Improved auxiliary for the synthesis of medium-sized bis(lactams)

Article abstract of DOI:10.1002/ejoc.200700832

Our auxiliary-based method for the synthesis of bis(lactams) has been optimized. A novel auxiliary is described that is inserted in the backbone of a linear peptide facilitating the mutually reactive terminal groups to approach one another for a cyclizati

Full text of DOI:10.1002/ejoc.200700832

FULL PAPER
DOI: 10.1002/ejoc.200700832
Improved Auxiliary for the Synthesis of Medium-Sized Bis(lactams)
Jasper Springer,[a] T. Paul Jansen,[a] Steen Ingemann,[a] Henk Hiemstra,[a] and
Jan H. van Maarseveen*[a]
Keywords: Bis(lactams) / Templated synthesis / Auxiliaries / Cyclic peptides
Our auxiliary-based method for the synthesis of bis(lactams)
has been optimized. A novel auxiliary is described that is
inserted in the backbone of a linear peptide facilitating the
mutually reactive terminal groups to approach one another
for a cyclization reaction. A subsequent ring contraction
mechanism leads to the bis(lactams) with the remainings of
the auxiliary still attached. Functionalized seven- and eight-
membered bis(lactams) have been prepared that are difficult
to access using traditional methods. Removal of the auxiliary
from the bis(lactams) has been described with the possible
side reactions that can occur.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
tical research, cyclic peptides find application in fields such
as materials science[4] and catalysis.[5]
Small cyclic peptides constitute an important class of
compounds.[1] Naturally occurring cyclic peptides often
Despite their interesting properties, especially 7–15-mem-
possess potent biological activities.[1d] Because of their re- bered cyclic peptides find limited application mainly be-
stricted conformational flexibility they often show en- cause of their troublesome synthesis. Ring-closure is often
hanced receptor selectivity.[2] Compared to their linear hampered by the backbone amide bonds possessing a
counterparts, cyclic peptides are more resistant against en- strong π-character with preferentially a transoid conforma-
zymatic degradation and show a better membrane perme- tion leading to an extended structure with the mutually re-
ability improving their bioavailability.[3] Besides pharmaceu- active terminal groups far apart.[6]
Scheme 1. General strategy for the synthesis of bis(lactams). Reaction conditions: (i) reductive amination; (ii) (Boc)2O; (iii) coupling
reaction; (iv) protecting group removal; (v) TFA; (vi) base; (vii) auxiliary removal.
[a] Van ’t Hoff Institute for Molecular Sciences, University of
Amsterdam,
Synthetic strategies using peptide coupling reagents and
high-dilution conditions often lead to low yields.[7] Other
strategies are based on the use of auxiliaries,[8] cyclizations
on solid phase,[9] intramolecular Staudinger ligation reac-
tions,[10] chemoenzymatic cyclizations[11] and on the site-
isolation effect exerted within dendrimeric nanoreactors.[12]
Nieuwe Achtergracht 129, 1018 WS, Amsterdam, The Nether-
lands
Fax: +31-20-5255670
E-mail: jvm@science.uva.nl
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
Eur. J. Org. Chem. 2008, 361–367
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
361

J. Springer, T. P. Jansen, S. Ingemann, H. Hiemstra, J. H. van Maarseveen
FULL PAPER
However, each application is still limited to specific se-
quences.
The smallest cyclic peptides that are difficult to address
by classical direct lactamization (Scheme 1, route A) are the
seven- and eight-membered bis(lactams) 2 (homodiketopip-
erazines), made up of α-, β- or γ-amino acids.[13] On the
basis of pioneering studies by Meutermans et al.[8a,8c]
(Scheme 1, route B) we have recently developed a general
and sequence-independent methodology for the efficient
synthesis of such bis(lactams) (Scheme 1, route C).[8b,8d]
In the strategy of Meutermans, which has been success-
fully applied in the synthesis of cyclic pentapeptides,[8a] the
backbone amide bonds still hamper the macrolactonization
step, thus leading to extensive epimerization. In addition,
we have previously shown the sequence dependency of
route B towards homodiketopiperazines.[8d]
Scheme 2. Synthesis of the auxiliary.
Auxiliary 3c was obtained from commercially available
2,3,4-trimethoxybenzaldehyde (3a). Selective “BCl3-medi-
ated” demethylation of 3a[16] was followed by alkylation
with isopropyl bromide.[17] Besides 3c, a mixture derived
from alkylation on the ortho position and alkylation on
both phenols was obtained. From this mixture 3c could be
isolated easily, although in a moderate 38% yield.
As a model compound to test the methodology (S)-3-
benzyl-1,4-diazepine-2,5-dione (2a) was chosen (Schemes 3
and 4). To date, this seven-membered bis(lactam) could not
be ring-closed by direct head-to-tail cyclization conditions
from both linear precursors.[8d]
Results and Discussion
In our approach, a salicylaldehyde-derived auxiliary 3 is
incorporated within the backbone of a linear peptide 5
(Scheme 1, route C). A macrolactamization reaction, facili-
tated by a combination of the templating effect of the auxil-
iary and an extension of the backbone by four atoms, re-
sults in the formation of lactam 6. Liberation of the Boc-
protected amine induces a ring-contractive OǞN acyl shift
providing the strained target lactam 7. Final removal of the
auxiliary residue liberates the lactam 2.
