Rapid and enantioselective synthetic approaches to germanicol and other pentacyclic triterpenes

Article abstract of DOI:10.1021/ja802730a

Two exceedingly short synthetic routes to the key intermediate 2 for the synthesis of the pentacyclic triterpene germanicol 1 have been developed. In the first, the (S)-epoxide of farnesyl bromide is transformed in just three steps to the tetracyclic intermediate 7, which is converted to chiral 2 by treatment with polyphosphoric acid. The second synthetic route to 2 involves the coupling of the (S)-epoxide 8 with vinyl iodide 9 to give 10 and two-stage acid-catalyzed cyclization of 10 to form 2. During the course of this work we have also discovered a very unusual intramolecular 1,5-proton shift from a carbocation to a C-C double bond. The details of the process have been confirmed by ²H-labeling experiments.

Full text of DOI:10.1021/ja802730a

Published on Web 06/14/2008
Rapid and Enantioselective Synthetic Approaches to
Germanicol and Other Pentacyclic Triterpenes
Karavadhi Surendra and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts, 02138
Received April 14, 2008; E-mail: corey@chemistry.harvard.edu
Abstract: Two exceedingly short synthetic routes to the key intermediate 2 for the synthesis of the
pentacyclic triterpene germanicol 1 have been developed. In the first, the (S)-epoxide of farnesyl bromide
is transformed in just three steps to the tetracyclic intermediate 7, which is converted to chiral 2 by
treatment with polyphosphoric acid. The second synthetic route to 2 involves the coupling of the (S)-
epoxide 8 with vinyl iodide 9 to give 10 and two-stage acid-catalyzed cyclization of 10 to form 2. During
the course of this work we have also discovered a very unusual intramolecular 1,5-proton shift from a
carbocation to a C-C double bond. The details of the process have been confirmed by 2H-labeling
experiments.
In 1970 the combined research groups of R. E. Ireland
and W. S. Johnson described a now classic synthesis of the
pentacyclic triterpenoid germanicol 1 in racemic form.1 The
difficulty of accessing the racemic structure can be readily
appreciated from the facts that (1) ca. 32 steps were required
and (2) only a 0.1% overall yield was reported. Because of
such difficulty shorter, more efficient, and enantioselective
syntheses of pentacyclic triterpenoids have remained a
formidable challenge to synthesis. The not unreasonable
possibility that the various parent pentacyclic triterpenes are
biosynthesized from (S)-2,3-oxidosqualene in a single step2
underscores the disparity between conventional multistep
synthesis and enzymically controlled biosynthesis. Nonethe-
less, until recent years there has not been significant progress
in this area because of the complexity of dealing with the
combination of numerous angular methyl groups and the large
steric repulsions that they cause. We disclose herein the
development of a short and quite efficient enantiocontrolled
route to germanicol that is based on methodology that has
recently been devised for targets of this sort.3,4 Our specific
plan was directed at the chiral pentacyclic target 2, the
racemic form of which was used by the Ireland and Johnson
groups to synthesize (()-germanicol. Two short and efficient
enantioselective routes to the pentacycle 2 have emerged, as
detailed herein.
The first synthetic pathway to 2 utilizes epoxide-initiated
cation-olefin polyannulation and starts with the readily
available chiral building block 3, which was obtained from
farnesyl acetate as described earlier.5 Coupling of 3 via the
corresponding bromide with the lithio derivative of the silyl
imine 4 provided the known acyl silane 56 (Scheme 1). The
epoxy triene 6 was assembled stereoselectively from 5,
2-propenyllithium, and 3-methoxybenzyl bromide in a single
step by a one-flask, three component coupling involving (1)
nucleophilic addition of 2-propenyllithium to the carbonyl
group of 5, (2) Brook rearrangement, and (3) 3-methoxy-
benzylation of the resulting allylic lithium intermediate.7 The
triene 6 was treated with 1.5 equiv of MeAlCl2 in CH2Cl2 at
-94 °C for 30 min to effect cationic cyclization. After
silylation with t-butyldimethylsilyl chloride (TBSCl), the
tetracyclic ketone 7 was obtained. Exposure of this product
to polyphosphoric acid at 23 °C for 30 min afforded directly
the target pentacycle 2, spectroscopically identical with the
Ireland-Johnson product. It is evident that the synthesis
outlined in Scheme 1 represents a major advance over the
original route to 2 in terms of brevity, efficiency, and
enantiocontrol.
The second effective approach to the synthesis of germa-
nicol via 2 is outlined in Scheme 2. The chiral epoxy diene
8, [R]D23 ) +8.7 (CHCl3), obtained from the (S)-epoxide of
geraniol5 by oxidation with activated MnO2 in C6H6 at 23 °C
followed by Wittig condensation with methylenetriph-
(1) Ireland, R. E.; Baldwin, S. W.; Dawson, D. J.; Dawson, M. I.; Dolfini,
J. E.; Newbould, J.; Johnson, W. S.; Brown, M.; Crawford, R. J.;
Hudrlik, P. F.; Rasmussen, G. H.; Schmiegel, K. K. J. Am. Chem.
Soc. 1970, 92, 5743–5746.
(5) (a) Corey, E. J.; Noe, M. C.; Shieh, W-C. Tetrahedron Lett. 1993,
34, 5995–5998. (b) Corey, E. J.; Noe, M. C.; Lin, S. Tetrahedron
Lett. 1995, 36, 8741–8744. (c) Corey, E. J.; Zhang, J. Org. Lett. 2001,
3, 3211–3214. (d) Huang, J.; Corey, E. J. Org. Lett. 2003, 5, 3455–
3458.
(2) Ku¨rti, L.; Chein, R.-J.; Corey, E. J. J. Am. Chem. Soc. , Submitted for
publication.
(3) (a) For recent enantioselective synthesis of erythrodiol, oleanolic acid,
and ꢀ-amyrin, see Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115,
8873–8874. (b) Huang, A, X.; Xiong, Z.; Corey, E. J. J. Am. Chem.
Soc. 1999, 121, 9999–10003. (c) For a very short synthesis of tritrepene
onorcerin, see Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem.
Soc. 2002, 124, 11290–11291.
(6) Corey, E. J.; Lin, S. J. Am. Chem. Soc. 1996, 118, 8765–8766.
(7) (a) For other examples of this sequence, see Corey, E. J.; Luo, G.;
Lin, L. S. J. Am. Chem. Soc. 1997, 119, 9927–9928. (b) Corey, E. J.;
Luo, G.; Lin, L. S. Angew.Chem., Int. Ed. 1998, 37, 1126–1128. (c)
Zhang, J.; Corey, E. J. Org. Lett. 2001, 3, 3215–3216. (d) Mi, Y.;
Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002, 124, 11290–
11291.
(4) For a recent review of epoxide-initiated cyclization, see Yoder, R. A.;
Johnston, J. N. Chem. ReV. 2005, 105, 4730–4756.
9
10.1021/ja802730a CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 8865–8869 8865

