Enantioselective total synthesis of all of the known chiral cleroindicins (C-F): Clarification among optical rotations and assignments

Article abstract of DOI:10.1021/jo900401k

(Chemical Equation Presented) Enantioselective syntheses of all of the named chiral members of the cleroindicin family (C-F) are reported. This effort demonstrates the synthetic utility of a 2,4-dihydroxybenzaldehyde as a starting material for natural pro

Full text of DOI:10.1021/jo900401k

Enantioselective Total Synthesis of All of the Known Chiral
Cleroindicins (C-F): Clarification Among Optical Rotations and
Assignments
Todd A. Wenderski, Shenlin Huang, and Thomas R. R. Pettus*
Department of Chemistry and Biochemistry, UniVersity of California at Santa Barbara,
Santa Barbara, California 93106
pettus@chem.ucsb.edu
ReceiVed February 23, 2009
Enantioselective syntheses of all of the named chiral members of the cleroindicin family (C-F) are
reported. This effort demonstrates the synthetic utility of a 2,4-dihydroxybenzaldehyde as a starting material
for natural product synthesis through the use sequential o-quinone methide chemistry and diastereoselective
dearomatization. Natural cleroindicin F was shown to be nearly racemic, and an optically pure synthetic
sample of cleroindicin F was found to racemize under slightly basic conditions. All other natural chiral
cleroindicins are shown to be partially racemic.
Introduction
of the other 4-hydroxy-cyclohexanones that we had previously
encountered,5 we began to suspect that the stereochemistry of
one or more of these compounds was incorrectly assigned.
Further investigation of the spectroscopic data ascribed to family
members in the literature illuminated several other discrepan-
cies.6 The assignment of (3S,4R) for the vicinal stereocenters
in cleroindicin C (3) by Sun et al. had largely been based on
the observation of a negative rotation in accordance with the
octant rule for ketones.2b This assignment subsequently led to
all future assignments of absolute stereochemistry for the
remaining structures. However, from our perspective, this
seemed rather dubious because cleroindicin D, which was
initially assigned by Sun as 4, displays a positive optical rotation
while cleroindicin F (7) was reported to display a small negative
rotation. Moreover, Ogasawara had reported that oxidation of
Extracts of the Clerodendrum genus of plants, found through-
out tropical areas of Asia and Africa, exhibit many desirable
medicinal properties.1 In an effort to discover the responsible
bioactive agents, Sun et al. isolated several oxidized cyclohex-
anones from the indicum and related japonicum and bungei
species.2 These compounds were designated as cleroindicins
A-F (1-4, 6-7, Figure 1).
The cleroindicins have been the focus of several synthetic
efforts.3 However, few reports have described their enantiose-
lective construction,4 and none in our opinion has fully resolved
the issues of absolute stereochemistry and optical rotation for
all constituents of the family of natural products. Like so many
(1) Cheng, H.-H.; Wang, H.-K.; Ito, J.; Bastow, K. F. T. Y.; Nakanishi, Y.;
Xu, Z.; Luo, T.-Y.; Lee, K.-H. J. Nat. Prod. 2001, 64, 915–919.
(2) (a) Tian, J.; Shao, Q.-S.; Lin, Z. W.; Sun, H.-D. Chin. Chem. Lett. 1996,
7, 279–282. (b) Tian, J.; Zhao, Q.-S.; Zhang, H.-J.; Lin, Z. W.; Sun, H.-D. J.
Nat. Prod. 1997, 60, 766–769. (c) Tian, J.; Zhao, Q.-S.; Zhang, H.-J.; Lin, Z.-
W.; Sun, H.-D. Chin. Chem. Lett. 1997, 8, 129–132. (d) Yang, H.; Hou, A.-J.;
Mei, S.-X.; Sun, H.-D.; Che, C.-T. J. Asian Nat. Prod. Res. 2002, 4, 165–169.
