Unified synthesis of C19-C26 subunits of amphidinolides B1, B2, and B3 by exploiting unexpected stereochemical differences in Crimmins' and Evans' aldol reactions.

Article abstract of DOI:10.1021/jo035829l

The efficient synthesis of the C(19)-C(26) subunit of amphidinolide B(1) and B(2) has been completed using a boron-mediated aldol reaction. The synthesis of the C(19)-C(26) subunit of amphidinolide B(3) has also been accomplished through an unexpected anti aldol reaction using a titanium-mediated process. In addition, the first reported examples of a stereochemical discrepancy between the Evans' boron-mediated oxazolidinone and the Crimmins' titanium-mediated oxazolidinethione aldol reactions are disclosed. A working hypothesis is put forth to explain the results.

Full text of DOI:10.1021/jo035829l

SCHEME 1. Gen er a lized Exa m p les of Cr im m in s’
a n d Eva n s’ Ald ol Ad d u cts
Un ified Syn th esis of C19-C26 Su bu n its of
Am p h id in olid es B1, B2, a n d B3 by
Exp loitin g Un exp ected Ster eoch em ica l
Differ en ces in Cr im m in s’ a n d Eva n s’ Ald ol
Rea ction s
Wei Zhang, Rich G. Carter,* and
Alexandre F. T. Yokochi†
Department of Chemistry, 153 Gilbert Hall,
Oregon State University, Corvallis, Oregon 97331
rich.carter@oregonstate.edu
Received December 16, 2003
Abstr a ct: The efficient synthesis of the C19-C26 subunit
of amphidinolide B1 and B2 has been completed using a
boron-mediated aldol reaction. The synthesis of the C19
-
SCHEME 2. Retr osyn th etic An a lysis of
Am p h id in olid e B1
C26 subunit of amphidinolide B3 has also been accomplished
through an unexpected anti aldol reaction using a titanium-
mediated process. In addition, the first reported examples
of a stereochemical discrepancy between the Evans’ boron-
mediated oxazolidinone and the Crimmins’ titanium-medi-
ated oxazolidinethione aldol reactions are disclosed. A
working hypothesis is put forth to explain the results.
The synthetic utility of chiral oxazolidinones has been
well-documented in the organic community.1 This power-
ful removable auxiliary has been shown to be effective
in the construction of a wide variety of carbon-carbon
and carbon-heteroatom bonds in a highly stereoselective
fashion. Numerous working models have been put forth
to explain and predict the resultant stereochemical
outcome from these reactions. These models have proven
to be highly reliable and general, with only isolated
examples of anomalies having been reported.2
In particular, the so-called “Evans-syn” aldol reactions
with chiral oxazolidinones using dibutylboron triflate and
the appropriate amine base have become the standard
by which new asymmetric and diastereoselective reac-
tions are judged against (Scheme 1).3 The recently
developed titanium-mediated oxazolidinethione aldol
reaction, from the Crimmins laboratory, has been shown
to provide comparable levels of selectivity on a wide range
of systems.4 There are several advantages to the Crim-
mins’ aldol methodology (e.g., relative ease of auxiliary
cleavage and use of the logistically easier titanium eno-
lates). One particularly attractive attribute is the flex-
ibility imparted by Crimmins’ chelated and nonchelated
models which is dependent on the amount of TiCl4 and
amine base (normally (-)-sparteine) that is added. This
modification provides access to both the Evans-syn
product via the nonchelated model and the non-Evans-
syn adduct via the chelated model (Scheme 1). The level
of syn/anti selectivity is high (normally > 20:1) and
comparable to traditional boron-mediated aldol reactions
for both the chelated and nonchelated titanium-mediated
conditions. It should be pointed out that Crimmins has
shown that the chirality of (-)-sparteine does not influ-
ence the stereochemical outcome of the transformation.4
We were attracted to the application of the Crimmins
and/or Evans methodologies for the construction the
eastern subunit 15 of the cytotoxic macrolide amphidi-
nolide B1 (11)5,6 (Scheme 2). Amphidinolide B1 has
attracted considerable synthetic interest,7 yet the total
synthesis of 11 remains an elusive target.8 Two additional
members of the amphidinolide B family, B2 (12) and B3
(13), have also been reported. These structures only differ
from the parent B1 structure by alternate stereochemis-
tries at C18 and/or C22. Compounds 11 and 12 should be
accessible from a common subunit 15 while C22 epimer
13 should be accessible from the anti,anti adduct 16.
