Asymmetric total syntheses of (-)-variabilin and (-)-glycinol

Article abstract of DOI:10.1021/ol201332u

Total syntheses of (-)-variabilin and (-)-glycinol have been accomplished, using the catalytic, asymmetric "interrupted" Feist-Benary reaction (IFB) as the key transformation to introduce both stereogenic centers. A monoquinidine pyrimidinyl ether catalyst affords the IFB products in over 90% ee in both cases. Other key steps include an intramolecular Buchwald-Hartwig coupling and a nickel-catalyzed aryl tosylate reduction.

Full text of DOI:10.1021/ol201332u

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3686–3689
Asymmetric Total Syntheses of
(ꢀ)-Variabilin and (ꢀ)-Glycinol
Michael A. Calter* and Na Li†
Department of Chemistry, Wesleyan University, Middletown, Connecticut 06459,
United States
mcalter@wesleyan.edu
Received May 17, 2011
ABSTRACT
ꢀ
Total syntheses of (ꢀ)-variabilin and (ꢀ)-glycinol have been accomplished, using the catalytic, asymmetric “interrupted” FeistꢀBenary reaction
(IFB) as the key transformation to introduce both stereogenic centers. A monoquinidine pyrimidinyl ether catalyst affords the IFB products in over
90% ee in both cases. Other key steps include an intramolecular BuchwaldꢀHartwig coupling and a nickel-catalyzed aryl tosylate reduction.
Variabilin (1a) and glycinol (1b) are members of the
phytoalexin family produced by certain plants in response
to fungal infection (Figure 1).1,2 Naturally occurring var-
iabilin occurs as the (þ)- and (ꢀ)-enantiomers, both of
which show antifungal activity toward Monilinia fructicola
(ED50 < 2 ꢁ 10ꢀ5 M).3 (ꢀ)-Glycinol was first isolated in
1978 by Lyne and Mulheirn from copper-treated soybean
cotyledons.4 It is believed that glycinol is the key precursor
in the biosynthesis of glyceollins.5 Burow et al. have
recently shown that glycinol exhibits a strong in vitro
estrogenic effect by binding to both estrogen receptor
ERR (IC50 = 13.75 nM) and ERβ (IC50 = 9.05 nM).6
Figure 1. Structures of variabilin (1a) and glycinol (1b).
† Present address: APAC Pharmatech Co., Ltd., Building 5, 2358 Chan-
gAn Road, Wujiang, Jiangsu, PR China 215222.
(1) (a) Bilton, J. N.; Debnam, J. R.; Smith, I. M. Phytochemistry
To date, only one asymmetric total synthesis of each
target has been accomplished, both of which set the stereo-
genic centers by asymmetric dihydroxylation in the pre-
sence of stoichiometric amounts of OsO4 and quinine or
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~
Gottlieb, O. R. Phytochemistry 1978, 17, 1417–1418. (c) Magalhaes,
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A. F.; Tozzi, A. M. G.A.; Magalhaes, E. V.; Sannomiya, M.; Soriano,
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(2) Banks, S. W.; Dewick, P. M. Phytochemistry 1983, 22, 2729–2733.
(3) Perrin, D. R.; Cruickshank, I. A. M. Phytochemistry 1969, 8, 971–
978.
(4) Lyne, R. L.; Mulheirn, L. J. Tetrahedron Lett. 1978, 34, 3127–
3128.
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Williams, K. Y.; Payton-Stewart, F.; Miraflor, A. P.; Howell, M. H.;
Shih, B. Y.; Carter-Wientjes, C. H.; Segar, C.; Beckman, B. S.; Wiese,
T. E.; Cleveland, T. E.; McLachlan, J. A.; Burow, M. E. Endocrinology.
2009, 150, 2446–2453.
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2001, 57, 7113–7126. (b) Luniwal, A.; Khupse, R. S.; Reese, M.; Fang,
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J. Ann. Rev. Phytopathol. 1986, 24, 235–264. (e) Matthews, D. E.;
Plattner, R. D.; VanEtten, H. D. Phytochemistry 1989, 28, 113–115.
r
10.1021/ol201332u
Published on Web 06/13/2011
2011 American Chemical Society

