Studies on the Total Synthesis of Formamicin: Synthesis of the C(1)-C(11) Fragment

Article abstract of DOI:10.1021/ol0069610

(Matrix Presented) An efficient and highly concise synthesis of 6, corresponding to the C(1)-C(11) fragment of formamicin (1), has been accomplished by a route utilizing a diastereoselective lactate aldol reaction to set the C(6) tertiary ether and the TE

Full text of DOI:10.1021/ol0069610

ORGANIC
LETTERS
2001
Vol. 3, No. 3
453-456
Studies on the Total Synthesis of
Formamicin: Synthesis of the
C(1)−C(11) Fragment
Noel A. Powell‡ and William R. Roush*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity,
Ann Arbor, Michigan 48109
roush@umich.edu
Received December 5, 2000
ABSTRACT
An efficient and highly concise synthesis of 6, corresponding to the C(1)−C(11) fragment of formamicin (1), has been accomplished by a route
utilizing a diastereoselective lactate aldol reaction to set the C(6) tertiary ether and the TES−OTf mediated transketalization of the C(6) tertiary
methoxymethyl ether and the C(25) PMB ether to set the seven-membered methylene acetal unit (see 37 f 38).
Formamicin, 1, was isolated in 1997 from Saccharothrix sp.
MK27-91F2, an actinomycete strain that was obtained from
a soil sample collected at Setagaya-ku, Tokyo, Japan.1
Besides showing strong activity against phytopathogenic
fungi and moderate activity toward Gram-positive bacteria,
formamicin displayed very potent cytotoxicity against murine
is noted for the presence of a 16- or 18-membered tetraenic
macrolactone ring, a conserved, stereochemically rich C(14)-
C(23) propionate segment and a six-membered hemiacetal
which is often glycosylated at the C(21) hydroxyl with a
2-deoxy-D-rhamnose unit. Formamicin possesses some unique
structural features, including the n-pentyl chain at C(25) and
a C(6) tertiary alcohol and C(25) secondary alcohol that have
been incorporated into a seven-membered methylene acetal.
Our retrosynthetic analysis (Figure 1) calls for formamicin
to be assembled from the key fragments 2,5 3, 5,6 and 6.
Fragment 5 is an intermediate in our recently completed total
synthesis of bafilomycin A1.6 We report herein a concise
synthesis of 6, corresponding to the C(1)-C(11) fragment
of formamicin (1).7
tumor cell lines in vitro, particularly leukemia cells (IC50
)
0.13-0.15 ng/mL for EL4, P388, and L1210 leukemia cell
lines). Slightly lower cytotoxicity was observed with IMC
carcinoma and S180 sarcoma cells (IC50 ) 0.29 and 3.45
ng/mL, respectively). The structure of 1 was elucidated by
mass spectral and high-field 2D NMR techniques, and the
absolute configuration was determined through degradation
and X-ray crystal analysis.
Formamicin belongs to the plecomacrolide family of
macrolide antibiotics that includes the hygrolidins,2 con-
canamycins,3 and bafilomycins.4 This natural products family
Our initial efforts to prepare fragment 6 began with the
(3) (a) Kinashi, H.; Someno, K.; Sakaguchi, K.; Higashijima, T.;
Miyazawa, T. Tetrahedron Lett. 1981, 22, 3857. (b) Westley, J. W.; Liu,
C.-M.; Sello, L. H.; Evans, R. H.; Troupe, N.; Blount, J. F.; Chiu, A. M.;
Todaro, L. J.; Miller, P. A. J. Antibiot. 1984, 37, 1738.
* To whom correspondence should be addressed.
‡ Present Address: Pfizer Global Research and Development, Ann Arbor
Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105.
(1) (a) Igarashi, M.; Kinoshita, N.; Ikeda, T.; Nakagawa, E.; Hamada,
M.; Takeuchi, T. J. Antibiot. 1997, 50, 926. (b) Igarashi, M.; Nakamura,
H.; Naganawa, H.; Takeuchi, T. J. Antibiot. 1997, 50, 932.
(2) Seto, H.; Tajima, I.; Akao, H.; Furihata, K.; Otake, N. J. Antibiot.
1984, 37, 610.
(4) Werner, G.; Hagenmaier, H.; Drautz, H.; Baumgartner, A.; Za¨hner,
H. J. Antibiot. 1984, 37, 110.
(5) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541.
(6) Scheidt, K.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush, W.
R. Angew. Chem., Int. Ed. 1999, 38, 1652 and references therein.
(7) References to total syntheses of other members of the plecomacrolide
family are provided in Supporting Information.
10.1021/ol0069610 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/09/2001

