Total synthesis of englerin A

Article abstract of DOI:10.1021/ja102927n

Total synthesis of englerin A, a recently reported sesquiterpenoid exhibiting potent and selective growth inhibition against renal cancer cell lines, has been accomplished. The successful strategy featured a [5±2] cycloaddition reaction to cast the seven-membered oxabicyclic key intermediate in both racemic and optically active forms. Synthetic (±)-englerin A, (±)-englerin B, (±)-englerin B acetate, a hydroxy acetate, a tert-butyldimethylsilyl ether, and hydrogenated (±)-englerin A (31) were tested for their cytotoxicity against a selected panel of cancer cell lines, and the results are path-pointing to more focused structure-activity relationship studies.

Full text of DOI:10.1021/ja102927n

Published on Web 05/24/2010
Total Synthesis of Englerin A
K. C. Nicolaou,* Qiang Kang, Sin Yee Ng, and David Y.-K. Chen*
Chemical Synthesis Laboratory@Biopolis, Institute of Chemical and Engineering Sciences
(ICES), Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, The Helios
Block, #03-08, Singapore 138667
Received April 14, 2010; E-mail: kcn@scripps.edu; david_chen@ices.a-star.edu.sg
Abstract: Total synthesis of englerin A, a recently reported sesquiterpenoid exhibiting potent and selective
growth inhibition against renal cancer cell lines, has been accomplished. The successful strategy featured
a [5 + 2] cycloaddition reaction to cast the seven-membered oxabicyclic key intermediate in both racemic
and optically active forms. Synthetic (()-englerin A, (()-englerin B, (()-englerin B acetate, a hydroxy acetate,
a tert-butyldimethylsilyl ether, and hydrogenated (()-englerin A (31) were tested for their cytotoxicity against
a selected panel of cancer cell lines, and the results are path-pointing to more focused structure-activity
relationship studies.
Introduction
Englerin A (1, Figure 1) is a newly discovered guaiane
sesquiterpene from the stem bark of Phyllanthus engleri collected
in Tanzania.1 Its importance derives from its potent and selective
growth inhibitory (GI) activities against renal cancer cells (i.e., 786-
O, A498, ACHN, RXF-393, VO-31, GI50 < 20 nM, ca. 1000-fold
selectivity as compared to most other cancer cell lines of the NCI-
60 panel tested).1 Its unique structure includes a tricyclic motif
carrying two esters, one to a cinnamic acid (C6, englerin A
numbering) and the other to a glycolic acid (C9) residue. The latter
is apparently crucial for its potency and selectivity, since englerin
B (2, Figure 1) and englerin B acetate (3, Figure 1) showed
significant loss of potency and selectivity toward renal cancer cells.1
Intrigued by the structure and biological properties of englerin A
(1) as a lead compound for drug discovery, we initiated a program
directed at its total synthesis. Herein we report the total synthesis
of englerin A [(()-1], englerin B [(()-2], and englerin B acetate
[(()-3] from simple starting materials. In addition, a formal
asymmetric synthesis of these compounds has also been ac-
complished by reaching a late-stage key intermediate in its optically
active form.2
Figure 1. Structures of (-)-englerin A [(-)-1], (-)-englerin B [(-)-2],
and (-)-englerin B acetate [(-)-3].
[5 + 2] cycloaddition reaction played the key role in the
formation of the bicyclo[3.2.1] ring framework of the molecule.
The envisioned [5 + 2] cycloaddition reaction between oxopy-
rilium species 5 and ethyl acrylate (6) was expected to lead to
oxabicyclic enone 4 in its racemic form, whereas an asymmetric
synthesis of either enantiomer of the natural product could, in
principle, arise through the use of this venerable reaction
engaging chiral sulfonamide acrylate derivative 7 or its enan-
tiomer.
Construction of Oxabicyclic Hydroxy Ketoester 16. The
synthesis of hydroxy ketoester 16 commenced from the readily
available propargylic alcohol 8,3 whose regioselective iodination
(Red-Al, I2) led to vinyl iodide 9 (87% yield) (Scheme 2).
