Enantioselective synthesis of the alcohol moiety of dolabriferol

Article abstract of DOI:10.1021/jo701524p

(Chemical Equation Presented) Dolabriferol is a marine polypropionate characterized by an unusual noncontiguous carbon backbone. The two polypropionate subunits are linked by an ester function. The protected alcohol moiety of dolabriferol was synthesized

Full text of DOI:10.1021/jo701524p

Enantioselective Synthesis of the Alcohol Moiety of Dolabriferol
Nicholas Pelchat, Dave Caron, and Robert Cheˆnevert*
De´partement de chimie, CREFSIP, Faculte´ des sciences et de ge´nie, UniVersite´ LaVal,
Que´bec (Qc), Canada, G1K 7P4
robert.cheneVert@chm.ulaVal.ca
ReceiVed July 12, 2007
Dolabriferol is a marine polypropionate characterized by an unusual noncontiguous carbon backbone.
The two polypropionate subunits are linked by an ester function. The protected alcohol moiety of
dolabriferol was synthesized via the enzymatic desymmetrization of meso-(anti-anti)-2,4-dimethyl-1,3,5-
pentanetriol.
SCHEME 1. Retrosynthetic Analysis of Dolabriferol (1)
Introduction
In 1996, Gavagnin and co-workers1 reported the isolation of
dolabriferol 1 (Scheme 1) from the anaspidean mollusk Dola-
brifera dolabrifera. The structure was elucidated by spectral
methods, and the relative configuration was unambiguously
established by single-crystal X-ray analysis. The absolute
stereochemistry was not assigned, and because of its limited
availability, its biological activity has not been explored.
Dolabriferol is a member of a large class of secondary
metabolites sharing a polyketide/polypropionate biosynthesis.2
These natural products are known to possess a wealth of
biological and pharmacological activities, including antibiotic,
antifungal, anticancer, anti-inflammatory, and immunosuppres-
sant properties.3 The structure of dolabriferol is characterized
by an unusual noncontiguous carbon backbone. The two
polypropionate subunits are linked by an ester function. This
structural motif is also found in a few other natural products
such as baconipyrones A-D4 and siserrone A5. They constitute
an exception to the normal polypropionic contiguous carbon
skeleton expected from polyketide biosynthesis and they have
been hypothesized to arise from retro-aldol rearrangements of
normal contiguous polypropionates.5,6
Although three approaches have been disclosed,7-9 the total
synthesis of dolabriferol has not yet been reported. Most notable
among the efforts is the synthesis reported by Lister and Perkins9
of a protected precursor to dolabriferol via the proposed retro-
Claisen rearrangement.
We have already described the enantioselective synthesis of
the acid moiety of dolabriferol8 and herein we report the
chemoenzymatic enantioselective synthesis of the more complex
alcohol moiety of dolabriferol.
(1) Ciavatta, M. L.; Gavagnin, M.; Puliti, R.; Cimino, G.; Martinez, E.;
Ortea, J.; Mattia, C. A. Tetrahedron 1996, 52, 12831-12838.
(2) (a) Davies-Coleman, M. T.; Garson, M. J. Nat. Prod. Rep. 1998, 15,
477-493. (b) Katz, L. Chem. ReV. 1997, 97, 2557-2575.
(3) (a) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380-
416. (b) Rohr, J. Angew. Chem., Int. Ed. 2000, 39, 2847-2849.
(4) Manker, D. C.; Faulkner, D. J.; Stout, T. J.; Clardy, J. J. Org. Chem.
1989, 54, 5371-5374.
(7) Dias, L. C.; de Sousa, M. A. Tetrahedron Lett. 2003, 44, 5625-
5628.
(8) Cheˆnevert, R.; Courchesne, G.; Caron, D. Tetrahedron: Asymmetry
2003, 14, 2567-2571.
(9) Lister, T.; Perkins, M. V. Org. Lett. 2006, 8, 1827-1830.
(5) Brecknell, D. J.; Collett, L. A.; Davies-Coleman, M. T.; Garson, M.
J.; Jones, D. D. Tetrahedron 2000, 56, 2497-2502.
(6) Socorro, I. M.; Taylor, K.; Goodman, J. M. Org. Lett. 2005, 7, 3541-
3544.