While the application of the titanium-mediated aldol
methodology has begun to appear,9 several important
combinations have yet to be fully explored. One such
example is the coupling of an O-benzyl-protected glyco-
† Director of X-ray Crystallographic Facility, Department of Chem-
istry, Oregon State University, Corvallis, OR 97331. E-mail: alexandre.
yokochi@oregonstate.edu.
(1) Evans, D. A.; Kim, A. S. In Handbook of Reagents for Organic
Synthesis: Reagents, Auxiliaries and Catalysts for C-C Bonds; Coates,
R. M., Denmark, S. E., Eds.; J ohn Wiley & Sons: New York, 1999; pp
91-101.
(2) (a) Clive, D. L. J .; Yu, M. Chem. Commun. 2002, 2380-81. (b)
Evans, D. A.; Kaldor, S. W.; J ones, T. K.; Clardy, J .; Stout, T. J . J .
Am. Chem. Soc. 1990, 112, 7001-31. (c) Iseki, K.; Oishi, S.; Kobayashi,
Y. Tetrahedron 1996, 52, 71-84.
(3) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc. 1981,
103, 2127-29. (b) Evans, D. A.; Nelson, J . V.; Taber, T. R. Top.
Stereochem. 1982, 13, 1-115.
(4) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J .
Org. Chem. 2001, 66, 894-902.
(5) Ishibashi, M.; Ishiyama, H.; Kobayashi, J . Tetrahedron Lett.
1994, 35, 8241-42.
(6) (a) Kobayashi, J .; Ishibashi, M.; Nakamura, H.; Ohizumi, Y.;
Hirata, Y.; Sasaki, T.; Ohta, T.; Nozoe, S. J . Nat. Prod. 1989, 52, 1036-
41. (b) Ishibashi, M.; Ohizumi, Y.; Hamashima, M.; Nakamura, H.;
Hirata, Y.; Sasaki, T.; Kobayashi, J . J . Chem. Soc., Chem. Commun.
1987, 1127-29.
10.1021/jo035829l CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/09/2004
J . Org. Chem. 2004, 69, 2569-2572
2569

SCHEME 3 a
alternate bases (e.g., TMEDA) did not affect the observed
stereochemical outcome.4 Thwarted by this unexpected
result, we turned to an achiral aldehyde (2-butenal) to
ensure the protocol was performing as expected. Aldol
reaction under the identical conditions [TiCl4 (1.0 equiv),
(-)-sparteine (2.5 equiv)] provided solely the expected
Evans-syn adduct 25 (H21-H22 J ) 3.3 Hz) in a 17:1 ratio.
One possible explanation would be a mismatched rela-
tionship between the directing effect of the auxiliary and
the inherent stereochemical preference of the aldehyde.
To this end, the experiment was conducted with the
achiral auxiliary 26; however, equal amounts of the two
previously observed anti stereochemistries (21R,22R and
21S,22S) were again the only observable products.
Given that the nonchelation approach provided none
of the desired syn adduct (e.g., compound 7), the comple-
mentary chelation aldol would appear to be the next
logical step (Scheme 5). Using the enantiomeric oxazoli-
dinethione auxiliary 27, treatment under the chelation
conditions [TiCl4 (2 equiv), (-)-sparteine (1 equiv)] pro-
ceeded poorly and in low yield. Crimmins has also
reported that the use of less TiCl4 [(1 equiv), (-)-sparteine
(1 equiv)] proceeds via the chelated model.4 Treatment
using these conditions provided some improvement in the
selectivity of the transformation, yielding a more respect-
a
Key: (i) ref 11, (R)-propylene oxide, 92%, 94:6 dr; (ii) TESCl,
Et3N, DMAP, CH2Cl2; (iii) LDA, BH3‚NH3, THF, 0 °C, 78% over
two steps; (iv) TPAP, NMO, CH2Cl2, 85%.