A R T I C L E S
Surendra and Corey
Scheme 1
Scheme 2
The synthesis of the E-vinyl iodide 9, which served as the
second building block for the synthesis of 2 shown in
(Scheme 2), was carried out by the sequence shown in
Scheme 3. The N,N-dimethylhydrazone 12, prepared in 99%
yield from 6-methoxy-1-tetralone and 1,1-dimethylhydrazine
and HOAc in C6H6 at reflux, was R-methylated by sequential
treatment with 1.0 equiv of LDA in THF at 0 °C followed
by methyl iodide11 and then transformed into the hydrazone
13 by heating with H2NNH2 in EtOH at reflux.12 Slow
addition of 13 to a solution of iodine in THF at 6 °C provided
the bicyclic vinyl iodide 14.13 Bis-homologation of 14 to form
the iodide 16 was accomplished by the sequence: (1) lithiation
followed by reaction with ethylene oxide to give the primary
alcohol 15 (88%) and (2) reaction of 15 with
Ph3P-I2-imidazole (92% of 16). Alkylation of 16 with the
dilithio derivative of acetone 2,4,6-triisopropylbenzenesulfo-
nyl (trisyl) hydrazone followed by a further deprotonation
with n-BuLi-tetramethylethelenediamine (TMEDA) afforded
a vinyllithium derivative (along with N2 and trisyl anion),
which upon iodination produced stereoselectively14 the
required E-vinylic iodide 9 (72%).10,14
enylphosphorane in THF (85% yield over two steps), was
coupled with the iodo diene 9 using Brown-Suzuki-Miyaura
methodology8 to form stereoselectively in a single step the
chiral epoxy triene 10 in good yield. In detail, the epoxy
diene 8 was hydroborated with 9-borabicyclo[3.3.1]nonane
(9-BBN) in THF and the resulting primary, homoallylic-
substituted 9-BBN was (without isolation) allowed to react
with vinyl iodide 9 in the presence of 5 mol % of
PdCl2-diphenylphosphinoferrocene (dppf)9 and aqueous
sodium hydroxide at 0 °C10 to give the epoxy triene 10 in
78% overall yield. Exposure of 10 to 3.0 equiv of MeAlCl2
in CH2Cl2 at -94 °C for 30 min produced a mixture of the
isomeric cyclization products 11 and 2 in a ratio of 3:7,
respectively, as determined by 1H NMR analysis. This
mixture was smoothly converted to pure 2 by further
treatment with a solution of triflic acid (5 equiv) in CH2Cl2
at 0 °C for 2 h. The formation of 2 from 11 by treatment
with triflic acid can occur by H+-catalyzed transposition of
the exocyclic, 11,12-double bond to the endocyclic, 12,13-
location. Pentacycle 2 obtained in this way was completely
identical (1H NMR, 13C NMR, TLC, and optical rotation)
with a sample of 2 produced by the sequence of reactions
outlined in above Scheme 1.
The formation of the coproduct 11 along with pentacycle
2 in the cyclization of 10 (Scheme 2) has been investigated
(11) Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 17, 3–6.
(12) Newkome, G. R.; Fishel, D. L. J. Org. Chem. 1966, 31, 677–681.
(13) (a) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron Lett.
1983, 24, 1605–1608. (b) Barton, D. H. R.; O’Brien, R. E.; Sternhell,
S. J. Chem. Soc. 1962, 470–476. (c) This preparation of 14 was first
carried out in these laboratories by Daniel Lieberman, Ph. D.
dissertation, Harvard University, 1986.
(8) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(9) (a) Hayashi, T.; Konishi, M.; Kumada, M. Tetrahedron Lett. 1979,
20, 1871–1874. (b) Brown, H. C.; Knights, E. F.; Scouten, C. G. J. Am.
Chem. Soc. 1974, 96, 7765–7777.
(10) Corey, E. J.; Lee, J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8919–
8920.
(14) Corey, E. J.; Dittami, J. P. J. Am. Chem. Soc. 1985, 107, 256–257.
9
8866 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008

