Synthesis of C13-C25 fragment of 24-demethylbafilomycin C1 via diastereoselective aldol reactions of a ketone boron enolate as the key step

Article abstract of DOI:10.1021/jo070624o

(Chemical Equation Presented) An efficient synthesis of the C13-C25 fragment is described for 24-demethylbafilomycin C₁, a new member of the plecomacrolide family isolated from fermentation broth of Streptomyces sp. CS which is a commensal microbe of Maytenus hookeri. The targeted C13-C25 fragment possesses five oxygenated and three methyl-substituted stereogenic centers. It is obtained through formation of the C17-C18 syn aldol by using an ethyl ketone boron enolate with diastereomeric ratios of 95:5 and 83:17, respectively, for the chiral aldehydes substituted with acetoxy and methoxyacetoxy groups at C15. The results confirm the observation that the stereochemistry at C22 of the ketone is determinant to the diastereoselectivity of the aldol reaction. The synthesized C13-C25 fragment having a methoxyacetoxy group at C15 is considered as a useful precursor for construction of the 16-membered ring lactone of 24-demethylbafilomycin C₁ through an aldol condensation of the methoxyacetate followed by formation of the C12-C13 double bond via a diene-ene RCM reaction.

Full text of DOI:10.1021/jo070624o

Synthesis of C13-C25 Fragment of 24-Demethylbafilomycin C1 via
Diastereoselective Aldol Reactions of a Ketone Boron Enolate
as the Key Step
Yucui Guan,† Jinlong Wu,† Liang Sun,† and Wei-Min Dai*,†,‡
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang UniVersity,
Hangzhou 310027, China, and Center for Cancer Research and Department of Chemistry, The Hong Kong
UniVersity of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
chdai@ust.hk; chdai@zju.edu.cn
ReceiVed March 26, 2007
An efficient synthesis of the C13-C25 fragment is described for 24-demethylbafilomycin C1, a new
member of the plecomacrolide family isolated from fermentation broth of Streptomyces sp. CS which is
a commensal microbe of Maytenus hookeri. The targeted C13-C25 fragment possesses five oxygenated
and three methyl-substituted stereogenic centers. It is obtained through formation of the C17-C18 syn
aldol by using an ethyl ketone boron enolate with diastereomeric ratios of 95:5 and 83:17, respectively,
for the chiral aldehydes substituted with acetoxy and methoxyacetoxy groups at C15. The results confirm
the observation that the stereochemistry at C22 of the ketone is determinant to the diastereoselectivity of
the aldol reaction. The synthesized C13-C25 fragment having a methoxyacetoxy group at C15 is
considered as a useful precursor for construction of the 16-membered ring lactone of 24-demethylba-
filomycin C1 through an aldol condensation of the methoxyacetate followed by formation of the C12-
C13 double bond via a diene-ene RCM reaction.
CHART 1. Structures of Bafilomycin A1 (1) and
24-Demethylbafilomycin C1 (2)
Introduction
Bafilomycin A1 (1, Chart 1)1 is the representative structure
of the class B subgroup of the plecomacrolides.2,3 It features
both a unique folding hemiacetal structure in the side chain and
an intramolecular hydrogen-bonding network among the mac-
rolactone carbonyl oxygen and the two hydroxyl groups at C17
and C19. The latter is believed to be critically important for
the biological function of the plecomacrolides as specific
vacuolar H+-ATPase (V-ATPase) inhibitors.4-6 A model was
* Corresponding author. Tel.: +852-2358-7365. Fax: +852-2358-1594
(HKUST). Tel./Fax: +86-571-8795-3128 (ZJU).
† Zhejiang University.
‡ Hong Kong University of Science and Technology.
(1) Werner, G.; Hagenmaier, H.; Drautz, H.; Baumgartner, A.; Za¨hner,
H. J. Antibiot. 1984, 37, 110-117.
(2) Bindseil, K. U.; Zeeck, A. Liebigs Ann. Chem. 1994, 305-312.
(3) Dai, W.-M.; Guan, Y.; Jin, J. Curr. Med. Chem. 2005, 12, 1947-
1993.
recently proposed for the binding site of bafilomycin A1 on
V-ATPase of Neurospora crassa.7 A number of other findings
indicate that a high rate of proton transport by V-ATPase seems
closely associated with development of diseases such as
10.1021/jo070624o CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/23/2007
J. Org. Chem. 2007, 72, 4953-4960
4953

Guan et al.
SCHEME 1. Key Retrosynthetic Bond Disconnections of 2 via RCM and Aldol Condensation
osteoporosis and cancer. Therefore inhibitors of V-ATPase are
considered as promising therapeutic drugs.8,9 Recently, Lu and
Shen reported 24-demethylbafilomycin C1 (2)10a and related
macrolides10b isolated from the fermentation broth of Strepto-
myces sp. CS, a commensal microbe of Maytenus hookeri. The
macrolide 2 exhibits strong cytotoxicity against P388 and A549
syntheses of bafilomycin A1 and other plecomacrolides have
been extensively studied by many research groups.12,13 Macro-
lactonization14 was generally used for ring closure while the
C10-C13 diene unit assembled via Pd-catalyzed cross-coupling
reactions.15
In connection with our ongoing research program on forma-
tion of macrolides via RCM strategies,16,17 we envisaged a
retrosynthetic analysis of 24-demethylbafilomycin C1 (2) as
outlined in Scheme 1. Critical bond disconnections between
C12-C13 and C2-C3 according to the diene-ene RCM18 and
an aldol condensation-â-elimination sequence12g disassemble
2 into the C3-C12 and C13-C25 fragments 3 and 4. Although
direct formation of the 16-membered macrolactone possessing
the tetraene functionality via the diene-ene RCM was not
possible,18a we have successfully tackled this issue in a model
system by using a sequence of aldol condensation (C2-C3
single bond formation) f diene-ene RCM (C12-C13 double
bond formation) f â-elimination (C2-C3 double bond forma-
tion).19 We planned to synthesize the C13-C25 fragment 4 by
employing a diastereoselective aldol reaction between the chiral
aldehyde 5 and the chiral ethyl ketone 6. Similar aldol reactions
between the chiral ketone 7a and the macrolactone-derived
aldehydes or simple achiral aldehydes were reported to afford
the desired syn-aldol products in high diastereoselectivity (>95:
5).12a,d In contrast, the C22 epimer 8 of our chiral ketone 6 gave
remarkably reduced diastereoselectivity of 75:25 in an analogous
aldol reaction used for the total synthesis of hygrolidin.20 It
tumor cell lines with ca. 80% and 90% inhibitions at 10-6
-
10-8 M concentrations, respectively. Structurally, 2 has one
methyl group less than bafilomycin C1 at C241 while it is a
homologue to PD118,576 A1 (C23-Et vs C23-Me).11 Total
(4) (a) Bowman, E. J.; Siebers, A.; Altendorf, K. Proc. Nat. Acad. Sci.
U.S.A. 1988, 85, 7972-7976. (b) Dro¨se, S.; Altendorf, K. J. Exp. Biol.
