Enantioselective Synthesis of the Spirotetracyclic Carbon Core of Mangicols by Using a Stereoselective Transannnnular Diels-Alder Strategy

Article abstract of DOI:10.1002/anie.200351750

"TADA!" is not the trumpet fanfare but the transannular Diels-Alder reaction concluding the synthesis of the tetracyclic core of the mangicols, a family of marine sesterterpenes. Further highlights in the synthesis include a novel chlorination and an intr

Full text of DOI:10.1002/anie.200351750

Angewandte
Chemie
Spirotetracycle Synthesis
Enantioselective Synthesis of the Spirotetracyclic
Carbon Core of Mangicols by Using a Stereo-
selective Transannular Diels–Alder Strategy**
Keisuke Araki, Keiji Saito, Hirokazu Arimoto, and
Daisuke Uemura*
The synthesis of complex natural products has been inves-
tigated extensively by chemists, but the construction of
architecturally novel carbon frameworks remains a challeng-
ing problem. Of particular importance is the effective syn-
thesis of extremely complex carbocycles incorporating qua-
ternary carbons and consecutive asymmetric centers.[1] Man-
gicols isolated from the marine fungus Fusarium heterospo-
rum by Fenical and co-workers in 2000 are new sesterterpe-
noids with a novel carbon framework (Figure 1) that exhibit
Figure 1. Structure of the mangicols.
cytotoxic and antiinflammatory activities.[2] The highly com-
plex spirotetracyclic skeleton of the mangicols was recognized
as an attractive target for total synthesis, since its stereo-
selective construction, especially at the quaternary carbons,
should be quite challenging.
We hypothesized that the stereoselective synthesis of the
tetracyclic framework of mangicols, including the spiro
carbon core, would be efficiently accomplished by employing
a transannular Diels–Alder (TADA) reaction. TADA reac-
tions are powerful tools for the construction of polycyclic
frameworks and have often been used as the key step in the
total synthesis of natural products.[3] The first report of a
TADA reaction was that by Deslongchamps et al., who
employed a 13-membered cyclic triene.[3b–d] Thereafter, this
research group extensively investigated the TADA reactions
of a 14-membered cyclic triene. Roush et al. investigated
TADA reactions of 12-membered cyclic trienes for the
[*] K. Araki, K. Saito, Prof. Dr. H. Arimoto, Prof. Dr. D. Uemura
Graduate School of Science, Nagoya University
Furo-cho, Chikusa, Nagoya 464-8602 (Japan)
Fax: (+81)52-789-3654
E-mail: uemura@chem3.chem.nagoya-u.ac.jp
[**] This work was supported in part byGrants-in-Aid (Nos. 11175101
and 12045235) for Scientific Research from the Ministryof
Education, Culture, Sports, Science and Technology, Japan.
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DOI: 10.1002/anie.200351750
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81

