Organosilanes in synthesis: application to an enantioselective synthesis of methyl-l-callipeltose.

Article abstract of DOI:10.1021/ol034582b

[reaction: see text] Methyl-l-callipeltose, the carbohydrate associated with callipeltoside A, has been synthesized in eight steps and 23% overall yield from enantioenriched allylsilane 6 and acetaldehyde. The key steps are a highly diastereoselective for

Full text of DOI:10.1021/ol034582b

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1991-1993
Organosilanes in Synthesis: Application
to an Enantioselective Synthesis of
Methyl-L-callipeltose
Hongbing Huang and James S. Panek*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment, Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
panek@chem.bu.edu
Received April 3, 2003
ABSTRACT
Methyl-L-callipeltose, the carbohydrate associated with callipeltoside A, has been synthesized in eight steps and 23% overall yield from
enantioenriched allylsilane 6 and acetaldehyde. The key steps are a highly diastereoselective formal [4 + 2] annulation and a Cr(VI)-catalyzed
oxidative C−C bond cleavage to produce lactone 11.
Callipeltosides A-C were isolated from the extracts of the
shallow water lithistid sponge Callipelta sp.1 and represent
a class of novel cytotoxic glycoside macrolides. They were
found to exhibit moderate cytotoxic activity against NSCLC-
N6 and P388 cell lines. The structure of the callipeltosides
features a hydroxylated hemiacetal oxane ring embedded in
a 14-membered macrolactone, which is connected to a trans-
chlorocyclopropane through a dienyne linkage. While cal-
lipeltoside C contains an evalose sugar moiety, callipeltosides
A and B possess unprecedented deoxyamino sugars (Figure
1). The initial structure elucidation of callipeltoside A
revealed the relative stereochemical relationships of callipel-
tose to the macrolactone. The relative stereochemistry of the
chlorocyclopropyl side chain section of the molecule and
the absolute stereochemistry of the callipeltoses remained
unresolved at the time this project was initiated. Two recent
total syntheses of callipeltoside A have established its
absolute stereochemistry as illustrated (Figure 1).2 In our
approach to callipeltoside A, synthetic routes have been
Figure 1. Proposed Structures of Callipeltosides A-C.
designed in order to access to both enantiomers of callipel-
toside aglycon and callipeltose. Here, we describe an efficient
asymmetric synthesis of methyl-L-callipeltose using a [4 +
2] dihydropyran construction.
(1) (a) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus, C.; Roussakis,
C. J. Am. Chem. Soc. 1996, 118, 11085-11088. (b) Zampella, A.; D’Auria,
M. V.; Minale, L.; Debitus, C.; Roussakis, C. Tetrahedron 1997, 53, 3243-
3248.
(2) (a) Trost, B. M.; Dirat, O.; Gunzner, J. L. Angew. Chem., Int. Ed.
2002, 41, 841-843. (b) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y.
H. J. Am. Chem. Soc. 2002, 124, 10396-10415. (c) Evans, D. A.; Hu, E;
Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654-5655.
10.1021/ol034582b CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/01/2003

Recently, several syntheses of callipeltose have been
reported exploiting starting materials obtained from the chiral
pool, including rhamnose,3 mannose,4 D-glucal5 and threo-
nine.6 Our approach is based on a stereoselective [4 + 2]
annulation of chiral allysilane 6 and illustrates the versatility
of the silane reagent in accessing functionalized pyrans
(Scheme 1).7
) 97%).10 The epoxide ring-opening reaction of 4 with
2-propenylmagnesium bromide proved to be sluggish and
resulted in significant amounts of Peterson olefination
product, which could not be suppressed even at low
temperature (-78 °C).11 However, the epoxide opening of
the TMS ether of 4 provided allylsilane 5 as a single
regioisomer in good yield (71%). This reaction has been
routinely scaled up to 10 g. After exchanging trimethylsilyl
ether to an acetate, allylsilane 6 was obtained in 85% yield.
The annulation of allysilane 6 with acetaldehyde proceeded
to give dihydropyran 7 in 80% yield (dr ) 10:1).12 Metha-
nolysis of acetate 7 gave pyran alcohol 8 in quantitative yield.
Our initial synthetic plan called for the synthesis of 9 by a
directed epoxidation,13 which would then be converted to
alcohol 10, a key intermediate to callipeltose (Scheme 3).2b
Scheme 1. Methyl-L-callipeltose Retrosynthetic Analysis
Scheme 3. Substrate-Directed Stereoselective Epoxidation
Given the ready availability of highly enantioenriched
organosilanes, this annulation process would prove to be an
efficient method for synthesizing functionalized dihydro-
pyrans, useful intermediates for natural product synthesis.
The chiral allylsilane 6 was prepared in high optical purity
using a regioselective epoxide ring-opening as described by
Chong and co-workers (Scheme 2).8 Accordingly, the enan-
Scheme 2. Synthesis of Chiral Allylsilane
Though the VO(acac)2-catalyzed epoxidation provided the
desired epoxide 9 as a single isomer, an unexpected side
product lactone 11 (∼10%) was observed by examination
of 1H NMR of the crude reaction mixture. Epoxidation using
Mo(CO)6 gave 9 with lower diastereoselectivity, but still
equal amounts of 11 could be detected by NMR. Initially
produced as a byproduct, we envisioned that lactone 11 could
be a useful intermediate en route to callipletose and may
have been generated by a transition metal-catalyzed oxidation
with C-C bond cleavage. Encouraged by reports concerning
C-H oxidation promoted by Cr[VI],14 several combinations
tioenriched 3-silyl epoxy alcohol 4 was prepared from allylic
alcohol 3 by a Sharpless asymmetric epoxidation8,9 and was
isolated in 91% yield and with high enantiomeric purity (ee
(3) Smith, G. R.; Finley, J. J., IV; Giuliano, R. M. Carbohydr. Res. 1998,
308, 223-237.
(4) Gurjar, M. K.; Reddy, R. Carbohydr. Lett. 1998, 3, 169-172.
(5) Pihko, A. J.; Nicolaou, K. C.; Koskinen, A. M. P. Tetrahedron:
Asymmetry 2001, 12, 937-942.
(6) Evans, D. A.; Hu, E.; Tedrow, J. S. Org. Lett. 2001, 3, 3133-3136.
For a racemic synthesis of methyl callipeltose, see 2b.
(7) (a) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836-
9837. (b) Huang, H.; Panek, J. S. Org. Lett. 2001, 3, 1693-1696.
(8) Chauret, D. C.; Chong, J. M.; Ye Q. Tetrahedron: Asymmetry 1999,
10, 3601-3614.
(10) Enantiomeric excess (ee) analysis was conducted by chiral HPLC
analysis.
(11) Peterson, D. J. J. Org. Chem. 1968, 33, 780-784.
(12) Stereochemistry of 8 was determined by NOE experiment. The cis
stereoselectivity is consistent with our previous reported observations. For
a discussion of the related transition state, see ref 7.
(13) Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136-6137.
(9) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
1992
Org. Lett., Vol. 5, No. 11, 2003

