Cyclofunctionalization and free-radical-based hydrogen-transfer reactions. An iterative reaction sequence applied to the synthesis of the C7-C16 subunit of zincophorin

Article abstract of DOI:10.1021/jo010310f

The strategy considered herein features an iodocyclofunctionalization/hydrogen-transfer reaction sequence for the elaboration of propionate motifs. Proceeding with excellent yield and diastereo-selectivity, the synthetic sequence proposed gives access to the anti-anti dipropionate motif when the reduction step is performed under the control of the exocyclic effect. The tandem sequence is applied successfully to the synthesis of the C₇-C₁₆ subunit of zincophorin, and iteration of the process gives the desired anti-anti-anti-anti polypropionate stereopentad. Modifications of the reaction sequence - including phenylselenocyclofunctionalization, carbonate hydrolysis, and chelation-controlled radical reduction reactions - lead to the formation of the anti-syn dipropionate motif with remarkable diastereocontrol.

Full text of DOI:10.1021/jo010310f

J . Org. Chem. 2001, 66, 5427-5437
5427
Cyclofu n ction a liza tion a n d F r ee-Ra d ica l-Ba sed
Hyd r ogen -Tr a n sfer Rea ction s. An Iter a tive Rea ction Sequ en ce
Ap p lied to th e Syn th esis of th e C7-C16 Su bu n it of Zin cop h or in
Yvan Guindon,* Lorraine Murtagh,† Vale´rie Caron, Serge R. Landry,† Grace J ung,
Mohammed Bencheqroun, Anne-Marie Faucher,† and Brigitte Gue´rin
Institut de recherches cliniques de Montre´al (IRCM), Bio-organic Chemistry Laboratory,
110 avenue des Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7, and Department of Chemistry
and Department of Pharmacology, Universite´ de Montre´al, C.P. 6128, Succursale Centre-ville,
Montre´al, Que´bec, Canada H3C 3J 7
guindoy@ircm.qc.ca
Received March 21, 2001
The strategy considered herein features an iodocyclofunctionalization/hydrogen-transfer reaction
sequence for the elaboration of propionate motifs. Proceeding with excellent yield and diastereo-
selectivity, the synthetic sequence proposed gives access to the anti-anti dipropionate motif when
the reduction step is performed under the control of the exocyclic effect. The tandem sequence is
applied successfully to the synthesis of the C7-C16 subunit of zincophorin, and iteration of the
process gives the desired anti-anti-anti-anti polypropionate stereopentad. Modifications of the
reaction sequencesincluding phenylselenocyclofunctionalization, carbonate hydrolysis, and chela-
tion-controlled radical reduction reactionsslead to the formation of the anti-syn dipropionate motif
with remarkable diastereocontrol.
In tr od u ction
the control of either the exocyclic3 effect leading to the
anti product or the endocyclic4 effect leading to the syn
The need for diverse synthetic approaches leading to
the anti-anti dipropionate motif has been well recognized
by many research groups, and significant advances in
this field of study have already been made.1 The strategy
considered herein features a cyclofunctionalization/
hydrogen-transfer reaction sequence for the elaboration
of this motif.2 The first step of the sequence involves a
stereoselective intramolecular addition of an oxygen,
concomitant to the addition of an electrophilic iodine or
phenylselenium, to a terminally disubstituted double
bond (see Figure 1 depiction of the cyclofunctionalization
reaction). The resultant tertiary halide or phenylselenide
is then reduced under free-radical-based conditions in the
second step of the sequence. We have already shown that
a high degree of diastereoselectivity can be obtained in
the hydrogen-transfer reaction of such substrates through
product (Figure 1).
This reaction sequence should, in principle, allow for
iteration. For instance, the first sequence involving the
tandem cyclofunctionalization/hydrogen-transfer reac-
tions (exocyclic effect) should lead to a 2,3-anti-3,4-anti-
dipropionate stereotriad, and the repeated sequence
should lead to the formation of a 2,3-anti-3,4-anti-4,5-
anti-5,6-anti-polypropionate stereopentad. Alternatively,
the syn motif could be introduced if a Lewis acid were
added during the hydrogen-transfer step (endocyclic
effect). A combination of both approaches with or without
Lewis acid would lead to four of the eight isomers for a
given stereopentad from a starting material bearing at
the origin one stereocenter (Figure 1).
In this study, the iterative reaction sequence is applied
to the synthesis of the C7-C16 subunit of zincophorin
(Figure 2), a synthon first realized by Danishefsky in the
total synthesis of this natural product.5 This C7-C16
subunit has since been considered by other chemists
interested in the synthesis of polypropionate motifs.6
Experiments providing for a better understanding of
cyclofunctionalization and hydrogen-transfer reactions
involving exocyclic and endocyclic radicals and their
mechanistic rationale are also discussed.
* To whom correspondence should be addressed. Tel: (514) 987-
5786. Fax: (514) 987-5789.
† Boehringer Ingelheim (Canada) Ltd., Bio-Me´ga Research Division,
2100 rue Cunard, Laval, Que´bec, Canada H7S 2G5.
(1) Selected examples: (a) Still, W. C.; Barrish, J . C. J . Am. Chem.
Soc. 1983, 105, 2487. (b) Hoffmann, R. W.; Angew. Chem., Int. Ed.
Engl. 1987, 26, 489. (c) Hoffmann, R. W.; Dresely, S. Chem. Ber. 1989,
122, 903. (d) Paterson, I.; Channon, J . A. Tetrahedron Lett. 1992, 33,
797. (e) Paterson, I.; Cumming, J . G. Tetrahedron Lett. 1992, 33, 2847.
(f) Harada, T.; Inoue, A.; Wada, I.; Uchimura, J .; Tanaka, S.; Oku, A.
J . Am. Chem. Soc. 1993, 115, 7665. (g) Hoffmann, R. W.; Dahmann,
G.; Andersen, M. W. Synthesis 1994, 629. (h) Tanimoto, N.; Gerritz,
S. W.; Sawabe, A.; Noda, T.; Filla, S. A.; Masamune, S. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 673. (i) Marshall, J . A.; Perkins, J . F.; Wolf,
M. A. J . Org. Chem. 1995, 60, 5556. (j) J ain, N. F.; Takenaka, N.;
Panek, J . S. J . Am. Chem. Soc. 1996, 111, 6429. (k) Roush, W. R.;
Chemler, S. R. J . Org. Chem. 1998, 63, 3800.
(3) Guindon, Y.; Faucher, A.-M.; Bourque, EÄ .; Caron, V.; J ung, G.;
Landry, S. R. J . Org. Chem. 1997, 62, 9276. See ref 2.
(4) (a) Guindon, Y.; Lavalle´e, J .-F.; Llinas-Brunet, M.; Horner, G.;
Rancourt, J . J . Am. Chem. Soc. 1991, 113, 9701-9702. (b) Guindon,
Y.; Rancourt, J . J . Org. Chem. 1998, 63, 6554.
(2) We have previously explored a combination of iodoetherification/
hydrogen-transfer reactions leading to tetrahydrofurans that could be
opened selectively by a Lewis acid (Me2BBr) to offer acyclic counter-
parts with an anti-anti dipropionate motif. This approach was applied
successfully to the synthesis of a C17-C22 subunit of ionomycin but
did not have the potential for iteration. See: Guindon, Y.; Yoakim, C.;
Gorys, V.; Ogilvie, W. W.; Delorme, D.; Renaud, J .; Robinson, G.;
Lavalle´e, J .-F.; Slassi, A.; J ung, G.; Rancourt, J .; Durkin, K.; Liotta,
D. J . Org. Chem. 1994, 59, 1166.
(5) (a) Danishefsky, S. J .; Selnick, H. G.; Zelle, R. E.; DeNinno, M.
P. J . Am. Chem. Soc. 1986, 51, 5032. (b) Danishefsky, S. J .; Selnick,
H. G.; Zelle, R. E.; DeNinno, M. P. J . Am. Chem. Soc. 1987, 109, 1572.
For the synthesis of the C7-C16 subunit of zincophorin, see: (c)
Danishefsky, S. J .; Selnick, H. G.; Zelle, R. E.; DeNinno, M. P. J . Am.
Chem. Soc. 1988, 110, 4368.
(6) (a) Cywin, C. L.; Kallmerten, J . Tetrahedron Lett. 1993, 34, 1103.
(b) Marshall, J . A.; Palovich, M. R. J . Org. Chem. 1998, 63, 3701. See
ref 1k.
10.1021/jo010310f CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/07/2001

5428 J . Org. Chem., Vol. 66, No. 16, 2001
Guindon et al.
F igu r e 1. Tandem cyclofunctionalization/free-radical-based reduction reactions, iterative synthetic sequence.
and C-4 is trans. The rationale for such a prediction is
evident from an analysis of possible transition states
(Figure 3). Trans predictive transition state A seems to
be the lowest in energy compared to the other transition
states, where steric interactions should contribute to an
increase in energy. Indeed, trans predictive transition
state B is destabilized from 1,3-diaxial methyl-NH2
interaction. Cis predictive transition state C is destabi-
lized from a bisecting 1,3-allylic interaction, while D is
destabilized from 1,3-allylic strain. Consequently, trans
product 2 should predominate. Furthermore, the anti-
periplanar addition of the oxygen to the double bond
activated by the iodine (I2) (i.e., through a π complex or
an iodonium ion) in transition state A should result in a
residual iodide that is anti to the newly formed C-O
bond.
If the iodocyclofunctionalization reaction is successful,
the resultant carbonate 2 should offer three elements
that will be essential to the diastereocontrol of the
subsequent free-radical hydrogen-transfer step: (1) the
presence of an oxygen on the stereogenic center R to the
iodide; (2) the presence of a ring on the stereogenic center
R to the iodide; and (3) an anti relative stereochemistry
between the C-O and C-I bonds. The effects of these
key elements will be discussed in greater detail in the
next section of this paper.
F igu r e 2. Structures of zincophorin and the C7-C16 subunit
of zincophorin.
Resu lts a n d Discu ssion
Stu d y of th e Cyclofu n ction a liza tion Rea ction . On
the basis of results from previous studies,7 the cyclofunc-
tionalization reaction proposed herein involves the con-
comitant addition of an electrophilic iodine and a corre-
sponding nucleophilic carbamate to a terminally disub-
stituted double bond (eq 1). This reaction is realized with
Stu dy of th e Fr ee-Radical-Based Hydr ogen -Tr an s-
fer Rea ction . The induction of new stereogenic centers
on acyclic substrates has always been an interesting
challenge in organic chemistry. In the past decade, free
radicals were shown to be useful intermediates in reac-
tions targeting such goals.10 Of particular interest to our
group has been the study of tertiary carbon-centered free
radicals flanked by an ester and a stereogenic center
bearing a heteroatom such as an oxygen.11 As illustrated
by Scheme 1, the hydrogen-transfer reaction of acyclic
radicals gives a major product of anti relative stereo-
chemistry. The level of diastereoselectivity in this kinetic
process is dictated mainly by the presence of the ester,
the steric bulk of R1, the presence of a heteroatom at the
a primary homoallylic alcohol, the carrier of the nucleo-
philic carbamate. The substituent R to the double bond
should impose at the transition-state level an allylic 1,3-
strain8 that will dictate the outcome of the reaction. One
should note that only a few examples of cyclofunctional-
ization reactions involving electron-poor olefins have been
reported to date.9
The kinetically controlled cyclofunctionalization reac-
tion of olefins such as 1 should produce a six-membered
ring in which the relative stereochemistry between C-3
(9) Selected examples: (a) Bongini, A.; Cardillo, G.; Orena, M.; Porzi,
G.; Sandri, S. Tetrahedron 1987, 43, 4377. (b) Misiti, D.; Zappia, G.