Communications
synthesis of spinosyn A;[3e] however, only poor stereoselec-
derived from the common intermediate aldehyde 7. Aldehyde
7 was reduced with NaBH4, followed by formation of the
TBDPS ether 12. Subsequent acidic removal[8] of the Tr group
gave alcohol 13. Elaboration to the sulfide 14 was followed by
oxidation of 14 with mCPBA to give sulfone 15. The Julia
coupling reaction[9] between the carbanion generated from
sulfone 15 and the common intermediate aldehyde 7 gave a
diastereomeric mixture of hydroxy sulfones. The Tr group was
removed under acidic conditions, and the resulting diol was
oxidized with Dess–Martin periodinane[10] to afford ketoal-
dehyde 16. Several attempts at an intramolecular aldol
cyclization reaction of 16 failed. However, a reductive aldol
cyclization reaction with SmI2 proceeded smoothly, and
subsequent treatment with Al2O3 gave cyclopentenone 17.
The Michael addition of thiophenol to cyclopentenone 17
afforded b-thiophenylcyclopentanone 18 as a mixture of
diastereomers (13:1).
tivity was achieved. The difficulties in controlling the stereo-
chemistry of TADA reactions arise from the small differences
in energy among the possible transition states. Thus, the
careful design of the triene intermediate is essential for the
stereoselective construction of the framework. As shown in
Scheme 1, we chose trienone 5 as the key intermediate; the
stereochemistry of the substituted positions—C5, C7, C9,
C13, and C15—is such that trienone 5 would be in the desired
conformation.
The conversion of b-thiophenylcyclopentanone 18 into b-
chlorocyclopentenone 11, a Stille coupling precursor, was
then examined (Scheme 3). We initially thought that this
conversion would take several steps, namely, 1) conversion of
b-thiophenylcyclopentanone 18 into vinylsulfide 19 by a
published procedure,[11] 2) oxidation of vinylsulfide 19, and
3) a Michael addition–elimination reaction with a chloride ion
to the intermediate 20 to give b-chlorocyclopentenone 11. We
found, however, that b-chlorocyclopentenone 11 could be
generated from b-thiophenylcyclopentanone 18 directly in a
novel one-pot process through oxidative chlorination. When
b-thiophenylcyclopentanone 18 was oxidized with trichloro-
isocyanuric acid, b-chlorocyclopentenone 11 was obtained in
good yield. We considered the possibility that this type of
oxidative chlorination proceeds via the Pummerer-type
intermediate 21. There are no published procedures for the
direct b-halogenation of cyclopentenones, and thus this
reaction was regarded as a promising strategy for the b-
chlorination of enones.
Scheme 1. Retrosynthetic analysis of tetracyclic compound 4.
Our synthesis commenced with the tosylation of alcohol
6,[4] derived from methyl (R)-3-hydroxy-2-methylpropionate
in two steps (Scheme 2). Substitution of the tosylate with
sodium cyanide gave the nitrile quantitatively. The resulting
nitrile was reduced with DIBAL-H and the product then
hydrolyzed to give the common intermediate aldehyde 7. The
addition of ethynylmagnesium bromide to aldehyde
7
afforded secondary alcohols in a diastereomeric mixture
(1:1), which were then oxidized with MnO2 to give ynone 8.
After the diastereoselective reduction of 8 was achieved by
Corey's method,[5] protection with benzyl bromide gave
benzyl ether 9. Transformation of benzyl ether 9 to vinyl-
stannane 10 was carried out in two steps: first, conversion to
bromoalkyne by treatment of benzyl ether 9 with N-bromo-
succinimide (NBS) and AgNO3,[6] and then hydrostannation[7]
of the bromoalkyne. b-Chlorocyclopentenone 11 was also
Stille coupling[12] between intermediates 10 and 11 was
then examined (Scheme 4). The coupling reaction was con-
Scheme 2. Synthesis of 10 and 18. a) TsCl, pyridine, RT, 20.5 h; b) NaCN, DMSO, 608C, 21 h; c) DIBAL-H, CH2Cl2, À788C, 30 min; then aq.
NH4Cl, 98% in 3 steps; d) ethynylmagnesium bromide, THF, 08C, 1 h; e) MnO2, CH2Cl2, RT, 3 h, 64% in 2 steps; f) (S)-2-methyl-CBS-oxazaboroli-
dine, BH3·SMe2, toluene, À408C, 30 min, 95%, >98:2 d.r.; g) BnBr, NaH, DMF, 08C, 2 h, 100%; h) NBS, AgNO3, acetone, RT, 1 h, 100%;
i) Bu3SnH, [Pd(PPh3)4], THF, 08C, 30 min, 76%; j) NaBH4, EtOH, 08C, 30 min; k) TBDPSCl, imidazole, DMF, RT, 1 h, 74% in 2 steps; l) TFAA,
TFA, CH2Cl2, RT, 1 h; then MeOH, NEt3, 08C, 1.5 h, 85%; m) PhSSPh, PBu3, DMF, RT, 1.5 h; n) mCPBA, NaHCO3, CH2Cl2, RT, 1.5 h, 89% in 2
steps; o) 15, nBuLi, THF, À788C, 30 min; then 7, THF, À788C, 1.5 h; p) HCOOH, Et2O, RT, 5.5 h; q) aq. NH3, MeOH, RT, 1.5 h, 75% in 3 steps;
r) Dess–Martin periodinane, CH2Cl2, RT, 1 h, 67%; s) SmI2, THF, RT, 1 h; then Al2O3, 73%; t) PhSH, NEt3, THF, RT, 7 h, 71%. BnBr=benzyl bro-
mide, CBS=Corey–Bakshi–Shibata, DIBAL-H=diisobutylaluminum hydride, DMF=dimethylformamide, DMSO=dimethyl sulfoxide, mCPBA=
m-chloroperbenzoic acid, NBS=N-bromosuccinimide, RT=room temperature, TBDPSCl=tert-butyldiphenylsilyl chloride, TFA=trifluoroacetic