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(5) Beutler, J. A.; McKee, T. C. Curr. Med. Chem. 2003, 10, 787-796.
(6) It was reported that the synthetic analogue of concanamycins lacking
the hydrogen-bond network retains V-ATPase inhibitory activity and induces
apoptosis to cancer cells that overexpressing epidermal growth factor
receptors (EGFR), see: Yoshimoto, Y.; Jyojima, T.; Arita, T.; Ueda, M.;
Imoto, M.; Matsumura, S.; Toshima, K. Bioorg. Med. Chem. Lett. 2002,
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Shen, Y. J. Antibiot. 2004, 57, 597-600.
(11) Hatfield, G.; Woodard, R. W.; Son, J.-K. J. Nat. Prod. 1992, 55,
753-759.
(12) For total synthesis of bafilomycin A1, see: (a) Evans, D. A.; Calter,
M. A. Tetrahedron Lett. 1993, 34, 6871-6874. (b) Toshima, K.; Jyokaaki,
T.; Yamaguchi, H.; Murase, H.; Yoshida, T.; Mastumura, S.; Nakata, M.
Tetrahedron Lett. 1996, 37, 1069-1072. (c) Toshima, K.; Yamaguchi, H.;
Jyojima, T.; Noguchi, Y.; Nakata, M.; Mastumura, S. Tetrahedron Lett.
1996, 37, 1073-1076. (d) Toshima, K.; Jyojima, T.; Yamaguchi, H.;
Noguchi, Y.; Yoshida, T.; Murase, H.; Nakata, M.; Mastumura, S. J. Org.
Chem. 1997, 62, 3271-3284. (e) Scheidt, K. A.; Tasaka, A.; Bannister, T.
D.; Wendt, M. D.; Roush, W. R. Angew. Chem., Int. Ed. 1999, 38, 1652-
1655. (f) Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall,
B. M.; Fegley, G. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 6981-
6990. (g) Hanessian, S.; Ma, J.; Wang, W.; Gai, Y. J. Am. Chem. Soc.
2001, 123, 10200-10206. Correction: J. Am. Chem. Soc. 2002, 124, 7249.
Also see: (h) Paterson, I.; Bower, S.; McLeod, M. D. Tetrahedron Lett.
1995, 36, 175-178. (i) Marshall, J. A.; Adams, N. D. J. Org. Chem. 2002,
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J.-P. Ricard, L. Synthesis 2005, 644-661.
(13) For reviews on total synthesis of plecomacrolides, see: Toshima,
K. Curr. Org. Chem. 2004, 8, 185-210 and ref. 3.
(14) For a recent review, see: Parenty, A.; Moreau, X.; Campagne, J.-
M. Chem. ReV. 2006, 106, 911-939.
(15) For a recent review, see: Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4442-4489.
(16) For selected reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413-4450. (b) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012-3043. (c) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18-29. (d) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003,
42, 4592-4633. (e) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-
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Int. Ed. 2006, 45, 6086-6101. Also see: Handbook of Metathesis, Grubbs,
R. H., Ed.; Wiley-VCH: Weinheim, Germany, 2003; Vols. 1-3.
(17) The results on total synthesis of amphidinolide Y via RCM were
presented at the 3rd Yoshimasa Hirata Memorial Lecture, Nagoya, Japan,
February 6, 2007.
4954 J. Org. Chem., Vol. 72, No. 13, 2007

C13-C25 Fragment of 24-Demethylbafilomycin C1
SCHEME 2. Synthesis of Chiral Aldehydes 5 and 15
seems that the stereochemistry at C22 of the chiral ethyl ketones
7a and 8 significantly influences the stereochemical course of
the aldol reaction.12a Moreover, the cyclic silyl ether motif in
7a is crucial for high diastereoselectivity because the related
cyclic acetal 7b gave ca. 80:20 ratio of diastereomeric aldols
formed from R,â-unsaturated aldehydes.12h In this article, we
describe our original results on the synthesis of the C13-C25
fragment 4 by employing a diastereoselective aldol reaction
between the chiral aldehyde 5 and the chiral ethyl ketone 6 as
well as the effect of the methoxyacetate moiety of 5 on
diastereoselectivity in formation of the C17-C18 bond.
Results and Discussion
Synthesis of Chiral Aldehydes 5 and 15. Our synthesis
started from methyl (S)-(+)-3-hydroxy-2-methylpropionate (9)
(Scheme 2). Initially we prepared the known trityl-protected
acetate 14′a from 912d and removed the trityl group by stirring
in HCO2H-EtOAc at room temperature to give a mixture of
the formate 14′b and the desired alcohol 14′c. Treatment of the
mixture in refluxing MeOH converted 14′b into 14′c, which
was obtained in 78% overall yield from 14′a. For a scale-up
synthesis, we changed the trityl protection group to TBDPS
ether. Thus, protection of 9 as the TBDPS ether 10 was followed
by Dibal-H reduction to furnish the alcohol 11 in 82% overall
yield. Swern oxidation converted 11 into the aldehyde 12 which
was then subjected to the Takai’s (γ-methoxyallyl)chromium
reagent21 prepared in situ from CrCl2 and acrolein dimethyl
acetal in the presence of trimethylsilyl iodide to afford the
homoallyl alcohol 13 in 60% yield along with 25% of two minor
diastereomers.22 The desired diastereomer 13 was transformed
(18) (a) Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J.; Yang, Z. Org.
Lett. 2006, 8, 1193-1196. For selected examples of diene-ene RCM used
in synthesis of macrocycles, see: (b) Cabrejas, L. M. M.; Rohrbach, S.;
Wagner, D.; Kallen, J.; Zenke, G.; Wagner, J. Angew. Chem., Int. Ed. 1999,
38, 2443-2446. (c) Dvorak, C. A.; Schmitz, W. D.; Poon, D. J.; Pryde, D.
C.; Lawson, L. P.; Amos, R. A.; Meyers, A. I. Angew. Chem., Int. Ed.
2000, 39, 1664-1666. (d) Garbaccio, R. M.; Danishefsky, S. J.; Org. Lett.
2000, 2, 3127-3129. (e) Garbaccio, R. M.; Stachel, S. J.; Baeschlin, D.
K.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 10903-10908. (f)
Biewas, K.; Lin, H.; Njardarson, J. T.; Chappell, M. D.; Chou, T.-C.; Guan,
Y.; Tong, W. P.; He, L.; Horwitz, S. B.; Danishefsky, S. J. J. Am. Chem.
Soc. 2002, 124, 9825-9832. (g) Paquette, L. A.; Basu, K.; Eppich, J. C.;
Hofferberth, J. E. HelV. Chim. Acta 2002, 85, 3033-3051. (h) Sedrani, R.;
Kallen, J.; Cabrejas, L. M. M.; Papageorgiou, C. D.; Senia, F.; Rohrbach,
S.; Wagner, D.; Thai, B.; Eme, A.-M. J.; France, J.; Oberer, L.; Rihs, G.;
Zenke, G.; Wagner, J. J. Am. Chem. Soc. 2003, 125, 3849-3859. (i) Yang,
Z.-Q.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 9602-9603. (j)
Yang, Z.-Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.; Danishefsky,
S. J. J. Am. Chem. Soc. 2004, 126, 7881-7889. (k) Barluenga, S.; Lopez,
P.; Moulin, E.; Winssinger, N. Angew. Chem., Int. Ed. 2004, 43, 3467-
3470. (l) Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, Jr., J. A. Angew.
