Synthesis and confirmation of the absolute stereochemistry of the (-)-af lastatin A C9-C27 degradation polyol

Article abstract of DOI:10.1021/ol051225n

(Chemical Equation Presented) The C₈-C₁₈ ethyl ketone and C₁₉-C₂₈ aldehyde aflastatin A fragments were synthesized and coupled using a diastereoselective anti aldol reaction. This adduct was successfully convert

Full text of DOI:10.1021/ol051225n

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3335-3338
Synthesis and Confirmation of the
Absolute Stereochemistry of the
(−)-Aflastatin A C9−C27 Degradation
Polyol
David A. Evans,* William C. Trenkle, Jing Zhang, and Jason D. Burch
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received May 24, 2005
ABSTRACT
The C8
reaction. This adduct was successfully converted into the C9
absolute stereochemistry of this region of the natural product.
−
C18 ethyl ketone and C19
−
C28 aldehyde aflastatin A fragments were synthesized and coupled using a diastereoselective anti aldol
−
C27 polyol degradation product of ( )-aflastatin A to confirm the relative and
−
In 1996, Sukuda and co-workers reported the isolation and
gross structure of aflastatin A from the mycelia of Strepto-
myces sp. MRI 142. This natural product exhibits strong
inhibitory activity against aflatoxin production without
significantly affecting the growth of A. parasiticus.1 The
same group subsequently reported the relative and absolute
structure of aflastatin A (1) (Figure 1).2 Stereochemical
assignments were based on both degradation and chemical
correlation studies; however, the relative and absolute
stereochemistry of the C9-C27 degradation polyol 2 was
predicted solely via extensive NMR studies. In this Letter,
we describe an asymmetric synthesis of polyol 2 that verifies
the stereochemical assignment of this region of aflastatin A.
The principal disconnections that were employed in the
synthesis of the C9-C27 polyol of aflastatin A are illustrated
in Scheme 1. The important fragment coupling event was
Figure 1. Sakuda’s structure of aflastatin A.
the anti aldol union of the (E) boron enolate derived from
ethyl ketone 4 with the complex aldehyde 5. In this case,
the dominant control element was the anticipated enhanced
Felkin selectivity from the C20 methyl-bearing stereocenter
on the aldehyde fragment.3 Our approach to fragments 4 and
(1) (a) Sakuda, S.; Ono, M.; Furihata, K.; Nakayama, J.; Suzuki, A.;
Isogai, A. J. Am. Chem. Soc. 1996, 118, 7855. (b) Kondo, T.; Sakurada,
M.; Okamoto, S.; Ono, M.; Tsukigi, H.; Suzuki, A.; Nagasawa, H.; Sakuda,
S. J. Antibiotics 2001, 54, 650.
(2) Ikeda, H.; Matsumori, N.; Ono, M.; Suzuki, A.; Isogai, A.; Nagasawa,
H.; Sakuda, S. J. Org. Chem. 2000, 65, 438.
10.1021/ol051225n CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/21/2005