acid, TFAA=trifluoroacetic anhydride, Tr=triphenylmethyl, TsCl=p-toluenesulfonyl chloride.
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Chemie
reported to date have given poor yields,[15c] intramolecular
cyclization of aldehyde 24 proceeded nicely to afford two
diastereomers of the desired trienones 25a (6%) and 25b
(38%), which were then easily separated by column chroma-
tography. Moreover, when this coupling reaction was carried
out at 508C, even higher yields of 25a (14%) and 25b (62%)
resulted.
With the cyclic triene precursor in hand, we attempted
TADA reactions of both 25a and 25b (Scheme 5). When
either trienone was heated in toluene at reflux, the TADA
Scheme 3. Synthesis of 11. a) Trichloroisocyanuric acid, benzene/Et2O
(2:1 v/v), 08C, 21 h, 79%.
Scheme 5. Transannular Diels–Alder reactions of 25a and 25b.
reaction proceeded smoothly to give the desired tetracyclic
compound. The stereochemistry of each tetracyclic com-
pound was determined by NOE experiments and NOESY
1
correlations in the H NMR spectra. Surprisingly, we found
that the stereoselectivity of the TADA reaction was primarily
dependent on the stereochemistry of the hydroxy group at C3.
The TADA reaction of trienone 25a afforded predominantly
the desired tetracyclic compound 26a, whereas reaction of
trienone 25b gave both the desired isomer 26b and the
undesired isomer 27b in a ratio of 1:1.
Scheme 4. Synthesis of 25. a) [Pd(PPh3)4], NMP, 1008C, 22 h, 98%;
b) ZnBr2, CH2Cl2, RT, 1.5 h, 94%; c) Dess–Martin periodinane, CH2Cl2,
RT, 1.5 h, 92%; d) CHI3, CrCl2, THF, RT, 40 min, 90%; e) TBAF, THF,
RT, 6 h, 88%; f) PDC, CH2Cl2, RT, 1 h, 86%; g) CrCl2, cat. NiCl2,
DMSO, 24 h, 508C. NMP=1-methyl-2-pyrrolidinone, PDC=pyridinium
dichromate, TBAF=tetrabutylammonium fluoride.
The diastereoselectivity of the TADA reaction can be
accounted for by the energy differences for the possible
conformations of the transition states (Figure 2). Obviously,
products 26 and 27 are formed by an exo approach. The
possibility of two endo approaches is excluded by severe ring
strain in the transition states. Although transition state A
shows allylic repulsion between the methyl group at C5 and
the hydrogen atom at C12, transition state B has severe
transannular interactions between the hydrogen atom at C11
and the methyl group at C15. As a result, transition state A is
formed prior to transition state B, and 26a is obtained as the
sole product. However, in the transition state for the 3R
alcohol 25b, small difference in energy between transition
state C and transition state D lead to dramatic changes in
stereoselectivity. Unlike transition state B, transition state D
does not have allylic repulsion between the hydrogen atom at
C1 and the hydroxy group at C3. At the same time, transition
state C has relatively higher energy due to the allylic
interaction with the C3 alcohol. Consequently, the energy of
ducted with [Pd(PPh3)4]as the catalyst and at a high
temperature (1008C) to afford dienone 22 in excellent yield.
However, a subsequent Luche reduction of dienone 22 was
low-yielding due to the instability of the reduced product.
Thus, we avoided reducing C7s carbonyl group in order to
stabilize the diene. After the Tr group of dienone 22 was
removed with ZnBr2,[13] subsequent oxidation of the primary
alcohol gave an aldehyde, which was converted by a Takai
reaction[14] into vinyliodide 23. The TBDPS group of 23 was
removed with TBAF to give an alcohol, which was oxidized to
afford the aldehyde 24. Because the 12-membered cyclic
trienone was expected to be unstable, mild reaction con-
ditions for the macrocyclization were thought necessary.
Macrocyclization of 24 was accomplished by an intramolec-
ular Nozaki–Hiyama–Kishi (NHK) coupling reaction.[15a]
Although the intramolecular NHK coupling reactions
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Communications
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Figure 2. Transition states of the transannular Diels–Alder reactions of 25a and 25b.
transition state C is equal to that of transition state D, and
thus 26b and 27b are produced in a ratio of 1:1.
In conclusion, we successfully completed the highly
stereoselective synthesis of the spirotetracyclic carbon core
of the mangicols. The present synthesis features a novel
chlorination step, an intramolecular NHK coupling reaction,
and the stereoselective construction of a tetracyclic com-
pound through a TADA reaction. The steric repulsion of the
hydroxy group of C3 was stereocontrolled in the TADA
reaction to predominantly afford the desired tetracyclic
compound. Compounds 26a and 26b are versatile intermedi-
ates for the synthesis of the mangicol family. Further studies
on the total synthesis of mangicol A (1) are currently
underway in our laboratory.
Received: April 25, 2003 [Z51750]
Keywords: cycloaddition · diastereoselectivity · natural
.
products · spiro compounds · synthesis design
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