An expeditious, non-iterative, and asymmetric synthesis of 3,5,7,9,11,13,15-heptahydroxypentadecanals

Article abstract of DOI:10.1002/ejoc.200300224

Ozonolysis of (1R,1′R,6R,6′R)-3,3′-methylenebis{6-[(benzyloxy) methoxy]cyclohept-3-en-1-ol} followed by the diastereoselective reduction of the resulting β-hydroxy ketone intermediates gives a rapid route to long-chain polyketides bearing unsymmetrical functions at their terminal positions. These can easily be converted into enantiomerically pure long-chain 1,3-polyol fragments. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300224

FULL PAPER
An Expeditious, Non-Iterative, and Asymmetric Synthesis of 3,5,7,9,11,13,15-
Heptahydroxypentadecanals
Sandrine Gerber-Lemaire*[a] and Pierre Vogel[a]
Keywords: Asymmetric synthesis / Cycloaddition / Ozonolysis / Polyketides / Reduction
Ozonolysis of (1R,1ЈR,6R,6ЈR)-3,3Ј-methylenebis{6-[(benzyl-
oxy)methoxy]cyclohept-3-en-1-ol} followed by the diastereo-
selective reduction of the resulting β-hydroxy ketone inter-
These can easily be converted into enantiomerically pure
long-chain 1,3-polyol fragments.
mediates gives a rapid route to long-chain polyketides bear- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
ing unsymmetrical functions at their terminal positions.
Germany, 2003)
Introduction
A great variety of natural products of biological interest
include polyketide (1,3-polyoxo, 1,3-polyols, aldols) compo-
nents,[1] and several approaches to their synthesis have been
proposed.[2] Inspired by the work of Lautens[3] and
Hoffmann and co-workers,[4] who have converted 8-oxab-
icyclo[3.2.1]oct-6-en-3-one into seven-carbon chain 1,3-po-
lyols and analogues,[5] and by that of Kaku et al.,[6] who
have transformed cyclohept-3-ene-1,6-diol into 1,3-polyols,
we have proposed a new, non-iterative asymmetric synthesis
of long-chain 1,3-polyols starting from the now readily
available 2,2Ј-methylenebis(furan) (1).[7] This method in-
volved a double [3ϩ4] cycloaddition between the 1,1,3-
trichloro-2-oxyallyl cation and 1 (Scheme 1). After re-
ductive workup, a 45:55 mixture of meso-2 and (Ϯ)-threo-
2 was obtained in 55% yield and separated by fractional
crystallization. The meso compound was converted into
meso-3, which was desymmetrized into diol (Ϫ)-4 by Sharp-
less asymmetric dihydroxylation.[8] Further transformations
allow one to prepare, in principle, all possible stereoisomers
of pentadecane-1,3,5,7,9,11,13,15-octol.[9] In the meantime
we have found a method to convert threo-2 into diacetate
Scheme 1. Strategy for polyketide synthesis by Sharpless desymme-
trization
try disclosed here significantly reduces the number of steps
necessary to convert 1 into enantiomerically pure long-
chain polyketides.
(ϩ)-5 (40% yield, 98% ee).[10] We now present an efficient Results and Discussion
route for its conversion into a 3,5,7,9,11,13,15-heptahyd-
Diacetate (ϩ)-5 was treated with BCl3 to give the corre-
roxypentadecanal derivative and into several pentadecane-
1,3,5,7,9,11,13,15-octol derivatives, based on the double
sponding double chloroborate, which was treated with
BnOCH2Cl and (iPr)2NEt in the presence of a catalytic
amount of tetrabutylammonium iodide to provide 6 in 60%
yield (Scheme 2). Dechlorination with Bu3SnH and AIBN
(toluene, 80 °C) afforded (Ϫ)-7 (70%), which was meth-
anolyzed (anhydrous MeOH, K2CO3) to give diol (Ϫ)-8
(97%). Ozonolysis of (Ϫ)-8, followed by reductive treatment
with Me2S and then with NaBH4 (8 equiv.) under Naza-
raka’s conditions,[11] afforded a mixture of hemiacetals (Ϫ)-
9 in 65% yield. Concentrations, a reaction temperature
(Ϫ10 °C), a reaction time (45 min), and workup conditions
ozonolysis
of
(1R,1ЈR,6R,6ЈR)-3,3Ј-methylenebis{6-
[(benzyloxy)methoxy]cyclohept-3-en-1-ol} [(Ϫ)-8]. Con-
ditions for the generation of long-chain polyketides in
which the two ends of the chain bear different functions
(chemical desymmetrization) have been found. The chemis-
[a]
Institute of Molecular and Biological Chemistry, Swiss Institute
of Technology, BCH,
1015 Lausanne, Switzerland