Tetrahedron Lett. 1990, 31, 7359. See ref 7b.
(10) (a) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991,
24, 296. (b) Liotta, D. C.; Durkin, K. A.; Soria, J . J . Chemtracts 1992,
5, 197. (c) Miracle, G. S.; Cannizzaro, S. M.; Porter, N. A. Chemtracts
1993, 6, 147. (d) Smadja, W. Synlett 1994, 1. (e) Giese, B.; Damm, W.;
Batra, R. Chemtracts 1994, 7, 355. (f) Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical ReactionssConcepts, Guidelines
and Synthetic Applications; VCH: New York, 1996.
(7) Selected examples: (a) Cardillo, G.; Orena, M. J . Org. Chem.
1986, 51, 713. (b) Guindon, Y.; Slassi, A.; Ghiro, EÄ .; Bantle, G.; J ung,
G. Tetrahedron Lett. 1992, 33, 4257-4260. See ref 2.
(8) For a review of the effects of 1,3-allylic strain on conformation
and stereoselectivity see: (a) J ohnson, F. Chem. Rev. 1968, 68, 375.
(b) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841.

Synthesis of the C7-C16 Subunit of Zincophorin
J . Org. Chem., Vol. 66, No. 16, 2001 5429
F igu r e 3. Trans and cis predictive transition states for the iodocyclization reaction.
Sch em e 2
a permanent or a temporary cycle is formed R to the
carbon-centered radical. These strategies have proven to
be effective in controlling diastereoselectivity in favor of
the anti reduced product. Considering that cyclofunc-
tionalization product 2 bears an oxygen embedded in a
ring R to the tertiary iodide, the anti preference should
also be attainable in hydrogen-transfer reactions involv-
ing this compound.
F igu r e 4. Anti and syn predictive transition states for the
free-radical reduction reaction.
Sch em e 1
Alternatively, chelation-controlled radical reduction of
carbonate 2 should give access to the syn reduced
product. Previous studies have shown that Lewis acids
such as MgBr2‚OEt2 can permit the formation of a stable
preorganized chelate between the carbonyl of the ester
and the oxygen adjacent to the iodide or the phenyl-
selenide.4,12 The resultant free-radical intermediate is
embedded in a ring, which allows the reduction to proceed
under the control of the endocyclic effect (Scheme 2). It
is important to note that the Lewis acid can also generate
other competing species that can influence the outcome
of the reaction. In hydrogen-transfer reactions involving
both monodentate13 and chelate species, MgBr2‚OEt2 has
been shown to accelerate 10 times more than the mono-
dentate species.4b From this observation, it is evident that
the stability of the preorganized chelate is fundamentally
important to the achievement of high syn diastereo-
selectivity in the endocyclic approach. We have shown
in this regard that optimal selectivity can be realized with
an excess of MgBr2‚OEt2.4b
In principle, the stereochemistry of the radical precur-
sor should not affect the free-radical process; however,
under chelation control, anti isomers (at carbon C-2 and
C-3) of halides or phenylselenides have generally led to
better ratios than their corresponding syn isomers.14 The
anti motif between the C-O and C-I bonds offered by
carbonate 2 will ensure a high ratio in favor of the syn
product under chelation-controlled radical reduction.
Syn th esis of th e C7-C16 Su bu n it of Zin cop h or in .
The R,â-unsaturated ester 1 required for the cyclofunc-
C-3 position, and the temperature at which the reaction
is performed.
Initially, our group began to evaluate the exocyclic
effect as a means of circumventing the low diastereo-
selectivity observed for molecules bearing a small R1.2,4
This work was based on an observation illustrated in
Figure 4,2 where a comparison of cyclic and acyclic
analogues shows that the ratio of anti products improves
when R1 and OR are embedded in a ring. Accounting for
the high anti selectivity in the cyclic series is the increase
in the difference in energy between transition states G
and H brought on presumably by a forced alignment of
the C4-C5 and C3-O bonds.2 For the acyclic series, the
small difference in energy between transition states E
and F precludes high stereocontrol. We have capitalized
on the exocyclic effect in the design of different strategies
involving the protection4 or the in situ derivatization12
of polyfunctionalized molecules such as diols and amino
alcohols as seen in Scheme 2. In these approaches, either
(11) (a) Guindon, Y.; Yoakim, C.; Lemieux, R.; Boisvert, L.; Delorme,
D.; Lavalle´e, J .-F. Tetrahedron Lett. 1990, 31, 2845. (b) Guindon, Y.;
Lavalle´e, J .-F.; Boisvert, L.; Chabot, C.; Delorme, D.; Yoakim, C.; Hall,
D.; Lemieux, R.; Simoneau, B. Tetrahedron Lett. 1991, 32, 27. (c)
Durkin, K.; Liotta, D.; Rancourt, J .; Lavalle´e, J .-F.; Boisvert, L.;
Guindon, Y. J . Am. Chem. Soc. 1992, 114, 4912. (d) Guindon, Y.; Slassi,
A.; Rancourt, J .; Bantle, G.; Bencheqroun, M.; Murtagh, L.; Ghiro, E.;
J ung, G. J . Org. Chem. 1995, 60, 288.
(13) Lewis acid complexes to the carbonyl of the ester in the case of
monodentate species.
(12) Guindon, Y.; Liu, Z., J ung, G. J . Am. Chem. Soc. 1997, 119,
9289.
(14) This observation has been made in chelation-controlled radical
allylation and in the hydrogen-transfer reaction (see ref 4a).

5430 J . Org. Chem., Vol. 66, No. 16, 2001
Guindon et al.
Sch em e 3a
Ta ble 1. Syn th esis of Ca r bon a te 2 by Iod ocycliza tion of
Ca r ba m a te 1
entry
solvent (time)
ratiob 1/2
yield (%)
1
2
3
THF (24 h)
MeCN
1:1
1:1
1:3
55
36
a
Key: (a) TBSCl, imidazole, CH2Cl2, 85%; (b) DIBAL-H (1
MeCN
70c
M/Hex), CH2Cl2, -78 °C, 75%; (c) Py‚SO3 complex, DMSO, Et3N,
80%; (d) (Ph)3PdC(Me)CO2-t-Bu (6), THF, 85%; (e) TBAF,
CH3CO2H, THF, 78%; (f) (i) CCl3CONCO, CH2Cl2, 0 °C; (ii) K2CO3
sat., t-BuOH reflux, 95%.
a
All the reactions were carried out at a concentration of 0.2 M
at 23 °C using 2.5 equiv of NaHCO3 and AgOTf and 2 equiv of I2.
After 1 h, 1 equiv of each additive was added to the reaction
b
mixture. Ratios were determined for crude reaction isolates
before chromatography. c When reaction was judged completed, 1
g of silica gel/0.5 mmol of substrate was added to the reaction at
0 °C.
tionalization step was achieved in good yield following
standard procedures as depicted in Scheme 3 starting
from the (R)-3-hydroxy-2-methylpropionate. The first
chiral center of the starting material corresponded to
position-8 of the targeted zincophorin subunit. (To facili-
tate the recognition of the different carbon centers as they
relate to the synthon in consideration, “zincophorin
nomenclature” will be used.) The alcohol was protected
under classical conditions,15 and the resulting ester 4 was
converted into aldehyde 5, which was reacted with ylide
616 to form the terminally disubstituted olefin 7 using a
Wittig reaction. Primary alcohol 8 generated from the
cleavage of silyl ether 7 was treated with trichloroacetyl-
isocyanate (CCl3CONCO) and potassium carbonate in
refluxing tert-butyl alcohol17 to ensure a complete conver-
sion of the isocyanate intermediate into carbamate 1,
which was then used for the cyclofunctionalization reac-
tion.
As seen in Table 1, treatment of carbamate 1 with I2
7
in the presence of silver triflate (AgOTf) and NaHCO3
led to a poor to mediocre recovery of cyclic carbonate 2.
Of interest were two experimental observations (Table
1, entry 1). First, an equal proportion of starting material
and product 2 was found, as seen in entries 1 and 2
(Table 1), regardless of the solvent used. Second, the
amount of starting material recovered contradicted TLC
indication that the reaction was complete. These obser-
vations supported the involvement of an intermediate
that seemed to have a tendency to revert back to the
starting material through a retro-Michael reaction mech-
anism. The discrepancy with the TLC result suggested
that an acidic workup could be beneficial to the reaction.
To test this hypothesis, acidic buffer solution (NaH2PO4‚
H2O) was added to the reaction mixture, but the yield of
cyclofunctionalization product 2 was found to be variable.
Finally, we resorted to reproducing the TLC conditions
by adding to the reaction mixture 1 g of silica gel for every
F igu r e 5. Proposed iodocyclofunctionalization and retro-
Michael mechanisms.
0.5 mmol of substrate used and a few equivalents of
water, a treatment that effectively decreased the amount
of starting material recovered and increased the amount
of desired product (Table 1, entry 3).
Figure 5 illustrates proposed mechanisms for the
iodocyclofunctionalization and the retro-Michael reac-
tions. In the first case, intramolecular addition of the
oxygen to the double bond activated by the I2 should
result in the formation of a dioxoiminium intermediate.
During workup, the dioxoiminium species can be at-
tacked by a water molecule to generate a tetrahedral
intermediate that, after proton transfer and elimination
of ammonia, can provide protonated carbonate 2. A final
proton transfer of this species to the ammonia should give
cyclofunctionalization product 2. Partitioning of the di-
oxoiminium intermediate between the formation of prod-
uct 2 and the reversion to the starting material can be
affected by the presence of different salts in the reaction
mixture as well as by the amount of water added during
workup. These salts could lead, if dissolved, to the release
of nucleophiles such as an iodide ion, which can attack
the iodide R to the ester resulting in a competing retro-
Michael-type reaction, thus recovering the starting mate-
rial (Figure 5).
(15) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(16) 4 was prepared in three steps using the following procedure
(see: Dauben, W. G.; Gerdes, J . M.; Bunce, R. A. Tetrahedron Lett.
1984, 25, 4293):
(17) Hirama, M.; Hioki, H.; Itoˆ, S. Tetrahedron Lett. 1988, 29, 3125.

Synthesis of the C7-C16 Subunit of Zincophorin
J . Org. Chem., Vol. 66, No. 16, 2001 5431
Ta ble 2. Ra d ica l Red u ction s of Su bstr a tes 2, 10, a n d 13a
when reduced under free-radical-based conditions but
gave poor yield and ratio of reduced products under
chelation-controlled conditions (Table 2, entry 4). In the
latter reaction, olefin 8 was still the major component in
the mixture. Fortunately, it was possible to hydrolyze
R-phenylselenocarbonate 10 into diol 13 using LiOH in
H2O-THF, and the reduction of 13 under chelation-
controlled radical conditions proved to be very effective
giving syn product 15 in good yield and with high
diastereoselectivity (Table 2, entry 5).
The proof of structure of the cyclofunctionalization
reaction product was then considered. NMR analyses of
2 and 10 were inconclusive since the coupling constants
of H8-H9 (J ) 6.6 Hz) were lower than those normally
seen for axial hydrogen atoms in a six-membered ring.18
Therefore, the common reduced product 11 was chosen
to be transformed into isopropylidene ketal 16 for further
analysis (Scheme 5). The coupling constant value of 16
was 10.3 Hz between H8-H9, which confirmed the anti
motif between the two protons and the trans relative
stereochemistry between the Me-C8 and C9-O bonds.
This result corroborated our predictions for the cyclo-
functionalization reaction.
