Synthesis and absolute stereochemistry of roseophilin

Article abstract of DOI:10.1021/ja011242h

The enantiospecific total synthesis of natural roseophilin has been completed in 7.0% overall yield over 15 steps by means of an asymmetric cyclopentannelation. This establishes the absolute configuration of the natural product as 22R,23R. Cyclopentenone

Full text of DOI:10.1021/ja011242h

J. Am. Chem. Soc. 2001, 123, 8509-8514
8509
Synthesis and Absolute Stereochemistry of Roseophilin
Paul E. Harrington and Marcus A. Tius*
Contribution from the Department of Chemistry, 2545 The Mall, UniVersity of Hawaii,
Honolulu, Hawaii 96822
ReceiVed May 21, 2001
Abstract: The enantiospecific total synthesis of natural roseophilin has been completed in 7.0% overall yield
over 15 steps by means of an asymmetric cyclopentannelation. This establishes the absolute configuration of
the natural product as 22R,23R. Cyclopentenone (+)-12 was prepared in 78% yield and 86% ee in the key
step.
Introduction
Several related variants of the classical Nazarov reaction have
been an area of research focus in our group for a number of
years.1 The classical Nazarov reaction can be thought of as
proceeding through the series of steps which are summarized
in eq 1. Divinyl ketone 1 is typically treated with strong Lewis
to aqueous NaH2PO4 in certain cases. Allenyl ketones 5 have
not been isolated as intermediates but have always undergone
cyclization to 8 during acidic workup. The low activation barrier
for this reaction is likely a consequence of the ease of approach
of allenic sp and vinyl sp2 carbon atoms, with partial release of
the strain energy of the allene during the rate-limiting transition
state. The (methoxy)methoxy allene substituent in 5 is essential
for the success of the cyclization. In particular, the distal oxygen
atom appears to play a role in the overall process.
or protic acid to generate pentadienyl cation 2 reversibly. This
step is followed by thermally allowed 4 π conrotation which
produces allylic carbocation 3. Loss of a proton from 3 leads
to cyclopentenone 4. The more highly substituted enone is the
reaction product.2
The variant of the Nazarov reaction which was used in the
key step of the roseophilin synthesis to be described in what
follows is summarized in eq 2. Allenyl ketone 5 is the precursor
of pentadienyl carbocation 6 which undergoes conrotation to
7. Loss of methoxymethyl cation 9 from 7 leads to cross-
conjugated cyclopentenone 8. We have described several
variants of this reaction and have applied the methodology as
the key step in a number of syntheses of simple, naturally
occuring cyclopentanoids. What sets the variant of eq 2 apart
from related processes is the mildness of the reaction conditions
for the cyclization, which can even take place during exposure
Results and Discussion
Roseophilin was isolated in 1992 by Seto and co-workers
from the fermentation broth of Streptomyces griseoViridis.3 The
compound has some activity in vitro against K562 human
erythroid leukemia cells (IC50, 0.34 µM) and also against KB
cells, a human nasopharyngeal carcinoma cell line (IC50, 0.88
µM). The unusual structure, which incorporates an azafulvene
(3) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron
Lett. 1992, 33, 2701-2704.
(4) Harrington, P. E.; Tius, M. A. Org. Lett. 1999, 1, 649-651.
(5) (a) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817-
2825. For other synthetic studies, see: (b) Nakatani, S.; Kirihara, M.;
Yamada, K.; Terashima, S. Tetrahedron Lett. 1995, 36, 8461-8464. (c)
Kim, S. H.; Fuchs, P. L. Tetrahedron Lett. 1996, 37, 2545-2548. (d) Kim,
S. H.; Figueroa, I.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 2601-2604.
(e) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1997, 119, 2944-2945.
(f) Luker, T.; Koot, W.-J.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem.
1998, 63, 220-221. (g) Mochizuki, T.; Itoh, E.; Shibata, N.; Nakatani, S.;
Katoh, T.; Terashima, S. Tetrahedron Lett. 1998, 39, 6911-6914. (h)
Fu¨rstner, A.; Gastner, T.; Weintritt, H. J. Org. Chem. 1999, 64, 2361-
2366. (i) Robertson, J.; Hatley, R. J. D. J. Chem. Soc., Chem. Commun.