In a previous study we found that introduction of a steri-
cally demanding substituent flanking the aryl ester
(Scheme 1; 3: R1 = H, R2 = OtBu) was necessary to prevent
premature intermolecular aminolysis during the macrolac-
tamization step.[8d] A drawback of this auxiliary, however,
is the harsh conditions required for removal of its remain-
ings after the final ring contraction step liberating the lac-
tam 2. More importantly, the sterically demanding OtBu
substituent prevented incorporation of two α-substituted
amino acids flanking the auxiliary,[14] thereby severely limit-
ing the synthetic scope of the target compounds. Herein,
we present 2-hydroxy-3-isopropoxy-4-methoxybenzalde-
hyde (3c) as an improved auxiliary overcoming these prob-
lems as will be shown by the synthesis of several substituted
seven- and eight-membered bis(lactams).
Scheme 3. Synthesis of the linear precursors.
To avoid racemization in peptide synthesis, removal of
The synthesis of the linear cyclization precursor peptides
protective groups is preferably done by treatment with was accomplished by reductive amination of auxiliary 3c
strong acid. with H–Phe–OBn or H–βAla–OBn (Scheme 3, routes I and
It was anticipated that incorporation of a methoxy sub- II, respectively), followed by Boc protection of the resulting
stituent on the para position with respect to the aldehyde secondary amine to give the phenols 4a and 4b in yields
group on the auxiliary (Scheme 1; R1 = OMe) should of 91% and 78%, respectively. Consecutive “EDCI/DMAP-
render the benzylic amide bond susceptible for acidolytic mediated” esterification of the phenol with Cbz–βAla–OH
cleavage.[15] To reduce the steric hindrance of substituent R2 (route I) or acyl fluoride coupling[18] with Cbz–Phe–F in
such that it still prevents premature aminolysis of the phe- the presence of DIPEA (route II), provided the protected
nolic ester during the macrolactamization step but allowing linear precursor peptides 5a and 5b in yields of 99% and
the introduction of two α-substituted amino acids, we chose 84%, respectively. These two coupling methods are comple-
to replace the tBu group by an isopropyl group to give aux- mentary, although acyl fluoride couplings are preferred
iliary 3c (Scheme 2).
during sterically hindered couplings (vide infra).
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Improved Auxiliary for the Synthesis of Medium-Sized Bis(lactams)
respectively (Scheme 5). For these two examples esterifica-
tion using the coupling reagents EDCI and DMAP only
gave low yields. To our delight the more powerful acyl fluo-
ride coupling using Cbz–Phe–F and DIPEA gave the esters
5d and 5e in good yields of 61% and 99%, respectively, for
these very hindered couplings.
Scheme 4. Synthesis of the seven-membered bis(lactams).
Scheme 5. Synthesis of the eight-membered bis(lactams).
Hydrogenolytic removal of the Bn and Cbz groups from
5a and 5b provided the precursors for the tethered macro-
The rest of the sequence was continued using the opti-
lactamization step (Scheme 4). Activation of the carboxylic mized conditions resulting in the formation of the products
acid by EDCI/HOBt under diluted conditions (10–3 m) 7d and 7e in yields of 30% over four steps. Macrolactami-
smoothly gave the medium-sized lactams 6a and 6b, respec- zation reactions were run at a concentration of 10–3 m to
tively, without the detectable formation of dimers or oligo- avoid any oligomerization. These two examples have shown
mers. Also, no premature intermolecular aminolysis was the efficiency of our method for substituted eight-mem-
observed, indicating that the isopropyl group exerts suf- bered bis(lactams) giving the products in acceptable overall
ficient steric bulk to shield the ester.
yields.
Evaluation of the enantiomeric purity of the products 7d
The obtained lactams 6a and 6b were not purified, as
this led to inevitable loss of the products, so the crude mix- and 7e was performed by hydrolysis of the products in
ture was carried on in further reactions. “TFA-mediated” strong acidic media and subsequent GC-MS analysis for
removal of the Boc group from both crude 6a and 6b was the presence of l-Phe and d-Phe. This revealed an enantio-
followed by “NaHCO3-mediated” neutralization inducing meric excess of 80% for 7d and 97% for 7e, indicating that
the final ring contraction providing the N-benzyl-substi- no extensive racemization had occurred.
tuted 1,4-diazepine-2,5-diones 7a and 7b in overall yields of
In the case of the seven-membered bis(lactams) the auxil-
72% and 85%, respectively, over four steps.
iary remainings were removed by treatment of both 7a and
We then turned our attention to the eight-membered bis- 7b with TFA in the presence of anisole at 60 °C liberating
(lactam) series. Only a few examples of substituted 1,4-di- the target (S)-3-benzyl-1,4-diazepine-2,5-dione 2a[8d,10] in
azocane-3,8-diones are known which show interesting bio- nearly quantitative yields after precipitation with diethyl
logical activities.[19] Herein it has been described that the ether/pentane (Scheme 4).
