Total synthesis of the fungal metabolite (±)-acremine G: Acceleration of a biomimetic Diels-Alder reaction on silica gel

Article abstract of DOI:10.1016/j.tetlet.2010.07.109

A total synthesis of the bioactive tetracyclic natural product acremine G has been achieved in which a regio- and stereoselective biomimetic Diels-Alder reaction between two readily assembled building blocks, accelerated on a solid support (silica gel), forms the key step.

Full text of DOI:10.1016/j.tetlet.2010.07.109

Tetrahedron Letters 51 (2010) 5116–5119
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of the fungal metabolite ( )-acremine G: acceleration
of a biomimetic Diels–Alder reaction on silica gel
*
Goverdhan Mehta , Tabrez Babu Khan, Y. C. Sunil Kumar
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of the bioactive tetracyclic natural product acremine G has been achieved in which a
regio- and stereoselective biomimetic Diels–Alder reaction between two readily assembled building
blocks, accelerated on a solid support (silica gel), forms the key step.
Received 23 May 2010
Revised 8 July 2010
Accepted 16 July 2010
Available online 25 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
prenyl benzoquinone dimer from the medicinal plant Ehretia micro-
Endophytic fungi, as they grow on their plant hosts, continually
interacting and exchanging evolutionary memories, produce a wide
range of novel and interesting secondary metabolites.1 In particular,
fungal metabolites of the genus Acremonium have proved to be a rich
repository of diverse natural products, endowed with broad-ranging
biological activity, encompassing immunosuppressant cyclosporins
to tremorgenic indoles.2 A research group3 in Italy has explored a
strain of Acremonium byssoides named A20, isolated from the grape-
vines of a Sicilian vineyard and found to parasitize Plasmopara vitico-
la, for new metabolites. From the cultures of this fungus, a dozen
structurally related metabolites named acremines A–F,3a G3b and
H, I, L–N,3c originating through a mixed polyketide and mevalonate
biosynthetic pathway, were isolated, characterized and their stereo-
structures elucidated.3 Among these, acremine G (1), whose struc-
ture was determined through single crystal X-ray crystallography,
is particularly interesting in view of its compact tetracyclic frame-
work and its dimeric relationship with respect to other acremines,
for example, acremine A (2). As with other acremines, 1 also exhib-
ited mild inhibition of sporangia in P. viticola.
phylla.4 Drawing on the earlier proposal for the biogenesis of allomi-
crophyllone 3, Nasini and co-workers3b proposed a Diels–Alder (DA)
cycloaddition–enzymatic oxidative coupling-based biosynthetic
pathway for acremine G, Scheme 1.5 The monomeric units 4a and
5 could readily arise from acremine A (2) involving appropriately
sequenced dehydration/oxidation steps. Stereoselective Diels–Alder
reaction to 6 and further oxidative coupling was expected to lead to
1. In view of our ongoing interest6 on acremines that recently cul-
minated in the synthesis of acremines A, B and I,6 we decided to em-
bark on a synthesis of acremine G (1) following the proposed
biogenetic pathway involving the Diels–Alder cycloaddition as the
pivotal step.7,8
To commence our study towards acremine G (1) via the biomi-
metic Diels–Alder cycloaddition strategy, the synthesis of the two
monomeric units, diene 4b and prenylated quinone 5, was under-
taken from readily available starting materials. Methyl hydroqui-
none 7a, obtained commercially, was methylated to 7b and
further Vilsmeier–Haack formylation furnished 8,9 Scheme 2. Wit-
tig–Horner olefination of 8 led to the cinnamate ester 9, which, on
addition of excess methyllithium, resulted in the tertiary alcohol
10. After some initial difficulties, we found that 10 could be readily
dehydrated with mesyl chloride in the presence of DMAP and Et3N
to deliver the desired diene 4b,10 Scheme 2.
In structural terms, acremine G (1) possesses an architecture
reminiscent of allomicrophyllone 3, a bioactive
O
O
R
O
R
The formylated compound 89 also served as the precursor for
the prenylated quinone 5. Demethylation of 8 led to diol 11 and
Horner–Wittig olefination furnished the cinnamate ester 12,
Scheme 3. Addition of excess methyllithium to 12 furnished the
tertiary alcohol 13. After investigating several reaction conditions
for the oxidation of hydroquinone 13 which would not be detri-
mental to the sensitive tertiary hydroxy group, we found that
aqueous NaIO4 fitted the requirement and delivered the prenylated
benzoquinone 5 in good yield.