10.1021/jo701524p CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/02/2007
8484
J. Org. Chem. 2007, 72, 8484-8488

EnantioselectiVe Synthesis of Dolabriferol
SCHEME 2. Preparation of Compounds 10 and 12
Results and Discussion
SCHEME 3. Stereochemical Model for 1,2- and
1,3-Asymmetric Inductiona
A retrosynthetic analysis of dolabriferol is outlined in Scheme
1. Bond disconnection of the ester linkage and ring opening of
the cyclic hemiacetal 3 generate two closely related fragments
2 and 3′ that, in turn, can be converted retrosynthetically to the
common precursors 4 and 5. This approach exploits the
structural symmetry of the polypropionate anti-anti stereotriad
D.10
The stereoselective acylation of meso-3-(tert-butyldimethyl-
siloxy)-2,4-dimethyl-1,5-pentanetriol 511 by vinyl acetate in the
presence of Candida rugosa lipase in hexane provided mo-
noester (2R,3R,4S)-4 in high yield (94%) on several gram
scale8,12 (Scheme 2). Desilylation of 4 with tetrabutylammonium
fluoride (TBAF) buffered with acetic acid afforded 6 in high
yield. Protection of 6 as a p-methoxybenzylidene acetal followed
by cleavage of the acetate group in KOH-MeOH gave alcohol
7. Conversion to aldehyde 8 was achieved using the Dess-Martin
periodinane reagent, which was subsequently alkylated with
isopropylmagnesium bromide. Protection of the secondary
hydroxyl of 9 as a TBS ether followed by a regioselective
reduction of the p-methoxybenzylidene acetal provided 10. The
stereochemistry of the Grignard isopropenylation reaction was
determined by conversion of 10 into tetrahydropyran 12 via
mesylation to give 11, desilylation, and ring closure. The
illustrated NOESY interactions between Ha, Hd, and He,
together with the small vicinal coupling constants between Ha-
Hc (axial-equatorial, 2.8 Hz) and Hb-Hc (equatorial-equato-
rial, 1.0 Hz), establish the configuration of the C-3 stereocenter
of 9 as (R)-(1,2 syn, 1,3 anti).
a LA, Lewis acid; Nu, nucleophile; PG, protecting group.
carbonyl function. The configuration of 9 may be rationalized
in terms of the stereochemical model for merged 1,2- and 1,3-
asymmetric induction proposed by Evans et al.13 (Scheme 3).
The stereochemistry at the C-3 center is epimeric to the natural
product fragment and, as a consequence, an inversion of
configuration is necessary. Ketone 13 was prepared in nearly
quantitative yield by oxidation of alcohol 9 with the Dess-Martin
periodinane (Scheme 4). Reduction with LiAlH4 proceeded with
the desired stereoselectivity to (3S)-14 (dr ) 10/1). This
inversion of configuration was inspired by a similar reaction
sequence reported by Lautens and Stammers.14 Here again, the
outcome of the reaction is in accordance with the model depicted
in Scheme 3 where the aldehydic hydrogen is replaced by an
isopropyl and the nucleophile is a hydride, thus leading to overall
inversion of configuration. The transformations of 14 followed
a route similar to that of its diastereomer 9. Silylation of 14
with TBSOTf followed by DIBALH-induced acetal opening
provided 15.
We initially surmised that the configuration was (S), arising
from an addition of the nucleophile on the Si face of the chelated
Conversion of 15 into the protected alcohol moiety of
dolabriferol 18 was readily accomplished in four steps (Scheme
4). Oxidation of alcohol 15 by the Dess-Martin periodinane,
followed by Grignard addition of ethylmagnesium bromide to
(10) (a) Koskinen, A. M. P.; Karisalmi, K.; Chem. Soc. ReV. 2005, 34,
677-690. (b) Hoffmann, R. W. Angew. Chem., Int. Ed. 2003, 42, 1096-
1109. (c) Hoffman, R. W.; Dahmann, G.; Andersen, M. W. Synthesis 1994,
629-638.
(11) Harada, T.; Inoue, A.; Wada, I.; Uchimura, J.; Tanaka, S.; Oku, A.
J. Am. Chem. Soc. 1993, 115, 7665-7674.
(12) Cheˆnevert, R.; Courchesne, G. Tetrahedron: Asymmetry 1995, 6,
2093-2096.
(13) (a) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am.
Chem. Soc. 1996, 118, 4322-4343. (b) Reetz, M. T.; Kesseler, K.; Jung,
A. Tetrahedron Lett. 1984, 25, 729-732.
(14) Lautens, M.; Stammers, T. A. Synthesis 2002, 14, 1993-2012.
J. Org. Chem, Vol. 72, No. 22, 2007 8485

Pelchat et al.
SCHEME 4. Preparation of the Alcohol Moiety of Dolabriferol (3)
h at rt before the reaction was quenched by the addition of KOH
(165 mg, 2.94 mmol). After 10 min at rt, methanol (17 mL) was
added and the solution was stirred for 3.5 h. The volatiles were
evaporated and the residue was dissolved in ether (50 mL) and
washed twice with saturated aqueous NaHCO3. The organic phase
was dried (MgSO4) and evaporated. The crude product was purified
by flash chromatography (gradient, 5% steps, ethyl acetate/hexanes,
15:85 to 60:40) to give 7 (72.0 mg, 92% for two steps) as a white
solid. mp: 96-97 °C; [R]D22 -22.7 (c 1.24, C6H6); IR (KBr) 3420,
3045, 2968, 1174, 1118, 1065 cm-1; 1H NMR (400 MHz, C6D6) δ
0.32 (d, J ) 3.4 Hz, 3H), 1.16 (d, J ) 7.2 Hz, 3H), 1.68 (m, 1H),
1.98 (m, 1H), 2.08 (s, 1H), 3.10 (dd, J ) 11.2 and 11.0 Hz, 1H),
3.13 (dd, J ) 2.2 and 10.2 Hz, 1H), 3.25 (s, 3H), 3.60 (dd, J ) 4.8
and 11.2 Hz, 1H), 3.76 (dd, J ) 4.0 and 11.2 Hz, 1H), 3.88 (dd, J
) 4.8 and 11.2 Hz, 1H), 5.25 (s, 1H), 6.77 (d, J ) 8.6 Hz, 2H),
7.55 (d, J ) 8.6 Hz, 2H); 13C NMR (100 MHz, C6D6) δ 11.9, 15.3,
31.4, 35.8, 54.6, 63.5, 72.9, 87.5, 101.7, 113.7, 127.5, 131.7, 160.2;
HRMS (EI, 70 eV) m/z calcd for C15H22O4 (M+) 266.1518, found
266.1512.
