Enantioselective syn and anti homocrotylation of aldehydes: Application to the formal synthesis of spongidepsin

Article abstract of DOI:10.1021/jacs.5b08858

Whereas crotylboration has been a useful method for synthesis of stereochemically complex products, we have shown that homocrotylboration can be achieved with cyclopropanated crotylation reagents, and that the stereoselectivity of the reaction can be predicted by analogous models. This paper presents a full account of this work, including the first examples of asymmetric anti homocrotylation. The scope of this reaction is demonstrated with highly enantioselective homocrotylation of both aliphatic and aromatic aldehydes, as well as double diastereoselection studies. An application of the synthesis of the marine natural product spongidepsin is presented, as well as streamlined syntheses of homocrotylation reagents.

Full text of DOI:10.1021/jacs.5b08858

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Article
Enantioselective syn and anti Homocrotylation of Aldehydes:
Application to the Formal Synthesis of Spongidepsin
Hongkun Lin, Leiming Tian, and Isaac J. Krauss
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Sep 2015
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Journal of the American Chemical Society
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Enantioselective syn and anti Homocrotylation of Aldehydes: Appli-
cation to the Formal Synthesis of Spongidepsin
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Hongkun Lin,† Leiming Tian† and Isaac J. Krauss*
Department of Chemistry, Brandeis University, Waltham, Massachusetts, 02454-9110, United States
ABSTRACT: Whereas crotylboration has been a useful method for synthesis of stereochemically complex products, we
have shown that homocrotylboration can be achieved with cyclopropanated crotylation reagents, and that the stereoselec-
tivity of the reaction can be predicted by analogous models. This paper presents a full account of this work, including the
first examples of asymmetric anti homocrotylation. The scope of this reaction is demonstrated with highly enantioselec-
tive homocrotylation of both aliphatic and aromatic aldehydes, as well as double diastereoselection studies. An applica-
tion of the synthesis of the marine natural product spongidepsin is presented, as well as streamlined syntheses of homo-
crotylation reagents.
tion, it was shown that optically pure boronate reagent 5
INTRODUCTION
(Scheme 2) enables asymmetric access to syn adducts of
aliphatic aldehydes (3s, Scheme 1).4b This paper is a full
account of that work, detailing the enantioselective prep-
Whereas asymmetric allyl- and crotylboration (Scheme 1,
aration of both syn and anti homocrotylation reagents 5
1 → 2) have been extensively developed and applied in
and 6 and their use in the asymmetric homocrotylation of
synthesis,1 methods for asymmetric homoallylation and
both aliphatic and aromatic aldehydes, together with
homocrotylation (1 → 3) are still very limited.2 Until re-
double diastereoselection studies on chiral aldehydes and
cently, the seemingly simple aldehyde addition to pro-
a formal synthesis of a marine natural product, spon-
duce optically pure 3a or 3s (anti or syn) has been accom-
gidepsin.6 Additionally, background studies are presented
plished only in sequences of 4-11 steps.3 However, we have
for the stereoselective cyclopropanation en route to boro-
Scheme 1. Homoallylation through allylation mecha-
nisms
nates 5 and 6, as well a second generation, large-scale
route to prepare these reagents.
Scheme 2. General route to optically pure 5 and 6
RESULTS AND DISCUSSION
Initial studies in asymmetric cyclopropanation of
vinylboronates. Reagents 5 and 6 can be prepared via
straightforward one-carbon homologation of the corre-
sponding chiral cyclopropylboronates 11 and 12, as out-
lined in Scheme 2. However, in the development of this
route, some trial and error was required to achieve a high-
ly stereoselective cyclopropanation yielding 11/12. Alt-
hough numerous enantioselective Rh- and Cu-catalyzed
methods have been reported for asymmetric cyclopropa-
nation using ester-substituted carbenoids “:CH(CO2R)”,
asymmetric cyclopropanation with “:CH2” remains a great
recently shown that 4-cis/trans react stereospecifically to
provide 3a/3s, respectively.4 This selectivity can be ex-
plained by a Zimmerman-Traxler model5 in a manner
analogous to allylboration. In a preliminary communica-
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challenge:7 Charette’s method using zinc carbenoid and a
Table 1. Scope of tartaramide-directed cyclopropana-
tion under Deng’s conditionsa
chiral director8 (15, Scheme 3) is the only highly selective
approach, and is itself limited to alkene substrates pos-
sessing an allylic hydroxyl (e.g., 13). Hoping that the
B(OH) moiety of a vinylboronic acid might fulfill the usu-
al requirement for an allylic hydroxyl, we attempted Cha-
rette cyclopropanation directly on 16 (Scheme 3); howev-
er, this resulted in minimal selectivity for 18a (3:2 er). Cy-
clopropanation was next attempted using Burke's9 and
Pietruszka's10 auxiliaries (see 18b and 18c), but still ob-
tained low to moderate selectivity, whether using zinc
carbenoid, diazomethane or TMS-diazomethane (selected
conditions listed). However, in agreement with Deng’s
reports,11 tartaramide auxiliary 19 promoted excellent ste-
reoselectivity (97 % de) in cyclopropanations using zinc
carbenoid.
