Intramolecular staudinger ligation towards biaryl-containing lactams

Article abstract of DOI:10.1055/s-2006-939059

Both 15- and 16-membered biaryl-type lactams were prepared in good yield using the intramolecular Staudinger ligation strategy. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939059

LETTER
865
Intramolecular Staudinger Ligation towards Biaryl-Containing Lactams
I
ntramolecular Sta
é
udinger Lig
r
ation tow
a
ards Biary
l
l-Type
d
Lactams ine Masson,a Tim den Hartog,a Hans E. Schoemaker,b Henk Hiemstra,a Jan H. van Maarseveen*a
a
Van’t Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam,
The Netherlands
b
DSM Research, Life Science Products, PO Box 18, 6160 MD Geleen, The Netherlands
Fax +31(020)5255670; E-mail: jvm@science.uva.nl
Received 23 December 2005
Abstract: Both 15- and 16-membered biaryl-type lactams were
prepared in good yield using the intramolecular Staudinger ligation
strategy.
O
S
H2O
– N2
N3
R2P
Key words: biaryls, macrolactams, cyclizations, atropisomerism,
ring contractions
N
HN
O
HS
PR2
O
O
R2P
S
Scheme 1
Various natural and synthetic compounds based on a
cyclic peptide scaffold with an endocyclic biaryl moiety
have been shown to possess important bioactivities (e.g.
biphenomycins A,B and RP-66453, Figure 1).1 In these
compounds rotation around the aryl–aryl bond is hindered
due to ring strain, even in the absence of ortho substitu-
ents, causing atropisomerism. Consequently, these
fascinating molecular architectures are attractive yet chal-
lenging synthetic targets.
present an efficient method for the synthesis of chiral
macrocyclic lactams I containing a meta–meta connected
biaryl moiety (Scheme 2). Retrosynthetic analysis of the
target macrolactams shows that disconnection via the
Staudinger-type macrolactamization can follow two pos-
sible pathways to give w-azido phosphinothioesters II or
III and that formation of the biaryl linkage via Suzuki
coupling gives two appropriately functionalized aryls IV
and V (Scheme 2).
OH
HO
O
OH
R
HO
R1
R2
R3 = H or
TBDPS
O
H
O
H
N
CO2H
Suzuki–Miyaura
coupling
H
CO2H
H2N
H2N
NH
N
NH
R2
NH
O
O
NH2
(HO)2B
BH3
O
O
N3
NH
O
OH
R1
R2
PR2
Biphenomycin A (R = OH), B (R = H)
RP 66453
( )n
S
II
R3O
+
Figure 1
IV
or
1 R2
O
I
R1
R
HN
NH
Recently, we disclosed a new strategy for the synthesis of
the otherwise difficult-to-prepare medium-sized lactams
based on the intramolecular Staudinger ligation.2 This
method involves a Staudinger reaction of a C-terminal
phosphinomethylene ester with an N-terminal azide re-
sulting in an intermediate iminophosphorane, which un-
dergoes an intramolecular ring-contracting S→N acyl-
transfer reaction, via a favored five-membered transition
state (Scheme 1).3
( )n
Br
n = 1, 2
Pathway B
O
Pathway A
O
Macrolactamization via
Staudinger ligation
t-BuO2C
HN
N3
S
V
O
( )n
R1, R2 = H or Me
H3B PR2
III
Scheme 2
The auxiliary residue is hydrolyzed in situ by the presence
of a small amount of water in the reaction mixture provid-
ing the liberated lactam. We envisaged that this approach
might be applicable to the construction of synthetically
challenging biaryl-type macrolactams displaying atrop-
isomerism as the only source of chirality. Herein, we
Our ultimate goal was to introduce an appropriate chiral
phosphinothioester that would enable enantioselective
lactamizations. In addition, we chose the highly nucleo-
philic bisalkylphosphine auxiliaries instead of the previ-
ously used bisarylphosphines.4 For this, we developed a
convenient synthesis of the air-stable borane-protected
phosphinothiol auxiliary 2 and its optically enriched
analogue 3 (Scheme 3).
SYNLETT 2006, No. 6, pp 0865–0868
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4.
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4.
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Advanced online publication: 14.03.2006
DOI: 10.1055/s-2006-939059; Art ID: G41205ST
© Georg Thieme Verlag Stuttgart · New York

866
G. Masson et al.
LETTER
acylated with the azido acids 13a and 13b,13 followed by
liberation of the acids 14a–c by tert-butyl ester cleavage
and thioesterification with the borane-protected auxiliary
2 (Scheme 5).
