An unprecedented silver salt effect switches the facial selectivity in the vinylogous mukaiyama aldol reaction

Article abstract of DOI:10.1002/adsc.201000420

Silver hexafluroantimonate was identified as a highly efficient agent to reverse the facial selectivity of the titanium chloride-mediated vinylogous Mukaiyama aldol reaction (VMAR), and this unprecedented reaction provides a concise, diastereoselective sy

Full text of DOI:10.1002/adsc.201000420

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DOI: 10.1002/adsc.201000420
An Unprecedented Silver Salt Effect Switches the Facial
Selectivity in the Vinylogous Mukaiyama Aldol Reaction
Yufan Liang,a Lin Wang,a Rong Zhu,a Lujiang Deng,a Yunfang Yang,b
Junmin Quan,b,* Jiahua Chen,a,* and Zhen Yanga,b,*
a
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National
Laboratory for Molecular Science (BNLMS), College of Chemistry and the State Key Laboratory of Natural and
Biomimetic Drugs, School of Pharmaceutical Science, Peking University, Beijing 100871, Peopleꢀs Republic of China
Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking
b
University, Shenzhen 518055, Peopleꢀs Republic of China
Fax : (+86)-755-2603-5326 (JQ), (+86)-10-6275-9105 (JC), (+86)-10-6275-9105 (ZY); e-mail: quanjm@pkusz.edu.cn,
jhchen@pku.edu.cn or zyang@pku.edu.cn
Received: May 29, 2010; Revised: August 1, 2010; Published online: September 23, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000420.
Abstract: Silver hexafluroantimonate was identified
as a highly efficient agent to reverse the facial se-
lectivity of the titanium chloride-mediated vinylo-
gous Mukaiyama aldol reaction (VMAR), and this
unprecedented reaction provides a concise, diaste-
reoselective synthesis of d-hydroxy-a,g-dimethyl-
a,b-unsaturated carbonyl units from readily avail-
able chiral vinylketene silyl N,O-acetal 6 and ethyl
glyoxylate 8.
methyl-hydroxy syn-stereochemical motif was made
via VMAR by using vinylketene silyl N,O-acetal 6
and b-dithiane-substituted aldehyde 7 as substratres.
As a potent antimitotic agent, maytansine was ex-
tensively evaluated in human clinical trials, but its
clinical advancement was hampered by its poor thera-
peutic index in vivo.[6] Stimulated by our interest in
the unusual biological properties of maytansinoids, to-
gether with their structurally intriguing architectures,
we therefore initiated a program for a combinatorial
synthesis of maytansinoids, and hoped that such a li-
brary would find its utilization in the improvement of
the therapeutic index of maytansinoids through profil-
ing their SAR. However, the early study in this pro-
gram has been impeded by lack of simple and stereo-
Keywords: chiral vinylketene silyl N,O-acetals;
ethyl glyoxylate; silver hexafluroantimonate; titani-
um chloride-mediated reaction; vinylogous Mu-
kaiyama aldol reaction
Asymmetric aldol reactions have been the subject of
intensive synthetic and mechanistic studies because of
their importance in the asymmetric construction of
carbon-carbon bonds.[1] The vinylogous Mukaiyama
aldol reaction (VMAR)[2] developed by Kobayashi
and co-workers[3] has emerged as an efficient method
for the rapid syntheses of d-hydroxy-a,g-dimethyl-
a,b-unsaturated unit 2 from chiral vinylketene silyl
N,O-acetal 1 via remote asymmetric induction[4]
(Scheme 1).
In the context of our recent studies aimed at syn-
theses of structurally diverse of maytansinoids, we
have demonstrated a concise strategy for the formal
synthesis of N-methylmaysenine, featuring VMAR
and RCM reactions as key steps (Figure 1).[5] In this
synthesis, the key intermediate 5 with an adjacent Scheme 1. Kobayashiꢀs remote asymmetric induction.
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Figure 1. Rationale for the synthesis of maytansinoids.
selective methods for the synthesis of the d-hydroxy- ducts 9 and 10 could be obtained in 82% yield and
a,g-dimethyl-a,b-unsaturated units. with moderate diastereoselectivity (Table 1, 9/10=
The use of chlorotitanium enolates of thiazolidine- 3.6:1). It is worth noting that the chiralities at C-6 and
thione as chiral auxiliaries to synthesize either C-7 in 9 are opposite to the corresponding chiralities
“Evans” or “non-Evans” syn-aldol products with high in 2 (Scheme 1) generated in Kobayashiꢀs VMAR.
diastereoselectivity by changing the stoichiometry and
The absolute stereochemistries of 9 and 10 were es-
nature of the amine base has been described by Crim- tablished by converting them to their corresponding
mins and his co-workers.[7] However, a method for the acetonides 13 and 14 by literature methods.[3b] Ac-
highly stereoselective synthesis of “Kobayashi” or cordingly, an efficient reduction-silylation sequence
“non-Kobayashi” anti-aldol products via VMAR has elaborated imide 9 into alcohol 11 in overall 66%
not been reported yet. In this communication, we yield in two steps.
