Total synthesis of (+)-discodermolide

Article abstract of DOI:10.1021/jo9811423

The total synthesis of (+)-discodermolide is described. The approach involves assemblage of three key stereotriad subunits through addition of nonracemic allenyltin, -indium, and -zinc reagents to (S)-3-silyloxy-2- methylpropanal derivatives, followed by reduction of the resulting anti,syn- or syn,syn-homopropargylic alcohol adducts to the (E)-homoallylic alcohols and subsequent Sharpless epoxidation. Addition of methyl cuprate reagents or Red-Al to the resultant epoxy alcohols yielded the key precursors, alkyne 4, aldehyde 9, and alcohol 24. Addition of alkyne 4 (as the lithio species 10) to aldehyde 9 afforded the propargylic alcohol 11 as the major stereoisomer. Lindlar hydrogenation and installation of appropriate protecting groups led to aldehyde 17. This was converted to the (Z)-vinylic iodide 18 upon treatment with α-iodoethylidene triphenylphosphorane. Suzuki coupling of this vinylic iodide with a boranate derived from iodide 25 led to the coupled product 27 with the complete carbon backbone of (+)-discodermolide and the correct stereochemistry. The synthesis was completed by cleavage of the cyclic PMP acetal at C1 with i-Bu₂AlH and three-step oxidation - esterification to the ester 31. Cleavage of the C19 Et₃Si ether and C19 carbamate formation followed by cleavage of the remaining alcohol protecting groups, first with DDQ and then aqueous HCl, afforded (+)-discodermolide (36).

Full text of DOI:10.1021/jo9811423

J . Org. Chem. 1998, 63, 7885-7892
7885
Tota l Syn th esis of (+)-Discod er m olid e
J ames A. Marshall* and Brian A. J ohns
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received J une 15, 1998
The total synthesis of (+)-discodermolide is described. The approach involves assemblage of three
key stereotriad subunits through addition of nonracemic allenyltin, -indium, and -zinc reagents to
(S)-3-silyloxy-2-methylpropanal derivatives, followed by reduction of the resulting anti,syn- or
syn,syn-homopropargylic alcohol adducts to the (E)-homoallylic alcohols and subsequent Sharpless
epoxidation. Addition of methyl cuprate reagents or Red-Al to the resultant epoxy alcohols yielded
the key precursors, alkyne 4, aldehyde 9, and alcohol 24. Addition of alkyne 4 (as the lithio species
10) to aldehyde 9 afforded the propargylic alcohol 11 as the major stereoisomer. Lindlar
hydrogenation and installation of appropriate protecting groups led to aldehyde 17. This was
converted to the (Z)-vinylic iodide 18 upon treatment with R-iodoethylidene triphenylphosphorane.
Suzuki coupling of this vinylic iodide with a boranate derived from iodide 25 led to the coupled
product 27 with the complete carbon backbone of (+)-discodermolide and the correct stereochemistry.
The synthesis was completed by cleavage of the cyclic PMP acetal at C1 with i-Bu2AlH and three-
step oxidation-esterification to the ester 31. Cleavage of the C19 Et3Si ether and C19 carbamate
formation followed by cleavage of the remaining alcohol protecting groups, first with DDQ and
then aqueous HCl, afforded (+)-discodermolide (36).
The polyketide marine natural product discodermolide,
by virtue of its potent immunosuppressant and potential
antitumor activity and in view of its limited availability,1
has stimulated significant interest as a target for total
synthesis.2 To date, three syntheses of the enantiomer2a-c
and one of the natural material2a have been described.
These synthetic efforts were initiated before the absolute
configuration had been established. In fact, Schreiber
and co-workers prepared both enantiomers of the natural
product, thereby establishing the correct absolute con-
figuration.2a
We viewed the synthesis of (+)-discodermolide as a test
of our allenylmetal-homoaldol approach to stereotriads
and their further elaboration to polypropionate sub-
units.3,4 The previous routes to discodermolide and
various subunits have utilized chiral allyl boronate
additions, Evans oxazolidinone-mediated aldol condensa-
tions and alkylations, and substrate-directed alkylations
and aldol condensations for the introduction of various
stereocenters.2 We have developed an approach, outlined
in Figure 1, in which key stereocenters are introduced
through additions of chiral allenylmetal reagents K to
the readily available aldehyde (S)-2-methyl-3-silyloxy-
propanal J .5 Subsequent reduction of the triple bond in
(1) For information about isolation of this compound, see: Gunasek-
era, S. P.; Gunasekera, M.; Longley, R. E. J . Org. Chem. 1990, 55,
4912; 1991, 56, 1346.
(2) (a) Hung, D. T.; Nerenberg, J . B.; Schreiber, S. L. J . Am. Chem.
Soc. 1996, 118, 11054. (b) Smith, A. B., III; Qui, Y.; J ones, D. R.;
Kobayashi, K. J . Am. Chem. Soc. 1995, 117, 12011. (c) Harried, S. S.;
Yang, G.; Strawn, M. A.; Myles, D. C. J . Org. Chem. 1997, 62, 6098.
(d) Paterson, I.; Schlapbach, A. Synlett 1995, 498. (e) Clark, D. L.;
Heathcock, C. H. J . Org. Chem. 1993, 58, 5878. (f) Golec, J . M. C.;
J ones, S. D. Tetrahedron Lett. 1993, 34, 8159 and two accompanying
papers.
(3) Marshall, J . A.; Perkins, J . F.; Wolf, M. A. J . Org. Chem. 1995,
60, 5556.
(4) Marshall, J . A.; Lu, Z.-H.; J ohns, B. A. J . Org. Chem. 1998, 63,
817.
(5) Roush, W. R.; Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc. 1990,
112, 6348.
F igu r e 1. Synthetic plan for (+)-discodermolide (R1 ) TBS;
R2 ) PMP).
adducts H and I leads to allylic alcohols F and G, which
are subjected to asymmetric epoxidation followed by
10.1021/jo9811423 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/09/1998

7886 J . Org. Chem., Vol. 63, No. 22, 1998
Marshall and J ohns
regioselective epoxide cleavage with hydride or a methyl
cuprate to provide subunits A and the precursor to C.6
The sequential allenylstannane addition, reduction,
epoxidation, and methyl cuprate reaction protocol rep-
resents an efficient assemblage of stereopentad arrays
common to various polypropionate natural products.7 In
the present report, we describe an improved synthesis
of the anti,syn subunits A and B and delineate our
successful merging of these with subunit C, which results
in a total synthesis of (+)-discodermolide.
In an earlier effort we prepared subunit B through
condensation of aldehyde J (R1 ) TBS) with the allen-
ylindium reagent derived from allenylstannane K (R )
H).4 This addition afforded the anti,syn product in 67%
yield as a 92:8 mixture of inseparable diastereomers. In
the interim, we developed an alternative method for the
equivalent conversion through use of chiral allenylzinc
reagents, prepared in situ by treatment of propargylic
mesylates with catalytic Pd(PPh3)4 and excess Et2Zn.8
Application of this methodology to aldehyde 19 led to the
adduct 3 as a 90:10 mixture of separable diastereomers
in 65-75% yield (eq 1). Conversion to the MOM deriva-
addition of formaldehyde affords the propargylic alcohol
7, which is subsequently reduced to allylic alcohol F (R2
) p-MeOC6H4CH) with Red-Al.4 Elaboration of subunit
F to aldehyde 9 was accomplished as previously described
in six steps and 70% overall yield.
Treatment of aldehyde 910 with lithiated alkyne 10
afforded a separable 85:15 mixture of alcohols 11 and 12
in 92% yield. The minor diastereomer 12 was efficiently
inverted by Mitsunobu displacement with benzoic acid11
and subsequent reduction of the benzoate 13 with i-Bu2-
AlH (eq 3).
The propargylic alcohol 11 was converted to the (Z)-
allylic alcohol 14 by hydrogenation over the Lindlar
catalyst,12 thus completing assemblage of the C1-C13
backbone of (+)-discodermolide (Scheme 1). The next
sequence of reactions involved further homologation of
14 to the (Z)-vinyl iodide 18, an intermediate that was
deemed suitable for coupling to an appropriate C15-C24
fragment (C in Figure 1). To that end, protection as the
MOM ether 15 followed by selective cleavage of the
triethylsilyl ether with HF-pyridine led to alcohol 16.
Oxidation with the Dess-Martin periodinane reagent13
afforded aldehyde 17 in near-quantitative yield. Conver-
sion to the vinyl iodide 18 was effected by condensation
with R-iodoethylidene triphenylphosphorane.14
This reaction was the most challenging of the entire
sequence. Yields were typically in the 40% range,
although on several occasions we obtained ca. 20% of the
desired product. The principal byproduct was a conju-
gated aldehyde, presumed to arise by deprotonation of
aldehyde 17 and subsequent loss of the â-OMOM group-
ing. The (Z)-vinyl iodide was the major product of the
tive was effected with MOMCl and i-Pr2NEt in the
presence of Bu4NI. In the present work, it was found
that triethylsilyl ethers are preferable to the previously
employed TBS ethers because of their more facile cleav-
age.
The next phase of the synthesis called for coupling of
the lithiated derivative of alkyne 4 with aldehyde 9 (eq
3). Our previous synthesis of aldehyde 9 entailed addi-
tion of the allenylindium reagent derived from stannane
K (R ) CH2OAc) to aldehyde J (R1 ) TBS) followed by
TBS cleavage and acetal formation leading to 8 in 58%
overall yield.4 A more expeditious synthesis of the
precursor 7 to aldehyde 9 employs the acetal 6, prepared
from the alcohol 3 via diol 5 (eq 2). Lithiation and
(8) Marshall, J . A.; Adams, N. D. J . Org. Chem. 1998, 63, 3812.
