Silyl-substituted spirodiepoxides: stereoselective formation and regioselective opening

Article abstract of DOI:10.1021/ol901948d

A short synthesis of the natural product epi-citreodiol and the method developed to gain access to this target are described. Key advances focus on silyl substituted allenes. Upon exposure to dlmethyldioxirane, spirodiepoxides form with high face selectiv

Full text of DOI:10.1021/ol901948d

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4672-4675
Silyl-Substituted Spirodiepoxides:
Stereoselective Formation and
Regioselective Opening
Partha Ghosh,† Joseph R. Cusick,† Jennifer Inghrim, and Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New
Jersey, New Brunswick, New Jersey 08903
lawjw@rci.rutgers.edu
Received August 21, 2009
ABSTRACT
A short synthesis of the natural product epi-citreodiol and the method developed to gain access to this target are described. Key advances
focus on silyl substituted allenes. Upon exposure to dimethyldioxirane, spirodiepoxides form with high face selectivity and subsequently react
at the silyl terminus.
Here we report direct entry to enantioenriched R′-hydroxy
enones and its derivative enediols. These motifs are widely
distributed among natural products, especially polyketides,
such as gabosine A,1 hypothemycin,2 picromycin,3 inced-
nine,4 and epi-citreodiol,5 among others. In principle, spiro-
diepoxide methodology offers a means by which to access
such motifs.6 The efficiency of the transformation from allene
to derivatized spirodiepoxide has been limited by the
selectivity of allene epoxidation. In other studies, we
described the challenges associated with epoxidation of 1,3-
disubstituted allenes.7 As briefly shown in Scheme 1, the
stereoselectivity of the first epoxidation of an allene of type
I (R1 ) R2) is excellent [IfII (major) and III (minor), dr
>20:1]. Epoxidation of allene oxides (e.g., II and III) is
usually less selective. For example, linear, unfunctionalized
substituents lead to low ratios of spirodiepoxide products
[II f IV (major) and V (minor), dr ∼ 2:1]. The situation is
complicated by issues of site selectivity as well. In cases
for I where R1 * R2 two different allene oxides could form,
each with high facial selectively, and thereby lead to a total
of three spirodiepoxides (I f IV-VI).7 Moreover, there is
an additional problem: subsequent nucleophilic or eliminative
opening would generate two regioisomeric products from
each spirodiepoxide (e.g., IV f VII and VIII). We
wondered whether the presence of a silyl substituent would
† These authors contributed equally to this work.
(1) Bach, G.; Breiding-Mack, S.; Grabley, S.; Hammann, P.; Huetter,
K.; Thiericke, R.; Uhr, H.; Wink, J.; Zeeck, A. Liebigs Ann. Chem. 1993,
241.
(2) Agatsuma, T.; Takahashi, A.; Kabuto, C.; Nozoe, S. Chem. Pharm.
Bull. 1993, 41, 373.
(3) (a) Brockmann, H.; Henkel, W. Naturwissenschaften 1950, 37, 138.
(b) Muxfeldt, H.; Shrader, S.; Hansen, P.; Brockmann, H. J. Am. Chem.
Soc. 1968, 90, 4748.
(4) Futamura, Y.; Sawa, R.; Umezawa, Y.; Igarashi, M.; Nakamura, H.;
Hasegawa, K.; Yamasaki, M.; Tashiro, E.; Takahashi, Y.; Akamatsu, Y.;
Imoto, M. J. Am. Chem. Soc. 2008, 130, 1822.
(5) Shizuri, Y.; Nishiyama, S.; Imai, D.; Yamamura, S.; Furukawa, H.;
Kawai, K.; Okada, N. Tetrahedron Lett. 1984, 25, 4771.
(6) (a) Katukojvala, S.; Barlett, K. N.; Lotesta, S. D.; Williams, L. J.
