Enantio- and diastereoselective additions to aldehydes using the bifunctional reagent 2-(chloromethyl)-3-(tributylstannyl)propene: Application to a synthesis of the C16-C27 segment of bryostatin 1

Article abstract of DOI:10.1021/jo048308m

(Chemical Equation Presented) Reactions of the bifunctional allylstannane 2-(chloromethyl)-3-(tributylstannyl)propene with aldehydes have been examined. These generally occur in high yields using Lewis acid promoters and the products can be isolated and p

Full text of DOI:10.1021/jo048308m

Enantio- and Diastereoselective Additions to Aldehydes Using the
Bifunctional Reagent
2-(Chloromethyl)-3-(tributylstannyl)propene: Application to a
Synthesis of the C16-C27 Segment of Bryostatin 1
Gary E. Keck,* Tao Yu,† and Mark D. McLaws‡
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112
keck@chemistry.utah.edu
Received September 22, 2004
Reactions of the bifunctional allylstannane 2-(chloromethyl)-3-(tributylstannyl)propene with alde-
hydes have been examined. These generally occur in high yields using Lewis acid promoters and
the products can be isolated and purified without incident. Good yields and high enantioselectivities
are also realized in catalytic asymmetric allylations (CAA reactions) using the previously described
BITIP catalyst system. Protection of the free hydroxyl can be accomplished without cyclization to
the derived tetrahydrofuran, although this transformation is also facile. The utility of the
incorporated allyl chloride functionality allows for the obvious use of such products in reactions
with nucleophiles. Use of these products in a less obvious connective strategy is demonstrated in
the synthesis of the C12-C27 segment of bryostatin 1 where a connective, or “lynchpin”, double-
allylation process was employed. The â-hydroxy allyl chloride obtained from an initial chelation-
controlled allylation of aldehyde 16 was converted to allylstannane 19 and applied in a second
allylation reaction, thus allowing for a highly convergent synthesis of the bryostatin C ring backbone
in a stereoselective fashion.
Introduction
prompted us to examine variations on the allylation
methodology further by using 2-substituted allylstan-
nanes possessing reactive functionality, which can serve
as a handle for subsequent chemistry.4 Herein, we report
the results of allylation studies using 2-(chloromethyl)-
3-(tributylstannyl)propene 1 in both BINOL titanium
The Lewis acid promoted additions of storable nucleo-
philes to aldehydes has proven to be an extremely
powerful bond construction. Allylstannanes have proven
particularly useful in this regard. The stereochemistry
of these reactions is of both interest and practical
importance, and examples in which stereochemistry is
controlled by stereoelectronic effects, by substrate pre-
organization via chelation, by the use of stoichiometric
chiral reagents, and by Lewis acid chirality are all
known.1 Our own studies initially utilized the parent
allyltributylstannane,2 but substituted allylstannanes3
can also be employed to good advantage. Synthetic
studies currently underway in our laboratories have
tetraisopropoxide (BITIP) catalyzed asymmetric addi-
tions to aldehydes1b and diastereoselective reactions
† Current address: Schering-Plough Research Institute, Kenilworth,
NJ, 07033.
(3) (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 1879-
1882. (b) Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883-
1886. (c) Keck, G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron Lett.
1987, 28, 139-142. (d) Keck, G. E.; Krishnamurthy, D.; Grier, M. C.
J. Org. Chem. 1993, 58, 6543-6544.
(4) (a) Keck, G. E.; Yu, T. Org. Lett. 1999, 1, 289-291. (b) Keck, G.
E.; Wager, C. A.; Wager, T. T.; Savin, K. A.; Covel, J. A.; McLaws, M.
D.; Krishnamurthy, D.; Cee, V. J. Angew. Chem., Int. Ed. 2001, 40,
231-234. (c) Keck, G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002,
4, 1189-1192.
‡ Current address: Albany Molecular Research, Inc., Albany, NY
12212.
(1) For reviews, see: (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993,
93, 2207-2293. (b) Marshall, J. A. Chem. Rev. 1996, 96, 31-48. (c)
Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763-2794.
(2) (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265-
268. (b) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467-8468.
10.1021/jo048308m CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/03/2005
J. Org. Chem. 2005, 70, 2543-2550
2543

Keck et al.
SCHEME 1. Asymmetric Allylation Using
Allylstannane 2
leading to the synthesis of the C17-C27 segment of the
bryostatins, a class of potent anticancer agents.5,6
Results and Discussion
An analysis of substructures found in the bryostatins
and other natural products being studied in our labora-
tories prompted research into the development of an
allylstannane-based isobutene synthon that could serve
as a coupling agent between two different aldehydes in
a stereoselective double allylation procedure as outlined
in eq 1. Our past experience in the synthesis of function-
alized piperidines7 led us to initially consider the known
reagent 2 as a suitable equivalent to such a synthon.
extent in 2-propanol. This unfortunate competing side
reaction would also explain the low levels of product
formation as such a process would rob the system of
protons which are thought to be important for catalyst
turnover.
Isolation and purification of the sensitive allylstannane
product was also quite problematic. The allylstannane
functionality was prone to acid catalyzed hydrolysis
making it necessary to carefully treat all glassware with
triethylamine to eliminate all residual acid sources.
Likewise, purification by silica gel chromatography re-
sulted in complete decomposition to give the methally-
lation product unless the silica gel was pretreated with
triethylamine. Given the sensitive nature of this reagent
and of the product from the initial allylation reaction,
we elected to pursue a different approach in which the
second tributylstannyl substitutent would be introduced
after the first allylation reaction. Thus allylstannane 1
was synthesized and investigated as a more robust
surrogate to the bis-stannane reagent 2 through eventual
conversion of the allyl chloride to the allylstannane. This
approach had the added benefit of providing for ad-
ditional useful synthetic applications, in that the allylic
chloride product could clearly be used in reactions with
a wide variety of nucleophiles (e.g. enolates, dithianes,
amines, etc.) which would lead to other convergent
approaches to more complex materials.
Recently reported syntheses of allylstannane 1 have
accessed the reagent through a two-step process begin-
ning with 2-methyl-1-propen-3-ol.9 The reported pro-
cesses require silica gel chromatography at each step and
the overall yield averaged approximately 45%. A more
simple and direct synthesis was sought that avoided
chromatography as a means of purification. Our approach
to allylstannane 1 was to selectively displace one of the
chloride groups of 3-chloro-2-chloromethyl-1-propene 5
with 1 equiv of lithium tributyltin (Scheme 2). This
strategy originated from the assumption that the steric
effect from the bulky stannane group would disfavor a
second chloride substitution. However, when the reaction
was carried out in THF, it was found by NMR analysis
of the crude reaction mixture that a statistical mixture
of starting material, product 1, and bis-stannane 2
formed, suggesting the displacement of the second chlo-
ride is a competitive process. After consideration of
possible transition states for these two processes, we
considered that the presence of an electron donating
stannane group in the transition state (7) may facilitate
the second chloride substitution by enhancing the SN1
nature of the process relative to the transition state (6)
for the first displacement. In an attempt to overcome this
It is well-known that the additional allylic stannyl
group creates a dramatic difference in reactivity between
2 and the subsequent mono-allylstannane intermediate
obtained after the initial addition reaction. This differ-
ence in reactivity has allowed for iterative additions to
electrophiles without isolation of intermediates.8 Our own
research interests, however, required that the sensitive
mono-stannane intermediate be isolated and the hydroxyl
group protected prior to the second addition reaction. We
were also concerned that the increased reactivity of the
bis-stannane reagent might adversely affect the degree
of stereoselectivity obtained under both chiral Lewis acid
controlled and substrate controlled additions. We began
to address these requirements and concerns in a study
where the bis-stannane reagent was employed in the
catalytic asymmetric addition reaction using the BITIP
catalyst.
