Synthesis of Stereopentad Subunits of Zincophorin and Rifamycin-S through Use of Chiral Allenyltin Reagents

Article abstract of DOI:10.1021/jo980137w

The anti,anti adduct 3, from addition of the allenic stannane (P)-2 to the a-methyl-β-OBn aldehyde (S)-1 promoted by SnCl₄, was converted to the stereopentad 6 by a sequence involving reduction to the (E)-allylic alcohol with Red-Al, Sharpless asymmetric epoxidation, and addition of the higherorder methyl cyanocuprate to the derived epoxide 5. Stereopentad 6 was converted to the acetonide acetal 15, an intermediate in Danishefsky's synthesis of zincophorin. By a similar sequence, adduct ent-4 was converted, via diol 19, to stereopentad 22, an intermediate in Kishi's synthesis of rifamycin-S. An alternative route to diol 19 was achieved from the MOM-protected derivative 28 of epoxy diol 18.

Full text of DOI:10.1021/jo980137w

J . Org. Chem. 1998, 63, 3701-3705
3701
Syn th esis of Ster eop en ta d Su bu n its of Zin cop h or in a n d
Rifa m ycin -S th r ou gh Use of Ch ir a l Allen yltin Rea gen ts
J ames A. Marshall* and Michael R. Palovich
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22901
Received J anuary 26, 1998
The anti,anti adduct 3, from addition of the allenic stannane (P)-2 to the R-methyl-â-OBn aldehyde
(S)-1 promoted by SnCl4, was converted to the stereopentad 6 by a sequence involving reduction to
the (E)-allylic alcohol with Red-Al, Sharpless asymmetric epoxidation, and addition of the higher-
order methyl cyanocuprate to the derived epoxide 5. Stereopentad 6 was converted to the acetonide
acetal 15, an intermediate in Danishefsky’s synthesis of zincophorin. By a similar sequence, adduct
ent-4 was converted, via diol 19, to stereopentad 22, an intermediate in Kishi’s synthesis of
rifamycin-S. An alternative route to diol 19 was achieved from the MOM-protected derivative 28
of epoxy diol 18.
SE2′ additions of chiral allenylmetal compounds to
aldehydes give rise to homopropargylic alcohols with the
creation of two contiguous stereocenters (eq 1).1 Though
little studied to date, such reactions have the potential
for widespread applications in the synthesis of natural
products, such as polypropionates, containing multiple
proximal stereocenters.2 Ideally, the allenylmetal re-
agent would be available in either enantiomeric form and
would be configurationally stable under the reaction
conditions.
deals with the conversion of the enantiomeric anti,anti
isomers of VI to subunits of zincophorin6 and rifamycin-
S.7
In his pioneering studies on polypropionate synthesis,
Kishi devised a reiterative epoxidation-methyl cuprate
sequence to transform allylic alcohols to syn or anti triad
units.7 This approach seemed well suited to our present
objectives, provided the intermediate allylic alcohols VII
could be epoxidized with acceptable diastereoselectivity
and the derived epoxy alcohols VIII could be induced to
undergo efficient regioselective addition of methylcopper
reagents (eq 3).
We have found that allenylstannanes and, to a lesser
extent, allenylindium halides fulfill these conditions in
reactions with aldehydes.3,4 With chiral R-methyl-â-
oxygenated aldehydes such as IV and the allenyl re-
agents V, it is possible to produce any of the four isomeric
stereotriads VI5 and the enantiomers through appropri-
ate matching of substrate and reagent stereogenicity and
proper choice of reaction conditions (eq 2).3
Our current efforts are concerned with the further
elaboration of stereotriads VI to stereopentad subunits
of polypropionate natural products. The present study
The anti,anti,anti,anti stereopentad 6 is relatively
(1) Yamamoto, H. in Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, 1991; Vol. 2, Chapter 1.3.
(2) Cf. Boeckman, R. K., J r.; Goldstein, S. W. In The Total Synthesis
of Natural Products; ApSimon, J ., Ed.; J ohn Wiley and Sons: New
York, 1988; Vol. 7, Chapter 1.
(3) Marshall, J . A.; Perkins, J . F.; Wolf, M. A. J . Org. Chem. 1995,
60, 5556.
(4) Marshall, J . A.; Palovich, M. R. J . Org. Chem. 1997, 62, 6001.