the resulting aldehyde 16, furnished a diastereomeric mixture
of alcohols, which were oxidized to ketone 17. Compound 18
was obtained by oxidative cleavage of the p-methoxybenzyl
ether with DDQ. Last, the silyl protecting group was cleaved
to produce hemiacetal 3. The spectroscopic data of 3 were in
good agreement with those reported by Dias and de Sousa,7
who have prepared the opposite enantiomer via an independent
route.
Conclusion
In conclusion, the enantioselective synthesis of the alcohol
moiety of dolabriferol has been achieved in 14 steps with an
18% overall yield. Both the alcohol and acid subunits of
dolabriferol have been prepared from the same chiral starting
material 4 obtained by enzymatic desymmetrization.15
Experimental Section
(R)-2-((2R,4R,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-
4-yl)propanal (8). To a solution of alcohol 7 (142.2 mg, 0.522
mmol) and pyridine (338 µL, 4.18 mmol) in anhydrous CH2Cl2
(4.5 mL) was added Dess-Martin periodinane (244 mg, 0.575
mmol). The solution was stirred for 3 h at rt before the addition of
a saturated NaHCO3 aqueous solution containing 25% of sodium
thiosulfate and stirred for an additional 15 min. The reaction mixture
was diluted with ether (50 mL) and washed with saturated aqueous
NaHCO3 (2 × 50 mL). The organic phase was dried (MgSO4) and
evaporated. The crude product was purified by flash chromatog-
raphy (ethyl acetate/hexanes, 1:4) to give aldehyde 8 (127.0 mg,
(2S,3R,4R)-3,5-Dihydroxy-2,4-dimethylpentyl Acetate (6). To
a solution of monoacetate 4 (101.4 mg, 0.333 mmol) in anhydrous
THF (5 mL) was added glacial acetic acid (63 µL, 1.1 mmol) and
the solution was stirred for 5 min at room temperature. Then,
tetrabutylammonium fluoride (480 mg, 1.83 mmol) was added and
the mixture was stirred at rt for 12 h. The volatiles were evaporated
and the crude product was purified by flash chromatography (ethyl
acetate/hexanes, 3:7) to give diol 6 (63.0 mg, 99%) as a colorless
22
22
oil. [R]D -26.5 (c 1.24, C6H6); [R]D -21.14 (c 1.99, CH2Cl2);
22
lit.16 [R]D 26 (c 4, CH2Cl2) for the complementary enantiomer;
1
IR (neat) 3413, 2967, 1739, 1245, 1113, 1068, cm-1; H NMR
22
90%) as a colorless oil. [R]D -26.74 (c 0.93, C6H6); IR (neat)
(400 MHz, C6D6) δ 0.78 (d, J ) 6.8 Hz, 3H), 0.89 (d, J ) 6.8 Hz,
3H), 1.61 (m, 1H), 1.65 (s, 3H), 1.86 (m, 1H), 3.18 (dd, J ) 5.6
and 6.4 Hz, 1H), 3.30 (dd, J ) 6.6 and 10.7 Hz, 1H), 3.51 (dd, J
) 3.6 and 10.7 Hz, 1H), 4.17 (dd, J ) 6.6 and 11.0 Hz, 2H), 4.27
(dd, J ) 4.6 and 11.0 Hz, 1H); 13C NMR (100 MHz, C6D6) δ 14.2,
14.9, 20.4, 35.9, 36.8, 66.1, 66.8, 78.9, 170.9; HRMS (CI, NH3)
m/z calcd for C9H19O4 (MH+) 191.1283, found 191.1280.
(S)-2-((2R,4S,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-
4-yl)propan-1-ol (7). To a solution of diol 6 (56 mg, 0.294 mmol)
and p-methoxybenzaldehyde dimethyl acetal (254 µL, 1.47 mmol)
in anhydrous CH2Cl2 (17 mL) was added p-toluenesulfonic acid
monohydrate (5.6 mg, 0.029 mmol). The solution was stirred for 4
1
3068, 2964, 1724, 1372, 1171, 1087, cm-1; H NMR (400 MHz,
C6D6) δ 0.29 (d, J ) 6.8 Hz, 3H), 1.06 (d, J ) 7.2 Hz, 3H), 1.87
(m, 1H), 2.26 (qdd, J ) 7.2, 2.4 and 2.4 Hz, 1H), 3.04 (dd, J )
11.2 and 11.2 Hz, 1H), 3.19 (dd, J ) 2.4 and 10.4 Hz, 1H), 3.27
(s, 3H), 3.80 (dd, J ) 4.8 and 11.2 Hz, 1H), 5.23 (s, 1H), 6.81 (d,
J ) 8.6 Hz, 2H), 7.52 (d, J ) 8.6 Hz, 2H), 9.65 (d, J ) 2.4 Hz,
1H); 13C NMR (100 MHz, C6D6) δ 11.0, 11.7, 31.5, 47.8, 54.6,
72.5, 84.3, 101.5, 113.6, 127.7, 131.5, 160.3, 202.2; HRMS (CI,
NH3) m/z calcd for C15H21O4 (MH+) 265.1440, found 265.1432.