wish to report that AgSbF6 can completely switch the
Alcohol 11 underwent ozonolysis and reduction to
facial selectivity of Kobayashiꢀs VMAR adducts 9 and give diol 12, which was then subjected to the treat-
10 (Table 1) when vinylketene silyl N,O-acetal 6 and ment with 2,2-dimethoxypropane in the presence of
ethyl glyoxylate 8[8] were utilized as the starting mate- PPTS to give acetonide 13 in 67% in three steps
rials. This versatile approach to the assemblage of d- (Scheme 2). Following the same synthetic sequence,
hydroxy-a,g-dimethyl-a,b-unsaturated units 9 and 10 compound 10 was transferred to 14, which shares the
may find application in the combinatorial synthesis of same spectroscopic data with acetonide 13, except for
maytansinoid libraries, as well as other natural prod- its opposite optical rotation.
ucts and biological active molecules.[9]
To further comfirm the stereochemical assignment
Our research started with the study of VMAR with of 9, acetonide 13 was independently made via the
6 and 8 as substrates. After preliminary screening of Evans aldol method[10] as illustrated in Scheme 3.
the VMAR conditions, we found that the aldol ad-
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An Unprecedented Silver Salt Effect Switches the Facial Selectivity
Table 1. Silver salts effects on the VMAR.
[a]
Isolated yield.
Determined by HPLC analysis.
[b]
Scheme 2. Stereochemistry of compounds 9 and 10.
In the event, substrate 15 was reacted with alde- chemistry of 10 was also verified by the modified
hyde 16 in the presence of Bu2BOTf and Et3N to give Mosher method (see Supporting Information for de-
aldol adduct 17 in 82% yield. Alcohol 17 was subject- tails).[11]
ed to a Mitsunobu reaction to afford its ester 18 in
This unusual observation led us to consider whether
64% yield. Ester 18 underwent a sequential reduc- the cationic Ti complex would improve the stereose-
tion-acetonification to give the acetonide 13 with the lectivity of the VMAR, considering its high rigidity
expected spectroscopic data. The absolute stereo- and reactivity.[12] To this end, AgSbF6
was utilized
[7a,c]
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Scheme 3. Synthesis of 13 via the Evans aldol reaction.
+
as an agent to generate the cationic TiCl3 -chelated at room temperature gave the best diastereoselectiv-
complex. Thus, the aldol reaction was carried out in ity (entries 1 and 4). (ii) In the presence of 2.0 equiva-
the presence of AgSbF6 under the conditions listed in lents of aldehyde, the reaction conducted at room
Table 1. To our surprise, the facial selectivity of the temperature gave the highest yield and excellent dia-
VMAR was reversed and, as a result, 10 became the stereoselectivity (entry 4). (iii) With catalytic amounts
major product in 89% yield with the ratio of 9/10 of TiCl4 and AgSbF6, VMARs could proceed at room
being 1:120.
temperature, but the yield and diastereoselectivity de-
To examine the effect of other silver salts on the creased (entries 7 and 8).
outcome of the VMAR, we employed AgClO4, AgF,
To account for the observed facial selectivity of the
AgOTf, AgBF4 and AgPF6 as additives under the con- anti VMAR products, we proposed the following
ditions listed above, however, no stereochemical re- mechanistic interpretations. As shown in Figure 2, in
versal was observed with any of these salts (see Sup- the absence of silver salt, aldehyde 8 could be at-
porting Information for details). Clearly, there is a tacked by the C-6 carbon of vinylketene silyl N,O-
strong dependence of the reaction pathway on the acetal 6 from either the re-face (TS-1) or si-face (TS-
nature of the counterion.
2). However, due to the dipole repulsion between the
To find the optimal reaction conditions to synthe- ester carbonyl group and the carbonyl group of the
size product 10, we studied the effect of various reac- oxazolidinone in the si-face (TS-2), the TS-1 is more
tion parameters on the outcome of the reaction, and favorable than TS-2, thus, product 9 turned out to be
the results are listed in Table 2.
the major product.
From Table 2, we can make the following observa-
On the other hand, in the presence of silver salt, we
tions. (i) Considering the temperature effect on the assumed that the resultitng bidentate cationic inter-
outcome of VMAR of 6 with 8, reactions carried out mediate A may have tendency to form hexacoordinat-
ed complex (TS-3) with substrate 3. As a result, the
+
product 10 would be derived dominantly, realizing the
reverse of the facial selectivity through chelation con-
trol.[13]
Table 2. Cationic TiCl3 -catalyzed VMAR.
To investigate the substrate effect on the outcome
of the coupling reactions, we selected five additional
substrates 19–23 to test their performance in this
VMAR, and the primary results are listed in Table 3.
From the results in Table 3, we can make the fol-
lowing observations. (i) In comparison to aldehydes
(entries 1–6) as substrates in the VMARs, ketones
gave lower yields of coupling products (entries 7–10),
a result presumably due to the favorable steric and
electronic effects of aldehyde. (ii) Considering the ef-
+
fects for the formation of bidentate cationic TiCl3
complexes on the outcome of the stereochemistry, it
is interesting to note that the five-membered ring
based bidentate cationic TiCl3 complexes give the
[a]
Isolated yield.
