Total synthesis of the marine-derived cyclic depsipeptide alternaramide

Article abstract of DOI:10.1055/s-0030-1259915

The first synthesis of the marine fungus derived natural product alternaramide is described using solution phase coupling protocols and via a macrolactonization and macrolactamization route. The structure of alternaramide was confirmed and was supported b

Full text of DOI:10.1055/s-0030-1259915

LETTER
797
Total Synthesis of the Marine-Derived Cyclic Depsipeptide Alternaramide
Total
S
ynthesis of
l
A
lterna
e
ramide xandra E. Horton, Oliver S. May, Mark R. J. Elsegood, Marc C. Kimber*
Department of Chemistry, Loughborough University, Loughborough, Leicester, LE11 3TU, UK
Fax +44(150)9223925; E-mail: M.C.Kimber@lboro.ac.uk
Received 19 November 2010
ies. This showed that the depsipeptide contained four ami-
no acid residues (two L-Pro and two D-Phe) and one
hydroxy acid residue (L-Hiv) linked by four amide and
one ester linkage. While all these peptides possess hydro-
Abstract: The first synthesis of the marine fungus derived natural
product alternaramide is described using solution phase coupling
protocols and via a macrolactonization and macrolactamization
route. The structure of alternaramide was confirmed and was sup-
ported by single crystal X-ray analysis which exhibited three similar phobic amino acid residues, the presence of the D-Phe res-
molecules in the asymmetric unit, each with transannular hydrogen
bonds.
idue in 1 is unusual since the only other depsipeptide in
this group to have D-amino acid residues is zygospora-
Key words: natural product, depsipeptide, peptide coupling, mac-
rolactonization, macrolactamization
mide (4; Figure 1). Additionally, the importance of a D-
amino acid in analogues of sansalvamide A, in relation to
anticancer activity, has been determined by McGuire and
McAlpine via SAR studies.6–10 Total syntheses of 311 and
Alternaramide (1; Figure 1) is a cyclic depsipeptide1 iso- 412 have been described previously, however the total syn-
lated from the marine-derived fungus Alternaria sp. SF- thesis of 1 has yet to be reported. Therefore, in this letter,
5016 by Oh and co-workers in 2009.2
we would like to report a short, efficient, solution phase
total synthesis of 1, confirmation of its reported structure
and a single crystal X-ray analysis.
O
O
L-Pro
The retrosynthesis of 1 is shown in Scheme 1. Alternara-
mide (1) can be obtained via either a macrolactonization
or a macrolactamization event on the precursor linear pep-
tides 5 and 6, respectively. While there are examples of
the use macrolactonization in the synthesis of depsipep-
tides,13–16 such a cyclisation performed on 5 may be prob-
lematic. However, due to the short synthetic sequence to
give the precursor 5 we thought this would be a viable
route to explore, alongside the macrolactamization ap-
proach. The synthesis of both precursor linear peptides 5
and 6 would be from the key tetrapeptide 7 using standard
peptide coupling protocols. The tetrapeptide 7 would be
obtained from L-Pro, D-Phe, and L-Hiv, which can be ob-
tained from L-Val via hydrolytic diazotization.
O
L-Hiv
N
O
O
O
N
HN
O
N
O
R
D-Phe
Ph
O
O
O
H
N
N
Ph
N
Ph
D-Phe
NH
N
H
O
O
Ph
L-Pro
alternaramide (1)
exumolide A R = Me (2a)
exumolide B R = H (2b)
Ph
O
O
O
O
O
NH
NH HN
O
O
HN
HN
NH
O
H
H
N
N
O
O
Ph
Ph
O
O
D-Leu
sansalvamide A (3)
zygosporamide (4)
Figure 1 The reported2 structure of alternaramide (1) and related
marine-derived depsipeptide natural products
The structure of 1 is related to several depsipeptides iso-
lated from marine-derived fungi, such as the exumolides
2 from Scytalidium sp.,3 sansalvamide A (3) from Fusar-
ium sp.,4 and zygosporamide (4) from Zygosporium maso-
nii.,5 and was confirmed using a mixture of 1H NMR/13C
NMR, degradation and Mosher’s ester derivatisation stud-
SYNLETT 2011, No. 6, pp 0797–0800
x
x.
x
x.