1999, 1455-1456. (j) Fagan, M. A.; Knight, D. W. Tetrahedron Lett. 1999,
40, 6117-6120. (k) Bamford, S. J.; Luker, T.; Speckamp, W. N.; Hiemstra,
H. Org. Lett. 2000, 2, 1157-1160. (l) Trost, B. M.; Doherty, G. A. J. Am.
Chem. Soc. 2000, 122, 3801-3810. (m) Robertson, J.; Hatley, R. J. D.;
Watkin, D. J. J. Chem. Soc., Perkin Trans. 1 2000, 3389-3396.
(1) For example, see: (a) Tius, M. A.; Chu, C. C.; Nieves-Colberg, R.
Tetrahedron Lett. 2001, 42, 2419-2422. (b) Tius, M. A.; Hu, H.; Kawakami,
J. K.; Busch-Petersen, J. J. Org. Chem. 1998, 63, 5971-5976. (c) Tius, M.
A.; Busch-Petersen, J.; Yamashita, M. Tetrahedron Lett. 1998, 39, 4219-
4222. (d) Tius, M. A.; Drake, D. J. Tetrahedron 1996, 52, 14651-14660.
For other work involving the Nazarov reaction, see: (e) Bender, J. A.; Arif,
A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 7443-7444. (f) Hashmi,
A. S. K.; Bats, J. W.; Choi, J.-H.; Schwarz, L. Tetrahedron Lett. 1998, 39,
7491-7494. (g) Denmark, S. E.; Wallace, M. A.; Walker, C. B., Jr. J. Org.
Chem. 1990, 55, 5543-5545. (h) Jacobi, P. A.; Armacost, L. M.; Kravitz,
J. I.; Martinelli, M. J.; Selnick, H. G. Tetrahedron Lett. 1988, 29, 6865-
6868, et seq.
(2) For a review, see: Dolbier, W. R. Jr.; Koroniak, H.; Houk, K. N.;
Sheu, C. Acc. Chem. Res. 1996, 29, 471-477.
10.1021/ja011242h CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/10/2001

8510 J. Am. Chem. Soc., Vol. 123, No. 35, 2001
Harrington and Tius
commercially available (+)-camphoric acid in five steps.11
Deprotonation of the allene ether took place with n-butyllithium
at -78 °C. Addition of amide 16 was followed by warming to
-30 °C over 1 h to ensure that the addition was complete.
Cooling the solution to -78 °C was followed by addition to a
1/1 (v/v) solution of HCl in 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) and 2,2,2-trifluoroethanol (TFE) at -78 °C. In our earlier
work we had determined that HFIP was essential for ensuring
high enantiomeric excesses of cyclization products; however,
the high melting point (-4 °C) of HFIP made it necessary to
use a mixed solvent system in order to conduct the reaction at
-78 °C, the optimal temperature for the cyclization. Under these
conditions 12 was isolated in 78% yield and in 86% ee. This
result represents a significant improvement over our earlier
efforts. Protection of the enolic hydroxyl group in 12 as the
benzoate led to 18 in 90% yield. The conversion of 18 to 1,4-
diketone 20 formally represents an acyl carbanion addition to
the exocyclic alkene of 18. The transformation was ac-
complished very conveniently through the Stetter reaction of
18 with 6-heptenal 19.12 Heating a dioxane solution of 18 with
2 equiv of aldehyde 19 in the presence of triethylamine and
3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride gave 20
in 77% yield. A small amount of the cis diastereomer was also
isolated from the reaction mixture and was separated by flash
column chromatography. Ring-closing metathesis using the
commercially available Grubbs catalyst13,14 led to an E/Z mixture
of macrocyclic alkenes 21 in 91% yield. Selective saturation
of the disubstituted alkene group in 21 took place under 1 atm
of hydrogen gas in the presence of palladium on carbon as the
catalyst. Diketone 22 was isolated in 89% yield and 86% ee.