Ester 16 was then converted into R,â-unsaturated ester
18 to test the iterative quality of the synthetic sequence
in Scheme 5. The Wittig reaction proved to be much more
difficult to realize for the sterically encumbered aldehyde
17, and conditions involving reflux of toluene had to be
maintained over 6 h for completion of the reaction. This
led to a mixture of olefins in a ratio of 9:1 in favor of the
desired product 18 (8,9-anti-9,10-anti). The transforma-
tions leading to 22, including hydrolysis of acetonide 18,
selective protection of the primary alcohol of 19 to afford
silyl derivative 20, and the formation and subsequent
iodocyclofunctionalization of secondary carbamate 21
were performed with mixtures of inseparable olefins.
Fortunately, only the major isomer 21 (8,9-anti-9,10-anti)
reacted under iodocyclofunctionalization conditions to
afford carbonate 22 in good yield and in an excellent ratio
>30:1. The resulting iodide 22, under free-radical-based
reduction conditions, gave a ratio >30:1 favoring product
23 with a relative anti diastereoselectivity between C12
and C11.
As seen in Figure 6, the large values of J H9-H10 (10.6
HZ) and J H10-H11 (10.4 Hz) determined from NMR analy-
sis of carbonate 23 confirmed the anti relative stereo-
chemistry between the C9-O and C10-Me bonds achieved
during the hydrogen-transfer reaction in the first se-
quence. The analysis also showed that the orientation of
the C10-Me and C11-O bonds was trans, confirming that
the second iodocyclofunctionalization reaction was similar
to the first, despite the presence of a secondary homoal-
lylic alcohol.
a
Conditions: (A) 2 equiv of Bu3SnH, 0.2 equiv of Et3B, THF,
-78 °C; (B) 5 equiv of MgBr2‚OEt2, 2 equiv of Bu3SnH, 0.2 equiv
of Et3B, CH2Cl2, 0 °C. All the reactions were carried out at a
concentration of 0.1 M. b Ratios were determined for crude reaction
isolates before chromatography. c Only olefin 8 was observed.
d
55% of olefin 8 was obtained.
Sch em e 4a
a
Key: (a) BOC2O, DMAP, Et3N, THF, 91%; (b) PhSeBr, AgOTf,
NaHCO3, MeCN, 50%; (c) LiOH, H2O-THF (1:3), 50%.
For the second step of the sequence, iodide 2 was
reduced under radical-based conditions giving an impres-
sive ratio >30:1 in favor of the 9,10-anti isomer (Table
2, entry 1). Attempts to obtain the syn motif in the
reduction of 2 under chelation-controlled conditions were
unfortunately unsuccessful (Table 2, entry 2). The pres-
ence of a very significant amount (55%) of olefin 8
suggested that a retro-Michael reaction followed by a
decarboxylation had occurred during the formation of the
chelate prior to reduction.
An approach involving the synthesis of an R-phenyl-
selenocarbonate was considered in the hopes that this
compound would be more stable than iodocarbonate 2
under chelation-controlled reduction conditions. Unfor-
tunately, carbamate 1 did not react under the phenyl-
selenocyclofunctionalization conditions, and the starting
material was recovered. The carbamate function was
replaced by a BOC group on primary alcohol 8, and the
resultant carbonate 9 was cyclized efficiently in aceto-
nitrile in the presence of phenylselenyl bromide, silver
triflate, and sodium bicarbonate (Scheme 4). As was the
case with iodide 2, phenylselenide 10 gave an excellent
ratio >30:1 in favor of anti product 11 (Table 2, entry 3)
The hydrolysis of cyclic carbonate 23 by LiOH gave a
mixture of the corresponding diol and lactone 24. The
mixture was treated with acidic conditions (p-toluene-
sulfonic acid in THF) to complete the conversion of the
diol to lactone 24 (Scheme 6). Analysis of this lactone
provided spectral evidence of the relative stereochemistry
between the C11 and C12 centers (Figure 6). The low value
of J H11-H12 (2.9 Hz) indicated a gauche orientation
between the protons and confirmed consequently that the
second free-radical reduction reaction had given the anti
(18) The low J H8-H9 value can be attributed to the imposed planarity
of the carbonate.

5432 J . Org. Chem., Vol. 66, No. 16, 2001
Guindon et al.
Sch em e 5a
a
Key: (a) LiOH, H2O-THF (1:3), 63%; (b) (CH3)2C(OMe)2, p-TsOH, 85%; (c) DIBAL-H (1 M/Hex), CH2Cl2, -78 °C, 75%; (d) (i) (COCl)2,
DMSO, CH2Cl2, -78 °C, (ii) Et3N, 1 h, -78 to +23 °C, 81% (crude); (e) (Ph)3PdC(Me)CO2-t-Bu (6), toluene, reflux, 6 h, 60%; (f) THF/HCl
(1 M) (1:1), 92%; (g) TBDPSCl, imidazole, CH2Cl2, 89%; (h) (i) CCl3CONCO, CH2Cl2, 0 °C, (ii) K2CO3 sat., (aq), t-BuOH reflux, 86%; (i) l2,
AgOTf, NaHCO3, CH3CN, 70%; (j) Bu3SnH, Et3B, THF, -78 °C, 80%.
for the synthesis of the same fragment.1k Additional
confirmation of stereochemistry was provided by a com-
parison of our spectral data and optical rotation of the
benzyloxymethyl (BOM) ether to the published values.5c
Con clu sion s
The iterative reaction sequence involving cyclofunc-
tionalization/free-radical-based hydrogen-transfer reac-
tions leading to the anti-anti-anti-anti polypropionate
F igu r e 6. NMR analysis of compounds 23 and 24.
motif was applied successfully to the synthesis of the C7-
C16 subunit of zincophorin. Excellent yield and diastereo-
selectivity were obtained for key steps throughout the
tandem process. The anti-syn dipropionate motif was also
realized with excellent diastereocontrol using the reaction
sequence of phenylselenocyclofunctionalization, carbon-
ate hydrolysis, and chelation-controlled reduction. We
have further shown that trans-selective cyclofunctional-
ization combined with free-radical reduction, under the
product 23. Furthermore, the J H9-H10 (11.7 Hz) and
J H10-H11 (2.2 Hz) values observed for 24 were consistent
with the stereochemical outcomes of the first free-radical
hydrogen-transfer reaction and the second iodocyclofunc-
tionalization reaction. These results were also consistent
with the NMR analysis of carbonate 23 (Figure 6).
Therefore, iteration of the tandem sequence proposed
herein was successful in the elaboration of the anti-anti-
anti polypropionate motif, as found on carbonate 23.
To complete the synthesis of the C7-C16 subunit of
zincophorin, lactone 24 was opened to generate an
N-methoxy-N-methylamide. Weinreb conditions19 involv-
ing N,O-dimethylhydroxyamine hydrochloride and Me3-
Al gave only 50% of the desired compound 25 after 8 h
of reaction. A 95% yield of the desired amide 25 was
obtained when a stronger Lewis acid such as Me2AlCl
was used (Scheme 6).20 The diol function of amide 25 was
protected with 2,2-dimethoxypropane and p-TsOH to
form acetonide 26, but the formation of lactone 24 was
still noted during the reaction. Other conditions were
tested, but the yield of 26 did not improve and lactone
24 continued to be present in the reaction mixture. On
the basis of these results, the former condition was
maintained. The addition of organolithium compound 27
to amide 26 gave in good yield the corresponding ketone
28,21 which was reduced using L-Selectride to give the
major syn alcohol 29 in a ratio of 7:1 through a mecha-
nism involving a putative chelated lithium intermedi-
ate.22 The desired synthon was obtained by protection of
alcohol 29 using conditions originally applied by Roush
(22) A study was done on model compound 29 to determine the best
reducing agent for the desired syn stereochemistry. L-Selectride has
proven to be the most effective, giving a ratio >20:1 in favor of 30;
see: Arai, Y.; Suzuki, A.; Masuda, T.; Masaki, Y.; Shiro, M. Chem.
Pharm. Bull. 1996, 44, 1765. Faucher, A.-M.; Brochu, C.; Landry, S.
R.; Duchesne, I.; Hantos, S.; Roy, A.; Myles, A.; Legault, C. Tetrahedron
Lett. 1998, 39, 8425. Alcohols 30 and 31 were transformed into
corresponding acetonides 32 and 33 following the steps illustrated
below in order to verify their C4-C5 stereochemistries. The 13C
resonances of ketal carbons for acetonide 32 were 25 and 24 ppm,
indicating that the two hydroxy groups were trans. Consequently,
alcohol 30 had to be syn. For 33, the 13C resonances were 19 and 30
ppm, indicating that the two hydroxyl groups were cis. Consequently,
alcohol 31 had to be anti. See Rychnovsky, S. D.; Rogers, B.; Yang, G.
J . Org. Chem. 1993, 58, 3511.
(19) Weinreb, S. M.; Basha, A.; Lipton, M. Tetrahedron Lett. 1977,
18, 4171.
(20) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38,
2685.
(21) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.

Synthesis of the C7-C16 Subunit of Zincophorin
J . Org. Chem., Vol. 66, No. 16, 2001 5433
Sch em e 6a
a
Key: (a) (i) LiOH, H2O-THF (1:3), (ii) p-TsOH, THF, 77%; (b) HNMe(OMe)‚HCl, Me2ALCl, THF, -78 °C, 95%; (c) (CH3)2C(OMe)2,
p-TsOH, 65%; (d) (i) 27, Et2N, (ii) NH4Cl aq sat. 75%; (e) L-Selectride, THF, -78 °C, 72%; (f) BOM-Cl, iPr2NEt, CH2Cl2, reflux, 24 h, 84%.
(100); HRMS calcd for C11H25O3Si (MH) 233.1573, found
233.1566 (2.8 ppm). Anal. Calcd for C11H24O3Si: C, 56.85; H,
10.41. Found: C, 56.49; H, 10.39.
control of either the exocyclic or the endocyclic effect, can
offer a powerful approach to the formation of a variety
of polypropionate motifs.
(R)-2-Met h yl-3-[(ter t-b u t yld im et h ylsilyl)oxy]p r op a -
n a l. (5) To a cold (-78 °C) stirred solution of ester 4 (9.48 g,
41 mmol) in CH2Cl2 (200 mL) under nitrogen atmosphere was
added dropwise DIBAL (1 M in hexane) (82 mL, 82 mmol).
The resultant mixture was stirred for 15 min at -78 °C and
then allowed to warm to room temperature over 1 h (TLC
analysis indicated that no starting material or aldehyde
remained after this time). The mixture was then cooled to -78
°C, quenched with pH 7.2 buffer solution (100 mL), and
allowed to warm to room temperature over 1.5 h. The mixture
was then filtered through Celite, and the organic layer was
washed with water (50 mL) and saturated aqueous NaCl (50
mL). The aluminum salts were washed with EtOAc (50 mL),
and the aqueous layers were re-extracted with EtOAc (2 × 25
mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated under vacuum. Purification of the
crude oil by distillation (60 °C/0.8 mmHg) afforded the alcohol
(6.25 g, 75%) as a colorless oil: Rf 0.48 (hexanes-EtOAc, 4:1);
[R]20D -7.5 (c 1, CHCl3); IR (neat) νmax 3350, 2900, 1470, 1380,
Exp er im en ta l Section
Gen er a l Met h od s. All reactions requiring anhydrous
conditions were conducted under a positive nitrogen atmo-
sphere in oven-dried glassware using standard syringe tech-
niques. Tetrahydrofuran (THF) and ether were distilled from
sodium/benzophenone under N2 atmosphere immediately prior
to use. The anhydrous THF used for radical reduction was
purchased from Aldrich and was used as received. Dichlo-
romethane (CH2Cl2), DMSO, and Et3N were freshly distilled
from CaH2 under N2 atmosphere. Methyl (R)-3-hydroxy-2-
methylpropionate, DIBAL-H (1 M solution in hexane), tri-
butyltin hydride, triethylborane (1 M solution in hexane), and
2,2-dimethoxypropane were also purchased from Aldrich and
used as received. Oxalyl chloride was purchased from Aldrich
and distilled prior to use. Flash chromatography was per-
formed on Merck silica gel 60 (0.040-0.063 mm) using air
pressure. Analytical thin-layer chromatography (TLC) was
carried out on precoated (0.25 mm) Merck silica gel F-254
plates. Melting points were determined on an electrothermal
melting point apparatus and are uncorrected. NMR spectra
were recorded on a Varian VXR-400S spectrometer and are
referenced to the residual pic of the solvent as internal
standard. IR spectra were recorded on a Perkin-Elmer 781
spectrophotometer. CI and EI mass spectra were recorded on
a MF 50 TATC instrument operating at 70 eV. FAB mass
spectra were performed on a VG AutospecQ. Optical rotations
were measured on a Perkin-Elmer 343 polarimeter at the
sodium D line with a 1 dm path length, 1 mL cell.
