Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids

Article abstract of DOI:10.3762/bjoc.15.116

(R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at -78 °C during 12-72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates 17, 24, 33a-f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13-78% yields). Separable trans-dialkylated tartrates 34a.f can be co-produced in small amounts (9-14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford-Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27 proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation-cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi-33a,d,f and epi-38a (54-67% isolated yields), possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products.

Full text of DOI:10.3762/bjoc.15.116

Alkylation of lithiated dimethyl tartrate acetonide with
unactivated alkyl halides and application to an asymmetric
synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of
squalestatins/zaragozic acids
Herman O. Sintim1,2, Hamad H. Al Mamari1,3, Hasanain A. A. Almohseni1,4,
Younes Fegheh-Hassanpour1 and David M. Hodgson*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1194–1202.
1Department of Chemistry, Chemistry Research Laboratory,
doi:10.3762/bjoc.15.116
University of Oxford, Mansfield Road, Oxford OX1 3TA, United
Kingdom, 2Department of Chemistry, Purdue University, West
Lafayette, IN 47907− 2112, USA, 3Department of Chemistry, College
of Science, Sultan Qaboos University, PO Box 36, Al Khoud 123,
Muscat, Sultanate of Oman and 4permanent address: University of
Kufa, Najaf Governorate, Iraq
Received: 21 March 2019
Accepted: 14 May 2019
Published: 31 May 2019
Associate Editor: T. P. Yoon
Email:
© 2019 Sintim et al.; licensee Beilstein-Institut.
License and terms: see end of document.
David M. Hodgson* - david.hodgson@chem.ox.ac.uk
*
Corresponding author
Keywords:
alkylation; cycloaddition; diazoester; epimerisation; tartaric acid
Abstract
(
R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at −78 °C during 12–72 h with
a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated
tartrates 17, 24, 33a–f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13–78% yields). Separable trans-dialkylated
tartrates 34a–f can be co-produced in small amounts (9–14%) under these conditions, and likely arise from the achiral dienolate 36
of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ke-
tones 21 and 26 and then Bamford–Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27
proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation–cycloaddition with methyl
glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxa-
bicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction
with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi-33a,d,f and epi-38a (54–67% isolated yields),
possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products.
Introduction
Since their isolation was reported in the early 1990s [1,2], the chemists, due to a combination of a synthetically challenging
squalestatins/zaragozic acids (e.g., squalestatin S1/zaragozic densely functionalised 2,8-dioxabicyclo[3.2.1]octane core [3-6],
acid A (1), Figure 1) have been of enduring interest to synthetic combined with an increasing range of intriguing biological ac-
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Beilstein J. Org. Chem. 2019, 15, 1194–1202.
tivities [7-11]. Here, we report in detail the evolution of chem- An alternative and asymmetric route to such substrates, ulti-
istry that provides an asymmetric entry to the tricarboxylate mately successful, built on stereoselective alkylation of enolates
core of these natural products, with particular focus on tartrate of tartrates (e.g., 7, Scheme 2) was originally reported by
alkylation methodology to establish the fully-substituted C-5 Seebach and co-workers for ‘activated’ (allylic, benzylic) alkyl
stereocentre (squalestatin numbering).
halides [17-19]. If an alkylated tartrate 9 could be accessed
from a silyloxy-substituted alkyl iodide 8 and subsequently
oxidised (for example via a second tartrate enolate) with
acetonide removal, this would give an α-ketoester 10. The latter
should in principle be a progenitor to the desired α-diazo
ester 3, following condensation with tosylhydrazide, then
Bamford–Stevens-type base-induced sulfinate elimination [20]
and oxidation of the secondary silyl ether.
Figure 1: Squalestatin S1/zaragozic acid A (1) and DDSQ (2).