Scheme 1
Figure 1. Retrosynthetic analysis.
N-acyl oxazolidinone 7 (Scheme 1).8 The Bu2BOTf-mediated
asymmetric aldol reaction between 7 and hexanal gave syn-
aldol 8 with excellent diastereoselectivity. Following
Me3Al-mediated transamidation of the N-acyl oxazolidinone
to the corresponding Weinreb amide,9 LiAlH4 reduction of
the amide gave diol 9 in good overall yield. The secondary
alcohol was selectively protected as a p-methoxybenzyl
(PMB) ether by formation of the p-methoxybenzylidine acetal
followed by DIBAL-H reductive cleavage of the less-
hindered C-O acetal bond to afford 10 in excellent yield.
Swern oxidation10 of the primary alcohol provided aldehyde
11, which was used without purification in the following
reaction.
natural product. Accordingly, the Z(O)-lithium enolate11b of
the MOM-protected lactate aryl ester 1212 was formed by
deprotonation with LDA at -78 °C. Addition of aldehyde
11 then gave an 81:19 mixture of aldols 13 and 14 in 91%
yield, with the desired all-syn diastereomer 13 predominat-
ing.13 Although 13 and 14 proved inseparable, LiAlH4
reduction of the mixture gave the corresponding mixture of
diastereomeric diols 15 and 16, which were easily separable
by flash chromatography.
We chose to install the C(6) tertiary and C(7) secondary
centers via a diastereoselective O-alkyllactate aldol reaction.11
This strategy allows the tertiary center to be introduced as a
methoxymethyl (MOM) ether, in a form suitable for subse-
quent elaboration into the seven-membered acetal of the
The primary hydroxyl of the major diol isomer 15 was
selectively protected as the pivalate ester 17 (Scheme 2).
Attempts to protect the remaining secondary alcohol as a
TBS ether were disappointing, giving the desired TBS ether
in 32% yield along with 52% of recovered diol 17.
(8) Kamenecka, T. M.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl.
1998, 37, 2995.
(9) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(10) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
Scheme 2
(11) (a) Heathcock, C. H.; Hagen, J. P.; Jarvi, E. T.; Pirrung, M. C.;
Young, S. D. J. Am. Chem. Soc. 1981, 103, 4972. (b) Heathcock, C. H.;
Pirrung, M. C.; Young, S. D.; Hagen, J. P.; Jarvi, E. T.; Badertscher, U.;
Ma¨rki, H.-P.; Montgomery, S. H. J. Am. Chem. Soc. 1984, 106, 8161. (c)
Heathcock, C. H.; Young, S. D.; Hagen, J. P.; Pilli, R.; Badertscher, U. J.
Org. Chem. 1985, 50, 2095. (d) Hoagland, S.; Morita, Y.; Bai, D. L.; Ma¨rki,
H.-P.; Kees, K.; Brown, L.; Heathcock, C. H. J. Org. Chem. 1988, 53,
4730.
(12) Lactate aryl ester 12 was prepared from methyl O-methoxymethyl
lactate by a three step sequence of ester hydrolysis (LiOH, MeOH/H2O),
acid chloride formation ((COCl)2, CH2Cl2), and condensation with lithium
2,6-di-tert-butyl-4-methylphenoxide (THF).11
(13) The stereochemical proof of aldol products 13 and 14 is presented
in the Supporting Information.
454
Org. Lett., Vol. 3, No. 3, 2001

