Formal total synthesis of mycoticin A [6]

Full text of DOI:10.1021/ja0035102

J. Am. Chem. Soc. 2001, 123, 341-342
341
Scheme 1
Formal Total Synthesis of Mycoticin A
Spencer D. Dreher and James L. Leighton*
Department of Chemistry, Columbia UniVersity
New York, New York, 10027
ReceiVed September 27, 2000
The polyene macrolide antibiotics (e.g., the clinically used
amphotericin B) commonly contain a (1,3,5,...) polyol section as
a recurring structural motif.1 We have been engaged in the
development of carbonylation-based approaches to the synthesis
of such structures, and the results of these studies include the
tandem intramolecular silylformylation/allylsilylation,2 and the
oxymercuration/formylation of homoallylic alcohol-derived hemi-
ketals.3 Herein we report the application of these reactions to an
efficient formal total synthesis of the polyene macrolide antibiotic
mycoticin A.
Scheme 2a
a (a) 4 mol % 5, 3,3-diethoxy-1-propene, CH2Cl2, reflux. (b) KH,
PMBBr, THF. (c) PPTS, acetone, H2O, reflux. (d) CH2dCHCH2MgBr,
(+)-B-methoxydiisopinocampheylborane, Et2O, -78 °C; 7, -90 to
23 °C; NaOH, H2O2. (e) HgClOAc, acetone, 20 mol % Yb(OTf)3, -78
to 0 °C. (f) 6 mol % Rh(acac)(CO)2, 6 mol % tris(2,4-di-tert-
butylphenyl)phosphite, 0.50 equiv DABCO, 800 psi 1/1 H2/CO, EtOAc,
50 °C. (g) MeMgBr, Et2O, 0 °C. (h) Dess-Martin periodinane, CH2Cl2.
There has been one total synthesis of mycoticin A, reported
by Schreiber and co-workers in 1993.4,5 We chose as our synthetic
target the fragment 1, a late stage intermediate in Schreiber’s
synthesis which comprises the entire polyol region of mycoticin
A (Scheme 1). In seeking a maximally convergent approach, our
retrosynthetic analysis envisioned cutting the target 1 roughly in
half to methyl ketone 2 and aldehyde 3, each of which might
efficiently be constructed using our carbonylation methodology.
Diastereoselective aldol coupling of these fragments followed by
functional group manipulation would give the completed polyol
fragment 1, and thereby complete a formal total synthesis of
mycoticin A.
The synthesis of ketone 2 (Scheme 2) commenced with
subjection of the known alkene 46 to intermolecular olefin cross-
metathesis with diethoxyacrolein,7 catalyzed by 1,3-dimesityl-
4,5-dihydroimidazol-2-ylideneRu(dCHPh)(Pcy3)Cl2 58 (4 mol %,
CH2Cl2, reflux, 4h), to give the desired (E)-alkene 6 with >20:1
E:Z selectivity. Following protection of the alcohol as its
p-methoxybenzyl (PMB) ether (KH, PMBBr, THF), the acetal
was hydrolyzed under mildly acidic conditions (pyridinium
p-toluenesulfonate (PPTS), acetone, H2O, reflux) to give aldehyde
7 in 62% overall yield from 4 (three steps). Aldehyde 7 was
subjected to Brown’s asymmetric allylation methodology9 to
produce a 10:1 mixture of diastereomers, from which the desired
homoallylic alcohol 8 could be isolated in 71% yield. Treatment
of a solution of 8 in acetone with HgClOAc and 20 mol % Yb-
(OTf)310 led to smooth oxymercuration to afford organomercury
chloride 9 (>20:1 ds) in 75% yield.3b Formylation of organo-
mercury chloride 9 (6 mol % Rh(acac)(CO)2, 6 mol % P(O-2,4-
di-t-BuPh)3, 0.50 equiv 1,4-diazabicyclo[2.2.2]-octane (DABCO),
800 psi 1/1 CO/H2, EtOAc, 50 °C)3c gave aldehyde 10, along
with small amounts of aldehyde byproducts attributable to
hydroformylation of the internal alkene. This mixture was treated
with MeMgBr (Et2O, 0 °C). The resulting alcohols (1:1 mixture
of diastereomers) could be easily purified and were subjected to
oxidation using the Dess-Martin periodinane11 to give the desired
ketone 2 in 58% overall yield from 9 (three steps). The synthesis
of ketone 2 proceeds in nine steps and 14% overall yield from
isobutyraldehyde.
(1) Isolation and structure: (a) Omura, S.; Tanaka, H. In Macrolide Anti-
biotics: Chemistry, Biology and Practice; Omura, S., Ed.; Academic Press:
New York, 1984; pp 351-404. Structure and synthesis: (b) Rychnovsky, S.