Our studies in this area have recently culminated in two
communicated syntheses of 6,7-dideoxysqualestatin H5 (DDSQ
(
2), Figure 1) [12,13]. The centrepiece of both of these strate-
gies is a rhodium(II)-catalysed tandem carbon ylide formation
from a diazoketone 3 (Scheme 1) and stereoselective [3 + 2]
cycloaddition with a glyoxylate (3 → 4 → 5) [14,15], followed
by an acid-catalysed rearrangement to generate the desired
dideoxysqualestatin core 6 with the requisite tricarboxylate
Scheme 2: Tartrate alkylation strategy to cycloaddition substrate.
functionality installed. While we had earlier established the Results and Discussion
viability of this approach in a racemic model study (X = H) The general viability of the α-ketoester to α-diazoester func-
[
(
14], extension to an asymmetric variant of our aldol route tional group interconversion envisaged in Scheme 2 (10 → 3)
α-diazoacetate ester anion addition to an α-ketoester) to the was readily established on a simpler but closely structurally-
cycloaddition substrate 3 (X = H) did not appear promising related system (Scheme 3). Thus, the known Z-hydrazone 12,
[
16].
previously prepared by us from α-ketoester 11 in 75% yield
21], gave α-diazo ester 13 in 76% yield following reaction with
[
NaOMe. Furthermore, our earlier racemic model study had
established that deprotection and oxidation of a secondary silyl
ether in the presence of α-diazo ester functionality was feasible,
which constitutes precedent for the generation of the ketone
functionality in 3 [14]. These observations led us to examine the
possibility of substrate assembly through Seebach’s tartrate
alkylation methodology.
Scheme 1: Carbonyl ylide cycloaddition–rearrangement to the
squalestatin core [12,13].
Scheme 3: Conversion of α-ketoester to α-diazoester.
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Beilstein J. Org. Chem. 2019, 15, 1194–1202.
In 1981, Seebach and Naef communicated that (R,R)-tartrate 1-iodobutane 16 did generate alkylated tartrates (Scheme 5).
acetonide 7 could be deprotonated and undergo stereoselective Following Seebach’s protocol, with warming overnight to room
alkylation (≈80:20 dr) with reactive organohalides (Scheme 4) temperature, gave a 50% yield (90% based on recovered iodide
[
17]. The process was valuable, because it allowed direct elabo- 16) of a separable 76:24 mixture of alkylated tartrates 17 and
ration of a chiral pool building block that was readily available 18, respectively. The relative stereochemistry was assigned by
as either antipode [22,23], with the major alkylated diastereo- analogy with Seebach’s findings for substituted tartrates: that
mer 15 being generated in 97:3 er [18]. The study was also the diastereomer with the ring methine cis to the ester group
notable in showing that the intermediate ester enolate 14 (i.e., 17) always displays the higher chemical shift (≈5 ppm vs
possessed sufficient stability not to undergo significant β-elimi- ≈4.5 ppm in CDCl3) [18], and was further supported by 1D
nation under conditions of its generation and its alkylation: slow NOESY experiments on both alkylated tartrates 17 and 18. The
addition of pre-cooled LDA (−70 °C) to a mixture of the use of DMPU as co-solvent [18,25] reversed the ratio, with the
acetonide and electrophile in THF/HMPA at −78 °C, followed currently undesired diastereomer 18 becoming favoured (37:63,
by slow warming to ≈−10 °C before work-up. Finally, the reac- 17:18). However, with HMPA the proportion of 17 improved
tion displayed remarkable stereoselectivity, in that the electro- significantly (>90:10, 17:18) if the reaction was maintained at
phile was introduced on ostensibly the more hindered face of −78 °C for several hours before quenching at that temperature,
the enolate (that is, cis (“contrasteric”) [24] to the unenolised giving isolated yields of 30–50% for 17. The absolute configu-
ester group). The former observation was rationalised due to the ration of 17 was based on the chemical correlation studies of
enolate π-system and potentially cleavable beta σ-C–O bond Seebach [17-19] and of Pan [26] for benzylations, and subse-
lying mutually orthogonal, while the latter was subsequently quently those of Nagano [27] and of Li [28] for allylations, i.e.,
ascribed to alkylation occurring from an envelope conforma- stereoretentive (contrasteric) alkylation. As noted above,
tion wherein the unenolised ester resided pseudoequatorial to Seebach recorded 97:3 er (by NMR using a chiral shift reagent)
avoid 1,3-steric interactions with a pseudoaxial methyl of the
gem-dimethyl group [18,24]; it was proposed that the axial
methyl group directed electrophile incorporation away from
itself (Scheme 4).
