Synthesis of termini-differentiated 6-carbon stereotetrads: An alkylative oxidation strategy for preparation of the C21-C26 segment of apoptolidin

Article abstract of DOI:10.1021/ol026377m

(graph presented) Two methods have been developed for the synthesis of epoxide 36. The first uses (+)-pulegone 25 as an enantiopure starting material and introduces the requisite intricacy of target 22 in 12 operations. The second method employs an enanti

Full text of DOI:10.1021/ol026377m

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3571-3574
Synthesis of Termini-Differentiated
6-Carbon Stereotetrads: An Alkylative
Oxidation Strategy for Preparation of
the C21−C26 Segment of Apoptolidin1
Yuzhong Chen, Jerry B. Evarts, Jr., Eduardo Torres, and Philip L. Fuchs*
Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
pfuchs@purdue.edu
Received June 17, 2002
ABSTRACT
Two methods have been developed for the synthesis of epoxide 36. The first uses (+)-pulegone 25 as an enantiopure starting material and
introduces the requisite intricacy of target 22 in 12 operations. The second method employs an enantiospecific catalytic Jacobsen epoxidation
of 1a and is five operations shorter. The second sequence features an oxygen-directed alkylative oxidation reaction that re-establishes the
dienyl sulfone functionality with concomitant 1,3-transposition of the sulfone moiety.
We have previously reported on vinyl epoxides 2a2a and 2b,2b
which are available by enantiospecific epoxidation of the
parent dienes 1a and 1b.3 Elimination and epoxidation
followed by nucleophilic addition places stereogenic centers
at three of the four possible ring atoms (stars, Figure 1).
Cyclohexenones 4 with 4-hydroxy4 and 4-alkyl5 substit-
uents are readily available in very high enantiopurity and
are suitable starting points for accessing the remaining
position in the triflate series since the parent compound is
itself derived from cyclohexenone6 The sulfone series either
requires starting with enantiopure dienes 6 or 7 or, alterna-
tively, devising a means of introducing functionality at the
“unstarred” position of 3a.
During our investigation, Arjona, Menchaca, and Plumet
published their seminal study of polypropionate stereotetrad
(1) Syntheses via vinyl sulfones #88. Chiral Carbon Catalog 12.
(2) (a) Hentemann, M. F.; Fuchs, P. L. Org. Lett. 1999, 1, 355. (b)
Hentemann, M. H.; Fuchs, P. L. Tetrahedron. Lett. 1999, 40, 2699.
(3) Hentemann, M. F.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 5615.
(4) Evarts, J.; Fuchs, P. L. Tetrahedron. Lett. 2001, 42, 3673.
(5) Evarts, J.; Torres, E.; Fuchs, P. L. J. Am. Chem. Soc. 2002, 124,
11093.
(6) All permutations of stereochemistry have been completed for the
4-hydroxy series. Evarts. J.; Fuchs, P. L. Tetrahedron. Lett. 1999, 40, 2703.
The 4-methyl triflate series has also been investigated. Evarts, J. Ph.D.
Thesis, Purdue University, West Lafayette, IN, 2001.
Figure 1.
10.1021/ol026377m CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/27/2002