1
2
3
4
5
6
7
8
entry
R
de %
97b
95b,c
93-94d
80-86d,e
9
1
2
3
4
Ph (21a)
Ph (21a)
Cy (21b)
Me (21c)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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49
50
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60
aAll reactions were run at the concentration of 0.1 M. bde was
measured by HPLC using a chiral stationary phase after oxi-
dation of 21a with NaBO3•4H2O to the corresponding alco-
Scheme 3. Preliminary cyclopropanation studiesa
c
d
hol. DCM, -50 °C. de was measured by HPLC using a chiral
stationary phase after oxidation of 21b,c with NaBO3•4H2O to
the corresponding alcohol and benzoylated with BzCl and
DMAP. eDCM, -78 °C.
Table 2. Effect of additives on cyclopropanation ste-
reoselectivity.a
entry
additive(s)
amount (mol %)
de (%)b
82
1
none
--
2
3
4
5
6
7
8
19
20
91
19
30
95
19
19
40
96
50
97-98
79
19 + H2O
diethanolamine
H2O
50 each
5
5
81
85
1,2-
9
5
84
dimethoxyethane
10
1,4-dioxane
5
83
aSelected er’s/dr's are shown in the scheme. Product 18a was
prepared from cyclopropanation of 16. Products 18b-d were
aReactions were performed by adding the solution of 20c
mixed with additive(s) to the solution of 3 equiv. of Et2Zn
and 4.5 equiv. of CH2I2 at concentration of 0.1 M at -78 °C.
bde’s correspond to ee’s measured by chiral HPLC after oxi-
dation of 21c to the corresponding alcohol followed by ben-
zoylation.
b
prepared from cyclopropanation of 17. dr's were measured
c
by RP-HPLC. er or dr corresponding to er measured by chi-
d
ral HPLC after oxidation of 18d with NaBO3•4H2O. DME =
1,2-dimethoxyethane, DCE = 1,2-dichloroethane.
Although the styrenylboronates 17 used in these studies
were convenient for comparison to previous reports, we
next moved to the more challenging and relevant Me-
substituted substrate 20c, which had not been reported in
Deng’s studies (Table 1). Under the same conditions, the
de of 21c was lower than for 21a,b, and varied from 80 to
86 %. Even when the reaction temperature was lowered
to –78 °C, no improvement was observed.
Not only was the de of 21c lower than desired, but the
variability was of concern. As the crude tartaramide boro-
nates 20 are used directly in the cyclopropanation (ob-
tained by mixing of chiral diol with boronic acid, followed
by simple drying over MgSO4), we hypothesized that im-
purities such as water or small amounts of excess tar-
taramide diol 19 could influence the de of the cyclopropa-
nation. Therefore, the effect of additives, including 19,
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Journal of the American Chemical Society
was investigated (Table 2). Selectivity was enhanced by
addition of 19, whereas water and other Lewis basic addi-
1
2
3
4
5
6
7
tives did not benefit the reaction. As described in our pre-
liminary report,4b synthesis of 5 was then completed
(Scheme 4) by one-carbon homologation of the pinacol
boronate 23, followed by conversion to the requisite pro-
panediol derivative. Truncation of the synthetic route to 5
will be presented in Scheme 9 (vide infra).
