Traceless chiral auxiliaries for the allene ether Nazarov cyclization

Article abstract of DOI:10.1021/jo801503c

(Chemical Equation Presented) The key stereochemical factors that determine transfer of asymmetry from the chiral auxiliary to the cyclopentenone in the allene ether version of the Nazarov reaction have been elucidated. On the basis of the new insights in

Full text of DOI:10.1021/jo801503c

VOLUME 73, NUMBER 21
November 7, 2008
Copyright 2008 by the American Chemical Society
Traceless Chiral Auxiliaries for the Allene Ether Nazarov
Cyclization
April R. Banaag and Marcus A. Tius*
UniVersity of Hawaii, Chemistry Department, Honolulu, Hawaii 96822, and The Cancer Research Center
of Hawaii, 1236 Lauhala Street, Honolulu, Hawaii 96813
tius@hawaii.edu
ReceiVed July 8, 2008
The key stereochemical factors that determine transfer of asymmetry from the chiral auxiliary to the
cyclopentenone in the allene ether version of the Nazarov reaction have been elucidated. On the basis of
the new insights into the mechanism, two highly effective chiral auxiliaries were designed and prepared.
Introduction
derives from the favorable polarization of the enol ether
function,4 the low barrier for approach of the allene sp-
hybridized carbon atom to the ꢀ-vinyl carbon atom, as well as
the relief of allene strain during the cyclization.5
The factors that underpin the high reactivity of ketones such
as 1 in the Nazarov cyclization are also an impediment toward
the development of a catalytic asymmetric version of the
reaction shown in eq 1 because the background reaction is likely
to overwhelm any catalyzed process.6,7 Nevertheless, because
of the utility of the process in total synthesis we had a strong
incentive to develop an asymmetric version, and we did so by
focusing our attention on the acetal carbon atom of 1. When
R4 * H this carbon atom is stereogenic, so there was the
The allene ether variant1 of the Nazarov cyclization2,3 has a
very low activation barrier and takes place under extremely mild
conditions. We have never isolated the allenyl vinyl ketone
precursors 1 (eq 1), because they do not survive workup, but
instead lead to cyclic products 2 spontaneously with loss of the
stable alkoxyalkyl cation 3. The ease of this particular Nazarov
reaction contrasts with the conditions for the conventional
process that involves cyclization of a divinyl ketone and usually
requires stoichiometric strong Lewis or Bronsted acid often at
elevated temperature. The ease of cyclization of 1 presumably
(1) Tius, M. A. Acc. Chem. Res. 2003, 36, 284–290.
(2) (a) For reviews of the Nazarov reaction, see: Harmata, M. Chemtracts
2004, 17, 416–435. (b) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577–
7606. (c) Pellissier, H. Tetrahedron 2005, 61, 6479–6517. (d) Tius, M. A. Eur.
J. Org. Chem. 2005, 219, 3–2206. (e) Habermas; K. L.; Denmark, S.; Jones,
T. K. In Organic Reactions; Paquette, L. A., Ed.; John Wiley & Sons, Inc.:
New York, 1994; Vol. 45, pp 1-158.
(3) (a) For recent examples of the Nazarov reaction, see: Li, W.-D. Z.; Wang,
Y-Q. Org. Lett. 2003, 5, 2931–2934. (b) Occhiato, E. G.; Prandi, C.; Ferrali,
A.; Guarna, A. J. Org. Chem. 2005, 70, 4542–4545. (c) Waters, S. P.; Tian, Y.;
Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 13514–13515. (d)
Janka, M.; He, W.; Haedicke, I. E.; Fronczek, F. R.; Frontier, A. J.; Eisenberg,
R. J. Am. Chem. Soc. 2006, 128, 5312–5313. (e) Grant, T. N.; West, F. G. J. Am.
Chem. Soc. 2006, 128, 9348–9349. (f) He, W.; Huang, J.; Sun, X.; Frontier,
A. J. J. Am. Chem. Soc. 2008, 130, 300–308. (g) Williams, D. R.; Robinson,
L. A.; Nevill, C. R.; Reddy, J. P. Angew. Chem., Int. Ed. 2007, 46, 915–918. (h)
Rieder, C. J.; Fradette, R. J.; West, F. G. Chem. Commun. 2008, 1572–1574.
(4) (a) Tius, M. A.; Kwok, C.-K.; Gu, X.-q.; Zhao, C. Synth. Commun. 1994,
24, 871–885. (b) Polarization in the opposite sense, through placement of an
electron-withdrawing substituent R to the carbonyl group in the acyclic precursor,
also accelerates the Nazarov cyclization. See: He, W.; Herrick, I. R.; Atesin,
T. A.; Caruana, P. A.; Kellenberger, C. A.; Frontier, A. J. J. Am. Chem. Soc.
2008, 130, 1003–1011.
(5) The strain energy of allene can be estimated as the difference between
the heats of hydrogenation of allene,-71280 ( 200 cal/mol, and of 1,5-
hexadiene,-60525 ( 150 cal/mol, i.e., 10755 ( 350 cal/mol or ca. 10.76 (
0.35 kcal/mol. Kistiakowski, G. B.; Ruhoff; J. R.; Smith, H. A.; Vaughan, W. E.
J. Am. Chem. Soc. 1936, 58, 146–153.
(6) Catalytic asymmetric Nazarov cyclizations are known: (a) Rueping, M.;
Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J. Angew. Chem., Int. Ed.