(9) Barrett, A. G. M.; Edmunds, J . J .; Hendrix, J . A.; Horita, K.;
Parkinson, C. J . J . Chem. Soc., Chem. Commun. 1992, 1238.
(10) The synthesis of aldehyde 9 was completed as previously
described,4 except for the final oxidation step which was effected in
essentially quantitative yield with the Dess-Martin periodinane
reagent.13
(11) Mitsunobu, O. Synthesis 1981, 1. Hsu, C.-T.; Wang, N.-Y.;
Latimer, L. H.; Sih, C. J . J . Am. Chem. Soc. 1983, 105, 593.
(12) The catalyst, Pd-CaCO3 poisoned with lead, was purchased
from Aldrich Chemical Co., Milwaukee, WI.
(13) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. Meyer,
S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(14) Chen, J .; Wang, T.; Zhao, K. Tetrahedron Lett. 1994, 35, 2827.
Smith and co-workers identified an epoxide as a significant byproduct
in an analogous condensation. We found none of a related epoxide in
any of our reaction mixtures. See: Arimoto, H.; Kaufman, M. D.;
Kobayashi, K.; Qiu, Y.; Smith, A. B., III. Synlett 1998, 765.
(6) Elaboration of the terminal diene unit of C was effected as
described by Paterson and Schlapbach.2d
(7) The epoxidation-cuprate addition sequence was first developed
by Kishi and co-workers. See: Nagoaka, H.; Kishi, Y. Tetrahedron
1981, 37, 3873.

Total Synthesis of (+)-Discodermolide
J . Org. Chem., Vol. 63, No. 22, 1998 7887
Sch em e 1a
F igu r e 2. Coupling strategies for the assemblage of major
segments of discodermolide.
a
Key: (a) H2, Pd/Pb-CaCO3 (99%); (b) MOMCl, i-Pr2NEt,
Bu4NI (95%); (c) HF-py, THF (99%); (d) Dess-Martin periodinane
(99%); (e) Ph3PdC(Me)I (40%).
19 and allenylstannane 20.4 However, problems with the
ultimate deprotection of the C19 TBS ether 22 forced us
to abandon this intermediate in favor of the triethylsilyl
analogue 23 (Scheme 2). Selective cleavage of the PMP
acetal with i-Bu2AlH18 gave the primary alcohol 24
exclusively. The derived iodide 25 was converted to the
trialkyl boranate 26 by lithiation and subsequent addi-
tion of B-methoxy-9-BBN. Suzuki coupling with vinyl
iodide 18 in the presence of the PdCl2(dppf) catalyst16
afforded the coupled product 27 in 74% yield, thus
completing all requisite carbon-carbon bond-forming
reactions for the discodermolide skeleton.
The final steps of the synthesis are summarized in
Scheme 3. Selective cleavage of the PMP acetal of 27
with i-Bu2AlH again proved successful, affording the
primary alcohol 28 in 79% yield. Alcohol 28 was oxidized
in two stages, first with the Dess-Martin periodinane
reagent13 to aldehyde 29, which then yielded acid 30 upon
treatment with buffered NaClO2.19 The methyl ester 31
was prepared with TMSCHN2.20
condensation. Generally an 85:15 inseparable mixture
of (Z) and (E) isomers was obtained, although ratios as
low as 70:30 and as high as 90:10 were realized from
several experiments. In addition, small amounts of
protonolysis product arising from the noniodinated ylide
were also formed. The most favorable isomer ratios and
the highest yields were obtained from experiments in
which the condensation was conducted at -78 °C for a
prolonged period. Although the protonolysis byproduct
could eventually be separated, products arising from the
(E) isomer of vinylic iodide 18 could not. Thus, inter-
mediates following the coupling step contain small
amounts (5-10%) of the 13E isomer.
We now reached a crucial point in these synthetic
studies: the coupling of subunits 18 and 24 to form the
C14-C15 carbon-carbon bond. An analogous connection
was employed by Smith and co-workers, who joined a
C9-C14 vinyl iodide with a C15-C21 iodozinc reagent
in a Pd(Ph3P)4-catalyzed coupling reaction which pro-
ceeded in 66% yield (Figure 2).2b Both Schreiber2a and
Myles2c utilized Nozaki-Kishi addition of a C8 acetylenic
or (Z)-vinylic chromium species to a C7 aldehyde as a
major coupling event. The diastereoselectivity of these
additions was 2:1 and 2.5:1, respectively. The C13-C15
segment of precursors to the foregoing additions was
fashioned through a (Z)-selective Still-Horner-Emmons
condensation.15
As noted above, the foregoing sequence was initially
carried out on the TBS ether 22. However, cleavage of
this ether in the coupled product 32 could not be
achieved. Treatment with TBAF was ineffective and
afford starting material or decomposition, depending on
conditions. Prolonged acid treatment (p-TsOH in MeOH
at 0 °C over 7 days) led to the δ-lactone 37 in 40% yield
(eq 4). Only a small amount of more polar material,
After several unpromising attempts to couple truncated
C14 vinyl cuprates and C15 iodides, we turned to the use
of a Suzuki coupling approach employing (Z)-vinyl iodide
and alkyl boranate prototypes.16 These studies proved
sufficiently promising to warrant examination of the
actual subunits 24 and 18. Accordingly, alcohol 24 was
converted to the iodide 25,17 a precursor of the requisite
boranate.
Our initial coupling experiments were conducted with
diene 22 derived from the syn,syn adduct 21 of aldehyde
(18) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett.
1983, 1593.
(15) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(16) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(17) Garegg, P. J .; Samuelson, B. J . Chem. Soc., Chem. Commun.
1979, 978.
(19) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1983,
37, 2091.
(20) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull.
1981, 29, 1475.

7888 J . Org. Chem., Vol. 63, No. 22, 1998
Marshall and J ohns
Sch em e 2a
a
Key: (a) t-BuLi, Et2O, -78 °C; 9-BBNOMe, THF, -78 °C to rt; (b) PdCl2(dppf), K3PO4, DMF.
Sch em e 3a
a
Key: (a) Dess-Martin periodinane (99%); (b) NaClO2, NaH2PO4, isobutylene, t-BuOH (98%); (c) TMSCHN2 (82%); (d) p-TsOH, MeOH,
0 °C (72%); (e) Cl3CC(O)NCO, CH2Cl2; K2CO3, MeOH (93%); (f) DDQ (85%); (g) 4 N HCl, THF at room temperature (72%).
judged to be the result of C19 TBS cleavage, was
produced in this reaction.
(∼5%) presumed to be the C13 (E) isomer from the minor
(E)-vinylic iodide produced in the Wittig condensation
leading to 18.
Attempted acidic cleavage of the TBS ethers at room
temperature led to complete decomposition within 6 h.
In view of these unpromising results, we turned to the
triethylsilyl ether 31. This modification proved success-
ful. Exposure of 31 to p-TsOH in methanol afforded the
C19 alcohol 33 selectively in 72% yield.
The present synthesis of discodermolide illustrates the
potential of chiral allenylmetal reagents for the synthesis
of polypropionate natural products. These reagents are
readily prepared in situ from easily available nonracemic
propargylic alcohols. Among the benefits to be gained
by this strategy are excellent stereocontrol in the addition
reactions and a range of options for further elaboration
of the alkynyl group in the homopropargylic alcohol
adducts.
The carbamate derivative 34 was obtained through
addition of trichloroacetyl isocyanate21 and in situ cleav-
age of the derived trichloroacetyl derivative with metha-
nolic K2CO3. Next the PMB protecting groups were
removed through oxidative cleavage with DDQ in aque-
ous CH2Cl2.22 Prolonged exposure of the resulting diol
35 to 4 N HCl in THF effected cleavage of the MOM
protecting groups and lactonization to yield discoder-
molide (36) as a white amorphous solid. The optical
rotation of our sample was of magnitude comparable to
the reported values (+17 compared with +14,2a -14,2c
Exp er im en ta l Section
(2S,3S,4S)-1-(Tr ieth ylsilyl)oxy-5-h exyn -3-ol (3). To a
cold (0 °C) solution of tetrakis-triphenylphosphine palladium-
(0) (287 mg, 0.25 mmol) in THF (225 mL) was added propargyl
mesylate 24 (2.66 g, 19.9 mmol) in THF (10 mL) and then
aldehyde 1 (2.01 g, 10.0 mmol) in THF (10 mL). Diethylzinc
(28.9 mL, 1 M in hexane, 28.9 mmol) was added dropwise over
20 min. The resultant solution was stirred for 18 h at 0 °C,
allowed to warm to room temperature over 3 h, and stirred
an additional 2 h. The reaction mixture was cooled to 0 °C
and quenched by the dropwise addition of saturated aqueous
NH4Cl (Ca u tion : vigor ou s evolu tion of ga seou s eth a n e).
Upon warming, Et2O was added, and the organic layer was
washed with brine. The aqueous layer was extracted with
1
and -162b). Furthermore, the H and 13C NMR spectra
matched those of the previously synthesized samples of
both (+)- and (-)-discodermolide. However, several small
extraneous peaks were present, indicative of an impurity
(21) Kocovsky, P. Tetrahedron Lett. 1986, 27, 5521.
(22) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885.

