Application of chiral cationic catalysts to several classical syntheses of racemic natural products transforms them into highly enantioselective pathways

Article abstract of DOI:10.1021/ja046154m

This paper describes the application of chiral oxazaborolidinium cations of type 2 to various enantioselective Diels-Alder reactions that have served as early key steps for the syntheses of complex natural products. In the original syntheses these Diels-A

Full text of DOI:10.1021/ja046154m

Published on Web 10/05/2004
Application of Chiral Cationic Catalysts to Several Classical
Syntheses of Racemic Natural Products Transforms Them
into Highly Enantioselective Pathways
Qi-Ying Hu, Gang Zhou, and E. J. Corey*
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
Received June 29, 2004; E-mail: corey@chemistry.harvard.edu
Abstract: This paper describes the application of chiral oxazaborolidinium cations of type 2 to various
enantioselective Diels-Alder reactions that have served as early key steps for the syntheses of complex
natural products. In the original syntheses these Diels-Alder reactions produced racemic adducts and led
to racemic target molecules unless a separation of enantiomers by classical resolution was employed. By
use of chiral catalysts of type 2, chiral products were obtained directly from Diels-Alder reactions of achiral
components in excellent yield and enantioselectivity and with the mechanistically predicted absolute
configuration. As a result, a number of classical syntheses could be converted to enantioselective versions,
including (1) cortisone/cortisol (Merck/Sarett), (2) dendrobine (Kende), (3) vitamin B12 (Eschenmoser), (4)
myrocin C (Chu-Moyer/Danishefsky), (5) coriolin and hirsutene (Mehta), (6) dendrobatid 251F (Aube´), (7)
silphinene (Ito), and (8) nicandrenone core (Stoltz/Corey).
The Diels-Alder reaction, one of the most powerful con-
structions for the assembly of carbon compounds, has been used
as a key step in many notable syntheses of complex natural
products in its original form, which converted achiral compo-
nents to racemic adducts. In this paper we describe the formal
conversion of eight of these classical syntheses to modern
enantioselective versions. This transformation has been made
possible by the recent invention of extraordinarily powerful
chiral catalysts of broad scope and predictable enantio- and
regioselectivity. These catalysts are generated simply by pro-
tonation of oxazaborolidines of type 1 by triflic acid, CF3SO3H,
or triflimide, (CF3SO2)2NH, to form the corresponding cis-fused
oxazaborolidinium cation, 2.1 The face selectivity of the
ketones having an R-C-H subunit, a preference for R-C-H‚‚‚O
hydrogen bonding1b,c favors reaction via complex 4. For 1,4-
benzoquinones a detailed set of selection rules have been
developed that allows the prediction of both enantioselection
and regioselection in Diels-Alder reactions promoted by the
chiral catalysts 2.1e,3 The following sections of this paper
describe the application of catalysts 2 to new enantioselective
versions of Diels-Alder reactions that were first used for some
of the most interesting multistep syntheses of natural products
of the 20th century.
Sarett’s Total Synthesis of Cortisone. The challenge of
producing cortisone/cortisol, one of the most important of all
modern therapeutic innovations, dominated synthetic organic
chemistry for two decades following World War II. The
development of the first workable total synthesis by a group at
Merck headed by Sarett was one of the crowning achievements
of that period.4,5 The initial step in this cortisone synthesis was
a thermal Diels-Alder reaction of 5 and the ethyl ether analogue
of 6, which produced the corresponding racemate of adduct 7
(Scheme 1). To obtain the natural enantiomer of cortisone by
enantioselective Diels-Alder reactions depends on the structural
type of the dienophile component. For 2-substituted R,â-enals,
formyl C-H‚‚‚O hydrogen bonding leads to a preferred pathway
via 3,1a,b,2 whereas for R,â-unsaturated esters, lactones, and
(1) (a) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124,
3808-3809. (b) Ryu, D. H.; Lee, T. W.; Corey, E. J. J. Am. Chem. Soc.
2002, 124, 9992-9993. (c) Ryu, D. H.; Corey, E. J. J. Am. Chem. Soc.
2003, 125, 6388-6390. (d) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett.
2003, 5, 3979-3982. (e) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem.
Soc. 2004, 126, 4800-4802. (f) Hu, Q.-Y.; Rege, P. D.; Corey, E. J. J.
Am. Chem. Soc. 2004, 126, 5984-5986.