OH
HO
O
OH
OH
2, acremine A
OH
1, R = Me, acremine G
3, R = H, allomicrophyllone
With somewhat labile diene 4b and the prenylated benzoqui-
none 5 in hand, we were keen to avoid thermal activation for the
Diels–Alder reaction and looked for mild conditions to affect the
cycloaddition. After evaluating several catalysts, we were delighted
* Corresponding author. Tel.: +91 4023134848; fax: +91 4023012460.
E-mail address: gmsc@uohyd.ernet.in (G. Mehta).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.109

G. Mehta et al. / Tetrahedron Letters 51 (2010) 5116–5119
5117
O
O
O
O
[O]
Diels-Alder
+
HO
HO
HO
O
O
O
OH
5
OH
OH
OH
1
OH
4a
6
Scheme 1. Proposed biogenesis of acremine G (1).
OH
CO Me
2
O
OR
OMe
OMe
OMe
OMe
b
c
d
e
RO
MeO
MeO
MeO
MeO
7a, R = H
8
9
10
4b
a
7b, R = Me
Scheme 2. Reagents and conditions: (a) Me2SO4, K2CO3, acetone, rt, 24 h, quant.; (b) DMF, POCl3, DCE, 80 °C, 12 h, 80%; (c) Ph3P@CHCO2Me, C6H6, reflux, 4 h, 80%; (d) MeLi
(3 equiv), THF, À78 °C, 30 min, 83%; (e) MsCl, Et3N, DMAP, CH2Cl2, 0 °C to rt, 1 h, 78%.
to find that commonly used chromatographic silica gel [100–200
mesh; SiO2/(4b+5) = 5:1] accelerated11 dramatically the DA reac-
tion between 4b and 5 and the reaction was complete within one
hour under ambient conditions to furnish two adducts, endo-1410
and exo-15,10 in a ratio of 4:1 and in 80% yield, Scheme 4. The
structures of 14 and 15 were determined from 2D NMR data, par-
ticularly NOE experiments; however, for the sake of unambiguity,
the structure of the required endo-adduct 14 was fully secured
through single crystal X-ray structure determination12 and its OR-
TEP diagram is displayed in Figure 1. The stereo- and regiochemical
outcomes of the Diels–Alder reaction between 4a and 5 are quite
notable and the preferential formation of the desired endo-adduct
14 among other regio- and stereochemical possibilities can be rec-
onciled through the endo transition state 16.13 Having obtained the
key DA adduct corresponding to 6 as envisaged in Scheme 1, the
next task was to attempt the crucial oxidative cyclization to the
natural product 1 and this a priori necessitated deprotection of
the aromatic methyl ether functionality in 14.10 However, given
the sensitivity of 14, this proved to be a major hurdle, and forced
us to seek a modified approach employing a more pliable protect-
ing group for the phenolic hydroxy groups.
of methyllithium led to the tertiary alcohol 18, Scheme 5. As ex-
pected, the tertiary hydroxy group in 18 proved to be amenable to
smooth dehydration and furnished the desired diene 4c to partner
the prenylated benzoquinone 5 in a DA cycloaddition. We were de-
lighted to observe that the DA reaction between 4c and 5 progressed
to completion under ambient conditions14 in the presence of silica
gel [100–200 mesh; SiO2/(4c+5) = 5:1] and two adducts, endo-19
and exo-20, were obtained in ꢀ4:1 ratio, Scheme 6. The structures
of 19 and 20 followed from their 2D NMR analyses and spectral com-
parison with their sibling adducts 14 and 15, respectively. The pre-
ferred formation of the endo-adduct 19 was once again along
expected lines (vide supra) with good regio- and stereocontrol.
At this stage, we attempted deprotection of the –OTBS groups in
19 to explore the key oxidative coupling (see Scheme 1). However,
this deprotection step proved to be surprisingly complicated in spite
of employing a variety of desilylation protocols. Thus, we decided to
adopt the very recently reported8 procedure of Stratakis and co-
workers to complete the synthesis of acremine G, Scheme 7. Indeed,
exposing endo-19 to in situ-generated HF under oxygen and careful
monitoring (TLC) of the reaction led to the isolation of acremine G
(1)10 in a satisfactory yield through successive desilylation, epimer-
ization and oxidative cyclization. The mechanism of this interesting
radical-mediated oxidative coupling reaction has already been dis-
Consequently, the phenolic hydroxy groups in cinnamate ester
12 were protected as the di-TBS derivative 17 and further addition
OH
OMe
OH
OH
O
a
b
c
d
O
O
OMe
O
OH
O
OH
OH
8
11
12
13
5
HO
HO
MeO
Scheme 3. Reagents and conditions: (a) BBr3, CH2Cl2, À78 °C, 24 h, 87%; (b) Ph3P@CHCO2Me, C6H6, reflux, 2 h, 88%; (c) MeLi (5 equiv), THF, À78 °C, 1 h, 63% (based on
recovered starting material); (d) NaIO4, MeOH/H2O (2:1), 0 °C to rt, 1 h, 83%.