Total Synthesis of (+)-Discodermolide
J . Org. Chem., Vol. 63, No. 22, 1998 7889
Et2O, and the combined extracts were dried over Na2SO4.
Filtration and concentration followed by flash chromatography
(14:1 to 8:1 hexanes-EtOAc) provided homopropargyl alcohol
-40 °C, the reaction was quenched by the dropwise addition
of H2O and allowed to warm to room temperature. Et2O was
added, and the mixture was filtered through Celite. The
organic layer was washed with brine. The aqueous layer was
extracted with Et2O, and the combined extracts were dried
over Na2SO4. Filtration and concentration followed by flash
chromatography (8:1 to 4:1 to 2:1 hexanes-EtOAc with 1%
triethylamine) provided alcohol 11 (650 mg, 76%) as a clear
syrup. Further elution provided the minor diastereomer 12
(135 mg, 16%) as a clear syrup. Excess alkyne 4 eluted from
the column first and was recovered (1.06 g, 99% recovery).
11: Rf 0.63 (2:1 hexanes-EtOAc); [R]20D -35.5 (c 1.9, CHCl3);
3 (1.58 g, 62%) as a clear oil: Rf 0.65 (4:1 hexanes-EtOAc);
1
[R]20 -4.3 (c 1.4, CHCl3); IR (film) 3488 (br), 3312 cm-1; H
D
NMR (CDCl3) δ 3.67 (d, J ) 4.8 Hz, 2H), 3.61 (ddd, J ) 7.2,
3.9, 3.9 Hz, 1 H), 2.77 (d, J ) 3.9 Hz, 1 H), 2.64 (qdd, J ) 6.9,
6.9, 2.4 Hz, 1 H), 2.12 (d, J ) 2.4 Hz, 1 H), 1.84-1.74 (m, 1
H), 1.18 (d, J ) 6.9 Hz, 3 H), 0.95 (t, J ) 7.8 Hz, 9 H), 0.95 (d,
J ) 6.6 Hz, 3 H), 0.59 (q, J ) 7.8 Hz, 6 H); 13C NMR (CDCl3)
δ 86.48, 76.13, 70.08, 66.99, 37.27, 30.53, 17.52, 10.11, 6.69,
4.22. Anal. Calcd for
C14H28O2Si: C, 65.57; H, 11.00.
1
Found: C, 65.72; H, 11.03.
IR (film) 3471 (br) cm-1; H NMR (CDCl3) δ 7.40 (d, J ) 8.7
(2S,3S,4S)-3-(Meth oxym eth yl)oxy-1-(tr ieth ylsilyl)oxy-
5-h exyn e (4). To a cold (0 °C) solution of alcohol 3 (1.58 g,
6.2 mmol) in CH2Cl2 (50 mL) were added N,N-diisopropyl-
ethylamine (21.5 mL, 123.2 mmol), chloromethyl methyl ether
(4.7 mL, 61.6 mmol), and tetrabutylammonium iodide (227 mg,
0.62 mmol). The reaction mixture was immediately allowed
to warm to room temperature and protected from light. After
18 h, saturated aqueous NaHCO3 was added along with Et2O.
The organic layer was washed with brine. The aqueous layer
was extracted with Et2O, and the combined extracts were dried
over Na2SO4. Filtration and concentration followed by flash
chromatography (16:1 hexanes-EtOAc) provided alkyne 4
Hz, 2 H), 6.86 (d, J ) 8.7 Hz, 2 H), 5.39 (s, 1 H), 4.74 (d, J )
6.6 Hz, 1 H), 4.68 (d, J ) 6.6 Hz, 1 H), 4.53 (dt, J ) 10.2, 3.0
Hz, 1 H), 4.54-4.49 (m, 1 H), 4.08-3.98 (m, 2 H), 3.79 (s, 3
H), 3.61-3.54 (m, 2 H), 3.48-3.44 (m, 2 H), 3.37 (s, 3 H), 2.71
(m, 1 H), 2.51 (d, J ) 6.9 Hz, 1 H), 2.01 (m, 1 H), 1.91-1.81
(m, 1 H), 1.78-1.65 (m, 2 H), 1.58 (m, 1 H), 1.15 (d, J ) 6.9
Hz, 3 H), 1.04 (d, J ) 6.9 Hz, 3 H), 0.95 (t, J ) 8.1 Hz, 9 H),
0.90 (s, 9 H), 0.89 (d, J ) 6.9 Hz, 3 H), 0.83 (d, J ) 7.2 Hz, 3
H), 0.58 (q, J ) 8.1 Hz, 6 H), 0.11 (s, 3 H), 0.10 (s, 3 H); 13C
NMR (CDCl3) δ 159.67, 131.48, 127.08, 113.42, 101.12, 98.15,
87.15, 82.92, 81.87, 80.70, 73.93, 68.36, 65.50, 59.91, 56.02,
55.22, 40.04, 38.18, 29.88, 29.81, 25.88, 18.03, 17.67, 11.35,
10.78, 8.16, 6.80, 4.37, -4.39, -4.66. Anal. Calcd for C39H70O8-
Si2: C, 64.78; H, 9.76. Found: C, 64.67; H, 9.83.
(1.73 g, 94%) as a clear oil: Rf 0.51 (4:1 hexanes-EtOAc); [R]20
D
+19.5 (c 1.4, CHCl3); IR (film) 3310, 1092, 1035 cm-1; 1H NMR
(CDCl3) δ 4.77 (d, J ) 6.9 Hz, 1 H), 4.72 (d, J ) 6.9 Hz, 1 H),
3.60 (dd, J ) 9.9, 6.0 Hz, 1 H), 3.52 (dd, J ) 9.9, 6.9 Hz, 1 H),
3.51 (dd, J ) 5.7, 4.2 Hz, 1 H), 3.41 (s, 3 H), 2.81-2.71 (m, 1
H), 2.07 (d, J ) 2.4 Hz, 1 H), 1.99-1.87 (m, 1 H), 1.22 (d, J )
6.9 Hz, 3 H), 0.95 (t, J ) 8.1 Hz, 9 H), 0.95 (d, J ) 6.9 Hz, 3
H), 0.58 (q, J ) 8.1 Hz, 6 H); 13C NMR (CDCl3) δ 98.22, 86.72,
81.99, 69.56, 65.37, 56.12, 38.61, 29.74, 18.04, 11.81, 6.79, 4.37.
Anal. Calcd for C16H32O3Si: C, 63.95; H, 10.73. Found: C,
63.97; H, 10.61.
12: Rf 0.46 (2:1 hexanes-EtOAc); [R]20D -38.0 (c 1.2, CHCl3);
1
IR (film) 3602-3226 (br) cm-1; H NMR (CDCl3) δ 7.38 (d, J
) 8.7 Hz, 2 H), 6.86 (d, J ) 8.7 Hz, 2 H), 5.39 (s, 1 H), 4.73 (d,
J ) 6.6 Hz, 1 H), 4.66 (d, J ) 6.6 Hz, 1 H), 4.48 (td, J ) 6.3,
1.5 Hz, 1 H), 4.36 (dt, J ) 10.8, 3.0 Hz, 1 H), 4.04 (dd, J )
11.1, 2.1 Hz, 1 H), 3.98 (dd, J ) 11.1, 1.2 Hz, 1 H), 3.78 (s, 3
H), 3.58 (dd, J ) 9.9, 1.5 Hz, 1 H), 3.54 (dd, J ) 9.9, 6.3 Hz,
1 H), 3.47-3.36 (m, 2 H), 3.36 (s, 3 H), 3.13 (br, 1 H), 2.65-
2.50 (m, 1 H), 1.98 (m, 1 H), 1.91-1.78 (m, 2 H), 1.67 (ddd, J
) 13.2, 6.3, 3.0 Hz, 1 H), 1.61-1.56 (m, 1 H), 1.15 (d, J ) 6.9
Hz, 3 H), 0.94 (t, J ) 7.8 Hz, 9 H), 0.94 (d, J ) 6.9 Hz, 3 H),
0.89 (s, 9 H), 0.86 (d, J ) 6.9 Hz, 3 H), 0.82 (d, J ) 6.9 Hz, 3
H), 0.58 (q, J ) 7.8 Hz, 6 H), 0.10 (s, 3 H), 0.08 (s, 3 H); 13C
NMR (CDCl3) δ 159.74, 131.42, 127.16, 113.42, 101.21, 98.13,
87.66, 82.09, 81.79, 80.54, 73.86, 70.51, 65.50, 61.75, 55.95,
55.18, 40.32, 38.25, 37.99, 29.81, 29.70, 25.79, 17.91, 17.54,
11.03, 10.67, 8.00, 6.76, 4.33, -4.35, -4.81.
(2S,3S,4S)-1,3-(4-Meth oxyben zylid en e)d ioxy-5-h ep tyn -
7-ol (7). To a cold (-78 °C) solution of alkyne 64 (598 mg, 2.3
mmol) in THF (15 mL) was added BuLi (1.58 mL, 1.6 M in
hexane, 2.5 mmol) dropwise. The solution was allowed to
warm to -40 °C, stirred for 1 h, and recooled to -78 °C. Solid
paraformaldehyde (140 mg, 4.6 mmol) was then added in one
portion, and the resultant cloudy solution was stirred for 10
min before being allowed to warm to room temperature. The
solution cleared within 1.5 h and was stirred for an additional
16 h. The mixture was quenched with water, and Et2O was
added. The organic layer was washed with brine. The
aqueous layer was extracted with Et2O, and the combined
extracts were dried over Na2SO4. Filtration and concentration
followed by flash chromatography (3:2 hexanes-EtOAc with
1% triethylamine) provided alcohol 7 (575 mg, 86%) as a
Mit su n ob u In ver sion of P r op a r gylic Alcoh ol 12.