synthesis using vinyl sulfones.7 The absolute asymmetry was
(or could be)8 achieved by using 7-oxabicyclo [2.2.1] starting
materials 109 and 15 prepared by Diels-Alder reaction with
furan 8. Key features of their methodology included use of
the bridging oxygen as a leaving group during nucleophilic
methylation of 11 and 16 as well as highly selective Schreiber
ozonolysis to establish the termini-differentiated stereotetrads.
Figure 2 shows two examples, but the entire family of eight
diastereomeric tetrads was prepared.
Figure 3.
sulfonic acid effects Pummerer elimination generating vinyl
sulfide 28 in 94% yield.12 Luche reduction of ketone 28
followed by addition to oxone-methanol gave sulfone 24
(Figure 4). Conversion of alcohol 24 to the corresponding
Figure 2.
In conjunction with synthesis of apoptolidin 2010 (Figure
3), we sought to construct the C21-C26 lactone precursor
22 of intermediate 21 via oxidative cleavage of the 6-carbon
vinyl sulfone 23. Enantiopure 23 can be accessed from both
methyl vinyl sulfone 24 and epoxy vinyl sulfone 2a.
Our initial synthesis began with the known epoxidation
of (R)-(+)-pulegone 25 followed by treatment with sodium
thiophenoxide providing R-ketosulfide 26.11 mCPBA oxida-
tion of 26 gave sulfoxide 27 in a 71% overall yield from
25. Reaction of 27 with acetic anhydride and methane-
Figure 4. (1) (a) 30% H2O2, LiOH, MeOH, 25 °C, 8 h 94%; (b)
PhSNa, THF reflux, 18 h 84%. (2) mCPBA, CH2Cl2, -30 °C, 2 h
90%. (3) Ac2O, CH3SO3H (cat.), CH2Cl2, 25 °C, 14 h, 94%. (4)
(a) CeCl3, NaBH4, MeOH, 25 °C, 30 min, 95%; (b) oxone, H2O,
MeOH, 25 °C, 24 h, 95%. (5) (a) MsCl, Et3N, CH2Cl2, 0°C, 1 h;
(b) LiHMDS, THF, -78 °C, 90%. (6) mCPBA, CH2Cl2, 25 °C, 3
h, 84% (30:31 ) 3:2), or (R,R)-Mn(salen)Cl (5 mol %), 30% H2O2,
CH2Cl2/MeOH (1:1), 0 °C, 8 h, 55% (30:31 ) 6:1).
(7) Arjona, O.; Menchaca, R.; Plumet, J. J. Org. Chem. 2001, 66, 2400.
(8) Compound 15 was used as a racemic mixture (Acena, J. L.; Arjona,
O.; Leon, M.; Plumet, J. Tetrahedron Lett. 1996, 37, 8957), but enantio-
pure material is now available via a chiral-catalyzed Diels-Alder reaction
of furan and prochiral vinyl amide-oxazolidinone: Evans, D. A.; Barnes,
D. M. Tetrahedron Lett. 1997, 38, 57. Two additional high-yielding
operations are included to formally enable comparisons in the enantiopure
series.
(9) Vieira, E.; Vogel, P. HelV. Chim. Acta 1983, 66, 1865.
(10) Hayakawa, Y.; Kim, J. W.; Adachi, H.; Shin-ya, K.; Fujita, K.-I.;
Seto, H. J. Am. Chem. Soc. 1998, 120, 3524. For efforts directed toward
the synthesis of apoptolidin, see: Nicolaou, K. C.; Li, Y.; Weyershausen,
B.; Wei, H.-X. Chem. Commun. 2000, 307. Sulikowski, G. A.; Lee, W.-
M.; Jin, B.; Wu, B. Organic Lett. 2000, 2, 1439. Schuppan, J.; Wehlan, H.;
Keiper, S.; Koert, U. Angew. Chem., Int. Ed. 2001, 40, 2063. Schuppan, J.;
Ziemer, B.; Koert, U. Tetrahedron Lett. 2000, 41, 621. Toshima, K.; Arita,
T.; Kato, K.; Tanaka, D.; Matsumura, S. Tetrahedron Lett. 2001, 42, 8873.
Nicolaou, K. C.; Li, Yiwei; F., Konstantina, C.; Mitchell, H. J.; Wei, H.-
X.; Weyershausen, B. Angew. Chem., Int. Ed. 2001, 40, 3849. Nicolaou,
K. C.; Li, Y.; Fylaktakidou, K. C.; Mitchell, H. J.; Sugita, K. Angew. Chem.,
Int. Ed. 2001, 40, 3854.
mesylate followed by careful, low-temperature treatment with
LiHMDS cleanly gave diene 29. Epoxidation with mCPBA
resulted in an unexpectedly inseparable 3:2 mixture of
diastereomeric epoxides 30 and 31. Attempts to improve this
oxidation by employing double stereoselection with Jacobsen
asymmetric epoxidation3 provided a 55% yield of 30/31 in
6:1 selectivity accompanied by 35% aromatization.
To avoid the separation and yield problem created by the
30/31 mixture, we returned to vinyl sulfone 24 and examined
base-catalyzed equilibration of this intermediate. Isomeriza-
tion of 24 (Figure 5) with 5 mol % DBU for 15 h generated
a 1:2.5 equilibrium mixture of 24/32, which upon crystal-
lization provided a first crop 46% yield of pure 32.13 Two
(11) (a) Mutti, S.; Daubie, C.; Decalogne, F.; Fournier, R.; Rossi, P.
Tetrahedron Lett. 1996, 37, 3125. (b) Caine, D.; Procter, K.; Cassell, R. A.
J. Org. Chem. 1984, 49, 2647. (c) Avery, M. A.; Chong, W. K. M.; Jennings-
White, C. J. Am. Chem. Soc. 1992, 114, 974. (d) Nangia, A.; Prasuna, G.
Synth. Commun. 1994, 24, 1989.
(12) Monteiro, H. J.; Gemal, A. L. Synthesis 1975, 75, 437.
(13) Structure verified by X-ray crystallography. X-ray data for com-
pounds 32 and 33 have been submitted to the Cambridge Crystallographic
database.
3572
Org. Lett., Vol. 4, No. 21, 2002