5118
G. Mehta et al. / Tetrahedron Letters 51 (2010) 5116–5119
O
OH
CO Me
2
+
MeO
OR
OTBS
OTBS
b
c
O
OMe
5
RO
a
TBSO
TBSO
OH
4b
12, R = H
17, R = TBS
18
4c
a
O
O
O
Scheme 5. Reagents and conditions: (a) TBSCl, imidazole, DMAP, DMF, 80 °C, 12 h,
90%; (b) MeLi (3 equiv), THF, À78 °C, 30 min, 88%; (c) MsCl, Et3N, DMAP, CH2Cl2,
0 °C to rt, 1 h, 80%.
H
H
+
MeO
MeO
O
O
H
OH
OH
OMe
OMe
TBSO
14
15
TBSO
O
OTBS
OH
O
OTBS
4c
19
a
O
+
+
H
O
O
MeO
O
OH
TBSO
OMe
16
O
OH
5
Scheme 4. Reagents and conditions: (a) silica gel, rt, 1 h, 80% overall (14 = 64%,
15 = 16%).
OH
OTBS
20
Scheme 6. Reagents and conditions: (a) silica gel, rt, 4 h, 77% overall (19 = 62%,
20 = 15%).
O
O
O
O
H
H
a
1
TBSO
HO
(ref. 8)
OH
OH
OTBS
OH
19
Figure 1. ORTEP diagram of 14, drawn at 30% probability.
Scheme 7. Reagents and conditions: (a) anhydrous KF, 30% HBr in glacial AcOH,
DMF, O2, rt, 36 h, 70%.
cussed.8 Our sample of synthetic 1 was found to be spectroscopically
(1H, 13C NMR) identical to the natural product.
In short, we have accomplished a total synthesis of the dimeric
natural product ( )-acremine G following a short and simple assem-
bly of the diene and dienophile monomeric units and employing a
silica gel-accelerated Diels–Alder reaction as the pivotal step. We
are currently extending this successful biomimetic Diels–Alder
cycloaddition strategy towards the synthesis of microphyllone, allo-
microphyllone and related bioactive natural products.4

G. Mehta et al. / Tetrahedron Letters 51 (2010) 5116–5119
5119
(M+Na)+: 241.1204; found: 241.1202; compound 14: mp 122–123 °C IR (thin
film)
max = 3436, 2968, 2926, 1675, 1502, 1466, 1210, 1044, 885 cmÀ1 1H
Acknowledgements
m
;
NMR (300 MHz, CDCl3) d = 6.54 (s, 1H), 6.37 (s, 1H), 5.89 (d, J = 1.5 Hz, 1H), 5.88
(d, J = 16 Hz, 1H), 5.79 (d, J = 16 Hz, 1H), 5.41 (d, J = 3 Hz, 1H), 4.23 (br s, 1H),
3.72 (s, 3H), 3.62 (s, 3H), 2.98 (d, J = 18 Hz, 1H), 2.93 (d, J = 8 Hz, 1H), 2.12 (s,
3H), 1.97 (dd, J = 18, 7 Hz, 1H), 1.83 (s, 3H), 1.52 (d, J = 1.5 Hz, 3H), 1.36 (s, 3H),
1.34 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) d = 200.62, 198.60, 151.19,
149.90, 147.55, 138.33, 136.14, 133.69, 128.91, 126.64, 126.00, 121.56, 113.79
(2C), 70.85, 57.59, 55.46, 55.32, 48.97, 40.48, 29.86, 29.62, 25.36, 23.40, 16.08,
15.63 ppm; HRMS (ES) m/z calcd for C26H32O5Na (M+Na)+: 447.2147; found:
T.B.K. and Y.C.S.K. thank UGC for support through a Dr. D. S. Kot-
hari post-doctoral fellowship. X-ray data were collected at the CCD
facility at IISc, supported by DST, India, and we thank Mr. Saikat
Sen for solving the structure. G.M. is grateful to CSIR for the award
of a Bhatnagar Fellowship.