(2S,3R,4S,5S,7S,10S,11S,12S)-7-Ben zoyloxy-5-(ter t-bu tyl-
d im eth ylsilyl)oxy-1,3-(4-m eth oxyben zylid en e)d ioxy-11-
(m eth oxym eth yl)oxy-13-(tr ieth ylsilyl)oxy-8-tr idecyn e (13).
A solution of alcohol 12 (135 mg, 0.19 mmol) in THF (8 mL)
was treated with triphenylphosphine (98 mg, 0.37 mmol),
benzoic acid (46 mg, 0.37 mmol), and diisopropyl azodicar-
boxylate (DIAD) (73 µL, 0.37 mmol). The resultant solution
was stirred at room temperature for 21 h, concentrated in
vacuo, and subjected to flash chromatography (12:1 to 8:1 to
4:1 hexanes-EtOAc with 1% triethylamine) to provide ben-
viscous syrup: Rf 0.26 (2:1 hexanes-EtOAc); [R]20 -88.9 (c
D
2.6, CHCl3); IR (film) 3421 (br), 2240 cm-1; H NMR (CDCl3)
1
δ 7.43 (d, J ) 9.0 Hz, 2 H), 6.87 (d, J ) 9.0 Hz, 2 H), 5.48 (s,
1 H), 4.13 (m, 2 H), 4.01 (m, 2 H), 3.77 (s, 3 H), 3.74 (dd, J )
9.9, 2.4 Hz, 1H), 2.66 (m, 1 H), 2.25 (br, 1 H), 1.64 (m, 1 H),
1.14 (d, J ) 6.6 Hz, 6 H); 13C NMR (CDCl3) δ 159.73, 131.08,
127.28, 113.46, 101.61, 88.07, 82.53, 79.16, 73.44, 55.15, 51.04,
29.66, 28.62, 15.79, 10.51.
zoate 13 (126 mg, 82%) as a clear oil: Rf 0.51 (4:1 hexanes-
1
EtOAc); [R]20 -47.5 (c 2.8, CHCl3); IR (film) 1725 cm-1; H
D
NMR (CDCl3) δ 7.77 (d, J ) 8.7 Hz, 2 H), 7.41 (m, 1 H), 7.37
(d, J ) 8.7 Hz, 2 H), 7.10 (t, J ) 7.8 Hz, 2 H), 6.79 (d, J ) 8.7
Hz, 2 H), 5.52 (m, 1 H), 5.50 (s, 1 H), 4.75 (d, J ) 6.6 Hz, 1 H),
4.63 (d, J ) 6.6 Hz, 1 H), 4.36 (dt, J ) 11.4, 3.0 Hz, 1 H), 4.10
(dd, J ) 11.1, 2.1 Hz, 1 H), 4.03 (d, J ) 11.1 Hz, 1 H), 3.77 (s,
3 H), 3.69 (dd, J ) 10.5, 2.1 Hz, 1 H), 3.58 (dd, J ) 9.9, 6.3
Hz, 1 H), 3.49 (dd, J ) 7.2, 3.6 Hz, 1 H), 3.45 (dd, J ) 9.9, 6.6
Hz, 1 H), 3.22 (s, 3 H), 2.75 (m, 1 H), 2.17-1.99 (m, 2 H), 1.92-
1.83 (m, 2 H), 1.62 (m, 1 H), 1.16 (d, J ) 6.6 Hz, 3 H), 1.15 (d,
J ) 6.9 Hz, 3 H), 0.93 (t, J ) 8.1 Hz, 9 H), 0.87 (d, J ) 6.9 Hz,
3 H), 0.87 (s, 9 H), 0.86 (d, J ) 6.9 Hz, 3 H), 0.56 (q, J ) 8.1
Hz, 6 H), -0.02 (s, 3 H), -0.13 (s, 3 H); 13C NMR (CDCl3) δ
165.36, 159.61, 132.50, 131.43, 130.05, 129.37, 128.12, 127.09,
113.51, 101.16, 98.17, 87.75, 81.78, 80.73, 79.79, 73.94, 66.54,
65.54, 62.02, 55.87, 55.17, 39.88, 38.05, 36.74, 30.01, 29.79,
25.83, 17.94, 17.50, 11.06, 10.70, 7.83, 6.76, 4.33, -4.50, -5.03.
Deben zoyla tion of th e Mitsu n obu In ver sion P r od u ct
13 (Alcoh ol 11). To a cold (-78 °C) solution of benzoate 13
(2S,3R,4S,5S,7S,10S,11S,12S)-5-(ter t-Bu tyld im eth ylsi-
lyl)oxy-1,3-(4-m et h oxyb en zylid en e)d ioxy-11-(m et h oxy-
m eth yl)oxy-13-(tr ieth ylsilyl)oxy-8-tr id ecyn -7-ol (11) a n d
(2S,3R,4S,5S,7R,10S,11S,12S)-5-(ter t-Bu tyld im eth ylsilyl)-
oxy-1,3-(4-m eth oxyben zylid en e)d ioxy-11-(m eth oxym eth -
yl)oxy-13-(tr ieth ylsilyl)oxy-8-tr id ecyn -7-ol (12). To a cold
(-50 °C) solution of alkyne 4 (1.4 g, 4.7 mmol) and 4 Å
molecular sieves (2 g) in THF (40 mL) was added BuLi (1.9
mL, 2.5 M in hexane, 4.7 mmol) dropwise. The solution was
allowed to warm to -40 °C over 1 h. Lithium bromide (0.68
mL, 4.0 M in THF, 2.7 mmol) was added, and the resultant
solution was stirred for 15 min. The solution was cooled to
-78 °C, a precooled (-78 °C) solution of aldehyde 94,10 (500
mg, 1.18 mmol) in THF (10 mL) was added dropwise, and the
resultant solution was placed in a -50 °C bath and allowed
to warm to -40 °C over 1 h. After being stirred for 1.5 h at

7890 J . Org. Chem., Vol. 63, No. 22, 1998
Marshall and J ohns
(110 mg, 0.13 mmol) in CH2Cl2 (10 mL) was added diisobutyl-
aluminum hydride (0.28 mL, 1 M in hexane, 0.28 mmol)
dropwise. After 30 min, saturated aqueous sodium potassium
tartrate (Rochelle’s salt) was added dropwise (Ca u tion : vig-
or ou s evolu tion of H2 m a y r esu lt), and the mixture was
allowed to warm to room temperature. Et2O and H2O were
added, and the biphasic mixture was stirred vigorously for 2
h. The layers were separated, and the organic solution was
washed with brine. The aqueous layer was extracted with
Et2O, and the combined extracts were dried over Na2SO4.
Filtration and concentration followed by flash chromatography
(2:1 hexanes-EtOAc with 1% triethylamine) provided alcohol
11 (90 mg, 94%) as a clear syrup. This material was identical
to authentic alcohol 11 (major diastereomer) from the acetyl-
ide/aldehyde addition step previously described.
) 8.1 Hz, 9 H), 0.90 (s, 9 H), 0.87 (d, J ) 6.9 Hz, 3 H), 0.79 (d,
J ) 7.2 Hz, 3 H), 0.58 (q, J ) 8.1 Hz, 6 H), 0.09 (s, 3 H), 0.08
(s, 3 H); 13C NMR (CDCl3) δ 159.58, 135.73, 131.76, 130.27,
127.22, 113.22, 101.26, 97.83, 94.08, 82.74, 80.87, 74.02, 69.56,
67.77, 65.62, 55.89, 55.51, 55.23, 40.54, 38.61, 38.06, 35.56,
29.85, 25.90, 18.47, 18.04, 10.89, 7.65, 6.80, 4.42, -4.52. Anal.
Calcd for C41H76O9Si2: C, 64.02; H, 9.96. Found: C, 64.24; H,
9.85.
(2S,3R,4S,5S,7S,8Z,10S,11S,12S)-5-(ter t-Bu tyld im eth yl-
silyl)oxy-7,11-d i(m eth oxym eth yl)oxy-1,3(4-m eth oxyben -
zylid en e)d ioxy-8-tr id ecen -13-ol (16). A polypropylene re-
action vessel was charged with silyl ether 15 (313 mg, 0.41
mmol) and THF (20 mL). To this solution was added 3 mL of
a stock solution of HF-pyridine complex in pyridine and THF.