Marshall, J . A.; Lu, Z. H.; J ohns, B. A. J . Org. Chem. 1998, 63, 817.
(5) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489.
difficult to access by aldol methodology.8 However, it was
(6) Cf. Danishefsky, S. J .; Selnick, H. G.; Zelle, R. E.; DeNinno, M.
P. J . Am. Chem. Soc. 1988, 110, 4368. Cywin, C. L.; Kallmerten, J .
Tetrahedron Lett. 1993, 34, 1103.
(7) Cf. Iio, H.; Nagaoka, H.; Kishi, Y. J . Am. Chem. Soc. 1980, 102,
7965 and preceding papers. Nagaoka, H.; Kishi, Y. Tetrahedron 1981,
37, 3873. Harada, T.; Kagamihara, Y.; Tanaka, S.; Sakamoto, K.; Oku,
A. J . Org. Chem. 1992, 57, 1637.
S0022-3263(98)00137-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/02/1998

3702 J . Org. Chem., Vol. 63, No. 11, 1998
Marshall and Palovich
Sch em e 1
This was achieved through protection as the primary
diphenyl-tert-butylsilyl (DPS) ether 7, formation of ac-
etonide 8, and hydrogenolysis of the benzyl ether. The
resulting alcohol 9 was oxidized to aldehyde 10 with
tetrapropylammonium perruthenate and 4-methylmor-
pholine N-oxide in excellent yield.12 In contrast, Swern
oxidation of 9 gave only products of decomposition.13
Addition of the dioxolanyl Grignard reagent 11 to
aldehyde 10 afforded a single adduct in 70% yield.14 It
was found that a large excess of the Grignard reagent
was required, presumably the consequence of multiple
basic oxygen centers in aldehyde 10. We had expected
the stereochemistry of the alcohol adduct 12 to be as
depicted based on a chelated transition state for the
addition. Support for this assignment was secured from
1H NMR analysis of the (R)- and (S)-Mosher esters 13
and 14.15 Additional confirmation of stereochemistry was
provided by comparison of spectral data and optical
rotation of the benzyloxymethyl (BOM) ether 15 with the
published values.6
As a second target of this synthetic methodology we
selected triol 19, a potential C21-C27 subunit of rifa-
mycin-S.7 The precursor, anti,anti stereotriad 17, was
prepared as before but starting with the enantiomeric
aldehyde (R)-1 and stannane (M)-16 (Scheme 2). The
derived allylic alcohol ent-4 was epoxidized by the same
Sharpless protocol to afford the â-epoxide 18 as the major
isomer of a 91:9 mixture. Evidently, allylic alcohol 4 (ent-
4) exhibits only modest facial preferences in these
directed epoxidations, thus allowing significant reagent
control. Surprisingly, epoxide 18 afforded a 64:36 mix-
ture of 1,3-diol 19 and 1,2-diol 21 upon treatment with
the higher-order cyanocuprate. The enantiomer of diol
19, an anti,anti,syn,anti stereopentad, has previously
been prepared by an aldol route.16 The reported rotation
is nearly equal and opposite in sign to that of 19. The
structure of diol 21 was confirmed by its cleavage with
NaIO4 to an epimeric mixture of lactols, which afforded
the γ-lactone 24 upon further oxidation.
envisioned that this steric array should be readily avail-
able by the proposed sequence (eq 3), and we therefore
selected triol 6, a potential C7-C13 subunit of zincoph-
orin, as the initial target of these investigations. The
anti,anti precursor 3 was readily obtained through ad-
dition of the allenylstannane (P)-2 to the aldehyde (S)-1
in the presence of 1 equiv of SnCl4, as previously
described (Scheme 1).3 Treatment with Red-Al in THF
effected removal of the acetate and reduction of the triple
bond to provide the (E)-allylic alcohol 4. Substrate-
directed epoxidation of 4 with m-CPBA yielded a 1:1
mixture of diastereomeric epoxides. The use of VO(acac)2
and t-BuOOH gave a somewhat better, but still unac-
ceptable, 1.5:1 mixture of diastereomers.10 However,
reagent controlled epoxidation by the Sharpless meth-
odology, with (+)-diisopropyl tartrate as the chiral ligand,
produced the desired â-epoxide 5 as the major component
of an 87:13 mixture.9
Epoxy alcohol 5 proved relatively unreactive toward
cuprates. Exposure to 10 equiv of the Gilman Me2CuLi
reagent afforded triol 6 in 70% yield after 30 h at 0 °C.
