Multicomponent linchpin couplings of silyl dithianes via solvent- controlled brook rearrangement [4]

Full text of DOI:10.1021/ja970371o

J. Am. Chem. Soc. 1997, 119, 6925-6926
6925
3
a
Multicomponent Linchpin Couplings of Silyl
Dithianes via Solvent-Controlled Brook
Rearrangement
In our syntheses of FK506, rapamycin and demethoxy-
3
b
3c
rapamycin, and discodermolide, treatment with t-BuLi in
9
1
0% HMPA/THF at -78 °C proved to be the optimum protocol
for rapid generation of 2-substituted dithiane anions. We
began the present study by using these conditions for bisalky-
10
Amos B. Smith, III* and Armen M. Boldi
11
lation of 2-tert-(butyldimethylsilyl)-1,3-dithiane (4), a substrate
also successfully employed by Tietze which leads to installation
of the more robust TBS hydroxyl protecting group. Metalation
of 4 in 10% HMPA/THF and immediate addition of epoxide
Department of Chemistry, Laboratory for Research on the
Structure of Matter, and Monell Chemical Senses Center
UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
(
-)-5 readily afforded (+)-6 in good yield (Scheme 2).12
ReceiVed February 4, 1997
We and others have extensively employed dithiane cou-
Scheme 2
1
,2
plings with epoxides, R-alkoxy iodides and tosylates, and
aldehydes for the stereocontrolled generation of protected aldol
linkages and the union of advanced fragments in complex
molecule synthesis.3 Recent studies have also established the
,4
5
tactical advantages of domino reactions and two-direction chain
extension.6 Herein we report the one-flask linchpin coupling
of 2-(trialkylsilyl)-1,3-dithiane with two different electrophiles
In the presence of HMPA, both the initial alkylation of 4
and the subsequent Brook rearrangement occur within minutes
at -78 °C. Accordingly, the attempted sequential reaction of
4 with epoxides (-)-5 and (-)-7 led to a mixture of symmetrical
and unsymmetrical products [(+)-6, (+)-8a, and (+)-8b Scheme
3]. This result suggested that linchpin coupling of different
electrophiles would be feasible only if the Brook rearrangement
could be suppressed until the first alkylation was complete.
7
via solvent-controlled Brook rearrangement.
8
In 1994 Tietze and co-workers described the symmetrical
bisalkylation of trimethylsilyldithiane (1) with 2 equiv of a
scalemic epoxide [e.g., (+)-2, Scheme 1]. Following initial
reaction of the lithio derivative of 1 with the epoxide, the
7
resultant alkoxide undergoes 1,4-Brook rearrangement, trans-
ferring the silyl group to oxygen and generating the 2-alkyl
lithiated dithiane; coupling with a second molecule of the
epoxide then yields (-)-3. This process requires a reaction time
of 2 days and is inapplicable to unsymmetrical couplings (vide
infra).
Scheme 3
Scheme 1
Fortuitously, an elegant recent study by Oshima, Utimoto,
and co-workers revealed dramatic solvent effects on similar
Brook rearrangements in the adducts of lithio dihalo(trialkyl-
13
silyl)methanes with epoxides (Scheme 4). Rearrangement did
not occur following metalation and initial alkylation in THF
but proceeded readily upon addition of HMPA; the resultant
(
1) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965, 4, 1075.
2) Reviews: (a) Seebach, D. Synthesis 1969, 17. (b) Seebach, D. Angew.
(
Chem., Int. Ed. Engl. 1969, 8, 639. (c) Gr o¨ bel, B.-T.; Seebach, D. Synthesis
1
977, 357. (d) Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239. (e)
Bulman Page, P. C.; van Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45,
643.
3) (a) Smith, A. B., III; Chen, K.; Robinson, D. J.; Laakso, L. M.; Hale,
Scheme 4
7
(
K. J. Tetrahedron Lett. 1994, 35, 4271. (b) Smith, A. B., III; Condon, S.
M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr.
J. Am. Chem. Soc. 1995, 117, 5407. (c) Smith, A. B., III; Qiu, Y.; Jones,
D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011.
