Pseudo-C3-Symmetric Tertiary Alcohol Building Block via Group-Selective Hydroalumination: A Synthesis of (-)-Malyngolide

Article abstract of DOI:10.1021/ol015943v

(matrix presented) The stereocontrolled preparation of tertiary alcohol 4 and its TMS surrogate 5, which share a pseudo-C₃-symmetry, is described. Compound 4 was used for the synthesis of (-)-malyngolide.

Full text of DOI:10.1021/ol015943v

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1741-1744
Pseudo-C -Symmetric Tertiary Alcohol
3
Building Block via Group-Selective
Hydroalumination: A Synthesis of
(−)-Malyngolide
Takao Suzuki, Ken Ohmori, and Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST, Japan Science
and Technology Corporation (JST), O-okayama, Meguro-ku, Tokyo 152-8551, Japan
ksuzuki@chem.titech.ac.jp
Received April 5, 2001
ABSTRACT
The stereocontrolled preparation of tertiary alcohol 4 and its TMS surrogate 5, which share a pseudo-C -symmetry, is described. Compound
3
4 was used for the synthesis of (−)-malyngolide.
Stereogenic tertiary alcohols are embedded in many biologi-
cally active natural products, such as malyngolide (1).1
“three-directional elaboration” schematically depicted in
Figure 1.
Recently, we developed a new approach to such structural
motifs by the group-selectiVe hydroalumination of bis-
alkynyl alcohols armed with an adjacent chiral center. The
reaction scheme is exemplified by eq 1, which gives 3 as
Figure 1.
This aspect would be highlighted if the n-butyl groups in
3 were replaced by hydrogens (see 4) or trimethylsilyls (see
5), since all three substituents (a, b, c) are two-carbon units
(1) For isolation of 1, see: Cardllina, J. H.; Moore, R. E.; Arnold, E.
V.; Clardy, J. J. Org. Chem. 1979, 44, 4039. For previous total syntheses,
see: (a) Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470. (b)
Trost, B. M.; Tang, W.; Schulte, J. L. Org. Lett. 2000, 2, 4013. Reference
1a reports the most recent synthesis and ref 1b the next most recent,
compiling the 27 previous syntheses.
the sole product under suitable conditions.2 Among the
potential utilities of this finding, we became particularly
intrigued by the structure of 3, which might allow us the
(2) Ohmori, K.; Suzuki, T.; Taya, K.; Tanabe, D.; Ohta, T.; Suzuki, K.
Org. Lett. 2001, 3, 1057.
10.1021/ol015943v CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/10/2001

that are nicely differentiated. This Letter reports the synthesis
of the aesthetically pleasing structures of 4 and the TMS
surrogate 5 with pseudo-C3-symmetry and its application to
the synthesis of malyngolide (1).3
The known glycerate derivative 6,4 readily available from
L-serine, was treated with Me3SiCtCLi to give the bis-TMS-
ethynyl alcohol 7 in 85% yield. Desilylation of 7 gave the
bis-ethynyl alcohol 8 in 94% yield, ready for the hydro-
alumination reaction (Scheme 1).
Figure 3.
aluminate at the opposite side, and the alkynyl group in the
vicinity is selectively reduced.
Scheme 1
Under the same reaction conditions, we next attempted
the hydroalumination of alcohol 8 possessing terminal
ethynyl groups, obtaining a 92/8 mixture of the corresponding
monoreduction products 4 and epi-4 in 84% combined yield
(Scheme 3). Although the diastereomers were inseparable,
Scheme 3
Thus, treatment of 7 with LiAlH4 in THF (-78 f 0 °C,
30 min) gave the monoreduction product 5 as the sole
stereoisomer in 91% yield (Scheme 2),5 whose stereochem-
Scheme 2
1
the H NMR spectrum of 4/epi-4 gave signals resolved
enough to assess the selectivity as a mixture.
Stereochemical assignment of 4 was based on NOE studies
of the cyclic carbonate derivatives (Figure 4). Again, the
istry was assigned on the basis of NOE studies on the cyclic
acetal derivative 9 [(1) 80% AcOH, (2) TBDPSCl, imidazole,
(3) Me2C(OMe)2, p-TsOH, 77% overall yield] shown in
Figure 2. The acetal 9 showed a diagnostic NOE between
the hydrogens as shown.6
Figure 4.
cyclic carbonates 10 and epi-10 gave a well-resolved
spectrum, allowing NOE study of the mixture [(1) 80%
AcOH, (2) TBDPSCl, imidazole, (3) triphosgene, pyridine,
0 °C, 40% overall yield].
(3) This marine natural product, which is a kind of symbolic compound
for synthetic practice, and as many as 29 chiral synthetic routes have been
documented with the present synthesis being the 30th one!
(4) Lok, C. M.; Ward, J. P.; van Dorp, D. A. Chem. Phys. Lipids 1976,
16, 115.
Figure 2.
(5) Experimental procedure for the hydroalumination of 7 with
LiAlH4: To a solution of LiAlH4 (77.5 mg, 2.04 mmol) in THF (4 mL)
was slowly added a solution of 7 (331 mg, 1.02 mmol) in THF (6 mL) at
-78 °C. The reaction was gradually warmed to 0 °C, and stirring was
continued for 30 min. After careful addition of Na2SO4‚10H2O, the mixture
was filtered through a Celite pad and evaporated. Flash column chroma-
tography (SiO2, hexane/EtOAc ) 95/5) gave 5 (302 mg, 91%, >99% ds)
as a colorless oil.
The perfect group selectivity observed for 7 can be
explained by the chelation model shown in Figure 3 as
previously reported.2 In the five-membered lithium chelate,
the steric repulsion of the cyclic acetal moiety puts the
1742
Org. Lett., Vol. 3, No. 11, 2001