yield
ee
entry
aldehyde
time
product
(%)b (%)c
8
9
Scheme 4. Conversion of trans cyclopropane to syn
homocrotylation reagent 5
32a
32b
32c
1
3 h
3 h
93
87
98
96
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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31
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46
47
48
49
50
51
52
53
54
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56
57
58
59
60
2
3
3 h
92
56
98
98
32d
4
11 h
32e
32f
32g
5
6
7
3 h
50 min
1 h
91
82
90
98
98
98
Scheme 5. Cyclopropanation of cis propenyl-
boronates and preparation of anti homocrotylation
reagent 6
32h
8
9
2 h
23 h
66 (99) 98
76 (96) 96
32i
32j
10
30 min
74
95
aReaction conditions: 3 equiv. of 6, 1.5 equiv. of PhBCl2,
b
1 equiv. aldehyde and 6 equiv. of K2CO3 (s). Isolated yields,
with NMR yields in parenthesis in the case of volatile prod-
ucts. ee’s were measured by chiral HPLC. dr’s > 20:1 by H
NMR for all entries.
c
1
Anti Homocrotylation of aliphatic aldehydes. With
optically pure cis boronate 6 in hand, asymmetric anti
homocrotylation was tested on a range of simple aliphatic
aldehydes. In the presence of PhBCl2 activator and solid
K2CO3 acid scavenger, we were pleased to see that the
desired anti products 32a-j were obtained in excellent
yields and uniformly high enantio- and diastereoselectivi-
ty (Table 3). The reaction conditions are compatible with
ester (entry 3), silyloxy (entry 6), and alkyne functionali-
ties (entry 10), as well as enolization-prone aldehyde 1b
(entry 2), and branched substrates (entries 7-9). The low-
er yield observed with substrate 1d (entry 4) is potentially
due to deactivation of the PhBCl2 promoter by the more
strongly Lewis basic amide group, which is also consistent
with the markedly longer reaction time required for this
substrate. Overall, these results are significant in that no
other method can provide optically active anti products
32a-j from aldehydes in a single step. These results com-
plement the equally selective syn homocrotylations re-
ported in our preliminary communication (Table 4).4b
After obtaining 5, we next turned to synthesis of 6, start-
ing with cyclopropanation of cis propenylboronate 2612
(Scheme 5). Pleasingly, the cyclopropanation under con-
ditions optimized for trans boronate 20c occurred with
equally high stereoselectivity (98 % de) in the case of 26.
Analogous homologation and diol exchange then afforded
optically pure anti homocrotylation reagent 6 (Scheme 5).
Interestingly, the opposite cyclopropane configuration
was obtained when Z-crotylboronate 30 was cyclopro-
panted under the same conditions, albeit the level of ste-
reoselectivity was less useful (80 % de).
Table 4 Syn homocrotylation of aliphatic aldehydesa
Table 3. Anti homocrotylation of aliphatic aldehydesa
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ee
yield
ee
yield
(%)b
entry
aldehyde
time product
entry
8
aldehyde
time product
(%)b (%)c
(%)c
1
2
3
4
5
6
7
8
1d
2
14 h
14 h
33a
33b
83
82
97
97
1 h
1 h
33k
33l
93
93
85
68
53
54
97
9
10
11
97
97
95
96
97
3
14 h
33c
89
97
15
min
4
5
6
7
14 h
14 h
50 h
7 d
33e
33g
33h
33i
89
89
97
97
33m
33n
33o
33p
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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37
38
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40
41
42
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44
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
min
72 (83) 98
62 (84) 98
10
min
12
13
aReaction conditions: 3 equiv. of 5, 1.5 equiv. of PhBCl2,
1 equiv. aldehyde and 6 equiv. of K2CO3 (s). Isolated yields,
b
35
with NMR yields in parenthesis in the case of volatile prod-
mine
c
1
ucts. ee’s were measured by chiral HPLC. dr’s > 20:1 by H
NMR for all entries. dThis reaction completed in 2 h.
aReaction conditions: 3 equiv. of 5 or 6, 1.5 equiv. of PhBCl2,
1 equiv. aldehyde and 6 equiv. of K2CO3. bIsolated yields. cee’s
were measured by HPLC using a chiral stationary phase. In
entries 1-6, no syn diastereomers were detected. In entries 8-
13, no anti diastereomers were detected. The values in paren-
Table 5. Homocrotylation with aromatic aldehydesa
d
theses are dr, measured by NMR. Rac-6 was used. Pentane,
4:1 pentane/DCM and 1:4 pentane/DCM gave the same mix-
ture. eThis reaction was run at 0 °C.