2007, 46, 2097–2100. (b) Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126,
9544–9545. (c) Aggarwal, V. K.; Belfield, A. J. Org. Lett. 2003, 5, 5075–5078.
10.1021/jo801503c CCC: $40.75
Published on Web 09/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8133–8141 8133

Banaag and Tius
SCHEME 1
possibility that transmission of stereochemical information from
the acetal to the cyclopentane ring might be observed. We felt
that such an approach, if successful, would be attractive for
another reason. Since cleavage of 3 from cyclopentenone 2 takes
place spontaneously, no additional step would be required for
removal of the chiral auxiliary from the product. We have
disclosed the results of our endeavors in this area in earlier
papers, and we have recently published a preliminary account
of what we believe to be the explanation of the effect that leads
to the transmission of stereochemical information from the acetal
to the ring carbon atom.8 In this paper, we provide additional
supporting evidence for our hypothesis and an overview of our
earlier work with chiral auxiliaries on the allene within the
framework of a unifying mechanistic proposal. The mechanism
whereby stereochemical information is transmitted from the
auxiliary appears to be unique, and can potentially find a number
of other applications.
presumptive tetrahedral intermediate 7. The reaction was
quenched by rapidly transferring the mixture to a stirred solution
of HCl in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) at 0 °C.12
Workup provided R-hydroxycyclopentenone 8 in 58% yield
and 83.5/16.5 er. A series of enamides was screened in the
reaction. Yields varied between 52% and 84%, whereas optical
purities varied between 76.5/23.5 and 84/16 er. Although the
optical purity of the products was modest, we were able to
demonstrate proof of principle by showing that stereochemical
information from the ether group to the ring carbon atom was
taking place.
At this early point, we had no mechanistic hypothesis with
which to explain our results. We were fortunate to observe
modest optical purities in our first experiment. Since cleavage
of the chiral auxiliary takes place during the stereochemistry-
determining operation, the timing of the bond-forming step that
closes the five membered ring and the bond cleaving step that
liberates the chiral auxiliary as a cationic fragment must be
critical. Premature loss of the chiral auxiliary would preclude
any transmission of stereochemical information during the
cyclization. An indication that this might be the case was
provided by the cyclization that led to 9. The only difference
between 8 and 9 is the p-methoxy group that is present in 9,
yet cyclization of 7 (Ar ) Ph) in the presence of HCl in ethanol
at -78 °C led to 8 in 71/29 er (65% yield), whereas under
identical conditions 9 was obtained from 7 (Ar ) p-MeOPh)
essentially as the racemate in 56% yield. This observation led
us to adopt HFIP as a solvent for the cyclization, since this is
a non-nucleophilic solvent of high ionizing power that is known
to stabilize carbocations to a greater extent than ethanol.13
Results and Discussion
The first chiral auxiliary that we prepared was derived from
permethylated D-glucose.9,10 Allene ether 4 (Scheme 1) was
converted to lithioallene 5 by exposure to n-butyllithium in THF
at -78 °C. The addition to enamide 6 (Ar ) Ph) was sluggish
in the absence of LiCl, presumably due to aggregation of the
anion.11 In the presence of 4 equiv LiCl, however, addition of
5 to 6 took place within 1 h at -78 °C to produce the
The cyclization of 7 (Ar ) p-MeOPh) in HFIP at 0 °C
produced 9 in 81.5/18.5 er (69% yield), underscoring the
important role that the conditions for the quench have on the
optical purity of the product.
Our immediate goal was to improve the optical yield of
products. We assumed that because of its proximity to the
reacting allene the C2 substituent of the sugar would play a
critical role, so we prepared allene ether 10 from 2-deoxy-D-
glucose.9 Although the optical purity of cyclic product derived
from 10 was lower than from 4, the difference was modest,
(7) (a) Pridgen, L. N.; Huang, K.; Shilcrat, S.; Tickner-Eldridge, A. C.;
DeBrosse, C.; Haltiwanger, R. C. Synlett 1999, 1612–1614. (b) Kerr, D. J.; Metje,
C.; Flynn, B. L. Chem. Commun. 2003, 1380–1381. (c) Dhoro, F.; Kristensen,
T. E.; Stockmann, V.; Yap, G. P. A.; Tius, M. A. J. Am. Chem. Soc. 2007, 129,
7256–7257. (d) Mazzola, R. D., Jr.; White, T. D.; Vollmer-Snarr, H. R.; West,
F. G. Org. Lett. 2005, 7, 2799–2801.
(8) Banaag, A. R.; Tius, M. A. J. Am. Chem. Soc. 2007, 129, 5328–5329.
(9) Harrington, P. E.; Tius, M. A. Org. Lett. 2000, 2, 2447–2450.
(10) (a) For sugar derived allenyl ethers, see: Rochet, P.; Vate`le, J.-M.; Gore´,
J. Synthesis 1994, 795–799. (b) Mereyala, H. B.; Gurrala, S. R.; Mohan, S. K.
Tetrahedron 1999, 55, 11331–11342. (c) Hausherr, A.; Orschel, B.; Scherer, S.;
Reissig, H.-U. Synthesis 2001, 1377–1385.
(12) Ichikawa, J.; Fujiwara, M.; Okauchi, T.; Minami, T. Synlett 1998, 927–
929.
(13) Schadt, F. L.; Schleyer, P. v. R.; Bentley, T. W. Tetrahedron Lett. 1974,
15, 2335–2338.