SCHEME 4 a
a
Key: (i) TiCl4 (1 equiv), (-)-sparteine (2.5 equiv), 21, CH2Cl2,
(7) (a) Cid, B.; Pattenden, G. Tetrahedron Lett. 2000, 41, 2573-76.
(b) Ohi, K.; Nishiyama, S. Synlett 1999, 571-72. (c) Ohi, K.; Nishiyama,
S. Synlett 1999, 573-75. (d) Eng, H. M.; Myles, D. C. Tetrahedron Lett.
1999, 40, 2275-78. (e) Eng, H. M.; Myles, D. C. Tetrahedron Lett. 1999,
40, 2279-82. (f) Chakraborty, T. K.; Thippewamy, D. Synlett 1999,
150-52. (g) Ishiyama, H.; Takemura, T.; Tsuda, M.; Kobayashi, J . J .
Chem. Soc., Perkin Trans. 1 1999, 1163-66. (h) Chakraborty, T. K.;
Thippewamy, D.; Suresh, V. R.; J ayaprakash, S. Chem. Lett. 1997,
563-64. (i) Chakraborty, T. K.; Suresh, V. R. Chem. Lett. 1997, 565-
66. (j) Lee, D. H.; Lee, S.-W. Tetrahedron Lett. 1997, 38, 7909-10. (k)
Ohi, K.; Shima, K.; Hamada, K.; Saito, Y.; Yamada, N.; Ohba, S.;
Nishiyama, S. Bull. Chem. Soc. J pn. 1998, 71, 2433-40.
(8) For total syntheses of other members of the amphidinolides: (a)
Williams, D. R.; Kissel, W. S. J . Am. Chem. Soc. 1998, 120, 11198-
99. (b) Williams, D. R.; Myers, B. J .; Mi, L. Org. Lett. 2000, 2, 945-48.
(c) Williams, D. R.; Meyer, K. G. J . Am. Chem. Soc. 2001, 123, 765-
66. (d) Lam, H. W.; Pattenden, G. Angew. Chem., Int. Ed. 2002, 41,
508-511. (e) Maleczka, R. E.; Terrell, L. R.; Geng, F.; Ward, J . S., III.
Org. Lett. 2002, 4, 2841-44. (f) Trost, B. M.; Chrisholm, J . D.;
Wrobleski, S. T.; J ung, M. J . Am. Chem. Soc. 2002, 124, 12420-21.
(g) Fu¨rstner, A.; A¨ıssa, C.; Riveiros, R.; Ragot, J . Angew. Chem., Int.
Ed. 2002, 41, 4763-66. (h) Ghosh, A. K.; Liu, C. J . Am. Chem. Soc.
2003, 125, 2374-75.
(9) (a) Crimmins, M. T.; King, B. W.; Zuercher, W. J .; Choy, A. L. J .
Org. Chem. 2000, 65, 8499-09. (b) Crimmins, M. T.; Choy, A. L. J .
Am. Chem. Soc. 1999, 121, 5653-60. (c) Crimmins, M. T.; Katz, J . D.;
McAtee, L. C.; Tabet, E. A.; Kirincich, S. J . Org. Lett. 2001, 3, 949-52.
(10) Only four reported examples of this combination have appeared
in the literature: (a) Crimmins, M. T.; Katz, J . D.; McAtee, L. C.; Tabet,
E. A.; Kirincich, S. J . Org. Lett. 2001, 3, 949-52. (b) Chakaborty, T.
K.; Suresh, V. R. Tetrahedron Lett. 1998, 39, 7775-78. (c) Piscopio, A.
D.; Minowa, N.; Chakraborty, T. K.; Koide, K.; Bertinato, P.; Nicolaou,
K. C. J . Chem. Soc., Chem. Commun. 1993, 617-18. (d) J ones, T. K.;
Reamer, R. A.; Desmond, R.; Mills, S. G. J . Am. Chem. Soc. 1990, 112,
2998-3017.
