were recorded on a Varian Mercury 300 MHz (75.5 MHz for
13C) or a Bruker 400 MHz (101 MHz for 13C) instrument. All spectral data was acquired at
295 K. Chemical shifts are reported in parts per million (ppm, δ), downfield from
tetramethylsilane (TMS, δ = 0.00 ppm) and are referenced to residual solvent (CDCl3, δ =
7.26 ppm (1H) and 77.16 ppm (13C)). Coupling constants (J) are reported in Hertz (Hz). The
multiplicity abbreviations used are: br broad, s singlet, d doublet, t triplet, q quartet, m
multiplet. Infrared (IR) spectra were recorded on a Perkin Elmer Spectrum 100 FTꢀIR
Spectrometer. Highꢀresolution massꢀspectra were obtained from the University of
Stellenbosch Mass Spectrometry Service and recorded in electrospray positive mode with a
timeꢀofꢀflight analyser system on a Waters Synapt G2 machine. Thin layer chromatography
was carried out on Merck silica gel 60F254 preꢀcoated aluminium foil sheets and were
visualised using UV light (254 nm). Column chromatography was carried out using silica gel
60 (Merck 7734), eluting with the specified solvent system. The diastereomeric ratios of
compounds 2aꢀi were determined by HPLC on an Agilent 1220 Series using a Zorbax Eclipse
Plus C18 (150 x4.6 mm) column, while the ees of quaternized amino acid esters 5aꢀi were
determined by HPLC on an Agilent 1220 Series using Daicel Chiralcel OD (250 × 4.6 mm)
or Daicel Chiralpak AD (250 × 4.6 mm) column. The full details of the HPLC solvents used
and the retention times obtained are given in the SI. Racemates of 5a, 5b and 5e for HPLC
comparison purposes were prepared via alkylation of the pꢀbromphenyl imine of the
respective amino acid Me ester (NaH for 5a and 5b, and KHMDS for 5e) according to a
literature procedure.17 Optical rotations were obtained using a Perkin Elmer 343 polarimeter
at λ = 589 nm and 20 ºC. The concentration c refers to g/100mL.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 34
1
2
3
4
Synthesis of 4ꢀmethoxybenzylꢀ3ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidinꢀ1ꢀ
5
6
yl)ꢀ3ꢀoxopropanoate 1
7
8
9
To a cooled solution of malonic acid (15.00 g, 0.144 mol) and pꢀmethoxybenzyl alcohol
(17.90 mL, 0.144 mol, 1 eq) in acetonitrile (350 ml) was added a solution of DCC (29.70 g,
0.144 mol, 1 eq) in acetonitrile (150 ml) via a dropping funnel over a period of 30 min, whilst
stirring vigorously. The cooling bath was then removed and the reaction mixture was left to
stir for 1 h at rt after which time the solid urea precipitate was removed by filtration through a
pad of Celite® and the filtrate evaporated. The residue was taken up in ethyl acetate (250 mL)
and the organic layer extracted with saturated aqueous sodium bicarbonate solution (2 x 200
mL). The combined aqueous extracts were washed once with ethyl acetate (100 mL),
acidified to pH 3 with 3M HCl and then extracted with ethyl acetate (1 x 300 and 2 x 150
mL). The organic extracts were dried over anhydrous MgSO4, filtered and evaporated to yield
monoꢀPMB malonic acid (26.80 g, 0.120 mol, 86%) as a lightꢀyellow liquid.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MonoꢀPMB malonic acid (6.00 g, 26.8 mmol, 1 eq) and (4R,5S)ꢀ1,5ꢀdimethylꢀ4ꢀ
phenylimidazolidinꢀ2ꢀone (5.10 g, 26.8 mol, 1 eq) were dissolved in dichloromethane (100
mL) and stirred at 0 ºC. A solution of DCC (6.63 g, 32.1 mol, 1.2 eq) and HOBt (0.721 g, 5.3
mmol, 20 mol %) in dichloromethane (50 mL) was gradually added to the mixture via a
pressureꢀequalizing dropping funnel.
Once addition was complete, the cooling bath was removed. The reaction was followed by
TLC, which indicated completion within 3 h at room temperature after which time it was
filtered through Celite®, the solvent was evaporated and the resultant residue purified by
column chromatography with ethyl acetate/hexane (30/70). The product 1 (9.03 g, 22.8
mmol, 85%) was obtained as a thick, clear gum.
[α]ꢁꢀꢂ = −30.3º, (c = 1, CH2Cl2); IR: vmax (cmꢀ1) 3067, 2961, 1732, 1687; 1H NMR (400 MHz,
CDCl3) δ 7.31−7.19 (m, 5H), 7.17−7.08 (m, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.28 (d, J = 8.7
ACS Paragon Plus Environment

Page 11 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Hz, 1H), 5.09 (s, 2H), 3.99 (m 2H), 3.87 (dq, J = 8.7, 6.6 Hz, 1H), 3.78 (s, 3H), 2.78 (s, 3H),
0.76 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.6, 164.9, 159.8, 155.6, 136.1,
130.2, 128.6, 128.2, 127.9, 127.2, 114.1, 66.9, 59.5, 55.4, 54.2, 43.5, 28.3, 15.1; HRMS (ES)
m/z: [M + H]+ Calcd for C22H25N2O5 397.1763; Found 397.1748.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure A: synthesis of α, α’ꢀdisubstituted auxiliary malonates (2aꢀi)
A solution of 1 (1 eq) in THF (0.1 M) was cooled to −78 ºC to which was added KHMDS in
toluene (0.5 M, 1.2 eq) dropwise. Stirring at this temperature was continued for a further 30
min after which time the electrophile in THF (1.5 eq) was added. The reaction mixture was
slowly warmed to rt and stirred for a further 18 h at this temperature. For 2h the reaction
mixture was stirred for an extra 1 h at 40 ºC, while for 2f and 2i the reaction mixture was
stirred for the 18 h at 60 ºC. The mixture was then quenched with saturated aqueous
ammonium chloride solution (ca. ½ reaction vol.) and extracted three times with EtOAc (3 x
reaction vol.). The combined organic extracts were dried over anhydrous MgSO4 and
evaporated to give the crude product, which was chromatographed using EtOAc/hexanes
mixtures as eluents to afford the monoalkylated derivatives of 1.
The monoꢀalkylated auxiliary malonate (1 eq.) in THF (0.1 M) in THF was cooled to −78 ºC
and KHMDS in toluene (0.5 M, 1.2 eq.) added. After 30 min the electrophile (1.5 eq. in THF)
was added dropwise. The reaction mixture was slowly warmed to rt and stirred for a further
18 h (for 2h the reaction mixture was then warmed to 30 ºC for an additional 5 h). The
solution was then quenched with saturated aqueous ammonium chloride solution (ca. ½
reaction vol.) and extracted three times with EtOAc (3 x reaction vol.). The combined organic
extracts were dried over anhydrous MgSO4 and evaporated to give the crude product which
was chromatographed using EtOAc/hexanes (20/80) to give 2aꢀi.