(2S,3R)-2-((2R,4R,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-di-
oxan-4-yl)-4-methylpentan-3-ol (9). To a suspension of powdered
Mg (0.457 g, 18.78 mmol) in anhydrous THF (40 mL) was added
dropwise 2-bromopropane (1.73 mL, 18.42 mmol) under a dry argon
atmosphere. After being stirred for 1 h at rt, the mixture was cooled
to -78 °C, and a solution of aldehyde 8 (0.974 g, 3.68 mmol) in
anhydrous THF (33 mL) was added dropwise via cannula. The
mixture was allowed to warm to rt and was stirred for 12 h. A
(15) (a) Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. ReV. 2005,
105, 313-354. (b) Schoffers, E.; Golebiowski, A.; Johnson, C. R.
Tetrahedron 1996, 52, 3769-3826.
(16) Domon, L.; Vogeleisen, F.; Uguen, D. Tetrahedron Lett. 1996, 37,
2773-2776.
8486 J. Org. Chem., Vol. 72, No. 22, 2007

EnantioselectiVe Synthesis of Dolabriferol
saturated aqueous solution of NH4Cl (30 mL) was slowly added
and the mixture was extracted with ether (300 mL). The organic
phase was washed with brine, dried (MgSO4), and evaporated. The
crude product was purified by flash chromatography (gradient, 4.5%
steps, ethyl acetate/hexanes, 1:9 to 3:2) to give alcohol 9 (0.693 g,
60%) as a white solid. mp: 92 °C; [R]D22 -2.8 (c 0.98, C6H6); IR
(d, J ) 2.4 Hz, 3H), 1.73 (m, 1H), 1.97 (m, 1H), 2.15 (s, 3H), 2.17
(m, 1H), 3.26 (dd, J ) 3.4 and 7.8 Hz, 1H), 3.30 (s, 3H), 3.77 (dd,
J ) 3.0 and 4.6 Hz, 1H), 4.08 (dd, J ) 7.6 and 10.0 Hz, 1H), 4.35
(dd, J ) 4.8 and 10.0 Hz, 1H), 4.46 (d, J ) 11.0 Hz, 1H), 4.51 (d,
J ) 11.0 Hz, 1H), 6.81 (d, J ) 8.8 Hz, 2H), 7.24 (d, J ) 8.8 Hz,
2H); 13C NMR (100 MHz, C6D6) δ -3.5, -3.2, 12.6, 16.2, 18.3,
18.9, 19.4, 26.5, 34.4, 35.7, 36.5, 38.9, 54.8, 71.8, 74.6, 76.9, 84.5,
114.2, 129.3, 131.1, 159.8; HRMS (CI, NH3) m/z calcd for
C25H47O6SSi (MH+) 503.2862, found 503.2851.
1
(KBr) 3513, 3076, 2973, 1518, 1463, 1167, 1068 cm-1; H NMR
(400 MHz, C6D6) δ 0.30 (d, J ) 6.8 Hz, 3H), 0.74 (d, J ) 6.8 Hz,
3H), 1.14 (d, J ) 6.8 Hz, 3H), 1.29 (d, J ) 6.4 Hz, 3H), 1.83 (m,
2H), 2.02 (m, 1H), 3.11 (dd, J ) 10.8 and 10.8 Hz, 1H), 3.20 (dd,
J ) 2.0 and 10.4 Hz, 1H), 3.23 (s, 3H), 3.49 (br s, 1H), 3.60 (d, J
) 8.8 Hz, 1H), 3.87 (dd, J ) 4.6 and 10.8 Hz, 1H), 5.22 (s, 1H),
6.72 (d, J ) 8.6 Hz, 2H), 7.49 (d, J ) 8.6 Hz, 2H); 13C NMR (100
MHz, C6D6) δ 10.9, 11.7, 18.9, 20.3, 30.6, 31.3, 33.9, 54.5, 72.7,
75.8, 89.3, 102.2, 113.8, 127.4, 131.3, 160.3; HRMS (EI, 70 eV)
m/z calcd for C18H28O4 (M+) 308.1987, found 308.1991.