Reaction of allylstannane 2 with benzaldehyde gave
the desired product 3 and the methallylation product 4
in low and variable yields (Scheme 1). Product 4 could
arise by one of two ways. Protiodestannylation of 3 could
occur to give the corresponding methallyl adduct, or
alternatively protiodestannylation of the tin reagent 2
could take place giving methallyl tributyltin followed by
addition of that reagent to benzaldehyde to give product
4. In the former scenario, both 3 and 4 would be produced
with the same enantiomeric excess, which is not neces-
sarily true for the second pathway. The observed ee
values suggest that both pathways contribute, but that
the major pathway to 4 is via protiodestannylation of 2.
In fact, NMR studies found that this highly reactive
stannane reagent undergoes rapid hydrolysis in the
presence of (1,1′-binaphthalene)-2,2′-diol, and to some
(5) (a) Pettit, G. R. J. Nat. Prod. 1996, 59, 812-821. (b) Pettit, G.
R. In Progress in the Chemistry of Organic Natural Products; Herz,
W., Ed.; Springer-Verlag: New York, 1991; No. 57, p 153. (c) Schuchter,
L. M.; Esa, A. H.; May, W.; Laulis, M. K.; Pettit, G. R.; Hess, A. D.
Cancer Res. 1991, 51, 682. (d) Kraft, A. S. J. Natl. Cancer Inst. 1993,
85, 1790. (e) Stone, R. M. Leukemia Res. 1997, 21, 399.
(6) For a review, see: Hale, K. J.; Hummersone, M. G.; Manaviazar,
S.; Frigerio, M. Nat. Prod. Rep. 2002, 19, 413-453.
(7) Keck, G. E.; Palani, A. Tetrahedron Lett. 1993, 34, 3223-3224.
(8) (a) Sano, H.; Okara, M.; Ueno, Y. Synthesis 1984, 933-935. (b)
Degl’Innocenti, A.; Dembech, P.; Mordini, A.; Ricci, A.; Seconi, G.
Synthesis 1991, 267-269.
(9) (a) Kang, K.-T.; Hwang, Y. B.; Kim, M. Y.; Lee, S. K.; Lee, J. G.
Bull. Korean Chem. Soc. 2002, 23, 1333-1336 and ref 19 therein. (b)
Mart´ın-Matute, B.; Bun˜uel, E.; Me´ndez, M.; Nieto-Oberhuber, C.;
Ca´rdenas, D. J.; Echavarren, A. M. J. Organomet. Chem. 2003, 687,
410-419.
2544 J. Org. Chem., Vol. 70, No. 7, 2005

Allylation Studies and Bryostatin C-Ring Synthesis
SCHEME 2. Synthesis of Allylstannane 1
its reactivity, the degree of impact was unknown. In one
case, however, we had shown that a mildly electron
withdrawing group at the 2-position was well tolerated
by the BITIP catalyst system.4a
Reactions of this allylstannane with benzaldehyde were
carried out to determine the optimal experimental condi-
tions. The outcome of the experiments showed that
reactions carried out in CH2Cl2 using BITIP catalyst
prepared by “method A”2b gave superior results; however,
catalyst prepared by “method B” gave results that were
not significantly different. A catalyst loading of 20 mol
% was initially used while determining optimal reaction
conditions, but then lowered to 10 mol % once reaction
parameters were established with no noticeable negative
effect on reaction outcome. The results of reactions using
a variety of aldehydes under “method A” condition are
summarized in Table 1. In most cases, both aromatic and
aliphatic aldehydes gave the corresponding â-hydroxy
allyl chlorides in good yields and with high levels of
enantioselectivity.
TABLE 1. Isolated Yields and Enantiomeric Excess for
the Reaction of 1 with Aldehydes
A number of synthetic transformations can be explored
utilizing the allyl chloride functionality found in the
resulting product. For example, employing the allyl
chloride in an intramolecular cyclization event gave a
chiral methylenetetrahydrofuran ring having a substitu-
tion pattern that can be found in a number of compounds
of biological interest (eq 2).10
The concept of exploiting the bifunctional nature of
allylstannane 1 as a linchpin for two different aldehydes
was realized while engaged in the synthesis of the C17-
C27 (C-ring) segment of bryostatin 1.11 The structural
features found in this segment also served as a vehicle
for evaluating substrate controlled diastereoselective
addition reactions using the stannane reagent.
The key features of our approach are shown retrosyn-
thetically in Scheme 3. Our approach to this segment was
aimed at providing an efficient synthesis of intermediate
11 (Scheme 3). We envisioned from the outset that the
hemiketal moiety present at C19 would be established
a 10 mol % of catalyst used except where noted. % ee determined
by chiral HPLC except where noted. b 20 mol % of catalyst was
used. c % ee determined by 1H and 19F NMR analysis of the
corresponding Mosher ester. d (R)-BITIP catalyst was used in this
example giving the enantiomer whose configuration is opposite
that depicted.
problem, experiments were performed in which the
polarity of the solvent was lowered in order to suppress
the impact such an electronic effect would have on the
system. In our study, we employed hexanes as a cosolvent
to reduce the overall polarity of the reaction medium, and
found the best result could be obtained when a 1:1
mixture of THF/hexanes was used. Under these condi-
tions, the desired mono-displaced product 1 could be
isolated in up to 60% yield. Only a trace amount of bis-
stannane was formed. The reaction has been performed
on multigram scale and the product can be easily isolated
through simple distillation. It should be noted that
nonpolar solvents also reduce the reactivity of bis-chloride
5. Therefore, a higher ratio of hexanes is not suggested
for the reaction, as a significant amount of starting
material will remain unreacted under such conditions.
With the reagent in hand, experiments were done to
ascertain its utility in BITIP catalyzed asymmetric
additions to aldehydes. Although it can reasonably be
assumed that the incorporation of an electron withdraw-
ing group on the allylstannane nucleophile would lower
(10) (a) Ochiai, M.; Fujita, E.; Arimoto, M.; Yamaguchi, H. Chem.