cyclizations of the linear precursors gave low yields only. To
Evaluation of the enantiomeric purity of the product 2a
show the applicability of the method, two substituted 1,4- by chiral HPLC showed that no extensive racemization had
diazocane-3,8-diones 7d and 7e were addressed. The latter occurred, especially during the coupling of the α-substi-
example also bears substituents next to the amine and car- tuted amino acid in route II (Scheme 3; route I: ee = 97%;
boxyl auxiliary connecting groups, a sequence that was in- route II: ee = 90%). Compared to experiments using more
accessible using the previously described auxiliary 3 (R1 = hindered templates (R2 = OtBu, OTIPS; data not shown)
H, R2 = OtBu).
giving extensive epimerization due to slow esterification re-
The reductive amination of γ-Abu–OBn and Glu(OMe)– actions (ee values only up to ca. 60%), the enantiomeric
OBn with the auxiliary and subsequent Boc protection purity had greatly improved especially during the hindered
smoothly gave the phenols in good yields of 69% and 54%, coupling along route II.
Eur. J. Org. Chem. 2008, 361–367
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Springer, T. P. Jansen, S. Ingemann, H. Hiemstra, J. H. van Maarseveen
FULL PAPER
Unexpectedly, removal of the auxiliaries from both the straightforward synthesis of the cyclization precursors and
eight-membered bis(lactams) 7d and 7e only led to side re- can be efficiently removed from the seven-membered bis-
actions. Treatment of 7d and 7e with TFA in the presence (lactams). However, removal of the auxiliary from the eight-
of anisole at 60 °C resulted, as became clear by careful LC- membered bis(lactms) is hindered by unwanted side reac-
MS and MS-MS analysis, in re-attack of the phenol to the tions and possible product instability. Currently, auxiliary
tertiary amide forming back the ester and the amine as it’s 3c is developed further to allow solid-phase combinatorial
TFA salt (Scheme 6; 7d shown). Most probably this is due access towards a library of medium-sized bis(lactams)[22] as
to the unfavored eight-membered ring as becomes apparent well as the use of auxiliary 3c in the synthesis of cyclic tetra-
from the amide carbonyl IR absorptions of 7e (1731 and peptides with all-l configuration.[23]
1664 cm–1) showing the ketone character of the tertiary
amide carbonyl moiety due to loss of planarity of this
amide to relief ring-strain. To prevent these side reactions
Experimental Section
it was tried to methylate the phenolic hydroxy group, but
General: All reactions were conducted under nitrogen unless stated
otherwise and monitored by TLC on silica gel coated aluminium
sheets. Flash column chromatography was performed on silica gel
300–400 mesh using the indicated solvent mixtures. All solvents
were distilled from sodium/benzophenone ketyl (THF, Et2O) or
CaH2 (DMF, CH2Cl2). The NMR spectra were determined in
CDCl3 solutions, using a Bruker ARX 400 and a Varian Inova 500
spectrometer unless indicated otherwise. Spectra are reported in δ
units (ppm) and J values (Hz) with Me4Si as the internal standard.
HRMS data (FAB+) were recorded with a JEOL JMS SX/SX 102A
four-sector mass spectrometer. The LC-MS experiments were per-
formed with the use of a Finnigan LXQ Ion Trap apparatus. LC
was carried out with an ODS-3 column using gradients between
H2O/0.1% HCOOH (solvent A) and CH3CN/0.1% HCOOH (sol-
vent B). The electronspray ionization mass spectra (positive ions)
were recorded in full scan mode (m/z = 100–2000). The MS-MS
experiments were performed by collision-induced dissociation with
an indicated collision energy of 30 eV. Infrared (IR) spectra were
obtained with a Bruker IFS 28 FTIR spectrometer and are re-
ported in wave numbers [cm–1]. Melting points were recorded with
a Büchi melting point apparatus B-545 and are uncorrected. HPLC
analyses were measured with an Agilent HPLC system equipped
with a C-18 column (Varian-Chrompack, inertsil-ODS-3, 3μ,
50ϫ4.6 mm), a maximum flowspeed of 2.0 mL/min, the UV/Vis
detector at λ = 220 or 254 nm as indicated, and a gradient of 100%
A to 100% B [A: H2O/CH3CN/HCOOH (95:5:0.04); B: H2O/
CH3CN/HCOOH (5:95:0.04)] as the eluent in 5 min. The enantio-
meric excess values of compounds 2a were determined at DSM
Pharma Chemicals and obtained from chiral HPLC analyses.
Measurements were taken on I.D. Chiralpack AD column
(25ϫ0.46 cm), a flowspeed of 1 mL/min, the UV/Vis detector at λ
all attempts were unsuccessful (not shown).[20]
Scheme 6. Possible auxiliary-mediated side reactions from 7.
Furthermore, by LC-MS imidazolone 9d was charac-
terized. The formation of 9d can be envisioned by an equi-
librium of 7d with the bicyclic hemiaminal 8d by transannu-
lar attack of the γ-amino acid amide nitrogen atom on the
opposite amide carbonyl moiety followed by loss of water
(Scheme 7).[21] This may also explain the difficulties in the = 210 nm, and n-heptane/iPrOH (55:45%v/v) as the eluent.
removal of the template from both products 7d and 7e by
treatment with TFA.