Fax: (internat.) ϩ 41-21/6939355
E-mail: Sandrine.Gerber@epfl.ch
Eur. J. Org. Chem. 2003, 2959Ϫ2963
DOI: 10.1002/ejoc.200300224
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2959

S. Gerber-Lemaire, P. Vogel
FULL PAPER
Scheme 2. New strategy for the expeditious preparation of long-chain polyketides; AIBN: Me2C(CN)NϭNC(CN)Me2, BOM ϭ
PhCH2OCH2, CSA: camphorsulfonic acid, Hünig base: (iPr)2NEt, PPTS: pyridinium p-toluenesulfonate
(AcOH, then NaHCO3) suitable for avoiding the reduction
of the hemiacetal moiety were found, thus providing an ef-
ficient chemical desymmetrization of the long-chain polyke-
tide. Application of a similar reaction sequence to ana-
logues of (Ϫ)-8 in which the BOM protecting groups had
been exchanged for other groups [Ac, benzyl, MOM, 4-Me-
OC6H4CO, (tBu)Me2Si] failed to give reasonable yields of
derivatives of 9 or of the corresponding polyols, so the
BOM groups in (Ϫ)-8 appear to be crucial for the success
of its conversion into 9. The relative configuration of the
Scheme 3. Possible intermediates in the reductions of the diketone
16 resulting from double ozonolysis of (Ϫ)-8
diol at C-7 and C-9, resulting from the reduction of the
corresponding pentadecane-7,9-dione intermediate, was de-
termined by conversion of 9 into hexol (Ϫ)-10, which was
then transformed into the corresponding bis(acetonide)
(Ϫ)-11. Typical 13C NMR signals[12] were observed for the
acetonide at δMe ϭ 30.3, 19.8 ppm (C-5, C-7) and for the
acetonide at δMe ϭ 25.0, 24.9 ppm (C-9, C-11). These re-
sults suggest that one of two hemiacetals is reduced first,
giving the corresponding 11,15-diol 16. The hydroxy group
at C-11 controls the syn-diastereoselective reduction of the
oxo moiety at C-9. The diastereoselective reduction of the
carbonyl group at C-7 is not controlled by the hydroxy
group at C-5 but by the newly generated alcohol group at
was expected that intermediate 16 should be reduced into
18. The hydroxy group at C-9 thus controls the anti-stereo-
selective reduction of the carbonyl moiety at C-7.
Since the enantiomer of (ϩ)-5 is also available and the
two acetoxy groups can be inverted, the chemistry disclosed
here opens an expeditious route to the synthesis of a num-
ber of stereomeric long-chain polyketides containing six
stereogenic centers.
C-9 (Scheme 3). Hydrogenolysis of hexol (Ϫ)-10 [H2, Experimental Section
Pd(OH)2, MeOH] provided the unprotected polyol (Ϫ)-12
General: Commercial reagents (Fluka, Aldrich) were used without
in 75% yield. Treatment of hemiacetal 9 with camphorsul-
fonic acid in anhydrous methanol afforded a 1:1 mixture of
pyranosides (Ϫ)-13.
Ozonolysis of (Ϫ)-8, followed by reductive treatment with
Me2S under Evans conditions [(Me4N)BH(OAc)3],[13] gave
(Ϫ)-14 as the major product in 60% yield. The anti,anti,anti
relative configuration of the tetrol at C-5, C-7, C-9, C-11
was established from the 13C NMR spectrum of the corre-
purification. Solvents were distilled prior to use: THF from Na
and benzophenone, MeOH from Mg and I2, DMF from P2O5, and
CH2Cl2 from CaH2. Light petroleum ether used refers to the frac-
tion boiling at 40Ϫ60 °C. Solutions after reactions and extractions
were concentrated in a rotary evaporator under reduced pressure.
Liquid/solid flash chromatography (FC): columns of silica gel
(0.040Ϫ0.63 mm, Merck No.9385 silica gel 60, 240Ϫ400 mesh).
TLC for reaction monitoring: Merck 60F254 silica gel plates; detec-
sponding bis(acetonide) (Ϫ)-15 (δMe ϭ 25.9, 25.4 ppm). It tion by UV light; Pancaldi reagent [(NH4)6MoO4, Ce(SO4)2,
2960  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2003, 2959Ϫ2963

Asymmetric Synthesis of 3,5,7,9,11,13,15-Heptahydroxypentadecanals
FULL PAPER
H2SO4, H2O] or KMnO4. IR spectra: PerkinϪElmer 1420 spec-
(300 mL, 3 times). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo to afford (Ϫ)-8 as a white solid
trometer. 1H NMR spectra: Bruker ARX 400 spectrometer
(400 MHz); δ(H) in ppm relative to the solvent’s residual 1H signal (3.83 g, 97%). M.p. 95Ϫ97 °C. Rf ϭ 0.38 (CH2Cl2/MeOH, 95:5).
