Enantioselective synthesis of renieramide

Article abstract of DOI:10.1055/s-2004-835623

A highly chemo- and enantioselective PTC alkylation has been developed that allows rapid access to orthogonally protected (S,S)-isodityrosine. Utility of this material in the construction of isodityrosine-containing cyclic peptides is demonstrated by synt

Full text of DOI:10.1055/s-2004-835623

LETTER
2809
Enantioselective Synthesis of Renieramide
Enantioselective
a
o
r
f
Renier
r
amide y Lygo,* Luke D. Humphreys
School of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK
E-mail: B.Lygo@Nottingham.ac.uk
Received 3 September 2004
MeO
Abstract: A highly chemo- and enantioselective PTC alkylation
has been developed that allows rapid access to orthogonally protect-
ed (S,S)-isodityrosine. Utility of this material in the construction of
isodityrosine-containing cyclic peptides is demonstrated by synthe-
O
Ph2C=N CO2R
4a: R = t-Bu
4b: R = CHPh2m
sis of the natural product renieramide.
Br
X
3a: X = Br
3b: X = Cl
Key words: amino acids, asymmetric alkylation, phase-transfer
catalysis, quaternary ammonium salts
Figure 2
access to orthogonally protected isodityrosine, and hence
the synthesis of targets such as renieramide (2) should
then be possible.
Isodityrosine (1) is a naturally-occurring bis-amino acid
that was originally identified as a cross-linking element in
plant cell wall glycoprotein.1 This structural component
has since been found in a range of natural products,2 in-
cluding a series of macrocyclic tripeptides3–6 of which
renieramide (2) is the most recently reported example
(Figure 1).7 These natural products have been reported
to exhibit a diverse range of biological activities and
hence have attracted significant attention from synthetic
chemists.
Preliminary experiments involving the alkylation of
glycine imines 4 with dibromide 3a suggested that the two
bromomethyl groups reacted at similar rates and so we
considered the possibility of using the alternative sub-
strate 3b. This material was prepared in four steps from
commercially available 4-bromobenzaldehyde 6 via the
sequence outlined in Scheme 1. Thus, Ullmann coupling
with phenol 5, followed by reduction of the resulting alde-
hyde and conversion into the corresponding chloride,
gave the intermediate 7 in good overall yield. Treatment
of this compound with NBS in the presence of AIBN then
led to selective bromination of the arylmethyl group,
providing target structure 3b.
HO
HO
O
O
O
H H
H
N
H
H
NH2
N
NH2
HO2C
H
H
HO2C NH2
O
HO2C
OMe
OMe
CHO
1 (S,S)-isodityrosine
O
OH
+
2 renieramide
i–iii
iv
3b
Figure 1
5
6
7
Cl
Br
We have recently reported an enantioselective approach
to isodityrosine (1), which employed a chiral phase-trans-
fer catalyst to promote a double asymmetric alkylation in-
volving reaction of dibromide 3a with two molecules of
glycine imine 4a.8 Although this approach provided rapid
access to isodityrosine (1), it is not applicable to the syn-
thesis of tripeptides such as 2 because it does not allow
straightforward differentiation of the the two amino acid
functions.
Scheme 1 Reagents and conditions: (i) CuO, K2CO3, pyridine
reflux; (ii) NaBH4, MeOH, r.t.; (iii) concd HCl, EtOAc, r.t. (78%
overall); (iv) NBS, AIBN, CCl4, hn, reflux (53%).