4ꢀMethoxybenzyl (S)ꢀ2ꢀbenzylꢀ3ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidinꢀ1ꢀyl)ꢀ2ꢀ
methylꢀ3ꢀoxopropanoate (2a)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 34
1
2
3
4
5
6
7
8
9
Prepared according to general procedure A from 1 (0.900 g, 2.27 mmol), using KHMDS (0.5
M, 5.45 mL, 2.73 mmol) and benzyl bromide (0.40 mL, 3.40 mmol) to give 4ꢀmethoxybenzyl
2ꢀbenzylꢀ3ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidinꢀ1ꢀyl)ꢀ3ꢀoxopropanoate (1.05
g, 2.16 mmol, 95%). A portion of this (0.900 g, 1.85 mmol) was then subjected to the second
alkylation using KHMDS (0.5 M, 4.44 mL, 2.22 mmol) and methyl iodide (0.18 mL, 2.90
mmol) to afford 2a as a colourless gum (0.889 g, 96%) in a de of 96%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
[α]ꢁꢀꢂ = −45.8º, (c = 1.0, CH2Cl2); IR (vmax/cmꢀ1) 3008, 2955, 1722, 1669; H NMR (400
MHz, CDCl3) δ 7.25−7.14 (m, 8H), 7.12−7.07 (m, 2H), 7.04−6.99 (m, 2H), 6.87−6.82 (m,
2H), 5.13 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 11.7 Hz, 1H), 4.93 (d, J = 11.7 Hz, 1H), 3.81 (s,
3H), 3.77 (dq, J = 8.5, 6.4 Hz, 1H), 3.37 (d, J = 14.8 Hz, 1H), 3.33 (d, J = 14.8 Hz, 1H) 2.75
13
(s, 3H), 1.46 (s, 3H), 0.73 (d, J = 6.4 Hz, 3H); C NMR (101 MHz, CDCl3) δ 172.4, 169.8,
159.7, 155.3, 137.2, 136.5, 130.6, 130.5, 128.5, 128.2, 128.1, 128.0, 126.9, 126.8, 113.9,
66.6, 60.5, 56.5, 55.5, 54.4, 41.7, 28.2, 22.1, 15.1; HRMS (ESI+) m/z: [M + H]+ Calcd for
C30H33N2O5 501.2384; Found 501.2390.
4ꢀMethoxybenzyl
(S)ꢀ2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀcarbonyl)ꢀ2ꢀ
methylpentꢀ4ꢀenoate (2b)
Prepared according to general procedure A from 1 (0.900 g, 2.27 mmol), using KHMDS (0.5
M, 5.45 mL, 2.73 mmol) and allyl bromide 0.30 mL, 3.47 mmol) to give 4ꢀmethoxybenzyl 2ꢀ
((4S, 5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀcarbonyl)pentꢀ4ꢀenoate (0.961 g, 2.20
mmol, 97%). A portion of this (0.820 g, 1.88 mmol), was then subjected to the second
alkylation using KHMDS (0.5 M, 4.50 mL, 2.25 mmol) and methyl iodide (0.18 mL, 2.90
mmol) to afford 2b as a colourless viscous oil (0.762 g, 90%) in a de of 86%.
1
[α]ꢁꢀꢂ = −46.2º, (c = 1.0, CH2Cl2); IR (vmax/cmꢀ1) 3063, 2937, 1723, 1676; H NMR (400
MHz, CDCl3) δ 7.31−7.26 (m, 2H), 7.25−7.16 (m, 3H), 7.07−7.02 (m, 2H), 6.91−6.85 (m,
2H), 5.71 (m, 1H), 5.23 (d, J = 8.6 Hz, 1H), 5.13 (d, J = 11.9 Hz, 1H), 5.05 (d, J = 11.9 Hz,
ACS Paragon Plus Environment

Page 13 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H), 5.02−4.96 (m, 2H), 3.81 (s, 3H), 3.79 (dq, J = 8.6, 6.6 Hz, 1H), 2.73 (s, 3H), 2.72−2.68
(m, 2H), 1.46 (s, 3H), 0.73 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.3, 170.2,
159.7, 155.2, 136.6, 133.8, 130.5, 128.6, 128.4, 128.1, 126.9, 118.2, 114.0, 66.5, 60.4, 55.5,
55.2, 54.3, 40.7, 28.2, 21.4, 15.1; HRMS (ESI+) m/z: [M + H]+ Calcd for C26H31N2O5
451.2233; Found 451.2233.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4ꢀMethoxybenzyl (R)ꢀ2ꢀbenzylꢀ2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀ
carbonyl)pentꢀ4ꢀynoate (2c)
Prepared according to general procedure A from 1 (0.900 g, 2.27 mmol) using KHMDS (0.5
M, 5.45 mL, 2.73 mmol) propargyl bromide (0.37 ml, 80%, 3.43 mmol) to give 4ꢀ
methoxybenzyl 2ꢀ((4S, 5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀcarbonyl)pentꢀ4ꢀ
ynoate (0.880 g, 2.02 mmol, 89%). This was then subjected to the second alkylation using
KHMDS (0.5 M, 4.88 mL, 2.44 mmol) and benzyl bromide (0.36 mL, 3.00 mmol) to afford
2c as a colourless gum (0.770 g, 73%) in a de of 67%.
IR (vmax/cmꢀ1) 3281, 3065, 2940, 2258, 1727, 1675; 1H NMR (300 MHz, CDCl3) δ 7.31−7.00
(m, 10H), 6.99−6.91 (m, 2H), 6.88−6.80 (m, 2H), 5.29 (d, J = 8.6 Hz, 1H), 4.99 (d, J = 11.7
Hz, 1H), 4.93 (d, J = 11.7 Hz, 1H), 3.86 (dq, J = 8.6, 6.6 Hz, 1H), 3.80 (s, 3H), 3.42 (br s,
2H), 3.13 (dd, J = 18.0, 2.7 Hz 1H), 2.83 (dd, J = 18.0, 2.7 Hz, 1H), 2.76 (s, 3H), 2.12 (t, J =
2.7 Hz, 1H), 0.74 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.5, 167.9, 159.6,
155.1, 136.1, 136.0, 130.5, 128.3, 128.0, 127.9, 127.7, 127.2, 126.8, 126.7, 113.7, 79.9, 71.9,
66.6, 60.7, 59.1, 55.3, 54.2, 39.2, 28.1, 23.0, 14.9; HRMS (ESI+) m/z: [M + H]+ Calcd. for
C32H33N2O5 525.2384; Found 525.2389.
4ꢀMethoxybenzyl (R)ꢀ2ꢀbenzylꢀ2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀ
carbonyl)ꢀ5ꢀ(trimethylsilyl)pentꢀ4ꢀynoate (2d)
Prepared according to general procedure from 1 (0.900 g, 2.27 mmol), KHMDS (0.5 M, 5.45
mL, 2.73 mmol) and benzyl bromide (0.40 mL, 3.36 mmol) to give 4ꢀmethoxybenzyl 2ꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 34
1
2
3
4
5
6
7
8
9
benzylꢀ3ꢀ((4S, 5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidinꢀ1ꢀyl)ꢀ3ꢀoxopropanoate (1.05 g,
2.16 mmol, 95%). A portion of this (0.900 g, 1.85 mmol) was then subjected to the second
alkylation using KHMDS (0.5 M, 4.44 mL, 2.22 mmol) and 3ꢀbromoꢀ1ꢀ(trimethylsilyl)ꢀ1ꢀ
propyne (527 mg, 2.78 mmol) to afford 2d as a colourless gum (0.800 g, 73%) in a de of
92%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
[α]ꢁꢀꢂ = −57.5º, (c = 1.0, CH2Cl2); IR (vmax/cmꢀ1) 3060, 3024, 2840, 2247, 1727, 1685; H
NMR (300 MHz, CDCl3) δ 7.34−7.07 (m, 12H), 6.95−6.84 (m, 2 H), 5.28 (d, J = 8.7 Hz,
1H), 5.08 (d, J = 11.7 Hz, 1H), 4.91 (d, J = 11.7 Hz, 1H), 3.85 (s, 3H), 3.85−3.74 (m, 1H),
3.60 (d, J = 14.1 Hz, 1H) 3.52 (d, J = 14.1 Hz, 1 H), 3.34 (d, J = 17.7, 1H), 2.88 (d, J = 17.7,
1H), 2.80 (s, 3H), 0.77 (d, J = 6.6 Hz, 3H), 0.06 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
169.8, 167.7, 159.6, 155.2, 136.7, 136.3, 130.5, 130.3, 128.4, 128.1, 128.0, 128.0, 127.1,
126.9, 113.8, 102.2, 89.4, 66.5, 60.4, 59.4, 55.4, 54.4, 38.7, 28.1, 24.9, 15.0, 0.0; HRMS
(ESI+) m/z: [M + H]+ Calcd. for C35H41N2O5Si 597.2779; Found 597.2781.
Compound 2d could be desilylated in quantitative yield using TBAF in THF, in preparation
for the Curtius sequence.