Chem., Int. Ed. 2004, 43, 3601-3605. (m) Lemarchand, A.; Bach, T.
Tetrahedron 2004, 60, 9659-9673. (n) Krishna, C. V.; Maitra, S.; Dev, R.
V.; Mukkanti, K.; Iqbal, J. Tetrahedron Lett. 2006, 47, 6103-6106. (o)
Va, P.; Roush, W. R. J. Am. Chem. Soc. 2006, 128, 15960-15961. (p) Va,
P.; Roush, W. R. Org. Lett. 2007, 9, 307-310. For diene-diene RCM used
in synthesis of macrocycles, see: (q) Wang, X.; Porco, Jr., J. A. J. Am.
Chem. Soc. 2003, 125, 6040-6041. (r) Evano, G.; Schaus, J. V.; Panek, J.
S. Org. Lett. 2004, 6, 525-528.
into the corresponding acetate 14 and methoxyacetate 16 in 92%
and 94% yields, respectively, which were isolated in isomeric
pure forms. Desilylation of 14 with TBAF-AcOH followed
by oxidation of the primary alcohol with Dess-Martin perio-
dinane (DMP)23 provided the acetoxy-substituted chiral aldehyde
15 in 84% overall yield from 14. Similarly, the methoxyacetate-
substituted chiral aldehyde 5 was obtained from 16 in 85%
overall yield.
Synthesis of Chiral Ethyl Ketone 6. Several approaches
have been reported for controlling the three consecutive ste-
reogenic centers at C21-C23 of bafilomycin A1. Toshima and
co-workers prepared the chiral ketone 7a (Scheme 1) starting
from a sugar derivative obtainable from D-glucose.12d In
Hanessian’s total synthesis of bafilomycin A1, the C20-C25
fragment (as the iodide) was assembled from D-valine by
utilizing a highly stereoselective conjugate addition-hydroxy-
lation protocol.12g Cossy and co-workers synthesized the same
(19) Preliminary results on successful formation of the tetraene core of
2 in a model system via diene-ene RCM were reported at The 9th
International Symposium for Chinese Organic Chemists (ISCOC-9), Sin-
gapore, December 17-21, 2006, p 85.
(20) Makino, K.; Nakajima, N.; Hashimoto, S.; Yonemitsu, O. Tetra-
hedron Lett. 1996, 37, 9077-9080.
(21) Takai, K.; Nitta, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 5263-
5266.
(23) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552. (c)
Boeckman, Jr., R. K.; Shao, P.; Mulins, J. J. Org. Synth. 2000, 77, 141-
146.
(22) It seems that the TBDPS group in 12 diminished diastereoselectivity
as compared to the trityl-protected aldehyde which gave a diastereomer
ratio of 86:10:4 as reported in ref 12d.
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Guan et al.
SCHEME 3. Synthesis of Chiral Aldehyde 20a
SCHEME 4. Synthesis of Chiral Ketone 6
iodide based on sequential enantioselective monoreduction of
2-alkyl 1,3-diketone and stereoselective reduction of the chiral
â-hydroxyketone.12j Marshall and Adams secured the C22-C23
anti aldol stereochemistry by addition of a chiral allenylzinc
reagent with isobutyraldehyde and then installed the C21 chiral
hydroxyl group through Sharpless asymmetric epoxidation and
regioselective reductive epoxide ring opening.12i Roush and co-
workers used the chiral aldehydes 20c,d (Scheme 3) in their
fragment assembly aldol coupling reactions of various methyl
ketones.12f,24 Diastereoselectivity was found to be dependent on
reaction conditions. In the total synthesis of bafilomycin A1,
the aldol reaction of 20c with the macrolactone-derived methyl
ketone afforded >95:5 diastereomer ratio.12f Evans and co-
workers systematically examined the merged 1,2- and 1,3-
asymmetric induction in Mukaiyama aldol reactions with methyl
ketone derived enol silyl ethers and found that 20c,d gave high
diastereoselectivity of >95:5 in most cases.25 Diastereoselec-
tivity of 95:5 was also reported for the Mukaiyama-type aldol
reaction of 20b with 3-methyl-2,4-bis(trimethylsilyloxy)penta-
1,3-diene.12 We selected a practical approach for gram-scale
preparation of the chiral aldehyde 20a according to a similar
sequence used by Roush for accessing 20c.24 As shown in
Scheme 3, the chiral alcohol 17, readily prepared from enan-
tioselective hydrogenation of methyl 3-oxo-pentanoate using (R)-
binap and (COD)Ru(2-methylallyl)2 as the catalyst precursors,26
was subjected to Fra´ter-Seebach anti alkylation27 to give 18
in 73% yield with a diastereomer ratio of 91:9. The minor
diastereomer could not be separated by column chromatographic
purification, and the mixture was carried forward in the
following reactions up to the alcohol 27 (Scheme 4). Protection
of the hydroxyl group in 18 with TESOTf and 2,6-lutidine
afforded the TES ether 19, which was directly converted into
the aldehyde 20a by controlled reduction of the ester group with
Dibal-H at -89 °C.
the stabilized phosphorus ylide in refluxing toluene to produce
the R,â-unsaturated ester 21 in 84% overall yield from 19. The
ester 21 was then reduced using Dibal-H at 0 °C to the allyl
alcohol 22 (91%), which underwent the Sharpless asymmetric
allylic epoxidation with L-(+)-DIPT as the chiral ligand to
furnish the epoxide 23 in 91% yield and in >99:1 diastereomer
ratio. A regioselective reductive epoxide ring opening12i was
carried out with Red-Al at 0 °C to form the triol 24 after
unexpected removal of the TES ether under the reaction
conditions, presumably due to the Lewis acidity of Red-Al.
Selective monoprotection of the triol 24 gave the desired pivalate
25 in 67% yield along with other undesired pivalates. Treatment
of the diol 25 with (t-Bu)2SiOTf2 in DMF resulted in formation
of the cyclic silyl ether 26 (80%). We found that at one time
Dibal-H reduction of 26 afforded the second alcohol 27′ which
gave the corresponding ketone after PCC oxidation. Fortunately,
Scheme 4 illustrates the synthesis of the chiral ethyl ketone
6. The aldehyde 20a was subjected to Wittig olefination with
(24) Roush, W.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.;
Scheidt, K. A. J. Org. Chem. 2002, 67, 4275-4283.
(25) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322-4343.
(26) Geneˆt, J. P.; Ratovelomanana-Vidal, V.; Can˜o de Andrade, M. C.;
Pfister, X.; Guerreiro, P.; Lenoir, J. Y. Tetrahedron Lett. 1995, 36, 4801-
4804.