2
0
1
1
Advanced online publication: 15.03.2011
DOI: 10.1055/s-0030-1259915; Art ID: D30610ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis of alternaramide (1)

798
A. E. Horton et al.
LETTER
Coupling of proline methyl ester 8 with HO-D-PheHNBoc was then trialed with a number of coupling reagents in-
9 was initially performed using two coupling methods, ei- cluding PyBOP®, DCC, EDC and 1,3,5-trichlorobenzoyl
ther with EDC or via formation of the mixed anhydride chloride.18 The only successful conditions were using ex-
which gave the diamino acid 12 in a good yield of 87% cess PyBOP® and diisopropylethylamine which provided
and 86%, respectively (Scheme 2). PyBOP® was also em- alternaramide (1) in a poor isolated yield of only 5% over
ployed but yields using this coupling reagent were moder- the three steps, presumably due to the low nucleophilicity
ate to poor. The TBS-protected a-hydroxy acid 13 was of the hydroxyl group. Consequently, route B (Scheme 1)
obtained in three steps in 65% yield via the hydrolytic di- with the final ring closure via a macrolactamization was
azotization of L-Val 10 followed by TBS protection.17
pursued.
The requisite substrate for the macrolactamization was
synthesized in four steps from the key tetrapeptide 7
(Scheme 4). A protecting group switch on the L-Hiv frag-
ment was achieved in two steps to give the benzyl ester
protected L-Hiv fragment 19 in 52% yield. This was then
successfully coupled to the saponified tetrapeptide 20 in
73% yield over the two steps. Finally, the free acid and
amine groups on 20 were revealed by sequential hydro-
genolysis followed by acid-mediated Boc deprotection.
The macrolactamization of 6 was then achieved using ex-
cess PyBOP® with diisopropylethyl amine and catalytic
DMAP, giving alternaramide (1) in 48% yield over the
three steps.19
a or b
HO-D-PheBoc
MeO-L-Pro-D-PheBoc
11
12
c, d
HO2C
NH2
HO2C
OTBS
10
13
Scheme 2 Reagents and conditions: (a) EDC, MeO-L-ProNH2·HCl,
CH2Cl2, i-Pr2NEt, 87%; (b) EtO2CCl, NMM, CH2Cl2, 0 °C, then
MeO-L-ProNH2·HCl, 86%; (c) NaNO2, H2SO4; (d) (i) TBSCl, DMF,
imidazole; (ii) K2CO3, MeOH, H2O, 65% over 2 steps.
The key tetrapeptide 7 was obtained in two steps from 12,
by Boc deprotection of 12 with 4 M HCl in 1,4-dioxine to
give 14, and the hydrolysis of 12 to the free acid using
LiOH to give 15, both of which were used without further
purification. The salt 14 and free acid 15 were then cou-
pled under EDC conditions to give the key tetra-amino
acid 7 in 52% yield over the two steps (Scheme 3).
a, b
HO2C
OTBS
BnO2C
19
OH
13
MeO-L-Pro-D-Phe-L-Pro-D-PheNHBoc (7)
HO-L-Pro-D-Phe-L-Pro-D-PheNHBoc (20)
c
d
19
12
BnO-L-Hiv-L-Pro-D-Phe-L-Pro-D-PheNHBoc (21)
HO-L-Hiv-L-Pro-D-Phe-L-Pro-D-PheNHBoc (22)
HO-L-Hiv-L-Pro-D-Phe-L-Pro-D-PheNH2⋅HCl (6)
e
f
a
b
g
MeO-L-Pro-D-PheNH2⋅HCl (14)
HO-L-Pro-D-PheNHBoc (15)
O
c
O
MeO-L-Pro-D-Phe-L-Pro-D-PheNHBoc (7)
MeO-L-Pro-D-Phe-L-Pro-D-PheNH2⋅HCl (16)
O
d
N
HN
O
O
e
13
Ph
N
Ph
NH
MeO-L-Pro-D-Phe-L-Pro-D-Phe-L-HivOTBS (17)
MeO-L-Pro-D-Phe-L-Pro-D-Phe-L-HivOH (18)
HO-L-Pro-D-Phe-L-Pro-D-Phe-L-HivOH (5)
f
O
g
alternaramide (1)
h
Scheme 4 Reagents and conditions: (a) BnC(O)Cl, CH2Cl2, Et3N,
DMAP; (b) TBAF, THF, 52% over 2 steps; (c) LiOH, MeOH, THF,
H2O; (d) PyBOP®, CH2Cl2, i-Pr2NEt, 73% over 2 steps; (e) Pd/C
(10%), H2, MeOH; (f) 4 M HCl in 1,4-dioxane; (g) PyBOP®, CH2Cl2,
i-Pr2NEt, DMAP (cat.) 48% over 3 steps.