The higher-order cyanocuprate proved more serviceable
as it provided 6 in 85% yield under comparable condi-
tions.11 The relative stereochemistry of this adduct was
confirmed by single-crystal X-ray analysis.
It was of interest to demonstrate the potential utility
of triol 6 by conversion to the acetal acetonide 15, a key
compound in Danishefsky’s synthesis of zincophorin.6
Stereopentad 19 was converted to the acetonide alcohol
23 through hydrogenolysis of the DPS benzyl ether 22.
The spectra and optical rotation of 23 were in accord with
the reported values.7
The formation of diol 21 from attack of the cyanocu-
prate at what we perceived as the more hindered epoxide
center was unexpected. None of the analogous product
was detected in the related displacement on the stere-
oisomeric epoxide 5. A closer inspection of epoxide 18
with the aid of molecular modeling showed that both of
the hydroxyl groups are well positioned to direct a
coordinated cuprate to the backside of the epoxide (Figure
1). Thus, we postulated that the secondary alcohol
moiety might be responsible for the formation of the 1,2-
diol 21. We therefore decided to protect this alcohol as
the MOM ether 28. This was done by starting from the
known propargylic derivative 25,3 prepared along the
lines of the pivalate analogue 17 (Scheme 3). The choice
of pivalate or acetate in these systems is somewhat
arbitrary. In this case a supply of the acetate intermedi-
ate happened to be on hand, whereas 17 was depleted.
(8) Cf. Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis
1994, 629.
(9) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(10) Marino, J . P.; de la Pradilla, R. F.; Laborde, E. J . Org. Chem.
1987, 52, 4898.
(12) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J .
Chem. Soc., Chem. Commun. 1987, 1625.
(13) Omurka, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(14) Buchi, G.; West, H. J . Org. Chem. 1969, 34, 1122.
(15) Ohtani, I.; Kusumi, T.; Kashman, K.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092.
(11) Lipshutz, B. H.; Parker D.; Kozlowski, J . A.; Miller, R. D. J .
Org. Chem. 1983, 48, 3334.
(16) Paterson, I.; Cannan, J . A. Tetrahedron Lett. 1992, 33, 797.

Stereopentad Subunits of Zincophorin and Rifamycin-S
Sch em e 2a
J . Org. Chem., Vol. 63, No. 11, 1998 3703
a
Key: (a) (+)-DIPT, Ti(O-i-Pr)4, t-BuOOH, CH2Cl2.
stereotriad array. This work, and our previous studies
based on the anti,syn triad,4 suggest that the allene
methodology can compliment more well-established routes
to such intermediates. Major advantages of the present
approach include the ease of preparing the chiral re-
agents and the use of all structural features of the
adducts for further structural and stereochemical elabo-
rations. The disposal of tin byproducts is perceived as a
possible problem. For that reason, alternative chiral
allenylmetal reagents are currently under investigation.18
Exp er im en ta l Section
1H NMR and 13C NMR spectra were measured at 300 and
75 MHz in CDCl3.
F igu r e 1. Chem 3D representation of a minimized structure
(Macromodel 4.5)17 of epoxy diol 18 illustrating the possible
involvement of the hydroxyl groups in the cuprate displace-
ment leading to diols 19 and 21.
(2S,3R,4R)-(-)-1-(Ben zyloxy)-2,4-d im eth yl-7-a cetoxy-5-
h ep tyn -3-ol (3). To a solution of allenic stannane (P)-2 (3.5
g, 8.5 mmol) in CH2Cl2 (20 mL) at 0 °C was added SnCl4 (8.5
mL, 8.5 mmol). After 40 min, the reaction was cooled to -78
°C, and aldehyde (S)-1 (1.3 g, 7.1 mmol) in CH2Cl2 (5 mL) was
added dropwise. After 4.5 h, the reaction was quenched with
10% HCl (20 mL) and extracted with ether. The combined
organic extracts were washed with brine and dried over
anhydrous MgSO4, and triethylamine (3 mL) was added. The
resulting slurry was stirred at 0 °C for 30 min and filtered
through Celite with ether. The filtrate was concentrated under
reduced pressure to give the crude alcohol contaminated with
tin byproducts. This material was chromatographed twice on
silica gel (eluting first with 35% ether in hexanes and then
with 35% ethyl acetate in hexanes) to give 1.9 g (87%) of
alcohol 33 as an inseparable 97:3 mixture of diastereomers:
[R]D -1.4 (c 1.6, CHCl3); 1H NMR δ 7.32 (m, 5H), 4.68 (d, J )
1.8 Hz, 2H), 4.52 (s, 2H), 3.58 (m, 2H), 3.35 (dd, J ) 8.4, 2.9
Hz, 1H), 2.73 (m, 1H), 2.09 (m, 1H), 2.07 (s, 3H), 1.28 (d, J )