Meth yl (R)-2-Meth yl-3-[(ter t-bu tyld im eth ylsilyl)oxy]-
p r op ion a te (4). To a stirred solution of (R)-3-hydroxy-2-
methylpropionate (15.08 g, 128 mmol) in CH2Cl2 (130 mL) at
0 °C were added sequentially imidazole (19.12 g, 281 mmol)
and tert-butyldimethylsilyl chloride (26.94 g, 179 mmol). The
mixture was allowed to warm to room temperature. After 1 h
at room temperature, the mixture was filtered through Celite,
and the organic layer was washed with 10% HCl (35 mL),
water (35 mL), saturated aqueous NaHCO3 (35 mL), and brine
(35 mL). The organic layer was dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification of the
crude oil by Kugelrohr distillation (59 °C/0.2 mmHg) afforded
silyl ester 4 (25.4 g, 85%) as a colorless oil: Rf 0.9 (hexanes-
EtOAc, 4:1); [R]20D -20 (c 1.1, CHCl3); IR (neat) νmax 2900, 1750,
1460, 1430, 1380, 1360, 1250, 1180, 1100 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.03 (s, 6H), 0.87 (s, 9H), 1.13 (d, J ) 7.1 Hz,
3H), 2.62-2.67 (m, 1H), 3.64 (dd, J ) 6.0, 9.7 Hz, 1H), 3.67 (s,
3H), 3.77 (dd, J ) 6.8, 9.7 Hz, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ -5.6, 13.3, 18.1, 25.7, 42.4, 51.4, 65.1, 175.4 (CdO)
ppm; MS (FAB) 233 (MH, 30), 217 (25), 201 (6), 175 (2), 91
1
1360, 1250 cm-1; H NMR (400 MHz, CDCl3) δ 0.05 (s, 6H),
0.82 (d, J ) 6.9 Hz, 3H), 0.88 (s, 9H), 1.88-1.95 (m, 1H), 2.90
(dd, J ) 4.2, 6.6 Hz, 1H), 3.53 (dd, J ) 8.1, 9.7 Hz, 1H), 3.58-
3.62 (m, 2H), 3.71 (dd, J ) 4.4, 9.7 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ -5.5, 13.1, 18.2, 25.9, 37.0, 68.4, 68.8 ppm;
MS (FAB) 205 (MH, 36%), 147 (22), 89 (31), 73 (100); HRMS
calcd for C10H25O2Si (MH) 205.1624, found 205.1624 (0.2 ppm).
To a cold (10 °C) stirred solution of the silyl alcohol (11.08 g,
54 mmol) in DMSO (270 mL) under nitrogen atmosphere were
added triethylamine (18 mL, 130 mmol) and pyridine sulfur
trioxide complex (17.26 g, 108 mmol). The mixture was stirred
for 3 h at room temperature, after which time TLC analysis
indicated no remaining alcohol. The mixture was then cooled
to 10 °C and quenched with water (100 mL). The mixture was
diluted with hexane (3 × 100 mL), and the organic layer was
separated, dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by distillation (60 °C/0.9 mmHg)
afforded aldehyde 5 (8.69 g, 80%) as a colorless oil: Rf 0.82
(hexanes-EtOAc, 4:1); [R]20 -36.6 (c 1.1, CHCl3); IR (neat)
D
νmax 2900, 1720, 1460, 1250, 1100, 840 cm-1
;
1H NMR (400
MHz, CDCl3) δ 0.05 (s, 6H), 0.87 (s, 9H), 1.08 (d, J ) 7.1 Hz,
3H), 2.49-2.58 (m, 1H), 3.80 (dd, J ) 6.1, 10.2 Hz, 1H), 3.86
(dd, J ) 5.2, 10.2 Hz, 1H), 9.74 (s, 1H) ppm; 13C NMR (100
MHz, CDCl3) δ -5.5, 10.3, 18.2, 25.8, 48.8, 63.4, 204.7 (CdO)
ppm; MS (CI, isobutane) m/e 203 (MH+, 100), 185 (5), 145 (35),
115 (2).
ter t-Bu t yl (4S)-5-[(ter t-Bu t yld im et h ylsilyl)oxy]-2,4-
d im eth ylp en t-2-en oa te (7). To a stirred solution of tert-
butoxycarbonylethylidenetriphenylphosphorane 616 (23.15 g,
60 mmol) was added dropwise a solution of aldehyde 5 (6.0 g,
30 mmol) in THF (150 mL). The mixture was stirred at room

5434 J . Org. Chem., Vol. 66, No. 16, 2001
Guindon et al.
temperature over 24 h. The THF was evaporated, and ether
(100 mL) was added to the crude mixture. The solution was
filtered through Celite and concentrated under reduced pres-
sure. Purification by flash column chromatography (hexanes-
EtOAc 95:5) afforded 7 (6.75 g, 72%) as a colorless oil (32:1
through a Celite pad, which had been rinsed well with EtOAc.
The filtrate was washed with water (50 mL), saturated
aqueous NaCl (50 mL), and saturated aqueous NaS2O3 (3 ×
50 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash column chromatogra-
phy (hexanes-EtOAc, 3:1) afforded 2 (1.81 g, 70%) as a yellow
mixture of olefin E/Z): Rf 0.96 (hexanes-EtOAc, 4:1); [R]20
D
-3.9 (c 1, CHCl3); IR (neat) υmax 2900, 1715, 1470, 1370 cm-1
;
oil: Rf 0.79 (hexanes-EtOAc, 5:1); [R]D -15 (c 1.1, CHCl3);
20
1H NMR (400 MHz, CDCl3) δ 0.03 (s, 6H), 0.88 (s, 9H), 0.99
(d, J ) 6.7 Hz, 3H), 1.48 (s, 9H), 1.81 (s, 3H), 2.64-2.68 (m,
1H), 3.48 (d, J ) 6.2 Hz, 2H), 6.44 (d, J ) 9.7 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) ) δ -5.4, 12.7, 16.3, 18.3, 25.9,
28.1, 36.2, 67.2, 79.9, 129.3, 143.5, 167.6 (CdO) ppm; MS (FAB)
315.5 (MH, 40), 259 (100), 241 (80), 201 (54), 127 (38). Anal.
Calcd for C17H34O3Si: C, 64.92; H, 10.90. Found: C, 64.65; H,
10.81.
IR (CDCl3) νmax 2995, 2270, 1750, 1400, 1250 cm-1; H NMR
1
(400 MHz, CDCl3) δ 1.33 (d, J ) 7.0 Hz, 2H), 1.50 (s, 9H),
2.09 (s, 3H), 2.45-2.51 (m, 1H), 4.03 (dd, J ) 7.7, 11.0 Hz,
1H), 4.28 (dd, J ) 4.8, 11.0 Hz, 1H), 4.53 (d, J ) 6.6 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 17.2, 25.6, 27.5, 31.2, 41.6,
70.8, 83.5, 87.4, 149.1, 169.0 ppm; MS (FAB) m/z 371 (MH+,
72), 315 (100), 253 (22), 225 (36), 154 (8); HRMS calcd for
C
C
12H20O5I 371.0356, found 371.0339 (4.5 ppm). Anal. Calcd for
12H19O5I: C, 38.93; H, 5.17. Found: C, 38.93; H, 5.22.
ter t-Bu tyl 2R-(5R-Meth yl-2-oxo[1,3]d ioxa n -4R-yl)p r o-
ter t-Bu tyl (4S)-5-Hyd r oxy-2,4-d im eth yl-2-p en ten oa te
(8). To a cold (0 °C) stirred solution of silyl ester 7 (9.95 g, 32
mmol) in THF (160 mL) under nitrogen atmosphere were
added sequentially acetic acid (3.6 mL, 63 mmol) and tetra-
butylammonium fluoride (1.0 M in THF, 64 mL, 64 mmol).
After 3 h at room temperature, the mixture was diluted with
a pH 7.2 buffer solution (100 mL), and the aqueous layer was
washed with EtOAc (3 × 75 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash column chromatogra-
phy (hexanes-EtOAc, 4:1) afforded 8 (5.0 g, 78%) as a colorless
p ion a te (11). To a -78 °C solution of iodide 2 (1.53 g, 4.13
mmol) in THF (21 mL) were added tributyltin hydride (2.2
mL, 8.25 mmol) and triethylborane (1 M in hexane, 0.82 mL,
0.82 mmol). The solution was stirred for 40 min at -78 °C,
and 0.2 equiv of 1,3-dinitrobenzene (radical inhibitor) was
added to terminate the reaction. The mixture was concentrated
under vacuum, and the resultant crude oil was partitioned
between acetonitrile (25 mL) and hexane (25 mL). The aceto-
nitrile layer was washed with hexane (2 × 25 mL) and then
concentrated under reduced pressure. Purification of the crude
oil by flash column chromatography (hexane 200 mL, then
EtOAc-hexane, 1:2) gave the reduced product 11 (1.0 g, 99%)
as a white solid: mp ) 80.5 °C; Rf 0.51 (hexanes-EtOAc, 1:1);
[R]20D -19.5 (c 1.07, CHCl3); IR (CDCl3) νmax 2995, 2260, 1750,
oil: Rf 0.5 (hexanes-EtOAc, 1:1); [R]20 -21° (c 1, CHCl3); IR
D
(neat) νmax 3450, 2990, 2940, 2880, 1700, 1650, 1460 cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.99 (d, J ) 6.8 Hz, 3H), 1.46 (s,
9H), 1.81 (s, 3H), 1.99 (s, 1H), 2.70 (ddd, J ) 3.5, 6.8, 9.9 Hz,
1H), 3.45-3.51 (m, 2H), 6.41 (ddd, J ) 1.5, 2.7, 9.9 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 12.7, 16.0, 28.0, 36.1, 67.0,
80.2, 130.3, 142.8, 167.5 (CdO) ppm; MS (FAB) 201 (MH, 29),
145 (100), 127 (82), 57 (84); HRMS calcd for C11H21O3 (MH)
201.1491, found 201.1497 (-3.2 ppm).