J. Am. Chem. Soc. 2004, 126, 15348. (b) Lotesta, S. D.; Hou, Y.; Williams,
L. J. Org. Lett. 2007, 9, 869. (c) Ghosh, P.; Lotesta, S. D.; Williams, L. J.
J. Am. Chem. Soc. 2007, 129, 2438. (d) Shangguan, N.; Kiren, S.; Williams,
L. J. Org. Lett. 2007, 9, 1093. (e) Lotesta, S. D.; Kiren, S.; Williams, L. J.
Angew. Chem., Int. Ed. 2007, 46, 7108. (f) Wang, Z.; Shangguan, N.; Cusick,
J. R.; Williams, L. J. Synlett 2008, 2, 213.
(7) Zhang, Y.; Cusick, J. R.; Shangguan, N.; Katukojvala, S.; Inghrim,
J.; Emge, T. J.; Williams, L. J. J. Org. Chem. 2009, 74, DOI: 10.1021/
jo901320f.
10.1021/ol901948d CCC: $40.75
Published on Web 09/21/2009
 2009 American Chemical Society

1-4 indicate that the position of the HOMO depends upon
the substitution pattern (Figure 1). For trisubstituted silyl
Scheme 1. Model for Stereoselective Spirodiepoxidation
Figure 1. DFT-calculated position of the HOMO of silyl-substituted
allenes.
allene 3, the HOMO resides at the double bond adjacent to
the silyl group and suggests that in the absence of overriding
factors epoxide formation for this type of allene will be
selective for this site as desired.
A preliminary assessment of silyl-substituted allenes and
the resultant spirodiepoxides is presented in Scheme 2 and
address each of these issues simultaneously and in so doing
achieve the selective conversion of allenes to substituted
ketone derivatives.
Scheme 2. Silyl-Directed Spirodiepoxidation
It was not clear at the outset if the presence of a silyl
substituent would successfully address the issues of regio-
and stereoselective allene epoxidation (Scheme 1). The
concern was that the first oxidation of an allene of type IX
might take place at the double bond distal to the silyl group
(IX f X). Since face selectivity in these systems is governed
by steric factors of the nonreacting terminus, the bulk of the
silyl substituent could well render the oxidation face-
selective. However, the second oxidation of the resulting
allene oxide would be expected to be low (X f XII and
XIII), in analogy to the conversion of II to IV and V;
compare this with the alternative scenario wherein the first
oxidation takes place on the double bond bearing the silyl
group (IX f XI). This oxidation should be highly selective
in analogy to I f II, and the second oxidation, XI f XII,
could well be selective due to the bulk of the silyl substituent.
The electronic effects of silyl substitution are well docu-
mented.8 In the context of allene epoxidation, the R-effect
favors the desired outcome (IX f XI), whereas the ꢀ-effect
does not. We evaluated the possibilities computationally.
Density functional calculations9 of silyl-substituted allenes
Table 1. Consistent with the above computational and
stereochemical analysis, exposure of silyl-substituted allene
5 to DMDO/chloroform solutions7 gave spirodiepoxide 6
along with a minor diastereomer (dr ) 10:1) as indicated
by 400 mHz 1H NMR analysis. This highly selective
formation of a spirodiepoxide strongly suggests that the silyl
group dictates site-selective epoxidation of the proximal
allene double bond (dr >20:1) and the stereoselective
epoxidation of the resultant allene oxide (dr ≈ 10:1). Such
spirodiepoxides appear stable toward many nucleophiles that
are known to react readily with nonsilyl spirodiepoxides, such
as water, alcohol, and azide (data not shown). Interestingly,
treatment of 6 with benzoic acid resulted in the selective
formation of R-hydroxy-R′-benzoyl ketone 7 in an overall
(8) For a review of the electronic effects of silyl groups, see: Brook,
M. A. Silicon in Organic, Organometallic, and Polymer Chemistry, 1st ed.;
Wiley: New York, 2000; pp 480-510, and references cited therein.