Pham. Bull. 1985, 33, 989-997. (b) Trost, B. M.; King, S. A.; Schmidt,
T. J. Am. Chem. Soc. 1989, 111, 5902-5915. (c) Kakinuma, K.; Hanson,
C. A.; Rinehart, K. L., Jr. Tetrahedron 1976, 32, 217-222. (d) Bartrol´ı,
J.; Carceller, E.; Merlos, M.; Garc´ıa-Rafanell, J.; Forn, J. J. Med. Chem.
1991, 34, 373-386. (e) Ishibashi, Y.; Ohba, S.; Nishiyama, S.; Yama-
mura, S. Bull. Chem. Soc. Jpn. 1995, 68, 3643-3649.
(11) For other approaches to the C-ring of the bryostatins, see: (a)
Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai, P.;
Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc. 1990, 112, 7407-
7408. (b) DeBrabander, J.; Vandewalle, M. Synthesis 1994, 855-865.
(c) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041-2114. (d)
Hale, K. J.; Lennon, J. A.; Manaviazar, S.; Javaid, M. H. Tetrahedron
Lett. 1995, 36, 1359-1362. (e) Gracia, J.; Thomas, E. J. J. Chem. Soc.,
Perkin Trans. 1 1998, 17, 2865-2871. (f) Baxter, J.; Mate, E. G.;
Thomas, E. J. Tetrahedron 1998, 54, 14359. (g) Wender, P. A.;
DeBrabander, J.; Harran, P. G.; Jimenez, J.-M.; Koehler, M. F. T.;
Lippa, B.; Park, C. M.; Shiozaki, M.; Pettit, G. R. J. Am. Chem. Soc.
1998, 120, 4534-4535. (h) Obitsu, T.; Ohmori, K.; Ogawa, Y.; Hosomi,
H.; Ohba, S.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1998,
39, 7349-7352. (i) Evans, D. A.; Carter, P. H.; Charette, A. B.; Prunet,
J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121, 7540-7552. (j) Hale,
K. J.; Frigerio, M.; Manaviazar, S. Org. Lett. 2003, 5, 503-505. (k)
Wender, P. A.; Koehler, M. F. T.; Sendzik, M. Org. Lett. 2003, 5, 4549-
4552. (l) Voight, E. A.; Roethle, P. A.; Burke, S. D. J. Org. Chem. 2004,
69, 4534-4537.
J. Org. Chem, Vol. 70, No. 7, 2005 2545

Keck et al.
SCHEME 3. Proposed Approach to the Bryostatin
C-Ring
SCHEME 4. Double-Allylation Approach
elaboration. Although we had found that such alcohols
cyclized readily, it was also found that 18 could be either
silyated or acylated without cyclization. After protection
of the resulting â-hydroxyl group, in this case as a
pivalate, the allyl chloride was converted to the allyl-
stannane by reaction with Bu3SnLi to give compound 19.
The second allylation now involved a nucleophile with
a preexisting stereocenter. Although this center is quite
remote, we had no previous examples of how that might
influence the stereochemical outcome of the upcoming
addition reaction. As the C21 hydroxyl group would be
used to establish the chirality of the crucial C23 stereo-
center, the chelation controlled addition of 19 to aldehyde
17 had to proceed with a high degree of stereoselectivity.
To our gratification, the coupling reaction between 17
and 19 under chelation controlled conditions did indeed
establish the C21 center with a high (20:1) level of
stereoselectivity, thereby affording the C19-C27 carbon
skeleton. To help confirm the stereochemistry of the
newly generated C21 center, the reaction was also per-
formed using BF3‚OEt2 to promote coupling under Felkin-
Anh control. The major product 21 isolated from this
reaction had the opposite stereochemistry from the
product obtained under chelation controlled conditions,
which indirectly provides evidence to support our assign-
ment of the C21 stereochemistry of 20. The stereochem-
istry of this center was ultimately established through
further chemistry and spectroscopy; these experiments
are detailed in the Supporting Information.12
from the corresponding hydroxy ketone, most probably
as its mixed methoxy ketal. We also planned to introduce
the prenyl moiety present at C16-C18 via reaction of an
aldehyde with a prenyl organometallic reagent. Finally,
we planned to introduce the unsaturated ester present
at C21 via a Horner-Emmons reaction, most probably
after the ring closure had occurred. A (protected) hydroxyl
substituent was thus needed at C21. The stereochemistry
of the C21 center was inconsequential since it was
destined for oxidation, thus we could choose its configu-
ration in a way that best accommodated our planned
synthetic route. By placing an (R)-configuration at the
C21 position, as in 13, a quasi C2 symmetry around the
C23 center with regard to the arrangement of the flanking
hydroxyl stereocenters is produced. If we consider that
the C23 hydroxyl could be obtained by reduction of the
corresponding ketone, as in 14, then it can be seen that
this material might be considered to arise from two
consecutive aldol reactions, or alternatively, through the
use of allylstannane additions as a surrogate for the aldol
process. With the C21 position configured as (R), it can
be seen that the vicinal pairs (C20-C21 and C25-C26) in
the allyl addition product 15 are both syn. This is the
stereochemical result that would be established by a
chelation controlled addition to an R-alkoxy aldehyde.2a
Based on this retrosynthetic strategy, our key intermedi-
ate 12 may be disassembled into the lactate derived
aldehyde 16, allylstannane 1, and aldehyde 17. In this
way, through a linchpin provided by the allylstannane
1, an advanced skeleton of our target can be constructed
in a highly convergent fashion.
Completion of the C17-C27 segment of the bryostatins
is shown in Scheme 5. Oxidative cleavage of the double
bond and subsequent syn-reduction of the resulting
hydroxy ketone under the conditions developed by Pras-
ad13 afforded the diol in high yields as a single isomer,
thus providing key intermediate 23 with all stereocenters
in place. The diol unit in 23 was then protected as its
acetonide, from which the syn-diol relationship was
confirmed by 13C NMR.14
(12) For additional experimentation confirming the relative stere-
ochemistry of the C21, C23, C25 triad, see the Supporting Information
section of this paper.
(13) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155-158.
(14) Rychnovsky, S. D.; Yang, G.; Powers, J. P. J. Org. Chem. 1993,
58, 3511-3515.
The reaction between stannane 1 and the lactate
derived aldehyde 16 under MgBr2‚OEt2 mediated condi-
tions afforded the desired alcohol 18 in high yield and
with a 30:1 diastereomeric ratio (Scheme 4).2a Protection
of the resulting alcohol is required prior to further
2546 J. Org. Chem., Vol. 70, No. 7, 2005

Allylation Studies and Bryostatin C-Ring Synthesis
SCHEME 5. Completion of the Bryostatin C-Ring
Deprotection and oxidation of the primary hydroxyl
group furnished the corresponding aldehyde, which was
treated with an in situ generated prenyl indium reagent15
to complete the carbon backbone of our target molecule.