D. Chem. ReV. 1995, 95, 2021-2040. Biological Activity: (c) Bolard, J.
Biochim. Biophys. Acta 1986, 864, 257-304. (d) Hartsel, S. C.; Hatch, C.;
Ayenew, W. J. Liposome Res. 1993, 3, 377-408.
(2) (a) Leighton, J. L.; Chapman, E. J. Am. Chem. Soc. 1997, 119, 12416-
12417. (b) Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587-
8588.
(3) (a) Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2, 403-405. (b) Dreher,
S. D.; Hornberger, K. R.; Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2,
3197-3199. (c) Sarraf, S. T.; Leighton, J. L. Org. Lett. 2000, 2, 3205-3208.
(4) Poss, C. S.; Rychnovsky, S. D.; Schreiber, S. L. J. Am. Chem. Soc.
1993, 115, 3360-3361.
(5) For a recent approach to the synthesis of mycoticin A, see: Smith, A.
B.; Pitram, S. M. Org. Lett. 1999, 1, 2001-2004.
(6) Ghosh, A. K.; Liu. W. J. Org. Chem. 1997, 62, 7908-7909.
(7) (a) O’Leary, D. J.; Blackwell, H. E.; Washenfelder, R. A.; Miura, K.;
Grubbs, R. H. Tetrahedron Lett. 1999, 40, 1091-1094. (b) Blackwell, H. E.;
O’Leary, D. J.; Chatterjee A. K.; Washenfelder, R. A.; Bussmann, D. A.;
Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58-71. (c) Chatterjee, A. K.;
Morgan, J. P.; Scholl, M.; Grubbs R. H. J. Am. Chem. Soc. 2000, 122, 3783-
3784.
The synthesis of aldehyde 3 (Scheme 3) began with subjection
of known aldehyde 1112 to Brown’s anti-diastereoselective
asymmetric crotylation to afford homoallylic alcohol 12 in 55%
overall yield (three steps from 1,3-propanediol).13 In anticipation
of a tandem intramolecular silylformylation/allylsilylation,2b
(9) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem.
1986, 51, 432-439.
(10) For this complex diene substrate 8, optimal results were achieved using
a lower temperature and a higher catalyst loading than recommended (5 mol%)
for most substrates. See ref. 3b.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4156-4158.
(b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(12) Angle, S. R.; Bernier, D. S.; El-Said, N. A.; Jones, D. E.; Shaw, S. Z.
Tetrahedron Lett. 1998, 39, 3919-3922.
(13) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54,
1570-1576.
(8) Scholl, M.; Ding, S.; Lee, C. W., Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
10.1021/ja0035102 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/21/2000

342 J. Am. Chem. Soc., Vol. 123, No. 2, 2001
Communications to the Editor
Scheme 3a
Scheme 4a
a (a) i. 2, TMSOTf, i-Pr2NEt, CH2Cl2, -78 to 0 °C. ii. 3, BF3‚OEt2,
CH2Cl2, -78 °C. (b) Me4NBH(OAc)3, AcOH, THF, CH3CN, -78 to
-20 °C. (c) PPTS, 2,2-dimethoxypropane, CH2Cl2. (d) n-Bu4NF, THF,
0 to 23 °C.
a (a) KO-t-Bu, n-BuLi, (E)-2-butene, THF, -78 °C; (+)-B-methoxy-
diisopinocampheylborane, BF3‚OEt2, 11, -78 to -30 °C; NaOH, H2O2.
(b) n-BuLi, HSiCl3, AllylMgBr, THF, -78 to 0 °C. (c) 3 mol %
Rh(acac)(CO)2, PhH, 1000 psi CO, 60 °C. (d) H2O2, NaHCO3, THF,
MeOH, reflux. (e) Acetone, 10 mol % CSA. (f) HgClOAc, acetone, 10
mol % Yb(OTf)3, 0 °C. (g) 8 mol % Rh(acac)(CO)2, 8 mol % tris(2,4-
di-tert-butylphenyl)phosphite, 0.50 equiv DABCO, 1000 psi 1/1 H2/CO,
EtOAc, 60 °C.
silane was treated with aldehyde 3 (1.0 equiv) and BF3‚OEt2 (1.05
equiv) in CH2Cl2 at -78 °C to afford aldol 18 and the C(21)
epimer in a ratio of 6:1 (Scheme 4). This inseparable mixture
was then subjected to anti-diastereoselective â-hydroxy ketone
reduction with Me4NBH(OAc)3 (AcOH, THF, CH3CN, -78 to
-20 °C) to give diol 19 and a diastereomer in a 6:1 ratio.17
Although we could not quantitatively determine the diastereose-
lectivity of the reduction, the fact that the product was a 6:1
mixture of diastereomers is certainly suggestive of a very selective
(>95:5) reaction. Protection of the mixture of diols as acetonides
(PPTS, 2,2-dimethoxypropane, CH2Cl2) provided a separable 6:1
mixture of tetraacetonides from which 20 could be isolated in
49% overall yield (from 2 and 3). Finally, cleavage of the TIPS
group with n-Bu4NF in THF provided the target compound 1 in
92% yield. Full spectral comparison (1H and 13C NMR, IR, MS,
optical rotation) with the Schreiber intermediate18 established the
structure of our material and confirmed the completion of the
formal synthesis.