In order to utilise bromide 3b in the synthesis of renier-
amide (2), we needed to develop a highly regio- and enan-
tioselective alkylation involving reaction of the
bromomethyl moiety with glycine imine 4b. Based on
previous studies within the group we considered that this
might be possible using phase-transfer catalyst 9
(Figure 3).9
One possible solution to this problem would be to effect
two separate asymmetric alkylations involving a substrate
such as 3. If a different glycine imine ester (e.g. 4a and 4b,
Figure 2) was employed in each alkylation it would allow
This proved to be the case and, after some experimenta-
tion, we were able to establish conditions that led to the
desired transformation (Scheme 2).10 This process
appears to be highly chemoselective as no alkylation in-
volving the chloromethyl group could be detected even
when larger excesses of imine 4b were employed. We
SYNLETT 2004, No. 15, pp 2809–2811
0
7
.1
2
.2
0
0
4
Advanced online publication: 22.10.2004
DOI: 10.1055/s-2004-835623; Art ID: D26804ST
© Georg Thieme Verlag Stuttgart · New York

2810
B. Lygo, L. D. Humphreys
LETTER
could also find no evidence of halogen exchange involv- the macrocycle 13 could be obtained in 55% overall yield
ing this function11 even though bromide ion is generated (from compound 12). Deprotection using TfOH/TFA,16
in stoichiometric amounts during the reaction. These ob- followed by purification via ion-exchange chromatogra-
servations provide a powerful illustration of the chemo- phy then provided synthetic renieramide (2) which exhib-
selectivity that can be achieved using phase-transfer ited optical rotation and 1H/13C NMR in reasonable
conditions.
agreement with that reported for the natural product.6,17,18
CF3
MeO
OMe
OMe
Et
O
t-Bu
t-Bu
N
Br-
i–iii
CF3
10
N+
Br-
11
H
H
N+
BnO
I
Ph2HCO2C NHBoc
H
8
CF3
MeO
O
9
iv, i
v–vii
NHBoc
CF3
H
12
H
Ph2HCO2C
Figure 3
NH2
t-BuO2C
MeO
To complete the construction of an orthogonally protected
dityrosine a second asymmetric alkylation is required. In
order to achieve this, the imine function in intermediate 10
was first converted into the corresponding tert-butyl car-
bamate via hydrolysis and treatment with (Boc)2O.
Finklestein reaction then provided iodide 11, which was
expected to be a suitable partner for reaction with glycine
imine 4a (Scheme 3). In this case we chose to employ
phase-transfer catalyst 8 in an effort to promote the asym-
metric alkylation as this catalyst has proved to be highly
effective for reactions involving imine 4a.12,13 The alkyla-
tion proceeded as anticipated and, after hydrolysis of the
imine function, the orthogonally protected isodityrosine
derivative 1214 could be isolated in good yield.15 At this
stage we were unable to accurately determine the stereo-
chemical purity of 12, however 1H NMR analysis of later
compounds indicated that this intermediate must have
been formed with high diastereoselectivity.
O
viii
2
13
H H
N
O
H
N
NHBoc
t-BuO2C
H
H
O
Scheme 3 Reagents and conditions: (i) 15% aq citric acid, THF, r.t.;
(ii) Boc2O, NaHCO3, dioxane, r.t.; (iii) NaI, acetone, r.t. (45% over-
all); (iv) 4a (1.2 equiv), 8 (10 mol%), 9 M aq KOH, PhMe, r.t. (83%
after imine hydrolysis); (v) (Z)-L-Leu-OSuc, CH2Cl2, r.t. (85%); (vi)
H2 (1 atm), Pd/C, MeOH, r.t.; (vii) slow addition of substrate to EDCI,
HOBt, NMM, PhMe, DMF, 60 °C (65% overall); (viii) TfOH, TFA,
PhSMe, –5 °C, Dowex 50WX8-200 ion-exchange chromatography
(54%).
In conclusion, we have established that it is possible to
employ two sequential asymmetric phase-transfer alkyla-
tions for the construction of orthogonally protected (S,S)-
isodityrosine. The utility of this material in the construc-
tion of isodityrosine-containing cyclic peptides has been
established by the synthesis of renieramide.
MeO
O
4b (1.2 equiv)
3b
9 (1 mol%),
9 M aq KOH,
PhMe, r.t.
H
Acknowledgment
Cl
Ph2HCO2C N=CPh2
We thank EPSRC for studentship support (to L.D.H.) and acknow-
ledge use of the EPSRC’s Chemical Database Service at Daresbury.
