Crotylation versus propargylation: Two routes for the synthesis of the C13-C18 fragment of the antibiotic branimycin

Article abstract of DOI:10.1021/jo062502m

The C13-C18 fragment 3 of the novel antibiotic branimycin was prepared along two highly stereocontrolled routes. The first one uses a standard Roush crotylation protocol, whereas the second one proceeds via an allenyl silane propargylation with unexpected stereochemical consequences, which are discussed in detail.

Full text of DOI:10.1021/jo062502m

Crotylation versus Propargylation: Two Routes for the Synthesis of
the C13-C18 Fragment of the Antibiotic Branimycin
Wolfgang Felzmann, Daniele Castagnolo,† Daniela Rosenbeiger,‡ and Johann Mulzer*
Institut fu¨r Organische Chemie, UniVersita¨t Wien, Wa¨hringerstrasse 38, 1090 Vienna, Austria
johann.mulzer@uniVie.ac.at
ReceiVed December 6, 2006
The C13-C18 fragment 3 of the novel antibiotic branimycin was prepared along two highly
stereocontrolled routes. The first one uses a standard Roush crotylation protocol, whereas the second one
proceeds via an allenyl silane propargylation with unexpected stereochemical consequences, which are
discussed in detail.
Introduction
Streptomyces Viridochromogenes combined with a low toxicity
and a considerable oral availability.
The classical drugs used for treatment of common bacterial
diseases are often characterized by serious side effects and high-
toxicity profiles.1 Additionally, in the past decade a rapid
development of multidrug-resistant (MDR) strains of bacterial
pathogens has been observed. Consequently, there is an urgent
need to discover new structural classes of antibacterial com-
pounds and to develop agents that are able to replace (or to be
associated with) the drugs that are currently in use.2
Several years ago, the Laatsch group in Go¨ttingen isolated
and characterized from the streptomyces stem GW 60/1571 a
new member of the nargenicin3 family, branimycin.4 This new
natural compound showed immediately a high activity against
Although such antibiotics are, in principle, available from
fermentation, total synthesis is indispensable for preparing
analogs to gain deeper insight into the mode of action and the
pharmacologically active moieties of the molecule.
As shown in Scheme 1, our synthetic approach to branimycin
is based on a late 1,2-addition of the vinyl lithium derivative 2
to the highly functionalized cis-decalin 15 with concomitant
epoxide opening and formation of the C7-C12 oxygen bridge.
The precursor for 2 is vinyl iodide 3, which in turn could be
easily obtained from alkyne 4. The protecting groups in 4 were
carefully chosen to fit into the overall plan of the synthesis.
We describe the stereocontrolled synthesis of 3 along two
alternative routes: A and B. Route A features a Roush-type
crotylation of isopropylidene glyceraldehyde 5, whereas route
B is based on the addition of a chiral allenyl silane 8 to alde-
hyde 7.
* To whom correspondence should be addressed. Fax: +43-1-4277-52189.
† Current address: Universita` degli Studi di Siena, Dipartimento Farmaco
Chimico Tecnologico, Polo Scientifico San Miniato, Via Aldo Moro 2, I-53100,
Siena, Italy.
‡ Current address: TU Mu¨nchen, Lehrstuhl fu¨r Organische Chemie 1,
Lichtenbergstrasse 4, D-85747 Garching, Germany.
(1) (a) Stein, G. E. Clin. Infect. Dis. 2005, 41, S293-S302. (b) Mandell,
L. A.; Ball, P.; Tillotson, G. Clin. Infect. Dis. 2001, 32, S72-S79.
(2) Antibiotic Resistance: Origin, EVolution, Selection and Spread;
Chadwick, D. J., Goode, J., Eds.; Wiley: Chichester, 1997. (b) Levy, S. B.
Sci. Am. 1998, 278, 46-53 and references therein. (c) For reviews on
antibiotic resistance, see: Walsh, C. T.; Wright, G. D. Chem. ReV. 2005,
105, 391-394.