alternaramide (1)
Scheme 3 Reagents and conditions: (a) 4 M HCl in 1,4-dioxane; (b)
LiOH, THF, MeOH, H2O; (c) EDC, CH2Cl2, i-Pr2NEt, 52% over 2
steps; (d) 4 M HCl in 1,4-dioxane; (e) PyBOP®, CH2Cl2, i-Pr2NEt,
71% over 2 steps; (f) TBAF, THF; (g) LiOH, THF, MeOH, H2O; (h)
PyBOP®, CH2Cl2, i-Pr2NEt, 5% over 3 steps.
The spectroscopic data for our synthetic alternaramide
sample agreed well with that reported by Oh and co-work-
1
ers and copies of the relevant H NMR and 13C NMR
spectra are contained within the supplementary informa-
tion.20,21 Crystals suitable for single crystal X-ray analysis
were obtained and Figure 2 shows the molecular depiction
of one of three similar molecules of (–)-1 in the asymmet-
ric unit.22 Despite the use of Mo-Ka radiation for this light
atom structure, determination of the absolute structure
Subsequently, 7 was Boc deprotected and the resultant
salt 16 then coupled with 13 using PyBOP® giving 17 in a
good yield of 71% over two steps. The free alcohol and
acid functions on 17 were then sequentially revealed by
deprotection using TBAF and followed by treatment with
excess aqueous LiOH. Attempted final ring closure of 5
Synlett 2011, No. 6, 797–800 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Alternaramide
799
parameter23 via Parson’s Q-value method24 led to a value
that supported the proposed absolute structure for the mol-
ecule. The molecular conformation is stabilised by tran-
sannular hydrogen bonds.
(9) Styers, T. J.; Kekec, A.; Rodriguez, R.; Brown, J. D.; Cajica,
J.; Pan, P.-S.; Parry, E.; Carroll, C. L.; Medina, I.; Corral, R.;
Lapera, S.; Otrubova, K.; Pan, C.-M.; McGuireb, K. L.;
McAlpinea, S. R. Bioorg. Med. Chem. 2006, 14, 5625.
(10) Vasko, R. C.; Rodriguez, R. A.; Cunningham, C. N.; Ardi,
V. C.; Agard, D. A.; McAlpine, S. R. ACS Med. Chem. Lett.
2010, 1, 4.
(11) Lee, Y.; Silverman, R. B. Org. Lett. 2000, 2, 3743.
(12) Wanga, Y.; Zhang, F.; Zhang, Y.; Liu, J. O.; Ma, D. Bioorg.
Med. Chem. Lett. 2008, 18, 4385.
(13) Cochrane, J. R.; McErlean, C. S. P.; Jolliffe, K. A. Org. Lett.
2010, 12, 3394.
(14) Doi, T.; Iijima, Y.; Shinya, K.; Ganesand, A.; Takahashia, T.
Tetrahedron Lett. 2006, 47, 1177.
(15) Palomo, C.; Oiarbide, M.; Garcia, J. M.; Gonzalez, A.;
Pazos, R.; Odriozola, J. M.; Banuelos, P.; Tello, M.; Linden,
A. J. Org. Chem. 2004, 69, 4126.
(16) Sarabia, F.; Chammaa, S.; López-Herrera, F. J. Tetrahedron
Lett. 2002, 43, 2961.
(17) Gonzalez, I.; Jou, G.; Caba, J. M.; Albericio, F.; Lloyd-
Williams, P.; Giralt, E. J. Chem. Soc., Perkin Trans. 1 1996,
1427.
Figure 2 Crystal structure representation of alternaramide [(–)-1]22
(18) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
In conclusion, we have reported the first total synthesis of
alternaramide [(–)-1] using standard solution phase pep-
tide coupling protocols. Two synthetic pathways have
been investigated using a macrolactonization and a mac-
rolactamization approach giving alternaramide in a best
overall yield of 11% in eight steps. Finally, the structure
of synthetic alternaramide [(–)-1] was confirmed by sin-
gle crystal X-ray analysis.
(19) Selected Physical Data for New Compounds:
MeO-L-Pro-D-PheNHBoc [(–)-12]: colourless oil (3.05 g,
87%); Rf (EtOAc–PE, 3:1) 0.65; [a]D19 –5.5 (c = 1, CHCl3).