7.0 Hz, 3H), 0.91 (d, J ) 7.0 Hz, 3H).
Sch em e 3a
a
Key: (a) (+)-DIPT, Ti(O-i-Pe)4, t-BuOOH, CH2Cl2; (b)
Me2Cu(CN)Li2.
(2S,3R,4R)-(+)-1-(Ben zyloxy)-2,4-d im eth yl-5-h ep ten e-
3,7-d iol (4). To a solution of alcohol 3 (1.84 g, 6.05 mmol) in
THF (70 mL) at 0 °C was added Red-Al (19.0 mL, 69.7 mmol).
The mixture was allowed to warm to room temperature, and
after 48 h, the reaction was quenched with a saturated solution
of sodium potassium tartrate and extracted with ethyl acetate.
The combined organic extracts were washed with brine, dried
Following a sequence parallel to that of Scheme 2, we
prepared the epoxy alcohol 28. In this case a single
diastereomer was formed in the epoxidation step. Treat-
ment with the higher order cyanocuprate effected conver-
sion of epoxy alcohol 28 to the 1,3-diol 29 as the sole
product. Confirmation of structure was achieved through
cleavage of the MOM ether to give triol 19.
(17) Mohamadi, F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.;
Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J .
Comput. Chem. 1990, 11, 440.
The foregoing syntheses illustrate the potential of
chiral allenic stannane methodology for the preparation
of polypropionate segments containing the anti,anti
(18) Marshall, J . A.; Adams, N. D. J . Org. Chem. 1997, 62, 8976.

3704 J . Org. Chem., Vol. 63, No. 11, 1998
Marshall and Palovich
over anhydrous MgSO4, and concentrated under reduced
pressure. The crude product was chromatographed on silica
gel (50% ethyl acetate in hexanes) to give 1.55 g (97%) of diol
7-(b en zyloxy)-2,4,6-t r im et h ylh ep t a n e-3,5-t r iol 3,5-Ace-
ton id e (8). To a solution of diol 7 (0.941 g, 1.76 mmol) in
2,2-dimethoxypropane (5 mL) at room temperature was added
CSA (0.041 g, 0.176 mmol). After 3 h, the reaction was
quenched with water (10 mL) and extracted with ether. The
combined organic extracts were washed with brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure.
The crude product was chromatographed on silica gel (3% ethyl
acetate in hexanes) to give 0.938 g (93%) of acetal 8 as a
colorless oil: [R]D -14.6 (c 2.06, CHCl3); 1H NMR δ 7.74-7.60
(m, 5H), 7.47-7.17 (m, 10H), 4.34 (q, J ) 16.8, 11.7 Hz, 2H),
3.87 (dd, J ) 10.3, 6.6 Hz, 1H), 3.56 (dd, J ) 9.2, 4.8 Hz, 1H),
3.44 (dd, J ) 10.3, 6.6 Hz, 1H), 3.33 (m, 2H), 3.24 (t, J ) 8.8
Hz, 1H), 2.06 (m, 2H), 1.89 (m, 1H), 1.32 (s, 3H), 1.27 (s, 3H),
1.03 (s, 9H), 1.01 (d, J ) 7.0 Hz, 3H), 0.94 (d, J ) 6.9 Hz, 3H),
0.72 (d, J ) 7.0 Hz, 3H); 13C NMR δ 139.5, 136.2, 134.6, 134.5,
130.1, 128.8, 128.2, 128.0, 98.4, 78.7, 78.4, 73.6, 72.1, 65.2, 37.0,
34.8, 33.8, 30.6, 27.5, 19.8, 19.7, 16.6, 16.2, 12.6. Anal. Calcd
for C36H50O4Si: C, 75.22; H, 8.77. Found: C, 75.29; H, 8.81.