(9) Geometry optimizations were performed using B3LYP/6-31G* and
the Gaussian 03 program suite. (a) Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A;. Cheeseman, J. R.; Montgomery, Jr.,
J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C. Gaussian 03, ReVision C. 02;
Gaussian, Inc.: Wallingford, CT, 2004 (see the Supporting Information for
the full citation). (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (c) Lee,
C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785.
Org. Lett., Vol. 11, No. 20, 2009
4673

In all cases studied, silyl migration occurred rapidly, and
the use of methanol promoted the loss of silyl altogether.
The conditions for migration leading to 8 and 9 are
remarkably mild. Regardless of solvent, there was no
evidence of the formation of intermediate structures. Al-
though silyl migration is known,12 in this case it appears to
be facilitated by the combination of the geminally positioned
sulfur, nitrogen, or oxygen and the vicinal hydroxyl.
Table 1. Single-Flask Preparation of Functionalized Azolesa
time
yield erb
Encouraged by the above results, we set out to realize the
eliminative opening of spirodiepoxides (XIV f XVII,
Scheme 3). Proteodesilylation of R-hydroxy silyl enones12,13
entry allene
amide
product (h) conditions (%) (%)
1
2
3
4
5
5
5
C6H6CSNH2
C6H6CONH2
C6H6CNHNH2
C6H6CSNH2
C6H6CNHNH2
10
12
13
10
13
12
48
48
24
48
A
A
B
A
B
80
52
72 >95
76 98
78 >95
97
95
5
11
11
a Conditions A: DMDO/CHCl3, -40 °C to rt, 2 h; 3 equiv amide, MeOH,
rt, then 10 mol % p-TSOH, reflux. Conditions B: DMDO/CHCl3, -40 °C
to rt, 2 h; 5 equiv amide, MeOH, rt. b er (enantiomeric ratio) was determined
by chiral HPLC except for entries 3 and 5, which were based on the dr
(diastereomeric ratio) assessed by Mosher ester analysis.
Scheme 3. Silyl-Directed Eliminative Opening
yield of 79%. The efficiency of this reaction was unexpected,
since acids effect decomposition of nonsilyl spirodiepoxides
to many products.6f,10 Structural analysis (1H NMR) supports
the assignment shown and indicates that benzoate added to
the carbon bearing the silyl substituent. Recently, we reported
a method for synthesizing carbinol-functionalized azoles from
spirodiepoxides.6e Accordingly, treatment of the epoxidation
product derived from allene 5 with thiobenzamide in
chloroform gave a 1:1 ratio of carbinol-functionalized
thiazolines 8a and 8b. Under these conditions, the silyl group
migrated to the adjacent oxygen. Use of methanol instead
of chloroform gave a 1:1 ratio of nonsilyl thiazolines 9a and
9b. Dehydrative aromatization of thiazolines 8 and 9 gave a
single thiazole (10). Crystallographic analysis of 8a con-
firmed the structure of the thioamide and by analogy 6-10,
12, and 13 (Table 1). Thus, silyl substitution dictates both
regio- and stereoselectiVe allene epoxidation and subsequent
regioselectiVe opening of the spirodiepoxide intermediate.
Table 1 catalogs data related to the behavior of enantioen-
triched allenes 5 and 11 and their stereoselective, single-
flask conversion to azoles of types 10, 12, and 13. The
enantiomeric ratios of the products are excellent and reflect
the stereoselectivity of spirodiepoxide formation. Addition
of thiobenzamide and benzamidine gave good yields of
thiazole and imidazole. Benzamide reacted, albeit slowly,
with the spirodiepoxide derived from 5 to give oxazole 12
in modest yield but did not react under these conditions with
the spirodiepoxide derived from 11. The addition is slow in
comparison to addition to nonsilyl spirodiepoxides. This is
despite the presense of methanol, an additive known to
facilitate spirodiepoxide opening.6b,d,11
and site-selective eliminative opening of silyl-substituted
epoxides are known.14,15 We examined this type of elimina-
tion for spirodiepoxides derived from 5, 14, and 15 (Table
2). Brønsted and Lewis acids in polar solvent were found to
effect enone formation (entries 1-3). Interestingly, so did
cyclopentadienyltitanium(IV) chloride in combination with
zinc dust (compare entries 1-3 with 4-6).16,17
In contrast to the titanium-mediated reaction, which favors
the R′-hydroxy-Z-enone product (16-18), the organolithium
and Grignard reagents gave R,ꢀ-dihydroxy olefins directly
(19-21, entries 7-12). Athough difficult to rationalize, the
E/Z selectivity appears to depend on both the substrate
structure and the reagents employed. When methyllithium
was used 21 was isolated in excellent yield (entry 9). The
E/Z geometry strongly favored the E product. No evidence
of the isomeric tertiary alcohol was obtained as only the
(12) (a) Brook, A. G. Acc. Chem. Res. 1974, 7, 77. (b) Moser, W. H.