10, 87% (97% e.e.)
Scheme 2
References
In order to demonstrate the utility of intermediate 12 in the
synthesis of isodityrosine tripeptides we next investigated
conversion into renieramide (2). To this end, the amino
function in compound 12 was first coupled with (Z)-L-
Leu-OSuc. This gave the corresponding dipeptide as a
single diastereoisomer in good yield. Simultaneous re-
moval of the benzyloxycarbonyl and benzhydryl func-
tions via hydrogenolysis then provided the
macrocyclisation precursor. It was found that cyclisation
could be achieved in good yield by slow addition of this
precursor to EDCI/HOBt at 60 °C. Using this approach,
(1) Fry, S. C. Biochem. J. 1982, 204, 449.
(2) Zhu, Z. Synlett 1997, 133.
(3) K13: (a) Kase, H.; Kaneko, M.; Yamada, K. J. Antibiot.
1987, 40, 450. (b) Yasuzawa, T.; Shirahata, K.; Sano, H. J.
Antibiot. 1987, 40, 455.
(4) OF-4949-I-IV: (a) Sano, S.; Ikai, K.; Kuroda, H.; Nakamura,
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39, 1674. (b) Sano, S.; Ikai, K.; Katayama, K.; Takesako, K.;
Nakamura, T.; Obayashi, A.; Ezure, Y.; Enomoto, H. J.
Antibiot. 1986, 39, 1685.
(5) Eurypamides A-D: Reddy, M. V. R.; Harper, M. K.;
Faulkner, D. J. Tetrahedron 1998, 54, 10649.
Synlett 2004, No. 15, 2809–2811 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of Renieramide
2811
(6) Renieramide: (a) Ciasullo, L.; Casapullo, A.; Cutignano, A.;
Bifulco, G.; Debitus, C.; Hooper, J.; Gomez-Paloma, L.;
Riccio, R. J. Nat. Prod. 2002, 65, 407. (b) Itokawa, H.;
Watanabe, K.; Kawaoto, S.; Inoue, T. Jpn. Kokai Tokkyo
Koho JP 63203671, 1988.
added. The mixture was stirred at r.t. for 18 h, then extracted
with CHCl3 (4 × 3 mL). The combined organics were
washed with 10% aq Na2CO3 (2 × 4 mL), dried (Na2SO4) and
concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (CHCl3–MeOH,
50:1) to yield the orthogonally protected isodityrosine 12
(269 mg, 85%) as a pale yellow oil. Rf = 0.3 (CHCl3–MeOH,
25:1). [a]D +1 (c 0.9, CHCl3). IR (film): nmax = 3376, 2977,
2632, 1714, 1505 cm–1. 1H NMR (500 MHz, CDCl3): d =
7.34–7.23 (10 H, m, ArH), 7.13 (2 H, d, J = 8.0 Hz, ArH),
6.84 (1 H, s, CHPh2), 6.81 (2 H, d, J = 8.0 Hz, ArH), 6.76 (1
H, d, J = 8.0 Hz, ArH), 6.68 (1 H, d, J = 8.0 Hz, ArH), 6.65
(1 H, s, ArH), 4.97 (1 H, br d, J = 8.0 Hz, NH), 4.68–4.60 (1
H, m, CHN), 3.78 (3 H, s, OCH3), 3.64–3.56 (1 H, m, CHN),
3.04 (1 H, dd, J = 6.0, 14.0 Hz, CHCHaHb), 2.99–2.95 (2 H,
m, CHCHaHb, CHCHaHb), 2.82 (1 H, dd, J = 8.0, 14.0 Hz,
CHCHaHb), 1.44 [9 H, s, C(CH3)3], 1.40 [9 H, s, C(CH3)3].