(3) (a) Chen, J.; Tian, J.; Wu, F. E.; Kawabe, N.; Tokuda, M. Chin. Chem.
Lett. 2001, 12, 771–774. (b) Honzumi, M.; Kamikubo, T.; Ogasawara, K. Synlett
1998, 1001–1003.
(4) (a) See ref 3b and. (b) Canto, M.; de March, P.; Figueredo, M.; Font, J.;
Rodriguez, S.; Alarez-Larena, A.; Piniella, J. F. Tetrahedron: Asymmetry 2002,
13, 455–459.
(5) Hoarau, C.; Pettus, T. R. R. Org. Lett. 2006, 8, 2843–2846.
(6) (a) Racemic cleroindicin F (7) has also been called rengyolone: Endo,
K.; Hikino, H. Can. J. Chem. 1984, 62, 2011–2014. Halleridone: (b) Messana,
I.; Sperandei, M.; Mulatari, G.; Galeffi, C.; Marini Bettolo, G. B. Phytochemistry
1984, 23, 2617–2619.
4104 J. Org. Chem. 2009, 74, 4104–4109
10.1021/jo900401k CCC: $40.75 2009 American Chemical Society
Published on Web 05/07/2009

Synthesis of the Known Chiral Cleroindicins (C-F)
SCHEME 1. Synthesis of the Non-Racemic
Cyclohexadienone 15a
a TMSE ) CH2CH2SiMe3, DIAD ) Diisopropyl azodicarboxylate.
employed an ortho-quinone methide (o-QM) for conjugate
addition to provide various 4-alkylated resorcinols that were
subsequently subjected to diastereoselective dearomatization.9
By application of this novel process to chiral members of the
cleroindicin family, we hoped to resolve the lingering spectro-
scopic issues and further substantiate the utility of our process
for addressing ornate cyclohexyl ring systems. Herein, we report
our enantioselective strategy and method for addressing all of
these chiral compounds, a pursuit that has unlocked much
knowledge concerning the intrinsic malleability of bromo-
cyclohexa-2,5-dienones, and resolved some of the discrepancies
surrounding the spectroscopic data and stereochemistry of these
compounds, as well as their speculated biosynthesis.
FIGURE 1. First named members of the cleroindicin family (blue)
are shown along with their reported optical rotations (red). Compound
4 was first assigned as cleroindicin D.2b The ranges of optical rotations
(black) for materials procured through prior “enantioselective” syntheses
are also presented. Our optical rotations for our synthetic materials
(green) suggest that all of the named chiral cleroindicins are partially
racemic, and these finding may have profound ramifications on the
speculated biosynthesis from cornoside.
Results and Discussion
Our drive toward cleroindins C-F began with the known
benzaldehyde 9,9 which is available in two pots from 2,4-
dihydroxy-benzaldehyde (Scheme 1). Treatment of compound
9 with [(2-(trimethyl-silyl)ethoxy)methyl]lithium 1010 resulted
in Boc migration, and afforded an intermediate phenoxide. This
phenoxide succumbed to in situ ꢀ-elimination to form an
o-quinone methide intermediate that underwent subsequent in
situ 1,4-reduction with sodium borohydride to produce the
phenol 11 in 68% yield. Our unusual one-pot cascade, which
we have extensively investigated,11 is driven by relative anion
stability. This particular example is noteworthy because addition
of the lithium reagent superseded lithium halogen exchange. A
standard Mitsunobu coupling of the amide 1212 afforded the
inverted amide 13 in an 85% yield and >99% enantiomeric
excess (ee) as confirmed by chiral HPLC analysis and com-
parison to a racemic standard prepared in a similar manner from
racemic lactic acid.
(-)-cleroindicin E (6), which was assumed to be the unnatural
enantiomer, afforded (-)-cleroindicin C (3), supposedly the
natural enantiomer.3b Clearly, there was a problem with
structural assignments and/or rotations.
