Total synthesis of the proposed structure of didemnaketal B

Article abstract of DOI:10.1021/ol4017518

Total synthesis of the proposed structure of didemnaketal B has been accomplished. The C7-C21 spiroacetal domain was synthesized by exploiting our Suzuki-Miyaura coupling/spiroacetalization strategy. The C1-C7 acyclic domain was constructed via an Evans syn-aldol reaction and a vinylogous Mukaiyama aldol reaction. Finally, the C22-C28 side chain was introduced by means of a Nozaki-Hiyama-Kishi reaction. Comparison of the NMR spectroscopic data of our synthetic material with those of the authentic sample revealed that the proposed structure requires stereochemical reassignment.

Full text of DOI:10.1021/ol4017518

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Total Synthesis of the Proposed Structure
of Didemnaketal B
Haruhiko Fuwa,* Kumiko Sekine, and Makoto Sasaki
Gradutate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba-ku,
Sendai 980-8577, Japan
hfuwa@m.tohoku.ac.jp
Received June 21, 2013
ABSTRACT
Total synthesis of the proposed structure of didemnaketal B has been accomplished. The C7ÀC21 spiroacetal domain was synthesized by
exploiting our SuzukiÀMiyaura coupling/spiroacetalization strategy. The C1ÀC7 acyclic domain was constructed via an Evans syn-aldol reaction
and a vinylogous Mukaiyama aldol reaction. Finally, the C22ÀC28 side chain was introduced by means of a NozakiÀHiyamaÀKishi reaction.
Comparison of the NMR spectroscopic data of our synthetic material with those of the authentic sample revealed that the proposed structure
requires stereochemical reassignment.
In 1991, Faulkner and co-workers reported the isolation
and characterization of the gross structure, including the
relative stereochemistry of the spiroacetal domain, of
didemnaketals A and B (1 and 2, respectively, Figure 1).1,2
Although these compounds were isolated from the magen-
ta ascidian Didemnum sp., collected from the Auluptagel
Island in Palau, Faulkner and Pika later reported that 1
and 2 were produced from didemnaketal C (3) during the
prolonged storage of the ascidian in methanol.2 The
complete stereostructure of 2 was proposed on the basis
of the combination of degradation/derivatization experi-
ments, X-ray crystallographic analysis, and application of
chiral anisotropic reagents.3 Specifically, the absolute con-
figuration of the C5, C7, C11, and C21 stereogenic centers
was assigned on the basis of the modified Mosher
analysis,4 and the relative stereochemistry of the C5/C6,
C6/C7, and C7/C8 stereogenic centers was correlated by
degradation/derivatization experiments, while the relative
configuration of the C10ÀC20 domain was established by
X-ray crystallographic analysis of a degradation product.
The absolute configuration of the C20 and C26 stereogenic
centers was determined by applying the phenylglycine
methyl ester (PGME) method.5
Significantly, 1 and 2 exhibited potent inhibitory activity
against HIV-1 protease (IC50 2 and 10 μM, respectively),1
while 3 turned out to be inactive.2 Rich and co-workers
have successfully discovered novel HIV-1 protease
dimerization inhibitors based on the acyclic domain of
didemnaketals, suggesting the possible biochemical mode-
of-action of the parent compounds.6 Because of their
complex molecular structure and intriguing biological ac-
tivity, didemnaketals represent attractive synthetic targets
(1) Potts, B. C. M.; Faulkner, D. J.; Chan, J. A.; Simolike, G. C.;
Offen, P.; Hemling, M. E.; Francis, T. A. J. Am. Chem. Soc. 1991, 113,
6321–6322.
(2) Pika, J.; Faulkner, D. J. Nat. Prod. Lett. 1995, 7, 291–296.
(3) Salomon, C. E.; Williams, D. H.; Lobkovsky, E.; Clardy, J. C.;
Faulkner, D. J. Org. Lett. 2002, 4, 1699–1702.
(5) Nagai, Y.; Kusumi, T. Tetrahedron Lett. 1995, 36, 1853–1856.
