Complex aldol reactions for the construction of dense polyol stereoarrays: Synthesis of the C33-C36 region of aflastatin A

Article abstract of DOI:10.1021/ol051226f

(Chemical Equation Presented) Facial selectivity in the addition of boron enolates of α-oxygenated ketones to anti-disposed α,β-bisalkoxy aldehydes is controlled by the aldehyde vicinal diol protecting group. Protection of the diol as an acetonide results in the exclusive formation of the anti-syn-anti stereoarray found in the C₃₃-C₃₆ region of aflastatin A.

Full text of DOI:10.1021/ol051226f

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3331-3333
Complex Aldol Reactions for the
Construction of Dense Polyol
Stereoarrays: Synthesis of the C33
Region of Aflastatin A
−C36
David A. Evans,* Frank Glorius, and Jason D. Burch
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
eVans@chemistry.harVard.edu
Received May 24, 2005
ABSTRACT
Facial selectivity in the addition of boron enolates of
r
-oxygenated ketones to anti-disposed
r
,
â
-bisalkoxy aldehydes is controlled by the
aldehyde vicinal diol protecting group. Protection of the diol as an acetonide results in the exclusive formation of the anti-syn-anti stereoarray
found in the C33 C36 region of aflastatin A.
−
In 1996, Sukuda and co-workers reported the isolation of
aflastatin A from the mycelia of Streptomyces sp. MRI 142.
This natural product exhibits strong inhibitory activity against
aflatoxin production without significantly affecting the
growth of A. parasiticus.1 In the initial publication, the
structure devoid of stereochemistry was disclosed. The same
group later reported the relative and absolute structure of
aflastatin A (1) (Scheme 1).2 Examination of the structure
reveals two regions possessing dense oxygenation: C27-
Scheme 1. Aldol Retron Present in Aflastatin A
C31 and C33-C37. Our group has had a long-standing interest
in the use of aldol reactions for the construction of poly-
acetate and polypropionate natural products, and this structure
presented the possibility of extending this chemistry into the
polyol realm. In particular, construction of the C33-C37 array
in this manner is especially attractive, as examination of this
lactol region in the open-chain tautomer reveals the presence
of an aldol retron in the correct oxidation state (Scheme 1).
At the outset, there were a series of concerns to be
addressed with C35-C36 aldol bond disconnection (Scheme
2): (a) enolate regioselectivity-enolization at the R′ position
would lead to the formation of undesired R′-alkylation
products; (b) enolate stereoselectivity-the Zimmerman-
Traxler transition state model3 predicts that the (E) enolate
will lead to the desired R,â-anti adducts, whereas the (Z)
(1) Sakuda, S.; Ono, M.; Furihata, K.; Nakayama, J.; Suzuki, A.; Isogai,
A. J. Am. Chem. Soc. 1996, 118, 7855.
(2) Ikeda, H.; Matsumori, N.; Ono, M.; Suzuki, A.; Isogai, A.; Nagasawa,
H.; Sakuda, S. J. Org. Chem. 2000, 65, 438.
(3) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920.
10.1021/ol051226f CCC: $30.25
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Published on Web 06/21/2005