Scheme 1. Disconnection of C9-C27 Degradation Polyol 2
Scheme 2. Synthesis of C19-C28 Aldehyde Fragment
5 relied on the two stereoselective aldol processes illustrated
in Scheme 1.
Scheme 3. Synthesis of C8-C18 Ketone Fragment
Synthesis of the C19-C28 fragment began with an enan-
tioselective [Cu(S,S)-PhPybox)](SbF6)2-catalyzed aldol ad-
dition followed by syn-selective reduction to give the
previously reported diol 10 in 99% ee and 84% overall yield.4
Treatment of 10 with anisaldehyde dimethylacetal afforded
the PMP acetal, which underwent selective deprotection of
the benzyl ether with Raney nickel to give hydroxy ester
11.5 Silylation followed by transamidation6 provided the
Weinreb amide 12, which was an appropriate substrate for
a carbonyl-directed acetal cleavage using MgBr2 and Bu3-
SnH.7 Allylation, Et2BOMe-mediated syn-reduction,8 and
acid-catalyzed acetonide formation furnished the protected
all-syn triol derivative 15. Ozonolysis provided aldehyde 16,
which underwent an auxiliary controlled syn-aldol reaction
with oxazolidinone 7 to deliver the corresponding aldol
adduct as a single diastereomer. Cleavage of the imide
auxiliary was achieved under standard conditions to provide
Weinreb amide 17. Silylation with TBSOTf and 2,6-lutidine
followed by DIBAL completed the synthesis of aldehyde 5
(Scheme 2).
Scheme 3 illustrates the synthesis of the C8-C18 ethyl
ketone fragment. The synthesis was initiated with our
recently reported MgCl2-catalyzed direct aldol addition to
provide the known anti-aldol adduct 18 (>20:1 dr, 92%
yield).9 Imide 18 was converted into the Weinreb amide 19,10
protected as the PMB ether, and reduced to afford the C8-
C11 aldehyde 20 in 91% yield. The C12-C15 carbon skeleton
was introduced by a boron-mediated anti-aldol reaction
between 20 and â-ketoimide 21.11 The high selectivity
observed in this reaction (>95:5 dr) was anticipated as a
result of the matched double stereodifferentiating nature of
the aldehyde and ketone components. The hydroxy ketone
(3) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Rieger, D. L. J. Am. Chem.
Soc. 1995, 117, 9073.
(4) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos,
K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999, 121, 669.
(5) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(6) William, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
(7) For free hydroxyl-directed reduction of PMP acetal with MgBr2 and
n-Bu3SnH, see: Zheng, B. Z.; Yamauchi, M.; Dei, H.; Kusaka, S. I.; Matsui,
K.; Yonemitsu, O. Tetrahedron Lett. 2000, 41, 6441.
(9) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392.
(10) All attempts to convert 18 directly into 19 using either Me2AlNMe-
(OMe) or ClMgNMe(OMe) failed because of preferred endocyclic cleavage.
(11) (a) Evans, D. A.; Clark, J. S.; Metternich, R.; Novak, V. J.; Sheppard,
G. S. J. Am. Chem. Soc. 1990, 112, 866. (b) Evans, D. A.; Kim, A. S. J.
Am. Chem. Soc. 1996, 118, 11323.
(8) Beck, G.; Jendralla, H.; Kesseler, K. Synthesis 1995, 1014.
3336
Org. Lett., Vol. 7, No. 15, 2005

hyde 25. A methyl ketone aldol reaction, mediated by (-)-
diisopinocampheylboron chloride (DIP-Cl), between 25 and
2-butanone furnished the desired aldol adduct with modest
diastereoselectivity (4:1 favoring the Felkin product).14
Silylation of the aldol adduct afforded the C8-C18 ethyl
ketone fragment 4.
Scheme 4. C18-C19 anti-Selective Fragment Coupling
In anticipation of the aldol fragment coupling, model
studies for the C18-C19 anti-aldol bond construction were
conducted (Scheme 4, eq 1). The dicyclohexylchloroborane-
mediated aldol reaction between ethyl ketone 26 and alde-
hyde 27 exhibited high stereoselectivity favoring the desired
Felkin product 28 (90:10 diastereomeric ratio) albeit in
moderate conversion.14 Equation 2 summarizes the results
of the anti-aldol reaction between C8-C18 ethyl ketone 4
and C19-C28 aldehyde 5. The desired Felkin selective aldol
adduct 29 was obtained as the major diastereomer, along
with a minor amount of syn-aldol adduct 30 and unreacted
ketone starting material.15-16
The major adduct 29 was converted into the C9-C27
degradation polyol 2 as shown in Scheme 5. Zn(BH4)2-
mediated reduction afforded the C17-C19 syn-diol, which was
protected as the derived acetonide 31. Although DDQ
deprotection resulted in overoxidation to enone 32, this
compound could still serve as a precursor for the polyol since
the C9 stereocenter is inconsequential. Thus, ozonolysis of
the styrenyl double bond followed by in situ NaBH4
reduction gave a triol intermediate (as a mixture of stereo-
isomers). Selective deprotection of the primary TIPS ether
with TBAF to provided the tetraol intermediate. NaIO4-
mediated diol cleavage of both termini followed by in situ
NaBH4 reduction furnished diol 33 in a 65% yield over three
steps. Treatment of 33 with 80% aqueous acetic acid at room
temperature afforded the C9-C27 degradation polyol 2 in
quantitative yield.
22 was protected as its derived triethylsilyl (TES) ether
followed by a chelation-controlled reduction mediated by Zn-
(BH4)2 to afford 23 as a single diastereomer with a 1,3-syn
relationship between C11-C13.12 The high selectivity for this
reduction can be rationalized through a bidentate chelate
formed between C13 and C15 carbonyls, with the C14 methyl
stereocenter controlling the subsequent hydride delivery.
Protecting group interconversion, followed by LiBH4 reduc-
tion and Dess-Martin oxidation,13 provided C8-C15 alde-
Scheme 5. Synthesis of C9-C27 Degradation Polyol
Org. Lett., Vol. 7, No. 15, 2005
3337