IR (solution, CHCl3): 3584, 3430, 2978, 1746, 1707, 1645,
1437, 1171 cm–1. 1H NMR (400 MHz, CDCl3): d = 7.24–
7.33 (m, 5 H), 5.55 (d, J = 8.8 Hz, 1 H), 4.69–4.71 (m, 1 H),
4.36 (dd, J = 3.6, 7.6 Hz, 1 H), 3.75 (s, 3 H), 3.60–3.62 (m,
1 H), 3.07–3.09 (m, 1 H), 2.98–3.02 (m, 1 H), 2.74–2.76 (m,
1 H), 1.90–1.98 (m, 4 H), 1.49 (s, 9 H). 13C NMR (100 MHz,
CDCl3): d = 172.21 (C), 170.22 (C), 154.91 (C), 136.42 (C),
129.40 (CH), 128.28 (CH), 126.81 (CH), 79.44 (C), 58.65
(CH), 53.53 (CH), 52.05 (Me), 46.66 (CH2), 40.07 (CH2),
28.85 (CH2), 28.25 (Me), 24.33 (CH2). HRMS: m/z [M +
Na+] calcd for C20H28N2O5: 399.1896; found: 399.1885.
MeO-L-Pro-D-Phe-L-Pro-D-PheNHBoc (–)-7: white foam
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
the 1H NMR and 13C NMR spectra of synthetic alternaramide [(–)-1]
and crystallographic data for (–)-1.
21
(0.97 g, 52% over 2 steps); Rf (EtOAc–PE, 3:1) 0.38; [a]D
–8.1 (c = 1, CHCl3). IR (solution, CHCl3): 3584, 3295, 2980,
1742, 1642, 1497, 1449, 1171 cm–1. 1H NMR (400 MHz,
CDCl3): d = 7.17–7.25 (m, 10 H), 5.51 (d, J = 7.6 Hz, 1 H),
4.86 (dt, J = 6.4, 8.4 Hz, 1 H), 4.54–4.57 (m, 1 H), 4.36 (dd,
J = 2.4, 8.0 Hz, 1 H), 4.27 (dd, J = 4.0, 8.4 Hz, 1 H), 3.68 (s,
3 H), 3.49–3.53 (m, 2 H), 2.93–3.02 (m, 4 H), 2.75–2.77 (m,
1 H), 2.60–2.63 (m, 1 H), 2.46 (s, 1 H), 1.98–2.03 (m, 1 H),
1.78–1.93 (m, 4 H), 1.50–1.61 (m, 3 H), 1.41 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 172.31 (C), 171.08 (C),
170.43 (C), 169.53 (C), 155.21 (C), 136.62 (C), 129.54
(CH), 129.50 (CH), 129.33 (C), 128.46 (CH), 128.34 (CH),
126.94 (CH), 126.84 (CH), 79.75 (C), 60.16 (CH), 58.80
(CH), 53.92 (Me), 52.42 (CH), 52.22 (CH), 46.84 (CH2),
46.69 (CH2), 39.63 (CH2), 39.00 (CH2), 28.91 (CH2), 28.37
(Me, masked CH2), 24.51 (CH2), 24.18 (CH2). HRMS:
m/z [M + Na+] calcd for C34H44N4O7: 643.3108; found:
643.3098.
Acknowledgment
The authors thank the Department of Chemistry at Loughborough
University for financial support.
References and Notes
(1) (a) Ballard, C. E.; Yu, H.; Wang, B. Curr. Med. Chem. 2002,
9, 471. (b) Li, W.; Schlecker, A.; Ma, D. Chem. Commun.
2010, 46, 5403.
(2) Kim, M.-Y.; Sohn, J. H.; Ahn, J. S.; Oh, H. J. Nat. Prod.
2009, 72, 2065.
(3) Jenkins, K. M.; Renner, M. K.; Jensen, P. R.; Fenical, W.
Tetrahedron Lett. 1998, 39, 2463.
(4) Belofsky, G. N.; Jensen, P. R.; Fenical, W. Tetrahedron Lett.
1999, 40, 2913.
(5) Oh, D.-C.; Jensen, P. R.; Fenical, W. Tetrahedron Lett.