20
20
20
20
20
[CHCl3: δ(H) ϭ 7.27 ppm; CH3OD: δ(H) ϭ 3.31 ppm; C6H6:
[α] ϭ Ϫ46, [α] ϭ Ϫ50, [α] ϭ Ϫ57, [α] ϭ Ϫ102, [α]
ϭ
589
577
546
435
405
δ(H) ϭ 7.3 ppm] as internal reference; all 1H assignments were
Ϫ126 (c ϭ 0.91, CHCl3). IR (KBr): ν˜ ϭ 3365, 3090, 3035, 2920,
confirmed by 2D-COSY-45 and 2D-NOESY spectra. 13C NMR 1655, 1455, 1380, 1265, 1185, 1165, 1090, 1040, 750, 700 cmϪ1. UV
spectra: same instrument as above (100.6 MHz); δ(C) in ppm rela-
tive to solvent’s C-signal [CDCl3: δ(C) ϭ 77.0 ppm; CD3OD: (CDCl3, 400 MHz): δ ϭ 7.39Ϫ7.28 (m, 10 H arom.), 5.23 (t, J ϭ
δ(C) ϭ 49.2 ppm; C6D6: δ(C) ϭ 128.5 ppm] as internal reference; 7.7 Hz, 2 H, H-4, H-4Ј), 4.32 [s, 4 H, 2 ϫ CH2(BOM)], 4.12 (s, 4
(MeCN): λmax (ε) ϭ 208 (11570 dm3·molϪ1·cmϪ1) nm. 1H NMR
3
coupling constants J in Hz. MS: Nermag R-10-10C, chemical ion-
ization (NH3) mode m/z (amu) [% relative base peak (100%)]. El-
emental analyses: Ilse Beetz, 96301 Kronach, Germany.
H, 2 ϫ CH2Ph), 3.37Ϫ3.27 (m, 4 H, H-1, H-1Ј, H-6, H-6Ј), 1.82
3
(s, 2 H, H2-8), 1.44 (dd, J ϭ 7.7, 7.4 Hz, 4 H, H2-5, H2-5Ј), 1.42
(dd, 2J ϭ 14.9, 3J ϭ 4.1 Hz, 2 H, H-2, H-2Ј), 1.37 (d, 2J ϭ 14.9 Hz,
2 H, H-2, H-2Ј), 1.14Ϫ1.00 (m, 4 H, H2-7, H2-7Ј) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ ϭ 137.9 (s, 2 C arom.), 128.5, 127.9, 127.7
(1R,1ЈR,6R,6ЈR)-3,3Ј-Methylenebis{6-[(benzyloxy)methoxy]-
cyclohept-3-en-1-yl} Diacetate [(؊)-7]: A solution of BCl3 in
CH2Cl2 (1 , 109 mL, 0.109 mol) was added dropwise at 0 °C to a
solution of (Ϫ)-5 (12.7 g, 3.647.10Ϫ2 mol) in CH2Cl2 (660 mL).
After the mixture had been stirred at 0 °C for 30 min, a satd. aq.
solution of NaHCO3 (200 mL) was added and the mixture was
stirred at 25 °C for 15 min. The mixture was extracted with CH2Cl2
(300 mL, twice). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. The residue was taken up in
CH2Cl2 (600 mL) and treated with Hünig base (75 mL, 0.438 mol),
BOMCl (40.6 mL, 0.292 mol), and Bu4NI (1 g). The mixture was
stirred at 25 °C for 13 h and then poured into an aq. solution of
HCl (1 , 800 mL). The solution was extracted with CH2Cl2
(800 mL, 3 times). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography on sil-
ica gel (EtOAc/light petroleum ether, 1:5) afforded 6 as a colorless
oil (14.4 g, 60%). Bu3SnH (6 mL, 2.275.10Ϫ2 mol) and AIBN
(250 mg) were added to a solution of 6 (4.3 g, 6.499 mmol) in tolu-
ene (25 mL). The mixture was stirred at 80 °C for 2 h. The solvent
was evaporated, the residue was taken up in MeCN (80 mL), and
the solution was washed with pentane (20 mL, twice) and concen-
trated in vacuo. Flash chromatography on silica gel (EtOAc/light
petroleum ether, 1:3) afforded (Ϫ)-7 as a colorless oil (2.7 g, 70%).
Rf ϭ 0.83 (EtOAc/light petroleum ether, 1:1). [α]25089 ϭ Ϫ60, [α]52707 ϭ
Ϫ60, [α]25046 ϭ Ϫ66, [α]42305 ϭ Ϫ73, [α]24005 ϭ Ϫ92 (c ϭ 0.96, CH2Cl2).
IR (film): ν˜ ϭ 3090, 3065, 3030, 2940, 1740, 1610, 1495, 1455, 1370,
1240, 1165, 1100, 1080, 1045, 975, 735, 700, 645 cmϪ1. UV
(MeCN): λmax (ε) ϭ 217, 205 (10710, 8205 dm3 molϪ1 cmϪ1) nm.
1H NMR (CDCl3, 400 MHz): δ ϭ 7.39Ϫ7.28 (m, 10 H arom.), 5.51
1
1
(3 d, JC,H ϭ 160, 158, 162 Hz, 10 C arom.), 124.0 (d, JC,H ϭ 150
1
Hz, C-4, C-4Ј), 93.0 [t, JC,H ϭ 163 Hz, 2 ϫ CH2(BOM)], 71.3 (d,
1JC,H ϭ 143 Hz, C-6, C-6Ј), 69.5 (t, JC,H ϭ 142 Hz, 2 ϫ CH2Ph),
1
1
1
65.7 (d, JC,H ϭ 145 Hz, C-1, C-1Ј), 51.5 (t, JC,H ϭ 130 Hz, C-8),
45.6 (t, JC,H ϭ 126 Hz, C-7, C-7Ј), 39.5 (t, JC,H ϭ 128 Hz, C-2,
1
1
1
C-2Ј), 33.3 (t, JC,H ϭ 126 Hz, C-5, C-5Ј) ppm. CI-MS: m/z ϭ 526
(100) [M ϩ NH4ϩ], 464 (5), 406 (13), 293 (6), 126 (82), 108 (92),
91 (91) [PhCH2ϩ]. C31H40O6 (508.65): calcd. C 73.20, H 7.93; found
C 72.58, H 7.77.