Coupling of the latter intermediate with trimethylsilyl (TMS)
acetylene [Pd(PPh3)4 cat.] furnished enyne 10, from which the
TMS group was removed (K2CO3, MeOH) to afford hydroxy
enyne 11 (89% yield for the two steps). Gold-catalyzed ring
closure of 11 (Ph3PAuCl, AgOTf)4 then generated furan system
12 in 91% yield. Formylation of the latter compound (POCl3,
DMF)5 led to aldehyde 13 (88% yield), which reacted with
i-PrMgCl to afford hydroxy furan 14. The latter intermediate
Results and Discussion
Retrosynthetic Analysis. Scheme 1 shows, in retrosynthetic
format, the key carbon-carbon bond disconnections employed
to devise the synthetic strategy toward englerin A (1) [and
therefore englerin B (2) and englerin B acetate (3)], in which a
(1) (a) Ratnayake, R.; Covell, D.; Ransom, T. T.; Gustafson, K. R.; Beutler,
J. A. Org. Lett. 2009, 11, 57–60. (b) Beutler, J. A.; Ratnayake, R.;
Covell, D.; Johnson, T. R. WO2009/088854, 2009.
(2) A recent synthesis of ent-englerin A [(+)-1] from the natural product
cis,trans-nepetalactone has recently been reported; it proved the
absolute configuration of englerin to be that depicted by structure
(-)-1: (a) Willot, M.; Radtke, L.; Ko¨nning, D.; Fro¨hlich, R.; Gessner,
V. H.; Strohmann, C.; Christmann, M. Angew. Chem., Int. Ed. 2009,
48, 9105–9108. For total synthesis of (-)-1, see: (b) Zhou, Q.; Chen,
X.; Ma, D. Angew. Chem., Int. Ed. 2010, 49, 3513–3516. (c) Molawi,
K.; Delpont, N.; Echavarren, A. M. Angew. Chem., Int. Ed. 2010, 49,
3517–3519.
(3) Nicolaou, K. C.; Veale, C. A.; Webber, S. E.; Katerinopoulos, H. J. Am.
Chem. Soc. 1985, 107, 7515–7518.
(4) Du, X.; Song, F.; Lu, Y.; Chen, H.; Liu, Y. Tetrahedron 2009, 65,
1839–1845.
(5) Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1–330.
9
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J. AM. CHEM. SOC. 2010, 132, 8219–8222 8219

A R T I C L E S
Nicolaou et al.
Scheme 1. Retrosynthetic Disconnection of Englerin A (1) Leading
to Oxabicyclic Enone 4, Oxopyrilium Species 5, Ethyl Acrylate (6),
and Chiral Sulfonamide Acrylate Derivative 7
Table 1. [5 + 2] Cycloaddition Reaction between Lactol 15 and
Ethyl Acrylate (6) Leading to Oxabicyclic Enone 4a
yield
(%)e
f
entry
conditions
C9ꢀ:C9R
1
i-Pr2NEt (1.2 equiv), toluene (0.15 M), 3 h
i-Pr2NEt (1.2 equiv), THF (0.15 M), 3 h
i-Pr2NEt (1.2 equiv), CH3CN (0.15 M), 3 h
47
5:1
2
3
4
UMg
50
1.5:1
i-Pr2NEt (1.2 equiv), ClCH2CH2Cl (0.15 M), UMg
3 h
5b
6
i-Pr2NEt (1.2 equiv), additive (1.0 equiv),
toluene (0.15 M), 3 h
i-Pr2NEt (1.2 equiv), LiCl (1.0 equiv),
toluene (0.15 M), 3 h
UMg
25
3.3:1
7c
i-Pr2NEt (1.5 equiv), toluene (0.13 M), 3 h
i-Pr2NEt (1.5 equiv), CH2Cl2 (0.13 M), 3 h
i-Pr2NEt (1.2 equiv), toluene (0.13 M), 3 h
26
19
49
46
5:1
3:1
5:1
8:1
8c
9c,d
10c,d i-Pr2NEt (0.9 equiv), toluene (0.04 M), 3 h
Scheme 2. Synthesis of Oxabicyclic Hydroxy Ketoester 16a
a 15 (1.0 equiv), 6 (10.0 equiv), MsCl (1.2 equiv), 23 °C f reflux.
b Yb(OTf)3, TiCl4, AgOTf, CuCl, and ZnBr2 were used as additives. c A
solution of 15 (1.0 M) was added to the reaction mixture at reflux via
syringe pump over 1 h, giving a final concentration of 0.13 M (entries
7-9) or 0.04 M (entry 10). d 20 equiv of 6 was used. e Yields refer to
chromatographically and spectroscopically homogeneous materials.