(11) Myers, A. G.; McKinstry, L. J . Org. Chem. 1996, 61, 2428-40.
(12) It should be noted that this stereochemical combination pro-
vides the epimeric stereochemistry at C25 versus the target 11;
however, the alkylation of the enantiomeric (S)-propylene oxide
proceeds in poor selectivity due to its mismatched relationship to the
approaching enolate. This stereocenter will be inverted later in the
synthetic sequence.
0.15 M, -78 °C, 40 min, 1.25:1 dr (23:24), 44% 23, 30% 24; (ii)
TiCl4 (1 equiv), (-)-sparteine (2.5 equiv), 2-butenal, CH2Cl2, 0.15
M, -78 °C, 40 min, 80%.
late such as 2 or 8 with an R-chiral aldehyde 3 to provide
a syn,syn coupled adduct such as 7 or 10 (Scheme 1). The
stereochemical “Felkin” relationship of the C22 and C23
positions (amphidinolide B1 numbering) would appear to
be ideally suited for this transformation as both the
auxiliary and the aldehyde appear to be directing the
outcome in a complementary fashion. Despite this com-
bination, the examples of a syn,syn adduct from an
O-benzyl-protected glycolate such as 1, 2, or 8 are
surprisingly rare.10 In fact, no examples of the aldol
reaction depicted with oxazolidinethione 2 or 8 have been
reported with R-chiral aldehydes. In this paper, we
disclose the first reported examples of these combinations
and the resulting synthesis of the C19-C26 subunits 15
and 16 for all amphidinolides B1-B3.
Construction of the necessary aldehyde precursor 21
was accomplished in four steps from commercially avail-
able Myers auxiliary 18. The known alkylation11 with the
commercially available (R)-propylene oxide provided
the C23,24-coupled material 19 in 94:6 dr.12 Subsequent
TES protection followed by reduction with BH3‚NH3/LDA
and Ley oxidation13 yielded the desired aldehyde 21
(Scheme 3).
Exploration into the aldol reaction commenced with the
known oxazolidinethione auxiliary 2214 (Scheme 4).
Treatment of the prescribed conditions for obtaining non-
chelation or “Evans-syn” aldol adducts [TiCl4 (1.0 equiv),
(-)-sparteine (2.5 equiv)] provided two diastereomeric
aldol adducts 23 and 24 in a 1.5:1 ratio. Unlike as
predicted in the Crimmins’ models for this transforma-
tion, none of the expected Evans-syn adduct was observed.
Instead, the anti adducts 23 (H21-H22 J ) 9.3 Hz) and
24 (H21-H22 J ) 8.4 Hz) were isolated in nearly equal
amounts.15 The addition of additives such as NMP or
(13) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-66.
(14) Crimmins, M. T.; McDougall, P. J . Org. Lett. 2003, 5, 591-94.
(15) It should be noted that Crimmins has recently reported the
development of a titanium-mediated oxazolidinethione method for the
synthesis of anti aldol adducts through an open transition state; how-
ever, this reaction protocol requires the addition of an additional 2.5
equiv of TiCl4 immediately prior to addition of the aldehyde. See ref
14.
2570 J . Org. Chem., Vol. 69, No. 7, 2004

that use of the auxiliary 3016 under boron-mediated
conditions did yield the desired Evans-syn adduct 31
(H21-H22 J ) 2.1 Hz) in a 95:5 syn,syn and syn,anti ratio
(72% isolated yield of 31). To the best of our knowledge,
these results represent the first reported examples of the
stereochemical divergence between the titanium-mediated
oxazolidinethiones and boron-mediated oxazolidinones.15
SCHEME 5 a
Stereochemical assignment of the aldol products 23-
25, 28-29, and 31 was accomplished via a series of
degradation experiments and X-ray crystallographic
analysis of 28 (Scheme 6). Reductive removal of the
auxiliaries from adducts 24 and 28 yielded an identical
diol 32, thereby confirming 24 vis-a`-vis X-ray structure
28. An analogous path was followed for the adducts 23
and 29 to yield the diol 34. The stereochemistry of 31
was confirmed via conversion to the TBDPS ether 36 and
correlation with the TBDPS ether 33 through TPAP
oxidation to the ketone 37. This degradation also indi-
rectly established one of the two unknown stereocenters
of 23 and 29 as 21S by assignment of both aldol adducts
28 and 31 as the 21R configuration. The 22S configura-
tion was confirmed by Mosher ester analysis of 35.17
Finally, the stereochemistry of 25 was confirmed by
reduction to a known compound 38.18
a
Key: (i) TiCl4 (1 equiv), (-)-sparteine (1 equiv), 21, CH2Cl2,
0.15 M, -78 °C, 40 min, 4:1 dr (28:29), 53% 28; (ii) Bu2BOTf (1
equiv), Et3N (1.1 equiv), PhMe, 0.15 M, -50 to -30 °C, 2 h, 72%.