(3R,5R,7R,9S,11R,13R)-3,13-Bis[(benzyloxy)methoxy]pentadecane-
1,5,7,9,11,15-hexol [(؊)-10]:
A
solution of (Ϫ)-8 (0.35 g,
0.69 mmol) in anhydrous CH2Cl2 (12 mL) was ozonolyzed at Ϫ78
°C for 4 min. A stream of dry O2 was then passed through the
solution for 2 min, and Me2S (0.2 mL, 2.75 mmol) was added drop-
wise. After the mixture had been stirred at Ϫ78 °C for 5 min, the
solvent was evaporated at Ϫ20 °C. The residue was taken up in
THF/MeOH (10:1, 8.8 mL) at Ϫ10 °C and a solution of Et2BOMe
in THF (1 , 4.1 mL, 4.13 mmol) was added dropwise. After the
mixture had been stirred at Ϫ10 °C for 45 min, NaBH4 (0.2 g,
5.5 mmol) was added portionwise and the stirring was continued
for an additional 15 min. AcOH (0.3 mL) was added and the solu-
tion was stirred at 25 °C for 2 min. After addition of a satd. aq.
solution of NaHCO3 (25 mL), the mixture was extracted with
EtOAc (25 mL, 4 times). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography on sil-
ica gel (CH2Cl2/MeOH, 12:1) afforded (Ϫ)-9 (259 mg, 65%) as a
colorless oil. A solution of 9 (100 mg, 0.173 mmol) in MeOH
(4 mL) was treated with NaBH4 (13 mg, 0.346 mmol) and the mix-
ture was stirred at 25 °C for 30 min. After addition of a satd. aq.
solution of NaHCO3 (10 mL), the mixture was extracted with
EtOAc (10 mL, 3 times). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Flash chromatography on sil-
3
(t, J ϭ 6.6 Hz, 2 H, H-4, H-4Ј), 5.00Ϫ5.05 (m, 2 H, H-1, H-1Ј),
4.79 [s, 4 H, 2 ϫ CH2(BOM)], 4.62 (s, 4 H, 2 ϫ CH2Ph), 3.95Ϫ3.89
(m, 2 H, H-6, H-6Ј), 2.68 (s, 2 H, H2-8), 2.35Ϫ2.45 (m, 6 H, H-2,
H-2Ј, H2-5, H2-5Ј), 2.26 (d, 2J ϭ 13.8 Hz, 2 H, H-2, H-2Ј), 2.10
3
(dd, J ϭ 5.8, 5.7 Hz, 4 H, H2-7, H2-7Ј), 2.01 (s, 6 H, 2 ϫ OAc)
ppm. 13C NMR (CDCl3, 100.6 MHz): δ ϭ 170.2 (s, 2 ϫ CϭO),
137.9 (s, 2 C arom.), 136.9 (s, C-3, C-3Ј), 128.4, 127.9, 127.7 (3 d,
ica gel (CH2Cl2/MeOH, 11:1, 1% NEt3) afforded (Ϫ)-10 (100 mg,
20
100%) as a colorless oil. Rf ϭ 0.23 (CH2Cl2/MeOH, 10:1). [α]
ϭ
589
Ϫ22, [α]25077 ϭ Ϫ30, [α]52406 ϭ Ϫ31, [α]42305 ϭ Ϫ31, [α]24005 ϭ Ϫ171 (c ϭ
0.3, MeOH). IR (film): ν˜ ϭ 3385, 3065, 3030, 2940, 1560, 1460,
1380, 1210, 1165, 1035, 825, 740, 700, 670 cmϪ1. UV (MeCN):
λmax (ε) ϭ 209 (7905 dm3·molϪ1·cmϪ1) nm. 1H NMR ([D4]MeOH,
400 MHz): δ ϭ 7.42Ϫ7.31 (m, 10 H arom.), 4.88 [s, 4 H, 2 ϫ
CH2(BOM)], 4.69 (s, 4 H, 2 ϫ CH2Ph), 4.06Ϫ4.00 (m, 6 H, H-3,
1
1JC,H ϭ 160, 159, 161 Hz, 10 C arom.), 124.0 (d, JC,H ϭ 161 Hz,
1
1
C-4, C-4Ј), 92.8 [t, JC,H ϭ 163 Hz, CH2(BOM)], 70.8 (d, JC,H
ϭ
1
142 Hz, C-1, C-1Ј), 69.5 (t, JC,H ϭ 142 Hz, CH2Ph), 68.8 (d,
1JC,H ϭ 145 Hz, C-6, C-6Ј), 50.8 (t, JC,H ϭ 127 Hz, C-8), 42.2 (t,
1
1JC,H ϭ 126 Hz, C-7, C-7Ј), 35.7 (t, JC,H ϭ 129 Hz, C-2, C-2Ј),
1
1
1
33.2 (t, JC,H ϭ 128 Hz, C-5, C-5Ј), 21.4 (q, JC,H ϭ 129 Hz, 2 ϫ
OAc) ppm. CI-MS: m/z ϭ 610 (6) [M ϩ NH4ϩ], 273 (1), 213 (4),
133 (7), 91 (100) [PhCH2ϩ]. C35H44O8 (592.73): calcd. C 70.92, H
7.48; found C 70.90, H 7.39.