(2R,3S,4R,5R)-2-Isopropyl-4-(4-methoxybenzyloxy)-3,5-dim-
ethyltetrahydro-2H -pyran (12). To a solution of mesylate 11 (83
mg, 0.165 mmol) in anhydrous THF (1.5 mL) was added tetrabu-
tylammonium fluoride in THF (1 M, 1.4 mL, 1.4 mmol). The
mixture was stirred at room temperature for 12 d. The solvent was
evaporated and the crude product was purified by flash chroma-
tography (ethyl acetate/hexanes, 1: 9) to give compound 12 (40
mg, 85%) as a white solid. mp: 65-66 °C; [R]D22 -11.1 (c 1.75,
(2R,3R,4R,5R)-5-(tert-Butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-2,4,6-trimethylheptan-1-ol (10). To a solution of
alcohol 9 (36.6 mg, 0.119 mmol) in CH2Cl2 (1 mL) at -78 °C
were added successively 2,6-lutidine (47.4 mg, 0.442 mmol) and
TBSOTf (81 mg, 0.306 mmol). After being stirred at -78 °C for
2 h, the solution was allowed to warm at rt over a 5 h period. The
reaction was quenched by the addition of 2-propanol (0.25 mL)
and the mixture stirred for 1 h. The mixture was diluted with ether
(50 mL) and the organic phase was washed with saturated aqueous
NH4Cl (75 mL) and brine (75 mL), dried (MgSO4), and evaporated.
The crude product was purified by flash chromatography (ethyl
acetate/hexanes, 7:93) to give the TBS derivative of 9 (49 mg, 97%)
as a colorless oil. HRMS (CI, NH3) m/z calcd for C24H43O4Si (MH+)
423.2930, found 423.2924. The product is a mixture of diastere-
omeric benzylidene acetals and was used for the next step without
further analysis. To a solution of the purified TBS derivative of 9
(540 mg, 1.28 mmol) in CH2Cl2 (10 mL) at -78 °C was added
dropwise DIBALH (1.5 M in toluene, 3.41 mL, 5.11 mmol). After
the mixture was stirred at -78 °C for 2 h, the reaction was warmed
to room temperature and the mixture stirred for an additional 1 h.
The reaction was quenched by the addition of a saturated aqueous
solution of Rochelle’s salt (10 mL). The mixture was diluted with
ether (100 mL), washed with a saturated aqueous solution of
Rochelle’s salt (100 mL) and brine (200 mL), dried (MgSO4), and
evaporated. The crude product was purified by flash chromatog-
raphy (gradient, 5% steps; ethyl acetate/hexanes, 1:9 to 3:7) to give
alcohol 10 (459 mg, 84%) as a colorless oil. [R]D22 -12.60 (c 3.42,
1
C6H6); IR (KBr) 3036, 2968, 1463, 1252, 1116, 1029 cm-1; H
NMR (400 MHz, C6D6) δ 0.72 (d, J ) 6.4 Hz, 3H), 1.13 (d, J )
7.2 Hz, 3H), 1.15 (d, J ) 6.4 Hz, 3H), 1.21 (d, J ) 7.2 Hz, 3H),
1.77 (m, 1H), 1.84 (m, 1H), 2.11 (m, 1H), 2.55 (dd, J ) 2.4 and
9.6 Hz, 1H), 3.25 (dd, J ) 2.8 and 11.5 Hz, 1H), 3.32 (s, 3H),
3.37 (dd, J ) 5.4 and 5.4 Hz, 1H), 3.73 (dd, J ) 1.0 and 11.5 Hz,
1H), 4.34 (s, 2H), 6.84 (d, J ) 8.6 Hz, 2H), 7.29 (d, J ) 8.6 Hz,
2H); 13C NMR (100 MHz, C6D6) δ 8.7, 14.1, 18.3, 20.6, 29.7, 33.2,
34.5, 54.8, 69.0, 72.8, 79.1, 86.6, 114.1, 129.1, 131.6, 159.7; HRMS
(EI, 70 eV) m/z calcd for C18H28O3 (M+) 292.2038, found 292.2043.
(R)-2-((2R,4R,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-dioxan-
4-yl)-4-methylpentan-3-one (13). Ketone 13 was prepared fol-
lowing the procedure used for 8. Ketone 13 (0.680 g, 99%) was
obtained as a colorless oil. [R]D22 -46.20 (c 2.11, C6H6); IR (neat)
1
3044, 2969, 1715, 1250, 1171, 1034 cm-1; H NMR (400 MHz,
C6D6) δ 0.37 (d, J ) 6.4 Hz, 3H), 0.92 (d, J ) 3.2 Hz, 3H), 0.94
(d, J ) 3.6 Hz, 3H), 1.04 (d, J ) 6.8 Hz, 3H), 1.79 (m, 1H), 2.70
(m, 2H), 3.04 (t, J ) 11.2 Hz, 1H), 3.18 (s, 3H), 3.35 (dd, J ) 4.4
and 5.6 Hz, 1H), 3.75 (dd, J ) 4.8 and 6.4 Hz, 1H), 5.23 (s, 1H),
6.75 (d, J ) 9.2 Hz, 2H), 7.51 (d, J ) 8.8 Hz, 2H); 13C NMR (100
MHz, C6D6) δ 12.5, 13.3, 18.6, 18.7, 32.7, 39.0, 49.2, 54.6, 72.7,
84.9, 101.4, 113.6, 127.6, 131.7, 160.2, 214.8; HRMS (CI, NH3)
m/z calcd for C18H27O4 (MH+) 307.1909, found 307.1914.
