Application of Newly Developed Anti-Selective Aldol Methodology: Synthesis of C6-C13 and C19-C28 Fragments of Miyakolide

Full text of DOI:10.1021/jo971863m

8978
J . Org. Chem. 1997, 62, 8978-8979
Ap p lica tion of New ly Develop ed
An ti-Selective Ald ol Meth od ology:
Syn th esis of C6-C13 a n d C19-C28
F r a gm en ts of Miya k olid e
Takehiko Yoshimitsu, J inhua J . Song,
Guo-Qiang Wang and Satoru Masamune*
Department of Chemistry, Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139
Received October 9, 1997
F igu r e 1.
Stereospecific aldol reactions have been the subject of
extensive investigation over the past two decades because
of their wide applicability to the synthesis of stereo-
chemically complex polyketide natural products exempli-
fied by macrolides. While many excellent chiral Z(O)
enolates have been employed for the construction of the
syn-3-hydroxy-2-methyl carbonyl structural motif,1 meth-
ods for the direct elaboration of the anti counterparts
have met with limited success.2 As a result, anti-selective
aldol reactions are rarely utilized in natural product
synthesis as strategic bond-forming reactions. To ad-
dress this problem, we have recently developed a highly
enantioselective anti-aldol reaction using the chiral E(O)
enol borinate 1 generated from the chiral ester 2.3
Application of this anti-aldol methodology, along with the
well-established syn-selective methods, allows greater
flexibility in the synthetic design of polyketide-type
compounds. We herein report that the chiral enol bori-
nate 1 (Figure 1) has been successfully utilized in the
synthesis of two key fragments of miyakolide via both
single and double asymmetric aldol reactions.
Sch em e 1
Miyakolide, a bryostatin-like marine metabolite, was
isolated from Polyfibrospongia sp. and shown to have the
structure 3 in Scheme 1.4 Our planned convergent
synthesis of 3 involves the two major fragments A (C19-
C28) and C (C6-C13), both of which contain the chal-
lenging anti-3-hydroxy-2-methyl carbonyl subunits. The
efficient, stereoselective syntheses of these units through
the anti-selective aldol methodology are shown below.
The synthesis of fragment A starts with the known
chiral aldehyde 4 (Scheme 2)5 and features a double
asymmetric anti-aldol reaction that was fully evaluated
with our newly devised methodology. Thus, aldehyde 4
was allowed to react with the enol borinate 1 (1S, 2R) to
provide aldol 5 along with compound 6 as the minor
isomer in a ratio of 15:1, whereas the reaction of 4 with
ent-1 (1R, 2S) resulted in the formation of aldol 7 as the
Sch em e 2
(1) For a good review of asymmetric aldol reactions in natural
product synthesis see: Kim, B.-M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon
Press: New York, 1991; Vol. 2, pp 239-275. For a recent review see:
Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
(2) (a) See ref 3 and references therein. For indirect methods for
this transformation, see: (b) Nagaoka, H.; Rutsch, W.; Schmid, G.; Iio,
H.; J ohnson, M. R.; Kishi, Y. J . Am. Chem. Soc. 1980, 102, 7962. (c)
Schmid, G.; Fukuyama, T.; Akasaka, K.; Kishi, Y. J . Am. Chem. Soc.
1979, 101, 259. (d) Boschelli, D.; Ellingboe, J . W.; Masamune, S.
Tetrahedron Lett. 1984, 25, 3395. (e) Evans, D. A. Aldrichim. Acta
1982, 15, 23.
(3) Abiko, A.; Liu, J .-F.; Masamune, S. J . Am. Chem. Soc. 1997, 119,
2586.
(4) Higa, T.; Tanaka, J .; Komesu, M.; Gravalos, D. G.; Puentes, J .
L. F.; Bernardinelli, G.; J efford, C. W. J . Am. Chem. Soc. 1992, 114,
7587.
(5) (a) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake, T.
Tetrahedron 1992, 48, 4067. (b) Meyers, A. I.; Lawson, J . P. Tetrahe-
dron Lett. 1982, 23, 4883.
only detectable isomer. This result is noteworthy because
it implies that the directing effect of the chiral enol
borinate 1 is high enough to overcome the intrinsic
stereochemical bias of the chiral aldehyde, thereby
dictating the stereochemical outcome in both matched
and mismatched double asymmetric aldol reactions.6
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Communications
J . Org. Chem., Vol. 62, No. 26, 1997 8979
Sch em e 3
Sch em e 4
a
Key: (a) ent-2 (1R, 2S), (c-Hex)2BOTf, Et3N, CH2Cl2, -78 °C,
then 14 -78 to 0 °C (85%); (b) (1) LAH, THF, 0 °C (85%); (2) 2,2-
dimethoxypropane, PPTS, CH2Cl2, 25 °C (91%); (c) (1) TBAF, THF,
25 °C (95%); (2) PPh3, CCl4, THF, reflux (87%); (d) AD-mix-â,
CH3SO2NH2, t-BuOH, H2O, 25 °C (65%); (e) (1) NaOH, THF, 0 °C
(60%); (2) TBSCl, imidazole, CH2Cl2, 25 °C (95%).
