Development of a double allylboration reagent targeting 1,5-syn-(E)-diols: Application to the synthesis of the C(23)-C(40) fragment of tetrafibricin

Tetrahedron 67 (20 1 1 ) 6497e6512

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Development of a double allylboration reagent targeting 1,5-syn-(E)-diols:

application to the synthesis of the C(23)eC(40) fragment of tetraﬁbricin

*

Philippe Nuhant, Jeremy Kister, Ricardo Lira, Achim Sorg, William R. Roush

Departments of Chemistry, The Scripps Research Institute, Florida, 130 Scripps Way, Jupiter, FL 33458, USA

a r t i c l e i n f o

a b s t r a c t

Article history:

Interest in the synthesis of the C(23)eC(40) fragment 2 of tetraﬁbricin prompted us to develop a new

method for the synthesis of 1,5-syn-(E)-diols. Toward this end, the kinetically controlled hydroboration of

allenes 6, 33, ent-39, 42, and 45 with the Soderquist borane 25R were studied. Tetrabutylammonium

allenyltriﬂuoroborate 45 gave superior results and was utilized in a double allylboration sequence with

two different aldehydes to provide the targeted 1,5-syn-(E)-diols in generally high yields (72e98%), and

with high enantioselectivity (>95% ee), diastereoselectivity (dr >20:1), and (E)/(Z) selectivity (>20:1).

This new method was applied to the synthesis of the C(23)eC(40) fragment 2 of tetraﬁbricin.

Received 23 March 2011

Received in revised form 1 June 2011

Accepted 2 June 2011

Available online 13 June 2011

Keywords:

Studies on the synthesis of tetraﬁbricin

Double allylboration

Allene hydroboration

Kinetically controlled

Tetrabutylammonium allenyltriﬂuoroborate

Stereoselective synthesis of syn-1,5-E-diols

1. Introduction

Our group has developed several chiral 1,3-bifunctionalized allyl-

borane reagents,^8ceeand have successfully utilized these reagents

The 1,5-syn-(E)-diol substructure is found in a variety of natural

products.¹One of the strategies used to access 1,5-syn-(E)-diols,

developed by Cossy and co-workers in their work on the total

synthesis of tetraﬁbricin (Fig. 1), involves an iterative allyltitana-

tionecross metathesis-allyltitanation sequence.^2,3This strategy

provides the 1,5-syn-(E)-diol motif with good levels of diaster-

eoselectivity. In 2004, Leighton published a method for synthesis of

1,5-syn-(E)-diols via a unique intramolecular alkyne silylformyla-

tioneallylsilylation reaction sequence that proceeds in modest

yield and with modest diastereoselectivity.⁴A key sequence in

Nicolaou’s total synthesis of marinomycin A involved a Hor-

nereWadswortheEmmons oleﬁnation and a syn-reduction of the

carbonyl group that provided the 1,5-syn-(E)-diol unit with good

diastereoselectivity.⁵In 2010, Friestad published a method for

synthesis of the 1,5-(E)-diol unit of tetraﬁbricin involving the iter-

ative JuliaeKociensky oleﬁnation of chiral aldehydes using a chiral

in studies on the synthesis of polyhydroxylated natural products.⁹

We report herein the development of a new 1,3-bifunctionalized

allylborane reagent that enables the targeted 1,5-syn-(E)-diol motif

to be synthesized with excellent stereochemical control. We dem-

onstrate the utility of this new method in the synthesis of the

C(23)eC(40) fragment of tetraﬁbricin (1).

Fig. 1. Tetraﬁbricin (1).

a

-silyloxy-g

-sulfononitrile.⁶As an alternative, we anticipated that

use of a bifunctionalized allylmetal reagent could provide conve-

nient, one-pot access to the 1,5-syn-(E)-diol motif.⁷Only a few

chiral bifunctionalized allylmetal reagents have been reported that

provide a high level of stereochemical control in such processes.⁸

2. Background

2.1. Studies on the synthesis of tetraﬁbricin

The present research was motivated by our interest in the

synthesis of tetraﬁbricin, and especially the C(23)eC(40) fragment

2 (Scheme 1). Tetraﬁbricin (1) is a structurally unique natural

* Corresponding author. Tel.: þ1 561 228 2450; fax: þ1 561 228 3052; e-mail

address: roush@scripps.edu (W.R. Roush).

doi:10.1016/j.tet.2011.06.008

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P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

product isolated in 1993 from Streptomyces neyagawaensis.¹⁰It

displays potent anti-aggregation properties against human plate-

lets by blocking the glycoprotein (GP)IIb/IIIa receptor on the

platelet surface, which is important for blood clotting.¹¹The ste-

reochemistry was assigned by Kishi based on ¹H NMR database

technology, including NMR measurements in chiral solvents.^1bThe

total synthesis of tetraﬁbricin has not yet been reported, which is

necessary to conﬁrm the relative stereochemistry assignment and

to set the stage for biological structure-function studies. Our group

reported the synthesis of the tetraﬁbricin C(1)eC(19) fragment,¹²

and contributions from several other laboratories have also

appeared.^2,6,13We recently published a preliminary communica-

tion describing the synthesis of the C(23)eC(40) fragment 2,¹⁴via

the fragment coupling of 3 and 4 with a new bifunctional allyl-

borane reagent. We provide herein the details of this effort, fo-

cusing on the studies leading to the development of the new double

allylborating agent.

Scheme 1. Retrosynthetic analysis of the C(23)eC(40) fragment 2 of tetraﬁbricin.

2.2. The double allylboration reaction

In 2002 our group reported highly diastereo- and enantiose-

lective syntheses of 1,5-anti-(E) (10) and 1,5-syn-(Z) (15) diols via

a double allylboration sequence (Scheme 2).^8c

Hydroboration of allenes 6^8cand 11^8cusing ^Ddiisopino-cam-

pheylborane (^DIpc₂BH)¹⁵provides the kinetic hydroboration prod-

ucts 7 and 12, which undergo rapid (Z) to (E) isomerization via

a [1,3]-boratropic shifts¹⁶to give the observed (thermodynamic)

allylboranes 8 and 13.

Scheme 2. Synthesis of 1,5-anti-(E) 10 and 1,5-syn-(Z) 15 diols via the double allyl-

boration reaction.

The allylboration reaction of these reagents with aldehydes

proceeds via chair-like transition states TS-1 or TS-3 to generate

and 18, respectively. Ifso, we expected (byanalogy totransitionstates

TS-2 and TS-4 in Scheme 2) that the subsequent allyboration of 16 or

18 would provide the 1,5-syn-(E)-diol 17 and 1,5-anti-(Z)-diol 19 with

synthetically useful selectivity (Scheme 3).

anti-

b

-alkoxyallylboronates 9 and 14, respectively. Treatment of

-alkoxyallylboronate 9 with a second aldehyde proceeds via

the chair-like transition state TS-2 with the methallylboronate a-

substituent in a pseudo-equatorial position. This leads to the for-

mation of the 1,5-anti-diol 10 with an intervening (E)-oleﬁn.

However, due to severe steric interactions the

a-substituent in

methallylboronate 14 occupies a pseudo-axial position in the sec-

ond allylboration transition state TS-4, leading to the formation of

the 1,5-syn-diol 15 with an embedded (Z)-oleﬁn. Accordingly, we

turned our efforts to the synthesis of the 1,5-syn-(E)-diol conﬁgu-

ration, which is not accessible via these ﬁrst-generation double

allylboration reactions, but which is required for the synthesis of

the C(23)eC(40) fragment of tetraﬁbricin.

3. Results and discussion

3.1. Initial attempts to extend the double allylboration

reaction to the synthesis of 1,5-syn-(E)-diols 17 via kinetically

controlled hydroboration of allenylboronates with Ipc₂BH

Scheme 3. 1,5-syn-(E)-diol 17 and 1,5-anti-(Z)-diol 19.

Accordingly, we attempted to generate (Z)-allylborane 21 via the

kinetic hydroboration of allene 20 with ^LIpc₂BH¹⁵under a range of

reaction conditions (including variations of the solvent, reaction

temperature, and time), including the use of Wilkinson’s catalyst to

We anticipated that if the [1,3]-boratropic shifts¹⁶of 7 and 12

could be prevented by performing the hydroboration of 6 or 11 at low

temperatures, we could access to the syn-b-alkoxyallylboronates 16

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

6499

perform the hydroboration at low temperature.¹⁷However, when

the reagent generated under these conditions was treated with

hydrocinnamaldehyde at ꢀ78 ^ꢁC, the targeted 1,5-syn-(E)-diol ent-

17a was consistently the minor product and was not obtained with

acceptable selectivity (Scheme 4 and Table 1).

Scheme 5. B-Crotyl-10-TMS-9-borabyciclo[3.3.2]decanes (Z)-23 and (E)-24 undergo

(Z) to (E) isomerization slowly at 25 ^ꢁC in CDCl₃.

This observation suggested that it might be possible to slow the

isomerization of 7 to 8, or of 12 to 13 (Scheme 2) by replacing Ipc₂BH

in the hydroboration step with the Soderquist borane, 10-TMS-9-

borabyciclo[3.3.2]decane hydride (TBBD-H; 25). If this hypothesis

was conﬁrmed, it would allow us to access the 1,5-syn-(E)-diol 17

starting from allene 6 and the 1,5-anti-(Z)-diol 19 starting from the

allene 11 with the tetraphenylethylene glycol boronate ester.

We began by studying the hydroboration of allene 11 with the

Soderquist borane 25, en route to the 1,5-anti-(Z)-diol ent-19. The

unstable TBBD-H 25R^8d,20,21was generated in situ from the borohy-

dride 26R (which we store in a glove box) by treatment with TMSCl.

The resulting solution of borane 25R was then treated with allene 11

at ꢀ10 ^ꢁC for 5 h. At that point, the solution of in situ generated reagent

27 was subjected to a standard double allylboration protocol, in-

volving treatment of 27 with an aldehyde (R¹CHO) at ꢀ78 ^ꢁC typically

for 4e12 h and thenwith a second aldehyde (R²CHO) at 0 ^ꢁCe20^ꢁC for

12e24 h. Pleasingly, this protocol provided 1,5-anti-(Z)-diols ent-19 in

67e86% yields, with ca. 12e13:1 diastereoselectivity and with

94e96% enantiomeric excess (% ee) (Scheme 6).^8d

Scheme 4. Studies of the kinetic hydroboration reaction of allene 20 with ^LIpc₂BH.

Table 1

Results of hydroborationeallylboration of allene 20 with ^LIpc₂BH^a

Entry

Catalyst

T (^ꢁC)

Time

Ratio ent-17a/

Yield^d

(%)

ent-10a^b/ent-19g^c

1

2

3

None

(Ph₃P)₃

RhCl (5%)

ꢀ20

ꢀ30

ꢀ78

30 min

1 h

4 h

1:11:1

1:6.2:0.8

1:0.9:1.2

40

36

17

a

Hydroboration reactions of 20 were performed in THF at the indicated tem-

peratures and times. The resulting allylborane was then treated with hydro-

cinnamaldehyde as speciﬁed in Scheme 4 to give the indicated products.

b

Product ratio determined by ¹³C NMR analysis.

c

Product ratio determined by ¹H NMR analysis.

d

Isolated yields.

When the hydroboration reaction of 20 was performed at ꢀ20 ^ꢁC

for 30 min followed by treatment with hydrocinnamaldehyde at

ꢀ78 ^ꢁC, a mixture of the 1,5-syn-(E)-diol ent-17a, the 1,5-anti-(E)-diol

diastereomer ent-10a, and the 1,5-anti-(Z)-diol 19g were obtained

with 1:11:1 selectivity, with favor of ent-10a predominating (entry 1,

Table 1). This result can be explained by a rapid [1,3]-boratropic

shift¹⁶that converts 21 to 22. This isomerization also occurred rap-

idly at ꢀ30 ^ꢁC (entry 2), as the hydroboration performed at this

temperature resulted in a 1:6.2:0.8 mixture of products, again fa-

voring the 1,5-anti-(E)-diol ent-10a. Allene hydroboration experi-

ments performed using Wilkinson’s catalyst at ꢀ78 ^ꢁC (entry 3) gave

a somewhat improved ratio of ent-17a to ent-10a, however the ratio

these two diols was only ca.1: 1, and a comparable amount of ent-19g

was also obtained. These experiments were compromised by the

poor solubility of ^LIpc₂BH especially at low temperatures, resulting in

incomplete conversion and poor overall yields.

3.2. Synthesis of 1,5-anti-(Z)-diols via the kinetically

controlled hydroboration of 11 using Soderquist’s borane

The inability to generate the bis-boryl reagent 21 with accept-

able selectivity for use as a precursor to 1,5-syn-(E)-diols ent-17a

prompted us to reevaluate our strategy. It was apparent from the

results in Table 1 that we needed to identify a chiral dialkylborane

for the allene hydroboration reaction such that the kinetic allylic

borane products would undergo the 1,3-boratropic shift very

slowly, if at all. Soderquist had published a series of papers in which

allylboration reactions were performed with crotylboranes con-

taining the 10-TMS-9-borabycyclo[3.3.2]decane auxiliary (TBBD).¹⁸

These reagents demonstrated remarkable stability toward thermal

isomerization:¹⁹the (Z)-crotyl-TBBD 23 isomer is reported to

isomerize to (E)-crotyl-TBBD 24 with a half-life of approximately

one week at room temperature (Scheme 5).

Scheme 6. Synthesis of 1,5-anti-(Z)-diols ent-19aef using TBBD-H and allene 11.

3.3. Studies of the kinetically controlled hydroboration of

2-allenyl-(1,3,2)-dioxaborinane 6 with the Soderquist borane

In view of the success demonstrated in Scheme 6 for the highly

stereoselective synthesis of 1,5-anti-(Z)-diols ent-19 via the kinet-

ically controlled hydroboration of 11 using the Soderquist borane

25,^8dwe attempted to extend this chemistry to the kinetically

controlled hydroboration of allene 6. Based on the examples sum-

marized in Scheme 2 for reagent 8,^8cwe expected that double

allylborations of 28 (Scheme 7) would provide the targeted 1,5-syn-

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P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

(E)-diols ent-17a with synthetically useful selectivity, assuming that

the hydroboration of 6 proceeded with kinetic control as demon-

strated in Scheme 6 for 11. Accordingly, studies of the hydroboration

of 6 were initiated with the experiments summarized in Scheme 7.

For these initial studies, the stereoselectivity of the hydroboration

was assessed by subjecting the derived allylboranes 28/29 to an

allylationeoxidation sequence with benzaldehyde, which provided 30

and its anti diastereomer 31.

This result (which is consistent with the results presented in

Scheme 4) indicated that there was incomplete control of the

transition states, with ca. 80% of the product (ent-17b) deriving

from TS-5, and the remaining ca. 20% deriving from TS-6. While the

reasons for the poor stereoselectivity of this transformation are not

certain, it is conceivable that non-bonded interactions between the

(1,3,2)-dioxaborinane unit and the group

a to boron might de-

stabilize TS-5 compared to TS-6, which are diastereomeric to TS-2

and TS-4 in Scheme 2 (discounting the differences in the structures

of the Ipc₂Bdunit in TS-2/TS-4 and the TBBD unit in TS-5/TS-6).