4ꢀMethoxybenzyl (R)ꢀ2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀcarbonyl)ꢀ2ꢀ
isobutylpentꢀ4ꢀenoate (2e)
In the case of the monoꢀalkylated precursor for 2e the first substituent was introduced at the
malonate level via a sequence involving malonate alkylation (NaH, DMF) with 1ꢀbromoꢀ2ꢀ
methylpropane, double ester hydrolysis (KOH, EtOH), followed by sequential DCC coupling
with PMBOH and auxiliary respectively. Thereafter, general procedure A using 4ꢀ
methoxybenzyl
2ꢀ((4S,
5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀcarbonyl)ꢀ4ꢀ
methylpentanoate (0.450 g, 0.996 mmol), KHMDS (0.5 M, 2.40 mL, 1.20 mmol) and allyl
bromide (0.13 mL, 1.50 mmol) gave 2e as a viscous oil (0.402 g, 82%) in a de of 97%.
ACS Paragon Plus Environment

Page 15 of 34
The Journal of Organic Chemistry
1
2
3
4
[α]ꢁꢀꢂ = −9.4º, (c = 1.0, CH2Cl2); IR (vmax/cmꢀ1) 3067, 2957, 1730, 1672, 1613; 1H NMR (300
5
6
7
8
MHz, CDCl3) δ 7.32−7.7.25 (m, 2H), 7.22−7.10 (m, 3H), 7.07−6.98 (m, 2H), 6.92−6.83 (m,
2H), 5.55−5.5.35 (m, 1H), 5.20 (d, J = 8.4 Hz, 1H), 5.09 (d, J = 12.0 Hz, 1H), 5.03 (d, J =
12.0 Hz, 1H), 4.99−4.83 (m, 2H), 3.81 (s, 3H), 3.81−3.72 (m, 1H), 2.80−2.72 (m, 1H), 2.73
(s, 3H), 2.06 (dd, J = 14.4, 4.2 Hz, 1H), 1.93ꢀ1.78 (m, 1H), 1.76−1.56 (m, 2H), 0.90 (d, J =
6.6 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H), 0.72 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 171.4, 170.2, 159.7, 155.2, 136.5, 133.6, 130.6, 128.4, 128.3, 128.0, 127.1, 118.1, 114.0,
66.5, 60.8, 58.3, 55.5, 54.3, 41.9, 39.1, 28.2, 25.1, 24.1, 23.5, 15.1; HRMS (ESI+) m/z: [M +
H]+ Calcd for C29H37N2O5 493.2697; Found 493.2698.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4ꢀMethoxybenzyl (R)ꢀ2ꢀallylꢀ6ꢀazidoꢀ2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀ
carbonyl)hexanoate (2f)
Prepared according to general procedure A from 1 (0.900 g, 2.27 mmol) using KHMDS (0.5
M, 5.45 mL, 2.73 mmol), 1ꢀazidoꢀ4ꢀbromobutane18 (0.603 g, 3.40 mmol) and TBAI (0.369 g,
1.14 mmol) to give 4ꢀmethoxybenzyl 6ꢀazidoꢀ2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀ
phenylimidazolidineꢀ1ꢀcarbonyl)hexanoate (0.951 g, 1.92 mmol, 85%) In this case, the
reaction mixture had to be warmed to 60 ºC to achieve full conversion. A portion of this
(0.930 g, 1.89 mmol), was then subjected to the second alkylation using KHMDS (0.5 M,
4.52 mL, 2.26 mmol) and allyl bromide (0.25 mL, 2.89 mmol) to afford 2f as a viscous oil
(0.960 g, 95%) in a de of 99%.
1
[α]ꢁꢀꢂ = −31.2º, (c = 1.0, CHCl3); IR (vmax/cmꢀ1) 3071, 2936, 2094, 1728, 1672, 1613; H
NMR (300 MHz, CDCl3) δ 7.33−7.26 (m, 2H), 7.25−7.15 (m, 3H), 7.10−7.03 (m, 2H),
6.93−6.84 (m, 2H), 5.44−5.28 (m, 1H), 5.26 (d, J = 8.7 Hz, 1H), 5.11 (d, J = 12.0 Hz, 1H),
5.04 (d, J = 12.0 Hz, 1H), 5.00−4.84 (m, 2H), 3.81 (m, 3H), 3.80 (dq, J = 8.7, 6.6 Hz, 1H),
3.26−3.12 (m, 2H), 3.02−2.91 (m, 1H), 2.79−2.67 (m, 4H), 2.03−1.02 (m, 6H), 0.74 (d, J =
6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.3, 169.5, 159.8, 155.2, 136.5, 133.0, 130.6,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 34
1
2
3
4
5
6
7
8
128.5, 128.2, 128.1, 127.2, 118.4, 114.0, 66.5, 60.5, 58.2, 55.5, 54.2, 51.2, 38.1, 32.9, 29.2,
28.2, 21.4, 15.1; HRMS (ESI+) m/z: [M + H]+ Calcd for C29H36N5O5 534.2711; Found
534.2721.
9
4ꢀMethoxybenzyl (S)ꢀ2ꢀ(4ꢀbromobenzyl)ꢀ3ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀ
phenylimidazolidinꢀ1ꢀyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoate (2g)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Prepared according to general procedure A from 1 (0.900 g, 2.27 mmol), using KHMDS (0.5
M, 5.45 ml, 2.73 mmol) and pꢀbromobenzyl bromide (0.843 g, 3.40 mmol). to give 4ꢀ
methoxybenzyl 2ꢀ(4ꢀbromobenzyl)ꢀ3ꢀ((4S, 5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidinꢀ1ꢀ
yl)ꢀ3ꢀoxopropanoate (1.260 g, 2.23 mmol, 98%). A portion of this (1.200 g, 2.13 mmol), was
then subjected to the second alkylation using KHMDS (0.5 M, 5.10 mL, 2.55 mmol) and
methyl iodide (0.40 mL, 6.42 mmol) to afford 2g (1.100 g, 89%) as a colourless gum in a de
of 99%.
1
[α]ꢁꢀꢂ = −36.5º, (c = 1.0, CH2Cl2); IR (vmax/cmꢀ1) 2936, 1724, 1676; H NMR (300 MHz,
CDCl3) δ 7.35−7.28 (m, 2H), 7.26−7.18 (m, 3H), 7.18−7.11 (m, 2H) 7.06−6.93 (m, 4H),
6.90−6.82 (m, 2H), 5.18 (d, J = 8.7 Hz, 1H), 5.03 (d, J = 11.9 Hz, 1H), 4.88 (d, J = 11.9 Hz,
1H), 3.82 (s, 3H), 3.77 (dq, J = 8.7, 6.6 Hz, 1H), 3.33 (d, J = 13.8 Hz, 1H), 3.18 (d, J = 13.8
Hz, 1H), 2.74 (s, 3H), 1.48 (s, 3H), 0.74 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
171.9, 169.7, 159.7, 155.1, 136.4, 136.2, 132.3, 131.1, 130.5, 128.6, 128.1, 127.9, 126.9,
120.8, 113.9, 66.6, 60.4, 56.5, 55.4, 54.3, 41.4, 28.2, 22.0, 15.0; HRMS (ESI+) m/z: [M + H]+
Calcd. for C30H32N2O5Br79 579.1489; Found 579.1475.