Oxidation of the resulting alcohol was found to be
problematic. With most commonly used oxidants, such
as TPAP, (COCl)2/DMSO/NEt3, Dess-Martin, and SO3‚
Py/DMSO, the reaction did not proceed to any extent
resulting in the recovery of starting material. Only
moderate success was achieved using PCC oxidation
conditions where a 40% yield of the ketone was isolated.
Fortunately, a solution was found in which oxidation
could be attained in greater than 85% yields using a 3:2:2
mixture of DMSO/Ac2O/NEt3, conditions considered most
suitable for oxidizing hindered alcohols.16 Operationally,
the steps of TPAP oxidation of compound 25, prenyl
indium addition, and DMSO/Ac2O/NEt3 oxidation were
routinely performed without purification of the interme-
diates giving compound 27 in an overall yield of 60%.
Thus far, as demonstrated by the successful synthesis
of ketone 27, we had developed a highly efficient ap-
proach to the complete carbon backbone of the C17-C27
segment of the bryostatins, with all the requisite stereo-
centers set and functionality in place. The completion of
our synthesis only required cyclization to form the C ring
and the construction of the C21 exocyclic olefin.
In theory, the C ring can be generated by acetonide
deprotection, which should also trigger concomitant
internal ketal formation. In practice, however, cyclization
after removal of the acetonide proved quite problematic.
Treatment of compound 27 with acidic methanol under
a variety of conditions did not provide any cyclized
product. Although the acetonide was efficiently removed
under acidic conditions, the resulting diol failed to
undergo cyclization. More forcing conditions resulted in
elimination of the C21 alcohol to give the corresponding
PMB enol ether. Additional studies in which the C21
hydroxyl group was inverted in an effort to minimize
unfavorable steric interactions with other ring substit-
uents gave only marginal yields of cyclized product.
A major breakthrough came when attempts were made
to accelerate the cyclization process by preforming the
dimethoxy ketal from ketone 27. For this transformation,
forcing conditions utilizing TMSOMe and a catalytic
amount of TMSOTf in CH2Cl2 were adopted.17 Surpris-
ingly, ketone 28 was isolated in good yields from the
reaction. In addition to its potential utility in our
synthesis, this transformation is remarkable in that it
is the net result of five different reactions, which include
deprotection of the acetonide, cyclization to form the
internal hemiketal, formation of the methoxy mixed
ketal, elimination of the C21 alcohol, and deprotection of
the PMB ether. An unfortunate and surprising aspect of
this transformation, however, is that the C21 oxygen
substituent (bryostatin numbering), which had been
intended to allow for installation of the unsaturated ester
via an Emmons reaction, was lost in this process. This
forced us to revise our strategy for completion of the C
ring segment by intercepting the chemistry previously
developed by Evans and by Wender for installation of the
unsaturated ester.
Thus, with ketone 28 in hand, our synthesis of the C
ring segment of the bryostatins was completed following
a known procedure.11g An aldol condensation of the
enolate derived from 28 with methyl glyoxylate, followed
by treatment of the resulting alcohol with MsCl and DBU
to effect elimination gave enone 30 in excellent yield and
as a single isomer with regard to the olefin geometry.
The 1H NMR spectrum of 30 revealed a significant
difference in the chemical shift between the two allylic
protons at the C22 position. The equatorial proton has a
chemical shift at δ 3.31, which is indicative of it residing
in the deshielding cone of the C21 unsaturated ester. As
expected, this proton also shows a weak coupling (J )
2.1 Hz) with the C23 axial proton. On the other hand, the
C22 axial proton has a chemical shift at δ 2.87, and
exhibits a strong coupling (J ) 12.5 Hz) with the C23
proton. All the spectral data strongly support the as-
signed structure. It is believed that the A-strain from the
C20 ketone controls the geometry of the newly created
(15) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988, 53, 1831-
1833.
(16) Albright, J. D.; Goldman, L. J. Am. Chem. Soc. 1967, 89, 2416-
(17) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,
1357-1358.
2423.
J. Org. Chem, Vol. 70, No. 7, 2005 2547

Keck et al.
olefin. Finally, a Luche reduction18 from the less hindered
face of the C20 ketone completed the synthesis of our
target compound 11 in high yield and as a single
stereoisomer.
Representative Example for BITIP Catalyzed Allyla-
tion Reactions. Preparation of (4S)-2-(Chloromethyl)-
9,9-dimethyl-9-siladec-1-en-7-yn-4-ol (9e). BITIP catalyst
was prepared according to method A. To a stirring solution of
(R)-(+)-1,1′-bi-2-naphthol (122 mg, 0.426 mmol) in methylene
chloride (25 mL) was added 4 Å molecular sieves (1.3 g) and a
1.5 M solution of titanium isopropoxide in methylene chloride
(284 µL, 0.426 mmol). The resulting mixture was heated at
reflux for 1 h and then cooled to room temperature before
aldehyde 8e (658 mg, 4.26 mmol) was added. The mixture was
stirred for 5 min and then cooled to -78 °C and allylstannane
1 (2.87 mL, 3.24 g, 8.53 mmol) was added dropwise. The
reaction was stirred an additional 15 min at -78 °C before
transferring to a freezer at -20 °C where it was allowed to
react for 5 days. The mixture was then filtered through a pad
of Celite (to remove the molecular sieves) with the aid of ethyl
acetate (50 mL), and the filtrate was washed with saturated
aqueous sodium bicarbonate solution (2 × 50 mL). The organic
layer was dried over anhydrous sodium sulfate, filtered, and
concentrated under reduced pressure. Purification of this
material was accomplished by flash chromatography eluting
with a gradient of 100 mL each of 5%, 15%, and 30% EtOAc/
hexanes, collecting 8 mL fractions. The product-containing
fractions were combined and concentrated under reduced
pressure to give 9e (991 mg, 95% yield) as a clear colorless
oil. Analytical data: Rf 0.71 (30% EtOAc/hexanes); [R]20D -7.6
(c 1.04, CHCl3); 500 MHz 1H NMR (CDCl3) δ 5.28 (s, 1H), 5.09
(app. d, J ) 1.0 Hz, 1H), 4.10 (ABq, JAB ) 11.7 Hz, ∆v ) 13.1
Hz, 2H), 4.01-3.96 (m, 1H), 2.45-2.35 (m, 3H), 2.29 (dd, J )
15.1, 8.8 Hz, 1H), 1.97 (d, J ) 3.9 Hz, 1H), 1.76-1.63 (m, 2H),
0.15 (s, 9H); 75 MHz 13C NMR (CDCl3) δ 142.1, 117.5, 106.6,
85.6, 68.8, 48.2, 41.3, 35.5, 16.6, 0.06; IR (neat) 3394 (broad),
2957, 2174, 1433, 1250, 1069, 910, 843, 760 cm-1. The ee was
determined to be >99% ee by HPLC analysis using a Chiralcel
OD-H column, using a mobile phase of 1% i-PrOH/hexanes and
a flow rate of 0.5 mL/min, which gave retention times for the
major and minor enantiomers of 21.9 and 24.0 min, respec-
tively. HRMS (CI at 120 eV) calcd for C12H22ClOSi (M + 1)
245.11284, found 245.11393.
