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Z. Chen, S. C. Sinha / Tetrahedron Letters 50 (2009) 6398–6401
(i) Oxalyl chloride, DMSO,
etherification of the resulting dihydroxymesylate in a sequence
(Table 1). Thus, using Co-OC reaction, the trans mono-THF alcohols
4.1t and 4.2t were converted to trans, trans bis-THF alcohols 5.1
and 5.2, and the cis mono-THF alcohols 4.1c and 4.2c to cis, trans
bis-THF alcohols 5.7 and 5.8. In all compounds, the new trans
THF ring was formed exclusively. As expected, these mono-THF
intermediates did not undergo second cyclization using Os-OC
reaction, and our attempt to prepare compounds 5.3–5.6 using
cis and trans 4’s by Os-OC reaction was unsuccessful. The remain-
ing four bis-THF intermediates, which possessed an erythro config-
uration between C-5,C-6 centers and the trans or cis B-ring, namely,
5.9, 5.11, 5.15, and 5.16, were all prepared using the above-de-
scribed three steps from the appropriate 4’s and AD ligands. The
Phal-DHQ ligand was used in the AD reaction to prepare interme-
diates 5.9 and 5.15, which possessed ‘S’ stereochemistry, and Phal-
DHQD for intermediates 5.11 and 5.16, with ‘R’ stereochemistry for
C-9 center. Using the above-described strategy, one could also pre-
pare four of the remaining six compounds, including 5.10, 5.12,
5.13, and 5.14, which are indeed the enantiomers of compounds
5.9, 5.11, 5.16, and 5.15, respectively, from the mono-THF interme-
diates, 4.1t, 4.2t, or 4.2c (see: Table 1 bottom section).
CH2Cl2, -78°C, then Et3N
°
(ii) C10H21MgBr, THF, 0 C
OH
10
(iii) Chromatographic separation
5.1
2
5
6
9
O
O
C10H21
HO
6.1a (10R), 33%
6.1b (10S), 38%
(i) TBSOTf, CH2Cl2, 0 °C
(ii) Cat. TsOH, MeOH
OTBS
Ref 2
10
1.1a-d
5
2
6
9
O
O
80-85%
C10H21
HO
7.1a (10R)
7.1b (10S)
Scheme 3. A combined nonselective and stereoselective approach to the synthesis
of stereoisomeric asimicins.
of four of the stereoisomeric 1’s can be prepared and separated giv-
ing all 64 1’s. Analysis of the compounds can be facilitated by care-
fully comparing the ratios of the products in each step using 1H
NMR and after purification.
In conclusion, 10 unique bis-THF intermediates, 5’s, were pre-
pared starting with the readily available diols 2’s or 3’s in good
yields. The synthetic processes used to produce 5’s were simple
and reproducible, and could be carried out on a large scale without
extra precautions. The bis-THF intermediates 5.1–5.4, 5.9, 5.11,
5.15, and 5.16, which were prepared from the stereochemically en-
riched mono-THF compounds, 4’s, (82% ee prepared from 2’s and
92% ee from 3’s) and using an AD step, were obtained with more
than 98% enantiomeric purity after purification, whereas com-
pounds 5.7–5.8 retained the enantiomeric purity identical to 4’s.
We expect that a complete library of 64 stereoisomeric asimicins,
and other related bis-THF acetogenins can be prepared from these
10 bis-THF intermediates rapidly using a combination of the ster-
eoselective and nonstereoselective methods, and obtained in enan-
tiomerically pure form by purification using HPLC.
All bis-THF compounds, 5’s, prepared in this manner, were most
likely to bear the desired configuration, yet we also confirmed
them by comparing the 1H and 13C NMR spectral data of these
compounds as well as the corresponding bis-THF diols, 5.x-D’s
(See Fig. 1). The latter compounds were either obtained en route
to the synthesis of 5’s, as in 5.1-5.4, or by hydrolyzing the benzo-
ate-protecting group in the remaining six bis-THF intermediates,
5.7–5.9, 5.11, and 5.15–5.16. First, we found that compounds 5.1,
5.3, 5.7, and 5.15 showed 1H and 13C NMR spectra identical to their
enantiomers 5.2, 5.4, 5.8, and 5.16, respectively, but different with
respect to compounds 5.9 and 5.11. Next, one compound from the
enantiomeric pairs, including 5.1, 5.3, 5.7, and 5.15, and com-
pounds 5.9 and 5.11, were chosen and their diol analogs, that is,
5.1-D, 5.3-D, 5.7-D, 5.9-D, 5.11-D, and 5.15-D, were obtained
either from their precursor pools (in 5.1-D and 5.3-D) or through
base hydrolysis, and analyzed. As expected, all six diols showed
distinct 13C NMR spectral data; and the symmetrical bis-THF diols,
5.1-D, 5.3-D, 5.9-D, and 5.11-D, showed only five C signals,
whereas the unsymmetrical diols, 5.7-D and 5.15-D, showed 10 C
signals (See Supplementary data). The data, together with the fact
that compounds 5.1 and 5.2 were prepared in two different ways,
assured us that all 5’s possessed the expected configurations.