This confusion over the stereochemistry, in turn, has clouded
the understanding of the biosynthesis for these compounds.7
Most have presumed that the cleroindicins are biosynthesized
by dearomatization of glycosylated p-(2-hydroxyethyl)phenol,
which results in the achiral cyclohexadienone cornoside, (cf.
Figure 1). Olefin reduction and deglycosylation provides cle-
roindicins A (1) and B (2). On the other hand, deglycosylation
and olefin desymmetrization by 1,4-addition of the freed oxygen
atom leads to cleroindicin F (7), whereupon further biomanipu-
lations can be imagined as leading to the remaining optically
active constituents of the cleroindicin family. Alternatively,
cornoside might become desymmetrized by reduction of an
olefin, and cleroindicin C (3) forms by deglycosylation and a
successive 1,4-addition. Subsequent reoxidations would then
lead to compounds 4-5 and 7. We believed that syntheses of
these materials could settle the lingering discrepancies and might
resolve the biogenesis for the family. In addition, dearomati-
zation of aromatic compounds has been of interest to us for
some time,8 and the chiral cleroindicins (3-8) offered chal-
lenging tests for demonstration of the malleability inherent in
our dissymmetric chiral cyclohexa-2,5-dienones building blocks.
Some time ago, we demonstrated that various cyclohexa-2,5-
dienones could be accessed by a transformative sequence that
The remaining Boc residue smoothly cleaved upon exposure
of 13 to aqueous lithium hydroxide to provide the phenol 14 in
a 95% isolated yield, after workup and chromatography.
Oxidative dearomatization of 14 with PhI(OCOCF3)2 afforded
a 76% yield of δ-lactone 15 as a single diastereomer. The
structure of the syn diastereomer (-)-15 has been established
(9) Mejorado, L.; Hoarau, C.; Pettus, T. R. R. Org. Lett. 2004, 6, 1535–
1538.
(10) (a) Kozikowski, A. P.; Okita, M.; Kobayashi, M.; Floss, H. G. J. Org.
Chem. 1988, 53, 863–869. (b) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481–
1487.
(11) (a) Van De Water, R.; Magdziak, D.; Chau, J.; Pettus, T. R. R. J. Am.
Chem. Soc. 2000, 122, 6502–6503. (b) Jones, R. M.; Van de Water, R. W.;
Lindsey, C. C.; Pettus, T. R. R. J. Org. Chem. 2001, 66, 3435–3441.
(12) (a) Patterson, I.; Wallace, D. J.; Cowden, C. J. Synthesis 1998, 639–
652. (b) Less, S. L.; Leadlay, P. F.; Dutton, C. J.; Staunton, J. Tetrahedron Lett.
1996, 37, 3519–3520.
(7) Hase, T.; Kawamoto, Y.; Kasai, R.; Yamasaki, K.; Picheansoonthon, C.
Phytochemistry 1995, 39, 235–241.
(8) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. ReV. 2004, 104, 1383–
1429.
J. Org. Chem. Vol. 74, No. 11, 2009 4105

Wenderski et al.
SCHEME 2a
a First planned formation of cleroindicin F (7) via 17 fails. Compound
19 forms instead when opening 17 with the aluminum amide of pyrrolidine.
FIGURE 2. Structure 15 shown in three dimensions as well as the
most plausible transition-state intermediates.
SCHEME 3a
by X-ray analysis of related intermediates13 and shows that the
(R) configured 2-alkoxyethyl alkyl chain exists in a pseudo axial
arrangement (15-3D, Figure 2) with regards to the 2-oxo-1,4-
dioxane ring, whereas the (S) configured methyl residue that is
adjacent to the lactone carbonyl occupies a pseudo equatorial
arrangement. We believe that this rigid and locked conformation
is what enables many of the subsequent chemoselective and
diastereoselective manipulations of the core cyclohexadienone
to occur.