The racemate of 22 was highly crystalline, and ether solutions
of this material precipitated as large cubes during solvent
evaporation. The optically enriched material showed a much
diminished tendency to crystallize; however, crystallization of
the racemate of 22, followed by filtration of the crystals, led to
material which was essentially a single enantiomer (99% ee) in
77% yield from 21. The optically pure material also crystallized
from a mixture of methanol and dichloromethane as delicate
Figure 1. Retrosynthesis of roseophilin.
which is congugated to a pyrrolylfuran and an ansa macrocycle,
made this an attractive and challenging target for total synthe-
sis.4,5 The first obvious retrosynthetic step (Figure 1) leads to
pyrrolylfuran 10 and ketopyrrole 11. Ketopyrrole 11, in turn,
can be prepared from cyclopentenone 12. To date, a single total
synthesis of racemic roseophilin has been described by Fu¨rstner.5a
Formal total syntheses, terminating in ketopyrrole 11 or some
protected form of 11, have been published by Fuchs,5c,d
Terashima,5g Hiemstra,5k Trost,5l Robertson,5i,m and our group.4
This paper and the accompanying one by Boger and Hong16
describe the first efficient enantiospecific total syntheses of
roseophilin.
In two Communications we have described the synthesis of
racemic 114 (Scheme 1) and the synthesis of each of the
enantiomers of 12 in good yield but in modest ee.6 5-Hexenal
13 was chosen as the starting material for the synthesis.
Conversion to the tert-butylimine 14 was accomplished in 94%
yield. The conversion of 14 to enal 15 was carried out
conventionally, by deprotonating 14 with LDA, and trapping
the lithio aldimine with trimethylchlorosilane. The silyl aldimine
was isolated, deprotonated once again, and intercepted with
isobutyraldehyde to give 15 in 71% yield following hydrolytic
cleavage of the imine by aqueous oxalic acid.7 Oxidation of
enal 15 with sodium chlorite, in the presence of 2-methyl-2-
butene and phosphate buffer,8 led to the corresponding car-
boxylic acid which was converted to R,â-unsaturated amide 16
in 88% overall yield for the two steps.9 From this point on, the
synthesis of Scheme 1 diverges from our earlier reported work.
The key step in this synthesis is the asymmetric cyclopen-
tannelation reaction which leads to 12. We have demonstrated
two distinct approaches to this problem. One approach makes
use of an axially chiral, nonracemic allene ether to transfer
asymmetry to the tetrahedral ring carbon of the product.10 The
alternative approach involves the use of a chiral auxiliary on
the allene, and it was this strategy which proved to be successful
for the roseophilin synthesis.6 Lithioallene 17 was prepared from
(11) See Supporting Information for details of the synthesis of 17-H.
The relative stereochemistry of 17-H was determined through NOE
experiments.
(12) Stetter, H.; Haese, W. Chem. Ber. 1984, 117, 682-693. For a review
of the Stetter reaction, see: Stetter, H.; Kuhlmann, H. In Organic Reactions;
Paquette, L. A., Ed.; John Wiley & Sons: New York, 1991; Vol. 40, pp
407-496.
(13) Bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride.
For a review of olefin metathesis chemistry, see: Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012-3043.
(14) It is noteworthy that we were unable to form (()-22 through the
intramolecular Stetter reaction of i nor through the intramolecular acyl
radical cyclization of ii. The failure of ii to cyclize, either with n-Bu3SnH
or with (TMS)3SiH as the hydrogen atom donor, is understandable, since
the lifetime of the reactive intermediate could be much shorter than the
half-life for macrocyclization. We cannot offer an explanation for the failure
of the intramolecular Stetter reaction of i, which proceeds through an
intermediate which is generated reversibly. For an example of an intramo-
lecular Stetter reaction, see: Trost, B. M.; Shuey, C. D.; DiNinno, F., Jr.;
McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1284-1285. For examples
of the intramolecular acyl radical cyclization, see: (a) Boger, D. L.;
Mathvink, R. J. J. Am. Chem. Soc. 1990, 112, 4008-4011. (b) Astley, M.
P.; Pattenden, G. Synlett 1991, 335-336.
(6) Harrington, P. E.; Tius, M. A. Org. Lett. 2000, 2, 2447-2450.
