3358
D. Matsumura et al. / Tetrahedron Letters 50 (2009) 3356–3358
9. A recent review on the IMDA reactions applied to natural product synthesis,
Me
Me
Me
Me
see: Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779–4807.
10. We expected that the attempted IMDA reaction would be effectively
accelerated in the presence of the unsaturated aldehyde moiety as the
dienophile part in place of the unsaturated ester used in the Baldwin/Lee’s
total synthesis. And we also expected higher reactivity and higher
stereoselectivity in the IMDA reaction for construction of the core bicyclic
H
H
H
TBSO
Me
R
a, b
c,d
OMOM
Me
OMOM
Me
24
Me
MOMO
H
RO
Me
Me
28 R=CH2OH
29 R=CHO
26 R=H
structure of
1 by using substrate 6, which possesses a sterically bulky
27 R=MOM
substituent such as a (tert-butyldimethylsilyloxy)methyl group in the diene
part. On the other hand, the Baldwin/Lee substrate for their IMDA approach
incorporated a linear styryl group in the diene part, which may deactivate in
the diene part to some extent.
Me
Me
Me
H
Me
H
g
h
OR
Me
O
11. According to the Fukumoto’s precedent, the starting material 7, that is, (2S)-2-
[(tert-butyldimethylsilyloxy)methyl]butan-1-ol, was synthesized using an
Evans’ aldol approach with the (S)-phenylalanine-derived chiral auxiliary,
see: Ihara, M.; Setsu, F.; Shoda, M.; Taniguchi, N.; Tokunaga, Y.; Fukumoto, K. J.
Org. Chem. 1994, 59, 5317–5323.
12. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919–5923.
13. The diastereomeric ratio of this asymmetric crotylboration products was
approximately 3 to 1 in favor of 14 based on 1H NMR analysis of the crude
e, f
1
Me
RO
Me
H
H
Me
H
O
Me
Me
30 R=MOM
31 R=H
32
Scheme 4. Conversion of the IMDA adduct 24 into 1. Reagents and conditions: (a)
NaBH4, MeOH/THF = 1:1, rt, 91%; (b) MOMCl, iPr2NEt, CH2Cl2, reflux; (c) nBu4NF,
THF, 50 °C, 99% over two steps; (d) DMSO, (COCl)2, CH2Cl2, ꢀ78 °C then Et3 N, rt,
90%; (e) diethyl (benzyl)phosphonate, nBuLi, THF, ꢀ78 °C then 29, 0 °C, 88%; (f) CSA,
MeOH, 40 °C, 6 d; (g) Dess–Martin periodinane, CH2Cl2, rt, 85% over two steps; (h)
NaClO2, 2-methyl-2-butene, phosphate buffer, tert-BuOH/H2O = 5:1, rt, 82%.
mixture. The monor anti-adduct, produced as a result of opposite
p-facial
selection, was clearly separated from 15 by chromatography on silica gel after
converting into the corresponding MOM ethers through the MOM ether
formation of the adducts mixture.
14. The anti-configuration of the b-methylhomoallylic alcohol part in 14 was
confirmed using advanced intermediates by examination of their 1H NMR
analysis.
15. Smithers, R. H. J. Org. Chem. 1978, 43, 2833–2838.
16. Takagi, J.; Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Am. Chem. Soc. 2002, 124,
8001–8006.
synthetic 1 were identical with those reported for the natural
product 1.1 Furthermore, [
a
]
of the synthetic 1 [½a D25
ꢂ
+102 (c
D
0.38, CH2Cl2)] coincided with that reported for the natural sample
17. The vinyl iodide 21 was synthesized starting from commercially available
diethyl ethylmalonate as follows: (1) diethyl ethylmalonate, NaH, Et2O, reflux,
1 h, then CHI3, reflux, 24 h; (2) KOH, EtOH/H2O = 3:1, reflux, 60 h: (3) LiAlH4,
THF, rt, 3 h, 30% over 3 steps; (4) TBSCl, DMAP, Et3N, CH2Cl2, rt, 1 h, 83%. For an
analogous procedure, see: Baker, R.; Castro, J. L. J. Chem. Soc. Perkin Trans.1
1990, 47–65.
18. The direct formation of the IMDA substrate 23 was also observed in the
Suzuki–Miyaura coupling of 20 and 21 when the cross-coupling was executed
with an excess amount of the Pd-catalyst in DMF in the presence of Cs2CO3 at
70 °C for a prolonged reaction time (more than 3 days). Under these conditions,
[[a]
+110 (c 0.1, CH2Cl2)], including its sign.25
D
In summary, we have achieved the first total synthesis of natu-
ral (+)-spiculoic acid A (1), which featured the IMDA reaction of the
trienic aldehyde 23 for the highly stereoselective and expeditious
construction of a core bicyclic structure with correct stereochemis-
try for the total synthesis of 1. The highly stereoselective outcome
of the IMDA reaction can be explained by the presence or by the
absence of the steric hindrance in the two possible transition
states. Relying on the mentioned transition state argument, we
have also accomplished the synthesis of a cis-fused spiculoic acid
A congener.
the formation of 23 and
a spontaneous IMDA reaction occurred. NaBH4
reduction of the crude reaction mixture and purification of crude product on
silica gel provided 26 in a less effective overall yield of 33% from 20. For an
example of the palladium-catalyzed oxidation of primary (allylic) alcohols,
See: Tamaru, Y.; Yamada, Y.; Inoue, K.; Yamamoto, Y.; Yoshida, Z. J. Org. Chem.