(11) (a) Myers, A. G.; Yang, H. C.; Gleason, J. L. J. Am. Chem. Soc. 1994,
116, 9361–9362. (b) Romesberg, F. E.; Collum, D. B. J. Am. Chem. Soc. 1994,
116, 9187–9197. (c) Seebach, D. Ang. Chem. Int. Ed. 1988, 27, 1624–1654.
8134 J. Org. Chem. Vol. 73, No. 21, 2008

Auxiliaries for the Allene Ether NazaroV Cyclization
SCHEME 2
leading us to the conclusion that the C2 substituent does not
strongly influence the stereochemical course of the cyclization.
without any erosion in optical purity. For example, cyclopen-
tenone R-8 was prepared in 71% yield and 88.5/11.5 er
from 11.15
We put allenyl ether 11 to use during our synthesis of
roseophilin.16 This is where things stood until allenyl ether 12
was prepared and evaluated.17 Changing the alcohol protecting
groups from methyl to tert-butyldimethylsilyl (TBS) ethers had
been expected to suppress the aggregation of the derived
allenyllithium species, resulting in a more reactive nucleophile
even in the absence of added LiCl. In practice LiCl was still
required for high product yields from the reactions of 12. The
surprise was that the cyclic products were obtained from 12 in
excellent optical purity in all cases, within the range of 92.5/
7.5 to 96.5/3.5 er.17 We were determined to learn the reason
for the superiority of 12 over allenyl ethers 4, 10, and 11 for
the Nazarov cyclization.
If rotation about the anomeric C-O bond were to take place
during the stereochemistry-determining operation it would be
difficult to understand why any of the chiral auxiliaries should
be effective. Therefore, in order for the pyranyl chiral auxiliary
to control the stereochemical course of the cyclization, there
must be a means to restrict rotation about this bond (see 14,
A shortcoming of the pyranose-derived chiral auxiliaries is
related to the attenuated nucleophilicity of the derived allenyl-
lithiums. As indicated above, this problem was addressed
through addition of LiCl to the anion solution. The optical purity
of products was acceptable on modest scale (up to 0.2 mmol)
but eroded noticeably when the reactions were scaled up to 4
mmol. We had assumed that a high concentration of lithium
ions might be deleterious to the efficient transmission of
stereochemical information since it might discourage the
organization of transition states like 15c. It is conceivable that
this problem might have been overcome by optimizing the
reaction more carefully. An alternative strategy was to avoid
chiral auxiliaries that incorporate methyl ether functions, the
thought being that aggregation of the allenyllithium might then
be suppressed, and addition of LiCl might not be required. With
this in mind, the camphor-derived chiral auxiliary shown in
structure 11 was developed.14 This proved to be a very good
choice, since the reactions of 11 led to cyclic products in higher
optical purity than from 4, and the reactions could be scaled up
(15) The major enantiomer of 8 that was prepared from 11 or from the
R-pyranose-derived chiral auxiliaries corresponded to the more mobile peak on
a Chiralcel-OD HPLC column. The absolute stereochemistry of the products
from 11 has been determined rigorously in two cases, through the total synthesis
of natural roseophilin and also crystallographically. See ref 16.
(16) Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001, 123, 8509–
8514.
(14) Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem. Soc.
2002, 124, 10091–10100.
(17) delos Santos, D. B.; Banaag, A. R.; Tius, M. A. Org. Lett. 2006, 8,
2579–2582.
J. Org. Chem. Vol. 73, No. 21, 2008 8135

Banaag and Tius
SCHEME 3
atom is an essential feature of the chiral auxiliary. There must
be an interaction between its equatorial nonbonding electron
pair and the pentadienyl carbocation before the cyclopentenone
C-C bond is fully formed. If there were no such interaction,
then rotation about the anomeric C-O bond would take place,
thereby limiting the transmission of stereochemical information
from the pyranose to the cyclopentenone. (2) The pyran ring
must invert before the cyclopentenone C-C bond is fully
formed. If it did not invert, then the equatorial C4 substituent
that is critical for obtaining cyclopentenone products in high
optical purity, would be too far to influence the torquoselectivity
of the ring closure. (3) The pyran ring inversion is induced by
the electrostatic attraction between the developing oxocarbenium
ion and the nonbonding electron pair on an axial oxygen atom,
according to Woerpel’s analysis. All this strongly suggests some
degree of simultaneity of bond forming and bond cleavage
during the conversion of 15c to R-8.