We attempted to improve the reaction diastereoselectivity by

changingthereactionsolventand usinghydrocinnamaldehydeasthe

substrate (Scheme 9). However, these experiments resulted in sig-

niﬁcant erosion of the reaction diastereoselectivity, compared to the

results summarized in Scheme 8 for reactions performed in CH₂Cl₂.

OH

(1.3 equiv)

H

O

1)

O

B

H

ent-17a

OH

6

B

H

-10 ^oC, 1 h

Me₃Si

Solvent

2) PhCH₂CH₂CHO (0.7 equiv)

-78 ^oC, 4 h

25R

OH

3) PhCH₂CH₂CHO (1.5 equiv)

-78 ^oC to r.t., 12 h

4) ethanolamine

ent-19g

Scheme 7. Hydroboration studies with TBBD-H 25R and allene 6.

Best results were obtained when the hydroboration reaction of 6

was performed at ꢀ10 ^ꢁC for 1 h with the Soderquist borane 25R

(entry 1, Scheme 7). This resulted in the formation of syn diol 30

with 10:1 diastereoselectivity. However, increasing the reaction

time from 1 h to 5 h led in an erosion of the diastereoselectivity,

with the 1,2-syn-diol 30 being favored by only 1.5:1 over its anti

diastereomer (entry 2). This result indicates that the [1,3]-

Scheme 9. Attempted optimization of the double allylboration sequence using TBBD-

H 25R, allene 6, and hydrocinnamaldehyde.

boratropic rearrangement¹⁶of the kinetically formed (Z)-

g-boryl

These results prompted us to abandon studies of allene 6 as

a precursor to the targeted 1,5-syn-(E)-diols ent-17a, and to explore

other options for their synthesis.

allylborane 28 occurs rapidly at ꢀ10 ^ꢁC to give the thermody-

namically favored (E)-g-boryl allylborane 29. Thus, control of the

reaction time and temperature for the hydroboration reaction of 6

is crucial.

By using the conditions for the hydroboration of 6 deﬁned in

Scheme 7, we examined the double allylboration sequence of 28

using benzaldehyde and hydrocinnamaldehyde (Scheme 8). This

experiment provided the targeted 1,5-syn-(E)-diol ent-17b as the

major product in 95% ee, but as a ca. 4:1 mixture with the 1,5-anti-

(Z)-isomer ent-19a.

3.4. Diisopropyl allenylboronate 33 as a possible precursor to

1,5-syn-(E)-diols ent-17a

In view of our speculation that non-bonded interactions in-

volving the (1,3,2)-dioxaborinane unit of 32 might contribute to the

destabilization of TS-5 (Scheme 8), we decided to examine alle-

nylboronate 33 with a conformationally ﬂexible diisopropylboro-

nate ester as the starting point for these experiments. The

hydroboration reaction of 33 with the Soderquist borane 25R was

optimized by using an allylationeoxidation sequence with benzal-

dehyde similar to the one described with the allene 6 (Scheme 10).

Scheme 8. Double allylboration sequence using TBBD-H 25R, allene 6, benzaldehyde

Scheme 10. Studies of the kinetic hydroboration of allene 33 with TBBD-H 25R.

and hydrocinnamaldehyde.

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

6501

A 5.3:1 mixture of 1,2-syn-diol 30 and the 1,2-anti diastereomer

31 was obtained when the hydroboration of 33 with 25R was

performed at ꢀ10 ^ꢁC for 1 h (entry 1, Scheme 10). Increasing the

hydroboration time from 1 h to 2 h led to a slightly decreased

diastereoselectivity (4.3:1 favoring 30, entry 2). This result suggests

that the [1,3]-boratropic rearrangement¹⁶of the kinetically formed

enantiomer ent-39 with TBBD-H 25R, followed by double allyl-

boration with the second allylboration step performed in the

presence of a Lewis acid, was expected to proceed via a transition

state similar to TS-7 to give the targeted 1,5-syn-(E)-diols ent-17a.

Accordingly, we optimized the hydroboration reaction by

using an allylationeoxidation sequence with benzaldehyde

(Scheme 13).

(Z)-g-boryl allylborane 34 to the (E)-g-boryl allylborane 35 is

competitive with the hydroboration at ꢀ10 ^ꢁC. The optimal dia-

stereoselectivity was obtained by performing the hydroboration at

ꢀ20 ^ꢁC for 1 h (entry 3). By using these optimized hydroboration

conditions, the double allylboration sequence using hydro-

cinnamaldehyde leading to 1,5-syn-(E)-diol ent-17a was examined

(Scheme 11). Unfortunately, the product was obtained with only

2.7:1 diastereoselectivity (ratio of ent-17a/ent-19g). Once again, it

became necessary to explore alternative strategies to improve the

diastereoselectivity of the second step of the double allylboration

sequence leading to ent-17a.

Scheme 11. Double allylboration sequence using allene 33, TBBD-H 25R, and

hydrocinnamaldehyde.

3.5. Studies of the kinetic hydroboration and allylboration

reactions of pinanediol allenylboronates 39 and ent-39

Scheme 13. Studies of the hydroborationeallylboration reactions of allenes 39 and

ent-39.

An (E)-selective allylboration of aldehydes leading to (E)-5-

hydroxy-2-pentenes 37 was developed in our laboratory (Scheme

12),²²via the BF₃$OEt₂promoted reaction of the

a-alkyl allylboro-

nate 36 with aldehydes.²³Of the two possible transition states, TS-7

and TS-8, we suggested that the Lewis acid selectively coordinates

with the most accessible a-face lone pair of electrons on the oxygen

The hydroboration reaction of allene 39 with borane 25R at

0

^ꢁC for 2 h resulted in the formation of 30 in less than 30% yield

and with a diastereoselectivity of 3.2:1, but with excellent

enantioselectivity (96% ee) (entry 1, Scheme 13). The same re-

action was performed, switching the allene 39 for its enantiomer

ent-39 to determine if there is a double diasteroselection²⁴

component to the selectivity of the allylation reaction. This ex-

periment led to the formation of the diol 30 with 48% yield, 3.2:1

diastereoselectivity and 97% ee (entry 2). These results showed

that the chirality of the pinanediol moiety does not affect the

stereoselectivity of the steps leading to diol 30. Decreasing the

reaction time from 2 h to 40 min led to an improvement of the

diastereoselectivity, 8.1:1 in favor of the 1,2-syn-diol 30 (entry 3).

Performing the hydroboration reaction at ꢀ10 ^ꢁC for 1 h resulted

in an increase in the diastereoselectivity of the overall reaction

process leading to 30 (12:1) (entry 4). However, increasing the

reaction time from 1 h to 2 h resulted in a lower selectivity

(8.1:1) (entry 5). Use of hydrocinnamaldehyde in the allylbora-

atom distal to the angular methyl group to minimize steric in-

teractions. The alternative TS-8, in which the Lewis acid co-

ordinates with the

b-face oxygen non-bonded lone pair, is

disfavored due to a 1,3-syn-pentane interaction between the

pseudoaxial methyl group and the BF₃unit.

tion sequence gave diol 40 in 85% yield with

a diaster-

eoselectivity of 7.3:1 (entry 6). Unfortunately, when these

optimized hydroboration conditions were applied in a double

allylboration sequence using hydrocinnamaldehyde and BF₃$Et₂O

during the second allylboration reaction, the 1,5-syn-(E)-diol ent-

17a and 1,5-anti-(Z)-diol ent-19g were obtained in 83% yield but

with a disappointing 2.7:1 ratio favoring the (Z)-diol ent-19g

(Scheme 14). Attempts to increase the selectivity of the double

allylboration reaction by performing the second allylboration in

the presence of other Lewis or Brønsted acids (TiCl₄, SnCl₄,

Et₂AlCl, BCl₃, TfOH, TFA, Sc(OTf)₃) were unsuccessful.

Scheme 12. (E)-Selective Lewisacid mediatedallylborationof the methallylboronate36.

These results suggested that an analogous strategy might be

applicable to the synthesis of the targeted 1,5-syn-(E)-diols 17.

Thus, hydroboration of the pinanediol allenylboronates 39 or its

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P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

We ﬁrst studied the hydroboration of 42 with the Soderquist

borane 25R by using an allylboration sequence with hydro-

cinnamaldehyde. This provided the unstable syn- -alkoxyallylsta-

b

nnane 44a with >4:1 selectivity when the hydroboration reaction

was performed in dichloromethane at 0 ^ꢁC for 1 h. In order to conﬁrm

the stereochemistry of 44a, we performed a subsequent allylstan-

nation of 44a with benzaldehyde in presence of BF₃$Et₂O at ꢀ78 ^ꢁC

for 4 h, which resulted in the formation of a 4:1 mixture of the 1,5-

syn-(E)-diol ent-17c and 1,5-anti-(E)-diol ent-10c in 81% yield; the

enantiomeric purity of ent-17c was 94% ee (Mosher analysis). In an

attempt to improve the diastereoselectivity, we examined the in-

ﬂuence of the solvent on the reaction. When the hydroboration re-

action of 42 was performed in Et₂O, product ent-17c was obtained in

only 2% yield, but with >15:1 diastereoselectivity. When the reaction

was made in toluene, we obtained a 2:1 mixture of ent-17c and ent-

10c in 40% yield (entry 3, Scheme 15). We also examined other Lewis

acids, such as Ti(OiPr)₄/S-Binol,²⁷Yb(OTf)₃,²⁸ZnBr₂, AgOTf/S-Binap,²⁹

FeCl₃to improve the selectivity of the second allylstannation re-

action, but without success. These experiments resulted either in no

Scheme 14. Double allylboration sequence using allene ent-39, TBBD-H 25R, and

hydrocinnamaldehyde.

3.6. Studies of double allylmetallation reactions starting with

allenyltributylstannane 42

Although double allylboration reactions starting with allenylbor-

onates 6, 20, 33, and 39 by using the Sodequist borane 25R failed to

provide 1,5-syn-(E)-diol ent-17 with acceptable diastereoselectivity,

the hydroboration step proved to be efﬁcient and kinetically con-

trolled for formation of the required (Z)-allylic borane species. Ac-

cordingly, we decided to explore the use of 25R as a hydroborating

reagent with other allenes that could be employed as precursors to

the targeted 1,5-syn-(E)-diols. In particular, we were attracted to the

use of allenylstannane 42 since the Lewis acid mediated reactions of

allylstannanes with aldehydes are well established.²⁵With the aim of

reaction, degradation or Peterson type elimination³⁰of the syn-

alkoxyallylstannane 44a.

b-

Attempts to improve the reaction diastereoselectivity by per-

forming the second allylation at lower temperatures met with some

success. When the second allylation reaction of 44a was performed

at 0 ^ꢁC, we obtained allylation products in 72% yield but with di-

minished selectivity (2:1 in favor of ent-17c, entry 1, Table 2).

However, performing the second allylation reaction at ꢀ90 ^ꢁC (entry

2) enabled us to obtain the 1,5-diol products in 81% yield, with

slightly better selectivity (5:1). Further reductions of the reaction

temperature, to ꢀ110 ^ꢁC, required that we use a co-solvent such as

Et₂O or pentane that does not freeze at this temperature. Use of Et₂O

as the co-solvent led to improvement in the selectivity (11:1) but the

yield was only 30% (entry 3). Use of pentane as co-solvent provided

ent-17c in 66% yield and 10:1 selectivity (entry 4). Because of the

difﬁculty maintaining the cold bath at such a low temperature for

a long period, we ran the reaction in a mixture of dichloromethane

and pentane (1:3) at ꢀ78 ^ꢁC for 3 h and were pleased to ﬁnd that the

1,5-syn-(E)-diol ent-17c was produced in 73% yield with 6:1 selec-

tivity (entry 5). Investigations by Keck and Denmark suggest that

employing syn-b-alkoxyallylstannanes 44a and 44b as double allyl-

metallation intermediates, our attention turned to the hydroboration

of the readily available allenylstannane 42²⁶with 25R, which would

provide the kinetic (Z)-bimetallic allylborane 43. This intermediate

was expected to undergo an allylboration reaction with an aldehyde

to provide 44a or 44b, which could react with a second aldehyde in

the presence of Lewis acid. Two transition states TS-9 and TS-10 could

be envisioned for the second allylation step. The synclinal transition

state^25dTS-9 would provide the desired 1,5-syn-(E)-diol ent-17a, ent-

17c or ent-17b. Alternatively, the antiperiplanar transition state²⁵TS-

10 would give the undesired 1,5-anti-(E)-diol ent-10a, ent-10c or ent-

10b, depending on the aldehydes employed (Scheme 15).

a synclinal arrangement of the

p-systems (C]O and C]C) in the

transition state (comparable to TS-9) is favored as this allows sta-

bilization of the transition state through frontier orbital interactions

and minimization of charge transfer³¹thus, performing the re-

actions at low temperatures in non-polar solvent systems might

accentuate these effects. Further reduction of the solvent polarity by

increasing the ratio of pentane/dichloromethane to 4:1 at ꢀ78 ^ꢁC

provided 1,5-syn-(E)-diol ent-17c with 7:1 ds (entry 6).

Table 2

Attempts to optimize the second allylboration reaction of 44a and 44b with benz-

aldehyde or hydrocinnamaldehyde and BF₃$Et₂O as per Scheme 15

a

Entry Solvent

T (^ꢁC), time Product ratio

Yield^b(%)

1

2

3

4

5

6

7

8

CH₂Cl₂

0, 4 h

ꢀ90, 3 h

ent-17c/ent-10c (2:1)

ent-17c/ent-10c (5:1)

ent-17c/ent-10c (11:1) 30

72

81

CH₂Cl₂/Et₂O (1/2) ꢀ110, 3 h

CH₂Cl₂/Pent (1/3) ꢀ110, 2.5 h ent-17c/ent-10c (10:1) 66

CH₂Cl₂/Pent (1/3) ꢀ78, 3 h

ent-17c/ent-10c (6:1)

73

81

CH₂Cl₂/Pent (1/4) ꢀ78, 4.25 h ent-17c/ent-10c (7:1)

CH₂Cl₂/Pent (1/4) ꢀ78, 4.25 h ent-17a/ent-10a (7:1) 57

CH₂Cl₂/Pent (1/4) ꢀ78, 4.25 h ent-17b/ent-10b (4:1) 51 (93% ee) ^c

Determined by ¹H NMR analysis.

Isolated yields.

Determined by Mosher ester analysis.

a

b

c

Similar diastereoselectivity but a lower yield (57%) was obtained

when hydrocinnamaldehyde was used instead of benzaldehyde

(compound ent-17a and ent-10a, entry 7). However, when benzal-

dehyde was used for ﬁrst allylboration, followed by use of

Scheme 15. Double allylmetallation sequence involving allenylstannane 42.

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

6503

Table 3

hydrocinnamaldehyde in the second allylstannation step, using the

Hydroboration of allene 45 and allylboration reactions of the derived reagent 46

same conditions described as above, a 51% yield of a 4:1 mixture of

1,5-syn-(E)-diol ent-17b and 1,5-anti-(E)-diol ent-10b was obtained

favoring of ent-17b (93% ee; entry 8). While these results were

encouraging, we sought

a signiﬁcantly more stereoselective

method for synthesis of the targeted 1,5-syn-(E)-diols.