of oxidants with Cr[VI] complexes were evaluated: the
combination of catalytic amounts of CrO3 with H5IO6
provided the unsaturated lactone 11 in good yield. Although
this reagent combination has been used to oxidize primary
alcohols to carboxylic acids,15 no reports of an oxidative
C-C bond cleavage had been documented (Scheme 4).16
DIBAL-H followed by workup with MeOH provided methyl
glycoside 12 as a single anomer. This material was used
without further purification. The standard SAD of 12 gave
diol 13 in low conversion (30%) even after prolonged
reaction periods (24 h), along with free lactol and lactone
11. However, 12 could be cleanly oxidized to the diol 13 as
a single diastereomer after addition of NaHCO3 (2 equiv) to
buffer the reaction mixture, using commercially available
AD-mix-R.17 The selective methylation of the secondary
hydroxyl of 13 (tBuOK/MeI) afforded the intermediate
tertiary alcohol, which was converted to the carbamate 14
upon reaction with CCl3C(O)NCO followed by K2CO3/
MeOH. The final stage of the callipeltose synthesis was based
on a Rh(I)-catalyzed oxidative insertion of a carbamate NH
to afford the oxazolidin-2-one.18 As reported by Trost and
co-workers, the insertion reaction proceeded to approximately
70% conversion in refluxing CH2Cl2 when 10 mol %
rhodium acetate was employed.2b Complete conversion could
be achieved by increasing catalyst loading to 20 mol %.
However, when this reaction was carried out in refluxing
benzene, complete conversion to callipeltose 2 was achieved,
using only 10 mol % catalyst (93%). The analytical data and
optical rotation values are fully consistent with those
reported.2, 6
Scheme 4. Sythesis of Methyl-L-callipeltose
In summary, an asymmetric synthesis of methyl-L-cal-
lipeltose has been accomplished in eight steps and 23%
overall yield from silane 6. A transition metal-catalyzed
oxidative C-C bond cleavage was employed for the produc-
tion of the key intermediate 11. The synthesis of the
callipeltose aglyon and of callipeltoside A will be reported
in due course.
Acknowledgment. Financial support was obtained from
the NIH-NCI (CA56304) and NIH (P50 GM067041).
Due to the electron-deficient nature of the unsaturated
lactone 11, the standard Sharpless asymmetric dihydroxy-
lation (SAD) was ineffective.17a Treatment of lactone 11 with
Supporting Information Available: General experimen-
tal procedures, including spectroscopic and analytical data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Muzart, J.; Piva, O. Tetrahedron Lett. 1988, 29, 2321-2324.
(b) Chidambaram, N.; Chandrasekaran, S. J. Org. Chem. 1987, 52, 5048-
5051. (c) Pearson, A. J.; Chen, Y.; Han, G. R.; Hsu, S.; Ray, T. J. Chem.
Soc., Perkin Trans. 1 1985, 267-273.
OL034582B
(15) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.; Grabowski,
E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323-5326.
(16) Study on the mechanism, scope, and limitation of this novel reaction
will be reported elsewhere. For a leading reference on Cr(VI)-catalyzed
oxidation of the C-H bond, see: Lee, S.; Fuchs, P. L. J. Am. Chem. Soc.
2002, 124, 13978-13979.
(17) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483-2547. (b) Stereochemistry of 13 was determined by
NOE experiment, see Supporting Information for detail.
(18) Espino, C. G.; Du Bois, J. Angew. Chem., Int. Ed. 2001, 40, 598-
600.
Org. Lett., Vol. 5, No. 11, 2003
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