Scheme 3 Reagents and conditions: a) s-BuLi, THF,–78 °C, 3 h; b)
S8, THF,–78 °C to r.t., 2 h; c) s-BuLi, (–)-sparteine, Et2O,–78 °C, 3 h;
d) S8, THF, –20 °C to r.t., 2 h. The ee was determined by HPLC ana-
lysis using a Chiralcel OJ column and heptane–i-PrOH (95:5) as the
eluent (UV detection at 210/240 nm).
tert-Butyl(dimethyl)phosphine borane (1)5 was deproto-
nated with s-BuLi (THF, –78 °C) and then trapped with S8
(1.1 equiv, THF, –20 °C to r.t.) to provide 2 in 72%
yield.6,7 The optically enriched analogue 3 was obtained
by asymmetric deprotonation by s-BuLi (THF, –78 °C) of
1 in the presence of (–)-sparteine providing 3 in 59% yield
and 92% ee.7–9
The construction of the C-terminal phosphinoester and an
N-terminal azide containing lactamization precursor is de-
picted in Scheme 5. The required biaryl frameworks were
prepared using the Suzuki–Miyaura coupling as the key
step (Scheme 4).10
R1
R1
B(OH)2
+
Br
a
t-BuO2C
OH
CO2t-Bu
OH
4
5a R1 = H, 5b R1 = Me
6a, 95% and 6b, 84%
Me
Me
Me Me
B(OH)2
+
Br
b, c
79%
t-BuO2C
OH
CO2t-Bu
OTBDPS
7
8
6c
Scheme 5 Reagents and conditions: a) MsCl, Et3N, CH2Cl2, 0 °C to
r.t., 1 h; b) NaN3, DMF, overnight, r.t.; c) TFA–H2O (7:3), r.t., 18 h;
d) 10a or 10b, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC), DMAP (cat.), NaHCO3, CH2Cl2, r.t., 18 h; e) 4 N NaOH,
EtOH, r.t., 5–10 h; f) 2, EDC, DMAP, CH2Cl2, r.t., 16 h; g) PPh3,
THF–H2O (1:9), 70 °C, 4 h; h) 13a or 13b, EDC, DMAP (cat.),
CH2Cl2, r.t., 18 h.
Scheme 4 Reagents and conditions: a) Pd(PPh3)4 (2 mol%), aq
Na2CO3, THF, 80 °C, 18 h; b) Pd(OAc)2 (2 mol%), S-Phos (5 mol%),
aq K3PO4, toluene, 90 °C 16 h; c) TBAF, THF, 0 °C to r.t., 4 h, 95%.
The mono ortho- and unsubstituted biaryl compounds 6a
and 6b were synthesized using classical Suzuki–Miyaura
[Pd(PPh3)4, aq Na2CO3, THF, reflux] conditions starting
from arylboronic acid 411 and aryl bromides 5a and 5b to
give 6a and 6b in yields of 95% and 84%, respectively. To
obtain the hindered o,o-disubstituted biaryl 6c in good
yield, S-Phos12 was required as the ligand.
The intramolecular Staudinger reaction was initiated by
liberation of the phosphane by decomplexation with
DABCO (5 equiv) in THF at 70 °C (Table 1).14,15 Based
on our preliminary investigation, we employed high-dilu-
tion conditions (10–3 M).2 Cyclization of 12a gave the
corresponding 16-membered lactam 17a in an isolated
yield of 67%.
For the preparation of pathway A precursors 12a–d, alco-
hols 6a–c were converted into azides by mesylation fol-
lowed by nucleophilic substitution with sodium azide
(Scheme 5). TFA-mediated tert-butyl ester cleavage of
9a–c resulted in acids 11a–d that were coupled with the
amino esters 10a and 10b. Ester hydrolysis was followed
by introduction of the phosphinothiol auxiliary 2 to pro-
vide the precursors 12a–d. To obtain pathway B precur-
sors 15a–c, the azides 9a and 9b were reduced to their
amines using triphenylphosphine in THF–water and
Cyclization of the substituted precursor 15c gave lactam
18 in 57% yield. On the other hand, formation of the more
strained 15-membered lactam 17c took two days to pro-
duce the product in a reasonable 40% isolated yield
(Table 1).16 The o,o-dimethyl substituted biaryl lactam
17d was isolated in 61% yield as a racemic mixture of
stable atropenantiomers separable by chiral HPLC.17 The
observation that 17a–c are all achiral suggests that the
Synlett 2006, No. 6, 865–868 © Thieme Stuttgart · New York

LETTER
Intramolecular Staudinger Ligation towards Biaryl-Type Lactams
867
presence of two methyl groups ortho to the biaryl linkage In conclusion, the intramolecular Staudinger ligation
is essential to obtain stable atropisomers. The degree of strategy is a powerful method to ring-closed biaryl-type
stability of the axial chirality of 17d was studied by dy- macrolactams. A 16-membered o,o-dimethyl substituted
1
namic H NMR spectroscopy. It was found that even at biaryl containing a medium-sized lactam has been pre-
150 °C (DMSO-d6), no signals coalesced, demonstrating pared featuring axial chirality as the only asymmetric ele-
the high rotational barrier of the aryl–aryl single bond.18
ment. The same product was also prepared using an
enantiomerically enriched P-chiral auxiliary but without
any detectable asymmetric induction. Further studies to
reach this ultimate goal are currently in progress.