1
1410, 1150 cm-1; H NMR (400 MHz, CDCl3) δ 1.02 (d, J )
6.8 Hz, 3H), 1.27 (d, J ) 7.1 Hz, 3H), 1.47 (s, 9H), 2.33-2.41
(m, 1H), 2.79 (qd, J ) 3.2, 7.0 Hz, 1H), 3.98 (t, J ) 10.6 Hz,
1H), 4.27 (dd, J ) 4.6, 10.8 Hz, 1H), 4.34 (dd, J ) 3.7, 9.5 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3) δ 11.9, 12.2, 27.5, 28.4,
42.3, 71.1, 81.2, 85.3, 148.5, 170.4 ppm; MS (FAB) m/z 245
(MH+, 9), 189 (100), 133 (20); HRMS calcd for C12H21O5
245.1389, found 245.1379 (4.1 ppm). Anal. Calcd for C12H20O5:
C, 59.00; H, 8.25. Found: C, 58.78; H, 8.37.
ter t-Bu t yl (4S)-5-Ca r b a m oyloxy-2,4-d im et h ylp en t -2-
en oa te (1). To a cold (0 °C) stirred solution of alcohol 8 (4.74
g, 24 mmol) in CH2Cl2 (120 mL) was added dropwise trichlo-
roacetylisocyanate (3.7 mL, 31 mmol). The mixture was stirred
for 1 h at room temperature (or until the TLC analysis
indicated that no starting material remained). The solvent was
then removed under reduced pressure, and the substrate was
dissolved in tert-butyl alcohol (60 mL). Saturated aqueous K2-
CO3 (30 mL) was added, and the mixture was stirred at reflux
for 6 h. The solution was cooled to 0 °C and acidified to pH 7
by adding aqueous 5 M HCl, and the resulting mixture was
diluted with EtOAc (75 mL). The organic layer was washed
with water (2 × 50 mL) and saturated aqueous NaCl (2 × 50
mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash column chromatogra-
phy (hexanes-EtOAc 3:1) afforded carbamate 1 (5.7 g, 98%)
ter t-Bu tyl-(4S)-5-ter t-bu toxyca r bon yloxy-2,4-d im eth yl-
p en t-2-en oa te (9). To a cold (0 °C) stirred solution of alcohol
8 (1.63 g, 8.1 mmol) in THF (20 mL) were added triethylamine
(2.3 mL, 16.3 mmol), di-tert-butyl dicarbonate (3.55 g, 16.3
mmol), and N, N-(dimethylamino)pyridine (198 mg, 1.6 mmol).
The mixture was stirred for 2 h at room temperature (or until
the TLC analysis indicated that no starting material re-
mained). The solvent was then removed under reduced pres-
sure, and the substrate was purified by flash column chroma-
tography (hexanes-EtOAc 9:1) to afford as a colorless oil
carbonate 9 containing ∼5% of impurities (2.0 g, 81%). Rf 0.34
(hexanes-EtOAc, 9:1); IR (neat) νmax 2979, 1811, 1707, 1652,
as a colorless oil: Rf 0.45 (hexanes-EtOAc, 1:1); [R]20 -14.1
D
1
(c 1, CHCl3); IR (neat) νmax 3450, 3370, 3200, 2990, 1720, 1600,
1458 cm-1; H NMR (400 MHz, CDCl3) δ 1.01 (d, J ) 7.0 Hz,
1
1460, 1370, 1150 cm-1; H NMR (400 MHz, CDCl3) δ 1.04 (d,
3H), 1.44 (s, 18H), 1.78 (s, 3H), 2.84-2.88 (m, 1H), 3.90 (d, J
) 7 Hz, 2H), 6.39 (dd, J ) 1.5, 9.6 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 13.0, 16.7, 27.7, 28.0, 28.1, 28.3, 33.2, 70.4,
80.5, 82.2, 85.4, 130.8, 141.6, 147.0, 153.8, 167.5 ppm.
J ) 6.8 Hz, 3H), 1.49 (s, 9H), 1.82 (s, 3H), 2.84-2.88 (m, 1H),
3.92 (dd, J ) 7.3, 10.0 Hz, 1H), 4.02 (dd, J ) 6.2, 10.0 Hz,
1H), 4.59 (bs, 2H), 6.44 (dd, J ) 1, 9.5 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3) δ 12.7, 16.3, 28.0, 33.0, 68.5, 80.2, 130.3,
141.7, 156.9, 167.3 ppm; MS (FAB) m/z 244 (MH+, 9), 188 (27),
133 (100), 127 (52), 109 (9); HRMS calcd for C12H22NO4 (MH)
ter t-Bu tyl 2R-2-P h en ylselen o[(4R,5R)-5-m eth yl-2-oxo-
[1,3]d ioxa n -4-yl)p r op ion a te (10). To a solution of carbonate
9 (722 mg, 2.4 mmol) in acetonitrile (12 mL) under nitrogen
atmosphere were added sequentially NaHCO3 (605 mg, 7.2
mmol), silver triflate (1.85 g, 7.2 mmol), and PhSeBr (1.70 g,
7.2 mmol). The mixture was stirred at room temperature in
the dark. One equivalent of each reactive species was added
after 30 min and then again after another 30 min until TLC
analysis indicated that no starting material remained. The
reaction mixture was then cooled to 0 °C and quenched by the
addition of silica gel (50 g), EtOAc (100 mL), and water (5 mL).
The resultant suspension was filtered through a Celite pad,
which had been rinsed well with EtOAc. The filtrate was
washed with water (50 mL), saturated aqueous NaCl (50 mL),
and saturated aqueous NaS2O3 (3 × 50 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
by flash column chromatography (hexanes-EtOAc, 3:1) af-
forded 10 (0.48 mg, 50%) as a yellow oil: Rf 0.31 (hexanes-
244.1549, found 244.1556 (-3.0 ppm). Anal. Calcd for C12H21
-
NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 59.06; H, 8.97; N,
5.81.
ter t-Bu tyl 2R-2-Iodo-[(4R,5R)-5-m eth yl-2-oxo[1,3]dioxan -
4-yl)p r op ion a te (2). To a solution of carbamate 1 (1.70 g 7
mmol) in acetonitrile (30 mL) under nitrogen atmosphere were
added sequentially NaHCO3 (1.46 g, 17 mmol), silver triflate
(4.48 g, 17 mmol), and iodine (3.54 g, 14 mmol). The mixture
was stirred at room temperature in the dark. One equivalent
of each reactive species (NaHCO3, silver triflate, and iodine)
was added after 30 min and then again after another 30 min
until the TLC analysis indicated that no starting material
remained. The reaction mixture was then cooled to 0 °C and
quenched by the addition of silica gel (50 g), EtOAc (100 mL),
and water (5 mL). The resultant suspension was filtered

Synthesis of the C7-C16 Subunit of Zincophorin
J . Org. Chem., Vol. 66, No. 16, 2001 5435
EtOAc, 3:7); [R]20 -6.3 (c 1.1, CHCl3); IR (CDCl3) νmax 2990,
sure. Purification by flash column chromatography (hexanes-
EtOAc 6:1) gave acetonide 16 (0.3 g, 85%) as a colorless oil:
D
1760, 1260, 1140 cm-1; H NMR (400 MHz, CDCl3) δ 1.31 (d,
1
J ) 7.0 Hz, 2H), 1.41 (s, 9H), 1.45 (s, 3H), 2.47-2.54 (m, 1H),
4.04 (dd, J ) 7.7, 11.0 Hz, 1H), 4.24 (dd, J ) 4.5, 11.0 Hz,
1H), 4.70 (d, J ) 6.7 Hz, 1H), 7.26-7.42 (m, 3H), 7.62 (d, J )
8 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ 17.0, 18.6, 29.2,
52.8, 70.9, 82.7, 87.6, 129.1, 129.8, 138.2, 149.5, 153.5, 170.1
ppm; MS (FAB) m/z 401 (MH+, 32), 345 (100), 283 (8), 255 (6),
Rf 0.57 (hexanes-EtOAc, 4:1); [R]20 -28 (c 1.2, CHCl3); IR
D
(CDCl3) νmax 2980, 1740, 1460, 1370, 1160 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.78 (d, J ) 6.8 Hz, 3H), 1.14 (d, J ) 7.1 Hz,
3H), 1.35 (s, 3H), 1.41 (s, 3H), 1.46 (s, 9H), 1.96-2.04 (m, 1H),
2.58 (qd, J ) 3.3, 7.1 Hz, 1H), 3.46 (dd, J ) 10.6, 11.5 Hz,
1H), 3.63-3.70 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ
12.8, 12.9, 19.1, 28.1, 29.3, 31.9, 42.9, 66.0, 80.1, 98.4, 172.6
ppm; MS (FAB) 259 (MH, 60), 243 (14), 203 (52), 149 (100),
91 (46), 57 (34). Anal. Calcd for C14H26O4: C, 65.09; H, 10.14.
Found: C, 64.75; H, 10.49.
154 (56); HRMS calcd for
C
18H25O580Se 401.0867, found
401.0880 (-3.2 ppm). Anal. Calcd for C18H24O5Se: C, 54.14;
H, 6.66. Found: C, 54.48; H, 6.37.
ter t-Bu tyl (2R,3R,4R)-3,5-Dih yd r oxy-2-p h en ylselen o-
2,4-d im eth ylp en ta n oa te (13). To carbonate 10 (180 mg, 0.45
mmol) in THF-H2O (3:1, 8 mL) at 0 °C was added lithium
hydroxide (20 mg, 0.90 mmol). The solution was stirred for 2
h at the same temperature. The mixture was diluted with
EtOAc (50 mL), washed with brine (3 × 50 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the crude oil by flash column chromatography
(hexanes-EtOAc, 7:3) gave diol 13 (84 mg, 50%) as a yellow
(2R )-2-[(4R ,5R )-2,2,5-t r im e t h yl[1,3]d ioxa n -4-yl]p r o-
p ion a ld eh yd e (17). To a -78 °C solution of ester 16 (1.84 g,
7.1 mmol) in THF (36 mL) under nitrogen atmosphere was
added dropwise DIBAL (1 M in hexane, 18 mL, 18 mmol). The
mixture was allowed to warm to room temperature over 24 h
and was then recooled to -78 °C and quenched with MeOH
(20 mL). The mixture was again allowed to warm to room
temperature over 1.5 h before being diluted with EtOAc (20
mL). The organic layer was washed with brine (50 mL), and
the aqueous layer was washed with EtOAc (2 × 25 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by flash
column chromatography (hexanes-EtOAc, 3:1) gave the alco-
hol (0.84 g, 63%) as a colorless oil: Rf 0.26 (hexanes-EtOAc,
4:1); [R]20D -23 (c 1, CHCl3); IR (CDCl3) νmax 3520, 2980, 1460,
oil: Rf 0.33 (hexanes-EtOAc, 4:6); [R]20 40.1 (c 1.0, CHCl3);
D
IR (CDCl3) νmax 3419, 2975, 2932, 1715, 1577 cm-1; H NMR
1
(400 MHz, CDCl3) δ 1.12 (d, J ) 7.0 Hz, 3H), 1.37 (s, 3H),
1.44 (s, 9H), 2.04-2.06 (m, 1H), 3.59 (dd, J ) 5.0, 11.0 Hz,
1H), 3.77 (dd, J ) 4.7, 11.0 Hz, 1H), 3.84 (d, J ) 4.3 Hz, 1H),
7.25-7.61 (m, 3H), 7.60 (d, J ) 7 Hz, 2H) ppm; 13C NMR (100
MHz, CDCl3) δ 17.7, 20.3, 27.9, 36.9, 55.7, 65.5, 80.8, 82.6,
126.8, 128.8, 129.4, 138.3, 173.6 ppm.