The synthesis of fragment C involves another anti-
selective aldol reaction and an asymmetric Sharpless
dihydroxylation (Scheme 4). Thus, the readily synthe-
sized aldehyde 14 was treated with chiral enol borinate
ent-1 (1R, 2S) to give aldol 15 in 85% yield with good
selectivity (ca. 15:1).9 After the removal of the auxiliary,
the diol was protected as its acetonide 16. Deprotection
and halogenation delivered the allylic chloride 17, which
then underwent standard asymmetric Sharpless
dihydroxylation10 to give the chlorohydrin 18 smoothly.
Brief treatment of 18 with freshly powdered sodium
hydroxide led to the formation of the R-hydroxy epoxide,10
which was subsequently silylated to furnish fragment C
in good yield. The synthesis of fragment D (Scheme 1)
was rather straightforward, and we are now in possession
of sufficient quantities of fragments A, C, and D for
further studies on the synthesis of miyakolide.
a
Key: (a) LAH, THF, 0 °C (60%); (b) (1) TBSCl, Et3N, DMAP,
CH2Cl2, 25 °C (83%); (2) BnBr, NaH, DMF, 25 °C (85%); (3) TBAF,
THF, 25 °C (94%); (c) (1) Swern, -78 °C; (2) 1 N HCl, THF, 25 °C
(98%;two steps); (d) (1) TBSCl, Et3N, DMAP, CH2Cl2, 25 °C (95%);
(2) PCC, CH2Cl2, 25 °C (93%); (e) LiHMDS, ethyl acetate, THF,
-78 °C (92%); (f) Et3SiH, BF3‚Et2O, CH3CN, -10 °C to rt (90%);
(g) (1) PDC, 4A MS, CH2Cl2, 25 °C; (2) isopropylphosphonium
bromide, NaHMDS, toluene, -78 °C to rt (75%, two steps).
With the required configurations established at C22
and C23 in 5, the chiral auxiliary was cleaved by LAH
reduction to give diol 8 (Scheme 3). Standard protecting
group manipulation afforded primary alcohol 9, which
was then oxidized to the aldehyde. Acid hydrolysis of
the acetonide, followed by in situ cyclization, gave hemi-
acetal 10 in good yield. Selective silylation and PCC
oxidation of the hemiacetal furnished lactone 11. The
last stereogenic center in fragment A was introduced by
a stereoselective reduction. Thus, treatment of lactone
11 with lithium ethyl acetate in THF gave the expected
aldol adduct 12, which was then reduced with triethyl-
silane in the presence of boron trifluoride etherate, via
an intermediate oxonium ion, to furnish compound 13
with excellent selectivity.7 Under these conditions, the
primary TBS group was cleanly removed. PDC oxidation
of alcohol 13 and subsequent Wittig olefination with
isopropylidene phosphorane completed the highly ste-
reoselective construction of fragment A.8
The successful construction of the two key fragments
A and C has demonstrated that anti-selective aldol
reactions with 1 are generally applicable and proceed
smoothly. The reactions are indeed reliable enough to
be incorporated in the synthetic schemes for complex
polyketide natural products.
Ack n ow led gm en t. This work was generously sup-
ported by a grant (CA48175) from the National Insti-
tutes of Health awarded to S.M. T.Y. was a postdoctoral
fellow supported by the Uehara Foundation (J apan).
Su p p or tin g In for m a tion Ava ila ble: The detailed ex-
perimental procedures and characterization data for com-
pounds A, C, and 5-18 in the synthesis of fragments A and
C, including the determination of the stereochemistry of the
aldol reaction in fragment C synthesis (13 pages).
(6) For a review of double asymmetric synthesis, see: Masamune,
S.; Choy, W.; Peterson, J . S.; Sita, L. R. Angew. Chem., Int. Ed. Engl.,
1985, 24, 1.
(7) Lewis, M. D.; Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982, 104,
4976.
J O971863M
(9) For the confirmation of the absolute stereochemistry of this
transformation, see the Supporting Information.
(8) The absolute stereochemical assignments of fragment A have
been achieved through NMR techniques. See the Supporting Informa-
tion for details.
(10) Vanhessche, K. P. M.; Wang, Z.-M.; Sharpless, K. B. Tetrahe-
dron Lett. 1994, 33, 3469. For a recent review, see: Kolb, H. C.;
VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483.