MeO-L-Pro-D-Phe-L-Pro-D-Phe-L-HivOTBS (–)-17:
colourless foam (0.52 g, 71% over 2 steps); Rf (EtAOc) 0.78;
[a]D16 –12.4 (c = 1, CHCl3). IR (solution, CHCl3): 3416,
3290, 2957, 1743, 1658, 1515, 1451, 1254, 1052 cm–1. 1H
NMR (400 MHz, CDCl3): d = 7.13–7.27 (m, 10 H), 7.07 (d,
J = 7.6 Hz, 2 H), 4.82–4.87 (m, 1 H), 4.73–4.77 (m, 1 H),
4.41 (dd, J = 2.4, 8.4 Hz, 1 H), 4.23 (dd, J = 4.0, 7.6 Hz, 1
H), 3.96 (s, 3 H), 2.88–3.01 (m, 4 H), 2.64–2.68 (m, 1 H),
2.52–2.57 (m, 1 H), 2.44–2.48 (m, 1 H), 2.02–2.09 (m, 1 H),
1.95–1.99 (m, 1 H), 1.75–1.88 (m, 5 H), 1.60–1.66 (m, 1 H),
2006, 47, 8625.
(6) Alexander, L. D.; Sellers, R. P.; Davis, M. R.; Ardi, V. C.;
Johnson, V. A.; Vasko, R. C.; McAlpine, S. R. J. Med.
Chem. 2009, 52, 7927.
(7) Carroll, C. L.; Johnston, J. V. C.; Kekec, A.; Brown, J. D.;
Parry, E.; Cajica, J.; Medina, I.; Cook, K. M.; Corral, R.;
Pan, P.-S.; McAlpine, S. R. Org. Lett. 2005, 7, 3481.
(8) Otrubova, K.; Styers, T. J.; Pan, P.-S.; Rodriguez, R.;
McGuire, K. L.; McAlpine, S. R. Chem. Commun. 2006,
1033.
Synlett 2011, No. 6, 797–800 © Thieme Stuttgart · New York

800
A. E. Horton et al.
LETTER
1.46–1.51 (m, 2 H), 0.90–0.92 (m, 15 H), 0.40 (s, 3 H), –0.05
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 173.83 (C),
172.28 (C), 170.63 (C), 170.51 (C), 169.91 (C), 136.72 (C),
135.69 (C), 129.44 (CH), 129.31 (CH), 128.68 (CH), 128.34
(CH), 127.33 (CH), 126.82 (CH), 77.38 (CH), 60.53 (CH),
58.72 (CH), 52.45 (CH), 52.28 (CH), 52.09 (Me), 46.77
(CH2), 46.68 (CH2), 38.79 (CH2), 38.76 (CH2), 32.62 (C),
29.39 (CH2), 28.91 (CH2), 25.76 (CH2), 24.40 (CH2), 23.69
(CH2), 19.60 (Me), 18.07 (Me), 16.00 (C), –5.00 (Me), –5.09
(Me). HRMS: m/z [M + Na+] calcd for C40H58N4O7Si1:
757.3972; found: 757.3955.
BnO-L-Hiv-L-Pro-D-Phe-L-Pro-D-PheNHBoc (–)-21:
colourless foam (0.19 g, 73% over 2 steps); Rf (EtOAc–PE,
3:1) 0.65; [a]D18 –6.4 (c = 1, CHCl3). IR (film): 3584, 3413,
2965, 2248, 1747, 1685, 1645, 1454, 1172 cm–1. 1H NMR
(400 MHz, CDCl3): d = 7.14–7.27 (m, 15 H), 7.05–7.07 (m,
1 H), 5.41 (d, J = 7.6 Hz, 1 H), 5.08 (dd, J = 12.0, 12.4 Hz,
2 H), 4.94 (t, J = 4.4 Hz, 1 H), 4.87 (q, J = 7.2 Hz, 1 H), 4.56–
4.59 (m, 1 H), 4.40 (dd, J = 3.6, 8.4 Hz, 1 H), 4.32 (dd, J =
2.8, 8.4 Hz, 1 H), 3.53–3.56 (m, 2 H), 2.94–2.99 (m, 4 H),
2.68–2.74 (m, 1 H), 2.49–2.61 (m, 2 H), 2.29–2.30 (m, 1 H),
2.24–2.27 (m, 1 H), 1.50–1.96 (m, 6 H), 1.39 (s, 9 H), 1.03
(d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H). 13C NMR (100
MHz, CDCl3): d = 172.10 (C), 171.12 (C), 170.60 (C),
169.68 (C), 169.46 (C), 168.93 (C), 136.59 (C), 135.21 (C),
135.02 (C), 129.53 (CH), 129.49 (CH), 128.63 (CH), 128.57
(CH), 128.45 (CH), 128.39 (CH), 128.32 (CH), 126.93
(CH), 126.84 (CH), 79.72 (CH), 77.58 (CH), 67.18 (CH2),
66.93 (CH2), 60.36 (CH), 58.42 (CH), 53.86 (CH), 52.44
(CH), 46.88 (CH2), 46.73 (CH2), 38.97 (CH2), 31.92 (CH2),
30.18 (Me), 29.69 (CH2), 28.38 (CH2), 24.23 (CH2), 18.62
(Me), 17.15 (Me); one carbon masked. HRMS: m/z [M +
Na+] calcd for C45H56N4O9: 819.3945; found: 819.3899.