1
1380, 1200 cm-1; H NMR (400 MHz, CDCl3) δ 0.74 (d, J )
ter t-Bu tyl (2R,3R,4R)-3,5-Dih yd r oxy-2,4-d im eth ylp en -
ta n oa te (14). To carbonate 11 (1.43 g, 5.8 mmol) in THF-
H2O (3:1, 120 mL) at 0 °C was added lithium hydroxide (0.28
g, 11.7 mmol). The solution was stirred for 2 h at the same
temperature. The mixture was diluted with EtOAc (50 mL),
washed with brine (3 × 50 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification of the
crude oil by flash column chromatography (hexanes-EtOAc,
1:1) gave diol 14 (1.2 g, 95%) as a white solid: mp ) 56 °C: Rf
6.6 Hz, 3H), 1.11 (d, J ) 7.1 Hz, 3H), 1.37 (s, 3H), 1.40 (s,
3H), 1.81-1.86 (m, 1H), 1.94-2.02 (m, 1H), 2.81 (d, J ) 8.0
Hz, 1H), 3.46-3.56 (m, 3H), 3.72 (dd, J ) 5.1, 11.5 Hz, 1H),
3.94 (d, J ) 11 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ
12.6, 14.9, 18.6, 29.5, 31.7, 34.7, 63.6, 66.0, 80.4, 98.5 ppm;
MS (CI, isobutane) m/e 189 (MH+, 97), 173 (15), 131 (100), 113
(69). To a -78 °C solution of oxalyl chloride (0.55 mL, 6.3
mmol) in CH2Cl2 (10 mL) was added dropwise dimethylsul-
foxide (0.8 mL, 11.1 mmol). The mixture was stirred for 15
min at -78 °C, and a solution of the alcohol (0.70 g, 3.7 mmol)
in CH2Cl2 (10 mL) was added dropwise with stirring. After 1
h at -78 °C, Et3N (3.2 mL, 18 mmol) was added, and stirring
continued for 15 min at the same temperature. The mixture
was allowed to warm to room temperature while being stirred
and was then diluted with CH2Cl2 (10 mL). The organic layer
was washed with water (2 × 25 mL) and saturated aqueous
NaCl, dried over MgSO4, filtered, and concentrated under
reduced pressure to give aldehyde 17 (0.69 g, 99%) as a
colorless oil, Rf 0.43 (hexanes-EtOAc, 4:1). The crude aldehyde
17 was used immediately for the next step without further
purification: 1H NMR (400 MHz, CDCl3) δ 0.78 (d, J ) 6.7
Hz, 3H), 1.19 (d, J ) 7.1 Hz, 3H), 1.37 (s, 3H), 1.43 (s, 3H),
1.89-1.98 (m, 1H), 2.50-2.54 (m, 1H), 3.49 (t, J ) 11.0 Hz,
1H), 3.68-3.74 (m, 2H), 9.77 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3) δ 11.2, 12.5, 18.7, 29.4, 31.9, 47.6, 65.8, 77.2, 98.5, 204.6
ppm.
0.34 (hexanes-EtOAc, 1:1); [R]20 -21.6° (c 1.0, CHCl3); IR
D
(CDCl3) νmax 3580, 3490, 2900, 1700, 1460, 1370, 1150 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.94 (d, J ) 7.0 Hz, 3H), 1.25 (d,
J ) 7.1 Hz, 3H), 1.47 (s, 9H), 1.76-1.83 (m, 1H), 2.65 (qd, J )
4.2, 7.2 Hz, 1H), 3.01 (dd, J ) 4.2, 7.1 Hz, 1H), 3.47 (td, J )
4.2, 8.1 Hz, 1H), 3.59 (d, J ) 8.1 Hz, 1H), 3.63-3.76 (m, 2H)
ppm; 13C NMR (100 MHz, CDCl3) δ 14.1, 14.6, 27.9, 38.1, 42.7,
66.7, 78.8, 81.2, 175.5 ppm; MS (FAB) 219 (MH, 31), 163 (100),
145 (40), 127 (10); HRMS calcd for C11H23O4 (MH) 219.1596,
found 219.1589 (3.4 ppm). Anal. Calcd for C11H22O4: C, 60.52;
H, 10.16. Found: C, 60.26; H, 10.51.
ter t-Bu tyl (2S,3R,4R)-3,5-Dih yd r oxy-2,4-d im eth ylp en -
ta n oa te (15). To a 0 °C solution of phenylselenide 13 (60 mg,
0.16 mmol) in CH2Cl2 (2 mL) was added MgBr2‚OEt2 (125 mg,
0.48 mmol). The solution was stirred for 5 min before the
addition of tributyltin hydride (87 µL, 0.32 mmol) and tri-
ethylborane (1 M in hexane, 32 µL, 0.03 mmol). The resulting
solution was stirred for 40 min at 0 °C, and 0.2 equiv of 1,3-
dinitrobenzene was added. The mixture was diluted with
EtOAc (15 mL), washed with brine (3 × 50 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the crude oil by flash column chromatography
(hexanes-EtOAc, 1:1) gave diol 15 (33 mg, 94%) as a colorless
ter t-Bu tyl (4S)-4-[(4S,5R)-2,2,5-Tr im eth yl[1,3]d ioxa n -
4-yl)]-2-m eth ylp en t-2-en oa te (18). To a solution of aldehyde
17 (0.69 g, 3.7 mmol) in toluene (19 mL) was added (tert-
butoxycarbonylethylidene)triphenylphosphorane 6 (2.89 g, 7.4
mmol). The mixture was heated at reflux for 6 h. The solvent
was then removed under reduced pressure, and the resultant
yellow solid was suspended in ether (20 mL), filtered through
Celite, and concentrated under reduced pressure. The crude
mixture was purified by flash column chromatography (hex-
anes-EtOAc 95:5) to afford ester 18 (0.66 g, 60%) as an 8:1
mixture of epimerized products (at C4, C10 in zincophorin as
oil: Rf 0.42 (hexanes-EtOAc, 3:7); [R]20 -29.8° (c 0.92,
D
CHCl3); IR (CDCl3) νmax 3500, 2990, 2970, 2240, 1715, 1440
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.79 (d, J ) 7.1 Hz, 3H),
1.18 (d, J ) 7.0 Hz, 3H), 1.46 (s, 9H), 1.82-1.86 (m, 1H), 2.51
(qd, J ) 2.3, 7.1 Hz, 1H), 3.65 (dd, J ) 3.8, 10.8 Hz, 1H), 3.71
(dd, J ) 7.5, 10.8 Hz, 1H), 3.86 (dd, J ) 2.3, 9.5 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3) δ 10.0, 13.3, 29.7, 36.6, 41.9, 68.7,
81.4, 173.4 ppm.
shown in Scheme 5): Rf 0.70 (hexanes-EtOAc, 8:2); [R]20
D
-10.9 (c 1.5, CHCl3); IR (CDCl3) νmax 2980, 1700, 1450 cm-1
;
1H NMR (400 MHz, CDCl3) major epimer: δ 0.69 (d, J ) 6.6
Hz, 3H), 1.04 (d, J ) 6.1 Hz, 3H), 1.39 (s, 3H), 1.42 (s, 3H),
1.49 (s, 9H), 1.56-1.66 (m, 1H), 1.80 (s, 3H), 2.70-2.78 (m,
1H), 3.43 (dd, J ) 2.4, 10.3 Hz, 1H), 3.47 (t, J ) 11.3 Hz, 1H),
3.65 (dd, J ) 5.1, 11.5 Hz, 1H), 6.80 (dd, J ) 1.5, 10.3 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) major epimer: δ 12.4, 16.6,
18.9, 28.1, 29.5, 31.9, 34.4, 66.0, 78.0, 79.9, 98.1, 128.9, 141.6,
168.0 ppm; MS (FAB) 299 (MH, 18), 283 (65), 243 (50), 185
ter t-Bu tyl (2R)-2-[(4R,5R)-2,2,5-Tr im eth yl[1,3]d ioxa n -
4-yl)]p r op ion a te (16). To a solution of diol 14 (0.3 g, 1.4
mmol) in 2,2-dimethoxypropane (20 mL) was added p-tolu-
enesulfonic acid (78 mg, 0.4 mmol). The mixture was stirred
for 2 h at room temperature, diluted with CH2Cl2 (30 mL),
washed with saturated aqueous NaHCO3 (3 × 25 mL), dried
over MgSO4, filtered, and concentrated under reduced pres-

5436 J . Org. Chem., Vol. 66, No. 16, 2001
Guindon et al.
(68), 167 (65), 129 (80); HRMS calcd for C17H31O4 (MH)
299.2222, found 299.2236 (-4.6 ppm). Anal. Calcd for C17H30O4:
C, 68.42; H, 10.13. Found: C, 68.50; H, 10.32.
ter t-Bu tyl (2R)-2-[(4R,5R,6R)-6-[(1R)-2-ter t-Bu tyldiph en -
ylsilyloxy-1-m et h ylet h yl]-5-m et h yl-2-oxo[1,3]d ioxa n -4-
yl]-2-iod op r op ion oa te (22). To a solution of carbamate
21 (0.21 g, 0.39 mmol) in dry acetonitrile (4 mL) under nitrogen
atmosphere at room temperature were added sequentially
NaHCO3 (81.7 mg, 0.97 mmol), silver triflate (0.25 g, 0.97
mmol), and iodine (0.20 g, 0.78 mmol). The mixture was stirred
at room temperature in the dark. After 3 h, 1 equiv of each
reactive species was added until TLC analysis indicated no
remaining carbamate (5 h). The reaction mixture was then
cooled to 0 °C and quenched by the addition of SiO2 (5 g),
EtOAc (5 mL), and water (1 mL). The resultant suspension
was filtered through a Celite pad, which had been rinsed well
with EtOAc. The organic layer was washed with water (20
mL), brine (2 × 25 mL), and saturated aqueous NaS2O3 (3 ×
25 mL) before being dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification by flash column
chromatography (hexanes-EtOAc, 4:1) afforded the iodocar-
bonate 22 (0.16 g, 60%) as a yellow oil: Rf 0.68 (hexanes-
ter t-Bu tyl (4S,5S,6R)-5,7-d ih yd r oxy-2,4,6-tr im eth yl-2-
h ep ten oa te (19). Acetonide 18 (0.66 g, 2.2 mmol), in a 1:1
mixture of THF and HCl (1 M) (44 mL), was stirred for 2 h at
room temperature under nitrogen atmosphere. The mixture
was then diluted with CH2Cl2 (40 mL) and washed with
saturated aqueous NaHCO3 (20 mL). The aqueous layer was
washed with CH2Cl2 (2 × 20 mL) and EtOAc (20 mL). The
combined organic layers were then dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification by flash
column chromatography (hexanes-EtOAc, 1:1) gave diol 19
(0.53 g, 92%) as a colorless oil: Rf 0.53 (hexanes-EtOAc, 1:1);
[R]25D -23.2 (c 1, CHCl3); IR (neat) νmax 3620, 3500, 2980, 1700
1
cm-1; H NMR (400 MHz, CDCl3) δ 0.88 (d, J ) 7.0 Hz, 3H),
1.06 (d, J ) 7.0 Hz, 3H), 1.49 (s, 9H), 1.76 (qd, J ) 3.5, 7.1
Hz, 1H), 1.83 (s, 3H), 2.63 (t, J ) 5.1 Hz, 1H), 2.71-2.76 (m,
1H), 2.87 (d, J ) 3.1 Hz, 1H), 3.49-3.52 (m, 1H), 3.61-3.67
(m, 1H), 3.78-3.83 (m, 1H), 6.71 (dd, J ) 1.3, 10.3 Hz, 1H)
ppm; 13C NMR (100 MHz, CDCl3) δ 12.8, 14.1, 16.8, 28.2, 36.8,
37.5, 67.6, 80.8, 84.6, 130.0, 141.1, 167.5 ppm; MS (FAB) 259
(MH, 30), 203 (95), 185 (100), 167 (32) 154 (36); HRMS calcd
for C14H27O4 (MH) 259.1910, found 259.1897 (4.8 ppm).
EtOAc, 4:1); [R]20 +3.4 (c 1.6, CHCl3); IR (CHCl3) νmax 2940,
D
1750, 1450, 1370, 1300, 1100 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.00 (d, J ) 7.1 Hz, 3H), 1.06 (s, 9H), 1.32 (d, J ) 6.6 Hz,
3H), 1.50 (s, 9H), 2.04 (s, 3H), 2.20-2.24 (m, 1H), 2.70-2.77
(m, 1H), 3.50 (dd, J ) 4.8, 10.8 Hz, 1H), 3.87 (dd, J ) 8.0,
10.9 Hz, 1H), 4.06 (dd, J ) 1.8, 10.8 Hz, 1H), 4.53 (d, J ) 8.4
Hz, 1H) 7.37-7.46 (m, 6H), 7.63-7.67 (m, 4H) ppm; 13C NMR
(100 MHz, CDCl3) δ 15.2, 17.5, 19.2, 25.9, 27.0, 27.5, 33.9, 36.2,
41.2, 63.9, 83.5, 85.2, 86.8, 127.8, 129.8, 133.1, 135.5, 150.0,
169.2 ppm. Anal. Calcd for C31H43O6SiI: C, 55.85; H, 6.50.
