Validation of lanthanide chiral shift reagents for determination of absolute configuration: Total synthesis of glisoprenin A

Article abstract of DOI:10.1021/ol048059o

(Chemical Equation Presented) The complete stereostructure of the natural product (+)-glisoprenin A had been predicted via a novel application of chiral lanthanide shift reagents. Confirmation of the predicted stereostructure of (+)-glisoprenin A and vali

Full text of DOI:10.1021/ol048059o

ORGANIC
LETTERS
2004
Vol. 6, No. 25
4723-4726
Validation of Lanthanide Chiral Shift
Reagents for Determination of Absolute
Configuration: Total Synthesis of
Glisoprenin A
Christopher M. Adams, Indranath Ghosh, and Yoshito Kishi*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
kishi@chemistry.harVard.edu
Received September 23, 2004
ABSTRACT
The complete stereostructure of the natural product (
reagents. Confirmation of the predicted stereostructure of (
+
)-glisoprenin A had been predicted via a novel application of chiral lanthanide shift
)-glisoprenin A and validation of the chiral lanthanide shift approach have now
+
been achieved through total synthesis.
In the preceding Letters,1,2 we have introduced a novel
approach for the determination of absolute configuration of
secondary and tertiary alcohols and used this method to
predict the complete stereostructure of the natural product
(+)-glisoprenin A. In this Letter, we address the validity of
this approach by confirming our stereochemical assignment
via total synthesis.
Retrosynthetically, we envisioned disconnection of the
C-16/C-17 bond to furnish sulfone 2 and allyl chloride 3,
available from (E,E,E)-geranylgeraniol (Scheme 1). Sulfone
Scheme 1
(+)-Glisoprenin A (1) is a novel acyl Co-A transferase
inhibitor isolated by Omura and co-worker in 1992 from the
fermentation broth of Gliocladium sp. FO-1513.3 Extensive
one- and two-dimensional NMR experiments combined with
mass spectra analysis led Omura to propose a polyprenoid
skeleton bearing four tertiary hydroxyls as the constitutional
structure for (+)-1. Further work in our laboratories, as
elaborated in the preceding Letter,2 has led us to predict the
complete stereostructure depicted in Scheme 1. To confirm
both the predicted constitutional and stereochemical (relative
and absolute) structure of (+)-1, we embarked on the total
synthesis of (+)-glisoprenin A.
(1) Ghosh, I.; Zeng, H.; Kishi, Y. Org. Lett. 2004, 6, 4715.
(2) Ghosh, I.; Kishi, Y.; Tomoda, H.; Omura, S. Org. Lett. 2004, 6, 4719.
(3) (a) Tomoda, H.; Huang, X.-H.; Nishida, H.; Masuma, R.; Kim, Y.
K.; Omura, S. J. Antibiot. 1992, 45, 1202. (b) Nishida, H.; Huang, X.-H.;
Tomoda, H.; Omura, S. J. Antibiot. 1992, 45, 1669.
10.1021/ol048059o CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/06/2004