Results and Discussion
Route A. The reaction between 5 and 6 is known to produce
the anti,syn-crotylation product 9 in excellent diastereoselec-
(3) (a) For a review, see: Kallmerten, J. Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1995; Vol. 17, pp
283-310. (b) Celmer, W. D.; Chmurny, C. N.; Moppett, C. E.; Ware, R.
S.; Watts, P. C.; Whipple, E. B. J. Am. Chem. Soc. 1980, 102, 4203-4209.
(c) Whaley, H. A.; Coates, Chidester, C. G.; Mizak, S. A.; Wnuk, R. J.
Tetrahedron Lett. 1980, 3659-3662. (d) Celmer, W. D.; Cullen, W. P.;
Moppett, C. E.; Jefferson, M. T.; Huang, L. H.; Shibakawa, R.; Tone, J.
U.S. Patent 4,418,883, 1979.
(4) Speitling, M.; Gru¨n-Wollny, I.; Hannske, F. G.; Laatsch, H. 12. and
13. IRSEER Naturstofftage der DECHEMA e.V. Irsee 2000, 2001, poster
sessions.
(5) For the synthesis of 1, see: (a) Enev, V. S.; Drescher, M.; Ka¨hlig,
H.; Mulzer, J. Synlett 2005, 14, 2227-2229. (b) Felzmann, W.; Arion,
V. B.; Mieusset, J.-L.; Mulzer, J. Org. Lett. 2006, 8, 3849-3851.
10.1021/jo062502m CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/08/2007
2182
J. Org. Chem. 2007, 72, 2182-2186

Synthesis of the C13-C18 Fragment of Branimycin
SCHEME 1. Retrosynthesis
SCHEME 2. Synthesis of anti,syn Stereotriad 10
SCHEME 3. First-Generation Synthesis of 4a
tivity6 (Scheme 2). The secondary hydroxyl group in 9 was
protected as its benzyl ether (the PMB ether turned out to be
too unstable in the subsequent reaction sequence), and the
acetonide was hydrolyzed to diol 10. To obtain the desired
syn,syn stereotriad, the secondary alcohol at C-17 had to be
inverted, and the most efficient way to do this was via an
epoxide ring formation/ring opening sequence: selective ben-
zoylation of the primary alcohol at C-18, followed by mesylation
of the C-17 OH function and subsequent treatment with NaOMe,
produced epoxide 11 under clean inversion of configuration
(Scheme 3). The epoxide was opened at the primary position
with an excess of NaOMe in MeOH, and the C-17 hydroxyl
group was silylated with TIPSOTf to give 12 in acceptable yield.
Ozonolysis furnished the unstable aldehyde 13, which was
immediately subjected to the Corey-Fuchs alkynylation.7 This
reaction, though successful on a small scale, led to elimination
of the benzyloxy group when scaled up. To overcome this
problem, conversion of the aldehyde 13 to the alkyne was
achieved using trimethylsilyl diazomethane.8 Methylation of the
resulting alkyne finally led to compound 4a (Scheme 3).
the sequence was linear and involved a significant number of
reactions. Thus we devised a more convergent alternative,
Route B.
Route B. On the basis of Marshall and Fleming’s work on
chiral allenylstannanes9 and allenylsilanes,10 it was decided to
introduce the C13-C15 unit in a single step using an asym-
metric propargylation reaction. To avoid too many functional
group interconversions at later stages, chiral aldehyde 7 was
designated to carry the OMe group at C-18 already in place.
Interestingly, in stark contrast to the numerous mechanistic
studies on diastereoselective propargylation with chiral allenyl-
stannanes, only limited investigations have been reported for
chiral allenylsilanes. On the basis of the experimental data
available for allenylstannanes,9a,b the propargylation of an achiral
aldehyde with allenylsilane 8 should proceed via an antiperipla-
nar transition state TS and lead to adduct P, which would have
the desired and absolute configurations at C-4 and C-5 (Scheme
4). It had not yet been determined how the two oxygen
substituents on the aldehyde would influence the trajectory of
the incoming allenyl unit and thus affect the stereochemical
outcome of the reaction.