The fragile nature of the lithium ester enolate of dimethyl
tartrate acetonide (to β-elimination with loss of acetone) was
evident from Seebach’s work, which concluded that only espe-
cially reactive halides (methyl, benzylic, allylic) were feasible
electrophiles; with iodoethane, 1-iodo-2-methylpropane and
chloromethoxymethane no alkylation products were formed
[
17-19]. Given these rather discouraging observations in the
context of our proposed chemistry (Scheme 2), we were pleased
Scheme 5: Tartrate alkylation with a non-activated alkyl iodide.
to find that initial studies with (R,R)-tartrate 7 and a 3-silyloxy-
Scheme 4: Seebach’s tartrate alkylation and rationalisation of stereoselectivity [17-19].
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Beilstein J. Org. Chem. 2019, 15, 1194–1202.
for a benzylated tartrate [18]; in the present case, chiral HPLC In contrast to a simple hydroxy acetonide (formally derived
comparison of 17 with the corresponding adduct from S,S- from an α-hydroxy aldehyde and acetone) [34], hydroxy
tartrate (ent)-7 indicated they were both of >98:2 enantiopurity acetonide 19a was found stable to mild bases such as Et3N
in the tartrate portion.
and iPr2NH, whereas the use of NaH or NaHMDS in THF
both decomposed 19a into unidentifiable polar products.
Before exploring the scope of the alkylation chemistry further, Attempted acid-induced loss of acetone with PTSA in MeOH,
it was considered prudent for the proposed asymmetric ap- PPTS in refluxing MeOH, or 80% AcOH at reflux [27] all led
proach to the dideoxysqualestatin core 6 (Scheme 1 and to quantitative recovery of hydroxy acetonide 19a, whereas 5%
Scheme 2) to establish the viability of the rest of sequence aq HCl resulted in acetonide removal and concomitant desilyl-
outlined in Scheme 2 from an alkylated tartrate. While further ation. Initial Lewis acids screened either failed to react
C–C bond formation by enolate formation at the remaining (PdCl2(MeCN)2), or led to complex mixtures (BF3, YbOTf,
methine on a monoalkylated tartrate acetonide had been re- TBSOTf). More encouragingly, both AlCl3 and FeCl3 were
ported by Molander and Harris [29], and by Kelly and found to cleave the acetonide 19a at rt, with the TBDPS group
co-workers [30]; the question whether such an enolate could be only being partially lost (≈15%) in both cases. AlCl3 was ob-
oxidised required investigation. Although the reaction of alky- served to deprotect the TBDPS ether more slowly than FeCl3,
lated tartrate 17 with NaHMDS/2-(phenylsulfonyl)-3-phenylox- and adjustment of the reaction conditions with AlCl3 (to 2 equiv
aziridine [31] gave an unidentifiable mixture, the use of LDA in CH2Cl2, −78 °C, followed by slow warming to −50 °C)
and MoOPH [32,33] at −78 °C followed by warming to −50 °C cleanly provided α-ketoester 20 (Scheme 6). α-Ketoesters can
for 3 h gave the hydroxy acetonide 19a (Scheme 6) in 92% be prone to hydrate easily (2D TLC analysis of 20 indicated de-
yield as a mixture of 4 diastereomers. Similarly, the enolate of composition); therefore, 20 and the derived tertiary TBS ether
the simpler propylated tartrate 33a [12] reacted with MoOPH to 21 were carried on directly to form hydrazone 22 (51% yield
give the analogous hydroxy acetonide 19b in 96% yield over 3 steps from hydroxy acetonide 19a). Unlike with hydra-
(
3:1 dr); if the MoOPH was added to the enolate which had zone 12 (Scheme 3), application of NaOMe was not conducive
been warmed to −40 °C, a more typical hydroxylation tempera- to effective diazo formation from hydrazone 22, giving a mix-
ture, then a reduced yield of 19b was observed (53%). Indirect ture of unidentified products; however, hydrazone 22 was
hydroxylation of the propylated tartrate enolate was also cleanly converted into α-diazo ester 23 (88%) using Et3N
attempted using CBr4 (at −78 °C) as a more readily available/ [35,36].
convenient electrophile, which also gave the hydroxy acetonide
1
9b presumably by way of hydrolysis on work-up of an inter- TBDPS protection for the secondary alcohol had originally been
mediate bromo acetonide, albeit in significantly reduced yield selected principally for its likely tolerance to potential
(
33%).