2-Hydroxy-3-isopropoxy-4-methoxybenzaldehyde (3c): Compound
3b (0.5 g, 3 mmol) was added in small portions to a solution of
sodium hydride (0.240 g, 60% w/w in mineral oil, 6 mmol) in dry
DMSO (8 mL). The solution was stirred for 20 min, after which
potassium iodide (0.498 g, 3 mmol) and 2-bromopropane
(0.282 mL, 3 mmol) were added. The reaction mixture was stirred
at room temperature for 16 h after which it was diluted with EtOAc
(30 mL) and washed with water (2ϫ40 mL). The organic phase
was then washed with brine, dried with Na2SO4 and concentrated
in vacuo. The crude product was purified by flash column
chromatography [silica gel; ethyl acetate/petroleum ether (boiling
range 40–65 °C), 1:9] to give aldehyde 1c as yellowish needles
(0.193 g, 0.92 mmol, 31%). M.p. 81–83 °C. 1H NMR (400 MHz,
CDCl3): δ = 11.14 (s, 1 H), 9.74 (s, 1 H), 7.27 (d, J = 8.4 Hz, 1 H),
6.59 (d, J = 8.8 Hz, 1 H), 4.46 (sept, J = 6.4 Hz, 1 H), 3.92 (s, 3
H), 1.32 (d, J = 6.4 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 194.9, 160.0, 156.3, 134.1, 129.9, 116.5, 103.9, 75.3, 56.2, 22.5
Scheme 7. Possible transannulation process providing 9d.
Conclusions
We have optimized our auxiliary-based approach
towards medium-sized bis(lactams) that are difficult to ac-
cess using traditional methodologies. Auxiliary 3c allows ppm. IR (neat): ν = 1639, 1502, 1439 cm–1.
˜
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Improved Auxiliary for the Synthesis of Medium-Sized Bis(lactams)
General Procedure for Reductive Amination and Boc Protection: The
appropriate amine (1.1 equiv.) and Na2SO4 (excess) was added to
a solution of the aldehyde in THF. The reaction mixture was then
stirred at room temperature for 3–5 h after which Na(OAc)3BH
(4 equiv.) was added and stirring was continued for 16 h. The reac-
tion mixture was then quenched by pouring it into saturated am-
monium chloride solution and stirring for 30 min. The remaining
mixture was quenched with saturated sodium hydrogen carbonate
solution and extracted with EtOAc. The organic phase was then
washed with brine, dried with Na2SO4 and concentrated in vacuo.
The product was used without purification in the next step. If nec-
essary the resulting oil can be purified by flash column chromatog-
raphy [silica gel, ethyl acetate/petroleum ether (40:65), 1:3]. To a
solution of the amine in dry CH2Cl2 was added (Boc)2O (1.1–
1.5 equiv.), and the reaction mixture was stirred at room tempera-
ture until completed. The reaction mixture was then washed with
NaHCO3 (sat.) and brine, dried with Na2SO4 and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy [silica gel; ethyl acetate/petroleum ether (boiling range 40–
65 °C), 1:9, then 1:4].
ral procedure, using aldehyde 3c (0.200 g, 0.95 mmol) and H2N–
Glu(OBn)–OMe (0.475 g, 1.3 mmol), the product 4e (0.277 g,
0.51 mmol, 54%) was obtained as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.43–7.27 (m, 5 H), 6.85 (d, J = 8.4 Hz, 1
H), 6.36 (d, J = 8.4 Hz, 1 H), 5.06 (m, 2 H), 4.70 (br. s, 1 H), 4.40
(m, 3 H), 4.08 (m, 1 H), 3.80 (br. s, 3 H), 3.58 (br. s, 3 H), 2.25 (br.
m, 4 H), 1.43 (s, 9 H), 1.28 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.9, 171.5, 156.4, 153.6, 151.5, 135.8, 134.0, 128.5,
128.2, 128.2, 127.6, 127.0, 125.3, 123.1, 116.3, 103.1, 102.6, 75.1,
74.9, 66.8, 66.4, 61.0, 60.5, 58.9, 55.7, 53.6, 52.2, 51.7, 46.3, 42.8,
30.8, 30.2, 28.2, 23.5, 22.4 ppm. IR (neat): ν = 1734, 1688, 1652,
˜
1506, 1456 cm–1. HRMS (FAB+): calcd. for C29H39O9N 545.2625,
found 545.2620.
General Procedure for Esterification: To a solution of the phenol in
dry MeCN was added the appropriate acid followed by EDCI and
DMAP. The reaction mixture was then stirred at room temperature
until completion, after which the solvent was evaporated and the
residue taken up in EtOAc and washed with a solution of potas-
sium hydrogensulfate (0.5 m, 2ϫ) and brine. The organic phase was
dried with Na2SO4 and concentrated in vacuo. The crude product
was purified by flash column chromatography [silica gel; ethyl ace-
tate/petroleum ether (boiling range 40–65 °C), 1:3–4] to yield the
product.