Homocrotylation of aromatic aldehydes. The homo-
crotylation of aromatic aldehydes 1k-q (Table 5) was also
explored. Aromatic substrates reacted very rapidly, giving
good yields as long as reactions were quenched shortly
after full conversion. In nearly all cases, diastereo- and
enantioselectivities were as high as with aliphatic sub-
strates. Highest yields were obtained with substrates
bearing strongly electron-withdrawing substituents (en-
tries 1-3, 8-10). The potentially chelating ortho nitro group
was also well tolerated (entry 2 and 9). Moreover, benzal-
dehyde (entry 4 and 11) and moderately electron rich o-
tolualdehyde (entry 6 and 13) were homocrotylated in
acceptable yields. However, homocrotylation of the very
electron rich p-anisaldehyde (entry 7) afforded a ~1:1 mix-
ture of syn and anti products after purification. GC-MS
yield
(%)b
ee
entry
1
aldehyde
time product
(%)c
1 h
1 h
32k
32l
95
94
95
73
98
98
98
95
98
98
2
3
15
min
32m
32n
32o
32p
15
min
4
5
6
10
min
66
Scheme 6. Benzylic chloride from homocrotylation of
electron rich aldehyde 1q
15
min
52
90
45
min
7d
32q/33q
N.D.
(1:1
syn/anti)
Scheme 7. Reagent-controlled additions to stereogenic α- and β- substituted aldehydesa,b
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Me
O
B
1
2
3
4
5
6
7
8
9
Me
Me
RO
OH Me
6
O
O
B
OH Me
PhBCl2,
Ph
6
O
Ph
Me
:
K2CO3(s)
PhBCl2,
K2CO3(s)
44
45
46
47
sa (R = TIPS) 33 %, >50:1 dr
sa (R = Ac) 58 %, >20:1 dr
sa (R = Piv) 60 %, >20:1 dr
sa (R = Bz) 73 %, 19:1 dr
37sa
Me
Me
:
:
:
77 %, >50:1 dr
O
O
O
O
B
B
OH Me
-6
ent
O
RO OH Me
6
ent-
O
Ph
Ph
RO
O
O
37
aa
73 %, 26:1 dr
Ph
Me
Ph
Me
:
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
44
aa (R = TIPS) 39 %, >50:1 dr
Me
Me
B
OH Me
Me
Me
36
47aa (R = Bz): 65 %, 19:1 dr
RO OH Me
5
O
Me
Me
B
40: R = TIPS
5
O
37
ss
41
: R = Ac
42
: R = Piv
43
: R = Bz
Me
83 %, >20:1 dr
Ph
O
B
Me
:
OH Me
-5
ent
44
ss (R = TIPS) 22 %, >50:1 dr
O
Ph
O
47ss (R = Bz): 76 %, 20:1 dr
RO OH Me
B
37as
Me
-5
ent
O
78 %, >20:1 dr
Ph
Me
:
44
47
as (R = TIPS) 52 %, >50:1 dr
as (R = Bz) 62 %, 23:1 dr
:
Me
Me
OH Me
O
O
B
B
OH Me
Me
RO
6
6
O
O
Et
PhBCl2,
K2CO3(s)
PhBCl2,
K2CO3(s)
39sa
76 %, >50:1 dr
50
51
:
sa (R = TBDPS) 41 %, >50:1 dr
Me
Me
c
Me
:
sa (R = Bz) 60 %, 45:1 dr
O
O
O
O
OH Me
Me
B
B
OH Me
-6
6
ent
ent-
O
O
Et
Et
39
aa
O
O
RO
Me
50
51
:
aa (R = TBDPS) 54 %, 35:1 dr
68%, >50:1 dr
Et
Me
c
:
aa (R = Bz) 69 %, 16:1 dr
Me
Me
B
Me
Me
B
OH Me
Me
RO
OH Me
5
5
O
O
38
48:
49c:
R = TBDPS
Me
39
ss
76 %, >50:1 dr
R = Bz
Me
RO
50
51
:
ss (R = TBDPS) 44 %, >50:1 dr
O
O
c
B
:
ss (R = Bz) 63 %,19:1 dr
B
OH Me
-5
-5
ent
ent
O
OH Me
Me
O
Et
39as
Me
81 %, >50:1 dr
RO
50
51
:
as (R = TBDPS) 63 %, >50:1 dr
c
:
as (R = Bz) 69 %, 21:1 dr
aReaction conditions: 3 equiv. of 5 or 6, 1.5 equiv. of PhBCl2, 1 equiv. aldehyde and 6 equiv. of K2CO3. dr's were measured on
b
crude products prior to chromatography, using the following mehods: RP-HPLC for all 37, 47, 51, GC for all 39, 44,and 50, and 1H
c
NMR for 45, 46. See Supporting Information for details. For reactions 49 → 51, the actual aldehyde and boronates used, and
product structures produced, are the enantiomers of those depicted in this scheme.