(4) (a) Corey, E. J.; Weigel, L. O.; Chamberlin, A. R.; Cho, H.; Hua, D.
H. J. Am. Chem. Soc. 1980, 102, 6613. (b) Corey, E. J.; Pan, B.-C.; Hua,
D. H.; Deardorff, D. R. J. Am. Chem. Soc. 1982, 104, 6816. (c) Redlich,
H.; Francke, W. Angew. Chem., Int. Ed. Engl. 1980, 19, 630. (d) Barrett,
A. G. M.; Capps, N. K. Tetrahedron Lett. 1986, 27, 5571. (e) Park, P.;
Broka, C. A.; Johnson, B. F.; Kishi, Y. J. Am. Chem. Soc. 1987, 109, 6205.
(10) For an insightful discussion of the ion-pair solution structures of
2-lithio-1,3-dithianes in THF and HMPA/THF, see: Reich, H. J.; Borst, J.
P.; Dykstra, R. R. Tetrahedron 1994, 50, 5869.
(f) Egbertson, M.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 11. (g) Mori,
Y.; Asai, M.; Furukawa, H. Heterocycles 1992, 34, 1281. (h) Nicolaou, K.
C.; Nadin, A.; Leresche, J. E.; Yue, E. W.; La Greca, S. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2190.
(11) We prepared 4 in multigram quantities by addition of tert-
butyldimethylchlorosilane to the lithio derivative of 1,3-dithiane in THF at
-78 °C f room temperature over 2 h.
(
5) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115. (b) Parsons, P. J.; Penkett,
C. S.; Shell, A. J. Chem. ReV. 1996, 96, 195. (c) Tietze, L. F.; Beifuss, U.
(12) All synthetic compounds were purified by flash chromatography
on silica gel. The structure assigned to each new compound is in accord
Angew. Chem., Int. Ed. Engl. 1993, 32, 131. (d) Posner, G. H. Chem. ReV.
1
13
1
986, 86, 831.
with its infrared, 500-MHz H NMR, and 125-MHz C NMR spectra as
well as appropriate parent ion identification by high resolution mass
spectrometry.
(6) (a) Schreiber, S. L. Chem. Scr. 1987, 27, 563. (b) Poss, C. S.;
Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9. (c) Magnuson, S. R.
Tetrahedron 1995, 51, 2167.
(13) (a) Shinokubo, H.; Miura, K.; Oshima, K.; Utimoto, K. Tetrahedron
1996, 52, 503. (b) Shinokubo, H.; Miura, K.; Oshima, K.; Utimoto, K.
Tetrahedron Lett. 1993, 34, 1951.
(14) Matsuda, I.; Murata, S.; Ishii, Y. J. Chem. Soc., Perkin Trans. 1
1979, 26.
(15) Mukhopadhyay, T.; Seebach, D. HelV. Chim. Acta 1982, 65, 385.
(16) HMPA appears to be more effective than DMPU.
(17) In preliminary studies, 2-(trimethylsilyl)- and 2-(triethylsilyl)-1,3-
dithiane afforded lower yields of coupling products.
(18) Pettit, G. R.; Cichacz, Z. A.; Gao, F.; Herald, C. L.; Boyd, M. R.;
Schmidt, J. M.; Hooper, J. N. A. J. Org. Chem. 1993, 58, 1302.
(7) (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (b) Brook, A. G.;
Bassindale, A. R. In Rearrangements in Ground and Excited States; de
Mayo, P., Ed.; Academic Press: New York, 1980; Vol. 2, p 149. (c) Brook,
A. G.; Chrusciel, J. J. Organometallics 1984, 3, 1317. (d) Jankowski, P.;
Raubo, P.; Wicha, J. Synlett 1994, 985. (e) Lautens, M.; Delanghe, P. H.
M.; Goh, J. B.; Zhang, C. H. J. Org. Chem. 1995, 60, 4213.
(
8) Tietze, L. F.; Geissler, H.; Gewert, J. A.; Jakobi, U. Synlett 1994,
11.
9) These conditions were first employed by Williams: Williams, D.
R.; Sit, S.-Y. J. Am. Chem. Soc. 1984, 106, 2949.