Conclusions
The application of 2-substituted allylstannane 1 in the
stereoselective allylation of aldehydes and in a synthesis
of the C17-C27 segment of the bryostatins has been
presented. The reagent was found to be compatible with
the BITIP catalyst and was successfully used in the
enantioselective synthesis of attractively functionalized
building blocks, namely certain â-hydroxy allyl chlorides.
These reactions were found to occur with very high
enantiomeric excess and in excellent chemical yields.
The inherent utility of the incorporated allyl chloride
substituent was demonstrated in a convergent and flex-
ible construction of the C ring subunit of the bryostatins
via a linchpin approach. Here successive chelation con-
trolled reactions were utilized effectively. The research
presented in this regard represents a preliminary effort
in the bryostatin area.19 There is still plenty of room for
improvement, which is evident by the fact that two of
the preestablished stereocenters (C20 and C21) were
destroyed during the cyclization step of this approach due
to an unexpected elimination process that we were unable
to circumvent. Consequently, based on the knowledge we
gained from this study, new strategies for the synthesis
of this segment of the bryostatins, with considerably
better efficiency, have been developed and will be re-
ported separately.
Experimental Section
Preparation of 4,4-Dibutyl-2-(chloromethyl)-4-stan-
naoct-1-ene (1). To a stirring solution of diisopropylamine
(1.70 mL, 13.0 mmol) in 30 mL of THF at 0 °C was added
n-BuLi (5.0 mL, 12 mmol, 2.5 M in hexanes). After 5 min,
tributyltinhydride (3.14 g, 10.8 mmol) was added. The result-
ing solution was stirred at 0 °C for 15 min and then added via
syringe pump over 1 h to a stirring solution of 3-chloro-2-
(chloromethyl)prop-1-ene (1.50 g, 12.0 mmol) in 50 mL of
hexanes at -78 °C. The mixture was stirred at -78 °C for 1 h
then quenched by the addition of 5 mL of water. The mixture
was diluted with 120 mL of 10% EtOAc/hexanes and washed
with 100 mL of water. The organic phase was dried over
anhydrous Na2SO4 and then concentrated by rotary evapora-
tion. The residue was distilled under reduced pressure. The
fraction at 100-120 °C/0.4 mmHg was collected to give 2.60 g
(63%) of stannane 1 as a light yellow oil, which is sufficiently
pure for most uses. A portion of the distilled material (260 mg)
was further purified by flash chromatography on a silica gel
column (1.5 × 28 cm), eluting with hexanes to provide 230
mg of analytically pure 1 as a colorless oil. Analytical data:
Rf 0.63 (hexanes); 1H NMR (300 MHz, CDCl3) δ 4.84 (dd with
Sn satellites, J ) 2.4, 1.0 Hz, JH-Sn ) 17.1 Hz, 1H), 4.71 (dd
with Sn satellites, J ) 2.4, 1.0 Hz, JH-Sn ) 17.9 Hz, 1H), 3.95
(d with Sn satellites, J ) 1.0 Hz, JH-Sn ) 6.7 Hz, 2H), 1.99 (d
with Sn satellites, J ) 1.0 Hz, JH-Sn ) 57.8 Hz, 2H), 1.54-
1.43 (m, 6H), 1.36-1.24 (m, 6H), 1.00-0.77 (m, 9H); 13C NMR
(75 MHz, CDCl3) δ 145.9, 110.1, 50.4, 29.3, 27.6, 16.1, 13.9,
9.9; IR (film) 2957, 2925, 1625, 1461 cm-1. Anal. Calcd for
C16H33ClSn: C, 50.63; H, 8.76. Found: C, 50.74; H, 8.92.
Preparation of (4R)-2-Methylene-4-(2-phenylethyl)-
3,4,5-trihydrofuran (10). To a 10 mL round-bottom flask was
added KH as a 30% w/w suspension in mineral oil (23.2 mg,
0.17 mmol). A nitrogen line was inserted and the flask
subjected to continuous nitrogen purge. Freshly distilled
hexanes was added with stirring. The heterogeneous solution
was allowed to settle and the hexanes was removed by pipet,
taking care not to remove any KH. This procedure was
repeated two more times. Then the nitrogen line was removed
and KI (20 mg, 0.12 mmol) was added and the flask sealed
with a septum. The flask was charged with dry THF (0.5 mL).
Compound 9d (26 mg, 0.12 mmol) was added as a solution in
THF (250 µL) via cannula washing with THF (0.5 mL). The
mixture was stirred at room temperature for 18 h before
quenching by the addition of saturated aqueous sodium
bicarbonate solution. The mixture was diluted with diethyl
ether (20 mL) and washed with saturated aqueous sodium
bicarbonate solution (10 mL) and water (10 mL). The combined
aqueous wash was extracted with diethyl ether (10 mL), and
the combined organic layers were dried over anhydrous
magnesium sulfate, filtered, and concentrated under reduced
pressure. Purification of the crude product was accomplished
by flash chromatography eluting with 50 mL each of a gradient
of 5% and 10% EtOAc/hexanes. The product-containing frac-
tions were combined and concentrated to give 10 (17.6 mg,
81% yield) as a clear, colorless oil. Analytical data: Rf 0.53
(20% EtOAc/hexanes); [R]20 -18.3 (c 0.63, CHCl3); 300 MHz
D
1H NMR (CDCl3) δ 7.12-7.16 (m, 5H), 4.97 (m, 1H), 4.91 (m,
1H), 4.32 (ABq, JAB ) 13.3 Hz, ∆v ) 3.8 Hz, 2H), 3.94 (dddd,
J ) 8.1, 8.1, 5.8, 5.8 Hz, 1H), 2.83-2.60 (m, 3H), 2.27-2.17
(m, 1H), 2.02-1.67 (m, 2H); 75 MHz 13C NMR (CDCl3) δ 148.3,
141.9, 128.4, 128.3, 125.8, 104.1, 79.1, 70.7, 38.6, 36.7, 32.3;
(18) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226-2227.
(19) For the development of chemistry relevant to the asymmetric
incorporation of the bryostatin B ring, see ref 3c.
2548 J. Org. Chem., Vol. 70, No. 7, 2005

Allylation Studies and Bryostatin C-Ring Synthesis
IR (neat) 2927, 2496, 1056, 883, 747, 700 cm-1. HRMS (CI at
EtOAc/hexanes); [R]20 -8.7 (c 2.00, CHCl3); 1H NMR (300
D
120 eV) calcd for C13H17O (M + 1) 189.12794, found 189.12657.