(The stock solution was prepared by adding 1.25 mL of HF-
pyridine complex and 5 mL of pyridine to 12.5 mL of THF in
a 30 mL polypropylene screw top vial. This solution was stored
at 5 °C and used over several months without any loss in
reactivity.) The resultant solution was stirred for 3.5 h, at
which time the reaction was judged complete by TLC. The
mixture was quenched by the careful dropwise addition of
saturated aqueous NaHCO3 until bubbling ceased. Et2O was
added, and the organic solution was washed with brine. The
aqueous layer was extracted with Et2O, and the combined
extracts were dried over Na2SO4. Filtration and concentration
followed by flash chromatography (1:1 hexanes-EtOAc with
1% triethylamine) provided alcohol 16 (266 mg, 99%) as a
viscous syrup: Rf 0.69 (1:1 hexanes-EtOAc); [R]20D -6.0 (c 1.9,
CHCl3); IR (film) 3599-3263 (br) cm-1; 1H NMR (CDCl3) δ 7.42
(d, J ) 8.7 Hz, 2 H), 6.84 (d, J ) 8.7 Hz, 2 H), 5.43 (s, 1 H),
5.42 (t, J ) 10.8 Hz, 1 H), 5.28 (dd, J ) 10.8, 9.0 Hz, 1 H),
4.63 (d, J ) 6.6 Hz, 1 H), 4.57 (d, J ) 6.6 Hz, 1 H), 4.51 (d, J
) 6.6 Hz, 1 H), 4.50-4.42 (m, 2 H), 4.37 (d, J ) 6.6 Hz, 1 H),
4.06 (dd, J ) 11.1, 2.1 Hz, 1 H), 4.00 (dd, J ) 11.1, 1.2 Hz, 1
H), 3.79 (s, 3 H), 3.61 (dd, J ) 10.5, 2.1 Hz, 1 H), 3.51-3.42
(m, 3 H), 3.38 (s, 3 H), 3.13-3.09 (m, 1 H), 3.10 (s, 3 H), 2.81-
2.68 (m, 1 H), 2.01-1.88 (m, 2 H), 1.71-1.57 (m, 2 H), 1.38
(dd, J ) 12.6, 9.6 Hz, 1 H), 1.16 (d, J ) 6.6 Hz, 3 H), 0.92 (d,
J ) 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.81 (d, J ) 7.2 Hz, 3 H), 0.79
(d, J ) 7.5 Hz, 3 H), 0.09 (s, 3 H), 0.08 (s, 3 H); 13C NMR
(CDCl3) δ 159.58, 135.62, 131.74, 130.71, 127.22, 113.22,
101.28, 98.62, 93.95, 82.77, 80.83, 74.01, 69.14, 67.75, 64.77,
56.12, 55.50, 55.25, 40.62, 38.19, 36.98, 35.64, 29.85, 25.91,
18.04, 17.76, 10.89, 10.04, 7.68, -4.45, -4.58. Anal. Calcd
for C35H62O9Si: C, 64.18; H, 9.54. Found: C, 64.19; H, 9.43.
(2S,3R,4S,5S,7S,8Z,10S,11S,12S)-5-(ter t-Bu tyld im eth yl-
silyl)oxy-1,3-(4-m eth oxyben zylid en e)d ioxy-11-(m eth oxy-
m eth yl)oxy-13-(tr ieth ylsilyl)oxy-8-tr id ecen -7-ol (14).
A
solution of propargyl alcohol 11 (338 mg, 0.47 mmol) in toluene
(6 mL) was treated with Pd/CaCO3 poisoned with Pb (5% Pd,
75 mg). Hydrogen was bubbled through the reaction mixture
for 20 min, and the resultant suspension was stirred vigorously
for 24 h under a balloon atmosphere of H2. After filtration
through Celite with Et2O, the solvents were removed in vacuo
to provide allylic alcohol 14 as a viscous syrup which did not
require any further purification: [R]20 -14.3 (c 1.7, CHCl3);
D
IR (film) 3570-3337 (br) cm-1; H NMR (CDCl3) δ 7.41 (d, J
1
) 9.0 Hz, 2 H), 6.87 (d, J ) 9.0 Hz, 2 H), 5.46-5.34 (m, 2 H),
5.40 (s, 1 H), 4.63-4.52 (m, 1 H), 4.59 (d, J ) 6.6 Hz, 1 H),
4.55 (d, J ) 6.6 Hz, 1 H), 4.42 (dt, J ) 8.7, 3.0 Hz, 1 H), 4.08-
3.99 (m, 2 H), 3.80 (s, 3 H), 3.64 (d, J ) 10.8, 2.1 Hz, 1 H),
3.53 (dd, J ) 9.9, 6.9 Hz, 1 H), 3.46 (dd, J ) 9.9, 6.9 Hz, 1 H),
3.43-3.37 (m, 1 H), 3.33 (s, 3 H), 2.80 (m, 1 H), 2.17 (d, J )
3.9 Hz, 1 H), 2.04 (m, 1 H), 1.82 (m, 1 H), 1.66-1.48 (m, 3 H),
1.16 (d, J ) 6.9 Hz, 3 H), 0.95 (t, J ) 8.1 Hz, 9 H), 0.95 (d, J
) 6.9 Hz, 3 H), 0.91 (s, 9 H), 0.86 (d, J ) 6.6 Hz, 3 H), 0.84 (d,
J ) 6.9 Hz, 3 H), 0.58 (q, J ) 8.1 Hz, 6 H), 0.10 (s, 3 H), 0.09
(s, 3 H); 13C NMR (CDCl3) δ 159.67, 134.46, 132.61, 131.50,
127.06, 113.47, 101.10, 98.02, 82.73, 80.89, 73.99, 68.24, 65.62,
65.33, 55.98, 55.23, 40.13, 38.39, 38.26, 35.58, 29.88, 25.90,
18.48, 18.04, 10.87, 10.65, 8.40, 6.81, 4.42, -4.46, -4.74. Anal.
Calcd for C39H72O8Si2: C, 64.60; H, 10.01. Found: C, 64.53;
H, 9.92. On occasion, analysis of the crude reaction mixture
by 1H NMR revealed the presence of starting alkyne (starting
material and product are indistinguishable by TLC). This
material could be resubjected to the above conditions (typically
decreasing the catalyst loading by 50%) until complete forma-
tion of the desired (Z)-allylic alcohol was realized without any
loss in yield or purity.
Ald eh yd e 17. To a solution of alcohol 16 (273 mg, 0.42
mmol) in CH2Cl2 (10 mL) was added the Dess-Martin perio-
dinane reagent (213 mg, 0.50 mmol). The resultant solution
was stirred for 35 min and quenched by the simultaneous
addition of saturated aqueous Na2S2O3 (3 mL) and saturated
aqueous NaHCO3 (3 mL). Et2O was added, and the solution
was stirred vigorously for 20 min. The organic solution was
washed with brine. The aqueous layer was extracted with
Et2O, and the combined extracts were dried over Na2SO4.
Filtration and removal of the solvent in vacuo provided
aldehyde 17 (273 mg, 99%) as a clear oil, and this material
was used immediately without further purification: Rf 0.63
(2S,3R,4S,5S,7S,8Z,10S,11S,12S)-5-(ter t-Bu tyld im eth yl-
silyl)oxy-7,11-d i(m eth oxym eth yl)oxy-1,3-(4-m eth oxyben -
zylid en e)d ioxy-13-(tr ieth ylsilyl)oxy-8-tr id ecen e (15). To
a cold (0 °C) solution of alcohol 14 (402 mg, 0.56 mmol) in CH2-
Cl2 (15 mL) were added N,N-diisopropylethylamine (1.9 mL,
11.1 mmol), chloromethyl methyl ether (0.42 mL, 5.6 mmol),
and tetrabutylammonium iodide (21 mg, 0.06 mmol). The
reaction was immediately allowed to warm to room temper-
ature and protected from light. After 19 h, saturated aqueous
NaHCO3 was added along with Et2O. The organic layer was
washed with brine. The aqueous layer was extracted with
Et2O, and the combined extracts were dried over Na2SO4.
Filtration and concentration followed by flash chromatography
(8:1 to 4:1 hexanes-EtOAc with 1% triethylamine) provided
allylic ether 15 (408 mg, 95%) as a clear oil: Rf 0.40 (4:1
(3:2 hexanes-EtOAc); [R]20 -43.2 (c 1.8, CHCl3); IR (film)
D
1728, 1616 cm-1; 1H NMR (CDCl3) δ 9.76 (s, 1 H), 7.43 (d, J )
8.7 Hz, 2 H), 6.83 (d, J ) 8.7 Hz, 2 H), 5.47 (t, J ) 10.8 Hz, 1
H), 5.43 (s, 1 H), 5.33 (dd, J ) 10.8, 9.3 Hz, 1 H), 4.65 (d, J )
7.2 Hz, 1 H), 4.56 (d, J ) 6.6 Hz, 1 H), 4.54 (d, J ) 7.2 Hz, 1
H), 4.49-4.39 (m, 2 H), 4.38 (d, J ) 6.6 Hz, 1 H), 4.06 (dd, J
) 11.1, 2.1 Hz, 1 H), 4.00 (dd, J ) 11.1, 1.2 Hz, 1 H), 3.83 (dd,
J ) 6.0, 3.3 Hz, 1 H), 3.79 (s, 3 H), 3.60 (dd, J ) 10.8, 2.1 Hz,
1 H), 3.27 (s, 3 H), 3.11 (s, 3 H), 2.75 (dq, J ) 16.8, 6.6 Hz, 1
H), 2.52 (qd, J ) 6.9, 3.3 Hz, 1 H), 1.97 (m, 1 H), 1.70-1.56
(m, 2 H), 1.36 (ddd, J ) 11.1, 9.9, 1.2 Hz, 1 H), 1.16 (d, J ) 6.9
Hz, 3 H), 1.12 (d, J ) 7.2 Hz, 3 H), 1.01 (d, J ) 6.9 Hz, 3 H),
0.89 (s, 9 H), 0.80 (d, J ) 6.9 Hz, 3 H), 0.08 (s, 6 H); 13C NMR
(CDCl3) δ 203.89, 159.58, 133.28, 131.94, 131.73, 127.21,
113.22, 101.24, 97.52, 94.11, 81.60, 80.88, 74.02, 69.33, 67.71,
55.84, 55.53, 55.24, 49.55, 40.53, 37.47, 35.32, 29.81, 25.88,
18.47, 18.05, 10.88, 8.07, 7.60, -4.48, -4.59.