In order for this model to be valid, the 3,4,5-triaxial
conformation of the pyran ring in 15c must be energetically
accessible, and one must postulate a late transition state for the
cyclization in which significant positive charge develops at the
anomeric carbon atom. The energetic accessibility of the triaxial
conformer is not in doubt, and is supported by a wealth of
precedent. In 1994, we prepared 2-deoxy C-glycoside 22 and
determined that the ground-state conformation is as shown, with
the three groups at C3, C4, and C5 axial and the C1 methyl
group equatorial.20 The configurational assignment of 22 is
supported by the small vicinal coupling constants that were
measured for the equatorial methine protons in the 500 MHz
1H NMR spectrum. Presumably the conformational preference
of 22 is determined by the relief of steric compression between
the adjacent C3 and C4 silyloxy groups. Suzuki and co-workers
showed that 2,6-dideoxyglucopyranosyl acetate 23 prefers the
3,4,5-triaxial conformation.21 In Suzuki’s example relief of steric
compression evidently overrides any stabilization of the 3,4,5-
triequatorial conformer through the anomeric effect. The bal-
ance, however, is delicate, as Yamada’s results demonstrate.22
Whereas the equatorial C3 and C4 OTBS groups in 24 are
accommodated, the larger OTBDPS groups in 25 induce
conformational inversion of the pyran resulting in the 2,3,4,5-
tetraaxial conformer. Roush’s work also supports the notion that
chair-to-chair conformational inversion of the pyran ring is
facile.23 The reasons for the preference for diaxial conformers
in trans-1,2-dihydroxycyclohexane trialkylsilyl ethers have
recently been described by Marzabadi.24
Scheme 2). We postulated that this was accomplished through
electron pair donation from the pyran oxygen atom to the
developing pentadienyl carbocation, or alternatively through a
charge-dipole interaction (see 15c, Scheme 2). This has the effect
of bringing the chiral auxiliary into closer proximity to the
pentadienyl cation, but this alone is not enough to explain why
there should be a large difference in the levels of asymmetry
transfer between 10 and 12. The only way there can be a large
difference between 10 and 12 is if the substituents on the sugar
were to move close enough to the pentadienyl cation to influence
the sense of conrotation. One way for this to happen is to
postulate conformational inVersion of the pyranose ring in the
stereochemistry-determining operation.8 If this were to happen,
the C4 ether group that is equatorial in 12 would become axial
in 15c, thereby blocking one face of the pentadienyl cation and
biasing the conrotation to take place so as to move the phenyl
group in 15c away from the bulk of the C4 OTBS group. This
leads to R-8 after loss of the chiral auxiliary as six-membered-
ring oxocarbenium ion 16. The key element is the conforma-
tional inversion of the pyran ring under the conditions for the
cyclization. This is supported by the work of Bowen18 and more
recently by Woerpel and co-workers who found that the
conformational preferences of six-membered-ring oxocarbenium
ions follow a pattern and are highly dependent on the electronic
nature of the substituents.19 Woerpel’s results that are sum-
marized in Scheme 3 are illuminating. Exposure of acetate 17
and allyltrimethylsilane to BF3 ·Et2O in dichloromethane leads
to a diastereomeric mixture of cis and trans products 18 and
19, respectively. When the substituent X is methyl the cis/trans
ratio is 94/6, whereas when X ) OBn the ratio of products is
inverted, 1/99. The result for X ) CH2Bn (93/7) suggests that
it is the electronic characteristic not the size of the substituent
that influences the diastereomeric ratio. Woerpel postulates an
equilibrium between conformers 20 and 21 of the six-membered-
ring oxocarbenium ion. When X is an alkoxy group, electron
pair donation from the oxygen atom to the positively charged
carbon atom favors conformer 20, resulting in top face attack
by the electrophile, leading to trans product 19. When X is an
alkyl group, conformer 21, in which the substituent is equatorial,
is favored and electrophilic attack takes place from the bottom
face, leading to cis product 18. According to this paradigm, the
conformational inversion leading to transition state 15c is driven
by the stabilization that results from bringing the nonbonding
electron pairs on the C4 OTBS group closer to the anomeric
carbon atom.
If the model that has been proposed in Scheme 2 is valid,
then the following four predictions can be made. First, deleting
the equatorial OTBS group from C3 in 12 should not affect the
optical purity of the product. In 15c this group is far from the
developing cyclopentenone C-C bond, and should not be able
to directly influence the stereochemical outcome of the cycliza-
tion. Second, deleting the equatorial C4 OTBS group from 12
should have a measurable deleterious effect on the optical purity
of the product. Third, if the C4 substituent is constrained to
The elements of the mechanistic hypothesis that has been
summarized in Scheme 2 are listed below: (1) The pyran oxygen
(20) Tius, M. A.; Busch-Petersen, J. Tetrahedron Lett. 1994, 35, 5181–5184.
(21) Hosoya, T.; Ohashi, Y.; Matsumoto, T.; Suzuki, K. Tetrahedron Lett.
1996, 37, 663–666.
(22) Yamada, H.; Tanigakiuchi, K.; Nagao, K.; Okajima, K.; Mukae, T.
Tetrahedron Lett. 2004, 45, 5615–5618.
(23) Roush, W. R.; Sebesta, D. P.; Bennett, C. E. Tetrahedron 1997, 53,
8825–8836.
(24) Marzabadi, C. H.; Anderson, J. E.; Gonzalez-Outeirino, J.; Gaffney,
P. R. J.; White, C. G. H.; Tocher, D. A.; Todaro, L. J. J. Am. Chem. Soc. 2003,
125, 15163–15173.
(18) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc. 1992,
114, 859–864.
(19) (a) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528. (b) Shenoy, S. R.; Woerpel,
K. A. Org. Lett. 2005, 7, 1157–1160. (c) Lucero, C. G.; Woerpel, K. A. J. Org.
Chem. 2006, 71, 2641–2647.
8136 J. Org. Chem. Vol. 73, No. 21, 2008

Auxiliaries for the Allene Ether NazaroV Cyclization
acyclic acetals, insofar as the yield of product was concerned.