2875, 2248, 1744, 1683, 1643, 1634, 1529, 1452, 1275, 1094
cm–1. 1H NMR (400 MHz, CDCl3): d = 8.12 (d, J = 9.6 Hz,
1 H), 7.17–7.32 (m, 11 H), 5.34 (d, J = 2.4 Hz, 1 H), 4.91–
5.02 (m, 2 H), 4.85 (d, J = 7.2 Hz, 1 H), 4.30 (dd, J = 5.2, 8.8
Hz, 1 H), 3.41–3.46 (m, 1 H), 3.35 (dd, J = 9.2, 13.2 Hz, 1
H), 3.26 (m, 2 H), 2.99–3.03 (m, 2 H), 2.90 (dd, J = 5.2, 13.2
Hz, 1 H), 2.49–2.54 (m, 2 H), 2.42–2.44 (m, 1 H), 1.93–1.99
(m, 2 H), 1.84–1.93 (m, 2 H), 1.72–1.78 (m, 1 H), 1.63–1.69
(m, 1 H), 1.46 (sept, J = 6.8 Hz, 1 H), 0.82 (d, J = 6.8 Hz, 3
H), 0.71 (d, J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
d = 171.16 (C), 169.66 (C), 169.19 (C), 168.86 (C), 167.26
(C), 136.49 (C), 135.00 (C), 128.66 (CH), 128.30 (CH),
127.58 (CH), 127.36 (CH), 126.29 (C), 125.48 (C), 75.95
(CH), 58.92 (CH), 57.28 (CH), 51.85 (CH), 51.13 (CH),
45.89 (CH2), 44.94 (CH2), 39.43 (CH2), 35.95 (CH2), 28.65
(CH), 28.50 (CH2), 23.75 (CH2), 23.48 (CH2), 18.09 (Me),
14.83 (Me). HRMS: m/z [M + Na+] calcd for C33H40N4O6:
611.2846; found: 611.2833.
(21) See Supporting Information for copies of the 1H NMR and
13C NMR spectra for synthetically prepared alternaramide
[(–)-1].
(22) Crystal data for (–)-1: C33H40N4O6, M = 588.69,
orthorhombic, P212121; a = 12.0808 (4), b = 22.0624 (7), c =
34.9650 (11) Å, V = 9319.3 (5) Å3; Dcalc = 1.259 g/cm3;
m(Mo–Ka) = 0.087 mm–1; l = 0.71073 Å, T = 150 (2) K;
104556 total reflections, 26198 unique data (Rint = 0.0456);
solved by direct methods and refined on F2 values to give R1
= 0.0473 [F2>2s(F2)] (19948 observed reflections), wR2 =
0.1107 (all data). Absolute structure parameter = –0.09
(22)23,24. CCDC 801185 contains the supplementary
crystallographic data for compound (–)-1. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/
data_request/cif or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK;
fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk.
(23) Flack, H. D. Acta Crystallogr., Sect. A 1983, 39, 876.
(24) Parsons, S., University of Edinburgh.
(20) Alternaramide [(–)-1]: colourless crystalline solid (77 mg,
48% over 3 steps); mp 217–218.5 °C (recrystallised from
CH2Cl2–PE); Rf (EtOAc–PE, 3:1) 0.48; [a]D19 –2.8 (c = 0.5,
MeOH). IR (film): 3584, 3480, 3300, 3029, 2961, 2929,
Synlett 2011, No. 6, 797–800 © Thieme Stuttgart · New York

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