Synthetic access to bent polycycles by cation-π cyclization

Article abstract of DOI:10.1021/ol101410g

(Equation Presented). The presence of an ether oxygen within a chain undergoing cation-polyene cyclization has a profound influence on the stereochemistry of this important construction, apparently due to nucleophilic participation of oxygen in the cyclization process and formation of an oxonium intermediate, leading to bent fused ring systems.

Full text of DOI:10.1021/ol101410g

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3548-3551
Synthetic Access to Bent Polycycles by
Cation-π Cyclization
Ryan A. Shenvi and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge,
Massachusetts 02138
corey@chemistry.harVard.edu
Received June 18, 2010
ABSTRACT
The presence of an ether oxygen within a chain undergoing cation-polyene cyclization has a profound influence on the stereochemistry of
this important construction, apparently due to nucleophilic participation of oxygen in the cyclization process and formation of an oxonium
intermediate, leading to bent fused ring systems.
The carbocation-initiated polycyclization of appropriate
polyunsaturated substrates is one of the most powerful
molecular constructions in synthetic chemistry. It is also an
extremely important biosynthetic process, for instance, in the
one-step tetracyclization of (S)-2,3-oxidosqualene1 to a sterol
(Figure 1, 1 f 2). The carbocation-π-cyclization process
is also the dominating pathway for the biosynthesis of cyclic
terpenoids. Cationic cyclization has served well for the
chemical syntheses of many complex terpenoids, e.g.,
pentacyclosqualene2a (an early example), dammarenediol,2b
Figure 1. Biosynthetic conversion of (S)-2,3-oxidosqualene (1) to
lanostenol,2c onocerin,2d serratenediol,2e ꢀ-amyrins, and
lupeol.2f,g However, there is still a large gap in efficiency
between biosynthetic polycyclizations and present chemical
syntheses. Unlike the enzymic cyclizations which proceed
with an efficiency of ca. 99% per ring formed, the chemical
cyclizations are, at best, only 70-80% efficient per ring
formed. This difference arises partly because the cyclization
protosteryl cation (2).
substrate is held by the enzyme in a prefolded conformational
arrangement which selects the proper π-face of a double bond
for attack by the propagating carbocation, minimizing the
decrease in the entropy of activation of enzymic cyclization.
Although there is no known way to mimic this template-
guided cyclization, the entropic problem may be diminished
by conducting cyclization at the lowest possible temperature
(to minimize the (positive) T∆Sq component of the free
energy of activation (∆Gq)) in CH2Cl2 with MeAlCl2 as
catalyst. Functional groups more basic than epoxide are not
tolerated. The studies described herein were undertaken to
gain a better understanding of the relationship between
substrate structure and π-facial selectivity and to extend the
(1) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew. Chem.,
Int. Ed. 2000, 39, 2812–2833.
(2) (a) Corey, E. J.; Sauers, R. R. J. Am. Chem. Soc. 1957, 79, 3925–
3926. (b) Corey, E. J.; Lin, S. A. J. Am. Chem. Soc. 1996, 118, 8765–
8766. (c) Corey, E. J.; Lee, J.; Liu, D. R. Tetrahedron Lett. 1994, 35, 9149–
9152. (d) Mi, Y.; Schreiber, J. V.; Corey, E. J. J. Am. Chem. Soc. 2002,
124, 11290–11291. (e) Zhang, J.; Corey, E. J. Org. Lett. 2001, 3, 3215–
3216. (f) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2009, 131, 13928–
13929. (g) For a review, see: Yoder, R. A.; Johnston, J. N. Chem. ReV.
2005, 105, 4730–4756.
10.1021/ol101410g  2010 American Chemical Society
Published on Web 07/12/2010