4956 J. Org. Chem., Vol. 72, No. 13, 2007

C13-C25 Fragment of 24-Demethylbafilomycin C1
SCHEME 5. Aldol Reactions of Chiral Ketone 6 with Chiral and Achiral Aldehydes
the rearrangement product 27′ could be suppressed with
precaution during Dibal-H reductive cleavage of the pivalate
26, and the alcohol 27 was isolated in an isomeric pure form in
77% yield. Oxidation of 27 with TPAP-NMO in the presence
of 4 Å molecular sieves afforded the aldehyde 28 (80%).
Addition of EtMgBr with 28 followed by TPAP-NMO oxida-
tion furnished the chiral ethyl ketone 6 in 89% overall yield
conditions used for 7a and obtained the syn-aldol products 29
(53%) and dia-29 (3%) in 95:5 diastereomer ratio. As compared
to >99:1 diastereomer ratio reported for the same aldol reaction
of 7a,12a the ethyl ketone 6 afforded slightly reduced diaste-
reoselectivity. The â,γ-bisoxygenated aldehydes 5 and 15 have
not been examined in the aldol reactions with 7a. We were
pleased to find out that the analogous aldol reaction between
15 and 6 gave 30 and dia-30 in 95:5 diastereomer ratio.30 The
major isomer 30 was isolated in 60% yield and in isomeric pure
form. The result is consistent with the diastereoselectivity
observed for the reaction of the macrolactone-derived aldehyde
with 7a used for the total synthesis of bafilomycin A1.12a,d To
our delight, the aldol reaction between the â-methoxyacetoxy-
substituted aldehyde 5 and the chiral ethyl ketone 6 took place
under the same boron enolate conditions (PhBCl2, i-PrNEt2,
CH2Cl2, -78 °C) to furnish the target C13-C25 fragment 4 of
24-demethylbafilomycin C1. The product 4 was obtained in 45%
isolated yield along with a minor isomer dia-4 (9%).31 The
diastereoselectivity for 4 and dia-4 is 83:17, suggesting that the
â-methoxyacetoxy group in 5 diminishes preference for anti-
Felkin selectivity in stereochemical communication among the
boron enolate and the aldehyde. Although the detail is not clear,
it appears that the methoxyacetoxy group in 5 might interact
with the boron enolate in the transition state, resulting in lower
from 28. The ketone 6 has an optical rotation value of [R]20
D
+80.2 (c 1.75, CHCl3), which is consistent with [R]20 +85.2
D
(c 0.89, CHCl3) reported for the homologous ketone 7a.12d
Aldol Reactions of Boron Enolate of Chiral Ethyl Ketone
6. With both the chiral aldehydes 5 and 15 and the chiral ketone
6 in hand, we performed the aldol reactions as shown in Scheme
5. As mentioned above, Evans and Calter examined the aldol
stereoselectivity of R-unsubstituted-â-silyloxy ethyl ketones
related to the total synthesis of bafilomycin A1.12a In the presence
of PhBCl2 and i-Pr2NEt in CH2Cl2, the chiral ethyl ketone
7a was converted into the (Z)-boron enolate (-78 °C, 30 min;
0 °C, 30 min).28 The latter reacted with both isobutyraldehyde
and several chiral aldehydes to afford exclusively the syn aldols.
Moreover, anti-Felkin29 selectivity was observed for the aldol
reactions of chiral syn-R-alkyl-â-oxygen-substituted aldehydes
in a matched double stereodifferentiating manner.30 We carried
out the aldol reaction of 6 with isobutyraldehyde under similar
CHART 2. Chem3D Structures of the Preferred Boron Enolates I and II of Ethyl Ketones 6 and 8
J. Org. Chem, Vol. 72, No. 13, 2007 4957

Guan et al.
(0 °C) was added slowly LiAlH4 (0.507 g, 12.70 mmol). After
stirring for 20 min at the same temperature, the resultant mixture
was cooled to -42 °C followed by sequential addition of acrolein
dimethyl acetal (1.0 mL, 8.46 mmol), iodotrimethylsilane (1.2 mL,
8.46 mmol), and a solution of the aldehyde 12 (1.380 g, 4.23 mmol)
in dry THF (5.0 mL) via syringes. After stirred for 6 h at -42 °C,
the reaction was quenched by 1 M aqueous HCl (50 mL) with ice-
cooling, and the resultant mixture was then extracted with Et2O
(60 mL × 3). The combined organic layer was washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (silica gel, 5% EtOAc in hexane) to give the
alcohol 13 (1.000 g, 60%) along with a mixture of two diastere-
omers (0.410 g, 25%). 13: a colorless oil; Rf ) 0.38 (10% EtOAc
in hexane); [R]20D +16.4 (c 0.25, CHCl3); IR (film) 3500 (br), 2931,
anti-Felkin/Felkin selectivity. For addressing the enolate face
selectivity, Evans and Calter constructed a model favored for
re-face attack based on the ground-state conformational prefer-
ence of the enol form of 7a.12a According to the preferred
conformation analogous to 7a, we illustrate the Chem3D-derived
boron enolate structures I and II of the ethyl ketones 6 and 8
in Chart 2.32 The re-face of enolate C18-C19 double bond is
much more open for approaching the aldehydes in both I and
II. In the latter case, the re-face is suffered from unfavorable
steric interaction with the C22-methyl group, which accounts
for the 75:25 diastereoselectivity in the aldol reaction of 8 with
the macrolactone-derived aldehyde used in the Yonemitsu and
Hashimoto’s total synthesis of hygrolidin.20
1
1112 cm-1; H NMR (300 MHz, CDCl3) δ 7.72-7.66 (m, 4H),
Conclusion
7.48-7.36 (m, 6H), 5.80 (ddd, J ) 17.4, 10.5, 8.4 Hz, 1H), 5.36
(dd, J ) 10.5, 1.8 Hz, 1H), 5.26 (ddd, J ) 17.4, 1.8, 0.9 Hz, 1H),
3.86 (dd, J ) 6.6, 3.9 Hz, 1H), 3.74 (dd, J ) 9.9, 4.5 Hz, 1H),
3.68 (dd, J ) 9.9, 5.1 Hz, 1H), 3.53 (dd, J ) 7.6 Hz, 1H), 3.27 (s,
3H), 2.79 (br s, 1H, OH), 2.05-1.95 (m, 1H), 1.06 (s, 9H), 1.03
(d, J ) 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 135.86 (×2),
135.8, 135.78 (×2), 133.4, 133.3, 129.94, 129.92, 127.92 (×2),
127.90 (×2), 119.9, 84.0, 75.3, 68.6, 56.6, 36.2, 27.3 (×3), 19.6,
11.4; HRMS (+ESI) calcd for C24H34O3SiNa (M + Na+), 421.2169;
found, 421.2155.
In summary, we have established an efficient synthesis of
the C13-C25 fragments 4 and 30 of 24-demethylbafilomycin
C1 by using a key aldol reaction of the chiral aldehydes 5 and
15 with the boron enolate derived from chiral ethyl ketone 6.