(hydroxy) acetonide removal conditions, and with the possibili-
Scheme 6: Alkylated tartrate to diazoester sequence.
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Beilstein J. Org. Chem. 2019, 15, 1194–1202.
ty [37,38] of its selective deprotection in α-diazo ester 23 in the the initial deprotection and TESCl in the silylation; the latter
presence of the tertiary TBS ether. It was considered important minimises formation of the undesired silylated six-membered
that the tertiary alcohol remain masked during projected oxida- lactol form of 26. The remaining steps to the model core 31
tion of the released secondary alcohol to give the ketone func- (Scheme 7) closely mirrored our previous racemic synthesis of
tionality in the cycloaddition substrate, as otherwise essentially 31 (from the corresponding 3° TBS ether) [14], and this strategy
irretrievable five-membered lactol formation would be ex- was subsequently also successfully applied in our most recent
pected [39]. Unfortunately, various reagents (TBAF/AcOH total synthesis of DDSQ (2) [13].
[
40], NaH/HMPA [41], Bu4OH/DMF [40], NaOMe/MeOH)
failed to selectively deprotect the secondary TBDPS ether in We now returned to study the Seebach alkylation chemistry in
α-diazo ester 23 in the presence of the tertiary TBS ether. more detail. In 2008, Lipton and co-workers had observed that
Reassessment of the protecting group strategy led us to TES the cyclopentylidene derivative of diethyl tartrate reacted with
protection at both alcohols, on the basis that this group should LiHMDS in the presence of LiCl and MeI, to give exclusively
be robust enough to withstand the enolate manipulation chem- the corresponding trans-monomethylated tartrate in 72% yield
istry, that desilylation of the secondary TES ether during [42]; this compares with methylation of acetonide tartrate 7 by
acetonide removal could be restored in the subsequent tertiary Seebach, which was reported to give an inseparable mixture of
alcohol silylation step, that selective 2° over 3° TES ether de- monomethylated product (86:14 dr), dimethylated, and recov-
silylation should be readily achievable using AcOH [14], and ered 7 (50%, 79:15:6, respectively) [17-19]. Application of
that the remaining tertiary TES ether should be potentially Lipton's conditions to tartrate 7, cleanly gave the trans-mono-
labile enough to be removed under typical transketalisation methylated product 32, albeit in moderate yield (39%,
conditions (TFA/CH2Cl2/H2O (10:20:1), 40 °C, 48–68 h [14], Scheme 8); however, extension to a higher alkylating agent
cf, Scheme 1), thereby circumventing the separate prior desilyl- (PrI) was unsuccessful, returning only ≈25% of tartrate 7 in an
ation step in our earlier racemic model study [14]. In the event, impure state.
application of this TES protection approach did provide access
to diazo alcohol 27 (Scheme 7). As anticipated from the above
deprotection studies with TBDPS ether 23, 1% aq HCl re-
moved both the acetonide and TES groups in hydroxy acetonide
2
5. Subsequent silylation using TESOTf gave the bis-TES ke-
tone 26, which was not purified but taken on through diazo for-
mation and desilylation to give diazo alcohol 27 (17% from 25).
The efficiency of the sequence from hydroxy acetonide 25 to
diazo alcohol 27 could be improved (to 37%) using ZnCl2 for
Scheme 8: Tartrate acetonide methylation.
Scheme 7: TES protection approach to the squalestatin core.
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Beilstein J. Org. Chem. 2019, 15, 1194–1202.
In contrast to the unsuccessful propylation with LiHMDS/LiCl modified reaction conditions, rather than the nature of the alky-
mentioned above, following our modified Seebach‘s protocol, lating agent, which leads to the improved diastereoselectivity
propylation could be achieved to give propylated tartrate 33a [43]. The trans stereochemistry assignment for the dialkylated
[
12] (Scheme 9), in 66% yield and 97:3 er by chiral HPLC, with products 34 follow from the observed equivalence of the
the trans-dipropylated product 34a also being separately isolat- acetonide methyl groups in all their proton and carbon NMR
ed, in 7% yield. Other primary ‘non-activated’ alkyl iodides spectra.