(2) Corey, E. J.; Lee, T. W. J. Chem. Soc., Chem. Commun. 2001, 1321-
1329.
(3) White, J. D.; Choi, Y. Org. Lett. 2000, 2, 2373-2376.
9
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J. AM. CHEM. SOC. 2004, 126, 13708-13713
10.1021/ja046154m CCC: $27.50 © 2004 American Chemical Society

Use of Chiral Cationic Catalysts for Enantioselection
A R T I C L E S
Scheme 1
7 was converted efficiently via intermediates 9 and 10 to the
crystalline diol 11, which was obtained enantiomerically pure
(by gas chromatographic analysis)7 simply by recrystallization
23
from CHCl3 (mp of pure 11, 194-195 °C; [R]D +91). The
enantiomeric purity of the original Diels-Alder adduct 7 was
determined after conversion in two steps to the R-methoxy-(R-
trifluoromethyl)phenylacetate (MTPA, Mosher) ester 12, as
1
shown below, and H and 19F NMR analysis. The absolute
configuration of 7 follows from previous studies of the closely
related enantioselective reactions, for example, of 1,4-benzo-
quinone (5) with 2-triisopropylsilyloxy-1,3-butadiene.3
Kende’s Total Synthesis of Dendrobine. In 1974 Kende
and Bentley8 described a simple total synthesis of (()-
dendrobine that derived much of its brevity from a key thermal
Diels-Alder reaction of 1,3-butadiene with methoxythymo-
quinone 13 to produce the racemic Diels-Alder adduct 14
(Scheme 2). When we conducted the reaction of these compo-
Scheme 2
the Sarett route, conventional resolution was applied to the
brucine salt of an advanced tricyclic intermediate corresponding
to the A/B/C network of cortisone.5 Partly because of the
cumbersome nature of this process and the unavoidable loss of
more than half of an advanced tricyclic synthetic intermediate,
this leap forward in chemical synthesis still fell short of
commercial application. In the present work, the key initial
Diels-Alder step has been recast into a new highly efficient
enantioselective version. Specifically, reaction of 5 and 6
occurred rapidly in the presence of 20 mol % chiral oxazaboro-
lidinium catalyst 8 in toluene solution at -78 °C to give the
chiral adduct 7 with 95:5 enantioselectivity and 100% regiose-
lectivity and diastereoselectivity (rs and ds) in 95% yield after
2.5 h.6 The chiral adduct 7 was shown to be spectroscopically
and chromatographically identical with racemic 7, produced by
thermal reaction of 5 and 6, the structure and relative stereo-
chemistry of which had been established.4 The orientation of
the methyl group in 7 corresponds to the expected endo
transition-state preference. Following the Merck route, adduct
nents in the presence of 20 mol % catalyst ent-8 in toluene at
-50 °C for 48 h, the chiral adduct 14 was obtained with 99%
enantiomeric purity in 99% yield.7 This highly successful result
opens the way for the enantioselective synthesis of (-)-
dendrobine via the Kende sequence.8 It should be noted that
the synthesis of chiral 14 in Scheme 2 is the first example of
the use of 1,3-butadiene as a component in an enantioselective
Diels-Alder pathway to a natural product.
Eschenmoser’s Photochemical Route to Vitamin B12. In
Eschenmoser’s ingenious photochemical synthesis of vitamin
B12, the cobryic acid core was assembled from four chiral
pyrrolidones, 15-18, representing the A, B, C, and D subunits
of the corrin ring system (Scheme 3).9 These intermediates, in
turn, were synthesized from the enantiomeric dilactones 19 (for
15-17) and 20 (for 18). Finally, the dilactones 19 and 20 were
obtained from the chiral keto acids 21 and 22, which were
produced as a racemic mixture by the Diels-Alder reaction and
(4) (a) Sarett, L. H.; Arth, G. E.; Lukes, R. M.; Beyler, R. E.; Poos, G. I.;
Johns, W. F.; Constantin, J. M. J. Am. Chem. Soc. 1952, 74, 4974-4976.
(b) Sarett, L. H.; Lukes, R. M.; Poos, G. I.; Robinson, J. M.; Beyler, R. E.;
Vandergrift, J. M.; Arth, G. E. J. Am. Chem. Soc. 1952, 74, 1393-1397.
(c) For assignment of configuration see Beyler, R. E.; Sarett, L. H. J. Am.