(2S,3S)-2-((2R,4R,5R)-2-(4-Methoxyphenyl)-5-methyl-1,3-di-
oxan-4-yl)-4-methylpentan-3-ol (14). To a solution of ketone 13
(0.680 g, 2.22 mmol) in anhydrous THF (73 mL) at -78 °C was
added LAH (0.163 g, 4.29 mmol). After the mixture was stirred
for 5 h at -78 °C, the reaction was quenched with saturated aqueous
NaHCO3 (10 mL). The solvent was evaporated and the residue was
dissolved in ether (200 mL). The organic phase was washed with
saturated aqueous NaHCO3 (2 × 100 mL) and brine (2 × 100 mL),
dried (MgSO4), and evaporated. The crude product was purified
by flash chromatography (ethyl acetate/hexanes, 1:4) to give alcohol
14 (0.536 g, 81%) as a colorless oil. [R]D22 -11.84 (c 1.47, C6H6);
IR (neat) 3530, 3044, 2961, 1248, 1171, 1112, 1035 cm-1; 1H NMR
(400 MHz, C6D6) δ 0.46 (d, J ) 6.4 Hz, 3H), 0.85 (d, J ) 2.4 Hz,
3H), 0.87 (d, J ) 2.8 Hz, 3H), 0.89 (d, J ) 6.8 Hz, 3H), 1.64 (m,
1H), 1.86 (m, 1H), 2.13 (br s, 1H), 2.32 (m, 1H), 3.09 (t, J ) 11.2
Hz, 1H), 3.18 (s, 3H), 3.26 (dd, J ) 2.0 and 8.0 Hz, 1H), 3.48 (br
d, J ) 9.2 Hz, 1H), 3.87 (dd, J ) 4.8 and 6.4 Hz, 1H), 5.29 (s,
1H), 6.73 (d, J ) 9.2 Hz, 2H), 7.52 (d, J ) 9.6 Hz, 2H); 13C NMR
(100 MHz, C6D6) δ 12.4, 14.6, 16.7, 20.6, 30.5, 32.8, 37.7, 54.6,
73.5, 77.3, 88.4, 101.7, 113.7, 127.6, 131.9, 160.2; HRMS (EI, 70
eV) m/z calcd for C18H28O4 (M+) 308.1987, found 308.1990.
(2R,3R,4R,5S)-5-(tert-Butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-2,4,6-trimethylheptan-1-ol (15). Compound 15 was
prepared following the procedure used for 10. Flash chromatography
(ethyl acetate/hexanes, 7:93) provided 15 (0.591 g, 81% for two
1
C6H6); IR (neat) 3440, 3034, 2957, 1463, 1250, 1038 cm-1; H
NMR (400 MHz, C6D6) δ 0.09 (s, 3H), 0.12 (s, 3H), 0.90 (d, J )
3.2 Hz, 3H), 0.92 (d, J ) 3.2 Hz, 3H), 0.94 (d, J ) 6.8 Hz, 3H),
1.02 (s, 9H), 1.11 (d, J ) 7.2 Hz, 3H), 1.75 (m, 1H), 1.86 (m, 1H),
2.03 (m, 1H), 2.59 (br s, 1H), 3.29 (s, 3H), 3.32 (dd, J ) 3.6 and
8.0 Hz, 1H), 3.61 (dd, J ) 4.8 and 10.8 Hz, 1H), 3.81 (m, 2H),
4.50 (d, J ) 10.6 Hz, 1H), 4.53 (d, J ) 10.6 Hz, 1H), 6.76 (d, J )
8.6 Hz, 2H), 7.23 (d, J ) 8.6 Hz, 2H); 13C NMR (100 MHz, C6D6)
δ -3.4, -3.1, 12.9, 16.7, 18.3, 18.9, 19.3, 26.5, 34.6, 36.9, 39.1,
54.8, 64.9, 75.0, 76.8, 87.4, 114.3, 129.4, 130.9, 159.9; HRMS (CI,
NH3) m/z calcd for C24H45O4Si (MH+) 425.3087, found 425.3080.