4ꢀMethoxybenzyl (S)ꢀ2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀcarbonyl)ꢀ2ꢀ
((1ꢀtosylꢀ1Hꢀindolꢀ3ꢀyl)methyl)pentꢀ4ꢀenoate (2h)
Prepared according to general procedure A from 1 (0.500 g, 1.26 mmol), using KHMDS (0.5
M, 3.8 mL, 1.90 mmol) and 3ꢀ(chloromethyl)ꢀ1ꢀtosylꢀ1Hꢀindole19 (0.525 g, 1.64 mmol, 1.3
eq) to give 4ꢀmethoxybenzyl 2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀ
ACS Paragon Plus Environment

Page 17 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
carbonyl)ꢀ2ꢀ((1ꢀtosylꢀ1Hꢀindolꢀ3ꢀyl)methyl)pentꢀ4ꢀenoate (0.750 g, 1.10 mmol, 87%). This
was then subjected to the second alkylation using KHMDS (0.5 M, 3.30 mL, 1.65 mmol) and
allyl iodide (0.15 mL, 1.66 mmol) to afford 2h as a gummy solid (0.700 g, 88%) in a de of >
99%.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
[α]ꢁꢀꢂ = −28.3º, (c = 1, CHCl3); IR (vmax/cmꢀ1) 3055, 2920, 1728, 1669, 1366, 1175; H NMR
(300 MHz, CDCl3) δ 7.94 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 7.5 Hz,
1H), 7.40 (s, 1H), 7.30−6.94 (m, 11H), 6.81 (d, J = 8.6 Hz, 2H), 5.61−5.46 (m, 1H),
5.05−4.80 (m, 5H), 3.80 (s, 3H), 3.57−3.36 (m, 3H), 3.03−2.79 (m, 2H), 2.71 (s, 3H), 2.31 (s,
3H), 0.67 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.0, 168.6, 159.7, 155.2,
144.8, 136.4, 135.5, 134.9, 133.2, 131.9, 130.5, 129.9, 128.5, 128.1, 127.8, 127.1, 126.9,
126.2, 125.9, 124.6, 123.0, 119.7, 118.8, 117.9, 113.9, 113.7, 66.7, 60.5, 59.3, 55.5, 54.1,
39.5, 28.2, 21.7, 15.0; HRMS (ESI+) m/z: [M + H]+ Calcd for C41H42N3O7S 720.2743; Found
720.2727
4ꢀMethoxybenzyl (R)ꢀ2ꢀbenzylꢀ5ꢀ(benzyloxy)ꢀ2ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀ
phenylimidazolidineꢀ1ꢀcarbonyl)pentanoate (2i)
Prepared according to general procedure A from 1 (0.900 g, 2.27 mmol), using KHMDS (0.5
M, 4.85 mL, 2.42 mmol, 1.2 eq), 1ꢀbenzyloxyꢀ4ꢀiodobutane (0.987 mg, 3.40 mmol,) prepared
by standard methods from 1,4ꢀbutanediol to give 4ꢀmethoxybenzyl 5ꢀ(benzyloxy)ꢀ2ꢀ((4S,
5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidineꢀ1ꢀcarbonyl)pentanoate (1.27 g, 2.23 mmol,
97%). In this case, the reaction mixture had to be warmed to 60 ºC to achieve full conversion.
A portion of this (1.200 g, 2.21 mmol), was then subjected to the second alkylation using
KHMDS (0.5 M, 5.20 mL, 2.60 mmol) and benzyl bromide (0.40 mL, 3.36 mmol) to afford
2i as a gummy solid (1.250 g, 89%) in a de of 93%.
[α]ꢁꢀꢂ = −4.2º, (c = 1.0, CH3Cl); IR (vmax/cmꢀ1) 3063, 2937, 1723, 1676; H NMR (300 MHz,
1
CDCl3) δ 7.38−6.92 (m, 15H), 6.88−6.77 (m, 4H), 5.25 (d, J = 8.7 Hz, 1H), 4.96 (d, J = 11.7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 34
1
2
3
4
5
6
7
8
9
Hz, 1H), 4.85 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 12.6 Hz, 1H), 4.41 (d, J = 12.6 Hz, 1H), 3.79
(s, 3H), 3.71 (dq, J = 8.7, 6.6 Hz, 1H), 3.51−3.26 (m, 4H), 2.70 (s, 3H), 2.10−1.88 (m, 2H),
1.83ꢀ1.68 (m, 1H), 1.52ꢀ1.38 (m, 1H), 0.72 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ 171.3, 169.8, 159.9, 155.4, 139.1, 137.0, 136.6, 130.8, 130.6, 128.4, 128.4, 128.0, 127.9,
127.9, 127.8, 127.7, 127.5, 126.5, 114.1, 73.0, 70.6, 66.5, 61.0, 60.0, 55.5, 54.4, 40.1, 30.6,
28.2, 25.1, 15.1; HRMS (ESI+) m/z: [M + H]+ Calcd for C39H43N2O6 635.3116; Found
635.3124.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure B: synthesis of αꢀtertiary amines (5aꢀ5i)
The appropriate α,α’ꢀdisubstituted auxiliary malonate (2aꢀi) (1 eq.) was dissolved in DCM
(0.3 M), and anisole (1.2 eq.) was added. Trifluoroacetic acid (5ꢀ6 eq.) was introduced slowly
via syringe, and the reaction mixture stirred at room temperature until the reaction was
complete by TLC (2ꢀ6 h), after which solvent and excess TFA were removed on the rotary
evaporator. Sat. NaHCO3 was then added to pH 8 and the neutral organic material extracted
three times into diethyl ether. The aqueous layer was then acidified with 1 M HCl until pH 2,
extracted with EtOAc and the organic extracts combined, dried over MgSO4 and concentrated
under reduced pressure to afford pure carboxylic acid 3. The acid was then dissolved in
acetonitrile (0.3 M), and Et3N (2 eq.) and diphenylphosphoryl azide (1.2 eq.) successively
added. The reaction mixture was allowed to stir at rt for 3 h after which time the solvent was
removed in vacuo and the residue filtered through a plug of silica with EtOAc/hexane (10/90)
to remove excess DPPA, affording the corresponding acyl azide as a clear gum. The acyl
azide was then dissolved in acetonitrile (0.3 M), which was refluxed at 85 °C. The
rearrangement to isocyanate was complete within 6 hours as evidenced by TLC. The reaction
mixture was cooled to 60 ºC, and HCl (6.0 M) was added to effect the hydrolysis (30
minutes). The reaction mixture was then cooled to rt and the amine isolated by extractive
workꢀup. This involved removal of acetonitrile, addition of water and extraction once with
ACS Paragon Plus Environment

Page 19 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
diethyl ether to remove nonꢀamine material. The resultant aqueous layer was then treated
with sodium hydroxide solution (5%) until pH 10ꢀ12 to liberate the amine from its
hydrochloride salt and then extracted three times with ethyl acetate and once with
chloroform/ethanol (75/25). The organic extracts were washed with brine, dried over
anhydrous MgSO4, filtered and concentrated to give the αꢀtertiary amines 4aꢀi, which were
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
pure enough by virtue of H NMR spectroscopy for auxiliary deprotection in which the
auxiliary αꢀtertiary amine ester (4aꢀi) was placed in anhydrous MeOH (0.1 M), and NaOMe
(1.0 M, 1.1 eq.) was introduced via dropwise addition. The reaction mixture was stirred for 1
h after which time water was added and the methanol removed on a rotary evaporator. The
aqueous mixture was extracted twice with ethyl acetate and once with chloroform/ethanol
(75/25), and the pooled organic fractions were dried with anhydrous MgSO4, filtered and
concentrated. Chromatographic purification of products 5aꢀi was carried out using MeOH/
DCM (5/95 to 10/90).
A full description of the sequence for 5a is now given, but thereafter only full
characterisation data will be given for final amine products 5bꢀi.
(S)ꢀ2ꢀBenzylꢀ3ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidinꢀ1ꢀyl)ꢀ2ꢀmethylꢀ3ꢀ
oxopropanoic acid (3a)
Compound 2a (0.820 g, 1.64 mmol) was subjected to general procedure B using anisole (0.21
mL, 1.97 mmol) and TFA (0.63 mL, 8.20 mmol) to give the corresponding acid 3a as a
colourless oil (0.592 g, 95%).
1
IR (vmax/cmꢀ1) 2964, 1726, 1683, 1431, 1399; H NMR (400 MHz, CDCl3) δ 7.80 (br s, 1H),
7.36−7.27 (m, 3H), 7.25−7.16 (m, 5H), 7.15−7.11 (m, 2H), 5.24 (d, J = 8.6 Hz, 1H), 3.96 (dq,
J = 8.6, 6.6 Hz, 1H), 3.47 (d, J = 14.0 Hz, 1H), 3.27 (d, J = 14.0 Hz, 1H), 2.81 (s, 3H), 1.49
13
(s, 3H), 0.80 (d, J = 6.6 Hz, 3H); C NMR (101 MHz, CDCl3) δ 177.2, 169.5, 155.7, 136.8,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 34
1
2
3
4
5
6
7
8
9
136.3, 130.5, 128.6, 128.2, 128.1, 127.0, 126.9, 60.6, 56.2, 54.5, 41.4, 28.3, 21.9, 15.0;
HRMS (ESI+) m/z: [M + H]+ Calcd for C22H25N2O4 381.1804; Found 381.1823.