quinidine derivatives.7 Here, we report total syntheses of
both 1a and 1b, using the catalytic, asymmetric “inter-
rupted” FeistꢀBenary (IFB) reaction developed by Calter
et al. to install the chirality into the target molecules
(Scheme 1).8 Completion of the synthesis would then
involve aromatization, intramolecular BuchwaldꢀHartwig
reaction to form the benzopyranoid ring, tosylate reduc-
tion, and finally deprotection in the case of glycinol. The
IFB reactions would require dione nucleophiles 2a or 2b
and the β-bromo-R-ketoester electrophiles 3a or 3b, which
were all either known compounds or close analogues.
in the presence of base produced keto ester 7, which was
subjected to Dieckmann condensation to give 2a in 47%
overall yield.
Pyruvate 3a was synthesized according to a well docu-
mented procedure beginning with the lithium trimethy-
lethylenediamine-directed ortho-bromination of p-
anisaldehyde to produce bromoaldehyde 8 (Scheme 3).10
Submission of 8 to a Darzens reaction led to epoxide 9,
which was converted into β-bromo-R-ketoester 3a by
treatment with MgBr2.9
Scheme 3. Synthesis of Pyruvate 3a
Scheme 1. Retrosynthetic Plan for 1a and 1b
With 2a and 3a in hand, the IFB reaction proceeded
smoothly with monoquinidine pyrimidinyl ether 10 as a
catalyst and provided 11 as an inseparable 8.5:1 E/Z
mixture of diastereomers (Scheme 4). Exposure of 11 to
iodobenzene bis(trifluoromethylacetate) (PIFA) produced
the corresponding, unstable dimethoxy acetal,11 which was
subjected to LiHMDS to give unstable phenol 13. Both 12
and 13 were prone to elimination to form the correspond-
ing furans. Tosylation of 13 afforded tosylate 14, still as a
mixture of diastereomers. However, we were able to use
analytical HPLC to determine the enantio- and diastereo-
purity of 14.
The synthesis of dithiane 2a began with the addition of
lithium propiolate with propylene oxide in the presence of
BF3 Et2O to afford alkynyl alcohol 4 (Scheme 2). Oxida-
3
tion of 4 with the Swern reagent or the DessꢀMartin
periodinane provided multiple products. A successful oxi-
dant was silica-gel-supported Jones reagent (SJR), which
gave a mixture of alkyne 5 and allene 6 in quantitative yield
after filtration. Compound 5 was the major initial product
of the reaction but converted into 6 at ꢀ25 °C in under 12
h. Addition of 1,3-propanedithiol to the mixture of 5 and 6
We were initially surprised with the (E)-selectivity of the
IFB reaction of 2a and 3a, as previous examples had
provided (Z)-selectivity, but further analysis of factors
governing the diastereoselectivity of the IFB reaction
provided a rationale (Figure 2). In general, the IFB
reaction of substituted bromoketoesters proceeds via a
dynamic, kinetic resolution, with tetrabutylammonium
iodide (TBAI) serving to convert the bromide into the
corresponding iodide and then constantly racemize this
compound. The previous examples using unsubstituted
aryl substituents yielded the (Z)-R,R-product, with both
the catalyst and the substrate favoring attack, via a
Scheme 2. Synthesis of Dithiane 2a
(8) Calter, M. A.; Phillips, R. M.; Flaschenriem, C. J. Am. Chem. Soc.
2005, 127, 14566–14567.
(10) (a) Tsuboi, S.; Furutani, H.; Takeda, A.; Kawazoci, K.; Sato, S.
Bull. Chem. Soc. Jpn. 1987, 2475–2480. (b) Coutrot, P.; Legris, C.
Synthesis 1975, 2, 118–120.
(9) (a) Merz, K.-H.; Muller, T.; Vanderheiden, S.; Eisenbrand, G.;
Marko, D.; Brase, S. Synlett 2006, 20, 3461–3463. (b) Lear, Y.; Durst, T.
Can. J. Chem. 1997, 75, 817–824. (c) Comins, D. L.; Brown, J. D. J. Org.
Chem. 1984, 49, 1078–1083.
(11) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287–290.
(12) (a) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem.
Soc. 2000, 122, 10718–10719. (b) Torraca, K. E.; Kuwabe, S.-I.;
Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907–12908.
Org. Lett., Vol. 13, No. 14, 2011
3687