(2S,3S,4S,5R,6R)-(-)-1-[(ter t-Bu tyld ip h en ylsilyl)oxy]-
4 as a clear oil: [R]D +13.0 (c 1.6, CHCl3); IR (neat) 3439 cm-1
;
1H NMR δ 7.41-7.20 (m, 5H), 5.84-5.60 (m, 2H), 4.51 (t, J )
12.8 Hz, 2H), 4.12 (d, J ) 5.5 Hz, 2H), 3.55 (m, 2H), 3.37 (dd,
J ) 8.1, 3.7 Hz, 1H), 2.38 (m, 1H), 1.91 (m, 1H), 1.10 (d, J )
6.9 Hz, 3H), 0.88 (d, J ) 6.9 Hz, 3H); 13C NMR δ 138.4, 133.8,
130.6, 128.9, 128.2, 128.1, 79.9, 75.3, 74.0, 63.8, 39.7, 36.8, 18.4,
14.7. Anal. Calcd for C16H24O3: C, 72.69; H, 9.15. Found:
C, 72.75; H, 9.14.
(2S,3S,4S,5S,6R)-(+)-1-(Ben zyloxy)-2,4-d im et h yl-5,6-
ep oxy-3,7-h ep ta n ed iol (5). To a solution of (+)-diisopropyl
tartrate (0.086 mL, 0.411 mmol) in CH2Cl2 (25 mL) at -25 °C
was added Ti(O-i-Pr)4 (0.102 mL, 0.342 mmol). After 10 min,
tert-butyl hydroperoxide (2.5 mL, 13.7 mmol) was added
dropwise. After 30 min, allylic alcohol 4 (1.81 g, 6.85 mmol)
in CH2Cl2 (3 mL) was added dropwise. After 18 h, the reaction
was quenched with water (20 mL) and stirred at 0 °C. After
1 h, brine (10 mL) and a saturated solution of NaOH (10 mL)
were added, and the mixture was stirred at room temperature.
After 1 h, the mixture was extracted with ethyl acetate, and
the combined organic extracts were washed with brine, dried
over MgSO4, and concentrated under reduced pressure. The
crude product was chromatographed on silica gel (60% ethyl
acetate in hexanes) to give 1.81 g (94%) of epoxide 5 as a
separable 87:13 mixture of diastereomers: [R]D ) +10.8 (c 1.57,
2,4,6-tr im eth ylh ep ta n e-3,5,7-tr iol 3,5-Aceton id e (9).
A
solution of acetal 8 (0.93 g, 1.6 mmol) in ethyl acetate (10 mL)
was stirred with 5% Pd/C (1.1 g) under an atmosphere of
hydrogen for 17 h. The mixture was filtered through Celite
with ether and concentrated under reduced pressure. The
crude product was chromatographed on silica gel (15% ethyl
acetate in hexanes) to give 0.66 g (85%) of alcohol 9 as a
1
CHCl3); IR (neat) 3431 cm-1; H NMR δ 7.39-7.23 (m, 5H),
colorless oil: [R]D -2.1 (c 1.71, CHCl3); IR (neat) 3487 cm-1
;
4.53 (s, 2H), 4.00-3.86 (m, 1H), 3.67-3.56 (m, 2H), 3.53-3.43
(m, 2H), 3.17 (dd, J ) 7.7, 2.6 Hz, 1H), 2.92, (m, 1H), 2.21 (m,
1H), 1.61 (m, 2H), 1.03 (d, J ) 6.9 Hz, 3H), 0.90 (d, J ) 6.9
Hz, 3H); 13C NMR δ 138.2, 129.0, 128.3, 128.2, 80.4, 76.0, 74.0,
62.8, 57.3, 56.9, 38.8, 36.6, 14.7, 14.6. Anal. Calcd for
1H NMR δ 7.74-7.63 (m, 4H), 7.49-7.32 (m, 6H), 3.86 (m, 2H),
3.42 (m, 4H), 2.05 (m, 1H), 1.94 (m, 1H), 1.81 (m, 1H), 1.33 (s,
3H), 1.32 (s, 3H), 1.11 (d, J ) 7.0 Hz, 3H), 1.04 (s, 9H), 0.94
(d, J ) 7.0 Hz, 3H), 0.68 (d, J ) 7.0 Hz, 3H); 13C NMR δ 136.2,
134.4, 130.1, 128.2, 98.8, 81.2, 78.1, 65.0, 64.1, 37.0, 34.8, 34.3,
30.7, 27.4, 19.7, 19.3, 16.1, 16.0, 12.5. Anal. Calcd for
C
16H24O4: C, 68.55; H, 8.63. Found: C, 68.20; H, 8.60.