This was one of the factors that had led us to postulate the model
in the first place. However, we lacked any evidence that the
ring oxygen atom was crucial for the high optical purity of the
product. To address this issue, allene ether 36, the carbacyclic
analogue of 26, was prepared (Scheme 4). Commercially
available 4-oxopimelate 31 was first converted to diethyl acetal
32, then the ester functions were reduced to aldehydes. The
unstable dialdehyde was immediately subjected to List’s condi-
tions for the asymmetric intramolecular aldol addition in the
presence of L-proline.25 Reduction of the aldehyde product with
NaBH4 was followed by simultaneous protection of the two
hydroxyls as OTBS ethers. Mild hydrolytic removal of the
diethyl acetal led to 33 in 51% overall yield from 32. The degree
of asymmetric induction during the intramolecular aldol reaction
was determined through Mosher analysis after reducing 33 to
axial alcohol 34. The optical purity of 34 was determined to be
88/12 er. Etherification of 34 by exposure to propargyl bromide
and base gave 35, which was isomerized to allenyl ether 36 by
exposure to potassium tert-butoxide at 60 °C in THF according
to Brandsma’s method.26 Exposure of 36 to n-butyllithium
followed by enamide 6 (R ) Ph) and quenching into HCl in
HFIP/TFE at -78 °C resulted in a complex reaction mixture
from which R-8 was isolated in <30% yield. The product was
slightly enriched in the R enantiomer (55.5/45.5 er). Since allene
36 was used as a 88/12 mixture of enantiomers, asymmetry
transfer was approximately 11%. The low yield and the low
level of asymmetric induction that was observed for 36 supports
the postulated dual role for the ring oxygen atom, which restricts
rotation about the anomeric C-O bond and also facilitates
cleavage of the chiral auxiliary from the product. In the absence
of an efficient means to terminate the reaction, the cyclic cation
is free to decompose along a multitude of pathways, leading to
an erosion of the yield.
If the model were valid, then one would predict only a minor
role for the C6 substituent that is oriented away from the
pentadienyl cation in 15 (Scheme 2). In order to probe this issue,
allenyl ethers 37, 38 and 39 (Table 1) were prepared and
evaluated in the Nazarov cyclization. The plan was to vary the
size of the ether protecting groups and to compare the results
with the one from 26. The difference in optical purity of the
product from bis TBS ether 26 (94/6 er) and bis TIPS ether 37
(92.5/7.5 er) was small, but the reaction was more selective
when the smaller -OTBS groups were present. Changing the
protecting groups to TBDPS in 38 resulted in further diminution
of the optical purity of product 8 (86.5/13.5 er). We were unable
to prepare the bis trityl ether, so we settled for the C4 OTBS,
C6 OTr compound 39 that led to essentially the same optical
purity of the product as 38 (87/13 er vs 86.5/13.5 er). These
results show that increasing the size of the protecting groups at
C4 and C6 from TBS through Tr does not lead to any
improvement, but rather to slight erosion of the optical yield of
product. The reasons for this are not clear.
remain in the equatorial position, for example by locking the
conformation of the pyran ring, then it will be prevented from
close approach to the developing pentadienyl cation. As a result,
the C4 substituent will be unable to influence the direction of
conrotation, resulting in attenuated optical purity of product.
Fourth, deleting the pyran oxygen atom from 12 and replacing
it with a methylene group should lead to low yield and low
optical purity. All four predictions have been verified.
Allenyl ether 26 was first prepared from 2,3-dideoxy-D-
glucose (Table 1). As predicted, the Nazarov product R-8 was
formed from 26 in 94/6 er (89% yield), essentially the same
result as from allene ether 12 (93/7 er). This shows conclusively
that the C3 equatorial silyloxy group in 12 does not contribute
to the optical purity of the cyclic product.
The 2,4-dideoxy-D-glucose derived allenyl ether 27 was
prepared next. The prediction here was that deleting the C4
silyloxy group would have the effect of eroding the optical purity
of the cyclic product. Indeed, R-8 was formed in 86.5/13.5 er
(46% yield) from 27. The absence of the large axial group at
C4 in 15 (Scheme 2) was responsible for the erosion in the
optical purity of product and supports a key role for the C4
equatorial group in 12 and in 26.
The prediction that locking the conformation of the pyran
ring would erode the optical purity of cyclic product was also
borne out. Allenyl ether 28, derived from the benzylidene acetal
of 2,3-dideoxy-D-glucose, led to R-8 in 86.5/13.5 er (89% yield).
In 28 the large group at C4 is prevented from assuming the
axial orientation and from effectively blocking one face of
the developing pentadienyl cation. This results in the
attenuation of the optical purity of 8 relative to the products
from 12 and 26.
We postulated that 28 could be converted into a highly
effective chiral auxiliary by introducing an axial silyloxy group
at C3. An axial C3 substituent would be ideally positioned to
block one face of the pentadienyl cation. This was indeed the
case, and allenyl ether 29 led to R-8 in 97/3 er (69% yield).
This structural modification leads to an exceptionally effective
chiral auxiliary.
2-Deoxy-D-galactose derived allenyl ether 30 was predicted
to be a poor chiral auxiliary on the basis of the model. If pyran
ring inversion were to take place in the stereochemistry-
determining operation, the C4 axial OTBS group would become
equatorial and would be unable to block the back face of the
pentadienyl cation. In fact the optical purity of R-8 that was
derived from 30 (86.5/13.5 er) was the same as for R-8 derived
from 27, which is what the model predicts.
Pyranoses might appear to be less than ideal chiral auxiliaries.
Although many D-sugars are available and cheap, the same is
not true for L-sugars. Fortunately, both enantiomeric series of
cyclopentenones are available from D-pyranose derived chiral
auxiliaries. For example, whereas the R-anomeric chiral aux-
iliaries lead to R-8, the ꢀ-anomers lead to S-8. ꢀ-2-Deoxy-D-
(25) (a) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int.