Figure 2. Trans-anti-trans cyclization of 3 to 4 producing 9R-H
stereochemistry.
Figure 4. Two modes of cyclization for the formation of ring B:
the 9R-H or 9ꢀ-H pathways.
strongly with the benzoate carbonyl, and essentially com-
pletely (with 3 equiv of EtAlCl2), and that coordination
removes electron density from the terminating double bond
which prevents formation of the second ring. Because of this
result, we next examined the two bulky silyl ethers of 10,11-
epoxyfarnesol 12a and 12b (Scheme 1), the assumption being
that Lewis acid complexation with the sterically hindered
silyloxy oxygen would not be a complication. Indeed, in each
case bicyclization was the principal reaction pathway (70-85%
isolated yield of 13 and 14 after desilylation and column
chromatography on silica gel). For each of these substrates
there was a near balance between 9R-H and 9ꢀ-H pathways
for cyclization, as indicated in Scheme 1. The 9R-H and 9ꢀ-H
products each consisted of a mixture of one endo- and one
exocyclic olefinic species.6
scope of cyclization. One motivation for this study was the
observation that the common stereochemical pathway for
cyclization, exemplified by the conversion of 3 to the A/B/
C/trans-anti-trans product 4 (Figure 2),3 is not universal
since cases such as 5 f 6 are known (Figure 3)4 which
would seem to involve cations 7 and 8 and a different
π-facial selectivity at the second olefinic linkage. This
difference in π-facial selectivity at the double bond involved
in closure of the second ring is of great interest since it is
clearly a branch point in the biosynthetic cyclizations which
lead to sterols or plant triterpenes.5
Scheme 1. Cyclization of Silyl Ethers 12a and 12b To Produce
Equimolar Mixtures of 9R-H and 9ꢀ-H Productsa
Figure 3. Cyclization of 5 to 6 through cation 8, which possesses
9ꢀ-H stereochemistry.
a Conditions: (1) EtAlCl2 (3 equiv added slowly), CH2Cl2 (0.01 M),
-78 °C, 3 h; (2) TBAF (1.5 equiv), THF (0.5 M), 25 °C, 6 h.
Our initial research of the relationship between the
structure of the substrate and the stereochemistry of closure
of the second ring in epoxide-initiated cation-olefin cy-
clizations was conducted with simple epoxyfarnesol deriva-
tives. In the discussion which follows, the two modes of
bicyclization will be referred to as the 9R-H or 9ꢀ-H
pathway, as structurally indicated with formulas 9-11
(Figure 4). This phase of our work was carried out with
CH2Cl2 as solvent, and RAlCl2 or R2AlCl (3 equiv, e.g.,
EtAlCl2) as catalytic Lewis acid at -78 °C, conditions which
generally are most favorable for epoxide-initiated cationic
polycyclization reactions.
The close similarity of ratios for the 9R-H and 9ꢀ-H
cyclization pathways came as a surprise, given the consider-
able number of reported examples in which the 9R-H product
is strongly preferred. One possible reason for the exceptional
behavior of the substrates 12a and 12b becomes apparent
when the reported sequence 5 f 6 (presumably via 7 and
8) is recalled. If it were generally true that the 9ꢀ-H pathway
is favored for reactions that proceed to bicyclic 6/6-fused
product via a bicyclic 6/5-fused intermediate, it is logical to
explain the formation of the 9ꢀ-H product 14 via the
oxonium intermediate 15, which then converts to 16 (Figure
5). To test whether the 9ꢀ-H pathway is made more favorable
if the incipient ring B is generated via a 5-membered-like
precursor, cyclization of the corresponding allylsilane 17 was
examined (Scheme 2).
When the benzoate of 10,11-epoxyfarnesol was examined
under standard conditions for cyclization only monocyclic
reaction products were obtained. The most obvious explana-
tion for this result is that the Lewis acid coordinates more
(3) Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2008, 130, 8865–8869.
(4) Corey, E. J.; Roberts, B. E. Tetrahedron Lett. 1997, 38, 8921–8924.
(5) Dev, S.; Nagasampagi, B. A. Triterpenoids; CRC Press: Boca Raton,
1986; Vol. 1.
(6) For details of analyses and quantitative data, see the Supporting
Information.
Org. Lett., Vol. 12, No. 15, 2010
3549

Scheme 3
.
Cyclization of Allylstannane 23 To Form a Mixture
of Diastereomers 24a and 24b
Figure 5. Intermediacy of an oxygen-stabilized secondary cation
15 may explain the formation of 9ꢀ-H products.
consequence of a much earlier transition state for ring B
closure, i.e., a much longer incipient C-C bond in the
transition state.
Behavior similar to that just described for 23 was observed
in the cyclization of epoxide 25 which leads to a 1:1 mixture
of 26a and 26b (Scheme 4). In this case also, there is no
π-face selectivity in the formation of ring B, probably for
the same reason: a longer C-C bond in the transition state
for B-ring closure and a small energy difference between
the diastereomeric transition states.7
The substrate 17 was synthesized from 9,10-epoxyfarnesyl
benzoate by coupling with the reagent derived from dim-
ethylphenylsilyllithium and copper(I) cyanide. Cyclization
of 17 under the conditions developed for 12a and 12b and
subsequent desilylation with TBAF afforded an equimolar
mixture of two products which were chromatographically
separated after conversion to their 3,5-dibromobenzoates 20
and 21 (chromatography on AgNO3-impregnated silica gel).
The stereochemistry of the decalin product 19 corresponds
to the usual 9R-H cyclization (confirmed by X-ray crystal-
lographic analysis of 21, mp 144-146 °C), whereas that of
the hydrindane 18 corresponds to the π-facial selection of
the 9ꢀ-H geometry (confirmed by NOE studies of 20). This
result for 18 is consistent with the proposal that cyclization
via a 5-membered B-ring structure can involve the opposite
π-face selectivity to that which is generally found for
6-membered B-ring formation.
Scheme 4
.
Cyclization of Allylsilane 25 To Form a Mixture of
Diastereomers 26a and 26b
Scheme 2
. Cyclization of Silane 17 Giving Rise To Hydrindane
18, Which Possesses 9ꢀ-H sStereochemistrya
It was found that 9,10-epoxyfarnesyl phenyl ether 27
underwent efficient conversion to the tetracyclic product 28a
in a single step (Scheme 5). Evidently, the phenolic oxygen
is sufficiently nonbasic to allow monocoordination of EtAlCl2
to the more basic epoxide function, in contrast to the benzyl
and cinnamyl ethers, which gave essentially no polycyclic
products under identical reaction conditions. Of great interest
is the fact that cyclization of 27 favored the 9ꢀ-H pathway
Scheme 5
.
Cyclization of Phenyl Ether 27 To Produce
Predominantly 9ꢀ-H Product 28a
a Conditions: (1) EtAlCl2 (3 equiv added slowly), CH2Cl2 (0.01 M),
-78 °C, 3 h; (2) TBAF (1.5 equiv), THF (0.5 M), 25 °C, 6 h; (3) DCC
(1.1 equiv), 3,5-dibromobenzoic acid (22) (1.1 equiv), DMAP (0.05 equiv),
CH2Cl2 (0.1 M), 25 °C, 1 h.
Further studies uncovered a surprising effect of π-bond
basicity on the stereochemistry of B-ring formation. The
more π-basic tri-n-butylstannyl analogue 23 of the allylic
silane 17 underwent cyclization under the standard conditions
to produce a 1:1 mixture of the two diastereomeric bicyclic
structures 24a and 24b (Scheme 3). This complete lack of
π-face selectivity in the formation of ring B may well be a
3550
Org. Lett., Vol. 12, No. 15, 2010