3
H-5, H-7, H-9, H-11, H-13), 3.71 (t, J ϭ 6.5 Hz, 4 H, H2-1, H2-
15), 1.88Ϫ1.82 (m, 4 H, H2-2, H2-14), 1.72Ϫ1.54 (m, 10 H, H2-4,
H2-6, H2-8, H2-10, H2-12) ppm. 13C NMR ([D4]MeOH,
100.6 MHz): δ ϭ 141.8 (s, 2 C arom.), 132.0, 131.6, 131.3 (3 d,
1
(1R,1ЈR,6R,6ЈR)-3,3Ј-Methylenebis{6-[(benzyloxy)methoxy]-
cyclohept-3-en-1-ol} [(؊)-8]: K2CO3 (1.1 g, 7.761 mmol) was added
to a solution of (Ϫ)-7 (4.6 g, 7.761 mmol) in MeOH (210 mL) and 73.4 (t, JC,H ϭ 142 Hz, 2 ϫ CH2Ph), 72.8, 70.7, 70.4, 68.4 (4 d,
1JC,H ϭ 160, 161, 159 Hz, 10 C arom.), 98.1 [t, JC,H ϭ 158 Hz, 2
1
ϫ CH2(BOM)], 77.0, 76.8 (2 d, JC,H ϭ 139, 140 Hz, C-3, C-13),
1
the mixture was vigorously stirred at 25 °C for 4 h. The solution
1JC,H ϭ 141, 139, 142, 138 Hz, C-5, C-7, C-9, C-11), 62.0 (t,
was poured into water (300 mL) and extracted with CHCl3 1JC,H ϭ 141 Hz, C-1, C-15), 48.9, 48.5, 47.2, 46.8 (4 t, 1JC,H ϭ 127,
Eur. J. Org. Chem. 2003, 2959Ϫ2963
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2961

S. Gerber-Lemaire, P. Vogel
FULL PAPER
1
126, 125, 128 Hz, C-4, C-6, C-8, C-10, C-12), 41.9 (t, JC,H ϭ 127 (3R,5S,7S,9R,11S,13R)-Pentadecan-1,3,5,7,9,11,13,15-octol [(؊)-
Hz, C-2, C-14) ppm. MS (ES): m/z ϭ 581 (100) [M ϩ Hϩ].
12]: A solution of (Ϫ)-10 (80 mg, 0.138 mmol) in MeOH (8 mL)
C31H48O10 (580.71): calcd. C 64.12, H 8.33; found C 64.26, H 8.29. was stirred at 25 °C, under 1 atm of H2, in the presence of Pd(OH)2/
C (50 mg) for 19 h. The mixture was filtered through a pad of Celite
(eluent: MeOH, 50 mL) and concentrated in vacuo. Purification by
(3R,5R,7S,9S)-3-[(Benzyloxy)methoxy]-10-{(2R,4S)-4-[(benzyloxy)-
methoxy]-6-methoxy-tetrahydro-2H-pyran-2-yl}decane-1,5,7,9-tetrol
[(؊)-13]: A solution of (Ϫ)-9 (85 mg, 0.147 mmol) and camphorsul-
fonic acid (5 mg) in MeOH (4 mL) was stirred at 25 °C for 45 min.
The mixture was neutralized with solid NaHCO3, filtered, and con-
centrated in vacuo. Purification by flash chromatography (CH2Cl2/
flash chromatography (MeCN/NH4OH, 4:1) afforded a white foam
20
(35 mg, 75%). Rf ϭ 0.19 (MeCN/NH4OH, 4:1). [α] ϭ Ϫ30 (c ϭ
589
0.4, H2O). IR (film): ν˜ ϭ 3200, 2940, 1415, 1135, 1080, 940, 895,
820, 800 cmϪ1. UV (MeCN): λmax (ε) ϭ 209 (5100 dm3 molϪ1
cmϪ1) nm. 1H NMR (D2O, 400 MHz): δ ϭ 3.98Ϫ3.89 (m, 6 H, H-
3, H-5, H-7, H-9, H-11, H-13), 3.65 (t, 3J ϭ 6.6 Hz, 4 H, H2-1, H2-
15), 1.69Ϫ1.51 (m, 14 H, H2-2, H2-4, H2-6, H2-8, H2-10, H2-12,
H2-14) ppm. 13C NMR (D2O, 100.6 MHz): δ ϭ 70.2, 68.7, 68.6,
67.8, 67.6, 67.1 (6 d, C-3, C-5, C-7, C-9, C-11, C-13), 61.1 (t, C-1,
C-15), 47.0, 46.8, 46.5, 46.1, 46.0 (5 t, C-4, C-6, C-8, C-10, C-12),
41.7, 41.6 (2 t, C-2, C-14) ppm. CI-MS: 341 (2, [M ϩ Hϩ]), 309
(2), 211 (8), 141 (56), 127 (100), 111 (63) ppm.