Synthetic Approaches to Pentacyclic Triterpenes
A R T I C L E S
Scheme 3
Scheme 5
Scheme 4
the addition of a t-butyl carbocation to isobutylene in CH2Cl2
has been calculated to be only ca. 3-5 kcal/mol.15
We have subjected the hypothetical pathway 18 f 19 f
11 to an experimental test because it is so poorly precedented.
Specifically, the tetradeuterated epoxide 20 (corresponding
to unlabeled 10) was synthesized as shown in Scheme 5.
Cyclization of 20 in CH2Cl2 with MeAlCl2 as catalyst at
-94 °C provided the tetradeuterated products 21 and 22 (ratio
of 3:7, as expected). Oxidation of the mixture of 21 and 22
provided the tetralone 23 and unchanged 22 (Scheme 5).
in more detail with very interesting results. Control experi-
ments confirmed that tetracycle 11 is not converted to
pentacycle 2 under the conditions shown in Scheme 2
(MeAlCl2, CH2Cl2, -94 °C) or even at much longer reaction
times. Nor was 2 transformed into 11 under these conditions.
Therefore, it is clear that 2 and 11 are formed independently
by a split pathway from the common precursor, cation 18
(Scheme 4). The branch leading from 18 to 11, as shown in
Scheme 4, would appear to involve a highly unusual acyclic,
1,5-migration of a proton from the C(9) (ꢀ- to the cationic
center at C(8) to C(13)) to form the benzylic cation 19 and
the further deprotonation of 19, as shown. This is a rare (and
possibly unprecedented) example of such an intramolecular
rearrangement. It is clear that ∆H‡ for the intramolecular
proton transfer to the vinyl arene subunit must be quite small,
if the pathway shown in Scheme 4 is correct, since ∆H‡ for
1
Analysis of 23 by H NMR and mass spectroscopy showed
it to be the R-monodeuterated ketone 23, which moreover
was racemic, as shown by HPLC analysis using a Chiralcel
technologies OD-H column (hexanes/i-PrOH 99.5:0.5, flow
rate 1.0 mL/min; retention times: 20.0, 22.1 min16).
(15) Jenson, C.; Jorgensen, W. L. J. Am. Chem. Soc. 1997, 119, 10846–
10856.
(16) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am. Chem.
Soc. 2006, 128, 11348–11349.
9
J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8867