hexanes-EtOAc); [R]20 -28.5 (c 0.85, CHCl3); 1H NMR
D
(CDCl3) δ 7.43 (d, J ) 8.7 Hz, 2 H), 6.84 (d, J ) 8.7 Hz, 2 H),
5.51 (t, J ) 10.8 Hz, 1 H), 5.43 (s, 1 H), 5.26 (dd, J ) 10.8, 9.3
Hz, 1 H), 4.61 (d, J ) 6.6 Hz, 1 H), 4.59 (d, J ) 6.6 Hz, 1 H),
4.57 (d, J ) 6.6 Hz, 1 H), 4.51-4.39 (m, 2 H), 4.38 (d, J ) 6.6
Hz, 1 H), 4.06 (dd, J ) 11.4, 2.1 Hz, 1 H), 4.01 (dd, J ) 11.4,
1.2 Hz, 1 H), 3.79 (s, 3 H), 3.60 (dd, J ) 10.5, 1.8 Hz, 1 H),
3.54 (dd, J ) 9.6, 7.2 Hz, 1 H), 3.44-3.39 (m, 2 H), 3.34 (s, 3
H), 3.11 (s, 3 H), 2.67 (m, 1 H), 1.97 (m, 1 H), 1.89-1.78 (m, 1
H), 1.69-1.57 (m, 2 H), 1.42 (ddd, J ) 13.8, 9.6, 1.5 Hz, 1 H),
1.16 (d, J ) 6.9 Hz, 3 H), 0.95 (d, J ) 6.9 Hz, 3 H), 0.95 (t, J

Total Synthesis of (+)-Discodermolide
J . Org. Chem., Vol. 63, No. 22, 1998 7891
Vin yl Iod id e 18. A suspension of ethyl triphenylphospho-
nium bromide (310 mg, 0.84 mmol) in THF (8 mL) was treated
with BuLi (0.33 mL, 2.5 M in hexane, 0.84 mmol) at room
temperature. The resultant red solution was transferred by
cannula to a cold (-78 °C) solution of iodine (212 mg, 0.84
mmol) and 4 Å molecular sieves (300 mg) in THF (20 mL).
After 10 min, the orange suspension was warmed to -20 °C
for 10 min. Sodium bis(trimethylsilyl)amide (0.75 mL, 1 M
in THF, 0.75 mmol) was added, and the resultant ylide was
reaction mixture was allowed to warm to -50 °C over several
hours and stirred for 18 h. Excess hydride was quenched by
the dropwise addition of saturated aqueous sodium potassium
tartrate (Ca u tion : vigor ou s evolu tion of H2 m a y r esu lt),
and the mixture was allowed to warm to room temperature.
After being stirred vigorously for 1 h, the organic solution was
washed with brine. The aqueous layer was extracted with
Et2O, and the combined extracts were dried over Na2SO4.
Filtration and concentration followed by flash chromatography
(2:1 hexanes-EtOAc with 1% triethylamine) provided alcohol
28 (103 mg, 79%) as a clear oil: Rf 0.46 (2:1 hexanes-EtOAc);
stirred for 2 min at -20 °C and then cooled to -78 °C.
A
solution of aldehyde 17 (273 mg, 0.42 mmol) in THF (3 mL)
was added by cannula, and the mixture was allowed to warm
to room temperature after 5 min. The solution was stirred
for 2.5 h and quenched with CH3OH. The solvent was removed
in vacuo, the residue was dissolved in a minimal amount of
CH2Cl2, and Et2O was added. The insoluble material was
removed by filtration through a plug of silica. Concentration
followed by flash chromatography (6:1 hexanes-EtOAc) pro-
vided vinyl iodide 18 (132 mg, 40%, 6:1 Z/E) as a viscous
syrup: Rf 0.38 (4:1 hexanes-EtOAc); [R]20D -9.6 (c 0.7, CHCl3);
IR (film) 1615, 1249, 1033 cm-1; 1H NMR (CDCl3) δ 7.43 (d, J
) 9.0 Hz, 2 H), 6.84 (d, J ) 9.0 Hz, 2 H), 5.54 (t, J ) 10.5 Hz,
1 H), 5.44 (s, 1 H), 5.37 (dd, J ) 8.7, 1.2 Hz, 1 H), 5.28 (m, 1
H), 4.62-4.58 (m, 3 H), 4.45-4.40 (m, 2 H), 4.39 (d, J ) 6.6
Hz, 1 H), 4.09-4.00 (m, 2 H), 3.79 (s, 3 H), 3.61 (dd, J ) 10.8,
1.5 Hz, 1 H), 3.37 (s, 3 H), 3.29 (t, J ) 5.1 Hz, 1 H), 3.11 (s, 3
H), 2.75-2.63 (m, 1 H), 2.60-2.53 (m, 1 H), 2.49 (d, J ) 0.9
Hz, 3 H), 1.97 (m, 1 H), 1.62-1.57 (m, 2 H), 1.42 (dd, J ) 12.9,
9.6 Hz, 1 H), 1.16 (d, J ) 6.6 Hz, 3 H), 1.04 (d, J ) 6.9 Hz, 3
H), 0.99 (d, J ) 6.9 Hz, 3 H), 0.90 (s, 9 H), 0.80 (d, J ) 6.9 Hz,
3 H), 0.09 (s, 3 H), 0.08 (s, 3 H); 13C NMR (CDCl3) δ 159.63,
138.43, 134.62, 130.82, 127.25, 113.26, 101.30, 97.83, 94.09,
85.23, 80.90, 77.20, 74.05, 69.56, 67.84, 56.03, 55.54, 55.26,
44.03, 40.62, 38.02, 35.23, 33.64, 29.89, 25.96, 18.48, 18.08,
14.32, 10.90, 7.85, -4.40, -4.60.
[R]20 -3.2 (c 2.8, CHCl3); IR (film) 3479, 1614 cm-1; 1H NMR
D
(CDCl3) δ 7.29 (d, J ) 8.4 Hz, 2 H), 7.27 (d, J ) 8.7 Hz, 2 H),
6.87 (d, J ) 8.4 Hz, 2 H), 6.85 (d, J ) 8.7 Hz, 2 H), 6.58 (dt, J
) 17.1, 10.8 Hz, 1 H), 6.02 (t, J ) 11.1 Hz, 1 H), 5.59-5.46
(m, 2 H), 5.28-5.09 (m, 4 H), 4.79 (d, J ) 10.8 Hz, 1 H), 4.65-
4.40 (m, 9 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.61-3.55 (m, 3 H),
3.39 (m, 1 H), 3.37 (s, 3 H), 3.18 (s, 3 H), 3.18-3.10 (m, 2 H),
2.86 (m, 1 H), 2.71-2.55 (m, 2 H), 2.20 (t, J ) 12.3 Hz, 1 H),
2.10-1.67 (m, 6 H), 1.64 (s, 3 H), 1.43 (m, 1 H), 1.01-0.93 (m,
12 H), 0.98 (t, J ) 7.8 Hz, 9 H), 0.91 (s, 9 H), 0.88 (d, J ) 7.2
Hz, 3 H), 0.84 (d, J ) 6.3 Hz, 3 H), 0.78 (d, J ) 6.9 Hz, 3 H),
0.63 (q, J ) 7.8 Hz, 6 H), 0.10 (s, 3 H), 0.08 (s, 3 H); 13C NMR
(CDCl3) δ 159.05, 158.78, 135.16, 134.97, 132.38, 131.59,
131.16, 130.44, 129.04, 128.60, 117.36, 113.74, 113.51, 97.82,
94.11, 86.82, 84.84, 80.21, 77.68, 74.66, 73.33, 69.66, 68.33,
66.09, 56.05, 55.67, 55.21, 42.76, 39.97, 38.17, 37.62, 36.19,
36.07, 34.80, 34.47, 33.92, 25.90, 23.31, 18.75, 18.24, 16.17,
13.97, 10.69, 9.80, 9.51, 7.19, 5.69, -4.22, -4.63. Anal. Calcd
for C64H110O11Si2: C, 69.14; H, 9.97. Found: C, 69.44; H, 10.02.
Meth yl Ester 31. To a solution of alcohol 28 (103 mg, 0.092
mmol) in CH2Cl2 (4 mL) was added the Dess-Martin perio-
dinane reagent (47 mg, 0.11 mmol). The resultant solution
was stirred for 1 h and quenched by the simultaneous addition
of saturated aqueous Na2S2O3 (2 mL) and saturated aqueous
NaHCO3 (2 mL). Et2O was added, and the solution was stirred
vigorously for 20 min. The organic solution was washed with
saturated aqueous Na2S2O3, saturated aqueous NaHCO3, and
brine. The aqueous layer was extracted with Et2O, and the
combined extracts were dried over Na2SO4. Filtration and
removal of the solvent in vacuo provided aldehyde 29 (102 mg,
99%) as a clear oil. This material was used immediately
without further purification.
An aqueous solution of NaClO2 (14 mg, ∼80% pure, 0.12
mmol) and NaH2PO4‚H2O (16 mg, 0.12 mmol) was added
dropwise to a solution of aldehyde 29 (102 mg, 0.092 mmol)
in t-BuOH (6 mL) and 2-methyl-2-butene (3 mL). The result-
ant mixture was stirred at room temperature for 1 h, and then
an additional 1 equiv of NaClO2/NaH2PO4‚H2O was added.