3.7. Development of the double allylborating agent 46

starting from tetrabutylammonium allenyltriﬂuoroborate 45

Entry Solvent

Hydroboration Yield (%) of

temp/time

ent-30^a(syn/anti)^bent-30/17d^c

^ꢁC/1 h

Ratio

We were intrigued by several publications from Batey’s labo-

ratory, who reported allylation and crotylation of aldehydes using

potassium allyl and crotyltriﬂuoroborates.³²These data stimulated

the idea that it should be possible to generate a double allylborating

1

2

3^d

4

5

6

7

8

9

CH₂Cl₂

0

39 (5.7:1)

38 (16:1)

3.0:1

2.9:1

3.3:1

3.2:1

3.7:1

4.3:1

7.1:1

>30:1

ꢀ10 ^ꢁC/1 h

ꢀ10 ^ꢁC/3 h

ꢀ30 ^ꢁC/1 h

ꢀ30 ^ꢁC/3 h

ꢀ30 ^ꢁC/1 h

39 (12:1)

reagent, speciﬁcally the (Z)-g-boryl allyltriﬂuoroborate 46, via the

41 (5.1:1)

52 (>20:1)

50 (>20:1)

51 (>20:1)

87^h(>20:1)

kinetically controlled hydroboration of tetrabutylammonium alle-

nyltriﬂuoroborate 45 with the Soderquist borane, 25S (Scheme 16).

Based on the Batey precedent, it was expected that allylic tri-

ﬂuoroborate 47 could be converted to allylboron diﬂuoride 48 upon

treatment with an appropriate Lewis acid. Further, and most im-

portantly, it was anticipated that 48 would undergo aldehyde

allylboration reactions with much greater stereoselectivity than

with 32 previously studied (Scheme 8), owing to the smaller size of

the diﬂuoroborane unit of 48 compared to the (1,3,2)-dioxabor-

inane unit in 32 (e.g., compare TS-11 for 48 with TS-5 for 32).

e

Et₂O/CH₂Cl₂

Toluene/THF^f

g

Toluene/CH₂Cl₂

a

Isolated yields.

Determined by ¹H NMR analysis.

Determined after isolation of ent-30 and 17d.

Dibal-H (2 equiv) added before the oxidation step.

Et₂O/CH₂Cl₂(2:1).

Toluene/THF (2:1).

Toluene/CH₂Cl₂(15:1).

Compound ent-30 obtained in 97% ee, determined by Mosher ester analysis.

b

c

d

e

f

g

h

diastereoselectivity for ent-30 (>20:1) was obtained from experi-

ments in which the hydroboration reaction was run at ꢀ30 ^ꢁC (en-

tries 5 and 6), which suggested that under these conditions the [1,3]-

boratropic isomerization of 46 to the corresponding (E)-isomer is

essentially suppressed. Examination of the reaction in other solvents

led to the discovery that the competitive abstraction of ﬂuoride ion

from 47 to give 48 (the precursor to 17d) could also be suppressed

(entries 7, 8, and 9). Best results were obtained (entry 9) when the

hydroboration/allylboration sequence was performed in a 15:1

mixture of toluene and CH₂Cl₂(CH₂Cl₂is needed owing to the poor

solubility properties of 45 in toluene). Under these conditions, the

1,2-syn-diol ent-30 was obtained in 87% yield, with 97% ee, and

>20:1 dr after oxidative workup. These data demonstrate that 46 is

obtained with very high stereoselectivity via the kinetically con-

trolled hydroboration of 45, and also that the ﬁrst allylboration re-

action provides the intermediate

b-alkoxyallyltriﬂuoroborate 47

with excellent stereochemical control.

Scheme 16. Synthesis of 1,5-syn-(E)-diols 17 from allenyltriﬂuoroborate 45.

Next, we applied these optimized reaction conditions to the

double allylboration reaction leading to the targeted 1,5-syn-(E)-

diols 17 (Table 4). This next phase of the reaction development was

Studies of the hydroboration of 45 commenced with the ex-

periments summarized in Table 3. Initially, the hydroboration of

allene 45 (1.3 equiv) was performed with the Soderquist borane,

25S, at 0 ^ꢁC for 1 h. The solution was cooled to ꢀ78 ^ꢁC and then

benzaldehyde (0.7 equiv) was added. The reaction was maintained

at ꢀ78 ^ꢁC for 4 h, then was worked up oxidatively. This provided

1,2-syn-diol ent-30 as a 5.7:1 mixture of diastereomers, along with

the unexpected (E)-1,5-syn-diol 17d (Table 3, entry 1). The forma-

tion of 17d suggested that allylboron diﬂuoride 48 was forming

during the reaction.

A signiﬁcant improvement of the product diastereoselectivity

(16:1) was realized by performing the hydroboration at ꢀ10 ^ꢁC for

1 h (entry 2), suggesting that the rate of boratropic isomerization of

46 can be controlled by keeping the reaction temperature below

ꢀ10 ^ꢁC. However, ent-30 and 17d were still formed in ca. 3:1 ratio.

Attempts to reduce any residual benzaldehyde, by addition of DIBAL

prior to the oxidative workup did not eliminate 17d as a reaction

product (entry 3), suggesting that 17d is formed during the allyl-

boration reaction at ꢀ78 ^ꢁC and not during workup. The best

facilitated by addition of BF₃$OEt₂to the intermediate

b-alkox-

yallyltriﬂuoroborate 47.³³This smoothly generated the allylic boron

diﬂuoride intermediate 48, which reacted with the second alde-

hyde to give the targeted 1,5-syn-diol 17. The amount of the alde-

hyde used in the ﬁrst allylboration reaction proved to be important

for avoiding the homo-coupling double allylboration products 17d

(deriving from the ﬁrst aldehyde) and 17a (deriving from the sec-

ond aldehyde). Optimized reaction conditions (Table 4, entry 2)

were found by using 1.3 equiv of the allene 45, 0.85 equiv of the ﬁrst

aldehyde, 1.5 equiv of BF₃$Et₂O and 1.2 equiv of second aldehyde.

This combination provided the 1,5-syn-diol-(E) 17 in 73% yield, with

excellent enantioselectivity (>95% ee), diastereoselectivity

(dr>20:1), and (E)/(Z) ratio (>20:1).

By using these optimized reaction conditions (Table 4, entry 2),

a series of double allylboration reactions were performed to dem-

onstrate the scope and utility of this new procedure (see Scheme

17). These results demonstrate that the long-sought 1,5-syn-(E)-

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P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

amine as a tert-butyl carbamate (Boc) provided 53 in 70% yield.³⁷

The cross oleﬁn metathesis³⁸of 53 with acrolein and using the

second-generation GrubbseHoveyda catalyst³⁹gave aldehyde 3 in

94% yield ((E)/(Z)¼25:1). Aldehyde 3 corresponds to the C(33)e

C(40) fragment of tetraﬁbricin (Scheme 18).

Table 4

Optimization of the double allylboration reaction of 46 generated by the hydro-

boration of allene 45^a

Entry

PhCHO

(equiv)

BF₃$OEt₂

(equiv)

Yield^b

(%) 17b

Ratio^c

(E)/(Z)

Ratio

17d/17b/17a^c

1

2

0.75

0.85

0.95

0.85

1.5

d

60

73

51

30

77

>20:1

6:1

0:89:11

0:100^d:0

8:92:0

0:100:0

3

4^e

5^f

6:1

a

Reaction conditions: solvent: toluene/CH₂Cl₂; hydroboration: ꢀ30 ^ꢁC, 1 h; ﬁrst

allylboration: ꢀ78 ^ꢁC, 4 h; second allylboration: ꢀ78 ^ꢁC, 4 h; workup: pH 7 buffer

(KH₂PO₄/NaOH).

b

Isolated yields.

c

Determined by ¹H NMR analysis.

d

Compound 17b obtained with >20:1 dr and 97% ee, determined by Mosher ester

analysis.

e

Second allylboration: 0 ^ꢁC, 2 h.

Second allylboration: ꢀ78 to 20 ^ꢁC, 12 h.

f

Scheme 18. Synthesis of aldehyde 3.

diols 17 are obtained in 72e98% yields, >95% ee, >20:1 dr, and with

>20:1 (E)/(Z) selectivity. Thus, use of the allenyltriﬂuoroborate 45

in combination with the Soderquist borane provides an efﬁcient,

highly stereoselective synthesis of the 1,5-syn-(E)-diols illustrated

by the structures in Scheme 17.

The synthesis of aldehyde 4 began with cross-metathesis be-

tween readily available oleﬁn 54⁴⁰and acrolein in the presence of

GrubbseHoveyda second-generation catalyst.³⁹This reaction pro-

vided the unsaturated aldehyde 55 in 85% yield. Subjection of 55 to

a Brown allylboration³⁵using (ꢀ)-di(isopinocampheyl)-allylborane

afforded alcohol 56 in 83% yield and 96% ee as veriﬁed by Mosher

ester analysis.³⁶Asymmetric epoxidation of alcohol 56 under the

standard Sharpless epoxidation conditions⁴¹delivered epoxy al-

cohol 57 in 69% yield as a single diastereomer. Reduction of the

epoxide using Red-Al in the presence of MeOH⁴²provided anti-1,3-

diol 58, the stereochemistry of which was veriﬁed by ¹³C NMR

analysis of the derived acetonide according to Rychnovsky’s

method.⁴³Protection of the diol in 58 with TBSCl and imidazole

gave 59. Finally oxidative cleavage of the vinyl group of 59 by using

Jin’s protocol (OsO₄/NaIO₄/2,6-lutidine)⁴⁴provided aldehyde 4,

which corresponds to the C(23)eC(29) fragment of tetraﬁbricin

(Scheme 19).

Scheme 17. 1,5-syn-(E)-Diols synthesized by using the optimal reaction Conditions. All

experiments were performed by using the conditions deﬁned in entry 2 of Table 4.

3.8. Application of the new double allylboration procedure to

the synthesis of the C(23)eC(40) fragment of tetraﬁbricin

The original objective of this methodology development project

was the synthesis of a double allylboration reagent that would fa-

cilitate the stereoselective synthesis of the C(23)eC(40) fragment of

tetraﬁbricin. As we presented in Scheme 1, we envisioned that this

fragment could be assembled from aldehydes 3 and 4 by a double

allylboration sequence. The synthesis of aldehyde 3 (Scheme 18)

started from the known 4-azidobutanal³⁴49, which was subjected

to an allylboration reaction with Brown’s (ꢀ)-di(isopinocampheyl)

allylborane reagent.³⁵This provided secondary alcohol 50 as an

inseparable mixture with isopinocampheol, 51. This mixture was

treated with TBSCl and imidazole which provided the TBS ether 51

in 73% yield over the two steps. The enantiomeric purity of alcohol

50 was determined to be 91% ee, by application of the Mosher ester

analysis.³⁶This analysis also enabled us to conﬁrm the absolute

stereochemistry of 50. Reduction of the azide by treatment with

Bu₃P in wet diethyl ether, followed by protection of the primary

Scheme 19. Synthesis of aldehyde 4.

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

6505

Studies performed on the coupling of aldehyde fragments 3

and 4 to give the targeted tetraﬁbricin intermediate 2 are sum-

marized in Scheme 20. Initial studies were performed using re-

agent 28 generated from allene 6 as described in Scheme 7. Use of

28 in this double allyboration sequence (using the conditions

deﬁned in Scheme 8) provided 60 in 67% yield, but as an in-

separable 6:1 mixture of diastereomers (entry 1, Scheme 20).

When reagent 43, generated from allene 42 as described in

Scheme 15 was used, the double allylmetalation product 60 was

obtained in 24% yield as an inseparable 4:1 mixture of di-

astereomers (entry 2, Scheme 20).

Scheme 21. Synthesis of the diastereomer 62.

highly convergent and has a high degree of stereochemical gener-

ality. In fact, the synthesis of several different diastereoisomers of

a 1,5-diol system can now be achieved simply by changing the

nature of the borane reagent (10-TMS-9-BBD-H or Ipc₂BH) or the

monosubstituted allene used to synthesize the double allylboration

reagent (e.g., see Schemes 2, 6, 17, 20, and 21). Thus, we expect that

our method will prove useful for the synthesis and conﬁrmation of

the relative and absolute stereochemistry of 1,5-diol units found in

other natural products.

4. Conclusion

In summary, we have developed an efﬁcient and highly dia-

stereoselective double allyboration reaction sequence starting from

the hydroboration of tetrabutylammonium allenyltriﬂuoroborate

45 and the Soderquist borane, TBBD-H 25. This method has enabled

us to synthesize the C(23)eC(40) fragment 2 of tetraﬁbricin and its

C(29)eC(33) diastereoisomer 62 with very high stereoselectivity.

Further progress toward the completion of the total synthesis of

tetraﬁbricin 1 will be reported in due course.

5. Experimental section

5.1. General

Tetrahydrofuran, dichloromethane, diethyl ether, and toluene

were puriﬁed by passing through a solvent column of activated

alumina (A-1). Hexanes, acetonitrile and trimethylsilyl chloride

were puriﬁed by distillation from calcium hydride. Anhydrous

pentane and methanol were purchased from Aldrich Chemical

Company. All commercially available aldehydes were puriﬁed by

vacuum distillation before use. Unless indicated otherwise, other

commercially available reagents were used as received without

puriﬁcation. Unless otherwise indicated, all reactions were con-

ducted under an atmosphere of argon using ﬂamed-dried or oven-

dried (140 ^ꢁC) glassware. Standard techniques for handling air-

sensitive compounds were also employed for all operations. Cel-

ite 545^Òwas dried at 140 ^ꢁC for at least 12 h prior to use. Removal of

solvents was accomplished on a rotary evaporator at reduced

pressure. Reaction mixtures were maintained at low temperature

by using a Thermo NESLAB CB-60 cold bath. Enantiomeric excess

and absolute conﬁgurations of all new alcohol products were de-

termined by using the Mosher³⁶method.

Scheme 20. Synthesis of the C(23)eC(40) fragment 2 of tetraﬁbricin.

Fortunately, excellent results were obtained when the double

allylboration coupling of aldehydes 4 and 3 was performed using

reagent 46 generated from allenyltriﬂuoroborate 45 (entry 3,

Scheme 20). This reaction provided 60 in 83% yield, with ex-

ceptional diastereoselectivity (>20:1) and (E)/(Z) ratio (>20:1).

The stereochemistry of the two hydroxyl groups in 45 were

conﬁrmed by using the Mosher method.³⁶This result demon-

strates that the fragment assembly reaction using reagent 46 is

compatible with protecting groups such as silyl ethers, PMB

ethers, and acid labile Boc carbamates. Treatment of 60 with

TBSCl and imidazole furnished the tetraﬁbricin C(23)eC(40)

fragment 2 in 94% yield. Furthermore, replacement of 25R by 25S

in the hydroboration reaction of allene 45 allowed the di-

astereomeric 1,5-diol 62 to be obtained in comparable yield and

stereoselectivity (Scheme 21).

¹H NMR spectra were recorded on a Bruker spectrometer at

400 MHz. ¹³C NMR spectra were recorded on a Bruker spectrometer

at 100 MHz. The proton signal for non-deuterated solvent (

d

7.24 ppm for CHCl₃) was used as an internal reference for ¹H NMR

spectra. For ¹³C NMR spectra, chemical shifts are reported relative

to the

d 77.24 ppm resonance of CDCl₃. Infrared (IR) spectra were

recorded as thin ﬁlms using CH₂Cl₂as the solvent or neat on

a PerkineElmer Spectrum 1000 FTIR. Optical rotations were mea-

sured on a Rudolph Autopol IV polarimeter using a quartz cell with

1 mL capacity and a 1 dm path length. Melting points were

In comparison with other methods^2e7described in the literature

for synthesis of 1,5-diol units, our double allylboration procedure is

6506

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

determined on a Mel-Temp II hot stage melting point apparatus and

are uncorrected. High-resolution mass spectra were recorded on

a spectrometer at the University of Florida Mass Spectrometry

Laboratory.