2 would derive from the diol 4. A series of chemoselective
and stereoselective oxidations would then reveal the known
polyprenol 6.4 Specifically, we envisioned that the Shi
epoxidation protocol,5 followed by reductive oxirane opening,
could be used to install the requisite tertiary hydroxyls.
Clearly, this strategy would require the temporary protection
of the terminal isopropylidene unit, which could be ac-
complished via chemoselective dihydroxylation.6
To this end, the known polyprenol 64 was synthesized in
six steps from geraniol according to the protocol developed
by Radetich and Corey.4 The stage was then set for
dihydroxylation of the terminal isopropylidene unit6 and Shi
epoxidation.5 However, model studies used to determine the
optimal conditions for the Shi epoxidation, coupled with
results by McDonald and co-workers,7 indicated that epoxi-
dation of the C-18/C-19 olefin may prove to be problematic
due to the electron-withdrawing nature of the pendant
hydroxyl. Therefore, a more stepwise approach, wherein the
C-18/C-19 olefin would first be epoxidized, was investigated
(Scheme 2).
to furnish diol (+)-8 in good yield with NMR analysis
indicating a high degree of diastereoselectivity (dr > 15:1).
We next turned our attention to the key epoxidation event.
To our delight, employing 1.8 equiv (0.6 equiv/olefin) of
catalyst 115a with a slow delivery (5 h) of aqueous solutions
of Oxone and K2CO3 via syringe pumps provided the desired
tetraepoxide in excellent yield (78%) with the mass recovery
after chromatographic purification being ca. 85% of a single
stereoisomer. Reductive opening of the four oxiranes with
excess LiAlH4 then gave heptaol (+)-9. Differentiation of
the seven hydroxyls was next accomplished by esterification
of the primary hydroxyl (PivCl, DMAP, pyr), followed by
benzylidene acetal formation, and silylation of the remaining
tertiary hydroxyls (Scheme 3). Hydrogenolysis in the pres-
Scheme 3a
Sharpless asymmetric epoxidation8 of polyprenol 6 smoothly
afforded the C-18/C-19 epoxide (+)-7 in 99% yield with
>90% ee based upon Mosher ester analysis.9 The terminal
isopropylidene unit was then chemoselectively protected via
dihydroxylation employing the Corey-Zhang ligand (10)6a
Scheme 2a
a Reagents and conditions: (a) (1) PivCl, DMAP, pyr, CH2Cl2,
-78° C; (2) PhCH(OMe)2, PPTs, DMF; (3) TESOTf, 2,6-lutidine,
CH2Cl2; (4) Pd(OH)2/C, EtOAc/EtOH (10:1), 58% over four steps.
(b) (1) Pb(OAc)4, THF; (2) (CH3)2CHPPh3I, n-BuLi, THF, 93%
over two steps. (c) (1) Dibal-H, CH2Cl2, -78 °C; (2) I2, PPh3,
imidazole, Et2O/MeCN (3:1); (3) PhSO2Na, DMF, 60 °C, 59% over
three steps.
ence of Pearlman’s catalyst then furnished diol (+)-12 in
good overall yield (58% overall yield for the four steps).
Reintroduction of the terminal isopropylidene was then
realized via lead tetraacetate-mediated glycol cleavage,
a Reagents and conditions: (a) Ti(Oi-Pr)4, D-(-)-DIPT, 3 Å MS,
cumene hydroperoxide, CH2Cl2, -30 °C, 99%. (b) K3Fe(CN)6,
K2CO3, CH3SO2NH2, 10 (1.6 mol %), K2OsO4‚2H2O (1.2 mol %),
t-BuOH/H2O (1:1), 0 °C, 61%, 77% BORSM. (c) (1) 11 (1.8 equiv),
Na2B4O7/Na2EDTA buffer, n-Bu4NHSO4, K2CO3, Oxone (5.2
equiv), H2O, MeCN, DMM, 0 °C; (2) LiAlH4 (12 equiv), 1,4-
dioxane, 90 °C, 52% over two steps.
(4) Radetich, B.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 2430.
(5) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
(b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem.
Soc. 1997, 119, 11224. (c) Frohn, M.; Dalkiewicz, M.; Tu, Y.; Wang, Z.-
X.; Shi, Y. J. Org. Chem. 1998, 63, 2948. (d) Wang, Z.-X.; Shi, Y. J. Org.
Chem. 1998, 63, 3099. (e) Cao, G.-A.; Wang, Z.-X.; Tu, Y.; Shi, Y.
Tetrahedron Lett. 1998, 39, 4425. (f) Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y.
Tetrahedron Lett. 1998, 39, 7819. (g) Tu, Y.; Wang, Z.-X.; Frohn, M.; He,
M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998, 63, 8475.
4724
Org. Lett., Vol. 6, No. 25, 2004