The chiral aldehydes 5 and 15 possess both â,γ-bisoxygenated
functionalities and an R-alkyl group, and they were readily
prepared by diastereoselective reaction of the chiral aldehyde
12 with the Takai’s (γ-methoxyallyl)chromium reagent.21 On
the other hand, the three consecutive stereogenic centers in the
ethyl ketone 6 were assembled by Fra´ter-Seebach anti alky-
lation27 followed by a sequence of Sharpless asymmetric allylic
epoxidation and regioselective reductive epoxide ring opening.
The aldol reaction between the â-acetoxy-substituted aldehyde
15 and the chiral ketone 6 gave 95:5 diastereoselectivity favored
for the anti-Felkin aldol 30 in 60% isolated yield. Similarly,
the analogous aldol reaction of the â-methoxyacetoxy-substituted
aldehyde 5 afforded the desired anti-Felkin aldol 30 in 45%
isolated yield and in isomeric pure form albeit in a slightly
diminished diastereomer ratio of 83:17. These results are
consistent with the diastereoselectivity reported for the C24-
homologous ethyl ketone 7a. Our study on the aldol reaction
also suggests that the poor diastereoselectivity of 75:25 recorded
for C22-epimeric ketone 8 originates from the unfavorable
orientation of the C22-methyl group as shown in II of Chart 2.
Moreover, our successful synthesis of the C13-C25 fragment
provides the basis for further study toward total synthesis of
24-demethylbafilomycin C1.
(3S,4R,5S)-6-[(tert-Butyldiphenyl)silyloxy]-3-methoxy-4-meth-
oxyacetoxy-5-methylhex-1-ene (16). To a solution of the alcohol
13 (220.0 mg, 0.55 mmol) in dry CH2Cl2 (5 mL) cooled in an ice-
water bath (0 °C) was added methoxyacetic acid (65 µL, 0.83
mmol), DCC (344.0 mg, 1.65 mmol), and DMAP (204.0 mg, 1.65
mmol). The resultant mixture was stirred overnight at room
temperature and then quenched with saturated aqueous NH4Cl. The
reaction mixture was extracted with CH2Cl2 (5 mL × 3). The
combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
(silica gel, 10% EtOAc in hexane) to give the methoxyacetate 16
(243.0 mg, 94%) as a colorless oil. Rf ) 0.55 (10% EtOAc-
hexane); [R]20D +28.3 (c 0.30, CHCl3); IR (film) 2933, 1759, 1192,
1
1108 cm-1; H NMR (400 MHz, CDCl3) δ 7.67-7.62 (µ, 4Η),
7.45-7.34 (m, 6H), 5.70 (ddd, J ) 17.2, 10.0, 7.6 Hz, 1H), 5.32
(dd, J ) 6.0, 4.8 Hz, 1H), 5.27 (dd, J ) 10.4, 1.6 Hz, 1H), 5.18
(dd, J ) 17.2, 1.2 Hz, 1H), 3.94 (s, 2H), 3.64 (dd, J ) 8.4, 6.4 Hz,
1H), 3.51 (dd, J ) 10.4, 7.2 Hz, 1H), 3.44 (dd, J ) 10.0, 6.4 Hz,
1H), 3.39 (s, 3H), 3.25 (s, 3H), 2.23-2.13 (m, 1H), 1.05 (s, 9H),
0.92 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5,
135.56 (×2), 135.55 (×2), 135.1, 133.6, 133.4, 129.52, 129.50,
127.5 (×4), 199.8, 82.5, 74.1, 69.7, 65.7, 59.2, 56.4, 35.9, 26.8
(×3), 19.1, 11.5; MS (+ESI) m/z 493 (M + Na+, 100); HRMS
(+ESI) calcd for C27H38O5SiNa (M + Na+), 493.2381; found,
493.2367.
Experimental Section
(3S,4R,5S)-6-[(tert-Butyldiphenyl)silyloxy]-3-methoxy-5-me-
thylhex-1-en-4-ol (13). To a stirred suspension of CrCl3 (4.020 g,
25.40 mmol) in dry THF (100 mL) cooled in an ice-water bath
(2S,3R,4S)-4-Methoxy-3-methoxyacetoxy-2-methylhex-5-en-
1-ol. To a solution of 16 (230.0 mg, 0.49 mmol) in THF (4 mL)
cooled in an ice-water bath (0 °C) was added TBAF (1.0 mL, 1.0
mmol, 1 M in THF) and acetic acid (58 µL, 1.0 mmol) followed
by stirring for 20 h at room temperature. The reaction was quenched
with saturated aqueous NaHCO3, and the reaction mixture was
extracted with EtOAc (5 mL × 3). The combined organic layer
was washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, 30% EtOAc in hexane)
(27) (a) Fra´ter, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269-
1277. (b) Zuger, M.; Weller, T.; Seebach, D. HelV. Chim. Acta 1980, 63,
2005-2009.
(28) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984, 1729-
1732.
(29) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 2199-
2204; 2205-2208.
(30) Diminished anti-Felkin selectivity was reported for an achiral ethyl
ketone lithium enolate, see: Evans, D. A.; Yang, M. G.; Dart, M. J.; Duffy,
J. L. Tetrahedron Lett. 1996, 37, 1957-1960.
to give the alcohol (99.0 mg, 86%) as a colorless oil. Rf ) 0.22
1
(30% EtOAc-hexane); [R]20 +41.9 (c 0.25, CHCl3); H NMR
(31) The syn-aldol structures were assigned according to the small
coupling constants of 1.6-4.4 Hz between C17 and C18 methine protons
as listed in Table S1 in Supporting Information.
D
(400 MHz, CDCl3) δ 5.65 (ddd, J ) 17.2, 10.8, 8.4 Hz, 1H), 5.35-
5.25 (m, 2H), 5.13 (dd, J ) 8.0, 4.0 Hz, 1H), 4.03 and 3.97 (ABq,
J ) 16.4 Hz, 2H), 3.66 (dd, J ) 8.0, 8.0 Hz, 1H), 3.51 (dd, J )
11.6, 5.6 Hz, 1H), 3.42 (s, 3H), 3.33 (dd, J ) 11.2, 8.8 Hz, 1H),
3.28 (s, 3H), 2.39 (br s, 1H, OH), 2.27-2.16 (m, 1H), 0.88 (d, J )
(32) The enolate structures I and II are used only for illustrative purpose.
The coordinates are found in Tables S2 and S3 in Supporting Information.
There are several enolate structures of similar stabilities minimized at MM2
level by Chem3D. All of them favor for re-face attack to the aldehydes.
4958 J. Org. Chem., Vol. 72, No. 13, 2007

C13-C25 Fragment of 24-Demethylbafilomycin C1
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.5, 135.4, 120.2,
81.8, 74.3, 69.5, 64.5, 59.2, 56.3, 36.0, 10.5; MS (+ESI) m/z 255
(M + Na+, 100); HRMS (+ESI) calcd for C11H20O5Na (M + Na+),
255.1208; found, 255.1202.