The ratio afforded by the dearomatization and lactonization
depends on the size of the R2 substituent (Figure 2). Four
transition states (A-D) define the energy surface leading to two
plausible diastereomeric lactone products. The transition-states
can be imagined as the ax-Boat D, the ax-Chair C and their
corresponding ring-flips, the eq-Boat A and eq-Chair B. The
latter two (A-B) contribute very little because steric interactions
between the amide residue and eq-methyl group. Given the
absolute stereochemistry of the major product, the ax-Boat D
transition is preferred. However, the terms “boat” and “chair”
apply loosely because five of the six contributing atoms in the
six-membered transition state are in planar sp2 configuration.
We speculate that transition-state D is preferred because the
sum of the minor dipoles, which are comprised by the
phenoxonium cation and the iminium zwitterion, is considerably
smaller than for transition-state C. The expected correlation of
diastereomeric effects and structural modifications to the chiral
amide tether strongly support this reasoning.14
We now faced the challenge of chemoselective differentiation
between the numerous functional groups within compound 15.
This task mandated removal of the linkage that had directed
the diastereoselective dearomatization, and which now served
as the group protecting two of the oxygen substituents. Some
time ago we developed several processes for removing related
glycolic linkages that were employed in our early racemic
studies of epoxysorbicillinol15 and rishirilide B.16 Unfortunately,
neither sequence used for the achiral tether proved successful
for cyclohexadienones derived from 12. Therefore, we consid-
ered another cleavage mode for the chiral directing group, a
a Failed formation of epi-cleroindicin D (4) via intermediacy of 22.
sequence that we had previously utilized with great success,
which involved sequential reduction of the vinylogous ester and
lactone, followed by ring-opening, a ring-flip, and a ꢀ-elimina-
tion of the remaining lactic acid linkage.9
To test this proposition, we treated the cyclohexadienone
15 (0.1 M in toluene, -78 °C) with Yamamoto’s Lewis acid
(methylaluminium bis(2,6-ditert-butyl-4-methylphenoxide,
MAD, 2.5 equiv), followed by the addition of L-Selectride
(1.05 equiv) (Scheme 2). As expected, the vinylogous ester
reduced in a stereoselective anti fashion. Next, we formed
the hydrofuran by submitting compound 16 (0.1 M in
nitromethane) to zinc bromide (4 equiv), which caused the
RO(CH2)2TMS functionality to cleave and thereby freed the
oxygen atom to participate in an in situ 1,4-addition with
the neighboring enone. The reaction smoothly resulted in the
tricyclic compound 17 in 80% yield. At this juncture, we
imagined that treatment of the R-bromo compound 17, or
the corresponding amide 18, with zinc could furnish clero-
indicin F (7) by formation of the corresponding zinc enolate
followed by ꢀ-elimination. However, neither approach proved
fruitful. We attribute this failure to an equatorially disposed
C-O linkage, as treatment of 17 with zinc simply afforded
the debrominated tricycle 20 (Scheme 3, reaction not shown)
without producing any of the desired ꢀ-elimination product.
On the other hand, our attempts to open the δ-lactone via
the aluminum amide of pyrrolidine and thereby facilitate a
cyclohexyl ring-flip and further ꢀ-elimination also failed, and
instead resulted in ꢀ-elimination of the opposite C-O bond
followed by bromide displacement to afford the [3.3.1]-
bicycle 19 in 55% yield.
(13) For an example, please see: Wenderski, T. A.; Huang, S.; Pettus, T. R. R.
Communication to the Cambridge Structural Database, deposition number CCDC
726677, 2009.
(14) Mejorado, L.; Pettus, T. R. R. J. Am. Chem. Soc. 2006, 128, 15625–
15631.
(15) Pettus, L. H.; Van de Water, R. W.; Pettus, T. R. R. Org. Lett. 2001, 3,
905–908.
(16) (a) Wang, J.; Pettus, L. H.; Pettus, T. R. R. Tetrahedron Lett. 2004, 45,
1793–1796. (b) Wang, J. H.; Pettus, T. R. R. Tetrahedron Lett. 2004, 45, 5895–
5899.