Chem. Soc. 1952, 74, 1406-1411. (d) Poos, G. I.; Arth, G. E.; Beyler, R.
E.; Sarett, L. H. J. Am. Chem. Soc. 1952, 74, 422-429. (e) Lukes, R. M.;
Poos, G. I.; Beyler, R. E.; Johns, W. F.; Sarett, L. H. J. Am. Chem. Soc.
1953, 75, 1707-1712. (f) Sarett, H. L.; Johns, W. F.; Beyler, R. E.; Lukes,
R. M.; Poos, G. I.; Arth, G. E. J. Am. Chem. Soc. 1953, 75, 2112-2118.
(5) See also (a) Fieser, L. F.; Fieser, M. Steroids; Reinhold Publishing Co.:
New York, 1959; pp 711-713. (b) Blickenstaff, R. T.; Gosh, A. C.; Wolf,
G. C. Total Synthesis of Steroids; Academic Press: New York, 1974; pp
182-187.
(6) On a larger scale the use of 5 mol % catalyst 8 would probably suffice
since the reaction could be run at higher concentrations of the Diels-Alder
components. In any event (S)-diphenylprolinol, from which catalyst 8 is
derived, is readily recovered for reuse.
(7) Enantiomeric purity was determined by gas chromatographic analysis on
a chiral γ-TA column.
(8) Kende, A. S.; Bentley, T. J. J. Am. Chem. Soc. 1974, 96, 4332-4334.
(9) Eschenmoser, A.; Witner, C. E. Science 1977, 196, 1410-1420.
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J. AM. CHEM. SOC. VOL. 126, NO. 42, 2004 13709

A R T I C L E S
Scheme 3
Hu et al.
Scheme 5
The synthetic pathway between 21 and vitamin B12 via 19 and
15, 16, and 17 has previously been established. Catalyst 24 (or
its analogue 24, Ar ) o-CF3C6H4) gave a significantly better
level of enantioselectivity than the corresponding B-o-tolyl
analogue (73% ee), which we have previously employed for
enantioselective syntheses of estrone and desogestrel.1f In a
similar way 23 and 1,3-butadiene were combined by use of the
catalyst 26 to form adduct 27 in 95% ee and 91% yield. The
transformation of 27 to 22, the required intermediate for B12
synthesis via 20 and 18, was accomplished as described just
above for 25 f 21.10
Scheme 4
Chu-Moyer/Danishefsky Synthesis of (()-Myrocin C. The
complex antitumor antibiotic myrocin C has been synthesized
in racemic form by Chu-Moyer and Danishefsky11 via an
impressive multistep sequence that commenced with the Diels-
Alder reaction of diene 28 and 1,4-benzoquinone to form (()-
adduct 29. We have been able to carry out this initial [4 + 2]
cycloaddition enantioselectively as outlined in Scheme 5 using
catalyst ent-8 (20 mol %) at -95 °C for 4 h to give the chiral
tricyclic dione 29 in 85% ee and 80% yield. The enantiomeric
purity of 29 was ascertained by reduction (LiAlH4) of the dione
to the corresponding diol, conversion to the MTPA ester of the
corresponding monohydroxy 4 f 6 cyclic ether, and 19F NMR
analysis. The Chu-Moyer/Danishefsky synthesis of (()-myrocin
C proceeded via the intermediates (racemic) shown at the bottom
of Scheme 5.
G. Mehta’s Synthesis of (()-Triquinanes Including Co-
riolin and Hirsutene. The elegant synthetic route developed
by Mehta to the triquinane family of natural products testifies
eloquently to the power and versatility of the Diels-Alder
reaction for the synthesis of complex molecules.12 The reaction
of cyclopentadiene with 2,5-dimethyl-1,4-benzoquinone in the
presence of 20 mol % catalyst 8 in CH2Cl2 proceeded to
completion at -95 °C in just 2 h to afford the endo adduct 30,
[R]D25 +11.3 (CHCl3) in 99% ee (by HPLC analysis) and 99%
yield in an enantioselective version of Mehta’s first step on the
pathway to triquinanes (Scheme 6). A few of the following key
obtained from that mixture by resolution of the salts with
1-phenylethylamine.9 In this research 21 and 22 have been
synthesized enantioselectively from the same components by
use of two different chiral catalysts. Scheme 4 details the
synthesis of the dextrorotatory keto acid 21. Reaction of the
aldehyde trifluoroethyl ester 23 with 1,3-butadiene in the
presence of 20 mol % catalyst 241f [Ar ) o-(i-propyl)phenyl]
at -78 °C afforded the adduct 25 in 95% ee and 89% yield.