The synthetic C9-C27 polyol 2 was identical in all respects
with the authentic sample derived from the natural product
(1H NMR, 13C NMR, HRMS). The optical rotation of the
HRMS) from material derived from the natural sample, and
the optical rotations were also in agreement (synthetic 34
[R]23 +10.0 (c ) 0.80, MeOH); lit.17 [R]23 +10.7 (c )
D
D
synthetic material ([R]23 -2.47 (c ) 0.59, EtOH)) was in
1.32, MeOH)).
D
agreement with that reported for degradation product 2 (lit.2
[R]23D -4.03 (c ) 0.60, EtOH)), indicating that the relative
and absolute stereochemistry of polyol 2 is correct as
assigned. As further proof of structure, polyol 2 was
converted into the polyacetate 34 using acetic anhydride and
pyridine (Scheme 5). Synthetic polyacetate 34 exhibited
indistinguishable analytical data (1H NMR, 13C NMR,
In summary, the C8-C18 and C19-C28 fragments of
aflastatin A have been efficiently synthesized, and prelimi-
nary conditions for their diastereoselective coupling have
been developed. The C8-C28 aldol adduct was successfully
converted into the C9-C27 polyol 2. By comparison of the
synthetic material with that derived from the natural product,
we conclude that the relative and absolute stereochemistry
of C9-C27 polyol was correctly assigned. The total synthesis
of aflastatin A will be reported in due course.
(12) (a) Direct reduction of hydroxy ketone 25 with Zn(BH4)2 provided
the 1,3-syn diol with only modest diastereoselectivity (4:1 syn/anti). The
diminished selectivity could be attributed to the preferred chelation between
C
11 hydroxyl and C13 carbonyl with C12 methyl stereocenter interfering with
Acknowledgment. Support has been provided by the
National Institutes of Health (GM 033327-19), Amgen, and
Merck. We thank professor Sakuda for kindly providing us
a sample of the C9-C27 degradation polyol.
the â-face hydride delivery. (b) Halstead, D. P. Ph.D. Thesis, Harvard
University, 1998.
(13) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(14) (a) Paterson, I.; Cumming, J. G.; Smith, J. D.; Ward, R. A.
Tetrahedron Lett. 1994, 35, 441. (b) Fernandez-Megia, E.; Gourlaouen, N.;
Ley, S. V.; Rowlands, G. J. Synlett 1998, 991.
(15) The stereochemistry of the aldol adducts was proven via Mosher
ester analysis; see Supporting Information. Ohtani, I.; Kusumi, T.; Kashman,
Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
(16) See Supporting Information for experiments that provide proof of
stereochemical assignments.
Supporting Information Available: Experimental pro-
cedures, characterization of compounds 2-34, and stereo-
chemical proofs for adducts 28-30. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Ono, M.; Sakuda, S.; Ikeda, H.; Furihata, K.; Nakayhama, J.; Suzuki,
A.; Isogai, A. J. Antibiotics 1998, 51, 1019.
OL051225N
3338
Org. Lett., Vol. 7, No. 15, 2005