After an additional 1 h, the solvents were removed in vacuo,
and the residue was taken up in Et2O. The solution was
acidified by the dropwise addition of 10% aqueous HCl. The
organic solution was washed with brine. The aqueous layer
was extracted with Et2O, and the combined extracts were dried
over Na2SO4. Filtration and concentration provide carboxylic
acid 30 (102 mg, 98%) as an oil. This material was used
immediately without further purification.
Su zu k i Ad d u ct 27. To a cold (-78 °C) solution of alkyl
iodide 25 (210 mg, 0.35 mmol) in Et2O (5 mL) was added
rapidly t-BuLi (0.44 mL, 1.7 M in pentane, 0.75 mmol). After
3 min, 9-methoxy-9-borabicyclo[3.3.1]nonane (0.82 mL, 1 M
in hexanes, 0.82 mmol) was added followed by THF (5 mL).
The solution was stirred for 10 min at -78 °C and then allowed
to warm to room temperature for 1.25 h. Aqueous 3 M K3PO4
(0.27 mL, 0.80 mmol) was added followed by the addition of
vinyl iodide 18 (126 mg, 0.16 mmol) in DMF (5 mL). PdCl2-
(dppf) (13 mg, 0.016 mmol) was added, and the resultant dark
solution was stirred for 16 h. Et2O was added, and the organic
solution was washed with H2O and then brine. The aqueous
layer was extracted with Et2O, and the combined extracts were
dried over Na2SO4. Filtration and concentration followed by
flash chromatography (6:1 to 4:1 hexanes-EtOAc with 1%
triethylamine) provided coupled product 27 (131 mg, 74%) as
1
a clear oil: Rf 0.55 (2:1 hexanes-EtOAc); H NMR (CDCl3) δ
7.43 (d, J ) 8.7 Hz, 2 H), 7.27 (d, J ) 8.7 Hz, 2 H), 6.87 (d, J
) 8.7 Hz, 2 H), 6.84 (d, J ) 8.7 Hz, 2 H), 6.58 (dt, J ) 17.1,
10.5 Hz, 1 H), 6.02 (t, J ) 11.1 Hz, 1 H), 5.58-5.46 (m, 2 H),
5.43 (s, 1 H), 5.26-5.19 (m, 2 H), 5.13 (d, J ) 10.2 Hz, 1 H),
5.07 (d, J ) 10.2 Hz, 1 H), 4.62-4.54 (m, 4 H), 4.46-4.36 (m,
4 H), 4.09-3.98 (m, 2 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.60-
3.56 (m, 2 H), 3.38 (s, 3 H), 3.15 (m, 1 H), 3.10 (m, 1 H), 3.09
(s, 3 H), 2.86 (m, 1 H), 2.68-2.53 (m, 2 H), 2.17 (t, J ) 12.3
Hz, 1 H), 1.96-1.72 (m, 4 H), 1.64 (s, 3 H), 1.59-1.51 (m, 2
H), 1.34 (m, 1 H), 1.16 (d, J ) 6.6 Hz, 3 H), 1.01-0.93 (m, 12
H), 0.98 (t, J ) 7.8 Hz, 9 H), 0.91 (s, 9 H), 0.82 (d, J ) 6.6 Hz,
3 H), 0.78 (d, J ) 6.6 Hz, 3 H), 0.63 (q, J ) 7.8 Hz, 6 H), 0.09
(s, 3 H), 0.07 (s, 3 H); 13C NMR (CDCl3) δ 159.58, 159.06,
134.85, 134.77, 132.35, 131.75, 131.14, 130.56, 130.40, 129.03,
127.24, 117.41, 113.72, 113.22, 101.28, 97.99, 93.88, 87.04,
84.89, 80.85, 77.69, 74.70, 74.01, 69.54, 67.81, 56.05, 55.50,
55.23, 40.57, 39.94, 37.94, 36.18, 35.99, 34.76, 33.92, 29.86,
25.90, 23.27, 18.76, 18.38, 18.03, 16.51, 14.14, 10.87, 10.63,
7.83, 7.20, 5.69, -4.39, -4.65. Anal. Calcd for C64H108O11Si2:
C, 69.27; H, 9.81. Found: C, 69.05; H, 9.65.
To a solution of carboxylic acid 30 (102 mg, 0.091 mmol) in
benzene (3.5 mL) and methanol (1 mL) was added dropwise
(trimethylsilyl)diazomethane (2 M in hexanes) until a yellow
tint persisted. After 15 min, the solvents were removed in
vacuo, and the residue was subjected to flash chromatography
(4:1 hexanes-EtOAc) to provide methyl ester 31 (84 mg, 82%)
as a clear oil: Rf 0.73 (2:1 hexanes-EtOAc); [R]20D -8.5 (c 1.4,
1
CHCl3); IR (film) 1739, 1616, 1035 cm-1; H NMR (CDCl3) δ
7.27 (d, J ) 8.7 Hz, 2 H), 7.25 (d, J ) 8.7 Hz, 2 H), 6.87 (d, J
) 8.7 Hz, 2 H), 6.82 (d, J ) 8.7 Hz, 2 H), 6.58 (dt, J ) 16.8,
10.8 Hz, 1 H), 6.02 (t, J ) 11.1 Hz, 1 H), 5.56 (d, J ) 11.1 Hz,
1 H), 5.48 (d, J ) 11.1 Hz, 1 H), 5.33-5.10 (m, 4 H), 4.67-
4.41 (m, 9 H), 4.31 (d, J ) 10.2 Hz, 1 H), 3.80 (s, 3 H), 3.79 (s,
3 H), 3.74 (dd, J ) 10.2, 2.4 Hz, 1 H), 3.68 (s, 3 H), 3.58 (t, J
) 5.4 Hz, 1 H), 3.37 (s, 3 H), 3.22 (s, 3 H), 3.14 (m, 2 H), 2.86
(m, 1 H), 2.71-2.55 (m, 3 H), 2.20 (t, J ) 12.0 Hz, 1 H), 1.95-
1.91 (m, 2 H), 1.85-1.67 (m, 3 H), 1.64 (s, 3 H), 1.43 (m, 1 H),
1.17 (d, J ) 6.9 Hz, 3 H), 0.94 (m, 21 H), 0.89 (s, 9 H), 0.82 (d,
Alcoh ol 28. A cold (-78 °C) solution of acetal 27 (131 mg,
0.12 mmol) in CH2Cl2 (5 mL) was treated with diisobutylalu-
minum hydride (1.16 mL, 1 M in hexane, 1.16 mmol). The

7892 J . Org. Chem., Vol. 63, No. 22, 1998
Marshall and J ohns
J ) 6.6 Hz, 3 H), 0.81 (d, J ) 6.9 Hz, 3 H), 0.62 (q, J ) 7.8 Hz,
6 H), 0.08 (s, 3 H), 0.04 (s, 3 H); 13C NMR (CDCl3) δ 175.97,
159.06, 158.75, 135.19, 135.01, 132.39, 131.30, 131.14, 130.52,
130.40, 129.03, 128.75, 117.34, 113.72, 113.39, 97.79, 94.16,
86.76, 84.87, 81.19, 77.65, 74.72, 73.03, 69.59, 68.11, 56.05,
55.70, 55.21, 51.62, 42.85, 41.37, 39.98, 38.14, 36.23, 36.07,
34.82, 34.40, 33.95, 25.88, 23.33, 18.75, 18.23, 18.06, 16.09,
13.94, 10.65, 9.79, 8.83, 7.19, 5.69, -4.30, -4.67. Anal. Calcd
for C65H110O12Si2: C, 68.50; H, 9.73. Found: C, 68.66; H, 9.76.
Alcoh ol 33. To a cold (0 °C) solution of triethylsilyl ether
31 (40 mg, 0.035 mmol) in methanol (5 mL) was added
p-TsOH‚H2O (∼2 mg, 0.010 mmol). The resultant mixture was
stirred for 1 h at 0 °C. Triethylamine (2 mL) was added, and
the mixture was concentrated under reduced pressure. The
residue was purified by flash chromatography (4:1 to 2:1
hexanes-EtOAc) to provide alcohol 33 (26 mg, 72%) as a clear
oil: Rf 0.58 (2:1 hexanes-EtOAc); [R]20D -12.2 (c 1.05, CHCl3);
NMR (CDCl3) δ 176.22, 159.09, 158.78, 156.91, 134.92, 133.69,
132.62, 132.14, 131.28, 131.02, 130.59, 130.23, 129.83, 129.07,
128.73, 117.88, 113.78, 113.42, 98.00, 94.15, 87.02, 84.79,
81.35, 78.51, 74.61, 73.07, 69.64, 68.08, 56.09, 55.71, 55.26,
55.23, 51.74, 42.90, 41.61, 38.09, 37.58, 36.57, 34.79, 34.47,
33.56, 29.69, 25.87, 23.12, 18.28, 18.04, 17.40, 16.45, 13.56,
9.80, 8.98, -4.23, -4.71. Anal. Calcd for C60H97NO13Si: C,
67.44; H, 9.15; N, 1.31. Found: C, 67.19; H, 9.39; N, 1.49.
(+)-Discod er m olid e (36). To a solution of methyl ester
34 (32 mg, 0.030 mmol) in CH2Cl2-H2O (18:1, 4 mL) was
added solid NaHCO3 (160 mg) followed by the dropwise
addition of a freshly prepared stock solution of DDQ (0.72 mL,
0.088 M in CH2Cl2, 0.063 mmol). The resultant green solution
was stirred for 1 h, and then an additional 0.5 mL (0.044 mmol)
of the stock solution of DDQ was added. After being stirred
for 1 h, the solvents were removed in vacuo, and the residue
was purified by flash chromatography (1:1 to 1:2 hexanes-
EtOAc) to provide diol 35 as a clear oil (21 mg, 85%).