(2S,3S,4R,5R,6R)-(-)-1-(Ben zyloxy)-2,4,6-tr im eth yl-3,5,7-
C
29H44O4Si: C, 71.86; H, 9.15. Found: C, 71.78; H, 9.18.
(2R,3R,4R,5R,6R)-7-[(ter t-Bu tyldiph en ylsilyl)oxy]-2,4,6-
h ep ta n etr iol (6). To a suspension of CuCN (0.66 g, 7.4 mmol)
in THF (0.25 mL) at -78 °C was added MeLi (11 mL, 15
mmol), and the mixture was allowed to warm to 0 °C. After
30 min, epoxide 5 (0.10 g, 0.37 mmol) was added dropwise.
After 36 h, the reaction was quenched with a 9:1 saturated
NH4Cl/NH4OH solution (200 mL) and stirred at room temper-
ature until a blue color persisted. The mixture was extracted
with ethyl acetate, and the combined organic extracts were
washed with brine, dried over anhydrous MgSO4, and concen-
trated under reduced pressure. The crude product was chro-
matographed on silica gel (50% ethyl acetate in hexanes) to
give 0.093 g (85%) of triol 6 as a white solid: mp 85.5-87 °C;
[R]D -7.5 (c 4.61, CHCl3); IR (neat) 3383 cm-1; 1H NMR δ 7.41-
7.24 (m, 5H), 4.52 (dd, J ) 13.6, 12.5 Hz, 2H), 3.91 (dd, J )
11.0, 2.6 Hz, 1H), 3.75 (dd, J ) 9.5, 3.7 Hz, 1H), 3.64-3.44
(m, 4H), 2.08 (m, 1H), 1.89 (m, 2H), 1.14 (d, J ) 7.3 Hz, 6H),
0.79 (d, J ) 6.6 Hz, 3H); 13C NMR δ 138.2, 129.0, 128.4, 128.2,
83.2, 82.6, 74.1, 73.0, 65.4, 39.5, 36.5, 35.7, 16.2, 15.8, 15.1.
Anal. Calcd for C17H28O4: C, 68.89; H, 9.52. Found: C, 69.04;
H, 9.56.
tr im eth yl-3,5-d ih yd r oxyh ep ta n a l 3,5-Aceton id e (10). To
a solution of alcohol 9 (100 mg, 0.21 mmol) in CH2Cl2 (2 mL)
were added NMO (0.036 g, 0.31 mmol) and crushed 4 Å
molecular sieves (0.10 g). After 15 min, TPAP (0.004 g, 0.01
mmol) was added. After 5 min, the mixture was diluted with
hexanes (10 mL), filtered through Celite with ether, and
concentrated under reduced pressure to give 96 mg (96%) of
aldehyde 10, which was used in the next step without further
purification: 1H NMR δ 9.71 (d, J ) 1.95 Hz, 1H), 7.78-7.59
(m, 4H), 7.48-7.29 (m, 6H), 3.85 (dd, J ) 10.3, 6.8 Hz, 1H),
3.61 (dd, J ) 10.7, 1.9 Hz, 1H), 3.42 (m, 2H), 2.51 (m, 1H),
2.03 (m, 2H), 1.37 (s, 3H), 1.32 (s, 3H), 1.13 (d, J ) 6.4 Hz,
3H), 1.04 (s, 9H), 0.93 (d, J ) 6.8 Hz, 3H), 0.74 (d, J ) 6.8 Hz,
3H).