Tetrahedron 2001, 57, 2065, and references cited therein. (c) Hudrlik, P. F.;
Misra, R. N.; Withers, G. P.; Hudrlik, A. M.; Rona, R. J.; Arcoleo, J. P.
Tetrahedron Lett. 1976, 1453. (d) Hudrlik, P. F.; Schwartz, R. H.; Kulkarni,
A. K. Tetrahedron Lett. 1979, 2233. (e) Hudrlik, P. F.; Nagendrappa, G.;
Kulkarni, A. K.; Hudrlik, A. M. Tetrahedron Lett. 1979, 2237.
(13) (a) Hudrlik, P. F.; Schwartz, R. H.; Hogan, J. C. J. Org. Chem.
1979, 44, 155. (b) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K. J. Am.
Chem. Soc. 1982, 104, 6809. (c) Simpson, G. L.; Heffron, T. P.; Merino,
E.; Jamison, T. F. J. Am. Chem. Soc. 2006, 128, 1056
.
(14) Of special note is the work by Marshall, which constitutes the only
example of eliminative opening of silyl spirodiepoxides. (a) Marshall, J. A.;
Tang, Y. J. Org. Chem. 1993, 58, 3233. (b) Marshall, J. A.; Tang, Y. J.
Org. Chem. 1994, 59, 1457
.
(10) (a) Crandall, J. K.; Machleder, W. H. Tetrahedron Lett. 1966, 48,
6037. (b) Crandall, J. K.; Machleder, W. H. J. Am. Chem. Soc. 1968, 90,
7292. (c) Crandall, J. K.; Machleder, W. H.; Thomas, M. J. J. Am. Chem.
Soc. 1968, 90, 7346. (d) Crandall, J. K.; Conover, W. W.; Komin, J. B.;
(15) Hudrlik, P. F.; Tafesse, L.; Hudrlik, A. M. J. Am. Chem. Soc. 1997,
119, 11689
.
(16) (a) Nugent, W. A.; RajanBabu, T. V. J. Am. Chem. Soc. 1988,
110, 8561. (b) Barrero, A. F.; Oltra, J. E.; Cuerva, J. M.; Rosales, A. J.
Org. Chem. 2002, 67, 2566. (c) Cuerva, J. M.; Justicia, J.; Oller-Lo´pez,
Machleder, W. H. J. Org. Chem. 1974, 39, 1723
.
(11) Even though methanol was used as solvent no detectable addition
of benzamide, or methanol, was observed (entry 1, Table 1). Solvolytic
spirodiepoxide opening is known for non-silyl-substituted spirodiepoxides;
however, silyl-substituted spirodiepoxides do not undergo ring opening in
alcohols even upon exposure for several days.
J. L.; Bazdi, B.; Oltra, J. E. Mini-ReV. Org. Chem. 2006, 3, 23.
(17) Other reagents surveyed for the eliminative opening, DBU, Et3N,
DIPEA, LDA, NaOH, KO-t-Bu, NaOAc, AcOH, HCl, Cy2BCl, PTSA, LiCl,
and LiClO4, failed to give the desired product or gave results inferior to
those shown in Table 2
.