(7) (a) Kang, S. H.; Jun, H.-S.; Youn, J.-H. Synlett 1998, 1045-1046.
(b) Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Lin, P. Tetrahedron
Lett. 1985, 26, 2391-2394. (c) Corey, E. J.; Enders, D.; Bock, M. G.
Tetrahedron Lett. 1976, 27, 7-10.
(8) (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175-
1176. (b) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27, 888-
890.
(9) Einhorn, J.; Einhorn, C.; Luche, J.-L. Synth. Commun. 1990, 20,
1105-1112.
(10) Hu, H.; Smith, D.; Cramer, R. E.; Tius, M. A. J. Am. Chem. Soc.
1999, 121, 9895-9896.

Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8511
Scheme 1a
a (a) t-BuNH2, rt, 94%; (b) LDA, TMSCl, THF, -78 to 10 °C; (c) LDA, i-PrCHO, -78 to 10 °C; (d) (COOH)2, THF, H2O, 71% (three steps);
(e) NaClO2, KH2PO4, 2-methyl-2-butene; (f) CBr4, PPh3, morpholine, 88% (two steps); (g) i. n-BuLi, THF, -78 °C; ii. -78 to -30 °C, 1 h 16; iii.
HCl, HFIP/TFE (1:1), -78 °C; 78%, 86% ee; (h) Bz2O, Et3N, DMAP, CH2Cl2, 90%; (i) 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride (10
mol %), Et3N (0.6 equiv), 1,4-dioxane, 19 (2 equiv), 70 °C, 23 h, 77%; (j) Grubbs’ catalyst (30 mol %), CH2Cl2, 0.0005 M, 40 °C, 30 h, 91%; (k)
H2, 10% Pd/C, THF, 89%; one crystallization from MeOH/CH2Cl2, 99% ee, 87% recovery; (l) NH4OAc (50 equiv), Ti(Oi-Pr)4 (2 equiv), 140 °C,
6 h, 54%; (m) KH, SEMCl, DMF, rt, 30 min, 89%.
needles; however, recrystallization to improve the optical purity
was not necessary.
Quite a bit of effort went into optimizing the Knorr reaction
leading to 11. One of the experiments in this series deserves
mention. Treatment of (()-22 with benzylamine in propanoic
acid at 200 °C for 10 d produced N-benzylpyrrole 26, an
intermediate in Fu¨rstner’s synthesis of (()-roseophilin, but in
only 34% yield. The reaction mixture contained ca. 5% of (()-
22. The harsh conditions and the long reaction time in the case
of 26 contrast starkly with the reaction conditions for the
preparation of 11. The likely reason for this large difference in
reactivity is outlined in eq 4. Intermediate iminium ions 27a or
27b probably represent minor species which are in equilibrium
with protonated ketoimines. In the case of 27a (R ) H), loss
of the proton from the nitrogen atom leads to imine 28 in a fast
reaction, whereas in the case of 27b (R ) Bn) a much slower
loss of a proton from C12 (roseophilin numbering) leads to
enamine 29. This analysis is likely to be correct if formation of
the five-membered heterocycle is rate-limiting for the Knorr
reaction.
Ketopyrrole 11 was prepared from 22 in 54% yield following
heating for 6 h in propanoic acid in the presence of excess
ammonium acetate and 2 equiv of titanium isopropoxide. The
Knorr reaction remains the low-yielding step in the synthesis
and has resisted all our attempts to improve the yield. We have
shown that the first step in the conversion of 22 to 11 is cleavage
of the benzoate protecting group. Presumably, loss of water (or
ammonia) from one of the protonated intermediate products of
the Knorr reaction is inhibited by the electron-withdrawing C9
ketone carbonyl group, leading to an attrition in the yield.
Support for this hypothesis comes from Trost’s roseophilin
work,5l in which the Knorr cyclization of 24 (eq 3) took place
in 86% yield to give 25 under much milder conditions than for
22. The synthesis of the ketopyrrole fragment was completed
by protecting the N-H function of 11 as the SEM derivative,
leading to 23 in 89% yield.

8512 J. Am. Chem. Soc., Vol. 123, No. 35, 2001
Harrington and Tius
Scheme 2a
such as 5 require a (1-alkoxy)alkoxy substituent on the allene.