Benzyl 2-[tert-Butoxycarbonyl(2-hydroxy-3-isopropoxy-4-methoxy-
benzyl)amino]-3-phenylpropionate (4a): According to the general
procedure, using aldehyde 3c (0.070 g, 0.33 mmol) and H2N–Phe–
OBn (0.084 g, 0.33 mmol), the product 4a (0.164 g, 0.30 mmol,
91%) was obtained as a colorless oil. 1H NMR (125 MHz, CDCl3):
δ = 7.32–7.14 (m, 10 H), 6.76 (d, J = 8.5 Hz, 1 H), 6.27 (d, J =
8.3 Hz, 1 H), 5.85 (br. s, 1 H), 5.07–4.95 (m, 2 H), 4.60–4.24 (m, 3
H), 3.79 (s, 3 H), 3.70 (m, 1 H), 3.38 (dd, J = 13.8, J = 5.1 Hz, 1
H), 3.25–3.13 (m, 1 H), 1.42 (s, 9 H), 1.27 (d, J = 6.3 Hz, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 170.6, 155.7, 152.7, 149.3,
137.9, 135.2, 129.2, 128.3, 128.2, 127.9, 127.8, 126.4, 125.3, 116.2,
103.0, 81.4, 74.9, 66.5, 61.7, 55.6, 47.4, 36.2, 28.1, 22.4 ppm. IR
Benzyl 2-[{2-[3-(Benzyloxycarbonylamino)propionyloxy]-3-isoprop-
oxy-4-methoxybenzyl}(tert-butoxycarbonyl)amino]-3-phenylpropi-
onate (5a): According to the general procedure, using phenol 4a
(0.100 g, 0.18 mmol) and Cbz–β-Ala–OH (0.080 g, 0.36 mmol), the
product 5a (0.096 g, 0.13 mmol, 71%) was obtained as a colorless
oil. 1H NMR (500 MHz, CDCl3): δ = 7.36–7.04 (m, 15 H), 6.80
(d, J = 8.5 Hz, 1 H), 6.53 (d, J = 8.1 Hz, 1 H), 5.65 (br. s, 1 H),
5.13–5.05 (m, 5 H), 4.36 (m, 2 H), 3.88 (br. s, 1 H), 3.79 (s, 3 H),
3.55 (br. s, 3 H), 3.34 (m, 1 H), 3.06 (m, 1 H), 2.71 (br. m, 2 H),
1.44 (s, 9 H), 1.16 (br. d, J = 6.1 Hz, 6 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.5, 169.8, 156.3, 154.6, 153.0, 143.6,
138.2, 136.4, 135.3, 129.2, 129.1, 128.3, 128.1, 127.9, 126.4, 124.5,
122.2, 109.4, 80.9, 75.2, 66.7, 66.4, 60.9, 55.7, 46.9, 36.5, 36.3, 34.2,
(neat): ν = 1710, 1697, 1616, 1506, 1455 cm–1. HRMS (FAB+):
˜
calcd. for C32H40O7N 550.2810, found 550.2801.
Benzyl 3-[tert-Butoxycarbonyl(2-hydroxy-3-isopropoxy-4-methoxy-
benzyl)amino]propionate (4b): According to the general procedure,
using aldehyde 3c (0.169 g, 0.8 mmol) and H2N–βAla–OBn
(0.179 g, 1 mmol), the product 4b (0.416 g, 0.73 mmol, 91%) was
28.2, 22.4 ppm. IR (neat): ν = 1723, 1698, 1498, 1454 cm–1. HRMS
˜
(FAB+): calcd. for C43H51O10N2 755.3545, found 755.3527.
1
obtained as a colorless oil. H NMR (400 MHz, CDCl3): δ = 7.64
6-({[2-(Benzyloxycarbonyl)ethyl](tert-butoxycarbonyl)amino}-
methyl)-2-isopropoxy-3-methoxyphenyl 2-(Benzyloxycarbonyl-
amino)-3-phenylpropionate (5b): Cbz–Phe–F (0.127 g, 0.42 mmol)
and DIPEA (0.073 mL, 0.42 mmol) were added to a solution of the
phenol 4b (0.100 g, 0.21 mmol) in dry CH2Cl2 (4 mL). The reaction
mixture was stirred at room temperature until completion. The
mixture was diluted with EtOAc (15 mL) and washed with water
(2ϫ15 mL) and brine. The organic phase was dried with Na2SO4
and concentrated in vacuo. The crude product was purified by flash
column chromatography [silica gel; ethyl acetate/petroleum ether
(boiling range 40–65 °C), 1:4] to yield the product 5b (0.133 g,
(br. s, 1 H), 7.40–7.35 (m, 5 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.42 (d,
J = 8.4 Hz, 1 H), 5.12 (s, 2 H), 4.52 (br. s, 1 H), 4.38 (s, 2 H), 3.38
(s, 3 H), 3.53 (br. s, 2 H), 2.60 (br. s, 2 H), 1.48 (s, 9 H), 1.31 (d, J
= 6.0 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.6,
135.7, 128.5, 128.2, 128.2, 127.6, 127.0, 124.6, 117.0, 103.2, 75.0,
66.3, 60.4, 55.8, 46.3, 42.8, 33.6, 28.4, 22.5 ppm. IR (neat): ν =
˜
1734, 1688, 1652, 1506, 1456 cm–1. HRMS (FAB+): calcd. for
C26H36O7N 474.2490, found 474.2429.