Hyd r oxy Aceta l 12. To a suspension of Mg turnings (0.12
g, 4.92 mmol) in THF (3 mL) at room temperature was added
2-(2-bromoethyl)-1,3-dioxolane (0.50 mL, 4.28 mmol). After 1
h, the mixture was cooled to 0 °C, and aldehyde 10 (0.10 g,
0.214 mmol) in THF (0.20 mL) was added. After 20 min, the
reaction was quenched with saturated NH4Cl (5 mL) and
extracted with ether. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and concen-
trated under reduced pressure. The crude product was chro-
matographed on silica gel (20% ethyl acetate in hexanes) to
give 0.088 g (70%) of the alcohol 12 as a colorless oil: [R]D
(2S,3S,4S,5R,6R)-(-)-1-[(ter t-Bu tyld ip h en ylsilyl)oxy]-
7-(ben zyloxy)-2,4,6-tr im eth yl-3,5-h ep ta n ed iol (7). To a
solution of triol 6 (0.572 g, 1.93 mmol) in DMF (5 mL) at 0 °C
were added imidazole (0.180 g, 2.70 mmol) and DPSCl (0.60
mL, 2.32 mmol), and the mixture was allowed to warm to room
temperature. After 18 h, the reaction was quenched with
water (10 mL) and extracted with ethyl ether. The combined
organic layers were washed with brine, dried over anhydrous
MgSO4, and concentrated under reduced pressure. The crude
product was chromatographed on silica gel (25% ethyl acetate
in hexanes) to give 0.974 g (94%) of diol 7 as a colorless oil:
1
+0.60 (c 5.65, CHCl3); IR (neat) 3519 cm-1; H NMR δ 7.76-
7.60 (m, 4H), 7.48-7.27 (m, 6H), 4.85 (t, J ) 4.4 Hz, 1H), 3.98-
3.73 (m, 6H), 3.51-3.33 (m, 3H), 2.06 (m, 2H), 1.87-1.43 (m,
5H), 1.34 (s, 3H), 1.33 (s, 3H), 1.05 (s, 9H), 1.00 (d, J ) 7.0
Hz, 3H), 0.93 (d, J ) 7.0 Hz, 3H), 0.68 (d, J ) 6.6 Hz, 3H); 13
C
[R]D -12.0 (c 1.36, CHCl3); IR (neat) 3423 cm-1
;
1H NMR δ
NMR δ 136.1, 134.2, 130.0, 128.2, 105.1, 98.9, 82.0, 78.1, 70.1,
65.3, 64.9, 36.9, 36.5, 33.7, 31.2, 30.6, 29.7, 27.4, 19.6, 19.3,
16.0, 12.3, 11.5. Anal. Calcd for C34H52O6Si: C, 69.82; H, 8.96.
Found: C, 69.85; H, 9.03.
7.74-7.60 (m, 5H), 7.48-7.19 (m, 10H), 4.46 (s, 2H), 3.76 (dq,
J ) 10.3, 9.9 Hz, 2H), 3.56 (m, 4H), 2.15-1.82 (m, 3H), 1.13
(d, J ) 7.3 Hz, 3H), 1.10 (d, J ) 7.0 Hz, 3H), 1.05 (s, 9H), 0.77
(d, J ) 6.6 Hz, 3H); 13C NMR δ 136.2, 136.1, 133.6, 130.4,
129.0, 128.4, 128.2, 128.1, 82.2, 81.9, 74.0, 73.0, 66.7, 39.9, 37.5,
36.0, 27.4, 19.7, 16.5, 16.2, 15.1. Anal. Calcd for C32H44O4Si:
C, 73.80; H, 8.52. Found: C, 73.77; H, 8.56.
Sta n d a r d P r oced u r e for F or m a tion of Mosh er Ester s.