also led to alkylated tartrates 33b,c and the corresponding
dialkylated side-products 34b,c (Scheme 9). Under our modi- In Seebach's original studies, which established retention on
fied alkylation conditions, ‘activated’ bromides (benzyl, allyl tartrate alkylation for the major diastereomer (formed, as noted
and prenyl), previously examined by Seebach [17-19], all gave above, in 97:3 er), a further intriguing observation was made:
the corresponding monoalkylated tartrates 33d–f also as single that the minor diastereomer was obtained in virtually racemic
diastereomers (along with separable trans-dialkylated material form (determined by NMR using a chiral shift reagent) [18,19].
3
4d–f, Scheme 9). These latter results indicate that it is the It was suggested that the latter principally arose from alkylation
then protonation, by unreacted 7) [19] of the (achiral) dieno-
(
late 36 (Scheme 10) of 7. In the current work, where the major
difference is prolonged reaction time at low temperature and no
warming before quenching, the minor diastereomer is not ob-
served – but dialkylated byproduct 34 is. An attempt to propy-
late the monopropylated tartrate 33a under our conditions
mainly returned starting 33a (68%), with only a trace of trans-
dipropylated product 34a being isolated (2%). Seebach’s obser-
vations, together with ours, indicate that the dienolate 36 does
form to some extent at −78 °C (Scheme 10) [44-46], and both it
and the derived alkylated mono-anion rac-35 are quite reactive
to alkylation, but protonation of the alkylated mono-anion
rac-35 (by unreacted 7) does not occur at that temperature; also,
once monoalkylation has occurred from the mono-enolate 14,
then 33a is not readily deprotonated at −78 °C. Clearly,
monoalkylated tartrate can be deprotonated and trapped with
electrophiles if the system is warmed above −78 °C: to −30 °C
by Molander and Harris [29], whereas −50 °C was sufficient for
the enolate oxidation steps in Scheme 6 and Scheme 7. Indeed,
propylation of the monopropylated tartrate 33a can be achieved
in 34% yield, if the reaction mixture is warmed to −50 °C
Scheme 9: Tartrate alkylation with various alkyl halides.
Scheme 10: Rationalisation of dialkylation observations.
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Beilstein J. Org. Chem. 2019, 15, 1194–1202.
(
Scheme 10). Chiral HPLC comparison of the trans-dipropy- slight excess of tartrate 7 and LDA (1.2 and 1.5 equiv, respec-
lated material 34a obtained as the byproduct from the alkyl- tively) for 72 h at −78 °C [13]. These examples demonstrate the
ation of tartrate acetonide 7, and from propylation of the mono- viability of the tartrate alkylation chemistry with more complex
propylated tartrate 33a, confirmed that the former was essen- and valuable electrophiles.
tially racemic (52:48 er), while the latter was 98:2 er. Therefore,
if one wishes to generate (R,R)- (or (S,S)-) C2-symmetric While monoalkylated tartrate acetonides were applied in
dialkylated tartrates [47-49], an important conclusion from the squalestatin syntheses as highlighted above, the monoalkylated
above observations and analysis is that monoalkylation should tartaric acid motif is also directly present in several natural
be carried out first, and the isolated monoalkylated material products, such as hydroxybenzyl-substituted piscidic acid (42)
then separately subjected to a second alkylation, allowing and congeners (fukiic and cimicifugic acids) [50], and the
warming to ≈−40 °C.