Benzyl 4-[tert-Butoxycarbonyl(2-hydroxy-3-isopropoxy-4-methoxy-
benzyl)amino]butyrate (4d): According to the general procedure,
using aldehyde 3c (0.300 g, 1.4 mmol) and H2N–γAbu–OBn
(0.348 g, 1.8 mmol), the product 4d (0.468 g, 0.96 mmol, 69%) was
1
0.18 mmol, 84%) as a colorless oil. H NMR (400 MHz, CDCl3):
1
δ = 7.33–7.15 (m, 15 H), 7.03 (bd, 1 H), 6.80 (d, J = 8.0 Hz, 1 H),
5.17–4.99 (m, 5 H), 4.51 (br. s, 1 H), 4.28–4.17 (br. m, 2 H), 3.86
(s, 3 H), 3.46–3.14 (br. m, 4 H), 2.59–2.50 (br. m, 2 H), 1.48 (s, 9 H),
1.23 (br. d, J = 14.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 171.8, 169.5, 155.8, 155.4, 152.1, 141.8, 137.0, 135.7, 129.5, 129.3,
128.6, 128.5, 128.4, 128.4, 128.1, 128.0, 127.0, 126.9, 124.0, 120.1,
110.2, 80.1, 75.2, 66.9, 66.3, 60.4, 55.8, 54.8, 45.2, 43.1, 37.8, 33.5,
obtained as a colorless oil. H NMR (400 MHz, CDCl3): δ = 8.02
(br. s, 1 H), 7.39–7.33 (m, 5 H), 6.81 (d, J = 8.8 Hz, 1 H), 6.40 (d,
J = 8.4 Hz, 1 H), 5.13 (s, 2 H), 4.50 (br. s, 1 H), 4.35 (s, 2 H), 3.83
(s, 3 H), 3.25 (br. s, 2 H), 2.36 (t, J = 7.2 Hz, 2 H), 1.89 (quint, J
= 7.2 Hz, 2 H), 1.47 (s, 9 H), 1.32 (d, J = 6.0 Hz, 6 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.9, 156.0, 140.9, 135.9, 133.0,
128.6, 128.6, 128.2, 127.6, 127.0, 124.7, 117.1, 103.1, 75.0, 66.4,
28.4, 22.4 ppm. IR (neat): ν = 1769, 1727, 1693, 1498, 1454 cm–1.
˜
66.3, 65.4, 55.8, 45.7, 31.5, 28.4, 23.3, 22.6 ppm. IR (neat): ν =
˜
HRMS (FAB+): calcd. for C43H50O10N2 754.3465, found 754.3450.
1737, 1690, 1654, 1504, 1455 cm–1. HRMS (FAB+): calcd. for
C27H37O7N 487.2570, found 487.2568.
Benzyl 4-[{2-[2-(Benzyloxycarbonylamino)-3-phenylpropionyloxy]-3-
5-Benzyl 1-Methyl 2-[tert-Butoxycarbonyl(2-hydroxy-3-isopropoxy- isopropoxy-4-methoxybenzyl}(tert-butoxycarbonyl)amino]butyrate
4-methoxybenzyl)amino]pentanedioate (4e): According to the gene- (5d): Cbz–Phe–F (0.579 g, 1.92 mmol) and DIPEA (0.334 mL,
Eur. J. Org. Chem. 2008, 361–367
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. Springer, T. P. Jansen, S. Ingemann, H. Hiemstra, J. H. van Maarseveen
FULL PAPER
1.92 mmol) were added to a solution of the phenol 4d (0.468 g,
0.96 mmol) in dry CH2Cl2 (15 mL). The reaction mixture was
stirred at room temperature until completion. The mixture was di-
luted with EtOAc (45 mL) and washed with water (2ϫ45 mL) and
brine. The organic phase was dried with Na2SO4 and concentrated
in vacuo. The crude product was purified by flash column
chromatography [silica gel; ethyl acetate/petroleum ether (boiling
range 40–65 °C), 1:4] to yield the product 5d (0.447 g, 0.58 mmol,
61%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.34–
7.18 (m, 15 H), 6.97 (br. d, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 5.13–
5.09 (m, 4 H), 4.99 (q, J = 7.6 Hz, 1 H), 4.52 (br. s, 1 H), 4.25–
4.13 (br. m, 2 H), 3.86 (s, 3 H), 3.45–3.14 (br. m, 4 H), 2.30 (m, 2
H), 1.88–1.63 (m, 2 H), 1.49 (br. s, 9 H), 1.36–1.22 (br. m, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 172.9, 169.5, 155.8, 135.9,
129.5, 128.7, 128.5, 128.4, 128.4, 128.1, 128.0, 127.1, 126.9, 124.0,
120.1, 110.2, 79.8, 75.2, 66.9, 66.2, 60.3, 56.0, 54.9, 45.2, 44.2, 37.9,
due can be purified by flash column chromatography [silica gel;
ethyl acetate/petroleum ether (40:65), 1:1 Ǟ ethyl acetate/10%
iPrOH] to yield the product.