4106 J. Org. Chem. Vol. 74, No. 11, 2009

Synthesis of the Known Chiral Cleroindicins (C-F)
SCHEME 4. Synthesis of (-)-epi-Cleroindicin D (4) and
(()-Cleroindicin F (7) from the Nonracemic Tricycle 20
DIBAL-H in CH2Cl2. After workup to remove aluminum
salts, the crude lactol was submitted to dimethyl hydrazine
and trace trifluoroacetic acid to break the C-O bond. The
two-step process afforded the diol 25 in 75% yield, and this
UV active compound displayed >99% ee by rigorous
comparison to a racemic HPLC standard. Subsequent cleav-
age of the ketal by hydrogenolysis afforded (-)-epi-clero-
indicin D (4), a structure previously misidentified as clero-
indicin D, in nine steps (19.3% overall yield) from
benzaldehyde 9. While Carren˜o recently reported clarification
of the structure of cleroindicin D (5) by its racemic
synthesis,18 it is interesting to note, that Yamasaki reported
synthesizing a structure identified as (()-57 in 1995, and
reported data that closely matched that which was subse-
quently reported by Sun for cleroindicin D (5) and incorrectly
assigned as the structure 4.
Since the synthetic compound 4 was evidently the undes-
ired diastereomer epi-cleroindicin D, we decided to invert
its secondary alcoholic stereocenter to prepare 5. We at-
tempted to employ standard Mitsunobu conditions17 with 25
(Scheme 4). However, instead of the desired ester, we
obtained the epoxide 26. We therefore targeted cleroindicin
F (7), thinking that it might be reached by ꢀ-elimination.
We independently converted the secondary alcohol into its
corresponding acetate and mesylate, and then subjected each
separately to hydrogenolysis of the respective benzylidene
ketal. This two-pot sequence afforded the relevant acetate
and mesylate (27, 28) in about 90% yield over the two steps.
Next, we exposed these materials to base. Treatment of the
acetate 27 with i-Pr2NEt or DBU had no effect. Both
conditions simply returned the starting material unchanged.
On the other hand, we found that treatment of the mesylate
28 with pyridine for 24 h afforded optically enriched (-)-
cleroindicin F (7) with 90% ee, as determined by chiral HPLC
comparison with a racemic standard. Moreover, application
of either i-Pr2NEt or DBU to mesylate 28 afforded nearly
racemic cleroindicin F (7) in less than twenty-five minutes,
presumably via the intermediacy of the achiral cyclohexa-
dienone. This rapid racemization of (+)-7 was further
confirmed by separate treatment of optically enriched 7 with
either i-Pr2NEt or DBU. We therefore recognized that in order
to prevent corruption of the optical activity, we would require
nonbasic, or perhaps nearly neutral conditions for the
formation and subsequent reactions of 7. We therefore chose
to install an even better leaving group and converted alcohol
25 into its corresponding tosylate 29 (Scheme 5).
Hydrogenation of the ketal proceeded to the expected
ketone bearing the ꢀ-tosylate. Upon silica gel chromatogra-
phy, elimination proceeded to afford the synthetic enone
(+)-7 ([R]D ) +59.0°, c ) 1.0, >99% ee). However, we again
found that compound 7 can racemize under basic conditions
[(0.1 M CH2Cl2, 1 equiv DBU, rt, 0% ee in 5 min) (0.1 M
CH2Cl2, 1 equiv pyridine, rt, 90% ee after 12 h)]. A
racemization might account for the very low rotation observed
in the natural product 7, and other supposed enantioselective
syntheses of 7.19 Moreover, this outcome suggested that we
would have to be especially vigilant in the nucleophilic
epoxidation of enone 7 to avoid loss of enantiomeric excess.