Although this synthetic sequence furnished the desired side
chain precursor 4a in good overall yield (48% over 11 steps),
(6) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Straub, J. A.;
Palkowitz, A. D. J. Org. Chem. 1990, 55, 4117-4126.
(7) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
(8) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Chem. Commun. 1973,
151-152.
(9) (a) Marshall, J. A. Chem. ReV. 1996, 96, 31. (b) Marshall, J. A.;
Wang, X. J. Org. Chem. 1992, 57, 1242-1252. (c) Marshall, J. A.;
Chobanian, H. Org. Synth. 2005, 82, 43-50.
(10) (a) Buckle, M. J. C.; Fleming, I. Tetrahedron Lett. 1993, 34, 2383-
2386. (b) Marshall, J. A.; Maxson, K. J. Org. Chem. 2000, 65, 630-633.
(c) Buckle, M. J. C., Fleming, I.; Gil, S.; Pang, K. L. C. Org. Biomol.
Chem. 2004, 2, 749-769.
J. Org. Chem, Vol. 72, No. 6, 2007 2183

Felzmann et al.
SCHEME 7. Propargylation-Based Synthesis of 4
SCHEME 4. syn-Preference of the Silyl-allene
SCHEME 5. Synthesis of Aldehyde 7
SCHEME 8. Structural Confirmation of 4b by PMB-acetal
Formation
SCHEME 6. Glycidol-Based Access to 16
Initially, the enantiomerically pure aldehyde 7 was prepared
from (R,R)-dimethyltartrate.11 The diol was protected as the
acetonide and was then reduced with LiAlH4 to afford diol 14
(Scheme 5). Under standard conditions (NaH, DMF, MeI) the
monomethyl ether 15 was formed predominantly and only small
amounts of the dimethyl ether were detected. The primary
alcohol in compound 15 was tosylated and converted to its
corresponding iodide. Reductive elimination of the acetonide
with activated Zn, furnished allylic alcohol 16. TIPS-protection
(now possible with TIPSCl), followed by ozonolysis afforded
enantiomerically pure (S)-aldehyde 7.
Alternatively, a much shorter route was employed where (S)-
glycidol was O-methylated and then treated with trimethylsul-
fonium ylide12 to give alcohol 16 directly (Scheme 6).
Nonracemic allenylsilane 8 was synthesized as previously
described in 41% overall yield.10c,13 The addition of 8 to
aldehyde 7 was mediated with TiCl4, the preferred Lewis acid
in these allenyl silane addition reactions. Under these conditions,
a homopropargyl adduct was formed as a 20:1 diastereomeric
mixture in 77% yield (Scheme 7). To our delight, after
O-benzylation, the main diastereomer was found to be identical
with 4a in all respects (1H and 13C NMR, MS, Rf, and optical
rotation).
using BF3‚OEt2 as a nonchelating Lewis acid. However, this
reaction produced methyl ketone 1814 in 49% along with only
a minute amount of 17.
The observed stereochemical outcome of the addition is the
result of an allenyl-re-aldehyde-si face combination (Scheme
9). For such allenylsilane-aldehyde additions, the two transition
states A and B are discussed in the literature.15 Normally, the
antiperiplanar geometry A is favored over its synclinal coun-
terpart B, and indeed, in our investigations A was preferred. It
is quite obvious that the C-3 carbon of the allenyl silane will
attack the aldehyde from the less hindered (i.e., Me-substituted)
re face. Much less obvious is the si face preference of the
aldehyde. The corresponding transition state could be described
as C or E, which are both non-conventional: C is an anti-
Felkin-Anh geometry, and E would imply an even less likely
chelate formation to an OTIPS group.16 It seems more likely
that either a chelate transition state F, previously postulated for
(14) A related transformation has been reported. See ref 15 and Danheiser,
R. L.; Kwasigroch, C. A.; Tsai, Y.-M. J. Am. Chem. Soc. 1985, 107, 7233-
7235.