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Org. Lett., Vol. 11, No. 20, 2009

Table 2. Spirodiepoxide Eliminative Opening
entry
allene
reagent
PTSA
MgBr2, Et3N
SiO2
Cp2TiCl2, Zn
Cp2TiCl2, Zn
Cp2TiCl2, Zn
CH3Li
CH3Li
CH3Li
CH3MgBr
CH3MgBr
CH3MgBr
conditions
product (E/Z)
yield (%)
1
2
3
4
5
6
7
8
9
14
14
14
14
5
15
14
5
CHCl3, -78 °C, 1 h
DCM, -40 °C, 2 h
CHCl3, rt, 6 h
17
17
17
17
16 (1:1)
18 (1:5)
20
19 (2.2:1)
21 (16:1)
20
58
54
60
66
72
74
85
83
86
48
40
38
THF, -60 °C, 10 min
THF, -60 °C, 10 min
THF, -60 °C, 10 min
Et2O, -40 °C to rt, 2 h
Et2O, -40 °C to rt, 2 h
Et2O, -40 °C to rt, 2 h
Et2O, -78 to 0 °C, 2 h
Et2O, -78 to 0 °C, 2 h
Et2O, -78 to 0 °C, 2 h
15
14
5
10
11
12
19 (1:3.4)
21 (1:12)
15
chelation controlled addition product was observed. Crystal-
lographic analysis of this product established the relative
stereochemistry and confirmed the olefin geometry assign-
ment. Methyl magnesium bromide, however, gave 21 favor-
ing Z enone albeit in lower yield.
with methyllithium in ether, and then proteodesilation13 in
acetonitrile gave 25 as a single isomer in 69% yield. This
sequence was run in a single flask. Although direct olefin
cross-metathesis of 25 with 28 failed to give the desired
product, the synthesis was nevertheless completed in a second
single-flask procedure. Olefin metathesis with acrolein and
catalyst 2620 (f 27) followed by Wittig olefination21 gave
22 as a single isomer in excellent overall yield. The structural
characteristics of synthetic 22 were identical to the published
NMR and optical rotation data for natural epi-citreodiol, e.g.,
[R]23 -7.5 (c ) 2.3, CHCl3), lit.5 [R]21 -7.1 (c ) 2.3,
Lastly, we used silyl-substituted allenes in the first total
synthesis of epi-citreodiol (22, Scheme 4). This natural
Scheme 4. Synthesis of epi-Citreodiol
D
D
CHCl3). Thus direct entry to this natural product was realized
without recourse to protecting group strategies with high
efficiency and selectively via the silyl-subsituted spirodiep-
oxide.
In summary, preliminary assessment of silyl substituted
allenes reveals that this arrangement is an excellent means
by which to control regio- and stereoselective spirodiepoxide
formation. Moreover, silyl-substituted spirodiepoxides are
shown to undergo subsequent site-selective nucleophilic and
eliminative opening. Further studies are ongoing and will
be reported in due course.
Acknowledgment. The NIH (GM-078145) is gratefully
acknowledged.
Supporting Information Available: Synthetic methods
and characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
product was isolated, along with citreodiol, from the myce-
lium of Penicillium citreoViride B. (IFO 6050)5 and is related
to the potent inhibitor of ATP-synthesis and ATP-hydrolysis,
citreoviridin (23).18 Our synthesis began with known allene
24.19 Exposure of 24 to DMDO in chloroform, treatment
OL901948D
(19) Available in three steps from commercial reagents. See: Buckle,
M. J. C.; Fleming, I.; Gil, S.; Pang, K. L. C. Org. Biomol. Chem. 2004, 2,
749.
(20) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2000, 122, 8168.
(18) Sakabe, N.; Goto, T.; Hirata, Y. Tetrahedron 1977, 33, 3077.
(21) Kishi, Y.; Johnson, M. R. Tetrahedron Lett. 1979, 20, 4347.
Org. Lett., Vol. 11, No. 20, 2009
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