This indicates that the distal oxygen atom on the auxiliary must
participate in the product-determining transition state. Equation
5 indicates the form that such an interaction may take in the
case of the camphor-derived auxiliary 17. Upon treatment with
acid, the adduct of 17 and morpholino amide 16 fragments to
an allenyl ketone which is rapidly protonated on the carbonyl
oxygen atom. This generates the pentadienyl carbocation in the
same way that 5 led to 6. As structure 34 (eq 5) indicates, the
pentadienyl cation is stabilized by donation of the axial electron
pair of the pyran oxygen atom, a process which limits the
conformational mobility of 34. This interaction also has the
effect of placing the ethylene bridge of the auxiliary in closer
proximity to the pentadienyl cation in such a way as to block
the R face of the cation. As a result, conrotation is favored to
occur in the indicated counterclockwise direction so as to move
isopropyl and butenyl groups away from the ethylene bridge of
the auxiliary. Oxo cation 35, which is the intermediate product
of the cyclization event, undergoes fragmentation to 12.
Equation 5 is a working hypothesis which can be tested by
designing and preparing the next generation of chiral auxiliaries.
The next generation of chiral auxiliaries are probably not
going to be sugars. Although the â-anomers of the sugar-derived
auxiliaries proved themselves to be capable of providing
products in good enantiomeric excesses, the nucleophilicity of
the allenyl anions was attenuated relative to 17. Whereas it was
necessary to add several equivalents of anhydrous LiCl to
solutions of sugar-derived allenyllithiums in order for addition
to morpholino amides to take place, no such additions were
required in the case of 17. The chemistry leading to 11 through
12 is robust: more than 1 g of 22 (>99% ee) has been prepared.
This prompted us to complete an enantiospecific synthesis of
the natural product.
Fu¨rstner and Terashima had independently reported syntheses
of the pyrrolylfuran fragment of roseophilin.5a,b We prepared
10 according to Fu¨rstner’s detailed procedure and attempted the
coupling with 23 (Scheme 3). Since Fu¨rstner had also reported
the conversion of (()-23 to (()-roseophilin,5a we were unpre-
pared for the difficulty that we experienced in duplicating his
work. Ketone 23 is readily enolizable; therefore Fu¨rstner’s
procedure called for lithiation of 10 at C8, transmetalation with
cerium trichloride, and addition of the furylcerium species to
23. Our initial attempts to duplicate this reaction failed
completely, and only starting materials were isolated. A series
of control experiments showed that lithiation of 10 was taking
place. Deuteration or stannylation at C8 of 10 took place
efficiently. Our suspicion that the quality of the cerium
trichloride was to blame for our failure did not appear to be
valid, since lithiation of 10 and treatment with cerium trichloride,
followed by cyclohexanone, led to the expected product.
Furthermore, addition of methylcerium dichloride or butylcerium
a (a) i. n-BuLi, LiCl, THF, -78 °C; ii. -78 °C, 1 h 16; iii. HCl,
EtOH, -78 °C; (b) i. n-BuLi, LiCl, THF, -78 °C; ii. -78 °C, 1 h 16;
warm to -40 °C; cool to -78 °C; iii. HCl, HFIP, 0 °C; (c) i. n-BuLi,
LiCl, THF, -78 °C; ii. -78 to -45 °C, 1 h 16; cool to -78 °C; iii.
HCl, HFIP, 0 °C.
The origins of the enantioselectivity of the cyclopentan-
nelation reaction are not known to us with certainty. Some
observations which have allowed us to form a working
hypothesis are summarized in Scheme 2, which shows the
reactions of four sugar-derived chiral auxiliaries with 16.
Comparison of the results from R-D-glucose-derived auxiliary
30 and R-D-2-deoxyglucose-derived auxiliary 32 reveals only
a small attrition in yield and enantiomeric excess (61% ee vs
67% ee) upon deletion of the methoxy group from C2 of 32.