Initial attempts to reduce 18 using the conditions of
Lipshutz and Kogan afforded 1a, but with irreproducible
conversions.13 After experimenting with different hydride
and nickel sources, we found that use of the THF-soluble
LiBH4 and the formation of nickel(0) from in situ reduc-
tion of NiCl2 reliably afforded variabilin 1a. The analytical
data for the product matched those reported previously for
(ꢀ)-variabilin.7a In total, this synthesis required 11 steps
with 5.7% overall yield. The bis-demethylation of varia-
bilin 1a into glycinol 1b afforded the furan under Lewis
acidic conditions and gave low and irreproducible con-
version under nucleophilic conditions. Therefore, we
developed an alternative synthesis of glycinol that em-
ployed more easily removable protecting groups from the
beginning.
Scheme 4. Synthesis of Tosylate 14
Scheme 5. Synthesis of Variabilin 1a
transition state favored by the FelkinꢀNguyen model with
a strongly electron-withdrawing substituent, on the Re-
face of the (S)-enantiomer of the haloketeoester. However,
the ortho-substituent in the current substrate sterically
disfavors this mode of attack, so the substrateꢀcatalyst
combination now favors Re-face attack on the R-enantio-
mer, leading to the (E)-R,S-stereoisomer. The ortho-bro-
mine cannot rotate away from this interaction, as to do so
would place the bromine in an electronically unfavorable
interaction with the carbonyl oxygen or the iodine.
This synthesis of glycinol began with the construction of
1,3-dioxane 2b (Scheme 6). Treatment of acetonedicar-
boxylic acid 19 with TMSO(CH2)3OTMS in the presence
of a catalytic amount of TMSOTf yielded 20.14 Exposure
of 20 to MeMgBr in CH2Cl2 at ꢀ78 °C for 12 h afforded
keto ester 21 in moderate conversion, but we were able
to recover the unreacted starting material. Dieckmann
condensation of 21 promoted by LDA provided 2b into
a similar fashion to the cyclization of 7 to 2a.
Scheme 6. Synthesis of Dioxane 2b
Figure 2. Transition-state models for the IFB reaction. Catalyst
omitted for clarity.
Continuing with the synthesis, the reduction of 14 first
provided the aldehyde, which was then immediately re-
submitted to a second reduction to afford 1,2-diol 15
(Scheme 5). Exposure of 15 to modified Buchwaldꢀ
Hartwig coupling conditions gave dihydrobenzopyran
18, which we were able to isolate in high diastereopurity.12
(14) Arnott, G.; Heaney, H.; Hunter, R.; Page, P. C. B. Eur. J. Org.
Chem. 2004, 5126–5234.
(13) (a) Lipshutz, B. H.; Frieman, B. A.; Butler, T.; Kogan, V. Angew.
Chem., Int. Ed. 2006, 45, 800–803. (b) Kogan, V. Tetrahedron Lett. 2006,
47, 7515–7518.
(15) (a) Bevan, M. F.; Euerby, R. M.; Qureshi, J. S. J. Chem. Res.
(M) 1989, 901–920. (b) Couture, A.; Deniau, E.; Lebrum, S.; Hoarau,
C.; Grandclaudon, P. Nat. Prod. Lett. 1999, 13 (1), 33–40.
3688
Org. Lett., Vol. 13, No. 14, 2011

We prepared β-bromo-R-ketoester 3b through known
bromoaldehyde 22 (Scheme 7).15 Addition of N,N0- di-
methylethylenediamine to 4-hydroxylbenzaldehyde in re-
fluxing toluene afforded the aminal. ortho-Metalation,
bromination, and hydrolysis provided aldehyde 22, which
was benzylated to give 23. Submission of 23 to the Darzens
reaction and subsequent ring opening afforded 3b.
Two-stage reduction of 27 with LiBH4 gave diol 28,
which was subjected to our modified BuchwaldꢀHartwig
conditions to give dihydropyran 29 (Scheme 9). Reduction
of the aryl tosylate afforded alcohol 30. We accomplished
removal of the propylene glycol group from 30 by oxida-
tion with DMP followed by elimination with NEt3. Final-
ly, deprotection of the aryl benzyl group by transfer
hydrogenation provided (ꢀ)-glycinol 1b in 90% yield.
The analytical data for this product matched those
reported previously for (ꢀ)-glycinol.4,7b This synthesis
required 13 steps with 3.0% overall yield.
Scheme 7. Synthesis of Bromoketone 3b
Scheme 9. Synthesis of Glycinol 1b
The IFB reaction of 2b and 3b proceeded smoothly with
10 as the catalyst and provided 25 in a 10:1 E/Z ratio
(Scheme 8). In this series chromatography allowed us to
remove most of the (Z)-diastereomer. Aromatization of 25
with tBuOK followed by tosylation afforded tosylate 27.
We were able to use analytical HPLC to determine the
enantio- and diastereopurity of this compound.
In conclusion, we have accomplished the catalytic,
asymmetric total syntheses of (ꢀ)-variabilin and (ꢀ)-gly-
cinol by employing the “interrupted” FeistꢀBenary reac-
tion as the key step to introduce both stereogenic centers
simultaneously. Both syntheses proceed in high enantio-
and diastereoselectivity. The methodology developed
should be applicable to the syntheses of other natural
products with dihydrobenzofuran moieties.
Scheme 8. Synthesis of Tosylate 27
Acknowledgment. The authors thank the NIH for
financial support of this project. We acknowledge
Dr. Ryan Phillips (IRIX Pharmaceuticals) for preliminary
experiments.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 14, 2011
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