analysis revealed that the crude reaction product from
homocrotylation of 1q was largely benzylic chloride 35,
likely resulting from SN1 decomposition of 34, the homo-
crotylation product prior to aqueous workup (Scheme 6);
alcohols 32q/33q were then produced by hydrolysis of 35
during chromatography on alumina.13
was next attempted with α- and β-silyloxy-substituted
aldehydes 40 and 48. Again, complete reagent control of
stereochemistry was observed in all cases, but yields were
low to modest, owing to competing desilylation and β-
elimination. Although silyl protection is effective at posi-
tions remote from the carbonyl (Table 3, entry 6), posi-
tions closer to the carbonyl are apparently more sensitive.
However, acetate, pivaloate, and particularly benzoate
ester protection proved much more robust at these posi-
tions, affording good yields of products 45-47 and 51
without a significant decrease in selectivity.
Double diastereoselection studies. We next studied
the selectivity conferred by reagents 5/ent-5 and 6/ent-6
in the presence of preexisting aldehyde stereochemistry
(Scheme 7). For all aldehydes tested, either Felkin
(syn/anti) or anti-Felkin (anti/anti) products could be
obtained in high selectivity by choice of 6 or ent-6. To-
gether with syn homocrotylation reagents 5,4b our reagents
6/ent-6 now provide reagent-controlled access to all possi-
ble stereotriads in products 37 and 39. Homocrotylation
Formal synthesis of (−)-spongidepsin. The utility of
reagents 5 and 6 was next demonstrated in a short formal
synthesis of spongidepsin (52), a cytotoxic natural prod-
uct isolated from the Vanuatu marine sponge Spongia sp.
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(Scheme 8).6 All previous syntheses3,15 have proceeded
intermediate 62, whose spectroscopic data were identical
to those previously reported.
1
2
3
4
5
6
7
8
through intermediates 53, 54, and 32f (or epi-32f), assem-
bling these pieces by a combination of esterification, am-
ide bond formation and metathesis. However, in all of
these studies, stereospecific preparation of 54 and
32f/epi-32f has required very lengthy synthetic sequences
(7-12 steps from commercial material for 54 and 8-14 steps
for 32f). In the present case, both 32f and 54 should be
accessible in a straightforward manner by asymmetric
anti and syn homocrotylation of 1f and 55, respectively.
Anti-homocrotylation of 1f3c with 6 (see Table 3, entry 6)
afforded 32f directly in 82 % yield and 98 % ee, as a single
diastereomer. Acid 54 was then prepared from acetalde-
hyde (55). Despite the small size of acetaldehyde, syn ho-
mocrotylation using ent-5 proceeded with undiminished
diastereoselectivity to afford exclusively syn alcohol 56
in78 % yield and 98 % ee. Mesylation, cyanide
Scheme 9. First versus second generation routes to 5
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Formal synthesis of (−)-spongidepsin
Improved large-scale route to homocrotylation rea-
gents 5 and 6. Our original route to 5 (Scheme 9), was
sufficient to yield several grams of reagent, but included
several unnecessary interchanges of the boronate ester
diol, merely to facilitate purification steps (recrystalliza-
tion of 65 and chromatography of 23, 24) which turned
out to be unnecessary. In our 2nd-generation streamlined
route, crude propenylboronic acid 64 from hydroboration
of propyne18 was condensed with diol 19,19 and the result-
ing unpurified 20c could be cyclopropanated directly,
followed by treatment with propanediol to yield boronate
66.20 Propanediol treatment is also accompanied by pre-
cipitation of 19, allowing most of the auxiliary to be re-
covered. Finally, one-carbon homologation of 66 afforded
5 (17 g, 51 % overall yield) after distillation, the only puri-
fication step in the sequence.