3-Benzyl-4-(2-hydroxy-3-isopropoxy-4-methoxybenzyl)-1,4-diaz-
epan-2-one (7a): According to the general procedure, using 5a
(0.089 g, 0.12 mmol), the product 7a (0.033 g, 0.080 mmol, 68%)
was obtained as a white amorphous solid. 1H NMR (400 MHz,
CDCl3): δ = 7.58 (br. s, 1 H), 7.38–7.20 (m, 10 H), 6.66 (d, J =
8.6 Hz, 1 H), 6.36 (d, J = 8.6 Hz, 1 H), 4.85 (AB, J = 14.5 Hz, 1
H), 4.59 (X part of ABX, JAX + JBX = 14.3 Hz, 1 H), 4.53 (sept,
J = 6.2 Hz, 1 H), 3.82 (m, 1 H), 3.80 (s, 3 H), 3.49–3.33 (m, 2 H),
3.37 and 3.24 (AB part of ABX, JAB = 13.6, JBX = 9.8, JAX
=
4.5 Hz, 2 H), 3.20 (AB, J = 14.4 Hz, 1 H), 2.79 (m, 1 H), 1.23 (d,
J = 6.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.7,
172.3, 152.7,149.0, 136.6, 133.3, 129.5, 129.3, 129.2, 129.0, 128.8,
128.6, 127.4, 125.3, 115.2, 103.4, 75.1, 55.8, 55.7, 48.7, 40.4, 40.0,
31.4, 28.4, 23.2, 22.4 ppm. IR (neat): ν = 1769, 1729, 1694, 1498,
˜
36.1, 22.5 ppm. IR (neat): ν = 2923, 2852, 1654, 1503, 1458 cm–1.
˜
1455 cm–1. HRMS (FAB+): calcd. for C44H52O10N2 768.3622,
found 768.3624.
HRMS (FAB+): calcd. for C23H29O5N2 413.2078, found 413.2095.
3-Benzyl-1-(2-hydroxy-3-isopropoxy-4-methoxybenzyl)-1,4-diaz-
epane-2,5-dione (7b): According to the general procedure, using 6b
(0.075 g, 0.1 mmol), the product 7b (0.028 g, 0.068 mmol, 68%)
was obtained as a white amorphous solid. 1H NMR (400 MHz,
CDCl3): δ = 7.35–7.24 (m, 5 H), 6.95 (d, J = 8.6 Hz, 1 H), 6.75 (s,
1 H), 6.43 (d, J = 8.6 Hz, 1 H), 5.59 (s, 1 H), 4.68 (AB, J = 14.3 Hz,
1 H), 4.56 (m, 2 H), 4.54 (AB, J = 12.0 Hz, 1 H) 3.87 (m, 1 H),
3.82 (s, 3 H), 3.49 (m, 1 H), 3.41 and 2.89 (AB part of ABX, JAB
= 14.7, JBX = 9.6, JAX = 4.7 Hz, 2 H), 2.50 (m, 2 H), 1.27 (d, J =
12 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 171.3, 170.2,
152.8, 149.0, 136.1, 133.6, 129.2, 129.1, 127.3, 125.3, 115.4, 103.8,
5-Benzyl 1-Methyl 2-[{2-[2-(Benzyloxycarbonylamino)-3-phenylpro-
pionyloxy]-3-isopropoxy-4-methoxybenzyl}(tert-butoxycarbonyl)ami-
no]pentanedioate (5e): Cbz–Phe–F (0.307 g, 1.02 mmol) and DI-
PEA (0.178 mL, 1.02 mmol) were added to a solution of the phenol
4e (0.277 g, 0.51 mmol) in dry CH2Cl2 (7 mL). The reaction mix-
ture was stirred at room temperature until completion. The mixture
was diluted with EtOAc (15 mL) and washed with water
(2ϫ15 mL) and brine. The organic phase was dried with Na2SO4
and concentrated in vacuo. The crude product was purified by flash
column chromatography [silica gel; ethyl acetate/petroleum ether
(boiling range 40–65 °C), 1:4] to yield the product 5e (0.421 g,
75.2, 55.8, 53.9, 45.8, 42.2, 36.9, 35.1, 22.5 ppm. IR (neat): ν =
˜
1
0.51 mmol, 99%) as a colorless oil. H NMR (400 MHz, CDCl3):
2925, 2853, 1649, 1504, 1454 cm–1. HRMS (FAB+): calcd. for
C23H29O5N2 413.2078, found 413.2069.
δ = 7.30–7.26 (m, 15 H), 7.06 (br. d, J = 8.0 Hz, 1 H), 6.75 (d, J =
8.4 Hz, 1 H), 5.08–4.95 (m, 5 H), 4.46 (br. s, 1 H), 4.37–4.29 (br.
m, 2 H), 4.06 (q, J = 6.8 Hz, 1 H), 3.81 (br. s, 3 H), 3.56 (br. s, 3
H), 3.44 (m, 1 H), 3.15 (m, 1 H), 2.31 (m, 3 H), 2.02 (m, 1 H), 1.66
(m, 1 H), 1.41 (s, 9 H), 1.18 (m, 6 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 172.7, 171.5, 169.5, 155.7, 155.0, 153.3, 143.4, 138.7,
136.3, 135.8, 129.4, 128.4, 128.3, 128.3, 128.1, 127.7, 127.1, 126.8,
124.6, 122.6, 109.8, 80.9, 75.1, 66.6, 66.1, 60.3, 58.6, 58.3, 55.9,
3-Benzyl-1-(2-hydroxy-3-isopropoxy-4-methoxybenzyl)-1,4-diaz-
ocane-2,5-dione (7d): According to the general procedure, using 5d
(0.400 g, 0.52 mmol), the product 7d (0.059 g, 0.35 mmol, 67%)
was obtained as a white amorphous solid. 1H NMR (400 MHz,
CDCl3): δ = 7.32–7.22 (m, 5 H), 6.75 (d, J = 8.4 Hz, 1 H), 6.38 (d,
J = 8.4 Hz, 1 H), 6.01 (d, J = 10.0 Hz, 1 H), 4.67 (AB, J = 14.4 Hz,
1 H), 4.52 (m, 2 H), 4.31 (AB, J = 14.4 Hz, 1 H), 3.83 (s, 3 H),
54.8, 51.8, 46.4, 37.7, 31.8, 28.2, 25.4, 22.4 ppm. IR (neat): ν =
˜
2977, 1731, 1500, 1454 cm– 1. HRMS (FAB+): calcd. for
C46H54O12N2 826.3677, found 826.3677.