This shows that the C2 methoxy group in 30 exerts only a small
influence on the optical purity of the cyclic product. Auxiliaries
31 and 33 are derived from â-anomers of D-glucose in the case
of 31 and L-6-deoxyglucose in the case of 33. Auxiliary 33 leads
again to 12, whereas 31 gives the enantiomer, ent-12. Enan-
tiomeric excesses of 12 and ent-12 from the two reactions were
essentially identical (81% ee vs 82% ee, respectively), whereas
the yield of product from 33 was significantly lower than in
any of the other cases. The results from 31 and 33 show that
the methoxy group at C6 of 31 exerts no influence on the optical
purity of the product. Consequently, neither of the two methoxy
groups on the auxiliary which are closest to the allene function,
the ones at C2 and C6, and which would have been expected
to exert the dominant influence on the stereochemical course
of the cyclization, have much effect on the optical purity of the
product. The results of Scheme 2 reveal something else, that
the absolute stereochemistry of the product correlates with the
absolute stereochemistry of the anomeric carbon atom, regard-
less of whether the allene is R or â. Putting all this together,
one is led to the conclusion that the critical interaction which
influences the absolute stereochemistry of the product in each
case involves the pyran oxygen atom of the auxiliary. This is
consistent with the observation, mentioned in the introductory
paragraph, that good yields for the cyclization of compounds

Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 123, No. 35, 2001 8513
Conclusions
Scheme 3a
This concludes a description of an enantioselective total
synthesis of natural (22R,23R)-roseophilin in 15 steps and in
7.0% overall yield from 5-hexenal 13, taking into consideration
the loss during crystallization of 22. The asymmetric cyclopen-
tannelation reaction proved to be very well-matched to this
problem: we were able to prepare slightly more than 100 mg
of optically pure roseophilin. It is noteworthy that the auxiliary
is “traceless”: it is lost during the cyclization step.
The difficulties that we and others have experienced16 in
carrying out the final steps according to Fu¨rstner’s protocols
highlights an often overlooked fact about total synthesis:
attention to seemingly trivial detail can be decisive to the success
or failure of a reaction. In this case, it is conceivable that the
particle size of the cerium trichloride was finer in Fu¨rstner’s
experiments than in ours. A larger surface area for the insoluble
(or partly soluble) reagent would have resulted in faster kinetics
for the transmetalation step.
a (a) i. s-BuLi, THF, -50 °C, 30 min; ii. CeCl3, -78 to -50 °C, 30
min; -50 °C, 1 h; iii. 23 (0.3 equiv), -78 °C to room temperature; (b)
i. xs TBAF, 50 °C, 18 h; ii. aqueous HCl, 65% (two steps from 23).
Experimental Section
dichloride to 23 also led to the anticipated tertiary alcohols.
The cerium trichloride for each of the experiments was dried,
in two ways, according to the procedure described by Imamoto
and according to Fu¨rstner’s protocol, which lent further support
to our conviction that the quality of the reagent was good.15
However, addition of cerium trichloride to the solution of lithio
10 always led to a heterogeneous mixture, and it is a truism
that heterogeneous reactions are often difficult to reproduce.
We were particularly perplexed by the ease with which we were
able to add methyl- and butylcerium dichloride to 23. Consid-
eration of this result led us to the solution of the problem.
Methyllithium and n-butyllithium are both strongly basic, and
the transmetalation to cerium is undoubtedly very fast. The
furyllithium species which is derived from 10 is much less basic,
and the transmetalation step with cerium trichloride is much
slower and was not proceeding to completion. By following
Fu¨rstner’s conditions which call for transmetalation to cerium
during 2 h at -78 °C and the use of 4 equiv of the furylcerium
species, we were generating mixtures of furylcerium and
furyllithium species. Since 10 was used in a 4-fold excess over
23, there was always enough furyllithium present in solution
to convert 23 to the enolate before any addition of the
furylcerium could take place. The key to success was to ensure
that the transmetalation proceeded to completion, and the key
modification of Fu¨rstner’s conditions was to warm the solution
of the furyllithium with cerium chloride from -78 to -50 °C
during 30 min, maintain that temperature for 1 h, and then cool
the solution containing the furylcerium species to -78 °C again
before adding 23. Under these conditions, complete consumption
of 23 took place to produce the labile alcohol 36. When the
addition reaction was performed on larger scale, it was possible
to detect a change in the appearance of the reaction mixture
after warming. After warming to -50 °C, the reaction was still
heterogeneous, but there was considerably less suspended
material than before. Warming the solution much above -50
°C led to extensive decomposition of the anion. Deprotection
of the two silicon-containing protecting groups in 36 with TBAF,
followed by exposure to aqueous HCl in a separatory funnel,
led to roseophilin hydrochloride in 65% overall yield from 23
as a brilliant purple solid. Synthetic roseophilin was identical
with natural material from Professor Seto’s group, which was
kindly provided by Professor Yoichi Hayakawa.