In the large scale preparation of 6, the only substantially
different step was preparation of the cis boronic acid 68.21
Lithiation of cis-1-bromopropene 67 under Whitesides
conditions,22 followed by trapping the intermediate cis-
propenyl lithium with B(OiPr)3, hydrolysis and condensa-
tion with 19 gave boronate 26 with >25:1 Z/E selectivity.
Subsequent steps were analogous to preparation of 5.
Large-scale cyclopropanation20 of 26 and subsequent diol
displacement,16 and hydrolysis of the resulting nitrile17
afforded optically pure 54. Fragments 32f and 54 were
then combined with commercial phenylalanine derivative
53, according to Negishi’s procedures,3c to yield advanced
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exchange and homologation afforded 6 (16 g, 51 % overall
yield) after distillation.
1
2
3
REFERENCES
Scheme 10. Second generation route to 6
(1) For reviews on allylation: (a) Yamamoto, Y.; Asao, N.
Chem. Rev. 1993, 93, 2207-2293; (b) Denmark, S. E.; Fu, J. Chem.
Rev. 2003, 103, 2763-2794; (c) Lachance, H.; Hall, D. G. In
Organic Reactions; John Wiley & Sons, Inc.: 2009. For seminal
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Angew. Chem. Int. Ed. Engl. 1979, 18, 306-307; (e) Hoffmann, R.
W.; Zeiss, H. J. J. Org. Chem. 1981, 46, 1309-1314; .
(2) Enantioselective homoallylation: (a) Weber, B.; Seebach,
D. Tetrahedron 1994, 50, 7473-7484; Enantioselective delivery of
homoallyl fragments with specialized substituents: (b) Yang, Y.;
Zhu, S.-F.; Duan, H.-F.; Zhou, C.-Y.; Wang, L.-X.; Zhou, Q.-L. J.
Am. Chem. Soc. 2007, 129, 2248-2249; (c) Saito, N.; Kobayashi,
A.; Sato, Y. Angew. Chem. Int. Ed. 2012, 51, 1228-1231. For an
excellent general method to produce racemic anti 3, see (d)
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(3) (a) Ghosh, A. K.; Xu, X. Org. Lett. 2004, 6, 2055-2058;
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Am. Chem. Soc. 2013, 135, 82-85; (c) Dugas, G. J.; Lam, Y.-h.;
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(5) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957,
79, 1920-1923.
4
5
6
7
8
9
O
O
NMe2
NMe2
1) Li, -30 °C
2) B(OiPr)3
19
, MgSO4
Me
O
B
Me
Br
Me
B(OH)2
3) HCl
O
67
26
68
>25:1 Z/E
Et2Zn, CH2I2
19
0.5 equiv.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
LiCH2Cl
DCM, -78 °C
Me
O
O
B
B
O
51 % overall
from
6
O
then
, Et2O
OH OH
69
94 % ee
67
19
Distillation
16 g
CONCLUSION
We have described the large-scale enantioselective prepa-
ration of asymmetric homocrotylation reagents 5 and 6,
and explored the scope their addition to a range of ali-
phatic and aromatic aldehydes including examples of
double diastereoselection. The utility of this chemistry
has been demonstrated in a very concise formal synthesis
of (−)-spongidepsin, which could be readily be altered to
provide materials for synthesis of any diastereomer of the
natural product. Further studies to explore alternative
boronate substitutions and other substrate classes, as well
as development of milder and potentially enantioselective
catalysts are under way and will be reported in due
course.
(6) Grassia, A.; Bruno, I.; Debitus, C.; Marzocco, S.; Pinto, A.;
Gomez-Paloma, L.; Riccio, R. Tetrahedron 2001, 57, 6257-6260.
(7) For reviews, see (a) Salaun, J. Chem. Rev. 1989, 89, 1247-
1270; (b) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911-
936; (c) Kirmse, W. Angew. Chem. Int. Ed. 2003, 42, 1088-1093;
(d) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem.
Rev. 2003, 103, 977-1050;
(e) Hansen, J.; Davies, H. M. L.
Coordination Chemistry Reviews 2008, 252, 545-555;
Pellissier, H. Tetrahedron 2008, 64, 7041-7095.
(f)
ASSOCIATED CONTENT
Supporting Information
(8) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am.
Chem. Soc. 1998, 120, 11943-11952.
(9) Li, J.; Burke, M. D. J. Am. Chem. Soc. 2011, 133, 13774-
13777.