The addition of methyl to the formyl group of 25 and ester
reduction produced a diol which upon two-stage oxidation
afforded the chiral keto acid 21 in good overall yield from 25.
(10) The enantiomer of catalyst 26 obviously could be used for the enantiose-
lective synthesis of 25.
(11) (a) Chu-Moyer, M. Y.; Danishefsky, S. J.; Schulte, G. K. J. Am. Chem.
Soc. 1994, 116, 11213-11228. (b) Chu-Moyer, M. Y.; Danishefsky, S. J.
J. Am. Chem. Soc. 1992, 114, 8333-8334.
(12) (a) Mehta, G.; Murthy, A. N.; Reddy, D. S.; Reddy, A. V. J. Am. Chem.
Soc. 1986, 108, 3443-3452. (b) Mehta, G.; Reddy, A. V. J. Chem. Soc.,
Chem. Commun. 1981, 756-757.
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Use of Chiral Cationic Catalysts for Enantioselection
A R T I C L E S
Scheme 6
Scheme 7
Scheme 8
steps in the Mehta approach to racemic triquinanes are shown
in Scheme 6, which also illustrates the new enantioselective
modification via 31 and 32.
Bicyclo[2.2.1]heptene Routes to Dendrobatid 251F and
Other Natural Products. Bicyclo[2.2.1]heptene intermediates
that are available from Diels-Alder reactions have served as
valuable intermediates for the synthesis of a number of complex
molecules, for example, gibberellic acid and prostanoids.13 In
this section we illustrate the application of the cationic oxaza-
borolidinium catalyst 24, Ar ) o-tolyl, to the synthesis of
intermediate 34 that has been used for the construction of various
natural products including E- and Z-â-santalols14 (important
perfumery components) and dendrobatid 251F.15 The previously
described syntheses have employed chiral controller groups to
achieve diastereoselective access to 34 in contrast to the present
methodology with a chiral catalyst. Reaction of E-crotyl
trifluoroacetate with cyclopentadiene in the presence of 10 mol
% catalyst 24, Ar ) o-tolyl, in CH2Cl2 at -50 °C for 16 h
produced the Diels-Alder adduct 33 in 91% yield with an endo/
exo ratio of 97/3 and an enantiomeric purity of the endo product
of 98% (Scheme 7). Base hydrolysis generated the correspond-
ing acid 34 (95%), recently used for the total synthesis of
dendrobatid 251F.
mol % catalyst 24, Ar ) o-CF3C6H4, afforded 35 in 95% yield
as an 82/18 mixture of endo and exo diastereomers, which were
separated by column chromatography on silica gel. The endo
adduct was analyzed by GC and found to be 96% enantiomeri-
cally pure.17 This highly enantioselective synthesis of 35
provides the missing link in a formal synthesis of the naturally
occurring form of silphinene.
Enantioselective Synthesis of the Tetracyclic Core of the
Nicandrenones. In 2000 we reported the development of an
enantioselective synthesis of the nicandrenone family of potent
insect antifeedants including NIC-1 lactone, NIC-1 lactol, and
NIC-10.18 An important step in the pathway of synthesis was a
remarkable exo-diastereoselective Diels-Alder reaction of the
chiral R,â-enone 38 and the achiral diene 39 to give 40 under
catalysis by MeAlCl2 in CH2Cl2 at -78 °C, as shown in Scheme
9.18-20 We report herein a catalytic enantioselective approach
to the construction of the chiral tetracyclic framework of 40
from achiral components that takes advantage of the cationic
catalyst 8 and provides ready access to the core ring system of
the nicandrenones. The key steps for this process are outlined
in Scheme 10. Reaction of the Dane diene 41 with the R,â-enal
ester 42 in the presence of 25 mol % catalyst 8 in toluene at
-50 °C for 72 h afforded the Diels-Alder product 43 in 95%
ee and 86% yield. The formation of adduct 43, assigned on the
A more challenging test for catalysts of type 2 is the synthesis
of silphinene via a bicyclo[2.2.1]heptene intermediate. The
synthesis of racemic silphinene has previously been carried out
from the racemic Diels-Alder adduct 35 via the intermediates
36 and 37 as indicated in Scheme 8.16 The catalytic enantiose-
lective synthesis of adduct 35 is especially interesting and
challenging because of the relative unreactivity of 2-cyclopen-
tenone in catalytic Diels-Alder reactions. We have examined
three catalysts of type 24, Ar ) o-CH3C6H4, o-i-PrC6H4, and
o-CF3C6H4, and have determined that the last of these affords
the best results. The reaction of cyclopentadiene and 2-cyclo-
pentenone in CH2Cl2 at -50 °C for 16 h in the presence of 10
(17) The absolute configuration of adduct 35 follows from analogy with a large
number of related examples (see ref 1).