additional crops of 32 were collected via further equilibration
of the crystallization residues for a final yield of 79%.
mCPBA epoxidation of 32 in methylene chloride at 25 °C
was slow, but afforded 3313 in 86% yield. Sequential
treatment of 33 with mesyl chloride and 2 equiv of LiHMDS
smoothly generated dienyl sulfone 35 in 92% yield, presum-
ably via the intermediacy of epoxyvinyl sulfone 30 (Figure
5).
Figure 6. (8) Mo(CO)6 (5 mol %), TBHP, C6H6, reflux, 1.5 h,
94%. (9) AlMe3, 2.2 equiv, CuMe (cat), THF, from -78 to 25 °C,
10 h, 91%. (10) (a) PPh3, DEAD, HCO2H, THF, 2 h; (b) NaHCO3,
MeOH, 30 min, 95%, two steps. (11) (a) TBSCl, 4 equiv of
imidazole, DMF, 70 °C, 20 h; (b) TBAF, 1.1 equiv of THF, 25
°C, 30 min, 84%, two steps. (12) (a) O3, NaHCO3, CH2Cl2, -30
°C, 1 h; (b) (CH3)2S, 25 °C, 5 h. (13) LiAlH(O-tBu)3, THF, -78
°C, 1 h, 50%, two steps.
Reaction of epoxyvinyl sulfone 2a with LiHMDS affords
oxido diene 40, which may be isolated as the dienyl alcohol
if desired.2 In most instances, we no longer isolate this
intermediate. For example, addition of 1.1 equiv of LiHMDS
to 2a followed by 2.5 equiv of MeLi generates dianion 41.
Further addition of (PhS)2 results in regiospecific capture of
allyl sulfonyl anion 41 to produce vinyl sulfide 43 (isolated
as the alcohol) in 82% yield after stirring for 8 h at 25 °C.
As has been shown in the seven-membered ring series,17
formation of intermediate 42 proceeds via conjugate addition
of methyllithium followed by γ-sulfenylation. The unusual
γ-regiochemistry of this process appears to result from the
interplay of the weak sulfenylation reagent in concert with
the high steric demand imposed by the proximally methylated
R-sulfonyl center.
NMR studies confirm that initial intermediate 42 suffers
thermodynamic base-catalyzed equilibration to γ-phenylthio-
allyl sulfone 43. TMS-triflate-promoted, lone-pair-assisted18
elimination of the crude diastereomeric mixture 44 to dienyl
sulfide 45 was readily accomplished in 94% yield by heating
44 with 5.0 equiv of TMSOTf and 6.0 equiv of Et3N in
methylene chloride at reflux for 4 h. The mixture was then
cooled to 0 °C, and 2.5 equiv of mCPBA was added in
portions; the mixture was left stirring for 6 h at 25 °C to
afford dienyl sulfone 35.
Figure 5. (5) DBU (5 mol %), CH2Cl2, 79%. (6) mCPBA, CH2-
Cl2, 3 days, 25 °C, 86%. (7) MsCl, 2 equiv of LiHMDS, -78 °C,
15 min, 92%.
Directed catalytic epoxidation14 of alcohol 35 with Mo-
(CO)6 (5 mol %) and TBHP in benzene at reflux for 1 h
smoothly gave 36 as a single diastereomer in 94% yield.
Treatment of alcohol 36 with trimethylaluminum in the
presence of a catalytic amount of methylcopper15 affords
37 in 91% yield. The nucleophilic methylation reaction has
the potential of both 1,2- and 1,4-addition modes. In this
instance, any competitive 1,2-trans-addition results in forma-
tion of the enantiomer of 37, an especially serious conse-
quence. Fortunately, chiral HPLC demonstrates that the
enantiomeric excess of 37 is >98%, which indicates a 1,4-/
1,2-selectivity ratio of >49:1 in the methylation process
(Figure 6).
The allylic hydroxyl of diol 37 can be selectively inverted
using the Mitsunobu reaction to give 23 in 95% yield.
Sequential treatment of 23 with excess tert-butyldimethylsilyl
chloride, followed by cleavage of the less-hindered silyl ether
with 1 equiv of TBAF delivers 38 in 84% yield. Finally,
ozonolysis of 38 in methylene chloride gives aldehyde 22.
For long-term storage, 22 is reduced with LiAlH(O-tBu)3 to
afford alcohol 39 in 50% overall yield from 38. (Figure 6).
Although acceptable in terms of material supply, the
synthesis was longer than desired. A superior synthesis of
key fragment 36 begins with scale-up and improvement of
the Jacobsen epoxidation reaction.3 Beginning with dienyl
sulfone 1a,16 we now produce epoxyvinyl sulfone 2a2 in 60%
yield on 50 g scale and >97% ee by using a 6-fold-reduced
catalyst load (2.5 vs 15%).
(16) Myers, D.; Fuchs, P. L. J. Org. Chem. 2002, 60, 200-204. The
2-phenylsulfonyl-1,3-cycloheptadiene 1a precursor to 2a is commercially
available from Aldrich.
(17) Torres, E.; Chen, Y.; Kim, I.; Fuchs, P. L. Submitted for publication.
(18) While ionization of the γ-phenylsulfonyl moiety of acyclic vinyl
ethers and vinyl sulfides is known to generate enones and enals (Trost, B.
M.; Ghadiri, M. R. Bull. Soc. Chim. Fr. 1993, 130, 433. Craig, D.; Etheridge,
C. J. Tetrahedron Lett. 1993, 34, 7487. Harmata, M.; Fletcher, V. R.;
Claassen, R. J., II. J. Am. Chem. Soc. 1991, 113, 9861. Ogura, K.; Iihama,
T.; Takahashi, K.; Iida, H. Tetrahedron Lett. 1984, 25, 2671. Craig, D.;
Etheridge, C. J.; Smith, A. M. Tetrahedron Lett. 1992, 33, 7445-7446),
the corresponding reaction for cyclic substrates is less common. Kim, S.
H.; Jin, Z.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 4537. Jin, Z.; Fuchs,
P. L. J. Am. Chem. Soc. 1995, 117, 3022; J. Am. Chem. Soc. 1994, 116,
5995.
(14) Broom, S. J.; Ede, R. M.; Wilkins, A. L. Tetrahedron Lett. 1992,
33, 3197. Sharpless, K. B.; Michaelson, R. C. J. Am. Chem. Soc. 1973, 95,
6136.
(15) Saddler, J. C.; Fuchs, P. L. J. Am. Chem. Soc. 1981, 103, 2112.
Org. Lett., Vol. 4, No. 21, 2002
3573