able 4:1 ratio of the two anti products (28/29) (28: H21
-
H22 J ) 8.8 Hz; 29: H21-H22 J ) 9.2 Hz) with none of the
predicted syn adduct. It is important to note that despite
the expected directing effect of the auxiliary (e.g., 22
should give the same absolute configuration at C21, C22
under nonchelation conditions as enantiomeric auxiliary
27 gives under chelation conditions), the major product
28 from the chelation-controlled conditions using 27 con-
tained the 21R,22R stereochemistry of the m in or product
from the nonchelation conditions with 22. Alcohol 28 is
synthetically useful as it possesses the correct anti,anti
C21-23 stereochemistry for amphidinolide B3. Interest-
ingly, use of the enantiomeric auxiliary 22 under chela-
tion conditions led to an equal mixture of the adducts 23
and 24. A similar result was observed with the achiral
auxiliary 26. It became apparent at this juncture that
the titanium-based aldol were unable to provide the
necessary stereochemical relationship (e.g., 7 or 10) for
amphidinolides B1 and B2. We were gratified to observe
A working hypothesis for the observed stereochemical
results invokes the use of the open transition state 40
and boat transition states19 41 and 43 to explain the
observed stereochemistry (Scheme 7). One possible ra-
tional for the inability of these transformations to proceed
through the chair transition states 39 and 42 could be
an unfavorable interaction between the benzyloxy sub-
stituent and the R-position of the aldehyde.20 As steric
bulk at these positions increase, this unfavorable interac-
tion should become more significant. We also hypothesize
that the bulk of the benzyloxy substituent may be in-
creased by an aggregation effect. While additional studies
SCHEME 6 a
a
Key: (i) LiBH4, MeOH, THF, 0 °C to rt; (ii) TBDPSCl, imid, DMAP, CH2Cl2, 0 °C to rt; (iii) (R)/(S) Mosher acid chloride, DMAP,
CH2Cl2; (iv) difference in ppm [(S)-Mosher ester-(R)-Mosher ester, CDCl3, 400 MHz NMR] shown on structure 35; (v) TPAP, CH2Cl2,
molecular sieves.
J . Org. Chem, Vol. 69, No. 7, 2004 2571

SCHEME 7. P ossible Exp la n a tion for Obser ved
Ster eoch em ica l Ou tcom e
SCHEME 8 a
a
Key: (i) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C; (ii) EtSH, KH
(cat.), THF; (iii) Me2CuLi, Et2O, -50 °C; (iv) TESOTf, 2,6-lutidine,
CH2Cl2, 0 °C.
A unified strategy for the synthesis of the C19-C26
subunits of amphidinolide B1-B3 13-15 has been ac-
complished. The first reported examples of the divergence
of the titanium-mediated oxazolidinethione aldol reaction
to provide the anti adducts 23-24 and 28-29 as the sole
products have been reported. A working model is put
forth to explain the stereochemical results.