Found: C, 55.48; H, 6.21.
ter t-Bu tyl (4S,5S,6R)-7-[(ter t-Bu tyld ip h en ylsilyl)oxy]-
5-h yd r oxy-2,4,6-tr im eth ylh ep t-2-en oa te (20). To a solution
of diol 19 (0.44 g, 1.72 mmol) in CH2Cl2 (17 mL) at 0 °C under
nitrogen atmosphere were added sequentially imidazole (0.23
g, 3.4 mmol) and tert-butyldiphenylsilyl chloride (0.45 mL, 1.74
mmol). The mixture was stirred at the same temperature for
2 h before being diluted with CH2Cl2 (20 mL) and washed with
HCl (1 M, 20 mL), water (20 mL), saturated aqueous NaHCO3
(20 mL), and brine (20 mL). The mixture was then dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the crude oil by flash column chromatography
(hexanes-EtOAc 93:7) gave silyl alcohol 20 (0.76 g, 89%) as a
colorless oil: Rf 0.76 (hexanes-EtOAc, 4:1); [R]20D -36.4 (c 1.5,
CHCl3); IR (CHCl3) νmax 3450, 2980, 1700 cm-1; 1H NMR (400
MHz, CDCl3) δ 0.72 (d, J ) 7.0 Hz, 3H), 1.06 (s, 9H), 1.09 (d,
J ) 7.0 Hz, 3H), 1.50 (s, 9H), 1.72-1.80 (m, 1H), 1.81 (s, 3H),
2.66-2.71 (m, 1H), 3.53 (dd, J ) 3.6, 8.1 Hz, 1 H), 3.67 (dd, J
) 4.0, 10.3 Hz, 1H), 3.69 (dd, J ) 7.9, 10.3 Hz, 1H), 6.86 (dd,
J ) 1.3, 10.0 Hz, 1H), 7.38-7.73 (m, 10H). 13C NMR (100 MHz,
CDCl3) 12.6, 13.7, 17.0, 19.1, 26.8, 28.2, 36.7, 37.9, 69.1, 79.9,
80.1, 127.8, 129.9, 135.6, 142.0, 167.0; MS (FAB) m/z 497
(MH+, 15), 441 (51), 199 (100), 135 (93). Anal. Calcd for
C30H44O4Si: C, 72.54; H, 8.93. Found: C, 72.56; H, 8.78.
ter t-Bu tyl (2R)-2-[(4R,5R,6R)-6-[(1R)-2-ter t-Bu tyldiph en -
ylsilyloxy-1-m et h ylet h yl]-5-m et h yl-2-oxo[1,3]d ioxa n -4-
yl]p r op ion oa te (23). To a -78 °C solution of iodocarbonate
22 (0.34 g, 0.51 mmol) in THF (3 mL) were added tributyltin
hydride (275 µL, 1.02 mmol) and triethylborane (1 M in
hexane, 100 µL, 0.1 mmol). The temperature was maintained,
and the reaction mixture was stirred for 3 h before 0.2 equiv
of 1,3-dinitrobenzene was added. After an additional 15 min
at -78 °C, the mixture was warmed and concentrated under
reduced pressure. The crude oil was then partitioned between
acetonitrile (4 mL) and hexane (4 mL). The acetonitrile layer
was washed with hexane (3 × 4 mL) and concentrated under
reduced pressure. The resultant crude oil was purified by flash
column chromatography (100 mL hexane, then hexanes-
EtOAc, 5:1) to give the reduced product 23 (0.24 g, 89%) as a
colorless oil: Rf 0.33 (hexanes-EtOAc, 1:1); [R]25D -31.2 (c 0.5,
1
CHCl3); IR (neat) νmax 2950, 1700, 1440, 1100 cm-1; H NMR
(400 MHz, CDCl3) δ 0.92 (d, J ) 6.6 Hz, 3H), 1.03 (d, J ) 7.1
Hz, 3H), 1.04 (s, 9H), 1.22 (d, J ) 7.1 Hz, 3H), 1.41 (s, 9H),
2.14-2.19 (m, 1H), 2.44-2.51 (m, 1H), 2.78 (qd, J ) 2.5, 7.1
Hz, 1H), 3.52 (dd, J ) 5.7, 10.5 Hz, 1H), 3.80 (dd, J ) 7.5,
10.5 Hz, 1H), 4.04 (dd, J ) 1.9, 10.5 Hz, 1H), 4.25 (dd, J )
2.7, 10.4 Hz, 1H) 7.36-7.45 (m, 6H), 7.62-7.65 (m, 4H) ppm;
13C NMR (100 MHz, CDCl3) δ 12.2, 12.5, 14.7, 19.1, 26.9, 28.0,
31.8, 36.6, 42.8, 63.7, 81.7, 84.9, 85.7, 127.8, 129.8, 133.2, 135.5,
149.8, 170.8 ppm; MS (FAB) m/z 563 (M+ + Na+, 84), (483,
40), 407 (100), 199 (70), 135 (84); HRMS calcd for C31H44O6-
SiNa 563.2805, found 563.2780 (4.4 ppm).
ter t-Bu tyl (4S,5S,6R)-7-[(ter t-Bu tyld ip h en ylsilyl)oxy]-
5-ca r ba m oyloxy-2,4,6-tr im eth ylh ep t-2-en oa te (21). To a
0 °C solution of alcohol 20 (0.56 g, 1.1 mmol) in CH2Cl2 (6 mL)
was added dropwise trichloroacetylisocyanate (147 µL, 1.2
mmol). The mixture was stirred for 30 min at the same
temperature, and the solvent was then removed under reduced
pressure. The resultant viscous oil was dissolved in tert-butyl
alcohol (3 mL), and saturated aqueous K2CO3 (1.5 mL) was
added. The mixture was heated at reflux for 6 h, cooled to 0
°C, acidified to pH 7, diluted with EtOAc (10 mL), and washed
with water (10 mL) and brine (10 mL) before being dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification of the crude oil by flash column chromatography
(hexanes-EtOAc 2:1) gave carbamate 21 (0.53 g, 86%) as a
colorless oil: Rf 0.43 (hexanes-EtOAc, 4:1); [R]25D +20.4 (c 1.4,
CHCl3); IR (CHCl3) νmax. 4530, 3420, 2980, 1740 cm-1; 1H NMR
(400 MHz, CDCl3) δ 0.94 (d, J ) 7.0 Hz, 3H), 0.99 (d, J ) 7.0
Hz, 3H), 1.05 (s, 9H), 1.49 (s, 9H), 1.78 (s, 3H), 1.86-1.90 (m,
1H), 2.82-2.87 (m, 1H), 3.48 (dd, J ) 6.8, 10.1 Hz, 1H), 3.63
(dd, J ) 4.6, 10.1 Hz, 1H), 4.40 (bs, 2H), 4.74 (dd, J ) 4.4, 8.0
Hz, 1H), 6.61 (dd, J ) 1.4, 10.1 Hz, 1H) 7.35-7.42 (m, 6H),
7.64-7.67 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3) δ 12.5,
14.1, 16.8, 19.2, 26.8, 28.1, 35.1, 38.2, 65.0, 78.4, 80.0, 127.5,
129.3, 129.5, 133.7, 135.6, 141.2, 156.9, 167.4 ppm; MS (FAB)
m/z 540 (MH+, 20), 484 (52), 426 (48), 345 (64), 242 (100), 199
(78), 135 (100); HRMS calcd for C31H46O5SiN (MH) 540.3145,
found 540.3123 (4.1 ppm).
(3R,4R,5S,6R)-6-[(1R)-2-(ter t-Bu tyld ip h en ylsilyloxy-1-
m eth yleth yl)]-4-h yd r oxy-3,5-d im eth yltetr a h yd r op yr a n -
2-on e (24). To carbonate 23 (0.10 g, 0.193 mmol) in THF-
H2O (1:1, 4 mL) at 0 °C was added lithium hydroxide (9.2 mg,
0.39 mmol). The mixture was stirred for 2 h at the same
temperature, and an additional 1 equiv of lithium hydroxide
was added. After 3 h, the mixture was concentrated under
reduced pressure, diluted with EtOAc (4 mL), and washed with
brine (2 × 4 mL). The aqueous layer was washed with EtOAc
(2 × 4 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
crude diol was then diluted in THF (4 mL), and p-toluene-
sulfonic acid (7.3 mg, 0.039 mmol) was added. The reaction
mixture was stirred 24 h, diluted with CH2Cl2 (2 mL), and
washed with saturated aqueous NaHCO3 (2 × 4 mL). The
organic layer was dried over MgSO4, filtered, and concentrated
under vacuum to give lactone 24 (0.065 g, 77%) as a colorless

Synthesis of the C7-C16 Subunit of Zincophorin
J . Org. Chem., Vol. 66, No. 16, 2001 5437
oil: Rf 0.75 (hexanes-EtOAc, 1:1); [R]20 6.9 (c 1.3, CHCl3);
°C. Amide 26 (37 mg, 0.68 mmol) in solution with Et2O (0.7
mL) was cannuled to organolithium 27, and the resultant
solution was stirred at room temperature for 20 min. The
mixture was then poured into a solution of 5% HCl in EtOH
(10 mL), cooled to 0 °C, and diluted with Et2O-CH2Cl2 (1:1,
10 mL). The organic layer was washed with brine (2 × 10 mL),
dried over MgSO4, filtered, and concentrated under vacuum.
Purification by flash column chromatography (hexanes-
EtOAc, 4:1) gave ketone 28 (26 mg, 65%) as a yellow oil: Rf
0.43 (hexanes-Et2O, 3:2); [R]20D -1.0 (c 1.8, CHCl3); IR (neat)
νmax 3070, 3030, 2960, 2930, 2880, 1710, 1595, 1470, cm-1; 1H
NMR (400 MHz, CDCl3) δ 0.69 (d, J ) 6.6 Hz, 3H), 0.94 (d, J
) 7.1 Hz, 3H), 1.04 (s, 9H), 1.14 (d, J ) 7.1 Hz, 3H), 1.30 (s,
3H), 1.35 (s, 3H), 1.63-1.72 (m, 2H), 1.88 (td, J ) 4.6, 7.5 Hz,
2H), 1.99-2.18 (m, 1H), 2.56-2.62 (m, 2H), 2.65-2.69 (m, 1H),
3.38 (d, J ) 10.4 Hz, 1H), 3.43 (dd, J ) 6.8, 10.0 Hz, 1H), 3.57
(dd, J ) 3.6, 10.2 Hz, 1H), 3.75-3.91 (m, 4H), 4.83 (t, J ) 4.6
Hz, 1H), 7.36-7.44 (m, 6H), 7.65-7.70 (m, 4H); 13C (100 MHz,
CDCl3) δ 12.2, 13.5, 15.5, 19.1, 26.9, 27.5, 29.9, 34.5, 35.3, 36.5,
50.2, 64.5, 64.9, 77.4, 98.0, 103.6, 127.6, 129.5, 133.9, 135.6,
211.8. Anal. Calcd for C34H50O6Si: C, 70.06; H, 8.65. Found:
C, 69.75; H, 8.99.