Figure 8.
is efficient in terms of yield per operation (EQ ) 87%) but
suffers badly from the overall number of operations, resulting
in an IQ (intricacy quotient) of only 0.50. The second
synthesis from 1a is lower-yielding per operation but enjoys
an IQ of ∼0.7, which places it in the middle of a group of
the “top 40” syntheses employed as the basis set to devise
the two analytical tools (Figure 8).
Figure 7. (2) (a) LiHMDS, THF, -78 °C, 98%; (b) 2.5 equiv of
MeLi, THF, -78 °C; (c) (PhS)2, THF, -78 f 25 °C, 82%. (3) (a)
5.0 equiv of TMSOTf, 6.0 equiv of Et3N, CH2Cl2, reflux 4 h; (b)
2.5 equiv of mCPBA, 0 f 25 °C, 6 h, 89%.
The net effect of the sulfenylation/elimination sequence is
the transposition of the sulfur-substituted dienyl system with
simultaneous and stereospecific introduction of a methyl
group at a preViously inaccessible position.
In conclusion, two methods have been developed for the
synthesis of epoxide 36. The first uses (+)-pulegone 25 as
an enantiopure starting material and introduces the requisite
intricacy of target 22 in 12 operations. The second method
employs an enantiospecific catalytic Jacobsen epoxidation
of 1a and is five operations shorter.
Acknowledgment. J.E. and E.T. thank Kodak and Pfizer,
respectively, for financial support in the form of graduate
fellowships. We acknowledge Arlene Rothwell and Karl
Wood for mass spectral data.
Supporting Information Available: Experimental pro-
cedures and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL026377M
Using a pair of formulas devised for analysis of organic
synthesis,19 it can be seen that the overall synthesis from 25
(19) Fuchs, P. L. Tetrahedron 2001, 57, 6855.
3574
Org. Lett., Vol. 4, No. 21, 2002