1H), 1.86-1.78 (m, 1H), 1.63-1.44 (m, 4H), 0.94 (t, J ) 7.2 Hz,
3H), 0.88 (d, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
73.2, 61.8, 41.5, 34.6, 28.0, 12.0, 9.6; HRMS (+ESI) calcd for
C8H18O3Na (M + Na+), 185.1148; found, 185.1142.
(3R,4R,5R)-3,5-Dihydroxy-4-methylheptan-1-yl Trimethylac-
etate (25). To a solution of the triol 24 (1.800 g, 10.8 mmol) in
dry CH2Cl2 (60 mL) cooled in an ice-water bath (0 °C) was added
dropwise pyridine (1.3 mL, 16.2 mmol) and trimethylacetyl chloride
(1.3 mL, 10.8 mmol). The resultant mixture was stirred for 1 h at
the same temperature followed by quenching with saturated aqueous
NH4Cl (60 mL). The organic layer was separated and the aqueous
layer was extracted with CH2Cl2 (60 mL × 3). The combined
organic layer was washed with brine, dried over anhydrous Na2-
SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash column chromatography (silica gel, 5% MeOH
in CH2Cl2) to provide 25 (1.800 g, 67%) as a colorless oil. Rf )
0.55 (10% MeOH-CH2Cl2); IR (film) 3418 (br), 2971, 1729, 1712,
(2R,3R,4S)-4-Methoxy-3-methoxyacetoxy-2-methylhex-5-
enal (5). To a solution of the previous alcohol (90.0 mg, 0.38 mmol)
in dry CH2Cl2 (4 mL) was added powdered NaHCO3 (65.0 mg,
0.80 mmol) and Dess-Martin periodinane (1.7 mL, 0.51 mmol,
0.3 M in CH2Cl2) at room temperature. The resultant mixture was
stirred for 10 min, and the reaction was quenched with saturated
aqueous Na2S2O3 and NaHCO3. The reaction mixture was extracted
with Et2O (3 mL × 3), and the combined organic layer was washed
with brine, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 20% EtOAc in hexane) to give the
aldehyde 5 (86.0 mg, 99%) as a colorless oil. Rf ) 0.50 (30%
EtOAc-hexane); [R]20 +11.2 (c 0.60, CHCl3); IR (film) 3021,
D
1
1186 cm-1; H NMR (400 MHz, CDCl3) δ 4.27 (ddd, J ) 10.8,
2936, 1758, 1720, 1192, 1127 cm-1; 1H NMR (400 MHz, CDCl3)
δ 9.61 (d, J ) 1.6 Hz, 1H), 5.66 (ddd, J ) 17.2, 10.0, 8.0 Hz, 1H),
5.42 (dd, J ) 8.0, 5.6 Hz, 1H), 5.35 (dd, J ) 10.0, 1.6 Hz, 1H),
5.30 (m, 1H), 3.99 and 3.94 (ABq, J ) 16.4 Hz, 2H), 3.61 (dd, J
) 8.0, 8.0 Hz, 1H), 3.40 (s, 3H), 3.26 (s, 3H), 2.90-2.82 (m, 1H),
1.12 (d, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.0,
169.4, 134.7, 121.1, 82.3, 72.5, 69.5, 59.3, 56.4, 48.0, 8.5; MS
(+ESI) m/z 253 (M + Na+, 100); HRMS (+ESI) calcd for
C11H18O5Na (M + Na+), 253.1046; found, 253.1048.
8.4, 5.2 Hz, 1H), 4.16 (dt, J ) 10.8, 5.6 Hz, 1H), 3.98 (dt, J ) 9.6,
2.8 Hz, 1H), 3.57-3.52 (m, 1H), 3.07 (br s, 2H, OH), 1.87-1.77
(m 1H), 1.73-1.46 (m, 4H), 1.18 (s, 9H), 0.94 (t, J ) 7.2 Hz,
3H), 0.93 (d, J ) 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
178.9, 76.9, 69.4, 61.9, 40.9, 38.7, 32.9, 28.1, 27.1 (×3), 11.7, 9.8;
HRMS (+ESI) calcd for C13H26O4Na (M + Na+), 269.1723; found,
269.1716.
Compound 26. To a stirred solution of the diol 25 (1.500 g, 6.2
mmol) in dry DMF (40 mL) cooled in an ice-water bath (0 °C)
was added dropwise t-Bu2Si(OTf)2 (3.2 mL, 9.4 mmol). The
resultant mixture was stirred for 2 h at room temperature followed
by quenching with ice-cold water (40 mL). The mixture was
extracted with EtOAc (50 mL × 3), and the combined organic layer
was washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatograph (silica gel, 2% EtOAc in hexane) to
provide 26 (2.100 g, 84%) as a colorless oil. Rf ) 0.91 (10%
EtOAc-hexane); IR (film) 2963, 2935, 2859, 1732, 1158, 1132,
(2S,3S,4S,5R)-2,3-Epoxy-4-methyl-5-[(triethylsilyl)oxy]heptan-
1-ol (23). To a suspension of anhydrous powdered 4 Å molecular
sieves (2.80 g) in dry CH2Cl2 (120 mL) was added l-(+)-diisopropyl
tartrate (6.0 mL, 27.2 mmol). The mixture was cooled to -20 °C
and Ti(Oi-Pr)4 (7.0 mL, 22.7 mmol) was added via a syringe. After
stirring for 10 min at -20 °C, tert-butyl hydroperoxide (8.4 mL,
5-6 M in decane, 42.0 mmol) was added dropwise. The mixture
was stirred for 30 min and then the allyl alcohol 22 (4.900 g, 18.9
mmol) in dry CH2Cl2 was added dropwise over a period of 10 min.
The resultant mixture was stirred at -20 °C for 20 h followed by
quenching with a minimal amount of H2O (10 mL). After warming
to room temperature, the heterogeneous mixture was stirred
vigorously for 20 min and filtered through a pad of Celite with
rinsing by CH2Cl2. Then 30% NaOH (100 mL, in brine) was added
to the filtrate, and the mixture was stirred for 2 h. The organic
layer was separated and dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel, 20% EtOAc in hexane)
to afford 23 (4.700 g, 91%) as a colorless oil. Rf ) 0.58 (20%
EtOAc-hexane); IR (film) 3444 (br), 2959, 2872, 1008 cm-1; 1H
NMR (400 MHz, acetone-d6) δ 3.79-3.64 (µ, 3Η), 3.47-3.42 (µ,
1Η), 2.86-2.84 (µ, 1Η), 2.84 (σ, 1Η), 2.71 (δδ, J ) 7.2, 2.2 Hz,
1H), 1.53-1.44 (m, 3H), 0.93 (t, J ) 8.0 Hz, 9H), 0.91 (d, J ) 6.8
Hz, 3H), 0.85 (t, J ) 7.6 Hz, 3H), 0.59 (q, J ) 8.0 Hz, 6H); 13C
NMR (100 MHz, acetone-d6) δ 86.5, 72.8, 69.1, 67.6, 50.7, 37.4,
22.7, 19.7, 17.0 (×3), 15.4 (×3); HRMS (+ESI) calcd for C14H30O3-
SiNa (M + Na+), 297.1856; found, 297.1849.
