Hetero-Diels-Alder synthesis of the spiroketal fragment of reveromycin A

Article abstract of DOI:10.1016/S0040-4039(00)01494-5

The asymmetric synthesis of the 6,6-spiroketal fragment 15 of the epidermal growth factor inhibitor reveromycin A (1) is described. A hetero-Diels-Alder reaction was utilized to construct the 6,6-spiroketal 14 and subsequent stereoselective hydroboration

Full text of DOI:10.1016/S0040-4039(00)01494-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8591–8594
Hetero-Diels–Alder synthesis of the spiroketal fragment of
reveromycin A
Mariana El Sous and Mark A. Rizzacasa*
School of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
Received 15 April 2000; accepted 5 September 2000
Abstract
The asymmetric synthesis of the 6,6-spiroketal fragment 15 of the epidermal growth factor inhibitor
reveromycin A (1) is described. A hetero-Diels–Alder reaction was utilized to construct the 6,6-spiroketal
14 and subsequent stereoselective hydroboration provided reveromycin A spiroketal 15. © 2000 All rights
reserved. Elsevier Science Ltd.
The reveromycins A (1), C (2), D (3) and B (4) are recent examples of natural products
containing 6,6- and 5,6-spiroketal moieties which were isolated from a soil actinomycete
belonging to the Streptomyces genus.1–3 All the reveromycins act as inhibitors of the mitogenic
activity of epidermal growth factor (EGF) which has been identified as a possible target for a
new type of antitumor drug.
Reveromycin A (1) also exhibits antiproliferative activity against human tumor cell lines KB
and K562 as well as antifungal activity.4 The first total synthesis of (−)-reveromycin B (4) was
reported in 19995 and a second total synthesis was communicated soon afterwards.6 We have
also recently reported the asymmetric total synthesis of (−)-reveromycin B (4)7 in which the
5,6-spiroketal segment was synthesized by a hetero-Diels–Alder reaction followed by a novel
stereoselective oxidation–rearrangement strategy.8
R1
O
O
R2
O
CO2H
H
Me
Me
4
HO2C
HO2C
O
Me
Me
H
18
5
23
O
15
O
CO2H
CO2H
11
9
HO2C
O
1
O
H
OH
Me
OH
Me
Me
1 R1 = R2 = H
Me
4
2 R1 = H; R2 = Me
3 R1 = Me; R2 = H
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 All rights reserved. Elsevier Science Ltd.
PII: S0040-4039(00)01494-5

8592
Reveromycin A (1) represents a greater synthetic challenge and so far, two independent groups
have reported the synthesis of the 6,6-spiroketal fragment found in this compound.9,10 In both
approaches, the 6,6-spiroketal was formed by acid catalysis under thermodynamic control which
lead to the generation of a mixture of bicylic acetal/6,6-spiroketal9 or 6,6-spiroketal isomers10
due to the strain present in the reveromycin A type spiroketal. It has been shown that the
spiroketal system in 1 is easily isomerized into the 5,6-spiroketal fragment found in 4.9,10 For
example, reductive ozonolysis of desucinnoylated reveromycin A dimethyl ester 5, followed by
acetylation gave the 5,6-spiroketal 6 (reveromycin B type) exclusively (Scheme 1).9 This result
can be explained by the presence of a steric interaction in the 6,6-spiroketal system I which is
alleviated upon acid induced rearrangement to the 5,6-isomer II.
1) O3, MeOH, –78˚C
then NaBH4
2) Ac2O, pyridine
OAc
OH
H
Me
8
Me
AcO
O
OAc
H
21
O
CO2Me
O
9
MeO2C
O
Me
H
OH
20
Me
Me
6
5
OH
H+
O
H
O
R2
R2
O
H
O
OH
1
Me
1
Me
R
R
Reveromycin A
Reveromycin B
spiroketal I
spiroketal II
Scheme 1.
We elected to examine an alternative kinetically controlled approach to the 6,6-spiroketal
system of 1 which utilizes a hetero-Diels–Alder reaction to construct the spiroketal system in a
stereoselective manner (Scheme 2).11 A [4+2] cycloaddition between a heterodiene 7 and a
methylene pyran 8 should provide the 6,6-spiroketal 9 as one isomer where the stereochemistry
at the spiro centre is controlled in the Diels–Alder reaction by the anomeric effect.8,12 Stereo-
and regioselective hydroboration of the alkene 9 should then occur from the less hindered face
as shown to give the reveromycin A type 6,6-spiroketal I exclusively. The 6,6-spiroketal I should
rearrange to the 5,6-isomer II upon treatment with a catalytic amount of acid.
BH3
H
OH
K2CO3
[4+2]
OH
O
R1
H
R1
BH3
[O]
H+
O
+
H
R2
O
O
R1
R2
O
R2
O
R2
O
Me
O
Me
H
9
7
8
II
Me
I
1
Me
R
Scheme 2.