(13) For a recent review of such enantioselective Diels-Alder routes see Corey,
E. J. Angew. Chem., Int. Ed. 2002, 41, 1650-1667.
(18) Stoltz, B. M.; Kano, T.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9044-
9045.
(14) Krotz, A.; Helmchen, G. Tetrahedron Asymmetry 1990, 1, 537-540.
(15) Wrobleski, A.; Sahasrabuhde, K.; Aube´, J. J. Am. Chem. Soc. 2002, 124,
9974-9975.
(19) See also Ge, M.; Stoltz, B. M.; Corey, E. J. Org. Lett. 2000, 2, 1927-
1929.
(20) For the synthesis of the chiral R,â-enone 38, see Sarakinos, G.; Corey, E.
(16) Tsunoda, T.; Kodama, M.; Ito, S. Tetrahedron Lett. 1983, 24, 83-86.
J. Org. Lett. 1999, 1, 811-814.
9
J. AM. CHEM. SOC. VOL. 126, NO. 42, 2004 13711

A R T I C L E S
Scheme 9
Hu et al.
Scheme 11
Scheme 10
42 under catalysis by 8 with the results that are summarized in
Table 1. It is apparent from these data that the catalyzed
reactions proceed with uniformly good yields and enantiose-
lectivities. In the case of 47, R ) CH2COOMe, the structure of
the product was determined unambiguously to be that shown
by single-crystal X-ray diffraction analysis (data included in
Supporting Information). It is noteworthy not only that these
reactions are exo-selective but also that they occur with the
opposite regioselectivity to that with the R,â-enal 48 (see
Scheme 11). The reaction of 48 with the Dane diene 41 under
catalysis by 24, Ar ) o-tolyl, has recently been used in a short
and efficient enantioselective synthesis of estrone via adduct
49 as summarized in Scheme 11.1f The contrasting regiopref-
erence in the Diels-Alder reactions of 41 with 48 vs 43, though
surprising at first sight, can be rationalized in terms of subtle
steric effects. First, the Dane diene 41 affords a stable cationic
intermediate regardless of whether it is attacked electrophilically
at the terminal CH2 of the diene (giving a disecondary allylic
cation) or at the endocyclic CH terminus (which gives a
p-methoxybenzylic cation). Diels-Alder reactions of 41 are
known to involve a delicate balance between both modes of
attack and to follow different pathways with different dieno-
philes and Lewis acids.21 For an asynchronous transition state,
attack by a bulky electrophile would normally be favored at
the terminal methylene of 41 rather than the endocyclic terminus
of the diene. Therefore, the effective steric bulk of the group
attached â to the formyl carbon of 46 (Table 1) relative to
COOEt in 48 may account in part for the orientational
divergence of 46 and 48 in the reactions with diene 41.
(Electronic differences may also play a secondary role since
the complex between 48 and 8 would clearly be more electron-
deficient than those between 46 and 8, possibly leading to a
more synchronous [4 + 2] cycloaddition.) Further support for
the significant role of the bulk of the â-substituent in determining
the regiochemistry of chiral Lewis-acid-catalyzed [4 + 2]
cycloaddition to 41 comes from the study of the reaction of
2-methylacrolein with 41 under catalysis by oxazaborolidinium
basis of X-ray crystallographic analysis of the lower homologue
(two CH2 groups between the MeOOC and the tricyclic nucleus;
see Table 1 below), requires an exo arrangement of 41 and 42
Table 1. Exo-Selective Diels-Alder Reactions of Diene 41 and
Catalyst 8
R in 46, 47
conditions
ee for 47, yield (%)
-COOMe
-50 °C, 48 h
92, 80
93, 92
98, 94
95, 86
-OTIPS
-50 °C, 48 h
-CH2COOMe
-(CH2)2COOMe
-78 to -50 °C, 56 h
-50 °C, 72 h
in the [4 + 2] cycloaddition transition state. As is discussed
below, the exo preference over the usually favored endo pathway
is a consequence of steric repulsions in the transition state
between the aromatic ring of 41 and the o-tolyl group of the
catalyst 8. Aldol ring closure of 43 provided the â-hydroxy ester
44, which was selectively oxidized to the corresponding â-keto
ester and demethoxycarbonylated by heating with wet NaCl in
dimethyl sulfoxide to give the nicandrenone core structure 45,
as shown in Scheme 10.