f Determined by 1H NMR analysis of the crude reaction mixture.
g Unidentified mixture.
gated, and the results are shown in Table 1. Of the solvents
examined (Table 1, entries 1-4), only toluene (Table 1, entry
1) and CH3CN (Table 1, entry 3) were productive for this
process, giving oxabicyclic enone 4 together with its 9R isomer
(englerin A numbering, separable) in comparable yields (47%
and 50%, respectively) but notably different diastereoselectivity
(C9ꢀ:C9R ca. 5:1 and ca. 1.5:1, respectively). Lewis acidic
additives (Table 1, entry 5) generally led to an unidentifiable
mixture of byproducts, apart from LiCl (Table 1, entry 6), which
led to oxabicyclic system 4 and its 9R isomer (C9ꢀ:C9R ca. 3.3:
1) in 25% yield. A reverse addition protocol [slow addition of
a solution of lactol 15 to a refluxing solution of MsCl, i-Pr2NEt,
and ethyl acrylate (6)] was examined next (Table 1, entries
7-10). Ultimately, the optimized conditions (Table 1, entry 10)
were established by employing substoichiometric amounts of
i-Pr2NEt (0.9 equiv) under high dilution (0.04 M) to furnish
bicycle 4 together with its 9R isomer (C9ꢀ:C9R ca. 8:1) in 46%
yield. Sequential exposure of pure 4 to catalytic hydrogenation
conditions (PtO2, H2; Pd/C, H2) resulted in reduction of the
olefinic bond and cleavage of the benzyl ether to afford,
stereoselectively, hydroxy ketoester 16 in 80% overall yield.
Completion of the Total Synthesis of (()-Englerin A
[(()-1], (()-Englerin B [(()-2], and (()-Englerin B Acetate
[(()-3]. Compound 16 was converted to (()-englerin B acetate
[(()-3], (()-englerin B [(()-2], and (()-englerin A [(()-1],
as shown in Scheme 3. Thus, dehydration of 16 through its
selenide derivative (ArSeCN, n-Bu3P; then m-CPBA, 84%
yield), followed by subjecting the resulting terminal olefin 17
to Wacker oxidation7 conditions (O2, PdCl2 cat., CuCl cat., 86%
yield), afforded diketone 18. Treatment of diketone 18 with
KHMDS at -10 °C, followed by warming the reaction mixture
a Reagents and conditions: (a) Red-Al (70% in toluene, 1.6 equiv), THF,
-15 f 0 °C, 24 h; then EtOAc (1.6 equiv), I2 (1.6 equiv), -78 f 23 °C,
1 h, 87%; (b) trimethylsilyl acetylene (1.5 equiv), Pd(PPh3)4 (0.05 equiv),
CuI (0.2 equiv), Et3N/i-Pr2NEt (2:1), 23 °C, 30 min, 92%; (c) K2CO3 (3.0
equiv), MeOH, 23 °C, 30 min, 97%; (d) Ph3PAuCl (0.02 equiv), AgOTf
(0.02 equiv), THF, 23 °C, 1 h, 91%; (e) POCl3 (1.5 equiv), DMF, 0 f 23
°C, 1 h, 88%; (f) i-PrMgCl (2.0 M in THF, 1.2 equiv), THF, -20 °C, 30
min, 83%; (g) m-CPBA (77% wt/wt, 1.2 equiv), CH2Cl2, 0 °C, 0.5 h, 84%;
(h) MsCl (1.2 equiv), i-Pr2NEt (0.9 equiv), ethyl acrylate (20 equiv), toluene,
1
85 °C, 3 h (8:1 mixture of diastereoisomers by H NMR), 46%; (i) Pt2O
(0.2 equiv), H2 (1 atm), benzene, 24 h, 88%; (j) Pd/C (10% wt/wt, 0.2
equiv), H2 (1 atm), MeOH, 2 h, 91%. Abbreviations: Red-Al, sodium bis(2-
methoxyethoxy)aluminum hydride; EtOAc, ethyl acetate; DMF, N,N′-
dimethylformamide; OTf, trifluoromethanesulfonate; m-CPBA, m-chloro-
peroxybenzoic acid; Ms, methanesulfonyl.
underwent Achmatowicz rearrangement6 upon exposure to
m-CPBA to give ring-expanded lactol 15 (84% yield). With the
stage set for the crucial [5 + 2] cycloaddition reaction, genera-
tion of oxopyrilium species 5 (see Scheme 1) from 15 (MsCl,
i-Pr2NEt) and its reaction with ethyl acrylate (6) were investi-
(6) Achmatowicz, O.; Bielski, R. Carbohydr. Res. 1977, 55, 165–176.