1
IR (film) 3551 (br), 1740, 1033 cm-1; H NMR (CDCl3) δ 7.28
(d, J ) 8.7 Hz, 2 H), 7.25 (d, J ) 9.0 Hz, 2 H), 6.86 (d, J ) 9.0
Hz, 2 H), 6.81 (d, J ) 8.7 Hz, 2 H), 6.65 (dt, J ) 17.1, 10.5 Hz,
1 H), 6.15 (t, J ) 10.8 Hz, 1 H), 5.55 (t, J ) 10.5 Hz, 1 H),
5.39-5.08 (m, 5 H), 4.66-4.47 (m, 8 H), 4.47-4.40 (m, 2 H),
4.30 (d, J ) 10.5 Hz, 1 H), 3.79 (s, 3 H), 3.78 (s, 3 H), 3.73 (dd,
J ) 10.5, 2.4 Hz, 1 H), 3.68 (s, 3 H), 3.39 (m, 1 H), 3.37 (s, 3
H), 3.21 (s, 3 H), 3.14 (t, J ) 5.4 Hz, 1 H), 2.81 (m, 1 H), 2.71-
2.58 (m, 3 H), 2.27 (t, J ) 12.0 Hz, 1 H), 2.04 (m, 1 H), 1.96-
1.89 (m, 3 H), 1.70 (m, 1 H), 1.67 (s, 3 H), 1.44 (dd, J ) 13.5,
10.8 Hz, 1 H), 1.17 (d, J ) 7.2 Hz, 3 H), 1.04 (d, J ) 6.9 Hz, 3
H), 0.99 (d, J ) 6.6 Hz, 3 H), 0.97 (d, J ) 6.3 Hz, 3 H), 0.94 (d,
J ) 6.9 Hz, 3 H), 0.89 (s, 9 H), 0.86 (d, J ) 6.9 Hz, 3 H), 0.80
(d, J ) 6.9 Hz, 3 H), 0.07 (s, 3 H), 0.04 (s, 3 H); 13C NMR
(CDCl3) δ 176.01, 159.16, 158.77, 135.17, 132.46, 132.15,
131.29, 130.72, 130.54, 130.48, 129.15, 128.76, 118.26, 113.79,
113.40, 97.90, 94.16, 87.38, 86.78, 81.21, 77.08, 74.37, 73.03,
69.59, 68.09, 56.08, 55.70, 55.23, 51.66, 42.91, 41.45, 38.10,
36.93, 36.45, 36.19, 34.87, 34.64, 33.51, 25.87, 23.44, 18.27,
18.06, 17.06, 16.11, 13.89, 9.79, 8.96, 8.18, -4.28, -4.69.
Ca r ba m a te 34. A solution of alcohol 33 (41 mg, 0.040
mmol) in CH2Cl2 (3 mL) was treated with trichloroacetyl
isocyanate (5 µL, 0.042 mmol) at room temperature. After 10
min, the solution was concentrated under reduced pressure,
and the residue was taken up in methanol (4 mL). To this
solution was added K2CO3 (30 mg), and the mixture was
stirred for 1.25 h. The reaction mixture was concentrated
under reduced pressure, and the residue was taken up in Et2O.
The organic solution was washed with H2O and brine. The
aqueous layer was extracted with Et2O, and the combined
extracts were dried over Na2SO4. Filtration and concentration
followed by flash chromatography (2:1 hexanes-EtOAc) pro-
vided carbamate 34 (39 mg, 93%) as a foam: Rf 0.37 (2:1
To a solution of diol 35 (16 mg, 0.020 mmol) in THF (2 mL)
was added an aqueous solution of 4 N HCl (2 mL). The flask
was fitted with a glass stopper, and the resultant solution was
stirred at room temperature for 65 h. Saturated aqueous
NaHCO3 was added dropwise followed by EtOAc. The organic
solution was washed with brine. The aqueous layer was
extracted with EtOAc, and the combined extracts were dried
over Na2SO4. Filtration and concentration followed by flash
chromatography (10% CH3OH-CH2Cl2) provided (+)-disco-
dermolide (36) (8.1 mg, 72%) as a white amorphous solid: Rf
0.25 (10% CH3OH-CH2Cl2); [R]20 +17.0 (c 0.41, CH3OH); 1H
D
NMR (CDCl3) δ 6.61 (dt, J ) 16.8, 10.5 Hz, 1 H), 6.02 (t, J )
11.1 Hz, 1 H), 5.52 (dd, J ) 11.1, 7.8 Hz, 1 H), 5.44 (t, J )
10.5 Hz, 1 H), 5.35 (t, J ) 10.5 Hz, 1 H), 5.21 (d, J ) 16.8 Hz,
1 H), 5.16 (d, J ) 10.0 Hz, 1 H), 5.12 (d, J ) 10.8 Hz, 1 H),
4.77-4.67 (m, 4 H), 4.62 (td, J ) 9.9, 2.1 Hz, 1 H), 3.74 (t, J
) 3.9 Hz, 1 H), 3.28 (m, 1 H), 3.19 (dd, J ) 6.9, 4.8 Hz, 1 H),
2.99 (m, 1 H), 2.77 (m, 1 H), 2.69 (qd, J ) 7.2, 4.5 Hz, 1 H),
2.60 (m, 1 H), 2.60-1.90 (m, 10 H), 1.67 (ddd, J ) 13.8, 10.2,
3.0 Hz, 1 H), 1.64 (d, J ) 0.9 Hz, 3 H), 1.31 (d, J ) 7.5 Hz, 3
H), 1.07 (d, J ) 6.9 Hz, 3 H), 1.02 (d, J ) 6.3 Hz, 3 H), 0.99 (d,
J ) 6.3 Hz, 3 H), 0.98 (d, J ) 6.9 Hz, 3 H), 0.94 (d, J ) 6.9 Hz,
3 H), 0.83 (d, J ) 6.0 Hz, 3 H); 13C NMR (CDCl3) δ 174.00,
157.14, 134.29, 133.65, 133.35, 132.83, 132.11, 129.91, 129.71,
117.96, 79.00, 78.79, 75.66, 73.17, 64.30, 43.12, 40.93, 37.30,
36.10, 35.95, 35.63, 35.31, 34.75, 33.03, 23.28, 18.36, 17.46,
15.71, 15.60, 13.69, 12.60, 8.98.
Ack n ow led gm en ts. This investigation was supported by
Research Grant R01-AI37422 from the National Institute of
Allergy and Infectious Diseases. B.J . is the recipient of an NIH
postdoctoral fellowship (GM19366) from the National Insti-
tutes of General Medical Sciences. We thank Professor David
Evans for helpful insight regarding the use of Et3Si protection
for R,R′-branched secondary alcohols. The 1H and 13C NMR
spectra of (-)-discodermolide in CDCl3 were provided by
Professor Amos B. Smith, III, to whom we are grateful.
hexanes-EtOAc); [R]20 -3.7 (c 1.1, CHCl3); IR (film) 3498,
D
1
3365, 1730, 1612 cm-1; H NMR (500 MHz, CDCl3) δ 7.30 (d,
J ) 8.5 Hz, 2 H), 7.24 (d, J ) 8.5 Hz, 2 H), 6.88 (d, J ) 8.5 Hz,
2 H), 6.82 (d, J ) 8.5 Hz, 2 H), 6.61 (dt, J ) 16.5, 11.0 Hz, 1
H), 6.04 (t, J ) 11.0 Hz, 1 H), 5.57 (t, J ) 10.0 Hz, 1 H), 5.38
(t, J ) 11.0 Hz, 1 H), 5.26-5.20 (m, 2 H), 5.14 (d, J ) 10.0 Hz,
1 H), 5.06 (d, J ) 9.5 Hz, 1 H), 4.75 (m, 1 H), 4.65-4.41 (m, 11
H), 4.30 (d, J ) 10.5, 1 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.71 (dd,
J ) 10.0, 2.5 Hz, 1 H), 3.68 (s, 3 H), 3.38 (s, 3 H), 3.20 (s, 3 H),
3.12 (m, 2 H), 2.97 (m, 1 H), 2.66-2.56 (m, 3 H), 2.24 (t, J )
12.0 Hz, 1 H), 2.07-1.99 (m, 2 H), 1.93 (m, 1 H), 1.77 (m, 1
H), 1.69 (dd, J ) 13.5, 11.0 Hz, 1 H), 1.64 (s, 3 H), 1.41 (dd, J
) 12.0, 10.5 Hz, 1 H), 1.17 (d, J ) 7.0 Hz, 3 H), 1.04 (d, J )
7.0 Hz, 3 H), 0.98 (d, J ) 6.5 Hz, 3 H), 0.96 (d, J ) 6.5 Hz, 3
H), 0.95 (d, J ) 6.5 Hz, 3 H), 0.89 (s, 9 H), 0.82 (d, J ) 6.5 Hz,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
1
cedures for 1, 23, 24, 25, and intermediates leading to 23. H
NMR spectra for 12, 13, 17, 18, 27, 28, 33, 34, and 36 and
comparison spectra for 36 (22 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
3 H), 0.81 (d, J ) 7.0 Hz, 3 H), 0.07 (s, 3 H), 0.04 (s, 3 H); 13
C
J O9811423