peratures with extended reaction time (Method B, entry 2)7
provided the desired aldol adduct in improved regioselection,
but the diastereoselectivity was diminished and conversion
was low.8,9 The improved regioselection indicated that the
thermodynamic enolization conditions resulted in equilibra-
tion to the desired R-enolate, while the diminished diaster-
eoselectivity implied that significant quantities of the un-
desired R-(Z) enolate were also formed under these condi-
tions. However, use of the aldehyde reaction partner as the
limiting reagent resulted in formation of the desired aldol
adduct with good regio- and diastereoselectivity (entry 3).
We thus conclude that whereas enolization of ketone 2 under
thermodynamic conditions (Method B) results in the forma-
tion of a mixture of enolates, the desired R-(E) enolate is
the more reactive.10
Scheme 2. Regio- and Stereochemical Issues
To address the issue of aldehyde facial selectivity, two
model aldehydes were prepared (Scheme 3). Aldehyde 5 was
Scheme 3. Syntheses of Model Aldehydes
enolate will lead to the undesired R,â-syn adducts; (c)
aldehyde facial selectiVity-anti-Felkin selectivity will lead
to the desired â,γ-syn adducts, whereas Felkin selectivity
will lead to the undesired â,γ-anti adducts.
Ketone 2 was selected as an appropriate model.4 To
address the issues of enolization selectivity, the aldol
additions of boron enolate derived from ketone 2 with
dihydrocinnamaldehyde was investigated (Table 1). Dicy-
Table 1. Optimization of Enolization Selectivity
available using the auxiliary-controlled addition of a Sn(II)-
glycolate enolate, which provided adduct 6 with moderate
diastereoselection.11 Aldehyde 7 was prepared from com-
mercially available 2,3-O-isopropylidene-D-erythronolactone.
When the boron enolate derived from ketone 2 was added
to these aldehydes under the optimized conditions (Table 1,
entry 2), aldol diastereoselectivity was found to be strongly
dependent on the choice of protecting groups (Scheme 4).
In the case of aldehyde 5, the undesired Felkin adduct 8b
was obtained as the major product in 79:21 diastereoselection
enoliztion
methoda
equiv
RCHO
conv
[%]
ratio
3:4
anti:syn
(3)
entry
1
2
3
A
B
B
1.5
1.5
0.5
100b
60b
93c
36:64
90:10
>97:3
90:10
80:20
92:8
a Method A: 1.5 equiv of Cy2BCl, 1.8 equiv of NEt3, Et2O, -78 °C, 1
h. Method B: 1.1 equiv of Cy2BCl, 2.0 equiv of EtNMe2, pentane, 0 °C to
room temperature, 15 h. b Based on ketone. c Isolated yield based on
aldehyde.
(7) Galobardes, M.; Gasco´n, M.; Mena, M.; Romea, P.; Urp´ı, F.;
Vilarassa, J. Org. Lett. 2000, 2, 2599.
(8) Adduct 4 was formed as a single diastereomer, consistent with the
formation of the (Z) enolate, which is expected for R′-siloxy ketones: Murga,
J.; Falomir, E.; Carda, M.; Gonzalez, F.; Marco, J. A. Org. Lett. 2001, 3,
901.
(9) See Supporting Information for experiments that support all stereo-
chemical assignments.
(10) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099. Similarly, it has been noted that (E) crotylboronates
react faster with aldehydes than the corresponding (Z) isomers: Roush, W.
R.; Adam, M. A.; Walts, A. E.; Harris, D. J. J. Am. Chem. Soc. 1986, 108,
3422.
(11) Evans, D. A.; Gage, J. R.; Leighton, J. L.; Kim, A. S. J. Org. Chem.
1992, 1961.
clohexylchloroborane was employed, as this reagent gener-
ally leads to high selectivity for the desired (E) enolate.5
Enolization at low temperatures (Method A, entry 1)6 led to
low levels of regioselectivity. Enolization at elevated tem-
(4) See Supporting Information for details of the synthesis of 2.
(5) Goodman, J. M.; Paterson, I. Tetrahedron Lett. 1992, 33, 7233.
(6) Marco, J. A.; Carda, M.; Falomir, E.; Palomo, C.; Oiarbide, M.; Ortiz,
J. A.; Linden, A. Tetrahedron Lett. 1999, 40, 1065.
3332
Org. Lett., Vol. 7, No. 15, 2005

Scheme 4. Diastereoselective Aldol Reactions
over the anti-Felkin isomer 8a (eq 1). When aldehyde 7 was
nonbonding interactions in the transition state leading to the
undesired Felkin isomer (TS IV).
used, however, the desired anti-Felkin isomer 9a was
obtained as a single diasteomer in excellent yield (eq 2).12
These results demonstrate the ability to control aldehyde
diastereofacial selectivity by variation of the protecting
groups on neighboring alcohol functionalities. As illustrated
in eq 3, the latter reaction has been applied to more complex
reaction partners, which resulted in the formation of the fully
elaborated C27-C48 subunit of aflastatin A.13
In conclusion, the C33-C36 region of aflastatin has been
prepared using a diastereoselective addition of an oxygenated
ketone enolate to a R,â-bisoxygenated aldehyde. The general
applicability of this method should allow its application to
other polyol natural products possessing either stereochemical
array. Progress toward a total synthesis of aflastatin A is
ongoing and will be reported in due course.
The divergence in stereoselectivity can be explained by
comparison of the Zimmerman-Traxler transition states for
these two processes. The free rotation about the CR-Câ bond
of aldehyde 5 allows transition states TS I and TS II to be
viable alternatives, leading to the formation of a mixture of
adducts 8a and 8b. Alternatively, the acetonide protecting
group of aldehyde 7 reduces the rotational freedom of the
R- and â-positions and results in the development of
Acknowledgment. Support has been provided by the
National Institutes of Health (GM 033327-19), National
Science Foundation, German Academic Exchange Service
(DAAD), and Merck.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 2-9 and 12 and
stereochemical proofs for adducts 3, 4, 8, 9 and 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) In no case were products derived from R′-enolization observed.
(13) The syntheses of compounds 10 and 11 will be reported in due
course.
OL051226F
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