(7) Clement, W. H.; Selwitz, C. M. J. Org. Chem. 1964, 29, 241–243.
9
8220 J. AM. CHEM. SOC. VOL. 132, NO. 23, 2010

Total Synthesis of Englerin A
A R T I C L E S
Scheme 3. Completion of the Total Synthesis of (()-Englerin A
[(()-1], (()-Englerin B [(()-2], and (()-Englerin B Acetate [(()-3]a
Figure 2. X-ray-derived ORTEP of hydroxy ketone 23 with thermal
ellipsoids shown at the 50% probability level.12
Scheme 4. Asymmetric Synthesis of Oxabicyclic Enone 4a
a Reagents and conditions: (a) MsCl (1.2 equiv), i-Pr2NEt (1.2 equiv), 7
(2.0 equiv), toluene, 85 °C, 3 h (2:1 mixture of diastereoisomers by 1H
NMR), 30%; (b) Dibal-H (1.0 M in CH2Cl2, 4.5 equiv), CH2Cl2, -78 °C,
30 min; (c) DMP (1.2 equiv), NaHCO3 (5.0 equiv), CH2Cl2, 23 °C, 30
min, 88% over the two steps; (d) NaClO2 (2.0 equiv), 2-methyl-2-butene
(10.0 equiv), t-BuOH/pH 7 phosphate buffer (1:1), 23 °C, 1 h; (e) H2SO4
(0.1 M in EtOH, 0.1 equiv), EtOH/toluene (1:1), 23 f 80 °C, 6 h, 75%
over the two steps. Abbreviations: Dibal-H, diisobutylaluminum hydride;
DMP, Dess-Martin periodinane.
a Reagents and conditions: (a) 2-nitrophenyl selenocyanate (1.4 equiv),
PBu3 (2.0 equiv), THF, 23 °C, 0.5 h; then m-CPBA (77% wt/wt, 2.0 equiv),
CH2Cl2, 0 °C, 0.5 h; DBU (2.0 equiv), toluene, 80 °C, 8 h, 84%; (b) PdCl2
(0.05 equiv), CuCl (0.2 equiv), O2 (1 atm), DMF/H2O (9:1), 23 °C, 6 h,
86%; (c) KHMDS (0.6 M in toluene, 2.2 equiv), THF, -10 f 0 °C, 2 h,
77%; (d) CeCl3 ·7H2O (2.0 equiv), NaBH4 (2.0 equiv), MeOH, 0 °C, 0.5 h,
95%; (e) Crabtree catalyst (0.3 equiv), H2 (1 atm), CH2Cl2, 12 h, 91%; (f)
MeNHOMe·HCl (4.0 equiv), i-PrMgCl (2.0 M in THF, 10.0 equiv), THF,
-15 f 0 °C, 3 h, 90%; (g) MeLi (4.0 equiv), THF/Et2O (1:1), -78 f
-60 °C, 1.5 h, 73%; (h) m-CPBA (77% wt/wt, 4.0 equiv), 1,2-dichloro-
ethane, 80 °C, 48 h, 65%; (i) cinnamic acid (2.0 equiv), 2,4,6-trichloroben-
zoyl chloride (2.2 equiv), Et3N (4.0 equiv), 4-DMAP (2.6 equiv), toluene,
80 °C, 2 h, 86%; (j) K2CO3 (3.0 equiv), MeOH, 23 °C, 1 h, 92%; (k) 25
(2.0 equiv), 2,4,6-trichlorobenzoyl chloride (2.2 equiv), Et3N (4.0 equiv),
4-DMAP (2.6 equiv), toluene, 80 °C, 1 h, 86%; (l) TBAF (2.0 equiv), THF,
0 °C, 10 min, 89%. Abbreviations: KHMDS, potassium hexamethyldisi-
lazane; TBS, tert-butyldimethylsilyl; 4-DMAP, N,N′-(dimethylamino)pyridine.