CDCl₃) d 219.2, 86.4, 78.4, 70.2, 51.5, 39.7, 38.4, 35.6, 28.8, 27.3, 26.7,

24.2; HRMS (ESI) calcd for C₁₃H₁₉BO₂[MþNa]^þ241.1376, found

241.1380.

Analytical thin layer chromatography (TLC) was performed on

Kieselgel 60 F₂₅₄glass plates precoated with a 0.25 mm thickness of

silica gel. TLC plates were visualized with UV light and/or by

5.2.4. N,N,N-Tributylbutan-1-aminium triﬂuoro(propa-1,2-dien-1-yl)

borate (45). An established procedure⁴⁶for synthesis of allylic tri-

ﬂuoroborate tetrabutylammonium salts was modiﬁed for prepara-

tion of allene 8. A 1 M aqueous solution of tetrabutylammonium

hydroxide (20.0 mL, 20.0 mmol, 1 equiv) was added to a suspension

of the known potassium allenyltriﬂuoroborate⁴⁷(2.92 g, 20.0 mmol,

1 equiv) in CH₂Cl₂(30 mL). The reaction was stirred at room for

30 min. The reaction mixture was then diluted with CH₂Cl₂(20 mL),

the organic layer was separated, dried over Mg₂SO₄, ﬁltrated, and

concentrated in vacuo to afford tetrabutylammonium allenyltri-

ﬂuoroborate 45 (5.81 g, 83%) as a hygroscopic colorless solid which

was stored in the glove box. IR (neat) 2963, 2936, 2876, 1930, 1473,

1382, 1248, 1071, 996, 968, 882, 795, 739, 600 cm^ꢀ1; ¹H (400 MHz,

staining with cerium molybdate (5 g Ce(SO₄)₂, 25

g (NH₄)

Mo₇O₂₄$4H₂O, 450 mL H₂O, 50 mL H₂SO₄). Preparative thin

layer chromatography (TLC) was performed on Kieselgel 60 F₂₅₄

glass plates precoated with a 0.5 mm thickness of silica gel. Column

chromatography was generally performed according to the method

of Still⁴⁵using Kieselgel 60 (230e400 mesh) silica gel.

5.2. Procedure for the preparation of the allenyl boronic

esters (6, 20, and ent-39)

Freshly distilled trimethyl borate (21.7 mL, 196 mmol) was

added to a round bottom ﬂask containing 150 mL of ether placed in

a ꢀ78 ^ꢁC cold bath. A 0 ^ꢁC solution of allenylmagnesium bromide

(1 M in ether, 196 mmol) was added via syringe or cannula at a rate

as to keep the internal reaction temperature below ꢀ65 ^ꢁC. A white

precipitate formed during this addition. The reaction mixture was

stirred 3 h at ꢀ78 ^ꢁC, then was warmed to 0 ^ꢁC over 1 h and stirred

at 0 ^ꢁC for an additional hour. Aqueous HCl (2 M, 392 mmol) was

added via an addition funnel. This mixture was stirred for 1 h and

then the organic layer was separated using a separatory funnel. The

aqueous layer was washed with ether (2ꢂ200 mL) and the com-

bined organic phases were dried over Na₂SO₄for 30 min. The so-

lution was ﬁltered under nitrogen and solvent removed in vacuo

until w250 mL of solvent remained (the rotary evaporator was

ﬂushed and backﬁlled using an argon balloon). The appropriate diol

(137 mmol) was added to the ﬂask and reaction stirred for 24 h at

room temperature, at which time 10 g of MgSO₄was added and the

mixture stirred for an additional 18 h at room temperature. The

reaction was ﬁltered under nitrogen using a coarse fritted funnel

and solvent removed in vacuo using argon to backﬁll the rotary

evaporator.

CDCl₃)

1.61e1.53 (m, 8H), 1.38 (sextuplet, J¼7.3 Hz, 8H), 0.95 (t, J¼7.3 Hz,

12H); ¹³C (100 MHz, CDCl₃)

210.6 (q, J¼4.3 Hz), 86.8 (br s), 65.6,

d 4.76 (br s, 1H), 4.09e4.06 (m, 2H), 3.18e3.14 (m, 8H),

d

58.6, 24.0, 19.8, 13.8; ¹⁹F (376 MHz, CDCl₃)

d

ꢀ137.1 (d, J¼48 Hz);

HRMS (ESI) calcd for C₃H₃BF₃[MꢀNBu₄]^ꢀ107.0280, found 107.0286.

5.2.5. Lithium B-H₂-(10R)-trimethylsilyl-9-borabicyclo[3.3.2] decane

diethyl etherate (26). Soderquist’s literature procedure was modi-

ﬁed as follows: a solution of ethyl acetate (0.488 mL, 5.00 mmol,

0.5 equiv) in Et₂O (4.5 mL) was added dropwise (0.5 mL/min) to

a 1 M solution of LiAlH₄in Et₂O (10.0 mL, 10.0 mmol, 1 equiv). The

resulting suspension of lithium monoethoxyaluminium hydride

was stirred at 20 ^ꢁC for 1 h (white precipitate). The reaction mixture

was cooled to 0 ^ꢁC and a solution of (ꢀ)-B-methoxy-10R-trime-

thylsilyl-9-borabicyclo[3.3.2.]decane (2.38 g, 10.0 mmol, 1 equiv)

64R²¹in Et₂O (20 mL) was added dropwise (1 mL/min). The re-

action was stirred at 0 ^ꢁC for 1 h then was allowed to reach room

temperature. The suspension was ﬁltered (fritted funnel with Cel-

ite) with care taken to prevent exposure of the borohydride to the

open atmosphere. The solid dialkoxyalane was washed with Et₂O

(3ꢂ10 mL). The combined washings and supernatant were con-

centrated in vacuo to afford mono-diethyl etherate 26 as a white

solid, which was dried under high vacuum for at least 12 h. The

known borohydride 26 can be stored without decomposition in

5.2.1. 2-Allenyl-1,3,2-dioxaborinane (6). The remaining clear yellow

oil was distilled under vacuum (bp 20 mm Hg, 81e82 ^ꢁC) to yield

76% of 6 as a clear colorless oil. The oil was transferred to small vials

and stored under nitrogen in a desiccator in a ꢀ20 ^ꢁC freezer. This

material could be used neat over several months without de-

composition. Spectroscopic data obtained for 6 matched that

reported in the literature.^8a

a glove box. ¹H (400 MHz, CDCl₃)

d

3.67 (q, J¼7.1 Hz, 4H), 2.37 (s,

1H), 1.66e1.37 (m, 13H), 1.29 (t, J¼7.1 Hz, 6H), 0.91 (s, 1H), 0.45 (br s,

1H), 0.00 (s, 1H), ꢀ0.07 (s, 9H); ¹³C (100 MHz, CDCl₃)

35.5, 34.8, 33.3, 33.0, 24.2, 23.4, 14.8, ꢀ0.1.

d 66.5, 37.3,

5.3. Procedure for titration of the borohydride 26

5.2.2. 2-Allenyl-5,5-dimethyl-1,3,2-dioxaborinane (20). The remain-

ing clear yellow oil was distilled under vacuum (bp 46e48 ^ꢁC/

0.5 mbar) to yield 69% of 20 as a clear colorless oil. The oil was

transferred to small vials and stored under nitrogen within a des-

iccator in a ꢀ20 ^ꢁC freezer and could be used neat over several

months without decomposition: IR (neat) 2963, 2935, 2889, 1936,

1479, 1426, 1379, 1350, 1331, 1259, 1227, 1184, 1088, 1009, 870, 814,

To a solution of borohydride 26 (0.073 g, 0.250 mmol, 1 equiv) in

Et₂O (1.0 mL) at 0 ^ꢁC was added TMSCl (0.048 mL, 0.375 mmol,

1.5 equiv). The reaction mixture was stirred at 0 ^ꢁC for 10 min before

4-methoxybenzaldehyde (0.121 mL, 1.0 mmol, 4 equiv) was added.

The reaction mixture was stirred at 20 ^ꢁC for 3 h then acetic acid

(0.286 mL, 5.00 mmol, 20 equiv) was added and the mixture was

stirred foran additional 4 h. Thesolvent was removed under reduced

pressure (rotary evaporator) and the residue was analyzed by ¹H

NMR spectroscopy. The yield of in situ generated 25 was determined

from the integrations of the methoxy groups of 4-methoxybenzyl

alcohol (Int1) and 4-methoxybenzaldehyde (Int2). The titration

reaction was run simultaneously in two different ﬂasks. The average

yields were generally in the range of 90e93%.

681, 666 cm^ꢀ1

;

¹H NMR (400 MHz, CDCl₃)

d

4.83 (t, J¼6.9 Hz, 1H),

4.61 (d, J¼7.0 Hz, 2H), 3.66 (s, 4H), 0.98 (s, 6H); ¹³C (100 MHz, CDCl₃)

d

217.9, 72.5, 69.7, 31.8, 21.8; HRMS (ESI) calcd for C₈H₁₃BO₂

(MþNa^þ) 175.0906, found 175.0908.

5.2.3. Pinanediol allenylboronate (ent-39). Puriﬁed by ﬂash column

26

chromatography (96/4: hexanes/EtOAc); [

a

]

þ10.4 (c 0.52,

D

CHCl₃); IR (neat) 2971, 2918, 1937, 1423, 1368, 1203, 1189 cm^ꢀ1; ¹H

(400 MHz, CDCl₃)

d

4.94 (t, J¼6.9 Hz,1H), 4.65 (d, J¼6.9 Hz, 2H), 4.34

ꢀ

ꢁ

Int1

(dd, J¼8.7, 2.0 Hz, 1H), 2.39e2.30 (m, 1H), 2.29e2.17 (m, 1H),

2.64e2.54 (dd, J¼6.0, 5.0 Hz, 1H), 1.94e1.87 (m, 2H), 1.42 (s, 3H),

1.29 (s, 3H), 1.17 (d, J¼11.0 Hz, 1H), 0.85 (s, 3H); ¹³C (100 MHz,

ꢂ

h_aldehyde

Int1 þ Int2

Yield ¼

h_borohydride

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

6507

5.4. Procedure A. Synthesis of 1,5-diols ent-17a and ent-10a

conditions. The resulting clear reaction mixture was then cooled to

ꢀ78 ^ꢁC and benzaldehyde or hydrocinnamaldehyde (0.175 mmol,

0.7 equiv) was added. The mixture was stirred at ꢀ78 ^ꢁC for 4 h,

then a second aldehyde (0.375 mmol, 1.5 equiv) (followed by

BF₃$OEt₂(0.125 mmol, 0.5 equiv) if using allene 39 was added and

the reaction mixture was stirred for an additional 4 h. The reactions

were quenched by using one of three general methods: (1) addition

from the hydroboration reaction of allene 20 with ^LIpc₂BH

^LIpc₂BH (287 mg, 1.0 mmol) was weighed in a glove box into

a round bottom ﬂask containing a stir bar (Note: the crystalline

Ipc₂BH should be crushed and pulverized with a glass rod prior to

use in order to ensure efﬁcient hydroboration). The ﬂask was

capped with a rubber septum and removed from the glove box

and placed in bath at the appropriate reaction temperature

(Table 1). THF (2 mL) was added to the ﬂask followed by the

allenyl boronic ester 20 (148 mg, 1.0 mmol) as a solution in THF

(1 mL). For hydroboration reaction time and temperatures,

see Table 1. After the hydroboration reaction was terminated, the

reaction mixture was cooled to ꢀ78 ^ꢁC. Distilled hydro-

of ethanolamine (75

mL, 1.25 mmol, 5 equiv); (2) addition of

aqueous 3 N NaOH solution (0.25 mL); and aqueous 50% H₂O₂

(0.1 mL); or (3) by addition of a pH 7 buffer solution (KH₂PO₄/

NaOH) (1 mL) followed by THF (1.5 mL) and MeOH (0.5 mL). In the

latter procedure, additional THF (1 mL) and MeOH (0.5 mL) were

added, and the mixture was stirred at 20 ^ꢁC for 12 h. The reaction

mixture was then poured into saturated aqueous NH₄Cl, and the

crude product was extracted with ethyl acetate (3ꢂ). The combined

organic layers were washed with brine, dried over MgSO₄, ﬁltered,

and concentrated under reduced pressure. The crude products

were then puriﬁed by ﬂash chromatography.

cinnamaldehyde (71

mL, 0.54 mmol) was added dropwise via

a microliter syringe. The ﬂask was stirred at ꢀ78 ^ꢁC for 4 h and

then additional hydrocinnamaldehyde (184

mL, 1.40 mmol) was

added dropwise via microliter syringe. The reaction was stirred an

additional 2 h. The ﬂask was then removed from the ꢀ78 ^ꢁC bath

and allowed to warm to room temperature and stirred overnight.

The reaction mixture was cooled in an ice bath and 1 mL of 3 M

NaOH solution was added dropwise followed by 0.4 mL of a 50%

H₂O₂solution. This mixture was stirred for 4 h at room temper-

ature at which time it was diluted with 40 mL of CH₂Cl₂and 20 mL

of a saturated aqueous solution of NaHCO₃and 5 mL of a saturated

aqueous solution of NaCl. The organic layer was separated and the

aqueous washed with CH₂Cl₂(2ꢂ10 mL). The combined organic

extracts were dried over Na₂SO₄, then ﬁltered and the solvent

removed in vacuo. The crude products were then puriﬁed by ﬂash

chromatography.

5.7. Procedure D. Synthesis of 1,5-diols ent-17a, ent-17b, ent-

17c from allene 42

To a 0 ^ꢁC solution of borohydride 25R (81 mg, 0.250 mmol,

1 equiv, considering a 90% yield for the conversion of borohydride

26R to borane 25R based on the borane 25R titration^8d) in CH₂Cl₂

(0.5 mL) was added TMSCl (32.0 mL, 0.250 mmol, 1 equiv). The re-

action mixture was stirred for 10 min, then was cooled to 0 ^ꢁC. At

this point, a solution of allenyltributylstannane 42 (80% purity from

SigmaeAldrich, 121 mL, 0.325 mmol, 1.3 equiv) in CH₂Cl₂(1.0 mL)

was added and the reaction mixture was stirred for 1 h. The mix-

ture was cooled to ꢀ78 ^ꢁC and hydrocinnamaldehyde or benzal-

dehyde (0.175 mmol, 0.7 equiv) was added. After 3 h, the reaction

was diluted with pentane (see Table 2) and a second aldehyde

5.5. Procedure B. Synthesis of 1,2-diols 30 and 40 from allenes

6, 33, 39, and ent-39

(0.325 mmol, 1.3 equiv) was added followed by BF₃$OEt₂(46

0.375 mmol, 1.5 equiv) and the reaction was stirred for an addi-

tional 4.25 h. Ethanolamine (75 L, 1.25 mmol, 5 equiv) was added

mL,

To a 0 ^ꢁC solution of borohydride 25R²¹(81 mg, 0.250 mmol,

1 equiv, considering a 90% yield for the conversion of borohy-

dride 26R to borane 25R based on the borane 25R titration^8d) in

m

and the reaction mixture was allowed to reach 20 ^ꢁC and stirred for

12 h. The mixture was poured into saturated aqueous NH₄Cl solu-

tion (20 mL) and the crude product was extracted with ethyl ace-

tate (3ꢂ10 mL). The combined organic layers were washed with

brine (20 mL), dried over MgSO4, ﬁltered, and concentrated under

reduced pressure. The crude products were then puriﬁed by ﬂash

chromatography.