3a was then committed to acyl azide formation with Et3N (0.43 mL, 3.12 mmol), DPPA (0.40
mL, 1.87 mmol) to afford (S)ꢀ2ꢀbenzylꢀ3ꢀ((4S,5R)ꢀ3,4ꢀdimethylꢀ2ꢀoxoꢀ5ꢀphenylimidazolidinꢀ
1ꢀyl)ꢀ2ꢀmethylꢀ3ꢀoxopropanoyl azide:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
IR (vmax/cmꢀ1) 2944, 2242, 2143, 1726, 1683, 1400, 1030; H NMR (400 MHz, CDCl3) δ
7.34−7.28 (m, 3H), 7.28−7.21 (m, 3H), 7.20−7.12 (m, 2H), 7.11−7.06 (m, 2H), 5.19 (d, J =
8.5 Hz, 1H), 3.92 (dq, J = 8.5, 6.6 Hz, 1H), 3.41 (d, J = 13.9 Hz, 1H), 3.24 (d, J = 13.9 Hz,
1H), 2.82 (s, 3H), 1.44 (s, 3H), 0.80 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
179.6, 168.8, 155.3, 136.4, 136.3, 130.4, 128.6, 128.3, 128.2, 127.1, 127.0, 60.6, 57.9, 54.4,
41.4, 28.3, 21.9, 15.0; HRMS (ESI+) m/z: [M + H]+ Calcd for C22H24N5O3 406.1879; Found
406.1882
The azide was refluxed in toluene for 6 h followed by hydrolysis with with HCl (5 M, 2 mL)
to afford αꢀtertiary amine (4S, 5R)ꢀ1ꢀ((S)ꢀ2ꢀaminoꢀ2ꢀmethylꢀ3ꢀphenylpropanoyl)ꢀ3,4ꢀ
dimethylꢀ5ꢀphenylimidazolidin2ꢀone (4a) as a colourless liquid (0.449 g, 1.28 mmol, 78%
from 2a).
1
IR (vmax/cmꢀ1) 3380, 2976, 1713, 1671, 1423, 1393, 1310; H NMR (400 MHz, CDCl3) δ
7.36−7.29 (m, 3H), 7.27−7.19 (m, 5H), 7.19−7.15 (m, 2H), 5.28 (d, J = 8.4 Hz, 1H), 3.94 (dq,
J = 8.4, 6.6 Hz, 1H), 3.27 (d, J = 13.2 Hz, 1H), 3.07 (d, J = 13.2 Hz, 1H), 2.86 (s, 3H), 2.37
(br s, 2H), 1.33 (s, 3H), 0.80 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.1,
156.0, 137.4, 137.0, 130.9, 128.7, 128.1, 128.1, 126.8, 126.6, 61.4, 60.6, 54.3, 44.5, 28.5,
25.6, 15.1; HRMS (ESI+) m/z: [M + H]+ Calcd. for C21H26N3O2 352.2027; Found 352.2025.
4a (0.380 g, 1.08 mmol) was reacted with NaOMe in MeOH (1.0 M, 1.20 mL, 1.20 mmol) to
afford quaternized amino acid methyl ester, methyl (S)ꢀ2ꢀaminoꢀ2ꢀmethylꢀ3ꢀ
phenylpropanoate 5a22 (0.159 g, 0.82 mmol, 76%) as a viscous oil in 99% ee.
ACS Paragon Plus Environment

Page 21 of 34
The Journal of Organic Chemistry
1
2
3
4
[α]ꢁꢀꢂ = −8.2º, (c = 0.67, CHCl3), [lit.23 [α]ꢀꢁꢂ= −14.1º, (c = 1.6, CHCl3)]; IR (vmax/cmꢀ1) 3374,
5
6
1
3027, 2956, 1731, 1601; H NMR (400 MHz, CDCl3) δ 7.31−7.20 (m, 3H), 7.17−7.12 (m,
7
8
9
2H), 3.70 (s, 3H), 3.13 (d, J = 13.2 Hz, 1H), 2.80 (d, J = 13.2 Hz, 1H), 1.72 (br s, 2H), 1.40
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 177.6, 136.7, 130.1, 128.4, 127.0, 59.0, 52.2, 47.1,
26.7; HRMS (ESI+) m/z: [M + H]+ Calcd. for C11H16NO2 194.1176; Found 194.1175.
(S)ꢀMethyl 2ꢀbenzamidoꢀ2ꢀmethylpentꢀ4ꢀenoate (Nꢀbenzamide of 5b)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 2b (0.760 g, 1.69 mmol) was subjected to general procedure B using anisole (0.22
mL, 2.03 mmol) and TFA (0.65 mL, 8.45 mmol) to give the corresponding acid 3b as a
colourless oil (0.525 g, 94%). This was then then committed to the general modified
procedure for the Curtius rearrangement with Et3N (0.44 mL, 3.18 mmol, 2 eq), DPPA (0.41
mL, 1.91 mmol) and HCl (5 M, 3 mL) for the hydrolysis affording αꢀtertiary amine 4b as a
colourless liquid (0.422 g, 1.40 mmol, 83% from 2b). 4b (0.400 g, 1.33 mmol) was
deprotected with NaOMe in MeOH (1.0 M, 1.46 mL, 1.46 mmol) to furnished the αꢀallyl
alanine methyl ester 5b as a lightꢀyellow gum which was then taken up in DCM (20 mL).
Anhydrous pyridine (0.12 mL, 1.52 mmol) was added followed by benzoyl chloride (0.18
mL, 1.52 mmol), and the reaction left to stir for 6 h. No workꢀup was performed; after
removal of solvents on the rotary evaporator the residue was chromatographed directly with
ethyl acetate/hexane (40/60) giving the Nꢀbenzamide of 5b (0.247 g, 1.00 mmol, 75% over 2
steps) as a lightꢀyellow gum in 89% ee.
[α]ꢁꢀꢂ = +9.80º, (c = 1.0, CHCl3), [lit.24 [α]ꢀꢁꢂ = +9.74º, (c = 1.0, CHCl3)]; IR (vmax/cmꢀ1) 3346,
1
3067, 2929, 1731, 1640; H NMR (400 MHz, CDCl3) δ 7.79−7.75 (m, 2H), 7.53−7.47 (m,
1H), 7.46−7.40 (m, 2H), 6.92 (s, 1H), 5.76−5.64 (m, 1H), 5.18ꢀ5.10 (m, 2H), 3.80 (s, 3H),
3.11 (ddt, J = 13.9, 7.3, 1.0 Hz, 1H), 2.67 (ddt, J = 13.9, 7.3, 1.0 Hz, 1H), 1.74 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 174.8, 166.6, 135.0, 132.6, 131.7, 128.7, 127.0, 119.7, 60.4, 52.9,
40.9, 23.1; HRMS (ESI+) m/z: [M + H]+ Calcd for C14H18NO3 248.1281; Found 248.1291.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 34
1
2
3
4
(R)ꢀMethyl 2ꢀaminoꢀ2ꢀbenzylpentꢀ4ꢀynoate (5c)
5
6
7
8
Compound 2c (0.620 g, 1.18 mmol) was subjected to general procedure B using anisole (0.13
mL, 1.18 mmol) and TFA (0.45 mL, 5.90 mmol) to give the corresponding acid 3c as a
colourless oil (0.420 g, 1.04 mmol, 88%). This was then committed to the general modified
procedure for Curtius rearrangement with Et3N (0.29 mL, 2.08 mmol), DPPA (0.27 mL, 1.25
mmol) and HCl (5 M, 2 mL) for the hydrolysis affording yielding αꢀtertiary amine 4c as a
colourless liquid (0.276 g, 0.74 mmol, 62% from 2c). Thereafter, 4c (0.300 g, 0.800 mmol)
was deprotected with NaOMe in MeOH (1.0 M, 0.88 mL, 0.88 mmol) to afford 5c (0.158 g,
0.73 mmol, 91%) as a viscous oil in 70% ee.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
IR (vmax/cmꢀ1) 3380, 3281, 3029, 2950, 2320, 1738; 1H NMR (400 MHz, CDCl3) δ 7.31−7.21
(m, 3H), 7.17−7.12 (m, 2H), 3.71 (s, 3H), 3.13 (d, J = 13.2 Hz, 1H), 2.87 (d, J = 13.2 Hz,
1H), 2.76 (dd, J = 16.4, 2.4 Hz, 1H), 2.51 (dd, J = 16.4, 2.4 Hz, 1H), 2.08 (t, J = 2.4 Hz, 1H),
1.82 (br s, 2H); 13C NMR (101 MHz, CDCl3) δ 175.4, 135.9, 130.0, 128.6, 127.3, 79.6, 71.9,
61.8, 52.4, 45.3, 29.8; HRMS (ESI+) m/z: C13H16NO2 [M + H]+ Calcd for 218.1176; Found
218.1180.