1983, 48, 1286–1292.
19. As the spontaneous IMDA reaction started at 70 °C under the Suzuki–Miyaura
coupling conditions, we kept continuing the IMDA reaction at 70 °C. The IMDA
reaction of 23 proceeded at 70 °C rather slowly but cleanly. For completion of
the IMDA reaction, it required 5 days. After heating for 1 or 2 days at 70 °C,
substantial amount of 23 remained intact. We did not execute the IMDA
reaction at other temperatures.
Acknowledgments
This work was supported by Grants-in-Aid for Scientific Re-
search on Priority Areas (A) ‘Creation of Biologically Functional
Molecules (18032069)’ from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
20. It is apparently obvious that the C-8 substituent (an ethyl group) cooperates in
realizing the high stereoselectivity of the IMDA reaction. In the two transition
states23-endoand 23-exo, p-facial selectivities arethe same as depicted inScheme
3. On the other hand, opposite p-facial attack in the endo-mode is significantly
unfavorable owing to a severe allylic interaction (A(1.3) strain) generated between
the ethyl group at C-8 and the ethyl group in the dienophile part.
Supplementary data
21. We obtained further evidence for this steric disadvantage generated by the
allylic strain in the IMDA reaction. Thus, we synthesized another IMDA
substrate, in which the configuration of methyl substituent at C-6 was opposite
to that in 23. The IMDA reaction of this substrate provided an exo-adduct
predominantly. In this case, a severe A(1,3) strain was most likely in an endo-
The experimental procedures and 1H and 13C NMR spectra for
all new compounds. Supplementary data associated with this arti-
mode transition state. This exo-adduct was eventually converted into
a
diastereomer of spiculoic acid A, namely, 2,5,6-tri-epi-spiculoic acid A, by the
analogous reaction sequence used for the synthesis of 1.
References and notes
22. In another approach, we obtained the following result: NaClO2 oxidation of the
aldehyde functionality in an endo-cycloadduct similar to 24, which possesses a
(4-methoxyphenyl)methyl (MPM) group in place of the TBS group, provided
the corresponding carboxylic acid. After methyl esterification, the removal of
the MPM group in the resulting ester with DDQ was investigated. As a result,
1. Huang, X.-H.; van Soest, R.; Roberge, M.; Andersen, R. J. Org. Lett. 2004, 6, 75–
78.
2. Berrué, F.; Thomas, O. P.; Fernández, R.; Amade, P. J. Nat. Prod. 2005, 68, 547–
549.
3. Berrué, F.; Thomas, O. P.; Laville, R.; Prado, S.; Golebiowski, J.; Fernández, R.;
Amade, P. Tetrahedron 2007, 63, 2328–2334.
4. Mehta, G.; Kundu, U. K. Org. Lett. 2005, 7, 5569–5572.
only
c
-lactonization occurred exclusively after deprotection of the MPM group.
-lactone formation occurred
It was, thus, obvious that the facile
c
spontaneously owing to the vicinal cis-relationship of the carboxylic acid
and the primary hydroxyl group. Furthermore, we could not find efficient
5. (a) Kirkham, J. E. D.; Lee, V.; Baldwin, J. E. Chem. Commun. 2006, 2863–2865;
The Baldwin/Lee group has pointed out the structural misassignment of
synthetic intermediates described in the Mehta/Kundu’s publication4, see: (b)
Kirkham, J. E. D.; Lee, V.; Baldwin, J. E. Org. Lett. 2006, 8, 5537–5540.
6. Crossman, J. S.; Perkins, M. V. Tetrahedron 2008, 64, 4852–4867.
7. The absolute stereochemistries of 2–5 are still unknown, and the structural
drawings for 2–5 in Figure 1 are arbitrary.
conditions to open this c-lactone for further functionalization. From this result,
we concluded that the synthetic route involving direct oxidation of the
aldehyde 24 to the corresponding carboxylic acid could not evade the above-
mentioned synthetic dead end.
23. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156; (b) Dess, D. B.;
Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–7287; (c) Ireland, R. E.; Liu, L. J.
Org. Chem. 1993, 58, 2899.
8. Although the IMDA approach to the total synthesis of (ꢀ)-spiculoic acid A
disclosed by the Baldwin/Lee group was straightforward for the construction of
the bicyclic structure possessing all the requisite functionalities, the desired
cycloadduct was obtained in a less satisfactory yield of 25% (100 °C in toluene).
24. (a) Kraus, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825–4830; (b) Bal, B. S.;
Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096.
25. The reported [
see Ref. 5a.
a]
D for unnatural (ꢀ)-spiculoic acid A: ½a D22
ꢀ97 (c 0.16, CH2Cl2),
ꢂ