Procedures for preparation of all new compounds, together
with characterization data and NMR spectra. This material is
available free of charge via the Internet at
http://pubs.acs.org.
(10) (a) Luithle, J. E. A.; Pietruszka, J. Liebigs Annalen 1997,
1997, 2297-2302; (b) Pietruszka, J.; Widenmeyer, M. Synlett
1997, 977-979; (c) Luithle, J. E. A.; Pietruszka, J.; Witt, A. Chem.
Commun. 1998, 2651-2652; (d) Luithle, J. E. A.; Pietruszka, J. J.
Org. Chem. 1999, 64, 8287-8297; (e) Luithle, J. E. A.; Pietruszka,
J. Eur. J. Org. Chem. 2000, 2000, 2557-2562.
(11) (a) Zhou, S.-M.; Deng, M.-Z.; Xia, L.-J.; Tang, M.-H.
Angew. Chem. Int. Ed. 1998, 37, 2845-2847; (b) Chen, H.; Deng,
M.-Z. Org. Lett. 2000, 2, 1649-1651. (c) For an earlier use of the
same auxiliary with Zn(Cu) couple, see Imai, T.; Mineta, H.;
Nishida, S. J. Org. Chem. 1990, 55, 4986-4988.
AUTHOR INFORMATION
Corresponding Author
kraussi@brandeis.edu
Author Contributions
†These authors contributed equally to this work.
Notes
(12) See Scheme 10 for synthesis of 27.
The authors declare no competing financial interests.
(13)
elimination.
(14) Yamamoto, Y.; Maruyama, K. J. Am. Chem. Soc. 1985,
107, 6411-6413.
(15) (a) Chen, J.; Forsyth, C. J. Angew. Chem. Int. Ed. 2004,
43, 2148-2152; (b) Chandrasekhar, S.; Yaragorla, S. R.;
Chromatography of 35 on silica gel resulted in
ACKNOWLEDGMENT
We thank Dr. Wenbo Pei and Ms Gabrielle J. Dugas for valu-
able discussions. I.J.K gratefully acknowledges the generous
financial support of Brandeis University, the Donors of the
American Chemical Society Petroleum Research Fund (51975-
DNI), and the National Science Foundation CAREER pro-
gram (CHE-1253363).
Sreelakshmi, L.; Reddy, C. R. Tetrahedron 2008, 64, 5174-5183.
(16) Hasegawa, T.; Kawanaka, Y.; Kasamatsu, E.; Ohta, C.;
Nakabayashi, K.; Okamoto, M.; Hamano, M.; Takahashi, K.;
Ohuchida, S.; Hamada, Y. Org. Process Res. Dev. 2005, 9, 774-
781.
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(17) Rössle, M.; Del Valle, D. J.; Krische, M. J. Org. Lett. 2011,
13, 1482-1485.
(18) Trans-propenylboronic acid (64) is commercially
available, but very expensive ($200/gram from Sigma-Aldrich).
By contrast, it is prepared from propyne by this route at a
materials cost of about $13/gram.
(19) D- and L- tartaramide diols (19) are available from Sig-
ma-Aldrich for $15/gram and $7/gram respectively, but can be
prepared from dimethyl tartrate and dimethylamine at a materi-
als cost of about $1/gram and 60¢/gram, respectively, by the
following procedure: Seebach, D.; Kalinowski, H.-O.; Langer, W.;
Crass, G.; Wilka, E.-M. Org. Syn. 1983, 61, 24.
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5
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17
18
19
20
21
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25
26
27
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31
32
33
34
35
36
37
38
39
40
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43
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45
46
47
48
49
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51
52
53
54
55
56
57
58
59
60
(20) It is noted that large-scale (~200 mmol) cyclopropana-
tions of 20c and 26 proceeded with slightly diminished stereose-
lectivity – 94 % compared with 97-98 % for reactions performed
on ~30 mmol scale. Nevertheless the selectivity obtained is syn-
thetically useful and further optimization of this procedure is
part of ongoing efforts.
(21) Cis-propenylboronic acid (67) is commercially available,
but very expensive ($60/gram from Sigma-Aldrich); however, it
is prepared from cis-propenylbromide by this route at a materi-
als cost of about $11/gram.
(22) Whitesides, G. M.; Casey, C. P.; Krieger, J. K. J. Am.
Chem. Soc. 1971, 93, 1379-1389.
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