(S)ꢀMethyl 2ꢀaminoꢀ2ꢀbenzylpentꢀ4ꢀynoate (5d)
Desilylated 2d (0.700 g, 1.33 mmol) was subjected to general procedure B using anisole
(0.15 mL, 1.33 mmol) and TFA (0.51 mL, 6.65 mmol) to give the corresponding acid 3d as a
colourless oil (0.510 g, 1.26 mmol, 95%). This was then committed to the general modified
procedure for Curtius rearrangement with Et3N (0.35 mL, 2.52 mmol), DPPA (0.33 mL, 1.51
mmol) and HCl (5 M, 2 mL) for the hydrolysis affording αꢀtertiary amine 4d as a colourless
liquid (0.335 g, 0.89 mmol, 67% from 2d). 4d (0.250 g, 0.67 mmol) was deprotected with
NaOMe in MeOH (1.0 M, 0.75 mL, 0.75 mmol) to afford 5d25 (0.140 g, 0.65 mmol, 97%) as
a viscous oil in 92% ee.
ACS Paragon Plus Environment

Page 23 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
1
[α]ꢁꢀꢂ = −29.0º, (c = 1.0, CHCl3); IR (vmax/cmꢀ1) 3370, 3265, 3034, 2950, 2320, 1733; H
NMR (300 MHz, CDCl3) δ 7.34−7.20 (m, 3H), 7.18−7.10 (m, 2H), 3.71 (s, 3H), 3.13 (d, J =
13.2 Hz, 1H), 2.87 (d, J = 13.2 Hz, 1H), 2.76 (dd, J = 16.4, 2.4 Hz, 1H), 2.51 (dd, J = 16.4,
9
13
2.4 Hz, 1H), 2.08 (t, J = 2.4 Hz, 1H), 1.82 (br s, 2H); C NMR (101 MHz, CDCl3) δ 175.4,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
135.9, 130.0, 128.6, 127.3, 79.6, 71.9, 61.8, 52.4, 45.3, 29.8; HRMS (ESI+) m/z: [M + H]+
Calcd for C13H16NO2 218.1176; Found 218.1181.
(R)ꢀMethyl 2ꢀaminoꢀ2ꢀisobutylpentꢀ4ꢀenoate 5e
Compound 2e (0.300 g, 0.61 mmol) was subjected to general procedure B using anisole
(0.08 mL, 0.732 mmol) and TFA (0.23 mL, 3.05 mmol) to give the corresponding acid 3e as
a colourless oil (0.200 g, 0.54 mmol, 88%), which was then committed to Curtius
rearrangement with Et3N (0.15 mL, 1.08 mmol), DPPA (0.14 mL, 0.648 mmol) and HCl (5
M, 2 mL) for the hydrolysis affording αꢀtertiary amine 4e (0.150 g, 0.44 mmol, 72% from 2e)
as a colourless liquid. 4e (0.130 g, 0.38 mmol) was deprotected with NaOMe in MeOH (1.0
M, 0.42 mL, 0.42 mmol) to afford 5e (0.052 g, 0.28 mmol, 74%) as an oil.
[ꢃ]ꢁꢀꢂ = +20.8º, (c = 1.0, CH2Cl2), [lit.26 [α]ꢁꢀꢂ = +41.3º, (c = 1.0, MeOH)]; IR (vmax/cmꢀ1)
1
3369, 2956, 1734; H NMR (300 MHz, CDCl3) δ 5.74−5.57 (m, 1H), 5.17−5.06 (m, 2H),
3.70 (s, 3H), 2.53 (dd, J = 13.4, 6.3 Hz, 1H), 2.15 (dd, J = 13.4, 8.4, 1H), 1.89−1.64 (m, 4H),
13
1.59−1.48 (m, 1H), 0.93 (d, J = 6.3 Hz, 3H), 0.82 (d, J = 6.3 Hz, 3H); C NMR (101 MHz,
CDCl3) δ 177.9, 132.7, 119.7, 60.6, 52.1, 48.7, 45.8, 24.7, 24.4, 22.9; HRMS (ESI+) m/z: [M
+ H]+ Calcd for C10H20NO2 186.1494; Found 186.1496
Compound 5e (0.020 g, 0.11 mmol) was dissolved in DCM (5 mL), and anhydrous pyridine
(0.01 mL, 0.13 mmol) and benzoyl chloride (0.02 mL, 0.13 mmol) were added, and the
reaction mixture was left to stir for 6 h. No workꢀup was performed; after removal of DCM
on the rotary evaporator the residue was chromatographed directly with ethyl acetate/hexane
to give the Nꢀbenzamide of 5e (0.015 g, 0.052 mmol, 48%,) as a colourless gum in 99% ee.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 34
1
2
3
4
1
IR (vmax/cmꢀ1) 3416, 2953, 1731, 1666; H NMR (300 MHz, CDCl3) δ 7.72 (m, 2H),
5
6
7
8
7.55−7.38 (m, 3H), 5.66−5.52 (m, 1H), 5.08−5.02 (m, 2H), 3.81 (s, 3H), 3.45 (dd, J = 13.8,
6.9 Hz, 1H), 2.70 (dd, J = 14.1, 5.1 Hz, 1H), 2.51 (dd, J = 13.8, 7.8 Hz, 1H), 1.78 (dd, J =
14.1, 5.1 Hz, 1H), 1.70−1.54 (m, 1H), 0.91 (d, J = 6.6 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 175.3, 166.3, 135.4, 132.4, 131.6, 128.8, 127.0, 119.2, 64.9, 52.8,
43.7, 40.5, 25.0, 24.0, 22.6; HRMS (ESI+) m/z: [M + H]+ Calcd. for C17H24NO3 290.1756;
Found 290.1748.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(R)ꢀMethyl 2ꢀallylꢀ6ꢀazidoꢀ2ꢀbenzamidohexanoate (Nꢀbenzamide of 5f)
Compound 2f (0.850 g, 1.59 mmol) was subjected to general procedure B using anisole (0.21
mL, 1.91 mmol) and TFA (0.61 mL, 7.95 mmol) to give the corresponding acid 3f as a
colourless oil (0.570 g, 1.38 mmol, 87%). All of the acid was then committed to the general
modified procedure for Curtius rearrangement with Et3N (0.38 mL, 2.76 mmol), DPPA (0.36
mL, 1.66 mmol) and HCl (5 M, 3 mL) for the hydrolysis affording αꢀtertiary amine 4f as a
colourless liquid (0.437 g, 1.14 mmol, 72% from 2f). 4f (0.400 g, 1.04 mmol) was
deprotected with NaOMe in MeOH (1.0 M, 1.2 mL, 1.20 mmol) to afford 5f (0.185 g, 0.82
mmol, 79%) as a gummy solid, which was taken up in DCM (10 mL), anhydrous pyridine
(0.17 mL, 2.06 mmol) and benzoyl chloride (0.14 mL, 1.25 mmol) added, and the reaction
mixture was left to stir for 6 h at rt. The DCM was then removed on the rotary evaporator and
the residue chromatographed directly with EtOAc/hexane (40/60) to give the Nꢀbenzamide of
5f (0.239 g, 0.72 mmol, 89% from 5f) as a lightꢀyellow gum in 98% ee.