13C NMR (125 MHz, CDCl3): d = 174.2 (C), 170.9 (C),
156.9 (C), 155.0 (C), 150.0 (C), 144.6 (C), 139.6 (C), 139.4
(C), 131.3 (C), 130.5 (CH), 128.6 (CH), 128.5 (CH), 128.2
(CH), 128.0 (CH), 127.5 (CH), 127.0 (CH), 125.7 (CH),
122.4 (CH), 116.9 (CH), 112.8 (CH), 81.3 (C), 80.0 (C), 78.0
(CH), 56.3 (CH), 56.0 (CH3), 54.5 (CH), 40.3 (CH2), 37.4
(CH2), 28.3 (CH3), 28.1 (CH3). MS (ES+): m/z (%) = 719
(28) [M + Na+], 697 (100) [M + H+], 641 (10) [M – t-Bu +
H+], 296 (68). HRMS: m/z calcd for C41H49N2O8 [M + H]+:
697.3489. Found: 697.3528.
(7) For leading references to the syntheses of K13, OF4949-I-IV
and the eurypamides see: (a) Ito, M.; Yamanaka, M.;
Kutsumura, N.; Nishiyama, S. Tetrahedron 2004, 60, 5623.
(b) Jackson, R. F. W.; Perez-Gonzalez, M. Chem. Commun.
2000, 2423. (c) Bigot, A.; Bois-Choussy, M.; Zhu, J.
Tetrahedron Lett. 2000, 41, 4573. (d) Janetka, J. W.; Rich,
D. H. J. Am. Chem. Soc. 1997, 119, 6488. (e) Pearson, A.
J.; Zhang, P. L.; Lee, K. J. Org. Chem. 1996, 61, 6581.
(f) Rao, A. V. R.; Gurjar, M. K.; Reddy, A. B.; Khare, V. B.
Tetrahedron Lett. 1993, 34, 1657. (g) Boger, D. L.;
Yohannes, D. J. Org. Chem. 1990, 55, 6000. (h) Evans, D.
A.; Ellman, J. A. J. Am. Chem. Soc. 1989, 111, 1063.
(i) Nishiyama, S.; Suzuki, Y.; Yamamura, S. Tetrahedron
Lett. 1989, 30, 379. (j) Schmidt, U.; Weller, D.; Holder, A.;
Lieberknecht, A. Tetrahedron Lett. 1988, 29, 3227.
(8) Lygo, B. Tetrahedron Lett. 1999, 40, 1389.
(9) (a) Lygo, B.; Allbutt, B. Synlett 2004, 326. (b) Lygo, B.;
Allbutt, B.; James, S. R. Tetrahedron Lett. 2003, 44, 5629.
(10) The enantioselectivity of this alkylation was determined by
chiral-phase HPLC comparison of the product 10 with
racemic material generated using n-Bu4NBr as the PTC. Use
of catalyst 8 led to similar regioselectivity and yield, but
gave 10 with only 50% ee.
(15) For an alternative approach to orthogonally protected (S,S)-
isodityrosines see: Jorgensen, K. B.; Gautun, O. R.
(11) Reinholtz, E.; Becker, A.; Hagenbruch, B.; Schäfer, S.;
Schmitt, A. Synthesis 1990, 1069.
Tetrahedron 1999, 55, 10527.
(12) (a) Lygo, B.; Andrews, B. I.; Slack, D. Tetrahedron Lett.
2003, 44, 9039. (b) Lygo, B.; Andrews, B. I. Tetrahedron
Lett. 2003, 44, 4499. (c) Lygo, B.; Humphreys, L. D.
Tetrahedron Lett. 2002, 43, 6677. (d) Lygo, B.; Andrews,
B. I.; Crosby, J.; Peterson, J. A. Tetrahedron Lett. 2002, 43,
8015. (e) Lygo, B.; Crosby, J.; Lowdon, T. R.; Wainwright,
P. G. Tetrahedron 2001, 57, 2391. (f) Lygo, B.; Crosby, J.;
Lowdon, T. R.; Peterson, J. A.; Wainwright, P. G.
Tetrahedron 2001, 57, 2403. (g) Lygo, B.; Crosby, J.;
Peterson, J. A. Tetrahedron 2001, 57, 6447. (h) Lygo, B.;
Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595.