(R)-3-But-3-enyl-2-hydroxy-5-methylene-4-(methylethyl)cyclopent-
2-en-1-one 12. To a solution of allene 17-H (1.240 g, 5.953 mmol) in
THF (30 mL) at -78 °C was added n-BuLi (2.50 mL, 2.46 M in
hexanes, 6.15 mmol). After 20 min, a solution of amide 16 (871 mg,
3.67 mmol) in THF (30 mL) at -78 °C was added via cannula. The
reaction mixture was warmed from -78 to -30 °C over 1 h, cooled to
-78 °C, and quenched by rapid addition, through a large bore cannula,
to HCl in HFIP/TFE (generated by addition of 7.5 mL of acetyl chloride
to a solution of 30 mL of HFIP and 30 mL of TFE) at -78 °C. The
flask was removed from the cooling bath, warmed to room temperature,
and diluted with saturated NaHCO3, pH 7 buffer, brine, and EtOAc.
The aqueous phase was extracted with EtOAc (3×), and the combined
organic extracts were washed with brine (1×) and dried over MgSO4.
Purification by flash column chromatography on silica (5% to 10%
EtOAc in hexanes) gave cyclopentenone 12 (589 mg, 78% yield, 86%
1
ee) as a colorless oil: Rf ) 0.35 (20% EtOAc in hexanes); H NMR
(300 MHz, CDCl3) δ 6.89 (s br, 1H), 6.10 (s, 1H), 5.83 (ddt, J ) 17.1,
10.5, 6.1 Hz, 1H), 5.41 (s, 1H), 5.07 (dd, J ) 17.1, 1.5 Hz, 1H), 4.99
(d br, J ) 10.5 Hz, 1H), 3.20 (s br, 1H), 2.77 (m, 1H), 2.45-2.22 (m,
3H), 2.15 (sept d, J ) 7.1, 2.9 Hz, 1H), 1.10 (d, J ) 7.1 Hz, 3H), 0.65
(d, J ) 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 189.8, 151.1, 144.4,
141.7, 137.4, 116.7, 115.3, 47.1, 30.7, 29.1, 25.9, 21.7, 16.3; IR (neat)
3310 (br), 2965, 1680, 1625 cm-1; EIMS m/z 206 (M+, 35), 164 (79),
163 (100), 135 (65), 123 (91), 122 (43), 117 (36); HREIMS calcd for
C13H18O2 206.1307, found 206.1283; chiral HPLC (25 × 1 cm Chiralcel
OD column, 1 mL/min, 254 nm; 2.5/97.5 2-propanol/hexanes) tR
23.8 min (major), tR ) 25.4 min (minor).
)
Roseophilin. To a solution of furan 10 (378 mg, 1.07 mmol) in
THF (15 mL) at -50 °C was added s-BuLi (1.10 mL, 0.97 M in
cyclohexane, 1.1 mmol). After 30 min, the solution was cooled to -78
°C and transferred via cannula to a suspension of CeCl3 (372 mg, 1.51
mmol; dried according to ref 15a; residual water was removed with
t-BuLi, see: Paquette, L. A. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: New York, 1995;
Vol. 2, p 1035) in THF (15 mL) at -78 °C. The solution was warmed
to -50 °C over 30 min, maintained at -50 °C for 1 h, and cooled to
-78 °C. A solution of ketone 23 (119 mg, 0.295 mmol) in THF (15
mL) at -78 °C was added. The reaction mixture was warmed from
-78 °C to room temperature over 15 h and diluted with saturated
NaHCO3, water, and ether. The aqueous phase was extracted with ether
(4×), and the combined organic extracts were washed with brine (1×),
dried over Na2SO4, concentrated, and filtered through neutral aluminum
oxide (activated, ∼150 mesh; eluted with hexanes followed by EtOAc).