8593
To test the above proposal, a cycloaddition between the appropriately functionalized diene 12
and the optically pure methylene pyran 138 (available in nine steps from 1,3-propanediol) was
investigated (Scheme 3). Lithiation of the stannane 1013 and addition of the resultant anion to
butylacrolein gave the alcohol 11.14 Oxidation with Dess–Martin reagent then provided the
sensitive diene 12 which was immediately allowed to react with dienophile 13 in the presence of
8
K2CO3 at 110°C to give the desired spiroketal 14 as the only detectable isomer. Other products
from this reaction included endo-isomerized pyran as well as unidentified byproducts from the
base induced degradation of diene 12. Spiroketal 14 was then subjected to hydroboration and
oxidation to provide the reveromycin A spiroketal 15,15 again as only one diastereoisomer,
which exhibited a chemical shift for the spiro carbon (97.0 ppm) that is characteristic for the
6,6-spiroketal.8–10 As expected, compound 15 completely rearranged to the reveromycin B
5,6-spiroketal 16 upon exposure to a catalytic amount of camphorsulfonic acid in CH2Cl2. The
spiro carbon atom in 5,6-spiroketal 16 exhibited a signal at 106.2 ppm in the 13C NMR
spectrum8,10 and the structure was further confirmed by its conversion into the known triacetate
616 which was identical to the naturally derived9 and synthetic compounds5,9,10 by all the usual
criteria.
b
a
H
OH
c
BnOCH2SnBu3
O
OTBS
O
(96%)
(83%)
10
11
+
(26%)
12
OBn
Me
OBn
13
δC 97.0
OR2
OH
H
H
e
O
O
OTBS
R1O
O
OR3
H
d
O
OTBS
O
(97%)
O
(54%)
H
BnO
Me
Me
δC 106.2
BnO
Me
14
15
16 R1 = Bn; R2 = H; R3 = TBS
6 R1 = R2 = R3 = Ac
f,g,h
(75%)
Scheme 3. Reagents and conditions: (a) nBuLi, THF, −78°C, then butylacrolein; (b) Dess–Martin reagent, CH2Cl2,
rt, 2.5 h; (c) K2CO3, 110°C, 22 h; (d) BH3·THF, 0°C, 2.5 h then NaOH/H2O2, rt, 2 h (e) cat. CSA, CH2Cl2, 2 h, rt;
(f) TBAF, THF, 16 h, rt; (g) Pd(OH)2, H2, MeOH, 2 h, rt; (h) Ac2O, pyridine, DMAP, rt, 16 h
In conclusion, we have achieved an asymmetric synthesis of the reveromycin A 6,6-spiroketal
via a hetero-Diels–Alder strategy. The synthesis is short (11 steps from 1,3-propanediol),
convergent and leads to the production of the desired 6,6-spiroketal isomer 15 exclusively. In
addition, the methodology could easily be applied to the synthesis of the other reveromycins C
(2) and D (3). Studies towards the total synthesis of this family of compounds are underway.17
Acknowledgements
We gratefully acknowledge the Australian Research Council for financial support.

8594
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11. (a) Paul, R.; Tchelitcheff, S. Bull. Soc. Chim. Fr. 1954, 672–678. (b) Ireland, R. E.; Ha¨bich, D. Chem. Ber. 1981,
114, 1418–1427. (c) Sauve´, G.; Schwartz, D. A.; Ruest, L.; Deslongchamps, P. Can. J. Chem. 1984, 62,
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1
14. All new compounds were fully charactized by H and 13C NMR, IR, [h]D and HRMS or combustion analysis.
15. Data for spiroketal 15: colorless oil (62 mg, 54%); Rf 0.32 (10% EtOAc/petrol); [h]2D1 +34.7 (c 0.75, CH2Cl2); IR
1
(film) wmax 3446, 2957, 2861, 1650, 1459, 1253 cm−1; H NMR (300 MHz, CDCl3) l 0.05 (s, 6H), 0.82 (d, J=6
Hz, 3H), 0.88 (s, 9H), 0.91 (t, J=6.6 Hz, 3H), 1.20–1.88 (m, 17H), 2.30 (m, 1H), 2.78 (s, 1H), 3.56–3.73 (m, 5H),
4.55 (ABq, J=11.7 Hz, 2H), 7.26–7.34 (m, 5H); 13C NMR (75.5 MHz, CDCl3) l −5.21, −5.23, 14.1, 17.9, 18.3,
23.4, 24.5, 26.0, 27.5, 29.7, 29.8, 31.8, 33.6, 34.8, 36.3, 59.2, 70.1, 71.3, 72.8, 73.6, 76.0, 97.0, 127.8, 127.9 128.5,
137.5; HRMS (ESI) calc. for C30H52O5SiNa [M+Na+]: 543.3482. Found: 543.3464.
16. Data for 5,6-spiroketal 6: colorless solid, m.p. 58–59°C; Rf 0.28 (15% EtOAc/petrol); [h]2D9 +45.6 (c 1.0, CHCl3);
lit.9 (naturally derived) [h]D +39.1 (c 0.13, CHCl3); lit.9 (synthetic) [h]D +44.3 (c 0.18, CHCl3); lit.10 (synthetic)
[h]2D5 +37.5 (c 1.0, CHCl3); IR (film) wmax 2958, 2934, 2874, 1744, 1459, 1438, 1371, 1243, 1187, 1128, 1047 cm−1
;
1H NMR (300 MHz, CDCl3) l 0.85 (d, J=6.3 Hz, 3H),0.90 (t, J=7.2 Hz, 3H), 1.20–1.97 (m, 17H), 2.02 (s, 3H),
2.03 (s, 3H), 2.06 (s, 3H), 3.48 (dt, J=2.7, 8.4 Hz, 1H), 4.12–4.23 (m, 2H), 4.31 (m, 1H), 4.50 (dd, J=2.3, 12 Hz,
1H), 5.17 (dd, J=2.3,8.7 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) l 14.1, 17.7, 20.9, 21.0, 21.1, 23.2, 25.5, 29.0,
31.4, 32.2, 34.3, 34.5, 34.6, 38.4, 61.7, 63.9, 73.6, 76.5, 86.2, 106.9, 170.3, 171.1. Anal. calc. for C23H38O8: C,
62.42; H, 8.65. Found: C, 62.19; H, 8.36.
17. Note added in proof. The total synthesis of reveromycin A has been reported recently: Shimiza, T.; Masuda, T.;
Hiramoto, K.; Nakata, T. Org. Lett. 2000, 2, 2153–2156.
.