At this stage, we hoped to improve this high, but imperfect
selectivity of the reaction of 8 (cf. Scheme 2). The clue was
our previous finding that one could expect to enhance the
selectivity by increasing the steric bulkiness of the Al ligands
by a modified procedure using n-BuLi and DIBAL (see eq
2).2
Scheme 4a
Indeed, we were delighted to observe a virtually perfect
group selectivity, upon treatment of 8 with n-BuLi (1.0 equiv,
-78 °C, 30 min) in THF followed by DIBAL (1.0 equiv) to
give alcohol 4 as the sole detectable product in 79% yield
(eq 2).7, 8
With the desired building blocks, 4 and 5, now in hand,
we turned our attention to the synthesis of (-)-malyngolide
(1). Figure 5 shows our plan of three-directional elaboration
a (a) BnBr, NaH, Bu4NI, THF, 22 h, 94%, (b) n-BuLi; C7H15I,
THF, HMPA, -78 f 0 °C, 91%, (c) O3, CH2Cl2, -78 °C; Me2S,
95%, (d) B, LiN(TMS)2, THF, 90% (E/Z ) 97/3), (e) Ca, NH3,
THF, 2 h, (f) H2, PtO2, MeOH, 1 h, 87% (two steps), (g) PDC,
pyridine, CH2Cl2, 3 days 16: 85%, epi-16: 3%, (h) CF3CO2H,
CH2Cl2, 0 f 25 °C, 3 h, (i) Pb(OAc)4, benzene, 15 min, (j) NaBH4,
MeOH, 77% (three steps).
treated with n-heptyl iodide (THF, HMPA, -78 f 0 °C) to
give the alkylated product 12 in 91% yield. Ozonolysis of
12 in CH2Cl2 at -78 °C followed by workup with Me2S
(-78 f 25 °C) cleanly afforded aldehyde 13 in 95% yield.
Introduction of the chiral, nonracemic four-carbon unit to
13 was first examined with the Wittig reagent derived from
(7) Procedure for the hydroalumination of 8 with n-BuLi and
DIBAL: To a solution of 8 (200 mg, 1.11 mmol) in THF (11 mL) was
added n-BuLi (1.50 M hexane solution, 0.74 mL, 1.1 mmol) at -78 °C.
After stirring for 30 min, DIBAL (1.01 M hexane solution, 1.10 mL) was
added. The temperature was gradually raised to 0 °C, and stirring was
continued for 30 min. After quenching with saturated aqueous potassium
sodium tartrate, extractive workup followed by flash column chromatography
(SiO2, hexane/EtOAc ) 85/15) gave 4 (160 mg, 79%, >99% ds) as a
colorless oil.
(8) Data for 4 (>99% ds): 1H NMR (400 MHz, C6D6) δ 1.44 (s, 3 H),
1.57 (s, 3H), 2.10 (s, 1H), 2.91 (brs, 1H), 3.78-3.85 (m, 2H), 3.96-4.04
(m, 1H), 5.04 (dd, 1H, J ) 9.8, 1.9 Hz), 5.61 (dd, 1 H, J ) 16.6, 1.9 Hz),
5.83 (dd, 1 H, J ) 16.6, 9.8 Hz); 13C NMR (100 MHz, C6D6) δ 25.4, 26.4,
65.9, 72.3, 74.9, 81.5, 82.8, 110.6, 116.5, 137.7; IR (neat) 3420, 3265, 3090,
2990, 2940, 2895, 2110, 1875, 1640, 1480, 1455, 1410, 1375, 1260, 1215,
Figure 5.
1155, 1075 cm-1; [R]22 +18 (c 1.1, CHCl3). Anal. Calcd for C10H14O3:
D
C, 65.92; H, 7.74. Found: C, 65.70; H, 8.04. 5: 1H NMR (400 MHz, CDCl3)
δ 0.09 (s, 9H), 0.19 (s, 9H), 1.37 (s, 3H), 1.48 (s, 3H), 2.74 (s, 1H), 3.95
(dd, 1H, J ) 8.3, 6.6 Hz), 3.99 (dd, 1H, J ) 8.3, 6.6 Hz), 4.08 (dd, 1 H,
of the two-carbon units in 4, and Scheme 4 shows the
synthesis executed along these lines.
The tert-hydroxyl group in 4 was first protected by a
benzyl group to give the benzyl ether 11 in 94% yield. The
alkyne 11 was lithiated (n-BuLi, 0 °C, 30 min) and then
J ) 6.6, 6.6 Hz), 5.93 (d, 1H, J ) 18.5 Hz), 6.27 (d, 1H, J ) 18.5 Hz); 13
C
NMR (100 MHz, CDCl3) δ -1.4, -0.2, 25.6, 26.4, 66.1, 74.0, 81.0, 92.3,
103.3, 110.5, 132.6, 143.3; IR (neat) 3440, 2990, 2960, 2920, 2170, 1945,
1615, 1480, 1455, 1370, 1305, 1250, 1215, 1160, 1075, 1015 cm-1; [R]20
D
+6.9 (c 1.1, CHCl3). Anal. Calcd for C16H30O3Si2: C, 58.84; H, 9.26.
Found: C, 58.54; H, 9.44. epi-5: 1H NMR (400 MHz, CDCl3) δ 0.16 (s,
9 H), 0.17 (s, 9H), 1.38 (s, 3H), 1.47 (s, 3H), 2.55 (s, 1H), 4.081 (d, 1H,
J ) 7.6 Hz), 4.084 (d, 1H, J ) 5.4 Hz), 4.15 (dd, 1H, J ) 7.6, 5.4 Hz),
5.77 (d, 1H, J ) 14.6 Hz), 6.23 (d, 1H, J ) 14.6 Hz); 13C NMR (100
MHz, CDCl3, TMS) δ -0.3, 1.4, 25.3, 26.3, 65.9, 72.6, 81.3, 91.0, 103.7,
110.4, 133.1, 145.6; IR (neat) 3420, 2985, 2955, 2900, 2360, 2170, 1730,
(6) Though no rationale is available, use of Et2O for the hydroalumination
of 7 only gave a 6/4 group selectivity of 5 and epi-5, which were separated
and used for the structure assignment. Thus, epi-5 was similarly converted
to the cyclic derivative epi-9, which showed again diagnostic NOE as shown
in Figure 2.
1610, 1480, 1455, 1380, 1370, 1340, 1250, 1215, 1160, 1075, 1010 cm-1
;
[R]21 +129 (c 1.07, CHCl3).
D
Org. Lett., Vol. 3, No. 11, 2001
1743