followed by Wittig olefination. The two-step process afforded
the desired alkene (-)-13 in excellent yield (93%).10
All that remained to complete the sulfone coupling part-
ner, (-)-2, was reductive removal of the pivaloate ester
(Dibal-H), followed in turn by conversion of the resulting
hydroxyl to the iodide (PPh3, I2, imidazole),11 and SN2
displacement with the sodium salt of benzenesulfinic acid.
With a reliable route to sulfone (-)-2 available, we
investigated the allylic oxidation of TBS-protected (E,E,E)-
geranylgeraniol necessary for the construction of the tetraene
coupling partner 3. After exploring several reaction condi-
tions, the Sharpless catalytic method12 proved to be the most
reliable. However, the desired terminal allylic alcohol 513
could only be obtained in low yield [ca. 10% (Scheme 4)].
Scheme 5 a
Scheme 4 a
a Reagents and conditions: (a) (1) n-BuLi, THF, 10% HMPA,
then 3; (2) 5% Na/Hg amalgam, Na2HPO4, MeOH/THF, 69% over
two steps. (b) TFA, THF/H2O, 96%.
which underwent reductive removal of the sulfone moiety
(Na/Hg amalgam) to furnish (+)-14 in 92% yield. Acid-
mediated global deprotection (TFA, THF/H2O) then afforded
synthetic glisoprenin A.
The synthetic compound was confirmed to be identical to
the natural product through the following two sets of NMR
experiments. First, the 1H and 13C NMR spectra (CD3OD)15
of the synthetic compound were found to be indistinguishable
from those of the natural product. Their identity was further
assured from the fact that no signal doubling was detected
a Reagents and conditions: (a) (1) TBSCl, imidazole, DMF; (2)
cat. SeO2, t-BuOOH, salicylic acid, CH2Cl2, ca. 10% over two steps.
(b) MsCl, LiCl, 2,6-lutidine, DMF, 86%.
1
in the H and 13C NMR spectra of a 2:1 mixture of the
synthetic and natural glisoprenin A, thereby demonstrating,
at least, that the synthetic and natural compounds possess
the same gross structure (Figure 1, panels A-C). Second,
the 13C NMR behaviors in the presence of chiral shift
reagents were studied; specifically, a 2:1 mixture of the
synthetic and natural glisoprenin A was subjected to 13C
NMR experiments in C6D6-CD2Cl2 (v/v 4:1) containing 25
mol % (R)- or (S)-Pr(tfc)3/OH. Under these conditions, all
eight R-carbons were observed as a separate resonance
(Figure 1, panel D). Critically, no signal-doubling was
detected for any of the eight resonances in the presence of
either (R)- or (S)-Pr(tfc)3, thereby further demonstrating that
the synthetic and natural compounds do indeed possess the
same absolute configuration at all four tertiary alcoholic
centers.
Chlorination in accordance with the Meyers protocol14 then
provided the allyl chloride 3 in good yield.
With both the sulfone (-)-2 and chloride 3 in hand, we
explored their coupling (Scheme 5). Lithiation of (-)-2
(n-BuLi, 10% HMPA/THF), followed by addition of chloride
3, gave the desired adduct as a mixture of diastereomeric
sulfones in 75% yield [93% based on recovered (-)-2],
(6) (a) Corey, E. J.; Zhang, J. Org. Lett. 2001, 3, 3211. (b) Corey, E. J.;
Noe, M. C.; Lin, S. Tetrahedron Lett. 1995, 36, 8741.
(7) McDonald, F. E.; Bravo, F.; Wang, X.; Wei, X.; Toganoh, M.;
Rodr´ıguez, J. R.; Do, B.; Neiwert, W. A.; Hardcastle, K. I. J. Org. Chem.
2002, 67, 2515.
(8) (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
(b) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(9) (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512. (b)
Sullivan, G. R.; Dale, J. A.; Mosher, H. S. J. Org. Chem. 1973, 38, 2143.
(10) Attempts to reintroduce the terminal isopropylidene earlier in the
synthesis, i.e., from (+)-12 via Corey-Winter olefination, met with limited
success.
(11) Garegg, P. J.; Samuelsson B. J. Chem. Soc., Chem. Commun. 1979,
978.
(12) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526.
(13) Two-dimensional NMR analysis and chemical correlation (i.e.,
desilylation of 5 afforded the known diol; see: Tago, K. Minami, E.;
Masuda, K.; Akiyama, T.; Kogen, H. Bioorg. Med. Chem. 2001, 9, 1781)
were used to confirm the site of oxidation.
In conclusion, the total synthesis of (+)-glisoprenin A,
highlighted by a series of asymmetric oxidations, has been
(15) All NMR experiments in the presence of (R)- or (S)-Pr(tfc)3 were
conducted in C6D6-CD2Cl2 (v/v 4:1). However, in the absence of shift
reagent the NMR spectra of both synthetic and natural glisoprenin A in
C6D6-CD2Cl2 (v/v 4:1) proved to be highly variable, presumably due to
issues associated with aggregation. Although NMR analysis of a 2:1 mixture
of synthetic and natural glisoprenin A did not indicate any signal doubling
in C6D6-CD2Cl2 (v/v 4:1), we felt it prudent to perform the analysis in
CD3OD, a solvent that precludes any aggregation. All spectra taken in CD3-
OD are provided in Supporting Information.
(14) Collington, E. W.; Meyer, A. I. J. Org. Chem. 1971, 36, 3044.
Org. Lett., Vol. 6, No. 25, 2004
4725

Figure 1. Panel A: 100 MHz 13C NMR of natural (+)-1 (80-10 ppm, in CD3OD). Panel B: 100 MHz 13C NMR of a 2:1 mixed sample
of synthetic (+)-1 to natural (+)-1 (80-10 ppm in CD3OD). Panel C: 100 MHz 13C NMR of synthetic (+)-1 (80-10 ppm, in CD3OD).
Panel D: 125 MHz 13C NMR spectra (the R-carbon region) of a 2:1 mixed sample of synthetic (+)-glisoprenin A to natural (+)-glisoprenin
A in C6D6-CD2Cl2 (v/v 4:1) containing 25 mol % (R)-Pr(tfc)3/OH. The asterisk (*) indicates resonance of the allylic carbon at C-4.
was provided by the NIH through Grant NS 12108, by Eisai
achieved. This work not only confirms the predicted stereo-
Research Institute, and by a Postdoctoral Fellowship from
the American Cancer Society (PF-03-134-01-CDD) to C.M.A.
structure of (+)-1, but also validates the chiral lanthanide
shift approach for determination of absolute configuration.
Supporting Information Available: Spectroscopic and
analytical data for compounds 1, 5, 7-9, and 12-14 and
selected experimental procedures. This material is available
Acknowledgment. We thank Professor S. Omura, The
Kitasato Institute, for a generous gift of natural (+)-
glisoprenin A, and we gratefully acknowledge Professor E.
J. Corey for a generous gift of ligand 10. Financial support
free of charge via the Internet at http://pubs.acs.org.
OL048059O
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Org. Lett., Vol. 6, No. 25, 2004