(13) For application of a related alkylation to the synthesis of the
dityrosine fragment of RP66453 see: Boisnard, S.;
Carbonnelle, A.-C.; Zhu, J. Org. Lett. 2001, 3, 2061.
(14) Representative Alkylation–Hydrolysis Procedure
(Preparation of 12): A solution of glycine imine 4a (161
mg, 0.54 mmol) in toluene (4 mL) was placed under a
nitrogen atmosphere. Iodide 11 (312 mg, 0.45 mmol),
catalyst 8 (36 mg 10 mol%) and 9 M aq KOH (400 mL) were
added sequentially, and the resulting mixture stirred at r.t.
for 18 h. The toluene layer was then separated and the
aqueous layer extracted with EtOAc (3 × 2 mL). The
combined organics were dried (MgSO4), and concentrated
under reduced pressure. The residue was dissolved in Et2O
(10 mL), filtered (to remove catalyst), and again
(16) Kiso, Y.; Nakamura, S.; Ito, K.; Ukawa, K.; Kitagawa, K. J.
Chem. Soc., Chem. Commun. 1979, 971.
(17) Selected data for synthetic renieramide (2): Mp 185–195 °C
(decomp). [a]D –32 (c 0.1, MeOH) (lit. [a]D –30 (c 0.1,
MeOH).6 1H NMR (500 MHz, CD3OD): d = 7.42 (1 H, dd,
J = 2.0, 8.0 Hz, ArH), 7.20 (1 H, dd, J = 2.0, 8.0 Hz, ArH),
7.01 (1 H, dd, J = 2.0, 8.0 Hz, ArH), 6.86 (1 H, dd, J = 2.5,
8.0 Hz, ArH), 6.81 (1 H, d, J = 8.0 Hz, ArH), 6.65 (1 H, dd,
J = 2.0, 8.0 Hz, ArH), 5.98 (1 H, d, J = 2.0 Hz, ArH), 4.52 (1
H, dd, J = 3.5, 11.5 Hz, CHN), 4.48 (1 H, dd, J = 3.5, 12.5
Hz, CHN), 3.97 (1 H, dd, J = 2.0, 6.0 Hz, CHN), 3.38 (1 H,
dd, J = 3.5, 13.0 Hz, CHCHaHb), 3.15 (1 H, dd, J = 2.0, 15.0
Hz, CHCHaHb), 2.91 (1 H, dd, J = 6.0, 15.0 Hz, CHCHaHb),
2.60 (1 H, app. t, J = 12.5 Hz, CHCHaHb) 1.70–1.62 [2 H, m,
CH2CH(CH3)2], 1.61–1.51 [1 H, m, CH2CH(CH3)2], 0.95 (3
H, d, J = 6.0 Hz, CH3), 0.93 (3 H, d, J = 6.0 Hz, CH3). 13
C
NMR (125 MHz, CD3OD): d = 178.1 (C), 172.7 (C), 169.1
(C), 154.6 (C), 149.8 (C), 147.2 (C), 137.1 (C), 133.0 (CH),
131.7 (CH), 125.0 (2 × CH), 123.1 (CH), 122.7 (CH), 117.2
(CH), 116.9 (CH), 58.1 (CH), 53.7 (CH), 52.1 (CH), 43.6
(CH2), 40.9 (CH2), 37.4 (CH2), 26.0 (CH), 23.8 (CH3), 21.6
(CH3).
(18) There is a typographical error in the 13C NMR (CD3OD)
reported for natural renieramide,6 the CH2 carbon of the L-
DOPA fragment occurs at d = 37.7 ppm (not 43.6). We thank
Prof. R. Riccio and Dr. A. Casapullo for kindly providing
this information.
concentrated under reduced pressure. The residue was then
dissolved in THF (5 mL) and 15% aq citric acid (1.5 mL)
Synlett 2004, No. 15, 2809–2811 © Thieme Stuttgart · New York