447.2145; compound 15 mp 142–143 °C IR (thin film)
mmax = 3448, 2966, 2926,
1685, 1507, 1466, 1208, 1045, 865 cmÀ1 1H NMR (300 MHz, CDCl3) d = 6.62 (s,
;
References and notes
1H), 6.52 (s, 1H), 6.49 (d, J = 1.2 Hz, 1H), 5.44 (s, 1H), 5.42 (d, J = 16 Hz, 1H), 5.30
(d, J = 16 Hz, 1H), 4.70 (s, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.35 (t, J = 8 Hz, 1H),
2.33 (br s, 2H), 2.17 (s, 3H), 1.95 (d, J = 1.2 Hz, 3H), 1.75 (s, 3H), 1.01 (s, 3H),
0.94 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) d = 201.23, 198.96, 151.53,
150.97, 146.27, 139.10, 135.72, 131.17, 127.27, 126.91, 126.10, 123.55, 114.06,
113.27, 70.28, 60.37, 56.69, 56.26, 56.24, 48.41, 29.65, 28.96, 28.83, 23.06,
16.05, 15.87 ppm; HRMS (ES) m/z calcd for C26H32O5Na (M+Na)+: 447.2147;
1. For a recent review, see: Guo, B.; Wang, Y.; Sun, X.; Tang, K. Appl. Biochem.
Microbiol. 2008, 44, 136–142.
2. For example, see: (a) Gehrt, A.; Erkel, G.; Anke, T.; Sterner, O. Nat. Prod. Res.
2000, 14, 281–284; (b) Gatenbay, W. A.; Munday-Finch, S. C.; Wilkins, A. L.;
Miles, C. O. J. Agric. Food Chem. 1999, 47, 1092–1097; (c) Mussaif, M.; Jacques,
P.; Schaarwachter, P.; Budzikiewicz, H.; Thonart, P. Appl. Environ. Microbiol.
1997, 63, 1739–1743.
3. (a) Assante, G.; Dallavalle, S.; Malpezzi, L.; Nasini, G.; Burruano, S.; Torta, L.
Tetrahedron 2005, 6, 7686–7692; (b) Arnone, A.; Nasini, G.; Panzeri, W.; Vajna
de Pava, O.; Malpezzi, L. J. Nat. Prod. 2008, 71, 146–149; (c) Arnone, A.; Assante,
G.; Bava, A.; Dallavalle, S.; Nasini, G. Tetrahedron 2009, 65, 786–791.
4. Yamamurs, S.; Simpol, L. R.; Ozawa, K.; Ohtani, K.; Otsuka, H.; Kasai, R.;
Yamasaki, K.; Padolina, W. G. Phytochemistry 1995, 39, 105–110.
5. For selected recent examples of biomimetic/bioinspired Diels–Alder reactions
in natural product synthesis, see: (a) Heckrodt, T. J.; Mulzer, J. J. Am. Chem. Soc.
2003, 125, 4680–4681; (b) Vanderwal, C. D.; Vosburg, D. A.; Weiler, S.;
Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393–5407; (c) Mehta, G.; Pan, S. C.
Org. Lett. 2004, 6, 3985–3988; (d) Mehta, G.; Ramesh, S. S. Tetrahedron Lett.
2004, 45, 1985–1987; (e) Dong, S.; Zhu, J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2008,
130, 2738–2739; (f) Mehta, G.; Roy, S. Tetrahedron Lett. 2008, 49, 1458–1460;
(g) Arkoudis, E.; Stratakis, M. J. Org. Chem. 2008, 73, 4484–4490.
found: 447.2131; ( )-acremine G (1) mp 132–133 °C IR (thin film)
mmax = 3370,
2925, 1674, 1420, 1264, 1018, 738 cmÀ1 1H NMR (300 MHz, CDCl3) d = 6.51 (s,
;
2H), 6.36 (q, J = 1.5 Hz, 1H), 5.76 (d, J = 16 Hz, 1H), 5.63 (d, J = 16 Hz, 1H), 5.62
(d, J = 6 Hz, 1H), 5.03 (br s, 1H, OH), 3.75 (d, J = 6 Hz, 1H), 2.72 (d, J = 19 Hz 1H),
2.47 (d, J = 19 Hz, 1H), 2.11 (s, 3H), 2.10 (s, 3H), 1.67 (s, 3H), 1.64 (br s, 1H, OH),
1.21 (s, 6H) ppm; 13C NMR (100 MHz, CDCl3) d = 196.05, 194.09, 150.00,
148.22, 144.35, 142.82, 135.15, 131.29, 124.85, 123.64, 122.51, 121.90, 118.67,
113.57, 80.59, 70.85, 54.85, 38.45, 36.15, 29.60 (2C), 22.6, 16.88, 15.72 ppm;
HRMS (ES) m/z calcd for C24H26O5Na (M+Na)+: 417.1678; found: 417.1621.