CH₂Cl₂(0.5 mL) was added TMSCl (32 mL, 0.250 mmol, 1 equiv).

The reaction mixture was stirred for 10 min, then was cooled to

ꢀ78 ^ꢁC and a solution of allene 6, 33, or 39 (0.325 mmol,

1.3 equiv) in CH₂Cl₂(1.0 mL) was added dropwise. For hydro-

boration reaction times and temperatures, see Schemes 7, 10,

and 13. The resulting reaction mixture was then cooled to

ꢀ78 ^ꢁC and a solution of benzaldehyde or hydrocinnamaldehyde

(0.175 mmol, 0.7 equiv) in CH₂Cl₂(0.3 mL) was added. The

mixture was stirred for 4 h at ꢀ78 ^ꢁC, then an aqueous 3 N NaOH

solution (0.25 mL) and aqueous 50% H₂O₂(0.1 mL) were added

follow by THF (1 mL) and MeOH (0.5 mL). This mixture was then

stirred at 20 ^ꢁC for 12 h. The biphasic mixture was poured into

saturated aqueous NH₄Cl, and the crude product was extracted

with ethyl acetate (3ꢂ). The combined organic layers were

washed with brine, dried over MgSO₄, ﬁltered, and concentrated

under reduced pressure. The crude products were then puriﬁed

by ﬂash chromatography.

5.8. Procedure E. Synthesis of 1,5-diols 17 and ent-17 from

allene 45

To a 0 ^ꢁC solution of borohydride 25 (81.0 mg, 0.250 mmol,

1 equiv, considering a 90% yield for the conversion of borohydride

26 to borane 25 based on the borane 25 titration^8d) in toluene

(0.5 mL) was added TMSCl (32.0 mL, 0.250 mmol, 1 equiv). The re-

action mixture was stirred for 10 min, then was cooled to ꢀ78 ^ꢁC

and a solution of allene 45 (0.114 g, 0.325 mmol, 1.3 equiv) in tol-

uene (1 mL)/CH₂Cl₂(0.1 mL) was added dropwise. The viscous

mixture was stirred at ꢀ30 ^ꢁC for 1 h. The resulting clear reaction

mixture was then cooled to ꢀ78 ^ꢁC and a solution of the ﬁrst al-

dehyde (0.213 mmol, 0.85 equiv) in CH₂Cl₂(0.25 mL) was added.

After 4 h, a solution of the second aldehyde (0.300 mmol, 1.2 equiv)

5.6. Procedure C. Synthesis of 1,5-diols ent-17a, ent-17b, ent-

19g from allenes 6, 33, and 39

To a 0 ^ꢁC solution of borohydride 25R (81.0 mg, 0.250 mmol,

1 equiv, considering a 90% yield for the conversion of borohydride

26R to borane 25R based on the borane 25R titration^8d) in CH₂Cl₂

in CH₂Cl₂(0.25 mL) followed by BF₃$OEt₂(47.0 mL, 0.375 mmol,

1.5 equiv) were added. The reaction mixture was stirred for an

additional 4 h at ꢀ78 ^ꢁC. A pH 7 buffer solution (KH₂PO₄/NaOH)

(1 mL) followed by THF (1.5 mL) and MeOH (0.5 mL) were then

added to the mixture, which was stirred at 20 ^ꢁC for 24 h. The bi-

phasic mixture was poured into saturated aqueous NH₄Cl solution,

and the crude product was extracted with ethyl acetate (3ꢂ). The

combined organic layers were washed with brine, dried over

(0.5 mL) was added TMSCl (32 mL, 0.250 mmol, 1 equiv). The re-

action mixture was stirred for 10 min, then was cooled to ꢀ78 ^ꢁC

and a solution of allene 6, 33, or 39 (0.325 mmol, 1.3 equiv) in

CH₂Cl₂(1.0 mL) was added dropwise. For hydroboration reaction

times and temperature, see Schemes 8, 11, 14 for optimal

6508

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

MgSO₄, ﬁltered, and concentrated under reduced pressure. The

crude products were then puriﬁed by ﬂash chromatography.

¹H (400 MHz, CDCl₃)

d 7.38e7.10 (m, 10H), 5.78e5.68 (m, 2H), 5.12

(d, J¼4.8 Hz, 1H), 3.68e3.58 (m, 1H), 3.20 (d, J¼3.2 Hz, 1H),

2.78e2.69 (m, 1H), 2.66e2.56 (m, 1H), 2.48 (d, J¼4.4 Hz, 1H),

2.28e2.21 (m, 1H), 2.18e2.08 (m, 1H), 1.78e1.69 (m, 2H); ¹³C

5.8.1. (3R,4E,7S)-1,9-diphenylnon-4-ene-3,7-diol (17a). [

a

]

²⁵ꢀ6.4 (c

D

0.64, CHCl₃); ee 96%; IR (neat) 3347, 3084, 3061, 3025, 2924, 2857,

(100 MHz, CDCl₃) d 143.0, 141.9, 135.7, 128.4, 128.3, 128.3, 127.52,

1668,1602,1495,1454,1312,1051,1030, 971, 923, 746, 698 cm^ꢀ1; ¹H

127.47, 126.1, 125.7, 74.6, 70.2, 39.9, 38.3, 31.2; HRMS (CI, NH₃) calcd

(400 MHz, CDCl₃)

J¼6.8 Hz, 1H), 3.72e3.62 (m, 1H), 2.85e2.65 (m, 4H), 2.34e2.13 (m,

2H), 1.84e1.67 (m, 4H); ¹³C (100 MHz, CDCl₃)

142.0, 141.9, 136.5,

d

7.35e7.18 (m, 10H), 5.72e5.57 (m, 2H), 4.11 (q,

for C₁₉H₂₆NO₂[MþNH₄]^þ300.1964 found 300.1974.

24

d

5.8.10. (3S,7S,4Z)-1,9-Diphenylnon-4-ene-3,7-diol (ent-19g). [a]

D

128.45, 128.41, 127.6, 125.88, 125.87, 72.1, 70.3, 40.5, 38.8, 38.6, 32.0,

31.8; HRMS (ESI) calcd for C₂₁H₂₆O₂Na [MþNa]^þ333.1831, found

333.1825.

ꢀ38.5 (c 1.04, CHCl₃); IR (neat) 3351, 3025, 2930, 1602, 1495, 1454,

1030 cm^ꢀ^{1 1}H (500 MHz, CDCl₃)

;

d

7.38e7.28 (m, 4H), 7.22e7.19

(m, 6H), 5.71e5.66 (m, 1H), 5.64e5.58 (m, 1H), 4.42 (ddd (app q),

J¼7.0 Hz, 1H), 3.77e3.71 (dddd (app quintet), J¼6.5 Hz, 1H),

2.83e2.66 (m, 4H), 2.45e2.38 (dddd, J¼14.0, 8.5, 4.5, 1.0 Hz, 1H),

2.37 (s, OH broad, 1H), 2.28e2.21 (m, 1H), 2.06 (s, OH broad, 1H),

1.99e1.92 (dddd, J¼13.5, 9.5, 7.0, 6.5 Hz, 1H), 1.86e1.77 (m, 3H);

25

5.8.2. (3S,4E,7R)-1,9-Diphenylnon-4-ene-3,7-diol

(ent-17a). [a]

D

þ6.4 (c 0.64, CHCl₃); ¹H NMR, ¹³C NMR and IR and HRMS data were

identical to 17a.

¹³C (125 MHz, CDCl₃)

d 142.1, 142.0, 136.1, 128.7, 128.63, 128.61,

24

5.8.3. (3S,4E,7S)-1,9-Diphenylnon-4-ene-3,7-diol

(ent-10a). [

a]

128.60, 127.8, 126.1, 126.0, 70.4, 66.8, 38.9, 38.2, 35.1, 32.4, 31.9;

HRMS (FAB, Na) calcd for C₂₁H₂₆O₂[MþNa]^þ333.1831, found

333.1817.

D

ꢀ12.8 (c 1.0, CHCl₃); IR (thin ﬁlm) 3350, 3026, 2928, 1603, 1495,

1454, 1051 cm^ꢀ^{1 1}H (500 MHz, CDCl₃)

;

d

7.35e7.18 (m, 10H), 5.70

(dt, J¼15.0, 7.0, 7.0 Hz, 1H), 5.63 (dd, J¼15.0, 6.0 Hz, 1 H), 4.11 (q,

23

J¼6.8 Hz, 1H), 3.72e3.62 (m, 1H), 2.85e2.65 (m, 4H), 2.34e2.13 (m,

5.8.11. (3S,4S)-6-Phenylhex-1-ene-3,4-diol (40)⁴⁸. [

a

]

ꢀ18.5 (c

D

2H), 1.84e1.67 (m, 4H); ¹³C (125 MHz, CDCl₃)

d

142.1, 142.0, 136.7,

0.99, CHCl₃); IR (neat) 3386, 2922, 1711, 1496, 1454, 1046, 992, 926,

128.45, 128.41, 127.5, 125.89, 125.87, 72.0, 70.3, 40.3, 38.8, 38.5, 32.1,

31.8; HRMS (CI, NH₃) calcd for C₂₁H₃₀NO₂[MþNH₄]^þ328.2277,

found 328.2275.

749, 699 cm^ꢀ1; ¹H (400 MHz, CDCl₃)

d

7.29e7.15 (m, 5H), 5.83 (ddd,

J¼17.2, 10.8, 6.4 Hz, 1H), 5.33 (dt, J¼17.2, 1.2 Hz, 1H), 5.23 (dt, J¼10.8,

1.2 Hz, 1H), 3.94 (tt, J¼6.0, 1.2 Hz, 1H), 3.49 (ddd, J¼9.2, 6.0, 3.2 Hz,

1H), 2.88e2.81 (m, 1H), 2.73e2.65 (m, 1H), 1.90 (br s, 2H), 1.88e1.71

5.8.4. (1S,2S)-1-Phenylbut-3-ene-1,2-diol (30)⁴⁸. [

a]

²³þ13.6 (c 1.17,

(m, 2H); ¹³C (100 MHz, CDCl₃)

d 142.1, 137.7, 128.61, 128.57, 126.0,

D

CHCl₃); IR (neat) 3391, 2919, 1710, 1453, 1197, 1125, 995, 928, 762,

117.8, 76.5, 73.8, 34.8, 32.0; HRMS (ESI) calcd for C₁₂H₁₆NaO₂

700 cm^ꢀ1

;

¹H (400 MHz, CDCl₃)

d

7.34e7.25 (m, 5H), 5.68 (ddd,

[MþNa]^þ215.1048, found 215.1042.

J¼17.4, 10.6, 5.6 Hz, 1H), 5.20 (dt, J¼17.2, 1.5 Hz, 1H), 5.10 (dt, J¼10.6,

25

1.5 Hz, 1H), 4.44 (d, J¼7.1 Hz, 1H), 4.19e4.15 (m, 1H), 2.98 (br s, 2H);

5.8.12. (1R,3E,5R)-1,7-Diphenylhept-3-ene-1,5-diol (17c). [

a]

þ31.2

D

¹³C (100 MHz, CDCl₃)

d

140.4, 136.5, 128.5, 128.3, 127.2, 117.2, 77.8,

(c 0.47, CHCl₃); ee 97%; IR (neat) 3356, 3061, 3027, 2925, 2858,

1602, 1494, 1453, 1308, 1051, 1029, 970, 748, 699, 546 cm^ꢀ^{1 1}H

(400 MHz, CDCl₃) 7.32e7.27 (m, 4H), 7.25e7.20 (m, 3H), 7.15e7.12

77.1; HRMS (ESI) calcd for C₁₀H₁₂NaO₂[MþNa]^þ187.0735, found

;

187.0730.

d

(m, 3H), 5.64e5.52 (m, 2H), 4.65 (td, J¼6.6, 3.1 Hz, 1H), 4.02

25

5.8.5. (1R,2R)-1-Phenylbut-3-ene-1,2-diol (ent-30). [

a

]

ꢀ4.2 (c

(q, J¼6.3 Hz, 1H), 2.66e2.52 (m, 2H), 2.43 (t, J¼6.3 Hz, 2H), 2.15 (br s,

D

0.66, CHCl₃); ee 97%; ¹H NMR, ¹³C NMR and IR and HRMS data were

2H), 1.86e1.68 (m, 2H); ¹³C (100 MHz, CDCl₃)

d 144.1, 142.1, 136.8,

identical to 30.

128.67, 128.65, 128.5, 127.92, 127.86, 126.01, 125.99, 73.9, 72.4, 42.3,

38.8, 31.9; HRMS (ESI) calcd for C₁₉H₂₂O₂Na [MþNa]^þ305.1517,

found 305.1524.

25

5.8.6. (1S,2E,5R)-1,5-Diphenylpent-2-ene-1,5-diol (17d). [

a]

D

þ49.6

(c 0.23, CHCl₃); ee 98%; IR (neat) 3360, 3085, 3061, 3029, 2921, 1667,

24

1602, 1493, 1452, 1318, 1197, 1028, 1007, 969, 913, 758, 699 cm^ꢀ1; ¹H

5.8.13. (1S,5S,3E)-1,7-Diphenylhept-3-ene-1,5-diol (ent-17c). [a]

D

(400 MHz, CDCl₃)

d

7.27e7.17 (m,10H), 5.69e5.66 (m, 2H), 5.08e5.06

ꢀ21.1 (c 0.75 CHCl₃); ¹H NMR, ¹³C NMR and IR, and HRMS data were

identical to 17c.

(m, 1H), 4.63 (t, J¼6.6 Hz, 1H), 2.56 (br s, 2H), 2.42e2.39 (m, 2H); ¹³C

(100 MHz, CDCl₃) d 144.1, 143.1, 136.3, 128.7, 128.1, 127.8, 127.7, 126.4,

126.0, 75.1, 73.8, 42.3; HRMS (ESI) calcd for C₁₇H₁₈O₂Na [MþNa]^þ

5.8.14. (1R,3E,5R)-1-Cyclohexyl-7-phenylhept-3-ene-1,5-diol

277.1204, found 227.1205.