A R T I C L E S
Surendra and Corey
Scheme 6
Table 1. MeAlCl2-Catalyzed Epoxide-Initiated Cation-Olefin
Cyclization Reactions
a All reactions were carried out at -94 °C and 3.0 equiv of MeAlCl2
in CH2Cl2. b Isolated yields of products that were fully characterized by
NMR, IR, and MS. c A mixture of two double bond position isomers
(1:1) resulted, which was converted to pure 25 by treatment with
CH3SO3H in CH2Cl2. d Reaction afforded a mixture of para-/ortho-
substituted products.
Table 2. MeAlCl2-Catalyzed Epoxide-Initiated Cation-Olefin
Cyclization Reactions
The formation of racemic tetralone shows that the tetra-
cycles 11 and 21 are actually a 1:1 mixture of C(14)
diastereomers formed by the two simultaneous diastereomeric
rearrangement pathways shown in Scheme 6.
The two synthetic approaches to 1 and 2 that are described
above confirm the utility and power of the newer synthetic
methods that were employed. In particular, the efficient
construction of chiral epoxy polyolefinic substrates by
stereoselective multicomponent coupling reactions, together
with the use of epoxide-initiated cation-olefin polyannulation
can lead to especially short and effective syntheses. The value
of this tactical combination could be increased to an even
higher level if the efficiency of the cationic polyannulation
could be increased. This need represents one of the outstand-
ing challenges to present day synthetic science. Overcoming
this obstacle probably requires the invention of a methodol-
ogy that folds the polyolefinic substrate into a conformation
that is ideal for polyannulation to the required stereoisomer
using some type of control element. Such a preorganization
would surely lead to a much less negative ∆S‡ for the
cyclization and a considerably higher yield. The enhancement
would be especially significant for cyclizations in which
a All reactions were carried out at -94 °C and 3.0 equiv of MeAlCl2
in CH2Cl2. b Isolated yields of products that were fully characterized by
NMR, IR, and MS. c A mixture of two double bond position isomers
(1:1) resulted, which was converted to pure 33 by treatment with
CH3SO3H in CH2Cl2. d Reaction afforded
ortho-substituted products.
a mixture of para-/
quaternary stereocenters and sterically congested products
are being formed.
We have also applied the present methodology to the
synthesis of a number of other tetra- and pentacyclic products.
We summarize some of the results in Table 1 (tetracyclic
products) and Table 2 (pentacyclic products), which display
various polyolefinic substrates and the products obtained from
them by MeAlCl2-catalyzed, epoxide-initiated cation-olefin
cyclization in CH2Cl2 as solvent. The details of these
cyclizations and routes for the synthesis of the various
substrates can be found in the Supporting Information.
9
8868 J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008

Synthetic Approaches to Pentacyclic Triterpenes
A R T I C L E S
In conclusion, this research has demonstrated the synthetic
efficacy of multicomponent chain-assembly using sulfonylhy-
drazone or acyl silane chemistry and the overall synthetic power
of the tactical combination of this methodology with cationic
polyannulation reactions. We have also described the occurrence
of a remarkable 1,5-proton shift reaction which is so facile that
it competes with carbocation-olefin addition.
Supporting Information Available: Experimental procedures
and characterization data for all reactions and products, including
1
copies of H NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA802730A
9
J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8869