We next focused our attention on atropenantioselective
lactamization19 by using the enantiomerically enriched
phosphine auxiliary, however, the cyclization of 12d con-
taining the optically enriched auxiliary 3 provided lactam
17d with no detectable enantioselectivity. Most probably,
no enantioselectivity was achieved because the chiral
phosphine is too remote from the prochiral biaryl system
to allow any stereocontrol during the macrolactamization.
Acknowledgment
G.M. gratefully acknowledges the European Community for a
Marie Curie grant. Dr. A.L.L. Duchateau (DSM, Geleen) is thanked
for determining the ee of the chiral phosphine.
Table 1 Lactamizations via Intramolecular Staudinger Ligation
References and Notes
R1
R2
pathway A
DABCO,
pathway B
DABCO,
(1) (a) Schmidt, U.; Meyer, R.; Leitenberger, V.; Griesser, H.;
Lieberknecht, A. Synthesis 1992, 1025. (b) Schmidt, U.;
Leitenberger, V.; Griesser, H.; Schmidt, J.; Meyer, R.
Synthesis 1992, 1248. (c) Bois-Choussy, M.; Cristau, P.;
Zhu, J. Angew. Chem. Int. Ed. 2003, 42, 4238.
12a–d
15a–c
O
R3
THF, 70 °C
THF, 70 °C
NH
NH
( )n
(d) Krenitsky, P. J.; Boger, D. L. Tetrahedron Lett. 2003, 44,
4019.
O
17a–d, 18
(2) David, O.; Meester, W. J. N.; Bieräugel, H.; Schoemaker, H.
E.; Hiemstra, H.; van Maarseveen, J. H. Angew. Chem. Int.
Ed. 2003, 42, 4373.
Entry Precursors Product
Time (h) Yield (%)
(3) (a) Köhn, M.; Breinbauer, R. Angew. Chem. Int. Ed. 2004,
43, 3106. (b) Lin, F. L.; Hoyt, H. M.; van Halbeek, H.;
Bergman, R. G.; Bertozzi, C. R. J. Am. Chem. Soc. 2005,
127, 2686. (c) Soellner, M. B.; Nilsson, B. L.; Raines, R. T.
J. Org. Chem. 2002, 67, 4993.
1
2
12a
15a
18
18
67
65
O
NH
NH
( )2
O
17a
(4) He, Y.; Hinklin, R. J.; Chang, J.; Kiessling, L. L. Org. Lett.
2004, 6, 4479.
Me
(5) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada,
H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am.
Chem. Soc. 1998, 120, 1635.
(6) For a similar approach using phenyl disulfide for the
introduction of sulfur, see: Sugama, H.; Saito, H.; Danjo, H.;
Imamoto, T. Synthesis 2001, 2348.
3
4
12b
15b
18
18
72
60
O
NH
NH
( )2
O
17b
(7) To a cooled (–78 °C) solution of sparteine (0.70 mL, 3.04
mmol) in Et2O (10 mL), s-BuLi (1.30 M in cyclohexane;
2.40 mL, 3.12 mmol) was added. After stirring for 15 min,
dimethylphenylphosphine borane (366 mg, 2.77 mmol) was
added via cannula as a solution in Et2O (10 mL). After 3 h at
–78 °C, the solution was slowly added to a suspension of
sublimed sulfur (98 mg, 3.06 mmol) in THF (40 mL), and
the reaction was warmed to r.t. The resulting mixture was
stirred for 16 h at r.t., then 2 N HCl (20 mL) was added and
the aqueous layer was extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude residue was purified by
flash chromatography (SiO2; PE–EtOAc, 95:5 to 9:1) to
afford 3 as a pasty white solid (268 mg, 59%). [a]D25 –8.9 (c
1.6, CHCl3); 92% ee. 1H NMR (400 MHz, CDCl3): d = 2.71
(dd, J = 5.2, 14.0 Hz, 1 H), 2.52–2.43 (m, 1 H), 1.97–1.92
(m, 1 H), 1.29 (d, J = 10.4 Hz, 3 H), 1.27 (d, J = 13.6 Hz, 9
H), 0.39 (qd, J = 96.0, 13.0 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 28.03 (d, J = 31.2 Hz), 25.4 (d, J = 1.8 Hz),
15.39 (d, J = 26.9 Hz), 4.00 (d, J = 35.5 Hz). 31P NMR (162
MHz, CDCl3): d = 31.41 (q, J = 59.0 Hz).
