[3 + 2] annulation of allylic silanes in acyclic stereocontrol: Total synthesis of (9S)-dihydroerythronolide A

Article abstract of DOI:10.1021/ja034865z

The [3 + 2] annulation reactions of allylic silanes can be utilized to achieve acyclic stereocontrol. This method was employed as a key step in an enantioselective total synthesis of (9S)-dihydroerythronolide A. The key annulation reaction served to estab

Full text of DOI:10.1021/ja034865z

Published on Web 04/25/2003
[3 + 2] Annulation of Allylic Silanes in Acyclic Stereocontrol: Total Synthesis
of (9S)-Dihydroerythronolide A
Zhi-Hui Peng and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
Received February 25, 2003; E-mail: kwoerpel@uci.edu
Scheme 1
The [3 + 2] annulation reactions of allylic silanes are powerful
methods for the stereoselective preparation of cyclopentanes and
five-membered ring heterocycles.1 These reactions have been used
as key transformations for the syntheses of five-membered ring-
containing natural products.2,3 While evidently useful for the
formation of cyclic compounds, these annulation reactions are not
obviously suited for the synthesis of acyclic compounds.4 In this
communication, we demonstrate that annulation reactions of allylic
silanes can be used in acyclic stereocontrol. We use this method
as a key step in an enantioselective total synthesis of (9S)-
dihydroerythronolide A (1), a molecule that has stimulated the
development of a host of new reactions and concepts for C-C bond
construction.5,6
Scheme 2
To demonstrate the transfer of the stereochemical information
introduced by the annulation reaction to an acyclic system, we
performed a ring-opening reaction of the highly substituted tet-
rahydrofuran 3. This heterocycle was obtained as a single diaste-
reomer from the annulation reaction of allylic silane 2 with ethyl
product possessing the relative configuration required to complete
the synthesis (eq 1).10,11
pyruvate (Scheme 1).2b Conversion of the carboethoxy group in 3
to the iodomethyl group followed by elimination formed the highly
functionalized acyclic intermediate 5.
If the tertiary silyl group, which was established during the
annulation reaction, is considered as a tertiary hydroxyl group,7
the synthetic utility of 5 becomes immediately apparent. This silane
represents a motif that can be found twice in the natural product
(9S)-dihydroerythronolide A (1). Disconnection of the seco acid 6
by an aldol reaction between the C8-C9 bond gives two similarly
sized fragments 7 and 8 (Scheme 2).8 These two fragments could
be prepared from alkene 9, which closely resembles silane 5.
While the synthetic plan outlined in Scheme 2 was appealing in
principle, the success of the aldol disconnection about the C8-C9
bond was not assured. Although the requisite stereochemistry of
the aldol adduct can be anticipated from an R-chelation-controlled
aldol reaction of the (Z)-enolate of R-benzyloxy ethyl ketone 8,
only a few examples of this transformation were reported with
simple R-oxygenated ethyl ketones.9 Model studies with analogous
substituted aldol partners suggested, however, that the key aldol
reaction of 7 and 8 would proceed according to plan. Addition of
the tin(II) enolate of the model ethyl ketone 10 to the model chiral
aldehyde 11 proceeded with high diastereoselectivity, favoring the
Encouraged by the result on the model aldol reaction, we began
the total synthesis of (9S)-dihydroerythronolide A by assembling
the aldol coupling partners 7 and 8 (Scheme 3). The annulation
reaction of the racemic allylic silane 2 with (S)-pantolactone
pyruvate ester followed by reduction afforded the chiral diol 13
with an ee greater than 98% (Scheme 3).2b The same diol 13 could
also be obtained with comparable enantiomeric purity from the
resolved chiral allylic silane (-)-2 using (R)-pantolactone pyruvate
ester.2b The derived iodide 14 underwent a ring-opening reaction
to afford the key acyclic intermediate 15 after protecting group
manipulations. Intramolecular hydrosilylation of allylic alcohol 15
followed by Tamao oxidation provided the desired diol 16 as a
single diastereomer.12 The C9-C15 fragment 7 was obtained from
diol 16 in three steps. Condensation of 7 with the titanium enolate
9
6018
J. AM. CHEM. SOC. 2003, 125, 6018-6019
10.1021/ja034865z CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
synthesis of (9S)-dihydroerythronolide A has been accomplished
with the longest linear sequence of 29 steps and in 5.4% overall
yield.
Acknowledgment. This research was supported by a CAREER
Award from the National Science Foundation (CHE-9701622).
K.A.W. thanks the Camille and Henry Dreyfus Foundation, Johnson
& Johnson, and Merck Research Laboratories for awards to support
research. We thank Dr. John Greaves and Dr. John Mudd for mass
spectrometric data. We thank Professor Kazunobu Toshima (Keio
University, Japan) for providing a 1H NMR spectrum of (9S)-
dihydroerythronolide A for comparison.