1
[α]ꢁꢀꢂ = −15.8º, (c = 1.0, CHCl3); IR (vmax/cmꢀ1) 3329, 3071, 2945, 2090, 1728, 1654; H
NMR (300 MHz, CDCl3) δ 7.83−7.75 (m, 2H), 7.55−7.39 (m, 3H), 7.15 (br s, 1H), 5.70−5.53
(m, 1H), 5.14−5.01 (m, 2H), 3.83 (s, 3H), 3.39 (m, 1H), 3.32−3.14 (m, 2H), 2.70 (m, 1H)
2.57 (m, 1H), 1.90 (m, 1H), 1.66−1.49 (m, 2H), 1.48−1.29 (m, 1H), 1.22−1.04 (m, 1H); 13C
NMR (101 MHz, CDCl3) δ 174.4, 166.5, 135.1, 132.3, 131.7, 128.8, 127.0, 119.3, 65.3, 53.1,
ACS Paragon Plus Environment

Page 25 of 34
The Journal of Organic Chemistry
1
2
3
4
51.2, 39.7, 34.5, 28.7, 21.7; HRMS (ESI+) m/z: [M + H]+ Calcd for C17H23N4O3 331.1770
5
6
Found 331.1771.
7
8
9
(R)ꢀMethyl 2ꢀallylꢀ2ꢀbenzamidoꢀ6ꢀ((tertꢀbutoxycarbonyl)amino)hexanoate (N2ꢀBz, N6ꢀBoc
allyllysine methyl ester)
αꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The Nꢀbenzamide of 5f (0.065 g, 0.197 mmol) and PPh3 (0.103 g, 0.393 mmol) were
dissolved in THF/H2O (6/1, 5 mL) and stirred at rt for 9 h to convert the azide to the primary
amine. This was followed by the addition of Boc2O (0.086 g, 0.393 mmol) in THF (5 mL) in
which Nꢀprotection was complete within 15 minutes as indicated by tlc. Thereafter, THF was
removed on the rotary evaporator, water (5 mL) was added and the solution extracted with
EtOAc (3 x 10 mL). The combined organic fractions were dried over MgSO4, filtered and
concentrated under reduced pressure to afford a residue that was chromatographed using
EtOAc/hexane (15/85) delivering N2ꢀBz, N6ꢀBoc αꢀallyllysine methyl ester as a thick, lightꢀ
yellow oil (0.060 g, 0.149 mmol, 76% over two steps) in 98% ee.
[α]ꢁꢀꢂ = −12.8º, (c = 1.0, CHCl3); IR (vmax/cmꢀ1) 3407, 3339, 3071, 2929, 1733, 1686, 1654;
1H NMR (300 MHz, CDCl3) δ 7.83−7.73 (m, 2H), 7.55−7.37 (m, 3H), 7.14 (s, 1H),
5.69−5.52 (m, 1H), 5.10−4.95 (m, 2H), 4.55 (br s, 1H), 3.81 (s, 3H), 3.34 (dd, J = 13.9, 7.3
Hz, 1H), 3.12−2.98 (m, 2H), 2.73−2.61 (m, 1H), 2.57 (dd, J = 13.9, 7.3 Hz, 1H), 1.95−1.80
(m, 1H), 1.52−1.30 (m, 3H), 1.39 (s, 9H), 1.14−0.94 (m, 1H); 13C NMR (101 MHz, CDCl3) δ
174.4, 166.4, 156.1, 135.1, 132.4, 131.6, 128.7, 127.0, 119.2, 79.2, 65.2, 53.0, 40.2, 39.7,
34.6, 29.8, 28.5, 21.5; HRMS (ESI+) m/z: [M + H]+ Calcd. for C22H33N2O5 405.2380; Found
405.2389.
(S)ꢀMethyl 2ꢀaminoꢀ3ꢀ(4ꢀbromophenyl)ꢀ2ꢀmethylpropanoate (5g)
Compound 2g (0.800 g, 1.38 mmol) was subjected to general procedure B using anisole (0.15
mL, 1.38 mmol) and TFA (0.53 mL, 6.91 mmol) to give the corresponding acid 3g as a
colourless oil (0.500 g, 79%). This was then committed to the general modified procedure for
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 34
1
2
3
4
5
6
7
8
9
Curtius rearrangement with Et3N (0.30 mL, 2.18 mmol), DPPA (0.28 mL, 1.31 mmol) and
HCl (5 M, 2 mL) for the hydrolysis affording αꢀtertiary amine 4g as a colourless liquid (0.411
g, 0.96 mmol, 69% from 2g). 4g (0.400 g, 0.93 mmol) was deprotected with NaOMe and
MeOH (1.0 M, 1.0 mL, 1.00 mmol) to give 5g (0.180 g, 0.66 mmol, 71%) as a viscous oil in
98% ee.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[α]ꢁꢀꢂ = −12.0º, (c = 1.0, CH2Cl2), [lit.27 [α]ꢀꢁꢂ = +17.4º for the (R)ꢀisomer, (c = 1.0, CHCl3)];
IR (vmax/cmꢀ1) 3384, 2938, 1725; 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J = 8.3 Hz, 2H), 7.00
(d, J = 8.3 Hz, 2H), 3.67 (s, 3H), 3.04 (d, J = 13.2 Hz, 1H), 2.73 (d, J = 13.2 Hz, 1H), 1.72
(br s, 2H), 1.35 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 177.2, 135.6, 131.8, 131.5, 121.1,
58.8, 52.2, 46.3, 26.5; HRMS (ESI+) m/z: [M + H]+ Calcd. for C11H1579BrNO2 272.0281;
Found 272.0294.
Methyl (S)ꢀ2ꢀaminoꢀ2ꢀ((1ꢀtosylꢀ1Hꢀindolꢀ3ꢀyl)methyl)pentꢀ4ꢀenoate (5h)
Compound 2h (0.500 g, 0.70 mmol) was subjected to general procedure B using anisole (0.09
mL, 0.83 mmol) and TFA (0.53 mL, 6.9 mmol, 10 eq) to give acid 3h as a colourless oil after
column chromatography (0.300 g, 0.50 mmol, 72%) This was then committed to the general
modified procedure for Curtius rearrangement with Et3N (0.14 mL, 1.00 mmol), DPPA (0.13
mL, 0.60 mmol). The acyl azide formed was dissolved in pꢀxylene and heated at 125 ºC for 6
h followed by HCl (1.0 M, 4 mL) for the hydrolysis affording αꢀtertiary amine 4h as a
colourless liquid (0.251 g, 0.44 mmol, 63% from 2h). 4h (0.050 g, 0.088 mmol) was
deprotected with NaOMe in MeOH (0.1 mL, 0.1 mmol, 1.0 M) to give 5h (0.027 g, 0.066
mmol, 75%) as a colourless oil in > 99% ee.
[α]ꢁꢀꢂ = +9.9º, (c = 1, CHCl3); IR (vmax/cmꢀ1) 3375, 2968, 1730, 1367; 1H NMR (300 MHz,
CDCl3) δ 7.95 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.39 (s,
1H), 7.33−7.17 (m, 4H), 5.78−5.64 (m, 1H), 5.21−5.14 (m, 2H), 3.60 (s, 3H), 3.20 (d, J =
14.1 Hz, 1H), 2.91 (d, J = 14.1 Hz, 1H), 2.71 (dd, J = 13.5, 6.6 Hz, 1H), 2.38−2.25 (m, 1H),
ACS Paragon Plus Environment

Page 27 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
2.33 (s, 3H), 1.61 (br s, 2H); 13C NMR (101 MHz, CDCl3) δ 176.6, 145.0, 135.4, 135.2,
132.5, 131.5, 130.0, 126.9, 125.1, 124.9, 123.3, 120.1, 120.0, 117.7, 113.8, 62.1, 52.3, 44.5,
35.2, 21.7; HRMS (ESI+) m/z: [M + H]+ Calcd for C22H25N2O4S 413.1535; Found 413.1528.