Subsequent DDQ deprotection of the PMB ether afforded
alcohol 18 in excellent yield. Treatment of 18 with excess
Me2BBr in the presence of 2,6-di-tert-butyl-4-methylpyridine
induced a rapid intramolecular transketalization and provided
the desired seven-membered acetal 19 in 91% yield.14
Although the transketalization strategy proved quite ef-
fective, the difficulties encountered in attempted protection
of 17 as a TBS ether prompted a search for a more suitable
protecting group. Reasoning that the low yield was a result
of the steric congestion about the C(7) alcohol, we turned
to the sterically smaller TES ether. Accordingly, we were
quite pleased to find that treatment of 17 with 4 equiv of
commerical grade TESOTf in the presence of 2,6-lutidine
(8 equiv) in CH2Cl2 not only led to silylation of the alcohol,
but also initiated a remarkable sequence of events involving
debenzylation of the PMB ether and transketalization of the
MOM ether to afford the seven-membered acetal 20 in 78%
yield (Scheme 3)! Further investigation revealed that TES
Scheme 4
Scheme 3
tion of the pivalate ester. However, the carbalumination16
of 26 proved extremely sluggish, proceeding only after
addition of a large excess of Me3Al in refluxing dichloro-
ethane over 18 h. The subsequent iodination of the vinylalane
intermediate provided an inseparable 1:1 mixture of the vinyl
iodide 27 and disubstituted alkene 28 in low mass recovery.
Following Swern oxidation of the alcohol,10 treatment of the
resulting aldehyde with Ph3PdC(Me)CO2Me, and HPLC
purification, the targeted vinyl iodide 29 was isolated in 16%
overall yield from 26.
Since introduction of the trisubstituted vinyl iodide through
a Negishi carbalumination sequence was very inefficient, we
redesigned the synthesis to allow for the introduction of the
trisubstituted olefin at an earlier stage. Since we anticipated
that a vinyl iodide would not be compatible with the LiAlH4
reduction step (e.g., conversion of 13 to 15), we chose to
use a vinyl silane as a vinyl iodide surrogate (Scheme 5).
Using the conditions of Danheiser and co-workers,17 treat-
ment of TMS ether 30 with t-BuLi initiated a retro-Brook
1,2-silyl migration to give the corresponding R-silyllithium
alkoxide which was trapped with Ac2O to afford acetate 31.18
Treatment of 31 with TBSOTf and Et2NEt in CH2Cl2 over
3 days promoted an Ireland-ester Claisen rearrangement19
which gave vinyl silane 32 as a single trans-olefin isomer.
Cleavage of the silyl ester with TMSOK gave the potassium
carboxylate salt,20 which was treated in situ with PivCl to
afford the mixed anhydride. Addition of the lithiated oxazo-
lidinone then provided the N-acyl oxazolidinone 33 in 54%
overall yield from 30. Asymmetric aldol coupling of 33 with
hexanal gave 34 in excellent yield and diastereoselectivity.
ether 21 was formed immediately along with the minor
byproducts 23 and 24 upon addition of 1 equiv of TESOTf
to 17. Further treatment with 3 equiv of TESOTf resulted in
the slower conversion of 21 to acetal 20. The use of fewer
equivalents of additional TESOTf resulted in slower conver-
sion rates and/or incomplete reaction. We believe that the
methoxymethyl ether is activated by traces of TfOH in the
commerical TESOTf, as use of distilled TESOTf again gave
much slower conversion rates. Intramolecular interception
of the activated MOM ether by the PMB ether oxygen gives
acetal 20 after debenzylation of the oxonium ion 24.
With an efficient synthesis of 20 in hand, we turned to
the elaboration of the trisubsituted vinyl iodide (Scheme 4).
Accordingly, the vinyl group of 20 was converted into the
corresponding alkyne 26 by oxidative cleavage to aldehyde
25, Gilbert-Seyferth homologation,15 and DIBAL-H reduc-
(15) (a) Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997.
(b) Seyfert, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36, 1379.
(16) Negishi, E.-I.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc.
1985, 107, 6639.
(17) Danheiser, R. L.; Fink, D. M.; Okano, K.; Tsai, Y.-M.; Szczepanski,
S. W. J. Org. Chem. 1985, 50, 5393.
(14) (a) Gustin, D. J.; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron
Lett. 1995, 36, 3447. (b) Guidon, Y.; Yoakim, C.; Morton, H. E. J. Org.
Chem. 1984, 49, 3912.
(18) Calter, P.; Evans, D. A. Ph.D. Thesis, Harvard University, 1993.
(19) Ireland, R. E.; Varney, M. D. J. Am. Chem. Soc. 1984, 106, 3668.
(20) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
Org. Lett., Vol. 3, No. 3, 2001
455