(17e). [

a

]

²⁵þ7.5 (c 0.59, CHCl₃); ee 96%; IR (neat) 3352, 3085, 3062,

D

3026, 2924, 2852, 1495, 1450, 1311, 1057, 1030, 969, 892, 746,

25

5.8.7. (1S,2E,5S)-1,7-Diphenylhept-2-ene-1,5-diol (17b). [

a

]

þ2.7

698 cm^ꢀ^{1 1}H (400 MHz, CDCl₃)

; d 7.28e7.23 (m, 2H), 7.18e7.13 (m,

D

(c 1.28, CHCl₃); ee 97%; IR (neat) 3360, 3084, 3061, 3026, 2923,

2854, 1602, 1494, 1453, 1319, 1069, 1048, 1030, 969, 748, 698 cm^ꢀ1

¹H (400 MHz, CDCl₃)

7.33e7.28 (m, 4H), 7.25e7.21 (m, 3H),

7.15e7.12 (m, 3H), 5.74e5.70 (m, 2H), 5.13 (d, J¼4.8 Hz, 1H),

3.66e3.60 (m, 1H), 2.77e2.70 (m, 1H), 2.66e2.58 (m, 1H),

2.28e2.22 (m, 1H), 2.17e2.09 (m, 1H), 1.75e1.70 (m, 2H); ¹³C

3H), 5.65 (ddd, J¼15.4, 7.3, 6.1 Hz, 1H), 5.58 (dd, J¼15.4, 6.6 Hz, 1H),

4.08 (q, J¼6.3 Hz, 1H), 3.38e3.33 (m, 1H), 2.74e2.60 (m, 2H),

2.30e2.24 (m, 1H), 2.13e2.05 (m, 1H), 1.93 (br s, 1H), 1.91e1.72 (m,

5H), 1.66e1.63 (m, 2H), 1.37e1.28 (m 1H), 1.27e094 (m, 5H); ¹³C

;

d

(100 MHz, CDCl₃) d 142.1, 136.3, 128.8,128.65,128.57, 126.0, 75.4, 72.4,

43.4, 38.9, 37.4, 32.0, 29.3, 28.3, 26.7, 26.5, 26.3; HRMS (ESI) calcd for

(100 MHz, CDCl₃)

d

143.2, 142.2, 136.1, 128.8, 128.63, 128.61, 128.1,

C₁₉H₂₈O₂Na [MþNa]^þ311.1987, found 311.1990.

127.9, 126.4, 126.0, 75.2, 70.5, 40.6, 38.8, 32.2; HRMS (ESI) calcd for

25

C₁₉H₂₂NaO₂[MþNa]^þ305.1517, found 305.1515.

5.8.15. (1E,3R,5E,7R)-1,9-Diphenylnona-1,5-diene-3,7-diol (17f). [a]

D

þ12.6 (c 0.45, CHCl₃); ee 95%; IR (neat) 3350, 3060, 3026, 2923,

2857, 1494, 1452, 1316, 1100, 1030, 967, 747, 694 cm^ꢀ^{1 1}H

(400 MHz, CDCl₃) 7.34e7.32 (m, 2H), 7.29e7.18 (m, 5H), 7.16e7.12

23

5.8.8. (1R,5R,2E)-1,7-Diphenylhept-2-ene-1,5-diol (ent-17b). [

a]

;

D

ꢀ14.1 (c 0.70, CHCl₃); ¹H NMR, ¹³C NMR and IR and HRMS data were

identical to 17b.

d

(m, 3H), 6.55 (d, J¼15.7 Hz, 1H), 6.19 (dd, J¼15.9, 6.6 Hz, 1H), 5.67

(dt, J¼15.4, 6.6 Hz, 1H), 5.60 (dd, J¼15.7, 6.1 Hz, 1H), 4.32e4.27 (m,

1H), 4.07 (q, J¼6.6 Hz, 1H), 2.70e2.58 (m, 2H), 2.41e2.28 (m, 2H),

24

5.8.9. (1R,5S,2E)-1,7-Diphenylhept-2-ene-1,5-diol (ent-10b). [a]

ꢀ16.52 (c 0.96, CHCl₃); IR (neat) 3351, 3026, 2929, 1493, 1453 cm^ꢀ^D¹

;

2.10 (br s, 2H), 1.90e1.73 (m, 2H); ¹³C (100 MHz, CDCl₃)

d 142.1,

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

6509

136.9, 136.7, 131.8, 130.7, 128.8, 128.63, 128.55, 127.9, 127.5, 126.7,

126.0, 72.4, 72.2, 40.6, 38.8, 31.9; HRMS (ESI) calcd for C₂₁H₂₄O₂Na

[MþNa]^þ331.1674, found 331.1679.

(72 mL) was added and the suspension was cooled to 0 ^ꢁC. Allyl-

magnesium bromide (1 M in Et₂O, 16.6 mL, 16.6 mmol) was added

dropwise. The mixture was stirred for 1 h, then was cooled to

ꢀ78 ^ꢁC and a solution of aldehyde 55 (3.04 g, 13.8 mmol) in Et₂O

(17.5 mL) was added via cannula. The mixture was stirred for 3 h,

then MeOH (1.8 mL), followed by NaOH (3 N, 17.4 mL, 52.3 mmol)

and H₂O₂(30% in H₂O,17.3 mL,169 mmol) were added. The solution

was warmed to 23 ^ꢁC and stirred overnight. The mixture was cooled

at 0 ^ꢁC and neutralize with HCl (3 N). The aqueous phase was

extracted with Et₂O. The combined organic phases were washed

with brine, dried over MgSO₄, ﬁltered and concentrated under re-

duced pressure. Puriﬁcation of the crude by ﬂash chromatography

5.8.16. (1E,3S,5E,7S)-1,9-Diphenylnona-1,5-diene-3,7-diol

(ent-

25

17f). [

a

]

ꢀ14.0 (c 0.59, CHCl₃); ee 95%; ¹H NMR, ¹³C NMR and IR

D

and HRMS data were identical to 17f.

5.8.17. (1R,2E,5R)-6-(Benzyloxy)-1-cyclohexylhex-2-ene-1,5-diol

25

(17h). [

2852, 1451, 1097, 1027, 1001, 971, 735, 697 cm^ꢀ1

CDCl₃)

a

]

ꢀ14.0 (c 0.59, CHCl₃); ee 96%; IR (neat) 3399, 2923,

D

;

¹H (400 MHz,

d

7.33e7.23 (m, 5H), 5.56 (dt, J¼15.4, 6.6 Hz, 1H), 5.49 (dd,

J¼15.4, 6.3 Hz, 1H), 4.50 (s, 2H), 3.84e3.78 (m, 1H), 3.72 (t, J¼6.6 Hz,

1H), 3.43 (dd, J¼9.3, 3.3 Hz, 1H), 3.31 (dd, J¼9.3, 7.3 Hz, 1H), 2.41 (br

s, 1H), 2.20e2.14 (m, 2H), 1.82e1.78 (m, 1H), 1.72e1.58 (m, 4H),

1.36e1.27 (m, 1H), 1.24e1.05 (m, 3H), 0.96e0.83 (m, 2H); ¹³C

(gradient elution 85/15 to 70/30: hexanes/ethyl acetate) provided

22

56 (2.99 g, 83%) as a colorless oil: ee 96%; [

a

]

D

ꢀ10.5 (c 0.89,

CHCl₃); IR (neat) 3419 (br), 2933, 2907, 2858, 1613, 1514, 1464, 1448,

1361,1302,1248,1174,1094,1035, 972, 916, 821 cm^ꢀ1; ¹H (400 MHz,

(100 MHz, CDCl₃)

d

138.1, 135.2, 128.6, 128.1, 128.0, 127.9, 77.6, 74.2,

CDCl₃)

d

7.28e7.24 (m, 2H), 6.90e6.86 (m, 2H), 5.80 (ddt, J¼17.3,

73.6, 70.1, 43.7, 36.6, 29.0, 28.9, 26.7, 26.32, 26.25; HRMS (ESI) calcd

9.9, 7.1 Hz,1H), 5.70 (dt, J¼15.5, 6.6 Hz,1H), 5.57 (dd, J¼15.5, 6.5 Hz),

5.16e5.14 (m, 1H), 5.11 (br s, 1H), 4.44 (s, 2H), 4.17e4.10 (m, 1H),

3.81 (s, 3H), 3.48 (t, J¼6.8 Hz, 2H), 2.35 (dt, J¼6.8, 6.7 Hz, 2H),

for C₁₉H₂₈O₃Na [MþNa]^þ327.1936, found 327.1942.

5.8.18. (2S,3E,6S)-1-{[tert-Butyl(dimethyl)silyl]oxy}-8-phenyloct-3-

ene-2,6-diol (17i). [

2.31e2.23 (m, 2H), 1.70 (m, OH); ¹³C (100 MHz, CDCl₃)

d 159.4,

a

]

D

²⁵ꢀ14.0 (c 0.59, CHCl₃); ee 96%; IR (neat) 3383,

134.50, 134.1, 130.7, 129.5, 128.5, 118.3, 113.9, 72.7, 71.8, 69.6, 55.5,

42.1, 32.8; HRMS (ESI) calcd for C₁₆H₂₂O₃[MþNa]^þ285.1467, found

285.1468.

3027, 2951, 2928, 2857,1471,1462,1455,1361,1254,1111,1052,1006,

971, 837, 778, 747, 699 cm^ꢀ1; ¹H (400 MHz, CDCl₃)

d 7.26e7.22 (m,

2H), 7.17e7.12 (m, 3H), 5.77e5.69 (m, 1H), 5.50 (ddd, J¼15.4, 6.1,

1.3 Hz, 1H), 4.13e4.09 (m, 1H), 3.65e3.60 (m, 1H), 3.59 (dd, J¼10.1,

3.8 Hz, 1H), 3.41 (dd, J¼10.1, 7.8 Hz, 1H), 2.77 (dt, J¼13.9, 7.6 Hz, 1H),

2.64 (dt, J¼13.9, 8.1 Hz, 1H), 2.28e2.22 (m, 1H), 2.14 (dt, J¼14.1,

7.8 Hz,1H),1.77e1.72 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H); ¹³C (100 MHz,

5.9.3. (S)-1-((2S,3S)-3-(2-(4-Methoxy-benzyloxy)-ethyl)oxiran-2-

yl)-but-3-en-1-ol (57). To a solution

L

-(þ)-DET (freshly distilled,

ꢀ

1.19 mL, 6.86 mmol, dried over MS 4 A for 1.5 h) in CH₂Cl₂(11.2 mL)

was added Ti(OiPr)₄(freshly distilled, 1.75 mL, 5.72 mmol) at

ꢀ40 ^ꢁC, resulting in a slightly yellow solution. This mixture was

stirred for 40 min, then a solution of alcohol 56 (3.0 g, 11.4 mmol,

CDCl₃)

d 142.3, 132.3, 129.3, 128.64, 128.57, 126.0, 72.8, 70.2, 67.3,

40.9, 38.7, 32.2, 26.1, 18.5, ꢀ5.13, ꢀ5.16; HRMS (ESI) calcd for

C₂₀H₃₄O₃NaSi [MþNa]^þ373.2175, found 373.2184.

dried over MS 4 A for 2 h) in CH₂Cl₂(9 mL) was added via cannula.

ꢀ

The mixture was stirred for 45 min at ꢀ20 ^ꢁC, then a cold solution of

24

ꢀ

5.8.19. (1R,5S,3E)-1,7-Diphenylhept-3-ene-1,5-diol (ent-10c). [

a

]

TBHP (5.5 M in decane, 2.08 mL, 11.4 mmol, dried over MS 4 A for

D

þ28.4 (c 1.08, CHCl₃); IR (neat) 3360, 3027, 2925, 1949, 1878, 1807,

2 h) in CH₂Cl₂(9 mL) was added via cannula. The solution was

stirred at ꢀ20 ^ꢁC for 7 h, then stored in a ꢀ20 ^ꢁC freezer for 20 h.

The mixture was allowed to warm to 0 ^ꢁC, then NaOH (1 M, sat with

NaCl, 17.6 mL) and H₂O (11 mL) were added. This mixture was

stirred for 2 h at room temperature. It was then ﬁltered through

a plug of Celite, which was rinsed with CH₂Cl₂. The combined ﬁl-

trates were washed with brine. The aqueous phase was extracted

with CH₂Cl₂, the combined organic extracts dried over MgSO₄, ﬁl-

tered and concentrated under reduced pressure. Puriﬁcation of the

crude product by ﬂash chromatography (gradient elution 85/15 to

1669, 1603, 1495, 1454 cm^ꢀ1; ¹H (500 MHz, CDCl₃)

d

7.38e7.17 (m,

10H), 5.72e5.66 (m, 1H), 5.62 (dd, J¼15.5, 6.5 Hz, 1H), 4.67 (td,

J¼6.6, 3.1 Hz, 1H), 4.04e3.96 (m, 1H), 2.74e2.62 (m, 2H),

2.54e2.52 (m, 2H), 2.01 (d, OH, J¼3.5 Hz, 1H), 1.92e1.76 (m, 2H),

1.54 (d, OH, J¼4.0 Hz, 1H); ¹³C (100 MHz, CDCl₃)

d 144.0, 142.1,

136.6, 128.6, 128.5, 127.8, 127.5, 126.01, 125.97, 73.8, 72.1, 42.1, 38.7,

31.9; HRMS (CI, NH₃) calcd for C₁₉H₂₆NO₂[MþNH₄]^þ300.1964

found 300.1951.

5.9. Synthesis of aldehyde 4

70/30: hexanes/ethyl acetate) afforded 57 (2.20 g, 69%) as a clear

22

oil: 99% de; [

a

]

ꢀ5.5 (c 1.02, CHCl₃); IR (neat) 3437 (br), 2933,

D

5.9.1. (E)-5-(4-Methoxybenzyloxy)-pent-2-en-1-al (55). To a solu-

tion of alkene 54⁴⁰(3.12 g, 16.2 mmol) in CH₂Cl₂(70 mL) under

argon, were successively added acrolein (freshly distilled, 3.25 mL,

48.7 mmol) and HoveydaeGrubbs second-generation catalyst³⁹

(weighed in a glove box, 254 mg, 0.40 mmol) as a solution in

CH₂Cl₂(3 mL). The reaction mixture was stirred overnight at room

temperature, then directly concentrated in vacuo. The residue was

puriﬁed by ﬂash chromatography (8/2: hexanes/EtOAc) to give 55

(3.04 g, 85%) as a brown oil; IR (neat) 2999, 2934, 2907, 2855, 1614,

1586, 1514, 1464, 1442, 1361, 1302, 1247, 1209, 1173, 1097, 1036,

2912, 2862, 1745, 1642, 1613, 1586, 1514, 1465, 1442, 1363, 1302,

1249, 1175, 1096, 1035, 917, 821 cm^ꢀ^{1 1}H (400 MHz, CDCl₃)

;

d

7.27e7.25 (m, 2H), 6.86e6.90 (m, 2H), 5.86 (ddt, J¼17.1, 10.1,

7.1 Hz, 1H), 5.17e5.14 (m, 1H), 5.13e5.11 (m, 1H), 4.50e4.43 (m, 2H),

3.81 (br s, 4H), 3.58 (t, J¼6.3 Hz, 2H), 3.14 (td, J¼9.1, 2.2 Hz, 1H), 2.84

(dd, J¼3.0, 3.0 Hz, 1H), 2.42e2.25 (m, 2H), 2.08 (br s, 1H), 1.91e1.76

(m, 2H); ¹³C (100 MHz, CDCl₃)

d 159.4, 133.9, 130.4, 129.5, 118.3,

114.0, 73.0, 68.4, 66.8, 60.5, 55.5, 53.4, 38.3, 32.3; HRMS (ESI) calcd

for C₁₆H₂₂O₄[MþNa]^þ301.1416, found 301.1415.