After examining many conditions, we found that treatment
With ꢀ-elimination as a method for removal of the chiral
directing group no longer available to us, we considered our
other options. Some time ago we reported a method for scission
of an alpha C-O bond in aldehydes by sequential treatment of
an aldehyde or its corresponding lactol with dimethylhydrazine
followed by acid (inset, Scheme 3).5,14 Thus, we imagined that
we could use this process to form 4, which at that time we still
believed to be the structure of cleroindicin D, by severing the
C-O bond in 23 (Scheme 3).
Treatment of 16 with TMSI caused cleavage of the bromide
of the R-bromo-ketone and the RO(CH2)2TMS ether to afford
the tricyclic compound (-)-20 in a respectrable 80% yield for
the two transformations (one-pot) (Scheme 3). The stability
of the tricyclic compound to these notoriously harsh conditions
is testimony to the sturdiness of the 2-oxo-1,4-dioxane ring as
a diol protecting group.
Reduction of the two carbonyls in compound 20 with DIBAL-H
(4.1 equiv) afforded a hemiacetal that we tentatively assigned with
the stereochemistry shown in 21. Further treatment of the lactol
21 with dimethyl hydrazine produced the chromatographically
unstable hydrazone 22. Unfortunately, our plan, to oxidize the
secondary alcohol and then to sever the C-O bond, also failed.
Attempts aimed at oxidation of the secondary alcohol with Dess-
Martin reagent led to either decomposition or returned the tricyclic
lactone 20.
We therefore decided to retain the original carbonyl
oxidation state by masking the ketone in (-)-20 as a ketal
that could be easily deprotected at some later stage. The
carbonyl functionality in 20 was readily transformed into the
desired benzylidene ketal by treatment with the appropriate
aryl diol in the presence of acid and azeotropic removal of
water (Scheme 4). Subsequent cleavage of the 1,4-dioxa-2-
one moiety trans-diol occurred over two pots. First, the
lactone was reduced to the corresponding lactol with excess
(17) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017–3020.
(18) Barradas, S.; Carren˜o, G.-L. M.; Latorre, A.; Urbano, A. Org. Lett. 2007,
9, 5019–5022.
J. Org. Chem. Vol. 74, No. 11, 2009 4107

Wenderski et al.
SCHEME 5. Enantioselective Synthesis of All Remaining
Cleroindicins 3, 5-8
mg, 1.55 mmol, 1 equiv) in THF (26 mL) at -78 °C. After 1 h,
the reaction was quenched with water and the cold bath was
removed. A solution of NaBH4 (469 mg, 12.4 mmol, 8 equiv)
in cold water (5 mL) was added. The reaction was stirred for
24 h at room temperature, then quenched with 1 N HCl, extracted
with Et2O four times. The combined organics were washed with
brine, dried with Na2SO4, and concentrated in vacuo. Flash
chromatography of the residue (5% EtOAc/hexanes, Rf ) 0.15)
1
yielded colorless oil 11 (457 mg, 1.05 mmol, 68% yield). H
NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 7.00 (d, J ) 8.4 Hz,
1H), 6.70 (d, J ) 8 Hz, 1H), 3.70 (t, J ) 4.8 Hz, 2H), 3.58 (t,
J ) 8.4 Hz, 2H), 2.92 (t, J ) 4.8 Hz, 2H), 1.57 (s, 9H), 1.03 (t,
J ) 8.4 Hz, 2H), 0.02 (s, 9H); 13C NMR (100 MHz. CDCl3) δ
154.3, 151.3, 148.4, 129.8, 126.0, 114.3, 106.7, 84.1, 71.5, 69.3,
33.6, 27.8, 18.3, -1.3; IR (thin film) 2980, 2953, 2870, 1763,
1151 cm-1; HRMS (ESI) calcd for C18H29BrO5SiNa: 455.0865.
Found 455.0872.