1
1065 cm-1; H NMR (400 MHz, CDCl3) δ 4.33 (ddd, J ) 11.6,
7.2, 4.4 Hz, 1H), 4.24 (ddd, J ) 8.4, 8.0, 6.8 Hz, 1H), 4.07 (ddd,
J ) 8.8, 5.6, 3.2 Hz, 1H), 3.77 (ddd, J ) 10.8, 7.6, 3.2 Hz, 1H),
2.14-2.08 (m, 1Η), 1.82-1.46 (m, 3Η), 1.40-1.30 (m, 1Η), 1.20
(s, 9Η), 0.99-0.95 (m, 18H), 0.96 (t, J ) 7.2 Hz, 3H), 0.74 (d, J
) 6.8 Hz, 3Η); 13C NMR (100 MHz, CDCl3) δ 178.5, 74.2, 73.1,
62.1, 40.4, 38.7, 30.2, 28.2, 27.6 (×3), 27.3 (×3), 27.2 (×3), 21.3,
20.6, 13.5, 8.7; HRMS (+ESI) calcd for C21H42O4SiNa (M + Na+),
409.2745; found, 409.2730.
Alcohol 27. To a solution of the ester 26 (2.000 g, 5.2 mmol) in
dry CH2Cl2 (50 mL) cooled in an ice-water bath (0 °C) was added
Dibal-H (12.0 mL, 1.0 M in hexane, 12.0 mmol) followed by
stirring at the same temperature for 3 h. The reaction was carefully
quenched with MeOH (10 mL), and then saturated aqueous sodium
potassium tartrate (Rochelle’s salt) (100 mL) and Et
2O (100 mL)
were added with vigorous stirring till the mixture became clear.
The organic layer was separated, and the aqueous layer was
extracted with Et2O (100 mL × 2). The combined organic layer
was washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. Purification of the residue
by flash column chromatography (silica gel, 10% EtOAc in hexane)
afforded 27 (1.200 g, 77%). Rf ) 0.27 (10% EtOAc-hexane); IR
(3R,4R,5R)-4-Methylheptane-1,3,5-triol (24). To a solution of
the epoxy alcohol 23 (4.000 g, 14.4 mmol) in dry THF (150 mL)
cooled in an ice-water bath (0 °C) was added Red-Al (26.4 mL,
65+ wt %, 87.0 mmol) dropwise. The resultant mixture was stirred
at 0 °C for 25 h followed by quenching with saturated aqueous
sodium potassium tartrate (Rochelle’s salt) (100 mL) carefully. Et2O
(100 mL) was added to the reaction mixture which was allowed to
warm to room temperature. The organic layer was separated, and
the aqueous layer was extracted with Et2O (100 mL × 3). The
combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was by flash column chromatography (silica gel,
5% MeOH in CH2Cl2) to provide the triol 24 (2.100 g, 90%) as a
colorless oil. Rf ) 0.42 (10% MeOH-CH2Cl2); IR (film) 3354 (br),
1
(film) 3358 (br), 2962, 2934, 2859, 1131, 1063 cm-1; H NMR
(500 MHz, CDCl3) δ 4.23 (ddd, J ) 5.6, 4.4, 1.2 Hz, 1H), 3.94-
3.86 (m, 2Η), 3.78 (td, J ) 9.0, 3.0 Ηz, 1Η), 2.15-2.08 (m, 1Η),
1.88-1.80 (m, 1Η), 1.64-1.57 (m, 2Η), 1.41-1.32 (m, 1H), 1.26
(s, 1H, OH), 1.01 (s, 18H), 0.96 (t, J ) 7.0 Hz, 3H), 0.77 (d J )
7.5 Hz, 3H); 13C NMR (100 MHz, acetone-d6) δ 75.3, 74.8, 60.1,
41.6, 34.6, 28.9, 28.1 (×3), 27.8 (×3), 21.9, 21.2, 13.9, 9.2; HRMS
(+ESI) calcd for C16H34O3SiNa (M + Na+), 325.2169; found,
325.2162.
1
2964, 1051 cm-1; H NMR (400 MHz, CDCl3) δ 4.12 (δτ, J )
Aldehyde 28. To a suspension of powdered 4 Å molecular sieves
(1.80 g) in dry CH2Cl2 (18 mL) was added the alcohol 27 (1.100
10.4, 2.0 Hz, 1H), 3.87-3.77 (m, 5H), 3.54 (dt, J ) 7.2, 3.6 Hz,
J. Org. Chem, Vol. 72, No. 13, 2007 4959

Guan et al.
g, 3.6 mmol) in dry CH2Cl2 (3 mL), NMO (660.0 mg, 5.4 mmol),
and TPAP (60.0 mg, 0.15 mmol). The resultant mixture was stirred
for 7 h at room temperature, and the reaction mixture was filtrated
through a pad of Celite with rinsing by EtOAc. The combined
filtrate was concentrated under reduced pressure, and the residue
was purified by flash column chromatography (silica gel, 10%
EtOAc in hexane) to afford 28 (868.0 mg, 80%) as a colorless oil.
Rf ) 0.55 (10% EtOAc-hexane); IR (film) 2964, 2935, 2860, 1716,
The resultant mixture was allowed to warm slowly to 0 °C and
was stirred for another 20 min. To the solution cooled again at
-78 °C was added the aldehyde 5 (12.0 mg, 0.05 mmol) in dry
CH2Cl2 (0.3 mL) followed by stirring at -78 °C for 2 h. The
reaction was quenched with pH 7 phosphate buffer (2 mL). The
resultant mixture was then extracted with Et2O (2 mL × 3). The
combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by flash column chromatography
(silica gel, 25% EtOAc in hexane) to afford 4 (28.0 mg, 45%) and
its diastereomer dia-4 (5.5 mg, 9%). 4: a colorless oil; Rf ) 0.49
1
1131, 1063 cm-1; H NMR (400 MHz, acetone-d6) δ 9.73 (dd, J
) 4.4, 0.8 Hz, 1H), 4.74 (ddd, J ) 8.8, 5.2, 3.2 Hz, 1H), 3.80
(ddd, J ) 10.8, 8.0, 3.2 Hz, 1H), 2.56-2.50 (m, 2H), 2.23-2.17
(m, 1H), 1.65-1.58 (m, 1H), 1.37-1.29 (m, 1H), 0.96-0.91 (m,
21H), 0.75 (d, J ) 6.8 Hz, 3H); 13C NMR (100 MHz, acetone-d6)
δ 202.3, 74.8, 73.6, 46.2, 41.2, 28.6, 27.9 (×3), 27.6 (×3), 22.0,
21.1, 13.6, 9.0; HRMS (+ESI) calcd for C16H32O3SiNa (M + Na+),
323.2013; found, 323.2014.