972, 821 cm^ꢀ1

;

¹H (400 MHz, CDCl₃)

d

9.51 (d, J¼7.8 Hz, 1H), 7.26

5.9.4. (3S,5S)-1-(4-Methoxy-benzyloxy)-oct-7-ene-3,5-diol (58). To

a solution of epoxide 57 (2.2 g, 7.90 mmol) in THF (39.5 mL) was

added MeOH (0.16 mL) and Red-Al^Ò(3.3 M in toluene, 6.0 mL,

19.8 mmol) at 0 ^ꢁC (gas evolution!) over a period of 10 min. After

being warmed to 23 ^ꢁC over 2 h, the solution was stirred for 16 h.

NaOH (3 N, 23.7 mL) was added at 0 ^ꢁC followed by water. The

aqueous phase was extracted with Et₂O and the combined organic

phases washed with brine, dried over Na₂SO₄, ﬁltered, and con-

centrated under reduced pressure. Puriﬁcation of the crude by ﬂash

chromatography (1/2: hexanes/ethyl acetate) afforded 58 (2.06 g,

(d, J¼8.7 Hz, 2H), 6.89 (d, J¼8.7 Hz, 2H), 6.87 (dt, J¼16.1, 6.0 Hz,

1H), 6.17 (ddt, J¼15.7, 7.8, 1.4 Hz, 1H), 4.46 (s, 2H), 3.81 (s, 3H), 3.61

(t, J¼6.2 Hz, 2H), 2.62 (tdd, J¼6.4, 6.4, 1.5 Hz, 2H); ¹³C (100 MHz,

CDCl₃)

d 194.1, 159.5, 155.4, 134.3, 130.2, 129.5, 114.1, 73.0, 67.8,

55.5, 33.3; HRMS (ESI) calcd for C₁₃H₁₆O₃[MþNa]^þ243.0997,

found 243.0995.

5.9.2. (S,E)-8-(4-Methoxybenzyloxy)-octa-1,5-dien-4-ol (56). (ꢀ)-

Ipc₂BOMe (5.68 g, 17.9 mmol) was weighed in a glove box. Et₂O

6510

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

24

93%) as colorless oil: [

a]

þ16.8 (c 1.06, CHCl₃); IR (neat) 3402,

22.0 mL, 66.3 mmol) and H₂O₂(30% in H₂O, 22.0 mL, 215 mmol)

D

2937, 1613, 1514, 1303, 1249, 1175, 1090, 1035, 821 cm^ꢀ1

;

¹H

were added. The solution was warmed to 23 ^ꢁC and stirred over-

night. The mixture was cooled at 0 ^ꢁC and neutralize with HCl (3 N).

The aqueous phase extracted with Et₂O. The combined organic

phases were washed with brine, dried over MgSO₄, ﬁltered, and

carefully concentrated under reduced pressure (removal of solvent

at 250 Torr/0 ^ꢁC owing to the volatility of the product). The azi-

(400 MHz, CDCl₃)

d 7.25e7.23 (m, 2H), 6.90e6.86 (m, 2H), 5.83 (ddt,

J¼17.1,10.2, 7.1 Hz,1H), 5.15e5.11 (m,1H), 5.11e5.09 (m,1H), 4.46 (s,

2H), 4.19e4.13 (m, 1H), 4.02e3.95 (m, 1H), 3.81 (s, 3H), 3.73 (q,

J¼4.8 Hz,1H), 3.67 (td, J¼9.2, 3.8 Hz,1H), 3.51 (d, J¼2.6 Hz, OH), 2.84

(d, J¼3.9 Hz, OH), 2.26 (ddt, J¼6.7, 6.7,1.2 Hz, 2H),1.94e1.86 (m, 1H),

1.71e1.61 (m, 3H); ¹³C (100 MHz, CDCl₃)

d

159.5, 135.1, 130.0, 129.6,

doalcohol 50 was obtained as a ca. 1:2 mixture with iso-

117.9, 114.1, 73.3, 69.8, 69.4, 68.3, 55.5, 42.3, 42.3, 36.4; HRMS (ESI)

pinocampheol 51 as a viscous oil. To this mixture of 50 and

isopinocampheol 51 in DMF (10 mL) were added TBSCl (11.3 g,

71.4 mmol) and imidazole (5.27 g, 77.4 mmol). After being stirred

overnight, the mixture was poured into water (100 mL) and Et₂O.

The aqueous phase was extracted with Et₂O and the combined

organic phases were washed several times with water, then with

brine. The combined extracts were dried over Na₂SO₄, ﬁltered and

concentrated under reduced pressure. Puriﬁcation of the crude

calcd for C₁₆H₂₄O₄[MþNa]^þ303.1572, found 303.1566.

5.9.5. (3S,5S)-3,5-Bis-(tert-Butyldimethylsilanyloxy)-1-(4-methoxy-

benzyloxy)-oct-7-ene (59). To

a solution of diol 58 (2.06 g,

7.35 mmol) in DMF (14.7 mL) were added imidazole (2.02 g,

29.4 mmol) and TBSCl (4.31 g, 27.2 mmol). The mixture was stirred

overnight and then poured into water (100 mL) and diluted with

Et₂O. The aqueous phase was extracted with Et₂O and the com-

bined organic phases were washed several times with water, then

with brine. The combined extracts were dried over Na₂SO₄, ﬁltered,

and concentrated under reduced pressure. Puriﬁcation of the crude

product by ﬂash chromatography (95/5: hexanes/ethyl acetate)

26

afforded 52 (3.4 g, 73% over two steps) as a clear oil: ee 91%; [a]

D

þ13.1 (c 1.09, CHCl₃); IR (neat) 2955, 2931, 2858, 2093, 1472, 1464,

1361, 1256, 1092, 1041, 1005, 939, 914, 837, 809, 775 cm^ꢀ^{1 1}H

(400 MHz, CDCl₃) 5.84e5.74 (m, 1H), 5.08e5.06 (m,1H), 5.03 (br s,

;

product by ﬂash chromatography (95/5: hexanes/ethyl acetate)

d

24

afforded the 59 (3.2 g, 86%) as pale yellow oil: [

a

]

D

þ3.4 (c 1.23,

1H), 3.73 (dddd, app. tt, J¼5.7 Hz, 1H), 3.27 (t, J¼6.9 Hz, 2H), 2.22

CHCl₃); IR (neat)¼2945, 2929, 2895, 2857, 1614, 1514, 1472, 1463,

1361, 1250, 1099, 1041, 1004, 836, 807, 884 cm^ꢀ^{1 1}H (400 MHz,

CDCl₃) 7.27e7.24 (m, 2H), 6.89e6.85 (m, 2H), 5.81 (m_c, 1H),

(dd, app. t, J¼6.0 Hz, 2H), 1.74e1.43 (m, 4H), 0.89 (s, 9H), 0.06 (s,

;

3H), 0.05 (s, 3H); ¹³C (100 MHz, CDCl₃)

d 134.8, 117.1, 71.3, 51.7, 41.9,

d

33.6, 25.9, 24.7, 18.1, ꢀ4.4, ꢀ4.6; HRMS (ESI) calcd for C₁₃H₂₇N₃OSi

5.06e5.02 (m, 2H), AB signal (d_A¼4.40, d_B¼4.42, J_AB¼11.5 Hz), 3.87

(m_c, 1H), 3.80e3.76 (m, 4H), 3.50 (t, J¼6.8 Hz, 2H), 2.28e2.14 (m,

2H), 1.83e1.53 (m, 4H), 0.87 (s, 9H), 0.86 (s, 9H), 0.05 (s, 9H), 0.03 (s,

[MþNa]^þ292.1821, found 292.1830.

5.10.2. tert-Butyl ((4R)-4-{[tert-butyl(dimethyl)silyl]oxy}hept-6-en-

1-yl)carbamate (53). To a room temperature solution of alkene 52

(1.0 g, 3.49 mmol) in wet Et₂O (9 mL) was added tributylphosphine

(1.07 mL, 4.19 mmol). The mixture was stirred for 1.5 h at ambient

temperature and then cooled to ꢀ50 ^ꢁC. Di-tert-butyl dicarbonate

(923 mg, 4.19 mmol) as a solution in Et₂O (2.6 mL) was slowly

added and the resulting mixture was stirred for 2 h. The reaction

was quenched with a solution of saturated NaHCO₃(11.6 mL), and

allowed to warm to room temperature and stirred overnight. The

aqueous phase was separated and extracted with Et₂O. The com-

bined organic phases were washed with brine, dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure. Puriﬁcation of

the crude product by ﬂash chromatography (gradient elution 98/2

3H); ¹³C (100 MHz, CDCl₃)

d 159.3, 135.2, 130.9, 129.4, 117.1, 113.9,

72.9, 69.8, 67.7, 67.0, 55.5, 45.6, 42.4, 37.9, 26.1, 18.32, 18.28, ꢀ3.86,

ꢀ3.91, ꢀ4.0, ꢀ4.1; HRMS (ESI) calcd for C₂₈H₅₂O₄Si₂[MþNa]^þ

531.3302, found 531.3305.

5.9.6. (3S,5S)-3,5-Bis-(tert-butyldimethylsilanyloxy)-7-(4-methoxy-

benzyloxy)-heptane-1-al (4). To a solution of alkene 59 (1.75 g,

3.44 mmol) in dioxane (26 mL) and water (8.6 mL) were added 2,6-

lutidine (freshly distilled, 0.865 mL, 7.43 mmol), OsO₄(2.5 wt% in 2-

methyl-2-propanol, 0.862 mL, 0.07 mmol), and NaIO₄(2.95 g,

13.7 mmol). This mixture was stirred for 5 h, then the brown sus-

pension was diluted with water and CH₂Cl₂. The aqueous phase was

extracted with CH₂Cl₂, the combined organic phases washed with

brine, dried over MgSO₄, and concentrated under reduced pressure.

to 80/20: hexanes/ethyl acetate) afforded 53 (845 mg, 70%) as clear

27

oil: [

a]

þ10.6 (c 0.5, CHCl₃); IR (neat) 3349, 2929, 2857, 1693

D

Puriﬁcation of the crude product by ﬂash chromatography (95/5:

(broad), 1513, 1365, 1251, 1172, 1117, 1002, 912, 835, 773 cm^ꢀ1

;

¹H

24

hexanes/ethyl acetate) afforded 4 (1.57 g, 89%) as yellow oil: [a]

D

(400 MHz, CDCl₃) 5.84e5.71 (m,1H), 5.06e5.02 (m,1H), 5.01 (br s,

d

ꢀ4.9 (c 1.23, CHCl₃); IR (neat) 2954, 2930, 2857, 1727, 1514, 1472,

1464, 1250, 1102, 1040, 1005, 837, 809, 776 cm^ꢀ^{1 1}H (400 MHz,

CDCl₃)

1H), 4.54 (br s, 1H), 3.71 (app quint, J¼5.7 Hz, 1H), 3.17e3.02 (m,

2H), 2.23e2.18 (m, 2H), 1.43 (s, 9H), 1.60e1.39 (m, 4H), 0.88 (s, 9H),

;

d

9.78 (t, J¼2.5 Hz, 1H), 7.26e7.23 (m, 2H), 6.89e6.85 (m,

0.044 (s, 3H), 0.037 (s, 3H); ¹³C (100 MHz, CDCl₃)

d 156.2, 135.3,

2H), AB signal (d_A¼4.39, d_B¼4.42, J_AB¼11.5 Hz), 4.24 (dddd, app. tt,

J¼6.0 Hz, 1H), 3.87 (dddd, app. tt, J¼6.1 Hz, 1H), 3.81 (s, 3H), 3.49 (t,

J¼6.6 Hz, 2H), 2.57 (ddd, J¼15.4, 4.5, 2.1 Hz, 1H), 2.49 (ddd, J¼15.4,

6.5, 3.0 Hz, 1H), 1.84e1.64 (m, 4H), 0.87 (s, 9H), 0.86 (s, 9H), 0.07 (s,

3H), 0.06 (s, 3H), 0.054 (s, 3H), 0.047 (s, 3H); ¹³C (100 MHz, CDCl₃)

117.1, 79.2, 71.7, 42.1, 40.9, 34.0, 28.6, 27.6, 26.1, 18.3, ꢀ4.2, ꢀ4.3;

HRMS (ESI) calcd for C₁₈H₃₇NO₃Si [MþNa]^þ366.2440, found

366.2449.

5.10.3. tert-Butyl ((4R,6E)-4-{[tert-butyl(dimethyl)silyl]oxy}-8-

d

202.3, 159.3, 130.7, 129.5, 113.9, 72.9, 67.5, 66.6, 66.5, 55.5, 51.5,

oxooct-6-en-1-yl)carbamate (3). To

a solution of alkene 53

46.3, 38.0, 26.1, 25.9, 18.2, 18.1, ꢀ4.0, ꢀ4.1, ꢀ4.2; HRMS (ESI) calcd

for C₂₇H₅₀O₅Si₂[MþNa]^þ533.3095, found 533.3099.

(273 mg, 0.79 mmol) in CH₂Cl₂(2.4 mL) under argon were suc-

cessively added acrolein (freshly distilled, 0.159 mL, 2.38 mmol)

and HoveydaeGrubbs second-generation catalyst³⁹(weighed in

a glove box, 12 mg, 0.020 mmol) as a solution in CH₂Cl₂(1 mL). The

reaction was stirred overnight at room temperature, then concen-

trated in vacuo and directly puriﬁed by ﬂash chromatography (8/2:

hexanes/EtOAc). This afforded aldehyde 3 (276 mg, 94%) as a clear

5.10. Synthesis of aldehyde 3

5.10.1. (R)-7-Azido-4-[(tert-butyldimethylsilanyloxy)]-1-hepten

(52). (ꢀ)-Ipc₂BOMe (6.64 g, 21.0 mmol) was weighed in a glove

box. Et₂O (84 mL) was added and the suspension was cooled to 0 ^ꢁC.

Allylmagnesium bromide (1 M in Et₂O, 19.3 mL, 19.3 mmol) was

added dropwise. The mixture was stirred for 1 h, then was cooled to

ꢀ78 ^ꢁC and a solution of known aldehyde 49³⁴(3.04 g, 13.8 mmol)

in Et₂O (22.0 mL) was added via cannula. The mixture was stirred

for 3 h at ꢀ78 ^ꢁC, then MeOH (2.1 mL), followed by NaOH (3 N,

oil, which solidiﬁed when stored in the freezer: [

a

]

²⁷þ10.0 (c 0.69,

D

CHCl₃); IR (neat) 3360, 2930, 2858, 1693 (broad), 1520, 1365, 1252,

1172, 836, 775 cm^ꢀ1; ¹H (400 MHz, CDCl₃)

d

9.51 (d, J¼8.0 Hz, 1H),

6.86 (dt, J¼15.6, 7.4 Hz, 1H), 6.13 (ddt, J¼15.6, 7.9, 1.3 Hz, 1H), 4.52

(br s, 1H), 3.87 (app quint, J¼5.6 Hz, 1H), 3.19e3.03 (m, 2H),

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

6511

2.56e2.41 (m, 2H), 1.56e4.46 (m, 4H), 1.44 (s, 9H), 0.88 (s, 9H), 0.06

(s, 3H), 0.035 (s, 3H); ¹³C (100 MHz, CDCl₃)

194.0, 156.2, 155.1,

135.1, 79.4, 70.8, 40.6, 34.5, 28.6, 26.0, 25.9, 18.3, ꢀ4.25, ꢀ4.27;

HRMS (ESI) calcd for C₁₉H₃₇NO₄Si [MþNa]^þ394.2390, found

394.2391.