9
(R)ꢀMethyl
2ꢀbenzylꢀ5ꢀ(benzyloxy)ꢀ2ꢀ((tertꢀbutoxycarbonyl)amino)pentanoate
(NꢀBoc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
derivative of 5i)
Compound 2i (1.20 g, 1.89 mmol) was subjected to general procedure B using anisole (0.25
mL, 2.27 mmol) and TFA (0.72 mL, 9.46 mmol) to give acid 3i as a colourless oil (0.900 g,
1.75 mmol, 92%). This was then committed to the general modified procedure for Curtius
rearrangement with Et3N (0.48 mL, 3.41 mmol), DPPA (0.44 mL, 2.05 mmol) and HCl (5 M,
3 mL) for the hydrolysis affording αꢀtertiary amine 4i as a colourless liquid (0.725 g, 1.49
mmol, 79% from 2i). 4i (0.370 g, 0.76 mmol) was deprotected with NaOMe in MeOH (1.0
M, 0.84 mL, 0.84 mmol) to afford 5i (0.170 g, 0.52 mmol, 68%) as a clear gum, which was
reacted with Boc2O (0.170 g, 0.78 mmol) in tꢀBuOH (10 mL) overnight at rt. Following
removal of tꢀBuOH on the rotary evaporator, the residue was chromatographed directly using
EtOAc/hexanes (10/90) to give the NꢀBoc derivative of 5i (0.169 g, 0.39 mmol, 76% from 5i)
as a gummy solid in 90% ee.
[α]ꢁꢀꢂ = −42.5º, (c = 1.0, CHCl3); IR (vmax/cmꢀ1) 3332, 2955, 2919, 1733, 1670; 1H NMR (300
MHz, CDCl3) δ 7.39−7.18 (m, 8H), 7.09−7.01 (m, 2H), 5.38 (br s, 1H), 4.49 (s, 2H), 3.74 (s,
3H), 3.60 (d, J = 13.5 Hz, 1H), 3.53−3.41 (m, 2H), 3.11 (d, J = 13.5 Hz, 1H), 2.58−2.36 (m,
1H), 2.08−1.90 (m, 1H), 1.76−1.57 (m, 1H), 1.48 (s, 9H), 1.52−1.31 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 173.6, 154.2, 138.7, 136.7, 130.0, 128.5, 128.3, 127.7, 127.6, 126.9, 79.3,
72.9, 70.0, 65.0, 52.6, 41.2, 32.5, 28.6, 24.8; HRMS (ESI+) m/z: [M + H]+ Calcd for
C25H34NO5 428.2431; Found 428.2440.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 34
1
2
3
4
(R)ꢀaꢀBenzylproline Methyl ester 6
5
6
7
8
NꢀBoc 5i (0.150 g, 0.35 mmol) was dissolved in deoxygenated MeOH (10 mL), and Pd/C (10
wt %, 0.040 g, 0.035 mmol) was carefully added under nitrogen gas flow. The reaction was
then placed under a hydrogen atmosphere and stirred at rt for 2 h, following which it was
filtered through Celite®, concentrated and committed to column chromatography directly
using EtOAc/hexanes (20/80) to yield the corresponding alcohol (0.101 g, 0.30 mmol, 85%)
as a viscous oil. The latter (0.060 g, 0.18 mmol) was dissolved in DCM (3 mL) and to this
was then added pyridine (0.30 mL, 0.35 mmol), DMAP (0.011 g, 0.03 mmol) and mesyl
chloride (0.030 mL, 0.35 mmol) and the reaction stirred at rt for 4 h. The mixture was
transferred to a separating funnel and washed with aqueous saturated sodium bicarbonate (15
mL) and the aqueous layer extracted with DCM (3 x 20 mL). Pooled organic fractions were
dried over anhydrous MgSO4, filtered and concentrated in vacuo and the residue was
committed to flash chromatography using EtOAc/hexanes (10/90) to yield the mesylate
(0.070 g, 0.17 mmol, 92% from the alcohol) as a colourless gum.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (300 MHz, CDCl3) δ 7.28−7.18 (m, 3H, aromatic), 7.07−6.98 (m, 2H, aromatic),
5.38 (broad s, 1H), 4.28−4.15 (m, 2H), 3.77 (s, 3H), 3.60 (d, J = 13.5 Hz, 1H), 3.06 (d, J =
13.5 Hz, 1H), 3.01 (s, 3H), 2.66−2.52 (m, 1H), 2.10−1.98 (m, 1H), 1.85−1.71 (m, 1H),
1.65−1.52 (m, 1H), 1.41 (s, 9H).
To the mesylate (0.070 g, 0.17 mmol) dissolved in DCM (2 mL) and cooled to 0 ºC was
added TFA (0.07 mL, 0.92 mmol). Stirring was continued at this temperature for 2 h, after
which time TLC analysis indicated complete deprotection of the starting material. The
intermediate free amine was not isolated and the reaction mixture was concentrated in vacuo
to remove solvent and TFA. The yellowish liquid was reꢀtaken up in THF (3 mL) and
triethylamine (0.27 mL, 1.93 mmol) was added. The solution was stirred at rt for 1h, after
which, following THF removal on the rotary evaporator, water (15 mL) was added and the
ACS Paragon Plus Environment

Page 29 of 34
The Journal of Organic Chemistry
1
2
3
4
5
6
aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic fractions were
dried over anhydrous MgSO4, filtered, concentrated and the resultant residue was
7
8
chromatographed using EtOAc/hexanes to furnish (R)ꢀαꢀbenzylproline methyl ester28
6
9
(0.032 g, 0.15 mmol, 86%) as a clear viscous liquid in 91% ee.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[α]ꢁꢀꢂ = −10.0º, (c = 1.0, CHCl3); IR (vmax/cmꢀ1) 3349, 3029, 2950, 1733; 1H NMR (300 MHz,
CDCl3) δ 7.32−7.11 (m, 5H), 3.66 (s, 3H), 3.17 (d, J = 13.1 Hz, 1H), 3.04−2.92 (m, 2H), 2.87
(d, J = 13.1 Hz, 1H), 2.29−2.19 (m, 1H), 2.15 (br s, 1H) 1.91−1.63 (m, 3H); 13C NMR (101
MHz, CDCl3) δ 177.0, 137.6, 129.8, 128.3, 126.8, 70.7, 52.1, 46.1, 45.5, 35.8, 24.5; HRMS
(ESI+) m/z: [M + H]+ Calcd C13H18NO2 220.1332; Found 220.1338.
SUPPORTING INFORMATION
1H and 13C NMR spectra and HPLC traces of all compounds are presented. This material is
available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENTS: We thank the South African National Research Foundation, the
Claude Leon Foundation, and Sasol Ltd for financial support towards this project.
REFERENCES
(1) For recent reviews, see: (a) Clayden, J.; Donnard, M.; Lefranc, J.; Tetlow, D. J. Chem.
Commun. 2011, 47, 4624−4639. (b) Aceña, J. L.; Sorochinsky, A. E.; Soloshonok, V. A.
Synthesis 2012, 44, 1591−1602. (c) Desmarchelier, A.; Coeffard, V.; Moreau, X.; Greck, C.
Tetrahedron 2014, 70, 2491−2513. (d) Zhou, F.; Liao, F.ꢀM.; Yu, J.ꢀS.; Zhou, J. Synthesis
2014, 46, 2983−3003. (e) Bera, K.; Namboothiri, I. N. N. Asian. J. Org. Chem. 2014, 3,
1234−1260. (f) Liu, Y.; Han, S.ꢀJ.; Liu, W.ꢀB.; Stolz, B. M. Acc. Chem. Res. 2015, 48,
ACS Paragon Plus Environment