To corroborate this stereochemical assignment, PMB-ether
4b was converted to cyclic acetal 19, and NOESY experiments
confirmed the proposed stereochemical assignment (Scheme 8).
The propargylation of 7 with allenyl silane 8 was attempted
(11) Rao, A. V. R.; Reddy, E. R.; Joshi, B. V.; Yadav, J. S. Tetrahedron
Lett. 1987, 28, 6497-6500.
(12) Alcaraz, L.; Harnett, J. J.; Mioskowski, C.; Martel, J. P.; Le Gall,
T.; Shin, D.-S.; Falck, J. R. Tetrahedron Lett. 1994, 35, 5449-5452.
(13) Bahadoor, A. B.; Flyer, A.; Micalizio, G. C. J . Am. Chem. Soc.
2005, 127, 3694-3695.
Product 18 might be the product of dihydrofuran hydrolysis followed by
proto-desilyation.
(15) Danheiser, R. L.; Carini, D. J.; Kwasigroch, C. A. J. Org. Chem.
1986, 51, 3870-3878.
2184 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of the C13-C18 Fragment of Branimycin
SCHEME 9. Rationale for Observed syn,syn Selectivity
SCHEME 11. Synthesis of (E)-Vinyliodide 3b
These results indicate that the aldehyde still prefers transition
state geometry C and thus the allenyl component must switch
to arrangement B. Consequently, we postulate that for our
system a combination of 7 and 8 represents the matched pair
and compounds 20 and 8 represent the mismatched one. In the
mismatched combination the aldehyde is the slightly dominating
partner.
To return to the overall synthesis of branimycin, alcohol 17
was protected as its PMB ether 4b. Initial attempts to convert
4b into the (E)-vinyliodide 3b via a Pd-catalyzed hydrostan-
nylation failed, despite literature precedence.18 Therefore 4b was
subjected to hydrozirconation,19 which, upon treatment with
iodine, gave the (E)-vinyliodide 3b, which was obtained in seven
steps and in an overall yield of 25% (Scheme 11).
SCHEME 10. Mismatched Combination
Conclusion
In conclusion, we have developed two different routes to the
C13-C18 side chain fragment of branimycin. Furthermore, we
have shown that allenyl silane additions to glyceraldehyde
derivatives can be performed with high stereocontrol; however,
the diastereofacial selectivity exhibited by the aldehyde does
not fit into the standard transition state models.20
We are currently underway to utilize compound 3 to complete
the total synthesis of branimycin, which will be reported in due
course.
Experimental Section
(2S)-3-Methoxy-2-[(1,1,1-triisopropylsilyl)oxy]propanal (7).
Compound 16 (255 mg, 2.5 mmol) was dissolved in 5 mL of
anhydrous DMF, and imidazole (510 mg, 7.5 mmol) and triiso-
propylsilyl chloride (1.1 mmol) were added. The mixture was stirred
for 14 h. Diethyl ether was then added to the reaction, and the
mixture was washed with a 5% solution of KHSO4 (1 × 2 mL),
water, and brine, dried over MgSO4, filtered, and concentrated.