by HPLC. LiAlH4 reduction of 36 gave the corresponding
diol in near quantitative yield. Attempts to protect the primary
alcohol as a pivalate ester were unsuccessful. However, the
diol could be selectively converted to the monoacetate 37
by treatment with Ac2O in pyridine and CH2Cl2. Treatment
of 37 with excess TESOTf and 2,6-lutidine using the
procedure developed for the conversion of 17 to 20 afforded
the seven-membered acetal 38 in 42% yield.22
Scheme 5
The vinyl silane was converted to the vinyl iodide (89%
yield) as a single olefin isomer by treatment of 38 with
N-iodosuccinimide. DIBAL-H reductive deprotection of the
acetate ester (96% yield) followed by Swern oxidation of
the resulting alcohol (88% yield) provided the sterically
hindered aldehyde 39 in very good overall yield. Wittig
olefination of 39 with Ph3PdC(Me)CO2Me in toluene at
reflux gave the corresponding enoate in 91% yield. DIBAL-H
reduction of the ester to the allylic alcohol (91% yield)
followed by Swern oxidation (84% yield) gave the unsatur-
ated aldehyde 40 in very good yield. Finally, the remaining
olefin was introduced by condensation of aldehyde 40
with Ph3PdCHCO2Me in warm benzene to provide the
trans,trans-dienoate methyl ester 6 in 91% yield as a single
olefin isomer.
In conclusion, we have developed an efficient, stereo-
selective synthesis of the C(1)-C(11) fragment of formami-
cin. Further progress toward completion of a total synthesis
of this interesting natural product will be reported in due
course.
Acknowledgment. This work was supported by the
National Institutes of Health (GM 38436). N.A.P. gratefully
acknowledges the NIH for a postdoctoral fellowship (GM
20278).
Supporting Information Available: References to syn-
theses of other members of the plecomacrolide family,
stereochemical assignments of aldols 13 and 14, and
experimental procedures for synthesis of 20, 30-39, and 6.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The oxazolidinone auxiliary was removed by NaBH4 reduc-
tion to provide the corresponding diol in 78% yield.21
Formation of the p-methoxybenzylidine acetal followed by
DIBAL-H reductive cleavage gave the PMB ether 35 in
excellent yield. Swern oxidation of the primary alcohol 35
and condensation of the resulting aldehyde with the lithium
enolate of aryl lactate ester 12 provided an 82:18 mixture of
aldols with the desired all-syn diastereomer 36 predominating
(79% yield). In this case, the diastereomers were separable
OL0069610
(22) An additional 18% of material was recovered in form of four minor
byproducts 43-46. Interestingly, products containing five membered acetals,
analogous to 23 and 24 (Scheme 3), were not observed.
(21) Prashad, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067.
456
Org. Lett., Vol. 3, No. 3, 2001