Ed. 2003, 42, 2785–2788. (b) List, B. Acc. Chem. Res. 2004, 37, 548–557.
(26) Hoff, S.; Brandsma, L.; Arens, J. F. Recl. TraV. Chim. Pays-Bas 1968,
87, 916–924.
The model predicts a critical role for the pyran oxygen atom.
We had some circumstantial evidence to support a role for the
ring oxygen atom, or the second oxygen atom in the case of
J. Org. Chem. Vol. 73, No. 21, 2008 8137

Banaag and Tius
TABLE 1. Pyranose-Derived Chiral Auxiliariesa
a Yields and enantiomeric ratios refer to the reaction of each allenyl ether with enamide 6 (R ) Ph).
SCHEME 4
glucose derived allenyl ether 40 (Table 1) was prepared.
Conversion to the allenyllithium species, addition to enamide
6 (R ) Ph) and cyclization as before led to S-8 as the major
enantiomer (11/89 er) in 68% yield. The optical purity of the
product was greatly improved using ꢀ-2-deoxy-D-galactose
derived allenyl ether 41 (3.5/96.5 er). This points to the central
role that the axial C4 OTBS group plays in the case of 41, and
implies that in the ꢀ-series of chiral auxiliaries conformational
change of the pyran ring does not take place during the
stereochemistry-determining operation. These results appear to
be consistent with Woerpel’s findings concerning six-membered-
ring oxocarbenium ion alkylations.
8138 J. Org. Chem. Vol. 73, No. 21, 2008

Auxiliaries for the Allene Ether NazaroV Cyclization
TABLE 2. Quench Conditions for the Reaction of 29a
entry
acid (equiv)
HCl (33)
solvent
er
1
2
3
4
5
6
7
8
HFIP/TFE (1/1)
HFIP/TFE (1/1)
HFIP/TFE (1/1)
THF
Et2O
PhMe
95/5 to 70/30
66.5/33.5
87/13
90.5/9.5
90.5/9.5
90.5/9.5
92.5/7.5
97/3
HCl (6)
ClCH2CO2H (33)
H3CCO2H (33)
H3CCO2H (33)
H3CCO2H (33)
H3CCO2H (33)
H3CCO2H (33)
MTBE
CH2Cl2
a All quenches were performed at -78 °C for 2 min.
TABLE 3. Examples of the Asymmetric Allene Ether Nazarov Cyclization
Optimizing the Quenching Conditions. According to the
model, the timing of the various bond-forming and bond
cleaving events that lead from 14 through 15 to R-8 and 16
must be critical for the success of the asymmetric process.
Premature cleavage of the chiral auxiliary will preclude good
asymmetric induction from taking place. Premature acid cata-
lyzed cleavage of any of the silyl ether protecting groups is
also very likely to be deleterious. Consequently, any change in
temperature, acid and especially solvent can be expected to have
a large effect on the optical purity of the products. These
considerations had guided our initial choice of HFIP as the
solvent for the quench. Modified conditions were developed for
the quench, 33 equivalents of anhydrous HCl in a 1/1 mixture
of HFIP/TFE at -78 °C, so as to ensure rapid cyclization. On
the basis of our early results with R-9 (Scheme 1) we surmised
that loss of stereochemical information and/or attrition of the
yield would result if cleavage of the auxiliary were slow. Since
HFIP freezes at -4 °C, it was mixed with TFE to allow the
quench to take place at -78 °C. These conditions worked very
well for the permethylated and the persilylated chiral auxiliaries
and led to reproducible yields and enantioselectivities. The
exception was 29 for which we observed irreproducibility in
both yield and enantioselectivity. We traced the problem to
premature cleavage of the acetal group, which led us to develop
alternative conditions for the quench that would preserve the
integrity of the acetal. Our results are summarized in Table 2.
The optical purity of R-8 varied greatly (95/5 to 70/30) when
our usual conditions were used (Table 2, entry 1). Reducing
the equivalents of HCl actually led to further erosion of the er.
Chloroacetic acid (entry 3), a much weaker acid, catalyzed the
cyclization but the er in this case was suboptimal. Changing to
acetic acid (entries 4-8) led to an effective cyclization. In THF,
ether or toluene the er was 90.5/9.5. Switching to tert-butyl
methyl ether (MTBE) led to a slight improvement in er to 92.5/
7.5. Thirty-three equivalents of acetic acid in dichloromethane
proved to be the best condition, leading to reproducible er’s of
97/3.
Since we had identified two highly effective chiral auxiliaries,
one for each enantiomeric series, we were curious to learn the
scope of each. Table 3 summarizes the results from the reactions
of a series of enamides with allenyl ethers 29 and 41. All
reactions were quenched with 33 equiv of acetic acid in
dichloromethane at -78 °C for 2 min and then neutralized with
aqueous NaHCO3. The optical purity of products was excellent
in all cases. There was some variability in the yields. The low
yield of 50 is due to decomposition of the product according to
the retro-Michael process indicated by the curved arrows as
shown in Table 3. Compound 50 was unstable to storage and
J. Org. Chem. Vol. 73, No. 21, 2008 8139

Banaag and Tius
also underwent significant decomposition during purification by
chromatography. The only difference between 49, which was
formed in excellent yield, and 50 is the presence of the protected
nitrogen atom in the latter, leaving no doubt that this was the
cause for the large difference in yields between the two. None
of the yields that are reported in Table 3 have been fully
optimized, so it is possible that some improvements can be
made. We have used the racemate of cyclopentenone 51 in our
recent total synthesis of (()-terpestacin,27 so the synthesis of
each of the enantiomers of 51 constitutes an asymmetric formal
synthesis of (+)- and of (-)-terpestacin. Preparation of cyclo-
pentenone 52 that incorporates a quaternary ring carbon atom
is noteworthy. Addition of the lithioallenes to tetrasubstituted
enamide 47 was quite slow and required warming of the reaction
mixture from -78 to 0 °C. Stirring at 0 °C for 2 h ensured that
the allenyllithium had been fully consumed.
determining process. It is especially noteworthy that cyclo-
pentenones incorporating a quaternary ring carbon can be
prepared in high er.