oxidation of methyl ketone 23 (m-CPBA, 65% yield), obtained
through Weinreb amide11 22 (MeLi, 73% yield), which in turn
was formed from ethyl ester 21 by reaction with
i-PrMgCl-MeNH(OMe)·HCl (90% yield). Ketone 23 (mp
)161-162 °C, hexane/CH2Cl2) yielded to X-ray crystal-
lographic analysis, confirming its structural assignment as shown
in Figure 2.12 All that separated hydroxy acetate 24 from
englerin A (1) was attachment of the proper ester side chains
on its cyclic framework. To this end, 24 was first coupled with
cinnamic acid through the Yamaguchi protocol13 to afford (()-
englerin B acetate [(()-3] (86% yield), from which the acetate
group was removed (K2CO3) to give (()-englerin B [(()-2]
(92% yield). Installment of the desired glycolic acid residue on
the latter compound proceeded smoothly under Yamaguchi
conditions (86% yield) to afford, upon desilylation (TBAF, 89%
yield), (()-englerin A [(()-1] through intermediate 26. The
physical data of synthetic (()-3, (()-2, and (()-1 matched
to 0 °C, led, through an intramolecular aldol/dehydration
sequence, to enone 19 in 77% yield. Stereoselective reduction
of ketone 19 under Luche8 conditions furnished allylic alcohol
20, which underwent stereoselective hydrogenation (C4-C5
olefinic bond) in the presence of Crabtree’s catalyst9 to afford
tricyclic system 21 in 91% yield and as a single diastereoisomer.
The directing effect of the neighboring hydroxyl group within
20 was crucial in the Crabtree hydrogenation, as confirmed by
the fact that enone 19 underwent hydrogenation (Pd/C, H2) from
the opposite face of the C4-C5 olefinic bond. The desired
oxygenation at C9 was achieved through a Baeyer-Villiger10
(11) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(12) CCDC-771308 contains the supplementary crystallographic data for
compound 20. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(13) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989–1993.
(8) (a) Molander, G. A. Chem. ReV. 1992, 92, 29–68. (b) Luche, J. L.
J. Am. Chem. Soc. 1978, 100, 2226–2227.
(9) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655–2661.
(10) Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625–3633.
9
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A R T I C L E S
Nicolaou et al.
Table 2. Cytotoxicity of (()-Englerin A [(()-1], (()-Englerin B [(()-2], (()-Englerin B Acetate [(()-3], Hydroxy Acetate 24, TBS Ether 26,
and Hydrogenated (()-Englerin A (31) against Selected Cancer Cell Lines (GI50 values in µM)a
cell line
entry
compound
MCF-7b
NCI-H460b
ACHNb
A498b
UO31b
1
2
3
4
5
6
7
8
doxorubicin
Taxol
(()-1
(()-2
(()-3
24
0.066 ( 0.004
0.010 ( 0.000
0.072 ( 0.006
0.076 ( 0.008
0.113 ( 0.071
>10
0.243 ( 0.062
0.078 ( 0.006
0.045 ( 0.004
>10
0.693 ( 0.221
0.721 ( 0.146
0.037 ( 0.005
>10
0.007 ( 0.001
0.006 ( 0.001
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
6.341 ( 0.229
>10
9.275 ( 0.013
>10
>10
>10
0.745 ( 0.166
26
31
>10
0.287 ( 0.139
>10
0.359 ( 0.006
a Antiproliferative effects of tested compounds against human tumor cell lines in a 48 h growth inhibition assay using the sulforhodamine B staining
method. Human cancer cell lines: breast (MCF-7), lung (NCI-H460), and renal (ACHN, A498, and UO31). Growth inhibition of 50% (GI50) is
calculated as the drug concentration which caused a 50% reduction in the net protein increase in control cells during drug incubation. GI50 values for
each compound are given in µM and represent the mean of 2-5 independent experiments ( standard error of the mean. b These cell lines were
provided by the National Cancer Institute (NCI), Division of Cancer Treatment and Diagnosis (DCTD).
Scheme 5. Synthesis of Hydrogenated (()-Englerin A (31)a
were tested against a panel of cancer cells, including breast
(MCF-7), lung (NCI-H460), and renal (ACHN, A498, and
UO31), using doxorubicin and Taxol as standards. The results
are summarized in Table 2. (()-Englerin A [(()-1] demon-
strated high potency and selectivity toward renal cancer cell
lines (Table 2, entry 3). Compounds (()-2, (()-3, 24, and 26
(Table 2, entries 4-7) failed to demonstrate any significant level
of biological activities [except for (()-3, see entry 5], evidence
which further supports the importance of the glycolic acid
residue.1 The most noteworthy finding was that hydrogenated
a Reagents and conditions: (a) Pd/C (10% wt/wt, 0.5 equiv), H2 (1 atm),
MeOH, 3 h, 100%.