alcohol 12 was treated with n-BuLi followed by HSiCl3 and then
allylmagnesium bromide to give diallylsilane 13. Subjection of
diallylsilane 13 to the action of 3 mol % Rh(acac)(CO)2 in benzene
under 1000 psi CO at 60 °C in a stainless steel pressure reactor,
followed by evaporation of solvent and subjection of the residue
to the conditions of the Tamao oxidation (H2O2, NaHCO3, THF/
MeOH, reflux) led to the isolation of triol 14 in 55% overall yield
(three steps from 12).2b Isolation of all products revealed that the
diastereoselectivity was >10:1 for 14:Σ all other diastereomers.
Triol 14 was then protected as its acetonide under equilibrating
conditions (camphorsulfonic acid (CSA), acetone, 16 h) to afford
a 7:1 mixture of the desired homoallylic alcohol 15 and the
isomeric acetonide 16, from which 15 could be isolated in 75%
yield. Subjection of homoallylic alcohol 15 to the hemiketal
oxymercuration (10 mol % Yb(OTf)3, HgClOAc, acetone, 0 °C)
gave organomercury chloride 17 in 71% yield and >20:1 dia-
stereoselectivity.3b Finally, formylation of organomercury chloride
17 (8 mol % Rh(acac)(CO)2, 8 mol % P(O-2,4-di-t-BuPh)3, 0.50
equiv DABCO, 1000 psi 1/1 CO/H2, EtOAc, 60 °C)3c afforded
the desired aldehyde 3 in 82% yield. The synthesis of aldehyde
3 proceeds in nine steps and 13% overall yield from 1,3-
propanediol.
In the aldol union of methyl ketone 2 with aldehyde 3, the
desired product is that resulting from 1,3-anti induction with
respect to the aldehyde, and 1,5-syn induction with respect to the
ketone. Ample precedent has established that â-alkoxy aldehydes
exhibit a preference for the 1,3-anti product in aldol addition
reactions with methyl ketone enolates and enol silanes.14 Remark-
able levels of 1,5-anti induction have been observed in the aldol
reactions of â-alkoxy methyl ketone dialkylboron enolates.15
However, it has also been shown that the 1,5-anti induction is
not expressed using enol silanes, and in these cases the aldehyde
dominates.15c Informed by the comprehensive work of Evans,
therefore, we focused on the Mukaiyama variant of the aldol
coupling.16 Thus, methyl ketone 2 was treated with TMSOTf
and i-Pr2NEt (CH2Cl2, -78 to 0 °C), and the resultant enol
The synthesis of mycoticin A polyol fragment 1 was ac-
complished with a longest linear sequence of 14 steps from
isobutyraldehyde and with an overall yield of 6%. This highlights
both the convergent nature of the present approach and the
efficiency of the carbonylation-based methodology used to prepare
the polyol fragments 2 and 3.
Acknowledgment. We thank the National Institutes of Health
(National Institute of General Medical Sciences - R01 GM58133) and
the Research Corporation (Cottrell Scholar Award to J.L.L.) for financial
support of this work. We thank Merck Research Laboratories and DuPont
Pharmaceuticals for generous financial support. J.L.L. is a recipient of a
Sloan Research Fellowship, a Camille Dreyfus Teacher-Scholar Award,
a Bristol-Myers Squibb Unrestricted Grant in Synthetic Organic Chem-
istry, an Eli Lilly Grantee Award, an AstraZeneca Excellence in Chemistry
Award, and a GlaxoWellcome Chemistry Scholar Award.
Supporting Information Available: Experimental procedures and
spectral data for 1-3, 7-10, 12-15, 17, and 20 (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
JA0035102
(16) For a comprehensive review of the Mukaiyama variant of the aldol
reaction, see: Gennari, C. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2, pp 629-660.
(17) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(18) Christopher S. Poss, Ph.D. Thesis, Harvard University, 1993. We are
grateful to Dr. Poss for providing copies of the relevant spectra and spectral
data.
(14) (a) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35
8537-8540. (b) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322-4343.
(15) (a) Paterson, I.; Oballa, R. M.; Norcross, R. D. Tetrahedron Lett. 1996,
37, 8581-8584. (b) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron
Lett. 1996, 37, 8585-8588. (c) Evans, D. A.; Coleman, P. J.; Coˆte´, B. J.
Org. Chem. 1997, 62, 788-789.