MeOH, 96:4) afforded (Ϫ)-13 (68 mg, 79%, 1:1 mixture of isomers)
20
as a colorless oil. Rf ϭ 0.29 (CH2Cl2/MeOH, 96:4). [α] ϭ Ϫ36
589
(c ϭ 0.18, MeOH). IR (film): ν˜ ϭ 3470, 3065, 3030, 2935, 1605,
1495, 1455, 1385, 1200, 1115, 1025, 965 cmϪ1. UV (MeCN): λmax
(ε) ϭ 208 (4830 dm3·molϪ1·cmϪ1) nm. 1H NMR ([D4]MeOH,
400 MHz): δ ϭ 7.37Ϫ7.29 (m, 10 H arom.), 4.83 [m, 4 H, 2 ϫ
CH2(BOM)], 4.63, 4.62 (2 s, 4 H, 2 ϫ CH2Ph), 4.37 (m, 1 H, H-
3
6Ј), 4.11 (dddd, J ϭ 7.2, 7.1, 3.4, 2.9 Hz, 1 H, H-4Ј), 4.08Ϫ4.01
(m, 4 H, H-3, H-5, H-7, H-9), 3.99 (m, 2 H, H2-1), 3.86 (m, 1 H, (3R,5S,7R,3ЈR,5ЈS,7ЈR)-7,7Ј-Methylenebis{3-[(benzyloxy)methoxy]-
H-2Ј), 3.37, 3.35 (2 s, 3 H, OMe-C-6Ј), 2.21Ϫ1.95 (m, 4 H, H2-2, heptane-1,5,7-triol} [(؊)-14]: solution of (Ϫ)-8 (0.12 g,
A
H2-3), 1.72Ϫ1.51, 1.48Ϫ1.22 (2 m, 10 H, H2-4, H2-6, H2-8, H2-10, 0.236 mmol) in anhydrous CH2Cl2 (6 mL) was ozonolyzed at Ϫ78
H2-5Ј) ppm. 13C NMR ([D4]MeOH, 100.6 MHz): δ ϭ 140.2 (s, C
arom.), 130.3, 129.8, 129.5 (3 d, 10 C arom.), 101.4, 101.1 (2 d, C-
°C for 2 min. A stream of dry O2 was then passed through the
solution for 2 min, and Me2S (69 µL, 0.944 mmol) was added drop-
6Ј), 94.8, 94.7 [2 t, 2 ϫ CH2(BOM)], 74.2, 74.1 (2 d, C-2Ј), 71.7, wise. After the mixture had been stirred at Ϫ78 °C for 5 min, the
71.5, 71.4 (3 d, C-3, C-4Ј), 71.3 (t, 2 ϫ CH2Ph), 69.7, 69.6, 68.6, solvent was evaporated at Ϫ20 °C. The residue was taken up in
68.5, 67.9, 67.8 (3 d, C-5, C-7, C-9), 66.2 (t, C-1), 56.0, 55.9 (2 q,
OMe-C-6Ј), 46.9, 46.7, 46.5, 45.7, 45.6, 45.3, 45.0 (7 t, C-4, C-6, 4.248 mmol) was added portionwise. After the mixture had been
C-8, C-10, C-5Ј), 40.6, 40.4 (2 t, C-3Ј), 38.9 (t, C-2) ppm. MS (ES): stirred at 0 °C for 40 min, the solvents were evaporated. The residue
593 (100) [M ϩ Hϩ]. C32H48O10 (592.721): calcd. C 64.84, H 8.16; was taken up in EtOAc (10 mL) and poured onto ice (15 mL). The
MeCN/AcOH (3:1, 4 mL) at 0 °C, and (Me4N)BH(OAc)3 (1.1 g,
found C 64.90, H 8.19.
mixture was neutralized with solid NaHCO3 and extracted with
EtOAc (15 mL, 3 times). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. The crude hemiacetal was
treated with NaBH4 (54 mg, 1.416 mmol) in MeOH (4 mL) at 25
°C for 15 min. AcOH was added (150 µL), and after stirring at 25
°C for 2 min, the solution was poured into a satd. aq. solution of
NaHCO3 (15 mL). The mixture was extracted with EtOAc (15 mL,
3 times). The combined organic extracts were dried (MgSO4) and
concentrated in vacuo. Flash chromatography on silica gel
(3R)-3-[(Benzyloxy)methoxy]-4-{(4S,6S)-6-[{(4R,6S)-6-{(2R)-2-
[(benzyloxy)methoxy]-4-hydroxybutyl}-2,2-dimethyl-1,3-dioxan-4-
yl}methyl]-2,2-dimethyl-1,3-dioxan-4-yl}butan-1-ol [(؊)-11]: A solu-
tion of (Ϫ)-10 (30 mg, 5.166.10Ϫ5 mol) in 2,2-dimethoxypropane/
acetone (2 mL/0.2 mL) was stirred in the presence of pTsOH (4 mg)
for 15 min at 0 °C. The mixture was neutralized with solid
NaHCO3 and filtered, and the solvents were evaporated in vacuo.