Purification by column chromatography using hexane/ethyl acetate
50:1 to 20:1 as an eluent yielded the TIPS-protected alcohol as a
colorless oil (594 mg, 92%). 1H NMR (CDCl3): δ 5.90 (ddd, J )
17.2, 10.4, 5.8 Hz, 1H), 5.33 (d, J ) 17.2 Hz, 1H), 5.17 (d, J )
10.4 Hz, 1H), 4.38 (m, 1H), 3.57-3.30 (m, 2H), 3.38 (s, 3H), 1.08
(m, 21H). 13C NMR (CDCl3): δ 139.7 (CH), 115.5 (CH2), 78.1
(CH2), 73.2 (CH), 59.5 (CH3), 18.1 (CH3), 12.8 (CH). IR [cm-1]:
2944, 2867, 1700, 1684, 1653, 1647, 1559, 1464, 1420, 1402, 1383,
1366, 1340, 1247, 1197, 1126, 1104, 1035, 1014. [R]20D +14.0 (c
0.2, CHCl3). Rf 0.42 (hexane/ethyl acetate 10:1).
allenylstannane additions to â-benzyloxy R-methyl propanals,10b
or a “standard” Felkin-Anh geometry D with the bulky OTIPS
group in the perpendicular position would be expected. Both
of these models would, however, lead to a re face attack at the
aldehyde, which was not observed.
To shed more light on this interesting outcome, allene 8 was
treated with the enantiomeric (R)-glyceraldehyde derivative 2017
(Scheme 10). If the reagent still prefers transition state A, then
adduct 22 (anti-diol configuration) should be formed in excess.
In this case, however, the aldehyde could not react via the
C-type geometry but would have to adopt a Felkin-Anh
transition state such as D. In reality, the reaction yielded
compounds 21 and 22 in a ratio of 7:3; after separation, the
relative configuration of each diastereomer was assigned via
the cyclic acetals 23 and 24, respectively.
The TIPS-protected alcohol (144 mg, 0.56 mmol) was dissolved
in CH2Cl2 (15 mL) and cooled to -78 °C, and O3-enriched air
was bubbled through the reaction mixture until a faint blue color
persisted. PPh3 (160 mg, 0.61 mmol) was then added, and the
mixture was stored at -18 °C overnight. After addition of 400 mg
(18) Benechie, M.; Skrydstrup, T.; Khuong-Huu, F. Tetrahedron Lett.
1991, 32, 7535-7538.
(19) Huang, Z.; Negishi, E.-i. Org. Lett. 2006, 8, 3675-3678.
(20) For examples where these rules are followed, see: (a) Williams,
D. R.; Wultz, M. W. J. Am. Chem. Soc. 2005, 127, 14550-14551. (b)
Reymond, S.; Cossy, J. Eur. J. Org. Chem. 2006, 4800-4804.
(16) For a review on influence of the TIPS-protecting group, see: Ru¨cker,
C. Chem. ReV. 1995, 95, 1009-1064.
(17) Prepared analogously from (R)-glycidol.
J. Org. Chem, Vol. 72, No. 6, 2007 2185

Felzmann et al.
of SiO2, the solvent was carefully removed under reduced pressure.
Loading the silica-adsorbed material on a column (preconditioned
and loaded with 6 g of SiO2) and fast chromatography using
pentane/ethyl ether 20:1 to 7:1 as eluent yielded 7 as a colorless
oil (131 mg, 90%). 1H NMR (CDCl3): δ 9.72 (s, 1H), 4.23 (t, J )
4.8 Hz, 1H), 3.65 (dd, J ) 4.8, 2.5 Hz, 2H), 3.38 (s, 3H), 1.09 (m,
21H). 13C NMR (CDCl3): δ 203.6 (C), 77.7 (CH), 74.5 (CH2),
59.9 (CH3), 18.2 (CH3), 12.7 (CH). IR [cm-1]: 3056, 2925, 2866,
1740 1701, 1653, 1617, 1465, 1437, 1381, 1306, 1247, 1120, 1028.
Rf 0.34 (hexane/ethyl acetate 10:1).
(4), 121 (100). HRMS(EI) calcd for C23H37O4Si 405.2461, found
405.2466. [R]20 -4.8 (c 1.9, CHCl3).