MHz, CDCl3) δ 7.37-7.26 (m, 5H), 5.14 (ddd, J ) 7.6, 5.5, 4.5
Hz, 1H), 4.83 (d, J ) 7.0 Hz, 1H), 4.80 (d, J ) 7.0 Hz, 1H),
4.67 (d, J ) 11.8 Hz, 1H), 4.61 (d, J ) 11.7 Hz, 1H), 4.60-
4.52 (m, 1H), 4.52-4.43 (m, 1H), 3.87 (qd, J ) 6.4, 4.5 Hz,
1H), 2.31-2.19 (m, 2H), 1.85 (d, J ) 11.8 Hz, 1H), 1.76 (d, J
) 11.7 Hz, 1H), 1.54-1.42 (m, 6H), 1.36-1.22 (m, 6H), 1.20
(s, 9H), 1.19 (d, J ) 6.5 Hz, 3H), 0.92-0.80 (m, 15H); 13C NMR
(75 MHz, CDCl3) δ 178.0, 145.6, 138.0, 128.6, 128.1, 127.9,
108.0, 94.0, 73.9, 73.1, 69.7, 39.1, 38.4, 29.3, 27.6, 27.5, 18.9,
Preparation of (2R,3R)-5-(Chloromethyl)-2-[(phenyl-
methoxy)methoxy]hex-5-en-3-ol (18). To a solution of al-
dehyde 16 (1.37 g, 7.06 mmol) in 60 mL of CH2Cl2 was added
MgBr2‚OEt2 (2.55 g, 9.88 mmol). The resulting mixture was
stirred at room temperature for 10 min before it was cooled to
-15 °C. The stannane 1 (3.22 g, 8.47 mmol) was then added.
The mixture was gradually warmed to room temperature over
a period of 1 h and stirred at room temperature for an
additional 20 min, then quenched by the addition of 20 mL of
saturated aqueous NaHCO3 solution. The mixture was diluted
with 60 mL of CH2Cl2 and then washed with water (100 mL)
and with brine (100 mL). The organic phase was dried over
anhydrous Na2SO4 and concentrated by rotary evaporation.
The residue was purified by flash chromatography on a silica
gel column (2.8 × 22 cm), eluting with 15% EtOAc/hexanes to
give 1.80 g (90%) of 18 as a colorless oil. Analytical data: Rf
16.3, 13.9, 9.6; IR (film) 2957, 2927, 1729, 1629, 1459 cm-1
.
Anal. Calcd for C32H56O4Sn: C, 61.64; H, 9.05. Found: C,
61.61; H, 9.30.
Preparation of 1-{(1R)-1-[(Phenylmethoxy)methoxy]-
ethyl}(1R,5R,6R)-5-hydroxy-6-[(4-methoxyphenyl)-
methoxy]-3-methylene-7-(1,1,2,2-tetramethyl-1-sila-
propoxy)heptyl 2,2-Dimethylpropanoate (20). To a stirring
solution of aldehyde 17 (496 mg, 1.54 mmol) in 20 mL of CH2-
Cl2 at -15 °C was added MgBr2‚OEt2 (795 mg, 3.08 mmol).
The resulting mixture was stirred at -15 °C for 15 min. A
solution of the stannane reagent 19 (960 mg, 1.54 mmol) in
5.0 mL of CH2Cl2 was then added. The mixture was gradually
warmed to room temperature over a period of 1 h and then
stirred at room temperature for 20 min. It was quenched by
the addition of saturated aqueous sodium bicarbonate solution
(10 mL). The resulting mixture was stirred at room temper-
ature for 10 min, then diluted with 100 mL of CH2Cl2 and
washed with water (60 mL), then with brine (60 mL). The
organic phase was dried over anhydrous Na2SO4 and concen-
trated by rotary evaporation. The residue was purified by flash
chromatography on a silica gel column (2.8 × 20 cm), eluting
with 15% EtOAc/hexanes to give 948 mg (93%) of 20 as a
colorless oil. Analytical data: Rf 0.28 (20% EtOAc/hexanes);
0.20 (20% EtOAc/hexanes); [R]20 -18.4 (c 2.60, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 7.39-7.26 (m, 5H), 5.30 (br s, 1H),
5.10 (dd, J ) 2.2, 1.3 Hz, 1H), 4.88 (d, J ) 7.0 Hz, 1H), 4.83
(d, J ) 7.0 Hz, 1H), 4.68 (d, J ) 11.8 Hz, 1H), 4.62 (d, J )
11.8 Hz, 1H), 4.15 (dd, J ) 11.7, 1.0 Hz, 1H), 4.10 (dd, J )
11.7,1.0 Hz, 1H), 3.76-3.71 (m, 2H), 2.63 (d, J ) 3.2 Hz, 1H),
2.53 (appt. d, J ) 15.3 Hz, 1H), 2.30 (ddd, J ) 14.6, 9.3, 0.8
Hz, 1H), 1.25 (d, J ) 6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 142.5, 137.6, 128.7, 128.1 (two carbons), 117.3, 94.0, 77.7,
73.2, 70.1, 48.6, 37.0, 16.9; IR (film) 3458, 3031, 2935, 1651,
1494 cm-1; HRMS calcd for C15H22ClO3 (M+) 285.1258, found
285.1260. Anal. Calcd for C15H21ClO3: C, 63.26; H, 7.43.
Found: C, 62.73; H, 7.30.
Preparation of (1R)-1-{(1R)-1-[(Phenylmethoxy)meth-
oxy]ethyl}-5,5-dibutyl-3-methylene-5-stannanonyl 2,2-
Dimethylpropanoate (19). To a solution of alcohol 18 (550
mg, 1.93 mmol) in 3 mL of CH2Cl2 was added PivCl (4.76 mL,
38.7 mmol) followed by pyridine (1.68 mL, 19.3 mmol) and
DMAP (24.5 mg, 0.2 mmol). The resulting solution was stirred
at room temperature for 24 h. It was then diluted with 100
mL of 10% EtOAc/hexanes and washed with 1 N aqueous HCl
solution (50 mL), saturated aqueous NaHCO3 solution (50 mL),
and brine (50 mL), then dried over anhydrous Na2SO4 and
concentrated by rotary evaporation. The residue was purified
by flash chromatography on a silica gel column (2.8 × 22 cm),
eluting with 8% EtOAc/hexanes to give 575 mg (81%) of the
product as a colorless oil. Analytical data: Rf 0.50 (20% EtOAc/
[R]20 +0.76 (c 2.88, CHCl3); 1H NMR (300 MHz, CDCl3) δ
D
7.36-7.24 (m, 7H), 6.90-6.84 (m, 2H), 5.09 (ddd, J ) 8.0, 5.3,
4.5 Hz, 1H), 4.89 (br s, 1H), 4.86 (br s, 1H), 4.81 (d, J ) 7.0
Hz, 1H), 4.78 (d, J ) 7.0 Hz, 1H), 4.68 (d, J ) 11.1 Hz, 1H),
4.65 (d, J ) 11.6 Hz, 1H), 4.59 (d, J ) 11.6 Hz, 1H), 4.50 (d,
J ) 11.2 Hz, 1H), 3.90-3.70 (m, 3H), 3.79 (s, 3H), 3.75 (dd, J
) 10.5, 6.5 Hz, 1H), 3.38 (ddd, J ) 5.5, 5.5, 3.5 Hz, 1H), 2.43
(d, J ) 6.0 Hz, 1H), 2.42-2.21 (m, 4H), 1.19 (s, 9H), 1.19 (d, J
) 6.3 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 178.1, 159.5, 142.2, 138.0, 130.7, 129.7, 128.6, 128.0,
127.9, 115.3, 114.0, 94.0, 80.9, 74.1, 72.9, 72.7, 69.7, 69.1, 63.0,
55.4, 39.9, 39.0, 36.4, 27.5, 26.1, 18.4, 16.3, -5.25, -5.27; IR
(film) 3528, 2954, 2931, 1727, 1613, 1514, 1460 cm-1. Anal.