The residual oil was taken up in CH2Cl2 (2 mL) with pyridinium
p-toluenesulfonate (2 mg) and stirred at 25 °C. After 1 h, the solu-
tion was neutralized with solid NaHCO3, filtered, and concentrated
in vacuo. Purification by flash chromatography (CH2Cl2/MeOH,
97:3) afforded (Ϫ)-11 (27 mg, 80%) as a colorless oil. Rf ϭ 0.1
(CH2Cl2/MeOH, 11:1, 1% NEt3) afforded (Ϫ)-14 (82 mg, 60%) as
20
a colorless oil. Rf ϭ 0.19 (CH2Cl2/MeOH, 10:1). [α] ϭ Ϫ3 (c ϭ
589
0.9, MeOH). IR (film): ν˜ ϭ 3390, 3055, 2940, 1605, 1550, 1425,
1380, 1265, 1205, 1160, 1025, 780, 710 cmϪ1. UV (MeCN): λmax
(ε) ϭ 209 (9080 dm3·molϪ1·cmϪ1) nm. 1H NMR ([D4]MeOH,
400 MHz): δ ϭ 7.41Ϫ7.29 (m, 10 H arom.), 4.87 [s, 4 H, 2 ϫ
CH2(BOM)], 4.68 (s, 4 H, 2 ϫ CH2Ph), 4.08Ϫ4.03 (m, 6 H, H-3,
20
20
20
(CH2Cl2/MeOH, 95:5). [α] ϭ Ϫ3, [α] ϭ Ϫ20, [α] ϭ Ϫ170,
589
577
435
20
[α] ϭ Ϫ298 (c ϭ 0.3, MeOH). IR (film): ν˜ ϭ 3405, 2945, 2870,
405
3
1495, 1455, 1430, 1405, 1380, 1250, 1205, 1165, 1100, 1035, 740,
H-5, H-7, H-3Ј, H-5Ј, H-7Ј), 3.70 (t, J ϭ 6.7 Hz, 4 H, H2-1, H2-
700 cmϪ1. UV (MeCN): λmax (ε) ϭ 210 (6420 dm3·molϪ1·cmϪ1
)
1Ј), 1.89Ϫ1.82 (m, 4 H, H2-2, H2-2Ј), 1.80Ϫ1.54 (m, 10 H, H2-4,
H2-6, H2-8, H2-4Ј, H2-6Ј) ppm. 13C NMR ([D4]MeOH,
100.6 MHz): δ ϭ 140.1 (s, 2 C arom.), 130.3, 129.9, 129.6 (3 d,
1
nm. H NMR (C6D6, 400 MHz): δ ϭ 7.34Ϫ7.31, 7.19Ϫ7.06 (2 m,
2
10 H arom.), 4.74 [m, 4 H, 2 ϫ CH2(BOM)], 4.62, 4.49 (2 d, J ϭ
12.6 Hz, 2 H, CH2Ph), 4.61, 4.52 (2 d, 2J ϭ 11.9 Hz, 2 H, CH2Ph),
4.15 (m, 2 H, H-3, H-2IV), 4.10Ϫ3.75 (m, 4 H, H-4Ј, H-6Ј, H-4ЈЈЈ,
H-6ЈЈЈ), 3.71, 3.61 (2 dm, 2J ϭ 12.2 Hz, 4 H, H2-1, H2-4IV),
2.02Ϫ1.81 (m, 4 H, H2-2, H2-3IV), 1.72, 1.35 (m, 10 H, H2-4, H2-
5Ј, H2-1ЈЈ, H2-5ЈЈЈ, H2-1IV), 1.50, 1.46, 1.30, 1.24 (4 s, 12 H, 2 ϫ
Me-C-2Ј, 2 ϫ Me-C-2ЈЈЈ) ppm. 13C NMR (C6D6, 100.6 MHz): δ ϭ
140.1 (s, 2 C arom.), 129.3, 129.1, 128.6 (3 d, 10 C arom.), 100.1,
98.4 (2 s, C-2Ј, C-2ЈЈЈ), 94.7, 94.6 [2 t, 2 ϫ CH2(BOM)], 74.4, 73.4
(2 d, C-3, C-2IV), 69.6 (t, 2 ϫ CH2Ph), 65.8, 65.5, 64.8, 63.5 (4 d,
1
1JC,H ϭ 160, 158, 161 Hz, 10 C arom.), 96.4 [t, JC,H ϭ 163 Hz, 2
ϫ CH2(BOM)], 75.1 (d, 1JC,H ϭ 143 Hz, C-3, C-3Ј), 71.7 (t, 1JC,H ϭ
1
143 Hz, 2 ϫ CH2Ph), 68.9, 68.8 (2 d, JC,H ϭ 142, 141 Hz, C-5,
1
C-7, C-5Ј, C-7Ј), 60.4 (t, JC,H ϭ 141 Hz, C-1, C-1Ј), 47.4 (t,
1
1JC,H ϭ 125 Hz, C-4, C-4Ј), 46.5 (t, JC,H ϭ 126 Hz, C-8), 45.1 (t,
1
1JC,H ϭ 125 Hz, C-6, C-6Ј), 40.2 (t, JC,H ϭ 126 Hz, C-2, C-2Ј)
ppm. MS (ES): m/z ϭ 581 (100) [M ϩ Hϩ]. C31H48O10 (580.71):
calcd. C 64.12, H 8.33; found C 64.02, H 8.25.