Ack n ow led gm en t. Financial support was provided
by the National Institutes of Health (NIH) (GM63723)
and Oregon State University. This publication was also
made possible in part by a grant from the NIHs
National Institute of Environmental Health Sciences
(P30 ES00210). We thank Professor Max Dienzer (Mass
Spectrometry Facility, Environmental Health Sciences
Center, Oregon State University) and Dr. J eff Morre´
(Mass Spectrometry Facility, Environmental Health
Sciences Center, Oregon State University) for mass
spectra data, Roger Kohnert (Oregon State University)
for NMR assistance, and Dr. Roger Hanselmann (Rib-X
Pharmaceuticals) for his helpful discussions.
are necessary to verify this aggregation effect, we do ob-
serve a modest correlation of concentration with diaste-
reoselectivity [0.15 M, 4:1 dr; 0.05 M, 2:1 dr (28:29)]. A
similar correlation is observed for this transformation by
even a slight variation in the ratio of auxiliary to alde-
hyde. The use of 1.5 equiv of auxiliary 27 with 1 equiv of
the aldehyde 21 yielded a 4:1 ratio (28/29), while 2.0
equiv of the same auxiliary 27 (1 equiv of 21) yielded a
2:1 ratio (28/29) under the described chelation conditions.
Phillips and co-workers have also commented on the
sensitivity of titanium-mediated aldol reactions to slight
modifications.19a In contrast to the titanium enolates, the
boron enolates are unable to aggregate in the Zimmer-
man-Traxler transition state due to the full valence shell
on boron. This important difference does appear to agree
with the observed stereochemical results. Finally, an
open transition state 40 is put forth to justify the anti
adduct 23.15 This proposed explanation allows for an ap-
proach of the aldehyde consistent with the Felkin model.
Completion of the C19-C26 subunits of amphidinolide
B1-B3 was accomplished in three steps (Scheme 8).
Silylation using TESOTf provided the bissilylated com-
pound 44. Conversion to the thioester using catalytic
amounts of KSEt followed by cuprate coupling gave the
methyl ketone 15.21 An analogous path was pursued with
anti,anti adduct 28 to provide the methyl ketone 16.
Interestingly, attempted introduction of TBS protecting
group on the adduct 31 led to competitive silyl migration.
This migration was not observed with the adduct 28.
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for aldol adduct 28 and experimental procedures, includ-
ing copies of spectral data (1H and 13C NMR), for compounds
15, 16, 21, 23-25, 28, 29, 31-34, 36-38, 44-46, and 49. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035829L
(16) Evans, D. A.; Gage, J . R.; Leighton, J . L.; Kim, A. S. J . Org.
Chem. 1992, 57, 1961-3.
(17) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092-96. (b) Dale, J . A.; Mosher, H. S. J . Am.
Chem. Soc. 1973, 95, 512-19. (c) Sullivan, G. R.; Dale, J . A.; Mosher,
H. S. J . Org. Chem. 1973, 38, 2143-47.
(18) Reduction using lithium borohydride revealed the known diol
which match the reported 1H NMR and 13C NMR spectrum. [[R]20
)
D
+17.5 (c ) 0.48, CHCl3) vs lit. +16.8 (c ) 2.0 in CHCl3)]. Fuhry, M. A.
M.; Holmes, A. B.; Marshall, D. R. J . Chem. Soc., Perkin Trans. 1 1993,
2743-46.
(19) The preference for a boat transition state in oxazolidinethione
aldol reactions has been proposed previously. (a) Guz, N. R.; Phillips,
A. J . Org. Lett. 2002, 4, 2253-56. (b) Evans, D. A.; Downey, C. W.;
Shaw, J . T.; Tedrow, J . S. Org. Lett. 2002, 4, 1127-30.
(20) For recent and somewhat related examples, see: (a) Evans, D.
A.; Siska, S. J .; Cee, V. J . Angew. Chem., Int. Ed. 2003, 42, 1761-65.
(b) Marco, J . A.; Carda, M.; D´ıaz-Oltra, S.; Murga, J .; Falomir, E.;
Roeper, H. J . Org. Chem. 2003, 68, 8577-82.
(21) White, J . D.; Carter, R. G.; Sundermann, K. F.; Wartmann, M.
J . Am. Chem. Soc. 2001, 123, 5407-13.
2572 J . Org. Chem., Vol. 69, No. 7, 2004