11. (a) Veselovsky, V. V.; Gybin, A. S.; Lozanova, A. V.; Moiseenkov, A. M.; Smit, W.
A.; Caple, R. Tetrahedron Lett. 1988, 29, 175–178; (b) Coperet, C.; Chabanas, M.;
Saint-Arroman, R. P.; Basst, J.-M. Angew. Chem., Int. Ed. 2003, 42, 156–181.
12. Single crystal X-ray diffraction data were collected on a Bruker AXS SMART
APEX CCD diffractometer at 291 K using graphite monochromated MoK
a
radiation (k = 0.7107 Å). The X-ray generator was operated at 50 KV and 35 mA.
6. A manuscript describing the first total syntheses of acremines A, B and I is
under the consideration of the Editor for publication in Tetrahedron Letters.
7. While the present research towards acremine G was underway, a biomimetic
Diels–Alder-based total synthesis of acremine G appeared in the literature.
Although there is convergence in the last step of the synthesis,8 our approach
to acremine G is noteworthy for its brevity and simplicity and the remarkable
acceleration of the key Diels–Alder cycloaddition.
The data were collected with an
set were collected using SMART in three different settings of
x
scan width of 0.3°. A total of 606 frames per
(0°, 90°, 180°
u
and 270°) keeping the sample at a detector distance of 6.062 cm and the 2h
value fixed at À28°. The data were reduced by SAINTPLUS; an empirical
absorption correction was applied using the package SADABS and XPREP was
used to determine the space group. The crystal structures were solved by direct
methods using SIR92 and refined by full-matrix least-squares method on F2
using SHELXL97. CCDC 783610 contains the supplementary crystallographic data
for this Letter. These data can be obtained free of charge from The Cambridge
8. Arkoudis, E.; Lykakis, I. N.; Gryparis, C.; Stratakis, M. Org. Lett. 2009, 11, 2988–
2991.
9. It was found that methylhydroquinone was not amenable to direct Vilsmeier–
Haack formylation and therefore required phenolic group protection.
10. All new compounds reported here are racemic and characterized on the basis
of spectroscopic data (IR, 1H, 13C NMR and mass). Spectral data for some of the
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.
ꢀ
Crystal data for 14:
b = 18.195(7), c = 20.491(7) Å,
V = 4894(3) Å3, Z = 8, calcd = 1.152 g/cm3, 39564 reflections measured, 19755
C
26H32O5, M = 424.52, triclinic, P1, a = 15.600(6),
a
= 115.182(7), b = 104.376(7), c = 98.049(7)°,
q
key compounds are as follows: compound 4b: IR (neat)
m
max = 1506, 1463, 1401,
unique (Rint = 0.071), R1 = 0.0858 and wR2 = 0.1725 for 7188 observed
reflections.
1210, 1045, 971, 872 cmÀ1 1H NMR (300 MHz, CDCl3) d = 6.97 (s, 1H), 6.88 (d,
;
J = 16 Hz, 1H), 6.82 (d, J = 16 Hz, 1H), 6.70 (s, 1H), 5.09 (s, 1H), 5.04 (s, 1H), 3.83
(s, 3H), 3.81 (s, 3H), 2.22 (s, 3H), 1.99 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d = 151.88, 150.8, 142.74, 130.97, 127.12, 124.09, 123.36, 116.41, 114.52,
107.89, 56.33, 55.92, 18.70, 16.41 ppm; HRMS (ES) m/z calcd for C14H18O2Na
13. For a discussion on stereoelectronic control of Diels–Alder reactions, see: (a)
Mehta, G.; Uma, R. Acc. Chem. Res. 2000, 33, 278–286; (b) Brocksom, T. J.;
Nakamura, J.; Ferreira, M. L.; Brocksom, U. J. Braz. Chem. Soc. 2001, 12, 597–622.
14. Refluxing toluene (110 °C) for 24 h.8