(6) Fan, X.; Flentke, G. R.; Rich, D. H. J. Am. Chem. Soc. 1998, 120,
8893–8894.
(4) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem.
Soc. 1991, 113, 4092–4096.
r
10.1021/ol4017518
XXXX American Chemical Society

for organic chemists.7À9 Very recently, Tu et al. have
reported the total synthesis of the proposed structure 1 of
didemnaketal A to show that the stereochemical assign-
ment of the structure postulated by the Faulkner group
needs to be re-examined.10 Here, we disclose the first total
synthesis of the proposed structure 2 of didemnaketal B.
Scheme 1. Synthesis Plan toward 2
Figure 1. Proposed structures of didemnaketals AÀC.
Our synthesis plan toward 2 is summarized in Scheme 1.
We envisioned the C22ÀC28 side chain to be introduced
at the final stage of the total synthesis by means of the
NozakiÀHiyamaÀKishi (NHK) reaction11 of the aldehyde
4 with the vinyl iodide 5.9 This obviates the need to dif-
ferentiate the C21 secondary hydroxy group from the others
and mitigates tedious protective group manipulations. The
aldehyde 4 would be obtained from the alcohol 6 through a
series of reactions that included a vinylogous Mukaiyama
aldol reaction.12 The C6 and C7 stereogenic centers within 6
would be generated from the precursor 7 in a stereoselective
manner by relying on the Evans syn-aldol methodology.13
We planned to construct the spiroacetal domain of 7 by
means of the SuzukiÀMiyaura reaction14 of the alkylborate
8 derived from the iodide 9 and the enol phosphate 10,9
followed by an acid-catalyzed spiroacetalization.15
The synthesisof the iodide 9 started from the diol 11,16 as
depicted in Scheme 2. The cleavage of the trityl ether under
acidic conditions, followed by a selective protection of the
resultant 1,2-diol moiety as its acetonide, led to the alcohol
12. The Mitsunobu reaction17 with 1-phenyl-1H-tetrazole-
5-thiol followed by oxidation under buffered conditions
delivered the sulfone 13. The JuliaÀKocienski olefina-
tion18 of 13 with the aldehyde 149 was optimally performed
by using LHMDS in THF/DMPU (7:1) atÀ78 °C to room
temperature, giving the olefin 15 in 79% yield with accept-
able stereoselectivity (E/Z = 5:1). Although the minor
Z-isomer could not be removed at this stage, it was of
no consequence since the ensuing Sharpless asymmetric
dihydroxylation19 of 15 preferentially proceeded on the
major E-isomer and delivered the 1,2-diol 16 in 78% yield
(dr >20:1),20 with the less reactive Z-isomer remaining
unreacted. The silylation of 16 followed by the cleavage of
the p-methoxyphenylmethyl (MPM) ether gave an alcohol
that was converted to the iodide 9.
(7) (a) Wang, P. Z.; Tu, Y. Q.; Yang, L.; Dong, C. Z.; Kitching, W.
Tetrahedron: Asymmetry 1998, 9, 3789–3795. (b) Jia, Y. X.; Wu, B.; Li,
X.; Ren, S. K.; Tu, Y. Q.; Chan, A. S. C.; Kitching, W. Org. Lett. 2001, 3,
847–849. (c) Jia, Y. X.; Li, X.; Wang, P. Z.; Wu, B.; Zhao, X. Z.; Tu,
Y. Q. J. Chem. Soc., Perkin Trans. 1 2002, 565–570. (d) Jia, Y. X.; Li, X.;
Wu, B.; Zhao, X. Z.; Tu, Y. Q. Tetrahedron 2002, 58, 1697–1708. (e) Li,
X. Q.; Zhao, X. Z.; Liu, P. N.; Tu, Y. Q. Chin. Chem. Lett. 2004, 15, 757–
758. (f) Zhao, X. Z.; Tu, Y. Q.; Peng, L.; Li, X. Q.; Jia, Y. X. Tetrahedron
Lett. 2004, 45, 3713–3716. (g) Zhao, X. Z.; Peng, L.; Tang, M.; Tu, Y. Q.;
Gao, S. H. Tetrahedron Lett. 2005, 46, 6941–6944.