in preference to the 9R-H path, since 28a predominated over
the C9 diastereomer 28b by 2:1 (see the Supporting Informa-
tion). The major tetracyclic product was isolated by chro-
matography after conversion to the 3,5-dibromobenzoate
(51% overall yield from 27). The assignment of stereochem-
istry to 28a and 28b was made unambiguously by 1H NMR
measurements at 500 MHz and NOE correlations. It should
be noted that decalin cation 29 must undergo a conforma-
tional change8 from initially formed boatlike conformer 29
to the chair form 30 before closure of ring C to produce
tetracycle 28a.
Scheme 7
.
Oxygen Substitution on the Arene Is Tolerated under
Cyclization Conditions
The contrast between the cyclization pathways 27 f 28a
and 3 f 4 (Figure 6) provides another indication of the
importance of the lone pairs of oxygen in influencing the
balance between the 9R-H and 9ꢀ-H modes of reaction.
We also investigated the cyclization of the difarnesyl 1,5-
naphthyl ether 37 (Scheme 8) which was synthesized in one
step from 1,5-dihydroxynaphthalene and (S)-10,11-epoxy-
farnesyl bromide. Treatment of 37 with EtAlCl2 (6 equiv)
in CH2Cl2 at -78 °C led to a mixture of diols, which were
converted to the corresponding 3,5-dibromobenzoates and
purified by chromatography to give octacycle 38 (31% from
37), the structure of which was confirmed by NMR and
single-crystal X-ray analysis.8
Scheme 8. Bidirectional Cyclization of 37 To Octacycle 38
Figure 6. Cyclization of 27 f 28a compared to the cyclization of
3 f 4.
Cyclization of the analogous 1-naphthyl ether 31 also
proceeded cleanly and afforded the pentacycle 32 as the
major product (Scheme 6). A slight increase in the diaste-
reoselectivity of cyclization (9ꢀ-H/9R-H, 2.4:1) was observed
relative to the cyclization of phenyl ether 27 (9ꢀ-H/9R-H,
2:1).
The unique twisted, rigid octacyclic structure of 38,
prepared in just a few steps from farnesol and commercially
available 1,5-dihydroxynapthalene, would be difficult to
make by other methods.9 It further demonstrates the power
of cationic polycyclization methodology to produce a wide
range of interesting structures.
Scheme 6. Cyclization of 31 To Produce Pentacycle 32
Acknowledgment. We thank the NIH for a Postdoctoral
Fellowship to R.A.S. and Dr. Shao-Liang Zheng (Harvard)
for X-ray diffraction analysis.
Supporting Information Available: Experimental pro-
cedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
Additional oxygen substitution on the aryl moiety is also
tolerated in the cationic polycyclization process and as such
can provide useful reactive centers for elaboration to more
complex structures (Scheme 7). The farnesyl ether derived
from hydroquinone (33) underwent efficient cyclization to
tetracycle 35 in good yield and in 2.3:1 excess over the 9R-H
epimer (70% combined yield of diastereomers). Similarly,
the phloroglucinol-derived bis-triisopropylsilyl (TIPS) ether
34 underwent cyclization to the corresponding tetracycle 36
with a 9ꢀ-H to 9R-H ratio of 3:1 (total yield 62%).
OL101410G
(7) A less likely extreme case can also be visualized in which electron
transfer occurs from the π-electron-rich terminating CdC subunit to the
monocyclic carbocation (without stereoselectivity) to give a diradical that
collapses to the 1:1 mixture of 24a and 24b.
(8) Corey, E. J.; Wood, H. B. J. Am. Chem. Soc. 1996, 118, 11982–
11983.
(9) Corey, E. J.; Luo, G.; Lin, L. S. Angew. Chem., Int. Ed. 1998, 37,
1126–1128.
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