(33% EtOAc-hexane); [R]20 +38.1 (c 0.40, CHCl3); IR (film)
D
1
3511 (br), 2966, 2934, 2859, 1758, 1706, 1197, 1128 cm-1; H
NMR (400 MHz, CDCl3) δ 5.69 (ddd, J ) 17.2, 10.0, 8.0 Hz,
1H), 5.44 (dd, J ) 8.0, 1.6 Hz, 1H), 5.30 (dd, J ) 10.0, 1.2 Hz,
1H), 5.27 (dd, J ) 17.2, 0.8 Hz, 1H), 4.64 (ddd, J ) 8.8, 5.6, 3.2
Hz, 1H), 3.98 and 3.92 (ABq, J ) 18.4 Hz, 2H), 3.75 (td, J ) 8.0,
3.2 Hz, 1H), 3.69 (dd, J ) 10.0, 2.0 Hz, 1H), 3.65 (t, J ) 8.0 Hz,
1H), 3.41 (s, 3H), 3.26 (s, 3H), 3.20 (br s, 1H, OH), 2.87 (qd, J )
7.2, 2.0 Hz, 1H), 2.74 (dd, J ) 15.2, 10.4 Hz, 1H), 2.47 (dd, J )
15.2, 3.2 Hz, 1H), 2.16-2.07 (m, 2H), 1.67-1.55 (m, 1H), 1.44-
1.33 (m, 1H), 1.14 (d, J ) 7.2 Hz, 3H), 0.98-0.94 (m, 21H), 0.87
(d, J ) 6.8 Hz, 3H), 0.77 (d, J ) 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 214.3, 167.0, 136.0, 120.1, 82.2, 74.5, 73.4, 73.1,
71.0, 69.7, 59.3, 56.4, 46.4, 44.1, 40.3, 35.4, 28.2, 27.4 (×3), 27.2
(×3), 21.4, 20.7, 13.5, 9.9, 8.7, 8.4; HRMS (+ESI) calcd for
C29H54O8SiNa (M + Na+), 581.3480; found, 581.3506. dia-4: a
colorless oil; Rf ) 0.45 (33% EtOAc-hexane); 1H NMR (400 MHz,
CDCl3) δ 5.62 (ddd, J ) 16.8, 10.4, 8.0 Hz, 1Η), 5.31 (δ, J )
10.4, 1.6 Hz, 1H), 5.28 (dd, J ) 16.8, 1.6 Hz, 1H), 4.98 (dd, J )
8.0, 4.0 Hz, 1H), 4.62 (ddd, J ) 9.2, 5.2, 3.6 Hz, 1H), 3.98 and
3.90 (ABq, J ) 16.4 Hz, 2H), 3.77 (dd, J ) 7.2, 4.4 Hz, 1H), 3.73
(dd, J ) 8.0, 4.4 Hz, 1H), 3.63 (t, J ) 8.0 Hz, 1H), 3.40 (s, 3H),
3.28 (s, 3H), 3.04 (qd, J ) 7.2, 4.4 Hz, 1H), 2.72 (dd, J ) 15.2,
10.0 Hz, 1H), 2.54 (dd, J ) 15.6, 3.6 Hz, 1H), 2.18-2.08 (m, 2H),
1.63-1.54 (m, 2H), 1.41-1.34 (m, 1H), 1.19 (d, J ) 6.4 Hz, 3H),
1.01 (d, J ) 7.2 Hz, 3H), 0.98 (s, 18H), 0.95 (t, J ) 7.2 Hz, 3H),
0.76 (d, J ) 7.2 Hz, 3H); HRMS (+ESI) calcd for C29H54O8SiNa
(M + Na+), 581.3480; found, 581.3454.
Ketone 6. To a solution of the aldehyde 28 (810.0 mg, 2.7 mmol)
in dry THF (25 mL) cooled at -78 °C was added dropwise EtMgBr
(5.6 mL, 1.0 M in Et2O, 5.6 mmol) followed by stirring at the same
temperature for 2 h. The reaction mixture was allowed to warm to
room temperature and quenched with saturated aqueous NH4Cl (10
mL). The resultant mixture was extracted with EtOAc (30 mL ×
3), and the combined organic layer was washed with brine, dried
over anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(silica gel, 10% EtOAc in hexane) to give the corresponding alcohol
which was used in the next step without further purification.
To a suspension of powdered 4 Å molecular sieves (1.20 g) in
dry CH2Cl2 (12 mL) was added the above alcohol (750.0 mg, 2.3
mmol) in dry CH2Cl2 (3 mL), NMO (552.0 mg, 4.6 mmol), and
TPAP (90.0 mg, 0.24 mmol) followed by stirring for 15 h at room
temperature. The reaction mixture was filtrated through a pad of
Celite with rinsing by EtOAc. The combined filtrate was concen-
trated under reduced pressure and the residue was purified by flash
column chromatography (silica gel, 5% EtOAc in hexane) to afford
6 (671.0 mg, 89% overall yield from 28) as a colorless oil. Rf )
0.81 (10% EtOAc-hexane); [R]20D +80.2 (c 1.75, CHCl3); IR (film)
1
2963, 2935, 2859, 1717, 1474, 1131, 1066 cm-1; H NMR (400
MHz, CDCl3) δ 4.60 (ddd, J ) 10.0, 5.2, 3.2 Hz, 1H), 3.75 (dt, J
) 8.4, 3.2 Hz 1Η), 2.69 (dd, J ) 14.4, 10.4 Hz, 1H), 2.60-2.47
(m, 2H), 2.38 (dd, J ) 14.4, 3.2 Hz, 1H), 2.16-2.11 (m, 1H), 1.62-
1.59 (m, 1H), 1.36 (dq, J ) 14.4, 7.6 Hz, 1H), 1.06 (t, J ) 7.2 Hz,
3H), 0.98 (s, 9H), 0.97 (s, 9H), 0.95 (t, J ) 7.2 Hz, 3H), 0.73 (d,
J ) 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 210.3, 74.1, 73.3,
45.4, 40.3, 36.1, 28.1, 27.5 (×3), 27.2 (×3), 21.4, 20.7, 13.5, 8.7,
7.6; HRMS (+ESI) calcd for C18H36O3SiNa (M + Na+), 351.2326;
found, 351.2314.
Aldol Reaction of Aldehyde 5 with Ethyl Ketone 6. Aldols 4
and dia-4. To a stirred solution of the ethyl ketone 6 (37.0 mg,
0.11 mmol) in dry CH2Cl2 (2.0 mL) cooled at -78 °C was added
dropwise PhBCl2 (30 µL, 0.22 mmol) and i-Pr2NEt (47 µL, 0.28
mmol) followed by stirring at the same temperature for 30 min.
Acknowledgment. This work is supported in part by the
research grants from Zhejiang University and The National
Natural Science Foundation of China (Grant No. 20572092).
W.-M. Dai is the recipient of Cheung Kong Scholars Award of
The Ministry of Education of China.
Supporting Information Available: General methods, proce-
dures, compound characterizations, and copies of 1H and 13C NMR
charts. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070624O
4960 J. Org. Chem., Vol. 72, No. 13, 2007