5
(
S0002-7863(97)00371-5 CCC: $14.00 © 1997 American Chemical Society

6926 J. Am. Chem. Soc., Vol. 119, No. 29, 1997
Communications to the Editor
O-silyl organolithium could then react with a second electro-
Table 2. Unsymmetrical Linchpin Couplings of Silyl Dithiane 4
phile. The analogous unsymmetrical bisalkylation of TM-
14
SCHLiCN with two epoxides in DME has also been reported,
although in this case it is unclear how the timing of the Brook
rearrangement was controlled.
Metalation of 4 and alkylation with epoxide (-)-5 in Et2O
or THF likewise furnished the unrearranged carbinol (+)-13
exclusively (Table 1, entries 1 and 2). In contrast, addition of
HMPA or DMPU1
5,16
(entries 3 and 4) induced the 1,4-Brook
rearrangement, affording predominantly silyl ether (+)-14.
Table 1. Solvent Effects on Brook Rearrangement in Coupling of
Silyl Dithiane 4 with Epoxide (-)-5
Yield 13
(%)
Yield 14
(%)
Entry
Solvent
THF
Additivea
1
2
3
4
-
-
60
74
9
-
-
56
66
Et
Et
Et
2
O
2
O
2
O
HMPA
DMPU
12
a
Following step b, the reaction mixture was cooled to -78 °C,
O, and warmed to -45
treated with 0.3-0.4 equiv of additive in Et
C for 1 h.
2
°
Encouraged by these results, we reinvestigated the one-pot
linchpin coupling of dithiane 4 with two different electrophiles.
Following deprotonation and addition of epoxide (-)-5 in Et2O,
introduction of HMPA plus a second epoxide or benzyl bromide
afforded the unsymmetrical bisalkylated products in 56-74%
a
+
was used. b After chromatography.
1
7
Only 1 equiv of E
2
yields (Table 2).
Scalemic epoxides are particularly well
suited to this process, because the configurations of the resulting
carbinol stereocenters are predetermined, circumventing the
formation and separation of unwanted diastereomers. Previous
studies of 2-lithio-2-alkyldithianes suggest that a variety of other
Scheme 5
2
electrophiles should also be accommodated in the second step.
Importantly, the substituents in several adducts (e.g., epoxides
2
2 and 24) are poised for further elaboration.
We have utilized the one-step coupling protocol to link
advanced intermediates in several of our ongoing synthetic
programs. For example, sequential alkylations of dithiane 4
with epoxides (+)-25 and (-)-26 gave exclusively the spong-
1
8
istatin fragment (+)-27 in 59% yield (Table 2, entry 6). A
survey of the literature suggests that the new protocol should
prove applicable to nearly all total syntheses utilizing dithiane
coupling strategies.
We have further extended this methodology by assembling
a fiVe-component coupling product in a single operation.
Following alkylation of dithiane 4 with epoxide (-)-5 (2.6 equiv
each) to generate the unrearranged alkoxy dithiane 28, sequential
addition of HMPA and (-)-epichlorohydrin (21, 1 equiv)
furnished the bis(silyloxy dithiane) carbinol (+)-29 in 66% yield,
accompanied by a minor amount (ca. 2%) of epoxide (+)-22
Acknowledgment. This article is dedicated to Professor Carl R.
Johnson, colleague and friend, on the occasion of his 60th birthday.
We also gratefully acknowledge financial support provided by the
National Institutes of Health (Institute of General Medicinal Sciences)
through Grant GM-29028 and a Postdoctoral Fellowship to A.M.B.
(
Scheme 5). This new strategy, if general, should result in
exceptionally concise routes to complex 1,3-polyol natural
products, including polyene macrocycles and macrolides such
as roflamycoin (30).19
The further development of one-step linchpin couplings of
silyl dithianes and applications to natural product synthesis are
currently under active investigation.
Supporting Information Available: Characterization data for
compounds 4, 6, 8a, 8b 13, 14, 16, 18, 20, 22, 24, 27, and 29 (6 pages).
See any current masthead page for ordering and Internet access
instructions.
(
19) (a) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021. (b) Oishi, T.;
Nakata, T. Synthesis 1990, 635.
JA970371O