3.52 (m, 2 H), 3.33 and 3.03 (AB part of ABX, JAB = 14.0, JBX
=
7.2, JAX = 7.2 Hz, 2 H), 2.53 (m, 2 H), 1.88 (m, 2 H), 1.30 (dd, J
= 12.6, J = 6.8 Hz, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
174.6, 172.6, 153.1, 149.4, 137.0, 134.0, 129.2, 128.7, 126.9, 124.8,
115.4, 103.4, 75.1, 55.8, 54.1, 49.0, 46.7, 36.7, 35.9, 25.6, 22.6 ppm.
General Procedure for Tethered Lactamisation and Consecutive Ring
Contraction: The starting material was dissolved in EtOAc/iPrOH
(4:1). Pd/C (20%) was then added, and the mixture was brought
under hydrogen and stirred for 16 h. The reaction mixture was then
filtered through Celite and concentrated in vacuo. The remaining
residue was dissolved in CH2Cl2/DMF (4:1; c = 10–3 m) followed
by addition of EDCI (4 equiv.) and HOBt (4 equiv.). The mixture
was then stirred at room temperature for 4–6 h, after which the
reaction mixture was diluted with diethyl ether, extracted (3ϫ) and
washed with saturated sodium hydrogencarbonate solution, a po-
tassium hydrogensulfate solution (0.5 m) and brine. The organic
phase was then dried with Na2SO4 and concentrated in vacuo to
give the crude medium-sized lactam, which was used in the consec-
utive ring contraction without purification. The medium-sized lac-
tam was dissolved in a mixture of TFA/CH2Cl2 (1:1) and stirred at
room temperature for 16 h. The solvent was evaporated, after
which the remaining TFA salt was dissolved in EtOAc (c = 10–2 m)
and an excess of solid sodium hydrogencarbonate was added. After
4–5 h, the reaction mixture was washed with a solution of potas-
sium hydrogensulfate (0.5 m, 2ϫ) and brine. The organic phase was
dried with Na2SO4 and concentrated in vacuo. The remaining resi-
IR (neat): ν = 2974, 2853, 1651, 1504, 1454 cm–1. HRMS (FAB+):
˜
fcalcd. or C24H30O5N2 426.2155, found 426.2158.
Methyl 2-Benzyl-4-(2-hydroxy-3-isopropoxy-4-methoxybenzyl)-3,8-
dioxo-1,4-diazocane-5-carboxylate (7e): According to the general
procedure, using 5e (0.400 g, 0.48 mmol), the product 7e (0.07 g,
0.014 mmol, 30%) was obtained as a white solid. Recrystallisation
from hexane/CH2Cl2 gave the product as white needles. M.p. 180–
181.2 °C. 1H NMR (400 MHz, CDCl3): δ = 7.32–7.23 (m, 5 H),
6.85 (d, J = 8.4 Hz, 1 H), 6.69 (d, J = 8.8 Hz, 1 H), 6.19 (d, J =
9.2 Hz, 1 H), 4.98 (q, J = 8.8 Hz, 1 H), 4.28 (quint, J = 6.4 Hz, 1
H), 3.80 (s, 3 H), 3.74 (s, 3 H), 3.54 (AB, J = 10.8 Hz, 1 H), 3.47
(AB, J = 10.8 Hz, 1 H), 3.36 and 3.09 (AB part of ABX, JAB
=
14.2, JBX = 8.0, JAX = 7.6 Hz, 2 H), 3.31 (dd, J = 10.0, J = 3.6 Hz,
1 H), 2.42 (m, 1 H), 2.08 (m, 3 H), 1.69 (br. s, 1 H), 1.09 (d, J =
6.0 Hz, 3 H), 1.01 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 174.2, 173.5, 167.5, 153.4, 143.8, 139.9, 136.5, 129.3,
129.0, 128.6, 126.9, 124.6, 124.2, 109.5, 75.4, 62.3, 56.0, 54.2, 51.9,
48.6, 36.3, 35.5, 26.6, 22.4 ppm. IR (neat): ν = 2973, 2838, 1749,
˜
366
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Eur. J. Org. Chem. 2008, 361–367

Improved Auxiliary for the Synthesis of Medium-Sized Bis(lactams)
1731, 1664, 1534, 1498 cm– 1. HRMS (FAB+): calcd. for
C26H32O7N2 484.2210, found 484.2199.
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Received: September 5, 2007
Published Online: November 12, 2007
Eur. J. Org. Chem. 2008, 361–367
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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