ꢀ3.5, ꢀ3.9, ꢀ4.06, ꢀ4.13, ꢀ4.2, ꢀ4.38, ꢀ4.45; HRMS (ESI) calcd for

d

C

₆₁H₁₂₁NO₉Si₅[MþNa]^þ1174.7785, found 1174.7780.

5.10.6. tert-Butyl {(4R,6E,8R,10E,12R,14S,16S)-4,14,16-tris{[tert-bu-

tyl(dimethyl)silyl]oxy}-8,12-dihydroxy-18-[(4-methoxy-benzyl)oxy]

octadeca-6,10-dien-1-yl}carbamate (61). To a 0 ^ꢁC solution of bo-

rohydride 25S (81.0 mg, 0.250 mmol, 1 equiv, considering a 90%

yield for the conversion of borohydride 26S to borane 25S based on

5.10.4. tert-Butyl {(4R,6E,8S,10E,12S,14S,16S)-4,14,16-tris{[tert-butyl(di-

methyl)silyl]oxy}-8,12-dihydroxy-18-[(4-methoxybenzyl)-oxy]octa-

deca-6,10-dien-1-yl}carbamate (60). To a 0 ^ꢁC solution of borohydride

26R (81.0 mg, 0.250 mmol, 1 equiv, considering a 90% yield for the

conversion of borohydride 26R to borane 25R based on titration³) in

titration^8d

) in toluene (0.5 mL) was added TMSCl (32 mL,

0.250 mmol, 1 equiv). The reaction mixture was stirred for 10 min,

then was cooled to ꢀ78 ^ꢁC and a solution of allene 45 (0.114 g,

0.325 mmol,1.3 equiv) in toluene (1 mL)/CH₂Cl₂(0.1 mL) was added

dropwise. The viscous mixture was stirred at ꢀ30 ^ꢁC for 1 h. The

resulting clear reaction mixture was then cooled to ꢀ78 ^ꢁC and

a solution of 4 (0.213 mmol, 0.85 equiv) in CH₂Cl₂(0.25 mL) was

added. After 4 h, a solution of 3 (0.300 mmol, 1.2 equiv) in CH₂Cl₂

toluene (0.5 mL) was added TMSCl (32.0 mL, 0.250 mmol, 1 equiv).

The reaction mixture was stirred for 10 min, then was cooled to

ꢀ78 ^ꢁC and a solution of allene 45 (0.114 g, 0.325 mmol, 1.3 equiv) in

toluene (1 mL)/CH₂Cl₂(0.1 mL) was added dropwise. The viscous

mixture was stirred at ꢀ30 ^ꢁC for 1 h. The resulting clear reaction

mixture was then cooled to ꢀ78 ^ꢁC and a solution of 4 (0.213 mmol,

0.85 equiv) in CH₂Cl₂(0.25 mL) was added. 4 hours later, a solution of

3 (0.300 mmol, 1.2 equiv) in CH₂Cl₂(0.25 mL) followed by BF₃$OEt₂

(0.25 mL) followed by BF₃$OEt₂(47 mL, 0.375 mmol, 1.5 equiv) were

added and the reaction mixture was stirred for an additional 4 h. A

pH 7 buffer solution (KH₂PO₄/NaOH) (1 mL) followed by THF

(1.5 mL) and MeOH (0.5 mL) were then added. The resulting mix-

ture was stirred at 20 ^ꢁC for 24 h. The biphasic mixture was poured

into saturated aqueous NH₄Cl solution, and the crude product was

extracted with ethyl acetate (3ꢂ). The combined organic layers

were washed with brine, dried over MgSO₄, ﬁltered, and concen-

trated under reduced pressure. The residue was puriﬁed by ﬂash

column chromatography (SiO₂, hexanes/ethyl acetate, gradient

(47.0 mL, 0.375 mmol,1.5 equiv) were added and the reaction mixture

was stirred for an additional 4 h. A pH 7 buffer solution (KH₂PO₄/

NaOH) (1 mL) followed by THF (1.5 mL) and MeOH (0.5 mL) were

then added and the mixture was stirred at 20 ^ꢁC for 24 h. The bi-

phasic mixture was poured into a saturated aqueous NH₄Cl solution,

and the crude product was extracted with ethyl acetate (3ꢂ). The

combined organic layers were washed with brine, dried over MgSO₄,

ﬁltered, and concentrated under reduced pressure. The residue was

puriﬁed by ﬂash column chromatography (SiO₂, hexanes/ethyl ace-

tate, gradient elution: 7:3 to 6:4 to 1:1) to afford 60 (163 mg, 83%) as

elution: 7:3 to 6:4 to 1:1) to afford 61 (153 mg, 78%) as a colorless

25

oil: [

a

]

D

ꢀ7.8 (c 0.50, CHCl₃); IR (neat) 3374, 2953, 2929, 2895,

2856, 1695, 1514, 1472, 1462, 1365, 1250, 1172, 1098, 1040, 1005, 971,

a colorless oil: [

a

]

²⁵ꢀ4.7 (c 0.64, CHCl₃); IR (neat) 3375, 2953, 2929,

835, 808, 774 cm^ꢀ^{1 1}H (400 MHz, CDCl₃)

;

d

7.24 (d, J¼8.6 Hz, 2H),

D

2896, 2856,1694,1514,1472,1463,1389,1365,1250,1172,1098,1041,

6.86 (d, J¼8.6 Hz, 2H), 5.70e5.47 (m, 4H), 4.67 (br s, 1H), 4.40 (dd,

J¼12.0, 11.6 Hz, 2H), 4.26e4.17 (m, 1H), 4.08 (app q, J¼6.3 Hz, 1H),

3.92e3.85 (m, 1H), 3.85e3.78 (m, 1H), 3.79 (s, 3H), 3.74e3.66 (m,

1H), 3.48 (t, J¼6.8 Hz, 2H), 3.15e3.02 (m, 2H), 2.31e2.14 (m, 4H),

2.10e1.90 (br s, 1H), 1.83e1.57 (m, 6H), 1.57e1.36 (m, 6H), 1.43 (s,

9H), 0.88 (s, 9H), 0.87 (s, 9H), 0.85 (s, 9H), 0.084 (s, 3H), 0.079 (s,

3H), 0.044 (s, 3H), 0.035 (s, 3H), 0.030 (s, 6H); ¹³C (100 MHz, CDCl₃)

1005, 971, 836, 809, 774 cm^ꢀ^{1 1}H (400 MHz, CDCl₃)

; d 7.24 (d,

J¼8.6 Hz, 2H), 6.87 (d, J¼8.6 Hz, 2H), 5.70e5.47 (m, 4H), 4.63 (br s,

1H), 4.41 (m, overlap, 1H), 4.40 (dd, J¼12.0, 11.6 Hz, 2H), 4.10 (app q,

J¼6.2 Hz, 1H), 4.06e3.99 (m, 1H), 3.82 (m, overlap, 1H), 3.79 (s, 3H),

3.74e3.66 (m, 1H), 3.50 (t, J¼6.8 Hz, 2H), 3.15e3.02 (m, 2H),

2.34e2.13 (m, 4H), 1.89e1.63 (m, 6H), 1.43 (s, 9H), 1.62e1.35 (m, 7H),

0.88 (s, 18H), 0.86 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.06 (s, 3H), 0.041

d

159.3, 156.2, 136.3, 134.9, 130.7, 129.5, 127.9, 126.6, 113.9, 79.2,

(s, 3H), 0.035 (s, 6H); ¹³C (100 MHz, CDCl₃)

d

159.3, 156.2, 136.8,

72.9, 71.8, 71.7, 71.3, 70.7, 67.5, 66.8, 55.4, 47.0, 44.6, 40.8, 40.6, 40.4,

37.6, 33.9, 28.6, 26.08, 26.06, 26.04, 25.9, 18.3, 18.2, 18.1, ꢀ3.6, ꢀ4.0,

ꢀ4.2, ꢀ4.3, ꢀ4.4; HRMS (ESI) calcd for C₄₉H₉₃NO₉NaSi₃[MþNa]^þ

946.6056, found 946.6060.

The absolute stereochemistry of the two hydroxyl groups in 61

was assigned by using the Mosher ester method.

134.9, 130.8, 129.5, 128.1, 126.2, 114.0, 79.23, 72.9, 72.1, 71.8, 69.4,

69.3, 67.7, 66.8, 55.5, 45.0, 42.8, 40.8, 40.6, 40.4, 37.5, 33.9, 28.7, 26.3,

26.1, 26.0, 18.3, 18.2, 18.1, ꢀ3.9, ꢀ4.1, ꢀ4.1, ꢀ4.3, ꢀ4.4; HRMS (ESI)

calcd for C₄₉H₉₃NO₉NaSi₃[MþNa]^þ946.6056, found 946.6063.

The absolute stereochemistry of the two hydroxyl groups in 60

was assigned by using the Mosher ester method.

5.10.7. tert-Butyl {(4R,6E,8R,10E,12R,14R,16S)-4,8,12,14,16-pentakis

{[tert-butyl(dimethyl)silyl]oxy}-18-[(4-methoxy-benzyl)oxy]octa-

deca-6,10-dien-1-yl}carbamate (62). To a solution of alcohol 61

(20 mg, 0.022 mmol) in CH₂Cl₂(0.25 mL) were added imidazole

(12 mg, 0.176 mmol) and TBSCl (20 mg, 0.126 mmol). The mixture

was stirred overnight and then concentrated in vacuo. The crude

product was directly puriﬁed by ﬂash chromatography (gradient

5.10.5. tert-Butyl {(4R,6E,8S,10E,12S,14R,16S)-4,8,12,14,16-pentakis

{[tert-butyl(dimethyl)silyl]oxy}-18-[(4-methoxybenzyl)oxy]octadeca-

6,10-dien-1-yl}carbamate (2). To a solution of alcohol 60 (20 mg,

0.022 mmol) in CH₂Cl₂(0.25 mL) was added imidazole (12 mg,

0.18 mmol) and TBSCl (20 mg, 0.13 mmol). The mixture was stirred

overnight, then concentrated in vacuo. The crude product was di-

rectly puriﬁed by ﬂash chromatography (gradient elution 99/1 to 90/

elution 99/1 to 90/10: hexanes/ethyl acetate) to give 62 (23 mg,

27

10: hexanes/ethyl acetate) to give 2 (24 mg, 94%) as clear oil: [

a

]

D

90%) as clear oil: [

a

]

ꢀ5.3 (c 1.47, CHCl₃); IR (neat) 2953, 2928,

D

ꢀ3.5 (c 0.45, CHCl₃); IR (neat) 2953, 2928, 2887, 2856, 1718, 1513,

2886, 2856, 1709, 1513, 1471, 1462, 1363, 1248, 1171, 1078, 1039,

1471, 1462, 1248, 1171, 1064, 1040, 1004, 971, 832, 807, 771 cm^ꢀ1; ¹H

1004, 832, 807, 772, 733 cm^ꢀ^{1 1}H (400 MHz, CDCl₃)

;

d

7.24 (d,

(400 MHz, CDCl₃)

d

7.24 (d, J¼8.8 Hz, 2H), 6.86 (d, J¼8.8 Hz, 2H),

J¼8.8 Hz, 2H), 6.86 (d, J¼8.8 Hz, 2H), 5.59e5.37 (m, 4H), 4.54 (br s,

1H), 4.41 (dd, J¼11.6, 11.6 Hz, 2H), 4.21 (app q, J¼6.7 Hz, 1H), 4.07

(app q, J¼5.9 Hz, 1H), 3.89e3.81 (m, 1H), 3.80 (s, 3H), 3.78e3.71 (m,

1H), 3.71e3.64 (m, 1H), 3.48 (t, J¼6.8 Hz, 2H), 3.16e3.01 (m, 2H),

2.27e2.12 (m, 4H),1.85e1.73 (m,1H),1.72e1.36 (m, 9H),1.43 (s, 9H),

0.89e0.88 (m, 27H), 0.87 (s, 9H), 0.86 (s, 9H), 0.045 (s, 9H), 0.04 (s,

5.59e5.37 (m, 4H), 4.53 (br s, 1H), 4.41 (dd, J¼11.6, 11.6 Hz, 2H),

4.21e4.14 (m,1H), 4.07 (app q, J¼6.1 Hz,1H), 3.91e3.78 (m, 2H), 3.80

(s, 3H), 3.73e3.64 (m, 1H), 3.50 (t, J¼6.8 Hz, 2H), 3.16e3.01 (m, 2H),

2.27e2.12 (m, 4H),1.89e1.79 (m,1H),1.43 (s, 9H),1.72e1.36 (m, 9H),

0.88 (s, 18H), 0.872 (s, 9H), 0.869 (s, 9H), 0.86 (s, 9H), 0.06 (s, 3H),

0.05e0.03 (m, 21H), 0.02 (s, 3H), 0.01 (s, 3H); ¹³C (100 MHz, CDCl₃)

9H), 0.03 (s, 6H), 0.02 (s, 6H); ¹³C (100 MHz, CDCl₃)

d 159.3, 156.1,

d

159.2, 156.1, 136.4, 135.8, 131.1, 129.4, 126.8, 126.4, 113.9, 79.2, 73.6,

135.6, 135.5, 131.0, 129.4, 127.0, 126.4, 113.9, 79.2, 73.4, 72.8, 71.9,

71.1, 67.7, 67.6, 66.9, 55.5, 47.1, 46.8, 41.8, 41.0, 40.5, 37.8, 33.9, 28.7,

26.21, 26.16, 26.1, 25.9, 18.5, 18.4, 18.31, 18.27, ꢀ3.5, 3.7, ꢀ3.8, ꢀ3.9,

72.7, 71.9, 71.3, 67.5, 67.4, 66.9, 55.5, 47.4, 46.9, 41.7, 40.9, 40.3, 37.5,

33.7, 28.7, 26.23, 26.19, 26.14, 26.11,18.5,18.4,18.30,18.25, ꢀ3.2, ꢀ3.3,

6512

P. Nuhant et al. / Tetrahedron 67 (2011) 6497e6512

21. Nonracemic borane 25R [10-TMS-9/BBD-H] is easily prepared from pseudoe-

phedrine complex 63R by using Soderquist’s procedure²⁰Both enantiomers of

63R are commercially available but also are easily prepared in two steps from

racemic B-OMe/9-BBN 64.^20bWe found, however, that generation of 25R from

the mono-diethyl etherate borohydride 26R is best performed in the presence

of allene, owing to the instability of 25R.^8d

ꢀ4.06, ꢀ4.14, ꢀ4.2, ꢀ4.3, ꢀ4.4, ꢀ4.5; HRMS (ESI) calcd for

C₆₁H₁₂₁NO₉Si₅[MþNa]^þ1174.7785, found 1174.7793.

Acknowledgements

We thank the National Institutes of Health (GM038436) for

support of this research, and the German Academic Exchange Ser-

vice (DAAD) for a postdoctoral fellowship to A.S.

References and notes

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Article Doi

Development of a double allylboration reagent targeting 1,5-syn-(E)-diols: Application to the synthesis of the C(23)-C(40) fragment of tetrafibricin

DOI: 10.1016/j.tet.2011.06.008

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Full text of DOI:10.1016/j.tet.2011.06.008

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