(8) Ito, H.; Inoue, T.; Iguchi, K. Org. Lett. 2008, 10, 3873–3876.
(9) Fuwa, H.; Noji, S.; Sasaki, M. Org. Lett. 2010, 12, 5354–5357.
(10) Zhang, F.-M.; Peng, L.; Li, H.; Ma, A.-J.; Peng, J.-B.; Guo, J.-J.;
Yang, D.; Hou, S.-H.; Tu, Y.-Q.; Kitching, W. Angew. Chem., Int. Ed.
2012, 51, 10846–10850.
(11) (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281–5284. (b) Jin, H.; Uenishi, J.; Christ,
W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644–5646.
(12) Mukaiyama, T.; Ishida, A. Chem. Lett. 1975, 319–322.
(13) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127–2129.
(14) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483. (b)
Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722–6737. (c) Fuwa, H.
Synlett 2011, 6–29.
Next, we focused our attention on the construction of
the spiroacetal domain of 2 (Scheme 3). Treatment of the
iodide 9 with t-BuLi in the presence of B-MeO-9-BBN
(Et2O/THF, À78 °Ctort)21 generated an alkylborate, which,
without isolation, was coupled with the enol phosphate 109 in
(17) Mitsunobu, O. Synthesis 1981, 1–28.
(18) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A.
Synlett 1998, 26–28.
(19) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483–2547.
(15) Fuwa, H.; Sasaki, M. Org. Lett. 2008, 10, 2549–2552.
(16) Deng, L.-S.; Huang, X.-P.; Zhao, G. J. Org. Chem. 2006, 71,
4625–4635.
(20) The stereochemistry of the C12 stereogenic center was subse-
quently confirmed by a NOESY experiment on the spiroacetal 18
(Scheme 3).
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Synthesis of Iodide 9
Scheme 3. Synthesis of Spiroacetal 18
center was opposite to that of the natural product, as
expected from the FelkinÀAnh model. The correction of
the C5 stereochemistry was effectively achieved by an
oxidation/reduction sequence. Thus, we found that the
oxidation of 22 (DMP, 98%), followed by reduction with
the presence of PdCl2(dppf) CH2Cl2 and aqueous Cs2CO3
3
in DMF at 50 °C to provide the endocyclic enol ether 17 in
84% yield. After desilylation with TBAF, the resultant
dihydroxy enol ether was exposed to a catalytic amount of
PPTS in CH2Cl2 at room temperature to afford the
spiroacetal 18 in 80% yield (two steps, dr >20:1). The
stereostructure of 18 was unambiguously established by a
NOESY experiment as shown.22
(R)-2-methyl-CBS-oxazaborolidine/BH3 THF,26 delivered
3
the desired alcohol 23 in 83% yield (dr >20:1).22
Completion of the total synthesis of 2 is depicted in
Scheme 5. The acylation of the C5 hydroxy group of 23
with propionic anhydride, acidic cleavage of the silyl
group, and acetylation of the resultant alcohol provided
the acetate 24. The removal of all the MPM groups within
24 by using DDQ, selective silylation of the C21 hydroxy
group, acylation of the remaining C8 and C11 hydroxy
groups with isovaleric anhydride, and removal of the silyl
group afforded the alcohol 25 in good overall yield. This
alcohol was oxidized with DMP,24 and the NHK cou-
pling11 of the resultant aldehyde with the vinyl iodide 59 under
the standard conditions furnished 2 and its C21 epimer,
21-epi-2, as an approximately 1:1.3 mixture in 52% combined
yield. These diastereomers could be separated by reversed-
phase HPLC. The C21 stereogenic center of 2 and 21-epi-2
was established by the modified Mosher method.4,22
Unfortunately, we found that neither 2 nor 21-epi-2 was
spectroscopically identical to the authentic sample,
although the COSY, HMQC, and HMBC correlations
observed in our synthetic 2/21-epi-2 supported the identity
of the gross structure with that of didemnaketal B. The 1H
