Communications
Scheme 3. Synthesis of the key oxatricyclic diols 8. Reagents and
conditions: a) l-(+)-diethyl tartrate, Ti(OiPr) , tert-butylhydroperoxide,
4
Scheme 4. Synthesis of (ꢀ)-englerins A (1) and B (2). Reagents and
conditions: a) CrO (2,5-dimethylpyrazole) (3 equiv), CH Cl , 238C, 2 h,
CH Cl , ꢀ408C, 5 h, 99%, 95:5 e.r.; b) CCl , PPh , 808C, 6 h, 84%;
2
2
4
3
c) nBuLi (3.5 equiv), THF, ꢀ408C, 2 h, 98%; d) TESOTf, Et N, CH Cl ,
3
2
2
3
2
2
7
3%; b) WCl (2 equiv), nBuLi (4 equiv), THF, 0 to 508C, 2 h, 82%;
2
38C, 3 h, quant; e) AD-mix-a, tBuOH/H O (1:1), 238C, 10 h, 98%;
6
2
c) 18 (30 mol%), H (80 bar), CH Cl , 238C, 4 days, quant (1:1 d.r.);
f) NaIO /SiO , CH Cl , 238C, 10 h 99%; g) 12 (1.6 equiv), benzene,
2
2
2
4
2
2
2
d) cinnamoyl chloride (3 equiv), DMAP (3 equiv), CH Cl /Et N (2:1),
reflux, 2 days, 76%; h) 14 (1.2 equiv), 15 (5 mol%), CH Cl , ꢀ788C,
2
2
3
2
2
8
08C, 4 h, 100%; e) TBAF, 238C, CH Cl , 6 h, 91% (yield over 2
4
h, 91% (>14:1 d.r.); i) [IPrAuNCPh]SbF (3 mol%), CH Cl , 238C,
2 2
6
2
2
steps); f) 20 (1.1 equiv), 2,4,6-trichlorobenzoyl chloride, DMAP, tolu-
ene, 08C, 1 h, 96%; g) TBAF, HOAc, CH Cl , 238C, 3 h, 90%.
5
h, 58%; j) TBAF, CH Cl , 238C, 10 h, 89%; k) TBSCl, DMAP, imida-
2
2
zole, 238C, 10 h, CH
2
Cl
2
, 238C, quant. DMAP=4-dimethylaminopyr-
2
2
ꢀ
ꢀ
3 4
BArF =(3,5-(CF ) C H ) B , Cy=cyclohexyl, TBDPS=tert-butyldiphe-
idine, IPr=1,3-bis(2,6-diisopropylphenyl)imidazolidene, TBAF=tetra-n-
butylammonium fluoride, TBS=tert-butyldimethylsilyl, TES=triethyl-
silyl, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran.
3
2
6
nylsilyl.
+
ꢀ
(
5 mol%) in CH Cl at ꢀ788C gave b-hydroxy ketone 5 (91%
rearrangement of 8c using TEMPO BF4 or TEMPO/NaIO4/
SiO2 (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyloxy, free
2
2
yield). Analysis of both (R)- and (S)-Mosher esters of 5
showed that the aldol reaction had proceeded with > 14:1 d.r.
This route is amenable to scale-up and 5–6 g of 5 was
routinely prepared. Remarkably, after testing a number of
protected derivatives of aldol 5 in gold(I)-catalyzed reactions,
we found that the best results were obtained by using
unprotected aldol
(
reaction conditions, oxatricyclic derivative 8a was obtained as
a single diastereomer in 58% yield, which corresponds to a
[
13,14]
radical) was not successful.
Reduction of 16 with WCl6
and nBuLi gave 17 in 82% yield. Catalytic hydrogenation
of the tetrasubstituted olefin of 17 using H /Raney Ni gave
exclusively diastereomer 19’. However, Pfaltzꢀs Ir catalyst
18 allowed us to partially overcome the steric bias of this
olefin and led to a separable 1:1 mixture of 19 and 19’ in
quantitative yield. The configuration of crystalline 19 was
confirmed by X-ray crystal structure analysis. Esterification
of the secondary alcohol of 19 with cinnamoyl chloride and
desilylation with TBAF led to (ꢀ)-englerin B (2; 91% yield
over 2 steps). The final esterification of 2 was achieved by
treatment with TBDPS-protected glycolic acid 20 under
[
15]
2
I
[16]
[9]
5 with catalyst [IPrAuNCPh]SbF6
3 mol%) at room temperature in CH Cl . Under these
2
2
[
10]
6
7% yield based on the major 5R,10S stereoisomer of aldol 5.
This reaction was usually performed in a 0.5–1 g scale. Other
catalysts gave poor results. Desilylation with TBAF provided
diol 8b (89% yield), whose structure was confirmed by X-ray
crystal structure analysis.
secondary alcohol of 8b gave 8c quantitatively, which
showed > 99% ee.
[
17]
Yamaguchi conditions
(96% yield), and subsequent
removal of the protecting group on the primary alcohol
with TBAF buffered with HOAc (90% yield). The H and
C NMR spectra and the optical rotations of synthetic 1 and 2
[
10]
Selective protection of the
1
1
3
[
1,18]
The isomerization of 8c into 17 was performed in two
matched with those reported for natural products.
[
5]
steps by an oxidation/reduction protocol (Scheme 4). Thus,
the treatment of 8c with CrO and 2,5-dimethylpyrazole
gave epoxy alcohol 16 in 73% yield. When the reaction was
carried out with Collins reagent 16 was afforded in similar
yield (71% yield), along with the corresponding epoxy ketone
We have completed the total synthesis of the natural
enantiomers of englerins A (1) and B (2) by a route that is
efficient (for 1: 18 steps and 7% overall yield from geraniol),
easily scalable, and provides access to intermediates such as
19 that could be used for the preparation of a variety of
analogues. This synthesis takes advantage of a stereoselective
aldol reaction developed by Denmark and features a remark-
[11]
3
[
12]
(
(
17% yield), which was quantitatively transformed into 16
88% yield over 2 steps) with NaBH and CeCl . Oxidative
4
3
3
518
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 3517 –3519