(21) (a) Quinkert, G.; Grosso, D. M.; Do¨ring, A.; Do¨ring, W.; Schenkel, R. I.;
Bauch, M.; Dambacher, G. T.; Bats, J. W.; Zimmermann, G.; Durner, G.
HelV. Chim. Acta 1995, 78, 1345-1391. (b) Stojanac, Z.; Dickinson, R.
A.; Stojanac, N.; Woznow, R. J.; Valenta, Z. Can. J. Chem. 1975, 53, 616-
618. (c) Das, J.; Kubela, R.; MacAlphile, G. A.; Stojanac, Z.; Valenta, Z.
Can. J. Chem. 1979, 57, 3308-3319. (d) Singh, G. J. Am. Chem. Soc.
1956, 78, 6109-6115. (e) Dane, E.; Eder, K. Liebigs Ann. Chem. 1939,
539, 207-212.
We have examined the Diels-Alder reactions of the Dane
diene 41 with three lower homologues/analogues of R,â-enal
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Use of Chiral Cationic Catalysts for Enantioselection
A R T I C L E S
Scheme 12
significant differences in steric repulsion between the endo and
exo pathways, so it is understandable that the normally favored
endo pathway (50, endo) is observed. In contrast for regiopref-
erence involved in the nicandrenone synthesis (51), the endo
pathway (endo-51) is greatly disfavored vs the exo (exo-51) by
serious steric repulsion between the aryl group on boron of
catalyst 8 and the aromatic ring of the diene component.
Conclusion. The recent development of catalysts for the
enantioselective construction of carbon rings has dramatically
changed the landscape of chemical synthesis of complex natural
products. The results described in this paper demonstrate that
the rapid rate of progress made over the past few decades13
continues unabated and has, if anything, accelerated in the last
three years because of the discovery of chiral catalysts of type
2. These catalysts and others still to be invented promise
important further improvements in the logic, power, and
sophistication of chemical synthesis. One remarkable feature
of the new catalysts is their ease of use and practicality. From
an intellectual point of view, the mechanistic clarity and
predictability of their catalytic action is both remarkable and
unsurpassed. The examples of catalytic enantioselective Diels-
Alder reactions described in this paper all followed the expected
course to give the predicted major enantiomer with high
selectivity and excellent yield. With the inclusion of our new
enantioselective methodology, each of the classical syntheses
discussed in this paper gains further luster and beauty.
reagent 8, which follows the same regiopath as 41 + 48 f 49,
as shown in Scheme 11.
Supporting Information Available: Experimental procedures
for the preparation of catalysts 8, 24, and 26 and the reactions
used for the enantioselective synthesis and analysis of Diels-
Alder products displayed in Schemes 1-11; NMR spectra of
Diels-Alder adducts 7, 14, 25, 29, 30, 33, 35, 43, 44, 45, and
47 (PDF); and X-ray crystallographic data for 47, R ) CH2-
COOMe (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
The preference for an exo-type transition state in the reaction
of 41 and 42 and 8 leading to 43, in contrast to the endo
preference that is involved in the synthesis of estrone from 41
and 48, can be explained readily in terms of the mechanistic
model that has been developed for Diels-Alder reactions under
oxazaborolidinium catalysis.1 Scheme 12 displays four pre-
transition-state assemblies for reactions involving catalyst 8, the
Dane diene 41, and dienophiles of type 46 or 48. In structures
50 of Scheme 12, which represent the regiopreference exhibited
with R,â-enal 48 in the synthesis of estrone, there are no
JA046154M
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J. AM. CHEM. SOC. VOL. 126, NO. 42, 2004 13713