D
IR (neat) νmax 3450, 2900, 1700, 1470, 1360 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.03 (s, 9H), 1.03-1.07 (m, 6H), 1.28 (d, J )
7.3 Hz, 3H), 1.76 (d, J ) 3.7 Hz, 1H), 2.06-2.12 (m, 1H), 2.29-
2.34 (m, 1H), 2.34-2.38 (m, 1H), 3.52 (dd, J ) 5.7, 10.4 Hz,
1H), 3.76 (dd, J ) 2.2, 2.9 Hz, 1H), 3.83 (dd, J ) 7.5, 10.4 Hz,
1H), 4.37 (dd, J ) 1.6, 11.0 Hz, 1H), 7.36-7.45 (m, 6H), 7.62-
7.65 (m, 4H) ppm; 13C NMR (100 MHz, CDC13) δ 12.8, 14.5,
15.5, 19.1, 26.9, 36.0, 36.9, 42.3, 64.3, 73.4, 76.7, 84.0, 127.8,
129.8, 133.4, 133.5, 135.5, 173.8 ppm; MS (FAB) 363 (M-C6H5,
96), 307 (18), 239 (44), 199 (74), 135 (100); HRMS calcd for
C
26H37O4Si 441.2461, found 441.2439 (5.0 ppm).
(2R,3R,4R,5R,6R)-7-(ter t-Bu tyld ip h en ylsilyloxy)-3,5-d i-
h yd r oxy-N ,N -m e t h oxym e t h yl-2,4,6-t r im e t h ylh e p t a n -
a m id e (25). To a suspension of N,O-methoxymethylhydroxy-
lamine hydrochloride (56 mg, 0.57 mM) in CH2Cl2 (2 mL) at 0
°C was added trimethylaluminum (1 M in hexane, 0.58 mL,
0.57 mM) (CAUTION: vigorous gas evolution). The cooling
bath was then removed, and the clear solution was stirred for
1 h at room temperature. The solution of lactone 24 (75 mg,
0.17 mM) in CH2Cl2 (4 mL) was added dropwise. The solution
was stirred at room temperature for 30 min (vigorous gas
evolution), and a buffer solution at pH 7.2 (1.7 mL) was added.
The reaction mixture was then stirred for an additional 10
min. The resultant gel was filtered through a Celite pad, which
had been rinsed well with CHCl3 (10 mL). The organic layer
was washed with brine (2 × 10 mL), and the aqueous layer
was extracted with CHCl3 (10 mL) and EtOAc (10 mL). The
combined organic layers were dried over MgSO4, filtered, and
concentrated under vacuum to give hydroxyamide 25 (81 mg,
95%) as a yellow oil: Rf 0.43 (hexanes-EtOAc, 1:1); IR (neat)
(2R,3R)-2-[(4R,5R,6R)-6-[(1R)-2-ter t-Bu t yld ip h en ylsi-
lyloxy-1-m et h ylet h yl]-2,2,5-t r im et h yl[1,3]d ioxa n -4-yl]-
5-[1,3]d ioxola n ep en ta n -3-ol (29).1k To ketone 28 (0.23
mg, 0.04 mmol) in THF (0.8 mL) at -78 °C was added dropwise
L-Selectride (1 M in THF, 79 µL, 0.08 mmol). The mixture was
stirred at the same temperature for 1 h, and an additional 1
equiv of L-Selectride was added to the solution, which was then
allowed to warm to -50 °C. After 2 h, the mixture was warmed
to 0 °C over 30 min and quenched by the addition of MeOH
(0.5 mL) and a small amount of SiO2. The resultant suspension
was filtered through a Celite pad, which had been rinsed well
with EtOAc. The organic layer was washed with brine (2 × 1
mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. The two diastereoisomers, in a 7:1 ratio,
were separated by flash column chromatography (hexanes-
EtOAc, 4:1) to give the major alcohol 29 (17 mg, 72%) as a
1
νmax 3450, 3070, 2960, 2860, 1740, 1630, 1470 cm-1; H NMR
(400 MHz, CDCl3) δ 0.87 (d, J ) 7 Hz, 3H), 0.98 (d, J ) 7 Hz,
3H), 1.04 (s, 9H), 1.33 (d, J ) 7.1 Hz, 3H), 1.92 (q, J ) 7.1 Hz,
1H), 2.06-2.12 (m, 1H), 3.15 (s, 3H), 3.30 (bd, J ) 4.2, 1H),
3.56 (t, J ) 5.5 Hz, 1H), 3.66-3.76 (m, 3H), 3.71 (s, 3H), 4.60
(bs, 1H), 4.83 (bs, 1H), 7.36-7.45 (m, 6H), 7.66-7.69 (m, 4H);
13C (100 MHz, CDCl3) 14.8, 15.2, 16.1, 19.1, 26.9, 29.3, 31.7,
36.0, 37.8, 40.2, 53.9, 61.6, 66.9, 69.5, 79.1, 80.5, 127.7, 129.7,
133.3, 135.6, 178.2, 211.0; MS (FAB) 502 (MH, 42), 239 (20),
199 (100); HRMS calcd for C28H44O5NSi 502.2989, found
502.3001 (-2.4 ppm).
yellow oil: Rf 0.38 (hexanes-EtOAc, 4:1); [R]20 1.07 (c 0.98,
D
CHCl3) [lit.1k [R]28 1.19 (c 1.01, CHCl3)]; H NMR (400 MHz,
1
D
CDCl3) δ 0.68 (d, J ) 6.6 Hz, 3H), 0.92 (d, J ) 7.0 Hz, 3H),
0.99 (d, J ) 7.1 Hz, 3H), 1.04 (s, 9H), 1.33 (s, 3H), 1.34 (s,
3H), 1.47-1.83 (m, 5H), 2.00-2.09 (m, 2H), 3.39-3.44 (m, 2H),
3.47 (dd, J ) 1.3, 10.4 Hz, 1H), 3.60 (bs, 1H), 3.79-3.95 (m,
6H), 4.85 (t, J ) 4.8 Hz, 1H), 7.36-7.45 (m, 6H), 7.67-7.71
(m, 4H); 13C (100 MHz, CDCl3) δ 11.0, 11.8, 15.5, 18.8, 19.1,
26.9, 29.2, 30.1, 30.7, 33.2, 36.0, 36.4, 64.4, 64.9, 69.6, 77.6,
81.5, 98.5, 104.6, 127.7, 129.6, 133.8, 135.7.
(2R)-2-[(4R,5R,6R)-6-[(1R)-2-ter t-Bu tyldiph en ylsilyloxy-
1-m eth yleth yl]-2,2,5-tr im eth yl[1,3]dioxan -4-yl]-N,N-m eth -
oxym eth ylp r op a n a m id e (26). To diol 25 (30 mg, 0.60 mM)
were added p-toluenesulfonic acid (1.1 mg, 0.006 mM) and 2,2-
dimethoxypropane (0.9 mL). The mixture was stirred for 1 h
at room temperature and concentrated under vacuum. Puri-
fication by flash column chromatography (hexanes-EtOAc,
7:3) gave a 2:1 mixture of acetonide 26 (20 mg, 63%) and
lactone 24 (10.8 mg, 37%): Rf 0.65 (hexanes-EtOAc, 1:1);
[R]20D -7.0 (c 1.4, CHCl3); IR (neat) νmax 3050, 2960, 1740, 1670,
(2R,3R)-3-Ben zyloxym et h oxy-2-[(4R,5R,6R)-6-[(1R)-2-
ter t-bu tyldiph en ylsilyloxy-1-m eth yleth yl]-2,2,5-tr im eth yl-
[1,3]d ioxa n -4-yl]-5-[1,3]d ioxola n ep en ta n e:5c Rf 0.43 (hex-
anes-EtOAc, 4:1); [R]20 24.5 (c 1.6, CHCl3) [lit.5c [R]28 26.2
D
D
1
1460 cm-1; H NMR (400 MHz, CDCl3) δ 0.78 (d, J ) 6.4 Hz,
(c 1.75, CHCl3)]; 1H NMR (400 MHz, CDCl3) δ 0.68 (d, J ) 6.2
Hz, 3H), 0.96 (d, J ) 6.7 Hz, 3H), 0.97 (d, J ) 6.7 Hz, 3H),
1.04 (s, 9H), 1.28 (s, 3H), 1.31 (s, 3H), 1.58-1.80 (m, 6H), 1.99-
2.04 (m, 1H), 3.31-3.38 (m, 2H), 3.46 (dd, J ) 6.8, 10.1 Hz,
1H), 3.77-3.93 (m, 6H), 4.60 (q AB, J ) 11.9 Hz, ∆υAB ) 89
Hz, 2H), 4.78 (q AB, J ) 6.4 Hz, ∆υAB ) 65.3 Hz, 2H), 4.84 (t,
J ) 4.6 Hz, 1H), 7.27-7.41 (m, 11H), 7.66-7.69 (m, 4H); 13C
(100 MHz, CDCl3) δ 12.7, 12.8, 15.6, 19.2, 26.9, 29.1, 30.0, 30.2,
33.5, 36.8, 38.8, 64.6, 64.9, 69.7, 77.2, 77.6, 77.9, 95.0, 97.9,
104.6, 127.4, 127.6, 127.8, 128.3, 129.5, 134.0, 135.6, 138.4.
3H), 0.95 (d, J ) 7.0 Hz, 3H), 1.05 (s, 9H), 1.12 (d, J ) 7.1 Hz,
3H), 1.29 (s, 3H), 1.35 (s, 3H), 1.81-1.88 (m, 1H), 2.04-2.09
(m, 1H), 2.99 (bs, 1H), 3.16 (s, 3H), 3.38 (dd, J ) 1.6, 10.4 Hz,
1H), 3.44 (dd, J ) 6.6, 10.3 Hz, 1H), 3.64 (s, 3H), 3.71 (dd, J
) 5.4, 10.0 Hz, 1H), 3.86 (dd, J ) 6.4, 10.0 Hz, 1H), 7.36-7.43
(m, 6H), 7.67-7.72 (m, 4H); 13C (100 MHz, CDCl3) δ 8.8, 9.3,
11.5, 14.9, 15.0, 22.6, 25.5, 25.7, 29.8, 32.0, 37.2, 50.1, 56.9,
60.4, 71.7, 72.9, 73.2, 93.5, 102.2, 123.3, 123.4, 125.3, 129.8,
131.4, 133.4, 211.0; MS (FAB) m/z 542 (MH+, 32), 484 (50),
199 (50), 146 (42), 135 (100); HRMS calcd for C31H48O5NSi
542.3302, found 542.3329 (-5.0 ppm). Anal. Calcd for C31H47O5-
NSi: C, 68.72; H, 8.74; N, 2.59. Found: C, 68.95; H, 8.83; N,
2.59.
Ack n ow led gm en t. This work was supported finan-
cially by NSERC. We thank LaVonne Dlouhy for her
assistance in the preparation of this manuscript.
(2R)-2-[(4R,5R,6R)-6-[(1R)-2-ter t-Bu tyldiph en ylsilyloxy-
1-m eth yleth yl]-2,2,5-tr im eth yl[1,3]d ioxa n -4-yl]-5-[1,3]d i-
oxola n ep en ta n -3-on e (28). Bromo-2-(2-ethyl)dioxolane (48
µL, 0.41 mmol) was dissolved in Et2O (0.7 mL) and cooled to
-78 °C in a two-necked round-bottom flask fitted with a
condenser. The tert-butyllithium (1.7 M in pentane, 0.4 mL,
0.68 mmol) was added dropwise, and the mixture was stirred
at -78 °C for 30 min. The solution was allowed to warm to 0
Su p p or t in g In for m a t ion Ava ila b le: NMR spectra for
compounds 5, 8, 9, 13, 15, 17, 19, 21, 23, 24, 25, and the C7-
C16 subunit of zincophorin. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O010310F