Supporting Information Available: Full experimental and analyti-
cal data for all new compounds; the chiral HPLC traces of (()-13,
(-)-13, and (+)-13; and 1H and 13C NMR spectra of selected
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) For leading references, see: (a) Masse, C. E.; Panek, J. S. Chem. ReV.
1995, 95, 1293-1316. (b) Kno¨lker, H.-J. J. Prakt. Chem. 1997, 339, 304-
314.
(2) (a) Peng, Z.-H.; Woerpel, K. A. Org. Lett. 2001, 3, 675-678. (b) Peng,
Z.-H.; Woerpel, K. A. Org. Lett. 2002, 4, 2945-2948. (c) Roberson, C.
W.; Woerpel, K. A. J. Am. Chem. Soc. 2002, 124, 11342-11348. (d)
Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949-1952.
(3) The related [2 + 2] annulation reaction has also been employed for the
synthesis of a four-membered ring-containing natural product: Kno¨lker,
H.-J.; Baum, G.; Schmitt, O.; Wanzl, G. Chem. Commun. 1999, 1737-
1738.
Scheme 4
(4) Panek, J. S.; Beresis, R. T. J. Am. Chem. Soc. 1993, 115, 7898-7899.
(5) For reviews on early synthetic work, see: (a) Paterson, I.; Mansuri, M.
M. Tetrahedron 1985, 41, 3569-3624. (b) Mulzer, J. Angew. Chem., Int.
Ed. Engl. 1991, 30, 1452-1454.
(6) For recent studies on the syntheses of erythromycins and erythronolides,
see: (a) Stu¨rmer, R.; Ritter, K.; Hoffmann, R. W. Angew. Chem., Int.
Ed. Engl. 1993, 32, 101-103. (b) Martin, S. F.; Hida, T.; Kym, P. R.;
Loft, M.; Hodgson, A. J. Am. Chem. Soc. 1997, 119, 3193-3194. (c)
Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J. J. Am. Chem.
Soc. 1998, 120, 5921-5942.
(7) (a) Tamao, K. AdVances in Silicon Chemistry; JAI: Greenwich, CT, 1996;
Vol. 3, pp 1-62. (b) Fleming, I. Chemtracts: Org. Chem. 1996, 9,
1-64.
(8) Previous synthetic studies showed that the macrolactonization of the seco
acid was favored with the (9S)-configuration and cyclic protecting groups
at C3/C5 and C9/C11 diols; see: (a) Woodward, R. B. et al. J. Am. Chem.
Soc. 1981, 103, 3213-3215. (b) Stork, G.; Rychnovsky, S. D. J. Am.
Chem. Soc. 1987, 109, 1565-1567.
(9) (a) Heathcock, C. H.; Arseniyadis, S. Tetrahedron Lett. 1985, 26, 6009-
6012. (b) Solsona, J. G.; Romea, P.; Urp´ı, F.; Vilarrasa, J. Org. Lett. 2003,
5, 519-522. (c) Choudhury, A.; Thornton, E. R. Tetrahedron Lett. 1993,
34, 2221-2224.
(10) Lithium and titanium enolates gave poor selectivities for the model aldol
reaction. For the chelation-controlled aldol reaction of â-benzyloxy ethyl
ketone using tin-enolate, see: Paterson, I.; Tillyer, R. D. Tetrahedron Lett.
1992, 33, 4233-4236. The details of the model aldol reaction are provided
in Supporting Information.
of (R)-4-benzyl-3-propionyloxazolidin-2-one afforded the desired
aldol adduct as a single diastereomer.13,14 Protection of the hy-
droxyl group by an anhydrous DDQ oxidation yielded a 4-meth-
oxybenzylidene acetal, which could be converted to the C1-C8
fragment 8.
With the two fragments in hand, efforts were focused on the
key aldol coupling reaction. In accordance with the model system
(eq 1), the aldol reaction of 7 and 8 gave the desired product 17 as
a single diastereomer in 90% yield (Scheme 4). Although an excess
of the aldehyde 7 (4.0 equiv) was used to consume all the ketone
8, unreacted aldehyde was easily recovered without epimerization.
The C7 oxygen atom was removed by a directed reduction15 and
protection of the C9 hydroxyl group followed by deoxygenation.6c,16
Unmasking of the carboxylic acid and removal of the silyl group
provided the seco-acid 6. Macrolactonization17 followed by global
deprotection afforded (9S)-dihydroerythronolide A (1), whose
subsequent conversion into erythronolide A and erythromycin A
is known.18,19
(11) The tin(II)-mediated aldol reaction of 10 with achiral isobutyraldehyde
afforded the chelation-controlled and nonchelation-controlled aldol prod-
ucts in a ratio of about 12:1. The stereochemistry of 12 reflected an anti-
Felkin aldehyde diastereofacial selection, which was usually the matched
case in the double-stereodifferentiating aldol reactions of (Z)-enolates;
see: Roush, W. R. J. Org. Chem. 1991, 56, 4151-4157.
(12) Tamao, K. Nakajima, T.; Sumiya, R.; Arai, H.; Higuchi, N.; Ito, Y. J.
Am. Chem. Soc. 1986, 108, 6090-6093.
(13) Gage, J. R.; Evans, D. A. Organic Syntheses; Wiley: New York, 1993;
Collect. Vol. VIII, pp 339-349.
(14) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894-902.
(15) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338-344.
(16) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975,
1574-1585.
(17) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989-1993.
(18) Nakata, M.; Arai, M.; Tomooka, K.; Ohsawa, N.; Kinoshita, M. Bull.
Chem. Soc. Jpn. 1989, 62, 2618-2635.
This work demonstrates that the [3 + 2] annulation of allylic
silanes can be a powerful method for the synthesis of highly sub-
stituted acyclic targets. Using this methodology, a convergent total
(19) Toshima, K.; Nozaki, Y.; Mukaiyama, S.; Tamai, T.; Nakata, M.; Tatsuta,
K.; Kinoshita, M. J. Am. Chem. Soc. 1995, 117, 3717-3727.
JA034865Z
9
J. AM. CHEM. SOC. VOL. 125, NO. 20, 2003 6019