This model may oversimplify the various interactions that
occur in the electrocyclization transition state, but it provides a
consistent rationale for the results seen with the chiral auxiliaries
prepared to date. Moreover, it has allowed us to make a number
of successful predictions concerning substituent effects and the
role of the pyran ring oxygen atom. On the basis of these
predictions, we have confirmed the role of the pyran ring oxygen
atom, identified the key substituents that control the direction
of conrotation and have optimized the reaction conditions. Our
mechanistic hypothesis can now be used to design optimal chiral
auxiliaries should further improvements in the reaction be
needed.
Summary and Conclusion
We have attempted to provide an explanation for the
observations made over the course of several years with chiral
auxiliaries for the allene ether version of the Nazarov cyclization.
In the process we have identified two broad classes of pyranyl
chiral auxiliaries, those that are able to undergo chair-to-chair
inversion and those that are conformationally locked. Pyran ring
inversion is induced by the electrostatic attraction between the
developing oxocarbenium ion and the nonbonding electron pair
on an axial oxygen atom, according to the paradigm described
by Woerpel and co-workers. Whether or not ring inversion takes
place during the stereochemistry-determining operation, there
is strong evidence that the pyran ring oxygen atom restricts the
conformational mobility of the pentadienyl cation and is
necessary for both high enantioselectivity and yield of cyclic
product. The key to high enantioselectivity is the presence of a
large axial or pseudoaxial substituent on the pyran ring that
shields one face of the pentadienyl cation. The buttressing effect
provided by the axial (or pseudoaxial) substituent biases the
conrotation to take place in a single direction. It is also
significant that this hypothesis about the origin of asymmetry
transfer explains our observations with camphor derived chiral
auxiliary 11. According to our hypothesis, in the reaction 11
with enamide 6 (R ) Ph) the stereochemistry is determined
through 53, where it is the C6 methylene group that effectively
blocks the back face of the pentadienyl cation. Comparison of
the structures of 53 and 15c (Scheme 1) reveals that in 53 the
C6 methylene group is analogous to the C4 OTBS group in 15.
This explains why our early efforts to improve levels of
asymmetry transfer from camphor derived chiral auxiliaries all
failed: we had explored analogs of 11 that were substituted either
at C4 or at C1.28 None of these chiral auxiliaries were any better
than 11. Modification of C6 in 11 so as to prepare an improved
chiral auxiliary is not straightforward. In the conformationally
locked R-pyranose-derived chiral auxiliaries in which ring
inversion is prevented from taking place, it is the axial C3
substituent that exerts the dominant effect in controlling the
sense of conrotation. This can be seen in 42.
Experimental Section
General Procedure for Nazarov Cyclization. Lithium chloride
(16 mg, 0.377 mmol) was added to a 10 mL round-bottom flask
equipped with a small stir bar and was flame-dried under vacuum.
(E)-2-Methyl-1-morpholino-3-phenylprop-2-en-1-one 6 (60 mg,
0.259 mmol) and allene 29 (53 mg, 0.128 mmol) were added into
separate 5 mL round-bottom flasks then were individually dried
by azeotropic distillation of toluene and purged with nitrogen (3x).
Allene 29 was dissolved into 2 mL of THF, dried over 4 Å MS,
and the solution was transferred Via cannula into the 10 mL flask
containing the 16 mg of LiCl. A small crystal of 1,10-phenanthroline
was added and the solution was cooled to -78 °C. Residual water
in the solution of allene was quenched using n-BuLi (1.62 M in
hexanes), turning the mixture from a lemon-yellow color to the
end point, a dark brown color. The brownish mixture was then
treated with n-BuLi (160 µL, 0.259 mmol, 1.62 M in hexanes) and
was stirred at -78 °C for 45 min. The solution of enamide 6 (Ar
) Ph) in 2 mL of THF was dried over 4 Å MS, cooled to -78 °C
and was transferred at a rate of one drop per 3 s to the solution of
lithioallene Via cannula. The mixture was maintained at -78 °C
for 2 h and was transferred rapidly Via cannula to a solution of 20
mL anhydrous CH2Cl2 and 220 µL of AcOH (3.90 mmol) at -78
°C. After being stirred for 5 min at -78 °C, the mixture was poured
into 20 mL of a 1:1 two-phase solution of saturated aqueous
NaHCO3:CH2Cl2 and the mixture was gradually warmed to 0 °C.
Under the mildly acidic conditions of the quench, no loss of the
oxygen protecting groups of the auxiliary took place, allowing the
auxiliary to be easily recovered during the purification of the product
by flash column chromatography. The aqueous layer was separated
and extracted with CH2Cl2 (3×). The combined organic layers were
extracted with brine, dried over MgSO4, and concentrated.