Calcd for C37H58O8Si: C, 67.44; H, 8.87. Found: C, 67.32; H,
8.94.
hexanes); [R]20 -5.47 (c 1.96, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.37-7.26 (m, 5H), 5.16 (br s, 1H), 5.12 (ddd, J )
10.4, 4.5, 3.0 Hz, 1H), 5.00 (m, 1H), 4.84 (d, J ) 7.0 Hz, 1H),
4.81 (d, J ) 7.1 Hz, 1H), 4.67 (d, J ) 11.7 Hz, 1H), 4.62 (d, J
) 11.8 Hz, 1H), 4.16 (dd, J ) 11.8, 0.9 Hz, 1H), 4.02 (d, J )
11.8 Hz, 1H), 3.88 (qd, J ) 6.5, 4.6 Hz, 1H), 2.65 (dd, J ) 14.7,
2.0 Hz, 1H), 2.45 (dd, J ) 14.9, 10.4 Hz, 1H), 1.22 (d, J ) 6.5
Hz, 3H), 1.18 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 178.1, 141.5,
137.9, 128.7, 128.0, 127.9, 117.7, 94.0, 74.0, 72.4, 69.8, 48.0,
39.1, 33.7, 27.4, 16.2; IR (film) 2975, 1726, 1480 cm-1; Anal.
Calcd for C20H29ClO4: C, 65.12; H, 7.92. Found: C, 65.30; H,
8.00.
Preparation of 1-{(1R)-1-[(Phenylmethoxy)methoxy]-
ethyl}(3S,1R,5R,6R)-3,5-dihydroxy-6-[(4-methoxyphenyl)-
methoxy]-7-(1,1,2,2-tetramethyl-1-silapropoxy)heptyl 2,2-
Dimethylpropanoate (23). To a solution of ketone 22 (564
mg, 0.854 mmol) in 12.5 mL of THF and 2.5 mL of water was
added diethylmethoxyborane (1.20 mL, 1.20 mmol, 1.0 M in
THF). The resulting solution was stirred at room temperature
for 30 min, then cooled to -78 °C and NaBH4 (67.8 mg, 1.79
mmol) was added. The reaction was stirred at -78 °C for 9 h,
then quenched by the addition of 30% aqueous H2O2 solution
(15 mL). The resulting mixture was allowed to stand in a -20
°C refrigerator for 10 h without stirring, then warmed to room
temperature and stirred for 10 min. It was diluted with 100
mL of 80% EtOAc/hexanes and then washed with water (50
mL) and with brine (50 mL). The organic phase was dried over
anhydrous Na2SO4 and concentrated by rotary evaporation.
The residue was purified by flash chromatography on a silica
gel column (2.8 × 20 cm), eluting with 35% EtOAc/hexanes to
give 520 mg (92%) of diol 23 as a colorless oil. Analytical
To a stirring solution of diisopropylamine (273 mg, 2.70
mmol) in 12 mL of THF was added n-BuLi (0.99 mL, 2.48
mmol, 2.5 M in hexanes) at 0 °C. It was stirred at 0 °C for 5
min, then Bu3SnH (721 mg, 2.48 mmol) was added. The
resulting solution was stirred at 0 °C for 15 min, then added
via syringe pump over 30 min into a solution of the above
product (830 mg, 2.25 mmol) in 12 mL of THF stirred at -78
°C. The mixture was stirred at -78 °C for an additional 30
min then quenched by adding 4 mL of water. The resulting
mixture was diluted with 100 mL of hexanes and washed with
water (50 mL). The organic phase was dried over anhydrous
Na2SO4 and concentrated by rotary evaporation. The residue
was purified by flash chromatography on a silica gel column
(2.8 × 20 cm), eluting with 4% EtOAc/hexanes to give 1.10 g
(78%) of 19 as a colorless oil. Analytical data: Rf 0.37 (5%
data: Rf 0.08 (20% EtOAc/hexanes); [R]20 +12.1 (c 2.55,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.37-7.23 (m, 7H), 6.90-
6.84 (m, 2H), 5.11 (ddd, J ) 8.6, 5.6, 4.4 Hz, 1H), 4.83 (d, J )
7.0 Hz, 1H), 4.79 (d, J ) 7.2 Hz, 1H), 4.69 (d, J ) 11.2 Hz,
1H), 4.65 (d, J ) 11.8 Hz, 1H), 4.60 (d, J ) 11.8 Hz, 1H), 4.50
J. Org. Chem, Vol. 70, No. 7, 2005 2549

Keck et al.
(d, J ) 11.4 Hz, 1H), 3.95-3.65 (m, 5H), 3.79 (s, 3H), 3.72
(dd, J ) 10.7, 5.5 Hz, 1H), 3.38 (m, 2H), 1.80-1.62 (m, 3H),
1.57 (ddd, J ) 14.2, 3.1, 2.9 Hz, 1H), 1.22 (s, 9H), 1.20 (d, J )
6.5 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 6H); 13C NMR (75 MHz,
CDCl3) δ 179.4, 159.4, 137.9, 130.7, 129.7, 128.6, 128.0, 127.9,
113.9, 94.0, 81.3, 74.3, 72.8, 72.7, 72.1, 69.8, 68.0, 62.9, 55.4,
39.4, 39.2, 38.3, 27.4, 26.1, 18.4, 16.3, -5.3 (two carbons); IR
(film) 3501, 2955, 2932, 1728, 1613, 1514, 1461 cm-1. Anal.
Calcd for C36H58O9Si: C, 65.22; H, 8.82. Found: C, 65.30; H,
8.88.
J ) 9.4, 6.5, 4.5 Hz, 1H), 4.23 (d, J ) 6.5 Hz, 1H), 3.83 (qd, J
) 6.3, 4.1 Hz, 1H), 3.81-3.72 (m, 1H), 3.79 (s, 3H), 1.77-1.64
(m, 2H), 1.35 (s, 6H), 1.33-1.15 (m, 2H), 1.23 (s, 3H), 1.21 (s,
12H), 1.14 (d, J ) 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
209.4, 177.8, 159.5, 141.9, 138.0, 130.3, 129.9, 128.6, 128.1,
127.9, 114.9, 113.9, 99.1, 94.0, 80.1, 74.0, 72.6, 71.7, 70.8, 69.7,
65.1, 55.5, 50.7, 39.1, 36.7, 32.8, 30.2, 27.5, 23.7, 23.4, 19.7,
16.0; IR (film) 2976, 2936, 1729, 1613, 1514, 1459 cm-1. Anal.