(2R,3R,4R,5R)-5-(tert-Butyldimethylsilyloxy)-3-(4-methoxy-
benzyloxy)-2,4,6-trimethylheptyl Methanesulfonate (11). To a
solution of alcohol 10 (19.5 mg, 0.046 mmol) and triethylamine
(24 µL, 0.168 mmol) in anhydrous CH2Cl2 (1 mL) was added
methanesulfonyl chloride (9.8 µL, 0.126 mmol). The reaction
mixture was stirred overnight at rt. The reaction mixture was then
partitioned between ether (50 mL) and saturated aqueous NaHCO3
(50 mL). The organic phase was washed with saturated aqueous
NaHCO3 (50 mL), dried (MgSO4), and evaporated. The crude
product was purified by flash chromatography (gradient, 5% steps;
ethyl acetate/hexanes, 1:9 to 3:7) to give mesylate 11 (23 mg, 99%)
22
22
as a colorless oil. [R]D -11.8 (c 1.15, C6H6); IR (neat) 3063,
steps) as a colorless oil. [R]D -9.56 (c 2.29, C6H6); IR (neat)
1
1
2957, 1734, 1587, 1250, 1178, 1052 cm-1; H NMR (400 MHz,
3432, 3036, 2956, 1249, 1173, 1040 cm-1; H NMR (400 MHz,
C6D6) δ 0.09 (s, 3H), 0.12 (s, 3H), 0.90 (d, J ) 5.6 Hz, 3H), 0.92
(d, J ) 6.0 Hz, 3H), 0.98 (d, J ) 7.2 Hz, 3H), 1.03 (s, 9H), 1.04
C6D6) δ 0.02 (s, 3H), 0.04 (s, 3H), 0.87 (d, J ) 4.8 Hz, 3H), 0.89
(d, J ) 4.4 Hz, 3H), 0.95 (s, 9H), 0.97 (d, J ) 6.8 Hz, 3H), 1.04
J. Org. Chem, Vol. 72, No. 22, 2007 8487

Pelchat et al.
(d, J ) 7.2 Hz, 3H), 1.75 (m, 1H), 1.87 (m, 1H), 2.11 (m, 1H),
2.29 (br s, 1H), 3.21 (s, 3H), 3.24 (dd, J ) 3.6 and 4.0 Hz, 1H),
3.54 (dd, J ) 4.8 and 6.4 Hz, 1H), 3.74 (m, 2H), 4.37 (dd, J ) 8.4
and 10.8 Hz, 2H), 6.71 (d, J ) 8.8 Hz, 2H), 7.17 (d, J ) 8.8 Hz,
2H). 13C NMR (100 MHz, C6D6) δ -4.4, -3.7, 12.5, 16.1, 18.4,
18.5, 22.4, 26.2, 30.5, 37.1, 42.8, 54.6, 64.7, 74.6, 77.3, 86.1, 114.1,
129.2, 130.8, 159.7; HRMS (CI, NH3) m/z calcd for C24H45O4Si
(MH+) 425.3087, found 425.3084.
(dd, J ) 8.4 and 10.4 Hz, 2H), 6.72 (d, J ) 8.8 Hz, 2H), 7.15 (d,
J ) 8.8 Hz, 2H); 13C NMR (100 MHz, C6D6) δ -4.3, -3.6, 7.7,
11.9, 12.9, 17.9, 18.5, 22.1, 26.2, 30.8, 35.9, 42.4, 48.4, 54.6, 73.2,
76.8, 83.2, 113.9, 129.3, 131.0, 159.6, 211.5; HRMS (CI, NH3)
m/z calcd for C26H47O4Si (MH+) 451.3243, found 451.3229.
(4S,5S,6R,7S)-7-(tert-Butyldimethylsilyloxy)-5-hydroxy-4,6,8-
trimethylnonan-3-one (18). To a solution of compound 17 (85.1
mg, 0.189 mmol) in CH2Cl2 (5 mL) at 0 °C were added water (0.5
mL) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (51.5
mg, 0.227 mmol). After being stirred for 1 h at room temperature,
the mixture was diluted with saturated aqueous NaHCO3 (10 mL).
Ethyl acetate (70 mL) was added and the organic phase was washed
with saturated aqueous NaHCO3 (50 mL) and brine (100 mL), dried
(MgSO4), and evaporated. The crude product was purified by flash
chromatography (ethyl acetate/hexanes, 1:19) to give compound
18 (55 mg, 88%) as a colorless oil. [R]D22 -16.55 (c 1.10, C6H6);
IR (neat) 3497, 2958, 1252, 1114, 1048 cm-1; 1H NMR (400 MHz,
C6D6) δ -0.02 (s, 3H), -0.01 (s, 3H), 0.80 (d, J ) 7.2 Hz, 3H),
0.85-0.93 (m, 9H), 0.90 (s, 9H), 1.04 (d, J ) 7.2 Hz, 3H), 1.81
(m, 2H), 2.00 (m, 1H), 2.16 (m, 1H), 2.47 (m, 1H), 3.36 (m, 1H),
3.60 (d, J ) 7.6 Hz, 1H), 3.79 (m, 1H); 13C NMR (100 MHz, C6D6)
δ -4.8, -4.2, 7.4, 13.8, 15.1, 18.3, 18.7, 21.2, 26.0, 31.1, 35.8,
43.3, 47.3, 77.3, 78.7, 216.1; HRMS (CI, NH3) m/z calcd for
C18H39O3Si (MH+) 331.2668, found 331.2665.