2-Hydroxy-3-methyl-5-methylene-4-phenylcyclopent-2-
enone 8:14 Rf ) 0.23 (20% EtOAc in hexanes). Purification via
flash column chromatography on silica gel (20% EtOAc in hexanes)
provided cyclopentenone 8 (33 mg, 0.166 mmol, 69% yield, 97/3
er via allene 29; 44 mg, 0.222 mmol, 92% yield, 3.5/96.5 er via
allene 41); chiral HPLC (2% 2-propanol in hexanes, Chiralcel OD-H
column (0.46 cm × 25 cm), 254 nm, 0.75 mL/min) tR ) 11.2, tR
) 12.7 min.
Two improved chiral auxiliaries, 29 and 41 that lead to each
enantiomeric series of cyclopentenones, were designed on
the basis of our understanding of the stereochemistry-
(27) (a) Berger, G. O.; Tius, M. A. J. Org. Chem. 2007, 72, 6473–6480. (b)
Berger, G. O.; Tius, M. A. Org. Lett. 2005, 7, 5011–5013.
(28) Forest, J. S. M.S. Thesis; University of Hawaii, Honolulu, HI, 2003.
2-Hydroxy-5-methylene-3,4-diphenylcyclopent-2-enone 48:14
Rf ) 0.23 (20% EtOAc in hexanes). Purification Via flash column
8140 J. Org. Chem. Vol. 73, No. 21, 2008

Auxiliaries for the Allene Ether NazaroV Cyclization
chromatography on silica gel (20% EtOAc in hexanes) provided
cyclopentenone 48 (37 mg, 0.142 mmol, 59% yield, 95/5 er via
allene 29; 36 mg, 0.137 mmol, 57% yield, 4/96 er via allene 41);
chiral HPLC (10% 2-propanol in hexanes (0.05% trifluoroacetic
acid in mobile phase), Chiralcel OD-H column (0.46 cm × 25 cm),
254 nm, 0.80 mL/min) tR ) 8.8, tR ) 9.7 min.
3-Hydroxy-1-methylene-5,6,7,7a-tetrahydro-1H-inden-2(4H)-
one 49:14 Rf ) 0.20 (20% EtOAc in hexanes); Purification Via flash
column chromatography on silica gel (20% EtOAc in hexanes)
provided cyclopentenone 49 (36 mg, 0.217 mmol, 90% yield, 97/3
er via allene 29; 37 mg, 0.224 mmol, 93% yield, 7/93 er via allene
41); chiral HPLC (5% 2-propanol in hexanes, Chiralcel OD column
(0.46 cm × 25 cm), 254 nm, 0.80 mL/min) tR ) 8.0, tR ) 10.9
min.
mg, 0.137 mmol, 57% yield, 93/7 er via allene 29; 71 mg, 0.200
mmol, 83% yield, 9/91 er via allene 41); chiral HPLC (3%
2-propanol in hexanes, Chiralcel OD-H column (0.46 cm × 25 cm),
254 nm, 1.00 mL/min) tR ) 14.1, tR ) 16.5 min.
2-Hydroxy-3,4-dimethyl-5-methylene-4-phenylcyclopent-2-
enone 52:14 Rf ) 0.23 (100% CH2Cl2). Purification via flash column
chromatography on silica gel (30% EtOAc in hexanes) provided
cyclopentenone 52 (28 mg, 0.130 mmol, 54% yield, 89/11 er via
allene 29; 40 mg, 0.188 mmol, 78% yield, 5/95 er via allene 41);
chiral HPLC (5% 2-propanol in hexanes, Chiralcel OD column (0.46
cm × 25 cm), 254 nm, 1.00 mL/min) tR ) 10.6, tR ) 13.9 min.
Acknowledgment. Acknowledgment is made to the National
Institutes of Health (GM57873) and to the Department of
Defense Breast Cancer Research Program (DAMD17-03-1-
0685) for generous support. Dedicated to Professor E. J. Corey
on the occasion of his 80th birthday.
tert-Butyl-7-hydroxy-5-methylene-6-oxo-4,4a,5,6-tetrahydro-
1H-cyclopenta[c]pyridine-2(3H)-carboxylate 50. (See the Sup-
1
porting Information for the H NMR spectrum of 50.) Rf ) 0.28
(25% EtOAc in hexanes). Purification via flash column chroma-
tography on silica gel (20% EtOAc in hexanes) provided cyclo-
pentenone 50 (19 mg, 0.070 mmol, 29% yield, 93/7 er via allene
29; 38 mg, 0.142 mmol, 59% yield, 5/95 er via allene 41); chiral
HPLC (10% 2-propanol in hexanes, Chiralcel OD-H column (0.46
cm × 25 cm), 254 nm, 1.00 mL/min) tR ) 6.2, tR ) 7.5 min.
Supporting Information Available: General methods and
experimental procedures for the preparation of 33-36, 12,
26-30, and 37-41 and of all intermediates leading to 26-30
and 37-41. Reproductions of 1H and 13C NMR data of 33-36,
12, 26-30, and 37-41 and of the intermediates leading to them.
Reproduction of 1H NMR spectra of 50. This material is
available free of charge via the Internet at http://pubs.acs.org.
2-Hydroxy-3-(2-hydroxyethyl)-5-methylene-4-(2-(triisopropyl-
silyloxy)ethyl)cyclopent-2-enone 51:27 Rf ) 0.27 (50% EtOAc in
hexanes). Purification via flash column chromatography on silica
gel (5-60% EtOAc in hexanes) provided cyclopentenone 51 (49
JO801503C
J. Org. Chem. Vol. 73, No. 21, 2008 8141