NMR data of 21-epi-2 and the authentic sample were in
close agreement, whereas significant chemical shift devia-
tions around the C21 stereogenic center were observed
between 2 [H19 (δ 1.38, 1.10), H20 (δ 3.72), H21 (δ 3.76)]
and didemnaketal B [H19 (δ 1.56, 1.07), H20 (δ 3.84),
H21 (δ 4.03)].27 Thus, it is likely that the relative
Having secured access to the spiroacetal domain, we
proceeded to elaborate the C1ÀC7 acyclic domain as
summarized in Scheme 4. The alcohol 7 was obtained from
18 by standard protective group manipulations. The oxi-
dation of 7 followed by the Evans syn-aldol reaction13
of the resultant aldehyde with 19 (n-Bu2BOTf, Et3N,
CH2Cl2, À78 to 0 °C) afforded the alcohol 20 in 87% yield
(two steps, dr >20:1).22 After the silylation of 20 (TESCl,
pyridine, AgNO3, 91%),23 the reductive removal of the
chiral auxiliary provided the alcohol 6 (LiBH4, H2O, THF,
84%). The oxidation of 6 with DessÀMartin periodinane
(DMP),24 followed by the vinylogous Mukaiyama aldol
reaction12 of the derived aldehyde with the dienol silyl
ether 2125 (BF3 OEt2, CH2Cl2/Et2O (5:1), À78 °C), gave
3
the homoallylic alcohol 22 in 74% yield (two steps, dr >
20:1).22 However, the configuration of the C5 stereogenic
(21) (a) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885–
7892. (b) Fuwa, H.; Ishigai, K.; Goto, T.; Suzuki, A.; Sasaki, M. J. Org.
€
Chem. 2009, 74, 4024–4040. (c) Seidel, G.; Furstner, A. Chem. Commun.
2012, 48, 2055–2070.
(22) For details on stereochemical assignment, see the Supporting
Information.
(23) Ogilvie, K. K.; Hakimelahi, G. H.; Proba, Z. A.; McGee,
D. P. C. Tetrahedron Lett. 1982, 23, 1997–2000.
(24) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277–
7287.
(26) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551–5553.
(25) Savard, J.; Brassard, P. Tetrahedron 1984, 40, 3455–3464.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Synthesis of Alcohol 23
Scheme 5. Completion of the Total Synthesis of 2
In conclusion, we have completed the first total synthesis
ofthe proposedstructure2 ofdidemnaketalB and revealed
its nonidentity with the authentic sample. Further studies
toward the elucidation of the correct structure of didem-
naketal B are currently ongoing and will be reported in due
course.
stereochemistry of the C20 and C21 stereogenic centers
was incorrectly assigned in the proposed structure. The
nonidentity of 21-epi-2 with authentic didemnaketal B
was indicated by discrepancies in their 13C NMR signals.28
Thus, it appears that more than one erroneous stereo-
chemical assignments are present in the proposed struc-
ture 2; we speculate that the relative stereochemistry of
the C8/C10 and C20/C21 stereogenic centers might be
misassigned.
Acknowledgment. We thank Kaneka Corporation and
Takasago International Corporation for their generous
gifts of (R)- and (S)-Roche esters and (S)-citronellal,
respectively. This work was financially supported in part
by Grants-in-Aid for Young Scientists (A) and (B) (Nos.
23681045 and 21710216) from Japan Society for the
Promotion of Science (JSPS).
Supporting Information Available. Experimental proce-
dures, spectroscopic data, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(27) Comparison tables for the 1H and 13C NMR chemical shifts for
2, 21-epi-2, and didemnaketal B are provided in the Supporting
Information.
(28) Faulkner et al. reported that the 13C NMR data of authentic
didemnaketal B showed signals at 70.6 and 16.2 ppm,1 but such signals
were not observed for 21-epi-2 (or 2) within Δδ = ( 1.0 ppm.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX