Enantioselective photocycloaddition mediated by chiral Bronsted acids: Asymmetric synthesis of the rocaglamides

Article abstract of DOI:10.1021/ja062621j

Enantioselective syntheses of methyl rocaglate and the related natural products rocaglamide and rocaglaol are outlined. The approach involves enantioselective [3 + 2] photocycloaddition promoted by chiral Bronsted acids (TADDOLs) to afford an aglain precursor followed by a ketol shift/reduction sequence to the rocaglate core. Copyright

Full text of DOI:10.1021/ja062621j

Published on Web 05/25/2006
Enantioselective Photocycloaddition Mediated by Chiral Brønsted Acids:
Asymmetric Synthesis of the Rocaglamides
Baudouin Gerard,† Sheharbano Sangji,‡ Daniel J. O’Leary,‡ and John A. Porco, Jr.*,†
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment, Boston UniVersity,
Boston, Massachusetts 02215, and Department of Chemistry, Pomona College, Claremont, California 91711
Received April 14, 2006; E-mail: porco@bu.edu
Table 1. Development of Enantioselective Photochemical
The genus Aglaia is the source of the rocaglamides, a unique
group of natural products featuring a cyclopenta[b]tetrahydroben-
zofuran skeleton.1 We recently reported the synthesis of (()-methyl
rocaglate 1 using [3 + 2] dipolar cycloaddition of an oxidopyrylium
betaine 2 derived from excited state intramolecular proton transfer
(ESIPT)2 of 3-hydroxyflavone (3-HF) 3 and methyl cinnamate 4.
The resulting cycloadduct 5 was transformed to methyl rocaglate
1 and stereoisomer 6 employing a base-mediated R-ketol rear-
rangement/hydroxyl-directed reduction sequence (Scheme 1).3
Cycloadditiona
Scheme 1. Synthesis of (()-Methyl Rocaglate
entry
additive
yield of 5, %b
yield of 1/6, %c
ee of 1/6, %d
1
2e
3e
4
5
6
7
8
9
32
60
61
51
92
90
70
54
79
73
58
22
45/19
41/15
49/7
35/4
52/9
71/14
69/14
72/22
67/19
47/9
racemic
7/5
25/18
15/7
40/36
60/58
25/22
racemic
71/51
53/30
82/68
89/78
7a
7b
7a
7b
7c
7d
7e
7f
10f
11
12
7f
7g
8a
61/16
52/7
Herein, we wish to report an asymmetric synthesis of methyl
rocaglate employing enantioselective [3 + 2] photocycloaddition
mediated by functionalized TADDOL derivatives.
a Reactions conducted with 1 equiv of 3-HF, 1 equiv of additive, and 5
equiv of methyl cinnamate in toluene/CH2Cl2 (2/1) at -70 °C for 12 h.
b Isolated yield. c Isolated yield for the R-ketol rearrangement/reduction
sequence. d Determined by chiral HPLC (see the Supporting Information).
e Reaction conducted at 0 °C in toluene. f Reaction conducted in the presence
of anhydrous CH3OH (5 equiv).
During our studies toward the synthesis of (()-methyl rocaglate,3
we found that the cycloaddition required polar protic solvents, such
as methanol, in order to proceed. It has been proposed that ESIPT
may be enhanced in such solvents due to the formation of solvated
complexes involving “double proton transfer”.4 To access chiral,
nonracemic methyl rocaglate, we therefore investigated use of chiral
Brønsted acids5 in aprotic solvents as host-guest6 complexes to
mediate photochemical cycloaddition. After screening a number
of hydrogen-bonding additives, we identified TADDOL5 reagents
as chiral mediators (Table 1). For example, photochemical cy-
cloaddition of 3 with methyl cinnamate 4 (5 equiv) using 1-phenyl
TADDOL 7a (1 equiv) in toluene at 0 °C afforded a 24% overall
yield and 7% ee of (-)-methyl rocaglate 1 after ketol shift and
reduction (entry 2).7 Use of naphthyl TADDOL derivative 7b led
to an increase in enantiomeric excess to 25% (cf. entries 2 and 3).
Investigation of reaction temperature showed noticeable effects on
the enantioselectivity of the cycloaddition (cf. entries 2 and 4, and
3 and 5). On the basis of optical rotation data, use of TADDOL
derivatives derived from L-tartrate was shown to favor the natural
(-)-enantiomer of 1.
1) at low temperature using a mixed solvent system (2:1 PhCH3:
CH2Cl2) to avoid low viscosity and poor substrate solubility. During
our investigations, we found that the nature of both the aryl
substituent and ketal side chain were important for high enantio-
selectivity. For example, use of additive 7f bearing a 9-phenan-
threnyl substituent and cyclohexyl ketal (entry 9) afforded 1 in 71%
ee (53% overall yield). The highest enantioselectivity was achieved
using dimeric TADDOL 8a (89% ee, entry 12) but with low
conversion. Fortunately, recrystallization of 1 obtained from TAD-
DOL 7g led to the formation of centrosymmetric racemate8 crystals
and the isolation of 1 (94% ee, 86% recovery) from the mother
liquor. The TADDOL complexing agent could be recovered in high
yield by precipitation from methanol. A control experiment
involving addition of 7f and 5 equiv of methanol (entry 10) led to
a loss of enantioselectivity presumably due to achiral background
reactions promoted by the protic cosolvent.9
Unexpectedly, when diphenyl (7e, entry 8) TADDOL acetal was
employed as additive, methyl rocaglates 1 and 6 were obtained as
racemates. X-ray crystal structure analysis of 7e showed the
presence of a TADDOL conformer10 involving intramolecular
H-bonding between the hydroxyl groups and the π system of the
Encouraged by these results, we proceeded to evaluate additional
TADDOL derivatives in the photochemical cycloaddition (Table
† Boston University.
‡ Pomona College.
9
7754
J. AM. CHEM. SOC. 2006, 128, 7754-7755
10.1021/ja062621j CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Enantioselective Syntheses of Rocaglamide and
Rocaglaol
photocycloaddition process and synthesis of other rocaglamide
derivatives are currently in progress and will be reported in due
course.
Acknowledgment. We thank the National Institutes of Health
(GM-073855), Bristol-Myers Squibb, and Merck Research Labo-
ratories for research support, Professor Viresh Rawal (The Uni-
versity of Chicago) and Professor Guilford Jones (Boston Univer-
sity) for helpful discussions, and Dr. Emil Lobkovsky (Cornell)
for X-ray crystal structure analyses. D.J.O. thanks the NSF for
financial support.
Figure 1. Alternate TADDOL conformers determined by infrared spec-
troscopy and X-ray analysis.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF), including X-ray
crystal structure coordinates and files in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
Figure 2. Proposed arrangement for enantioselective photocycloaddition.
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To explain the enantioselectivity observed in the [3 + 2]
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In conclusion, we have developed an enantioselective synthesis
of the rocaglamides and related natural products. The key strategy
involves enantioselective dipolar cycloaddition of an oxidopyrylium
species derived from excited state intramolecular proton transfer
of 3-hydroxyflavones using specifically functionalized TADDOL
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