D
[(1S,2S,3R)-5-Iodo-2-(4-methoxybenzyloxy)-1-(methoxymethyl)-
3-methyl-(4E)-hexenyl]oxy(triisopropyl)silane (3b). Cp2ZrCl2 (59
mg, 0.20 mmol) was dissolved in a Schlenk flask in 1.5 mL of
anhydrous THF and cooled to 0 °C. DIBAL-H (0.2 mL, 0.20 mmol,
1 M in hexanes) was added, and the resulting slurry was stirred at
room temperature for 1.5 h. The stirring was stopped, and after 5
min the supernatant liquid was removed with a syringe. To the
white precipitate was then added a solution of 4b (30 mg, 0.07
mmol) in 2 mL of freshly destilled benzene. The mixture was then
heated to 40 °C; after 5 min the solution became clear, and stirring
was continued at this temperature for 3 h. Then, the oil bath was
removed, and the reaction mixture cooled to 0 °C. A solution of
iodine (51 mg, 0.20 mmol) in 2 mL of benzene was then added
slowly. Immediately after completion of the addition, the reaction
was quenched by addition of 5 mL of a 1 M Na2S2O3 solution.
After both layers became colorless, the organic layer was separated,
and the aqueous layer was extracted 4 times with diethyl ether.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was subjected to flash chromatography, using hexane/ethyl
acetate 50:1 to 20:1 as eluant, affording pure 3b (38 mg, 98%). 1H
NMR (400 MHz, CDCl3): δ 7.26 (d, J ) 8.6 Hz, 2H), 6.88 (d,
J ) 8.6 Hz, 2H), 6.13 (dq, J ) 9.7, 1.5 Hz, 1H), 4.61 (d, J ) 11.1
Hz, 1H), 4.47 (d, J ) 11.1 Hz, 1H), 4.07 (ddd, J ) 6.2, 4.1, 4.1
Hz, 1H), 3.80 (s, 3H), 3.56 (dd, J ) 9.5, 3.6 Hz, 1H), 3.34 (m,
2H), 3.31 (s, 3H), 2.71 (m, 1H), 2.36 (d, J ) 1.5 Hz, 3H), 1.08 (m,
21H), 1.00 (d, J ) 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
158.1 (C), 143.7 (CH), 129.8 (C), 128.3 (CH), 128.2 (CH), 112.7
(CH), 112.6 (CH),91.6 (C), 82.2 (CH), 73.7 (CH2), 72.3 (CH2),
71.8 (CH), 57.8 (CH3), 54.3 (CH3), 35.6 (CH), 26.7 (CH3), 17.3
(CH3), 15.5 (CH3). 11.8 (CH). IR [cm-1]: 2962, 2866, 1612, 1586,
151, 1463, 1382, 1302, 1250, 1196, 1172, 1110. MS (EI) m/z 533
(M+ - 43, 3), 407 (1), 285 (2), 187 (6), 121 (100). HRMS(EI)
(2S,3S,4R)-1-Methoxy-4-methyl-2-[(1,1,1-triisopropylsilyl)-
oxy]-5-heptyn-3-ol (17). A mixture of 7 (150 mg, 0.5 mmol) and
allene 8 (105 mg, 0.75 mmol) in CH2Cl2 (6 mL) was cooled to
-78 °C. TiCl4 (0.5 mL of a 1 M solution in CH2Cl2) was then
added. After 2 h the solution was warmed to -20 °C and quenched
with a solution of NH4Cl. After warming to room temperature the
solvent was removed under vacuum. The residue was redissolved
in diethyl ether and then washed with water and brine, dried over
MgSO4, filtered, and concentrated. The crude product was purified
by flash chromatography, using pentane/ethyl ether 4:1 as eluant,
affording 17 as a mixture of diasteroisomers, syn:anti ) 20:1 (126
mg, 77%). 1H NMR (400 MHz, CDCl3): δ 4.44 (dd, J ) 6.7, 5.7
Hz, 1H), 3.48 (dd, J ) 9.3, 6.7 Hz, 1H), 3.41 (dd, J ) 9.3, 5.7 Hz,
1H), 3.35 (s, 3H), 2.49 (m, 1H), 2.36 (bd, J ) 9.9 Hz, 1H), 1.77
(d, J ) 2.6 Hz, 3H), 1.26 (d, J ) 6.8 Hz, 3H), 1.21 (m, 21H). 13
C
NMR (100 MHz, CDCl3): δ 81.4 (C), 78.5 (C), 75.6 (CH), 75.1
(CH2), 71.4 (CH), 59.3 (CH), 30.8 (CH), 18.5 (CH3), 18.2 (CH),
13.4 (CH3), 3.9 (CH3). [R]20 +19.8 (c 2, CHCl3).