(2S,3S,4R,5S)-5-(tert-Butyldimethylsilyloxy)-3-(4-methoxyben-
zyloxy)-2,4,6-trimethylheptanal (16). Aldehyde 16 was prepared
following the procedure used for 8. Flash chromatography (ethyl
acetate/hexanes, 6:94) provided 16 (0.440 g, 84%) as a colorless
22
oil. [R]D 2.78 (c 1.71, C6H6); IR (neat) 3029, 2956, 1720, 1249,
1
1172, 1046 cm-1; H NMR (400 MHz, C6D6) δ -0.02 (s, 3H),
-0.01 (s, 3H), 0.77 (d, J ) 7.2 Hz, 3H), 0.83 (d, J ) 7.2 Hz, 3H),
0.89 (d, J ) 6.8 Hz, 3H), 0.92 (s, 9H), 1.01 (d, J ) 7.2 Hz, 3H),
1.74 (m, 1H), 2.05 (m, 1H), 2.43 (qd, J ) 1.6 and 2.0 Hz, 1H),
3.22 (s, 3H), 3.57 (dd, J ) 2.8 and 5.6 Hz, 1H), 3.67 (dd, J ) 4.0
and 4.4 Hz, 1H), 4.19 (d, J ) 11.2 Hz, 1H), 4.21 (d, J ) 11.2 Hz,
1H), 6.73 (d, J ) 8.8 Hz, 2H), 7.13 (d, J ) 8.8 Hz, 2H), 9.65 (d,
J ) 2 Hz, 1H); 13C NMR (100 MHz, C6D6) δ -4.3, -3.8, 10.5,
12.2, 18.4, 18.5, 21.7, 26.2, 30.6, 41.6, 48.4, 54.6, 72.2, 77.4, 81.9,
113.9, 129.2, 130.6, 159.7, 202.5; HRMS (CI, NH3) m/z calcd for
C24H43O4Si (MH+) 423.2930, found 423.2920.
(4S,5S,6R,7S)-7-(tert-Butyldimethylsilyloxy)-5-(4-methoxyben-
zyloxy)-4,6,8-trimethylnonan-3-one (17). To a solution of alde-
hyde 16 (0.440 g, 1.04 mmol) in anhydrous THF (15 mL) at -78
°C was added ethylmagnesium bromide (1 M in THF, 3.13 mL,
3.13 mmol). After being stirred for 4 h at -78 °C, the solution
was allowed to warm to room temperature and the reaction was
quenched by the addition of saturated aqueous NH4Cl (10 mL).
Ether was added (150 mL) and the organic phase washed with
saturated aqueous NH4Cl (150 mL), saturated aqueous NaHCO3
(2 × 75 mL), and brine (2 × 75 mL), dried (MgSO4), and
evaporated. The crude product was purified by flash chromatog-
raphy (ethyl acetate/hexanes, 1:19) to give an inseparable mixture
of alcohol diastereoisomers (0.408 g, 87%) as a colorless oil. HRMS
(CI, NH3) m/z calcd for C26H49O4Si (MH+) 453.3400, found
453.3393. The mixture was oxidized by the Dess-Martin periodinane
following the procedure used for 8. Flash chromatography (ethyl
acetate/hexanes, 1:19) provided 17 (0.391 g, 96%) as a colorless
oil. [R]D22 17.18 (c 1.56, C6H6); IR (neat) 3064, 2956, 1715, 1249,
1173, 1043 cm-1; 1H NMR (400 MHz, C6D6) δ 0.04 (s, 3H), 0.10
(s, 3H), 0.90 (d, J ) 2.0 Hz, 3H), 0.92 (d, J ) 2.4 Hz, 3H), 0.94-
1.06 (m, 9H), 0.96 (s, 9H), 1.93 (m, 1H), 2.02 (m, 1H), 2.14 (m,
1H), 2.25 (m, 1H), 2.65 (m, 1H), 3.21 (s, 3H), 3.73 (m, 2H), 4.31
(2R,3S,4S,5R,6S)-2-Ethyl-6-isopropyl-3,5-dimethyltetrahydro-
2H-pyran-2,4-diol (3). Hemiacetal 3 was prepared following the
procedure used for 6. Hemiacetal 3 (36.5 mg, 88%) was obtained
22
as a white solid. mp: 86 °C; [R]D -66.2 (c 1.82, CHCl3), lit.7
[R]D22 52.8 (c 1.04, CHCl3) for the complementary enantiomer; IR
1
(KBr) 3254, 2946, 2932, 1485, 1158, 1132, 1028 cm-1; H NMR
(400 MHz, CDCl3) δ 0.84 (d, J ) 6.8 Hz, 3H), 0.89 (t, J ) 7.6
Hz, 3H), 0.92 (d, J ) 7.2 Hz, 3H), 1.00 (d, J ) 6.8 Hz, 3H), 1.09
(d, J ) 7.2 Hz, 3H), 1.54-1.71 (m, 4H), 1.78-1.86 (m, 1H), 3.04
(d, J ) 7.6 Hz, 1H, OH), 3.52 (br s, 1H, OH), 3.59 (dd, J ) 2.0
and 12.8 Hz, 1H), 3.61 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
7.5, 13.4, 13.9, 14.4, 20.7, 28.3, 32.5, 37.9, 39.5, 72.3, 76.3, 100.5.
Acknowledgment. The authors would like to acknowledge
the support of this work by the Natural Sciences and Engineering
Research Council of Canada (NSERC).
Supporting Information Available: General experimental
1
procedures and H and 13C NMR spectra for all compounds are
provided. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO701524P
8488 J. Org. Chem., Vol. 72, No. 22, 2007