Me
O
5
6
15c
12c
18
48
57
40
CbzHN
( )2
NH
NH
NH
O
O
18
O
HN
17c
Me
Me
O
atropos
7
12d
18
61
HN
NH
( )2
O
17d
(8) Recrystallization to increase the ee was impossible because
the product is a pasty solid.
Synlett 2006, No. 6, 865–868 © Thieme Stuttgart · New York

868
G. Masson et al.
LETTER
(9) The absolute configuration of 3 was determined by
comparison with the known (R)-tert-butyl(hydroxy-
methyl)methylphosphine borane. The alcohol was converted
to the thioacetate in two steps followed by acetyl group
removal to give the chiral thiol, see: Nagata, K.; Matsukawa,
S.; Imamoto, T. J. Org. Chem. 2000, 65, 4185.
(10) (a) Suzuki, A. Acc. Chem. Res. 1982, 15, 178. (b) Miyaura,
N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(11) The boronic acid component for the Suzuki coupling from 7
was prepared by lithium–halogen exchange with n-BuLi and
treatment with triethyl borate.
(12) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S.
L. Angew. Chem. Int. Ed. 2004, 43, 1871.
(13) w-Azido acids were obtained from w-amino acids by a diazo-
transfer reaction: Lundquist, J. T.; Pelletier, J. C. Org. Lett.
2001, 3, 781.
(14) For an extensive review on applications of borane-protected
phosphines see: Brunel, J. M.; Faure, B.; Maffei, M. Coord.
Chem. Rev. 1998, 180, 665.
(15) Intramolecular Staudinger Ligation Reaction: General
Procedure
was stirred for 1 h then the aqueous layer was extracted with
EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and concentrated in vacuo. The residue was
purified by flash chromatography (SiO2; PE–EtOAc, 9:1 to
EtOAc) to afford 17d as a white solid (52 mg, 61%). 1H
NMR (400 MHz, MeOD): d = 7.66 (dd, J = 2.0, 8.0 Hz, 1
H), 7.47 (d, J = 2.0 Hz, 1 H), 7.37 (d, J = 7.6 Hz, 1 H), 7.25
(s, 1 H), 7.20–7.15 (m, 2 H), 4.74 (d, J = 14.4 Hz, 1 H), 3.94
(d, J = 14.4 Hz, 1 H), 3.71–3.78 (m, 1 H), 3.07–3.01 (m, 1
H), 2.30 (s, 3 H), 2.21 (s, 3 H), 2.27–1.99 (m, 2 H), 1.80–1.58
(m, 4 H), 1.57–1.39 (m, 2 H). 13C NMR (100 MHz, MeOD):
d = 175.9, 170.9, 143.1, 143.0, 140.8, 139.7, 135.7, 134.2,
133.9, 132.2, 131.6, 130.7, 128.2, 127.5, 43.8, 41.2, 37.3,
30.5, 29.1, 27.4, 30.0, 19.6.
(16) Attempts to produce 17c via lactamization of the
pentafluorophenyl ester analogue of 12c using an aza-Wittig
reaction failed.
(17) The atropenantiomers were separated by analytical HPLC
analysis using a chiral Daicel OD-H column with heptane–
i-PrOH (98:2) as the eluent.
(18) Eshdat, L.; Shabtai, E.; Saleh, S. A.; Sternfeld, T.; Saito, M.;
Okamoto, Y.; Rabinovitz, M. J. Org. Chem. 1999, 64, 353.
(19) For the first example of atropenantioselective
macrocyclizations see: Islas-Gonzalez, G.; Bois-Choussy,
M.; Zhu, J. Org. Biomol. Chem. 2003, 1, 30.
Precursor 12d (132.0 mg, 0.24 mmol) and DABCO (110.0
mg, 0.98 mmol) was dissolved in THF (240 mL) and then
heated at reflux. Upon completion of the reaction a sat. aq
solution of NH4Cl (excess) was added. The resulting mixture
Synlett 2006, No. 6, 865–868 © Thieme Stuttgart · New York