Crude alcohol 36 was dissolved in THF (40 mL), and TBAF (2.0 mL,
1.0 M in THF, 2 mmol) was added. The reaction mixture was heated
(15) (a) Takeda, N.; Imamoto, T. Org. Synth. 1998, 76, 228-238. See
also: (b) Dimitrov, V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996,
37, 6787-6790.
(16) We thank professors Dale Boger and Barry Trost for discussing
their results with us prior to publication. Boger, D. L.; Hong, J. J. Am.
Chem. Soc. 2001, 123, 8515-8519.

8514 J. Am. Chem. Soc., Vol. 123, No. 35, 2001
Harrington and Tius
to 50 °C for 18 h and diluted with ether, water, and saturated NaHCO3.
The aqueous phase was extracted with ether (4×), and to the combined
organic extracts was added 1 M HCl. After 5 min of agitation, the
two-phase system was neutralized with saturated NaHCO3 and diluted
with brine, and the organic phase was dried over Na2SO4. Purification
by flash column chromatography on neutral aluminum oxide (activated,
∼150 mesh; eluted with CH2Cl2 to 10-20% EtOAc in CH2Cl2; fractions
containing roseophilin were combined, concentrated, diluted with ether,
and acidified with concentrated hydrochloric acid) gave synthetic
roseophilin hydrochloride (94 mg, 65%) as a red solid: Rf ) 0.58 (20%
453.2 [M + 1]+; chiral HPLC (25 × 1 cm Chiralcel OD column, 1
mL/min, 306 nm; 1/99/0.1 2-propanol/hexanes/Et2NH) tR ) 22.3 min.
Acknowledgment. We thank the National Institutes of
Health (GM57873) for generous support, Professor Dale Boger
for sharing his results with us prior to publication, and Professor
Yoichi Hayakawa for sending us a sample of authentic roseo-
philin.
Supporting Information Available: Experimental proce-
dures and spectroscopic data for 17-H, 32, and 33. Experimental
procedures for 18-23 and 11. 1H and 13C NMR, IR, and mass
spectra for 17 and for roseophilin. Chiral HPLC traces for the
recrystallization of 22, and for racemic, natural, and synthetic
roseophilin. Circular dichroism spectra for natural and synthetic
1
EtOAc in hexanes; aluminum oxide); H NMR (500 MHz, CDCl3) δ
13.89 (s br, 1H), 13.64 (s br, 1H), 7.28 (t, J ) 2.7 Hz, 1H), 6.94 (s,
1H), 6.30 (t br, J ) 2.0 Hz, 1H), 6.20 (s, 1H), 4.15 (s, 3H), 3.84 (dd,
J ) 4.6, 3.2 Hz, 1H), 3.60 (m, 1H), 2.85 (ddd, J ) 13.2, 5.4, 3.7 Hz,
1H), 2.72 (d, J ) 6.1 Hz, 1H), 2.10 (m, 1H), 2.03 (dt, J ) 14.6, 5.4
Hz, 1H), 1.86-1.79 (m, 2H), 1.40-1.29 (m, 2H), 1.21 (m, 1H), 1.08-
0.83 (m, 6H), 1.02 (d, J ) 6.6 Hz, 3H), 0.80 (d, J ) 6.6 Hz, 3H),
0.47-0.36 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 166.7, 165.9, 160.3,
159.3, 144.7, 135.6, 132.8, 126.7, 119.5, 116.8, 112.0, 110.9, 96.3,
60.0, 55.4, 51.6, 34.0, 33.0, 28.22, 28.20, 27.9, 27.5, 26.9, 24.8, 24.4,
21.4, 19.6; IR (neat) 3015 (br), 2940, 1615, 1575 cm-1; ESIMS m/z
1
roseophilin. H NMR spectra for 11, 12, 14-16, 18-20, 22,
23, and 30-33 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA011242H