D
[(1S,2S,3R)-2-(4-Methoxybenzyloxy)-1-(methoxymethyl)-3-
methyl-4-hexynyl]oxy(triisopropyl)silane (4b). Compound 17
(186 mg, 0.24 mmol) was dissolved in 5 mL of anhydrous DMF
and cooled to 0 °C, and then NaH (34 mg of 60% dispersion in
mineral oil, 0.85 mmol) was added. The mixture was stirred for 30
min at 0 °C, then PMBCl (177 mg, 1.13 mmol) and tetrabutyl
ammonium iodide (18 mg, 0.06 mmol) were added, and the mixture
was warmed to room temperature and stirred for overnight. The
reaction was then quenched with ice-cold 1 M NaOH. After stirring
for 15 min, the solution was extracted 4 times with Et2O. The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was subjected to flash chromatography, using hexane/ethyl
acetate 50:1 to 20:1 as eluant, affording pure 4b (180 mg, 71%).
1H NMR (400 MHz, CDCl3): δ 7.28 (d, J ) 8.6 Hz, 2H), 6.86 (d,
J ) 8.6 Hz, 2H), 4.64 (d, J ) 11.2 Hz, 1H), 4.54 (d, J ) 11.2 Hz,
1H), 4.34 (ddd, J ) 6.5, 6.1, 2.7 Hz, 1H), 3.79 (s, 3H), 3.54 (dd,
J ) 9.1, 6.5 Hz, 1H), 3.43 (m, 2H), 3.31 (s, 3H), 2.89 (m, 1H),
1.75 (d, J ) 2.3 Hz, 3H), 1.21 (d, J ) 7.1 Hz, 3H), 1.08 (m, 21H).
13C NMR (100 MHz, CDCl3): δ 159.0 (C), 131.3 (C), 129.0 (CH),
113.6 (CH), 82.7 (CH), 82.1 (C), 77.1 (C), 74.3 (CH2), 72.8 (CH2),
72.4 (CH), 58.7 (CH3), 55.3 (CH3), 27.1 (CH), 18.2 (CH3), 18.2
(CH3), 18.0 (CH3), 12.9 (CH), 3.6 (CH3). IR [cm-1]: 2941, 2866,
1613, 1586, 1514, 1464, 1383, 1302, 1248, 1172, 1096, 1062, 1038.
MS (EI) m/z 405 (M+ - 43, 4), 375 (0.3), 267 (1), 187 (4), 145
calcd for C23H38O4ISi 533.1584, found 533.1598. [R]20 -2.5 (c
D
1.3, CHCl3).
Acknowledgment. We thank the Universita` degli Studi di
Siena for a leave of absence for D.C. We are indebted to
Schering AG for a generous gift of chemicals. We gratefully
acknowledge the helpful discussion with Valentin Enev and Neil
A. Sheddan (both University of Vienna). We also thank
Hanspeter Ka¨hlig (U. Vienna) and Lothar Brecker (U. Vienna)
for NMR determinations.
Supporting Information Available: General experimental
methods, detailed procedures, and analytical data for compounds
3, 4, 7-19 and selected 1H and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO062502M
2186 J. Org. Chem., Vol. 72, No. 6, 2007