(3S,8aR)-5-Bromo-3-methyl-8a-(2-(2-(trimethylsilyl)ethoxy)-
ethyl)benzo[b][1,4]dioxine-2,6(3H,8aH)-dione (15). Phenol 14 (0.605
g, 1.35 mmol) was dissolved in CH3NO2 (13.5 mL) and cooled
to -10 °C. [Bis(trifluoroacetoxy)iodo]benzene (0.871 g, 2.03
mmol, 1.50 equiv) was added in one portion. The reaction
mixture was stirred at -10 °C for 15 min, and gradually turned
light yellow. When residual water was present in the phenol, a
darker reaction mixture was observed, and a lower yield was
obtained. To quench the reaction, deionized water (20 mL) was
added, immediately followed by CH2Cl2 (20 mL) and it
was stirred vigorously at 0 °C for 15 min. Upon initial addition
of water, the solution turned dark green then faded to yellow
after several minutes. The aqueous layer was extracted with
CH2Cl2 (4 × 20 mL). The combined organics were washed with
brine (10 mL), dried (Na2SO4), and concentrated. The crude
product was purified by flash chromatography with 10% EtOAc/
hexanes (Rf ) 0.15) to afford 15 (0.414 g, 1.03 mmol, 76%
of 7 with Ph3COOK, prepared from 4 equiv of Ph3COOH
and 2 equiv of KH, afforded the epoxide 30 in greater than
99% ee. Further treatment of 30 with aluminum-mercury
amalgam18 afforded synthetic cleroindicin D (5) ([R]D
)
-38.0°, c ) 0.5), which proved identical in all other respects
with natural cleroindicin D. Further hydrogenation of syn-
thetic (+)-cleroindicin F (7) afforded synthetic (-)-cleroin-
dicin C (3) ([R]D ) -79.0°, c ) 0.1), which when compared
to the rotation of the natural material also suggests that natural
cleroindicin C is partly racemic. Reduction of synthetic
cleroindicin C (3) proceeded primarily on the convex face
of the carbonyl to afford iso-cleroindicin E (8). On the other
hand, reduction of 3 with samarium diiodide afforded a 2:1
ratio favoring cleroindicin E (6).
1
yield) as a colorless oil. H NMR (400 MHz, CDCl3) δ 6.85 (d,
J ) 10 Hz, 1H), 6.37 (d, J ) 10 Hz, 1H), 4.95 (q, J ) 7.2 Hz,
1H), 3.35 (m, 4H), 2.35 (m, 2H), 1.84 (d, J ) 7.2 Hz, 3H), 0.83
(t, J ) 9.2 Hz, 2H), -0.04 (s, 9H); 13C NMR (100 MHz. CDCl3)
δ 179.5, 166.4, 161.4, 142.1, 127.5, 108.0, 78.8, 74.4, 68.6, 64.2,
42.2, 19.2, 18.1, -1.3; IR (thin film) 2950, 2866, 1762, 1670,
1250 cm-1; HRMS (ESI) calcd for C16H23BrO5SiNa: 425.0396.
Conclusion
In summary, the enantioselective syntheses of the all the
named chiral cleroindicins have been completed from 2,4-
dihydroxybenzaldehyde. These synthetic materials were
constructed in nearly enantiopure form. From the measured
optical rotations of these synthetic materials, it appears that
all of the named natural chiral cleroindicins are either
partially or nearly racemic, as are many of the compounds
obtained from prior ‘claimed’ enantioselective syntheses.19
Because all of the named chiral cleroindicins (C, D, E) are
partially or nearly racemic, it would seem that each is derived
from cleroindicin F, which racemizes during the biosynthesis.
We further extrapolate from our data and the earlier data of
Hase,7 that cornoside may be produced from cleroindicin F,
and that an unnamed chiral cleroindicin ((3aS,6R,7aS)-
25
Found 425.0409. [R]D ) -52.9 (CHCl3, c ) 0.9).