the known phosphonium salt A.9 However, under a variety
of reaction conditions, the yield of the desired olefin 14 was
poor (30-40%), which can be attributed to steric hindrance
around the formyl group in 13. At this juncture, use of the
Julia protocol by exploiting the benzothiazolyl sulfone
derivative B10 offered a nice solution to the problem. Thus,
the sulfone B was lithiated with LiN(TMS)2 in THF (0 °C,
30 min), which was allowed to react with aldehyde 13 (-78
f 25 °C, then 9 h), with smooth olefination occurring to
afford the corresponding olefin in excellent yield with high
(E)-selectivity.
The remaining tasks were (1) saturation of the CdC and
the CtC bonds, (2) removal of two benzyl groups, and (3)
one-carbon degradation. Thus, hydrogenation of 14 was
attempted by using 10% palladium on charcoal in MeOH.
However, steric hindrance made the reaction extremely slow,
and moreover, product 15 was found to suffer from sub-
stantial epimerization at C2. Judging from the 1H NMR, the
epimer ratio was 80/20. To suppress this stereomutation,
various attempts to optimize the reaction were conducted
with limited success.
The final solution was achieved in the following manner.
The benzyl protecting groups were detached under Birch
conditions (Ca, NH3, THF, -45 °C, 2 h),11 in which part of
the diol product underwent partial saturation of the triple
bond. Subjection of this mixture to hydrogenation (PtO2,
MeOH, 25 °C, 1 h) gave the corresponding fully saturated
diol 15 in 87% yield with minimal epimerization (95:5).
Upon treatment of diol 15 with PDC (pyridine, CH2Cl2, 3
days), the oxidation proceeded cleanly to give lactone 16 in
85% yield and the epimer epi-16 in 3% yield, which were
easily separated by SiO2 column chromatography.
Acid hydrolysis of the acetal 16 followed by glycol
cleavage and borohydride reduction gave (-)-malyngolide
(1) in 77% yield. The spectroscopic data coincided with those
of the natural product.1
In summary, we have described an easy route to the
pseudo-C3-symmetric tertiary alcohol 4 and its TMS sur-
rogate 5, which will find versatile use in organic synthesis.
(9) Gargiulo, D.; Blizzard, T. A.; Nakanishi, K. Tetrahedron 1988, 45,
5423.
OL015943V
(10) (a) Baudine, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175. (b) Bellingham, R.; Jarowicki, K.; Kocienski, P.;
Martin, V. Synthesis 1996, 285. (c) Drew, M. G. B.; Harwood; L. M.; Jahans,
A.; Robertson, J.; Swallow, S. Synlett 1999, 2, 185.
(11) (a) Birch, A. J. J. Chem. Soc. 1944, 403. (b) Evans, D. A.; Kaldor,
S. W.; Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc. 1990, 112,
7001.
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