Calcd for C38H54O9: C, 69.70; H, 8.31. Found: C, 69.48; H,
8.39.
Preparation of (1R,2R)-1-[(6-{(1S)-1-[(4-Methoxyphe-
nyl)methoxy]-3,3-dimethyl-2-oxopent-4-enyl}(4S,6R)-2,2-
dimethyl(1,3-dioxan-4-yl))methyl]-2-[(phenylmethoxy)-
methoxy]propyl 2,2-Dimethylpropanoate (27). To a solution
of alcohol 25 (316 mg, 0.537 mmol) in 18 mL of CH2Cl2 were
added sequentially oven-dried powdered 4 Å molecular sieves
(840 mg), NMO (83.0 mg, 0.708 mmol), and TPAP (15.1 mg,
0.0429 mmol). After being stirred at room temperature for 20
min, the resulting dark green mixture was diluted with 30
mL of 30% EtOAc/hexanes and filtered through a pad of Celite
(1 cm) and Florisil (4 cm). The pad was washed with 170 mL
of 30% EtOAc/hexanes and the filtrate was concentrated by
rotary evaporation. The crude aldehyde was used immediately
in the subsequent reaction without further purification.
To a mixture of the crude aldehyde (315 mg, 0.537 mmol,
theoretical) and prenyl bromide 26 (321 mg, 2.15 mmol) was
added 3.5 mL of DMF, followed by indium powder (247 mg,
2.15 mmol). The reaction mixture was stirred at room tem-
perature for 40 min, then diluted with 15 mL of EtOAc and
filtered through Celite. The filtrate was further diluted with
50 mL of 30% EtOAc/hexanes, and then washed sequentially
with 1 N aqueous HCl solution (50 mL), saturated aqueous
NaHCO3 solution (50 mL), and brine (50 mL). The organic
phase was dried over anhydrous Na2SO4 and concentrated by
rotary evaporation. The resulting crude alcohol was then
dissolved in 3 mL of DMSO. To this solution was added 2 mL
of Ac2O with stirring. After stirring at room temperature for
10 min Et3N (2 mL) was added, and stirring was continued at
room temperature for 17 h. The resulting dark brown solution
was diluted with 10 mL of EtOAc and poured into a separatory
funnel. It was further diluted with 100 mL of 30% EtOAc/
hexanes and washed with water (2 × 60 mL), then with brine
(60 mL). The organic phase was dried over anhydrous Na2-
SO4 and concentrated by rotary evaporation. The residue was
purified by flash chromatography on a silica gel column (2.8
× 23 cm), eluting with 15% EtOAc/hexanes to give 225 mg
(64% over three steps) of 27 as a colorless oil. Analytical data:
Rf 0.56 (30% EtOAc/hexanes); [R]20D +15.4 (c 1.95, CHCl3); 1H
NMR (300 MHz, CDCl3) δ 7.38-7.19 (m, 7H), 6.88-6.82 (m,
2H), 5.92 (dd, J ) 17.3, 10.7 Hz, 1H), 5.24-5.16 (m, 1H), 5.17
(dd, J ) 10.8, 0.9 Hz, 1H), 5.15 (dd, J ) 17.4, 0.9 Hz, 1H),
4.80 (d, J ) 7.0 Hz, 1H), 4.77 (d, J ) 7.0 Hz, 1H), 4.62 (s, 2H),
4.52 (d, J ) 11.0 Hz, 1H), 4.48 (d, J ) 11.0 Hz, 1H), 4.32 (ddd,
Preparation of (1R,2R)-1-{[(6S)-6-(1,1-Dimethylprop-
2-enyl)-6-methoxy-5-oxo(3,4,6-trihydro-2H-pyran-2-yl)]-
methyl}-2-[(phenylmethoxy)methoxy]propyl 2,2-Dime-
thylpropanoate (28). To a stirring solution of ketone 27 (114
mg, 0.174 mmol) in 1.5 mL of CH2Cl2 at -78 °C was added
TMSOMe (0.150 mL, 1.09 mmol) and TMSOTf (6.0 µL, 0.033
mmol). The mixture was stirred at -78 °C for 4 h then warmed
to -40 °C and stirred for 8 h. Finally, the solution was further
warmed to 0 °C and stirred for an additional 1 h, then 2 mL
of saturated aqueous NaHCO3 solution was added, and the
resulting mixture was stirred at room temperature for 10 min.
The mixture was diluted with 20 mL of CH2Cl2 and washed
with saturated aqueous NaHCO3 solution (20 mL), then with
brine (10 mL). The organic phase was dried over anhydrous
Na2SO4 and concentrated by rotary evaporation. The residue
was purified by flash chromatography on a silica gel column
(1.3 × 25 cm), eluting with 10% EtOAc/hexanes to give 58 mg
(68%) of 28 as a colorless oil. Analytical data: Rf 0.51 (20%
EtOAc/hexanes); [R]20 +3.9 (c 2.30, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 7.38-7.26 (m, 5H), 6.16 (dd, J ) 18.0, 10.4
Hz, 1H), 5.25 (ddd, J ) 9.8, 4.2, 2.3 Hz, 1H), 5.00 (dd, J )
18.0, 1.4 Hz, 1H), 4.98 (dd, J ) 10.6, 1.3 Hz, 1H), 4.82 (s, 2H),
4.65 (s, 2H), 3.95 (qd, J ) 6.6, 4.1 Hz, 1H), 3.94-3.86 (m, 1H),
3.22 (s, 3H), 2.58-2.37 (m, 2H), 2.00 (ddd, J ) 14.6, 9.4, 2.4
Hz, 1H), 1.96-1.87 (m, 2H), 1.81 (ddd, J ) 14.6, 9.8, 3.2 Hz,
1H), 1.19 (s, 9H), 1.18 (d, J ) 6.6 Hz, 3H), 1.14 (s, 3H), 1.08
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 206.8, 177.9, 144.3, 137.9,
128.6, 128.1, 127.9, 112.8, 103.8, 93.7, 73.0, 71.6, 69.8, 69.0,
51.9, 44.9, 39.0, 37.2, 35.7, 30.0, 27.4, 22.6, 22.4, 15.4; IR (film)
2975, 2935, 1729, 1477 cm-1; HRMS (CI) calcd for C27H39O6
(MH+ - MeOH) 459.2746, found 459.2731. Anal. Calcd for
C28H42O7: C, 68.54; H, 8.63. Found: C, 68.29; H, 8.64.
Acknowledgment. Financial support from the Na-
tional Institutes of Health (through GM-28961) is grate-
fully acknowledged.
Supporting Information Available: Additional synthetic
procedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO048308M
2550 J. Org. Chem., Vol. 70, No. 7, 2005