Cleroindicin F (7), Nonracemized. To a solution of diol 25
(7.0 mg, 0.024 mmol) in pyridine (0.3 mL) was added TsCl (14.0
mg, 0.072 mmol, 3.0 equiv). After 18 h of stirring, the reaction
mixture was diluted with CH2Cl2, washed with CuSO4 (aq),
extracted with CH2Cl2 (4×), washed with water and brine. The
organic phase was dried over Na2SO4 and concentrated under
reduced pressure. The resulting monotosylate 29 was purified
by flash chromatography (40% EtOAc/hexanes, Rf ) 0.2).
A solution of the above monotosylate 29 in THF/MeOH/CH2Cl2
(0.16 mL/0.16 mL/0.16 mL) containing 5% Pd/C (3 mg) was stirred
under 1 atm of hydrogen at room temperature for 12 h. The reaction
mixture was filtered through a pad of Celite, and concentrated under
reduced pressure. The crude product was purified by flash chro-
matography (70% EtOAc/hexanes, Rf ) 0.15) to provide cleroin-
dicin F (7) as colorless oil (6.3 mg, 0.041 mmol, 72% yield over
2 steps, >99% ee). Note: Base-induced elimination, or treatment
of 7 with base (pyridine or DBU), yielded partially or fully
racemized cleroindicin F (7).19 The enantiomeric ratio was deter-
mined by HPLC (Chiralcel AD-H, 4% IPA/Hexanes, tR1 ) 48.78
2,3,3a,6,7,7a-hexahydrobenzofuran-3a,6-diol, 31, ([R]D
)
+102.0°)7 (see Supporting Information) may immediately
precede cleroindicin F in the biosynthesis.
Experimental Section
2-Bromo-3-hydroxy-4-(2-(2-(trimethylsilyl)ethoxy)ethyl)phe-
nyl tert-Butyl Carbonate (11). n-BuLi (0.34 mL, 4.8 M, 1.05
equiv) was added in a dropwise fashion to a stirring solution of
trimethyl(2-((tributylstannyl)methoxy)ethyl)silane (685 mg, 1.62
mmol, 1.05 equiv) in THF (0.65 M) at -78 °C. After stirring
for approximately 20 min, the Still alkoxy lithium solution was
transferred via cannula to a solution of benzaldehyde 9 (645
1
min, tR2 ) 57.30 min) for each reaction. H NMR (500 MHz,
CDCl3) δ 6.77 (d, J ) 10 Hz, 1H), 6.04 (d, J ) 10 Hz, 1H), 4.25
(t, J ) 6.0 Hz, 1H), 4.08 (dd, J ) 8.5 Hz, J ) 15 Hz, 1H), 3.96
(dd, J ) 8.5 Hz, J ) 15 Hz, 1H), 3.50 (bs, 1H), 2.80 (dd, J ) 4.5
Hz, J ) 17 Hz, 1H), 2.63 (dd, J ) 6 Hz, J ) 17 Hz, 1H), 2.32 (m,
1H), 2.24 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 196.7, 147.8,
129.2, 81.9, 76.0, 66.5, 40.5, 39.8; IR (thin film) 3418, 2920, 2851,
1666 cm-1; HRMS (ESI) calcd for C8H10O3: 154.0630. Found
(19) You, Z.; Hoveyda, A. H.; Snapper, M. L. Angew. Chem., Int. Ed. 2009,
48, 547–550. Consider the Supporting Information for cleroindicin F.
4108 J. Org. Chem. Vol. 74, No. 11, 2009

Synthesis of the Known Chiral Cleroindicins (C-F)
154.0625. [R]D ) +59.0 (MeOH, c ) 1.0). H and 13C NMR,
IR, and HRMS data were consistent with that reported in the
literature, though our rotation is significantly higher.2b,7
25
1
Supporting Information Available: Additional procedures
and spectral data for all new compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Continued research support for explora-
tion of this cyclohexadienone chemistry from the National
Institutes of Health (GM-64831) is greatly appreciated.
JO900401K
J. Org. Chem. Vol. 74, No. 11, 2009 4109