(R)-Mosh er Ester 13. To a solution of alcohol 12 (17.0 mg,
0.029 mmol) in CH2Cl2 (0.5 mL) at room temperature were
added (R)-MPTA (68.0 mg, 0.29 mmol), DCC (60.0 mg, 0.299
mmol) and DMAP (35.0 mg, 0.29 mmol). After 24 h, the
(2S,3S,4S,5R,6R)-(-)-1-[(ter t-Bu tyld ip h en ylsilyl)oxy]-

Stereopentad Subunits of Zincophorin and Rifamycin-S
J . Org. Chem., Vol. 63, No. 11, 1998 3705
reaction was quenched with water (1 mL) and extracted with
ether. The combined organic layers were washed with brine,
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The crude product was chromatogrpahed on silica
gel (15% ethyl acetate in hexanes) to give 19.1 mg (82%) of
Mosher ester 13: 1H NMR δ 7.75-7.65 (m, 4H), 7.63-7.56
(m, 2H), 7.45-7.30 (m, 9H), 5.46 (m, 1H), 4.75 (t, J ) 4.4 Hz,
1H),19 3.95-3.70 (m, 6H), 3.55 (s, 3H), 3.47 (dd, J ) 10.3, 6.6
Hz, 1H), 3.36 (dd, J ) 9.9, 2.2 Hz, 1H), 3.27 (dd, J ) 10.3, 2.9
Hz, 1H), 2.02 (m, 1H), 1.95-1.39 (m, 6H), 1.30 (s, 3H), 1.21
(s, 3H), 1.05 (s, 9H), 0.99 (d, J ) 7.0 Hz, 3H), 0.95 (d, J ) 7.0
Hz, 3H), 0.68 (d, J ) 6.6 Hz, 3H).19
(S)-Mosh er Der iva tive 14. The standard procedure was
followed with alcohol 12 (10.9 mg, 0.019 mmol), (S)-MPTA
(0.045 g, 0.19 mmol), DCC (0.039 g, 0.19 mmol), and DMAP
(0.023 g, 0.19 mmol) in CH2Cl2 (0.5 mL) at room temperature
for 26 h to give 3.5 mg of recovered alcohol and 9.5 mg (91%;
based on recovered starting material) of Mosher ester 14: 1H
NMR19 δ 7.74-7.63 (m, 4H), 7.61-7.51 (m, 2H), 7.45-7.28 (m,
9H), 5.43 (m, 1H), 4.82 (t, J ) 4.0 Hz, 1H),17 3.95-3.71 (m,
6H), 3.50 (s, 3H), 3.32 (m, 1H), 3.20 (dd, J ) 9.9, 4.0 Hz, 1H),
2.00 (m, 1H), 1.90-1.57 (m, 6H), 1.27 (s, 3H), 1.14 (s, 3H), 1.04
(s, 9H), 0.96 (d, J ) 7.0 Hz, 3H), 0.91 (d, J ) 7.3 Hz, 3H), 0.62
(d, J ) 6.6 Hz, 3H).19
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and concentrated under reduced
pressure. The crude product was chromatographed multiple
times (5% ethyl acetate in hexanes) to remove impurities
present from the BOMCl to afford 10.0 mg (44%) of the known
BOM ether 156 as a colorless oil: [R]D +25.0 (c 0.60, CHCl3)
(lit.6 [R]D +21.9 (c 1.83, CHCl3)); 1H NMR δ 7.73-7.60 (m, 4H),
7.44-7.19 (m, 11H), 4.83 (s, 1H), 4.77 (q, J ) 38.8, 6.9 Hz,
2H), 4.60 (q, J ) 57.2, 11.7 Hz, 2H), 3.94-3.67 (m, 6H), 3.46
(dd, J ) 10.3, 6.9 Hz, 1H), 3.38-3.27 (m, 2H), 2.00 (m, 1H),
1.86-1.57 (m, 6H), 1.31 (s, 3H), 1.28 (s, 3H), 1.03 (s, 9H), 0.96
(d, J ) 7.0 Hz, 3H), 0.95 (d, J ) 6.9 Hz, 3H), 0.67 (d, J ) 6.2
Hz, 3H).
Ack n ow led gm en t. This work was supported by
research grant AI31422 from the National Institutes of
Health. M.P. was the recipient of an NIH postdoctoral
fellowship. The X-ray structure analysis was performed
by Dr. Michael Sabat of this department.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 17, ent-4, 18, 19, 23, 24, 28, and 29, 1H NMR
spectra of key intermediates, a Chem3D representation of the
chelated transition state leading to alcohol 12, and an ORTEP
representation for triol 6 (30 pages). This material is con-
tained 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.
BOM Eth er 15. To a solution of alcohol 12 (19.0 mg, 0.032
mmol) in diisopropylethylamine (0.17 mL, 0.96 mmol) was
added BOMCl (0.19 mL, 0.96 mmol). After 6 days, the reaction
was quenched with water (1 mL) and extracted with ether.
(19) The boldface signals are diagnostic for the absolute configura-
tion of the alcohol. The signals at 0.62 and 0.68 ppm are assigned to
one of the methyl groups on either C8, C10, or C12. The signals at
4.82 and 4.75 ppm are assigned to the proton on carbon 16.15
J O980137W