Determined by HPLC analysis.
+
[b]
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An Unprecedented Silver Salt Effect Switches the Facial Selectivity
Figure 2. Mechanistic interpretation.
expected inversed stereochemical outcomes (entries 2, selective synthesis of d-hydroxy-a,g-dimethyl-a,b-un-
4, 8 and 10), however, the ratios of their selectivity saturated carbonyl units from readily available chiral
are less satisfied. On the other hand, substrate 21, vinylketene silyl N,O-acetal 6 and ethyl glyoxylate 8
with a potential to form a six-membered ring based simply by using AgSbF6 as a switch. A further rational
+
bidentate cationic TiCl3 complex (entry 6), did not analysis of this unprecedented VMAR by a combina-
give any inversion effect. (iii) In the presence of the tion of experimental and computational studies is cur-
silver effect, the tested VMARs generally gave higher rently underway in our laboratories and will be re-
yields (entries 2, 4, 6 and 8) than the ones without the ported in due course.
silver effect (entries 1, 3, 5 and 7), except for the last
case (entries 9 and 10). The structural information for
the synthesized compounds (24a, 24b to 28a, 28b) is
provided in the Supporting Information.
Experimental Section
In conclusion, AgSbF6 was identified as an efficient
agent to reverse the facial selectivity of titanium chlo-
Procedure A
ride-mediated Kobayashiꢀs VMAR, and this unprece-
dented reaction provides a concise, highly diastereo- w/w in toluene, 0.52 mmol) in dry CH2Cl2 (2 mL) was slowly
To a solution of ethyl glyoxylate 8 (53.1 mg, 106 mL, 50%
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Table 3. VMARs with different electrophiles.
[a]
[b]
Isolated yield.
Determined by HPLC analysis.
added TiCl4 (260 mL, 1M in CH2Cl2, 0.26 mmol) at À788C,
and the mixture was stirred at the same temperature for
30 min. To this solution was added a solution of vinylketene
silyl N,O-acetal 6 (100.8 mg, 0.26 mmol) in CH2Cl2 (3 mL) at
À788C, and the reaction mixture was warmed up to room
temperature and stirred for 2 h. The reaction mixture was
quenched by addition of a saturated aqueous Rochelleꢀs salt
(10 mL), and the mixture was extracted with ethyl acetate
(3ꢂ5 mL). The combined organic layers were washed with a
saturated aqueous solution of NaHCO3 (2ꢂ5 mL) and brine
(5 mL), and then dried over anhydrous Na2SO4. The solvent
was removed under vacuum, and the residue was purified by
a flash column chromatography on silica gel (hexane/ethyl
acetate=4:1) to give products 9 and 10. The ratio was deter-
mined by HPLC with Chiralcel OJ-H column (90:10 hex-
slowly at À788C, and the formed mixture was warmed up to
room temperature and stirred vigorously for 15 min until a
precipitation was observed. To this solution was added a so-
lution of ethyl glyoxylate 8 (53.1 mg, 106 mL, 50% w/w in
toluene, 0.52 mmol) at À788C, and the mixture was stirred
at the same temperature for 30 min. After addition of a so-
lution of vinylketene silyl N,O-acetal
6
(100.8 mg,
0.26 mmol) in CH2Cl2 (3 mL) to the above solution at
À788C, the formed mixture was warmed up to room tem-
perature and stirred for 2 h. The reaction mixture was
quenched by addition of a saturated aqueous Rochelleꢀs salt
(10 mL), and the mixture was extracted with ethyl acetate
(3ꢂ5 mL). The combined organic layers were sequentially
washed with a saturated aqueous solution of NaHCO3 (2ꢂ
5 mL) and brine (5 mL), and then dried over anhydrous
Na2SO4. The solvent was removed under vacuum, and the
residue was purified by a flash column chromatography on
silica gel (hexane/ethyl acetate=4:1) to give products 9 and
10, and their ratio was determined by HPLC with Chiralcel
OJ-H column (90:10 hexanes:i-PrOH), 1.0 mLminÀ1,
254 nm; for isomer 10, tr =70.4 min, and for isomer 9, tr =
90.2 min.
ACHTUNGTRENNUNG
anes:i-PrOH), 1.0 mLminÀ1, 254 nm; for isomer 10, tr =
70.4 min, and for isomer 9, tr =90.2 min.
Procedure B
To a solution of silver salt (0.26 mmol) in dry CH2Cl2
(2 mL) was added TiCl4 (260 mL, 1M in CH2Cl2, 0.26 mmol)
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An Unprecedented Silver Salt Effect Switches the Facial Selectivity
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Acknowledgements
This work is supported by grants of the National Basic Re-
search Program of China (973 Program, Grants
2006CB504200, 2006CB504202), the National Science and
Technology Major Project “Development of key technologies
for the combinatorial synthesis of privileged scaffolds”
(2009ZX09501-012), the National Science Foundation of
China (20325208 and 20521202), and the Shenzhen munici-
pal “Shuang Bai Project” (to Junmin Quan).
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