Cephalotaxus alkaloids isoharringtonine (43) and cephale-
zomine C (44) [51]. In these latter natural products, the
Our first synthesis of 6,7-dideoxysqualestatin H5 (DDSQ (2), monoalkylated tartaric acid residues typically possess 2R,3S
Figure 1), required extension of the above tartrate alkylation stereochemistry (Figure 2); one exception is cephalezomine D
chemistry to a homoallylic halide as the electrophile [51], which is the 3R-epimer of cephalezomine C (44). Since
(
(
Scheme 11) [12]. An initial experiment with 4-bromobut-1-ene the chiral (R,R- S,S-) tartrate acetonides undergo stereoretentive
37a) was not encouraging, delivering the homo-allylated prod- alkylation, then direct access to the stereochemistry present in
uct 38a in only 13% yield. It was suspected that competing the majority of these natural products is not possible. Neverthe-
elimination (to give butadiene) contributed to the low yield. less, a couple of isolated examples in the Chinese chemical lit-
Support for this was found with the real system, where the cor- erature from the late 1980s indicated that subsequent base-in-
responding diene 39 was isolated in up to 36% yield. In our duced epimerisation of monoalkylated (p-(benzyloxy)benzyl-
earlier studies, typically approximately equimolar quantities of
tartrate and alkylating agent were used, but with the halide now
being synthetically more valuable, efforts focused on condi-
tions which gave the best yields using it as the limiting agent. A
slight excess of tartrate relative to iodide produce the homo-
allylated tartrate 38b in 34% yield, but this could be improved
to 60–78% by using 100% excess of tartrate [12]. It was also
noted that minimal contact time between the sensitive iodide
3
7b and HMPA at low temperature before slow addition of the
pre-cooled LDA minimised diene formation, with the excess
residual unreacted tartrate being most conveniently removed by
distillation on large-scale. Our second synthesis of DDSQ (2)
introduced the full side-chain through alkylation with iodide 40
to give the alkylated tartrate 41 in 71% yield, and used only a
Figure 2: Natural product examples containing the monoalkylated
tartaric acid motif.
Scheme 11: Tartrate alkylation chemistry with more complex alkyl iodides [12,13].
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Beilstein J. Org. Chem. 2019, 15, 1194–1202.
ated and prenylated) tartrate acetonides favours R,S stereochem- tartrate alkylation with non-activated alkyl halides, on origins of
istry, providing access to piscidic acid (42) [26] and the tartrate side-products, and on conditions for epimerisation of the
residue of isoharringtonine (43) [28].
monoalkylated tartrates, significantly broaden the scope and
understanding of Seebach’s alkylation chemistry.
We studied the previously reported epimerisation of prenylated
tartrate 33f, on 0.5 mmol scale ([28] 5 mmol), using NaOMe
Supporting Information
(
1 equiv) in MeOH (0.5 M) at room temperature for 12 h. Under
these conditions we observed only partial epimerisation
33f/epi-33f 75:25, [[28] 12:88]), but a 25:75 ratio in favour of
epi-33f could be achieved in MeOH (0.06 M) at reflux for 30 h
Scheme 12). That equilibrium had been reached was estab-
Supporting Information File 1
(
Experimental procedures, characterisation data and 1H and
1
3C NMR spectra for all new compounds.
https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-116-S1.pdf]
(
[
lished by subjecting epi-33f to these latter reaction conditions,
which returned the same 25:75 ratio of 33f/epi-33f. Other
monoalkylated tartrates were found to give similar levels of
epimerisation (Scheme 12), generating the chromatographically Acknowledgements
separable epimerised tartrates in 54–67% isolated yields.
We thank the University of Oxford, the Sultanate of Oman, the
Higher Committee for Education Development in Iraq, and the
EPSRC for studentship support (to H.O.S., H.H.A.M.,
H.A.A.A., and Y.F-H., respectively), and Dr. Anne Valade for
the butylation result in Scheme 9.
ORCID® iDs
Herman O. Sintim - https://orcid.org/0000-0002-2280-9359
David M. Hodgson - https://orcid.org/0000-0001-7201-9841
References
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Conclusion
Contrary to the seminal observations of Seebach and Naef, we
have demonstrated that lithiated dimethyl tartrate acetonide can
undergo stereoretentive alkylation even with “non-activated”
alkyl halides, in synthetically useful yields and high er. Optimal
reaction conditions are prolonged reaction time at −78 °C, fol-
lowed by quenching at that temperature; these conditions also
avoid cogeneration of the (racemic) diastereomer side-product
originally observed on warming. Essentially racemic dialkyl-
ated tartrate is observed as a minor side-product under our
modified conditions. The reaction pathways that lead to these
racemic products under the different reaction conditions have
been rationalised. Application of this methodology to generate
the 6,8-dioxabicyclo[3.2.1]octane core of the squalestatins/
zaragozic acids in an asymmetric fashion, is shown to evolve
from a carefully orchestrated sequence of oxidation and judi-
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tion of the monoalkylated tartrates favours cis-disposition of the
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