With the stereoisomeric intermediate 5’s in hand, one can con-
vert them to the desired asimicin library or their analogs, as well as
numerous related bis-THF acetogenins, including goniodenin- and
glabracin A-type compounds,1 which unlike asimicin possess only
one hydroxy function adjacent to the bis-THF ring. In the context of
the asimicin library, we can use the previously described synthetic
scheme and optimize the Carreira’s enantioselective alkynylation
reaction13 to give stereochemically pure 1’s. Alternatively, we ar-
gue that the library of 1’s can be prepared rapidly from 5’s using
a combination of stereoselective and the nonstereoselective meth-
ods. For example, in one approach, the aldehyde of compound 5.1
underwent nonstereoselective alkylation using decyl-magnesium
bromide giving an essentially 1:1 mixture of compounds 6.1a
and 6.1b. The latter was separated and protected as di-TBS ether
and then selectively deprotected to give compounds 7.1a and
7.1b (Scheme 3), which were previously converted to four bis-
THF acetogenins, 1.1a–d. Alternatively, a mixture of 7.1a and
7.1b can also undergo Carreira’s alkynylation reaction using a chi-
ral ligand giving a mixture of two isomeric compounds 1.1’s after
deprotection and hydrogenation. If the Carreira’s alkylation is less
selective, one can get a mixture of two 1.1’s each from pure 7.1a
and 7.1b, or all four 1.1’s as a mixture of two major and two minor
products, in one set of reactions. In this manner, 32 pairs or 16 set
Acknowledgment
We are thankful to the Skaggs Institute for Chemical biology for
the financial support.
Supplementary data
Supplementary data (spectroscopic data and experimental pro-
cedures) associated with this article can be found, in the online
References and notes
1. (a) Alali, Q.; Liu, X.-X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62, 504; (b) Bermejo,
A.; Figadere, B.; Zafra-Polo, M.-C.; Barrachina, I.; Estornell, E.; Cortes, D. Nat.
Prod. Rep. 2005, 22, 269; McLaughlin, J. L. J. Nat. Prod. 2008, 71, 1311; and
references cited therein.
2. Sinha, S. C.; Chen, Z.; Huang, Z.-Z.; Nakamaru-Ogiso, E.; Pietraszkiewicz, H.;
Edelstein, M.; Valeriote, F. J. Med. Chem. 2008, 51, 7045.
3. (a) Derbre, S.; Roue, G.; Poupon, E.; Susin, S. A.; Hocquemiller, R. ChemBioChem
2005, 6, 979; (b) Abe, M.; Kenmochi, A.; Ichimaru, N.; Hamada, T.; Nishioka, T.;
Miyoshi, H. Bioorg. Med. Chem. Lett. 2004, 14, 779.
4. For our earlier strategies on the asimicin library synthesis, see: (a) Sinha, S. C.;
Sinha, A.; Yazbak, Y.; Keinan, E. J. Org. Chem. 1996, 61, 7640; (b) Keinan, E.;
Sinha, A.; Yazbak, A.; Sinha, S. C.; Sinha, S. C.; Keinan, E. Pure Appl. Chem. 1997,
69, 423; (c) Das, S.; Li, L.-S.; Abraham, S.; Chen, Z.; Sinha, S. C. J. Org. Chem. 2005,
70, 5922.
5. (a) For the bis-THF acetogenin’s synthesis from this laboratory, see: Refs. 2,4,8.;
(b) Yazbak, A.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1998, 63, 5863; (c) Sinha, A.;
Sinha, S. C.; Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 2381; (d) Sinha, S. C.;
Sinha, S. C.; Keinan, E. J. Org. Chem. 1999, 64, 7067; (e) Avedissian, H.; Sinha, S.
C.; Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org. Chem. 2000, 65,
6035; (f) Han, H.; Sinha, M. K.; D’Souza, L. J.; Keinan, E.; Sinha, S. C. Chem. Eur. J.
2004, 10, 2149.