C-4Ј, C-6Ј, C-4ЈЈЈ, C-6ЈЈЈ), 59.1 (t, C-1, C-4IV), 43.4, 42.9 (2 t, C- (3R)-3-[(Benzyloxy)methoxy]-4-{(4S,6R)-6-[{(4R,6S)-6-{(2R)-2-
5Ј, C-5ЈЈЈ), 42.8 (t, C-1ЈЈ), 42.7, 42.3 (2 t, C-4, C-1IV), 38.3, 38.2 (2 [(benzyloxy)methoxy]-4-hydroxybutyl}-2,2-dimethyl-1,3-dioxan-4-
t, C-2, C-2IV), 30.3, 19.8 (2 q, 2 ϫ Me-C-2Ј), 25.0, 24.9 (2 q, 2 ϫ
Me-C-2ЈЈЈ) ppm. CI-MS: 678 (10) [M ϩ NH4ϩ], 645 (21), 495 (10),
yl}methyl]-2,2-dimethyl-1,3-dioxan-4-yl}butan-1-ol [(؊)-15]: A solu-
tion of (Ϫ)-14 (30 mg, 5.166 ϫ 10Ϫ5 mol) in 2,2-dimethoxypropane/
437 (30), 387 (5), 329 (10), 91 (100) [PhCH2ϩ]. C37H56O10 (660.84): acetone (2 mL/0.2 mL) was stirred in the presence of pTsOH (3 mg)
calcd. C 67.25, H 8.54; found C 67.23, H 8.79.
at 0 °C for 1 h. The mixture was poured into a satd. aq. solution
2962
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2959Ϫ2963

Asymmetric Synthesis of 3,5,7,9,11,13,15-Heptahydroxypentadecanals
FULL PAPER
D. Rychnovsky, O. Fryzman, U. R. Khine, Tetrahedron Lett.
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A.
20
Rf ϭ 0.29 (EtOAc/light petroleum, 3:1). [α]
ϭ Ϫ56 (c ϭ 0.35,
[2i]
589
B. Smith III, S. M. Pitram, Org. Lett. 1999, 1, 2001Ϫ2004.
CH2Cl2). IR (film): ν˜ ϭ 3445, 3065, 3030, 2990, 2940, 1495, 1455,
1380, 1225, 1165, 1025, 940, 740, 700 cmϪ1. UV (MeCN): λmax
(ε) ϭ 206 (9890 dm3·molϪ1·cmϪ1) nm. 1H NMR (C6D6, 400 MHz):
δ ϭ 7.36Ϫ7.31 (m, 10 H arom.), 4.82 [m, 4 H, 2 ϫ CH2(BOM)],
4.73, 4.59 (2 d, 2J ϭ 11.9 Hz, 2 ϫ CH2Ph), 4.07Ϫ4.04 (m, 2 H, H-
3, H-2IV), 3.99Ϫ3.96 (m, 4 H, H-4Ј, H-6Ј, H-4ЈЈЈ, H-6ЈЈЈ), 3.84 (dm,
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A. G. M. Barrett, D. C. Braddock, P. D. de-
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2
2J ϭ 11.2 Hz, 2 H, H-1, H-4IV), 3.75 (dm, J ϭ 11.2, 2 H, H-1, H-
[2n]
375Ϫ380.
403Ϫ405.
S. T. Sarraf; J. L. Leighton, Org. Lett. 2000, 2,
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m, 10 H, H2-4, H2-5Ј, H2-1ЈЈ, H2-5ЈЈЈ, H2-1IV), 1.38, 1.37, 1.36, 1.34
(4 s, 12 H, 2 ϫ Me-C-2Ј, 2 ϫ Me-C-2ЈЈЈ) ppm. 13C NMR (C6D6,
100.6 MHz): δ ϭ 137.4 (s, 2 C arom.), 128.5, 127.9, 127.8 (3 d,
1JC,H ϭ 160, 161, 159 Hz, 10 C arom.), 100.1 (s, C-2Ј, C-2ЈЈЈ), 95.04
[2o]
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1
1
[2s]
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I. Pater-
[2t]
3, C-2IV), 70.0 (t, JC,H ϭ 141 Hz, 2 ϫ CH2Ph), 65.4, 65.2 (2 d,
1
son, L. A. Collett, Tetrahedron Lett. 2001, 42, 1187Ϫ1191.
1JC,H ϭ 140, 142 Hz, C-4Ј, C-6Ј, C-4ЈЈЈ, C-6ЈЈЈ), 59.4 (t, JC,H
ϭ
1
T. J. Hunter, G. A. OЈDoherty, Org. Lett. 2001, 3, 1049Ϫ1052.
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ϭ
1
1
[2v]
40, 3224Ϫ3227.
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[2w]
S. A. Burova, F. E.
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437 (10), 387 (5), 329 (7), 91 (100) [PhCH2ϩ]. C37H56O10 (660.84):
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Received April 10, 2003
Eur. J. Org. Chem. 2003, 2959Ϫ2963
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2963