(()-englerin A (31, Table 2, entry 8) also demonstrated excellent
selectivity toward renal cancer cells with moderate activities,
suggesting structural tolerance of the saturated cinnamate ester
domain. Future work in this area should serve to uncover more
insightful structure-activity relationship information, particu-
larly concerning the cinnamate and glycolic ester side chains.
(except for optical rotations) those reported for the naturally
derived materials.1
Asymmetric Synthesis of Oxabicyclic Enone 4. Having
secured a racemic entry to (()-englerin A [(()-1] [together with
(()-englerin B [(()-2] and (()-englerin B acetate [(()-3]], as
Conclusion
The described chemistry provides a ready access to englerins
A and B and englerin B acetate (1-3). A formal asymmetric
total synthesis of these compounds has also been demonstrated
through the synthesis of optically active advanced key inter-
mediate bicyclic enone 4. The synthetic strategy employed
features a [5 + 2] cycloaddition reaction of an oxopyrilium
species 5 with appropriate acrylate esters, stereoselective Luche
and Crabtree reductions, and a Baeyer-Villiger oxidation to
secure the tricyclic core onto which the two ester side chains
were attached through Yamaguchi esterifications. Biological
evaluations of selected synthesized compounds provided valu-
able structure-activity relationships for future investigations
toward drug discovery and development in cancer chemotherapy.
outlined in our retrosynthetic blueprint (Scheme 1), an asym-
metric synthesis of oxabicyclic enone 4 through the [5 + 2]
cycloaddition reaction between oxopyrilium species 5 and chiral
sulfonamide acrylate derivative 714 was pursued, as shown in
Scheme 4. Thus, generation of oxopyrilium species 5 (see
Scheme 1) from 15 (MsCl, i-Pr2NEt) in the presence of chiral
sulfonamide acrylate derivative 7 delivered oxabicyclic enones
27 and 28 (30% yield, unoptimized) as a chromatographically
separable mixture (27:28 ca. 1:2). Although ultimately proven
unwarranted, caution was exercised at this stage for possible
epimerization at C9 under basic saponification conditions for
28. Therefore, enone ester 28 was subjected to a two-step
reduction/oxidation (Dibal-H; then DMP) sequence to afford
aldehyde 29 in 88% yield overall yield. Oxidation of aldehyde
29 to acid 30 (NaClO2), followed by esterification of the latter
under acidic conditions (H2SO4, EtOH, 75% yield over the two
steps), proceeded smoothly to furnish optically active enone
ethyl ester (-)-4 [[R]D25 ) -95 (CHCl3, c ) 0.18)]. The 1H and
13C NMR data of (-)-4 were in full agreement with those of
racemic 4 (Scheme 2). The arrival at optically active 4, therefore,
constitutes a formal asymmetric synthesis of (-)-englerin A
[(-)-1], (-)-englerin B [(-)-2], and (-)-englerin B acetate [(-)-
3].
Acknowledgment. K.C.N. is also a member of the Department
of Chemistry and The Skaggs Institute for Chemical Biology, The
Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla,
CA 92037, and the Department of Chemistry and Biochemistry,
University of California, San Diego, 9500 Gilman Dr., La Jolla,
CA 92093. We thank Mr. Rong-Ji Sum (CSL-ICES) for assistance
in the biological studies, Dr. Aitipamula Srinivasulu (ICES) and
Ms. Chia Sze Chen (ICES) for X-ray crystallographic analysis, and
Ms. Doris Tan (ICES) for assistance with HRMS. Financial support
for this work was provided by A*STAR, Singapore.
Biological Studies. (()-Englerin A [(()-1], (()-englerin B
[(()-2], (()-englerin B acetate [(()-3], hydroxy acetate 24, TBS
ether 26, and hydrogenated (()-englerin A (31, see Scheme 5)
Supporting Information Available: Experimental procedures
and compound characterization. This material is available free
of charge via Internet at http://pubs.acs.org.
(14) Oppolzer, W.; Chapuis, C.; Bernardinelli, G. Tetrahedron Lett. 1984,
25, 5885–5888.
JA102927N
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